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Dedication
Contributors xiii
Preface xvii
Index 1247
WEBSITE
The publication of the previous (ninth) edition of Hunter’s into account their huge rise in prevalence and the sparse
coincided with the millennium, when in celebratory mood the evidence base for their successful management. At the
preface referred to how in the previous 40 years a revolution same time, it is shocking that classic ‘industrial’ diseases
in biomedical knowledge had led to a transformation of due to asbestos and silica that dominated occupational
workplace health and safety, accelerating a decline of medicine in the twentieth century, including cancers, still
occupational diseases in advanced economy countries that remain as worldwide scourges, and new chapters have
ranked as one of the greatest triumphs of preventive health of been included on their clinical epidemiology to highlight
the twentieth century. This success would not have been the continuing and serious problems they present.
possible without governments legislating and providing Donald Hunter’s original work was not only a source
resources to enforce controls in the workplace, with the most of reference: it stood as a bulwark against the tide of
radical changes occurring in the 1970s. global occupational disease. We thank the many authors
The tenth edition goes to press at a very different time, who have contributed to this tenth edition and whose
however, with the world reeling in financial crisis and with skill, we believe, will continue to make the volume an
voices calling for the regulatory ‘burden’ of health and safety invaluable and constant force in the goal of disease
on industry in the richest countries to be lifted. On the prevention. As in previous editions, the book is intended
world scale, the concern is that the existing huge disparities to be an accessible, up-to-date and comprehensive text
in life expectancy between high and low income countries on occupational and related environmental conditions
will get worse. These health inequalities stem from the written for a wide range of clinical practitioners, for
circumstances in which people are born, grow, live, work consultants writing legal reports, for lawyers, and for
and age. Despite the impressive improvements in advanced others seeking medical guidance on the risks to health of
industrialized countries at the end of the twentieth century, work activities and industrial processes.
the millennium predictions were for an increase in the global With this edition, readers will have the additional
burden of occupational diseases, especially in those bonus of on-line access to Hunter’s original chapters on
economies with large populations and undergoing rapid the history of occupational medicine and a selection from
industrialization, such as Brazil, Russia, India and China, his personal archive of photographs of patients and work
where the basic protections are still mostly lacking. processes, many of which illustrated his own editions. We
The need for an updated and comprehensive reference anticipate that the publication of this unique material will
text on occupational diseases is therefore as great as ever. be useful to students and many other readers interested in
The early detection and diagnosis of occupational diseases the history of disease.
depends upon knowledge of the workplace and the likely We are grateful to Dr Paul Grime for providing us
risks of exposure to workplace hazards, while the elimi- with access to the Hunter collection located at the Royal
nation of occupational diseases depends upon an effective Free Hospital, London. Finally, we acknowledge the
regulatory framework, adequate risk assessments, and outstanding commitment and indefatigable efforts of
putting in place effective measures to control hazardous Jo Koster, Head of Health Science Textbooks at Hodder
exposures. The tenth edition has new chapters on exposure Arnold, and Susie Bond, Project Editor, in so ably
and risk, and on the attribution of disease. The predo- nurturing the book and bringing it to press.
minant types of work-related ill health have indeed
changed over recent years in high income countries. Not Peter J Baxter
all conditions encountered in the modern workforce fit Tar-Ching Aw
the traditional pattern of defined exposures leading to Anne Cockcroft
specific diseases, and the sections on mental health and Paul Durrington
musculoskeletal disorders have been expanded to take J Malcolm Harrington
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List of abbreviations used
GENERAL CONSIDERATIONS
1 Donald Hunter and the history of occupational health: precedents and perspectives 5
Joseph Melling and Tim Carter
2 The changing face of occupational diseases 24
Peter J Baxter, Tar-Ching Aw, Anne Cockcroft, Paul Durrington and J Malcolm Harrington
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1
Donald Hunter and the history of occupational
health: precedents and perspectives
DONALD HUNTER: CLINICIAN, INVESTIGATOR, below.3 Each had some sense of historical perspective and
TEACHER, AUTHOR AND HISTORIAN frequently drew on a range of classical and modern sources
to exemplify their studies. However, it was Hunter’s own
Donald Hunter, the son of a Post Office engineer, was born contemporaries who undertook detailed historical research
in 1898 in East London. He trained in medicine and quali- on the identification and treatment of occupational dis-
fied in 1922. After a year spent researching lead poisoning eases, particularly in the mining industries. Notable publi-
at Harvard in 1926, he worked at the London Hospital cations in the United States, often undertaken by European
from 1927 until retiring in 1963. By the 1930s, Hunter émigrés sympathetic to the cause of organized labour, were
had firmly established his life-long interest in occupational George Rosen’s The history of miners’ diseases (1943) and
health and a growing reputation as a commentator and Ludwig Teleky’s History of factory and mine hygiene
teacher. In 1943, he became director of the Department of (1948).4 In the United Kingdom, renewed interest in occu-
Industrial Medicine at the London, funded by the Medical pational health during the 1930s was fired by a group of
Research Council. The following year, he became the first researchers, such as Archie Cochrane, Philip D’Arcy
editor of the British Journal of Industrial Medicine and in Hart and Ronald Lane, whose sympathies clearly lay with
1955 he published The Diseases of Occupations.1 Hunter’s the social and political cause of the industrial working
encyclopaedic narrative has been compared with the pion- class.5
eering works of Bernardino Ramazzini and Charles We can locate Hunter’s own investigations and literary
Thackrah, physicians who completed monumental studies concerns, therefore, within a genre of contemporary toxicol-
of workpeople’s diseases in the eighteenth and nineteenth ogy research, historical writing and social compassion. His
centuries.2 Hunter remained deeply interested in the his- extensive reading was combined with the vigorous pursuit
torical origins of occupational medicine, as well as the of a wide variety of cases of industrial poisoning in the east
trends of disease and injury in the workplace. end of London and beyond. He assiduously sought out
Hunter’s predecessors in Britain as authoritative writers details of cases, questioning his patients on the incidence of
in the field of occupational health were Thomas Arlidge illness among fellow employees, corresponding with other
(1822–99), Thomas Oliver (1852–1942) and Thomas physicians on their industrial background and case history.6
Legge (1863–1932). They received their medical training in Notably, Hunter investigated the effects of methyl mercury
the Victorian period when industrial disease emerged as a poisoning from seed dressings on the visual cortex (later of
serious subject for investigation. Their work is discussed world importance when methyl mercury effluent entered
6 Donald Hunter and the history of occupational health
the food chain and poisoned people in Minamata, Japan). In confronted by industrial specimens presented at oral examin-
these years, Hunter sought out intriguing cases of deformity ations and questions posed on subjects relating to them. He
and occupational stigmata, particularly for photographic continued to be an inspired teacher into the 1970s, entertain-
records (presumably to show his students).7 He was also ing students long after the scheduled finish of his lecture with
sensitive to the geographical origins of illness. Not only were historical exhibits produced from a large cardboard box.15
occupations, such as billiard table makers, closely examined
for distinguishing signs of pneumoconiosis (lung disease)
caused by silica dust from slate rather than tuberculosis, but HUNTER’S HISTORICAL PERSPECTIVE
the diverse case histories of international mining engineers
with similar complaints were carefully reconstructed.8 Hunter brought to the study of industrial illness the distinct
In pursuing his research, Hunter had kept in touch with scientific and historical perspective of British medicine in
notable members of the Home Office’s factory inspect- the mid-twentieth century. His survey of workplace mal-
orate, such as Edward Merewether, requesting items for adies begins with a broad panorama of human history
the collection that Hunter was assembling.9 In 1943, before he engages in a long narrative of progress in the
Hunter was asked if he would be willing to take charge of a industrial world. Hunter relies not only on classical texts to
research department funded by the Medical Research illuminate different periods of industrial development, but
Council at the London Hospital.10 London was to be one of follows Rosen and others in attempting a serious economic
a proposed network of university departments in industrial and social history of production since the earliest years of
medicine that did not come into being, Hunter believed industrialization. His historical writing bears the impress of
that Clydeside, Merseyside and Tyneside were the most his own time and his own text has become a significant his-
obvious candidates for such centres.11 From his depart- torical document which should be read in the light of sub-
ment in the London Hospital, he also followed Legge’s sequent research by both economic and medical historians.
example of studies in the Great War (1914–18) by investi- Hunter acknowledges the progress made in the prevention
gating industrial hazards associated with aircraft produc- of occupational diseases and notes the role of politics and
tion and other essential munitions supplies during the social concern in this, but the approach he adopts has been
Second World War (1939–45). seen by more recent historical commentators as focusing on
Hunter fought to raise the status of occupational health the ‘grand narrative’ and the role of medical investigators in
and medicine during the late 1940s. In a report on indus- it, rather than acknowledging the views of non-specialists
trial medicine written in 1949, Hunter argued that England concerned with the harmful effects of work.16
(sic) was the leading country in protecting workers against Together with Rosen, Siegerist, Teleky and others, we
accidents and disease, though the scanty resources allo- may reasonably identify Hunter as one of the founding fig-
cated by the Treasury to the Factory Department of the ures in occupational health history. In the half-century since
Ministry of Labour, deprived it of the capacity to under- his work was published, the discipline of historical writing
take original research and limited its powers of inspection has been transformed. Medical historians have been influ-
and regulation.12 He strongly argued that the industrial enced by arguments in social and cultural history which
physician should be closely linked to general medicine and have identified how different insights may be gained into
that the university centres should forge ties within experi- familiar historical processes by examining the experiences of
mental pathology, pharmacology, physiology and with individuals and groups not usually included in the story. By
scientists more generally. He considered that the basic retrieving the documents and oral testimonies left by less
practice of industrial medicine should remain within the prominent and powerful individuals, including many of
grasp of the general practitioner.13 the patients treated by medical personnel, we can derive a
In the 1950s, Hunter continued his research into occupa- deeper understanding of the perceptions and motives of
tional health, visiting Charles Fletcher’s Pneumoconiosis those involved in medical treatment. Many of those who
Unit in Llandough Hospital (also funded by the Medical received medical attention, such as the workers suffering
Research Council), noting privately the animosity between occupational diseases, have left few testaments and even
Fletcher’s unit and the engineers at the mining school in their employers rarely spent time and resources expressing
Cardiff. He also visited the Wool (Anthrax) Disinfecting their own views of injuries or ‘malingering’ outside official
Station at Liverpool and commented on the innovative work enquiries and legal documents. It is not merely a matter of
at the Slough Industrial Health Service under Austin Eager.14 discovering new sources which might enable us to hear
This was one of a series of ‘group occupational health ser- those who were left without a voice in older historical stud-
vices’ set up in the immediate post-war years with financial ies: there is also the challenge of re-reading recognized
support from the Nuffield Foundation. In 1955, Hunter materials to trace the circumstances in which scientific
finally published his massive work, which rapidly established knowledge itself (and its authors) became the authoritative
a reputation as the single most authoritative English language account of the natural world and the aetiology of illness.
medical reference source on occupational illness. Hunter’s While there is considerable force in recent challenges to
influence was also extended through his tireless efforts as a the older, more heroic, genre of medical history represented
teacher and examiner in London, countless doctors being by Hunter, it can be argued that many of his judgements
Industrialization and risk 7
have withstood the test of time and scholarly criticism. More recent historical research suggests that the open-
Hunter’s portrayal of his historical subjects may have ing themes of the historical section of his book, in which he
encouraged a view of workers mainly as victims of economic outlines the human condition and man’s relationship to
change, but the empathy his writing shows with the labour work before he provides a broad narrative of industrializa-
force is in many ways comparable to those social historians tion, would, if written now, be recast to include the atti-
who set out to tell a story of events ‘from below’. His discus- tudes of a wider range of people and note their distinctive
sion of mining reveals interplay between society, work and contribution to the workplace, the identification of occu-
health in a stark perspective as the growing scale and depth pational hazards and the alleviation of illness. Hunter’s
of coal mining led to the employment of women and chil- work is, however, far more than just a record of power and
dren alongside an expanding army of adult male colliers attitudes of the (mainly male) medical profession of the
(Figure 1.1). He discusses how public concern in the 1840s mid-twentieth century. It is worth recalling the turbulent
about the morality of partially clothed women and children political struggles which marked his professional life and
working underground in these conditions provoked moral the intellectual battles of the years before the rise of fascism
alarm rather than merely regard for physical welfare of and during the cold war era in which his own major work
those labouring in primitive conditions. was published. Hunter’s long historical introduction to
Technological change and the introduction of rock Diseases of occupations does present a portrait of progress
drills are similarly presented in their social context, as in which clinical investigators played a significant and
Hunter notes, a lethal new threat to the lungs of workers often heroic part in achieving positive change, but it is
arose as unprecedented amounts of dust were generated by also a testimony to the social conscience of a minority of
these ‘widow makers’ powered by compressed air. distinguished medical investigators in an age of hardship,
tension and war, whose legacy remains strong.
metal grinding trades gradually led to the introduction of the reputation of the early investigators of occupational ill-
exhaust ventilation on the sandstone grindstones which ness in the United Kingdom and other countries: lead,
caused serious lung damage or ‘grinders’ rot’ in areas such phosphorus and anthrax. Lead poisoning had long been a
as Sheffield and the Midlands. While factory and mine serious problem in a range of industries including the
workers were subject to some state regulation, small work- manufacture of white lead pigment for use in paints,
shops and those who were self-employed or contracted to ceramic and pottery manufacture (lead glazes), and expos-
small masters and intermediaries were notoriously unpro- ure to the element in mining and smelting operations. The
tected throughout the nineteenth century.26 employment of women in a number of these occupations
It was the legislation which dealt with lead poisoning in led to the recognition that, as well as the abdominal, neuro-
the years leading up to the Factory Act of 1891 which can logical and haematological effects of poisoning, they also
reasonably be described as the foundation of both modern suffered from repeated miscarriages. The Home Office
occupational health regulation and the use of specialist established a committee to investigate white lead which rec-
expertise in the public management of hazardous work- ommended basic controls which were refined by later
places. The Act of 1891 empowered the Home Secretary (in Dangerous Trades Committees and leading factory inspect-
practice his Inspectors at the Factory Department of the ors, including Thomas Legge on his appointment as first
Home Office) to compel any trade designated as ‘danger- Medical Inspector of Factories in 1898. Ceramic and pottery
ous’ to adopt special rules for the control of hazardous manufacturers resisted any changes to the lead glazes, blam-
agents to protect workers. The last decade of the nine- ing their workers for poor hygiene and they maintained
teenth century and the first decade of the new century stubborn opposition to state interference in the early twen-
deserve particular attention in the history of state attempts tieth century. While significant reductions were recorded in
to regulate occupational dangers, for they saw the regula- notified cases from lead poisoning in the decade before
tion of toxic substances and dusts, as well as establishing 1914, probably as a result of more precise diagnosis, as well
the reputation of several leading figures who studied these as the diligence of the Factory Inspectorate and increased
materials and advised government on their control. publicity given to the problem by women’s campaigners as
well as health reformers, the mortality rates were little
improved in the early twentieth century.30 One indication of
DANGEROUS TRADES AND INDUSTRIAL the persistence of problems can be found in the continuing
DISEASES research during the interwar years, including Hunter’s
period as a researcher at Harvard under Aub.
The growth in government regulation of hazards at work Phosphorus poisoning leading to necrosis of the jaw
arose in part from greater scientific understanding of the affected those working in the match-making industry,
nature of the risks posed by particular substances and their yellow phosphorus being used for strike-anywhere ‘Lucifer’
widespread use as chemistry was revolutionized in the late matches in the nineteenth century. ‘Phossy jaw’, the
nineteenth century. The new chemistry furnished tech- painful, frequently foul-smelling decay of the lower jaw led
niques for the measurement of contaminants in the work- to disfigurement and death in both women and men who
place and a more precise assessment of the relationship were involved in the making of inflammable paste and dip-
between exposure and harm to health. The effects of ping of matches. Bryant and May presented themselves as
changes in levels of oxygen, nitrogen and carbon dioxide, model employers at their east London works until a famous
as well as methane (in mines) and carbon monoxide (from industrial dispute brought the ‘match girls’ out on strike in
fires) were investigated by innovative physiologists such as 1889. Soon afterwards the press exposed the company’s
John Scott Haldane, whose field observations and experi- policy of concealing phosphorus poisoning cases by pen-
ments, often on himself in an exposure chamber, led to sioning off afflicted workers. Similar problems in other
improvements in a range of industries, as well as in tunnels countries led to proposals in 1900 for an international con-
and wells.27 Investigators in Germany, such as Lehmann, vention prohibiting yellow phosphorus in favour of safety
contributed to accurate measurements of toxic vapours in matches, but the British government refused to support an
the atmosphere and their effects on the human body.28 The international convention, seeing it as an unwarranted inter-
birth of modern bacteriology and immunology with the ference with free trade.
work of Koch in Germany and Pasteur in France led to In contrast with the risks to the mostly unskilled females
the specific identification of infectious organisms and meth- and males involved in lead and phosphorus trades, anthrax
ods of treating them from the 1880s, supplanting earlier dis- rose to prominence in Britain because of the rapid deaths
ease theories of miasma, but also provoking wide-ranging from lung infection and septicaemia among the skilled
and sustained controversies on the nature of infection.29 men who were employed as wool sorters in the Bradford
As the technologies for assessing risks and the methods area of West Yorkshire. Suspicions had also been growing
for understanding diseases and their control steadily that labourers who worked with imported animal hides
improved in the later nineteenth century, cases of poison- and hairs in places as distant as Glasgow, London and
ing affecting specific trades were more clearly identified. Liverpool were also suffering from a sometimes fatal skin
Three agents attracted particular attention and established infection associated with these materials. Dr JH Bell of
12 Donald Hunter and the history of occupational health
Bradford, an ophthalmic specialist, who also contributed Staffordshire Infirmary and drew on his own encounters
to the identification of miners’ nystagmus, achieved a with cases of lead poisoning and lung disease. Arlidge also
national reputation in 1879–80 after linking pulmonary developed the methods of Thackrah and Greenhow by
fatalities among wool workers with the Bacillus anthracis using census and mortality data to map the distribution of
recently described in detail by Pasteur.31 The remarkable illness. Thomas Oliver was a Newcastle physician who
success of Pasteur and Koch’s work helped to establish the advised the Factory Inspectorate on lead poisoning in the
germ theory of disease among the British medical commu- 1890s. His book Dangerous trades (1902) brought together
nity, although heated debates continued long after about leading authorities to describe not only industrial illnesses,
the proper role of laboratory research in tackling disease.32 but also the changing industrial technologies of the period.
More practically, the association of anthrax with raw mater- Oliver contributed several chapters and again made use of a
ials used in one of Britain’s staple industries provoked mass of statistical information on mortality and mor-
fresh activism in the local labour force and a strong cam- bidity.35 Oliver resisted currently fashionable inclinations
paign resulted in the adoption in the early 1880s of a vol- to explain the origins of industrial lung disease in bacterio-
untary code of preventive measures, including the use of logical terms and emphasized the primary importance of
tables with downdraught ventilation for sorting fleeces mineral dusts (such as silica) in causing lung disease among
from regions most associated with dangerous wools. workers. Both Arlidge and Oliver recognized the central
There was some improvement in recorded fatalities from role of the state in disease prevention, but saw workers as
anthrax and the earlier voluntary rules were extended to passive victims rather than recognizing the role of organ-
cover more groups of workers, tightened and made statu- ized labour in debates on disease prevention.
tory (following a review by the Home Office’s Committee Thomas Legge’s Industrial maladies never achieved the
on Dangerous Trades after 1896). The incidence of the more reputation secured by his predecessors and was completed
common skin form of ‘malignant pustule’ remained rela- by his successor as senior medical inspector, John Bridge,
tively constant, with death in about 15 per cent of cases. after his sudden death in 1932.36 Yet Legge (Figure 1.10)
While Thomas Legge appears to have been convinced of the rose to early distinction and influence in a public career
case for further legislation well before 1914, the response which his predecessors hardly contemplated. Legge was the
from the Factory Department of the Home Office can at best son of a distinguished missionary in China and sinologist.
be described as lethargic. A contested legal decision taken on He travelled widely in Europe before his appointment in
appeal to the Law Lords in 1905 that an employee infected 1898 to the new post of Medical Inspector of Factories, at
by the bacillus should, for the purposes of compensation, be the early age of 34 years.37 The growth of government
considered to have suffered an accident, helped to prompt expertise in industrial toxicology and particularly the analy-
the decision to schedule six occupational diseases as qualify- sis of dust problems in the workplace which dominated
ing for compensation under the Workmen’s Compensation the agenda for regulation until the 1960s can be dated from
Act of 1906. Anthrax remained a feature of the industrial
scene in the early decades of the century. Hunter himself col-
lected details from patients such as Elsie Mitchell, a horse
hair worker aged 19 infected in 1913 and a male agricultural
worker whose eye was infected after working with manure in
1921. Ever the indefatigable researcher, in 1935 Hunter
interviewed the widow of a horse hair worker who had been
infected in 1922 with ‘filthy hair from Russia’ and died. As
late as 1938, Hunter examined a Harpenden man admitted
to hospital with anthrax symptoms contracted at the artifi-
cial manure factory where he worked with wool processing
waste or shoddy.33
his appointment. Legge’s writings were influenced by the Hunter’s account of the progress of occupational medi-
socialist and egalitarian leanings of the late nineteenth cen- cine provides a heroic view of the pioneering efforts of
tury arts and crafts movements and he frequently acknow- enlightened individuals such as Arlidge, Oliver and Legge.
ledged the contribution of workers and their representatives Such an approach was common in many mid-twentieth
to the cause of disease prevention. During the 27 years century studies of medical history, where the concentration
Legge served in the Home Office he investigated a wide on eminent medical men tended to obscure the now current
range of diseases, undertaking systematic surveys such as views on the impact of labour activists and interest groups
that comparing the health of workers in Birmingham and at and the complex political and legal context in which they
Woolwich Arsenal to isolate the effects of brassworking on were active. These physicians worked within a legislative
health.38 Legge continued his early interests in lead poison- framework which defined the terms of their involvement
ing and anthrax infection, developing criteria to be used in with industrial disease, as well as their legal responsibilities
diagnosis and supporting laboratory arrangements for to patients and government. The passage of Workmen’s
anthrax investigation. His Milroy lectures of 1904 were a Compensation legislation, in 1897 and 1906, established
wide ranging review of industrial anthrax, its bacteriology, employers’ liability for specific illnesses contracted at work,
presentation, treatment and prevention. From his European as well as accidents in industry. This placed medical knowl-
visits, he became familiar with Sclavo’s anthrax antiserum edge in the witness box when claims were verified – at times
and subsequently served on the committee which sat dur- pitting a doctor representing the employer and their insur-
ing the First World War and recommended reforms which ers against another who represented the worker and their
were embodied in the 1919 Anthrax Act and led to the trade union, and increased the requirement for valid evi-
building of the Liverpool disinfection station.39 dence on the causes and extent of disease affecting employ-
In researching the effects of lead poisoning on workers, ees. It also narrowed the definition of occupational diseases
Legge struggled against the opposition of employers who to those conditions that were either notifiable to the
sought to blame the dirty habits of their workers for poison- Inspectorate or prescribed for compensation.
ing to establish the primary importance of inhalation of lead Historians have long been aware of the importance of
particles rather than their ingestion by unclean eating habits. social insurance in the building of state medical services
In collaboration with Kenneth Goadby, he refined the meas- across Europe and in other continents. In the United
urement of toxicity within the body and worked with other Kingdom, National Health Insurance was introduced in
colleagues to restrict the hazards of lead in such booming 1911, providing for the creation of ‘approved societies’ to
sectors as the manufacture of lead-acid automobile batter- administer the sickness benefits of workers and to engage
ies.40 The contribution of government controls to the panels of doctors who would attend to those insured under
reduction in fatal lead poisoning is doubtful. The fruits of a state scheme funded by contributions from employers
prevention and treatment were rather more apparent in and workers as well as the Treasury. One of the concerns of
anthrax where modest improvements were recorded in cases nation states which created new social and health services
and fatality rates just before the First World War (Table 1.1). during the late nineteenth and early twentieth centuries
There was then a deterioration due to the use of poor qual- was the growing economic and military competition
ity wool to make good shortages of raw materials and to sup- that required human, as well as industrial and territorial,
ply the enormous demand for military supplies. Long-term resources. In this race for efficiency and supremacy, the
improvements followed legislation in 1919, but government health, and hence military potential, of ‘human stock’ was
measures probably had less impact than falling imports of emphasized while eugenicists, in addition to their concerns
more dangerous fleeces and gradual improvements in ani- about breeding, stressed the vital importance of maternal
mal husbandry across the world. Legge’s efforts to secure and infant welfare in an age when unfitness for military
international cooperation in the control of anthrax and lead service could undermine the foundations of national
met insurmountable obstacles as outlined below. success. Feminist historians have subsequently argued that
Table 1.1 Anthrax and lead poisoning cases, deaths and fatality rates (male and female) Britain.
Cases Deaths Fatality rate (%) Cases Deaths Fatality rate (%)
governments developed policies for occupational as well as governments, as well as private organizations and legal
public health which reflected their concerns about manag- experts.46 The maintenance of the male breadwinner as the
ing the (male) human resources of civil society. Such ini- foundation for stable household income among the work-
tiatives also reflected the gender bias and distinctive ing population remained a theme in welfare reform and
expectations of males and females in contemporary soci- concerns about the occupational health of the workforce.
ety, where adult men were expected to serve as breadwin- International awareness of common health problems and
ners for the family household and to accept physical risks the scope for similar approaches to resolving them certainly
and working conditions from which females and children, increased after Germany embarked on Bismarck’s pioneer-
living in a ‘separate sphere’, were protected. The reproduc- ing social insurance arrangements in the 1880s, although
tive and maternal health of fertile females was particularly important differences can be seen in the way nation
emphasized by physicians, such as Arlidge and Oliver, who states addressed the question of compensation for injured
examined the dangers posed by lead during pregnancy and workpeople and the liability of employers for different
attributed poor infant mortality to working after child- kinds of diseases. Crossnational projects, such as the build-
birth. Women and girls were also considered to be vulner- ing of the Alpine railway tunnels at the end of the nine-
able to mental, social and personal hazards which men teenth century, revealed the appalling hazards to which
were assumed to tolerate along with physical dangers or labourers were exposed, as diseases such as hookworm
abuse at work.41 Lady Factory Inspectors appointed from (ankylostomiasis) spread from the tunnels to many of the
the 1890s were particularly responsible for investigating mining areas of Europe and its colonies.
and reporting on the hazards faced by females in the work- Tunnelling and mining projects around the world pro-
place.42 This topic remains controversial as other scholars vided a working laboratory for health researchers and con-
have cast doubt on the claims that pre-1914 governments tributed to the establishment in 1906 of the Permanent
were particularly concerned with females in the measures Commission for Occupational Health, an international
passed to promote industrial health.43 grouping of occupational health experts. The huge growth in
Similar debates have surrounded the attitudes of trade gold mining using dry drilling in siliceous rocks on the Rand
unions towards compensation and safety. A common criti- of South Africa produced many cases of silicosis and these
cism of the labour unions is that they have historically were seen in other countries, especially the United Kingdom,
shown more interest in pursuing monetary settlements for when miners returned home to die. Contributions to inter-
injured members than in promoting health and accident national understanding of serious respiratory illness in dusty
prevention in the workplace.44 Such arguments appear to trades were also made by the published investigations of
be based on an assumption that unions and their members medical experts such as Oliver and Legge. The promising
can effectively choose whether to give priority to receiving moves being made towards greater international cooperation
monetary returns for injury rather than to securing safe in regard to workers’ injuries were interrupted by the out-
working conditions. In practice, as writers since Ramazzini break of mass warfare in Europe in 1914, spreading to many
have noted, workers commonly believe they have few alter- parts of the world by 1916. Embattled states created a huge,
natives to tolerating hazardous working conditions and unprecedented demand for essential war supplies, thereby
their representatives often pursue compensation payments introducing new risks to employees, exemplified by out-
as a necessary means of support for injured workers and breaks of toxic jaundice among workers applying tetra-
their dependants. Labour leaders repeatedly expressed the chloroethane to aircraft wings and filling shells in plants
largely unrealized belief that significant compensation pay- handling TNT.47 Governments responsible for munitions
ments would deter the employers (and their insurers) from production were drawn into investigating and regulating
persisting with dangerous work practices.45 However, the conditions of work to reduce the toxic effects of chemicals
lethargy of employers, the cover provided by their insurers used for armaments manufacture, to provide canteens and
and the apparent collusion of their medical advisers, as welfare services for workers away from home and to control
well as governments with poor safety standards has the adverse effects of long hours on productivity and safety.48
remained a constant feature of trade union concern since At the same time, government ministers in the United
the late nineteenth century, hardly indicating widespread Kingdom and other countries were acutely aware of the
union tolerance of hazards in the workplace. risks of labour unrest and disruption of production in the
extraordinary market conditions of ‘total’ warfare.
Concessions to organized workers included guarantees to
THE INTERNATIONAL DIMENSION IN PEACE reserve jobs for returning servicemen on the cessation of
AND WAR hostilities. The legacy of the war for research into and regu-
lation of occupational hazards was a disappointing one for
In the years when nation states were introducing central- contemporary enthusiasts, such as the Industrial Welfare
ized health insurance, actuarial experts employed by insur- Society. The wartime research on fatigue led to the creation
ance companies and friendly societies were assembling of the Industrial Health Research Board and was eventually
statistics which provided risk profiles of the working popu- incorporated into the Medical Research Council’s efforts
lation. Statistical returns assumed a fresh importance for on workplace health in the interwar period, though it
The international dimension in peace and war 15
was not until the late 1930s and the outbreak of another
international war in 1939 that fresh impetus was given to
specific war-related industrial problems, where Hunter
played a significant role as an investigator.49
Another legacy of the 1914–18 war was the creation of the
League of Nations based in Geneva and its International
Labour Office (ILO), which developed transnational conven-
tions to improve labour conditions and reduce the incidence
of illness at work. The ILO’s conventions gave a formal status
to agreements on the control of dangerous working condi-
tions and enabled trade unions to contribute to such instru-
ments. Dr Carozzi played a notable bridging role as both a
staff member at the ILO and as secretary of the Permanent
Commission for Occupational Health. Legge contributed to
these innovative gatherings and sat on specialist commis-
sions of enquiry, including one on anthrax, where other
nations were unwilling to adopt the use of centralized disin-
fection stations, although they acknowledged the work of the
United Kingdom in this area. Legge also played a key role in
negotiating the convention to ban lead from interior paints.
The British Government’s decision to renege on its earlier
undertaking to support this initiative led to Legge’s widely
publicized resignation from his post at the Home Office.50 Figure 1.11 Alice Hamilton, a leading expert in the field of
One topic on which the British Government was keen to occupational health. Reproduced from www.nlm.nih.gov.
contribute was silicosis. An international conference was
convened at Johannesburg in 1930 at which national experts
on silicosis exchanged views and agreed standards for classi- early ‘scientific management’ practices with the emerging
fication of disease and methods of diagnosis based on South professions of occupational psychology and industrial
African and other international developments in radiography hygiene as firms sought to minimize labour problems by
and pathology. As a major maritime nation, Britain also using psychometric tests for staff recruitment and to
helped to draft several new ILO conventions which were increase production by optimizing working conditions.51
important for the eradication of the worst abuses of seafarers The emergence and growing employment of these specialists
by the global shipping industry. has remained a subject of some controversy. Criticism has
President Woodrow Wilson had played a leading role in come not only from trade unions who claim that these spe-
setting up the League of Nations, but the United States elect- cialists tend to prioritize performance and output before
orate turned their back on international commitments and employee safety, health and welfare, but also from other sci-
Washington maintained only loose connections with the entific and government experts who have questioned the
ILO through conventions and correspondence in the inter- methods and objectivity of such personnel. Similar criticism
war years. Historically weaker than central governments in has been extended to those doctors in industry whose jobs
Europe, federal authorities played only a limited role in were mainly structured in terms of providing support and
health and safety before the New Deal of the 1930s, although solutions for the employer.
pioneering investigators such as Alice Hamilton publicized The international dissemination of technological and
poor working conditions, especially where weakly protected scientific information between the wars should be under-
immigrant and female workers were involved (Figure 1.11). stood, therefore, within the strained political and indus-
The early decades of the century marked the emergence of trial relations that overshadowed many societies during
scientific and Fordist (after Henry Ford’s production line these years. These were also years of economic depression,
manufacture of automobiles) management practices, ini- industrial restructuring and rapid technological change in
tially in the American automobile assembly industry, but the global economy. The innovative use of chemicals had
soon transferred to other sectors and countries. These accelerated since the late nineteenth century, for instance
included the widespread use of timed production line oper- using carbon disulphide in the manufacture of materials
ations specified and costed by ‘work study’ experts. The such as rayon (artificial silk), resulting in reappearance of
techniques of scientific or ‘Taylorist’ (after FW Taylor) its well-established neurological and behavioural harm in
management were vigorously criticized by early industrial new workforces. The uses of lead featured in a variety of
psychologists such as Elton Mayo in America and by ethical trades including the development of ethyl lead to slow the
employers such as Cadbury in the United Kingdom, who ignition of motor gasoline and this caused widespread poi-
insisted on the importance of ‘human factors’ in planning soning where it was manufactured or blended. At the same
production. It is also possible to detect some convergence of time, traditional industries, such as coal, textiles, ceramics,
16 Donald Hunter and the history of occupational health
it became apparent that the boundaries of risk within acro-osteolysis in their fingers and subsequent animal stud-
industry, and more importantly between occupational and ies revealed disproportionate cancer rates, including the
public health hazards, were extremely difficult to draw. rare liver cancer angiosarcoma which was identified in
International scientific collaboration was needed as the dif- exposed workers soon after the study results became
ferent interest groups demanded new techniques and more available to the industry. Delays in the release of results
rigorous epidemiological investigations to understand the occurred largely because of American concerns about regu-
dose–effect relationship between levels of asbestos dust and latory implications, as the criticisms of historians Rosner
the incidence of illness. Competition as well as cooperation and Markowitz make clear.58 A familiar dilemma faced reg-
between leading scientists characterized the convening of ulators in confronting the health risks from PVC produc-
medical conferences in Europe and the United States which tion: its supporters pointed to the safety benefits of electrical
sought to determine the hazards associated with blue and insulation and other uses, as well as disruption to supplies of
other forms of asbestos. In the 1960s and 1970s, the indus- other essential chemical products (such as caustic soda), if
try (and their medical advisers) campaigned to present PVC production was halted. Critics demanded immediate
chrysotile (non-blue) asbestos-containing products as essen- action. A compromise was adopted where producers agreed
tial to society and relatively safe. In particular, they empha- to reduce exposure levels over three years and new monitor-
sized the need for long-term research before enforcing any ing techniques were developed. In the longer term, the con-
prohibition. As public regulators came under increasing firmation of cancer risks led to more comprehensive testing
pressure, bodies such as the British Occupational Hygiene of other large volume industrial chemicals, resulting in only
Society provided standards that addressed, in a flawed analy- equivocal evidence of cancer risks in a few cases, though the
sis, the risk of asbestosis from chrysotile rather than that of principle of prior testing of substances and the need for
cancer. The resultant controversy was sharpened by inves- valid risk assessments was established and later came to be
tigative journalism and media coverage (including the televi- incorporated into law. International bodies such as the
sion documentary ‘Alice: a fight for life’), forcing the British International Agency for Cancer Research (IARC) and the
Government to introduce a battery of controls, including a International Programme on Chemical Safety also assumed
licensing regime for asbestos insulation and a register of a more significant role in such discussions.
mesothelioma cases. It was the demonstration of a link Asbestos and especially its effects at low concentrations,
between specific industrial products and public, as well as as well as a wholly unexpected risk with vinyl chloride both
occupational, health which forced politicians to venture focused attention on the large toll of disease that could
beyond the limited controls which had been proposed by arise from any substance with fatal effects that only become
civil servants and expert advisers. apparent after many years. This dented earlier confidence
A further and decisive blow against the continued use of in the idea that the classic industrial poisonings were yes-
asbestos and the interests of the producers came with the terday’s diseases and that the major challenge of dust dis-
escalation of litigation, most particularly in the United States eases of the lungs was now coming under control. It also
from the 1970s, by aggrieved plaintiffs who sought massive led to a questioning approach to the pathology of diseases,
damages for the legacy of human and material losses which such as the byssinosis of cotton workers delineated by
they faced from exposure to the material or from its incorp- Richard Schilling, where the effects of the agent in cotton
oration into buildings. The scale of these claims forced the and the less specific effects of pollution and smoking on the
largest asbestos producer (Turner and Newall, Manchester, lungs had to be disentangled. Successful examples of pre-
UK) to sell its assets and cease operations while damages also vention could be identified but there was now an expect-
threatened the international insurance market at Lloyds ation of diseases becoming apparent from new and even
with collapse at the end of the twentieth century. As a com- not so new technology, as well as uncertainty about the role
plete ban on all future use of asbestos became politically of occupational sources of contamination in exacerbating
necessary in the United States and Europe, global mining or contributing to conditions that also occurred in the gen-
and manufacture of the mineral went into steep decline, eral population. Low level exposures also became promi-
although mining continues and asbestos use persists in some nent, especially as causes of cancer and mutation. The logic
lower-income regions of the world. of a risk at any dose had been the basis on which protection
While the risks from asbestos overshadowed inter- against ionizing radiation had been founded for a number
national concerns for workplace health in the later twenti- of years, but now there was evidence of similar patterns
eth century, other occupational hazards were identified in with asbestos and this fed into concerns about many other
the ‘new’ consumer materials of the period. Some of these widely used products, such as pesticides, cosmetics and
toxic risks were known to earlier generations in different food additives. Indeed, the results of occupational epi-
forms and the lesson of industrial poisoning was painfully demiology provided much of the evidence for the environ-
relearned.57 The serious risk of liver cancer presented by mental contribution to cancers in general – a topic that
vinyl chloride, the raw material for PVC plastic, was identi- remains contested.
fied in 1973–74 in workers who had been heavily exposed for The use of epidemiology to help frame regulations has
over 20 years. Cleaners of polymerization vessels developed depended on the examination of large groups of workers
18 Donald Hunter and the history of occupational health
with comparable levels of exposure to risk whose pattern of A FUTURE HISTORY FOR OCCUPATIONAL
illness could be compared either with the unexposed or HEALTH?
with those who had a different level of exposure. A series of
major studies of relatively specific risks was undertaken in Hunter first published his major work at a point when the
the 1970s and 1980s by the Health and Safety Executive, by most lethal consequences of asbestos were still to be revealed
the Medical Research Council and by academic departments, and it was still possible to see the history of medicine as an
with governmental or industry support. almost unbroken trajectory of scientific improvement and
The controversy surrounding asbestos and vinyl chlor- heroic discovery. Within 20 years of his first edition, the bit-
ide coincided with a major review of state regulation of ter and escalating controversy around asbestos had blown
occupational safety and health in the United Kingdom by away the notion of benign technology and consensual regu-
the Robens Committee. The United States had already lation. A few years after Hunter’s work Rachel Carson’s
undertaken a not dissimilar review leading to the creation Silent spring was published, graphically depicting the impact
of the Occupational Safety and Health Administration and of chemical production and toxic pollution on the American
the National Institute of Safety and Health in 1970. The landscape and confirming a dawning consciousness of envir-
aim of Robens was to rationalize and reduce the dense onmental damage which reoriented public health politics in
mass of regulations and inspection regimes which had the United States during the following three decades. The
developed since the nineteenth century. The 1974 Health growing challenge to assumptions about the beneficial con-
and Safety at Work etc. Act fulfilled Robens’ vision of a sequences of new technology and medical research was
governance framework which separated the executive and strengthened by pharmaceutical tragedies, such as the mar-
enforcement functions of safety from the tripartite com- keting of thalidomide to pregnant women and the initial
mission that decided on policy matters.59 The new regime reluctance of the Distillers Company to reach a compensa-
incorporated the recently formed Employment Medical tion settlement with those families affected. We still do not
Advisory Service (EMAS), as well as several inspectorates, know at the end of the first decade of the twenty-first cen-
into a Health and Safety Executive (HSE). EMAS’s original tury what the final toll of deaths and disability will be from
purpose was to freely provide accurate information on the asbestos disaster.
occupational health to industry, trade unions and individ- As the promise of scientific progress and new technolo-
uals, although while its connection to HSE’s enforcers gies has been subjected to more critical scrutiny in the half-
probably made it less palatable to employers it became century since Hunter’s text was published, philosophers,
better placed to function as a source of medical expertise social scientists and historians have attempted to offer a
within the new executive. Another feature of the new sys- more searching analysis of the way science itself is con-
tem was the inevitable difficulties which arose from ducted and the terms in which knowledge about the world
Robens’ definition of health and safety in fairly narrow (and the human body) is authenticated and accepted. Social
occupational terms, leaving unresolved the familiar prob- scientists have also contributed to explanations about
lem of drawing the boundaries of causation between work- human behaviour in the face of risks and hazards as well as
place and the wider physical and social environment. to broader questions of social interaction at the workplace
Since the 1974 Act, a number of new health regulations and individual assessment of competing responsibilities.60
have been adopted including controls on chemicals, lead, The expanding disciplines of psychology, sociology and
asbestos and ionizing radiation, as well as for noise expos- organizational studies have also exerted greater influence
ure, manual handling, working with pathogens and at dis- over the ways in which workplace health and risks are
play screens. The framework of international directives has understood and analysed. Although the diagnosis and treat-
been strengthened by European Union agreements that ment of occupational diseases had traditionally depended
place penalties for non-compliance on nation states, as on a clinical examination and frequently on the sufferer’s
well as on offending employers. The agenda of occupa- own history of their working life, industrial toxicologists
tional health and the expertise of government regulators had been largely concerned with the pathology of illness
has also changed in recent years as the historic concern and establishing the nature of the link between environ-
with hazardous substances had to be refocused towards a ment and illness. In determining the provisions made for
range of conditions which extended from musculoskeletal both treatment and financial maintenance of the individual
pain and dermatitis to asthma, mental distress and the worker, a range of social and political considerations has
non-specific symptom syndromes which have been attrib- almost inevitably come into play. Governments, as well as
uted to ‘sick buildings’, solvent exposure, pesticide use and scientists, often appeared anxious in the earlier twentieth
other complicated environmental factors. As in the late century to preserve the distinction, however artificial in
nineteenth and early twentieth centuries, however, a key practice, between the research problem of industrial hazard
driver in the changing priorities and concerns of employers and the legal and administrative procedures by which
and governments has been the award of compensation financial compensation might be decided.
settlements in cases of workplace stress and upper limb Preserving these distinctions was particularly difficult
disorders. This has prompted defensive and preventative when a new range of work-related ailments emerged,
action by industries and their insurers. including asthma, dermatitis, musculoskeletal pain and
A future history for occupational health? 19
mental strain where the link between illness and specific commitment of China to industrialization and world
occupational conditions was less robust than in circum- trade, in the past two decades.
stances where toxins or dust might be measured with the These changes were reflected in renewed concern with
prospect of defining clear dose–effect relationships. While the productivity of the workforce and with devising effective
an increase in prevalence might be established, the nature models for managing human, as well as material, resources
of individual exposure and susceptibility was much less of production. The last three decades have followed the free
clear. Greater reliance had to be placed on epidemiological market ethos that has dominated in politics and business
studies of large groups of workers rather than on individ- and have been marked by a cultural, as well as a political,
ual case notification. acceptance that the idea that personal fulfilment and self-
The limitations of epidemiological studies provoked fur- realization depends on individual responsibility for self-care
ther debates about the appropriate methodologies which and personal well-being, as well as on the conditions created
could be utilized in the discovery of health and illness at by others both in the workplace and elsewhere. Public insti-
work. In many industries, such as oil, chemicals and pharma- tutions, as well as private corporations came to set policy
ceuticals, only a small number of workers were exposed to a goals of transparency and accountability – reflecting increas-
particular hazard. Statistical testing of unusual patterns and ing customer and consumer rights – as well as agreed
isolated clusters of disease yielded unsatisfactory results. performance targets, self-monitoring or peer assessment of
Researchers also found it difficult to establish valid methods performance, open-plan office spaces and technological
to study the apparent increase in musculoskeletal and screening of inappropriate behaviour. The collective protec-
psychosocial symptoms reported in British and overseas tion offered by trade unions has been weakened by the
workplaces as reports depended so heavily on subjective decline of older, often male-centred sectors of production,
evaluation and self-reporting. Psychologists became con- alongside the growth of ‘flexible’ working, temporary and
tributors to HSE research projects from about 1980. Within short-term contracts and self-employment. In parallel to the
the expanding research field of work-related psychology, expansion of the practice and language of management, a
divisions were also apparent between laboratory-trained significant feature of the renewed drive for productivity and
personnel who followed the experimental model of study controlled flexibility in global labour markets has been the
laid down during and after the 1939–45 war, and those who erosion of the authority and autonomy of the elite profes-
embraced a qualitative and more flexible social approach to sions. The titles and status of professionalism have been
the investigation of workplace attitudes and the conse- stretched to include less skilled and lower status groups,
quences of monotony, overload and conflict in different while the capacity of professional bodies to govern their
occupations. members has been subjected to intense scrutiny by govern-
Most historians of work would place these trends in ment, media and private litigants.
occupational health and the debates among experts on the This changing landscape of global production and unre-
nature and causes of workplace illness within the larger stricted labour markets has powerfully influenced the terms
social and institutional context of economic and political in which occupational health and safety have developed in
change during the later twentieth century. Discussions recent decades. During the middle decades of the twentieth
about workers’ welfare had moved from assessments of century, tensions between occupational medical goals and
basic physical and mental capacity to considerations of satis- production management were apparent in large companies
faction and fulfilment as conceptions of human well-being and organizations where much of the key research was con-
expanded during the long boom and rising affluence of the ducted and policies were implemented. Employers pro-
post-war period. European countries that developed com- moted safety selectively and most enthusiastically where
prehensive welfare systems funded by near-full employment productivity gains and corporate risk reduction were most
and corporate bargaining between employers, unions evident. This is illustrated by the unintended consequences
and government embraced at least some principles of of initiatives, such as audiometry programmes established
improved job fulfilment, as well as rigorous safety stan- to reduce damage to hearing from noise. While firms often
dards. Scandinavian research was particularly influential in ignored the representations from occupational health
a burgeoning concern with improving or ‘enriching’ occu- departments showing the need for better controls, the data
pational satisfaction, as well as in an escalating literature on recorded subsequently provided strong evidence for com-
sources of ‘stress’ at work and in wider society.61 The con- pensation claimants. As employment was rationalized and
text of these debates was radically changed in the last two reorganized in the harsher competitive conditions of the
decades of the twentieth century as the post-war consensus late twentieth century, the problem of risk was more closely
on national fiscal management and collective bargaining aligned to problems of output and poor performance rather
was disrupted in Europe and other continents by the reor- than a duty of care to employees. A countervailing force
ganization of global production and the election of free- appeared in the greater readiness of employees to resort to
market conservative governments in the United Kingdom, litigation on the grounds of discrimination, as well as
the United States and other countries. The transformation unreasonable exposure to risk, blurring further some of
of the global economy was confirmed by the collapse the boundaries between their obligations as employees
of planned economies and Soviet power, as well as the and their expectations of social responsibility from their
20 Donald Hunter and the history of occupational health
employer. Concurrently, the ‘balance’ of occupational and lines of labour rights, gender, ethnic immigration and rival
non-work life became a familiar theme in discussions of advocates of scientific and legal expertise.
personal and organizational stress. Perhaps most fundamentally, historians now seek to
Faced with the conflicting pressures and repeated recover the voices of the patients and workplace witnesses
demands for public engagement in questions which had who were most directly affected by disease and diagnoses.
previously been a domain of specific expertise, researchers The identity of those who can be considered as the clients
into workplace health increasingly adopted broader and for expertise on occupational health risks has changed in
less technical approaches to the problem of occupational the half-century or more since Hunter’s classic text was
risk. This ‘ecological’ view of ill health rephrased many ear- first published. Nineteenth century commentators were
lier concerns about the origins and causation of problems acutely aware that workplace hazards and effluents were
by posing questions about the nature of the health issue likely to affect not only the workforce but the surrounding
raised and the circumstances in which concerns began to community and to result in damage to public health. From
be expressed about it. Practitioners, as well as investigators, the mid-Victorian years, responsibility for workplace and
who adopted an ecological approach now had to consider environmental health was allocated to different agencies
novel links between possible causes and effects in terms of and government departments and this overview was lost.
the psychosocial context of the problem and the belief sys- Hunter was writing at the dawn of a new environmental
tems of those involved with it, as well as nature of the cause politics, emanating principally from the United States, but
or harm that is being investigated. Rather than seek to evident also in Europe by the 1960s, that was returning to
exclude and control any stated or implicit values and sub- the nineteenth century model with raised awareness of the
jective meanings attached to problems and policies, such dangers presented to wider society by pollution from toxic
studies of workplace health now often share the perspec- products and discharges. Consumers, as well as producers,
tive of historians and social scientists when they study the began to articulate their concerns in ways that compelled
effects of the power of different interested parties, the rea- medical scientists, as well as policymakers, to reappraise
sons for disputes about the significance of subjective com- the connections between production and public health.
plaints and scientific studies and the ethical and expedient The example of asbestos illustrates the fault lines in the
basis for taking decisions about action on health concerns scientific community and the employers’ lethargic response
and risks at work. to key research and government controls in the post-war
years both in relation to worker and public risk. The differ-
ent ways in which this story has been interpreted by histo-
CONCLUSIONS rians also reveals the deep philosophical divisions which
prevail among historians, as well as contemporaries in
An early reviewer of Donald Hunter’s massive work noted regard to the management of information and risk by some
his regular visits to industrial factories to fire a stream of of the key players concerned with the hazards presented by
questions at all and sundry, before departing usually such materials. Debates over the practical limits of technol-
with trophies to illustrate his lively lectures. These voyages ogy for securing workers’ safety provoke bitter exchanges
of discovery into the occupational life extended to an over the legal and moral responsibility for adequate disclo-
abiding interest into the afflictions of musicians, as well as sure of historic risk levels. There is much less readiness
metalworkers.62 Hunter’s remarkable enterprise bears than in Hunter’s day to accept the veracity of pure science,
comparison with the famous surveys of Ramazzini and although it is arguable that historical research often repli-
Oliver, for its encyclopaedic scope and detail. The work cates Hunter’s tendency to present history as a polarity
also bears the imprint of its time and the assumptions between the forces of truth and selfish ignorance. In
which informed occupational medicine in the first half of uncovering a multitude of new historical contributors and
the twentieth century. His text offers us an authorised ver- fresh complexities in the process of scientific enquiry, his-
sion of the heroic role of brilliant individual scientists torians of workplace illness face the challenge of providing
and medical specialists in a progressive struggle against ill- an explanation of human intervention which captures the
ness at work, confirming the fundamental importance of diversity of occupational injury and political capacity
toxicology and studies of dust in the rise of the modern described so vividly in Hunter’s text. It must still be recog-
specialist and the framework of regulations introduced by nized, as Hunter did, that investigators using the tech-
government and industry. Such an approach may appear niques of medical science have played a leading part in the
dated now that historical scholarship has challenged many identification of health risks at work. They have worked
of the assumptions which underlay such a grand narrative effectively with other technical colleagues and with indus-
of scientific enlightenment, celebrating the role of brilliant try, regulators and trade unions to remove many of the
medical men who battled selflessly against the dark forces more serious risks to workers. Both the agendas set for
of ignorance and vested interests. Social and political histor- investigators and the actions that follow from the results of
ies of occupational health have, since Hunter, uncovered their investigations are, clearly, part of a social and political
the contribution of a much larger range of people and a process involving a wide range of interest groups. Clinical
more complex pattern of struggles, including battles along vigilance and a readiness to challenge remain essential both
References 21
for recognizing new risks and for ensuring that those that and occupational diseases at the beginning of state
are known remain under control. intervention followed by a distinct decrease in consequence
of this interaction’. Teleky L. History of factory and mine
hygiene. New York: Columbia University Press,
1948: 282.
Key points
Rosen G. A history of miners’ diseases. New York: Schuman’s,
1943.
● Donald Hunter was a major contributor to
5. D’Arcy Hart P. Chronic pulmonary disease in South Wales
occupational disease prevention as an
coal mines: An eye witness account of the MRC surveys,
investigator, writer and as the teacher of a
1937–42. Social history of medicine. 1999: 459–68.
generation of physicians.
Schilling RSF. Donald Hunter – the first editor of the British
● The historical sections of Hunter’s text book
Journal of Industrial Medicine. British Journal of Industrial
provide important insights into the development
Medicine. 1977; 36: 242.
of occupational disease identification and
Schilling RSF. Assessing the health of the industrial worker.
prevention, as well as reflecting the historical
British Journal of Industrial Medicine. 1957; 14: 145–9.
approaches among ‘practitioner historians’ at
Schilling was one of the key figures in the renewed
the time when it was written.
emphasis on industrial health in the 1940s.
● Occupational disease recognition and
6. Hunter Papers, Wellcome Library, PP/HUN/C 1/56, Letter
prevention are now seen by historians as
Hunter to O’Loughlin of Oldchurch Hospital, 15 March 1933:
processes to which medical investigators make a
‘A patient of mine employed in bath enamelling, and
fundamental contribution, but these processes
therefore suffering from a pulmonary silicosis, says that his
and the guiding assumptions of investigators are
work-mate, Thomas Thompson, is in No. 4 ward at your
decisively influenced by the social, political and
hospital suffering from the same complaint.’ O’Leary to
economic climate of the period.
Hunter, 17 March 1933. Hunter to T Andrews (Hunter’s
● Successful prevention has reduced many risks to
patient and workmate of Thompson) requesting work
the health of workers markedly, although high
history and Andrews to Hunter, 28 March 1933 and
levels of risk are still found, particularly in
30 March 1933 regarding another workplace case
developing countries. Current concerns in
example.
developed countries now focus on conditions
7. Wellcome Library, London, Archives: Parkes Weber Papers,
less specific to work and which may be seen as
Box 137, B75/1, Hunter to Parkes Weber 9 September 1936.
part of a wider environment for workers and
‘Where I most require your help is in such things as
communities.
deformities of the ears in boxers and rugby football players,
● Hunter’s precept that constant vigilance and a
and … frostbite of the tenna in Smithfield porters who carry
readiness to try and secure remedial action
frozen meat’.
remains relevant today if we are to identify and
8. Hunter Papers, Wellcome Library, PP/HUN/C 1/56. File 48:
pre-empt new risks or retain control over known
case of William Norris, 28 years levelling tables rubbing ‘on
hazards.
sand with iron float’. Suffering from slate pneumokoniosis
15 October 1931. Hunter to CHC Touissant, Clinical
Tuberculosis Officer to London Hospital, 30 October 1931,
REFERENCES Touissant to Hunter, 3 November 1931. File 49: case of
Charles Stewart. Hunter [?] to Howells, 31 August 1932
1. Ellis J. Donald Hunter (1898–1978). In: Oxford dictionary of requesting case be written up for ‘my folders of industrial
national biography. Oxford: Oxford University Press, 2004. disease … I should be grateful for details of the mines in
2. Wright WC. Introduction to Diseases of workers: The Latin which he has worked and of all sources of exposure to silica.
text of 1713 by B Ramazzini, University of Chicago reprint He is, of course, highly intelligent on the subject …’.
(1940), also New York: Hafner 1964. p. xxix. Ramazzini’s 9. Hunter Papers, PP HUN B.12, Correspondence 1943–60.
work was first published in 1700 and pirated from 1705 Hunter to ERA Merewether, 28 January 1932, Merewether
onwards. It was republished in 1746 as Diseases of to Hunter, 29 January 1932, Hunter to Merewether,
tradesmen by Dr Robert James of London. Thackrah CT. The 1 February 1932.
effects of arts, trades, and professions on health and 10. PP HUN B.12, MRC Correspondence: Landsborough
longevity, 1832. Reprint: London: WH Smith/Longman, Thompson to Hunter 20 April 1943. Hunter was expected to
1989. devote one third of his working time to the department for
3. Legge TM. Industrial maladies. Oxford: Oxford University his salary of £800.
Press, 1934. See preface by Henry SA. 11. PP HUN B.12, FJ Nattras of Newcastle to Hunter 15 March
4. Teleky’s sympathy for state intervention is apparent in his 1944, Hunter to Nattras 20 March 1944, where he argued:
text: ‘As far as it is possible to evaluate the situation from ‘Academic work in industrial medicine must follow the
available statistics, we find a high incidence of accidents scientific ideal, and must agree to exclude rigidly from its
22 Donald Hunter and the history of occupational health
activities all political issues. Propaganda is not excluded Potts P. Chirurgical observations relative to the cataract, the
from such a department, but it must be undertaken with polypus of the nose, the cancer of the scrotum, the different
great care’. kinds of ruptures and the mortification of the toes and feet.
12. PP HUN B.12, Report on Industrial Medicine by Hunter for London, 1775. ‘When they get to puberty become liable to a
Himsworth 29 June 1949. ‘The Factory Department has 387 most noisesome, painful and fatal disease … in the inferior
lay, and only 13 medical inspectors to deal with some part of the scrotum, where it produces a superficial, painful,
250 000 establishments covered by the Factories Act of ragged, ill-looking sore, with hard and rising edges: the
1937. … [It] has no funds for the modern investigation of trade call it the soot wart.’
disease, cannot order x-rays, and has no laboratory facilities 21. Lind J. An essay on the most effectual means of preserving
of its own. Neither has it any control over mines and the health of seamen in the Royal Navy. London, 1779. In:
quarries which come under a separate department … Health of seamen. London: Naval Records Society, 1965.
These considerations suffice to show why the Medical Vale B. The conquest of scurvy in the Royal Navy
Research Council entered the field of research in industrial 1793–1800: A challenge to current orthodoxy. The Mariner’s
medicine’. Mirror. 2008; 98: 160–75.
13. Ibid. Hunter was not uncritical of industrial employers: ‘The 22. Gaskell P. The manufacturing population of England: Its
present-day industrialist knows that doctors in general are moral, social, and physical condition and the changes which
ignorant of conditions in industry. Too often he regards with have arisen from the use of steam machinery, with an
contempt and annoyance the efforts of the medical examination of infant labour. London: Baldwin and
profession to certify illness in his employees. … It is in the Craddock, 1833.
same spirit that industrial firms so often aim at conditions Kay-Shuttleworth J. The moral and physical conditions of the
which are just tolerable instead of setting out to design working classes of Manchester. London: James Ridgeway,
factories with the idea that they should be a joy to 1832.
work in.’ Novels include: Dickens C., Hard times. Disraeli B. Sybil.
14. HUN D1/1 and D1/2, Manuscript diary entries for 1947–8, Gaskell E. Mary Barton, North and south.
mostly undated, but 15 May 1948 for the Liverpool visit. 23. Williamson JG. English workers’ living standards. A new look.
15. Author’s (TC) personal recall. Economic History Review 1983; XXXVI. Crafts NRF. British
16. Pickstone JV. Ways of knowing: A new history of science, economic growth during the Industrial Revolution. Oxford:
technology and medicine. Manchester: Manchester Oxford University Press, 1985, chapters 3, 4 and 6.
University Press, 2000. 24. Huzzard G. The role of the certifying surgeon in the state
17. Paracelsus. Von de Bergsucht und anderen regulation of child labour and industrial health 1833–1973.
Bergkrankenheiten, 1567. Agricola G. De re metallica, 1553. MA thesis, University of Manchester, 1976.
(trans. Hoover HC, Hoover LH). New York: Dover, reprinted 25. See Adisesh LA. Dr Edward Headlam Greenhow: A resume of
1950. ‘The Bergmeister in order to prevent workmen from his life and an account of his work, unpublished paper,
being suffocated gives no one permission to break veins or 2004. Copy in possession of authors.
rock by fire in shaftes or tunnels where it is possible for the 26. Knight A. On the grinders’ asthma. North of England Medical
poisonous vapouers and smoke to permeate the veins and and Surgical Journal. 1830; 170–9.
pass into neighbouring mines.’ Holland GC. Diseases of the lungs from mechanical causes.
‘In the mines of the Carpathian Mountains women are London, 1843.
found who have married seven husbands, all of whom this Blackburn S. A fair day’s wage for a fair day’s work?
terrible consumption has carried of prematurely.’ Sweated labour and the origins of minimum wage legislation
18. Ramazzini B. Diseases of workers, p. 57. ‘With regard to the in Britain. Aldershot: Ashgate, 2007.
treatment of workers of this class [potters], it is hardly ever 27. Haldane JS. The air of mines. In: Oliver T (ed.). Dangerous
possible to give them any remedies that would completely trades. London: John Murray, 1902: 540–56.
restore their health. For they do not ask for a helping hand 28. Lehmann KB. List of tolerable concentrations. Munich:
from the doctor until their feet and hands are totally Munich Department of Hygiene, 1895.
crippled and their internal organs have become very hard; 29. Worboys M. Spreading germs: Disease theories and medical
and they suffer from yet another drawback, I mean that practice in Britain, 1865–1900. Cambridge: Cambridge
they are very poor and prescribe remedies that will at least University Press, 2000: 1–6, 232.
mitigate the disease; but first of all they must be warned to 30. Harrison B. Not only the dangerous trades: Women’s work
give up their trade.’ For miscarriages, Ibid, p. 137. and health in Britain 1880–1914. London: Taylor and Francis,
19. Thackrah CT 1832. Introduction by Meiklejohn A in 1989 1996.
reprint. Malone C. Women’s bodies and dangerous trades in England
Cleeland J, Burt S. Charles Turner Thackrah: A pioneer in the 1880–1914. London: Boydell, 2003, c.f. Bartrip for more
field of occupational health. Occupational Medicine. 1995; sceptical note. Bartrip PWJ. The Home Office and the
45: 285–97. dangerous trades. Rodopi, 2002.
20. Carter T. British occupational hygiene practice 1720–1920. 31. Mortimer I, Melling J. The contest between commerce and
Annals of Occupational Hygiene. 2004; 48: 299–307. trade on one side and human life on the other. British
References 23
government policies for the regulation of anthrax infection London: London School of Economics Centre for Risk and
in the wool textile trades 1880–1939. Textile History. 2000; Regulation Discussion Paper. 2004: 18.
31: 222–36. 47. Legge TM. Tetrachloroethane poisoning. Chief Inspector of
32. Pemberton N, Worboys M. Mad dogs and Englishmen. Rabies Factories Report 1914. London: HMSO, 1918: 107–12.
in Britain, 1830–2000. London: Palgrave Macmillan, 2007. Legge TM. Trinitrotoluene poisoning. Chief Inspector of
33. Hunter Papers, PP/HUN C.1/6 Case of Elsie Mitchell, 19, Factories Report 1917. London: HMSO, 1918: pp 21–4.
from April 1913. Admitted 25 April 1913 and discharged 48. Ineson A, Thom D. TNT poisoning and the employment of
25 May 1913. Walter Shead, 38, infected 23 February 1921 women workers in the First World War. In: Weindling P (ed.).
and recovered 2 April 1921. Thomas Jevons, aged 36, died The social history of occupational health. London: Croom
1922, Hunter to Mrs Jevons, 9 December 1935. Robert Helm, 1985: 89–107.
Campbell, aged 25, admitted 13 June 1938 as ‘very ill 49. Waldron HA. Occupational health during the Second World
patient … laboured respiration.’ He recovered seven weeks War: Hope deferred or hope abandoned? Medical History.
later. 1997; 41: 197–212.
34. Arlidge JT. The hygiene, diseases and mortality of 50. Sir Thomas Legge resignation letter. The Times December 1,
occupations. London: Percival, 1892. 1926.
35. Oliver T. Dangerous trades. London: John Murray, 1902. 51. Sellers CG. Hazards of the job: From industrial disease to
36. Legge (1934). environmental health science. Chapel Hill, NC: North
37. Waldron T. Thomas Morison Legge (1863–1932): The first Carolina University Press, 1997.
medical factory inspector. Journal of Medical Biography. 52. Chief Inspector of Factories and Workshops Annual Report
2004; 12: 202–209. Obituary. Lancet. 14 May 1932 1898. London: HMSO, 1899: Ptii. 171.
reproduced in HSE, The changing nature of occupational 53. Merewether ERA, Price CW. Report on effects of asbestos
health. London: HSE Books, 1998. dust on the lungs and dust suppression in the asbestos
38. Legge TM. The health of brassworkers. Appendix 1 Factories industry. London: HMSO, 1930.
and Workshops Annual Report 1905. London: HMSO, 1906: 54. Tweedale G. From magic mineral to killer dust. Oxford:
388–97. Oxford University Press, 2000. Bartrip PWJ. The way from
39. Legge TM. Industrial anthrax. Milroy Lectures 1904. Lancet. dusty death; Turner and Newall and the regulation of
1905; i: 689–96, 764–76, 841–6. occupational health in the British asbestos industry
Report of the Departmental Committee on Anthrax. Vol. 2. 1890s–1970. London: Athlone Press, 2001.
Report of the committee. London: HMSO, 1918. Melling J. An inspector calls: Perspectives on the history of
40. Legge TM, Goadby KW. Lead poisoning and lead absorption. occupational diseases and accident compensation in the
London: Edward Arnold, 1912. United Kingdom. Medical History. 2005; 49: 102–6.
41. Harrison B. 1996. Not only the dangerous trades. Women’s 55. Tweedale 2000: 150.
work and health in Britain, 1880–1914. London: Taylor & 56. Mount Sinai Hospital Archives, Selikoff papers (mainly
Francis, 1996. unsorted but filed by name of recipient) Gilson file: Selikoff
42. McFeely M. Lady inspectors: The campaign for a better to JC Gilson, August 3, 1965; JC Wagner to Selikoff,
workplace, 1893–1921. Athens, GA: University of Georgia July 22, 1966; Selikoff to Eunic T Miner, August 3, 1966.
Press, 1988: 5–22 and passim. 57. Blanc P. How everyday products make people sick. Berkeley:
43. Bartrip PWJ. The Home Office and the dangerous trades. University of California Press, 2007.
Regulating occupational disease in Victorian and Edwardian 58. Markowitz G, Rosner D. Deceit and denial: The deadly politics
Britain. Amsterdam and New York: Rodopi, 2002. of industrial pollution. Berkeley: University of California
44. Bartrip PWJ. The rise and fall of workmen’s compensation. Press, 2002. It should, however, be noted that the problem
In: Weindling P (ed.). The social history of occupational was only recognized because the producers funded the
health. London: Croom Helm, 1985: 157–79. animal studies.
Bartrip PWJ, Burman S. Wounded soldiers of industry. 59. Safety and Health at Work: Report of the Committee
Oxford: Oxford University Press, 1983. McIvor A. Social 1970–72. Chair: Lord Robens. London: HMSO, 1972. Robens’
history of work. London: Macmillan, 2000. background in the coal industry probably informed this
45. Bufton M, Melling J. Coming up for air. Industrial silicosis model of corporate (tripartite) discussions.
and compensation provisions for workers in the United 60. Barnes B. T. S. Kuhn and social science. New York: Columbia
Kingdom, 1900–1939. Social History of Medicine. 2005; 18: University Press, 1982: 135.
63–86. 61. Cooper CL, Levi L. Promotion of occupational and public
46. Milles D. Dynamis. 1993; 13: 139–53, 141–3, 147. health: The European experience and challenge. Ergonomia.
Melling J. The risks of working versus the risks of not 2006; 28: 283–93.
working: Trade unions, employers and responses to the risk 62. Lane RE. Review of Diseases of occupations. Journal of Royal
of occupational illness in British industry, c. 1890–1940s. Society for the Promotion of Health. 1955; 75: 762.
2
The changing face of occupational diseases
Hunter’s Diseases of Occupations published in 20001 marked Membership of the Royal College of Physicians, which at
the culmination of a generation of sociopolitical pressures that time was a hurdle of terrifying difficulty. Hunter’s
and technological changes in occupational health and safety book became required reading for a whole generation of
that began with the governments of most industrialized candidates in case they were confronted in the pathology
countries adopting radical legislation in the 1960s and viva by Hunter himself as one of a number of regular and
1970s which, by the end of the century, had led to a dra- distinguished college examiners. As Seaton writes,2 ‘If you
matic fall in the incidence of work-related ill health and had not done this and had the misfortune to meet him, you
injury. The whole of the twentieth century saw a revolution were sunk’, as he passed you a hunk of rock or a steel bit
in public health and preventive medicine which acceler- across the table. However, Donald Hunter’s retirement
ated with scientific and medical advances during a time coincided with the beginning of a long decline in occupa-
of unprecedented material growth as the century ended. tional medicine in Britain: occupational diseases no longer
Fundamental to progress in occupational medicine over feature as strongly in medical examinations, while medical
this period were developments in the medical sciences and, undergraduates may receive hardly any teaching in the sub-
in particular, toxicology, but it was in the application of the ject at all. Many occupational physicians in high income
new field of chronic disease epidemiology, spearheaded by countries feel a sense of loss to their professionalism
epidemiologists in the United States and the United through this rapid decline in incidence of the traditional
Kingdom after the Second World War, where many of the occupational diseases, which has been due only in part to
most important advances in understanding and tackling effective prevention in the workplace. Globalization has
occupational diseases took place. This was the era when brought a rise in service industries and a shift of the tradi-
occupational cancer rose to prominence as epidemiologists tional manufacturing industries to newly industrializing
and toxicologists identified increasing numbers of suspect countries. Yet the UK, for example, remains the sixth
human carcinogens, and public anxiety was being spurred largest manufacturing economy in the world, with a partic-
by revelations over the toxicity of asbestos and the disas- ularly strong presence in industries such as aerospace,
trous global legacy of the asbestos industry. The inertia of health and construction. This concentration of added-
some industries to adopt costly controls to protect workers value manufacturing is still a one and a half times larger
was not new, and has always been behind the need for gov- contributor to the economy than the financial sector. In
ernment regulation in health and safety at work, but the some UK regions, however, the largest employers are the
uncertainties inherent in epidemiological and toxicological main universities or district hospitals, not foundries, steel
studies were too often cited as a justification to delay or mills or vehicle manufacturing plants. Before the Health
obfuscate, rather than incorporate the lessons of research, and Safety at Work Act in 1973, the health and education
as the asbestos saga has shown. sectors did not even fall under the old Factories Acts, and
This edition’s opening chapter is a historical panorama of had never been formally inspected, let alone employed
occupational diseases with an interpretation that deliberately occupational health professionals. Yet no occupational
owes more to Herodotus, the father of history, than to health professional working in these sectors today can
Donald Hunter. Many Hunter readers have lamented our doubt that new challenges in work-related ill health have
exclusion in recent editions of Donald Hunter’s own history emerged as the old industries have moved elsewhere.
from the Bronze Age to the twentieth century, a tour de force
occupying nearly a fifth of his book which he had already
packed with fascinating historical vignettes. (This edition is THE CONTINUING BURDEN OF
accompanied by a reproduction of his chapter on the web- OCCUPATIONAL DISEASES
site.) Hunter marked advances in prevention with a pageant
of heroic reformers and medical figures, who often ran up Just as the worst global recession since the Second World
against stout resistance from vested interests. Colourful War has shattered illusions that the global banking system
personalities included Sir Humphrey Davy (1778–1829), had eliminated financial risk, it is premature to assume that
as the brilliant researcher, who achieved world fame by the health risks of occupational diseases have been assigned
inventing his famous safety lamp after a brief trial of to history in high income countries, or to forget that they
inspired experimentation, and thereby saved thousands are much more prevalent in the developing world, espe-
of miners from death in gas explosions, and John Scott cially in the rapidly growing BRIC (Brazil, Russia, India,
Haldane (1860–1936), the physician–physiologist and China) economies, where statistics are unavailable for
‘medical detective’, who uncovered the toxic hazards of gases making meaningful comparisons. Meanwhile, the Health
in mines by performing dangerous experiments on himself and Safety Executive estimates that in the United Kingdom
and investigating well-publicized, fatal incidents. However, every year still more than 10 000 people die from past expo-
Hunter’s narrative neglected a whole uncharted terrain of sure to chemicals, fumes and dusts, a figure that far exceeds
social, political and economic history, an omission that the death toll from accidents at work (200–240 annually).3
Herodotus would have regretted. Respiratory and skin sensitizers have become common
When Donald Hunter was practising, physicians in causes of significant morbidity, and dusts may act synergis-
England seeking specialist status had to pass the London tically with smoking and other causal factors in the aetiology
26 The changing face of occupational diseases
of chronic obstructive pulmonary disease (COPD) (see By 2009, the death rate from mesothelioma in the
Chapter 69, Work and chronic air flow limitation and United Kingdom had become the highest in the world.8 The
Chapter 72, Occupational asthma). occupation with the highest risk was carpenters and this
Industrial carcinogens remain a special problem due to has been attributed to the cutting of board made from
their number and the lack of adequate exposure controls in amosite (brown asbestos), which was widespread in the UK
many of the smaller workplaces where they may be found. construction industry through the 1970s into the 1980s.
In a key study by Rushton et al.,4 on the burden of cancer at Large amounts of amosite were imported into the UK after
work in the United Kingdom, occupation contributed to crocidolite (blue asbestos) had been banned in 1968, at a
around 8 per cent of cancer deaths in men and almost 2 per time when the carcinogenic potency of amosite had not
cent in women, for six selected sites: lung, nasal sinus, blad- been established. The mesothelioma risk of amosite is now
der, non-melanoma of skin, leukaemia and mesothelioma. known to be two orders of magnitude greater than that for
Asbestos contributed over half of the occupational cancer chrysotile (white asbestos).8
deaths, and more than half of these were due to exposures Globally, there are an estimated 90 000 asbestos-related
in the construction industry. Respirable crystalline silica deaths every year and in high income countries the compen-
(RCS) is judged to cause about 800 lung cancers each year sation for asbestos-related diseases is likely to reach US$300
in the United Kingdom, mostly in construction workers billion over the coming years.9 All forms of asbestos are
who are exposed to silica present in many common build- now recognized to be carcinogenic and to date, more than
ing materials. 40 countries, including all member states of the European
Annually, at least 4000 people die in the United Kingdom Union, have banned the use of asbestos. However, chrysotile
from all diseases linked to asbestos, about twice the figure of asbestos continues to be mined and exported to developing
deaths in road traffic accidents.3 Around half of these deaths countries by Canada and Russia, with Brazil having its own
are due to mesothelioma, which is still on the increase and mines. The largest importer is India. Its use continues to be
set to peak in incidence over the next decade. The mesothe- promoted by the industry as a safer form of asbestos for such
lioma epidemic is also occurring across other countries in purposes as the manufacture of asbestos cement pipes for
Western Europe5 and throughout the world.6 Despite the long distance water distribution and in construction, even
use of asbestos in factories being banned in the UK since though substitute materials are available for all uses of
1998, its legacy continues to give rise to exposures leading asbestos. Unless international action for a worldwide ban is
to cancer; these exposures were not envisaged early on by taken, as called for by the World Health Organization (WHO)
scientists or government agencies and have only recently and the International Labour Office (ILO), another asbestos
featured in legislation and awareness campaigns. As disaster is looming, indeed probably already underway, this
asbestos production declined in the 1970s and with expo- time in the developing world.9
sure in buildings containing asbestos supposed to be negli-
gible, it was widely assumed that mesothelioma deaths
would soon peak and then fall. However, this reckoning NEW TECHNOLOGIES, NEW HAZARDS
was based on cohorts of factory workers and ignored the
exposures of tradesmen engaged in building and mainte- Even though the health hazards of old scourges, such as
nance work – plumbers, electricians, joiners, carpenters, asbestos and silica dusts, are now well understood, they
painters – who were mostly unaware of the hazard the remain important causes of occupational disease. By the
asbestos in buildings presented if it became disturbed in the 1970s, the traditional industries were already in decline in
course of their work. An epidemiological study published in western countries, while the chemical industry had expanded
19957 provided new projections of mesothelioma deaths rapidly since the Second World War. One chemical, vinyl
and for the first time included the substantial contribution chloride monomer (VCM), used in many countries in the
from these building and maintenance occupations, which manufacture of the highly profitable plastic PVC, had been
to date amounts to a quarter of the total number of widely assumed to be safe due to its deceptively simple
mesothelioma deaths. These findings raised new concerns chemical formula (CH2 CH.Cl), and its derivation from
about asbestos in buildings, such as schools, hospitals and ethylene in the cracking of oil, but evidence from labora-
homes, and the risk from inadvertent low but cumulative tory animals in 1973 showed that it could cause angiosar-
exposures, as well as brief exposures to the dust in coma of the liver in humans, a rare tumour and one which
bystanders. It was not until 2002 that the Health and Safety could therefore be easily spotted in chemical workers as a
Executive (HSE) in the UK updated its workplace regula- cause of death. Within months, cases of angiosarcoma
tions to compel workplace property owners to hold registers had been reported in VCM workers in several countries,
of asbestos in their buildings, and embarked on media cam- including the United States and the United Kingdom, and
paigns to raise awareness in these small groups of workers, rapid action was taken to drastically reduce exposure levels
who together numbered 1.9 million in 2009. Asbestos may in the chemical plants. This finding of an incontrovertible
be present in any building constructed or refurbished before cancer risk in a chemical previously thought to be safe led
the year 2000, amounting to at least 500 000 workplace to widespread changes in the attitude of the chemical
premises in the UK. industry and legislators to the health hazards of the large
The new wave of work-related illness 27
numbers of chemicals that by then had been introduced There are now many international and national initia-
into commercial usage, the vast majority of which had not tives addressing occupational, environmental and consumer
been as adequately tested for carcinogenicity as VCM. issues in relation to the control of toxic substances. Much
VCM also represented the hazard of new technologies as better control technologies and the adoption of risk assess-
it was one of a range of new and very useful compounds ments under legislation, such as the Control of Substances
synthesized by halogenating hydrocarbons, an industrial Hazardous to Health (COSHH) in the UK have radically
process which started in the 1930s and grew rapidly. A whole altered attitudes and led to far better control of exposure to
range of chlorinated compounds were synthesized in large chemicals, and mixtures of chemicals, in all employment
quantities which only later came under suspicion of being sectors in recent years. In Europe, future regulations for
potentially toxic to humans and wildlife, with some having controlling toxic substances in the workplace, including
added dangers because of their biopersistence and their carcinogens, will flow from EU Directives and technical
inability to be easily degraded in the environment (e.g. DDT, guidance, with the latest initiative being REACH – a new
PCBs). Some became classified as recognized or suspect EU regulation concerning the Registration, Evaluation,
human carcinogens. The concerns of long-term health Authorization and restriction of Chemicals.11
hazards arising from exposure also apply to many other
chemical groups: by 2009, about 75 000 compounds were in
regular commercial usage, but the vast majority of these THE NEW WAVE OF WORK-RELATED ILLNESS
have not been fully tested for their long-term toxicity or car-
cinogenicity.10 Following the shock to the chemical industry In the last two editions we included for the first time syn-
provided by vinyl chloride, a general consensus arose that all dromes (stress, upper limb pain and lower back pain) that
chemicals need to be treated with caution and none should were beginning to change our conceptual framework of
be assumed to be of low toxicity without good evidence. occupational disease. The dominant risk paradigm of the
During the latter part of the twentieth century, it twentieth century which has been so successful in control-
became clear that carcinogenesis was a multistep process. ling diseases from chemical, physical and biological haz-
Biomarkers now play a significant role in identifying key ards, is based on being able to define the relationship
events in the process, including occupational carcinogene- between the degree of exposure to an agent at work and the
sis. For many carcinogenic chemicals, there has been much development of a disease outcome, and then controlling
research interest in measuring haemoglobin adducts. In the risk by eliminating or reducing exposure. Founded in
the last decade, one of the most studied genes in epidemi- toxicology, this framework became enshrined in epidemio-
ology has been the TP53 tumour suppressor gene (see logical studies of workers in the form of exposure–response
Chapter 85, Occupational cancer: epidemiology, biological relationships and is implicit in the drawing up of risk assess-
mechanisms and biomarkers). Its role in causing liver and ments in the workplace and for a clinician to establish when
skin tumours is a focus for much research activity. a patient is suffering from an occupational disease. Diseases
Intermediate biomarkers, such as chromosomal damage with high morbidity and fatality, such as chemical-induced
and altered DNA repair also point towards evidence of cancers and pneumoconioses, had identifiable causes and
early, non-clonal and potentially non-persistent effects, so proved readily preventable. However, the paradigm was
which if halted or reversed, could decrease the risk of full- no longer so apt when dealing with the new wave of health
blown malignancy. In the past, evidence of family history problems that became the most common single cause of
susceptibility has been a crude marker for inherited sus- referral to occupational health clinics and a new burden of
ceptibility to cancer. Occupational cancer studies have not illness, disability and sickness absence across all employ-
shown much evidence of family history as being an impor- ment sectors. Features of these disorders include a relation-
tant factor, but the possible interaction between NAT2 ship with work that cannot be wholly explained by their
acetylation status, benzidine exposure and the develop- assumed occupational causes and they are rarely associated
ment of bladder cancer is one positive example. The role of with evidence of underlying pathology.12 In one group of
so-called ‘molecular epidemiology’ in the study of cancer conditions, the symptoms can be remarkably similar, or
aetiology, so far of little practical value in occupational non-specific, despite their causal exposures being very dif-
cancer, is likely to expand in this century. ferent, examples being Gulf War syndrome, exposure to
Newer concerns over cancer have arisen with the rapid organophosphates and sick building syndrome. It has become
introduction of technologies such as mobile phones whose necessary to clearly distinguish between illness and disease in
use became widespread before studies of their potential occupational disorders: illness is by definition a subjective
health hazard were embarked upon (Chapter 55, Extremely state and disease is a pathological process that at least in the-
low frequency electric and magnetic fields). The precedent ory is amenable to objective, external verification.12
and lessons of asbestos loom large in attitudes towards syn- We are still far from understanding the implications of
thetic fibres, in particular engineered nanomaterials, such as these latest disorders not being a simple function of exces-
carbon nanotubes and nanoparticles, which have a growing sive exposure to noxious agents or activities, and we need
number of commercial uses (see Chapter 70, Health effects of more research on the role of psychological risk factors or
ultrafine particles). psychologically mediated responses in these conditions, and
28 The changing face of occupational diseases
8. Rake C, Gilham C, Hatch J et al. Occupational, domestic 11. Health and Safety Executive. What is REACH? Available
and environmental mesothelioma risks in the British from: www.hse.gov.uk/reach/about.htm.
population: A case–control study. British Journal of Cancer. 12. Coggan D. Occupational medicine at a turning point.
2009; 100: 1175–83. Occupational and Environmental Medicine. 2005; 62:
9. Editorial. Asbestos-related disease – a preventable burden. 281–3.
Lancet. 2008; 372: 1927. 13. Freburger JK, Holmes GM, Agans RP et al. The rising
10. Straif K. The burden of occupational cancer. Occupational prevalence of chronic low back pain. Archives of Internal
and Environmental Medicine. 2008; 65: 787–88. Medicine. 2009; 169: 251–8.
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SECTION TWO
TAR-CHING AW
On visiting a poor home, a doctor should be satisfied contact with biological materials that might pose a risk
to sit on a three-legged stool, in the absence of a gilt of sensitization or infection.
chair, and he should take time for his examination:
and to the questions recommended by Hippocrates he A suggested template for recording the occupational
should add one more – What is your occupation?1 history is shown in Figure 3.1.2
Taking the occupational history is an important part of
Bernadino Ramazzini, 1713 the general medical history obtained when a patient is seen
by an examining physician. Unfortunately, this is often
overlooked or not taken in sufficient detail. Clinical man-
WHAT IS THE OCCUPATIONAL HISTORY? agement of a patient without information on what a person
does at work can be incomplete or inadequate. This is
The occupational history because of a possibility of missing a condition caused by
work or not recognizing the work-related nature of a
TAKING AND RECORDING INFORMATION ABOUT WORK common condition, such as asthma. The necessary clinical
advice regarding fitness to return to work or dealing with
The occupational history refers to obtaining details from possible occupational factors contributing to the disease
an individual about his job. It has two main components: will then be lacking.
In taking the occupational history, the physician should
1. The present job. This includes not just the job title, be a good listener. Much information can be obtained
but also the work tasks, chemicals used, the work from a patient’s description of what job activities are done
environment, and availability and use of personal at work, and how work tasks are performed. This can give
protective equipment. It is also important to enquire an indication of workplace exposures and possible risks.
about the duration of the job, whether there is shift In addition, the patient’s occupational history may provide
work, overtime work and whether the person has a additional insight about a workplace, which might not be
second job. apparent even after a worksite visit. Listening to the patient
2. Previous jobs. Similar details are required about the may provide information on issues such as the morale of
different jobs (paid or unpaid) that the person has the workforce, commitment to health and safety measures
done before. It is best to be systematic when obtaining by both employer and employees, and whether other
the past work history; either starting from the present workers have similar health problems.
job and working back to the first job, or beginning Sometimes, evidence of significant occupational expo-
from the first job and working forward to the present sure or disease is discovered by chance in the course of
employment. Periods of unemployment, voluntary investigations for other diseases. For example, the inciden-
work locally and overseas, part-time work, casual or tal detection of calcified pleural plaques from asbestos
temporary work, and hobbies should be included, exposure may be detected on a chest or upper abdominal
especially if these involve exposure to chemicals or radiograph performed for other clinical reasons. In these
34 The occupational history
Fill in details of each job, listing all jobs since leaving school till the present.
Workplace Date Date Full/part Type of Job Workplace Preventive measures Time off work for
(employer’s name worked worked time industry duties hazards and use of personal illness or injury
and address) from to protective equipment
circumstances, all clinicians should make further enquiry Mesotheliomas from asbestos exposure typically have a
about relevant occupational and environmental exposure. latency of 20–40 years, and the exposure at that time could
have been brief. The link with previous occupational exposure
ASKING ABOUT SYMPTOMS IN RELATION TO WORK may be harder to investigate when the patient has left the
ACTIVITIES suspected job some years before the illness is diagnosed.
migrant or even illegal workers who can be subject to the severity of effect. If handling sheets of paper at work is
exploitation by unscrupulous employers. Contract work- just as likely to cause cuts (paper cuts) to the skin, as sharp-
ers are often asked to perform a variety of different tasks ening knives, the probability of injury from both processes
from day to day, usually with little information, instruc- is the same, but cuts from knives are more severe than
tion and training regarding those tasks, known risks and ‘paper cuts’. Therefore, of the two processes with equal
preventive measures. likelihood of skin injury, sharpening knives is viewed as
A job title may give some indication about the work tasks, more risky because of the severity of the effect. The distinc-
but some job titles can be vague and encompass a variety of tion between hazard and risk is important in regards to
activities, while the same job title in different industries or in choice of suitable measures to reduce the likelihood of
different countries may on occasions refer to completely dif- occupational injury or disease. Minimizing risk may be
ferent jobs. Thus, a ‘general labourer’ may dig holes in roads more cost-effective than eliminating hazards.
or carry bricks up ladders; they can also work in such diverse
places as a chemical factory, a foundry or a cotton mill. The EXTENT OF EXPOSURE
job title ‘dresser’ may indicate someone who treats seeds
with pesticides, or assists a stage actor with costumes and A careful occupational history will indicate not only the
cosmetics, or removes excess sand from metal castings, or materials a person has been exposed to, but also the
deals with cuts and wounds in a village hospital in a develop- extent of exposure. Recent overtime work, or weekend
ing country. A ‘linesman’ assists a referee in a game of working can indicate acute exposure. The number of
soccer. A ‘linesman’ (or ‘lineman’) is also a technician who weeks or years spent on the job will give some idea of
deals with electric powerlines, telephone lines or installs chronic exposure.
wiring for cable television. A process worker on an assembly Hobbies, such as home maintenance and do-it-your-
line for plastic toys may not be exposed to many chemical self (DIY) home improvement, may involve hazardous
hazards, whereas a process worker in the electronics indus- exposures away from the workplace. A worker in a shoe
try can be exposed to a wide range of hazardous materials factory with contact dermatitis may suspect the adhesives
(see Chapter 45, The semiconductor industry). at work as being responsible for his skin problems.
History is full of interesting and often cryptic job titles. However, this can also be the result of his hobby using
The Dictionary of Occupational Titles,3 published by the glues at home for building model aeroplanes. Employers
US Department of Labor, Employment and Training and employees can have differing views on the relative
Administration has a compilation and description of sev- contribution of work duties versus hobbies and social
eral hundred job titles, including puzzling jobs such as activities to the development of ill health.
‘barrel scraper’, ‘dope-house operator’ (may not be quite
what you think it is), ‘egg smeller’, ‘frickertron checker’, DETERMINING SPECIFIC EXPOSURE
‘head beater’ and many more.
A good way of finding out precisely what an individual When taking the occupational history, there can be uncer-
does at work, what materials he works with, and what haz- tainty regarding the nature of the materials to which workers
ards are encountered, is to ask the patient directly. The are exposed. This may arise in a number of ways:
immediate supervisor at work would be another good
source for such information. Even if a patient is not aware Caution on chemical names
of the exact chemical that he handles daily, the availability It is essential when investigating a case of possible exposure
of a trade name or a label from the container, or a copy of to a workplace chemical that the exact identity and nature
the material safety data sheet (MSDS) might be a starting of the chemical involved is obtained.
point for finding out the hazards of the material. Benzene (C6H6), used in industry as a solvent and
known to cause aplastic anaemia and leukaemia, is fre-
‘HAZARD’ AND ‘RISK’ quently confused with benzine, which is also used as a sol-
vent, but is a mixture of liquid hydrocarbons (generally
‘Hazard’ is the potential for causing harm and ‘risk’ is the straight chain) and without the same serious haematologic
likelihood (or the probability) that such harm will result. effects. Another common confusion is between dioxin and
The term ‘risk’ is now extended to include consideration of dioxan (see Figure 3.2).
CH2 CH2 O
CI CI
O O
CI CI
CH2 CH2 O
Dioxan Dioxin
2, 3, 7, 8 tetrachlorodibenzo-p-dioxin (TCDD)
Figure 3.2
36 The occupational history
Dioxan (dioxane) has been used for many years as a sol- 10 per cent) as a stabilizer, in addition to paraformalde-
vent for fats and other materials. It has narcotic properties hyde and formic acid. Hence, formalin solution is not
similar to other organic solvents and has been reported to pure formaldehyde.
be toxic to the liver and kidneys. Dioxin has a different
Decomposition
chemical formula. It was the chemical released in the Seveso
incident in Italy when an uncontrolled exothermic reaction When industrial processes go wrong, the chemical composi-
resulted in workers and the surrounding population being tion or physical properties of the materials can alter and
exposed to dioxin causing chloracne, peripheral neuropa- increase the risk from exposure. Trichloroethylene, a widely
thy and an increased risk of lympho-haemopoietic system used degreasing agent, if overheated, may produce phosgene
malignancy.4 gas which causes delayed pulmonary oedema. Methyl iso-
Chlordecone (Kepone™), a pesticide known to cause cyanate heated above 400°C under pressure may decompose
spermatogenic effects in occupationally exposed male work- to hydrogen cyanide:8 CH3NCO H2 HCN CO.
ers5,6 is sometimes confused with the similar-sounding Cadmium-plated bolts do not pose a risk unless cut with an
‘dodecane’7 – an aliphatic hydrocarbon used as a solvent. oxyacetylene, oxypropane or oxybutane torch giving rise to
Chlordecone is no longer produced commercially, although cadmium oxide fumes, capable of causing chemical pneu-
dodecane is available and used widely. monitis (see Chapter 17, Cadmium).9
‘Methanal’ is the systematic name for formaldehyde and
can be confused with ‘methanol’, which is an alcohol.7 The PHYSICAL NATURE OF MATERIALS
former is an irritant, allergen and carcinogen, while the lat-
ter is best known for causing optic nerve damage leading to Metallic lead in solid form presents a physical not a toxico-
blindness in people ingesting illicit alcohol containing logical hazard, but once heated to above its melting point,
more methanol than ethanol. it is converted into fume which if inhaled will cause lead
Patients may know only the commonly used name of a poisoning. Metallic mercury, on the other hand, is liquid at
chemical that they are exposed to at work, e.g. ‘trike’ for room temperature, and can vapourize easily to cause dan-
trichloroethylene, or ‘perk’ for perchloroethylene. It can gerous air concentrations to develop, especially in poorly
therefore be difficult for a clinician not familiar with these ventilated rooms (see Chapter 26, Mercury).
short names to recognize the specific chemical. Trade Both toluene diisocyanate (TDI, or 2,4-tolylene diiso-
names are generally not helpful. cyanate) and methylene diphenyl diisocyanate (MDI, or
diphenyl methane 4,4 diisocyanate) (see Figure 3.3) are
Impure chemicals well known as potent causes of occupational asthma (see
Even when the correct chemical name is obtained from the Chapter 72, Occupational asthma). However, because TDI
occupational history, the physician must always bear in has a much higher vapour pressure, at room temperature,
mind that books or journals sometimes refer to the than the viscous MDI, it might be expected that MDI is
toxicity of the pure or relatively pure substance whereas, safer to handle. So it is, unless the process is exothermic or
when sold commercially, chemicals will often not be pure involves spraying. In either of those circumstances, the
and may well carry contaminants. For example, toluene advantage of the low vapour pressure of MDI in regards to
(methyl benzene), apart from narcotic properties, does not safety is negated, and it has been found on a number of
have the same haematotoxic effects as benzene, because it occasions to be a potent respiratory sensitizer.
is metabolized along the side chain (the methyl group),
whereas benzene is metabolized on the ring, initially by the OBTAINING FURTHER INFORMATION ON CHEMICALS
formation of an epoxide which may react with the macro-
molecules of the cell. Toluene is therefore recommended In the United Kingdom, the Control of Substances
and used as a ‘safe’ substitute, but commercial toluene has Hazardous to Health (COSHH) regulations10 require
been known to contain up to 15 per cent of benzene. employers to provide adequate information, instruction
Formalin solution used as a tissue preservative con- and training in such matters, with the result that patients
tains formaldehyde, but methanol is also present (about may arrive at the surgery or the outpatient clinic carrying
CH3
CH2
NCO
Figure 3.3
What is the occupational history? 37
specially prepared leaflets (material safety data sheets) on prolonged periods may lead to permeation of the gloves
chemicals, if they suspect that these may be responsible for by solvents, and spillage of liquids into gloves can prolong
their ill health. Material safety data sheets are prepared by contact between the skin of the hands and irritant or
suppliers for users and also for importers. A standard for- allergic substances.
mat for the preparation of such sheets is suggested by the
Occupational Safety and Health Administration (OSHA) SMOKING STATUS
for suppliers in the United States and by European
Community legislation in Europe. Most MSDS contain Smoking affects the development of some occupational
some data on the properties of the chemical, the possible diseases. For example, both smoking and asbestos expo-
health effects, first aid treatment and safe handling and sure independently increase the risk of lung cancer, and
use of the chemical. There is unfortunately often some concomitant exposure to both factors multiplies the risk.
confusing variation between MSDS produced by different This is also the case with smoking and exposure to radon
organizations in different countries. gas,13,14 as shown in studies of underground uranium min-
A clinician can pursue enquiries on properties and tox- ers who are exposed to radon in their work environment.
icity of chemicals directly with an employer, preferably While smoking increases the likelihood of byssinosis devel-
through the firm’s occupational physician if there is one, oping in cotton workers (see Chapter 73, Byssinosis and
or from the firm’s health and safety officer. In the UK, other cotton-related diseases), the evidence for smoking
information on chemicals can also be sought from the causing an increased risk of occupational asthma is contro-
Health and Safety Executive or from the National Poisons versial (see Chapter 72, Occupational asthma). However,
Information Service. Section 6 of the UK’s Health and smoking apparently decreases the risk of extrinsic allergic
Safety at Work Act requires manufacturers, suppliers and alveolitis, possibly because of impaired function of alveolar
others to provide adequate information about measures macrophages (see Chapter 74, Extrinsic allergic alveolitis).
that are necessary to protect the user. An employer should Sometimes patients claiming compensation (or disability
therefore know about any possible harmful effects (or the benefit) for occupational respiratory diseases may be reluc-
absence of harmful effects) of a substance used or pro- tant to admit to smoking, or to their true level of smoking
duced on his or her premises. Furthermore, where such (or prepared to admit to smoking but only at home and not
information is not available, the manufacturer or supplier at work, because of restrictions in smoking at the work-
may be obliged to undertake research to eliminate or min- place). This may be due to a concern that it may prejudice
imize any risks to health and safety. A patient is often able their chances of being diagnosed with an occupational
to obtain from his workplace the name and address of the condition or reduce any financial settlement or pension.
supplier of a chemical or provide a copy of the MSDS. The ascertainment of current smoking status and
Databases, such as Haz-Map11 and CCINFO,12 also pro- smoking history, in addition to the occupational history,
vide information on hazardous chemicals and toxic effects, is especially important for assessing patients with respi-
and websites, such as www.ilpi.com/msds, allow access to ratory disorders.
thousands of MSDSs.
COMPENSATION
USE OF PERSONAL PROTECTIVE EQUIPMENT
A physician may be asked by a patient about entitlement to
A patient may have been provided with, and may claim to compensation if there is an indication that his condition is
have used for all or part of the time, some form of personal work-related. The occupational history will have been
protective equipment (PPE). A careful occupational his- instrumental in coming to a decision about any likely
tory should explore the adequacy or suitability of PPE, and occupational aetiology. However, a diagnosis of an ‘occu-
the availability and use by the individual. This will give pational disease’ does not necessarily lead to compensa-
some indication as to the extent of protection provided. A tion. State compensation schemes are governed by their
‘mask’ can be anything from a simple gauze pad, a filter rules regarding eligibility for benefits. For example, State
device, to a full face respirator with an external fresh air benefits in the UK15 are only payable for specific prescribed
supply, or self-contained breathing apparatus (SCBA). occupational diseases. Claims for benefits must also be
Similar considerations will apply to enquiries about pro- made within a specified time frame, e.g. within five years of
tective measures for skin and eyes, e.g. whether gloves, an leaving an employment where exposure to noise resulted
eye shield or safety spectacles, have been used and the in occupational deafness, and within ten years of leaving a
length of time that they are used for that work cycle. job with exposure to a sensitizer causing occupational
Inappropriate use of, or care for, gloves can increase the asthma. For many prescribed conditions, no benefits are
risk of dermatitis instead of protecting the skin. For paid if the extent of disablement is assessed as <14 per cent
example, the use of powdered latex gloves in healthcare (often referred to as the ‘14 per cent rule’). In Australia,
workers has been linked to allergic reactions in sensitized Commonwealth government employees need to be
individuals and therefore is detrimental to health instead assessed as having >20 per cent impairment to be eligible
of preventing ill health. Use of the same pair of gloves for for hearing loss compensation.16 How a decision is reached
38 The occupational history
regarding percentage disablement is a separate issue. A developed ill health from workplace activities or exposures.
patient with an occupational disease may therefore not The affected worker may be torn between concerns for his
receive state benefits despite a doctor’s diagnosis of the health, and the need to keep his job despite the risk. From
condition and a clear occupational history of a relevant the information provided in the occupational history, the
exposure, if eligibility criteria are not met. clinician can advise on individual preventive measures, but
An occupational history is also important in civil cases the implementation of any measures at work inevitably
where a worker sues his employer or ex-employer for expo- requires the involvement of the employer. The employer
sures in the workplace that have caused or contributed to ill may want to know what the specific health issue is, and this
health or injury. Again, a firm diagnosis of an occupational may intrude into areas of confidential clinical information.
disease supported by an occupational history, does not neces- The guidance resources mentioned above cover issues of
sarily guarantee that there will be financial recompense. In patient confidentiality.
many countries, there is also a requirement to demonstrate
negligence of the employer. In New Zealand, a ‘no-fault’
system16 is in place that ensures compensation for all occu- How reliable are occupational histories?
pational injuries and some occupational disorders, e.g.
occupational noise-induced hearing loss, without the need to Occupational histories can be obtained during a face-to-face
prove negligence. Good doctor–patient communication is encounter with a patient as during a clinical consultation; or
essential in making clear the distinction between obtaining an by use of an interviewer-administered or self-administered
occupational history to make a clinical diagnosis versus using structured questionnaire. Occupational history question-
an occupational history as evidence to obtain compensation. naires have been shown to provide information that is reli-
able and valid. They are relatively free from bias, and are
acceptable to both patients and doctors.19–21 However, the
ETHICS AND CONFIDENTIALITY
accuracy of self-reported work history appears lower in those
Clinicians may face ethical dilemmas, including issues of with frequent job changes and accuracy of information is
confidentiality, in handling information obtained from an affected by number and duration of jobs.22
occupational history. For example, a worker may provide
information on workplace exposure to chemicals that are
deemed confidential trade secrets (such as exact ingredi- WHY TAKE AN OCCUPATIONAL HISTORY?
ents and amounts of materials used for a specific process –
a trade secret for the employer, but an essential piece of The two main reasons why an occupational history is
information for the doctor in order to assess the extent of important are: (1) because of the effects of work on health
exposure and likely contribution to ill health). A patient and (2) because of the effects of health on the safe and effi-
may describe a novel work process that is the subject of a cient performance of work. The value of the occupational
patent application. A patient may indicate that other history lies in the use of the information gathered in assess-
co-workers have ill health possibly from contact with a ing the nature and extent of exposure to hazards in the
workplace chemical. If the outcome of identifying affected workplace. This assessment is necessary for a physician to
colleagues is their transfer to other jobs or ill-health retire- advise on possible occupational aetiology of a disease, and
ment or redundancy, this may not be their wish nor will on fitness for work.
it necessarily be in their best interest. How should the
clinician handle the information provided?
Published guidance is available on the ethical responsi- Effects of work on health
bilities of a doctor when there appears to be a conflict
between responsibility to an individual patient and any The occupational history is used when a physician has to
responsibility to the employer. UK occupational physicians decide if an occupational factor might have caused or
have access to advice from the ethics committee of the contributed to a patient’s illness. If there is an occupa-
Faculty of Occupational Medicine. A helpful chapter tional aetiology, failure to take an adequate occupational
is one on ‘Relationships with others’ in the Faculty of history will lead to inappropriate management of the
Occupational Medicine’s guidance on ethics for occupational patient. The patient may be treated and then sent back
physicians.17 Guidance on ethical issues for all physicians is to work in the same environment that has caused the
also available from the British Medical Association, covering disease, and therefore full recovery will not occur. An
areas such as confidentiality, consent and disclosure of example is a patient with a rash that is treated with a
health information.18 steroid cream, and then sent back to work in an environ-
A patient may be reluctant to reveal the identity of ment where exposure to the causative chemical contin-
his/her employer. This may be because of the perceived ues. The rash may improve temporarily with treatment,
consequences for continued employment if the employer but will invariably worsen with continuing contact with
should become aware that one of their workers has the causal agent.
Why take an occupational history? 39
Work can affect health in several ways: allergens in individuals with asthma,32 for example
exposure to cat fur or animal dander in a vet or a
● Occupational exposures may be a direct cause of ill technician in an animal laboratory).
health, for example exposure to hydrogen cyanide gas 3. The patient’s condition is likely to make it unsafe to do
encountered by firefighters during their work can cause the job (e.g. liability to sudden loss of consciousness
cyanide poisoning,23 or exposure to metallic mercury in while working alone and at heights).
gold miners24 or in dentists25 causes mercury poisoning. 4. The patient’s condition is likely to make it unsafe for
● Workplace exposures, while not necessarily being the third parties, such as co-workers, visitors or members
sole factor causing a disease can be one of a number of of the public. For example, a bus or train driver who is
contributory causes. Cigarette smoking, as mentioned prone to episodes of unconsciousness with no warning
earlier, multiplies the risk for lung cancer if there is symptoms may cause an accident affecting other crew
exposure to asbestos fibres or radon gas. Each of these members, passengers and the public.
can cause lung cancer independently, but a worker 5. The patient’s condition might make it unsafe for the
who smokes, lives in a high environment radon area, community (e.g. for consumers of the product, if a
and is exposed to asbestos from work activities has a food-handler transmits infection33).
much increased risk of lung cancer. Another example
is that of exposure to carbon monoxide which can Some of the above areas are concerned with direct risk to
result from smoking, following exposure to methylene the patient and some relate to risks to others, either risks to
chloride26,27 (used as a paint stripper), and working in the health and safety of third parties or substantial financial
an enclosed space such as a garage which is heated by a risks to employers.
gas-fired heater, and has a car engine running. All The occupational history will help a doctor in encour-
these factors can act independently to increase blood aging a timely return to appropriate work, and to retain
carboxyhaemoglobin, but when several of these people at work that will not harm their health. The
sources of carbon monoxide are present, there is an emphasis in the UK today is on changing perceptions of
elevated risk of carbon monoxide poisoning. fitness for work by discouraging stigmata around health
● The nature of the job may worsen pre-existing non- and disability.34 In the UK, proposals to reduce sickness
occupational disease, e.g. hairdressing procedures or absence include replacing the ‘sick note’ signed by the
working in a kitchen can result in a worsening of family physician with a ‘fit note’ involving discussion as
endogenous eczema. necessary between the patient, the doctor, occupational
● The work environment may give easy access to health professionals and the employer.34,35 This was
potentially harmful materials, increasing the risk of implemented in April 2010.
their abuse. Examples of adverse health effects resulting For occupations such as drivers, divers, airline pilots and
from availability of toxic agents are effects of anaesthetic seafarers, specific guidance is published by different agen-
gases in anaesthetists or other health-care staff,28,29 cies. In the UK, the Driver and Vehicle Licensing Agency
suicide in farm workers using pesticides,30 and (DVLA) has produced a guide to medical standards for fit-
alcoholism in publicans.31 ness to drive.36 The guidance covers drivers of motor cars
and motor cycles (group 1 licence holders), as well as profes-
sional drivers of large lorries (group 2, category C) and buses
The effects of disease on occupation (group 2, category D). There are special provisions for
drivers in the police force, ambulance drivers and taxi
Following a period of sickness absence, it is in a patient’s drivers. The information is updated online periodically.
and society’s interest to encourage a return to work. Most The latest guidance is accessible via the DVLA website
patients are able to return directly to their own job after an (www.dvla.gov.uk). Telephone advice is also available from
illness or injury but some, because of residual disability, are the DVLA for medical professionals in regards to the health
unable to return to their former work. Many people with status of drivers and fitness to drive. The Department of
some impairment of function either seek work or seek to Transport has also produced a manual with advice on fitness
remain at work and may ask for medical advice. to drive for patients with medical conditions, and this
The main areas where this advice is needed are: includes the basis behind the standards recommended.37 In
the United States, similar standards for commercial drivers
1. The patient’s condition may limit, reduce or prevent are produced by the US Department of Transportation.38
him performing the job effectively (e.g. musculoskeletal For other occupations, Fitness for Work: The Medical
conditions that reduce mobility or diminish Aspects39 gives authoritative guidance using as its starting
manipulative ability). points the diseases (impairments) and disabilities from
2. The patient’s condition might be made worse by the which a patient might suffer. It also has appendices on
job (e.g. excessive physical exertion in some the medical standards for civil aviation, divers, offshore
cardiorespiratory conditions; exposure to certain workers and seafarers. Advice regarding fitness for work of
40 The occupational history
seafarers was updated in 1999 by Merchant Shipping Notice harmonizing occupational hygiene standards in all
No. MSN 1746 issued by the Department of Environment, European Union member countries. There are
Transport and the Regions. The International Labour differences between the standards from the various
Organisation (ILO) has also produced guidelines for the organizations, and the basis of how they are set should
medical fitness of seafarers. In the UK, NHS Plus and the be understood as a prerequisite for use. Caution must be
Royal College of Physicians have produced national guide- exercised in the use of occupational hygiene monitoring
lines on occupational aspects of managing infected food results for diagnosing occupational disease. Even if
handlers,33 shift work in pregnancy40 and other clinical exposure levels are above current workplace exposure
conditions related to occupations or work activity.41,42 limits (in the United Kingdom) or threshold limit values
(in the United States), it does not necessarily point to
the agent concerned as the cause. There are safety factors
DIAGNOSING AN OCCUPATIONAL DISEASE introduced in the development of exposure standards.
The standards are also not purely health-based levels,
The occupational history is an important component for but can be influenced by cost–benefit considerations.
diagnosing an occupational disease. It can provide critical Susceptibility of exposed individuals is a factor that can
information on relevant occupational exposures, and on cause health effects at levels of exposure even below
the link between the onset of symptoms and work. In gen- current standards. Readings showing excursions above
eral, several criteria should be met before concluding that a current standards on a single occasion may be less
patient has an occupational disease.43 The main criteria important than frequent measured excessive levels. The
which should be satisfied are: frequency and intensity of the exposures exceeding
current standards demonstrate poor workplace control
1. The effect, i.e. symptoms and signs, must fit with what of exposures, and give an indication of the likelihood of
is known about the clinical features of the suspected the exposures causing disease. Some of the limitations in
occupational disease. The less the features match what the use of exposure information as an aid for diagnosing
is expected, the less likely the diagnosis. occupational disease apply to both occupational hygiene
2. The exposure must be sufficient to cause the disease. readings, as well as biological monitoring data (see
Information on exposure may be obtained from the Chapter 5, Biological monitoring). Workplace exposure
patient’s occupational history and a description of what standards proposed by different agencies in different
hazards are encountered at work. It is not sufficient just countries for some chemicals vary. In part, this reflects
to know that there is exposure. It is essential to estimate the imprecision of estimating the limit of exposure
the extent of exposure. i.e. number of substances to needed to protect against ill health. There is continuing
which the patient was exposed, intensity, frequency and debate for some substances, such as silica, about
duration of exposure. Sometimes, occupational hygiene whether disease (silicosis) may develop despite
data or biological monitoring records may be available exposures below the current standards (see Chapter 79,
and these can provide further evidence of the extent of Silica and silica-related diseases).
exposure. Interpretation of exposure information for 3. The time sequence must be correct. This includes the
the most widely used substances can be assisted by consideration of the latent period between exposure and
reference to published occupational exposure standards. effect. For occupational cancers, generally a very short
In the UK, the Health and Safety Executive publishes time interval (less than five years) between first exposure
updated standards annually for about 500 substances in and the diagnosis of cancer suggests that the exposure
a document referred to as ‘EH40’. This contains may not be the relevant causative agent. For
workplace exposure limits and biological monitoring occupational asthma and allergic contact dermatitis,
guidance values, and is available free via the internet.44 there may be several weeks, months or even years
In the United States, there are several sets of similar between first exposure and clinical manifestations. Some
standards, e.g. threshold limit values and biological acute exposures produce clinical effects immediately or
exposure indices produced by the American Conference within minutes of exposure, e.g. hydrogen cyanide gas,
of Governmental Industrial Hygienists (ACGIH),45 or upper respiratory irritants, such as sulphur dioxide,
permissible exposure limits produced by the ammonia or chlorine gas (see Chapter 39, Gases), while
Occupational Safety and Health Administration the time interval between exposure and effect may be
(OSHA), and recommended exposure limits from the several hours or one or two days for agents that cause
National Institute for Occupational Safety and Health delayed pulmonary oedema. It may appear obvious that
(NIOSH). In Germany, the equivalent standards are for a diagnosis of occupational disease due to a specific
known as MAK values.46 In 1995, the European agent, the exposure to that agent must precede the
Commission established a Scientific Committee on occurrence of clinical effects. However, there are
Occupational Exposure Limits (SCOEL)47 to obtain situations where even though a disease has developed
independent scientific expert opinion on chemicals in earlier in life, subsequent occupational exposures may
the workplace. SCOEL’s efforts could contribute to trigger an episode or worsen the condition,
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31. Baker A. Alcohol-related deaths by occupation: What do 46. Deutsche Forschungsgemeinschaft (DFG). MAK and BAT
data for England and Wales in 2001–2005 tell us about values list, 2009. Last accessed March 13, 2010.
doctors’ mortality. Alcohol and Alcoholism. 2008; 43: Available from: www.dfg.de/aktuelles_presse/
121–2. reden_stellungnahmen/download/mak2009.pdf.
32. Berger Z, Rom WN, Reibman J et al. Prevalence of 47. European Commission (DG for Employment, Social Affairs
workplace exacerbation of asthma symptoms in an urban and Equal Opportunities). The Scientific Committee on
working population of asthmatics. Journal of Occupational Occupational Exposure Limits (SCOEL): SCOEL
and Environmental Medicine. 2006; 48: 833–9. Recommendations (list). Last accessed March 13, 2010.
33. NHS Plus, Royal College of Physicians, Faculty of Available from: http://ec.europa.eu/social/.
Occupational Medicine. Infected food handlers: 48. Landrigan PJ, Baker DB. The recognition and control of
Occupational aspects of management. A national occupational disease. Journal of American Medical
guideline. London: Royal College of Physicians, 2008. Association. 1991; 266: 676–80.
4
Occupational exposure to hazardous substances
static or area sampling, where the sampler is located at a examples, we will look at the process of attributing a
fixed point, is performed. It is generally considered that, in disease to an exposure.
most circumstances, static sampling will underestimate
exposure of individual workers due to periodic close
contact or handling of the exposure source. EXPOSURE AND EXPOSURE ROUTES
Quantification of the exposure allows the process of
evaluation of risk to begin. The concentration of a dust or Exposure is defined as contact between an individual and
vapour in the air can be compared to occupational expo- a hazardous substance.1 Workers may be exposed to haz-
sure limits (OELs). In the United Kingdom, these are called ardous substances by inhalation, inadvertent ingestion of
workplace exposure limits (WELs) and are provided by the chemical contamination, skin or eye contact and direct
Health and Safety Executive (HSE) through the COSHH injection where a sharp object punctures the skin and the
regulations for many chemicals. These limits are produced chemical enters directly.
by considering toxicological and epidemiological data on Exposure occurs at the interface between the environ-
health effects observed where possible after human expo- ment and the person and is measured on the outside of
sure, but more often as a result of controlled exposure of the body. For inhalation, exposure is conventionally
animals or cellular models. The basic premise is that expo- defined as the concentration close to the nose or mouth
sures below the WEL will limit the risk to the worker to multiplied by the duration of the exposure – sometimes
‘acceptable levels’, but it is important to be aware that not referred to as ‘cumulative’ exposure. Therefore, someone
all limits are set at levels that will achieve no adverse effects exposed to a concentration of 0.1 mg/m3 of benzene for
and for some carcinogenic or sensitizing substances any four hours would have an exposure of 0.4 mg/m3 hour.
exposure will carry some degree of risk. Other countries However, to simplify the measurement and assessment of
have their own OELs. risk, it is conventional to express workplace exposure over
Treatment of the patient may be modified with knowl- a fixed time interval, e.g. eight hours. In the example
edge of what workplace exposure has or has not caused above, the benzene exposure would be 0.05 mg/m3, as
their condition. Reduction or elimination of the exposure an eight-hour average, i.e. 0.4 (mg/m3 hour) divided by
experienced by the worker may form one part of the med- 8 (hours).
ical intervention and this can have an effect on both the Other factors may influence the amount of hazardous
worker’s health and also the current and future health substance taken up into the body by inhalation, most
status of other workers within the facility. notably the breathing rate of the worker, with a greater
Exposure control is the final part of the role of the occu- mass of contaminant being inhaled when a person is
pational health professional. Control of exposure to haz- undertaking physical work than when they are sedentary.
ardous substances in the workplace is enshrined in the Although this factor will affect the risk for an individual, it
legislative framework of most nations. In the United is seldom taken into consideration when evaluating risk.
Kingdom, the COSHH regulations, the Control of Lead at There is much less consensus about the definition of
Work regulations and the Control of Asbestos regulations dermal exposure, although Schneider et al.2 described a
are the three principal pieces of law aimed at encouraging conceptual model of the processes involved. Chemicals
control of workers’ exposure. All are based on a hierarchi- that come into contact with the skin may permeate
cal approach to control beginning with elimination of the through the stratum corneum and diffuse towards the
hazard, substitution with less hazardous materials, control peripheral blood supply. The ideal measure of dermal
by containment, ventilation and process changes and mov- exposure would be related to the potential uptake, which is
ing to the control method of last resort, namely personal mainly driven by the concentration of the chemical in the
protective equipment worn by the employee. There is now surface layers on the skin (the skin contamination layer
a wealth of guidance available to those using hazardous (SCL)), the area of skin exposed and the duration of expo-
substances on best practice and methods of control that sure. Other factors, such as the composition of the mixture
will lead to exposures that are less than the OELs. COSHH of substances present in the SCL and the integrity of the
Essentials is a web-based tool that provides the user with stratum corneum, will also affect dermal uptake.
targeted guidance based on easily obtainable information It is difficult to measure the concentration of chemicals
from the safety data sheets, the quantity and frequency of in the SCL and so the mass of chemical in the SCL or the
use, and how the material is being used in the workplace. mass that impinges onto the SCL during a period of time
The system uses simple hazard banding and exposure are often used as surrogate measures of exposure. In these
model estimates to recommend the type of control options cases, exposure may be expressed as mass per unit area
that should be considered as best practice for the generic over a defined part of the body, e.g. mg/cm2 on the torso,
type of task being performed. or as the mass on a specific body part, e.g. mg on both
This chapter will explore in more detail how we can hands. There are no OELs for dermal exposure.
understand workers’ exposures, both within and beyond There is no consensus about how exposure by inadver-
the workplace, how to interpret measurement data and tent ingestion should be assessed, although this is gener-
compare these to limit values and, by using illustrative ally associated with hand-to-mouth contacts. Key factors
What is the level of exposure? 45
involved with this type of exposure are the extent of hand Where existing information is not available then it may
contamination, the type of work, whether protective gloves be possible to measure current exposure of the worker.
are worn and personal traits of individual workers, e.g. nail Depending on the chemical hazard to be assessed there
biting. are a wide range of methods available for measurement.
For injection exposure, crude measures, such as the The HSE Methods for Determination of Hazardous
number of injuries per day involving contaminated objects, Substances (MDHS) series of guidance notes are freely avail-
are often used, e.g. in the case of needle stick injuries. able via the internet (www.hse.gov.uk/pubns/mdhs/index
The term ‘aggregate’ exposure refers to the risks over .htm). MDHS 14/3 covers sampling and analysis of total
time from multiple sources, pathways and routes for a inhalable and respirable dusts,3 while MDHS 39/4 provides
single chemical, and so for example, someone exposed to guidance on sampling asbestos fibres in air and MDHS 70
pesticides in their job as a farmer and then in their own details general methods for sampling airborne gases and
garden when they spray their flowers would get aggre- vapours. Similar descriptions of methods for measurement
gate exposure from these two sources. The term ‘cumu- of particular chemicals is provided by the US National
lative’ exposure is then often used for assessments where Institute for Occupational Safety and Health (NIOSH)
there is exposure to a mixture of different chemicals that all through their online Pocket Guide to Chemical Hazards
have the same potential to cause an adverse health effect (www.cdc.gov/niosh/npg/).
and some attempt is made to combine the overall exposure For most measurements of airborne exposures, the
to produce some estimate of the overall risk. As noted ear- basic premise is in the gravimetric sampling of workplace
lier, the term ‘cumulative’ may also be used in the context air. This involves drawing air at a defined rate through a
of exposure in units of concentration multiplied by dura- sampling medium which allows collection of a mass of the
tion of exposure, e.g. mg/m3 hour, as for example might chemical being assessed. Simple division of the mass col-
be the case in an epidemiological study investigating the lected by the volume of air sampled during the collection
relationship between the lifetime exposure to a hazardous period produces a concentration typically milligrams per
substance, where the duration would be the working life of cubic metre of air (mg/m3), although units of parts per
the individual. million (ppm) are more commonly given for gases and
In some circumstances, biomarkers may be used as an vapours by conversion using the molar constant.
index of aggregate exposure, for example the concentra- For dust and particulate matter, air sampling is
tion of lead in blood among workers exposed to inorganic achieved by using a small battery-operated pump to draw
lead compounds. These are not measures of exposure, air through a filter (glass fibre, PVC or PTFE are the most
although they are related to exposure and may offer some common types) held in a holder that selectively samples
advantages in providing an estimate of aggregate exposure the aerosol by its size. When measuring total inhalable
arising from more than one route. For example, blood lead dust, that is the fraction of airborne dust that is inhaled
will reflect exposure by inhalation and inadvertent inges- through the nose and mouth, an IOM (Institute of
tion. Considerable care has to be taken in interpreting bio- Occupational Medicine) head (see Figure 4.1) set at a flow
monitoring data in relation to exposure because of the rate of 2.0 L/min can be used. For respirable dust (the finer
complex relationship between the pattern of exposure and fraction of dust that will reach the gaseous-exchange areas
the biological half-life of the biomarker. of the lung), samplers such as the cyclone (Figure 4.2) are
used at flow rates of 2.2 L/min. After sampling, the filters
are then reweighed and the mass increase is divided by the
WHAT IS THE LEVEL OF EXPOSURE? volume sampled, which is the product of flow-rate and
duration expressed as m3.
Developing methods to assess the amount of contact The approach for sampling for gases and vapours is
between a worker and a chemical over a given time period generally similar to that for particulates with a pump
has been the core of much occupational hygiene work in pulling air at typically 50–200 mL/min through a small
the past 50 years. Methods of exposure assessment can sampling tube with a collecting substrate, often charcoal,
range from detailed, objective quantification using real- on which the gas or vapour is absorbed. The analysing lab-
time direct-reading instruments through to subjective oratory then desorbs the chemical from the charcoal and
qualitative categorization into broad bands such as ‘low’, quantifies the mass before dividing this by the volume of
‘medium’ and ‘high’. air sampled during the measurement period to produce a
The first place to start is to examine what exposure resulting concentration (e.g. mg/m3).
monitoring information exists in the workplace. Larger Fibres, such as asbestos, are measured in a slightly dif-
worksites, in particular, may have records of regular ferent way with the concentration expressed not by mass,
monitoring taken as part of programmes to demonstrate but as a count of the number of fibres on the filter per unit
compliance with legislation. Others may have sporadic volume of air sampled (fibres/mL).
records collected at the time of inspection by regulators or All of the above examples are suited for collection of
before/after the introduction of new processes or control personal sampling data and are typically employed when
equipment. determining if workers are exposed at levels above or
46 Occupational exposure to hazardous substances
Filter
support
grid
Membrane
filter
Cassette
‘O’ Ring seal
Cassette
lower part
25 mm filter
Cassette
upper part
Dusty
air
Grit pot
Connection
to pump
End cap Figure 4.2 Cyclone sampler for measuring respirable dust.
Reproduced with permission from Ref. 3.
Figure 4.1 Institute of Occupational Medicine (IOM) total
inhalable dust sampling head. Reproduced with permission
from Ref. 3.
2.5
2.0
Aerosol. mg/m3
1.5
1.0
0.5
0.0
18:00 21:00 Sat 18 Figure 4.3 Real-time fine particulate dust
Date and time exposure measured over a workshift.
below statutory limits. They all have the disadvantage that intensity of this colour stain providing an instantaneous
they take some time to collect and analyse, and generally indication of the airborne concentration. There are many
involve expensive chemical analysis and involvement of a different types of these tubes with the media generally spe-
laboratory. In addition, these methods only provide infor- cific to a small number of chemicals, so proper selection is
mation on the average concentration over the duration of important. More accurate and sensitive portable direct
the sampling and do not indicate anything to do with reading instruments for gases and vapours using flame
temporal changes and peaks of exposure while performing ionization with gas chromatography or infrared or ultravi-
specific tasks. Direct reading instruments can assist when olet photometry exist, although these instruments tend to
there is a need to have either immediate results or data involve large capital investment and need frequent calibra-
about changes in exposure over a workshift. tion. For particulate matter measurement, small logging
Direct-reading instruments, which provide an instanta- personal aerosol monitors can now be purchased. These
neous reading, range from simple tubes through to expen- operate by using light scattering methods coupled to size-
sive electrochemical or photo-electric devices that can selective air inlets that mechanically remove dust above a
provide a log of changing concentrations in real-time. particular size.
Colorimetric tubes undergo a reaction with the chemical Figure 4.3 shows the type of concentration-time output
under study to produce a colour change, with the length or that can be generated from direct reading instruments and
Exposure variability and exposure determinants 47
mg/m3
1
be collected with the resources available and will cover
issues such as the timing and duration of sampling, how 0.1
many samples should be collected to give a representative
indication of exposures, the type of instruments that can be 0.01
used and how to transport and analyse the resulting sam-
ples. The British Occupational Hygiene Society (BOHS) 0.001
has a listing of members who carry out hygiene consul- 10 20 30 40 50 60 70 80 90
tancy work in the UK. Similar occupational or industrial %
hygiene societies and associations exist across the world Figure 4.4 Output from the Stoffenmanager webtool showing
with details of national organizations available via the estimated xylene concentrations for a particular task.
International Occupational Hygiene Association website
(www.ioha.net).
Measurement is expensive, labour intensive and not how to interpret exposure data in light of exposure vari-
always a practical option when the worksite has been ability and how to judge the likelihood of measurements
closed or access is restricted due to geographical, political failing to identify exposures that exceed given limits.4
or budgetary constraints. In recent years, there has been a
growing push to use existing workplace information to
model exposures. Modelling can range from complex sta- EXPOSURE VARIABILITY AND EXPOSURE
tistical examination of large datasets of previous measure- DETERMINANTS
ments to tease out determinants of exposure through to
relatively simple logic structures that utilize readily avail- Exposure for a single worker varies from minute to minute
able information on the chemical properties of a material, throughout the day as she undertakes different tasks and
the quantities being used, the environment within which it interacts with work equipment or processes. Two workers
is being handled (confined, open, well-ventilated, outside), performing the same job in a factory will have different
and the methods of application or use (contained, disper- exposures because of differences in their work tasks, the
sive, low energy, high energy, etc.). The online software way they do their work and their location in the plant.
tool Stoffenmanager (www.stoffenmanager.nl) allows the Workers doing a different job may have higher or lower
user to enter data on each of these parameters and then average exposure from the first two workers, depending on
produces an estimated distribution of exposure concentra- how their work brings them into contact with the contam-
tions generated for the scenario provided. inant, their work and other exposure determinants. In all
Figure 4.4 shows the distribution provided for expo- of these cases, some of the variation can be explained by
sures to xylene during a spray painting task. The exposure exposure determinants, such as job, process, equipment,
distribution is broadly log-normal and so the median environment or other factors, and some is less clearly
value, or 50th percentile is 203 mg/m3, while the 95th defined and is attributed to random influences. It is not
percentile is over 3400 mg/m3. Understanding ‘worst case’ unusual for the exposure measurements on a single day
exposures is extremely important in determining disease from two individuals doing the same job in the same
causation and Figure 4.4 clearly demonstrates how some factory to differ by more than one or two orders of magni-
workers at certain times may perform the task in a rushed tude. It is, therefore, very important when measuring
manner, without the ventilation system in operation, with- exposure to make a careful record of the key exposure
out their usual protective equipment and perhaps with determinants, e.g. the materials handled, the way that they
much greater quantities than they would normally use. are handled, the presence and effectiveness of workplace
In these cases, the exposure will be towards the upper end control measures, the size of the workroom, the amount of
of the distribution and may be many times higher than the general ventilation, the use of personal protection and the
median value. There has been a great deal of recent work amount of time spent doing specific tasks or activities. In
in understanding variability in exposure and the factors addition, the extent of the typical variation in exposure
that influence both the measured level and degree of vari- means that one or two measurements of exposure made in
ability across a population of workers performing similarly a specific workplace may not be particularly informative
described jobs. The British and Dutch Occupational about average exposure and a more extensive dataset may
Hygiene Society have recently published draft guidance on be needed before clear conclusions can be made as to the
48 Occupational exposure to hazardous substances
extent of exposure of a group of workers in a particular e.g. during filling of drums with a volatile liquid or when
workplace. cleaning a store contaminated with a toxic dust.
Some workers may be consistently exposed to higher or
lower levels than a typical worker doing their job, either
because of the way they do the work or because of the work EXPOSURE LIMITS
tasks they undertake. It is important to understand these
intraindividual differences in exposure when attempting to Risk is most often judged by comparing the exposure to an
understand the role of exposure to hazardous substances in appropriate occupational exposure limit. OELs are derived
the causation of disease. by a number of scientific and/or policy bodies and typically
have legal status in the country where they were derived.
Scientific limits are often set to protect the health of those
INHALATION EXPOSURE METRICS exposed, i.e. exposure below these health-based OELs
would not be expected to give rise to any adverse effects.
Adverse health effects can broadly be categorized as either Where it is either not possible to define a health-based
acute or chronic, reflecting the timescale over which the limit or where compliance with this type of limit would
effects of exposure occur. For simplicity and practicability, be impracticable on either technological or economic
exposures related to acute effects are generally measured grounds, a limit may be set to restrict the risks to health
over a 15-minute averaging period and for those related to some societal acceptable level.
to chronic effects over an eight-hour period. For some In the European Union, health-based limits are derived
substances, there may be both acute and chronic effects by the Scientific Committee on Occupational Exposure
and in these cases exposure should be assessed against both Limits (SCOEL).5 These limits are then implemented in
time bases. each country within the EU by national legislation. Outside
For chronic hazards, measurements would typically the EU, most countries have their own regulatory systems,
be made over less than eight hours and an assumption although limits from different countries are often broadly
would be made about the exposure during the missing comparable. A key influence on limits worldwide is the
time in calculating the eight-hour average exposure. For list from the American Conference of Governmental
example, a worker exposed to ethylene oxide was sampled Industrial Hygienists (ACGIH). These limits, which are
for six hours and the measured concentration was known as Threshold Limit Values (TLVs), were first pub-
5 mg/m3. If the sample had been collected over the whole lished in the 1940s and now provide guidance on exposure
of the time when the individual was exposed, i.e. the levels for about 650 substances (www.acgih.org/TLV).
remaining two hours of his work shift did not involve any In the United Kingdom, the OELs are known as work-
exposure, then the eight-hour average exposure would place exposure limits (WELs) and they are given legal force
be 3.75 mg/m3, i.e. ((5 6) (0 2))/8. If, however, the through the COSHH regulations. There are WELs for a few
unmeasured period was judged similar to the measured hundred of the most common chemicals used at work,
period, the eight-hour average exposure would be which incorporates the limit values that have been agreed
5 mg/m3, i.e. ((5 6) (5 2))/8. by the European Commission following the recommenda-
When a worker performs several distinct tasks, then the tions of the SCOEL; details are available from the HSEs
process of calculating a time-weighted average (TWA) is website (www.HSE.gov.uk/COSHH).
often employed. This combines the product of the expo- OELs are straightforward to understand and make for
sure intensity and duration of each task and divides by easy management of the risks from chemicals in the work-
the total work duration. So, for example, a baker who place. However, they do not explicitly consider exposure
spends two hours decanting sacks of flour to small tubs by routes other than inhalation and they do not take
may have an exposure to flour dust of 15 mg/m3 for that account of some of the individual factors that may influ-
period, followed by four hours of general baking activity, ence risk, e.g. genetic determinants of risk or the person’s
when the intensity of exposure is 2 mg/m3 and a final two work rate and its effect on the quantity of chemical inhaled.
hours of bakery cleaning with an exposure of 5 mg/m3. However, despite this, they are the internationally accepted
The time-weighted average is calculated using the equa- way of judging whether occupational chemical exposure is
tion below: acceptable.
(d) (e)
Figure 4.5 Respirators used in the workplace. (a) Disposable half-mask; (b) reusable half-mask; (c) reusable full-face masks; (d) air-fed
visor; (e) breathing apparatus. Reproduced with permission from Draeger Safety UK Ltd.
not those other workers in the vicinity who do not have A final approach may be to remove the worker from the
access to, or have decided not to wear, the same level of exposure by changing their work tasks or even recommend-
protection. Second, it only protects the worker while it is ing that they change job. The worker themselves may initi-
being worn and worn correctly. Workers will remove ate this change once they identify the cause of their ill
masks during breaks or to hold conversations and during health. This option should be considered carefully and only
these times no protection is afforded. Then there is the when other appropriate measures in the control hierarchy
problem of proper fitting – respiratory protective equip- have been reviewed. Simply removing the worker from the
ment is typically of one size and takes little account of dif- causative agent without first attempting to intervene will
ferent face shapes and sizes to ensure a good seal between leave conditions unchanged and the other remaining work-
the mask and skin. Proper fit-testing of respiratory protec- ers exposed to the same conditions that produced the illness
tion is extremely important if PPE is part of the workplace in the sentinel patient. In the same way that this would be
intervention programme. Finally, there is evidence that deemed an unacceptable strategy for handling an outbreak
wearing PPE can encourage less careful working practices of infectious disease, it should not be the primary mecha-
that actually increase exposures. nism for dealing with worker ill health.
Attribution of a disease to an exposure 51
for chrysotile. Data from work on naval shops in the late during the summer dip the jacket was not worn because of
1960s showed that men working with amosite asbestos problems with the heat. Also, Mr P was provided with one
ropes could be exposed to between 5 and 340 fibres/mL set of protective clothing each year and he reported that
(average 100 fibres/mL). There is good evidence from other after a few weeks of use it was no longer completely water
sources to substantiate that amosite products were dustier resistant. Occasionally, he fell into the full dip tank while
than those containing chrysotile. dipping. Mr P also prepared the solution used in dipping by
Mr A’s exposure was likely to have been lower than the diluting concentrate organophosphate-based products. At
men working with the caulking because he generally the end of the dipping, Mr P had to clean and drain the tank.
worked 2–3 metres from the task and it can thus be esti- The work involved potential dermal exposure to the
mated that his personal exposure would have been about a concentrated and dilute dip (from direct contact and
third of their exposure. Also, the respirator would have splashes), but there was little opportunity for inhalation
reduced his exposure by approximately 90 per cent. Based exposure (these dips are of low volatility and there is little
on these assumptions, his exposure can then be estimated opportunity for a fine aerosol to form). The main focus of
as shown in Table 4.1. the exposure assessment is therefore on skin exposure.
The majority of his exposure occurred before 1970 Ingestion exposure during accidental immersions of Mr P
and there was probably sufficient cumulative exposure may also have contributed significantly to his overall dose,
(33 fibres/mL years) to more than double his risk of but this is difficult to quantify.
lung cancer, so it is reasonable to attribute his cancer to his There are a number of epidemiological studies that have
asbestos exposure. It is generally assumed that there must supported the hypothesis that pesticide exposure may
be at least a ten-year gap between first exposure to asbestos increase risk of Parkinson’s disease. However, the studies
and there being a risk of disease, i.e. a ten-year latency do not present a consistent picture and they do not provide
period, and this was the case for Mr A. Given that he was a evidence on specific compounds or even classes of com-
non-smoker and there are no other identifiable risk fac- pounds, such as organophosphates. In 2008, the UK
tors, it seems probable that his disease was caused by his Industrial Injuries Advisory Council (IIAC) examined the
asbestos exposure. case for prescribing pesticide exposure and Parkinson’s
disease for state compensation and concluded that the
evidence base was not sufficiently strong, i.e. the existing
Case 2: Organophosphates epidemiological studies do not consistently support a dou-
bling of risk. Despite this, it is important to understand
Mr P was born in 1940 and left school at the age of 14 to whether this man’s exposure could have been implicated in
work as an under-shepherd at a hill farm in the Scottish causing his disease.
borders. In 1960, he became head shepherd and he contin- There are no universally accepted ways of estimating
ued in this job until 1970 when he left farming. exposure to chemicals on the skin and very few measure-
Throughout his employment, Mr P was required to treat ments of dermal exposure from such situations. The most
sheep with pesticides to prevent scab and other conditions. appropriate method of assessing skin exposure combines
This was done by immersing sheep in a pool of dilute the concentration of the chemical on the skin, the area of
organophosphate pesticide, a process known as ‘dipping’ skin exposed and the duration of exposure. This measure
and took place four times each year during June, August, should be related to the amount of chemical taken up into
October and November. Between 2000 and 3000 sheep the body through the skin.7 Tahmaz et al.8 developed an
were dipped every year. Mr P has been diagnosed with exposure model based on this approach for sheep dipping
Parkinson’s disease and it has been suggested that his expo- to assist in a study of farmers with chronic fatigue. They
sure to organophosphate compounds while dipping sheep defined the skin exposure (Esk) as the product of the con-
could have caused his disease. centration of the active compound (organophosphate) on
Mr P used a large 2000-litre dip tank. Sheep were pushed the skin (Csk), the duration that the skin is contaminated
into the tank and then submerged using a T-shaped pole. (tsk) and the area of skin contaminated (Ssk). In mathemat-
He wore waterproof leggings, an oilskin jacket – which he ical form, this is:
wore back-to-front for added protection – Wellington
boots and rubber gloves. He did not wear a respirator and Esk Csk tsk Ssk
Attribution of a disease to an exposure 53
Table 4.2 Mr P’s estimated exposure to organophosphates. woman was employed on a process making a photo poly-
mer resin product, in a fully enclosed process. One of the
Circumstances Estimated exposure
main raw ingredients in the process was toluene diiso-
(m2 days)
cyanate (TDI). During the TDI loading task, the operator
wore a full-face filtering respirator, fitted with a combina-
Mr P 1400 tion gas and dust filter (note these are not recommended
For people with high chronic 490–1000 for use with TDI and would not provide reliable protec-
fatigue scores8 tion). She also wore cotton overalls and natural rubber
People with low chronic fatigue scores8 30–670 (latex) gauntlets. A rubber apron was available, but was not
worn. Self-contained breathing apparatus (BA) was pro-
vided for use in emergency situations and one BA set was
The measurement units for this assessment are m2 days, located in the main process control room and a second set
i.e. area multiplied by the duration (concentration being was located outside the building. The majority of Mrs I’s
dimensionless, i.e. without measurement units). For exam- work time was spent in the air-conditioned control room.
ple, 100 m2 days skin exposure could be the result of The company regularly undertook air monitoring for
1000 days of exposure where 0.1 m2 of skin was exposed to isocyanate (NCO) using the method recommended by
concentrated pesticide (Csk 1). the Health and Safety Executive (MDHS 25/3 Organic
To ensure that the estimate of exposure is representative isocyanates in air). Samples were obtained using IOM
of different areas of skin that may become contaminated sampling heads loaded with chemically impregnated glass
and the pattern of exposure, the exposure estimate was fibre filters, treated with 1-(2-methyoxyphenyl) piperazine
further subdivided by Tahmaz et al. into skin exposure to (1-2MP) solution. The sampling head was attached to the
dilute pesticide during dipping sheep (Esk,dip), exposure to lapel of the operator and connected to a battery-operated
concentrate while preparing the dilute dip (Esk,conc), expo- personal sampling pump drawing air at 2 L/min through
sure while handling sheep (Esk,handling), inhalation exposure the filter. The samples were analysed for total isocyanate
during dipping (Einhalation) and skin exposure on occasions content using high performance liquid chromatography.
where the person accidentally fell into the dipping bath None of their measurements showed detectable iso-
(Esk,falls). Mathematically, this is expressed as: cyanate exposure for Mrs I, all the measurements being
0.001 mg/m3 as total NCO (the long-term occupational
Esk Esk,dip Esk,conc Esk,handling Einhalation Esk,falls exposure limit is 0.02 mg/m3). The only detectable iso-
cyanate levels have been obtained for quality assurance
Each of the above terms is further elaborated in the technicians who have to extract a sample of resin for test-
Tahmaz et al. approach to take account of the use of pro- ing (maximum reading 0.004 mg/m3).
tective clothing and other factors that influence the expo- An interview with Mrs I indicated that in the months
sure. The estimated exposure can then be calculated using before she first started to experience symptoms there
a computer spreadsheet. had been a series of maintenance issues on the plant and that
The results from the calculation of Mr P’s exposure are two pumps in the process had been replaced because they
shown in Table 4.2, along with the range of lifetime expo- were leaking. No measurements of airborne isocyanate level
sures from Tahmaz et al. for 95 per cent of the farmers in had been made during this time, but it seems plausible that
that study – subdivided by whether or not they scored there was episodic peak exposure to TDI vapour during this
highly in terms of the questionnaire on chronic fatigue. time. The exposure of the quality control technician arises
Mr P’s estimated lifetime exposure was above the 95th from a short period when the containment of the process is
percentile of farmers who had high chronic fatigue scores. breached, typically 20 minutes each day. If it was assumed
Note that the highest estimated exposure from Tahmaz that the leak was continuous and that the room ventilation
et al. was about 8500 m2 days. was sufficient to provide ten air-changes per hour then a
Despite Mr P having very high exposure to organophos- simple calculation suggests that an eight-hour average expo-
phate compounds during sheep dipping, it is not possible, sure level of 0.004 mg/m3 could be associated with peak
given the current state of scientific evidence, to clearly exposure of about 0.1 mg/m3 during the short period of sam-
attribute his exposure to his disease. However, it would pling. Using the exposure modelling software package IH-
seem prudent to advise him to avoid further exposure to Mod (which is freely available at: www.aiha.org/insideaiha/
organophosphate compounds at work or in other situa- volunteergroups/Documents/EASCIHMOD.xls), the expo-
tions, such as home gardening. sure over a full shift can be calculated. As can be seen from
Figure 4.6, the concentration with a continuous leak similar
to that during quality control sampling gives rise to a level of
Case 3: Isocyanates 0.2 mg/m3.
There are no good exposure–response epidemiological
Mrs I, who works in a factory making various adhesives, studies for asthma associated with TDI exposure, but
sealants and coatings, was diagnosed with asthma. This there is evidence that a significant proportion of exposed
54 Occupational exposure to hazardous substances
6. Health and Safety Executive. Respiratory protective equipment Gardiner K, Harrington JM. Occupational hygiene, 3rd edn.
at work. A practical guide. Sudbury: HSE Books, 2005. Oxford: Blackwell Publishing, 2005.
7. Cherrie JW, Robertson A. Biologically relevant assessment of Kromhout H, Symanski E, Rappaport SM. A comprehensive
dermal exposure. Annals of Occupational Hygiene. 1995; 39: evaluation of within- and between-worker components of
387–92. occupational exposure to chemicals. Annals of Occupational
8. Tahmaz N, Soutar A, Cherrie JW. Chronic fatigue and Hygiene. 1993; 37: 253–70.
organophosphate pesticides in sheep farming: A retrospective Nieuwenhuijsen M. Exposure assessment in occupational and
study amongst people reporting to a UK pharmacovigilance environmental epidemiology. Oxford: Oxford University Press,
scheme. Annals of Occupational Hygiene. 2003; 47: 261–7. 2003.
Ramachandran G. Toward better exposure assessment strategies –
the new NIOSH initiative. Annals of Occupational Hygiene.
FURTHER READING 2008; 52: 297–301.
Seixas NS, Checkoway H. Exposure assessment in industry specific
Cherrie JW, Howie RM, Semple S. Monitoring for health hazards retrospective occupational epidemiology studies. Occupational
at work, 4th edn. Chichester: John Wiley & Sons, 2010. and Environmental Medicine. 1995; 52: 625–33.
5
Biological monitoring
Biological
Environmental Biological Diagnosis
effect
monitoring monitoring well-being
monitoring
Occupation
Hazard
Disease or
Exposure Uptake Effects
toxicity
Environment
keep systemic exposure as low as is reasonably practical samples collected from workers can help provide a
and to the left of the spectrum in Figure 5.1. personal message and influence worker behaviour or
Monitoring techniques can be divided into those that give reassurance.
assess exposure and those that assess the consequences of
exposure. Thus, BM relates to exposure assessment and
BEM is usually part of effects assessment, and can help in Legal framework
the diagnosis of disease. The distinction is important
because the motivation for doing the monitoring influ- In most countries, there is a legal requirement for health
ences the way results are interpreted. A physician in the surveillance of workers who may be significantly exposed
workplace may initiate BM as part of health surveillance, to lead. In the UK, the Control of Lead at Work (CLAW
but the results can often only be interpreted in terms of 2002) regulations requires the regular monitoring of work-
exposure and not (directly) health. There are international ers exposed to lead. This involves both clinical examina-
differences regarding the role of BM, e.g. between Europe tion by an appointed physician and analysis of blood
and the United States, with BM historically performed as a samples for lead with defined action levels based on the
medical activity in European countries, while in the United results. Some countries have compulsory biological moni-
States and now in the United Kingdom, BM also belongs toring for a few other substances, but the legal framework
within the specialism of occupational hygiene. for BM usually comes under the regulations to control
Biological monitoring guidance values are produced by hazardous substances in the workplace, and biological
various organizations to aid the interpretation of results, monitoring is not compulsory.
but the majority of guidance values relate to exposure In the UK, biological monitoring has roles under the
assessment with the aim of controlling occupational Control of Substances Hazardous to Health (COSHH) and
exposure at levels below those causing noticeable health in particular regulation 10 (Exposure Assessment), regula-
effects. In contrast, there are comparatively few biological tion 11 (Health Surveillance) and regulations 6 and 7
effect guidance values. (Assessing and Controlling Exposure/Risks). In the case of
A recent development, under the auspices of the health surveillance, it is used when it is possible to link the
European Centre of Ecotoxicology and Toxicology of results of biological monitoring to an adverse health effect.
Chemicals, has been the development of a framework for Implicit in this requirement is that a ‘no-adverse effect
the interpretation of BM data through evaluation of their level’ has been established. However, often there is insuf-
analytical integrity, their ability to describe dose (toxicoki- ficient data available to do this and there are many
netics), their ability to relate to effects, and an overall eval- substances in the workplace where it is not possible (e.g.
uation and weight of evidence analysis.1 This framework carcinogens and allergens), and then the prudent approach
may provide a rational basis to allow better use of current is to try to minimize exposure to as low as possible.
biomarkers and the development of novel, interpretable In the absence of a recognized ‘no-adverse effect’ level
BM and BEM markers. for a chemical, an alternative, pragmatic approach is to
establish an appropriate level based on the levels (usually
the 90th percentile) seen in workplaces with good control
BIOLOGICAL MONITORING of exposure. This approach does not require knowledge of
a dose–response relationship or yield a health-based value.
Roles Instead, it allows exposure to be monitored, controlled
and reduced to minimize risk of ill health, and any reduc-
Unlike air or surface monitoring which assess potential tion of exposure is then reflected in reduced health risk.
exposure, biological monitoring can help to assess actual This approach is in line with the current approach to
systemic exposure, from all routes. BM is particularly controlling exposure based on good occupational hygiene
useful where air monitoring alone will not give a complete practice and is comparatively easy to establish. Thus,
picture of exposure. These roles include monitoring sub- although BM is not compulsory, its simplicity and utility
stances where the dermal route can contribute signifi- mean that it is increasingly being used and incorporated
cantly to systemic toxicity such as those with ‘Sk’ or ‘skin’ into codes of practice and in-house guidance for working
notations in tables of exposure limits. Biological monitor- with and controlling exposure to chemicals.
ing also has a role where the control of an inhalation haz-
ard relies on personal respiratory protective equipment.
In such situations, it is not very helpful to measure the Ethics
ambient air levels of the substance and often difficult to
measure the effectiveness of the respirators in use. A third Since BM involves the collection and analysis of biological
role for biological monitoring is the overall assessment of samples from people, it is essential that the rights of the
exposure controls, including worker behaviour. The best individual are protected. These rights can be protected
exposure controls may not protect the worker if they are by obtaining informed consent to collect and analyse the
not used correctly. The individual nature of biological samples, and gaining their permission regarding who will
58 Biological monitoring
see the results and understanding what action will be taken ● Provide feedback and interpretation of the results.
on the results. The programme should be discussed and ● Take appropriate action on results, if required.
agreed with all concerned, employees, employers and
worker representatives. In the UK, with the exception of For many of the most common substances in the work-
lead, BM is not compulsory, and workers need reassurance place, there is guidance available on the technical
that their participation or non-participation will not affect aspects of biological monitoring. The UK Health and
their conditions of employment. To get their informed Safety Executive (HSE), the American Conference of
consent to participate, the purpose of the BM programme Governmental Industrial Hygienists (ACGIH) and the
must be explained along with the type of biological samples German Deutsche Forschungsgemeinschaft (DFG) all pro-
that will be collected, and any associated risks. Workers duce guidance documents that detail the type of sample,
need to be made aware of what will be analysed in the when to collect it, the substance to be analysed and a guid-
samples and reassured that no other tests (e.g. alcohol, ance value to aid in interpreting the results.4–6
drugs, HIV) will be performed. They need to know what
action might follow depending on the BM results and what
Sample collection
the benefits (if any) are to them as individuals. Workers
should be informed that the results will be treated as
The collection of non-invasive samples (e.g. urine, breath,
personal data, treated as confidential and only revealed
saliva) is preferred, provided a validated method is avail-
as grouped data without identifiers, and/or to others with
able. Non-invasive samples are more acceptable to workers
specific consent, e.g. to health professionals or managers.
compared to collecting blood samples. Non-invasive
Within the UK, the Information Commissioner has also
sampling also reduces the risks from venepuncture and
produced guidance that relate to such issues.2
disposal of blood-contaminated material. Appropriate
The programme must be supervised by a competent
precautions should be taken when collecting and handling
person, often (but not exclusively) an occupational health
biological samples and particular attention should be taken
professional. In our experience, these arrangements do
with regulations for sending pathological samples through
not pose any particular problems and a well-designed
the post or by courier. Within the United Kingdom,
and executed biological monitoring programme can be
appropriately packaged and labelled samples may be sent
an effective way of protecting workers’ health.
by first class post or special delivery, and the Royal Mail
offers a prepaid packaging system for diagnostic biological
samples. Where samples need to be sent internationally,
SETTING UP A BIOLOGICAL MONITORING
courier rather than postal service must be used and
PROGRAMME
International Air Transport Association (IATA) regula-
tions followed, sending BM samples assigned to UN3373
Guidance is available to aid setting up biological monitor-
or as ‘exempt human specimen’.7 In essence, sending BM
ing programmes for a wide range of substances and covers
samples within the UK or internationally as ‘exempt
the basics of the ethical issues, consultation, choice of ana-
human specimens’, should involve primary and secondary
lyte, sample collection, analysis and guidance on interpret-
leak-proof packaging, the latter of appropriate strength,
ing results.3 The main steps include:
with enough absorbent material between the packaging to
●
absorb the entire contents and also appropriately labelled,
Define the purpose of the programme as exposure
including a return address. Any laboratory involved in BM
assessment or part of health surveillance.
●
will be able to advise on ensuring compliance with postal
Appoint a competent person to oversee the programme.
and transportation regulations.
If the programme is for health surveillance, a health
Most biological monitoring is based on collection of
professional should be appointed.
●
urine samples. If the analyte is the substance to which the
Select a biological monitoring strategy (who to monitor,
workers are exposed, e.g. metals, care should be taken to
how often, what samples to collect, when to collect them,
avoid contamination of the sample during collection. If
methods to analyse them, availability of guidance for
the analytes are volatile, e.g. most solvents, care needs to be
results). A competent laboratory should be employed
taken to avoid loss of analyte, usually by supplying a urine
and can help with developing the strategy. The laboratory
sample where there is little headspace remaining in the
should run appropriate internal quality control schemes
sample bottle. Most BM analytes are stable enough that
and participate, if available for the analyte in question, in
refrigeration is not necessary during their transport by first
external quality assurance schemes.
●
class post to the laboratory.
Consult on the programme with employees and their
representatives.
● Discuss and agree the programme with the individuals When to sample
concerned.
● Establish procedures for sample collection, storage, The optimum time for sample collection is determined by
transport, analysis and quality assurance. the toxicokinetics of the substance and depends mainly on
Setting up a biological monitoring programme 59
the half-life of elimination. This toxicokinetic parameter attribute exposure to occupational and dietary sources.9
also largely defines the relationship between a BM meas- Where a biomarker is derived from external exposure
urement and the period of exposure that it reflects.8 Ideal and also endogenously, it may be advisable to collect
sampling times are often compromised by the practicalities pre-exposure or baseline samples. Smoking can contribute
of sample collection in the workplace that usually dictates to a wide range of biomarkers, including thiocyanate
samples are to be collected at the ‘end-of-exposure’, ‘end- used to monitor exposure to cyanide and napthols.10
of-shift’ or prior to the start of the next shift. The route of Consideration should also be given to the possibility that
exposure (inhalation or dermal absorption) may also have the chosen biomarker may also be a metabolite of another
an impact on sample collection times. The apparent half- substance, e.g. mandelic acid is a widely used BM metabo-
life of an inhaled substance will generally differ from the lite of styrene, but is also formed from ethyl benzene, while
same substance if dermally absorbed, where it is subjected carboxyhaemoglobin is formed from both carbon monox-
to a lag phase due to transit across the stratum corneum ide and dichloromethane. Alcohol and some drugs can
with the skin acting as a reservoir for the substance. Table 5.1 compete for metabolism of many solvents, tending to
gives a generalized relationship between elimination half-life, extend their half-life of excretion. However, chronic intake
sampling time and exposure reflected in the BM sample of alcohol and some drugs can also induce enzymes poten-
taken at the sampling time. tially involved in metabolism of some solvents and chemi-
cals, again altering the normal relationship between BM
measurement and exposure.
Interfering factors Physiological factors, such as work rate, can also influ-
ence BM results for some substances where increased
Biological monitoring results can be influenced by inter- respiration leads to increased absorption and consequently
fering factors. These may include additional exposure increase systemic dose, e.g. someone exposed to xylene
through a non-occupational route, by exposure to a chem- working moderately hard will have two to three times the
ical that is also metabolized to the BM analyte being mon- respiration rate and urinary metabolite levels compared to
itored, and also by altering the metabolism of the BM a worker at rest with the same airborne xylene levels.
analyte of interest.
Sometimes, the collection of additional information by
questionnaire or analysis is necessary. For example, con- Choice of analyte
sumption of seafood may increase total urinary mercury
and total arsenic levels, but more complex analysis of the The choice of analyte will depend on the purpose of the
species contributing to total urinary arsenic can help monitoring. If the level of exposure is being assessed, then
Table 5.1 Relationship between elimination half-lives, the practical time of sampling for a biological monitoring strategy and the
exposure duration that the sample reflects.
2 End of exposure. With such short Large uncertainty due to variable retention time of urine
half-lives, the time between exposure in bladder
and urine voiding becomes influential
2–10 End of exposure, end of shift For t 12 of 2 hours, BM sample reflects a 35% contribution
from exposure in the hour before sampling, the rest from
exposure over shift. For t 12 of 10 hours, BM sample reflects
a 70% contribution from exposure over the prior 24 hours,
with smaller contribution (approximately 10%) from exposure
in the last hour
10–100 End of exposure at the end of week or With increasing the t 12 10 hours to t 12 100 hours,
after several exposures the contributory influence of exposure during the 24 hours prior
to sampling diminishes from 70 to 15% and the importance of
exposure in the previous week increases from 20 to 60%
100 Sampling time not critical Contribution from exposure during the week prior to sampling
decreases from 60% and with longer t 12 the influence of
exposure over the previous month or months becomes more
important
60 Biological monitoring
for inorganic substances such as metals, the element itself concentration or dilution effects. The two most common
is usually measured. The choice for organic substances types of adjustment are based on urine specific gravity or
depends on the metabolism and kinetics of the substance creatinine concentration, both of which largely adjust for
and the possible interference from other endogenous the rate of urine production. However, the use of creati-
sources. As an example, biological monitoring for toluene nine or other adjustment is not without ongoing
was once based on the analysis of its major metabolite debate.13–15 Some authorities take the stance that no
hippuric acid, but as regulatory exposure limits for toluene correction is the default position, others use creatinine
were reduced the interference from dietary sources of correction as their default position, and there is ongoing
hippuric acid made this approach no longer viable and work proving the value of such correction for an analyte on
monitoring switched to using the minor metabolite a case-by-case basis.16,17
o-cresol or the measurement of toluene itself in urine. Adjustment of analytical results for certain analytes
Biomarkers that reflect flux in the toxic metabolic (e.g. urine methanol) using either creatinine or specific
pathway are preferred over those that reflect detoxification gravity adjustment is not appropriate, where the chemi-
and simple elimination. Examples include haemoglobin cal simply equilibrates between intra- and extracellular
adducts after exposure to aromatic amines or alkylating fluids, including urine. For other analytes, creatinine
reagents. correction is not advised if the creatinine concentration
A relatively recent and comprehensive review of BM is less than 3 mmol/L or more than 30 mmol/L suggesting
analytes and strategies for monitoring workplace chemical the extremes of urine flow rate. Interpretation may be
exposures is available.11 subject to considerable error, and a further sample is
warranted.
Analysis
Interpreting results: Guidance values
Confidence in the results of laboratory analysis is essential.
The laboratory should have analytical methods with suffi- To aid the interpretation of BM data, various international
cient sensitivity and specificity to accurately and repro- organizations produce biological monitoring guidance
ducibly measure the analytes of interest. The laboratory values (Table 5.2). These are derived from review of data in
should have internal quality assurance procedures and, the peer-reviewed literature and the objective, if possible, is
where possible, take part in external quality assurance to produce a health-based guidance value. However, for
schemes. many substances, there is insufficient data to be able to
Quality assurance begins with sample collection and the derive a BM value linked to the absence of health effects
use of appropriate equipment to prevent contamination or from the dose–response relationship, and guidance values
loss of analyte. Samples must be unambiguously labelled based on good occupational hygiene practice and ‘achiev-
and must be transported to the laboratory in a way that ability’ are used instead.
ensures the integrity of the sample. A few analytes may Examples of health-based guidance values are the
require preservatives or refrigeration prior to transport. biological exposure indices (BEIs) of the ACGIH5 and
Some analyses are within the scope of routine clinical the biological tolerance values (BATs) from the DFG.6
laboratories but many may require a specialized labora- These are derived from dose–response relationships
tory. A good laboratory will provide sample collection between a biological parameter and either the absence
equipment, packaging materials and guidance on sample of health effects or, more usually, from a relationship
collection, transport and interpretation of results. between a biological parameter and an airborne exposure
A recent review has suggested that the potential avail- limit that is itself health based. For substances where a
ability of both sensitive analytical techniques and quality health-based dose–response relationship cannot be estab-
assurance schemes for BM means that interpretation of lished, e.g. for many carcinogens and respiratory sensitiz-
results has become the key, important issue.12 ers, biological monitoring guidance values can be based
on a relationship between a biological parameter and the
airborne exposure limit. Examples of this type of guidance
Creatinine correction value are the DFG biological exposure equivalent values
(EKA values).6 An alternative approach is to base the
Urine concentrations of metabolites can vary widely not biological monitoring guidance value on the levels of a
only due to variations in exposure, but also as a result of biological parameter found in samples from workplaces
variations in fluid intake and insensible losses, such as employing good occupational hygiene practice, and exam-
sweating, which can alter urinary flow rate over a wide ples are the HSE’s published guidance values for carcino-
physiological range. Most biological monitoring is based gens and suspect carcinogens like hexavalent chromium,
on spot samples and it is common to make some adjust- methylene-bis-2-chloroaniline (MbOCA) and methyl-
ment to the analytical results to compensate for short-term enedianiline.4 HSE has also adopted this approach for
Table 5.2 Biological monitoring guidance values for common substances.
Substance Analyte Medium Sampling time BMGV4 BEI5 BV6 Health concern
Substance Analyte Medium Sampling time BMGV4 BEI5 BV6 Health concern
30 μg/dLd
50 μg/dLe
40 μg/dLf
25 μg/dLg
Mercury Mercury Urine Random 20 μmol/mol 15 μg/L 25 μg/g (BAT) Nephrotoxic, CNS
effects
4,4methylene-bis-2-chloroaniline ‘Total’ MbOCA Urine End of shift 15 μmol/mol Cancer
(MbOCA)
Methylenedianiline (MDA) ‘Total’ MDA Urine End of shift 50 μmol/mol Cancer
4-methylpentan-2-one (MIBK) 4-methylpentan-2-one (MIBK) Urine End of shift 20 μmol/mol 2 mg/L Irritant, CNS
Nickel metal, oxide, carbonate, Nickel Urine End of shift at end 70 μg/L (EKA) Cancer
sulphide of week
Soluble nickel compounds, 45 μg/L (EKA)
e.g. actetate, chloride,
hydroxide, sulphate
Polyaromatic hydrocarbons (PAHs) 1-hydroxypyrene Urine End of shift at end 4 μmol/mol Cancer
of week
Styrene Mandelic acid phenylglyoxylic Urine End of shift 400 mg/g 600 mg/g (BAT) Irritant, CNS
acid
Tetrachloroethylene Tetrachloroethylene Blood Pre-shift 0.5 mg/L Irritant, CNS
Breath Pre-shift 3 ppm
Toluene o-Cresol Urine End of shift 0.5 mg/L Visual impairment,
female reproduction
Trichloroethylene Trichloroacetic acid Urine End of shift at end 15 mg/L CNS
of week
Xylene Methyl hippuric acid Urine End of shift 650 mmol/mol 1.5 g/g 2 g/L CNS
Results expressed as ‘/g’ or ‘/mol’ are expressed as /g or /mol of creatinine.
BAR, reference value for background or non-occupational exposure; BAT, biological tolerance value; BLW, uncertain value based on little data; BV, biological value (BAT, BAR, BKW, EKA); EKA, biological equivalent to
an airborne limit.
a
Without hydrolysis.
b
Suspension limit.
c
Suspension limit for young people.
d
Suspension limit for women of reproductive capacity.
e
Action limit.
f
Action limit for young people.
g
Action limit for women of reproductive capacity.
Biological effect monitoring 63
Response
30
BM value
20
Dermal absorption?
Or breathing
hard? 10
RPE? 0
Or breath holding? 0 25 50 75 100 125
Blood Pb (μg/dL)
WEL or Dose
TLV or Figure 5.3 The relationship between blood lead and zinc
MAK
protoporphyrin in a sample of UK workers monitored under
Figure 5.2 Biological monitoring idealized dose–response graph. Control of Lead at Work Regulations (CLAW) 2002.
64 Biological monitoring
haemopoiesis in bone marrow. Pb has a number of effects effect monitoring’ and ‘diagnosis’, are clearly delineated, in
on both the production of erythrocytes, and on formed red practice there are grey areas and debate. There are some
blood cell that can ultimately lead to anaemia. Increased areas of uncertainty about where some analyses may be
ZPP in blood largely reflects Pb inhibition of the insertion better considered as biological monitoring, biological
of the ferrous iron into protoporphyrin IX, which is a key effect monitoring or better defined as diagnosis of overt
step in the formation of the haem molecule involved in occupational disease.
oxygen carriage by blood to tissues. For example, blood carboxyhaemoglobin (HbCO)
There is a significant statistical relationship between could be considered a classical BEM marker for situations
these BM and BEM markers (Figure 5.3), but it would be where there is direct exposure to carbon monoxide, from
difficult to predict the likely blood Pb level from a ZPP an industrial process or, often more hazardously, the use of
measurement and vice versa in any single subject. It has internal combustion engines in confined spaces,22 and
sometimes been wrongly thought that BEM markers are through the metabolism of dichloromethane and smoking
surrogates for BM measurements reflecting absorbed dose. status. Circulating levels of HbCO are both a direct indica-
The variability in the relationship between blood Pb and tor of the reduced oxygen-carrying capacity of blood and
ZPP is influenced by toxicokinetics and the pattern of an indirect marker of likely tissue anoxia. The relationship
exposure of the metal, and the interindividual variations in between HbCO and the classical toxic symptoms are well
Pb transport and storage within the body, as well as at spe- defined, so that health-based occupational limits have been
cific enzyme pathways within the bone marrow. The influ- readily set. Breath carbon monoxide is a non-invasive
ence of analytical imprecision in the two measurements is measurement that can be assessed on site using readily
relatively small compared to these biological factors. In available instrumentation and showing a good relationship
terms of dose, blood Pb can be considered as a measure of with HbCO levels.23 Thus, in this case, the distinction
absorbed metal, while ZPP indicates the influence in an between BM and BEM is arbitrary, and in higher exposures
individual of the Pb concentration at the target site(s) of HbCO is the diagnostic test confirming possible symptoms
interference in haemopoiesis. Figure 5.3 also shows a gen- of frank toxicity and the possible need for aggressive
eral feature of the relationship between BM and BEM therapy, such as hyperbaric oxygen.
reflecting the same exposure, in that the former is more The influence of susceptibility factors on the move from
sensitive in detecting low-level exposure than the respec- exposure and frank ill health, are often linked with biolog-
tive BEM marker, e.g. comparison of urinary alkyl phos- ical effect markers. Susceptibility factors may be protective
phates (BM) and depressions in blood cholinesterase in an individual, as well as increase the risk of possible
measurements (BEM) resulting from organophosphate toxicity and disease. While there are a few examples where
pesticide exposure.18 distinct susceptibility factors can be identified as significantly
An ideal BEM marker should be able to measure a altering the risk of adverse outcome (e.g. α1-antitrypsin
change in a biological parameter within an understood deficiency and exposure to lung irritants24,25), altered
toxicological pathway that links exposure to clinical disease risk is often related in a complex manner to a range of
or frank toxicity. It should also be able to detect an early factors. In some cases, metabolic polymorphisms have
change, at a preferably reversible stage. However, even been shown to be a risk factor for one ill-health outcome,
some well-established BEM do not necessarily fully meet but protective for another outcome (e.g. acetylator status
such a definition. For example, urinary retinol binding for N-acetyltransferase-2 and risk of bladder and colorectal
protein (RBP) (or other low molecular weight proteins, cancer when exposed to carcinogenic aromatic amines26).
such as β2-microglobulin), has long been considered as The use of biomarkers of susceptibility in occupational
a useful BEM marker in those exposed to cadmium.19–21 monitoring has raised considerable and ongoing ethical
The urinary increase in RBP is a sensitive marker of the concerns, and the emphasis remains on keeping chemical
metal’s toxic effects on renal proximal tubular reabsorp- exposure as low as possible to protect all workers, rather
tion. RBP can be readily measured in urine, and is sensitive than identifying a cohort within a possible workforce who
to very small cadmium-induced changes in the proximal are best able to handle exposure.
renal tubular reabsorptive process. However, the evidence An ‘ideal’ BEM marker would have both high sensitivity
is that any significant measured increase in RBP is not and specificity, low analytical impression and physiological
reversible even with complete removal of the subject from variation, low cost and measureable in as non-invasive a
further exposure. sample as possible. These would be the same ideal charac-
teristics for a clinical diagnostic test or test for an occu-
pational disease. Therefore, a blurring between a BEM
Biological effect monitoring, susceptibility marker and diagnostic test is possible for the ‘ideal’ test,
and diagnosis and this transfers to the real world where often tests are
very much less than ideal. The difference between a test
While the exposure-disease model in Figure 5.1 suggests used as BEM or diagnosis may be defined by the rationale
that ‘uptake’, ‘effect’ and ‘disease’, and the associated for their use and the interpretation put on the results. The
analytical categories of ‘biological monitoring’, ‘biological value of a test used to diagnose an (occupational) disease
Biological effect monitoring 65
may be expressed in terms of ‘likelihood ratios’ reflecting circulating nucleated cells remain almost exclusively
how much a positive (or negative) test is likely to change a within the research area. Historically, DNA-adduct analy-
physician’s opinion of the presence (or absence) of specific sis has relied on highly sensitive, but non-specific radiolog-
disease in a patient before the test was performed. The ical techniques, such as 32P post-labelling techniques.
same test used within an occupational monitoring/BEM Recently, sophisticated chromatographic and some
context can be viewed as similar to ‘screening’ within a immunoassay-based methods have been developed.29
population where there is a significant risk of relevant However these techniques, in particular 32P post-labelling,
ill-health outcome, where the ‘positive (or negative) pre- suffer from technical difficulties and complexities that
dictive value’ of the test is more relevant in terms of the would hamper their widespread adoption even if their
test’s value. In practice, most tests are primarily developed value as risk biomarkers of cancer was better validated.
for use in clinical diagnosis and their investigation in terms Another approach for monitoring DNA adducts takes
of value in occupational monitoring is secondary, often the advantage of the generally efficient DNA repair mecha-
evidence for evaluating the value of a test within occupa- nisms, which leads to the urinary excretion of excised
tional monitoring is scant in comparison to its clinical adduct-nucleic acids, e.g. urinary markers of oxidative
validation. Also, the problems of tests with less than ideal DNA adduction.31,32
sensitivities and specificities in the context of screening in Further measurements in the exposure-disease model
terms of false positives and negatives are well understood, (Figure 5.1) in terms of a mutagenicity/carcinogenicity
which may have limited the wider spread of BEM. pathway have been the measurements of genotoxic BEM
In contrast, in the last 10–15 years there has been a markers, such as DNA strand breaks, chromosomal abnor-
very significant increase in the number of candidate BEM mality, sister chromatid exchange, micronuclei, COMET
markers. This is due to the development of the experi- assay, modified bases, e.g. 8-hydroxy-2-deoxyguanosine
mental laboratory ‘-omics’ disciplines (e.g. proteomics, (8-OHdG) within circulating blood lymphocytes. These
genomics and metabolomics) in identifying changes in markers certainly reflect alterations in genetic material,
large numbers of proteins, enzymes and cellular control although less specific generally in relation to exposure and
mechanisms after a toxic insult in experimental studies. influenced by non-occupational lifestyle issues, especially
Whether some or any of these potential BEM markers smoking habits. Recent reviews still caution about the
develop into routine occupational monitoring proce- lack of dose–response relationships that allow some risk
dures is uncertain. assessment of the relevant health end point from such
The following sections deal with BEM with regard to measurements, and therefore their value in routine moni-
specific potential outcomes or sites of toxicity. toring.33–35 There is some evidence that DNA repair capac-
ity within an individual may be an important determinant
CARCINOGENS of cancer risk.35,36 This may be related to the concept of
susceptibility and polymorphism with DNA repair or
Protein–chemical conjugates involving haemoglobin may metabolic enzymes systems. Some studies continue to find
be considered as BM markers reflecting cumulative chem- clear relationships between metabolic polymorphisms and
ical exposure over the lifetime of haemoglobin. However, evidence of DNA damage in peripheral cells37 and actual
DNA-chemical adducts could be considered as BEM mark- risk of cancer in some cases, for example, polymorphism of
ers, showing the potential of reactive electrophilic chemical acetylator status of NAT2 can be associated with a doubled
species, or their metabolites, to become both intracellularly risk of bladder cancer among individuals with high expo-
located and then covalently adduct to DNA with direct sures to carcinogenic arylamines, with possible other
relevance to a potential carcinogenic pathway. Other metabolic polymorphisms in glutathione-S-transferases
authorities have coined the term ‘biological effect dose being additional risk factors.38
monitors’ for such DNA adducts. Over the last decade or There is considerable international effort to define the
so, a number of assays have been developed to investigate relationship between biomarkers of specific chemical
the measurements of DNA adducts in readily available adduction to DNA or exposure-induced changes in DNA,
nucleated cells (e.g. lymphocytes in blood) which fits genetic polymorphisms in metabolic enzyme systems
within a genotoxic model of how some chemicals may and the risk of cancer. Until such progress, Hb adducts
cause cancer,27–29 but their actual relationship to risk of as measures of exposure have gained a higher practical
cancer is uncertain.30 However, both haemoglobin- and use on a worldwide basis than DNA adducts. Other
DNA-adducts reflect that an absorbed chemical can cross protein–chemical adducts, such as albumin adducts39 have
cell membranes to produce intracellular reactive elec- also been used in monitoring genotoxic chemical expo-
trophilic species capable of covalently linking to structural sure. While albumin adducts reflect a shorter time frame of
or functional cell elements.27 exposure estimation than Hb adducts, and introduce the
On an international basis, the use of haemoglobin con- possibility of non-invasive urine monitoring, they do not
jugates have become an acceptable routine biomarker, reflect that a reactive species that has become intracellu-
highlighted by the development of guidance values for larly located before covalent adduction, as albumin is
some chemicals by the DFG.6 In contrast, DNA adducts in an extracellular protein.
66 Biological monitoring
CENTRAL AND PERIPHERAL NERVOUS SYSTEM sensitizers capable of producing an allergic status in
exposed workers remains relatively poor.48,49 Specific IgE
The classical BEM markers associated with nervous system measurements in sera have a long history in aiding or con-
toxicity are the inhibition of the blood cholinesterase firming the diagnosis of allergy or confirming sensitization
enzymes, namely plasma butyrylcholinesterase (BChE) and to a specific chemical or protein. The sensitivity and speci-
erythrocyte acetylcholinesterase (AChE) for anticholinergic ficity of specific IgE in reflecting symptoms or clinical
pesticide exposure. Such pesticides inhibit AChE, mainly diagnosis of respiratory allergy appears much better for
found at neuromuscular junctions and cholinergic synapses proteinaceous allergens than low molecular weight chemi-
in the central nervous system, where its activity serves to cals, where the sensitivity of specific IgE tests appears
terminate synaptic transmission. Excessive absorption of poorer. The restricted availability of radiolabelled anti-
anticholinergic pesticides, namely organophosphate (OP) human IgE and the availability of large automated analy-
and carbamates, block the function of acetylcholinesterase sers for immunoassays in hospital laboratories has
and thus cause excessive acetylcholine to accumulate in the meant that the radioallergosorbent test (RAST) has been
synaptic cleft, causing a number of symptoms in various superseded by non-isotopic commercial assays for specific
body functions, but potentially leading to death by asphyx- IgE measurements. These commercial non-isotopic assays
iation through neuromuscular paralysis.40 cover both occupational and environmental allergens that
Monitoring is based on identifying an OP-induced can be used to investigate an individual’s sensitization
depression in the enzyme activity of AChE and BChE. status (Table 5.3), but tend to focus on commonly encoun-
Given the extent of normal, physiological inter- and tered allergens. Therefore, IgE tests add to symptom ques-
intraindividual variation, especially in BChE, OP-induced tionnaires, longitudinal peak expiratory flow monitoring
depressions are detected through comparisons with base- in the workplace and, in the clinical setting, bronchial chal-
line, unexposed measurements or changes in serial meas- lenge testing that can be used to investigate an individual
urements within an individual.41 There have been attempts with asthmatic-type respiratory symptoms.50 Specialized
to produce a BChE monitoring system, based on specific flow cytometry analysis also allows measurement of the
activity measurements, that does not rely on serial moni- T-cell populations, including the TH1/TH2 balance, and
toring within an individual.42 While this more complex T-regulatory cells, which have been implicated in the
specific activity measurement does not show a substantial mechanism underlying sensitization and symptoms of
improvement in sensitivity over the simple enzyme meas- asthma.
urement to detect OP-induced inhibition, it has value in In contrast to specific IgE, the measurement of specific
detecting subclinical OP exposures where baseline meas- IgG to proteins and low molecular weight has tended to be
urements are not available. seen as only indicating significant, historical exposures
While AChE in erythrocytes is the same enzyme as that which the immune system has recognized and responded
inhibited by OPs in nervous tissue and neuromuscular to, without necessarily reflecting an altered increased risk
junctions causing their frank toxicity, it is usually less of work-related respiratory disease.51,52 However, recent
sensitive than BChE in terms of absorption and inhibition evidence in a longitudinal study of paint sprayers exposed
by OPs, so BChe is often also measured, or is the sole BEM to di-isocyanates has suggested that increases in specific
measurement. While BChE is sensitive to OP (and carba- IgG and IgG4 appear to have a protective effect on the
mate) inhibition, BChE inhibition has no toxicological incidence of work-related lower and upper respiratory
relevance in itself and the relationship between BChE symptoms, respectively.53
inhibition and the risk of, or actual severity of OP poison- Other toxic effects on the lung have been identified
ing is weak, with very significant inhibition of BChE having in the occupational context, largely through the use of
been noted in the presence of minimal symptoms.43 The symptom questionnaires and simple physiological meas-
relationship between erythrocyte AChE and symptoms/ urements, such as FEV1, out of a much larger armoury of
toxicity is much better. Thus, in this case, two BEM mark- diagnostic procedures used clinically. Biochemical markers
ers may be employed together to monitor workers using were only measured in an aggressively invasive sample,
OP pesticides, with one marker a closer index of exposure such as bronchial lavage fluid, which has no role in any
and the other of toxicity. Alternative BM for anticholinergic routine occupational monitoring strategy. However
OP exposure can be based on either a specific metabo- recently, interest has been stimulated in the measurement
lite44,45 or a generic group of metabolites, such as urinary of specific lung proteins in blood plasma as biomarkers of
alkyl phosphates, that can certainly detect OP absorption toxicity in the lung. The change in plasma levels of these
far more sensitively than using BChE depressions.18,46,47 ‘pneumoproteins’ generally reflect the relationship between
the increased synthesis or depletion of the proteins in the
RESPIRATORY AND LUNG BIOMARKERS lung and alteration in the integrity of the blood–airspace
barrier within the lung.
Respiratory sensitization and occupational asthma The proteins most investigated are the lung surfactant
remains a significant occupational problem. The ability proteins (e.g. SP-A, SP-B and SP-D) involved in the innate
to predict, or test, whether chemicals may be respiratory immune response system of the lung, Clara cell protein
Biological effect monitoring 67
Table 5.3 Routine specific IgE tests available for a range of occupational allergens. Other, less common tests may be available through
discussion with the laboratory supplying analyses.
Occupational allergens
(CC16) and KL-6 (Krebs von den Lungen-6). Serum levels as it is also increased in lower respiratory tract inflammation
of the immunoregulatory CC16 protein are derived from and chronic bronchitis, an increased level may be useful in
secretions of Clara cells, largely found in the bronchio- differentiating asthma from other causes of chronic cough.
tracheal tree, with passive transudation of the CC16 Its diagnostic value in distinguishing between healthy sub-
through the lung–blood barrier. Decreases in serum CC16 jects with or without respiratory symptoms and patients
in chronic exposure to gases and dusts reflect the sensitiv- with confirmed asthma has been identified with a speci-
ity of Clara cells to toxic insult. Increases in serum SP-A or ficity of 90 per cent and positive predictive value of 95 per
SP-D are ascribed to increased lung–blood membrane per- cent using a NO cut-off of 1 5 ppb in exhaled breath.60
meability by toxic insult. Such pneumoproteins continue Furthermore, non-volatile biomarkers can be con-
to be investigated in the clinical context,54 and a number of densed from exhaled breath and analysed. The collection
research studies relevant to occupational exposure and of this exhaled breath condensate (EBC) for analysis of
using serum measurements are now being published.55–58 non-volatiles is somewhat more difficult and involved
Whether these invasive biomarkers, using blood measure- than direct measurement of volatiles in exhaled breath.
ments, may move from research studies into routine occu- Standardized physiological conditions for collection, the
pational monitoring or health surveillance, is unclear. development of more robust, cheaper collection equip-
However, these tests do show a high degree of specificity ment and high sensitivity methods for measuring the
for reflecting abnormalities in the lung. biomarkers in the EBC are necessary.61 Thus, the technique
Other recent interest has been in the analysis of exhaled remains at a research stage, but recent work has shown the
breath in inflammatory lung diseases, including asthma, potential for the non-invasive measurement of inflamma-
chronic obstructive pulmonary disease (COPD) and inter- tory markers61–63 reflecting pathophysiology in the lung.
stitial lung diseases.59 Analysis of various biomarkers, While biomarkers in EBC are in their infancy, with their
including volatile chemicals and gases such as nitric oxide relevance and use within an occupational context still to be
(NO), carbon monoxide and many non-volatile molecules, completely mapped out, publications with direct relevance
such as inflammatory markers/mediators, oxidation and to occupation are beginning to appear.64–67
nitration products in exhaled breath allows non-invasive
monitoring of inflammation and oxidative stress in the res- RENAL MARKERS
piratory tract. The measurement of NO in exhaled breath
can be increasingly measured using available, relatively low A number of specific chemicals such as mercury, cadmium
cost equipment, with some devices having Food and Drug and more diffuse ill-defined chemical occupational expo-
Administration (FDA) approval for monitoring asthma sta- sures, such as solvents, have been associated with occupa-
tus.60 While NO in exhaled breath is not specific for asthma, tional exposure and renal toxicity.68–70
68 Biological monitoring
Serum creatinine, more recently cystatin C, and urinary exposure conditions, and may have a large genetic
albumin and total protein are accepted biomarkers of component. Large increases in urine levels of high molecu-
altered glomerular filtration rate and glomerular perme- lar weight proteins, which are not usually filtered by the
ability, respectively. They are the classically used general glomeruli, and cellular proteins (such as NAG) are a
clinical biomarkers reflecting such pathological alterations, marker of the glomerulopathic and general inflammatory
but without any relationship to any occupational involve- nature of this mercury-associated condition, but there
ment of chemical exposure. appears no good evidence that regular monitoring of, for
Over a number of years, there have been investigations example, urinary albumin can predict or identify early
into possible early renal biological effect markers reflecting development of the mercury-induced glomerulonephritis.
the various renal effects of chemical exposures, and a num- However, mercury as a general nephrotoxicant can cause
ber of markers have been suggested as of potential value.71–73 some increase in the excretion of proteins and enzymes
These markers are usually urinary protein or enzymes (e.g. suggesting some subclinical toxicity.87,88 There is some
N-acetylglucosaminidase) reflecting direct renal cellular evidence that occupational mercury exposure leads to
damage, functional changes (e.g. albumin, retinol-binding small reversible increases in urinary enzymes, such as
protein, transferrin), structural components (e.g. colla- urinary N-acetylglucosaminidase.89 This probably reflects
gen/laminin fragments) or induction of protection mecha- that NAG is a lysosomal enzyme involved in the normal
nisms (e.g. metallothionein). However, currently there is process of exocytotosis of heavy metals from renal tubular
no universal agreement on a validated panel of effect cells into forming urine, possibly together with other
biomarkers that may be suitable to detect or monitor tubular cell membrane enzymes.
chemical-induced nephrotoxicity in the context of occupa-
tional and environmental exposure. Neutrophil gelatinase- BLADDER
associated lipocalin (NGAL) appears increasingly useful
in clinical nephrology74 and specifically as a sensitive The bladder as a site of occupational toxicity has been
marker of clinically encountered nephrotoxins, such as sustained largely by the actual and suspected additional
contrast media,75 cisplatin.76 Increases in urine NGAL risk of bladder cancer in those exposed to a number of
have been found to precede changes in urinary NAG and toxic chemicals, including rubber fumes, dyes and various
β2-microglobulin, or serum creatinine.77 Even more aromatic amines, including those in cigarette smoke.90,91
recently, kidney injury molecule-1 (KIM-1) has been Urine cytology in normally voided urine has been histori-
found to be a sensitive marker of tubule-interstitial cally part of health monitoring or health surveillance for
damage.78–80 Thus, NGAL and KIM-1 appear potential current and ex-workers in high-risk industries. However,
useful candidate damage markers in terms of monitoring in order to get meaningful analysis, there is a need for
occupational or environmental exposure to nephrotoxins fresh urine samples to be delivered to a centre where there
to add to the tests historically employed. is the appropriate expertise in this microscopical analysis.
Urinary biomarkers, such as the low molecular weight Centralization of hospital pathology units in the United
proteins, retinol-binding protein (RBP), β2-microglobulin Kingdom has increased the logistic difficulties in pro-
(with its more pH-dependent stability problems) and viding such occupational monitoring for workforces or
alpha-1-microglobulin reflect abnormality in the specific ex-employees. Also urine cytology, while it has high sensi-
renal tubular process of protein reabsorption and are widely tivity in detecting high-grade tumours, has low sensitivity
used to monitor the possible effects of cadmium.17,81,82 in detecting low-grade tumours.92
Cadmium is a cumulative nephrotoxic where its concen- There has been considerable clinical effort in investigat-
tration within the nephron finally overcomes defensive ing molecular biomarkers that might reduce the need
mechanisms and leads to measureable changes in reab- for periodic, invasive cystoscopies or, ideally, offering
sorptive processes in the proximal tubule.20,83 Significant a non-invasive test with better sensitivity than urine
cadmium-induced effects appear non-reversible; however, cytology. Recently, some urinary biomarkers have been
the ability to measure very small induced changes in the suggested as fulfilling a similar role, based on the excre-
proximal tubular process of low molecular weight protein tion of altered cellular process and components at the
reabsorption does allow exposure modification in an indi- pre-cancerous and cancerous stages. Some commercially
vidual at an early stage to save the latter, grosser cadmium- available biomarkers, e.g. BTA, ImmunoCyt™, NMP22
induced changes due to the loss of substantial numbers and UroVysion™, have already been approved by the US
of functioning nephrons. FDA for bladder cancer surveillance, while many other
In contrast, mercury, another acknowledged metal markers are still undergoing development for preclinical
nephrotoxin, does not have suitable specifically associated and clinical investigation. However, the clinical trial data
BEM biomarkers, as with cadmium. Mercury has been on the majority of these markers are conflicting in terms
associated with an immunologically mediated, rapidly pre- of their diagnostic power compared against cystoscopy
senting glomerulonephritis84 or nephrotic syndrome,85,86 as the gold standard diagnosis. Individual case–control
with little clear understanding of dose–response rela- studies have produced indices of diagnostic power for one
tionships, except that it is rare in current occupational or more biomarkers, e.g. NMP22 has been shown to have
Biological effect monitoring 69
Table 5.4 A review of published sensitivities and specificities neither urine cytology nor proposed biomarkers can be
for commercially available ‘new’ biomarkers for bladder cancer. considered as early markers reflecting a reversible stage.
While there is some evidence that susceptibility markers
Test Sensitivity Specificity
related to metabolism (NAT-2), slow metabolism and
(%) (%)
GST null/low activity may indicate some increased risk
of bladder cancer in those exposed to carcinogenic
Novel commercially available biomarkers arylamines.38 Such tests of susceptibility remain in the
BTA Stat (point-of-care device) 53–78 69–87 research arena, with concerns about their ethical applica-
BTA Trak (laboratory test) 51–100 73–93 tion and interpretation in workforces.
NMP22 Bladder Cancer Test
(laboratory test) 35–100 60–95
LIVER
NMP22 BladderChek 50–65 40–90
(point-of-care device) The panel of liver function routinely used in clinical
ImmunoCyt/uCyt 63–85 62–78 diagnosis has also been employed in monitoring workers
ImmunoCyt/uCyt and cytology 81–89 61–78 exposed to hepatotoxic chemicals. These tests include ala-
UroVysion 69–100 65–96 nine transaminase (ALT), aspartate transaminase (AST),
Traditional tests gamma glutamyl transferase (GGT), alkaline phosphatase
Cytology 12–85 78–100 (ALP) and bilirubin.96 Such tests reflect heptocellular
Haematuria by dipstick 47–93 51–84 damage (ALT, AST), bile duct obstruction and cholestasis
(ALP, bilirubin). GGT is a microsomal enzyme widely
distributed in the liver and hepatobiliary tree, as well as
other organs. It is sensitive to enzyme-inducing drugs and
sensitivity and specificity of 76 and 87 per cent, respec- chemicals, and can also be elevated in chronic alcohol con-
tively, in diagnosing transitional cell carcinomas, although sumption. Other tests in this standard liver function test
the sensitivity does decrease significantly for the lowest (LFT) panel may also show some abnormalities due to
staging.93 However, a review of such studies (Table 5.4),94 chronic alcohol abuse. There is a lack of published evi-
while suggesting that the novel markers tend to have better dence about the value of such a panel of tests in detecting
sensitivity than voided urine cytology (although traditional early occupational hepatotoxic effects, and the frequency
voided urine cytology generally has high specificity) high- of idiopathic low level abnormalities in such tests unre-
lighted the variation in reported sensitivity and specificity lated to liver disease has been highlighted.96 The prevalence
between studies for individual biomarkers. They suggested of alcohol abuse in many communities means that any
that the variation in sensitivity and specificity was due abnormalities in such LFT in workers, and especially the
to varying case definitions between studies. The use of highly inducible GGT, may be unrelated to occupational
cross-sectional studies with cystoscopy as the ‘gold stan- exposure,97 or that effects of occupational exposure may
dard’ to validate these new bladder biomarkers has also be masked.
been criticized.95 If the occupational physician considers that the identifi-
In general, the uptake of such tests in clinical diagnosis cation of chronic alcohol abuse is legitimately part of
has been relatively low, although with wide international their role in maintaining a healthy workforce, then identi-
differences. This probably reflects that none evaluated over fication of workers with such problems can be done
the last years showed remarkable improvements in sensi- with better sensitivity and specificity by the measurement
tivity or specificity for the identification of any of the of serum carbohydrate-deficient transferrrin (CDT). This
diverse types of bladder cancer in clinical practice.92 can also be used in the monitoring of compliance by any
A combination of tests may be necessary for screening in workers undergoing an alcohol abstinence regime.98,99
occupational cohorts at risk, in order to detect real cases of Serum bile acid measurements have had some use as
bladder cancers, without causing concern to much larger sensitive routine liver function tests. It has also been shown
numbers of normal subjects through false-positive results. that bile acids can be measured in urine, and reflect serum
Some of these new commercially available biomarkers levels, therefore there is the potential for a non-invasive
(e.g. NMP22) have begun to be used in the United States, measurement of liver function,100,101 particularly in detect-
Europe and Japan in specifically monitoring occupational ing chemically induced cholestasis.
cohorts considered at risk. However, the evidence is scant Other widely available tests for potential occupational
for the value of traditional tests, such as voided urine cytol- hazards involving liver abnormality include immunoassays
ogy and detection of microscopic haematuria. Similarly, for antibody status in those exposed to hepatitis B or
there is lack of evidence for the effectiveness of newer hepatitis C or determination of antibody titre in high-risk
FDA-approved biomarkers, in screening current and past occupational groups who undergo protective immuniza-
workers identified with occupational risk factors in order tion regimes, e.g. for leptospirosis. DNA-based detection
to detect bladder tumours at an early stage. This is essential tests offer potential advantage over tests based on antibody
for improved prognosis and long-term survival. As such, detection for early diagnosis of leptospirosis102 since
70 Biological monitoring
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54. Tzouvelekis A, Kouliatsis G, Anevlavis S, Bouros D. Serum detect significant effects of environmental and
biomarkers in interstitial lung diseases. Respiratory occupational exposure to nephrotoxins. 3. Minimal battery
Research. 2005; 6: 24. of tests to assess subclinical nephrotoxicity for
55. Hamaguchi T, Omae K, Takebayashi T et al. Exposure to epidemiological studies based on current knowledge. Renal
hardly soluble indium compounds in ITO production and Failure. 1997; 19: 535–52.
recycling plants is a new risk for interstitial lung damage. 72. Taylor SA, Chivers ID, Price RG et al. The assessment of
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56. Nogami H, Shimoda T, Shoji S, Nishima S. Pulmonary database. Environmental Research. 1997; 75: 23–33.
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Vasculitis and Diffuse Lung Diseases. 2005; 22: 51–7. (NGAL): A new marker of kidney disease. Scandinavian
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SECTION THREE
DAVID COGGON
difficult to decide whether or not a tumour is malignant, number of deaths from all causes is sometimes used as a
most people can be classified with some confidence as being proxy index of the population at risk. Thus, we might com-
either cases or non-cases of cancer. Many other disorders pare the proportion of all deaths that were ascribed to
occur in a continuous spectrum of severity, in which the dis- pleural mesothelioma in carpenters with that in other
tinction between normality and abnormality is ill defined. occupations. This use of proportional mortality is less sat-
For example, it is debateable at what point mild impairment isfactory than analysis based on mortality rates insofar as
of hearing on audiometry should be classed as deafness, or the total number of deaths in a population depends on its
how much lower than the expected value forced expiratory overall (all cause) death rate, as well as its size (see Routine
volume in one second (FEV1) should be before a patient is surveillance of occupational mortality, p. 84).
considered to have chronic obstructive pulmonary disease
(COPD). However, to simplify their consideration, dis- Crude and specific rates
orders of this type often are also classified dichotomously, so Disease rates may be ‘crude’ (i.e. relating to a population in
that, for example, a person is deemed either to be a case of its entirety), or sex- and age-specific (i.e. relating to specific
COPD or not. Where this dichotomization is performed, the subsets of the population defined by sex and age). Because
definition of a case should be unambiguous, even if some- the occurrence of most disorders varies substantially by
what arbitrary. Otherwise, findings cannot be interpreted sex and age, sex- and age-specific rates usually allow more
satisfactorily. useful comparison between populations than crude rates.
They can, however, be rather unwieldy, especially if there
Incidence, mortality and prevalence are a large number of sex and age strata in an analysis.
Various measures are used to summarize the frequency with
which disease or illness occurs in populations. The inci- Standardized rates
dence of a disorder is the rate at which new cases occur over One way of overcoming this difficulty is to summarize
a defined period of time. For example, in 2004, the incidence the sex- and age-specific rates for each population by a
of newly diagnosed mesothelioma among men in England weighted average, the weighting factors being derived from
was 6.2 per 100 000 per year. The mortality or death rate the demographic distribution of a defined ‘standard popu-
from a disease is the incidence of deaths for which it is lation’. This technique is known as direct standardization.
thought to be the underlying cause. The prevalence of a dis- Another method of accounting for sex and age when
order is the proportion of a population who are cases at a summarizing disease occurrence in a population is indirect
defined point in time or over a defined period. For example, standardization. Here, the number of cases that occur in
the prevalence of low birthweight (2.5 kg) in a sample of the study population over a defined period is compared with
babies born over the course of two years might be 5 per cent. the number that would have been expected had the study
In contrast to incidence, which relates to an event (becom- population experienced the sex- and age-specific rates of a
ing a case), prevalence refers to a state (being a case). defined standard population. The ratio of observed to
Each of the above measures has its particular applica- expected cases, expressed either as a decimal or as a percent-
tions. Incidence is the index of disease occurrence that is of age, is known as a standardized morbidity ratio, or if the
most immediate relevance to understanding of causation. cases are deaths, standardized mortality ratio (SMR).
For reasons of practicality and availability of data, mortal-
ity or prevalence may sometimes be used as a proxy for
incidence in studies of causation, but care is then needed in Measures of association
interpretation. For example, a factor might be associated
with increased mortality from a disease not because it Much of epidemiology involves comparing rates of disease
increases people’s risk of developing the disorder, but or illness between populations. For example, to assess the
because it makes them more likely to die from it should risk from a chemical in the workplace, the incidence of
they get it. Similarly, a factor could be associated with a adverse outcomes might be compared in people with dif-
higher prevalence of a disease because it delays recovery or ferent levels of exposure to the chemical. Various measures
promotes survival (i.e. people remain cases for longer) can be used to summarize associations between risk factors
rather than because it increases incidence. (characteristics or exposures that might influence or pre-
dict the risk of a health outcome) and health outcomes.
Proportional mortality Attributable risk is the difference in risk between some-
All of the measures that have been described are rates in one who is exposed to a risk factor and someone who is not.
which the occurrence of cases is related to a population ‘at According to the nature of the health outcome, this might
risk’. Sometimes, however, the size of the population that correspond to a difference in incidence, mortality or preva-
gives rise to a group of cases is unknown. For example, we lence rates between exposed and unexposed populations.
may know from death certificates how many carpenters Attributable risk is the measure of association that is most
died from pleural mesothelioma in Scotland over the relevant to the management of risk for the individual. For
course of a year, but not the total population of carpenters example, when deciding whether or not it is acceptable for
from which these cases came. In these circumstances, the a person with a history of asthma to work with a respiratory
Concepts and terminology 79
sensitizer, it is the attributable risk of illness and disability systematic tendency to underestimate or overestimate a
from undertaking the job that must be considered. parameter of interest because of a deficiency in the design or
Relative risk is the ratio of risk in a person who is exposed execution of a study. It may arise, for example, if the study
to a risk factor to that in someone who is unexposed. This sample is systematically unrepresentative of the wider popu-
corresponds to a ratio of incidence, mortality or prevalence lation because of the way in which it has been recruited, or if
rates in exposed relative to unexposed populations. the information about risk factors or health outcomes in the
An odds ratio compares the odds of a health outcome in study sample is inaccurate. Because of the practical con-
people with and without an exposure (odds being defined straints on research in human subjects, complete elimin-
such that a risk of 1/N equates to odds of 1/(N 1). In most ation of bias from epidemiological studies is virtually
circumstances, odds ratios approximate closely to relative impossible. However, studies should be designed to min-
risks. Unlike relative risks, however, they can be estimated imize bias and their interpretation should take into account
directly from case–control studies (see Case–control stud- the possible impact of any bias that remains. It should be
ies, p. 83). noted that bias is specific to the parameter that is being esti-
Population attributable fraction is the proportion of mated. A low response rate from people invited to take part
cases in a population that would be eliminated if risk of the in a study might seriously bias estimates of one parameter,
health outcome in exposed people were reduced to that in while not materially influencing estimates of another.
the unexposed. It is useful in characterizing the impact of a
causal factor in a population, and therefore in the manage- CHANCE
ment of risk at a population level.
The attributable fraction in exposed persons (AFexp) is Even where the method of recruitment to a study is
the proportion of cases among exposed members of a popu- unbiased with regard to the parameter of interest, the study
lation that would be eliminated if their risk of the health sample may still be unrepresentative simply by chance.
outcome were reduced to that of the unexposed. It pro- Thus, another study sample selected in a similar fashion,
vides an index of the confidence with which a disease can but perhaps a different time period, would not be expected
be attributed to a causal factor in a case that has been to give exactly the same estimate for the parameter. The
exposed to that factor. For example, if the AFexp for lung scope for chance variation of this type depends partly on the
cancer from a given exposure is greater than 0.5, this size of the study sample. Other things being equal, larger
implies a more than 50 per cent chance that lung cancer samples are less likely to be unrepresentative by chance than
occurring in an exposed person would not have occurred smaller samples. Therefore, studies should be designed to
in the absence of the exposure. AFexp is thus relevant to ensure that they have adequate size and ‘statistical power’.
decisions about compensation for occupational diseases. Furthermore, the uncertainties relating to chance variation
It is related to relative risk (RR) by the formula: between samples must be taken into account when inter-
preting studies. This will be assisted by calculations of stat-
AFexp (RR 1)/RR istical significance or (more informatively) of confidence
intervals around parameter estimates.
Considerations in the design and
interpretation of epidemiological studies STATISTICAL SIGNIFICANCE
POPULATIONS AND SAMPLES A test of statistical significance starts with a ‘null hypothesis’
about the wider population to which the findings of the
Epidemiological investigations normally collect and analyse study will be extrapolated (e.g. that there is no association
data from a sample of individuals or populations with the between occupational lifting and hip osteoarthritis in this
aim of drawing conclusions that apply more widely. For wider population). With the assumption that this null
example, a study might assess the association between hypothesis applies, it then calculates the probability of
occupational lifting and hip osteoarthritis in a sample of obtaining findings as or more extreme than those observed
people selected from the general population, with the aim in the study sample, simply through chance variation in
of characterizing the association in the population as a sample selection. If this probability (p-value) is low, the null
whole. A ‘statistic’ for the study sample (the relative risk of hypothesis becomes less tenable, and may be rejected in
hip osteoarthritis from occupational lifting in the sample) favour of an alternative (e.g. that occupational lifting is truly
is used to estimate a corresponding population ‘parameter’ associated with hip osteoarthritis).
(the relative risk of hip osteoarthritis from occupational
lifting among people in general). CONFIDENCE INTERVALS
calculated in such a way that, in the absence of bias, 95 per STUDY DESIGNS
cent of study samples would be expected to produce confi-
dence intervals that included the true value of the population The most natural way to test a causal hypothesis or to quan-
parameter. Because they are less likely to be unrepresentative tify the impact of a cause on an outcome is to conduct a
by chance, larger samples tend to give tighter confidence planned experiment. For ethical reasons, human experi-
intervals. mental studies are not widely used in occupational health
research – it is not usually acceptable deliberately to expose a
CONSISTENCY WITH OTHER STUDIES volunteer to a hazardous agent. However, experimental
studies have been used to assess the benefits of strategies to
Importantly, assessment of the possible contribution of prevent illness, to investigate determinants of exposure
chance to the findings of a study depends not only on statis- when handling hazardous materials, such as pesticides
tical analysis of the data obtained in the study, but also on (using an innocuous surrogate marker such as a dye), and to
the weight of relevant evidence from other research, both explore biochemical consequences of exposure to hazardous
epidemiological and in other disciplines. For example, an chemicals at levels well below those at which any adverse
association between a chemical and cancer might be attrib- effects on health would be expected. More often, occupa-
uted to chance even though it was statistically significant (i.e. tional studies are observational in nature. In other words,
carried a low p-value), if other similar epidemiological stud- the investigator does not change participants’ exposures as
ies had found no association and toxicological testing in ani- part of the investigation, but rather studies people as they
mals did not suggest that the chemical was a carcinogen. happen to have been exposed. Some observational studies
analyse data at a population level (ecological studies), but
CONFOUNDING most collect and analyse information about individuals.
with regard to potential confounding factors (including exposure is introduced. If there are differences between the
even those of which the investigator is unaware). However, intervention and control groups before exposure, perhaps
if desired, even tighter control on confounding can be because of unrecognized confounders, these can then be
ensured by stratifying subjects before randomization, controlled statistically when evaluating the impact of the
according to important determinants of outcome, and by intervention.
‘blocking’ the randomization so that within each stratum,
there is always a close balance between the numbers of sub-
jects assigned to each exposure. For example, exposures to Ecological studies
two interventions might be randomly allocated within suc-
cessive blocks of six (three to each intervention). In this Ecological studies are observational investigations which
way, within the matching stratum, the difference in num- collate and analyse information about exposures and/or
bers assigned to each exposure would never be greater than health outcomes at a population level. For example, a study
three. might compare death rates from pleural mesothelioma in
different countries according to their historical rates of
importing asbestos and asbestos products. In occupational
Randomized crossover studies epidemiology, ecological studies are most often based on
populations defined geographically, by occupation, by
A special type of randomized experiment is the random- time or by combinations of these variables. They have the
ized crossover study, a design in which each subject serves advantage that the data used are often readily available
as his or her own control. The method is appropriate for from routinely published statistics. However, because the
investigation of short-lived effects of exposure. Again, sub- information is only for populations and not individuals,
jects who meet specified eligibility criteria are identified it may be difficult to control for possible confounding
and recruited (after giving informed consent). Each partici- effects. The main applications of ecological studies are in
pant then receives each of the exposures under investiga- monitoring trends, and in the generation and early explor-
tion sequentially, but in a randomly determined order ation of causal hypotheses.
(often with a ‘wash-out’ period between successive expos-
ures). Outcomes are assessed during or immediately after
each exposure, and are compared. Because comparisons
Cohort studies
are within rather than between participants, the method is
particularly suited to investigation of subjective outcomes
In a cohort study, individuals who differ in their exposure
such as levels of pain, especially if the subject can be
to known or suspected risk factors for a health outcome are
blinded to the exposure received.
identified. They are then followed up systematically to
ascertain the subsequent occurrence of the outcome, which
Non-randomized controlled experiments is compared according to the earlier presence or level of the
risk factors. For example, a ‘cohort’ of pregnant women
The benefits of randomization in control of confounding might be identified when they attend hospital for antenatal
are only realized when the randomization is carried out on care, and their exposure to occupational activities during
a sufficiently large scale. If 200 subjects are randomly allo- the first trimester of pregnancy assessed. They could then be
cated, half to one exposure and half to another, it is unlikely followed up systematically to term, and the prevalence of
statistically that there will be a major imbalance of con- outcomes, such as preterm delivery and low birthweight,
founding factors between the two exposure groups. compared according to their activities early in pregnancy.
However, this does not apply where the number of units Where the outcome in a cohort study is the incidence of a
randomized is small. For example, in a study to evaluate an disease (or a proxy for incidence such as mortality) esti-
ergonomic intervention involving the installation of new mates can be made of both attributable and relative risk.
lifting equipment in workplaces, only six workforces might The subjects in a cohort study may be selectively sam-
be available for study. If three workforces were randomly pled according to their exposure to risk factors of interest.
allocated to the intervention and three to serve as a control, For example, a study might follow up a group of workers
there could easily be important differences between the chosen because they were known to have high exposure to
workers in the two exposure groups just by chance. In this lead and a control group who were unexposed to the metal
situation, it would be better to use a non-randomized in their work. Alternatively, the cohort may be selected
experimental design, in which allocation of the intervention from the general population without regard to likelihood or
to workforces was carefully planned in a way that minim- levels of exposure. A well-known example of this approach
ized such differences between the intervention and control is the Framingham study, which has followed up adult resi-
groups. dents of the town of Framingham in Massachusetts over
Sometimes non-randomized controlled experiments many years, collecting information about a wide range of
can be further enhanced by including a comparison of risk factors (including occupational exposures) and health
exposure groups both before and after the experimental outcomes.1
82 Epidemiological methods and EBM
Various sources of information can be used to character- they are based on large numbers of cases). However, it is
ize exposures in cohort studies, including employment important that the method for ascertaining cases in the
records (giving data on job history), questionnaires, direct study cohort be similar to that for the general population
observation (e.g. of physical activities at work), environ- (e.g. both based on cancer registrations) or risk estimates
mental or personal monitoring of exposure to chemical or will be liable to bias. A further limitation may be a lack of
physical hazards, and measurement of relevant biomarkers information about important confounders in the general
in tissues and body fluids. Sometimes, the assessment of population.
exposure is made at a single point in time and sometimes In cohort studies that compare mortality or cancer inci-
information about exposure is collected on repeated occa- dence with rates in the general population, risk estimates are
sions over a period of time. Often in occupational cohort often presented in the form of standardized mortality ratios
studies, the classification of exposures combines informa- (SMRs) or standardized incidence ratios (SIRs) based on a
tion on individual occupational history with generic data person-years analysis. This involves computing the time that
on patterns of exposure in different jobs (and perhaps time each cohort member was at risk (i.e. under follow up and
periods) held in the form of a ‘job–exposure matrix’. Where eligible to become a case if he/she developed the relevant
possible, information is collected about potentially con- health outcome) for different combinations of sex, age and
founding exposures, as well as the risk factors of primary calendar period. The person-years at risk for each combin-
interest. Their effects can then be taken into account statis- ation are summed across all cohort members, and multiplied
tically when the study is analysed. by the corresponding sex-, age- and calendar period-specific
Methods for ascertaining health outcome vary accord- outcome rates in the comparison population to give an
ing to the nature of the outcome. They include the use of expected number of cases for that combination. These
health records (e.g. cancer registrations), death certificates expected numbers are then summed across all combinations
(which give causes of death), questionnaires, physical of sex, age and calendar period to derive an overall expected
examination and clinical investigations (e.g. spirometry, number of cases. The ratio of the number of cases observed
radiographs or biochemical measurements). to the number expected is the SMR or SIR.
A major strength of the cohort study method is the The second modification is to conduct the cohort study
assessment of exposures, which is the starting point for the retrospectively. With this approach, the cohort is defined
investigation and often more reliable than with other study according to historical criteria (e.g. all of the workers who
designs. The method is relatively efficient for the investiga- were employed at a particular manufacturing plant for at
tion of rare exposures, since participants can be selectively least six months during a specified period), and eligible sub-
sampled according to their known or likely exposures. jects are identified from preserved records. Health out-
Furthermore, if desired, the same study can often be used to comes are then examined in the time since each subject
examine multiple health outcomes with little additional fulfilled the criteria for entry to the study. To be amenable
effort. For example, a cohort study using cancer registra- to this approach, the relevant health outcome must be
tions to ascertain outcome, could provide information ascertainable at the time the study is conducted. For
about risk for each of a number of malignancies. On the example, in many countries, mortality by cause of death
other hand, cohort studies are less efficient for the investiga- can be established retrospectively from death certificates
tion of rare health outcomes, since large numbers of people and cancer incidence from records of cancer registrations.
must be followed for long periods in order that the number In other studies, the assessment of outcome may depend on
of observed cases is sufficient for meaningful statistical being able to trace and contact a sufficiently large and rep-
analysis. Prolonged follow up may also be required where a resentative proportion of the original cohort so that they
hazardous exposure only increases the risk of a health out- can be questioned about their health during the follow-up
come after a long latent interval. For example, most occupa- period or examined for changes in health measures, such as
tional cancers do not occur in excess until ten or more years pulmonary function. Importantly, the identification of the
after people are first exposed to the relevant carcinogen. cohort should not depend on factors associated with subse-
Two modifications to the cohort study method some- quent health outcome. For example, a retrospective cohort
times help to address these limitations. One involves the use study of lung cancer at a coke oven could be seriously biased
of incidence or mortality rates in the general population as if the records of ex-employees who were known to have
a comparator for disease experience in a cohort exposed to died had been selectively removed from archived files.
a risk factor. For example, the incidence of leukaemia in a While the main use of cohort studies in occupational
cohort of hospital employees exposed to the sterilant, ethyl- medicine is to identify and characterize occupational
ene oxide, has been compared with that expected from causes of disease, they may also inform decisions in case
cancer registration rates in the national population.2 This management. For example, systematic follow up of a
approach is reasonable where relevant exposures in the gen- cohort of patients presenting with a first epileptic seizure
eral population are trivial in comparison with those experi- could provide information on the risk of further seizures
enced by the study cohort, and it has the advantage that the that was useful in deciding whether and when such indi-
rates for the general population that are used for compari- viduals should be allowed to drive professionally or work
son are readily available and statistically stable (because at heights.
Study designs 83
in each exposure category (and thereby the expected A major advantage of the case–crossover method is that,
numbers of cases) are estimated by sampling controls at because the subject serves as his or her own control, it
random from the total cohort. eliminates the potential for confounding by long-term
Apart from its efficiency, especially when the assessment characteristics that might complicate interpretation of a
of individual exposures is relatively costly, the case–cohort case–control study.
method has the advantage that it is readily amenable to
simultaneous investigation of multiple health outcomes.
Furthermore, if follow up is subsequently extended, only Cross-sectional surveys
the exposures of the new cases are required to update the
analysis (this is in contrast to the nested case–control In a cross-sectional study, information is collected from a
design, in which exposure would have to be characterized sample of individuals at a single point in time, about health
also for additional controls selected to match the new outcomes and/or exposure to possible determinants of
cases). However, bias could arise if the method for assessing health. The information obtained may relate to the sub-
the exposures of new cases differed from that carried out ject’s health or exposures at the time of the survey, or at
earlier for the baseline sample of cohort members. One rea- some time in the past. For example, a cross-sectional study
son why this might occur is that where exposure assessment might be used to assess the current prevalence of sen-
is limited only to new cases, the assessor cannot easily be sorineural deafness in a sample of adults from the general
‘blinded’ with regard to health outcome. population, and also their lifetime prevalence of exposure
to noisy working conditions. The people studied in a cross-
sectional survey may be selected without regard to their
Case–crossover studies exposure, or they may be chosen because they have known
exposures (e.g. to allow a comparison of health between
Case–crossover studies are used to investigate known and exposed and unexposed groups).
suspected causes that have only a short-lived impact on the Where information is collected about both exposures
risk of a health outcome. The method is in some ways simi- and health outcomes, the study can be used to investigate
lar to that of a case–control study, but instead of comparing their statistical association. However, care is needed in
cases with non-cases, the exposures of cases immediately interpretation. Because of the cross-sectional design, there
before development of the health outcome are compared may be difficulty in distinguishing the direction of cause
with those of the same individuals at some other time. Thus, and effect. For example, if barmen were found to drink
each subject serves as his or her own control (rather like in a more alcohol than other occupational groups, that could
randomized crossover experiment). A case–crossover design be because work in a job with ready access to alcohol
might be used, for example, to assess the risk of road traffic encourages higher consumption. On the other hand, it
accidents from using a mobile phone while driving. Drivers could reflect a tendency for people who enjoy alcohol pref-
who were involved in accidents would be asked about their erentially to seek work in bars. Also, there is a danger that
use of a mobile phone in the minutes before the accident, selection effects may distort associations. For example, a
and during one or more earlier control periods of similar cross-sectional comparison of the prevalence of asthma
duration. between people working with laboratory animals and unex-
The method is not as well developed and has not been as posed controls could be misleading if people who devel-
widely implemented as the other study designs described oped allergies to animal proteins tended selectively to move
in this chapter. In particular, more thought is needed on to other jobs because of their symptoms. Such people
the criteria by which control periods are optimally speci- would be under-represented in a cross-sectional sample of
fied. By analogy with the case–control method, one might laboratory workers, leading risks to be underestimated.
expect the control period to be representative (in terms of Despite these limitations, cross-sectional surveys can be
relevant exposures) of the times when the subject was ‘at a valuable source of information about the occurrence of
risk’ of becoming a case. However, statistical efficiency occupational illness and its causes.
may be increased if control periods are matched to case
periods for one or more potential confounders. Control
periods should then be representative of ‘at-risk’ times ROUTINE SURVEILLANCE OF OCCUPATIONAL
within the relevant stratum of matching. DISORDERS
A further challenge is that the subject will almost always
be aware of when the relevant health outcome occurred. One of the major applications of occupational epidemi-
Thus, assessment of exposures that depends on the subject’s ology is in the routine surveillance of work-related illness
recall cannot be blinded. This could bias estimates of risk if and disease. Information about the occurrence of occupa-
exposures in different time periods were not uniformly tional disorders is used to target and prioritize control meas-
remembered. It would not be a problem, however, where ures, and to monitor the success of preventive strategies.
the assessment of exposures was from contemporaneous The methods used to assess the frequency of occupa-
records rather than from memory. tional disorders vary according to the way in which they are
Routine surveillance of occupational disorders 85
related to work. Some diseases occur only as a consequence interpreted with appropriate caution, useful conclusions
of occupational exposure (e.g. coal workers’ pneumoconi- can be drawn.
osis, silicosis). For disorders of this type, the burden of dis- While it can be helpful to know the overall burden of a
ease attributable to work is indicated by its overall disease or illness that is attributable to an occupational
frequency in the population of interest. If the disease is exposure, it is often useful also to break down the total by,
commonly fatal, the required information could come for example, occupation, industry or geographical region.
from analysis of death certificates. If the disease normally This is possible with all of the approaches to monitoring
attracts social security compensation, its incidence may be that have been described.
indicated in social security statistics. Otherwise, some form
of reporting scheme may be required (see below).
Other disorders, although not specific to work, can never- Routine analyses of occupational mortality
theless be attributed to occupation with confidence in the
individual case, either because of specific clinical features One important source of information in the surveillance of
(e.g. the demonstration of skin sensitization to an agent occupational diseases is the routine analysis of occupational
found only in the workplace), or because the relative risk mortality at a national or regional level. Analyses of this sort
and AFexp for an occupational exposure are sufficiently have been carried out periodically in the UK for many
high that attribution can reasonably be assumed in any years,4 and have been performed also in the United States.5,6
case that has been exposed. In these circumstances, it is Their value lies not only in monitoring well-established
sufficient simply to ascertain and enumerate attributable occupational causes of mortality, but also in generating
cases. Again, social security statistics may be a useful source clues to previously unrecognized hazards. For example,
of information if the disorder is compensable (provided an increased risk of infectious pneumonia following occu-
that the uptake of compensation by eligible cases is suffi- pational exposure to metal fume first came to light in
ciently high and does not vary importantly over time). routinely generated statistics of mortality by cause among
Alternatively, attributable cases may be ascertained through welders.7
a reporting scheme designed specifically for surveillance Two methods of estimating risk have been applied in
purposes. For example, in the UK, the University of the routine analyses of occupational mortality carried out
Manchester has for some years operated a scheme in which in the UK. In the first, the analysis focuses on deaths occur-
cases of various occupational diseases are centrally notified ring in a period of up to five years surrounding a national
by nationally representative panels of physicians.3 census. Information about the number of deaths in a par-
More challenging is the situation in which a disorder is ticular occupation from a specific underlying cause is
caused by occupational exposures, but cannot be attributed obtained from death certificates (which in the UK include
to work with confidence in the individual case. For example, a record of the deceased’s last full-time job). This is then
lung cancer is a hazard of work in coke ovens, but the rela- compared with an expected number of deaths, calculated
tive risk is not so high that attribution can be assumed sim- by applying sex- and age-specific rates for the country as a
ply because a person with the disease has at some time whole to the estimated numbers of people in the occupa-
worked in a coke oven. Moreover, there are no special clin- tion nationally in the corresponding sex and age strata.
ical features that can establish coke ovens as the cause of These estimates of the populations at risk in each sex and
lung cancer in an individual case. For hazards of this type, age group are derived from information supplied by a
the burden of illness or disease that is attributable to work representative subset of participants in the census. The
can be established only by controlled comparisons of risk. ratio of observed to expected deaths gives a cause-specific
For example, the burden of lung cancer nationally from SMR for the occupation under study.
work in coke ovens could be estimated from a large The other method uses only information obtained from
case–control study of a nationally representative study death certificates. The number of deaths by cause in each
population. Alternatively, the attributable risk of lung cancer occupation is derived in the same way as for the SMR
from work in coke ovens might be estimated by comparing calculation described above. However, the expected
mortality rates in coke oven workers with those in other number of deaths for a given occupation and cause of
occupations (e.g. in a cohort study) and this risk estimate death is calculated by multiplying the sex- and age-
then combined with information on the national preva- specific proportions of deaths in all occupations combined
lence of employment in coke ovens. In practice, assessment that are ascribed to that cause by the number of deaths
of disease burden in this way is often far from straightfor- from all causes in the occupation of interest in the corres-
ward. In particular, since individual risk varies according ponding sex and age bands. In this case, the ratio of
to the level and timing of relevant exposures, it may be observed to expected deaths is a proportional mortality
difficult to extrapolate risk estimates from cohort studies ratio (PMR).
of workforces, which often have been chosen for study Each of these methods has its strengths and limitations.
because they have experienced unusually high exposures to A weakness of the SMR method is that data on occupation
a hazardous agent, to the patterns of exposure to the same for the numerator and denominator of the risk estimate
agent that occur nationally. Nevertheless, if findings are come from different sources, and this can lead to bias. For
86 Epidemiological methods and EBM
example, there is a tendency for the next of kin to promote EVIDENCE-BASED OCCUPATIONAL MEDICINE
their deceased relative when registering his or her death.
Thus, a shopkeeper might be described as a company Like other medical disciplines, occupational medicine is
director. Where this occurs, the effect will be to inflate both an art and a science. While practitioners always bring
SMRs for more prestigious jobs. Another limitation is that their own unique personal skills and expertise to their
SMR analyses can only be carried out for periods sur- work, their handling of occupational health problems
rounding a census year. The PMR method is not restricted should at the same time be consistent with the sum of rele-
in this way, but has the disadvantage that PMRs are influ- vant scientific evidence. Over recent decades, output from
enced not only by mortality from the cause of interest, but medical research, and specifically occupational health
also by the overall death rate in an occupation. For example, research, has grown rapidly, making it much more difficult
if an occupation had unusually low death rates from com- for the individual practitioner to keep abreast of and
mon causes, such as heart disease and cancer, its PMR for a assimilate new information as it becomes available. Even
rarer cause, such as fibrosing alveolitis, could be elevated with the help of computerized literature searches and elec-
even when it was not a hazard of the occupation. These tronic publication of papers, there is a limit to the material
limitations must be taken into account when interpreting that one individual can review for himself.
SMRs and PMRs from routine statistics of occupational To address this problem, increasing emphasis is now
mortality. given to formal secondary research, which attempts sys-
Similar methods of analysis can be applied to data on tematically to identify, collate and interpret published (and
occupation from cancer registrations to generate standard- sometimes unpublished) scientific evidence on questions
ized or proportional registration ratios (SRRs or PRRs). that are relevant to occupational health policy and practice.
However, this is only possible where reliable information Reviews of this type initially focused mainly on the assess-
about occupation is available for at least the majority of ment of hazard and risk from occupational exposures, and
cancers registered. were used to underpin regulatory policy, for example on
exposure limits. More recently, however, the application
of systematic reviews has extended to questions relevant
HEALTH OUTCOMES OTHER THAN to individual clinical decisions in the prevention and
DISEASE OR ILLNESS management of occupational disorders.
where appropriate, the additional reports are added to the repeatability. For example, a study showing a positive asso-
shortlist. This exercise not only guards against omission of ciation between an exposure and disease might suffer from
important publications, but also serves as a check on the a bias, the effect of which was to reduce risk estimates.
performance of the original search criteria. The identifica- If the findings from this study were downgraded because
tion of large numbers of new reports may suggest that the of the bias, the evidence for a hazard could be assessed as
search criteria need revision. Each of the reports in the weaker than it really was.
shortlist is then examined and summarized. The informa- Some guidelines for systematic review have attempted to
tion abstracted is that which relates to the study questions grade the strength of evidence provided by different study
and often this abstraction is facilitated by the use of a stand- designs, with for example, randomized controlled experi-
ardized format in which to record the information. ments ranking higher than cohort studies and cohort stud-
To reduce the chance of error, all stages of the process ies higher than case–control studies. However, while in
that are not automated are normally carried out independ- general, cohort studies are less prone to bias than case–
ently by at least two members of the study team and any control investigations, this is not universally true. Thus, it is
differences reconciled by discussion. better if the strength of evidence from each study is evalu-
Once the required information has been abstracted, it is ated on its own merits rather than according to simple rules
evaluated and synthesized. In some cases, the synthesis of thumb.
may extend to a formal meta-analysis in which summary
estimates of outcome measures are calculated with confi-
dence intervals. However, this is only appropriate where Translation into practice
the design of the primary studies is sufficiently uniform, a
requirement that is more often met for randomized con- Once an evidence-based review is completed, its value will
trolled experiments than for the observational studies that only be realized if its findings are translated into policy or
are more common in occupational health research. Where practice. Where the express purpose of the review is to
studies addressing the same question produce apparently inform regulation, this is usually straightforward, but where
discordant results, possible explanations should be con- the aim is to guide the practice of individual healthcare
sidered systematically (Table 6.1). workers or managers, a planned communication exercise
Some systematic reviews specify criteria in advance that may be required. The methods used will depend on the
will be used to grade the quality of studies, and greater target audience, but may be assisted by early involvement
weight is then given to findings from those that are classed and commitment of representatives from the groups whose
as stronger. An attraction of this approach is that it helps to practice will be affected. These representatives can then
standardize assessment and interpretation, making it more advise on the optimal methods of communication and
reproducible. Thus, if a different group of researchers car- assist in conveying findings to their constituency. A good
ried out the review to the same protocol, they should come example of this is the set of evidence-based guidelines pub-
to the same conclusions. However, there is a danger that lished by NHS Plus on the management of chronic fatigue
evidence will be given inappropriate weight in the quest for syndrome in relation to work.10 These were drawn up fol-
lowing a review process that involved practising occupa-
tional physicians, and these individuals subsequently
helped to disseminate the findings to their colleagues.
Table 6.1 Possible explanations for discordant results from
epidemiological studies investigating the same association.
FURTHER READING
Differences in Even where exposures are defined in the
exposure same way, the mix of exposures may differ. For readers seeking a more detailed account of epidemio-
For example, within an exposure category logical methods and the use of statistics in interpretation
of 2 ppm-years, the mean exposure might of epidemiological data, a number of textbooks are
be 15 ppm-years in one study, but only available.11–14
2.5 ppm-years in another
Differences in The same case definition may encompass a
health varying mix of cases with different
outcome causation. For example, oesophageal Key points
cancers might be mainly squamous cell
tumours in one study and mainly ● Epidemiology is the branch of science that is
adenocarcinomas in another concerned with the distribution and determinants
Bias of health outcomes in populations.
Chance ● Epidemiology is used in occupational medicine
Confounding to identify, confirm and characterize health
Effect modification hazards in the workplace; monitor the
88 Epidemiological methods and EBM
Attribution of a disease to a particular cause in an individual Whenever I look at my watch and see the hand
is usually a matter of informed judgement. The judgement is pointing to ten, I hear bells beginning to ring in the
based on the degree of certainty required, together with church close by; but I have no right to assume … the
knowledge of causation in relation to the particular disease movement of the bells is caused by the position of
and the particular circumstances of the case. The level of cer- the hands of my watch.
tainty commonly applied, in medicine and the law, is ‘on the
balance of probabilities’ or ‘more likely than not’. As Lord War and Peace, Tolstoy
Denning put it, ‘If the evidence is such that the tribunal can
say “we think it more probable than not”, the burden of Cause of disease: Something that at least in some
proof is discharged, but if the probabilities are equal it is not’. circumstances, makes a disease more likely if it is
Attribution of disease in the individual case implies a introduced or less likely if it is removed.
sufficient knowledge of causation to answer the questions:
Coggon and Martyn1
1. Is the agent a cause of the disease, at least in certain
defined circumstances? The characteristics which allow inference of causation
2. If so, were the circumstances of the individual case have been the subject of long-standing disagreement and
such that the factor is more likely than not to have debate, as exemplified by the quotations above from Hume
caused the disease to occur? and Tolstoy. For our purpose the definition, proposed by
Coggon and Martyn, provides a practical foundation:
This chapter will address these two questions: disease cau- ‘something which at least in some circumstances makes a
sation and attribution in the individual case. The develop- disease more likely if it is introduced or less likely if it is
ment of epidemiology during the past 60 years has refined removed’.1 Cigarette smoking is a cause of lung cancer and
our understanding of the ways in which causes relate to high blood pressure a cause of stroke; stopping smoking
disease outcome, which has informed medical and legal reduces the risk of lung cancer and lowering blood pres-
understanding of causation and attribution. sure reduces the risk of stroke.
90 Attribution of disease
No condition has a single cause; rather all conditions There are two common approaches to observational
have multiple causes, some of which act through one studies of disease causation:
another. Aristotle distinguished necessary from sufficient
causes, a distinction which can be applied to disease causa- 1. Demonstration that those exposed to the putative
tion. In the absence of a necessary cause, a disease will not cause develop the disease more frequently than those
occur. Infection with Mycobacterium tuberculosis is neces- not exposed.
sary for the disease tuberculosis, as cases of tuberculosis do 2. Demonstration that those with the disease have more
not occur in its absence. Similarly, inhalation of respirable frequently been exposed to the putative cause than
crystalline silica dust is a necessary cause of silicosis. those without the disease.
However, infection with M. tuberculosis is not a sufficient
cause of tuberculosis: only some 10 per cent of those The first forms the basis of the cohort design; the second,
infected with M. tuberculosis will develop tuberculosis. the basis of the case–control (case–referent) design of
Other factors including poverty, malnutrition, age, over- epidemiological study.
crowding, HIV infection and silicosis increase the risk for
those infected with M. tuberculosis of developing tubercu-
losis. While the focus of physicians in individual cases of Threats to the inference of causation
tuberculosis will be on the successful application of antitu-
berculous chemotherapy, the importance of these other In general epidemiological studies, particularly analytical
factors in determining the risk of tuberculosis in the popu- studies, are concerned with cause and effect. The essence of
lation is appreciable. English mortuary registers in the an epidemiological investigation is comparison within or
1830s showed clear evidence of the socioeconomic deter- between population samples to determine whether differ-
minants of tuberculosis: ‘the proportion of consumptive ences in frequency of disease are associated with the
cases in gentlemen, tradesmen and labourers was 16, exposure or factor of interest. Cohort studies are designed
28 and 30 per cent, respectively’.2 McKeown showed that to ensure that, to the extent possible, like is compared with
during the twentieth century, by the time streptomycin was like in all respects other than for the factor under investi-
introduced around 1950, the death rate had fallen to about gation. In case–control studies, the aim is that exposure
20 per cent of its level in 1900, an improvement he attrib- to the risk factor in the controls should be representative
uted primarily to improved nutrition in the population.3 of exposure in the population at risk of becoming cases.
Identification of a cause or combination of causes Bias in a study is a systematic tendency to overestimate
sufficient to cause a disease is uncommon other than for or underestimate a characteristic of interest, because of
single gene disorders and chromosomal abnormalities. deficiencies in study design or execution. Bias can lead to
The presence of two abnormal haemoglobin genes (HbS) is false inferences about causation.
sufficient to cause sickle cell disease and three copies of In thinking about potential bias in a study, it is helpful
chromosome 21 sufficient to cause Down syndrome. to consider three questions:
The majority of diseases are caused by a combination of
factors (both genetic and environmental) which, when 1. In what way does the study sample (healthy or
present, can be shown to increase the frequency of the unhealthy) differ from the population from which
disease, or when absent to reduce it, but which alone are it was drawn?
neither necessary nor sufficient. Cigarette smoking is a 2. What is the potential for inaccurate information about
potent cause of lung cancer, but not all cases of lung cancer study participants (e.g. from errors in measurement or
have smoked cigarettes (cigarette smoking is not neces- recall)?
sary), and only a minority of smokers develop lung cancer 3. How might such differences affect the results?
(cigarette smoking is not sufficient).
Investigation of a factor as a potential cause of a disease An informative example is of osteoarthritis of the hip in
would ideally be undertaken in a representative popula- farmers. Farmers were over-represented among hospital
tion, half of whom were randomly allocated without their patients with osteoarthritis of the hip. This did not nec-
knowledge to exposure to the factor in question. This is the essarily imply that the incidence of osteoarthritis of the
basis of the randomized controlled trial, whose major hip was increased among farmers, as hospital cases are
strength is in minimizing the problem of confounding not representative of the population as a whole. Cases
biases (recognized and unrecognized), which can lead to coming to hospital are likely to include a higher propor-
false inferences of causation. Randomized controlled trials tion of more severely affected cases, and might over-
are now the bedrock underpinning decisions about the represent farmers, whose livelihood depended on their
efficacy of therapeutic interventions and, in a few cases, physical capacity. In fact, subsequent population studies
about adverse effects of drugs. Not least for ethical reasons, confirmed farming to be an important risk factor for
such studies are usually not feasible in addressing questions osteoarthritis.
of disease causation, which normally rely upon inferences Three important sources of bias are recognized in
from observational studies. epidemiological studies, as discussed below.
Causation 91
●
Selection bias is associated with the disease;
● is associated with the exposure;
● is not simply an effect of the exposure.
This arises when the sample of subjects for whom informa-
tion is collected is systematically unrepresentative of the
wider population about which conclusions are to be drawn In contrast, effect modification occurs when the
with regard to the parameter (e.g. odds ratio or disease strength of the association with one risk factor varies
prevalence) being estimated in the study. An important according to the presence or level of another factor (the
example of this is the health of workforces as compared to risk modifier). For example, in a study of the association
the general population. In general, those who enter work between occupational lifting and low back pain, risk esti-
are likely to be healthier than those not in work (healthy mates differed according to stature. In the shortest
selection effect) and those who remain in work are health- males, the estimated relative risk was 4.5, in those of
ier than those who leave work (healthy survivor effect). In intermediate height it was 1.6–2.4, and in the tallest
a study of workers engaged in the manufacture of polyvinyl males it was 1.0.5 A similar pattern was observed in
chloride (PVC), Fox and Collier4 quantified the magnitude females, suggesting that stature modifies the risk of low
of these contributions to a lower than expected mortality back pain from lifting.
in the workforce: Observational studies are inevitably subject to potential
for bias and therefore to false inference. For this reason,
● Selection of a healthy population for employment. no single study is usually considered definitive and con-
The mortality experience within five years of starting clusions are therefore based on the overall weight of the
work in a factory where PVC was made was 37 per evidence accumulated from several studies.
cent expected for circulatory and 21 per cent expected Robert Koch, the discoverer of the tubercle bacillus
for respiratory disease. The standardized mortality as the microbial cause of tuberculosis formulated four
ratio (SMR) for these conditions progressively postulates which needed to be met before a causal rela-
increased with increasing duration of employment, tionship could be inferred between a particular microbe
becoming similar to the general population after and disease:
15 years.
● Survival in employment of healthier males. Those 1. The agent must be shown to be present in every case
who had left the industry during the 15 years from of the disease, by isolation in pure culture.
first employment experienced an SMR 50 per cent 2. The agent must not be found in cases of other
higher than those who remained employed in the diseases.
industry. 3. Once cultured, the agent must be capable of
reproducing the disease in experimental animals.
For cardiovascular and respiratory disease, valid com- 4. The agent must be recovered from the experimental
parisons of mortality experience between a workforce and disease produced.
the general population are likely to be difficult, particularly
during the first 15–20 years of employment. The criteria are apt in the consideration of necessary,
infectious causes of disease, but are not appropriate for
determining non-infectious causality in chronic diseases,
Information bias such as chronic obstructive pulmonary disease (COPD)
where, for example, inhaled coal dust is a cause, but is not
Information bias arises from error in measuring exposure a necessary cause.
or disease. Retrospective investigation of risk factors for Others have explored alternative criteria, more appro-
congenital malformations from answers to questions to priate to cancer and chronic disease. Bradford Hill is
their mothers is likely to be subject to recall bias: mothers responsible for the best known criteria on which to base
whose children have congenital malformations are more judgements about causal inferences from the findings of
likely than those whose children are without congenital observational studies.6 However, he emphasized that
malformations to recall drugs taken, infections acquired these criteria should not be applied rigidly and recognized
or workplace chemical exposures experienced during that concepts of causation are necessarily provisional,
pregnancy. dependent on knowledge at that time.
Of the Bradford Hill criteria, the most important are:
Confounding and modifying factors 1. Strength of the association, i.e. the ratio between the
incidence of disease in those exposed to the putative
A confounder is an extraneous factor which is associated cause and those not exposed – relative risk (or, in
with the risk factor under investigation and which inde- case–referent studies, the ratio of the odds of being
pendently determines the risk of disease outcome. exposed in those with the disease to those without the
A confounding factor is therefore one which: disease). In general, the greater the relative risk or odds
92 Attribution of disease
The final question to be addressed having taken these ● the agent or exposure can cause the disease at least in
others into account is: Is there any alternative hypothesis some circumstances (causation);
that can explain the observations equally well or better? ● the circumstances of the individual case are such that
Demonstration of disease causation is clearest, and the agent or exposure caused or made a sufficient
attribution in the individual case most confidently made, contribution to the development of the disease.
where the cause is necessary or nearly so. In these circum-
stances, the cause is described as specific for the condition. The answer to the first will be based on judgement of
Such conditions include chemical poisonings, such as by the strength of the scientific evidence and the anwer to the
lead and mercury, pneumoconiosis caused by inhaled coal second will be based on the level of probability required to
and silica, mesothelioma caused by inhaled asbestos, and accept attribution in the individual case. For this purpose,
haemangiosarcoma of the liver caused by inhaled vinyl we can distinguish five levels of probability:
chloride monomer. For these diseases, the probability of
causation for those exposed at work in sufficient concen- 1. almost certainly true (‘beyond reasonable doubt’);
tration to the particular agent is comparable to that for an 2. more likely than not (‘on the balance of probabilities’);
acute occupational injury and can approach certainty. It is 3. as likely as not;
not surprising that the earliest diseases to be recognized in 4. less likely than not;
the United Kingdom under the Workmen’s Compensation 5. almost certainly false.
Act in the early part of the twentieth century included a
number of such disorders. In general, the level of probability adopted for the purposes
Other diseases (such as lung cancer, COPD, osteoarthri- of attribution is ‘more likely than not’ (on the balance of
tis (OA) of the hip), which now form the majority of dis- probabilities).
eases of occupational cause, are not specific to exposures in The question of causation has been addressed in the
the workplace, but the outcome of multiple causes, none previous section. The question of attribution will depend
necessary or sufficient. In these circumstances, evidence on potency of the causal agent in the particular circum-
for attribution to an occupational cause depends on infer- stances of the individual case. These will include the nature
ence from observational studies of workforces which con- and level of exposure and the presence of modifying factors.
sistently demonstrate a sufficient increase in disease Some diseases, such as lung cancer, can be considered as
incidence, not explained by chance, bias or confounding. ‘all or none’ diseases. The effect of a cause in these conditions
No studies are perfect and determination that an observed is to increase the probability of the occurrence of the disease.
association is causal is a matter of judgement, based on the Others, such as hypertension or COPD, are ‘more or less’ dis-
strength and consistency of the evidence and its coherence. eases. Whereas ‘all or none’ diseases are or are not present,
The strongest evidence for causation is a reduction in dis- ‘more or less’ diseases occur in a continuum of severity,
ease incidence following avoidance or removal of exposure where the question is not, ‘Do you or do you not have the dis-
(Figure 7.1).7 ease?’, but ‘How much of the disease do you have?’.
Attribution 93
RR 2 implies that in these circumstances the occur- The attributable fraction (and RR) can vary in relation
rence of the disease in an exposed person can be attributed to the level of exposure, usually, as with asbestos and lung
to the particular cause on the balance of probabilities, i.e. cancer, increasing with increasing cumulative exposure
more likely than not: where the RR is 2, there is a less (intensity duration) (Figure 7.2).
than 50 per cent chance that the particular case of disease
would have been prevented if the exposure had not
occurred. ‘More or less’ diseases
This test of more likely than not has been the basis for
attribution used by the Industrial Injuries Advisory Lung cancer is an ‘all or none’ disease with a clear distinc-
Council (IIAC) in determining whether a disease should be tion between cases and non-cases. The same is not true of
prescribed for the purposes of statutory compensation and diseases, such as hypertension (high blood pressure) and
by the UK courts in determination of negligent damage. COPD (chronic obstructive pulmonary disease character-
An informative example is the relationship of lung can- ized by low forced expiratory volume in 1 second or FEV1)
cer to asbestos exposure. In the absence of any specific which have a continuum of severity without a clear distinc-
identifying characteristics to distinguish a case of lung can- tion between cases and non-cases. Blood pressure and
cer caused by asbestos from one which would have FEV1 (a measure of limitation of airflow) are unmodally
occurred in the absence of asbestos exposure, attribution distributed in the general population and disease repre-
of lung cancer to asbestos in the individual case can only be sents the extreme of the distribution curve. As Geoffrey
based on the attributable fraction in the exposed and there- Rose put it, for these conditions the question is not ‘does
fore the relative risk in comparison to those not exposed to he have it?’ (an appropriate question for lung cancer), but
asbestos. The relative risk of lung cancer for an asbestos ‘how much does he have?’.
textile worker employed in the 1950s and 1960s is more COPD can be defined (somewhat arbitrarily) in relation
than doubled in those employed for ten years or longer, to the lower extreme of distribution curve. In its prescrip-
implying that 50 per cent or more of the cases of lung can- tion of COPD in coal miners, IIAC took as a case definition
cer which occurred in these workforces would not have of COPD an FEV1 of 1 L or more below the average (mean)
occurred had they not worked with asbestos in these facto- value for a person of the same age and height. This repre-
ries. Although it is not possible to be certain whether or not sented an impairment of lung function sufficient on aver-
the individual case would not otherwise have occurred, it is age to be associated with a significant level of disability
more likely than not, in these circumstances, that it is (inability to keep up with others of the same age when
attributable to asbestos exposure. walking on the level). Studies in the United Kingdom had
94 Attribution of disease
shown that the proportion of miners with this level of FEV1 ATTRIBUTION IN THE INDIVIDUAL PATIENT
loss increased with increasing cumulative coal dust
exposure and that at the highest levels of exposure the These principles can be applied to the question of attribu-
probability of this occurring was more than doubled tion of disease to a particular cause in patients seen in
(Figure 7.3).8 From knowledge of the levels of coal dust clinical practice. For this purpose, it can be helpful to
exposure in coal miners, underground and on the surface consider attribution of disease to an occupational cause
in the UK, it was possible to identify the circumstances of as a hierarchy of probability of causation and associated
exposure where the risk of this level of FEV1 loss was more difficulty of attribution (Figure 7.4).
than doubled (AFexp 50 per cent). This was found to Demonstration of disease causation and attribution in
occur in coal miners who had worked underground for 20 the individual case can be made most confidently for
years or more, which became the basis for the prescription. diseases which have followed a clearly defined accident
More recently, it has been shown that comparable (e.g. chemical pneumonitis following an acute inhalation
cumulative levels of exposure are also experienced by sur- accident) or for diseases with specific clinical features that
face workers employed on the screens for 40 years (i.e. the link them to exposure: these include pneumoconioses and
levels of exposure are on average about one half of those occupational asthma. Others, which now form the major-
underground) and prescription of COPD in coal miners ity, occur at increased incidence among those with relevant
has been amended to reflect this. occupational exposures as compared with the general pop-
ulation; many, such as COPD and OA hip, are common in
16 2.4 2.8 RR (high versus low) the general population with cases of occupational cause
representing a small minority. Attribution in such cases
14 requires knowledge of the epidemiological evidence for the
12 potency of the cause in different circumstances and
whether, in the particular circumstances of the case, attri-
% FEV165%
10
bution is more likely than not. This is easier for otherwise
8 unusual diseases, such as mesothelioma, caused by levels
6 of exposure of asbestos above background, than for lung
cancer, COPD and OA hip, where the doubling of risk
4
occurs only in well-defined circumstances of exposure.
2 Before attribution can be made, knowledge is needed of
0 these circumstances together with the circumstances of
Non- Smokers exposure experienced by the individual case.
smokers
Low
Intermediate (174 g hour/m3) ATTRIBUTION AND DISEASE REGISTERS
High (348 g hour/m3)
The strength of good epidemiological studies is their study
Figure 7.3 Increasing relative risk of FEV1 65 per cent with of populations (or a representative sample) at risk, which
increasing cumulative exposure to coal mine dust. Follow up of allows valid estimation of the level of increased risk of dis-
3380 British coal miners (mean age 47 years) with exposure of ease in relation to exposure. Disease registers, in contrast,
more than ten years in 20 UK coal mines with monitoring of depend on reporting by physicians of cases they have seen,
exposure over ten years. At highest cumulative exposures, the which they consider attributable to occupation. Clearly,
risk is more than doubled in both non-smokers and smokers. only cases seen by the physician and, of these, only those
Data from Marine et al.8 considered by the physician attributable to occupation,
Causation Example
Compensation: recompense for loss or damage. this principle, until the Industrial Injuries Act (1946) when
government took responsibility for funding the scheme as
Shorter Oxford English Dictionary part of the social security system. Increasing costs, particu-
larly in relation to asbestos, have recently led several other
countries to provide government funding to supplement
INTRODUCTION social insurance funding.
The intention of the majority of schemes is replacement of
Statutory compensation for industrial accidents and dis- lost earnings (at least in part) because of the inability to work,
eases was enacted first in Germany and then in the United as a consequence of accident or disease caused by work.
Kingdom in the late nineteenth and early twentieth cen- Again the UK system is different, providing benefit for phys-
turies, and subsequently during the twentieth century in ical and mental disablement, although some other countries’
the great majority of countries of Western Europe, as well schemes now also include this. Coverage of many European
as in North America. The moral basis of these schemes is schemes has now also broadened to include prevention
that workers contributing to the national good through and rehabilitation, as well as compensation. This is most
their work should not be economically disadvantaged as a developed in Germany where the employer’s liability insur-
result of accident at, or disease caused by, their work. One ers constitute an important element of the mandatory regu-
of the earliest proponents, the nineteenth century German latory system, as well as taking a lead in prevention and
Chancellor Bismarck, also recognized that such a scheme rehabilitation initiatives. A ‘first principle’ of the German sys-
could enable social peace by ameliorating potential conflict tem is ‘rehabilitation before pension’, with the intention of
between workers and employers. permanent reintegration into the workforce to the extent
The current schemes in each country provide no fault that the individual’s disability allows. Sadly in the United
compensation, for accidents and diseases attributed to Kingdom, despite considerable urging for more than a
work. However, between the United Kingdom and main- decade, the government has yet to introduce the means for
land Western European countries, there are important vocational rehabilitation into the Industrial Injuries Scheme.
differences in coverage and funding. Which diseases are compensated can in principle be
The majority are self-governed social insurance schemes, decided on the basis of ‘individual proof’ – attribution of
with mandated funding by employers, based on the scheme disease to occupational causation in the individual case –
introduced by Bismarck in Germany in the Worker’s or from a list of ‘prescribed diseases’, where the scientific
Accident Insurance in 1884, which created the first modern evidence of causation in particular circumstances is suffi-
system of ‘no fault’ worker’s compensation. Workmen’s cient to allow claimants the ‘benefit of presumption’. In
Compensation in the United Kingdom was also based on practice, a combination of these principles is found in
Current pattern of claims for industrial injuries benefit in the United Kingdom 97
different schemes. In all European countries, diseases not expected or designed’, Lord McNaughton:
compensated through the scheme are covered in a list. Fenton v Thorley 1903).
There is also a European community list. Which diseases b. Prescribed diseases
are included in the list varies between countries, both on i. which are a recognized risk to workers in an
the basis of their determination and in their comprehen- occupation or exposed to a particular agent.
siveness. In Sweden for instance, only infectious diseases ii. where the disease can be attributed to
are listed; eligibility for other conditions is open and based occupation or an agent at work on the balance
on individual proof. Finland has an indicative list, but its of probabilities, i.e. more likely than not.
system does not exclude other conditions, effectively
In general, attribution of a disease to a specific cause can
allowing individual proof in addition to the listed condi-
be based on:
tions. On the other hand, the United Kingdom and France
are more prescriptive in generally only allowing listed dis- a. Specific clinical features
eases, although in the United Kingdom individual proof b. By inference from the results of population studies
exists for some conditions, such as occupational asthma to causation in the individual patient.
(in addition to the listed prescribed causes) and dermatitis.
In the absence of any specific characteristics to distin-
Eligibility of the self-employed for compensation also
guish a case of disease attributable to an occupational cause
varies between countries. In general, social insurance
from those which would have occurred in the absence of
schemes are more open to inclusion of the self-employed,
the occupational exposure, attribution in the individual
with eligibility based on their payment of insurance pre-
case is based on an attributable fraction of more than
miums. The self-employed are excluded from the United
50 per cent in the exposed workforce, and therefore a
Kingdom scheme.
relative risk of greater than two, when compared to those
not exposed (see Chapter 7).
INDUSTRIAL INJURIES COMPENSATION 2. The second important benefit introduced in the 1946
IN THE UNITED KINGDOM Act was Special Hardship Allowance (SHA),
subsequently renamed Reduced Earnings Allowance
The current scheme for the statutory compensation of
(REA). Arguably the most enlightened part of the
accidents and diseases attributable to occupation in the
Industrial Injuries Scheme, SHA (later REA) provided
United Kingdom is the Industrial Injuries Scheme, initially
an earnings replacement benefit to enable those with
enacted under the National Insurance (Industrial Injuries)
occupational disease, whose health would be adversely
Act, 1946. It differs in many important respects from com-
affected by remaining in their current job, to move to
parable schemes in Europe and North America.
other less well paid work. It provided the means to
The United Kingdom Industrial Injuries scheme is a
prevent disease progression to a severe and irreversible
no-fault, government-funded compensation scheme, for
level of disability. Reduced Earnings Allowance was
employed earners, which provides benefits to those disabled
abolished by the government of the day in 1990,
by accidents or suffering from listed ‘prescribed diseases’, i.e.
although claimants in relevant employment before
attributable to occupation. In some circumstances, claimants
1990 remain eligible to claim.
for a prescribed disease have ‘the benefit of presumption’:
Where a person has developed a disease which is pre- CURRENT PATTERN OF CLAIMS FOR
scribed in relation to him … that disease shall, unless INDUSTRIAL INJURIES BENEFIT IN THE
the contrary is proved, be presumed to be due to the UNITED KINGDOM
nature of his employment, if that employment was in
any occupation (listed in the Schedule) and he was At present some 350 000 people are in receipt of IIDB, REA
employed on or at any time within one month imme- or both, at a total cost of £776 million p.a. The current (2009)
diately preceding the date on which he is treated as maximum weekly benefit is £127.10 for IIDB and £50.84 for
having developed the disease. REA. IIDB payments range from £25.42 to £127.10, the
The 1946 Industrial Injuries Scheme provided two major amount received based on the level of disablement that
benefits: arises from the accident or prescribed disease. IIDB is not
normally paid where the level of disablement is less than
1. Industrial Injuries Disablement Benefit (IIDB), payable 14 per cent. However, for pneumoconiosis, byssinosis or
for ‘loss of faculty’ (‘in proportion to loss of health, mesothelioma, IIDB is paid with a minimum disablement
strength and the power to enjoy life attributable to assessment of 1 per cent. Since 2002 awards for mesothe-
industrial accident or prescribed disease’) for: lioma and since April 2006 awards for asbestos-related lung
a. Accidents ‘arising out of and in the course of cancers, have been paid at 100 per cent. Some 13 000 new
employment’ (an accident has been defined as ‘an claimants receive benefit each year, three-quarters of whom
unlooked for mishap or untoward event which is are of working age. Ninety-four per cent of accident claims,
98 Compensation schemes
4000 2000
3500 1800 2002–2003
3000 1500
No. of claims
2005–2006
No. of claims
1400
2500
1200
2000 1000
1500 800
1000 600
500 400
0 200
0
Mining and quarrying
Manufacturing
Construction
Wholesale,
retail and motor
Synovial inflammation
Occupational deafness
Pneumoconiosis
Diffuse mesothelioma
Unilateral or bilateral
diffuse pleural thickening
Others
Figure 8.1 New Industrial Injuries Disablement Benefit and
Reduced Earnings Allowance claims (>500) put into payment Figure 8.2 New prescribed disease claims put into payment
by industry.1 by disease.1
which constitute 60 per cent of new claims, are of working at common law in tort and benefits under the statutory
age, whereas 60 per cent of new claimants for prescribed industrial injuries scheme. Whereas success in the former
disease, which constitute 35 per cent of new claims, are over requires proof of negligence or breach of statutory duty,
state age pension. Eighty per cent of those currently in the latter is a no-fault scheme, which in many instances
receipt of benefit are male, with women constituting 30 per provides the benefit of presumption in the individual
cent of new claims for prescribed disease and 7 per cent for case.
accidents, reflecting the predominantly male workforces Statutory compensation in the United Kingdom for
in industries and occupations in which the majority of accidents and disease attributable to work has been avail-
accidents and prescribed diseases have occurred. able since the Workmen’s Compensation Act of 1897. This
The pattern of current payments for IIDB and REA in scheme was replaced in 1946 by the Industrial Injuries
the United Kingdom reflects the industrial history of the Scheme which, in a modified form, exists today. During
country during the second half of the twentieth century. the long century from 1897 to the present day, workmen’s
Accidents are most likely to occur in manufacturing, compensation in the United Kingdom has adapted to the
construction and mining industries with 26 per cent of changing nature of hazardous exposures at work, the dis-
major accidents occurring in manufacturing, 16 per cent in eases associated with them and to the advances in medical
construction and 13 per cent in mining and quarrying.1 New technology (e.g. diagnostic x-rays), which have allowed the
benefit recipients for IIDB and REA in industries with more differentiation of occupational disease (e.g. pneumoconi-
than 500 claims in 2005–2006 are shown in Figure 8.1. osis from tuberculosis). In addition, advances in under-
New claims for prescribed diseases are dominated by standing the nature of occupational disease, in particular
diseases associated with mining and asbestos. Some two- the occupational contribution to the incidence of diseases
thirds of new benefit recipients for a prescribed disease are common in the population, have, more recently, allowed
for pneumoconiosis or mesothelioma. The number of new the inclusion of non-specific diseases (e.g. chronic obstruct-
claims for the most common prescribed diseases put into ive pulmonary disease (COPD) in coal miners and osteo-
benefit in 2002–2003 and 2005–2006 is shown in Figure 8.2. arthritis of the hip in farmers) in addition to the diseases
Although the incidence of pneumoconiosis is falling in specific to occupation, such as poisoning by lead or mer-
the United Kingdom, the incidence of mesothelioma is cury, which have been included since 1906. The scheme of
increasing and the long latency of both diseases makes it compensation has also been influenced by the develop-
likely they will continue to form a large proportion of IIDB ment of public policy and statute: in 1897 with the first
benefit recipients for many years. Workmen’s Compensation Act, making employers liable
for compensation for accidents at work, without the need
to prove negligence; and the 1948 Industrial Injuries Act,
THE DEVELOPMENT OF UK COMPENSATION which transferred responsibility for payment and adminis-
SCHEMES tration of benefit from employers and their insurers to
government, and provided benefit primarily for loss of
Two main types of compensation for accidents and dis- faculty, and associated disablement, in place of loss of
eases caused by work are available in English law: damages earnings.
The development of UK compensation schemes 99
Workmen’s Compensation Acts (from 1897) employment’, effectively abolishing legal barriers to
employee’s compensation.
Statutory compensation for accidents at work and indus- The principle of a duty of employers to compensate
trial diseases in the United Kingdom originated in the late employees for loss of earnings due to accidents at work,
nineteenth century as a statutory remedy for the failure of introduced in the 1897 Workmen’s Compensation Act, was
civil courts to provide compensation to workers injured or revolutionary in its implications: it provided the employee
killed by accidents at work. At that time, fatal accidents in with the legal right to compensation at no cost to himself; it
the United Kingdom numbered some 5000 each year, with imposed on the employer a legal obligation to compensate
about 1000 each year in the mining industry. workers for loss of earning capacity as a result of accidents
The Workmen’s Compensation Act of 1897 reflected an at work, with the cost to be regarded as a cost of production,
extension of the principle of automatic compensation for comparable to depreciation of capital assets; employer
those serving in the armed forces injured in war, which had liability was irrespective of any negligence on the part of the
its origins in Elizabethan England. Joseph Chamberlain, employer or of the employee; and for the common law, strict
the architect of the 1897 Workmen’s Compensation Act, liability, i.e. liability without imputation of fault was written
referred in a speech at Birmingham Town Hall in 1894, to into statute. Beveridge later described the Workmen’s
the victims of industrial accidents as the ‘wounded soldiers Compensation Act of 1897 as ‘the pioneer system of social
of industry’. Later in the same speech, he stated that in his security in Britain’.
opinion, ‘the cost of every accident in every employment is The 1897 Act did not cover industrial disease, but
rightly a charge on the cost of production’. The subsequent this omission was soon remedied. The Workmen’s
1897 Act embodied this radical new principle of automatic Compensation Act of 1906 listed six diseases for which
compensation of employees for industrial accidents, with- compensation was payable: anthrax, ankylostomiasis
out the need to prove his employer’s negligence. (hookworm), poisoning by lead, mercury, phosphorus or
Prior to the 1897 Act, employees had the right to seek arsenic, and their sequelae. Workers were entitled to com-
compensation from their employers through the courts for pensation if they could establish that the disease was due to
accidents in the course of employment, by demonstrating the nature of their employment and they had been engaged
negligence or breach of statutory duty. However, during in that employment at any time during the 12 months
the nineteenth century, the courts had accepted a number preceding the date of disablement. The Home Secretary,
of defences which provided considerable barriers to suc- who was responsible for the administration of the Act, was
cessful action by workers. These included three in particu- empowered to add further diseases to the schedule. In the
lar, known as the ‘unholy trinity of defences’. (1) Violenti absence of specified criteria to enable this, he set up a
non fit injuria: accidents were an ordinary hazard of review committee under Herbert Samuel.
employment and by taking the job the workman was The Samuel Committee, which reported in 1907, pro-
accepting the risk, expressly or by implication; (2) contribu- posed three criteria for the addition of new diseases under
tory negligence: negligence or want of ordinary care on the the Act.2
part of the workman, i.e. in order to succeed the workman The disease had to be:
had to prove his freedom from negligence; and (3) com-
mon employment: the employer was not liable where an ● outside the category of diseases already covered by
injury was due to the negligence of a fellow worker in the the Act;
same employment. ● such as to incapacitate a worker for more than one
Of these, the defence of common employment was the week;
most important and aroused the most antagonism and ● so specific to the employment that causation could be
hostility. In practice, it meant an employee had a claim assumed in the individual case.
only if the employer had been personally negligent. In
companies with a large number of employees such as rail- The important implication of the third criterion was
ways and mines, which had the highest rates of accidental that diseases undoubtedly associated with certain indus-
injury and death, the workman was left without the means tries would not be scheduled if they were also fairly com-
to pursue a successful claim. Steps were first taken to mon in the general population. The committee did recognize
abolish the defence of common employment by Act of that where a disease was common to a particular trade, but
Parliament in 1880, but it was not effectively overcome also occurred rarely outside the trade, it could be included
until 1897. It was during debates in and outside parliament in the schedule.
during the 1890s that Joseph Chamberlain first advanced The committee used bronchitis in flax workers as an
the principle of automatic compensation by employers for example of the difficulties of adding a disease common in
accidents at work, irrespective of cause and without the the population to the schedule:
need to prove negligence. He was the architect of the first
Workmen’s Compensation Act of 1897, of which this was Bronchitis, for example, is a trade disease among flax-
the underlying principle, taking compensation out of the workers; a larger proportion of that class suffer from
courts for accidents, ‘arising out of and in the course of it than of other people; but it is not specific to the
100 Compensation schemes
employment, for numbers of people who are not flax- (the Workmen’s Compensation Acts) it has been open
workers contract it also. Unless there is some symp- to the employer, and in some cases obligatory on
tom which differentiates the bronchitis due to dust him, to insure himself against this liability; while it
from the ordinary type, it is clearly impracticable to has been for the workman to make his claim and to
include it as a subject of compensation; for no one take steps to enforce it, if challenged in the Courts of
can tell, in any individual case, whether the flax- Law. Inevitably compensation has thus become a
worker with bronchitis was one of the hundreds of disputable issue between the two parties or their
persons in the town whose bronchitis had no connec- representatives.4
tion with dust irritation, or whether he was one of the
additional tens or scores of persons whose illness was In his report,5 Beveridge recognized this ‘disputable’
due to that cause. To ask a court of law to decide system imposed a disproportionate cost of administering
would be to lay upon it an impossible task. If the the scheme compared with the payment issued in benefit
workman were required to prove his case, he might be to sick and injured workers.
able to show that a larger percentage of his trade suf-
fer from bronchitis than do the rest of the population,
but he could never show that he himself was a unit in Industrial Injuries Act, 1946
the excess, and not in the normal part, of that per-
centage. If it were the employer who was required to Beveridge proposed that social security should be an insur-
disprove a claim, he could rarely, if ever, show that the ance, rather than a tax-based scheme, funded from National
workman did not contract the illness through his Insurance contributions made by employers and employees.
employment, and he would be compelled to compen- His proposals included a new industrial injuries scheme.
sate not only those labourers whose bronchitis was in Enactment of the Beveridge report, including a new
no degree an industrial disease. Industrial Injuries Act, was the responsibility of the Minister
for National Insurance, Jim Griffiths, who personally initi-
The problem of statutory compensation for diseases ated the inclusion of Special Hardship Allowance as an
common in the population whose risk was increased in earnings replacement, in addition to disablement benefits,
some occupations, was the subject of continuing debate consequent upon ‘loss of faculty’. The new Act transferred
and disagreement, which was only resolved in the last responsibility for payment and administration of benefit
quarter of the twentieth century. from employers and their insurers to government. Benefit
On the basis of their original criteria, the Samuel was payable for accidents and prescribed diseases for ‘loss of
Committee recommended a further 18 diseases should be faculty’ (‘in proportion to loss of health, strength and the
included in the scheme and a further three in 1908.3 The power to enjoy life attributable to industrial accident or
diseases recommended included conditions such as chrome prescribed disease’) in place of lost earnings replacement.
ulceration and scrotal cancer in chimney sweeps. It did not Loss of earnings was compensated in one provision of
include ‘fibrous phthisis’ (silicosis and silico-tuberculosis). the Act – Special Hardship Allowance – introduced as an
Although recognized as a hazard of stonemasons, grinders, earnings replacement for those unable to return to prior
potters and tin miners, they considered the long latency of employment. An early example of the value of Special
the disease would make it difficult to apportion liability Hardship Allowance was in making up lost earnings for those
among different employers. The committee also considered with category 2 simple coal workers’ pneumoconiosis (and
asbestos, but were unable to include it because of lack of therefore at significant risk of progressive massive fibrosis
evidence. Further diseases were subsequently added, includ- (PMF)) who moved to ‘dust approved conditions’, with a
ing silicosis in 1919 through a special scheme, Workmen’s reduced risk of disease progression, but less well paid work.
Compensation (Silicosis) Act 1918, which required employ- The 1946 Act maintained the distinction between acci-
ers to contribute to an insurance scheme, overcoming the dents ‘arising out of and in the course of employment’ and
problem of identifying which employer was liable. prescribed (i.e. listed) diseases. The Act allowed that:
However, the operation of the Workmen’s Compensation
Acts was the subject of increasing dissatisfaction. Employers A disease or injury may be prescribed … in relation to
insured against their liability for compensation. This led to any insured persons, if the Minister is satisfied that:
claims for compensation under the Act becoming adversar-
ial, with high administrative costs, delay in settlement and ● it ought to be treated, having regard to its causes
workers being bought off by low value lump sum payments. and incidence and any other relevant considera-
A Parliamentary report in 1944 expressed this dissatis- tions, as a risk of their occupation and not a risk
faction: common to all persons
● it is such that, in the absence of special circum-
For nearly half a century the compensation of work- stances, the attribution of particular cases to the
men for industrial injury has been a liability, imposed nature of employment can be established or
by law, on their employer. Under the existing scheme presumed with reasonable certainty.
Examples of the development of disease prescription 101
The Dale Committee,6 which reported in 1948 inter- of employers and employees, should advise the minister on
preted these new statutory criteria for prescription as less which diseases should be considered for prescription.
restrictive than the Samuel Committee criteria. They con-
sidered the meaning of a disease which is ‘a risk of their
occupations and not a risk common to all persons’ as EXAMPLES OF THE DEVELOPMENT
including both diseases specific to occupation and those OF DISEASE PRESCRIPTION
diseases where the occupation ‘causes a special exposure to
the risk of the disease, such risk being inherent in the con- The development of disease prescription, particularly in
ditions of that employment’. They further interpreted the relation to broadening the scope of prescription to include
test of ‘reasonable certainty’ as being the level of proof in diseases not specific to occupation, can be shown in three
civil courts, i.e. ‘on the balance of probability’ or ‘more examples.
likely than not’. This level of proof was succinctly encapsu-
lated by Lord Denning:
Workmen’s compensation and coal
If the evidence is such that the tribunal can say ‘we
think it more probable than not’ the burden of proof is The Samuel Committee had been unable to recommend
discharged, but if the probabilities are equal, it is not. prescription for silicosis, in part because it was not possible
at that time to distinguish silicosis from other pulmonary
Miller v Minister of Pensions, 1947 diseases, particularly tuberculosis. The development of the
chest radiograph in the early twentieth century allowed the
The contentious issue of the criteria for prescription in differentiation of silicosis from other respiratory diseases.
relation to disease specificity was considered again by the Silicosis was recognized as an industrial disease under the
Beney Committee in 1955.7 Workmen’s Compensation (Silicosis) Act, 1918. The Act
While the majority report of the Beney Committee required employers to contribute to an insurance scheme,
agreed in principle with the conclusions of the Dale report, from which compensation would be paid, overcoming the
a minority report of three dissenting members, highlighted problem, highlighted by the Samuel Committee, of identify-
the failure to prescribe Raynaud’s Phenomenon as evi- ing employer liability. It also introduced regular medical
dence of the difficulty in adding new diseases to the pre- examinations authorizing medical examiners to suspend
scribed list. They argued that, workers compulsorily at the early stages of disease, to pre-
vent the development of incapacitating disease. Coal miners
The fundamental difficulty is the inadequate cover for were included in the scheme in 1928, when they could
diseases common among the general public which demonstrate exposure to dust of silica rock and were ‘totally
may also be due to special occupational risk, e.g. disabled’. The scheme was further extended to include ‘par-
chronic bronchitis (including emphysema) and rheum- tially disabled’ workers three years later. In 1934, the scheme
atic diseases. We consider that these diseases should was extended to include any coal miner with silicotic nod-
be eligible for prescription and that the existing test ules, whether or not they were working with rock. All coal
requiring attribution of individual cases to the miners with radiological evidence of pneumoconiosis from
employment is a bar to their inclusion. coal dust exposure were included in the scheme in 1943.
Workers compensated for Coal Worker’s Pneumoconiosis
They proposed that prescription should be satisfied in rela- (CWP) were ‘certified’ with benefit of a weekly payment or
tion to a disease where it was probable that more cases than a lump sum and compulsory suspension from mining to
not were occupational in origin, whether or not individual protect workers from further lung deterioration. The certi-
cases could be attributed to the nature of employment. fication of large numbers of workers resulted in unforeseen
This proposal overcame the problem identified origin- social problems in South Wales as identified in 1948 by
ally by the Samuel Committee in 1907 providing the basis Fletcher.8 By the end of 1945, 12 000 men had been certified
for widening the scope of disease prescription to include in South Wales and new cases were being certified at a rate
diseases common in the population, such as chronic obstruc- of 100 men per week. Most of these men (66 per cent) were
tive pulmonary disease, lung cancer and osteoarthritis of under 50 years old and 25 per cent were under 40 years old.
the hip, where the frequency of the disease is more than The majority of the men had been coal hewers and faced the
doubled in certain occupations, in certain well-defined cir- prospect of being out of work with no training for alterna-
cumstances of work, but the disease has no specific charac- tive employment. In 1951, Hugh Jones and Fletcher9 noted
teristics which allow the distinction of occupational from that ‘at present some 5000 men with pneumoconiosis, three
non-occupational cause. quarters of whom are probably capable of work, under
The Dale Committee (1948) had also recommended normal industrial conditions, are unemployed’.
that the Industrial Injuries Advisory Council, a recently The nature and progression of coal worker’s pneumo-
formed tripartite committee of independent members with coniosis had become better by the 1960s. Inhaled coal dust
relevant expertise and an equal number of representatives reaching the peripheral gas exchanging parts of the lungs is
102 Compensation schemes
removed, primarily through engulfment by scavenging working 20 years in the Turner and Newall
macrophages, which migrate centrally to the mucociliary asbestos textile factory in Rochdale, Lancashire,
escalator. If the dose of respirable dust overwhelms this UK.11
removal mechanism, coal dust accumulates in the lungs as 1930: Merewether and Price12 report the increased
centriacinar macules, which appear as rounded nodules on prevalence of asbestosis in the Rochdale
chest radiographs. The nodules themselves, composed of workforce of asbestos textile workers.
retained dust, do not cause impairment or disability. This 1947: Merewether13 reports excess lung cancer deaths
form of the condition, characterized by retained coal dust in those with asbestosis compared to those with
in the lungs, was classified as simple pneumoconiosis. The silicosis.
severity of pneumoconiosis was graded according to the 1955: Doll14 provides definitive evidence of the
size and profusion of nodules seen on the chest radiograph. increased risk of lung cancer in the Rochdale
Some cases of simple pneumoconiosis developed progres- asbestos textile workforce.
sive massive fibrosis, which was associated with significant 1960: Wagner et al.15 provides evidence of the
disability and reduced life expectation. During the 1940s association between mesothelioma and
and 1950s, PMF had been considered an atypical form of occupational and non-occupational exposure to
tuberculosis. However, Cochrane provided substantial evi- blue asbestos (crocidolite) in NW Cape
dence against this hypothesis and showed that the risk Province, South Africa.
of PMF was related to the category of simple pneumoconio-
sis, i.e. correlated with the quantity of coal dust in the ASBESTOSIS
lungs.10 His findings implied that if workers with category 2
pneumoconiosis were removed from further dust exposure, Merewether and Price12 reported an increased risk of fibro-
the risk of progression to PMF would be reduced. Jacobsen sis in asbestos textile workers, which increased in preva-
et al. subsequently showed that on average coal dust inhaled lence with longer duration of employment (Table 8.1).
over a 35-year working lifetime with exposures of 4 mg/m2 Although remarkably high by modern standards, the
were associated with a 4 per cent risk of developing category number of prevalent cases of fibrosis was almost certainly an
2 pneumoconiosis. Measures were put into place to reduce underestimate of the true size of the problem, as employees
dust concentrations to 4 mg/m2 and workers with category whose health was most affected by asbestos were likely no
2 pneumoconiosis moved to less dusty (‘dust approved’) longer to be at work because of disease severity or death.
working conditions. Special Hardship Allowance helped Statutory compensation of asbestosis
facilitate the redeployment of workers to less dusty condi-
tions, by providing compensation for loss of earnings Asbestosis was enacted in the Workers’ Compensation
consequent on the move to less hazardous work. Special (Silicosis and Asbestosis) Act, 1930, which extended the
Hardship Allowance, which later became Reduced Earnings provisions of the Workmen’s Compensation (Silicosis) Act
Allowance, was arguably the most enlightened part of the to asbestosis, i.e. compulsory employer liability insurance
Industrial Injuries Scheme, enabling workers to remain in and regular medical examinations with the powers of
work while preventing further health deterioration. suspension.
Asbestosis continues to be compensated as a
pneumoconiosis.
Asbestos and asbestosis, lung cancer and
mesothelioma MESOTHELIOMA
Table 8.2 Mesothelioma in NW Cape Province, South Africa Table 8.3 Association between pneumoconiosis (asbestos and
(1960).15 lung cancer) and lung cancer (at post-mortem).17
Exposure (crocidolite) Mesothelioma (No.) Latency (years) Deaths (No.) Lung cancer (%)
this was not the case but that in certain workers, such as the same age and height was associated with shortness
asbestos textile workers, there was a doubling of the risk of of breath when walking with others on the level.21
lung cancer in those working with asbestos. ● Is there evidence of at least a doubling of risk of this
In 2006, lung cancer in the absence of asbestosis was FEV1 loss? Evidence indicated that a doubling of risk of
prescribed for ‘exposure to asbestos for at least five years this level of FEV1 loss occurred at cumulative exposures
before 1975 and ten years after 1975 in the following to coal dust of 60–120 mg/m2 per year.20
occupations (i) workers in asbestos textile manufacture, ● What is the nature of occupational exposure in which this
(ii) asbestos sprayers and (iii) asbestos insulation work, occurs? Hygiene data from the Institute of Occupational
including those applying and removing asbestos-containing Medicine (IOM) in Edinburgh showed exposures for
materials in shipbuilding’. Since 2006, cases of asbestos- UK miners to be:
related lung cancer have received 100 per cent disablement Coal face workers 2.5–6.5 mg/m2
benefit. Development operations 1.5–5.5 mg/m2
Other underground workers 1.0–3.0 mg/m2
Chronic obstructive pulmonary disease and Surface workers 0.2–0.7 mg/m2
coal workers ● Can this be translated into job titles and duration of
employment for purposes of prescription? IIAC trans-
Cancer is an ‘all or none’ disease: you have cancer or you lated this into 20 years employment underground in a
do not. In contrast, some other diseases may be ‘more or coal mine.
less’, with degrees of disease such as high blood pressure or
airway narrowing in chronic bronchitis and emphysema. Chronic bronchitis and emphysema was prescribed in
Lung function can be assessed by measuring the amount 1992 as an FEV1 of 1 L less than the average value for a man
of air a person can exhale during a forced expiratory of similar age and height, in coal miners who had worked
manoeuvre. The total volume of air that can be exhaled is underground for 20 years, who had Category 1 Simple
the forced vital capacity (FVC) and the volume of air that Coal Workers Pneumoconiosis on a chest radiograph. The
can be exhaled in 1 second is the forced expiratory volume in requirement for Category 1 pneumoconiosis was later
1 second (FEV1). A person with airflow limitation will have withdrawn. More recently, on the basis of additional evi-
a lower FEV1 and lower FEV1/FVC ratio than a normal indi- dence from IOM about coal dust exposure to surface
vidual. In a study in 1961, Cochrane and Higgins18 found workers, prescription has been extended to include surface
that miners and ex-miners had lower lung function than screen workers, employed for 40 years, allowing a 2:1
non-miners. However, no gradient of lung function loss was aggregation of duration of exposure below ground and on
observed in miners and ex-miners with increasing category the surface, i.e. 15 years underground plus ten years on the
of simple pneumoconiosis. In contrast, lung function was screens above ground qualifies for prescription.
decreased in miners and ex-miners with PMF, with lung
function loss increasing with increasing severity of PMF. On
this basis, Cochrane considered that coal dust did not cause OTHER UK COMPENSATION SCHEMES
airway obstruction, but recognized he was using the cat-
egory of simple pneumoconiosis measurements as a surro- Pneumoconiosis (Workmen’s Compensation)
gate for airborne coal dust exposure. In 1982, Cockcroft Act, 1979
et al.19 found evidence that emphysema at post-mortem was
considerably more frequent in coal miners than in non- This is a state-funded scheme which provides lump sum
miners, in individuals referred for post-mortem because of payments to those who have developed respiratory disease
sudden death (i.e. a reason for post-mortem unrelated to through their employment, for workers unable to recover
occupation overcoming potential selection bias), with an compensation through the courts or through a private
odds ratio of 10.35 after adjusting for age and cigarette no-fault compensation scheme, because their employer is
smoking. In a large study of UK coal miners, Marine et al.20 no longer in business. The Act originally covered pneumo-
in 1988 showed the proportion of coal miners with a FEV1 coniosis, byssinosis and mesothelioma, but has since
65 per cent was more than doubled in those with high, as been extended to include lung cancer with asbestosis or
compared to low, exposure to coal dust, in both smokers prescribed in relation to asbestos and bilateral diffuse
and non-smokers. This evidence together with other similar pleural thickening.
observations, particularly from the United States, provided To succeed, the claimant has to satisfy three criteria:
the basis for prescription for chronic bronchitis and emphy-
sema (now COPD) in coal workers. 1. Disablement benefit must be payable under the
In considering the terms of prescription for coal work- industrial injuries scheme in respect of the disease in
ers with COPD, the Industrial Injuries Advisory Council question.
addressed the following questions: 2. Every relevant employer must have ceased to carry on
business.
● What is a disabling loss of FEV1? A study of miners 3. No action must have been brought or any claim
found an FEV1 of 942 mL less than average for a man of compromised by common law.
Compensation schemes in continental Europe 105
Successful claimants under the scheme are paid lump sum Denmark, private insurers carry the risk for occupational
compensation in addition to IIDB. The average lump sum accidents, while occupational diseases are insured by spe-
under the scheme is £13 000 with payments made on a slid- cific funds financed by contributions from employers. In
ing scale based on age and level of disablement. Norway and Finland, insurers carry the risk for both acci-
dents and disease, but in Norway there is a state system and
a private employers’ insurance system which ‘tops up’ the
Diffuse Mesothelioma Scheme, 2008 state system. In some countries, the usual system of social
insurance for incapacity resulting from occupational
The Diffuse Mesothelioma Scheme, which commenced on injury and disease, designed to replace lost earnings, is sup-
October 1, 2008, extends coverage for compensation for plemented by additional schemes, usually resulting from
mesothelioma to those exposed to asbestos in the UK, who agreements between trade unions, to provide additional
are otherwise unable to claim compensation. This includes benefits for their members. In Sweden, higher pensions are
the self-employed exposed to asbestos in their work and available through the labour market insurance scheme
those exposed to asbestos in the home from asbestos known as AFA Insurance.
brought home on a worker’s clothes. It excludes employed Coverage of the original social insurance systems was
earners able to claim IIDB under the 1979 Pneumoconiosis intended for employed people in private sector industry,
Act. Compensation is made as a lump sum payment. which remains the basis of coverage. While coverage has
In order to qualify under the scheme: been extended to provide benefits for public sector employ-
ees, for part or all of those in agriculture and, in some cases,
● There must be evidence to show the claimant has a the self-employed, many of these still remain outside the
malignant mesothelioma. general coverage of this form of social insurance and are
● The claimant must have been exposed to asbestos in the subject to separate schemes in many countries. Workers
United Kingdom. who are unable to demonstrate a legal form of employment
● The claim must be made within one year of diagnosis or in relation to a claim for benefits for accident or disease
in the case of a claim made by a dependant, within one while engaged in work remain ineligible for these types of
year of the date of death. benefits under most systems.
● The third requirement, to claim within one year of In many countries, work injury/disease insurance sys-
death, does not apply to those diagnosed before the tems are now also involved in prevention and rehabilitation.
introduction of the scheme. This is most developed in Germany where the employer’s
liability insurers constitute an important element of the
mandatory regulatory system, as well as taking a lead in pre-
COMPENSATION SCHEMES IN CONTINENTAL vention and rehabilitation initiatives. A ‘first principle’ of
EUROPE the German system is rehabilitation before pension, with the
intention of permanent reintegration into the workforce to
There are broadly two main bases for the compensation sys- the extent that the individual’s disability allows.
tems found in continental Europe. One is modelled on the In all European countries, diseases that are compensated
German approach with self-governed sectoral insurance are covered in a list. There is also a European Union list.
associations funded by employers’ contributions, providing Which diseases are included in the list varies between coun-
a comprehensive prevention, rehabilitation and compensa- tries, both on the basis of their determination and in their
tion service. In the second form, the state administers the comprehensiveness. In Sweden, only infectious diseases are
system for compensating occupational injuries and disease listed; eligibility for other conditions is open and based on
as part of its wider provision for social security and levies individual proof. Finland has an indicative list, but its sys-
contributions from employers to finance it. tem does not exclude other conditions, effectively allowing
There are further differences in the arrangements and in individual proof in addition to the listed conditions. On the
those responsible for governance and administration in dif- other hand, the United Kingdom and France are more pre-
ferent countries. The degree of federalization and regional scriptive in generally only allowing listed diseases, although
autonomy differ with some countries such as Sweden and in the United Kingdom individual proof exists for some
France having highly regionalized administrative structures conditions, such as occupational asthma (in addition to the
and others, such as Germany, having a well-developed sec- prescribed listed causes) and dermatitis.
toral focus in addition to regionalization. The mix of public The role of the list in determining specific cases of com-
and private insurance organizations that make up the sys- pensation also varies. There are two extremes of the legal
tems vary between countries. In many countries, there is and administrative principles of the different systems con-
now a mixture of these two approaches, with participation cerned. At one extreme is the ‘open system’, in which each
of both the state and private insurance systems. claim for an occupational disease is treated on its own
In Belgium, there is a separate scheme for occupational merits, as in Sweden where the occupational disease list
accidents, based on private employers’ insurance, and a includes only infectious diseases, with all other conditions
state system for occupational diseases for industrial and treated individually. At the other extreme, the French list
commercial sector workers. This is also true in Portugal. In of 112 occupational diseases appended to its social security
106 Compensation schemes
code specifies symptoms or pathological lesions required represents lower proportional expenditure on this form of
to be present, the type of work that is known to cause the support than is found elsewhere. Whereas the majority of
condition and the time limits for compensation claims. In schemes provide partial earnings replacement, the UK scheme
theory, any disease meeting the medical, occupational and compensates loss of faculty and associated disablement. Also
administrative criteria in the list is presumed to be occupa- in contrast with some other countries, it makes no provision
tional in origin. In the other 15 EU countries, the function at present for either prevention or rehabilitation. However,
of the ‘list’ falls somewhere between these extremes in deci- there are also similarities. The legacy of the industrial era is
sions concerning the eligibility of conditions. A trend evi- found in most systems. As long as conditions that are eligible
dent in many countries has been the increasing recourse to for compensation are based on lists primarily based on the
‘open’ systems in recent years. Despite this, well over 90 ‘classic’ industrial diseases, the number of claims (and there-
per cent of diseases recognized as occupational remain on fore costs of compensation) are unlikely to increase greatly.
the basis of their inclusion in the national list. The gender distribution of successful claimants under these
Whether the condition is on a list or identified individu- systems will be predominantly male. How compensation sys-
ally as part of a mixed system, the process by which evidence tems deal with the predominant and very different current
is assessed and decisions taken as to its ‘occupational’ cause conditions of ill health associated with work is a major issue
in most cases concerns two issues – the extent to which the for all systems. While in some countries musculoskeletal dis-
disease can be ascribed to an occupational cause and the orders now feature more prominently, stress-related condi-
extent to which a claimant can show they have experienced tions still represent a significant challenge. The move to
relevant exposures. The means by which the first of these ‘open’ systems may partly address this problem, but evidence
issues is resolved in most countries, as in the UK, is defined to date suggests that it does not do so entirely.
in legislation or the guidance to it. Determining the recogni- A trend evident in several countries is some reorienta-
tion of occupational associations with the cause of condi- tion of ‘no-fault’ compensation systems towards a closer fit
tions involves review of epidemiological and other scientific/ with civil law models. Perceived inadequacies in levels of
medical evidence and the achievement of broad expert compensation available through social insurance combined
agreement concerning increased risk in relation to occupa- with perceptions of injustice over employer immunity from
tional exposure. Practice in other European countries does redress under the civil law have led to these changes.
not follow exactly the rule adopted in the UK, where deci- The traditional protection from actions in civil law that
sions for prescription are based on robust epidemiological being part of such schemes afforded to employers in many
evidence of a greater than doubled risk of the disease in an countries, in contrast to the UK, is increasingly seen as
exposed occupational group compared to a comparable inappropriate. At the same time, the level of individual
unexposed group or the general population. However, there employer contributions has become increasingly debated.
are broad similarities in the approach in all countries in so Tensions in existing systems are evident and movement
far as there is emphasis on the need for robust evidence of towards a closer alignment with the benefits available
occupational risk and agreement of expert opinion. under civil law is a common international trend.
In Belgium, Italy and Luxembourg, both the occupa- Current data on occupationally related ill health com-
tional risks of a disease and the occupations in which such pared with the number of claims made for occupational
risks occur are defined on the list of prescribed diseases disease and those claims recognized suggest that only a
appended to legislation, as in the UK. As in France, it is suf- minority of those whose health is affected by their work
ficient for individuals in these countries to demonstrate seek compensation and in any European system, recogni-
that they are suffering from a disease on the list and that tion of such claims rarely exceeds 50 per cent. Several
they have been exposed to a relevant hazard or undertaken explanations have been proposed, which include the limi-
a job on the list. In Austria, Denmark, Finland, Germany, tations of the experience and ability of doctors to recognize
Switzerland, Portugal, Spain and Switzerland, the list occupational causes, ignorance of workers concerning
serves as a guide to insurance organizations investigating both the hazards of their work and their entitlements to
the claim that the disease is occupationally caused; the compensation and the complexity of the administration of
insurance companies will seek to establish if the disease in the system for compensation. It is also important to appre-
question could have been caused by a causal agent marked ciate that not only does the complexity of making a claim
on the national list, while at the same time excluding any exclude many, but the claim process itself may also have
non-occupational factors that could have caused the dis- negative consequences for recovery and return to work.
ease. These lead to differences in the number of claims for While one of the great virtues of ‘no-fault’ systems for
compensation for occupational diseases and the recogni- compensation is that they act to eliminate adversarial
tion rates for such claims between different countries. approaches to claims, the use of experience rating by some
Some clear differences emerge when comparing arrange- insurance systems destroys this advantage since it provides
ments for work injury/disease benefits in other countries a strong incentive for employers to contest claims. It is also
with the IIDB scheme in the UK. Partly as a consequence argued that the growth in precarious employment in
of its different origins, the UK approach provides for consid- advanced market economies has eroded the coverage of
erably lower benefits than other European systems and workers’ compensation systems, creating administration
Compensation schemes in the United States 107
difficulties, undermining the coverage and objectives of sets the rules; an insurer provides coverage on the basis of the
compulsory insurance, as well as weakening processes for payroll for eligible workers; cases are adjudicated in the first
making claims. There is also evidence that the costs of instance by the insurer and subsequently, if contested, by an
compensating injured workers are being shifted from appeals system. Despite the original intention to avoid litiga-
workers’ compensations systems to those concerned with tion, legal advocacy remains part of the process, particularly
public health or social security. in complicated or disputed appeals. Because of deadlines by
As is the case in the UK, recognition of some of these which time an insurer must decide claims, many requests for
problems means that reform of the present system is planned compensation are initially rejected, forcing claimants to
or called for in most countries. Generally, the main thrust retain legal counsel and file lengthy appeals. The conse-
of such reforms is to seek to address issues of affordability quences for the worker can include uncompensated legal
and efficiency, while at the same time dealing with per- expenses and economic hardship.
ceived weaknesses in cover and redress of harm. It seems Federal schemes include the Black Lung Programme
unlikely that these changes to existing systems will lead to for coal miners, the Longshoremen and Harbour Workers’
greater access to benefits for potential claimants. Compensation Programme, the Federal Employers’
Compensation Act, the Radiation Exposure Compensation
Act and the Energy Employees’ Occupational Illness
COMPENSATION SCHEMES IN THE Compensation Program Act. In several instances, these
UNITED STATES federal programmes replace or are intended to complement
state-based compensation programmes.
The development of workers’ compensation in the United In the majority of states, compensation is limited to
States has its origins as a response to the development by two-thirds of previous wages and coverage of medical
employers of defences to litigation by employees, for acci- costs. Funding of the schemes by employers, of whom the
dents at work, very similar in kind to ‘the unholy trinity of majority are insured, is intended to internalize the cost of
defences’ employed in the UK. These included contribu- work-related accidents and disease, providing an incentive
tory negligence, the ‘fellow servant’ rule (comparable to to employers to ensure job safety and health. However, risk
the defence of ‘common employment’) and the ‘assump- pooling, the basis of insurance, blunts the financial conse-
tion of risk’ (equivalent to violenti non fit injuria). Not quences of accidents and diseases caused by work, dimin-
surprisingly, therefore, much of the early development of ishing the impact of such incentives.
workers’ compensation in the United States was based on All claims for compensation schemes are handled by
principles derived from the German and UK schemes. state compensation boards. Insurers are entitled to dispute
Although workmen’s compensation schemes in the permanent disability claims. In any contested claim, the
United States are now insurance-based schemes, organized burden of proof is on the worker. This can cause consider-
state by state, the federal government took the lead in the able difficulty in substantiating the claim, particularly for
early twentieth century in providing compensation to its conditions of long latency, where the relevant exposure
workforce for accidents at work. The Federal Employers’ occurred many years before.
Liability Act of 1908 covered federal employees engaged Apart from federal schemes, workers’ compensation
in hazardous work and employees of certain carriers engaged varies from state to state. This is particularly the case for
in interstate and foreign commerce. It was adopted at the diseases. State schemes cover accidents without regard to
urging of President Theodore Roosevelt, who in a speech to fault unless self-inflicted or caused by intoxication. In most
Congress said that the ‘burden of accident falls upon the states, disease coverage was originally covered by sched-
hapless man, his wife and children’ which was ‘an outrage’. ules, which provided guidance for compensation boards
The turning point in the development of worker’s com- and courts. However, the continuous need to update the
pensation legislation in the United States was the adoption schedules, and their being considered restrictive and
by Wisconsin in 1911 of Worker’s Compensation, which was inflexible, has led to their being generally abandoned.
the subject of considerable debate. Employers lobbied suc- Many states only compensate diseases which are ‘pecu-
cessfully for what has become known as the ‘great trade off’. liar to’ or ‘characteristic of ’ occupation, i.e. specific to
Employers agreed to provide medical and wage replacement occupation. This creates particular difficulty for conditions
benefits in exchange for the employee giving up his/her right which have multiple causes and are of long latency, when it
to sue the employer. Several states subsequently adopted can be difficult to identify the particular workplace where
this model. However, it took until 1976 for all 50 states to the relevant exposure occurred. This is particularly true of
have some form of coverage for occupational disease. respiratory tract diseases, such as lung cancer, which has a
Workers’ compensation schemes in the United States predominant non-occupational cause, cigarette smoking,
are no-fault schemes: in return for relinquishing the right as well as several well-recognized occupational causes,
to sue his or her employer, the employee has the right to including asbestos, which is compensated uncommonly.
fair and timely compensation. This contrasts with mesothelioma caused by asbestos, hae-
The basic structures of workers’ compensation in the mangiosarcoma of the liver caused by vinyl chloride
United States and Canada are similar. A board or commission monomer and leukaemia caused by benzene, the first two
108 Compensation schemes
20. Marine WM, Gurr D, Jacobsen M. Clinically important 21. Soutar C, Campbell S, Gurr D et al. Important deficits of
respiratory effects of dust exposure and smoking in British lung function in three modern colliery populations:
coal miners. American Review of Respiratory Disease. 1988; relations with dust exposure. American Review of
137: 106–12. Respiratory Disease. 1993; 147: 797–803.
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SECTION FOUR
Legal issues
DIANA M KLOSS
The need for a medical opinion is a daily requirement of Criminal law is concerned with offences against society as a
those who work in the field of compensation for personal whole. Prosecution is therefore brought in almost all cases
injury. In disputes between employers and employees, the by a public official (Crown Prosecution Service in England
doctor may be asked to decide whether the employee is fit and Wales, Procurator Fiscal in Scotland). Prosecutions for
for work and, if not, whether he is likely to be able to return offences against the criminal law of health and safety at
in the foreseeable future. Doctors also regularly appear in work are brought by the Health and Safety Executive or
criminal courts to give an account of the victim’s injuries local authority. Crimes are divided according to the ser-
or to advise on the time and cause of injury. They may be iousness of the alleged offence. The less serious crimes are
asked for an opinion on the mental state of a person tried summarily by the magistrates courts in England and
accused of crime. In other areas, they may be drawn into a Wales, the district and sheriff courts in Scotland. The most
case where relatives doubt the validity of a will signed by serious crimes, such as murder and rape, are tried by a
a testator who was allegedly incompetent, or they may judge and jury in the Crown Court in England and Wales
become involved in child care cases. In a growing number and the High Court in Scotland. When a defendant is found
of cases, it is the doctor who stands accused of negligence guilty by the criminal court he is punished by imprison-
and must rely on other doctors to support what he has ment, fines, probation orders etc., but although the crim-
done, or omitted to do. This chapter will centre on inal courts now also have power in some cases to order
medicolegal reports requested by a lawyer in a case of per- compensation to the victim, this is very much secondary to
sonal injury arising out of a work-related accident or dis- the primary function of punishment. The Criminal Injuries
ease and will then deal with the role of the expert medical Compensation Board awards compensation out of public
witness appearing in a court of law. funds to the victims of crimes of violence.
The medical expert will be confronted with a totally dif- Civil law is concerned with the adjudication of property
ferent regime: a world of reasonable probabilities and rea- rights and the award of compensation to those injured by
sonable doubt which is foreign to his scientific training. He another’s unlawful act. A civil action is brought by the per-
may sometimes be asked to give evidence that may damage son who has suffered injury: the claimant (formerly known
his patient, and be unable to refuse. It is important that he as the plaintiff) in England and Wales, the pursuer in
understand a little of the legal process and of the needs of Scotland. In England, cases of major importance are tried
the courts. in the High Court; where less money is at stake, the County
114 Medicolegal reports and the role of the expert witness
Court is the proper venue. The equivalent courts in Scotland domestic courts to the Court of Justice of the European
are the Court of Session and the Sheriff Court. Jury trials Communities in Luxembourg.
are rarely found in civil actions: most cases are tried by a
single judge sitting without a jury. A defendant who is
found liable will most commonly be ordered to pay mone- THE ROLE OF THE DOCTOR IN PROVIDING
tary compensation or damages. Parties to civil actions MEDICOLEGAL REPORTS
have to finance themselves, unless they qualify for legal aid
or are backed by a trade union or an insurance company. There are two main circumstances where a medical report
The loser is ordered to pay the costs of the winner, though might be requested:
the party who wins in a contest with a legally aided defen-
dant cannot as a general rule recover his costs from the 1. When a doctor has been involved in a case as an active
legal aid fund. In recent years, however, lawyers have been participant and is asked to give evidence based on his
permitted to charge conditional fees whereby the amount knowledge of what has occurred. He may have treated
of legal costs depends on the success or otherwise of the the victim of a crime or accident in his surgery (office)
action. or in hospital.
In addition to the civil courts, there are a number of 2. When the doctor is asked after the event to bring his
administrative tribunals which deal with cases in a limited professional skill and knowledge to bear as to how an
area. Examples are the employment tribunals for employ- injury was caused, its effect on the person injured or
ment disputes and the first tier tribunals for disputes over the prognosis for the future. Here, the doctor acts as an
entitlement to welfare benefits. Of particular interest to expert witness, not as a participant in the event being
doctors are medical appeal tribunals, whose work includes scrutinized by the court.
the determination of issues of medical assessment related
to claims for industrial injuries benefits.
A vitally important distinction between the criminal and Witnesses of fact
civil process is that in the criminal courts the prosecution
must prove the defendant’s guilt beyond a reasonable The duty of confidentiality enshrined in the Hippocratic
doubt, whereas in the civil action the burden is to prove Oath yields to a conflicting duty to give evidence of events
liability on a balance of reasonable probabilities (‘more likely when called upon to do so by a court of law. Doctors, unlike
than not’). lawyers, have no privilege against disclosure of their patients’
In both civil and criminal courts, the British procedure secrets. A doctor who refused to obey the court’s order
is adversarial rather than inquisitorial. Each side must call could be punished for contempt. However, courts will
evidence to support its case. The judge acts as a referee to sometimes rule that a doctor need not give evidence of con-
see fair play and to make the final decision. Experts are fidential material if it is not necessary to assist the court to
called by both sides, not appointed by the judge, as in the make a decision. The judge may be asked to peruse the
civil law system adopted in most other European countries, relevant material in order to permit its non-disclosure.
derived from Roman law. In the United Kingdom, the Sometimes a claimant will be unable to decide whether
coroners’ courts, which deal with sudden, accidental he has a cause of action at all until he has seen medical evi-
and unnatural deaths, exceptionally follow an inquisitorial dence. He may have been told by fellow workers that he is
procedure. exhibiting classic symptoms of an occupational disease,
Membership of the European Union has added an extra but be unsure of the medical details of his condition or of
dimension to English and Scottish law. Since the aim of the the doctor’s diagnosis. Under the Civil Procedure Rules, he
community at its inception was primarily to create an eco- may apply to the court for an order that records be
nomic community, domestic laws relating to compensation disclosed. The court has a discretion to restrict disclosure
for personal injury have been unaffected. In other areas, to the plaintiff’s legal or medical advisers.
however, where laws directly or indirectly restrict competi- A health professional, including an occupational phys-
tion, sweeping changes have been directed by the Council ician, is obliged by the Data Protection Act 1998 to disclose
of Ministers, the legislature of the Community. Medical health records to the subject of those records, unless such
and other professional qualifications obtained in one mem- disclosure would damage his physical or mental health or
ber state must be recognized in other states. The criminal reveal the identity of a third party who wishes to remain
law of health and safety at work and laws relating to prod- anonymous. This also applies to records held by the
uct safety now stem mainly from Brussels, since a country National Health Service and foundation trusts and private
which failed to achieve minimum safety standards at work hospitals, and to all medical records, both manual and held
or which imposed unnecessarily strict standards for con- on computer.
sumer goods to exclude foreign imports would have an A report of this kind should begin with factual informa-
unfair advantage in an open market. Each member state tion about the doctor, his qualifications and position, and the
must enforce Community law through its own courts and patient. It should state how the doctor met with the patient,
other institutions, but a reference may be made from giving time, place and general circumstances, together with
The role of the doctor in providing medicolegal reports 115
the names of any other people present at the time. It should a new expert because of loss of confidence in an existing
go on to give details of the results of the examination, and expert. In Beck v Ministry of Defence (2003),1 a Flight
end with a summary of conclusions. At this stage, the doctor Lieutenant in the RAF developed psychiatric illness. He was
may give an opinion – for example, as to the cause of the treated by an RAF general practitioner and consultant
injury or the likely prognosis for the future. This evidence psychiatrist. He alleged that the treatment was negligent. The
may be vital later when the court has to apportion blame for MOD instructed an expert psychiatrist, but lost confidence
the accident or fix the amount of damages. in him because he had insufficient knowledge of the MOD
psychiatric referral system. They wanted a new expert, but
the claimant refused to be psychiatrically examined a second
Expert witnesses time. The MOD applied to the court for permission to
instruct a new expert. The Court of Appeal held that this
Expert witnesses are called upon, not because they know would be granted only on condition that they disclosed
anything about the facts of the case but because they can give to the claimant’s lawyers the report of the first expert.
an opinion as to a relevant issue. It is for the judge to decide Otherwise, the court would be encouraging the practice of
whether someone is truly an expert. In medical cases, formal ‘expert shopping’. A claimant can reasonably object to hav-
qualifications are of course important, as is experience in the ing to be examined again if this is, or may be, because the
relevant specialty. Any expert report, therefore, should be conclusions of the first expert have proved more favourable
prefaced with the qualifications and status of the doctor. In to him than the defendants had anticipated.
2000, a voluntary system of accreditation of experts of all In 2005, the Civil Justice Council approved the Protocol
kinds was created with the launch of the Council for the for the Instruction of Experts to Give Evidence in Civil
Registration of Forensic Practitioners (CRFP). The impetus Claims (the Protocol) and it was annexed to the Civil
for this was a number of criminal convictions which were Procedure Rules as guidance for the courts. This sets out the
quashed on appeal as unsafe and unsatisfactory because of duty of experts. They have an overriding duty to the court,
the quality of expert evidence. Registration, which depends which takes precedence over any obligation to the person
on demonstrated competence against defined standards, is instructing or paying them. ‘Experts must not serve the
voluntary. The council ceased trading in 2009. There are two exclusive interest of those who retain them’. Experts should
other well-respected voluntary organizations created to rep- provide opinions which are independent. A useful test of
resent and advise experts, the Expert Witness Institute and independence is that the expert would express the same
the Academy of Experts. opinion if given the same instructions by the opposing party.
In 1999, a major revolution occurred in the system of Experts should confine their opinions to matters which
civil justice in new Civil Procedure Rules (CPR), imple- are material to the disputes between the parties and pro-
menting reforms recommended by Lord Woolf in his vide opinions only in relation to matters which lie within
report: Access to Justice. Before this, lawyers and their their expertise. They should take into account all material
clients managed litigation for the most part. It was for the facts before them at the time they give their opinion. Their
parties to decide which witnesses they wished to call, and reports should set out those facts and any literature or
experts often regarded themselves as ‘hired guns’, tending other material on which they have relied in forming their
to be partisan in their evidence. Under the new rules, it is opinions. They should indicate whether an opinion is pro-
for the court to further the overriding objective of dealing visional, or qualified, and whether further information is
justly with the case. This involves active management by required to express a final opinion.
identifying the issues at an early stage, encouraging parties Experts should inform those instructing them without
to cooperate, fixing timetables and giving instructions delay (and preferably not in the middle of giving evidence)
about evidence. As regards expert evidence, though parties of any change in their opinions on any material matter and
remain free to instruct experts as they think fit, the court the reason for it. As Lord Justice Stuart-Smith said in
has complete control over the use of evidence in court. Vernon v Bosley (No 2) (1997):2
Where the court has not sanctioned the appointment of an
expert, the party may not be able to recover the costs of the If a doctor whom it is proposed to call to give evi-
expert’s report, and will not be permitted to rely on it in dence relating to the plaintiff’s expectation of life
the proceedings. writes in any accompanying letter or subsequently
Rule 35.1 states that expert evidence shall be restricted to that he has discovered that the plaintiff is suffering
that which is reasonably required to resolve the proceed- from a life-threatening disease unrelated to the acci-
ings. Courts may refuse to give permission for any expert dent, that letter must clearly be disclosed, if the
evidence to be called, may order that it be given in writing doctor is to be called to give evidence on the question
rather than orally in the proceedings, may limit the number of expectation of life.
of expert witnesses, or order that expert evidence may only
be given by a single joint expert. This is a matter for the It would be the doctor’s ethical duty to refuse to give
judge to decide and not for the parties and their lawyers. evidence if he knew that a material fact was being withheld
Sometimes, a party asks the judge for permission to instruct from the other side and that his evidence would therefore
116 Medicolegal reports and the role of the expert witness
be misleading. The Protocol advises that experts should can also make orders for costs directly against expert wit-
not be asked to, and should not, amend, expand or alter nesses who cause significant expense to be incurred in fla-
any parts of reports in a manner which distorts their true grant and reckless disregard of their duties to the court
opinion, but may be invited to amend or expand their (Phillips v Symes (2005)).5
reports to ensure accuracy, internal consistency, complete- Although Rule 35 obliges a party to disclose to the other
ness and relevance to the issues and clarity. In Noble v an expert report on which he intends to rely at the trial, this
Robert Thompson (1979),3 a psychiatrist wrote a report on does not extend to draft reports prepared at a preliminary
a depressed mother with the hope that it would assist her in stage to assist the lawyers to advise their client. The law of
obtaining access to her children. The doctor wrote that litigation privilege is that disclosure will not be ordered of
access should not be enforced against the wishes of the any report prepared with a view to legal proceedings, unlike
children themselves. He refused to delete this when asked the patient’s medical records which, as has already been
to do so and sued for his fee when the solicitors refused to discussed, do not attract the same privilege. In Lee v SW
pay. The judge gave judgement for the psychiatrist: ‘It Thames Regional Health Authority (1985),6 a child with
would be of no assistance to the courts if doctors were severe burns was transported from one hospital to another
encouraged to abandon their professional approach and in an ambulance. He was found to have suffered brain dam-
write reports designed to achieve particular objects, at the age, probably caused by lack of oxygen. The plaintiff’s
behest of the patient or anyone else’. lawyers asked the court to order disclosure of a memoran-
It is now mandatory for all reports to be signed and to dum prepared by the ambulance crew which had been sent
contain the following declaration: to the health authority with a view to obtaining legal advice
on liability. It was held that the court had no power to do
I confirm that insofar as the facts stated in my report this: the report was privileged. However, an accident report
are within my own knowledge I have made clear what prepared partly to make a finding as to causation and future
they are and I believe them to be true, and that the preventive measures and partly to prepare for legal pro-
opinions I have expressed represent my true and com- ceedings is not privileged against disclosure (Waugh v
plete professional opinion. British Rail (1980)).7 The Protocol recognizes that from
time to time parties instruct experts before proceedings are
Part 35 Practice Direction commenced or at any early stage in order to assess the
strengths and weaknesses of a claim, without the intention
In addition, where there is a range of opinion on the mat- of relying on those reports in litigation. Such reports are
ters dealt with in the report, the expert must summarize confidential and do not have to be disclosed to the other
the range of opinions and give reasons for his own opinion. side, neither do preliminary reports made in preparation of
The report must also contain a statement that the expert the final report. In Johnson v Marley Davenport Ltd (2004),8
understands his duty to the court and has complied and the claimant suffered an accident on a construction site in
will continue to comply with that duty. which he badly damaged his head and spinal cord. A profes-
The House of Lords held in Bolitho v City and Hackney sor of forensic pathology was instructed by the claimant’s
Health Authority (1998),4 a clinical negligence claim, that solicitors to give expert advice on the possible cause of the
as a general rule a consensus of opinion among distin- accident, of which the claimant could remember nothing.
guished experts in a specialty that a doctor has taken rea- He wrote a preliminary draft report for the purpose of a
sonable care will be accepted by the courts, but that the conference with the lawyers and a final report which was
court has to be satisfied that such an opinion has a logical disclosed to the defendants. The defendants asked the court
basis. As Lord Browne-Wilkinson put it: to order disclosure of the draft report, but disclosure was
refused by the Court of Appeal.
In particular, in cases involving, as they so often do, Rule 35.10 removes from the ambit of privilege the
the weighing up of risks against benefits, the judge lawyers’ instructions to the expert, who is now required to
before accepting a body of opinion as being reason- set out in his report ‘the substance of material instructions
able, responsible and respectable, will need to be sat- whether written or oral’. In Lucas v Barking Havering and
isfied that, in forming their views, the experts have Redbridge Hospitals NHS Trust (2003),9 it was held that this
directed their minds to the questions of comparative did not give a right to the opposing party to see every docu-
risks and benefits and have reached a defensible con- ment referred to in the expert’s summary of his instruc-
clusion on the matter. tions (as, for example, a witness statement), as long as the
expert’s summary was complete and not misleading.
Experts should be aware that any failure by them to However, if the expert is relying on published or unpub-
comply with the Civil Procedure Rules or court orders or lished literature, this must be disclosed.
any excessive delay for which they are responsible may A novel situation arose in W v Egdell (1990).10 W was
result in the parties who instructed them being penalized detained as a patient in a secure hospital without limit of
in costs and even, in extreme cases, being debarred from time as a potential threat to public safety after he shot and
placing the expert’s evidence before the court. The judge killed five people. Ten years later, he applied to a mental
The purpose of expert medical reports 117
health review tribunal to be discharged or transferred to a THE PURPOSE OF EXPERT MEDICAL REPORTS
regional secure unit. His responsible medical officer, who
had diagnosed him as suffering from schizophrenia which It is suggested that the doctor should always keep clearly in
could be treated with drugs, supported the application. His mind what it is that must be proved to the court. In an
solicitors instructed Dr Egdell, a consultant psychiatrist, to action for damages for personal injury, for example, the
examine W and report on his mental condition with a view claimant has to prove, on a balance of reasonable probabil-
to using the report to support his application to the tribu- ities, first that the defendant was negligent or in breach of
nal. In the event, Dr Egdell strongly opposed the transfer. his statutory duties, second that the negligence of the
The solicitors decided that as the report was unfavourable defendant caused the claimant’s injury and third that the
they would not place it before the tribunal and withdrew claimant suffered some material injury to his physical or
the application for time being. The doctor sent a copy, in mental health. The amount of the damages (the legal term
breach of confidence, to the health authority, the Secretary is ‘quantum’) will depend on the state in which the
of State and the tribunal, and the solicitors withdrew the claimant is left after the accident. If a young healthy girl
application for the time being. It was held by the Court of aged 17 years is very severely brain damaged in an accident
Appeal as follows: at work caused by the negligence of her employer and dies
almost immediately, her parents will receive only the statu-
A consultant psychiatrist who becomes aware, even in tory amount for bereavement, currently £10 000. However,
the course of a confidential relationship, of informa- if the doctors say she will live for another 20 years, though
tion which leads him, in the exercise of what the court paralysed and insentient, she will be able to claim damages
considers a sound professional judgment, to fear that of £1 million or more for the necessary nursing care, spe-
decisions may be made on the basis of inadequate cial accommodation and the loss of the earnings she would
information and with real risk of consequent danger have made if she had not been injured. Courts now have
to the public is entitled to take such steps as are rea- power to award periodic payments of damages rather than
sonable in all the circumstances to communicate the a lump sum (Courts Act 2005).
grounds of his concern to the responsible authorities. When a claimant has suffered such catastrophic injury
and the damages are large, defendant insurance companies
In Kapadia v London Borough of Lambeth (2000),11 the consider structured settlements. Until recently, these had
claimant was pursuing a claim for disability discrimination to be agreed between the parties, but the Courts Act 2005
against his employer in an employment tribunal. The gives a discretion to the judge to order periodic rather than
employer’s solicitors instructed an expert occupational lump sum payments. A structured settlement involves the
physician to examine Kapadia and write a report. Kapadia purchase of an annuity which then guarantees the claimant
gave his consent in writing, but when the case went to the a sufficient income for the rest of his or her life, with no
tribunal he objected to the report being shown to his danger of damages running out if the doctors’ predictions
employer without his having the opportunity to read and of life expectancy prove to be incorrect. The Inland
approve it first. It was held that by consenting to be exam- Revenue has agreed that these payments will not be subject
ined on behalf of the employers he was consenting to the to income tax.
disclosure in legal proceedings to the employers of a report In another case, a man in his 50s is diagnosed as suffer-
resulting from that examination. ing from asbestosis due to exposure to asbestos by his
The Civil Proceedings Rules do not apply to employment employer. He is breathless and unable to work. There is a
tribunals, but the Employment Tribunals (Constitution and possibility that he may contract mesothelioma or lung
Rules of Procedure) Regulations 2004 follow a similar cancer. He has been a moderate cigarette smoker all his
pattern. In De Keyser v Wilson (2001),12 the claimant com- adult life. The lawyers need from the doctor an estimate as
menced proceedings against her employer in the employ- to the percentage of disability caused by the cigarettes and
ment tribunal for constructive dismissal. She alleged that she a forecast of what may happen to him in the future.
had a depressive illness which had been caused by stress at Because the course of disease and injury is often unpre-
work. Solicitors for the employers asked that she undergo a dictable in the early stages, the doctor may write in his first
psychiatric examination by an expert occupational physician. report that he wishes to examine the patient again after a
The letter of instruction set out a number of facts about the specified period has elapsed. Settlement of the claim may
claimant, for example the death of her brother, a contested be deferred, not through lawyers’ delays but to allow the
custody case, an adulterous affair and the criminal conviction full extent of the damage to become apparent. When the
of a man described as her lover, and invited the doctor to development of a further disability, such as epilepsy, is pos-
conclude that her illness had been caused by these events sible only in the longer term the lawyers may apply for an
rather than her employment. The Employment Appeal award of provisional damages. Such a settlement allows the
Tribunal directed that the case should be allowed to proceed, claimant to return for more if his medical condition deteri-
but that another expert should be appointed, to be instructed orates after his award of damages. However, it was held in
in more general terms, because the instructions contained Willson v Ministry of Defence (1991)13 that the mere pro-
material that was irrelevant and abusive. gression of a particular disease was not appropriate for a
118 Medicolegal reports and the role of the expert witness
provisional award. The plaintiff had slipped on a polished insurance policy is extant the claimant will not suffer,
floor at work, injuring his ankle. Medical reports a year though he can never recover more than 100 per cent of his
later stated that there would be degeneration of the ankle loss.
joint, that the plaintiff would remain prone to further
injuries and that there was a possibility of arthritis. It was
decided that this was not a suitable case for an award of THE FORM OF THE EXPERT REPORT
provisional damages and that damages would be awarded
on a lump sum basis. The report should begin with the name and qualifications
Damages are of two kinds: special damages to compen- of the expert, the date and circumstances of his examin-
sate for losses up to the date of settlement or trial, and gen- ation. The first section should deal with the history of the
eral damages to make up for future loss. By section 22 of the disease or injury. The date of birth of the patient should
Social Security Act 1989 (amended in 1997), the defendant always be given. In an occupational injury case, the work is
must deduct from the damages for loss of earnings paid to as important as the victim, but the lawyers will probably be
the claimant in respect of an accident or injury occurring asking for a separate report from an engineer on the tech-
after January 1, 1989 the gross amount of any relevant social nical aspects. In the past, lawyers were concerned about the
security benefits paid or likely to be paid to the victim. The non-admissibility of hearsay evidence, that is evidence of
defendant then reimburses the Secretary of State with this which the witness has no personal knowledge, but which
sum. Relevant benefits for this purpose include attendance has been reported to him. The Civil Evidence Act 1995 now
allowance, disablement benefit, income support, incapacity permits hearsay evidence in civil proceedings, subject to
benefit, disability living and working allowance and job- safeguards.
seeker’s allowance up to the end of the period of five years The second section of the report should elucidate the
following the accident. present state of the injury. Obviously, this will be made up
Causation is a particularly difficult area in which med- partly of what the patient says and partly of objective
ical evidence may be vital. In cases of occupationally examination, such as radiographs or scans. At this stage,
induced disease, evidence of research may be more import- the doctor should consider whether there is any indication
ant than examination of the claimant. The rate of hearing that the patient is inventing all or some of the symptoms
loss of workers exposed to high levels of noise in the ship- and signs. Accusations of malingering should not be made
yards was a central part of the evidence in Thompson v lightly, however, although the patient cannot sue the
Smiths Shiprepairers (1984).14 The court decided that most doctor for defamation if he makes such an allegation. Later
of the loss had occurred in the first years of exposure at a reports when injuries appear not to have responded to
time when employers could not reasonably be expected to treatment may contain references to ‘functional overlay’ or
guard against it – a ruling that considerably lowered the ‘compensationitis’. The law is that genuine psychological
awards of damages. consequences of an injury do not preclude the award of
In Fairchild v Glenhaven Funeral Services Ltd (2002),15 a damages: only if the patient is consciously inventing or
worker who had been exposed to asbestos dust or fibres exaggerating his symptoms is he not entitled to compensa-
while working for several different employers had died of tion. Defendant insurance companies may hire a photo-
mesothelioma, a cancer caused by one or more asbestos grapher to catch such a claimant up a ladder repairing his
fibres entering the pleura (or peritoneum). Did the fatal roof when he is supposed to be in agony from a bad back.
fibre or fibres which caused the cancer arise from the neg- Courts have held that such covert surveillance is not a
ligence of defendant A or defendant B or defendant C? It breach of the Human Rights Act 1998 (Jones v University of
was impossible to identify the source of the rogue fibre and Warwick (2003)).17
if the law demanded that degree of proof, the claimant At this stage in the report, the doctor should give an
would be bound to fail. The House of Lords held that, in opinion as to the cause of the symptoms, setting out any
such a case, it is enough for the claimant to prove that the possible alternative causes and any causes related to the
employer’s negligence materially increased the risk of con- conduct of the patient (e.g. obesity or cigarette smoking).
tracting the disease. All the employers who had negligently As previously indicated, it is important to try to put a
exposed the claimant to asbestos were potentially liable. In percentage figure on alternative causes, for example, ‘the
Barker v Corus (2006),16 it was held that each employer’s patient’s smoking has contributed 50 per cent to his reduced
insurance company could be liable only to pay a propor- lung function’. To write a fully comprehensive report, it is
tion of the damages related to the extent of the exposure important to gain access to the patient’s general practi-
for which they were responsible, but this was reversed for tioner and hospital records. The patient’s written consent
mesothelioma claimants by the Compensation Act 2006. will, of course, be necessary. Some doctors follow the policy
The effect is that, where companies A, B and C have all of writing a report and accompanying it with a covering
been negligent in exposing a claimant to asbestos fibre, the letter pointing out inconsistencies or weaknesses in the
claimant can sue any one of them for the whole of his dam- patient’s case. ‘The patient says he has been in pain for
ages. The company held liable can then sue the others for a months, but he has never visited his general practitioner
contribution, but if they have gone out of business and no during that time, nor has he been off work’. This practice is
Going to court 119
not to be encouraged. The doctor’s duty to the court means most defendants, who are usually insurance companies,
that his report must be as objective as possible. are willing to settle any claim which contains some merit.
The next section should assess the effect of the disability However, some claims have to be fought, because they are
on the patient both now and in the future. The following regarded as being without any justification or, more often,
are important factors: because they are in some way a test case on which other
cases may depend.
● Is there pain? Will it continue? The best medical expert witness from a lawyer’s point of
● Is there loss of mobility? Will it continue? view is one who writes fair and balanced reports which he
● Has the patient lost work? If still off work, how long will is able to defend under cross-examination. Such experts
this continue? Will the patient be able to resume his job, are likely to have long waiting lists. In some cases, doctors
or will he be permanently unfit? What job will he be able give up their medical practice in order to concentrate
to do, if any? on medicolegal work. This may eventually be counter-
● What jobs around the house is the patient unable to productive, if the other side is able to argue that the expert
do? Child care? Housework? Gardening? Do-it-yourself? is out of date or lacks recent ‘hands-on’ experience.
Will the situation improve? Experts are encouraged to agree reports if this is pos-
● What hobbies is the patient now unable to enjoy? Will sible. It would be unusual for two eminent doctors to
the situation improve? have totally opposing views of a particular case. The Woolf
● How has the disability affected the patient’s general Report on civil proceedings recommends that every attempt
quality of life? Relationships? Enjoyment of life? What is should be made to resolve any conflict of evidence between
the future likely to hold? doctors before the trial. The court may limit the parties to
one expert if that is all that is necessary.
The report should state clearly what future complications
are possible in the medical condition, if any. Arthritis? The basic premise of my new approach is that the
Epilepsy? Cancer? Again, the degree of risk should be esti- expert’s function is to assist the court. There should be
mated and the possible time scale for example, ‘80 per cent no expert evidence at all unless it will help the court,
likelihood of arthritis within five years’. If an injury has and no more than one expert in any one speciality
brought forward the onset of a condition that would other- unless this is necessary for some real purpose … In
wise have remained dormant, an estimate should be made cases where opposing experts are involved, the court
of the number of years of dormancy lost. The likely expect- already has power to direct the parties’ experts to
ation of life should be given. meet, before or after the experts have disclosed their
A typical expert report prepared for a civil court in a per- reports, so as to identify and reduce areas of differ-
sonal injury claim should contain the following elements: ence. Under the new rules the experts will be required
(not simply authorized, as at present) to produce a
● A coversheet with the name of the case and the case report identifying matters agreed and outstanding
number, the name of the expert and the name of his areas of difference after such a meeting.18
instructing solicitors
● A table of contents As has been previously stated, the expert’s role should
● A brief curriculum vitae of the expert be that of an independent adviser to the court. Lack of
● A summary of conclusions objectivity is to be avoided, especially if it arises from
● The expert’s instructions improper pressure by solicitors. As Lord Wilberforce said
● Documents examined (e.g. medical records) and other in Whitehouse v Jordan (1981):19
sources of evidence (e.g. any examinations or tests
carried out) It is necessary that expert evidence presented to the
● Chronology court should be, and should be seen to be, the inde-
● Scientific or technical background, with reference to pendent product of the expert uninfluenced as to
relevant literature form or content by the exigencies of litigation.
● Opinion
● Literature citations It is not the function of the expert to comment in evidence
● Declaration that the expert acknowledges that his first about the parties’ credibility as witnesses, merely to assess
duty is to the court, and the statement of truth as set out the likelihood of the truth of their story by objective criteria.
in the Practice Direction (above). If the case does go to court, and the expert is called,
certain practical points must be borne in mind. The first
is that the expert must be available to give evidence, which
GOING TO COURT may necessitate complicated arrangements if he or she is
still in practice. Some solicitors follow the policy of sub-
Most actions for damages for personal injury are settled poenaing their own witness, to be certain of his presence.
out of court. The costs of legal proceedings are such that Courts will be sympathetic to the needs of patients, but the
120 Medicolegal reports and the role of the expert witness
doctor may have to wait for a considerable time before was instructed as an expert witness. Some time after the
being called. issue of proceedings, Callaghan agreed with the insurance
Obviously, an expert should try to make a good impres- company’s expert that another and cheaper solution would
sion on the judge. Attire should be sober, and hands should be equally effective and as a result the claimant was forced
be kept out of pockets and away from jewellery. When giv- to settle the claim for an amount of money which covered
ing evidence, it is important to address the judge, not his legal costs, but not the costs of the remedial work. He
merely the advocate who is asking the questions. If there is therefore sued Callaghan for negligence. It was held that an
to be reference to reports, these should be held in a pagin- expert is not immune from an action for negligence in
ated bundle, of which the judge and the other side should respect of advice as to the merits of a party’s claim in litiga-
also have a copy. The expert should be positive and firm, yet tion, but that in this case, where the surveyor’s advice was
reasonable, in approach and keep calm, especially under for the principal purpose of his eventually giving evidence
cross-examination. He should remember that counsel may in court, he did have immunity from civil liability.
attempt to cast doubt on his credibility by making him lose In Hughes v Lloyd’s Bank plc (1998),22 in contrast, the
his temper or contradict himself. If the expert does not plaintiff was injured in a road accident. She attended her
understand a question, or needs time to consider it, he general practitioner who was asked to report on the sever-
should ask for it to be repeated. If he does not know the ity of her injuries for the purpose of a claim for compensa-
answer to a question, he should say so and not be tempted tion. He wrote that her condition was not serious, on the
to venture speculative opinions which cannot be substanti- faith of which the plaintiff settled her claim for £600. It
ated. It may be that in the course of the proceedings the then became apparent that the injury was far more severe
expert’s opinion has changed, because new facts have come than the doctor had predicted and the plaintiff sued him
to light. If this is the case, it is vital for him to inform his for negligence. The Court of Appeal held that he was not
barrister before giving evidence. He should never try to tell immune from civil liability. When he made his report he
jokes or upstage the judge when in the witness box. The was not an expert witness, merely a paid adviser at a pre-
judge will respect expert medical qualifications, but only if liminary stage. If he had failed to take reasonable care, he
he is treated with respect. could be sued for compensation.
In civil proceedings, the witness is first subjected to an In Phillips v Symes (2004),23 Mr Justice Peter Smith held
examination by his own counsel. Although this should be a that an expert witness can be ordered to pay costs where he
friendly process, it is important to answer questions, rather has been guilty of ‘flagrant reckless disregard of his duties
than volunteering information. Counsel will have planned to the court’.
how best to elucidate the evidence he needs. This is fol- The question later arose as to whether expert witnesses
lowed by cross-examination by counsel for the other side have immunity from the disciplinary powers of profes-
who is, of course, likely to be more hostile, though not sional bodies, such as the General Medical Council (GMC).
discourteous, since bullying a witness can be counter- Sally Clark, a solicitor, was convicted in 1999 of the murder
productive. Finally, a re-examination is permitted to clar- of two of her three infant children. At the trial, Sir Roy
ify points which have been raised in cross-examination, Meadow, an eminent paediatrician, gave evidence for the
but not to repeat the original evidence. prosecution that the risk of two children in the same house-
No one can be liable for defamation or negligence in hold dying from accidental ‘cot death’ was 1 in 73 million.
respect of anything done in the course of judicial proceed- Mrs Clark’s conviction was later quashed because the pros-
ings, which are protected by absolute privilege, that is even ecution had not disclosed relevant medical evidence to the
if the witness giving oral or written evidence to a court defence (not because Professor Meadow’s evidence was
spoke maliciously without belief in the truth of what he misleading), but Professor Meadow was referred to the
was saying he cannot be sued for it, although he can be GMC’s Fitness to Practise Panel by Mrs Clark’s father. They
prosecuted for the crimes of perjury and contempt of court concluded that he had gone outside his field of expertise
if he makes a false statement without an honest belief in its and given erroneous and misleading statistical evidence.
truth. It was established by the House of Lords in Watson v Although he had acted in good faith, he was convicted of
M’Ewan (1905)20 that the same immunity attaches to state- serious professional misconduct and his name was erased
ments made by the expert witness while preparing for trial. from the medical register. Professor Meadow appealed to
In Stanton v Callaghan (2001),21 the Court of Appeal the High Court. Mr Justice Collins held that he was not
considered how far that immunity extends. The claimant guilty of serious professional misconduct and restored his
owned a house which had suffered subsidence damage. name to the register. He also held that an expert witness
Partial underpinning was carried out, paid for by insurance, should, in general, be immune from fitness to practise
but this failed to stabilize the property. An expert surveyor, (FTP) proceedings unless the trial judge found his short-
Mr Callaghan, was engaged by the claimant and reported comings so serious that he should be referred to his profes-
that partial underpinning had been an inappropriate solu- sional body, if he or she had one. The GMC appealed to the
tion. He recommended total underpinning, but the insurers Court of Appeal which held that expert witnesses did not
rejected the claim. The claimant therefore commenced have immunity from FTP proceedings, but agreed that
proceedings against the insurance company, and Callaghan Professor Meadow, though guilty of misconduct in going
References 121
Occupational toxicology
Table 10.1 Toxicity rating of chemicals by probable lethal oral dose in adults.
the occupational physician must be able to recognise haz- Lipid solubility is a major factor determining the extent
ardous situations, know about the absorption and detoxi- and rate of simple diffusion through a lipoprotein mem-
fication of chemicals and have a detailed knowledge of brane: lipophilic molecules diffuse more readily than those
their potential toxic effects. that are hydrophilic. The rate of transport is dependent
An additional factor is the interindividual variation in on the partition coefficient (i.e. the ratio of solubility in
specific detoxifying enzyme activities which may differ octanol/water). Non-ionized molecules are often more
markedly (greater or lesser) between individuals within lipophilic and ions generally more hydrophilic, so the
a population. These variations constitute subgroups, or movement of electrolytes, such as organic acids and bases,
genetic polymorphisms, in the population; some sub- is related to the degree of ionic dissociation and the lipid
groups are small in size (poor metabolizers of debrisoquine solubility of the non-ionized form of a compound.
constitute about 10 per cent of the general population) or The extent of dissociation is expressed in the Henderson–
large (the general population are more or less equally Hasselbach equation:
divided into either fast or slow acetylators). Subgroups
with greater activity may produce toxic metabolites more pKa pH log[A]/[HA]
rapidly (fast acetylators are more likely to develop isoni-
or
azid hepatotoxicity), whereas poor metabolizers may be at
more risk because they are unable to detoxify a chemical pH pKa log[base]/[acid]
adequately (slow acetylators are more likely to develop an
isoniazid neuropathy and poor debrisoquine metabolizers where [HA] is the concentration of the non-ionized form,
a perhexiline neuropathy). The role of interindividual vari- [A] is the concentration of the ionized form and pKa is
ation in susceptibility to toxicity requires greater general the negative log of the dissociation constant.
consideration, since, in certain combinations of circum- The cell membrane controls the movement of chemi-
stances, it may contribute to the ‘dirty worker’ phenom- cals in or out of the cytoplasm and several methods have
enon. At present, most work on genetic polymorphisms been identified by which xenobiotics are transported
relates to drug metabolism and toxicity, but the relevance across membranes:
to non-drug chemicals is increasingly recognized.
Within species differences in susceptibility are usually ● Simple diffusion down a concentration gradient is the
of a lesser magnitude than the variation between species. most common and simple method, does not require
Most toxicity data are derived from animal toxicity tests expenditure of energy and is the principal mechanism
and the models generated subsequently applied to man. for the transport of most lipid soluble, non-ionized
Apart from the ethical considerations related to this use of compounds.
animals, serious scientific problems may arise in extrapo- ● Filtration allows water, ionic and hydrophilic molecules
lating from animal models to human health risks. Ideally, of appropriate size to pass through small pores (about
data generated from animals should be supplemented or 0.4 nm in diameter) in the cell membrane.
replaced with information derived from human studies. ● Facilitated diffusion is carrier-mediated, transports
chemicals with specific common structures across the
cell membrane and at high concentrations may become
ABSORPTION AND DISTRIBUTION OF saturated.
CHEMICALS ● Active transport allows the absorption of substances
against a concentration gradient, but requires the
Foreign compounds (also referred to as exogenous chem- expenditure of energy and so is linked to the metabolic
icals or xenobiotics) must be absorbed from the surround- activity of the cell.
ing environment and transported to a target site in the ● Phagocytosis and pinocytosis enable particulates and
body for a toxic effect to occur. The chemical may have to solutions to be taken into a cell by the extrusion or
cross the many cell membranes which form a lipoprotein invagination of an area of the membrane and engulfing
barrier to the extracellular environment, as well as main- of part of the extracellular environment.
taining the integrity of the cell. Specific transport mecha-
nisms evolved to facilitate the absorption and distribution These absorption processes, although at a cellular level,
of nutrients, rather than toxic chemicals, and most xenobi- influence the degree and nature of absorption through the
otics are transported by simple methods and not complex lungs, skin and gastrointestinal tract and are, therefore,
carrier-associated processes (some compounds do enter relevant at the macro level of hazard assessment.
cells on such carriers, e.g. paraquat transport into lung
cells3). A carrier is usually specific for an endogenous sub-
stance and unless the xenobiotic compound has a very sim- TOXICOKINETICS
ilar structure, it will not usually be able to bind to the
carrier (paraquat has a similar structure to endogenous Toxicokinetics is the study of the dynamic (kinetic) rela-
diamines, such as putrescine4). tionships between the concentration of a chemical (toxicon)
Toxicokinetics 129
in body fluids and tissues and its biological effects (toxico- kabs kel
dynamics). The investigation and management of an Blood concentration
individual exposed to toxic chemicals require a basic absorbed chemical eliminated chemical
knowledge of toxicokinetic concepts, alongside under-
standing of the mechanisms by which chemicals gain entry
to the body and are biotransformed into non-toxic or pos-
sibly toxic metabolites. Toxicokinetic analysis produces a
mathematical description of the dynamics of absorption,
distribution and elimination of a chemical. Although this
involves the descriptive use of mathematical expressions Other compartments
and models, it does have a practical use in evaluating the
significance of blood concentrations obtained from bio-
logical monitoring and then determining the nature of
exposure control (i.e. risk management). (Pharmacokinetic Figure 10.1 Compartmental model.
analysis quantifies the dynamic changes in the concentra-
Exponential decay curve for chemical elimination
tion of a drug (pharmacon) and has been incorporated 80
into toxicokinetics as there are no fundamental differences
between a drug and a toxin – the major toxic effect of a
Toxicokinetic concepts 0
0 2 4 6 8 10 12 14
The body is composed of a multitude of real ‘compartments’ Time (hours)
in the form of cells, tissues and organs. However, the analy-
Exponential decay curve linearized by using log scale
sis of kinetic data necessarily models a limited number of
theoretical compartments. These models are one solution to 100
the analysis of data but it must always be remembered that
Chemical concentration in blood
(saturation) kinetics. In first-order kinetics, a constant elimination of a compound since clearance by a particular
fraction of the chemical is eliminated in unit time. In zero- organ can be estimated (similar to measuring renal clear-
order kinetics, a constant mass of the chemical is elimi- ance of insulin, etc.).
nated in unit time and, consequently, the process can In simple terms,
become saturated and toxic effects occur following a very
Cl VD Kel
small increase in dose.
The half life (t 1⁄2) of a chemical is the time period during Changes in the VD may alter the t 1⁄2, but leave clearance unal-
which the blood concentration decreases by one-half and is tered. Chemicals with a large VD may have a high clearance
inversely related to the elimination rate constant (β): yet persist in the body and have a long t 1⁄2 of elimination.
The total systemic clearance is dependent on the specific
t 1⁄2 0.693/β (where 0.693 is loge (ln) 2). clearances of each organ:
The half-life can be determined from the slope (elimina- Clsystemic Clrenal Clhepatic Clother routes
tion rate) of the log plasma concentration/time graph fol- The clearance of a chemical by an organ (Clorgan) can be
lowing a single dose of a compound (Figure 10.2). measured and is principally dependent on blood flow and
The concept of a half-life is useful for studying the the degree of extraction (extraction ratio, ER) of the chem-
uptake and elimination of compounds as it can be shown ical from blood:
that after 3.3 half-lives the plasma concentration reaches
90 per cent of the equilibrium concentration, and 95 per Clorgan Q ER
cent after five half-lives. Hence, 5 t 1/2 is the time taken for where Q is the organ blood flow and ER is the extraction
95 per cent of a dose of chemical to be eliminated from the ratio.
body after absorption, or to reach 95 per cent of its steady- The ER is determined from the arterial and venous con-
state value. The half-life is also the minimum time interval centration difference across an organ:
between chemical exposure (or drug administration) that
avoids progressive accumulation. Data about the elimin- C A CV
ER
ation half-life of a compound can be used to assess the CA
importance of the duration of exposure and increase the value
of either blood or breath monitoring of exposed workers. where CA is the concentration in blood flowing into organ
The volume of distribution (VD) is a theoretical esti- (arterial) and CV is the concentration in blood flowing out
mate of the extent of the distribution of a chemical in the of organ (venous).
body, provides a measure of the relative magnitude of For those organs with a high ER (e.g. liver, kidney),
differential tissue uptake and is expressed in units of litres clearance will be high and directly dependent on organ
or litres/kg: blood flow. Chemicals with a high liver clearance undergo
extensive first-pass metabolism (e.g. nitrites). Organs with
VD χ/C0 a low ER (e.g. muscle, bone) have a clearance that is not
where χ is the total amount of chemical (i.e. body burden, dependent on blood flow.
if bioavailability is 100 per cent) and C0 is the plasma con-
centration at t0. KINETICS OF EXPOSURE
Compounds with a large volume of distribution are
widely and extensively distributed throughout the tissues The principal routes of exposure in the workplace are by
of the body and the plasma concentration constitutes a inhalation or skin absorption.
small fraction of the total body burden. A small volume of
distribution implies limited tissue distribution and indi-
cates that the plasma concentration is a good indicator of Inhalation kinetics
the total amount in the body (chemicals with a VD approxi-
mating to blood volume (3–5 litres) are almost totally The lungs enable the efficient transfer of gases between the
restricted to systemic circulation); VD is apparent and not body and the environment. The tissue barrier separating
real, so a chemical which is concentrated in a tissue (such air and blood is only 0.5–1.0 μm thick and the 300–400
as fat) and has a low blood concentration, will have a VD so million alveoli provide a large surface area for diffusion. In
high that may markedly exceed the total volume of the addition, the media on either side of this barrier are con-
body (e.g. 200 litres for some organic solvents). tinuously renewed; the air is changed 12–15 times per
Clearance (Cl) is the volume of the VD that is com- minute and the pulmonary blood flows at a rate of 3.5–5
pletely cleared of a chemical per unit time (i.e. mL/min, litre per minute at rest. It is not surprising, therefore, that
litre/hour). Clearance is a more independent measure of volatile chemicals can be both efficiently absorbed from,
elimination than half-life since it is a physiologically mean- and eliminated in, the breath.7
ingful measure of the efficiency of elimination from the Analysis of expired air has been used to diagnose dia-
body. It provides the most reliable measurement of the betes and uraemia and, more extensively, to detect ethanol
Kinetics of exposure 131
consumption in motorists (although only about 1 per cent Solubility is inversely related to temperature and propor-
of the total body burden of ethanol is eliminated via this tional to the pressure of the chemical in the surrounding gas.
route). Real-time monitoring of the breath of workers The partial pressures of constituent volatile compounds vary
exposed to volatile compounds in industry is a potentially with the absolute pressure but, at a fixed pressure, the con-
useful non-invasive technique for determining the degree centration of each gas or vapour varies directly with its par-
of absorption, but does require that the factors affecting tial pressure and indirectly with the total pressure of the
the absorption, distribution, metabolism and elimination gas/vapour mixture. A gas or vapour present at a partial
(i.e. the toxicokinetics) of compounds have been previ- pressures of 100 per cent can still have its concentration
ously determined for this route in man.8 (wt/unit vol) varied over a range that is determined by the
A number of volatile organic compounds can be iden- absolute pressure.
tified in the breath of the normal general population9,10 at The rate of delivery of an inhaled mixture of air and a
concentrations of parts per billion (in hospital practice volatile compound depends upon alveolar ventilation.
the inhalation kinetics of volatile compounds are of A doubling of alveolar ventilation from 4 litre/min to
importance to the anaesthetist); in industrial workers the 8 litre/min produces a minimal increase in the blood concen-
concentrations are generally in parts per million. Breath tration of a poorly water soluble substance, but an appre-
analysis has been used in experimental toxicology to ciable increase for highly water-soluble substances. Cardiac
study lipid peroxidation and in the investigation of defec- output has an opposing effect on alveolar concentration
tive intestinal absorption, but monitoring of marker and this is most noticeable for highly water soluble, or
metabolites in the expired breath remains a relatively extensively metabolized substances, rather than poorly sol-
unexploited technique. However, there is renewed inter- uble compounds. An increase in cardiac output results in a
est in the potential of breath monitoring in the diagnosis larger amount of the inhaled substance passing from the
of certain disease states. lungs to the blood. A decrease has the opposite result and
Routine monitoring of the workplace usually assumes causes a rise in alveolar concentration.12
the level of contamination of air with a compound is a reli- An insoluble substance that does not pass into the
able indicator of worker exposure and, by implication, bloodstream will increase in alveolar concentration until it
probable absorption of the chemical. However, this is not a is equal to the environmental air concentration, the time
direct relationship; the environmental concentration merely taken being equivalent to the lung wash-in time. A sub-
indicates the potential for absorption. Under continuous stance with an infinite solubility could in theory never
exposure, any change in the inhaled air concentration will increase the alveolar concentration and, although such
have a corresponding effect on the alveolar air concentra- substances do not exist, there is a broad range of solubili-
tion. Increasing the duration of exposure produces a pro- ties. The concentration in alveolar or expired air, expressed
gressive increase in blood concentration towards a plateau relative to the environmental air concentration is inversely
value (equilibrium is reached). A progressive saturation of proportional to the blood solubility of a compound. Relative
blood and tissues with the compound involves a reduction concentrations of 0.5 are poorly soluble and those 0.5
in the difference between arterial and venous blood with are highly soluble. The effect of solubility on alveolar con-
less of the inhaled compound moving from the alveoli to centration is seen in Figure 10.3.
capillary blood. For volatile compounds that are highly The aerodynamic particle sizes of aerosols, mists and
lipophilic and selectively taken up by fatty tissues, tissue sprays also affect their accessibility to alveoli and large par-
saturation is never reached in the normal exposure period ticles may be deposited in the larger airways, or in the
in the workplace. In contrast, the elimination of such com- pharynx, and swallowed.
pounds from the body is extremely slow and the potential The arterial concentration of an inhaled compound can
exists for progressive accumulation following frequent be estimated from the alveolar concentration using the
modest exposures.11 blood–air partition coefficient of the chemical (if partial
Other factors influencing the inhalation kinetics of a pressure equilibrium is attained rapidly). This is not attained
volatile compound include the environmental air concen- immediately, but requires a finite time that depends on the
tration, duration of exposure, rate of alveolar ventilation, half-life of the compound:
cardiac output, blood and tissue solubility and the degree of
metabolism of the chemical. Volatile compounds are usually Pc
t 12 0.693 V
inhaled as a gas mixture with air and most are completely F
miscible in all proportions. The concentration of gases and
volatile compounds in a mixture is expressed in terms of where V is the tissue volume, Pc is the tissue–blood parti-
partial pressures, which are often incorrectly considered tion coefficient and F is the rate of blood flow to the tissue.
equivalent to concentrations; the relative concentrations of A high relative alveolar concentration is found for com-
dissolved materials can be expressed in terms of partial pres- pounds that undergo little metabolism. As the degree
sures which add up to a total pressure of 100 per cent. How- of biotransformation increases so does the level of
ever, a limit is set on the concentration (wt/unit vol) which metabolites in pulmonary blood. The combined effects of
this represents by the solubility of the volatile materials. metabolism and solubility affect the blood kinetics of a
132 Occupational toxicology: general principles
Table 10.2 Comparative capability for biotransformation. reduction or hydrolysis of the parent compound, and
phase 2, in which the metabolite is conjugated to glucuronic
Organ Approximate comparative capability
acid, glutathione, glycine, sulphate or some other endoge-
for biotransformation of foreign
nous compound.
agents (% relative to activity of
In phase 1, a polar reactive group is introduced into the
liver)
molecule to increase water solubility and make the com-
pound suitable for phase 2 where the altered molecule is
Liver 100 combined with an endogenous substrate to produce a
Adrenal cortex 75 water-soluble conjugate that is more readily excreted in the
Lungs 30 urine. Consequently, the principal function of biotransfor-
Kidney 30 mation is to facilitate the elimination of a foreign agent by
Testes 20 its conversion to a more polar (water soluble) metabolite
Skin 10 and is, therefore, a detoxification mechanism. In some
Gastrointestinal tract 10 cases, the intermediate metabolites or final products may
Spleen 5 be more toxic than the parent compound (i.e. an entoxifi-
Heart muscle 3 cation). Such metabolites may be systemically toxic or,
Skeletal muscle 1 because they are produced locally by an organ, have toxic
effects in the tissue of biotransformation. Most cells, par-
ticularly in the liver, have protective biochemical systems
an iron atom that can change between divalent and trivalent to prevent damage to vital cell processes from locally pro-
oxidation states. This enzyme combines with the substrate duced toxic metabolites.
and molecular oxygen as part of a process through which the In phase 1 metabolism, biotransformation may result in
substrate is oxidized. The group of enzymes are classified as the formation of compounds with a variety of properties
mixed function oxidases, the specific oxidizing enzyme, depending on whether toxicity has been increased or
cytochrome P450, having a characteristic peak in the reduced decreased.
form at 450 nm in a carbon monoxide adduct difference
spectrum (hence P450). The enzyme requires an electron INCREASED TOXICITY
transport chain for its reduction. This consists of a flavopro-
tein enzyme, cytochrome c reductase (cytochrome P450 Parathion, an organophosphate pesticide, is relatively non-
reductase) that transfers electrons (e) from the flavine to toxic to man, but in insects is rapidly metabolized (activated)
cytochrome P450. Cytochrome c reductase requires NADPH by desulphuration to paraoxon, a potent cholinesterase
as a coenzyme; microsomal oxidation requires both NADPH inhibitor. There is some evidence for variability in man of
and O2. Cytochrome P450 exists as a family of isoenzymes parathion activation by P450 and of activity of the enzyme,
with differing and overlapping specificities and more than paraoxonase, which further metabolizes the paraoxon.21
eight gene families have been identified.19,20
Cytochrome P450 is abundant in the liver, which is the
primary site of protection against systemic poisons, but
may occur in other parts of the body, such as the kidney,
ovaries, testes and olfactory mucosa. The presence of the
enzyme in the lungs, skin and gastrointestinal tract reflects
a defensive role in these organs against local toxic xenobi-
otics. Oxidase enzyme activity is mainly associated with the Although biochemical activation may present some
smooth endoplasmic reticulum. When tissues, such as liver, human hazard, it may have a useful application in the
are homogenized, the ER is broken down to form small development of new pesticides or prodrugs that are con-
vesicles known as microsomes. Microsomes are the fraction verted into active products only following metabolic trans-
collected from centrifugation of tissue homogenate at formation in a target species.
about 100 000 g and, essentially, contain the rough and
smooth endoplasmic reticulum and Golgi apparatus. There DECREASED TOXICITY
is evidence that the microsomal enzymes are associated
with a lipid membrane and are lipid-dependent. Sonic Phenobarbitone is detoxified by hydroxylation of the
vibration, or the use of hypotonic solutions, fail to solu- aromatic ring to form parahydroxyphenobarbitone.
bilize them, whilst the treatment of microsomes with deoxy- Amphetamines are similarly detoxified by aromatic hydrox-
cholic acid, which solubilizes lipid membranes, destroys the ylation to parahydroxyamphetamines and by deamination
activity of oxidative enzymes. to a benzyl methyl ketone. Both of these metabolites are less
Biotransformation of xenobiotics usually consists of active than the parent compound.
two phases: phase 1, which involves oxidation (via the Specific chemical reactions can occur in phase 1
cytochrome P450-dependent mixed function oxygenases), metabolism.
134 Occupational toxicology: general principles
Epoxidation
Epoxidation is the insertion of an oxygen atom between
two carbon atoms. It is an important mechanism for the
initial metabolism of aromatic compounds and cytochrome
P450 is involved. This reaction can increase the toxicity of
the parent compound, but many epoxides are unstable and Other metabolites that can be formed by hydroxylation
undergo further reactions, such as hydroxylation. Unstable of the aromatic ring include hydroquinone, catechol and
epoxides are often toxic because they bind to proteins and 1,2,4-trihydroxybenzene. These hydroxylated metabolites
other macromolecules. For example, vinyl chloride is con- can be further oxidized to quinones and semiquinones.
verted to an intermediate, chlorethylene oxide, which Urinary excretion of muconic acid, a short chain dicar-
spontaneously transforms to chloracetaldehyde. The two boxylic acid, suggests that the benzene ring may be opened
metabolites are mutagens and considered to act as proxi- by biotransformation.
mate carcinogens. The principal target organ for benzene toxicity is bone
marrow. Marrow cells contain peroxidases and mixed func-
tion oxidases capable of metabolizing benzene. The metab-
olites produced may bind covalently to cell macromolecules
causing disruption of cell growth and replication. The
specific target of benzene is probably the DNA in the
pluripotential stem cells and lymphocytic cells. Cytogenetic
abnormalities of bone marrow cells and circulating lympho-
Since both of these intermediates can bind directly with cytes have been observed in workers exposed to benzene.
cellular macromolecules, such as DNA and proteins, it Myelodysplasia may be seen in the bone marrow of individ-
would be expected that local hepatic biotransformation of uals with chronic exposure to benzene. Benzene-induced
vinyl chloride is associated with liver damage. Many epi- leukaemia has a latency period of 5–15 years and in many
demiological studies have confirmed the association of cases is preceded by an aplastic anaemia (see Chapter 90,
chronic vinyl chloride exposure with the development of a Haematopoeitic effects of workplace exposures).
hepatic angiosarcoma, an otherwise rare primary liver Hydroxylation may involve the addition of one or more
cancer. Carcinogenicity appeared to follow chronic exposure epoxide groups and both reactions are responsible for
to relatively low levels of vinyl chloride (50–100 ppm or making several xenobiotic compounds more toxic, such as
less). Chronic exposure to higher levels of exposure the production of the carcinogenic 7,8-diol-9,10-epoxide
(500–1000 ppm) was more commonly associated with ser- of benzo[a]pyrene. Benzo[a]pyrene is classified, therefore,
ious hepatotoxicity, the hepatocytes dying before malig- as a procarcinogen since metabolic activation is required to
nant transformation could occur. Vinyl chloride-induced convert it to a carcinogenic species.
angiosarcoma of the liver can have a latency of between 15
and 40 years. As a result of stringent workplace controls
limiting exposure to below 1 ppm, vinyl chloride-associated
diseases are now rarely seen (see Chapter 39, Gases and
Chapter 88, Hepatotoxic effects of workplace exposures).
Another example of epoxide formation is the conver-
sion of the pesticide aldrin to dieldrin, a stable epoxide.
Oxidation
Oxidation of nitrogen, sulphur or phosphorus is another
important metabolic reaction in biotransformation that
may increase toxicity. The oxidation of nitrogen in
2-acetylaminofluorene produces the carcinogen N-hydroxy-
2-acetylaminofluorene.
Hydroxylation
Hydroxylation is the attachment of a hydroxyl group to
hydrocarbon chains or rings and may follow epoxidation.
An example is the metabolism of benzene epoxide, an
intermediate in the biotransformation of benzene, to phe-
nol. Benzene is initially metabolized by oxidation, primar- With parathion, the oxidative desulphuration of phos-
ily in the liver, with phenol as the major metabolite. phorus produces paraoxon which is more effective than
Detoxification and elimination 135
the parent compound as an inhibitor of acetylcholinesterase conjugation, this is a more potent carcinogen than the
(see Increased toxicity, p. 133). parent compound, N-hydroxyacetylaminofluorene.
Glutathione, a tripeptide of glutamic acid, cysteine and
Dealkylation glycine, is another endogenous compound used in phase 2
Dealkylation is the removal of an alkyl group (such as a reactions. The thiol groups (SH) in glutathione form
methyl group) and its replacement by a hydrogen atom. covalent bonds with xenobiotic compounds and glu-
The reactions are carried out by mixed function oxidases. tathione conjugates may be excreted directly, or after fur-
Examples include O-dealkylation of methoxychlor insecti- ther metabolism to mercapturic acids (compounds with
cides, N-dealkylation of the insecticide carbaryl and N-acetylcysteine attached). The enzyme glutathione trans-
S-dealkylation of dimethyl mercaptan. ferase is generally required for the conjugation process and
is found throughout the body.
Reduction Sulphate conjugates are completely ionized and, there-
Reduction of some of the major functional groups in xeno- fore, highly efficient in eliminating xenobiotics in the urine.
biotics is carried out by reductases. Examples include the The major species that form sulphate conjugates are alco-
reduction of nitro groups by nitroreductases, which are hols, phenols and arylamines. Phenols are conjugated with
found mainly in the liver, but to a lesser extent in other either glucuronic acid or sulphate to form phenol glu-
organs, such as the lung and kidney. They may occur also in curonide and phenol sulphate. Sulphation is a saturable
intestinal bacteria and reduction of xenobiotics may take pathway and so may have limited capacity for detoxification.
place locally in the intestinal tract (e.g. dinitrotoluene). Other reactions can occur. Acetyltransferase involves
acetylation such as in the final step in the production of
Hydrolysis mercapturic acid conjugates. Amino acids, such as glycine,
Hydrolysis is the addition of water to a molecule prior form peptide conjugates. Some compounds, such as sali-
to its division into two chemical species. Two types of cylic acid, can be metabolized by several different mech-
compounds that undergo hydrolysis are esters (such as anisms, as well as glucuronide conjugation. Cyanide is
organophosphates) and amines, many of which are pesti- detoxified by conjugation with sulphur to form thio-
cides. Hydrolases occur predominantly in the liver, cyanate (which can be monitored in blood or urine).
but also in the gastrointestinal tract, nervous tissue, blood, Most compounds undergo both metabolic transform-
kidney and muscle. Aromatic esters are hydrolysed by ation and conjugation, but occasionally only one of these
the action of aryl esterases and alkyl esters by car- reactions. Biotransformation may produce a metabolite
boxylesterases (an example being the metabolism of syn- that is sufficiently water soluble to be easily excreted, so
thetic pyrethroids). Esterases were originally subdivided that conjugation is not necessary. If the compound already
into A, B or C esterases on the basis of their interaction possesses groups which will easily conjugate then phase 1
with organophosphates.22 metabolism may not be required.
Depending on their degree of water solubility, the prod-
ucts of metabolic transformation are either excreted directly OTHER MECHANISMS
or undergo further metabolism by conjugation (phase 2
reaction). Some xenobiotics are detoxified by linkage to a large mol-
In phase 2 reactions, the functional groups on a mole- ecule, such as a protein. This produces a complex that is less
cule (e.g. carboxyl, amino, hydroxyl and sulphydryl groups) toxic and which can be stored in the body. Metallothionein,
are conjugated with endogenous compounds, such as a low molecular weight cysteine-rich protein, binds to
glutathione, glucuronic acid, amino acids (e.g. glycine) or heavy metals such as cadmium, zinc and copper and is
sugars, to form water-soluble, polar derivatives that can found in high concentrations in the liver and kidneys.
be more readily excreted and are less toxic. A reduction in
lipid solubility decreases the ability to diffuse back across Other sites of xenobiotic biotransformation
membranes.
Conjugation with glucuronic acid is the most important The liver is not always the most important site of metab-
and most common mechanism. The enzyme UDP- olism. Reactions can occur in extrahepatic sites as a result of
glucuronyltransferase catalyses the transfer of glucuronic the activity of both microsomal and non-microsomal
acid from uridine diphosphate glucuronic acid. Glucuronide enzymes. For example, microsomal UDP-glucuronyltrans-
conjugation products are classified by the site of bindings: ferase is found in skin and the gastrointestinal tract. Many
a hydroxyl functional group forms an ether glucuronide, a non-microsomal enzymes occur in plasma, the gastro-
carboxyl acid group an ester glucuronide. Glucuronides intestinal tract, lungs and kidneys. Alcohol dehydrogenase
may be attached directly to nitrogen as the linking atom in the liver, kidney and lungs oxidizes an alcohol to its alde-
(e.g. aniline glucuronide) or through an intermediate hyde and a number of amino-oxidases and esterases are
oxygen atom, such as occurs in the conjugation product found in plasma. Bacterial flora in the gut may also have a
in N-hydroxyacetylaminoglucuronide. In contrast to the role in xenobiotic metabolism (see above under Reduction)
usual decrease in toxicity that results from glucuronide and first-pass metabolism by this route of exposure.
136 Occupational toxicology: general principles
If these metabolic reactions did not occur then xenobi- route of elimination of unchanged carbon tetrachloride is
otics of high lipid solubility would remain and accumulate via the breath.
in the body with the resultant risk of toxicity. A more The profile of the isoenzymes of cytochrome P450-
detailed review of the principles of biochemical toxicology dependent monooxygenases in the lung cells is important for
can be found in standard texts.23 understanding of the toxicity of substances that undergo
metabolic activation. The heterogeneity of cellular distribu-
tion and the high levels of enzyme activity in certain cells can
Pulmonary biotransformation explain specific cell toxicity for some compounds (such as
ipomeanol for the Clara cell), but it is not so clear why other
Over 40 histologically different cell types have been toxins (e.g. butylated hydroxytoluene and trialkylphospho-
identified in the lungs but the susceptibility of a lung cell to rothioates) appear to be specifically toxic to the type 1 alveo-
toxic compounds or metabolites depends partly upon the lar epithelial cells. Butylated hydroxytoluene appears to be
specific biochemical activity of that cell.24 The lungs can be species-specific in causing murine lung damage but, despite
the target organ for toxicity and, in some cases, there is extensive human safety evaluation, the potential for buty-
a selective toxicity to a particular type of lung cell.25 lated hydroxytoluene in food to cause toxic lung damage in
The level of metabolic activity of a cell depends upon its man has not been determined. Similarly, the trialkylphos-
degree of specialization and the nature of the enzymes and phorothioates, as impurities in many organophosphorus
substrates. thionates manufactured for use as pesticides (e.g.
The lung is capable of metabolizing many xenobiotics malathion), may be environmental causes of cell-specific
by both phase 1 and phase 2 reactions.26 The non-ciliated lung damage in man. The type 1 alveolar epithelial cells do
bronchiolar, or Clara cell, is the most metabolically active not demonstrate significant cytochrome P450 activity and
lung cell and has a high activity of mixed-function oxi- their potential for xenobiotic biotransformation is unknown.
dases.27 The mycotoxin 4-ipomeanol has been widely stud- It is possible that there is metabolic activation in another cell
ied in animals as a model substrate for investigating type, or even organ, and transport of the toxic metabolite to
organ-specific toxicity, since it undergoes selective metab- the type 1 cell. There is some evidence to suggest that certain
olism and activation in the lung. It appears that the Clara conjugates may dissociate at a remote site after conjugation
cell metabolizes ipomeanol to a reactive metabolite.28,29 and release the toxic compound. Type 1 cells are derived
Significant amounts of the cytochromes P4502B1 and from type 2, which have demonstrable metabolic capability,
P4504B1 are found in the Clara cell of the rabbit lung. but in vitro the total enzyme activities of a lung preparation
In vitro these isoenzymes are effective at converting cannot be accounted for by the sum of just the Clara and type
ipomeanol to its reactive metabolite. A specific Clara cell 2 cells. The other enzyme systems that may be involved in the
lesion is seen also following the administration of the hepa- activation of toxins in the lung include pulmonary flavin-
totoxin, 1-nitronaphthalene. monooxygenases (Clara and alveolar type 2 cells) and
Carbon tetrachloride (CCl4) is a recognized hepatotoxin- pulmonary prostaglandin synthetase which is capable of acti-
producing fatty degeneration and centrilobular necrosis of vating chemicals by co-oxidation with prostaglandin precur-
the liver (see Chapter 88, Hepatotoxic effects of workplace sors. This pathway, in particular, could be relevant to the
exposures). Biotransformation of carbon tetrachloride pulmonary toxicity of α-naphthylthiourea (ANTU) and
takes place in the liver and toxicity is believed to be linked N-methylthiobenzamide. The latter compound has a similar
to the production of a CCl 3 radical that causes lipid perox- toxicity profile to ANTU and has been shown to be metabo-
idation and irreversible damage to membrane systems. lized by a pulmonary flavin adenine dinucleorotide (FAD)-
Bioactivation of CCl4 is a classical model for free radical- dependent monooxygenase. ANTU produces severe,
induced toxicity. The first metabolic step is the formation non-haemorrhagic, pulmonary oedema with fibrin-rich
of the trichloromethyl-free radical (CCl 3 ) by a cytochrome pleural effusions in animals and has been used as a model
P450 enzyme. This free radical binds directly to microso- for the study of the pathophysiology of pulmonary
mal lipids and other cellular macromolecules causing the oedema. Pulmonary prostaglandin H-synthase-mediated
breakdown of membrane structure, energy production co-oxygenation has been shown to activate procarcinogens,
and protein synthesis. The trichloromethyl-free radical such as benzo[a]pyrene and aflatoxin B1.
may also undergo both anaerobic and aerobic reactions The role of glutathione (GSH) in pulmonary detoxifica-
leading to the further production of toxic metabolites. tion has been investigated for ipomeanol and naphthalene,
Although the liver is the target organ of toxicity for this both of which selectively damage Clara cells in mice. GSH
chemical, damage to the metabolically active Clara cells, as and GSH-S transferase concentrations are lower in the
well as types 1 and 2 alveolar epithelial and pulmonary lungs than in liver and the cellular distribution is unclear,
endothelial cells, has been reported. Gould and Smuckler30 although there appears to be more activity in the Clara cells
found focal atelectasis and haemorrhages with ultrastruc- than the type 2 cells. Consequently, the protective detoxifi-
tural changes in type 2 cells which suggested damage to the cation mechanisms of the lungs are less effective than those
pulmonary surfactant system. Carbon tetrachloride prob- of the liver. Low glutathione transferase activity in the
ably also has toxic effects on lung phospholipids as the main lung, compared with aryl hydroxylase activity, has been
Variation in susceptibility to xenobiotics 137
associated with the increased risk of lung cancer in tobacco systems is highly localized in the basal layer of the epider-
smokers. mis and appendages. Consequently, specific activities for
The lung is a target organ for toxicity of many other dermal biotransformation may be more significant than
compounds.31 Some of the mechanisms involved in sys- values from tissue homogenates suggest. The lower meta-
temic lung toxicity have been identified in animal toxicity bolic capacity of human skin compared with animals must
models. Administration of paraquat to animals causes lung be considered when extrapolating from animals to man in
fibrosis, the herbicide entering types 1 and 2 lung cells by quantitative risk assessment.
a selective active uptake process.32,33 Hydrazine, given
intraperitoneally in mice, can produce lung tumours, and
chlorphentermine, after chronic oral dosing, accumulates VARIATION IN SUSCEPTIBILITY TO
in the fatty tissue of the lung (and the adrenals) and causes XENOBIOTICS
a phospholipidosis. Polycyclic aromatic hydrocarbons may
be activated in the lungs or metabolized elsewhere and Disorders following occupational exposure to chemicals
transported to the lungs. There are significant species are well documented and some have been known for hun-
differences between animals and humans in susceptibility dreds of years. In a population exposed to toxic xenobi-
to the toxic effects of butylated hydroxytoluene (BHT), otics in the workplace, or general environment, there is a
the trialkylphosphorothioates, ANTU, ipomeanol and broad range of responses between individuals. The causes
paraquat.34 of this variability, in the nature and degree of acute
response or susceptibility to long-term health effects from
intermittent or chronic low-dose exposure, remain largely
Dermal biotransformation unanswered.37 Research into the role of genetic polymor-
phisms, and the contribution of epigenetic factors, in pre-
The importance of dermal metabolism, during absorption disposing individuals to disease is beginning to identify
through the skin in vivo, for disposition and local toxicity is important differences within populations. Recent advances
now recognized. Esterase activity in skin is exploited in the in genetics have identified the genetic basis of many human
delivery of ester prodrugs; lipophilic prodrugs (containing diseases and it is probable that similar genetic mechanisms
an alkyl group ester-linked to the pharmacophore) are able will underlie some of the effects of occupational and envir-
to penetrate the stratum corneum. Esterase activity in the onmental exposures to xenobiotics.38 Genetic polymor-
viable epidermis cleaves the ester linkage and liberates the phisms for xenobiotic metabolism are likely to play an
pharmacophore. Metabolic activity plays a key role in acti- important role in an individual’s level of susceptibility.
vation of procarcinogens such as benzo[a]pyrene in the The clinical consequences of slow acetylator phenotype
skin of experimental animals and is believed to have a simi- have been well studied following drug exposure and this
lar role in humans. Metabolic activation also appears to pathway may have a role in some occupational exposures
have a key role in haptenation during skin sensitization (examples include exposure to isoniazid and hydrallazine). It
reactions. Dermal absorption and metabolism has been is also known that phenotypic variation in plasma esterases,
assessed in tissue homogenates and in intact skin in vitro, especially cholinesterases, can contribute to the relative toxi-
using flow through diffusion systems and more recently city of some anticholinesterases by affecting both the specific
short-term organ culture. The viability of skin in these toxicity of these compounds and influencing the efficiency of
systems and the maintenance of metabolic capacity are their metabolism and elimination. Thiomethyl transferase
important but still require complete verification for all produces S-methylation and masks functional chemical
enzyme systems, especially those requiring energy. Never- groups, reducing water solubility and impairing further con-
theless, expression and enzymatic activity for a wide range jugation. Thiomethyl transferase is involved in the detoxifi-
of enzymes in cutaneous systems has been demonstrated in cation of substances, such as hydrogen sulphide and other
vitro as well as in vivo.35 free sulphydryl groups, including the thioesters of glu-
The degree of skin metabolism depends on the physico- tathione conjugates (a final common pathway for many toxic
chemical characteristics of the compound, the rate of xenobiotics). Hydrogen sulphide has a similar toxic mecha-
absorption, as well as the capacity of any metabolizing nism, as a mitochondrial poison, to cyanide and can cause an
enzymes. A suitable choice of model systems is important acquired defect in mitochondrial function leading to disease
to reflect not only absorption characteristics in vivo, but similar to that found in Parkinson’s disease.39 Heavy metals,
also metabolic capacity.36 Metabolism may be relatively such as mercury, can form toxic derivatives with the enzyme
unimportant quantitatively in vivo, compared with metab- thiomethyl transferase and increased activity, such as that
olism by the liver, but may be highly significant when con- reported in motor neurone disease, may predispose individ-
version to toxic metabolites causes local toxicity or where uals to heavy metal poisoning.
rapid detoxification follows absorption and enables the An individual’s response to toxic xenobiotics is influenced
skin to act as a protective metabolic barrier against a toxic by the rates of absorption, distribution, biotransformation
xenobiotic entering the system circulation. Furthermore, and excretion, as well as the toxicodynamics of the chemi-
metabolic activity for the majority of cutaneous enzyme cal. The body’s defences against toxic effects are complex
138 Occupational toxicology: general principles
4. Smith LL. The identification of an accumulation system for 20. Nelson DR, Koymans L, Kamataki T et al. P450 superfamily:
diamines and polyamines into the lung and its relevance to Update on new sequences, gene mapping accession numbers
paraquat toxicity. Archives of Toxicology. 1982; 5 (Suppl.): and nomenclature. Pharmacogenetics. 1996; 6: 1–42.
1–14. 21. Williams FM, Mutch E, Blain PG. Paraoxonase distribution in
5. Woollen BH, Guest EA, Howe W et al. Human inhalation Caucasian males. Chemico-Biological Interactions. 1993;
pharmacokinetics of 1,1,2-trichoro-1,2,2-trifluorethane 87: 155–60.
(FC113). International Archives of Occupational and 22. Aldridge WN. Two types of esterase (A and B) hydrolysing p-
Environmental Health. 1990; 62: 73–8. nitrophenylacetate, propionate and butyrate, and a method
6. Woollen BH, Marsh JR, Mahler JD et al. Human inhalation of their determination. Biochemical Journal. 1900; 53: 110–17.
pharmacokinetics of chlorodifluoromethane (HCFC22). 23. Hodgson E, Guthrie FE (eds). Introduction to biochemical
International Archives of Occupational and Environmental toxicology. New York: Elsevier North Holland, 1984.
Health. 1992; 64: 383–7. 24. Sorokin SP. The cells of the lungs. In: Nettesheim P,
7. Blain PG. Inhalation kinetics. In: Brewis RAL, Gibson GJ, Hanna MG, Deatherage JW (eds). Conference on morphology
Geddes DM (eds). Textbook of respiratory medicine. London: of experimental carcinogenesis. Washington DC: Atomic
Baillière Tindall, 1990: 158–62. Energy Commision, 1970: 3–43.
8. Pietrowskie J. The application of metabolic and excretion 25. Kehrer JP, Kacew S. Systematically applied chemicals that
kinetics to problems of industrial toxicology. Washington damage lung tissue. Toxicology. 1985; 35: 251–93.
DC: US Government Printing Office, 1971. 26. Blain PG. Toxic lung injury: Ingested agents. In: Brewis RAL,
9. Conkle JP, Camp BJ, Welch BE. Trace composition of human Gibson GJ, Geddes DM (eds). Textbook of respiratory
respiratory gas. Archives of Environmental Health. 1975; 30: medicine. London: Baillière Tindall, 1990: 1488–97.
290–5. 27. Boyd MR. Biochemical mechanisms in chemical-induced
10. Krotoszynski B, Gabriel G, O’Neil H. Characterisation of lung injury: Roles of metabolic activation. CRC Critical
human expired air; a promising investigation and diagnostic Reviews in Toxicology. 1980; 7: 103–76.
technique. Journal of Chromatographic Science. 1977; 15: 28. Boyd MR, Burka LT, Wilson BJ, Sasame HA. In vitro studies
239–44. on the metabolic activation of the pulmonary toxin
11. Fiserova Bergerova V, Vlach J, Cassady JC. Predictable 4-ipomeanol by rat lung and liver microsomes. Journal of
‘individual differences’ in uptake and excretion of gases and Pharmacology and Experimental Therapeutics. 1978; 207:
lipid soluble vapours. Simulation study. British Journal of 677–86.
Industrial Medicine. 1980; 37: 42–9. 29. Boyd MR, Burka LT. In vivo studies in the relationship
12. Kelman GR. Theoretical basis of alveolar sampling. British between target organ alkylation and the pulmonary toxicity
Journal of Industrial Medicine. 1982; 39: 259–64. of a chemically reactive metabolite of 4-ipomeanol. Journal
13. Scott RC, Dugard PH. The properties of skin as a diffusion of Pharmacology and Experimental Therapeutics. 1978; 207:
barrier and route of absorption. In: Greaves MW, Shuster S 687–97.
(eds). Pharmacology of the skin II. Heidelberg: Springer 30. Gould VE, Smuckler EA. Alveolar injury in acute carbon
Verlag, 1989: 93–114. tetrachloride intoxication. Archives of Internal Medicine.
14. Bos JD, Meinardi MMHM. The 500 Dalton rule for the skin 1971; 128: 109–17.
penetration of chemical compounds and drugs. 31. Brewis RAL, Keaney NP. Respiratory disorders. In: Davies DM
Experimental Dermatology. 2000; 9: 165–9. (ed.). Textbook of adverse drug reactions. Oxford: Oxford
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formation of a skin reservoir for topically applied solutes. 32. Rose MS, Lock EA, Smith LL, Wyatt I. Paraquat
Skin Pharmacology and Physiology. 2004; 17: 3–16. accumulation: Tissue and species specificity. Biochemical
16. van de Sandt JJM, van Burgsteden JA, Cage S et al. In vitro Pharmacology. 1976; 25: 419–23.
predictions of skin absorption of caffeine, testosterone, and 33. Blain PG. Aspects of pesticide toxicology. Adverse Drug
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Toxicology and Pharmacology. 2004; 39: 271–81. 34. Marino AA, Mitchell JT. Lung damage in mice following
17. Wilkinson SC, Williams FM. The relationship between in intraperitoneal injection of butylated hydroxytoluene.
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HI (eds). Percutaneous absorption: Drugs, cosmetics, 35. Macpherson SE, Scott RC, Williams FM. Metabolism of
mechanisms, methodology, 4th edn. New York: Taylor and pesticides during percutaneous absorption. In: Scott RC, Guy
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140 Occupational toxicology: general principles
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11
Risks and hazards in occupational and
environmental exposures
ROBERT L MAYNARD
INTRODUCTION complete, but this is less satisfactory (and less certain) than
removing the hazard itself.
Occupational physicians and hygienists identify hazards,
estimate risks and seek to reduce both. The most direct way
to assess a health risk to physical and chemical hazards aris- HAZARD IDENTIFICATION
ing in the workplace is through exposure assessment: this is
also an essential tool by which an occupational physician can Many, perhaps all, occupations involve exposure to hazard.
attribute a health problem to an individual’s occupation. Office work involves exposure to hazard: poor ergonomic
For further details, the reader is referred to Chapter 4, conditions, stress, danger associated with repetitive move-
Occupational exposure to hazardous substances (p. 43). ments, such as typing, etc. Industrial work is likely to
This companion chapter provides an introduction to the involve exposure to greater hazards: moving machinery,
concepts of risk and hazard assessment. chemicals, high temperatures, etc. In many cases, identifi-
A hazard may be identified as: cation of hazards involves little more than common sense:
a circular saw is a rather obvious hazard, as is a hydraulic
A phenomenon, an act, a toxic substance or a living press or a conveyor belt. Chemicals pose hazards, but these
organism that can, but does not always, pose a threat are less easy to recognize. Occupational health studies
to health. For example lightning, jumping, hydrogen and toxicological work form the bases for identifying
cyanide, a lion or a bacterium. hazardous chemicals. In the case of most chemicals, haz-
ards can only be identified by in vivo – laboratory animal –
toxicological studies; in the case of genotoxic carcinogens,
Risk may be defined:
in vitro mutagenicity studies may be sufficient. However,
discovering that a chemical poses a hazard is very differ-
Risk is the probability of an adverse effect associated ent from estimating the risk associated with exposure to
with a hazard. For example, the risk of being struck by that chemical. In vivo studies may allow exposure or
lightning or of contracting tuberculosis. dose–response relationships to be defined: extrapolating
from such data to estimates of risks in man is difficult,
In estimating risk, it is assumed that exposure to the almost always impossible. Because of this, toxicological
hazard occurs. This is important: risk may be reduced data tend to be used for identifying levels of exposure likely
to zero if exposure to the hazard is made impossible. to be associated with low risk. The application of safety
Removing the hazard completely achieves this, reducing factors (better described as uncertainty factors) to the
exposure to the hazard can achieve this if the reduction is results of in vivo toxicological studies has long been used
142 Risks and hazards in occupational and environmental exposures
for this purpose. The use of such factors should not be too difficult, to prevent exposure entirely. As soon as ques-
confused with risk estimation. If we assume that a no tions about costs and benefits are raised, as they often are,
adverse effect level (NOAEL) can be defined or estimated the need for quantitative estimation of risk becomes press-
in animals then dividing this by ten, to allow for unknown ing. Such estimates can be made on the basis of:
factors that may control for interspecies variations in sen-
1. Real data that allow risks at relevant levels of exposure
sitivity, may yield a level of exposure unlikely to have
to be assessed – as in the air pollution field.
effects in man. However:
2. The use of predictive models.
● There is no guarantee that exposure to such a level of The use of predictive models has been the cause of
exposure will not have effects in man and much debate among toxicologists.
● There is no guarantee that greater exposure will have Let us take an example. Studies conducted in occupa-
effects in man. tional settings show that exposure to measured concentra-
tions of some compound (for given periods) produce
The assertion that exposure to the calculated level of adverse effects. We need to be able to predict effects on
exposure (NOAEL/10) is unlikely to have effects, can only exposure to lower concentrations. Thus, some form of
be based on experience with other chemicals, and experi- extrapolation is needed. To the purist, extrapolation ‘beyond
ence may be misleading. the data’ is always a risky process and one likely to be beset
It will be obvious that hazard identification based on with errors. Some assumptions regarding the shape of the
animal studies is less satisfactory than that based on studies exposure (dose)–response relationship at low levels of
in man. Human data showing adverse effects on health of exposure need to be made. If the mechanism of effect of the
occupational exposure to chemicals used to be more com- chemical is well understood, it may be possible to construct
monly available than at present. We should be glad to an equation that relates exposure to effects. In practice, this
know that modern standards of occupational hygiene have is very difficult and fitting a line to the available data and
reduced access to such data. For some chemicals, data can then producing or extending that line beyond the data is the
be obtained from population studies if the general public is common approach. However, we are, at once, in difficul-
exposed to the chemical in question. This has been the case ties. Is there a threshold of effect and, if so, what is it?
with common air pollutants. It is a fact that such studies, Consider exposure to ozone, which may occur to
often large and therefore statistically powerful, reveal workers in the chemical industry and to the general popu-
effects at levels of exposure well below those shown to pro- lation as a ubiquitous air pollutant. Exposure to 120 ppb
duce effects in animal studies, volunteer studies or smaller (240 μg/m3) without exercise produces a small change in
scale occupational studies. For example, the World Health indices of lung function, such as FEV1. Exposure to 80 ppb
Organization (2006) Air Quality Guidelines1 for nitrogen (160 μg/m3), with intermittent vigorous exercise, for about
dioxide and sulphur dioxide include the following recom- six hours produces small changes in FEV1. If we assume
mendations: that the body has natural defences against the adverse
effects of ozone (airway surface antioxidants such as
NO2: Annual average concentration: 40 μg/m3 reduced glutathione, vitamins C and E, and uric acid), we
SO2: 24-hour average concentration: 20 μg/m3 might reasonably assume that for each individual there was
some level of exposure that would not produce an effect on
In occupational circles, these would be regarded as very FEV1. This is, in fact, widely assumed. However, it is
low and challenging guidelines. The reader is advised to known that levels of antioxidants in the airways differ from
examine the World Health Organization report for the jus- person to person and in some hardly any exists – at least in
tifications behind these figures. One important conclusion the upper airways (nose) where measurements have been
from the epidemiological studies that form the basis of the done.2 If, in lieu of anything better, we assume that the
guidelines is that expected thresholds of effect may not be level of antioxidant defences varies amongst people in a
demonstrable at a population level. This conclusion has way that conforms to a normal distribution curve then, at
been generally accepted in the air pollution field and has a population level, the notion that a threshold of effect
serious implications for risk assessment. These include a exists disappears. There is nothing revolutionary or sur-
move away from identification of no adverse effect levels as prising about this. The Probit slope, once used so widely in
a substitute for quantitative risk assessment (QRA). toxicology, is based on such assumptions and the now
rather less used LD50 is derived from such thinking. Of
course, the problem with such thinking is that the mid
RISK ASSESSMENT range of such curves inevitably tends to be better defined
than the extremes of the curve and the confidence limits
At its simplest, risk assessment involves deciding on whether about the curve tend to veer away from the curve at its
a given level of exposure to a chemical is or is not associated extremities. Even in a large toxicological study in animals
with some risk of adverse effects on health. Such an assess- one would expect to have much more confidence in the
ment is of limited value unless it proves easy, or at least not reliability of an LD50 value than in an LD1.0 or LD99 value.
Ambient levels of carcinogens 143
It will be appreciated that we have moved away from ‘one hit’ or ‘multi-stage’ characteristics of the mechanism
predicting effects on a truly mechanistic basis to predict- by which benzene causes leukaemia are included. The
ing them on a statistical basis. Statistical models have authors of the World Health Organization report recog-
been extensively used in quantitative risk assessment of nized the assumptions made:
risks associated with exposure to genotoxic carcinogens.
Many such models exist. Some are entirely statistical and ● Response (measured as relative risk) is some function of
are based on assumptions regarding the distribution of sen- cumulative exposure.
sitivity in the population (Probit and Logit models); others ● There is no threshold of effect for genotoxic carcinogens.
are based on assumptions regarding mechanisms of effect ● Linear extrapolation of the dose–response curve
or, rather, characteristics of mechanisms of effect as towards zero gives the upper bound conservative esti-
assumed in ‘one hit’ or ‘multi-stage’ models. However, all mate of the true risk function if the unknown (true)
these models are just models and their predictions of effects dose–response curve has a sigmoidal shape.
or risks at low levels of exposure cannot be verified. ● There is constancy of the relative risk in the specific
Cannot? Well – cannot as yet. It is assumed that if mecha- study situation. It was noted that in a strict sense, con-
nisms of effect were perfectly understood, then a perfect stancy of the relative risk means that the background
model could be constructed: this is still very far away. age/cause specific rate at any time is increased by a con-
A very simple model has been used by the World Health stant factor. The advantage of the average relative risk
Organization in predicting unit risks for carcinogens. Let method is that this needs to be true only for the average.
us examine the derivation of the unit risk for benzene.3
A cohort of workers studied in the United States by the One important drawback of the method was noted:
National Institute for Occupational Safety and Health background rates vary from country to country and thus
(NIOSH) comprised 748 workers who had been exposed the incremental unit risk will also vary from one country to
to benzene in the production of rubber film material for another. This should be borne in mind if the World Health
15 years. The cohort was followed for 25 years. Seven Organization unit risk estimates are applied in calculations
workers died from leukaemia. The expected number of of benefits to health expected to be produced by reducing
deaths, based on national figures, was 1.25 and thus the exposure to carcinogens.
relative risk was calculated as 5.6. The average duration of
exposure was found to be 8.5 years and the average level
of exposure was 30–300 mg/m3. Peak exposures of up to AMBIENT LEVELS OF CARCINOGENS
2170 mg/m3 were recorded. So much for the data: it will be
noted that the actual exposure was only rather inaccurately It was noted by the authors of the World Health
known and that peaks of exposure far above the average Organization report that the method outlined above was
may have occurred. This raises the question of overloading easy to use – easier than more sophisticated methods of
of defence mechanisms by occasional very high exposures: extrapolation from the results of occupational studies to
an unresolved problem. possible effects of exposure to ambient concentrations of
Now for the assumptions. It was assumed that exposure carcinogens. The authors also pointed out that the use
had been to 300 mg/m3 for 8.5 years. This was taken as of more sophisticated models led to similar results to
equivalent to a lifetime exposure of: those obtained with the average relative risk model, as
described above. This is an important but controversial
8 240 8.5 point. The UK Department of Health Committee on
300 mg/m3
24 365 70 the Carcinogenicity of Chemicals in Food, Consumer
Products and the Environment (COC) in 1991 published
i.e. 8 mg/m3 (8000 μg/m3). a report entitled ‘Guidelines for the evaluation of chemi-
The unit risk was calculated as the increase in risk asso- cals for carcinogenicity’,4 which included a discussion
ciated with lifetime exposure to 1 μg/m3 of benzene. pointing out that the application of a range of models pro-
Let Po background risk (in this case 0.007). Then duced very different predictions of the risk (expressed as
putting RR as the relative risk associated with lifetime number of cases of cancer per lifetime) for a given expo-
exposure to 8000 μg/m3 as 5.6: sure to a carcinogen. The wide range of results caused the
committee to question this quantitative approach. It
Po RR Po Po (RR 1) 0.007(5.66 1) should be noted, again, that the accuracy of predictions
Unit risk
8000 8000 8000 produced by all such models cannot be verified.
4 10 6 Examination of the results yielded by different models
show that the mechanistic ‘one hit’ model produced the
The unit risk was more accurately defined as the ‘incre- largest risk estimate, for a given dose, of all the models
mental unit risk’. examined. This model might be used to produce a worst
It will be seen that the model used here is the simplest case estimate of risk to a specified level of exposure. In
possible: it is entirely linear. No assumptions regarding 2003, the Committee on Carcinogenicity of Chemicals in
144 Risks and hazards in occupational and environmental exposures
Food, Consumer Products and the Environment agreed Many doctors would reply No to (1). Point (2) is more diffi-
that if human data were available and if groups of similarly cult, but many would agree that an episode of irritant-
acting compounds (e.g. PAH compounds) were being con- induced bronchoconstriction need not necessarily imply
sidered, then the ‘one hit’ model might form the basis for a induction of a permanent asthmatic state. This may be dis-
ranking of carcinogenic potency.5 This is not at all the puted and reactive airways disorder syndrome (RADS) (see
same as predicting risks, but can be useful in setting prior- Chapter 40, Reactive airways dysfunction syndrome and
ities for regulatory action. irritant-induced asthma, p. 310) provides an example of how
transient exposure to pollutants can induce long-lasting air-
ways dysfunction. The phrase ‘need not necessarily’ is the
EXPLAINING RISK: COMMUNICATING WITH key to the above assertion. Such words are commonly used
THE PUBLIC and might well be used in a case such as this by many pro-
fessional scientists or doctors. To the layman, their use is
If estimating risk is difficult, communicating ideas about likely to be seen as an example of sophistry. Indeed, by
risk to the public is very difficult and failure is common. including these words the assertion has been rendered
The following brief account draws heavily on a UK vague and probably immune to falsification or, for that
Department of Health Report ‘Communicating about risks matter, confirmation. It seems to say: in some cases this
to public health: pointers to good practice’.6 may be true but it does not follow that it is true in all cases,
People respond to information about risks, including or better, it does not follow that it must be true in all cases.
risks to health, in a variety of ways, sometimes unpre- In terms of Popperian logic, the assertion would be
dictably. Understanding the bases of these variable regarded as unscientific. An honest opinion would be that
responses has been seen as a useful starting point for we do not know whether exposure to irritant air pollutants
improving risk communication. Whether this has been can, sometimes, induce asthma. The reader will have
startlingly successful may be doubted but what more noticed a flaw in all this: asthma is not defined, except in
rational basis for risk communication can be proposed? the sense that it is not the only condition characterized by
We shall consider a number of points. bronchoconstriction. Can asthma be defined? The layman
might well say, yes of course: the diagnosis is made every
day, by doctors. The respiratory physician might agree that
Lay perspectives
this is certainly true, but might add that a universally
acceptable definition of asthma is still awaited despite
It is generally believed that scientists (and doctors) adopt a
many international conferences on this subject. The lay-
critical approach to evidence bearing on causality. The
man is, by now, likely to be annoyed or alarmed: what
hypothesis-testing approach to research, as advocated by
began as an observation and an apparently simple proposi-
Karl Popper, identified falsification of bold hypotheses, as a
tion seems to have drowned in a welter of philosophical
reliable, perhaps the only reliable, means of making
argument and dispute about terminology. He could hardly
scientific progress.7 This philosophy was embraced by
be blamed for saying: well, until the experts make up their
distinguished scientists8 and philosophers, but disputed by
minds, might it not be safer to assume that exposure to irri-
others.9 This has led to the perception that scientists are
tant pollutants can cause asthma? At first glance this seems
instinctive non-believers, or falsifiers, in the causality of
a reasonable proposal; only when its implications are con-
associations: until, that is, the hypothesis of non-causality is
sidered might we ask for better proof. We shall return to
disproven. Put simply in this example, scientific method
this point when the precautionary principle is considered.
leads to a tendency for scientists to choose to believe that
proximity of residence to high power cables is not associated
with cancer until this assertion is disproven. Thus, the statis-
tical framework used (the null, or no effect, hypothesis) can
Causality
make it appear that scientists are themselves more interested
It is widely accepted that mere association is not proof of
in avoiding false-positive findings (type 1 errors) rather than
causality. Less well known is that causality can seldom be
false-negatives (type 2 errors) in situations of uncertainty.
proven. Following Popper, we may feel that causality can
This can lead to conflict with public opinion. Many argue as
only be disproven. Causality is closely bound up with the
follows: it is known that exposure to high concentrations of
concept of risk. We may say, using the example given above,
air pollutants, such as sulphur dioxide, causes bronchocon-
that exposure to benzene is causally related to the develop-
striction, bronchoconstriction is a characteristic of asthma,
ment of leukaemia. The risk of developing leukaemia, how-
therefore exposure to high concentrations of air pollutants
ever, as a result of a specified exposure benzene is less than
causes asthma. Two points arise at once:
100 per cent. Why is this? Presumably individuals differ in
1. Is bronchoconstriction only seen in asthma? their capacity to resist the effects of benzene: perhaps their
2. Does the use of the word ‘causes’ imply induction of DNA repair processes differ in efficiency. If this is the case,
symptoms and signs associated with asthma or the then increasing the exposure should increase the risk – let
induction of a permanent asthmatic state? us assume this is so. Thus, we might argue that if the
Explaining risk: communicating with the public 145
exposure was increased sufficiently all those exposed would association is more likely to be causal than if a is found
develop leukaemia. Risk of developing leukaemia associ- to be associated with b, c, d and e, etc. I accept this point,
ated with a specified exposure to benzene is thus an expres- but propose a modification: if a is found to be only asso-
sion of interpersonal variation. This sort of risk seems ciated with a single mechanism of effect, then though a
different from the risk associated with random events. is found to be associated with b, c, d and e, etc., the asso-
Interpersonal variability has nothing to do with the likeli- ciation remains likely to be causal. In the air pollution
hood of winning a lottery or being struck by lightning or field, the generation of free radicals has linked exposure
throwing a double six at dice. Yet, are the risks really so dif- to particulate air pollutants with a range of outcomes.
ferent? Perhaps the binding of benzene (or some metabolic The specificity of mechanism seems, to me, to support
derivative) to a critical point on the DNA molecule is just the case for causality.
an event controlled by what we describe, in lieu of a better ● Biological plausibility. Bradford Hill argued, cogently,
explanation, as chance. The more often you throw the dice, that this characteristic should not be demanded. An
the more likely it is that you will get a double six eventually association may be demonstrated long before it can be
(although the likelihood on each throw is unchanging); explained. This has sometimes proved a difficulty for
the more benzene molecules to which you are exposed, toxicologists who perceive that their efforts cannot
the more likely you are to develop leukaemia. Unless the refute the findings of epidemiological studies: they can
association between exposure to benzene and leukaemia is only support them or fail to explain them. Of all the
causal however, the risk of developing leukaemia as a result characteristics of causal associations discussed above,
of exposure to benzene must be zero. Deciding on causality only temporal plausibility seems an inevitable require-
must, therefore, precede any discussion of risk. ment. The horse must be seen to precede the cart, but as
Discussion of causality is bedevilled by one particular Bradford Hill acknowledged, this presupposes that the
misconception. This is that the nine characteristics or fea- cart can be confidently distinguished from the horse.
tures of causal associations set out so clearly by Sir Austin This is not always easy. It was pointed out above that
Bradford Hill10 are singly, or in total, tests of causality. causality cannot, perhaps, be proven: the possibility of
The features defined by Bradford Hill were: an undetected confounding factor playing a part can
never be completely disregarded. Thus, discussion
1. Strength of association focuses on the strength of belief in the hypothesis of
2. Consistency (of observed associations) causality. This difficult area was not discussed by
3. Specificity Bradford Hill. In describing levels of certainty, descrip-
4. The relationship in time tive terms such as ‘probably’, ‘possibly’, ‘unlikely’ etc.,
5. The biological gradient are often added to the term ‘causal’. These do not lend
6. Biological plausibility themselves to quantification, but it will be seen that
7. Coherence of the evidence uncertainty here needs to be combined with the risk
8. The experiment estimate used to predict the likelihood of effects at an
9. Reasoning by analogy. individual or population level. Attempts to refine the
wording used to convey uncertainty regarding causality
We might contend that (8) and (9) are not features or char- have sometimes led to confusion.
acteristics of causal associations but, rather, lines of evidence
or argument that might be advanced in support of the con- The following series indicates a declining level of confi-
tention that an association is causal. It is not possible to dis- dence in causality:
cuss all these features here. A few points, only, will be made:
● imprudent not to regard the association as causal;
● There is no a priori reason why a strong association ● prudent to regard the association as causal;
should be more likely to be causal than a weak associa- ● not imprudent to regard the association as causal;
tion. But, as Bradford Hill pointed out, if a strong asso- ● not prudent to regard the association as causal;
ciation is actually caused by a confounding factor ● imprudent to regard the association as causal.
closely associated with the proposed causal agent, then
that factor should be easily identifiable. It follows that The first of these formulations was used some time ago
if the association is weak, but caused by some weak in a report by the Committee on the Medical Effects of
confounding factor, then that factor may be difficult to Air Pollutants (COMEAP)11 and provoked criticism that
identify. This is Popperian: Bradford Hill is saying that the committee was taking refuge in a double negative: so
the putative causality of a strong association is more much for subtlety! Of course, it might have been easier had
easily falsified than that of a weak association. the committee’s level of confidence in causality been
● Specificity. Bradford Hill argued that a specific effect scored from 1 to 5 or from 0 to 4. Why is this important?
was more likely to represent the operation of causal The answer is because it bears on the application of the
association than a number of different effects. Put precautionary principle as a device with which to manage
simply, if a is found to be associated with b, then the risk.
146 Risks and hazards in occupational and environmental exposures
Metals
12 Introduction 151
Tar-Ching Aw
13 Aluminium 153
Perrine Hoet
14 Antimony 159
Malcolm R Sim
15 Arsenic 160
Malcolm R Sim
16 Beryllium 162
Lee S Newman and Holly M Christensen
17 Cadmium 167
Perrine Hoet
18 Chromium 173
Tom Sorahan
19 Cobalt 175
Perrine Hoet
20 Copper 180
Peter Aggett
21 Gold 183
Peter Linnett
22 Iron 185
Peter Aggett
23 Lead 188
Peter J Baxter and Hideki Igisu
24 Magnesium 199
Peter Aggett
25 Manganese 201
Grant McMillan and Finlay D Dick
26 Mercury 214
Peter J Baxter and Hideki Igisu
27 Molybdenum 221
Malcolm R Sim
28 Nickel 223
Tom Sorahan
29 Phosphorus 225
Malcolm R Sim
30 Platinum group metals 226
Peter Linnett
31 Polonium 231
Iain Blair
32 Silver 234
Peter Linnett
33 Thallium 236
Hideki Igisu and Tar-Ching Aw
34 Tin 238
Tar-Ching Aw and Hideki Igisu
35 Tungsten 241
Perrine Hoet
36 Uranium 243
Iain Blair
37 Vanadium 246
Finlay D Dick
38 Zinc 249
Peter Aggett
12
Introduction
TAR-CHING AW
The term ‘metal’ refers to those elements in the periodic A number of the metals considered to be toxic in an occu-
table (of just over a hundred elements) that have specific pational setting are essential for some metabolic processes
characteristics. They are good conductors of heat and in humans. Examples of essential metals are iron (for haem
electricity; they are bright, shiny and malleable; and they synthesis), copper (for enzymes such as ceruloplasmin and
produce a ringing sound when struck. Metals lose elec- cytochrome-c oxidase), zinc (for development of skin,
trons to form cations, and the resulting electropositivity hair and nails), cobalt (in cyanocobalamin or vitamin B12),
gives it an affinity to bind with sulphur, chlorine and manganese (for transferases), and magnesium (cofactor
other non-metals to form compounds. Alloys are formed for enzymes). These metals create a dilemma in terms of
from a homogenous mix of metals with other elements. the extent to which overexposure and intake should be
Examples are brass (copper and zinc), bronze (copper reduced to balance toxicity against deficiency. In theory,
and tin) and steel (iron and carbon). These often have the U-shaped relationship between dose and effect can be
physical properties that are different from their compo- used to determine the ideal range for exposure and intake
nents. The term ‘superalloy’ has been used for alloys with levels which will prevent deficiency, as well as toxicity.
excellent mechanical strength, and the ability to resist The toxicity of any metal depends upon a number of
deformation at high temperature. Many superalloys are factors, including:
based on nickel or cobalt. Metalloids are elements such as
antimony, arsenic, polonium and tellurium. They have ● those related to the nature of the metal, e.g. the
properties in between those of metals and non-metals. chemical species, including its valency and particle size;
Some metalloids with doumented health effects on humans ● exposure circumstances, the route of exposure, the mode
have been included in this chapter. of entry to the body, other concomitant exposures, use
Gold, silver, copper, iron, tin, lead and mercury have of protective equipment; and
been mined and used extensively before and during the ● the reaction of the body to the metal, and the capability
times of the ancient Greek and Roman civilizations. Today, for clearance.
metals have considerable benefits for industry, for example
in engineering, construction, electronics and for dental Absorption from the lungs is generally more effective
and pharmaceutical applications. However, they have also than from the gut. About 40 per cent of an inhaled dose of
been well recognized as a cause of human health effects, a metallic aerosol may be retained in the lungs, whereas
and adverse effects on the environment. Measures to limit usually only 10 per cent or less of an ingested dose will be
occupational exposure, while allowing safe use of metals absorbed. Other than particle size and solubility, relatively
and their compounds remains an ongoing challenge for few factors affect uptake from the lungs. Only particles that
industry. are of respirable size of around 4 μm or less penetrate to the
152 Introduction
alveoli and thus become available for absorption from the precedents and perspectives and Chapter 2, The changing
lungs. The uptake of metals from the gastrointestinal tract face of occupational diseases, about the circumstances of
varies inversely with age. This is especially relevant in exposure and their relationship to the course of the
younger workers and in parts of the world where child patient’s illness. Also, the important difference between
labour continues to exist. Interactions with other con- hazard (the inherent property of a substance to cause
stituents of the diet can affect the rate of uptake from the gut. harm) and risk (the likelihood of harm being caused
For example, the absorption of lead varies inversely with the because of the way in which the substance is handled at
amount of calcium and iron in the diet and it may also be work) should be emphasized. The clinician will also need
influenced by the presence of fat, protein and vitamin D in to know what laboratory tests may be available to aid
the gut. The uptake of cadmium is affected by the zinc con- diagnosis and where such tests are best carried out.
tent of the diet and that of manganese by the iron content. Furthermore, it may be necessary to seek specialist advice,
Recognition of ‘speciation’ is fundamental to the under- perhaps from a university department of occupational
standing of metal toxicology. Chemical species refers to medicine, a poisons centre or from organizations with
chemically identical molecular entities, such as specific com- statutory responsibility for health and safety at work, or
pounds of a metal or specific forms or isomers of a com- other government agencies. In the United Kingdom, a use-
pound. The concept of speciation includes the organic and ful contact will be the Health and Safety Executive (HSE)
inorganic compounds, as well as the elemental metal, and is and the Health and Safety Laboratory (HSL), in the United
based on the expected differences in physical, chemical and States of America, the National Institute for Occupational
toxicological properties of different metal species. Toxicity is Safety and Health (NIOSH) and the Occupational Safety
related to physicochemical characteristics, such as solubility and Health Administration (OSHA), and in Finland, the
and valency. As a general rule, the water-soluble forms are Finnish Institute of Occupational Health (FIOH).
associated with acute toxicity, and may be cleared more eas-
ily by the body compared to water-insoluble compounds
which tend to be retained for longer periods in bones and tis-
sues. However, those forms that are slightly soluble in the Key points
biological matrix, if they allow a slow release of toxic ions, are
frequently associated with chronic diseases, such as fibrosis ● Some metals, such as iron, copper, zinc, cobalt,
or malignancy. Several metals can exist in different valency manganese and magnesium, are essential for
states, with properties differing depending on the valency. metabolic function, although overexposure causes
The valency of a metal refers to the maximum number of harm (a U-shaped dose–response relationship).
hydrogen or chlorine (or univalent) atoms that may combine ● Metal toxicity is dependent on factors related to
with one atom of the element. It has also been defined as the the agent (speciation, physical and chemical
number of chemical bonds formed by the atoms of a specific properties), the circumstances of exposure and
element. Iron, for example, can exist as ferrous (valency 2) or the body’s reaction.
ferric (valency 3) forms. Chromium has a range of valencies, ● A diagnosis of metal poisoning requires
including trivalent, hexavalent and other rarer valency forms. confirmation of the nature, extent and
Trivalent chromium is considered essential, while several duration of exposure.
hexavalent chromium compounds are toxic and carcinogenic.
ACKNOWLEDGEMENTS
DIAGNOSIS OF METAL POISONING
The editors would like to acknowledge those individuals who
For a clinician faced with a case of possible metal poison- contributed material to the Metals chapters in the eighth and
ing, the diagnosis of occupational metal poisoning is not ninth editions of Hunter’s Diseases of Occupations, some of
always easy, for few cases present as clear clinical entities which may persist in updated form or otherwise here.
and, usually, an occupational cause will be part of a list of
different possibilities. Exposure to a metal (or, indeed, any
other substance) at work does not prove that it is the cause FURTHER READING
of the patient’s illness. The diagnosis often depends on the
balance of probability. The higher or greater the extent and Agricola G. De re metallica, 1556. Hoover HC and Hoover LH
duration of occupational exposure, the more likely it is to (trans). New York: Dover Publications, 1950.
be a cause of the illness. Epidemiological studies may pro- Stern BS, Solioz M, Krewski D et al. Copper and human health:
vide evidence for the range of exposures that are relevant, Biochemistry, genetics, and strategies for modeling
but when an individual patient is being assessed, an addi- dose–response relationships. Journal of Toxicology and
tional difficulty is that there may be considerable individ- Environmental Health. 2007; 10: 157–222.
ual variation in susceptibility. It is therefore necessary to Riihimaki V, Luotamo M. Health risk assessment report for metallic
obtain reliable information, as explained in Chapter 1, chromium and trivalent chromium. Paris: International
Donald Hunter and the history of occupational health: Chromium Development Association, 2006.
13
Aluminium
PERRINE HOET
aluminium levels caused by haemodialysis, oral consump- cause bone toxicity (e.g. impaired mineralization, osteo-
tion of large amounts of Al-containing antacids/phosphate malacia). Although the use of Al-containing drugs can
binders by individuals with impaired renal function, as result in aluminium overload, skeletal effects are more
well as irrigation of the urinary bladder with massive likely to be secondary to hypophosphataemia and phos-
amounts of alum to stop haemorrhaging or reconstructive phate depletion caused by decreased phosphorus absorp-
otoneurosurgery with Al-containing material have resulted tion due to Al binding with dietary phosphorus.59,60 In the
in encephalopathy (dialysis dementia, a degenerative neu- general population, accumulated aluminium content in
rological syndrome, characterized by the gradual loss of bone throughout life does not substantially influence
speech, motor and cognitive functions). the extent of osteoporosis or the occurrence of hip
Cross-sectional studies investigating the neurological fracture.61,62 Bone toxicity has not been documented in
effects of Al in occupationally exposed workers have pro- aluminium-exposed workers.
vided controversial results. Some data support the hypoth- An excess of pulmonary and bladder cancer has been
esis of a relationship between chronic aluminium exposure observed in aluminium production workers, and alu-
in welders and subclinical neurological effects (impair- minium production has been recognized by the
ment on neurobehavioural tests) or an increased incidence International Agency for Research on Cancer (IARC)63 as
of subjective neurological symptoms. However, there is causing human cancer. The excess risk of both lung and
still no firm conclusion as to whether occupational alu- bladder cancers has been attributed to coal tar pitch
minium exposure can result in neuropsychological disor- volatiles and benzo(a)pyrene exposure in this process.64–68
der.3,36–47 In an investigation on steel welders in shipyards, There is no evidence that aluminium metal per se or any of
Riihimaki et al.44 reported a threshold for central nervous its compounds are carcinogenic.
system adverse effects in the concentration range of Contact dermatitis to aluminium has been recognized
108–162 μg Al/L urine and 6.75–9.5 μg/L in serum. A lon- and can be confirmed with patch tests,69 but is relatively
gitudinal study over a period of four years in welders, in rare. Such reactions have been reported following injection
the train and truck construction industry, did not support of aluminium-containing vaccines.70,71
a neurotoxic effect of aluminium at a level of 88–140 μg Al/g
creatinine in urine and 13–16 μg Al/L plasma (preshift
samples) and a mean exposure of 15 years.46 No neurolog- Medical surveillance
ical effects related to the exposure to aluminium were
found in smelters (Al-urine, median 4.0 μg/L; range, from Workers exposed to Al dusts or fumes should be submitted
detection limit up to 34 μg/L), aluminium welders (median, to periodic health checks, including clinical examination
22.0; range, 4–255) and a small group of flake powder with special attention to the lungs and central nervous
production workers (median, 83.0; range, 12–282).45 Data system. Depending on the clinical findings from such
from Letzel et al.47 indicate that chronic exposure to Al, in surveillance, pulmonary function testing, periodic chest
an Al powder plant, at median (range) level up to 110 μg/L radiographs and neuropsychological testing may be con-
(5–337), 87.6 μg/g creatinine (4.6–605), and 8.7 μg/L sidered as additional investigations.
plasma (5.1–25) did not induce measurable cognitive Al concentrations 5 μg/L serum and 30 μg/L urine
deficits. According to a review by Krewski et al.,3 evidence are generally expected in the general population. Analysis
of an association between inhalation exposure and neuro- of serum concentration is performed for follow up of
logical effects is limited. However, a meta-analysis on neu- aluminium status in dialysis patients. Routine biological
robehavioural data obtained by epidemiological studies monitoring in occupationally exposed workers is recom-
in occupational settings concluded that there is concur- mended by some authors.13,44,72 Samples collected imme-
ring evidence from different studies that urinary Al con- diately after a work shift are strongly related to the current
centrations below 135 μg/L have an impact on cognitive exposure, whereas samples taken later after exposure (e.g.
performances.48 Monday morning after a weekend free from exposure) are
Despite numerous epidemiological studies investigating more likely to reflect the body burden of aluminium.12,45
the possible relationship between Al levels in drinking The Deutsche Forschungsgemeinshaft73 adopted 200 μg/L
water and Alzheimer’s disease, the association is highly urine (end of shift sample) as a biological tolerance value
controversial and although it cannot be excluded that it based on a MAK value of 6 mg/m3 for welding fumes
may play a role in the disease, the available data do not (Al 2.34 mg/m3). The biomonitoring action limit recom-
indicate that aluminium has a causal role.49–58 mended by the Finnish Institute of Occupational Health74
is 160 μg/L urine (Monday morning sample). However,
data are scant and it is not known how well serum and
Other manifestations urine concentrations of aluminium reflect the concentra-
tions in the target tissues among workers exposed to
Long-term dialysis and administration of aluminium con- different species of aluminium.45 Moreover, because Al is
taining phosphate-binders used to control hyperphos- ubiquitous, great care should be taken to avoid contamina-
phataemia or aluminium-containing antacid drugs can tion at all stages of sampling and analysis.
156 Aluminium
27. Saric M, Marelja J. Bronchial hyperreactivity in potroom 43. Sjogren B, Iregren A, Frech W et al. Effects on the nervous
workers and prognosis after stopping exposure. British system among welders exposed to aluminium and
Journal of Industrial Medicine. 1991; 48: 653–5. manganese. Occupational and Environmental Medicine.
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primary aluminium smelting. Occupational and aluminum in relation to central nervous system function
Environmental Medicine. 2004; 61: 604–8. among metal inert-gas welders. Scandinavian Journal of
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among aluminum workers. Journal of Occupational and 45. Iregren A, Sjogren B, Gustafsson K et al. Effects on the
Environmental Medicine. 2006; 48: 275–82. nervous system in different groups of workers exposed to
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inflammation in aluminium potroom asthma. Occupational in the train and truck construction industry over 4 years.
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14
Antimony
MALCOLM R SIM
Antimony was previously one of a group of important epidemiological studies of antimony-exposed workers is
occupational toxins, but is now largely of historical interest that the workers are often exposed to several other metals,
in the workplace setting. While this is true in most devel- such as arsenic, a known cause of cancer.3 The American
oped countries, where good workplace control has elimi- Conference of Governmental Industrial Hygienists (ACGIH)
nated antimony as a major cause of disease, this is not has set a threshold limit value (TLV) of 0.5 mg/m3 and
necessarily the case in newly developing countries. considers antimony to be a suspected human carcinogen.
Antimony is a brittle, silver-white metalloid, usually
obtained from the sulphide ore stibnite, which is mined in
many counties worldwide. It is mixed into alloys and used
in solder, sheet and pipe metal, motor bearings, castings, Key points
semiconductors and pewter, and is a byproduct of smelting
lead and other metals. Antimony oxide is added to textiles, ● Antimony can cause respiratory effects such as
plastics, rubber, adhesives, pigments and paper to prevent irritation and a form of simple pneumoconiosis.
them from catching fire. It is also used as a flame retardant ● Other effects include a type of dermatitis and
for plastics, paints, textiles, paper, rubber and adhesives, in gastrointestinal symptoms.
the form of the trioxide. ● In the form of stibine, antimony can cause a
Antimony and its compounds have been found to cause profound haemolytic anaemia.
several health effects in miners and other exposed workers,
although these are less common now in the United Kingdom
and other developed countries.1 Such effects included irrita-
tion of mucous membranes, dermatitis (antimony spots), REFERENCES
nose bleeds, gastrointestinal symptoms, bronchitis and a
simple pneumoconiosis, characterized by fine nodular opac- 1. McCallum RI. Occupational exposure to antimony compounds.
ities close to the hilum with little effect on lung function. Journal of Environmental Monitoring. 2005; 7: 1245–50.
Antimony can also form another compound, stibine (SbH3), 2. International Agency for Research on Cancer Monographs on
which is known to cause a profound haemolytic anaemia, the Evaluation of Carcinogenic Risks to Humans. Some
similar to that caused by arsine. organic solvents, resin monomers and related compounds,
The International Agency for Research on Cancer pigments and occupational exposures in paint manufacture
(IARC) has concluded that antimony trioxide is possibly and painting, vol. 47. Lyon: IARC, 1989.
carcinogenic to humans (group 2B) on the basis of suffi- 3. Jones SR, Atkin P, Holroyd C et al. Lung cancer mortality
cient evidence in experimental animals and inadequate at a UK tin smelter. Occupational Medicine. 2007; 57:
evidence of carcinogenicity in humans.2 One problem with 238–45.
15
Arsenic
MALCOLM R SIM
Arsenic is one of a group of previously important occupa- non-malignant effects of inorganic arsenic exposure are
tional toxins, but which is now largely of historical interest becoming less common in developed countries, there is
in the workplace setting. While this is true in most devel- still concern over their impact in low to medium income
oped countries, where good workplace control has elimi- countries.1 There is no effective treatment for chronic
nated this group as a major cause of disease, this is not arsenic poisoning, but removal from exposure can help to
necessarily the case in newly developing countries. In addi- at least partially reverse some of these effects.
tion, inorganic arsenic has become more important as a While the health impact of inorganic arsenic in the
cause of disease in the environmental health setting, as its workplace setting is waning in many countries, arsenic has
importance in the workplace has waned. become a major cause of ill health throughout the world in
Arsenic is a metal which has been known since antiq- many communities through contamination of drinking
uity, but it differs from other ancient metals in that it was water. While such effects were first documented in Taiwan,
not extracted and used in its elemental form, but is used in in more recent times the country with the highest degree of
compounds such as sulphides. It occurs as an impurity in exposure over a substantial proportion of its population is
the ores of other metals, such as copper, lead and zinc, and Bangladesh, where exposure occurs through drinking con-
has been found in considerable quantities in some bronzes taminated water from the millions of tube wells widely
from archaeological sites. Arsenic can be found in industry used in rural areas of the country. Elevated levels of arsenic
in its inorganic or organic forms, but the inorganic forms in drinking water have also been documented in commu-
have been the most important in terms of worker exposure nities in many other countries across most continents,
and toxicity, especially the trivalent forms. including India, Chile, Mongolia, Mexico and countries in
Most current inorganic arsenic exposure in the work- Eastern Europe.2 Arsenic in drinking water in Bangladesh
place occurs through the application of pesticides and has led to widespread health effects, such as arsenical ker-
herbicides, metal smelting, timber treatment and in the atosis and alterations in skin pigmentation in the exposed
chemical and pesticide manufacturing industries. Another population,3 and considerable public health concern has
traditional use is in pigments such as Paris green (cupric been raised for action to deal with this problem.4 The con-
acetoarsenite) and Scheele’s green (cupric arsenite). In the tamination in Bangladesh groundwater has been thought
middle of the nineteenth century, the use of these pigments to be naturally occurring, but recent evidence suggests that
was so common that chronic arsenical poisoning from this may be contributed to by man-made ponds.5
their dusts was widespread. Arsenic has a half-life in blood of approximately
Chronic, rather than acute, poisoning is the more com- 60 hours and about 75 per cent of absorbed inorganic
mon form of arsenic poisoning in the occupational setting arsenic is excreted as methylated forms, which are less toxic
and can affect many systems of the body, causing hyperpig- than inorganic arsenic and so this in vivo methylation rep-
mentation and hyperkeratosis in the skin, a sensorimotor resents a true detoxification process. With normal renal
peripheral neuropathy, megaloblastic anaemia, hepatotox- function, the biological half-life of arsenic in the urine after
icity and liver cirrhosis. Many of these effects are caused by exposure to inorganic arsenic is between one and two days.
arsenic reacting with the thiol groups of proteins and Therefore, urinary arsenic monitoring, preferably with a
enzymes and inhibiting their catalytic activity. While these 24-hour sample and corrected for creatinine, is the most
References 161
CHEMICAL AND PHYSICAL PROPERTIES leached with sulphuric acid to form beryllium sulphate,
which is converted to basic beryllium carbonate by reac-
Beryllium has chemical and physical properties that make tion with aqueous ammonium carbonate. Subsequent
it desirable for high technology applications, but which heating yields beryllium hydroxide, which is the basis for
unfortunately lead to pernicious use of this highly toxic metal, alloy and oxide production.
metal. The fourth lightest element (atomic weight, 9.012), Beryllium oxide is prepared by calcining beryllium
beryllium is corrosion resistant, non-sparking, non- hydroxide and has applications in the automotive,
magnetic, has a low density (1.85 g/cm3), is heat resistant electronic and computer industries. As a ceramic, it is
(melting point, 1278°C), and has high tensile strength and an excellent heat conductor and can be used as an electric
thermal conductivity. Beryllium differs chemically from insulator in automotive ignition systems, lasers, electronic
other alkaline-earth metals, forming covalently bonded circuits for computers, heat sinks and microwave oven
compounds rather than ionic.1 components. Pure beryllium metal is used primarily in
aerospace, nuclear and defence applications because of its
stiffness, light weight and temperature stability. The metal
COMPOUNDS AND ALLOYS is an integral part of nuclear reactor technology because
it is an excellent neutron reflector and moderator.
Beryllium is found in industry in many different forms. Beryllium is used in nuclear weapon triggering devices
Beryl and bertrandite ore are processed into beryllium because it emits a large number of neutrons when bom-
hydroxide, which is used to produce beryllium metal, alloy barded with alpha radiation.
and oxide. Chemical forms of beryllium include beryllium The most common alloy, beryllium-copper (up to 4 per
salts, sulphate, fluoride and chloride. Beryllium is most cent beryllium), is obtained by fusing beryllium oxide with
commonly alloyed with copper, aluminium and nickel.2 copper and has many desirable properties including
strength, high electrical conductivity, high fatigue strength,
wide temperature tolerance, high elasticity and corrosion
PRODUCTION AND USE resistance. Beryllium-copper alloys are useful in parts sub-
ject to abnormal wear or subject to extreme vibration, such
The United States is the leading producer of beryllium as bearings, cams and gears. It is used in corrosion-resistant
metals, alloys and oxide. The applications for beryllium springs, electrical contacts, switches, relays and connectors
and its alloys are widespread, including use in aerospace, in automobiles, computers and radar, satellite, and
the automotive industries, dental alloys, electronics, telecommunications equipment. Beryllium-aluminium
computers, nuclear weapons and telecommunications. alloy (1–60 per cent beryllium) is used in high technol-
Bertrandite is extracted via open-pit mining. The ore is ogy applications, such as aircraft, scientific devices on
Biomarkers 163
spacecraft, defence avionics packaging, high resolution The major emission source of beryllium in the environ-
medical and industrial x-ray equipment. Beryllium-nickel ment is from the combustion of coal and fuel oils and
alloy (0.275–7 per cent beryllium) has high tensile strength industrial processing of beryllium. The average concentra-
and has age-hardening characteristics. It is used for tion of beryllium in the general atmosphere in the United
diamond drill-bit matrices, watch balance wheels and States is 0.03 ng/m3. The median atmospheric concentra-
airplane brakes.3 tion of beryllium in cities is 0.2 ng/m3.3 The ambient air
standard in the United States was set at 0.01 μg/m3 by the
AEC in 1949.23
EXPOSURE AND HEALTH EFFECTS In the late 1940s, cases of CBD were diagnosed in resi-
dents living in the neighbourhood of a beryllium plant, in
Beryllium exposure assessment is focused on controlling Lorain, Ohio. In an evaluation of beryllium in the commu-
exposure and preventing beryllium-related health effects in nity, almost all the cases resided within 0.25–0.75 miles
the workplace (see also Chapter 83, Berylliosis). Exposure to (1.2 km) of the plant and had ambient exposures of
beryllium dust and fumes can cause an immune hypersensi- 0.004–0.02 μg/m3. Disease rates were comparable to rates
tivity reaction, dermatitis and lung diseases, including acute found among beryllium plant workers. These studies
berylliosis, chronic beryllium disease and lung cancer. Most helped form the basis for setting the beryllium community
hazardous exposures to beryllium come from dust or fume air standard at 0.01 μg/m3 as a 30-day average.24 Later, 21
generated by disturbing the surface of a beryllium product community cases were reported in Reading, Pennsylvania,
through machining and polishing processes. Health effects within 5.3 miles from a beryllium facility.25 Eight addi-
can result from exposures to beryllium metal dust, tional cases in that same community were published
powdered and fired forms of beryllia ceramic, beryllium recently by Maier and colleagues among individuals who
hydroxide, beryllium fume, and mists and dusts of soluble never worked in the plant.14
beryllium salts.
The dose and duration of beryllium exposure that
causes adverse health effects is the subject of ongoing BIOMARKERS
research. There is strong evidence, for example, that
sensitization and chronic beryllium disease can occur at Biomarkers for beryllium include exposure, disease sus-
levels as low as 0.02 μg/m3 lifetime weighted exposure.4,5 ceptibility, effect and disease progression. The most useful
Current governmental permissible exposure limits may biomarkers for disease are found in the blood and lung.26
not be sufficiently protective. Certain beryllium indus- The most widely used beryllium biomarker is the blood
trial processes and job tasks increase the risk of develop- beryllium lymphocyte proliferation test (BeLPT), which is
ing an immune response to beryllium and disease.6–13 commonly used to determine beryllium sensitivity. High
Even seemingly trivial and bystander exposures have in sensitivity, specificity and both negative and positive
caused beryllium sensitization and chronic beryllium predictive value, beryllium-reactive blood lymphocytes
disease.7,8,12–22 proliferate when presented with beryllium antigen. The
Because of these health effects, beryllium has been BeLPT is widely used in industry as part of workplace
monitored in industry since the 1940s. In the United medical screening and surveillance. To a much lesser
States, for example, the US Atomic Energy Commission extent, the BeLPT can be considered a biomarker of expo-
(AEC) adopted the first beryllium permissible exposure sure. If the test is abnormal, it is indicative of past exposure
limit (PEL). This limit was the basis for the US to beryllium since it is a prerequisite for this immune
Occupational Safety and Health Administration (OSHA) response. However, a negative test does not rule out past
permissible exposure limit for beryllium adopted in 1971. exposure.7,8,21,27–31 Serum neopterin levels in the blood
The limit is an eight-hour time-weighted average of have been found to be higher in patients with CBD com-
2 μg/m3, a ceiling level of 5 μg/m3 and a maximum peak pared to those who are sensitized, suggesting that it may
concentration of 25 μg/m3 for no more than 30 minutes discriminate between sensitization and disease.32,33 The
per eight-hour workshift. The PEL is currently under most promising new test of immune response to beryllium
review, upon recognition that cases of chronic beryllium is the beryllium ELISPOT assay which measures beryllium-
disease (CBD) continue to occur at exposure levels 50–100 stimulated T-cell production of the cytokine gamma
times lower than the PEL. interferon. Class II MHC HLA-DP and -DR gene variants
In the workplace, beryllium is measured using various are blood biomarkers of CBD susceptibility, but are not
sampling methods including area and stationary sampling, recommended for screening workers because of their low
and personal breathing zone sampling. The latter is consid- positive predictive value and ethical considerations.
ered the preferred method. Whether particle size sampling Although a high percentage of beryllium-sensitized and
should be performed is open to debate. It is known that CBD patients carry these genes, the genes are also common
the majority of beryllium particulate generated by most in the general population.3,23 Blood biomarkers of disease
machining operations creates a high percentage of respirable- progression include markers of inflammation, such as
sized particles. cytokines.
164 Beryllium
Bronchoalveolar lavage (BAL) fluid obtained from the are to inhibit inflammation and slow disease progression
lung during bronchoscopy is used to distinguish between using oral glucocorticoids as the first-line therapy.
beryllium sensitization and CBD. The lung cells of CBD Those with more severe disease may require additional
patients proliferate in response to beryllium indicating supportive measures and use of other immunosuppressive
lung-specific sensitization, measured by the BeLPT using pharmaceuticals.
lung cells instead of blood. BAL white blood cell count and
lymphocytosis in CBD patients correlate with pulmonary
gas exchange and reflect disease severity.34
Key points
7. Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium workplace applications. Washington DC: Joseph Henry Press,
disease screening in the ceramics industry. Blood lymphocyte 1998: 285–300.
test performance and exposure-disease relations. Journal of 23. Hanifin JM, Epstein WL, Cline MJ. In vitro studies on
Occupational Medicine. 1993; 35: 267–74. granulomatous hypersensitivity to beryllium. Journal of
8. Kreiss K, Mroz MM, Zhen B et al. Risks of beryllium disease Investigative Dermatology. 1970; 55: 284–8.
related to work processes at a metal, alloy, and oxide 24. Eisenbud M, Wanta RC, Dustan C et al. Non-occupational
production plant. Occupational and Environmental Medicine. berylliosis. Journal of Industrial Hygiene and Toxicology.
1997; 54: 605–12. 1949; 31: 282–94.
9. Schuler CR, Kent MS, Deubner DC et al. Process-related risk 25. Lieben J, Metzner F. Epidemiological findings associated with
of beryllium sensitization and disease in a copper-beryllium beryllium extraction. American Industrial Hygiene
alloy facility. American Journal of Industrial Medicine. 2005; Association Journal. 1959; 20: 494–9.
47: 195–205. 26. Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening
10. Stange AW, Hilmas DE, Furman FJ, Gatliffe TR. Beryllium blood test identifies subclinical beryllium disease. Journal of
sensitization and chronic beryllium disease at a former Occupational Medicine. 1989; 31: 603–8.
nuclear weapons facility. Applied Occupational and 27. Mroz MM, Kreiss K, Lezotte DC et al. Reexamination of the
Environmental Hygiene. 2001; 16: 405–17. blood lymphocyte transformation test in the diagnosis of
11. Welch L, Ringen K, Bingham E et al. Screening for beryllium chronic beryllium disease. Journal of Allergy and Clinical
disease among construction trade workers at Department of Immunology. 1991; 88: 54–60.
Energy nuclear sites. American Journal of Industrial 28. Stange AW, Furman FJ, Hilmas DE. The beryllium lymphocyte
Medicine. 2004; 46: 207–18. proliferation test: Relevant issues in beryllium health
12. Newman LS, Mroz MM, Maier LA et al. Efficacy of serial surveillance. American Journal of Industrial Medicine. 2004;
medical surveillance for chronic beryllium disease in a 46: 453–62.
beryllium machining plant. Journal of Occupational and 29. Deubner DC, Goodman M, Iannuzzi J. Variability, predictive
Environmental Medicine. 2001; 43: 231–7. value, and uses of the beryllium blood lymphocyte
13. Rodrigues EG, McClean MD, Weinberg J, Pepper LD. proliferation test (BLPT): Preliminary analysis of the ongoing
Beryllium sensitization and lung function among former workforce survey. Applied Occupational and Environmental
workers at the Nevada Test Site. American Journal of Hygiene. 2001; 16: 521–6.
Industrial Medicine. 2008; 51: 512–23. 30. Harris J, Bartelson BB, Barker E et al. Serum neopterin in
14. Maier LA, Martyny JW, Liang J, Rossman MD. Recent chronic chronic beryllium disease. American Journal of Industrial
beryllium disease in residents surrounding a beryllium Medicine. 1997; 32: 21–6.
facility. American Journal of Respiratory and Critical Care 31. Maier LA, Kittle LA, Mroz MM, Newman LS. Beryllium-
Medicine. 2008; 177: 1012–17. stimulated neopterin as a diagnostic adjunct in chronic
15. Infante PF, Newman LS. Beryllium exposure and chronic beryllium disease. American Journal of Industrial Medicine.
beryllium disease. Lancet. 2004; 363: 415–16. 2003; 43: 592–601.
16. Sackett HM, Maier LA, Silveira LJ et al. Beryllium medical 32. Newman LS, Bobka C, Schumacher B et al.
surveillance at a former nuclear weapons facility during Compartmentalized immune response reflects clinical
cleanup operations. Journal of Occupational and severity of beryllium disease. American Journal of Respiratory
Environmental Medicine. 2004; 46: 953-61E. and Critical Care Medicine. 1994; 150: 135–42.
17. Eisenbud M, Lisson J. Epidemiologic aspects of 33. Balkissoon RC, Newman LS. Beryllium copper alloy (2 per
beryllium-induced non-malignant lung disease. Journal cent) causes chronic beryllium disease. Journal of
of Occupational Medicine. 1983; 25: 196–202. Occupational and Environmental Medicine. 1999; 41:
18. Newman LS, Lloyd J, Daniloff E. The natural history of 304–8.
beryllium sensitization and chronic beryllium disease. 34. Kim Y. Acute beryllium disease in metal workers. European
Environmental Health Perspectives. 1996; 104 (Suppl. 5): Respiratory Journal. 2004; 24: 149S.
937–43. 35. Hardy HL. Beryllium poisoning – lessons in control of
19. Newman LS. Immunology, genetics, and epidemiology man-made disease. New England Journal of Medicine. 1965;
of beryllium disease. Chest. 1996; 109 (Suppl. 3): 273: 1188–99.
40S–43S. 36. Finkel AJ, Hamilton A, Hardy HL. Hamilton and Hardy’s
20. Newman LS. Significance of the blood beryllium lymphocyte Industrial toxicology, 4th edn. Boston, MA: John Wright,
proliferation test. Environmental Health Perspectives. 1996; 1983.
104 (Suppl. 5): 953–6. 37. Martyny JW, Hoover MD, Mroz MM et al. Aerosols generated
21. Occupational Safety and Health Administration. Final rule air during beryllium machining. Journal of Occupational and
contaminants permissible exposure limits. Washington DC: Environmental Medicine. 2000; 42: 8–18.
OSHA, 1989. 38. Stefaniak AB, Hoover MD, Dickerson RM et al. Surface area
22. Newman LS. Beryllium biomarkers: Application of of respirable beryllium metal, oxide, and copper alloy
immunologic, inflammatory, and genetic tools. In: aerosols and implications for assessment of exposure risk of
Mendelsohn LC, Peeters JP (eds). Biomarkers: Medical and chronic beryllium disease. AIHA J. 2003; 64: 297–305.
166 Beryllium
39. Kent MS, Robins TG, Madl AK. Is total mass or mass of 45. International Agency for Research on Cancer. Meeting on
alveolar-deposited airborne particles of beryllium a better the IARC working group on beryllium, cadmium, mecury, and
predictor of the prevalence of disease? A preliminary study exposures of the glass manufacturing industry. Scandinavian
of a beryllium processing facility. Applied Occupational and Journal of Work, Environment and Health. 1993; 19:
Environmental Hygiene. 2001; 16: 539–58. 360–3.
40. Reeves AL, Preuss OP. The immunotoxícíty of beryllium. In: 46. Mancuso TF. Occupational lung cancer among beryllium
Dean JH, Luster MI, Munson AE (eds). Immunotoxicology and workers. In: Lemen R, Dement J (eds). Dust and diseases.
immunopharmacology. New York: Raven Press, 1985: 441–55. Forest Park: Pathatox, 1979.
41. McCawley MA, Kent MS, Berakis MT. Ultrafine beryllium 47. Mancuso TF. Mortality study of beryllium industry workers’
number concentration as a possible metric for chronic occupational lung cancer. Environmental Research. 1980;
beryllium disease risk. Applied Occupational and 21: 48–55.
Environmental Hygiene. 2001; 16: 631–8. 48. Mancuso TF, el-Attar AA. Epidemiological study of the
42. Stefaniak AB, Day GA, Hoover MD et al. Differences in beryllium industry. Cohort methodology and mortality
dissolution behavior in a phagolysosomal stimulant fluid for studies. Journal of Occupational Medicine. 1969; 11:
single-constituent and multi-constituent materials 422–34.
associated with beryllium sensitization and chronic beryllium 49. Infante PF, Wagoner JK, Sprince NL. Mortality patterns from
disease. Toxicology In Vitro. 2006; 20: 82–95. lung cancer and nonneoplastic respiratory disease among
43. Newman LS, Mroz MM, Balkissoon R, Maier LA. Beryllium white males in the beryllium case registry. Environmental
sensitization progresses to chronic beryllium disease: A Research. 1980; 21: 35–43.
longitudinal study of disease risk. American Journal of 50. Wagoner JK, Infante PF, Bayliss DL. Beryllium: An etiologic
Respiratory and Critical Care Medicine. 2005; 171: 54–60. agent in the induction of lung cancer, nonneoplastic
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on the evaluation of the carcinogenic risk of chemicals to exposed workers. Environmental Research. 1980; 21:
humans. Lyon: IARC, 1980. 15–34.
17
Cadmium
PERRINE HOET
After long-term low-level exposure, about half the body These effects occurred in the absence of renal toxicity.
burden of cadmium is localized in the kidneys and liver, a Primary olfactory neurons may therefore represent early
third of the total being in the kidneys mainly in the renal targets for cadmium toxic action. It seems most likely
cortex. At higher levels of exposure, a greater proportion of that cigarette smoking, which is a considerable source of
the body burden is found in the liver. The ratio between cadmium, can intensify this dysfunction.7–9
the cadmium concentration in the kidney and that in the
liver decreases with the intensity of exposure. Cadmium is
excreted in the urine, largely as a cadmium–metalloth- Kidney manifestations
ionein complex, but the rate of excretion is low (hence the
long biological half-life) unless there is concomitant kid- The kidney is generally considered to be the principal
ney damage. Small amounts of cadmium may also appear target organ affected by chronic exposure to Cd. An early
in the bile, saliva, hair and nails.2–4 sign of cadmium poisoning is tubular proteinuria.
The increased excretion of low molecular weight (LMW)
proteins (such as retinol binding protein (RBP),
2-
TOXICITY microglobulin (
2-MG), 1-microglobulin (1-MG) (or
protein HC) or a urinary enzyme leakage such as N-acetyl-
Respiratory manifestations
-D-glucosaminidase (NAG)) is particularly characteristic
of this tubular toxicity. The proteinuria may be accompa-
Acute effects may be noted after the inhalation of cadmium nied by other evidence of tubular damage, such as
oxide fumes which are generated from welding or brazing calciuria, aminoaciduria, glycosuria and phosphaturia.
on cadmium or its alloys. Because of its low boiling point Hypercalciuria might be responsible for the increased inci-
(765°C) by comparison to other metals such as zinc, Cd dence of renal stones reported in some cadmium-exposed
fumes are generated in potentially toxic concentrations in workers.2,4,10–12
Cd alloy production and welding, during oxyacetylene Less commonly, an increased urinary excretion of
cutting of Cd-coated steel and rivets and in the smelting, high molecular weight (HMW) proteins (albumin,
melting and refining of metals that contain Cd. There is gen- immunoglobulin G or transferrin) can occur indicating an
erally a lag period of up to ten hours after the inhalation of effect of Cd on the glomerulus which can develop with or
the fumes before any untoward effects become apparent. without tubular LMW proteinuria.2
The patient then notices retrosternal pain, dyspnoea and Many other parameters have been investigated and
cough. With heavy exposure, pulmonary oedema may suggested as early biomarkers of Cd nephrotoxicity
develop after one or two days. The first stage is very similar (e.g. enzymes (intestinal alkaline phosphatase, alanine
to ‘metal fume fever’ (see Chapter 44, Welding), but it is aminopeptidase, lactate dehydrogenase, glutathione-
essential not to confuse both conditions, since the lung S-transferase), other proteins (Tamm–Horsfall glycopro-
effects from Cd exposure can include delayed pulmonary tein, cystatin C, Clara cell protein, kidney injury molecule-1),
oedema and possibly death. Subjects who survive acute cad- extracellular matrix components (laminin, fibronectin,
mium poisoning may recover without damage, although proteoglycans), tubular antigens or serum antibodies,
some authors have reported delayed development of lung eicosanoids, thromboxane B2, kallikrein activity, sialic
impairment.2 acid, glycosaminoglycans, cytokines). Changes in renal
Long-term occupational exposure has been reported in biomarkers of unknown health significance and predictive
earlier studies to cause emphysema and dyspnoea. Other value can occur at very low levels; the health significance
studies, however, have not shown a cadmium-related of most of these biomarkers and their predictive value for
impaired respiratory function.2,5 Lung function tests, the development of end-stage renal failure are largely
which have sometimes been reported to be abnormal in unknown.
cadmium workers, do not seem to show any dose– Cadmium-induced LMW proteinuria is presently the
response relationship and are certainly not as sensitive only renal effect of Cd with documented health risk signif-
indicators of cadmium damage as the excretion of tubular icance. The critical concentration of cadmium in the renal
proteins (see under Kidney manifestations).6 cortex associated with increased incidence of LMW pro-
Anosmia was also noted to be a common finding in teinuria is estimated to be about 200 ppm, equivalent to a
early reports. More recent investigations observed olfac- urinary Cd excretion of about 10 g Cd/g creatinine.
tory disorders in workers exposed to cadmium levels much When the concentration of Cd in urine exceeds 10 g/g
lower than those reported in the past. A statistically signif- creatinine, the risk of developing tubular proteinuria is
icant correlation was found between olfactory dysfunction well established. This risk increases almost linearly with the
and cadmium concentrations in the blood and urine, but urinary Cd concentration from an expected prevalence of
not between olfactory dysfunction and the duration of tubular proteinuria around 10 per cent for CdU (cadmium
exposure. It was postulated that the action of the metal was in urine) values slightly above 10 g/g creatinine to more
due to an elective tropism for the olfactory epithelium and than 20 per cent when CdU values exceed 20 g/g creati-
not to a non-specific irritant effect on the nasal cavity. nine.13 This threshold has been considered as clinically
Toxicity 169
relevant because several studies have indicated that ongo- on bone metabolism (with impairment of bone formation
ing overexposure with CdU 10 g/g creatinine may lead and/or increased bone resorption) and loss of bone cal-
to irreversible renal damage, an exacerbation of the age- cium is a first possibility. The second putative mechanism
related decline in the glomerular filtration rate and a includes several factors resulting from kidney damage.
decrease in the filtration reserve capacity.2 Cd-induced Increased calciuria, caused by cadmium-induced tubular
microproteinuria is often considered as irreversible, except damage is a possibility. Moreover, kidney damage may
at the incipient stage of the intoxication where a partial or cause other changes capable of disturbing bone metabo-
complete reversibility has been found in some studies. In lism: loss of phosphate, reduced hydroxylation of 25-OH-
some studies on exposed workers, microproteinuria was vitamin D, and acidosis. The increase in parathyroid
reversible when reduction or cessation of exposure hormone secretion secondary to kidney damage may
occurred, while tubular damage was still mild (
2-MG further aggravate bone disease.2,27–29
1500 g/g creatinine) and CdU had never exceeded
20 g Cd/g creatinine.14
Although the concept of a critical concentration refers Other manifestations
to the total amount of cadmium in the renal cortex, it is
only the small amount of the metal not bound to metal- Cadmium exposure has been linked to lung and prostate
lothionein that is capable of causing nephrotoxicity. It has cancer in humans. In 1993, a Working Group of the
been suggested that the concentration of free cadmium International Agency for Research on Cancer30 concluded
which will produce
2-microglobulinuria is 2 ppm or 1 per that there was sufficient evidence in humans for the car-
cent of the critical concentration of the total cadmium cinogenicity of cadmium and cadmium compounds on the
concentration in the kidney. There is some evidence that lung. More recent studies have indicated the importance of
factors, such as the capacity to synthesize metallothionein confounding exposures, such as arsenic, and do not sup-
and ageing, may decrease the critical concentration of cad- port the hypothesis that cadmium compounds are human
mium which is associated with the development of tubular lung carcinogens.2,31–33 The association between cadmium
damage. Workers that have higher plasma metallothionein exposure and prostate cancer was not confirmed in more
antibody levels might more readily develop cadmium- recent reviews.33,34 A recent meta-analysis indicated that
induced renal dysfunction.15,16 exposure to cadmium appears to be associated with renal
cancer, but this conclusion is tempered by the inability of
studies to assess cumulative cadmium exposure from all
Bone manifestations sources including smoking and diet.35
Cadmium does not appear to be directly genotoxic.
High cadmium exposure is known to cause bone damage. Indirect effects of cadmium are mediated by the generation
‘Itai-itai disease’ was the name given to an outbreak of of reactive oxygen species (ROS). Cadmium also modulates
osteomalacia found in postmenopausal multiparous gene expression and signal transduction and reduces activi-
women in Japan. The women in whom the condition was ties of proteins involved in antioxidant defences. Several
first noted lived in an area where crops had become con- studies have shown that it interferes with DNA repair.36–40
taminated with cadmium from water that had drained It has been suggested that cadmium in the environment
through an old zinc mine and had been used for irrigation. may be involved in the aetiology of hypertension.41 In exper-
The women had pains in the back and legs (itai-itai literally imental animals, exposure to cadmium modifies a number
means ‘ouch-ouch’) and some developed pathological of mechanisms that regulate cardiovascular function, but
fractures. Vitamin D and other nutritional deficiencies are there are some important differences between species.42 In
thought to be cofactors in the aetiology of itai-itai disease. epidemiological studies, cadmium workers do not have an
The metabolic changes in cadmium-induced osteomalacia increased prevalence of hypertension. The role of cadmium
have been described by Stanbury and Mawer.17 in the aetiology of hypertension in those who are exposed to
Environmental exposure to cadmium has been associ- it only in the general environment is uncertain.
ated with an increased loss of bone mineral density in both Neurobehavioural disturbances have been dose-
sexes, leading to osteoporosis and increased risk of frac- dependently associated with CdU in cadmium-exposed
tures, especially in the elderly and in females.2,18–24 Data on workers. The possibility of a promoting role by increased
workers are scant, although there is some evidence sup- cadmium body burden in the development of peripheral
porting the existence of an association between cadmium neuropathy in the elderly has been raised.43,44 At present,
at low exposure level and alterations in the vitamin D this remains speculative.
metabolic pathway25 or bone mineral density.26 However, Yellowing of the teeth has been associated with long-
more supporting evidence on this relationhip is required. term ingestion and/or inhalation of cadmium.45,46
Whether disturbances in the calcium balance and the However, studies reporting these effects are subject to a
effects on the skeleton are mediated directly on bone or are number of uncertainties, including the measurements of
secondary to kidney damage is still unclear. Several mech- cadmium exposure, the magnitude of confounding by
anisms have been postulated. A direct effect of cadmium other toxicants and the evaluation of the effect.
170 Cadmium
Although cadmium can accumulate in the liver, inhala- dysfunction (e.g. diabetes) and the fact that no treatment
tion of Cd fumes does not appear to have significant effects to remove Cd from its storage sites is presently available, it
on the liver. Liver damage is not a prominent feature of seems prudent to recommend that occupational exposure
chronic cadmium poisoning. to Cd does not result in CdU levels exceeding 5 g Cd/g
creatinine3,4,50 or possibly even as stringent as 2 g Cd/g
creatinine.3
HEALTH SURVEILLANCE OF CADMIUM The assessment of renal function relies on the measure-
WORKERS ment of the excretion of both LMW and HMW proteins.
Increased excretion of LMW proteins indicates tubular
Biological monitoring of cadmium workers is necessary to damage and failure of reabsorption, whereas excretion of
prevent excessive uptake leading to renal damage.3,47 The HMW proteins, such as albumin, reflects glomerular dam-
interrelationships between cadmium exposure and cad- age. Measurement of urinary
2-MG has been widely used
mium concentration in blood and urine are complex and as an indicator of tubular function. This protein is, how-
reflect the accumulation of cadmium in liver and kidney ever, degraded rapidly in the bladder when urinary pH is
over considerable periods of time. The maximum value of less than 5.5. RBP is stable at all urinary pH values and is
CdB (blood cadmium), which is about twice as high in therefore a more suitable indicator for tubular function
smokers than non-smokers, is generally below 3 g/L in (see Chapter 5, Biological monitoring). Protein HC and
European subjects not occupationally exposed to cad- NAG are other biomarkers of Cd-induced subclinical tubu-
mium. In workers, after the start of exposure Cd concen- lar dysfunction.2 The levels of plasma metallothionein anti-
tration in blood increases linearly then levels off when an body have been suggested as a biomarker of susceptibility
equilibrium is reached. Blood Cd is a useful indicator of to renal dysfunction in occupational cadmium exposure.15
recent exposure. After long-term high Cd exposure, an The following guidelines for interpreting CdU,
2-MG
increasing proportion of blood Cd will be related to body and RBP measurements in workers exposed to Cd have
burden. After cessation of exposure, CdB may reflect the been recommended:13
body burden and the decrease of CdB displays an initial
fast component with a half-life of three to four months ● CdU between 2 and 5 g/g creatinine: sign of an
and a slow component with a half-life of about ten increased body burden. Exceptionally, such levels can
years.2,3,14,40,48,49 also be found in heavy smokers. At this stage, periodic
In subjects with no occupational or environmental screening for tubular dysfunction is usually not
exposure, concentrations of Cd in urine are normally recommended.
below 1–2 g/g creatinine. The urinary excretion of Cd is ● CdU between 5 and 10 g/g creatinine: risk of
influenced by smoking habits, but not to the same extent as developing tubular proteinuria remains unlikely, except
blood Cd levels. At low exposure levels (general environ- perhaps in particularly vulnerable subjects or in subjects
mental exposure), the amount of Cd absorbed may be who have been exposed in the past and progressively
insufficient to saturate all the body binding sites (e.g. lose their body burden of Cd. Screening for tubular
induced metallothionein). Urinary excretion increases in proteinuria is recommended in subjects who persistently
proportion to the amount of Cd stored in the body and not show an urinary Cd above 5 g/g creatinine.
proportionally to the exposure levels. In such circum- ● CdU exceeding 10 g/g creatinine: risk of developing
stances, there is a significant correlation between urinary tubular proteinuria well established.
Cd and Cd in kidney. In high exposure conditions, the Cd
binding sites become progressively saturated and any fur- A persistent increase of urinary LMW proteins over
ther absorption of cadmium cannot be retained in the intervals of months or years may be a sign of irreversible
kidney: it is rapidly excreted in the urine. In these situa- degenerative changes likely to compromise renal function.
tions, the urinary Cd concentration would be a better Several stages can be identified from incipient tubular
reflection of current exposure levels. The relative influence damage to overt nephropathy with decreased renal func-
of the body burden and recent exposure on CdU depends tion (adapted from Ref. 13):
on the exposure intensity. If exposure continues and
kidney damage occurs, urinary Cd excretion is increased ● 300 g/g creatinine: normal;
even more. Eventually, the amount of Cd that can be ● 300–1000 g/g creatinine: incipient cadmium tubular
released from the kidney decreases progressively and the damage with a possibility of reversibility after removal
urinary Cd concentration follows the same trend. In newly from exposure. No change in GFR (glomerular
exposed subjects, a latent period may thus be observed filtration rate);
before Cd in urine correlates with exposure.2,3 ● 1000–10 000 g/g creatinine: irreversible tubular
In workers, the critical CdU level (based on LMW proteinuria which may lead to accelerated decline in
microproteinuria) is around 10 g/g creatinine. However, GFR with age.
for several reasons, including the long biological half-life ● 10 000 g/g creatinine: overt cadmium nephropathy
of Cd, the possible interaction with other causes of renal usually associated with decreased GFR.
References 171
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It is possible to measure cadmium concentrations in 9. Sulkowski WJ, Rydzewski B, Miarzynska M. Smell impairment
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2-microglobulin in the urine of cadmium pigment workers.
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11. Lauwerys R, Bernard AM. Cadmium and the kidney.
British Journal of Industrial Medicine. 1986; 43: 433–5.
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Transplantation. 2002; 17 (Suppl. 2): 35–9.
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half-life. Smokers have a higher body burden controlling occupational and environmental risks of
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● Acute cadmium oxide inhalation exposure 15. Chen L, Jin T, Huang B et al. Critical exposure level of
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using cadmium containing solders. British Journal of exposure and forearm bone density. Biometals. 2004; 17:
Industrial Medicine. 1986; 43: 657–68. 499–503.
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Medicine. 1998; 55: 435–9. lead concentrations and their relation to blood pressure in a
27. Kazantzis G. Cadmium, osteoporosis and calcium population with low exposure. British Journal of Industrial
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28. Berglund M, Akesson A, Bjellerup P, Vahter M. Metal–bone 42. Boscolo P, Carmignani M. Mechanisms of cardiovascular
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29. Coonse KG, Coonts AJ, Morrison EV, Heggland SJ. Cadmium British Journal of Industrial Medicine. 1986; 43: 605–10.
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32. Sorahan T, Esmen NA. Lung cancer mortality in UK nickel- cadmium smelter workers. Scandinavian Journal of Work and
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36. Bertin G, Averbeck D. Cadmium: Cellular effects, previously exposed to cadmium. Scandinavian Journal of
modifications of biomolecules, modulation of DNA repair Work and Environmental Health. 1997; 23: 31–6.
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cadmium induced mutagenicity. Human and Experimental chemicals, 2nd edn. Amsterdam: Kluwer Academic,
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as targets of cadmium toxicity. Toxicology and Applied transportable system for measurement of kidney cadmium
Pharmacology. 2006; 213: 282–90. in vivo. International Journal of Applied Radiation and
39. Verougstraete V, Lison D, Hotz P. A systematic review of Isotopes. 1981; 32: 109–12.
cytogenetic studies conducted in human populations 52. Grinyer J, Byun SH, Chettle DR. In vivo prompt gamma
exposed to cadmium compounds. Mutation Research. 2002; neutron activation analysis of cadmium in the kidney and
511: 15–43. liver. Applied Radiation and Isotopes. 2005; 63: 475–9.
18
Chromium
TOM SORAHAN
Figure 18.2 Healed nasal perforation from inhalation of the MONITORING OF WORKERS EXPOSED TO
vapour from a chrome-plating tank. Courtesy of the late CHROMIUM
Professor RI McCallum.
Special attention should be given to the skin and nose of
chrome workers. It may also be prudent to conduct peri-
odic tests of lung function if cases of asthma are suspected.
The inhalation of large concentrations of hexavalent The chromium concentration in the urine at the end of
chromium compounds may cause coughing, wheezing, a work shift is an index of recent exposure to soluble hexa-
inspiratory pain, fever and loss of weight. Prolonged skin valent chromium compound. Levels in unexposed people
contact may lead to local irritation and, if skin damage is are below 12 nmol/L in blood and 0.2–3 mmol/mol creati-
extensive, enough of the compound may be absorbed to nine in urine.3
cause renal damage and death.
Key points
THE CARCINOGENICITY OF CHROME
COMPOUNDS ● Chromium is an essential element.
● Heavy chrome exposure can cause chrome
The most serious consequence of exposure to chromium ulcers.
compounds is the risk of developing lung cancer (see ● Hexavalent chromium compounds are potent
Chapter 85, Occupational cancer: epidemiology, biological human lung carcinogens.
mechanisms and biomarkers). The carcinogenicity of
hexavalent chromium compounds is well established and
markedly elevated lung cancer rates have been found in
workers engaged in primary chromate production, in the REFERENCES
chrome pigment production industry, and in chrome plat-
ing.1 The direct evidence relating to stainless steel welders 1. Cross HJ, Faux SP, Sadhra S et al. Criteria document for
and workers in the ferrochromium industries is inconclu- hexavalent chromium. Paris: International Chromium
sive. The human evidence relating to trivalent chromium is Development Association, 1997.
also inconclusive. 2. Norseth R. The carcinogenicity of chromium and its salts.
In short-term tests, hexavalent chromium produces British Journal of Industrial Medicine. 1986; 43: 649–51.
mutations in bacterial systems without prior activation 3. McAughey JJ, Samuel AM, Baxter PJ, Smith NJ. Biological
and, in vitro, the mutagenic potential of soluble and monitoring of occupational exposure in the chromate
slightly soluble compounds does not differ. Trivalent production industry. Science of the Total Environment.
chromium has a limited mutagenic effect, although it has 1988; 71: 317–22.
19
Cobalt
PERRINE HOET
mechanisms possibly involved.26,27 Contrary to what is 1 g/L.2,39 Elevated levels have been reported in cobalt
generally assumed for most metals, the biological activity metal, oxide and salt production workers, hard metal
of cobalt metal is not exclusively mediated by the ionic workers, battery plant workers, pottery painters, as well as
form dissolved in biological media.27 in dental technicians.4,15,40–42 Metal-on-metal hip and
Cobalt and cobalt compounds have skin-sensitizing knee arthroplasties can cause increased blood and urine
properties which may lead to occupational contact der- levels.43–46
matitis, particularly of the hands.28–32 Concurrent reaction In Germany,47 exposure equivalents for carcinogenic
to cobalt, nickel and chromate may occur.33,34 materials (Expositionsäquivalente für krebserzeugende
At one time, cobalt salts were added to beer as a foam Arbeitsstoffe (EKA)) are derived for substances in carcino-
stabilizer and a number of outbreaks of congestive car- gen categories 1 to 3. These substances are not given bio-
diomyopathy were linked to that use. Those affected suf- logical tolerance values (BAT) because it is considered that,
fered from an abrupt onset of left ventricular failure with at present, it is not possible to specify safe levels of such
pericardial effusion and polycythaemia. It was generally substances in biological materials. However, the relation-
considered that the aetiology was multifactorial since the ship between the concentration of the substance in the
amount of cobalt consumed, even by the most heavy workplace air and that of the substance (or metabolite) in
drinkers, was far less than that given therapeutically for biological materials is investigated for the occupational
anaemia. The fact that the condition was seen almost exclu- medical detection and quantification of the individual
sively in heavy drinkers suggested that there was a synergis- exposure to the substance. For cobalt, the EKA values are
tic action between the cobalt in the beer, the direct effects of 15, 30, 60 and 300 g/L urinary cobalt (sampling time not
alcohol on the myocardium and an inadequate intake of fixed) for 0.025, 0.05, 0.10 and 0.50 mg/m3 cobalt in air.
proteins and vitamins.35 Isolated cardiomyopathy cases The biological exposure indices (BEI) recommended by
have been reported among workers exposed to cobalt or the American Conference of Governmental Industrial
hard metals.36 Cumulative exposure to cobalt in cobalt pro- Hygienists (ACGIH)48 for cobalt are 15 g/L urine and
duction workers was found to be associated with echocar- 1 g/L blood (end of shift at end of work-week samples),
diographic changes indicating altered left ventricular corresponding to an atmospheric exposure level of
relaxation and early ventricular filling, but not associated 0.02 mg/m3 (TLV-TWA, inhalable fraction).
with clinically significant cardiac dysfunction.37 A possible Exhaled breath condensate (EBC), a fluid formed by cool-
mechanism for the findings could be the accumulation of ing exhaled air, is postulated to be a suitable matrix to assess
cobalt in the myocardium, the result being an increase in target tissue dose and the effects of inhaled cobalt and tung-
myocardial stiffness and the inhibition of cellular respira- sten. It was speculated that Co-EBC reflects not only expo-
tion due to inhibition of mitochondrial dehydrogenase.36,37 sure, but also the amount of the element retained in the lung
Cobalt has an effect on thyroid function. It inhibits and eliminated with exhaled air after its interaction with –
tyrosine iodinase which prevents the synthesis of thyrox- and possibly damage to – resident cells.49 However, this
ine. This, in turn, leads to an oversecretion of thyroid- technique is still at an exploratory stage and generally not
stimulating hormone and to thyroid hyperplasia. available for routine surveillance of cobalt-exposed workers.
Cobalt also mimicks hypoxia and induces the produc-
tion of erythropoietin, leading to polycythaemia.
34. Ruff CA, Belsito DV. The impact of various patient factors on exposures in a battery plant. International Archives of
contact allergy to nickel, cobalt, and chromate. Journal of Occupational and Environmental Health. 2007; 80: 527–31.
the American Academy of Dermatologists. 2006; 55: 32–9. 43. Daniel J, Ziaee H, Pradhan C et al. Blood and urine metal ion
35. Alexander CS. Cobalt-beer myopathy. American Journal of levels in young and active patients after Birmingham hip
Medicine. 1972; 53: 395–417. resurfacing arthroplasty: Four-year results of a prospective
36. Seghizzi P, D’Adda F, Borleri D et al. Cobalt myocardiopathy. longitudinal study. Journal of Bone and Joint Surgery. British
A critical review of literature. Science of the Total volume 2007; 89: 169–73.
Environment. 1994; 150: 105–9. 44. Luetzner J, Krummenauer F, Lengel AM et al. Serum metal
37. Linna A, Oksa P, Groundstroem K et al. Exposure to cobalt in ion exposure after total knee arthroplasty. Clinical
the production of cobalt and cobalt compounds and its Orthopaedics and Related Research. 2007; 461: 136–42.
effect on the heart. Occupational and Environmental 45. Williams S, Schepers A, Isaac G et al. The 2007 Otto Aufranc
Medicine. 2004; 61: 877–85. Award. Ceramic-on-metal hip arthroplasties: A comparative
38. Lauwerys R, Hoet P. Industrial chemical exposure guidelines in vitro and in vivo study. Clinical Orthopaedics and Related
for biological monitoring, 3nd edn. London: Lewis Publishers, Research. 2007; 465: 23–32.
2001. 46. Witzleb WC, Ziegler J, Krummenauer F et al. Exposure to
39. Lison D, Buchet J-P, Swennen B et al. Biological monitoring chromium, cobalt and molybdenum from metal-on-metal
of workers exposed to cobalt metal, salts, oxides and hard total hip replacement and hip resurfacing arthroplasty. Acta
metal dust. Occupational and Environmental Medicine. 1994; Orthopaedica. 2006; 77: 697–705.
5: 447–50. 47. Deutsche Forschungsgemeinshaft. List of maximum
40. Burgaz S, Demircigil GC, Yilmazer M et al. Assessment of concentration at the workplace and biological tolerance
cytogenetic damage in lymphocytes and in exfoliated values. Report No.43. Commission for the Investigation of
nasal cells of dental laboratory technicians exposed to Health Hazards of Chemical Compounds in the Work Area.
chromium, cobalt, and nickel. Mutation Research. 2002; Berlin: VCH, 2007.
521: 47–56. 48. American Conference of Governmental Industrial Hygienists.
41. Kraus T, Schramel P, Schaller KH et al. Exposure assessment Threshold limit values for chemical and physical agents and
in the hard metal manufacturing industry with special biological exposure indices. Cincinnati: ACGIH, 2007.
regard to tungsten and its compounds. Occupational and 49. Goldoni M, Catalani S, De Palma G et al. Exhaled breath
Environmental Medicine. 2001; 58: 631–4. condensate as a suitable matrix to assess lung dose and
42. Yokota K, Johyama Y, Kunitani Y et al. Urinary elimination of effects in workers exposed to cobalt and tungsten.
nickel and cobalt in relation to airborne nickel and cobalt Environmental Health Perspectives. 2004; 112: 1293–8.
20
Copper
PETER AGGETT
Copper is absorbed by a carrier-mediated process and linear and nodular interstitial fibrosis and granulomatous
by passive diffusion in the proximal small intestine. disease of the lungs and liver.
Absorbed copper is carried in the portal circulation bound Exposure to fumes causes metal fume fever and may
to albumin, amino acids and a specific carrier, tran- occur during smelting, brassing, welding, and working on
scuprein, to the liver where it is taken up by the hepato- preserved woods; and from the burning of coal and waste
cytes and is incorporated into apocaeruloplasmin to form incineration. Exposure standards to atmospheric copper
caeruloplasmin. The liver contains at least four pools of dust have been set at 0.5–1 mg Cu/m3 and to copper fumes
copper, one is the cuproenzymes, another is caeruloplas- at 0.1–0.2 mg Cu/m3.
min which is the major means for systemic distribution of Water can leach copper from copper conduits, particularly
copper, the third pool is a depot of copper bound to a cys- if it is acid. The metallic, bitter and salty taste of copper in
teine-rich protein, metallothionein, and which is probably water can be detected by healthy adults at concentrations of
a reserve of the element, and the fourth pool is that of cop- 2.5–3.5 mg copper/L which is just below the threshold for the
per principally accrued from recirculated caeruloplasmin onset of gastrointestinal effects of nausea, abdominal pain
from which copper is transferred to a pool destined for bil- and vomiting which are associated with drinking water con-
iary excretion. The regulation and exchange of copper taining 4–5 mg copper/L. This threshold does not, of course,
between these pools within the liver is unknown. represent actual exposure levels, and in some areas higher
Copper is distributed peripherally mostly bound to concentrations are tolerated. The regulatory upper limit for
caeruloplasmin (70–80 per cent) from which copper is copper in drinking water has been set at 3 mg copper/L.1,4
taken up by endocytosis. The role of caeruloplasmin is not Suicidal drinking of copper solutions involving doses of
absolutely clear. It is a copper donator, but in individuals 20–70 g of copper is associated with the above gastrointesti-
with acaeruloplasminaemia copper metabolism is unaf- nal features which progress to haematemesis, diarrhoea,
fected, so the residual 20–30 per cent of circulating copper headache, dizziness, and, some hours later, more severe sys-
which is bound to albumin, transcuprein and amino acids temic features, such as tachycardia, respiratory difficulty,
is also available to peripheral tissues, and can compensate intravascular haemolysis, haematuria, gastrointestinal haem-
the absence of caeruloplasmin. orrhagic necrosis, hepatocellular necrosis and liver failure,
The major route of copper excretion is in the bile, in hypovolaemic shock, and acute tubular necrosis and kidney
which it is associated with low molecular-weight copper- failure, coma and death. The stools and vomit may be green.
binding components, as well as macromolecular binding In young children, similar copper overload syndromes
species. Reabsorption of biliary copper is negligible, but the have been described: Indian childhood cirrhosis (ICC) and
reason for this is unclear. At high intakes of copper, intes- idiopathic copper toxicosis (ICT). The former arises from
tinal uptake and transfer is downregulated by reduced drinking milk that has been heated or stored in brass ves-
expression of enterocytic copper carriers, and by the induc- sels first described in India, classically buffalo milk, and the
tion of metallothionein which binds copper and blocks its latter from high copper content in water supplies, for
transfer to the body. Urinary losses of copper are small.1 example local well water, in North America and Europe.
Both are associated with progressive hepatic inflammation,
steatosis, fatty infiltration, necrosis, fibrosis, cirrhosis and
EXPOSURE AND HEALTH EFFECTS liver failure. These appear to be ecogenetic conditions in
that affected individuals have a genetic susceptibility to a
Mining and extraction of copper causes exposure to copper high exposure to copper.1 It is not known if such popula-
particulates, as does processing and working on the metal. tions, or other individuals who are heterozygous for the
Copper powder is pink-red, but it turns green on exposure copper overload syndrome, Wilson disease, are at increased
to moist air; prolonged exposure to this may cause an risk when exposed to copper occupationally.
asymptomatic superficial discolouration of the exposed The diagnosis of these conditions depends on history.
skin, hair and the tongue, and of the teeth. Occasionally, There are no reliable markers of copper excess. Serum cop-
copper dust induces a contact dermatitis. Copper in copper per or caeruloplasmin concentrations are tightly controlled
carbonate and oxide minerals can be released by gastric acid and are more responsive to elevations during infection and
from ingested dust and particles, and might increase sys- stress than they are to increased body burdens which are
temic exposure. Copper in copper sulphide and other com- predominantly in the liver. Thus, liver biopsy is needed for
plexes is not released by gastric acid and is thought not to a definitive diagnosis of systemic overload.
pose such a risk. Some workers exposed to high atmospheric Acute ingestion of copper can be managed by early gastric
levels of copper, estimated to provide 200 mg/day (the rec- lavage if possible. In this situation, serum copper values
ommended dietary intake is around 2.0 mg/day) have devel- may be of prognostic value. Concentrations below 3 mg/L
oped elevated serum copper levels and hepatomegaly.2,3 (50 mol/L) suggest moderate toxicity, and levels above
However, such exposure is seldom limited to copper 8 mg/L (125 mol/L) indicate severe poisoning. Treatment
alone, and simultaneous exposure to arsenic, nickel, silica, with standard systemic metabolic support and with the chela-
lead, cadmium, zinc and iron needs to be considered in the tor D-penicillamine (25 mg/kg body weight daily) will reduce
assessment of occupational exposure. Workers using the copper load, in both acute and chronic copper overload.
Bordeaux mixture have developed diffuse pulmonary Other treatments include unithiol and N-acetyl cysteine.3,5
182 Copper
REFERENCES
Key points
1. Stern BR, Solioz M, Krewski D et al. Copper and human
● Systemic copper toxicity can arise via inhalation health: Biochemistry, genetics, and strategies for modelling
and ingestion of particulates and salts in dose–response relationships. Journal of Toxicology and
solution. Environmental Health. Part B, Critical Reviews. 2007;
● Industrial exposure often involves potentially 10: 157–222.
toxic co-exposure to other metals. 2. International Programme on Chemical Safety. Copper
● Inhalation of copper fumes and salts causes Environmental Health Criteria 200. Geneva: World Health
metal fume fever and pulmonary fibrosis. Organization, 1998.
● Acute oral toxicosis includes necrosis of the 3. Barceloux DG. Copper. Journal of Toxicology. Clinical
gastrointestinal tract, liver and kidneys with Toxicology. 1999; 37: 217–30.
resultant organ failure. 4. Araya M, Olivares M, Pizarro F et al. Gastrointestinal
● Chronic systemic copper toxicosis is associated symptoms and blood indicators of copper load in apparently
with progressive hepatic fibrosis and failure. healthy adults undergoing controlled copper exposure.
● Treatment includes D-penicillamine, Unithiol, American Journal of Clinical Nutrition. 2003; 77: 646–50.
and N-acetyl cysteine. 5. Walshe JM. Treatment of Wilson’s disease: The historical
background. Quarterly Journal of Medicine. 1996; 89: 553–5.
21
Gold
PETER LINNETT
INTRODUCTION For thousands of years, gold has been valued and used
for jewellery and as a monetary unit and for investment. It
Gold has been found in countries throughout the world is applied as decorative finishes on fine ceramic and glass-
and, though present as a trace element in many ore bodies, ware and on conductive surfaces in electronics. As it is bio-
the important sources are South Africa, Australia, North logically inert, the metal is used for medical and dental
America and South America. Due to its high value, there is prostheses, although gold compounds, such as aurothioma-
considerable recycling and refining of this precious metal. late, may be used therapeutically for rheumatoid arthritis.
Many hazards are associated with the mining of gold,
including silicosis, barotraumas, noise-induced hearing
loss, hand and arm vibration and heat exhaustion, as well OCCUPATIONAL TOXICOLOGY
as those due to public health issues in underdeveloped
countries which may include losses of mercury in the Metallic gold is biologically inactive, but gold compounds
recovery process.1 Refining of gold may be accompanied may be toxic, e.g. gold cyanide used for plating solutions,
by exposure to toxic contaminants, e.g. mercury, cad- and cases of dermatitis have been attributed to this, as well
mium, selenium and lead, depending on the source of the as gold sodium thiosulphate. Cyanide salts are used in the
metal ore and processes used.2,3 Chlorine may be used, for extraction of gold and other metals, and fatalities from
example in the Miller process by which base metals and cyanide poisoning have been reported in these extraction
silver are removed from molten gold as metal chlorides, processes (see also Chapter 39, Gases). Aurothiomalate is
some of which are corrosive. If platinum is present, highly nephrotoxic and therefore when used for therapy requires
allergenic chloroplatinates may accumulate in the conden- close monitoring of the patients.
sates from this process. Electrorefining uses a solution of Splashes of gold chloride during the electrorefining
gold chloride or gold cyanide. Lead oxides are used in fire process result in a temporary purple discolouration of the
assay and in cupellation for concentration of gold. Gold is underlying skin which is shed by normal desquamation.
very dense and, even with small volumes, there are consid-
erable manual handling challenges particularly in handling
molten metal and heavy moulds. EXPOSURE LIMITS
Key point
● Risks associated with gold are those of the
extractive process and contamination of the
refining and fabrication processes by other
contaminants, such as mercury and lead.
22
Iron
PETER AGGETT
probably six, two of dominant inheritance and four with Chronic exposure to large doses of iron interferes with
autosomal recessive inheritance, all involve defects in this the intestinal uptake and absorption of zinc and copper. It
regulatory control and feedback.2,4 is speculated that this interaction may cause systemic
In the circulation, iron is distributed by transferrin; this defects in the utilization of these elements causing defi-
takes up iron from specific carriers at the enterocytic baso- ciency features, such as growth retardation and anaemia.
lateral membrane and distributes it to the hepatocytes. However, these considerations apply principally to chil-
Iron in the Kupfner cells of the liver arises from the break- dren rather than the workforce.5
down of erythrocytic haemoglobin by the reticuloendothe- Most cases of acute iron toxicity occur accidentally and
lial system. The systemic pool of iron and its turnover is also predominantly in children.6 There are no systematic
also tightly regulated, and there is no means of specifically dose–response data for acute toxicity. Doses in the order of
excreting iron. The only way that the body loses iron is 20 mg elemental iron/kg body weight are said to precipitate
through the adventitious losses mentioned above. intestinal features, whereas systemic manifestations occur
Intracellular iron is mainly bound in ferritin. In situa- at a threshold around 40–60 mg/kg, and exposures in the
tions of iron overload, ferritin is degraded to haemosiderin order of 100 mg/kg body weight are usually lethal. Features
which can be further degraded within the lysosomes. Iron include initial nausea, vomiting and loose stools resulting
in ferritin can be released when it is needed, but once fer- from corrosive damage and haemorrhagic necrosis of the
ritin has been degraded to haemosiderin, it is only released gastrointestinal mucosa. Four to six hours later, the loss of
during lysosomal breakdown of the protein. This can result the gastrointestinal barrier may result in fluid loss leading
in ‘free’ iron in the liver and tissues, which in turn can to early hypovolaemic shock and increased systemic
cause oxidative damage to membrane lipids, proteins, uptake of iron. The increased iron load causes multiorgan
nucleic acids and other components. The resultant inflam- damage, particularly affecting the liver. This may take
mation and fatty degeneration may progress to necrosis 12–48 hours to develop. The shock worsens, and metabolic
and fibrosis, leading to liver cirrhosis, and similar func- acidosis, coagulopathies and cardiovascular collapse may
tional and architectural damage in the heart, adrenals and progress to death. After recovery, intestinal scarring may
endocrine organs. Classically, this degree of overload lead to strictures and mechanical obstruction.
occurs only in people with one of the haemochromatoses, Treatment6,7 is with induced vomiting or gastric lavage.
or in patients who have secondary iron overload from These are useful if they can be done within two hours of
repeated transfusions for the management of defective ingestion. Further management involves supportive meas-
haemoglobin synthesis or haemolytic anaemias.2,4 ures for shock, acidosis and chelators such as desferroxam-
ine (15–30 mg/kg) with which there is most experience for
acute poisoning. Secondary iron overload may also be
EXPOSURE AND HEALTH EFFECTS managed with desferroxamine or with deferiprone.8
3. Ganz T. Hepcidin: A regulator of iron absorption and iron 6. Mills KC, Curry SC. Acute iron poisoning. Emergency Medicine
recycling by macrophages. Clinical Haematology. 2005; Clinics of North America. 1994; 12: 397–413.
18: 171–82. 7. Porter JB. Practical management of iron overload. British
4. Pietrangelo A. Hereditary hemochromatosis – a new look at Journal of Haematology. 2001; 115: 239–52.
an old disease. New England Journal of Medicine. 2004; 350: 8. Cohen AR, Galanello R, Piga A et al. Safety profile of the
2383–97. oral iron chelator deferiprone: A multi-centre study.
5. Fischer WC, Kordas I, Stoltzfus RJ, Black RE. Interactive British Journal of Haematology. 2000; 108: 305–12.
effects of iron and zinc on biochemical and functional
outcomes in supplementation trials. American Journal of
Clinical Nutrition. 2005; 82: 5–12.
23
Lead
Lead is a bluish-grey metal with the symbol Pb, atomic Lead has been used for at least 6000 years and is a most
number 82 and atomic weight 207.2. Due to the high spe- attractive metal for cultures that employ simple technol-
cific gravity (sg 11.34), ease of casting and fabrication, low ogy. It is easy to extract from its principal ores, has a low
melting point (327.4°C), resistance to corrosion and opac- melting point so that it can be cast and moulded with ease,
ity to x-rays, it has had a wide range of uses, such as solder- is malleable and so can be worked without undue effort. It
ing, printing type, ammunition, brass, piping and shielding can easily be joined together with moderate heat and it
against x-rays.1,2 Inorganic lead has been used in paint resists corrosion by the elements. Moreover, galena (lead
pigments, glass and ceramics. Among organic lead com- sulphide), which was the ore from which lead was derived
pounds, tetraethyl lead was used extensively as an anti- in antiquity, contains variable amounts of silver. Indeed, it
knocking agent in gasoline. Because of the health problems was for its silver and not its lead that galena was first mined
caused by lead, its use in, for example, solder, printing type and the so-called ‘silver mines’ of the ancient world were,
and water pipes, has been replaced by other materials. in fact, lead mines.
Use of tetraethyl lead in petrol for cars has ceased in high During the mediaeval period in Europe, the practice
economy countries. developed of adulterating wines of modest vintage with
In advanced economy countries, lead poisoning no lead and this must have caused much harm. The pernicious
longer occupies the predominant position it once held, and habit persisted well into the eighteenth century and there
few physicians will see a case during their working lifetime. were also a number of epidemics of lead poisoning attrib-
By contrast, in developing countries, lead poisoning is still utable to the drinking of wines that were (accidentally
commonplace, and on a worldwide scale it remains the or deliberately) contaminated with lead. The ‘Devonshire
most common of the occupational poisonings. However, it colic’ was extensively investigated in 1767 by Sir George
is essential that physicians who encounter lead workers Baker who showed, by a mixture of observation and exper-
have an understanding of the clinical effects of lead and can imentation, that it was caused by lead being incorporated
detect symptoms of poisoning at an early stage, as faulty into the Devonshire cider during the course of its produc-
work practices with lead can in some instances be tion, from the cider pounds and presses which had lead in
extremely hazardous to health. Concerns over exposure to their structure.
low levels of lead fume or dust in small workshops are jus- In Europe, the eighteenth and nineteenth centuries were
tified and regular blood lead monitoring is usually the heyday for lead poisoning and there are dozens of
required, as elevated blood lead levels are easily attained in remarkable accounts of the conditions to which lead workers
the absence of sufficient awareness of the hazard lead were subjected. Most workers in the lead trades could expect
working can present. to develop symptoms of some sort and, in the potteries,
Present-day exposures 189
women who dipped the wares into lead glazes had a still- There is still a demand for lead in the building industry.
birth rate which might approach 60 per cent. Lead poison- Significant quantities of lead were used in the manufacture
ing also afflicted great numbers of the general population of motor vehicles, although the practice has now been
who were exposed to contaminated water supplies and to mostly phased out. Repairing car radiators involved rebuild-
adulterated food. ing them using lead, but the trade has almost ceased with the
Because of its widespread occurrence, physicians in the introduction of radiators made from plastic, although it
nineteenth century became expert on lead poisoning, per- lives on in the restoration of radiators in antique vehicles
haps none more so than Tanquerel des Planches whose and aeroplanes.
‘Traite des maladies de plomb ou saturnines’ in 1839 was a Airborne lead dust, sufficient to cause poisoning, may be
synthesis of his experience with more than 120 patients produced during the manufacture of lead batteries, paints
with lead poisoning whom he had treated in Paris. One of and colours, lead compounds, rubber products and glass,
the features of lead poisoning that Tanquerel described was and during the dry disking, grinding and cutting by power
the blue line on the gums which was described in the tools of lead. Exposure may also arise from ‘sanding down’
Lancet the following year by Burton and which has since (rubbing down) and from the application of lead paints and
been known (in English-speaking countries at least) as the glazes, unless they are low solubility lead compounds.
burtonian line; clearly, Burton had not read the Traite! Stained glass workers and roofers who renovate ancient
Concern about occupational lead poisoning in the sec- buildings and churches may be exposed to large amounts of
ond half of the nineteenth century contributed to the fine, oxidized lead dust when removing weathered lead.
establishment of the Medical Inspectorate of Factories. Archaeologists and paleopathologists can also have inadver-
Thomas Legge devoted much energy to reducing the toll tent exposure to the dust when handling old lead coffins.
from this disease, which he accomplished with considerable Poisoning from the inhalation of lead oxide fume may occur
success. in the demolition industry where lead-painted metalwork is
In more recent years, much has been written about lead cut up with gas-powered burning torches. Figure 23.1 shows
poisoning, but perhaps the most influential work has been the use of local extraction and personal protective wear to
that of Robert Kehoe who first put forward the notion that, protect against lead dust and fume.
if the blood lead concentration was kept below 80 mg/dL, Firearms instructors and members of rifle clubs have
the probability of a worker contracting lead poisoning also been found to have increased lead absorption resulting
was remote. Although this concept has been challenged from exposure to lead dust from bullets and lead azide
in recent years, with the possibility that ‘subclinical’ forms fume from the explosive charge. Some enthusiasts have
of lead poisoning might occur, experience has tended been known to make their own bullets on the kitchen
to support Kehoe’s point of view and it is only in recent stove.
years that the maximum blood lead concentration consid- Lead compounds, such as dibasic lead phthalate, lead
ered safe for male lead workers has been lowered from chlorosilicate and basic lead carbonates, are frequently
80 mg/dL. incorporated into polyvinyl chloride (PVC) plastics when
thermal stability and high tensile strength are needed.
Some exposure to lead may occur during the manufacture
PRESENT-DAY EXPOSURES of these plastics, although there is no risk from the finished
materials.
Worldwide, about 2.5 million tonnes of lead are produced Organic lead compounds have been added to petrol as
each year, almost half of which is consumed in the United anti-knock agents for over half a century. The most impor-
States. Workers engaged in primary or secondary lead tant additives are tetraethyl and tetramethyl lead; the for-
smelting may have heavy exposures and they may also be mer is extremely toxic, but the latter is less so. Exposure
exposed at the same time to other metals, such as arsenic or may result from the handling of these compounds in
cadmium. Primary lead smelting is the process by which refineries or during the cleaning out of tanks that have
lead is extracted from its ore, usually lead sulphide (galena). contained leaded petrol. Because of the strict control meas-
High temperatures are used and, although large amounts of ures in industrialized countries, lead poisoning among
respirable lead oxide fume are evolved, the processes are workers who put the additives into petrol is exceptionally
usually well enclosed and ventilated. Secondary smelting rare. Poisoning has also been reported when leaded petrol
involves the melting of scrap lead to reclaim the metal. This has been inadvertently used as a solvent in the manufacture
is usually carried out at temperatures below 500°C, with of cheap shoes or as a degreasing agent. A few cases of
little evolution of lead oxide fume provided that tempera- organic lead poisoning have also occurred in those who
ture control is effective. The ‘dross’ (oxidized lead) that is habitually sniff petrol.
skimmed off the surface of the molten metal may, how- The International Agency for Research on Cancer
ever, give rise to considerable quantities of lead-bearing (IARC) has determined that inorganic lead compounds are
dust which may be inhaled or ingested by workers. Lead in probably carcinogenic to humans (group 2A), and that
any of its forms may be processed by secondary smelting organic lead compounds are not classifiable as to their
and breaking down lead storage batteries is a main source. carcinogenicity to humans (group 3).3
190 Lead
exchangeable pool in the compact bone and dentine. By far Small amounts of lead are also eliminated in other body
the greatest part of the total body burden is in the skeletal fluids, e.g. sweat, saliva and breast milk, but they are not
tissues. important routes of excretion compared with urine.
The rapidly exchangeable pool in the blood is toxicolog- Tetraethyl lead is dealkylated in the liver to the triethyl
ically the most important, although it represents only form which then spontaneously dealkylates to the diethyl
about 2 per cent of the total body burden and has a biolog- form. Diethyl lead is excreted into the bile and is further
ical half-life of about 30 days. The blood lead concentra- dealkylated in the gut to ionic lead. Diethyl lead is the only
tion is the most commonly used index of lead exposure, metabolite of the tetraethyl form that appears in the urine.
but it should be remembered that it reflects only recent
exposure and is not necessarily related in any way to the
total body burden. BIOCHEMICAL EFFECTS OF LEAD
Lead is excreted through the kidney and the urinary lead
concentration was used for many years to estimate expo- Lead has two important biochemical properties that largely
sure until reliable methods of blood lead analysis became determine its toxic manifestations. First, it has a very high
available. Furthermore, there is a considerable circadian affinity for sulphydryl (-SH) groups and thus is able to
variation in excretion but, although urinary lead analyses inhibit the activity of enzymes which depend upon -SH
no longer have a role in the monitoring of inorganic lead groups for their proper functioning. Two enzymes that
exposure, they are the most useful form of monitoring are inhibited by lead are of particular interest. They
exposure to organic lead. A small amount of lead is excreted are delta-aminolaevulinic acid dehydratase (ALAD) and
into the bile to appear in the faeces, but most of the lead in ferrochelatase, and both are concerned with haem synthe-
faeces is that which was ingested but not absorbed. sis (Figure 23.2).
Second, the metabolism of lead mimics that of calcium than 20 g/dL; 1 mmol/L) and somewhere around 85 per cent
in many respects and it is able competitively to inhibit the of the activity of this enzyme may be suppressed before an
action of calcium at some important sites, such as the increase in ALA in the blood is observed. Frank anaemia is
synapse, and during mitochondrial respiration. It is this usually a late phenomenon in lead poisoning. The mild
feature of its metabolism that determines its bone-seeking anaemia of lead poisoning is mainly due to the impairment
properties. of haem synthesis, but there is also some evidence that red
cell life span is somewhat shortened.4 This may be due to an
increase in the mechanical or osmotic fragility of the red
INORGANIC LEAD POISONING cells which, in turn, may be related to a loss of potassium
caused by the inhibition of Na-K-ATPase.5
Lead gradually accumulates until critical body burdens
are reached, when symptoms may appear suddenly and
progress rapidly, although subclinical manifestations (e.g. Symptoms and signs of overexposure to
depression of ALAD activity, reduced motor nerve con- inorganic lead
duction velocity) will have been demonstrable earlier. The
outline of haem synthesis is shown in Figure 23.2, begin- Classically, the patient with lead poisoning presents with
ning with the reaction of glycine and succinyl coenzyme A a history of abdominal pain, colic and constipation.
to form delta-aminolaevulinic acid (ALA). Two molecules However, in high economy countries, not many patients
of ALA move from the mitochondrium into the cell where now reach that stage. More likely, they will complain of the
they condense to form porphobilinogen (PBG) through premonitory symptoms of undue fatigue, lassitude, gener-
the action of ALAD; from PBG are formed a series of por- alized aches and pains in the muscles and joints with, per-
phyrinogens and porphyrins. The molecule then moves haps, some abdominal discomfort. A few patients have
back into the mitochondrium where final rearrangement diarrhoea; some may have a bad taste in the mouth. Because
of the side chains produces protoporphyrin IX. The incor- these symptoms are non-specific, the diagnosis of lead poi-
poration of ferrous iron into protoporphyrin IX, through soning is not immediately considered, but a careful occupa-
the action of ferrochelatase, leads to the formation of tional history will be an important pointer. The diagnosis is
haem. Normal functioning of this synthetic pathway is a clinical one and the term ‘lead poisoning’ should not be
essential for the production of both haemoglobin and the used for asymptomatic workers who simply have abnormal
oxidative enzymes in all body tissues. biological tests. In the absence of clinical symptoms and
Depression of ALAD and of ferrochelatase, results in signs, the term ‘excessive lead absorption’ may be more
increased amounts of ALA in the urine and increased appropriate.
amounts of protoporphyrin in the circulating red cells.
Because of the ferrochelatase suppression, protoporphyrin
forms a metal chelate with zinc instead of with iron, giving Cardiovascular system
increased amounts of zinc protoporphyrin (ZPP). Other
stages of the synthetic pathway are also affected and large In the British Regional Heart Study, a very weak but statis-
amounts of coproporphyrin III are excreted in the urine. tically significant positive association was found between
The rate-limiting enzyme in this series is ALA synthase, blood lead and both systolic and diastolic blood pressure.6
so decreased formation of haem has the effect of increasing The data also indicated that an estimated mean increase of
the amount of ALA formed. This process produces what is 1.45 mmHg in systolic blood pressure occurs for every
essentially a lead-induced porphyria. Depression of haem doubling of blood lead concentration. In a recent system-
synthesis in many tissues (not only the erythropoietic) atic review, Navas-Acien et al. concluded that the evidence
leads to progressive impairment of their ability to synthe- is sufficient to infer a causal relationship of lead exposure
size oxidative enzymes. There may also be competitive with hypertension and that the evidence is suggestive, but
inhibition by ALA of transmission by gamma-amino- not sufficient, to infer a causal relationship of lead expo-
butyric acid (GABA), a putative brain neurotransmitter. sure with clinical cardiovascular outcomes (e.g. coronary
The similarity in their chemical structures is shown below: heart disease).7
NH2CH2COCH2CH2COOH
5-aminolaevulinic acid (ALA) Kidneys
NH2CH2CH2CH2COOH Lead is nephrotoxic, and when occupational exposures
gamma-aminobutyric acid (GABA) were considerably greater, renal damage was common (see
Chapter 86, Nephrotoxic effects of workplace exposures).
This pattern of effects is unique to lead poisoning and The early effects of lead poisoning on the kidneys are directed
may be a useful adjunct in arriving at the diagnosis. The against the cells of the proximal tubule, but with continued
effects on ALAD occur at very low blood lead levels (less exposure, severe and progressive renal insufficiency may
Inorganic lead poisoning 193
occupational studies from 1996 to 2006, Shih et al. con- 1920s, before the advent of microchemistry, the stippled
cluded that there is moderate evidence for an association cell count was used to monitor the exposure of lead work-
between psychiatric symptoms and lead dose, but only at ers. That has now been replaced by the biochemical meas-
high levels of current occupational lead exposure or with ures described below. Stippled cells are not unique, as was
cumulative dose in environmentally exposed adults. Further at one time thought, but may be found, for example, in
work is needed to confirm if chronic lead exposure is related severe secondary anaemia, malignant disease and malaria.
to a syndrome of mild cognitive impairment.18 The importance of stippled cells today is that the haema-
tologist may spot them in the blood film of a patient ‘under
investigation’ and alert the clinician to consider the possi-
Reproductive system bility of lead poisoning. In lead poisoning, iron entering
the erythrocyte precursors is not fully utilized and accu-
Lead may lower the fertility of men having blood lead lev- mulates. This non-haem iron, together with ferruginous
els higher than 30–40 g/dL.2 Sperm abnormalities may micelles, fragments of damaged mitochondria, and some
appear when the blood lead level is higher than 40 g/dL.2 RNA is believed to comprise the basophilic granules (see
Chapter 90, Haemopoietic effects of workplace exposures:
anaemias, leukaemias and lymphomas).
Endocrine system A band of increased density may be seen on radiographs
at the growing ends of the long bones and the phalanges
At blood lead levels higher than 40–60 g/dL, serum thy- in children with lead poisoning, but not in adults. This
roxine may be lowered and thyroid-stimulating hormone increased density is caused by an alteration in the architec-
(TSH) may not be appropriately released.2 Delayed puberty ture of the bone and not by deposition of lead. This may be
(manifesting as delayed appearance of pubic hair and breast comparable to ‘growth arrest lines’. In severe cases, there
development) has been found in girls with higher blood may be changes in the shape of the bone, which revert grad-
lead levels.19 ually to normal once the child is removed from exposure
and recovers.
Musculoskeletal system
TREATMENT
Arthralgia has been recognized as a manifestation of acute
lead poisoning for well over 100 years, but is usually a non- The basis of the treatment of lead intoxication is immedi-
specific symptom. Lead also interferes with normal urate ate removal from any source of exposure to lead. If symp-
metabolism and may precipitate attacks of gout sometimes toms are mild, further treatment is unnecessary and the
associated with nephropathy.20 The condition affects those blood lead level will gradually fall towards normal and
who consume large quantities of home-distilled spirits, should be monitored periodically. The process may take up
which may contain significant quantities of lead derived to several months, so blood testing every few days is unnec-
from solder within the still – hence ‘saturnine gout’. essary and the clinician should not be anxious provided the
patient’s condition is improving. If the condition is more
severe, treatment with chelating agents should be consid-
INVESTIGATION OF LEAD POISONING ered, but should be based on occurrence of severe symptoms
and not on biochemical or haematological measurements.
There are few clinical signs to aid the diagnosis of lead poi- In some countries, chelation is carried out simply because
soning. The patient may be pale and there may be some the blood lead level is high: there is no evidence that this
muscle weakness if there is a peripheral neuropathy; wrist confers any long-term benefit and there is always the risk
drop is one of the classic signs of lead poisoning, but is now of an adverse reaction to the drug.
rare (Figure 23.3). A burtonian or blue line may be present The agents most commonly used for chelation are peni-
on the dental margin of the gums. It is caused by bacterial cillamine and sodium calcium edetate. Penicillamine is
deposition of lead sulphide, is associated with poor dental given orally, 1 g/day for adults in divided doses for five
hygiene and is absent from the edentulous. It indicates lead days. If after a few days the blood lead level rises again and
exposure, not lead poisoning. There may be general ten- the symptoms recur, the course of treatment might have to
derness of muscles and joints, and on palpation of the be repeated. Sodium calcium edetate is used at 50–75 mg/kg
abdomen. The pallor of lead poisoning is not caused by per day in two divided doses as a slow intravenous infusion
anaemia, but by cutaneous vasoconstriction. for five days.11 This will relieve colic within a few hours.
Laboratory investigations are important in the diagno- With both drugs, the full blood count should be tested at
sis of lead poisoning. About a century ago, the appearance the beginning and end of each treatment period. Because
of basophilic granules in the red blood cells was recognized of their nephrotoxicity, the urine should be tested for
as a concomitant, almost as a sign, of lead poisoning. By the proteinuria and haematuria, although renal disturbance
Evaluating lead exposure 195
is unlikely with the doses and the relatively short duration elevated at all, and ZPP and porphyrin levels are usually
of therapy in acute lead poisoning. During the course of within normal limits. A raised urinary lead is the most
treatment, 24-hour specimens of urine should be taken to important confirmatory laboratory test.
monitor the rate of lead excretion; this should be contin- Poisoning is not seen at concentrations below
ued for five to seven days after the end of treatment. Blood 150 g/dL (0.7 mmol/L), but may occur at concentrations
lead concentrations should be estimated at 48 hours and above 350 g/dL (1.8 mmol/L). The use of chelating agents
at five days, by which time symptoms will usually have in the treatment of organic lead poisoning is of little value
subsided. and symptomatic therapy, such as with diazepam, is
After treatment, it is important that no further exposure required. Adequate sedation (which may need to be pro-
occurs until symptoms have completely remitted and the longed) and nutritional support are important and,
patient’s blood lead concentration has returned to an because sedation is symptomatic, it should be used only as
acceptable level, preferably below 40 g/dL (2.0 mmol/L). long as is necessary to control symptoms. Complete recov-
It follows that once workers have developed symptoms ery is usual, but the illness may be prolonged and charac-
they must be carefully supervised thereafter. If they require terized by periodic and sudden psychotic relapses. The
further treatment, it is prudent that they should not have main features of a clinical case are shown in Figure 23.4.
any further exposure to lead.
If symptoms persist or recur, it may be necessary to repeat
the chelation, or perhaps use one of the newer chelating EVALUATING LEAD EXPOSURE
agents, such as 3-dimercaptopropane sulphonate (DMPS)
or dimercaptosuccinic acid (DMSA), both of which are In the United Kingdom and the United States, most
derivatives of dimercaprol (BAL). lead workers and establishments working with lead come
under specific regulations and there are criteria laid
down for deciding whether lead exposure is going to be sig-
ORGANIC LEAD POISONING nificant enough to warrant this legal requirement. In the
UK, the Control of Lead at Work Regulations and accom-
Poisoning with tetraethyl lead causes a toxic organic panying Approved Code of Practice provides detailed
psychosis and so the picture is dominated by psychiatric stipulations on working with lead, including medical sur-
symptoms which may appear suddenly. There is nothing in veillance. Physicians monitoring the workers under these
the clinical picture that is pathognomonic of organic regulations have to be appointed by the Health and Safety
lead poisoning and the diagnosis is made by establishing Executive.21 In the UK and other countries, the general
exposure. Occupational cases are uncommon and, as physician seeing a patient who has been working with lead
noted previously, usually occur in those who have been should obtain further advice from the statutory health
cleaning out tanks in which leaded petrol has been stored and safety body of their country, or from an occupational
or who have been using leaded petrol inappropriately as a physician, when they suspect that the exposure may be
solvent or degreasing agent – tetraethyl lead is well causing ill health.
absorbed through the skin. Occasionally, cases are seen Among the methods to evaluate lead exposure in
arising from the abuse of solvents containing organic lead workers, lead levels in whole blood are the most widely
compounds. used because of their relative ease and accuracy. The
Tetraethyl lead decomposes slowly in air, rapidly in blood lead concentration in the normal UK population is
bright sunlight, to yield needle-like crystals of tri-, di- and less than 10 g/dL (0.5 mmol/L). Occupationally exposed
monoethyl lead compounds with a garlic-like odour. In workers can have levels much higher than this, but acute
their dry state, they may be dispersed mechanically in air poisoning seldom occurs if the blood lead level is below
to be inhaled or deposited on the skin. Their inhalation 80 g/dL (4 mmol/L), as described above. Data on the
induces vigorous, often paroxysmal sneezing, irritation of correlation between the clinical effects of lead and blood
the upper respiratory tract and, in sufficient dosage, mild lead concentrations have been summarized in publica-
organo-lead poisoning. In contact with warm, moist skin tions such as the International Programme on Chemical
or unprotected ocular membranes, they induce itching, Safety (IPCS) Environmental Health Criteria on inor-
burning and transient redness. ganic lead.22 Abdominal colic and renal effects are
The symptoms found in inorganic lead poisoning do unlikely to arise if blood leads are below 100 g/dL, and
not occur in organic lead poisoning, although patients may the risk of developing significant anaemia is small below
have some abdominal discomfort and anorexia. It is, how- 50 g/dL. As far as severe neurological effects are con-
ever, important to remember that both forms of lead poi- cerned, life-threatening encephalopathy is unlikely to
soning may occur together, particularly in workers involved occur at blood levels below 100–120 g/dL in adults
in the demolition or refurbishment of leaded-fuel storage (80–100 g/dL in children). There are no firm quantita-
tanks, which may be lead painted. The blood lead is usually tive data for the development of the classical sign of
not raised above 50 g/dL (2.5 mmol/L) and sometimes not peripheral neuropathy.
196 Lead
Lead workers may need to be removed from continuing Action levels are also laid down which warn the employer
exposure to lead if the blood levels rise too high. In the UK, that the blood lead concentration is reaching the suspension
there is a statutory requirement for doing this in asympto- level and action needs to be taken to control exposure with
matic men with blood lead levels greater than 60 g/dL the aim of reducing the worker’s blood lead below the action
(3 mmol/L) and women of reproductive capacity with level. The action levels are for women of reproductive
blood lead levels above 30 g/dL (1.5 mmol/L), and for capacity 25 g/dL (1.25 mmol/L), young people (aged 16 and
young people (under 18 years) with blood lead levels above 17) 40 g/dL (2.0 mmol/L), and for any other employee
50 g/dL (2.5 mmol/L). All such cases are reportable by the 50 g/dL (2.5 mmol/L).
employer to the Health and Safety Executive and poisoning The frequency of blood testing for lead depends upon
by lead or compound of lead is also a prescribed disease the levels found and is stipulated in the information
(see Chapter 5, Biological monitoring). provided with the regulations on medical surveillance.
A woman of reproductive age who has a medical or A high blood lead is not synonymous with lead poison-
physical condition that would make it impossible for her ing, so additional tests may be useful. The ZPP level in the
to conceive (e.g. she is sterilized, or had a hysterectomy, normal population is usually less than 2.0 mg/g Hb. It
or is post-menopausal), would be suspended at 60 g/dL begins to rise when blood lead concentrations reach the
(3.0 mmol/L). The reason for this higher level is that range 35–45 g/dL (1.75–2.25 mmol/L) in males or
30 g/dL is set to protect the developing fetus, which does 25–35 g/dL (1.25–1.75 mmol/L) in females. Levels rise
not apply in this situation. rapidly at blood lead concentrations higher than 50 g/dL
The blood lead should be urgently repeated to confirm (2.5 mmol/L). In lead poisoning, the ZPP level will be above
the level and the suspended worker can continue working 20 mg/g Hb, often at least one order of magnitude greater.
(away from lead exposure) until the level falls, usually over The only other common condition that causes a rise in ZPP
a period of two weeks or more. There is a concession to is iron deficiency anaemia. It is important, however, to
workers who may have been in the lead industry for many remember that the ZPP does not immediately increase fol-
years and who have built up a large body burden of lead lowing lead exposure as it depends upon the formation of
(not a likely eventuality in the UK nowadays) which could new red cells, and lag periods of up to two months have
take a long time to fall below the suspension level of been reported. For recent exposures, it is better to measure
60 g/dL. They may be asymptomatic, with normal levels urinary ALA concentrations. Normal values for subjects
of ZPP. Further official guidance should be sought on their not exposed to lead are less than 5 mg ALA/g creatinine
management. (4 mg/mmol creatinine) and the increase consequent upon
References 197
6. Pocock SJ, Shaper AG, Ashby D et al. The relationship 18. Shih RA, Hu H, Weisskopf MG, Schwartz BS. Cumulative
between blood lead, blood pressure, stroke, and heart lead dose and cognitive function in adults: A review
attacks in middle-aged British men. Environmental Health of studies that measured both blood lead and bone
Perspectives. 1988; 78: 23–30. lead. Environmental Health Perspectives. 2007; 115:
7. Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead 483–92.
exposure and cardiovascular disease – a systematic review. 19. Selevan SG, Rice DC, Hogan KA et al. Blood lead
Environmental Health Perspectives. 2007; 115: 472–82. concentration and delayed puberty in girls. New England
8. Gerhardsson I, Lundstrom NG, Nordberg G, Wall S. Mortality Journal of Medicine. 2003; 348: 1527–36.
and lead exposure: A retrospective study of Swedish smelter 20. Batumen V, Maesaka JK, Haddad B et al. The role of lead in
workers. British Journal of Industrial Medicine. 1986; 43: gout nephropathy. New England Journal of Medicine. 1981;
707–12. 304: 520–3.
9. Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity: 21. Health and Safety Executive. The control of lead at work
A review of the epidemiologic evidence. Kidney regulations. Approved code of practice and guidance,
International. 2006; 70: 2074–84. 3rd edn. Sudbury: HSE Books, 2002.
10. Cory-Schlecta DA, Schaumburg HH. Lead, inorganic. In: 22. International Programme on Chemical Safety (IPCS).
Spencer PS, Schaumburg HH (eds). Experimental and clinical Inorganic lead. Environmental Health Criteria 165. Geneva:
neurotoxicology, 2nd edn. New York: Oxford University World Health Organization, 1995.
Press, 2000: 708–20. 23. Seppalainen AM, Hernberg S, Kock B. Relationship between
11. Whitfield CL, Ch’ien LT, Whitehead JD. Lead encephalopathy blood levels and nerve-conduction velocity. Neurotoxicology.
in adults. American Journal of Medicine. 1972; 52: 289–98. 1979; 1: 313–32.
12. Atre AL, Shinde PR, Shinde SN et al. Pre- and posttreatment 24. Baker EL, White RF, Pothier LJ et al. Occupational lead
MR imaging findings in lead encephalopathy. American neurotoxicity: Improvement in behavioural effects after
Journal of Neuroradiology. 2006; 27: 902–3. reduction of exposure. British Journal of Industrial Medicine.
13. Kumar S, Jain S, Aggarwal CS, Ahuja GK. Encephalopathy 1985; 42: 507–16.
due to inorganic lead exposure in an adult. Japanese Journal 25. Weisskopf MG, Hu H, Sparrow D et al. Proton magnetic
of Medicine. 1987; 26: 253–4. resonance spectroscopic evidence of glial effects of
14. Valpey R, Sumi SM, Copass MK, Goble GJ. Acute and chronic cumulative lead exposure in the adult human hippocampus.
progressive encephalopathy due to gasoline sniffing. Environmental Health Perspectives. 2007; 115: 519–23.
Neurology. 1978; 28: 507–10. 26. Hu H. Bone lead as a new biologic marker of lead dose: Recent
15. Schaumburg HH. Lead, organic. In: Spencer PS, Schaumburg findings and implications for public health. Environmental
HH (eds). Experimental and clinical neurotoxicology, 2nd Health Perspectives. 1998; 106 (Suppl. 4): 961–7.
edn. New York: Oxford University Press, 2000: 720–1. 27. Kosnett MJ, Wedeen RP, Rothenberg SJ et al.
16. Canfield RL, Henderson CR Jr, Cory-Slechta DA et al. Recommendations for medical management of adult lead
Intellectual impairment in children with blood lead exposure. Environmental Health Perspectives. 2007; 115:
concentrations below 10 g per deciliter. New England 463–71.
Journal of Medicine. 2003; 348: 1517–26. 28. Schwartz BS, Hu H. Adult lead exposure: Time for a change.
17. Balbus-Kornfeld JM, Stewart W, Bolla KI, Schwartz BS. Environmental Health Perspectives. 2007; 115: 451–4.
Cumulative exposure to inorganic lead and neurobehavioural 29. Silbergeld EK, Weaver EM. Exposure to metals: Are we
test performance in adults: An epidemiological review. protecting the workers? Occupational and Environmental
Occupational and Environmental Medicine. 1995; 52: 2–12. Medicine. 2007; 64: 141–2.
24
Magnesium
PETER AGGETT
PROPERTIES AND USES transport of compounds and cations (e.g. sodium, potas-
sium, calcium, copper, iron and zinc) across membranes.1
Magnesium comprises 2 per cent of the earth’s crust and as Magnesium is ubiquitous in the body: 40 per cent of
such is the eighth most abundant element. It is an alkaline systemic magnesium is in soft tissue and 60 per cent is in
earth metal and its salts are highly soluble in water. Its the skeleton. At customary intakes (200–600 mg daily),
major industrial uses are in alloys with aluminium, to magnesium is absorbed by specific carrier-mediated path-
produce light and strong materials employed in manufac- way across the enterocytes, and by a paracellular route
turing automobiles, missiles, aircraft and ships, and in con- driven by solvent drag. About 50 per cent of the daily
tainers of all sizes down to cans. It is used in refining steel intake is absorbed, and this is in essence unregulated,
and titanium, and in the extraction of uranium. Its reactiv- though it might increase in response to vitamin D. The
ity with oxygen in air is exploited in flares and fireworks element is distributed in the circulation principally (70–80
and magnesite (magnesium carbonate) is used as furnace per cent) unbound, of which about half is ionized; the
linings for the production of metal, glass and cement. remainder is bound to proteins, particularly albumin.
Magnesium salts, such magnesium hydroxide, are used as There is a rapid exchange of the cation between pools. The
an antacid (milk of magnesia), and the sulphate has histor- mechanisms and regulation of the systemic distribution
ical popular usage in topical applications to wounds and and uptake of magnesium are becoming better under-
pustules, and as a laxative (Epsom salts).1 stood.2 Overall, homeostasis is achieved by renal adapta-
There are many potential magnesium ores, such as tion; with increasing body burdens of magnesium renal
magnesite, dolomite, calcite, talc, serpentine and olivine. clearance of the element is increased and when systemic
Dolomite and magnesite are mined extensively throughout needs increase, renal excretion is reduced. Magnesium is
the world. Magnesium is also commercially produced as reabsorbed in the thick part of the ascending loop of Henle,
magnesium chloride by electrolysis of seawater. and this is influenced by calcitonin, thyroxin, glucocorti-
coids, glucagon and angiotensin. On typical dietary
intakes, 95 per cent of the filtered load of magnesium is
ESSENTIALITY AND METABOLISM reabsorbed.1,2
Key points
● Magnesium salts can cause metal fume fever.
● Magnesium toxicity is unusual in healthy
individuals, but the risk is increased in those
with impaired renal function.
● Magnesium salts cause gastrointestinal
symptoms predominated by diarrhoea.
● Systemic features of magnesium excess include
neuromuscular symptoms, alkalosis and
hypokalaemia which arise from altered
calcium-dependent functions.
● Treatment is by calcium infusion.
25
Manganese
INTRODUCTION CHARACTERISTICS
Manganese is relatively non-toxic to the adult human, but After mining, the ore must be milled and further
exposures can cause serious disease of the respiratory and processed before it can be used commercially. The metal
central nervous systems. is whitish-grey in colour, very hard but ordinarily too
brittle to be of structural value itself yet, paradoxically,
has proved over centuries to be an irreplaceable alloying
SOURCES material imparting strength and hardness to iron and
steel.
Manganese (Mn), a ubiquitous naturally occurring element
found in rocks, soil, water and food, is the twelfth most
abundant element in the Earth’s crust, about 0.1 per cent of PRINCIPAL USES AND SOURCES OF
it. It is the fourth most widely used metal in the world in OCCUPATIONAL EXPOSURES
terms of tonnage, yet does not occur naturally as the free
metal. Some 46 million tons of manganese ore are extracted Mining and preliminary treatment of ore
annually (2008) from shallow underground mines or open
pits – some of colossal size. Ninety per cent is used in steel Manganese ore must be mined, milled, separated from
production. Commercially important ores include those other minerals, dried, sometimes crushed or ground again,
containing pyrolusite (MnO2), the main manganese ore, often packed and mixed with other minerals before it can
and the much less commonly found rose-red to pink be refined for commercial use. Considerable amounts of
rhodochrosite (MnCO3).1 The principal producers of man- airborne dust are liable to be produced during all these
ganese ore are South Africa (23 per cent), China (23 per processes, with the attendant risk of exposure unless
cent), Australia (18 per cent), Gabon (13 per cent), Brazil effective dust suppression and other protective measures
(11 per cent), India (8 per cent) and Ukraine (4 per cent).2 are taken.
202 Manganese
●
Refining manganese and making iron and steel Manganese dioxide: dry cell batteries, porcelain and
glass-bonding materials, amethyst glass production,
The ore must be refined. Pure manganese used for the incendiaries, fireworks, matches, the starting material
production of non-ferrous alloys is produced by for other manganese compounds.
● Manganese sulphate: fertilizer, ceramics, glazes,
hydrometallurgical and electrolytic processes. Blast or
electric furnaces are used to process the much greater varnishes, fungicide, livestock nutritional supplement.
● Potassium permanganate: produced by the electrolytic
quantities of ore required in the manufacture of basic iron
and in steelmaking. In the former, it is added directly to oxidation of MnO2 in potassium hydroxide (KOH) is
the furnace charge. For steelmaking, alloys such as ferro- used as a disinfectant, anti-algal agent, water purifier;
manganese (50–80 per cent Mn), silicomanganese (60–70 in metal cleaning, bleaching and tanning; and as a
per cent Mn) and spiegeleisen (10–35 per cent Mn) are preservative for fruit and flowers.
● Manganese ethylene-bis-dithiocarbamate (MANEB):
made containing industry-specified amounts of man-
ganese, iron ore, carbon and silica oxide. The furnaces are which is widely applied to edible crops as a fungicide
tapped into pots and moulds. After cooling, the alloy against many foliage diseases and is therefore a potential
ingots may be cut for easier handling and/or are often source of manganese in soil and in food crops.
● Methylcyclopentadienyl manganese tricarbonyl:
crushed or milled for transport. This allows better control
of formulation during steel manufacture when specified (MMT) is used to improve combustion in boilers and
quantities of such alloys are added to the furnace charge to motors and may be used as a substitute for lead as an
impart the properties (including hardness and wear resist- anti-knock agent in petrol/gasoline.
● Manganese dipyridoxyl diphosphate and other
ance, stiffness and strength) which equip them for partic-
ular fabrication or manufacturing tasks. No substitute for manganese compounds have been recommended to
manganese has been found to provide these essential replace gadolinium complexes as tissue-specific
qualities of steel. contrast agents.
Occupational exposures to manganese oxide com-
pounds may occur at each and any of these stages in
manufacture.3 The composition and structure of the METABOLIC ACTIVITY
aerosol particles in the emissions are complex and vary
from process to process. The compositional complexity of Manganese is an essential trace element for humans.5 It
these particles is such that toxicological investigations of acts across a broad spectrum of activities within or as a
the kinetics of pure compounds may not easily be cofactor for enzymes, such as superoxide dismutase and
associated with the work situation exposures.4 xanthine oxidase.6
manganese are released into the air. Almost all manganese- Manganese deficiency can affect fertility adversely and
related disease is related to occupational exposures. be teratogenic – but this is unlikely to be a practical prob-
lem in humans as deficiency is rare. Large amounts of
manganese salts also affect fertility in mammals, can pene-
ABSORPTION, TRANSPORT, DISTRIBUTION trate the placenta and are toxic to the embryo and fetus.
AND HOMEOSTASIS It has been stated that pregnant women should not be
exposed to manganese at the workplace.10
Manganese compounds may be absorbed into the body
Information on cancer due to organic and inorganic
through the gastrointestinal tract and the lung, can cross the
compounds of manganese exposure is scanty, but the
intact blood–brain barrier9 and penetrate the placenta.10
results available do not demonstrate that manganese is
The route of exposure can influence the distribution, metab-
carcinogenic.10,23,24
olism and potential for toxicity of manganese-containing
compounds.11 The respiratory inhalation route is usually
much more important than the oral route for risk assess-
ACUTE EFFECTS ON HEALTH
ment of occupational exposures.11,12 A direct neuronal route
from the nose to the brain, circumventing the blood–brain
Acute injury or illness due to manganese exposure appears
barrier, has been demonstrated in animal studies, but not in
to be rare. Exposure to freshly formed oxides of
humans.13–15
manganese may cause metal fume fever (which is described
There is a paucity of information on the rate and degree
in Chapter 44, Welding, fumes and inhalational fevers).
of absorption of inhaled and respirable particles contain-
Inhalation of particulate manganese compounds has
ing inorganic manganese. Both relate significantly to the
been linked causally to the development of pneumonitis,
respiratory load; the solubility of the particles,11,16 which is
an association first reported in a group of British work-
affected by structure and formulation – notably the degree
ers manufacturing potassium permanganate.25 A statistical
of oxidation; the capacity of manganese transport systems
association was observed between deaths from pneumo-
across the alveolar membrane and beyond, including
nia and manganese exposure in Norwegian ferroalloy
through the blood–brain barrier; and the availability of
plants.26 Iron deficiency, resulting in skin lesions, has
these systems in the face of competition, notably from
been observed in manganese mine workers and attrib-
iron.17–19 In animal studies relative iron deficiency has
uted to the cumulative effects of high levels of man-
been shown to increase susceptibility to manganese load-
ganese in the drinking water in addition to dust, in the
ing in the brain and elsewhere,15,19,20 whereas iron over-
workplace.7
loading is associated with decreased uptake.21 This may
Solutions of potassium permanganate 1:5000 are
have an as yet unexplored practical effect on the risks of
corrosive and mistaken ingestion carries the risk of local
toxicity associated with some occupational exposure to
and possibly life-threatening burns of the upper
manganese-containing compounds, e.g. some steel welders
gastrointestinal tract.27 Manganese may be absorbed
have been shown to be iron overloaded.22
through damaged skin, for example following burning
Absorbed manganese is rapidly eliminated from blood,
with a hot acid solution containing 6 per cent man-
initially mainly to the liver which seeks to maintain home-
ganese.28 Manganese has also been implicated in the
ostatic control between absorption and requirement and
development of allergic contact dermatitis in a worker
where excesses are stored in the first instance. It is then
handling aluminium alloy which contained man-
widely distributed in the body. Some 98 per cent of excess
ganese.29 The acute onset of clinical neurological or psy-
amounts of manganese are excreted in the bile for disposal
chotic symptoms was described over 40 years ago in a
in faeces with the remainder being excreted in urine.
small number of mine labourers exposed to high concen-
Homeostatic mechanisms can be overwhelmed by excess
trations of dust from drilling rock containing manganese
exposure and absorption through the lungs and/or gas-
compounds.30
trointestinal tract and/or by liver dysfunction. This may
result in accumulation of manganese in the brain (see
below Acute effects on health).
CHRONIC EFFECTS ON HEALTH
A rare manifestation of manganese poisoning known as exposure. It has been hypothesized that exposure to man-
Morvan’s fibrillary chorea has been postulated in a case ganese may accelerate the onset of Parkinson’s disease.
report from Germany, but there is no definite proof.32 These remain controversial areas41–44 and are discussed
One group has reported that there may be toxic effects on under Occupational manganism (p. 207).
the cardiovascular system.33
Advanced manganism is a chronic crippling disease lower than those at which clinical manganism has been
with permanent disability, particularly with regard to the observed. It is important to be able to detect the disease at
use of the legs, but does not appear to be life-shortening. this stage as this will allow intervention by stopping expo-
Manganism bears a superficial similarity to idiopathic sure. Reviewers have concluded that insufficient soundly
Parkinson’s disease but, as summarized in Table 25.1, can be based evidence of a consistent pattern of significant test
distinguished from it by careful clinical examination and outcomes or of a dose–response relationship has been pub-
appropriate imaging investigations.46–51 Differentiating these lished to permit subclinical identification of occupational
two conditions is an important practical consideration for manganism in isolation, as part of a continuum of disease
several reasons, but possibly none more vital than preventing or as a basis for health surveillance of potentially exposed
further exposure if manganism is shown to be the correct workers.42,53 That said, the published conclusions drawn in
diagnosis as the longer the delay the more likely it is that some of the studies cast sufficient doubt on the level of
symptoms will persist or worsen. In practice, in the current protection afforded by the then extant occupational expo-
state of knowledge it may be thought prudent to at least con- sure standards to have prompted changes in regulatory
sider preventing occupational exposure to manganese in all action (see under Workplace exposure limits, p. 208).
those found to have idiopathic Parkinson’s disease as the
possibility of an additive effect cannot be excluded and no
safe threshold has been established.52 Stage 2
There is often a prodromal clinical period with insidious
Stage 1 onset of non-specific symptoms. It is not seen in idiopathic
Parkinson’s disease. Diagnosis relies on awareness to
Subclinical performance deficits may be the first mani- include manganism in the differential diagnosis then rec-
festations. These may be undetectable without special ognizing a source of exposure through taking and using a
neuropsychological testing and occur at exposures much good occupational history.
Table 25.1 Key features differentiating idiopathic Parkinson’s disease and manganism.46–51
Exposure history Postulated environmental influences, Must have history of excess occupational or
e.g. pesticide exposure environmental exposure to manganese
May have incidental exposure to May have regression of symptoms after removal from
manganese exposure
Early Non-specific complaints, including May be prodromal psychiatric ’manganese madness’ (but
discomfort in the limbs, paraesthesia and this stage may be bypassed)
fatigue
Established Asymmetric Not asymmetric
Resting tremor No resting tremor
Speech impairment
Gait dysfunction – cock gait or slapping broad-based
gait
Balance dysfunction with propensity to fall backwards
when displaced
Treatment trial Responds to L-dopa and other Failure to have sustained response to L-dopa and other
dopamine-mimetic drugs that stimulate dopaminomimetrics. Response in early stages may be
the D2 dopamine receptors (levadopa and placebo effect. Mixed views on chelation
the synthetic dopamine agonists)
Imaging MRI usually normal. Substantia nigra May be abnormal with diagnostic bilateral signal
may appear smudged and there may be changes in T1-weighted images if concentrations are
some non-specific atrophy, but neither are high
sufficiently specific or severe to be of
diagnostic value
Fluorodopa PET abnormal with reduced 18 Fluorodopa PET scan normal
uptake in the striatum, particularly in
the posterior putamen
MRI, magnetic resonance imaging; PET, positron emission tomography.
206 Manganese
Symptoms include the onset of general weakness, irri- various disorders, especially those affecting the gait, grow
tability, anxiety, nervousness, anorexia, headache, sleep steadily more pronounced. The patient’s mind works only
problems and confusion. These may be accompanied by or slowly. There may be a postural tremor, frequently in the
progress to loss of libido and/or autonomic symptoms, lower limbs but even generalized. As the disease progresses,
such as impotence, bladder and sphincter dysfunction. walking and turning round become increasingly difficult
Specific to the disease, there may be ‘manganic madness’ and the handwriting becomes irregular with some words
and ‘locura manganica’ – disorientation, indifference and illegible. Soon the patient cannot walk backwards, falling
apathy, lethargy, emotional lability such as uncontrollable if this is attempted; has difficulty in maintaining his bal-
laughter or tears, impulsive/compulsive behaviour, aggres- ance with his feet together and in walking downhill, going
sive/hostile behaviour, bouts of excitability, excessive and uncontrollably faster and faster until he has to run and
incoherent garrulity, hallucinations, illusions and delu- then will fall over if he cannot catch hold of something to
sions,54,55 accompanied by heaviness or stiffness in the stop and steady him. Attempts to counter this unsteadiness
lower limbs. The emotional symptoms may be the first may result in a broad-based slapping gait. Alternatively, as
indication of toxicity. a result of increasing muscular rigidity, there may be devel-
opment of the characteristic ‘cock gait’ – slow, spasmodic,
unsteady, walking or strutting on extended feet and toes,
Stage 3 putting weight on the metatarsus, with elbow flexion and
a straight spine. Tendon reflexes become exaggerated.
The intermediate clinical stage is marked by the appear- Sensorial functions remain normal. At this stage, the dis-
ance of more specific signs and symptoms related to dys- ease becomes evolutive and irreversible or may worsen
function of the basal ganglia. This may be the first even after withdrawal from exposure,39,55 although some
indication if the subtle changes of the first stage have been affected workers may show limited recovery.55,56
missed and, as appears to happen in some cases, the second
stage has been ‘bypassed’. The voice becomes quiet and
monotonous; speech is slow and halting without tone or IMAGING
inflection; the face vacant, mask-like, dull and expression-
less with a fixed stare. The victim may be euphoric with, Imaging of the brain using MRI and, to detail the function
perhaps, uncontrolled laughter or crying. Tremor may of dopamine cells, positron emission tomography (PET)
develop at this or the next stage. It is less common than in with fluorodopa (a radioactive form of levodopa) can
idiopathic Parkinson’s disease and, when present, it tends contribute to the diagnosis of manganism and assist in
to be fine (as against coarse) and is described as postural, differentiating it from idiopathic Parkinson’s disease,
intentional or kinetic because it accompanies voluntary although this may be difficult in the early stages.
movements, rather than occurring at rest. The arrangement of electrons in the manganese ion
In this and the final stage, the movement disorder is (Mn2+) results in it having a large magnetic moment
dominated by dystonia and increasing bradykinesia allowing it to be imaged by MRI scan to provide evidence
(movement and gestures are slow and awkward) perhaps of its accumulation and deposition in the brain.
with a waving movement of the arms. Forward walking Characteristically, in manganese intoxication, the scan will
gait is normal at this third stage, but the patient is unable to show a high signal in the globus pallidum on T1-weighted
run and can walk backwards only with difficulty, some- images, but with no alteration on the T2-weighted image.
times with retropulsion. Adiadochokinesia (an inability to It is likely that this reflects recent manganese exposure
perform rapidly alternating movements, such as pronation rather than toxicity.57 Patients with idiopathic Parkinson’s
and supination or flexion and extension) may develop, but disease have normal T1-weighted MRI images. Functional
neurological examination often reveals no changes except, imaging of patients with manganism, using 18-fluorodopa-
in some cases, exaggeration of the tendon reflexes. labelled PET, does not show the reduced striatal uptake
If exposure to manganese is terminated soon after the typically seen in idiopathic Parkinson’s disease,58 so nor-
neurological effects appear, the individual often recovers mal uptake favours the diagnosis of manganism rather
but some speech and balance problems may remain. In than IPD.
some cases, clinical progression continues even ten years These typical manganese accumulation images may be
after cessation of exposure, and after tissue concentrations seen in patients with occupational overexposure to man-
and T1-weighted images on MRI have returned to normal. ganese (even without symptoms), liver disease (and thus
accumulated manganese), and those receiving total par-
enteral nutrition with excess manganese intake. The signals
Stage 4 must be differentiated from increased intensities due to
other causes such as fat, iron deposits, haemoglobin break-
The final clinical stage may be seen only a few months down products, melanoma, lesions of neurofibromatosis
later. The patient’s condition deteriorates noticeably and and calcification.
Occupational manganism 207
The T1 changes in the MRI in manganism tend to start that allege neurological effects in current or former
to disappear within some eight months of withdrawal from welders had been filed in courts throughout the United
the source of manganese accumulation, despite there being States by 2005.99
permanent neurological damage and even progressing ‘Welding’ is an occupation that involves highly diverse
clinical manifestations of the intoxication. environments and mixed exposures to numerous chemi-
cals. Moreover, those who describe themselves as ‘welders’
may actually be more involved with metal cutting or other
OCCUPATIONAL MANGANISM processes allied to welding rather than joining metal – the
traditional and correct usage of ‘welding’. This is an
The occupational groups in which manganism has been important distinction as it is thought likely that, unlike
described include miners, ore mill workers, smelter work- particles from other processes, a substantial proportion of
ers, workers exposed to high doses of manganese dioxide in the manganese compound-containing particles in fume
the manufacture of dry batteries, enamellers and potters, from welding have a complex shell-core structure which
those coating welding electrodes, and welders using these may seal manganese within the core to a degree which
and other manganese-containing consumable electrodes reduces its bioavailability (see Chapter 44, Welding).
or filler metals. Of the 45 workers said to have had clinical manganism
Mining was the original major cause of manganism in case and group study reports in the literature between
but, usually, this is now a much more controlled environ- 1965 and 2005, a maximum of 29 (and possibly only 15)
ment where dust exposure is minimized. Cases, usually had been engaged in welding as a joining process.42 The
from mines using dry methods of extraction, especially other processes through which the workers may have been
dry drilling, were described in Silesia,59 Morocco,54 exposed to fumes and dust containing manganese com-
Chile,55,60,61 Cuba,62 Egypt30 and India.63,64 pounds included hard facing and arc burning, cutting or
By 1924, there had been so many cases associated with gouging. It has been asserted that only five of the 29 met
ore crushing, sorting and grinding in Germany that factory sufficient criteria for manganism to even just cross the
regulations had been modified to prevent the workers diagnostic threshold and even then they carry a degree of
coming into contact with ‘brownstone’ ore dust containing doubt with them.42
manganese dioxide. Reports of adverse effects of exposure Individual100 and group studies101 have been reported
to these and associated processes were seen elsewhere, for seeking to determine that some workers exposed to welding
example in baggers in Singapore65,66 and in a range of tasks fume are at risk of developing subclinical manganism,
in mills in the United States,67–72 notably after concern in i.e. neuropsychological effects of occupational exposure to
the 1930s and 1940s that more than 90 per cent of the man- manganese. It has been said that some of the studies are
ganese ore used there was imported prompted a successful flawed.102 The results of more focused analysis of data103 do
national campaign to stimulate domestic production of not weigh sufficiently to tip the balance of the conclusions of
manganese. an earlier meta-analysis that a convincing argument has yet
Whereas studies may not have provided definitive to be made for there to be a causal relationship between
evidence of manganism in workers involved in the produc- occupational exposure to manganese as the source of an
tion of manganese salts and oxides73–75 or manganese- individual’s cognitive, sensory or motor impairments based
containing enamels,76 it does seem to have occurred, mainly on neuropsychological testing or symptom reports.104 It
but not always at the subclinical stage, in workers exposed would, however, be imprudent to dismiss the warnings
to high concentrations of powders rich in manganese com- which have been sounded and not to act to minimize
pounds during the manufacture of dry cell batteries.77–79 exposure and introduce effective exposure monitoring
Rarely, cases may have occurred in those exposed to man- and health surveillance for those employed in welding and
ganese compounds while making, glazing or firing pottery cutting.
and other ceramics.80,81 As mentioned earlier, a hypothesis was advanced that
Exposure to manganese compounds through work in employment as a welder was causally associated with early
smelting and ferromanganese foundries and other steel onset of Parkinson’s disease.105–107 The suggestion was that
works has been linked to development of clinical and/or manganese in the fume was the causative agent. A number
subclinical manganism.34–37,82–97 Manufacture of cast iron, of large case–control studies of occupational risk factors for
which may contain small concentrations of manganese, or Parkinson’s disease,108–112 cohort studies of welders113,114
its recycling, can expose foundry workers to excessive and literature reviews41–43 have been conducted. These have
amounts and has been said to be associated with reversible failed to find evidence of an increased risk of Parkinson’s
non-specific neurological symptoms of manganism.98 disease among welders or any other evidence to support the
Metal cutting and arc welding have been centres of hypothesis that manganese causes Parkinson’s disease. In
attention as putative causes of clinical and subclinical fact, the evidence leads to the conclusion that manganese-
manganism and/or causing or accelerating the onset induced parkinsonism and Parkinson’s disease are distinct
of idiopathic manganism. Several thousand lawsuits and separate disease entities.
208 Manganese
33. Jiang Y, Zheng W. Cardiovascular toxicities upon manganese 52. Haber LT, Maier A. Scientific criteria used for the
exposure. Cardiovascular Toxicology. 2005; 5: 345–54. development of occupational exposure limits for metals
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26
Mercury
so bad that he was hardly able to find an adult male in the their families who were the main victims of the disease,
trade with a single tooth in his head. In addition to saliva- had been intoxicated with methyl mercury due to the
tion and stomatitis, he described reddening of the pharynx consumption of contaminated fish.4 The first case was
(Kussmaul’s sign) and ulceration of the buccal mucosa and officially reported in 1956 from the Minamata Bay area
palate. He described how the condition advanced in three (Kumamoto Prefecture), and in 1964–65 in the Agano
clinical stages: erethism (abnormal irritability), tremor and River basin (Niigata Prefecture) where the pollution was
cachexia. Publication of his findings led to stringent regu- less severe than in the Minamata area. In each area, it was
lations which resulted in the mercurial silvering of mirrors caused by discharges of methyl mercury into the sea from a
being abandoned altogether. During the nineteenth cen- factory. Tsubaki,5 who examined many patients in the
tury, mercurial poisoning was so common among hat Niigata area, emphasized the following as important symp-
makers, who used mercuric nitrate in the carotting of felt – toms and signs: sensory impairment (bilateral, marked in
a process in which the hairs obtained from rabbit pelts extremities), ataxia and dysequilibrium, weakness, perioral
were flattened and meshed together to form felt, that sensory impairment, abnormalities in eye movement,
phrases such as ‘hatter’s shakes’ and ‘mad as a hatter’ narrowing of the visual fields and hearing difficulty.
passed into common use. As an aside, the Mad Hatter in Importantly, there was a cluster of births of children
Alice in Wonderland almost certainly did not have mercu- with cerebral palsy in mothers suffering from Minamata
rial poisoning despite the many assertions that he did. The disease – clear evidence of a teratogenic effect of methyl
toxicity of mercury became clearer during the eighteenth mercury.
century, when the use of mercurial ointments to treat The largest outbreak of organic mercury poisoning
syphilis became popular. When the patient complained of occurred in 1971–72, when at least 6000 people were poi-
excessive salivation or his teeth began to blacken and fall soned and 459 persons died in Iraq, where in the midst of a
out, his physician could be sure that he was complying with famine they had knowingly consumed toxic wheat and
the therapeutic regimen and that large amounts of mer- barley seeds that had been treated with methyl mercury.6
cury were being absorbed. Ramazzini noted that the sur- In the United States, a family was poisoned by eating con-
geons who themselves rubbed ointment into their patients taminated meat from a hog which had been inadvertently
were by no means immune from its harmful effects. fed on seed grains dressed with methyl mercury.7 Four
Mercury is unique among all the toxic metals in that it children showed very severe neurological disturbances 22
has accounted for several epidemics of environmental poi- years later. The two eldest had cortical blindness or con-
soning. The best known of these, but by no means the most stricted visual fields, diminished hand proprioception,
serious, was Minamata disease which was first noted at the choreoathetosis and attention deficits. The two youngest
end of 1953 when an unusual neurological disorder began suffered from quadriplegia, blindness and severe mental
to affect the villagers living on Minamata Bay on the south- retardation. One of them, who was exposed at age 8 and
west coast of the most southerly of the main islands of died aged 30, had brain mercury levels over 50 times those
Japan. It was commonly referred to as ‘kibyo’, that is, the of the control patients, whereas mercury levels in systemic
mystery illness. Both sexes and all ages were affected, and organs were comparable with controls. These and other
the signs and symptoms were those of a polyneuropathy similar incidents have led to the use of organic mercury as
with cerebellar ataxia, dysarthria, deafness and disturbance a seed dressing being prohibited in most countries.
of vision. The prognosis for the condition was poor; many
patients became disabled and bed-ridden and the case
fatality rate was about 40 per cent. The elucidation of the PRESENT-DAY EXPOSURES TO MERCURY
cause of the disease owed much to the work of Donald
Hunter and his colleagues, who first reported cases of The toxicity of mercury is so well known nowadays in high
occupational methyl mercury poisoning2 in a British fac- economy countries that exposure to mercury metal and its
tory manufacturing mercury seed dressings. Four workers compounds in industrial processes has become sufficiently
were affected among 16 who were exposed to dusts con- well controlled to pose few problems to the limited num-
taining methyl mercury (nitrate and iodide salt). Three to ber of workers involved in its use. Mercury is still a serious
four months after first exposure, they began to have sen- hazard in developing countries, for example in gold extrac-
sory difficulties in the extremities and loss of peripheral tion in remote prospecting areas using liquid mercury
vision, with problems walking and speaking. On examina- (vapour hazard). Inadvertent high exposure to workers can
tion, visual field constriction, ataxia, dysarthria, hearing still occur through a failure in control measures or aware-
impairment and sensory disturbance (vibration and two- ness, or in the general population as a result of accidental
point discrimination) were observed. In one autopsied contamination of offices or homes, as well as to a failure to
case, localized atrophy in the cerebrum (area striata) and adequately decontaminate industrial buildings or labora-
cerebellar atrophy associated with profound loss of granu- tories before being put to other uses.8–10
lar cells were found.3 It was subsequently suggested by Next to dietary sources, such as fish, the main source of
Douglas McAlpine that Minamata disease resembled this exposure to mercury in the general population is from
syndrome and a source of organic mercury should be dental amalgam.11 Mercury vapour is released from dental
sought. It was eventually confirmed that the fishermen and amalgam fillings into the oral cavity from where it is
216 Mercury
the tissues. In the blood, inorganic mercury is distributed from occupational exposure. The toxicity of inorganic
almost equally between the red cells and the plasma, whereas compounds is proportional to their solubility in the gastric
the alkyl compounds (such as methyl mercury) are concen- juices and, for example, the ingestion of less than 100 mg of
trated 10- or 20-fold in the red cells. The principal target mercuric chloride (corrosive sublimate) may cause severe
organs for mercury are the central nervous system and the symptoms. Soon after taking it, vomiting and abdominal
kidney. Within the kidney, mercury binds to metalloth- pain may develop and watery diarrhoea, haematemesis, and
ionein and the resultant metal protein complex may protect then shock cause death. Even without these, oliguria (renal
against the toxic effects of the free metal, and only when the tubular dysfunction) associated with unconsciousness may
metallothionein receptors are saturated does renal damage occur in 48 hours. In severe cases, acute papillary necrosis
occur. The blood–brain barrier is crossed rapidly and read- will occur. A chemical colitis may develop after 24–72 hours
ily by elemental mercury and by alkyl mercury compounds, with the passage of bloody diarrhoea containing mucosal
but not so well by inorganic compounds. The post-mortem slough. There may be shock, oedema, tremor and ataxia.
findings in a man who developed classical signs of mercuri- Specific diagnostic tests are of limited value, but will
alism after working for 18 months filling mercury ther- demonstrate raised blood mercury levels and increased uri-
mometers, and who died 16 years later after a slow but nary and faecal excretion. Poisoning from the inhalation of
incomplete recovery, are interesting. While there was no his- large amounts of mercury, including the vapour from
tological evidence of mercury toxicity, mercury was detected exploding mercury lamps, may cause an acute, life-
in lysosomal dense bodies in many nerve cells. It is not clear, threatening chemical pneumonitis with cough, dyspnoea,
however, how the presence of neuronal mercury was related retrosternal pain, basal, late-inspiratory crackles, abnormal
to the mental and psychological state of the patient.18 blood gases and patchy shadowing on chest radiograph. In
By contrast, inorganic mercury accumulates rapidly in severe cases, there may be fever, expectoration of blood-
the cortex of the kidney, but more slowly in the brain. These stained sputum and pulmonary oedema.
differences in distribution obviously contribute to the differ-
ent toxic effects exerted by the various mercury compounds,
but it is not merely a matter of tissue concentration. Methyl Chronic poisoning
mercury concentrations in the kidney, for example, are con-
siderably higher than those in the central nervous system The classic symptoms of chronic mercury poisoning
but, whereas the brain may be severely affected in methyl (noted by Kussmaul) are tremor, gingivitis and erethism
mercury poisoning, renal damage occurs only rarely.19 (Greek erethismos, irritate). In addition, there may be evi-
dence of renal damage and organic damage to the central
nervous system. The earliest findings are usually gingivitis,
EXCRETION hypersalivation (mercurial ptyalism) and an unpleasant,
bitter, metallic taste in the mouth. A bluish line on the den-
Mercury is excreted in the urine and faeces and may also be tal margin of the gums, similar to that seen in lead workers,
found in the sweat, saliva and breast milk. The concentra- and a slate-grey or reddish, punctate pigmentation of the
tion of mercury in breast milk may be as much as 5 per cent buccal mucosa are sometimes described, but rarely seen.
of the concentration in the blood and so be a risk to breast- Gingivitis is most marked in those with poor oral hygiene
fed infants of mothers who are exposed to mercury. and may be severe enough to cause loosening or loss of
Organomercury compounds are excreted in bile and reab- teeth. Tremor, generally considered to be the first neuro-
sorbed from the gut. The half-life of mercury compounds logical indication of poisoning by elemental mercury or its
in the body is about 70 days; thus, the excretion of absorbed inorganic compounds, is usually present at rest especially
material is slow and there is a tendency for the metal to in the hands. It may be slight and accompanied by mild
accumulate with time. The urinary excretion of mercury motor retardation (mercurial micro-parkinsonism). There
shows considerable circadian variation and urinary concen- is often an intentional component to the tremor, resem-
trations are not always a good indicator of acute exposure, bling that seen in cerebellar disease, which may seriously
but are used for the monitoring of exposed workers over a impair the ability to carry out fine and complex move-
period of time. Blood mercury concentration, on the other ments, such as handwriting. The tremor in mercury poi-
hand, reflects absorption well, once equilibrium has been soning may fluctuate in severity and be accompanied by
achieved,20 and is a suitable marker for acute exposure. ataxia resulting in difficulties in walking and in speaking.
In poisoning with methyl mercury, cerebellar ataxia and
dysarthria predominate, sometimes with constriction of
MERCURY POISONING the visual fields as the result of damage to the visual cortex.
The clinical picture may resemble parkinsonism, multiple
Acute poisoning sclerosis or cerebellar disease, but nystagmus is not a
feature. Inability to release an object gripped in the hand
Acute poisoning usually results from the accidental or has also been reported but, unlike the situation found
deliberate ingestion of mercury compounds and seldom in myotonia, it persists after repeated movements. When
218 Mercury
the term ‘erethism’ was first coined, towards the end of the and renal damage. First-aid treatment involves the admin-
eighteenth century, it was used to describe the whole range istration of four glasses of milk as an emulsient. If there is
of symptoms of mercury poisoning, but it is now reserved corrosive damage to the oropharynx as in the case of mer-
for the psychogenic manifestations. It is a form of toxic curous and mercuric chlorides, attention must be paid to
organic psychosis characterized by excessive timidity, the patency of the airway. Emergency cricothyroidotomy
morbid irritability, mental hyperactivity and outbursts may be required if the airway cannot be secured by endo-
of temper. There may be other features such as impairment tracheal intubation. A stomach tube should be passed and
of memory, difficulty in concentration, depression and gentle (bearing in mind the corrosive action of some mer-
somnolence. Short-term memory may also be slightly cury compounds) gastric lavage carried out using, prefer-
impaired in workers exposed to mercury who are other- ably, warm, 10 per cent sodium bicarbonate solution. If
wise normal.21 Mercury poisoning may present as a periph- organo-mercury is involved, between three and six sachets
eral neuropathy which is predominantly sensory and is most of the basic anion-exchange resin cholestyramine should
common in those with organic mercury poisoning. be administered before the tube is withdrawn, as seques-
Prolonged distal latencies in nerve conduction have been tration of bile salts increases faecal excretion of these
reported in some asymptomatic mercury workers and the compounds. Chelation therapy should be started, using
neurophysiological changes correlate with time-integrated oral penicillamine (1–4 g daily, in four divided doses). It
urinary mercury concentrations.22 In advanced cases, there has been suggested26 that in chronic mercury poisoning,
are paraesthesiae of the extremities and around the mouth. although penicillamine may hasten the excretion of an
In fatal cases, the dorsal and ventral roots of the spinal cord easily mobilized extracellular fraction, it does not increase
have been found to have undergone axonal degeneration the excretion of mercury over a long period of time. Care
and to have suffered a loss of myelin (see Chapter 87, must be exercised as the chelation of mercury may
Neurotoxic effects of workplace exposures).23 enhance its passage across the blood–brain barrier and for
The usual effect on the kidneys is tubular damage. this reason the use of dimercaprol (BAL) is contraindi-
Necrosis is more common in inorganic than organic cated in poisoning with organic mercury compounds.27 It
poisoning. The glomerulus may also be damaged, leading is, however, extremely effective in the treatment of acute
to albuminuria in workers who have been exposed to poisoning with inorganic mercurials when given by intra-
mercury for many years. Rarely, a nephrotic syndrome muscular injection. The recommended dose is 2.5 mg/kg
may present as a manifestation of inorganic mercury body weight, repeated at four-hour intervals for two days;
poisoning.24 Poisoning by mercury or a compound of after this, the injections are given twice daily for ten days
mercury is a prescribed disease in the United Kingdom or until recovery is complete. In the absence of these
(see Chapter 8, Compensation scheme). drugs, intravenous administration of 100 mL of 5 per cent
sodium sulphate or 500–1000 mL of Ringer–Locke solu-
tion may be helpful. There is some evidence that alkaline
LABORATORY DIAGNOSIS diuresis, as described for salicylate poisoning in standard
medical textbooks, with physiological saline, 5 per cent
The finding of mercury in the urine or blood of those
dextrose and 1.26 per cent bicarbonate solution affords the
exposed to elemental mercury or to its inorganic or organic
kidney some protection against mercury damage and
compounds confirms that absorption has occurred. Blood
might prevent the onset of anuria. This technique, how-
mercury concentrations in those exposed to methyl mercury
ever, is not without serious risk and ought to be carried
are a good index of exposure. If poisoning has occurred, the
out under continuous observation of fluid replacement
blood mercury concentration may be well above 95 mol/L
and of electrolyte and acid-base status, as in an intensive
and the urinary level above 120 nmol/mmol creatinine
care or high dependency unit.
for inorganic compounds and 15 nmol/mmol creatinine for
Inhalation of large quantities of mercury vapour may
organic compounds.
lead to the onset of chemical pneumonitis 24–48 hours
Diagnosis of organic mercury poisoning depends on its
after exposure which may require treatment with bron-
characteristic clinical picture and diagnostic radiology,
chodilators. Intercurrent infection will necessitate the use
especially magnetic resonance imaging (MRI).25 In cases of
of appropriate antibiotics. If the condition is severe and
methyl mercury or dimethylmercury intoxication, MRI may
respiratory failure threatens, mechanical ventilation with
reveal atrophic changes in the occipital lobe, cerebellum and
positive end-expiratory pressure will be required. If the
post-Rolandic region in the cerebrum.
risk of permanent damage is high, it would be prudent to
give steroids prophylactically, but these have no proven
TREATMENT OF MERCURY POISONING value once the condition has developed.
There is no effective treatment for chronic mercury poi-
Acute poisoning by elemental, inorganic and organic mer- soning. Penicillamine and BAL may be tried, but are unlikely
cury compounds is a medical emergency and is dealt with to alter the course of the illness, and the neurological effects
in texts on poisoning. The purpose of treatment is to encour- of intoxication may never completely reverse. Mercaptopro-
age the excretion of mercury and to limit gastrointestinal pionyl glycine has been used for the treatment of organic
References 219
6. Bakir F, Damluji SF, Amin-Zaki L et al. Methylmercury 19. Clarkson TW. The pharmacology of mercury compounds.
poisoning in Iraq. Science. 1973; 181: 230–41. Annual Review of Pharmacology. 1972; 12: 375–406.
7. Davis LE, Kornfeld M, Mooney HS et al. Methylmercury 20. Buchet JP, Roels A, Bernard A, Lauwerys R. Assessment of
poisoning: Long-term clinical, radiological, toxicological, and renal function of workers exposed to inorganic lead,
pathological studies of an affected family. Annals of cadmium or mercury vapor. Journal of Occupational
Neurology. 1994; 35: 680–8. Medicine. 1980; 22: 741–50.
8. Agocs MM, Etzel RA, Parrish RG et al. Mercury exposure 21. Smith PJ, Langold GD, Goldberg J. Effects of occupational
from interior latex paint. New England Journal of Medicine. exposure to elemental mercury on short term memory.
1990; 323: 1096–101. British Journal of Industrial Medicine. 1983; 40:
9. Centers for Disease Control. Mercury exposure in a 413–19.
residential community – Florida, 1994. Morbidity and 22. Levine SP, Cavender GD, Langold GD, Albers JW. Elementary
Mortality Weekly Reports. 1995; 44: 436–43. mercury exposure: Peripheral neurotoxicity. British Journal
10. Orloff KG, Ulirsch G, Wilder L et al. Human exposure to of Industrial Medicine. 1982; 39: 136–9.
elemental mercury in a contaminated residential building. 23. Takeuchi T, Morikawa N, Matsumoto H et al. A pathologic
Archives of Environmental Health. 1997; 52: 169–72. study of Minamata disease in Japan. Acta Neuropathologica.
11. International Programme on Chemical Safety (IPCS). 1962; 2: 40–57.
Inorganic mercury. Environmental Health Criteria, 181. 24. Kazantzis G, Schiller KFR, Asscher AW et al. Albuminuria and
Geneva: World Health Organization, 1991. the nephrotic syndrome following exposure to mercury and
12. Halbach S. Amalgam tooth fillings and man’s mercury its compounds. Quarterly Journal of Medicine. 1962; 31:
burden. Human and Experimental Toxicology. 1994; 13: 403–18.
496–501. 25. Korogi Y, Takahashi M, Okajima T et al. MRI findings
13. Barregård L, Sällstein G, Järvolm B. People with high mercury of Minamata disease – Organic mercury poisoning.
uptake from their own dental amalgam fillings. Occupational Journal of Magnetic Resonance Imaging. 1998; 8:
and Environmental Medicine. 1995; 52: 124–8. 308–16.
14. Lindbolm M-L, Ylöstalo P, Sallmén M et al. Occupational 26. Gledhill RF, Hopkins AP. Chronic inorganic mercury
exposure in dentistry and miscarriage. Occupational and poisoning treated with N-acetyl-D-penicillamine. British
Environmental Medicine. 2007; 64: 127–33. Medical Journal. 1972; 29: 225–8.
15. Kark RAP. Clinical and neurochemical aspects of inorganic 27. Magos L. Effect of 2,3-dimercaptopropanol (BAL) on urinary
mercury intoxication. In: Vinken PJ, Bruyn GW (eds). excretion and brain content of mercury. British Journal of
Handbook of clinical neurology. Intoxications of the nervous Industrial Medicine. 1968; 25: 152–4.
system. Part I. Amsterdam: Elsevier, 1994: 367–411. 28. Tsubaki T, Trukayama K. Minamata disease. Amsterdam:
16. Kulig K. A tragic reminder about organic mercury. Elsevier, 1977.
New England Journal of Medicine. 1998; 338: 1692–4. 29. Health and Safety Executive. Mercury Criteria Document
17. Marsh DO. Organic mercury: Clinical and neurotoxicological Summaries. EH64, 1995 supplement. Sudbury: HSE Books,
aspects. In: Vinken PJ, Bruyn GW (eds). Handbook of clinical 1995.
neurology. Intoxications of the nervous system. Part I. 30. International Programme on Chemical Safety (IPCS).
Amsterdam: Elsevier, 1994: 413–29. Methylmercury. Environmental Health Criteria, 101. Geneva:
18. Hargreaves RJ, Evans JG, Janota I et al. Persistent mercury in World Health Organization, 1990.
nerve cells 16 years after metallic mercury poisoning. 31. Baughman TA. Elemental mercury spills. Environmental
Neuropathology and Applied Neurobiology. 1988; 14: 443–52. Health Perspectives. 2006; 114: 1147–52.
27
Molybdenum
MALCOLM R SIM
Along with arsenic, phosphorus and antimony, molyb- relationship, after adjusting for the effect of potential
denum is one of a group of previously important occupa- confounders and other metals.2
tional toxins, but which is now largely of historical interest The International Agency for Research on Cancer
in the workplace setting. While this is true in most (IARC) has concluded that there is limited evidence for
developed countries, where good workplace control has the carcinogenicity of metal alloys containing cobalt,
eliminated them as major causes of disease, this is not chromium and molybdenum in experimental animals;3
necessarily the case in newly developing countries. In however, a case–control study has found an association
addition, some of these substances, such as inorganic between occupational exposure to molybdenum and lung
arsenic, have become more important as causes of disease cancer.4 The American Conference of Governmental
in the environmental health setting, as their importance in Industrial Hygienists (ACGIH) has set a threshold limit
the workplace has waned. value (TLV) for molybdenum of 5 mg/m3 for soluble
Molybdenum is a silver-white metal which is mined compounds and 10 mg/m3 for insoluble compounds, the
mainly in the form of molybdenum ore (MoSO2). It is an latter being the nuisance dust level.
essential element for humans and is required for the
enzyme xanthine oxidase. It is used as a hardener in steels,
in the production of some special alloys, ceramics and Key points
pigments, and in electrical wire. Other sources of occupa-
tional exposure include fertilizers, coal-powered electricity ● Occupational exposure to molybdenum is
generation, and as a byproduct of copper smelting, pig- known to cause mucous membrane irritation.
ments and paints. It forms many soluble and insoluble ● There is also evidence for longer term effects in
compounds, including molybdenum trioxide (MO3), the respiratory system, such as hard metal disease.
sulphides and halides. ● There is limited evidence that molybdenum
Most evidence for toxicity comes from animal studies, causes cancer.
with effects in several body systems, including anaemia,
stunted growth, deformities of the bones and joints and
degeneration of the central nervous system. In humans, the
type of toxic effect is dependent upon the molybdenum REFERENCES
compound involved and the duration of exposure. Acute
exposure to molybdenum trioxide is known to be irritant 1. Ott HC, Prior C, Herold M et al. Respiratory symptoms and
to mucous membranes of the eyes, nose and throat, bronchoalveolar lavage abnormalities in molybdenum
while chronic exposure is thought to cause a type of hard exposed workers. Wiener Klinische Wochenschrift. 2004; 116
metal lung disease and allergic alveolitis.1 There may also (Suppl. 1): 25–30.
be other, as yet, unrecognized health effects from molyb- 2. Meeker JD, Rossano MG, Protas B et al. Cadmium, lead, and
denum exposure. For example, a recent study has found other metals in relation to semen quality: Human evidence for
evidence for adverse effects on sperm concentration and molybdenum as a male reproductive toxicant. Environmental
morphology and molybdenum exposure in a dose–response Health Perspectives. 2008; 116: 1473–9.
222 Molybdenum
3. International Agency for Research on Cancer Monographs on 4. Droste JH, Weyler JJ, Van Meerbeeck JP et al. Occupational
the Evaluation of Carcinogenic Risks to Humans. Cobalt in risk factors of lung cancer: A hospital based case–control
hard metals and cobalt sulfate, gallium arsenide, indium study. Occupational and Environmental Medicine. 1999;
phosphide and vanadium pentoxide, vol. 86. Lyon: IARC, 2006. 56: 322–7.
28
Nickel
TOM SORAHAN
Nickel is a hard silvery metal. It was first isolated by recently the cancer effects have been attributed to the very
Cronstedt in 1751 and takes its name from ‘Old Nick’ high levels of dust and fume pertaining in these early work-
because of the ‘devilish’ difficulties it caused during the places.2 A major epidemiological study3 concluded that
refining of Saxony copper ores. nickel sulphides (especially the subsulphide) and oxides
It is a transition metal and is thus capable of having a involved in the processes were the principal culprits. A
number of oxidation states with markedly different proper- later cohort study of workers at the Kristiansand refinery in
ties. Some of the water insoluble or slightly soluble salts are Norway has found that soluble nickel salts, such as nickel
soluble in biological matrices. Nickel forms important alloys, sulphate, are also human lung carcinogens, but it is possi-
a number of oxides and also organometallic compounds. ble that the role of arsenic has not been fully accounted for
Nickel tetracarbonyl is remarkable in being a gaseous metal- in this study.4
lic compound at ambient temperatures. Although nickel The National Toxicology Program in the United States
tetracarbonyl was known to be acutely toxic, little was known undertook an animal inhalation study, and exposed both
of any other hazards associated with the refining or use of rats and mice to three different nickel compounds.5 The
nickel until in 1923 when a case of nasal cancer at a refinery investigators found that nickel subsulphide was the most
in Wales saw the beginning of modern nickel toxicology. potent metal species, nickel oxide less so and nickel sul-
The cancer problem was subsequently noted in other phate, which is a soluble salt, did not cause cancer under the
refineries processing sulphuride ores at high temperatures. conditions of the study. Modern processes technology has
Nickel is widely distributed in the Earth’s crust. Mining, essentially eliminated the exposure of workers to the hazards.
crushing and grinding and flotation followed by pyromet- There is no firm direct evidence of any excess cancer risk in
allurgy and then electrodeposition, or the carbonyl process user industries, including welding of stainless steel, nickel
are used to recover the metal.1 plating and the production of nickel alloys.
Ninety per cent of nickel is used in alloys, mostly stainless Primary sensitization may result from close and pro-
steel, but the high nickel alloys (containing around 30–50 per longed contact which may be occupational or domestic,
cent nickel) are important in the aero engine industry, desali- especially skin piercing with the subsequent use of nickel in
nation plants and where corrosion resistance is needed. ‘sleepers’ to maintain the patency of the skin. The skin
Other uses include plating, foundry work and catalysts. reaction may be local or remote.6 Sensitized people may
Electroplated nickel silver (EPNS) is used on cutlery. Nickel subsequently react to contact with nickel at work or in
powders find application in rechargeable batteries and other clothing or jewellery. Since the introduction of automation
uses include the coating of fibres and foam for use in elec- and improved hygiene in the workplace, as well as new
tronics. In combination with other metal oxides, nickel oxide legislation limiting nickel in jewellery, ‘nickel itch’ is
forms commercially important alloys, called spinels. now less common, but occupational nickel contact der-
Markedly increased risks of pulmonary and nasal sinus matitis has been observed in people handling nickel-plated
cancer have been found to be associated with high temper- instruments or tools. Clinical diagnosis is by patch tests
ature oxidation of nickel matte and nickel–copper matte and the lymphocyte proliferation test.
and with electrolytic refining of nickel. The problem in some Asthma may be associated with the inhalation of
of these refinery studies was first thought to be associated droplets of soluble nickel and also possibly the fine nickel
with arsenic exposure or nickel carbonyl gas, but more oxide fume resulting from welding of nickel-containing
224 Nickel
MALCOLM R SIM
Phosphorus is among a group of previously important been found to occur in patients treated with bisphospho-
occupational toxins, but which are now largely of historical nate for multiple myeloma or secondary cancer in bone,1
interest in the workplace setting. While this is true in most which demonstrates the importance of retaining knowledge
developed countries, where good workplace control has of what might be considered historical occupational
eliminated them as major causes of disease, this is not diseases, which may recur in modern times in new guises.
necessarily the case in newly developing countries. Another important effect of white phosphorus is burn-
Phosphorus is highly reactive, as it oxidizes extremely ing on contact with the skin and such burns must be washed
rapidly on contact with air. There are three allotropes of as rapidly as possible with a solution of a suspension of 5 per
phosphorus: white (or yellow), red and black, of which the cent sodium bicarbonate and 3 per cent copper sulphate in
white variety is the most toxic. In modern industry, phos- 1 per cent hydroxyethyl cellulose.2 The resultant blackened
phorus and its compounds have many uses including the appearance facilitates the removal of the phosphorus parti-
manufacture of munitions and other incendiary devices, cles from the skin. Phosphoric acid and phosphoric com-
the production of fertilizers, detergents, animal foods, pounds are irritant to the eyes, the mucous membranes and
pharmaceuticals and pesticides. They are also used in the respiratory tract. On this basis the American Conference
engraving, electropolishing, photography, metal cleaning, of Governmental Industrial Hygienists (ACGIH) has set a
as scale inhibitors in water treatment and in the manufac- threshold limit value (TLV) of 1 mg/m3 and a short-term
ture of semiconductors, so exposure may occur in many exposure limit (STEL) of 3 mg/m3.
industries.
The use of white phosphorus in match-making began in
1832 and ushered in what Donald Hunter referred to as Key points
‘the greatest tragedy in the whole story of occupational
disease’. This was phosphorus-induced necrosis of the jaw, ● Phosphorus causes ‘phossy jaw’, an important
known as ‘phossy jaw’. The onset of the disease was slow, disease in the history of occupational medicine,
taking an average of about five years for the symptoms to which has now virtually disappeared as an
develop after first exposure. Phossy jaw was an extremely occupational disease.
painful and disfiguring condition with the mandible ● Phosphorus is also a potent cause of skin burns,
becoming necrotic and the formation of abscesses which which require specialist treatment.
discharged foul-smelling pus. The mortality rate was about ● Some patients treated with bisphosphonate for
20 per cent, usually due to septicaemia. Surgical removal of cancer have been found to develop a type of bone
the mandible was often required. A complete ban on white necrosis with features similar to phossy jaw.
phosphorus was slow to be introduced, one of the last
countries being the United States in 1931, although the
Berne Convention of 1906 prohibited the manufacture and REFERENCES
import of all white phosphorus matches into Europe.
Phossy jaw is now very uncommon and when it does 1. Ashcroft J. Bisphosphonates and phossy-jaw: Breathing new
occur, such as in the manufacture of munitions, it is a much life into an old problem. Lancet Oncology. 2006; 7: 447–9.
milder disease. Interestingly, osteonecrosis in the oral cav- 2. Chou TD, Lee TW, Chen SL et al. The management of white
ity, with features similar to those of phossy jaw, has recently phosphorus burns. Burns. 2001; 27: 492–7.
30
Platinum group metals
PETER LINNETT
Chloroplatinate salts produced by subsequent treatment of and the complicated test is not useful for investigation of
the liquors are equally allergenic and platinum refinery an individual.
workers have a very high risk of becoming sensitized to Refining of platinum is associated with exposure to
these salts.4,5 The risk of naive workers being sensitized other respiratory irritants, e.g. chlorine and ammonia
has been as high as 50 per cent in the first five years of which will aggravate pre-existing respiratory disorders
employment,6 although the risk has been reduced by new especially asthma. Appropriate respiratory surveillance is
technologies, such as solvent extraction and improved required for this.13
containment of liquors and suppression of airborne Biological monitoring in workers exposed to chloro-
aerosols and powders. The allergenicity is restricted to the platinates has not been found to correlate with evidence
halogeno-complex salts of platinum, such as ammonium of absorption with sensitization.17 A significant confounder
hexachloroplatinate (yellow salt) which is reduced ther- may be the presence of PGM in dental prostheses. Platinum
mally to the non-toxic metal, while other neutral platinum in blood has been determined in nurses in an oncology unit
compounds such as tetraammine platinum dichloride are who administer platinum-containing chemotherapy, but
non-allergenic.6,7 this reflects exposure and not sensitization.
Medical surveillance
Environmental risks
Personal risk factors have been studied at pre-placement
medical examination. Originally, atopy was considered to The environmental risk posed by release of platinum into
be relevant but this has not been confirmed, although the environment, particularly from autocatalysts, was
smoking is a significant risk factor.6,8–10 Some human reviewed by the International Programme on Chemical
leukocyte-associated antigens (HLA) have also been stud- Safety of the World Health Organization in the 1991
ied and shown to correlate with sensitization.11 Eczema Environmental Health Criteria 125 – Platinum.18 The
and dermatitis is aggravated by the work conditions and levels of platinum in the environment are too low to be a
rapidly leads to sensitization and asthma is aggravated by risk to human health.
the irritant environment during refining.
Medical surveillance of workers exposed to chloroplati-
nates is directed to the early identification of sensitization.
This includes direct questioning for symptoms of respira- PALLADIUM
tory and dermal sensitization, as well as skin prick testing
with a standardized dilute solution of sodium hexachloro- Palladium like platinum is a lustrous, malleable, ductile
platinate 103 g Pt salt/mL.12–14 The suggested frequency of and electroconductive metal with good catalytic proper-
testing is at least annually, but should be more frequent if ties. It is used as a catalyst in the chemical industries, as well
the exposure levels are high and if there is a high rate of as in autocatalysts. Significant amounts are used in elec-
sensitization in the exposed workforce. tronic components.3 Palladium is used in dental prostheses
Immediate cessation of exposure following diagnosis of with geographic variations in the amount used.
sensitization by skin prick test prevents the development of
asthma.13,15 Investigation of occupational asthma in the
absence of a positive skin prick test requires monitoring of Occupational toxicology
peak flow16 and confirmation by specific bronchial chal-
lenge. In cohort studies, specific IgE has been shown to Reports on patch testing from dermatology clinics indicate
correlate with skin prick test, but only for grouped results a high potential for people who are allergic to nickel to
228 Platinum group metals
react also to palladium chloride, though not to palladium wires, in jewellery often as a surface plating to provide a
metal.19,20 As there have been positive patch test cases with hard bright finish and in the glass industry for production
no previous exposure to palladium compounds, a cross- of thin glass sheets for flat screens.
reactivity between nickel and palladium has been sug- Rhodium compounds have a deep rose hue. Its major
gested. Cross-reactivity between palladium and cobalt use is in the production of autocatalysts.3
may also occur. Palladium chloride may induce sensitiza- There are a few reports of dermatitis attributed to
tion in guinea pigs by repeated open application, but rhodium compounds.
this does not occur with the metal. Cases of stomatitis The occupational exposure limit assigned to rhodium
have been attributed to the presence of palladium in the compounds of 0.001 mg/m3 has not been supported by
alloys of dental prostheses.19 A case of asthma has been epidemiology. The value was extrapolated from the limit
reported in a worker exposed to palladium tetraammine value for platinum and, as rhodium has half the atomic
dichloride.21 weight of platinum, it was assigned half the exposure limit
value of platinum compounds.
No specific medical surveillance has been advised for
Occupational exposures to palladium workers exposed only to rhodium compounds; however,
compounds many of them will have mixed exposures to other PGM
and will be subject to medical surveillance for platinum
Exposure to palladium compounds occurs in the refining compounds.
process and production of chemical process catalysts and There have been no reviews of the environmental risks.
autocatalysts. Palladium plating solutions are used in the Rhodium is rarer than platinum and is considerably more
electronics industry. Dental technicians may be exposed to valuable so losses to the environment are minimized and
metal dusts in the preparation of dental prostheses, but no environmental levels are insignificant.
adverse consequences have been reported.
IRIDIUM
Medical surveillance
Iridium is a hard shiny metal. It is resistant to corrosion
Routine medical surveillance for people exposed to palla- and has a high melting point.
dium compounds has not been prescribed. In many occu- It is used in chlor-alkali production for anode coating.
pational situations, exposure to palladium compounds Iridium crucibles are used for the production of high
occurs together with exposure to platinum compounds. purity crystals for electronics. Its resistance to heat has
These workers will normally be under regular medical sur- encouraged the use of iridium tips in spark plugs for inter-
veillance for platinum exposure. In some cases, e.g. the nal combustion engines and iridium compounds may be
electronics industry, platinum may not be present, used as process catalysts in the chemical industry.
although salts of other metals may be used. Increased Positive skin prick test reactions to iridium salts have
attention should be paid to dermal health with special con- been reported.
cern for cross-reactivity to palladium chloride in people There are no workplace exposure limits set for iridium.
who are allergic to nickel. No specific medical surveillance has been advised for
workers exposed only to iridium compounds; however,
many of them will have mixed exposures to other PGM
Exposure limits and environmental risks and will be subject to medical surveillance for platinum
compounds.
There are no workplace exposure limits for palladium There have been no reviews of the environmental risks
compounds. The environmental concerns about the from iridium. Environmental levels are insignificant.
potential effects of palladium released from autocatalysts
was reviewed in the IPCS Environmental Heath Criteria
226 – Palladium and palladium compounds. The environ- RUTHENIUM
mental levels are very low and do not pose a risk to the
community.19 Ruthenium may be used as a catalyst and is also used in the
electronics industry in the production of resistor chips and
hard disks.3 Ruthenium tetroxide is used as a fixative in
RHODIUM electron microscopy.
There are no reports of adverse reactions in workers
Rhodium is a bright, lustrous metal resistant to corrosion exposed to ruthenium metal or its compounds, but fumes
with good catalytic properties. It is harder than platinum of ruthenium tetroxide are corrosive, affecting the cornea
and more difficult to work with. It is used for thermocouple and conjunctiva, as well as the respiratory mucosa.
References 229
Osmium
Toxicology
● Osmium tetroxide causes corneal oedema and is
Osmium tetroxide is very irritant to the respiratory tract. a respiratory irritant.
Acute exposure causes conjunctivitis and corneal oedema
with the effect of causing the appearance of haloes around
bright lights. Impaired vision lasts for one or two days.
Inhalation causes severe pain in the nose with rhinorrhoea REFERENCES
and difficulty in breathing. Transient haematuria, protein-
uria and pyuria have been reported. Chronic exposure has 1. McDonald D, Hunt L. A history of platinum and its allied
been associated with corneal ulceration and opacification, metals. London: Johnson Matthey, 1982.
as well as contact dermatitis. 2. Allison S. Processing ore. In: Stellman JM (ed.).
Encyclopaedia of occupational health and safety, vol. III.
Geneva: International Labour Office, 2001: 82.10–11.
Occupational exposures 3. Platinum Today. The world’s leading authority on platinum
group metals. Last accessed September 2009. Available from:
Major exposures may occur in refining of PGM and release www.platinum.matthey.com.
of osmium tetroxide. Minor exposure episodes may occur 4. Hunter D, Milton R, Perry KMA. Asthma caused by the
in electron microscopy and in histology laboratories. complex salts of platinum. British Journal of Industrial
Medicine. 1945; 2: 92–8.
5. Pepys J, Pickering CAC, Hughes EG. Asthma due to inhaled
Exposure limits chemical agents – complex salts of platinum. Clinical Allergy.
1972; 2: 391–6.
No workplace exposure limits have been set for osmium. 6. Linnett PJ, Hughes EG. 20 years of medical surveillance
on exposure to allergenic and non-allergenic platinum
compounds: The importance of chemical speciation.
Occupational and Environmental Medicine. 1999; 56: 191–6.
Medical surveillance 7. Cleare MJ, Hughes EG, Jacoby B, Pepys J. Immediate (type I)
allergic responses to platinum compounds. Clinical Allergy.
Routine medical surveillance has not been advised. 1976; 6: 183–95.
Symptomatic treatment is suggested for acute exposures. 8. Venables KM, Dally MB, Nunn AJ et al. Smoking and
occupational allergy in workers in a platinum refinery. British
Medical Journal. 1989; 299: 939–42.
Environmental risks 9. Calverley AE, Rees D, Dowdeswell RJ et al. Platinum salt
sensitivity in refinery workers: Incidence and effects of
Environmental risks due to this very rare metal have not smoking and exposure. Occupational and Environmental
been investigated. Medicine. 1995; 52: 661–6.
230 Platinum group metals
10. Niezborala M, Garnier G. Allergy to complex platinum salts: 16. British Occupational Health Research Foundation.
A historical prospective cohort study. Occupational and Occupational asthma: Identification, management and
Environmental Medicine. 1996; 53: 252–7. prevention: evidence based review and guidelines. Last
11. Newman Taylor AJ, Cullinan P, Lympany PA et al. Interactions accessed September 2009. Available from:
of HLA phenotype and exposure intensity in sensitization to www.bohrf.org.uk/content/asthma.htm.
platinum salts. American Journal of Respiratory and Critical 17. Merget R, Kulzer R, Kniffka A et al. Platinum concentrations
Care Medicine. 1999; 160: 435–8. in sera of catalyst production workers are not predictive of
12. Hughes EG. Medical surveillance of platinum refinery platinum salt allergy. International Journal of Hygiene and
workers. Journal of the Society of Occupational Medicine. Environmental Health. 2002; 205: 1–5.
1980; 30: 27–30. 18. World Health Organization. Environmental health criteria
13. Linnett PJ. Concerns for asthma at pre-placement 125 – Platinum. Geneva: World Health Organization,
assessment and health surveillance in platinum refining – a 1991.
personal approach. Occupational Medicine. 2005; 55: 595–9. 19. World Health Organization. Environmental health criteria
14. Merget R, Schultze-Werninghaus G, Bode F et al. 226 – Palladium. Geneva: World Health Organization,
Quantitative skin prick and bronchial provocation tests with 2002.
platinum salt. British Journal of Industrial Medicine. 1991; 20. Todd DJ, Burrows D. Patch testing with pure palladium metal
48: 830–7. in patients with sensitivity to palladium chloride. Contact
15. Merget R, Caspari C, Dierkes-Globisch A et al. Effectiveness Dermatitis. 1992; 26: 327–31.
of a medical surveillance program for the prevention of 21. Daenen M, Rogiers P, Van de Walle C et al. Occupational
occupational asthma caused by platinum salts. A nested asthma caused by exposure to palladium. European
case–control study. Journal of Allergy and Clinical Respiratory Journal. 1999; 13: 213–16.
Immunology. 2001; 107: 707–12.
31
Polonium
IAIN BLAIR
Polonium (Po) is a rare, unstable radioactive element that Following ingestion about 10 per cent of polonium is
was discovered in 1898 by Marie Curie and named after her absorbed into the bloodstream and is subsequently cleared
native land of Poland. Polonium has 25 known isotopes, all by the kidneys with a biological half-life of 30–50 days.
of which are radioactive. Polonium-210, an alpha emitter, Clearance may be accelerated using chelating agents,1
is the most widely distributed isotope and it decays although significant amounts of polonium-210 are deposited
directly to its daughter isotope lead-206, with a half-life of in tissues within a few hours of ingestion.
138 days. Polonium dissolves in dilute acids and will The main hazard is its intense radioactivity (166 TBq/g).
readily form compounds including oxides and halides. Alpha particles emitted by polonium will readily damage
It vapourizes in a few hours at 55°C. Polonium can be tissue if it is ingested or inhaled, but do not penetrate the
detected and measured by alpha-particle spectroscopy. skin and so are not hazardous if the polonium remains
Polonium is found in uranium ores at about one part outside the body. The median lethal dose (LD50) for acute
in 10.10 These amounts are not harmful. Polonium is pres- radiation exposure is about 4.5 Sv and this dose can be
ent in tobacco smoke from tobacco leaves grown with delivered by ingesting about 50 ng of polonium or inhaling
phosphate fertilizers. Synthetic polonium can be created in about 10 ng.
nuclear reactors by bombarding bismuth with neutrons. The general population is naturally exposed to small
About 100 g are produced each year in this way, nearly all amounts of polonium in food, water, tobacco smoke and
in Russia. as decay products of indoor radon. Increased exposure to
polonium-210 from environmental sources is unlikely,
although polonium-210 is present in devices that are easily
USES available. Potentially lethal amounts of polonium are
present in anti-static devices that are readily available in
A single gram of polonium-210 generates 140 watts of photographic stores or by mail order. Polonium-210 from
power and because of this property it has been used as a a static eliminator source contaminated equipment and
heat source for space travel. As a source of charged parti- flooring at a soft-drink manufacturing plant.2 Disposal of
cles polonium-210 is used in anti-static devices. When solid radioactive waste at a waste disposal facility did not
mixed with beryllium, it is a source of neutrons that can be appear to result in increased environmental levels of polo-
used as a trigger for nuclear weapons. Because of its very nium.3 Follow up of a large cohort of workers employed at
high toxicity, polonium has been used as a poison (see a nuclear plant between 1944 and 1972 when polonium-
under Health effects, p. 232). 210 operations were being conducted did not show any
232 Polonium
excess mortality. Among workers specifically monitored visiting places that were contaminated with polonium-210.
for polonium-210, mortality was less than expected, Many of these provided samples for measuring 24-hour
although more lung cancers were observed. No dose– urinary excretion of polonium-210. By applying biokinetic
response trends were observed.4 models, it was possible to calculate intakes by ingestion or
inhalation and the resulting radiation doses. Of the 695
people examined, 560 had urinary levels of 30 mBq per day
EXPOSURE LEVELS or less which is the natural background level. Eighty-five
had levels greater than this, but had received an estimated
Maximum exposure levels for polonium in food and dose of less than 1 mSv, 34 had received an estimated dose
for the workplace have been published by national and of more than 1 mSv but less than 6 mSv, and 16 had
international authorities including the US Nuclear received an estimated dose of 6 mSv or more. For those who
Regulatory Commission,5 the International Commission had received doses of more than 1 mSv, it was estimated
on Radiological Protection6 and the Food and Agriculture that their lifetime risk of death from cancer was increased
Organization of the United Nations.7 For example, the by between 0.03 and 0.5 per cent.8
maximum allowable body burden for ingested polonium- Extrapolating from animal studies indicates that inges-
210 is only 1.1 kBq, which is equivalent to a particle weigh- tion (or inhalation) of a few tenths of a milligram of
ing only 6.8 pg. The maximum permissible workplace polonium-210 is likely to be fatal to all exposed persons.
concentration of airborne polonium-210 is about Such intakes will cause fatal damage to the bone marrow
10 Bq/m3. and other organs, including the kidneys and liver. Deaths
will occur within about a month with levels of 1 MBq/kg
body mass, but will occur over a longer period for lower
HEALTH EFFECTS exposures. Below 0.02 MBq/kg body mass, deaths from
deterministic effects are not expected to occur, but the risk
Alexander Litvinenko, a Russian living in London, died of cancer could be significant.9
in November 2006 after being poisoned with polonium- One study has estimated that Litvinenko might have
210 a few weeks earlier. Litvinenko was probably the first ingested between 27 and 1408 MBq (0.2–8.5 g).10 A sec-
person ever to die of the acute alpha-radiation effects of ond study concluded that 0.1–0.3 GBq absorbed into the
polonium-210. bloodstream of an adult male would probably be fatal
Following ingestion, polonium distributes widely through within one month. Assuming 10 per cent absorption into
the tissues of the body leading to whole body radiation expo- the bloodstream, this would correspond to ingestion of
sure. Most exposure occurs in the first 30 days. After a mini- 1–3 GBq. There would be reductions in white cell count
mum lethal dose, no initial illness would result due to the due to bone marrow failure complicated by damage to
time it takes for exposure to accumulate, but death would be other organs, such as the kidneys and liver. Damage to
expected from the poisoning within two or three months. these other organs would most probably be fatal even if the
However, Litvinenko was ill on the day he was poisoned, bone marrow could be rescued.11
was seriously ill on day 11 and died on day 23. This indicates
that he was poisoned with many times the lethal dose of
polonium-210 with the initial burden of exposure falling on Key points
the gastrointestinal tract. Two other people who were with
Litvinenko on the day of the presumed poisoning became ill ● The general population is naturally exposed to
about 36 days after Litvinenko, which is consistent with small amounts of polonium in food, water,
absorption of a sublethal dose. tobacco smoke and indoor radon.
There are unsubstantiated reports that Irène Joliot-Curie, ● Synthetic polonium has commercial uses.
the Nobel prize winning chemist and daughter of Marie ● Polonium is highly toxic when ingested or
Curie, died from leukaemia in Paris in 1956 as a result of inhaled due to the emission of alpha particles.
exposure to polonium in a laboratory accident ten years ● Alexander Litvinenko was fatally poisoned with
earlier. Similarly, it has been suggested that four deaths polonium-210 in November 2006.
among staff at a research institute in Israel between 1957
and 1969 were due to a polonium leak.
REFERENCES
2. Wallace JD, Williamson MR. Contamination of a soft-drink limits. Last accessed November 2008. Available from:
manufacturing plant by 210Po. Health Physics. 1990; 58: www.fao.org/DOCREP/U5900T/u5900t08.htm#radionuclide
469–75. %20contamination%20of%20foods:%20fao%20recommend
3. Arthur WJ III, Markham OD. Polonium-210 in the ed%20limits.
environment around a radioactive waste disposal area and 8. Health Protection Agency. Followup of public health
phosphate ore processing plant. Health Physics. 1984; 46: surveillance following polonium 210 incident. Last accessed
793–9. January 2010. Available from: www.hpa.org.uk/web/
4. Wiggs LD, Cox-DeVore CA, Voelz GL. Mortality among a HPAweb&HPAwebstandard/HPAweb_C/1195733719534.
cohort of workers monitored for 210Po exposure: 9. Scott BR. Health risk evaluations for ingestion exposure
1944–1972. Health Physics. 1991; 61: 71–6. of humans to polonium-210. Dose Response. 2007; 5:
5. United States Nuclear Regulatory Commission. Last 94–122.
accessed November 2008. Available from: www.nrc.gov/ 10. Li WB, Gerstmann U, Giussani A et al. Internal dose
reading-rm/doc-collections/cfr/part020/appb/. assessment of 210Po using biokinetic modeling and urinary
6. International Commission on Radiological Protection (ICRP). excretion measurement. Radiation and Environmental
Last accessed November 2008. Available from: www.icrp. Biophysics. 2008; 47: 101–10.
org/index.asp. 11. Harrison J, Leggett R, Lloyd D et al. Polonium-210 as a
7. Food and Agriculture Organization of the United Nations. poison. Journal of Radiological Protection. 2007; 27:
Radionuclide contamination of foods: FAO recommended 17–40.
32
Silver
PETER LINNETT
water is required. If the burn is superficial, there is initial there is some staining, although early changes are very
erythema. On exposure to light, the colour then deepens to subtle and difficult to identify.
black. The skin dries and following the process of desqua- Biological monitoring has been performed and deter-
mation is replaced by normal healthy skin. If the silver mination of silver in blood has demonstrated that workers
compound is in contact with subcuticular tissues, there exposed to soluble silver compounds as in plating
will be staining deep to the epidermis. Such cases have been processes have higher levels than those whose exposure is
reported from the excessive use of silver sulphadiazine for to silver metal or fume alone.4 The levels reported were not
the treatment of wounds and burns. associated with argyria and routine biological monitoring
Intradermal or implantation of splinters of silver metal has not been recommended as integral to a medical sur-
during the fabrication of metal products may result in veillance programme.
localized pigmentation causing a cosmetic change with no Most cases of argyria now reported are the result of
systemic effect.2 self-medication.
EXPOSURE LIMITS
REFERENCES
The American Conference of Governmental Industrial
Hygienists (ACGIH) exposure limit3 for silver metal is 1. Drake PL, Hazelwood KJ. Exposure-related health effects
0.1 mg/m3 and for soluble silver compounds it is of silver and silver compounds: A review. Annals of
0.01 mg/m3. This reflects the differences in absorption of Occupational Hygiene. 2005; 49: 575–85.
silver from soluble compounds compared with the limited 2. Sarsfield P, White JE, Theaker JM. Silverworkers finger:
absorption from insoluble compounds and metallic silver. An unusual occupational hazard mimicking a melanocytic
lesion. Histopathology. 1992; 20: 73–5.
3. American Conference of Governmental Industrial Hygienists
MEDICAL SURVEILLANCE (2007) Threshold limit values for chemical substances and
physical agents and biological exposure indices. Cincinnati:
No specific measures have been advised for medical sur- ACGIH.
veillance for silver exposure. Compliance with the expo- 4. Armitage SA, White MA, Wilson HK. The determination of
sure limits will prevent systemic absorption and argyria. silver in whole blood and its application to biological
Examination of the sclera and mucous membranes of monitoring of occupationally exposed groups. Annals of
workers handling soluble silver compounds may indicate if Occupational Hygiene. 1996; 40: 331–8.
33
Thallium
Thallium is a soft, malleable, bluish-white metal with the vomiting and abdominal pain, which may be associated
symbol ‘Tl’, atomic number 81, atomic weight 204.38 and with the passage of bright red blood per rectum.
specific gravity 11.85.1,2 Although the annual global pro- Tachycardia and hypertension may result from autonomic
duction of thallium reduced from 15 to 10 tons between (vagus nerve) dysfunction. Characteristic symptoms of
1995 and 2004,3 its use is wide-ranging, including semi- paraesthesia and pains in the lower limbs, reflecting
conductors, optical fibres, optical lens, imitation jewellery, polyneuropathy, appear after several days. Decrease of sen-
fireworks and as a rodenticide. Radioisotope 201Tl is used sation in the distal extremities and weakness, especially in
for cardiac imaging. In addition, due to recent research and the lower limbs, may be present. There can be difficulties
development activities, the use of thallium may greatly with swallowing and speech, as well as other cranial nerve
expand in the future as a material for high-temperature effects (e.g. optic nerve, ocular movement and facial mus-
superconductors.3 Since thallium and many thallium salts cle dysfunction). Central nervous system involvement
are highly toxic and yet tasteless and odourless, accidental leads to seizures, unconsciousness, ataxia and involuntary
or intentional thallium poisoning has occurred.4,5 Cases movements. Alopecia appears approximately two weeks
with clinical effects that may have resulted from occupa- later. It is usually most evident in the scalp, but hair in
tional thallium exposure have been described.6 These other parts of the body can also be lost. This latent period
include a worker engaged alone in the production of a ‘new for alopecia to appear corresponds to the maturation
type of special glass’ containing thallium.7 The worker period of the new epithelial cells of the hair matrix.9 Mees
deployed to replace him also succumbed to similar effects. lines (transverse white stripes) in the nails appear three to
Thallium can be absorbed through the gastrointestinal four weeks later. In subacute or chronic poisoning, the
tract, respiratory tract and skin, and is then rapidly distrib- onset is associated with loss of appetite, headache, irritabil-
uted to all organs.1,2 It passes through the placenta and ity, insomnia and loss of body weight.
blood–brain barrier. In the early phase of poisoning, its con- The lethal dose varies from 6 to 40 mg/kg, but on average
centration is high in the kidneys, but low in adipose tissue is between 10 and 15 mg/kg. Death occurs within 10–12 days
and the brain, but the cerebral concentration increases subse- if not treated. In extreme cases, death occurs within hours.2
quently.2 In an autopsied case (from a patient who died nine Thallium poisoning should be considered if there is a
days after taking 5–10 g of thallium nitrate), the thallium history of exposure, and the clinical effects are gastroin-
concentration exceeded 100 mg/g in the colon, testis, cardiac testinal disturbances followed by neurological impairment
ventricles, pituitary and several regions of the brain (thala- and then alopecia. Alopecia is seen only two to three weeks
mus, corpus striatum, cerebellar cortex and cerebral cortex).8 after the neurological signs have appeared. Microscopic
Thallium may be excreted into the gastrointestinal tract, examination of the hair root by polarized light may show
kidneys, hair, skin, sweat, saliva and breast milk.2,9 black discolouration at the base, but this is non-specific.
Reabsorption takes place in the gastrointestinal tract (mainly Determination of thallium in urine and saliva can provide
the colon). The biological half-life in humans is estimated to an important clue for the diagnosis. Blood thallium levels
be approximately ten days, but can be as long as 30 days.2 may be elevated, but it does not reflect the tissue concen-
Characteristic features of thallium poisoning are gas- tration because thallium is rapidly taken up by the cells.
trointestinal disturbance, neurological impairment and To treat thallium poisoning, Prussian blue is adminis-
alopecia. In acute poisoning, initial symptoms are nausea, tered orally, dissolved in 10–15 per cent mannitol,
References 237
250 mg/kg body weight, per day in three to four divided REFERENCES
doses. Prussian blue forms an insoluble complex with thal-
lium, suppresses its reabsorption and enhances excretion 1. American Conference of Governmental Industrial Hygienists.
of thallium via faeces. Without treatment, the excretion Thallium and soluble compounds. In: Documentation of the
half-life of thallium is approximately eight days, but the TLVs and BEIs with other worldwide occupational exposure
administration of Prussian blue shortens it to three days.2 values, CD-ROM, 2005.
In the early stages (within 48 hours after exposure), 2. World Health Organization. International programme on
charcoal haemoperfusion and haemodialysis is used, chemical safety. Environmental health criteria 182: Thallium.
although it has been suggested that haemodialysis can be Geneva: WHO, 1996.
effective even in the third week of poisoning.10 Forced 3. US Geological Survey. Thallium statistics. Available from:
diuresis may also be effective. Chelators, such as dimer- http://minerals.usgs.gov/ds/2005/140/thallium.pdf.
caprol, EDTA and penicillamine, are not effective and 4. Moore D, House I, Dixon A. Thallium poisoning. Diagnosis
dithiocarbamate is contraindicated because it enhances the may be elusive but alopecia is the clue. BMJ 1993; 306:
distribution of thallium into the brain. Following recovery 1527–9.
from thallium overexposure, hair growth usually reappears, 5. Meggs WJ, Hoffman RS, Shih RD et al. Thallium poisoning
whereas neurological disturbances, such as ataxia, tremor, from maliciously contaminated food. Clinical Toxicology.
dementia and mental signs, often persist. 1994; 32: 723–30.
6. Richeson EM. Industrial thallium intoxication. Industrial
Medicine and Surgery. 1958; 27: 607–19.
Key points 7. Hirata M, Taoda K, Ono-Ogasawara M et al. A probable case
of chronic occupational thallium poisoning in a glass factory.
● Thallium has wide-ranging applications, with a Industrial Health. 1998; 36: 300–303.
potential for use in high-temperature 8. Davis LE, Standefer JC, Kornfeld M et al. Acute thallium
semiconductors. poisoning: Toxicological and morphological studies of
● Thallium poisoning is characterized by the nervous system. Annals of Neurology. 1981; 10:
gastrointestinal effects, neurological impairment 38–44.
and alopecia. 9. Tromme I, Van Neste D, Dobbelaere F et al. Skin signs in
● The lethal dose for thallium is from 6 to the diagnosis of thallium poisoning. British Journal of
40 mg/kg body weight. Dermatology. 1998; 138: 321–5.
● Oral administration of Prussian blue and 10. Misra UK, Kalita J, Yadav RK et al. Thallium poisoning:
mannitol is used for treating thallium poisoning. Emphasis on early diagnosis and response to haemodialysis.
Postgraduate Medical Journal. 2003; 79: 103–5.
34
Tin
Tin is a malleable, silvery-white metal with the symbol ‘Sn’, Organotins, in comparison to the inorganic tin com-
atomic number 50, atomic weight 118.69, melting point pounds, are relatively toxic to humans. Tri-organotin
232°C and a boiling point of 2000°C.1 Metallic tin is used compounds are more toxic than mono- and di-organotin
for protective coatings including tin-plated steel containers compounds, with the toxicity of trialkyltins decreasing
to preserve food, in the manufacture of solder, and in with an increase in the number of carbon atoms in the alkyl
alloys such as bronze, brass, pewter and gunmetal. Tin chain. Organotin compounds are skin and eye irritants.
compounds exist in two valency states – valency II (stan- Tributyltin, dibutyltin and dioctyltin are immunotoxic in
nous compounds) and valency IV (stannic compounds). rodents, and organotins have been shown to be embry-
Stannous chloride is used as a stabilizer in soaps and otoxic and teratogenic in laboratory animals, with cleft
perfumes, as a mordant for textiles, and in toothpaste with palate and other facial malformations as the most common
stannous fluoride to prevent dental caries. Organotins, abnormalities. Alterations of enzyme activities in sex hor-
which have at least one covalent carbon–tin bond, are mone synthesis and haematological effects by organotins
deployed mainly as stabilizers for polyvinyl chloride poly- have been reported in vitro and in vivo, but there is no
mers, catalysts in the production of polyurethane foams, evidence of similar effects in humans.1
and as biocides.2 Triphenyltin is used in disinfectants, By contrast, the neurotoxicity of organotins, especially
molluscides and anti-fouling agents in marine paints. triethyltin (TET)3,4 and trimethyltin (TMT),5,6 has been
clearly shown in humans, as well as in animals. Lethal
poisoning due to TET or TMT has also been observed in
INORGANIC TIN COMPOUNDS humans. TET and TMT are colourless liquids under
normal pressure, and the boiling point is relatively low for
Acute effects following consumption of foods contami- TMT (18°C). Both compounds are soluble in organic
nated with inorganic tin include nausea, vomiting and solvents but not in water, and they can be absorbed via the
diarrhoea. There is no evidence that inorganic tin damages respiratory and gastrointestinal tracts, as well as through
the immune or the nervous system or that it is mutagenic the skin. Poisoning by TET or TMT has occurred following
or carcinogenic in humans.1 Chronic exposure to dusts occupational exposure.
or fumes of inorganic tin such as stannic oxide causes
a benign form of pneumoconiosis (stannosis) in which
widespread mottling appears on a chest x-ray due to the Triethyl tin
high radiodensity of tin, but lung function is not compro-
mised despite the x-ray changes. Patients with stannosis are In 1954 in France, approximately 1000 people took stali-
also asymptomatic. non (an oral preparation containing 15 mg of diethyltin
References 239
diiodide) to treat a variety of clinical conditions, such as seizures. Animals given TMT also show aggressiveness,
staphylococcal skin infections, osteomyelitis and acne. As a seizures, learning and memory impairment, and self-
result, more than 200 individuals were poisoned and there mutilation (biting their own tail). Central nervous system
were approximately 100 deaths.3,7 Impurities identified in changes in affected animals revealed changes in the
stalinon were monoethyltin triiodide and triethyltin iodide. hippocampus, cerebral cortex6 and the cerebellum.11 The
Triethyltin iodide, approximately 1.5 mg per capsule, was clinical presentation includes nystagmus and ataxia.
believed to be the primary cause of the poisoning. Judging Tinnitus and hearing difficulty may develop due to impair-
from these cases, oral intake of 70 mg of triethyltin iodide ment of the brainstem and/or inner ear.
over eight days will lead to tin intoxication. The clinical In the case of two individuals who consumed contami-
features of poisoning are severe headache approximately nated wine (containing an unknown quantity of TMT),
four days from initial exposure and absorption, with asso- tinnitus began within 10 minutes and abnormal behaviour,
ciated vomiting, dizziness, dysuria and visual disturbances, such as agitation, occurred three hours after drinking the
such as photophobia. Loss of appetite, hypothermia, som- wine.10 It is uncertain how much of the alcohol consumed
nolence and mental signs may also be seen. Disturbance in contributed to the behavioural effects.
consciousness leading to coma may occur in severe cases. Determination of organotins in urine may provide an
On spinal tap, the cerebrospinal fluid pressure is often ele- important clue for the diagnosis. In six workers exposed to
vated, but cell count, sugar and protein concentrations in TMT vapour, while cleaning a tank in Germany, urinary
the cerebrospinal fluid are normal. Death may follow organotin levels reached a peak within four to ten days.11
coma, epileptic attacks or cardiopulmonary insufficiency. (A mean normal urine level for tin has been reported at
Triethyl tin has been well recognized as a cause of cyto- 16.6 μg/L.12) Electroencephalography (EEG) may show
toxic brain oedema.8 In laboratory animals, vacuoles occur abnormalities in the temporal regions (spikes and/or slowing
diffusely in white matter. These are associated with split- of EEG waves). Complete recovery occurs in mild cases, but
ting of myelin lamellae, but no changes in major chemical clinical abnormalities often persist. In the above six workers,
compositions of the myelin are observed. In human one died and two remained seriously disabled following the
cases of TET poisoning, the main signs reflect diffuse incident.11 In a 23-year-old postgraduate student acciden-
leukoencephalopathy without any localized abnormalities. tally exposed to TMT while performing laboratory experi-
Fundoscopy and cerebrospinal fluid pressure may be ments, memory impairment and EEG abnormalities (slow
normal.3 The severe headaches and vomiting reported are waves in the temporal region) were observed 43 months
most likely due to increased intracranial pressure. later, but with no MRI changes.13 Hence, the prognosis is
From the effects observed in animals, magnetic resonance poor for severely affected individuals.
imaging (MRI) (especially T2-weighted images) may be a
useful tool for following up patients with TET intoxication,9
although experience of the use of MRI in affected humans is Key points
limited. In a Japanese worker intoxicated with TET while
engaged in manufacturing a large amount of tetraethyltin ● Tin exists as the pure metal (inorganic stannous
over a period of about ten days, the organotin level was (valency II) and stannic (valency IV)
elevated in whole blood, but not in serum or urine.7 compounds) and as organotins.
There is no specific antidote for TET poisoning. In cases ● Exposure to inorganic tin dust leads to
of stalinon poisoning, surgical decompression to relieve ‘stannosis’ – a benign effect despite widespread
the increased cerebrospinal fluid pressure was considered mottling on chest x-ray.
the only clinically effective treatment.3 ● Organotins are generally more toxic than
As for prognosis, complete recovery may take place, but inorganic tin compounds. They are irritant to
in many cases it takes a long time and the recovery may be the skin and eyes, and are neurotoxic.
incomplete, leaving disabilities including paraparesis and
visual disturbances. In the case of the affected Japanese
worker, it took approximately six months before the
cerebrospinal fluid pressure returned to normal.7 REFERENCES
3. van Heijst ANP. Triethyltin (PIM 588). International 8. Kimelberg HK. Current concepts of brain edema. Review of
Programme on Chemical Safety 1997. Accessed on October laboratory investigations. Journal of Neurosurgery. 1995;
26, 2009. Available from: www.inchem.org/documents/pims/ 83: 1051–9.
chemical/pim588.htm. 9. Barnes D, McDonald WI, Tofts PS et al. Magnetic resonance
4. Krinke GJ. Triethyltin. In: Spencer PS, Schaumburg HH (eds). imaging of experimental cerebral oedema. Journal of
Experimental and clinical neurotoxicology, 2nd edn. New Neurology, Neurosurgery, and Psychiatry. 1986; 49:
York: Oxford University Press, 2000: 1206–8. 1341–7.
5. van Heijst ANP. Trimethyltin compounds (PIM G019). 10. Kreyberg S, Torvik A, Bjorneboe A et al. Trimethyltin
International Programme on Chemical Safety 1999. poisoning: Report of a case with postmortem examination.
Available from: www.inchem.org/documents/pims/chemical/ Clinical Neuropathology. 1992; 11: 256–9.
pimg019.htm. 11. Besser R, Krämer G, Thümler R et al. Acute trimethyltin
6. Krinke GJ. Trimethyltin. In: Spencer PS, Schaumburg HH limbic-cerebellar syndrome. Neurology. 1987; 37: 945–50.
(eds). Experimental and clinical neurotoxicology, 2nd edn. 12. Goyer AG, Clarkson TW. Toxic effects of metals. In: Klaassen
New York: Oxford University Press, 2000: 1211–14. CD (ed.). Casarett and Doull’s Toxicology: The basic science
7. Nishikawa M, Tsukiyama K, Matsumoto I et al. A case of of poisons, 6th edn. New York: McGraw-Hill, 2001: 811–67.
alkyltin compounds intoxication. Clinical Neurology. 1965; 13. Feldman RG, White RF, Eriator II. Trimethyltin encephalopathy.
5: 88–94. Archives of Neurology. 1993; 50: 1320–4.
35
Tungsten
PERRINE HOET
Tungsten (wolfram) is a naturally occurring element. 94.4 g/g creatinine and a maximum value of 177.5 g/g
Two kinds of tungsten-bearing mineral rocks, called wol- creatinine. High urinary tungsten concentrations were also
framite and scheelite, are mined commercially. Tungsten is detected in workers from the departments producing
an extremely hard metal and highly resistant to heat. It is tungsten carbide (mean, 42.1 g/g creatinine; maximum,
used in the filaments of incandescent light bulbs and in the 79.9 g/g creatinine) and heavy alloys (mean, 24.9 g/g
steels for producing metal tools. Most of the tungsten used creatinine; maximum, 84.8 g/g creatinine). The 95th
in industry is in the manufacture of sintered tungsten percentile for the general population is 1 g/g creatinine.1
carbide (cemented carbides). In this process, a mixture of Exhaled breath condensate (EBC), obtained by cooling
powders, including tungsten carbide, cobalt, nickel or exhaled air under condition of spontaneous breathing, has
chromium metal, are shaped into the form of cutting tools also been proposed as a matrix to assess target tissue dose
and then heated at high temperatures to produce machine and effects of inhaled cobalt and tungsten.2
tools that are almost as hard as diamond. Some of the The main hazard associated with the use of tungsten
soluble compounds of tungsten, such as tungsten molyb- carbide is hard metal disease (see Chapter 19, Cobalt
denate, are used in the textile industry as mordants or fire- and Chapter 82, Metal dusts and fumes). Although cobalt
proofing agents, and some of the highly coloured tungsten probably plays a critical role in the pathogenesis of hard
salts are used as pigments in paints, inks, ceramics and metal lung disease (HMLD), it is suggested that tungsten
textiles. carbide has a contributory synergistic effect. Animal
In the hard metal manufacturing industry, there is experiments have shown that pure tungsten carbide is
exposure to: inert.3 In lung biopsy samples from patients with HMLD,
tungsten particles were found to be mainly distributed in
● tungsten carbide in the forming, pressing and sintering centrilobular fibrosing lesions, suggesting that inhaled
workshops; hard metal was trapped at the bronchioles and triggered
● a combination of tungsten carbide, tungsten oxide and the inflammation seen in HMLD.4
tungsten metal in the tungsten carbide production A case of tungsten-induced occupational asthma, with
workshop; immediate hypersensitivity reaction at the scratch test has
● tungsten metal alone in the powder processing been reported.5 However, tungsten as a cause of allergy is
department. rare.
IAIN BLAIR
Military personnel and local civilians may be exposed in Studies of these few cases indicate that kidney failure is
areas where DU munitions have been used. Exposure may likely to occur within a few days at concentrations above
also occur in areas where soil and groundwater have high about 50 g uranium per gram of kidney. The levels of
levels of naturally occurring uranium. The main routes of kidney uranium that may cause minor kidney dysfunction
exposure are by inhaling dust, ingesting contaminated in humans are not well established, but are considered to
water and food, or in the case of DU munitions, through be at least ten-fold less than the value of 3 g uranium per
injury causing open wounds and embedded fragments. gram of kidney that has often been used as the basis for
Absorption of uranium from the gastrointestinal tract occupational exposure limits. Acute exposures that lead to
is low and depends on the solubility of the particular concentrations of about 1 g uranium per gram kidney
uranium compounds. Over 95 per cent is eliminated in the have been associated with minor kidney dysfunction, but
faeces and two-thirds of the absorbed fraction is filtered by the levels that can occur for short periods without causing
the kidney and excreted in the urine in 24 hours. Uranium long-term kidney damage have not been defined.
within the body deposits at bone surfaces and is slowly Epidemiological studies have examined the health of
cleared via blood and kidneys with a half-life of up to one workers potentially exposed in uranium-processing plants
year. Inhaled uranium particles may be retained in the lung and community studies have examined health outcomes in
and may lead to irradiation damage and lung cancer as populations living near uranium plants. Lack of exposure
they are slowly absorbed into the bloodstream. Exposure to data, confounding factors and the expected ‘healthy
uranium can be monitored by measuring urinary uranium worker’ effect make interpretation of the results difficult.
excretion. Chelation is ineffective. Generally, there is no consistent evidence for any increase
Uranium is weakly radioactive, but of greater signifi- in cancer or serious kidney disease due to uranium expo-
cance is its chemical toxicity which it shares with other sure in these settings.
heavy metals. The health effects of uranium which are Incidents involving acute or subacute exposure to
known from animal studies and human epidemiology uranium have occurred in a variety of settings. Workers at
include lung cancer, kidney damage and DNA damage. a uranium-processing plant where there was poor dust
Uranium is less toxic than lead. control had evidence of increased urinary uranium levels
The World Health Organization (WHO)1 and most and impaired renal function.7 Following the uranium
national regulatory agencies2 have set minimum, recom- enrichment process, large quantities of depleted uranium
mended or permissible exposure limits for soluble and hexafluoride (HF) are produced and have to be stored
insoluble uranium compounds by ingestion and inhala- indefinitely in steel containers. Inevitably accidental
tion. These limits consider both renal toxicity and radia- releases occur. In one such release in 1986, one worker died
tion exposure and apply to both the general population from HF inhalation and 31 other workers were exposed
and the workplace. Levels are also available for air and and showed evidence of short-term kidney damage. None,
drinking water. The levels vary depending on the method- however, had lasting kidney toxicity from the uranium
ology that is used and the levels of risk and uncertainty exposure. Magdo and others reported nephrotoxicity with
that are deemed acceptable. For example, the WHO rec- raised beta-2-microglobulin excretion rate in a three-year-
ommends that the general public’s intake of soluble ura- old child as a result of drinking water from a well at their
nium compounds should not exceed 0.5 g/kg of body home in Connecticut with naturally elevated concentra-
weight per day by ingestion and 1 g/m3 by inhalation. tions of uranium (866 and 1160 g/L).8
Occupational exposure to soluble and insoluble uranium Depleted uranium has been widely studied as a possible
compounds, as an 8-hour time-weighted average should contributory factor in ‘gulf war syndrome’: the immune
not exceed 0.05 mg/m3. system disorders and other wide-ranging symptoms
reported in about 25 per cent of combat veterans of the
1991 Gulf War. There have been several authoritative
HEALTH EFFECTS reports and a precautionary approach is advised.9
Thirty-five American Gulf War I veterans who had sig-
Epidemiological studies have shown an association nificant DU-retained shrapnel burden as a result of combat
between uranium mining and lung cancer. It is exposure were assessed 16 years after initial exposure. They contin-
to radon gas and other radioactive decay products rather ued to have elevated concentrations of urinary uranium
than uranium per se that explains this association.3,4 Radon with minor abnormalities of renal tubular function and
exposure also explains the increase in lung cancer seen in bone formation, but without clinically significant related
other groups of miners. Uranium miners may also have health effects.10
an increased risk of developing leukaemia as a consequence A follow-up study after eight years of 2499 firefighters,
of radon exposure,5 although this outcome may require police officers and hangar workers who were potentially
lengthy occupational exposure to longer-lived radio- exposed to uranium from the balance weights of a crashed
nuclides and gamma-radiation.6 aircraft in the 1992 Amsterdam air disaster found no
Only a few humans have had sufficiently large acute evidence of higher urinary uranium concentration or
intakes of uranium compounds to lead to kidney failure. disturbed renal function.11
References 245
Animal studies suggest that DU is a teratogen and there exposure rates and modifying effects of time since exposure
is some evidence that human parental DU exposure may and age at exposure. Radiation Research. 2008; 169: 125–37.
be associated with an increased risk of abnormality in their 4. Grosche B, Kreuzer M, Kreisheimer M et al. Lung cancer risk
progeny.12 Persistent chromosome abnormalities have among German male uranium miners: A cohort study,
been reported in a cohort of uranium miners.13 1946–1998. British Journal of Cancer. 2006; 95: 1280–7.
5. Rericha V, Kulich M, Rericha R et al. Incidence of leukemia,
lymphoma, and multiple myeloma in Czech uranium miners:
A case–cohort study. Environmental Health Perspectives.
Key points 2006; 114: 818–22.
6. Möhner M, Lindtner M, Otten H, Gille HG. Leukemia and
● Uranium is a very dense, weakly radioactive exposure to ionizing radiation among German uranium
metal which, when enriched, is used in nuclear miners. American Journal of Industrial Medicine. 2006;
reactors and nuclear weapons. Depleted 49: 238–48.
uranium-238 is used in the defence industry 7. Shawky S, Amer HA, Hussein MI et al. Uranium bioassay and
and is controversial because of its potential radioactive dust measurements at some uranium processing
health effects. sites in Egypt – health effects. Journal of Environmental
● Exposure to uranium can occur in various Monitoring. 2002; 4: 588–91.
settings by inhalation, ingestion or embedded 8. Magdo HS, Forman J, Graber N et al. Grand rounds:
fragments. Nephrotoxicity in a young child exposed to uranium from
● Although poorly absorbed, like other heavy contaminated well water. Environmental Health Perspectives.
metals, uranium is toxic to kidney and other 2007; 115: 1237–41.
tissues. 9. The Royal Society Working Group on the Health Hazards of
● Inhaled uranium particles may lead to Depleted Uranium Munitions. The health effects of depleted
irradiation damage and lung cancer. uranium munitions: A summary. Journal of Radiological
● In epidemiological studies, the health effects of Protection. 2002; 22: 131–9.
uaranium exposure are often confounded by 10. McDiarmid MA, Engelhardt SM, Dorsey CD et al. Surveillance
radon exposure. results of depleted uranium-exposed Gulf War I veterans:
Sixteen years of follow-up. Journal of Toxicology and
Environmental Health. 2009; 72: 14–29.
11. Bijlsma JA, Slottje P, Huizink AC et al. Urinary uranium and
REFERENCES kidney function parameters in professional assistance
workers in the Epidemiological Study Air Disaster in
1. World Health Organization. Depleted uranium. Accessed Amsterdam (ESADA). Nephrology, Dialysis, Transplantation.
November 2008. Available from: www.who.int/ionizing_ 2008; 23: 249–55.
radiation/env/du/en/. 12. Hindin R, Brugge D, Panikkar B. Teratogenicity of depleted
2. Agency for Toxic Substances and Disease Registry. Minimal uranium aerosols: A review from an epidemiological
risk levels (MRLs) for hazardous substances. Accessed perspective. Environmental Health. 2005; 4: 17. Available
November 2008. Available from: www.atsdr.cdc.gov/mrls/ from: www.ehjournal.net/content/pdf/1476-069X-4-17.pdf.
index.html. 13. Mészáros G, Bognár G, Köteles GJ. Long-term persistence of
3. Tomasek L, Rogel A, Tirmarche M et al. Lung cancer in French chromosome aberrations in uranium miners. Journal of
and Czech uranium miners: Radon-associated risk at low Occupational Health. 2004; 46: 310–15.
37
Vanadium
FINLAY D DICK
a metal fume fever-like syndrome in a man exposed to a as likely normal values in unexposed populations, although
catalyst containing vanadyl pyrophosphate dust.13 Skin these will be influenced by environmental factors such as
sensitization to vanadium, confirmed on patch testing, has residency near steel works or oil-burning power stations.25
also been described in a worker in a vanadium pentoxide
manufacturing plant exposed to dust containing vana-
dium.3 Vanadium interferes with iron metabolism and
haem synthesis causing elevated zinc protoporphyrin Key points
(ZPP).14 Barth et al.15 suggested that vanadium pentoxide
has short-term effects on cognitive function, but these
● Vanadium pentoxide (V2O5) is a skin and
findings have yet to be replicated. respiratory irritant.
In 2006, vanadium pentoxide was classified as a ‘possi-
● Industrial boiler cleaning is an important
ble human carcinogen’ (2B) by the International Agency occupational exposure owing to the high level
for Research on Cancer (IARC) based on animal studies of vanadium in the residual oil fuel ash.
showing an excess of lung adenomas and cancer.16 This
● Vanadium exposure has been associated with
assessment has, however, been disputed.17 Recent work has occupational asthma.
shown increased DNA damage in a group of workers
● Skin sensitization to vanadium has very rarely
exposed to vanadium pentoxide dust with median serum been described.
vanadium of 2.2 g/L.18
● Treatment for overexposure to vanadium is
mainly supportive.
● Vanadium pentoxide is classified as a ‘possible
TREATMENT human carcinogen’ (group 2B) by the
International Agency for Research on Cancer
Treatment for overexposure to vanadium or its com- (IARC).
pounds is mainly supportive.
There are no specific antidotes that have been shown to
be effective in humans.
REFERENCES
Measuring exposure 1. Monakhov IN, Khromov SV, Chernousov PI, Yusfin YS.
The flow of vanadium-bearing materials in industry.
The current United States Occupational Safety and Health Metallurgist. 2004; 48: 381–5.
Administration (OSHA) exposure limit for vanadium 2. Dutton WF. Vanadiumism. Journal of the American Medical
respirable dust (as V2O5) is 0.5 mg/m3 and the exposure Association. 1911; 56: 1648.
limit for vanadium fume (as V2O5) is 0.1 mg/m3.19 3. Sjöberg S-G. Health hazards in the production and handling
The American Conference of Governmental Industrial of vanadium pentoxide. Archives of Industrial Hygiene and
Hygienists (ACGIH) has assigned respirable vanadium Occupational Medicine. 1951; 3: 631–46.
pentoxide a threshold limit value of 0.05 mg/m3 as an 4. Barceloux DG. Vanadium. Clinical Toxicology. 1999;
eight-hour time-weighted average based on the upper and 37: 265–78.
lower respiratory tract irritancy of vanadium pentoxide.20 5. McTurk LC, Hirs CHW, Eckardt RE. Health hazards of
The UK work exposure limit (WEL) for vanadium pentox- vanadium-containing residual oil ash. Industrial Medicine
ide is 0.05 mg/m3 (eight-hour time-weighted average).21 and Surgery. 1956; 25: 29–36.
There is currently no German maximale Arbeitsplatz- 6. Wyers H. Some toxic effects of vanadium pentoxide. British
Konzentration or maximum concentration at the work- Journal of Industrial Medicine. 1946; 3: 177–82.
place (MAK value) assigned for vanadium.22 7. Williams N. Vanadium poisoning from cleaning oil-fired boilers.
British Journal of Industrial Medicine. 1952; 9: 50–5.
8. Lewis CE. The biological effects of vanadium: II. The signs
HEALTH SURVEILLANCE and symptoms of occupational vanadium exposure. AMA
Archives of Industrial Health. 1959; 19: 497–503.
Biological monitoring may be undertaken using post-shift 9. Lees REM. Changes in lung function after exposure to
urinary vanadium at the end of the working week. vanadium compounds in fuel oil ash. British Journal of
Creatinine-adjusted urinary vanadium is highly correlated Industrial Medicine. 1980; 37: 253–6.
with serum vanadium values.23 Vanadium is rapidly 10. Kiviluoto M. Observations on the lungs of vanadium
excreted in the urine24 and in workers with long-term workers. British Journal of Industrial Medicine. 1980;
exposure most vanadium is excreted within 24 hours.23 37: 363–6.
Ingested vanadium is largely excreted unabsorbed in the 11. Woodin MA, Liu Y, Neuberg D et al. Acute respiratory symptoms
faeces.4 Blood and serum values of around 1 nmol/L and in workers exposed to vanadium-rich fuel-oil ash. American
urinary vanadium values of 10 nmol/L have been proposed Journal of Industrial Medicine. 2000; 37: 353–63.
248 Vanadium
12. Irsigler GB, Visser PJ, Spangenberg PAL. Asthma and 19. United States Department of Labor Occupational Safety
chemical bronchitis in vanadium plant workers. American and Health Administration. Chemical sampling
Journal of Industrial Medicine. 1999; 35: 366–74. information: Vanadium, respirable dust (as V2O5). Last
13. Vandenplas O, Binard-van Cangh F, Gregoire J et al. Fever and accessed October 19, 2009. Available from: www.osha.gov/
neutrophilic alveolitis caused by a vanadium based catalyst. dts/chemicalsampling/data/CH_275100.html.
Occupational and Environmental Medicine. 2002; 59: 785–7. 20. American Conference of Governmental Industrial Hygienists.
14. Missenard C, Hansen G, Kutter D, Kramer A. Vanadium 2009 TLVs and BEIs based on the documentation of the
induced impairment of haem synthesis. British Journal of threshold limit values for chemical substances and physical
Industrial Medicine. 1989; 46: 744–7. agents and biological exposure indices. Cincinnati, OH:
15. Barth A, Schaffer AW, Komaris C et al. Neurobehavioural ACGIH, 2009: ISBN: 978-1-882417-95-7.
effects of vanadium. Journal of Toxicology and 21. Health and Safety Executive. Workplace exposure limits.
Environmental Health. Part A. 2002; 65: 677–83. EH 40/2005. Last accessed August 24, 2009. Available from:
16. International Agency for Research on Cancer. Vanadium www.hse.gov.uk/coshh/table1.pdf.
pentoxide. IARC Monographs on the Evaluation of 22. Deutsche Forschungsgemeinschaft (DFG). List of MAK and
Carcinogenic Risks to Humans, vol. 86. Lyon: World Health BAT values 2009: Maximum concentrations and biological
Organization, International Agency for Research on Cancer, tolerance values at the workplace, Report 45. Weinheim:
2006: 227–92. Last accessed September 20, 2009. Available Wiley-VCH, 2009: ISBN 978-3-527-32596-2.
from: www.monographs.iarc.fr/ENG/Monographs/vol86/ 23. Kiviluoto M, Pyy L, Pakarinen A. Serum and urinary vanadium
mono86-10.pdf. of workers processing vanadium pentoxide. International
17. Duffus JH. Carcinogenicity classification of vanadium Archives of Occupational and Environmental Health. 1981;
pentoxide and inorganic vanadium compounds. The NTP 48: 251–6.
study of carcinogenicity of inhaled vanadium pentoxide, 24. White MA, Reeves GD, Moore S et al. Sensitive
and vanadium chemistry. Regulatory Toxicology and determination of urinary vanadium as a measure of
Pharmacology. 2007; 47: 110–4. occupational exposure during cleaning of oil fired boilers.
18. Ehrlich VA, Nersesyan AK, Hoelzl C et al. Inhalative exposure Annals of Occupational Hygiene. 1987; 31: 339–43.
to vanadium pentoxide causes DNA damage in workers: 25. Sabbioni E, Kuèera J, Pietra R, Vesterberg O. A critical review on
Results of a multiple end point study. Environmental Health normal concentrations of vanadium in human blood, serum
Perspectives. 2008; 116: 1689–93. and urine. Science of the Total Environment. 1996; 188: 49–58.
38
Zinc
PETER AGGETT
PROPERTIES AND USES nitrogen and sulphur donors. These characteristics enable
it to have catalytic, structural and regulatory roles in
Zinc is the twenty-fifth most abundant element in the enzymes, and structural and regulatory roles in other
Earth’s crust and is the fourth most widely used metal. proteins, histones, nucleic acids (zinc finger proteins) and
Zinc is more reactive with oxygen than either iron or receptor binding. The metal is involved in over 200
steel, and it is therefore used to coat (galvanize) these to enzymes representing all classes of activity and involving
protect them from oxidation and corrosion. Half of every metabolic pathway and function in the body, includ-
zinc’s production is used for galvanizing. It is also used ing for example protein digestion and synthesis, vision,
in alloys, such as: brass; wrought zinc (zinc, copper and carbohydrate metabolism, bone health, free radical protec-
titanium) for example in roofing; ‘nickel silver’ type- tion, cell turnover and new tissue synthesis.
writer metal and other die casting alloys with copper, Zinc is absorbed predominantly in the proximal, but
aluminium and magnesium; catalysts, batteries and, with also throughout the small intestine. There are specific
a copper coating, in coins. Other uses include pigments, carrier-mediated pathways and also diffusional routes
medicines, ointments and topical lotions such as calamine, for its uptake and transfer. It is distributed in the
eye drops (zinc sulphate), cosmetics, deodorants contain- circulation to the liver, and systemically from the liver
ing zinc chloride and anti-dandruff shampoos with zinc bound to albumin, transferrin and alpha-2-macroglobulin.
pyrithione. Organic zinc is used as a fungicide and zinc Zinc is in pancreatic and biliary, and other intestinal
phosphide, which releases phosphine, as a rodenticide. secretions. This contributes to an enteropancreatic
It is also found as feed additives and in over-the-counter circulation of zinc, within which the intestinal reabsorp-
mineral supplements.1,2 tion of the secreted zinc is an important regulator of
Zinc occurs naturally in soils and in most rocks as the systemic zinc accumulation and an important compo-
sulphide (ZnS) in blende and sphalerite, which accounts nent of zinc homeostasis. Thus the principal route of
for 95 per cent of that used commercially. Other sources zinc loss is in the faeces, which also contain unabsorbed
include calamine, zinc spar, wilemite and zincite (zinc dietary zinc.1,3
oxide). Many of these ores also contain copper, lead, iron No specific systemic zinc store has been identified. It
and silicate. accumulates in the liver where it induces and binds to a low
molecular weight cysteine-rich protein, metallothionein.
At high exposures or when the system has no need for zinc,
ESSENTIALITY AND METABOLISM its systemic accumulation is further regulated by down-
regulation of the mucosal zinc transporters to reduce
Zinc is an essential trace element. It has a single oxidation uptake and the induction of enterocytic metallothionein
state and therefore does not transfer electrons, but it read- which blocks transfer of the element and traps it in the
ily acts as a Lewis acid, and forms complexes with oxygen, mucosa.3
250 Zinc
Gases
39 Gases 253
Peter J Baxter
40 Reactive airways dysfunction syndrome and irritant-induced asthma 310
Jon G Ayres
41 Deliberate use of chemicals in warfare and by terrorists 314
Robert L Maynard
This page intentionally left blank
39
Gases
PETER J BAXTER
INTRODUCTION (45 per cent), with chlorine and oxides of nitrogen the most
commonly reported gases.1 Irritant gases (unspecified, 42 per
Inhalation accidents have been a threat to workers since cent) again dominated reporting in 1992–2001.2
early times from encounters with gases in fires, mines and Flammable and toxic gases stored in large quantities
fermentation processes. Volcanic and geothermal gases under pressure are an important cause of disaster. In 1974,
formed the earliest atmosphere of the Earth. Scientists laid an explosion at a chemical plant in Flixborough, England,
the foundations of the chemical industry with the isolation caused by a leak of cyclohexane vapour, had an explosive
and identification of individual gases. One of the foremost force equivalent to 32 tonnes of TNT, destroying the plant
of these, Joseph Priestley (1733–1804), while working as a and killing 28 workers on site, with extensive damage
schoolmaster in England, is credited with the discovery of to houses and shops as far as 10 km away. This event
‘alkaline air’ (ammonia), vitriolic acid air (sulphur dioxide), profoundly influenced the approach to regulating major
nitrous oxide, nitrogen dioxide and methane, as well as hazards (see under Exposure to gases in major industrial
isolating what he called ‘dephlogisticated air’ in 1774. incidents, p. 256). In 1984, over 500 people died in Mexico
Lavoisier, after meeting Priestley, gave the latter the name City when a liquid petroleum gas plant exploded. Even
oxygen and demonstrated its role in respiration and com- greater hazards are posed by the release of a cloud of toxic
bustion, though the disputed claim for priority for its irritant gas, which may cause death or pulmonary injury
discovery is one of the most famous episodes in the history in populations for many kilometres downwind, as highly
of chemistry. toxic irritant gases can be extremely dangerous in even very
Early experience with gases in manufacturing industries dilute concentrations. The disaster at Bhopal, India, in
inevitably included avoidable deaths among workers from 1984, involving the release of methyl isocyanate was the
leaks or as a result of faulty working practices; today, how- world’s worst industrial incident of this kind, resulting in
ever, deaths from occupational exposure to gases are rare in over 10 000 deaths either immediately or subsequently
high economy countries, even though inhalation incidents from their lung injuries, while hundreds of thousands
are not uncommon. In the United Kingdom during the have been reported to be suffering from disabling
period 1990–3, a total of 1180 inhalation incidents was chronic respiratory symptoms. These incidents have led
reported to SWORD, a national scheme for the surveillance to a concerted and successful worldwide effort by national
of work-related and occupational respiratory diseases involv- and international agencies to reduce the hazard of acci-
ing occupational and chest physicians. Gases and combus- dental toxic releases during chemical manufacture, storage
tion products comprised by far the largest group of agents and transport.3
254 Gases
Chemical and other industrial installations may also The concentrations of gases and vapours in the air can
become military or terrorist targets. The first recorded be expressed in three main ways:
mass civilian casualty incident due to a toxic release in
warfare was during the London Blitz, when 47 people were 1. As the ratio of the volume of the gas to the volume
overcome by ammonia gas. They were sheltering in a bre- of air in which the gas is contained usually expressed
wery cellar which received a direct hit in a heavy air raid in parts per million (ppm) or parts per billion
and a fragment of flying metal pierced a pipe of an ammonia (ppb);
condenser.4 The use of gases as military weapons has a long 2. As the mass of gas in a specified volume of air usually
history, but in modern combat dates from the First World expressed as mg or g per cubic meter (mg/m3 or
War (see Chapter 41, Deliberate use of chemicals in warfare g/m3);
and by terrorists). 3. In physiological terms as the partial pressure of a gas,
In recent years, renewed attention has been given to air such as in the oxyhaemoglobin dissociation curve.
pollution and respiratory health with the recognition of the
effects that exhaust emissions from the growing number of The mass concentration as expressed above will be
motor vehicles are having on air quality. Carbon dioxide, dependent on the ambient temperature and pressure. The
carbon monoxide, sulphur dioxide and nitrogen oxides are volume mixing ratio is independent of the ambient tem-
produced in the combustion of fossil fuels, whether as coal perature and pressure, if ideal gas behaviour is assumed.
or petroleum products, and so are common pollutants of The two systems of units are interchangeable using a
the outdoor and indoor air. The worst episodes of air pol- conversion formula:
lution occurred during the era when coal burning was the
prime source of energy. The most dramatic of these was the molecular volume
London smog of December 1952 when there were an esti- Concentration in ppm
molecular weight
mated 4000 excess deaths over a five-day period provoked
by a dense blanket of pollutants which included smoke and concentration (as mg/m3 or g/L)
sulphur dioxide. This episode was a defining moment in where molecular volume 22.41 T / 273 1013/P L
Clean Air legislation in the UK, eventually followed by (T is the ambient temperature (K) and P is the atmospheric
many other countries in the world. pressure (in millibars)..)
especially susceptible to a particular irritant gas, for Gases with a drug-like action
example, because they suffer from asthma. All the expo-
sure limits cited for individual gases in this chapter are This group includes anaesthetic gases, hydrocarbons and
taken from published Health and Safety Commission solvents. They can have systemic effects after they have
Workplace Exposure Limits, unless indicated otherwise. been absorbed through the lungs into the blood.
Thus, in this chapter, gases have been classified as follows:
Irritant gases
CHARACTERISTICS OF HAZARDOUS GASES
As a rule, the irritant gases are substances which chemically
The general characteristics of gases which most relate to
are regarded as corrosive. They injure surface tissues and
their health hazard are their density, water solubility and
induce inflammation of the air passages and the parenchy-
flammability. The air has a relative molecular mass of
mal region. Primary irritants are those which have little or
about 29 and the relative density of a gas compared with
no systemic toxic effect in the concentrations that cause
air is important in determining its tendency to disperse
death. Secondary irritants produce systemic toxic effects in
or accumulate at normal temperature and atmospheric
addition to the surface tissue irritation.
pressure. When released from an industrial point source,
Workers may sometimes be exposed to a mixture of irri-
denser than air gases, such as carbon dioxide or chlorine,
tant gases, for example in welding. In these circumstances,
can displace the air and flow under gravity or be blown
there is little information on how different gases interact,
by the wind along the ground, adding to their danger to
but additive or synergistic effects should be allowed for
workers and the population in the vicinity.
when comparing the concentrations of gases in the air to
Flammable gases also have lower and upper flammable
their work exposure limits. Thus, if the effects of the differ-
(explosive) limits within which the resultant mixture with
ent gases are believed to be additive, the mixed exposure
air may ignite. When ignited in a confined space an explo-
should be assessed using the formula:
sion may result, but in an unconfined space, such as the
open air, the consequence may be a flash fire. Most flam-
C1 / L1 C2 / L2 C3 / L3 mable gas clouds cease to be dangerous when diluted to
about 2 per cent by volume. Alarm levels for flammable
where C1, C2, etc., are the concentration of contaminants gases are set at 20 per cent of the lower explosive/flamma-
in the air and L1, L2, etc., are the corresponding exposure ble level so as to avoid the risk. Liquefied petroleum gases
limits. The sum of the C/L fractions should not exceed are stored or transported by road, rail and sea in large
unity. amounts and are major fire and explosion hazards. The
flammability limits of flammable gases are usually much
higher than the toxic levels, except for gases which sponta-
Asphyxiant gases neously ignite on contact with air (pyrophoric gases), such
as silane. Other exceptions are the flammable, simple
This group of gases interferes with the supply and utiliza- asphyxiant gases such as hydrogen and methane whose
tion of oxygen in the body. Simple asphyxiants, for lower flammable limits are exceeded before they can cause
example methane and hydrogen, exclude oxygen from the asphyxia by displacing air.
lungs. Chemical asphyxiants cause death by preventing The localization of the effects of irritant gases in the res-
the transportation of oxygen by the blood (e.g. carbon piratory tract depends upon the water solubility and con-
monoxide) or inhibit cellular respiration (e.g. hydrogen centration of the gas. At low-to-moderate concentrations
cyanide). Many simple asphyxiants are odourless and are of highly soluble gases, such as ammonia, hydrogen chlo-
not readily detectable. They are not given occupational ride, hydrogen fluoride and hydrogen bromide, injury
exposure standards and the best means of ensuring safety is greatest from the nasopharynx to the bronchi. Nose
is by monitoring the oxygen content of the air. Under breathing of these gases may confine injury to the nasal
normal atmospheric pressures, the oxygen content of the passages. For less water-soluble gases, for example, nitro-
air should not be allowed to fall below a minimum of gen dioxide, the main localization is from the proximal to
18 per cent by volume. the distal acinus. At high concentrations of soluble gases,
256 Gases
or if the gases are dissolved in fine aerosols, damage may formed by chemical changes to the primary pollutants.
extend throughout the respiratory tract. Solubility will also Thus, nitrogen dioxide is produced by rapid atmospheric
determine whether the gas will be rapidly taken up by sus- oxidation of nitric oxide emitted by motor vehicles, and
pended droplets in the workplace atmosphere, for example subsequently may undergo photochemical oxidation to
hydrogen chloride and hydrogen fluoride will readily com- form ozone. Important combustion sources of gases in the
bine with water to form hydrochloric and hydrofluoric home are gas cookers, which produce much higher con-
acids, respectively. Acid gases rarely exist in a purely centrations of nitrogen dioxide inside houses compared
gaseous state, but in a form that is partitioned between the with the ambient air, and faulty gas or paraffin heaters
gas and aqueous phases. Inhalation kinetics are dealt with emitting carbon monoxide. Ambient air quality standards
further in Chapter 10, Occupational toxicology: general for pollutants set on health criteria alone are almost invari-
principles. ably lower than occupational exposure standards, includ-
Hydrogen chloride and sulphur dioxide, being soluble ing for gases. No standards have yet been established for
in water, readily form acid aerosols. Occupations, such indoor air.
as battery-making and galvanizing, used to be associated A different concept again is the exposure to gases as
with dental erosion in people working above acid baths,6 pollutants of indoor air in offices and homes. No limits or
but the condition is now seen more commonly in low guideline values have as yet been set for indoor air and in
economy countries where exposures to aerosols are less such cases where workers are being inadvertently exposed
controlled. to gases in indoor or outdoor ambient air, then separate
air quality criteria should be applied, not occupational
exposure limits, which are inappropriate for this type of
OCCUPATIONAL EXPOSURE TO GASES exposure.8 Carbon dioxide levels are sometimes used in
IN INDUSTRY office buildings as a surrogate measure of the rate of air
exchange.
In practice, zero exposure to chemical agents at work is an
unattainable goal in industry and instead exposure limits
are set to protect the worker. Under UK legislation the EXPOSURE TO GASES IN MAJOR
Health and Safety Executive defines a work exposure limit INDUSTRIAL INCIDENTS
as the concentration that is not likely to be injurious, aver-
aged over a reference period. These limits for many gases Major chemical disasters can be caused by large vapour
are long-term time-weighted average (TWA) (eight hours) or flammable gas explosions, fires and toxic releases. The
and short-term exposure limit (STEL) (15 minutes) for accidental release of gases and chemicals during their
peak exposures.7 STELs are typically used to protect distribution by pipeline, water, rail or road can also have
against effects which may occur rapidly, such as irritation severe consequences.9 The gases that most often feature
of the eyes or nose/throat. A worker’s sense of smell is not in toxic releases from plants are chlorine, ammonia,
a reliable guide to the presence of a gas, let alone a safe sulphuric acid, hydrogen chloride, phosgene, hydrogen
level. Apart from individual variability some gases, for sulphide and nitrous fumes.
example hydrogen sulphide and hydrogen cyanide, actu- In modern industry, with control measures in place, the
ally induce olfactory fatigue at higher and more dangerous plant operative, engineer or technician is only likely to
concentrations. Nevertheless, information on olfactory receive heavy exposure to an industrial gas through a fail-
levels may be useful for a clinician when taking a patient’s ure in the plant or other inadvertent event. Occupational
history. Objective measures of exposure require the use of exposure limits are set for workers who receive repeated
chemical sensors or infrared detectors, colorimetric detec- daily exposures to hazardous substances on the basis of
tion tubes and other specialized measuring devices. eight-hour work days over a working lifetime and are set
to protect as far as is reasonably practicable against acute
and chronic effects. They are obviously not set to protect
EXPOSURE TO GASES IN THE OUTDOOR against risks of unconsciousness, incapacitation or intoler-
AND INDOOR AIR able irritation which would greatly reduce the chances of
escape in an emergency arising from a chemical release or
The main sources of outdoor air pollution in high econ- a fire.
omy countries are motor vehicle emissions. Primary pollu- Information on the effects in humans of a single expo-
tants are those released directly into the air, and include sure to substantially higher levels of toxic gases and vapours
carbon monoxide and nitric oxide, as well as benzene and under these life-threatening circumstances is sparse and
particulate material. Diesel engines burn an excess of air consists mainly of case reports almost invariably without
and so produce little carbon monoxide, but they do give the recording of the level or duration of the acute exposure.
out more nitrogen dioxide and fine particles. The main Yet it is following just such inadvertent incidents that
single sources of sulphur dioxide in the UK are coal-fuelled the physician will be consulted for advice, as the conse-
electric power stations. Secondary pollutants are those quences may be life-threatening or lead to concerns about
Exposure to gases in major industrial incidents 257
long-term respiratory or systemic health effects. Toxicity exposure conditions (Table 39.1). These irritant gases have
data relating to routes of exposure other than inhalation, a similar toxic mechanism acting on the respiratory tract
such as contact with the skin in some gases, should be and lungs.
treated with caution unless it is known that the toxicoki- Unplanned releases of gases may lead to exposure
netics and sites of action for the different routes are com- off-site in a sudden large release from a tank failure or a
parable. Knowledge of the long-term effects of single pressurized leak of long enough duration. For emergency
exposures, such as carcinogenicity, teratogenicity and other planning for such an eventuality and for land use planning
target organ damage, is very inadequate. Extrapolation around a major hazard site (all part of a ‘safety case’ which
from single exposure studies in animals to humans is also has to be prepared before a plant under the Control of
fraught with problems, such as species difference. Industrial Major Accident Hazards (CIMAH) Regulations
The ultimate harm caused by an acute high exposure to is allowed to operate) can be derived by using animal data
a toxic gas will depend primarily upon the concentration (e.g. LC50 data over a known duration) to estimate the spec-
of gas and the period of exposure.10 Experimental studies ified level of toxicity for land use planning purposes, which
suggest the following general relationship may hold for the Health and Safety Executive calls the LUP SLOT and
acute lethality for many gases and vapours: defines as the concentration at which there is:
toxic load concentrationn time ● severe distress to almost everyone on the area;
● substantial fraction of the exposed population requires
where n is any number other than zero. Thus the toxicity of medical attention;
an inhaled irritant gas is not necessarily the product of the ● some people are seriously injured requiring prolonged
concentration in the inhaled air and duration of exposure, treatment;
which is known as Haber’s rule, a simple relationship that ● highly susceptible people are possibly killed.
applies to some gases and vapours. For hydrogen chloride
n 1, sulphur dioxide n 2, and hydrogen sulphide A similar procedure can be used to derive a toxic load
n 4. For chlorine, n 2, and so for incidents involving equation to predict exposure conditions for any other
exposure to chlorine lasting between 5 and 20 minutes, it is specified level of toxicity, such as the mortality of
the concentration which is more important than the dura- 50 per cent of an exposed population: this is known as
tion in determining the effects on health.10 In practice, the Specified Level of Death Dangerous Toxic Load (SLOD
most releases will last a short time until emergency meas- DTL).11 For land use planning, allowance needs to be made
ures at the plant bring the release under control, but the for the proportion of the population indoors, as this will
risk of death and risk of dangerous dose for chlorine, provide a level of protection compared to being outdoors.
ammonia (n 2), hydrogen fluoride (n 1) and sulphur Any assessment of the toxic impact of a release into the
dioxide, can be calculated for different time periods and general population must take into account the presence
Table 39.1 Health effects levels for the most common irritant gases
Occupational ‘n’ value SLOT DTL SLOD DTL ERPG-1 ERPG-2 ERPG-3
exposure (ppmn.min) (ppmn.min) (ppm) (ppm) (ppm)
limit (ppm)
15 min 8h
SLOD DTL, Dangerous toxic load for significant likelihood of death (mortality of 50% population); SLOT DTL, Dangerous toxic load for specified level of
toxicity (land use planning value).
ERPG levels: Exposure up to 1 hour without causing in most people:
ERPG-1, More than mild transient and irreversible effects.
ERPG-2, Irreversible effects or effects that may affect the ability to take preventive action.
ERPG-3, Life-threatening effects.
258 Gases
of the young, old, pregnant and individuals with pre- in the United States, one of the few countries with compre-
existing illness, particularly those who may be already hensive reporting, chlorine remains the most common
suffering from acute or chronic respiratory conditions at substance involved in hazardous chemical releases result-
the time of the release. Little information is available about ing in personal injury.
the susceptibility of these vulnerable groups, and the toxic- Computer models of the dispersion of chlorine and
ity data used for these planning criteria contain significant other dense gases can be applied to determine risk
uncertainty. contours, so that the impact of a gas release on a nearby
The American Industrial Hygiene Association’s Emergency populated area can be predicted for different likely wind
Response Planning Guidelines (ERPGs) are another attempt and weather conditions (Figure 39.1). The outer contour
at setting community exposure limits for use in community defines the consultation distance around major hazard
emergency response planning for anticipating the adverse sites, outside of which the risk to the population is not
health impacts from chemical release emergencies; they deemed as significant. The probability and size of prevent-
are planning tools, as there is usually no time for making able releases can be estimated to determine the serious but
exposure measurements and acting upon these in an actual reasonably foreseeable event, such as a fracture of a liquid
release.12 One use of such data, for example, would be to gas pipe or failure of a road tanker delivery coupling to a
model the health consequences in a population living near a storage tank (Figure 39.2). Plotting the concentration
plant who would be told in an emergency to shelter inside contours for a predicted plume on to maps of the area
their houses in the event of an unplanned gas release. The around a plant is a useful planning guide for police, fire
ERPGs are maximum airborne concentrations below which brigade and ambulance services, as COMAH requires on-
nearly all individuals could be exposed up to one hour site and off-site response plans to be prepared by emer-
without experiencing or developing: gency services as part of the consent process. Engineers
can provide well-established failure rates for tanks, pipes
ERPG 1. More than mild, transient adverse health effects and process functions, including human factors, which
or without perceiving a clearly defined objectionable are used to quantify risks using gas dispersion modelling.
odour; In the UK, the Buncefield explosion and fire in 2005, not
ERPG 2. Irreversible or other serious health effects or long after the fatal Texas City refinery explosion in the
symptoms that could impair an individual’s ability to same year, led to an important re-evaluation of the opera-
take preventive action; tion of COMAH and the interested reader is referred to
ERPG 3. Life-threatening health effects. the Major Incident Investigation Board Report for further
information.16
Experience in making evacuation decisions in actual
chemical emergencies is still very limited.13
In accordance with the EC Seveso Directive 1982 (revised EXPOSURE TO GASES IN FIRES
as Seveso II in 1996), the UK introduced the Control of
Industrial Major Accident Hazards (CIMAH) Regulations The main threats to life in fires are toxic gases, heat and
1984 which included a requirement for emergency plan- oxygen deficiency.17 The temperature in a room in a
ning to be undertaken for on-site and off-site air releases at house fire can easily reach 500–1000°C, and as many as
plants storing or using dangerous substances in larger than 400 toxic compounds can be demonstrated in the smoke.
the threshold quantities laid down in the regulations; these The principal toxic constituents of smoke are soot,
chemicals include commonly used toxic or flammable carbon monoxide, carbon dioxide, nitrogen oxides,
gases.14 The CIMAH regulations were superseded by the hydrogen cyanide, hydrogen chloride, sulphur dioxide,
Control of Major Accident Hazards (COMAH) regulations hydrogen fluoride, hydrogen sulphide, isocyanates,
in 1999, which treat risks to the environment as seriously acrolein, benzene, phenol, formaldehyde and a range of
as those to people. Chlorine is the most widely used gas for chlorinated hydrocarbons. Carbon monoxide is an
which emergency planning and land use planning to miti- important factor in 50–80 per cent of all fire fatalities.
gate the effects of a major incident on the local population The role of hydrogen cyanide is less clear, although it is
is undertaken; it is an example of a denser than air, highly formed in many fires especially those involving wool,
corrosive gas that can cause injury to the respiratory tract silk, nylon and polyurethane products.17,18
ranging from irritation to incapacity or death from bron- The chemistry involved in combustion reactions is
chospasm, laryngeal oedema or toxic pulmonary oedema.15 extremely complex, even in the simplest example, such as
Fortunately, no large-scale releases of chlorine gas have the burning of a jet of natural gas or methane in oxygen or
occurred in recent times, the last being in Romania in 1936 air, when numerous reactive species, including free radicals
when 40 people were killed. While engineering measures (such as OH, O and CH3) are produced which eventually
directed towards successful containment of stored gases, form mainly carbon dioxide, water and large particles of
such as chlorine, are clearly proving to be successful, small- carbon (soot).
scale releases of gases and other chemicals do inevitably
occur from fixed sites or during their transportation. Thus, CH4 2O 2 CO2 2H2O
Exposure to gases in fires 259
Inner zone:
Risk greater than 3 in 10 million
COMAH site chances per year of receiving
a dangerous dose or worse (DD)
Middle zone:
> 1 in 1 million
chance per year
of a DD
Inner zone:
> 1 in 10 000
chance per year
of a DD
Consultation distance
(a)
Smoke comprises a mixture of gases, liquid and solid par- been reported in a Gulf War veteran and a Kuwaiti child
ticles which arise as combustion and pyrolysis products. exposed to the fumes.21 Fortunately, the fires were extin-
Predicting the products of combustion (oxidative degener- guished by November 1991, and since then the debate on
ation) and pyrolysis (thermal decomposition) of burning whether there were any chronic ill effects from this incident
materials and hence determining in retrospect the effects has not been resolved. In contrast, the massive unplanned
of exposure of firemen or other victims to the constituents explosion and fire at a large fuel storage site in Buncefield,
of a smoke plume is not straightforward. Some general England, which supplied London Heathrow airport, in 2005
principles can be considered.18 Materials consumed by set off a blaze and a huge plume of smoke on 11 December
fires contain carbon, hydrogen and oxygen as their main that traversed southern England and was blown across the
elements, and hence the bulk of all combustion products English Channel to France until it was extinguished on
will consist of compounds formed from these, for example 14 December. Analysis of the plume using a special aircraft
carbon monoxide and carbon dioxide. The next important showed that it mainly comprised harmless soot particles
elements are halogens (mostly chlorine) and nitrogen, with as the burning was very complete; fortunately the weather
smaller amounts of elements such as sulphur and phos- allowed the buoyant plume to remain aloft and no signifi-
phorus. Almost all the inorganic anions are released as the cant particulate air pollution occurred at ground level.16
irritant acid gases, hydrogen chloride and hydrogen fluo- There were 660 firefighters deployed during the burn
ride, if fluorine is present. For the nitrogen present the phase, about three-quarters of whom reported inhaling
products depend upon the availability of oxygen: in well- smoke, but no major acute health symptoms were identi-
ventilated fires oxides of nitrogen are released, but in large fied in a comprehensive occupational health surveillance
fires in buildings, where the ventilation is poorer, a larger programme.
proportion of the nitrogen is released as hydrogen cyanide. Even if not directly fatal themselves, carbon monoxide
Organic compounds may form a number of partially and hydrogen cyanide singly or in combination may lead
decomposed products, for example formaldehyde, acrolein, to the rapid incapacitation of the individual who is then
crotonaldehyde and possibly free radicals that add to the unable to escape.18 The other toxic gases can cause acute
irritancy of the smoke. Other compounds, such as decom- airways and lung injury or may obscure vision through
position products from isocyanates, styrene and phenol, causing eye irritation. An elevated carbon dioxide level
may also be important.18 Fires in warehouses storing chem- will induce hyperventilation and hyperpnoea, and increase
icals will potentially release a cocktail of irritants and toxic exposure to the combustion gases. In most fires, these toxic
substances which may greatly add to the hazard of the fire factors are usually more important to survival than heat.
plume. However, intense fires can lead to severe burning from
Polyvinyl chloride (PVC) is the most widely used plastic hot convected air or thermal radiation and in some fires
and fires involving large amounts of this material at storage direct burning from the heat of the flame can be the cause
sites and recycling installations are not uncommon and of death. Thermal injury to the airways and lungs is not
attract notoriety because they are difficult for the fire serv- as common as toxic damage, since the upper respiratory
ices to put out while they generate toxic plumes.19 At over tract rapidly conducts heat away from the inspired air.
300°C, PVC decomposes to form hydrogen chloride and Nevertheless air containing hot, respirable particles or
carbon monoxide together with small amounts of about 50 steam can cause injury as deep as the bronchioles. Less
various hydrocarbons. About 50 per cent of the polymer’s important is oxygen depletion except in major conflagra-
weight comes off as hydrogen chloride, and the irritancy of tions or in intense building fires.
the plume is added to by the presence of acrolein, ammo-
nia, sulphur dioxide, nitrogen dioxide, aldehydes and par-
ticles. Phosgene is produced only in rare circumstances. Firefighters
There is now no doubt that dioxins are formed whenever
chlorinated plastics are burned: in a large-scale plastics fire In the past, many firefighters did not always use respiratory
typically involving 500–1000 tonnes of PVC as much as protection equipment, but nowadays as the equipment
1–2 kg of dioxins could be produced.19 and training have improved, breathing apparatus and
In February 1991, during the Gulf War, about 600 chemical suits are routinely donned at fires emitting toxic
naturally pressurized oil wells were set alight in Kuwait.20 smoke (Figure 39.3). As a result, firefighters are now much
Close to the fires the smoke rained oil drops which coated less likely to be exposed to the injurious effects of smoke
large areas of desert. The plume contained carbon dioxide, than in the past. However, accidental inhalation exposure
carbon monoxide, sulphur dioxide and particles, including may occur if the firefighters make a faulty judgement on
soot. The major health concern revolved around the particle their assessment of the fire conditions, or if the smoke
fallout that contained elemental carbon, rock/soil particles, plume unexpectedly blows towards unprotected firefight-
metal oxides, silicates, vanadium, nickel and polycyclic ers, or if an immediate rescue of a victim has to be made.
aromatic hydrocarbons. Exposure studies and air monitor- Skin contamination by noxious combustion products may
ing started too late to ascertain the health risk to ground also occur when the protective clothing is removed unless
troops or the general population. Aplastic anaemia has decontamination procedures are adequate.
Exposure to gases in fires 261
nuclear power facilities and may be released into the acidity, associated with a range of properties, such as
atmosphere in an incident and threaten local populations. aqueous and lipid solubility, and other tissue components
In 1985, a uranium processing plant in Gore, Oklahoma, that may compete with receptor stimulation. Other patho-
released a cloud of hydrogen fluoride. A plume from a physiological mechanisms will relate to the special proper-
nuclear reactor incident may contain radioactive inert ties of individual gases, such as free radical formation with
gases which are fission products of uranium. At Three Mile chlorine. The stimulation of nerve receptors in the airways
Island in 1979, very slight amounts of krypton-85 and triggers subjective sensations such as cough, chest tightness
xenon-133, together with iodine-131, were emitted follow- and breathlessness and also reflex responses that can
ing core damage to this commercial reactor. In the fire in provoke bronchoconstriction, increased mucous secretion
the graphite reactor at Chernobyl in 1986, which lasted for and vascular engorgement, all of which may contribute to
several days, several million curies of these gases, together symptoms. These effects can be very rapid following even a
with radioactive iodine-131 and -133, caesium, strontium single, brief exposure.
and plutonium, were released in radioactive clouds that Irritant gases in high concentrations may kill the victim
blew across Europe, making this event the worst nuclear outright after a few deep breaths and before pulmonary
accident in the world.29 During the following eight days, oedema has had time to develop, an effect probably
the iodine-131 was absorbed by the thyroid glands of people due to oxygen having been displaced from the air: there
living nearby. More than 350 000 people were relocated. may be no sign of a death struggle. Exposure of the eyes
Since 1990, a marked rise in cases of thyroid cancer in chil- or skin to corrosive gases should be treated by thorough
dren has occurred in the Belarus region around Chernobyl, irrigation or washing with water or sterile physiological
a condition which fortunately has a good survival rate with (0.9 per cent) saline, and all contaminated clothing must
early treatment.30 be removed.
Victims of gassing accidents should be initially consid-
ered to be hypoxic. Central cyanosis (a blue colouration of
PRINCIPLES OF FIRST AID AND TREATMENT the tongue and mucous membranes) is a variable clinical
IN GASSING INCIDENTS finding and when present is a sign of central hypoxia,
although hypoxia may occur in the absence of cyanosis.
Regardless of the kind of gas involved, the victim should Methaemoglobinaemia is another cause of cyanosis and
be moved immediately to fresh air and given life support. hypoxia. In poisoning by carbon monoxide and hydrogen
If breathing has stopped or cardiac arrest has supervened cyanide, the skin retains its pink colour even in the presence
then cardiopulmonary resuscitation should be begun. If of tissue hypoxia.
hydrogen cyanide poisoning is suspected, then a manual Even in the absence of clinically obvious signs of hypoxia
resuscitator should be used to maintain respiration so that or respiratory distress, the patient can nevertheless be
mouth-to-mouth resuscitation is avoided. severely hypoxic and may collapse on slight exertion. This
Simple asphyxiant gases or lack of oxygen will cause loss was first emphasized in First World War casualties in the
of consciousness without irritation of the eyes or mucous management of phosgene gassing on the battlefield, and
membranes of the respiratory tract, but complications may which was attributed to the increased efflux of pulmonary
include patchy consolidation of the lungs. Unless the hypoxia oedema fluid during exertion.31 In hospital, arterial blood
is severe, the victim will recover consciousness in fresh air. gases should be tested at the earliest opportunity to assess
If the patient is breathing and if oxygen is available, 100 per the degree of hypoxaemia (PaO2), partial pressure of carbon
cent oxygen should be given by oronasal mask until more dioxide (PaCO2), and acid-base state. Hypoxaemia is
specific treatment can be instituted. The treatment of over- treated with oxygen therapy, but in advanced respiratory
exposure to anaesthetically active gases is similar. Oxygen failure the patient may require endotracheal intubation
reverses hypoxaemia and accelerates the elimination of and mechanical ventilation. Positive end-expiratory pres-
carbon monoxide and helps to support persons poisoned sure is recommended in the presence of pulmonary oedema
by cyanide or hydrogen sulphide. (acute chemical pneumonitis).32 The possibility of laryn-
Inhalation of irritant gases and smoke gives rise to simi- geal oedema causing respiratory obstruction should not be
lar effects on the respiratory tract ranging from mild irrita- forgotten, for example after ammonia exposure, but it may
tion to mucous membranes lining the airways, leading to also be present in fire victims if burns are present on the
cough and bronchospasm, to severe non-cardiogenic pul- face and around the mouth and lips, or if soot is found in
monary oedema and respiratory failure. Sensory irritant the anterior nares and larynx.
potency depends upon the interactions between the sub- High concentration oxygen treatment (100 per cent
stance and irritancy nerve receptors. Acid gases, such as the given by a tight fitting oronasal mask or intermittent
halogens and hydrogen halides, dissociate forming high positive-pressure ventilation (IPPV) and hyperbaric oxygen
concentrations of hydrogen ions that, along with the in severe cases) is essential in carbon monoxide poisoning
chemical nature of the reactive base, give rise to the tissue despite a normal PaO2, as the oxygen will compete with
response. The irritant potency is mostly accounted for by carbon monoxide for haemoglobin binding sites and reduces
Principles of first aid and treatment in gassing incidents 263
the half-life of carboxyhaemoglobin from about 320 to Convulsions caused by certain gases, e.g. methyl
80 minutes. Pulse oximetry can be misleading in carbon bromide, should be treated with anticonvulsant drugs as
monoxide poisoning as it detects carboxyhaemoglobin appropriate, although more intensive therapy may be
as oxyhaemoglobin, and thus may overestimate the actual needed if they prove resistant.
concentration of oxyhaemoglobin; erroneous readings Even mild gassing incidents can induce severe anxiety
may also arise in methaemoglobin states.33 The use of if individuals suddenly experience respiratory symptoms
hyperbaric oxygen should be urgently considered in cases such as acute tightening of the chest and difficulty breath-
of poisoning by the chemical asphyxiant gases (carbon ing, especially if they are asthma sufferers. Further alarm
monoxide, hydrogen sulphide and hydrogen cyanide). can be generated if their or other lives are perceived to be at
Most experience of this treatment has been gained with imminent risk. Health professionals called to such inci-
carbon monoxide. dents need to be aware that affected individuals may subse-
Skin burns from corrosive or acid gases and vapours quently suffer post-traumatic distress syndrome or other
should be treated as for chemical burns. Hydrofluoric acid emotional disturbances requiring psychological support.
burns may also need the administration of local and Several of the physical conditions arising from inhalation
parental calcium antidotes. Contaminated clothes, jew- of toxicants are described below.
ellery, boots, etc., should be removed, and all affected areas
should be washed or showered with water for at least ten Acute lung injury and acute respiratory
minutes. Eye irrigation may also be needed. It is widely distress syndrome
assumed that burns caused by corrosive gases and vapours
will cause damage similar to thermal burns, for example The inhalation of irritant agents may produce a common
irritation, erythema and bullae formation, but there is a reaction in the lungs of rapid onset referred to as high
dearth of hard facts on this in the literature. Certain permeability pulmonary oedema, or pulmonary oedema
agents, such as methyl bromide and vesicant warfare of non-cardiogenic origin, otherwise known as chemical
agents (e.g. mustard gas, see Chapter 41, Deliberate use of pneumonitis. Pathologically, there is diffuse alveolar dam-
chemicals in warfare and by terrorists), are recognized as age.35 Mild cases recover rapidly and most without residual
causing bullae formation, but erythematous lesions which effects, but many authorities would nowadays regard
may progress to intraepidermal or subepidermal vesicles chemical pneumonitis as belonging to the less severe end of
(bullae) with sweat gland necrosis can also occur in some a clinical spectrum of acute lung injury that extends to
cases of coma caused by carbon monoxide poisoning. The acute respiratory distress syndrome at the other. Acute
mechanism of bullae formation in human skin is not respiratory distress syndrome is diagnosed in acute lung
understood. Bullae can occur in prolonged coma from injury after inhaling a toxic fume or gas if there is acute
various causes, for example in barbiturate poisoning, and lung injury and severe refractory hypoxaemia – using the
could be caused by pressure, hypoxia or direct toxic effects PaO2 to FiO2 ratio.36
to the tissues.
Cold injury from the accidental contact of the unpro- Bronchiolitis obliterans
tected skin with the liquid, vapour or gas of very cold lique-
fied gases resembles the local effects of severe cold which This rare and life-threatening form of fixed obstructive
are described in Chapter 49, Heat and cold, together with lung disease is due to damage to the epithelium of the
their treatment. The damage to the skin can be similar to small airways and usually manifests itself pathologically as
heat burns, or to frostbite if exposure of unprotected parts a proliferation of tufts or plugs of granulation tissue in the
is prolonged or severe. lumen of bronchioles. Diffuse alveolar damage and epithe-
The hospital management of victims of poisoning by lial injury of the bronchioles may occur together after
irritant gases such as chlorine is outlined in Table 39.2. inhalation exposure to a single noxious agent leading to
It should be noted that the treatment of the high perme- inflammation or fibrosis narrowing or blocking the airway.
ability pulmonary oedema caused by irritant gases has not Bronchiolitis obliterans is a recognized complication in
been well studied. In response to damage to the capillary gassing accidents involving nitrogen dioxide, and sporadic
endothelium, water accumulates in the interstitial space cases have been reported after incidents with fire smoke,
and then in the alveoli. The value of diuretics has not been sulphur dioxide, ammonia, chlorine, hydrogen chloride,
confirmed and these should be used cautiously, if at all. phosgene, hydrogen sulphide, hydrogen selenide and
Glucocorticosteroids may not be of value. Chest infection hydrogen bromide.35
is common after severe gassing because of the denuded Diagnosis is made on the basis of the history, fixed air-
bronchial epithelium; vigorous antibiotic therapy is often way obstruction with normal diffusing capacity, and typical
required. The oedema fluid can have a higher protein con- findings on high resolution computed tomography (HRCT).
tent than in cardiogenic oedema, which may more readily The diagnosis is likely to be missed in the initial stages, and
coagulate and the residual coagulum then becomes the mistakenly identified as asthma, bronchitis, emphysema or
skeleton on which lung fibrosis develops.34 bronchiectasis.
264 Gases
Immediate decontamination on arrival at hospital Remove all contaminated clothing and thoroughly wash skin and eyes as
(ideally decontamination should occur at the necessary
scene of the incident):
Assessment of patient: Examine mucous membrane, eyes, and skin for signs of corrosive injury
Check lung sounds, peak flow and vital signs: if patient is known to have
been heavily exposed or has a cough or difficulty in breathing at rest perform
baseline chest x-ray examination
Take brief medical history, with particular attention to any history of respiratory
or cardiovascular disease
Initial treatment: Oxygen: all patients identified as being at risk (see Assessment of patient, above)
should initially receive 100% oxygen. Oxygen concentration may
subsequently be adjusted to the need of the patient
Bronchodilators: salbutamol or terbutaline, used by nebulizer, may help relieve
respiratory difficulties
Dose: Salbutamol Adults 2.5–5 mg as required
Children 2.5–5 mg as required
Terbutaline Adults 2.5–10 mg as required
Children up to 200 mg/kg
Corticosteroids have not been proved to produce improvement in chlorine
poisoning but have caused pronounced improvement after smoke inhalation.
If patient exposed less than 4 hours previously and at risk of pulmonary
injury (as defined above) steroids should be given
Dose: Methyl prednisolone Adults 2 g i.v. stat (or equivalent)
Children 400 mg i.v. stat (or equivalent)
Laryngeal oedema: give corticosteroids (dosage as above) if patient develops
laryngeal oedema. Obtain early and expert help from anaesthetist as
tracheal intubation may be needed. If tracheal intubation is not needed, then
a trial of continuous positive airway pressure by mask or hood may be
attempted. In less severely poisoned patients non-invasive ventilation may
be tried for a short period and continued if there is improvement.
Skin burns should be treated as thermal burns
Eye damage requires ophthalmic referral
Monitoring: Monitor respiratory function, particularly respiratory rate and arterial blood
gases regularly
Pulmonary oedema may occur up to 24 hours after exposure
Patients who are well 24 hours after exposure may be discharged
Pulmonary oedema: If pulmonary oedema occurs, give oxygen by face mask
If pO2 still cannot be maintained above 60 mmHg, or the respiratory rate
40 bpm, intubate the trachea and start mechanical ventilation with
positive end expiratory pressure. Intravenous fluids should be given with
great caution as fluid overload is extremely dangerous in such patients: if
this occurs diuretics such as frusemide are indicated
Reactive airways dysfunction syndrome and ethylene oxide, phosgene, welding fumes and smoke.35 The
irritant-induced asthma term was coined by Brooks in 1968 to describe a syndrome
of respiratory symptoms after gas or chemical exposure at
Irritant-induced asthma and vocal cord dysfunction (or irri- work.37 Occupational health practitioners are quite likely to
table larynx syndrome) are conditions classified as reactive have patients referred to them at some time with suspected
airways dysfunction syndrome (RADS) when they arise after reactive airways dysfunction syndrome following an inad-
exposure to a toxic gas. Gases reported to induce RADS vertent exposure to an irritant substance at work, and so a
following unplanned high exposure at work form a long list detailed account of this important condition is given in
which includes hydrogen sulphide, nitrogen dioxide, sul- Chapter 40, Reactive airways dysfunction syndrome and
phur dioxide (and sulphuric acid), ammonia, chlorine, irritant-induced asthma.
Gases in the ambient air 265
by the Kyoto Protocol, as mentioned above. HFC emis- readily ignited and cause severe burns. Oxygen and other
sions have been rising rapidly as demand for refrigerators compressed gases should only be used in well-ventilated
and air conditioning grows in countries such as China. areas.
Occupational exposure to CFCs will potentially continue
long after 2010 because of the continuing use of old air
conditioning and fire-fighting systems that contain them. Anaerobic fermentation
Methyl bromide, a fumigant pesticide, is also being
phased out under the Montreal Protocol. Natural biological processes produce toxic gases in the
absence of oxygen. In anaerobic fermentation, bacteria that
are methanogens or sulphate reducers remove hydrogen
Oxygen lack ions in the form of methane or hydrogen sulphide, respec-
tively. Excessive or abnormal colonic gas production has
Oxygen-deficient atmospheres can be encountered in mines been hypothesized to play a role in the pathogenesis of irri-
and other underground or confined spaces. The main dan- table bowel syndrome40 and inflammatory bowel disease.41
ger of suddenly entering an atmosphere devoid of oxygen About a litre of human flatus is produced a day and typi-
is that it will lead to an almost immediate loss of conscious- cally contains nitrogen (68 per cent), oxygen (less than
ness without warning; even very quiet breathing will pro- 1 per cent), carbon dioxide (9 per cent), hydrogen (16 per
duce sudden loss of consciousness within 50 seconds when cent) and methane (6 per cent), while the malodorous
all the remaining oxygen in the lungs has gone.39 gases (ammonia, skatole, hydrogen sulphide) comprise less
It is the partial pressure of oxygen, not its percentage, than 1 per cent of the total. In contrast, the rumen of ani-
which is of physiological importance, but gas measuring mal species such as the cow, sheep, goat and deer contain
instruments and alarms record volume concentrations. A mostly methanogenic bacteria.
drop of 3–4 per cent of oxygen by volume is of little physi- Fermentation of human or animal excrement releases
ological significance in humans, but it will extinguish a toxic gases which can be a threat to sewer workers or work-
candle flame. (A candle flame will continue to burn at levels ers in confined spaces on farms and in swine confinement
of atmospheric pressure well below those at which humans buildings, among others (Figure 39.4). Farm animal-house
will be asphyxiated: it will not go out until 10 per cent of air can be contaminated by ammonia, hydrogen sulphide
normal pressure.) The level of oxygen has to fall to 13 per and carbon dioxide. The mixing or pumping of slurry,
cent volume (equivalent to a 33 per cent asphyxiant gas in for example in cowsheds, can release lethal amounts of
air mixture) before symptoms become very noticeable. hydrogen sulphide into enclosed spaces.
The effects of low oxygen concentration (oxygen (per cent Anaerobic fermentation of sheep intestines and their
vol. in air)) are as follows: contents can cause hydrogen sulphide keratoconjunctivitis
in sausage makers, the same condition that Ramazzini
● 16–13 per cent: Dizziness and shortness of breath on recorded in workers who emptied ‘jakes’ (privy vaults).
exertion; pulse rate accelerated and volume of breathing ‘Sewer gas’ is methane with small amounts of hydrogen
increased. Ability to maintain attention is diminished sulphide and it also occurs in septic tanks and cesspits. JS
but it can be restored with conscious mental effort. Haldane investigated a fatal incident in a sewer in East Ham,
● 13–10 per cent: Judgement faulty. Rapid fatigue and London in 1895 and proved the deaths had been caused by
fainting on exertion. Severe injuries cause no pain. hydrogen sulphide gas; he had shown earlier using bacterio-
Emotional lability. logical experiments that sewer gas or ‘miasma’ was not a
● 10–6 per cent: Nausea and vomiting. Loss of ability to cause of typhoid.42 The smell of putrefaction had a long
perform any vigorous muscular movements or even to history of being associated with disease and being known
move at all. as ‘miasma’ or bad air, and it was a central tenet of Edwin
● 6 per cent: Loss of consciousness with fainting or coma. Chadwick and other nineteenth century sanitarians. At the
Rapidly fatal. time of his epidemiological investigations into cholera, the
celebrated pioneer of anaesthesia in England, John Snow
(1813–58), used his knowledge of gases and the properties
Oxygen excess of air to support the overthrow of this ancient belief. In
doing so, he used statistics from the registrar general to
Industrial and medical oxygen supplies can enrich atmos- show that male workers in the ‘offensive trades’, i.e. malodor-
pheres in a room to dangerous levels. At 25 per cent oxygen ous ones involving animal remains, such as rendering and
in air, even damp vegetation will continue to burn once a bone boiling, had lower mortality rates than the male
fire has started, and substances which do not normally general population.43
burn easily in air may burn vigorously. Lubricants must Gases from decaying fish can be a hazard to workers
never be used on oxygen equipment as they may react unloading catch from poorly refrigerated and unventilated
explosively with pressurized oxygen. Even in the open air, holds. Decay of organic matter generally provides hydrogen
oxygen may remain trapped in clothing which can then be sulphide, ammonia, methane and carbon dioxide; levels of
Gases in the ambient air 267
carbon monoxide in air can sometimes also be dangerously tanks. The risk of fire and explosion may be increased by
elevated in manure storage areas. Bacterial action on enrichment of the air by oxygen in the event of a leak from
nitrogenous compounds may form nitrogen dioxide, and an oxygen cylinder forming part of welding equipment.
fermentation of silage can produce high concentrations of A fatal explosion occurred in 2007 in a compartment of
this gas within two days of silo filling. Carbon dioxide and a British nuclear submarine beneath the Arctic ice when
methane concentrations, if elevated, depress oxygen levels, an oxygen generator canister exploded after becoming
or oxygen may be depleted anyway. Following gassing acci- contaminated with grease.
dents in confined spaces, it is important to measure as soon Oxygen deficiency in pits can arise from an ingress of
as possible for oxygen depletion and elevated levels of methane or absorption of oxygen by certain constituents of
carbon dioxide, as well as the full range of gases mentioned soils. The rotting of vegetation and the rusting of metalwork
above, to determine what was responsible for the incident. inside tanks also consume oxygen. Manholes, tunnels and
A condition occasionally, but not exclusively, reported trenches in limestone soils can partly fill with carbon dioxide
in hog farmers is organic dust toxic syndrome, which may formed by the action of acid groundwater. Apparently
present as an acute systemic illness characterized by fever, safe atmospheres can become suddenly dangerous if the
malaise, aches and pains in the limbs, vomiting and a dry residues and sludges in tanks or in sewers are disturbed by
cough. The onset is within a few hours of heavy exposure the worker walking in them, or by water surges following
to endotoxin-producing Gram-negative bacteria, as may sudden heavy rainfall. Underground spaces may be in
occur in swine confinement buildings. The condition, ground which is contaminated or near old refuse tips, or
which resolves completely within 72 hours, should not be they may be connected to sewers. In the construction indus-
confused with the toxic effects of gases produced by try, pipe-freezing work is carried out using liquid nitrogen
fermentation. Pig farming exposes workers to a mixture of to solidify soil to enable drilling to be performed in wet
ammonia, organic dusts and high levels of endotoxins, conditions and fatalities have occurred from the cold gas
and the types of disinfectants in regular use can contain pushing out the available air.
respiratory sensitizers.44 In order to avoid gassing accidents, safe systems of work
must be adhered to and these often require the use of elec-
tronic monitors or detector tubes to test for toxic, flamma-
Confined spaces ble and asphyxiating gases before initial entry to a confined
space and while the work continues. The space should be
Confined spaces include trenches, pits, tanks, sewers, tunnels well ventilated before entry, otherwise appropriate breath-
and also submarines and spacecraft. Working in enclosed ing apparatus has to be worn. In the UK, safe working prac-
spaces with inadequate natural ventilation is a well-known tices are followed under the Confined Spaces Regulations
cause of death from asphyxia due to oxygen deficiency or (1997).45
from a build up of toxic gases and vapours, such as carbon There is no formal medical examination laid down for
dioxide, carbon monoxide, methane, ammonia, hydrogen workers in confined spaces in the UK, but the competent
sulphide, petroleum vapour and liquid petroleum gas. Toxic person who carries out the risk assessment under the
substances can accumulate where workers are welding or Regulations45 will need to consider the physical suitability
flame-cutting. In addition, the presence of flammable gases of the individuals involved and to check that they are of
such as butane, propane and petrol, all of which are nor- suitable build. Medical advice on an individual’s suitability
mally heavier than air, can be responsible for explosions in may be needed. A history of claustrophobia, fits, blackouts
268 Gases
and fainting attacks would be reasons for exclusion, as are the risk of catastrophic explosions in mines. The flame of
chronic respiratory problems such as asthma, bronchitis the lamp is surrounded by a fine metal gauze that offers
or exertional dyspnoea, and other evidence of lack of fit- little resistance to gases, but which leads heat away from
ness to wear breathing apparatus. The presence of heart them so effectively that the flame cannot cross it. The oil
disease or severe hypertension might also be a contraindi- flame gave warning of the presence of fire damp (1–4 per
cation. Physical limitations, such as deafness, lack of a cent methane makes the flame burn taller, so the concen-
sense of smell, visual defects, and problems with balance tration of methane can be estimated from its height) and is
(e.g. Menière’s disease) should also be considered. also extinguished before the oxygen levels fall to dangerous
Prospective workers with limited mobility from back or levels. After an explosion of methane and coal dust, the
joint trouble, certain physical handicaps or psychiatric mixture of gases produced in the mine is called ‘afterdamp’:
problems may also be unsuitable. it can contain toxic levels of carbon monoxide, responsible
Routine sewer work is normally safe as long as standard for the deaths of miners and rescuers in numerous mining
measures to detect toxic and flammable gases and oxygen- disasters. JS Haldane showed that odourless carbon
deficient atmospheres are performed. However, the possi- monoxide was the main cause of death in explosions of
bility of unusually toxic substances entering sewage systems methane and coal dust and it was due to his advocacy that
must always be borne in mind. it became a legal requirement for canaries to be kept at
all coal mines to give warning of the presence of carbon
In an unusual incident in Aberdeen, Scotland, a group monoxide, which would otherwise not be detectable using
of 26 workers went down a sewer to investigate an the safety lamp alone.42,47
unusual smell, and 14 became unwell. The symptoms,
which included cough, chest discomfort, breathless-
ness and fatigue, developed over several days. The more
severely affected also complained of thirst, sweating, PROPERTIES AND EFFECTS OF INDUSTRIAL
irritability and loss of libido. Five workers with persist- GASES
ent symptoms were investigated and in one a desmo-
pressin test was abnormal and he was diagnosed Simple asphyxiant gases
as suffering from cranial diabetes insipidus; other
endocrine organ tests included thyroid function, follicu- METHANE (CH4)
lar stimulating hormone, luteinizing hormone, prolactin
[CAS No. 74-82-8]
and testosterone which were all normal. The causal
Relative density: 0.56
agent and its possible source were not identified, but
Flammability in air: 5.0–15.4 per cent (vol.)
the coincidence of autonomic symptoms and diabetes
insipidus suggested that the gas exposure was responsi- Methane is a colourless flammable gas with a non-detectable
ble. Organic sulphur compounds with intense odours, or a sickly sweet oily odour which is normally too faint to
such as dimethyldisulphide, were also considered. provide warning of its presence. The main global sources of
methane are rice paddies and wetlands from the anaerobic
Watt et al.46 fermentation of organic material, but it is released from
coal mining, biomass burning, the leakage of natural gas
This episode shows the importance of all workers donning from the earth, as well as pipelines and well-heads, landfills
full positive-pressure breathing apparatus when investigat- and enteric fermentation in mammals (mainly ruminants).
ing unusual problems in sewers. Total global emissions of methane are about 500 million
tonnes a year, two-thirds of which come from anthro-
pogenic sources. It is second only to carbon dioxide as a
Mines cause of global warming. Natural gas contains methane as a
major constituent combined with significant amounts of
‘Black damp’ was the name given to the residual gas ethane, propane and butane, together with diethyl sulphide
encountered in mines where the oxygen has been removed as a deodorant. Some natural gas sources contain substantial
by natural chemical oxidative processes such as in the oxi- amounts of mercury, which can be an occupational haz-
dation of coal, timber and iron sulphide.47 It typically con- ard.48 Coal gas, which it replaced as a fuel, contains methane
tains 12–15 per cent carbon dioxide but can be higher, with together with hydrogen and a little carbon monoxide and
the rest of the gas as nitrogen. ‘Fire damp’ is methane ethylene plus small amounts of carbon dioxide, nitrogen,
which is present under pressure in coal seams and may be oxygen, ammonia and hydrogen sulphide. Marsh gas is
given off with carbon dioxide and nitrogen accompanied mostly methane with a little hydrogen, carbon dioxide and
by audible hissing noises during mining. The main hazard nitrogen. It has been widely believed that marsh gas can
is explosion. The introduction of a form of safety lamp by undergo a spontaneous combustion, producing a pale,
Sir Humphrey Davy in 1812 was a sensation, making the ghostly light (Will o’ the Wisp or Jack o’ Lantern), but
inventor internationally celebrated, as it markedly reduced another fermentation product is likely to be responsible.
Properties and effects of industrial gases 269
One minute it darted like a kingfisher, and the next it Another important methane mixture is landfill gas pro-
entirely disappeared. At times it grew as big as an ox’s duced by putrefaction of municipal and other wastes buried
head, and then straightaway shrank to a cat’s eye … in an excavation and covered with clay and topsoil. Huge
finally … it returned to frisk in the reeds. amounts of landfill gas may be generated containing typi-
cally a methane/carbon dioxide mixture in the ratio 60:40.
George Sand 184849 Volatile organic compounds may also enter and add to the
toxicity of the gas. The gas can migrate long distances
Mixtures of methane and air do not ignite spontaneously, through the ground and cause a hazard to workers by flood-
otherwise flames would be seen around the tails of cows. ing into trenches. Nearby residential areas may be at risk
Methane burns with a hot, yellowish flame and not cold, from soil gas. To help avoid these hazards, special vents are
bluish-white. Fermentation may also produce traces of incorporated into landfill sites to provide adequate escape
phosphine, PH3, but this does not ignite spontaneously in for the copious amounts of gas produced (Figure 39.5).
air either, although it commonly contains an impurity,
phosphoretted hydrogen, P2H4, which does. CARBON DIOXIDE (CO2)
As methane is much lighter than air it does not form an
[CAS No. 124-38-9]
explosion hazard in the open as it readily disperses, but the
Exposure limits:
gas can accumulate as an upper layer in the air of poorly
LTEL (8 h TWA) 5000 ppm or 0.5 per cent
ventilated spaces where it may cause asphyxia by displacing
(9000 mg/m3)
oxygen or, at much lower concentrations, become an explo-
STEL (10 min) 15 000 ppm or 1.5 per cent
sive risk if ignited by a flame or spark. Methane blasts in coal
(27 000 mg/m3)
mines are not uncommon tragedies in Russia and China
Relative density: 1.53
due to safety breaches: in 2007 at the Ulanovskaya mine in
Russia 110 miners died in the worst mining accident in Joseph Priestley was the first to establish the biological
60 years, followed by 38 deaths in a blast later that year in the properties of this gas and in 1772 came upon the art of
same region. A major incident involving methane took place manufacturing carbonated water, which was made popular
at Abbeystead, England, in 1984 when 34 local residents and by Joseph Schweppes who started a business in Bristol in
eight employees were visiting the valve house at the local 1794. The dangers of carbon dioxide were, however, known
water pumping station. The pipe system had been drained to wine producers in Roman times, if not earlier. Today,
down and, unknown to the engineers, methane gas from the carbon dioxide is encountered in numerous ways, for
surrounding methane-rich soils had permeated the pipes. example as a refrigerant, in fire extinguishers, arc welding,
When the pumping began, the methane entered the atmos- breweries and wineries, flue gases, fermentation processes
phere of the valve house and exploded, killing 16 people. which deplete oxygen (including in unventilated mines,
Carboniferous geological strata are methane rich and soil wells, tunnels) and in the manufacture and use of dry ice.
emissions may increase with rapid falls in atmospheric pres- It is often regarded as a simple asphyxiant, yet it has been
sure. The air near the ground in oil-rich regions may contain known since the turn of the last century that it has a toxic
as much as 1 per cent methane. action which is independent of oxygen deficiency. The toxic
properties of carbon dioxide were demonstrated on a large 15 per cent, not enough to cause loss of consciousness
scale in the disaster at Lake Nyos, Cameroon, in 1986, where from hypoxia, but death will occur if the carbon dioxide
over 1700 people were killed when as much as a quarter of level is maintained. Thus, it is important to note that
a million tonnes of carbon dioxide held in the depths of the monitoring oxygen in air is an inadequate guide to the car-
lake under hydrostatic pressure were suddenly released and bon dioxide hazard; carbon dioxide should be directly
flowed down into the nearby valleys (Figure 39.6). The measured. A working or living area should be immediately
water was saturated with dissolved gas ready for some mod- evacuated when concentrations exceed 1.5 per cent by
est disturbance to trigger its rapid rise to the surface and volume (the occupational short-term exposure limit
exsolution. The sparse medical findings and the accounts value). Experimental studies show that carbon dioxide
of survivors strongly suggested that the carbon dioxide had exerts a narcotic action at the higher concentrations
mixed with air to give rise to prolonged states of coma due through a disturbance of acid-base balance resulting in a
to carbon dioxide narcosis in many of the victims.50 Skin fall in pH of arterial blood and the cerebrospinal fluid.51
bullae were another unusual finding. This unprecedented Industrial carbon dioxide poisoning is a rare occur-
massive release contrasts with incidents in industry when rence. Survival after severe intoxication by carbon dioxide
isolated deaths from carbon dioxide are normally attributed has been described (in a patient in Bristol in 1972):
to oxygen lack or simple asphyxia, and there are no charac-
teristic findings on autopsy. A 34-year-old male worker was overcome by an acci-
Carbon dioxide is dangerous because it is colourless and dental release of the gas from a fire extinguishing sys-
odourless, but when breathed from an anaesthetic machine tem, filling the room ‘like a cold, thick fog.’ There were
it has a faintly acid smell. The effects of breathing the gas two others present, one died and the other managed to
are very characteristic.51 A 2–3 per cent carbon dioxide rescue the patient and save himself. The patient was
level in air will pass unnoticed at rest, but tidal volume is given artificial respiration, but breathed by himself
increased by 30 per cent and the minute volume by 5 per within a very short time whilst remaining deeply uncon-
cent; on exertion there may be marked shortness of breath. scious. On admission to hospital within 15–20 minutes
At 3 per cent carbon dioxide in air, breathing becomes of the accident he was still deeply unconscious, but was
noticeably deeper and more frequent at rest, with the effect maintaining a free airway. He had a respiratory rate
becoming more marked until at 5 per cent carbon dioxide of 24 per minute, but was grossly hypernoeic, flushed
in air there is severe dyspnoea, which limits exposure for and markedly vasodilated. He was normotensive, with
most people. Subjects complain of headache and are a heart rate of 120 per minute, and his chest was clear.
sweaty and have a bounding pulse. At 10 per cent carbon He became rousable after 35 minutes in the hospital
dioxide in air, respiratory distress develops rapidly with whilst being treated with oxygen through an MC mask.
loss of consciousness in 10–15 minutes, even though the Soon he was rational, and complained of headache and
oxygen concentration is reduced to 19 per cent only. feeling stiff all over. He developed pre-renal uraemia,
Exposures to carbon dioxide levels above 15 per cent are which spontaneously resolved over several days, and he
intolerable, and rapid loss of consciousness ensues after was eventually discharged well.
a few breaths of a mixture of 30 per cent carbon dioxide
in air. Even at this level, the oxygen concentration is Brighten52
Properties and effects of industrial gases 271
Figure 39.7 Carbon dioxide concentrations measured with an infrared analyser in five domestic water wells in Vulcano, Sicily.
Carbon dioxide measured from the top of the well above ground level to the water surface. The carbon dioxide concentration is lethal
(30 per cent) in all the wells within 1 m of the top and a worker would lose consciousness almost immediately on entry using a ladder.
On this volcanic island, carbon dioxide diffuses into wells from the soil. Courtesy of Jean Claude Baubron.
Soil gas emissions in volcanic and geothermal areas can oxygen level falls to 17.6 per cent in the presence of nitro-
be a silent hazard to workers. In Mammoth Mountain, gen, but carbon dioxide has a stronger effect, causing the
California, a popular ski resort, park rangers have been flame to be extinguished at 18.8–18.9 per cent (or 8–10 per
overcome due to an unsuspected increase in gas flow asso- cent carbon dioxide).
ciated with volcanic unrest.53 In the largest island of the Carbon dioxide levels can be used to measure the quality
Azores, San Miguel, the town of Furnas is built in an active of indoor air. At a ventilation rate of 4.6 m3/min per person
caldera where soil gas emissions have overwhelmed work- the carbon dioxide level in an office would be expected to be
ers digging roads. The phenomenon is not new, with approximately 800–1000 ppm in the absence of unvented
Loudon reporting in 1832 on the famous ‘Valley of Death’ combustion sources. Higher levels of carbon dioxide would
in Java which contained the skeletal remains of many wild indicate the need to increase ventilation to improve the
animals and birds that had strayed into the layer of carbon outdoor air supply.55
dioxide floating above the ground.51 Drilling boreholes in
certain urban areas in Italy associated with old volcanism ARGON A (A OR Ar)
has triggered hazardous gas blowouts that need to be
capped, placing emergency workers and other people at [CAS No. 7440-37-1]
risk.54 Relative density: 1.4
The danger of entering an enclosed space containing
Argon is the most abundant ‘rare’ gas in the atmosphere
carbon dioxide is illustrated by the concentration gradient
and, together with helium and neon, makes up nearly 1 per
of the gas in wells on Vulcano, Sicily, a volcanic island with
cent of air: all three gases are of inorganic origin. Argon is
areas which have strong ground emissions of carbon diox-
inactive, colourless and odourless. It is used in the control
ide (Figure 39.7). The breathing zone of a worker entering
of high technology refining and semiconductor processes.
such a well by ladder will be at a narcotic level of carbon
It is also used in lamps, as a shielding gas in welding, and in
dioxide without warning and within a very short descent
many gas-filled devices.
(less than 2 m) below the top. The worker would lose con-
sciousness after a few breaths and fall to the bottom of the
well. The carbon dioxide gradient is so steep that there HELIUM (He)
would be no opportunity for the worker to become aware
[CAS No. 7440-59-7]
himself that he was hyperventilating before consciousness
Relative density: 0.14
was lost. Spaces where carbon dioxide may build up can
therefore be much more dangerous than is commonly sup- Helium is colourless, inert, non-flammable and very light.
posed because of diffusion of the gas. It has been known It is found with natural gas deposits in the United States and
from ancient times (in wine production) that the flame of Poland. Extraction from air is not commercially viable. It is
a candle can be used to give adequate warning of the pres- used as a shielding gas in welding, in electric lighting tubes,
ence of lethal levels of carbon dioxide. A vertically held lit as a substitute for nitrogen in diving gas mixtures and as a
candle or oil lamp is normally extinguished when the balloon gas.
272 Gases
Chemical asphyxiant gases inhaling exhaust gases in an enclosed space; death may in
certain circumstances be more likely due to carbon dioxide
CARBON MONOXIDE (CO) instead.
Propane-fuelled equipment is commonly believed to be
[CAS No. 630-08-0] safe, but hazardous emissions of carbon monoxide have
Exposure limits: been reported in indoor environments with the use of ice
LTEL (8 h TWA) 30 ppm (35 mg/m3) resurfacing machines56 and in forklift trucks with poorly
STEL (15 min) 200 ppm (232 mg/m3) adjusted carburettors.57
Relative density: 0.97 Carbon monoxide is a chemical asphyxiant because it
Flammability range: 12.5–74.2 per cent (vol.) combines with haemoglobin with an affinity some 250 times
that of oxygen to form carboxyhaemoglobin (COHb).
Carbon monoxide is a colourless, odourless, non-irritating Carbon monoxide also increases the oxygen affinity of
gas which is slightly soluble in water and burns in air with haemoglobin and causes the oxygen dissociation curve to
a bright blue flame. It is the most widely encountered shift to the left by impeding the release of oxygen to the tis-
toxic gas in industry and the general environment, com- sues. With 50 per cent saturation of the blood with COHb
monly as the result of incomplete combustion of fossil the oxygen pressure must fall to less than half the usual value
fuels. Although Ramazzini (1633–1714) remarked on the in order to dissociate half the oxygen present.58 The clinical
danger of gases from burning coal and Harmant in manifestations of poisoning and tissue hypoxia are known
France gave the first clinical description of coal gas poi- to be greater than can be accounted for by loss of the
soning in 1775, it was Leblanc in 1842 who identified oxygen-carrying capacity of the blood alone. Experimental
carbon monoxide as the toxic agent. The potential for studies suggest that carbon monoxide exerts a direct action
dangerous exposures to carbon monoxide arises in metal by combining with other haem-containing proteins in cells
production in iron foundries, steel works and electrical such as cytochrome oxidase, myoglobin and cytochrome
arc furnaces; in the chemical industry, in the manufacture P450. The interaction with cytochrome oxidase may result
of methanol, the catalytic cracking of hydrocarbons, in mitochondrial dysfunction and a prolonged impairment
around gas generating and purification plant, and in the of oxidative metabolism. An alternative hypothesis is that
synthesis of carbon black. Vehicle exhausts may pose haz- carbon monoxide damages mitochondria by provoking the
ards from carbon monoxide to workers in roll-on/roll-off release of free nitric oxide. Central nervous system injury
vehicle ferries, as well as in multi-storey car parks and may also be due to reoxygenation injury as a result of the
enclosed garages. production of partially reduced oxygen species, which in
Typical carbon monoxide concentrations in gas mixtures turn can oxidize essential proteins and nucleic acids, and
are: blast furnace gas 20–25 per cent; coal and coke oven induce brain lipid peroxygenation.
gas 7–16 per cent; petrol or LPG (liquid petroleum gas) Normal metabolism produces some endogenous car-
engine exhaust gas 1–10 per cent; and diesel engine exhaust bon monoxide and the normal COHb concentration is less
gas 0.1–0.5 per cent. Water gas is formed by passing steam than 1 per cent. Tobacco smoke contains carbon monoxide
through a bed of white-hot coke and consists of carbon and it is the most common cause of an elevated blood
monoxide and hydrogen. A mixture of carbon monoxide COHb. Cigarette smokers on average have a COHb level of
and nitrogen, known as producer gas, is used to fire metal- 5–6 per cent and heavy smokers can have levels in excess of
making furnaces and is produced by passing air over hot 10 per cent. Typically urban non-smokers will have levels
coke. of 1–2 per cent COHb. A level greater than 5 per cent in
Potentially dangerous sources of carbon monoxide in non-smokers and 10 per cent in most smokers suggests a
homes and workplaces are faulty heaters that produce source of carbon monoxide in the inhaled air. Levels in
excessive fumes or burn in a restricted air supply, whether excess of 10 per cent can sometimes be found in groups
using natural gas, propane, butane, coal, coke or wood. such as drivers, firefighters, garage employees and dock
Reducing ventilation in buildings in the winter to conserve workers, especially if they are smokers.58
heat may unwittingly elevate carbon monoxide levels in The proportions of COHb and oxyhaemoglobin in
the indoor air to hazardous levels. Carbon monoxide from blood depend upon the partial pressure of carbon
faulty gas appliances kills nearly 30 people in the UK every monoxide and oxygen. Several empirical equations have
year, and at least 100 are known to suffer ill health from been proposed for estimating per cent COHb at different
this cause. The elderly and the very young are most at risk. levels of exposure to carbon monoxide in combination
In the United States, approximately 600 accidental deaths with sedentary, light or heavy work and which take into
due to carbon monoxide poisoning are reported each year, account the duration of exposure, pulmonary ventilation
while the number of intentional carbon monoxide-related and the COHb present before inhalation of contaminated
deaths is between five and ten times higher. The use of air. The relation is not necessarily a simple one and there-
catalytic converters in car exhausts has reduced carbon fore exposure should be assessed measuring both COHb
monoxide emissions, making suicide more difficult by and the levels of carbon monoxide in the air, but the
274 Gases
following formula first proposed by Forbes and others59 exposure to this solvent by inhalation as a result of strip-
may be used: ping paint in an inadequately ventilated working area for
two to three hours may result in levels of COHb high
% COHb = k × % CO in air × minutes of exposure enough to precipitate angina or myocardial infarction in
The constant k is 3 for an individual at rest, 5 for light workers with pre-existing cardiovascular disease.62
activity, 8 for light work, and 11 for heavy work. More Clinical features of carbon monoxide poisoning
refined formulae, such as Coburn–Forster–Kane equa-
tions,60 are also available. Figure 39.8 can be used to pre- Acute poisoning
dict COHb in an individual with a continuing exposure to Exposure to carbon monoxide resulting in levels of
a specified concentration of carbon monoxide at different 10–30 per cent COHb may produce throbbing headaches
levels of exertion. and mild exertional dypnoea. At 30–50 per cent, additional
Performance of light-to-moderate work (up to 70 per symptoms include dizziness, nausea, weakness and collapse.
cent of maximum aerobic capacity) is not affected at low Acute heavy exposures may result in loss of consciousness
levels of carbon monoxide, that is COHb levels of 4–6 per without warning, followed by coma, convulsions and death.
cent, but short-term maximal exercise duration is reduced Fatal levels of COHb in healthy people are usually in excess of
in young healthy men. The effect is small and is only likely 50 per cent; anaemia predisposes to carbon monoxide poi-
to be of concern for competing athletes. Subtle impairment soning. The classic cherry pink colour of the skin is a rare
of mental functioning has been reported in volunteers sign, and if present suggests a carboxyhaemoglobin level over
when COHb levels exceed about 5 per cent. These changes 20 per cent, but venous blood frequently looks arterial.
include impairment of memory, learning ability, attention Carboxyhaemoglobin levels in heparinized blood samples
span, coordination and abstract thinking.58 are measured by dedicated co-oximeters or by spectropho-
A less well-known hazard arises from the use of methyl- tometry by second derivative.63 In post-mortem blood, gas
ene chloride (dichloromethane), a widely used solvent and chromatographic analysis is the preferred method because of
a main ingredient of commonly used removers of paint and the breakdown of haemoglobin.
varnish from wood. Dichloromethane is readily absorbed There is no diagnostic symptom complex for carbon
through skin contact and in the lungs as a vapour and is monoxide poisoning and the diagnosis can be easily missed.
metabolized in the liver. Carbon monoxide is an important The clinical presentation can vary widely, with vomiting,
metabolite of dichloromethane and forms COHb: peak headaches, malaise, weakness, fatigue, chest pain, palpita-
levels can occur within three hours of exposure associated tions and dyspnoea. It is as well to know that the signs
with elevated alveolar carbon monoxide levels, and there is and symptoms of non-lethal exposure may mimic those
a return to pre-exposure levels in 24–48 hours after the of a non-specific viral illness.64 While blood carboxy-
exposure has ceased.61 Approximately 5 per cent COHb haemoglobin concentrations are diagnostic, the levels are
saturation is obtained following exposure of non-smokers not a good guide to prognosis and the clinical condition is
to 200 ppm dichloromethane for four to eight hours. High more important, especially if the patient is or has been
20 Limit value
Carbon monoxide (% CO Hb)
18
concentration (ppm)
16
14
100 14.0
12
%CO Hb (increase)
10
8
50 7.6
6 40 6.1
4 30 4.7
25 3.9
20 3.2
2 15 2.4
10 1.6
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2324 rest
light
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 activity
0 1 2 3 4 5 6 7 8 9 walking
0 1 2 3 4 5 6 7 hard work
Figure 39.8 Uptake of carbon monoxide by
Time (hours) blood. Adapted from Ref. 72, with permission.
Properties and effects of industrial gases 275
unconscious. This is because tissue hypoxia through hippocampus and white matter on computerized axial
unmeasured tissue uptake of carbon monoxide is the pri- tomography or magnetic resonance imaging (MRI),69,70
mary insult and it correlates poorly with carboxyhaemo- but delayed neurological sequelae may also occur in the
globin levels. Without adequate treatment, 10–30 per cent absence of such findings. Positron emission tomography
of severely poisoned patients may develop late neuropsy- scanning can detect regions of the brain affected by
chiatric manifestations 3–240 days after exposure.64 The ischaemia in the acute poisoning stage, and which may be
prevention of this adverse outcome is the main reason for at risk of late complications, but the technique is no better
advocating aggressive early treatment. at predicting the eventual outcome.71 Neuropsychometric
The half-life of COHb is normally about four hours assessment will show impairment in acute poisoning and
(longer if induced by methylene chloride exposure), but may reveal cognitive deficiency consistent with organic
without treatment coma can last for 24 hours or longer. brain damage in the delayed syndrome. The diagnosis of
The relatively short half-life of COHb means that by the delayed neurological sequelae may be missed, and the
time the patient is seen, measurement of COHb may not be patient assumed to have even made a good recovery, until
a good guide to the initial exposure. Therapy is directed a return to work reveals a failure to perform to the
towards reducing the half-life of COHb which falls to expected level.
80 minutes when the patient is given 100 per cent oxygen at The neurological examination should include tests of
sea level. Most authorities now advocate giving hyperbaric fine movement and balance (finger–nose movement;
oxygen where there is access to a hyperbaric chamber.65 Romberg’s test, normal gait and heel–toe walking), testing
Hyperbaric oxygen at 2.5 atmospheres (252 kPa) reduces of short-term memory, and the ability to subtract 7 serially
the half-life to 20 minutes and increases the amount of from 100.
oxygen dissolved in the blood to a concentration sufficient
to meet the needs of the body even without functioning Ambient air exposure to carbon monoxide
haemoglobin. By far the principal source of carbon monoxide in the gen-
Hyperbaric oxygen should be considered for pregnant eral outdoor atmosphere is general pollution by vehicle
women and for patients who have evidence of: exhausts. Uptake of carbon monoxide from multiple
sources, such as smoking and traffic, is not additive.
● a period of unconsciousness; Smokers who already have a carboxyhaemoglobin level
● neurological or psychiatric symptoms; above the equilibrium value that would be reached by
● cardiac complications; breathing air in their surroundings are liable to act as
● carboxyhaemoglobin levels above 40 per cent. ‘source’, breathing out carbon monoxide rather than
absorbing more. Air quality standards therefore in effect
Neuropsychiatric damage can be immediate or a clear protect non-smokers from peak concentrations close to
period of several days may be followed by the development heavy traffic. The most important adverse health impact
of neuropsychiatric symptoms within the next two to three from environmental exposure to carbon monoxide is the
weeks or longer. Carbon monoxide has a predilection for effect on people with angina and disease from the coronary
the ‘watershed’ areas of the brain where there is a meagre arteries. In the EU, the air quality standard has been set
blood supply: the basal ganglia, with their high oxygen at a level at which the carboxyhaemoglobin should not
consumption, are most often affected. Other commonly exceed 2.5 per cent in people breathing the air over a pro-
affected areas are the cerebral white matter, hippocampus longed period, that is, 10 ppm measured as a running
and cerebellum. eight-hour average.72 This level equates to 25 ppm for one
Neurological manifestations such as vegetative state, hour, 50 ppm for 30 minutes and 87 ppm for 15 minutes
akinetic mutism, parkinsonism, agnosia, visual impair- when breathing at maximum levels of activity. The reader
ment, and amnestic-confabulatory states have all been should note that this standard is substantially below the
described.64,66,67 The patient can develop changes in work exposure limit for an eight-hour period, and its
personality typified by increased irritability, verbal aggres- rationale is about the need to ensure the adequate protec-
siveness, violence, impulsiveness and moodiness. Up to tion of people who suffer from ischaemic heart disease if
40 per cent of patients develop memory impairment, and they are likely to come into contact with the gas.
33 per cent can suffer late deterioration of personality. Recent studies indicate that even a circulating blood
Depression and suicidal tendencies are also reported. concentration of COHb of 2–3.9 per cent is associated with
Although many patients improve after some months, a impairment of cardiovascular function in patients with
proportion will be found not to have improved three years angina pectoris, who may show detectable changes in the
later.68 The syndrome of delayed neurological sequelae is cardiac ischaemic threshold on light-to-moderate exercise
more characteristic of carbon monoxide poisoning than (as assessed on the electrocardiogram (ECG) by a reduc-
other types of anoxia, and the cause remains speculative, tion in time to the ST end point) and an earlier develop-
but it seems likely that carbon monoxide has a specific ment of angina pectoris.73 In healthy workers, there is no
cytotoxic action. Bilateral necrosis of the globus pallidus is clear evidence that these levels of COHb (or indeed levels
common, and lesions may also be found in the basal ganglia, as high as 10 per cent COHb) impair the functioning of the
276 Gases
central nervous system. Nevertheless, deterioration in physi- methacrylate. The gas is also evolved when acids come
cal work (maximum work capacity or maximum aerobic into contact with cyanide salts. Firemen may be exposed
capacity) can be demonstrated with increasing levels of to the gas in fires involving the combustion of nitrogen-
COHb. It is possible that healthy individuals are able to containing synthetic materials. The main route of poison-
adapt to the mild hypoxia of chronic exposure to carbon ing by hydrogen cyanide is inhalation, although in solution
monoxide. Experimental studies have shown that carbon it can also readily penetrate the skin.
monoxide has an atherogenic effect in rabbits and rats, but At room temperature, hydrogen cyanide is a clear,
it is not generally accepted that low-level occupational highly volatile liquid (boiling point 26°C). The gas has
exposures contribute to atherosclerosis in man; more a characteristic odour of bitter almonds which is recogniz-
information is needed on the effects of carbon monoxide able at 2–5 ppm, but its detection by odour is unreliable;
on vascular endothelium and lipid metabolism. An epi- at higher concentrations, it causes olfactory fatigue. At
demiological study of a cohort of bridge and tunnel work- 18–36 ppm, warning symptoms of poisoning may occur,
ers regularly exposed to traffic fumes concluded that such as irritation of the eyes, nose and throat, dizziness,
carbon monoxide may be a contributory factor in increas- nausea, general weakness and headaches, flushed or occa-
ing cardiovascular mortality, but the mechanism was not sionally pale skin, and palpitations. Rapid and sudden loss
clear.74 of consciousness and cessation of breathing may occur
There is no available evidence to suppose that carbon on exposure to levels over 100 ppm. Levels of hydrogen
monoxide is mutagenic or carcinogenic, but exposure is cyanide above cyanide plating baths normally vary around
suspected to be a contributory factor for low birthweight in 1–5 ppm and workers do not complain of symptoms;
the babies of pregnant women who smoke. The teratogenic headache and vertigo may be reported at slightly higher
effects of carbon monoxide have been attributed to the concentrations.
transfer of carbon monoxide across the placenta and a Cyanide paralyses mitochondrial respiration by binding
consequently reduced oxygen supply to the fetus. Studies reversibly with enzymes containing ferric ions, in particu-
have predicted significant changes in fetal oxygenation as lar cytochrome aa3, thereby blocking intracellular respira-
a result of maternal carboxyhaemoglobin levels of about tion. Its direct action on the respiratory centre may also
5 per cent. Severe acute exposures have caused fetal death; induce respiratory failure.
and developmental and other neurological abnormalities Victims of acute poisoning present with headache, dizzi-
have been recorded in live births.75 ness and vertigo. There may be marked agitation and confu-
The pregnant worker should avoid occupational sion, with nausea and vomiting. Dyspnoea is accompanied
exposure to carbon monoxide or methylene chloride by hyperpnoea due to lactic acidosis. Acute cyanide poison-
(dichloromethane) and exposure to carbon monoxide ing induces sustained seizures, endogenous catecholamine
should be especially prevented in workers with sympto- release and cardiovascular shock. On examination, the
matic ischaemic heart disease. It is also important to external findings may be normal with a pink appearance
appreciate that the effects of carbon monoxide in people even when the blood pressure is immeasurable. The diagno-
living or working at high altitude (or at a reduced partial sis can be confirmed by measuring cyanide in a sample of
pressure of oxygen) are greater than at sea level. heparinized whole blood. Cyanide is concentrated in the
red blood cells and plasma cyanide measurements are not
recommended. Concentrations greater than 50 mmol/L are
HYDROGEN CYANIDE (HCN) associated with altered consciousness, and the lethal level is
above 100 mmol/L. Blood thiocyanate is a metabolite which
[CAS No. 74-90-8]
can be measured after the acute event. Other useful tests
Exposure limit: (STEL 15 min) 10 ppm (11 mg/m3)
include plasma lactate and arterial blood gases. In fatal
Relative density: 0.95
cases, there are no specific pathological changes and in
Flammability limits: 6–41 per cent (vol.)
particular the blood remains well oxygenated.
As well as hydrogen cyanide, the gaseous cyanides include The treatment of cyanide poisoning remains controver-
cyanogen (CN)2, once used as a fumigant, and cyanogen sial because the effectiveness of the recommended antidotes,
chloride (CICN), a fumigant and industrial intermediate. and so the treatment of choice, is not proven. Immediate
Exposure to cyanide in industry may also be the result first-aid measures include removing the patient to fresh
of the accidental or intentional ingestion of cyanide salts air, keeping the patient warm and at rest, and removing
(e.g. sodium, potassium, calcium and copper cyanide) and contaminated clothing. Contaminated skin should be
from exposure to the vapour of nitrites, such as acryloni- washed thoroughly. Oxygen should be administered if
trile (vinyl cyanide) and acetonitrile (methyl cyanide). available. First-aiders should wear suitable protective
Cyanide salts are used widely for metal cleaning or harden- clothing, including impervious gloves, to avoid skin
ing, in metal refining, gold extraction and film recovery absorption of cyanide. Where there is the potential for a
and electroplating. Historically, hydrogen cyanide used to large release of hydrogen cyanide, first-aiders should be
be widely used as a fumigant, but today its main industrial trained in the use of self-contained or airline breathing
usage is in the production of acrylonitrile and methyl apparatus for the rescue of victims. However, in most
Properties and effects of industrial gases 277
biological laboratories the amount of cyanide in routine of amyl nitrite is broken into a handkerchief and the
use does not normally warrant this precaution. patient inhales the vapour for 15–30 seconds. This process
The UK Health and Safety Executive (HSE) issued new must be repeated every two to three minutes until the
advice on the first-aid treatment of cyanide poisoning at capsule is exhausted. There is, however, little scientific evi-
work in 1997, since when little has changed. The HSE dence that it is of significant benefit. If the patient is coma-
no longer recommends the use of any antidote in the first- tose, or starts to become drowsy and has the features of
aid treatment of cyanide poisoning and does not require cyanide poisoning, then dicobalt edetate (300 mg in 20 mL
employers to keep supplies. Instead, the administration of glucose solution) may be administered by slow intra-
oxygen is regarded as the most useful initial treatment venous injection over 3–4 minutes. The second-line treat-
using a bag and mask device connected to an oxygen sup- ment, if there is no return to consciousness, is to give
ply. The latest advice is summarized in Table 39.4. There is sodium thiosulphate (12.5 g – i.e. 25 mL of 50 per cent
growing animal and human evidence that oxygen is itself solution) intravenously over 5–6 minutes. Dicobalt edetate
an antidote to cyanide or improves the response to treat- is a chelating agent that combines with cyanide to form an
ment with specific antidotes. inert complex, cobalticyanide. This antidote is not innocu-
The main antidotes recommended in the UK are amyl ous and if administered in the absence of cyanide will cause
nitrite and dicobalt edetate. A conservative approach to cobalt poisoning, hence the need to be cautious about its
their use is recommended. Any patient exposed to hydrogen use. Thiosulphate is a sulphur donor and accelerates the
cyanide who reaches hospital fully conscious will probably detoxification of cyanide by assisting in its conversion to
not need treatment with antidotes, their use being reserved the non-toxic thiocyanate.
for the patient who is unconscious or who has a clear his- If the patient is not breathing, then artificial respiration
tory of exposure to cyanide and has deteriorating physical should be commenced using a manual resuscitator. Mouth-
signs.76 To be effective, the antidotes should be adminis- to-mouth artificial respiration may put the first aider at
tered immediately the diagnosis of cyanide poisoning is risk of absorbing cyanide from the patient’s mouth or
made, but the problem is that the uninitiated could readily breath. The manual methods of artificial ventilation, such
mistake an ordinary collapse for poisoning. Accidental as Holger–Nielsen, are no longer recommended because
cyanide poisoning is rare in British industry today, but the they have poor efficiency and cause problems in maintain-
risk of suicide bids from swallowing cyanide in solid form ing an adequate airway.
or in liquids, such as acetonitrile, is also a possibility of Hydrogen cyanide may be formed when cyanides come
which occupational physicians need to be aware. into contact with acids. The cyanogen halides cyanogen
The rationale of treatment is the rapid fixation of cyanide chloride (CNCl) and cyanogen bromide (CNBr) also have
ion which can be achieved by direct fixation with the local irritant effects on the eyes and respiratory tract and
antidote dicobalt edetate or by inducing methaemoglobin can cause inflammation of the bronchioles and pulmonary
formation with amyl nitrite. The resultant methaemo- oedema, as well as having a similar toxic action as hydro-
globin binds strongly with cyanide as cyanmethaemoglo- gen cyanide. The cyanonitriles have a slower rate of intoxi-
bin. Experience with gassing incidents suggests that after cation than cyanide gas or cyanide salts as the cyanide is
the unconscious casualty has been removed from further released when they are metabolized by the body over sev-
exposure, he should be observed for any deterioration of eral hours; they also have their own toxic properties.
vital signs before administering cyanide antidotes as patients Cyanide is not produced in the metabolism of isocyanates
often recover spontaneously and quickly from apparently or diisocyanates.
severe poisoning. A rapid method of diagnosing cyanide Despite evidence that hydrogen cyanide can be inhaled in
poisoning is to test the patient’s breath for hydrogen fires, the use of dicobalt edetate is not routinely recom-
cyanide with a gas detector tube. Amyl nitrite by inhalation mended in the treatment of fire casualties. The relatively
and oxygen delivered by face mask are relatively safe and safer antidotes amyl nitrite and sodium thiosulphate, as
may be administered if the patient is conscious. A capsule well as hyperbaric oxygen, have been used to treat fire
278 Gases
casualties in hospital, but amyl or sodium nitrite reduce in large quantities at industrial installations. In the United
blood oxygenation by displacing oxygen from carboxy- States, railroad tanker incidents during transit are infre-
haemoglobin, and so may add to the oxygen-depriving quent but may lead to large-scale releases of chlorine with
effects of carbon monoxide. Hydroxocobalamin (the pre- substantial injury and deaths; wherever possible hazardous
cursor of vitamin B12), which reacts with cyanide to form materials should be re-routed away from densely populated
cyanocobalamin, is being increasingly advocated by some areas.
experts as an alternative in smoke inhalation victims.77 As There are two mechanisms of action of chlorine, both
it is relatively safer to use than the other drugs, it is being involving the generation of free radicals. The chlorine
actively considered by some countries as the drug of choice atom itself is a free radical; when released, it reacts with
in cyanide poisoning in general.78 other molecules to oxidize them. The second pathway is
The evidence for chronic health effects arising from via the indirect generation of reactive oxygen species, by
long-term exposure to cyanides at work is limited. Workers first reacting with water in the respiratory tract to form
may experience recurrent mild acute, or subacute, symp- hypochlorous acid and hydrochloric acid:
toms if exposures are not being adequately controlled.79
In the clinical setting, a neurotoxicological role for cyanide Cl 2 H2O ↔ HCl HOCl
has been suggested in tobacco amblyopia, and tropical
ataxic neuropathy associated with the ingestion of certain The hypochlorous acid is a strong oxidizing agent and
types of cassava which have not been adequately prepared on dissolution releases hydrochloric acid and reactive
before cooking. Cyanides are mostly metabolized to thio- oxygen species, both of which initiate inflammatory
cyanates in the body, and a toxic side effect of thiocyanate responses:
administration was found to be goitre when it was advo-
.
cated in the past for the treatment of hypertension. Evidence HOCl ↔ HCl + O
for goitre, but not for neurological complications, has been
reported in association with chronic cyanide exposure in a Despite its widespread commercial exploitation since
group of electroplating workers.80 before the First World War, human data on dose–effect
relations are sparse and instead the results of animal exper-
iments extrapolated to man are used to estimate lethal
PRIMARY IRRITANT GASES or dangerous concentrations of chlorine gas. Its odour can
be detected by most people at 0.2 ppm and by some at
CHLORINE (Cl2) 0.02 ppm. For irritant or potentially inflammatory effects
on the upper and lower airways in fit individuals and
[CAS No. 7782-50-5]
subjects with some degree of pre-existing airway hyper-
Exposure limits:
responsiveness, a NOAEL is 0.5 ppm over six to eight
LTEL not available
hours. In susceptible individuals, significant changes in
STEL (15 min) 0.5 ppm (1.5 mg/m3)
lung function occur at 1 ppm after four to eight hours.
Relative density: 2.47
Exposures in the range 15–150 ppm may be dangerous
Chlorine is a greenish, highly irritant gas with a pungent after 5–10 minutes, particularly at the higher end of this
odour; it is moderately soluble in water. It is widely used range or in susceptible individuals, for example with
in the manufacture of chemicals, the bleaching of pulp chronic respiratory disease. At 400–500 ppm, the gas is
and paper, for disinfecting water and in waste treatment. estimated to be fatal in 50 per cent of active healthy people
Workers may also be exposed in the production of exposed for 30 minutes, and exposure to 1000 ppm will be
chlorine by diaphragm cell or mercury electrolytic cell fatal after a few breaths.
processes. Chlorine is used in the manufacture of The effects of chlorine are mainly confined to the respi-
polyvinyl chloride and thousands of organochlorine com- ratory system.82 Because of its moderate solubility, it will
pounds, most of which do not occur in nature and persist act in the upper and lower respiratory tract. Acute expo-
in the environment, the most toxicologically potent being sure to raised concentrations in air can cause immediate
the ‘dioxins’. irritation of the mucous membranes of the eyes, nose and
Chlorine was discovered by the Swedish pharmacist, throat, producing cough, choking, substernal pain and
CW Scheele, in 1774, who was the first to observe its bleach- tightness. Abdominal pain, nausea and vomiting have also
ing properties. Chlorine-based bleaching agents have been been reported in inhalation incidents. Upper respiratory
used in the pulp industry for more than a century. Chlorine tract obstruction from laryngeal oedema should always be
dioxide was first synthesized in 1811 by Humphrey Davy, considered, but the most frequently encountered severe
but was not introduced in the pulp and paper industry until effect is toxic pneumonitis with interstitial oedema which
1946. This gas is at least as toxic as chlorine.81 Exposure to leads to impairment of gas diffusion and hypoxaemia; a
workers and occasionally the public is by the accidental restrictive and obstructive defect in lung function may be
release of chlorine from closed systems under pressure. In due to bronchospasm or interstitial oedema. Death may
the UK, it is the most common hazardous chemical stored occur from respiratory failure or cardiac arrest due to
Primary irritant gases 279
non-cardiogenic pulmonary oedema. Irritation and necro- has led to a mass casualty event involving inhalation of
sis of the skin can be caused by contact with a jet of gas, but chlorine gas.92
mild erythema resembling first-degree burns may follow There is no evidence that chlorine is carcinogenic or that
lesser exposure. Most mildly affected patients will settle typical industrial exposures affect reproductive outcome.
quickly with rest, but symptomatic treatment for cough The use of chlorine to disinfect drinking water has been one
and soreness of eyes and throat may need to be given. of the greatest public health advances of the twentieth cen-
Symptomless casualties should rest for at least eight hours tury, saving countless lives, but chlorine reacts with organic
and be told to report any change in their health to a doctor. matter in untreated water to form trihalomethanes – of
The treatment of severe chlorine poisoning is as for irritant which chloroform is the most common – and these are
gases in general (see under Principles of first aid and treat- potentially carcinogenic.93 Spatial epidemiological studies
ment in gassing incidents, p. 262). have not identified a significant risk.
After acute gassing incidents with chlorine, persistent
reactive airways dysfunction syndrome may occur: bronchial
hyper-responsiveness may persist for at least 18–24 PHOSGENE (COCl2)
months.83 Pre-existing bronchial hyper-responsiveness
[CAS No. 75-44-5]
may also be aggravated in some individuals for weeks or
Exposure limit:
months afterwards. In most people, however, the evidence
LTEL (8 h TWA) 0.02 ppm (0.08 mg/m3)
of a deterioration in airway function is transient. More
STEL (15 min) 0.06 ppm (0.25 mg/m3)
studies are needed to determine whether chronic low-level
Relative density: 3.48
exposures to chlorine can lead to long-term respiratory
effects.84,85 The recent follow-up studies of acute chlorine Phosgene is a colourless, relatively insoluble gas.94 At low
gassing among pulp mill and other groups of workers do concentrations (1 ppm), it smells like new-mown hay, but
indicate that the health effects of major incidents involving is pungent and irritating at higher levels. The gas dissolves
the accidental release of the gas may be much more in water and moist air to form carbon dioxide and hydro-
extensive and persistent than was previously supposed for gen chloride, but only a small amount will hydrolyse in the
irritant exposures.86 upper and lower airways when inhaled, most of the reac-
Several studies have reported a relationship between tion taking place in the alveoli. It is not reported to affect
indoor chlorination swimming pools and the prevalence of the skin. The danger of phosgene is that it may cause only
wheeze, asthma, hay fever, rhinitis and atopic eczema in mild transient irritation of the mucous membranes of the
swimmers and swimming pool attendants.87 Chlorination eyes and respiratory tract at concentrations which can
of public swimming pools results in free chlorine reacting nevertheless cause delayed and fatal damage to lung tissue,
with nitrogenous compounds (sweat and urine) intro- the symptoms of which may not begin until 30 minutes
duced by bathers to form chloramines, especially nitrogen to 48 hours later. In having a latent asymptomatic period
trichloride with dichloramine (NH2Cl2) and monochlo- following exposure, the gas resembles nitrogen dioxide,
ramine (NH2Cl). These can be in the atmosphere in the but the mechanism of its toxicity is unknown.
form of droplets or gas and are irritant in their own right, Exposure is usually confined to the chemical industry
but they may also decompose to form hydrochloric acid where it is used in many organic syntheses requiring
and ammonia. The main putative agent is considered to be chlorination, such as in the manufacture of isocyanates,
nitrogen trichloride (NCl3), which is an upper airway irri- polyurethane and polycarbonate resins. Gassing may occur
tant as powerful as chlorine and may build up in the air of from accidental releases from plant. It may also arise when-
indoor pools.88 Few direct measurements of NCl3 have ever a volatile chlorine compound or its vapour comes into
been made. Free chlorine and hypochlorite are unlikely to contact with a flame or very hot metal and this could give
be present in the swimming pool atmosphere. A similar rise to dangerous exposures in confined spaces; for exam-
type of problem can arise in the processing of green salads ple, welders in the hold of a ship in Sweden welding steel
in water containing hypochlorite.89 plates which had been degreased by trichloroethylene all
Cleaners have suffered near fatal pulmonary oedema suffered pulmonary oedema. In fires, polystyrene may burn
from chlorine liberated by the mishandling of standard to form phosgene, as well as chlorine.
household bleaches (5.25 per cent sodium hypochlorite The odour of phosgene is recognizeable at concentra-
solution – NaOCl), for example by mixing bleach with tions exceeding 0.5 ppm, above which level it is probably
a cleaning agent containing acids, such as phosphoric dangerous to inhale the gas for prolonged periods. At expo-
acid, when chlorine gas and water are released.90 Another sures above 10–20 ppm for 1–2 minutes severe lung injury
hazard may arise in the chlorination of swimming pools can follow, and inhalation of 90 ppm is said to be rapidly
using hydrochloric acid and sodium hypochlorite if the fatal. The main feature of phosgene poisoning is massive
two chemicals are accidentally mixed in a way to cause a pulmonary oedema.94 In most fatal cases, pulmonary
release of a cloud of chlorine gas.91 Mixing bleach with a oedema reaches a maximum in 12 hours followed by death
solution of ammonia produces monochloramine and in 24–48 hours. The trachea and bronchi are usually normal
dichloramine, and an accident, involving cleaning agents in appearance, which contrasts with chlorine poisoning in
280 Gases
which there is typically damage to the epithelial lining with 10–50 ppm, although partial tolerance does occur. A lethal
desquamation. Exposure to high concentrations may also level in air is often quoted as 500–1000 ppm for short
cause severe conjunctivitis and subsequent turbidity of the exposures, but this is probably an overestimate of toxicity.
cornea. Chronic bronchitis and emphysema have been The gas is highly irritant to the eye, causing conjunctival
reported as a consequence of acute exposure. irritation and superficial corneal damage; on contact with
No animal studies are available on the carcinogenicity the skin, it will dissolve in the perspiration and produce
of phosgene. No information is available on its reproduc- epidermal inflammation. Repeated elevated exposures
tive toxicity or carcinogenicity in humans.94 Because it to the mist may cause ulceration of the nasal septum.
is a highly reactive electrophilic compound it would be Inhalation can cause choking, coughing, laryngeal oedema
expected to bind in biological systems at the point of con- and non-cardiogenic pulmonary oedema depending upon
tact and so systemic absorption of unchanged phosgene by the severity of exposure. Chronic, elevated exposures to the
the inhalation or dermal route of exposure is not likely to mist can give rise to the discolouration and erosion
be significant. of teeth, particularly the incisors. It is some 30 times less
A notable escape of phosgene gas from storage tanks irritant to the respiratory tract than chlorine and major
occurred in Hamburg in 1928, leaving at least 11 people incidents involving the public have not been recorded.92
dead and 250 casualties. Hydrogen chloride was one of the first gases to have its
factory emissions controlled by legislation with the passing
of the Alkali Acts in 1863. The alkali industry of the
Hydrogen halides nineteenth century manufactured sodium sulphate which
was used in glass making and to produce alkalis, such as
The irritant effect of hydrogen halides arises from the fact sodium carbonate and sodium hydroxide. The Leblanc
that they behave as strong acids in aqueous media, i.e. they process was based upon the reaction of common salt with
dissociate forming high concentrations of hydrogen ions. sulphuric acid, and the unwanted byproduct hydrogen
Hydrochloric acid, hydrofluoric acid, hydrobromic acid chloride was discharged into the air around the factories
and hydroiodic acid all behave as very strong acids and for where it blighted vegetation over wide areas.96 Hydrogen
equal molar concentrations they are expected to behave chloride is one of the most common gases emitted by vol-
very similarly in their capacity to release hydrogen ions and canoes and it readily dissolves in rainwater to form acid
cause irritation to the respiratory system. Incidents involv- rain. The gas is also formed in voluminous white clouds
ing inhalation of high concentrations of hydrogen chloride when liquid lava flows into sea water.
in the workplace can lead to reactive airways dysfunction Hydrogen chloride is emitted from a variety of indus-
syndrome; it seems plausible that high levels of exposure trial sources including incinerators and coal-burning power
to hydrogen bromide and hydrogen iodide would have plants. It is not one of the major ambient air pollutants.
similar consequences. It undergoes rapid dry deposition from the air and low
ambient air levels do not seem to pose a direct health
risk. Subjects with asthma do not appear to respond with
HYDROGEN CHLORIDE (HCl) adverse respiratory effects on exercising while breathing
air containing less than 2 ppm hydrogen chloride.95
[CAS No. 7647-01-0]
Limited experimental and epidemiological studies do not
Exposure limit:
provide any evidence that the gas is a human carcinogen.97
LTEL (8 h TWA) 1 ppm (2 mg/m3)
There are concerns that co-exposure to hydrogen chloride
STEL (15 min) 5 ppm (7.6 mg/m3)
and formaldehyde may enhance the known carcino-
Relative density: 1.27
genicity of formaldehyde possibly by the formation of
Hydrogen chloride is a colourless to light yellow gas which bis(chloromethyl) ether (BCME), a human and animal lung
has a sharp, suffocating odour perceptible at 0.8 ppm. carcinogen, but the amounts of this carcinogen formed by
It is highly soluble in water and will produce a mist con- this mechanism are probably too low to be significant.
taining hydrochloric acid in moist air. Occupational expo- There are no studies on the potential effects of the gas
sure will therefore usually be to a mixture of gas and on human reproduction.
aerosol. It has a wide range of uses in the chemical indus-
try. In parallel with chlorine consumption anhydrous HCl
is used in the synthesis of vinyl chloride and other chlori- Compounds which hydrolyse to
nated hydrocarbons, and in steel pickling. Hydrogen hydrochloric acid
chloride is also formed in the exhaust gases of many types
of missile. The following gases are highly soluble in water and hydrol-
A NOAEL for irritant or potentially inflammatory yse to hydrochloric acid; the treatment of overexposure is
effects on the lower respiratory tract and outer eye is a con- the same as hydrogen chloride and for irritant gases in gen-
centration in the air of 1 ppm.95 The maximum levels of eral (see under Principles of first aid and treatment in
exposure that can be sustained over several hours are gassing incidents, p. 262).
Primary irritant gases 281
BORON TRICHLORIDE (BCl3) but less severe than, those seen in exposure to a similar
concentration of hydrogen chloride.98 A NOAEL based on
[CAS No. 10294-34-5] this comparison is 2 ppm. Exposure to 2–6 ppm for several
Exposure limit: not established minutes causes nasal and throat irritation, but no eye
Relative density: 4.1 irritation.
Other severe exposures to hydrogen bromide have been
Boron dichloride is a colourless gas which will form a mist
rarely reported. These have been as a result of inadvertent
in moist air to give hydrochloric acid and boric acid. It has
pyrolysis of fire extinguisher compounds and home fumi-
a sharp odour and is non-flammable. It is used in metal
gant agents containing methyl bromide.
refining and as a catalyst.
No studies on the carcinogenicity of hydrogen bromide
are available.
DICHLOROSILANE (SiH2Cl2)
HYDROGEN FLUORIDE (HF) Acute health effects of hydrogen fluoride and fluorides
[CAS No. 7664-39-3] In industrial exposures to gaseous and particulate fluoride,
Exposure limit: absorption of fluoride is mainly through the respiratory
LTEL 1.8 ppm (1.5 mg/m3) tract. Of fluoride in the body, 99 per cent is found in the
STEL (15 min) 3 ppm (2.5 mg/m3) skeleton since fluoride is not retained in soft tissue and
Relative density: 1.86 is not metabolized. There is rapid renal excretion of an
acutely absorbed dose so that about half is lost in the urine
Hydrogen fluoride, or anhydrous hydrofluoric acid, is a in a few hours. Only a very small amount is excreted in
colourless, corrosive liquid which boils at 19.4°C and reacts sweat or in the faeces. Occupational fluoride exposure has
in moist air to form a mist. Its main uses are in the manu- not been shown to cause liver or kidney injury and evi-
facture of fluorocarbons, the etching and polishing of glass dence is inadequate to implicate hydrogen fluoride and
and as a fluoridating agent in organic and inorganic reac- fluoride-derived gases as carcinogens or teratogens.
tions; it is handled in the form of gaseous hydrogen fluoride The maximum concentration of hydrogen fluoride in
or as an aqueous solution of hydrofluoric acid which on air tolerated by humans for one minute is about 120 ppm
contact with the skin can cause severe burns. when it causes smarting of the skin, conjunctivitis and
Industrial exposure to fluoride may also arise in mining irritation of the respiratory tract.100 The gas has a sour
and use of fluoride-containing materials. Fluorspar (CaF2) taste. At 60 ppm, there are no skin symptoms but irritation
is mined in many countries (in Derbyshire, England, local of the eyes and nose with discomfort in the pharynx and
deposits are known as ‘Blue John’) and is used throughout trachea is present. A level of 30 ppm can be tolerated for
the world as a flux in high temperature smelting and refin- several minutes.101 In magnitude of acute toxicity, studies
ing processes for the production of metals and alloys. It is of human volunteers and experimental animals suggest
reacted with concentrated sulphuric acid to produce hydro- that the halide gases hydrogen fluoride, hydrogen chloride
gen fluoride. Cryolite (3NaF AIF3) used to be mined in and hydrogen bromide are of the same order;98 their high
Greenland until deposits became exhausted and is now pro- water solubility ensures a rapid absorption in the nose and
duced by chemical synthesis instead: it is used in the manu- upper respiratory tract.
facture of aluminium. Fluorapatite (CaF2–3Ca3(PO4)3) is Inadvertent inhalation of high levels of hydrogen fluo-
present in rock phosphate which is mined in vast quantities ride can cause rapid death from intense inflammation of
in the production of phosphate fertilizers, phosphoric acid the respiratory tract and gross haemorrhagic pulmonary
and phosphorus. oedema. Inhalation of hydrogen fluoride and fluorine and
Exposure to hydrogen fluoride and silicon tetrafluoride, most fluorine-derived gases may cause coughing, choking
as well as fluoride particles, may occur in a wide range and chills lasting 12 hours after exposure.102,103 After an
of processes. Silicon tetrafluoride is also produced when asymptomatic period of one or two days, pulmonary
hydrofluoric acid is used to etch glass, and in water this oedema may develop followed by regression over a period
toxic gas hydrolyses to form fluosilicic acid (H2SiF6) which of 10–30 days. Advice to patients who have been in gassing
is the agent most commonly used to fluoridate water. accidents involving fluorine gases should therefore be
Processes with the potential to create large fluoride emis- cautious and should include the need for admission to
sions include: phosphate fertilizer production, which hospital for 24–48 hours’ observation.
involves the crushing and drying of phosphate rock; the The NOAEL for irritant effects on the face, eye and
manufacture of bricks, tiles, pottery and cement products respiratory airways is 1 ppm.104,105
when fluoride is released during the firing of clays contain-
ing fluoride; glass enamel and glass fibre production;
metal casting; steel and petroleum refining; coal combus- Chronic fluoride toxicity – osteofluorosis
tion; and aluminium production. Calcium fluoride and Osteofluorosis was first recognized as an occupational dis-
other inorganic fluorides are used as fluxing agents in arc ease in Danish cryolite workers in 1932, since when cases
welding. In uranium processing plants, isotopes of ura- have been reported in aluminium production, magnesium
nium are separated using the extremely corrosive solid foundries, fluorspar processing and superphosphate man-
uranium hexafluoride; emissions of fluoride compounds ufacture. The accumulation of fluoride in the skeletal tis-
are usually negligible, but a cloud of hydrogen fluoride sues is associated with pathological bone formation. The
was released from a uranium plant in Gore, Oklahoma, condition appears to be identical to endemic skeletal fluo-
in 1985, killing one worker and affecting numerous rosis found in parts of the world where drinking water con-
others. tains fluoride in excess of 5–10 ppm and which was first
In 1989, an accidental release of about 24 tonnes of described several years after the report of the first case of
hydrogen fluoride occurred over a 48-hour period at a occupational fluorosis was published.106
petroleum plant in Texas; 94 local residents were hospitali- The disease is detected by osteosclerotic changes in
zed and many others suffered from the irritant effects of spongey and other bones on the radiograph. There may be
the gas ‘fog’.99 no symptoms even in the presence of radiological changes,
Primary irritant gases 283
The manufacture of carbon anodes in the carbon plant application of 2.5 per cent calcium gluconate gel which
is associated with the release of polycyclic aromatic hydro- should always be available for use at locations where work-
carbons from coal tar pitch volatiles and substantial expo- ers may be exposed. In hospital, subcutaneous injections of
sure to these in the past has been found to be associated 5 per cent calcium gluconate solutions may be necessary.
with an excess risk of lung cancer in several epidemiologi- Systemic effects from skin burns may be fatal; in one
cal studies.109 Gaseous and particulate fluoride are given patient, as little as 2.5 per cent of the body surface area was
off in the two reduction processes.110 affected.113
Exposure of susceptible individuals to the pot room The first-aid procedures in the event of exposure to
atmosphere may provoke bronchial hyper-reactivity or hydrofluoric acid are shown in Table 39.5.
precipitate symptoms in those with subclinical asthma, but
the mechanism is probably irritant rather than allergic.
The syndrome tends to persist in some individuals even Other gases which hydrolyse to
after stopping exposure. A study of Norwegian pot room hydrofluoric acid
workers over six years of follow up found an increased
decline in FEV1.111 The following gases hydrolyse to hydrofluoric acid. Their
effects and treatment of overexposure are as for hydrogen
Occupational systemic poisoning by fluorides fluoride.
Acute systemic toxicity may arise from the ingestion of
fluoride salts, e.g. sodium fluoride, or from absorption of BORON TRIFLUORIDE (BF3)
fluoride in hydrofluoric acid burns.112 There is no single
cause of death in fluoride poisoning. Fluoride causes [CAS No. 7637-07-2]
enzyme inhibition involving vital functions, such as the ori- Exposure limits: not available
gin and transmission of nerve impulses. Calcium complex Relative density: 2.4
formation, with a rapid fall in plasma calcium, may inter-
Boron trifluoride is colourless and forms a mist in moist
fere with blood clotting and cell membrane permeability.
air to give hydrogen fluoride and boric acid. It is highly
Deaths associated with profound hypocalcaemia, hyper-
corrosive and has severe irritant effects on body tissues.
magnesaemia and hyperkalaemia have all been reported.
It has a sharp odour and is non-flammable. It is used
In addition, there may be specific organ injury involving
mainly as a catalyst in many chemical processes.
cell damage and necrosis. Terminally, there is a shock-like
syndrome in which tetany is a prominent characteristic.
There is no specific antidote, but the slow infusion of intra- CHLORINE TRIFLUORIDE (ClF3)
venous calcium gluconate may be life-saving.112
[CAS No. 7790-91-2]
Accidental exposure of the skin to hydrofluoric acid
Exposure limits: not available
solutions can cause severe, deep tissue injury. The treat-
Relative density: 3.2
ment is beyond the scope of this chapter, but it relies on
immediate removal of contaminated clothing, thorough Chlorine trifluoride is extremely reactive. The utmost care
washing of the skin with water and rigorous topical must be taken in ensuring that no contact with living tissue
Skin contact Remove contaminated clothing while protecting your hands with suitable gloves
Flood the skin with plenty of water for at least 5–10 minutes
Apply calcium gluconate gel on and around the affected area and continually massage it into the skin until
at least 15 minutes after pain is relieved. Cover the area with a dressing soaked in the gel and lightly
bandage. These procedures an be continued during transit to hospital
Send the patient urgently to the Emergency Department of the local hospital
Eye contact Flush the eye with water for at least 20 minutes. This can be continued during transit to hospital.
Gassing Remove the casualty from the contaminated area and place in fresh air
If necessary resuscitate the casualty
If suitably trained give oxygen
Send to the hospital Emergency Department
Swallowing Never attempt to induce vomiting
If the casualty is conscious rinse out their mouth with water
Send to the hospital Emergency Department
Source: Health and Safety Executive.
Primary irritant gases 285
is possible. It is used for specialized purposes, such as (H2SiF6) and thence cryolite and aluminium fluoride.
rocket propellants and fluorinating agents. Fluosilicic acid has the same general effect as hydrogen
fluoride and the treatment is the same.
CARBONYL FLUORIDE (COF)
SULPHUR TETRAFLUORIDE (SF4)
[CAS No. 353-50-4]
Exposure limit: not established [CAS No. 7783-60-0]
Relative density: 2.29 Exposure limits: not available
Relative density: 3.8
Carbonyl fluoride is a colourless, pungent gas used mainly
for the preparation of organic fluorine compounds. It Sulphur tetrafluoride is a very reactive, colourless and
is also produced during the thermal decomposition of corrosive gas with a sharp odour. It is rapidly hydrolysed
polytetrafluoroethylene (PTFE). to hydrogen fluoride and thionyl fluoride, which in turn is
slowly hydrolysed further into hydrogen fluoride and
sulphur dioxide. It is used to batch produce fluorinated
PERCHLORYL FLUORIDE (ClO3F)
compounds by replacing oxygen with fluorine.
[CAS No. 7616-94-6]
Exposure limits: TETRAFLUOROHYDRAZINE (N2F3)
STEL (15 min) 6 ppm (26 mg/m3)
Relative density: 3.6 [CAS No. 10036-47-2]
Exposure limit: not established
Perchloryl fluoride is a colourless, stable, non-flammable,
Relative density: 3.7
sweet-smelling gas. It is a strong oxidizing agent used in
fluorination processes and for rocket fuels. Tetrafluorohydrazine is a colourless gas with a musty
odour and which slowly hydrolyses to hydrazine and
hydrogen fluoride. Hydrazine is suspected of being a
PHOSPHORUS PENTAFLUORIDE (PF5)
potential carcinogen in man. Tetrafluorohydrazine is used
[CAS No. 7647-19-0] for the preparation of specialized fluorides.
Exposure limit: not established
Relative density: 4.5 OXYGEN DIFLUORIDE (OF2)
Phosphorus pentafluoride is a colourless gas with a
[CAS No. 7783-41-7]
sharp odour. It produces a mist in contact with moist air.
Exposure limit: not established
With large quantities of water it will ultimately yield
Relative density: 1.9
phosphoric acid. It is used in laboratory and experimen-
tal work. Oxygen difluoride is a highly toxic, colourless gas with a
foul smell. It is a very strong oxidizing agent used in the
preparation of complex fluorides.
PHOSPHORUS TRIFLUORIDE (PF3)
irritant effects.114 It is one of the most potent greenhouse pulmonary compliance. The pyrolysis products of CFCs
gases known. include chlorine, hydrogen chloride, hydrogen fluoride
and phosgene, and these may be a hazard to firefighters.
NITROGEN TRIFLUORIDE (NF3) CFC-22 (chlorodifluoromethane) has been reported to
cause cardiac arrhythmias (palpitations) in hospital work-
[CAS No. 7783-54-2] ers who sprayed tissue with an aerosol preparation in order
Exposure limits: not available to ‘speed up’ the work of a cryostat machine,115 but these
Relative density: 2.46 adverse effects have not been found in studies of refrigera-
This gas is used as an oxidizing agent in rocket fuel and in flu- tor repairmen. CFC-113 (Freon-113 or Genetron-113) has
orination reactions. Its principal hazard on inhalation is that been implicated in fatalities from cardiac arrhythmia,
it readily oxidizes haemoglobin to form methaemoglobin. asphyxiation or both in those working in confined spaces
or in poorly ventilated areas.
SULPHURYL DIFLUORIDE (SO2F2) The following gases are representative of the group and
include some related compounds.
[CAS No. 2699-79-8]
Exposure limits: DICHLORODIFLUOROMETHANE (FREON-12, GENETRON-12)
LTEL (8-h TWA) 5 ppm (21 mg/m3) (CCl2F2)
STEL (15 min) 10 ppm (42 mg/m3)
Relative density: 3.7 CHLOROTRIFLUOROMETHANE (FREON-13, GENETRON-13)
(CClF3)
Sulphuryl difluoride is a colourless, odourless non-
flammable gas with minimal smell. Its main use is as a TETRAFLUOROMETHANE (FREON-14) (CF4)
fumigant. Overexposure has been reported to cause respi-
ratory tract irritation, nausea and vomiting with crampy This substance occurs naturally in significant traces in
abdominal pain. natural gas and is a potent greenhouse gas, being inert like
The following gases contain fluorine and are usually rel- silicon hexafluoride.
atively inert, but they can undergo pyrolysis to produce
respiratory irritants. DICHLOROFLUOROMETHANE (FREON-21) (CHCl2F)
on its health effects are available. At high concentrations in Sulphur dioxide from anthropogenic sources, such as
animal studies, delayed fetal development has been found. coal- or oil-fired power stations, is oxidized in the atmos-
For a review of the health effects of the fully halogenated phere to sulphate at a rate of about 1–5 per cent per hour,122
chlorofluorocarbons, see Ref. 116. but it can be faster in the presence of catalysts, such as metals
Substitutes for the phased out chlorofluorocarbons or their particulate compounds in a plume. Sulphate is
are the partially halogenated hydrochlorofluorocarbons much more soluble than the gas and readily forms fine
(HCFCs), the most important being 1,1-dichloro-2,2,2- sulphuric acid aerosols or combines with rainwater and
trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetraflu- cloud droplets to produce acid rain, often at long distances
oroethane (HCFC 124). These have only recently become from the source of the pollution. Acid rain has no direct
available for commercial and industrial use.117,118 An out- health impact, but it blights vegetation, acidifies surface
break of liver disease has recently been reported in workers waters and corrodes buildings. The major natural sources
who received repeated accidental exposure to a mixture of of sulphur dioxide are volcanic activity, and the oxidation
these two compounds.119 They were drivers of an overhead of dimethyl sulphide released from marine organisms.
gantry in a secondary smelting depot and were exposed to Occupational exposures to the gas may arise in petroleum
a leaking air-cooling system in their cabin. Three out of processing, wood pulping, food preservation, sulphuric acid
nine workers presented with acute hepatitis, the remainder production, and in paper mills. The uses of sulphur dioxide
progressively developed varying degrees of liver abnormali- include bleaching and refrigeration. Quite high exposures
ties. Liver biopsy showed hepatocellular necrosis which to sulphur dioxide are common in many smelting operations
was prominent in perivenular zone three and focally extend- since most ores contain sulphide; it is also a contaminant
ing from portal tracts to portal tracts and centrilobular of the air of non-ferrous metal foundries. Explosions of
areas. Autoantibodies against human liver cytochrome sulphide dust may occur when blasting in massive sulphide
P4502E1 and P58 protein disulphide isomerase isoform ores, and workers may become exposed to dangerously
(P58) were found in the serum of five of the workers.119 elevated concentrations of sulphur dioxide in such acci-
dents.123,124 Particulate matter will arise during many
BROMOTRIFLUOROMETHANE (HALON 1301) (CF3Br) industrial processes, as well as in the combustion of fossil
fuels, and the respiratory effects of the accompanying
[CAS No. 75-63-8]
particle concentrations may also need to be considered.
Exposure limits: not available
Sulphur dioxide concentrations of 3–5 ppm in the air
STEL (15 min) 1200 ppm (7430 mg/m3)
are easily noticeable and at these levels a few sensitive indi-
This gas is commonly used as a fire extinguishant in computer viduals will show a fall in pulmonary function at rest.125
and high technology facilities. A group of workers exposed Healthy individuals do not respond to sulphur dioxide
in an accidental discharge of a halon fire-extinguishing sys- below 1 ppm, but may respond on exercise or deep breath-
tem reported irritation symptoms of the eyes, nose and ing at levels of 1–5 ppm; healthy individuals may show an
throat, and light-headedness, but there may also have been effect with an increase in airflow resistance when exposed
exposure to irritant breakdown products of halon 1301 to concentrations of 4–5 ppm or higher for five minutes.
and Freon-22.120 Asthma sufferers, on the other hand, are especially sensitive
to sulphur dioxide and can respond at rest to short-term
SULPHUR DIOXIDE (SO2) concentrations of about 0.4 ppm and very sensitive subjects
as low as 0.2 ppm, although no discernible threshold exists.
[CAS No. 7446-09-5]
The odour threshold is in excess of 1 ppm and so this crite-
Exposure limits:
rion does not provide warning of potentially harmful lower
LTEL (8-h TWA) 2 ppm (5.3 mg/m3)
levels. In the past, regular exposures in industry to over
STEL (15 min) 5 ppm (13 mg/m3)
30 ppm have been recorded, but marked irritation of the
Relative density: 2.26
eyes, throat and upper respiratory tract usually occur at
Ambient air quality standard: 100 ppb (15 min)
concentrations around 10 ppm. The maximum concentra-
Sulphur dioxide is a colourless, highly irritating, non- tion that healthy individuals can endure for a few minutes
flammable toxic gas. It is a common pollutant of urban air, is 150 ppm,125 a level which can be fatal in the elderly asthma
wherever fossil fuels are burnt. Being moderately soluble sufferer.126
in water, it will dissolve easily in the layer of fluid on the ‘Dark-room disease’ is a term coined for radiographers
surface of the epithelium of the nasal passages and upper reporting eye and upper respiratory irritation during the
airways. The upper respiratory tract and the large bronchi course of working in x-ray film processing under poorly ven-
are the major site of absorption and toxicity of sulphur tilated conditions. Although the precise cause has not been
dioxide, but at high concentrations it behaves like other ascertained, a study showed that the main airborne contami-
soluble irritant gases in causing acute lung injury and nants were sulphur dioxide and acetic acid at concentrations
damage to the front of the eye.121 Survivors of gassing inci- of about 0.1 ppm, as well as detectable glutaraldehyde.127
dents with sulphur dioxide may develop reactive airways With the introduction of automated film development and
dysfunction syndrome. processing, this condition is now rarely encountered.
288 Gases
Much attention has been paid to sulphur dioxide as one SULPHUR TRIOXIDE (ANHYDRIDE OF SULPHURIC ACID)
of the main pollutants in smogs that occurred in cities in the (SO3)
nineteenth century and the first half of the twentieth cen-
tury as a result of the widespread burning of coal in homes [CAS No. 7446-11-9]
and factories. In the London smog of 1952, many deaths Oleum (‘fuming sulphuric acid’) is a complex mixture of sul-
occurred in London when daily black smoke (particulate phuric acid and sulphur trioxide. Sulphur trioxide can exist
matter) concentration exceeded 5000 g/m3 and was asso- as a gas, liquid or solid, and is used primarily as a sulphating
ciated with very high levels of sulphur dioxide: 4000 g/m3 or sulphonating agent, for example in the manufacture of
(1.5 ppm). With changing patterns of energy production, detergents, dyestuffs, drugs and insecticides. Dense clouds of
the emissions of the gas have been much reduced. In the sulphuric acid mist are formed when sulphur trioxide comes
United Kingdom, the highest levels’ peak levels may be into contact with moisture in the air.
mainly found 30–40 km downwind of fossil-fuel power sta-
tions where the plume may fumigate at ground level.128 Sulphuric and other inorganic acid mists
At low concentrations, sulphur dioxide is thought to act on
contact with the nose, throat and bronchi by stimulating Erosion of the enamel of the teeth has been reported with
neural reflexes which cause the smooth muscle of the air- occupational exposure to sulphuric and other strong
ways to contract. This causes a reflex cough, irritation and a inorganic acid mists (nitric, hydrochloric and phosphoric
feeling of chest tightness. Other mechanisms contributing acids).6 They are irritating to mucous epithelia and pro-
to airway narrowing include the development of mucosal voke respiratory symptoms and changes in pulmonary
oedema, vascular congestion of the mucosa and increased function and, at high concentrations, death.131 Acid mists
airways excretions. Although exposure studies have focused may also cause pulmonary irritation by adhering to fine
on asthma sufferers, it is likely that similar effects may be particles. There is sufficient evidence that occupational
observed in patients with other chronic lung diseases. The exposure to strong inorganic mists containing sulphuric
evidence for longer-term effects and whether exposure to acid is carcinogenic; laryngeal and lung cancer have been
sulphur dioxide actually causes lung disease rather than implicated in certain strong acid processes.97,132
only provoking attacks of asthma, remains conflicting. An interesting incident demonstrating the impact of
Pre-employment health screening in workplaces where factory emissions containing concentrated sulphuric acid
exposure to sulphur dioxide may be high enough to affect aerosols occurred in Japan between 1960 and 1969 when
susceptible individuals should aim to advise patients with asthmatic symptoms were reported in about 600 individuals
asthma or other chronic lung disease to seek alternative living within 5 km of a titanium dioxide plant during this
employment, although the occupational physician should period.133
carefully evaluate individual cases.
A proportion of the population are, when exposed to AMMONIA (NH3)
inhaled irritants over time, prone to develop mucous gland
[CAS No. 7664-41-7]
hyperplasia and chronic obstructive pulmonary disease.
Exposure limits:
Epidemiological studies of smelter and pulp mill workers
LTEL (8-h TWA) 25 ppm (18 mg/m3)
exposed to sulphur dioxide at regular concentrations of
STEL (15 min) 35 ppm (25 mg/m3)
1–5 ppm or over have shown inconclusive results on measures
Relative density: 0.59
of respiratory symptoms or chronic reduction in pulmonary
Flammability limits in air: 15–28 per cent (vol.)
function. Because of its irritant properties, sulphur dioxide has
been thought possibly to act as a co-carcinogen in the causa- Anhydrous ammonia is a colourless gas with a distinctive
tion of lung cancer. Studies of workers in copper smelters have pungent odour. It is extremely soluble in water, forming
shown an increased risk in relation to exposure to arsenic, but a caustic alkaline solution of ammonium hydroxide.
no independent effect of sulphur dioxide was seen.129 There is Ammonia is one of the most widely used industrial gases,
little information available on teratogenic effects, but the gas is as a catalyst and reagent, and has been used for many years
not considered to be a human carcinogen.97 as a refrigerant and in the manufacture of fertilizers.
‘Smelter disease’ has been recognized in workers replacing Although the gas is lighter than air, it can behave paradox-
pipes in sulphuric acid manufacturing plants. Characterized ically, as in an accidental release from storage in liquid
by dyspnoea, diarrhoea, colicky pain, muscle pain and der- form under pressure by undergoing rapid cooling to form
matitis, it was attributed to sulphur dioxide in the past, but it a dense cloud that hugs the ground.
is due to mercury fume exposure when burning through the Most people will recognize the odour of ammonia at
pipes containing sludge.130 30–50 ppm. At or above 50 ppm, the gas is irritant to the eyes
Sodium metabisulphite is widely used in the food and and mucous membranes of the respiratory tract, although
beverage industry and in the fishing industry as a preserva- partial tolerance does develop. Being readily hydroscopic, it
tive. It may have an irritant effect on the airways through a is absorbed by the mucous coating of the upper respiratory
mechanism leading to the release of sulphur dioxide when tract. Human data are sparse, but the only clearly estab-
it is dissolved in water. lished effect arising from exposure to low concentrations
Primary irritant gases 289
(200 ppm) in humans is irritation of the skin, eyes and TRIMETHYLAMINE (CH3)2N
upper respiratory tract. There is no evidence that ammonia
is genotoxic, carcinogenic or reprotoxic. Exposure to con- [CAS No. 75-50-3]
centrations up to 500 ppm for a few minutes can be tolerated Exposure limits: not available
by healthy adults, but at this level there is cough, hoarseness
and tightness of the throat, as well as marked eye irritation They are flammable, highly soluble, alkaline, colourless
and conjunctivitis. At estimated levels of between 5000 and gases which have a fishy odour at low concentrations and an
10 000 ppm, ammonia is likely to damage the lower respira- ammoniacal odour at higher concentrations. They are all
tory tract and be life-threatening, and concentrations in denser than air and act as irritants to the eyes, nose, throat,
excess of 10 000 ppm may be rapidly fatal.134,135 At life- respiratory tract and skin. Trimethylamine (TMA) is a
threatening levels, the gas causes chemical burns of the nose, major component of the odour produced by decaying fish.
mouth and throat which become red and raw, and corneal In fish odour syndrome, an uncommon inherited autoso-
burns. The tracheal epithelium and bronchi may become mal recessive condition, the oxidation of trimethylamine
denuded of epithelium. Pulmonary oedema by itself or with in the body is impaired. Unoxidized trimethylamine is
subsequent bronchopneumonia is the main cause of death, increased in urine, breath, sweat and other secretions, caus-
but fatalities can also be caused by the very rapid onset of ing the fish smell.139
acute laryngeal oedema which initially can manifest itself by
hoarseness and dyspnoea.136,137 OZONE (O3)
The strongly irritant nature of ammonia has led to
the oft-repeated view that laryngeal spasm is a frequent [CAS No. 10028-15-6]
cause of death in gassing accidents, but it is more likely to Exposure limits:
be due to rapid onset of laryngeal oedema. Although spasm STEL (15 min) 0.2 ppm (0.40 mg/m3)
of the glottis could persist long enough to induce asphyxia, Relative density: 1.66
the spasm would normally relax during unconsciousness
and then breathing would recommence. Ozone is a faintly bluish gas with a characteristic pungent
Apart from respiratory tract irritation, injury to the eyes odour. Because it is irritant to mucous membranes and
at high concentrations can be severe. Irrigation of the eyes as it is only moderately soluble in water, it readily pene-
should be instituted immediately after exposure to prevent trates to the small airways and alveoli, even with brief
rapid absorption of ammonia by the eye. Ophthalmic exposure, and at elevated concentrations causes pul-
sequelae include corneal opacities, cataract and glaucoma. monary oedema. Exposure to moderately elevated levels
A jet of anhydrous ammonia on to the moist skin can cause of ozone causes a measurable fall in FEV1 and FVC (forced
second-degree burns, as will splashes of liquid ammonia. vital capacity) associated with symptoms in susceptible
The literature reports a case of severe gastritis continuing adults, and children. These changes are compatible with
for months after a gassing accident.137 an inflammatory bronchiolitis causing reflex inhibition
There is good evidence that some individuals who have of respiration. They are related to the duration of exposure
survived an acute gassing incident may go on to develop and to exercise and have been recorded at concentrations
permanent respiratory disability with complications such as low as 0.08 ppm over periods of 6.6 hours.140 There is
as progressive airway obstruction, diminishing diffusion no evidence that asthma sufferers or subjects with chronic
capacity (low transfer factor), bronchiolitis obliterans, obstructive pulmonary disease are more sensitive to ozone
bronchiectasis, and continuing cough and sputum. than others. Distinct irritation to the eyes and respiratory
In contrast, exposure to ammonia in pig farmers is tract occurs at 0.5 ppm and prolonged exposure to this
around a few ppm. Respiratory symptoms are common in concentration is reported to cause pulmonary oedema or
these workers. However, exposure to dust, disinfectants could increase susceptibility to respiratory infections
and endotoxins may contribute to the respiratory irritants (bacterial and viral). Even brief exposure to 1 ppm is
in the air of livestock confinement buildings.44,138 inadvisable as it may cause severe cough and malaise.
The lethal level is not known precisely but inhalation of
Alkyl amine gases
50 ppm for 30 minutes is regarded as a potentially fatal
The following aliphatic amine gases are used widely in exposure.
industrial processes and pharmaceutical manufacturing: Ozone is used in industry as an oxidizing agent in
chemical reactions, for water fumigation and for the
MONOMETHYLAMINE (CH3NH2) bleaching of synthetic and natural fibres, oils, paper and
DIMETHYLAMINE (CH3)2NH flour. It is also generated by electrical storms and by
discharges in electrical equipment, for example during
[CAS No. 124-40-3] processes involving arc welding or emission of ultraviolet
Exposure limits: radiation. In offices with poor ventilation electrostatic
STEL (15 min) 6 ppm (11 mg/m3) photocopiers which utilize the action of high intensity dis-
LTEL (8-h TWA) 2 ppm (3.8 mg/m3) charge lamps, and laser printers, particularly older models,
290 Gases
airways. Individuals with mild asthma are more sensitive an hour to 100–150 ppm can result in fatal pulmonary
than unaffected people to exposure to nitrogen dioxide. At oedema arising between 3 and 72 hours later, with the ini-
relatively high concentrations, the gas causes acute inflam- tial irritant effects comprising throat irritation, cough,
mation of the airways. Nitrogen dioxide reduces mucociliary headaches, tightness in the chest and sweating, all of which
clearance and in animal studies has been shown to affect the may pass off within 30 minutes. Thus, people who are
immune cells of the airways and increase susceptibility to believed to have received significant exposure should be
bacterial and viral respiratory infections.141,142 admitted to hospital and placed under observation for
In the indoor environment, the burning of natural gas 48 hours. At more elevated concentrations, a few breaths
as a cooking fuel in homes is an important source of nitro- can produce severe and immediate hypoxaemia which may
gen dioxide as are paraffin space heaters: indoor air con- be fatal. In less severe cases, the delayed symptoms will be
centrations may readily exceed those outside the home. dyspnoea, chest pain with haemoptysis, and headache
An unvented gas cooker may typically provide peak levels followed by an uneventful recovery in most patients,
of 200–400 ppb in a kitchen. although the cough may last several weeks.
In industry, nitrogen dioxide is released as a byproduct Apollo astronauts were accidentally exposed in an
whenever nitric acid acts on metals or on organic materi- incident to an average of 250 ppm of nitrogen dioxide for
als, such as in the nitration of cotton or other cellulose, and 4 minutes before splashdown. They developed chest symp-
in the manufacture of many chemicals. Certain welding toms and evidence of pneumonia over the next day.
operations also produce nitrogen dioxide. Fermentation of Poisoning by oxides of nitrogen is a prescribed disease.
silage will produce high concentrations of gas within two The initial treatment of nitrogen dioxide poisoning is as
days of silo filling and exposure to farmers entering the for non-cardiac pulmonary oedema induced by irritant
confined silo space may give rise to acute fatalities or the gases. However, with this gas a second episode of pul-
respiratory effects of exposure to nitrogen dioxide known monary oedema may occur, and following apparent recov-
as ‘silo fillers’ disease’. The hazard from oxides of nitrogen ery bronchiolitis obliterans (see above under Bronchiolitis
in silos was first reported from the United States where obliterans, p. 263) may develop after an asymptomatic
farmers commonly silage maize stalks.143,144 Under certain period that can last up to six weeks.146
growth conditions, for example drought or in soils with Nitrogen dioxide exposure should always be considered
elevated nitrates, the content of nitrate in the grass or in workers who have suffered an acute onset of pulmonary
maize stalks used for silage may be increased enough to symptoms with haemoptysis associated with minimal
release an abundance of nitrous acid during fermentation evidence of preceding respiratory irritation. Such incidents
which then breaks down into oxides of nitrogen. Warning have also involved ice hockey players and spectators due to
signs to farmers are dead birds or rodents and a yellow- nitrogen dioxide emitted by malfunctioning combustion
brown haze around the silage surface. Elevated carbon engines in ice surfacing machines that use propane.147
dioxide and reduced oxygen concentrations may also Symptoms attributed to high levels of nitrogen dioxide
occur at the same time. Similar reactions can arise if silage have been reported in blast furnace workers when the slag
grass is treated with ammonium salts. To prevent the build is under cooling conditions (cold blast furnace syndrome).
up of gases, silos should have adequate mechanical ventila- Methaemoglobin determinations should be routinely
tion. Nitro-explosive fumes contain oxides of nitrogen, and performed: in an accident involving the deaths of three
when dynamite or gun cotton burn quietly instead of deto- men entering a silo that had been filled with corn the previous
nating, nearly the whole of the nitrogen is given off as nitric day post-mortem blood samples showed a methaemo-
oxide instead of free nitrogen. Thus, numerous inhalation globinaemia in the range of 38–44 per cent in the three
accidents have occurred in mining and tunnelling from the men.148
imperfect detonation of nitro-explosives, or from dynamite Information on the effects of chronic low-level occupa-
catching fire in poorly ventilated spaces. Armed services tional exposures is currently inadequate. A meta-analysis of
personnel may also be exposed to the fumes in gun-pits, epidemiological studies of the effects of exposure to nitrogen
armoured vehicles, ships’ magazines and turrets. dioxide in the indoor air from domestic gas cookers on respi-
Increased airways resistance has been measured in ratory disease in children was inconclusive.140 Nitrogen diox-
healthy human volunteers exposed to two-hour concen- ide is not considered to be carcinogenic or teratogenic.141
trations as low as 2.5 ppm of nitrogen dioxide. Asthma
sufferers may respond at concentrations as low as 0.3 ppm HYDROGEN SULPHIDE (H2S)
when exercising and exposure may enhance their response
to common allergens.145 The main danger of nitrogen [CAS No. 778306-4]
dioxide is that it is only a mild upper respiratory tract Exposure limits:
irritant so that exposure to up to 50 ppm may produce no STEL (15 min) 10 ppm (14 mg/m3)
immediate symptoms to warn of its potential hazard. LTEL (8-h TWA) 5 ppm (7 mg/m3)
However, exposure to 4–25 ppm may result in severe Relative density: 1.19
cough, haemoptysis and chest pain. Exposure for less than Flammability limits: 4.3–46 per cent (vol.)
292 Gases
Hydrogen sulphide is a colourless gas which burns in air with Hydrogen sulphide is an irritant to the upper airways,
a pale blue flame and is moderately soluble in water. It is but asthma sufferers do not appear to so readily respond to
rapidly converted to sulphur dioxide in the atmosphere by a low levels of hydrogen sulphide as they may do to sulphur
reaction with hydroxyl groups and carbonyl sulphide. In the dioxide.150 An exposure study of asthma patients who
body, the sulphide ion is oxidized to thiosulphate and sul- required regular medication, but excluding patients with
phate in the liver and kidneys and is mostly eliminated in the severe asthma, found that an effect on airways resistance
urine. The toxic effects of the gas are caused through the inhi- (but not FEV1 or FVC) was discernible in two of ten sub-
bition of cytochrome oxidase and through a direct depressant jects exposed to a concentration at 2 ppm, a level which is
effect on the respiratory centre of the brain.149 At high con- regarded as a lowest observed adverse effect level.151,152
centrations, hydrogen sulphide is very poisonous, but recent On volcanoes, scientists can be totally unaware of
research has found that at low levels it normally behaves in the hydrogen sulphide because its smell may be undetectable,
body as a cell messenger emitted in red blood cells. even at low levels, in mixtures of fumarolic gases for rea-
Hydrogen sulphide poisoning is a frequently met haz- sons which are not clear. As with other toxic gases, a safe
ard in the oil, gas and petrochemical industries where the system of work that includes air monitoring is essential.
risks of exposure are well known. Less well recognized are While the toxic hazard of hydrogen sulphide depends on
the dangers from the release of hydrogen sulphide as a the duration of exposure as well as its concentration, levels
result of the fermentation of proteinous material, e.g. the above 500 ppm should be regarded as very dangerous and
decay of ‘trash’ fish in boat holds and on farms which store immediate evacuation from a contaminated atmosphere
slurry and liquid manure. It may also be found in danger- should begin well below this level.
ous concentrations in the vicinity of fumaroles and the The symptoms of acute intoxication (1000 ppm) are
craters of volcanoes, as well as in geothermal and hot rapid breathing and distress, with nausea and vomiting, and
spring areas (Figure 39.10). Occupations associated with these may be rapidly followed by loss of consciousness usu-
hydrogen sulphide exposure include carbon disulphide ally in association with cessation of breathing. Loss of con-
production, viscous rayon production, sewer and tunnel sciousness without warning can occur on sudden exposure
work and mining, petroleum production or processing, to a high concentration of hydrogen sulphide (2000 ppm)
rubber vulcanizing, pulp industry, sulphuric acid produc- after only one or two breaths (‘knock down’) and there is a
tion, tanning and glue manufacture. Its characteristic smell high probability of death unless emergency resuscitation is
of rotten eggs is normally readily detectable below 1 ppm: commenced. Hydrogen sulphide is also a pulmonary irri-
the threshold of detection of the gas is 0.02 ppm and the tant and brief exposures above 500 ppm may cause acute
rotten egg smell is detectable at levels several times higher. non-cardiogenic pulmonary oedema; this potentially fatal
However, the sense of smell to hydrogen sulphide is soon complication can occasionally occur with prolonged expo-
lost at over 20 ppm and so the worker may have little, sures at concentrations exceeding 250 ppm.153
if any, warning of the presence of the gas at dangerous Eye irritation has been reported in workers exposed to
concentrations. Inhalation of concentrations of 10 ppm 10–20 ppm hydrogen sulphide for six to seven hours.152
hydrogen sulphide has no effect on pulmonary function in Exposure at concentrations greater than 50 ppm for one
exercising healthy subjects150 and levels of 20 ppm can be hour or more may severely damage eye tissues.152 Hydrogen
tolerated for some hours without harm (Figure 39.10), and sulphide keratoconjunctivitis is usually a feature of suba-
there is no cumulative action. cute intoxication by the gas that may arise after prolonged
exposure above 50–60 ppm, the symptoms being related to absence of scientific data on which to base opinions on the
blepharitis and irritant conjunctivitis with lacrimation and carcinogenicity, teratogenicity or reproductive effects of
photophobia. Sensations of grittiness or pain in the eye are the gas in this or other locations.161,162 The World Health
associated with superficial punctate corneal erosions. Organization has issued a guideline concentration limit in
Usually, the eyes recover within 24 hours following removal ambient air of 7 g/m3 (30-minute averaging period), based
from exposure, or after treatment with chloramphenicol on odour annoyance.8,152 Natural gas may contain as much
eye ointment, but corneal ulceration has been recorded. as 50 per cent hydrogen sulphide that must be removed
With prompt first aid and hospital treatment, the overall through refining. In 1950, an escape of hydrogen sulphide
fatality rate from hydrogen sulphide poisoning with loss of from a refining plant into the local neighbourhood occurred
consciousness is low and recovery is normally complete.153 in Poza Rica, Mexico, resulting in 320 hospitalized persons
However, in a small minority of patients, neurological and 22 deaths.163
sequelae may be found after an episode of unconsciousness.
There is no specific treatment for hydrogen sulphide poi- Malodorous sulphur compounds
soning and the use of nitrite therapy is controversial. There Hydrogen sulphide and methyl mercaptan are present in
is no specific finding at autopsy. Blood sulphide concentra- the breath of individuals with halitosis as a result of prote-
tions can be measured in fatal and non-fatal poisonings olytic activity by microorganisms residing on the tongue
using an ion-selective electrode method,154 but blood and and teeth. Both substances, together with dimethyl sul-
urine thiosulphate are believed to be more reliable by most phide and dimethyl disulphide are the principal air pollu-
laboratories,155,156 although experience remains limited. tants emitted by pulp mills. For safety reasons, odorants
As sulphaemoglobin is not formed in vivo by hydrogen are added to natural domestic gas, namely diethyl sulphide,
sulphide, sulphaemoglobinaemia is not evidence of expo- tertiary butyl mercaptan, ethyl mercaptan and methyl ethyl
sure to the gas.157 sulphide. Evidence for health effects of low level exposure
Evaluating the long-term effects of hydrogen sulphide to reduced sulphur compounds in the ambient air rests in
poisoning is complicated when case reports often lack studies of communities in the vicinity of sulphate paper
good information on exposure levels, in particular, the mills in Finland, where concentrations of total reduced sul-
presence or absence of other gases, such as ammonia and phur compounds in excess of 40 mg/m3 (one-hour or daily
carbon monoxide, which may be present due to fermenta- means) have been associated with daily reported symp-
tion processes. There is also a dearth of good follow-up stud- toms of headache, depression, tiredness and nausea.164
ies. Reports of interstitial fibrosis and chronic disability Dimethyl sulphide is allegedly the principal component of
following pulmonary oedema (pneumonitis) are uncom- foetor hepaticus.165
mon.158 Clinical experience and animal experiments sug-
gest that neurological damage due to hydrogen sulphide CARBONYL SULPHIDE (COS)
poisoning is similar to hypoxic brain damage from any
[CAS No. 463-58-1]
other cause, and case reports of delayed sequelae as in
Exposure limit: not established
carbon monoxide poisoning are rare.159 However, there is
Relative density: 2.1
a group of patients occupationally exposed to hydrogen
Flammability range: 12–29 per cent (vol.)
sulphide who present with non-specific symptoms, such as
hypersusceptibility to gas smells and other strong odours, The most abundant sulphur species in the atmosphere
fatigue, lack of energy, poor memory, irritability, decreased is carbonyl sulphide, being naturally produced from soil
libido and disturbances of equilibrium. There may even be decomposition, wetlands and marshes, etc. The gas is often
signs of vestibular dysfunctioning on clinical investigation. encountered with hydrogen sulphide in processes involv-
Ahlborg160 concluded that the majority of these patients ing the destructive distillation of coal and the purification
have suffered repeated episodes of intoxication without of petroleum. It is a colourless gas with an odour of rotten
loss of consciousness. They may also fall into the category eggs that decomposes in moist air to carbon dioxide and
of those patients who develop non-specific symptoms hydrogen sulphide. The gas is less irritant to the lungs than
following chemical exposure incidents. There is insuffi- hydrogen sulphide and probably acts in the same way on
cient evidence in the literature to justify the entity of the central nervous system to cause respiratory paralysis.
cumulative or chronic hydrogen sulphide intoxication at
prolonged exposures at 50–100 ppm, and such levels above SILANE (SiH4)
the occupational exposure standard should not be regu-
[CAS No. 7803-62-5]
larly encountered anyway in modern industry.
Exposure limits:
Chronic exposures to low levels in the environment,
LTEL (8-h TWA) 0.5 ppm (0.67 mg/m3)
such as in geothermal areas, as well as at workplaces, have
STEL (15 min) 1 ppm (1.3 mg/m3)
not been shown to be harmful, although its unpleasant
Relative density: 1.1
smell can be a considerable nuisance. The New Zealand
city of Rotorua sits on a geothermal field, and the air is Silane is a colourless gas with a repulsive odour and even
polluted by low levels of hydrogen sulphide, but there is an at low concentrations is spontaneously flammable in air at
294 Gases
room temperature. When silane burns in pipelines carry- use in the manufacture of semiconductors in the micro-
ing the gas, silicon oxide dust is formed. The main use of electronics industry, its evolution is almost always acciden-
silane is in the semiconductor industry as a source of high tal.168 It can be produced by the action of water on a
purity silicon where, because of its fire hazard, it has to be metallic arsenide, and an ore contaminated with arsenic
used under special control technology with the result that will liberate arsine when treated with acid. Poisoning may
human exposure has tended to be minimal. There is little arise in metal smelting and extraction, but exposure may
information on the effects of human exposure, but as it will also occur in galvanizing, soldering, etching and lead plat-
form silicic acid in the presence of moisture, it is assumed ing, as well as in the disposal of toxic waste containing
that silane will have an irritant effect on the eyes, mucous arsenic or arsenides.
membranes and respiratory tract. The gas may lead to incidents in the most unexpected
ways. In a classical incident off the British coast involving
METHYL MERCAPTAN (METHANETHIOL) (CH3SH) the Asiafreighter, a cylinder of arsine stored in the ship’s
hold leaked through a cylinder valve: four crew members
[CAS No. 74-93-1] who inspected the hold were inadvertently exposed to the
Exposure limits: not available gas and suffered severe poisoning, but exchange transfu-
Relative density: 1.7 sion was life-saving, the diagnosis having been made by a
Flammability limits: 3.9–21.8 per cent physician-toxicologist over the telephone.169 The occupa-
tional and general physician should be alert to arsine poi-
Methyl mercaptan (methanethiol) is colourless and flam-
soning and its characteristic features. The gas is a powerful
mable with a very foul odour detectable at very low concen-
haemolytic agent and its effects are usually fatal if exposure
trations. It is reported to have similar toxic properties to
is severe enough to cause anuria, unless the diagnosis is
hydrogen sulphide, being capable of causing central respira-
made quickly and exchange transfusion is employed as a
tory paralysis and pulmonary oedema. In a rare case of death
mainstay of treatment.
by overexposure, acute severe haemolytic anaemia and
The presenting symptoms are nausea, vomiting and
methaemoglobinaemia were found in the comatose victim,
headache which can arise 2–24 hours after a casual expo-
although this effect was probably unique to the patient who,
sure to arsine which may have lasted only 1–2 minutes.
in addition, suffered from glucose-6-phosphate dehydroge-
There may be no olfactory or other warning of the presence
nase deficiency.166
of the gas. Exposure to only 3–10 ppm of arsine in air can
produce symptoms after several hours of exposure and
HYDROGEN SELENIDE (H2Se) 25–50 ppm for 30 minutes is potentially lethal in humans.
Early on, the victim may pass dark red urine, and the com-
[CAS No. 7783-07-5]
bination of haemoglobinuria (without intact red blood
Exposure limits: not available
cells in the urine), jaundice and abdominal pain should
Relative density: 2.8
alert one to the diagnosis. The abdominal pain and jaun-
Hydrogen selenide is an irritant gas capable of causing pul- dice typically arise in 24–48 hours; and anuric or oliguric
monary oedema. In one reported case of acute poisoning, renal failure sets in by 72 hours.
the effects were acute severe cough and wheeze which were Other causes of haemoglobinuria to be considered in
followed by a lasting obstructive lung disorder.167 Effects of the differential diagnosis are leptospirosis, malaria and
chronic selenium exposure include extreme lassitude and paroxysmal nocturnal haemoglobinuria. Other chemical
fatiguability, garlic odour on the breath, tremor, excess agents capable of causing haemoglobinuria include potas-
perspiration, abdominal pain and vomiting, and a metallic sium chlorate, pyrogallic acid and stibine gas.
taste in the mouth. The gas is used in the preparation of Diagnosis is made on the history of exposure and the
selenides and is important as a doping gas in the semicon- finding of elevated urinary arsenic.
ductor industry, but routine biological monitoring for Because acute poisoning produces rapid and fulminant
selenium is not undertaken. haemolysis, many body organs, particularly the kidney, are
at risk from the sludging of red cell debris within the
microcirculation, hypoxia and the direct effect of arsine,
IRRITANT OR OTHER GASES WITH SYSTEMIC but the mechanisms involved are not fully understood.
TOXIC EFFECTS There is reticulocytosis and leukocytosis with an elevated
plasma haemoglobin, and methaemoglobin may form in
ARSINE (AsH3) the plasma and urine. Renal failure from severe tubular
necrosis is the main clinical complication and requires
[CAS No. 778442-1]
treatment with exchange transfusion to remove the arsine
Exposure limit:
adequately.170 In mild cases of haemoglobinuria, forced
LTEL (8-h TWA) 0.05 ppm (0.16 mg/m3)
diuresis is recommended. Recovery from the acute tubular
Relative density: 2.69
necrosis may be followed by the development of chronic
Arsine is a colourless, non-irritating gas with a garlicky renal failure with glomerular sclerosis, atrophic tubules
odour and is moderately soluble in water. Apart from its and interstitial fibrosis. A wide spectrum of clinical
Irritant or other gases with systemic toxic effects 295
manifestations may arise including damage to the liver, if it contains other phosphorus anhydrides as impurities.
myocardium, nervous system and bone marrow. Pure phosphine will auto-ignite above 38°C and forms an
A chronic form of poisoning from low-level exposure explosive mixture in air at concentrations greater than
to arsine has been described in workers engaged in the 1.8 per cent by volume. The pure gas is considered odour-
cyanide extraction of gold and in zinc smelting. This gave less, but impurities will give it a characteristic smell of dead
rise to severe anaemia, mildly elevated serum bilirubin and fish or garlic which may be imperceptible at low, but
raised urinary arsenic.168 hazardous, concentrations.171
Phosphine is used as an intermediate in the synthesis
STIBINE (SbH3) of organophosphines and organic phosphonium deriva-
tives. It is widely used in its pure form as a dopant in the
[CAS No. 7803-52-3] manufacture of semiconductors, but it has chiefly gained
Exposure limits: not available notoriety through its use as a fumigant against insects and
Stibine is a highly toxic, colourless gas which is formed rodents in grain stores, in grain elevators and on board
when an acid reacts with a metal containing antimony as ships. It is an unwanted byproduct in various metallurgical
an impurity, or when nascent hydrogen comes into contact reactions and in the manufacture of acetylene using
with metallic antimony or a soluble antimony compound. impure calcium carbide. It may also be generated when
The gas is not used in industry and its evolution is uninten- water or acids come into contact with metals containing
tional. Exposure may occur in metallurgy or chemical lab- phosphide as a contaminant, such as ferrosilicon and
oratories but, unlike arsine, it has an extremely unpleasant spheroidal graphite iron.
odour. Stibine poisoning is rare in industry. The manifes- Aluminium phosphide is a common poison used in sui-
tations of poisoning and the physiological action of the gas cide in India where it is widely used to fumigate stored
resemble arsine, but are less fulminant. Haemolysis, myo- grains. When consumed, it reacts with hydrochloric acid in
globinuria, haematuria, renal failure, nausea, vomiting and the stomach to liberate phosphine, where it can become an
headache have been reported after inhalation. Antimony unsuspecting hazard to pathologists performing autopsies
trioxide is used as a fire retardant in plastics manufacture, as the gas will escape when the stomach is opened.
and the release of stibine from PVC cot mattresses was Phosphine may arise transiently in the anaerobic degrada-
considered, and later discounted, as a cause of sudden tion of phosphorus-containing matter, as in marsh gas, but
infant death syndrome. Urine antimony measurements may is otherwise rare in nature.
be used as a guide to overexposure to the gas in workers. Aluminium or magnesium phosphide pellets are inserted
into the cargo of wheat on board ships for fumigation
GERMANE (GeH4) purposes. The moisture causes a chemical reaction which
releases phosphine and leaves a harmless residue of alu-
[CAS No. 7782-65-2] minium hydroxide. Peak concentrations will arise in a
Exposure limits: sealed hold during a voyage and it is necessary that the gas
LTEL (8-h TWA) 0.2 ppm (0.64 mg/m3) is dissipated by opening the hatches to the air for at least
STEL (15 min) 0.6 ppm (1.9 mg/m3) 24 hours before the cargo is discharged. Acute poisoning
Relative density: 2.6 incidents used to be reported with grain cargoes if the gas
escaped into living or working areas of the ship.172 If the
Germane is flammable and colourless and has a pungent
cargo is too dry, the gas is liberated after the hold is opened
odour. Unlike its cousin arsine, it is not encountered as an
when the phosphide pellets come into contact with moist
incidental product in ore or scrap processing. It is used to
air: workers in the mill processing of the discharged cargo
deposit pure germanium in semiconductor manufacturing.
can then be affected.
The toxicity of the family appears to be in the order Ge,
Initial symptoms of exposure to low concentrations of
As, Sb. Although germane produces haemolysis, no indus-
the phosphine include headache, weakness, fainting, pain in
trial poisonings have been reported. By analogy with arsine,
the chest, cough, chest tightness and difficulty in breathing.
any victim of significant exposure should be removed to an
With prolonged exposure, nausea, vomiting and diarrhoea
intensive care facility and assessment of blood, kidney and
may occur. The main hazard is pulmonary oedema which
cerebral function continued for some days.
usually occurs within 24 hours, but may be delayed for up
to two days. Central nervous system signs and symptoms,
PHOSPHINE (PH3) progressing to convulsions, coma and death, have been
reported; so too, have gastrointestinal symptoms such as
[CAS No. 7803-51-2]
nausea, vomiting, diarrhoea and severe epigastric pain.171
Exposure limit:
Unlike arsine, phosphine does not cause haemolysis, but
LTEL (8-h TWA) 0.1 ppm (0.14 mg/m3)
a case of purpura ascribed to phosphine poisoning is
STEL (15 min) 0.2 ppm (0.28 mg/m3)
known.169 However, some sources of exposure to phos-
Relative density: 1.18
phine may also lead to exposure to arsine whose haemolytic
Phosphine or hydrogen phosphide is a colourless, flam- effects should therefore be sought. Chronic poisoning does
mable gas which can auto-ignite at ambient temperatures not appear to have been recorded.
296 Gases
The reported maximum concentration that can be tol- anticonvulsant therapy. Health effects may also arise from
erated for several hours is 7 ppm. A level of 2000 ppm is chronic exposure to lesser concentrations, resulting in
regarded as rapidly fatal and the maximum exposure that nervous system involvement with manifestations such as
can be tolerated for 30–60 minutes without serious effects numbness (especially of the feet), visual disturbance
is 100–200 ppm. Recovery from phosphine poisoning is (including optic atrophy), mental confusion, psychiatric
usually complete.171 disturbances and tremor.174
The evidence for genotoxic effects of phosphine in Exposure above 25 ppm is dangerous and acute central
humans is inconclusive.173 nervous system symptoms with possible permanent effects
on the vision, hearing and balance are reported to occur
above 120 ppm. Concentrations greater than 250 ppm are
METHYL BROMIDE (BROMOMETHANE) (CH3Br) associated with pulmonary oedema, coma and convulsions.
Exposure of the skin to high concentrations of vapour or
[CAS No. 74-83-9]
liquid produces erythema with blister formation and severe
Exposure limits:
burns, particularly if the gas or liquid is trapped under
LTEL (8-h TWA) 5 ppm (20 mg/m3)
clothing. Blisters are usually large and surrounded by areas
STEL (15 min) 15 ppm (59 mg/m3)
of redness and swelling; they may take a long time to heal.
Relative density: 3.36
Severe inflammation of the eyes induced by the vapour
Flammability limits: 10–16 per cent (but practically non-
may lead to conjunctivitis and temporary blindness.
flammable)
First-aiders must not use mouth-to-mouth resuscita-
Methyl bromide (bromomethane) is a colourless, odourless tion. Treatment of acute poisoning should concentrate on
and relatively insoluble gas, but it is said to have a faintly controlling the convulsions and, if there is no response to
detectable sweet odour at high concentrations. The gas has drug therapy, muscular paralysis and positive pressure
been widely used as a fumigant, but it is being phased out. It ventilation should be considered early on. The toxic mech-
is highly toxic against mammals, insects, mites and patho- anism is unknown and no specific antidotes are recognized,
genic organisms in soil and compost.174 Thus, it has been but the administration of dimercaprol and glutathione
used to fumigate soil in compost under gas-proof sheets; have been suggested.174–176
fruit in ships’ holds or freight containers; and in aircraft and Regular users of methyl bromide should notify the local
special fumigation chambers. Fire extinguishers containing hospital of the hazard and appropriate treatment measures.
methyl bromide are no longer manufactured. Biological monitoring should be undertaken by measuring
Methyl bromide is the most abundant gaseous bromine serum bromide levels. According to the UK Health and
species in the atmosphere, being emitted from a wide range Safety Executive, a level of serum bromide of 0.18 mmol/L
of natural as well as industrial sources. Atom for atom, (1.45 mg/dL) or more suggests occupational exposure, and
bromine is about 50 times more effective than chlorine in above 0.35 mmol/L (2.8 mg/dL, equivalent to a concentra-
destroying stratospheric ozone, and hence countries are tion of 28 ppm methyl bromide in air) symptoms may arise,
moving to cease production and importation of methyl but dietary intake of bromide should also be excluded as a
bromide, although it is proving difficult to find substitutes cause of increased levels.177 The toxic symptoms of methyl
for some specialized applications. bromide are not directly related to the levels of circulating
Sporadic cases of acute poisoning may still occur but, bromide and so the results must be interpreted with caution.
because of its severe toxicity and low warning properties, Methyl bromide is a methylating agent and is mutagenic
only qualified operators are normally permitted to under- in short-term tests, but it is not carcinogenic in rodents.178
take fumigant work with this gas and they are well versed in Poisoning by methyl bromide is a prescribed disease.
the dangers and protective measures.
Occupational exposure is by inhalation or skin absorp-
tion. Although the hazards are well known, serious exposure METHYL CHLORIDE (CHLOROMETHANE) (CH3Cl)
incidents continue to occur due to lapses in the standard
[CAS No. 74-87-3]
protective measures laid down for working with this gas.
Exposure limits:
At low but dangerous concentrations, it has no irritating
LTEL (8-h TWA) 50 ppm (105 mg/m3)
effects, thus dangerous exposure may occur without ade-
STEL (15 min) 100 ppm (210 mg/m3)
quate warning, with onset of symptoms usually delayed
Relative density: 1.78
from 30 minutes up to 48 hours later. Symptoms of mild
Flammability limits: 10.7–17.4 per cent
exposure can come on within a few hours and include
headache, eye and nose irritation, cough, nausea and Methyl chloride is a colourless, flammable and sweet-
malaise. At high exposures, the gas typically causes injury smelling gas which is widely used in the chemical industry,
to the central nervous system as well as the lungs, produc- for example to produce methyl silicone polymers and
ing headache, nausea, vomiting, pulmonary oedema (up to resins, as a methylating agent in the production of butyl
30 hours after exposure), tremors and convulsions followed rubber and tetramethyl lead and as a blowing agent for
by coma; the convulsions may not respond to standard polystyrene foams. The gas is a natural source of chlorine
Irritant or other gases with systemic toxic effects 297
in the atmosphere, being released from the oceans and the potential long-term pulmonary changes, as well as the
biomass burning. adverse effects to other organs, including teratogenicity.
The effects of methyl chloride and methyl iodide are
similar to methyl bromide in that their primary target organs
are the brain, liver, kidneys and lungs. All three are muta- ETHYLENE OXIDE (CH2CH2O)
gens and potential carcinogens, and methyl chloride is a
[CAS No. 75-21-8]
suspect occupational teratogen. However, the evidence for
Exposure limit:
carcinogenicity or teratogenicity in humans is inadequate.
LTEL (8-h TWA) 5 ppm (9.2 mg/m3)
Because methyl chloride is almost odourless, hazardous
Relative density: 1.49
levels of exposure may occur with little warning. In mild
Flammability limits in air: 3.0–80 per cent (vol.)
poisoning, there is a staggering gait, dizziness, headaches,
nausea and vomiting resembling acute alcoholism, fol- The main use of ethylene oxide is as a chemical intermedi-
lowed by recovery. In more severe poisoning, symptoms ate in the production of ethylene glycol, polyester fibres and
and signs include vertigo, confusion, drowsiness, seizures, detergents, but it has been used on a much smaller scale
ataxia and diplopia; these effects may last for weeks and since the 1950s as a sterilizing agent for medical supplies
even months or lead on to coma and death. and foodstuffs. Most hospital gas sterilizers are automatic
general purpose sterilizers and many of these use ethylene
oxide, the gas being mixed with dichlorodifluoromethane
METHYL ISOCYANATE (NCOCH3) to reduce the flammability and explosion risk. Exposures
in hospitals and production facilities in Europe and North
[CAS No. 624-83-9]
America are today generally well controlled using exhaust
Exposure limits: as NCO
systems, and air levels should be routinely monitored using
LTEL (8-h TWA) 0.02 mg/m3
sensor and alarm systems. The odour detection level is at
STEL (15 min) 0.07 mg/m3
least 500 ppm and is therefore of no value in warning the
Relative density: 2
worker of significant exposure.182
Methyl isocyanate is not a widely used chemical, but it Ethylene oxide is a narcotic and depresses the central
gained worldwide notoriety after its disastrous release nervous system, as well as being a primary irritant of the
from the Union Carbide pesticide plant in Bhopal in India respiratory tract. Acute exposure to high concentrations
in 1984.179 It was being used in the chemical synthesis of leads to nausea, vomiting and headache; also reported are
carbaryl pesticides, and had been stored in liquid form in excitement, muscular weakness, sleeplessness and diarrhoea.
two steel tanks. The cause of the incident is still not known, Four men were exposed to an intermittently leaking steril-
but at 00:30 on December 3, 1984 an exothermic reaction izer (around 500 ppm) for between two and eight weeks,
took place in one of the storage tanks, resulting in the and three developed a reversible peripheral neuropathy,
escape over a few hours of 40 tonnes of methyl isocyanate. and one reversible acute encephalopathy. Irreversible neu-
A dense cloud of methyl isocyanate flowed over an area of ropathy and encephalopathy have been described in other
the city about 40 km2 at a time when there was a tempera- operators of leaking sterilizers at similar levels of intermit-
ture inversion and a light wind. It is considered that more tent exposure.182
than 10 000 people were killed and hundreds of thousands The gas condenses to a liquid at 10°C and is infinitely sol-
injured in the disaster. uble in water. Excessive exposure to the vapour causes irrita-
Respiratory involvement was the most common serious tion of the eyes, while contact of the skin with even dilute
health problem, with many victims suffering breathless- solutions may cause erythema, oedema, blistering and
ness, cough, throat irritation or choking, chest pain and necrosis. Allergic contact dermatitis has also been reported.
haemoptysis. Death was mostly from bronchial necrosis or Ethylene oxide is considered to have potential for caus-
pulmonary oedema. Eye reactions were also prominent, ing cancer and adverse reproductive effects in humans. It is
and included severe watering, photophobia, lid oedema a highly reactive epoxide and a direct alkylating agent, as
and corneal ulceration. well as being a recognized animal carcinogen associated
A follow-up study of survivors after three years reported with leukaemia and brain cancer in rodents. Chromosome
an increased risk of eye infections and hyper-responsive aberrations and sister chromatid exchange have been found
phenomena, possibly related to immune disturbance.180 in studies of exposed workers. Epidemiological studies
A cross-sectional survey conducted ten years after the gas have not unequivocally demonstrated an association with
leak suggested that many survivors had symptoms com- human cancer, in particular of the haemopoietic system,
mensurate with persistent small airways obstruction and but it is viewed as a human carcinogen by the International
with obliterative bronchiolitis.181 Agency for Research on Cancer (IARC).183,184
There was scarcely any toxicological information avail- Medical surveillance of exposed workers using complete
able on the effects of methyl isocyanate in humans at the blood count and differential was recommended in the
time of the incident. Unfortunately, follow-up studies of United States (lymphocytosis had been reported in symp-
the survivors have been too few to adequately document tomatically exposed workers), but no longer. Ethylene
298 Gases
oxide is a potent sensitizing agent: occupational asthma odour detectable at 1–3 ppm. Nickel carbonyl is prepared
associated with measurable IgE antibodies to ethylene by passing carbon monoxide over finely divided nickel. In
oxide used to sterilize latex gloves and adsorbed on to the the Mond process, the gas is used to isolate nickel from its
glove powder has been reported in a healthcare worker.185 ore. The effects of occupational exposure to nickel car-
bonyl have only been documented in workers engaged in
HEXAFLUOROACETONE (F3CCOCF3) the Mond process which has also been associated with an
elevated incidence of carcinoma of the nasal cavities, lung
[CAS No. 684-16-2] and pharynx.
Exposure limit: Acute inhalation effects of nickel carbonyl fall into
LTEL (8-h TWA) 0.1 ppm (ACGIH) two categories, immediate and delayed. The immediate
Relative density: 5.7 response includes headache, dizziness, nausea, vomiting
and dyspnoea, which may resolve within a day in mild
Hexafluoroacetone is colourless, non-flammable, fumes in
cases on removal from exposure. The worker should be
moist air, and has a stale smell. It is very reactive and is
kept under observation or admitted to hospital because
used to prepare a variety of chemicals.
symptoms of pulmonary oedema may arise 12–120 hours
It is irritating to mucous membranes and especially
after exposure. The patient becomes febrile and cyanosed
to the lung. Chronic exposure has been shown to lead to
with a rapid pulse and develops a leukocytosis. Delirium
cumulative effects in the testes, kidney and bone marrow of
may precede other central nervous system changes, such as
experimental animals. It is teratogenic in rats.
cerebral oedema. Death may follow in 4–11 days after
exposure. Exposure to 30 ppm for 30 minutes is said to be
DIBORANE (B2H6)
potentially lethal in humans.
[CAS No. 19287-45-7] Nickel carbonyl is rapidly absorbed by the lungs and
Exposure limit: nickel levels rise in the blood and urine soon after expo-
LTEL (8-h TWA) 0.1 ppm (0.12 mg/m3) sure. Measurement of nickel in the blood and urine is an
Relative density: 0.96 important guide for diagnosis and management. In severe
Flammability limits in air: 0.9–98.0 per cent cases, therapy with chelating agents to remove nickel from
the body is recommended (e.g. disulfuram), as well as
As well as a doping agent for semiconductor manufacture, treatment with oxygen and corticosteroids. Concomitant
diborane has uses in organic syntheses and in rocket fuel. poisoning by carbon monoxide from the Mond process
It is a colourless gas with a sickly sweet odour. The ability should be excluded by measuring carboxyhaemoglobin.186
to detect the odour is rapidly lost with exposure. It is spon- Poisoning by nickel carbonyl is a prescribed disease.
taneously flammable in air, but because its ignition
temperature (40–50°C) is above room temperature it may
remain for several days in air at room temperature without GASES WITH MAINLY ANAESTHETIC ACTION:
igniting. Diborane is used as a dopant gas, a catalyst in GENERAL ANAESTHETICS
polymer manufacture, and as a rubber vulcanizer. It is
hydrolysed to boric acid in the moisture of the respiratory The inhalational anaesthetics consist of gases and volatile
tract and exposure can cause dizziness, headache, drowsi- liquids. The first deliberate use of an inhaled gas to produce
ness, chest tightness, cough and nausea. Severe poisoning anaesthesia for the performance of surgical operations was
with boranes is marked by convulsions and pulmonary in animals, being carried out by Henry Hill Hickman in
oedema. The gas is also irritant to the eyes and skin and 1823 using carbon dioxide, but his work went unrecognized
should be treated with the same respect as phosgene or by medical opinion at the time. (Later in the century, carbon
chlorine. dioxide was tried out on humans, but was found to be
The other boron hydrides are pentaborane and decabo- unsuitable as it induced convulsions at anaesthetic concen-
rane. These are more toxic than diborane and they can be trations.) The first general anaesthetic to be used in surgery
readily absorbed through the skin and conjunctivae, as well was diethyl ether in 1846 by William Morton in the
as by inhalation. Boranes are neurotoxic. Massachusetts General Hospital and later that year in a leg
amputation performed by Robert Liston at University
NICKEL CARBONYL (TETRACARBONYLNICKEL) (Ni(CO)4) College Hospital, London. This agent was subsequently
replaced by chloroform as the most widely used inhala-
[CAS No. 13463-39-3]
tional agent following its introduction by Sir James Simpson
Exposure limit: as nickel
and John Snow in 1847. Snow was later to achieve fame in
LTEL (10 min) 0.1 mg/m3
public health when he ordered the removal of the Broad
Relative density: at 50°C, 5.95
Street pump handle in the cholera epidemic of 1854. Joseph
Lower flammability limit in air: 2 per cent (vol.)
Priestley discovered nitrous oxide in 1772 and in 1800
Nickel carbonyl is actually a liquid with a boiling point at Humphrey Davy had proposed the use of the gas as an
43°C, but its vapour is highly toxic. It has a ‘brick dust’ anaesthetic: surprisingly, it was not adopted until much
Gases with mainly anaesthetic action 299
later. Cyclopropane was popular for induction anaesthesia and active or passive scavenging should be incorporated
in children until the 1980s. into operating theatre design (Figure 39.11). A meta-
As for volatile agents, trichloroethylene later became analysis of the epidemiological studies based on data in the
popular in obstetrics, but it has now been discontinued in pre-scavenging era indicated an increased risk of sponta-
the United States and in the United Kingdom. Since 1956, neous abortion.189 Some of the earlier reports of adverse
the CFC halothane (CF3CHClBr) has been one of the most reproductive outcome may have been related to much
popular agents. Isoflurane has been used since 1971 and, higher exposures than occur today. Even now, high levels
because about 2 per cent of the gas inhaled is biotrans- of nitrous oxide can be achieved in poorly ventilated deliv-
formed compared with 18 per cent of halothane, it is ery rooms where a mixture of half nitrous oxide and half
considered safer for patients. Other agents in use are enflu- oxygen (Entonox, BOC Gases) is used for analgesia. These
rane and the newer agents, desflurane and sevoflurane. high levels could impair mood and cognitive functions in
Fluorinated anaesthetics undergo metabolic breakdown in staff, but in a study of more typical average time-weighted
the liver to inorganic fluoride with potential for nephro- exposure levels (nitrous oxide 58 ppm and halothane 1.4 ppm
toxicity, but this is not a consideration for the occupational average) no changes were found.190 However, high levels of
exposure of anaesthetists. Airway irritation may occur in nitrous oxide may impair fertility in female staff.191
patients with halogenated anaesthetics particularly when Suspicion that the health of anaesthetists is poorer than
used for inhalation induction of anaesthesia. other medical specialists keeps recurring and studies have
Most concern over the health effects of anaesthetic gases suggested a higher risk of suicide, lymphomas and reticu-
has centred on the hazard to the reproductive system in loendothelial tumours, as well as an increased rate of early
anaesthetists and operating theatre staff. This was first retirement on grounds of ill health.192 A mortality study of
highlighted in 1968 in a report describing a marked increase British anaesthetists found a doubling of deaths from sui-
in spontaneous abortions among a group of female anaes- cide compared with other men in social class 1, but the rate
thetists in the former USSR. The combined results of sub- was not significantly different from that among doctors as
sequent epidemiological studies in Denmark, the United a whole.192 It may be speculated that adverse health effects
States and the United Kingdom seemed at first to confirm could be related to job factors, such as sustained mental
this finding and in addition raised the possible risk of stress, long hours or inadequate time to rest and eat.
congenital abnormalities in pregnant women and in the Occupational hygiene studies in the UK showed that the
offspring of male anaesthetists. In 1976, the UK Department geometric mean time-weighted average exposure to nitrous
of Health released a circular advising the use of scavenging oxide among anaesthetists is 94 ppm in unscavenged
systems in operating theatres. By 1980, the considered theatres compared with 32 ppm in scavenged theatres, the
opinion was that spontaneous abortions in operating room corresponding means for halothane being 1.7 ppm and
staff were likely to be linked with exposure to inhalational 0.7 ppm. Active scavenging systems are much more effec-
agents. However, in the mid-1980s detailed evaluation tive than passive ones.193 A further study by the Health and
of the evidence available then did not show support for any Safety Executive in 14 veterinary practices showed similar
of the risks raised.187,188 The current prudent view is that results, although the duration of exposure of veterinarians
exposure to anaesthetic gases should be kept to a minimum and nurses was shorter than in hospital operating room
staff; halothane is the most common inhalational agent reproductive health effects, but this lack of evidence should
used in veterinary practice.194 Dental practices may also not foster complacency in its usage.
operate with inhalational agents for only a few hours a
week. A high level of efficient forced general ventilation is Other common anaesthetically active gases
important for reducing exposure levels by removing con-
taminants not handled by scavenging. Leakages readily ACETYLENE (ETHYNE) (C2H2)
occur from mask use, and intubation is to be preferred
whenever it is clinically feasible. [CAS No. 74-86-2]
Occupational exposure standards for anaesthetic gases Exposure limit: not established
were introduced in the UK in 1996, and these are equally Relative density: 0.9
applicable to manufacturing facilities, as well as hospi-
Acetylene is a colourless, highly flammable gas. It is regarded
tals.195 These are (8-h TWA): halothane 10 ppm (82 mg/m3),
as a simple asphyxiant, but marked intoxication will occur
enflurane 50 ppm (383 mg/m3) and isoflurane 50 ppm
at 20 per cent mixture in air. Very pure acetylene has a
(383 mg/m3). As anaesthetic gases are toxic agents, they
pleasant sweet smell, but commercial acetylene smells of
all call for consideration under the Control of Substances
garlic. It burns at a very high temperature with oxygen, up
Hazardous to Health Regulations. In hospitals, compliance
to approximately 3500°C.
with the occupational exposure standards is achievable
Acetylene is used in the manufacture of many organic
through balanced supply and extract ventilation with high
chemicals and polymers. Its fierce flame is used for oxyacety-
rates of air change in, for example, delivery rooms and
lene cutting and welding and wherever there is an applica-
recovery areas, as well as by the use of gas scavenging
tion for great heat.
equipment in operating theatres.
Key points
● Inhalation incidents involving gases are still
common in industry in all countries.
● Chlorine remains the most common gas stored
under pressure and is the most frequent gas
cited in major toxic hazard planning.
● Gases, such as carbon monoxide, hydrogen
sulphide and nitrogen dioxide can present as
occupational hazards in a wide range of settings
and a high degree of vigilance is needed.
● Anaesthetic gases are potential health hazards if
exposure to healthcare workers is not adequately
controlled.
● Workers in emerging economies may still be
exposed to the carcinogenic hazards of gases,
such as vinyl chloride, and the risk of explosion
Figure 39.13 Steam venting from a geothermal power plant in disasters from the build up of flammable gases in
Tuscany, Italy. Mount Amiata is an extinct volcano where mercury deep mines.
ore was mined until 1980.
304 Gases
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40
Reactive airways dysfunction syndrome and
irritant-induced asthma
JON G AYRES
TERMINOLOGY AND DEFINITIONS This definition covers all forms of IIA, including classical
RADS and low-dose exposure to irritants over time. This
Brooks used the term ‘RADS’ to define an asthma-like issue of a changing definition was highlighted in a review of
state occurring shortly after a high exposure to a chemical this area3 where it was recognized that in a number of
or gas, usually in the workplace. He described fairly strict reported cases authors included multiple acute exposures
criteria for the definition of RADS describing it as an as causing IIA, some allowing up to a week after exposure
asthmatic-like state occurring within 24 hours of an for the onset of symptoms to occur, and some allowing
acute, very high-dose exposure and which was character- lesser degrees of exposure – so-called low-dose RADS or
ized by the presence of bronchial hyper-responsiveness to ‘not so sudden IIA’ in their definition of IIA.4 The possibil-
methacholine in an individual with no pre-existing lung ity of exposures such as those which are recognized to lead
disease. However, in the early 1990s the issue of persistent to RADS/IIA could cause a stepwise worsening of patients
(repeated) lower-dose exposure to chemicals or gases with pre-existing respiratory disease is equally plausible,
resulting in airways disease was raised. As a consequence, perhaps even more so, but does not fall under these defini-
in 1995 a consensus statement on asthma in the work- tions. However, in the context of considering the health
place2 recommended that the term ‘irritant-induced effect of the specific ambient exposures considered here
Clinical picture 311
this should be regarded as possible although difficult to to chlorine were reported to have developed asthma as did
prove particularly where litigation is an issue. 26 (20 per cent) of those exposed to hydrochloric acid.
The likelihood that repeated exposure to chemicals or The occupational group in which exposures were most
gases might cause more than simple short-term irritancy likely to occur was chemical, gas and petroleum operators
symptoms and to more established airways disease fits with (10 per cent for chlorine, 8.5 per cent for hydrogen chlo-
reports of asthma developing in cleaners and workers ride). In some cases, the exposure is not simple, the best
exposed to solvents5,6 and with the finding that 18 per cent example being those individuals developing RADS who
of cases of occupational asthma reported to the SHIELD were rescue workers at the World Trade Center disaster,14
scheme in the West Midlands were due to irritants such as where no clear individual causal agent could be implicated,
cleaning agents.7 A wider European survey8 also showed although alkalinity of the aerosol (pH 10) might have played
similar associations between persistent respiratory symp- a part.15 While the majority of cases of RADS and IIA
toms (cough, wheeze and breathlessness) in workers (around 80 per cent) occur in the workplace, a significant
exposed to irritants. In the occupational setting, small but number occur in the home or in the wider environment.10
above normal exposures have been reported to result both As most of these events are reported post hoc, it is very rare
in accelerated fall in FEV1 over time and enhanced for measured levels of exposure to have been reported so
bronchial responsiveness.9 attempts at dose–response relationships are not possible.
Prevalence The most important causal factor is the dose of the agent,
as the nearer individuals are to a spill the greater is the risk
Because of the variation of definitions over the time since of developing RADS16,17 which was also the key factor in
RADS was first described, clear information on the epi- determining the risk of developing RADS after exposure to
demiology is difficult to secure, in particular in terms of World Trade Centre dust.14 Characteristically, males are
prevalence and prognosis.10 Much of the published litera- more represented in the RADS literature with approximate
ture in this area has been as case reports or short case series gender equality for IIA, the average age for both being in
which do not allow prevalence data to be defined, although the late 30s.10 Atopy does not appear to be a risk factor,
do identify causal agents. Depending upon the diagnostic although in much of the literature, atopy was not reported
criteria used, estimates of the prevalence of RADS or IIA which makes generalizations insecure.10 Whether current
range from 2 to 3 per cent1,11 to 18 per cent from the UK’s cigarette smoking is a risk factor for either RADS or IIA is
SWORD reporting scheme12 to 23 per cent for a range of unclear.
occupational populations, although most estimates lie in
the 3–6 per cent range.10 Even then, there are issues with
what population to use as a denominator – the total work- CLINICAL PICTURE
force exposed or the total workforce within that industry,
although using those exposed as the true denominator is In someone with RADS, by definition, symptoms should
both logistically better when reporting a series and more begin within 24 hours of exposure, although in some for
logical as those unexposed will not have had the chance to whom there is good evidence for causality there is delay in
develop symptoms. For example, one report of approxi- onset of symptoms of a few days. This is likely to be due to
mately 3000 people exposed to a pesticide spill (metam acceptance of minor symptoms as ‘normal’ or to the fact
sodium: monoalkyl dithiocarbamate which part decom- that the development of inflammation in some individuals
poses to methyl isocyanate) showed that 30 individuals is only at a later stage sufficient to induce symptoms.
(1 per cent of those exposed) fulfilled the criteria for IIA. In Symptoms are dominated by breathlessness and cough
this study, the authors included those with exacerbation which are reported in over two-thirds of cases, but wheeze
of pre-existing asthma,13 which again raises the issue of and chest tightness are reported in just under a half.10
variation in diagnostic criteria. Upper airway irritation, eye irritation and mucus produc-
tion are seen in fewer cases, usually between 10 and 20 per
cent. Clinical signs if present are non-specific with only
Causal agents occasional wheeze being heard in some cases. Lung func-
tion in RADS is either normal or shows a mild obstructive
The most important causal agents are gases, with chlorine pattern, whereas in IIA (when recorded, which is more
the most reported, but including also sulphur dioxide and often the case not reported) lung function is more likely to
nitrogen dioxide,10 a pattern which applies to both RADS be normal.10 In some affected individuals, particularly
and IIA. Between 1989 and 2003 in the United Kingdom, those in whom cough is the main symptom, good quality
over 330 cases of chlorine exposure causing respiratory lung function can be impossible to obtain, as forced expi-
symptoms were reported to the SWORD database, mostly ration results in coughing before expiration is complete.
as inhalation accidents, but 69 (20 per cent) of those exposed Bronchodilator reversibility has not often been recorded in
312 Reactive airways dysfunction syndrome and irritant-induced asthma
these individuals, although frequently symptomatic relief appears that, in contrast to individuals with occupational
over short time periods is reported by patients with use of asthma, patients with RADS do not necessarily develop a
beta-agonist bronchodilators. recurrence of their symptoms when re-exposed to a low
Vocal cord dysfunction (VCD) may also be present fol- level of the substance that initiated their problem.
lowing single exposures, a diagnosis which is difficult to Consequently, a worker with RADS may be able to return
make.18 Clinically, individuals complain of wheezy breath- to work if they can tolerate the prevailing exposure levels in
lessness or cough, classically inspiratory and often with their workplace.22
inspiratory or throat tightness. Dysphonia is a common
associated complaint. Diagnosis is made by direct laryn-
goscopy while inhaling an irritant which the individual PATHOLOGY
knows will cause symptoms, the classical appearance being
paradoxical adduction of either the false or true cords (or Thus, both single high-dose and repeated lower-dose expo-
both). Deformation of the flow volume loop with trunca- sures to relevant agents (alone or as complex mixtures) may
tion of the expiratory peak and flattening of the inspiratory result in persistent airway symptoms, but whether this is
limb if found is a helpful finding, although in most cases through the same mechanism(s) is not known. Cumulative
this test is normal. exposure over years may result in a chronic inflammatory
Treatment of RADS is based on that used in conven- response,23 but while there is some suggestion that in RADS
tional asthma therapy largely depending on inhaled steroids histologically there is less eosinophilic infiltration and more
and relief beta-agonists, but the response is often poor.10 One fibrosis,1 in general such differences are difficult to interpret
study found that patients with RADS showed considerably as the reported literature on the histology of RADS is very
less improvement when treated with inhaled
2-agonists limited. Nevertheless, the pattern of relative steroid resist-
alone than did patients with classical sensitization-associated ance might suggest a condition which in some individuals
occupational asthma with a latency period.19 In the reported may be more akin to the picture of chronic obstructive
literature, around one-third of patients are reported to be pulmonary disease or bronchitis than to asthma.24
taking inhaled steroids which would support the view that It is possible that specific exposures, such as exposures to
they may have limited benefit.10 The role of oral steroids is chlorine, may induce specific pathological responses.16,25
debatable, although anecdotally they may be of some help; One worker underwent bronchial biopsies on four occasions
supportive evidence for benefit has been demonstrated in a following exposure to chlorine.26 The histology revealed
mouse model.20 initial epithelial desquamation with a fibrinous exudate fol-
Treatment of IIA has not been subject to critical assess- lowed later by proliferation of basal cells, subsequent regen-
ment, but the condition is often more refractory to con- eration of the epithelium leading to collagen deposition
ventional asthma treatment much as in classical RADS. in the submucosa and basement membrane thickening,27
Treatment of VCD is also difficult, as inhaled therapy is which might explain the attenuated airflow reversibility seen
rarely effective. in RADS. Animal models have confirmed these stages28 but,
interestingly, inflammatory cells do not seem to play an
essential role. However, this proposed model is not consis-
PROGNOSIS tently supported in larger studies.29 There is no information
on the histopathology of RADS occurring in rescue workers
In classical RADS, the tendency is for improvement to involved in the World Trade Center disaster.14
occur over time, although in many individuals symptoms
continue for years. There is much less evidence about what
happens with IIA more broadly, although the impression is
Key points
that this is a much more permanent state of affairs.
However, there are as yet no longitudinal studies of out- ● Reactive airways dysfunction syndrome and
come in either of these particular groups. Prognosis can be
irritant-induced asthma are linked conditions
assessed by persistence of symptoms or by changes in
associated with single high exposures or
measures of bronchial hyper-responsiveness. Overall,
repeated lower-dose exposures to a range of
duration of symptoms is poorly recorded in the literature10
substances, most commonly gases such as
often because the case was reported before symptoms had
chlorine and chemicals.
ceased, the reason for publication being the need to report ● More than 60 agents have now been implicated
the causal agent before the long-term outlook had become
in the development of these conditions. In some
clear. Consequently, attempts to define likely average dura-
cases, the acute exposure was to a mixture of
tion of symptoms or rates of change in symptoms over time
substances where the mixture itself rather than
for prognostic purposes should be regarded with caution.
any specific single component may have been
However, in one follow-up study, normalization of both
the driver of effect such as has been suggested
FEV1 and PC20 to methacholine was seen in approximately
for workers exposed during the World Trade
a quarter of subjects two and a half years post-exposure.21
Center disaster.
This makes advice on return to work difficult although it
References 313
ROBERT L MAYNARD
What lessons can be learned from the above history? It Organophosphorus nerve agents
is clear that chemicals have great potential as weapons, that
this is known and that a number of groups (nations and Nerve agents comprise a group of highly toxic compounds
terrorists) have sought to use them in this way. It is also with the general formula:
clear that chemicals are likely to be most effective against
unprotected troops or civilians. That chemicals would be R1 O
used on a large scale in war seems unlikely, indeed attempts P
to destroy chemical weapons and to prohibit their use are R2 X
proceeding rapidly.3 Those at greatest risk today are prob-
ably civilians targeted by terrorist groups and, importantly,
Sarin (GB) has the formula:
those asked to rescue victims and care for them. It is with
this aspect of the deliberate use of chemicals to cause injury CH3
and death that this chapter deals.
CH3CHO O
P
TERRORISM CH3 F
Terrorism is by no means a recently developed activity. and is volatile (vapour pressure at 20°C 2.10 mmHg).
Terrorist organizations see themselves as fighting for a cause VX has the formula:
and, in general, may not feel bound by international agree-
ments regarding the ‘normal usages of warfare’. In particular, CH3CH2O O
terrorist groups may show little reluctance regarding attacks
P CH(CH3)2
on civilians and, indeed, may focus on these rather than on
CH3 SCH2CH2N
better protected military targets. The range of weapons avail-
CH(CH3)2
able to terrorist groups is wide: explosives being the most fre-
quently used. That chemicals have been so little used is
difficult to explain: access to chemicals by purchase or theft is and is not volatile (vapour pressure at 20°C
not difficult and dispersion of chemicals can be readily man- 0.00044 mmHg).
aged. Though it may be unprofitable to speculate as to why Nerve agents bind to and inhibit, effectively irreversibly,
chemicals have not been much used, it would be decidedly the enzyme acetylcholinesterase and thus cause an accu-
unwise to ignore the possibility that they could be used and mulation of acetylcholine at central and peripheral sites of
to fail to prepare to deal with the consequences of their use. transmission of nerve impulses. This leads to increased
The incidents in Japan are likely to have been noted and per- secretion from glands (salivary, nasal mucosal glands,
haps studied by other terrorist organizations. Recent events bronchial glands), bradycardia, contraction of the pupil
(early–mid 2007) in Iraq suggest that bulk carriers of chlo- (miosis) and skeletal muscle twitching. Death is caused by
rine have been targeted by terrorist groups. A completely suc- inhibition of the medullary respiratory centres and depo-
cessful defence against the use of chemicals by terrorists is larizing blockade of the diaphragm. Nerve agents may be
difficult or perhaps impossible to achieve: this, again, makes absorbed by the lung and across the skin: a volunteer at
preparations for dealing with the consequences of such use Porton Down died in 1952 after sarin was placed on his
importance. forearm under clothing that prevented evaporation. At
high concentrations, collapse occurs rapidly and death fol-
lows quickly. Low level exposure causes miosis, eye pain,
Chemicals that might prove attractive to conjunctival injection and headache. Fortunately, anti-
terrorists dotes exist: atropine to block the effects of acetylcholine at
muscarinic receptors and oximes (e.g. pralidoxime mesy-
It will be understood that all countries which perceive that late P2S) to reactivate the inhibited acetylcholinesterase.
they may be at significant risk of attack by terrorists will Diazepam is useful in preventing convulsions. These drugs
have prepared lists of chemicals that they anticipate might should be given as soon as possible by intravenous or intra-
be used. Such lists are, for obvious reasons, classified and muscular injection. Autoinjection devices containing 2 mg
no attempt will be made here to predict their contents. of atropine, 500 mg of P2S and 5 mg of a diazepam–lysine
However, it is obvious to all, including, presumably, conjugate (Avizafone) are commercially available. Assisted
terrorist organizations, that the so-called classical chemical ventilation is essential in all severely poisoned casualties.
warfare agents might prove attractive and certain toxic Exposure to nerve agents is unlikely to cause delayed
industrial chemicals (TIC) might be chosen for use as have peripheral neuropathy (OPIDN), but the intermediate
been recently reviewed by Marrs et al.4 Only a brief account syndrome may occur and long-lasting effects on the elec-
of classical chemical warfare agents not dealt with in other troencephalogram (EEG) and on memory function have
chapters of this book will be provided here. been reported.5
316 Deliberate use of chemicals in warfare and by terrorists
Sulphur mustard 1995. This account should be read by all interested in this
area.6 Only a brief summary, in note form, is provided here.
‘Mustard gas’ is a liquid of low volatility (vapour pressure
● On March 20, five terrorists punctured plastic bags
at 20°C 0.0650 mmHg). The structural formula is:
containing an impure preparation of sarin on Tokyo
CH2 CH2 Cl subway trains.
● Twelve people died, 5654 were affected, 999 people
S
were admitted to hospital, 4643 needed treatment (the
CH2 CH2 Cl large numbers are estimates and vary according to
source).
It is rather immiscible with water. ● Atropine was used as the major antidote and atropine
Exposure to the liquid and to the vapour causes intense, eye drops proved useful – this had been questioned in
but delayed, eye irritation and skin blistering. Blisters may earlier accounts.
contain up to a litre of fluid, but this fluid does not pose a ● Oxime (2-PAM, pralidoxime chloride) was not thought
hazard to the patient or to attendants: mustard binds rapidly to have been life saving, although it was used.
to proteins. Sulphur mustard has a radiomimetic effect: ● Secondary contamination led to medical and paramedical
damaging bone marrow and the airway and gut epithelium. staff being affected.
Its lethality is low, but patients require weeks of care to make ● A ‘field test’ for sarin failed to identify or detect the
a full recovery. Eye damage may cause delayed keratitis lead- agent.
ing to blindness. No antidote is known and management is ● Long-term effects, including visual disturbances, eye
supportive. Eye damage can be severe and sticking of the discomfort, headache, fatigue and vestibulocerebellar
eyelid margins can be a problem. Vaseline to prevent this disturbance, were reported. Measures of visual evoked
and saline irrigation are useful. Hoscine (0.25 per cent) potentials (P300 and VEP) and heart rate variability
drops to relieve spasm of the iris are also helpful. (R–R interval) also showed long-lasting effects. Post-
Photophobia may be severe. Ascorbate and citrate eye drops traumatic stress disorder (PTSD) questionnaire scores
have been recommended. In cases of bone marrow depres- were high. That medical and paramedical staff were
sion advice regarding bone marrow stimulation with affected by off-gassing of sarin from patients was
colony-stimulating factors should be sought. Skin lesions notable and in some ways surprising. Casualties had
are slow in healing and flamazine cream can be useful in pre- been exposed only to vapour (not to liquid) and yet
venting secondary infections. Caring for a patient exposed enough was retained on clothing to produce secondary
to a high concentration of sulphur mustard: temporarily effects. It should also be noted that though the number
blinded, coughing sloughed respiratory epithelium, with dying was low, some thousands of people attended
widespread skin blisters and a collapsing bone marrow is a hospitals. This overloading of medical facilities is likely
major challenge. Despite this, the death rate in the First to occur as a result of the use of chemicals and to be a
World War was 2 per cent. Other classical chemical war- serious logistical problem in a terrorist incident. That
fare agents (hydrogen cyanide, chlorine and phosgene, and the medical and paramedical staff coped as well as they
arsenical compounds) are dealt with in Chapter 8, Gases. did with a frightening and unique challenge can only be
One group of compounds that might prove attractive to a matter for congratulation regarding their training and
terrorists are the so-called riot control agents. Of these CS dedication.
(sometimes called CS gas though it is usually encountered as
a finely divided powder dispersed as an aerosol) is perhaps
the best known. Riot control agents are remarkable in that
they cause intense and incapacitating eye irritation, but are
Dealing with a terrorist incident involving
characterized by remarkably large LD50 values. The intra-
the use of chemicals
venous LD50 of CS in the male mouse is 48 mg/kg and yet the
The key to success is teamwork. Emergency services,
TC50 (concentration intolerable to 50 per cent of the popula-
medical services and local authorities need to combine to
tion) is 3.6 μg/L. Exposure to the aerosol produces no lasting
(1) assess risks, (2) plan how to deal with incidents and
effects and the acute effects on the eye disappear rapidly on
(3) exercise their plans. Detailed accounts of this have
the patient being removed from the source of exposure. Eye
been provided by Baker7 and by Roberts and Maynard.8
damage as a result of spraying directly into the eye can occur.
Here, we focus on patient care, but other issues including
provision of appropriate protective equipment and chem-
Japanese experience with nerve agents ical detectors for first responders are also very important.
deployed by terrorists Modelling the dispersion of chemicals is also vital for
planning. Real-time modelling of dispersion during
Okumura and colleagues6 have provided a disturbing an incident is difficult, but may be possible, especially if
account of the consequences of the release of sarin (GB) by the area affected has been studied in advance. Much, of
the Aum Shinnikoy cult on the Tokyo subway on March 20, course, depends on the nature of the incident. In Tokyo, a
Terrorism 317
chemical was released in a closed (not outdoor) environ- Medical care at the scene
ment and it is likely that the release, though not instanta-
neous as would be produced by an explosion, was short-lived. The organization of medical care at the scene of a chemi-
A slow release, for example, from cylinders or a tanker is also cal incident is a hotly debated topic. Some authorities
possible and this would present a different set of problems. recommend dispatching a medical team to the scene with a
In approaching chemical casualties a number of golden consultant in intensive care to take charge of casualty man-
rules should be noted: agement.7 Others argue that holding medical staff at hospi-
tals and allowing paramedics to take the lead at the scene is
1. Attendants and rescue workers must be protected – if more appropriate. The former approach is adopted in
not, they may soon become casualties. Paris, the latter in London. Whichever staff are present at
2. Casualties must be decontaminated before admission the scene, they must be trained in the rapid identification
to hospitals or other facilities where unprotected staff of the effects of chemicals. It is important to note that the
are working. incident may not be known to involve chemicals and rec-
3. Life supporting care is the first priority. ognizable effects may provide the first clue to this. Having
4. Specific antidotes are few but, if available, should be an experienced clinical toxicologist at the scene would
given as soon as possible. clearly help. However, such trained medical staff are few
5. The identity of the chemical producing the casualties and form a resource that should be carefully deployed.
may not be known at first and treatment of effects will Sending medical staff into the hot zone is also debated: the
be needed. For example, lung injuring agents may level of protective equipment sometimes recommended
cause bronchospasm. Management of effects does not, may significantly reduce the diagnostic skills of even senior
in general, depend on knowing the exact identity of the doctors and closed circuit breathing apparatus plus an
causative agent. impermeable protective suit may make such tasks as intu-
bation and establishing an intravenous line difficult. This
leads to the question of what level of protection needs to
Decontamination of casualties be worn. If the nature of an incident is unknown, there is
likely to be a tendency to overprotect staff.
Removing a casualty’s clothing may remove 80 per cent of
liquids or powder contamination. This, then, is the first step
towards decontamination. Water is the key decontaminant. What drugs can be given in the hot zone?
If a little dilute bleach can be added to the water, this will
improve decontamination by aiding hydrolysis. The logisti- It has already been noted that there are very few effective
cal problems of decontaminating a few hundred casualties antidotes of proven value in chemical poisoning. This is
are formidable and need to be addressed by planning and sometimes forgotten and it is imagined that medical staff at
exercises. Crowd control is critically important and close the scene of an incident will have a battery of effective
liaison between the police and resource services is needed. It drugs with which to treat casualties.
should be noted that in Tokyo the majority of subjects made In fact, the effects of only two chemicals that might be
their own way to hospital undecontaminated. In many used by terrorists can be treated by means of antidotes.
countries, mobile decontamination units have been devel- Casualties exposed to nerve agents causing collapse and
oped and facilities for showering and reclothing in clean gar- impairment of respiration should be treated at once with
ments are provided. Preventing hypothermia is obviously atropine and oxime. Delay can be fatal and provision of
important and some facilities provide warmed water. autoinjection devices that can be used to give an intramus-
Decontamination of collapsed patients presents special cular injection through clothing is important. This should
problems: at its simplest a ‘bucket and sponge’ approach is be done as soon as the diagnosis is made. A patient with
satisfactory. Decontamination using solid decontaminants, breathing difficulties, who has small pupils and who is
such as fullers’ earth, is now not generally recommended. salivating or twitching needs atropine and oxime at once.
Separating the contaminated (or potentially contami- The second cause of poisoning that calls for rapid antidote
nated) from the decontaminated is important. In many therapy is cyanide. Exposure to hydrogen cyanide is rap-
countries, the incident area is divided into ‘hot’, ‘warm’ idly fatal and the likelihood that rescuers will reach patients
and ‘cold’ zones. In the hot zone, there is a risk of primary at risk of dying sufficiently quickly to give an antidote is
contamination by the released chemical or chemicals: only low. Whether Kelocyanor® or the combination of sodium
well-protected staff can enter this area. In the warm zone, nitrite and sodium thiosulphate is used, the antidote must
the risk to staff is from contaminated patients: the level of be given intravenously. This presents difficulties in the hot
protection needed by staff will be less than in the hot zone. zone. Cyanide casualties who survive exposure and who
In the cold zone, only decontaminated patients are allowed are breathing spontaneously on being brought out into the
and here the risk to staff is small and only normal clinical fresh air do not need antidote therapy: this is unlike the
measures, e.g. gloves, are needed. Maintaining the integrity case of nerve agent poisoning where antidote therapy is
of these zones is clearly important. needed for some time. It is important to stress again that
318 Deliberate use of chemicals in warfare and by terrorists
Table 42.1 Examples of aliphatic hydrocarbons with their molecular structures and main hazards.
H2C
Table 42.2 Alkanes and their boiling points. contains small amounts of n-hexane. Exposure to n-hexane
in workplaces occurs primarily via inhalation.
Alkane Boiling point (°C)
Clinical effects and epidemiology
Methane 162 n-Hexane is not irritating and its acute toxicity is low.
Ethane 89 Acutely it may result in central nervous system (CNS) depres-
n-Propane 42 sion at exposure levels of approximately 1000–5000 ppm
n-Butane 0.5 (3500–17 000 mg/m3). (In this chapter, the ppm to mg/m3
n-Pentane 36 conversion is performed assuming a temperature of 20°C
n-Hexane 69 and an atmospheric pressure of 101.3 kPa, used in most
n-Heptane 98 European countries.) Its main hazards are, however, related
n-Octane 126 to long-term exposure resulting in neurotoxicity. n-Hexane
n-Nonane 151 has been shown to induce peripheral neuropathy in humans,
n-Decane 174 which was first observed in the shoe-manufacturing indus-
try in Japan and Italy. In an early epidemiological study
carried out in sandal manufacturing in the 1960s, 93 cases
of polyneuropathy (both sensory and sensorimotor neu-
ethylene. Alkenes have a molecular formula of CnH2n. ropathy) were diagnosed out of 296 examined workers.1
Ethylene is followed by propene (propylene) and butenes Exposure levels were said to range from 500 to 2500 ppm
(1-butene, 2-butene and isobutylene). Like corresponding (1700–9000 mg/m3). Common signs and symptoms of
alkanes, ethylene, propylene and butenes are highly flam- n-hexane polyneuropathy include numbness in the distal
mable gases. With increasing chain length, the boiling portions of the extremities, muscle weakness, hypoactive
points of alkenes increase. reflexes, coldness, reddishness and roughness of the skin.
In contrast to alkenes, dienes contain two carbon– Numbness in the feet and hands are the first symptoms
carbon double bonds in their hydrocarbon chain. Rubber to appear, followed by weakness in the lower legs and feet.
is a natural polymer of isoprene (2-methyl-1,3-butadiene). The severity of the symptoms depends on the exposure:
1,3-butadiene is a compound used in the manufacture of occupational exposure to 500 ppm (1700 mg/m3) may result
synthetic rubbers like styrene-butadiene rubber and in overt neuropathy, whereas subclinical reductions in nerve
polybutadiene rubber. conduction velocities may be observed after a few years of
Alkynes contain a carbon–carbon triple bond in their exposure at air levels of 100 ppm (350 mg/m3).2–4
hydrocarbon chain. They have a general molecular for- Muscle wasting and atrophy have been reported in indi-
mula of CnH2n2. The simplest alkyne is acetylene, which is viduals with severe n-hexane neurotoxicity, although CNS
commonly used as a welding gas. Like alkanes and alkenes, symptoms may not be present. In EMG examination, abnor-
the first compounds in this series are highly flammable malities in conduction velocity, distal latency and action
gases at room temperature, whereas higher homologues potential amplitudes have been reported.4 The findings
are liquids. Acetylene has a low toxicity, but it may act as a may be subclinical. Biopsies of peripheral nerves may show
simple asphyxiant by lowering the oxygen content of the demyelination and infiltration of leukocytes. After cessa-
air in confined spaces. tion of exposure, gradual improvement may be seen. A
Generally, many aliphatic hydrocarbons may cause follow-up study5 of shoe manufacture workers diagnosed in
acute central nervous system depression at high exposure the past with n-hexane polyneuropathy showed some
levels. Some of them, like methane and acetylene, work as improvement in motor nerve conduction velocities and
simple asphyxiants. In occupational medicine, the most distal latencies one year after the cessation of exposure.
important compounds in this group are n-hexane and However, sensory nerve conduction velocities and distal
1,3-butadiene, which are discussed in detail below. latencies, while improved from those at diagnosis, were still
statistically significantly worse than in controls. The neuro-
n-HEXANE toxicity of n-hexane is caused by one of its metabolites,
2,5-hexanedione, which is formed by P450-mediated oxida-
[CAS No. 110-54-3] tive metabolism.4 The mechanism of action of n-hexane
polyneuropathy may involve formation of lysine adducts
H3C
CH3 and cross-linking, resulting in neurofilament accumula-
tion, axonal swelling and ultimate axonal degeneration.4
n-Hexane is a volatile, colourless liquid with a characteris- Methyl ethyl ketone (MEK) and methyl iso-butylketone
tic disagreeable odour and a high vapour pressure. It is (MiBK) have been shown to enhance the neurotoxicity of
produced from the refining of crude oil, and has been used n-hexane via metabolic interaction.4 It has also been sug-
in special glues, for example in shoe-making, as a solvent in gested that acetone potentiates n-hexane neurotoxicity by
certain processes and as a laboratory chemical. Gasoline decreasing the body clearance of 2,5-hexanedione.6
324 Organic chemicals
MFO
O GSH-S-TRANSFERASE
CH 2 - CH - CH - CH2
O O
DIEPOXYBUTANE CH2 - OH - CHOH - CH = CH2 BUTENEDIOL
GLUTATHIONE CONJUGATE
EPOXIDE HYDROLASE
Other significant compounds in this group are ethyl- cyclohexane, nitrobenzenes, alkylbenzenes, chlorobenzene
benzene, cumene and vinyl toluene. Irritation and central and maleic anhydride.14 Only very small quantities are
nervous system effects are the main hazards related to these used nowadays as a laboratory reagent or as a solvent.
substances. Similar to styrene, ethylbenzene is metabolized Cigarette smoke also contains benzene.
to mandelic acid and phenylglyoxylic acid. Urinary mandelic
acid can be used for the biomonitoring of ethylbenzene Clinical effects and epidemiology
exposure. Occupational exposure to benzene occurs mainly by
inhalation, but it is also well absorbed through the skin.
BENZENE Acute (few hours) exposure to benzene at exposure
levels of 50–150 ppm (160–500 mg/m3) can cause
[CAS No. 71-43-2] headache, weakness and drowsiness.14 However, the
most relevant health hazard of benzene in occupational
settings is related to its long-term toxicity to the
haemopoietic system.
Haematotoxicity
Benzene is a clear colourless liquid with a vapour pressure Benzene has been shown to induce haematotoxic effects
of 10 kPa at room temperature. Crude oil is the main natu- varying from depression of white and red blood cell counts to
ral source of benzene. Motor fuel and coal tar also contain potentially life-threatening aplastic anaemia and leukaemia.
benzene. In motor fuel, benzene exists usually at concen- Decreases in white and red cell counts have been seen after
trations of 1–5 per cent. Exposure to benzene has occurred long-term exposure to levels of 10–20 ppm (30–60 mg/m3)
especially in the petroleum industry. Benzene is used also of benzene. These effects on blood cell counts have usually
as an intermediate for chemical synthesis; it forms the basis been reversible, whereas aplastic anaemia resulting from
for the production of a great variety of aromatic and bone marrow failure may be irreversible. According to
cycloaliphatic compounds such as ethylbenzene, cumene, recent studies,15,16 the most sensitive reaction in humans
326 Organic chemicals
to long-term benzene exposure is lymphocytopenia. When stress induced by benzene metabolites (especially phenolic
compared to controls, statistically lower lymphocyte metabolites, but also benzene oxide, trans, trans muconalde-
counts have been reported in workers exposed to benzene hyde), which may result in DNA damage in bone marrow
levels of 1–31 ppm (3–100 mg/m3).15,16 cells.24 Benzene is regarded as a genotoxic carcinogen since
it has been shown to induce chromosomal aberrations
Leukaemia and micronuclei in animal tests. However, most of the bac-
Benzene is classified by IARC as a group 1 carcinogen17 terial tests for gene mutations for benzene have been nega-
because of its ability to cause leukaemia in humans. Acute tive.14,25,26 Genetic differences in benzene-metabolizing
myeloid leukaemia (AML) has been shown to be related to enzymes (especially CYP2E1) may affect the sensitivity of
benzene exposure. Also an association between benzene different individuals to benzene toxicity.
exposure and other types of haematological malignancies,
such as multiple myeloma and non-Hodgkin’s lymphoma, Metabolism and monitoring
has been suggested.18,19 Leukaemias caused by benzene Once absorbed, benzene is rapidly distributed throughout
have often been associated with predisposing myelodys- the body (Figure 42.2). Because of its lipophilicity, lipid-
plasia or aplastic anaemia. rich tissues have been found to contain the highest levels of
Estimates on the exposure–response relationships of benzene.26 Benzene is metabolized to a number of metabo-
benzene-induced cancer vary between different studies, with lites by the cytochrome P450 mixed-function oxidase
some studies suggesting significant increases at cumulative system. CYP2E1 is one of the most important isoenzymes
exposures of 40 ppm years (e.g. exposure to 1 ppm con- metabolizing benzene. It has been shown that oxidative
centration for 40 years) and some only at dose levels of metabolism of CYP2E1 is needed for the induction of
200 ppm years.20,21 Other studies have suggested the role of haematotoxic and genotoxic effects of benzene. Since
high peak exposures.22 The latency period for benzene- ethanol is able to induce CYP2E1, alcohol consumption
induced leukaemia may be up to ten years.23 can enhance benzene toxicity.
Mechanisms behind benzene haematotoxicity and Excretion of benzene metabolites occurs mainly in the
leukaemia are still unclear, but may include oxidative urine, whereas after inhalation unchanged benzene is rapidly
Benzene
dihydrodiol Catechol
Benzene OH OH
DHDD
O
OH OH
H3C NH
OH CYP2E1 EH
O
ADH OH
S FE/OH· ALDH
CYP2E1 O O O
O O
GSH
trans,trans-Muconaldehyde OH
O
S-Phenylmercapturic Benzene Benzene trans,trans-Muconic acid
acid oxide oxepin
Rearrangement
Hydroquinone
Phenol Catechol
OH OH
OH
CYP2E1 CYP2E1
HO OH
CYP2E1
CYP2E1
NQO1 MPO NQO1 MPO
O 1,2,4-Benzenetriol
OH
O O
1,4-Benzoquinone HO OH O
1,2-Benzoquinone
eliminated in exhaled air. The main metabolites measured well-known and widely used aromatic hydrocarbons with
in urine include S-phenyl mercapturic acid, trans, trans- a benzene ring-based structure. Toluene has one methyl
muconic acid, phenol and phenolic metabolites. Trans, group bound to benzene ring, whereas xylene has two
trans-muconic acid is commonly used for biological mon- methyl groups allowing three different isomers: ortho-,
itoring of benzene exposure, but at low exposure levels diet meta- and para-isomers. Styrene has a vinyl group with a
may interfere with the assessment since sorbic acid present double bond bound to benzene ring making it possible to
in diet is also metabolized to trans, trans-muconic acid. form polymers.
S-phenyl mercapturic acid is not as sensitive to dietary Toluene (methyl benzene) is a volatile, highly flamma-
effects and it has been shown to correlate well with blood ble liquid with a vapour pressure of 3 kPa at 20°C. It has a
benzene levels.27 Since cigarette smoke contains benzene, sweet benzene-like odour. Toluene is produced by differ-
smoking is one of the confounding factors in the interpre- ent petroleum conversion processes. The main use of com-
tation of biomonitoring results. mercial toluene is as an intermediate in the production of
other chemicals, but it is also widely used as a solvent in
Management and diagnosis paints, thinners, adhesives, inks and as an extraction sol-
Monitoring and controlling of exposure to levels as low vent in the production of pharmaceutical and other chem-
as technically feasible is important in the prevention of ical products.28 Significant exposure to toluene may occur
benzene-caused cancers. At the dose levels following in painting, gluing (for example, in car or boat upholstery)
modern standards for controlling exposure (e.g. to below or in rotogravure printing.
the American Conference of Governmental Industrial Xylene (dimethylbenzene) is a colourless liquid with a
Hygienists (ACGIH) threshold limit value (TLV) of 0.5 ppm sweet benzene-like odour. Technical xylene is a mixture of
(1.6 mg/m3)), risks of developing health effects are likely to xylene isomers with 4–20 per cent o-xylene, 44–60 per cent
be very low. m-xylene and 12–20 per cent p-xylene. Some technical
If AML has been diagnosed, the classical circumstances grades may also contain ethylbenzene and small amounts
that might support benzene as a potential cause are:23 of benzene or toluene as an impurity. Xylene has a vapour
pressure 0.8 kPa at 20°C. Like toluene, it is produced by
● occurrence of certain forms of myelodysplastic syndrome; petroleum conversion processes. Xylene is used as a solvent
● defects in chromosome 5 or 7; in a variety of different applications, but also to a great extent
● a substantial exposure history with a cumulative dose of for further separation into the three isomers through distil-
at least 40 ppm-years during the preceding ten years; lations and fractionated crystallization. Separated isomers
● a poor response to anti-leukaemic chemotherapy.23 are used for the production of other chemicals, e.g. ortho-
xylene is used for the synthesis of phthalic acid anhydride,
Confounding aetiologic factors include heavy cigarette and para-xylene for the production of dimethylterephtha-
smoking, previous exposure to chemotherapy or radiation, or late and terephthalic acid, which are then used for the pro-
certain underlying constitutional disorders, such as Down’s duction of polyethyleneterephthalate (PET). All three
syndrome or pernicious anaemia.23 However, the occurrence isomers are also raw materials for the synthesis of vitamins,
of de novo AML and myelodysplasias in the general popula- pharmaceuticals and flavouring agents. Significant expo-
tion increases dramatically with advancing age and these dis- sure to xylene may occur in painting, especially in spray
eases may exhibit similar chromosomal changes as those painting with xylene.
found in benzene-caused AMLs in younger individuals, even Styrene (vinyl benzene) is a colourless to slightly yellow
without any specific history of hazardous exposures.23 volatile liquid with a sweet and pungent odour. It has a
vapour pressure of 0.6 kPa at 20°C. On exposure to light
TOLUENE, XYLENE AND STYRENE and air styrene polymerizes, but it can also oxidize to form
certain aldehydes and ketones. Styrene is mainly produced
CH2 commercially from crude oil. The main use of styrene is as a
precursor to polystyrene, an important synthetic material.
It is also used in the production of co-polymers, e.g. acry-
H3C lonitrile–butadiene–styrene, styrene–acrylonitrile, methyl
methacrylate–butadiene–styrene and in the production of
Toluene Styrene styrene–butadiene rubber (SBR) and related latices (e.g. SB
H3C
latex). In the production of glass-reinforced plastics, styrene
is added to unsaturated polyester resins to act as a cross-
H3C CH3
linking agent and reactive diluent. It also acts as a solvent
H3 C H3C CH3 for the resins. Significant styrene exposure may occur in
glass-reinforced plastic plants and in boat manufacturing.
o-, m-, p-xylenes
All three compounds are well absorbed by inhalation.
Toluene (CAS No. 108-88-3), xylene (CAS No. 1330-20-7, Dermal absorption also occurs and it contributes to total
mixed isomers) and styrene (CAS No. 100-42-5) are systemic exposure.
328 Organic chemicals
Clinical effects and epidemiology Since occupational exposure to solvents usually involves
Acute effects mixtures of different solvents, it is difficult in epidemiologi-
cal studies to show associations between a specific solvent
The main target organ for these compounds is the central exposure and long-term CNS effects. However, rotogravure
nervous system. In uncontrolled situations, all three com- printers are exposed almost purely to toluene and past
pounds can easily form air concentrations resulting in exposure levels may have been considerable. There are some
acute central nervous system effects like headache, dizzi-
studies suggesting an increased risk of organic brain syn-
ness, drowsiness and drunkenness. Dose–response rela-
drome in these toluene-exposed workers. A higher frequency
tionships on these acute effects are presented in Table 42.3.
of organic brain syndrome in subjects exposed to toluene
Accidental high-level exposures have also caused liver and
for more than 12 years has been observed.36 In another
kidney changes.28–30
study,37 toluene-exposed workers had substantially more
neurasthenic symptoms and scored lower in psychometric
Solvent-induced, long-term neurotoxicity tests. However, in more recent studies no significant effects
Long-term, low-level exposure to solvents may cause have been seen in rotogravure printers.38,39 It appears that
chronic neurotoxicity, which may become evident as so- at low exposure levels in modern industry, the risk of long-
called ‘chronic solvent encephalopathy’ (CSE) or ‘chronic term CNS effects from toluene is low.
toxic encephalopathy’ (CTE).31 Symptoms related to Workers occupationally exposed to solvent mixtures
chronic toxic encephalopathy are unspecific, including including xylene have been reported to have neurophysio-
fatigue, poor memory, difficulties in concentration, emo- logical and psychological disorders,30 but since xylene is
tional lability and depression.32 Memory is suggested to be one of several different components of the solvent mixtures,
the first mental property to be impaired in chronic toxic it is difficult to attribute these effects to xylene alone.
encephalopathy.32 The most persistent dysfunction in Since high styrene exposures have occurred in the glass-
chronic toxic encephalopathy seems to be difficulties in reinforced plastics industry, there are many studies evalu-
tasks demanding working memory processing, which is a ating the neuropsychological effects of long-term styrene
good predictor of the CSE status.33 The memory deficits in exposure. In some of these studies, effects on neurological
CTE may resemble those seen in moderate or severe and neuropsychological function have been seen but the
Parkinson’s disease.33 results have been variable.29,40 Benignus and co-workers41
Other neurobehavioural disorders related to CTE conducted a meta-analysis of several studies on styrene
include possible defects in colour vision and visual exposure and effects on reaction times (simple and choice
perception. CSE patients may have impaired colour reaction times: in simple reaction time (SRT), the subject
discrimination ability, despite their eyes and their must simply react to a predefined stimulus as quickly as
other visual functions being normal.34 Visual search possible, whereas in choice reaction time (CRT), the sub-
performance may also be impaired when compared ject must first select between options before deciding
to healthy controls.35 whether to respond or not and how to respond) and colour
Table 42.3 Acute effects of toluene, xylene and styrene and their dose–response relationships.28–30
Eye or mucosal irritation 75–100 ppm (300–400 mg/m3) 460 ppm (2000 mg/m3) Slight: 200 ppm (900 mg/m3)
Severe: 375 ppm (1600 mg/m3)
Mild CNS effects 75–100 ppm (300–400 mg/m3): 200–300 ppm (900–1300 mg/m3): 200 ppm (900 mg/m3):
headache, dizziness, feeling of slight effects on neuro- impairment in neuro-
intoxication and sleepiness. psychological performance, psychological test
Impaired performance in including increased reaction performance
neuropsychological tests times
700 ppm (3000 mg/m3): headache, 400–600 ppm (1700–2600 mg/m3):
dizziness, feeling of intoxication headache, dizziness, feeling
and sleepiness of intoxication and sleepiness
Serious CNS effects
5000 ppm (20 000 mg/m3): 5000 ppm (22 000 mg/m3): 800 ppm (3500 mg/m3): signs
and death unconsciousness and death unconsciousness and death and symptoms of pronounced
CNS depression
2500–5000 ppm
(11 000–22 000 mg/m3):
unconsciousness and death
Hydrocarbons 329
vision (using a colour confusion index that measures the related to hearing loss. The odds ratio estimates for hearing
ability to discriminate between colours). According to this loss were 1.76 times greater for each gram of hippuric acid
analysis, eight years of exposure to 20 ppm (90 mg/m3) of per gram of creatinine.
styrene was estimated to produce a 6.5 per cent increase in
Other long-term hazards
CRT, whereas no significant effect was observed on SRT.
An increase in colour confusion index (CCI) was seen; Styrene has caused lung tumours (mainly adenomas) in can-
with similar exposures estimated to cause a 2.23 per cent cer bioassays in mice. In humans, no clear and consistent
increase in CCI, which is the same as the expected effect of epidemiological evidence for the causal link between can-
1.7 additional years of age in men. cer and exposure to styrene exists. Mutagenicity of styrene
is equivocal, although some studies show that styrene may
Aromatic hydrocarbon solvents and ototoxicity be weakly clastogenic in humans. The possible genotoxicity
Organic solvents have also been suggested to induce and carcinogenicity of styrene is considered to be mediated
ototoxicity. A review found the incidence of sensorineural through reactive metabolites, especially styrene 7,8 oxide
hearing loss to be higher than expected in noise-exposed (SO) and 4-vinylphenol (4-VP). Clara cells in mice bron-
workers who were also exposed to solvents.42 Aromatic chioles can metabolize styrene to these active metabolites.
hydrocarbon solvents are among the best studied occupa- Since Clara cells are not as abundant in humans as in mice,
tional toxicants suggested to cause ototoxic effects in there has been discussion regarding whether or not these
humans. carcinogenic effects seen in mice are relevant in humans.
The most convincing data on the ototoxicity of indus- The IARC has classified styrene as a group 2B carcinogen.48
trial chemicals are those relating to styrene. Exposure to Based on animal studies, all these aromatic solvents may
low levels of styrene and noise was studied in a cross- cause developmental toxicity.28–30 The effects seen include
sectional study in Sweden.43,44 According to the results, decreases in birthweight, delayed development and devel-
noise exposure (past and current) and urine mandelic acid opmental neurotoxicity. In the case of toluene, data on
levels (the biological marker for styrene exposure) were pregnant women sniffing toluene showed low birthweight
significantly related to the incidence of hearing loss; the and neurological dysfunction in their offspring.
odds ratios for hearing loss were 2.44 times greater for These aromatic solvents have a degreasing effect on the
each mmol of mandelic acid per gram of creatinine, 1.18 skin of humans, resulting in dermatitis on repeated skin
times greater for each dB of current noise exposure, and exposure. They are not known to be skin sensitizers.
1.19 times greater for each year of age. Workers exposed Metabolism and monitoring
to noise and styrene had significantly poorer pure-tone
thresholds in the high-frequency range (3–8 kHz) than the Toluene
controls or, for example, noise-exposed workers. Supporting Most of absorbed toluene is metabolized in the liver by the
results have been obtained in a Polish study in which hear- P450 system and excreted in urine (Figure 42.3). Around
ing loss was observed in 76 per cent of the workers exposed 20 per cent of absorbed toluene is eliminated in expired air.
to styrene and noise or styrene and toluene, in 57 per cent Toluene is metabolized via benzyl alcohol and benzalde-
of the styrene-only group, 56 per cent in the noise-only hyde to benzoic acid, which is then conjugated with glycine
group, and 33 per cent in the unexposed group. Hearing loss and excreted in the urine as hippuric acid. If insufficient
was observed in styrene-exposed workers (seen as higher glycine is available, the benzoic acid may be conjugated
mean audiometric thresholds, especially at 2–6 kHz, but with glucuronic acid to form benzoylglucuronide. Small
also at 8 kHz frequencies).45 Noise levels ranged from 78 to amounts of toluene undergo ring hydroxylation to form o-,
86 dB and styrene levels in the styrene-exposed groups m- and p-cresol, which are excreted in the urine as sulphate
were from 11 to 38 ppm (48–160 mg/m3) on average. or glucuronide conjugates.28
According to recent studies, styrene may also affect Toluene exposure can be monitored by measuring
balance. Toppila and co-workers46 evaluated the effects of blood toluene levels or hippuric acid levels in urine.
low concentrations of styrene on balance among Finnish Although good correlation between toluene air levels and
fibreglass-reinforced plastic boat manufacturers. They concentration of hippuric acid in post-shift urine samples
found impairment in postural stability in those working as have been demonstrated, background levels of hippuric
laminators. acid formed as a product of endogenous metabolism, and
There are also some data suggesting an association metabolism of substances present in food may decrease the
between toluene exposure and an increase in the occur- sensitivity of the method. At exposure levels below 100 ppm
rence and severity of noise-induced hearing loss. Prevalence as eight-hour time-weighted average (TWA) (380 mg/m3),
of hearing loss caused by toluene was evaluated in a study urine hippuric acid cannot be used to separate an exposed
involving 124 rotogravure printing workers exposed to person from an unexposed one.49 In some developing
various levels of noise and an organic solvent mixture of countries, low urinary hippuric acid background levels are
toluene, ethyl acetate and ethanol.47 Forty-nine per cent of found, and so it can be used as a biological marker for
the workers had hearing loss. Age and urinary hippuric acid toluene exposure even at exposure levels lower than 100 ppm
(the biologic marker for toluene in urine) were significantly (380 mg/m3).28
330 Organic chemicals
CONHCH2COOH
CH 2OH COOH
EXHALED
UNCHANGED
25–40% 60–75% BENZYL BENZOIC ACID
ALCOHOL
CH3
Glucuronic
10–20% acid
~0.1% OH
TOLUENE
~1% o-CRESOL
GLUCURONIDE AND
SULPHATE CONJUGATES
CH3 CH3
OH
OH
m-CRESOL
p-CRESOL Figure 42.3 Metabolism of toluene.50
conjugates
OH
CH=CH3
CH=CH2 + CH=CH2 1-phenylethanol
CH=CH2 H2O
O
H H
O CH2-CH2OH
H styrene
styrene 1, 2-oxide styrene 3, 4-oxide H
2-phenylethanol
C CH2
H
O CH2 C
CH=CH2 CH=CH2
styrene O
OH HO 7, 8-oxide
2-vinylphenol 4-vinylphenol phenylacetaldehyde
H OH
SG OH C CH2 ?
CH2 COOH
CH CH2 + CH CH2 OH
OH SG phenylethylene
GSH conjugate 1 GSH conjugate 2 glycol phenylacetic acid
glucuronide O
acetate
H CH2 C N CH2 COOH
1-phenyl- 2-phenyl-
2-hydroxy- 2-hydroxy- C COOH
ethylmercapturic ethylmercapturic H
acid acid OH phenylaceturic acid
O mandelic acid O
C COOH
COOH C N CH2 COOH
H
phenylglyoxylic
acid benzoic acid hippuric acid
CONJUGATION
WITH GLYCINE
EXPIRED CH2OH CHO COOH OR TO A SMALL
UNCHANGED EXTENT WITH
alcohol aldehyde GLUCURONIC
dehydro- dehydro- ACID
genase genase
CH3 CH3 CH3
m-Methyl-benzyl m-Methyl- m-Methyl-
CH3 alcohol benzaldehyde benzoic acid
microsomal
oxidation
CH3
m-Xylene OH
CH3
CONJUGATION WITH
SULPHATE OR (MINOR PATHWAY)
GLUCURONIC ACID
CH3
2,4-Xylenol
disease, brain injuries, tumours and infections, vitamin B12 stops after the cessation of exposure. If clear progression
deficiency, disturbances in cerebrospinal fluid circulation of organic brain disease occurs after the cessation of
and effects caused by other toxic agents, for example exposure, other aetiological causes for the disease should
alcohol and medicines. The progression of CSE usually be considered.
332 Organic chemicals
Naphthalene Anthracene
Polycyclic aromatic hydrocarbons from crude oil contain 10–100 times less PAHs than cre-
osote produced from coal tar.
Polycyclic aromatic hydrocarbons (PAHs) are formed in Occupational exposure to PAHs occurs via the inhalation
incomplete combustion processes. They exist almost always of fumes or aerosols containing PAHs, or via skin contact.
as mixtures of several different compounds, except single Most PAH compounds have low vapour pressure and exist
compounds such as naphthalene, which has been widely in particulate phase in workplace air, but some lighter PAHs,
used in moth repellents for clothing. like naphthalene and phenanthrene, are found almost exclu-
PAHs consist of two or more fused benzene rings, the sively in gaseous phase. Occupations in which exposure to
simplest being naphthalene, anthracene and naphthacene PAH mixtures may occur are listed in Table 42.4.
(Figure 42.6). The most well-known PAH compound is
benzo[a]pyrene. Industry, traffic and heating produce NAPHTHALENE
PAH compounds in the environment. Thus, all individuals
are exposed to PAHs via the environment, from cooking Naphthalene (CAS 91-20-3) is used as an intermediate for
food, and from tobacco smoke. phthalic anhydride production and in the production of
Industrially important mixtures containing polycyclic azo dyes and naphthalene sulphonic acids. The use of naph-
aromatic hydrocarbons include coal tar creosote, which is thalene as a moth repellent and insecticide has decreased in
used for wood impregnation (Figure 42.7), coal tar pitch Europe since the introduction of chlorinated compounds,
and its distillation products, bitumen used for road paving, such as p-dichlorobenzene,61 but it is still used for the pro-
heating oils and diesel oils. Bitumen and diesel oil produced duction of moth balls in other countries. Naphthalene is a
Hydrocarbons 333
Table 42.4 Occupations in which there is significant exposure In animal tests, different PAHs have been reported to
to polycyclic aromatic hydrocarbons.62 have immunosuppressive effects. The relevance of these
Occupation effects to human exposures is, however, unclear.
Carcinogenicity of PAHs
Coke oven work The main hazard related to polycyclic aromatic hydrocar-
Coal gasification bons is their potential mutagenicity and carcinogenicity.
Foundry work The first occupational cancers caused by PAHs were
Aluminium production described in 1775 when Sir Percival Pott described scrotal
Impregnation of wood with creosote cancers in chimney sweeps exposed to soot. The ability of
Handling of creosote-impregnated wood individual PAHs to induce cancer varies. Since human
Asphalt and pavement work exposure to PAHs is almost exclusively a mixed exposure,
Use of coal tar in roofing data on the carcinogenicity of the individual PAHs come
Chimney sweeping from animal tests. Although some individual PAHs are
Graphite electrode production extensively tested, there are many PAH compounds for
Petroleum refineries which the toxicological data are very limited. The IARC has
Smokehouses (for smoked meat and fish) recently classified several PAH compounds according to
their carcinogenicity; the results of the IARC classification
are shown in Table 42.5.
white solid, which has a vapour pressure (sublimation pres- Many PAH compounds have shown mutagenic activity
sure) of 10 Pa at room temperature. It has a characteristic in mutagenicity tests. The mechanism of the carcinogenic-
odour with a very low odour threshold of 0.08 ppm ity of PAH compounds is considered to be related to the
(0.4 mg/m3). formation of DNA binding species, mainly diol epoxides in
the body resulting in mutagenicity.64
Clinical effects and epidemiology Naphthalene has caused nasal cancers in carcinogenic-
ity tests in animals after inhalation exposure. Naphthalene
Non-cancer effects is, however, not genotoxic and it has been suggested that
The acute toxicity of PAHs varies from moderate to low. the mechanism of naphthalene-caused nasal cancers is
Systemic toxicity, other than carcinogenicity, is very rare. mainly related to local tissue damage. This may, therefore,
The only PAH compound known to cause significant acute be relevant for humans only at high exposure levels that
or systemic toxicity in humans is naphthalene. cause considerable local nasal irritation.62
Naphthalene causes haemolytic anaemia. It has caused The carcinogenicity of several work tasks involving sig-
several poisoning accidents when naphthalene-containing nificant PAH exposures has been studied in epidemiologi-
moth balls have been eaten. Serious poisonings after der- cal studies. In the case of coal gasification, epidemiological
mal or inhalation exposures have been described mainly in studies have consistently shown an excess of lung cancer
small children who have been exposed to naphthalene via associated with gas production.64 Also, most of the epi-
moth ball-treated nappies, clothing or blankets.61,62 The demiological studies have provided evidence of an excess
lethal oral dose of naphthalene in humans is 5–15 g in risk for lung cancer among coke production workers.64,65
adults. The first signs and symptoms of naphthalene poi- Additionally, in the case of aluminium production, an
soning include nausea, vomiting, diarrhoea, dark urine, association between cancer and PAH exposure has been
pallor, fever and abdominal pain. On clinical examination, demonstrated.64,65 A recent meta-analysis of PAH exposure
the liver and spleen may be enlarged and jaundice may be and lung cancer estimated the risk equivalent to a relative
present. On haematology, fragmentation of red blood cells risk of 1.06 for a working lifetime at 1 μg/m3 exposure to
with anisocytosis and poikilocytosis, and reduction in benzo[a]pyrene for exposures in the coke ovens, gas works
haemoglobin and haematocrit levels are seen. More severe and aluminum industries.65 All these work tasks have been
reactions include Heinz body formation, haemoglobinuria recently evaluated by the IARC and designated as carcino-
and mild methaemoglobinaemia. Individuals who are genicity group 1 (carcinogenic to humans).64,100 Other
deficient in G-6-PD (glucose 6-phosphate dehydrogenase) work tasks evaluated by the IARC and assigned to
are particularly sensitive to haemolytic anaemia produced carcinogenicity group 1 because of the PAH exposure
by naphthalene.63 Occupational exposure has not, how- include coal tar distillation, paving and roofing with coal
ever, been reported to cause naphthalene poisoning or tar pitch, and chimney sweeping.64,100
haemolytic anaemia. Creosote has been shown to induce local skin cancers
PAH mixtures, like coal tar pitch and coal tar creosote, in mice at the site of application.66 In cohort studies of
have been shown to induce phototoxicity in humans. The Swedish and Norwegian wood impregnators and in
symptoms appear when PAH-exposed skin parts are Finnish round-timber workers, increased risks for lip and
exposed to sunlight. Skin irritation, dermatitis, hyper- skin cancers have been observed.66–68 However, epidemio-
pigmentation and even blisters may be observed. logical data on the carcinogenicity of creosote are still
334 Organic chemicals
Table 42.5 Carcinogenicity classification of different polycyclic metabolism product of pyrenol, has been commonly used
aromatic hydrocarbons according to a recent IARC evaluation.64 as a biological marker of exposure to PAH compounds.
1-Naphthol has been used as a marker of naphthalene
Group Polycyclic aromatic hydrocarbons
exposure.
Table 42.6 Three different types of white spirits, which can be separated by their different production processes (modified from Ref. 74).
Kerosene and other fuel oils have also been studied for countries is towards increased use of low aromatic white
carcinogenicity, but the results are inconclusive. Certain spirits.
types of fuel oils may contain significant amounts of poly- Straight-run white spirit (type 0, CAS 64742-88-7) is a
cyclic aromatic hydrocarbons in addition to aliphatic and white spirit that has not been treated beyond the process of
aromatic hydrocarbons, but the PAH content of, for exam- distillation. Types 1, 2 and 3 are further divided into three
ple, kerosene and diesel fuel is less than 5 per cent.72 The technical grades defined by flash point: ‘low flash’ white
IARC has determined that residual (heavy) fuel oils and spirit, ‘regular flash’ white spirit and ‘high flash’ white spirit.
marine diesel fuel are possibly carcinogenic to humans White spirits are widely used in paints and varnishes, in
(group 2B). However, evidence on the carcinogenicity of cleaning products and as a degreasing and extraction sol-
distillate (light) fuel oils or distillate (light) diesel fuels is vent. The main use is in paints and as a paint diluent. The
inconclusive (IARC group 3).73 odour threshold of white spirit is quite low; vapours can be
Bitumen (asphalt) is a complex mixture of naphthenic, detected at air levels of 0.5–5 mg/m3. Exposure to white
aliphatic and/or aromatic hydrocarbons and heterocyclic spirits occurs mainly through inhalation, but absorption
compounds containing sulphur, nitrogen and oxygen. through the skin may also occur.74
It is mainly used for paving roads. It has been studied
extensively for the possible carcinogenicity of its vapours
and aerosols formed during paving. These vapours and Clinical effects and epidemiology
aerosols also contain polycyclic aromatic hydrocarbons.69 Vapours of white spirit can cause eye and mucous mem-
brane irritation at air levels of 600 mg/m3 (100 ppm). At
WHITE SPIRITS higher levels, dizziness, drowsiness, headache and nausea
may be induced. In controlled volunteer studies, exposure
White spirits are colourless liquids with boiling points to white spirit for seven hours at 600 mg/m3 or more has
between 130 and 230°C and vapour pressures between resulted in impaired balance and increased reaction
0.1 and 1.4 kPa at 20°C (Table 42.6). They are mixtures of times.74 Skin exposure may result in defatting of the skin
saturated aliphatic and alicyclic hydrocarbons (mainly from repeated exposure.
C7–C12) and aromatic hydrocarbons (C7–C12). In the According to several studies in painters, white spirits may
past, they have contained benzene, but modern white spir- cause chronic solvent encephalopathy. The clinical picture
its usually contain very little or no benzene. The most of the disease is the same as described in the case of aromatic
widely used quality of white spirit (white spirit type 1, stod- hydrocarbon solvents, with symptoms including fatigue,
dard solvent, CAS 8052-41-3) contains 80–85 per cent (by poor memory, difficulties in concentration, emotional labil-
weight) aliphatic and alicyclic alkanes and 15–20 per cent ity and depression.31,74,75 The incidence of symptoms
(by weight) aromatic hydrocarbons.74 increases with increasing number of years of exposure.75
The various types and grades of white spirit are produced Impaired performance in neuropsychological tests may be
from straight-run naphtha and straight-run kerosene, which seen. Chronic solvent encephalopathy induced by white
are refinery streams obtained from the distillation of crude spirits may also be associated with defects in colour
oil. Fractional distillation into appropriate boiling ranges vision and visual perception, which has been suggested in
and different kind of treatments are used to obtain the studies of patients with a diagnosis of chronic solvent
desired type of white spirit. The current trend in western encephalopathy.34,35
336 Organic chemicals
In the past, white spirits contained small amounts of occasionally up to two days. Thereafter, dizziness, headache,
benzene. However, nowadays benzene levels are very mini- nausea, vomiting, gastrointestinal pain, blurred vision and
mal or negligible. The carcinogenicity of white spirit has pain and light-sensitivity of the eyes follow. The late symp-
not been fully evaluated. toms are caused by the accumulation of the toxic metabo-
lite, formic acid, which causes a metabolic acidosis (low
Metabolism and monitoring blood pH, anion gap, compensatory low arterial pCO2).
Since white spirits are complex mixtures of several differ- Untreated metabolic acidosis may lead to death. The
ent hydrocarbons with varying composition, general meta- ocular effects are likely to be induced by inhibition of the
bolic pathways or specific monitoring methods cannot be cytochrome oxidase by formate.
provided for white spirits. The damage to the retina may be permanent and varies
from slight visual disturbance to complete blindness. In
Management and diagnosis mild cases, visual disturbances may disappear with time.
The diagnosis of chronic solvent-induced encephalopathy Epidemics with high mortality have been described
follows the principles described above under Toluene, from the ingestion of illicitly distilled spirits containing
xylene and styrene, p. 327. methanol.76–78 There are case reports and case series of
serious, even fatal methanol poisoning following inhala-
tion, and even dermal exposure.79–81
ALCOHOLS Limited testing in animals has revealed no carcinogenic
effects of methanol in animals. Methanol is not genotoxic.
Alcohols share the common property of an -OH group in a Oral and inhalation exposure (usually at exposure levels
carbon chain; primary alcohols in the form of R-CH2OH, 10 000 ppm; 13 000 mg/m3) to methanol induced terato-
secondary alcohols R1R2CHOH and tertiary alcohols genesis (usually neural and ocular defects, cleft palate,
R1R2R3C-OH. With increasing chain length, the volatility, hydronephrosis, deformed tails and limb (paw and digit)
water solubility and skin penetration capacity of the alcohol anomalies) in mice. This effect apparently is not mediated
decrease. Toxicity per mole absorbed increases with increas- by the action of formate.82–86
ing chain length, but methanol is an important exception.
Alcohols are very extensively used as solvents and also Metabolism and monitoring
as building blocks in organic synthesis. Methanol is oxidized by alcohol dehydrogenase to
The acute toxic effects of alcohols, notably of the low- formaldehyde, and this is further oxidized by aldehyde
boiling alcohols, such as methanol, ethanol and propanols, dehydrogenase to formic acid (Figure 42.8). Formic acid is
is mostly due to the ingestion of large quantities, but the actual toxic species: it induces metabolic acidosis, and
adverse effects have also been described after occupational in humans is cleared slowly, with the half-times generally
inhalation and dermal exposure. The common and most being between three and ten hours, but cases with a half-
apparent effect of alcohols on humans, is the effect on the time of 77 hours have been reported.87,88
central nervous system.
Management and diagnosis
METHANOL Methanol intoxication should be suspected when a patient
with a history of exposure to methanol presents with meta-
[CAS No. 67-56-1]
bolic acidosis, with or without effects on vision. Diagnosis
OH may be aided by the analysis of methanol and formate in
serum. Elevated concentration of formate in serum is not
H
H H Primates CH3OH Rodents
Methanol
Methanol is a clear, colourless, volatile flammable liquid Alcohol dehydrogenase Catalase
with a mild alcoholic odour. It is, as measured by produc-
tion volume, one of the most used organic chemicals. It is HCHO
Formaldehyde
used in the production of acetic acid and formaldehyde
and as a starting material for the synthesis of methyl-tert- Formaldehyde dehydrogenase Formaldehyde dehydrogenase
specific for methanol intoxication (there may have been with tachycardia and hypertension. Finally, haematuria,
exposure to formate itself), but it is useful in the monitor- renal tubular necrosis and renal failure may develop.93,94
ing of the efficacy of treatment and also in the assessment Following inhalation exposure, ethylene glycol toxicity
of the need for haemodialysis. observed in humans has been low, nose and throat irrita-
The traditional management of methanol poisoning tion being the major findings. Notably, metabolic acidosis
makes use of the fact that the toxicity of methanol is due and renal effects have not been reported after inhalation
to the oxidation of methanol to formate: this reaction is exposure. Ethylene glycol is a mild irritant to the eyes and
blocked by administration of ethanol, which competitively skin. Contact dermatitis has not been reported.
and effectively blocks methanol oxidation. The same effect In experimental animals, ethylene glycol is not muta-
may be achieved by administration of methylpyrazole genic and limited carcinogenicity testing has not shown
(fomepizole). Fomepizole has recently gained popularity evidence of carcinogenicity. Ethylene glycol is teratogenic
over ethanol as the main therapeutic choice, as it is easier in rats and mice at doses lower than those overtly toxic to
to maintain the therapeutic concentration with fomepizole the dams.
than with ethanol – for which there is a wide variation in
the clearance kinetics.90 Metabolism and monitoring
Formate may be removed from the body by haemodial- Ethylene glycol is effectively absorbed from the gastroin-
ysis. It has been recommended that haemodialysis should testinal tract and by inhalation. Dermal absorption is
be started if the blood methanol concentration exceeds slower and less complete, but has reached 20–30 per cent in
50 mg/dL (15.8 mmol/L).87 six hours in experimental animals.93 Ethylene glycol is oxi-
In addition to the methods chosen to decrease the gen- dized by alcohol dehydrogenase to glycol aldehyde, and
eration of formate from methanol, the metabolic acidosis subsequently to glycolic acid, formic acid and oxalic acid
has to be corrected by use of sodium bicarbonate. Further- (Figure 42.9).
more, it may be advantageous to facilitate the conversion Acidosis and subsequent renal toxicity after high oral
of formic acid to carbon dioxide by the administration of doses of ethylene glycol is caused by metabolites of ethylene
folinic acid. glycol, notably by oxalic acid, which crystallizes in the kid-
Occupational exposure to methanol may be assessed neys. Cytotoxicity of other metabolites, such as glycoalde-
through biological monitoring by the analysis of methanol hyde, glycolic acid, and glyoxylic and formic acids, may
in urine.91 As an alternative, analysis of urinary formate has contribute to the renal damage (with the acids contributing
also been suggested.92 However, meaningful interpretation to the acidosis).
is only possible if the sample is collected in the morning
after the exposure (16 hours after the cessation of the expo- Management and diagnosis
sure) because of accumulation in the body over time. Ethylene glycol poisoning should be suspected in cases with
metabolic acidosis with anion and osmolal gap. A diagnosis
ETHYLENE GLYCOL may be reached from the analysis of oxalic acid and ethylene
glycol in urine or blood.
[CAS No. 107-21-1] As the renal toxicity ensues from the action of metabo-
OH
lites, toxicity may be prevented by the inhibition of ethylene
HO
HOCH2CH2OH
Ethylene glycol is a clear, colourless, odourless, relatively Ethylene Glycol
non-volatile, viscous liquid. It is used primarily in the
production of polyesters for fibres and films, and poly- HOCH2CHO
ethylene terephthalate. It is also used in a broad range of Glycoaldehyde
glycol metabolism. The treatment includes correction of (0.1 mg/m3). At higher concentrations, formaldehyde may
the acidosis, hyperkalaemia and hypocalcaemia, treatment also contribute to the induction of obstructive effects on
of seizures, and inhibition of the metabolism of ethylene lung function, which are usually quantitatively minor and
glycol with ethanol infusion, or fomepizole. Ethylene reversible.96 The respiratory effects of formaldehyde may
glycol and the toxic metabolites may be removed by be mediated by an immunological mechanism, but respi-
haemodialysis.95 ratory sensitization to formaldehyde is apparently rare.
Dermal exposure to formaldehyde in solution causes
skin irritation and can provoke contact eczema through
ALDEHYDES irritation, but also through an immunological mechanism
affecting susceptible individuals. Contact dermatitis may
Aldehydes have the common structure R-CHO. They react be elicited in sensitized individuals following exposure to
avidly especially with thiols and amines. Because of the formaldehyde at concentrations as low as 30 mg/L.98
reactivity, many of them are irritants or even corrosive, A large number of epidemiological studies have investi-
and in experimental systems, genotoxic and cytotoxic. Also gated the possible role of formaldehyde as a causative agent
because of the reactivity, they tend to have a short half-life, for cancer in different parts of the respiratory tract and of
and their effects are mostly limited to the site of entry. leukaemia. In October 2009, IARC concluded that ‘there is
Exposure to liquid aldehydes tends to cause contact sufficient evidence in humans of an increased incidence of
eczema by irritation or sensitization. nasopharyngeal carcinomas among formaldehyde-exposed
people’, and the epidemiological evidence on leukaemia has
FORMALDEHYDE become stronger with new studies. For both cancer types,
the group 1 classification is supported by strong mechanistic
[CAS No. 50-00-0] evidence.99,100
O
Inhalation exposure to formaldehyde induced squamous
cell carcinoma in the nasal cavity in rats. Formaldehyde is
genotoxic in vitro; it also induced protein–DNA crosslinks
H H and cellular proliferation in respiratory epithelium in
experimental animals after inhalation exposure. It is likely
Formaldehyde is a flammable, colourless and readily poly- that both genotoxicity and cell proliferation contribute to
merized gas at ambient temperature with a pungent, suffo- the carcinogenic action of formaldehyde.96,99,100
cating odour. Formaldehyde solution (formalin) is a clear,
colourless liquid with a pungent odour. The most common Metabolism and monitoring
commercially available form of formalin is a 30–50 per cent
Formaldehyde is rapidly absorbed from the respiratory
aqueous solution containing methanol. Formaldehyde is
tract and metabolized mainly to formic acid and carbon
used mainly as an intermediate in the chemical industry for
dioxide. Part of the inhaled formaldehyde undergoes inter-
the production of resins for the wood, paper and textile
mediary metabolism. Elevated formaldehyde levels in the
processing industries and in the synthesis of methylene
plasma or urine have not been demonstrated after inhala-
dianiline, diphenylmethane diisocyanate, hexamethyl-
tion exposure to formaldehyde in humans or experimental
enetetraamine, trimethylol propane, neopentylglycol, pen-
animals.
taerythritol and acetylenic agents. Aqueous solutions of
formaldehyde are employed as germicides, bactericides and
fungicides. Tobacco smoke, release from urea-formalde- GLUTARALDEHYDE
hyde foam insulation, formaldehyde-containing disinfec-
tants and preservatives in consumer products, as well as [CAS No. 111-30-8]
from engine exhausts are important sources of formalde- O O
hyde exposure. Formaldehyde is also a product of inter-
mediary metabolism.96,97
It is quickly metabolized and even at high inhalation
exposure levels, elevated concentrations of formaldehyde Glutaraldehyde is a colourless, oily liquid which crosslinks
have not been observed in the blood. Thus, the most likely with proteins and, in aqueous solutions, partially polymer-
targets for formaldehyde action are the sites of immediate izes to form oligomers. Glutaraldehyde is used as an immer-
contact, i.e. the respiratory tract epithelium and the skin. sion disinfectant in a 1 or 2 per cent aqueous solution for
sterilizing endoscopes and other surgical instruments; as a
Clinical effects and epidemiology hardener in x-ray film processing; for the prevention of
Irritation of the eyes and respiratory tract by formaldehyde microbial growth and metal corrosion in circulating water
has been observed consistently in clinical studies and epi- systems, including off-shore operations; as a biocide in the
demiological surveys, usually when the concentration of petroleum, pulp and paper industries; and as a preservative
formaldehyde in the air exceeds approximately 0.1 ppm in industrial cleaning agents for example, in the food,
Ketones 339
beverage and tobacco manufacturing industries, and in volatile, and thus use of acetone may lead to substantial
retail detergents. It is used to disinfect animal housing and inhalation exposure.
bird cages in the form of sprays and by fogging, and to con- Acetone is produced endogenously in intermediary
trol microorganisms in fish farming. Aqueous solutions of metabolism mainly from fatty acid oxidation, and its con-
glutaraldehyde are used to soften leathers and to improve centration may be high among patients with uncontrolled
their resistance to water, alkalis and mould. It is also used diabetes mellitus. Fasting and strenuous exercise also
as a tissue fixative in histology and electron and light elevate body acetone concentrations.
microscopy. Glutaraldehyde is allowed as a preservative for
cosmetics in Europe, but not in the form of aerosols or Clinical effects and epidemiology
sprays.101 Acetone has low toxicity. At high concentrations, acetone
vapour can cause CNS depression, cardiorespiratory failure
Clinical effects and epidemiology and death. Eye and nose irritation have been reported at
Glutaraldehyde is an irritant at high concentrations and is concentrations
250 ppm (600 mg/m3), with headache,
corrosive to the skin, eyes and respiratory membranes. The dizziness, mood changes and ‘confusion’ at 1000 ppm
irritative effect is accentuated by the presence of bicarbon- (2400 mg/m3). Vomiting and fainting have been reported
ate which is added to the glutaraldehyde solutions in use to in workers exposed to acetone vapour at concentrations
improve their efficacy as a disinfectant. 12 000 ppm (29 000 mg/m3) for approximately four hours.
In some patients with glutaraldehyde-induced contact Experimental exposure to 250 ppm (600 mg/m3) of acetone
dermatitis, there is a positive reaction in patch testing, was reported to induce changes in neurobehavioural tests.104
indicating an immunological mechanism. Immunological Acetone is negative in mutagenicity tests, only slight
processes may also be involved in the respiratory effects developmental effects were observed in rats and mice at
(asthma, rhinitis) of glutaraldehyde.102,103 exposure levels in excess of 6600 ppm (16 000 mg/m3). No
In experimental animals, glutaraldehyde is positive carcinogenicity studies are available on acetone, but it has
in genotoxicity studies in vitro, but usually negative in been used extensively as a negative control in skin painting
in vivo studies. Exposures causing maternal toxicity induce carcinogenicity studies.
embryo- and fetotoxicity, but teratogenicity has not been
reported.101 Metabolism and monitoring
Acetone is metabolized to acetate and formate; these are
intermediate steps in metabolic pathways (e.g. to fatty acids,
KETONES amino acids and in gluconeogenesis). Acetone is mainly
excreted unchanged by exhalation, and as the ultimate step
The basic structure of ketones is R1R2CO. The most in its catabolism, to carbon dioxide. Small amounts of
commonly used ketones are acetone, methylethylketone, acetone are also excreted in urine.
methyl isobutylketone, cyclohexanone, 4-hydroxy-4-methyl- Acetone induces the cytochrome P450 2E1 enzymes,
2-pentanone, isophorone, mesityl oxide and acetophenone. and may thus effect the metabolism of chemicals that rely
Ketones are very extensively used notably as solvents, as on this pathway (e.g. ethanol, benzene, N-nitrosodimethy-
they dissolve organic compounds. Ketones are irritating lamine, N-nitrosodiethanolamine, haloalkanes).
to the mucous membranes and skin. They induce central
nervous system depression. Ketones have no sensitizing
METHYLETHYL KETONE
potential; they are generally not mutagenic, or toxic to
reproduction, and have not been shown to be carcinogenic. [CAS No. 78-93-3]
O
ACETONE
hypodermic needles, syringes, and dental instruments; as the metabolite responsible for hexane neuropathy (see under
an extraction solvent for hardwood pulping and vegetable n-Hexane, p. 323). Consistent with this finding, many cases of
oil; and as a solvent in pharmaceutical and cosmetic peripheral neuropathy have been reported among workers
production.105 MEK is also found in tobacco smoke and exposed to 2-hexanone;109–111 the disease has also been
exhaust gases from gasoline engines. reproduced in experimental animals.
MEK is more irritating than acetone to mucous mem- Hexanone, and also 2,5-hexanedione, have induced
branes. It has low acute toxicity, but it potentiates the adverse testicular effects in rodents.109
neurotoxicity of n-hexane and methyl-n-butylketone (see
under n-Hexane, p. 323) and the liver and kidney toxicity
of carbon tetrachloride and trichloromethane. The mecha- ETHERS
nism for the latter may be induction of cytochrome P450,
although an inducing effect of MEK on this enzyme activity Ethers have the general formula R1–O–R2, the simplest of
is not observed at low exposure levels.106 The mechanism them being dimethyl and diethyl ethers (CH3OCH3,
could be the same for the potentiation of hexacarbon neu- C2H5OC2H5). Ethers are used as solvents, and intermedi-
rotoxicity, but this has not been clearly demonstrated.107 ates in synthetic processes.
MEK is readily absorbed via the respiratory tract, and
metabolized to 2-butanol, 2-hydroxy-2-butanone, and 2,3-
CHLOROMETHYLMETHYLETHER AND
butanediol and further to products that are incorporated in
BIS(CHLOROMETHYL)ETHER
intermediary metabolism. Smaller amounts are exhaled
unchanged; MEK is also found in urine at low levels. Cl O Cl O Cl
Chloromethylmethylether Bis(chloromethyl)ether
METHYL ISOBUTYL KETONE
Chloromethylmethylether (CMME) (CAS No. 107-30-2) is
[CAS No. 108-10-1] a colourless liquid with a characteristic odour. It is a direct-
acting alkylating agent and it has been extensively used as a
O
cross-linking agent in ion exchange resins and as an inter-
mediate in chemical syntheses. It is a potent irritant to
mucous membranes. In 1968, it was demonstrated to be a
potent carcinogen in experimental animals. The impurity
Methyl isobutyl ketone (MiBK) is a clear liquid with a sweet
bis(chloromethyl)ether (BCME) (CAS No. 542-88-1), which
odour. The primary use of methyl isobutyl ketone is as a
occurred in technical chloromethylmethylether, was an
solvent in protective coatings. It is also used as a solvent in
even more potent carcinogen. Bis(chloromethyl)ether can
specialty adhesives, in ink formulations, in dewaxing min-
form spontaneously from the reaction of hydrochloric acid
eral oil, and in textile coatings and leather finishing. As a
with formaldehyde. Several studies, starting in the 1970s,
process solvent, methyl isobutyl ketone is used in the sepa-
have convincingly demonstrated that exposure to technical
ration and purification of certain metal ions, such as zirco-
chloromethylmethylether – apparently always containing
nium from hafnium; in the extraction and purification of
BCME as an impurity at a level of a few per cent – is a very
antibiotics and other pharmaceuticals; and in the manu-
potent carcinogen in humans, causing lung cancer, usually
facture of insecticides and other pesticides. It is also used
of the microcellular type.100,112–114 IARC concluded in 1987
in purifying stearic acid, refining tall oil and extracting
that bis(chloromethyl)ether and technical chloromethyl-
rosin from softwood, especially pine.108 It is used as a car-
methylether are carcinogenic to humans;17 they induce cancer
rier in riot control sprays, for example CS gas.
of the lung.100 The homologues bis(2-chloroethyl)ether and
Exposures to MEK in the range of 25–50 ppm
bis(2-chloro-1-methylethyl)ether were not classifiable as to
(260–530 mg/m3) have been reported to cause respiratory
their carcinogenicity to humans.115,116
tract irritation. Inhalation exposure to concentrations in
excess of 1000 ppm (11 000 mg/m3) causes central nervous
system depression. METHYL-tert-BUTYLETHER
United States requiring the use of gasoline oxygenates, ether mixture added to gasoline. The proportion of TAME
consumers in some areas complained about headache, eye in gasoline may exceed 10 per cent.122 The advantage of
and nose irritation, cough, nausea, dizziness and disorien- TAME over MTBE is that it is less volatile, and since it is
tation. Epidemiological studies of occupationally and non- less water soluble, it is not an equal threat to groundwater.
occupationally exposed people, and studies of exposed TAME is slightly irritating to the eyes and respiratory tract,
volunteers, have not been able to identify a basis for these and at high concentrations, narcotic. In a 78-week gavage
complaints.118 study in rats, with limited data reported, statistically
Inhalation exposure to methyl-tert-butyl ether increased non-significant increases were observed for tumours at
the incidence of hepatocellular adenomas in female mice several sites, and a significant increase was observed for
and that of renal tubular tumours in male rats in a non- lymphomas and leukaemias combined.123 Noting the non-
dose-related manner. In a gavage study in rats, MTBE mutagenicity of TAME, and the uncertainties in the assess-
increased the incidence of Leydig-cell tumours of the testis ment of the only available carcinogenicity study, the
in males, and of lymphomas and leukaemias in females. European Union decided not to use carcinogenicity as the
The IARC concluded from these carcinogenicity data that end point for the risk assessment of TAME.122 In develop-
there is limited evidence for the carcinogenicity of MTBE mental toxicity studies in mice, cleft palate was observed
in experimental animals. MTBE does not appear to be in mice at inhalation exposure levels that only induced
genotoxic, and does not induce adverse developmental hepatic enlargement in the dams. In rats, weight reduction
effects in experimental animals at exposure levels that are of the litters was observed at inhalation exposure levels that
not overtly toxic to the dams.117,119 also induced maternal weight reduction. Based on these
MTBE is oxidatively demethylated to formaldehyde and findings, the European Union did not consider there to
t-butanol (TBA). Formaldehyde is rapidly biotransformed be sufficient evidence to classify TAME as hazardous to
(and has not been measured in vivo following MTBE expo- human reproduction.122 TAME is metabolized to several
sures) further to formic acid, CO2, or becomes incorpo- metabolites (2-methyl-2,3-butanediol, 2-hydroxy-2-methyl-
rated into the one-carbon pool. The biotransformation butyric acid and 3-hydroxy-3-methylbutyric acid), after an
of TBA yields 2-methyl-1,2-propanediol and -hydroxy- initial hydrolysis of the ether bond to tert-amyl alcohol.
isobutyric acid (Figure 42.10). Concentration of tert-amyl alcohol in morning urine spec-
Concentration of tert-butyl alcohol in morning urine imens may be used for biomonitoring.120,121
specimens (16 hours after the cessation of the exposure)
may be used for biomonitoring of MTBE.120,121 Glycol ethers
CH3 CH3
P450
H3C C O CH3 H3 C C OH + H2C = O
oxidation (formaldehyde)
CH3 CH3
(MTBE) (TBA)
oxidation
CH3
H3 C C OH
CH2OH
(2-methyl-1,2-propanediol)
oxidation
CH3
H3 C C OH
O C O
(a-hydroxyisobutyric acid) Figure 42.10 Metabolism of methyl-tert-butyl ether.119
342 Organic chemicals
H2
O C OH
HO C
CH2 H2
methoxyacetic acid in the urine in a post-shift specimen Clinical effects and epidemiology
collected towards the end of the working week.130–133 While some cases of acute intoxication by ethoxyethanol
after ingestion of large doses have been described,
ETHOXYETHANOL (ETHYLENEGLYCOL MONOETHYL ethoxyethanol and its acetate have low acute toxicity in
ETHER) AND ETHOXYETHYL ACETATE occupational settings. They have low irritant potential, and
O there are no data to indicate that they cause dermal or
respiratory sensitization.
OH O Three studies point to a possibility that ethoxyethanol
O O induces semen abnormalities following occupational
Ethoxyethanol Ethoxyethyl acetate
exposure.134–136 Two other studies, one of which was
performed in workers involved in silk screening with a rea-
Ethoxyethanol (CAS No. 110-80-5) and ethoxyethyl sonably pure exposure to ethoxyethanol, indicated that the
acetate (CAS No. 11-15-9) are stable flammable liquids exposure induced a deficit in erythropoiesis.137,138
with a slight odour at normal room temperature and pres- While studies in exposed humans are quite limited and
sure. They have been used in paints, coatings, inks, clean- often involve mixed exposure with regard to both these end
ers, polishes, brake fluids and jet fuels, as well as a solvent, points, they are amply supported by studies in experimen-
chemical intermediate and solvent coupler of mixtures and tal animals, which clearly demonstrate that ethoxyethanol
water-based formulations. Ethoxyethyl acetate is readily causes sperm abnormalities in males and is embryotoxic,
hydrolysed to ethoxyethanol, and has practically identical fetotoxic and teratogenic in different animal species at
effects at equimolar exposure levels. exposure levels that are not overtly toxic to the dams – and
Because of the risk to reproduction, ethoxyethanol has after both inhalation and dermal exposure.139 Similarly, the
been widely abandoned; however, it is not self-evident that effect on haematopoiesis is demonstrated convincingly in
its use has completely stopped in different parts of the world. experimental animals.139
344 Organic chemicals
H2
O C OH
HO C
H3C C H2 HO OH
H
CH CH
Ethylene glycol H2 H2
Acetaldehyde C C O HC CH OH
H3C
O C
Cytochrome H2 O HC
P450
O C OH
H2 H2
H3C H3C 2-Ethoxyethyl glucuronide
O C C O C Glucuronyl O
C C O CH3 C C OH transferase
H2 H2 H2 H2
H2
H3C O C
C C O 2-Ethoxyethyl sulphate
H2 H2
2-Ethoxyacetaldehyde
Aldehyde
dehydrogenase HO OH
Glucuronyl CH CH
O transferase H2 H2
O H3C C C O HC CH OH
Dealkylase O C H3C O C
C
C C OH O HC
O Carboligase H2 H2 O
C OH
Carbon dioxide 2-Ethoxyacetic acid
2-Ethoxyacetyl glucuronide O
Acyltransferase
O
H3C H2
O C C OH
C C N C
H2 H2 H
O
2-Ethoxyacetyl glycine
CO2
carboligase
oxidase
O
dehydrogenase
CH3CH2CH2COOH CH3CH2CH2CH + HOCH2CH2OH
dealkylase
glucuronyl sulphotransferase
CH3(CH2)3OCH2CH2OGluc CH3(CH2)3OCH2CH2OH CH3(CH2)3OCH2CH2OSO3-
transferase
butoxyethanol glucuronide butoxyethanol butoxyethanol sulphate
alcohol dehydrogenase
(liver)
CH3CH2CH2CH2OCH2CHO
butoxyacetaldehyde
aldehyde dehydrogenase
(liver)
N-butoxyacetylglycine
or acyltransferase
CH3(CH2)3OCH2COOH
butoxyacetylglutamine
butoxyacetic acid
dealkylase carboligase
CO2
O OH
Metabolism and monitoring
Butoxyethyl acetate (CAS No. 112-07-2) is readily hydrol-
1-methoxy-2-propanol 2-methoxy-1-propanol
ysed by esterases to butoxyethanol. The main metabolites α-isomer β-isomer
of butoxyethanol are butoxyaldehyde and butoxyacetic
acid, the formation of which is catalysed by alcohol and Commercially produced propyleneglycol methylether
aldehyde dehydrogenases (Figure 42.14). De-ethylation of (PGME) is a colourless liquid with a characteristic odour.
346 Organic chemicals
It is a mixture of two isomers, 1-methoxy-2-propanol, also dehydrogenase to methoxypropionic acid. Direct conjuga-
called α-isomer, i.e. secondary alcohol, and 2-methoxy-1- tion with glucuronic acid and metabolism to carbon diox-
propanol, also called β-isomer, i.e. primary alcohol. This is ide are minor pathways.
important, as the two isomers have distinct metabolic dif- As dermal exposure may significantly contribute to the
ferences, and are also toxicologically different. In many total exposure, biomonitoring is useful for the assessment
countries, limits have been set for the maximal proportion of exposure. Analysis of total 1-methoxy-2-propanol in urine
of the β-isomer allowed in the commercial product. is the best validated urinary marker of exposure.172,173
Propyleneglycol methylethers are soluble in water and
solvents, are not very volatile, have low irritation capacity,
and have no offensive smell. They have found extensive CARBOXYLIC ACIDS AND THEIR DERIVATIVES
use as solvents for surface coatings, inks, lacquers, paints,
resins, dyes, agricultural chemicals, oils and greases.156–158 Carboxylic acids form a large and heterogeneous group of
chemicals, with the generic formula R–COOH. This family
Clinical effects and epidemiology includes aliphatic acids, saturated and unsaturated, all of
In experimental inhalation exposure, no irritation or dis- which may be mono- or polycarboxylic, as well as aromatic
comfort was observed at concentrations of 100 ppm acids. Carboxylic acids may contain substituents other than
(370 mg/m3), with slight discomfort reported at 150 ppm carbon, oxygen and hydrogen. Acids containing halogens
(560 mg/m3).159 No data on reproductive or long-term have important industrial applications, and many are of
effects in humans are available. occupational health interest.
Inhalation exposure to 1000 ppm PGME for two years Carboxylic acids are generally soluble in water; the solu-
induced renal tubular adenomas in male Fischer rats; this bility decreasing with increasing molecular mass. The most
was accompanied by renal accumulation of α-2 microglob- conspicuous characteristic of carboxylic acids from the
ulin and hyaline-drop degeneration.160 This phenomenon human health point of view is that they are strongly irritat-
has been considered to be specific to male rats and thus not ing or even corrosive to the mucous membranes and the
fully relevant to humans.161 No increased incidence of skin. Systemic adverse effects from carboxylic acids are rare
tumours in other tissues of rats or mice were observed. in occupational settings, although serious and fatal intoxi-
PGME had no effect on the fertility, did not affect sperm cations have been described after oral and dermal exposure.
quality in rats, was not embryo- or fetotoxic in mice, rats The main toxicological feature in such cases is usually meta-
or rabbits and did not induce teratogenesis.162–165 The bolic acidosis with its sequelae, such as hyperkalemia and
β-isomer in contrast was fetotoxic and teratogenic,166 and hypocalcaemia. Several case reports have been published
decreased testicular and epididymal sperm counts in describing fatal intoxications due to dermal exposure to
rats.167 It has been thought that the difference in the toxic- monochloroacetic acid [CAS No. 79–11–8]. The poisoning
ity of the α-isomer and β-isomer is due to the formation of cases have involved epidermal and superficial dermal
the methoxypropionic acid from the latter, but not from burns, with disorientation, agitation, cardiac failure, meta-
the former (see below). It is the alkoxyacid which appar- bolic acidosis, rhabdomyolysis, renal insufficiency and
ently is the cause of the reproductive, developmental and cerebral oedema occurring within a few hours.174–180
even haematotoxic effects of methoxy-, ethoxy- and butoxy-
ethanols, but methoxypropionic acid only caused develop-
FORMIC ACID
mental effects at exposure levels that also were toxic to the
dams.168 It has been proposed that if the content of the [CAS No. 64-18-6]
β-isomer in PGME is below 0.5 per cent, it is unlikely to
O
cause reproductive toxicity.168 2-Methoxy-1-propanol (but
not 1-methoxy-2-propanol) is classified as reproductive
toxicity category 2 by the European Union.127,128 H OH
Metabolism and monitoring Formic acid is a colourless, fuming liquid, with a pungent
Like ethyleneglycol ether acetates, propyleneglycolethylether odour. It is used in dyeing and finishing of textiles and
acetate is rapidly hydrolysed in vivo and in vitro to PGME; the paper, treatment of leather, electroplating and brewing, sil-
two seem to be toxicologically equivalent.169,170 vering glass, and as an intermediate in the manufacture of
At low exposures, most of inhaled PGME is metabolized many chemicals, as a silage additive and prophylactic in
to carbon dioxide and exhaled. At increasing doses, PGME animal feeds.179
is increasingly conjugated with glucuronic acid and sul-
phate. A smaller fraction is O-demethylated to propylene Clinical effects and epidemiology
glycol. PGME is also excreted in urine unchanged. Oxidation Human data on the toxicity of formic acid are limited.
to methoxypropionic acid apparently does not take Severe burns have been reported after dermal exposure to
place.171 The β-isomer is mainly oxidized by alcohol undiluted formic acid.180,181
Esters 347
Acute poisoning after oral or dermal exposure has ACRYLIC ACID ESTERS
resulted in metabolic acidosis, intravascular haemolysis
and haemoglobinuria.180–185 Many cases of fatal formic acid O
poisoning after ingestion exposure have been described; a O
dose of 60 g has invariably led to death.182,186 Ocular toxic-
ity, similar to methanol intoxication, has been observed in O
O
animals treated with formic acid. In inhalation studies in Ethyl acrylate Methyl methacrylate
rats and mice, microscopic examination showed lesions
(squamous metaplasia, necrosis, degeneration, inflamma- Acrylic acid (CAS No. 140-88-5) and methacrylic acid
tion) of the nose, larynx and pharynx at concentrations of (CAS No. 80-62-6) esters readily polymerize and are used
60 ppm (120 mg/m3) and higher. Formic acid is immedi- extensively for polymer production.
ately transformed to formate in the body. Formate tested Methyl methacrylate is commonly used in a mixture
negative in bacterial mutagenicity tests using different with pre-polymerized oligomers to prepare medical and
Salmonella strains.187 Formic acid has apparently not been dental prostheses and orthodontic devices that are often
studied for carcinogenicity in experimental animals. In a finished with the technician’s bare hands to obtain the
limited developmental toxicity study, formic acid was not desired dimensions before final hardening of the product.
teratogenic, while methanol, causing similar blood formic In this respect, dental uses of the monomer differ from
acid concentrations, induced brain abnormalities.84 industrial application, which do not generally require
manual handling of monomer-containing products. Thus,
it is understandable that reports on adverse effects from
Metabolism and monitoring methyl methacrylate come mainly from its use in dentistry.
Formate is partly metabolized in the one carbon pool and
is partially excreted unchanged in the urine. The concen- Clinical effects and epidemiology
tration of formate in urine has been used for the biological Acrylic and methacrylic esters are irritating to the eyes,
monitoring of formate exposure.92 respiratory tract and the skin.
Methyl methacrylate is well known to cause allergic con-
Management and diagnosis tact dermatitis, typically at the fingertips, spreading along the
nail walls, with painful desquamation.188–190 Among dental
Formate intoxication is rare, and as a distinction from laboratory technicians, the most common allergens include
methanol poisoning, it is likely that there are symptoms at methyl methacrylate, 2-hydroxyethyl methacrylate and ethyl-
the point of entry: skin burns and severe gastric discomfort. eneglycol dimethacrylate.191 Sensitization to a large number
Poisoned patients also have metabolic acidosis and usually of other acrylates has also been described in a variety of occu-
haemolysis. Vision may be affected. A diagnosis may be made pations with skin contact to monomer-containing products.
by the analysis of methanol and formate in blood. Elevated Acrylate derivatives to which sensitization has been demon-
blood levels of formate, but not of methanol, suggest formic strated include methylmethacrylate, ethylmethacrylate,
acid poisoning. 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacry-
Formate poisoning has been successfully treated with late, N,N-dimethylaminoethyl methacrylate, glycidyl
haemodialysis, intravenous bicarbonate, administration of methachrylate, tetrahydrofurfuryl methacrylate, ethyl-
folinic acid to facilitate the incorporation of formate to the eneglycol dimethacrylate, diethyleneglycol dimethacry-
one carbon pool, and general supportive measures.181,184 late, triethyleneglycol dimethacrylate, polyethyleneglycol
dimethacrylate, urethane dimethacrylate, ethyl acrylate,
hydroxyethyl acrylate, hydroxypropyl acrylate, phe-
ESTERS noxyethoxy ethylacrylates, hexandediol diacrylate and
trimethylolpropane triacrylate.192–197
Esters are condensation products of an acid and an alcohol, In addition to dentistry, occupations with reported cases
and have a general formula R1COOR2; the simplest ester include manufacture of printed circuit boards,198 opticians
being methylformate CH2OOCH3. Esters comprise a very working with polymethyl(meth)acrylate199 and optical fibre
large group of chemicals, the acid moiety may be an alkane, manufacture (UV-curable acrylate resin coating).200
alkene or an aromatic compound, and similarly, the Skin exposure to methyl methacrylate (usually in the
alcohol part may vary. Small molecular weight esters are presence of dermatitis) may lead to neurological damage.
soluble in water and readily volatile. With an increasing In an early study, 17 per cent of a group of dental techni-
molecular size, both these characteristics decrease. Esters are cians, their assistants, and students of the Dental
extensively used as solvents. They are generally inert, with Technician Institute in Finland reported current or previ-
their most important adverse effects usually being narcotic ous hand dermatitis, and 25 per cent reported other fin-
effects at high concentrations, and eye and airway irritation, ger symptoms, such as whitening, numbness, coldness or
also skin irritation, from liquid esters. Other than irritation, pain.201 Slowed distal sensory conduction velocity from
toxicity is mostly due to the acid part of the molecule. digits I, II and III of the right hand, and also of the radial
348 Organic chemicals
aspects of the digits II and III of the left hand was NITROGEN-CONTAINING HYDROCARBONS
observed among the dental technicians. These findings
represent mild axonal degeneration on the areas with the Amides
closest and most frequent contact with methyl methacry-
late.202 Finger paraesthesia may also develop without Amides are of the general form R1CONR2R3, the simplest of
overt dermatitis.203 them being formamide -HCONH2. Dimethylacylamides,
Asthma, rhinitis and conjunctivitis have been reported such as dimethylformamide, and dimethylacetamide are
among workers exposed to acrylates, methacrylates and used extensively. They are miscible in water in all ratios, and
cyanoacrylates. Hypersensitivity pneumonitis has also been are soluble in organic solvents. They are chemically stable,
observed in methacrylate-exposed dental techncians.204–209 with low vapour pressure, and they are used as solvents,
Available epidemiological evidence does not point to a car- in acrylic and cellulose triacetate fibre production,
cinogenic effect of methyl methacrylate.210,211 The IARC polyurethane coating, electronics industry, varnishing, sur-
has categorized it into group 3 (i.e. not classifiable). face coating, polyamide coating, absorbents, cleaners,
Methyl methacrylate has been tested in rats and mice for extractants, and in pharmaceuticals and plant protection
carcinogenicity by inhalation; IARC concluded that there is products.213–216
evidence suggesting lack of carcinogenicity.210 For ethyl
acrylate, the IARC concluded that there is sufficient evi-
DIMETHYLFORMAMIDE
dence of carcinogenicity in animals (group 2B).212 Many
acrylates, including methyl methacrylate, are mutagenic to [CAS No. 68-12-2]
bacteria and/or mammalian cells in vitro, but are mostly
O
negative in genotoxicity tests in vivo. Methyl methacrylate
was not toxic to reproduction in experimental animals.210
H N
Metabolism and monitoring
Acrylates are absorbed effectively through the respiratory
tract and also the skin. They are metabolized rapidly. For N,N-dimethylformamide (DMF) is a colourless liquid at
several (meth)acrylate esters, metabolism yields small room temperature with a faint amine odour. It is exten-
amounts of thioethers, indicating electrophilic metabo- sively used in the chemical industry as a solvent, an
lites. No validated biomonitoring methods exist for intermediate catalyst, and as a paint stripper and addi-
acrylates. tive.214,215,217
(CH3)2NCHO
N,N-dimethylformamide (DMF)
?
HN(CH 3)2
P4502E1 Dimethylamine
CH3(CH2OH)NCHO
N-(hydroxymethyl)-N-methylformamide (HMMF)
? HCHO O
formaldehyde H3C NH CH3
[reactive pathway, NH S
possibly methyl isocyanate] O
O OH
CH3NHCHO
N-methylformamide (NMF) N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC)
P4502E1, GSH
?
(CH2OH)NHCHO H2NCHO HCOOH NH3
+
N-(hydroxymethyl)formamide (HMF) formamide formic acid ammonia
HCHO
formaldehyde
in Taiwan. There was no relationship with the airborne Metabolism and monitoring
concentrations of DMF, and the reasons for this may be Dimethylformamide is effectively absorbed by the respira-
dermal absorption from splashes, or to the mediation of tory and also dermal route. Dermal absorption is significant
the effect by an active metabolite, instead of to the parent not only for liquid dimethylformamide, but also for the
compound.219 Although several experimental studies have gaseous form. Dermal exposure may be more important
indicated that DMF may adversely affect sperm quality, than respiratory exposure in occupational settings.222,223
these effects have only been seen at exposure levels consid- Dimethylformamide is hydroxylated to N-hydroxy-
erably higher than those inducing hepatic damage. The methyl-N-methylformamide, which is the main metabolite
irritation potency of DMF is low; no consistent informa- in humans (Figure 42.15). A minor further oxidation path-
tion is available on any sensitizing capacity. An early study way, also catalysed by cytochrome P450 2E1, leads through
reported an increased incidence of testicular tumours in N-methylformamide (or maybe directly) to a reactive
men exposed to DMF; later studies have not been able to intermediate, probably methyl isocyanate, and further
confirm this finding.213,217 via glutathione conjugation, to N-acetyl-N-methylcar-
The IARC evaluated data on the carcinogenicity of bamoyl)cysteine (AMCC).224,225 This minor pathway, and
dimethylformamide in experimental animals, and con- probably the intermediate methyl isocyanate, is responsi-
cluded that based on adequate findings in one study on rats ble for the liver toxicity of dimethylformamide. This
and one using mice, there was evidence suggesting lack of notion is supported by the finding that individuals with
carcinogenicity.217 However, a subsequent study reported heritable lack of glutathione S-transferase T1 are at a con-
that inhalation exposure to dimethylformamide led to siderable higher risk to hepatic damage, when exposed to
an increased incidence of liver adenomas and carcinomas dimethylformamide at work.226
in both rats and mice.220 Dimethylformamide has been Because of the likelihood of dermal absorption, biolog-
extensively studied for genotoxicity in vivo and in vitro, ical monitoring of exposure to dimethylformamide is a
with consistently negative results.215 Fetotoxic and terato- useful tool for exposure and risk assessment. Most often,
genic effects have been reported in several animal studies at N-methylformamide is measured in after-shift urine spec-
doses that are toxic to the dams, but also in some studies at imens. In the analytical methods used, because the main
doses that are not overtly toxic to the dams.221 In the metabolite HMMF is converted to N-methylformamide,
European Union, dimethylformamide has been classified the sum of the two metabolites is measured. These
as being toxic to reproduction in category 2.128 metabolites have the advantage in that the precursor of the
350 Organic chemicals
putative toxic metabolite is being measured.91 Analysis of to N-methylacetamide, and to a minor extent also to
N-methylcarbamoylated haemoglobin (lysine or N-termi- hydroxymethylacetamide, acetamide and S-acetamidomethyl-
nal valine) in blood has also been proposed as a long-term mercapturic acid.216,235
indicator of exposure to N-methylformamide,227–229 but
the experience is very limited, and the analytical technique Management and diagnosis
more demanding. Because of the likelihood of dermal exposure, biological
monitoring of exposure to dimethylacetamide is a useful
Prevention
tool for exposure and risk assessment. N-methylacetamide is
In keeping with the importance of dermal exposure in the usually measured in after-shift urine specimens.235–238
uptake of dimethylformamide at work, it was noted that in
synthetic leather production, protection of the skin was
ACRYLAMIDE AND N-METHYLACRYLAMIDE
more effective than respiratory protection against absorp-
tion of dimethylformamide.223 [CAS No. 79-06-1 and CAS No. 1187-59-3]
NH
N,N-DIMETHYLACETAMIDE NH2
skin sensitization tests, but in humans skin sensitization several types of tumours in different organs.239,243,244 No
appears to be rare.239 clear evidence of acrylamide carcinogenicity is available
from epidemiological studies in exposed workers,
Neurotoxic effects of acrylamide although two most recent updates of epidemiological
There are several studies in animals showing the develop- cohort studies found increased rates of pancreatic cancer,
ment of peripheral neuropathy after repeated exposure which were, however, not clearly related to increasing
to acrylamide.239 Also, in occupationally exposed workers, exposure levels.245,246 The IARC evaluation is 2A (proba-
neurotoxic effects have been described.240 In a Chinese fac- bly carcinogenic to humans).243 There are substantial data
tory producing monomeric and polymeric acrylamide, available showing that acrylamide is a genotoxic sub-
neurotoxic effects were experienced by the workers. stance.239,244 It has also been shown to induce heritable
Symptoms including numbness of hands and feet, lassi- genetic damage.
tude, sleepiness, muscle weakness, clumsiness of hand, Attempts have been made to estimate the potential
anorexia, unsteady gait and coldness of hands and feet; dif- carcinogenicity risk of low level acrylamide exposure.
ficulty in grasping and stumbling and falling were reported One of the most recent estimates is from the Dutch
significantly more in workers than in a control group. Expert Committee on Occupational Standards (DECOS),
Peeling of the skin and excessive sweating of the hands which has calculated so-called health-based occupational
were the first effects described. Other symptoms, like mus- cancer risk values (HBC-OCRVs) for acrylamide.244
cle weakness of the legs, numbness and tingling of hands Based on the results of animal studies, the committee
and feet appeared only after a few months of exposure. On estimated that an acrylamide exposure of 0.4 μg/m3
clinical examination, signs observed in exposed workers (time-weighted average) for 40 years leads to a cumula-
included impairment of vibration sense, pain, diminished tive excess cancer incidence of 105, and at 40 μg/m3 to an
touch and altered propioception. Some workers had mus- excess cancer incidence of 103.
cular atrophy, and diminished or loss of reflexes in the
extremities. In electroneuromyographic studies, findings Metabolism and monitoring
suggestive of partial denervation and axonal degeneration
Once absorbed, acrylamide undergoes a complex metabo-
were also seen in some workers who did not have any
lism involving direct conjugation with glutathione and the
apparent clinical signs of neurotoxicity.240
formation of an epoxide intermediate glycidamide.239
In the late 1990s, two incidents of significant occupa-
The main urinary metabolites include acrylamide-based
tional and environmental acrylamide exposure occurred in
mercapturic acid N-acetyl-S-(propionamide)-cysteine
Scandinavia in tunnel construction when N-methyloacry-
(APC), glycidamide-based mercapturic acids N-acetyl-
lamide-based grouting agents were used.241,242 The first
S-(carbamoylethyl)-1-cysteine and N-(R,S)-acetyl-S-2-
incident occurred in Hallandsås in 1997 during the con-
carbamoyl hydroxyethyl-1-cysteine (GAMA).247,248 All
struction of a railway tunnel. Due to leakage of the chemi-
of these have been suggested as markers for biological
cal, a nearby creek was also contaminated by acrylamide
monitoring of acrylamide exposure.247,248 Acrylonitrile
and N-methyloacrylamide resulting in fish deaths and neu-
exposure and smoking are potential confounding factors
rological symptoms in cows that drank water from the
in biological monitoring especially when N-acetyl-
creek. Some of the tunnel construction workers were sus-
S-(propionamide)-cysteine (APC) is used as a bio-
pected of being heavily exposed and regular medical exam-
marker.248 Since the excretion of acrylamide into urine is
inations, including neurophysiological and dermatological
rapid, urine biomarkers represent very recent exposure
assessment and analysis of acrylamide haemoglobin
(Figure 42.16).
adducts were performed. The results of this study showed
Haemoglobin adducts have been used as a biological
exposure-related signs and symptoms of peripheral nerv-
marker for acrylamide exposure, but the invasive nature of
ous system dysfunction. An association of symptoms with
blood sampling and complex analytical methodology limit
acrylamide-haemoglobin adduct levels was demonstrated.
the routine application of this approach.
More than half of the symptomatic workers showed
improvement in the symptoms and signs of peripheral
nervous system dysfunction after six months of follow up, Management and diagnosis
and after 12 and 18 months almost all were asymptomatic Diagnosis of acrylamide-induced polyneuropathy is
showing reversibility of the acrylamide neuropathy after based on typical symptoms, neurophysiological exami-
cessation of exposure.241 Similar results were also obtained nation and the assessment of exposure. Other possible
in Norwegian tunnel construction workers showing slight causes of polyneuropathy, e.g. long-term alcohol abuse,
demyelinating and axonal changes in peripheral nerves diabetes, neurotoxic drugs, vitamin B1, B6 and B12 deficien-
which were reversible after a year of follow up.242 cies, and some inflammatory, infectious or malignant
diseases, must be excluded. According to current knowl-
Carcinogenicity and mutagenicity edge, the signs and symptoms of acrylamide-induced
Data on the carcinogenicity of acrylamide is based on ani- neuropathy are at least partially reversible after the cessa-
mal experiments showing an increase in the incidence of tion of exposure.
352 Organic chemicals
O O
Cytochrome P450? C NH2 DNA adducts
NH2 H 2C CH
O
Glycidamide
Acrylamide
Glutathione
transferase GSH GSH GSH
CH2OH
O
C NH2
Epoxide hydratase?
H 2C CH
CH2OH
O
N-AcCys-S-CH2CHOHCONH2 Glycidamide HOCH 2-CHOH-CONH2 N-AcCys-S-CHCONH2 N-AcCys-S-CH2CH2CONH2
Figure 42.16 Acrylamide. Metabolism of acrylamide.243 Urinary metabolites are shown on the bottom row.
H2N NH2
H 2N H 2N NH2
Cl Cl
Figure 42.17 Molecular structures of aniline,
Aniline Benzidine MOCA benzidine and MOCA (4,4-methylenebis(2-
CAS No. 62-53-3 CAS No. 92-87-5 CAS No. 101-14-4 chloroaniline).
HO
HO OH N
H2N OH N OH
H
HO
Ethanolamine Diethanolamine Triethanolamine Figure 42.18 Molecular structures of
CAS 141-43-5 CAS 111-42-2 CAS 102-71-6 ethanolamine, diethanolamine and triethanolamine.
356 Organic chemicals
in the body in phospholipids.283 Triethanolamine is not of polyvinylpyrrolidone (used for pharmaceuticals, cos-
incorporated in phospholipids and is readily eliminated in metics and food additives) and co-polymers (used as vis-
urine.283,284 Urinary triethanolamine can be used for bio- cosity improvers in oils and in water-borne paints and
logical monitoring. However, urinary limit values indica- adhesives), and as a reactive thinner in UV-cured inks and
tive of safe exposure have not been established. lacquers and in the manufacture of contact lenses.286
In occupational settings, exposure to N-methyl- and
Management and diagnosis N-vinylpyrrolidone can occur through inhalation, espe-
The management of sensitization caused by ethanolamines cially when aerosols are formed or when heated. Both com-
is based on prevention of exposure by appropriate protec- pounds are also well absorbed through the skin.286,287
tive clothing and gloves, and follow up and prevention
of air contamination with ethanolamines. Diagnosis of Clinical effects and epidemiology
ethanolamine-caused skin sensitization is based on a NMP can cause skin irritation and dermatitis. Its use as a
history of exposure and patch-testing. Diagnosis of cleaner or as a paint stripper has been described to result in
ethanolamine-caused asthma is based on work-related redness, swelling, thickening and painful vesicles of the
symptoms, serial peak-flow readings, and on an exposure skin.285,288 At high air levels, eye irritation and headache
chamber challenge with the suspected agent, if necessary. have also been reported.289 Headaches and irritation of the
skin, eyes and the upper airways have been reported among
graffiti removers exposed to mixtures of NMP and glycol
Heterocyclic nitrogen compounds ethers.290 In animal tests, NMP has caused developmental
toxicity resulting in delayed development, malformations
This group of compounds includes substances whose com- and early fetal resorptions after oral exposure.291 Fetal toxic-
mon chemical feature is a ring structure with nitrogen as a ity has also been observed after inhalation or dermal expo-
part of the ring. sure, but mainly at maternally toxic levels.292,293 No
Examples of heterocyclic nitrogen compounds are epidemiological data on the effects of NMP in humans are
piperazine, pyrrolidone and its derivatives N-methyl available.
pyrrolidone and N-vinylpyrrolidone. Many piperazine N-vinylpyrrolidone can cause respiratory tract irrita-
derivatives are successful medicines. Piperazine is used in tion when inhaled. It has also caused liver damage in
the pharmaceutical industry and in the manufacture of animals at relatively low exposure levels. In long-term
plastics and resins. Pyrrolidone derivatives are widely used inhalation exposure studies in animals, it has resulted in
industrial chemicals. tumour formation in the liver, larynx and nasal cavity
at exposure levels close to those experienced at occupa-
N-METHYLPYRROLIDONE AND N-VINYLPYRROLIDONE tional settings.286 The mechanism of tumour formation
is unclear, but in the absence of evidence to the contrary,
[CAS No. 872-50-4 and CAS No. 88-12-0] these tumours must be considered of relevance to humans.
The IARC has allocated NVP to group 3.294
H3C
N H2C N Metabolism and monitoring
Since NMP is well absorbed through the skin, biological mon-
O O itoring may be valuable in the assessment of exposure.287
N-Methylpyrrolidone N-Vinylpyrrolidone NMP is hydroxylated to 5-hydroxy-N-methyl-2-pyrrolidone
(5-HNMP), which is oxidized to N-methylsuccinimide (MSI)
N-methylpyrrolidone (NMP) is a colourless liquid with a and further hydroxylated to 2-hydroxy-N-methylsuccinimide
vapour pressure of 39 Pa at 20°C. It is widely used nowadays (2-HMSI). All these metabolites can be found in the urine of
as a solvent, for example, for extraction purposes in the exposed workers.285 2-Pyrrolidone (2-P) is a urinary metabo-
petrochemical industry, as a remover of graffiti, as a paint lite which is probably formed by demethylation of NMP.295
stripper, and for stripping and cleaning applications in the 5-HNMP in plasma or urine is recommended for
microelectronics fabrication industry, as well as a reactive biomonitoring of NMP exposure.296
medium in polymeric and non-polymeric chemical No information on the metabolites of N-vinylpyrroli-
reactions. It is also used as a formulating agent in done in humans is available. According to animal experi-
pigments, dyes and inks; in insecticides, herbicides and ments, it is metabolized to polar metabolites and excreted
fungicides; and in the pharmaceutical and cosmetics mainly in the urine.286
industry.285 There are no known natural sources of
N-methylpyrrolidone. Management
N-vinylpyrrolidone (NVP) is a colourless to light yellow Management of the health risks from NMP and NVP
liquid with a relatively low vapour pressure at ambient is based on the monitoring and control of exposure.
temperatures (12 Pa at 20°C). It is used in the production Attention should be paid to dermal exposure.
Phenol and phenol derivatives 357
nitrophenols, diphenyl ethers, halogen phenols and other chlorophenols, which have been used as biocides and pes-
chemicals. A small amount serves as a component in cos- ticides, cresol (o-, p-, m-cresol) and resorcinol, as well as
metics and medical preparations. It can also be used for the nonylphenol and bisphenol A. Some phenol derivatives
production of paints and lacquers, adhesives, impregnat- have been shown to produce skin toxicity resulting in
ing agents and biocides. vitiligo. These include p-tert-butylphenol and certain
catechol derivatives (4-tert-butylcatechol) and hydro-
Clinical effects and epidemiology quinone.
Phenol is a corrosive and acutely toxic chemical. It can
cause serious poisoning by skin absorption, inhalation of CHLOROPHENOLS
vapours or by ingestion.313 Skin contact following spillage Chlorophenols are a group of chemicals in which one to
of phenolic solutions can lead to rapid absorption, col- five chlorine atoms have been added to the phenol mole-
lapse and death within 30 minutes.313 Death has resulted cule (Figure 42.19). Thus, five basic types of chlorophenols
from the absorption of phenol through a skin area as are monochlorophenols, dichlorophenols, trichlorophe-
small as 400 cm2.313 Because of the analgesic properties of nols, tetrachlorophenols and pentachlorophenol. There
phenol, the sensation of pain due to local exposure to are 19 different chlorophenols altogether. Chlorophenols
phenol may be diminished leading to less awareness of have been used as biocides and pesticides and as chemical
contact with the chemical and thus resulting in higher intermediates in the production of other chemicals. In
degrees of local damage. Affected skin areas turn brown North America and in Scandinavia, mixtures of chlorophe-
and gangrenous. Prolonged exposure may result in depo- nols, containing mainly 2,3,4,6-tetra-, penta- and 2,4,6-
sition of a dark pigment in the skin (ochronosis). Clinical trichlorophenols, have been widely used as wood
features of phenol poisoning include shock, collapse, preservatives, but after national restrictions this use has
coma, convulsions, cyanosis, damage to internal organs declined. Chlorophenols have, however, contaminated
and death. Cardiac manifestations including different many old sawmill sites. In a Finnish study, exposure of
kinds of arrhythmias are also typical. A recent case report workers to chlorophenols in the clean up of these contam-
describes a 47-year-old male who had 90 per cent phenol inated sawmill sites has been generally low.317
spilled over his left foot and shoe (3 per cent of body
Chlorophenols can be absorbed into the body by all
surface area). After a 4 12 -hour exposure, clinical manifesta-
routes of exposure. In occupational settings, skin absorp-
tions included confusion, vertigo, faintness, hypotension,
tion may be significant. Chloracne, acquired porphyria
ventricular premature beats, atrial fibrillation, dark-green
cutanea tardia, hyperpigmentation, folliculitis, keratosis
urine, swelling, blue-black discoloration and numbness of
the affected area. His peak serum phenol level was
21.6 mg/L, which was considered to be in the fatal range.314 OH
There is a wide variety of phenol derivatives with different Figure 42.19 Molecular structures of 4-chlorophenol, 2,4-
toxicological profiles. These include for example dichlorophenol, 2,4,6-trichlorophenol and pentachlorophenol.
Phenol and phenol derivatives 359
and hirsutism have been observed in workers employed in Vitiligo may become evident a few months to several years
the manufacture of 2,4-DCP- and 2,4,5-TCP-based herbi- after the beginning of exposure. Depigmented patches occur
cides.318,319 However, since chlorophenols may contain especially at the skin of exposed body sites, such as the hands
other chlorinated compounds, especially 2,3,7,8-tetra- and forearms, although in some cases it can also be seen at
chlorodibenzo-p-dioxin (TCDD; see under Chlorinated body sites covered by clothing.328 Some reports have sug-
dioxins and furans and related compounds, p. 370) as impu- gested liver and thyroid effects in exposed workers.
rities, it is difficult to ascribe these effects specifically to The mechanism by which 4-tert-butylphenol and other
chlorophenols. Acute toxicity of chlorophenols varies phenol derivatives cause occupational vitiligo is still uncer-
between the individual compounds, pentachlorophenol tain, but probably relates to their structural similarity with
being the most toxic with an estimated lethal oral dose for the melanin precursor tyrosine. This structural similarity
humans about 30 mg/kg body weight.320 It decouples of to tyrosine possibly leads to a tyrosinase-related protein-1-
oxidative phosphorylation resulting in a general increase of mediated mechanism in which the generation of reactive
metabolic activity. oxygen species causes melanocyte death (apoptosis).328
Pentachlorophenol has shown carcinogenic activity in
animal tests, causing for example liver tumours in mice.
According to the IARC’s evaluation, there is sufficient NONYLPHENOL AND BISPHENOL A
evidence in experimental animals for the carcinogenicity
of pentachlorophenol.321 Also 2,4,6-trichlorophenol has [CAS No. 25154-52-3 and CAS No. 80-05-7]
shown increased incidences of cancer in carcinogenicity HO
tests in mice. The epidemiological evidence on the carcino-
genicity of chlorophenol exposure is limited, although in
some studies significant associations with several types
CH3
of cancer, e.g. with soft-tissue sarcoma and non-Hodgkin’s
lymphoma have been suggested.322,323 Potential co-expo- Nonylphenol
sure to TCDD complicates the interpretation of these
studies. IARC has classified combined exposures to poly- CH3
chlorophenols or to their sodium salts as possibly carcino-
HO OH
genic to humans (group 2B).321
Exposure to chlorophenols can be assessed by measur- CH3
ing the levels of chlorophenols in urine.324 Bisphenol A
marked with longer alkyl chains; at the same time, the BISPHENOL A DIGLYCIDYL ETHER
volatilit also decreases. In addition to irritation and a slight
narcotic effect, little information is available on the adverse [CAS No. 1675-54-3]
effects of these epoxides in humans. Polyneuropathy, similar
O O
to that observed in humans, has been reported in experimen-
tal animals after exposure to propylene oxide and butylene O O
oxide.338
Propylene oxide is a colourless, highly volatile liquid at Bisphenol A diglycidyl ether (BADGE) is the building
room temperature and normal atmospheric pressure. It is block of epoxy resins; it is synthesized from epichlorohy-
highly flammable. Inhalation exposure to propylene drin and bisphenol A. Epoxy resins are used extensively for
oxide induced nasal tumours in rats and mice, and less sealing, encapsulating, making castings and pottings, and
consistently tumours in other organs. Propylene oxide formulating lightweight foams. Resins are used as binders
administered by oral gavage to rats produced tumours in the preparation of laminates of paper, polyester cloth,
of the forestomach. Propylene oxide was consistently fibreglass cloth and wood sheets. Epoxy resins have out-
mutagenic in several in vitro test systems, and also standing adhesive properties.348 Fully hardened resin has
induced cytogenetic changes in experimental animals low toxicity; it is the monomers and oligomers with free
in vivo. Haemoglobin adducts, but not cytogenetic effects or epoxide groups that are responsible for the different
DNA damage, has been reported in exposed humans.339–342 aspects of epoxy resin toxicity.
Propylene oxide caused reproductive toxicity (decreased The key toxic characteristic of BADGE is contact der-
fetal weight and delayed ossification) with no teratogenic matitis (Figure 42.20), which has been amply demon-
effects in rats, only at doses overtly toxic to the dams.343 strated in numerous case reports; it is apparently the most
Epoxybutane is a colourless liquid with a characteristic common causative agent for epoxy resin-induced contact
odour. It induced degenerative changes in the nasal
mucosa in rats and mice in two-year inhalation studies. It
also induced a low frequency of nasal adenomas in male
and female rats, as well as alveolobronchiolar carcinomas
in male rats.344 The IARC working group considered these
data to provide limited evidence of carcinogenicity in ani-
mals, but based on extensive data demonstrating genotoxic
activity concluded that epoxybutane is possibly carcino-
genic to humans (rather than the ‘not classifiable’ normally
deduced from limited evidence in animals in the absence of
epidemiological data).345
EPICHLOROHYDRIN
Cl O
dermatitis (other possibilities being reactive diluents, develops rhinitis and asthma. The diagnosis has been based
amine hardeners and epoxy acrylates).349–351 It also elicits on the exposure, symptoms and a cause–effect relationship
sensitization in experimental animals. Cases of contact supported by immunological tests or challenge tests. The
urticaria have also been described after exposure to disease is apparently an IgE-mediated immediate-type
BADGE.352 Carcinogenicity studies with BADGE have asthma.359 In patients with asthma related to the anhy-
given conflicting results, the IARC evaluation being drides, induction of specific IgE antibodies to phthalic
‘limited evidence in experimental animals’.353 anhydride, trimellitic, maleic, methyltetrahydrophthalic,
Workers exposed to BADGE exhibited elevated urinary tetrachlorophthalic, hexahydrophthalic, methylhexahy-
concentrations of bisphenol A.354 Bisphenol A has oestro- drophthalic, himic and chlorendic anhydride has been
genic and anti-androgenic characteristics in studies on detected.360–374 Cross-reactivity between some acid anhy-
endocrine disruption.355,356 It is not clear whether this drides has been reported.360,369,375,376
has significance from the human health point of view. Specific IgG antibodies against trimellitic anhydride-
However, in one study, blood concentrations of FSH, but human serum albumin have been correlated with late-onset
not of LH or testosterone, were lower in workers exposed occupational asthma due to trimellitic anhydride.368,377–380
to BADGE than in referents.354 BADGE did not give The potency to induce respiratory sensitization varies
rise to developmental toxicity in standard experimental between different cyclic anhydrides, phthalic and tetra-
tests.353,357 chlorophthalic apparently being less potent than trimel-
litic, methyltetrahydrophthalic, methylhexahydrophthalic
or hexahydrophthalic anhydrides (Table 42.7).
CYCLIC ACID ANHYDRIDES
Metabolism and monitoring
Cyclic acid anhydrides are a group of reactive chemicals,
Cyclic anhydrides are metabolized to the corresponding
which are used in the manufacture of polyester and alkyd
carboxylic acids. The concentrations of phthalic and
resins and plasticizers and as epoxy resin hardeners. At
methyltetrahydro-, hexahydro- and methylhexahydroph-
room temperature, cyclic anhydrides are powders or crys-
thalic acids in the urine have been reported to be related to
tals, and exposure is mostly to dusts. Hot processes, such as
the time-weighted average concentrations in the breathing
hardening of epoxy resins, welding or burning of painted
zone air. Their analysis thus offers the possibility for bio-
metals, or curing of the paints, may also involve exposure
logical monitoring.381–384 The information, however, at
to fumes.
present is limited and reliable prediction of sensitization
Cyclic acid anhydrides in use, and with similar clinical
risk in an individual from urinary carboxylic acid concen-
effects, include phthalic, hexahydrophthalic, methyl hexa-
trations is not possible.
hydrophthalic, tetrahydrophthalic, methyl tetrahydro-
Anhydrides react with proteins with lysine residues, and
phthalic, tetrachlorophthalic and tetrabromophthalic
the conjugates are a likely mediator of the immunological
hydrides, as well as trimellitic, maleic, himic, succinic,
response. A relationship between the concentration of the
dodecenylsuccinic, chlorendic anhydrides and pyromel-
protein conjugates, and air-borne exposure to hexahydro-
litic dianhydride (Figure 42.21).
and methylhexahydrophthalic anhydride has also been
Clinical effects and epidemiology demonstrated.
Exposure to cyclic acid anhydrides causes irritation of the
skin, eyes and the respiratory tract as an immediate effect Management and diagnosis
after direct contact. Trimellitic anhydride especially is a For some cyclic anhydrides, information is available of
very potent eye irritant. Irritation is caused by exposure to concentrations likely to induce sensitization (Table 42.7).
both dusts and to vapours.358 Individuals already sensitized are likely to develop symp-
Contact dermatitis and a positive result on prick testing toms at considerably lower exposures, and it is not likely
has been reported in a worker exposed to dodecenylsuc- that people once sensitized will be able to carry out tasks
cinic anhydride, and in another worker exposed to methyl with exposure to anhydrides. Cross-reactivity between
hexahydrophthalic anhydride. Contact urticaria has been different anhydrides has been reported.
reported in a few cases after exposure to chlorendic, Diagnosis is based on exposure, and exposure-related
phthalic, maleic, methyl tetrahydrophthalic and methyl- symptoms. Specific IgE and also IgG concentrations in the
hexahydrophthalic anhydrides. Urticaria usually occurs serum are often elevated among exposed groups; and posi-
after direct dermal contact, but also cases induced by tive skin prick test results have also been reported. However,
inhalation exposure have been reported. no reliable information is available on the sensitivity or
Occupational asthma and rhinitis have been described specificity of these analyses. Positive challenge tests have
after exposure to many different cyclic anhydrides. been reported, but these tests have been seldom used for
Typically, after an exposure of 1–35 months, the worker investigating effects of cyclic anhydrides.358,359
Cyclic acid anhydrides 363
HO
O O
O O
Maleic anhydride (CAS 108-31-6) Hexahydrophthalic anhydride (CAS 85-42-7)
O
O O
O
O O
O O
O O
Tetrahydrophthalic anhydride (CAS 85-43-8) Tetrachlorophthalic anhydride (CAS 117-08-8)
Cl
O O
O O Cl
Cl
O
Cl
Pyromellitic dianhydride (CAS 89-32-7) Himic anhydride (CAS 826-62-0)
O O O
O O O
O O
O
Succinic anhydride (CAS 108-30-5) Dodecenyl succinic anhydride (CAS 25377-73-5)
O O
O O
O O
Chlorendic anhydride (CAS 115-27-5) Tetrabromophthalic anhydride (CAS 632-79-1)
Cl Br
O O
Cl Br
Cl O O
Cl Cl Br
O O
Cl Br
N
N N O O
C
N C O C C
O O O N N
Polymeric MDI
CAS 97568-33-7
N
Isophorone diisocyanate (IPDI)
CAS 4098-71-9 O
Chlorinated hydrocarbons 365
threshold lies between 20 and 30 ppm. It has a vapour pres- odds ratio of 5.6 (CI, 0.93–34.3) for psycho-organic
sure of 8.6 kPa at 20°C. The main use of trichloroethene is syndrome in the medium-exposed group and 42.2
in cleaning of metal parts. According to industry data, 82 (CI, 1.9–66.6) in the most highly exposed group of work-
per cent of trichloroethene is used for metal degreasing, ers. None of four other potential confounders (arterioscle-
9 per cent in adhesives, 6 per cent for consumer uses and rotic disease, neurologic/psychiatric disease, alcohol abuse
3 per cent for other uses (e.g. extraction, leather prepara- and current solvent exposure) had any significant associa-
tion, pharmaceuticals).399 In Europe, use of trichloroethene tion with psycho-organic syndrome.404
in metal cleaning has decreased over the past few years.392 Exposure-related effects on neuropsychological per-
Tetrachloroethene (tetrachloroethylene, perchloroeth- formance have also been observed in dry cleaners exposed
ylene) is a colourless liquid with an ethereal odour. It has a to tetrachloroethene. Impairments in visual reproduction,
vapour pressure of 1.9 kPa at 20°C. The major uses of tetra- pattern memory and pattern recognition have been seen in
chloroethene are as a chemical intermediate and as a dry dry cleaners with high chronic exposure.405 These impair-
cleaning agent. Other uses include metal cleaning and ments of visually mediated function were consistent with
extraction processes.400 the impairment of visuospatial functions observed in
Exposure to trichloroethene or tetrachloroethene in the patients diagnosed earlier with tetrachloroethene
occupational settings may occur by inhalation or through encephalopathy. Effects on visuospatial function were con-
the skin.399,401 sistently found in subjects employed as dry cleaners for an
average of 14.6 years and exposed to an estimated tetra-
Clinical effects and epidemiology chloroethene eight-hour TWA air concentration of
Acute exposure to high trichloroethene concentrations 280 mg/m3. Effects of tetrachloroethene on colour vision
causes central nervous system (CNS) depression. have also been reported.406
Concentrations of 5000 ppm causes narcosis and poten- In animal experiments, trichloroethene has caused mid-
tially serious arrhythmias including ventricular tachycar- frequency hearing loss in animal tests.407 Synergistic effects
dia. In controlled volunteer studies, marked changes in with noise on hearing thresholds have been reported in
visual-motor performance and subjective symptoms like animals.408 In humans, specific evidence on the effects of
dizziness, light-headedness and lethargy have been trichloroethylene on hearing is lacking. One report sug-
observed following acute exposure to trichloroethene for gests ototoxic effects in jet engine repair workers resulting
two hours at 1000 ppm, whereas exposure to 300 ppm in balance disturbances. However, they may have also been
caused only slight, non-significant changes in tests measur- exposed to other neurotoxicants.409
ing visual-motor performance.399 Alcohol potentiates the The carcinogenicity of trichloroethene has been investi-
acute neurotoxicity of trichloroethene.402 The consump- gated in a number of long-term animal studies. These
tion of alcohol following exposure to trichloroethene may studies provide clear evidence on trichloroethene’s car-
cause ‘degreaser’s flush’. This is a transient redness of the cinogenicity in rodents. It has induced hepatocellular and
face and neck, often accompanied by chest discomfort and lung tumours in mice and kidney tumours in rats.399
dyspnoea. It only affects a minority of exposed individuals, Recent epidemiological studies provide support for the
and the mechanism is uncertain. carcinogenicity of trichloroethene. Associations between
Acute inhalation of high concentrations of tetra- trichloroethene exposure and kidney cancers, liver and bil-
chloroethene induces CNS depression, dizziness, fatigue, iary tract cancers, and lymphomas have been suggested.410
headache, loss of coordination and narcosis, and liver Two recent cohort studies show statistically significant
damage with some deaths having been reported. CNS associations between kidney cancer and increasing
depression and mild respiratory tract irritation may occur trichloroethene exposure.411,412
at air levels of 690 mg/m3.401 In addition, subclinical Trichloroethene has been shown to have genotoxic
deficits in vision, cognitive and motor function have potential. However, there are still uncertainties related to
occurred in a randomized exposure chamber study at mode of action and metabolites responsible for
340 mg/m3.403 Both trichloroethene and tetrachloroethene trichloroethene-induced cancers. The available data sup-
can irritate the skin and mucous membranes, and cause port the likelihood that toxicity is due to multiple metabo-
occupational dermatitis due to their defatting properties. lites through several modes of actions.413 The IARC
Based on animal data and human experience, they are has classified trichloroethene as class 2A. Some studies
unlikely to cause skin or respiratory sensitization.399,401 have tried to characterize specific mutations related
Long-term exposure to trichloroethene or tetra- to trichloroethene-induced renal cancers. Currently, how-
chloroethene has been suggested to cause chronic solvent ever, no specific pattern of mutations in trichloroethene
encephalopathy (see under Toluene, xylene and styrene, cancers has been identified.
p. 327). A cohort of nearly a hundred metal degreasers Tetrachloroethene has caused liver and kidney tumours
showed a significantly increased risk of psycho-organic in animal carcinogenicity tests. Epidemiological evidence
syndrome from solvent exposure characterized by cogni- on the association between occupational exposure to tetra-
tive impairment, personality changes and reduced motiva- chloroethene and cancer is limited. However, because
tion, vigilance and initiative.404 In this study, there was an of the strong animal evidence and the evidence of the
Chlorinated hydrocarbons 367
genotoxicity of its main metabolites, the IARC has classi- Management of tri- and tetrachloroethene-related risks
fied tetrachloroethene as group 2A.414,415 is mainly related to monitoring and controlling of expo-
sure to as low as technically feasible.
Metabolism and monitoring
Trichloroethene is predominantly cleared from the body after METHYLENE CHLORIDE
metabolism, accounting for 50–99 per cent of the absorbed
dose. The major metabolic pathway for trichloroethene [CAS No. 75-09-2]
involves the initial conversion of trichloroethylene by Cl
cytochrome P450 to a transient epoxide, which subse-
quently undergoes intramolecular rearrangement to form Cl
trichloroacetaldehyde. Trichloroacetaldehyde is hydrol- Dichloromethane
ysed to form chloral hydrate, which is converted by alcohol
dehydrogenase and chloral hydrate dehydrogenase to Methylene chloride is a clear, highly volatile liquid with a
trichloroethanol and trichloroacetic acid, respectively. characteristic ether-like odour. It is used because of its good
Other minor metabolites, which have been suggested to be solvent properties in many different applications. One of
of relevance for trichloroethene-induced cancers include the most widespread applications is its use as a paint
dichloroacetic acid (DCA) and S-(1,2-dichlorovinyl)- remover. This use is likely to decrease in Europe due to the
L-cysteine (DCVC), which may be involved in liver and
planned restrictions on methylene chloride use in paint
kidney carcinogenicity of trichloroethene, respectively.413 removers. Methylene chloride is well absorbed by inhala-
Unmetabolized trichloroethene is mostly exhaled, tion or through the gastrointestinal tract. Absorption
whereas metabolites of trichloroethene are predominantly through the skin also occurs.
eliminated in urine. Urine trichloroacetic acid (U-TCA) is
Clinical effects and epidemiology
commonly used to assess exposure to trichloroethene.
Most (98–99 per cent) of absorbed tetrachloroethene is Since methylene chloride is a highly volatile liquid, it can
excreted unchanged in exhaled air, regardless of expo- result in high air concentrations especially when it is used in
sure route. The rest is metabolized by two main pathways, closed spaces. There are several poisoning cases described in
cytochrome P450-mediated oxidative route and glutathione- the literature, which have been caused by methylene chlo-
S-transferase (GST)-mediated conjugation. The major ride use in confined spaces.418 Acute exposure to air levels
metabolite detected in human blood and human urine is of 700 mg/m3 causes slight central nervous system effects
trichloroacetic acid (TCA), formed by cytochrome P450- (behavioural disturbances), with more significant effects
dependent oxidation of tetrachloroethene to epoxide inter- being seen at concentrations in excess of 2000 mg/m3.418
mediate, but even TCA is formed only in small quantities. Methylene chloride is metabolized in the body to carbon
The second pathway involves conjugation of tetra- monoxide resulting in elevated carboxyhaemoglobin (CO-
chloroethene with glutathione and is associated with gen- Hb) levels. Exposure to 100 or 530 mg/m3 for 7.5 hours
eration of reactive metabolites via initial cleavage to leads to CO-Hb levels of 3.4 and 5.3 per cent, respectively,
S-(1,2,2-trichlorovinyl)-L-cysteine and further degradation in human volunteers.418 Fatal poisonings are considered to
of the cysteine conjugate by beta-lyase to a reactive be due to the narcotic effects of methylene chloride rather
dithioketene and ultimately dichloroacetic acid. Metabolites than directly due to carbon monoxide poisoning.418–421
derived from P450 metabolism, specifically TCA and DCA, Poisoning cases in which methylene chloride has been
have been linked to hepatotoxicity and liver tumorigenesis, heated resulting in the formation of phosgene have been
whereas reactive metabolites formed through the GSH also described in the literature.422,423
conjugation pathway have been associated with tetra- Methylene chloride has caused cancer in mice bioassays.
chloroethene-induced renal toxicity and carcinogenicity.416 According to current knowledge, this effect is related to the
The available data indicate that tetrachloroethene concen- specific metabolism of methylene chloride in mice, and the
trations in blood and exhaled air give a reliable impression of cancer risk in humans is low.418 No epidemiological data
the exposure over the previous several days. Trichloroacetic on the carcinogenicity of methylene chloride in humans
acid is a less suitable exposure indicator, as it is also the major are available. IARC classification is that methylene chloride
metabolite of trichloroethene and trichloroethane, which is possibly carcinogenic to humans (2B).424
are often present as impurities in tetrachloroethene, or can
be used in the same location as tetrachloroethene.401 Metabolism and monitoring
Tetrachloroethene in urine has also been suggested for bio- When inhaled, most of the absorbed methylene chloride is
monitoring of tetrachloroethene.417 exhaled unchanged and the remainder is metabolized to car-
bon monoxide, carbon dioxide and inorganic chloride.418
Management and diagnosis At lower doses, the main route of metabolism is medi-
The diagnosis of chronic solvent-induced encephalopathy ated by cytochrome P450, whereas at high-dose levels
follows the principles described under Toluene, xylene and (
1800 mg/m3) this route is saturated and the metabolism is
styrene, p. 327. transferred to involve glutathione transferase (GST) resulting
368 Organic chemicals
in the formation of formaldehyde, formate and finally car- exposure.425 In a study426 on 725 workers exposed to signif-
bon dioxide. In mice, the GST pathway is the major pathway. icant VC levels, 3 per cent developed acro-osteolysis, 10 per
Methylene chloride can be monitored by measuring the cent Raynaud-type phenomenon and 6 per cent scleroder-
solvent itself in exhaled air or blood, or by analysis of car- moid skin lesions. Genetic susceptibility has been suggested
bon monoxide in exhaled air, or by measuring carboxy- as a possible reason for variability in the clinical picture.
haemaoglobin (CO-Hb) in blood, which is currently the Exposure to VC is also associated with hepatomegaly
preferred method. Smoking is a significant confounding and/or splenomegaly.425 Early histological lesions in VC
factor in increasing CO-Hb levels. workers showed focal hepatocellular hyperplasia and
hyperplasia of sinusoidal cells along with hyperplasia of
Management and diagnosis hepatocytes.427 Later effects preceding angiosarcoma include
Because of the high volatility and acute toxicity, methylene subcapsular fibrosis, progressive portal fibrosis and a border-
chloride should always be handled only in well-ventilated line increase of intralobular connective tissue, all associated
areas. Diagnosis of methylene chloride poisoning is based with focal stimulation and proliferation of sinusoidal lining
on a history, symptoms and carboxyhaemoglobin meas- cells and hepatocytes.
urement. Treatment is symptomatic including administra- The ability of vinyl chloride to cause liver angiosarcoma
tion of oxygen and follow up of liver, nervous system and is well known. A recent meta-analysis of two recently
renal functions. updated multicentre cohorts and six smaller studies evalu-
ated the relationship of cancer mortality and vinyl chloride
exposure.428 Six studies suggested an increased risk of liver
VINYL CHLORIDE cancer. For four of these studies, excesses persisted when
known cases of angiosarcoma of the liver were excluded. It
[CAS No. 75-01-4]
was noted however, that these results may have been influ-
H2C Cl enced by the underdiagnosis of angiosarcoma. Also
increased standardized mortality ratios (SMRs) were sug-
Vinyl chloride is a colourless, flammable gas with a slightly gested for brain cancer, soft tissue sarcomas and lymphatic
sweet odour and was previously used as an anaesthetic and haematopoietic neoplasms. Mortality from other neo-
agent. It is now mainly used for the production of plasms, including lung cancer, did not appear to be
polyvinyl chloride (PVC) plastics in closed systems. It is increased according to this meta-analysis. Gennaro and co-
not known to occur naturally, but is present in cigarette workers429 recently published a reanalysis of updated mor-
smoke. The level of residual vinyl chloride (VC) in tality experience among Italian vinyl chloride and PVC
polyvinyl chloride has been regulated since the late 1970s workers exposed in a large petrochemical plant in Porto
in many countries and nowadays the release of VC from Marghera between July 1950 and July 1985. In this study,
the thermal degradation of PVC is either not detectable or elevated risks for liver cancer, including angiosarcoma,
is at very low levels.425 Exposure to vinyl chloride occurs haemolymphopoietic system cancers and lung cancer,
mainly by inhalation. were observed in exposed workers. The IARC concluded in
2009 that vinyl chloride causes angiosarcoma of the liver
and hepatocellular carcinoma.100
Clinical effects and epidemiology The mechanism for liver cancer caused by vinyl chlo-
Vinyl chloride has low acute toxicity, but long-term expo- ride has been well studied. Mechanistic events resulting to
sure causes severe adverse effects including a specific type cancer include:430,431
of cancer, liver angiosarcoma, in humans.
Prior to the mid-1950s, exposure levels in PVC produc- ● metabolic activation to form chloroethylene oxide;
tion could easily exceed 1000 ppm and a specific syndrome ● DNA binding of the chloroethylene oxide to form
called ‘vinyl chloride illness’ was described in workers. exocyclic etheno adducts;
Symptoms included headache, dizziness, earache, blurred ● ability of these adducts to cause base mutations; and
vision, fatigue, nausea, sleeplessness, breathlessness, stom- ● effects of such mutations on proto-oncogenes/tumour
ach ache, pain in the liver/spleen area, pain and tingling suppressor genes at the gene and gene product levels.
sensation in the arms and legs, cold sensation in the extrem-
ities, loss of appetite, loss of libido and weight loss.425 Specific mutations associated with vinyl chloride-
Specific findings in the skin and bones caused by vinyl chlo- induced liver tumours include GA transitions at codon
ride included acro-osteolysis accompanied by scleroderma- 13 of Ki-ras proto-oncogene and AT transversions in
like changes in the fingers and peripheral circulatory tumour suppressor protein p53.431 Also serum anti-p53
changes resembling Raynaud’s disease. Acro-osteolysis is antibodies have been found in angiosarcoma patients and
caused by the decalcification of the terminal phalanges of in some workers with occupational exposure to VC.431
the hands and feet, which may be reversible after cessation There are some published risk estimates of cancer risk
of exposure. Also Raynaud’s disease caused by vinyl chlo- from VC at low exposure levels based on different sets of
ride may show some improvement after cessation of the data.430 According to these estimates, an angiosarcoma
Chlorinated hydrocarbons 369
risk of approximately 3 104 for exposure to 1 ppm (a rubber-like latex from tropical trees used for wire
vinyl chloride over an entire human working lifetime has insulation, and for root canal fillings in dentistry) and
been suggested. resins, as a cleansing agent, in fire extinguishers, and in the
rubber industry.432
Metabolism and monitoring Carbon tetrachloride is a colourless, volatile liquid with
a characteristic sweet odour. It has been used especially in
Vinyl chloride undergoes rapid oxidative metabolism the production of chlorofluorocarbons (CFCs) used widely
to yield reactive metabolites, the most reactive being as refrigerants and propellants, but this use has decreased
chloroethylene oxide (CEO) and its derivative chloro- in recent years due to restrictions on the use of CFC com-
acetaldehyde (CAA). pounds. It has also had many other uses as a grain fumi-
CEO is formed by cytochrome P450 isoenzyme CYP2E1 gant, pesticide, solvent, metal degreaser, fire extinguisher
and detoxified by epoxide hydrolase and glutathione-S-trans- and flame retardant, and in the production of paint, ink,
ferase.431 Polymorphism of the genes of these xenobiotic plastics, semiconductors and petrol additives, but many of
metabolizing enzymes may affect the cancer susceptibility of these uses have decreased or stopped.433
individual exposed workers. According to current knowledge, Both substances are well absorbed through the lungs,
CEO is the most biologically relevant metabolite and it is skin and gastrointestinal tract.
likely that VC biotransformation into CEO occurs in the
hepatocytes, thus allowing the epoxide to reach and hit the Clinical effects and epidemiology
adjacent sinusoidal lining cells that are the target for angiosar- Chloroform has been used in the past to induce and main-
comas. This results in the formation of exocyclic etheno tain medical anaesthesia. Induction levels were approxi-
adducts identified in exposed animals and in humans.430,431 mately 24–73 g/m3 and maintenance levels 12–48 g/m3 air.
This practice was discontinued because chloroform anaes-
Management and diagnosis thesia caused deaths due to respiratory effects and arrhyth-
At current exposure levels in PVC manufacturing mias and cardiac failure. In addition, jaundice and hepatic
(1 ppm), the risk for cancer is low, but because of the dysfunction resulting in lethal liver necrosis have been
assumed linear dose–response relationship it is not exclud- described after chloroform anaesthesia.432 Some reports
able. Liver angiosarcoma is an uncommon tumour type suggest toxic liver jaundice and hepatitis in workers
and therefore if the occupational history shows possible exposed to varying levels of chloroform for less than six
vinyl chloride exposure, the possibility of occupational months to four years.434,435 In animal tests, chloroform has
cancer must be considered. Since there is increasingly caused liver damage and increased kidney weight after
more information on specific features of VC-induced liver repeated inhalation exposure at high doses.432
cancers including specific mutations, these may provide The liver and kidney are also target organs for carbon
some new tools for the differential diagnosis of VC- tetrachloride toxicity. Symptoms of acute intoxication
induced cancers in future. The prognosis of angiosarcoma after accidental or suicidal high level exposure are inde-
of the liver is poor. pendent of the route of intake and include nausea, vomit-
The risk of non-cancer effects from VC exposure is ing, headache, dizziness and dyspnoea. Liver damage
related to high-dose exposures and these are unlikely to appears after 24 hours or more, but kidney damage is evi-
occur from current work processes. dent often only after two to three weeks following the poi-
soning.433 No association between occupational, long-term
low-level exposure to carbon tetrachloride and liver
CHLOROFORM AND CARBON TETRACHLORIDE disease has been described.
Both substances have induced cancer in animals.
[CAS No. 67-66-3 and CAS No. 56-23-5]
Chloroform has been negative in genotoxicity tests and its
Cl Cl carcinogenicity (hepatic and renal cancers) is most likely
Cl Cl
secondary to hepatotoxicity and nephrotoxicity observed
Cl
in animal tests at high dose levels.432 In addition, carbon
Cl tetrachloride has been mainly negative in genotoxicity tests
Cl
and hepatomas and hepatocellular carcinomas seen in
Chloroform is a clear, colourless, volatile liquid with a long-term cancer bioassays in animals have been observed
characteristic, ether-like odour. Its main use is in HCFC- mainly at the dose levels producing liver toxicity.433 No
22 production. HCFC-22 is used in refrigerant applica- clear epidemiological evidence on their carcinogenicity in
tions (decreasing use) and increasingly as the feedstock for humans is available.
fluoro-polymers, such as polytetrafluoroethylene (PTFE).
Metabolism and monitoring
Earlier use of chloroform as an anaesthetic has been
largely discontinued in the western world. Worldwide, Chloroform is metabolized mainly by CYP2E1. The end-
chloroform is also used in pesticide formulations, as a sol- product of oxidative metabolism by CYP2E1 is carbon
vent for fats, oils, rubber, alkaloids, waxes, gutta-percha dioxide and reactive intermediates include phosgene.
370 Organic chemicals
Carbon tetrachloride is metabolized by cytochrome P450 Table 42.9 Relative toxicity of dioxin-like compounds.439
enzymes (CYP2E1 and CYP2B1/2B2), leading to the forma-
Compound CAS No. TEF
tion of reactive trichloromethyl and trichloromethylperoxyl
radicals, which can further react to form phosgene.432,433
Chlorinated dibenzo-p-dioxins
Management and diagnosis 2,3,7,8-TCDD 1746-01-6 1
1,2,3,7,8-PeCDD 40321-76-4 1
Liver and kidney diseases caused by chloroform and carbon
1,2,3,4,7,8-HxCDD 57653-85-7 0.1
tetrachloride are mainly related to high level accidental
1,2,3,6,7,8-HxCDD 57653-85-7 0.1
exposures or anaesthesia (chloroform). The treatment of
1,2,3,7,8,9-HxCDD 19408-74-3 0.1
acute carbon tetrachloride or chloroform poisoning is
1,2,3,4,6,7,8-HpCDD 35822-46-9 0.01
symptomatic, including follow up of liver and kidney func-
Octachlorodibenzodioxin 3268-87-9 0.0003
tion. N-acetylcysteine and pyridoxine (administered orally)
may provide some protection against carbon tetrachloride- Chlorinated dibenzofurans
caused hepatic injury, if administered early following acute 2,3,7,8-TCDF 51207-31-9 0.1
exposure.260 1,2,3,7,8-PeCDF 57117-41-6 0.03
2,3,4,7,8-PeCDF 57117-31-4 0.3
CHLOROBENZENES 1,2,3,4,7,8-HxCDF 70648-26-9 0.1
1,2,3,6,7,8-HxCDF 57117-44-9 0.1
Chlorobenzenes, like 1,4-dichlorobenzene and hexa- 1,2,3,7,8,9-HxCDF 72918-21-9 0.1
chlorobenzene, are examples of aromatic halogenated 2,3,4,6,7,8-HxCDF 60851-34-5 0.1
hydrocarbons. 1,4-Dichlorobenzene (CAS No. 106-46-7) is 1,2,3,4,6,7,8-HpCDF 67562-39-4 0.01
a substance used in the chemical industry for the production 1,2,3,4,7,8,9-HpCDF 55673-89-7 0.01
of other chemicals, but also in moth repellants, air freshen- Octachlorodibenzofuran 39001-02-0 0.0003
ers and toilet blocks. The main health concern related to 1,4- Non-ortho substituted PCBs
dichlorobenzene is its ability to cause liver tumours in PCB 77 (3,4,3,4-tetraCB) 32598-13-3 0.0001
mice.436 The mechanism of this effect is unknown, but PCB 81 (3,4,5,3-tetraCB) 70362-50-4 0.0003
appears to be related to high experimental doses. PCB 126 (3,4,5,3,4- 57465-28-8 0.1
Hexachlorobenzene (CAS No. 118-74-1) is an environ- pentaCB)
mental contaminant released from a number of sources, PCB 169 (3,4,5,3,4,5- 32774-16-6 0.03
including the use of some chlorinated pesticides, incomplete hexaCB)
combustion, old waste removal sites and inappropriate
Mono-ortho substituted PCBs
manufacture and disposal of waste from the manufacture of
105 (2,3,4,3,4-pentaCB) 32598-14-4 0.00003
chlorinated solvents, chlorinated aromatics and chlorinated
114 (2,3,4,5,4-pentaCB) 74472-37-0 0.00003
pesticides.437 Hexachlorobenzene caused poisoning of more
118 (2,4,5,3,4-pentaCB) 31508-00-6 0.00003
than 600 people in Turkey when they consumed bread made
123 (3,4,5,2,4-pentaCB) 65510-44-3 0.00003
from wheat that was contaminated with hexachlorobenzene
156 (2,3,4,5,3,4-hexaCB) 38380-08-4 0.00003
used as a fungicidal seed dressing in the 1950s. The clinical
157 (2,3,4,3,4,5-hexaCB) 69782-90-7 0.00003
manifestations were porphyria cutanea tarda with distur-
167 (2,4,5,3,4,5-hexaCB) 52663-72-6 0.00003
bances in porphyrin metabolism, dermatological lesions,
189 (2,3,4,5,3,4,5- 39635-31-9 0.00003
hyperpigmentation, hypertrichosis, enlarged liver, thyroid
heptaCB)
gland and lymph nodes, osteoporosis and arthritis.437
Acquired hepatic porphyrias have also been described fol- TEF, toxicity equivalence factor.
lowing exposure to vinyl chloride, some halogenated
biphenyls, chlorinated naphthalenes, and organophosphate Cl Cl
and organochlorine pesticides. Hexachlorobenzene has
been carcinogenic in animal tests producing liver tumours.
IARC classified it under group 2B.438 Cl Cl
O
Chlorinated dioxins and furans, and related 2,3,7,8-Tetrachlorodibenzofuran
compounds TCDD (more accurately, 2,3,7,8-tetrachlorodibenzo-p-
dioxin (CAS No. 1746-01-6), is the most potent of a large
O
Cl 1 10 9 Cl group of halogenated chemicals, which share qualitatively
2 8
similar toxicological properties, while differing widely in
3 7
Cl 5 Cl
their potency. The key to the toxicity of these chemicals is
4 6
O the planar molecular configuration, with 3–4 halogen
2,3,7,8-Tetrachlorodibenzo-p-dioxin atoms at the corners. This molecular form fits a receptor
Chlorinated hydrocarbons 371
molecule in the body, and this is apparently the reason for of dioxin-like chlorinated dibenzofurans and dioxin-like
the unique toxicity of these compounds. polychlorinated biphenyls.100
While the most studied group is compounds with chlo- From a meta-analysis of studies performed (but not all
rine substituents, other halogenated compounds have sim- published), it was concluded that there was an elevated fre-
ilar effects. One of the best studied is polybrominated quency of all malformations among babies born to moth-
biphenyls (PBBs), previously used as flame retardants. The ers exposed to Agent Orange (containing dioxins) during
most toxic of these compounds are listed in Table 42.9, the Vietnam war.442 The data are strongest for spina bifida
with an estimated relative toxicity for each as assessed by and anencephaly.443 Exposure to TCDD was related to
WHO in 1998 and 2005.439 semen quality and serum testosterone levels in exposed
Dioxins cause chloracne, peripheral neuropathy, liver men.444,445 In experimental animals, TCDD is toxic to
damage, hepatic porphyria and hypercholesterolaemia. reproduction and to development; the developing fetus
Changes in the immune system and glucose metabolism seems to be orders of magnitude more sensitive to TCDD
have been described in adults, as well as alterations in than adult animals. The spectrum of malformations
thyroid hormone levels, and possible changes in neuro- induced varies between species.
behavioural tests, and infection resistance.440,441
The best information on cancer and dioxins comes POLYCHLORINATED BIPHENYLS
from cohorts exposed to dioxin-contaminated herbi-
cides in herbicide production.440 In these cohorts, the Polychlorinated biphenyls (PCBs) have been produced
risk of cancer at all sites was elevated and showed a commercially since 1929 (Figure 42.23). They have been
relationship with the estimated intensity of the exposure. used in plasticizers, surface coatings, inks, adhesives, flame
The cancer types that show the most consistent rela- retardants, pesticide extenders, paints and microencapsu-
tionship to dioxin exposure, are cancer of the lung, lation of dyes for carbonless duplicating paper, as well
non-Hodgkin’s lymphoma and soft tissue sarcoma. The as dielectric fluids in transformers and capacitors. Many
best studied dioxin, 2,3,7,8-tetrachlorodibenzodioxin, countries have severely restricted or banned the pro-
is clearly a carcinogen in experimental animals. The duction of PCBs and at present, occupational exposure
mechanism of carcinogenicity apparently is tumour should be limited to waste disposal. The pyrolysis of PCB
promotion through modification of cellular replication mixtures produces hydrogen chloride and polychlorinated
and apoptosis. The IARC evaluation is group 1 for dibenzofurans (PCDFs), and pyrolysis of mixtures con-
2,3,7,8-TCDD and 2,3,4,7,8-pentachlorodibenzodi- taining chlorobenzenes also produces polychlorinated
oxin.100 Recently, the IARC group 1 classification was dibenzodioxins (PCDDs). Commercial PCBs are mixtures
extended also to 2,3,4,7,8-pentachlorodibenzofuran of (theoretically) 209 different isomers and the trade names
(CAS No. 51207-31-9) and 3,4,5,3,4-pentachloro- used include Aroclor, Pyranol, Pyroclor (United States),
biphenyl, which are indicator chemicals for a larger class Phenochlor, Pyralene (France), Clopehn, Elaol (Germany),
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl Cl
Cl Cl
Cl
Cl Cl
Cl
Cl Cl
Cl
2, 3, 4, 2´, 3´, 4´ -Hexachlorobiphenyl 3, 4, 5, 3´, 4´, 5´ -Hexachlorobiphenyl
CAS 38380-07-3 CAS 32774-16-6 Figure 42.23 Molecular structures of various
non-substituted adjacent carbons no non-substituted adjacent carbon atoms polychlorinated biphenyls.
372 Organic chemicals
refrigerant, aerosol propellant and blowing agent for cell adenomas and Leydig cell adenomas in males. With
polystyrene. It is an intermediate in the production of the exception of clastogenicity reported in vitro, studies
tetrafluoroethylene.450 on mutagenicity were negative. All tumour types
observed were benign; HCFC123 is apparently non-
Clinical effects and epidemiology mutagenic in vivo, and the carcinogenic mechanism is
Increased palpitations were reported in a limited study therefore probably not through a genotoxic mechanism.
among people exposed to HCFC22, but the study is However, in the view of the International Programme
very difficult to interpret. In a 24-hour electrocardio- on Chemical Safety (IPCS) of the World Health
gram (ECG) recording of a small number of people Organization (WHO), the elevated incidence of several
exposed to HCFC12 and 22, no clear-cut connection types of tumours raises a concern for possible carcino-
between the exposure and different arrhythmias was genicity in humans.453
observed.451 HCFC123 did not show teratogenicity or other repro-
In mice and dogs, exposure to HCFC22 in most studies ductive toxicity in experimental animals.
at concentrations in excess of 1000 g/m3 has been reported
to increase the sensitivity of the animals to adrenaline- Metabolism and monitoring
induced arrhythmias.450 Based on findings of an increased HCFC123 is metabolized by cytochromes P450 reductively
incidence of subcutaneous fibromas and Zymbal gland and oxidatively. Both reaction pathways lead to the
tumours in male rats, and no evidence of carcinogenicity metabolites trifluoroaldehyde and trifluoroacetic acid that
in mice or female rats, the IARC concluded that the evi- are common to halothane (CHClBrCF3), a known hepato-
dence of carcinogenicity of HCFC22 in experimental ani- toxic anaesthetic.
mals is limited.452 HCFC22 induced base-pair substitution
mutations in Salmonella typhimurium, but was otherwise CHLOROTETRAFLUOROETHANE
negative in genotoxicity testing. High concentrations of
HCFC22 induced eye malformations in rats. [CAS No. 63938-10-3]
Metabolism and monitoring F
F
Clinical effects and epidemiology
Cl F
Human health effects from exposure to HCFC124 have not
Dichlorotrifluoroethane (HCFC123) is a non-flammable been reported. The main effects seen in experimental stud-
volatile liquid with a faint ethereal odour. The principal ies are lethargy and other signs of depression of the central
use for HCFC123 is as a refrigerant in commercial and nervous system. No liver toxicity was observed in rats in
industrial air-conditioning installations, in fire extinguish- 90-day or two-year studies at exposure levels up to
ers, as a foam-blowing agent, and in metal and electronics 50 000 ppm. Benign mammary fibroadenomas were
cleaning.453 observed in female rats exposed to 50 000 ppm for two
years. HCFC124 was not genotoxic and did not result in
Clinical effects and epidemiology adverse developmental or fertility effects in animals.
Inhalation exposure to 2.5 per cent or more of HCFC124
Four case series convincingly demonstrate that repeated
to dogs increased the sensitivity of the animals to adrena-
occupational exposure to HCFC123 leads to liver dam-
line-induced arrhythmias.458–461
age.454–457 This effect has also been seen in experimental
animals. No reports are available on cardiac arrhythmias
in humans exposed to HCFC123. In dogs, exposure to Metabolism and monitoring
HCFC combined with an adrenaline challenge induced HCFC124 is metabolized by cytochrome P450 IIE1 to tri-
fatal arrhythmias. In a carcinogenicity study in rats, there fluoroaldehyde and trifluoroacetic acid (which are the
was an increased incidence of hepatocellular adenomas in hepatotoxic metabolites from halothane produced by the
females and males, of cholangiofibromas in females oxidative pathway); however, to a much smaller extent
administered the highest dose, and of pancreatic acinar than HCFC123.461
374 Organic chemicals
C
GSH CO2 (vii)
O ?
(viii)
(2-oxothiazolidine-4-
OH O-
Carbonic anhydrase + H2O (x)
carboxylic acid) S C O S C O- HS C O
Urea (ix)
cycle
S
H2O
H2N C NH2
Thiourea
vessels.476–478 NMR of the brain also revealed cerebral Cancer has not been well studied in the epidemiological
effects even among workers whose neuropsychological studies on carbon disulphide-exposed worker groups. In
testing results have not been adversely affected.479 the limited studies available, there is no consistent picture
Increased mortality from cardiovascular disease after of an increase in any specific cancer type.473 No adequate
exposure to carbon disulphide was described in the 1970s carcinogenicity studies have been published on carbon
in a rayon producing facility. When the exposure was low- disulphide in experimental animals. The database to assess
ered to below 10 ppm (30 mg/m3), this effect was not the genotoxicity of carbon disulphide is limited. In bacter-
observed.480,481 Several larger studies have since verified ial mutagenicity assays, it has been negative, while mam-
the potential of carbon disulphide to cause cardiovascular malian cell studies are equivocal. The available limited data
mortality, notably at levels in excess of 30 mg/m3.473,482,483 on genotoxicity in vivo are generally negative.
However, at these low exposure levels, i.e. less than While there are several reports of reduced libido and/or
30 mg/m3, some studies have demonstrated a decrease in impotence in male workers exposed to carbon disulphide in
carotid artery elasticity.484,485 the viscose rayon industry, there is no clear evidence of
Carbon disulphide exposure also leads to elevated effects on male fertility or on fetal development.492 An
serum cholesterol levels and blood pressure, both recog- exploratory study reported an increased frequency of spon-
nized as risk factors for cardiovascular disease.473,486 While taneous abortions among female workers of a company
some studies have reported elevated cholesterol levels at producing rayon fibre;493 conflicting reports on the study
estimated exposure levels of 30 mg/m3,487 cholesterol have been published thereafter. In experimental animals,
levels were not elevated among workers, where exposures no effect on semen quality has been reported. Fetotoxicity
have mainly remained below 3 ppm (10 mg/m3),488 and has been clearly demonstrated at dose levels toxic to the
also in workers with an average of 20 years of exposure at mother only, and teratogenicity is seen mostly at dose levels
mean exposure levels of 5 ppm (15 mg/m3).489 higher than those needed to produce fetotoxicity.128,473
Carbon disulphide exposure potentiates the effect of
noise on hearing loss490 and induces ophthalmologic Metabolism and monitoring
effects, including those on colour vision and damage to the Carbon disulphide is absorbed by inhalation and via
blood vessels of the retina.473,491 the skin. It is extensively metabolized (Figure 42.24) and
376 Organic chemicals
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43
Pesticides and other agrochemicals
2. Plant pesticides that plants may produce from genetic including private indoor use and treatment of human
material that has been added to the genome of the external parasites, such as pediculosis. During the second
plant (genetic modification or manipulation). half of the 1960s, the first concern for the bioaccumulation
3. Biochemical pesticides which are naturally occurring potential of DDT arose, and the suspicion of possible
substances that control pests by non-toxic effects of this on human health resulted in a significant
mechanisms. They include substances such as insect reduction of DDT production and use in the 1970s.
sex pheromones that interfere with mating, as well as Today, DDT is still authorized for selected use in public
various scented plant extracts that attract insect pests health, such as indoor residual application or mosquito net
into traps. treatment in tropical countries.5,6
Apart from these selected uses in vector-borne disease
Integrated pest management (IPM) programmes are a control, DDT was substituted, from the end of the 1960s,
series of pest management evaluations, decisions and con- by organophosphorous compounds (OPs), characterized
trols which rely on comprehensive information on the life by a highly effective insecticidal activity (cholinesterase
cycles of pests. IPM is a tiered approach which starts from inhibition) and by low or absent bioaccumulation and bio-
defining ‘action thresholds’, points at which pest popula- magnification characteristics. At the very start of their use,
tions or environmental conditions indicate that pest con- cases of acute poisonings and fatalities attributable to the
trol action must be taken. Once pest control is required high toxicity of these compounds were reported. Research
and preventive methods are no longer enough, IPM pro- thereafter focused on the development of less toxic but
grammes provide for effective, less harmful pest control, equally effective, or more specifically targeted chemicals.
from highly targeted chemicals or mechanical control to (if This objective was at least partially met with the synthesis
less risky controls are not effective) additional pest control of OP compounds that were easily metabolized by car-
methods including specific pesticides.1 boxylesterase, which is very well represented in mammals,
With regard to health risks in organic farming, products but poorly represented in insects, or the less toxic
of biological origin may have different properties from ‘con- cholinesterase inhibitors, such as the carbamates. In 1978,
ventional’ agrochemicals, but they cannot be considered fenvalerate, the first representative of pyrethroids, a chem-
‘risk free’. Pesticides such as natural pyrethrum derivatives ical class derived from natural pyrethrum, was synthesized.
or some essential oils are not completely safe, and some pes- Due to their effective insecticidal activity and low toxicity
ticides with complex molecules may possess sensitizing to mammals, pyrethroids are the most commonly used
properties. group of insecticides today.
The use of different compounds to control pests is The examples and the history described above indicate
reported in ancient Greek and Roman texts, highlighting that the major challenge has been the production of highly
that since the beginning of agricultural production, the selective molecules toxic to their target species, but at the
need for plant protection was important. Seed treatment, same time characterized by low toxicity to non-target
fumigation and tree banding were the first practices per- species, including humans. The presence of biological activ-
formed, based on easily available products, such as plant or ity in products deliberately spread into the environment
animal derivatives, and minerals.2 Examples of these uses requires specific risk assessment and management. Tests
are seed treatment with ashes, or macerated pounded roots carried out before a new pesticide is released on to the
and leaves of wild cucumber for mildew control, use of market (pre-marketing phase) and after its release (post-
soaking lupin flowers as herbicides, the practice of smearing marketing phase) include an assessment of any unacceptable
pruning knives with bear’s blood or fat or using fumes from risk to human or non-target species, and the environment. A
various vegetables, locusts, animal faeces, bones or horns as safe pesticide management programme is achieved through
insect repellents. Among the substances used from antiq- action at international, national and local level. At the high-
uity, alum, antimony, arsenical compounds, chalk, cobalt, est strategic level, international agencies and organizations
copper sulphate, sodium sulphate, iron and iron salts, lime, such as the FAO (Food and Agriculture Organization of the
mercury and sulphur derivatives are listed.3 United Nations), WHO (World Health Organization), EU
In 1874, the first chemical pesticide was synthesized, (European Union) and OECD (Organisation for Economic
known properly as 1,1,1-trichloro-2,2-bis[4-chlorophenyl] Co-operation and Development), produce directives and
ethane or the dichlorodiphenyltrichloroethane (DDT), but guidelines for adoption at a national and local level within
this compound did not find any commercial use until the existing legislation of a country. The process includes
1939, when Muller and co-workers discovered its insectici- consideration of best practices, health surveillance and
dal properties.4 After 1939, its production and use grew training of operators.
and DDT found use either in public health, mainly against
the Anopheles mosquito in an effort to eradicate malaria,
and since 1946, in agriculture for the protection of cotton, CLASSIFICATION OF PESTICIDES
deciduous fruits, cereals and potatoes. The effective insec-
ticidal activity, together with low acute toxicity to humans, The basis for classifying pesticides can be structural (by
brought about a continuous increase in the use of DDT, chemical formula) or functional (by mode of action). Data
The mechanisms for pesticide toxicity 397
Pesticide
Acaricide Nematicide
Molluscicide Rodenticide
Insecticide Herbicide
Fungicide
Figure 43.1 Classification by target organism.
on lethal dose 50 per cent (LD50) can also be used to rank Although mammals and insects share much in common
pesticides by toxicity, although there are species differences with regards to their respective nervous systems, there are
in terms of pathophysiological responses. The World Health some very important differences which affect the toxicity
Organization recommends the use of a specific pesticide clas- of insecticides, for example:
sification system by member states, international agencies
and regional bodies;7 this uses a range of toxicity based on the ● Insects have non-myelinated nerve fibres.
LD50 for the rat model. An LD50 of 5 mg/kg, for an orally ● Cholinergic (acetylcholine) transmission in insects only
dosed solid, is classed extremely hazardous, whereas an LD50 occurs in the central nervous system (CNS). In mammals,
of more than 500 mg/kg is classed slightly hazardous. it occurs in the CNS and many peripheral nerves.
● Carboxylesterase activity is significantly less represented
Classification by target organism in insects than in mammals.
● Neuromuscular junctions in mammals are cholinergic
The simplest primary classification is illustrated in Figure 43.1. (in insects, they are glutaminergic if excitatory and
GABA-ergic if inhibitory).
Table 43.1 The system or organ affected, with subcategories indicating the principal biochemical effect.
occurs. This relationship between enzyme and carbamate The action of anticholinesterase compounds is to allow
substrate is one of electrochemical alignment rather than the normal neurotransmitter, acetylcholine, to accumulate
chemical binding and competitive reversal may occur when at the active site and cause excessive stimulation of the
the normal substrate ACh is in excess. post-synaptic cells. In the normal course of events, ACh is
The mechanisms for pesticide toxicity 399
Table 43.2 Examples of insecticides. action potential in cells where the channels are normally
Class Subclass Example
closed at the resting potential) are affected. Pyrethroids
affect both activation (opening) and inactivation (closing)
of the channel resulting in a hyperexcitable state as a conse-
Anticholinesterase Organophosphates Chlorpyrifos quence of a prolonged negative after-potential and therefore
(OPs) Diazinon producing abnormal repetitive discharges (Figure 43.6).
Dichlorvos There is also evidence that pyrethroids affect calcium
Malathion channels and voltage-sensitive calcium-independent chloride
Carbamates Aldicarb channels,9 and this would also contribute to the excitability.
Carbaryl Sodium and calcium channels are common in both insects
Organochlorines DDT and mammals and the difference in toxicity between the
(OCs) Aldrin species to synthetic pyrethroids is directly related to the
Dieldrin slightly different stereochemistry between mammalian and
Endosulfan insect ion channels (mammalian ion channels are far less
Lidane (-HCH) sensitive). Mammals also possess specific enzyme systems
Pyrethrins and Pyrethrum
that can rapidly metabolize and detoxify the synthetic
synthetic Permethrin
pyrethroids, rendering them harmless.
pyrethroids Cypermethrin
Tetramethrin
Herbicides
Chemicals that disrupt Ecdysis agonists Tebufenozide
insect growth Chitin synthesis Difubenzurion Herbicides are substances that are designed and selected
inhibitors to kill plants with different degrees of specificity. As a
Juvenile hormone Cyromazine general rule, the greater the specificity, the lower the
analogues mammalian toxicity.
Natural compounds Nicotine The main groups in approximate order of toxicity and
other than Totenone specificity are listed in Table 43.3.
pyrethroids Abumectin
SODIUM CHLORATE
Axon of neurone
Organophosphates
Carbamates
Pyrethroids
Skeletal muscle fibre
Post-synaptic membrane
Figure 43.2 Typical motor neurone and site of action of neurotoxic insecticides.
under Acute effects, p. 403, and The management of acute hormone. There is no equivalent hormone in animals.
pesticide poisoning, p. 409). Chlorophenoxy acids have both agricultural and domestic
Diquat ingestion does not usually cause pulmonary uses. A number of compounds are included in this
fibrosis, but can produce early onset acute renal failure, group, most notably 2,4-dichlorophenoxyacetic acid
although toxic effects are rarely reported.11 (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA),
2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and mecoprop
CHLOROPHENOXY COMPOUNDS (MCPP). Chlorophenoxy herbicides are used widely for the
control of broadleaved weeds. They exhibit a variety of mech-
The organic chlorophenoxy acid herbicides are more selective anisms of toxicity including dose-dependent cell membrane
as they are chemical analogues of auxins, a plant growth damage, disruption of acetyl coenzyme A metabolism and an
The mechanisms for pesticide toxicity 401
Acetylcholine
H 3C CH2 O O
N CH2 C
Enzyme–substrate
Histidine serine tetrahedral intermediate
Anionic
subsite
Esteratic subsite
H 3C CH2 OH O
N CH2 C
N: O
Acetylated
One molecule of enzyme
enzyme will hydrolyze
300 000 molecules of
acetylcholine per min
Acetic acid
O Figure 43.3 Under normal circumstances,
acetycholine, a chemical neurotransmitter, is
HO C broken down by the enzyme acetylcholinesterase.
CH3
Accumulation of acetylcholine is thus prevented.
Reproduced with permission from Brown I.
N: H O Agriculture (pesticides). In: Sadhra SS, Rampal KG
(eds). Occupational health: Risk assessment and
Regenerated management. Oxford: Blackwell Science, 1999:
enzyme 361–8.
effect related to their degree of chlorination (uncoupling are not a major toxic risk to humans. Triazines and triazoles,
oxidative phosphorylation). Details are given under Acute and the non-cholinesterase inhibiting herbicide organophos-
effects, p. 403. phates, e.g. glyphosate, are highly plant specific and of low
Epidemiological studies suggest that an association toxicity to humans.
exists between the manufacture and application of phe-
noxy herbicides, non-Hodgkin’s lymphomas and soft tis-
Fungicides
sue sarcomas. However, many of the studies have been
confounded by an absence of quantitative data on expo-
These are a mixed group of substances that do not easily fit
sure, multiple exposures to other substances and possible
into a toxicological or chemical classification. They are in
contamination of the phenoxy acids with other chemicals
general of low to moderate acute toxicity to mammals and
during manufacturing, especially highly carcinogenic and
can vary from simple organic compounds, such as sulphur
teratogenic dioxins (see under Cancer, p. 409).
and copper sulphate, to complex metal-containing deriva-
tives of organic chemicals, such as thiocarbamic acid. Acute
OTHER HERBICIDES toxicity varies from greater than 10 000 mg/kg (oral LD50 in
the rat) for substances, such as vinclozolin (a dicarbox-
Substituted anilines, ureas and thioureas are not of high tox- imide), to around 400 mg/kg for some dithiocarbamates
icity, but may cause methaemoglobinaemia and interfere and chlorinated alkenes, and then down to 150 mg/kg for
with red blood cell survival. Nitriles, such as ioxynil, act by some fungicides with cholinesterase inhibitory effects, such
inhibiting or uncoupling oxidative phosphorylation, but as pyrazophos. This gives a relative toxicity of less than ethyl
402 Pesticides and other agrochemicals
Organophosphate
F O
One molecule of
enzyme will hydrolyze P
0.008 molecules of
organophosphate H7C3O OC3H7
per min N H O
Enzyme–inhibitor
intermediate
O
HF
P
H7C3O OC3H7
N: O
Phosphorylated
enzyme
+H2O
Figure 43.4 Organophosphate insecticides
Diisopropylphosphoric acid
can phosphorylate the active site on the
HO O
acetylcholinesterase enzyme, preventing it from
P breaking down acetylcholine. Reproduced with
permission from Brown I. Agriculture (pesticides).
H7C3O OC3H7
In: Sadhra SS, Rampal KG (eds). Occupational
N: H O health: Risk assessment and management. Oxford:
Blackwell Science, 1999: 361–8.
Control
mVolts
Table 43.3 The main groups of herbicides in approximate order amounting to an estimated 300 000 cases annually.12 Safe
of toxicity and specificity. storage promotion projects have been identified as a prior-
Class Subclass Example ity in the prevention of serious accidental pesticide poison-
ing, since poor storage of pesticides and bad management
of used containers is an important determinant of risk.
Inorganic Sodium chlorate Epidemiological surveillance is an important tool to
Bipyridyl Paraquat monitor acute pesticide-related illness and to identify asso-
derivatives Diquat ciated risk factors. Some attempts to monitor pesticide-
Organic acids Chlorophenoxy 2,4-D related illness have been undertaken across the globe. In
compounds 2,45-T the United States, the National Institute for Occupational
Other organic Haloxyfop Safety and Health (NIOSH), Centre for Disease Control and
acids Dicamba Prevention (CDC), through the Sentinel Event Notification
Substituted Alachlor System for Occupational Risks (SENSOR) programme has
anilines Propachlor provided technical and financial support for state-based sur-
Propanil veillance of acute occupational pesticide-related illness and
Ureas and Diuron injury since 1987.13 According to data generated by SEN-
thiomens Linuron SOR, workers employed in agriculture have been found to
Nitriles Ioxynil have a greater incidence rate of acute occupational pesticide-
Bromoxynil related illness when compared to non-agricultural workers.
Triazines and Atrazine Most of the cases (69.7 per cent) were of low severity.
triazoles Amitrole Severity was moderate in 29.6 per cent of the cases and high
Organophosphates Glyphosate in 0.4 per cent. Insecticides were found to be the causative
(non-cholinesterase agent in 49 per cent of all cases.
inhibitor)
The arrow indicates increasing toxicity.
CLINICAL EFFECTS OF PESTICIDE TOXICITY
Acute effects
EPIDEMIOLOGY AND INCIDENCE OF
PESTICIDE POISONING Acute effects are described as any effect on the human
organism in which symptoms develop rapidly and often
Pesticide poisoning is one of the most common causes of subside after the exposure stops, and can be divided into
chemical poisoning. Acute poisoning can cause a range of local and systemic. In some cases, acute effects may arise
symptoms in adults and children, depending on the type following the storage in the body of large amounts of
and quantity of pesticide, and can result in death, either slowly metabolized compounds. Local acute effects consist
rapidly or delayed, depending upon the characteristics of mainly of dermal or mucosal injuries, from mild irritation
the formulation. Individuals can be exposed to pesticides to severe ulceration. Local acute effects are the result of
while working, via food, soil, water or air, or by directly both toxicological properties of the compound and physi-
ingesting pesticide products. Pesticides are known to cause cal/chemical properties of the formulation used and usu-
millions of acute poisoning cases per year. It has been esti- ally consist of damage to the body barriers, such as skin and
mated that 1–3 per cent of agricultural workers in the world respiratory tract, the eyes or gastric mucosa. Irritation, cor-
suffer in their lifetime from at least one acute pesticide poi- rosion and ulcerative lesions are examples of such effects.
soning episode. Among acute intoxications worldwide, no Systemic effects consist of organ or system impairment
less than one million require hospitalization with deaths following the absorption of an effective dose.
404 Pesticides and other agrochemicals
Insecticides can easily affect non-target organisms since ● the central nervous system, with restlessness, emotional
they are often non-selective and the target sites and toxicity liability, ataxia, lethargy, mental confusion, memory
mechanisms may be similar in all species (see under The loss, convulsions and coma.
mechanisms for pesticide toxicity, p. 397). The target organ
Increased pulmonary secretions and respiratory failure
of the majority of chemical insecticides presently used is the
are the usual causes of death from organophosphorus poi-
nervous tissue. Since a certain analogy can be found in the
soning and recovery depends on regeneration of the enzyme
organization and function of the central and peripheral
within the critical tissues. The phosphorylation of AChE is
nervous system between insects and humans, insecticides
irreversible in the case of the esters of phosphoric or phos-
can elicit (following adequate exposure in terms of dose and
phorothioic acid (organophosphorus compounds) and
duration), similar effects in the two species. Generally, insec-
temporary for the derivatives of carbamates, leading to a
ticides interfere with the membrane transportation of
wide ranging clinical picture in terms of seriousness and
sodium, potassium, calcium or chloride ions.11
signs of the illness and the risk to life. The carbamyl–acetyl-
Organochlorine insecticides exert their toxicity on the
cholinesterase combination dissociates more readily than
intact reflex arc consisting of a peripheral, afferent (sen-
the phosphoryl–acetylcholinesterase complex produced by
sory) neurone, inter-neurones and a peripheral, efferent
organophosphorus compounds. Thus, carbamate poisoning
(motor) neurone which in turn innervates a muscle. DDT
tends to be of shorter duration and less serious. Most clini-
is known to interfere with potassium, sodium and calcium
cal manifestations of acute organophosphorus poisoning
transport across the neuronal membrane, leading to repet-
are resolved within days or weeks, although some symp-
itive discharges in neurones and, consequently, to repeti-
toms, especially those of neuropsychological nature, can
tive tremors, seizures and electrical activity triggered by
persist for months or longer.11,14
tactile and auditory stimuli (see Figure 43.5). The clinical
A second phase of organophosphorus insecticide poison-
picture following organochlorine acute intoxication is
ing is termed the ‘intermediate syndrome’, a paralytic condi-
characterized by tremors, motor seizures and respiratory
tion consisting of neurological signs which appear 24–96
failure. Organochlorine pesticides and their metabolites can
hours after the acute cholinergic crisis. Major effects are mus-
be measured in blood samples by gas-liquid chromatography
cle weakness primarily affecting muscles innervated by
within a few days of exposure.
cranial nerves, as well as those of the limbs. This is a life-
Anticholinesterase insecticides comprise the esters of
threatening condition due to the unresponsiveness of the res-
phosphoric or phosphorothioic acid and those of carbamic
piratory depression to atropine or oximes.15 A third phase
acid (carbamates), and share a common mechanism of
termed ‘delayed neuropathy’ (also termed ‘organophospho-
toxic action: the inhibition of the nervous tissue acetyl-
rus pesticide-induced delayed polyneuropathy’) is caused by
cholinesterase (AChE), the enzyme responsible for the
some, but not all OPs, and is characterized by initial flaccid-
destruction of the neurotransmitter acetylcholine (see
ity (second motor neurone syndrome), followed in some
Figures 43.3 and 43.4). This inhibition leads to the accu-
cases by spasticity, hypertonicity, hyperreflexia and clonus
mulation of free ACh at the endings of all cholinergic
indicative of a damage to the pyramidal tract. At a patholog-
nerves which results in a prolonged stimulation of electrical
ical level, the delayed neuropathy is accompanied by a
activity at:
Wallerian ‘dying-back’ degeneration of large diameter axons.
● muscarinic receptors of the parasympathetic autonomic Biochemical studies have demonstrated an inhibition of
nervous system, with consequent increased secretions, the neuropathic target esterase, a neuronal non-specific
bronchoconstriction, miosis, gastrointestinal cramps, carboxylesterase, which is involved in the lipid metabolism of
diarrhoea, micturition and bradycardia; neurones.16,17 The time scale for the acute and more chronic
● nicotinic junctions between nerves and muscles, with effects is shown in Figure 43.7, and greater detail is given
tachycardia, hypertension, muscle fasciculation, tremors, about the ‘chronic syndrome’ and ‘dippers’ flu’ under
muscle weakness and flaccid paralysis; Chronic and long-term effects, p. 406.
Acute cholinergic
symptoms Organophosphorus pesticide- May lead to permanent
induced delayed polyneuropathy spastic paralysis
(OPIDP)
Unprotected
exposure
Intermediate May last
syndrome 5–18 days The chronic syndrome?
0 12 hrs 1–4 days 5–18 days 2–3 weeks 1 year 10 years Figure 43.7 The spectrum of human
Time scale (non-linear) response to organophosphorus chemicals.
Clinical effects of pesticide toxicity 405
Pyrethroids represent a group of widely used pesticides, QT interval prolongation. Neurotoxic features include
obtained from chemical synthesis, but similar to the natural coma, hypertonia, hyper-reflexia, ataxia, nystagmus, mio-
pyrethrum, a complex chemical mixture found in some sis, hallucinations, convulsions, fasciculation and paralysis.
species of chrysanthemum flowers, while the compounds Respiratory failure can develop because of hypoventila-
obtained through extraction from a vegetable matrix are tion, usually in association with central nervous system
called pyrethrins. Pyrethroids and pyrethrins are similar depression, or because of myopathic symptoms including
from a toxicological point of view; in particular, they impair respiratory muscle weakness. Clinical signs include loss of
ion transport through the membrane of nerve axons, caus- tendon reflexes and myotonia, together with increased cre-
ing a rapid uncoordinated hyperactivity and then muscular atine kinase activity. Other clinical features are metabolic
paralysis in the insect, through an effect on sodium channels acidosis, rhabdomyolysis, renal failure, increased amino-
(see Figure 43.6). Systemic non-target species toxicity is lim- transferase activity, pyrexia and hyperventilation. Dermal
ited because of low dermal and gastrointestinal absorption or inhalation exposure to 2,4-dichlorophenoxyacetic acid
and their rapid degradation by mammalian liver enzymes occasionally leads to systemic features, but no fatalities have
and urinary excretion. Therefore, they usually do not cause ever been reported. Substantial dermal exposure has been
any severe acute effect in humans, even after relatively high reported to cause mild gastrointestinal irritation after a
exposure. The main symptom observed is skin paraesthesia latent period followed by a progressive mixed sensory-
involving the face, hands or arms (without inflammatory motor peripheral neuropathy.11,20
signs), caused by the contact of the active ingredient with
dermal nerve endings and consequent hyperstimulation. A FUNGICIDES
further sign of exposure is the so-called ‘upper respiratory
tract sensory irritation’, similar in mechanism of action to Pentachlorophenol (PCP), a very toxic, but nowadays
paraesthesia, but involving the mucosa.18,19 rarely used fungicide, is readily absorbed by ingestion and
inhalation in humans, but is less well absorbed by dermal
HERBICIDES contact. Its systemic distribution is limited, its metabolism
extensive and it is slowly excreted. Severe exposure by any
Chlorophenoxy herbicides are largely excreted unchanged route may result in an acute and occasionally fatal illness
in urine. They have long plasma half-lives of up to 220 caused by the uncoupling of oxidative phosphorylation.
hours in humans. The acute toxicity of the phenoxy acids is Tachycardia, tachypnoea, sweating, altered consciousness,
moderate to low and large doses are required to produce hyperthermia and convulsions are the most notable fea-
major toxic effects, which include alterations in conscious- tures. Pulmonary oedema, intravascular haemolysis, pan-
ness, muscle fasciculation, vomiting and convulsions, all of creatitis, jaundice and acute renal failure have been
which may be associated with a metabolic acidosis. reported. Survivors often display dermal irritation and
After acute exposure to lethal doses of paraquat, mor- exfoliation, irritation of the upper respiratory tract and
tality is delayed by at least two days, although may take possible impairment of autonomic function and circula-
much longer. Damage is initially to the alveolar epithelial tion.21 Apart from the ‘historical example’ of PCP poison-
cells and progresses to the loss of large areas of alveolar ing, modern fungicides are, as a general rule, less toxic
epithelium followed by oedema, inflammatory infiltration than insecticides and their acute toxicity to human beings
and fibrosis which rapidly leads to death due to anoxia. is non-specific.
Paraquat is by far the most toxic bipyridyl and is a non-
specific herbicide that has caused worldwide accidental RODENTICIDES
and suicidal deaths since its introduction as a pesticide in
1962. Once absorbed, paraquat accumulates in the lung Rodenticides comprise a diverse range of chemical structures
and kidney and it is these two organs that are the most sus- with a variety of mechanisms of action. Although most
ceptible to injury. The major toxicological concern is the rodenticides are formulated in baits that are unpalatable to
acute localized effects, particularly in the lung and more humans, several rodenticide intoxications are registered
specifically the affect on type 1 and type 2 alveolar epithe- each year. Among rodenticides, anticoagulants derived
lial cells and Clara cells. This specific toxicity is due to at from coumadin are listed. Their toxicity is exerted through
least three biochemical mechanisms involving redox recy- the antagonism of vitamin K in the synthesis of clotting
cling, the formation of free radicals and eventually cell factors (factors II, VII, IX and X). The emergence of
death. Poisoning can take place by ingestion, inhalation or warfarin-resistant strains of rats led to the introduction of
dermal exposure. Following ingestion, an early clinical a new group of anticoagulant rodenticides variously referred
feature is vomiting, accompanied by abdominal pain, to as ‘superwarfarins’, which are very long acting. This group
diarrhoea and, occasionally, gastrointestinal haemorrhage. includes the second-generation 4-hydroxycoumarins: brod-
Gastrointestinal fluid loss can lead to severe hypotension ifacoum, bromadiolone, difenacoum, flocoumafen, and
with cardiogenic shock and multiorgan failure. Hypotension the indanedione derivatives chlorophacinone and diphaci-
can also result from direct myocardial toxicity, demonstrated none. Over 95 per cent of all rodenticides used in United
by ECG changes such as T-wave flattening or inversion and States consist of superwarfarin, and brodifacoum is the
406 Pesticides and other agrochemicals
most commonly used substance. Since the introduction of the existing evidence for these health outcomes is provided in
superwarfarins, a number of cases of ingestion resulting in the following paragraphs.
coagulopathy have been reported, usually with minor out- As a general rule, the epidemiological evidence suggests
comes, rapidly resolved and with no residual disability. that agricultural workers experience a lower overall mor-
Moderate outcomes (defined as more pronounced signs tality rate with respect to the general population with a
and symptoms of exposure with some form of treatment lower incidence of some specific causes of death, such as
required), but no residual disability present or major out- respiratory, cardiovascular diseases and tumours.24–27 These
comes (life-threatening event, resultant disability or death) findings are reasonably attributable to a healthier lifestyle
have been reported. This is especially so with a prolonged and to the lower tobacco consumption of this employment
coagulopathy due to the superwarfarin brodifacoum. The sector.27 However, pesticide exposure may also be associ-
anticoagulant effect appears from eight to 12 hours after the ated with specific diseases. In particular, some pesticides
ingestion, according to the half-lives of the various clotting may cause allergic or irritant dermatitis and, in some cases,
factors. Following consumption over a period of days, the same compound may cause both of these problems.28
bleeding of the gingival membranes and nose occurs, with The effects might also be attributable to co-formulants,
haematomas at the knee and elbow joints. Gastrointestinal instead of the active ingredients themselves, e.g. the sol-
bleeding with spontaneous haemoperitoneum, haematuria vents often present in the plant protection product. Irritant
and cerebrovascular accidents can also occur. Patients may effects may also affect the respiratory tract and eye mucous
remain anticoagulated for several days (warfarin) or days, membrane, which can be avoided by the use of personal
weeks or months (longer-acting anticoagulants), after protective equipment. The liver may be a target of the toxic
ingestion of large quantities.11,22,23 effects of pesticides, but severe damage is now mainly a his-
torical finding, with liver cirrhosis described in workers
exposed to arsenical compounds in France in the 1940s
Chronic and long-term effects and 1950s, or metabolic disturbances, such as diabetes
observed in subjects heavily exposed to organochlorine
The term ‘chronic toxic effects’, usually means effects as a compounds, such as DDT, hexachlorobenzene and lin-
consequence of prolonged exposure to toxic substances, at dane.29 Inorganic metallic compounds and some solvents
doses lower than those able to cause acute effects, or effects used as co-formulants may also affect the kidney. The res-
characterized by a prolonged latency, after exposure peri- piratory tract may suffer non-specific irritant effects due to
ods not necessarily prolonged, such as the appearance of chronic exposure to some pesticides, and more unusually
tumours (‘long-term effects’). A typical property of chronic vineyard workers exposed to a mixture of calcium hydride
effects is their slow development over time, and their per- and copper sulphate (Bordeaux mixture) develop an uncom-
sistence after the end of the exposure. Long-term pesticide mon pulmonary granulomatosis also known as ‘vineyard
exposure might affect farmers, professional pesticide appli- sprayer’s lung’.30 The reproductive system may be a target
cators, and, to a lesser extent, the general population, of pesticide effects and a historical example is represented
exposed to pesticide residues via the environment, food and by the cases of reduction in spermatocyte count, up to
water consumption. complete azoospermia, observed in workers exposed to the
The causal attribution of such effects is complicated nematocide, dibromochloropropane (DBCP) which led to
because of temporal considerations. For chronic and long- its ban in the United States.31 Ethylene dibromide can also
term effects, the identification of subjects who might have affect fertility by reducing semen quality (decreased sperm
been chronically exposed to pesticides at the workplace is count, increase of percentage of morphologic abnormali-
relatively easy, but the identification of the compound and ties).32,33 The effect is usually reversible after 12 to 18 months
source of exposure is less easy, because of the time elapsed following the end of the exposure, but in the most severe
since exposure and the exposure of agricultural workers to cases permanent sterility has been observed. More recently,
several different chemical substances over their working concerns have been focused on less direct effects, such as
lifetime. Therefore, the identification of a single substance, an alteration in the rate of male to female births, possibly as
or group of substances, to which the effects might be a consequence of a disturbance to the endocrine system.
attributed, is difficult with poor historical exposure data
and because most people are exposed to low doses of pesti- THE IMMUNE SYSTEM
cide mixtures where delayed health effects are difficult to
link to specific past exposures. Exposure assessment is There is evidence that pesticides may cause direct
therefore a crucial process in studying these associations, immunotoxicity in exposed workers. Pesticides may affect
but the collection of historical exposure data is a compli- the immune system by a variety of mechanisms of action,
cated and often uncertain task. causing structural and functional alterations possibly result-
The chronic and long-term effects that have been variably ing in decreased immunity, as well as an increase in immune
attributed to pesticide exposure are carcinogenesis, neurotox- response.34 The immunotoxicological effects of xeno-
icity (including behavioural impairment), immunotoxicity, biotics include histopathological changes in immune tis-
reproductive effects and endocrine disruption. A summary of sues and organs, cellular pathology, altered maturation of
Clinical effects of pesticide toxicity 407
immunocompetent cells, changes in B- and T-cell sub- consequence of a severe acute poisoning, with brain injury,
populations, in addition to functional alterations of but this may not be a specific toxic effect as similar impair-
immunocompetent cells.35 Chemical immunotoxicity can ments have been observed in subjects with evidence of
be modulated by several factors, including nutritional other types of brain injury, including traumatic events and
status, concurrent pathological conditions, biotransforma- carbon monoxide poisoning.40 Studies conducted on
tion and activity of resulting metabolites, physical and subjects chronically exposed to OPs, but never acutely
emotional stress, and oxidative stress.36 poisoned, do not provide evidence of neurological impair-
While some pesticides show effects on the immune ment, but data do suggest that neurobehavioural impair-
system in the experimental model, the evidence of human ment can be observed in workers heavily exposed to OPs
immunotoxicity in environmental or occupational expo- such as, for example, sheep dippers.40 Major limitations for
sure to pesticides is weaker. This topic, though, is very the interpretation of the existing data are demonstrated by
relevant for occupational health practice, because direct the difficulties in the comparison of the single studies, the
immune function suppression might be associated with an limited knowledge of exposure levels, and the absence of a
increase of infection rates and cancer, while an enhance- study protocol validated and accepted by most of the
ment of the immune response might bring about disease researchers. In conclusion, the only fully described effect
states related to autoimmunity and allergy.34 Current epi- on the peripheral nervous system is the OP-induced
demiological evidence in western countries indicates that ‘delayed neuropathy’, which is a sequelae of acute poison-
the prevalence of diseases associated with alterations of the ing, rather than a long-term or chronic effect (see under
immune response (such as asthma, certain autoimmune Acute effects, p. 403). As for other pesticides, some limited
diseases and cancers) are increasing. Some researchers data suggest that chronic exposure to DDT and fumigants
have queried whether such an observation could be attrib- might be associated with a change in neurobehavioural
uted to improved diagnosis alone,37 and there is also con- functioning and increase in psychiatric symptoms, but this
cern that this trend could be at least partially attributable to is inconclusive.41
new or modified patterns of exposure to chemicals, includ- Greater detail on the organophosphate-induced ‘chronic
ing pesticides.38 In some studies, allergic contact dermatitis syndrome’ and ‘dippers’ flu’ is given below.
has been reported, as well as a possible immunomodulatory
activity (increase in the immune response) observed in The chronic syndrome and sheep dippers’ flu
exposed agricultural workers.35 However, apart from some The clinical effects of acute exposure to OPs has been thor-
specific chemicals used in the past, such as some chlori- oughly investigated and documented with thousands of
nated compounds,39 studies conducted on different groups animal studies and reports of human poisoning. The
of pesticide-exposed workers show only minor changes in pathophysiology of these acute effects is well understood.
some cell populations or in the blood concentration of The possibility of more long-term effects, where there are
mediators, without any sign of overt disease. Even though no measurable cholinergic signs is less well understood and
some doubt remains on the significance of these changes, it remains controversial. An extensive review of the literature
is evident that direct pesticide immunotoxicity in low-dose was undertaken in 1997 and 1998 by the European Centre
chronic exposure conditions, if present at all, is very low or of Ecotoxicology and Toxicity of Chemicals.42,43 This
undetectable. review investigates published work and other studies on
the long-term effects of OP exposure in humans, discrimi-
THE NERVOUS SYSTEM nating between the chronic effects of acute exposure or
repeated acute exposure with the dose being large enough
Apart from the well-described, pesticide-induced acute to produce clinical signs and symptoms and the effects
neurological effects (insecticides, especially OPs and carba- of chronic low level, apparently asymptomatic exposure.
mates), a small body of evidence is available suggesting that The report concludes the evidence at that time (1998) for
chronic exposure to some neurotoxic compounds may be chronic effects arising from low level exposure to be insuffi-
responsible for the development of neurological disorders, cient. The report goes on to state that there is no pharmaco-
affecting the central and/or peripheral nervous system kinetic evidence for cumulative effects of chronic exposure
(parkinsonism, neurobehavioural changes, suicidal ideation to OPs at levels which are not acutely toxic and sensitivity
or behaviour). In particular, some studies conducted on even starts to decrease because of the development of toler-
(pesticide) exposed workers have shown increased preva- ance. The authors also state that there is insufficient evi-
lence of neurological symptoms and changes in neuro- dence in the epidemiological literature for the description
behavioural performance, reflecting cognitive and of a ‘chronic syndrome’ resulting from chronic, apparently
psychomotor dysfunction.40,41 Most of the studies avail- asymptomatic OP exposure. The task force did recommend
able suffer major limitations due to the different method- that further epidemiological studies should be undertaken.
ologies applied by the researchers, and to the possibility of A further report was published in November 1998 by
bias related to significant differences in education between the Royal College of Physicians and Royal College of
the exposed and the control population. There is good Psychiatrists.44 This was the result of the findings of a
evidence that neurobehavioural impairment can be the working party on OP sheep dip exposure with a widely
408 Pesticides and other agrochemicals
drawn membership to hear evidence from sufferers, from up specialist centres in appropriate areas to complement
those representing them, and from experts in the field. existing clinical services.
They concluded that the symptoms and distress were quite Perhaps, most importantly, two themes for research have
genuine and in some cases very long-standing. The report emerged from the working party’s original deliberations:
goes on to suggest that OP-exposed populations have shown
subtle cognitive changes, perhaps suggesting that OPs may 1. epidemiological studies aimed at developing a means
underlie some of the symptoms or perhaps that there are of quantifying OP sheep dip exposure and relating this
co-morbidities, such as severe anxiety or depression, that to clinical symptoms;
have been intuitively attributed by the sufferers to OP 2. prospective trials to assess the efficacy of treatment.
exposure. The report does though, make the point that the
In the United Kingdom, a number of government
severity of the symptoms and the consequent disturbance
expert scientific advisory committees are again reassessing
to family life and work, make it essential to provide an ade-
the evidence and will, in due course, make further
quate level of clinical care for those who experience symp-
recommendations.
toms following OP sheep dip exposure and existing clinical
services do not appear to provide satisfactory management
Other neurological disorders
of the cases in the UK. The report recommended that the
exposed patient with symptoms required particularly sym- The 30–35 studies exploring the relationship between
pathetic handling with the symptoms and signs treated Parkinson’s disease and pesticide exposures40 are hardly
seriously and at face value. They also suggested that over- comparable with different criteria used even for the defini-
investigation is not recommended, as many of the patients tion of parkinsonism, and they show major limitations in the
have been found not to have abnormalities on specialized assessment of the levels of exposure. The available data
testing. More recently (2007), an extensive questionnaire- suggest that the relationship between pesticide exposure and
based survey on acute symptoms following work with pesti- Parkinson’s disease is therefore weak and there is no evidence
cides was undertaken by Solomon et al.45 They analysed of the development of a peripheral neuropathy without a
10 765 responders in three rural areas of England and Wales. previous history of severe, possibly life-threatening, OP
They were particularly interested in the occurrence of flu- poisoning.
like symptoms following the use of sheep dip, although the
study did not specify the nature of the chemical in the dip- THE ENDOCRINE SYSTEM
ping solutions. They concluded that flu-like symptoms did
not cluster unusually among the users of sheep dip and that Few human data studies are available suggesting a possible
acute symptoms were common following work with pesti- effect of some pesticides on the endocrine system. Some
cides, but in many cases the illness may have arisen through organochlorinated compounds, such as DDT (and its
psychological rather than toxic mechanisms. There is still metabolites), chlordecone, dicofol, methoxychlor, endo-
considerable ongoing work on the aetiology and susceptibil- sulfan and lindane46 exert oestrogenic activity, while
ity of individuals to ‘dippers’ flu’, but the present evidence fungicides, such as vinclozolin and iprodione, may act as
does not appear to support this reported disorder as a spe- anti-androgens.47 Some triazine herbicides, such as atrazine,
cific syndrome and its relationship to organophosphate may also interfere with oestrogens via indirect pathways.48
chemical exposure remains uncertain. Menstrual abnormalities, prolonged time-to-pregnancy and
Evidence describing long-term neuropsychological or miscarriage have been described in some studies of pesti-
neuropsychiatric effects in humans following low-dose cide-exposed women, but firm conclusions could not be
chronic exposure appears contradictory and relatively drawn because of potential bias, uncertainty on exposure
recent expert reviews conclude that the evidence does not levels, concurrent exposure to a complex mixture of chemi-
support the existence of clinically significant neuropsycho- cals and other risk factors for miscarriage, such as heavy
logical effects, neuropsychiatric abnormalities or peripheral workload and high temperatures.49–51 Due to the vulnerabil-
nerve dysfunction.43,45 ity of mother and fetus during pregnancy, endocrine disrup-
Despite a 2004 summary of their 1998 report and con- tion might potentially alter fetal and neonatal development,
sideration of more recent concerns about OPs (www.opin. with the highest risks during prenatal and early post-natal
info/rcp.php), the joint report of the Royal College of development. In some studies, pesticide exposure has been
Physicians and Psychiatrists, recommend an open-minded, associated with defects, such as cleft lip and palate, limb
eclectic and pragmatic approach to the management of defects, cardiovascular malformations, spina bifida, hydro-
OP-related illness. This would include establishing a thera- cephaly, cryptorchidism and hypospadias.52
peutic alliance with the patient and agreeing specific treat- Pentachlorophenol, a rarely used wood preservative,
ment and management goals. Cognitive-behavioural binds to human thyroid binding protein and may directly
therapy has been found to be useful and specific symptoms, reduce the thyroxine uptake (T4) into the brain.53 Ethylene
such as depression, fatigue, sleep disorders and suicidal bisdithiocarbamate fungicides exert, at high doses, an
thoughts, should be managed vigorously in the usual way. inhibitory effect on thyroid hormone synthesis, and other
They also state that consideration should be given to setting currently used pesticides, including dicofol and bromoxynil,
The management of acute pesticide poisoning 409
have, at least in the experimental model, effects on thyroxine toxaphene.64 Chlorophenols have also been associated
binding, as does the restricted dinoseb.53 Due to their short with thyroid cancer.65
environmental persistence and low acute toxicity, ethyl- Organochlorine exposure has been linked with a variety
enebisdithiocarbamate (EBDCs) fungicides are largely of gastrointestinal and pancreatic malignancies.66,67 The
used worldwide.54 As a consequence, these compounds are pesticides involved are DDT, chlordane, heptachlor, endrin,
a potential source of fungicide exposure for many agricul- aldrin and dieldrin, which are no longer used in developed
tural workers. While the low acute toxicity of EBDCs is countries. However, exposure to these compounds may
well known, data on possible effects due to prolonged, low- still occur because of their environmental persistence and,
dose exposure are lacking. In the case of very high exposure in some cases, illegal use. Some studies demonstrate small
to EBDCs, a goitrogenic effect has been observed, attribut- but significant correlations between prostate cancer and
able to the main metabolite of these compounds, ethyl- specific jobs involving pesticide exposure.68
enethiourea (ETU). ETU exerts its effect by the inhibition The fungicide ethylenebisdithiocarbamate, the main
of the iodine peroxidase enzyme, with an impairment of metabolite of which is ethylenethiourea, has also been sus-
the synthesis of thyroid hormones, and a consequent feed- pected of possible carcinogenic activity (thyroid neoplasm)
back activation of thyroid stimulation hormone (TSH) but it is now known that the tumours observed in the
and a goitrogenic effect. experimental model (rat) are attributable to a specific
One of the possible outcomes of endocrine disturbance metabolic mediated susceptibility of these animals and the
may be cancer, especially in organs strongly dependent on existence of a carcinogenic risk to humans, under the usual
hormonal control (see under Cancer). conditions of exposure, has been excluded.69
Despite the enormous amount of variable work under-
CANCER taken, the results of positive studies are often contradicted
by negative studies, and significant limits and confounders
In the context that the risk of cancer is lower than pre- affect the interpretation of the results. It is therefore rea-
dicted in agricultural workers, some studies have shown sonable to conclude that, apart from the well-known histor-
an increased risk of certain specific malignancies, in par- ical carcinogens, e.g. arsenic, there is not at present a
ticular leukaemia, myeloma, non-Hodgkin’s lymphomas convincing body of evidence to show that repeated expo-
(NHL), lip, stomach, skin, brain and prostate tumours.27 sure to pesticides at the workplace causes cancer in humans.
In some cases, the observed excesses might, at least in the- Pesticide carcinogenicity is usually fully evaluated in the
ory, be attributed to quite specific risk factors, for exam- experimental model before the formal registration of a
ple, skin and lip tumours and exposure to ultraviolet compound, and compounds shown to be carcinogenic in
radiation, or endocrine-mediated tumours and exposure, animal models do not enter the market. However, the
mainly during fetal life, to endocrine disruptors.55 The compounds that have been in use for some considerable
epidemiology of cancer in agricultural workers is complex time may not have been subject to such thorough testing.
and a clear picture of the risk in relation to agricultural The International Agency for Research on Cancer (IARC)
exposure is still unavailable.56 Apart from the problem of has evaluated more than 60 active pesticide substances and
multiple exposures, a further confounding factor is the only a few of them are still in use today (ethylene dibromide
concurrent exposure of agricultural workers to different in group 1A (carcinogenic in humans) and amitrole and
non-pesticide risk factors, e.g. zoonotic viruses, solvents, dichlorvos in class 2B (possibly carcinogenic in humans)).
oils and fuels, dusts, paints and welding fumes.27 The use of the most toxic and carcinogenic compounds
The mechanisms by which pesticides could contribute to (for example, arsenical derivatives) has been forbidden in
cancer causation vary, and one pesticide may operate by many countries for many years. Therefore, the present risk
more than one mechanism. These include genotoxic effects is significantly reduced, but due to the long latency period
(producing direct changes in DNA), promotion, causing for most occupational cancers, a comprehensive personal
fixation and proliferation of abnormal clones, immunotoxic history together with accurate exposure data remain of
effects, disturbing the body’s normal cancer surveillance paramount importance for the diagnosis and reporting of
mechanisms, and epigenetic effects, causing enhancement suspected tumours and malignancies caused by exposure
or inhibition of specific genes involved in cell proliferation to pesticides.
or apoptosis.
In respect of data available on specific compounds,
some studies have linked phenoxy acid herbicides, in par- THE MANAGEMENT OF ACUTE PESTICIDE
ticular 2,4-D, with NHL.57–62 Although phenoxy herbi- POISONING
cides and their contaminants, mainly dioxins, are the
most consistently NHL-associated chemicals, some inves- The general principles of management
tigators have raised carcinogenic and NHL concerns
about other pesticides, including lindane (used also in Most pesticide-related diseases have a presentation that is
some head and body lice treatments),63 carbaryl, chlor- similar to other common medical conditions and display
dane, DDT, diazinon, dichlorvos, malathion, nicotine and non-specific symptoms and physical signs. Diagnosis of
410 Pesticides and other agrochemicals
mild poisoning can be difficult and this results in significant Symptoms usually develop within 12 hours and in severe
worldwide under-reporting. Only the suspicion of a possi- poisoning symptoms occur within four to six hours. How-
ble poisoning in relation to the patient’s specific signs and ever, this may be delayed in highly fat soluble organophos-
symptoms and the accurate recording of the personal phates, such as fenthion. Blood samples should be taken in
history and exposure data, can lead to the correct diagnosis. order to measure plasma pseudocholinesterase or prefer-
It is very important to obtain further information on the ably red blood cell acetylcholinesterase levels. In any remote
suspected product from the pesticide label or the manufac- rural area, it is strongly recommended that health person-
turer’s material safety data sheet. nel have available specific kits that are able to provide a
In the case of suspected pesticide intoxication, some quick and reliable estimate of the levels of cholinesterase
general rules need to be followed. The management of inhibition based on a few drops of blood collected from a
acute poisoning consists largely of appropriate decontami- finger of the patient (the so-called ‘paper test’). The severity
nation, supportive measures including the administration of the clinical picture is directly proportional to the level of
of oxygen, respiratory assistance, removal of secretions enzyme inhibition. Symptoms may arise when 50 per cent
from the respiratory tract, maintenance of fluid balance of cholinesterase activity is inhibited, with the most life-
and general symptomatic care. Intravenous fluids to rehy- threatening situation occurring at 90 per cent or more
drate the patient and ensuring an adequate urine output enzyme inhibition. An excellent guide is provided by the
will be part of supportive care in most cases. Skin deconta- Health and Safety Executive Laboratories in the United
mination should be performed through showering the Kingdom and this can be found in the Appendix.
patient with soap and water, while avoiding direct contact In addition to support of vital functions, specific thera-
with contaminated clothing and biological fluids by using peutic pharmacological agents should be used. Intravenous,
personal protective equipment. The airways must be main- intramuscular or endotracheal atropine sulphate is used to
tained and in the case of respiratory depression cuffed counter the effects of excessive concentrations of acetyl-
endotracheal intubation should be performed. choline at the muscarinic nerve endings in target organs.
Once vital functions have been supported, therapy Atropinization should be maintained through repeated
should address reducing the potential absorbed dose doses according to clinical status and AChE levels. The
through gastric lavage which may be considered when the administration of an oxime, usually pralidoxime chloride
patient presents within one hour from contamination (2-PAM chloride), a highly specific antidote, is effective in
through ingestion. Activated charcoal administered orally reactivation of acetylcholinesterase when administered
(or through an orogastric tube if the patient has a depressed within 48 hours. However, pralidoxime is far less effective
level of consciousness) is an effective absorbent for many if used later when the phosphorylation of the enzyme is
poisons. Ipecacuana syrup, an emetic agent, is no longer strengthened by the loss of one organophosphate alkyl
recommended for routine use, being contraindicated in group, a phenomenon known as ‘ageing’.
patients with diminished airway protective reflexes and in Blood pressure should also be monitored during treat-
the case of ingestion of a corrosive substance. ment because of the occasional occurrence of a hyperten-
In addition to general decontamination, specific phar- sive crisis. Favourable prognostic signs are the reversal of
macological agents to control symptoms may be needed. In muscarinic symptoms and signs and the improvement of
case of seizures, lorazepam or phenobarbitone are the respiratory function and blood oxygenation. In organophos-
drugs of choice. Moreover and when available, highly spe- phate poisoning, treatment with activated charcoal is of lit-
cific antidotal therapy may need to be used, but general tle benefit because of the rapid absorption of the pesticide
supportive measures will remain the keystone of therapy. into the bloodstream. Management of a moderate to severe
It is very important, during first aid activities, to collect poisoning case (50–90 per cent cholinesterase inhibition),
and store biological samples from the subject (vomit, urine, is best undertaken in an intensive care unit as mortality
blood and faeces) and to continue collection before the from severe poisoning is around 10 per cent and prompt
diagnosis is made. In some cases, the diagnosis can be con- skilled management will improve outcomes.71
firmed by the detection in the biological sample of the
toxic active ingredient or its metabolites.70 Specific clinical detail
The effects of organophosphates on human physiology are
complex, but inhibitions of esterases, particularly acetyl-
The treatment of pesticide poisoning cholinesterase is the most clinically important and leads to
a collection of symptoms known as the ‘acute cholinergic
INSECTICIDE POISONING crisis’. This will be a mixture of muscarinic and nicotinic
Organophosphate poisoning receptor responses, initially stimulation and then blockade.
The balance depends upon the particular organophosphate
General principles of treatment and its absorption and activation characteristics, but mus-
Any suspected case of organophosphorus pesticide intoxi- carinic responses are essentially ‘secretory and excretory’
cation must be considered a serious medical emergency and are a mixture of diarrhoea, bronchorrhoea, urinary
and the patient should be hospitalized as soon as possible. frequency, emesis, lacrimation and salivation, together with
The management of acute pesticide poisoning 411
meiosis, bradycardia, bronchoconstriction, hypertension 3. Benzodiazepines. These agents will control some of
and possibly cardiac arrhythmia. These can be treated the central nervous system effects, especially agitation
symptomatically and may not be life-threatening; although and seizures. Most benzodiazepines are suitable and
very severe bronchorrhoea can occur with some organo- should be administered by an intravenous route.
phosphates, such as chlorpyrifos. Nicotinic responses are Diazepam is the most commonly given, at a starting
primarily neuromuscular, initially with fasciculation and dose of 0.05–0.03 mg/kg.
then muscle weakness that may progress to paralysis and
life-threatening respiratory failure. Mydriasis, tachycardia For greater practical detail on managing organophos-
and hypertension may also paradoxically occur depending phate poisoning, the authors strongly recommend the clin-
upon the balance of muscarinic to nicotinic responses. ical review by Roberts and Aaron73 published in the British
Central nervous system responses always accompany Medical Journal in March 2007. This has a particularly use-
this constellation of symptoms and signs and can be quite ful ‘decision tree’ which compares the treatment of minor
non-specific, for example anxiety, but severe poisoning toxicity with major toxicity.
will cause altered levels of consciousness and convulsions
and will contribute to the respiratory distress. Respiratory Carbamate poisoning
embarrassment and even failure may reoccur after the Carbamates very rarely cause life-threatening events, even
acute cholinergic crisis and this is known as the ‘interme- with attempted suicide. In occupational poisoning, symp-
diate syndrome’. This occurs some 24–96 hours after the tomatic treatment and fluid balance support is usually all
primary symptoms and the patient may well be starting to that is required to manage the patient. A prompt differen-
recover. A useful early sign of the intermediate syndrome tial diagnosis from OP poisoning is essential since symp-
is weakness of the neck flexors and cranial nerve palsies72 toms are similar, but the use of pralidoxime is not
and this ‘secondary’ or type 2 paralysis usually lasts from recommended. Early management of the more severe cases
five to 18 days and recovers spontaneously if the patient is relies on the early stabilization of the patient and the
supported. The cause is postulated to be later dysfunction titrated administration of atropine to treat muscarinic
of the nicotinic receptors situated at the neuromuscular symptoms. Assisted ventilation may rarely be required.11
junction.
Organochlorine poisoning
The use of antidotes in acute organophosphate poisoning Treatment involves supportive care and avoiding exoge-
Antidotes in the treatment of any poisoning are the excep- nous sympathomimetic agents, since organochlorine pesti-
tion rather than the rule and decontamination and support cides are toxic to the central nervous system and sensitize
of vital functions remain the cornerstone of preliminary the myocardium to catecholamines. Apart from decontami-
clinical responsibilities. Organophosphate poisoning is, nation and general supportive measures, diazepam and phe-
however, exceptional and there are three broad classes that nobarbitone are used to control irritability and seizures.11
are used as specific antidotes:
Pyrethrum and pyrethroid poisoning
1. Muscarinic antagonists. Atropine is the most Apart from the allergic reactions observed as a consequence
commonly used agent and the dose is carefully titrated of exposure to natural pyrethrum compounds contami-
to reverse the muscarinic effects. This will reduce nated by allergens (such as resins), acute occupational or
bronchorrhoea and increase the heart rate (which is a intentional poisoning from these compounds are only very
good measure of atropinization and should be kept at seldom observed and, never so severe as to become a life-
more than 80 beats per minute). The dose is much threatening event.11
larger than that used in other therapeutic indications
and in adults may be 1–3 mg initially by an intravenous HERBICIDE POISONING
route (0.02 mg/kg in children). Atropine will have no
effect on the neuromuscular junction or on muscle Paraquat and diquat (bipyridyl compounds)
weakness and therefore breathing will still be Paraquat is poorly absorbed from the gastrointestinal tract
compromised. and the skin, and if its absorption can be prevented death
2. Oximes. These are administered as an infusion and will may be avoided. Speed of interventional therapeutic action
facilitate dephosphorylation of the acetylcholinesterase is therefore very important. Treatments have therefore
enzyme, thereby restoring the catalytic site. This is only focused on the prevent of absorption, removal of the chemi-
possible before ‘ageing’ of the enzyme–organophosphate cal from the bloodstream by haemodialysis or haemoper-
complex and therefore early use is recommended in a fusion, prevention of its accumulation in the lung, the use
confirmed case and the infusion should be continued of free-radical scavengers and the prevention of lung fibro-
until recovery. With praladoxime chloride, (2-PAM sis.11 In practice, only the prevention of absorption by eme-
chloride), a loading dose of 30 mg/kg is given sis or purgation of the gastrointestinal tract has been found
intravenously over 20 minutes followed by an infusion to be effective. To avoid accidental ingestion, the manufac-
8 mg/kg per hour. turers have added a blue pigment, a stenching compound
412 Pesticides and other agrochemicals
and an emetic substance to the formulation and this has and the likelihood of serious systemic sequelae or death.
been effective in reducing morbidity and mortality. Advancing age is associated with a less favourable progno-
A dose of 20–30 mg/kg of paraquat can cause mild poi- sis and corrosion of the gastrointestinal tract has been
soning, while 40–50 mg/kg can cause delayed development observed. Renal and hepatic impairment are also frequent
of pulmonary fibrosis, which can be lethal. Higher doses findings in significantly large absorbed doses and usually
usually cause death within a few days due to pulmonary reflect reduced organ perfusion. Respiratory distress,
oedema and renal and hepatic failure. Levels can be moni- impaired consciousness, pulmonary oedema with infiltra-
tored by measuring the unchanged chemical in the urine. tion shown on the chest radiograph, shock, arrythmias,
The similar herbicide diquat is different toxicologically renal failure (requiring haemodialysis), metabolic acidosis
and does not accumulate in the lungs. On chronic exposure, and hyperkalaemia may all occur in severe cases. Bradycardia
the target organs for toxicity are the gastrointestinal tract, and ventricular arrhythmias are often present in the preter-
the kidney and in particular the eye. Diquat has been found minal phase. Management is symptomatic and supportive.11
to cause cataracts in mammals by a free-radical mechanism.
Acute clinical symptoms include nausea, vomiting and Triazine herbicides
diarrhoea, ulceration of the mouth and oesophagus, decline Severe poisonings have rarely been observed and over-
in renal function and neurological effects. There have been exposure has resulted mainly from accidental or suicidal
very few cases of human intoxication with diquat and the ingestion. In these cases, administration of activated char-
treatment remains the prevention of absorption and coal is recommended.
enhancing elimination, as with paraquat.74
Chlorate RODENTICIDES
Poisoning following ingestion of chlorate salts is character- With aluminium phosphide poisoning, no antidote is
ized by methaemoglobinaemia (MetHb), haemolysis, available and many patients die despite intensive care and
disseminated intravascular coagulation and renal failure. supportive measures are all that can be offered.76 Some
The clinical features include nausea, vomiting, diarrhoea, studies suggest a beneficial effect of magnesium sulphate,
cyanosis and dyspnoea. Very few data are available regard- but available data are not sufficiently robust to recommend
ing the pathophysiology and specific effective treatment this treatment in standard treatment protocols.
of sodium chlorate poisoning. Chlorate salts, which are In anticoagulant rodenticide poisoning, the international
powerful oxidizing agents, induce the formation of normalized ratio (INR) should be measured 36–48 hours
methaemoglobin from the oxidation of the ferrous ion in post-exposure. If the INR is normal at this time, no further
haemoglobin to the ferric state. Methylene blue, an effec- action is required. If active bleeding occurs, prothrombin
tive reducing agent, is unfortunately unable to ‘reduce’ complex concentrate, recombinant activated factor VII or
methaemoglobin from chlorate salts because of the con- fresh frozen plasma and phytomenadione i.v. should be given.
comitant denaturation of glucose-6-phosphate dehydroge-
nase caused by the chlorate per se. In severe poisonings, MOLLUSCICIDES
haemodialysis is recommended.10
Although some cases of acute metaldehyde poisoning have
Chlorophenoxy herbicides been reported, the occurrence of severe poisonings is very
In the absence of a specific antidote for chlorophenoxy uncommon. Supportive measures are all that is required
herbicides, urinary alkalinization is the treatment of choice (correction of acid-base balance, ventilatory support, cor-
in promoting elimination. Alkalinization increases urinary rection of haemodynamic instability and anticonvulsant
flow and will dilute the concentration of chlorophenoxy therapy, when appropriate).77
herbicide in the glomerular filtrate which also decreases
the rate of passive reabsorption (often termed ‘forced
diuresis’).75 THE MONITORING OF EXPOSURE
Glyphosate-containing herbicides Operator exposure
The mechanisms of toxicity of glyphosate formulations are
complicated since it has at least five different salts and Risk assessment for exposure to pesticides in occupational
commercial formulations contain a number of different settings starts with the definition of the hazard, as for any
surfactants. Human poisoning usually follows exposure to other chemical. Labelling the pesticide provides useful
a variable mixture where the toxicity of the surfactant information about intrinsic toxicity and possible effects due
polyoxyethyleneamine (POEA) contributes more to the to acute and chronic exposure. The next concern is opera-
toxicity than glyphosate alone. Accidental ingestion of tor exposure which has to be defined in both qualitative and
glyphosate formulations is generally associated with only quantitative terms, so that it can be compared with the
mild, transient, gastrointestinal effects, although there is acceptable operator exposure level, when available, or with
a reasonable correlation between the amount ingested any other appropriate occupational exposure limit (OEL).
The monitoring of exposure 413
Biological effects
activities are performed outdoors and with typical seasonal
variability, exposure levels show a significant variability over
time. It is therefore often difficult to perform representative Bystander exposure
environmental monitoring. Thus, more than in any other
occupational setting, exposure assessment has to be tailored
General population
to the worker.
As a general rule, exposure to pesticides in agriculture –
especially in open field crops – is almost exclusively dermal.
Dermal exposure occurs in part from direct physical contact Increasing log dosage (mg/kg body wt)
with the pesticide and in part from cross-contamination
of surfaces and work instruments. Respiratory exposure is Figure 43.8 Biological effect on a human population increases
minimal and does not significantly affect the overall exponentially if plotted against the log of the dosage in milligrams
operator’s contamination.78 per kilogram of body weight. Reproduced with permission from
Operator exposure can be estimated by the measure- Ecobichon DJ. Toxic effects of pesticides. In: Klaassen CD (ed.).
ment of the total amount of pesticide that can be found on Casarett and Doull’s Toxicology. The basic science of poisons,
patches applied on the surface of various parts of the body. 6th edn. New York: McGraw-Hill, 2001: 763–810.
The US Environmental Protection Agency (EPA) sets out
in detail how dermal exposure assessment is to be per-
formed.79 Personal air sampling and environmental moni- residues in the treated crop or environment where spraying
toring can also be applied when inhalation can contribute or distribution has taken place. The biological effect on a
to the overall exposure, such as in greenhouse work and in human population increases in an exponential fashion if
pesticide production factories. Pesticide exposure can be plotted against the log of the dosage in milligrams per
significantly reduced through the prudent use of personal kilogram of body weight and can be illustrated as shown in
protection equipment (PPE). Due to the previously Figure 43.8.
described characteristics of agricultural work, dermal Acute symptomatic poisoning may occur at dosage
protection is in general more important than respiratory levels hundreds if not thousands of times greater than
protection. Overalls and gloves are essential personal pro- exposure to the general population in food, air and water,
tection devices, taking into account the covered body but occupational exposure is on the upward slope and can
surface (see Table 43.4) and the relative importance of dif- end in an acute poisoning if poor systems of work practice
ferent body areas in dermal contamination. Also, the wear- are adopted (e.g. failure of enclosure of process, poor
ing of protective boots has been shown to significantly separation of employees and inadequate personal protec-
reduce dermal exposure.80 tive equipment).
There is a continuity of exposure to the human popula- Pesticide use in agriculture runs through three major
tion from manufacturing of the active product to possible phases: mixing and loading, application and re-entry.
Pesticide exposure during mixing and loading contributes
to less than 10 per cent of the total exposure.81 A more
Table 43.4 Percentage of body surface of different body
practical approach to workplace exposure is illustrated in
regions.
Figure 43.9, which follows the manufactured pesticide
Body region Surface area (% of total) from the reaction vessel of the manufacturing plant to the
end user and end usage, where some residual contamina-
tion may remain. This pathway history of the active ingre-
Head 5.6
dient pesticide is divided into distinct stages.
Neck 1.2
Exposure to the active product on the manufacturing
Upper arms 9.70
plant must always be a safety consideration as the finished
Forearms 6.70
product will need to be tested and then dispatched to stor-
Hands 6.90
age, usually in a holding tank (see stage (1)). It is rare for
Chest, back, shoulders 22.80
chemical processes to be completely contained, and worker
Hips 9.10
exposure can occur during product sampling, maintenance,
Thighs 18.00
during decanting to bulk storage and packaging into con-
Calves 13.50
tainers for onward distribution (see stages (2) and (3)).
Feet 6.40
Once the concentrate is bottled and packaged, exposure is
Total 100
minimized until the concentrate bottle or container is
414 Pesticides and other agrochemicals
Manufacturing plant
Maintenance 1
Operator
Sampling
Storage
Distribution to
wholesaler and retailer 3
Concentrate to
spray contractor 4
or farmer
Dilution into
spray tank and
spraying 5
On to possible
On to crop
bystander
opened and decanted into a spray tank for dilution and techniques with improved concentrate containers to
distribution to the target crop or other environment (see facilitate this. Sole reliance on following the manufacturer’s
stages (4) and (5)). A thorough review of organophosphate instructions and correct PPE may not always give adequate
contamination risk in agricultural workers by the Com- protection. Studies undertaken on manufacturing plants syn-
mittee on Toxicity of Chemicals in Food, Consumer thesizing the organophosphorus compound chlorpyrifos83
Products and the Environment82 demonstrated that poten- revealed statistically significant depressions of the enzyme
tial exposure was greatest at the concentrate to dilution stage cholinesterase in apparently well-protected employees.
because of splashing and inadequate personal protective The total operator’s exposure during application of
equipment and they suggested better pouring and dilution a pesticide on to the crop can be higher than during
The monitoring of exposure 415
mixing, loading and re-entry, with the most important clinically important measurement in a suspected case of
determinant of a worker’s contamination being the applica- significant exposure and possible OP poisoning.
tion technique.84 Backpack sprayers have higher exposure Health surveillance is not merely the diagnosis of
potential compared to tractor applicators.78 During tractor occupational disease or acute toxic effects. It should be
application, the use of an air-conditioned closed tractor can carried out even when exposure is below permitted levels
reduce exposure to negligible levels. Re-entry consists of all and to monitor the exposure and the safety of the work
manual and/or mechanical activities performed on the crop activity, including the effectiveness of personal protective
after pesticide application. In re-entry activities, the skin is equipment.
the major route of operator exposure and shows a linear Health surveillance of pesticide workers include:
correlation with the dislodgeable foliar residue (DFR),
which is the amount of pesticide deposited on crop surfaces ● a pre-employment medical examination to detect
that is also available for operator contamination.85,86 The allergies or medical conditions which can be exacerbated
occurrence of symptoms has been used to monitor expo- by pesticide exposure, and to establish a baseline for
sure to backpack sprayers in some developing countries. comparison in any further evaluation of the worker;
This is far from safe or sensible and effectively adds to the ● periodic medical examinations aimed at detecting any
pesticide poisoning burden in these countries.87 early specific adverse health effects attributable to the
Biological monitoring, intended as the measurement of pesticide exposure;
the dose that has been absorbed in the subject, is poten- ● a medical examination after prolonged or repeated sick-
tially the most useful tool for monitoring pesticide expo- ness absence to detect any significant change in health
sure of agricultural workers. The route of exposure for most status which may compromise the ability to continue
farm workers is dermal and most pesticides in current use the assigned job, and to ensure that any illness is not
are metabolized rapidly, with the metabolites eliminated in pesticide related.
urine. Urinary levels of pesticides or their metabolites can
be performed with the aim of monitoring the exposure Biological effect monitoring should be considered espe-
level indirectly. cially when determination of a specific marker of biological
Biological monitoring has several limitations, such as effect is available, such as cholinesterase activity in plasma
the difficult choice of the sampling time due to the variabil- or red blood cells in pesticide manufacturers or applicators
ity (over time) of the exposure levels, the lack of biological (see Appendix). Other parameters that have been consid-
exposure limits or reference values (for most of the com- ered as possibilities for biological effect monitoring include
pounds used) and poor knowledge of the toxicokinetics of cytogenic analysis of lymphocyte micronuclei and semen
most pesticides in humans. A single exposure is very time quality. Presently, these remain as research procedures
dependent, while repeated exposure measurements are which have not been field tested for practicality or applica-
more representative of the average with approximation to bility. Liver and renal function tests may be indicated
a steady state for blood or urinary level metabolites. Blood depending on the compounds used and the estimated
levels are usually more specific as the parent chemical is levels of exposure, but abnormal liver function tests often
measured instead of the metabolite, but these are much lack specificity.
more time dependent. Collection of 24-hour urine samples For determination of inhibition of cholinesterase levels in
are inconvenient with poor compliance by exposed workers. workers exposed to organophosphates and carbamates,
Spot urine samples are more acceptable, but as the urine venous blood is taken from the employee at regular intervals
volume varies, correction factors must be used, the most after potential exposure. For acute exposures, the samples
common being micrograms of pesticide (or metabolite) are best taken immediately after exposure. Sampling
per gram of creatinine. towards the end of the day avoids the ‘diurnal variation’
Urinary measurements are specific if the parent com- effect. During collection of venous blood samples, precau-
pound is excreted in the urine unchanged, for example tions should be taken to avoid contamination of the blood
(2,4-dichlorophenoxy)acetic acid and glyphosate. Most by exposure to cholinesterases in the air or on the skin of the
organophosphates can be found unchanged in the blood donor or sampler. Cholinesterases are also unstable when
for only very short periods of time and are then rapidly kept at room temperature for long periods and samples
metabolized, often to an even more active intermediate. should therefore be stored on ice or frozen prior to analysis.
They may then be subsequently broken down to a specific Levels of red blood cell acetylcholinesterase, plasma
leaving group and non-specific alkyl phosphates, which are cholinesterase or both can be measured. The greater the
found in the urine, usually well within 24 hours. These are inhibition of the cholinesterase levels, the greater the
useful tools for assessing exposure, especially at low doses, extent of absorption of the pesticide. If activity is reduced
but this may not be as useful as measuring the biological to 30 per cent or more of the pre-exposure level, the test
effect of these chemicals (which is the inhibition of acetyl- should be checked immediately, and removal of the indi-
cholinesterase), but this measurement in itself may well vidual from further exposure considered. Cholinesterase
be complicated by inter- and intraindividual variability. levels are very variable in the population, and the variabil-
However, cholinesterase inhibition remains the major ity in a single individual can be by as much as 16 per cent
416 Pesticides and other agrochemicals
Interpretation of results
manufacturing plant and thereafter declines
exponentially to exceedingly low doses in food, With the analytical precision attained in the Health
water and the environment. and Safety Laboratory, significant absorption of OPs
● Biological and biological effect monitoring of is indicated if the percentage drop between successive
pesticide users is very complex and usually estimations is:
undertaken during field trials of the chemical
before formal registration for commercial use. ● plasma 15 per cent;
Correct study design is essential for the ● erythrocyte 12 per cent.
generation of valid results.
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44
Welding
GRANT McMILLAN
INTRODUCTION means accepting that welding and allied processes and the
workplaces wherein these are used may indeed be damag-
‘Welding’ is a generic term for any of the processes of join- ing to health unless health and safety professionals are on
ing materials at areas or points softened or liquefied by the hand to assess and ensure the many associated risks of
application of heat derived in a variety of ways. Welding harm are controlled.
metal is the most ubiquitous of the industrial processes Over the last decade, specific concerns for the occupa-
and welders are among the last craftsmen in industrialized tional health and safety of welders and related workers
and industrializing economies. Several sources of heat are have resurfaced yet again. This has been prompted by leg-
used. These include friction, electron beams, lasers, ultra- islation, research findings, impending legislation on pro-
sound and combustion of fuel gases, but by far the most tection from electromagnetic fields and, from the United
common source is an electric arc struck between two elec- States, a catalyst for research provided by litigation over
trical conductors. Further consideration of the health and assertions that inhaled manganese compounds in fume
safety hazards of welding here will be limited almost from very commonly used welding and related processes
entirely to arc welding processes. may exert significant irreversible neurotoxic effects on
Estimates suggest that well over three million workers exposed workers.
worldwide use welding to some extent in their work. The industry’s desire to shake off the ‘dirty and danger-
Welders and the many other individuals who work with ous’ mantle has helped to prevent these new developments
them, or in their vicinity, may be exposed to emissions that totally overshadowing and diverting attention from the
pose a wide range of potential health hazards. With such need for more to be done about long-recognized hazards
large numbers of workers involved, a sound knowledge of and their effects. These include wholly avoidable deaths at
welding processes and their emissions is important for work; the damage done daily to hundreds of thousands of
controlling the hazards to health. workers by ‘minor’ but painful injury accidents related to
There is also economic pressure to improve the reality welding processes; respiratory diseases and the long-term
and perception of health and safety in the welding indus- toll of largely avoidable wear and tear of the musculoskele-
try. Increasing global demand for these skilled workers is tal system which is one of the main causes of ‘medical
not being met. Recruiting is down and, after years of train- wastage’.
ing, retention of qualified welders working through to nor- In the area of respiratory diseases, the spotlight has
mal retirement age is poor. International opinion-formers widened to highlight not only continuing uncertainty
in the industry believe this is due in large part to the about causal links with chronic obstructive pulmonary dis-
perception that welding is ‘dirty and dangerous’. They are ease (COPD), and chronic bronchitis and emphysema
seeking to change that view. They recognize that this (CBE), and the long-standing apparent excess risk welders
422 Welding
have for lung cancer, but also to include the hypothesis for a gas shield to be formed over and around the arc and
that inhaling welding fume may facilitate pneumonic weld pool creating a bubble-like stable and reproducible
infections. micro-environment restricting access of oxygen and other
Making health and safety of welders a naturally inte- gases, thus minimizing oxidation and other inclusions
grated part of education, training and good practice at all which could weaken the weld. This shield may be produced
levels of the workforce and from project conception by combustion of components of the core or coating of the
through to completion, and beyond to maintenance and filler metal wire or be provided directly as a flow of inert or
repair, must be at the heart of moves to make welding less active gas, such as argon or carbon dioxide, respectively.
‘dirty and dangerous’. There is an urgent need to conclude In manual metal arc (MMA) welding (Figure 44.1), the
research to clarify the situation regarding hazards such as arc is struck between the workpiece and a consumable elec-
manganese; for more pro-active measures to recognize, trode in a holder held by the welder. The wire of the elec-
evaluate and control exposure to welding fumes without trode is short to allow it to be controlled and is usually
significant loss of productivity; and to make improvements coated with a mixture of chemicals and alloying metals. In
to the ergonomics of the processes and workplaces. addition to forming a shield of combustion gases over the
Welders need to be better trained, motivated and equipped arc and weld pool this may contribute to the properties of
to exercise their responsibility to contribute to protecting the weld. It forms a temporary ‘slag’ over the weld bead to
their own health and that of fellow workers by using their reduce oxidation and slow cooling. Slag is chipped off once
skills, knowledge and common sense to better effect, for the weld has cooled. This is a common source of foreign
example, to reduce exposure to potentially harmful mate- body eye injuries.
rials by using the ventilation which is provided and keep- In tungsten inert gas (TIG) welding (Figure 44.2), the
ing their head out of the plume of fume. arc is formed between the workpiece and a contoured non-
consumable electrode in the form of a conical spike of
tungsten alloy in a pen-type holder. This may contain tho-
PRINCIPAL WELDING PROCESSES rium (see under Radiation, p. 423). The electrode tip must
be kept correctly contoured by periodic grinding at inter-
A basic understanding of the principal welding processes is vals of up to several weeks depending on use. Metal may
necessary to understand and appreciate the source and be added from a filler wire fed into the weld pool by the
nature of the emissions and the potential which exists to operator independently of the electrode, resulting in both
control them. The main welding and allied processes are
arc welding, resistance welding, gas welding, forge welding,
brazing and soldering. Prime among these in terms of Consumable electrode
usage is arc welding, the main topic in this chapter,
probably followed by resistance welding. Much informa-
Flux covering
tion and technical details on these and the range of joining Core wire
and related processes such as hardfacing, arc air gouging
Evolved gas shield Weld pool Slag
and burning are available at ‘Job Knowledge’ and other
sections within the technical information area of the Arc
website of TWI World Centre for Material Joining Weld metal
Technology.1
Parent material
Arc welding processes Figure 44.1 Schematic diagram of manual metal arc welding.
hands being used. The arc and weld pool are shrouded in of the arc on ambient air. The formation and emission
inert (and thereby asphyxiant) shielding gas, such as argon rates and the composition of each and all of these pollu-
and/or helium. tants may vary within and between welding processes.
In metal inert gas (MIG) and metal active gas (MAG) This can be troublesome when sampling and when pre-
welding, the electrode is a continuous consumable small scribing control solutions, but can be turned to advantage
diameter bare wire fed at a constant speed on to the parent to select, use and perhaps modify processes to ensure the
metal of the workpiece. This wire is melted in its own arc to maximum reduction of the risk of harm being caused by
contribute directly to the weld pool. The wire may contain their emissions.
a flux in its core (flux core arc welding). The weld pool, tip Variations in emissions within a process are influenced
of the electrode and arc are shrouded in a shield of piped by many factors including the materials to be welded, those
inert and/or active gas. As the operator does not have to be in the filler wire or other consumable, electrical parame-
concerned with controlling the arc length, this process is ters, shield gas and the individual welder’s skill and self-
much favoured by amateur welders. protection measures,3 the latter being a most powerful
influence which can be reinforced by good education,
training and motivation.
New processes The air in the welding operator’s breathing zone may
also contain compounds originating from the surrounding
Although these arc welding processes are generally cheap workplace atmosphere, rather than the welding process, as
and reliable, limitations in all of them have become evi- was observed in a recent UK Health and Safety Executive
dent.2 Improvements and new technologies are required. investigation in which samples taken for analysis from
Whether it is an established welding process which is being three different arc welding techniques frequently con-
optimized or a new process being introduced, it is neces- tained commonly used solvents, such as acetone, cyclo-
sary to include an assessment of its impact on the health hexane and dichloromethane.4 These and other materials
and safety of welders, and others, in the multidisciplinary may originate from surface coatings and contaminants or
development process of proving its suitability for purpose. from other processes, such as degreasing, being carried out
New processes, such as laser and laser-hybrid processing, in the workplace.
electron beam welding, magnetic pulse welding and fric-
tion stir welding, have been developed and are being or
have been introduced with advantage to productivity and Radiation
the health of workers.
Of the new technologies mentioned, friction stir weld- Arc welding is one of the most intense artificial sources of
ing (FSW) is of particular interest for improved occupa- optical radiation. Each type of welding emits a different
tional health because it welds in the solid phase – there is and continually changing spectrum and intensity.5 For
no melting and so no fume, and no arc so no ozone. Put most processes ultraviolet (UV) (A, B and mainly C) and,
simply, in friction stir welding, a wear-resistant, specially to a much less extent, infrared radiation (IR), are the com-
shaped tool is rotated at a very high speed and slowly ponents of health and safety concern.
plunged under a downward force by a machine into the UV radiation is a known carcinogen. Excessive expo-
joint line between the parts to be joined. These have to be sure to solar radiation increases risks of cancer of the lip,
clamped together so that the abutting faces cannot be basal cell, and squamous cell carcinoma of the skin and
forced apart. As it rotates, the tool heats the material by cutaneous melanoma, particularly in fair skin populations.
friction to about 70–85 per cent of its melting temperature The short distance between the arc and the welders’ and,
so that it softens sufficiently for the rotating tool to traverse sometimes, other workers’ skin and eyes is likely to be
the joint line softening as the material goes. Its contoured insufficient to absorb much of the potentially damaging
shape ensures that, as it passes, it leaves material trailing UVB and UVC, so they will be at significantly increased
behind it which forms into a solid phase bond between the risk of eye and skin damage, including malignancy, if they
two pieces. FSW is now well established worldwide espe- have inadequate protection.
cially for the welding of aluminium. Work is in hand to The possible health hazard of electromagnetic fields
greatly extend its application. (EMF) is one of the most recent subjects of special interest
in the health of welders. There is no clear-cut evidence of
harm being caused to humans by this radiation other than
SOURCE, NATURE AND VARIATION occasional cases of local heating of the eye and male
OF EMISSIONS gonads. There is, however, a high level of suspicion that
as-yet-undetected harm results from EMFs. It is anticipated
The emissions from arc welding processes comprise ultra- that employers will be required to assess and measure lev-
violet and infrared radiation, visible light, an often biolog- els of EMFs to which workers are exposed; where these
ically active mixture of particles termed ‘welding fume’ and levels exceed ‘action values’, to assess whether exposure
a mixture of gases derived from the process and the action limits are exceeded; to ensure that these limits are not
424 Welding
exceeded; to erect warning signs when EMF exposure levels and chemical composition, it emerges that they can be
may cause exposure limits to be exceeded; and to provide classified into two main groups. The first of these com-
appropriate information and training. prises fractionated mixed metal oxide particles formed
Arc welders are among those groups who may be from metal vaporized in the high temperature of the arc,
exposed to the highest intensities of fields.1 Although arc often oxidized following reactions with oxygen in the
welding uses relatively low voltages, it requires high cur- ambient air. These are present as individual irregular parti-
rent. This flows through welding electrical equipment and cles, individual spherical particles, and chains and aggre-
cables. If that equipment is close to the welder and/or the gates formed by condensation of particles. They reflect the
welding cables are wrapped over or in direct contact with composition of the electrode with the more volatile con-
the body, as is often observed, then the welder may be stituents predominating. Many of the particles have a core-
exposed to relatively high intensities of field compared to shell structure which suggests that surface composition can
other occupations. Much can be done to reduce the arc be quite different from the bulk composition.6
welder’s exposure and relatively simple steps can have a The second group of particles is termed ‘spatter’. These
tremendous benefit. Expert advice can be obtained from a are coarse, unfractionated particles of electrode, usually
reputable source, such as the national health and safety larger than respirable, but providing a secondary source of
regulatory body or from an international1 or the within- smaller respirable oxide particles as the hot metal spatter
country national centre of welding expertise. reacts with oxygen in the air, often explosively.
Ionizing radiation may be introduced into the welding The size of the particles is critically important in assess-
scenario through ancillary processes, such as non-destructive ing the bioavailability of their constituents as the lung is
testing radiography and, now unnecessarily, by the contin- the principal potential route of entry. An important char-
ued use of thoriated tungsten electrodes in TIG welding and, acteristic is the particle diameter (aerodynamic diameter
to a lesser extent, in plasma cutting. Tungsten is used because for particles 0.1 μm, diffusion equivalent diameter for
it can withstand very high temperatures with minimal melt- particles 0.1 μm). The size variation of welding fume
ing or erosion. Performance is further improved by alloying particles is quite large.6,7 It has long been known that many
the tungsten with small quantities of oxides of other metals. are in the respirable range. Whereas it had been estimated
One such additive is thorium oxide which is radioactive, that some 50 per cent of the fume inhaled reached the
emitting mainly alpha particles. The main source of danger lower respiratory tract and 35 per cent to the alveolar level,
is in the ingestible and respirable dust produced during with most then being exhaled,8 more recently it has been
periodic grinding of the electrodes to maintain the neces- found that a substantial proportion comprises submicron/
sary sharp point – but there is also a small external radioac- ultrafine/nanoparticles.9–11 This may change our under-
tive hazard. standing and appreciation of the power of welding fume
Thorium-free tungsten electrodes incorporating alter- particles to initiate and promote inflammatory processes
native and only marginally radioactive additives, such as and systemic oxidative stress deriving from the soluble
cerium, lanthanum, yttrium and zirconium oxides are transition metals and, perhaps, to greatly facilitate the
available. These are technically acceptable in most welding transfer of metals to various organs, such as manganese to
situations and should be used, either as the only modifica- the brain.12
tion to the process or with equipment that eliminates the An indication of the range of metallic oxides which may
need for thoriated electrodes for arc starting. When this is be present in the fume from several processes is given in
not possible, strict precautions must be taken to minimize Table 44.1 which was developed in discussion with fellow
exposure to thorium-containing dust at all stages from experts meeting under the aegis of the International
receipt and storage of the electrodes through welding and Institute of Welding. In this context a principal compo-
grinding to cleaning and disposal of waste. nent is of some occupational hygiene significance, while
the key component has the greatest occupational hygiene
significance and therefore requires the most stringent con-
Particle emissions trol measures to ensure that a welder is not exposed to an
excessive level of the substance concerned.
Welding fume particles are derived from evaporation, con- While, as remarked earlier, emissions vary within and
densation, oxidation, decomposition and combustion of between processes, in general terms, of the most com-
materials involved in the joining process. The fume com- monly used arc processes TIG welding gives the least fume
position is largely (up to 95 per cent) determined by the followed by MIG/MAG and MMA, then flux cored weld-
composition of the filler metal and, when present, its flux ing which gives the most.
core or coating. Usually less than 10 per cent of the partic- Although the metal compounds found in fume are
ulate emissions derive from the metal being welded. considered in Section two, Metals, three (chromium, nickel
Twenty-first century technologies in imaging and and manganese) merit brief mention here solely in regard
analysing particles have provided an overall picture of to their presence in welding fume. Further information
welding fume previously unattainable.6 When particles are on these substances in welding is available in separate
characterized by size distribution, morphology, structure publications.13–15
Source, nature and variation of emissions 425
Table 44.1 Principala and keyb components of fumes from commonly encountered arc welding processes.
Type of process Type of consumable Typical principal Other possible Typical key
components principal components component
MMA (SMAW) Unalloyed and low alloy steel Fe, Mn, Cr, Cr(VI), Ni, Cu F Mn, Cr, Cr(VI)
High alloy steel Cr, Cr(VI), Fe, Mn, Ni F Cr(VI), Ni
Aluminium Al, Cu, Mg, Mn, Zn Be, Cl, F Al, Mn or Zn
Cast iron Ni, Cu, Fe, Mn Ba, F Ni or Cu
Hardfacing Co, Cr, Cr(VI), Fe, Ni, Mn V Co, Cr, Cr(VI) Ni or Mn
Work hardening Fe, Mn, Cr Mn
Nickel-based Co, Cr, Cr(VI), Mn, Ni Fe Cr, Cr(VI) or Ni
Copper-based Cu, Ni Cu or Ni
MIG/MAG (GMAW) Unalloyed and low alloy steel Fe, Mn, Cr, Cr(VI), Ni, Cu Mn, Cr, Cr(VI)
and GTAW
High alloy steel Cr, Cr(VI), Fe, Mn, Ni Cr, Cr(VI) or Ni
Aluminium alloys Al, Cu, Mg, Mn, Zn Be Al, Mn or Zn
Nickel-based Co, Cr, Cr(VI), Mn, Ni Fe Cr, Cr(VI) or Ni
Copper-based Cu, Ni Cu or Ni
Gas-shielded FCAW Unalloyed and low alloy steel Fe, Mn, Cr, Cr(VI), Ni, Cu F Mn, Cr, Cr(VI)
High alloy steel Cr, Cr(VI), Fe, Mn, Ni F Cr(VI) or Ni
Hardfacing Co, Cr, Cr(VI), Fe, Ni, Mn V Co, Cr, Cr(VI) Ni or Mn
Nickel-based Co, Cr, Cr(VI), Mn, Ni Fe Cr, Cr(VI) or Ni
Self-shielded FCAW Unalloyed and low alloy steel Fe, Mn, Cr, Cr(VI), Ni, Cu, Al Ba, F Mn
High alloy steel Cr, Cr(VI), Fe, Mn, Ni, Al Ba, F Cr(VI) or Ni
Hardfacing Co, Cr, Cr(VI), Fe, Ni, Mn, Al V Co, Cr, Cr(VI) Ni or Mn
a
A principal component is a component that is of occupational hygiene significance.
b
A key component is the component that has the greatest occupational hygiene significance and therefore requires the most stringent control measures to
ensure that a welder is not exposed to an excessive level of the substance concerned, i.e. it is the component whose limit value is exceeded at the lowest
welding fume concentration.
FCAW, flux-coated arc welding; GMAW, gas metal arc welding; GTAW, gas tungsten arc welding; MAG, metal active gas welding; MIG, metal inert gas
welding; MMA, manual metal arc welding; SMAW, shielded metal arc welding.
Trivalent and hexavalent chromium compounds are trivalent chromium compounds. The International Agency
found in fume from welding on or with materials that for Research on Cancer (IARC) has found there to be
contain chromium or chromates. These include high inadequate evidence for classification regarding the
chromium nickel alloys and low alloy steels, high alloy carcinogenicity of trivalent chromium for humans,16 nor
flux covered wires, chromate paints and coatings, and has metallic chromium been found to be carcinogenic in
chromium plating. Chromium is typically not added inten- humans.
tionally to mild steel or mild steel welding consumables but, When compounds containing hexavalent chromium
because of the nature of steel making and the use of scrap are present in welding fume they can be absorbed and
metal, it is not unusual to find low levels. excreted. The extent to which retention, reduction and
Fume from welding stainless steel is rich in hexavalent excretion of hexavalent chromium compounds and their
chromium and trivalent chromium compounds, the solubility act as an important determinant of carcinogenic
amounts varying within and between processes. Hexavalent potential is uncertain.
chromium compounds are a cause of occupational asthma IARC has classified nickel compounds as carcinogenic
(see under Occupational asthma, p. 434). Some hexavalent to man.16 Evidence suggests that, in highly nickel-polluted
chromium compounds are known to be carcinogenic to environments, the risk appears to be stronger for water-
the respiratory system by inhalation in a range of industrial soluble compounds of chromium rather than those which
processes other than welding, e.g. chrome plating and in are water-insoluble. Nickel is found in welding fumes
the production of chromates, chromate pigments and almost exclusively as nickel oxide and only when welding
ferrochromium. Dose–response relationships have been with pure nickel or nickel alloy filler material. The choice
established for hexavalent chromium and cancer and of welding process has a strong influence on the emission
the possibility of a threshold effect has been suggested. rate. The carcinogen nickel carbonyl has not been found in
There is coincident exposure in most circumstances to welding fume.
426 Welding
Manganese compounds have been proven to be occu- gas-shielded arc welding processes and that, in recent
pational neurotoxins in a range of activities other than years, the increasing use of aluminium and stainless
welding. Manganese is an essential component of steel. steels, along with raised productivity, has increased the
There is no suitable substitute. Compounds containing likelihood of unacceptable welder exposure.17 This appears
manganese, in complexes with iron and other oxides, are to be related more to achieving control down to at least
present in fume particles from steel welding and allied within national occupational exposure limits, many of
processes. which have been reduced in recent years, than to there
In recent years, it has been asserted by a few authors in being evidence in the literature of exposures to ozone in
the scientific literature, and during litigation in the United workplaces causing ill health in welders – as this has not
States, that occupational exposure to manganese com- been found.
pounds in fume from welding of steel causes or promotes There is, however, no doubt that ozone is an irritant to
the onset of Parkinson’s disease and/or parkinsonism/ mucous membranes, can cause acute discomfort to the
manganism in welders and those around them at work. eyes and upper respiratory tract, readily penetrates to small
These assertions have been vigorously contested. airways and alveoli and, even with brief exposures, if con-
Clinical manganism and Parkinson’s disease are two centrations are sufficient, will cause a disabling inflamma-
separate diseases, which, with care and thorough investiga- tory response with pulmonary oedema. The possibility of
tion, can be differentiated from one another.15 Follow-on there being as-yet-undetected harm occurring in welders
studies have not supported the conclusion that welders are cannot be ignored – and so exposure to ozone must be
or have been at any greater risk of developing Parkinson’s minimized to at least within the national standards.
disease at all or at an earlier age than others of similar The generation of ozone is due to photodissociation of
background in other occupations in their community. molecular oxygen in the ambient air around the welding
Whereas vast numbers of workers worldwide use arc weld- process under the influence of direct or reflected UV radi-
ing to join metal, the literature contains reports of very few, ation emitted from the arc. The gas forms in two distinct
if any, who have developed clinical manganism as a result regions: approximately half within a 10–15 cm radius of
of exposure to welding fume. The risk may be slightly the arc by the action of UV in the 130–175 nm range and
greater in allied processes, such as thermal cutting and the remainder in relatively low concentrations further
gouging or hardfacing in which fume emission levels are from the arc, up to a metre, due to UV of wavelengths
inherently higher, but again there have been very few cases. 175–240 nm. It decomposes when subjected to higher
Furthermore, there is no convincing evidence that exposure wavelengths. Usually, the ozone reaches the breathing zone
to manganese-containing fume during employment as a in a few seconds after the arcing starts and the concentra-
welder can result in an increased risk of developing neu- tion returns to the background level almost within the
robehavioural deficiencies and loss of fine control of same time after arcing has ended.17
movements. There is, however, insufficient evidence to the Ozone concentration is affected by the number of
contrary to dismiss the possibility with absolute certainty. welders at work (as several together can build up significant
concentrations during welding in an inadequately venti-
lated space), the welder’s care and skill, and any of the large
Gaseous emissions number of other variables which influence the rate of
formation and decomposition of the gas produced by each
Gaseous emissions comprise those formed in the arc and operator. These include the magnitude of the UV in the
by the action of the arc on the ambient air, plus any shield- critical ranges for production – and beyond for decomposi-
ing gases remaining after they have performed their role, tion of the gas once formed; the presence of fume particles,
and gases released from combustion or heating of surface dust or other gases; the composition of the filler wire; the
coatings. The number of variables affecting workplace welding process and its parameters; and, often most com-
exposures means that a wide range of exposures is possible. plex and variable, the shielding gas. Together these, and the
Exposures of individual welders may come from general need for specialized equipment based on chemilumines-
workshop levels rather than their own work. cence, make measuring welders’ exposure problematic.17
The principal gases formed are ozone, oxides of nitro- All else being equal, ozone concentration is greatest in
gen (NOx) and carbon monoxide – each considered in processes with low fume emission and vice versa as it
detail in Chapter 8, Gases. The arc plays a key role in their reverts to oxygen in contact with particles.
formation. When arcing is not continuous, for example in Process selection is a powerful influence on ozone expo-
manual processes, formation and emission of these gases sure. For example, there tends to be a very fierce arc in TIG
peaks during and diminishes or is absent between arcing, welding and so a great deal of ultraviolet radiation and
so welders may be exposed for repeated short periods to much ozone are produced, particularly when welding on
concentrations very much higher than those indicated by aluminium and stainless steel. Process modification may
an averaging sampling and measuring technique.3 be useful in reducing ozone levels, at least experimentally,
It has been said that exposure to ozone is currently as small changes to the process and its parameters can have
a major occupational hygiene problem with almost all disproportionate effects.18,19
Sampling and analysis 427
Oxides of nitrogen or nitrous gases (nitrogen monox- equipment. The main hazard arising from shielding gases
ide, dioxide and peroxide) are generated as byproducts is asphyxiation (see under Asphyxia, p. 432).
in most arc welding, cutting and heating processes as a
result of heating the air in the arc or flame region. Emission INFLUENCE OF COATINGS AND CONTAMINANTS
rates during arc welding are very low compared to allied ON EMISSIONS
processes especially plasma cutting and oxyacetylene
processes.20 The rate of formation of nitric oxide is initially The composition and amount of fumes and gases pro-
slower than that of ozone as the rapid production of the duced may be influenced significantly in complexity and
former is partly dependent on the air achieving a high tem- potential to cause harm when the metal to be welded has a
perature, whereas ozone production peaks in a fraction of surface coating applied, e.g. by galvanizing, electroplating,
a second after the arc is struck and UV is emitted.3 painting on primer, thermal coating, or is contaminated by
The first stage in the formation of these NOx is oxidation materials such as oil, degreasers or the products/byprod-
of atmospheric nitrogen to nitrogen monoxide, a gas of very ucts of manufacturing processes, e.g. lead, manganese.
low toxicity. This occurs in contact with the very hot gas It is becoming increasingly common, particularly with
emanating from the arc and weld pool. Between 75 and resistance welding in the auto and white goods industries,
97 per cent of the oxides of nitrogen emitted may be nitrogen to weld through or close to organic materials, such as shop
monoxide. Its rates of formation and emission peak during primers, other coatings, adhesives, etc. This can generate a
arcing as the temperature goes above 500–1000°C. They wide range of degradation products. Their composition
then fall, sometimes dramatically, as the NO is diluted by may be difficult to predict even if knowledge of the compo-
the ambient air and cools to its temperature whereupon it sition of the product is available.23
oxidizes, at rates dependent on concentration and tempera- Chlorinated hydrocarbons, such as trichloroethylene,
ture, to the biologically more active gases, nitrogen dioxide may still be found in use for degreasing. These may present
and peroxide, which have the potential to cause harm. as vapour particles in the ambient air having passed from
The ratio of nitrogen monoxide and dioxide can change an adjacent tank or remain on metal parts which have just
if ozone or other oxidants are present in the air. In gas- been cleaned but have not yet dried. The radiation from
shielded arc welding, because of ozone formation by the welding arcs may cause chlorinated hydrocarbons to
UV of the arc, almost all of the total oxides of nitrogen decompose in the air or on the parts. The very toxic gas
generated is nitrogen dioxide.20 phosgene may be formed.
The very low emission rates during arc welding com- In many cases, the risk assessment will indicate that it
pared to processes, such as plasma cutting or oxyacetylene would be best for the surface coatings and contaminants to
burning where much higher rates may be encountered, be removed before welding. An exception may be made
may be of practical importance for occupational physicians when the coating is classified as ‘weld-through’ and suffi-
and epidemiologists when seeking to select samples of cient is known about it to conduct and act upon a properly
workers for research studies as mixing those with superfi- informed risk assessment. With these coatings, fume com-
cially similar jobs may result in mixing those with notably position and thus the risk of harm may be dependent on
different potential exposures to these gases, e.g. arc welders welding method as some processes produce more volatile
(low NOx) and flame burners (higher NOx). organic compounds and less particulate than others when
Carbon monoxide is generated by thermal decomposi- used on metal coated with the same primer.4
tion of carbon dioxide in metal active gas welding shielded
by that gas and by the incomplete combustion of flux
materials containing carbonates and/or cellulose in all or SAMPLING AND ANALYSIS
almost all processes. The amounts of carbon monoxide
generated by fluxed arc welding processes are small and, Air samples should be collected and analysed by qualified
generally, the risk of overexposure is low. people using approved standardized methods and devices.
The dynamism of the fume and the variation in gas emissions
SHIELDING GASES can present challenges to meaningful sampling. When assess-
ing exposure, it is best to collect the fume in the breathing
Shielding gases used in processes such as TIG, MIG/MAG zone behind the welder’s helmet – although this may not be
and flux-cored arc welding (FCAW) may be inert, such as possible with modern close-fitting helmets. If there is a
argon, helium or nitrogen, or active argon-based mixtures national or international standard for sampling, this should
containing carbon dioxide, oxygen or both. Helium may be followed. Even with care, standardized methods and long
be added to argon/carbon dioxide mixtures to improve experience, it can prove difficult to get reproducible results.
productivity. Carbon dioxide may be used on its own. The content of the fume measured in the breathing zone
None of the gases can be seen and none has a smell21 – may include significant contributions from neighbourhood
although a method for odorization was described two activities, such as grinding and, as mentioned earlier,
decades ago.22 Their presence in hazardous concentrations degreasing,4 indicating the wider than perhaps expected
is difficult to detect without prior knowledge or measuring range of exposure the workers may be experiencing. There
428 Welding
are so many variables at work that often it will be imprudent sensitive to such changes. Process automation should be
to extrapolate results obtained in one situation, or even from considered as this may greatly improve the possibilities for
one welder,3 to another. control of welding exposures in the welding environment.
Selection, substitution and process modification require
knowledge of emissions of alternative processes and the
CONTROL OF WORKPLACE EXPOSURES effect of selected process parameters (such as weld speed,
IN WELDING current and voltage), shielding gas or other consumables to
allow meaningful comparisons to be made. In practice,
The hazards associated with welding and its allied processes process or parameter substitution or modification may be
are largely the same all round the world, yet the standards limited to situations where the product quality and overall
set for precautions to be taken to control the risks of harm production costs (including the cost of control measures)
vary greatly between countries.24 Local enquiries must be are not significantly adversely affected by the proposed
made to determine the minimum levels to be achieved. changes. Experience has shown that opportunities for sub-
The multiplicity of situations in which welding and stitution lie in the selection of consumables using fume
allied processes are used, the variations between and within data provided by suppliers. It is important to ensure that
them, and in legislation in many countries, make it obliga- hazards are not removed only to be replaced by others of
tory for measures for control of workplace exposures to be equal or greater concern.
selected following risk assessment of all relevant aspects of Isolation or segregation is often appropriate for auto-
the individual work situation – including when this is off- matic or semi-automatic processes, perhaps using remote
site, e.g. at the customer’s premises.25,26 control and/or an enclosure closely surrounding the
Accurate risk assessment of exposure to welding emis- source. It should be applied to the full range of manual
sions can be a difficult task. The assessment must consider processes in both stationary and non-stationary work-
not only the operators, but also the people working in the places by reducing the number of people who are in the
vicinity of welders. It should include the workers involved area of emissions to an absolute minimum and separating
in the processes in discussions from the outset if at all pos- them from others by exclusion instructions and screens.
sible. Guidance on assessment is available.23,25,26 Means Local extraction ventilation (LEV) is usually required
have been suggested to remove the requirement for expen- for welding and often provides the necessary control. It
sive analysis of every fume sample.23 The extent and method should be designed to capture the particulate fume and
of health surveillance required must be included. This is gases at source before these enter the breathing zone of the
considered under Health surveillance, p. 435. operator. It may be fixed, flexible or portable, or integrated
The basic traditional occupational hygiene hierarchical in the welding equipment and should introduce air move-
approach must be taken to achieve adequate control of ment sufficient to capture and transport the pollutants
exposure:27–30 away from the breathing zones of welders and those work-
ing with them. General ventilation is usually required as a
● prevent emission by selection/substitution of process; supplement to LEV to supply fresh air and dilute pollu-
improve working practices by modification of process, tants. Guidance is available for self-help.1,25,27,28 It may be
process parameters or consumables to lower fume and prudent to seek specialist advice on the design and selec-
gas emission rates or toxicity of the constituents; tion of extraction and general ventilation systems in all but
● prevent exposure by natural ventilation and/or the most straightforward situations.
engineering controls, including isolation or segregation, Use of personal respiratory protection equipment is
control of pollutants at the source by local exhaust essential where previous steps cannot provide sufficient
ventilation; and finally, protection against exposure to fumes and gases. There are
● prevent exposure by wearing respiratory protection two aspects to be considered: (1) the selection and care of a
equipment (RPE). suitable device and (2) the human aspects of achieving the
expected level of respiratory protection. Both can present
It is not appropriate to go directly to or rely solely on challenges.
personal respiratory protection equipment. Although much The requirement may be met by filtering or air-fed res-
guidance is available,1,31 specialist advice may be required at pirators or helmets.1,29–31 These should be fitted and sup-
any or every stage. plied to the individual welder. All apparatus used should be
Selection of the process at the outset should include marked with the appropriate nationally-used protection
consideration of health risks alongside technical suitability, classification and quality scheme logo. Filters must protect
product quality, productivity and cost. In the last 25 years, against gases, as well as fumes – or alternative arrange-
technological improvements designed primarily to give ments made for removal of gases. This should have been
better welds and improve productivity have also provided achieved by arrangements for ventilation. There must be
opportunities to reduce emissions. For example, enhanced adequate support arrangements (including education and
control of power sources has allowed finer control of elec- training, cleaning and maintenance) and for supervision
trical parameters giving the potential to reduce emissions over such matters as length of use of filters.
Adverse health effects of employment as a welder 429
ADVERSE HEALTH EFFECTS OF Arc welding has been reported as affecting the exposed
EMPLOYMENT AS A WELDER skin in other ways, including siderosis40 and contact der-
matitis due to chromium and nickel.41 Atopic dermatitis
Sudden deaths has been exacerbated by UVC radiation from the arc42 and
the much rarer photodermatitis has been reported in a
Though fortunately rare, welders and allied workers are resistance welder.43
killed in the course of their work by electrocution, explo-
sion or fire, and, as discussed below, asphyxia or acute MALIGNANT SKIN LESIONS
chemical exposures. It would be hard to argue that these
Exposure to UVR, whether solar or of artificial origin,
deaths were not entirely avoidable had a safe system of
carries potential risks to human health. It is a known
work based on sound risk assessment been followed. Much
carcinogen. Excess exposure to solar radiation increases
excellent guidance and direction are available from
the risk of cancer of the lip, basal cell and squamous cell
national and other health and safety agencies to assist in
carcinoma of the skin and cutaneous melanoma, particu-
avoiding these and other potentially fatal hazards and how
larly in fair skin populations. Artificial UVR from welding
appropriate safe systems of work should be designed and
torches may also contribute to the burden of disease from
operated.1,31
UVR.44 It is possible that welders are at greater risk of
developing these skin cancers than the general population,
Other injury accidents but there is a dearth of case reports or well-designed
studies of that question.
The Health and Safety Executive estimates that there are The first of only two case–control studies found no
over 1000 work-related accidents to welders reported in excess of skin tumours in the welders45 but, as has been
the United Kingdom each year with around 300 classified remarked,46 the welders examined were all well protected
as major accidents, such as fractures and amputations.31 (so the dose level may have been unusually low) and young
The three most common types of reported accidents to so the length of their exposure was relatively short com-
welders in the UK are related to handling, slips and trips, pared to long-serving career welders and, moreover, they
and being hit by a moving or falling object – which may be may not have had time to develop skin cancers as a
a foreign body heading for the eye! response. The second case–control study found no persua-
sive evidence of occupational risk factors for melanoma.47
Reports have been published of basal cell carcinoma
BURNS AND OTHER NON-MALIGNANT SKIN LESIONS occurring after frequent episodes of cutaneous erythema
Welders suffer a high incidence of burns and other skin and peeling induced by welding,48 a group of five welders
lesions from hot metal, UV and IR radiation burns of unpro- with non-melanoma skin cancer,49 a welder with five squa-
tected areas of skin. UVR and IR radiation from electric arc mous cell carcinomas on his hands46 and a woman who
welding processes commonly cause ‘ray burn’ (erythema) had presented with numerous squamous cell carcinomas
and, ultimately, persistent pigmentation in unprotected areas on her hands and commented that she had frequently
of skin, neck and chest exposed at the V-opening of an experienced ‘sunburn’ on her hands after assisting her son
unbuttoned shirt or overall, the wrists due to stretching over- with his welding business.50 Interestingly, in regard to this
head, forehead and the fronts of the ankles in welders who last case, a case–control study of uveal melanoma has
squat to weld and allow their trousers to ride up.32,33 The shown an increased risk associated with ‘welding burn’.51
back of the ears may be affected by reflected radiation,
e.g. when welding within an aluminium container. EYES
Almost all welders have been burned by sparks, spatter
and droplets of molten metal or slag and bear the scars of Welders normally require stereoscopic vision with good
these repeated injuries. The occupational stigmata of ray acuity to strike the arc and produce high quality joints.
burn and multiple small burn scars found on many welders Their eyes should be especially precious to them, yet the
can cause difficulties in ‘blinding’ controlled studies as it is eye is the part of the body most commonly injured by
so easy to distinguish the welders from others. Rarely, such welding and related processes in industrial settings. It has
burns occur inside the ear. These are particularly painful been reported from the United States that, as a group, they
and may give rise to serious complications including perfo- sustain a higher number of eye injuries than most other
ration of the tympanic membrane with deafness and facial types of workers52 and that eye injuries account for 25 per
paralysis and unusually high rates of residual and recurring cent of insurance compensation claims by welders.53 In a
perforations.34–37 survey of consumer product-related eye injury trauma
High velocity metal projectiles causing deep penetrating treated in emergency rooms in hospitals across the United
injuries with residual foreign body material may be emit- States in the period 1998–2000, welding equipment was
ted during spot or resistance welding, probably due to poor estimated to be the product most commonly associated
cleaning and maintenance of the equipment.38,39 with eye injuries,54 perhaps reflecting the increasing
430 Welding
availability and unprotected use of that equipment by epithelial cells have sequestered. Symptoms usually resolve
DIY amateurs, in addition to professional workers. spontaneously within 48 hours of exposure.
Foreign body eye injuries relate, in the main, to spatter Although the history may appear to make the diagnosis
during welding and to associated processes, such as chip- obvious, care must be taken to examine the eye carefully
ping slag from the formed weld, or grinding metal in prepa- under local anaesthetic, such as proparacaine 0.5 per cent58
ration for welding or after the joint has been made. The to exclude trauma (including foreign body), conjunctivitis,
foreign body ‘missile’ may be set in flight by the actions of corneal ulceration and ulcerative keratitis, and iritis and
the injured welder or someone working closely adjacent. uveitis. The cornea must be stained with fluorescein to
The particles may be carried on the wind or fall into the eye demonstrate the characteristic lesions. A full clinical record
from the hair or skin or a protective goggle as it is moved should be kept and this should include a note recording
from its perch on the welder’s brow to cover his eyes; the that other diagnoses, especially foreign body injury, were
process is completed by the welder rubbing his eye. positively excluded.
The high risk of injury makes it essential for the As a first aid measure, some relief may be gained by
welder and those working around him to wear well-fitting flushing the eyes for several minutes with water or saline
goggles or spectacles with side pieces all the time in the solution. Medical treatment involves administering a
workplace – including when the protection of the helmet short-acting cycloplegic drug,58,60 such as 1 per cent
or handheld shield is added before the arc is struck. cyclopentolate or 2 per cent homatropine to relieve the
When a patient has a history of a known intraocular or pain of reflex ciliary spasm, a single drop being all that is
periorbital foreign body or of occupational exposure to usually necessary. It is essential to check for glaucoma as
potential metallic ocular injury, as do welders, grinders these drugs may induce acute glaucoma – though the risk
and metalworkers, it is necessary to screen them with may be small. The use of topical antibiotics in the absence
plain radiography before they have a magnetic resonance of infection remains controversial but, as a secondary
(MR) scan to ensure the latter is not undertaken during infection is a rare but devastating consequence of a corneal
the continued presence of intraorbital metallic foreign abrasion, their use has been said to be ‘a very reasonable
bodies.55 course of action’ in that situation.60 An eye patch is not
Despite the periodic welding flashes from the arc, when recommended as routine treatment, but may give relief
the appropriate protection is worn, the UV radiation in those with large corneal abrasions.60 These patients
exposure levels reaching the eye are below those needed to and others with extensive damage should be seen by an
cause permanent damage to the corneal endothelium and ophthalmic specialist without delay.
long-lasting eye damage is reported only very occasion- Patients should not leave the medical facility after
ally.56,57 In contrast, the acute injury ‘arc eye’ is frequently treatment until the effects of the local anaesthetic have
recorded as the most commonly occurring eye injury of worn off and must be advised not to drive while the cyclo-
welders. plegic agent is still acting (it is usually safe after about
In that injury, the UV rays from the arc irritate the 8–12 hours). They should be told to return if symptoms
superficial corneal epithelium of the inadequately pro- persist without steady diminution or are unresolved in
tected eyes provoking an inflammatory response which 48 hours. They should not be given local anaesthetic to
includes oedema, congestion of the conjunctiva and stip- reapply as this introduces risks of further injury and may
pling of the corneal epithelium (superficial punctuate ker- delay healing.
atitis (SPK)), the latter characterized by small pinpoint Retinal injuries attributed to radiation in the visible and
defects in the superficial corneal epithelium which stain near-infrared spectrum emitted by a range of arc welding
with fluorescein. If SPK is severe, it may be followed by processes have been reported in the literature under several
total epithelial desquamation with conjunctival chemosis, titles,61–72 but are all the same basic pathology. The radia-
lacrimation and blepharospasm. Re-epithelization occurs tion penetrates the eye to be absorbed by the retina and
within 36–72 hours and long-term sequelae are rare.58 rarely causes clinically apparent photochemical or thermal
This is the classical ‘arc eye’. It may occur in the welder damage. This may be permanent and sight-threatening.
who is actually producing the harmful emissions. It is often It has been reported that the prescription anti-psychotic
said to occur more commonly in neighbouring welders, medication fluphenazine may render workers particularly
other workers and in onlookers who are in the UV radia- susceptible to retinal photic damage.71
tion area, but are not wearing appropriate eye protection. Early diagnosis of the maculopathy may be difficult
A recent report showed that whereas 85 per cent of cases because it can be masked in the first few days by ‘arc eye’.
received their overexposure from welding, only 3.8 per Multifocal electroretinography (ERG)73 and automatic
cent were professional welders with the remainder other perimetry have been shown to be useful tools for the detec-
occupations with occasional use of welding.59 tion and quantification of the functional defects.66 In most
Typically, arc eye is characterized by increasingly cases, retinal injuries heal spontaneously without loss of
intense eye pain, photophobia, a feeling of grittiness, excess vision, but severe burns of the macula may lead to perma-
lacrimation and reduced visual acuity beginning some nent complete or partial loss of central vision. They need to
4–12 hours after the exposure, by which time the damaged be seen by an ophthalmologist without delay.
Adverse health effects of employment as a welder 431
After a controlled study of a group of welders,68 it was catch sparks. This should be worn closed at the neck and be
concluded that the usual protective measures prescribed in of a size which allows all exposed skin to be covered, even
professional welding to guard against radiation from the when the wearer is stretching or squatting.32,33
arc are sufficient to prevent an occupational risk of macu- A broad-spectrum high factor, e.g. 50, sunscreen could
lopathy and that its occurrence seems to be rather the be a useful adjunct affording extra protection against UVA
result of a sequel of occupational accidents and neglect of and UVB in solar radiation should the welder be working
safety regulations. outside, but reliance should not be placed on such a prepa-
Ocular melanoma is the most common primary malig- ration to protect against the high intensity of UVC from
nancy of the eye. A rare disease, it usually develops in the arc welding as they are usually formulated to be effective
uveal tract, most commonly in the choroid which under- between the wavelengths of 297 to 400 nm – with UVC
lies the retina. Diagnosis tends to be late as it is quite liter- being those wavelengths below 270 nm.
ally ‘out of sight’. It tends to metastasize before diagnosis, Welders should also wear fire-resistant gauntlet gloves,
often to the liver, and this makes it a usually fatal disease. a helmet or handheld shield and suitable footwear. The
The first large case–control study seeking occupational headgear should be chosen to give protection from direct
links with melanoma found no persuasive evidence in their and reflected UV80 and incorporate a filter selected to
data or the scientific literature to link this neoplasm with counter the expected emissions. The welding helmet filter
welding – or any other occupation.47 At about the same may be ‘passive’ (constantly dark), in which case the
time, a large and more focused case–control study for helmet or shield will have to be lifted repeatedly to allow
intraocular melanoma found a significantly increased risk the worker to see the workpiece, or ‘auto-darkening’ with a
for occupations with welding exposure.74 This view found light or other sensor to trigger lenses to automatically
some support from a study in France where the investiga- darken to the correct level of protection. Footwear must
tors considered that they had demonstrated an elevated have insulating rubber soles which will not melt if hot spat-
risk of ocular melanoma in welders, increasing with job ter or metal splashes are stood upon. The uppers must also
duration, and suggested that exposure to ultraviolet light be impervious to these hot materials. Ankle boots with
was the likely causal agent.75 A study in Australia found anti-crush toecaps are advised for all processes. Shoes with
the risk of choroid and ciliary melanomas increased protective toecaps may be adequate for use with TIG.
with increasing duration of welding exposure, although the Appropriate hearing protection should be added when
trend was not significant overall.76 A meta-analysis soon working in a noise hazard area. Other additional protec-
followed showing that there was evidence implicating tion may be needed in particular situations, e.g. a flame-
welding as a possible risk factor for ocular melanoma.77 retardant hood, cape with sleeves, chaps and leggings, bib
The most recent and largest case–control study covering and waist apron, and spats. Comfortable clothing and
nine European countries found an excess risk for welders equipment is more likely to be used, so modern lighter-
in only one, France.78 weight materials should be used whenever possible, pro-
Accounts of contact lenses adhering to the cornea fol- vided these give adequate protection.
lowing exposure to UV and IR radiation from welding Because much time at risk is spent with the welding hel-
circulate periodically. None has been substantiated and met raised or shield discarded, welders should also wear pro-
there is no evidence to support the contention that welders tective goggles or eyewear to guard against non-radiation
should not wear contact lenses. Welders may do so, pro- hazards and arc radiation from neighbouring workers.
vided they observe the normal rules for their care and Prevention of arc eye requires more than eyewear alone
limitation on wear. and should follow the full gambit of risk assessment and
control from elimination or substitution of the process
HEARING through to improved personal protection. For example,
MIG produces more UV than MMA and TIG. UV radia-
The high sound pressure levels which can be found as tion also varies within the same process and with the metal
background in some welding shops and are emitted by being welded. Factors which increase UV emission such as
some welding and cutting processes may cause noise- arc energy, arc duration, electrical current and using argon
induced hearing loss.79 That injury may be seriously as the shielding gas offer an opportunity to reduce the risks
disabling to a welder as they use their hearing to detect by process modification. Welders working on aluminium,
changes in the sound of the welding arc which reflect what and those in their vicinity, are at the greatest risk of heavy
is going on at the weld. exposure to UV radiation and need the greatest protection,
including from reflected rays.
PROTECTION OF SKIN, EYES AND HEARING Those in the vicinity of, but not involved in, the welding
processes, and this includes passers-by in the street, should
Care must be taken to protect the skin, eyes and hearing of be protected from emitted radiation by containing it
arc welders and those working with them. Those within within the work area by strategically placed screens or cur-
2–3 metres of the arc should wear spark-, fire- and UV- tains. These should absorb the radiation rather than reflect
proof protective clothing, without cuffs or pockets that it back at the welder and those working with him/her.
432 Welding
connections in supply pipes. Argon is heavier than air so measuring urinary cadmium concentration and seeking
tends to collect in low areas displacing oxygen-bearing air. evidence of renal damage.
Inhaling such a gas mixture, which contains little or no
oxygen, can cause rapid loss of consciousness. A classic sce-
nario is the welder welding with a gas-shielded process in a Pneumonitis and adult respiratory distress
confined space with inadequate ventilation and, as he syndrome
bends down, e.g. to retrieve a dropped object, his head
enters the deadly concentration of argon, he loses con- Rarely, freshly formed oxides of metals, notably zinc or
sciousness, he falls into the gas – and asphyxiates. A Safe cadmium, produced by welding on coated or plated
System of Work devised before the welding task is begun metal107,109,110 or using allied processes, such as flame
with inert gases in confined spaces, and followed during cutting,111,112 brazing with cadmium-containing solder113
the work, should avert the risk of such tragedies. Workers or metal spraying with an arc process,114 cause chemical
should not enter an atmosphere that contains less than pneumonitis or adult respiratory distress syndrome. These
18 per cent oxygen. conditions may have a fatal outcome due to respiratory
Foolish measures to counter the perceived risks of failure. Survivors may be left with persistent pulmonary
asphyxia by ‘freshening the air’ in hot ill-ventilated spaces function abnormalities.107 In the initial stages, these condi-
with oxygen provided as a fuel gas have led to ferocious tions may mimic metal fume fever. Sufficient investigation
fires with loss of life in the ‘oxygen-enriched’ workplace. to allow an accurate differential diagnosis to be made is
There is merit in reducing the risk of undetected accumu- essential. It is better to err well on the side of caution,
lation of oxygen supplied as a fuel gas or of inert shield should there be any doubt.
gas by odorizing them.22
Lobar pneumonia
NASAL SEPTUM PERFORATION
This is a rarely reported finding in welders. Once trauma, National statistics of occupational mortality for England
diseases and other conditions that cause this lesion have and Wales over two,115 then three,116 decades suggested
been excluded then, provided the welders have been weld- that welders have an excess risk of dying from pneumonia
ing stainless steel or other chromium-containing alloys, attributable to exposure to metal fumes – and that this was
the perforation may be due to chronic exposure to low not pneumonitis, but rather an excess of pneumococcal
concentrations of hexavalent chromium from the fume and unspecified pneumonia. There was no excess in men
directly or carried from the process by the contaminated over retirement age adding weight to the conclusion that
hand.95,96 this was a work-related effect. It was suggested that metal
components of welding fume, or possibly ozone or oxides
of nitrogen, might reversibly increase the susceptibility of
Metal fume fever the lung to pneumonic infection116 and, after case–control
studies, that this may be attributable specifically to ferrous,
Metal fume fever97–103 is one of the most common acute and possibly other metal, fumes.117
harmful effects of exposure to welding fume. It is usually Animal studies first showed that pre-exposure to fumes
an unpleasant, but short-lived, self-limiting flu-like toxic from MMA welding of stainless steel might result in sup-
illness beginning some hours after welding has ceased. pression in immune response and an increase in suscepti-
It may mimic other more serious diseases104 and has been bility to infection118 and more recently have demonstrated
associated with development of symptoms of welding- that short exposure to these fumes caused significant lung
related asthma105 and other serious long-lasting health damage and suppressed lung defence mechanisms to bac-
consequences.106 It may well be that other effects remain to terial infections.119 Investigations on experienced welders,
be identified, particularly in those who have had repeated fresh from exposure at the workplace where they had
attacks. Metal fume fever and other ‘inhalation fevers’ are received a high iron challenge from welding, found a ‘note-
discussed in more detail under Inhalation fevers, p. 436. worthy’ absence of an inflammatory response.120 The con-
Great care must be taken to consider a diagnosis of pneu- clusion was drawn that chronic exposure to metal fume
monitis during the initial assessment and observation.107,108 blunts responsiveness to inhaled particulate matter by an
Lest they actually have as-yet undeveloped and undetected as-yet-undefined mechanism.
chemical pneumonitis – which can progress to serious and
even fatal consequences – before sending them home to
recover, it is essential to warn workers thought to have metal Chronic obstructive pulmonary disease
fume fever to seek further medical assistance without delay if
they develop worsening respiratory symptoms. Be especially It might be expected from the nature of the mixture
cautious when cadmium is or may be involved. If this is the of fumes and gases arising from welding processes that,
case, initial and monitoring investigations should include given sufficient time and concentration of exposure, the
434 Welding
detect any evidence of pulmonary fibrosis in the study emissions from welding processes to at least the nationally
group of 64 aluminium welders.134 The welders had a defined occupation limits.
higher prevalence of chronic bronchitis than their controls
and it is reported that these respiratory symptoms were
related to ozone concentrations. ADVERSE EFFECTS ON REPRODUCTION
The necessity and design of such health surveillance of pain and difficulty breathing and/or breathlessness – the
welders should be determined after a formal risk assess- latter ringing alarm bells.
ment has been completed. Surveillance should be under- Diagnosis depends largely on pinpointing the cause
taken by appropriately trained healthcare workers.158 by way of an appropriately focused and analysed occupa-
Other personnel may be used for monitoring specific tional and environmental history – and excluding more
aspects or possible effects. Personal records must be kept. serious illness. Physical examination of the chest may be
These should allow easy analysis of group health. A basic unremarkable or reveal rales and rhonchi. Pulmonary
scheme would start with a baseline assessment for each function is commonly unaffected. Although there is likely
worker, initially before they started work, with the pro- to be an inflammatory lung infiltrate of polymorphonu-
gramme being rolled out to encompass all welders and oth- clear leukocytes, the chest radiograph should be clear.
ers identified by the risk assessment. This would include an There is a peripheral blood leukocytosis.
occupational history and record of current work circum- Management of the uncomplicated case of inhalation
stances (place, process, exposures, protection, etc.); com- fever is conservative and supportive. It is usual for the dis-
pletion of a standardized, previously validated, respiratory order to resolve within two to three days. Of course, the
questionnaire enquiring about work-related upper and best management is by prevention – seeking to anticipate
lower respiratory symptoms including pre-existing sensiti- and control the exposure before cases result, and protect-
zation to substances they might be exposed to in their ing others who may be at risk of exposure to the damaging
(new) job; and standardized assessment of lung function pollutant by investigating occupational and environmental
(peak expiratory flow and/or FEV1 and FVC). There sites from which cases arose.
should then be periodic review at intervals determined by Inhalation fevers may closely mimic or, by their similari-
the risk assessment and the health of the individual worker ties, mask another lung disorder which may be progressive,
and an annual formal expert review of absence said to be potentially fatal and result from exposure to pollutants which
due to ill health or injury. The workers should be given arise in similar circumstances. It is vital to differentiate
information, advice and education about the risk, how it specifically between inhalation fever and much more serious
should be controlled, recognizing and reporting symp- conditions. The principal differential diagnosis relevant to
toms, and stopping smoking tobacco. To this may be inhalation fever includes acute lung injury, infection, hyper-
added an interview on return from absence and special sensitivity pneumonitis and other immunologic responses.
tests, such as audiometry and biological monitoring, as An alternative diagnosis is likely if improvement does
indicated by the risk assessment. not begin early in the course of the illness and is not com-
pleted within two to five days, if at any stage respiratory
function is compromised, and/or if infiltrates or other
INHALATION FEVERS changes are apparent on the chest radiograph. While in
inhalation fever occasionally there may be transient acute
Inhalation fevers are related to many occupations other impairment with reduced lung volume and transfer factor
than welding, but are discussed here because the most and rarely an asthma-like response, these features should
common is metal fume fever – and welding is the activity be treated with special suspicion.
most frequently associated with that disorder. Before sending those thought to have an inhalation fever
The term ‘inhalation fever’ collectively describes a group home to recover, it is prudent to consider these alternative
of acute, non-allergic, usually benign and, importantly, diagnoses – and record that this process has been completed
self-limiting flu-like illnesses, some with colourful names, and why the decision has been made. Be especially cautious
which may follow shortly after exposure to any one of a when cadmium is or may be involved. If this is the case, the
disparate range of inhalable occupational and environ- patient should be kept under observation and initial and
mental pollutants. The attack rate is usually higher in those monitoring investigations should include measuring uri-
with the highest exposure. Unlike allergic response disor- nary cadmium concentration and seeking evidence of renal
ders, there is no discrimination between those with and damage. If the patient is sent or left at home, it is essential to
without previous exposure. Putative pollutants may be warn them to seek further medical assistance without delay
grouped, in order of overall population incidence, as metal if they develop worsening respiratory symptoms. If recovery
fumes; pyrolysis products of polymers, principally polyte- does not occur as expected, the diagnosis must be reviewed
trafluoroethylene; and bioaerosols. Each of these groups is and the possibility of pneumonitis reconsidered.
considered separately below. The pathogenesis of inhalation fever has yet to be
There is often a latent period between exposure and the elucidated. The symptoms cannot be engendered by
onset of clinical features of an inhalation fever, so the ingestion or intravenous injection of the causative agent,
worker may have left the workplace when the illness first only by inhalation. It is, however, apparent that the lung is
becomes apparent. Features may include undulating low- not only the sole entry portal and principal target organ,
grade – but sometimes high – fever, chills and difficulty but also the source of whatever substance or substances the
keeping warm, shivering, muscle aches and joint pains, inhaled pollutant stimulates to initiate the typical adverse
headache, malaise and nausea – even vomiting, thirst, chest pulmonary and systemic clinically apparent responses.
Inhalation fevers 437
Research indicates the likelihood of pro-inflammatory (see under Polymer fever). If the decision is made to send
cytokines playing a pivotal role. them home, it is essential to warn them to seek further med-
ical assistance without delay if they develop worsening respi-
ratory symptoms. Be especially cautious when cadmium is,
Metal fume fever or may be, involved. If this is the case, on referral of the indi-
vidual to hospital, initial and monitoring investigations
Metal fume fever is one of the few ancient occupational should also include measuring urinary cadmium concentra-
diseases still encountered in modern industrial practice in tion and seeking evidence of renal damage.
developed countries. Caused by inhaling freshly formed For completeness, it should be noted that inhalation of
fumes, and perhaps very finely divided dusts, of some zinc chloride, as distinct from zinc oxide, while not precip-
metal oxides, most commonly zinc oxide, it is the most fre- itating an ‘inhalation fever’ can cause serious lung injury.
quently encountered of the inhalation fevers and rejoices Exposures can occur through the use of zinc chloride-
in a wide range of names including ‘Monday morning containing smoke bombs in military or police training
fever’, ‘Monday ague’ and ‘welder’s shakes’. Sometimes, exercises. It is important not to confuse the effects of these
quite moderate concentrations of the pollutant can pro- two different exposures.
voke an attack, especially if the exposure time is prolonged
over the work period. Clinical features typical of an inhala-
tion fever (see under Inhalation fever, p. 436) tend to begin Polymer fever
some hours after exposure began and often after work has
ceased. Symptoms include thirst, chills, muscle aches, First described in 1951, this fever has the general clinical
shivering and fever, headache and nausea. characteristics of an inhalation fever. It may occur within
If asked, the affected worker will often admit to welding eight hours or so of the inhalation of pyrolysis products of
or being in the vicinity of welding on zinc-containing mate- fluorocarbon polymers or copolymers, the most com-
rial, galvanized metal being most commonly involved, but monly reported being polytetrafluoroethylene (PTFE) or
the oxides of several other metals have been implicated. Teflon®), exposed to temperatures between 250/300 and
These include magnesium, copper, cadmium, chromium, 750°C. Under normal usage, Teflon is among the most
antimony and iron, but the evidence for these is sparse. inert non-toxic and non-inflammable substances, but if it
A worker with straightforward metal fume fever requires is heated in excess of 750–800°C, it will decompose to form
only conservative and supportive treatment while he recovers hydrogen fluoride, tetrafluoroethylene, hexafluoropropy-
over one to three days (five days at most). Rarely, he or she lene and octofluoroiso-butylene. Other common pyroly-
will develop pneumonitis when the concentration of fumes sis products include organic fluorides, carbonyl fluoride
has been unusually high or when the situation is complicated and perfluoropropane, depending upon the fluorocarbon
by specific acute metal toxic damage, e.g. due to cadmium. polymer and the temperature and humidity at which it
As previously mentioned, it is vital to seek to exclude this ini- is burnt.
tially and to advise the patient of this risk, how to recognize Outbreaks of polymer fever have been described in
that all is not well and to seek further medical aid promptly. workers in an aircraft repair shop and in factories mould-
Some welders believe that an attack of metal fume fever ing or extruding PTFE, welding on PTFE-coated metal,
early in the working week confers temporary immunity or testing electronic equipment, using mould release sprays
resistance. There is no scientific evidence for this view, and and shoe sprays containing fluoropolymers, and in the
it may be that the affected welder is more cautious about manufacture of synthetic fabrics, plastics and chemicals,
minimizing his exposure in the days following such an paint and rubber stamps.
unpleasant illness! Cigarettes rolled or smoked at the workplace and con-
In common with all inhalation fevers, the pathology of taminated with particles of polymer may be a source of
metal fume fever is poorly understood. It may mimic other the fever, pyrolysis products being inhaled with the smoke.
more serious diseases and has been associated with devel- A no-smoking rule should be enforced and employees
opment of symptoms of welding-related asthma and other instructed to wash their hands before rolling or smoking
serious long-lasting health consequences. It may well be cigarettes in permitted areas. Smoking immediately after
that other effects remain to be identified, particularly in using a waterproofing spray is thought to have caused an
those who have had repeated attacks. It has been concluded acute respiratory illness in a young man in Japan.160
in a prospective study that it could be a predictor for the Higher temperature breakdown of PTFE and related
development of respiratory symptoms, but not functional polymers produces highly irritant fumes that can cause
abnormalities, in welders.159 acute lung injury, rather than inhalation fever. Severe,
Treatment is conservative and supportive. Before send- acute non-cardiogenic pulmonary oedema has been
ing those thought to have metal fume fever home to recover, reported after such exposures, e.g. after overheating a
it is prudent to consider the diagnosis lest they actually have Teflon-coated cooking pan.161 This may have been the
as-yet-undeveloped and undetected chemical pneumonitis – situation in a reported case of a syndrome resembling
which can progress to serious and even fatal consequences polymer fever, but with chest radiographs consistent with
438 Welding
in Welding and Allied Processes, Copenhagen, Denmark, May 35. Fisher EW, Gardiner Q. Tympanic membrane injury in
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45
The semiconductor industry
SEMICONDUCTOR DEVICES
from a ‘seed’ – a small piece of pure silicon placed in the mask to the wafer. The exposed areas of photoresist become
molten silicon bath. The seed is gradually drawn up from softened by the ultraviolet light and are subsequently
the bath to form the ingot. washed away with a solvent. The areas of exposed silicon
The ingot is sliced into thin wafers by a diamond blade, dioxide are etched away with chemicals such as hydro-
ground smooth and chemically polished. These wafers are fluoric acid (wet etching) or plasma etching/reactive ion
the base for the manufacture of integrated circuits. Some etching (dry etching). The rest of the photoresist is then
companies list another step known as epitaxy, in which removed and the wafers are visually inspected for accuracy
another 0.5–20 micron-thin layer of ultrapure silicon is of image transfer before being transferred to the next step.
grown over the wafer to enhance subsequent processes and Doping or ion implantation is the next process, where
overall performance of the wafer. The techniques for epitaxy impurities (dopants) are introduced into the exposed areas
vary from chemical vapour deposition to the newer molecu- of the wafer to alter the electrical conductivity of the sili-
lar beam epitaxy. con. Arsenic, boron, antimony and phosphorus are some
commonly used dopants.
PRODUCTION OF MASKS The above steps are repeated many times to achieve
multiple differently patterned layers on the wafer.12,13
The required patterns for the integrated circuits are drawn Atoms of metal (usually aluminium or copper) are
on to chromium-plated quartz glass plates to form reticles deposited into windows created in the wafer, interconnect-
or stencil-like instruments. The chromium plating is ing the individual devices. This process is known as ‘metal-
removed by lasers or electron beams to form a negative lization’. Dielectric films (insulators) are also inserted to
image of the pattern. This plate will subsequently be used separate the components. The circuit is then coated with
as a mask or stencil in photolithography to imprint the another protective insulating layer (passivation).
patterns on to the silicon chips. Hundreds of microprocessors are created on one wafer.
Every wafer is inspected both macroscopically and with the
FABRICATION use of a microscope for scratches and defective patterns.
This is a key step in any semiconductor manufacturing, Every single microprocessor is also tested to ensure it is
and takes from 1.5 to more than 4 weeks to complete, all functioning properly. Defective chips are marked for auto-
within the highly controlled clean room environment. matic rejection.
The wafers are rinsed with deionized water and chemi- At the back end processing factory, a diamond saw cuts
cals (such as diluted hydrochloric/hydrofluoric acid) and the wafer, separating the individual microprocessors
then exposed to high temperature and oxygen concentra- (dicing). The chips are mounted on lead frames (‘lead’ as in
tion to induce thermal oxidation – the growth of a uni- ‘leader’, not the metal Pb) and connected to the frame by
formly thin insulating film of silicon dioxide on the surface. wire bonding. Either gold, aluminium or copper is used to
Next, the wafers are coated with photoresist – a light- connect the chip to the package. The chips are then inspected
sensitive polymer film which becomes soluble when again before being encapsulated in resin for protection.
exposed to ultraviolet light (Figure 45.3). The substances used in the manufacturing process are
In a process known as photolithography, ultraviolet light presented in Table 45.1. This is by no means an exhaustive
is passed through a patterned glass mask (a stencil) on to list, but serves to illustrate the large number of chemicals
the wafer. Thus the pattern is transferred from the glass involved.
Recent advances
Substance Use(s)
Semiconductors and metals Aluminium Integrated circuit metallization, conductor between components
Boron Dopant
Copper Lead frame component, metallization
Germanium Semiconductor substrate, often as compound or alloy
Gold Interconnecting wires between integrated circuit to lead frame
Silicon Semiconductor substrate
Silver In assembly, packaging
Acids Hydrofluoric acid Etching of silicon dioxide
Hydrochloric acid Etching
Sulphuric acid Stripping plastic and organic material
Nitric acid Etching, plastic package decapsulation
Phosphoric acid Removal of aluminium and silicon nitride
Chromic acid Cleaning and etching
Alkalis Ammonium hydroxide In etching processes
Potassium hydroxide As above
Sodium hydroxide As above
Amines and amides Trimethylamine Photoresist coating and stripping
Triethylamine
Dimethylacetamide
Organic solvents Acetone Solvents are mainly used for cleaning, rinsing and drying
Ethylene glycol
Isopropyl alcohol Ethylene glycol is used in etching
Methyl alcohol
Methyl ethyl ketone
Xylene
Oxidizers Hydrogen peroxide Cleaning and etching
Oxygen Thermal oxidation, plasma etching
Gases Arsine Source of arsenic for doping
Ammonia Source of nitrogen; wafer cleaning and polishing
Boron trifluoride Doping
Chlorine Etching
Diborane Doping agent and source of boron
Nitrogen trifluoride Cleaning of chemical vapour deposition reactors
Ozone Chemical vapour deposition, oxide growth, photoresist removal
Phosphine Source of phosphorus for doping
Silane
Tungsten hexafluoride
imagers.15 The use of dip-pen nanolithography in semicon- or health hazards. Two issues arise from this. First, multi-
ductor manufacture processes is also being explored for use ple concurrent chemical exposures from daily operations
in the fabrication of multilayered metal-semiconductor and maintenance work are likely to cause health issues that
nanostructures.16 are very different from those resulting from single chemi-
cal exposure. There are few data on this issue. Second, pos-
sible health effects of other chemicals which might be
HAZARDS IN SEMICONDUCTOR overlooked (such as byproducts from the reactions
MANUFACTURING between various process chemicals, as well as chemicals
used for maintenance and cleaning) need to be considered.
Chemical hazards Fortunately, most of these chemicals are used within
contained systems in the high-tech environment of semi-
Numerous chemicals are used in semiconductor wafer conductor factories, and thus typically exposure to employ-
fabrication, many of which present either safety, corrosion ees would be minimal. Many companies have sophisticated
448 The semiconductor industry
(such as x-rays) is used in ion-transfer processes and in automation reduces the physical strain on workers, they
quality-control inspection of wafers. Non-ionizing radia- are often still required to lift the wafer cassettes in and out
tion like ultraviolet light, infrared light or microwave is of the machines and monitor the running of multiple
used in photolithography to harden the photoresist layer machines. The Semiconductor Health Study indicated a
and to transfer the required patterns from the mask to the dose–response relationship between the numbers of hours
wafer. Shorter wavelength light or ‘extreme ultraviolet spent on fabrication work and distal upper extremity
light’ is used if even greater precision is required. pain.30 A study conducted in 2004 on 906 female semicon-
Some workers may be exposed to high noise levels, ductor workers from different factories in Malaysia found
although it is not usually considered to be a major issue that 80.5 per cent of the workers had experienced pain in
within semiconductor factories. Vertical laminar flow the past year in at least one part of the body, including
hoods and ceilings normally create a background noise the neck, shoulders, back, upper and lower limbs. The
level of about 75–78 dBA in clean rooms. Core building Malaysian factories studied dealt mostly with back end
areas which house the equipment for running the factory processing.31
operations (for example, air-conditioner compressors, Workers who are required to inspect the chips visually
chillers or boilers) are usually the noisiest areas of the with the use of microscopes at various stages of the manu-
factory – often at about 85 to 95 dBA. The main group of facturing process may be subject to visual fatigue and other
workers at risk of noise exposure here would be the main- ergonomic problems, such as prolonged or repeated neck
tenance personnel. However, the total duration of work in flexion. However, much of this work can and has been
the core building areas may not be sufficient to cause automated.
noise-induced hearing loss.25 Administrative and research and development staff may
The relative humidity level in clean rooms needs to be be subject to the ergonomic issues of office workers from
kept low to protect the components from corrosion. The prolonged work at the computer terminal.
levels are generally kept at or below 40–50 per cent relative
humidity. Low humidity has been linked to skin disorders,
such as physical irritant contact dermatitis.26,27 Relative Biological
humidity of less than 35–40 per cent can induce pruritus
and skin changes related to xerosis, especially in suscepti- Although biological hazards are not routinely encountered
ble individuals.28 Workers exposed to relative humidity of in semiconductor manufacturing work processes, the recy-
2.5 per cent in an ultradry clean room of a high-tech cling of air in clean rooms may aid the spread of commu-
device-developing laboratory had significantly higher nicable diseases, such as upper respiratory tract infections.
prevalence of skin complaints, such as itch, dryness, rash The risk cannot be overlooked, especially with the expe-
and pain.29 rience of the severe acute respiratory syndrome (SARS)
epidemic and concerns with influenza outbreaks and pan-
demics. During the 2003 SARS crisis in Singapore, a
Psychosocial worker in an electronics company was diagnosed to have
SARS. This resulted in a temporary shut down of the entire
Shift work is common in the semiconductor industry, as electronics line, as all 305 workers on the same shift as the
most factories run continuously. Rotating shifts are a well- infected worker had to be quarantined.32
documented source of psychosocial stress. Monotonous An outbreak of conjunctivitis in a microelectronics fac-
and repetitive work at a fast and unvarying pace also tory resulted in a temporary plant shut down after safety
contributes to psychosocial stress in the semiconductor glasses and routine hand-washing instructions failed to
industry. curb the spread of the infection. A total of 145 workers
This industry also has sizeable numbers of non- had been affected by that time, and the mode of disease
production workers. Sales and marketing staff are usually transmission was believed to have been via the sharing of
required to travel frequently, and are often under high microscopes among workers.33
stress levels due to intense competition between companies
to promote their products.
Research and development engineers in the semicon- HEALTH ISSUES IN THE SEMICONDUCTOR
ductor industry are also under pressure to design smaller INDUSTRY
and faster chips with wider capacities and applications,
within tight time lines. Cancer incidence
that prolonged night shift work increases the risk of breast The current data on cancer experience among workers
cancer in women.34 As previously mentioned, night shift is in the semiconductor industry is patchy and inconclusive.
common in the semiconductor industry, especially among Other studies are currently ongoing in an attempt to estab-
female line workers. lish more clearly the relationship between occupational
A study conducted in two major semiconductor com- exposures and cancer incidence.
panies in Taiwan found that the workers were exposed to
high levels of arsenic, as well as to gallium and indium. The
arsenic level in inhalable air for operators ranged from 5.26 Reproductive problems
to 106.12 g/m3. This was above the permissible exposure
limit set by the United States Occupational Safety and The association between semiconductor work and reproduc-
Health Administration (OSHA). The levels for gallium and tive disorders remains a controversy. The main reason for
indium were between 0.34 to 101.26 g/m3 and 0.14 to this is the inherent difficulty of obtaining sufficient sample
100.62 g/m3, respectively. Mirroring these results were sizes of pregnancy-related epidemiological studies. In a
the high metal levels in the urine of exposed workers, with United States retrospective cohort study, the spontaneous
a mean level of 39.35 g/L of urinary arsenic, 10.15 g/L of abortion rate of 904 female workers with eligible pregnancies
gallium and 6.98 g/L of indium. Cancer risk was calcu- was studied. The risk of spontaneous abortions was slightly
lated by the US EPA Carcinogen Assessment Group’s mul- higher in fabrication-area workers (adjusted risk ratio, 1.43)
tistage model to predict dose-specific cancer risk associated compared with non-fabrication workers. Further analysis of
with inhalation of inorganic arsenic. The workers were specific work exposures showed a dose–response association
found to have a cancer risk higher than the allowable risk- of spontaneous abortions with photoresist and developer
based US EPA’s acceptable risk limits.4 solvents. The main constituent of these would be ethylene-
In a large retrospective study of over 100 000 staff work- based glycol ethers.39 A later study that was conducted by the
ing in IBM factories, the mortality rates and causes of death Health and Safety Executive in the United Kingdom found
were noted. No conclusive evidence of causal association no evidence of increased risk of spontaneous abortion among
between work and increased mortality from any form of female workers in the British semiconductor industry who
cancer was found, although there was some suggestion of were also exposed to ethylene glycol ethers. This was a nested
increased rates of central nervous system cancer in process case–control study that was based on a retrospective cohort
equipment maintenance workers in one plant and prostate of 2203 females. From these, 116 were selected as cases or
cancer among facilities/plant engineers and laboratory controls. The adjusted odds ratio for spontaneous abortions
workers in another plant.35 was 0.58 for fabrication workers.40
A retrospective study was conducted based on 4388 In Taiwan, 292 pregnancies from 173 female workers
workers in a Scottish semiconductor manufacturing from a wafer manufacturing company were studied and the
facility. Fifty per cent of the male workers and 79 per cent relative fecundability as reflected by the fecundability ratio
of the female workers were recorded to have been involved (FR) was calculated. The waiting time to pregnancy was
in fabrication work in this factory. Although total cancer prolonged (FR, 0.77) among female workers in the photo-
registrations were close to expected levels for both males lithography area compared to non-fabrication workers. In
and females, the authors identified increased rates of can- addition, among fabrication workers, those who worked in
cers of the respiratory tract, stomach and breast in females, areas where they were potentially exposed to ethylene glycol
and mortality from cancer of the brain among males. In ethers had longer time to pregnancy (FR, 0.59) compared to
females, the standardized registration ratio (SRR) for those who were not likely to be exposed.23
malignant neoplasms of the trachea, bronchus and lung Another Taiwan-based study of 606 female workers
was 273, for malignant neoplasms of the stomach the SRR compared workers in the fabrication areas with those
was 438 and the SRR for breast malignancies was 134. (The working in non-fabrication areas. Fabrication workers had
SRRs were calculated for specific types of malignant neo- a 2.0 odds ratio for long menstrual cycles (defined as cycles
plasms and adjusted for deprivation using Carstairs index.) that were more than 35 days long) compared to workers in
For males, the main finding was a standardized mortality non-fabrication areas. Fabrication workers in the photo-
ratio (unadjusted) of brain cancer of 401.36 lithography areas, who were likely to be exposed to ethyl-
Another retrospective study published in 2005 that ene glycols and isopropyl alcohol had the highest odds of
focused on 1807 workers from a semiconductor factory in long cycles (5.0, compared to non-fabrication workers).22
the United Kingdom found significantly elevated stan- However, this is in contrast to other earlier studies that
dardized registration ratios for malignant melanoma (SRR, found shortened menstrual cycles in relation to ethylene
217) and rectal cancer (SRR, 199) in males and females, glycol ether exposure, underscoring the need for further,
and pancreatic cancer (SRR, 226) in females. Detailed more conclusive evidence.41
work history was not analysed in this study.37 A case– Male fertility was also assessed during the Semiconductor
control study conducted in 1993 found increased risk of Health Study in 1990 to 1991, comparing men working in
cutaneous melanoma (odds ratio, 2.03) in individuals who fabrication rooms with those in non-fabrication areas. Men
had previously worked in the electronics industry.38 who worked in the furnace, thin-film or ion implantation
Conclusion 451
areas of fabrication sections were more likely to report pre- exposed to intermediate products formed by a variety of
vious difficulty conceiving (defined as needing one or more chemicals during the plasma etching process. These inter-
years to achieve conception; relative risk, 1.79) and to have mediate products were not individually identifiable, but
lower past fertility (adjusted fertility ratio, 0.79). However, had the potential to cause genotoxicity.44
contraception data were not collected in this study.42
Genotoxicity
CONCLUSION
In a 1991 German study, the genotoxic effect of exposure to
chemicals including boron compounds was assessed by The semiconductor industry is large and rapidly growing
looking for the formation of micronuclei in lymphocytes. in many aspects. The industry employs millions of people
Twenty workers who had contact with open plasma etching worldwide, and is an important driving force behind the
processes had significantly higher mean frequency of economies of many countries. Cutting-edge research and
micronuclei (9.2 micronuclei per 500 billion cells) than a development is a cornerstone of the industry, designing
control group of 21 workers who were not exposed (5.7 smaller yet faster and more complex products within a short
micronuclei per 500 billion cells). This was despite the fact time and finding more efficient ways to manufacture them.
that environmental levels of boron trifluoride and boron The work processes within the industry are diverse,
trichloride were under the detection rate. Urinary boron varying from country to country, and depending on con-
fluoride measurements also did not indicate significant sumer demand. Many hazardous chemicals and agents are
chemical exposure. A second survey was conducted in 2004, used, albeit within enclosed and automated processes. The
12 years after the implementation of numerous control potential for exposure still exists, and occupational health
measures. The levels of micronuclei in exposed workers had personnel need to be aware of this and understand the
decreased to 3.2 per 500 billion cells. The conclusion drawn unique work experiences of each set of workers under
by the authors was that the workers could have been their care.
452 The semiconductor industry
26. Koh D. Occupational dermatitis – What’s new? Electronics 37. Nichols L, Sorahan T. Cancer incidence and cancer mortality
industry. Clinics in Dermatology. 1997; 15: 579–86. in a cohort of UK semiconductor workers, 1970–2002.
27. Morris-Jones R, Robertson SJ, Ross JS et al. Contact Occupational Medicine (Lond). 2005; 55: 625–30.
dermatitis and allergy: Dermatitis caused by physical 38. Nelemans PJ, Scholte R, Groenendal H et al. Melanoma and
irritants. British Journal of Dermatology. 2002; 147: occupation: Results of a case-control study in The
270–5. Netherlands. British Journal of Industrial Medicine. 1993;
28. White IR, Rycroft RJ. Low humidity occupational dermatosis – 50: 642–6.
an epidemic. Contact Dermatitis. 1982; 8: 287–90. 39. Schenker MB, Gold EB, Beaumont JJ, Eskenazi B. Association
29. Sato M, Fukayo S, Yano E. Adverse environmental health of spontaneous abortion and other reproductive effects with
effects of ultra-low relative humidity indoor air. Journal of work in the semiconductor industry. American Journal of
Occupational Health. 2003; 45: 133–6. Industrial Medicine. 1995; 28: 639–59.
30. Pocekay D, McCurdy SA, Samuels SJ, Hammond SK. A cross- 40. Elliott RC, Jones JR, McElvenny DM. Spontaneous abortion
sectional study of musculoskeletal symptoms and risk in the British semiconductor industry: An HSE investigation.
factors in semiconductor workers. American Journal of American Journal of Industrial Medicine. 1999; 36: 557–72.
Industrial Medicine. 1995; 28: 861–71. 41. Cordier S, Multigner L. Occupational exposure to glycol
31. Chee HL, Rampal KG. Work-related musculoskeletal ethers and ovarian function: Commentary on the paper by
problems among women workers in the semiconductor Hsieh et al. Occupational and Environmental Medicine.
industry in Peninsular Malaysia. International Journal of 2005; 62: 507–8.
Occupational and Environmental Health. 2004; 10: 63–71. 42. Samuels SJ, McCurdy SA, Pocekay D, Hammond SK. Fertility
32. Prime Minister Lee Hsien Loong’s 2003 May day rally history of currently employed male semiconductor workers.
speech. Cited September 25, 2007. Available from: American Journal of Industrial Medicine. 1995; 28: 873–82.
http://app.mfa.gov.sg/pr/read_content.asp? View,1881. 43. Luo JCJ, Hsieh LL, Chang MJW, Hsu KH. Decreased white
33. Doyle L, Gallagher K, Heath BS, Patterson WB. An outbreak blood cell counts in semiconductor manufacturing workers
of infectious conjunctivitis spread by microscopes. Journal in Taiwan. Occupational and Environmental Medicine. 2002;
of Occupational Medicine. 1989; 31: 758–62. 59: 44–8.
34. Schernhammer ES, Kroenke CH, Laden F, Hankinson SE. 44. Winker R, Roos G, Pilger A, Rüdiger HW. Effect of
Night work and risk of breast cancer. Epidemiology. 2006; occupational safety measures on micronucleus frequency in
17: 108–11. semiconductor workers. International Archives of
35. Beall C, Bender TJ, Cheng H. Mortality among Occupational and Environmental Health. 2008; 81: 423–8.
semiconductor and storage device-manufacturing workers. 45. Dooley EE. EHPnet – Silicon Valley toxics coalition.
Journal of Occupational and Environmental Medicine. 2005; Environmental Health Perspectives. 2002; 110: 4.
47: 996–1014. 46. Suzuki Y, Watanabe I, Oshida T et al. Accumulation of trace
36. McElvenny DM, Darnton AJ, Hodgson JT et al. Investigation of elements used in semiconductor industry in Formosan
cancer incidence and mortality at a Scottish semiconductor squirrel, as a bio-indicator of their exposure, living in
manufacturing facility. Occupational Medicine (Lond). 2003; Taiwan. Chemosphere. 2007; 68: 1270–9.
53: 419–30. 47. Perry TS. Cleaning up. IEEE Spectrum. 1993; February: 20–6.
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PART THREE
Noise
1 Wavelength
Pressure
Velocity
Distance
Figure 46.1 A sound wave generated by alternating
areas of condensation and rarefaction of the medium
through which it travels. Reproduced with permission
Displacement from Ref. 1.
microphone and is expressed in newtons per square metre Using this decibel scale for measuring sound pres-
(N/m2) (pascals (Pa)). The auditory system, however, is sure levels (SPL), the reference sound pressure is
sensitive to a vast range of sound pressures: 2 105 N/m2 2 105 N/m2 (20 μPa), 0 dB SPL corresponds to the
for the threshold of hearing to around 1 108 N/m2 next threshold of hearing and 130 dB SPL the threshold of pain.
to a jet aircraft at take off. With such a wide numerical Audiometrically, however, the reference pressure is fre-
range, the impracticalities of quantification and calcula- quency dependent as the threshold sensitivity of the
tion are obvious. Second, the ear does not respond in a human ear is frequency dependent (see Sound wave fre-
linear manner to linear changes in sound pressure. In fact, quency, p. 461). These reference pressures have been
the ear perceives changes in intensity more closely to loga- defined by the International Standards Organization (ISO
rithmic changes in power or sound pressure. The use of the 389: 1991)2 and are the same as those of the British
logarithm of the ratio of the measured pressure to a refer- Standards Institution (BS 2497: 1992).3 Using these refer-
ence pressure or ratios of intensity or indeed power over- ence pressures, an audiometric sound level of say 30 dB is
comes the two difficulties cited. written as 30 dB hearing level (HL) and if this corresponds
Logarithms to the base 10 of these ratios are termed to the threshold of hearing of an individual’s ear then the
‘bels’ after Alexander Graham Bell, as the scale was first threshold is said to be 30 dB HTL (hearing threshold level)
used in telephony. In practical terms, one-tenth of a bel or for that ear.4 Conveniently, the minimum detectable
decibel (dB) is more convenient for the sizes of the num- change in intensity is 1 dB SPL and an increase of 10 dB
bers involved. Thus: SPL gives a subjective sensation of doubling the loudness
of a sound, although the intensity of the sound has
Sound pressure level in bels (SPL) increased ten-fold.
log RMS measured sound pressure Table 46.1 shows the internationally agreed
100 reference levels for the calculation of decibels of sound
Reference soun nd pressure
with respect to power, sound pressure and intensity.
Sound pressure level in dB (SPL) One other relevant consideration relating to sound
10 log10 RMS measured sound pressure intensity is the effect of distance from the sound source.
For a theoretical point sound source in a homoge-
Reeference sound pressure
nous medium, the intensity of the sound is a function
of the power per unit area. Since the area increases as
To express the sound intensity which varies as the the square of the distance from the source, the intensity
square of the pressure: is inversely proportional to the square of the distance
from the source of the sound. In reality, the presence of
Intensity (dB SPL) physical obstructions with the resultant reflection,
20 log10 RMS measured sound pressure diffraction and absorption effects tend to confound this
Reference sound pressure relationship.
Anatomy and physiology of the ear 461
Table 46.1 The internationally agreed reference levels for the Noise
calculation of decibels of sound.
Scale Abbreviation Reference quantity The preceding discussion examines sound in terms of its
physical properties. Physically, noise is a complex sound
whose characteristics are not easily amenable to analysis
Power level PWL 1.0 pW (10–12 W) and has little or no measurable periodicity. Physiologically,
Intensity level IL 10–12 W/m2 noise is an uninformative signal with variable intensity.
Pressure level SPL 20 μPa (20 106 N/m2) Psychologically, any sound that is unpleasant, noxious or
unwanted is noise irrespective of its waveform.5 Noise may
be classified as continuous (steady-state or fluctuant) or
intermittent (impulse or impact). Impulse noise, such as
Sound wave frequency the noise generated from a gun blast, is characterized by
its short duration and shock-front pressure waveform.
The number of complete cycles of a sound wave per second Impact noise, such as in pile driving, is characterized by lit-
is its frequency, expressed in hertz (Hz). At sea level with tle or no shock-front, but considerable reverberant sound.
an ambient temperature of 15°C, the velocity of sound The characteristics of intermittent noise merge into those
waves is 330 m/s in free air. Therefore, a sound wave with a of continuous noise if the former is repeated very rapidly.
frequency of 330 Hz has a wavelength of 1 m and as the fre-
quency increases, the wavelength decreases. The human
ear in a child or young adult has a frequency perception ANATOMY AND PHYSIOLOGY OF THE EAR
range between 20 Hz and 20 kHz. The high frequency sen-
sitivity diminishes with age such that few adults over the Structurally and functionally, the human ear is divided
age of 30 years can detect sound with a frequency greater into three parts, namely the outer ear, middle ear and inner
than 16 kHz. ear (Figure 46.2). Together with the central connections of
The frequency of a sound broadly correlates with the the ear in the brain, each part plays a role in the process of
subjective sensation of pitch. The threshold of human hearing and therefore merits further consideration.
hearing, however, varies with frequency with maximum
sensitivity between 2 and 3 kHz which encompasses the
The outer ear
important speech sounds. This necessitates the use of a
correction factor or weighting when measuring sound
The outer or external ear comprises the auricle (pinna) and
pressure levels or hearing thresholds and several such
the external auditory canal. Collectively, these serve to
weighting curves exist. Of these, the ‘A’ weighting scale
modify incoming sound in two specific ways. First, the
(low and extremely high frequencies weighted less heavily)
combination of the auricle behaving as an ear trumpet,
is commonly utilized as it best correlates with measured
concentrating sound from a large area to the smaller area
and perceived sound. A statement of a sound pressure level
of the external canal and the natural resonances of the
should also, therefore, indicate the weighting utilized by
external canal itself serves to increase the sound pressure
means of a suffix, e.g. 30 dB (A) SPL.
level at the tympanic membrane by about 10 dB over a fre-
As with sound intensities, the ear subjectively responds
quency range of 2–7 kHz.1 Second, based on the above
to incremental changes in frequency ratios, rather than in a
phenomenon and the fact that a proportion of incident
linear manner. Hence, doubling the frequency of a tone
sound is reflected off the head in a manner dependent on
produces a perceived change in pitch of one octave.
the direction of the sound, the outer ear provides some
Conventionally therefore, tuning fork tests and audiomet-
information about sound localization.
ric testing is undertaken in multiples of 256 Hz (middle C)
though among musicians, middle C corresponds to a fre-
quency of 261 Hz. Everyday sounds, of course, are more The middle ear
complex than those of a simple sinusoid (sine wave).
Analysis of a complex waveform by breaking it down into Embryologically derived from the outer and middle ear,
its component sinusoids (Fourier analysis) allows the rela- the tympanic membrane (drumhead) constitutes the
tive contribution of the components to be determined by major component of the lateral or outer wall of the tym-
frequency and relative amplitude. Periodic sounds (wave- panic cavity. Within this cavity are the three ossicles,
forms in the same time interval) are shown to have compo- the malleus, incus and stapes, linking the drumhead to the
nents that are multiples of the fundamental frequency or inner ear. The middle ear cavity communicates with the
harmonics. These in part give a musical note, for example, pharynx at the back of the nose by the Eustachian tube and
its particular timbre. For non-periodic sounds, such as the with the mastoid air cells by the aditus ad antrum. The fun-
spoken voice, analysis shows that rather than discrete com- damental function of the middle ear is mechanically to
ponent frequencies, there is a continuous range of frequen- couple acoustic energy to the cochlea. To do this effec-
cies or spectrum. tively, the middle ear has to match the impedance of air to
462 Sound, noise and the ear
Scala
vestibuli
Stria
vascularis
Basilar
membrane
Spiral
organ
The sensory cells of the organ of Corti are arranged in one specialized transducer. From the sensory cells, afferent nerve
inner row and three to five outer rows. Microfilaments fibres pass together as the cochlear nerve to the brainstem
(stereocilia) from the sensory cell surface have given rise to and ultimately to the auditory cortex of the brain.
the descriptive term sensory hair cells (Figure 46.6). This The incident mechanical energy at the oval window sets
represents the interface where mechanical energy is con- up a series of waves in the perilymph of the scala vestibuli
verted to electrical energy: the organ of Corti is thus a which in turn distort the membranes of the cochlear duct.
464 Sound, noise and the ear
arrival of the Industrial Age, however, that led to a more as the level and nature of noise exposure, its duration and
widespread recognition of the deleterious effects of intense hearing conservation programmes, adjunctive factors are
or prolonged noise on hearing: Roosa and Holt in the also recognized. Variations in individual susceptibility
United States of America, Bezold in Germany and Barr in are now considered to be multifactorial, but nonetheless a
Great Britain.5 real entity.25 The evidence for differences in susceptibility
The work of Thomas Barr merits further consideration. between men and women or between dark- and fair-
He undertook field studies comparing the hearing in 100 skinned individuals is conflicting.25,26 Indeed, a recent
boilermakers, 100 ironmoulders and 100 postmen.19 He pilot study showed that in view of their ambivalence to
wrote, ‘It is familiarly known that boilermakers and others their disorder, women with noise-induced hearing loss are
who work in very noisy surroundings are extremely liable less likely to be reported than men in studies examining
to dullness of hearing. In Glasgow, we would have little dif- noise-induced hearing loss.27 With regard to children, a
ficulty in finding hundreds whose sense of hearing has thus study that screened over 14 000 Swedish schoolchildren
been damaged, by the noisy character of their work. We found a greater than 20-dB, 4-kHz dip in 2.3 per cent with
have therefore in our city ample materials at hand for nearly two-thirds having an identifiable noise exposure
investigation on this subject’. Barr found that 75 per cent factor, such as firearms and crackers.28 Perhaps the greatest
of the boilermakers had difficulty in hearing at church or at area of concern, however, is that while developed countries
a public meeting compared with 12 per cent of the iron- are slowly bringing noise under control, the developing
moulders and 8 per cent of the postmen. Four years later, nations are witnessing an ever increasing level of urban and
in 1890, the pathology of noise-induced hearing loss was industrial noise.
described by Habermann. Partial loss of the organ of Corti
with destruction of the hair cells, particularly in the basal
Effects of sound stimulation and
turn was noted.20
hazardous noise
Following the introduction of audiometry, Fowler in
1929 observed the characteristic 4-kHz dips and the first
ADAPTATION (PERSTIMULATORY FATIGUE)
systematic audiometric studies were reported in 1939 by
Bunch and by Larsen.21–23 The technological advance- This is an immediate physiological phenomenon that
ments seen after the Second World War were paralleled by occurs when a sound is presented to the ear. For sound
ever-increasing noise levels in the workplace. While loss of pressure levels up to 80 dB, the greatest elevation in thresh-
earnings due to hearing loss caused by acute trauma at old occurs at the same frequency of the stimulating tone.
work was compensatable from the early part of the last There follows an exponential recovery which occurs within
century, it is only in the last 35 years that the legislative 1 second. Electrophysiological animal studies have shown
bodies of developed countries have recognized occupa- that adaptation correlates with a reduction in auditory
tional noise-induced hearing loss, put into place mecha- nerve action potentials.29 For higher stimulating sound
nisms to confer responsibility on the manufacturing intensities, true temporary threshold shift sets in though
industries and compensate those individuals deemed to the intensity of stimulation required varies from individual
suffer this disorder. to individual and depends on the frequency of the stimu-
lating tone.
Figure 46.9 Pure tone audiogram, right ear, showing the typical
4-kHz notch after excessive noise exposure.
Figure 46.8 Most of the range of human audibility categorized
with respect to the risk of hearing loss and injury. Reproduced
with permission from Ref. 5.
(c)
(a)
(d)
Figure 46.12 Change in the stereocilia of guinea pigs. (a) Exposure to 110 dB for 30 min;
half an hour after exposure, there is swelling of the cuticular plate (arrow) 2800.
(b) Exposure to 110 dB for 30 min; 80 days after exposure, 9.5 mm from the round window.
The inner and outer hair cells appear normal as was the hearing threshold (1900).
(c) Exposure to 120 dB for 150 min; half an hour after exposure, there is total loss of the
stereocilia on the outer hair cells (4300). (d) Exposure to 120 dB for 150 min; 80 days after
exposure, 9 mm from the round window. The surface is devoid of both sterocilia and hair cells,
correlating with a 30–35 dB permanent threshold shift at 2 and 4 kHz. Reproduced with
(b) permission from Ref. 5.
The effects of middle ear disease Hinchcliffe has discussed the reasons for such disparate
findings and reduces them to two main factors.4 First, the
The widely held belief that a conductive hearing loss due two most common causes of adult conductive hearing loss,
to middle ear disease serves to protect the inner ear from otosclerosis and chronic inflammatory middle ear disease,
hazardous noise is open to debate as the literature is some- may be associated with sensorineural hearing loss – the
what conflicting. Alberti and colleagues46 studied a group former as cochlear otosclerosis and the latter as a compli-
of individuals with otosclerosis and presumed occupa- cation of the disease. The pathological status of the middle
tional noise-induced hearing loss and found that there was ear in terms of extent, nature and activity also has a bearing
no difference in the bone conduction threshold curves on inner ear function. Ossicular fixation (whether due to
between the operated and non-operated ear, even though otosclerosis or otherwise) alters the middle ear resonance
the individuals concerned had continued to work in a and may give rise to the 2-kHz Carhart notch in the bone
noisy environment after their surgery. Similarly, Simpson conduction threshold. Second, the temporal relationship
and O’Reilly47 could not demonstrate a protective effect on between the onset of the conductive hearing loss and noise
the inner ear in a worker with chronic middle ear disease. exposure is also relevant. Clearly, the interaction between
In contrast, a study by McShane and colleagues48 examined middle ear disease and inner ear function is complex
the hearing in workers with unilateral unoperated otoscle- and one cannot draw the intuitive conclusion that a
rosis and demonstrated a small protective effect (around conductive hearing loss acts as some form of hearing
4 dB) in the affected ear at 4 kHz. protective device.
Acoustic trauma and blast trauma 469
Diagnosis of occupational noise-induced with systemic symptoms and these should be enquired
hearing loss about. The examination of the ear, nose and throat must be
complete. Much information regarding the health of the
The process of establishing a diagnosis of occupational external and middle ear can be gleaned from pneumatic
noise-induced hearing loss should be no different from the otoscopy and if the clinician is in any doubt, microscopic
process of reaching a diagnosis when faced with any other examination of the ear should be readily available, if noth-
clinical problem. The fundamental principles of taking ing else, to clear the external meatus of wax that precludes
a comprehensive and pertinent history, conducting a a view of the drumhead. Aside from the audiometric eval-
thorough examination and undertaking appropriate inves- uation, additional investigations are dictated by the clinical
tigations are just as applicable. However, certain factors assessment and include haematological, serological and
cloud this process and as a result the diagnosis is usually relevant immunological laboratory tests, in addition to
circumstantial.5 When faced with an individual with hear- radiology if indicated. Evaluation of the historical, clinical
ing loss and a history of occupational noise exposure, the and investigative evidence usually allows, if present, the
clinician has to make a decision as to whether the former is causal relationship between hearing loss and noise expo-
a result of the latter. This gives rise to the first problem. sure to be established, but as there is currently no single
Of the 12 per cent of adults found to have a sensorineural clinical or investigative feature unique to noise-induced
hearing loss in the Medical Research Council study cited hearing loss, the diagnosis remains one of clinical proba-
earlier under Epidemiology (p. 465), only 40 per cent of bility and audiometric compatibility.
these could be accounted for by the effects of age or noise
exposure.24 Some of the remaining 60 per cent were no
doubt due to the myriad of less common or rare disorders ACOUSTIC TRAUMA AND BLAST TRAUMA
(in population terms) that cause a sensorineural hearing
loss, but a significant proportion were idiopathic (cause The preceding discussion has primarily focused on the
unknown). If the diagnostic process is one of exclusion of auditory effects of prolonged exposure to hazardous noise.
known causes, Williams has put forward the argument that The term ‘acoustic trauma’ describes permanent hearing
attempting to exclude that which cannot be identified loss following brief exposure to a single very loud noise.
defies logic.49 However, appraisal by an appropriately This encompasses, for example, the effects of gunfire, but
trained clinician remains paramount as there is no reason also includes the effects of industrial impulse noise associ-
why the prevalence of other otological disorders should ated with drop forging and riveting. Gunfire noise in par-
be any different in the individual with noise-induced deaf- ticular has the potential to be extremely hazardous. Peak
ness than in the general population. The Department of sound pressure levels of 160 dB for hand-held weapons to
Health and Social Security publication ‘Occupational deaf- 190 dB for field weapons have been recorded and therefore
ness’ states that apart from the characteristic audiometric permanent injury to the inner ear may arise from the first
changes, there are no signs or symptoms specific to noise- exposure.5 It is worth bearing in mind that with rifle fire,
induced deafness.50 This implies that the diagnosis of the forward ear (left ear in a right-handed individual) is
occupational noise-induced hearing loss is an audiometric closer to the muzzle, thereby bearing the greater brunt of
one. However, the characteristic audiogram with its the acoustic trauma than the opposite ear and this is often
4-kHz notch is not a pathognomonic feature of noise- discernible audiometrically. Second, occupational noise-
induced deafness. The notch may lie between 3 and 6 kHz induced hearing loss and acoustic trauma may coexist in
(a notch centred at 6 kHz is considered to be an artefact), the same individual.
and with progression over time the notch may widen and Blast trauma (otic blast injury) is due to the effects of
be lost as the thresholds at the higher frequencies rise. an explosion such as a bomb blast, but may also be a com-
Additionally, noise exposure is not the only cause of a ponent of the acoustic trauma from large calibre weapons.
4-kHz notch and the hearing loss may not necessarily be It is characterized by a greater severity and may be associ-
symmetrical.51 ated with damage to the tympanic membrane and the
The history must include not only audiovestibular middle ear structures.52 The shock wave from an explosion
symptoms, but also details of previous and intercurrent is longer than that of hazardous sound and consists of a
focal and systemic disorders that may affect the ear. This short (5 ms) positive pressure followed by a longer (30 ms)
includes the administration of potentially ototoxic drugs. negative pressure. Clinically, there may be a history of
The history of noise exposure, whether occupational, mili- bleeding from the ear following the injury and examina-
tary or otherwise, can be difficult to construct in temporal tion shows a spectrum of tympanic membrane changes
terms as individuals may have difficulty in recalling past ranging from hyperaemia to frank perforation of the pars
events and employment accurately. Increasing recognition tensa which may be ‘clean’ or ragged. It is the initial posi-
of non-syndromic familial sensorineural deafness and the tive pressure that perforates the drumhead and the subse-
familial nature of otosclerosis and some cases of Menière’s quent negative pressure that leads to the characteristic
disease underline the importance of obtaining a good everted edges of the perforation. The resultant deafness
family history. Autoimmune deafness may be associated and tinnitus is immediate and severe but recovery, though
470 Sound, noise and the ear
incomplete for the higher pitches, is not uncommon did not sign up to the final document because of problems
and over three-quarters of drumhead perforations heal on the definition of disability and on agreeing the scale of
spontaneously.52 degrees of disablement. The group considered every aspect
of hearing disability and its assessment. They stated that,
‘hearing disability assessment should provide an accurate
ASSESSMENT OF HEARING DISABILITY quantitative assessment of the actual disability suffered by
the individual, appropriately weighted according to the
Impairment, disability and handicap way he uses his auditory facilities and the extent to which
difficulties in hearing interfere with those activities’. The
These consequences of disease are differentiated by the authors recognize, however, that the ideal is impossible to
World Health Organization.53 attain in an easily measurable, scientific and quantitative
way because of the subjective nature of disability and
● Impairment relates to a loss or impairment of the handicap and the great variability between individuals.
structure or function of an organ or system. Within the They identify instead a typical (median or average) indi-
auditory system, there are a number of impairments of vidual and relate disability to that notional individual, and
function which could be measured. The one which has they recognize that such a concept may underestimate
most relevance for the assessment of hearing disability disability in some people and overestimate it in others.
is the alteration in the pure tone threshold. They also recognize the need to identify an audiometric
● Disability is an index of the loss of an individual’s surrogate (i.e. a measure of impairment) as a means of
functional performance as a consequence of impairment quantifying disability.
to the diseased organ or system. It thus represents a Several studies have been carried out to identify the
disturbance at the level of the individual. Hearing audiometric descriptors which best relate with disability
disability has been described as the restriction or lack of including those by Atherley and Noble,57 Lutman et al.58
ability to perceive everyday sounds in the manner that is and the Medical Research Council’s National Study of
considered normal for healthy young people.54 Hearing from the early 1980s. These studies, by and large,
● Handicap encompasses the disadvantages experienced looked at the different patterns on pure tone audiometry
by an individual as a consequence of impairments and which were the best predictors of disability. It was con-
disabilities. It thus reflects interactions between the cluded that the three-frequency average of 1, 2 and 3 kHz
individual and his social and working environment. was the best predictor. Errors were introduced by the
Hearing handicap is the disadvantage to an individual inclusion of 0.5 Hz and 6 kHz.59 It may seem strange that
resulting from a hearing impairment or disability, that 4 kHz is excluded from this formula, when one considers
limits or prevents the fulfilment of a role that is normal that this is the frequency most likely to be affected by occu-
for that individual. Disability and handicap are thus pational noise; however, the notches at 4 kHz may be
seen to be multifaceted. A given degree of hearing narrow but quite deep, so that there is a danger of obtain-
impairment could represent a much greater handicap ing an inflated average hearing threshold measurement
for a professional musician than for a sculptor for which does not truly reflect the degree of disability.
example. The complex picture of disability and handi- Furthermore, it is convenient not to include 4 kHz in the
cap that may result from occupational noise-induced estimate because of the difficulty in obtaining accurate
hearing loss has been painted by Hetu et al.55 bone conduction thresholds above 3 kHz. Finally, the
three-frequency average coincides with the UK statutory
In 1981, a working party of members of the British hearing loss criteria, even though the fence values of the
Association of Otolaryngologists (BAOL) and the British latter may be subject to some criticism.
Society of Audiologists (BSA) was set up to address the
problem of assessment of hearing disability for the purpose
of compensation. Up to then, there was a plethora of con- Fence values
flicting recommendations, from a number of different
sources. The results of the working party’s deliberations The low fence is that notional point on the continuum
were published in the so-called ‘Blue Book’ of 1983.56 of elevation of the hearing threshold level at which dis-
Because of some misgivings about its conclusions, a new ability is deemed to commence. It has never been satisfac-
group called the Inter-Society Working Group was estab- torily identified, and indeed cannot be seen as anything
lished in 1986 with a wider membership including repre- other than an artifice erected for administrative conven-
sentatives of the British Association of Audiological ience, with little relevance to the individual case. Robinson
Physicians (BAAP), and the British Association of et al.60 identified a 30 dB hearing threshold level averaged
Audiological Scientists (BAAS). over 1, 2 and 3 kHz as the threshold of disability, and this
The results of this group’s efforts are published in coincides with British Standard BS 5330 (1976).61 A low
‘Guidelines for medicolegal practice’, although the BAAP fence as high as 50 dB HL (1, 2, 3 kHz average) is employed
Hearing conservation programmes 471
Table 46.2 Noise level and duration of exposure are combined to give 'noise exposure points'.
according to the equal energy principle. A peak sound pres- ACTIVE NOISE CONTROL
sure level of 140 dB is defined as the ‘peak action level’. At this
level, the use of ear protectors is mandatory. The principles of active noise control (or active cancella-
It is clearly the responsibility of employers to ensure tion) have been known for 60 years, but the techniques
that all measurement equipment is accurately and regu- remain rather experimental. One sound is cancelled by the
larly calibrated. introduction of a second sound of equal amplitude but
Employers in the music and entertainment industries reversed phase, derived electronically from the first sound.
were given an additional period of two years to comply There are considerable difficulties in designing and com-
with the 2005 regulations, while continuing to comply with missioning these systems, but the technique does show
the 1989 regulations.67,68 considerable promise in the reduction of low frequency
noise where control by passive measures can be difficult.
Commercial interest in the technique is increasing.
Noise reduction
EAR PROTECTION
This can be helped, inter alia, by the enclosure of noisy
machines, the use of mufflers, damping, silencers and anti- Ear protection provides a system of attenuation of the
vibration mountings, the treatment of reflective surfaces incoming sound and thus minimizes the sound arriving at
with absorbing materials, the limitation of the use of noisy the tympanic membrane. Various types of protector are
equipment to times when it is actually required, and the available.71,72
distancing of workers from the areas of maximum noise.
There are many more suggestions for the reduction of Ear muffs
noise in the workplace in the consultative document Ear muffs (Figure 46.13) fit over the ears and are sealed to
‘Prevention of damage to hearing from noise at work’ pub- the side of the head by soft cushion seals filled with soft
lished by the Health and Safety Commission in 1987.69 The plastic foam or a viscous fluid. They are usually held in
publication ‘Sound solutions’ published by the Health and position by means of a headband, but may alternatively be
Safety Executive in 1995 provides employers with many attached to a safely helmet. Attenuation may be ‘frequency
examples of techniques to reduce noise in the workplace.70 selective’, protecting some frequencies more than others,
Hearing conservation programmes 473
Table 46.3 Total daily exposure points converted to a daily more resistance at high pressures. ‘Active devices’ incorpo-
personal exposure. Note the first and second action levels at rate electronic circuitry which limits the transmission of
80 and 85 dB. sound at high intensity, and are of value when workers are
exposed to short bursts of high intensity sound or impulsive
Total exposure points Noise exposure LEP,d (dB)
sounds. ‘Anti-noise’ devices incorporate circuitry which
cancels out incident noise especially at low frequency. These
3200 100 devices are still largely experimental. Many of the newer
1600 97 muffs incorporate an inbuilt communication system.
1000 95 While ear muffs usually provide an effective level of atten-
800 94 uation, their value may be limited by any effect which
630 93 decreases the efficiency of the seal, for example spectacle
500 92 frames, goggles, beards and long hair, or scarves worn under
400 91 the muffs. Furthermore, wear and tear may decrease the effi-
320 90 ciency of the seal. It should also be emphasized that if protec-
250 89 tion is removed in noisy areas, even for a short period, the
200 88 amount of protection will be severely limited. For example
160 87 if a protector with an ‘assumed protection’ of 20 dB(A) is
130 86 removed for 30 minutes per day the actual reduction in noise
100 85 dose received by the wearer will be only 12 dB(A).
80 84
65 83
Ear plugs
50 82 Ear plugs are generally thought to be less efficient attenua-
40 81 tors of sound than muffs, but have the advantage that they
32 80 are easy to use. They may be disposable or permanent.
25 79 Disposable plugs are made of a compressible or conforma-
20 78 ble material and fit most people without individual fitting.
16 77 They are readily available commercially, but have a finite
Reproduced with permission from Ref. 67.
‘life expectancy’ after which their effectiveness decreases.
Permanent and custom moulded plugs have a longer sur-
vival, and are usually comfortable if made by an experi-
enced technician. One of the main disadvantages of plugs
is the increased propensity to otitis externa, although this
too can occur with muffs.
Dual protection with the use of both muffs and ear
plugs may be indicated when the noise levels are extremely
high (e.g. when LEPd exceeds about 115 dBA).
Noise-excluding helmets
At extremely high levels of sound (e.g. in tunnelling), the
protection offered by muffs and plugs, either alone or in
combination, may be insufficient. Sound may still reach
the ears through the nose, mouth, eye sockets and the skull
itself. Experimental studies with helmets to protect the
whole skull are at present under evaluation.
The attenuation provided by a protector should comply
with British Standard BS 510866 (ISO 4869),73,74 and the
basic design features should comply with BS 6344.75 The
‘assumed protection’ of a device will vary with frequency
and most will attenuate higher frequency sound better
than low frequency sound. The ‘assumed protected level’
Figure 46.13 Sound-excluding ear muffs. of noise exposure is obtained by subtracting the assumed
protection of the device at each octave band frequency
from the sound pressure level at each frequency.
particularly the higher frequencies rather than the speech Conversion should then be made to A-weighted sound
frequencies. ‘Amplitude selective’ devices are designed to levels (dBA). All this sounds complicated. Attempts to sim-
provide attenuation that increases with sound level. Such a plify the rating of devices by using a ‘single number’ rating
device usually has a small hole which acts as a mechanical which does involve frequency analysis, tends to sacrifice
filter, allowing low sound pressures to pass but offering accuracy in the cause of simplicity. It is important that ear
474 Sound, noise and the ear
protection zones be identified within which use of ear fitting and appropriate ear protectors. The attitude that it
protectors are advisable or mandatory. is somehow ‘macho’ not to wear ear protectors must be
changed. Workers should recognize and report the first
symptoms of deafness, such as temporary threshold shift
Measurement of hearing: Audiometry in the and tinnitus. Warning signs should be attached to
workplace machines or displayed in all areas likely to cause workers to
receive a daily personal noise exposure of 90 dBA or a peak
Measurement of hearing using electroacoustic devices is gen- pressure of 200 Pa (the levels at which the use of ear protec-
erally referred to as audiometry. Pure tone audiometry tors becomes mandatory). Oral explanations, individual
records the threshold for each ear separately, at a series of test counselling and lectures, as well as leaflets, posters, films
frequencies at octave intervals covering the frequencies most and videos may all be employed. Education must be
commonly encountered in everyday life and in particular in extended to management so that their responsibilities are
everyday speech. The frequencies usually tested in the clinical clearly defined, and managers exposed to potentially dam-
setting are 125 Hz, 250 Hz, 500 Hz, 1 kHz, 2 kHz, 4 kHz and aging sound levels must themselves be seen to be conscien-
8 kHz. In the medicolegal and compensation fields, 3 kHz is tious in their observation of safety measures.
always tested, and 6 kHz may be. Air and bone conduction
thresholds are measured to establish the presence or absence LEGAL DUTIES OF EMPLOYERS
of a conductive component of the overall hearing loss.
Bone conduction thresholds are inaccurate above 3 kHz. The general obligations of employers in the United
Audiometry may be carried out by an audiometrician Kingdom to safeguard the health of their employees (includ-
(manual audiometry) or using a self-recording audiometer. ing hearing) were laid out under the Health and Safety at
Hinchcliffe has pointed out the possible shortcomings Work Act of 1974. Specific requirements with regard to
of manual audiometry.4 Two different audiometricians hearing were covered by the Noise at Work Regulations
might obtain significantly different thresholds at 3 and 1989, which came into force on January 1, 1990. These have
4 kHz on the same patient on the same day. Test–retest been superseded by the Control of Noise at Work
reliability on the same patient by the same audiometrician Regulations 2005 which were enforceable from April 6,
may yield differences of up to 25 dB. Self-recording 2006. The reader is referred to ‘Noise at work: Guidance for
audiometry eliminates the variability due to the audio- employers on the Control of Noise at Work Regulations
metrician. By utilizing a combination of continuous and 2005’ published by the Health and Safety Executive for full
pulsed test tones, there is a greater likelihood of picking up details,67 but certain salient points can be highlighted here.
a spurious (non-organic) hearing loss. A permanent record
is obtained without the need for transcription with the risk ● Regulation 5.1. An employer who carries out work which
of errors. Sweep frequencies are used because this tech- is liable to expose any employees to noise at or above a
nique may pick up notches at intervals not tested on fixed lower exposure action value shall make a suitable and
frequency audiometry. Thus, the preferred technique is sufficient assessment of the risk from that noise to the
sweep frequency self-recording audiometry using both health and safety of those employees, and the risk
continuous and pulsed tones. An audiometry programme assessment shall identify the measures which need to be
ideally should consist of a pre-employment test followed taken to meet the requirements of these regulations.
by tests at regular intervals. Important side issues include ● Regulation 6.1. The employer shall ensure that risk from
the calibration of equipment, the acoustic requirements of exposure of his employees to noise is either eliminated at
the test area, instructions to the subject and the format and source or, where this is not reasonably practicable,
storing of records. These are all covered in detail in the reduced to a low a level as is reasonably practicable.
discussion document, ‘Audiometry in industry’, published ● Regulation 7.1. Without prejudice to the provisions of
by the Health and Safety Executive.76 Electric response regulation 6, an employer who carries out work which
audiometry is an objective method of assessing hearing is likely to expose any employees to noise at or above
thresholds which has no place in the routine evaluation of the lower exposure action value shall make personal
hearing loss, but has a role in the medicolegal arena. It is hearing protectors available on request to any employee
described under Electric response audiometry (evoked who is so exposed.
response audiometry, p. 477). ● Regulation 7.2. Without prejudice to the provisions of
regulation 6, if an employer is unable by other means to
reduce the levels of noise to which an employee is likely
Information and education to be exposed to below an upper exposure action value,
he shall provide personal hearing protectors to any
Workers at risk of occupational noise-induced hearing loss employee who is so exposed.
need to be educated about the harmful effects of noise and ● Regulation 8.1. The employer shall (a) ensure so far
the importance of hearing conservation measures. They as is practicable that anything provided by him in
need to understand the importance of wearing properly compliance with his duties under these regulations to or
Management 475
for the benefit of an employee, other than personal feature of cochlear deafness, may limit the usefulness of
hearing protectors provided under regulation 7.1 is amplification. This is characterized by a disproportionately
fully and properly used, and (b) ensure that anything great increase in the perceived loudness for a small increase
provided by him in compliance with his duties under in the actual sound pressure level. This is a major factor in
these regulations is maintained in an efficient state, in causing distortion with hearing aids, and may limit their use.
efficient working order and in good repair. The ability to discriminate speech in the presence of back-
● Regulation 9.1. If the risk assessment indicates that ground noise is lost early in the evolution of sensorineural
there is a risk to the health of his employees who are, or deafness, and involves factors other than a simple elevation
liable to be, exposed to noise, the employer shall ensure of the hearing threshold. It is not restored by fitting a hear-
that such employees are placed under suitable health ing aid and it remains one of the main grievances of hearing
surveillance, which shall include testing of hearing. aid users who find it impossible to converse with one indi-
● Regulation 9.2. The employer shall ensure that a health vidual in a noisy environment, such as a bar, cocktail party,
record in respect of his employees who undergo health or if the television or a stereo system is on.
surveillance in accordance with paragraph 9.1 is made Despite these shortcomings it is, however, clear that
and maintained and that the record or a copy thereof is individuals with noise-induced hearing impairment can
kept in a suitable form. derive appreciable benefit from hearing aids provided that
careful attention is given to the type of aid and the design
In addition, the regulations define the responsibilities of and engineering of the ear mould.
the employer in the provision of ear protection zones, in Different hearing aids have different frequency
the maintenance and use of equipment and the provision responses. Some preferentially amplify the higher frequen-
of information, instruction and training to employees. cies and this would intuitively seem a sensible type of
The employees’ obligations under the regulations are also device for a subject with a high frequency hearing loss.
emphasized. The document also deals with the legal obliga- The prescription of an aid with a customized frequency
tions of designers, manufacturers, importers and suppliers response for an individual hearing loss is beguiling and has
of plant and machinery for use at work to provide noise commanded much attention in recent years. It is, never-
information and control the noise emission of machinery. theless, a much more challenging problem than the pre-
scription of spectacles for a simple refractive error, for
reasons mentioned earlier in this section. Different hearing
MANAGEMENT aids have different gain or amplification (i.e. some are
stronger than others), and again it is clearly important to
With the exception of the transient phenomenon of tem- have the appropriate aid for the severity of the deafness.
porary threshold shift, the hearing loss caused by noise Hearing aids, like car engines, have a point or a range at
exposure is permanent and is due to the loss of or damage which they function best. If one attempts to get more per-
to the organ of Corti and neuronal structures in the inner formance from an underpowered aid, there is a marked
ear. There is, as yet, no medical or surgical treatment that fall off in the efficiency of the device. It is better to get a
can reverse the damage to these structures. Management of stronger aid and have it working at its most efficient level.
occupational noise-induced hearing loss is therefore based Compression aids incorporating automatic gain control,
on prevention of further damage, suitable amplification attempt to overcome the problem of the loud sound which
with hearing aids, and the provision where indicated of exceeds the discomfort level of the listener.
other assistive devices. It is generally felt that the process of Systems which address the problems of understand-
injury to the inner ear ceases when the subject is removed ing speech in the presence of background noise have been
from, or protected from, his noisy working environment, developed and in the UK are at present only available in
but subjects should be warned of further possible damage the private health sector, where they cost considerably
from other sources, such as recreational noise exposure. over £1000.
These effects on the inner ear are, as has been previously The other factor of considerable importance is the
stated, most marked in the high frequencies commencing at design and fitting of the hearing aid mould. The aid must
4 kHz, but spreading downwards across the frequency range. fit comfortably in the ear, but must be secure enough to
The early effects, therefore, are most marked for the high prevent acoustic feedback problems – the whistling that
frequency components of speech, the consonants, the sibi- one often associates with hearing aids is usually the result
lants and fricatives. It is these elements which convey most of a poorly fitting mould or an underpowered aid with the
of the meaning in speech. Neuronal damage causes a further volume setting too high. The effect of occlusion of the ear
loss of speech discrimination which may not be correctable canal may be to cause otitis externa in susceptible individ-
by simple amplification. In addition, there are other psy- uals. Some wearers develop an allergic reaction in the skin
choacoustic deficits which may come into play and for of the meatus to the mould material. Hypoallergenic alter-
which hearing aids cannot compensate, such as impaired natives are available to overcome such problems.
frequency discrimination, frequency selectivity or temporal The physical properties of the mould have an effect on
acuity. Furthermore, the phenomenon of recruitment, a the acoustic output of the aid and modifications to the
476 Sound, noise and the ear
mould may influence the performance of the device. condition. Glutathione has been shown to limit noise-
Venting entails the creation of a second hole next to the induced hearing loss in the guinea pig both on auditory
existing sound tube. This has a considerable effect in evoked brainstem response audiometry and on histological
increasing the low frequency responses of the aid. It also studies of cochlear hair cell loss.78 Kopke et al.79 looked at
incidentally may decrease the tendency to otitis externa by three strategies for enhancing the cochlea’s intrinsic stress
decreasing the greenhouse effect within the ear canal. defences in a chinchilla model. Acetyl-L-carnitine is an
Funnelling of the outlet tube where the sound leaves the endogenous mitochondrial membrane compound that
mould may increase the high frequency response. Acoustic helps maintain mitochondrial function in the face of oxida-
filters can be introduced into the tube. These may alter the tive stress. Carbamathione is a glutamate antagonist.
shape of the frequency response curve. All of these facilities Glutathione levels are reduced in the noise damaged
are available in the United Kingdom on the standard ear cochlea. Kopke and co-workers administered acetyl-L-
level hearing aids. The National Health Service does not, at carmine, carbamathione and a glutathione repletion drug
present, provide small in-the-ear aids. D-methionine to three groups of chinchillas and demon-
In addition to hearing aids, there are other assistive strated protection from cochlear damage by showing signif-
devices or environmental aids that can be used with or icant reduction in hearing threshold elevation and
independent of conventional hearing aids70 including significant reduction in cochlear hair cell loss at post-
amplifying devices, alerting and alarm systems, telephone mortem examination. The same team80 demonstrated a
modifications and speech-to-text transcription. They are strong protective effect on the chinchilla model of the
not necessarily expensive and may provide significant antioxidants acetyl-L-carnitine (ALCAR) and N-L-acetyl cys-
personal benefit. They include induction loop systems, teine (NAC). Hight et al.81 administered a combination of
television listening aids, tactile and visual devices activated two antioxidants, glutathione monoethylester and R-PIA, to
by sound stimuli (door bells, fire alarms, alarm clocks, chinchillas subsequently exposed to impulse (145 dB SPL)
telephone). Inductive coupling between coils in the hand- or continuous (105 dB, 4 kHz) noise and demonstrated a
piece and the hearing aid greatly helps telephone conversa- significant protection from both. They also demonstrated
tion. Text telephones using a computer link, or a relay raised glutathione levels in the perilymph. Other workers
service via an operator may help the very deaf. Speech-to- have looked at the effect of magnesium administration on
text transcription, such as Palantype, is a major help at the susceptibility to damaging noise levels in the guinea pig82
public meetings, but is expensive and the system operators and found that there was a protective effect if the magne-
are relatively few. A simple overview of the devices avail- sium was administered immediately after noise exposure.
able is given by Martin.77 The magnitude of the effect lessened with the length of time
that elapsed from the noise exposure and the administration
of the drug. It seems that there may be a synergistic effect
Cochlear implantation between magnesium and free radical scavengers, such as
vitamins A, C and E in reducing noise trauma.83
The cochlear implant is an electric device inserted into the How these animal observations relate to the protection
inner ear of certain profoundly deaf individuals to take of the ear from noise in human beings in an industrial
the place of a severely damaged organ of Corti and convey environment is not yet clear, but they are a very encourag-
to the brain a processed sequence of electric stimuli which ing pointer to future developments in the field. Human tri-
the brain perceives as sound. Cochlear implants have als have not yet commenced, but the animal results would
now reached such a level of sophistication that the best suggest that they cannot be far off, assuming safety factors
implantees can converse almost effortlessly even over the have been addressed. Early clinical trials with the anti-
telephone. To ‘qualify’ for an implant, a subject must have oxidant N-acetylcysteine (NAC) are anticipated.84
a degree of deafness that cannot be aided with any conven- Another phenomenon to attract increasing interest is
tional hearing aid. Pure occupational-induced hearing loss that of ‘cochlear toughening’. A sound of sufficient mid-
very rarely if ever produces deafness of that degree of sever- intensity produces a temporary threshold shift (TTS) fol-
ity, and with the present selection criteria for implantation, lowing exposure. If the same exposure is repeated on a daily
cochlear implantation is not a treatment option for such basis the TTS gets progressively less compared with the orig-
individuals. There are indications, however, that selection inal shift. The cochlea has become conditioned by the so-
criteria may become less strict in the future. called toughening exposures.85 Again it is not yet clear if and
how this observation can be put to practical use in humans.
industrial deafness case has to be constantly aware of the by means of a transtympanic needle electrode. The poten-
possibility of exaggeration of a hearing loss. Experienced tials recorded are of very low voltage and are difficult to
clinicians and audiometricians may develop a finely honed differentiate from random background electrical activity.
sixth sense, based on the inappropriate or pantomimic They have to be extracted by the process of ‘time domain
behaviour of an individual subject. There may be a clear averaging’ of the responses to a series of stimuli, then
discrepancy between the perceived hearing of the subject in amplified for display on a visual display/computer unit
interview, and the volunteered thresholds on pure tone where they can be studied, manipulated and stored for
audiometry. Further discrepancies may exist between the future recall. The better the signal-to-noise ratio of the
pure tone thresholds and the score on speech audiometry. response the fewer stimulus repetitions will be required to
There may be test–retest unreliability on audiometry, and produce a reliable recording. Near field responses, such as
there may be a lack of agreement between pure tone ECochG, therefore, require fewer stimuli that far field
thresholds obtained with ascending and descending stimu- responses, such as the ABR. A greater number of stimuli
lus intensity. Sweep frequency audiometry may reveal a are needed to produce a response as the threshold is
pattern suggestive of non-organic hearing loss. Suspicion approached.
may be heightened if the threshold for the stapedial reflex Electric response audiometry is employed in the neuro-
(acoustic reflex) is found to be close to, or better than, the otological diagnosis of certain disease states. For example,
volunteered pure tone threshold. Sometimes, these contra- ECochG, yields typical patterns in Menière’s disease. The
dictions can be ironed out and the true threshold estab- ABR frequently demonstrates latency abnormalities in
lished by the employment of low cunning on the part of the tumours of the cerebellopontine angle or brainstem of
tester. Not infrequently, however, one may have to turn to which vestibular schwannoma is the most common exam-
electric response audiometry for verification. ple. The other main use for ERA is to help establish the true
hearing threshold when it is difficult to obtain reliable
thresholds using conventional techniques. In addition to
ELECTRIC RESPONSE AUDIOMETRY its role in the case of suspected non-organic hearing loss, it
(EVOKED RESPONSE AUDIOMETRY) is used to test very young children, or children or adults
with multiple handicaps who are unable to cooperate
Electric response audiometry (ERA) provides a method in the performance of standard hearing tests. The great
of objectively estimating the auditory thresholds, by the advantage of the technique is that the patient cannot influ-
recording of the electrical events which occur in the audi- ence the generation of the potentials.
tory pathways following the exposure of the ear to an There are, however, certain disadvantages with ERA,
acoustic stimulus. The stimuli used are either broadband some of which are common to all techniques, and some of
clicks containing a wide spectrum of frequencies, or more which are specific to the individual test. Subjectivity on
frequency-specific stimuli, such as filtered clicks or tone the part of the tester remains, in that it is not always easy,
bursts. A single such stimulus will give rise to electrical when tracing an ever-decreasing response to a stimulus of
potential changes in a series of neural structures from the decreasing intensity, to determine at exactly what point the
cochlea to the auditory cortex. These events have a charac- response disappears (the end point). Thus, the threshold
teristic form and latency depending upon which part of the estimation is not always as precise as one might wish. All
auditory pathway is being studied. ERA techniques tend to give more accurate information
The cochlea and eighth nerve give rise to near field about high frequency thresholds than about thresholds at
potentials of very short (or no) latency, such as the cochlear frequencies below 1 kHz. In the industrial deafness case,
microphonic (CM), the summating potential (SP) and the this is not always such a problem as in pure clinical work,
eighth nerve action potential (AP). The components of the because most of the desired information is in the higher
auditory brainstem response (ABR or BSER) have a latency frequencies anyway. One misconception about ERA needs
of up to 7–8 ms, and arise from structures in the lower to to be corrected. It is not a better test of hearing than con-
mid brainstem. The middle latency response (MLR) takes ventional hearing tests. The best estimate of hearing is a
origin higher in the brainstem and at higher subcortical standard pure tone audiogram carried out on a willing and
levels. The slow vertex response (SVR), recorded on corti- cooperative subject; ERA is used when that ability or will-
cal ERA (CERA) is thought to take origin from the highest ingness are absent. The preferred technique in the evalua-
levels in the auditory pathways and naturally has the tion of a subject suspected of exaggerated hearing loss is
longest latency (50–300 ms). CERA, but two other techniques (ABR and ECochG) are
Most of these responses are recorded through simple occasionally employed and will also be described.
disc electrodes located on the skin of the scalp and are
thus non-invasive. The exception is the recording of
cochlear potentials by the process of electrocochleography Auditory brainstem response
(ECochG, ECoG), which entails the siting of a recording
electrode deep in the ear canal on the surface of the ear The ABR comprises a series of five potentials (N1–N5)
drum, or sometimes from the medial wall of the middle ear which occur in the first 7–8 ms after acoustic stimulation.
478 Sound, noise and the ear
The generators of these potentials are still the subject of time-consuming because as the threshold is approached
debate, but have been suggested to be: many hundred stimuli may be required to produce a good
response, and in order to demonstrate reproducibility, the
● N1, cochlear nerve/nucleus; test may have to be repeated several times. The informa-
● N2, cochlear nucleus; tion it yields is greatest in the high frequencies, although as
● N3, superior olivary complex; stated above this may be less of a problem in the industrial
● N4, lateral lemniscus; deafness case.
● N5, inferior colliculus.
Of these, the largest component and the one most usu- Electrocochleography
ally employed in the estimation of hearing threshold is
N5 (Figure 46.14). Stimuli are presented initially at a The most important component of the ECochG is the
moderately high intensity, say 70 dB, and if an N5 eighth nerve action potential. The signal–noise ratio is
response is observed, the stimulus intensity is decreased much more favourable than with ABR, so large and reliable
stepwise. As threshold is approached, the latency of the responses can be obtained after very few stimuli, even at
N5 response increases and the amplitude decreases, until quite low stimulus intensities, at which the response again
it is no longer recordable. In a subject with normal hear- decreases in amplitude and increases in latency. Threshold
ing, the N5 response can usually be recorded down to estimation is usually more accurate than with ABR (prob-
stimulus intensities of 25–30 dB. The reason it cannot be ably to within 10–15 dB), but as with ABR the higher
recorded at lower intensities is largely due to the small frequency responses are more reliable than the low. The
voltage of the response and distance of the recording main disadvantage is the fact that the recording electrode
scalp electrodes from the generators in the brainstem. has to be sited in the ear. An ear canal electrode may be
Most workers in this field would state that if responses are satisfactory, but the best responses are obtained from a
recordable down to 25–30 dB, the hearing is likely to be transtympanic electrode which has to be passed through
close to normal. the tympanic membrane to lie on the cochlea. This is per-
The advantages of ABR are that in the hands of an formed under topical anaesthesia using EMLA® (eutectic
experienced audiologist, it produces clear and repro- mixture of local anaesthetics) cream, and the tiny perfora-
ducible waveforms, is non-invasive and carries no risk to tion created nearly always heals rapidly. Nevertheless, the
the subject. It is also unaffected by general anaesthesia, invasiveness of the technique means that it is not the tech-
which is of value in the assessment of the young and unco- nique of first choice, although there are occasions when its
operative. There are certain disadvantages. It is quite reliability might be desirable.
Figure 46.14 Auditory brainstem response. The stimulus intensity is marked on wave N5. Note that the latency of the N5 response
increases and the amplitude decreases as the hearing threshold is approached.
Electric response audiometry (evoked response audiometry) 479
Cortical evoked response audiometry threshold and the SVR threshold agree to within 10 dB, the
behaviour threshold is confirmed. If the pure tone thresh-
CERA records a response, the slow vertex response (SVR) old exceeds the SVR threshold by 15 dB or more, exagger-
which occurs between 50 and 250 ms after the delivery of ated hearing loss should be strongly suspected.
sound to the ear (Figure 46.15). This long latency suggests
that it is not a primary response. It is best recorded from
scalp electrodes placed at the vertex.86 The precise genera- Otoacoustic emissions: the possible use as a
tors of the response are unclear, but it is known to arise predictor of noise-induced hearing loss
from cortical structures. It thus has the theoretical advan-
tage over ABR and ECochG of getting closer to recording Otoacoustic emissions (OAE) are sounds that are pro-
‘hearing’ than the other techniques which record events duced by the outer hair cells of normal ears. They are an
lower in the auditory pathway. The components of the epiphenomenon that seem to be the result of non-linearities
waveform are two vertex positive waves and one vertex in the way that the cochlea functions in reponse to acoustic
negative wave (the P1, N1, P2 complex). stimulation. Spontaneous otoacoustic emissions (SOAEs)
Although frontal lesions do not affect the waveform, occur in about 40–50 per cent of normally hearing people.
extensive temporoparietal lesions may eliminate the N1 Transient otoacoustic emissions (TOAE) are the most
component, but not P1. The SVR is influenced by general useful clinically. These are low intensity sounds that are
anaesthesia and to a lesser extent by sedation, so it is of produced instantaneously by the cochlea in response to
little value in children. It is also influenced by EEG alpha an acoustic stimulus. They are transmitted through the
activity, so is best tested with the subject’s eyes open. In middle ear to the outer ear canal where they can be
about 5 per cent of subjects, high levels of alpha activity recorded using a small hand-held probe that delivers the
make it very difficult to obtain an accurate SVR threshold.87 test tone and records the response. TOAEs usually arise
In such a situation, ABR or ECochG might be preferred. in frequency bands where hearing is normal so are fairly
The test is carried out with the subject reclining, perhaps frequency-specific responses. They are very sensitive to
reading. The scalp electrodes are non-invasive. In most changes in the cochlear hair cells. The technique is the
cases, an audiogram at 500 Hz, 1 kHz, 2 kHz and 3 kHz can basis for the newborn hearing screening programme. In
be obtained in an hour. In adults, it is usually accurate to general, the presence of a TOAE is a good indication that
about 10 dB of the true threshold88 and furthermore its fre- the hearing in that frequency band is within 30 dB HL of
quency specificity is better than that of ABR and ECochG. It normal. The question arises as to whether the test or a
is the technique of choice for verification of the pure tone modification of it could have any value in detecting
audiogram in cases of suspected NOHL. If the pure tone preclinical changes in the hearing in individuals exposed to
Figure 46.15 Cortical evoked response audiometry showing the slow vertex response. The vertex negative N1 wave is marked with the
stimulus intensity.
480 Sound, noise and the ear
noise – in other words, does the OAE change before the of health, high sound intensities are required to evoke
pure tone audiogram (PTA) threshold. A study from the this response. In various otological disorders, however,
Naval Submarine Medical Research Laboratory in lesser sound levels may have a similar effect in certain
Connecticut looked at just this issue in 338 volunteers individuals. Firm evidence that occupational noise-
working on aircraft carriers. While the average amplitude induced vertigo is a real entity is lacking. However, three
of the TOAE decreased significantly, the PTA average did more recent studies merit consideration. Shupak and
not change. The best predictor was the TOAE amplitude in colleagues97 demonstrated a reduced vestibulo-ocular
the 4-kHz half octave frequency band. The authors con- reflex and reduced caloric response of the inner ear in 22
clude that OAE may have predictive value for noise- individuals with occupational noise-induced hearing loss
induced hearing loss risk.89 Another study looked at 135 compared with 21 controls, although all those evaluated
ship engine room workers and concluded that, although were subclinical in terms of vestibular complaints. Manabe
TOAE changes after one year showed a high sensitivity (88 and colleagues98 evaluated 36 patients with occupational
per cent) in predicting noise-induced hearing loss (NIHL) noise-induced hearing loss cases, half of whom com-
after two years of exposure, the test was a very poor screen- plained of vertigo. In the symptomatic group, a reduced
ing tool because of the very low specificity (33 per cent) caloric response was also shown, as were electrophysio-
with an unacceptable false-positive rate.90 The case for logical changes suggestive of endolymphatic hydrops.
adoption of the technique for screening workers with noise Histopathological evidence of endolymphatic hydrops in
exposure has not therefore yet been made, but it does seem two patients with late onset vertigo and noise-induced
likely that the test can be improved in the future using hearing loss was provided by Kemink and Graham.99 Thus,
mathematical modifications of the technique, such as there is some evidence to substantiate a link between
Volterra Slice techniques.91 acoustic trauma and delayed endolymphatic hydrops, but
further investigation into this aspect of hazardous noise
exposure is required.
OCCUPATIONAL NOISE-INDUCED TINNITUS
Many individuals have experience of the tinnitus that occurs INFRASOUND AND ULTRASOUND
after exposure to loud music, such as that of a rock concert or
discotheque. This temporary tinnitus may be short-lived or Evidence that excessive sound above or below the normal
last for days, depending on the duration and intensity of the human auditory range may have an adverse effect on inner
exposure and may be associated with a measurable tempo- ear function remains scant.
rary threshold shift.92 Similarly, tinnitus is reported often to Infrasound (conventionally sound below 20 Hz) is
accompany industrial noise exposure and while initially it is commonly felt as vibration rather than heard and is a com-
temporary, over a period of years it may become permanent ponent of natural phenomena such as earthquakes and
in as many as 60 per cent, particularly in those exposed to thunder.100 Heavy industrial machinery, high speed car
impact noise.93,94 There is some debate, however, regarding travel with open windows and ship’s engine rooms are
the importance of tinnitus in the assessment of occupational potential sources of infrasound. More specifically, Pyykkö
noise-induced hearing loss: Hinchcliffe and King suggest that and colleagues101 examined 203 lumberjacks over a six-
tinnitus is often a symptom of those seeking compensation.95 year period, compared the hearing in those with and with-
In contrast, a study of 647 individuals with occupational out vibration-induced white finger syndrome and found a
noise-induced hearing loss, showed a prevalence of tinnitus statistically significant difference in thresholds at 4 kHz
in 23.3 per cent, nearly one-third of whom felt that the tinni- in those with the syndrome than those without. They
tus was intrusive to the point of having an effect on daily postulated that the higher thresholds in the lumberjacks
activities.96 The issue is complicated further by the observa- with vibration-induced white finger was due to reflex
tion that solicitors advertising their services to potential sympathetic vasoconstriction in cochlear blood vessels in
claimants may do so with provocative statements linking response to vasospasm of the hands rather than a direct
noise exposure at work with tinnitus. The debate then is not mechanical effect on the cochlea (see Chapter 47, Hand–
so much as to whether tinnitus and occupational noise- arm vibration syndrome, p. 489).
induced hearing loss go hand in hand, but the weight that The auditory effects of ultrasound (sound above
should be attributed to the tinnitus component during the 20 kHz) have been reviewed by Acton.102 These include a
evaluation of a claimant. full feeling in the ear, tinnitus and headaches. Utilizing
low frequency ultrasound (10–28 kHz) in guinea pigs,
Ishida and colleagues103 noted auditory electrophysiologi-
OCCUPATIONAL NOISE-INDUCED VERTIGO cal effects, including alteration in the cochlear micro-
phonic and increased thresholds. Currently, the adverse
Temporary vestibular disturbance in response to loud auditory effects of hazardous levels of both infrasound and
noises is referred to as the Tullio phenomenon. In a state ultrasound in humans remain to be defined.
Systemic effects of noise pollution 481
SYSTEMIC EFFECTS OF NOISE POLLUTION causal relationship. There are uncertainties in quantifying
noise exposure, in separating the effects of noise from
Recently, the World Health Organization Noise other variables, and in agreeing and in quantifying out-
Environment Burden of Disease (BoD) Working Group come measures. Pooling of data for meta-analysis is
has identified environmental noise (as distinct from occu- fraught with hazard because of differences in the assess-
pational noise) as a stressor in the evolution of cardiovas- ment of exposure and outcome.114
cular disease.107 In addition, there is increasing concern In 2004, the World Health Organization published a
about the burden of sleep disturbance, of annoyance, of guide for occupational health professionals aimed at the
hearing impairment, of tinnitus and of cognitive impair- provision of a tool for carrying out detailed disease burden
ment from environmental noise. It has been estimated107 estimates of the hearing loss from occupational noise.115 In
that the severe annoyance due to noise from traffic, trains Europe, environmental noise is becoming a major health
and aircraft may account for approximately 3 per cent of concern for policy-makers. The European Directive related
coronary heart disease deaths in Europe each year (or to the assessment and management of environmental noise
about 210 000 deaths). Chronic noise exposure has been (Directive 2002/49/EC) addresses the action plans to
incriminated in elevation of systolic blood pressure in reduce harmful effects of noise exposure.116
workers in the metal manufacturing industry, and in ship- The summary policy implications of these initiatives are:
yard workers.108,109 Risk tends to be associated with night-
● Estimates of the incidence of occupation-related NIHL
time noise exposure and the noise threshold for
cardiovascular disease has been stated to be a night-time in a given country or study population will provide
exposure of 50 dBA. The mechanism is thought to be the quantitative information on the importance of the
high levels of stress hormones, such as cortisol, adrenaline problem and help motivate interventions to reduce the
and noradrenaline, released into the circulation at times of risks and impact on health.
● While incurable and irreversible, NIHL is nevertheless
stress at a subcortical level in the amygdala. This mecha-
nism may be active during sleep and there are several preventable and it is essential that preventative pro-
reports in the literature that indicate that exposure to traf- grammes are implemented.
● Hearing conservation programmes should be inte-
fic noise and aircraft noise during sleep may cause auto-
nomic changes, leading to hypertension and myocardial grated into the overall hazard prevention and control
infarction.110,111 It has been suggested112 that the neuroen- programme for the workplace.
docrine changes associated with noise stress may modify
immune function. Willich et al.113 reported that the risk of On this basis, the WHO publication stipulates that such
myocardial infarction from chronic noise burden appears programmes require political will and decision-making,
more closely associated with sound levels than with subjec- high-level management and workforce commitment, ade-
tive annoyance. quate human and financial resources, technical knowledge
As a means of further assessing the noise-related disease and experience, communication and monitoring mecha-
burden, the WHO Working Group have devised disability nisms and continuous programme improvement. The
adjusted life years (DALY). These allow one to quantify the WHO also recognizes the importance of local sociocultural
amount to which life expectancy is reduced by premature aspects and financial climate, and that in developing coun-
death or disease-related disability. It was estimated that in tries a large proportion of the population works in the
2002, Europeans lost 880 000 DALYs to coronary heart dis- informal sector – a group that represents a major challenge
ease related to road traffic noise. The group also recognized in terms of occupational hazard prevention.
the possible interaction between traffic noise and air pollu- In an attempt to provide a common basis for tackling
tion in the increased BoD. Outdoor air pollution repre- the environmental noise problem across the European
sents approximately 2 per cent of cardiopulmonary disease Union (EU), the European Parliament and Council have
mortality, and it is not clear whether the impact of noise on adopted Directive 2002/49/EC of June 25, 2002 which
ischaemic heart disease is independent, additive or syner- encompasses the following environment policy directives:
gistic to the impact of outdoor air pollution.
It is also suggested that sleep disturbance caused by 1. Monitoring the environmental problem through
environmental noise (noise-induced insomnia) can be a member states drawing up strategic noise maps for
contributory factor to loss of performance and predispose major roads, railways and airports.
to accidents at home, at work and when driving. The dele- 2. Informing and consulting the public about noise
terious effects of noise on cognitive function are also under exposure and measures considered to address it.
scrutiny. There are four components of cognitive impair- 3. Addressing local issues whereby competent authorities
ment (reading, recall, recognition and attention) which will need to devise action plans to reduce
appear to show a consistent relationship with noise expo- environmental noise.
sure. It must be emphasized, however, that there are 4. Developing a long-term EU strategy to reduce the
immense difficulties in acquiring robust data to establish a number of affected individuals.
482 Sound, noise and the ear
The deadlines relating to the implementation of this 9. Ulehlova L, Voldrich L, Janisch R. Correlative of sensory cell
Directive spanned from 2004 to July 2009, by which time density and cochlear length in humans. Hearing Research.
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Commission must submit a report on the implementation membrane with sinusoidal variations. Journal of the
of the Directive to the European Parliament and Council. Acoustical Society of America. 1947; 19: 452.
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SECTION TWO
Vibration
IAN J LAWSON, FRANK BURKE, KENNETH L MCGEOCH, TOHR NILSSON AND GEORGE PROUD
purposes of industrial injuries disability benefit. This led to Inaccuracy in both measurement of vibration and
amended regulations in 2007. assessment of clinical effects has meant that a robust
Exposure to hand–arm vibration (HAV) from hand- dose–response model has been elusive. The most fre-
held vibrating tools and equipment is common, particularly quently cited is in ISO 5349. This model bases the predic-
in construction and engineering. The number of workers tion of vascular symptom prevalence on groups of workers
exposed to HAV varies significantly between countries. who use tools with vibration predominantly above the
A national survey estimated that approximately 4.9 million 30–50 Hz range such as grinders, rock drills and chain
workers are exposed in the United Kingdom alone.10 An saws. Other factors thought to affect the severity of an indi-
estimated 350 000 workers are regularly exposed in Sweden, vidual’s condition include temporal exposure patterns,
6.7 million in Germany, and 1.5 million in the United intermittency of exposure, direction of vibration transmit-
States.11 A European Working Conditions Survey 2005 ted to the hand, including push and other ergonomic
(EWCS) suggested usage was five times more common in factors that may ultimately affect the transmission of vibra-
men. Sources of HAV that can lead to HAVS are numerous tion into the hand–arm system. Recent studies suggest that
and varied, including both electrically and pneumatically even low level vibration may lead to HAVS.20 Individual
powered percussive and rotary tools, such as fettling tools, susceptibility, particularly those with pre-existing Raynaud’s
impact wrenches, needle guns, hammer drills, chipping phenomenon, peripheral neuropathy and nerve entrap-
hammers, nibblers, hand-held polishers, sanders, grinders, ment, also plays a part.9
pedestal grinders, rock drills, road breakers, tampers, chain An understanding of the relationship between the onset
saws, brush saws, strimmers and concrete scabblers.12 of symptoms and first exposure can be assisted by a general
Foundry workers, construction workers, metal workers, understanding of the group prevalences at given vibration
miners and forestry workers are at greatest risk.13 magnitudes. It was accepted at an international workshop
Prevalence studies in HAVS have mostly considered that the first onset of finger blanching in relation to expo-
finger blanching and may be confounded by differences in sure (the latent interval) might range from a few months
climate. One prevalence study in the United Kingdom after the start of vibration exposure to approximately one
reported 670 000 men and 104 000 women with episodes of year after vibration exposure ceased7 and can be 20 years or
finger blanching in response to cold.14 These types of study more. In turn, reversibility depends on age of the subject,
have been mostly from developed countries, but other the severity of symptoms, duration of exposure to vibra-
regions are now adding to the literature.15 tion and the type of vibration tool used.7
The occupational health professional needs to have
some understanding of vibration measurement and its
implications when assessing individual cases. Vibration is
CLASSIFICATION
an oscillatory motion that can be represented by a simple
harmonic sine wave with the properties of displacement, a
The vascular and sensorineural components of HAVS are
velocity and acceleration. In practice, the wave is a com-
graded separately in the SWS (see Table 47.1). The scale is
plex, of differing frequencies and acceleration. Vibration
a clinical grading and not a disability scale. It has, however,
can move in three orthogonal directions (x, y and z axes)
been used to make recommendations on employability.21
and it is the vector sum that is normally calculated (ISO
Limitations in definitions used in the scale has led to sug-
5349).16 The measurement of interest, in terms of a biolog-
gested modifications (see Table 47.3).22
ical effect, is the magnitude of vibration or ‘A(8)’ which
It has been difficult to carry out powerful prospective
incorporates intensity, duration and direction.17
studies because of the diminishing levels of manufacturing,
The daily exposure to vibration of a person is ascer-
and from younger employees more readily choosing to
tained using the formula:
seek job alternatives.23
A(8) = ahw T / To
Table 47.1 The Stockholm Workshop Scale for the classification of the hand–arm vibration syndrome.
Vascular component
0 No attacks
1V Mild Occasional attacks affecting only the tips of one or more fingers
2V Moderate Occasional attacks affecting distal and middle (rarely also proximal) phalanges of one or more fingers
3V Severe Frequent attacks affecting all phalanges of most fingers
4V Very severe As in stage 3, with trophic changes in the fingertips
Sensorineural component
0SN Vibration-exposed, but no symptoms
1SN Intermittent numbness with or without tingling
2SN Intermittent or persistent numbness, reduced sensory perception
3SN Intermittent or persistent numbness, reduced tactile discrimination and/or manipulative dexterity
Note. The staging is made separately for each hand. The grade of the disorder is indicated by the stage and number of affected fingers on both hands,
e.g. stage/hand/number of digits.
Normal physiology of the skin be different from one person to another. An absent ulnar
pulse reflects no more than an innocuous variant from the
The skin regulates body temperature, stores blood and normal: it does not necessarily reflect pathology.
provides protection from uncontrollable fluid loss and The cutaneous circulation is controlled by sympathetic
sepsis. Cutaneous sensation allows an awareness of the vasoconstrictors and vasodilator nerves.25 Sympathetic
environment. Sweating and the adjustment of blood flow vasoconstrictor and vasodilator nerves innervate all areas
are part of the homeostatic regulation of body tempera- of hairy skin (non-glabrous), whereas hairless (glabrous
ture. Thermoreceptors in the skin provide local tempera- skin) is innervated by sympathetic vasoconstrictor nerves
ture control and neurons in the pre-optic area of the only. In glabrous skin, arteriovenous anastomoses are
anterior hypothalamus contribute to central control.24 numerous and opening and closing of AVA can cause sub-
Local skin temperature reflexes help prevent excessive heat stantial change in blood flow.25 Secondary Raynaud’s phe-
exchange from locally cooled or heated portions of the nomenon related to functional changes in blood flow
body. These reflexes are weak in comparison with hypo- would be expected more often to present in glabrous skin,
thalamic control. Moderate cooling or a brief exposure to for the second to the fifth digits and in relation to cold. In
severe cold leads to constriction of arterioles (resistance practice, the phenomenon is often circumferential.
vessels) and venules (capacitance vessels) and arteriove- Cutaneous sensation entails a variety of modalities
nous anastomoses (AVA). The radial and ulnar arteries including tactile (touch, pressure, vibration), thermal (heat
divide into the deep and superficial palmar arches. The and cold) and pain sensations carried through the periph-
ulnar artery is the main arterial input to the superficial pal- eral nerves for interpretation in the central nervous system.
mar arch usually receiving a branch from the radial artery,
but which may be small. The digital arteries, one of which
lies on each side of the finger, are derived from the superfi- Pathogenesis of neurosensory dysfunction
cial palmar arch for the little, ring and middle fingers. The
radial artery supplies the deep palmar arch and this pro- Manifestations of neurosensory dysfunction can include
duces the digital arteries to the thumbs and the index fin- reduced or absent sensibility, symptoms of pain or dysaes-
gers. The deep arch also gives anastomotic arteries to the thesia and changed perception of cold (cold sensitivity).
digital arteries from the superficial arch. The digital arter- Disturbances of central nervous integration may be
ies may anastomose with each other in the digits, more implied by reduced hand coordination and manual dexter-
especially at their tips. Acting together, the digital arteries ity. Investigations on the sympathetic and parasympathetic
are effectively end arteries: in digital arterial vasospasm the autonomic activity have demonstrated an altered balance,
blood supply is effectively cut off and the finger skin with increased sympathetic drive in vibration-exposed
becomes diffusely white. Acute injury to both digital arter- subjects.26 It is postulated that neurosensory pathogenesis
ies may result in loss of the digit unless microvascular may occur at multiple levels. These include changes to sen-
repair can be carried out. sory receptors, compression or changes in nerve fibres and
The arterial blood supply anatomy can be variable and intrinsic muscles, and to the somatosensory and motor
the relative contribution of radial and ulnar arteries may cortex.27
492 Hand–arm vibration syndrome
Takeuchi et al.28 analysed finger biopsies from 30 patients conditions, including vibration exposure. The phenome-
with vibration-induced white fingers, and conducted elec- non may be triggered or modified by emotion and stres-
tron microscopy biopsies from three additional patients sors. The pathogenesis varies between the underlying
with VWF.29 The impairment of large myelinated fibres has conditions. From physical principles (Poiseuille’s law)
been documented in both morphologic studies and nerve alone, three general mechanisms can be identified that
conduction studies. Histological assessments of patients influence peripheral microcirculation:
with VWF revealed an increase in the thickness of the per-
ineurium, and a decrease in the number of myelinated nerve 1. perfusion pressure
fibres and thick lamellar fibrosis of the perineurium.28,29 The 2. the luminal radius of the digital artery
nerve fibres were often reduced in size with an increase of 3. blood viscosity.
collagen with fibroblasts in the endoneurium. The impair-
ment arising from small diameter nerve fibres (A-delta and Abnormalities in all three mechanisms have been
C-fibres) is documented in disturbed thermal perception described among vibration-exposed subjects. The vascular
studies. Ultrastructural studies using different neural mark- dysfunction may be due to functional or structural abnor-
ers for small diameter nerve fibres showed a significant malities or both.39,40 Some dysfunction is better under-
reduction of epidermal nerve density (END) over the fore- stood, while others are speculative.41 The pathogensis of
arm among vibration-exposed subjects.30 Raynaud’s phenomenon either primary or secondary
Sensory and motor dysfunction could also be due to remains uncertain.
changes in cortical somatotopic mapping of the hand in
the brain.31 Here, Lundborg et al. conducted an fMRI PERFUSION PRESSURE ABNORMALITIES
study to compare the somatotopic cortical representation
of the hands of workers exposed to vibration with controls. Both sympathetic vasoconstrictor and vasodilator systems
Cortical activation did not differ significantly between in the skin participate in blood pressure regulation via the
patients and controls, thus favouring a peripheral mecha- baroreflex. A decrease in perfusion pressure can be caused
nism. The findings did show some shift in cortical activa- by systemic hypotension or by a proximal arterial obstruc-
tion suggesting a possible cortical remodelling. tion. Raynaud’s phenomenon has been associated with
Several different experimental animal models have been obstructive vascular disorders, such as cervical ribs40 and
used to study vibration-induced neuropathology. Most thromboses. Subjects with entrapment in the carpal tunnel
studies have been conducted on rats. Early experiments exhibit increased prevalence of RP.42 Thenar- and
often used the paws and assessed the results with light hypothenar hammer syndrome are disorders with reduced
microscopy, while more recent studies use a rat-tail blood flow and may appear similar in their manifestation
model,32 and electron microscopy with immunostaining. to RP. The baseline cutaneous blood flow of healthy
Long-time exposure of a rat limb induces swelling (intra- females is lower than that in males and may in part explain
neural oedema) and permanent damage to the sciatic the higher prevalence of RP in women.
nerve.33 Ultrastructural changes (such as detachment of
myelin sheath from the axolemma at the nodes of Ranvier, DYSREGULATION AND ABNORMALITIES OF THE LUMINAL
axonal loss, and constriction of the axon) increase with RADIUS
the dose of vibration.34 Axonal damage is seen both in
myelinated and non-myelinated axons. Non-myelinated The regulation of the luminal radius is balanced by vaso-
axons have also been found to be oedematous.35 Rat tails constrictors and vasodilators. The neural vasoconstrictor
exposed to vibration also exhibit elevated nitrotyrosine system is tonically active in thermoneutral environments.
immunoreactivity indicative of free-radical damage.36 Sympathetic vasoconstrictor nerves release norepineph-
Short-term vibration exposures have been associated with rine, which interact with postsynaptic a1- and a2-receptors
disrupted axoplasmic transport, and the experimental on cutaneous arterioles and arteriovenous anastomoses.
results indicate a cumulative effect.37 Vibration and cold Noradrenergic vasoconstrictor nerves also release
generate similar percentages of myelinated axons with dis- neuropeptide-y and adenosine triphosphate. Cold aug-
rupted myelin. Cold with and without vibration caused ments smooth muscle 2-adrenoreceptor function.
intraneural oedema, whereas vibration alone did not.38 Adrenoreceptor (AR) dysfunction among VWF cases
causes weakened 1-receptor-mediated response and pre-
dominance of 2-receptor function. Cold-induced vaso-
Pathogenesis of vibration-induced constriction is usually a protective response to prevent heat
Raynaud’s phenomenon loss and is mediated by a reflex increase in sympathetic
nerve activity. The 2-adrenoreceptors comprise three
Raynaud’s phenomenon (RP) denotes an exaggerated subtypes and only the 2C AR seems to be sensitive to cold.
vasospastic response to cooling. The aetiology of the Results from rat-tail models indicate that vibration can
phenomenon can be either primary (idiopathic) or second- augment sympathetic vasoconstriction by selectively
ary, where secondary RP relates to a number of different increasing 2 AR reactivity.43 Cooling activates 2C AR.
Pathophysiology 493
Intraneural swelling occurred in the rat model when the early stages, there is evidence for oedema formation and
skin temperature was below 15°C.44 vascular insufficiency manifested as nocturnal paraesthe-
In addition to the neural regulation, there are endothe- sias, while in the advanced stage, there is severe injury with
lium-produced vasoconstrictors and vasodilators. The severe nerve fibre lesions of neuropractic and axonotometic
most potent vasoconstrictor is endothelin-1. Patients with type. Evidence from meta-analysis of studies on CTS and
VWF seem to exhibit lower endothelin-1 levels than pri- work supports and extends previous conclusions that there
mary RP45 in response to cold provocation tests, but more is a relation to vibration and to certain hand activities.53
advanced cases of VWF show an exaggerated response
compared to normal subjects.46 Cutaneous injection of
endothelin-1 results in a large area with vasospasm, but Pathogenesis of Dupuytren’s disease
a reduced vasodilator response which indicates a local
axon-reflex deficit,47 with abnormality in unmyelinated Dupuytren’s disease (DD) is characterized by thickening,
‘C-fibres’ and thinly myelinated A-delta fibres. nodule formation and contracture of the palmar fascia,
Nerves supplying blood vessels produce several vasodila- resulting in flexion deformity of the fingers. Heredity,
tory substances. Temperature increase normally causes alcohol abuse, epilepsy, diabetes and smoking have been
vasodilation by stimulating local release of neuropeptides associated with DD.54 When reviewing studies focusing
from sensory nerves, such as calcitonin gene-related peptide on the relation between intensive manual work, trauma,
(CGRP), substance P (SP) and neurokinin-A (NKA). It also vibration exposure and the development of DD, Liss and
stimulates release of endothelin-related nitric oxide (NO). Stock55 concluded that there was good support for an
Immunohistochemical studies have shown a reduction association between vibration and DD. However, a recent
in the number of sensory-motor nerves containing the study including almost 100 000 subjects failed to show
vasodilator CGRP in finger skin biopsies of patients with this association.56 Biomolecular advancements at gene
hand–arm vibration syndrome. There was also a reduction and cellular level have brought new insights to the patho-
in the pan-neuronal marker protein gene product 9.5, sug- genesis of DD. Studies of gene expression using DNA
gesting that the CGRP depletion might be a consequence microarray technology54 revealed that several genes were
of damage with neuronal loss.48 upregulated, while at the same time others were downreg-
Biopsies from patients with VWF reveal thickening of ulated in tissue samples of DD. Contractile myofibroblasts
the muscular layers of the artery walls, with hypertrophy of are involved in contracture deformity. Histologically, the
individual muscle cells without intimal fibrosis.28,29 cords of DD consist of a dense collageneous matrix with
fibroblasts. The cause of myelofibroblast profileration on
the cellular level in DD is unknown. One hypothesis is that
INTRAVASCULAR DYSFUNCTION
reduced peripheral blood flow causes ischaemia and the
Changes in leukocytes, erythrocytes and the intima have generation of free radicals, which damage the surrounding
been reported in long-term exposure to vibration.41 Where tissue and cause fibroblast proliferation.54 Initially, in the
reduced blood viscosity has been found, it has been inter- pathogenesis, there is a proliferative stage characterized
preted as a compensatory mechanism in reaction to tissue by an increase in myelofibroblasts. In the subsequent
ischaemia. involutional stage, the microvessels within this tissue are
considerably narrowed. It has been suggested that the
pathogenesis of DD is a result of vessel narrowing causing
Pathogenesis of carpal tunnel syndrome local hypoxia and chronic ischaemia, activating the xan-
thine oxidase pathway, releasing free radicals that stimu-
Recent studies have demonstrated neuropathies proximal late fibroblasts to proliferate.57
to the hand among vibration-exposed workers49 or at
multifocal levels.50 Structural changes found just proximal
to the wrist may be involved in the development of Pathogenesis of vibration-associated
carpal tunnel syndrome in vibration-exposed workers.51 muscular disease
Histological findings in the wrist of post-mortem speci-
mens showed synovial membrane hyperplasia, endothelial Reduction of neuromuscular function and strength may
reduplication and increased epineural density inside the occur following long-term exposure to work with vibrating
carpal tunnel. The findings are interpreted as steps in the machines.58 Farkkila and co-workers reported loss of
pathogenetic path based mainly on pressure produced by extrinsic hand muscle strength among lumberjacks with
forces and displacement of tendons.52 This mechanical fac- hand–arm vibration syndrome. More recent studies have
tor in the aetiogenesis of carpal tunnel syndrome (CTS) confirmed reduction in both extrinsic and intrinsic hand
has later been modified and extended by supporters of an muscle strength.59 The results of Necking et al. demonstrate
additional vascular pathogenesis for CTS. The pathophysi- thenar muscle strength loss in subjects with long-term
ology of the microcirculation and the subsequent neuropa- exposure to hand-held vibrating machines. The mor-
thy varies with the various stages of the CTS lesion.27 In the phological assessments demonstrated centrally located
494 Hand–arm vibration syndrome
myonuclei with fibre type grouping, angulated muscle As there is no gold standard to diagnose sensorineural
fibres, ring fibres, regenerating fibres and fibrosis. The HAVS, and no single test with sufficient specificity or sen-
observed muscle necrosis, fibrosis and the structural disor- sitivity, researchers have recommended the use of a battery
ganization were all interpreted as suggestive of direct mus- of tests.21,61
cle damage, whereas the angulated fibres and fibre type The appreciation of touch, vibration, temperature, joint
grouping suggests muscle denervation and reinnervation.59 position and motion are transmitted by nociceptors, ther-
These findings are in accordance with those observed in moreceptors, mechanoreceptors and nerve fibres. Tests
short-term vibration in animal models.60 Several theories have been designed to detect abnormalities in these recep-
regarding the pathogenesis have been suggested, including tors and transmission pathways. Their main value is in
vibration, tonic vibration reflex with continuous elevation assessing the severity of sensory loss.
of muscle tone, blood flow reduction, and mechanical and Simple tests, such as cotton wool and moving two-point
metabolic changes. The evidence suggests that working with aesthesiometry, can demonstrate a loss of sensation, but
vibrating machines may cause both damage to the muscle are limited by inter-observer error, and generally will only
units within the contractile muscle fibres and nerves. pick up the later stages of sensory loss. These clinical find-
ings have no normative data available for comparison.
Semmes–Weinstein monofilaments have been used to
CLINICAL FEATURES grade such loss and are considered a better validated exam-
ple of these types of test.62
Sensorineural hand–arm vibration syndrome Other psychophysical or quantitative sensorineural
tests (QST) with a sound anatomical and physiological
In the natural history of the condition, neurological (sen- basis have been developed. As all these tests have a subjec-
sorineural) symptoms tend to occur first. Most surveys tive input, they are not truly objective and are often
record them as twice as common as vascular symptoms referred to as ‘standardized tests’.
and generally causing greater disability. The latent period These tests derive from the work on mechanoreceptors
for sensorineural symptoms varies from a few months to by Mountcastle.63 Vibration stimulates mechanoreceptors,
many years. end organs and nerve fibres. The superficial Meissner cor-
puscles or fast adapting 1 (FA1) respond to frequencies
SIGNS AND SYMPTOMS between 5 and 60 Hz, while the deep Pacinian corpuscles
or fast adapting 11 (FA11) react to frequencies between
Use of vibratory tools causes transient paraesthesia in the 50 and 400 Hz. These signals are transmitted by the large
fingers of most users. This usually passes off within 20 myelinated A-alpha and A-beta fibres.
minutes. Often, the first abnormal symptoms are an exten- There are also cold and warm receptors in the finger-
sion of this time. Tingling or numbness usually starts at the tips. Messages from the cold receptors are transmitted by
fingertips, but can affect all, or the whole, of the fingers. small myelinated A-delta fibres, while those from warm
With continuing exposure, these symptoms may become receptors use unmyelinated C fibres.
persistent lasting for hours or even all day. Although aggra- The vibrotactile threshold test (VTT)64,65 and thermal
vated by coldness, the tingling and numbness can occur in aesthesiometry test (TA)66 have had their integrity
a warm environment, causing considerable distress. The investigated.67–69 These tests must be performed in a
sensory loss causes workers to describe their fingers as feel- temperature-controlled environment. As they are psy-
ing thick or ‘like bananas’ in many instances. chophysical tests, a random element should be built in to
There is a loss of feeling, of temperature appreciation eliminate any deliberate exaggeration. In both tests, the
and of pain sensation. In severe cases, workers can experi- flexor surface of the distal phalanx of the index and little
ence clumsiness and loss of manual dexterity, with poor fingers is tested to assess the median and ulnar innerva-
finger coordination causing inability to do fine work. tion. The VTT requires a constant downward pressure of
Assessing a case of suspected neurological HAVS 1 Newton. Thresholds are generally measured at 31.5 Hz
requires details of vibration exposure, past medical history (Meissner corpuscles) and 125 Hz (Pacinian corpuscles),
and a clinical history of date of onset of symptoms, site of although some equipment includes a broader range of
paraesthesia, time of occurrence and duration of symp- frequencies.
toms. Nocturnal symptoms may occur, but are less fre- Change of the temperature in TA is 1°C per second. The
quent than in cases of carpal tunnel syndrome. ‘pulse method’ should be used.70 The zone in which change
Before reaching a diagnosis of sensorineural HAVS, all in temperature cannot be felt is known as the temperature
other causes of peripheral neuropathy must be considered neutral zone (TNZ), and is calculated by subtracting the
(see under Diagnosis, p. 505). cold threshold from the warm threshold.
There are no visible signs of neurological damage. This A test, such as the Purdue pegboard test (PPT), may
makes the use of tests all the more important before advice demonstrate loss of dexterity against age-related normative
can be given to the worker on the severity of the condition data.71,72 As an isolated test, it is of little discriminatory
and implications of further exposure to vibration. value.
Vascular clinical features 495
Scoring system
As the mechanism and proportion of damage is unclear, Table 47.3 Modification of Stockholm Workshop Scale for
the VTT and TA should be given equal weighting. A scor- classification of the sensorineural component of hand–arm
ing system can be used to record the extent of this damage vibration syndrome staging.
(see Table 47.2).69
Stage Criteria
The first attempt to grade the stages of vibration dam-
age was the Taylor/Pelmear classification in 1967.
Unfortunately, the only neurological category was the ear- 0SN Vibration exposure, but no symptoms
liest stage 0N (numbness) or 0T (tingling). Once the 1SN Intermittent numbness and/or tingling with
importance of the neurological damage was recognized a sensorineural score of
3–6
this neurological grading became inadequate and was 2SN (early) Intermittent or persistent numbness and/or
replaced by the sensorineural component of SWS (see tingling, reduced sensory perception with
Table 47.1).4 a score of
6–9
A very large contract examining more than 100 000 2SN (late) As 2SN (early), but with a score of
9–16
miners with the use of VTT and TA gave the opportunity 3SN Intermittent or persistent numbness and/or
to recommend refinements to the sensorineural staging of tingling, reduced manipulative dexterity
the SWS.6 As tingling was thought to be as important as and a SN score of
19
numbness, the wording ‘with or without tingling’ was
changed to ‘numbness and/or tingling’.
Stage 2SN was thought to cover a very wide range of
episodic attacks of digital arterial vasospasm, causing
neurological damage from patients with relatively minor
‘whiteness’ of the affected parts of the fingers. It is more
handicap to those with severe sensory loss, but without a
common in colder climates. Overall, it affects up to about
dexterity problem in a warm environment. For this reason,
15 per cent of the community with a female preponderance
the combined VTT and TA score was used to divide this
of approximately 3:1 compared with males. In temperate
stage into 2SN early and 2SN late (see Table 47.3).
European countries, a prevalence of about 5 per cent for
True 3SN cases have severe persistent neurological
males and 30 per cent for females would be expected.
damage. For a grading of stage 3SN, there had to be a loss
In warm countries, fewer manifestations of Raynaud’s
of dexterity in a warm environment, VTT and TA score of
phenomenon have been reported.
equal to or greater than 9, and an abnormal Purdue peg-
Raynaud’s description in 1862 included a variety of
board test. As the maximum single test score per hand was
conditions, but as time has passed, the condition has
8, a score of
9 was required to show evidence of damage
become much more clearly described and primary and
in both tests. When these criteria were met, 10 was added
secondary Raynaud’s conditions are now recognized.
to the combined VTT and TA score.
Primary Raynaud’s phenomenon is otherwise known as
In the United Kingdom, the use of these tests, scoring
Raynaud’s disease. This condition affects younger people,
system and modified sensorineural staging has been
mostly under the age of 40 years, and usually females.
accepted by the Health and Safety Executive in their
Individuals suffer episodic attacks of whiteness of the fin-
Guidance on Health Surveillance for Occupational Health
gers and/or toes occurring in response to cold. Fingertips
Professionals 2005.22
are affected first and, as the condition progresses, the entire
fingers are affected in late cases. Although some or all of
VASCULAR CLINICAL FEATURES the digits can be affected, the extent of the blanching is
usually variable from attack to attack and is diffuse.
The vascular component is one of arterial vasospasm, and The extensive use of vibrating powered tools in indus-
the clinical features are indistinguishable from Raynaud’s trial processes is responsible for most cases of secondary
phenomenon. Raynaud’s phenomenon is a very common Raynaud’s phenomenon. However, there are other well-
condition in the community manifested by cold-induced recognized diseases (many under the heading of collagen
496 Hand–arm vibration syndrome
vascular disorder, for example, systemic sclerosis and experienced ‘attack’ lasting more than two hours is
CREST syndrome). These are all associated with digital more likely to be a description of a natural physiological
artery vasospasm occurring in response to cold. In these response to the cold. Recovery can be hastened by warming
conditions, the symptoms can come on at any age and may of the hands, although this may be painful. True digital
be rapidly progressive leading to ischaemia of the fingers artery vasospasm is accompanied by numbness in the fin-
and toes necessitating amputation. Investigations will nor- gers due to the transient ischaemia of the digital nerves.
mally show antibodies in the blood enabling the diagnosis The area of blanching is normally sharply demarcated
to be made, and although these may be absent initially, from the surrounding normal skin.
they frequently emerge with time and it may be some years In the recovery phase, the circulation is restored to the
after first presentation of the disease that they become digit from the base towards the tip, and there is usually a
detectable. Severe Raynaud’s disease is often said to be an reactive hyperaemia, reflecting the acidosis or acidaemia
autoimmune secondary Raynaud’s phenomenon without that will have developed in the digit during the period
the antibodies, yet being identifiable. It is rare for of ischaemia. The finger often appears a prominent red
Raynaud’s disease or Raynaud’s phenomenon secondary colour as recovery proceeds, with ultimately a normal pink
to vibration to be as severe in its effect as secondary hue being resumed. Many individuals describe this phase
Raynaud’s phenomenon arising in association with as being one of hot aches, and a comparison is often made
autoimmune vascular disease. A systematic review found with the sensation in the hands remembered from child-
evidence that vascular symptoms could occur in the lower hood after playing in the snow. In some people, the red
limbs in those diagnosed with HAVS, providing symptoms discolouration does not occur, but a cyanotic colour is
were apparent in the hands.9 present instead. In addition, some people give a descrip-
Vibration-induced Raynaud’s phenomenon is graded tion of arterial vasospasm without whiteness, only cyanosis
on the Stockholm scale according to the severity of the of the fingers. This is likely to be compatible with a diagno-
symptoms and the extent of the blanching. In stages 0, 1, 2 sis of HAVS.
and 3, there is a transition from vibration exposed, but no Blotchiness of the fingers may be a complaint. This is
blanching to extensive blanching affecting all of the fingers not normally considered to be Raynaud’s phenomenon,
in their entirety. A stage 4 category is reserved for those which causes a uniform blanching. Mottling is a common
individuals who have trophic or ischaemic changes evident normal skin appearance.
in the fingers: while it is true that some vibration-exposed Another common complaint is of cold fingers or cold
workers will show trophic changes in the fingertips, it is sensitivity. In isolation, this is not Raynaud’s phenome-
the experience of the authors that all of these cases have non, nor does it necessarily reflect any underlying vascular
another reason for the trophic change to be present. pathology, although some consider it to be to a presympto-
Almost certainly, stage 4 HAVS does not exist and if a matic phase.
case is seen in which stage 4 seems a likely diagnosis, full Some individuals describe a whiteness of the skin that is
blood investigations for autoimmune vascular disease simply a normal appearance or a physiological response to
should be instigated, and repeated if the results are initially cold. Some drug therapy is associated with the potential
negative. side effect of cold extremities (for example
-blocker ther-
The onset of HAVS is dependent on two factors. The apy). These drugs do not per se cause Raynaud’s phenome-
first is the susceptibility of the individual using vibrating non, although if an individual suffers from cold extremities
tools to the harmful effects of vibration, and the second is when taking them, they may be more likely to suffer an
the vibration dose received: higher dose leads to an earlier attack of arterial vasospasm.
onset. Some individuals develop symptoms early in their Eliasson and colleagues73 reviewed the effects of
careers, yet others may never develop symptoms or have
-blockers and concluded that when propranolol was used
the onset of symptoms delayed for many years. (propranolol is one of the earlier non-cardioselective
The first symptom or sign of digital arterial vasospasm agents) that around 3 per cent of patients experienced
is the onset of blanching affecting the tips of one or more troublesome vasospastic phenomena of the periphery. The
digits and occurring in response to cold. Gradually, the symptoms occurred within two months of starting the
extent of the blanching increases until the full length of treatment and usually affected the extremities of all four
each finger may be affected. The thumbs tend to be spared, limbs. At about the same time, Marshall and colleagues74
but they can be affected particularly in more severe cases of published higher figures for the development of Raynaud’s
HAVS, or when the thumb is particularly exposed to vibra- phenomenon, although the diagnosis was based only
tion. The blanching of the fingers may just extend on to the on the results of a questionnaire. Fifty-nine per cent of
most distal aspect of the palms. The blanching is circum- patients on propranolol had Raynaud’s phenomenon
ferential and sometimes obliquely so, affecting the territory compared with 35 per cent on atenolol. Overall, patient
of one digital artery, but not both. numbers were small; however, this study is important for it
A typical attack lasts for between 20 and 30 minutes, found that all patients with Raynaud’s phenomenon attrib-
although it can last longer for up to an hour or so. Longer- utable to
-blockers had developed it in both the hands
duration attacks are highly unusual and a regularly and feet simultaneously.
Carpal tunnel syndrome 497
These factors relating to the vasospastic phenomena of of Trade and Industry.6,77 The results showed that the test
HAVS are probably of greater importance in the litigation employed was of little or no value in assessing these min-
arena than in the occupational health environment. It is ers. The Health and Safety Laboratory of the HSE reported
suggested below that the management of the individual similar findings.78 An alternative to measurement of finger
exposed to vibration, who has arterial vasospastic symp- skin temperature using a thermocouple is to use a thermo-
toms and signs, is based on the presence of the Raynaud’s graphic measurement of the digital rewarming, but the
phenomenon, and not on whether
-blockers or other principle remains the same.
factors might be causing the symptoms. Other techniques have included the measurement of
People affected by HAVS present in either the occupa- finger systolic blood pressure after controlled cooling of
tional health setting or in the medicolegal arena. In the for- the fingers.79 This test is technically difficult to perform in
mer, the symptoms may be under-reported, for there may the field setting, but is suited to an occupational health
be a genuine concern about continuing employment, but laboratory. However, considerable overlap of results has
in the latter the symptoms may be exaggerated to try and been documented in a study of dockyard workers with and
increase the financial compensation. Much time and effort without symptoms of HAVS.80 Some researchers have sug-
has been expended in trying to identify a test that might gested that the sensitivity and specificity of these tests
be useful in this respect (e.g. cold water provocation). might be improved after body cooling. Others suggest that
Attempts to do this are confounded by the fugitive nature a cooling test, with measurement of changes in the recov-
of the disease itself. There currently is no objective assess- ery phase, does offer a test of high sensitivity, specificity
ment of a sufficiently high sensitivity, specificity and posi- and positive predictive value.81 Despite this, the Faculty of
tive predictive value to enable decisions to be made at an Occupational Medicine evidence review9 concluded ‘no
individual level regarding the presence, absence or severity current vascular test has been shown to accurately stage the
of the disease. extent of an abnormality in an individual as defined by the
While vibration causes the underlying disease to be Stockholm Workshop Scale’.
present, it is cold which provokes an attack of arterial There is no test or process which will enable a decision
vasospasm. The affected person knows the circumstances to be taken with absolute certainty as to whether Raynaud’s
that might lead to an attack occurring, but whether an phenomenon is secondary to vibration or is simply due
attack will occur in those circumstances cannot be pre- to Raynaud’s disease. The main potential causes, when
dicted. The attacks tend to be random. There are a number considering the differential diagnosis, are presented in
of variables that can confound the application of these Table 47.4 (see under Diagnosis, p. 505).
tests. These include core body temperature, recent smok-
ing and alcohol intake, recent vibration exposure, anxiety,
drug therapies and the state of the arterial tree. CARPAL TUNNEL SYNDROME
The nature of Raynaud’s phenomenon means the
response to cold in any individual varies from day to day. Carpal tunnel syndrome (pressure on the median nerve at
The sufferer knows the circumstances which may provoke the wrist) has a high prevalence in the adult community.
an attack of blanching and also knows that an attack may Episodes of intermittent mild numbness in the median
or may not occur under those circumstances. The response innervated fingers will not necessarily take a person to their
is unpredictable. Despite these caveats, a number of these primary care physician for investigation or treatment. Two
tests have been studied. These have included uncontrolled studies in the 1990s sought to identify the prevalence of
cold provocation tests, in which the worker’s hands are carpal tunnel syndrome in the community by patient ques-
plunged into ice or iced water for a variable period of time. tionnaire and nerve conduction studies. De-Krom et al.82
The response is observed without any criteria having been identified a prevalence of 3.4 per cent of adult females
established against which the results of the challenge can be with known carpal tunnel syndrome, but an additional
assessed. These unpleasant and potentially dangerous tests 5.8 per cent of females where the diagnosis had been previ-
are of no value and should be abandoned.75 ously undetected. The figures for men range from 0.6 to
In an attempt to produce an objective test to evaluate 8 per cent depending on the criteria used. Ferry et al.83 felt
the vascular component of HAVS, some researchers have the prevalence estimate lay between 7 and 18 per cent of
produced a test of controlled finger cooling with measure- the adult population (and was similar for male and female
ment of rewarming times of the digits.76 Comparing the populations).
results with known normative data might allow for an Patients complain of pain and paraesthesia in the distri-
objective assessment to be made. In this situation, ‘objec- bution of the median nerve, with numbness in the fingers
tive’ means that the test cannot be manipulated either by especially at night, and aggravation of symptoms when
the observer or the subject. The test involves cooling the using the hand. There may be wasting of abductor pollicis
fingers for a defined time and then measuring, by means of brevis in long-standing cases. Provocation tests may be
thermocouples, the rewarming time. The application of useful in diagnosing carpal tunnel syndrome; Phalen’s test
this test on over 40 000 miners was assessed in the UK min- increases the pressure on the median nerve, as the wrist
ers’ compensation scheme established by the Department is moved from neutral dorsipalmar flexion to maximum
498 Hand–arm vibration syndrome
Table 47.4 Differential diagnosis of hand–arm vibration by adjustments of working height, and the use of appropri-
syndrome. ately designed tools with suitably sized handles. Repetitive
Diagnosis
and forceful activities should, if possible, be shared
through the entire working day, to minimize the prospect
of difficulties. An ergonomic programme outlined by
Hand conditions Arteritis Eversman84 reduced a workforce incidence of carpal tun-
Drugs nel syndrome by 60 per cent. Nerve and tendon gliding
Carpal tunnel syndrome exercises have been shown to be of benefit in reducing the
Regional problems Thoracic outlet syndrome (including need for carpal tunnel decompression.85,86 Wrist splints
cervical rib) can also be extremely helpful in the earliest stages of the
Atherosclerotic vascular disease disease. The volume of the carpal tunnel is maximal in the
Systemic disease Primary Raynaud’s phenomenon neutral flexion extension range and the wrist splint should
Connective tissue disorders, including be applied in this position for maximal benefit.87
CREST syndrome, rheumatoid arthritis Harrington et al.88 considered the surveillance criteria
and systemic lupus erythematosus for carpal tunnel syndrome to be pain or paraesthesia or
Diabetes mellitus sensory loss in the median nerve distribution and one of
Hypothyroidism the following, Tinel’s test positive, Phalen’s test positive,
Chronic micro-embolism – from nocturnal exacerbation of symptoms, motor loss with
valvular heart disease and atheroma wasting of abductor pollicis brevis or abnormal nerve con-
Polycythaemia duction studies. Additional features that might aid the
Neurological disease Any peripheral neuropathy diagnosis included no signs or symptoms in the little finger
Cervical spondylosis or dorsum of the hand, no other cause apparent or a suc-
Multiple sclerosis cessful outcome following steroid injection or surgery.
Blood-borne factors Malignant disease including multiple Carpal tunnel syndrome presenting in its classical form
myeloma is readily diagnosed on history and examination alone.
Cryoglobulinaemia and cold agglutinins However, the diagnosis of carpal tunnel syndrome in the
Raised plasma viscosity presence of neurosensory impairment arising from hand–
Drugs and chemicals Beta-adrenergic blockers, ergot, some arm vibration syndrome is more complex.
anti-cancer drugs, PVC exposure
Metronidazole, anti-epileptic drugs,
chronic alcohol excess, cyclosporine, Carpal tunnel syndrome in workers exposed to
anti-depressants – all cause vibration
neurological complications
(The list of drugs is only indicative of A variety of papers have identified a high prevalence of
some agents causing problems. carpal tunnel syndrome in vibration-exposed workers
Always check the side effects of drugs (Table 47.5). The studies mentioned are composed of rela-
especially when the worker is on tively small numbers of workers. Stromberg et al.95
long-term medication) reviewed 100 vibration-exposed workers and noted that 48
CREST, calcinosis, Raynaud phenomenon, oesophageal dysmotility, per cent had isolated neurosensory symptoms, 20 per cent
sclerodactyly and telangiectasia. isolated vasospastic problems and 32 per cent combined
This list is not a complete list, but it does cover some of the more neurosensory and vascular problems. Twenty-two per cent
common potential causes of doubt in the diagnosis. Inclusion here does of the cases were also considered to have carpal tunnel syn-
not necessarily mean the second pathology or the presence of drugs is the
cause of symptoms. Only a very small number of people on
-blocker
drome. The Industrial Injuries Advisory Council96 in the
therapy will develop Raynaud’s-like symptoms; only a very small number United Kingdom has accepted carpal tunnel syndrome as a
of diabetic patients will have a peripheral neuropathy. prescribed industrial disease, having reviewed the evidence
and concluded a doubling of relative risk in vibration-
exposed workers. The council did not consider there was
passive flexion. The test is considered diagnostic if the sufficient evidence to offer an opinion on qualifying expo-
onset of paraesthesia occurs within 60 seconds of flexing sure, but would expect the symptoms to begin during
the wrists. Tinel’s sign may be demonstrated by gently per- employment when hand-held vibrating tools were used.
cussing over the median nerve just proximal to the flexor The relationship between carpal tunnel syndrome and
retinaculum. A positive test produces paraesthesia in the hand–arm vibration is unclear. If there is an association, its
fingers in the median nerve distribution. pathological process is not known. Those exposed to vibra-
Advice on workplace or home task modification may be tion commonly use their hands for high force, high repeti-
very helpful in controlling symptoms of mild to moderate tion activities, which Silverstein et al.97 consider a potent
carpal tunnel syndrome. This may take the form of avoid- cause of higher prevalence of carpal tunnel syndrome.
ing end range posture of joints during the working process Lundborg et al.98 believe that vibration creates oedema
Dupuytren’s disease 499
Table 47.5 Papers advising of an association between complaints. Vibration exposure may be an aetiological risk
hand–arm vibration syndrome and carpal tunnel syndrome. factor for carpal tunnel syndrome, or alternatively a risk
factor for provocation of symptoms of carpal tunnel syn-
Author No. vibration- Number with
drome. However, the relationship between carpal tunnel
exposed workers carpal tunnel
syndrome and hand–arm vibration remains uncertain.106
in study syndrome (%)
disease combining skilled manual, partly skilled manual disease in this study. An accurate assessment of vibration
and unskilled manual workers as a group and compared exposure throughout previous employment cannot usually
them with a group of professional, managerial and techni- be obtained, and employees who may overestimate time
cal and skilled non-manual workers. Accumulative stan- spent holding the vibrating tool (the ‘anger time’ or ‘trigger
dardized incidence of Dupuytren’s disease rose in a similar time’) by as much as a factor of four.121 However, the vibra-
way with increasing age until normal retirement age tion exposure in years (in all industries) was known for this
(65 years), but a divergence then occurred between the large group of miners. There was no statistically significant
manual and non-manual groups. The non-manual group correlation between the years of exposure to vibration and
were found to have a higher incidence than manual the prevalence of Dupuytren’s disease (controlling for age).
workers. Their findings are in conflict with those of Stockholm vascular and neurosensory grading and thermal
Mikklesen,114 who found a higher incidence in retired aesthesiometry and vibrotactile threshold scores (when
manual workers in an epidemiological study involving corrected for age) were found not to be predictors of
16 000 citizens of a small Norwegian town. Khan et al.115 Dupuytren’s disease. This study does not support Liss and
concluded that manual occupations were not associated Stock’s view that there is an association between vibration
with an increased incidence of Dupuytren’s disease. exposure and the development of Dupuytren’s disease.
Ross116 reviewing the available literature considered that The prime determinant for the prevalence of
most authors believed there was no association between Dupuytren’s disease is age, and any study of a possible
occupation and the risk of developing Dupuytren’s disease. association between Dupuytren’s disease and occupation
The effect of a single traumatic event on the develop- must be tightly controlled for age. On the available evi-
ment of Dupuytren’s disease has been investigated. Stewart dence, Dupuytren’s disease is unlikely to occur more fre-
et al.117 studied patients who had sustained a Colles frac- quently in manual workers and is probably not more
ture and observed that 11 per cent of the 235 patients common in vibration-exposed workers.
developed features of Dupuytren’s disease between three
and six months from injury. Contractures were mild and
were not progressive when reassessed at a later date. HAND–ARM VIBRATION AND MUSCLE
WEAKNESS
Dupuytren’s disease in vibration-exposed Normative data for grip are available from the United
workers States122,123 and in the United Kingdom.124 All three studies
used a Jamar dynamometer on the second grip setting, with
Some studies of vibration-exposed workers have revealed a mean of three grips in standard positioning. Mathiowetz
an increased prevalence of Dupuytren’s disease. Liss and et al. obtained values from 310 males,122 Hanten et al. 533
Stock55 reviewed the literature and felt that there were three males123 and Gilbertson and Barber-Lomax 130 males.124
papers which offered reasonable evidence of an association. The Hanten series, and Gilbertson and Barber-Lomax are
Cocco et al.118 matched 180 cases of Dupuytren’s dis- broadly supportive of Mathiowetz’s male grip normative
ease against controls with age matching five years. They values. Grip reaches a maximum in the late 20s and early
found a statistically significant increase in the risk of 30s and halves in old age. Males are noted to be almost
Dupuytren’s contracture in vibration-exposed workers, 50 per cent stronger than females in comparable age bands.
and there appeared to be a dose–response relationship. There was a slight preponderance to the right hand being
Bovenzi et al.119 reviewed 570 quarry workers who had stronger than the left, and minimal difference in the power
been exposed to vibration, using stone workers as controls. of grip between dominant and non-dominant hands. Seven
They considered the odds ratio for developing Dupuytren’s per cent of Mathiowetz’s males and 11 per cent of Hanten’s
contracture was 2.6, although no dose response was identi- study were left-handed. Bohannon125 reviewed ten studies
fied. Thomas and Clarke120 identified a prevalence of and concluded that in all but one study, strength was
Dupuytren’s disease of almost 20 per cent in vibration- greater to the dominant right hand. For dominant left-
exposed workers (double the prevalence in the controls). handers the results were equivocal.
They found no correlation between the Taylor Pelmear Patients suffering from HAVS are frequently noted to
stagings for hand–arm vibration and the prevalence of suffer from weakness of grip.68 Farkkila et al.126 noted muscle
Dupuytren’s disease. The sample size of the three studies is forces to be significantly diminished among workers report-
relatively small and age matching relatively loose. ing numbness in the hands. Weakness was not found in
However, age does have a major effect on the prevalence forestry workers who had been exposed to less than 5000 hours
of Dupuytren’s disease. A review of over 97 000 miners of sawing. Farkkila et al.58 explored the matter further,
seeking compensation for hand–arm vibration syndrome, reassessing grip after a two-year interval. Lumberjacks with
revealed a Dupuytren’s disease prevalence of 1.7 per cent in HAVS (described as white finger) lost 21 per cent of grip
claimants in the 35–39 year age group.56 The prevalence in over the two years, while lumberjacks not suffering from
80–84 year olds was 19.6 per cent. Age was found to be the HAVS only lost 5 per cent of grip. The numbers in the
prime determinant of the prevalence of Dupuytren’s study are small. The HAVS group comprised 11 subjects
Hand–arm vibration and muscle weakness 501
with a mean age of 45 8 years. The mean age of the 44 ten patients who had been chronically exposed to vibra-
subjects considered to have normal grip and no HAVS was tion. A variety of pathological changes to the nerve was
39 (10) years. Mirbod et al.127 performed a similar study noted (including myelin breakdown and intraneural fibro-
over a four-year interval. Fifty-three grinders were assessed sis). These features were not found in a similar number of
for grip over a four-year interval. None were considered to cadaver controls that had not been exposed to vibration.
have HAVS at the first assessment, two at the second Necking and co-workers60 in the same research insti-
assessment. The average diminution of grip was 7.4 per tute, explored the short-term effects of vibration exposure
cent over the four-year interval. The mean age rose from to the hind paws of rats (five hours daily for two days).
42.3 years (range, 37–59) to 46.3 years (range, 41–63). Exposure was noted to expand muscle fibres, and nuclei
Sorensson and Burstrom128 assessed the translation of took on a more central position within the fibre. In a more
vibration to different parts of the arms (knuckle, wrist and recent study, the same group biopsied abductor pollicis
elbow). They confirm that energy transmission decreases brevis in 20 patients known to be suffering from HAVS.132
with increasing distance from the source. There is progres- A variety of abnormalities were noted (centrally located
sive dampening more proximally in the limb. If vibration myonuclei, angulated muscle fibres, ring fibres, regenerat-
causes nerve or muscle injury, the parts most at risk would ing fibres and fibrosis). Most of these changes are indica-
be the intrinsic muscles of the hand, rather than the long tive of direct muscle injury, but angulated fibres were
flexor and extensor muscles of the forearm. Necking et al.129 considered to likely arise from muscle denervation and
explored the effects of vibration on the intrinsic and extrin- re-innervation, suggesting not only direct muscle damage,
sic muscles of the arm in 81 workers exposed to vibration but additional injury to the motor nerve fibres.
and 45 controls. They noted a 7 per cent reduction in In a separate study, Necking observed reduced index
extrinsic muscle power in vibration-exposed patients and a abduction power in patients suffering from hand–arm
19 per cent reduction in intrinsic muscle power compared vibration syndrome.59
to controls. Their study supports the view that the principle Grip strength assessments in 97 581 miners seeking
cause of weakness of grip in vibration-exposed workers compensation for hand–arm vibration syndrome revealed
relates to intrinsic muscle dysfunction in the hand rather weakness of grip in two-thirds of cases.133 Figure 47.1 com-
than the forearm, where energy transmission is less. pares the miner’s grip, by age band, to UK and US norma-
Intrinsic muscle mass may be considered relatively tive values. The effect of vibration exposure on grip was
small compared with the forearm muscles, but the intrinsic not dose-related and was small when corrected for age
contribution to grip is significant. Kozin et al.130 explored (Figure 47.2). The Stockholm neurological and vascular
the contribution of extrinsic and intrinsic muscles to grip stagings had little correlation with grip, except those with a
in 21 volunteers, who were subjected to low median and 3SN rating. Thermal aesthesiometry and vibrotactile
low ulnar nerve blocks. A low nerve block to the ulnar threshold staging also had little correlation with grip, when
intrinsics reduced grip by 38 per cent and a low nerve block corrected for age. The claimants’ low grip values in all age
to the median innervated intrinsics reduced grip by 32 per bands, when compared to normative data were not
cent. Blocks to both median and ulnar innervated intrin- explained. An early vibration effect on grip during the first
sics reduced grip from pre-injection levels by 49 per cent. five years of exposure was not identified.
A series of studies from Malmo in Sweden have indi- Workers exposed to the use of vibrating tools frequently
cated that chronic vibration exposure can damage nerves complain of weakness of grip and research studies have
at the level of the wrist. Stromberg et al.131 biopsied the shown that vibration can cause damage to the small mus-
posterior interosseous nerve at the level of the wrist in cles of the hand and the nerves that supply them. The onset
60
US norms
50 UK norms
Miners
Mean grip strength
40
30
20
10
Figure 47.1 Mean grip by age
0 band: The miners compared to
25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79
United Kingdom and United States
Age band normative data.
502 Hand–arm vibration syndrome
40
5 years exposure
35 40 years exposure
30
Mean grip strength
25
20
15
10
5
Figure 47.2 The effect of vibration
0 exposure of five and 40 years on mean
30 35 40 45 50 55 60 65 70 75 grip right hand by age band (line of
Age (years) best fit).
of weakness requires further investigation to identify any Scientific reviews on the diagnosis of HAVS are collected in
possible dose response. This will allow development of the supplementary issues of the International Archives of
guidelines for working practice. All studies concerning grip Occupational and Environmental Medicine135 which report
strength need to be tightly controlled for age. the First International Workshop on Diagnosis of Injuries
2000 and from the corresponding second workshop held in
Göteborg, 2006.136 The Faculty of Occupational Medicine
HAND–ARM VIBRATION AND BONE AND has reviewed the evidence on clinical testing and manage-
JOINT DISORDERS ment of individuals exposed to hand–arm vibration.9
A number of textbooks,137 websites (for example, www.
Gemne and Saraste134 reported a low frequency of bone and
humanvibration.com) and articles present guidance in the
joint disorders with the use of percussive tools. These dis-
diagnostic process for investigating subjects with suspected
orders take the form of bone cysts or osteoarthritis to elbow
HAVS.
or wrist. Other authors have found cysts to be present in the
The level of diagnostic precision required is determined
carpal bones as frequently in controls as in those exposed
by the outcome required. Screening in the workplace
to vibration. Local attitudes are to an extent moulded by
for disease needs to be simple and easy to carry out, yet
variations in national compensation schemes. Most coun-
alert the professional to the possible presence of disease.
tries do not consider that the available evidence justifies
When disease is suspected more sophisticated diagnosis
compensation for bone and joint disorders routinely.
will be required especially when outcomes may be expen-
sive, such as workers’ compensation claims or when decid-
DIAGNOSIS AND TERTIARY CASE ing on ongoing fitness for work, or in terms of future
ASSESSMENT harm occurring to the individual. The clinical picture of
severe cases presenting to a tertiary care setting will be
Examination models for the diagnostic work up of subjects different from those manifesting early signs in a surveil-
with possible injury from work with vibrating tools and lance setting.
equipment vary with the purpose of the assessment. These Neurological symptoms are usually the first manifesta-
models range from questions about symptoms, signs, the tion of HAVS. Finger blanching, although visible, is almost
possible association between exposure and injury; to invariably the second symptom or sign. Sensory symptoms
questions on fitness for work, disability; through to the can be classified as positive (paraesthesia, dysaesthesiae
evaluation for medicolegal assessment and workers’ com- or pain), negative (motor or sensory loss) or provocable.
pensation. In those instances where the purpose of the Symptom disturbance in early cases of HAVS usually pres-
clinical examination is to confirm a possible association ents with tingling or numbness. Symptoms following
between vibration exposure at work and injury, the assess- immediately after vibration exposure (temporary thresh-
ment may include the following aspects: old shift) are physiologically normal if they disappear
within 20 minutes. Workers may refer to a reduced ability
● evaluation and judgement of symptoms and signs, and to withstand cold and damp conditions (cold sensitivity).
grading of severity; For some susceptible individuals, symptoms may result in
● exposure assessments that include both vibration and early incapacity and reduced workability, while others just
ergonomic aspects; have discomfort. Some cases may present with nothing
● excluding other potential differential diagnoses. more than a loss of sensitivity in the fingertips. As the
Diagnosis and tertiary case assessment 503
condition progresses, more severe symptoms including a the hands and fingers for signs such as as scarring, callosi-
reduction in finger precision, manual dexterity, grip force ties, trophic changes, nail abnormality or Dupuytren’s
or an increase in extent and frequency of finger blanching contacture.
lead to a progressive reduction in hand function and resist- Tinel’s and Phalen’s tests should be performed if carpal
ance to cold. tunnel syndrome is suspected. Grip strength can be
In the occupational health setting, the medical inter- assessed by Jamar dynamometer and dexterity by Purdue
view is currently widely accepted as the best available pegboard test and compared to age-related normative data.
method of diagnosing ‘white fingers’ (Raynaud’s phenom- These along with Semmes–Weinstein monofilaments can
enon). The medical interview should include information be used for assessment in an office environment.
on symptoms, distribution, time and duration of blanch- The assessment should include an assessment of upper
ing. The course, pattern and symptom distribution should limb circulation, including blood pressure in each arm,
ideally be specified pictorially on an upper limb or hand auscultation of the major vessels at the base of the neck
manikin or diagram. Identification of ‘white fingers’ by and upper arm for bruits indicating possible presence
comparison with a standardized colour chart has long of atheromatous disease and thoracic outlet syndrome
since been advocated.138 The medical history should entail (TOS). Roos test and Adson’s manoeuvre can be useful if
assessment of other diseases, injuries or medication that TOS is suspected by symptoms presenting on shoulder
might be related to neuropathy139,140 or those related to abduction. These clinical tests for TOS are of low discrim-
Raynaud’s phenomenon,141 such as autoimmune diseases, inatory value.
endocrine disorders, blood and vessel abnormalities, Allen’s test assesses the patency of the radial and ulnar
malignant diseases and infections (see Table 47.4). arteries supplying the hands. It has always been of doubtful
Several drugs used to treat hypertension, asthma and significance for it cannot distinguish between the normal,
cancer are also vasoactive. Medications such as beta- abnormal and simple anatomical variations that are of no
blockers (see under Vascular clinical features, p. 495), clinical relevance. However, an 8-mHz hand-held Doppler
ergotamine, clonidine, metysergide, bleomycin, vinblas- probe is a more informative method for assessing arterial
tine, lithium and methylamphetamine may be relevant.140 patency in the hands. The Doppler wave-form or laser
Enquire about potentially relevant occupational exposures – Doppler may show evidence of conditions such as occlu-
rarely specific organic solvents and heavy metals can cause sive vascular disease and hypothenar hammer syndrome.
neuropathy139,140 and chemicals, such as arsenic, vinyl Capillary recirculation time (Lewis–Prusik test) is of very
chloride and lead, are likely to influence the occurrence of limited diagnostic use.
Raynaud’s phenomenon.141 Exposure to stress and tobacco If, after history and examination, there is no or low sus-
consumption may add to the interpretation of the medical picion of an underlying disease, then there is no need for
history. further specialized testing. If there is a suspicion that the
A history of exposure to a significant degree of vibration patient has secondary RP, then further evaluation is
is required when diagnosing a presentation of Raynaud’s needed.140 The musculoskeletal examination should follow
phenomenon as VWF, or a sensory neuropathy as a standard clinical orthopaedic examination,142 specifically
vibration-associated neuropathy. An understanding of the looking for signs of carpal tunnel syndrome, Dupuytren’s
level of vibration magnitude and its limitations is an contracture and osteoarthritis (Figure 47.3).
essential stage in reaching a diagnosis. Mean frequency,
intensity level, trigger times and overall duration are all
important. The amount of vibration transmitted to the Laboratory tests
hand is modified by ergonomic factors such as grip and
push forces and if possible an inspection of the job may BLOOD TESTS
provide valuable information especially where symptoms
are asymmetric. Work organization and work technique For subjects with a suspected neuropathy, blood tests will
may influence the amount of exposure indirectly. include blood count, sedimentation rate, blood glucose
determination, serum protein electrophoresis, thyroid
studies and vitamin B12 level. Although where a peripheral
Physical examination neuropathy exists it is unlikely that blood tests will reveal
an unknown pathology.139
Guided by a differential diagnosis from the history, a care- If secondary RP is suspected, blood tests should also
ful examination should be performed. Both upper and include renal and liver function, rheumatoid factor, cold
lower extremities should be examined in order to exclude agglutinins, complement (C3 and C4) and ANA (if posi-
possible signs of neuropathy, upper limb pain or other tive, tests for antitopoisomerase I and anticentromere anti-
systemic disease. (This examination will assist in inter- bodies are indicated). Although country-specific medical
preting abnormal findings in subsequent quantitative custom will determine who carries out these tests, it is
sensory threshold (QST) and electrodiagnostic testing.) recommended that they are performed in the tertiary
The examiner inspects the appearance of the distal parts of specialist setting.
504 Hand–arm vibration syndrome
(a) (d)
(b)
(e)
There is currently no established algorithm that unam- ● likely to be regularly exposed above the action level of
biguously identifies the specific diagnosis of HAVS. A his- 2.5 m/s (A8); or
tory of increase of tingling and/or numbness suggests ● likely to be exposed occasionally above the action value
possible sensorineural abnormalities requiring further and where the risk assessment identifies that the
investigation. A clinical description comprising cold- frequency and severity of exposure may pose a risk to
induced whitening of the skin of the distal phalanges, health; or
with a clear demarcation from the normal proximal skin, ● have a diagnosis of HAVS (even when exposed below
constitutes a minimum criterion for the diagnosis of the action value).
506 Hand–arm vibration syndrome
The application of this directive in six European countries interval can vary from six months to 20 or more years
has been reviewed and several countries, such as Italy, between first exposure and onset of vascular symptoms.
Sweden and Germany, have adopted local guidelines with Some workers are peculiarly resistant to the effects of
differing approaches.11 vibration.
The Control of Vibration at Work Regulations 2005 Accepting differing national regulatory frameworks, it
implemented in July 2005 in the United Kingdom would seem reasonable that HAVS cases diagnosed at
describes a five-step tiered approach to health surveil- stage 1 on the SWS should be allowed to continue with
lance.22 This includes a pre-employment or pre-placement exposure, unless there has been a particularly short latent
baseline check by a qualified person, and annual review by interval or rapid progression of symptoms. Stage 1 cases
either a qualified person or a responsible person. A positive should be reviewed annually with recommendations for
result is referred to tier 3 for health assessment by a quali- reduction in exposure along with a review of control meas-
fied person, normally a suitably trained occupational ures to reduce exposure as far as possible and ideally not
health nurse. A tentative diagnosis of HAVS should lead to exceed an A(8) value of 1.0 m/s2.
referral to tier 4 which involves a formal diagnosis carried For later stages, consensus statements and evidence
out by a suitably trained doctor qualified in occupational reviews have recommended exposure cessation that pre-
health, who can advise on fitness for work. An optional tier vents the development of either stage 3 vascular or stage 3
5 involves referral to a specialist centre for standardized sensorineural on the Stockholm Workshop Scale.21,151 At
vascular and sensorineural tests. the onset of stage 2, there should be closer monitoring,
say six monthly, and a similar review of exposure and
control measures. Follow up of existing cases after cessa-
MANAGEMENT OF CASES tion of exposure should continue until they are free of
symptoms. A more recent recommendation from the
Management of individual cases Health and Safety Executive (HSE) in the United
Kingdom is to prevent HAVS stage 3 developing, as this
The approach to managing individual cases of HAVS is represents a more severe form of disease with associated
limited by our understanding of the natural history and loss of function and disability.22 The National Institute
prognosis of the condition. Objective evidence of of Occupational Safety and Health recommends the
reversibility in HAVS is weak. Reversibility is greater for removal from exposure at neurosensory or vascular
vascular symptoms than sensorineural symptoms, but Stockholm stage 2 or above.19 Stage 2, however, ranges
unlikely in those with stage 3 symptoms.148 from minimal neurosensory symptoms, through to
Regardless of the stage the condition has reached, imminent functional disability. Lawson and McGeoch
there are a number of generic recommendations that divided stage 2 into an early and late stage.6 The progres-
may reduce the chance of progression. These include reduc- sion to late stage 2 then becomes a stronger criterion for
tion in exposure and advice on maintaining general recommending cessation of exposure. The ultimate deci-
body warmth, avoiding cold damp conditions and specifi- sion for removing an employee from exposure is between
cally smoking cessation.149,150 In practice, the progression the employer and the employee. The employer’s duty of
in an individual case very much depends on intangible care needs to be offset by the rights of the employee to
variables including whether the employer has a policy, have an informed acceptance of risk. The tipping point in
individual susceptibility and inadequate exposure–response favour of the employer’s duty of care to accept a recom-
models.146 mendation of removal from exposure is at late stage 2.
The Physical Agents Vibration Directive exposure Terms ‘intermittent’, ‘persistent’ and ‘constant’ have
action value (EAV) for the introduction of health surveil- been suggested as a way of separating ‘2 early’ from ‘2
lance effectively accepts a likely prevalence of 10 per cent late’ in a sceening environment.22 The HSE subsequently
finger blanching after nine years of exposure.17 The went on to recommend that an employee will only be
apparently pragmatic recommendation to reduce expo- declared unfit when the disease has reached ‘a late stage 2’.
sure may not be practicable for the employee’s patterns They qualify this for older employees, closer to retire-
of work. The effective vibration dose can depend on ment, who fully understand the ongoing risks. They
intermittency of exposure, the magnitude and direction may continue work with limited exposure and regular
of applied grip forces and adopted body postures. surveillance.
Vibration magnitudes from the same tools can vary In many respects, the ideal management of someone
greatly depending on the background tool maintenance affected by HAVS is to remove them from vibration expo-
programmes. sure altogether. Continuing exposure is a compromise
International Organization for Standardization dose– between the ideal and the practical. Medically, however, it
response models suggest no observed effect levels at expo- makes little sense to continue to expose someone to a phys-
sures of less than 1 m/s2, although this cannot be regarded ical agent which has already caused harm. From follow-up
as a ‘safe level’ (ISO 5349, Annex C 2001).16 The latent studies, once established sensorineural-only HAVS shows
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48
Whole body vibration
4 000 000
3 500 000
mechanical truck drivers, farm owners and managers, farm
3 000 000 workers and drivers of road goods vehicles (Figure 48.2).
2 500 000 The highest estimated median occupational eVDVs were
2 000 000 found in forklift truck drivers, drivers of road goods vehi-
Males
1 500 000 cles, bus and coach drivers, and technical and wholesale sales
1 000 000 representatives, among whom a greater contribution to total
500 000 Females
dose was received from occupational exposures than from
0
0 2 4 5 6 8.5 10 12 14 15
non-occupational ones; but in many other occupations the
Minimum eVDVT (ms1.75) reverse applied. Leisure time and commuting exposures are
also very common.
Figure 48.1 Minimum estimated numbers of men and women Other measurements of vibration magnitude (vibration
in Great Britain whose daily equivalent estimated vibration dose total value (or vector sum) of the frequency-weighted rms
(eVDV) from all occupational sources in the past week exceeded accelerations) have been made in industrial surveys cover-
the values indicated. Reproduced with permission from BMJ ing specific vehicles, with reported values varying from
Publishing Group.5 0.25 to 0.67 ms2 in cranes, 0.36 to 0.56 ms2 in buses, 0.35
to 1.45 ms2 in tractors, and 0.79 to 1.04 ms2 in forklift
trucks and freight-container tractors.10
COMMON SOURCES OF EXPOSURE
Figure 48.2 Occupations in which significant exposures to whole body vibration most commonly arose in the past week among
employed men. Reproduced with permission from BMJ Publishing Group.5
Thus, for example, a systematic review by the US National musculoskeletal symptoms, but medical records and radio-
Institute for Occupational Safety and Health (NIOSH) logical investigations were sometimes also available.
described evidence on the association with LBP as ‘strong’ Table 48.1 presents meta-analyses for four outcomes
(15 of 19 studies positive),37 while a review by Bovenzi and where results could be combined10 – 12-month and acute
Hulshof 10 reached similar conclusions and offers a model of LBP, sciatic pain and herniated disc – all based on self-
the generally available evidence. In a systematic search using reports in the original cross-sectional surveys. It may be
several databases and a broad definition of outcome, these seen that summary prevalence odds ratios (POR) are raised
authors retrieved 45 articles. The quality of each study was for all outcomes and by up to two-fold. A recent further
evaluated in terms of methodology and the care taken in meta-analysis, carried out by the first author, of cross-
assessing vibration exposure and health effects; then a meta- sectional studies published between 1986 and 2006, con-
analysis was conducted to combine the results of independ- firms previous findings, with a summary POR of 2.4 (95
ent studies of sufficient quality. Altogether, 17 articles per cent CI, 2.0–2.8) for 12-month LBP in 16 driver groups
reporting the occurrence of back disorders in 22 WBV- (Figure 48.3). On the basis of such evidence, WBV is con-
exposed occupational groups, met the inclusion criteria. sidered one of the best-established risk factors for LBP.
Most of these studies were cross-sectional in design (13 occu- However, longitudinal data are still relatively sparse and
pational groups), but in four groups longitudinal data were cross-sectional studies suffer some well-known limitations.
available. The main reasons for exclusion of studies were These include the potential for affected workers to be
insufficient quantitative information on exposures to WBV, selected out of exposure (healthy worker effect), with
lack of control information and a failure to consider impor- underestimation of risks, or (less likely) the selection of
tant confounders. Typically, the qualifying studies focused workers with back pain into driving jobs as an alternative
on crane operators, bus drivers, tractor drivers and forklift to, say, heavy manual work, with overestimation of risks.
truck drivers with administrative or manual workers as con- Cross-sectional studies are also limited by inaccuracies in
trols. Vibration measurements on the vehicles were per- the assessment of prior exposures. In addition, a problem of
formed according to ISO 2631-1, and vibration total value or interpretation arises in that prevalence depends not only on
vector sum of the frequency-weighted rms acceleration incidence but also on duration, and could be higher
ranged from 0.25 to 1.45 ms2. Outcome assessment through prolongation of, rather than initiation of, symp-
focused mostly on symptoms reported at medical interview toms. Thus, to strengthen the evidence base and to define
or in response to the standardized Nordic questionnaire on safe working limits of exposure, interest has focused on
516 Whole body vibration
Table 48.1 Meta-analysis of several cross-sectional surveys of back problems and whole body vibration (1986–97).10
Forklift truck drivers14,22 1.7 (0.9–3.1) 1.7 (0.7–4.2) 2.7 (0.6–1.2) 0.8 (0.2–2.6)
7.3 (2.5–22) 2.8 (1.3–6.3) 1.0 (0.5–2.2)
1.6 (1.0–2.6)
Tractor drivers19,26 2.0 (1.2–3.4) 1.0 (0.5–1.9) 1.6 (0.9–3.0) 2.1 (0.8–5.6)
2.4 (1.6–3.7) 3.0 (1.8–5.0) 3.9 (1.8–8.7) 1.8 (0.7–4.7)
Wheel loaders17 1.3 (0.5–3.2) 0.5 (0.2–1.5) 1.0 (0.3–3.1)
Bus drivers24 3.0 (1.8–5.1) 1.9 (1.2–3.3) 1.9 (1.2–3.3) 1.3 (0.6–3.0)
Crane operators20 3.3 (1.5–7.1)
Straddle-carrier drivers20 2.5 (1.2–5.4)
Subway train operators21 3.9 (1.7–8.6)
Summary prevalence OR (95% CI) 2.3 (1.8–2.9) 1.7 (1.1–2.7) 2.0 (1.3–2.9) 1.5 (0.9–2.4)
Combined
0.5 1 2 4 16
Prevalence odds ratio, log scale
Figure 48.3 Prevalence odds ratios (POR) and 95 per cent confidence intervals (CI) for 12-month low-back pain in 16 driving
occupations with exposure to whole body vibration compared to control groups. The POR of each study is adjusted for several confounders
(individual characteristics, ergonomic risk factors and/or psychosocial variables). The area of each box is inversely proportional to the
estimated variance in the study. Random effects estimation of the combined POR and 95 per cent CI is shown.
longitudinal studies and on evidence on exposure–response age-adjusted risk ratio for disability pension was raised
relations. almost three-fold and increased with years of driving experi-
Current information in these areas comes largely from a ence,15 while age-adjusted rates of prolonged sickness
series of studies commissioned by the Dutch Ministry of absence (
28 days) were also somewhat higher.16 However,
Social Services and Employment, in the 1980s. Retrospective prolonged sickness absence was somewhat less common for
cohort studies in crane operators,15,16 tractor drivers19 and non-specific LBP and back disorders overall.16 Similarly, in
other transportation workers examined risks for prolonged tractor drivers, an increasing trend of sick leave with increas-
sick leave and disability pensioning, as demonstrated by ing dose was found for disc complaints, but not for non-
social insurance and medical records. Findings were supple- specific LBP19 – using a Cox model, estimated RRs were 2.47
mented with in-fill cross-sectional surveys in other exposure and 0.94, respectively, for a dose increase of five years m2/s4.
groups.17,18,22,23 A complex picture emerged. In one survey, In the cross-sectional surveys, there tended to be
a relation was found between intervertebral disc disorder excesses of back complaints, but a less clear picture accord-
and working for more than five years as a crane operator: the ing to dose and disorder. In a small study involving drivers
Health effects 517
Table 48.2 Effects of cumulative vibration exposure and postural load on chronic low-back pain in a
population of 1155 tractor drivers and 220 controls unexposed to whole body vibration.
of wheel loaders,17 for example, back pain was somewhat Table 48.3 Odds ratiosa for the combined effect of cumulative
less common in those from the low exposure band and vibration exposure and postural load on the occurrence of chronic
somewhat more common in those from the high band, but low-back pain in tractor drivers.26
in lift-truck and freight-container tractor drivers, back pain Cumulative vibration
lasting several weeks was marginally less common in the exposure Postural load (grade)
high exposure group.19 Back pain was more common than (years m2s4)b
in non-driver referents, but within the exposed group was Mild Moderate Hard Very hard
more common at younger ages, related largely to dose
within the short term (the five years preceding back pain 5 1.29 1.79 2.50 3.48
onset). In a cross-sectional survey of helicopter pilots,18 10 1.41 1.96 2.73 3.79
much higher odds ratios were reported than in other sur- 20 1.55 2.15 2.99 4.16
veys involving higher levels of exposure to WBV. LBP and 30 1.63 2.27 3.16 4.39
lumbago were more prevalent in pilots from the least and 40 1.70 2.36 3.29 4.58
most exposed bands, defined by dose and cumulative dur- a
With reference to controls exposed to mild postural load and unexposed
ation of flying (a U-shaped relationship), whereas these
to vibration.
outcomes increased with hours of daily flight time, as did b
Cumulative vibration exposure was estimated as in Table 48.2.
back pain lasting more than two weeks. Prevalence of sciat- Odds ratios were adjusted for age, body mass index, smoking, education,
ica showed a monotonic relationship to estimated vibration sport activity, car driving, marital status, mental stress, climatic
dose, but peaked with intermediate durations of lifetime conditions and previous back trauma.
and daily flight time.
Such differences may reflect real differences in the risks postural load were found to be independently associated
of different outcomes (e.g. LBP versus prolapsed disc) in with chronic LBP, defined as daily experience of LBP or
relation to different metrics of exposure (e.g. short versus several episodes of LBP lasting more than 30 days in the
long term). However, they may also reflect a combination previous 12 months (Table 48.2). A significant trend was
of measurement errors, selection effects and uncontrolled found with higher levels of both vibration dose and pos-
confounding. The high rates of back pain in helicopter tural load, such that tractor drivers with high exposure to
pilots, for example, have been attributed partly to the both factors had a more than three-fold elevated risk of
cramped space of cockpits as a source of transient discom- chronic LBP relative to subjects who scored low on these
fort.18 Other potential confounders common among pro- counts (Table 48.3). The analysis also took account of
fessional drivers include heavy lifting (e.g. loading and other risk factors for LBP such as age, body mass index,
unloading of delivery vehicles by hand), and twisting with smoking, sporting activity, mental health and previous
a non-neutral trunk position (e.g. looking behind when back trauma.
manoeuvring a forklift truck). However, even with great care in execution, a problem
In a growing number of surveys, special effort has been exists in disentangling the separate risks of sitting and
made to control for confounding by known causes of back WBV. Intradiscal pressure is higher when sitting, and so
disorders. A cross-sectional study of tractor drivers by prolonged sitting is a biologically plausible confounder,
Bovenzi and Betta26 provides one example. In an epidemi- especially given that both exposures are almost always
ological survey of 1155 tractor drivers and 220 controls present together. Estimates of dose often incorporate an
unexposed to WBV, cumulative vibration exposure and allowance for time as well as vibration magnitude, so
518 Whole body vibration
(pain can occur in the absence of demonstrable pathology, Table 48.4 Daily exposure action values and daily exposure
disc changes are common even in people without LBP,41 limit values for whole body vibration (WBV) according to the
and symptoms come and go without a change in imaging European Directive 2002/44/EC on mechanical vibration.4
status), and the same may be true of LBP associated with
A(8) (rms) VDV
professional driving. Symptoms can arise from local soft
tissue injury, or be moderated, reinforced or perpetuated
by higher level inputs from the central nervous system.46 Daily exposure action value 0.5 ms2 9.1 ms1.75
Reflecting this, experience of LBP is common across all Daily exposure limit value 1.15 ms2 21 ms1.75
jobs and influenced importantly by psychological factors, A(8) is the daily vibration exposure value normalized to an eight-hour
including illness beliefs and mental health. Nociception, reference period and VDV is the Vibration Dose Value (see text for
pain, suffering, pain behaviour and disability are only definitions).
partially correlated.47
Local injury may be an initiating event, but a question offset under the averaging method by periods of low vibra-
arises as to whether high peak of exposures matter most tion, whereas this does not reduce VDV. Griffin suggests
(acute injury) or long-term steady exposures with insuffi- that the Directive does rule out ‘extraordinarily high’
cient recovery (chronic wear and tear). Some epidemi- vibration of short duration if assessed by the rms method –
ological studies have found a greater risk of back symptoms severe enough to be intolerable to those exposed to vibra-
and referred pain with more years of driving, but this does tion.52 He suggests it would be prudent to base actions on
not necessarily favour a long time course of pathogenesis – qualitative guidance, to reduce risks to a minimum, rather
more time could simply give more opportunity for acute than relying on this quantitative guidance.
injury – and other studies have reported raised risks within Uncertainty is compounded because the thresholds
quite short intervals of driving (e.g. in a study by Boshuizen chosen are not rooted in a clear understanding of the
et al.,23 ORs were raised by five-fold for frequent or long- exposure–response relationship.
lasting LBP or prolapsed disc in tractor drivers with as little
as 0–5 years of exposure) and at young ages.19
Animal experiments have demonstrated that excessive FACTORS AFFECTING EXPOSURES AND
mechanical overload can result in structural injury and CONTROL MEASURES
degeneration of the tissues of bones and joints.48 Repeated
impact loading can lead to cumulative microdamage and In addition to the magnitude, duration and pattern of
metabolic changes in bone and cartilage of the rabbit WBV, several other factors may relate to the injury poten-
tibia;49 and there is evidence that heavy vibration loads and tial, including individual susceptibility to injury, the
repetitive mechanical shocks can cause stress damage in dynamic response of the human body (mechanical imped-
porcine intervertebral discs.50 Animal experiments, how- ance, vibration transmissibility, absorbed energy), body
ever, have seldom been undertaken to explore mechanisms posture and health status. Dose may be related to the
and the impact of different controlled patterns of vibration design of the vehicle, the cabin seating, the suspension, the
exposure.51 road conditions, the road speed and ultimately the behav-
iour and training of the driver.
Consistent with these notions, Article 4 of Directive
CONTROL STANDARDS 2002/44/EC4 requires the employer to assess and, if neces-
sary, measure the levels of WBV to which workers are
Reflecting current uncertainty, the distinction between exposed, giving particular attention to such items as:
shocks and steady continuous exposures is glossed over in
current control standards. Table 48.4 sets out exposure a. the level, type and duration of exposure, including any
standards for WBV according to the European Directive exposure to intermittent vibration or repeated shocks;
2002/44/EC,4 defined in terms of an exposure action value b. the Exposure Limit Values and the Exposure Action
(EAV) – the daily amount above which employers must act Values laid down in Article 3 of the Directive;
to control exposure, and an exposure limit value (ELV) – c. workers specially sensitive to risks;
the maximum amount an employee may be exposed to on d. any indirect effects on worker safety resulting from
any given day. (Regulations in member countries permit a interactions between mechanical vibration and the
transitional period until July 2010 for work equipment in workplace or other work equipment;
use before July 2007.) EAVs and ELVs are expressed either e. information provided by the manufacturers of work
in terms of A(8) (rms), an averaging method, or VDV, a equipment in accordance with the relevant Community
dose measure that accumulates exposures in accord with a Directives;
fourth power time dependency. However, as Griffin52 points f. the existence of replacement equipment designed to
out, these methods are not equivalent and show ‘a large reduce the levels of exposure to mechanical vibration;
internal inconsistency … for short duration exposures to g. the extension of exposure to WBV beyond normal
WBV’. Specifically, high short-term peaks (shocks) can be working hours under the employer’s responsibility;
520 Whole body vibration
h. specific working conditions such as low temperatures; Implementation is problematic however, in that LBP is
i. and appropriate information obtained from health so common in the general population as to be expected in
surveillance, including published information. many workers, drivers and non-drivers alike, while there
are differing views on the added value of physician’s exam-
Where exposures exceed the EAV, employers must elim- ination over screening questionnaires (the HSE recom-
inate or reduce risks as far as reasonably practicable and mends a simple system of health monitoring for workers at
exposures should not exceed the ELV (Article 5). greater risk).53 Surveillance implies pre-employment and
The prevention of ill health and injury requires adminis- regular periodic inquiry, but back pain episodes may come
trative, technical and medical responses, many of which are and go in-between inquiries, and the immediate manage-
specified in or supported by the Directive. Administrative ment of cases will mostly be dictated by severity of symp-
measures include adequate information and advice to toms and incapacity in the acute phase, extremes of which
employers and employees (Articles 6 and 7), organiza- normally lead to consultation independent of regular
tional changes in the work, and training to instruct the inquiry. Thus, the main virtues of health monitoring may
operators of vibrating machinery in safe and correct work lie in identifying extremes of unacceptable exposure, in
practices. Work schedules should be arranged to include ensuring systematic coverage, and in gaining a group level
rest periods. impression of the success in controlling health problems.
Technical measures include the choice of vehicles with Where surveillance is undertaken, it should be managed by
the lowest vibration and best ergonomic designs. An EC certified occupational health personnel.
Directive concerning the safety of machinery [89/392/EEC]
obliges manufacturers to state whether the frequency-
weighted acceleration of WBV exceeds 0.5 ms2 rms, to
facilitate informed choice. Key points
Within the United Kingdom, where the Directive is
● Whole body vibration is a very common
implemented as the Control of Vibration at Work
Regulations 2005, the Health and Safety Executive53 advises component of the working environment,
on several preventive precautions: drivers should adjust especially when account is taken of the many
their seating, avoid rough, poor or uneven surfaces, and professional drivers with low-level exposures in
moderate their speed to suit road conditions; vehicle sus- delivery and transport duties.
● Substantial industrial exposures are less
pensions should be maintained as should site roadways,
‘safer systems of work’ should be encouraged with sufficient common, but many workers still approach the
rest breaks and care should be taken in the choice of seating. exposure standards set in European legislation
and many contribute additionally to total dose
during leisure-time travels and commuting.
● Exposure to WBV is generally thought to be a
HEALTH SURVEILLANCE
cause of work-related back pain and a great deal
The Directive also requires health surveillance, assuming a of epidemiological evidence supports this, while
reasonable likelihood of health problems arising, a valid not excluding a role for other concurrent risk
means of detection and sensible options for response. factors, such as posture and prolonged sitting.
● Knowledge of the exposure–response relation is
According to article 8, para 1: ‘health surveillance, the
results of which are taken into account in the application of incomplete and the current control standards
preventive measures at a specific workplace, shall be intended are to an important extent arbitrary.
● In spite of this uncertainty, many practical steps
to prevent and diagnose rapidly any disorder linked with
exposure to mechanical vibration. Such surveillance shall be can be taken to mitigate risks of ill health which
appropriate where: can be supported, to a greater or lesser extent, as
sensible occupational health and safety practice.
● Control by engineering means is preferable to
● the exposure of workers to vibration is such that a link can
be established between that exposure and an identifiable measures aimed at changing behaviour. Both,
illness or harmful effects on health; however, offer scope for intervention.
● it is probable that the illness or the effects occur in a
worker’s particular working conditions;
● there are tested techniques for the detection of the illness or REFERENCES
the harmful effects on health.
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daily Exposure Action Values] shall be entitled to appropri- evaluation of human exposure to whole body vibration – Part
ate health surveillance.’ 1: General requirements. ISO 2631-1. Geneva: ISO, 1997.
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37. National Institute for Occupational Health and Safety. 1965; 50: 971–9.
Musculoskeletal disorders and workplace factors. A critical 47. Waddell G. The back pain revolution. Edinburgh: Churchill
review of epidemiologic evidence for work-related Livingstone, 1998.
musculoskeletal disorders of the neck, upper extremity, 48. Waters T, Rauche C, Genaidy A, Rashed T. A new framework
and low back. Cincinnati, OH: US Department of Health and for evaluating potential risk of back disorders due to whole
Human Sciences/NIOSH, 1997 (publication no. 97–141). body vibration and repeated mechanical shock. Ergonomics.
38. Burdorf A, Sorock G. Positive and negative evidence on risk 2007; 50: 379–95.
factors for back disorders. Scandinavian Journal of Work, 49. Radin E, Martin R, Burr D et al. Effects of mechanical
Environment and Health. 1997; 23: 243–56. loading on tissues of the rabbit knee. Journal of Orthopaedic
39. Bovenzi M, Hulsof CTJ. An updated review of epidemiologic Research. 1984; 2: 221–34.
studies on the relationship between exposure to whole-body 50. Tsai K, Lin R, Chang G. Rate-related fatigue injury of
vibration and low back pain. Journal of Sound and Vibration. vertebral disc under axial cyclic loading in a porcine
1998; 215: 595–612. body – disc-body unit. Clinical Biomechanics. 1998; 13:
40. Ling S, Leboeuf-Yde C. Whole-body vibration and low back S32–S39.
pain: A systematic, critical review of the epidemiological 51. Seidel H. Selected health risks caused by long-term, whole-
literature 1992–1999. International Archives of body vibration. American Journal of Industrial Medicine.
Occupational and Environmental Health. 2000; 73: 290–7. 1993; 23: 589–604.
41. Lawrence JS. Disc degeneration – its frequency and 52. Griffin MJ. Maximum health and safety requirements for
relationship to symptoms. Annals of Rheumatic Diseases. workers exposed to hand-transmitted vibration and
1969; 28: 121–38. whole-body vibration in the European Union: A review.
42. Hulshof CTJ, Verbeek JHAM, Braam ITJ et al. Evaluation of Occupational and Environmental Medicine. 2004; 61:
an occupational health intervention program on whole body 387–97.
vibration in forklift truck drivers: A controlled trial. 53. Health and Safety Executive. Vibration at work. Last
Occupational and Environmental Medicine. 2006; 63: accessed July 27, 2007. Available from:
461–8. www.hse.gov.uk/vibration/index.htm.
SECTION THREE
E HOWARD N OAKLEY
applied stress (thermally, the physiological and behav- PHYSICAL AND PHYSIOLOGICAL PRINCIPLES
ioural responses that result from thermal load). The use-
fulness of this distinction should not be underestimated: Overall, the human body is subject to the law of conserva-
for example, the measurement of stress is useful in predict- tion of energy, succinctly expressed in the equation:
ing the safe exposure for groups, while measurement of
M (R C K E) S
strain can assess how well a given individual is coping with
a certain stress, and thus whether or not that person should where M is the heat generated by metabolism (always
be withdrawn or treated. positive); R is the net radiant heat exchange with the envir-
This chapter reviews the fundamental factors in human onment (negative for loss from the body); C is the convect-
heat exchange, describes the reactions to thermal stress and ive heat exchange with the surrounding fluid (negative for
their adverse consequences, and outlines approaches to the loss); K is the conductive heat exchange with any contact-
modification of both stress and strain. Although coverage ing solid (negative for loss); E is the evaporative heat loss
includes discussion of local cold injury, such as frostbite, resulting from the evaporation of liquid from the body or
thermal burns are omitted in deference to authoritative its clothing (almost always positive for a loss from the
accounts elsewhere. body, or zero); and S is the heat stored (positive) or lost
1. Sedentary, in balance. In sedentary work, M will be heat that they generate, perhaps 200 W or more, will be
approximately 100 W. For S 0, thermal equilibrium, stored at S. This results in a rapid rise in body temperature,
most of that 100 W will be lost in C, with a small loss in perhaps as high as 10°C per hour, and rapid onset of heat
E as a result of ‘insensible perspiration’. illness.
M 100
S0 M 250
S 250
M 100
S –700
(negative) by the body, and thus reflected in a change in Should heat production not match heat loss, heat will
mean body temperature. either be gained or lost from the body, according to the
Basal metabolic heat generation remains relatively sign of S defined above, and it is this which results in a
constant in health, but is diminished in hypothermia, change in body temperature. The over-simplistic single-
endocrine disorders such as hypothyroidism, certain drug element model of the body then fails to show the change in
intoxications, and other disorders. It rises following a meal internal thermal gradients that occurs. If excessive heat is
(the ‘specific dynamic effect’), and in some endocrine and being lost from the skin, the peripheries will cool first and
other disorders. However, the greatest variation in metab- there will be little effect on the ‘core’ other than its shrink-
olism is seen in the additional heat generation resulting ing in effective volume; this strategy of ‘sacrificing’ the
from physical activity. Depending on the intensity of that homeostasis of the peripheries in order to preserve the core
activity, total metabolic heat production can vary from less environment is important in paving the way for local cold
than 80 W when asleep, to over 500 W during short-duration injury. Insufficient heat loss and a rising ‘core’ temperature
intense exercise by a trained athlete. tends to externalize the core by reducing thermal gradients
The four modes of heat exchange (R, C, K and E defined with the peripheries, and increasing the volume of the
above) are each governed by physical laws that, in theory at body at core temperature.
least, allow their precise computation. In practice though,
information is seldom sufficiently complete, and more
empirical relationships have to be used. Most popular are Responses to cold
lumped equations analogous to Ohm’s law:
The primary physiological responses to cold exposure
q t/h are peripheral vasoconstriction, piloerection, and the
increase in metabolic heat production by shivering. Skin
where q is the heat flux by that route, t is the thermal differ- temperature falls first, a result of local cooling without a
ential driving that mode of heat exchange, typically the dif- corresponding increase in the delivery of heat to the skin
ference between the surface and ambient temperatures, but by the flow of blood. This fall in skin temperature stimu-
notably the difference between fourth powers of tempera- lates peripheral cold receptors and leads to both locally
tures in the case of radiant heat transfer (R), and h is the mediated and centrally regulated vasoconstriction, which
coefficient of resistance to that mode of heat exchange. in turn allows a further fall in skin temperature. If the rest
Although empirical, such equations are valuable in of the body is sufficiently warm, cyclical cold vasodilata-
demonstrating the crucial importance of temperature gra- tion (‘cold induced vasodilatation’ or the ‘hunting reaction’)
dients in determining the direction and size of heat flows. may ensue, with skin temperatures falling below 12°C, rising
Heat cannot flow against a temperature gradient. with the vasodilatation, and then falling again. The mechan-
The magnitude of each mode of heat exchange is thus ism responsible for this phenomenon remains controver-
set by a combination of environmental conditions, includ- sial, but extensive experimentation has shown that it is very
ing ambient radiation, air movement, temperature and variable between and within individuals, and absent if the
water content, together with skin temperature and cloth- rest of the body is cold.1 Sustained peripheral vasoconstric-
ing worn. For example, some industrial environments tion may be accompanied by fluid shifts resulting in a
impose a high radiant heat load (R) from hot machinery, reduction in plasma volume. Shivering first appears as
molten metals and flame; this can be usefully attenuated by short bursts in a few groups of muscles, becoming continu-
garments coated with an outer metallized reflective layer. ous and generalized as a rectal temperature of about 35°C
However, this may in turn render the garments imperme- is reached. Further cooling or exhaustion results in shiver-
able to water vapour transfer, resulting in evaporative heat ing gradually tailing off, until it is replaced by generalized
loss (E) falling to zero. Another major factor that affects rigidity and finally the flaccidity of imminent death.
thermal resistance is the difference in physical properties of
fluids: convective exchange with water is much greater
than that with air. Responses to heat
A common error in the application of physics to human
thermoregulation is to assume that the body can be treated Under heat stress, changes in blood flow to the periphery
as a single inert and undifferentiated entity. Regulatory are again the earliest response, followed by an increase in
mechanisms respond to central (or ‘core’) temperatures evaporative heat loss by sweating. The normally low nutri-
quite differently from those in the periphery. When some- ent skin capillary flow is augmented by the opening of arte-
one who is hyperthermic immerses their hands in cold riovenous anastomoses in the skin, which allow high rates
water, peripheral vasodilatation is maintained and they can of heat transfer from the deeper body to its surface without
lose substantial amounts of heat into the water; euthermic altering capillary exchange. This increases skin tempera-
or hypothermic subjects will not only vasoconstrict on ture, driving higher rates of heat loss as long as the ambient
(cold) hand immersion, but may not be able to vasodilate temperature is lower than that of the skin. When this tem-
even if the hands are immersed in warm water. perature difference becomes too small to support adequate
528 Heat and cold
the cold, as it is depressed by cold saliva, and infrared tym- to this is earlier and more marked cold vasodilatation,
panic techniques are likely to be dangerously misleading.4 which may be a result of reduced vasoconstriction, described
Skin temperatures can give warning of lesser degrees of in occupational groups subjected to repeated peripheral
general cold strain, and are necessary measures of local cold cold exposure, such as fish filleters.7
strain, particularly when there is a risk of cold injury.
Techniques are based on thermistors or thermocouples, or
infrared emission measurement systems for uncovered skin. Freezing cold injury
Repeated efforts have been made to estimate core tempera-
ture from measurements of skin temperature taken under Local freezing of tissues, the most rapid and dramatic form
insulation. In cold environments at least, these are doomed of cold injury, may occur when people are exposed to
to failure because of the great variation in subcutaneous temperatures below 0°C without adequate protection or
insulation and local skin blood flow. Electromyography opportunities to return to warm environments when the
(EMG) and oxygen uptake can be used to assess shivering extremities become chilled.
and total metabolic heat production, although these are of The areas most commonly affected include fingers and
limited value outside the laboratory. toes, followed by nose, cheeks and ears, and occasionally
the male genitalia. The last can occur in association with
excessive consumption of alcohol or drugs of abuse, or as a
Adaptation and habituation result of running without windproof underwear.8 Such
injuries may be associated with hypothermia, in which case
Repeated brief exposures to cold produce clear reductions the potentially life-threatening condition must be treated
in both the vasoconstrictor and metabolic responses to first, or with local or general trauma.9 Although most com-
cold stress. A course of just eight repeated cold (15°C for monly seen in wartime and the military, freezing cold
40 minutes) immersions has been shown to attenuate the injury is also seen in those undertaking winter sports and
initial hyperventilation and tachycardia found during the in outdoor workers in cold climes, sometimes when the air
initial responses to cold immersion.5 Adaptation of more temperature is not particularly low.10 Cases can occur in
sustained responses has been seen to be more variable and those working in cold stores and other processing plants.
difficult to demonstrate, although they may play a part in Those who now appear most vulnerable are maintenance
the physiology peculiar to long-distance sea swimmers,6 engineers, who may need to work with limited hand pro-
and in the reduced response to cold by aboriginal peoples tection, and lubricants may contaminate their clothing and
in Australia and Ama divers. It may be that this ‘hypother- reduce the effectiveness of its insulation. The damage is
mic’ adaptation has an advantage in increasing comfort mainly caused by high concentrations of electrolytes left in
during cold exposure, in particular permitting sleep, tissue fluids when most of the water turns to ice. While
though it could be hazardous in cold exposure of longer frozen, the skin is white and hard; on thawing, there is first
duration. Many other attempts to demonstrate central hyperaemia and then, in severe cases, pallor and a woody
adaptation or acclimatization to prolonged cold have failed feel to the skin as local blood vessels become occluded by
to provide clear or consistent effects. The signal exception red cells.
530 Heat and cold
LONG-TERM SEQUELAE OF FREEZING COLD INJURY found with freezing injuries, may be underestimates: African
and Caribbean groups were found to have a relative inci-
Military campaigns and civil disaster, such as an earth- dence of NFCI of 30 compared to Caucasians, and they
quake in winter, may leave swathes of the population appeared to suffer more severe injuries too.
recovering from the acute effects of freezing cold injury. The great majority of cases of NFCI affect the feet alone,
Although often not as severe as the long-term conse- although recent series in the UK claim that a quarter of cases
quences of non-freezing cold injury, those resulting from are found to have suffered NFCI of the hands as well as the
freezing injuries may be just as frequent.11,15 Reviews of feet. Apart from military personnel in cold wet climates,
veterans as long as 45 years after their original injuries the main groups affected by classical NFCI are survivors
reveal many suffering from chronic problems as a result. in the water, in liferafts, or during flooding. Immersion of a
The most common sequelae include cold sensitization hand for as little as 45 minutes in water at 0°C may produce
(which is more usually associated with non-freezing cold mild NFCI, but three hours are needed to result in overt
injury, see below), chronic pain, residual neurological injury. Because seawater freezes at a temperature below 0°C
defects that rarely may involve loss of proprioception (normally around 1.9°C), tissues immersed in very cold
rather than touch, joint pain and stiffness, hyperhidrosis, seawater may sustain freezing rather than non-freezing
skin and nail abnormalities. Radiographic examination injury. Although circumstantial evidence points to depend-
may reveal characteristic appearances of ‘frostbite arthritis’, ence on a function of duration of exposure and low temper-
but long-term changes in gait may be more commonly ature, variation between individuals may obscure this. In the
responsible for overuse injuries in more proximal joints, same person, the same injury might result from a short
particularly in the lower limb. Although hyperhidrosis may period at a low temperature, or a longer period exposed to a
lead to chronic fungal infection, the skin is often dry and milder temperature. There also appear to be relationships
scaly, and may crack painfully; topical application of lano- with other similar conditions: long immersion in luke-warm
lin cream, or preparations intended for the care of cows’ water results in ‘paddy foot’, which is clinically indistin-
udders, can alleviate this. Fungal infections of the nails may guishable from NFCI. The pathogenesis of these conditions
respond little to treatment and, together with disturbances remains obscure; factors that have been proposed include
of nail growth, can result in thickening and frank ony- the direct effect of cooling on nerves, prolonged ischaemia
chogryphosis, making a high standard of podiatry essential during cold exposure and the liberation of reactive oxygen
if mobility is to be maintained. compounds during reperfusion. Some or all of these may be
More unusual sequelae include recurrent ulceration important in the evolution of vibration injuries, complex
and breakdown of old scars, which may in turn lead to an regional pain syndromes (formerly known as reflex sympa-
increased risk of local skin cancers. It is not clear whether thetic dystrophy) and other similar syndromes.12
this is specifically related to the frostbite or is common to
other causes of recurrent ulceration. Although rare, com-
plete local loss of proprioception is a neurological abnor- PRESENTATION AND MANAGEMENT
mality that is characteristic of old cold injury. In the hands, Clinical appearances have been divided into four stages:
this can make dressing very hard, while in the feet it may
threaten mobility. 1. Injury: in which the foot is very cold, ischaemic and
numb.
Non-freezing cold injury 2. Rewarming: in which the foot becomes mottled blue-
pink and exquisitely painful.
Longer exposures to less severe temperatures, particularly 3. Hyperaemia: in which the pulses are full and
when coupled with other conditions liable to cause circula- bounding, but there is slow capillary refill, there is
tory stasis, can result in injuries that appear generally mild in marked swelling, some degree of anaesthesia and
comparison with frostbite. A wide variety of terms have been paraesthesia, and severe pain (primarily nocturnal).
applied to non-freezing cold injury (NFCI) since it was first 4. Recovery: in which the foot gradually returns towards
described in the eighteenth century, including trench foot, normal, with residual sequelae including cold
immersion foot, shelter limb and Flanders foot, depending sensitization.
on the circumstances in which the variant was described. It
often coexists with freezing injury, but in spite of its appar- Stage 1 is seen throughout the period in which the injury is
ent innocence during the acute phase, NFCI frequently actually occurring, ranging from minutes to days in dur-
results in more severe long-term sequelae. In common with ation. It is therefore usually only witnessed by the patient,
freezing injuries, NFCI is overtly more frequent in certain who may provide the diagnostic description of numbness
ethnic groups, most notably Africans and Caribbeans, even or other sensory impairment. Stage 2 is seen fleetingly dur-
when their antecedents migrated to colder areas, such as ing rewarming, typically lasting just a few minutes. The
northern Europe. However, most recent studies in the great majority of cases present in stage 3, which lasts
British army16 have shown that previously reported relative for several days or weeks. Stage 4 may then supervene for
incidences of up to five times those of Caucasian groups, months, years, possibly lifelong.
532 Heat and cold
arterial gas embolism) can be invaluable in enabling suc- method of choice for those who are cold, but not clinically
cessful escape. Hyperventilation not only makes the inhal- hypothermic. Aggressive or active rewarming techniques
ation of water, thus primary drowning, more likely, but its should be avoided unless they are applied in sophisticated
effects on blood chemistry can be disabling. Cardiovascular medical facilities, such as intensive therapy units; they
responses may be dramatic, such as the sudden onset may hasten complex and life-threatening problems during
of lethal cardiac arrhythmia, and combine to produce a rewarming, and good evidence that they improve outcome
sharp rise in blood pressure, which may be sufficient to burst is still lacking. Another pitfall is the decision to start exter-
arterial aneurysms. nal cardiac massage (ECM) should it be thought that
Those who survive the first 2–3 minutes of cold water cardiac output is insufficient in the hypothermic. Because
immersion and thus suffer ‘cold shock’, may drown in the this is likely to precipitate ventricular fibrillation (if still
ensuing 10–15 minutes, apparently failing to swim even alive), and the cold heart cannot be defibrillated, starting
though they may be close to safety. Such ‘swimming ECM commits the first-aider to maintaining it – effectively –
failure’ is largely independent of warm water swimming until the casualty is delivered to a place of definitive care. If
ability and appears related to the direct cooling of periph- this will only take 30 minutes, ECM may prove life-saving;
eral nerves (making muscular control harder), failure to if evacuation could take many hours or even days, it is
synchronize breathing with swim-stroke and other subtle probably wisest to avoid starting ECM for this reason.
effects. It is only when the casualty has been immersed for Those who have inhaled insufficient water to cause
more than about 20 minutes that immersion hypothermia primary drowning may exhibit signs of adult respiratory
becomes a serious threat, and even then it may lead to dis- distress during the first one to three days after immersion;
ablement and thus drowning long before core tempera- this is secondary drowning and requires immediate aggres-
tures reach lethal levels below about 28°C. sive intensive therapy. All those who have become
Divers have been claimed to be prone to two forms of immersed and could have aspirated water, and thus could
hypothermia that may occur with minimal physiological be at risk of secondary drowning, should be cautioned of
responses. One may affect saturation divers who are the unlikely chance of the condition, and the need to seek
dependent on careful control of breathing gas temperature medical aid as a matter of urgency.
and their hot water suits to maintain thermal balance.21 If The ideal protection from cold immersion is an inte-
their inspired gas is slightly too cool, large amounts of heat grated survival system, consisting of personal protective
could be lost from the core, while skin temperatures are equipment to provide appropriate buoyancy and thermal
held high. In the absence of stimulus to the peripheral cold protection, if necessary with underwater escape supported
receptors, the body may make little or no physiological by a breathing system.24 Those who may need to hold their
response to the falling core temperature. The other form of breath to permit escape to the surface can have their initial
insidious hypothermia may affect slightly underdressed responses attenuated by cold habituation, for example a
free-swimming divers in water temperatures between daily cold shower,5 or even psychological skills training.25
about 20 and 25°C. Although cold enough to result in It would appear that surfers, kayakers and others who sub-
falling core temperature, such water may not elicit any sen- merge themselves out of choice have already learned their
sation of cold, and once again peripheral vasoconstriction own techniques for coping with cold shock, including
and shivering may not occur. These conditions remain habituation and breath-hold training.
controversial, and extensive review of thermal aspects of For longer-term survival, as when abandoning a ship in
diving is sceptical of their occurrence in real life.22 the ocean, dry-shod entry into a seaworthy and thermally
The hazards of immersion do not stop when rescue effective liferaft should be the goal.
starts. As high as 20 per cent of all those conscious, but The prediction of survival during immersion is very
thought to be hypothermic at the time of rescue, die during important in determining how long search and rescue
the following minutes. Golden et al.23 have reviewed the efforts should be maintained. As immersion incidents com-
causes, which are related to the mode of rescue and subse- monly happen when sea and weather conditions are most
quent treatment. Because the ailing circulation receives threatening to those engaged in searching, accurate predic-
substantial hydrostatic support during immersion, during tion not only determines the cost of expensive assets such as
which the margin for cardiac compensation is being helicopters, but also the risk to which the rescuers are
eroded, vertical modes of recovery can result in sudden loss exposed. National coastguard manuals include aids for the
of venous return and complete circulatory collapse. The prediction of survival during immersion, and these should
adoption of horizontal modes of rescue, such as double improve considerably in the coming years with the ongoing
rescue strops, can reduce this risk, provided that they do analysis of a large survey of immersion incidents in UK
not compromise the chances of successful recovery. waters.26 Traditional approaches to survival prediction gen-
Another risk following rescue is that of rewarming col- erally work best in colder water temperatures, below 20°C.
lapse, which appears to be the result of peripheral vasodi- In warmer waters, in particular, there are many survivors’
latation during rewarming. For this reason, casualties accounts of very long periods of complete or partial immer-
should not be left unattended nor rewarmed in an upright sion that imply that several days could be the norm.
position, for example in a shower. Hot baths are often the However, the strong currents associated with movement of
534 Heat and cold
floodwater, and rough seas encountered during shipwrecks, sometimes other variables. Although different indices
appear much less forgiving, with high death tolls. There is come into vogue at different times and for different pur-
an urgent need for objective study of this area. poses, that with perhaps the best all-round record is the
wet bulb globe temperature (WBGT) index, which also has
the advantage of being simple to compute and easily meas-
The effect of cold on performance ured with compact instruments. More detailed work may
require a psychrometric chart on which the relationship
Although opinion and anecdote invariably assert the dele- between air temperature, moisture content and relative
terious effects of cold on a wide range of aspects of human humidity is shown. Body heat production is again import-
performance,27 objective assessments are less frequent and ant, and can be measured in the field by expired gas
not as clear-cut.28 There are many methodological problems analysis using a portable respiratory system, or more
to be overcome before the body of scientific evidence can crudely estimated from activity levels against standard
be considered to be substantial enough either to confirm scales. Methods for doing this are given in ISO 8996.32
opinion or to modify it. The presence of large variations
between individuals and differences between performances WET BULB GLOBE TEMPERATURE INDEX
of the same individual on different occasions, have been
of particular hindrance. Broadly speaking, cold has been ISO 724333 prescribes a standard method for the estima-
described as impairing three different aspects of perform- tion of heat stress using three temperature measurements:
ance: sensory, motor and higher brain function. The first those of a standard dry bulb, a wet bulb and one inside a
two are commonly combined in measures of dexterity, blackened globe of 150-mm diameter. The three tempera-
which are reduced either by cooling, or by the protective tures are combined into the WBGT index using the follow-
clothing worn to prevent cooling. Where studies have been ing equation:
able to show significant effects on dexterity, they are usually
related to both local and central cooling.29 In actual occupa- WBGT 0.7Twet bulb 0.2Tglobe 0.1Tdry bulb
tional settings, impairment of performance is commonly a Under this ISO standard, it is permissible to ignore the dry
result of many factors. The combination of cold, physical bulb temperature if there is little difference between it and
exertion and protective clothing can be particularly that of the globe (e.g. indoors with little radiant heat load),
dangerous, as rest periods may result in rapid and severe in which case the equation becomes:
peripheral cooling,30 while the metabolic cost of submaxi-
mal work increases and maximal aerobic performance falls. Indoor WBGT 0.7Twet bulb 0.3Tglobe
Observations that accident rates increase during cold
periods of the year27 are too crude to permit conclusions to The standard provides a set of reference index values for
be drawn about the influence of moderate cold on higher five levels of metabolic rate for both acclimatized and
mental functions. However, a particularly disturbing study unacclimatized people, which may be of value in assessing
by Coleshaw et al.31 demonstrated that even slight levels of the relative stress. For example, on a warm summer’s day
body cooling (above those diagnosed as hypothermia) can in a temperate climate the dry bulb temperature may rise
have dramatic effects on simple measures of mental function, as high as 34°C. When the relative humidity remains low,
such as memory registration and the speed of reasoning. at 40 per cent, the wet bulb will remain low at 24°C. In full
shade, the globe temperature should be close to that of the
dry bulb, giving a WBGT index of 27, the threshold for
HEAT STRESS sustaining moderate exercise in acclimatized individuals.
If the air is wetter, with a higher relative humidity, the wet
Assessment of heat stress bulb will be higher, hence the WBGT index will exceed
that threshold and make it impossible to exercise for long.
Because of the greater capacity for warm air to contain In the full radiant heat load of the sun, the globe tempera-
water vapour and the importance of evaporative heat loss ture will soar, with similar effects on WBGT index and
in higher temperatures, the simple dry measures made in exercise.
cold environments are insufficient to assess warmer condi- Related indices can be derived for environments in
tions quantitatively. The one exception to this is when per- which formal measurement of the WBGT index are not
sonnel are clad almost entirely in impermeable clothing, as possible. For example, Nunneley and Stribley34 developed
they might be when working in toxic or radioactive envir- a ‘fighter index of thermal stress’ (FITS) for the cockpit of
onments, for instance. Then the exclusion of evaporative aircraft at low altitude, but using measurements taken at
heat transfer permits simplification of the measurements ground level on clear days:
detailed below. FITS 0.83Tpsychrometric wet bulb 0.35Tdry bulb 5.08
Most measures of heat stress therefore attempt to com-
bine weighted values of dry bulb temperature with some Unfortunately, none of the temperatures used to derive
estimate of humidity, together with radiant heat load and the WBGT index is routinely measured in standard
Heat stress 535
Figure 49.1 A psychrometric chart. The grid is laid over a graph of water vapour pressure against dry bulb air temperature. On this,
curves of equal percentage relative to humidity are superimposed, as are lines of equal wet bulb temperature. Thus, the graph may be
entered using any pair of dry bulb air temperature, water vapour pressure, relative humidity or wet bulb temperature. For a given garment
assembly and work rate, it is possible to plot a straight line which determines the upper limit of the exposure envelope, marked as the
‘linear portion’ in this figure. Those conditions to the left of and below this line are acceptable. However, there are two additional linear
segments which are also shown: at higher relative humidities, the small vapour pressure gradient from clothing to ambient limits
tolerance, whilst at low relative humidities sweating endurance is limited and thus restricts the envelope.
‘predicted mean vote’ (PMV) and predicted percentage of in hot conditions) or by repeatedly raising the body
dissatisfied (PPD) indices are given in ISO 7730,40 based on temperature by undertaking sustained physical exercise, or
measurements of air temperature, mean radiant tempera- by a combination of both. Pure fitness training produces
ture, humidity, air velocity, metabolic rate and clothing similar changes to heat acclimatization and so improves
insulation. Indeed, in any situation in which clothed indi- tolerance to heat stress.
viduals are being assessed, reference will need to be made During the first week of acclimatization, the ability of
to the estimation of the thermal insulation and resistance the body to sweat is increased, so that thermal sweating
to evaporative heat loss imposed by clothing; ISO 992041 occurs more rapidly under heat stress, and the amount of
provides a sound practical basis for this. sweat produced is increased. Cardiovascular changes sus-
tain peripheral vasodilatation and the blood flow required
by active sweat glands. Salt is retained by the kidneys and
Assessment of heat strain salt content of the sweat declines, so that increased sweat-
ing does not result in severe hyponatraemia. Consequently,
The principal measurement of heat strain, like that of cold, some individuals may need to increase dietary salt intake
is core body temperature. However, core temperature can slightly during the first week of acclimatization, but sel-
rise rapidly in the heat and the fact that rectal temperature dom after that. It should be noted that required water
changes later and more slowly than other sites makes it less intake may actually be increased in those who are acclima-
suitable for safety purposes. Accordingly, it is more com- tized: popular belief that those conditioned to living in the
mon to estimate deep body temperature in the heat from a tropics are also able to do without water, or even worse to
tympanic membrane or auditory canal reading; this has the substitute alcohol, is completely erroneous.
added advantage that this site should usually be a good indi- The process of acclimatization continues more gradually
cator of the temperature of the brain, which is not only the over the remainder of the first three months or so spent in
central temperature controller, but is also one of the more the tropics, at the end of which the temperate-born individ-
critical organs in heat illness. Unfortunately, the otherwise ual is almost physiologically indistinct from those who have
convenient infrared tympanic membrane thermometers spent their entire lives under a heat stress. However, behav-
that have become so popular in general clinical practice are ioural adaptation, in which dress and habits are changed to
again a potential source of error, and should not be trusted: those most appropriate in the heat, may never occur.
a thermistor or thermocouple needs to be placed just short De-acclimatization can occur surprisingly rapidly, after
of the tympanic membrane, and the auditory meatus just a few days of withdrawal from heat stress. Those
occluded and carefully insulated if the temperature recorded who spend a period working in air-conditioned comfort, or
is to be a reliable estimate of core temperature. who return to more temperate climates for a holiday, there-
Three other variables are commonly recorded in heat fore need to undergo supervised re-acclimatization on their
studies: heart rate is the simplest of all to measure, loss of return to heat exposure. This introduces a dilemma in
body mass due to sweating is also very easily determined, choosing optimal living and working conditions in hot cli-
whilst skin temperatures are sometimes of value if judi- mates: while many find it more comfortable and sleep better
ciously interpreted. in conditioned accommodation, more constant exposure to
Heart rate is well correlated with heat strain, provided heat stress will maintain a better level of acclimatization.
that changes due to exercise are taken into consideration. It
is often used, in conjunction with aural temperature, in
establishing criteria for the withdrawal of people exposed Immediate consequences of heat strain
to heat loads. The simple estimate of body weight loss is a
useful measure of fluid loss in laboratory conditions. Skin The continuing popularity of prolonged physical exercise in
temperatures can prove misleading, as they fall if there is temperate climates, such as marathons and triathlons in the
good evaporation from the skin, but climb close to core populous countries of the northern hemisphere, reinforces
if evaporation is limited or absent. These methods are the need to move away from the traditional classification
described in ISO 9886.3 of heat illness. The latter, evolved during British Imperial
days, endeavoured to distinguish acute, subacute and
chronic disorders involving overheating, and water and elec-
Acclimatization trolyte losses in a complex and probably misleading termi-
nology. Setting aside a few discrete disorders, such as
Temperate residents cannot perform as well under heat prickly heat and salt and water deficiencies, true heat illness
stress as those used to living in the tropics. Careful studies can be spread along a continuum from heat exhaustion to
during the middle of the twentieth century demonstrated heat stroke.43 At the one extreme, this consists of little
that unacclimatized temperate residents show significant change in body temperature and overt hyperventilation,
acclimatization after only two weeks of exposure to heat.42 and at the other, a core temperature in excess of 41°C,
This can be produced by prolonged exposure to an envir- absence of sweating and complete circulatory collapse.
onmental heat load (e.g. by living in the tropics or working Patients can move rapidly from minor heat exhaustion to
Heat stress 537
life-threatening heat stroke; so no matter how mild the infusion according to clinical indications and the perceived
symptoms may appear to be, anyone suffering from a heat risk of hypervolaemia leading to pulmonary oedema. Such
illness should be considered to be in incipient heat stroke fluids should not be warmed, but neither should they be
and thus in imminent danger of death. cooled below 15°C. Elevation of the legs to assist venous
return, administration of oxygen and possibly sedatives,
are of value. However, vasodilators and platelet inhibitors,
HEAT EXHAUSTION
such as aspirin, should be avoided. Rapid but careful evacu-
Heat exhaustion is typified by the moderately well-trained ation to an intensive care unit is essential, where urinary
athlete competing in a marathon during the warmer months output, blood biochemistry and direct measurement of the
in a temperate country. It may also be seen in military per- central venous pressure can be monitored closely. Cooling
sonnel during fitness training in similar conditions and in is normally discontinued when the rectal or aural temper-
groups of manual workers with moderate environmental ature has reached 38°C, lest it overshoot. A useful if empir-
heat loads. The first sign of impending heat exhaustion is ical guide to prognosis is the area under a curve of
usually hyperventilation, in someone who appears ill at ease core temperature against time, during which core temper-
with the exercise that they are performing.43 ature exceeds 39°C: the greater the duration and elevation
Classic signs and symptoms from the disturbance of the above that temperature, the poorer the likely outcome.
body’s acid-base balance and the calcium–phosphate ratio Unfortunately, the outcome of true heat stroke is not
in the blood follow, with dizziness, nausea, paraesthesiae in good. If core temperature rises to around 45°C, irreversible
the peripheries and around the mouth, progressing to con- heat denaturation of proteins causes multiple organ failure
fusion, collapse, vomiting and even seizures. Core tempera- or disseminated intravascular coagulation. If this is not
ture at this stage is below 40°C, and usually between 37° and immediately fatal, renal dialysis may be necessary during
39°C. Early cases respond rapidly to rest in a recumbent recovery. Heat illness, associated with exercise, can produce
position, rebreathing from a paper bag to restore end-tidal subacute rhabdomyolysis (necrosis of muscle) that can in
CO2 levels and simple cooling. Fluids may also be beneficial turn lead to late renal failure. Follow up of military person-
and should always be given by appropriate means. If these nel who made complete recoveries from an initial episode
patients are allowed or even encouraged to continue exer- of heat illness have suggested that subsequent episodes are
cising, they may rapidly develop frank heat stroke. more common than among those who have not suffered
heat illness.45 However, numbers were small and further
HEAT STROKE work is merited. At least two national armed forces have
now introduced work-in-heat testing of those who have
Those working in very hot surroundings, particularly when suffered an episode of heat illness during military training.
evaporative cooling is ineffective due to high humidity, Although experience is limited and the optimal test
may undergo a rapid rise in core temperature, to the point protocol remains controversial, these have enabled the
at which thermoregulation fails.44 The classic victim of identification of individuals with metabolic disorders
heat stroke has stopped sweating and is dry to the touch. related to malignant hyperthermia, cases of anhidrosis and
They may still maintain peripheral circulation and thus be other conditions that predispose to further heat illness.
red, or may have undergone circulatory collapse, in which
case their skin colour is not diagnostic. They are very hot, HYPONATRAEMIA
semiconscious or comatose, and prone to convulsions,
cardiac and respiratory arrest. The onset of this dramatic For much of the nineteenth and twentieth centuries, an
illness may have been very rapid, although many will important task in preventing heat illness among athletes,
have shown evidence of earlier heat exhaustion. service personnel and workers in hot environments has
Cooling is best achieved in the field by stripping the been to encourage the replacement of body fluid lost by
patient in the shade, drenching with tepid water and fan- sweating with sufficient quantities of aqueous fluid. For a
ning if there is little natural wind. Cold water or ice is less surprisingly long period in history, athletes and others
useful in adults because of the intense vasoconstriction consumed very little in the way of fluid, and the drinks
which it can precipitate, which limits heat transfer from used were often physiologically unsuitable, such as beer or
the core to the skin; however, there are recent claims that even spirits. In the early decades of professional cycle
ice-water baths may still produce the most rapid fall in core racing, for instance, some competitors consumed at least a
temperature even in adults, as they do in infants with their bottle of brandy a day when taking part in arduous stage
much greater surface area to volume ratio. Alternating races, while foundry workers were at one time notorious
litres of isotonic dextrose and saline intravenously are the for drinking many pints of beer during their working day.
best means of fluid administration, but cannot be a substi- Recent years have seen a dramatic change, in which fluids
tute for immediate and effective cooling. The precise quan- are thrust at athletes in particular in considerable quan-
tity given may be based on an estimate of fluid loss, but in tities, to the point where many are now at risk of becoming
unconscious cases it is probably best to give the first litre hyponatraemic, which can cause collapse, death and severe
over 15 minutes or less, thereafter reducing the rate of neurological disturbances in those who survive.46
538 Heat and cold
The aim of drinking during exposure to heat stress The effect of heat on performance
should be to replace fluid and electrolyte losses in sweat.
Even when acclimatized and fit, few humans are capable of Reconciling the subjective and objective is no easier for the
losing more than 2 litres an hour in sweat, so drinking possible effects of heat than were noted above for cold.
should never exceed that rate. Over a typical extended Ramsey47 has reviewed more than 150 studies that attempted
working day, a ceiling of 10–12 litres of fluid intake is to find differences in ‘perceptual motor performance’ in the
advisable. Most western diets provide ample daily sodium heat and commented on the remarkable lack of objective
intake, but it is common for meals to be lightened or evidence of dominant effects. It appears that there is no sig-
skipped when exercising in the heat. If a normal diet of nificant detectable impairment in the performance of the
three meals per day is not maintained, careful consid- great majority of tasks until the level of heat stress reaches a
eration needs to be given to supplementation with fluids WBGT index of approximately 30°C. This is broadly in
containing electrolytes so that proper balance can be main- accordance with the criteria originally laid down by NIOSH
tained. This is potentially very complex, and the margins in their original recommended exposure limit (REL).48
for error can be narrow: injudicious consumption of sports Paradoxically, when revised 14 years later, NIOSH omitted
gels and fluids can be as dangerous as inadequate intake this REL because of lack of supporting evidence.49
of salt. It is far simpler to maintain a normal diet and A few studies cast interesting and potentially different
balanced fluid intake. light on the area. There is much stronger support for adverse
effects in circumstances in which core temperature has risen;
OTHER CONDITIONS when core temperature is 38°C or greater, a prominent
effect is an increase in irritability independent of the rise in
Classic salt depletion, due to salt loss in sweat while on a subjective discomfort.50 Critics of studies which have used
low salt diet, with adequate water intake, is now rarely more artificial and perhaps oversimplified measures of per-
seen. The classic accompaniment of cramp (e.g. miner’s formance may find some comfort in the work of Wyon
cramp) only occurs in association with hard exercise and is et al.,51 who examined the effect of moderate heat stress on
now very unusual. Plasma sodium only falls in more severe driving performance. While they observed a heat-related
cases, with milder cases showing a fall in extracellular fluid increase in overt driving errors, it was found to occur only in
volume with normal plasma sodium. In the worst cases, women.
vigorous treatment with oral or intravenous saline may be Perhaps the most useful tool (beyond tenuous attempts
required. Subacute and other variants of this condition, to relate accident statistics to heat stress or strain) in the
sometimes attributed to different combinations of water practical examination of performance effects is the expres-
and electrolyte depletion and ‘disacclimatization’, are sion of subjective judgement scales. ISO 1055152 lays down
similarly uncommon. They are best treated by cooling, a standard approach to these, which allows inclusion
rest, rehydration and the restoration of a normal diet. of comfort, acceptability and tolerance in the assessment of
Those whose appetite has been suppressed and who have thermal environments.
overindulged in alcohol, should recover quickly in this
way. The blind administration of salt, even with the copi-
ous quantities of fluid that are required, is potentially PRINCIPLES OF THE REDUCTION OF
dangerous and should be avoided. THERMAL STRAIN
One possible danger is that of hyperkalaemia; many
young people often rehydrate following exercise in the heat Given that there are many industrial processes and situ-
using some form of orange juice, or a ‘sports rehydration’ ations that could lead to injury or illness resulting from cold
fluid, which may be high in potassium. They should be or heat, and the potential consequences of such injuries or
advised to ensure that their rehydration fluid is well diluted illnesses, the importance of prevention cannot be overem-
with water. phasized. In addition to specific remarks in previous sec-
Perhaps the most common of the ‘mild’ heat disorders tions, the following provides general principles to form the
is prickly heat or miliaria rubra, which results from block- basis of systematic plans for prevention. There are already a
ing of the orifices of sweat glands. Because of the blockage, number of good examples of codes of practice that illustrate
the glands rupture their ducts, raising a weal within an ery- how preventive measures can be implemented.53–57
thematous area, which is intensely itchy. Removal from the
heat both abolishes sweating and prevents the body over-
heating as a result of its impaired ability to sweat. Other The worker
less well-understood conditions which may appear during
heat stress include a transient ankle oedema (which Working in particularly cold or hot environments makes
may result from the thermal attenuation of the veno- many demands of the individual. The body and mind
arteriolar reflex) and mild muscular cramps. Some indi- may be taken to the limits, something that is often viewed
viduals experience dizziness and fainting that may have a as an attraction for those who voluntarily expose them-
common aetiology. selves to thermal extremes in their leisure-time pursuits.
Principles of the reduction of thermal strain 539
Any condition that impairs the physiological mechanisms Once they do start, the period for which they work should be
responsible for compensating for heat or cold stress risks carefully controlled according to the heat stress and strain,
the safety of the individual and thus is contraindicated making due allowance for accidents and emergencies which
in workers exposed. Margins for such compensation gen- might happen. For example, firefighting teams wearing
erally decline with age, although experience in coping breathing apparatus are limited in duration by the air supply
behaviourally increases with maturity, and the very young which they carry with them; this supply should not encour-
may be limited on both counts. The additional metabolic age them to stay so long in the full heat of the fire that they
and cardiovascular demands of pregnancy make exposure suffer from heat illness, but at the same time it must allow
to heat stress inadvisable for women during those times. for delays in withdrawing once their anticipated working
Any form of concurrent illness, especially if febrile, time is over. The total number of teams should allow for a
increases risks whether the worker is exposed to heat or reasonable number of entries to be made, with adequate
cold. The consumption of alcohol or drugs of abuse, even cooling and rest periods in between. In some cases, three
in small quantities, or of most medications, can compro- teams will be needed to provide these breaks, but each team
mise some or all of the physiological mechanisms; in the may then be limited in the number of entries that it can
case of medication, it needs to be ascertained from recog- make. It should be borne in mind that, in these circum-
nized pharmacological authorities that the treatment in stances, cooling down takes longer than heating up.
question is not likely to do this. On the other hand, general In environments in which all other methods have failed
physical fitness of a cardiorespiratory or endurance nature and personnel are required to work hard physically, the
is usually a great benefit. only solution may be to plan that they undertake only brief
If called upon to assess the fitness of an individual to periods of work, interspersed with rest periods in which
undergo thermal stress, detailed knowledge of the environ- they may cool. Although many factors have to be taken into
ment, activities and clothing to be worn are essential. For consideration, guideline WBGT indices above which this
those undertaking work in the cold, obesity is actually may be required are 29–33°C for the sedentary, 24–28°C for
highly undesirable, as it impairs the mobility of someone those working moderately hard, and 20–26°C for those per-
required to wear already bulky protective clothing, and forming heavy exercise. Those who have acclimatized to the
increases the likelihood of their being subject to heat stress heat can generally tolerate higher temperatures for longer
when wearing that clothing. The level of physical fitness periods (provided that they are both kept well hydrated and
required is at least that of a person undertaking the same are able to sweat effectively), and at higher work rates
activity in more comfortable temperatures, while carrying increased air movement may also reduce heat stress at a
the whole protective clothing ensemble. given WBGT index. In extremely hot environments, such as
Sedentary work in the heat, particularly following coke ovens, it may be necessary to restrict exposure to a very
acclimatization, is not normally too physically demanding. short period, which must be strictly enforced.
However, those who have to wear restrictive protective Although there is little physiological advantage to pro-
clothing, breathing apparatus, and then have to perform gressive training in the cold, it is psychologically and behav-
arduous physical work, need to be physically very fit. For iourally of great benefit. Circumstantial evidence suggests
example, in both laboratory and field studies of firemen,58 that the experienced individual develops many small but
it is more usual that their ability to carry out work is lim- very effective techniques for minimizing their cold stress,
ited by physical exhaustion than by dangerous elevation of such as an ability to don and doff clothing quickly and with
body temperature; factors of particular importance include minimum cooling. The naive person in a cold environment
the duration of work and the use of breathing apparatus. can quickly run into trouble, particularly when things start
In the face of these demands, firemen should have good going wrong or there is an accident or emergency. On the
pulmonary and cardiovascular function, and significant other hand, those who have had adverse effects, such as pre-
pathology such as myocardial ischaemia or lung disease vious cold injury or any other evidence of cold intolerance,
should contraindicate further exposure. Formal tests of should be prevented from further cold exposure. This
physical fitness, such as step tests and even the measure- includes a small number of people with conditions which
ment of maximal oxygen uptake, are only guides in the predispose to local cold injury, including those with vibra-
overall assessment of individuals. In all cases, the examin- tion white finger, any form of Raynaud’s disease, impaired
ing doctor should ask the question as to whether the per- circulation, skin grafts or other cold sensitivity (whether
son presenting for examination is capable of undertaking resulting in excessive vasoconstriction or allergic responses
the specific tasks in the given environment in reasonable as in cold urticaria). Similarly, those with a history of previ-
safety, and not whether they have achieved an arbitrary ous heat illness should only be re-exposed under careful
standard in an artificial test. supervision, as further episodes are likely, and anyone with
Good progressive training, coupled with conditioning or a skin disorder should avoid heat stress, as most will impair
acclimatization, is very valuable in preparing the individual thermally effective sweating.
for work in stressful environments. In the case of heat, every Care also needs to be taken in considering the nature of
effort should be made to allow personnel to acclimatize work to be performed, with regard to the effects of its impair-
before they are required to carry out any exercise in the heat. ment. In spite of the equivocal results from experimental
540 Heat and cold
Box 49.3 The office worker Box 49.4 Disabilities and thermal stress
Traditionally, legislative requirements for sedentary work- Although other types of disability may have subtle thermal
ers, particularly those in offices, have set a minimum implications, the most prominent considerations need to be
temperature for their environment, but no maximum. It is given to those with generally impaired mobility, and
not hard to arrive at a reasonable minimum temperature disabilities that specifically impair thermoregulation.
based on acceptable dress and the need to keep hands Mobility impairment usually results in lower average
warm enough to undertake typical tasks. However, healthy metabolic rates and lower peripheral perfusion, making
sedentary workers are physiologically capable of dissipating individuals more susceptible to whole body and peripheral
their metabolic heat output over a wide range of thermal cooling when they are exposed to cold environments
environments. Whether or not an employer deems it with the same thermal protection provided to more mobile
acceptable for office workers to have to sweat 2 litres workers. This requires consideration in workplace assess-
or more over the course of their working day, as long as ment, potentially the provision of more efficient personal
they maintain adequate hydration and are fit and healthy protective equipment and shortened periods of exposure to
(and preferably acclimatized to the heat), they should compensate.
thermoregulate and there should be no danger to their The most common disabilities that result in dramatic
health. alteration in thermoregulation are spinal injuries. From the
In climates with seasonal differences in environmental approximate level of the injury distally, normal peripheral
heat stress, office environments can follow those changes, vasoconstriction and vasodilatation may be impaired or
to exploit seasonal acclimatization in workers. In the completely absent. Deprived of these fundamental defences
winter, the tendency to wear warmer clothing can be used against thermal stress, those with spinal injuries can quickly
to lower office temperatures by a couple of degrees below cool or heat up in environments that others may find
their annual average. Once warmer summer temperatures perfectly comfortable. Assessment may need consultation
have become established, office temperatures can be with their neurologist to establish the nature of an
allowed to rise a couple of degrees above annual average. individual’s problems, followed by thorough planning of the
Allowing approximately two weeks lag in these changes of workplace to accommodate their needs. Contingency plans
office environment should suffice to allow for changes in may also be needed to protect them in the event of failure
clothing and acclimatization. of environmental conditioning.
Careful consideration also needs to be taken of the effects
on human performance, social interaction and psychology.
In times of austerity, workers have been motivated to try
healthy and have no form of disability, but this is increas-
to press on even when wearing multiple layers of heavy
ingly inaccurate, as endurance sports become popular
clothing and gloves, but current social attitudes would not
among even severely disabled athletes, and a greater
tolerate that now. Those working under mental rather than
proportion of the disabled population expects to pursue
physical pressure may deliver their best when their thermal
a full range of working and leisure activities. Detailed
expectations are met, or at least they perceive that they
understanding of the sometimes severe thermoregulatory
are. Uneven heating or cooling is as likely to result in
problems in certain types of spinal injury, for example, can
discomfort and complaints as more uniform discomfort.
help tackle the problems that individuals may face, but
Consideration must also be given to those whose health
there are no general solutions. Even in those working in
is not perfect, or are pregnant, growing old, or have a
the relative shelter of conditioned office environments,
disability; it is usually necessary to reduce the potential
achieving thermal comfort needs careful attention to the
thermal stress posed by an environment to ensure sufficient
individual.59
margin of comfort for those individuals.
33. ISO 7243. Hot environments – estimation of the heat stress 51. Wyon DP, Wyon I, Norin F. Effects of moderate heat stress on
on working man, based on the WBGT-index (wet bulb globe driver vigilance in a moving vehicle. Ergonomics. 1996; 39:
temperature). Geneva: International Organization for 61–75.
Standardization, 1989. 52. ISO 10551. Ergonomics of the thermal environment –
34. Nunneley SA, Stribley RF. Fighter index of thermal stress (FITS): assessment of the influence of the thermal environment
Guidance for hot-weather aircraft operations. Aviation, Space, using subjective judgement scales. Geneva: International
and Environmental Medicine. 1979; 50: 639–42. Organization for Standardization, 1995.
35. Parsons KC. International heat stress standards: A review. 53. RFIC. Guidance on work in cold indoor environments.
Ergonomics 1995; 38: 6–22. Bracknell: Refrigerated Food Industry Confederation,
36. ISO 11399. Ergonomics of the thermal environment – principles undated.
and application of the relevant international standards. Geneva: 54. BSI. Draft British Standard: Ergonomics of the thermal
International Organization for Standardization, 1995. environment – code of practice for the design and evaluation
37. ISO 7933. Ergonomics of the thermal environment – of working practices for cold indoor environments. London:
analytical determination and interpretation of thermal stress BSI Standards, 1996.
using calculation of the predicted heat strain. Geneva: 55. Griefahn B. Arbeit in mässiger Kälte. Report no. Fb 716.
International Organization for Standardization, 2004. Dortmund: Bundesanstalt für Arbeitsschutz, 1995.
38. Peters H. Testing climate indices in the field. Ergonomics. 56. Malchaire J, Mairiaux P. Strategy of analysis and
1995; 38: 86–100. interpretation of thermal working conditions. Annals of
39. Mairiaux P, Malchaire J. Comparison and validation of heat Occupational Hygiene. 1991; 35: 261–72.
stress indices in experimental studies. Ergonomics. 1995; 38: 57. American College of Sports Medicine. Prevention of cold
58–72. injuries during exercise. Medicine and Science in Sports and
40. ISO 7730. Ergonomics of the thermal environment – Exercise. 2006; 38: 2012–29.
analytical determination and interpretation of thermal 58. Smith DL, Petruzzello SJ, Kramer JM, Misner JE. The effects of
comfort using calculation of the PMV and PPD indices and different thermal environments on the physiological and
local thermal comfort criteria. Geneva: International psychological responses of firefighters to a training drill.
Organization for Standardization, 2005. Ergonomics. 1997; 40: 500–10.
41. ISO 9920. Ergonomics of the thermal environment – 59. Parsons KC. The effects of gender, acclimation state, the
estimation of the thermal insulation and evaporative opportunity to adjust clothing and physical disability on
resistance of a clothing ensemble. Geneva: International requirements for thermal comfort. Energy and Buildings.
Organization for Standardization, 1995. 2002; 34: 593–9.
42. Clark RP, Edholm OG. Man and his thermal environment. 60. Allsopp AJ, Poole KA. The effect of hand immersion on body
London: Edward Arnold, 1985. temperature when wearing impermeable clothing. Journal of
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regulation. Sydney: Academic Press, 1983. 169–76.
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SECTION FOUR
Barometric pressure
Overview of the need for diving and tunnelling Diving tasks 556
and the hazards 547 Current hazards and risks 559
The increased pressure environment 547 Long-term health effects 561
Physics of the pressure environment 548 Tunnelling tasks 562
Pressure-related physiology and pathophysiology 549 Decompression illness in compressed air work 564
Decompression sickness 551 Legal framework 565
Bone necrosis 553 Assessment of fitness for work at pressure 565
Loss of consciousness 555 References 567
OVERVIEW OF THE NEED FOR DIVING AND works. Workers in caissons do not dive, but do share expo-
TUNNELLING AND THE HAZARDS sure to increased pressure with divers, and hence many of
the same problems and hazards. In the last 20 years, due to
The history of mankind is inextricably linked with the sea. increasing health concerns, several of the techniques previ-
The sea and inland lakes and waterways have been vital as ously developed in military and commercial diving are now
sources of food and for exploration and travel. As a result, used within tunnelling operations involving compressed
numerous food stuffs and items of value have been sought air work.
from beneath the sea surface throughout the history of This chapter deals with the occupational health issues of
man. These driving forces, enhanced by military require- both diving and compressed air work.
ments, have resulted in enormous efforts to explore the
subsea environment for profit, military advantage, scien-
tific research and for pleasure. The history of diving begins
with simple breath-hold diving as is still practised for gath- THE INCREASED PRESSURE ENVIRONMENT
ering pearls and by recreational snorkellers, and moves
through the development of breathing apparatus to mod- On the surface of the Earth at sea level, we live in an air
ern saturation diving methods. Practical solutions have environment where the air pressure results from the mass
been found for many of the problems encountered in of the air in the atmosphere above and the effect of the
exploration of the subsea environment which now allow Earth’s gravitational field. On ascent to altitude on moun-
man to conduct a wide range of work activities underwater. tains or in aircraft, the mass of air above is less and hence
However, the underwater environment remains alien to the pressure is also lower. On descent underwater, the
man and is always hazardous. environmental pressure results from both the mass of air
Within the last 200 years, the technological advances above and the mass of water. Since water is many times
have also been applied in civil engineering situations where denser than air, there is a very rapid increase in pressure
excavation beneath a water table results in ingress of water. with progressive descent underwater and pressure changes
By enclosing the excavation and applying increased pres- occur when compressed air is used in engineering works.
sure, the ingress of water can be prevented allowing contin- This change in pressure is the most critical environmental
ued excavation in a dry environment. These enclosures factor in both diving and compressed air work.
are called ‘caissons’ and have been extensively used in the Pressure can be measured in many alternative units
building of bridge piers, tunnels and other civil engineering which are in everyday use. The pressure on the Earth’s
548 Diving and work at increased pressure
Table 50.1 Equivalent units of pressure. compression chambers and hence work in an enclosed
space and while divers inevitably require breathing appara-
Unit Abbreviation Value
tus, compressed air workers may also need to use breathing
apparatus for breathing alternative gases or protection in
Standard atmosphere absolute ata 1 potentially contaminated environments.
Bar (bar) bar 1
Torr torr 760
Millimetres of mercury mmHg 760 PHYSICS OF THE PRESSURE ENVIRONMENT
Kilopascal kPa 100
Pounds per square inch psi 14.7 The physical properties of the environment are defined by
Kilogram force per sq centimetre Kgf.cm2 1.033 the gas laws. The following are of critical importance in
Feet of seawater fsw 33 understanding the pressure environment.
Metres of seawater msw 10 Boyle’s law states that for a fixed mass of gas at constant
temperature the volume is inversely proportional to the
absolute pressure. Hence, if pressure is doubled, the vol-
surface at sea level has been defined as 1 bar (1000 ume is halved.
millibar). (Fluctuations in pressure reported in millibar Charles’ law states that for a fixed mass of gas at con-
form an important measurement in weather forecasting.) stant pressure, the volume is proportional to the absolute
One standard atmosphere absolute (ata) is almost equiva- temperature.
lent to 1 bar. Other measures in regular use are torr and Dalton’s law states that ‘in a mixture of gases, the pres-
millimetres of mercury (mmHg), pounds per square inch sure exerted by each of the constituent gases is the same as
(psi), kilogram force per square centimetre (Kgf.cm2), it would exert if it alone occupied the same volume’. The
meters of seawater (msw), feet of seawater (fsw) and pascals pressure exerted by each constituent is called a partial pres-
(Pa). Many of these will be familiar in everyday medical sure. The total pressure in a gas mixture is the sum of the
or scientific use. Table 50.1 provides equivalent values. partial pressures of the constituents, and these partial pres-
Pressure is most usefully measured in absolute terms where sures can be calculated from the total pressure and the frac-
zero equals an absolute vacuum, but is often measured rel- tional concentrations of the constituents. Hence, in air at
ative to surface air pressure (called gauge pressure) which sea level where oxygen forms 20.9 per cent of the gas mix-
introduces confusion in physical calculations. Although sci- ture, the partial pressure of oxygen is 20.9 per cent of 1 ata
entifically it is most appropriate to use SI units (Pa), the or 760 mmHg, i.e. 0.209 ata, 159 mmHg.
units in most common use in the diving and compressed air Henry’s law states that ‘at constant temperature, the
industry have been retained in this chapter. Care should be amount of gas which dissolves in a liquid with which it is in
taken when comparing different pressure units to avoid contact is proportional to the partial pressure of that gas’.
mistakes and confusion, particularly where pressure is Hence, while the amount or mass of gas which dissolves
measured either as absolute or total pressure or gauge pres- in a liquid is also dependent on that gas’s solubility, an
sure (where the pressure above ambient is recorded). increase in partial pressure of the gas will increase the
Gases are compressible, so become denser as pressure amount that goes into solution.
increases. As a result on ascent to altitude, air density The effects of these laws can be seen in Table 50.2.
reduces with ascent and so the pressure reduction is not lin- The constituent gases of the diver’s breathing mixture
ear with height. Water is not compressible and hence have important pathophysiological effects. Oxygen is criti-
underwater the pressure rises linearly with depth by cal to metabolic processes and a reduced partial pressure of
1 atmosphere for every 10 m additional depth. The absolute oxygen will result in hypoxaemia. However, the increase in
pressure underwater in ata can simply be calculated from oxygen partial pressure may also be toxic. Oxygen toxicity
the water depth in meters divided by 10 and adding 1 for is more likely with increasing pO2 and with duration of
surface air pressure. Hence, pressure at 50 m depth is exposure. The lung may be affected with prolonged expo-
50/10 1 6 ata. In compressed air work, 1 bar (gauge) is sure to a pO2 above 0.6 ata1–3 and, in the central nervous
equivalent to 2 bar absolute pressure (i.e. 1 bar atmospheric system (CNS), prolonged exposure often manifests as con-
pressure 1 bar gauge pressure). vulsions with relatively short duration exposure to pO2
Both divers and compressed air workers operate in an above 1.6 ata.4 CNS toxicity is enhanced by exertion,4,5 so a
environment where the ambient pressure is raised. diver at rest in a chamber can tolerate a pO2 of 2.8 ata which
Historically, compressed air work has rarely involved pres- would result in convulsions if the diver was active in the
sures above 3–4 ata, but in recent years the development of water. Oxygen tolerance can be extended if exposure is
tunnel boring machines used in modern tunnel excavation intermittent.6 Nitrogen which is normally an inert compo-
has led to much higher pressures being required. Diving is nent of the air we breath has narcotic and anaesthetic
regularly undertaken at pressures of up to 35 ata and the effects7 at high partial pressures, which limits the depth at
world record exceeds 70 ata. which air can be used as a breathing mixture and represents
Divers and compressed air workers also share other a distinct safety hazard. The narcotic effects begin to be
environmental problems. Both commonly require to use noticeable at a depth of about 30 msw (pN2 approximately
Pressure-related physiology and pathophysiology 549
Table 50.2 Some implications of breathing air at increased the tympanic membrane. The body tissues behave like
pressure. a fluid and transmit pressure so any change in environ-
mental pressure is transmitted to gas-containing spaces in
Depth Pressure Volume Density MVV pN2 pO2
the body. An increase in pressure results in a reduction
(msw) (ata) (L) (g/L) (L/min) (ata) (ata)
in middle ear gas volume and causes movement of the
tympanic membrane. This is readily sensed and can cause
0 1 8 1.2 200 0.8 0.2 pain if the membrane is stretched enough. If the diver
10 2 4 2.4 1.6 0.4 opens the Eustachian tube, air at ambient pressure passes
20 3 2.66 3.6 2.4 0.6 up into the middle ear and the tympanic membrane moves
30 4 2 4.8 100 3.2 0.8 back to the normal position. As a diver descends in the
40 5 1.66 6.0 4.0 1.0 water or a tunneller is compressed in a gas environment,
50 6 1.33 7.2 80 4.8 1.2 this action of ‘equalizing’ ear pressures is required recur-
70 8 1 9.6 6.4 1.6 rently until the diver reaches stable depth. If equalization
160 17 0.47 20.4 13.6 3.4 is not performed, the differential pressure across the
Volume column shows the lung volume changes during a breath-hold Eustachian tube may effectively prevent the diver from
dive from total lung capacity at the surface. MVV (maximum voluntary opening the tube and result in pain and trauma to the
ventilation) shows the restriction of ventilation imposed by increasing gas tympanic membrane or inner ear organs. The tympanic
density. pO2 column shows how an inspired partial pressure of 1 ata can membrane may be bruised and haemorrhagic or may rup-
be achieved either by breathing 100% oxygen on the surface or by
ture, an event, which although painful, equalizes pressure.
breathing air at a depth of 40 msw.
In most cases, middle ear barotrauma resolves within two
weeks with complete healing of the ear drum. It is impor-
3 ata) and increase as the pressure goes up. Nitrogen narco- tant to ensure Eustachian function has returned to normal
sis and gas density issues become an important safety issue before returning to diving or other pressure exposure.
deeper than 30 msw and an important contributor to acci- However, the transmitted pressure effects may also damage
dents or errors. Breathing air is considered to be a medical the organ of Corti and produce a permanent hearing loss.
contraindication for routine commercial diving applica- Vigorous attempts to equalize pressure by holding the nose
tions at depths greater than 50 m. In practice, this is the and doing a valsalva manoeuvre increase intracerebral
reason the Royal Navy prohibit air diving for military pur- pressure and hence the pressure difference across the
poses at depths greater than 50 m and in the Health and round window. Rupture of this membrane results in leak
Safety Executive (HSE)-approved compressed air tables of endolymph into the middle ear and a gradual onset of
breathing air is limited to a 3.45 bar (gauge) maximum vertigo, nausea and hearing loss. This is an emergency and
pressure in the United Kingdom.8 At higher pressures, the requires urgent otological assessment.
nitrogen requires to be replaced either partially or com-
pletely by an alternative ‘inert’ gas usually helium. Helium
SINUS BAROTRAUMA
has the advantages of having no narcotic effect and being
very light, so also overcomes some of the respiratory prob- Other gas-containing spaces in the body may also cause
lems caused by gas density. However, it diffuses very easily, problems. Sinus cavities should normally communicate with
has high thermal conductivity, and so introduces signifi- the nasal airways and hence not behave as closed spaces.
cant thermal control problems and produces speech distor- However, minor inflammatory change in the nasal mucosa
tion which affects vocal communications. Other gases may may readily close sinus ostia and so prevent free gas move-
also be encountered. Argon is used as a shielding gas in ment. These spaces are of fixed volume in bony cavities so
welding operations. It is breathable but more narcotic than cannot change volume. In the event of the gas content reduc-
nitrogen and hence a hazard. Hydrogen has been used in ing in volume interstitial fluid and blood is effectively sucked
some experimental deep dives for its minimal density. It into the mucosa, a process which can generate some pain.
has high thermal conductivity and introduces the potential On subsequent ascent, the trapped gas expands again and
for explosive gas mixtures. may force mucous and blood out of the ostia into the nasal
cavity. Although the presentation can be dramatic, the injury
PRESSURE-RELATED PHYSIOLOGY AND is usually minor and resolves spontaneously. Persistent
PATHOPHYSIOLOGY inflammatory change in the sinus mucosa may result in per-
sistent obstruction of the ostia and long-term inability to
Barotrauma dive. Rarely, the acute event may result in local nerve injury
to the fifth or seventh cranial nerves.
MIDDLE EAR BAROTRAUMA
PULMONARY BAROTRAUMA
The most immediately recognized effect of change in envi-
ronmental pressure is the result on the middle ear cavity. The lungs are the largest gas-containing space in the
The Eustachian tube is normally closed and hence the mid- body. In normal breathing, the lungs communicate
dle ear cavity is a closed gas space with one flexible side, freely with the upper airways and mouth so changes in
550 Diving and work at increased pressure
A commercial diver with 12 years’ experience of civil Figure 50.3 Appearance of a diver’s torso following a deep air
engineering diving at depths to a maximum of 22 msw dive. The diver reported the presence of a rash. The widespread
obtained work in oil field diving which involved dives to patchy rash, which is erythematous but may also have petechial
45 msw. In the course of three months, he developed three areas, is characteristic of cutaneous decompression sickness. It is
episodes of illness after uneventful diving, the first involving most commonly seen on the trunk and proximal limbs. For colour
mainly gastrointestinal symptoms which resolved image, see www.hodderplus.com/hunters.
spontaneously, the second involved minor neurological
features which resolved on recompression and the third
obvious lower limb weakness which also responded rapidly
areas of oedema of the skin may occur which are probably
to recompression treatment. Investigation following
due to local lymphatic obstruction.
recovery demonstrated the presence of patent foramen
ovale which was subsequently closed by percutaneous
catheter technique. He has subsequently been able to Constitutional
return to normal diving activity with no further episodes.
Many patients also report constitutional symptoms of
tiredness, nausea, feeling cold or weak. These symptoms
are most likely a result of hypovolaemia resulting from
Limb pain loss of fluid through damaged capillary endothelium into
interstitial tissues and often improve rapidly with rehydra-
Limb pain (bends) symptoms most commonly affect larger tion and therapeutic recompression.
joints, typically the shoulder, elbow wrist and knee, but can
affect any joint. Joint pain varies from being a mild ache
(niggle) to severe and incapacitating pain, tends to be con- Pulmonary
stant and unaffected by movement of the joint. Limb pain
not localized to a joint sometimes occurs and may be due Pulmonary involvement (chokes) results from massive
to oedema and swelling of a muscle. This is historically the bubble load in the venous circulation and obstruction of
most common presentation in compressed air workers the pulmonary circulation. This results in cough, breath-
often affecting the knees and typically presenting 4–12 lessness and haemoptysis. The resulting high pulmonary
hours after exposure. arterial pressure results in intrapulmonary shunting and
passage of bubbles to the arterial circulation and severe
neurological symptoms usually follow. Individuals with
Cutaneous significant pulmonary involvement are critically ill and
there is a high mortality.
Cutaneous symptoms, include itching which is probably The underlying pathology results from the formation of
due to gas diffusing through the skin, urticaria and a more gas within tissues from molecules previously dissolved in
persistent rash, called cutis marmorata which comprises a tissues and hence the mechanisms relate to the appearance
patchy rash of erythematous and petechial lesions inter- of microbubbles. These may occur in many tissues, but
spersed with normal skin spread over variable areas but have been most commonly identified in the bloodstream
usually over the trunk or proximal limbs (Figure 50.3). It is using Doppler methodology.25 Microbubbles in tissue may
usually painless and not itchy and hence not observed until migrate into the vascular bed. It is recognized that some
the diver removes their suit. This rash is often associated gas microbubbles occur commonly after symptom-free
with more serious neurological manifestations of the ill- decompressions, so it appears that the onset of disease may
ness which may be concurrent or follow later. Localized relate to a threshold which may be volume, number or rate
Bone necrosis 553
of appearance.26 It is clear that the passage of microbubbles tunellers. However, the pattern is complicated by travel
results in damage to the endothelium which results in fluid involving ascent to altitude after exposure either by road
leak into interstitial tissues.27 This is important within the or in commercial aircraft. Such altitude exposure may
cerebral circulation resulting in cerebral oedema, but also provoke symptoms during a period of 24–48 hours follow-
results in significant haemoconcentration. Correction of ing exposure that may prove to be slow to resolve even with
haemoconcentration with large volumes of intravenous appropriate hyperbaric oxygen therapy.
fluid often results in peripheral oedema and pleural effu- Immediate first aid treatment includes administration of
sion. Within the bloodstream, microbubbles trigger the 100 per cent oxygen and rehydration by the most effective
coagulation cascade and stimulate platelet aggregation, means available. Patients presenting with decompression
and activate the complement system contributing to illness should receive specialist assessment and transfer to a
haemoconcentration.28 recompression unit for further treatment with intravenous
These effects are well established; however, how these fluids and recompression. Those patients with severe neuro-
effects relate to specific organ-related symptoms is less logical illness or paraplegia may also require the expertise of a
clear. There is evidence that pulmonary symptoms are specialist spinal injury unit in their continuing management.
associated with the venous vascular bubble load. Increasing
obstruction to the pulmonary capillary bed results in
hypoxia and increasing pulmonary arterial pressure29,30 A 32-year-old compressed air diver made an emergency
with symptoms of breathlessness, haemoptysis and chest rapid ascent from a 12 minute dive to a depth of 30 msw.
tightness. Endothelial leak results in the development of This was followed immediately by an impairment of
pulmonary oedema. consciousness and hemiparesis which resolved
As pulmonary arterial pressure rises, bubbles begin spontaneously within minutes. Some 20 minutes later,
to appear in the arterial circulation. This is associated with he noticed woolliness in his feet which progressed into
the development of neurological manifestation, particularly classic paraplegia. He was evacuated by air to a chamber,
of spinal cord origin. Whether spinal cord injury occurs pri- where some 24 hours later he was recompressed but
marily as a result of arterial bubble embolization or as a with little response. While in the chamber, a surgeon
result of bubble formation in situ or a combination of both conducted a laparotomy ‘because of paralytic ileus’ and
or other mechanisms is uncertain. The close association after decompression the wound dehisced. The patient
between spinal cord injury and right to left intracardiac emerged still paraplegic, but six months later was able to
shunt supports the theory that bubble embolization plays a walk with two sticks.
role.31,32 Conversely, animal experimental work has demon-
strated that autochonous (in situ) bubble formation can Comment
occur.33,34 The end result is the appearance of punctuate It may be speculated that after a relatively short dive
haemorrhagic lesions scattered in spinal cord tissue most with little nitrogen gas load, the rapid ascent resulted in
obvious in white matter associated with axonal swelling and pulmonary barotrauma and cerebral gas embolism.
subsequent myelin degeneration.35 Although these symptoms resolved spontaneously, either
Other symptoms of decompression sickness are also diffi- the pulmonary injury, or diffuse endothelial injury
cult to explain in terms of pathogenesis. The characteristic interfered with normal nitrogen elimination and resulted
musculoskeletal pain symptom has been explained on the in neurological decompression illness. Severe neurological
basis of gas present within the joint, within soft tissues illness does not always respond to recompression
around the joint, within marrow cavities of adjacent bone therapy and the delay in recompression may have
and as referred pain of neurological origin. Constitutional contributed to the lack of response. Paralytic ileus is
symptoms have been explained on the basis of the proinflam- common after severe spinal injury and may complicate the
matory processes associated with decompression sickness, decompression phase of treatment. Surgical intervention
but might readily be explained by the hypovolaemia. The in a chamber is best avoided.
classical cutaneous manifestation of cutis marmorata shows
evidence of an acute vasculitis on biopsy, but its origin may
relate to embolization of cutaneous vessels or the direct tran-
scutaneous migration of gas. The close association of this BONE NECROSIS
rash with right to left intracardiac shunt suggests emboliza-
tion is more relevant. Vestibular decompression illness may Both divers and compressed air workers are at risk of
result from gas formation from endolymph with subsequent developing dysbaric osteonecrosis.36 This is a form of
damage to the semicircular canal sensor cells. aseptic bone necrosis which occurs as a long-term health
Symptoms may develop at any time after the com- effect (Figure 50.4). It may occur after a single pressure
mencement of the ascent phase of a dive, but are most com- exposure, but is more likely after deeper and longer pres-
mon in divers in the first one to two hours following sure exposures and it is more likely to occur in individuals
surfacing. Over 90 per cent of cases present within 24 hours with a history of acute decompression illness. It is dis-
of completion of the last exposure in both divers and cussed in detail below.
554 Diving and work at increased pressure
BUOYANCY
CARDIOVASCULAR WETNESS
Apart from fluid shifts which raise right atrial pressure, Divers’ skin is exposed to water or damp conditions during
immersion of the face in water, particularly when it is cold much of their work. In wet or flooded suits, the diver is wet
provokes the diving reflex manifest by vagal stimulation throughout the period in the water. Drysuits are totally
and bradycardia. This is not a potent effect, but may be enclosed waterproof enclosures and if the physical work
part of the mechanism which results in the rare develop- rate is high, there is very high humidity as a result of sweat-
ment of arrhythmias in some divers and the development ing. Saturation diving environments using heliox as the
of immersion-induced pulmonary oedema. breathing gas require to be maintained at 28–32°C to
maintain thermal balance. Keeping the humidity level
under control generates significant problems, so divers
THERMAL may be exposed to high humidity for periods of weeks at a
The water in which divers immerse themselves is com- time with potential effects on the skin.39
monly cold so rapid loss of body heat is an important
physiological challenge. Divers with more subcutaneous
fat are better protected, but in almost all situations some LOSS OF CONSCIOUSNESS
form of thermal protection is required. A basic neoprene
wetsuit traps a thin layer of water between suit and the Disturbance of consciousness or incapacitation while in
diver’s skin which is heated by the diver’s body heat. The the water prevents the diver from maintaining those
suit restricts water movement and provides some insula- actions essential to preserve life while underwater and
tion, thereby reducing heat loss. Drysuits enclose the hence may prove fatal. The ultimate cause of many diving
diver in a watertight suit which traps a layer of air or gas fatalities is drowning, although this commonly results
within the suit, which acts as insulation. The suit mem- from an initial event which might be a preceding illness,
brane is often thin. Fibre pile or other insulated clothing injury or equipment failure. A detailed investigation of
worn inside the suit provides a medium to hold and trap diving incidents, which should include assessment of
the insulating gas. Drysuits provide better protection equipment in use, is crucial in understanding how the
than wet-suits, but have buoyancy problems and still do incident occurred and hence how further events may be
not really allow comfortable long dives. Flooded hot prevented in the future.
water suits are commonly used. These are essentially a The causes of loss of consciousness fall into several
baggy wetsuit with an internal pipe network. Hot water is categories:
pumped down to the diver and perfuses the suit. Multiple
perforations in the suit pipe network provide a constant ● The presence of a gas phase within the body either from
supply of hot water to the whole body in a fairly even dis- a cerebral gas embolism or decompression sickness may
tribution. Although the diver is wet, body heat can be well cause loss of consciousness either immediately after
maintained for long periods in the coldest water environ- ascent or during the first few hours.
ments. Unfortunately, these suits do not provide any pro- ● The toxic effects of normal air constituents at pressure
tection from other hazards, e.g. chemical. In these may result in loss of consciousness from nitrogen
circumstances, a liquid heated membrane suit can be narcosis, but only at high pressures (pN2 greater than
used. These are a drysuit containing a network of thin- 6 ata) or from cerebral oxygen toxicity, where the pO2
walled tubing in the suit material wall, which can be exceeds 1.5 ata. The latter may occur when breathing an
heated with a supply of hot water to maintain the temper- oxygen-enriched gas mixture (pure oxygen or nitrox) at
ature of the suit environment. shallow depth or a heliox or trimix mixture at deeper
A diver’s thermal comfort can be important in the depths.
control of decompression illness. Cold and poorly per- ● Hypoxia can occur when breathing a gas mixture with a
fused peripheral tissues take up and release dissolved gas low pO2 which can occur as a result of an error in dive
less readily. A diver who takes up inert gas while warm planning or on ascent when breathing a gas which had
during a dive, but becomes cold during the following adequate pO2 at depth, but as pressure falls on ascent
decompression may have a higher inert gas load at the end the pO2 falls. This may occur when making an
of the dive and hence an increased risk of decompression emergency ascent after losing an air supply. Hypoxia
sickness. also results in loss of consciousness when it occurs as a
Water has very high thermal conductivity compared to result of drowning, aspiration of vomit or breathing a
air. This is why garments and suits which trap a layer of air gas supply contaminated with carbon monoxide.
provide insulation for a person in either a cold environ- ● Hypercapnia can occur when ventilation is restricted by
ment or water. Unfortunately, helium also has high ther- gas density, for example when breathing air at depths
mal conductivity, so when the air used for insulation below 40 msw. The high pO2 of air at that depth
purposes is replaced with helium–oxygen mixtures, there prevents hypoxia and allows a diver to undertake high
is a substantial loss of insulation effect. levels of physical exertion. The high metabolic rate
556 Diving and work at increased pressure
Comment
High workload when struggling and an element of panic
while breathing dense air at 5.5 ata resulted in hypoventi-
lation and acute carbon dioxide retention, leading to a
period of anaesthesia. The high partial pressure of oxygen
prevented severe hypoxaemia and the reduction of ambient
pressure during ascent reduced gas density and alveolar
pCO2 allowing rapid recovery with only residual headache.
Figure 50.5 Diver entering water wearing ‘standard dress’ – a
totally enclosed suit and rigid brass helmet supplied with
compressed air from the surface.
DIVING TASKS
hazard in most working diving environments, but the tech-
Diving methodology nique is still used in a limited range of applications including
some scientific (marine science), media diving, police (search
Modern commercial diving may involve a number of and rescue) and sea food harvesting, but has very restricted
different diving methods. application elsewhere. More complex versions of SCUBA,
Breath-hold diving is only in use for commercial pur- such as closed or open circuit rebreather devices, have
poses in traditional pearl diving communities. However, limited military or recreational applications.
breath-hold dives may be undertaken as part of work activ- Surface-supplied diving (SSD) provides a breathing gas
ity, for example in helicopter underwater escape training supply from the surface by hose or umbilical. The diver
(Figure 50.5). normally wears a helmet and breathes through an oronasal
Self-contained underwater breathing apparatus (SCUBA) mask, rather than a mouthpiece (Figure 50.6).
allows a diver to carry a compressed breathing gas supply These two factors allow communications, so the umbil-
and hence be entirely independent in the water. This is most ical also contains electric cables for communications and
extensively used by recreational divers. The diver carries a commonly a hot water supply and a depth/pressure moni-
cylinder of compressed gas with a regulator which reduces tor (pneumofathometer). The communication link allows
the pressure to a few ata above the diver’s actual environmen- the supervisor to listen to the diver’s breathing pattern and
tal pressure. The regulator supplies a demand valve which is talk with the diver and as the umbilical is attached to the
usually attached to a mouthpiece held by the diver’s teeth. diver’s harness, it provides a means by which the diver can
The demand valve provides a supply of breathing gas as the be recovered. No buddy diver is required, but a standby
diver inhales at the diver’s ambient pressure. In the event of diver is available on the surface to follow the diver’s umbil-
emergency, help can only be obtained from the immediate ical to provide rapid support if necessary. Wearing a
vicinity and hence divers dive with a buddy. Complete helmet, rather than using a mouthpiece, provides much
independence which is attractive to sport divers represents a greater security in the event of any incident involving loss
Diving tasks 557
Decompression procedures or tables they have only limited application in commercial diving
and are not used in compressed air operations. The ability
The practical application of decompression algorithms at to measure depth and duration of the dive accurately with-
the dive site can be achieved either by the use of tables40 or out the need to rely on the diver reading a watch and a
by the use of a portable computer device. Decompression depth gauge underwater represents a major advance and
tables comprise a list of procedures defining the ascent the opportunity to eliminate many calculation errors made
profile required following dives of varying depth and dura- in table selection. The computer can then accurately apply
tion. Typically, if a dive is planned to a depth of, for exam- the decompression algorithm and provide a guide to the
ple 32 msw, the dive supervisor would select a table for the decompression profile required. However, in the use of
next deeper depth which might be 35 msw. There will tables, there was a consistent methodology to apply safety
already be an approximate estimate of the time required margins to the algorithm by using a deeper depth than
for the dive, so in the course of the dive the supervisor actually dived, a longer bottom time and using the deepest
would have available 35-msw tables for time intervals depth reached as the depth of the dive rather than an aver-
around the estimate. In the course of the dive, the supervi- age. The computer enables an absolute calculation of depth
sor would ensure that the planned depth was not exceeded time profile to calculate gas uptake and then applies the
and after the work is complete, would note the time at algorithm. Effectively, this means that the algorithm is
which the ascent is started. The duration of the dive from operated close to its limits at all times, whereas when using
leaving the surface to commencement of ascent is called tables there would commonly be additional inbuilt safety
‘bottom time’. The supervisor selects the table time which allowances.
is the next longer than the actual bottom time and then Computers are so widely used that direct comparison of
directs the diver to make stops during the ascent at depths table use versus computer use is now impossible.
and for times defined by the table procedure. Computers inevitably permit more time in the water than
Recreational divers plan their dive in advance and then would tables and hence are attractive to recreational divers.
stick to the plan since their access to table data during a The ease with which a diver can conduct a decompression
dive is limited to what can be recalled from memory or dive has contributed to the increasing depth of recreational
written on a waterproof slate. Not surprisingly, a hand- or diving. It is important that divers fully understand the
wrist-held computer, which accurately measures depths background and limitations of diving computers and use
and time and can then compute the required decompres- them in a knowledgeable and sensible manner.
sion profile while the diver is in the water, overcomes many
practical difficulties and is an attractive option.
Diving tables are produced and published by various Mixed gas methods
organizations including navies,40 recreational diving organ-
izations,41 commercial diving contractors and others. The As dive depth gets deeper, an increasing number of
efficacy of decompression tables is somewhat variable, but problems occur. First, when breathing compressed air,
in general continues to improve and as a result the inci- nitrogen narcosis becomes increasingly important at pres-
dence of decompression illness is falling. Diving tables are a sures above 4 ata and a major safety risk. Replacing the
critical component of a commercial diving contractor’s nitrogen with helium overcomes the narcotic effect and
equipment and a legal requirement in some countries. also some of the respiratory limitation resulting from
Despite gradual improvements, there remain consider- increased breathing gas density. The elevated partial pres-
able differences between tables in the decompression sure of oxygen in compressed air may result in cerebral
requirement for the same dive. This highlights the fact that oxygen toxicity when the partial pressure exceeds 1.5 ata,
decompression table procedures reduce risk, but do not i.e. at 65 msw, particularly where gas density results in
eliminate it. Individuals also differ in susceptibility to some CO2 retention.
decompression illness when exposed to identical pressure These problems can be overcome by using a mixture of
exposure, working activity and conditions. Intraindividual helium and oxygen (heliox) at depth. The oxygen content
variations must also occur to explain why individuals is reduced to ensure that the partial pressure of oxygen at
sometimes develop acute decompression illness, for no the dive depth is not toxic and narcosis is eliminated.
obvious reason, after many years of similar previous An important disadvantage is that the high rate of diffu-
uneventful exposures. These factors have confounded the sion of helium contributes to a rapid uptake during the
further development of decompression procedures and the dive so that the diver approaches saturation more rapidly.
study of associated risk factors. As a result, decompression times for surface-orientated
diving with heliox are longer than with air. Since decom-
pression times get exponentially longer as the dive depth
Computers and duration increase, this becomes an important limita-
tion on the use of heliox for surface-orientated diving. To
The dive computer has revolutionized the conduct of enhance decompression rate, oxygen-enriched breathing
recreational diving and their use is widespread. Currently, gas mixtures and 100 per cent oxygen are used during the
Current hazards and risks 559
decompression; however, the potential for development of when additional support workers, for example medical
oxygen toxicity limits the extent of oxygen use. staff, are compressed rapidly in an emergency situation.
Although deep heliox dives can be conducted using an Saturation diving has completely revolutionized subsea
umbilical from the surface, this technique presents high engineering. Large numbers of ships have been purpose-
risk and the use of a closed bell is more appropriate. built to conduct saturation diving and subsea intervention
Recreational deep divers, attracted to surface-orientated and the associated technology is being applied to diving
techniques as a result of cost and logistical factors, usually tasks in progressively shallower water.
take a different approach to commercial divers, replacing While the saturation method largely protects divers
some but not all of the nitrogen with helium to produce from decompression illness,44 the mode of work intro-
a ‘trimix’ in which the oxygen partial pressure is con- duces a wide range of different medical problems. Perhaps
trolled, and narcosis controlled but not eliminated, while most important of these is the isolation of the divers who
not suffering all the decompression disadvantage of using cannot be returned to the surface in less than their decom-
heliox. pression time, usually several days. This presents difficul-
ties in the management of illness or injury. Although the
concept of transporting an injured diver in a portable pres-
Saturation diving sure chamber to a hospital-based hyperbaric facility has
been explored, it is always simpler to transport a medical
In deep diving, where safety demands the use of a closed team and equipment to the dive vessel and provide care on
diving bell, the number of personnel required to support site. Medical staff who attend a diver in saturation are
the operation is large, the amount of time a diver can spend likely to require the same prolonged decompression.
working on the seabed is very limited and a large compo-
nent of time is taken up with the decompression. Deep
surface-orientated dives carry a high risk of decompression Dive planning
illness. The logical solution to all these issues is saturation
diving. A team of divers is ‘stored’ in a pressure chamber at The methodology selected for an underwater diving proj-
a pressure which is very close to the depth at which work is ect depends on a number of factors which include water
required. Each small diving team comprising a standby depth, duration of work activity, cost, available equipment
diver and one or two working divers is transported by and personnel, and acceptable risk. For example, a single
closed bell from the storage chamber to the worksite. The dive to a depth of 40 msw for a task lasting a few minutes
small pressure difference between the bell and the water at might be safely conducted by a single surface-orientated air
the worksite is equalized and the diver(s) can leave the bell dive involving no decompression stops. A substantial work
to work. At the end of their shift they return to the bell programme requiring many hours of work at a depth of
which is then closed and sealed and the divers return to the 30 msw could be conducted by an air diving operation, but
storage chamber. Because there have been only very small would require numerous dives which would all need to be
pressure changes, there is no time limitation on the dura- of reasonable duration (30–40 minutes) and hence would
tion of the dive and no requirement for a staged decom- involve decompression procedures. There would therefore
pression at this point. Another shift of divers can continue be a significant risk of one or more episodes of decompres-
the work immediately. In this way, divers can work on the sion illness. The same work programme might be more
seabed for more than 20 in every 24 hours. rapidly achieved using saturation methodology in which a
The divers become ‘saturated’ or equilibrated with the smaller number of divers could complete the work in
gas at the pressure they are stored at over a period of six shifts, all working for six hours at a time with a very low
hours. Once equilibrated, no more inert gas can dissolve in risk of decompression illness. It would, however, require
body tissues and hence the decompression time required is expensive equipment and trained personnel, so would
no longer after four weeks than after approximately six represent a more costly option.
hours. At the completion of the work, decompressing the
divers to the surface may take five to six days or even
longer, but the system allows a much more effective use of CURRENT HAZARDS AND RISKS
divers’ time and of plant and equipment and at the same
time dramatically reduces the risk of decompression Divers are exposed to a wide range of hazards. These may be
illness. At depths exceeding 150 msw, divers compressed considered under two major headings, environmental and
rapidly may experience a complex neurological effect related to the work activity. It is important to remember
known as high pressure neurological syndrome,42,43 char- that diving is simply a method of getting workers to the
acterized by tremor, incoordination and episodes of workplace and while diving itself carries significant inher-
microsleep. In operational diving, this is readily avoided by ent hazards, there remain significant hazards of the work
appropriate compression profiles, but is a potential cause activity itself, many of which are shared by workers on the
of poor diver performance and hence accidents during surface (Figure 50.7). Some of these hazards are modified
very deep saturation dives. It may also generate problems by the underwater environment and may be difficult to
560 Diving and work at increased pressure
Figure 50.8 The hand of a diver whose fingers had been sucked
into a valve as a result of pressure difference during a mechanical
Figure 50.7 Extensive chemical dermatitis affecting the engineering task on the sea bed. Pressure differences between the
ankle and foot of an oilfield diver who had been working on the ambient pressure at which the diver is working and gas spaces in
sea bed contaminated with drilling mud. For colour image, mechanical components have caused major injury and fatalities.
see www.hodderplus.com/hunters. For colour image, see www.hodderplus.com/hunters.
hazardous and contingency planning for the management the provision of medical care at the dive site. In evacuation,
of incidents remains an important part of diving operation the possible risk of decompression sickness in the period
planning. after the dive and the possibility of provocation during
In the event of an incident resulting in illness or injury, evacuation by air needs to be considered, but in most cir-
the most immediate assistance is provided by other mem- cumstances the risks associated with delay in receiving
bers of the dive team and hence appropriate first aid training medical treatment are greater.
of divers is important. Divers may be subject to the normal
range of accidents which occur in working environments
and in addition are at risk of specific diving-related illness. Outcome of incidents
The immediate first aid management of the decompression
illnesses, near drowning, hypoxia and carbon monoxide Most incidents require careful investigation to ensure that
poisoning or contaminated gas supply includes oxygen the cause is fully understood and particularly that the
administration and all divers should have this expertise and sequence of events leading up to injury or the presentation
be familiar with the oxygen equipment available. of illness is fully established. This may be critical in estab-
Most cases of decompression illness are treated with lishing a diagnosis. For example, the onset of symptoms at
fluid replacement and recompression.45 Divers presenting stable depth before any decompression has taken place
with symptoms on the surface are most commonly treated effectively excludes decompression illness as a cause of that
with an oxygen breathing procedure, such as Royal Navy symptom.
Table 62 (United States Navy Table 6), in which the indi- After illness or injury, reassessment of medical fitness to
vidual is compressed in a chamber to a depth equivalent of dive should be carried out by a doctor with diving medical
18 msw and given 100 per cent oxygen to breath for peri- knowledge and with complete information about the
ods of 20 minutes interspersed with breathing air for prognosis and the impact of any disability.
five minutes. After three to five periods of oxygen breath-
ing, the pressure is reduced slowly to 9 msw and further
periods of oxygen breathing lasting an hour are continued LONG-TERM HEALTH EFFECTS
before a final decompression to the surface. A substantial
proportion of cases resolve during this primary procedure, Divers are at risk of acute diving-related illness, such as
but others require further hyperbaric oxygen treatments decompression sickness and barotrauma, as well as other
before the condition has either resolved or reached a stable work-related injury. Incomplete recovery from these
state. A variety of more complex procedures may be events may leave the diver with a significant residual deficit
applied in specific situations based upon individual clinical or disability which will never recover.20
assessment.46–48 In addition, divers are at risk of health effects which result
Immediate access to specialist diving medical expertise is in the presentation of symptoms with a substantial delay
critical to ensure that continued care follows appropriate after any pressure exposure and without a history of acute
lines, and evacuation to an appropriate medical and/or decompression illness or other overt symptomatology.
hyperbaric facility occurs when necessary. This is particularly Dysbaric osteonecrosis is the best example of this phe-
important when a recompression facility is available at the nomenon.36 This is a form of aseptic bone necrosis which
dive site where the opportunity exists for recompression is associated with previous experience of decompression.
treatment to be given without any direct medical assessment. Although the precise pathogenic mechanism remains
In the past, a number of inappropriate and unsupervised unclear, it is assumed that decompression involving the
recompression procedures conducted without adequate clin- release of inert gas from solution in body tissues is the
ical support or medical advice have led to tragic outcomes. underlying precipitant. The mechanism may involve
Where medical care at a more advanced level than microbubble emboli causing infarction in end arteries
immediate first aid is required at the dive site, for example within bone49 or pressure change within bone marrow.50
if a recompression facility is available or if the dive site is The lesions which may occur in many bones are painless.
remote either geographically or because the affected diver The end result is areas of dead bone which usually remain
is saturated in a storage living chamber, then it is appropri- asymptomatic for many years. The radiological classifica-
ate for at least a proportion of the diving team to have tion of dysbaric osteonecrosis affecting divers and
more advanced first aid training. This is commonly called compressed air workers was established by the Medical
‘diver medic training’ and involves a two-week training Research Council Decompression Sickness Panel in the
course which covers more medical procedures, such as 1960s and has been widely used internationally ever
venous cannulation and intravenous fluid administration, since.51 Two distinct types of lesion are defined. ‘B’ lesions
drug administration, advanced resuscitation, urinary are found in the shafts of long bones, particularly the
catheterization, vital sign recording, aspects of neurologi- femur, tibia and humerus. ‘A’ (juxta-articular) lesions
cal examination and wound care. occur adjacent to articular surfaces of large joints, particu-
In the event of serious incident, there must be a contin- larly the shoulder and hip. Lesions are almost entirely
gency plan for evacuation of the diver to medical care or painless and those in long bone shafts cause no symptoms
562 Diving and work at increased pressure
and can be regarded as of no clinical significance. Over the psychosocial compounding factors, including the overall
course of years, some lesions adjacent to articular surfaces sickness absence rates, cultural factors, compensation
may result in a gradual collapse of the articular surface fol- and medicolegal issues as UK divers working at the same
lowed by the development of secondary osteoarthritis. time and often at the same worksites do not appear to
Symptoms of joint pain and stiffness develop at this late have similar problems.
stage and may require joint replacement due to severe dis-
ability. The prevalence of dysbaric osteonecrosis in differ- Pulmonary
ent working populations appears to relate closely to the
efficacy of the decompression tables or algorithm used. Divers have been demonstrated to have larger lungs than
Although the prevalence in the UK commercial diving the normal population55 and this has been associated with
population was considered to represent a significant abnormalities in the expiratory flow pattern consistent
potential risk to the diving population as deep saturation with small airway obstruction.56 However, although some
diving developed,52 this has not proved to be the case and of these changes appear to progress in the early part of a
the incidence of new cases in commercial (or military) div- diver’s career,57 no specific pathological outcome has yet
ing appears to be very low. It is however, not possible to be been identified.
certain because routine radiological screening is no longer
considered to be acceptable from a radiation hazard aspect,
and magnetic resonance imaging (MRI), which is the alter- Recent studies
native screening method, has not yet been widely applied
because of cost implications. A number of recent reports have addressed the concerns
The reported incidence of dysbaric osteonecrosis in about development of long-term health effects in the com-
compressed air work projects in the past has reached as mercial diving population. Some uncontrolled studies
high as 25 per cent in the mid-1900s with a wide variation from Norway58,59 have suggested that long-term disability
between different projects. The incidence rates appear to due to unspecified neurological deficit is common in a
have reduced with improved safety and decompression population with experience of diving within the offshore
procedures over many years. However, because of the oil industry. However, a large questionnaire survey of
latency before the appearance of radiological abnormality commercial divers in the United Kingdom,60 compared to
and even longer period before onset of symptoms, accurate the offshore non-diving population revealed no major dif-
incidence rates are difficult to establish. Cases of disability ference in health status, although divers did report more
resulting from dysbaric osteonecrosis still present through symptoms, particularly of forgetfulness and loss of concen-
the courts representing a significant ongoing work-related tration. More detailed evaluation of symptomatic divers
morbidity for previous compressed air workers. The risk showed only small differences in formal tests of memory,61
remains significant particularly considering the relatively which appeared to be related to work in the offshore oil
small number of exposures when compared to the com- industry, rather than any particular diving technique, sug-
mercial diving industry. Unfortunately, any beneficial gesting that other factors associated with work in the
effect on dysbaric osteonecrosis in compressed air workers industry, for example chemical exposure may be relevant.
from the use of oxygen decompression techniques has not
yet been proven due to the lack of accurate data. TUNNELLING TASKS
In the past, much of the work conducted at pressure of the intervention. As the TBM progression is effectively
was manual excavation using hand-held pneumatic tools halted until the intervention is completed, it is an opera-
to progress the tunnel. Tunnelling, therefore, required tional priority to maximize working time under pressure
many man hours of hard manual work in compressed air and to minimize the risk of decompression sickness (since
and the relatively large tunnel labour force (sometimes this removes the worker from the compressed air work-
hundreds of men on large projects) consisted mostly of force for the duration of that intervention).
labourers who worked on a daily shift system with five or Most UK tunnel projects using compressed air in the
six days’ exposure, sometimes during a project which past have been at relatively low pressure (often below 2 ata
could last several years. Although some small projects and rarely above 4 ata, but exposures tended to be long
still require this activity, most tunnels are now con- (six to eight hours)). However, increasing health concerns
structed mechanically using a sophisticated tunnel bor- in the late 1980s and early 1990s led to much shorter pres-
ing machine (TBM) which lines the tunnel as it is sure exposures being adopted by contractors following
constructed and hence the only human work requiring a recommendations from their medical advisers, especially
pressurized environment is maintenance work con- where working pressure exceeded 2 ata and this was even-
ducted at the front face of the machine, such as blade or tually prescribed by HSE in the 1996 regulations. Working
tool changing (often called ‘interventions’) or technical pressures greater than 3 ata restrict shift duration and the
or geological inspections (Figure 50.9). As a result, the limit of current air tables is set at 4.45 ata as a result of
number of man hours required at pressure and the num- physiological factors and safety issues. This has led to the
ber of workers exposed, is greatly reduced in comparison need for the development and implementation of safer
to historical projects. The type of work is often now of a decompression techniques that give longer working time
more technical nature rather than simple manual activ- at higher pressures (4 ata or greater) and with reduced risk
ity, but may still be physically demanding, in very con- of decompression sickness or dysbaric osteonecrosis.
fined spaces under extreme conditions of temperature Inevitably, this means the application of diving technolo-
and humid or wet conditions. TBM interventions or gies in the civil engineering context, which includes the use
inspections are usually conducted on a periodic basis of mixed gas and saturation techniques, in addition to
during the project with the pressure exposure varying oxygen decompression.
from 0.5 to 2 hours (for single inspections) to interven- Like divers, tunnel workers may also require a gradual
tions with shift lengths of two to ten hours (subject to the return to surface pressure to prevent the onset of decom-
maximum working pressure and conditions) and daily pression illness. The decompression or ascent is conducted
exposures for two to six days. in a pressure lock so can be very accurately controlled.
TBMs require short intense periods of compressed air Whole shifts will compress together and decompress at the
interventions, sometimes at high pressures (4–8 ata), but end of the working shift.
use a relatively small compressed air workforce (typically Decompression procedures for tunnelling in the past
30–60 personnel). The number of workers per shift have been quite different from diving procedures and
depends on the tunnel diameter and other factors, but usu- appeared to permit much more rapid decompression from
ally only three to five men will work under pressure at any a given pressure exposure. The incidence of decompression
one time on a rotating 24-hour shift basis for the duration illness has often been quite high and dysbaric osteonecrosis
a more frequent result than in divers, often appearing between management, engineering, hyperbaric and med-
many years after the pressure exposure. ical staff at all times.
Civil engineering projects requiring work at pressure
are intermittent and relatively rare. As a result, the work-
force only occasionally takes part in pressure-related activ- DECOMPRESSION ILLNESS IN COMPRESSED
ities while doing a wide range of other work usually within AIR WORK
the construction industry. Long-term health surveillance
has been difficult in this situation as most compressed air Historically, decompression sickness was common among
workers are not in long-term employment with any given tunnel workers and many factors contributed. Long
contractor and thus health screening has usually only been exposure times associated with hard manual work activity,
managed on a project-specific basis when the need arises. ineffective decompression procedures, inadequate tunnel
The development of TBMs has also led to a different ventilation and avoidance or incorrect application of
type of workforce being involved. Due to the skills required the decompression procedure have all contributed. Limb
and the technical complexity of the projects, there is now pain has been a more common presentation than any
always a minority of workers with previous compressed air other, although sensory neurological or other clinical
or pressure exposure experience and the health and safety manifestations are not uncommon. Severe neurological
culture is mainly derived from the construction industry. decompression illness occurs rarely. As decompression is
This has implications for the induction training, lock always conducted in a chamber lock which is usually of a
supervision and site management of the pressure systems significant size, very rapid ascent is virtually unknown and
with significant differences from the management hence pulmonary barotrauma is very rare. In the recent
approaches employed with commercial offshore divers past, considerable effort has been directed at improving the
who will work under pressure usually as a long-term career decompression procedures without substantially prolong-
choice. Where mixed gas or saturation techniques are ing overall working hours and this has been achieved by
required in civil engineering projects, the selection and the use of oxygen breathing during decompression for
training of the workforce (who will optimally require a pressures up to 3.45 bar (gauge). While this is a major
mixture of tunnelling and diving experience within teams) advantage in terms of decompression safety, there remain
will always require careful consideration. some concerns about the safety aspects of using com-
Tunnel and caisson environments have other signifi- pressed oxygen in some situations, particularly where a
cant safety issues. They are enclosed spaces and require lock on a tunnel boring machine may be at the closed end
appropriate ventilation. Carbon dioxide retention may be of a tunnel several kilometres long. In practice, this has
a contributory factor in decompression illness. It is critical implications for the competency of hyperbaric technical
to ensure that the environment is not contaminated by staff (lock attendants), training and supervision of the
toxic chemicals, particularly carbon monoxide, and that all workforce and strict management and fire prevention
possible sources of ignition are controlled to avoid fire. procedures which must be fully implemented on site.
Fire in a pressurized tunnel burns more intensely for a The risk of decompression illness requires the develop-
given flame size, spreads more vigorously and is harder to ment of a contingency plan which covers surveillance of
extinguish than at atmospheric pressure and all of these workers during the at-risk period after pressure exposure,
effects are magnified by oxygen enrichment. Hence, the and the provision of a recompression facility with appro-
fire risk depends on both pressure and percentage of oxy- priate medical support sufficient to manage a patient with
gen in the environment and it remains a major safety con- severe neurological decompression illness.
sideration in compressed air work. Oxygen decompression
techniques were effectively delayed in the United Kingdom
within the civil engineering industry, until the Health and Treatment of decompression illness in
Safety Executive had fully assessed the possible increase in compressed air work projects
safety risk from fire compared to the reduction in risk of
decompression sickness from breathing oxygen during The treatment of decompression illness arising during
decompression. tunnelling operations is now identical to that used in the
While it is possible to ensure that the structure con- management of diving illness. In the past, recompression
structed to enclose the tunnel is sound and adequate to procedures using air alone were extensively used with sev-
withstand the applied pressure, it is equally important to eral therapeutic and practical disadvantages, but now that
ensure that the surrounding ground cover and tunnel wall the use of oxygen at the worksite has been accepted, the use
itself is secure. While tunnelling under a river for example, of oxygen treatment tables has become normal practice.
if the depth of ground between the bed of the river and the Therapeutic recompression is carried out using on-site
upper part of the tunnel wall is too thin, then the tunnel chambers operated by medical lock attendants under the
may blow out with rapid loss of pressure and flooding of the clinical supervision of the contract medical adviser or by
tunnel. Good management of any compressed air project referral to the nearest appropriate hyperbaric facility if the
therefore requires effective and regular communications compressed air worker is remote from site.
Assessment of fitness for work at pressure 565
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University Hospital prospective study of Norwegian compressed natural air in the working chamber. Addendum
occupational divers – CNS effects of diving. Undersea and to ‘A guide to the Work in Compressed Air Regulations
Hyperbaric Medicine. 2006; 33: 666. 1996’. Bootle: HSE, 1996.
60. Ross J, Macdiarmid J, Osman L et al. A questionnaire study of 66. Health and Safety Commission. Medical examination and
health effects in United Kingdom male professional divers assessment of divers, MA1. UK: Health and Safety
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61. Taylor CL, Macdiarmid JI, Ross JAS et al. Objective Guidelines on respiratory aspects of fitness for diving.
neuropsychological test performance of professional divers Thorax. 2003; 58: 3–13.
reporting a subjective complaint of ‘forgetfulness or loss of 68. Koo KH, Kim R, Kim YS et al. Risk period for developing
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Regulations 1997. London: HMSO, 1997. osteonecrosis in military divers using magnetic resonance
63. Health and Safety at Work Act. London: HMSO, 1974. imaging. European Radiology. 2005; 15: 368–75.
51
Working at high altitude
PETER JG FORSTER
HIGH ALTITUDE ILLNESS puna (high altitude pulmonary oedema) and nervous puna
(high altitude cerebral oedema).3 It is tribute to Ravenhill’s
The journals of intrepid mountaineers give clear testimony astute clinical acumen and observational skills that his
to the discomforts and perils of life at high altitude. In 1879, classification of the ‘benign’ (acute mountain sickness) and
on Chimborazo in Ecuador, Edward Whymper, conqueror ‘malignant’ (high altitude pulmonary oedema, high alti-
of the Matterhorn in 1865 and the foremost mountaineer of tude cerebral oedema) forms of altitude sickness remains
his time, suffered intense headache which ‘rendered us in use in the modern era.
almost frantic or crazy’ and an ‘indescribable feeling of illness Acute mountain sickness is a self-limiting condition
which pervaded the whole body … and we were preoccupied characterized by headache, sleep disturbance, anorexia,
by the paramount necessity of obtaining air’.1 Whymper nausea, vomiting and cerebral symptoms, such as profound
succeeded in reaching the summit of Chimborazo (6290 m). fatigue, dizziness, irritability, lack of concentration and
However, Edward Fitzgerald failed to achieve his personal confusion. Physical signs include periorbital and peripheral
ambition of the first ascent of Aconcagua (6980 m), the oedema and manifestations of normal physiological response
highest mountain in the western hemisphere, because, as he to high altitude exposure, such as shortness of breath on
records in his book published in 1899: ‘I got up, and tried exertion and tachycardia. Acute mountain sickness (AMS)
once more to go but I was only able to advance from two to affects unacclimatized visitors at elevations above 2500 m.
three steps at a time and then to stop, panting for breath, my Symptoms become manifest after a period of approximately
struggles alternating with violent fits of nausea.’2 six hours at high altitude and reach their maximum severity
The discomfort experienced by mountaineers on ascent at 24–48 hours. Symptoms subside gradually after two or
to high altitude is compounded by the additional hard- three days’ acclimatization. If the condition is ignored and
ships of exertion, fatigue, exposure, low temperature, ascent to greater altitude is attempted, AMS may progress to
gastrointestinal upsets, alteration in diet and dehydration. potentially fatal high altitude cerebral oedema (HACO) or
Fitzgerald’s discomfort was intensified by a diet which on high altitude pulmonary oedema (HAPO).4
Christmas morning 1896, camping cold and hungry at The incidence of AMS in sea-level residents ascending
4900 m, consisted of ‘some tins of Irish Stew … melting the to altitudes greater than 3000 m has been estimated from
great white frozen lumps of grease slowly in our mouths, large population studies of trekkers and soldiers on single
and then swallowing them’. In 1913, TH Ravenhill, med- ascents. Hackett and Rennie5 reported an incidence of
ical officer to a mining district in the Chilean Andes, 43 per cent in 200 hikers reaching Pheriche (4243 m) on
described the features of altitude sickness affecting miners the trail to Mount Everest. One-third of the hikers were
transported by rail from Antofagasta, a seaport on the symptom free. Of the thousands of climbers making the
Pacific Ocean, to mines situated above 4600 m. The miners rapid ascent to the summit of Mount Rainier (4392 m)
in Ravenhill’s study were subject to the effects of altitude every year, 50–75 per cent suffer from AMS.6 Of over 250
without other complicating influences. Based on his clin- hikers walking the Mount Everest base camp trek from
ical observations, Ravenhill identified three types of altitude Namche Bazaar (3440 m) to a final altitude of over 5500 m,
sickness: normal puna (acute mountain sickness), cardiac 57 per cent developed AMS; concomitant symptoms of
High altitude illness 571
respiratory and gastrointestinal infection were common altitude, mild symptoms in one-third and one-third are
(87 per cent of the study group) and were more prevalent symptom free.10
in AMS sufferers.7 Singh et al.8 reported an 8.3 per cent A study of sea-level residents transported rapidly to
incidence of severe AMS in thousands of soldiers trans- high altitude, similar to the experience of the Andean min-
ported from sea level to above 3500 m. These published ers in Ravenhill’s paper, was conducted in 1980 on person-
studies have involved young, physically fit and, predomi- nel manning astronomical observatories at the summit
nantly, male subjects. In a general population of visitors of Mauna Kea (4200 m, 13 796 ft), on the island of
(age range 16–87 years, one-third female) to modest eleva- Hawaii.11,12 In 1980, four major telescopes were situated
tions (1900–3000 m) in the Rocky Mountains of Colorado, at the summit which because of the dry atmosphere,
25 per cent suffered AMS) within the first 12 hours of absence of pollution and ready access, was the pre-eminent
arrival.9 Males and females are affected equally by altitude site for terrestrial infrared and submillimeter astronomy
sickness: the young suffer more than the old. As a rough (Figures 51.1–51.3). At the summit, barometric pressure is
guide a rule of thirds applies: moderate to severe symptoms 625 mbars (62.5 kPa, 475 mmHg) and the ambient partial
of AMS occur in one-third of sea-level residents at high pressure of oxygen is 60 per cent of the sea-level value.
The partial pressure of oxygen in inspired air is 12.6 kPa within days of return to sea level. Telescope personnel who
(95 mmHg) compared with 20 kPa (150 mmHg) at sea commuted to the summit for a single day did not suffer
level and 7.6 kPa (57 mmHg) in alveolar air, compared from severe AMS symptoms. However, commuters were
with 14 kPa (105 mmHg) at sea level. Telescope personnel only at an advantage if the duration of the visit to the sum-
make frequent ascents by four-wheel drive vehicle from sea mit was limited to less than six hours, the period of time
level to the summit with minimal provision for acclimati- that elapses usually between arrival at high altitude and the
zation above 3000 m. They remain on the mountain for development of AMS: symptoms of headache, poor con-
five day shifts working at the telescopes and sleeping in centration, lethargy and dyspnoea were developing as
dormitories at 3000 m. On Mauna Kea, 80 per cent of the commuters descended after five hours. The disadvantage
shift workers were affected by altitude sickness symptoms of the commuter’s work schedule was that commuters did
on the first day. Headache and breathlessness were the not acclimatize.
most common and troublesome complaints. Other com- A 2007 study on Mauna Kea used the Lake Louise AMS
mon symptoms were insomnia, lethargy, poor concentra- Questionnaire (Appendix 51.1) to survey AMS amongst
tion and impairment of memory. telescope shift workers and day visitors.13 Using this stan-
After five days on the mountain, 60 per cent of workers dardized self-report symptom assessment, which was not
were free of symptoms, while the remainder continued to available in 1980, AMS was detected in 69 per cent of shift
experience minimal symptoms of exertional dyspnoea, workers. Over 65 per cent of the telescope staff reported
headache and insomnia. There was no difference in the headache with 13 per cent suffering incapacitating
incidence of AMS in shift workers who worked at the sum- headache. Difficulties with sleeping were common (70 per
mit following a four-day sojourn at sea level compared to cent), as were nausea and lethargy. The majority of
a 30-day rest period at sea level; acclimatization to altitude workers (70 per cent) were aware that symptoms reduced
achieved during five days above 3000 m appeared to be lost their level of activity.
High altitude pulmonary oedema (HAPO) is a non- An incidence of HAPO has been reported as high as
cardiogenic form of pulmonary oedema. Pulmonary 15.5 per cent in thousands of lowland troops flown up to
hypertension is the principal pathological process causing the Himalayas.18 Seven cases of HAPO were encountered
leakage of oedema fluid from intravascular space into the amongst 278 unacclimatized hikers at 4243 m in Nepal, an
alveolar bed in association with an exaggerated pulmonary incidence of 2.5 per cent.19 At the Regina Margherita hut
vasoconstrictive response to hypoxia and exercise, which is (4559 m) in the Alps Valais, 4 per cent of climbers were
distributed unevenly throughout the lung vasculature. In diagnosed as suffering from HAPO as indicated by
addition, abnormal endothelial synthesis of vasoactive pulmonary crepitations on auscultation.20 On Mauna Kea,
substances disturbs the balance between vasodilators (e.g. one case of HAPO was diagnosed in 41 shift workers dur-
nitric oxide) and vasoconstrictors (e.g. endothelin-1).14 ing a two-year study (Table 51.1). Calculated in terms
HAPO may follow viral respiratory infections in children15 of the 2000 ascents per annum to a single telescope, this
and HAPO victims may exhibit infective and inflammatory low incidence of HAPO may reflect the lack of physical
signs: low-grade pyrexia, peripheral leukocytosis and exertion involved in ascent to 4200 m. However, in
raised ESR. However, examination of bronchoalveolar contrast to the low incidence of HAPO reported in earlier
lavage fluid collected from climbers within hours of arrival studies, a 2002 prospective study of 262 climbers to Monte
at 4559 m has shown no increase in inflammatory markers Rosa (4559 m) found clinical and radiographic evidence of
or neutrophils.16 Hence, inflammation is thought to be a interstitial oedema in 40 subjects (15 per cent) without
secondary response to extravasation of fluid into alveoli HAPO-related symptoms. Using airway closing volume as
rather than a primary pathological process in HAPO.4 a proxy for interstitial water, 74 per cent of the healthy
The signs of HAPO are marked breathlessness at rest, a climbers had subclinical pulmonary oedema without clini-
rapid respiratory rate (30 breaths/min) and a dry cough, cal or radiographic evidence. The researchers concluded
which as the condition worsens may be productive of white, that ‘even at modest altitudes and rates of ascent, with
frothy or blood-streaked sputum. The victim appears deeply heavy but not extreme exertion, the healthy lung is on the
cyanotic and may complain of chest discomfort. Extensive edge of failure in terms of fluid balance’. Hypoxia was
bilateral crepitations (rales) are heard on auscultation. In proposed as the putative agent rather than exercise.21,22
extreme cases, gurgling sounds from the lungs may be audi- Individuals with an over-exaggerated pulmonary
ble to the victim and his companions without the use vasoconstrictive response to hypoxia and exertion or
of a stethescope. Signs of cardiac failure are not evident, abnormalities of cardiopulmonary circulation leading to
although tachycardia (pulse rate 120 beats/min) and a low increased pulmonary artery pressure (e.g. unilateral absent
systemic blood pressure are frequently present. Cardiac pulmonary arteries, primary pulmonary hypertension) are
murmurs are not a feature of HAPO. However, the second at increased risk of HAPO.23–25 Although it is not possible
heart sound is accentuated and sometimes palpable, to predict who will suffer from HAPO on a particular
reflecting elevation of pulmonary artery pressure. An ascent, individuals who have suffered a previous episode
erroneous diagnosis of bronchopneumonia may be sug- have a risk of recurrence of 60 per cent on reascent to over
gested by the presence of low-grade pyrexia and moderate 4500 m.26 A genetic predisposition to HAPO may be linked
leukocytosis, but respiratory infection may coexist with to up- or downregulation of the genes that control synthe-
HAPO. sis of the vasodilator nitric oxide and the vasoconstrictor
Arterial blood gas measurements confirm severe hypox- endothelin-1. Other studies of genetic predisposition to
aemia with low arterial partial pressure of oxygen (PaO2) HAPO have included investigations of polymorphisms in
and decreased arterial carbon dioxide tension (PaCO2) angiotensin-converting enzyme genes, HLA haplotypes
from hyperventilation resulting in respiratory alkalosis. and the amiloride-sensitive epithelial sodium channel
Prominence of the pulmonary arteries and patchy infil- which has a key role in clearance of fluid and sodium from
trates seen in chest radiographs in early disease progress to the alveolar space.27
homogenous bilateral infiltration in severe cases. Right Failure to descend or to treat HAPO effectively may
ventricular overload pattern (right axis deviation, right result in a fatal outcome within a few hours of onset; the
bundle block and right ventricular strain) is present mortality rate is quoted in the range 4–11 per cent. In a
on electrocardiograph tracings. Echocardiography may review of 166 reported cases of HAPO, untreated victims
demonstrate incompetence of the tricuspid valve. Cardiac had a mortality rate of 44 per cent compared to a 3 per cent
catheterization studies performed on HAPO victims mortality in subjects who were treated by descent and oxy-
before treatment or descent show a high pulmonary arter- gen administration.28 Half of HAPO sufferers who die have
ial pressure and low or normal pulmonary artery wedge coexistent HACO evident at post-mortem.29
pressure.17 Descent to low altitude and administration of Cerebral oedema (HACO) presents typically with
oxygen lowers pulmonary artery pressure, clears radio- intense headache, profound lethargy, ataxia, impaired
graphic pulmonary infiltrates and relieves symptoms coordination, confusion, disorientation and hallucin-
within one to two days. The development of HAPO is ations. Convulsions and focal features, such as cranial nerve
related to the speed of ascent, the altitude achieved, the palsies and visual field loss, may occur. Cerebral oedema
exertion involved and the susceptibility of the individual. occurs in people exhibiting ‘benign’ AMS: the progression
Table 51.1 Medical emergencies at United Kingdom Infrared Telescope (UKIRT) on Mauna Kea.
Case 1: High altitude Male, aged Progressive dyspnoea, tachypnoea, cyanosis; occurred at rest Immediate descent and Clinical examination at sea level –
pulmonary oedema 29 years camp (3000 m) following third night shift at summit oxygen administration symptoms and signs of HAPO
(6 L/min) resolved; chest radiograph normal;
subsequent work at summit
without recurrence of HAPO
Case 2: High altitude Male, age Slurred speech, frontal headache with neck stiffness, temporary Descent and oxygen Complete resolution of signs and
cerebral oedema 30 years loss of peripheral vision, impaired coordination, ataxic gait; symptoms at sea level; no
symptoms presented on first day at summit subsequent work at telescope
Case 3: Acute mountain Male, aged Headache, nausea, lethargy, poor concentration, impaired memory, Acetazolamide prophylaxis Exemption from work at high altitude
sickness 30 year cyanosis, periodic respiration: no focal central nervous system (dose 500 mg to 1.5 g/day);
signs. Symptoms present on first day of work at summit of every minimal reduction in AMS
shift, necessitating descent. Subject attempted, unsuccessfully, symptoms. Adverse effects –
to ameliorate symptoms by gradual staging of ascent paraesthesia, diuresis
Case 4: Migraine headache Male, age History of classical migraine. Eighth day on mountain – symptoms Descent, anti-emetic Neurological symptoms resolved at
29 years of expressive dysphasia, loss of right peripheral visual field, for nausea sea level, EEG, isotope brain
numbness right arm; nausea: no headache scan – normal
Case 5: Bronchopneumonia Male, aged Cough productive of purulent sputum, dyspnoea at rest, fever, Descent under supervision by Uneventful return to summit
34 years anorexia, ataxic gait – following flu-like illness colleague (patient exhibited after 4 days
marked loss of insight),
antibiotics, bed rest
Case 6: Bronchopneumonia Male, aged Two episodes on consecutive visits to Mauna Kea, cough productive Descent to sea level, antibiotics, Completed work schedule at
30 years of purulent sputum, severe dyspnoea, central cyanosis bronchodilators, bed rest observatory after 3 days sojourn at
sea level; following second episode,
persistent dyspnoea; astronomical
research aborted, returned home;
subsequent examination by
respiratory physician – no
underlying chest disease
Case 7: Perforation of Male, aged Contracted coryza at sea level, developed right otitis media on Remained on mountain, Healing of perforation
ear drum 55 years Mauna Kea. Impaired hearing, ‘pressure in right ear’, antibiotics, decongestant
discharge from ear
Assuming a complement of three day staff and three night observers, approximately 2000 ‘man-days’ were worked each year at the UKIRT facility during the two-year period of study. An average working day
constituted nine hours at the summit.
High altitude illness 575
to HACO is indicated by deterioration in existing AMS, Most of the cases I have instanced were men to all appear-
despite treatment and no further ascent, or the appearance ances perfectly sound. Young, strong and healthy men
of neurological signs, such as ataxia on walking (poor heel may be completely overcome: stout, plethoric individuals
to toe walking) or sitting (truncal ataxia), cranial nerve of the chronic bronchitic type may not even have a
palsies and visual field loss.30 Convulsions may occur. headache.’ Edward Whymper, a proud man, could not
Features of HAPO may coexist and complicate diagnosis hide his irritation with one of his fellow travellers: ‘strange
and management of HACO. Papilloedema develops in to relate Mr Perring did not appear to be affected at all.
over 50 per cent of HACO victims. Retinal vein engorge- Except for him, we should have faired badly … yet at sea
ment and retinal haemorrhage are of minor prognostic level, in the normal course of things he was a rather debili-
significance in HACO as these fundoscopic abnormalities tated man and was distinctly less robust than ourselves.
are not uncommon in asymptomatic subjects at high He could scarely walk on a flat road without desiring to
altitude. Rapid deterioration in conscious level leading to sit down.’
death has been widely reported.31 Investigations off the
mountain show raised cerebrospinal fluid pressure on
lumbar puncture and increased signal in white matter Cognitive and psychomotor function at high
reflecting oedema of the corpus callosum on T-2 and altitude
diffusion-weighted magnetic resonance imaging (MRI).29
Post-mortem examination reveals extensive cerebral In a series of papers published in the late 1930s, RA
oedema, intracerebral haemorrhages and thrombosis in McFarland reported several studies from the Andes of the
cerebral veins and dural sinuses.32,33 effects of high altitude on psycho-physiological perform-
Current thinking is that HACO is due to vasogenic ance. Comparing sudden ascent to 5000 m in unpressur-
oedema related to disruption of the blood–brain barrier ized airplanes while flying over the Andes with slower
with extravasation of fluid into the interstitial space rather ascent to 4700 m by road or rail, he observed that the per-
than cytotoxic oedema related to cell death due to increased formance of mental tests of complex reactions (e.g. mental
intracellular osmolarity.4 Damage to the blood–brain arithmetic, writing) were more impaired than motor and
barrier may be ‘mechanical’ induced by impairment of sensory tests and that there was a ‘close interdependence
cerebral vascular autoregulation or ‘chemical’ related to between the partial pressure of oxygen in the internal envir-
release of mediators of barrier permeability, such as onment of the organism and the functional capacity of
bradykinin and hydroxyl-free radicals. Cerebral hypoxia is the central nervous system’: the rate of ascent was an
exacerbated by exercise which reduces oxygenation fur- important variable.36 In a second paper, sensory (auditory
ther.34 If swelling of the brain is commonplace in all people threshold, visual after images) and motor functions (reac-
on ascent and AMS is a mild form and precursor of HACO, tion times, hand–eye coordination) showed significant
the ‘tightfit’ hypothesis proposes that susceptible individ- deterioration only above 5330 m; acclimatization lessened
uals have less cranial capacity to accommodate the swollen deterioration.37 In the third paper, memory, speed of word
brain. Capacity would depend on the ratio of cranial cere- recognition and mental flexibility were not significantly
brospinal fluid to brain volume which varies between indi- affected until an altitude of above 4700 m was achieved.
viduals and could explain variability of response to high The research subjects noted ‘that the effort of mind needed
altitude exposure.29 Perhaps people aged over 50 years to carry out a task was greater than the loss of capacity to
are more tolerant of high altitude because of a degree of do it’.38 In his fourth paper, McFarland reported that
cerebral atrophy.35 Andean sulphur miners working at 5330 m had slower
Cerebral oedema occurs usually in unacclimatized reaction times and blunted auditory sensitivity than age-
people above 3000-m elevation, although cases of HACO in and race-matched workmen at sea level.39
well acclimatized climbers at extreme altitudes (7000 m) Impairment of higher cerebral functions has been
have been documented. Typically, HACO appears as a pro- reported at lower altitudes than the threshold altitude of
gression of AMS developing over 24–36 hours: the risk 4700 m in McFarland’s studies. Psychomotor efficiency
factors for both conditions are the same. HACO is less com- (eye–hand coordination test) was compromised in accur-
mon than HAPO. In a study of 278 trekkers in the acy and speed in a group of Indian soldiers over a period of
Himalayas, five cases were diagnosed at 4243 m, an inci- ten months at 4000-m altitude. Although accuracy recov-
dence of 1.8 per cent (compared to 2.5 per cent for ered over the next 13 months, presumably due to acclima-
HAPO).12 Singh et al.18 described 24 cases of ‘severe’ neuro- tization, recovery of speed of performance did not return
logical abnormality amongst 1925 AMS victims at altitudes to sea-level values, while the subjects remained at high
between 3350 and 5486 m.18 A single episode of HACO altitude.40 Psychomotor and information processing tests
occurred during the Mauna Kea study (Table 51.1). were not impaired in Mauna Kea telescope staff at 4200 m.
Physical fitness offers no protection against altitude Numerate memory was impaired on the first summit day,
sickness. Ravenhill3 records in his 1913 paper: ‘There is, in but corrected by the fifth day.
my experience, no type of man whom one may say that Elite climbers who had reached summits over 8000 m
he will, or will not, suffer from puna (altitude sickness). without supplementary oxygen were found to have residual
576 Working at high altitude
cognitive impairment in short-term memory, cognitive known teratogenic properties of sulphonamide drugs.
flexibility and ability to concentrate two to six months after Recommendations for pregnant women going to high alti-
the last of repeated exposures to extreme altitude. The three tude, including who should not go high, based on a com-
most severely affected individuals exhibited EEG abnor- prehensive review of the literature has been published in an
malities.41 In a group of young fit mountaineers using International Mountaineering and Climbing Federation
supplemental oxygen to climb Everest (altitude 8850 m, consensus paper.47
29 029 ft: barometric pressure 337 mbars, 33.7 kPa, Combined oestrogen and progestogen oral contracep-
253 mmHg), transient mild deterioration in learning, tives (COCP) can be taken to control the menstrual cycle
memory and expression of verbal material was detected in wilderness conditions, but there is a theoretical risk
within three days of descent to Kathmandu, but had recov- of increased thrombotic episodes due to dehydration and
ered by one year. Reduction in motor speed (finger tapping an increase in haematocrit occurring at high altitude.
test) characterized by rapid muscle fatigue persisted for a Synthetic progestogen formulations may be more suit-
year.42 In a study of mountaineers before and 1–30 days able for stabilizing the menstrual cycle and for use as
after ascent to altitudes above 5488 m and altitude chamber contraceptives due to the theoretical reduction in risk
‘ascent’ to 8848 m, neuropsychological testing revealed a of thrombosis. However, different preparations have dif-
decline in visual and verbal long-term memory expres- ferent characteristics and advantages (see Table 51.2).
sion.43 However, in an earlier study, Clark et al.44 found no Newer progestogen-only pills containing desogestrel (75 μg)
evidence of cerebral impairment as judged by neurophysio- may have advantages over conventional COCPs by inhibit-
logical tests performed before and 16–221 days after climbs ing ovulation as do COCPs without the increased throm-
ranging from 5335 to 8848 m in the Himalayas. botic risk. Alternatives to oral preparations include the
Magnetic resonance imaging of the brains of nine progestogen-releasing (levonorgestrel) intrauterine system
climbers before and after a 7500-m climb without supple- or etonorgestrel implants. To establish effectiveness for the
mentary oxygen showed cortical atrophy (high signal areas) individual female, these formulations should be tried for a
in five before the expedition with new areas of cortical minimum of three months, ideally six months, before travel.
atrophy in two of the group. Both had suffered severe
neurological symptoms during the climb.45 In a more
Children
extensive study, MRI abnormalities were present in 61 per
cent (13/21) of climbers who had ascended to altitudes over
Children are susceptible to the adverse effects of altitude
8000 m, but in only 14 per cent (1/7) of Himalayan sherpas
and suffer AMS, HAPO and HACO.50 Most studies have
with similar high-altitude exposure. Although no relation-
shown a similar incidence of AMS in children and adults.
ship was found between the MRI changes and the number
Children living at high altitude are more susceptible than
of climbs or the duration of exposure to high altitude, these
adults to ‘re-entry HAPO’ when they return home after a
studies confirm the risk to the brain of hypoxia at extreme
sojourn at lower altitude.
altitude with over half of sea-level native climbers affected
The inherent risks to children travelling to high altitude
and relative sparing of high altitude natives.46
demand special attention in the planning for and manage-
ment of altitude-related illness and subsequent specialist
follow up.51
Female gender
At high altitude, females are equally likely to suffer from Lake Louise acute mountain sickness
AMS as men. Peripheral oedema is more common in scoring system
females, but the incidence of HAPO is lower. There are no
data regarding difference in the incidence of HACO To aid diagnosis and to assess the severity of altitude sick-
between the genders.47 Acclimatization is similar as is exer- ness, the Lake Louise acute mountain sickness scoring
cise performance at high altitude.48 Although females have system was developed at consensus meetings held in Lake
an increased ventilatory response to hypoxia which is Louise, Canada in 1991 and 1993.52 The scoring system was
assumed to be due to the protective effect of the respiratory formulated initially to allow standardization of diagnosis
stimulant hormone progesterone, this does not appear to and severity of illness for research studies. Nevertheless,
confer benefit in terms of ventilatory acclimatization.49 the simple and short self-reporting questionnaire of five
Females lose less weight at high altitude than males pos- key symptoms has sufficient sensitivity and specificity for
sibly because they recover from hypoxia-induced anorexia use by non-medical trekkers and mountaineers for the
more quickly. detection of altitude sickness in themselves and their
Women are advised to confine their ascents to modest companions (Appendix 51.1).
altitudes (2500 m) during early pregnancy because of the The Lake Louise score can be confounded by extrane-
possible risk of hypoxia to fetal development. During the ous factors (e.g. concomitant illness) leading to over-
first trimester, prophylaxis with the carbonic anhydrase diagnosis of altitude sickness, hence the score should
inhibiter acetazolamide is contraindicated because of the be calculated in the context of a recent gain in altitude.
Table 51.2 Contraception and menstrual cycle control for women at high altitude.
Combined oral contraceptive Daily oral pill to be taken Yes, may be reduced if Yes 3 months Good, no period if taken continually, but in
pill (COCP) within 12-hour window on antibiotics this case risk of breakthrough bleeding
Progesterone only Daily oral pill to be taken Yes, may be difficult to No 3 months Variable
pill (POP) within 3-hour window take on time
Desogestrel (POP) Daily oral pill to be taken Yes No 3 months Generally good, variable
within 12-hour window
Levonorgestrel IUDs Intrauterine system lasts Yes No 6–9 months Generally good after 6 months, may well
for 5 years result in little or no period
Etonogestrel implant Subdermal implant lasts Yes No 3 months Variable, may try desogestrel POP first to
for 3 years establish efficacy and side-effect profile
Medroxyprogesterone Intramuscular injection Yes No 4 months Variable but if suits, generally excellent,
acetate injection lasts for 12 weeks may result in no period
Medroxyprogesterone acetate Oral daily medication No No 2 months Generally good, may have no bleeding
orally 30 mg daily but risk of breakthrough bleeding
Norethisterone 5 mg tds Oral three times daily No No 3 months Good, will have a period, should be
days 5–26 medication fairly light
Reproduced with permission of Dr Jane Preston, Consultant Obstetrician and Gynaecologist, James Paget University Hospital, Gorleston, Great Yarmouth, UK.
578 Working at high altitude
A clinical assessment score involving change in mental visitors (30 per cent) suffered AMS defined as a LLSS of
status, ataxia (heel–toe walking test) and the presence of 3 or greater. Headache was recorded in all sufferers, mental
peripheral oedema, as well as an overall functional score status changes in 17 per cent and shortness of breath in
can be added to the Lake Louise self-assessment score for 29 per cent.13 The authors of this study observed that to
research purposes. The Lake Louise scoring system is not differentiate symptoms induced directly by hypoxia from
suitable for the detection of altitude sickness in preverbal those caused by changes in vascular permeability, which
children (i.e. under the age of three years). A modified are involved in the pathogenesis of AMS,58 would be diffi-
scoring system (Children’s Lake Louise Score) has been cult. Nevertheless, the time scale of the onset of symptoms
developed for this purpose.53 indicates that these novice visitors to high altitude experi-
enced either AMS of unusually rapid onset or a different
condition altogether.
Susceptibility to altitude sickness
Susceptibility to altitude sickness varies greatly between Illness at high altitude which is not high
individuals; however, in general, individuals respond altitude illness
consistently on each ascent. On Mauna Kea, mean arterial
oxygen tension (PaO2) recorded in the study group A personal account by a senior physician and experienced
ranged from 4.4 kPa (33 mmHg) to 7.6 kPa (57 mmHg) at researcher emphasizes that not all sickness at high altitude
the summit. The worker with the highest PaO2 during the is high altitude sickness. At Pheriche (4243 m) on the path
first ascent (7.0 kPa, 52.5 mmHg) recorded the highest to the Everest base camp, his dyspnoea, chest discomfort
PaO2 on a subsequent ascent (7.6 kPa, 57 mmHg). (‘a severe weight on my chest – like a dead yak’) and tachy-
Similarly, one subject recorded the lowest PaO2 (4.4 kPa, cardia were due to atrial flutter with 2:1 block and left
33 mmHg: 5.1 kPa, 38 mmHg) on both ascents.54 The ventricular failure and ‘not real AMS’.59
reproducibility of individual response to high altitude The number of confounding conditions which can
exposure implies that the surest means of predicting an mimic or confuse the diagnosis of altitude sickness is
individual’s performance at high altitude is their response legion. Neurological conditions reported include sub-
on previous ascents. Inevitably, anomalies do occur: the arachnoid haemorrhage, transient global ischaemia, tran-
healthy 29-year-old male astronomer who suffered from sient ischaemic attacks and strokes, convulsions, migraine
HAPO on Mauna Kea worked for two years before the and isolated sixth nerve palsies. Ophthalmic diagnoses,
episode of HAPO, and three years subsequently, without such as radial keratotomy and retinal haemorrhages, need
incident. to be recognized. Pulmonary embolism and respiratory
Predisposition to AMS may be related to individual sen- infection, so often a mimic of HAPO, occur at high altitude
sitivity of hypoxic drive.55 Subjects with a low ventilatory and may be hypoxia-related. Miscellaneous problems may
response to hypoxia are liable to develop AMS.56 The mag- be linked to alcohol and recreational drug use, exhaustion,
nitude of the increase in pulmonary arterial pressure in hypothermia, dehydration and carbon monoxide poison-
response to hypoxia is a further risk factor. The search for ing occurring in snow holes and tents. The authors of a
a genetic marker for AMS predisposition is wide-ranging comprehensive review of acute medical problems in the
and on-going. Himalayas outside the setting of acute altitude sickness
recommend ‘in most instances and when the diagnosis is
uncertain it is best to descend’.60
Rapid ascent by sea-level residents to high
altitude
AT-RISK GROUPS
As previously stated, there is a time delay of several hours
on arrival at high altitude before the development of Ischaemic heart disease
AMS; nevertheless, ‘high altitude novice’ sea-level resi-
dents report unpleasant symptoms on immediate arrival On the first day of work on the summit of Mauna Kea,
at high altitude before the onset of ‘classical AMS’. mean PaO2 was 5.6 kPa (42 mmHg) measured in 27 sub-
Tourists visiting mountain tops report impaired mental jects on 40 ascents. Hypoxaemia induces increased sympa-
and physical performance. Businessmen on tight sched- thetic stimulation. As pulse rate increases, so does cardiac
ules feel so unwell on reaching La Paz (3600 m) that their work and systemic blood pressure. The increase in cardiac
presentations are poor and multimillion dollar contracts work can be expressed in terms of the ‘double product’, i.e.
are lost.57 the product of heart rate and systolic blood pressure.
In the 2007 survey of AMS on Mauna Kea, day visitors Among the Hawaiian telescope workers, the mean sea level
to the summit by vehicle were invited to complete a ‘double product’ was 8925 units (mean resting pulse rate 75
self-report assessment Lake Louise Symptom Score (LLSS) beats/minute mean systolic blood pressure 119 mmHg).
on descent. The majority were at the summit for less than At 4200 m, the ‘double product’ rose to 10 285 units, an
two hours. Despite the lack of exertion on ascent, 60 day increase in cardiac work of approximately 15 per cent.
At-risk groups 579
By five days, sympathetic activity had fallen and the ‘double three-year period. In the 23 fatalities, the cause of death
product’ stood at 9840 units. This indicates that the period were trauma (11), ‘illness’ (8) and AMS (3); no cardiac
of greatest risk for exacerbation or precipitation of deaths were reported. Hultgren63 reports that in the
ischaemic heart disease is the first three days at high alti- 25 years of his experience, the Chief Medical Officer at
tude: the threat to coronary patient diminishes by five to La Oroya (altitude 3750 m) never witnessed a myocardial
seven days. Modest increases in cardiac output at high alti- infarction in a known sufferer from ischaemic heart disease
tude will have little deleterious effect on people with con- among the hundreds of visitors who ascend each year from
trolled ischaemic heart disease and these people can work Lima, near sea level, to La Oroya.
safely at high altitude. However, subjects experiencing
angina or exertional dyspnoea at sea level may suffer a
worsening of symptoms shortly after arrival at high altitude Hypertension
when cardiac output is highest. Common-sense advice
should include recommendations for a slower than usual There is no consistent change in blood pressure reported
ascent profile with additional rest days at intermediate alti- in normotensive sea-level residents at high altitude. On
tudes, limitation of physical activity to less than the level Mauna Kea, systolic pressure rose after two days at high
that precipitates symptoms at sea level and control of blood altitude (mean 124 versus mean 118 mmHg at sea level)
pressure.61 People whose level of activity is severely cur- and returned to baseline levels on return to sea level.
tailed by ischaemic symptoms at sea level are likely to suffer Diastolic pressure rose on arrival at 3000 m, remained ele-
a marked deterioration at high altitude and must be cau- vated during five days on the mountain and fell on descent.
tioned against ascent. For such people who decide to No adverse effects related to elevation in systemic pressure
ascend, facilities for rapid retreat down the mountain are occurred (Table 51.3). Hypertensive individuals demon-
mandatory taking precedence over other precautions, e.g. strate both increases and decreases in blood pressure at
provision of oxygen or medical supervision. altitude.48 Controlled hypertensive subjects can be reas-
In a population study, Shlim and Houston62 surveyed sured regarding ascent and advised to continue their pre-
reports of illness in 148 000 trekkers in Nepal during a scribed antihypertensive medication.
Table 51.3 Effect of repeated exposure to high altitude (4200 m) on subjects with pre-existing medical conditions.
Case A: Bronchial asthma Male, aged 32 years Exercise-induced asthma since childhood;
modest severity – no regular medication,
bronchodilator by inhalation as required.
No asthmatic attacks on mountain during
2.5 year work programme; single attack of
bronchospasm at 3000 m precipitated by
cardiac exercise test – self-limiting, no
medication required
Case B: Mitral valve prolapse Male, aged 34 years Single episode of tachycardia during 3 years
and paroxysmal work on Mauna Kea; episode curtailed
supraventricular tachycardia by carotid massage performed by subject
Case C: Paroxysmal atrial Male, aged 40 years No episodes of tachycardia on mountain; Self-treatment with β-blocker
tachycardia cardiac stress test (3000 m) normal drug (oxyprenolol 80 mg)
Case D: Wolff–Parkinson–White Male, aged 26 years No episodes on Mauna Kea. Normal cardiac
syndrome (pre-excitation stress test (3000 m)
syndrome)
Case E: Essential hypertension Male, aged 45 years Moderate increase in blood pressure on each Salt-restricted diet; diuretic
ascent to 4200 m; no deterioration in (hydrochlorthiazide); β-blocker
blood pressure control during 3 years of (propranolol 80 mg three times
supervision daily)
Case F: Crohn’s disease Male, aged 29 years No deterioration in bowel condition during Diet, sulphasalazine;
2 years at Mauna Kea telescopes corticosteroid (oral and rectal
administration)
580 Working at high altitude
latency is increased and rapid eye movement (REM) sleep environment) to 3200 m. Between altitudes of 3000 and
is decreased.73 Disruption of the normal respiratory rhythm 6000 m, each 1 per cent of oxygen enrichment results in a
produces marked hypoxaemia during sleep. Sleep quality reduction of equivalent altitude of about 300 m.48
can be improved and sleep hypoxaemia alleviated by aceta- Oxygen enrichment was first used at the El Tambo mine
zolamide.74 The use of hypnotic drugs by climbers at in Northern Chile (4200 m) where 16 dormitory rooms
extreme altitude is not recommended because of the were supplied with 24–26 per cent oxygen from a liquid
accompanying depression of ventilation which exacerbates oxygen source. Sleep quality was enhanced. The miners
nocturnal hypoxia. Nevertheless, the prescription of a improved in the performance of psychometric tests assessing
short-acting benzodiazepine at low doses (e.g. 10-mg ability to concentrate, short-term memory, visual percep-
temazepam) in conjunction with acetazolamide reduces tion, attention span and auditory and topographical mem-
sleep onset latency and increases sleep efficiency at 4000 m ory.78 Oxygen enrichment technology has developed with
to values comparable to sea level.73 the introduction of oxygen concentrators and can be imple-
mented without an increase in fire risk at high altitude.79 In
a study at White Mountain (3800 m), Luks et al.80 con-
ANAESTHESIA AT HIGH ALTITUDE firmed that oxygen enrichment enhanced sleep, but cogni-
tive function improvement did not occur after one night of
In a review of anaesthesia at high altitude, Stoneham75 breathing oxygen-enriched air in this environment. In a
advises that the greater the altitude the greater the risks of 1972 paper, McFarland reported that cognitive function
anaesthesia and the less the likelihood of available anaes- was only minimally impaired at this altitude.81 However, at
thetic expertise. At all altitudes, general anaesthesia will a simulated 5000-m altitude, oxygen enrichment improved
cause an increase in the alveolar to arterial gradient with motor function (hand–eye coordination) and response
physiological shunting. In addition, anaesthetic agents act times, although not cognitive function. Undoubtedly,
as respiratory depressants and abolish peripheral chemo- oxygen enrichment does increases the sense of well-being
receptor hypoxic drive upon which hyperventilation and in workers at high altitude and over the seven years of
survival at high altitude depend. At altitudes of 2000 m operation, oxygen enrichment has shown benefit.82 At
(e.g. Denver, Colorado) general anaesthesia should pro- Chajnantor, construction of the multinational Atacama
vide no particular problems. At altitudes above 3500 m large millimeter array (ALMA) started in 2003 and will be
(e.g. La Paz, Bolivia), the anaesthetic gas mixture should be completed in 2012: it will become operational in 2010.
oxygen enriched: close attention must be given to avoid ALMA is a single instrument composed of 66 high-
post-operative hypoxia. At altitudes above 4000 m, general precision antennas which can be moved across the altiplano
anaesthesia should be avoided unless life saving. Every desert over distances up to 15 km. In living and enclosed
attempt must be made to evacuate to a lower altitude. work areas (e.g. main control room, electronics and com-
puting areas, engineering offices and antenna receiver cab-
ins), the atmosphere will be oxygen enriched to 27 per cent.
Oxygen enrichment at high altitude In a 1984 review of high altitude medicine and physi-
ology, Cudaback83 concluded that the detrimental effect
The pre-eminence of Mauna Kea as the highest terrestrial of hypoxia on performance and health at 4000-m high
observatory in full-time operation has been superseded by telescopes was sufficiently severe to warrant intervention.
the establishment of telescopes on the Chajnantor plateau Considering the options of oxygen enrichment of enclosed
in Northern Chile (5050 m, 16 470 ft). At this site, the air spaces, raising inside ambient barometric pressure or
California Institution of Technology has been operating a administration of medication, he concluded that oxygen
cosmic background imager (CBI) since 1999. enrichment was the answer. However, none of the 13
At 5050-m elevation, the barometric pressure is Mauna Kea observatories in operation employ oxygen
551 mbars (55.1 kPa, 419 mmHg) and the partial pressure of enrichment, although the capability exists at two telescopes
oxygen in inspired air is 10.3 kPa (78 mmHg), only 52 per and neither is this provision available at the dormitory and
cent of sea-level values. These figures compare with a living facilities at 3000 m. The opinion and experience of
barometric pressure of 625 mbars (475 mmHg) and partial Mauna Kea staff was that the evidence of the need for
pressure of inspired oxygen of 12.6 kPa (95 mmHg) at the oxygen enrichment at 4000-m altitude was not convincing.
Mauna Kea summit. The CBI workers are exposed to
approximately 10 per cent less oxygen than their Mauna Kea
colleagues. To reduce the deleterious effects of hypoxia at ALTITUDE SICKNESS
over 5000 m, the atmosphere in the CBI control room and
laboratory is enriched with oxygen to 27 per cent using Prevention
oxygen concentrators.76,77 Enrichment of oxygen to 27 per
cent reduces the equivalent altitude (i.e. the altitude at which Wise mountaineers who wish to avoid the debilitating
the moist inspired PO2, when a subject is breathing ambient effects of high altitude respect the maxims ‘climb high,
air, is the same as the inspired PO2 in the oxygen-enriched sleep low’ and ‘hasten slowly’. These precepts are of
582 Working at high altitude
An alternative remedy for AMS prophylaxis is ginkgo managed at intermediate altitudes between 3000 and
biloba. This herbal extract is reputed to have anti-oxidant 4000 m, particularly if the victim is able to sleep at a lower
and anti-hypoxic properties which led to its use in patients altitude. Exercise induces sodium and water retention,
with cerebral and peripheral vascular disease. Ginkgo biloba decreases oxygen saturation and increases pulmonary
is reputed to stabilize the cerebral blood–brain barrier, artery pressure, thus aggravating the pathological processes
hence the rationale for its use in AMS. A study in the leading to altitude sickness: rest is an important component
Himalayas of 44 mountaineers ascending to 5200 m showed of treatment for all grades of severity of AMS.98 In difficult
a significant reduction in AMS with none of the gingko- circumstances, the need for rest may be outweighed by
treated group (five days of 120-mg gingko) suffering from the need for exertion to descend. Abstinence from alcohol,
AMS compared to 41 per cent of placebo group.94 In a study adequate fluid intake and frequent small meals of carbohy-
on Mauna Kea, with subjects following an ascent profile drate content are recommended. Non-steroid anti-
similar to that of shift workers in the 1980 study, gingko inflammatory drugs (e.g. ibuprofen) have been proven
(60 mg tds) taken one day before ascent reduced the severity effective in relieving high altitude headache in a placebo-
of AMS in the treated group, but there was no significant controlled double-blind trial.99 The association of nausea,
reduction in incidence of AMS. This study was discontinued vomiting and visual disturbance with debilitating headache
early because of the unexpected and unexplained incidence has led to the supposition that AMS could share a similar
of severe AMS with 42 per cent (11/26) of subjects needing pathophysiological mechanism to classical migraine.100
evacuation from the summit. No difference in oxygen satu- However, selective stimulation of 5-hydroxytriptamine
ration was found between the treatment and placebo receptors by sumatriptan (100-mg dose), a rapid and com-
groups.95 The case for gingko prophylaxis requires further prehensive treatment for migraine, was not efficacious for
study; however, with few adverse effects (occasional high altitude headache.101 To ease nausea and vomiting,
headaches) and available without prescription, gingko will anti-emetics (e.g. prochlorperazine 10-mg oral, or intra-
appeal to those unable or reluctant to take acetazolamide or muscular injection three times a day) may be administered.
dexamethasone as AMS prophylaxis. To aid sleep short-acting sedatives (e.g. temazepam) should
Chemoprophylaxis for HAPO is an important therap- be used at the lowest effective dose for the shortest time
eutic intervention because of the recurrent nature of possible. The use of carbonic anhydrase inhibitor drugs for
the condition. The calcium channel blocker nifedipine is the treatment of AMS has been established in several stud-
effective as a slow-release preparation at a dose of 20 mg ies. In a double-blind, placebo-controlled trial on Mt
every eight hours and has been demonstrated to prevent McKinley (4200 m), low-dose acetazolamide (250 mg) was
HAPO after rapid ascent to 4559 m. Individuals with a his- prescribed at diagnosis and eight hours later. Symptoms
tory of HAPO who wish to climb should consider nifedip- were relieved, arterial oxygenation improved and pulmonary
ine prophylaxis.26 However, nifedipine is not recommended gas exchange was stabilized.102 High-dose acetazolamide
as prophylaxis or treatment of AMS or HACO.96 HAPO- (1.0–1.5 g) and methazolamide (400–500 mg) were studied
susceptible individuals have an impairment of sodium- on three separate expeditions at between 3200 and 5486 m:
dependent alveolar fluid clearance. The beta-sympathetic as in the low-dose study, AMS symptoms and arterial oxy-
agonist salmeterol facilitates clearance of alveolar fluid by genation improved significantly.103 High-dose acetazolamide
stimulating trans-epithelial sodium transport via effects on was associated with more adverse effects and a quarter of
the amiloride-sensitive channel and Na/K-ATPase subjects suffered headache. This is sufficient reason to
pump. Prophylactic inhalation of salmeterol (125 μg by favour the lower-dose treatment regime.
pressurized metered-dose inhaler connected to a spacer The treatment for severe AMS, HAPO and HACO is
every 12 hours), administered on the morning of a day-long immediate descent to the lowest altitude feasible and
ascent to 4559 m, decreased the incidence of HAPO by over administration of oxygen. All other therapeutic measures
50 per cent in a group of HAPO-susceptible mountaineers.97 are of secondary importance. The consequences of delayed
Manipulation of pulmonary vasoactive mediators is another descent may be fatal pulmonary and cerebral disease.104
possible HAPO chemoprophylactic avenue to explore. The Once HAPO or HACO are established, oxygen therapy
phosphodiesterase-V inhibitor sildenafil is a potent vasodila- may not be beneficial even at the recommended flow rate of
tor of both peripheral and pulmonary vessels. Combined 6–8 L/min; the failure of supplementary oxygen to be
with red wine, a known antioxidant and endothelin-1 sup- invariably effective is because hypoxia, the initiating insult,
pressor, sildenafil may, in the words of one reviewer, ‘lead to triggers increased capillary permeability causing oedema of
an enthusiastic number of subjects going to high altitude for the lungs and brain which can only be reversed by retreat
more than just the enjoyment of the view’.27 from a hypoxic and hypobaric environment. In addition to
descent and oxygen, dexamethasone is administered in
severe AMS (4 mg every six hours for 24 hours) and HACO
Treatment at a dose of 8 mg initially followed by 4 mg every six hours
by mouth, i.m. or i.v. injection.105 Nifedipine, a calcium
Acute mountain sickness of moderate severity – without channel blocker, reverses hypoxic pulmonary hypertension
respiratory distress or neurological dysfunction – may be and lowers pulmonary artery pressure in HAPO victims.
584 Working at high altitude
Oxygenation improves and the clinical manifestations of of this success is shown in Figures 51.1 and 51.2: between
HAPO are relieved.106 Nifedipine is prescribed at a dose of 1989 and 1998 the number of telescopes increased from
10 mg sublingually and 20 mg slow release capsule stat fol- six major telescopes with one under construction to 11
lowed by 20-mg slow release capsule every six hours until telescopes sited at the summit.
descent for established HAPO. HAPO is not caused by According to management staff at Mauna Kea, in a 2007
cardiac failure and the use of frusemide may worsen the survey of AMS, there had not been any reported deaths or
condition of a hypotensive, shocked HAPO victim. permanent morbidity related to HAPO or HACO on the
In remote high altitude regions of the world, many mountain.13 Remote observation technology has advanced
miles from medical attention, the sick climber suspected of since the early days; nevertheless, in 1999 staffing require-
HACO and HAPO can be administered dexamethasone ments at one telescope (United Kingdom Infra Red
(8 mg stat followed by 4 mg six-hourly for 24 hours) and Telescope, UKIRT) still necessitated 2000 man-days per
nifedipine (20 mg tablet six-hourly for 24 hours) simultan- annum. Overall, 30 000 man-days per annum are spent at
eously to allow for repatriation to a lower altitude. the major telescopes on Mauna Kea. There has been a single
Carrying these medications for use in an emergency has cardiac death at the summit among the telescope personnel.
been recommended by physicians experienced in high A 37-year-old smoker and diabetic suffered a myocardial
altitude medicine. It must be emphasized that such treat- infarction after staying at the summit all night and working
ment should neither exceed 24 hours nor be a substitute through the days. Post-mortem examination revealed
for descent.107 extensive coronary disease. Following this fatality, revised
The practical problems of transporting cylinders to high health screening protocols were established (Table 51.4).
altitude limit the availability of oxygen in an emergency. All UKIRT personnel undergo a medical evaluation at
Simulated descent in a portable fabric hypobaric chamber sea level which includes physical examination, a compre-
(Gamow bag®, Certec bag®, portable altitude chamber) is a hensive range of blood tests, resting ECG and treadmill
popular alternative. The Gamow bag (weight 6.6 kg, stress test, chest x-ray and pulmonary function tests.
including foot pump) is inflated to an inside pressure of Recommendations are that medical evaluations should be
103 mmHg above ambient atmospheric pressure. At this repeated annually for individuals above age 40 years, every
inflation pressure, a patient inside the chamber experi- two years between ages 30 and 39 years and every three
ences a simulated descent;108 for example, at 4500 m years for those younger than age 30 years. In the late 1990s,
(ambient atmospheric pressure 433 mmHg), a treated a 40-year-old construction worker suffered a fatal car-
subject experiences a pressure of 536 mmHg equivalent to diopulmonary arrest at the summit: construction company
an altitude of 2780 m, a ‘descent’ of 1720 m. Hyperbaric employees were not required to undergo a rigorous screen-
treatment alleviates symptoms and PaO2 rises for the dur- ing programme.115 The confidence of the workforce – tech-
ation of treatment in the chamber, but falls within minutes nical, scientific and managerial – in operating the telescopes
of return to the outside atmospheric pressure.109,110 on Mauna Kea has been greatly facilitated by ease of descent
Symptom relief is greater and quicker with pressurization from the mountain and ready access to high quality medical
treatment than with oral dexamethasone (8 mg initially, care in the event of an emergency. Within two hours of
4 mg after six hours), but the benefits of corticosteroids are leaving the summit by road, a victim of HAPO or HACO
of greater duration: both treatments can be administered could be undergoing MRI or computed tomography (CT)
together to AMS patients.111 It is possible to place an oxy- scanning at sea level. Provision of sleeping and living facili-
gen cylinder in the bag for use by the victim. The inevitable ties at a mid-level station (Onazaku Center, Hale Pohaku,
build up of exhaled carbon dioxide in the bag, despite vent- 3000 m) affords protection and comfort for the staff.
ing by foot pump action, has a measurable beneficial effect Education of the workforce is essential. The initial trepi-
in increasing peripheral and cerebral oxygenation possibly dation of the telescope staff at the prospect of working in a
by stimulation of the respiratory centre or dilatation of hypoxic and hypobaric environment has been supplanted
cerebral vasculature.112 Hyperbaric treatment is not to be by knowledge of the consequences of altitude exposure,
recommended as a substitute for descent, but may obviate and the awareness that problems can be predicted and cop-
the need for storing large quantities of oxygen at high ing strategies developed. The converse ‘machismo’ attitude
altitude work stations. Other novel methods to improve of denial of the hazards of altitude has been replaced by
gas exchange and oxygenation include the use of a portable respect for the mountain site and acceptance that people
continuous positive airways pressure in HAPO113 and react to altitude exposure in an individual manner irre-
the addition of 3 per cent carbon dioxide to inhaled air spective of age, fitness, gender or ‘toughness’. Information
in AMS.114 cards describing the serious symptoms requiring immedi-
ate evacuation from the summit are displayed at the tele-
scope. Bottled oxygen is available on site. Experience has
Safe working at high altitude established clear directives for the workforce. No individ-
ual is allowed at the summit alone and sufficient unlocked
Assessed against the parameters of the quality of astronom- vehicles must always be available at the telescope: the
ical research and safety of the work force, the Mauna Kea so-called ‘two man, two vehicle’ rule. No one sleeps at the
Observatory has been an outstanding success. A visible sign telescope. No alcohol is permitted on the mountain. Staff
Altitude sickness 585
Prevention/ Treatment
treatment
are only allowed to drive on the mountain road after international level, there is controversy that adaptation to
having experienced three return trips as a passenger. It is life at high altitude may confer unfair advantage to high
clearly understood that a staff member is the responsible altitude natives over sea-level opponents when playing ‘the
officer at the summit and has the authority to close the beautiful game’ in thinner air. In May 2007, football’s
facility if hazard threatens. Many of these measures international governing body (FIFA) banned World Cup-
have been adopted at the Chajnantor site to complement qualifying matches from being played at more than 2750 m
the two elements underpinning safe operation at the site – elevation because of ‘possible distortion of competition’ to
the establishment of an operations support base at a the delight of the Brazilians (Rio de Janiero, sea level) and
modest altitude (2400 m) and oxygen enrichment of the air the outrage of the Bolivians (La Paz, 3600 m). Under pres-
inside the buildings at 5000 m.116 sure from the Bolivian president Evo Morales, who enlisted
Over several decades of scientific endeavour on Mauna the support of Diego Maradona in a campaign against
Kea, the calibre of astronomical research produced has ‘football apartheid’ and the South American Football
demonstrated that high altitude is not detrimental to high Confederation, FIFA relented and awarded a special dis-
performance. Men endure high altitude for reasons more pensation for Bolivia to host World Cup-qualifying games
prosaic than gazing at the stars. At the Aucanquilcha sul- in La Paz.118
phur mines in the Chilean Andes, native miners live and On May 23, 2007, medical researchers sampled femoral
sleep at 5330 m and each day ascend to the mines at arterial blood at the ‘Balcony’ (8400 m) on their descent
5950 m. Miners refuse to inhabit the camp erected at the from the summit of Everest (8850 m). PaO2 was in the
mine because of difficulty with sleep at the higher eleva- range of 2.55–3.93 kPa. One of the key objectives of
tion; nevertheless, the top camp is occupied by a gang of the Caudwell Xtreme Everest expedition was to investigate
caretakers. Each Sunday, the caretakers descend to the how humans could survive in environmental hypoxia,
comfort of 4220 m to play football.117 However, at the when at sea level artificial ventilation would be required to
586 Working at high altitude
preserve life. It is hoped that the experiments will extend Appendix 51.1 Calculating the Lake Louise Acute Mountain
knowledge which will aid the care of critically ill patients in Sickness (AMS) score.121
whom hypoxia is a fundamental problem.119
Add up the responses to each of the questions of the self-report
‘Because it is there’, answered George Mallory,
score (questions 1–5).
reputedly, when asked why he wanted to climb Everest.
A diagnosis of AMS is based on a recent rise in altitude, the
Mallory and Andrew Irvine died in the attempt. And yet
presence of a headache and at least one other symptom and a
men and women still climb and die on the mountain: some
total score of at least 3.
alone and cold, some overwhelmed by avalanche, ice falls
AMS Altitude Gain AND Headache AND at least one other
or falling rocks, some in the depths of crevices, and some
symptom AND a total score of 3 or more.
stumbling exhausted and incapacitated by high altitude
illness.120 Humans, ascending mountains for many differ-
Self-Report 1. Headache 0. No headache
ent reasons as well as science and commerce, can find there
Questionnaire: 1. Mild headache
an unforgiving world.
2. Moderate headache
3. Severe headache,
incapacitating
2. Gastrointestinal 0. No gastrointestinal
Box 51.1 Useful sources of information
symptoms symptoms
●
1. Poor appetite or nausea
Birmingham Medical Research Expeditionary Society:
2. Moderate nausea or
www.bmres.org.uk/
●
vomiting
CIWEC Clinic, Travel Medicine Centre, Kathmandu,
3. Severe nausea and
Nepal: www. ciwec-clinic.com/
●
vomiting, incapacitating
Diabetes at high altitude: www.idea2000.org/
●
3. Fatigue and/or 0. Not tired or weak
International Society for Mountain Medicine:
weakness 1. Mild fatigue/weakness
www.ismmed.org/
●
2. Moderate
Medex: Travel at high altitude: www.medex.org.uk/
●
fatigue/weakness
Wilderness Medical Society: www.wms.org/
3. Severe fatigue/
weakness, incapacitating
4. Dizziness/ 0. Not dizzy
lightheadedness 1. Mild dizziness
2. Moderate dizziness
Key points 3. Severe dizziness,
●
incapacitating
Altitude sickness affects unacclimatized sea-level
5. Difficulty 0. Slept as well as usual
residents ascending to altitudes above 2500 m.
●
sleeping 1. Did not sleep as well
The clinical diseases associated with high
as usual
altitude sickness are ‘benign’ acute mountain
2. Woke many times,
sickness (AMS) which is usually self-limiting
poor nights sleep
and resolves after two to three days and
3. Could not sleep at all
‘malignant’ high altitude cerebral oedema
(HACO) and high altitude pulmonary oedema
Additional Lake Louise Scoring: The Self-Report Score above
(HAPO), both of which are potentially fatal.
●
(questions 1–5) stands alone and this is recommended for
Altitude sickness is avoided by slow, staged ascent
non-medical mountain travellers. Additional observations are
(‘hasten slowly’) allowing acclimatization, sleeping
sometimes used by researchers. The Clinical Assessment score
at the lowest possible altitude (‘climb high, sleep
(questions 6–8) can be added to the Self-Report Score, in which
low’) and avoidance of strenuous exertion.
●
case, in the context of a recent rise in altitude, a score of 5 or
The essential treatment for severe AMS, HACO
more would be taken as AMS (AMS altitude rise AND headache
and HAPO is immediate descent to lower
AND at least one other symptom (from questions 1–5) AND a
altitude. All other treatments (e.g. drugs, oxygen
total score of 5 or more (questions 1–8)
administration) are adjuncts to descent.
● Experience derived from decades of work at high
Clinical 6. Change in 0. No change in mental
altitude mines and astronomical observatories
Assessment: mental status status
have shown that working at high altitude is
1. Lethargy/lassitude
possible, safe and effective if appropriate
2. Disorientated/confused
working practices are established and if the
3. Stupor/semi-conscious
means for descent is always available.
(Continued)
References 587
31. Houston CS, Dickinson J. Cerebral form of high altitude 48. Ward MP, Milledge JS, West JB. High altitude medicine and
illness. Lancet. 1975; 2: 758–61. physiology. London: Arnold, 2000.
32. Dickinson J, Heath D, Gosney J, Williams D. Altitude related 49. Hultgren HN. High altitude medical problems. Western
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52
Flying and spaceflight
FLYING safer than road travel. Every day, 1.7 million passengers
board aircraft in the United States.2 At any one time, over
INTRODUCTION half a million passengers are airborne in some part of the
world and over 2 billion people fly every year. Civilian air-
Flying can be an exciting occupation or hobby, providing crew live longer than the general population of England
exposure to unfamiliar environmental and physiological and Wales and their patterns of death do not appear to be
stressors. Although over 200 years have passed since the attributable to their occupation.3
first manned balloon flight by Pilâtre de Rozier, François Although flying has become so much safer since the
Laurent and the Marquis d’Arlandes, most of the under- pioneering days, the risks of exposure to an unforgiving
standing of the effects of the aviation environment on the environment cannot be ignored. Physiologically, man has
human body has come since 1900. In the first 70 years of evolved to live at ground level, at normal gravity (1 Gz),
aviation, when mankind progressed from Kitty Hawk to within strict temperature limits and with certain limita-
the moon, aircraft flew ever higher, ever faster. Since then, tions to his special senses and his psychology. Adaptation
development has tended to be limited to improvements in and acclimatization can increase the physiological range
noise reduction, range and payload by environmental and to an extent, while training can improve performance.
economic considerations. However, flying is usually an acute exposure, so physiolog-
In 1909, there was one fatality for every 1500 miles ical adaptations have a limited role to play. Protection
flown. By 1912, the safety of aircraft had developed to the from the environment, by means of engineering solutions,
extent that the mileage flown for each fatality had risen can increase the operating range of the human, but it also
100-fold.1 Even in the first half of the First World War, has limitations. The potential for failure of that protection
accidents accounted for some 25 per cent of all pilot fatali- necessitates the provision of back-up systems or a restric-
ties, more than attributed to enemy action. Flying is now tion in the operating envelope of the aircraft. Thus, human
592 Flying and spaceflight
tolerances have increasingly set the limits to which aircraft pneumothorax unless a Heimlich valve or similar device is
can be engineered. in place. In addition, penetrating injury of the eyeball can
People work in the air in a variety of capacities. Military produce subluxation of the lens on ascent to altitude and
aviators fly in aircraft ranging from helicopters to high a case of sudden blindness has been reported caused by
speed, single-seat jets. Crews of military transport aircraft expansion of an air bubble introduced during retinopexy.5
may face additional challenges that do not affect crews of Patients with these conditions may be flown, but only if the
commercial aircraft. Civilian flight in small aircraft can cabin pressure of the aircraft is held at the ambient pressure
range from recreational flight to instructional duties to of the departure airfield. Similarly, a small gas bubble
crop spraying. Many people, of course, fly just as passen- beneath a badly filled tooth can cause excruciating pain on
gers and many need to be fit for work on arrival at their ascent (aerodontalgia) which usually improves on descent,6
destination, but some also work while they are flying. This although occasional dental fracture may occur.7
chapter outlines the stresses and hazards of flight, describes Where the gas is incompletely enclosed, there is less of a
the ways of overcoming them and considers fitness for problem. The gut normally contains between 100 and
flight, both for professional aviators and passengers. 200 mL of gas at ground level in the stomach and large
bowel. The rise in intra-abdominal pressure limits the vol-
ume increase. The usual symptom is of abdominal fullness
PRESSURE CHANGE or bloating and is reduced by eructation or passing flatus.
The problem can be limited by avoiding dietary items
As altitude increases, pressure decreases exponentially. For which predispose to flatulence, such as fizzy drinks or cer-
fliers, this gives rise to four potential problems: gas expan- tain vegetables. Gas in the middle ear also has an outlet to
sion, hypoxia, decompression sickness and rapid decom- ambient air. On ascent, the gas expands easily along the
pression (Figure 52.1). Eustachian tube and the ears ‘pop’ automatically. On
descent, however, the increased pressure in the pharynx
causes the Eustachian tube to act as a flap valve. The result-
Gas expansion ing pressure differential causes the eardrum to be inverted,
causing pain (which is often severe) and deafness. In severe
As ambient pressure decreases, volume increases in accor- cases, vertigo and nausea may occur. Rarely, facial palsy
dance with Boyle’s law. Where the gas in the human body is may result.8 The way to equalize pressures is to yawn, swal-
enclosed, this may cause problems. Gas is enclosed in the low or waggle the jaw if the pressure change is gradual, or
body after surgery. Thus, 30 mL of intracranial air would to perform a Valsalva manoeuvre (holding the nose and
expand by 30 per cent at a cabin altitude of 8000 ft, resulting straining against a closed glottis) or Frenzel manoeuvre
in a rise of intracranial pressure from 10 to 21 mmHg or (holding the nose and raising the pressure in the naso-
from 20 to 31.8 mmHg.4 Therefore, it is unwise to fly within pharynx without increasing intrathoracic pressure) if the
ten days of laparotomy (unless a drainage tube is left in change is rapid. Topical decongestants before or during
place), within three weeks of craniotomy or air contrast x-ray flight may be effective. There is no evidence that earplugs
studies of the spine, or within two weeks of thoracotomy or which claim to equalize pressure are effective.9 Future
developments may include the use of surfactants which of consciousness and death. The gradual onset explains
play a role in maintaining patency of the Eustachian tube.10 those cases where loss of cabin pressure has led to all on
If descent is continued without the pressure equalizing, board becoming unconscious, the aircraft then flying on
there is haemorrhage into the drum and it may perforate automatic pilot until it crashed when fuel was exhausted.
with subsequent relief from pain. Colds and upper respira- A survey of helicopter crew showed most had experienced
tory tract infections predispose to this inability to ‘clear the symptoms suggestive of hypoxia at an average altitude of
ears’. Since ear pain, deafness and vertigo are flight safety just over 8000 ft. The most common signs were difficulty
hazards, aircrew with these conditions should not fly until with calculations, delayed reaction time and confusion;
they can clear their ears. Inability to clear the ears during non-pilots were more affected than pilots.13 It is widely
flight can, if possible, be helped by a re-ascent to altitude quoted in the literature that mild hypoxia (8000 ft) impairs
and a more gradual descent. Otitic barotrauma usually the learning of a novel task,14 but later research failed to con-
clears spontaneously in two to three weeks. firm this.15 Smokers may take longer to detect hypoxia than
The frontal and paranasal sinuses usually vent to ambi- non-smokers.16 Tolerance to hypoxia is reduced by exercise,
ent easily on ascent and equally easily repressurize on exposure to cold, the presence of illness and after taking
descent. Again, infection may interfere with this, causing alcohol.
pain. Nasal polyps or deviated nasal septum can also pre- The insidious nature of the symptoms of hypoxia has
dispose to sinus barotrauma. Topical decongestants before led many military air forces to adopt a training regime in
or during flight may help. Symptomatic treatment may be decompression chambers to allow aviators a greater chance
required on the ground for a few days afterwards. of spotting hypoxia in themselves. In one survey of military
Finally, at an altitude of 63 000 ft, the total ambient aircrew, 76 per cent of cases of hypoxia were recognized by
pressure is 47 mmHg. This is also the pressure exerted by the aviator involved.17 The symptoms of hypoxia are very
water vapour at body temperature. At this altitude (known difficult to distinguish from those of hyperventilation. Any
as the Armstrong Line), body tissues begin to vaporize. symptoms in flight which could be either, must be treated
Small pockets of gas appear beneath the skin within 2–3 as hypoxia until proved otherwise. On acute exposure to
seconds, there is gas evolution within the abdominal cavity high altitude, either from failure of a pressure cabin or of
in 10 seconds and in the heart in about 20 seconds. Although the oxygen supply, the oxygen stored in the tissues allows a
man can recover from brief exposures, it is better to protect ‘time of useful consciousness’ before capability is lost. This
an individual at risk by means of a pressure cabin or pres- time ranges from about 4 minutes at 25 000 ft to about
sure suit. 20 seconds at 40 000 ft and 10–15 seconds at 52 000 ft.
Impairment of performance occurs sooner (45 seconds at
25 000 ft, 12–15 seconds at 40 000 ft).
Hypoxia Hypoxia can be prevented by ensuring that the aircraft
does not fly above 10 000 ft, by providing supplemental
At all altitudes, the fractional concentration of oxygen in oxygen to breathe or by pressurizing the aircraft to main-
the air remains at 21 per cent. However, as pressure falls tain a cabin pressure of equivalent to an altitude below
on ascent to altitude, the partial pressure exerted by that 10 000 ft. The alveolar oxygen tension (PAO2) at sea level
oxygen also falls, in accordance with Dalton’s law of partial can be maintained up to 33 000 ft by breathing 100 per cent
pressures. Up to an altitude of about 10 000 feet, the oxygen and the 10 000 ft equivalent can be maintained up to
amount of oxygen available to the body remains almost 40 000 ft. However, there are two disadvantages to provid-
the same because of the shape of the oxygen–haemoglobin ing 100 per cent oxygen. First, if the aircraft has an aerobatic
dissociation curve. However, the oxygen saturation can fall capability, the gravitational forces may occlude small air-
below 90 per cent even in commercial pressurized aircraft11 ways in the lung leading to absorption of all the oxygen
and this may have detrimental effects on some patients. distal to the occlusion. The localized pulmonary collapse is
Although it is unlikely to affect the occurrence of acute called ‘acceleration atelectasis’. Second, a similar problem
mountain sickness, it may contribute to increased reporting may occur in the middle ear after landing, causing pain
of discomfort in passengers in medium duration flights.12 (oxygen ear). The usual solution is to provide oxygen/air
The most common causes of hypoxia in flight are ascent mix sufficient to allow a ground level PAO2 (103 mmHg)
to altitude without supplementary oxygen, failure of per- until 33 000 ft when 100 per cent oxygen is supplied. The
sonal breathing equipment to provide an adequate supply PAO2 then falls to a 10 000 ft equivalent at 40 000 ft.
of oxygen and decompression of the cabin at high altitude. Above this altitude, oxygen has to be provided under
Human failure to turn on the supply, check hoses are con- pressure to maintain adequate oxygenation (pressure
nected or to ensure the mask seals to the face properly, breathing). In military aircraft, pressure breathing is usu-
plays a significant role in hypoxia in military aircrew. ally applied through an oronasal mask. The barometric
The symptoms of hypoxia are insidious and include pressure at 40 000 ft is 141 mmHg. The aim of pressure
euphoria, loss of insight, impairment of cognitive functions, breathing is to maintain that absolute pressure delivered to
reduction of visual acuity (including colour vision), inco- the lungs. Thus the breathing pressure will be (141-ambient
ordination, cyanosis, hyperventilation and, eventually, loss pressure) mmHg. Breathing pressures up to 70 mmHg
594 Flying and spaceflight
will protect against hypoxia at altitudes up to 56 000 ft. symptoms at altitude, with 24 per cent in the first hour
However, there are disadvantages. Pressure breathing gives after return to ground level and 21 per cent between one
rise to physiological problems. The increased work of expi- and six hours).23
ration, which is usually passive, produces discomfort, as The incidence of DCS in those individuals exposed to
does the distension of cheeks, mouth and respiratory pas- an altitude of 25 000 ft or less is low. The U-2, however, had
sages. The nasolachrymal duct can be forced open causing an altitude ceiling of 73 500 ft for more than 15 hours
severe blepharospasm and the Eustachian duct can also be unrefuelled, at a cabin altitude of 29 500 ft. Despite precau-
forced open causing ear pain. Blood return to the heart is tions, more than 75 per cent of U-2 pilots experienced
compromised. Peripheral pooling of the blood and the symptoms of DCS, and 13 per cent had, at some stage, to
passage of fluid from the circulation into the tissues reduce alter the flight profile or abort the mission.24
effective blood volume, leading to reduced tolerance to Treatment25 depends on the severity and resolution of
gravitational stresses and syncope. The likelihood of syn- the symptoms. If the symptoms clear on descent and neu-
cope during pressure breathing is increased in the presence rological examination is normal, the patient should ideally
of hypoxia, hypocapnia, heat stress, anxiety, infection or breathe 100 per cent oxygen for two hours and undergo
after alcohol. The effects of pressure breathing can be aggressive oral rehydration. The patient should be observed
minimized by providing counterpressure to bladders in a for 24 hours. If pain or cutaneous symptoms persist
sleeved or sleeveless partial pressure jacket and to the anti-G after descent, in addition to 100 per cent oxygen and
trousers. An alternative in military aviation is to use a full oral rehydration, the patient should be exposed to treat-
pressure suit with either a full or a partial pressure helmet, ment in a hyperbaric chamber. In Scotland, advice may be
but these have the significant disadvantages of reduced obtained from Aberdeen Royal Infirmary (Tel. 0845
mobility and increased heat load. One significant flight 4566000, asking for the diving doctor on call). For the rest
safety hazard remains. It is very difficult to talk when of the United Kingdom, guidance is obtained from the
pressure breathing. Sudden loss of cabin pressure in a Duty Diving Medical Officer at the Institute of Naval
multicrew aircraft flying above 40 000 ft will lead to the Medicine (Tel. 07831 151523). If the symptoms are not
requirement to read through check lists. Practice is vital. relieved within 10 minutes of compression on Royal Navy
Treatment Table 61 (equivalent to US Navy Treatment
Table 5), subsequent decompression should follow RN
Decompression sickness Treatment Table 62 (USN Table 6).26 Travel to the cham-
ber should be by road. If air travel is absolutely necessary,
Decompression sickness (DCS) during diving activities is then either a cabin altitude of sea level or an absolute
dealt with fully in Chapter 50, Diving and work at increased aircraft altitude of 1000 ft should be maintained. The
pressure. It is commonly believed that altitude DCS does not patient should be supine, intubated if necessary, or in
occur below 18 000 ft. However, bubbles in the circulation the lateral decubitus position. Intravenous fluids should be
have been recorded at altitudes down to 13 000 ft. Bubbles either normal saline or Ringer’s solution (i.e. isotonic),
do not form at low altitude unless the individual has been 1 litre in the first hour and then ⬃1.5 mL/kg per hour.
diving in the preceding 24 hours. The rate of symptoms of Avoid solutions (oral or intravenous) containing glucose.
DCS is related to the final altitude and the time spent at alti- If there are spinal cord symptoms, there may be benefit in
tude. Other predisposing factors are known susceptibility, giving a bolus of 30 mg/kg of methylprednisolone and then
exercise at altitude,18 age, body build, general health and 5.4 mg/kg per hour for 23 hours. It is important to control
previous exposure to altitude within the preceding 24 hours. the body temperature of the patient. On recovery from
Female gender per se does not appear to be a risk factor,19 mild DCS without central nervous system (CNS) compli-
although women may be more at risk during the first week cations, the pilot can return to flying within 72 hours if
of their cycle than mid-cycle.20 Flying after diving is particu- there are no symptoms and examination is normal.
larly dangerous.21 At least 12 hours should be spent at Prevention is based on three factors: (1) selection of
ground level after diving; this time should be doubled if individuals who are not susceptible to DCS by testing them
the dive lasted more than four hours and redoubled if the in a decompression chamber; (2) limiting exposure to
subsequent flight is to be at a cabin altitude above 8000 ft. altitude by use of pressurized aircraft; and (3) denitrogena-
The symptoms in one series of over 400 cases arising tion by breathing 100 per cent oxygen before take-off.
from decompression chamber experience ranged from joint Prebreathing schedules are a mixture of experience and
pains (the bends, 83 per cent, with the knee accounting for pragmatism. Pre-oxygenation for 30 minutes will protect
70 per cent), respiratory effects (the chokes, 2.7 per cent), against short exposure to 48 000 ft as long as total time
skin symptoms (formication or the creeps, 2.2 per cent), above 25 000 ft is less than 10 minutes. Exposure to
paraesthesia (10.8 per cent) to neurological manifestations 40 000 ft for 3 hours requires 3 hours of pre-oxygenation
(0.5 per cent).22 Visual symptoms include blurred vision, at ground level. U-2 pilots prebreathe for 60 minutes.
loss of vision, scintillation and scotoma. Neurological Exercise while denitrogenating can reduce the time that
symptoms and collapse can occur after return to ground prebreathing is necessary while retaining the same level of
level (one study demonstrated a 45 per cent incidence of protection, although this effect may be limited.27
Gravitational stress 595
new generation of helmets which carry helmet-mounted lower than for positive Gz. The general effects include
sights and displays or, when required, night vision goggles. heaviness of the limbs, fullness and pressure in the head
Exposure to high G flight causes a temporary diminution (which can produce severe headache), congestion of the air
in height of up to almost 5 mm due to spinal compres- passages which can cause difficulty in breathing, bradycar-
sion29 and musculoskeletal symptoms,30 fatigue,31 cervical dia, epistaxis, eye discomfort, subconjunctival haemor-
disc bulges32 and premature cervical spine degeneration33 rhages and petechiae in unsupported skin. The transition
have been reported. from Gz to Gz (sometimes called the ‘push-pull’) can
Acceleration in the Gz axis has a hydrostatic effect on reduce tolerance to Gz,41 which is worsened by the dura-
the circulation. The mean arterial pressure at the level of tion of the preceding Gz.42
the heart is 100 mmHg at both 1 and 4 Gz. At eye level,
some 30 cm vertically above the heart, the respective
pressures are 100 mmHg minus the hydrostatic pressure Protection against ⴙGz
exerted by the column of blood (22 mmHg at 1 Gz and
88 mmHg at 4 Gz), i.e. 78 and 12 mmHg. Similarly, the The major ways of increasing tolerance to Gz are by use
corresponding pressures in the posterior tibial artery, some of an Anti-G Straining Manoeuvre (AGSM), anti-G suits,
80 cm below the heart in the sitting individual, can be posture, positive pressure breathing (PPB) and training, or
calculated to be 157 and 324 mmHg. by various combinations of these. The commonly used
The blood pressure changes at head level affect vision, AGSMs, which all include isometric muscle tensing, are
cerebral blood flow, cerebral oxygenation and the level of the M-1 manoeuvre (exhaling forcibly against a partially
consciousness. Eyeball pressure is 20 mmHg. Thus, the closed glottis with a rapid inspiration every 4–5 seconds),
blood pressure at head level has to be above that for retinal the L-1 manoeuvre (periods of raised intrathoracic pres-
perfusion to occur. Application of G results in constriction sure with a closed glottis separated by short inspiratory and
of the pupils which may help to maintain vision.34 In the expiratory gasps) and the Qigong manoeuvre (rapid pant-
relaxed individual, peripheral vision starts to deteriorate at ing with tensed muscles).43 Training in a centrifuge can
about 3 Gz (grey-out) and totally disappears near 4 Gz. help to maximize the effectiveness of the AGSM.44
The symptom takes a few seconds to develop because of Without an anti-G suit, increasing Gz lowers the
retinal oxygen stores and, at sustained, low rates of Gz diaphragm, increasing the functional residual capacity.
will often fade in a few seconds because of adaptive changes Inflation of the abdominal bladder of the anti-G suit
in the circulation. At 5 to 6 Gz, consciousness is lost reverses this. The closing volume of the lung increases lin-
(G-induced loss of consciousness, known as G-LOC) but early with Gz, and use of an anti-G suit, by raising the
at higher rates of Gz, consciousness can be lost before diaphragm, increases the number of non-ventilated alveoli
visual symptoms arise. The incidence of G-LOC is lower in the base of the lung. Thus there is a change to the venti-
than would be predicted because of various physiological lation/perfusion ratio from the apex to the base of the lung,
mechanisms which tend to maintain regional cerebral per- with the apex tending to be ventilated, but underperfused,
fusion. In one survey, 21 per cent of aircrew reported that and the base tending to be perfused, but underventilated.
they had experienced black-out and 20.1 per cent reported This is of particular importance when air enriched with
G-LOC.35 Not all aircrew who experience G-LOC in cen- oxygen is breathed, for it assists in the development of
trifuge training remember the episode, so the incidence acceleration atelectasis. The increased respiratory work of
may be much higher than reported. The US Air Force lost anti-G straining manoeuvres produces respiratory fatigue
29 aircraft in crashes attributed to G-LOC in one 20-year that may contribute to the degree of overall tolerance to
period.36 There is no evidence that relaxed Gz tolerance prolonged Gz.45
and endurance on simulated air combat manoeuvring
(SACM) are any different in females than males.37,38 In this
respect, the shorter stature (and hence smaller heart–eye ADVANCED LIFE SUPPORT SYSTEMS
vertical distance) of females may compensate for lack of
physical strength. In the most modern generation of combat fast jet aircraft,
Below the heart, the effects of Gz produce pooling of the requirements to provide protection against exposure to
blood in the periphery, transudation of fluid from the altitude and high acceleration have driven the development
blood to the tissues and rupture of unsupported skin capil- of advanced life support systems. Commonly, the require-
laries to produce petechiae. The pooling and loss of blood ment for protection against hypoxia is addressed by the
volume eventually produce intense peripheral vasodilata- provision of a continuous supply of oxygen derived from
tion and bradycardia, leading to syncope. In addition to compressed air taken from the compressor stages of the
the effects described above, rupture of the diaphragm39 aircraft’s engines and passed through a two or three bed
and acute inguinal hernia40 in response to Gz and/or the molecular sieve oxygen concentrator (MSOC). Such systems
effects of straining against G have been reported. cannot produce 100 per cent oxygen, since argon is also con-
Negative acceleration (Gz) is experienced in outside centrated, but do remove the requirement to replenish the
loops and spins and in inverted flight. Tolerance is much main oxygen supply between sorties. A back-up supply of
Extremes of temperature 597
100 per cent oxygen is therefore required to cope with high impermeable materials. In addition, some advanced anti-G
altitude decompressions and ejection. systems are associated with an incidence of arm pain, where
Above 40 000 feet, there remains a requirement to pro- the vasculature is unprotected by counter-pressure.
vide positive pressure breathing for altitude protection
(PBA) in the event of a decompression, but this can be
combined in a common system with pressure breathing for EXTREMES OF TEMPERATURE
G protection (PBG). Counter-pressure layers can be incor-
porated in the life preserver, whose main function is to Details on heat and cold can be found in Chapter 49, Heat
provide buoyancy, allied with inflation of the anti-G and cold. This chapter will highlight those aspects relevant
trousers to provide lower body counter-pressure. Inflation to flying.
of the counter-pressure layer of the upper garment, to the
same pressure as oxygen is delivered to the mask, prevents Cold
over-distension of the chest and relieves the fatigue of
breathing against pressurized gas. Inflation of the lower Exposure to extreme cold may occur when operating at
garment improves venous return and reduces the likeli- high altitude, on the ground in very cold countries and fol-
hood of pressure breathing-induced syncope. In the most lowing accidents in isolated locations. At very low cockpit
advanced systems, the lower garment inflation pressure is temperatures, simple oxygen systems run the risk of the
1.5–2 times the breathing pressure, as this has been found expiratory valve freezing open because of the accumulation
to enhance the circulatory support provided. of condensed and frozen water vapour from the expirate.
Modern anti-G trousers cover a greater part of the body This may lead to hypoxia because the resistance of inspir-
surface than traditional (so-called skeletal) anti-G trousers ing through an open expiratory valve is less than that of
and are often termed full coverage anti-G trousers cracking open an inspiratory valve. Most military oxygen
(FCAGTs). Such garments are mechanically more efficient systems overcome the problem by design of the expiratory
and provide enhanced G protection, as well as reducing the valve, by the use of safety pressure in the mask above
fatigue associated with ‘pulling G’. When combined with certain altitudes (which would lead to continuous flow
PBG, there is a very substantial improvement in G protec- being sensed and shown on the flow indicator if there was
tion, commonly allowing a ‘relaxed’ exposure to up to 9 Gz a leakage) and by the use of cockpit heating.
with little or no requirement for physical straining to retain
full vision and reduce the risk of loss of consciousness
(Figure 52.3). Heat
Such systems carry the additional burdens of increased
resistance to movement and greater thermal load because of There are several ways in which a flier may become hot in
the additional layers and greater coverage of the body with the aircraft. First, thermal radiation from the sun becomes
trapped in the cockpit rather like a greenhouse. In small cockpit noise level of 117 dBA at start up with levels of
aircraft, the large relative size of the cockpit transparency 92–99.5 dBA in the cruise.49 Noise in helicopters is related to
exacerbates the problem. Surface temperatures of seats can the rotors (at about 20 Hz) and the gearbox and transmis-
exceed 60°C. Second, electrical components, of which sion chains (from 400–600 Hz). In propeller-driven aircraft,
there are many in military aircraft, consume power ineffi- the noise is primarily related to the number of propeller
ciently, radiating heat to the aircrew. Third, aerodynamic blades and the speed of rotation. In passenger jet aircraft, the
heating of the aircraft exterior can conduct heat into the major contributors are aerodynamic noise and noise from
cockpit. Temperatures above 110°C have been recorded on the conditioning systems; the noise in a window seat may be
the skin of aircraft flying at high speed and low level. as much as 6 dB higher than in the centre of the aircraft.
Finally, individuals produce heat from their own metabo- Protection is obtained by careful engineering of the
lism. These sources of heat would not be an embarrass- aerodynamic properties of the aircraft and (less frequently)
ment to the aircrew if they were able to dissipate the heat of the cabin conditioning system. In military aircraft, an
load. Unfortunately, particularly in military aviation, the important degree of protection is afforded by the aircrew
clothing worn interferes with heat loss by being bulky and helmet. Attenuation is generally low at low frequencies
insulating and also by incorporating materials imperme- but attenuation of 30 dB at 500 Hz to 50 dB at 4 kHz can
able to water vapour, thus preventing sweat evaporation. be achieved. Careful attention to fitting can maximize the
Moreover, the specialized flying ensemble of military avia- attenuation of perceived noise at the ear. In addition, active
tors is multilayered, increasing the work required to move noise reduction (ANR, a mechanism of destructive interfer-
while wearing it. Certainly, deep body temperatures of ence by sampling the noise field, inverting the phase and
above 38°C have been measured in aircrew at cockpit tem- then reintroducing it to the headset to cancel the original
peratures below a wet bulb globe temperature (WBGT) noise) can produce a further benefit of up to 10 dB.
index of 30°C. Laboratory simulations of aircrew wearing Passengers in noisy aircraft will benefit from the use of
ensembles including nuclear, biological and chemical earplugs. Even with protection, workers on the ground and
(NBC) protection, in cockpit temperatures previously in the air may be at risk of hearing loss50,51 and thickening
measured in flight suggest that sortie length may be limited of the mitral valve with a higher incidence of prolapse than
in the heat46 or performance affected.47 the general population.52
There are two main approaches to solving the problem
of heat in the cockpit: cabin and personal conditioning
systems. The former are frequently not as effective as they Vibration
could be, occasionally even being de-rated to reduce cock-
pit noise. Furthermore, the aircrew are insulated from the Vibration is considered in detail in Chapter 48, Whole
cooling air by their flying clothing. Personal conditioning body vibration. This chapter will address only those
systems do have the advantage that the cooling fluid is aspects relevant to flying. Complex structures, such as
circulated where is it most required – next to the skin. human bodies and aircraft, can vibrate in one or more of
However, cool air systems cannot be used in potential NBC the six geometric degrees of freedom (three rotational:
conditions and liquid systems, whilst physiologically effec- yaw, pitch and roll; three translational: heave, surge and
tive, are not yet in widespread use. Both systems require sway). In flying, the sources of vibration are the power unit
the aircrew to wear yet another layer of clothing. and the air through which the aircraft is travelling.
In helicopters, vibration is generally related to the rotor
rate and to the number of rotor blades. The former is gen-
NOISE AND VIBRATION erally four revolutions per second, which gives rise to
vibration within the helicopter of 4 Hz. The rotor rate mul-
Noise tiplied by the number of blades gives the blade pass fre-
quency which can give vibrations generally in the region of
Noise is covered in Chapter 46, Sound, noise and the ear. 8–20 Hz. Further vibration is generated at higher harmon-
The human tolerance to noise is exceeded in many aircraft ics of the blade pass rate and also at levels related to the tail
with the risks of interference with performance of the flying rotor. Vibration is usually similar in intensity in each of the
task, fatigue, degradation of communication and hearing x, y and z axes and is worse on transition to the hover.
damage. Noise in flight arises from the aircraft power In fixed-wing aircraft, the vibration from the engines is
source, subsidiary noise from equipment, flow of air over usually at a higher frequency than in helicopters. A single-
aircraft surfaces and weapon firing. Sonic booms do not stage turbine usually produces vibration at about 130 Hz,
affect the occupants since the aircraft leaves the sonic boom while a dual stage one produces 230 Hz. In propeller-
behind. The noise profile will differ between aircraft types, driven aircraft, the blade pass frequency is about 100 Hz,
seat positions and profiles flown. Cabin noise levels up although desynchronized propellers may give beating at
to 120 dB have been measured in fixed wing aircraft when lower frequencies. In fixed-wing aircraft, the most notice-
flying at 480 knots at 250 ft,48 with the highest peaks being able turbulence is caused by the atmosphere, for example
in the 0.5–4.0-kHz range. Even motor gliders can reach a during cloud penetration, during low level flight or in
Vision 599
‘clear air turbulence’. In military aircraft, the firing of When there are no visual clues, the eye tends to focus at
weapons can also give rise to vibration. a point 1–2 m away. This functional short sight, called
The effects of vibration in the aviator can range from ‘empty field myopia’, can reduce the chances of a pilot see-
imperceptible to inconvenient to unpleasant. The body is ing another aircraft, since objects at infinity are blurred.
least tolerant of vibration between 4 and 8 Hz. The main This is an important cause of road accidents in fog. Pilots
symptoms limiting tolerance in the laboratory are precor- should be trained to look at their wing tips from time to
dial and abdominal pain. However, in flying, the most time to relax their accommodation. If a pilot looks at the
important effect for the pilot is on vision. The instrument instruments and then outside again, the gaze can be dis-
panel and the pilot’s eyes are usually vibrating out of phase. tracted for 2.5 seconds or more and the requirement to
This results in degraded visual acuity. This is often exacer- refocus frequently from infinity to near vision can be
bated when helmet-mounted display systems are in use, fatiguing. It was for these reasons that the first head-up
particularly at frequencies of 4–6 Hz.53 Outside the aircraft, display (HUD) – where the instrument image is focused at
the image is stable in space and at optical infinity, with infinity on a glass screen in front of the pilot – was devel-
other aircraft unlikely to be moving so fast that they exceed oped for the Beaufighter in the Second World War.58
the angular velocity limitations of the pursuit reflex. In It can take up to 5 seconds from the time an image first
addition, vibration can also give rise to illusions of motion falls on the pilot’s retina for an aircraft to change course.
and to symptoms of motion sickness. At normal levels of During this time, the aircraft can cover almost a mile if
vibration in flight, there are no great effects on the cardio- travelling at 500 knots. However, if two aircraft are on a
vascular system, although there may be an increase in meta- collision course, they will remain on a constant bearing
bolic rate reflecting an increase in muscular activity from each other, thus denying the pilots the stimulus of a
required to maintain posture. Vibration can cause hyper- moving object in the visual field.59 Objects are more easily
ventilation. A fall in PaCO2 to less than 25 mmHg has been seen in the peripheral visual fields, especially if they are
recorded after 2 minutes of vibration at 9.5 Hz with an moving. Tracking is optimal up to 30° per second, but
acceleration-amplitude of 1 Gz.54 This is sufficient to reduce visual acuity is halved at 40° per second. Pilots must there-
cerebral blood flow by 35 per cent.55 Vibration has also fore be trained to maintain a good lookout at all times.
been implicated in orthopaedic problems in helicopter
aircrew, although seating, posture and ergonomic factors
undoubtedly play a part. Eye protection
Protection can be afforded against vibration by careful
engineering of the aircraft, the use of dynamic vibration In civil flight and military transport aircraft, protection
absorbers and by vibration isolation of the aircrew seat or from glare is given by sunglasses. Sunglasses and visors
of stretcher mounts and the use of seat cushions.56 Finally, should have a transmittance of 10–15 per cent. In addition
if the source of vibration is turbulent air, the effects may to increasing visual acuity in bright sunlight, they also pro-
be minimized by routing away from it, changing cruising tect the eye from the effects of UV light.
altitude and by ensuring passengers remain in their seats Military fast jet aircrew usually wear helmets whose
with seat belts fastened. polycarbonate visors (one clear, one tinted) afford protec-
Casualties from military operations tend to be evacuated tion against glare, birdstrike and blast. Ideally, the cockpit
by helicopter before definitive surgery is conducted away transparency should be tough enough to withstand bird-
from the front line. Vibration of unstabilized fractures can strike, but this often conflicts with the need for rapid
cause severe pain and may contribute to complications. escape in an emergency. About 95 per cent of birdstrikes
Casualties evacuated by helicopter must be given adequate occur below 750 ft60 and therefore are more commonly
analgesia and their fractures adequately stabilized. suffered during take off, landings and high speed, low-level
flight. The clear visor can also protect against lead spatter
from canopy fragmentation devices used to clear the ejec-
VISION tion path. Although lead spatter usually causes superficial
damage only, cases of ocular penetration have occurred.
The importance of vision in aviation was first recognized Visors also form an integral part of the overall protection
during the First World War.57 Despite the increase of against windblast during the ejection sequence. Design of
equipment to increase flight safety, vision is still important the ensemble of helmet, visor and mask is important so
in collision avoidance and target identification. Intact that they remain on the head during ejection. Current RAF
colour vision is more than ever necessary in the ‘glass cock- systems provide adequate protection up to 650 knots and
pit’ where displays and warnings are presented in a wider aircrew are advised to have at least one visor selected down
variety of hues than ever before. Aircrew need to be pro- at all stages of flight.
tected from insults such as glare, lasers and chemicals with The fireball from a nuclear explosion can cause direct
the addition in military aircraft of birdstrike, blast, explo- and indirect flash blindness and may even cause a retinal
sive devices and nuclear flash. Visual illusions are covered burn. The problem is worse at night when, theoretically, a
below under Types of illusion, p. 601. pilot could be effectively blind for as long as a minute after
600 Flying and spaceflight
exposure. Various protective devices have been proposed, move under conditions of vibration or G. Tinted spectacles
ranging from an eyepatch which could be raised after should not be worn with tinted visors (see below).
exposure to complex electro-optical devices. Photochromatic lenses are not yet sufficiently reactive to
Lasers, on the other hand, are more likely to pose a respond quickly enough on entering a cloud layer from
problem. Damage can range from transient stress tempo- high sunlight. Many military aircrew have reported losing
rary conditions (e.g. acute keratitis) to permanent damage, a lens from their spectacles in flight and thus it seems sensi-
such as cataract, corneal opacity or retinal burning. The ble to carry a spare pair. In the RAF, most spectacles and
international aviation community is attempting to mini- helmets are retained on the head during ejection. In
mize the problem by legislation controlling the use of such the US Air Force, on the other hand, sorties are flown
devices near airfields. In military flying, lasers are used for higher with clear visors up and up to 80 per cent lost their
target designation and thus may be deliberately aimed at eyewear.67
aircraft. Protection is best provided by distance, but visor
coatings designed to protect against specific wavelengths
may be necessary. These have the diasadvantages that they Eye surgery
only protect against specific threats, they produce a blend-
ing of surface colours and loss of terrain features, a reduc- As laser techniques have evolved, radial keratotomy (RK)
tion in depth perception and difficulties with warning has declined as a surgical method of correcting myopia.
lights and displays, maps and weapons displays. Photorefractive keratotomy (PRK) usually produces visual
stability in three to six months. Laser in-situ keratomileusis
(LASIK) produces a more predictable and safer method of
Spectacles and contact lenses correcting higher levels of myopia than PRK. The results
are good for both PRK and LASIK. About 85 per cent
The clinical indications for visual correction and visual of such patients achieve 6/6 or better.68 The eye often
standards are covered below. Approximately 27 per cent of becomes dry and requires lubricants for up to six months
pilots, 51 per cent of navigators and 40 per cent of other air- after operation and some patients experience night vision
crew in the US Air Force need to wear glasses. Over 12 per problems, such as haloes or starbursts around light
cent need bifocals.61 More then half of civilian pilots need sources. Recertification for military flying depends on the
lenses to correct defective vision in order to satisfy licensing outcome and the type of procedure. For civilian flying, the
requirements.62 Evidence suggests that there is no differ- Civil Aviation Authority (CAA) will consider class 1 certi-
ence in civil accident rates or in US naval carrier landing fication three months after LASIK and six months after
accidents in pilots who wear visual correction.63 One survey PRK as long as certain criteria are met.
has reported that glasses cause more flight safety incidents The use of intraocular lenses is compatible with both
in military aviation than contact lenses.64 Generally speak- military and civil flying once vision has stabilized. In one
ing, contact lenses are the preferred option for visual reported case, the implanted lens remained stable during
correction for aircrew. ejection when the imposed acceleration reached an esti-
Both soft (SCL) and hard contact lenses (HCL) have mated 14 Gz for 200 ms.69
been used in flight. High water content SCL are preferred
in the low humidity of aircraft cockpits, but HCL are still
required in some conditions such as keratoconus. Rigid, Night vision
gas-permeable lenses may offer advantages for this group
in the future. Daily, disposable contact lenses are conven- During the Second World War, interceptors had to pick up
ient and give rise to fewer problems for aviators with sim- their targets before they themselves were spotted, bomb-
ple myopia. The major difficulties quoted in flight are aimers needed to be able to place their bombs accurately
foreign body incursion and movement off-centre. In both despite the attentions of searchlights and tracer and pilots
of these, the incidence is greater for HCL than SCL.65 The had to be capable of judging their landings correctly on
greatest difficulty experienced in the Gulf War related to darkened airfields. In the Second World War, much
resupply problems with replacement lenses.66 Some US Air emphasis was given to dark adaptation of aircrew before
Force aircrew have lost SCL or HCL during ejection, but take-off.
the overall experience is small. The introduction of night vision goggles (NVG) has
Overall, sunglasses and visors should give as wide a field changed things, but has introduced new problems. Some
of vision as possible. The optical quality should be high and accidents have been directly linked to the use of NVG. In
it may be necessary to incorporate anti-scratch and anti- effect, NVG present an isochromatic view of the world lim-
reflection coatings. Corrective flying spectacles must be ited in contrast and detail. Visual acuity, as well as visual
capable of integration with the rest of the aircrew equipment fields, are degraded. For example, switching from forward-
without impairment of hearing protection or interference looking infrared (FLIR) to NVG gave a 4-second visual
with the seal of an oxygen mask. They must be comfortable, loss, a two-fold reduction in visual acuity and a three-fold
resistant to fogging, minimize internal reflections and not reduction in contrast sensitivity.70 The cockpit lighting
Spatial disorientation 601
needs to be compatible with the use of such devices and set launch from an aircraft carrier, gives an apparent nose-up
carefully.71 Careful fitting and training are required. In one attitude of 5° for a minute or more. There is little time to
study, training improved visual acuity from 6/15 to 6/12.72 overcome this particular illusion on take-off. If the pilot
pushes the stick forward, he introduces a radial accelera-
tion that will make matters worse. When performed at
SPATIAL DISORIENTATION high altitude, pilots approaching the vertical in a bunt
manoeuvre have reported feeling as if the aircraft was
Spatial disorientation (SD) occurs when a pilot does not flipped on its back. Similarly, a pilot in a flat turn will feel
sense correctly the position relative to the ground, motion as if he is rolled out of the turn and a pilot in a banked turn
or attitude of himself or his aircraft. The broader term may feel himself to be level. Head movement during these
‘situational awareness’ (SA) is taken to include a tactical manoeuvres can induce further illusions.
appreciation of the position of other aircraft, as well as a When external visual clues are inadequate, for example
sense of geographical location. SD is caused by inadequate at night, the apparent movement of light sources in the
or erroneous cues to the brain and by central processing external environment may be interpreted as a change in
errors, such as errors of perception or coning of attention. attitude of the aircraft. For example, during linear acceler-
SD is a significant cause of aircraft accidents. The ation, the backward rotation of the resultant force vector
majority of accidents occur in poor visibility when the pilot may make a bright star appear to move upwards. This
may not be aware that his interpretation of aircraft attitude may be interpreted as a nose-down change in the aircraft
is incorrect. However, some occur in good conditions attitude.
when visual cues are misinterpreted. The type of incident One of the most common illusions is ‘the leans’. If a
where the pilot is aware that there is a mismatch between pilot is in a gentle turn to the right, at a rate below that
his aircraft instruments and what his brain is telling him is which would stimulate the otoliths, he could feel that the
less likely to lead to an accident if appropriate training is wings are level. If he then rolls wings level abruptly, he can
given. Spatial disorientation is more likely at times of high feel that he is banking to the left. Even though this can
workload, when undergoing treatment with certain drugs be recognized as level flight on the instruments, there is a
or with upper respiratory tract infections. It is also more distinct temptation to lean to align the body with the
prevalent in poor weather, at night, at high altitude and perceived vertical.
during flight over sea or featureless terrain. Certain flight In the same way that the otoliths can misinterpret linear
manoeuvres contribute, such as prolonged linear accelera- accelerations, so can the semicircular canals misinterpret
tion or deceleration and prolonged angular motion, partic- angular accelerations in yaw, pitch and roll. At constant
ularly when combined with head movement. Transfer to angular speed, the body’s sensors will only give the correct
instrument meteorological conditions (IMC) when land- information during the first 8 seconds of the manoeuvre.73
ing in helicopters, when the downwash from the rotor During recovery from a prolonged spin, not only is there
kicks up dust or snow, is also a potent cause of SD. a somatogyral illusion that the aircraft is turning in the
Subthreshold changes in attitude are unlikely to be opposite direction, but vision may also be degraded by the
detected and thus can also lead to SD. nystagmus induced by the spin; this will make reading of
instruments difficult at a critical time. In reduced light
conditions, oculogyric illusions may occur with an illusory
Types of illusion perception of movement of an isolated light. Responses
during banking may be complicated by the optokinetic
The illusions may be caused by false information from the cervical reflex where pilots tend to move their heads to
otoliths and kinaesthetic receptors during sustained accel- keep a constant horizon rather than keep them in line with
eration (somatogravic illusions) and on moving the head the vertical axis of the aircraft.74
in an atypical force environment (G excess illusions) or Movement of the head during angular accelerations
from the semicircular canals on recovery from prolonged can produce quite compelling sensations of movement by
rotation (somatogyral illusions) and on moving the head cross-coupled or Coriolis forces. For example, a head
during rotation (cross-coupled or Coriolis illusions). movement in roll from 45° left to 45° right while rotating at
Man is habituated to expect any sustained acceleration a steady speed about the z body axis will produce a strong
to be due to gravity. When a sustained acceleration is sense of pitching forward. In highly manoeuvrable aircraft,
applied, the resultant combined acceleration is interpreted there is a potential for cross-coupling illusions independ-
as the vertical. For example, when an aircraft accelerates on ent of pilot head motion.75
take-off, the resultant acceleration from the rearward iner- Imbalance between middle ear pressure on ascent or
tial force and downwards gravity is between the two; the descent can also cause vertigo which, although usually last-
pilot senses this resultant force and mentally orientates it ing only seconds, can last some minutes. It is more com-
so that it is vertical. He thus senses that the aircraft nose is mon when there is a respiratory tract infection. The flicker
high and tends to want to push the stick forwards. A brief of propellers or rotor blades have also caused vertigo and
Gx acceleration of 5 G for 2–3 seconds, such as in a catapult nausea, but the more usual presentation is irritation.
602 Flying and spaceflight
motion.81 In the RAF, about 85 per cent of those affected resynchronized, the nadir of psychomotor performance no
have been salvaged by a programme of increasing exposure longer coincides with sleep. After flights westward, when
to cross-coupled stimuli on the ground before a similarly the normal sleep onset is delayed, individuals tend to fall
progressive exposure to aerobatic flight in a dual controlled asleep quickly and sleep more deeply. Sleep later in the
aircraft.82 Later work has suggested that it is the number of night is more disturbed. By the third night, the sleep pat-
challenges rather than the severity of malaise achieved that tern is more adapted to the new time zone and this is
is the important factor determining habituation.83 reflected in daytime alertness and general well-being.
The number of remedies available is large and none can Eastward flights impose an advanced sleep onset time. If
completely prevent everyone from experiencing air sickness sleep during the flight and during daytime at the destina-
in all conditions. One of the most effective drugs is tion is avoided, the first night’s sleep may be good.
L-hyoscine hydrobromide (L-scopolamine hydrobromide in However, once the immediate effects of sleep loss are over-
the United States; Kwells®). In conditions where 10 per cent come, the sleep pattern does not adapt to local time for
of the population would be airsick, 0.4 mg of the drug can several days. Sleep quality is reduced and there are more
increase protection so that only 2 per cent suffer symptoms. night-time awakenings.
In more severe conditions, when 50 per cent of those exposed
would be sick without prophylactic treatment, 1.0 mg of the
drug can provide protection for all but 8 per cent.84 Unfortu- Protection
nately, most of the drugs used have side effects unacceptable
for use by aircrew.85 Hyoscine can cause blurred vision, dry Airline scheduling is largely governed by commercial fac-
mouth, sedation, dizziness and significant performance tors. In an ideal world, an overnight, eastwards flight, after
decrements. Promethazine (Phenergan®, Avomine®) 25 mg a period of desynchronization caused by the flight west,
can also impair psychomotor performance, while dimenhy- would be timed to arrive when alertness and performance
drinate (Dramamine®, Gravol®) is a central depressant. would be high. However, this is not always possible and
For short-term protection in passengers, oral L-hyoscine flight safety is maintained by imposing statutory flight time
hydrobromide (0.3–0.6 mg) is the drug of choice. For longer limitations. For aircrew required to work overnight, an
benefit, transdermal administration of hyoscine by patch anticipatory sleep of about four hours in the afternoon or
may be useful if placed at least six hours before protection evening will improve overnight performance. Light visor
is needed. Antihistaminic drugs, such as cinnarizine treatment for jet lag may accelerate circadian re-entrainment,
(Stugeron®) give protection for six hours, while related but the effect is modest and unaccompanied by subjective
drugs, for example, promethazine can give protection for improvement in symptoms.90 An alertness device based on
12 hours. One study found that a combination of 25-mg wrist inactivity may be useful in preventing long-haul
promethazine and 200-mg caffeine (to counteract the seda- pilots from falling asleep in the cockpit, but does not
tive effect of the promethazine) was most helpful.86 Other obviate the need for sensible rostering.91
proposed prophylactics, such as wristbands, which claim to For the statesman or businessman, there are two ways of
work by pressure on the acupoints, have not proved effec- limiting the effects of time zone changes. One is to time the
tive.87 Although the severity of symptoms can be reduced by trip so that adaptation to the local time zone is complete by
the use of stroboscopic illumination or shutter glasses with a the time important business is transacted and to allow ade-
frequency of 4 Hz (to reduce retinal slip),88 such devices are quate time for recovery on return. Another is to travel by
not yet practicable in aviation. supersonic aircraft (if and when these are available again),
conduct the business and then return by supersonic air-
craft; adaptation to a new time zone is therefore unneces-
FATIGUE AND JET LAG sary. For those who have neither the time nor the money to
adopt these techniques, napping when necessary and the
Chapter 91 (Shift work and extended hours of work) use of hypnotics may be the only answer.
addresses the subject of shift work and extended hours of Hypnotics have been used for some years to impose sleep
work. For crews of both short-haul and long-haul flights, at unusual times or in unusual conditions. A rapidly
sleep deprivation occurs because of the work schedules.89 absorbed drug with a short half-life, such as temezepam
For the short-haul pilot, the adaptation to encroachment 10–20 mg has been found to have an acceptable margin of
of duty hours on sleep is mainly by prolongation of sleep safety when used sparingly. It was used successfully in the
periods. Rapid and large time zone changes, coupled with Falklands campaign92 and in the Gulf War. Psychostimulants
sleep disturbance related to overnight flights, are particu- have not been used by the RAF since the Second World War,
larly important in flying. Jet lag adds to the acute fatigue but dextroamphetamine (5 mg every two to four hours) has
for the crews of long-haul, transmeridian flights. Older been used extensively and effectively by the US Air Force93
people tend to be more affected than younger individuals. and 20 mg doses of caffeine every hour have been reported
Time zone changes may lead to lethargy, loss of to be useful after sleep deprivation.94 More recently, atten-
appetite, a general feeling of malaise and disruption to the tion has been focused on the use of melatonin, which has
normal pattern and quality of sleep. Until rhythms are been reported to prevent jet lag symptoms in east and west
604 Flying and spaceflight
transmeridian flight.95 A dose of 10 mg can advance bed and selected, thereby avoiding inhalation of air from the cock-
rise times by two to three hours and maintain sleep duration pit environment. Exposure of crop sprayers to chemicals
between seven and eight hours compared to placebo, and may require skin decontamination and systemic treat-
produces fewer performance errors on awakening than ment. Protection of aircrew against chemical warfare
placebo.96 In general terms, all use of such drugs requires agents is provided by deployment of detection devices, a
medical oversight.97 robust reporting system, training, protective clothing
including respirators which maintain a positive internal
pressure to prevent inward leaks, decontamination sched-
FOOD AND DRINK ules, filtered air in accommodation for briefing and rest
and, finally, medical treatment if required. Pyridostigmine
Food 30 mg every eight hours may be given as pre-exposure
treatment against nerve agents.
Food has been recognized as an important factor in flight The aviation worker is also exposed to jet fuel fumes.
safety from the earliest days of flying.98 First, gastrointesti- Chronic exposure can affect neurocognitive functioning in
nal upsets are the most common cause of in-flight incapac- refuelling workers.107 The effect is greater at the end of the
itation.99 For this reason, flightdeck crew must select working day and in smokers, who smoke downwind of the
different menu items for meals both in-flight and when site. From time to time, claims are made about exposure to
down the route. In addition, it is sensible, for obvious rea- other chemicals in the normal cabin environment. To date,
sons, for the flightdeck crew to stagger their times of eating no evidence has been found of exposure to toxic sub-
when in flight. Second, hypoglycaemia can reduce tolerance stances at levels that would be expected to cause acute or
to Gz and has been cited as a significant finding in more cumulative embarrassment.
than 50 per cent of incidents of unconsciousness in the
air.100 This has led to a requirement to eat sensibly before
flying and to provide in-flight rations during long flights. AIRCRAFT ACCIDENTS
The most common pilot errors in an analysis of American Escape from helicopters offers different challenges. Up
civil crashes over a period of 14 years were mishandling to half of military helicopter accidents involve ditching in
of the aircraft, inattention and poor decision making.113 water.124 The problems of escape include physical restric-
However, there is no evidence of an increase in pilot error tion from equipment or trapped air, limited air supply,
with increasing age of the pilot up to the early 60s.114 The poor underwater visibility, exit design and fear. The solu-
majority of crashes occur in the vicinity of an airfield, being tions include comprehensive training in a crash simulator,
related to take-off or landing. Many crashes occur during better design of exits and hatches, more streamlined per-
training; in one series of civilian crashes, an instructor sonal equipment, underwater lighting and breathing aids.
was present for 50 per cent of crashes following stalls and The death rate in helicopter crashes on land is reduced by
32 per cent of those resulting from fuel mismanagement.115 using the shoulder restraint harness.125
Aircraft have notoriously been used for acts of terorism At a crash, the first priority is to save life. The next prior-
but are also used as a method of committing ordinary sui- ity is to preserve evidence. Fire and crash sites are controlled
cide,116 accounting for between 0.72 and 2.4 per cent of all by incident commanders who restrict access depending on
accidents.117 Such pilots have tended to be younger than risk. The risks to accident investigators can range from bugs
those involved in other accidents; 24 per cent had used to bears, encompassing explosive, chemical, biological, ter-
alcohol and 14 per cent illicit drugs. Other factors involved rain, meteorological and psychological hazards. The chem-
were domestic and social issues (46 per cent), legal prob- icals involved at a crash site include aviation fuels, hydraulic
lems (40 per cent) and pre-existing psychiatric disorder fluid, metals (such as cadmium, beryllium, chromium,
(38 per cent).118 mercury and their salts), plastic resins and surface coatings
Most accidents involve ground impact. Injury can result and products of combustion. Unexploded ordnance, for
from sudden deceleration, crushing loads on the fuselage, example ejection seat cartridges when ejection was not
break up of the floor structure or by fire. Protection from initiated, may also be present.
mechanical forces is given by restraint harnesses and, in
military aircraft, energy-attenuating seating. The more
efficient the restraint in the seat, the higher is the likelihood FITNESS FOR FLIGHT
of survival. In one study of fire in 134 fatal civil aircraft
accidents, 360 individuals had insignificant antemortem The formation of the Special Royal Flying Corps Medical
injury, but carboxyhaemoglobin levels 20 per cent, Board in 1916 significantly improved the proportion of can-
enough to impair chances of escape.119 Almost 60 per cent didates who passed flying training.126 Nowadays, it can cost
of fires start during the impact sequence, with another over £1 million to train a military fast jet pilot. The aircraft
17 per cent occurring after the aircraft has come to rest. flown can cost over 100 times that figure. Moreover, medical
Rescue is then hampered by terrain, bad weather and the factors frequently feature in accident reports. One study cited
dark.120 Smoke hoods for passengers have been developed medical factors as causing or contributing to 4.7 per cent of
but are not in use by the airlines.121 fatal accidents.103 Aviation medicine policy must therefore
Many military aircraft have ejection seats which can balance the risks to individual health, flying safety and mis-
allow the aviator to be on a fully deployed parachute within sion completion against conservation of resources, flying
3 seconds of initiating ejection. The risks are of not initiat- experience and training costs. Civilian aviation authorities
ing ejection soon enough, of back injury as a result of the have set a goal of one fatal accident in multicrew aircraft in
forces of ejection, of collision with canopy or canopy frag- each 107 flying hours.127 If the medical contribution to this is
ments, windblast and flail injuries and landing injury. The an arbitrary 10 per cent, then incapacitation in flight should
design of the seat, the use of miniature detonating cord cause an accident no more than once in every 108 flying
(MDC) to fragment the canopy to clear the escape path hours. This is attainable if the risk to an individual pilot of
and use of leg and arm restraint can minimize the risks. incapacitation is 1 per cent a year,128 although there has
Although more modern aircraft are associated with a lower been recent discussion about the logic of reducing this to
risk of injury from ejection,122 there will always be injuries 2 per cent.129 The actual figure for the United States Air
caused by ejection outside the design specifications of the Force over a ten-year period was 1.9 in 107 flying hours.130
ejection seat. However, injury can occur from anticipated, Although some doubt has been expressed regarding the pre-
in-envelope, ejection forces alone, with anterior wedge dictive value of periodic aircrew medical examination,131 one
fractures of the thoracolumbar region being the most com- retrospective study showed that there were no important risk
mon. The risk is greater with taller and heavier aircrew.123 factors that could have been detected at such examinations in
After ejection, a full spinal radiographic screen from C1 to a series of military aircraft crashes.132 The only blood test that
the sacrum should be carried out. Even with a negative has shown any value is a blood lipid profile which should be
screen, a Technetium-99 bone scan will often demonstrate carried out on initial examination and repeated at age 40.133
‘hot spots’ indicative of fresh bony injury. Treatment is by It is a generally accepted principle that not only should
total bed rest for three weeks in hospital followed by grad- aircrew be protected against the rigours of the aviation
ual mobilization. Resumption of flying on ejection seats is environment, but also that the general public should be
possible after three months. protected from accidents caused by aircrew illness. This is
606 Flying and spaceflight
achieved by agreeing to medical standards which are the whether or not to return an aviator to flying rests with the
minimum compatible with professional flying. Aircrew are appropriate national authorities, civil or military.
then selected for training who meet those standards. They
are required to be not abnormally susceptible to the stresses
of flying, either by disease or by unusual physiological Miscellaneous conditions caused or affected
response. Once the aircrew are trained, they are regularly by flight
examined to ensure that they continue to meet medical
standards. Military aircrew are subject to the standards Backache is one of the most common conditions reported by
imposed by their parent armed force. Civilian aircrew in aircrew and this is related to the relatively poor ergonomics
the United Kingdom are subject to licensing by the CAA. often found in aircraft. Helicopter pilots have a greater inci-
The frequency and content of the examination depends on dence of prolapsed intervertebral disc,139 osteoarthritis of the
the age of the pilot, the type of flying envisaged and the exis- spine140 and backache than controls.141 Over half of Sea King
tence of risk factors. For many years, the upper age limit for helicopter crew reported backache in the previous two years,
captaincy of civilian passenger aircraft was set at 60 years. sufficient to interfere with performance, and this incidence
Experience reduces, but does not eliminate, age-related increased with the total numbers of hours flown.142 In addi-
decline. However, the Aerospace Medical Association has tion, almost all flight attendants report musculoskeletal
concluded that there is insufficient evidence to support symptoms in one year, particularly in the lower back.143
restriction of pilot certification based on age alone.134 Active female flight attendants report more menstrual irreg-
To allow any aircrew to fly with particular medical ularity than former flight attendants.144 In addition, an
conditions, the following criteria must be satisfied: increased incidence of skin cancer has been reported in civil-
ian airline pilots;145 this may be related to behavioural factors
● There must be minimal risk of sudden incapacitation. but some influence of exposure to cosmic radiation could be
● There must be minimal risk of subtle performance implicated.146 An elevated risk of brain cancer and carci-
decrement. noma of the prostate for male pilots and of breast cancer
● The condition must have resolved or be stable and be for female flight attendants compared to the ground-based
expected to remain so under the stresses of the aviation population has been described, but both occupational and
environment. non-occupational risk factors may have contributed.147
● If there is a risk of progression or recurrence, the symp- Most airlines are now smoke-free. The withdrawal of
toms and signs must be easily detectable and must not nicotine from an addicted smoker may cause decrements in
pose a risk to the safety of the individual or others. psychomotor performance. Aircrew who try to stop smok-
ing should ideally be grounded for one to two weeks.
In addition, for professional aircrew, the condition must Nicotine replacement therapies, such as patches or gum,
not need exotic tests, regular invasive procedures or fre- may be allowed but systemic drugs such as buproprion
quent absences to monitor for stability or progression. (Zyban®) should not be permitted when on flying status.148
Finally, for military aircrew, the condition must be com- Most aircrew who have had a hip replacement may be
patible with performance of sustained flying operations in able to return to civilian flying. The risk for military air-
austere environments worldwide.135 The role of the doctor crew would be expected to be greatest during the ejection
dealing with aircrew must be clearly understood. Most avi- sequence,149 but some methods of ingress to and egress
ators regard doctors as only marginally better than the angel from cramped cockpits may predispose to dislocation and
of death because of the risk of being grounded. The medical vibration may contribute to loosening of the prosthesis.
officer must work to obtain and hold the trust of the aircrew
and make it clear that his main aim is to maintain their
flying status – but that he also has a responsibility to the Use of therapeutic drugs
employer and the general public as one of the guardians of
flight safety. The three most common conditions seen by The use of therapeutic agents, whether by self-medication
the United States Navy requiring a decision on fitness for or prescribed, may be particularly dangerous in aviation.
flying are allergic rhinitis, obesity and decreased visual Most have side effects, some of which may be hazardous in
acuity.136 In one series in a European airline, the rate of aviation. Particular care should be taken with over-the-
grounding was 9.2/103 crew members a year. Ear, nose and counter medication and unlicensed, herbal remedies. The
throat disorders accounted for 30.1 per cent, musculoskele- key questions that have to be asked are:
tal disorders for 21.3 per cent and psychiatric conditions for
12.5 per cent.137 The rate of disqualification on medical ● Does the condition for which the drug is being taken
grounds in the United States Air Force declined from necessitate grounding in its own right?
4.1 per cent a year in 1984 to 0.18 per cent by 1999, largely as ● What monitoring of the condition is required?
a result of the use of clinical management groups to provide ● What are the potential side effects relevant to aviation?
an evidence base, new therapies and effective preventive ● Does the patient have any untoward reaction to the
medicine efforts.138 In the final analysis, the decision on drug on the ground?
Background 607
The use of statins to reduce cholesterol levels has been found made available. Kerbside check-in of baggage may be
to be aeromedically safe provided side effects are minimal.150 recommended. The airlines reserve the right not to accept
Hypertensive patients undergoing treatment with selected infectious patients, patients who would be expected to
anti-hypertensive agents may be returned to flying duty deteriorate in flight or those whose conditions would be
once their blood pressure is within limits, provided there are offensive to fellow travellers. Carriage of unstable patients is
no untoward side effects and other risk factors are under a skilled business which should only be undertaken by
control. In the end, the final decision on medication and specially trained operators.
flying rests with the relevant licensing authority.
Transmission of disease
Fitness for flight as a passenger
Worldwide flight exposes aircrew and passengers, as well
Passengers fly with all sorts of medical conditions every day as ground personnel, to a variety of disease vectors. For
and survive. However, with some conditions there is a example, transmission of Mycoplasma tuberculosis from
degree of risk. The doctor asked to advise a patient must one crew member to another on a single flight has been
bear in mind the inactivity of a long flight, the relative reported.153 Communicable disease can enter the country
hypoxia, the low humidity, the hassle, the ready availability by an infected person, infected vector or by infected mate-
of alcohol and the time zone changes. These may all impact rial. International Health Regulations exist to detect,
on the timing of medications, particularly relevant to reduce and eliminate sources of infection, improve sanita-
insulin-dependent diabetics. The swelling of legs may tion around airports and prevent the dissemination of
cause circulatory embarrassment to patients in plaster of vectors. Despite disinfection, cases of malaria have occurred
Paris leg casts. Susceptible passengers may be at increased in non-travellers living in the vicinity of airports in non-
risk of deep vein thrombosis.102 Risk factors are:151 malarious countries. The regulations provide for notifica-
tion of disease, health organization at airports, procedures
● Low: Age over 40, active inflammation, minor surgery at and between airports, documentation and disinfection.
in last three days. These passengers should be given In the United Kingdom, the Public Health (Aircraft)
information about mobilization and hydration. Regulations 1979 cover cholera, plague, yellow fever, the
Support tights or non-elasticated long socks may be viral haemorrhagic fevers and rabies.
helpful. It should be remembered that aircrew travel and there-
● Medium: Varicose veins, uncontrolled heart failure, fore need to be immunized.154 The number of mandatory
heart attack in the last six weeks, the taking of either immunizations is small, but there are additional ones that
hormone replacement therapy (HRT) or the oral may be recommended. Aircrew should not fly immediately
contraceptive pill, polycythaemia, paraplegia, injury to after immunization because of the risk of side effects. Some
the lower limb in the last six weeks, pregnancy or six malaria prophylaxis, for example mefloquine, should not
weeks post-natal. These passengers should follow the be taken by aircrew for the same reason. Chloroquine
advice above and use graduated compression stockings. (300 mg weekly, despite an occasional, temporary effect on
The doctor may advise the use of aspirin if there are no visual accommodation) and proguanil (200 mg daily) have
contraindications. been overtaken as the mainstay of malaria prophylaxis for
● High: previous stroke or pulmonary embolus, major aircrew by malarone. Other drugs, such as doxycycline,
surgery within the last six weeks, malignancy, family may be given in areas of chloroquine resistance. The main
history of pulmonary embolus. The advice for the above actions to be taken are avoidance involving use of mos-
two groups should be followed, but the doctor may quito nets, sprays, long-sleeved and long-legged clothing.
recommend the use of low molecular weight heparin For aircrew staying overnight in malarial areas in air-
instead of aspirin. conditioned hotels in urban or semi-urban areas, and trans-
ferring there in air-conditioned cars, the risks are very low,
Airlines expect that passengers with known medical condi- provided al fresco dining or safari trips are eschewed.155
tions will need to be medically cleared before flight, either
by their own or an airline doctor. One survey found one
request for medical clearance for almost every 11 000 pas- SPACEFLIGHT
sengers.152 Almost one-quarter of requests were for muscu-
loskeletal disorders or fractures, with psychiatric patients BACKGROUND
accounting for 17.6 per cent. Three-quarters required either
a qualified escort or travel companion. Wheelchairs were ‘Never before has medicine been called upon to certify that
needed by 30 per cent, in-flight oxygen by 28 per cent and an individual will be healthy enough to perform for three
stretchers by 27 per cent. When such patients are accepted years following the examination’.156 On July 21, 1969, Neil
as passengers, on-board oxygen, special diets or individual Armstrong became the first man to walk on the moon. It is
embarking, debarking or transfer arrangements may be only a matter of time before some nation or group of
608 Flying and spaceflight
nations will return to the moon and then go on to explore PRE-LAUNCH AND LAUNCH
Mars. Such plans depend on political will and support.
When this happens, the success of the mission will depend Safety of both astronauts and ground crew is of paramount
upon the health of the crew. importance to the on-site flight and occupational physi-
Over 500 people have flown in space since Yuri Gagarin cians. In 1967, a ground test of the Apollo 1 spacecraft killed
became the first in 1961. Space travel has changed greatly three astronauts when the pressurized 100 per cent oxygen
over the intervening decades and is set to progress dramat- atmosphere caught fire from a spark from an electrical cable.
ically in our lifetime. The space shuttle programme is Cabin atmosphere composition was changed as a result.
drawing to a close and plans are being made to return to Launch of the spacecraft is a dangerous time with high levels
the moon and on to Mars. Space travel will become more of vibration and noise. Risk of fire, explosion and toxins on
available to paying ‘space tourists’. Man will be spending the launch pad are posed by the large quantities of pressur-
longer in space and at greater distances from Earth. ized highly explosive propellants present. Gravitational pull
Maintaining astronaut health is vital to the success of reaches 3 G on the shuttle and 4 G on the Russian Soyuz
future missions. Space medicine studies the effects of capsule. In 1986, the space shuttle Challenger disintegrated
microgravity on the human body and develops strategies shortly after launch killing all seven astronauts on board.
for dealing with medical conditions and emergencies in
space. This section summarizes the most important issues
affecting the health of astronauts. THE SPACECRAFT ENVIRONMENT
The spacecraft is a pressurized vehicle which provides atmos-
THE SPACE ENVIRONMENT pheric control, waste management and shielding against
micrometeorites and some radiation. The international
The space environment is inhospitable. Space starts at space station is maintained at 1 atm, 80 per cent nitrogen and
63 000 feet above sea level (Armstrong’s Line) and has a 20 per cent oxygen.161 CO2 is actively removed using lithium
barometric pressure of less than 1 mmHg. Temperatures hydroxide filters to keep levels below 0.01 per cent. Charcoal
range from 1500°C to 130°C. Astronauts experience in the mixture removes odours. Toxicology, water quality,
microgravity since spacecraft are in a state of freefall. microbiology and radiation levels of the spacecraft
Objects retain their mass, but have no weight. environment are regularly monitored. Noise levels on the
Space radiation poses a serious threat to astronaut health international space station are 75 dB mainly generated by the
since there is little protection from Earth’s atmosphere or environmental control system, avionics and experiments.
magnetic field. Three main sources of space radiation exist: This may affect hearing, concentration and sleep.
galactic cosmic radiation (very high energy electrons, pro- Toxic chemical exposure is a potential hazard. Chemicals,
tons and heavy atom nuclei), solar radiation (mainly x-rays such as freon, from cooling loops are toxic in small quantities
and high energy electrons and protons) and trapped radia- if the leak enters the spacecraft, the airlock or crystallizes
tion in the van Allen belts (energetic protons and electrons). on extra-vehicular activity (EVA) suits. Chemicals used for
Solar particle storms generate potentially lethal fluxes of orientation control systems, such as hydrazine and nitrogen
radiation approximately every 11 years, so future explo- tetroxide, can immediately irritate the respiratory tract and
ration class spacecraft will require a ‘storm shelter’ to protect eyes or be absorbed through the skin. More long-term effects
crews. Spacecraft may not protect the crew from back- include kidney failure, hepatic failure and respiratory arrest.
ground cosmic radiation, which has the highest energy and Analysis of the space shuttle atmosphere detected
so is the most penetrating and potentially damaging. When benzene, acetaldehyde and dimethyl sulphides162 at levels
solar activity is at a minimum, astronauts are exposed to a below the maximum allowable concentration limits.
dose equivalent of 0.78 mSv/day on the international space Dichloromethane and formaldehyde have also been
station (ISS).157 Career limits for low-Earth orbit astronauts detected and are potentially toxic.163 Toxic contamination
are 1500 mSV for males and 900 mSv for females aged 45. of the spacecraft occurred in 1975 when nitrogen tetroxide
Annual limits for astronauts en route to Mars are yet to be was released into the Apollo craft as it undocked from
determined, but astronauts are likely to be exposed to Soyuz. Three astronauts developed pneumonitis as a
several sieverts during a three-year Mars mission.158 result; one lost consciousness briefly as they were putting
Effects of radiation on the body are covered in Chapter on the oxygen masks.164
53, Ionizing radiations. Chronic effects relevant to space Damage to the spacecraft’s protective shell could lead to
are the increased risk of carcinogenesis, CNS damage and decompression sickness. Astronauts had a ‘near miss’ in 1997
cataract formation.159 Acute radiation sickness (ARS) from when the unmanned Progress module collided with and
solar particle events would cause nausea, gastrointestinal punctured the Spektr module of the MIR space station caus-
upset, pancytopenia, seizures and even death. Drugs, such ing it to lose pressure. Fire in a spacecraft is even more dan-
as amifostine, may be used to scavenge radiation-induced gerous than on Earth since it behaves differently and more
free radicals and protect tissues from ionizing radiation unpredictably. Oxygen canisters caught fire on MIR releasing
damage.160 smoke and particles (Ewald, personal communication).
Space physiology and pathophysiology 609
including decreased central blood volume, decreased Several countermeasures have been tried, but none
inability to increase peripheral vascular resistance, cardiac found to be completely effective. Bisphosphonates, resis-
atrophy, baroreflex dysfunction and increased venous com- tive exercise and artificial gravity may work synergistically
pliance. Left ventricular mass falls by an average of 14 per to combat osteoporosis.191
cent after just ten days in space.178 Stroke volume falls
significantly post-flight.179 As a result, VO2max measured in
astronauts in space for 9 and 14 days decreases by an aver- Renal/urinary
age of 22 per cent post-flight.180 This means that astronauts’
endurance is reduced in flight, which may be of particular Urinary calcium and phosphate levels increase as a result of
importance during an EVA. the decreased BMD.192 This increases the risk of renal calculi
Several countermeasures are used to counteract the which are expected in 0–5 per cent of astronauts. Other rea-
cardiovascular deconditioning seen in astronauts, none sons for the increased risk of renal stones are decreased urine
with complete success. These include fluid loading before output, dehydration, decreased urine pH, magnesium and
re-entry, medication (e.g. midodrine181), anti-G suits citrate. These factors increase urinary super-saturation of
inflated to 1 psi during re-entry, exercise and lower body renal stone-forming salts. Hypercalciuria may affect sodium
negative pressure. Astronauts may re-enter the atmosphere and water balance. There was one incidence of calculi in
in the recumbent position to try to minimize the Gz load flight which would have caused early evacuation of the astro-
on re-entry. It is uncertain how a reduced gravitational naut, but the stone was passed spontaneously. Eleven US
field, such as occurs on Mars (0.38 G) and the moon astronauts have had 14 calculi after flights of over a fortnight.
(0.18 G) will affect the incidence of OI. There have been four cases of urinary retention requiring
Whether exposure to microgravity increases the risk of catheterization on the Shuttle. Ten per cent of astronauts fly-
cardiac arrhythmias or not is still disputed. The QT inter- ing on the Shuttle between 1981 and 1998 (89 missions, 438
val is increased in space182 and an episode of asymptomatic males, 69 females) suffered from genito-urinary symptoms
ventricular tachycardia has been recorded,183 the signifi- during flight. Good hydration and potassium citrate may be
cance of which has yet to be ascertained. Although debated, a useful countermeasure to this problem.191
the NASA Bioastronautics Roadmap recognizes arrhyth-
mia as a potential risk during spaceflight.184
Immunology
mission and coping strategies for being in such a remote Not every mission flies a medical doctor, but each
environment are required. The unique dynamics of mixed mission has a designated medical officer. Crew medical
sex, race and multicultural groups are important. Behav- officers (CMO) receive at most 40–60 hours of training.
ioural, cultural and social differences are all important. They refresh their training using one hour of computer
Problems which have occurred during spaceflight to date training per month. Non-CMO crew receive 17 hours of
include stress, anxiety, altered concentration, depressed medical training. In close Earth orbit, astronauts can take
mood, malaise and fatigue. Sleep disturbance is common: on guidance from flight surgeons in Mission Control.
average, astronauts get six hours sleep a night.200 The poten- However, signals take approximately 20 minutes to travel
tial for dysfunctional relationships between crew members to Mars and back, so exploration-class crews will need to
and ground staff is possible. Careful crew testing, selection become more medically autonomous.
and training may decrease the likelihood of this occurring. Equipment is limited because it costs €20 000
(US$28 000) to launch 1 kg into space. Storage space and
power are restricted.161 However, medical capabilities are
ASTRONAUT SELECTION similar to those available on board a submarine or Antarctic
mission. Capabilities for basic first aid, treating minor med-
Selecting healthy astronauts aims to minimize medical and ical problems, performing a physical examination, wound
behavioural problems in space. Physical requirements dif- closure, inject medications, minor dentistry, advanced life
fer depending on whether the astronauts are to become support (drugs and defibrillator with pacing capabilities),
pilots, commanders, mission specialists or payload special- maintaining an airway, ventilation and patient monitoring
ists. Pilots and mission specialists must pass a NASA class I are present. Monitoring includes electrocardiogram, blood
or II space physical, respectively (similar to a military or pressure, PETCO2, pulse oximetry (Christgen, personal
civilian class I or II flight medicals). Selection criteria for communication).
astronauts and cosmonauts differ. Commercial spaceflight Administration of intravenous fluids requires a pump
participants (‘space tourists’) have a different set of selec- due to bubbles forming in intravenous bags in microgravity.
tion criteria, likely to be less stringent than typical current The problem of inadequate supplies of intravenous fluids
astronaut selection. Psychological testing is as important as for treatment of haemorrhage, for example, may be solved
fitness testing. Future crews will need to be cross-trained by onboard production of sterile intravenous fluids using
and multi-skilled, perhaps in several specialities, e.g. doctor reverse osmosis and other ultrafiltration methods (Scarpa,
and geologist (Cockrell, personal communication). personal communication). Hypotension in such a situation
could be exacerbated by pre-existing low blood volume and
increased gravitational forces during emergency re-entry
MEDICAL EMERGENCIES IN SPACE (e.g. 8 G during an emergency Soyuz trajectory).
the shoulder has been performed successfully on the interna- The best way of securing an airway is likely to be
tional space station.211 These images can be relayed to physi- the laryngeal mask airway (LMA). Intubating LMA and
cians back on Earth for interpretation, although transmission endotracheal tubes are flown (Christgen and Williams,
delays require acute medical problems on an exploration personal communications). Tracheal intubation may be
mission be diagnosed initially by a well-trained, on-board difficult because of facial oedema and the need to tether
clinician. On-board computer training may help astronauts both the patient and the intubator. Gastric motility is
retain and improve their diagnostic skills.207 decreased in microgravity so the risk of aspiration during
general anaesthesia increases.
Anaesthesia could be altered on return from micro-
Surgery in space gravity. Two rhesus monkeys who flew 14 days in space on
the Bion 11 mission experienced significant complications,
It has been predicted that one medical event requiring one dying, after anaesthesia to obtain biopsies.
anaesthesia and/or surgery will occur every three to four
years of spaceflight.212 As missions increase in length and
leave Earth’s orbit, space crews will require the capability Adult life support
to perform surgery on board the spacecraft since return to
Earth may not be possible or timely. Alternative approaches Should chest compressions be required in microgravity,
to surgical conditions may be required. For example, non- a modified technique will be required to maintain
operative treatment of appendicitis has been shown to be contact between the patient and provider.204 Studies on
effective in remote environments213 as has prophylactic mannikins and pigs during microgravity on parabolic flights
appendicectomy. Protection of the surgical field from the have demonstrated that successful chest compressions
surrounding air will be needed in microgravity. There are
more antibiotic-resistant bacteria in space, so sterile tech-
niques are paramount.
Surgery in a microgravity environment has been shown
to be possible, although conditions are clearly different.
The surgeon’s tactile sensation and proprioception are
altered.214 Laparotomies on rabbits were carried out by
Russian research teams on board parabolic flights in the
1960s.215 Rats have been operated on in a neutral buoyancy
tank, during which a variety of surgical techniques were
practised, including nephrectomy, small bowel resection
and splenectomy.214 Tissue planes separate more easily and
comments have been made on improved visualization dur-
ing laparotomy (Campbell M, personal communication).
Bleeding behaves differently in microgravity. Arterial bleed-
ing forms droplets and streamers, while venous bleeding
stays close to the wound because of surface tension.214
Surgical instruments float and so attachment aids (e.g.
Velcro, magnets) are necessary for safety and ease of use.
Anaesthesia in space
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620 Flying and spaceflight
216. Jay GD, Lee P, Goldsmith H et al. CPR effectiveness in FURTHER READING
microgravity; comparison of three positions and a
mechanical device. Aviation, Space, and Environmental Committee on Creating a Vision for Space Medicine During Travel
Medicine. 2003; 74: 1183–9. Beyond Earth Orbit. Ball JR, Evans CH (eds). Safe passage:
217. Dalmarco G, Calder A, Falcao F et al. Evaluation of external Astronaut care for exploration missions. Washington DC:
cardiac massage performance during hypogravity National Academies Press, 2001.
simulation. Engineering in Medicine and Biology. 2006; Clement G. Fundamentals of space medicine. Dordrecht: Kluwer
(Suppl.): 2904–7. Academic, 2003.
218. Jennings RT, Murphy DMF, Ware DL et al. Medical Harding RM. Survival in space. London: Routledge, 1989.
qualifications of a commercial spaceflight participant: Not Nicogossian AE, Huntoon CL, Pool SL (eds). Space physiology and
your average astronaut. Aviation, Space, and Environmental medicine, 2nd edn. Philadelphia: Lea & Febiger, 1989.
Medicine. 2006; 77: 475–84. Rainford DJ, Gradwell DP (eds). Ernsting’s Aviation medicine, 4th
219. Aerospace Medical Association Task Force on Space edn. London: Hodder Arnold, 2006.
Travel. Medical guidelines for space passengers. Rayman RB, Hastings JD, Kruyer WB et al. Clinical aviation medicine,
Aviation, Space, and Environmental Medicine. 2001; 72: 4th edn. New York: Professional Publishing Group, 2006.
948–50.
SECTION FIVE
Radiation
the orbits. So, an undisturbed atom is electrically neutral. interact with tissues and cells, energy is deposited within
The number of protons defines the atomic number of the the tissue.
element. The mass of the atom is determined by the num- The different radiations penetrate matter in different
ber of protons and neutrons and the total number is called ways, the properties being determined by the size, charge
the mass number. The same element can have different and energy of each type; α-particles are stopped by a thin
numbers of neutrons and consequently different mass piece of paper or the dead layer of the skin, while β-particles
numbers. These variants of the elements are known as iso- can penetrate the hand but will be stopped by a thin sheet of
topes. Some of these isotopes are unstable and eventually aluminium; x- and γ-rays penetrate the body and an alu-
transform into atoms of another element with the simulta- minium sheet, but are stopped by lead. Neutrons penetrate
neous emission of alpha (α)- or beta (β)-particles and most materials, but may be stopped by thick polythene or
accompanied usually by gamma (γ)-rays. This property of concrete (hydrogenous materials); high energy neutrons
the unstable atom is called radioactivity; the change itself is have a high penetrance in tissue but low energy neutrons
called radioactive decay and the unstable atom is said to be can be absorbed in the body because of the body’s high
a radionuclide. The time necessary to reach a stable form water content (see Table 53.1). These overall properties of
depends on the particular isotope and may take a few frac- radiation affect the degree of cellular damage following
tions of a second to several thousand years. The time for exposure and the methods needed for protection.
the activity to decay by one-half is termed the half-life In general α-particles do not constitute a significant
(t1/2). For example, sodium-23 (23Na) is the stable form hazard as an external source, but are hazardous when taken
of sodium and 24Na is a radioactive isotope with a t1/2 of into the body. When incorporated, they can irradiate adja-
15 hours. The latter decays emitting a β-particle to become cent cells in, for example, the liver. Neutrons, because of
24
Mg, a stable isotope of magnesium. This activity is meas- their absence of electrical charge, produce ionization indi-
ured by the numbers of disintegrations per unit time. The rectly and tend to be more penetrating. Ionizing radiations
unit by which radioactivity is measured is the becquerel have sufficient energy to break chemical bonds and ionize
(Bq) and 1 Bq equals one atomic disintegration per second; atoms and molecules, producing an ion pair. These ions
60 Bq is the average amount of natural potassium-40 (40K) are charged and capable of causing further ionization and
in every kilogram of the average person. This means that energy deposition leading to physicochemical changes in
about 15 million 40K atoms disintegrate inside a person cellular constituents.
each hour.
DOSE QUANTITIES
What are ionizing radiations?
Some of these changes may be of no biological conse-
Ionizing radiation may be higher energy electromagnetic quence and others may be repaired, but there is a finite
radiations (x-rays and γ-rays) or energetic subatomic par- probability that damage may cause cell death or irreparable
ticles such as α- and β-particles and neutrons. According damage to vital cell constituents. The absorbed dose is a
to their energy, x-rays and γ-rays interact with matter and measure of the mean energy absorbed by unit mass of
tissue and although the mechanisms may be different, they tissue, and the absorbed dose in grays (Gy) is equal to the
all produce positively and/or negatively charged ions, deposition of one joule (J) of energy in 1 kilogram (kg) of
which then interact with the absorbing matter to produce tissue. Overall, the greater the dose, the greater the likeli-
physicochemical changes by adding or subtracting elec- hood of a biological effect being seen. Energy is deposited
trons. The energy of these electromagnetic radiations will along the path of ionizing radiation as it traverses tissues in
also determine their penetration, higher energy photons the form of ionizations. The average deposition of energy
penetrating further than low energy ones. When they do per unit length is called the linear energy transfer (LET).
Health effects of ionizing radiation 625
Charged particles tend to have higher LET values individual doses on dosemeters (generally called film
than x- or γ-rays. The International Commission on badges). Measurements made with such dosemeters can be
Radiological Protection (ICRP) has introduced a weighting interpreted to represent the energy deposited in the body or
factor related to LET to take into account these differences.5 in a particular part of the body by the radiation concerned.
These radiation weighting factors (wR) may range from
1 to 20 for different radiations. Thus photons, such as
x- or γ-rays, are assigned a wR of 1 (low LET) and α-particles Biological
20 (high LET). Tissues are also assigned weighting factors
(wT) to differentiate the wide variation in tissue sensitivity When a radionuclide is deposited in an internal organ, for
to radiation, the lymphopoietic stem cells and gonadal instance via ingestion or inhalation, doses are generally cal-
germ cell cells being the most sensitive and bone being rela- culated, because the activities are too small to be measured.
tively insensitive. These radiation and tissue weighting The dose (or activity) can be assessed or measured by tak-
factors are used to convert the absorbed dose in grays to an ing urine or blood samples and applying biokinetic models
effective dose in sieverts (Sv). This system allows external or be measured directly by special detection systems, e.g.
and internal exposures to be combined into one dose – on whole body monitors. These systems are only available at
the basis of equality of risk. Once a radionuclide is incorpo- special sites in the United Kingdom, such as British
rated, it will continue to expose surrounding tissues until Nuclear Fuels, the Atomic Weapons Establishment, the
final decay or it is excreted. It is usual to calculate this com- Health Protection Agency, Sellafield Ltd or Harwell.
mitted effective dose following the ingestion or inhalation In an accident situation, estimating the whole body
so that extra care can be taken to reduce future external dose by changes in circulating absolute lymphocyte counts
exposures. in the first 48 hours is possible and by cytogenetic assays
Submultiples of the sievert are commonly used, such for chromosome aberrations in cultured lymphocytes.
as the millisievert (mSv), which is one-thousandth of a These techniques use either dicentric counting or more
sievert; for example, the world average individual dose recently fluorescence in situ hybridization (FISH) painting
received due to exposure to natural background radiation of chromosomes and measuring the translocation of
is about 2.4 mSv per year compared with the occupational genetic material. The threshold for whole body dose-
dose limit of 20 mSv average per year over defined periods validated chromosomal changes is around 1–200 mSv.
of five years.5 It is sometimes useful to have a measure of More recently, electron paramagnetic spin resonance tech-
the total dose to groups of people or a population. The niques have been developed using teeth or, in the case of
quantity used to express this total is the collective effective cadavers, bone, which permits a retrospective assessment
dose: it is obtained by summing the product of all the doses of the dose. The accurate range for this technique is from
in a group and the number of people in the group and is around 100 mGy to lethal doses. Another technique using
usually expressed in person-sieverts. Throughout this post-subcapsular lens opacities also offers a possible way
chapter, these various dose quantities will be referred to as to assess historic doses; however, its accuracy is not yet
dose, except where further clarification is required. proven.
Radiation of natural origin pervades the whole environ- Any organ or tissue may be affected, the degree varying
ment. Cosmic rays reach the earth from outer space, the with the dose and the radiosensitivity of the given organ or
earth itself is radioactive, and natural activity is present in tissue. Distinguishing two types of effects is possible,
our diet and in the air. Everybody is exposed to natural somatic and hereditary. The somatic effects relate to the
radiation to a greater or lesser extent, and for most people individual who is exposed, and may be early or late, and in
it is the major source of exposure.6 the embryo or fetus may be teratogenic. The hereditary
effects would occur in the offspring, through genetic dam-
age to germ cells of the exposed individual.
DETECTION OF RADIATION
5 Gy, after homogeneous exposure. The slope of the organ irradiated and the dose. An acute exposure of both
dose–response curve is relatively steep, expressing a rapidly lungs shows a threshold at about 6–7 Gy, with an ED50 at
increasing probability of death for small increments of about 9 Gy.8
dose without medical treatment.
Thyroid
Gastrointestinal tract The adult thyroid is not especially sensitive to radiation;
There is considerable variation in response as the different however, it should always be considered if iodine isotopes
parts of the gastrointestinal tract have markedly different are inhaled or ingested by some employees as it accumu-
radiosensitivity. The oesophagus and rectum are relatively lates rapidly in the gland. The radiation-induced diseases
radioresistant, while the stomach and small intestine are include acute radiation thyroiditis and hypothyroidism.
much more sensitive.14 The small intestine is the most sen- Total ablation of the thyroid requires high doses, about
sitive because of the rapidly proliferating mucosal cells of 1000 Gy delivered within a short period (two weeks).8
the mucosal epithelium in the crypts of Lieberkühn.15 Hypothyroidism is produced by much lower doses, with
Single acute doses to the abdomen of around 6–16 Gy pro- 50 per cent incidence at about 60 Gy for acute external
duces early onset of nausea, vomiting and diarrhoea, the exposure and 300 Gy for prolonged internal exposure. The
symptoms occurring earlier and being prolonged broadly childhood thyroid is more sensitive to radiation (see under
in proportion to the dose. These symptoms are thought to Carcinogenesis, p. 629).
be caused by the release of 5-hydroxytryptamine (5-HT)
into the bloodstream which stimulates the nausea/vomit- Skin
ing centres in the brain and other 5-HT receptors.16 There The skin is a relatively radioresistant organ, but is likely
is a concomitant increase in bowel motility which may be to be exposed in any type of accident. Skin responses
caused by bile salts and other substances acting on the depend upon various factors, such as size of the irradiated
damaged mucosa. Very few human data are available on area, depth distribution of dose, duration of exposure and
this gastrointestinal syndrome. It is known, however, that dose rate.18 Radiation damage to the skin may be observed
cancer patients given whole body doses of 10 Gy or more as erythema, moist desquamation and necrosis, with
(generally as a single dose delivered in about four hours, thresholds of 2, 12–20 and 18 Gy, respectively.18 Moist
in conjunction with bone marrow transplantation) have desquamation often results in chronic changes, with
survived the gastrointestinal syndrome.17 Data obtained hyperkeratosis and telangiectasia of the capillaries and of
from studies in which x-rays were used to irradiate acutely superficial and deep blood vessels. The chronic phase may
the gastrointestinal tract of rats indicate an LD50 of about lead to ulceration, atrophy and necrosis.
15 Gy, an LD10 of 10 Gy and an LD90 of 20 Gy. Protraction of exposures for 1–14 days will increase the
For gastrointestinal symptoms, the following figures threshold and ED50 values by a factor of about two com-
are given as guidelines for adults; anorexia may be seen in pared with acute exposure.8 As radiation burns involving
5 per cent of those at 0.4 Gy and 95 per cent at 3 Gy, nausea large areas can precipitate the same systemic effects as
in 5 per cent at 0.5 Gy and 95 per cent at 4.5 Gy, vomiting thermal injury, overall management may be complicated
in 5 per cent at 0.6 Gy and 100 per cent at 7 Gy, and diar- especially where other body systems have been affected,
rhoea in 5 per cent at 1 Gy and over 20 per cent at 8 Gy. If e.g. bone marrow.
the time from exposure to onset of any of the above symp-
toms is less than one hour, the whole body dose is likely to Eye
be 3 Gy, if more than three hours 1 Gy and if they last Experience has shown that radiation doses received by the
for more than 24 hours, the dose is likely to be 6 Gy. The lens may result in lenticular opacities or cataracts. There is
onset of symptoms within 30 minutes indicates an abdom- currently a debate as to whether these changes are deter-
inal dose 3 Gy. These signs and symptoms are sometimes ministic or stochastic. The eye may be exposed either after
referred to as the acute radiation syndrome. local irradiation – acute or protracted – or after whole
body irradiation. The threshold level for detectable opacity
Lung is estimated to be less than 0.5 Gy.19 Protraction does not
The lung can be exposed to external radiation from a beam increase the threshold so much as for some other organs.
or internal radiation after inhalation of radioactive materi- The cataract does not appear early after exposure; the
als. Radiation pneumonitis appears some weeks or months latent period varies from six months to 35 years, with an
after exposure. It is a complex phenomenon, including average of three years.
oedema, cell death, cell desquamation, fibrin exudate in
the alveoli, fibrous thickening of alveolar septa and prolif- Gonads
erative changes in the blood vessels. The main effect is The germ cells of the reproductive system are highly
interstitial pneumonitis, followed by pulmonary fibrosis, radiosensitive. The threshold dose for transient sterility
resulting principally from the damage and response of the lasting for several weeks averages 0.15 Gy for men and
fine vasculature and the connective tissues. Development about five to ten times higher for women.8 Recovery time
of the lesions is highly influenced by the volume of the in men is dose dependent and may take many years. Doses
628 Ionizing radiations
of 2.5–6 Gy or more are required for permanent sterility in Effects of acute whole body radiation exposure
both men and women. The effects which are likely to be seen following a
Embryo and fetus homogenous whole body irradiation over a short period
(minutes or hours) are shown in Table 53.3. Experience
The embryo and fetus should also be considered, as from several accidents has shown that most casualties
women in the workforce may become pregnant. The have only part of their bodies exposed to the radiation.
developmental effects of radiation in the embryo and The non-uniform and heterogeneous nature of the expo-
fetus are strongly related to the gestational age at which sure leads to variable signs and symptoms and the out-
the exposure occurs, i.e. whether it occurs during organo- comes are different. Some high localized doses do not
genesis.20 The most serious health consequences of present with the classical prodromal signs of nausea and
prenatal exposure are embryonic death, gross congenital vomiting. This complicates the initial triage and subse-
malformation, growth retardation or severe mental retar- quent therapy. For example, in patients with severe but
dation. For exposures at high dose rates, severe mental partial bone marrow irradiation residual stem cells in
retardation has been shown for exposure occurring during unaffected bone marrow can reject bone marrow grafts
the 8th–15th week and to a lesser degree during the causing host-versus-graft disease. This was one of the
16th–25th week after conception. The threshold dose is prime reasons why most of the transplantations at
estimated to be around 0.4 Gy between the 8th and Chernobyl were unsuccessful.4
15th week and 0.1–0.2 Gy between the 16th and 25th,
respectively.21 Effects of whole body chronic radiation exposure
In a chronic exposure (measured in days, weeks, months),
Central nervous system the symptoms are usually more subtle. The usual feature is
The acute central nervous system effects are generally of general malaise, with influenza-type symptoms, fever
reached only when the whole body radiation dose exceeds and or diarrhoea and vomiting. Several cases have arisen
about 50 Gy. The survival time is usually less than 48 where people have been exposed chronically to an indus-
hours.8,22 Death is believed to be a function of several trial or a medical therapy radiation source, sometimes dis-
causes, including vascular damage, meningitis, myelitis carded or procured illegally. In one case (unpublished),
and encephalitis. Fluid also infiltrates the brain causing where a radiation source had been taken into a house, it
marked oedema. However, any person who exhibits even was only after an elderly member of the household died
mild symptoms of central nervous system syndrome would and others started to suffer from general malaise that radi-
inevitably die from gastrointestinal or haematopoietic ation exposure was suspected. It has been reported that
damage. chronic radiation exposures have been implicated in life
Table 53.3 Expected signs and symptoms following whole body irradiation.
Dose Signs/symptoms
shortening, accelerated ageing and premature atheroscle- from those occurring ‘spontaneously’ or from other causes.
rosis, but the evidence was inconclusive, when the data Since the probability of cancer resulting from the radiation
were critically reviewed by UNSCEAR in 2006. They con- is related to dose, this type of effect of radiation can only be
cluded that while there was an increase in circulatory dis- detected by statistical means in epidemiological studies car-
eases at doses in excess of several grays, the evidence for an ried out on exposed population groups. If the number of
association in the range of 1–2 Gy comes only from the people in an irradiated group and the doses that they have
atomic bomb survivors and that at lower doses there was received is known, and if the number of cancers eventually
not sufficient evidence to establish a causal relatonship. observed in the group exceeds the number that could be
For other non-cancer diseases, there was even less evidence expected in an otherwise similar but non-irradiated group,
of a radiation dose–response relationship.23 Chronic the excess number of cancers may be attributed to radia-
fatigue has also been reported in other accidents and is a tion, and the risk of cancer per unit dose may be calculated,
characteristic seen in patients who have undergone radio- i.e. the risk factor. The probability of causation can be
therapy.24 Some researchers consider that a chronic radia- ascribed based on radioepidemiological tables (see below).
tion syndrome exists; however, the signs and symptoms are A major source of information on the risk of radiation-
non-specific and do not present as a defined syndrome. In induced cancer following whole body irradiation is the
many places where these complaints have been reported, follow-up studies of the survivors of the atomic bombing
other environmental hazards exist, such as extensive envi- in Hiroshima and Nagasaki in Japan in 1945.26,27 Data have
ronmental heavy metal contamination. also been obtained for a number of tissues from other
exposed human population groups, for example, tubercu-
Effects of partial body exposure to radiation
losis patients who had high x-ray doses during treat-
In almost all partial body exposures, whether acute or ments,28–32 and from people exposed to nuclear weapons
chronic, the skin will be affected. Table 53.4 shows the fallout in the Marshall Islands.33 Risk estimates have also
severity of skin damage with increasing dose. The effects been developed for cancers of some individual organs,
would only be seen in accident situations or where flagrant based on information on the effects of incorporated
breaches of safety practices have occurred.25 Depending on radionuclides, in miners exposed to radon and its decay
the type of exposure, deeper tissues may also be affected. products,34 from employees exposed to radium in the
Incidents where small sources have been carried in shirt luminizing industry,35 and from patients given the x-ray
pockets for short periods have given rise to exceptional contrast medium thorotrast (thorium oxide).36 Some of
doses (measured in hundreds of Gy) leading to serious the available epidemiological data of second cancers, for
necrotic lesions of the chest wall. example of the breast, in patients who have been irradiated
for Hodgkin’s disease37 are far from ideal for calculating
STOCHASTIC EFFECTS risk estimates because of the confounding influence of var-
ious chemotherapy and radiotherapy regimes. A further
Carcinogenesis example is the significant increase in childhood thyroid
Following irradiation, a viable but modified somatic cell cancer in Belarus, the Ukraine and the Russian Federation
may retain its mitotic capacity and may result, after a pro- following the inhalation and ingestion of radio-iodines
longed and variable period, in the development of a malig- after the Chernobyl accident. It has proved difficult to
nancy. The cancers induced by radiation, with or without reconstruct the thyroid doses and so the risk estimates are
the contributions of other agents, are indistinguishable not yet robust. Furthermore, the accuracy of the dosimetry
involved in many of the large epidemiological studies is
also a potential source of error and needs careful evalua-
Table 53.4 Effects of radiation on the skin.
tion. Recent risk estimates are based largely on the
Skin dose Signs Japanese bomb survivor data,26 and one drawback to the
use of these data for risk estimates at low dose and dose
rates, is the contribution from neutron exposure, although
0–100 mGy Nil
this forms only a small part of the total exposure. Estimates
100–400 mGy Nil expected
of the dose were revised in 200238 which has led to a revi-
400 mGy–4 Gy Transient erythema expected within
sion downwards of about 8 per cent in the risk estimates.
3 days of exposure
Information of this nature has been reviewed in BEIR
4–8 Gy As above followed by fixed erythema after
VII,39 in ICRP 1035 and in the 2006 report of UNSCEAR.40
variable latent period
These reports assess the risks of radiation-induced cancer,
Temporary hair loss
based predominantly on data on the Life Span Study (LSS)
8–15 Gy Prompt erythema followed by vesiculation
of the atomic bomb survivors. Recent risk assessments have
Permanent hair loss
used data on cancer incidence in the A-bomb survivors,27
15 Gy Severe vesiculation, tissue slough
as well as data on mortality in this population.26 Where risk
Very slow to heal
factors are not available from the LSS, they have been
Possible site of malignant change
developed from the many other epidemiological studies.
630 Ionizing radiations
The risks have increased partly as a result of new estimates doubling of the risk, relative to that in the absence of expo-
of tissue doses received by the Japanese population, sure. This gives a probability of causation of
because more cancers have appeared in the longer period of
follow up to 1990, and because different models have been PC 1/(1 1) 0.5
used to predict the risk over a lifetime. However, there is
uncertainty in how many cancers will arise in the future as i.e. a 50 per cent chance that the cancer was induced by
almost half of the Japanese cohort were still alive in 1997. radiation. The ERR can depend on a number of factors.
The research on the atomic bomb survivors in Japan has Among them, the size of the radiation dose is very impor-
shown that leukaemia appears first after whole body irradi- tant. Generally, the ERR varies in direct proportion to the
ation, with a latent period of two years and peaks at six to dose, although in some circumstances the trend in risk
seven years. Solid tumours generally begin to appear after with dose is more complex. For example, data on the
about ten years and their incidence continues to increase Japanese survivors indicate that the risk of leukaemia
for several decades. No threshold is detectable and statisti- varies not as a simple linear function of dose, but according
cally significant increased risks exist at doses down to to both linear and quadratic functions of dose. As well as
150 mSv.26 This is important for setting acceptable occupa- dose, ERR can be affected by factors such as sex, the age at
tional dose limits (see under Occupational doses, p. 632). which the exposure occurred, and the time between expo-
However, as discussed earlier, the cancer risks derived sure and the development of the disease. For example, for
from such exposed groups are influenced largely by expo- leukaemia and for many solid cancers, data from the
sures to high doses, which were delivered over a short Japanese survivors and other studies indicate that the ERR
period of time. In practice, most people are exposed occu- is greater for exposure in childhood than in adulthood.
pationally to low doses of radiation received over relatively Also, the ERR for leukaemia tends to be higher soon after
long periods. On the basis of available information, there- exposure than at later times whereas – at least for expo-
fore, UNSCEAR6 and ICRP5 have assessed that the risk fac- sures in adulthood – the ERR of solid cancers is fairly stable
tors obtained directly from observations at high doses and over time. The degree to which the dose was protracted
high-dose rates should be reduced by at least a factor of may also need to be taken in calculating the ERR, since var-
two to give more realistic risk factors for low doses and ious animal studies have suggested that, for a given total
dose rates. The risk factor or lifetime fatality probability dose, radiation risks may be higher if received acutely
coefficient from ICRP for a reference population of both rather than over a prolonged period.
sexes and of working age is 4.1 102/Sv for the sum of all For a given exposure scenario, i.e. the size of the dose,
fatal malignancies, i.e. a dose of 1 Sv in a working lifetime the sex of the person exposed, the age of exposure, the time
results in a 4 per cent chance of a fatal cancer occurring.5 between exposure and the onset of disease, the degree of
More recent epidemiological studies involving lower dose dose protraction, it is therefore possible using models such
exposures from the UK National Registry for Radiation as those developed by the US BEIR VII Committee39 to
Workers have shown that the leukaemia incidence trend derive an estimate of the ERR. This can then be used, via
with dose is consistent with the ICRP risk estimates.41 the approach described above to estimate the PC.
However, in instances where the dose is not known or
Probability of causation where there are differing views about its magnitude, the
The concept of the probability of causation (PC) has been calculation can be reversed to obtain the dose required
developed to answer the question: if a person has been to produce a given value for PC. For example, it was
exposed to ionizing radiation and subsequently develops a explained earlier than a 50 per cent probability of causa-
cancer, what is the probability that the cancer was due to tion (i.e. a PC of 0.5) corresponds to an ERR of 1. For a
the earlier exposure? The US National Institutes of Health42 given person and a likely time of exposure, it is then possi-
used data on the Japanese atomic bomb survivors to com- ble using a standard risk model to derive an estimate of the
pile tables on the probability of causation relating an indi- dose required to give such an ERR. This approach could be
vidual’s cancer to a prior radiation dose. This topic has also used to calculate the doses required to attain various values
been reviewed by the International Atomic Energy Agency for the PC in individual employees who have cancer.
(IAEA).43 In essence, the probability that a radiation dose In the United Kingdom, the nuclear industry has set up
to an organ of a person’s body leads to the subsequent a no-fault compensation scheme based on PC calculations,
development of cancer can generally be calculated as: to avoid unnecessary litigation and allow the current scien-
tific risk factors to be used in a generous manner for those
ERR claiming a radiation-induced cancer.
PC
(1 ERR)
Hereditary effects
where ERR is the excess relative risk associated with the
exposure, i.e. ERR is the relative increase in risk, with the The other main late effect of radiation is the concept of
value 1 subtracted. For example, an ERR of 1 represents a hereditary damage and arises through irradiation of the
Health effects of ionizing radiation 631
germ cells. Ionizing radiation induces mutations which are FACTORS INFLUENCING RADIOSENSITIVITY AND
frequently harmful in the germ cells or their precursors. MODIFICATION OF EFFECTS OF EXPOSURE
The hereditary diseases that mutations may cause range
from afflictions, such as colour blindness or minor disor- Susceptibility to the carcinogenic effects of radiation is
ders of metabolism (e.g. disorders of amino acid metabo- summarized in BEIR VII,39 and can be affected by a num-
lism) to serious defects which may cause early death or ber of factors, such as genetic constitution, sex, age, physi-
severe mental retardation (e.g. Down’s syndrome). ological state, smoking habits, drugs and various other
The study of genetic or hereditary effects caused by physical and chemical agents. The genetic basis of some
radiation is even more difficult than the study of cancer. diseases including increased cancer susceptibility is
However, no conclusive evidence for hereditary effects becoming clearer. For example, it has been shown that the
attributable to exposure to radiation has been found in full expression of ataxia telangiectasia, including enhanced
human offspring.6,44 Genetic and cytogenetic studies of the cancer susceptibility, results from homozygous mutated
progeny born to the atomic bomb survivors in Japan have genes on chromosome. In addition, the heterozygous car-
so far yielded no evidence of a statistically significant riers, who do not express the full-blown disease, are known
increase in severe hereditary defects.45 Extensive studies to be subject to a higher cancer incidence, especially for
made on experimental animals provide some information breast cancer. This mutation is thought to act through
of the frequency with which genetic effects, including inactivation of repair mechanisms.50,51 The mechanisms
chromosome aberrations (numerical or structural) and through which these factors influence the radiosensitivity
mutations of genes (dominant and recessive), can be are, however, not fully understood. They depend on the
expected to occur. The research so far suggests that the particular type of cancer, the tissue at risk and the specific
doubling dose for all genetic effects is around 1–1.5 Gy.46 modifying factor under consideration.
ICRP estimates that for exposures at low dose rates, the Cancer rates are highly age dependent and, in general,
radiation detriment due to hereditary effects is a few per increase exponentially in older age groups. The expression
cent of the corresponding detriment for cancer.5 of radiogenic cancers varies with age in a similar way, so
Follow up of the atomic bomb survivors and their off- that the age-dependent increase in the excess risk of radi-
spring has not yielded evidence for a statistically significant ogenic cancer is conventionally expressed in terms of rela-
excess of malignancy in those children conceived after tive risk; that is, the increased risk tends to be proportional
exposure;47 a study in the UK suggested a link between to the baseline risk in the same age interval. However, in
paternal occupational exposure to radiation at the some cases such as breast cancer, the change in the baseline
Sellafield nuclear reprocessing plant (West Cumbria, UK) cancer rate with age is more complicated. For lung cancer,
and the incidence of leukaemia in the offspring.48 the situation is also not simple. Smoking and prolonged
However, this finding has generally not been confirmed in exposure to inhaled α-particle emitters interact synergisti-
other studies and the UK Committee on the Medical cally and this is then said to be a multiplicative effect.
Aspects of Radiation in the Environment (COMARE) has For lung cancer and most other non-sex-specific solid
concluded that those excesses that have been reported may cancers, it is unclear how a person’s sex affects the risk of
be associated with lifestyle factors, work practices or popu- radiogenic cancer. In general, baseline rates for such cancer
lation mixing.49 in males exceed those in females, possibly because of
increased exposure to carcinogens and promoters in occu-
pational activities and lifestyle factors, such as increased
BIOLOGICAL BASIS FOR RADIATION EFFECTS smoking and consumption of alcohol. While sex-specific
It is generally accepted that for carcinogenesis, the cellular excess rates of cancer can generally be modelled adequately
DNA of the genome is the critical molecule. Damage to this as being proportional to the corresponding sex-specific
molecule leading to cancer can be mediated through direct baseline rates, in many cases an additive excess risk model
ionization by the radiation or by its indirect action in the fits the data equally, that is, the number of radiation-
formation of free radicals in the fluid in close proximity to induced cancer per unit dose is nearly the same in both
the genome. This indirect effect accounts for about two- sexes.
thirds of the biological effect in the case of low LET radia- For example, as it is known, the carcinogenic process
tion, but the direct effect predominates with high LET includes the successive stages of initiation, promotion and
radiation. Evidence is building that there are fragile sites progression. The promotion phase, appears to be particu-
unusually prone to breakage and rearrangement in DNA, larly sensitive to cigarette smoking.
which could explain particular sensitivities.
In some medical conditions, such as ataxia telangiecta- SOURCES AND MAGNITUDES OF HUMAN EXPOSURE
sia and Li-Fraumeni syndrome, there exist genetic defects
in cell repair mechanisms which produce an increase in Cosmic radiation
individual sensitivity to ionizing radiation. At high doses, Cosmic rays come mainly from our galaxy and some come
cell death will predominate leading to organ malfunction, from outside it. In addition, they may arise from the sun
whose severity is dependent on the dose. in bursts during solar flares. The numbers of cosmic rays
632 Ionizing radiations
entering the earth’s atmosphere are also affected by the Total doses
earth’s magnetic field: more enter near the poles than at The total dose from radiation of natural origin is, on aver-
the equator. As they penetrate the atmosphere, they are age, about 2.2 mSv in a year in the UK. Differences in
gradually absorbed, so that the dose decreases as altitude average doses from one locality to another may exceed
decreases. The average annual dose from cosmic rays at 10 mSv in a year, and differences in individual doses
ground level in the UK is about 0.3 mSv. The intensity of may exceed 100 mSv in a year owing to the existence of
cosmic rays for a typical flying altitude is greater than on dwellings with particularly high concentrations of radon.
the ground and also varies with latitude.
Occupational exposures
Gamma rays from the earth
Radiation is used in electricity generation (nuclear power),
All materials in the earth’s crust are radioactive. For exam- general industry (primarily for process and quality con-
ple, uranium is dispersed throughout the soil and rock at trol), and for diagnostic purposes in medicine, dentistry
various low concentrations around a few parts per million and veterinary practice. Furthermore, it is used as a
(ppm). Potassium-40 constitutes 120 ppm of the stable research tool in colleges, universities and industry. All
element, which in turn makes up 2.4 per cent by weight of these processes result in occupational exposures to ioniz-
the earth’s crust. The γ-rays are emitted by the radionu- ing radiations and in the first years of the twenty-first cen-
clides in the earth and since building materials are tury, the total numbers of people working with ionizing
extracted from the earth, they too are radioactive, and peo- radiations in the UK was about 34 000 in the nuclear power
ple are irradiated indoors as well as outdoors. Doses are industry, and about 115 000 in general industry, health,
affected by the geology of the area and the structure of the defence and research. Some employees receive increased
buildings, but the average dose from earth γ-rays in the exposure to natural sources of radiation, the most notable
United Kingdom is about 0.35 mSv in a year. being underground miners to radon and aircrew exposed
to elevated levels of cosmic rays. About 96 000 employees
Radon
are exposed to elevated levels of natural radiation.
The average annual effective dose in the UK from radon
decay products is estimated to be 1.3 mSv. There are pro- Occupational doses
nounced variations about this mean, and in some dwellings Legal controls (see under Legislation, p. 634) require that
the dose to the occupants was found to be more than the doses received by the more exposed employees are rou-
two orders of magnitude higher (range 0.1–500 mSv). The tinely assessed and records kept of their doses. These
indoor radon levels depend on the geology of the area and employees are often referred to as ‘classified’ persons.
also building structures. Poorly ventilated properties or A significant proportion of the non-classified employees
workplaces, e.g. mines, have higher levels (see Chapter 36, are also monitored, but the records for this group, who
Uranium, p. 243). Radon-affected areas have been identified generally receive low doses anyway, are less comprehen-
in Cornwall, Devon, Derbyshire, Northamptonshire and sive. Approximately every four years, the Radiation
Somerset and in parts of Scotland and Northern Ireland. Proection Division of the Health Protection Agency, UK
The UK action level for radon in homes is 200 Bq/m3. A life- (formerly the National Radiological Protection Board)
time exposure in dwellings at this level would lead to a 50 per conducts a major review of the radiation exposure of the
cent increase in fatal lung cancer. Among smokers and non- UK population, which along with public and medical
smokers combined, about 6 per cent of deaths in the UK are exposure routes, also provides comprehensive data on all
due to lung cancer. A lifetime exposure at the UK action occupational exposure. The last such review was published
level of 200 Bq/m3 would increase the risk of fatal lung can- in 2005 and related to data from 2001–2003.55 It is these
cer from 6 to 9 per cent. Many other parts of the world have data that are primarily quoted below.
higher radon levels (e.g. Finland and Germany). A number In the period, no nuclear power industry workers
of large pooled studies of residential radon exposure have received annual doses in excess of the dose limit of 20 mSv
validated the risk of residential radon.52–54 in a year. Most employees, however, received doses that are
a relatively small fraction of the limit. The average dose in
Activity in diet the nuclear power industry was 0.4 mSv and the collective
Other radionuclides from the uranium and thorium series dose was 14.6 person-Sv. The measure of the collective
are present in air, food and water, in particular lead-210 dose allows the employer and the regulators to assess
and polonium-210 which irradiate the body internally. whether the total dose for a site has remained static or been
Potassium-40 is taken into the body in the diet and is reduced and acts as a method of assessing the amount of
the major source of internal irradiation apart from sharing of dose. Doses had decreased significantly from the
radon decay products. A number of radionuclides, such as previous survey. The averages and collective doses are
carbon-14, are created in the atmosphere by cosmic rays, around a third of that in the 1990s.
and these also contribute to internal irradiation. The aver- The equipment used in general industry is normally
age annual dose from these sources of internal radiation in well shielded and doses to employees are generally very
the UK is estimated to be 0.25 mSv in a year. low. One major exception had been where radiographers
Health effects of ionizing radiation 633
Occupational doses from natural radiation sources The main principles of radiation protection are set out and
promulgated by the ICRP in Publication 103.5 They can be
The average annual dose to crew members of subsonic air- summarized as follows:
craft is currently estimated to be about 2.4 mSv. Higher
dose rates were experienced by the crews of Concorde 1. No practice involving exposure to radiation should be
(now out of service) with the result that the annual doses adopted unless it produces at least sufficient benefit to
were somewhat higher at ⬃3 mSv, at the hours typically the exposed individuals or to society to offset the
flown. The introduction to service of long-range aircraft radiation detriment it causes (termed ‘justification of a
has increased the potential for higher doses for subsonic practice’).
flight crews, with the possibility of doses up to 5–6 mSv per 2. In relation to any particular source of radiation within
year for some personnel. However, when ICRP reviewed a practice, all reasonable steps should be taken to
the most recent scientific information it came to the con- adjust the protection so as to maximize the net benefit,
clusion that the weighting factor for protons was too high economic and social factors being taken into account
and reduced this from 5 to 2. This would have the effect of (termed ‘optimization of protection’).
reducing doses by around 50 per cent, in most aviation 3. Finally, a limit should be applied to the dose (other than
circumstances.5 from medical exposures) received by any individual as
The average radon daughter concentrations in non-coal the result of all the practices to which he is exposed
mines, such as gypsum, tin and fluorspar mines, were gen- (termed ‘application of individual dose limits’).
erally high in the past. However, the size of the industry has
dramatically reduced to under 6000 and the types of mines In simple terms, this framework is derived from three prin-
have changed leading to an average dose of about 0.7 mSv, ciples that apply to many human activities, and especially
a seven-fold decrease from the previous survey. to medicine:
In some parts of the UK, radon concentrations in
buildings, such as offices, schools and libraries, are much ● The justification of a practice implies doing more good
higher than the national average. Tentative analysis indi- than harm.
cates some 5000 premises with levels above that at which ● The optimization of protection implies maximizing the
the Ionizing Radiations Regulations 1999 apply.56 The margin of good over harm.
average dose was estimated to be 5.3 mSv with 10 per cent ● The use of dose limits implies an adequate standard of
of the employees exceeding 20 mSv. More attention is protection even for the most highly exposed individuals.
being given to this area because of the significance of the
doses. These three principles overall avoid the possibility of deter-
In round terms, some 96 000 people are considered to ministic effects and minimize the risk of stochastic effects
be exposed to elevated levels of natural radiation at work. in normal operations.
634 Ionizing radiations
Protection against external irradiation Table 53.5 Current UK annual dose limits (mSv).56
The general principles deployed in the workplace to keep Part of the body Classified Non-classified General
external doses as low as reasonably practicable are to keep person person public
exposures as short as possible, keep as far away from the
source as possible and wherever possible place shielding
between the source and the employee. This simple concept Whole bodya 20 6 1
of time, distance and shielding is practised routinely in all Any single organ
clinical radiography departments with screens, lead aprons or tissue 500 150 50
and special rooms for exposures. Hands, forearms,
feet and ankles 500 150 50
Protection against external contamination Lens of the eye 150 50 15
The use of protective clothing prevents contamination of a
The dose limit in any three-month interval for female employees of
the skin; however, loose contamination on such clothing reproductive capacity is 13 mSv to the abdomen, concurrent with a
will still irradiate the skin and so exposure times need to be whole body dose limit of 20 mSv. Once a female employee has declared
pregnancy, the employer must ensure the dose to the fetus is unlikely to
strictly limited. Containment of contamination is essential
exceed 1 mSv in the rest of the pregnancy. This is practically interpreted
wherever possible to prevent activities producing an as an external dose limit of 2 mSv to the abdomen over the declared term
inhalation hazard. of pregnancy.
programme. Three situations may arise where special working in designated areas or on handling radioactive
surveillance may be required: sources, but does imply restriction where there is the
potential for high-dose exposures. Separate dose limits
1. Fitness for wearing respiratory protection devices; apply to pregnant women.
2. Fitness for handling unsealed sources in the case of In the case of accidental exposure or overexposure, the
employees with skin diseases or skin damage; physician needs to liaise with the management and other
3. Fitness of employees with psychiatric or psychological safety specialists to ensure that all suitable arrangements
disorders. for evaluating the scale of the exposure are undertaken.
The medical aspects of the management of overexposed
Employees who wear respiratory protective equipment in employees is dealt with below.
the course of their radiation work, for example, inside con-
taminated confined spaces, need to be checked periodically MEDICAL MANAGEMENT OF ACCIDENTALLY
to verify their lung function. Employees with skin diseases, EXPOSED EMPLOYEES
such as psoriasis, may need to be excluded from work with
unsealed radioactive materials, unless the levels of activity As soon as an unexpected exposure is suspected, manage-
are low and appropriate precautions are taken, such as cov- ment should undertake an investigation to determine the
ering the affected parts of the body. However, there may be dose to the employee. If a dose is established, an injury is
a need for periodic medical checks to ensure that unpro- sustained, or contamination occurs, then the appointed
tected areas have not become affected by the skin disease. doctor or occupational health service should be informed.
In employees with psychiatric or psychological disorders,
the primary concern is whether the employees could pose a External exposures
danger to themselves or their colleagues, particularly in The majority of unexpected exposures are determined to
high radiation dose-rate areas and the handling of unsealed be false alarms, such as the improper use of a dosemeter,
and portable sources. and no further action is required. However, once the dose
There is no particular reason why employees who have is deemed to have been received, the appointed doctor or
previously been treated for malignant disease should be occupational health service must be informed. The investi-
excluded from work with radiation if they are otherwise gation should include the dose estimates from all types of
fit for the job. Any additional risk of radiation-related available dosimetry. It is convenient to divide exposures
disease caused by future occupational exposure is likely to into three categories of increasing doses.
be small in comparison with the risks from the treatment
with surgery, chemotherapeutic agents and/or radio- Doses close to the dose limits
therapy. However, it may be necessary to restrict their Normally, such doses do not require any special clinical
employment in emergency teams where high doses in investigations or therapy. The role of the occupational
accident situations might be permissible, and essential health personnel is to counsel the overexposed employee
when saving life. that the exposure is unlikely to produce adverse health
effects.
Once the physician or the management has been informed Doses at or above the threshold for deterministic effects
that a woman believes she is pregnant, arrangements may If the assessed external doses are around the threshold for
need to be made to change her conditions of work. The deterministic effects, therapeutic action may need to be
physician is often the best person to advise management on undertaken. In order to make this decision, the over-
the need for any particular precautions or procedures to be exposed employee needs to be examined clinically and any
adopted regarding the working conditions of pregnant abnormal findings or symptoms recorded. Haematological
women. The physician should also be able to inform the examination will need to be undertaken in order to moni-
pregnant woman of the risks to her conceptus associated tor the clinical course of the overexposure. If the exposure
with her work and, in particular, reassure her on all the is severe enough to lead to the acute radiation syn-
health issues. Pregnancy does not require a ban from drome, early transfer to a designated hospital is essential.
636 Ionizing radiations
The occupational physician should institute the initial contamination. This is particularly true where skin con-
investigations and treatment of the early symptoms. tamination occurs with tritiated water and with some
Immediate life-threatening injuries, such as fractures compounds of iodine and caesium.
and burns, must be treated as a priority before transfer to a
hospital. Return to radiation work
The clinical management of such highly exposed indi- Exposures which do not approach deterministic levels
viduals is dealt with below. need not affect an employee’s fitness for further radiation
work. An employee should be advised by the physician on
Internal exposures
the level of the increased risk for stochastic effects. Where
Where the exposure is internal in origin (internal contam- their own actions contributed to an overexposure, consid-
ination), the employee should be removed temporarily eration should be given by management to retraining
from the workplace to prevent any further exposure, even before return to work. Return to work after internal
when the dose is expected to be close to, but below, the contamination may be delayed until an adequate dose
dose limit. This action will allow more accurate dose esti- assessment has been made.
mates from sequential counting either of the body, an Where there is partial body overexposure which
organ or body fluids. produces deterministic effects, for example, in industrial
High exposures may warrant interventional therapy to radiography where the source is handled producing skin
accelerate the excretion of radionuclides. Such therapeutic and deep tissue hand damage, the employee should be
measures might include the administration of chelating advised on the future risks involved not only in radiation
agents to enhance the excretion of transuranic radionu- work (e.g. the stochastic risks), but also on future manual
clides, as for example in lead poisoning, forced diuresis work involving exposure to cold and other physical agents,
for high doses from tritium intakes and pulmonary lavage such as chemicals.
for some inhaled plutonium compounds. For plutonium
internal contamination intravenous administration of Medical records of overexposures
diethylene triamine pentoacetic acid (DTPA) will enhance The medical record should be as complete as possible. It
excretion by chelation. Incidents involving radionuclides, should contain details of all examinations, treatment and
such as plutonium, can only occur in specialist industries advice. It will also require copies of any dose reconstruc-
and they usually hold supplies of DTPA. tion or assessment performed by health physics staff.
Medical procedures are not without risk and should
only be undertaken when the expected benefit from saving
the future dose from the incorporated radionuclide (com- MEDICAL ASPECTS OF A MAJOR RADIATION ACCIDENT
mitted dose) outweighs the risk of the intervention. Many
of these therapeutic procedures would be undertaken only The overall medical role will involve those responsible for
at a major hospital, for example lung lavage for a large the management and treatment of casualties, the provision
inhalation of plutonium. of public health information, advice on the health hazards
The occupational physician should be prepared to of ionizing radiation and the application of any public
administer the first dose of chelating agents (such as DTPA health countermeasures.
for transuranic radionuclides) or give stable iodine (see
under Additional aspects of treatment of internally con- Treatment of casualties
taminated casualties, p. 638) for radio-iodine uptake. It is likely that most non-essential personnel would be
evacuated from a nuclear site as soon as an emergency was
External contamination declared and before any serious release or irradiations
Where an employee has been externally contaminated, could occur and so an accident, for example to a nuclear
decontamination, by simple washing, should be under- reactor, should not result in many casualties. At the
taken as quickly as possible. Significant skin contamination Chernobyl accident, however, there was no warning and
with β-emitting radionuclides can result in radiation burns there were many casualties.4 Casualties can be considered
if not treated quickly. It should be remembered that ther- under three headings.
mal burns could complicate skin decontamination and
both may need to be treated simultaneously. The only jus- Conventional injury
tification for delay would be the immediate treatment of These could arise from events, such as fires or steam leaks,
life-threatening physical injuries. or follow incidents and panic.
It is emphasized that a contaminated casualty will not
represent a hazard to the physician or attending staff wear- External irradiation
ing standard medical dress, such as a gown, gloves and Personnel bringing the plant under control or attempting
simple face mask. to save life, and injured individuals immobilized close to
Some radionuclides may be absorbed through the skin the reactor or plant, could receive significant doses of
depending on their chemical form, and can lead to internal whole body external radiation.
Health surveillance 637
Localized more often to hands Localized erythema with possible Clinical observation and treatment
development of blisters, Specialist advice may be sought
ulceration and necrosis
Total or partial body with minimal No clinical manifestation for 3 h or more Clinical observation and symptomatic treatment
and delayed clinical signs following exposure Sequential haematological investigations
Not life-threatening
Minimal haematological changes
Total or partial body with early Acute radiation syndrome of mild or Start treatment as above
prodromal signs severe degree dependent on dose Patient requires specialized treatment
Full blood count and HLA typing are essential
before transfer to a designated hospital,
if feasible
Total or partial body with thermal, Possible severe combined injuries, Treat life-threatening conditions
chemical or radiation burns life-threatening Carry out actions as above and early transfer
and/or trauma to a designated hospital
HLA, human leukocyte antigen.
Low-level intact skin which can be Unlikely; possible mild radiation burns Decontaminate skin and monitor
cleaned promptly
Low-level intact skin where cleaning Possible radiation burns; possible Specialist advice may be sought
is delayed percutaneous intake of radionuclides
Low level with thermal, chemical Possible internal contamination Specialist advice should be sought
or radiation burns and/or trauma
Extensive with associated wounds Likely internal contamination Specialist advice should be sought
Extensive with thermal, chemical Possible severe combined injuries and First aid, plus treatment of life-threatening
or radiation burns and/or trauma internal contamination injuries; early transfer to a designated hospital
638 Ionizing radiations
Inhalation and ingestion of radionuclides insignificant No immediate Specialist advice must be sought
quantity (activity)
Inhalation and ingestion of radionuclides significant No immediate Nasopharyngeal lavage important
quantity (activity) Early transfer to a designated hospital is
essential to enhance excretion of radionuclides
Absorption through damaged skin (see Table 53.7) No immediate Specialist advice should be sought
Major incorporation with or without external total, Severe combined Treat life-threatening conditions and transfer
or partial body or localized irradiation, serious radiation injury to a designated hospital
wounds and/or burns
Table 53.9 Examples of treatments for internal contamination. gland, but late administration does not enhance excretion.
The normal dose of potassium iodate for an adult is 200 mg
Isotope Treatment
orally, but the blocking efficacy depends on early adminis-
tration (ideally when an accident is threatened and before
Iodine Administration of stable iodine a release occurs) with approximately 50 per cent effective-
Tritium Forced diuresis ness if administered six hours after the exposure.59,60
Plutonium Chelating agents, e.g. diethylene triamine
pentaacetic acid (DTPA). May be given i.v.
KEY FACTORS FOR HOSPITAL STAFF AND FACILITIES
or as an aerosol inhalation
Caesium Prussian blue given orally inhibits intestinal Protection of medical staff
reabsorption
All paramedical and medical staff involved in the handling
and treatment of contaminated patients should wear
simple protective clothing consisting of overalls, surgical
rubber gloves, boots or overshoes (operating theatre dress)
(3) the solubility, generally soluble substances are more
and a face mask or respirator. A simple gown and mask
hazardous than insoluble ones. Alpha emitters are the most
would be adequate if other clothing was not available.
hazardous isotopes when incorporated. Particle size is
important in inhalation, smaller particles penetrating Designated treatment areas
deeper into the lungs than larger ones and overall the stay
Treatment areas should be clearly demarcated from adja-
time in body (effective half-life) which is determined by a
cent clean areas and have adequate space to allow an initial
combination of the radioactive decay or half-life (t1/2
triage and resuscitation and then space for decontamina-
(physical) and the biological half-life (t1/2 (biol)):
tion and treatment. Wherever possible, only decontami-
nated casualties should be allowed into the clean areas of
t 12 (biol)t 12 (physical) the hospital. Monitoring of patients for radiaoactive con-
Formula: t 12 (effective)
t 12 (biol) t 12 (physical) tamination should take place at a suitable barrier between
clean and dirty areas.
Areas designated to receive contaminated casualties
The overall management aspects of treating internally
must have an adequate water supply for decontamination
contaminated patients are shown in Table 53.8. Examples
and consideration should be given to control of ventilation
for accelerating the decorporation of some isotopes in
systems to prevent spread of contamination.
internally contaminated patients are shown in Table 53.9.
in accordance with their detailed plans. These plans are ● Casualties on admission can be classified into four
usually required by the national legislation, such as the treatment categories: mild, moderate, severe and lethal.
Ionizing Radiations Regulations in the UK56 or recom- ● Stating specific dose ranges for these categories is not
mended by the International Atomic Energy Agency. The possible, primarily because of the difficulty in convert-
initial medical triage should be undertaken by the most ing an exposure to a meaningful tissue dose; however,
experienced medical staff member available, which could equivalent whole body dose ranges would be 2, 2–5,
be a first-aider. This triage should identify any personnel 5–10 and 10 Gy, respectively.
requiring immediate despatch to a hospital without any ● The most reliable prognostic guides for treatment in the
radiation or contamination assessment. early stage are the change in absolute lymphocyte
counts and cytogenetics, levels of blood cells, which will
Hospitals give a good estimate of dose.
● The degree of radiation-induced marrow aplasia
Local plans to deal with accidents should include a desig-
nated hospital where radiation or contamination casualties (reversible or irreversible) may not be known for days
should be taken. Where possible, these should be National because of the uncontrolled nature of the exposure
Health Service providing assistance within the National and the likelihood that it was non-uniform and
Arrangements for Incidents involving Radioactivity heterogeneous.
● Assessment of the dose, while important, is secondary
(NAIR). This applies to Great Britain (England, Scotland
and Wales) only. If the hospital designated to receive the to the treatment.
● Reliable triage and good clinical care based on compre-
radiation and contamination casualties is not the nearest
accident and emergency unit, the local plan should also hensive biological data will ensure the best chance of
include the use of that unit to receive uncontaminated recovery, provided some critical stem cells survive the
casualties. While the plan should include the transfer of radiation exposure (see Table 53.10).
● Professional help may be necessary to treat psychologi-
radiation and contamination casualties to the specialized
hospitals, it must also include instructions to direct casual- cal problems accompanying radiation accidents.
ties requiring immediate life-saving treatment to the near- Sepsis
est unit whatever the patient’s radiation exposure status.
● The suppression of bone marrow activity will reduce the
resistance to bacterial and viral infections.
CLINICAL TREATMENT OF RADIATION INJURIES ● For febrile neutropenic casualties blood, urine and fae-
cal samples for cultures need to be taken on admission.
Periodically, consensus treatment conferences on the treat- ● Patients need to be started on broad-spectrum anti-
ment of radiation injuries have been held.61 At the last held
microbials and these should be given until the patient is
in Geneva in 2009,62 it was agreed that four main medical
afebrile.
effects determined the treatment, which interlink: sepsis, ● Experience has shown that fungal lung infections can be
marrow aplasia, gastrointestinal injury and cutaneous
the cause of late deaths, when all the other radiation
injury. The consensus publication has an excellent sum-
effects have been stabilized.
mary for the treatment of radiation casualties. If conven- ● Early use of antifungal agents and gamma globulin for
tional injuries are present, then the patient is deemed to
viral infections is essential.
have a combined injury and the prognosis is worse. The
World Health Organization (WHO) has set up a worldwide Marrow aplasia
Radiation Emergency Medical Preparedness Assistance ● Following a suspected high radiation exposure, initial
Network (REMPAN). Physicians who need advice or assis-
patient assessment should be based on dosimetric test-
tance should contact WHO at Geneva, who can then
ing (biological, physical), daily full blood counts, viral
suggest suitable therapies and arrange for the nearest
titres (e.g. cytomegalovirus, human immunodeficiency
REMPAN Centre to give direct advice.
virus), human leukocyte antigen subtyping for possible
bone marrow transplantation and the administration
CLINICAL CARE OF RADIATION CASUALTIES of haematopoietic growth factors (colony-stimulating
factors, such as G or GM-CSF) (see Table 53.10).
General ● Particular care is needed if the patient has other
● Experience from many accidents has shown that the injuries, such as pulmonary infections, burns or smoke
heterogeneous nature of the exposures tends to con- inhalation.
found both the clinical and pathological picture, so that ● Subsequent supportive therapy might include platelet
estimating the scale of the radiation damage and expo- transfusions particularly if surgery is indicated for other
sure is difficult. injuries. Other treatments might include the use of
● The early treatment of conventional injuries is the main thrombopoietic drugs.
factor that determines survival in patients who have ● Bone marrow transplants should only be given if an
been accidentally irradiated. autologous donor is available.
640 Ionizing radiations
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54
Non-ionizing radiation and the eye
Far ultraviolet Ultraviolet C 200–280 Excimer Sunlight Cornea Epithelium Photochemical Photokeratitis
Arc lamps Corneal opacity
Germicidal lamps
Mercury lamps –
Far ultraviolet Ultraviolet B 280–315 Excimer Sunlight Cornea Epithelium Photochemical Photokeratitis
Sun lamps Corneal opacity
Welding arcs
295–315 Lens Epithelium Photochemical Cataract
Nucleus
Near ultraviolet Ultraviolet A 315–400 Excimer Sunlight Lens Epithelium Photochemical Cataract
UV-A sun lamps Nucleus
Sunbeds –
Visible Visible 380–780 Argon Sunlight Retina Pigment Thermomechanical
Dyes Incandescent lamps Epithelium Thermal
Helium-neon Fluorescent lamps Photochemical Visual loss
Krypton Arc lamps Haemoglobin Thermal Visual loss
Macular pigment Thermal Visual loss
Visual cells Photochemical Insidious visual loss
Colour vision problems
Accelerated ageing
Near infrared Infrared A 780–1400 Gallium arsenide Sunlight Retina Pigment epithelium Thermal Visual loss
Neodymium YAG Arc lamps
Electric fires
Furnaces
Iris Pigment epithelium Thermal Cataract
Lens Nucleus
Far infrared Infrared B 1400–3000 Erbium Sunlight Cornea Epithelium Thermal Corneal opacity
Furnaces Aqueous flare
Lens Epithelium Thermal Cataract
Far infrared Infrared C 3000–10 000 Carbon dioxide Furnaces Cornea Epithelium Thermal Cataract
Modified from Ref. 2.
646 Non-ionizing radiation and the eye
wavelengths of visible light (although transmission charac- the segments of two spheres; the anterior segment, the
teristics do vary with age).2 In considering the basic prin- transparent cornea, occupies about one-sixth of the whole
ciple of vision, we will briefly describe the anatomy of the surface, while the opaque posterior segment, the sclera,
eye and phototransduction. A more comprehensive review occupies the remainder of the exterior surface. Anatomy
of these areas can be acquired from a variety of general textbooks classically consider the eye to consist of three
texts.3–6 layers: (1) the fibrous tunic (cornea and sclera), (2) the
vascular or uveal tunic (choroid, ciliary body and iris) and
(3) the retina (neural retina and retinal pigment epithe-
Ocular anatomy lium) (Figure 54.1a). Within lie the internal media,
aqueous humor, lens and vitreous. Since this chapter con-
The eyeball is situated in the anterior part of the orbital centrates on ocular light damage, the following description
cavity, towards the roof and to the temporal side. of ophthalmic anatomy will concentrate on those tissues
The eyeball is not completely spherical being made up of which lie on the optic axis.
Cornea Iris
Aqueous
Anterior chamber
humor
Posterior chamber
Ciliary body
Lens
Vitreous
humor
Retina
Choroid
Sclera
Optic
(a) nerve
Intermediate
neurons
Neural
retina
Photoreceptor
cells
Retinal pigment
epithelium Bruch’s membrane
Choroidal capillaries
Choroid Figure 54.1 (a) Cross-section of an
(b) eyeball. (b) Cross-section of the retina.
Basic principles of vision 647
nerve impulses to the visual cortex. In addition, the neural within the photoreceptor outer segments which results in
retina also contains supporting glial cells and the retinal the closure of ion channels such that the receptor potential
vasculature. takes the form of a hyperpolarization and a decrease in the
rate of neurotransmitter release. The generator potentials
The retinal pigment epithelium produced by the photoreceptor cells induce signals in both
The retinal pigment epithelium is a single layer of polar- bipolar neurons and horizontal cells which are transmitted
ized hexano-cuboidal cells located beneath the neural as a partially processed excitatory visual signal to the gan-
retina and separated from the choroid by Bruch’s mem- glion cells. The ganglion cell axons connect via the optic
brane (Figure 54.1b). These cells contain melanin (an nerve and optic chiasma to the visual areas located in the
absorber of stray light), form the outer blood retinal occipital lobes of the cerebral cortex.
barrier (controlling the supply of nutrients to the photo-
receptors) and maintain the integrity of photoreceptor
outer segments by ingesting the spent tips of photoreceptor BASIC MECHANISMS OF LIGHT DAMAGE
outer segments. IN TISSUES
At the posterior pole of the eye, approximately 3 mm
lateral to the optic disc, is a shallow depression in the retina While optical radiation is essential for visual perception it
which forms the centre of the macula. The macula is an can also, given the appropriate conditions, produce tissue
oval yellowish area approximately 5.5 mm in diameter. The damage.8 Such damage, although generally considered
yellowish colouration of the macula is caused by the macu- detrimental to visual function, can be of considerable ther-
lar pigment which principally consists of the carotenoid apeutic value if used appropriately. Radiation damage is
xanthophyll. The fovea is a depression in the centre of the thought to occur via at least one of three fundamental
macula and is about 1.5 mm in diameter. The floor of this processes:9 mechanical (or ionization), thermal and photo-
depression, about 0.35 mm in diameter, is called the ‘fove- chemical (Figure 54.2). It should be noted that although
ola’. The depressed area is formed by the nerve cells being this broad classification is used for simplicity, light damage
displaced peripherally, leaving only densely packed photo- often results from more than one of these processes through
receptors in the centre. There are no blood vessels and no a continuum of photoinduced events.
rod photoreceptor cells in the foveola, i.e. this is an all-
cone region of the retina. The macula is anatomically
adapted to permit light to have greater access to the photo- Mechanical damage
receptors than elsewhere in the retina and explains in part
why this is the area of the most acute vision. Mechanical damage results from extremely short wavelength
In addition to the ocular structures which lie on the light exposures (nanosecond or less) at high irradiance
optical axis, the eye is also made up of: levels causing sonic transients or shock waves that
mechanically disrupt the tissue.9 The injury may be due to
● the sclera – the outer, opaque, fibrous coat constituting ionization where electrons are stripped from the outer
the posterior 83 per cent of the outer surface of the eye; orbitals of atoms resulting in a plasma. In the eye, such
● the iris – a contractile diaphragm which forms a central mechanical damage is normally associated with radiation
aperture, the pupil, which controls the amount of light originating from Q-switched or mode-locked lasers.
entering the eye and impinging on the retina;
● the ciliary body – an annular portion of the uvea
Thermal damage
extending from the ora serrata to the root of the iris
which provides the necessary muscular changes for
Thermal damage can occur if incident energy is trapped or
accommodation and produces the aqueous fluid;
●
absorbed in a substrate molecule resulting in a significant
the choroid – predominantly a vascular structure
increase in temperature. A rise in temperature of 10°C
whose principal function is to nourish the retinal
or more in the retina is considered sufficient to cause
photoreceptors and pigment epithelium; this tissue
coagulative tissue damage.10 Such damage usually occurs
contains melanocytes whose melanin granules absorb
light and xenobiotics.
Phototransduction
at longer wavelengths than for mechanical damage with the retinal pigment epithelium has been proposed as
exposure duration usually between 10–6 and 10–3 seconds the major chromophore, although more recent evidence
and is dependent on the absorption of light by specific suggest that the age-pigment lipofuscin which accumulates
chromophores.9 The retina contains a number of chro- within retinal pigment epithelium cells with age may be the
mophores which readily absorb visible light, i.e. melanin, primary chromophore in man.17
blood, xanthophyll and lipofuscin. Typical sources of ther-
mal energy are xenon arc and laser photocoagulators, the
extent of tissue damage being dependent on exposure time. LIGHT ABSORPTION BY OCULAR TISSUES
The depth of penetration is dependent on wavelength, e.g.
optical radiation from argon lasers (457–524 nm) is pri- Visual perception results from a response to visible radi-
marily absorbed at the retinal pigment epithelium, while that ation (400–780 nm) reaching the retina. The light pathway
from the krypton red (around 650 nm) and diode lasers to the retina is almost completely transparent to all wave-
(790–830 nm) is absorbed by the choroid, as well as the lengths of visible light (although transmission characteris-
retinal pigment epithelium. tics do change with age). However, these ‘transparent’
tissues do have the ability to absorb varying amounts of
non-ionizing radiation normally present in the environ-
Photochemical damage ment.2,11 Thus, the various structures of the eye can also be
considered as a consecutive series of spectral filters with
This has been the most extensively studied form of light each component absorbing exclusive wavelengths and
damage owing to its ability to cause damage under ambient preventing/reducing the likelihood of retinal photodamage
conditions and its potential role in ocular pathologies (Figure 54.3).18 Table 54.1 provides details of spectral
(e.g. cataract and age-related macular degeneration). domain, wavelength, non-ionizing radiation sources,
Photochemical damage is brought about by prolonged absorption site and type of light damage for different
exposure (seconds to years) to the more energetic short ocular tissues.
wavelengths of light, such as blue and UV, which, when All non-ionizing radiation below approximately 295 nm
absorbed by a chromophore, lead to an electronic transi- is cut off by the cornea and does not reach the lens. The
tion of the substrate to an excited state with a potential for cornea is thus capable of absorbing the UV-C (100–280 nm)
causing tissue damage.9 and the short wavelengths in the UV-B between 280 and
Although photochemical damage is reported to occur in 295 nm. It should be noted that the cornea is only exposed to
most ocular structures, it has been most studied in the lens UV-C from artificial non-ionizing radiation sources since
and the retina.11 The interactions of endogenous, as well as this solar component is blocked by the atmosphere. The
exogenous, biomolecules with UV radiation has demon- lens absorbs strongly in the long UV-B (300–315 nm) and
strated that the major UV absorbers in the lens are free or the full UV-A (315–400 nm); appreciable irradiances of
bound aromatic amino acids, as well as numerous age pig- UV-B and UV-A reach the retina only in aphakic eyes.
ments and fluorophores.11 Photochemical changes in the Both the cornea and the lens absorb in the infrared
lens appear to be cumulative and certainly contribute to (1400–10 000 nm). Neither the aqueous nor the vitreous
ageing changes and the development of cortical cataract.12 demonstrates any significant absorption of radiant energy
Retinal photochemical damage is currently classified as
either type 1 or type 2 on the basis of animal studies.9 Type 1
damage is caused by prolonged exposure (hours or days)
to low irradiances, which at threshold result in damage to Vitreous
the retinal photoreceptors. The action spectra of type 1 Lens
damage corresponds reasonably with the absorption spec- UV B and C Sclera
trum of the visual pigments thus supporting the view that UV A
these pigments are the prime chromophores responsible
for the generation of type 1 damage.13 By contrast type 2
damage is considered to originate in the retinal pigment
Macula
epithelium and appears to correlate with relatively higher
retinal irradiances than for type 1 damage delivered over
shorter time spans (seconds to minutes).14 However, cur-
rent evidence suggests that prolonged exposure to low ret- Visible Infrared
inal irradiances can result in cumulative damage similar to Optic nerve
that of type 2 (see Chronic light damage, p. 654). Ham and Cornea
colleagues15,16 measured the action spectrum of type 2 Retina
damage and reported that its sensitivity increased with
decreasing wavelength, a feature which led to this type of Figure 54.3 The penetration/absorption of ultraviolet, visible
damage being referred to as ‘blue light damage’. Melanin in and infrared radiation by the different structures of the eye.
650 Non-ionizing radiation and the eye
under non-pathological conditions. Thus, the light reaching can be broadly divided into acute and chronic depending
the retina is the so-called ‘visible component’ of the elec- on the immediacy of the response, type of damage and the
tromagnetic spectrum (380–760 nm). The most obvious ability of the damaged tissue to recover.
absorber in the retina is the visual pigment which has a
broad band absorption across the whole of the visible
spectrum. In addition, the retina contains a number of ACUTE LIGHT DAMAGE
chromophores which readily absorb visible light:
Ultraviolet damage most commonly occurs in the superfi-
● the broad band absorbers melanin and lipofuscin – cial structures of the eye and is caused by excessive exposure
absorption increases with decreasing wavelength and to UV light (e.g. photokeratitis, photoconjunctivitis).19,20
thus these chromophores have been implicated in blue There is usually a latent period of up to 12 hours following
light damage to the retina; UV exposure before damage to ocular tissues becomes
● haemoglobin which has absorption properties between apparent. The adverse effects of UV are related to the dura-
400 and 600 nm; tion, intensity of the exposure and the degree of penetration
● macular pigment which strongly absorbs between 400 (i.e. UV-A will reach the lens, while the majority of UV-B is
and 530 nm – this spectral absorption may protect the absorbed by the cornea). By contrast, light in the visible
macula from potential blue light damage. spectrum will usually affect the retina (e.g. solar retinopathy,
welding arc maculopathy).21 Infrared damage is discussed
It should be noted that the absorption characteristics of dif- under Damage by infrared and microwaves, p. 654.
ferent ocular tissues vary with age, e.g. the yellowing of the
lens increases its absorptive characteristics between 300 and
400 nm with end absorptions extending to 500 nm. Photokeratitis and photoconjunctivitis
A final point that should be emphasized is that the com-
bined refractive powers of the cornea and lens can increase The acute damage to ocular tissues by exposure to excessive
the light intensity reaching the fovea. UV is well documented and usually affects the corneal
(photokeratitis) and conjunctival (photoconjunctivitis)
epithelia. This damage is photochemical and is most com-
OCULAR LIGHT DAMAGE monly caused by exposure to UV-A, B and/or C. The acute
inflammatory reaction of the superficial part of the cornea
Although light is essential for vision its absorption by vari- (and conjunctiva) to UV was originally termed ‘photo-
ous tissues can result in tissue damage (Figure 54.4). As phthalmia’. One of its forms (snowblindness, photokeratitis)
discussed earlier, dependent on wavelength, irradiance was first described in 1722, although the condition became
energy and exposure duration, three different types of light more common and better recognized after the introduction
damage can be identified: ionizing, thermal and photo- of the electric arc furnace and lighting in 1879. Epithelial
chemical. The damaging effect of non-ionizing radiation damage is observed within 8–12 hours of exposure. The
Figure 54.4 International Commission on Illumination (CIE) spectral bands with their corresponding effects. The direct biological effects
of optical radiations are frequency dependent. In the visible and infrared (IR) regions, the interaction mechanism is primarily thermal. In
the ultraviolet (UV) region, the interaction mechanism is predominantly photochemical, although thermal injury is also present. The
biological effects for IR radiation are corneal burns and cataracts. The biological effects for visible radiation are retinal burns, cataracts
and degradation of colour or night vision. The biological effects for UV radiation are photokeratitis, cataracts and erythema. UV-A and
UV-B also cause skin cancer. Reproduced from Ref. 1.
Acute light damage 651
Welding arc maculopathy wave lasers, are not hazardous within the eye’s aversion
response (i.e. 0.25 second). Normally only procedural
Photic retinopathy may occur, due to photochemical controls such as not directly pointing the laser at the eye
damage by the blue light component of the welding arc, to are required. Class 2M laser products pose the same risk
individuals welding without goggles. In general, patients if viewed without optical aids, but otherwise are
present with a decrease in vision which occurs immediately potentially hazardous to view with telescopes.
● Class 3 – divided into class 3R and class 3B. Class 3R –
or soon after the injury; fundus appearance and visual
recovery resemble those described for solar retinopathy low to medium power lasers where the risk is minimal
(see Chapter 44, Welding).21,31 largely because of the extremely low probability of the
pupil being large, of all the beam energy entering the eye
Laser and the eye accommodated to focus the beam to a
minimal spot. Nevertheless, the eye may be exposed
Laser is an acronym for Light Amplification by the technically to levels up to five times the maximum
Stimulated Emission of Radiation. Lasers are sources of permissible exposure (MPE). Hazard can be controlled
non-ionizing radiation that can operate in the UV, visible by relatively simple procedures (e.g. use of beam stops
and infrared region of the electromagnetic spectrum. The and ensuring that beam paths are not at eye level). The
light emitted has a unique combination of spatial coherence only documented injuries from this type of laser have
(i.e. all the waves are in step), monochromaticity (one occurred from intentional direct-beam exposure. Class
colour or narrow wavelength range) and usually high colli- 3B – medium power lasers where the viewing beam
mation. Furthermore, the emission may be continuous wave either directly or by specular reflection is hazardous, but
or pulsed for either long or short (Q-switched) duration. diffuse reflections are almost always safe. Hazard can be
The known effects of acute light damage to ocular tis- controlled by the use of beam enclosures, beam stops
sues are exploited in preventive ophthalmology. Optical (ensuring that beam paths are not at eye level) and, if
breakdown damage from Q-switched or mode-locked needed, laser eye protection.
● Class 4 – high power lasers which are not only a hazard
lasers are important procedures in iridotomy and posterior
capsulotomy. Photoreactive keratectomy is now a standard from direct viewing and from specular reflections, but
procedure in Europe for the correction of refractive error also from diffuse reflections. The direct beam may also
less than 4 dioptres, as well as becoming fashionable for the be a skin and fire hazard. Their use requires extreme
treatment of high myopia and is routinely undertaken caution.
using an Excimer laser emitting in the UV-C region of the
spectrum.32 Providing irradiance, exposure time, pulse Most laser accident experience comes from careless use of
rate and beam alignment are optimal, the operation is suc- lasers in the research laboratory, with fewer in industry and
cessful, however, poor quality control can result in corneal military applications.1,36–42 A review of the accident data
fibrosis and opacification.33 Argon, krypton and diode suggests that at least one type of laser is responsible for the
lasers are routinely used in retinal scatter photocoagulation majority of accidental injuries that result in a significant
to induce the regression of subretinal and preretinal vessels visual loss: the Q-switched neodymium: YAG (Nd:YAG)
in conditions such as proliferative diabetic retinopathy. laser which emits invisible, near-infrared radiant energy at
Lasers are commonly used both in the industrial (e.g. 1064 nm. Although a continuous wave (CW) laser causes
drilling, cutting, welding, communication) and military (e.g. thermal coagulation of tissue, a Q-switched laser having a
rangefinders, tactical target designators, night vision) settings pulse of only nanoseconds duration disrupts tissue by ther-
and there have been numerous reports of accidental expos- momechanical processes. A visible or near-infrared laser can
ure resulting in immediate loss of central vision. Depending be focused on the retina, resulting in a vitreous haemorrhage
on the type of laser, damage occurs by either a thermal or (Figure 54.6). Despite macular injuries43 and an initially
mechanical mechanism.34,35 In the case of retinal damage, a serious visual loss, the vision of many patients recovers sur-
gliotic scar develops and a paracentral or central scotoma prisingly well.44,45 Others may have severe vision loss.
may persist. Lasers are divided into four major classes Corneal injuries resulting from exposure to reflected laser
depending on the potential safety hazard. These classes are energy in the far-infrared account for surprisingly few
defined by British Standard BS/EN/IEC 6082:2007 and ANSI reported laser accidents. The explanation for this accident
Z136.1: 2007. statistic is not really clear. However, with the increasing use
of lasers operating at many new wavelengths, the ophthal-
● Class 1 – non-hazardous lasers; (i) the output is so low mologist may see more accidental injuries from lasers. Not
the laser is inherently safe or (ii) the laser is part of a all laser incidents result in injury, and temporary visual
totally enclosed system. A class 1M laser product is safe effects are now also of concern.46
to view without optical aids, but otherwise is potentially As discussed, the eye is particularly vulnerable to injury
hazardous. in the retinal hazard region from 400 nm at the short-
● Class 2 – low power visible continuous wave and pulsed wavelength end of the visible spectrum to 1400 nm in the
lasers which, whether repetitively pulsed or continuous near-infrared part of the spectrum.1,2,47,48 In this spectral
Acute light damage 653
Table 54.2 Selected occupational exposure limits for some sun exposure and cataract was undertaken on 838
common lasers. Chesapeake watermen in Maryland and a 60 per cent
increase in risk of cortical cataract with a doubling of
Type of laser Wavelength Exposure limit
cumulative sun exposure was noted.52 This observation was
subsequently supported by the smaller study undertaken by
Argon-fluoride 193 nm 3.0 mJ/cm2 over 8 h Bochow and colleagues.53 Other less detailed studies have
Xenon-chloride 308 nm 40 mJ/cm2 over 8 h reported that the risk for posterior subcapsular cataract is
Argon ion 488, 514.5 nm 3.2 mW/cm2 for 0.1 s slightly increased in people with moderate and high light
2.5 mW/cm2 for 0.25 s exposures.12 Surprisingly, no association has yet been noted
Helium-neon 632.8 nm 1.8 mW/cm2 for 1.0 s between light exposure and nuclear cataract. Studies organ-
1.0 mW/cm2 for 10 s ized by a group at Kanazawa, Japan, have pointed to a
Helium-neon 632.8 nm 100 μW/cm2 for 8 h strong correlation of nuclear cataract and ambient lifetime
Neodymium-YAG 1064 nm 5.0 μJ/cm2 for 1 ns ambient termperature; whereas – as in the other studies –
to 100 μs cortical cataract was associated with UV exposure.54,55
5 mW/cm2 for 10 s Severe cases of age-related macular degeneration have been
Erbium glass 1540 nm 1.0 J/cm2 for 1 ns–10 s shown to have received significantly greater exposures to
Erbium: YAG 2940 nm 10 mJ/cm2 for 1–100 ns either blue and/or full spectrum visible light over a 20-year
Hydrogen-fluoride 2.7–3.1 μm 10 mJ/cm2 for 1–100 ns period compared with controls especially in older subjects.56
Carbon dioxide 10.6 μm 100 mW/cm2 for 10 s to 8 h, However, the role of light in the initiation and progression
limited area of early age-related macular degeneration remains a subject
10 mW/cm2 for >10 s for debate.57 Thus, high levels and chronic exposure of
Source: ACGIH EL. individuals to all or part of the visible light spectrum can
Note: To convert exposure limits in mW/cm2, multiply by exposure time in manifest as ocular disease later in life.
seconds, e.g. the He-Ne or Argon EL at 0.1 s is 0.32 mJ/cm2.
Fluorescent lights
to detect; an individual will be aware of a large retinal
lesion due to visual loss. Many of the animal studies of light damage to the retina
have employed fluorescent lamps, and this has given rise to
CHRONIC LIGHT DAMAGE concerns about human exposure to fluorescent lighting. It is
important to recognize that the typical light exposure condi-
Chronic light damage has been clearly demonstrated in tions for the test animals employed ring fluorescent lamps
animal models, but is difficult to prove in man; subclinical such that the animals (rats) could not look in any direction
photodamage is believed to accumulate through a lifetime, without seeing a bare fluorescent lamp. Under such condi-
eventually exceeding a threshold at which overt clinical tions, where the luminance exceeded that of sunlight
damage is evident. However, to what extent such damage, reflected from snow, retinal damage resulted after some days
particularly in the aged population, is primarily due to of exposure for 12 hours per day. Such conditions simply do
light exposure or other factors is open to debate. not occur in human activity, where such a luminance would
Furthermore, the major source of chronic light exposure preclude seeing and result in almost continued ‘bleaching’
has shifted dramatically over the last 50 years. Sunlight of the retinal pigment. It was necessary to dilate an animal’s
used to be the major non-ionizing radiation source; how- eyes in order to obtain this result in primates. There is no
ever, fluorescent lighting (and even lighting from light- evidence of any detrimental effect in humans to date.
emitting diodes (LEDs) is now a common feature both at VISUAL DISPLAY UNITS
home and in the workplace. Furthermore, computers are
now commonplace. Thus, an increasing number of indi- There is a large amount of literature on the viewing of
viduals are being exposed to non-ionizing radiation from visual display units and the suspected health hazards.
visual display units in an environment of fluorescent light- Fundamentally, the research over the past two decades
ing. Only time will tell if these changes in lighting sources shows that while ergonomic (human-factor), refractive
will increase or reduce ophthalmic conditions attributable and visual comfort problems are real, there is no long-term
to chronic light exposure. adverse effect upon the visual system.58,59
welding, the sun, various heating appliances, lasers (both ultraviolet are identical to those caused by other types of
commercial and opthalmic) and military weapons. IR-A thermal exposure.22 In most flash burns, the blink reflex
damage is predominantly observed in the choroid, retina, protects the eyes from damage; however, in some instances
iris and lens, while the longer wavelength IR-B and IR-C the cornea is involved. The condition results in a painful
are absorbed by the cornea and lens but do not reach the eye which resolves within a few days. Treatment normally
retina (Table 54.1). Specific sources of IR-B and IR-C consists of topical antibiotics if epithelial defects and cyclo-
are the erbium and carbon dioxide lasers, respectively. plegia for discomfort. In more severe burns, there is
Tissue damage is normally thermal, and in the case of the corneal thinning, neovascularization and scarring.
retina, largely irreversible.
Ocular damage from exposure to IR-A was common in
workers involved with furnaces, molten glass or molten Microwaves
metals at temperatures over 1500°C. It was recognized as
long ago as 1786 by Wenzel who observed that glass blowers Microwave radiation is the high-frequency end of the
had an increased incidence of cataract. Cataract formation radiofrequency region of the electromagnetic spectrum
appeared to be more common in the left eye probably due with a wavelength range of 1 mm to 1 m. Sources of
to the tendency for greater exposure to infrared on the left microwaves include household ovens, radar, satellite
side as a result of common working practice.60 It was calcu- communication, insect control appliances and surgical
lated that the temperature of a human lens can increase diathermy apparatus. It is unlikely that domestic appliances
by 9°C if the eye is exposed to molten glass at 1 foot will pose a risk to the individual, but military and civilian
(0.3048 m) distance for one minute.61 radar/communications workers may be at risk of exposure
Infrared-induced cataract was ‘prescribed’ as an occu- to dangerous levels of microwave radiation during service
pational disease in the United Kingdom in 1907 and the procedures near the antenna.1 It has been hypothesized that
subsequent introduction of shields and goggles reduced in some tissues, especially the lens, repeated exposure
the incidence of cataract in glass blowers dramatically, causes cumulative damage and can manifest as cataract.
such that in 1908 some 20 per cent of workers had cataract However, evidence from chronic exposure animal and epi-
while by 1945 only one case was reported in the United demiological studies have failed to confirm a direct cor-
Kingdom in a whole year. Subsequently, the bulk of glass relation between microwave irradiation and cataract.
production and foundry work has been mechanized, leaving Acute, accidental exposure of the eyes to microwave radia-
only a small number of workers, especially in craft centres, tion may lead to skin burns, conjunctival infection and loss
at risk. However, a significant problem will still exist in of corneal epithelium, as well as stromal oedema and opaci-
developing countries where mechanization and safety fication. Epithelial loss can be managed with topical antibi-
procedures are minimal. otics (e.g. chloramphenicol or fuscidic acid) and cycloplegia
Lens damage appears to be cumulative as a posterior (e.g. cyclopentolate), while topical steroids (e.g. pred-
cataract begins to develop after a decade or two of working nisolone acetate) may also be considered if stromal damage
near high intensity infrared sources. Cataract presents with and inflammation occur (indicated by corneal oedema and
a blurring of vision and associated lens opacities. Clinically, opacification). Exposure limits vary from approximately 1
the infrared cataract starts as a cobweb-like opacity which to 10 mW/cm2 in different standards and with animal ocu-
increases in size and density and develops into a saucer- lar injury thresholds being in the order of 100 mW/cm2.63,64
shaped posterior cataract.62 The opacity will continue to More recent studies by Kues et al.65 suggest that short-pulse
grow and will ultimately form a complete opacity resem- exposures at 2.45 GHz may produce effects at lower average
bling a senile cataract. Treatment is by cataract extraction power densities. Individuals usually recover within two
and intraocular lens implantation. Retinal damage often weeks, although some stromal haze could persist for more
goes unnoticed since infrared is invisible and the retina has than 12 months.
no pain receptors. However, pain may be experienced if the
choroid is affected. Damage is thought to result from
absorption of energy by melanin in the retinal pigment PHOTOSENSITIZATION
endothelium and choroidal melanocytes. This can result in
a scotoma which, if at or near the fovea, can produce a pro- Photosensitizers, often given as drugs, can contribute to
found loss of visual acuity. Examination may reveal local- light-induced ocular damage.8 Two groups of compounds,
ized areas of retinal oedema or patches of pigmentary phenothiazides and psoralens, have been clearly identified
disturbance, lesions often not appearing until 48 hours after as intraocular photosensitizing agents, capable of causing
exposure (fluorescein angiography can be used to identify photochemical damage to the choroid, retina and lens in
burn areas not apparent by ophthalmoscopic examination). man, as well as experimental animals. 8-Methoxypsoralen
There is no recognized treatment for this condition. (8-MOP) is a typical example of such a photosensitizer
Flash burns to the cornea may occur by the flashback of which is used in the photodynamic therapy of psoriasis and
large artillery and by the flash of an atomic explosion. other skin diseases.66 Interaction between 8-MOP and the
These burns which are a combination of infrared and lens or retina results in the photobinding of the dye to these
656 Non-ionizing radiation and the eye
PROTECTION AGAINST LIGHT DAMAGE Figure 54.7 Eye protectors. Eye protection for optical radiation
hazards are produced in a variety of configurations from
The eye is well adapted to protect itself against acute optical spectacles with and without sideshields to goggles, face shields
radiation (ultraviolet, visible and infrared radiant energy) and welding helmets. The choice of protector is dependent on the
injury from ambient sunlight. It is protected by a natural specification of the optical hazard together with local and
aversion response to viewing bright light sources that nor- national health and safety directives.
mally protects against injury from viewing sources such as
the sun, arc lamps and welding arcs, since this aversion
limits the duration of exposure to a fraction of a second
(about 0.25 s). However, sources rich in ultraviolet radia- Eye protector design and standards
tion without a strong visual stimulus can be particularly
hazardous. One can force oneself to stare at the sun, a The design of eye protectors for welding and other indus-
welding arc or a snow field and thereby suffer a temporary trial optical sources (foundries, steel and glass manufacture,
loss of vision, which in some cases may be permanent. In etc.) began at the beginning of this century with the devel-
the industrial setting, when bright lights appear low in the opment of Crooke’s glass.69 Eye protector standards which
field of view, the eye’s protective mechanisms are less effec- evolved later followed the general principle that since
tive, and hazard precautions are particularly important.68 infrared and ultraviolet were not needed for vision, those
spectral bands should be blocked as best as possible by
the then currently available glass materials. Figure 54.7
Safety standards illustrates the wide variety of design from spectacles to
goggles and full-face welding helmets.
Safety standards for arc welding have long existed and The empirical standards for eye protective equipment
specify eye protectors, curtains and barriers. Safety stan- were tested in the 1970s and shown to have large safety fac-
dards for lasers are also well developed worldwide; most tors for infrared and ultraviolet when the transmissions
following the general equipment and user guidance in IEC factors were tested against current occupational exposure
60825-1-2007. Lasers are grouped into several hazard limits, whereas the protection factors for blue light were
classes and so labelled by manufacturers; the user then fol- just sufficient. Some standards’ requirements were there-
lows certain specified control measures based upon the fore adjusted. Table 54.3 summarizes recommended eye
laser class. However, standards for lamp safety are actually protectors for different types of optical sources.
more recent. In the United States, the Illuminating Laser protective eyewear was developed after occupa-
Engineering Society of North America (IESNA) issued tional exposure limits had been established, and specifica-
photobiological safety standards for lamps and lighting tions were drawn up to provide the optical densities (a
systems for the first time in 1996 and lamp groups are logarithmic measure of attenuation factor) that would be
placed in risk groups somewhat similar to laser hazard needed as a function of wavelength and exposure duration
classes. Since then, this approach has been followed in the for specific lasers. Although specific laser eye protector
joint standard CIE-S009 of the International Commission standards exist in Europe, guidelines for laser eye protec-
on Illumination (the CIE) and in standard IEC-62471:2006 tion are provided in the American National Standard
of the International Electrotechnical Commission (IEC). ANSIZ136.1 and ANSIZ136.7 in the US.30,70
Protection against light damage 657
Welding Shade based on Welding helmet 10–14 Protection from optical radiation Protectors that do not
electric arc visual comfort directly related to filter lens provide protection from
density; select the darkest shade optical radiation
that permits adequate task
performance
Welding gas Shade based on Welding goggle 4–8 Face shield can be
visual comfort or welding worn over the primary protector
face shield
Cutting 3–6
Torch brazing 3–4
Torch soldering Shade based on Spectacles or 1, 3–5 Face shield can be worn over
visual comfort welding the primary protector
face shield
Glare Shade based on Spectacle frontal 1–4 Shaded or special purpose lenses,
visual comfort protection as suitable
Laser specified Optical density as Laser protective Optical density Choose filter lens based on Uncomfortable goggles,
maximum laser goggle units used comfort, optimal visual users fail to wear
exposure divided or spectacle performance
by exposure limit
RF/microwave Psychological Goggles made NA NA Not effective
but not
recommended
Adapted from Ref. 68. This table was published in Opthalmology Clinics of North America, 8, Vinger P, Sliney D, Issues in ocular trauma. The prevention of
sports and work related injury, 709–21, copyright Elsevier (1995).
NA, not applicable.
and optical sources, ordinary impact-resistant clear safety e.g. a protection factor of 1000 (103) is an OD of 3.0, and a
eyewear will provide good protection (e.g. clear polycar- protection factor of one million (106) is an OD of 6.0. Since
bonate lenses effectively block the 10.6 μm CO2 wave- most lasers emit powers or energies of the order of thou-
length). However, absorbers such as metal oxides in glass sands to millions of times the maximum permissible
or organic dyes in plastics, must be added to eliminate UV- exposure limit, optical densities of 4–6 are most typical.
A and UV-B up to about 380–400 nm, and infrared beyond The ANSI standard Z136.1 Safe use of lasers provides
780 nm to 3 μm.30,70 Depending upon the material, this detailed methods for determining the appropriate eyewear
may be easy, or very difficult or expensive, and the stability and ANSI standard Z136.7 Testing and labelling of laser
of the absorber may vary somewhat. Filters that meet ANSI protective equipment provides extensive technical detail.
Z87.1 must have the appropriate attenuation factors in Although some eyewear vendors and laser safety promot-
each critical spectral band. ers have argued for very robust filters of coated glass to
withstand extremely high beam irradiances of many kilo-
FOUNDRY AND GLASS INDUSTRY EYEWEAR watts per cm2, this is overkill, and polycarbonate laser pro-
tective lenses are quite adequate (the skin will be severely
Spectacles and goggles designed for ocular protection charred at much lower irradiances). Polycarbonate has
against infrared radiation generally have a light greenish superior burn-through characteristics70 compared with
tint, although the tint may be darker if some comfort other plastics and is also superior to all other lens materials
against visible radiation is desired. Such eye protectors for industrial impact protection.
should not be confused with the blue lenses used in the At present, prescription lenses in laser filter materials
steel and foundry operations where the objective is to visu- are only available on a limited basis for glass lenses, but
ally check the temperature of the melt; these blue spectacles there are a number of companies which supply cover
do not provide protection, and should only be worn goggles for laser protection. The Laser Institute of America
briefly.69 in Orlando, FL is a useful source of information on laser
safety and laser eye protectors.
FIREFIGHTING
procedure, some welders frequently initiate the arc with a not be hazardous. The UV radiation and IR filtration
conventional helmet in the raised position – leading to should be checked in the manufacturer’s specification sheet
‘welder’s flash’ (arc-eye or photokeratitis). Under normal to make sure that the unnecessary bands are filtered out.
ambient lighting conditions, a welder wearing a helmet fit- A few repeated arc strikings should give the welder a sense
ted with an autodarkening filter can see well enough with of whether discomfort will be experienced from transient
the eye protection in place to perform tasks such as align- adaptation, although a one-day trial would be best.
ing and fixturing the parts to be welded, precisely position- The resting or failure state shade number of an auto-
ing the welding equipment and striking the arc. Then, in darkening filter (e.g. if the battery fails) should provide
the most typical helmet designs, light sensors detect the arc 100 per cent protection of the welder’s eyes for at least one
flash and direct an electronic drive unit to switch a liquid to several seconds. Some manufacturers use a dark state as
crystal filter from a light shade to a preselected dark shade. the ‘off’ position and others use an intermediate shade
The aforementioned drawbacks of fixed shade filters are between the dark and the light shade states. In either case,
largely eliminated by autodarkening filters which explains the resting state transmittance for the filter should be
the widespread popularity of these newer systems. appreciably lower than the light shade transmittance to
Questions have frequently been raised whether there are preclude a retinal hazard. In any case, the device should
hidden safety problems with the new autodarkening filters. provide a clear and obvious indicator to the user when the
For example, can after-images (flash-blindness) result in filter is switched off or when a system failure occurs. This
impaired vision in the workplace? Do the new types of fil- will ensure that the welder is warned in advance when the
ters really offer equivalent or better protection than con- filter is not switched on or is not operating properly before
ventional fixed filters? The answer to the second question is beginning to weld. Other features, such as battery life, per-
Yes, but not all autodarkening filters are equivalent. Filter formance under extreme temperature conditions, etc. may
closure speeds and light and dark shade values vary, as does be of importance to certain users.
the weight of each unit. The temperature dependence of
performance, variation of shade with electrical battery
degradation, the ‘resting state shade’ and other technical CONCLUSIONS
factors vary depending upon each manufacturer’s design.
These are being addressed in new standards. Although technical specifications can appear to be some-
Since adequate filter attenuation is afforded by all sys- what involved for eye protectors against optical radiation
tems, the single most important attribute specified by the sources, safety standards exist which specify shade num-
manufacturers of autodarkening filters is the speed of filter bers, and these standards provide a conservative safety
switching. Current autodarkening filters vary in switching factor for the wearer. However, should damage occur the
speed from 1/10th second (0.1 s) to faster than 1/10 000th recipient should be immediately referred to a doctor for a
second (100 μs). Buhr and Sutter72 have indicated a means medical opinion.
of specifying the maximum switching time, but their for-
mulation varies relative to the time-course of switching.
Switching speed is crucial, since it gives the best clue to the
really important (but unspecified) measure of how much Key points
light will enter the eye when the arc is struck compared with
● Excessive non-ionizing radiation can damage
when wearing a fixed filter of the same working shade num-
ber. If too much light enters the eye for each switching dur- the eye.
● Damage is usually to the cornea or retina and
ing the day, the accumulated light energy dose produces
transient adaptation and complaints about eye strain, etc. can result in visual deterioration.
● Users exposed to acute or chronic non-ionizing
Current products with switching speeds of the order of
10 ms or less will provide adequate protection against pho- radiation should be aware of exposure limits,
toretinitis. However, the shortest switching time of the safety standards and the appropriate eye
order of 30–100 μs (0.03–0.1 ms) has the advantage of protection.
reducing ‘transient adaptation’ effects.71,73 Transient adap-
tation is the visual experience caused by sudden changes in
one’s light environment which may be accompanied by
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55
Extremely low frequency electric and
magnetic fields
Nature of electric and magnetic fields 663 Magnetic resonance imaging 670
Occupational exposures 663 Conclusions 671
Acute effects in humans 664 References 671
Long-term health effects 664
NATURE OF ELECTRIC AND MAGNETIC FIELDS machines, electrical heating equipment and other high
current-carrying devices.
Electricity use has grown throughout the industrialized Measurement of 50–60-Hz electromagnetic fields
world since the first public power station began operation (EMF) is easily carried out with hand-held field meters.
in London on January 12, 1882. Electricity is generated and However, extreme variability of fields, both in space and
usually transmitted as alternating current (ac) in the time, make exposure assessment and the development of
United States at 60 cycles per second, or 60 Hertz (Hz), and proper exposure surrogates of past exposures difficult. This
in Europe at 50 Hz. is further complicated by the lack of knowledge regarding
Electricity is generally considered safe, but it is not com- what aspects of exposure are biologically relevant and what
pletely without hazard. For example, in the United States might constitute a dose.
each year there are about 1100 deaths attributed to electric
shocks. Approximately three-quarters of these deaths occur
from unsafe operation of electrical appliances in the home OCCUPATIONAL EXPOSURES
and the remainder are from accidents in the workplace.1
However, the subject of clinical treatment of electric shocks Occupational EMF exposures are considerably higher
and burns resulting from direct contact with electrical con- than non-occupational ones, which are usually in the
ductors is beyond the scope of this section, which considers 0.01–0.3 μT range (Figure 55.1). Occupational exposures
health effects postulated from exposure to electric and mag- have been studied most extensively in the electric utility
netic fields associated with the delivery and use of electricity. industry. Average exposures have been found to be higher
Electric and magnetic fields are ubiquitous in modern in electrical occupations than in other occupations, such as
societies. The magnitude of electric fields, measured in office work, ranging from 0.4–0.6 μT for electricians and
kV/m, is directly proportional to line voltage, while mag- electrical engineers to approximately 1.0 μT for power line
netic fields, measured in tesla (T) or microtesla (μT), are workers. Welders have the highest average exposures at
determined by the magnitude of the electric current. These 3.7 μT. Average measurements or arithmetic means, how-
fields are found around every electrical conductor, motor ever, can be strongly influenced by a few high measure-
and appliance. In office buildings, computers and copy ments. Geometric means, which are not thus influenced,
machines are common sources of magnetic fields. Power are much lower. Geometric means are 0.2–0.3 μT for elec-
distribution facilities and large motors used to drive build- tricians and electrical engineers, 0.4 μT for power line
ing air conditioning systems can also contribute signifi- workers and 0.6 μT for welders.
cantly to the magnetic field environment. In factories, high Much less is known about exposures in non-electrical
magnetic fields are encountered near large electric occupations. Few data, if any, are available for many jobs
664 Extremely low frequency electric and magnetic fields
People with exposure time greater than indicated (%)
double at average residential exposure levels above A brief summary of the numerous studies investigating
0.3–0.4 μT.12,13 Studies of residential exposure in adults and occupational EMF exposures and several cancers is pre-
biological effects from EMF are largely negative thus far. sented below. Leukaemia and brain cancer, and, more
Detailed discussion of the studies of residential exposures is recently, breast cancer have received the most attention,
outside the scope of this chapter, for a review, see Ref. 28. although many of the breast cancer studies focused on res-
Occupational studies of EMF have employed several idential exposures. Also, occupational exposures to electric
designs such as proportionate mortality, case–control and fields have re-emerged as an issue of potential importance.
cohort analysis. The occupational groups studied included Because of the large number of occupational studies of
the following categories of workers: linemen, substation EMF and leukaemia and brain cancers, specific study refer-
workers, welders, electricians, motion picture projection- ences which have been included in meta-analyses are omit-
ists, electronic assemblers and electrical engineers. ted below. Reference should be made to Kheifets et al.22–24
Unfortunately, the definition of electrical workers in these
studies is broad, varies considerably among investigations LEUKAEMIA
and does not always reflect a high EMF exposure. More
recent and better quality studies have assessed magnetic The risks of leukaemia associated with occupational expo-
field exposures through job–exposure matrices (JEMs) sure to magnetic fields are generally low. A meta-analysis of
populated with personal measurements of time-weighted occupational epidemiologic studies suggested an excess of
average (TWA) magnetic fields. JEMs for electric utility all leukaemias with a risk estimate of 1.18 (95 percent confi-
workers14,15 and for the general population16,17 have been dence interval (CI) 1.12–1.24),22 with slightly higher risks
constructed from extensive full-shift measurements. These for the various leukaemia subtypes. Although most studies
data are combined with activity records to calculate the reported a small elevation in risk, the apparent lack of a clear
TWA and other metrics, such as time above a threshold, pattern of exposure to EMF substantially detracts from the
that summarize a worker’s exposure. hypothesis that magnetic fields in the work environment are
A major limitation of magnetic field JEMs is that occu- responsible for it. These findings were not sensitive to
pation is not the main determinant of exposure. A person’s assumptions, influence of individual studies, weighting
occupational exposure depends on the performed job schemes or modelling. Some evidence of publication bias
tasks, field sources encountered during work, the average was noted.22 A pooled analysis of large cohort studies of elec-
strength of sources and the proportion of time spent at dif- tric utility workers showed similar weak but positive associ-
ferent locations relative to sources. Consequently, meas- ations between occupational magnetic field exposure and
ured exposure varies widely among individuals within the adult leukaemia. More recent cohort studies of electric util-
same occupations.18 Furthermore, JEMs based on contem- ity workers in the United Kingdom and Denmark showed
poraneous measurements may not properly represent no elevation in leukaemia risk in association with occupa-
historical exposures. tional magnetic field exposure (Figure 55.2).
Several improvements to JEMs have been tried. Miller A recent update to the previous meta-analyses on occu-
developed a JEM that classifies exposure measurements by pational EMF and adult leukaemia collected and evaluated
location as well as by job.19 Renew et al.20 assessed expos- all relevant 1993–2007 publications.24 Combining the new
ures of power station workers with a magnetic field model and past studies leads to a small overall increase in risk of
that takes account of the engineering design, layout and 17 per cent for all leukaemia with little indication of het-
operational history for each power station. Results from erogeneity. A more detailed look indicates somewhat
this model were combined with data on the proportion of higher risk increases for specific leukaemia subtypes (an
time spent in specific plant areas for each job and with excess ranging from 15 to 37 per cent), but the excess is
occupational history to give individual exposure values. largely limited to the previous analysis with newer studies
Good agreement was found between modelled and meas- providing little indication of risk. Additionally, while in the
ured exposures. This approach had the added advantage of past analysis the highest estimate was obtained for chronic
reconstructing historical exposures. While this approach is lymphocytic leukaemia now the highest risk appears for
valuable for power plant occupations with fixed working acute lymphocytic leukaemia.
locations, exposures for transmission and distribution Improvements in study quality have not clarified the
workers are still best assessed by JEMs. relationship between occupational EMF exposure and
Elevated electric field exposures occur only where there leukaemia. While recent studies represent substantial
are unshielded, high-voltage conductors and therefore do improvements over earlier research, each has unique limi-
not normally occur in indoor facilities, such as power tations. The most recent studies do not point to strong
stations or factories. Moderate-to-high levels (0.1 to biases or confounding in the earlier studies. However, so
1 kV/m) are found only near high-voltage transmission little is known of the risk factors for adult leukaemia that
lines or exposed, energized busbars in substations. In these confounding from an as yet unidentified risk factor
limited environments, adequate estimates of TWA electric remains a possibility. Also, the lack of an exposure–
field exposures can be obtained from spot measurements response relationship and the inconsistencies in results
or computer modelling.21 from different studies makes it difficult to conclude that
666 Extremely low frequency electric and magnetic fields
McMillan83
Vagero85
Lin85
Milham85
Olin85
Tornqvist86
Coggon86
McLaughlin87
Thomas87
Magnani87
Speers88
Pearce89
Guberan89
Preston-Martin89
Preston-Martin89
Loomis90
Juutilainen90
Schlehofer90
Spinelli91
Gallagher91
Tornquist91
Study reference
Demers91
Ryan92
Tynes92
Sahl93
Floderus93
Guenel93
Theriault94
SavitzLoomis95
Guenel96
Alfredsson96
Beall96
Baris96
Fear96
Feychting97
Rodvall98
Cocco98
Robinson99
Pira99
Floderus99
Ronneberg99
Savitz00
Minder01
Sorahan01
Hakansson02
Villeneuve02
Klaeboe05
Karipidis07
Johansen07
Figure 55.2 Leukaemia estimates with
0.16 0.40 1.00 2.51 6.31 confidence intervals. For study details, see Refs
Risk estimate 22–24.
occupational EMF exposure is a risk factor for adult brain cancer and an 18 per cent increase for glioma, with
leukaemia. Large increases in adult leukaemia risk in asso- some presence of heterogeneity.
ciation with occupational EMF exposure, however, are While some studies reported a slight elevation in risk for
unlikely based on the available results. adult brain tumours among people in electrical occupa-
tions, the lack of a dose–response relation in some studies
and the lack of knowledge of other risk factors for brain
BRAIN CANCER
tumours which could be confounding variables limit our
Similarly, there is a small but significant increase in brain ability to reach conclusions about the risks for adult brain
cancer risk associated with estimates of potential work- cancer from occupational exposure to EMF. Similar to
place magnetic field exposure (relative risk (RR) 1.21, CI leukaemia, however, large increases in the risk of adult
1.11–1.33).23 While most studies reported a small elevation brain cancer in relation to occupational EMF exposure
in risk, there was considerable heterogeneity in the results. may be excluded on the available epidemiologic results
Pooled risk estimates (based on inverse-variance weighted (Figure 55.3) and previously observed risk patterns are not
pooling) decreased over time. The findings of this meta- strengthened by new and better quality data.24
analysis were not affected by inclusion of unpublished
data, influence of individual studies, weighting schemes or BREAST CANCER
model specification. A pooled analysis of large utility
cohort studies showed a weak-positive association between Numerous studies have examined cancer in electrical occu-
occupational exposure to EMF and adult brain cancer. pations, with many considering breast cancer as one of
More recent electric utility cohort studies from Denmark the outcomes. These studies were motivated by a specific,
and the United Kingdom observed no increases in brain biologically based hypothesis, which proposed that mag-
cancer risk. An update to the earlier meta-analysis for brain netic field exposure suppresses melatonin production at
cancer24 leads to an overall 14 per cent increase in risk for night and that reduced melatonin levels would result in an
Long-term health effects 667
Polednak81
Milham82
Coleman83
McDowall83
Howe83
Morton84
Gillman85
Olin85
Calle85
Blair85
Stern86
Olsen87
Milham88
Tola88
Guberan89
Pearce89
Garland90
Juutilainen90
Loomis90
Gallagher90
Robinson91
Spinelli91
Simonato91
Richardson92
Tynes92
Study reference
Ciccone93
Floderus93
Guenel93
Matanoski93
Sahl93
London94
Floderus94
Theriault94a
Theriault94b
Theriault94c
Tynes94
Tynes94
Savitz95
Guenel96
Alfredsson96
Baris96
Fear96
Feychting97
Robinson99
Pira99
Floderus99
Ronneberg99
Villeneuve00
Savitz00
Blair2000
Bethwaite01
Minder01
Harrington01
Hakansson02
Oppenheimer02
Adegoke03
Tynes03
Willet03
Johansen0 6
0.16 0.40 1.00 2.51 6.31
Figure 55.3 Brain estimates with confidence
Risk estimate intervals. For study details, see Refs 22–24.
increased risk of breast cancer. Male breast cancer is very but these have been inconsistent and none has been suffi-
rare and most of the studies were not based on sufficiently ciently strong to warrant further discussion here. Overall,
large populations, so estimates of risk for male breast can- epidemiologic results do not indicate that occupational
cer were often not included in the tables of results unless an EMF exposure may be a risk factor for these types of cancers.
excess risk had been observed. This makes it difficult to
evaluate the risk of male breast cancer. Although several
ELECTRIC FIELDS
reports were suggestive of a positive association, the more
recent large studies of electrical workers25–27 did not iden- Magnetic, rather than electric, fields have been identified as
tify any excess of male breast cancer. the exposure of potential interest in most epidemiologic
Few occupational studies of electrical workers included studies. In addition to the plethora of well-known difficul-
sufficient numbers of females to address the potential associ- ties in measuring magnetic field exposures today and
ation of occupational EMF exposure and female breast can- extrapolating them to workers who held similar jobs in the
cer. Although some studies supported a possible association past, measuring electric field exposure presents unique dif-
between EMF exposure and oestrogen receptor-positive ficulties. Electric fields are perturbed by conducting objects,
breast cancer among premenopausal women, other studies such as humans and their surroundings. The interaction of
did not. Most recently, a very large and well-designed occu- the subject with the field affects the reading of a field meter
pational case–control study of Swedish women using a placed on the body. The field that is recorded by the instru-
sophisticated female-occupation specific job–exposure ment is therefore very dependent on where the device is
matrix found no increase in breast cancer risk with exposure worn, the posture of the subject and the relative location of
to magnetic fields. Available epidemiologic results, overall, sources of fields. This makes measurements of the electric
do not provide support for an association between occupa- fields difficult to perform and interpret, often yielding rela-
tional exposure to EMF and breast cancer. tive, as opposed to absolute, values of exposure for different
individuals. Because most of the exposure assessments in
OTHER CANCERS the occupational environments have focused on magnetic,
rather than on electric fields, little is known about the reli-
Sporadic reports of elevated risks for other cancers, such as ability and validity of electric field measurements. However,
malignant melanoma, non-Hodgkin’s lymphoma, testicular reanalyses of two cohorts of the Canada–France study29–32
cancer and prostate cancer,28 have appeared in the literature and of a study in Los Angeles County33 considered electric
668 Extremely low frequency electric and magnetic fields
field exposure (the original focus of these studies was LABORATORY STUDIES
magnetic fields).
In the first, Miller et al.29 reported an association of all No biophysical mechanisms operating at low levels have
leukaemias and leukaemia subtypes (but not for brain can- been identified, in particular: effects below 5 μT are
cer) with increasing electric field exposures. The primary implausible, at about 50 μT, no specific mechanism has
effect occurred when both electric and magnetic field been identified, but the basic problem of implausibility is
exposures were considered together. In contrast to these removed. Above about 500 μT, there are established or
results, the second reanalysis30 found no evidence of an likely effects from accepted mechanisms.34
increased risk of leukaemia and some evidence of an As a whole, laboratory research does not support EMF
increased risk of brain tumours among utility workers exposure as a carcinogenic agent. Multiple studies have
exposed to electric fields. Finally, a limited reanalysis of failed to show those cellular or tissue findings usually associ-
data from Los Angeles County did not find an association ated with the transformation of normal cells into neoplastic
between leukaemia and electric field exposures in a variety cells.35 For example, with certain rare exceptions, EMF has
of occupations.33 The two further analyses of the Ontario not been shown to be mutagenic,36 clastogenic or terato-
portion of the Canada–France electric utility worker study genic, nor has any mechanism been established for weak to
found an increased risk of leukaemia and non-Hodgkin’s moderately strong fields.37
lymphoma with elevated exposures to electric fields.31,32 A review of animal models for carcinogenicity con-
Due to the inconsistency of results and the special diffi- cluded that long-term continuous exposure to magnetic
culties in assessing electric field exposure, there is currently fields in the range of 2–5000 μT is not likely to result in car-
little research studying possible associations between elec- cinogenesis in rats or mice.38 Based on available evidence, a
tric field exposure and cancer. weak promoting effect of EMF under certain exposure con-
ditions cannot be ruled out. Most of the studies addressing
promotion and progression, however, were negative.
SUMMARY OF EPIDEMIOLOGIC RESEARCH The absence of laboratory evidence of EMF as a cancer-
In summary, over 100 occupational studies have examined initiating agent has led to some speculation and evaluation of
magnetic fields as a potential risk factor for a variety of EMF as synergetic with other agents. Juutilainen et al.39
cancers. A few of these studies also considered electric reviewed effects of such co-exposures in cell culture and
fields as a risk factor and one investigated the combination short-term animal studies. The results of this analysis showed
of electric and magnetic fields appearing together. These a high percentage of positive studies, suggesting that EMFs
studies have varied widely in the design, types of study do interact with other physical and chemical exposures. All
subjects, methods of exposure assessment, outcomes con- studies on apoptosis and embryotoxicity were positive while
sidered and quality. it was not the case for genotoxicity. Most of these studies on
Of the many cancers and exposures examined, a weak combined effects used magnetic fields of 100 μT or higher.
positive association exists between occupational exposure Overall, the majority of animal and in vitro studies have
to magnetic field and leukaemia and brain tumours; the found no evidence of genotoxic effects of extreme low fre-
epidemiologic literature is consistent with either no associ- quency (ELF) magnetic fields at field strengths relevant to
ation or a small association for these cancers. Based on epi- human exposure.
demiologic results, overall, breast cancer is not likely to be
related to magnetic field exposure. Reproductive effects
The likelihood of positive findings due to chance alone
is difficult to evaluate. Many of the studies were not specif- Reports of the effects of EMF on human reproductive out-
ically designed to test the EMF hypothesis, but rather were comes, particularly in the occupational setting, are fewer
secondary analyses of existing data collected for other pur- than those of cancer. While there are a number of reports
poses. Biases are undoubtedly present in many or all of the linking some forms of adverse reproductive outcome to
epidemiologic studies. However, the magnitude and direc- occupational EMF exposure, overall, the body of evidence
tion of biases in the studies of EMF are not well under- does not support an association between occupational expo-
stood. These potential biases vary from study to study and sure and reproductive outcomes, such as miscarriages or
over time some sources of bias have been largely elim- intrauterine growth retardation.40 Among occupationally
inated, while others remain. exposed populations, a variety of effects has been examined.
EMF exposure is an uncertain risk factor for the cancers
studied based on the small to modest elevation in risk PREGNANCY OUTCOMES AND VIDEO DISPLAY UNIT USE
reported in some studies, general lack of a dose–response
relationship, possible uncontrolled confounding, and The potential influence of occupational EMF exposure on
inconsistencies among the studies in specific cancers and in reproduction has been examined among women working
exposures identified as most important. As the method- with video display units (VDU). Initial concern was based
ology of studies improved, the estimates of risk have become on reports of several clusters of spontaneous abortions
lower, making it unlikely that a large risk is being missed. and congenital malformations among VDU operators.
Long-term health effects 669
Subsequently, several epidemiologic studies41,42 provided children of fathers whose work presumably exposed them
very limited or no evidence of an association between VDU to EMF.54–61 As in most occupational studies, exposure
use and spontaneous abortion or other adverse pregnancy assessment was based on job title. Elevated relative risks
outcome. A study by Goldhaber et al.43 offered some (above 2.0) reported in two of the studies56,67 were not
evidence that extensive work with VDUs had a detrimental confirmed in later studies. Selective reporting in earlier
effect on pregnancy outcome. However, the results of this reports may account for the discrepancy. More recent
study did not show consistent increases in risk with either analyses of childhood brain tumour studies45,51,54,55,62,63
extent of VDU use or particular job categories. Moreover, found no association.
both recall and information biases could explain the study In summary, there is little evidence to implicate occupa-
findings. With the exception of the study by Schnorr et al.,42 tional EMF exposure in the adverse pregnancy outcomes.
all of these investigations did not involve any measure- However, because of methodological problems such as the
ments of fields produced by VDUs. EMF exposures from potential for omission of early miscarriages, recall bias and
VDUs in the Schnorr et al.42 study were found to be similar the fact that the level of EMF exposure under study was not
to the exposures encountered in the home. substantially different from the background level, addi-
tional studies designed to address these issues may be
CONGENITAL MALFORMATIONS necessary to resolve this question definitively.
disease is mostly provided by hospital-based studies.72,73,76 to the machine during typical use may be as high as 10 mT.
The results of population-based studies are less supportive This field decreases to 1 mT at 3 m from the machine where
and more inconsistent. For ALS, epidemiologic evidence a technician may stand for a few minutes. Farther away at
appears to suggest that workers in electrical occupations the operating console, the technician is exposed to a consid-
may be at an increased risk. However, studies with meas- erably lower field level. The development of interventional
ured fields showed less consistent association between ALS magnetic resonance techniques will increasingly involve the
and magnetic fields than between ALS and self-reports of exposure of staff involved in clinical procedures during
experiencing electric shocks. Further research on ALS real-time MRI scanning and at much higher levels. From
which includes better exposure assessment, larger numbers the available scientific data and the magnitude of measured
and consideration of potential confounding due to electric fields, it is unlikely that the health of operators is affected by
shock and occupational exposures to solvents is needed. their exposure to these magnetic fields, but studies capable
of rigorously addressing this issue have not been con-
ducted.4,79 There are some contraindications for using MRI
Cardiovascular effects
for individuals with metal implant and pacemakers80 or
who have had operations involving metal aneurysm slips or
The first epidemiologic study77 specifically examining the
metal sutures. In addition, caution is indicated for patients
association between occupational magnetic field exposure
who are pregnant and infants.
and cardiovascular diseases was motivated by a hypothesis
suggesting that magnetic fields reduce heart rate variability
which in turn results in acute cardiovascular events. In sup-
Exposure guidelines
port of their hypothesis, Savitz et al.77 found an increase in
risk for death due to acute myocardial infarction and
Exposure standards are based on studies that provide infor-
arrhythmia, but not due to chronic heart disease. The
mation on the health effects of EMF, as well as the physical
hypothesis was supported by the initial findings in a human
characteristics and the sources in use, the resulting levels of
volunteer study which showed an effect of magnetic field
exposure and the people at risk. Exposure standards gener-
exposure on heart rate variability, and by several prospective
ally refer to maximum levels to which whole or partial body
cohort studies which suggested that reductions in some com-
exposure is permitted from any number of sources. This
ponents of heart rate variability are associated with increased
type of standard normally incorporates safety factors and
risk for heart disease, overall mortality rate in survivors of
provides the basic guide for limiting personal exposure.
myocardial infarction and sudden cardiovascular death.
There are two main international standards or guidelines:
Most of the epidemiologic studies with rigorous and varied
the International Commission on Non-Ionizing Radiation
designs which followed showed no effect. In a detailed review
Protection (ICNIRP) and the Institute of Electrical and
and analysis of the totality of evidence, Kheifets et al.78 con-
Electronic Engineers (IEEE).81,82 Additionally, many
clude that the weight of evidence speaks against an aetiologic
national authorities have developed their own guidelines,
relation between EMF exposure and cardiovascular disease.
which often adopt or modify ICNIRP guidelines. The
The potential for interference with implanted medical
European Union’s directive to limit occupational exposure
devices, such as pacemakers, needs to be considered in the
to EMF in its member countries, and which was based
case of very high electric and magnetic fields. All patients
on ICNIRP guidelines, was introduced in 2004.83 Its
with pacemaker and defibrillators should be informed of the
implementation, however, was recently delayed for four
potential problems that could be associated with exposure to
years84 due to concerns that proposed guidelines for occu-
EMF. Interference of electric and magnetic fields is usually
pational MRI exposures are overly cautious and would pre-
temporary and moving away from the source will alleviate
vent researchers and practising physicians from using the
the response. Advice to patients with these devices is to
most recent generations of MRI technology.
consult their cardiologist and the device manufacturers if
Acute effects on the nervous systems form the basis of
concerned about potential EMF interference.
international guidelines. None of the guidelines consider
potential long-term effects, such as cancer, to be sufficiently
MAGNETIC RESONANCE IMAGING established to serve as a basis for standards. In particular,
exposure limits are based on the acute effects on electrically
Magnetic resonance imaging (MRI) is now widely used in excitable tissues, particularly those in the central nervous
clinical medicine and new applications with the potential system (CNS). The current ICNIRP81 limits for workers are
fields of 10 T and higher are being developed. These imag- 10 kV/m and 500 μT for 50 Hz and 8.3 kV/m and 420 μT for
ing devices produce static, time-varying magnetic and 60 Hz. The IEEE82 exposure levels are 20 kV/m and 2710 μT
radiofrequency fields. While the patient is exposed to all of at 60 Hz. The differences in the guidelines, derived inde-
these fields, technicians and other occupational personnel pendently by the IEEE and the ICNIRP, result from the use
are exposed mostly to the static fields. Occupational expo- of different adverse reaction thresholds, different safety fac-
sure during construction and testing of these devices may tors and different transition frequencies, i.e. those frequen-
result in exposure levels above 1 T. Field strengths very close cies at which the standard function changes slope.
References 671
The occupationally exposed population consists of concern over adverse health effects from electric and mag-
adults who are generally exposed under known conditions netic fields generated by electric power delivery and use has
and are trained to be aware of potential risks and to take been a concern since the 1960s. Much has been learned
appropriate precautions. By contrast, the general public from the many years of research on EMF and the many
comprises individuals of all ages and of varying health sta- studies that have been published to date. It is clear that
tus and may include particularly susceptible groups or EMF do not pose a large public health or occupational haz-
individuals. Therefore, typically, exposure limits for the ard. The widespread use of electricity justifies research
general public are lower by a factor of 5 than occupational designed to resolve the remaining uncertainties.
exposure limits or exposures in the ‘controlled environ-
ments’, as they are referred to in some guidelines.
Key points
CONCLUSIONS
● Exposures to extremely low frequency electric
A large body of epidemiologic literature examined the and magnetic fields (ELF, EMF) are widespread
potential health effects of residential and occupational mag- and highly variable in many work environments.
netic field exposure. A number of national and international ● Acute effects on the nervous systems form the
expert panels uniformly concluded that an association basis of international ELF guidelines. None of
between residential exposure and childhood leukaemia the guidelines consider potential long-term
development provides the strongest evidence. This relation- effects, such as cancer, to be sufficiently
ship, however, cannot be considered causal since alternative established to serve as a basis for standards –
explanations, such as bias, could not be excluded with cer- mainly due to a lack of generally accepted
tainty. Lack of a plausible biophysical mechanism and lack mechanism or replicated laboratory evidence
of evidence showing carcinogenic effects of magnetic fields below guideline limits.
in laboratory studies also weakens the argument for a causal ● Although a small risk increase for leukaemia and
effect. This uncertainty of the nature of the observed rela- brain cancer from occupational exposures
tionship is reflected in the classification of power-frequency cannot be entirely excluded, the lack of a clear
magnetic field exposure as a possible human carcinogen exposure–outcome pattern suggests that
(group 2B) by the International Agency for Research on magnetic fields as presently measured are by
Cancer and World Health Organization.28,85 themselves not responsible. No consistent
Previous epidemiologic evidence also suggested an asso- indication of an association has been found for
ciation between occupational magnetic field exposure or other cancers, including breast cancer.
work in electrical occupations and adult leukaemia and can- ● The evidence speaks against an aetiologic role
cer of the brain. However, the inadequate quality of expo- for EMF exposure in cardiovascular disease.
sure assessment, small elevations in risk, general lack of a ● Among the major neurodegenerative disorders,
dose–response relationship, possible uncontrolled con- amyotrophic lateral sclerosis (ALS) has been most
founding and inconsistencies among the studies in specific strongly and consistently related to electrical
cancer types and exposures identified as the most important occupations, thus warranting further investigation.
made the interpretation of the data difficult. Furthermore, Multi-country collaborative studies of ALS are
more recent studies, presumably of better quality, have not needed to clarify this relationship.
strengthened this association – thus real risk increases for
these and other cancers, including breast cancer, are
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56
Radiofrequency fields
non-thermal in nature, have been reported in recent stud- broad implications for our understanding of the plausibil-
ies. Generally, it is thought that such interactions are ity of non-thermal RF effects in general.
unlikely to be biologically significant at the RF levels below
guidance values, but much of the ongoing research focuses
on the search for non-thermal mechanisms. CHRONIC EFFECTS
Cancer
Exposure guidelines
EPIDEMIOLOGIC STUDIES
RF exposure guidelines are currently based on avoiding the
risk to health that results from localized rises in tissue tem- Several epidemiologic studies examined potential long-
perature and from the physiological stress engendered by term effects, most notably cancer development, in associ-
excessive whole-body heat loads. An SAR of at least 4 W/kg ation with RF exposure from various sources. Among
is required to result in an increase of 1°C in the tissue tem- cancer types, brain cancer and leukaemia were addressed
perature. Present guidance on occupational exposure is most extensively in the literature. These epidemiologic
based on restricting the RF-induced whole body SAR to studies are generally grouped into three categories based
less than 0.4 W/kg (a safety factor of 10); a heat-load suffi- on the source of RF exposure: exposure from occupational
ciently small that its contribution to other possible heat sources, residential exposure from radio and television
loads, generated from hard physical work and/or imposed broadcast antennae, and exposure from use of hand-held
by high ambient temperatures, can be neglected. Basic mobile phones. Only the first type of epidemiologic studies
restrictions on localized SARs, averaged over any 10 g of investigated directly the potential health effects of occupa-
contiguous tissue, are 10 W/kg in the head and trunk and tional RF exposure and is the focus of this section.
20 W/kg in the limbs. These are intended to restrict local Additionally, mobile phone studies are also briefly dis-
tissue temperature rises to acceptable levels. Guidance on cussed here because mobile phones produce relatively high
public exposure incorporates an additional safety factor of exposures to the head and are increasingly part of many
five, reducing the basic restrictions to 0.08 W/kg for the occupational environments.
whole body and to 2 W/kg for localized exposures. Available case–control studies generally examine spe-
Temperatures are derived from dosimetric calculation and cific types of cancer and presumed occupational RF expos-
thermal modelling. SARs are also related to external field ure in the general adult population, while cohort studies
values via dosimetric calculation.1,2 typically focus on well-defined groups of people exposed to
Of note are recent calculations indicating that for the a specific source through their work or hobby. All studies
frequencies in the GHz range far field waves, the whole suffer from major methodological weaknesses. None of the
body SAR is substantially larger for short subjects.5,6 studies included RF exposure measurements and exposure
classification is often based on job title alone. In addition,
no or only limited control for confounding has been made
Cognitive and neurobehavioural effects in these studies.
Cognitive and neurobehavioural effects may result in occu- Occupational case–control studies
pational safety hazards if workers’ judgement is impaired. Two studies, conducted in the United States, showed a small
Several studies examined potential cognitive effects of RF increase in the risk of brain tumours in association with
exposure from mobile phones in humans in laboratory set- assumed occupational exposure to RF.18,19 One of them
tings. Earlier studies by Preece et al.7 and Koivisto et al.8 investigated brain tumours among US Air Force personnel,
showed shortening reaction times in various cognitive tests and assessed exposure through job title and reports of expos-
but no impairment in overall accuracy. The effects were ure incidents above permissible limits.18 Based on 230 cases
seen for analogue but not for digital phones. It was hypothe- and 920 controls, a small but statistically significant risk
sized that these effects were thermal effects due to local tis- increase was observed (odds ratio 1.4, 95% confidence inter-
sue heating. Later replication attempts, however, did not val (CI) 1.0–1.9). The other study compared 435 deaths due
show consistent and statistically significant cognitive or to brain cancer to 386 deaths due to other causes identified
neurobehavioural effects.9–12 Nevertheless, electroencephalo- through death certificates.19 Exposure was assessed based on
gram (EEG) changes, effects on regional cerebral blood job titles ascertained through interviews with relatives of the
flow and on sleep have been repeatedly reported in associ- deceased subjects. The study reported a risk increase for
ation with RF exposure from mobile phones in human brain tumours with assumed occupational exposure with
laboratory studies.13–17 The clinical significance of these RF (odds ratio 1.6, 95% CI 1.0–2.4); the risk increase,
EEG changes, however, are unclear. As human laboratory however, was only seen with RF in electrical or electronics
studies have been generally conducted at levels generally occupations and not with RF in other occupations. A third
assumed to be too low to induce significant heating, if case–control study of occupational RF exposure and brain
robust and replicable effects are identified this will have cancer, recently conducted in Germany included 366 glioma
Chronic effects 677
and 381 meningioma cases.20 A slight, statistically not signifi- obtained from service records.28,29 These observations,
cant, increase in risk was observed for both glioma and menin- however, were later attributed to methodological limita-
gioma. The odds ratios and 95% CI were 1.2 (0.7–2.2) and 1.4 tions of the study rather than actual risk increases.30
(0.7–2.9), respectively. When the analyses were restricted to Two studies that evaluated cancer mortality among US
the exposure for more than ten years, the observed odds ratios Navy personnel and veterans in relation to potential radar
further increased. Finally, in an Australian occupational epi- exposure showed no risk increases for cancer in general, or
demiologic study of RF exposure and glioma risk, exposure for leukaemia or brain cancer risks in particular.31,32
was estimated for 416 cases of glioma and 422 controls based Although a statistically significant risk increase was seen for
on job titles linked to a job–exposure matrix (JEM) from a non-lymphocytic leukaemia in one of the studies, it was
study in Finland.21 No increased risks were observed for self- only observed in one of the three highly exposed occupa-
reported exposure, exposure based on expert assessment or tions in that study,32 and was conflicting with the results
exposure based on JEM. from the other study.31
Both male and female breast cancers were investigated Milham examined mortality among about 67 000 regis-
in case–control epidemiologic studies. Demers et al.22 tered amateur radio operators in California and Washington
compared potential exposure to occupational RF of states.33 Statistically significant increases were observed in
227 male breast cancer cases to that of 300 controls. Based acute myeloid leukaemia and cancers of other lymphatic tis-
on seven cases, the authors reported a three-fold but statis- sue. Statistically decreased risks were also observed, how-
tically not significant risk increase among radio and com- ever, for cancers of the respiratory tract and the pancreas.
munications workers. A 1995 US case–control study Occurrence of cancer was investigated in a cohort of about
compared possible exposure to RF based on job titles from 2600 Norwegian female radio and telegraph operators.34
death certificates of women who died of breast cancer to Statistically significant risk increases were observed for breast
that of women who died of other causes.23 The authors and uterine cancers; no other types of cancer showed elevated
found no trend in breast cancer risk with either likelihood risks. This risk increase may also be explained by potential
or level of occupational RF exposure. confounding by shift work. Shift work has recently been clas-
Ocular melanoma was examined in two case–control sified as a probable human carcinogen by the International
occupational epidemiologic studies.24,25 The first of these Agency for Research on Cancer (IARC).35
studies examined 221 cases of ocular melanoma and Among operators of RF sealers in a small Italian manu-
447 controls, and obtained exposure information through facturing plant, a non-significant increase in cancer mor-
interviews on a large number of chemical and physical tality and overall mortality was observed. The results,
agents.24 The authors reported a roughly two-fold risk however, were based on very small numbers.36
increase of ocular melanoma for subjects ever exposed to An excess risk for melanoma and testicular cancer was
microwave or radar through their occupations (odds ratio also found among police officers in Ontario.37 No infor-
2.1, 95% CI 1.1–4.0). A German case–control study of mation was available on radar use (potential source of RF
118 cases of ocular melanoma and 475 controls found a exposure) in this study.
three-fold risk increase with occupational exposure to radio Researchers at McGill University in Montreal and Institut
set or mobile phones, but no risk increase with occupational National de la Santé et de la Recherche Medicales in Paris
exposure to radar units.25 The authors acknowledged that examined cancer incidence in a cohort of about 170 000
methodological limitations of the study may have con- workers at two electric utility companies in Quebec and
tributed to the observed inconsistent pattern of associations. France.38 They assessed exposure to pulsed electromagnetic
A case–control study of testicular cancer relying on two fields (PEMF) based on a JEM that was developed based on
methods for exposure assessment also reported inconsist- extensive full-shift measurements using meters calibrated to
ent results; while with self-reported RF exposure, the risk measure exposure in the 5–20-MHz range. Characteristics of
appeared to increase three-fold, with RF exposure deter- detected fields are unclear because the meters used to meas-
mined through job titles no risk increases were observed.26 ure them were very sensitive to fields at frequencies other
A study of 694 cases of non-Hodgkin’s lymphoma and than those originally intended by the manufacturer. The
the same number of controls in Australia investigated RF authors reported a statistically significant risk increase for
and other occupational exposures based on a Finnish lung cancer in the highest exposure category of PEMF. The
JEM.27 Based on very small numbers, the authors observed apparent risk increase persisted even when adjustments were
a three-fold, but statistically non-significant risk increase made for various potential confounding variables. Although
in the upper tertile of RF exposure (odds ratio 3.2, 95% adjustments were made for exposure to cigarette smoke, a
CI 0.6–15.9). potent lung carcinogen, they may have been incomplete
because information on smoking was incomplete. Findings
Occupational cohort studies were not confirmed in several follow-up analyses of existing
Szmigielski et al. reported statistically significant risk data.39–41 Limitations of these follow-up analyses include
increases with RF exposure for several cancer types of the suboptimal exposure assessment (as they had to use a JEM
haematopoietic and gastrointestinal systems and the brain from the original work) and no information on smoking.
among Polish military personnel based on information Improved assessment of relevant exposures in the workplace,
678 Radiofrequency fields
as well as better information on cigarette smoking, may In summary, the currently available epidemiologic litera-
clarify inconsistencies in these studies. ture does not provide sufficiently convincing evidence to
Cancer mortality of about 200 000 workers of a US wire- link RF exposure to brain cancer or other types of cancer.
less communication products company was examined over Due to severe limitations in RF exposure assessment and
a 20-year period by Morgan et al.42 Exposure to RF was other methodological problems in most occupational RF
assessed by a qualitative JEM. An expert panel categorized and mobile phone use epidemiologic studies, the available
job titles into one of four categories (background, low, epidemiologic evidence is also insufficient to rule out any
moderate, high). No excess risk was found for any type of potential effects. Most of the non-cancer outcomes are yet
cancers when the high exposure group was compared to to be properly investigated.
either the background and low exposure groups, or the
general population. The validity of the exposure assessment LABORATORY STUDIES ON CARCINOGENICITY
has not been assessed as no measurements were included.
Several two-year bioassays with rodents, such as Sprague–
Mobile phone studies Dawley rats, Fischer rats and mice, were conducted to
Most epidemiologic studies of mobile phone use examined study the potential carcinogenic effect of long-term, daily
tumours of the head and neck, mostly brain tumours and RF exposure in typical mobile phone frequency ranges
tumours of the acoustic nerve. Some of these studies relied (0.8–1.6 GHz). The exposure systems in most cases were set
on billing records from mobile phone companies to deter- up to achieve SAR levels of 1–2 W/kg in the brain and about
mine use and estimate exposure. This method is often con- a magnitude lower (0.1–0.4 W/kg) averaged over the whole
strained by limited access to billing records and is prone to body.46–50 The results of these studies, overall, do not suggest
exposure misclassification due to people sharing phones, that RF exposure, at these levels, are associated with
using more than one phone, using company phones and increased incidence of brain tumours or other tumours.
switching carriers. Other studies assess exposure based on Similar long-term exposure studies with rodents genetic-
number and duration of calls, and duration of use in years ally susceptible to tumour development (e.g. transgenic
as reported by study participants. Additionally, type of mice) were also conducted to investigate the effect of RF
phone, urban/rural environment and use of hands-free exposures on cancer development. Although two initial
devices can also be assessed in the interview-based studies. studies showed increased development of lymphoma and
The main limitation of this exposure assessment method is mammary tumours,51,52 these results were not reproduced
the potential for recall bias, which might be particularly in later replication studies.50,53,54 Other rodent studies com-
important for outcomes with impaired brain capacity. bined exposure to RF fields with known carcinogenic
Both exposure assessment methods tend to be limited by agents, such as ENU and DMBA.46–48,55,56 These studies,
lack of information on other factors greatly influencing RF overall, do not suggest that RF exposure modifies the effects
exposure (e.g. signal strength, relative position of antenna, of other carcinogenic agents.
etc.). A novel exposure assessment method incorporating Most genotoxicity studies in animals and cell cultures
interviews, records and measurements is needed. showed no effect when examining mutation, DNA and
Most notable of the mobile phone epidemiologic studies chromosome damage, or cytogenetic effects. Positive find-
is the ongoing Interphone study, which is a multinational ings in individual studies could not be replicated independ-
population-based case–control study of mobile phone use ently, and most of these observations may be explained by
and cancer of the brain (glioma and meningioma), the thermal effects.
acoustic nerve and the parotid gland among adults in
13 countries.43 Exposure is assessed by computer-assisted REPRODUCTIVE EFFECTS
interviews of subjects using standardized structured ques-
tionnaires on aspects of mobile phone use, demographic A number of experimental studies examined possible
characteristics and exposure to potential other risk factors, teratogenic effects of RF exposure among various non-
such as ionizing radiation and smoking. The study overall mammalian and mammalian species.57 Teratogenicity was
will include more than 2700 glioma cases, about 2400 clearly demonstrated at RF exposure levels that result in
meningioma cases, about 1100 cases of acoustic nerve maternal body temperature increases of 2°C or more.
tumour and about 100 cases of parotid gland tumour. The These exposure levels, however, are well above current
overall Interphone results are yet to be published. guideline limit values. No consistent laboratory evidence is
Combined results available from five countries suggest no available to suggest non-thermal teratogenic effects at RF
overall association between regular mobile phone use and exposure levels below guideline values. This research area,
tumours of the brain and the acoustic nerve.44,45 Subset however, has received much less attention.
analyses, however, suggest the possibility of a slight increase Potential reproductive effects of occupational RF
in the risk of glioma and, particularly, of acoustic nerve exposure were mostly investigated by epidemiologic studies
tumours among long-term users (more than ten years). conducted among physiotherapists using therapeutic
The relatively small number of cases among long-term microwave or shortwave diathermy.58–63 The examined out-
users, however, does not allow firm conclusions. comes included delay in conception, miscarriage, stillbirth,
References 679
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PART FOUR
57 Repeated movements and repeated trauma affecting the musculoskeletal system 687
Cyrus Cooper and Keith Palmer
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57
Repeated movements and repeated trauma
affecting the musculoskeletal system
1. Which upper limb and neck conditions may be caused ● the background level of the disorder and its natural
or aggravated by work, and which conditions make history in unexposed populations (how unusual is its
work difficult to perform? presentation?);
688 Repeated movements and the musculoskeletal system
● factors personal to the worker (such as age, sex, the Table 57.1 Upper limb and neck conditions that may be work
individual’s anthropometrics and physical strength, related.a
medical history, mental health and threshold for Condition
complaint);
● factors particular to the working environment (e.g. job
tasks and ergonomic stressors, workplace psychosocial Shoulder Shoulder tendinitis
conditions); and Rotator cuff tendinitis
● factors arising outside work (such as sport, housework Bicipital tendinitis
and home craft activities). Shoulder capsulitis (frozen shoulder)
Neck Cervical spondylosis
Thoracic outlet syndrome
He might turn to the epidemiologist for further guidance Tension neck
and would then find that these issues have been studied,
Elbow Lateral epicondylitis
to a greater or lesser extent, but that knowledge is incom-
Medial epicondylitis
plete and that its interpretation would be carefully quali-
fied. For example, in general terms, there are data on the Wrist and forearms Tenosynovitis of the wrist
prevalence and incidence of complaints in the commu- De Quervain’s disease of the wrist
nity, and how these vary by age and sex;3–6 many studies Carpal tunnel syndrome
describe associations between job title and musculoskele- Non-specific diffuse forearm pain
tal complaint,7 and many others report a link in working (repetitive strain injury, RSI)
groups between mental well-being and upper limb a
Some authorities include ganglia, Dupuytren’s contracture and trigger
complaint.8 However, the epidemiologist would point finger within the definition.
out that most surveys of WMSD have been cross-
sectional in design, and may therefore have suffered from
the problem of selection bias (for example, those worst SHOULDER PROBLEMS
affected may have selected themselves out of employment
and escaped observation, leading to an underestimate of The glenohumeral joint has a greater range of movement
the problem); also that this study design does not permit than any other joint and this is permitted at the expense of
the time sequence of events to be observed, and makes it stability. The glenoid fossa is shallow, the capsule is lax and
harder to separate cause from effect. (For example, does there are no strong traversing ligaments. Stability, there-
the association between poor mental well-being and fore, mainly depends on the muscles and tendons of the
upper limb symptoms stem from a causal relationship, or rotator cuff (supraspinatus, infraspinatus, teres minor and
do anxious and depressed workers simply complain more subscapularis), while the deltoid muscle provides a further
often than others about their aches and pains?) He would mechanical support. The joint is protected superiorly by an
point out that some studies are of pain reports rather arch formed by the coracoid process, the acromion and the
than specific diagnoses and that cross comparison is hin- coracoacromial ligament.
dered because diagnostic criteria have varied, been ill-
defined or not been applied in a uniform or standardized
way; and he would say that it has proved difficult to grade Epidemiology
the complex biomechanical workplace exposures that
combine elements of force, frequency, repetition and Fraying and tearing of the rotator cuff tendons, thickening
movement and then vary them so thoroughly, so that in of the bursae and proliferative changes of the synovium are
assessing causality there is scant information on common age-related phenomena. They are often asympto-
dose–response relationships. The net result is that doc- matic in life, but may be discovered at post-mortem.
tors entertain different views on the relation between However, shoulder pain is also fairly common in commu-
work and particular symptom patterns presenting to nity prevalence surveys. Bergenudd et al.5 reported that 14
them. per cent of middle-aged men and women in a sample from
Two broad groups of musculoskeletal disorders that Malmo, Sweden, had experienced shoulder pain lasting a
may be related to work will be considered in this chapter: day or more in the preceding month, and 3 per cent had
neck/upper limb pain (Table 57.1) and osteoarthritis. We taken sick leave because of it in the preceding year. A study
describe for each principal disorder in turn, its epidemiol- of 15 268 Stockholm residents reported a point prevalence
ogy, the evidence for its apparent association with work, its of shoulder pain of 20 per cent in subjects aged 40–74
clinical presentation and its management. Later in the years9 and Dimberg et al.4 found that 13.1 per cent of
chapter we consider aspects of detection and prevention, as workers in an aeroengineering factory had current shoul-
well as the current path on which research enquiries are der pain. Complaints become more common with age,
headed. although the Stockholm data suggest a peak around ages
Shoulder problems 689
Male shipyard workers and plate Office workers C 11–13 Herberts et al.14
workers
Female packers Female shop assistants C 2.6 Luopajarvi et al.15
Male and female packers Knitters C 2.2
Sewers Knitters C 2.4 McCormack et al.3
Board manufacturers Knitters C 2.1
Garment workers Health service workers C 2.2 Punnett et al.16
Assembly workers General population C 3.4 Ohlsson et al.17
Female data entry workers Other female office workers C 0.54 Kuorinka and Koskinen et al.18
Male industrial workers with shoulder Age and workshop matched CC 11a Bjelle et al.19
tendinitis non-cases
a
Relative risk for work with hands at or above shoulder level.
C, cross-sectional study; CC, case–control study.
55–60 years.9 In the younger age group, there appears to be exposure contrasts have been defined in terms of work
little difference in prevalence between the sexes, but in the activity, rather than the cruder measure of job title. A num-
50s and thereafter men complain more commonly.9 ber of exposures (e.g. repetitive movements, vibration, high
Data on incidence derive principally from the National psychological demands) have been studied in this way. Van
Morbidity Surveys in General Practice in England and der Windt et al.,20 in their systematic review, comment that
Wales, a general practice-based surveillance system which in studies of good methodological quality associations were
collects details of consultations in participating practices ‘generally not strong’; while another review by National
over a one-year period. The 1981 survey indicated an Institute for Occupational Safety and Health (NIOSH)21
annual incidence for all shoulder syndromes of 6.6 per referred to ‘evidence’ (meaning some degree of support)
1000 practice-registered patients.10 In the Stockholm survey, for associations with repeated or sustained shoulder pos-
a subset of the cross-sectional respondents was interviewed tures with greater than 60° of flexion or abduction, but
and examined a year on, also providing incidence data: ‘insufficient evidence’ in relation to vibration and forceful
around 1–2.5 per cent had developed a painful shoulder, movements. Only recently have prospective studies been
which included clinically verified restricted movement.9 undertaken. However, in an Arthritis Research Campaign
The peak annual incidence rate occurred in the fifth decade cohort study of new employees, lifting, carrying, pushing/
and there was little difference between the sexes. pulling, monotonous employment and work with the
hands above shoulder height were all found roughly to
double risks of the relatively softer outcome of new onset
Occupational studies shoulder pain during a two-year follow up.22
It should be noted that these studies have mainly inves-
Injury appears to arise because of regular impingement of a tigated the occurrence of rotator cuff tendinitis (defined
relatively hypovascular area of the cuff against the acromio- operationally as localized shoulder pain and tenderness
clavicular arch, an event that may be aggravated functionally over the humeral head23) or shoulder pain; the relation
through superior migration of the humeral head in abduction of other shoulder problems to work activity has not been
and elevation, or by an acromial spur or degenerative examined in detail, although they may arise, coexist or
acromioclavicular joint. Studies of blood flow in the become confused with tendinitis, and may certainly con-
supraspinatus muscle11,12 and muscle fatigue13 confirm the tribute to work incapacity when they occur. For this
importance of postural risk factors in the development of reason, they are described separately under Rotator cuff
shoulder disorders. Occupational studies have therefore tendinitis, Calcific tendinitis, Bicipital tendinitis and
concentrated on working groups who elevate the shoulder Shoulder capsulitis (frozen shoulder).
repeatedly or for sustained periods at work, such as crop pro-
duction workers, assembly line and other production workers. Clinical aspects
Table 57.2 summarizes some of the older findings, based
upon a comparison of occupational titles. Although risk ROTATOR CUFF TENDINITIS
estimates vary, most reports have concluded that there is
good evidence of an association between overhead work Rotator cuff tendinitis (most commonly an inflammation of
and shoulder problems. In more recent investigations, the supraspinatus tendon), tends to have an insidious onset,
690 Repeated movements and the musculoskeletal system
causing a dull shoulder aching or discomfort in the absence SHOULDER CAPSULITIS (FROZEN SHOULDER)
of a trauma history. Nocturnal pain is a prominent feature.
Pain is felt over the deltoid region, and difficulty is encoun- The primary form of this condition is characterized by
tered in reaching up, in dressing and in overhead work. global restriction of glenohumeral movement in all planes
On examination, there may be tenderness over the in the absence of significant underlying joint disease. It is
humeral head and greater tuberosity, and the diagnosis is believed to affect 2–3 per cent of the population28 and
confirmed by reproducing the pain in resisted movement onset nearly always occurs after the age of 40 years.
of the affected tendon. Supraspinatus tendinitis causes Classically, there are three phases in the natural history of
discomfort on abduction with a painful arc occurring the condition, each lasting several months: a painful shoul-
between 70–120 degrees of abduction. der (phase 1) becomes painful and stiff (phase 2), and then
Chronic rotator cuff tears are often found at autopsy,24,25 profoundly stiff with slow natural resolution (phase 3). A
and in life these tend to be associated with falls on the minority of patients (7–15 per cent) have persistent func-
outstretched hand, as well as overuse, and are noteworthy tional difficulties afterwards.29,30
clinically because of weakness and muscle wasting, and The onset is insidious, with pain in the deltoid area
because of the inability to maintain abduction (a positive increasing gradually until sleep is disturbed. In the adhe-
‘drop off’ sign). sive phase, there is equal restriction of active and passive
Plain x-rays show evidence of calcification in the rotator glenohumeral movement in a capsular pattern (external
cuff tendons in 8 per cent of the asymptomatic population rotation more than abduction, more than internal
over age 30 years,26 and sometimes cystic and sclerotic rotation). The aetiology of the condition is poorly under-
changes at the greater tuberosity insertion. Ultrasound and stood and a particular relation with work has not been
magnetic resonance imaging (MRI) may be used to demon- demonstrated thus far.
strate rotator cuff tears, while arthrography will demonstrate
full thickness tears.
Management of shoulder problems
CALCIFIC TENDINITIS A Cochrane review by Green et al.,31 in summarizing the
evidence base on management of shoulder problems, found
Calcific tendinitis often arises against a background of
that certain physical therapies (exercise, laser therapy,
chronic shoulder pain on movement and arises at the site
ultrasound, pulsed electromagnetic field therapy) offered
of rotator cuff injury and calcification, but it has a clinical
some benefit over placebo in certain disorders (e.g. rotator
pattern distinctive enough to be separately described. Pain
cuff disease, adhesive capsulitis, calcific tendonitis), but that
is severe, localized to the deltoid area and quite abrupt in
more robust conclusions were undermined by small studies
onset. Passive and active shoulder movements are greatly
with weak statistical power and other methodological
limited by pain, and there is extreme tenderness over the
limitations. This information gap notwithstanding, a num-
humeral head. X-rays reveal well-defined or fluffy calcium
ber of treatment options have gained currency in clinical
deposits in the affected tendon (usually the supraspina-
practice.
tus). The erythrocyte sedimentation rate (ESR) and white
The treatment of rotator cuff tendinitis is often difficult.
cell count are normal. Acute calcific tendinitis is a self-
Rest and modification of aggravating activities are necessary
limited process, lasting one to two weeks. Sometimes it
to prevent the problem becoming chronic. Initial treatment
occurs spontaneously and not in apparent relation to
should be directed at reducing inflammation by means of
injury.
physical therapy (for example, ultrasound) and a non-
steroid anti-inflammatory agent. If symptoms fail to settle
BICIPITAL TENDINITIS within three weeks, a subacromial injection of corticos-
teroid is useful. Once pain has eased and normal shoulder
The long head of the biceps tendon tends to become movements have been restored, a muscle-strengthening
inflamed as part of a more generalized shoulder problem exercise programme should be instituted, concentrating on
(such as rotator cuff or adhesive capsulitis), rather than in rotator cuff exercises. Failure to respond to a conservative
primary overuse. However, it has occurred following programme within a year or so is a reasonable indication
weight lifting, and may well arise occupationally from for surgical repair of the rotator cuff and release of acromial
prolonged repetitive carrying. impingement.
Pain occurs over the anterior shoulder, radiates into the Many therapies have been tried to modify the natural
biceps and is felt in overhead work and in shoulder exten- history of adhesive capsulitis of the shoulder joint. The
sion, abduction and rotation. Tenderness is usually found mainstay of treatment remains intra-articular corticos-
over the tendon as it passes through the bicipital groove. In teroid injection during the early phase when pain is the
Yergason’s test,27 pain is provoked over the anterior inner most prominent clinical complaint. During the phase of
shoulder in resisted active supination of the forearm with movement restriction without pain, it has been difficult
the elbow bent at 90°. to demonstrate the efficacy of any modality of treatment
Neck problems 691
(including injection therapy, physiotherapy and anti- research are cervical spondylosis, cervical syndrome, ten-
inflammatory drugs). Carefully directed corticosteroid sion neck syndrome and thoracic outlet syndrome, while
injections also comprise the mainstay of treatment for the most popular classification schemes are those by Waris
a number of other shoulder problems, including et al.,42 Viikari-Juntura43 and Ohlsson et al.44
acromioclavicular joint dysfunction, bicipital tendinitis
and subacromial bursitis.
Occupational studies
TENSION NECK SYNDROME register operators (32 per cent)52 and plate workers (31 per
cent),53 but by contrast a UK expert workshop of occupa-
Tension neck syndrome (TNS) is reported in Scandinavian tional physicians, rheumatologists and orthopaedic surgeons
and American studies of occupation, but is not described in considered it so rare as to obviate the need for consensus
standard textbooks of rheumatology and orthopaedics, and definition. This is in addition to the many sensory motor
not widely recognized in the UK. However, it most closely and vascular symptoms ascribed to thoracic outlet syn-
corresponds to a regional pain disorder of the neck– drome (TOS) which does not permit a ready description of
shoulder area. It has been defined as a constant feeling established diagnostic criteria.
of fatigue or stiffness in the neck associated with other
subjective symptoms (such as neck pain or headache)
and tender spots, palpable hardenings and neck muscle Management
tightness.23
Such clinical patterns have been described in excess in The management of cervical pain syndromes is predomi-
assembly line workers,46 data entry operators,47 scissor nantly non-surgical. Acute exacerbations of neck pain are
makers,18 lamp assemblers48 and other groups, with managed with a soft cervical collar, an eight-week course of
reported risk ratios of 2.3 to 7.3. In keeping with this liter- combined analgesic and anti-inflammatory therapy and a
ature, a recent systematic review49 found ‘moderate’ evi- physiotherapy programme. The physical therapy should
dence that neck pain with palpation tenderness (TNS) and include the use of heat pad, neck exercises, ultrasound/
mixed neck–shoulder disorder (predominantly TNS) were short-wave diathermy and massage. Traction and transcu-
causally related to repetition at the shoulder and neck taneous electrical nerve stimulation (TENS) are helpful in
flexion allied with repetition, but only limited evidence in controlling brachial root irritation. Manipulative therapy
relation to other factors, such as hand–wrist repetition and and acupuncture may assist in selected resistant cases. The
static loading in the absence of repetition. In the high principal indication for structural imaging (MRI or com-
quality Danish Project on Research and Intervention in puted tomography (CT)) is objective neurological deficit. If
Monotonous Work (PRIM) health study50 – which severe foraminal encroachment or myelopathy is discov-
involved pain-staking reconstruction of work tasks, video- ered, surgical decompression may become necessary.
tape analysis of rates of repetition and proportion of time
spent with the neck in various postures, and prospective
blinded standardized assessment of outcome – strong ELBOW
exposure–response gradients were seen with the physical
risk factors investigated, and odds ratios were raised by The elbow joint actually comprises a compound synovial
two- to three-fold in those whose jobs typically involved joint with articulation between the ulnar notch and the
>15 versus 0 shoulder movements per minute or with the trochlea of the humerus, and also between the radial head
neck flexed 20° for at least two-thirds of the time. and the humeral capitellum. In consequence, a large vari-
Various mechanisms have been suggested for occupa- ety of movements are possible, including flexion of 150°,
tionally related TNS, including local muscle ischaemia, pronation of 75–80° and supination of 85–90°. Apart from
disturbed muscular microcirculation and sensitized pain epicondylitis and olecranon bursitis, soft tissue problems
receptors, but no specific pathological lesion has been of the elbow are uncommon.
identified. It seems plausible that tasks involving dynamic
loading and tension of the shoulder and neck muscles pro-
duce such symptoms, but less clear whether they constitute Epidemiology
a defined, discrete WMSD. (This may be a semantic point
for occupational physicians who are interested in good Epicondylitis is a pattern of pain at the origins of the exten-
ergonomic practice and worker comfort.) sors of the fingers and wrists on the lateral epicondyle (lateral
epicondylitis), or at the origin of the flexors on the medial
epicondyle of the humerus (medial epicondylitis). Lateral
THORACIC OUTLET SYNDROME
epicondylitis (tennis elbow) is about seven times more
A constellation of neurological and vascular features common than medial epicondylitis (golfers’ elbow). The
ascribed to entrapment of the brachial nerve plexus and point prevalence of elbow pain has been reported at 11–13
subclavian vessels by a cervical rib or congenital fibrous per cent in aeroengineering workers4 and textile workers3
band. The frequency of this condition is highly contentious – and in a population survey the period prevalence of elbow
some orthopaedic authors regard the syndrome as very pain during the previous year was 7 per cent in 40–50 year
rare in the general population, whereas others describe olds and 14 per cent in those over 50 years.54 However,
large panels of successfully treated patients.51 A similar clinically verified epicondylitis is less common: among the
divergence of opinion exists in occupational medicine: textile workers only 2 per cent had tender as well as painful
some authorities have described high prevalences of the elbows3 and in a Swedish community survey that included
condition in assembly line workers (14–44 per cent),52 cash clinical examination the prevalence in 31–74 year olds was
Tenosynovitis and peritendinitis 693
2.5 per cent.9 Clinical epicondylitis reaches a peak preva- case–control and one cohort study point in the same
lence and incidence in the fifth decade of life, and becomes direction. Haahr et al.63 compared work exposures in 267
increasingly less common after the age of 50 years.9 It more cases and 388 referents, recruited from Danish general
commonly affects the dominant hand. Although 40–50 per practices and found associations with various activities
cent of tennis players have the condition,55 less than 5 per performed for three-quarters or more of the time versus
cent of cases arise from the sport.56 never/almost never – namely, arms lifted in front of the
body (odds ratio (OR) 4.0 for women), hands bent or
twisted (OR 7.4 for women, 3.2 for men), same move-
Aetiology
ments of the arm (OR 3.7 for women) and work requiring
precise movements (OR 5.2 for men). In France, where
Lateral epicondylitis is believed to arise principally from
workers have routine statutory medicals, Leclerc et al.64
overexertion of the finger and wrist extensors – in repeated
reported that jobs that involved repetitive turning and
hand dorsiflexion or in alternating forearm pronation and
screwing doubled the risks of incident epicondylitis after
supination.56 In those cases coming to clinical attention,
allowing for other factors.
there is often a history of unaccustomed, forceful, repeti-
tive use.
However, the pathological lesion remains a point of
debate, and there have been at least 25 suggested causes.57
Clinical aspects
The most widely held theory is that macroscopic or micro-
The hallmark of lateral epicondylitis is slow onset pain and
scopic tears occur between the common extensor tendon
tenderness over the lateral epicondyle. The pain is repro-
and the periosteum of the lateral humeral epicondyle,58 and
duced by resisted dorsiflexion of the wrist with the elbow
such tears have been identified in surgical procedures,59 but
extended. Grip is impaired and this may limit working
not consistently enough to resolve the argument.56
ability. In medial epicondylitis, the pain and tenderness
(which are medially located) are often less prominent. Pain
Occupational studies is reproduced over the medial epicondyle by resisted pal-
mar flexion of the wrist. Investigations are generally
Over 20 epidemiological studies have examined workplace unhelpful and unnecessary.
physical risk factors and their relation to epicondylitis. A
major review by NIOSH21 found ‘insufficient’ evidence for
associations with repetition and postural factors when Management
considered individually, and only weak evidence in rela-
tion to forceful work, but the evidence was considered Many treatments have been proposed, though not all have
‘strong’ when these factors existed in combination. As been validated. Placing the arm in a sling or plaster cast may
examples of the evidence base, in three cross-sectional sur- help, but recovery often requires six weeks of immobility.
veys comparing meat cutters, sausage makers and packers A wrist splint (to prevent wrist dorsiflexion) sometimes
with workers in less strenuous jobs, Viikari-Juntura et al.60 provides symptomatic relief. Pulsed ultrasound has been
found that elbow symptoms were 1.6–1.8 times more com- shown to be efficacious,65 while up to 90 per cent of
mon in the exposed groups, but the prevalence of clinically subjects respond to local injection of corticosteroids. In
verified epicondylitis was identical (0.8 per cent). Dimberg resistant cases, surgery may be required as a last resort.
et al. reported a higher prevalence in aircraft factory workers After conservative treatment relapse is fairly common
(7.4 per cent), but found no difference between white- and (18–50 per cent within six months66,67), especially in man-
blue-collar workers.4 McCormack et al. described a relative ual workers such as mechanics and builders.68 In a case
risk of 1.5 in packers and sewers compared with knitters,3 a series of 88 workers visiting an occupational health depart-
moderate excess of clinical epicondylitis has been described ment,69 splint therapy combined with indomethacin was
in a cross-sectional survey of public gas and water workers compared with cortisone therapy; neither duration of
with long-term exposure to strenuous elbow work61 and absence from work, nor recurrence rate differed between
Luopajarvi et al. described a similar-sized effect when the treatment groups.
women packers were compared with non-cashier shop It is said that lateral epicondylitis resolves spontaneously
assistants,15 but these differences are comparatively modest in eight to twelve months,57 but in one rheumatology clinic
and the confidence intervals for the risk estimates were a majority of sufferers were still symptomatic at the one
compatible with chance. year stage.68
In 1997, when the review was written, just one cohort
study had been published,62 with strongly positive find-
ings: an incidence rate 7–10 times higher in meat cutters TENOSYNOVITIS AND PERITENDINITIS
and sausage makers (designated as jobs with high force and
repetition) relative to other workers. Ten years on, the There is some confusion in the literature about the appro-
evidence base is scarcely more extensive, although one priate terminology for this lesion. Some authors draw a
694 Repeated movements and the musculoskeletal system
distinction between inflammation of the tendon sheath when people were required as part of the war effort to
of the wrist (tenosynovitis), the paratendon at the muscle– undertake unaccustomed work in factories and in agricul-
tendon junction rather further up the arm (peritendinitis), ture.75 Initially, a dull aching is experienced, but continua-
and the tendon itself (tendinitis), but such a distinction is tion of the work can give rise to severe pain. In the classical
not often drawn in the classification criteria adopted in case, a sausage-shaped swelling is present on the radial side
occupational and community surveys. For this reason, we of the lower part of the dorsal surface of the forearm, prox-
use the terms interchangeably in this account. imal to the radial styloid process. The swelling, which is
generally about 4 cm long, is tender and crepitus is often
palpable and audible over it, sometimes extending up
Epidemiology the forearm. Local redness and warmth may occur. In the
less florid case, the diagnosis may be confused with
In the US National Health Interview, 20 per 1000 adults osteoarthritis of the thumb base, but radiological assess-
reported that a doctor had told them they had ‘tendinitis’,70 ment assists in this differential diagnosis.
while in the UK Primary Care Study for 1981, the incidence The treatment consists of local heat, non-steroidal anti-
of tenosynovitis, tendinitis, synovitis and bursitis com- inflammatory drugs (NSAIDs), and wrist and thumb
bined was 10.9 per 1000 persons per year.10 The incidence immobilization by thermoplastic splinting. In patients
was more common in women than men at all ages, and with severe or persistent pain, one or more local corticos-
peaked in middle age. teroid injections can be helpful, giving complete and lasting
relief in about 70 per cent of patients. Surgical decompres-
sion of the first extensor compartment (with or without
Occupational studies tenosynovectomy) is indicated in those with persistent
symptoms lasting longer than six months.
There have been several cross-sectional surveys of
hand–wrist tendinitis in the workplace. In a recent system-
TRIGGER FINGER
atic review,71 elevated relative risks (RRs) were found in
four studies of assembly and packing – one in the shoe Trigger finger is the result of tenosynovitis affecting the flexor
industry (prevalence ratio (PR) 3.7),46 one in automobile tendons of the finger or thumb. The consequent fibrosis and
workers (PR 2.5),72 one of assembly line packers (PR 4.1)15 constriction impair the tendon’s motion at the first annular
and one of meat packers (RR 36).62 In addition, two posi- pulley, which overlies the metacarpophalangeal joint. The
tive surveys were found of meat cutters. A longitudinal most common cause of trigger finger is said to be overuse of
study by Kurppa et al.62 found an incidence rate ratio of the hands in repetitive gripping activities. Management con-
13.9, while an odds ratio (OR) of 3.1 was reported in a sists of modification of hand activity, local heat treatment,
smaller investigation by Roto et al.73 The first of these stud- gentle exercises and NSAIDs as required. One or more cor-
ies also indicated a high RR (24.1) in women making ticosteroid injections to the affected flexor tendons cure the
sausages.62 Finally, in a cross-sectional study that exam- majority of patients. Surgical transection of the fibrous
ined risks by physical activity, jobs that combined high annular pulley is rarely required.
force and high repetition carried a 29-fold greater risk of The evidence of benefit in these various treatments usu-
tendinitis than those lacking such features.74 ally relates to short-term improvement, and there is clearly
a need to demonstrate their longer-term benefit in con-
trolled trials of adequate design. Such trials should reflect
Clinical aspects the occupational environment in which the pain syndrome
developed and the effect of ergonomic interventions insti-
The tendons most frequently involved are the radial exten- tuted during the trial period.
sors of the wrist and the long abductor and short extensor
of the thumb. The flexor tendons are affected far less often.
CARPAL TUNNEL SYNDROME
TENOSYNOVITIS OF THE WRIST (DE QUERVAIN’S DISEASE)
As it passes through the carpal tunnel into the wrist, the
Tenosynovitis of the wrist (De Quervain’s disease) is char- median nerve lies immediately beneath the palmaris longus
acterized by pain on movement, localized to the tendon tendon and anterior to the flexor tendons. Conditions that
sheaths in the wrist and reproduced by resisted active decrease the size of the carpal tunnel or increase the volume
movement. Pain is centred on the radial aspect of the wrist of structures contained within it, tend to compress the
and thumb base, and particularly aggravated in grasping median nerve against the transverse ligament which bounds
and employing the pinch grip. Typically symptoms appear the tunnel’s roof. Such circumstances can arise traumati-
following return to work after a long lay off, or following a cally, congenitally or due to systemic or inflammatory effects
change to unfamiliar work requiring new, rapid move- (for example, diabetes mellitus, rheumatoid arthritis,
ments. For example, many cases occurred in the 1940s acromegaly, hypothyroidism, pregnancy and tenosynovitis).
Carpal tunnel syndrome 695
Table 57.3 Case–control studies of carpal tunnel syndrome and its relation to work activities.
body of evidence that highly repetitious flexion and exten- determine the correct therapeutic approach. Other meas-
sion of the wrist can more than double risks of CTS, and ures which are known to be of benefit include splinting,
recently this association has been accepted for compensa- local corticosteroid injection, the use of anti-inflammatory
tion purposes witin the terms of the UK State Industrial drugs and, ultimately, surgical release.
Injuries Benefits Scheme.
It should be remembered that case–control studies, like
cross-sectional surveys, are susceptible to well-recognized CHRONIC UPPER LIMB PAIN
biases. The association with a particular exposure may be
spuriously inflated by recall bias, or by the effect of disease In describing upper limb disorders, different physicians
on work (if the decision to consult relates especially to dif- have used a variety of terms in a variety of ways. For some,
ficulty in getting the job done). In CTS investigations, ‘work-related upper limb disorders’, ‘cumulative trauma
however, the studies have been in broad agreement. The disorders’ and ‘repetitive strain disorders’ are synony-
more classically specific the case definition, the stronger mous, and describe collectively the full range of recognized
the association with physical risk factors.92 Furthermore, it and ill-defined disorders arising (or appearing to arise)
can be demonstrated experimentally that extreme flexion from frequent, forceful overuse of the upper limb at work.
and extreme extension of the wrist increase the pressure in For others, repetitive strain injury (RSI) refers to a particu-
the carpal tunnel sufficiently to impair blood perfusion of lar diagnosis made by exclusion, i.e. chronic upper limb
the median nerve, so that epidemiological and physiologi- pain ascribed to overuse at work, for which no clinical
cal investigations provide a coherent view of causation. diagnosis can be made. Inevitably, confusion has ensued
among doctors and especially in medical litigation.
The problem can be illustrated by reference to some
Clinical aspects topical cases that have attracted publicity. In 1981, an
enquiry over upper limb complaints in an Inland Revenue
The history is typically one of gradual onset of numbness office accepted that complaints, such as lateral epicondyli-
and tingling in the median nerve distribution of the hand. tis and tenosynovitis, could sometimes arise from the use
Strenuous use of the hand usually aggravates symptoms, of the visual display unit (VDU). In December 1991, Judge
although this may not become apparent until several hours Byre found in the High Court that two British Telecom
after the activity. Night-time pain commonly disturbs keyboard operators had RSI that had been induced by the
sleep and patients often hang the affected hand over the side nature of the work (at least 10 000 depressions per hour
of the bed in an effort to gain relief. Many sufferers also with a bonus for higher totals) and long hours in con-
complain of progressive weakness and clumsiness in their strained postures on defective seating (the complaints were
hands and tend to drop things. diagnosed as tenosynovitis and epicondylitis). In 1994, a
Tinel’s test (percussion over the flexor retinaculum legal secretary received an award for tenosynovitis pro-
reproducing parasthesiae over the median nerve distribu- voked by periods of intense typing. By contrast, in 1993
tion) is positive in about three-quarters of sufferers, and Judge Prosser, dismissed the complaints of a Reuters jour-
Phalen’s test (sustained complete flexion of the wrist for 1 nalist, concluding that ‘RSI did not exist’. Such a ruling
minute producing symptoms over the median nerve distri- plainly does not disprove the existence of well-established
bution) is positive in a similar proportion.93 In one large entities, like lateral epicondylitis and tenosynovitis, and the
case series, clinical impairment of sensation could be debate is really on two different fronts: (1) how often such
demonstrated over the median nerve in a quarter of cases, specific complaints can arise from work activity and (2)
and thenar atrophy in a fifth. whether there is a condition of chronic upper limb pain
The most important diagnostic test is nerve conduction. which presently defies clinical diagnosis, and which may be
A slowed sensory nerve conduction velocity across the caused by work. Information on these questions has been
carpal tunnel and a prolonged distal motor latency support tainted by studies that have drawn no distinction between
the diagnosis. Electrodiagnostic tests are often quoted as potentially dissimilar clinical end points.
the gold standard, but even the most sensitive latency tests In this chapter we have attempted to draw a clearer dis-
confirm no more than 90 per cent of ‘classical’ clinical tinction. The term RSI in the text that follows refers to
cases. chronic upper arm pain for which no diagnosis can be
made and which has been ascribed to occupational overuse.
Management
Epidemiology
The specific treatment of carpal tunnel syndrome depends
to a large degree on whether there is an identifiable cause of It has proved difficult to define the epidemiology of a con-
the entrapment. Conservative measures may suffice when dition for which no clear definition and no validated or
symptoms are of short duration. Electromyographic accepted diagnostic criteria exist. Routinely collected sta-
determinations repeated over time may help the clinician tistics tend to involve umbrella classifications that make it
Chronic upper limb pain 697
Table 57.4 Incidence rates of compensated repetitive strain work in surveys than can be explained by known physical
injury (RSI) by industry in Australia, 1985–86 (adapted from risk factors from the workplace.97 By the 1990s, the com-
Gun94). pensation rate in Australia had declined to a more normal
level without any reduction in occupational physical
Industry Male Female
demands. Similar transient epidemics have been seen in
incidencea incidencea
other countries and other time periods: in Japan, an epi-
demic of ‘occupational cervicobrachial disorders’ was
Manufacturing reported between 1958 and 1982 and an epidemic of
Food, beverages 4.5 7.4 writer’s cramp occurred among male clerks in the British
Textiles, clothing, footwear 4.7 4.2 Civil Service in 1830. In the Japanese outbreak, the workers
Public administration 3.9 4.8 who most frequently complained were typists and keyboard
Agriculture 3.1 1.7 operators, punchcard operators and telephone operators
Transport equipment 3.0 16.2 (10–28 per cent of people claimed to be affected in some of
Basic metal manufacture 2.5 16.7 the occupational groups98). As a result, the Japanese
Finance, business services 0.2 3.0 Ministry of Labour introduced guidelines that restricted
Mining 0.5 1.5 working time at the keyboard to no more than five hours a
Health services 0.3 1.2 day and the maximum number of key strokes to 40 000 per
All industries combined 1.4 2.6 day, and this was followed by a fall in the frequency of
a
Per thousand person-years. complaints.99 Another crop of upper limb complaints
developed in the Inland Revenue Department of the
British Civil Service in 1981.
The time variation in these various data sets suggests
hard to disentangle information on non-specific upper that psychosocial variables play an important part in the
limb pain. However, in Australia, the Bureau of Statistics presentation and recognition of the condition, if not also
separately codes compensation awards for injuries without in its development.
explicit diagnosis ascribed to repetitive movement. Table
57.4 illustrates the variation in incidence rate of compen-
sated RSI between men and women, and by industry.94 Clinical aspects
Overall, RSI was more common in blue-collar workers
than in clerical workers. For men, the highest rates Miller et al.100 have described a series of 200 consecutive
occurred in the manufacture of textiles, clothing and patients referred for specialist opinion with suspected RSI
footwear, food and beverages. In women, very high inci- in whom no other specific diagnosis could be made. In 75
dence rates occurred in parts of the manufacturing sector. per cent, the onset of pain was gradual, beginning as local-
Sequential data over the period 1980–87 showed dra- ized distal pain, but more diffusely spread by the time of
matic changes with time. The number of successful claims clinic attendance. Nearly all of the patients described
among women in 1984–85 was five times greater than in parasthesiae and 73 per cent described subjective swelling
1980–81, and that amongst men 50 per cent greater. of the limb. The dominant hand was more commonly
Hocking95 reported on the Australian RSI epidemic as it affected, but bilateral disease was also common. Anxiety,
affected one large employer, the nationalized telephone irritation, mood change, fatigue and sleep disturbance
operator Telecom Australia between 1981 and 1985. were nearly always present. Clinical signs were generally
Nearly half of the 3976 reports within the company arose absent, although most of the patients described tenderness
in telephonists, providing an incident rate of 343 cases per at multiple sites.
thousand keyboard workers over the five years, as com- In this respect, RSI has many similarities with
pared with 284 per thousand in clerical workers, 116 per fibromyalgia, a chronic musculoskeletal disorder of uncer-
thousand in process workers and 34 per thousand in tain cause characterized by chronic widespread pain and
telegraphists. Women accounted for 83 per cent of all multiple tender points. Fibromyalgia sufferers also tend to
reports. Sixteen per cent of subjects had symptoms lasting complain of fatigue, sleep disturbance, stiffness and paras-
longer than six months and the cost of the epidemic was thesiae, and the clinical similarity between these two
estimated at more than $15 million dollars. conditions has led to the suggestion that RSI is a fibromyalgia
Of course, the decision to lodge a complaint or to com- variant.100,101 Fibromyalgia is fairly common, affecting
pensate a claim, or even to pay attention to a symptom, can around 1–2 per cent of the population,102,103 5–8 per cent
be heavily influenced by local awareness and health beliefs, of hospital attendees104 and 14–20 per cent of patients
fuelled by media publicity. It has been found, for example, referred to a rheumatology clinic.105,106 The diagnostic crite-
that arm pain is far less commonly reported by Indian ria of the American College of Rheumatologists requires the
workers in Mumbai (who have a very low awareness of pain of fibromyalgia to be present for at least three months
RSI) than in UK Asian workers doing essentially similar in all four quadrants of the body and axial skeleton, with
work,96 and that arm pain is far more often attributed to tenderness at 11 of 18 defined examination points.107 The
698 Repeated movements and the musculoskeletal system
key point of clinical distinction is that fibromyalgia, pain associated with cigarette smoking and alcohol consump-
and tender points occur in the trunk and lower limbs, as tion.110 It is also known to be more common in patients
well as in the arm, shoulder and neck. with diabetes and epilepsy.
It has been suggested that RSI is a condition of pain
amplification leading to abnormally low cutaneous pain
threshold (allodynia), muscle stiffness and vasomotor Occupational studies
changes. However, these ideas remain largely untested.
Clinical and some epidemiological observations suggest The relation between Dupuytren’s contracture and acute
that personality, emotional state, health beliefs, culture and or cumulative traumatic injury is controversial. Case reports
psyche are important too, and pessimism about recovery is exist of Dupuytren’s contracture arising soon after an
a poor prognostic indicator in arm pain sufferers, even acute injury to the hand, such as a penetrating wound,
when account is taken of case severity.108 crush injury or fracture,111 although epidemiological
No standard scheme exists to classify case severity in studies have not been conducted so far to investigate the
suspected cases of RSI, but the Australian Occupational association more formally. The relation between Dupuytren’s
Repetitive Strain Injuries Advisory Committee of the New contracture and chronic cumulative trauma has been
South Wales Government of Industrial Relations proposed reviewed recently by Liss and Stock.112
a three-stage clinical grading scale. The first stage was char- Bennett113 observed a standardized morbidity ratio of
acterized by aching and tiredness occurring at work but 1.96 for Dupuytren’s contracture among bagging and
settling overnight. In stage 2 disease, symptoms failed to packing plant workers as compared with the expected age-
settle overnight and disturbed sleep, a condition that could adjusted prevalence from an earlier survey, and an odds
persist for several months. Finally, in stage 3 disease symp- ratio of 5.5 compared with workers from the local plant
toms persisted at rest, prevented even light duties and were who did not undertake these activities. While Mikkelsen114
persistent over months or years. The relation between this reported a sex-adjusted odds ratio of 3.1 for heavy versus
proposed clinical grading scheme and the various specific light manual work in a population-based sample from
and non-specific disorders that may be encountered in Norway. However, the literature is comparatively sparse.
practice remains unclear. The relation with use of vibrating tools has been inves-
tigated more extensively. Thomas and Clarke115 observed
that Dupuytren’s contracture was twice as common in 500
Management men claiming vibration-induced white finger than in 150
controls admitted to hospital for elective surgery. An
These aetiological components suggest and support a biopsy- Italian case–control study116 reported an odds ratio of 2.3
chosocial approach to treatment. A structured rehabilitation for exposure to vibration at work after adjustment for alco-
programme including graduated exercises, behavioural hol. In another Italian investigation, Bovenzi et al.117
approaches to pain control, analgesic medication and assis- observed an increased frequency of Dupuytren’s contrac-
tive devices, such as short-term splinting, may achieve dra- ture among quarry drillers and stone carvers compared
matic benefits in the small number of severely affected with stone workers who performed manual work but were
patients. In this subgroup, there is otherwise a very low not exposed to vibration (odds ratio 2.6, 95 per cent CI
probability of returning to gainful employment. 1.1–6.2). Other researchers, by contrast, have failed to
observe such an association.112
In summary, there is some evidence that Dupuytren’s
contracture may arise from occupational activities and this
DUPUYTREN’S CONTRACTURE evidence is strongest for exposure to hand-transmitted
vibration. The relation between Dupuytren’s contracture
Dupuytren’s contracture is a nodular proliferation of and other manual work is uncertain at present.
fibrous tissue of the palmar fascia which leads to contrac-
ture and permanent flexion of the fingers (especially the
fourth and fifth fingers) of one or both hands. OTHER SOFT TISSUE RHEUMATIC
CONDITIONS
Epidemiology Two other categories of complaint that may be related to
repetitive physical activity are recognized (prescribed) for
Dupuytren’s contracture is a common condition. In north- state compensation under the UK Department for Work
ern Europe, for example, it affects about 10 per cent of and Pensions (DWP)’s Industrial Injuries Disablement
men aged over 65 years. The condition is more common in Benefits (IIDB) provisions:
men than women, and the prevalence increases with age.109
The condition is frequently bilateral. In a recent case– ● cramp of the hand or forearm ‘due to repetitive
control study, the condition was found to be independently movements’;
Osteoarthritis 699
● the ‘beat’ conditions – subcutaneous cellulitis of the by the age of 65 years, and in about 80 per cent of those
hand (beat hand) and subcutaneous cellulitis or bursitis aged 75 years and over.118 The disorder is second only to
of the knee (beat knee) or elbow (beat elbow). ischaemic heart disease as a cause of work-related disability
in men over 50 years of age.
The epithet ‘beat’ has been removed in a recent revision of OA is defined as focal loss of articular cartilage with
IIDB terminology. Carpal tunnel syndrome in vibrating variable subchondral bone reaction. There is incomplete
tool users and tenosynovitis are also prescribed. concordance between these pathological features and
radiographic or clinical characteristics of the disorder.
However, the difficulties encountered in using a patholog-
Writer’s cramp, telegraphist’s cramp, ical definition for epidemiological studies of OA have led
twister’s cramp or craft palsy to the widespread use of radiological and clinical markers.
The radiographic features conventionally used to define
This is said to be a condition of occupations that involve a the severity of OA include joint space narrowing, osteo-
great deal of handwriting, typing or other repetitive move- phyte, subchondral sclerosis, cyst formation and abnor-
ment of the hand or arm. According to Department for malities of bony contour. These radiographic features can
Work and Pensions examiners’ guidelines, it manifests as be incorporated in rating scales at the commonly affected
symptoms of spasm, tremor and pain in the hand or joint sites (for example, the hand, knee and hip), permit-
forearm (Focal dystonia) brought about by attempts to per- ting standardized grading of disease severity.119 The two
form a familiar repetitive muscular action, and occurs in clinical sequelae of OA that are most relevant are joint pain
the absence of physical signs or detectable abnormalities on and functional impairment.
investigation. Many physicians would question whether The development of OA at any joint site depends upon
such an entity exists as a defined disease. The time course a generalized predisposition to the condition, and biome-
and chronicity of disease is not clearly defined, and it would chanical abnormalities that act at specific joints.118,120
appear difficult in practice to distinguish this condition Individual risk factors that may be associated with a gener-
from transient occupational discomfort or chronic non- alized susceptibility to the disorder include obesity, a
specific upper limb pain. Despite these uncertainties, family history and hypermobility. Those that reflect local
around 120 new cases undergo assessment each year for biomechanical insults include trauma, abnormalities of
prescription purposes. joint shape and physical activity, including work.
These observations have been extended by a register- women from Framingham,131 the risk of radiographic knee
based Swedish cohort study,126 in which the risk of knee OA was highest in subjects whose earlier jobs were classi-
OA coming to arthroplasty in various occupational groups fied as both physically demanding and likely to involve
was compared with the baseline population risk. Men bending of the knees.
employed as firefighters, farmers and construction workers In each of these studies, data on knee use in the work-
presented significantly more often for surgery. Among place was obtained by extrapolation from job title rather
women, there was a significant excess among cleaners. The than through direct questioning about workplace activity,
risk estimates for these occupations varied from 1.4 to 3.0. but two British population-based case–control studies of
These observations agree with the findings of three knee OA examined specific occupational activities in some
case–control studies of knee OA in the United States,127 the detail. Cases with symptomatic knee OA from a defined
Netherlands128 and Sweden.129 When workplace activity population in Bristol were compared with age- and sex-
was classified as heavy or light, the cases in all of these stud- matched controls who had no evidence of knee pain or
ies were between two and three times more likely to have radiographic abnormality.132 A lifetime occupational history
been engaged in heavy activity occupations before the was obtained, as well as details of specific workplace physi-
occurrence of knee OA. However, the risk estimates in all cal activities (kneeling, squatting, stair climbing, walking,
three studies failed to attain statistical significance. standing, heavy lifting, sitting and driving). The risk of
Perhaps the most compelling evidence linking knee OA symptomatic knee OA (after adjustment for body mass index
with occupational activity comes from two population-based and the presence of Heberden’s nodes) was significantly
surveys in the United States. In an analysis of cross- increased among men and women whose major previous
sectional data from the HANES I study,130 radiographic occupation had entailed prolonged squatting (greater than
OA of the knee at age 55–64 years was three times more 30 minutes daily), prolonged kneeling (greater than 30
common in people whose jobs were judged likely to entail minutes daily) and repeated stair climbing (greater than
knee bending. In a follow-up study of 1400 men and ten flights daily). There was no increase in risk associated
with prolonged walking, standing, sitting or driving.
Regular heavy lifting (25 kg daily) was not independently
Clerks
associated with an increase in risk, but subjects whose
Ref.122 Miners occupations involved heavy lifting and repeated knee flex-
Civil servants
ion in combination had a substantial increase in risk
Ref.123 (Figure 57.2). Jobs frequently reported by the cases as
Dockers
Concrete involving squatting or kneeling included teaching and
Ref.124 workers nursing in women and steel erecting, electrical mainte-
Painters
Clerks
nance, roofing and other construction work in men. It was
Ref.125 Shipyard workers estimated from the data that around 5 per cent of all symp-
0 1 2 3 4 5 6 7 8 tomatic knee OA might result from occupations involving
repetitive knee use. Extrapolation from the Framingham
Figure 57.1 Observational studies examining the prevalence of study suggests an even greater attributable risk.
radiographic knee osteoarthritis among various occupational A second British case–control study by Coggon et al.133
groups. compared patients listed for surgical treatment of knee
Neither
Table 57.5 Medical management of patients with osteoarthritis of the knee or hip.
Therapy
Non-pharmacological therapy Patient education (self-management programmes (e.g. Arthritis Self-Help Course))
Health professional social support (via telephone contact)
Weight loss (if overweight)
Physiotherapy
Range of motion exercises
Quadriceps strengthening exercises
Assistive devices for ambulation
Occupational therapy
Joint protection and energy conservation
Assistive devices for ADLs
Aerobic exercise programmes
Pharmacological therapy Intra-articular steroid injections
Analgesics (e.g. paracetamol), topical analgesics (e.g. capsaicin) and topical anti-inflammatory
creams, nonsteroidal anti-inflammatory drugs, opioid analgesics
ADL, activities of daily living.
osteoarthritis with age- and sex-matched controls from the among farmers was 3.8 (95 per cent CI, 2.9–3.9). However,
same communities. After statistical adjustment for body farmers may seek treatment more often than other occupa-
weight, history of knee injury and the presence of markers of tional groups, not because they have a higher incidence of
Heberden’s nodes, risks were more than doubled in subjects the disorder, but because they are more handicapped by it
kneeling or squatting at work for more than one hour per when it occurs. This issue may be addressed by population-
day over at least one year and raised 1.7-fold in those lifting based radiographic studies comparing the prevalence of
weights of
25 kg more than ten times per week for at least hip OA in farmers and other workers. In a British study134
a year. There was also an association with occupational comparing men from a defined population aged 60–75
climbing of ladders and stairs in men (odds ratio 2.3), but years who had ever been in farming with a group of con-
not in women. Even greater risks were reported from work trols who had spent their entire careers in clerical work, the
that entailed both kneeling/squatting and heavy lifting (OR prevalence of moderate/severe radiographic hip OA
relative to neither activity 2.9 in men and 4.2 in women). (defined as a minimal joint space 1.5 mm) was found to
The balance of evidence thus favours occupational be 18 per cent in the former group, as compared with 2.4
physical workload as a risk factor for knee OA, with risks per cent in the controls. This gave a summary odds ratio
being notably high in workers with non-occupational risk for hip OA among the farmers of 7.8 (95 per cent CI,
factors, such as morbid obesity. 1.8–33.8), a risk estimate comparable with a Swedish study
in which 15 000 agricultural workers were asked about pre-
HIP OSTEOARTHRITIS vious hip radiography: 565 men and 151 women had had
such examinations and the prevalence of hip OA in male
The risk factor profile for hip OA is somewhat different farmers was increased more than ten-fold compared to the
from that for knee OA. There is a weaker association with male population of similar age.
obesity, hip injury and Heberden’s nodes118,120 and a The evidence on farmers has proved sufficiently com-
greater influence from developmental disorders of the hip pelling for hip OA in farmers to be added to the list of
joint, such as congenital dislocation of the hip, slipped prescribed diseases recognized for Industrial Injuries
upper femoral epiphysis and Perthes’ disease. Disablement Benefit in the UK. However, the precise risk
Data on the relationship between specific work activi- factors for hip OA in farmers have not been defined with
ties, such as heavy lifting, and the risk of hip OA are not certainty and it is not known whether an excess risk also
currently available. However, some studies have compared exists in other heavy manual workers, such as construction
the occurrence of hip OA according to occupational title. workers and labourers. In a second British case–control
Strong evidence has emerged that one such occupation – study,135 the risk of hip OA was found to be related to
farming – is associated with high rates of the disorder.134 occupations that entailed regular heavy lifting (for exam-
Early studies from France, Norway and Sweden suggested ple, the daily moving of weights greater than 25 kg by
that farmers had higher rates of total hip arthroplasty for hand), prolonged standing and walking over rough
OA than other occupational groups. In the large Swedish ground, but the magnitude of risk associated with these
cohort study, which included 250 000 people in the blue- exposures was much lower than that found in farmers, and
collar occupations,126 the relative risk for hip arthroplasty further research is warranted.
702 Repeated movements and the musculoskeletal system
disorders and reduced weekly pain scores. Whether these the maximum voluntary contraction. Furthermore, the
findings can be taken as evidence in support of work increasing use of a computer mouse encourages typists to
causation is, of course, a matter of interpretation. spend more time with their wrist in ulnar deviation and
However, cohort studies of arm pain and work activity are with their shoulder externally rotated.
being undertaken in increasing numbers across Europe The concurrence of risk factors matters particularly as
and the United States, including studies that include they may act synergistically. The study of carpal tunnel
planned elements of intervention, so the evidence base on syndrome by Silverstein et al.74 described under Carpal
work causation is set to grow significantly. tunnel syndrome, p. 694, provides an example of synergis-
In the meantime, a variety of physiological, biomechan- tic interaction between force and repetition: when either
ical and ergonomic investigations underpin the causal was present the risk increased about two- to three-fold, but
hypotheses, so WMSDs have come to be described as repe- when present together the risk of CTS was raised many
tition strain injuries or cumulative trauma or overuse dis- times over.
orders. The mechanisms of injury are unclear (and perhaps Approaches to risk assessment and risk reduction take
different for different outcomes), but it is generally felt that their cue from the putative risk factors, attempting to
undesirable permutations of force, repetition, duration measure or control some combination of unwanted forces,
and posture contribute to disease onset. repetitions and work positions. Many assessment methods
Unfortunately, work factors of this kind are only too have been attempted, though none has achieved primacy.
common in industry. High productivity targets and Some techniques are time consuming, expensive and
machine pacing encourage highly repetitive actions of research focused. Others have been advocated for use in
short cycle time with limited opportunity for respite. the workplace in the assessment and planning of control
Persistent static loading arises in jobs that involve pro- measures.
longed standing, holding objects at arms’ length and work- Most elaborate are the video recording methods. These
ing above shoulder height for long periods. Work in often employ pairs or panels of cameras providing alterna-
confined spaces often requires awkward postures that load tive views of the work, with markers on the body (such as
joints asymmetrically and require prolonged kneeling or reflective spots or small lights) to provide measurement
squatting. Other common work circumstances include points. The results can be digitally encoded and analysed
ill-considered workstation, tool and task design, and the by computer, providing detailed spatial and temporal
manipulation of heavy loads, sometimes under adverse information on work postures and movements.
conditions (such as a slippery or uneven footing). Figure 57.3 Alternatively, workers have worn electronic pendulum
illustrates some typical situations. potentiometers and flexible lightweight tubes containing
The different risk factors often coexist and in practice strain gauge strips that allow reconstruction of postures
it is difficult to disentangle their effects. Thus, undesir- and movements (again computerized analysis is possible).
able forces matter because of the load they impose on Static work activity has been assessed by mapping the
muscles and the torques they impose on joints, but the various joint angles (for example, using photographs or
outcome probably depends upon the degree and direc- goniometers), while static workloads and muscle fatigue
tion of loading (posture), its duration and its frequency, have been investigated using electromyography (EMG). A
muscle fatigue and recovery times. The effort of work can high correlation has been shown between EMG activity
be minimized by ‘good’ postures that allow as many and muscular force (for both static and dynamic activi-
strong muscles to contribute as possible, or exaggerated ties), and muscle fatigue can be detected as an increase in
by ‘bad’ ones, such as poor grip and ulnar or radial devi- the amplitude of the low frequency range of EMG activity.
ation of the wrist (which may reduce grip strength by up For research purposes, needle electrodes have been lodged
to 50 per cent) – hence force and posture are inter- in particular muscles, but in workplaces the technique has
related. In general, avoidance of prolonged static loading been adapted so that records can be obtained from surface
is desirable, as high intramuscular tensions interrupt the electrodes.
blood supply and enforce anaerobic metabolism, but the These various analytical approaches enable biomechan-
problem is heightened if high forces are required, the pos- ical measurements of force, posture, frequency and dura-
ture is awkward or effort needs to be maintained for any tion to be compared with known human capability and the
length of time. Work by Monod and Scherrer139 and outcomes of health investigations. They further allow
Rohmert140 indicates that effort that exerts 50 per cent of comparison across jobs, so that those expected to carry
the maximal force can last no more than a minute, while higher risk can be identified.
field studies suggest that loads of 15–20 per cent at maxi- However, they require special expertise and skills. In
mum will induce painful fatigue if kept up for days or occupational practice, simpler more rapid assessment
months. techniques are required, and a number of systems have
There are reasons for considering some occupational been proposed. In one of the earliest, the Ovako Working
groups such as typists to be at special risk from these fac- Posture Analysing System (OSWAS) method,141 postures
tors. The static loading of the neck and trapezius muscles were observed and recorded using a six-figure code
in VDU workers has been reported to be 20–30 per cent of during each stage of a representative task cycle. The first
704 Repeated movements and the musculoskeletal system
(a) (e)
(b)
(f)
(g)
(c)
(d) (h)
Figure 57.3 Examples of some ergonomic risk factors in the workplace. (a, b) Some tasks requiring high force levels to be applied. (c–h)
Some examples of static or awkward posture. Material taken from HS(G) 60 – Work related upper limb disorders – a guide to prevention,
Health and Safety Executive, ISBN 0717619783.147 © Crown copyright material is reproduced with the permission of the Controller of
HMSO and Queen’s Printer for Scotland.
Identifying work-related musculoskeletal disorders 705
three digits represented a fairly crude description of Table 57.6 Checklist for identifying work-related upper limb
trunk and limb postures. The fourth figure indicated the disorders.
load or force employed, and the remainder were task des-
Checklist
ignated. The procedure, which requires observer training
and standardization, is to glance, look away and record it.
For frequent activities the proportion of time in which 1 Organizational factors
particular postures are adopted and loads incurred can be Is operator training thorough enough?
estimated. Is repetitive work arranged without a break or with
Other analogous scoring procedures exist for the compulsory overtime?
upper limbs and neck, such as the Rapid Upper Limb Do bonus systems encourage the exceedance of good
Assessment (RULA) technique,142 and these generally working practice?
result in a risk score that is marked against advice on the 2 Task and equipment design factors
urgency of corrective action. An alternative approach Applied forces
employs a risk factor checklist. Table 57.6 provides an Is excessive force being used?
example. In some cases, it has been suggested that the Are there static muscle loads?
priority for remedial action should be determined by the Are forces applied with the joints at or near extremes of
number of risk factors identified: the situation is clearly their range of movement?
more complicated than this, but in the absence of better Movements
information this provides a convenient means for assem- Are the same movements repeated frequently?
bling an action plan. Are they repeated rapidly?
In some cases, these pragmatic tools have been tested Do they include forceful twisting or rotation of the wrist,
empirically against levels of discomfort at work,142 but at movement of the wrist from side to side, highly flexed
present there is no hard evidence concerning their predic- fingers and wrist, or upper limb motions beyond a
tive value for occurrence of WMSDs, and hence for the comfortable range?
adequacy of the risk assessment produced. Nonetheless, Postural factors
they have evident attractions: they can be readily under- Are the arms raised high or outstretched at the shoulder?
stood and applied, and facilitate attempts to prioritize Is the forearm held above the horizontal?
remedial actions in an area where knowledge is far from Is the upper arm held away from the vertical?
complete. Do poor overall postures exist?
Duration of effort
Are tasks performed for long periods without relief?
Are short bursts of energetic work included in longer
IDENTIFYING WORK-RELATED periods of activity?
MUSCULOSKELETAL DISORDERS Tool and equipment factors
Are women using tools designed for men?
WMSDs arise in the context of a background incidence of Do the tools vibrate, without vibration dampening?
musculoskeletal complaint, in workers who do not always Do the tools impose shock loading upon the user?
seek medical advice. In some cases (as in hip and knee OA), Do the tools need to be held firmly to resist reaction torques?
they may present after retirement. Their multifactorial Do tools have a jerking action?
character and, for some disorders their transience, tend to Is considerable pressure required to hold/operate the tool?
impede detection. In clinical practice a high level of aware- Are the handles too large/too small/too short/too slippery
ness is required if early recognition and intervention are to to be gripped easily?
be achieved. Do operators have to twist and turn to reach everyday items?
The starting point should be a knowledge of the occu- Do the operator’s gloves affect grip or dexterity?
pations and tasks most likely to generate concern. Health 3 Personal and anthropometric factors
professionals and safety managers should also be alert to Do operators suffer from work or domestic stress?
the possibility of disease clustering. An ‘outbreak’ of appar- Are operators at one or other of the extremes of height/
ently related symptoms in workers with a shared exposure reach/strength of the working population?
suggests the need for wider investigation – for example, a 4 Environmental factors
health survey and a review of the work activity. The prob- Do levels of noise cause mental stress or interfere with
lem may be circumscribed, or bigger than first appreciated, communications?
and the process or materials may have changed, adding Do lighting levels encourage awkward postures?
unrecognized risk to the job. Do flickering lights and glare cause visual difficulties?
Many soft-tissue studies have used the Nordic question- Does protective clothing constrain posture and affect grip?
naire143 as the basis of health enquiry. This simple self-
Material taken from HS(G) 60 – Work related upper limb disorders – a
completed questionnaire has been developed to standardize
guide to prevention, Health and Safety Executive, ISBN 0717619783.147
the data collected by the researchers, and has been © Crown copyright material is reproduced with the permission of the
validated to some extent. It allows an estimate of the Controller of HMSO and Queen’s Printer for Scotland.
706 Repeated movements and the musculoskeletal system
(a) (b)
Figure 57.4 Examples of some simple ergonomic solutions. (a) Redesigning the handles of a tool can lead to more comfortable hand
positions and reduce the force required to do the job. (b) In this press operation repositioning of the control panel has eliminated the need
for prolonged overhead work. Material taken from HS(G) 60 – Work related upper limb disorders – a guide to prevention, Health and Safety
Executive, ISBN 0717619783.147 © Crown copyright material is reproduced with the permission of the Controller of HMSO and Queen’s
Printer for Scotland.
one-week and one-year period prevalences of limb and 2. An induction period, to allow new employees to
neck complaint (such as pain and interference with work), start work at a slower pace than the established
but further assessment would be required before making a workforce.
clinical diagnosis. Other questionnaires of similar scope 3. Job rotation or job enlargement, to provide respite
have been developed for use in surveys and screening, and from work that requires repetitive monotonous use of
some authors have given advice on analysing and inter- the same muscles and tendons.
preting the findings.144 4. Rest breaks. These are often advocated as an alternative
to job rotation, although little information exists on
their value or the length that the break should be.
PREVENTING AND MANAGING 5. A rehabilitation programme, to ease affected workers
WORK-RELATED MUSCULOSKELETAL back into productive work.
DISORDERS 6. Redeployment, in recalcitrant and recurrent cases.
7. Task optimization. Better design of tools and equip-
Success in the prevention of work-related musculoskeletal ment, and a better work layout make the task easier to
disorders depends upon an informed assessment of risk, a perform. Often only a little thought is required to
sharing of information between medical personnel and reduce work effort and to avoid undesirable working
employees, and a package of risk reduction measures, postures. Figure 57.4 illustrates, for example, how one
underpinned by suitable management systems for moni- tool and one task were redesigned to eliminate unde-
toring and enforcement. sirable wrist and shoulder postures. The HSE website
A similar approach will help the affected worker to provides further useful further guidelines
return to work, and to avoid a recurrent problem. (www.hse.gov.uk/msd/hsemsd.htm).
Preventive measures may include:
Work with visual display units in Great Britain now falls
1. Advice and training, to ensure a higher risk awareness under the Health and Safety (Display Screen Equipment)
and better working practices. Regulations 1992,145 which are based on the premise that
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SECTION TWO
was then attributed to the discomfort and injuries endured restricted diagnostic procedures and a non-inference policy
by travelling by train when railways became more common for most cases of acute low back pain.8 At about the same
around 1850. Many injuries occurred while travelling by time, Waddell published an influential conceptual article in
train due to low safety measures, with resulting legal liabil- which he proposed to use a biopsychosocial model for the
ity of railroad companies for compensation of passengers diagnosis and management of low back pain.9
injured during collisions. This increased the epidemic of Medical practice also changed as a result of the introduc-
railway spine injuries. However, after thorough discussion tion of clinical practice guidelines based on research evidence
in the medical literature, the railway spine sank into obliv- from systematic reviews. The American Agency for Health
ion around 1900. Care Quality and Research produced one of its first guide-
Rheumatism was debated as the cause of back pain lines on back pain in 1994. It contained many of the notions
through new medical discoveries and measurement tech- on back pain that we currently still use: such as diagnostic
niques. For example, the availability of x-rays around 1900 triage and continuing ordinary activities in spite of the back
made anatomical changes in the spine, such as disc and joint pain. To date, occupational medicine associations have made
degeneration, visible and the German anatomist Schmorl practice guidelines on the management of low back pain at
related these findings to autopsy findings. The first opera- work specifically for occupational health practitioners.10–12
tions for herniated intervertebral discs were performed in The Cochrane Collaboration started its programme on
the 1930s by Mixter and Barr in the United States and these reviewing the effects of healthcare interventions in 1992.
were very influential in research on back pain.5 The now Given the enormous amount of literature on back pain,
visibly ruptured disc led to an increasing belief that injury systematic reviewing is needed to be able to transform this
was the most important mechanism behind back pain. information into knowledge that can be used in practice.
Based on these medical developments, the injured back To date, the Cochrane Collaboration has produced 46
became the model for work-related back pain after the systematic reviews of prevention and treatment for back
Second World War. The back injury was explained as an pain. The reviews are used as input for the development of
overload of the structures in the back. Measuring spinal practice guidelines.
load thus became an important aspect of research into The various drivers for change of management of low
occupational causes of back pain. Nachemson was one of back pain have probably led to considerable changes in
the first to measure the pressure in the intervertebral disc practice even though this is difficult to measure.13 Waddell
directly.6 He showed that the pressure was highest when is one of the strongest advocates of these changes and sees
sitting on a chair without a backrest. This led to increased this as ‘the back pain revolution’.14
interest in seating with a proper back support as a means to
prevent back pain among workers.
The more recent introduction of magnetic resonance PREVALENCE OF BACK PAIN
imaging techniques made it possible to view different struc-
tures in the back, such as vertebral endplate signal changes Because back pain is a symptom, it is fairly easy to ask
and their relation to low back pain. Even though there people about their back pain experience to shed light on
might be an association with low back pain, it is unclear the prevalence of back pain. However, different ways of
what their role is in its development.7 phrasing questions about back pain experience lead to
Attention being paid to work as the cause of back pain enormous differences in back pain prevalence. Both recall
coincided with improved social security in the twentieth and the intermittent course of back pain lead to biased
century. This led to an exponential increase in the number results. In addition, there is a gradual increase from no
of people on sick leave due to back pain and later to an pain to severe and disabling pain. It has been agreed that
increase in the number of people on disability benefit. asking about pain in the past four weeks, limitation of
During the 1970s and 1980s, the main strategy to counter- usual activities, radiation into the leg, the duration of the
balance these increases was to improve working condi- pain episode and a numerical pain rating scale probably
tions. At the same time, the emphasis of working life in give the best results for measuring back pain prevalence.15
industrialized countries changed, at least for men, from Given the uncertainties surrounding back pain preva-
heavy physical work in manufacturing industry to admin- lence, the following figures give a rough indication of the
istrative work in the service sector. situation.16,17 The lifetime prevalence, meaning a positive
Medical opinions on the treatment of back pain have answer to the question did you ever have back pain in your
changed over time. Until about 1990, the prevailing opin- life, is around 70 per cent with variations between studies
ion was that rest was needed to cure the injured structures. from 11 to 84 per cent. The one-year prevalence (Did you
One of the landmark studies on the management of back have back pain in the past 12 months?) lies around 50 per
pain was published by the Quebec Task Force in 1987. The cent and varies from 31 to 65 per cent. The point preva-
group was one of the first to perform a systematic review of lence (Do you have back pain now?) ranges from 12 to 33
the literature and to critically appraise its quality. They pro- per cent. The incidence of new episodes of back pain is esti-
posed a standard nomenclature for back pain diagnosis, mated to be considerably lower, with population studies
diagnosing subgroups with acute, subacute or chronic pain, reporting an incidence of new episodes of 4 per cent.18
Causes of back pain at work 717
The prevalence of back pain increases from early adult Burdorf and Sorock28 gathered evidence on a relation
life to the late 40s or early 50s and remains relatively between individual characteristics or exposure at work
constant thereafter, at least to the mid-60s. In those who and back disorders from the literature. They used a simple
continue to have back pain, it is more likely to be more vote-counting method to combine the results of 35 cross-
frequent or more constant with increasing age.19 sectional and cohort studies and did not stratify according
Worldwide, 37 per cent of low back pain is estimated to be to study type. They concluded that there is evidence for a
attributable to occupational risk factors. This fraction varies relationship between exposure due to manual material
among different regions in the world and is higher in areas handling, frequent bending and twisting, heavy physical
with lower health status in general, mostly due to the high load and whole body vibration. They found contradictory
proportion of farmers.20 Overall, the attributable risk frac- evidence for psychosocial factors. For individual character-
tion was higher for males than for females, largely because istics, there was evidence for a relation with back pain for
of men’s higher participation in the labour force and in age, smoking and education, and no evidence for a relation
occupations with heavy lifting and whole body vibration. for gender, height, weight, exercise and marital status.
In a methodologically better systematic review,
Hoogendoorn et al.29 used a rating system to assess the
CAUSES OF BACK PAIN AT WORK strength of the evidence for a relation between physical
load at work and back pain. They based the rating on the
Research on occupational back pain, especially epidemio- methodological quality of 19 cohort and two case-referent
logical research, is fraught with difficulties. Both measur- studies which had looked into work-related factors. They
ing the outcome and the exposure are difficult and easily found strong evidence for manual materials handling,
subject to bias.21 Over the past few years, many research bending and twisting, and whole body vibration as risk fac-
groups have worked on obtaining consensus about which tors for back pain. The evidence was moderate for patient
are the best measures to use and how to measure them.22–26 handling and heavy physical work, and no evidence was
Despite these efforts, there are still a considerable number found for standing, walking or sitting.
of measurement options which makes comparison between Later, Lotters et al.30 carried out a systematic review and
studies difficult. meta-analysis partly based on similar material as Burdorf
The measurement problems also relate to how the devel- and Sorock’s 1997 study.28 The review included 40 studies,
opment of back pain is conceptualized. We suggest that the 35 cross-sectional and five cohort studies. They adjusted the
clinician should look at back pain as a process starting with risk estimates for possible confounders and were able to sta-
pain and finally leading to disability and unemployment. tistically combine the study results. The pooled OR was 1.5
Some people experience only one clearly limited episode of (95 per cent confidence interval (CI) 1.3–1.7) for manual
back pain, but for most new episodes occur or the pain materials handling, 1.7 (95 per cent CI 1.4–2.0) for frequent
becomes a diffuse chronic problem. For others again, these bending or twisting, 1.4 (95 per cent CI 1.2–1.6) for whole
chronic problems lead to disability and loss of employment body vibration, 1.3 (95 per cent CI 1.2–1.5) for job dissatis-
over time. At different phases of this process, work and other faction. Since the proportion of people with back pain in
factors have a varying influence on back pain outcome. In the the studies is around 30 per cent, the reported odds-ratios
first phase of incident back pain, back pain is thought to be are overestimations of the real risk. Transforming the odds-
related to work through biomechanical overloading that ratios to risk ratios would yield, respectively, 1.3, 1.4, 1.2
damages structures in the back. In general, genetic and bio- and 1.2 for the risk factors mentioned above. This means
logical determinants probably play a major role. Which that the prevalence of back pain of 30 per cent in a non-
structures cause the pain is unclear and also the relation exposed population would increase to 39 per cent due to
between overload, damage and back pain is unclear. Personal exposure to manual materials handling.
factors, such as an individual’s beliefs about back pain, play Biomechanics provides another important part of the
a major role in reporting sick or becoming disabled. evidence underpinning the relation between spinal loading
There are a few older systematic reviews of epidemio- and back pain.31 Over the years, there has been considerable
logical studies on work-related aetiology of back pain. The progress in measurement techniques that can predict the
reviews differ considerably in the methodology used, but compression and shear forces on the lumbar intervertebral
all come to more or less similar conclusions. discs.32,33 Co-contraction of trunk muscles has been identi-
A NIOSH review of epidemiologic research on low back fied as an important factor in spinal loading. It has also been
pain and occupational risk factors with 42 studies up to observed that due to inappropriate muscle contraction,
1997 concluded that there was strong evidence for an asso- patients with low back pain exhibit a greater than necessary
ciation between lifting and forceful movements and back spinal loading that might maintain their back pain. Waddell
disorders. Thirteen of 18 studies found an association very strongly argues that mechanical overloading leads to
between these work factors and back pain. They also found dysfunction which he defined as any disturbance of normal
evidence for an association between work-related awkward strength, endurance, flexibility, coordination or balance,
postures and back disorders, but not for an association but he also admits that there is little evidence to support
between static work postures and back disorders.27 his theory.14
718 Occupational back pain
Biomechanical modelling using a so-called linked seg- Pre-employment strength testing and ergonomic job
ment model can be used to better understand the forces design together were seen as the most promising interven-
that are elicited by various work tasks and it can be used for tion methods in review articles in the 1980s and 1990s.44,45
preventive purposes. However, it is difficult to translate Snook46 concluded that it appears possible to control back
biomechanical findings to effective interventional strate- pain by reducing the probability of the initial episode,
gies. For example, most of our knowledge about lifting reducing the length of the disability, and reducing the
techniques is derived from biomechanical models. However, chance of recurrence. Realization of these goals was deemed
training workers in lifting techniques to prevent back pain possible with a combination of job design, job placement
has so far led to disappointing results.34 and education/training. However, recent evaluation studies
Various other approaches to measure spinal load have have shown disappointing results from these preventive
been tried in the past. Spinal shrinkage has been postulated interventions.
as a biomarker for spinal load. It is a precision measure-
ment of body length that enables a measurement of the
Exposure limits
shrinkage of the spine due to water loss of the interverte-
bral discs during loading. However, it is unclear what the
If spinal loading at work is a main risk factor for back pain,
benefits are over biomechanical modelling.
then it makes sense to try to reduce spinal load by setting
The advances in research on cartilage structure and
maximum permissible limits. The American National
metabolism have induced a search for biomarkers that could
Institute of Occupational Safety and Health (NIOSH) has
be used as either markers for spinal loading or as markers
greatly contributed to this idea by developing a relatively
for early damage. Even though there have been promising
simple risk assessment tool that can be used to assess a
studies, the contribution to unravelling the causes of
‘recommended weight limit’. The maximum recommended
occupational back pain is still unclear.35
weight limit is 23 kg. The lifting conditions, such as distance
The evidence for psychosocial occupational risk factors
of the load to the body and the degree of trunk rotation,
for low back pain is more difficult to interpret. There are no
have to be specified and entered into a formula which
objective criteria for psychosocial load and the evidence on
returns a recommended weight limit for these conditions.47
this topic has been somewhat contradictory. A systematic
Even though the tool covers a wide range of situations,
review by Hoogendoorn et al.36 published in 2000 found 13
there remain difficulties in applying it to all workplaces.48,49
studies, of which five were high quality studies that dealt
It is a serious drawback for its application that there are no
with social support in the workplace. The authors con-
studies that have evaluated the effectiveness of the NIOSH
cluded that there was strong evidence for a positive associ-
standard in reducing back pain due to lifting. Moreover,
ation between low social support and back pain based on
there are no exposure limits for bending and twisting.
four studies with risk estimates of 1.3 to 1.9. For job satis-
Based on the risk for back disorders, exposure to whole
faction, they also concluded that there was a positive associ-
body vibrations has been regulated in the EU. Exposure
ation with back pain based on seven studies.
beyond an intensity of more than 0.25 m/s2 is considered
A systematic review published in 2001 of 21 studies
potentially dangerous and, beyond 0.50 m/s2, it is required
concluded that there was evidence for a relation between
to take action to remediate the danger of exposure. The
the following six psychological risk factors and back pain:
most frequently occurring whole body vibration in forklift
job satisfaction, monotonous work, work relations, work
trucks would be around 1.0 m/s2. There are some studies
demands, stress and perceived ability to work. The strength
that have evaluated the effectiveness of measures to reduce
of the relationships varied between the studies, but was
whole body vibration if the exposure were above the stan-
consistent according to the authors.37
dard, but they could not show a decrease of exposure.50
In a more recent systematic review of cohort studies,
Hartvigsen et al.38 concluded, based on 40 cohort studies of
which ten were considered high quality, that there was no Workplace improvements, participatory
evidence for an association between back pain and percep- ergonomics
tion of work, organizational aspects of work or social
support at work. Ergonomics is commonly known as ‘the scientific study of
Person-related factors, such as smoking and obesity, have human work’ or ‘the application of scientific information
been studied to find a possible relation with the risk for low concerning human beings to the design of objects, systems
back pain.39,40 No clear evidence was found for a causal rela- and environments’. Recently, participatory ergonomics
tion. A previous episode of low back pain is the most strong has stressed the importance of a participatory approach to
predictor for future sick listing because of low back pain.41–43 prevention and solution finding to increase effectiveness.51
In a review of participatory ergonomic interventions, Cole
et al.52 found five studies of which two were randomized
PREVENTION OF BACK PAIN AT WORK controlled trials. In these studies, they found limited evi-
dence that participatory interventions decreased muscu-
Researchers have proposed various interventions to loskeletal symptoms with four studies reporting a decrease
prevent occupational back pain. and one no effect. Effect size could be estimated only in
Clinical management and return to work 719
one study and it was small. In a recently published study on Reporting of occupational back pain to inform
the effectiveness of kitchen ergonomics, the intervention policy-making
did not reduce physical work load nor musculoskeletal
disorders.53 In a partly overlapping review on workplace Reporting of occupational diseases by physicians has been
interventions for computer users, Van Eerd et al.54 found advocated as a useful instrument to inform policy-makers
four studies that showed no effect of workstation adjust- about preventive policy.58 Many countries maintain a sys-
ments on musculoskeletal symptoms. In another four tem through which physicians can report cases of occupa-
studies, ergonomics training yielded contradictory results tional diseases often including occupational back pain. The
on musculoskeletal outcomes. Even though ergonomic quality of these systems varies and many do not provide
improvements may improve comfort and efficiency, they guidelines for diagnosis of the diseases to be reported but
apparently contribute little to the prevention of back pain. rely entirely on the professional expertise of the reporting
physicians. Moreover, there is little evidence that reporting
Pre-employment examinations of occupational diseases to national registries leads to
actual policy changes.
In general, researchers are sceptical about the possibilities of Occupational back pain can best be defined as back
reducing health problems through pre-employment selec- pain that for a major part is caused by exposure at work. As
tion. The problem is that, at the individual level, it is difficult a clinical disorder, occupational back pain cannot be distin-
to tell who is at risk for the disease and who is not. The pos- guished from back pain in general by specific symptoms or
itive predictive value of tests is low which means that there signs, nor are there specific tests that can elicit these symp-
will be a high number of applicants who will be rejected, but toms or signs. Dutch researchers have constructed a model
that would never have been afflicted with the occupational to calculate the probability of work-relatedness. This three-
disease.55 As part of an ongoing systematic review, we found step method calculates this probability on the basis of data
three low-quality studies that evaluated pre-employment on exposure to established risk factors in the work situation.
strength testing with contradictory results.56 The calculated probability of work-relatedness provides
information that can be used to support professional assess-
ment of the work situation and proposals for improving it in
Worker education and training the interests of workers with non-specific low-back pain.30
The diagnosis of occupational back pain at the individual
A recent Cochrane systematic review found six randomized
level can be at odds with the prevailing advice to continue
controlled trials and five cohort studies that evaluated worker
ordinary activities as much as possible. If back pain is attrib-
training and advice on manual material handling. The
uted to work, it will be difficult to return to the same job
included studies all had follow-up times of at least one year
which caused the back pain in the first place. On the other
and had varying degrees of training intensity and hands-on
hand, leaving a job because of back pain could easily lead to
training. None of the studies showed that the intervention
unemployment. A practical solution could be to discuss the
decreased the occurrence of back pain.34 In their review on
pros and cons of continuing in the same job with the worker.
workplace interventions for computer users, Van Eerd et al.54
found four studies on ergonomics training that yielded
contradictory results on musculoskeletal outcomes. CLINICAL MANAGEMENT AND RETURN TO
WORK
Exercise
Many workers will experience back pain without occupa-
Exercise is believed to be beneficial for many disorders, tional exposure, but there will still be a risk of long-term
including back pain. The following three mechanisms are disability and unemployment. These risks are related to
held responsible for the preventative effect of exercise: personal beliefs about the cause of back pain and the fear of
(1) strengthening of the back muscles and increasing trunk reinjury. Proper management of back pain both within the
flexibility, (2) increasing the blood supply to the spine mus- work organization and by the attending physician prob-
cles, joints and intervertebral discs and (3) improving mood ably decrease the risk of long-term disability.59
and thereby altering the perception of pain. A review found The management of back pain is the topic of clinical
six randomized controlled trials that evaluated the effective- guidelines that have been developed in many countries and
ness of an exercise programme for various types of workers in languages. In principle, the clinical management of occu-
2001. Four out of five studies that compared exercise with no pational back pain is no different from management of
intervention found a significant reduction in back pain expe- back pain in general and the authors refer readers to those
rience and reduced work absenteeism. One study reported clinical guidelines. We will summarize the general princi-
inconsistent findings. The conclusion of this review was that ples of clinical management of back pain in the following
there is consistent evidence that exercise may be effective paragraphs.
in preventing back pain. One other study reported that For any health professional, it is important to differen-
exercises are more effective than training in back care, but tiate at an early stage between non-specific low back pain,
this result was contradicted in another study.57 radicular syndrome and specific low back pain. Based on
720 Occupational back pain
the medical history and the physical examination, symp- ● lack of ‘motivation’ and readiness to change, failure to
toms and signs for specific diseases can be detected. These take personal responsibility for rehabilitation, awaiting
signs and symptoms are called red flags because they a ‘fix’, lack of effort;
potentially indicate serious disease. The absence of red ● illness behaviour.
flags excludes specific disease and thus leads to a diagnosis
of non-specific back pain. The following red flags are The list should be interpreted with caution because not
mentioned in most clinical guidelines: all of these factors are based on findings from rigorous
research. Pincus et al. reported conflicting findings on the
● back pain in workers less than 20 or more than 55 years relation between fear-avoidance and both short- and long-
old; term pain in a review of nine prospective cohort studies.65
● constant progressive back pain; In another review of six cohort studies, she found psycho-
● trauma; logical distress, depressed mood and somatization to be
● history of malignancy; prognostic for chronic pain and to some extent also cata-
● prolonged use of corticosteroids; strophizing as a coping strategy.66
● immunosuppression, drug use, HIV;
● general malaise or unexplained weight loss;
● neurological dysfunction (motor dysfunction, sensory
Prognosis
abnormalities and/or miction disturbances);
● lumbar kyphosis and/or past history of lumbar lordosis;
●
Assessment of prognosis is important because it is impor-
complaints that might relate to an infectious disease.
tant information for workers and employers based on
If one or more of these symptoms or signs are observed, which they can adapt their personal circumstances or
further investigations should be carried out to exclude spe- work. In addition, it will help the clinician to focus on
cific causes, such as a radicular syndrome due to a herniated those patients who need help most as they are at greatest
disc, malignancy, osteoporotic vertebral fracture, vertebral risk of becoming a chronic patient. Most people will
canal stenosis, spondylitis ankylopoetica (Bechterew’s dis- recover rapidly from an episode of acute low back pain and
ease) and or forms of spondylolisthesis. most of those absent from work with back pain also return
In the history, it is also important to identify psychosocial to work within one month.67 Further but smaller improve-
factors, potential obstacles to recovery and to identify work- ments occur up to three months, after which pain and
place factors (physical and psychosocial) that may be related disability levels remain almost constant. Pengel et al.’s67
to the back pain problem and return to work.10,11,60–62 systematic review on prognosis of acute low back pain con-
People with non-specific back pain can generally be cluded that, although most people return to work within
expected to recover, because most episodes settle unevent- 12 months, low levels of pain and disability persist. From
fully with or without formal health care. Most patients the studies included, it was not clear if these levels of long-
recover at least enough to return to most normal activities, term pain and disability reflect a small subgroup with high
even if with some persistent or recurrent symptoms. levels of pain and disability or a large subgroup with low
Waddell and Burton63 state that only 1 per cent progress to levels of pain and disability. Nor is it clear whether chronic
long-term incapacity, but this is not backed up by evi- low levels of pain and disability are due to persistence of
dence. The problem is not what makes these people the original episode or to recurrences.
develop long-term incapacity, but more so why do some Steenstra et al. studied prognosis for duration of sick leave
people with a problem such as non-specific back pain not in patients absent from work because of low back pain. They
recover as expected.63 Biopsychosocial factors, separately found that the following factors were prognostic for longer
and in combination, can aggravate and perpetuate disabil- sick leave: specific low back pain, higher disability levels,
ity. Workplace factors, such as the attitude of the employer older age, female gender, more social dysfunction and more
towards low back pain, attitudes of co-workers, commu- social isolation, heavier work and receiving higher compen-
nication at the workplace, rules and regulations around sation. A history of low back pain, job satisfaction, educa-
sickness absence management, and occupational health tional level, marital status, number of dependants, smoking,
provision are examples of obstacles for recovery. working more than eight-hour shifts, occupation, and size of
The following psychosocial factors have been listed by a industry or company did not influence duration of sick leave
group of experts as yellow flags for risk of chronicity:63,64 due to low back pain.68
and psychosocial factors. The concept is not unequivocal ● Most preventive interventions, such as lifting
due to a lack of evidence that exposure, physical damage advice and ergonomic improvements, do not
and back pain are interrelated. Attribution of specific lead to a reduction of back pain prevalence.
causes to back pain has changed considerably over time as ● Exercise after treatment might help in preventing
a result of social and political factors. Back pain research is recurrences of back pain.
complicated due to the difficulty of measuring both expo- ● Better understanding of the mechanisms behind
sure and outcome. pain and disability is needed for progress in
Preventative efforts to redesign workplaces, screen prevention and treatment.
workers with limited physical capacities, train and educate
workers in proper lifting techniques or the use of office
ergonomics have not been shown to be effective in decreas-
ing back pain outcomes.
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PART FIVE
Occupational infections
them to frequent contact with blood and body fluids.3 It is that in the general population, the result of improvements in
well recognized that hepatitis B can be transmitted via transfusion and dialysis safety, the implementation of stan-
infected blood and other body fluids, either from those with dard (‘universal’) infection control precautions, and the use
acute infection or from individuals who have become of hepatitis B vaccine.15,16
virus carriers. Hepatitis B virus is usually transmitted by Even in countries where hepatitis B infection is endemic
unprotected sexual intercourse, by sharing of blood- and the background seroprevalence is high, serosurveys
contaminated needles or injecting equipment between drug provide evidence that there is an additional occupational
users, and by transmission from an infected mother to her risk among healthcare workers. Among 234 dentists in the
child at or during delivery. It may also be transmitted by Philippines, the prevalence of markers of hepatitis B infec-
transfusion of infected blood, particularly in countries tion was found to be 58 per cent, similar to the prevalence
where the prevalence of infection is high and resources for in the general population, but increasing with the number
transfusion services are small, and by accidental exposure to of years in dental practice.17 In Japan, a seroprevalence
blood and other body fluids. It is the transmission by study found that over a third of hospital workers had evi-
blood-exposure incidents that is particularly relevant to dence of previous hepatitis B infection, about the same as
occupational risk. that in a group of healthy controls, but that the seropreva-
Surveys undertaken before the hepatitis B vaccine lence among nurses and surgeons was significantly higher
became widely available show an excess of serological than in other staff or the controls.18 A study in Cairo
markers of hepatitis B infection in workers exposed to revealed a higher prevalence of hepatitis B infection markers
blood and body fluids. West4 reviewed evidence from a among non-professional staff (60 per cent) than among
number of seroprevalence studies in the United States and doctors and nurses, presumably as a result of non-
concluded that the overall risk to people employed in occupational infection in early life, but still found a rela-
health-related fields was four times that of the general adult tionship between infection markers and blood exposures
population; physicians and dentists were at five to ten times and years of practice among the physicians.19 A serosurvey
the risk of the general population; groups with over ten of healthcare workers in Belize found that 29 per cent had
times the risk included surgeons, clinical workers in dialysis markers of past hepatitis B infection and 1 per cent had
units and mental handicap units, and laboratory workers detectable HBsAg. Prevalence of hepatitis B markers
having frequent contact with blood samples. Later studies reached 57 per cent in workers from one ethnic group.20
confirmed these findings.5–8 Among 5813 Italian healthcare Similarly, a recent serosurvey of 167 surgeons working in
workers tested prior to hepatitis B immunization, 23 per hospitals in Lagos, Nigeria, found that 25 per cent were
cent had markers of past or present hepatitis B infection, hepatitis B surface antigen positive, compared with 15 per
including 2 per cent who were HBsAg positive.9 A study cent of a control group of 193 administrative staff.21
from Stockholm of healthcare workers enrolling for hepa- Occupations allied to health care may also carry a risk of
titis B immunization found a prevalence of hepatitis B hepatitis B infection. A serosurvey of 133 embalmers22
markers of 4 per cent, not greater than in the general popu- found that they had hepatitis B infection markers at about
lation, but related to age, duration of healthcare work and twice the rate of a blood donor comparison group and com-
history of blood-exposure incidents.10 In the United States, monly gave a history of needlestick injuries at work. A
a survey of hospital-based surgeons showed a significant Canadian study reported that 13 per cent of staff (and more
rate of hepatitis B infection; 17 per cent of 770 surgeons than 20 per cent of specialized teachers) in a day school for
tested had markers of infection and 0.4 per cent were mentally handicapped children had markers of hepatitis B
HBsAg positive.11 Risk factors for infection were non- infection.23 Emergency medical workers, such as emergency
vaccination and surgical practice for ten years or more. ambulance staff and paramedics, have been reported to have
In the United Kingdom, in the 1970s and 1980s, there an increased risk of hepatitis B infection.24–26 However,
was an excess rate of acute hepatitis B among healthcare other studies of groups of emergency workers and public-
workers compared with the general population. In 1975–79, safety workers have not found an excess of hepatitis B infec-
the average annual rate for men in the whole population was tion markers. Morgan-Capner and Wallice27 found no
4 per 100 000, while healthcare workers had rates of up to 36 excess of hepatitis B markers among Lancashire ambulance
per 100 000.12 In 1980–84, the average annual rate in men in personnel compared with blood donors; their subjects
the general population was 6 per 100 000 and again up to 37 undertook both routine and emergency work. Studies of
per 100 000 among healthcare workers.13 However, cases of police officers,28–30 prison officers31 and firemen32 have not
acute hepatitis B acquired occupationally in the United documented an increased risk of hepatitis B infection.
Kingdom are now rare.14 This is likely to reflect the results of Occupational hepatitis B infection has also been
the campaign to ensure hepatitis B immunization of health- reported in professions unrelated to health care or the
care workers and pre-entry medical students; the few cases emergency services. Outbreaks of hepatitis B have been
that did occur in the period of review were in people who reported in butchers’ shops33,34 apparently spread from
had not had hepatitis B vaccine. A similar effect has been infected employees to colleagues as a result of frequent cuts
seen in the United States, where the reported incidence of sustained at work. Several studies have found an excess of
acute hepatitis B in healthcare workers is now lower than hepatitis B infection among naval personnel and merchant
Healthcare workers and related occupations 731
seamen; this can be partly explained by work in a health- The occupational risk of hepatitis C is lower than that of
care setting for some personnel, but appears to be related hepatitis B. In a study of hospital-based surgeons in the
mainly to para-occupational factors, such as injecting drug United States, 0.9 per cent of the 770 surgeons had anti-
use, unprotected sexual contact and tattooing performed bodies to hepatitis C, compared with 17 per cent who had
in areas of high endemicity.35–37 markers of hepatitis B infection11 and in a study of 3411
orthopaedic surgeons in the United States, 13 per cent
Hepatitis C virus (HCV) without non-occupational risk factors had markers of
Seroconversion after occupational percutaneous exposure HBV infection and 1 per cent had HCV antibodies.48 The
to HCV infected blood is well documented,38 although prevalence of infection markers for both HBV and HCV
most serosurveys of healthcare workers have indicated that was higher in older workers.
the prevalence of hepatitis C antibodies is low. Abb found
hepatitis C antibodies in eight of 738 healthcare workers Human immunodeficiency virus (HIV)
(1 per cent), compared with much higher seroprevalences In contrast to hepatitis B and C, the studies that have
among certain patient groups.39 In another study, although examined the seroprevalence of HIV among healthcare
only 0.58 per cent of 1033 hospital employees had anti- workers have found a low seroprevalence and no evidence
bodies to hepatitis C, this prevalence was significantly greater of an excess related to occupation; most healthcare workers
than the 0.24 per cent of 2113 blood donor controls.40 with HIV will have acquired it non-occupationally. For
Klein et al.41 found antibodies to hepatitis C among example, in a study of orthopaedic surgeons in the United
2 per cent of 456 dentists in New York compared with 0.1 States, none of the 3267 surgeons without non-occupa-
per cent of 723 controls; among a small group of oral sur- tional risk factors had antibodies to HIV.49 In six urban
geons, the prevalence was 9 per cent. Dentists who had areas of the United States, only two of 8519 healthcare
antibodies to hepatitis C reported more exposure inci- workers who had donated blood were HIV positive; infor-
dents, and having treated more intravenous drug users in mation was not available on non-occupational risks.50
the previous month than did seronegative dentists. Among
those dentists who had not been immunized against hepa- TYPES OF EXPOSURE AND RISK OF TRANSMISSION
titis B, 25 per cent had anti-HBs. Some 6 per cent of these IN THE HEALTHCARE SETTING
had antibodies to hepatitis C, compared with only 2 per
cent among those who were anti-HBs negative. This sug- The most important means of transmission of blood-borne
gests a common mode of transmission for the two viruses, viruses in the occupational setting is by percutaneous expo-
though with a lower risk for hepatitis C. sure to infected blood, either by skin-penetrating injuries
Later studies confirmed the low prevalence of hepatitis with blood-contaminated needles (needlestick injuries) or
C antibodies among healthcare workers and investigated by cuts with scalpels or other sharp instruments contam-
risk factors. In Argentina, a survey of 439 healthcare work- inated with blood (sharps injuries). There is a lower risk of
ers found antibodies to hepatitis C by enzyme immunoas- transmission associated with mucocutaneous exposure:
say in 1.6 per cent.42 In the Johns Hopkins Hospital in the blood contamination of eyes, mouth and broken skin. In
United States, antibodies to hepatitis C were found in 0.7 addition, cases of hepatitis B, hepatitis C and HIV transmis-
per cent of 943 healthcare workers and 0.4 per cent of local sion by skin-penetrating bite have been reported. Blood-
blood donors.43 Similarly, a study in a London teaching borne viruses do not cross intact skin, and faeco-oral
hospital among 1053 healthcare workers exposed to blood transmission does not occur.
and body fluids found antibodies to hepatitis C in 0.28 per Blood exposure is particularly common in surgery.
cent, no higher than reported in blood donors in the same Lowenfels et al.51 contacted surgeons in New York by letter
area.44 Another UK study, from Nottingham, reported or telephone and reported a median rate of puncture
similar findings, with antibodies to hepatitis C in 0.2 per injuries of 4.2 per 1000 operating room hours, with 25 per
cent of 1949 healthcare workers enrolled in a hepatitis B cent of the surgeons having injury rates of nine or more per
immunization programme.45 Among 343 oral surgeons 1000 operating room hours. Hussain et al.52 asked 18
and 305 general dentists in the United States, 2 and 0.7 per surgeons in Saudi Arabia to record all accidental injuries
cent, respectively, were found to have antibodies to hepa- during surgery and reported that sharps injuries occurred
titis C.46 Hepatitis C infection was more prevalent in those in 5.6 per cent of operations. An observational study of
who were older, had more years of practice and had sero- 1307 surgical procedures at San Francisco General Hospital
logical markers of hepatitis B infection; but hepatitis C revealed accidental blood exposures in 6.4 per cent of pro-
infection was much less common than markers of previous cedures and percutaneous exposure to blood in 1.7 per
hepatitis B infection (8 per cent in general dentists and 21 cent.53 The risk of blood exposure was highest for proce-
per cent in oral surgeons). In serosurveys at 16 Italian hos- dures lasting more than three hours, when blood loss
pitals, 2 per cent of 3073 healthcare workers had antibodies exceeded 300 mL, and for major vascular and gynaecologi-
to hepatitis C.47 Infection was associated with previous cal procedures. The lower rate of injuries in San Francisco
acute hepatitis, blood transfusions, poor housekeeping and was thought to reflect greater attention to safe practices
older age, but not with occupational risk factors. because of the high rate of HIV infection among the patients.
732 Occupational infections
However, in a later prospective observational study in four Relatively few injuries in reported studies occur to doctors.
hospitals in the United States, sharps injuries were noted in Sharps injuries and other blood and body fluid exposures
6.9 per cent of procedures54 and injuries were recorded by have also been found to be frequent among embalmers.67
operating theatre staff in Glasgow at a rate of 1.6 per cent per Surveys of routinely reported incidents must be inter-
surgeon per operation, calculated to give 4.6 per cent per preted with caution because of the high rate of under-
operation overall.55 Williams56 studied blood exposures in reporting, particularly among doctors. Some authors have
theatre staff during 6096 operations over a six-month attempted to quantify this under-reporting. Astbury and
period. Sharps injuries occurred in 1.6 per cent of opera- Baxter,68 using questionnaire responses to estimate the
tions. The risk was increased with long procedures, high incidence of sharps injuries and bites and scratches over
blood loss, major operations, wound closure with staples the preceding year, found that only 5 per cent of injuries
and the main surgeon wearing corrective spectacles. It was had been reported by staff to the hospital occupational
concluded that wearing spectacles could be a surrogate for health service. The low (45 per cent) response rate to their
increased age and reduced manual dexterity or that the spec- questionnaire may have biased their results. McGeer et al.69
tacles themselves could be obscuring the operative field. reported a less than 5 per cent reporting rate for sharps
Blood exposures other than sharps injuries are also injuries among medical students, interns and residents in
common in surgical practice. These include glove tears and Toronto, but they asked respondents to recall incidents
perforations,57–59 and eye splashes with blood and other occurring over several previous years, which may have led
body fluids.60–62 It has been reported that even minor to inaccuracies. A questionnaire study of 158 operating
suturing procedures undertaken in the Accident and department staff at the Royal Free Hospital in London on
Emergency Department are associated with one or more reporting of needlesticks recorded 26 sharps injuries and
glove perforations in 11 per cent of cases.63 240 other blood-exposure incidents during the preceding
The risk of blood exposures is not confined to surgery. month; only 15 per cent of the sharps injuries and none of
Albertoni et al.64 found an overall rate of needlestick the other blood exposures were reported to the occupa-
injuries over a one-year period of 29 per cent among 20 000 tional health department (or indeed to anywhere else).70
Italian healthcare workers interviewed in 1985; the rate was
highest among surgeons (55 per cent) and nurses (35 per TRANSMISSION RISKS
cent). Collins and Kennedy65 have reviewed a number of
studies of sharps injuries among groups of healthcare The risk of transmission of HBV to a susceptible person
workers and compared the results in terms of needlestick following a single needlestick from a source who is HBeAg
injuries per 100 employee-years for different occupational positive may be as high as 30 per cent. The risk of transmis-
groups. Nurses appear to suffer the highest number of sion when the source is HBsAg positive but HBeAg nega-
injuries, even allowing for the number of nurses employed. tive is much lower, with studies reporting rates of
A group of workers at particular risk are phlebotomists, transmission of between 1 and 6 per cent (see Table 59.1
who spend most of their working day using needles to gain for a description of HBV serology).71–74 The risk of hepa-
access to veins.66 Other groups at risk include domestic and titis C transmission is around 2 per cent,75–79 ranging from
portering staff, who get injured from improperly disposed 0 to 10 per cent depending on the clinical status of the
needles and other sharp instruments, and laboratory staff. source patients and the tests used to identify infection in
the workers, markedly lower than for hepatitis B. The over- urticaria. Reports of acute infections acquired occupationally
all risk of transmission of HIV after percutaneous exposure in the United Kingdom and other countries that have
to infected blood has been extensively studied and is effective systems for ensuring that healthcare workers are
around 0.3 per cent.80,81 vaccinated against hepatitis B are now rare.
Some exposures may be of higher risk than others. A Confirmation that a case of hepatitis is due to HBV
case–control study suggested that factors increasing the risk infection requires serological testing. The serology of HBV
of HIV seroconversion after a percutaneous exposure to infection is described in Table 59.1. This shows the pattern
HIV-infected blood include: a ‘deep’ injury; the presence of of hepatitis B markers found in different situations, includ-
visible blood on the instrument; procedures involving inser- ing acute infection, natural immunity, the carrier state, and
tion of a device into an artery or vein; and exposure to a immunity as a result of vaccination.
source patient who is terminally ill.82 These are probably During the acute infection, supportive treatment is usu-
proxy measures for increased risks associated with exposure ally all that is required. Severe cases should be managed in
to a greater volume of blood and exposure to higher titres of specialist units. Sexual partners and other family and close
HIV. Similarly, a recent European case–control study found contacts should be investigated and offered vaccination if
that the risk of HCV seroconversion after percutaneous they are non-infected and non-immune.
exposure increased with deep injuries and procedures Fewer than 10 per cent of adults with acute hepatitis B
involving placement of a hollow-bore needle in the source infection will fail to clear the virus and become carriers. The
patient’s vein or artery, and also suggested that the transmis- carrier state is indicated by either the presence of hepatitis B
sion risk increased with titre of virus in the source patient.83 surface antigen (HBsAg) on two occasions at least six months
By 2002 (the latest date for which aggregate data from apart or the finding of HBsAg in the absence of anti-core
published reports worldwide are available), there were 106 antibody of IgM type (anti-HBc IgM). Those carriers who
reported cases of documented HIV seroconversion after remain positive for HBeAg have much greater infectivity
occupational exposure and a further 238 reported cases of than those who clear the HBeAg, but remain positive for
possible occupationally acquired infection.81 Most (87 per HBsAg (see above). Treatment with antiviral drugs, such as
cent) of the documented seroconversions were reported alpha-interferon and other new agents, may sometimes be
from the United States or Europe; relatively few were effective in helping to clear HBeAg or suppress viral replica-
reported from high-prevalence low-income countries, which tion. Long-term sequelae of chronic hepatitis B infection
have limited resources for occupational health and the include chronic liver disease and hepatocellular carcinoma.
enhanced surveillance needed to document seroconversion. Healthcare workers found to be infected with hepatitis B
Of the 57 documented seroconversions reported from the should be referred for specialist care.
United States between 1991 and 2006, only three occurred Acutely or chronically infected healthcare workers who
after 1995, with the most recent in 1999.84 This decline in undertake exposure-prone procedures can transmit hepa-
incidence probably reflects a combination of factors: titis B infection to their patients. An exposure-prone
improved exposure prevention; improved post-exposure procedure is one where there is a risk that the patient’s open
management, and the widespread use of highly active anti- tissues may be exposed to the blood of a healthcare worker,
retroviral therapy for HIV infection, which, by reducing the as in surgery, dentistry and midwifery during complicated
numbers of HIV-infected people needing inpatient treat- or instrumental deliveries. The risk of transmission depends
ment for advanced HIV-related disease, reduced the overall on the types of procedure being performed, the role of the
transmission risks for healthcare workers.85 worker and the infectivity of the worker. In outbreaks asso-
ciated with HBeAg-positive surgeons, overall transmission
CLINICAL FEATURES IN INFECTED HEALTHCARE WORKERS rates have been around 5 per cent, but transmission rates of
AND RISK OF TRANSMISSION TO PATIENTS 20 per cent have been recorded in groups of patients under-
going longer and more complex procedures.86 There is also
The clinical features of infections with blood-borne viruses evidence that some healthcare workers who are HBsAg posi-
acquired occupationally by healthcare workers are essen- tive but HBeAg negative can also transmit hepatitis B to
tially no different from the features of these infections patients during exposure-prone procedures, probably
acquired by any other means. because of carriage of variants of hepatitis B virus, in which
there is continuing viral replication, even though HBeAg is
Hepatitis B not detectable in the blood.87
Acute icteric hepatitis, sometimes fulminant, can occur three
to six months after occupational exposure to the virus in Hepatitis C
non-immune workers; though only around a third of adults It is now known that HCV is the cause of a large propor-
who become infected will develop clinically significant symp- tion of cases of what was formerly called ‘non-A, non-B
toms. In clinically apparent hepatitis, a prodromal illness hepatitis’. Acute and even fulminant hepatitis can occur
with fever, nausea, anorexia and abdominal discomfort pre- after occupational transmission of HCV but is rare. The
cedes the development of jaundice and dark urine. In some majority of infections will be anicteric, and many will be
cases of acute hepatitis B infection, the first symptom may be asymptomatic, occupational transmission being indicated
734 Occupational infections
by a rise in liver enzymes or by the detection of HCV RNA reported occupational exposure, or by testing during
or of antibody to HCV on testing. Treatment with antiviral investigation of the source of infection in one or more
drugs, especially if instituted early, may help to prevent the infected patients.
carrier state being established. In chronic HCV carriers, In the United Kingdom, all healthcare workers who
there is sometimes a fluctuating hepatitis with ‘yo-yo’ undertake exposure-prone procedures are required to
transaminases. Sequelae can be serious, including cirrho- demonstrate by testing of an identified validated blood sam-
sis, chronic liver disease and hepatocellular carcinoma. ple that they are immune to hepatitis B as a result of immun-
Healthcare workers infected with hepatitis C virus can ization or that they are not hepatitis B infected (HBsAg
transmit the infection to patients during exposure-prone positive). Hepatitis B-infected healthcare workers who are
procedures.88–92 The transmission rate has not been quan- HBeAg positive, or who are HBeAg negative but have a
tified precisely, but, by analogy with the evidence on trans- hepatitis B virus DNA level (HBV DNA) of more than 105
mission to healthcare workers from needlestick exposures, genome equivalents per mL (geq/mL), may not perform
it is likely to be substantially less than for hepatitis B (with exposure-prone procedures. Hepatitis B-infected healthcare
HBeAg). workers who are HBeAg negative and have a baseline HBV
DNA level of below 1000 geq/mL may practise unrestricted
Human immunodeficiency virus provided that their HBV DNA level is monitored annually,
A seroconversion illness typically occurs about four to six and remains below 103 geq/mL. HBeAg-negative healthcare
weeks after the exposure. This is characterized by fever, workers whose baseline viral load is 103–105 geq/mL may,
generalized lymphadenopathy and a rash. Thereafter, the if on continuous oral antiviral treatment, and closely
infection is asymptomatic until an HIV-related illness or monitored by a consultant occupational health physician
full-blown AIDS occurs. The first AIDS illness in a young and a designated hepatologist, practise exposure-prone
healthcare worker with undiagnosed HIV infection may be procedures, provided that their hepatitis B infection
pneumonia due to Pneumocystis jirovecii. This may present remains well controlled (i.e. HBV DNA level remains below
with unexplained breathlessness on exertion or as failure of 103 geq/mL).96–98
a chest infection to respond to the usual antibiotics. Healthcare workers in the United Kingdom who have
Immunocompromised people with AIDS can develop a hepatitis C (HCV) infection and who are HCV RNA posi-
variety of bacterial and fungal infections, sometimes tive must not perform exposure-prone procedures; success-
with opportunistic organisms and parasitic infestations. ful antiviral treatment may permit a return to practice.92
Tuberculosis is a particular problem, especially in areas HIV-infected healthcare workers must not undertake
with a high prevalence in the population. There is a risk of exposure-prone procedures.99 Recent guidance on health
infection with atypical mycobacteria or with multidrug- clearance in the United Kingdom recommends that all new
resistant Mycobacterium tuberculosis. Modern combin- and returning healthcare workers should routinely be
ation antiretroviral therapy for HIV infection and primary offered hepatitis B vaccine (with post-vaccination testing of
prophylaxis against opportunistic infections have greatly response) and testing for HCV and HIV infection. If the
improved the prognosis of HIV infection in developed worker is to undertake exposure-prone procedures, the
countries, prolonging survival and delaying the onset of worker should be shown, by testing of an identified vali-
AIDS in people infected with HIV. The prognosis remains dated blood sample, to be non-infectious for HBV, HIV
very poor in countries where this effective but expensive and HCV before the offer of appointment is confirmed.98
treatment is not available. Anyone with HIV antibodies is The guidance also requires that healthcare workers who
considered to be infectious through sexual contact or con- believe they might have been exposed to HIV or HCV
tact with their blood, but infectivity is higher at times when (whether sexually, through injecting drug use or occupa-
the level of virus in the blood is higher, for example during tionally) promptly seek advice on whether they should be
seroconversion and in the late stages of AIDS. tested to confirm their status. National authorities in other
The potential for HIV-infected healthcare workers to European countries and the United States have made simi-
transmit to patients during exposure-prone procedures is a lar, though usually less prescriptive, recommendations. In
cause of great concern, given the very serious consequences of the United Kingdom, recommendations on testing medical
such an occurrence. There are three reports of transmission and dental students for blood-borne virus infections have
from a healthcare worker to patients: a dentist in Florida,93 an recently been revised and are closely aligned to new health
orthopaedic surgeon in France94 and a gynaecologist in clearance guidance. They require post-admission testing of
Spain.95 The estimated risk of transmission to patients is medical students, and pre-entry clearance of dental stu-
much lower than for either hepatitis B or hepatitis C. dents, and set out the roles and responsibilities of the col-
lege, the occupational health service and the student. They
MANAGEMENT OF INFECTED HEALTHCARE WORKERS also make it clear that being infected with a blood-borne
virus is not, of itself, a barrier to medical school entry or to
A healthcare worker may be found to have an infection medical registration.100
with a blood-borne virus, either as a result of routine It is recommended in the United Kingdom that, where
testing (see below), or by testing in relation to an illness or there is evidence of HIV transmission from a healthcare
Healthcare workers and related occupations 735
worker to a patient, all patients on whom the worker has for healthcare workers’ in order to demonstrate compli-
undertaken exposure-prone procedures should be con- ance, but it is not clear to what extent this requirement has
tacted and offered testing to confirm that they have not been implemented.106
acquired HIV infection from the healthcare worker. In the In the laboratory setting, the use of sharp instruments
absence of evidence of transmission, the decision on or equipment can be virtually eliminated. Suitable per-
whether to undertake a ‘look-back exercise’ should be con- sonal protective equipment (PPE) and safe laboratory
sidered on a case-by-case basis.99 Recommendations on practice prevents exposure of broken skin and the mucosae
HCV are similar.92 of the eyes and mouth.
More general issues about fitness to work may arise in However, not all occupational blood-exposure incidents
HIV-infected healthcare workers and other people in jobs are preventable and some will occur even where preventive
of high responsibility. These include concerns about their measures have been well implemented. Other preventive
risk of acquiring infection if they become immunocom- strategies are available. For hepatitis B, the most infectious of
promised and about the effects of the neurological compli- the agents, there is fortunately an effective and safe vaccine.
cations of HIV infection. The infection in most people, Immunization of all healthcare workers who may have con-
including healthcare workers, will have been acquired non- tact with blood and body fluids is recommended. Vaccines
occupationally. The issues about HIV infection and fitness against hepatitis C and HIV have not yet been developed.
to work are considered in detail elsewhere.101 Around 90 per cent of young, fit healthcare workers
If a healthcare worker is found to be infected with a produce an adequate anti-HBs response to hepatitis B vac-
blood-borne virus, it is important to establish whether the cine. Response rates are lower in males, smokers, older
infection is likely to be occupational, since they are eligible people and those who are immunosuppressed. Response
for certain benefits if this is the case. In the United Kingdom, rates are also lower when vaccine is given intradermally
since hepatitis B and hepatitis C are prescribed industrial (rather than intramuscularly), or given intramuscularly
diseases, all that is needed is to show that the person is into the gluteal muscles rather than the deltoid. True vac-
infected and that their work involves (or has involved) cine failure is rare.107 Apparent non-responders (no or low
exposure to potentially infected blood, whether in the clinical level anti-HBs response) should be tested for evidence of
setting or the laboratory. HIV infection is not a prescribed HBV infection. True non-responders, with no evidence of
industrial disease, but infected workers in the UK may be eli- previous HBV infection, should be informed they are not
gible for National Health Service Injuries Benefit if it can be protected and strongly advised to report any occupational
shown that their infection is likely to be occupational in ori- exposures to blood. Non-response to vaccine should not
gin. For all blood-borne viruses, the most obvious way to be considered a bar to employment as a healthcare worker
demonstrate an occupational origin is to show seroconver- in any capacity. Although a quarter of a century has passed
sion following an occupational exposure incident. since hepatitis B vaccine first became available, there are
still reports of under-vaccination of healthcare workers at
PREVENTION OF INFECTION WITH BLOOD-BORNE risk: a study of transplant surgeons in the United States in
VIRUSES 2003 found that a fifth (70/311) of respondents were inad-
equately vaccinated, and that surgeons under-estimated
Prevention rests mainly on reduction of the risk of expos- the risks of having a percutaneous exposure while operat-
ure to blood or other infected body fluids. The most ing, and of becoming infected if exposed; the authors sug-
important risk is percutaneous exposure to blood, so gest that the most expedient way to ensure protection is to
reducing the use of sharp instruments, developing safer require documented evidence of vaccination and testing
techniques and types of equipment, and making proper for all staff at risk.108
use of suitable containers and systems for disposal of used Once an exposure to infected blood has occurred, other
needles and sharp instruments are important.102 Advances measures can reduce the risk of infection in the worker. For
in the last decade include the widespread adoption of stand- hepatitis B, active immunization with the vaccine, using an
ard infection control precautions (formerly ‘universal accelerated course in those not previously immunized, is
precautions’), the introduction of safety-engineered intra- recommended. Passive protection may also be provided
venous cannulae and phlebotomy devices, which have using hepatitis B immune globulin (HBIG). However,
been shown to reduce needlestick injury rates,103–105 and, HBIG gives incomplete protection and should be given in
in the United States, legislation that makes provision of conjunction with the first dose or booster dose of vaccine;
safety-engineered devices to healthcare workers manda- in workers who have failed to respond to the vaccine, it is
tory. Together, these have resulted in a decline in hollow- the only protection available. For hepatitis C, no effective
bore needle injury rates, most marked for the injuries that post-exposure prophylaxis is available at present, but follow
present the greatest risk.85 In the United Kingdom, the up to six months is recommended to check that transmis-
Health and Social Care Act 2008 requires that NHS trusts sion has not occurred.92,109
consider making ‘provision of medical devices that incorp- For HIV, recommendations about post-exposure pro-
orate sharps protection mechanisms where there are clear phylaxis (PEP) have recently been revised in the United
indications that they will provide safe systems of working Kingdom110 and in the United States.111 A retrospective
736 Occupational infections
case–control study suggests that the use of prophylactic Other viruses as occupational risks for
zidovudine is associated with a reduced risk of HIV serocon- healthcare workers
version after percutaneous (needlestick) exposure to
HIV-infected blood.82 By extrapolation from the effective- VIRAL HAEMORRHAGIC FEVERS
ness of combined antiretroviral therapy in established infec-
tion, and in preventing mother-to-child HIV transmission, Viral haemorrhagic fevers, caused by a range of viruses
current guidelines on PEP now recommend routine use of (from the arenavirus, flavivirus, filovirus and bunyavirus
three antiretroviral drugs in the United Kingdom (or two, families), are severe and potentially life-threatening dis-
sometimes three in the United States) for four weeks after a eases. They are endemic in Africa, parts of South America,
significant occupational exposure to HIV. The recom- and in rural Eastern Europe and the Middle East. Cases in
mended three drugs for PEP in the UK and USA are zidovu- the United Kingdom are very rare and virtually always
dine, lamivudine and indinavir, with modification of this imported, but laboratory-acquired infection has been
regime if the source patient is believed to have infection reported.
resistant to any of these drugs. The prophylaxis should be The infections are transmitted to humans by mosquito
started as soon as possible after the exposure and preferably bite (yellow fever, dengue, Rift valley fever, Chikungunya);
within one hour. The effectiveness of this regime in reducing tick bite (Omsk haemorrhagic fever, Kyanasur Forest dis-
the rate of seroconversion (in any case small) is unknown, ease, Crimean Congo haemorrhagic fever (CCHF)); or
and seroconversion despite prompt prophylaxis has been through contact with virus excreted by infected rodents
reported. A significant proportion of those given PEP will or other animal reservoir (the arenaviruses, including
experience side effects, which may be severe enough to Lassa virus; Hantaan virus); the geographic distribution of
require time off work. Although higher adverse event rates the viruses matches that of any animal reservoir. However,
are reported among those given a three-drug regime, the only four of these infections are known to be readily capa-
discontinuation rates for three-drug regimes are similar to ble of spreading from person to person and thus present a
those for two-drug regimes.112 potential risk of transmission to healthcare workers: Lassa
Initiation of suitable post-exposure prophylaxis depends fever, CCHF, Marburg disease and Ebola haemorrhagic
upon knowledge of the worker’s immunity (for hepatitis fever. A newly described arenavirus, presumptively termed
B) and the source patient’s infection status. Post-exposure Lujo virus, may also fit into this category: a safari booking
testing of source patients for blood-borne virus infection is agent, who had a possible history of a recent tick bite and
therefore important. Patients should be tested only with contact with horses, was transferred by air from Zambia to
their consent and with appropriate pre-test discussion. If South Africa with an undiagnosed, but clearly severe, ill-
approached sensitively, few patients will refuse testing. ness in early October 2008 and died soon afterwards. Three
If immediate testing is not feasible, or the patient refuses fatal secondary cases occurred in healthcare workers (a
testing, but there is a strong suspicion of infection, for paramedic who accompanied the transfer, an intensive
example with HIV, then PEP should be considered. care nurse and the worker responsible for terminal clean-
Healthcare workers who have been involved in blood- ing of the index case’s hospital room); a tertiary case (a
exposure incidents, especially when the source patient is nurse) survived; all had potential for exposure to the index
known to be infected with a blood-borne virus, are under- case’s blood or body fluids.114
standably anxious and may become extremely anxious; CCHF was first recognized in the USSR in 1944, and the
post-traumatic stress syndrome has been reported.113 They virus isolated from the patients was subsequently shown to
should have access to timely, sympathetic and knowledge- be identical to that isolated in 1956 from a sick child in
able advice from an experienced designated physician (the Zaire. The virus is now known to be widely spread
occupational physician often takes on this responsibility). in Africa, Central Asia, southern Europe and parts of the
Giving accurate information and providing immediate and Middle East, though there appear to be geographical vari-
ongoing support is an important, though not always recog- ations in virulence, the disease being more severe in Asia
nized, part of the management of blood exposures at work. than in Africa.115 Lassa fever was first described in 1969
Other workers may have occasional contact with blood after three missionary nurses working in Lassa in north
or contaminated sharp instruments, for example emer- eastern Nigeria became seriously ill with an unknown
gency care workers, refuse workers, police and prison offi- infection, from which two died. The third nurse, who had
cers. These workers should be trained to take appropriate cared for the other two, was flown to North America for
precautions to reduce the risk of exposure to blood (espe- treatment, and a new arenavirus was isolated from her
cially sharps injuries) and should know how to obtain serum, and subsequently from similar cases in Nigeria, and
immediate post-exposure care. The need to offer them named Lassa virus.
routine pre-exposure hepatitis B immunization is less Marburg virus takes its name from an outbreak of haem-
clear-cut, although this may be appropriate for selected orrhagic fever among laboratory workers in Marburg,
subgroups. Arrangements should be made for them to Germany in 1967. Workers in laboratories in Frankfurt and
have access to expert advice, and treatment if necessary, if Belgrade also became infected. All 25 with primary infec-
they are involved in a blood-exposure incident. tions had been in contact with organs, blood or cell cultures
Healthcare workers and related occupations 737
from a batch of wild-caught African green monkeys from is direct contact with infected blood (for example, by
Uganda; six secondary cases occurred amongst those who needlestick injury or contamination of broken skin or
had contact with infected patients’ blood. Small numbers of mucous membranes). In the ebolavirus epidemic in the
cases have since occurred in South Africa, Zimbabwe, Sudan in 1979, it was reported that staff providing direct
Kenya and Uganda; large outbreaks, amplified by nosoco- clinical care for ill patients had a five times higher risk of
mial transmission, occurred in the Democratic Republic of contracting infection than staff with less physical contact
the Congo (formerly Zaire) in 1998–2000, and in Uige with the patients, and there were no cases of infection in
province, Angola in 2004–2005. Ebola haemorrhagic fever staff who entered the room but had no physical contact.119
was recognized in 1976, when outbreaks of a new haemor- UK guidelines on management and control of viral haem-
rhagic fever, with a high case fatality rate and considerable orrhagic fevers115 advise that patients returning from
secondary spread through blood contact, occurred simultan- abroad with a fever should be categorized on the basis of a
eously in Zaire and in the Sudan. Five ebolavirus species risk assessment that covers: area visited, clinical features
have so far been recognized: Zaire ebolavirus, Sudan and time of onset in relation to travel, household or occu-
ebolavirus, Reston ebolavirus, Cote d’Ivoire ebolavirus and, pational contact with known or suspected cases, or contact
most recently, in an outbreak in Uganda in 2007–2008, with potentially infected blood or body fluids. Any patient
Bundibugyo ebolavirus.116,117 Outbreaks have occurred in known or suspected to be suffering from a viral haemor-
Gabon, Sudan, the Democratic Republic of the Congo, and rhagic fever, or in whom the diagnosis cannot immediately
the Republic of the Congo. Cote d’ Ivoire ebolavirus was isol- be excluded, should be urgently discussed with a senior
ated from a zoologist working in the country who became infectious disease clinician working in a specially desig-
accidentally infected while doing a post-mortem on a chim- nated high security infectious disease unit. Nearly all
panzee found dead in the wild. Reston ebolavirus was first suspected cases will in fact have malaria. The guidelines also
isolated from batches of cynomolgus macaques imported to cover the special precautions needed to obtain, transport
the United States and Italy from the Philippines, and has and examine laboratory specimens from a patient with a
since also been isolated from domestic pigs in the suspected viral haemorrhagic fever and the management of
Philippines. An animal caretaker in the Reston primate patients’ contacts. The first investigation should always be
facility became viraemic after a virus-contaminated scalpel to confirm or refute a diagnosis of malaria. If there is doubt,
injury, and he and three other asymptomatic workers had empirical treatment for malaria should be instituted.
serological evidence of infection. Antibody has also been
detected in workers in primate-supply facilities in the SARS CORONAVIRUS
Philippines and, more recently, in pig farmers, but human
illness associated with this ebolavirus species has not been In 2002, a new infection, severe acute respiratory syn-
reported.118 drome (SARS) emerged in Guandong province, China.
The clinical illnesses are characterized by fever, haemor- Rapid person-to-person spread of virus caused outbreaks
rhage and collapse, although serosurveys have suggested in Hong Kong SAR, Vietnam, Singapore and Canada in
that subclinical and mild infections also occur. For Lassa 2003, with more than 8000 cases in more than 30 coun-
fever, reported mortality rates range from 3 per cent (in a tries.120 Transmission was amplified within hospitals, as
community outbreak) to 66 per cent (in hospitalized cases). early cases were cared for without effective routine infec-
Lassa fever tends to have a more insidious onset than tion control measures; 22 per cent of SARS cases in Hong
Marburg or Ebola disease and can therefore be difficult to Kong and nearly half (43 per cent) of SARS cases in
diagnose. The differential diagnosis of a fever in a patient Toronto and Singapore (41 per cent) occurred in health-
who has been in rural West Africa within the previous three care workers. Further cases in Singapore, Taiwan and
weeks includes Lassa fever, typhoid fever and malaria. In China in late 2003 and 2004 were associated with labora-
Lassa fever, there is usually fever and headache followed by tory-acquired infections.121,122 Overall, 20 per cent of hos-
pharyngitis, abdominal tenderness, sometimes with vomit- pitalized patients required mechanical ventilation and 15
ing and diarrhoea, and evidence of pleural effusion. There per cent of hospitalized cases died. Mortality was greater in
may be little or no evidence of haemorrhage other than the elderly and in those with co-morbidity. The usual incu-
some bleeding of the gums. Severe haemorrhage is unusual bation period is three to five days (range, two to ten days).
in Lassa fever, but more common in Marburg or Ebola dis- Clinical features include fever, chills, rigors, malaise and
ease. Treatment is largely a question of providing intensive myalgia, sometimes accompanied by diarrhoea, followed
supportive care; antiviral drugs (specifically, ribavirin) two to four days later by a non-productive cough, dys-
reduce the mortality of Lassa fever, if started early, and may pnoea and pneumonia, with progression to respiratory
also be helpful in CCHF, but have not been shown to influ- failure in severe cases.123 However, there is a spectrum of
ence the course of either Marburg or Ebola disease. disease, and many cases are mild and will not require hos-
The viral haemorrhagic fevers pose a significant risk of pital admission. Antiviral drugs (e.g. ribavirin) or other
infection to healthcare workers caring for cases, laboratory drugs, such as steroids, have not been shown to be effect-
workers handling specimens from them, and to research ive; treatment is essentially supportive. Asymptomatic
laboratory workers. The main risk in the healthcare setting contacts are not infectious; cases are non-infectious from
738 Occupational infections
in immunocompetent females is its potential to cause fetal females, it can cause arthropathy which is usually self-
damage if acquired in pregnancy. limiting. It can cause complications in people with haemo-
globinopathies and those who are immunosuppressed, and
MEASLES, MUMPS AND RUBELLA fetal damage. There is no specific treatment. Diagnosis is
made serologically. Outbreaks in healthcare settings may
Measles is a highly transmissible acute viral illness, charac- necessitate ward closures to interrupt transmission.134
terized by a prodromal illness (fever, conjunctivitis, coryza
or cough) followed by the development of an erythema- HERPETIC WHITLOW OR PARONYCHIA
tous maculopapular rash which spreads over the body
from the head downwards over three to four days. Koplik These lesions on the fingers are due to direct contact with
spots may be seen on the mucous membranes of the mouth herpes simplex virus and used to be quite a common prob-
24–48 hours before the rash appears. Complications lem in healthcare workers. Diagnosis is by culture of virus
include diarrhoea, pneumonia, convulsions, encephalitis from the lesions, electron microscopy or immunofluores-
and subacute sclerosing panencephalitis. In the United cence. Contact with the mouth area, such as in mouth care
Kingdom, it is estimated that 1 in 5000 cases is fatal. The or dentistry, with ungloved hands seems to be the major
case fatality-rate is age-related; disease tends to be more risk, and infection is therefore preventable by adherence to
severe in infants and in teenagers and adults than young standard infection control precautions.135
children, and is also more severe in the chronically ill,
under-nourished or immunosuppressed. Other infectious risks for healthcare workers
Rubella infection in children (German measles) is usu-
ally a mild, self-limiting illness characterized by fever and a TUBERCULOSIS
morbilliform rash. In adults, however, infection is more
severe, with rash, fever, debility and prominent symptoms The clinical features of pulmonary tuberculosis include
in small joints. Maternal infection in the first 16 weeks of fever, weight loss, cough, malaise, sweats and haemoptysis.
pregnancy, particularly if in the first trimester, causes The diagnosis should be considered in any healthcare
severe fetal damage. Healthcare workers are unlikely to be worker who presents with such symptoms and no other
at increased risk of rubella, especially since many countries apparent cause. Radiographs may be normal in early infec-
now vaccinate infants as well as adolescents against rubella. tion or show a rather diffuse bronchopneumonia, but in
However, healthcare workers have been the source of more advanced cases there may be the more typical upper
rubella outbreaks. lobe pneumonia with cavitation. Healthcare workers in the
Mumps is an acute viral infection caused by a paramyxo- United Kingdom remain at increased risk of tuberculosis
virus, with an incubation period of around 16 days (range, (TB), where although TB incidence rates have stabilized,
12–25 days). It is characterized by a short prodromal illness they remain at higher levels than in the 1980s.136
(fever, headache, myalgia, anorexia) followed by bilateral or Guidelines in the United Kingdom cover the health clear-
unilateral parotid swelling. Asymptomatic infection is ance of new and transferring National Health Service work-
common, particularly in children. Meningism occurs in ers, protection of workers against infection (including the
15 per cent of cases; other complications include orchitis use of BCG (bacillus Calmette-Guérin)) and safe working
(25 per cent of post-pubertal men), oophoritis (5 per cent of practices (Figure 59.1).98,100,132,137 BCG is recommended for
post-pubertal women), pancreatitis (4 per cent) and sen- healthcare workers, whatever their age, who will have con-
sorineural deafness. The virus is spread by droplet and air- tact with patients or clinical material and who are not tuber-
borne transmission. Non-immune healthcare workers who culin skin test positive as a result of previous BCG
have an unprotected exposure to the virus must be excluded immunization. BCG should not be used in HIV-infected
from work from the 12th to the 25th day after exposure. workers; workers should be individually risk-assessed for
Measles, mumps and rubella (MMR) vaccine prevents HIV before BCG is given. Healthcare workers from high TB
all three of these infections; vaccination of healthcare incidence countries, or who have worked in high TB
workers is particularly important because they may trans- prevalence settings who have a positive tuberculin test (or a
mit infection to vulnerable groups. Self-reported immune positive interferon gamma test) should be referred to a chest
status may be inaccurate. In the United Kingdom, satisfac- clinic. Healthcare workers from low TB incidence countries,
tory evidence of protection is documentation of receipt of such as the United Kingdom, who are tuberculin test (or
two doses of MMR vaccine or serological evidence of interferon gamma test) positive and have not previously had
immunity to measles and rubella.132 BCG should have a medical assessment and a chest x-ray,
but should also be referred to a chest clinic for consideration
PARVOVIRUS of treatment of disease or latent infection. Healthcare work-
ers who are found to be HIV positive during employment
Parvovirus B19 infection (which is not vaccine prevent- should have medical and occupational assessments of TB
able) produces a febrile illness with a transient macular rash risk, and may need to be offered redeployment to reduce
which may be mistaken for rubella. In adults, particularly exposure. Guidance is also given on the management of
740 Occupational infections
Pre-employment
questionnaire
Suspicious
symptoms
Yes No
Medical
assessment
chest radiograph
No Yes
Normal
Working with
patients or clinical
specimens
Yes
No
Yes Prior BCG
No
scar or
document
Heaf test
Yes Grade No
0,1
Further history
No Suspicious
symptoms
Yes
Chest radiograph and medical
assessment
Yes No
Normal
Figure 59.1 Screening of healthcare workers
Chest No Give Inform and Chest for tuberculosis. Reproduced with permission
clinic action BCG advise clinic
from Ref. 137.
healthcare workers who have a significant occupational multidrug-resistant M. tuberculosis and, coupled with imple-
exposure to TB, and of those who are infected with TB, mentation of a national TB control strategy, have resulted in
regardless of source. Tuberculosis acquired through an a reduction in TB incidence.140 The guidelines, which were
occupation involving contact with sources of tuberculous recently revised, include several levels of control: administra-
material is a prescribed disease in the United Kingdom. tive controls to prevent exposing uninfected individuals to
In the last 20 years, multidrug-resistant tuberculosis people who have infectious tuberculosis; then engineering
(MDR-TB) has become a problem. It remains uncommon controls to reduce spread of infectious droplet nuclei, such as
in the United Kingdom, accounting for around 1 per cent of local exhaust ventilation, air flow control and air filtration;
new isolates, but worldwide, about 20 per cent of isolates are and finally, the use of personal respiratory protective
multidrug resistant. MDR-TB strains are not more trans- equipment in areas where there is still a risk of exposure to
missible, or more virulent, but are considerably more diffi- infection. The guidelines stress the need for early identifica-
cult, and more costly, to treat. The more recently described tion and treatment of patients with tuberculosis. Infection
extensively drug-resistant strains of Mycobacterium tubercu- control guidelines for preventing the spread of tuberculosis
losis, which first emerged in South Africa against a back- in relation to HIV and multidrug-resistant tuberculosis have
ground of high HIV prevalence, may not be treatable. also been produced in the United Kingdom, designed to
Occupational transmission of MDR-TB to workers has been protect both patients and healthcare workers.141,142
described.138,139 HIV-infected workers and patients or those
who are immunosuppressed for other reasons are at greater SCABIES
risk. In the United States, detailed guidelines for preventing
transmission of M. tuberculosis in healthcare facilities were This skin disease is caused by the mite Sarcoptes scabei
produced in response to several serious outbreaks of and transmitted by close personal contact. The itchy rash
Laboratory research workers and animal handlers 741
characteristically presents on the finger webs, wrist and Workers should carry a medical contact card which gives
elbow flexures, and axillae but may sometimes present as a details of their work and provides the name of the doctor
more widespread generalized dermatitis (Norwegian sca- who should be contacted if the worker develops an
bies). Linear burrows on the skin are present, but will not unexplained fever or other signs of infection. Workers
always be visible, particularly if hypersensitivity to mite seeking medical advice should tell the doctor about their
antigen has developed. Nurses and other workers who pro- work, as well as doctors asking their patients about their
vide physical care to patients are at risk. Cases are usually occupations.
sporadic, but more extensive outbreaks have been
described.143 The use of gloves and gowns when handling
patients who may have scabies is advisable. Treatment of Human immunodeficiency virus infection
the case and family members is with malathion or permeth-
rin, which should be applied to the whole body from the At least three research laboratory workers worldwide have
neck down and left for 24 hours. Benzyl benzoate can also acquired HIV infection after exposure while working with
be used, but often causes irritation and may need to be concentrated HIV.66,80 Workers should have the same
applied on up to three consecutive days. access to post-exposure prophylaxis and care as described
Occasionally, strains of mites from infected pets can above for clinical healthcare workers.
also cause a highly pruritic papular urticarial rash. In this
case, it is pet owners (and possibly veterinary surgeons) Work with primates
who are at risk, rather than healthcare workers.
Staff working with primates may be exposed to a number
STAPHYLOCOCCAL INFECTIONS of infections, including herpes B virus, Marburg virus,
Reston ebolavirus, monkeypox virus, rabies, tuberculosis,
Healthcare workers can become colonized with meticillin- hepatitis A and enteric infections. Primates from reputable
resistant Staphylococcus aureus (MRSA), carried in the nose, suppliers will, if wild caught, have been quarantined for six
throat, axillae, perineum and on damaged skin. Such col- months and screened for these infections, although nega-
onized workers pose a risk of transmitting to patients an tive serological tests do not guarantee absence of infection.
infection which can be extremely difficult to treat and may Primates for use in research which will involve human
be fatal in immunocompromised patients, including those contact should, therefore, ideally have been bred in captiv-
who have undergone recent surgery. Even non-colonized ity and be herpes B virus seronegative. All primates should
healthcare workers can spread the infection between be regarded as potentially infective and handled with
patients. Scrupulous attention to hand washing and to extreme care by trained staff. Suitable protective clothing
changing any barrier garments (gloves, aprons) between should always be worn.
each patient is vital. Where a colonized worker has been Infected animals shed herpes B virus from the orophar-
detected as a result of an outbreak investigation, eradication ynx and genital tract; workers may acquire infection
of the organism may be attempted, but sometimes proves through bites or skin abrasions and subsequently develop a
difficult to achieve. In rare cases, for example a cardiovascu- severe encephalomyelitis with a fatality rate of around 70
lar surgeon or a nurse on the intensive care unit, failure to per cent. There is no evidence of asymptomatic infection in
eradicate MRSA may, if there is evidence of continuing primate handlers. Guidelines have been published for the
transmission to patients, mean that they require long-term prevention and treatment of herpes B virus infections in
redeployment. exposed people. Wounds should be gently irrigated with
In the United Kingdom, where reporting MRSA bacter- soap and water or normal saline. Antibiotic prophylaxis
aemia to the national surveillance system is a mandatory against oropharyngeal bacteria (including anaerobes)
requirement, recent guidelines cover the prevention and should also be given for bites. Aciclovir may be given as
management of MRSA in hospitals and other institu- prophylaxis after an exposure to a source known or poten-
tions.144,145 tially infected with herpes B virus, and should also be used
to treat any worker with suspected infection.146–148
LABORATORY RESEARCH WORKERS AND
ANIMAL HANDLERS Work with vaccinia virus
The infection risk to laboratory research workers will A number of occupationally acquired infections with vac-
depend on the precise nature of the work in which they are cinia virus have recently been reported in research workers;
engaged and the techniques applied. Risk assessments of any worker who will be handling cultures or animals con-
individual processes are necessary under the COSHH taminated or infected with non-highly attenuated vaccinia
(control of substances hazardous to health) regulations, virus or other orthopox viruses that infect humans should
and should result in the development, implementation have vaccinia vaccine before any exposure.149 If vaccine is
and monitoring of safe standard operating procedures. contraindicated, redeployment may be necessary.
742 Occupational infections
INFECTIONS ASSOCIATED WITH parasite are in practice rarely useful in diagnosis. It is impor-
OCCUPATIONAL TRAVEL tant to have a high index of suspicion of malaria in anyone
with an unexplained fever who has been in an endemic area.
The risk to travellers will depend on the countries visited, Particularly for falciparum malaria, sudden and catastrophic
the proportion of time spent abroad, and working and liv- deterioration in clinical condition may occur; deaths can
ing conditions while abroad. The most important hazard and do result. Complications of malaria include pulmonary
for occupational travellers is non-infectious: injury, particu- oedema, coma, fits, hypoglycaemia, anaemia, renal failure
larly in road traffic accidents, is common and may often be and abortion.152 Widespread haemolysis can lead to haemo-
fatal. There is good evidence that risk-taking behaviour globinuria, so called ‘black water fever’. Falciparum malaria
abroad may differ from that at home; travellers should be should be treated as a medical emergency. The diagnosis of
counselled that unprotected sexual intercourse poses a malaria is made by identification of the parasite in thick
clear risk of HIV and other infections and should be blood films; specialist help may be needed for interpretation.
avoided. A single negative film does not exclude the diagnosis, partic-
ularly in a first episode of malaria when severe symptoms
can occur with a low parasitaemia, and empirical treatment
Malaria against P. falciparum may be appropriate.
The treatment regime depends on the known or sus-
Malaria is a major infectious risk for travellers. Around 2000 pected species of parasite and its likely sensitivities (depend-
cases are imported into the United Kingdom each year, of ing on area of origin) as well as the severity of the clinical
which rather more than half are due to Plasmodium falci- illness.153 Expert advice should be sought about the appro-
parum, which is the most serious of the four species of priate treatment regime in each case. Chloroquine-resistant
malaria parasite which cause disease in man, and is poten- P. falciparum is now so widespread that choroquine should
tially fatal. P. vivax, P. ovale and P. malariae are less likely to no longer be used for the treatment of falciparum malaria in
cause life-threatening illness. Most malaria infections will the United Kingdom, although it remains the drug of choice
have been acquired through being bitten by an infected mos- for P. malariae and P. ovale and uncomplicated P. vivax
quito, but transfusion-acquired infection, transplacental infections. Additional treatment with primaquine is needed
transmission and acquisition through needlestick exposure for infection with P. vivax and P. ovale to eradicate the hyp-
to infected blood are also well recognized. Prevention nozoite stage of the parasite in the liver and prevent relapse.
requires risk recognition; travellers should be encouraged to If this is not done, there is a risk of late relapse, which may
take measures to avoid being bitten by mosquitoes (appro- occur years after the primary infection. Oral treatment can
priate clothing, insect repellents (used directly on the skin or be used unless the patient is severely ill, confused or uncon-
impregnated in wrist or ankle bands), insecticide-treated scious. Supportive care is an integral part of management
mosquito nets and insecticide sprays). They should comply and may include fluid replacement, management of fits,
with an appropriate chemoprophylactic regimen, but should control of blood glucose, ventilation and renal dialysis.
understand that there is no chemoprophylactic regime which
is 100 per cent effective. In choosing a regime, the risk of
adverse reactions to any drug must be balanced against the Traveller’s diarrhoea
risk of acquisition of disease.150 Guidelines for the prevention
of malaria in travellers from the United Kingdom have In developed countries, Campylobacter sp. and salmonellae
recently been revised,151 and are regularly reviewed and are the most common causes of infective diarrhoea.
updated. These contain up-to-date information about rec- However, enterotoxin-producing strains of Escherichia coli
ommended chemoprophylaxis regimes by geographical (ETEC) are the most common cause of diarrhoea in trav-
area, and advice on the use of regimes for emergency self- ellers to less developed countries, where other infections
treatment. The drugs most commonly used currently for which have a human, rather than an animal, reservoir are
prophylaxis include chloroquine, proguanil and mefloquine. also more likely to be acquired. Diarrhoea caused by ETEC,
Specialist advice should be sought on prophylaxis for people shigellae and Giardia lamblia, although unlikely to be life
who will be sent on long-term postings, or who intend to live threatening, may cause considerable morbidity, misery
in a malaria-endemic area. and loss of efficiency.
The incubation period for malaria varies depending on
the species. Malaria due to P. falciparum usually presents PREVENTION
either in the endemic area or within two months of leaving
and typically 9–14 days after a bite from an infected mos- In theory, travellers’ diarrhoea is wholly preventable if sim-
quito. Malaria due to other species, particularly P. vivax, can ple precautions are followed faithfully. These include eating
take up to 12 months to present. Symptoms, especially in the only thoroughly cooked food freshly prepared; washing and
early stages, are non-specific and include fever, headache, peeling all fruit; avoidance of salads, shellfish, unpasteurized
malaise and myalgia. The classically described fevers of spe- milk or milk products, and tap water (including ice in
cific periodicity associated with different species of malaria drinks). In practice, it may be difficult to follow this advice
Others 743
to the letter, especially for those who have little control over through contaminated food (particularly bivalve molluscs)
catering arrangements (e.g. delegates at an international or water. Travel to countries of high or intermediate
conference). Some clinicians would advocate antibiotic endemicity is a well-recognized risk for infection. Other
chemoprophylaxis, which has also been shown to reduce the potential occupational risks include directly handling the
incidence of travellers’ diarrhoea. However, although this virus in the laboratory, direct contact with untreated
approach might perhaps be justifiable in people who are sewage and direct contact with faeces of infected patients.
susceptible to infection or who suffer from inflammatory In the United Kingdom, where the numbers of cases
bowel disease, it cannot be generally endorsed, since it may reported annually have been declining for a decade, recent
increase susceptibility to infection with a resistant pathogen, outbreaks have occurred amongst men who have sex with
will be ineffective against viral or parasitic causes of trav- men, injecting drug users and the homeless.132 After an
ellers’ diarrhoea, and may engender a false sense of security. incubation period of two to six weeks, symptoms of fever,
Bismuth subsalicylate has also been shown to reduce the anorexia, nausea, abdominal pain, pale stools, dark urine
incidence of traveller’s diarrhoea and could be considered as and jaundice develop. Disease severity is age-related; 70–80
an adjunct provided there are no contraindications. per cent of adults will develop jaundice, but young children
are usually asymptomatic or have non-specific symptoms
MANAGEMENT of viral illness. Viral excretion is at a maximum towards the
end of the prodromal period, in the 48 hours before the
Most cases of travellers’ diarrhoea occur while the traveller onset of jaundice. Hepatitis A infection cannot be distin-
is abroad, are self-limiting (90 per cent resolve within a guished from other causes of viral hepatitis by clinical
week) and are never investigated. Travellers can treat examination alone; diagnosis is made by testing for specific
themselves effectively. They should be instructed on how IgM antibody to HAV. The infection is usually self-
to replace lost fluids using a suitable oral rehydration solu- limiting. There is no carrier state, but full recovery may
tion (proprietary packs are available). It is, of course, take three to six months. Treatment is largely supportive.
essential to make up the solution using clean water. Short- The mortality rate is below 0.1 per cent overall, but some-
term use of a simple anti-diarrhoeal agent (such as lop- what higher in those aged 45 years or over, and in those
eramide) may be helpful in limiting symptoms, but should with pre-existing liver disease.
not be used by patients with fever or bloody diarrhoea, and An inactivated hepatitis A vaccine is available, either as
has been associated with adverse events, including toxic a monovalent vaccine or combined with either hepatitis B
megacolon and severe sepsis. Where fever persists for more vaccine or typhoid vaccine. Passive prophylaxis, with
than 48 hours, or diarrhoea is severe, self-treatment with human normal immunoglobulin (containing antibody to
short course antibiotic therapy could be started. Appropriate HAV) can provide immediate protection against infection
agents would be ciprofloxacin or other fluoroquinolone for up to three months, but is no longer recommended for
(doxycycline or trimethoprim are no longer recommended travellers, though it is still used, alone or in combination
because of the high level of drug resistance); bismuth sub- with vaccine, for post-exposure protection of contacts of a
salicylate can also be used in treatment. case and in outbreak control. Hepatitis A vaccine is recom-
Travellers who have bloody diarrhoea should seek med- mended for those aged one year and over, travelling to
ical advice. Causes include Entamoeba histolytica, which countries of high or moderate endemicity for prolonged
may cause liver abscess, and is usually treated with metron- periods, and those who are posted to or will reside in,
idazole.154 hepatitis A endemic countries. Vaccine may also be useful
Diarrhoeal symptoms that persist despite simple for those likely to make frequent short trips to endemic
measures require further investigation, including stool areas. Vaccine is also recommended for patients with
microscopy and culture. Blood cultures are appropriate in chronic liver disease and for those with lifestyle risks for
febrile patients. Symptoms beginning more than a week after infection.
travel or which persist for more than ten days suggest the
possibility of Giardia lamblia infection. This infection may
become chronic and cause malabsorption. Diagnosis is usu- OTHERS
ally by stool microscopy, but this may be negative in chronic
cases. Treatment is with metronidazole or tinidazole. Sex workers
Food handlers who have suffered traveller’s diarrhoea
following a trip abroad should consult their occupational Sex workers are clearly at risk of a variety of sexually trans-
health department before returning to work. mitted infections and, if their transactions involve sex for
drugs rather than money, may also be at risk of infective
conditions associated with injecting drug use, including
Hepatitis A hepatitis C, abscesses, endocarditis and severe clostridial
infection. The risks of sexually transmitted infection may
Hepatitis A virus (HAV) is transmitted by the faeco-oral be reduced by the use of condoms, although this may be
route, through close contact with an infected person or difficult to negotiate with clients.
744 Occupational infections
Sex workers in the United Kingdom with local symp- 2. Prüss-Ustün A, Rapiti E, Hutin Y. Estimation of the global
toms of a sexually transmitted infection will usually pres- burden of disease attributable to contaminated sharps
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eradicated in 1980, but there is concern that viable virus 9. Petrosillo N, Puro V, Ippolito G and the Italian Study Group
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Key points
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● Many infections can be transmitted by
Journal of the American College of Surgeons. 1995; 180:
occupational exposure, but a relatively small
16–24.
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● Healthcare workers are at particular risk, but
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occupational infections also occur in a wide
13. Polakoff S. Acute viral hepatitis B: Laboratory reports
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● Knowledge of the worker’s occupation may
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provide a key clue to the diagnosis of an infection.
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● Many occupational infections are preventable if
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15. Goldstein ST, Alter MJ, Williams IT et al. Incidence and risk
● Where a safe and effective vaccine is available, it
factors for acute hepatitis B in the United
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60
Zoonoses
Contact with live animals Contact with animal Laboratory exposure to Environmental exposure
carcasses or byproducts infectious animal specimens
Veterinary workers Abattoir workers, Veterinary laboratory workers Arable agricultural workers
slaughtermen
Animal farmers Butchers Animal researchers Forestry workers
Zoo workers Meat inspectors Medical laboratory workers Sewage workers
Hunters, trappers Workers with animal Outdoor activity instructors/
skin/hides/hair guides
Fishermen, fish farmers Fishmongers, catering
industry workers
Animal trainers
Animal sanctuary workers,
cruelty inspectors
Pet shop workers
Skin lesions Fever Diarrhoea (fever) Chest symptoms (fever) Miscellaneous (fever)
equipment (PPE)) accompanied by training to use it effec- Table 60.3 Zoonotic infections in England and Wales, 2006.144
tively; safe disposal of animal carcasses and waste products;
Infection Human cases Comment
environmental engineering (e.g. ventilation and/or filtra-
tion to reduce dust exposure, caging systems); standard
good hygiene (e.g. hand washing), and pre-exposure Campylobacter 46339
vaccination (e.g. against rabies or anthrax) in some occu- Salmonella 14060
pational groups. Escherichia coli 0157 1002
Cryptosporidia 3618
Bovine tuberculosis 25
OCCUPATIONAL ZOONOSES PRESENTING Brucellosis 11 All acquired overseas
AS CHEST DISEASE Anthrax 1 One fatality in Scotland
Anthrax
many areas of the world especially in Africa, the Middle
Anthrax is a bacterial infection caused by a Gram-positive East and Asia, but the concentration of spores is higher
spore-forming organism, Bacillus anthracis. The term when infection in animal herds (principally herbivores,
‘anthrax’ is derived from the Greek word for coal and such as cattle, sheep and goats) is highest so annual vacci-
refers to the black eschar that is characteristic of cutaneous nation of at-risk herds, coupled with case-finding and safe
anthrax. It is the vegetative bacilli that cause diseases in disposal of animal carcasses remains the mainstay of
animals and man and when they are excreted in body flu- disease control.
ids or when the host dies, then the bacilli will sporulate and Man becomes infected either by inoculation of spores
spores may survive in the soil and remain viable for many through the skin to produce cutaneous anthrax, by inhala-
years. They may even replicate in the soil.7 After the tion of spores to give inhalational anthrax (historically,
Scottish island of Gruinard (Figure 60.1) was used for ‘wool sorter’s disease’, caused by exposure to spore-
anthrax experiments during the Second World War, it contaminated fleeces) or by ingestion of contaminated meat
remained quarantined for 48 years. Soil is contaminated in containing viable vegetative bacilli to give gastrointestinal
752 Zoonoses
The former presents as oral ulceration, with oedema and Chlamydophila infection (chlamydiosis,
membrane formation, so may be difficult to distinguish ornithosis, psittacosis)
from diphtheria. The intestinal form may present as a
generalized abdominal catastrophe and has a high mortal- The two most important zoonotic chlamydial infections
ity, particularly if presentation is late. Ascites may be a are caused by Chlamydophila psittaci and Chlamydophila
prominent feature.10,15 abortus. Both are found worldwide.
The differential diagnosis of anthrax is wide and Chlamydophila psittaci infects a wide range of wild and
depends on the clinical form. For cutaneous disease, this caged birds, but human infection is usually the result of
includes rickettsial infections, tularaemia, pseudomonal exposure to pet psittacine birds (e.g. parrots, parakeets,
bacteraemia (ecthyma gangrenosum), orf, herpes virus macaws, budgerigars) or to poultry. Infected birds may be
infection, spider bites and other bacterial skin infections. asymptomatic, but nevertheless shed the organism in nasal
In gastrointestinal anthrax, any severe abdominal pathol- discharges and faeces; infection in imported, quarantined
ogy may be included in the differential diagnosis; inhala- birds may pass undetected. Chlamydophilae can survive in
tional anthrax can be confused with any severe chest the environment for months. Human infection follows
infection. The diagnosis is established by culture of inhalation of the organism, usually during activities like
B. anthracis from appropriate clinical specimens. A poly- cage cleaning, pet handling, or carcass evisceration or
merase chain reaction (PCR)-based test is also available. dressing.17 Outbreaks have been described in poultry
A high index of suspicion is required and diagnosis may processors, pet shop workers, vets and veterinary medicine
be delayed unless other recent cases have been reported. students, bird-fanciers, zoo and wildlife workers, and
Treatment is with appropriate antibiotics. B. anthracis others (for example, customs officials exposed to birds
is sensitive to benzyl penicillin and this was traditionally at work may also be at risk).18–23 Human infection is
the treatment of choice. Naturally occurring penicillin- probably underdiagnosed. The incubation period ranges
resistant B. anthracis is extremely rare. However, because from one to four weeks; infection typically presents as
of concern about genetically manipulated resistance in an influenza-like illness with features of a community-
organisms destined for deliberate release, and because acquired pneumonia, although milder and asymptomatic
beta-lactams do not penetrate so well into cells and tissues, infections also occur. Diagnosis is made by serology
the treatment of choice these days is usually ciprofloxacin, on paired sera; PCR-based assays can be used to deter-
supplemented, in inhalational anthrax, with at least two of mine the infecting serovar, which may give a clue to the
rifampicin, clindamycin and vancomycin. B. anthracis is source. Clinical algorithms for the management of severe
not sensitive to cephalosporins. Prior to the 2001 cases in community-acquired pneumonia usually now include
the United States, the mortality of inhalational anthrax was treatment with a macrolide (clarithromycin, azithromycin,
reported as being greater than 80 per cent, but with early erythromycin), which will treat the infection; doxycycline
combination antibiotic therapy, pleural fluid drainage, and is an alternative.
modern intensive care the mortality in 2001 was less than Chlamydophila abortus is the most common cause of
50 per cent. Presentation with fulminant late-stage disease abortion and fetal loss in sheep (ovine enzootic abortion,
and a requirement for intubation or tracheostomy were enzootic abortion of ewes), and also causes abortion in
poor prognostic features.13 goats and cattle. The organism is found in quantity in
Prevention of occupationally acquired anthrax requires birthing fluids and placentae from infected animals;
careful management and handling of animal products to human infection is thought to occur by inhalation, and
minimize exposure to the infective spores. Hair, wool, hide there may be a greater risk of transmission when birthing
and bone meal should be sterilized or disinfected before takes place in barns or lambing sheds rather than outdoors.
processing; in industrialized countries, importation of However, infection after handling footwear and clothing
these products is tightly regulated. An inactivated vaccine contaminated during contact with infected animals has
is available, and recommended in the UK for selected also been reported. Infection is a particular risk for preg-
workers at risk of exposure in higher-risk occupations, nant women, as it may cause a severe febrile systemic
including veterinary medicine, research laboratory work, illness, with multiorgan involvement, disseminated
wool or hide-processing plants, and certain military set- intravascular coagulation, and fetal death or premature
tings.16 Following a known exposure, post-exposure delivery. Treatment (with a macrolide or, provided that the
antibiotic prophylaxis may be offered. Ciprofloxacin and effects of tetracycline use in pregnancy have been consid-
doxycycline are the two agents that are favoured. ered, a tetracycline) of severe disease should not await
Antibiotics will be inactive against the spores and because confirmation of diagnosis, which is made serologically, or,
of the long incubation period from acquisition of the if the test is available, by direct detection by PCR. Pregnant
spores to germination, post-exposure treatment is pro- women should therefore avoid risk exposure (e.g. lambing,
longed (up to 60 days was recommended in the 2001 kidding, bottle-feeding young, milking, handling boots,
outbreak in the United States). An alternative is to start a clothing or other possibly contaminated objects), and
vaccination course and give antibiotics for 30 days until it should also avoid exposure to the live vaccine used to
is felt that the vaccine will be effective. prevent infection in animals.24,25
754 Zoonoses
sheep and camels, and has recently emerged as a problem unimpressive lymphadenopathy has been described
in cattle in southern Europe. B. abortus was shown by Bang together with an enlarged liver and/or spleen.48,51
to cause abortion in cattle, and also occurs in buffalo, bison There is not thought to be any major distinction
and elk. B. suis was first isolated from aborted pigs, and is between the clinical syndromes produced by the different
also found in wild boars and hogs, and cattle; one serovar species. In a review of 530 cases of disease caused by
is host adapted to reindeer and caribou. The other species – B. melitensis approximately one-third developed a local-
B. ovis (found in sheep), B. neotomae (found only in desert ized complication.47 These may include bone and joint
wood rats), B. canis (dogs), B. maris (possibly three sepa- infection (especially sacroiliitis and/or spondylitis), aseptic
rate species, found in marine mammals) and B. microti meningitis, endocarditis (which is uncommon, but may
(voles and red foxes) are either rarely (B. canis, B. maris) or account for much of the mortality from brucellosis),
never (B. neotomae) associated with human disease.45–48 hepatic abscess (granulomatous hepatitis on liver biopsy
Nearly all human cases of brucellosis are acquired when investigating pyrexia of unknown origin (PUO) is a
directly or indirectly from animals, and disease incidence common finding, but very non-specific) and epididymo-
in humans reflects the prevalence of infection in local orchitis. Rarer complications include pneumonitis, uveitis,
domestic animal herds. Infection is found worldwide, but other abscesses (e.g. paraspinal, spleen, brain) and occa-
is especially prevalent in the Mediterranean countries, the sionally infection of prosthetic material.
Middle East, South Asia, Africa and parts of Latin America. Initial laboratory findings are non-specific and include
Humans acquire infection by direct contact with infected evidence of an acute-phase response often accompanied
animals, or their birthing or abortion products (when the by pancytopenia. Liver function tests may show a low-
organism gains entry through cut or abraded skin, or con- grade hepatitis. Various imaging modalities may be used
junctivae or mucous membranes) or by inhalation of to demonstrate abscess or other localized infection in
aerosolized animal material. Infection can also follow areas that may then be accessible for biopsy or fine needle
ingestion of raw milk or unpasteurized dairy products. aspiration.
Human-to-human spread by sexual contact has been Diagnosis is achieved either by isolation of brucellae
described, but is uncommon.49 Test and slaughter policies from blood cultures or by demonstrating a definitive
combined with vaccination programmes have led to the serological response to brucella infection. It is important to
near eradication of B. abortus in cattle in the United States, consider the diagnosis on the basis of the clinical picture
United Kingdom and other industrialized countries, and together with a detailed travel, occupational, recreational
this has been paralleled by a decline in the incidence of and dietary history. Cultures may be positive in up to
cases in humans. Programmes to control B. melitensis have 90 per cent of cases and the yield may be greater if
been less effective. Many countries in Northern Europe are bone marrow and liver biopsy (or other clinical material,
animal brucellosis free, although infections may occur e.g. from an abscess) samples are cultured in addition to
in returning migrants occupationally exposed abroad, in blood.52 It is essential that clinicians inform laboratory
travellers who have eaten unpasteurized dairy products, colleagues that a diagnosis of brucellosis is suspected: this
and in older or retired workers infected when animal not only ensures that the samples will be processed safely,
disease was still prevalent. but also ensures that they will be processed in a way that
Brucellosis is an occupational hazard for agricultural will provide the optimum diagnostic yield, by prolonging
workers, veterinary workers, abattoir workers and meat the period for which samples are incubated.
packers, hunters and laboratory personnel. Although Serological testing usually uses the tube agglutination
laboratory work on brucellae has long been recognized as test or an ELISA technique. A single titre of antibody at a
hazardous, and work with the organisms requires biosafety dilution greater than 1:160 in the context of a compatible
level 3 containment, laboratory-acquired infection still clinical picture is regarded as diagnostic. Demonstration of
occurs.50 Cases are often attributable to open-bench a greater than four-fold change in titre over 4–12 weeks
exposure to cultures derived from patients in whom the provides even stronger evidence of infection. The ELISA
diagnosis had not been suspected. test is generally felt to have higher sensitivity and specificity
The clinical syndrome of brucellosis usually develops than tube agglutination. Tests for antigen detection are in
between two and four weeks after exposure. The onset may development.
be acute or more insidious and the features can be divided Treatment of brucellosis with antibiotics improves
into general systemic features and those features related to symptoms, shortens the duration of illness and reduces
more specific sites of infection. The initial features are risk of complications and relapse. Single-drug therapy has
usually those of non-specific pyrexia of unknown origin – produced an unacceptably high level of relapse, so combi-
fever, malaise, sweats, headache, back pain and anorexia. nation therapy with doxycycline and an aminoglycoside
Chronic brucellosis has been described as causing a depres- and/or rifampicin is recommended.53 Most of the early
sive illness and cases of suicide in farmers have been attrib- aminoglycoside studies used streptomycin, whereas these
uted to this, but the evidence is not convincing. days most clinicians would probably be more familiar and
Objective physical findings are not usually promi- comfortable with gentamicin. Doxycycline should be given
nent. Rash is rarely apparent and apart from the fever, in a dose of 100 mg twice daily together with rifampicin
756 Zoonoses
600–900 mg once daily for six weeks. Some clinicians may Henipavirus infections
wish to add gentamicin at 5 mg/kg for the first one or two
weeks of treatment. Monotherapy with any agent, and Two highly pathogenic zoonotic paramyxoviruses, Hendra
regimes based on cotrimoxazole or quinolones, are all felt virus and Nipah virus, together form the genus henipavirus.
to be inadequate.53 Both have pteropid bats (‘flying foxes’) as their natural
reservoir, but both have a wide host range. Hendra virus
(once named equine morbillivirus) was first recognized in
Hantavirus infection Australia in 1994.61,62 A horse trainer and a stablehand in
Hendra, Brisbane developed severe influenza-like illness
Hantaviruses, RNA viruses that form a genus in the bun- after exposure to horses that had developed a lethal respi-
yavirus family, generally each have a single species of ratory infection. The trainer died; severe interstitial pneu-
rodent (e.g. cotton rat, striped field mouse, deer mouse, monitis was found at post-mortem. At the same time, a
bank vole) as their primary reservoir.54 The viruses do not trainer in Mackay, Queensland who had cared for two sick
cause overt illness in the rodent hosts, but an infected ani- horses, and later helped with their necropsies, developed
mal excretes virus in urine, saliva and faeces. Hantaviruses acute meningitis two weeks later, recovered, but a year
cause two clinical syndromes: haemorrhagic fever with later developed fatal encephalitis.63 Since then, around a
renal syndrome (HFRS) and hantavirus pulmonary syn- dozen clusters of infection have occurred in horses in east-
drome (HPS). Infection is thought to be usually acquired ern Australia, with a further four infections in humans
by inhalation of dust containing virus-contaminated saliva (three veterinarians and a veterinary nurse), of which
or excreta; infection has also followed the bite of an two (in 2008 and 2009, both in veterinarians) were fatal.64
infected rodent. In the most recent outbreak, exposed workers were given
Four hantaviruses (Hantaan, Seoul, Puumala and post-exposure prophylaxis with intravenous ribavirin and
Dobrava viruses) found largely in Europe and Asia, cause oral chloroquine; full details have not yet been reported.
HFRS of varying severity. Hantaan virus infection (first The virus has not been detected outside Australia.
described in the English language literature as Korean In 1997, Nipah virus emerged in Malaysia in pigs in
haemorrhagic fever, but occurring more widely in eastern Ipoh and subsequently spread to pigs farmed in villages in
Asia, in China and Russia) is the most severe, with a mor- Negri Sembilan. An outbreak of severe acute encephalitis
tality rate of up to 15 per cent. By contrast, Puumala virus, in pig farmers, and others who had close contact with
which occurs throughout northwestern Europe, and is the pigs (e.g. pen cleaners, abattoir workers, vaccine sellers and
cause of ‘nephropathia epidemica’, has a mortality rate pig cullers) followed in 1998–99.61,65,66 Most had a febrile
of less than 1 per cent. Seoul virus occurs worldwide; illness and acute encephalitis, but a pneumonic illness
infection after exposure to infected laboratory rats has occurred in about a quarter of cases. Workers in an abat-
been described.55 toir in Singapore exposed to infected pigs from Malaysia
HPS occurs in North and South America. Hantaviruses also became infected.67 The infection has a high acute
were identified as the cause in 1993, when Sin Nombre virus mortality rate (40 per cent in Malaysia), with neurological
was discovered during the investigation of an outbreak of sequelae in survivors, some of whom develop relapsed
adult respiratory distress syndrome with a high case fatality encephalitis months or years after initial infection. More
rate in the southwestern United States.56,57 HPS is relatively recently, clusters of Nipah virus infection have been
uncommon in the United States, where fewer than 100 reported from Bangladesh and India. In these incidents,
cases are reported annually; most are caused by Sin Nombre risk factors for infection have variously included climbing
virus, although other hantaviruses (New York, Bayou, trees, exposure to pigs, drinking date palm sap possibly
Monongahela and Black Creek Canal) are also known to contaminated by fruit bat urine or saliva, and exposure to
cause disease.55,58 HPS is more common in South America, an infected case. At least one outbreak was amplified by
where it has been caused by Andes, Oran, Lechiguanas and nosocomial transmission, and limited person-to-person
Juquitiba viruses; Andes virus is unusual in that it is the spread by the respiratory route may be possible, but occu-
only hantavirus known to have been transmitted from pational risks have generally been less clear cut than in the
person to person, and nosocomially.59 outbreak in the Malay peninsula.68
Hantavirus infection is diagnosed serologically; refer- Henipaviruses are categorized as hazard group 4
ence laboratory testing is usually required. Intravenous pathogens, and diagnosis and research work must there-
ribavirin is effective in the treatment of HFRS, but not use- fore be undertaken only in BSL4/ABSL4 facilities.
ful in HPS, for which treatment is essentially supportive.
Guidelines on risk reduction highlight precautions that
may limit the occupational risk (likely to be greatest for Hepatitis E
those whose work involves frequent handling of wild
rodents, e.g. field biologists, mammologists, rodent opera- Hepatitis E virus is a non-enveloped single-stranded RNA
tors), including the use of personal protective respiratory virus, which is usually transmitted by the faeco–oral route,
equipment.60 causing fever and acute hepatitis, with anorexia, jaundice
Occupational zoonoses presenting as fever 757
and hepatomegaly. Infection late in pregnancy may be climates. Infection rates may rise after heavy rainfall or
especially severe, with fulminant hepatitis and a high flooding.74
(20 per cent) mortality rate. In industrialized countries, Occupational risk groups include dairy and pig farmers,
infection is usually sporadic, but large epidemics, associ- vets, abattoir workers, hunters and trappers, rodent con-
ated with contamination of water supplies, have occurred trol workers, sewage and canal workers, fish workers and
in developing countries. Swine and wild boar may act as fish farmers, sugar cane cutters and banana farmers, and
an animal reservoir; viruses found in sporadic human cases the military. In a western setting, infection is also acquired
in non-endemic areas have been found to be closely related by recreational exposure to water, and has been reported in
to hepatitis E viruses detected in pigs. There are case canoeists, wild-swimmers, cavers, white-water rafters and
reports of infection in butchers and slaughterhouse work- triathletes, and in the UK, an increasing proportion of
ers without a history of travel to an endemic area, and there infections are reported in travellers exposed on adventure
is some evidence also from seroprevalence surveys of a holidays abroad.6
possible occupational risk from work that involves expo- Leptospires invade through mucous membranes, con-
sure to swine.69–72 Diagnosis is made serologically; infec- junctivae or microabraded or water-sodden skin; it is not
tion is clinically indistinguishable from other causes of known whether they can penetrate intact skin. They are
viral hepatitis. There is no carrier state, nor is there a disseminated via the bloodstream and are therefore widely
specific treatment. A vaccine is not available; prevention of distributed throughout the body where they produce a
sporadic infection involves adoption of standard infection vasculitis, the exact mechanism of which remains obscure.
prevention measures, including good hand hygiene. The clinical features are very variable. Many of those
infected will have an asymptomatic seroconversion. Others
may have a mild non-specific febrile illness and others may
Leptospirosis have one of the more easily appreciated syndromes. The
average incubation period seems to be about ten days,
Leptospirosis is a zoonotic infection that can cause a vari- although it is often difficult to establish exactly when expo-
ety of different clinical pictures in man ranging from sure occurred and a range of incubation periods from two
asymptomatic infection to severe multiorgan disease with to 26 days has been reported. The majority of symptomatic
hepatorenal failure (Weil’s disease). It has a worldwide cases present with sudden onset of fever, rigors, myalgia
distribution (except for the polar regions), but is particu- and headache. Nausea, vomiting, diarrhoea and cough
larly prevalent in the tropics. The taxonomy of leptospires are also common features. On examination, the most char-
(spirochaetes with hooked ends) is complex and still evolv- acteristic finding is conjunctival suffusion and muscle
ing. Historically, two phenotype-based species – Leptospira tenderness, but these probably only occur in a minority
interrogans (containing pathogenic strains) and L. bireflexa of cases. Less common physical findings include lym-
(containing non-pathogenic strains) – were further subdi- phadenopathy, hepatosplenomegaly, chest signs and a
vided on the basis of serological tests into more than 250 rash. Clinical features of meningitis may also be present.
serovars, with antigenically related serovars grouped into a Although the illness is often described classically as
smaller number of serogroups. Each serovar has a defined ‘biphasic’, in practice such a pattern is rarely recognized.
host range, and the number of serovars present in any However, as the immune response appears the patient may
given geographical area tends to be restricted, particularly deteriorate and develop one or more of the more specific
in temperate zones. Advances in molecular biology have syndromes associated with leptospiral infection. These
led to a genotype-based classification, which recognizes at include aseptic meningitis, Weil’s disease (with the classic
least 17 different species. For the moment, the two systems triadic presentation of jaundice), thrombocytopenia and
exist in parallel.73 renal failure (where, despite the jaundice, liver function is
Rodents and other small mammals are the most impor- usually relatively well preserved), cardiac syndrome (with
tant animal reservoir. They become infected in infancy, myocarditis leading to cardiac failure), and pulmonary
develop a chronic renal infection and excrete leptospires in syndrome. The pulmonary syndrome has been described
their urine throughout their life. Excreted organisms may particularly in South America, and may vary from mild
remain viable in soil or water for weeks. Larger mammals, respiratory symptoms and signs to severe pulmonary
such as dogs, cattle and pigs, develop a symptomatic infec- haemorrhage and adult respiratory distress syndrome.
tion that may be fatal, or become chronically infected and A recent review in Peru suggested that nearly 4 per cent
shed leptospires into the environment. People who have of patients with serologically confirmed leptospirosis
direct contact with animals, water or soil are at greatest had severe pulmonary manifestations, but would not have
risk of occupationally acquired leptospirosis, which was been otherwise diagnosed if they had not been part of
first described in miners in the early twentieth century, the study.75
although jaundice in rice-paddy workers has been recog- The differential diagnosis during the non-specific
nized since ancient times in China. Infection is seasonal, febrile phase is wide and includes malaria, typhoid,
with a peak in incidence in the rainy season in the tropics, influenza, rickettsial infection (especially scrub typhus)
and in the summer or autumn in countries with temperate and arbovirus infection (including dengue fever). Routine
758 Zoonoses
laboratory investigations are similarly non-specific – the chemoprophylaxis from 1984 showed significant benefit
white cell count may be elevated or lowered (usual range of weekly doxycycline 200 mg among American troops in
3000–25 000/mm3) often with a left shift. About half the the jungles of Panama.78
patients have elevations of liver transaminases (fairly mild)
and creatinine kinase. The urine is often abnormal with
proteinuria, white cells, casts and occasional microscopic Streptococcus suis infection
haematuria. In Weil’s disease, renal function deteriorates
and the bilirubin may be very high. The chest x-ray may Streptococcus suis is a porcine pathogen with a worldwide
show non-specific shadowing. The platelet count may distribution, found wherever pigs are farmed. It causes
sometimes be reduced. The cerebrospinal fluid may show septicaemia, meningitis, arthritis and meningitis in pigs;
an elevated white cell count with neutrophils or lympho- illness is more common when pigs are intensively farmed
cytes, minimal to moderately elevated protein concentra- in suboptimal conditions. Human infection is associated
tions and normal glucose. with direct contact with sick or carrier pigs, and with eating
Because of the non-specific nature of the clinical picture undercooked pork products (particularly traditional
and the laboratory findings, a high index of suspicion must foods, e.g. pig’s blood), so there is an occupational risk for
be maintained if the diagnosis is not to be missed. pig farmers (including ‘backyard farmers’), abattoir
Leptospira can be seen by dark ground microscopy of workers, slaughterers, butchers and veterinarians. Wild
blood or urine, but sensitivity and specificity are low and boar hunters may also be at risk.79,80
the technique is rarely used in practice. The organism can Although more than 30 serotypes of S. suis have been
be cultured from blood (taken in the first ten days of the recognized, human infection is usually caused by S. suis
illness and before antibiotics have been administered) and serotype 2. Infection is uncommon and sporadic in the
from urine from the end of the first week and for some United Kingdom and the United States, but the organism
time afterwards, but culture requires special media, pro- has recently been recognized as an important zoonotic
longed incubation, and is also relatively insensitive. Most pathogen in China and Southeast Asia.81 In 2005, it caused
patients have their infection identified serologically. The an outbreak of streptococcal toxic shock syndrome (STSS)
traditional gold standard test has been the microscopic and meningitis that affected 204 people (with 38 deaths),
agglutination test (MAT), which uses live organisms and mostly men who had slaughtered or eaten sick pigs; recent
can be technically demanding to perform. Therefore, most surveys suggest that S. suis is a common cause of acute
laboratories use a screening test first, such as an ELISA bacterial meningitis in adults in Thailand, Vietnam and
for IgM antibodies – these are usually detectable on day Hong Kong SAR.82,83 The infection has a short incubation
5 of illness. PCR-based methods are in development, but period (from a few hours to three days); cases present with
are not yet in widespread use. clinical features of meningitis (fever, headache, neck stiff-
Leptospira are susceptible to many antibiotics in vitro, ness, photophobia, nausea or vomiting) or septicaemia,
including penicillins, third-generation cephalosporins, and may in addition have signs of STSS, including purpura
macrolides and tetracyclines; intravenous penicillin has or a haemorrhagic rash. Septic arthritis and endocarditis
been used in the treatment of severe infection for decades. may also occur. Diagnosis is made by culture of blood and
There is debate about the effectiveness of antibiotics if cerebrospinal fluid (CSF); a PCR-based test is also avail-
given any later than early in infection, doubt about able. The organism is sensitive to penicillins (although
whether mild disease needs to be treated, and few trials on resistant strains have been reported), cephalosporins and
which to base recommendations. Nevertheless, in endemic vancomycin. Mortality rates (particularly in STSS) may be
areas, where it is common for leptospirosis to be misdiag- high; deafness is a common sequel of meningitis.
nosed as a rickettsial infection or vice versa, oral doxycy- Prevention involves standard good hygiene (e.g. using
cline 100 mg bid is a sensible option,76 as it will treat both appropriate PPE during slaughtering, hand hygiene) and
conditions empirically while serological diagnosis is ensuring that all pork products are thoroughly cooked
awaited. If the patient is very unwell, then intravenous before being eaten.
penicillin 1.2 g six-hourly or ceftriaxone 1 g once daily
should be used. There are no trials on duration of therapy,
but ten days is usually recommended. Toxoplasmosis
Infection risks can be reduced by effective rodent con-
trol, avoidance of high risk exposure, and use of personal This is the clinical condition caused by infection with the
protective equipment (e.g. boots, goggles, rubber gloves, intracellular protozoon parasite Toxoplasma gondii. Cats
waterproof overalls, depending on the type of exposure are the definitive host; humans, other mammals and birds
expected) and standard veterinary infection control pre- serve as intermediate hosts. In sheep and goats, infection
cautions when dealing with potentially infected animals.77 may cause abortion or fetal loss, with considerable
A human vaccine has been used, but is not widely avail- economic costs. Humans become infected either by expo-
able. Animal vaccines are more widely used, but most sure to oocysts excreted from cats (e.g. by handling cat lit-
do not prevent the excretion of leptospires. A study on ter or through gardening), by handling raw meat, or eating
Occupational zoonoses presenting as gastrointestinal infection 759
undercooked meat derived from an infected intermediate The greatest concern about T. gondii infection is in
host. Seroprevalence of infection increases with age patients who are immune compromised as a result of
(because of cumulative exposure), but is generally falling malignancy (especially myelo- or lymphoproliferative dis-
with increased standards of living. Overall, between 20 and ease), iatrogenic immune suppression or by HIV. In these
70 per cent of adults in the United States have serological individuals, latent toxoplasma infection can reactivate,
evidence of previous exposure (and therefore have long- causing encephalitis, pneumonitis and chorioretinitis.
term subclinical infection).84 Diagnosis of cerebral toxoplasma in an HIV-positive
There may be an occupational risk for workers exposed patient is made by diagnostic imaging (magnetic resonance
to animals with clinical toxoplasmosis or to aborted lambs, imaging (MRI), plus possibly positron emission tomogra-
kids, piglets and their placentas (e.g. farmers, shepherds, phy (PET)). The majority of patients have positive serology
vets, animal shelter employees), and those who may be for toxoplasma. Primary prophylaxis reduces the incidence
exposed to infected animal carcasses or raw meat (e.g. of reactivation-associated disease; treatment of established
hunters, abattoir workers, meat packers, butchers, chefs disease is with pyrimethamine and sulphadiazine.
and zoo workers). Infection might be acquired orally (by
transfer of organisms on unwashed hands to the mouth),
or through inoculation via damaged skin. Laboratory- West Nile virus
acquired infections have been reported (including infec-
tion caused by needlestick injury while performing the West Nile virus is a flavivirus that is a pathogen for birds
Sabin Feldman dye test, which requires the use of live (the natural hosts), equines and humans. The virus was
organisms), but a study of workers in a toxoplasma refer- first identified in Uganda, and recognized as a cause of
ence laboratory concluded that the risks to workers were acute meningoencephalitis in Israel 20 years later. It is
low.85 The live attenuated vaccine used to control infection endemic in Africa and the Middle East, and since 1999 has
in sheep may cause human infection if accidentally inocu- emerged as a cause of meningoencephalitis throughout the
lated, and should not be administered by women of child- United States, with spread to adjacent countries.88–90 The
bearing age. In practice, most infections are probably majority of clinically apparent infections are mild, with
acquired non-occupationally. However, an information fever, headache and occasionally a rash on the trunk.
sheet on preventing exposure in pregnant women during Neuroinvasive disease occurs in less than 1 per cent of
the lambing season is available.86 infections, but mortality in hospitalized cases is significant;
Most acute infections result in an asymptomatic the risk of severe disease increases with age. Treatment is
seroconversion. A small proportion of immunocompetent essentially supportive. Human infection is usually mos-
adults develop a ‘glandular fever-like syndrome’ of quito borne, but infection in laboratory workers after
malaise, fever, headache and lymphadenopathy. Atypical exposure via needlestick or aerosol while working with
lymphocytes may be found in the peripheral blood and infected animal tissues or cell cultures has been reported.91
there may be a pharyngitis, although this is probably less A cluster of cases among turkey breeder farm workers in
prominent than with the infectious mononucleosis pro- Wisconsin led to recommendations to include the use of
duced by Epstein–Barr virus (EBV) infection. Monospot insect repellents, alongside standard infection prevention
or Paul Bunell testing is negative, as is IgM serology for measures that include good hand hygiene and use of
EBV. The differential diagnosis includes cytomegalovirus personal protective equipment.92 Infection in an alligator
(CMV), human herpes virus 6, lymphoma, HIV serocon- farm worker who had cared for sick alligators has also
version illness and cat scratch disease. Toxoplasmosis is been reported.93,94 Recommendations to prevent West
sometimes diagnosed histologically when lymph nodes are Nile virus exposure in outdoor and field workers (likely to
excised, but is more often diagnosed by tests for specific be primarily mosquito-borne) also emphasize the impor-
antibody. Acute toxoplasmosis is usually a benign self- tance of insect repellents and protective clothing.94,95
limiting condition with no sequelae; no active treatment is A vaccine has been developed for prevention of equine
needed. If a woman acquires toxoplasma infection during infection, but a vaccine for humans is not yet available.
pregnancy, there is a significant risk of transmission to the
unborn child, which can result in congenital toxoplasmosis
and disability in the infant. Infection early in pregnancy is OCCUPATIONAL ZOONOSES PRESENTING
less likely to transmit to the fetus, but more likely to cause AS GASTROINTESTINAL INFECTION
severe damage, whereas infection later in pregnancy is
more likely to transmit to the fetus, but less likely to result Salmonellosis
in organ damage, although infants who have subclinical
infection at birth may develop signs of disease much later. The nomenclature of the salmonellae has recently been
As most acute infections are asymptomatic, some coun- revised to accommodate advances in taxonomy. DNA
tries (e.g. France) have serological screening programmes. hybridization studies showed that the ‘one serotype, one
Elsewhere, prevention is dependent on exposure reduction species’ concept – which, as the number of organisms
through education.87 distinguishable by serotyping increased, had led to an
760 Zoonoses
accumulation of over 2000 pathogenic species – was no a salmonella reference laboratory or on livestock farms),
longer tenable because the organisms had such closely but not from households without such exposure.104
related DNA. All clinically important salmonellae are now The gastrointestinal illness produced by infection with
classified as a single species – Salmonella enterica – with non-typhoidal salmonella is clinically indistinguishable
serotypes (now grouped within one of six subspecies) from that caused by many other gastrointestinal pathogens.
referred to with a capital letter and in plain, rather than Diarrhoea is the main feature and this may be initially, or
italic, type. For example, Salmonella typhimurium becomes may become, bloody. It may often be associated with vom-
S. enterica subsp. enterica ser Typhimurium, or is short- iting, abdominal pain and cramps, and sometimes with
ened to S. Typhimurium.96,97 fever. The usual incubation period following ingestion of
Despite their microbiological similarities, there are contaminated food or water is 12–72 hours (in contrast
major clinical and epidemiological distinctions between to typhoid where the incubation period is 10–14 days
the so-called ‘typhoidal’ and ‘non-typhoidal’ salmonellae. and the initial presentation is with fever, often accompa-
The former group, which includes S. Typhi and nied by constipation). Approximately 5 per cent of patients
S. Paratyphi, are exclusively human infections that are with salmonella gastroenteritis will develop a salmonella
spread from person to person. Infection is acquired by bacteraemia; this is more likely with S. Typhimurium
the faeco–oral route, but the major manifestations (at least infection, especially if the organism is quinolone resist-
in the early stages) of infection are due to bacteraemia ant.105 Localized infection (e.g. of bones or joints) may
rather than luminal infection within the gastrointestinal then follow; more rarely endocarditis may occur.
tract. By contrast, the non-typhoidal salmonellae are Salmonellae have also been reported as a cause of pustu-
mainly zoonoses and having been acquired via the lar dermatitis (usually of the forearm), without gastroin-
faeco–oral route, their initial pathogenesis is within the gut testinal symptoms, in veterinarians who had delivered
to produce ‘gastroenteritis’, although they may go on to calves without adequate personal protective equipment.106
produce invasive disease, with bacteraemia and subsequent A recent Cochrane review found no clinical evidence of
localized infection. Most infections are caused by ingestion benefit in treating otherwise healthy adults (or children)
of contaminated food or water, and are not occupationally with antibiotics for non-severe salmonella gastroenteritis,
acquired. Many cases are associated with overseas travel confirming previous reports that giving antibiotics increases
and several serotypes of salmonella can also be acquired the risk of adverse events and of prolonged stool carriage
from pet animals, including amphibians, and reptiles of salmonellae.107 Antibiotics are recommended in those
and the small rodents used to feed them.98,99 The main who are ill enough to require hospitalization, especially if
occupational groups at risk are veterinary and agricultural they have high fever suggestive of invasive infection.
workers, and laboratory workers. Infection of workers in Quinolones remain the first choice of treatment, although
a vaccine production plant has also been reported.100 reports of resistance in typhoidal and non-typhoidal sal-
Food handlers may transmit infection; food safety and monellas mean that sensitivity should not be assumed.
hygiene regulations cover employment and exclusion Third-generation cephalosporins (cefotaxime or ceftriax-
practices.101,102 one) or azithromycin are potential alternatives.
Salmonellosis as a cause of gastrointestinal infection has
been declining in the west since a peak in the mid-1990s.5,6
S. Enteritidis and S. Typhimurium are the most frequently Campylobacteriosis
isolated serotypes. The former organism is a particular
problem in the poultry and egg production industries, Campylobacters are colonizing organisms found in the
though rates of infection in breeder flocks have fallen in the gut of many vertebrates and were first shown to be human
last decade; the latter organism is found in dairy products, pathogens in the early 1970s. By the mid-1980s, they
pork, turkey, beef and lamb. Monitoring farm premises for had become the most commonly identified bacterial cause
control purposes often reveals widespread environmental of acute infectious intestinal disease in the United
contamination, with reports of isolation of salmonellae Kingdom.6,108 Two species, Campylobacter jejuni (found in
from farm offices, tractor cabins, boots and animal pens poultry and a broad range of farm animals) and C. coli
post-disinfection.6 Workers who are occupationally (found in swine) are responsible for most human infec-
exposed to salmonellae may inadvertently contaminate tions. Studies suggest that a high proportion of fresh
their home environment. In New Zealand, where S. chicken may be contaminated with campylobacter.
Brandenburg has emerged as a pathogen only in the last Campylobacter gastroenteritis is clinically indistin-
decade, a case–control study found that infection was sig- guishable from any other cause of gastroenteritis and pres-
nificantly associated with occupational contact with sheep, ents with diarrhoea that is often bloody, associated with
or having a household member who had occupational abdominal pain and nausea. Vomiting seems to be less
contact with sheep.103 In the United States, S. enterica was common than with salmonella infection, and bacteraemia
isolated from the contents of vacuum cleaner bags in is less frequently identified, although it may be underesti-
27 per cent (15/55) of households where one or more mated. The abdominal pain may be severe, may precede
occupants had workplace exposure (in veterinary practice, the diarrhoea and may mimic an acute abdomen. The role
Occupational zoonoses presenting as gastrointestinal infection 761
of antibiotics in the treatment of campylobacter is not ranges from mild diarrhoea to severe haemorrhagic colitis,
clear. A meta-analysis suggested that antibiotic treatment haemolytic uraemic syndrome (HUS), thrombotic throm-
shortened the duration of diarrhoea by 1.32 days.109 bocytopenic purpura (TTP) and death.116 The disease is
Quinolones and erythromycin are effective treatments, but more severe and mortality is higher in children and the
there is concern because of increasing resistance to elderly. There is usually the onset of abdominal cramps
quinolones (perhaps worsened by their use in veterinary followed by diarrhoea that initially may be watery, but in
medicine). In practice, most illness is self-limiting, and the majority of cases becomes bloody at some stage in the
infection is often not diagnosed sufficiently early for illness. Fever is often absent, which may, in the absence of
antibiotic therapy to be beneficial. Guillain–Barré a known outbreak, lead attending clinicians to entertain
syndrome is a well-recognized complication.108 diagnoses of non-infectious diarrhoea, such as ischaemic
The greatest risk for campylobacter infection is eating colitis or inflammatory bowel disease. A detailed occupa-
undercooked poultry or food cross-contaminated by con- tional and food history is important; cases should be
tact with poultry; infection is also associated with foreign promptly reported to relevant public health authorities to
travel. However, agricultural workers and those employed enable rapid outbreak detection and control.
by the meat and poultry industries are at risk of campy- HUS is a syndrome of acute renal failure, microangio-
lobacter infections, as are veterinary staff. Outbreaks pathic haemolytic anaemia and thrombocytopenia. It can
among workers on poultry (including turkey and pheas- occur in between 5 and 10 per cent of those infected with
ant) farms have been reported.109,110 The risk of infection E. coli 0157; young children are especially vulnerable. At
may be greater early in the course of employment: least half of those diagnosed with HUS will need acute renal
an explosive outbreak among workers in a poultry abattoir support and the long-term sequelae are not insubstantial –
occurred when temporary student workers were employed there is a 12 per cent risk of death or end-stage renal disease
to provide cover during the holiday season.111,112 In the and a 25 per cent risk of other sequelae, such as hyperten-
United States, a case–control study of sporadic C. jejuni sion, persistent proteinuria or some degree of chronic
infection estimated that 18 per cent of infections in rural kidney disease.117 If HUS does not develop then there are
areas were attributable to poultry husbandry, although generally no renal sequelae from E. coli 0157 diarrhoea.
poultry husbandry was not necessarily the primary TTP has similar underlying mechanisms, but is more likely
occupation.113 These infections are largely preventable, to occur in the elderly, and to also affect the central nerv-
by good hand hygiene. ous system to produce stroke syndromes or the colon to
produce ischaemic colitis.
Treatment is essentially supportive; prompt, effective
Enterohaemorrhagic Escherichia coli infection volume repletion may prevent the development of HUS.
The effect of antibiotic therapy on the subsequent risk of
In the United Kingdom, these organisms are called Vero developing HUS, TTP or other complications remains
cytotoxin-producing E. coli (VTEC), whereas in the United controversial, but most authorities advise against it on the
States they are called Shiga toxin-producing E. coli (STEC). grounds that no benefit of antibiotic treatment has been
These organisms are also known as enterohaemorrhagic demonstrated and some studies have suggested that anti-
E. coli (EHEC), and cause a characteristic, toxin-mediated, biotics induce the expression and release of toxin and may
bloody diarrhoea, first recognized in 1982, when two out- precipitate HUS.
breaks of haemorrhagic colitis were associated with eating Prevention of EHEC infection requires scrupulous
hamburgers from a national restaurant chain.114 There are attention to hygiene in handling of animal carcasses in
a number of serotypes in the group: E. coli 0157: H7 is the abattoirs and butchers’ premises, and to standard good
most frequently identified in Europe and the United States; practice in the catering industry, including adequately
in Australia E. coli 0111: H- is more common. Their main cooking meat. Patients admitted to hospital with bloody
‘natural’ habitat is the gut of healthy cattle and other diarrhoea should be isolated and strict enteric precautions
ruminants; carcasses become contaminated at slaughter. must be taken by all staff to minimize the risk of person-to-
Outbreaks have been associated with inadequately cooked person transmission. There is specific guidance about
contaminated beef and exposure to other foodstuffs avoiding risks of zoonotic infection at farms and petting
(including raw milk, cured sausages and cheese) or contam- zoos that have been opened to the public.118
inated water.115 Infection may also follow direct contact
with live animals; risks extend to visitors to open farms and
petting zoos. VTEC present occupational risks similar to Cryptosporidiosis
those of campylobacter and salmonella, although the lower
infective dose may make infection after direct exposure and Cryptosporidia are coccidian protozoa that were first
transmission from person to person more likely. described in the stomach of mice in 1907. By the early
The incubation period after ingestion of organisms is 1970s, they were recognized as a cause of diarrhoea in
about three or four days, although a range from one to cattle, but were not really thought of as a human pathogen
nine days has been reported. The spectrum of disease until the 1980s, when it was recognized that they were the
762 Zoonoses
cause of a severe, intractable, diarrhoeal syndrome in the United States and Europe. In the United States, more
patients with AIDS or other severe immune suppression. than 90 per cent of cases are reported from the northeast-
It is now realized that cryptosporidia can cause an unpleas- ern states with just a few reports from the southwest.
ant diarrhoeal illness even in the immune-competent. It occurs in the United Kingdom, but is more often
Although 16 species of cryptosporidia are now recognized, reported from other European countries, particularly
C. hominis (usually not zoonotic) and C. parvum (usually Austria, Germany, Slovenia and Sweden, usually from
zoonotic) cause most human infections. Cattle farmers are rural areas that have the requisite mammal and tick popu-
at particular risk of cryptosporidia infection119 and it is a lations. The distribution of Lyme disease outside North
risk to others on farm visits and open days. America and Europe remains unclear: there is controversy
Cryptosporidian oocysts are excreted by infected ani- about whether infection occurs in Australia, and few data
mals (especially calves and lambs) and may survive in the for Africa, Asia or Latin America.
environment for some time. They are resistant to chlorina- Occupational exposure may occur in forestry workers,
tion and have a low infective dose, so waterborne spread – agricultural workers, veterinarians and those employed in
either from drinking water or recreational or occupational the leisure industry in endemic areas.
use of water – is possible. The oocysts are infective at the The clinical manifestations are conventionally divided
time they are released, so person-to-person spread can into three stages: (1) early localized cutaneous involvement,
occur. Cryptosporidia are found worldwide, although infec- (2) disseminated infection to heart, nervous system and
tion is probably underdiagnosed in developing countries. joints and (3) persistent or late Lyme disease.122 In most
The diarrhoea is usually watery and free of blood. It may patients with Lyme disease (80 per cent), the initial indica-
be accompanied by nausea, anorexia and abdominal dis- tion of infection (stage I) is the characteristic skin rash
comfort. Fever is uncommon. Infection is generally self- known as erythema (chronicum) migrans (Figure 60.4).
limiting and resolves within about two weeks. In AIDS
patients, the diarrhoea generally improves as immune
restoration takes place in response to antiretroviral drugs;
nitazoxanide may be an effective specific therapy. Treatment
is not indicated in the immune-competent.
In the developed world, prevention has focused on
reducing the risk of cryptosporidial contamination of
drinking water supplies, by fencing off reservoirs from
animals and improvement of water treatment processes.
Lyme disease
Figure 60.3 A hard tick. Vector for a number of zoonotic
Lyme disease is the most common tick-borne infection
infections including Lyme disease. See website
in the northern hemisphere. It was first formally described
(www.hodderplus.com/hunters) for colour plate.
in 1977, after an outbreak of arthritis associated with a
characteristic skin rash affected residents of the towns of
Lyme and Old Lyme in southeast Connecticut over a five-
year period.120 Transmission by an arthropod vector was
postulated, but it was not until 1982 that the causative
organism was isolated both from humans and ticks.121
The condition is caused by infection with organisms of
the genus Borrelia. The main species responsible for Lyme
disease is Borrelia burgdorferi sensu strictu, although in
Europe the condition may be caused by two closely related
organisms, B. afzelii and B. garinii. The bacterium is trans-
mitted by hard ticks of the genus Ixodes (Figure 60.3).
Forest rodents and small mammals, such as deer, are the
usual animal hosts. Man is infected by the bite of
an infected tick (usually the nymph stage). Lyme disease
can theoretically occur wherever there is the pool of
infected mammals and the appropriate hard ticks to main- Figure 60.4 The classical rash of Lyme disease. See website
tain transmission. In practice, it is mainly reported from (www.hodderplus.com/hunters) for colour plate.
Occupational zoonoses presenting with skin problems 763
This is a red lesion centred on the site of the tick bite. There 100 mg twice daily, amoxicillin 500 mg three times daily or
is often some fading of the rash in the middle zone of oral cefuroxime axetil 500 mg twice daily for treatment of
the lesion so that the rash is said to resemble a ‘bull’s eye’. early disease, whether localized or disseminated (stages I
This usually appears any time between three and 30 days and II), unless there is a suggestion of cardiac or neurolog-
after the tick bite and may be accompanied by systemic fea- ical involvement. Macrolides are not recommended unless
tures of general malaise, fever, arthralgia and headache. the three first-line drugs are inappropriate or unavailable
The rash fades slowly over a few weeks with or without for some other reason. For early Lyme disease with a
treatment and may be the only manifestation of infection. suggestion of neurological or cardiac involvement, intra-
The early disseminated stage (stage II) is initially venous ceftriaxone 2 g once daily for two weeks is recom-
characterized by disseminated erythema migrans lesions mended (although oral treatment with first-line drugs is a
and then later by neurological or cardiac involvement. possible strategy for cardiac problems). Late Lyme arthritis
The main neurological symptoms are isolated cranial nerve can be treated with first-line oral therapy, whereas late
palsies (especially Bell’s palsy), a lymphocytic meningitis, Lyme neurological involvement is an indication for four
a radiculopathy and more controversially a form of weeks of intravenous ceftriaxone (or cefotaxime).
encephalitis. These are described in about 15 per cent A controversial area in the management of Lyme disease
of patients with initial Lyme disease. Cardiac involvement is whether the condition of ‘chronic Lyme disease’ really
is more rare and includes conduction disturbances or a exists. Campaign groups in the United States and to a lesser
myocarditis that can be severe and lead to long-term extent in Europe believe that a variety of medically unex-
cardiac damage. Cardiac involvement occurs in about plained symptoms, such as those that make up the chronic
5 per cent of untreated initial infections. fatigue syndrome, are caused by Lyme disease, even if
Late Lyme disease may develop months or years after there is no serological evidence of exposure to infection.
initial infection especially if the initial episode was The main medical and scientific view is that this condition
unrecognized or inadequately treated. It can affect up to does not exist and that long-term antibiotic therapy
60 per cent of those initially infected. The most common (longer than 30 days) should not be offered.127,128 However,
manifestation is a chronic or intermittent arthritis that this view is vigorously disputed by campaign groups, and
affects large joints, especially the knee. The arthritis may the area remains contentious.
become established and chronic and may fail to improve
even after long-term high-dose antibiotic therapy.123
Neurological late Lyme disease (sometimes known as Erysipeloid
chronic neuroborreliosis) can afflict up to 5 per cent of
those initially infected.124 This may present as sensory Erysipeloid (‘pork finger’, ‘whale finger’, ‘fish-handler’s
disturbances, radicular pain, and sometimes as muscular disease’) is caused by the Gram-positive bacterium
weakness. The pathology seems to be an axonal neu- Erysipelothrix rhusiopathiae, which is widely distributed
ropathy with characteristic features on electromyography in nature and found in a wide range of vertebrates and
(EMG). A picture of encephalitis with cranial nerve involve- invertebrates, including domestic swine (causing swine
ment or cognitive impairment has also been described. erysipelas), sheep, poultry, shellfish and fish (where it
Cerebrospinal fluid serology for B. burgdorferi antibody is survives in mucoid exterior slime).129,130 Most human
commonly positive in those with late neuroborreliosis, but infections are occupationally acquired, by direct contact
PCR testing is usually negative. with infected animals, fish or their products; minor
The diagnosis should be suspected on the basis of the trauma (e.g. puncture wounds from crab claws, fish
clinical features and the history of potential exposure in hooks or bone spicules; cuts during autopsy or butchery)
an endemic area. If Lyme disease is suspected, serological facilitates transmission. Infection usually presents five
tests for antibody to B. burgdorferi should be carried out; days to two weeks after exposure as an extremely painful,
positive serology in the appropriate geographical and well demarcated, slightly raised cellulitis on the finger
clinical setting is diagnostic. During the first few weeks or hand, centred on the site of inoculation, which is
of infection (even when erythema migrans is present) only characteristically violaceous at the spreading edge with
20–30 per cent of those infected have positive serology central clearing. Fever is unusual. Less commonly, dis-
(usually IgM antibodies), but in the convalescent phase, seminated cutaneous infection, with bulla formation,
several weeks later, up to 80 per cent have positive serol- occurs. E. rhusiopathiae is a rare cause of endocarditis
ogy, even after antibiotic therapy. However, a significant (usually of a native aortic valve); around 40 per cent of
proportion of those who are treated rapidly and appropri- cases have a recent history of an erysipeloid-like skin
ately never develop a serological response.125 Antibody lesion, or a concurrent one.
titres may fall slowly after antibiotic treatment and may Diagnosis requires culture (blood, needle aspirate or
persist for several years. biopsy from the leading edge of the cellulitis); the organism
Evidence-based guidelines for the treatment of Lyme is sometimes misidentified as a ‘diphtheroid’ or a lacto-
disease were published by the Infectious Diseases Society of bacillus. E. rhusiopathiae is sensitive to penicillins,
America (IDSA) in 2006.126 They recommend doxycycline cephalosporins and macrolides, but intrinsically resistant
764 Zoonoses
to vancomycin – important because the empirical treat- builders). After an incubation period of several weeks, a
ment of severe sepsis in penicillin-allergic patients often reddish tender papule develops (usually on the hand or
relies on vancomycin to cover Gram-positive organisms. forearm, or other cooler, exposed area of the body) which
Although the localized skin infection will heal naturally may ulcerate, but eventually heals with scarring. Less often,
within three to four weeks, healing is faster with antibiotic multiple papules develop in a sporotrichoid distribution,
therapy. or infection may involve deeper tissues, e.g. tendon or
bone. Disseminated infection may occur in the immuno-
suppressed. Diagnosis is by histology and culture of the
Listeriosis organism from a tissue biopsy. It is important to inform
the laboratory of the suspected diagnosis, as the organism
Although Listeria monocytogenes, the usual cause of liste- grows at a lower temperature than that routinely used for
riosis (septicaemia, meningitis, or, in pregnant women, incubation. Treatment is usually with doxycycline,
abortion or congenital infection of the fetus) in humans, is minocycline, clarithromycin or rifampicin with ethambu-
a frequent cause of similar disease in animals, infection is tol; surgical debridement may also be required.133 Strong,
usually sapronotic rather than zoonotic, and normally not water-impermeable gloves, and covering cuts and lacera-
associated with occupational exposure. However, cuta- tions with waterproof dressings will prevent exposure, but
neous infection, presenting as pustular dermatitis, may there may be a lack of awareness of the hazard amongst
occur in farmers and veterinarians one to four days after those at risk.134
exposure to an infected animal (e.g. during delivery of
an infected calf), usually affecting the forearm or hand.131
Diagnosis is made by culture of the organism, which is Orf
usually sensitive to penicillins and macrolides.
Orf is a classic occupationally acquired zoonotic infection.
It is caused by a DNA parapox virus that usually infects
Monkeypox sheep and goats, and is sometimes called ‘contagious pus-
tular dermatitis’. It can also occur in cattle and reindeer.
Monkeypox, an uncommon zoonotic orthopox viral infec- In ewes, pustular and scabby lesions develop on the teats
tion that can mimic smallpox, occurs mainly in tropical and udder. Lambs then become infected when suckling,
central and west Africa. In 2003, a cluster of 47 confirmed and develop lesions on the lips and nostrils, and inside the
and probable human cases occurred in the midwestern mouth. The occupationally at-risk population includes
United States among people who had direct or close contact farm workers and shepherds (particularly after bottle-
with sick pet prairie dogs, which had become infected when feeding lambs or after shearing), abattoir workers and
they were co-housed with wild-caught rodents imported as slaughterers, veterinarians and others with frequent expo-
exotic pets from Ghana. Common clinical features included sure to sheep and goats.
fever, headache, chills, lymphadenopathy (unusual in Orf infections in flocks are controlled by vaccination
smallpox) and a vesiculopustular rash.132 Occupational with a live, non-attenuated vaccine. Vaccinated sheep
exposure was identified as a risk: cases included veterinari- develop a mild form of orf, and recently vaccinated
ans and clinic staff, pet shop employees and animal distrib- animals therefore also present a transmission risk to
utors, as well as prairie dog owners.132 Investigators noted their handlers.135 Infection may also follow needlestick
that standard veterinary infection control precautions had exposure.
not been universally implemented: although their use Three to five days after exposure, an erythematous,
would not have prevented the outbreak, it might have itchy, macule develops, usually on the finger, hand or
limited transmission. Control measures included expan- forearm. This becomes papular, and then develops into a
sion of existing restrictions on the importation and sale of vesicle surrounded by erythema. The lesion may grow to
animal species likely to carry monkeypox virus. about 2–3 cm in diameter and may progress to ulceration
within two to three weeks (Figure 60.5). Complete healing
generally takes place by four to six weeks. The lesions may
Mycobacterium marinum be solitary or there may be several at the point of inocula-
tion; infections in the immune-suppressed may be much
Mycobacterium marinum, the cause of ‘fish tank finger’ is a more severe. The differential diagnosis includes
non-tuberculous mycobacterium that is widely distributed erysipeloid, tularemia and cutaneous anthrax. If there is
in aquatic environments and is also recognized as a diagnostic doubt, then a skin biopsy will show characteris-
pathogen of fish, including farmed food species and tic histological features; a PCR-based test (of vesicle fluid,
farmed tropical species (e.g. Siamese fighting fish). scab debris or tissue sections) is also available. There is no
Cutaneous infection in humans follows exposure of cut or specific treatment. Secondary bacterial infection can be
damaged skin while cleaning fish tanks or inoculation via a treated with standard antibiotics. There is anecdotal
scratch or puncture wound (e.g. in fish filleters, boat support for the use of cidofovir cream.136 In practice, orf is
Other important zoonotic infections 765
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128. Health Protection Agency. HPA statement on IDSA 142. Cliquet F, Picard-Meyer E. Rabies and rabies-related
guidelines on Lyme disease diagnosis and treatment. May viruses: A modern perspective on an ancient disease.
21, 2009. Last accessed September 18, 2009. Available Revue Scientifique et Technique (International Office of
from: www.hpa.nhs.uk/web/HPAweb&HPAwebStandard/ Epizootics). 2004; 23: 625–42.
HPAweb_C/1213603246853. 143. Nathwani D, McIntyre PG, White K et al. Fatal human
129. Sheard K, Hicks DG. Skin lesions among fishermen at rabies caused by European bat lyssavirus type 2a infection
Houtman’s Abrolhos, Western Australia, with an account of in Scotland. Clinical Infectious Diseases. 2003; 37:
erysipeloid of Rosenbach. Medical Journal of Australia. 598–601.
1949; 2: 352–4. 144. Department for Environment, Food and Rural Affairs. UK
130. Reboli AC, Farrar WE. Erysipelothrix rhusiopathiae: An Zoonoses report 2006. Last updated July 20, 2009.
occupational pathogen. Clinical Microbiology Reviews. Available from: www.defra.gov.uk/animalh/diseases/
1989; 2: 354–9. zoonoses/ncp.htm.
SECTION TWO
61 Bioterrorism 773
Julia Heptonstall
62 Genetic modification and biotechnology 782
David Roomes
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61
Bioterrorism
JULIA HEPTONSTALL
approach, with planning for infectious disease emergencies suppressed, or have a close contact who has any of these con-
(including pandemic influenza), natural disasters and ditions. Adverse events after smallpox vaccination include
other public health emergencies. inadvertent inoculation, generalized vaccinia, eczema vacci-
The Centers for Disease Control (CDC) in the United natum, fetal vaccinia, progressive vaccinia and post-vaccinial
States has combined the risk assessment concepts used to encephalomyelitis.23 In 2001, concerns about the possible
develop laboratory biosafety guidance (which assign bioterrorist use of smallpox led many industrialized coun-
pathogens to a risk category by considering the severity of tries to develop national smallpox preparedness plans, to
human infection, transmission potential and the availa- stockpile vaccine supplies and to vaccinate selected military
bility of effective treatment or prophylaxis) with assessments personnel and healthcare workers in ‘smallpox response
of ease of dissemination and estimates of the overall impact teams’ – infectious disease clinicians, public health workers
that any accidental or deliberate dissemination of the and first responders – who would be involved in the diagno-
pathogen would have, and used the results to identify the sis and immediate management of any initial cases. In the
pathogens for which preparedness is most essential. These most extensive programme, in the United States, 39 566 civil-
‘category A agents’ are: variola virus (smallpox), Bacillus ian volunteers had been vaccinated by June 2004; vaccination
anthracis (anthrax), Yersinia pestis (plague), Clostridium of military personnel is ongoing, but more than 1.4 million
botulinum toxin (botulism), Francisella tularensis defence staff and contract workers had been vaccinated by
(tularaemia), filoviruses (Ebola and Marburg haemor- June 2007.24–26 Since so few clinicians were expected to have
rhagic fevers) and arenaviruses (Lassa fever). ‘Category experience of smallpox vaccination, intense preparation and
B agents’ include Burkholderia pseudomallei (melioidosis), training were required: around 1.7 million people accessed
Burkholderia mallei (glanders), Coxiella burnetii (Q fever), the smallpox training materials provided on the CDC web-
and Brucella abortus, B. suis and B. melitensis (brucellosis), site, and the 318 people who attended central ‘train the train-
staphylococcal enterotoxin B, and Venezuelan equine ers’ courses subsequently trained a further 15 349 people in
encephalitis virus.17 The global eradication of smallpox disease recognition, differential diagnosis of fever rash-
was certified in 1980, and infections caused by the other illness syndromes, pre-vaccination screening, vaccination
agents listed above are rare in industrialized countries, technique (which requires multiple punctures with a bifur-
where few clinicians will have direct clinical experience of cated needle) and vaccination site care and follow up.25
them. It is nevertheless essential that all clinicians maintain Adverse events mostly occurred at, or below, the frequency
a working knowledge of their epidemiology, clinical fea- expected, perhaps because the civilian programme (though
tures, differential diagnosis and initial investigation and not the military programme) preferentially selected workers
management (Table 61.1). Extensive web-based and other with a history of previous smallpox vaccination and because
training materials, including pathogen-specific guidelines, of the intensive education on deferring those at risk and on
fact sheets, slide sets and decision-based algorithms for vaccine site care. Safety monitoring also confirmed an associ-
clinical management, have been developed since 2001, can ation between vaccination and myo/pericarditis, but did not
be readily accessed through national authorities’ websites confirm an association between vaccination and ischaemic
and are particularly useful for self-directed learning when cardiac events, though amended selection criteria for pre-
formal face-to-face training is not readily available.18–20 event vaccination exclude people with a history of ischaemic
heart disease, or three or more cardiac risk factors (including
hypercholesterolaemia, smoking, diabetes and hyperten-
SMALLPOX sion), or an immediate family member with onset of cardiac
disease before the age of 50 years.27–29
The last community-acquired case of smallpox – a severe
infection with a case-fatality rate of around 30 per cent
in susceptible people – occurred in Somalia in 1977. The last ANTHRAX
case of laboratory-acquired infection occurred in
Birmingham, UK, in 1978.21 Smallpox (variola) virus is now Anthrax is a zoonosis, caused by Bacillus anthracis, which
held only in two secure repositories, in Russia and the United primarily affects sheep, cattle and goats. The organism has
States, and research work on the virus is strictly regulated. a spore form that is extremely well adapted for environ-
Routine smallpox vaccination programmes ceased around mental survival and can persist in soil for decades:
30 years ago, although vaccination is still recommended for Gruinard Island, off the northwest coast of Scotland, was
those who directly handle vaccinia (smallpox vaccine) virus contaminated during experiments in the 1940s; spores
cultures, infected dressings or other potentially infectious remained detectable until the island was decontaminated
materials, recombinant vaccinia virus or other orthopox in 1987.30 Naturally acquired human infection follows
viruses (e.g. monkeypox), or handle animals infected or con- contact with an infected animal, carcass or animal product
taminated with any of these viruses.22 In the pre-outbreak (e.g. hide, wool, bone). The clinical features of infection
setting, vaccination is contraindicated in those who have depend on the route of exposure to the spores: contact with
atopic dermatitis, eczema or any other active or chronic skin abraded skin (e.g. while butchering an animal or handling a
condition involving the epidermis, are pregnant or immuno- hide) causes cutaneous anthrax; breathing the spores
Table 61.1 Potential bioterror agents: Clinical features and differential diagnoses.
Smallpox (Variola 12 days (range 7–19 Abrupt onset moderate fever, severe Febrile prodrome: influenza, malaria, Eradication certified 1980
virus) days) prostration meningitis
Evolving rash (maculopapular vesicular Erythematous stage: measles, rubella, Public health emergency: seek immediate
pustular), begins on day 3 of illness parvovirus B19 public health advice
Rash denser on face and extremities; all pocks Papular stage: measles, chickenpox Transmission usually airborne, but also occurs
on any one part of body at same stage of via contact with vesicle fluid, saliva, scabs
development or virus-contaminated fomites
Death can occur early, before rash develops Later rash: chickenpox, monkeypox, drug rash, Airborne infection isolation essential
disseminated herpes simplex, hand foot and Treatment is supportive; mortality rate in
mouth disease, disseminated herpes zoster, outbreaks 25–30%
contact dermatitis, erythema multiforme Tracing and post-exposure vaccination of
contacts essential
Asymptomatic, afebrile contacts are not
infectious
Anthrax (Bacillus 1–7 days (range 1–60 Depend on route of exposure (contact, Cutaneous: staphylococcal or streptococcal Naturally acquired human anthrax is the
anthracis) days) inhalation, ingestion) cellulitis, necrotizing soft tissue infection, result of contact with an infected animal,
orf, ecythema gangrenosum, brown recluse carcass or animal product; now rare in
spider bite, rickettsial pox, tularaemia industrialized countries, but remains
endemic elsewhere
Cutaneous anthrax: fever, painless skin lesion Pulmonary: pneumonic plague (haemoptysis Occupational risks: working with animals or
evolves over 2–6 days to form black eschar, uncommon in anthrax), severe community- animal hides (e.g. drum-making), skins or
extensive local oedema, lymphadenopathy acquired pneumonia, tularaemia hair, or working with the organism in the
laboratory
Pulmonary anthrax: fever, malaise, rapid onset No person-to-person transmission: standard
sepsis, non-productive cough, dyspnoea, infection control precautions sufficient
wide mediastinum on x-ray, haemorrhagic Cutaneous disease responds rapidly to
meningitis antibiotic therapy; high mortality in
pulmonary anthrax despite multidrug
regimens
Plague (Yersinia 2–4 days (range 1–8 Depend on route of exposure Bubonic plague: staphylococcal/streptococcal Naturally acquired human disease is zoonotic,
pestis) days) adenitis, cat scratch disease, usually bubonic form, the result of a bite
lymphogranuloma venereum, chancroid, from an infected flea
strangulated inguinal hernia, tularaemia,
syphilis, mycobacterial infection
(Continued)
Table 61.1 Continued
Bubonic plague: fever; bubo – a swollen, very Pneumonic plague: severe community 1500–3000 reported cases worldwide each
painful, tender lymph node (usually in the acquired pneumonia (Streptococcus year from Africa, Asia and Americas
groin, axilla or on the neck); overlying skin is pneumoniae, Staphylococcus aureus, etc.), (including US)
red and indurated, usually unilateral; hantavirus infection, anthrax (but
hypotension, confusion haemoptysis uncommon), tularaemia,
non-infective causes of haemoptysis
Pneumonic plague: fever, severe malaise; Person-to-person transmission of pneumonic
cough, increasing dyspnoea; watery, bloody (but not bubonic or septicaemic) plague can
sputum; chest pain; respiratory failure occur: respiratory standard infection
control precautions required; post-exposure
antibiotic prophylaxis for close contacts
Occupational risks: laboratory work on
organism; in endemic areas outside UK,
animal trapping, hunting or skinning
Botulism 1–3 days (range Symmetrical descending flaccid paralysis Guillain–Barré syndrome Toxins lethal, but inactivated by normal
(Clostridium 1–8 days) cooking of food and chlorination of water
botulinum
toxins A–G)
Alert, afebrile, with normal sensation Myasthenia gravis Toxin blocks acetylcholine release at
neuromuscular junction
Early prominent bilateral cranial nerve signs: Lambert–Eaton syndrome Natural food-borne disease rare in UK, less so
facial weakness, ptosis, dysphonia, where home-canning common
dysarthria, diplopia, dysphagia
Respiratory failure, death Organophosphates, belladonna, other toxins Mortality reduced by early antitoxin
administration (usually held by national public
health authority) and good supportive care
Stroke or CNS mass lesion No person-to-person transmission: standard
infection control precautions sufficient
CNS viral infection, polio
Tularaemia 3–5 days (range 1–14 Depend on route of exposure: inhalation Differential diagnosis broad, initial symptoms Zoonosis, common in parts of rural Europe
(Francisella days) causes pneumonia; infection via bite or non-specific and diagnosis easily missed: (not UK), Asia, Americas and Australasia,
tularensis) abraded skin causes ulcero/glandular disease; with small mammal reservoirs, e.g. rabbit,
ingestion causes oropharyngeal disease; eye lemming, vole, muskrat
inoculation causes oculoglandular disease;
all can disseminate, to sepsis syndrome
Fever, malaise, headache, plus tender local Local disease: orf, anthrax, syphilis, herpes Naturally acquired human disease follows
lymphadenopathy painful ulcer/exudate at simplex infection, chancroid, exposure by: bite of infected vector (tick,
site of infection staphylococcal/streptococcal infection, cat mosquito, deerfly); handling infected animal
scratch disease, mycobacterial infection, or carcass; breathing infected aerosol (from
rickettisial infection, sporotrichosis infected animal or carcass, contaminated
hay, lawn mowing); eating contaminated
food or water
Pneumonia: fever, dry cough, pleuritic pain Pneumonia: community-acquired pneumonia Occupational risks: laboratory work; hunting,
(bacterial or viral), Q fever, tuberculosis, trapping, or farming
lung abscess/empyema, anthrax, plague
Deliberate release most likely to be via
aerosol, causing pneumonic tularaemia
Very low risk of person-to-person spread: use
standard precautions
Mortality low given appropriate antibiotic
therapy (aminoglycoside or quinolone)
Viral Disease-specific Febrile prodrome (fever, malaise, nausea, Malaria All are zoonoses; distribution of natural
haemorrhagic (range 1–21 days) vomiting, myalgia, prostration) of up to disease is governed by the geographic
fever (including seven days, followed by signs of vascular distribution and ecology of the animal
Marburg, Lassa, involvement reservoir
Congo Crimean In second week of illness, cases either recover Typhoid, shigellosis Imported cases are rare in industrialized
haemorrhagic or deteriorate rapidly countries
fever and Ebola High mortality in outbreaks, particularly for Meningitis High risk of person-to-person spread via
viruses and filoviruses percutaneous or mucocutaneous exposure
others, e.g. to blood or infected body fluids; nosocomial
dengue virus) amplification of outbreaks
Leptospirosis Occupational risk for: healthcare workers,
laboratory workers
Tularaemia, plague Asymptomatic afebrile contacts are not
infectious
Other causes of DIC (including Gram-negative Ribavirin effective against Lassa virus and
sepsis, leukaemia, lymphoma, liver failure Congo Crimean haemorrhagic fever virus
CNS, central nervous system; DIC, disseminated intravascular coagulation.
778 Bioterrorism
causes pulmonary anthrax; eating undercooked spore- anthrax spores, and emphasizes the importance of risk
contaminated meat causes gastrointestinal anthrax. There assessment-based selection of control measures. These
are an estimated 2000–20 000 cases of human anthrax each include engineering controls (e.g. avoiding the use of com-
year, largely in countries where animal infection is still pressed air to clean machinery and advice to use industrial
endemic; human anthrax in industrialized countries is vacuum cleaners fitted with HEPA filters to clean high-
rare. Cutaneous infection accounts for 95 per cent of speed mail sorting machinery); administrative controls
reported cases.31 (developing strategies to limit the numbers of personnel
The intentional dissemination of anthrax via the US and visitors exposed); housekeeping (e.g. using ‘wet’ dusting
Postal Service (USPS) in 2001, in envelopes containing techniques in preference to ‘dry’ dusting) and the selection
B. anthracis-positive powder and addressed to prominent and use of appropriate personal protective equipment,
media or government figures, led to 22 cases of anthrax (11 which may include protective clothing, gloves and masks
pulmonary, 11 cutaneous) among residents in seven states or respirators. All workers who process, handle or receive
in the eastern United States. These were the first cases of mail should be trained to recognize and manage a ‘suspect
pulmonary anthrax in the USA since 1976; five (45 per package’, and every worksite should have an emergency
cent) were fatal.16,32–37 Cases occurred in two clusters, asso- plan that describes the actions that should be taken if a sus-
ciated with at least two separate mailings of spore-containing pect package incident or a potential exposure to B. anthracis
envelopes. Most occurred in people who worked either at occurs.41,42 Pre-exposure vaccination is recommended for
the USPS sites through which the contaminated mail laboratory workers who will work directly with the organ-
passed (mail processor, three cases; mail worker, four ism or with high-risk specimens, and for occupational
cases; mail machine mechanic, one case) or at sites where groups at risk of exposure to infected animals or their
the contaminated mail was received (government office or byproducts.43
media company mail room worker, three cases; media
company employee, six cases). Widespread contamination
with anthrax spores was detected at these sites by environ- EMERGENCY PREPAREDNESS
mental testing. Cases also included a seven-month-old
infant, who was probably exposed while visiting one of the It is important that all clinicians remain open to the possi-
media companies, and four other people (a mail carrier, a bility that a deliberate release may occur – and that they
book-keeper, a hospital storeroom worker and a retired may be the first to recognize it. Clinicians must be pre-
elderly female) who were thought to have become infected pared to consult urgently with their local infectious disease
after exposure to mail that had been cross-contaminated as specialist, clinical microbiologist or public health depart-
it passed through the postal system.38 It was not initially ment on the basis of suspicion alone, and should keep
realized that anthrax spores could leak through sealed, a regularly updated list of relevant emergency contacts.
intact envelopes, and lack of familiarity with the clinical Although the initial cases in any deliberate release are most
signs of cutaneous anthrax (which should be included in likely to present to primary care or emergency medicine
the differential diagnosis of an unusual skin lesion, parti- clinicians, occupational health clinicians are well placed
cularly if the lesion is relatively painless, but is accompanied to identify unusual or unexpected sickness absence, and
by intense, extensive oedema) may have led to delays in should remain alert for changes in expected patterns and
diagnosis of the cases in the first cluster, many of which for the case that ‘just doesn’t fit’. Examples include an
had already occurred before the index case of pulmonary unusual number of cases of the same illness presenting in a
anthrax was diagnosed in Florida by an alert clinician who short time-frame; an illness unusual for the time of year
had recently undergone bioterrorism preparedness train- (influenza in summer); an illness unusual for the patient’s
ing. Post-exposure antimicrobial prophylaxis (a 60-day age group (chicken pox in a middle-aged adult) or with an
course of ciprofloxacin, doxycycline or amoxicillin) was unusual clinical presentation (chicken pox rash concen-
recommended for approximately 10 000 people assessed as trated on the extremities), or an illness, or report of a diag-
being at risk of pulmonary anthrax; no cases of anthrax nosis of an illness acquired in an unusual place (e.g.
occurred in this group. In a follow-up study, over half of tularaemia in a worker who has not travelled outside the
those (3032/5343; 57 per cent) who reported taking at least United Kingdom).
one dose of prophylaxis reported adverse events during As a result of the resurgence in biodefence-related
treatment. Fewer than half (2712, 44 per cent) reported research, and the recent expansion in the numbers of BSL3
completing the 60-day course; reasons for stopping treat- and BSL4 (high and maximum containment) laboratories,
ment reported by the 2631 who did not complete the more laboratory workers are working with category A and
course included: adverse events (43 per cent); low per- other high-risk pathogens than at any time in the last 50
ceived risk of anthrax (25 per cent) and concerns about the years, increasing the risks of occupational exposure and
effects of long-term antimicrobial use (7 per cent).39,40 occupationally acquired infection. Since 2000, there have
Health and safety guidance for workers at sites where been reports of occupationally acquired glanders (in a
mail is handled or processed is designed to reduce the worker in a military research laboratory; the first case of
potential for inhalational or cutaneous exposure to glanders in the United States since 1945);44,45 tularaemia
References 779
(three cases, in research scientists working on vaccine management, decontamination, surveillance and emer-
development using an attenuated strain of F. tularensis that gency and clinical management of exposed people, with
was subsequently found to have become contaminated with relevant contact details so that access to specialist medical
a virulent strain);46 staphylococcal enterotoxin B-related ill- advice can be rapidly obtained. Guidelines on the evalua-
ness (three cases, in workers in a military research laboratory tion and management of exposures to potential bioterror
between 1989 and 2002)47 and Ebola haemorrhagic fever (a agents have been published.54 It is recommended that all
research scientist in a Russian laboratory who developed procedures and protocols should be tested and practised
infection and died after a needlestick injury sustained while through a programme of regular drills or exercises, thus
working with ebolavirus-infected guinea pigs in 2004;48 in improving emergency preparedness.
the same year a virologist in a military laboratory in the Preparedness for a bioterrorist incident – a ‘low likeli-
United States was isolated, but did not become infected, hood, high impact’ event – should be integrated with
after scratch from a needle potentially contaminated with major incident and business continuity planning; occupa-
ebolavirus;49 a similar incident occurred in Germany in tional health clinicians have key roles to play in such plan-
2009).50 Laboratory workers in clinical laboratories may be ning. All major events – whether accidents, natural disasters
exposed while working on diagnostic or surveillance- or outbreaks caused by newly emergent infections – and
related samples (a case of cutaneous anthrax was reported the fear and uncertainty associated with them – have pro-
in a laboratory worker in Texas who processed environ- found psychosocial effects on individuals and communi-
mental samples associated with the 2001 anthrax out- ties. Provision of, and access to, psychosocial support for
break),51 or during laboratory proficiency testing. In 2007, those involved, either directly, or indirectly, is essential.
a US laboratory participating in an exercise designed to test
laboratory preparedness inadvertently processed a test sam-
ple containing B. abortus RB51 on the open bench, poten-
tially exposing 24 laboratory workers to the organism, Key points
which, although attenuated, has been associated with
human infection. Written information about safe process- ● The risk of a bioterror event is small, but real.
ing had been provided with the test samples, but further ● Integrated preparedness planning of emergency
investigation identified 916 potentially exposed workers responses is essential.
in 254 of the 1316 laboratories involved in the exercise. ● Occupational health clinicians have key roles to
Post-exposure prophylaxis was recommended for workers play in planning, surveillance, response and
assessed as having had a high-risk exposure; no infections recovery.
were identified.52 ● Know the main clinical features of illnesses
Guidelines on laboratory biosafety advise that labora- caused by potential bioterror agents.
tory workers should have access to expert occupational ● Remain alert to the unusual and the unexpected –
health advice, including, where appropriate, pre-exposure and be prepared to consult urgently with local
prophylaxis. An occupational history is an integral part of public health clinicians on suspicion.
the initial management of any sick patient, and, if a labora-
tory or animal house worker presents with an unexplained
febrile illness, further information should be sought
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36. Freedman A, Afonja O, Chang MW et al. Cutaneous anthrax Public Health Commission, Boston, March 28, 2005. Last
associated with microangiopathic hemolytic anemia and cited April 2, 2009. Available from: www.bphc.org/reports/
coagulopathy in a 7-month old infant. Journal of the pdfs/report_202.pdf.
American Medical Association. 2002; 287: 869–74. 47. Rusnak JM, Kortepeter M, Ulrich R et al. Laboratory
37. Barakat LA, Quentzel HL, Jernigan JA et al. Fatal inhalational exposures to staphylococcal enterotoxin B. Emerging
anthrax in a 94-year old Connecticut woman. Journal of the Infectious Diseases. 2004; 10: 1544–9.
American Medical Association. 2002; 287: 863–8. 48. ProMed-mail. Ebola, laboratory accident death – Russia
38. Jernigan DB, Raghunathan PL, Bell BP et al. Investigation of (Siberia) (04), August 23, 2004. Archive number
bioterrorism-related anthrax, United States, 2001: 20040823.2350. Last accessed April 2, 2009. Available from:
Epidemiologic findings. Emerging Infectious Diseases. 2002; www.promedmail.org.
8: 1019–28. 49. Kortepeter MG, Martin JW, Rusnak JM et al. Managing
39. Centers for Disease Control and Prevention. Update: potential laboratory exposure to ebola virus by using a
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guidelines for exposure management and antimicrobial Diseases. 2008; 14: 881–7.
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Reports. 2001; 50: 909–19. (Hamburg). Archive number 20090331.1243, March 31,
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postexposure prophylaxis for anthrax: Adverse events and www.promedmail.org.
adherence. Emerging Infectious Diseases. 2002; 8: 1124–32. 51. Centers for Disease Control and Prevention. Update:
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43 Centers for Disease Control and Prevention. Use of anthrax resources/publications/biosafety/Biosafety7.pdf.
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62
Genetic modification and biotechnology
DAVID ROOMES
attributable specifically to work with genetically modified Table 62.1 Therapeutic or prophylactic products of
microorganisms and recombinant DNA (rDNA) cells are biotechnology.
rare.13 Although exposure to these genetically modified Protein Date Host Indication
microorganisms, biologically active products and process- system
ing chemicals constitutes a potentially serious risk to the
health of employees, it is concluded that biotechnology
processes are safe if practised with appropriate risk control Blood grouping 1990 Hybridoma Blood
measures in place. reagents transfusion
Human insulin 1982 E. coli Diabetes
Growth hormone 1985
DEVELOPMENT OF BIOTECHNOLOGY Interferon-a 1986 E. coli Hypopituitarism/
leukaemia
Traditionally, biotechnology has been based on the purifi- Hepatitis B surface 1986 E. coli Prevention of
cation and enhancement of the products of naturally antigen hepatitis B
occurring organisms through selection and mutation, in Tissue plasminogen 1987 S. cerevisiae Myocardial
processes such as brewing and baking. Alcohol remains activator infarction
one of the main products of the biotechnology industry, Erthropoietin 1989 CHO Anaemia of
not only ethanol, but also alcohol for industrial use. renal failure
In the last four decades, the introduction of genetic mod- Factor IX 1992 CHO, Haemophilia B
ification has improved the yield and purity of products, and hybridoma
allowed the development of new ones. In the 1950s, anti- Factor VIII 1992 CHO Haemophilia A
biotics and vaccines were produced using biotechnology Interferon-b 1993 E. coli Multiple sclerosis
methods, and in the 1960s, single cell protein as a source of
food for animals and humans was developed. The early
1970s saw the development of recombinant DNA tech- the use of biotechnology, including genetic modification of
niques. This had a major effect on biomedical research crops to increase yields and disease resistance. 2005 saw the
and diagnostics, on agriculture, and on food, chemicals and planting of the billionth acre of biotech seed, an increase
pharmaceutical manufacture.14 from only 5 million acres in 1997. Public interest (and
The first pharmaceutical products made were human concern) in biotechnology has been significantly heightened
insulin, somatostatin and growth hormone. Development in the past ten years following a series of high profile
since then has been in the area of pharmacologically active advances, including the first cloned animal from an adult
mammalian peptides, such as hormones, enzymes and anti- cell, a sheep named Dolly in Scotland in 199615 and the
bodies. Biological response modifiers, such as the interferons, completion of the Human Genome Project in 2002.
and growth factors, such as epidermal growth factor, fibro- The increasing use of genetically modified organisms in
blast growth factor and platelet-derived growth factor, have laboratory research and large-scale industrial processes
also been manufactured using biotechnology techniques. resulted in concern about the potential health and environ-
Tissue plasminogen activator was a successful product of the mental hazards of the organisms and their products. These
late 1980s which has been used extensively as thrombolytic concerns led to the introduction of legislative measures to
therapy for coronary artery disease. Erythropoietin was devel- ensure adequate control of any risks.
oped for use in the treatment of anaemia secondary to renal The traditional applications of biotechnology have usually
disease and various clotting factors have also been produced. been within the scope of general health and safety law.
Since the turn of the century, there has been a rapid growth in However, the European Union has legislation to cover work
approvals for new pharmaceutical products made possible by in this area; specifically European Directives 98/81/EC
new biotechnological techniques, most notably in the fields of for Contained Use and 1990/220/EEC and 2001/18/EC for
vaccines and cancer treatments. A multitude of healthcare Deliberate Release of GM organisms. In the UK, these
applications is currently in development utilizing techniques directives on GMOs and also the requirements of the
such as monoclonal antibody technology, stem cell technol- Environmental Protection Act 1990, have been implemented
ogy, cell culture, cloning, nanobiotechnology, microarrays by specific regulations made under the Health and Safety at
and protein engineering. Table 62.1 shows a list of peptides, Work Act 1974, namely the Genetically Modified Organisms
their host systems and clinical indications. (Contained Use) Regulations 2000 and the Genetically
There are many other industrial applications of biotech- Modified Organisms (Contained Use) (Amendment)
nology, including bacterial enzymes used in the manufacture Regulations 2005 (for work involving contained use of
of detergents, the treatment of leather, and the brewing and GMOs) and also the Genetically Modified Organisms
baking industries; fungal enzymes used in the preparation of (Deliberate Release) Regulations 2002 (for work involving
fruit juices; and yeast enzymes in ice-cream manufacture. deliberate release of GMOs).
The water treatment industry also makes extensive use of The EU also has a directive (EU86/609/EEC) (currently
biotechnology. Agriculture has seen a massive increase in under active revision) covering the protection of laboratory
784 Genetic modification and biotechnology
animals, together with the European Convention for by organizations receiving federal funding, and the latter
Protection of Vertebrate Animals (ETS No. 123), as assigns biosafety levels to organisms and specifies the
amended in 1993 (ETS No. 170). These are implemented in equipment and procedures to be used within each biosafety
the UK under the Animals (Scientific Procedures) Act 1986 containment level.
and the Animals (Scientific Procedures) (Amendment)
Order 1993, and are applicable to any work with laboratory
animals, including any transgenic animals. NANOTECHNOLOGY
The UK regulations specify the following requirements:
Nanotechnology (which includes the field of nanobiotech-
1. To assess the risk to human health and the nology) is a rapidly developing area of science with a
environment, and to keep records. worldwide market for commercial application estimated to
2. To establish a local genetic modification safety reach US$1 trillion by 2015.19 Man-made nanoparticles
committee to advise on risk assessments. have existed for many years, mainly in the form of inhaled
3. To classify organisms and operations. air pollutants as a byproduct of the burning of fossil fuels
4. To notify the Health and Safety Executive (HSE) of the or occupations such as welding and tyre manufacture. The
intention to use premises for genetic modification health effects following inhalation of such particles have
work for the first time and of subsequent individual been widely studied and the detrimental effects thereof on
activities above the lowest risk class and, in some cases the cardiorespiratory system are well understood.20–23 The
of higher risk, to seek consent from the HSE. term ‘nanotechnology’ was first used in 1974 to refer to the
5. To adopt controls, including suitable containment ability to engineer materials precisely at the nanometer
measures. level,24 although a more complete definition is ‘the pur-
6. To inform the HSE of accidents involving genetically poseful engineering of matter at scales of less than 100 nm
modified organisms. to achieve size-dependent properties and functions’. It is
believed that some of the health effects of inhaled nanopar-
Guidelines have been produced by the HSE and the ticles may be predicted from the epidemiological study of
Department for Environment, Food and Rural Affairs available occupational and environmental aerosol exposure
(DEFRA), which give further information on procedures for information and that an initial assessment of risk can be
risk assessment and control. Independent expert commit- made using these data.25 What is less well understood is the
tees have been established to advise government in this ability of manufactured nanoparticles to penetrate the sys-
complex area (the Scientific Advisory Committee for Genetic tem via the intestinal tract and skin and once taken up, the
Modification (SACGM) and the Advisory Committee for pharmacokinetics and end organ effects that may occur.26
Releases to the Environment (ACRE), for contained use and As the science advances, it is expected that nanobiotech-
deliberate release, respectively). In the UK, some techniques nology will be a major area of development in biology and
are exempt from the regulations, including mutagenesis, medicine with applications in current development includ-
the construction and use of somatic hybridoma cells (for ing biological labelling, drug and gene delivery, tissue
the production of monoclonal antibodies), plant cell engineering and the biodetection of pathogens.27 For the
fusion where the resultant organisms can be produced by occupational health professional, it will be necessary to
traditional breeding methods and self-cloning. work closely with toxicologists and other experts in allied
In the United States, the Federal Government has fields to understand the possible health effects and to
developed a coordinated, risk-based system to ensure new implement appropriate controls and risk management
biotechnology products are safe for the environment and strategies.28
human and animal health. Established as a formal policy in
1986, the Coordinated Framework for Regulation of
Biotechnology16 describes the federal system for evaluating GENETIC MODIFICATION
products developed using modern biotechnology. The
Coordinated Framework is based upon health and safety Genetic modification has proved an immensely powerful
laws developed to address specific product classes and a tool for the biotechnology industry enabling discovery of
number of different agencies are involved including the novel drugs, as well as directly being the driving force for
Food and Drug Administration (FDA), the Environmental production of biopharmaceuticals, such as human growth
Protection Agency (EPA) and the Department of Agriculture. hormone and interferon. The development of organisms
The US Government has written new regulations, policies for use in biotechnology commonly involves the improve-
and guidance to implement these laws for biotechnology as ment of desirable properties, such as the level of production
products have developed. Additional guidance includes of a metabolite, as well as eliminating properties that are
guidelines for research involving recombinant DNA mole- less useful. Such modification, either incidentally or delib-
cules17 and guidelines for biosafety in microbiological and erately as a control measure, may also reduce the ability of
biomedical laboratories.18 The former constitutes regulatory the organism to survive outside the bioreactor. Traditional
guidelines for laboratory research which must be followed methods for altering such characteristics included mutation
Organisms used in biotechnology 785
by either chemical or physical means followed by selection Bacterial host cell Donor cell
of organisms with the desired properties.29 Because muta-
genesis is a random process, laborious and careful screening
is necessary to isolate organisms with the required proper- Chromosome Chromosome
ties and thus it is rarely used today within the biotechnology Plasmid
industry. An alternative method for improving the process
characteristics of organisms is hybridization; for example,
by conjugation between closely related species or strains of
bacteria, or by recombination between different mating Cleavage of
types of yeast. Protoplast fusion offers an additional method nucleic acid
using restriction
of strain improvement, particularly between organisms of
endonucleases
different species.
A specific example of hybridization is the formation of Insertion of
‘hybridomas’ for the production of monoclonal antibodies. donor DNA using
In this technique, antibody-producing cells from the ligase enzymes
spleen of an immunized animal (normally a rat or mouse)
are fused with homologous myeloma cells and the result-
ing mixture of cell types grown in selective media. The Recombinant
fusion products are then screened to obtain clones of plasmid
‘hybridoma’ cells that produce useful amounts of antibody
against the antigen used for the immunization. These
clones are genetically identical and the resulting antibody
Recombinant
will be a pure species, or ‘monoclonal antibody’. Chromosome
plasmid
A more recent development for obtaining essentially
similar antibodies has been ‘phage display’, where genes for
an antibody with extensive variation of the ‘variable regions’ Recipient cell containing
have been fused to a surface protein on a bacteriophage, to recombinant plasmid
create a library of recombinant bacteriophages displaying
the antibodies on their surfaces.30,31 This library can be Figure 62.1 Principles of genetic modification.
panned by trapping the phage on to the desired target,
immobilized on a suitable support, and washing away the The underlying technology for modern biotechnology
unbound bacteriophage before releasing the bound ones. is the ability to manipulate DNA. A typical manipulation is
These can then be grown up further, to produce a popula- outlined in Figure 62.1. Initially, the target gene of interest is
tion enriched for those binding to the target protein, since identified and isolated32 and the selected gene is cleaved using
the gene for the antibody is now linked to its presence on the restriction endonuclease enzymes and inserted into a vector
surface of the bacteriophage, and the panning repeated until capable of being inserted or incorporated into the recipient
a population with high and specific affinity is obtained. cell (either a circular piece of DNA termed a plasmid, or a
Individual bacteriophage can then be cloned from this pop- virus). The ‘new’ gene is joined to the vector’s nucleic acid
ulation, to give clones containing the wanted gene using ligase enzymes. The vector can then be used to intro-
sequences, which can then be recloned into appropriate duce the gene into the recipient or host cell, to which it is able
expression vectors for the production of the antibody. to pass on the characteristics coded in the gene from the
Much of the current interest in biotechnology is over the donor organism. Host species have included Saccharomyces
use of techniques to develop microorganisms that produce cerevisiae, Bacillus spp. and Streptomyces spp., but the most
products coded for by genes from a wide variety of sources. frequently used is Escherichia coli through which nearly all
Potential donor organisms include viruses and eukaryotic genetic manipulations are made before using the vector DNA
microorganisms (i.e. microorganisms in which DNA is and introducing into the final destination host.
contained in a distinct nucleus), such as bacteria, plant and
animal cells. The choice of organism is dependent on a
number of factors including the ability to express functional ORGANISMS USED IN BIOTECHNOLOGY
products, the cost of manufacture and ultimate use of the
product. Hormones and antibodies tend to be produced These come from a wide range of taxonomic groups, includ-
from animal cells, whereas biotechnology enzyme manufac- ing bacteria, fungi and viruses, as well as animal and plant
turers, making components for polymerase chain reaction cells. The most common organisms used for biotechnology
kits, might use a thermophilic microorganism, e.g. medicines are animal cells and bacteria; however, fungi are
Thermophilus aquaticus, to produce the Taq enzyme. Virus still widely used in other industrial (i.e. non-pharmaceutical)
donors include hepatitis B virus, whose DNA is used to processes. Viruses can carry and donate DNA and are most
make vaccines by expression in a heterologous organism. commonly used during vaccine production. Viruses are also
786 Genetic modification and biotechnology
used extensively as vectors in molecular biological research metabolites have built up, growth eventually stops and the
and in therapeutic delivery systems. Routinely used organ- culture enters the stationary phase. During the stationary
isms such as Escherichia coli, have been genetically modified, phase, products termed ‘secondary metabolites’ are pro-
selected and improved to enable a number of factors. duced which play no obvious role in cell growth and are usu-
Examples include the inability to undergo homologous ally specific to particular groups of organisms. Secondary
recombination, modification of biochemical pathways to metabolites include the antibiotics, alkaloids and some other
enable growth on only certain types of media, removal of molecules. Genetic modification has extended the range of
genes that might enable the bacteria to transfer genetic mate- metabolites that may be produced by microorganisms. For
rial to other cells by conjugation and removal of resistance example, microbial cells may be developed with the ability
genes from the chromosome. The resultant organism is opti- to synthesize compounds normally associated with plant
mized for genetic manipulation, but severely impeded in its or animal cells, including hormones, growth factors and
ability to grow outside the laboratory environment, such that proteins, such as serum albumin.
the safety profile for the worker and the environment is
enhanced. The modification of host microorganisms in this
way plays a major role in assessment of biosafety hazards. Recombinant pharmaceutical products
The pharmaceutical industry is also using this technology 2. non-aseptic processes using specified inocula which
to research the amino acid sequence of naturally occurring include brewing and milk fermentation;
bioregulatory proteins. This will allow the development of 3. aseptic processes using specified inocula, as in
analogues which act as inhibitors or promoters of activity. antibiotic and single-cell protein production;
Many vaccines are now produced using biotechnology. 4. aseptic and contained processes using potentially
Genes can be cloned and expressed, which code for specific hazardous organisms, such as vaccine production.
antigens of viruses, bacteria and parasites. An early example
of this is the hepatitis B vaccine which utilizes yeast to pro-
duce hepatitis B surface antigen. Also, DNA from genetically BIOTECHNOLOGY PROCESSES AND THEIR
modified vaccinia virus has been used to produce protective HEALTH HAZARDS
antigens for hepatitis B, rabies and malaria vaccines.36 With
increasing concern regarding the possibility of a global A typical industrial, biotechnology process involves a
influenza pandemic, the development of DNA vaccines number of stages: inoculum preparation (for processes
whereby an individual is not given the protein antigen, but using specific inocula); large-scale growth of the organism
DNA encoding the antigen, is seen as a greatly improved in a bioreactor; separation of the organism from its growth
method of delivering vaccination on a large scale.37 medium; and product recovery and purification. These
Monoclonal antibodies (produced from a combination stages are summarized in Figure 62.2. The process may be
of myeloma cells and antibody-producing cells from the aerobic or anaerobic, depending upon the organism used,
spleen of an immunized mouse) are used in diagnostic kits, and may be carried out in bioreactors ranging from open
in protein purification and as therapeutic agents in cancer pan vessels to highly enclosed systems that may require
and organ transplant rejection. At present, monoclonal mechanical agitation or aeration. Downstream processing
antibodies account for the largest product category of all depends on whether the product is intracellular or extra-
biotechnology-derived drugs.38 cellular. Intracellular product requires extraction, whereas
Recombinant DNA technology has also been applied to extracellular product is purified from spent medium
the production of antibiotics, and in the development of (Figure 62.3) and the health hazard and effluent issues may
direct-acting gene therapies, e.g. for cystic fibrosis and be quite different. Extraction of intracellular product
rheumatoid arthritis. The ‘normal’ gene is administered to generally requires that the cells are disrupted, usually by
patients with the aim of incorporating this ‘good’ genetic chemical lysis or by physical disruption, such as homogen-
material into cells to influence the course of the disease. ization. The potential for release of aerosols is greatest dur-
While there has been some success in obtaining expression ing disruption stages. The final processing stages are
of the new transgene, major problems have occurred due to purification and concentration of the product, through
the integration of the vector and further work is needed, to some of the operations listed in Table 62.2.
develop safer vectors, before this technique can be applied Biotechnology processes may result in risk of exposure
more generally. to biological, chemical, ergonomic, physical and other
hazards.
Transformation processes
1. non-aseptic processes using indigenous organisms, Figure 62.2 A generalized schematic representation of a typical
such as in traditional wine production; biotechnology production process.
788 Genetic modification and biotechnology
Fermentation
Harvesting
Cells
Liquor
Extraction/cell rupture
Concentration
Debris removal
Precipitation/adsorption
Concentration/drying
biologically active molecules, such as enzymes, Another potential source of biological hazard is
hormones or toxins to target tissues. contaminating organisms present in the culture. This may be
2. Risk of transmissible spongiform encephalopathy from of particular concern in animal cell cultures, where viruses
exposure to modified prion genes. (retro, simian, polyoma, herpes or hepatitis), mycoplasma
3. Exposure to cloned human genes that could lead to an and prions may exist as contaminants. Tasks involving
immune response and subsequent autoimmune potential aerosol generation or manipulation of sharps could
disorders. expose the employee to a risk of potentially serious infection.
4. Exposure to a gene product, leading to induction of an
immune response that could cause therapeutic Toxic effects
complications if treatment with that product were
required. Toxic effects may result from inhalation of Gram-negative
5. Respiratory sensitization related to exposure to bacterial endotoxin.44,45 The reaction may follow exposure
foreign proteins, with the possibility that inclusion to the dust of single-cell protein after it has been cultured in
bodies and fusion proteins may increase the risk of fermenters and subsequently dried in a spray drier. Workers
sensitization. exposed to the end-product as a result of inadequate pro-
6. Exposure to cloned oncogenic sequences or genetically tective measures can develop flu-like febrile reactions 4–12
modified retroviruses that could pose a carcinogenic risk. hours later, with shivering, fever, tightness of the chest,
aching limbs and cough. Blood tests reveal neutropenia fol-
Special consideration should be given to work with lowed by leukocytosis46 and a decline in forced expiratory
DNA-containing genes coding for potent toxins or for volume in one second (FEV1)47 has been described. These
oncogenes. Theoretically, there is the possibility that the symptoms may start during the evening or the night after a
introduction of oncogenic sequences into a human, as a day’s work, but subside by the morning or over the next
result of an occupational accident or cumulative exposure, day. Acute symptoms of conjunctivitis, rhinitis or cough
could cause cell transformation and lead to tumour may start immediately after exposure. Sore red eyes with a
growth.43 No cases of this have been reported. Particular persistent discharge have also been reported. Exposed work-
concern has been raised about possible oncogene exposure ers can be found to have precipitating antibodies to the
through inhalation, since the newer potential therapies use organism, but the responses have been regarded as more
airborne viruses, such as adenovirus. likely to be due to endotoxin rather than an immunological
Much recombinant DNA work has used E. coli K12 as the reaction to the organism. Endotoxin intolerance can
recipient organism. Its modification demonstrates how many develop on subsequent challenge.48,49
rDNA organisms are disabled so that they can no longer Inadequate protection against exposure to single-cell
survive in the human host. Because E. coli K12 lacks certain proteins (protein products developed for animal and human
surface antigens, the fimbriae which enable it to adhere to gut food (e.g. mycoprotein) or enzymes, may result in allergic
epithelial walls, resistance to lysis by serum complement, effects such as asthma50–53 or contact dermatitis. Extrinsic
resistance to phagocytosis and part of an important liposac- allergic alveolitis can follow exposure to fungal spores.
charide, it is thus unable to colonize the human gut and is Type 1 immediate or anaphylactic response is a theoretical
non-pathogenic as a result of these modifications. possibility after exposure to enzymes or antibiotics.54
790 Genetic modification and biotechnology
Table 62.4 Tissue culture additives. Table 62.5 Chemical solvents and extractants.
Management of Health and Safety at Work Regulations non-mobilizable plasmid which requires to be
(MHSWR), to advise the employer on safety of any GM work transfected into a bacterium), at other times the vector
undertaken. However, for larger premises, where the total may be a virus with the potential to enter human cells
workload may be high, or when more specialist knowledge is and even insert into the genomic DNA, posing
required, it may be desirable to appoint a biological safety potential hazards not only from the genes which it
adviser to assist the BSO, as well as advising the employer. contains, but also from the possibility of insertional
In general, health surveillance will not be required for mutation in the human genome. Examples of
most GM activities and it is not a requirement under the potentially hazardous vectors include any lentiviral, or
Contained Use Regulations, although it might be under even viral, vectors containing the enhancer of gene
COSHH and MHSWR, depending upon the risks and bene- expression derived from woodchuck hepatitis virus.57
fits under particular circumstances. If a supervisory medical 3. Hazards associated with the genomic insert. Often the
officer is appointed, then they would usually be a member inserted gene will code only for a harmless protein,
of the GMSC, even if mainly receiving papers rather than which is to be produced in bulk for subsequent
attending meetings. purification, but on occasion the inserted DNA itself,
Previous regulations made a distinction between different or its product, might be harmful. Hazardous DNA will
scales of work at the risk assessment stage. This distinction include potentially oncogenic sequences, since these
has now been abandoned for the risk assessment, although it have been shown to be capable of causing increased
is clearly still relevant when deciding the details of the physi- tumours (e.g. when rubbed on to the skin of mice).58
cal containment to be applied, in particular when large-scale 4. Hazardous products from the inserted gene. These
production occurs outside usual laboratory style contain- could include potentially hazardous RNA, such as
ment (e.g. during manufacture of GM influenza vaccine in siRNA targeted against tumour suppressor proteins
embryonated eggs) or during clinical studies involving GM (which would be potentially oncogenic if expressed in
agents administered to humans in a hospital. Under the cur- a human cell), and hazardous proteins, either because
rent regulations, the initial assessment is concerned to deter- they are toxic or else have a physiological function
mine the relative risks to human health and the environment, (e.g. allergens, cytokines, growth factors or
considering the potential severity, likelihood of occurrence oncogenes).
and any uncertainty. Based upon this initial assessment, the 5. Possible modification of the pathogenicity of the host
main assessment will then be aimed at reducing these factors microorganism. Obvious examples include
and assigning sufficient containment measures to bring the pathogenicity-determining genes from a related
likelihood to an acceptable probability. The GM class of the microorganism (e.g. adhesion factors or transport
work is then determined from the containment measures factors) and any gene whose product might lower the
required. Subsequently, consideration is given to whether susceptibility of the host to the immune system.
these containment measures will also give sufficient protec-
tion to the lesser hazard, between human health and environ- Assessment of potential hazards to the environment is
ment, and any necessary additional measures added. The less systematized, as clearly factors of the local environment
final overall class is then reassessed, to allow for any such are relevant, e.g. if the potential target for harm from the
additional containment. The overall class determines genetically modified microorganism is not in the immediate
whether it is necessary to notify the Health and Safety locality the likelihood of hazard may be substantially
Executive of the particular project (initial notification of all reduced. Risk assessment is carried out by assessing both the
GM centres is necessary) or even, for the higher risk classes, consequence of the hazard and also its likelihood separately,
to seek consent before the work can be commenced. and then combining these to obtain an overall risk assess-
In considering the potential hazards to human health ment. Among the factors which need to be considered are:
from a genetically modified microorganism, the following
should be considered: 1. Any hazard associated with the recipient strain of
microorganism, considering whether it might either
1. Any hazard associated with the recipient strain of infect or compete with any organism naturally present
microorganism, particularly whether it has the in the environment. Usually disabled host strains are
potential to enter human cells or establish an infection employed, but this is not always the case and
in human hosts. Usually disabled host strains are sometimes the wild-type host might be sufficiently
employed, but this is not always the case and pathogenic or dominant that even a disabled strain
sometimes the wild-type host might be sufficiently would still present a significant hazard. In general, the
pathogenic that even a disabled strain would still starting containment considered will be that required
present a significant hazard. In general, the starting for the host alone.
containment considered will be that required for the 2. Any hazard presented by the vector. While this will
host alone. frequently be minimal (e.g. when the vector is a non-
2. Any hazard presented by the vector. While this will mobilizable plasmid which requires to be transfected
frequently be minimal (e.g. when the vector is a into a bacterium), at other times the vector may be a
Health surveillance 793
virus with the potential to infect a host present in the methods employed for their maintenance in a barrier unit,
environment. to ensure their pathogen-free status, will be fully sufficient
3. Hazards associated with the genomic insert. Often the to ensure that the likelihood of escape is negligible, and the
inserted gene will code only for a harmless protein, risk to the environment effectively zero.
which is to be produced in bulk for subsequent The containment measures required by the risk assess-
purification, but on occasion the inserted DNA itself, ment should be adequate to protect a worker of average
or its product, might be harmful. susceptibility. However, additional consideration should
4. Hazards associated with products from the transgene. be given to anyone who might be more vulnerable, partic-
These will usually involve consideration of whether any ularly those on immunosuppressive therapy (e.g. under
protein product might be harmful to any species treatment for rheumatoid arthritis or following a trans-
present in the environment. plant) or who are otherwise immunosuppressed. A wider
category for whom special consideration should be given is
The consequence and likelihood of hazard are combined, women who are, or might be, pregnant or breastfeeding.
to produce an overall assessment of risk, as shown in Most low class GM work will not present any specific risks
Table 62.6, and additional containment measures are to such women, or their child, but consideration should be
considered until the risk to the environment is ‘low’ or taken if work is planned with any host known to have
‘effectively zero’. adverse effects, or any transgene which codes for any agent
Once the appropriate containment measures have been which is suspected of affecting the fetus or newborn child.
determined for the more important of the human health or An important aspect of risk assessment is the communica-
environmental risk, any additional measures necessary for tion of any hazards which are found to the relevant members
the other risk are added, and then the appropriate GM of the workforce, so that they have a good appreciation of
class is determined from the containment measures. why the containment measures are necessary, together with
The containment measures necessary for genetically appropriate training so that they can use these measures for
modified microorganisms depend upon the scale of the their own, and their colleagues’, protection.
work. Those for small scale (i.e. laboratory scale) activities
are the same as those for different hazard group pathogens
and a number of the main ones are summarized in Table HEALTH SURVEILLANCE
62.7. In the case of GM plants, the risk to the environment
will almost always outweigh that to human health and the Health surveillance was a prominent risk control measure in
main assessment will be that necessary to protect the envi- the past when the health risks arising from genetic modifica-
ronment, paying particular attention to the possibilities of tion were considered to be uncertain. National guidance in
dispersal, whether of pollen or seed. In consequence, the several countries promoted highly prescriptive health
health risks are usually negligible, unless some product of surveillance procedures, with a hierarchy of measures linked
the plant poses such a risk, including potential allergenicity to categories of containment levels. However, with growing
giving rise to hay fever symptoms. experience of occupational health outcomes showing little
For the majority of activities involving GM animals, the evidence of health problems related to genetic modification
primary consideration is the potential of harm to the work,10,59 it is clear that these traditional measures have
environment, should it be able to escape and become been out of proportion to the risks to health.
established in the environment (e.g. by breeding and pass- The role of health surveillance has been revised in recently
ing on its transgene(s)), and the risk to human health is updated guidance, such as that produced by the Scientific
similar to that posed by the wild-type animal. The issues of Advisory Committee on Genetic Modification in the UK in
containment are very different, with a range in sizes from 2007.56 The emphasis has been placed on determining
farm animals to small invertebrates requiring very differ- appropriate health surveillance procedures based on a risk
ent consideration. In the case of laboratory animals, the assessment of the likelihood of health effects resulting from
794 Genetic modification and biotechnology
Table 62.7 Examples of containment measures for small scale work with genetically modified microorganisms.
Building/ Laboratory suite isolation Not required Not required Required Required
physical Laboratory sealable for Not required Not required Required Required
measures fumigation
Negative pressure Not required Required where risk Required Required
relative to surroundings assessment shows
Extract and input air Not required Not required HEPA filters required HEPA filters
HEPA filtered for extract required for both
input and extract
Microbiological safety Not required Required where and Required, and all Class III cabinet
cabinet or enclosure to extent risk procedures with required
assessment shows infective materials
required to be
contained within
cabinet/enclosure
Laboratory to contain Not required Not required Required, so far as Required
its own equipment is reasonably
practicable
Safe storage of GMMs Required where and Required Required Secure storage
to extent risk required
assessment shows
Staff Access restricted to Not required Required Required Required via air
authorized personnel only lock key procedure
Written records Not required Required where and Required Required
of staff training to extent risk
assessment shows
Waste Inactivation of GMMs Not required Not required Required where and Required
inactivation in effluent from to extent risk
handwashing sinks, assessment shows
showers and similar
effluent
Inactivation of Required by Required by Required by validated Required by
GMMs in contaminated validated means validated means means, with waste validated means,
material inactivated in the with waste
laboratory suite inactivated within
the laboratory
Adapted with permission from SACGM Compendium of Guidance, HSE © Crown Copyright.56
exposure to all the potential hazards involved in genetic identification of subsequent ill health, identify health fac-
modification work. Health surveillance is likely to be tors which are likely to increase vulnerability or suscepti-
appropriate when all of the following criteria are fulfilled: bility to exposure-related health effects or permit early
detection of such effects. Additional aims could be to eval-
1. An identifiable health effect may be related to uate the efficacy of control measures or provide data for
exposure. subsequent epidemiological study. There is also an oppor-
2. There is a reasonable likelihood that the disease or tunity to communicate health risks and to counsel employ-
effect may occur under the conditions of the work. ees about any health concerns.
3. There are valid techniques for detecting indications of Decision-making on the indications for, and content of,
the disease or health effect. health surveillance programmes should be made by an occu-
pational physician who is experienced in this field and who is
The purpose of any health surveillance programme involved with the organization’s biological safety committee
could be to collect baseline information to assist in the that has responsibility for reviewing risk assessments of
Health surveillance 795
genetic modification work. If health assessment procedures symptoms and lung function assessment would be an
are indicated, an occupational health nurse can perform appropriate method of surveillance if occupational asthma
these and obtain advice from the occupational physician were assessed to be a foreseeable health effect. For lower
overseeing the programme. risk situations, providing information about re1evant
symptoms and encouraging self-reporting may be all that
Low risk genetic modification work is indicated.
Biological effect monitoring could be used to detect
For work with genetically modified microorganisms that antibody to the genetically modified microorganism in
present no identifiable risk to human health, it is unlikely use, either to establish immune status prior to exposure or
that there will be any indication for health surveillance. to detect seroconversion after a period of potential expo-
However, health surveillance may still be appropriate if sure. Immunization may be indicated for work with cer-
there are identifiable health effects related to an allergenic tain organisms. In the past, immunization with smallpox
response to the genetically modified microorganism or to vaccine was recommended for work with modified strains
toxic effects from expressed products. of vaccinia virus, but there would be few circumstances
It may still be appropriate to conduct an initial health now when this would be indicated as a result of a risk
assessment to identify individuals who may be at greater assessment of work with this virus. Maintaining records of
risk because of pre-existing illness or an underlying medical exposure may be an appropriate method of health surveil-
condition. The aim of such an assessment would be to lance for work with oncogenic sequences where there is
consider the need for additional control measures or to likely to be a long latency period between exposure and
identify adjustments to allow the individual to carry out the possible carcinogenic effects.
work with tolerable control of health risks. The following
factors may require special consideration: Storage of serum samples
● relevant medical history, such as a history of asthma or Long-term storage of serum samples taken prior to expo-
recurrent infections; sure as a baseline reference has been widely practised in the
● health problems which reduce the efficacy of barriers to past. The idea was that if antibody responses relevant to the
infection, such as disorders of the skin, respiratory tract genetically modified microorganisms being handled were
and alimentary canal; subsequently detected, the baseline sample could be tested
● reduced immune competence, including treatment with for comparison. However, there are few circumstances
immunosuppressive therapies; when the health benefits to the individual justify conduct-
● treatment with antibiotics, in particular those used in the ing such an invasive procedure and the implementation of
work, or systemic steroid therapy and other treatments that the Human Tissue Act 2004 in the United Kingdom rein-
could increase susceptibility to infection. forces the view that this practice should be restricted to
situations where consideration of the risk assessment for
Higher risk genetic modification work the work indicates a justifiable health or social benefit to
the individual.
Health surveillance may be indicated if there is likelihood Previously, it was believed that the immunological
that any of the following potential health hazards may response to exposure to a genetically modified microor-
result in exposure-related health effects: ganism or an expressed product could cause confusion
during diagnostic tests for infection with the same or a
● infection, particularly with modified viruses which related microorganism. Examples include expressed HIV
exhibit altered tissue tropism, reduced susceptibility to proteins, where antibodies to these proteins form the basis
therapeutic agents or where conventional immunization of serological tests for HIV infection; however, previously
would result in reduced protection; held concerns regarding the impact that having submitted
● oncogenic or tumorigenic sequences that could give rise to for HIV testing could have on an individual’s life insurance
a risk of carcinogenesis if incorporated into human cells; are no longer valid. In 2005 in the UK the Association of
● modified prion protein genes that could cause British Insurers implemented new practice60 that ensures
transmissible spongiform encephalopathy; that applicants will not be penalized for having taken
● biologically active substances expressed by genetically an HIV test and are not required to declare negative tests
modified microorganisms, such as enzymes, hormones nor will occupation be used to assess HIV risk. In general,
or toxins; there is only likely to be an indication for baseline serum
● cloned human genes that may lead to an immune storage when the current diagnostic tests would have diffi-
response and subsequent autoimmune disease; culty distinguishing true infection from immunological
● substances that are asthmagens. response to a related protein, or acute from chronic infec-
tion states, and where such confusion could have substan-
There is a range of health surveillance procedures that tial health or social consequences. The usefulness of the
could be applied. Periodic enquiry about respiratory baseline sample is of limited medicolegal value, however,
796 Genetic modification and biotechnology
when one considers the implication of the window period and the onset of ill health related to infection or carcino-
that an employee could be in at the time of submitting genesis. These records should include personal identify-
a sample. ing information, details of the nature of the hazards, the
If serum storage is practised, then it is important that dates when the work started and finished and informa-
the purpose of the procedure is explained to the employee tion that links the record to the relevant risk assessment
and informed consent obtained. It should be emphasized and any exposure monitoring data. Such non-clinical
that the individual is only consenting to the sample being records can be maintained by the employer. The records
stored and that subsequent testing would only be con- could also be used to provide retrospective information
ducted with the individual’s express consent, even after the on health and related exposures for epidemiological
individual has left the organization where the sample is investigation.
stored. A sample of approximately 5 mL of serum should
be labelled to allow later identification of the donor and
stored in a secure freezer at –20°C or below, with arrange- CONCLUSION
ments made for dealing with sample salvage in the event
of freezer malfunction. The period of long-term storage The clinician may be puzzled at the contrast between the
before discarding the sample should be agreed with the complexities of biotechnology with its surrounding myriad
donor. It is unlikely that there would be advantages in stor- of regulations and control measures and the dearth of data
ing such samples for longer than 40 years. As can be seen, a on ill health in the scientists and production workers
multitude of practical and legal considerations regarding involved. The industry is perceived to have a good health
ensuring cold custody, informed consent, maintenance of record, but, to be able to demonstrate the absence of
accurate registers, notification to the occupational health a problem or to provide early warning of an unforeseen
department of staff leavers and disposal of samples need to health hazard in this novel and rapidly expanding techno-
be weighed in the balance prior to embarking on any logy, it will be important to ensure that health surveillance
programme of serum storage. measures based on sound theoretical considerations,
including epidemiological studies where appropriate,
are maintained. The challenge for the future will be to
Medical contact cards ensure that any potential hazards to human health or the
environment are controlled to the satisfaction of employ-
In the past, issuing medical contact cards to employees ees, health and safety professionals, regulatory authorities
involved in genetic modification work with higher hazard and, ultimately, the general public.
genetically modified microorganisms was common prac-
tice. The rationale for doing so was to alert other medical
personnel to the possibility of occupationally acquired
Key points
infection and provide details on how to contact someone at
the employing organization who would be able to give the ● The field of biotechnology has an excellent
clinician information about relevant biohazards. In prac-
health and safety record, but consideration must
tice, however, there is the likelihood that employees may
be taken of associated traditional risks such as
lose or not carry their cards and as any occupationally
chemical, physical and ergonomic.
acquired infection is unlikely to present with unconscious- ● Work with genetically modified microorganisms
ness or an acute confusional state, this practice would seem
is highly regulated and occupational health
to be of limited benefit. Any unusual symptoms not readily
practitioners should familiarize themselves with
diagnosed by standard means would lead to a thorough
relevant legislation and guidance.
assessment that would include a complete occupational ● Health surveillance activities should be
history, thus yielding the required information.
risk-based and outdated practices such as
routine serum save discontinued.
● The field of biotechnology is developing rapidly
Health records and the risks posed by emerging technologies
such as nantechnology are as yet not fully
Health records should be maintained of all health assess-
characterized.
ments conducted as part of any health surveillance related to
genetic modification work. Records that contain clinical
information must be held in confidence by healthcare
professionals. ACKNOWLEDGEMENTS
Records of exposure may also be indicated for work
which involves higher hazard microorganisms, prion This chapter is updated from Hunter’s Diseases of Occupations,
proteins or oncogenic sequences where there is known to ninth edition, Chapter 25 Genetic modification and biotech-
be a long latent period of many years between exposure nology by AM Finn et al.
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18: 120–9. 58. Burns PA, Jack A, Neilson F et al. Transformation of mouse
48. DeMaria TF, Burrell R. Effect of inhaled endotoxin-containing skin endothelial cells in vivo by direct application of plasmid
bacteria. Environmental Research. 1980; 23: 87–97. DNA encoding the human T24 H-ras oncogene. Oncogene.
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changes in the lung induced by inhaled bacterial endotoxin. 59. Cohen R, Hoerner CL. Recombinant DNA technology:
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derivatives of Bacillus subtilis containing proteolytic enzyme. 60. Association of British Insurers. Statement of best practice on
Lancet. 1969; i: 1177–81. HIV and insurance. London: ABI, October 2004.
PART SIX
According to Hayward,1 stress derives from the Latin word by Lipsedge and Calnan. William Blake’s ‘dark, satanic
stringo (stringere), meaning to bind or draw tight. It mills’ may have finally receded into history in high-income
entered the English language in the fourteenth century, nations, where in this age of globalization the entrepreneur
when it referred to physical hardship and later, a form of employer is seen less as a villain than as the wealth creator
injury. It was not until the seventeenth century that the we desperately need. However, employees in almost all
word began to refer to an inner state.1 Its modern usage employment sectors complain increasingly of such prob-
to describe a combination of harmful environmental lems as overwork, or fear of making mistakes, or of being
pressures and pathological physiological responses was marginalized, bullied and harassed, to the point of intoler-
popularized in the research work of the biochemist Hans able distress. These three chapters agree on at least two
Selye (1907–82). The notion that the body’s response to things: first, that the evidence on the management of indi-
the environment might have adverse health consequences, viduals presenting with stress at work is still controversial,
especially on the heart, was proposed by the famous and second, most employees who have work-related dis-
clinician Sir William Osler (1849–1919).1,2 Experimental tress do not need to be medicalized. In the chapters by
evidence on the effects of stress emerged in the laboratory Glozier and colleagues, and Lipsedge and Calnan, the
work of the physiologist Walter B Cannon in the 1930s, mental effects of exposure to life-threatening trauma and
when he showed a range of physiological responses, such involvement in warfare as part of work are also described,
as adrenaline release and cardiac arrythmias, in response along with the medicolegal minefield of post-traumatic
to external ‘strains’.1 These concepts, part developed by stress disorder.
pioneers in an era that preceded modern scientific
medicine, took firm root with the public and the medical Peter J Baxter
profession. Tar-Ching Aw
Readers turning to Hunter’s Diseases of Occupations for Anne Cockcroft
authoritative guidance on stress disorders arising out of
work will find the following three chapters covering the
topic from separate, but overlapping, angles: a review of REFERENCES
the evidence base, the reflections of a psychiatrist on the
psychosocial aspects and a clinical psychologist’s perspec- 1. Hayward R. Historical keywords: Stress. Lancet. 2005; 365:
tive on intervention. Stress at work manifests in many dif- 2001.
ferent ways, but occupational physicians should have little 2. Brotman DJ, Golden SH, Wittstein IS. The cardiovascular toll of
difficulty in recognizing the ‘work-stress victim’ described stress. Lancet. 2007; 370: 1089–100.
64
Work, stress and sickness absence: a psychosocial
perspective
The main aim of this chapter is to identify the cultural The theoretical perspective adopted here provides a general
and psychosocial influences on the illness behaviour of framework for understanding the arguments and explana-
employees with problems that manifest under the title of tions which are presented for the relationship between
‘work-related stress’. Much of the previous work on the work-stress and sickness absence. It draws, at least in part,
relationship between work and stress has tended either on cultural sociology3 as it focuses on the cultural construc-
to focus on the social epidemiological factors,1 which tion of the ‘epidemic’ of work stress and the creation of the
put workers at risk of stress-related ill health, or has social identity of the ‘work stress victim’. The argument
adopted a psychological approach and focused on the runs as follows: The ‘popular’ discourse of work stress sug-
personal characteristics of the worker and their influence gests that the labour process is being intensified and making
on the perception of threat and the ability to cope greater demands on the worker, which may lead to poor
(see Ref. 2). What appears to have been neglected is the mental and physical health. The apparent increases in strain
link between the two and how aspects of the structure of and tension across workplaces are claimed to be due to
the working environment to do with social relations changes in work characteristics, such as technological inno-
that affect health need to be incorporated into the psychi- vation, introduction of new managerial techniques, greater
atric assessment of the individual. This psychosocial per- job insecurity or increases in working hours. These changes
spective combines occupational psychiatry and medical in the organization and character of work are increasingly
sociology and anthropology and is illustrated with case conceptualized in terms of the ‘medical’ category of stress
examples. which emphasizes their consequences for the physical and
The discourse of work stress 805
mental health of the individual worker. There are essentially emotional and physiological manifestations. It not only
two strategies for addressing the work stress ‘epidemic’.3 provides a seemingly ‘scientific’ explanation of lived embod-
The first emphasizes strengthening the individual through ied experiences, it also offers a range of strategies for
stress management techniques and therapeutic interven- action: therapies and sick leave for some, exit from the
tions, such as counselling or medication. The second workplace through early retirement on medical grounds
focuses on job redesign as a means of reducing job strain, for others, and for a few the opportunity to seek financial
although even here the emphasis is still on health and safety redress through the courts.
at work.3 The adoption of the identity of a work-stress victim is a
The reaction to problems at work depends mainly on choice and thus the question is how far the discourse of
how employees interpret their experiences, and how they work stress which appears to dominate public debate about
decide to respond. However, employees do not make sense changes in work at the macro level has been taken on by
of their experiences in a vacuum, rather they make sense of workers at the micro level. Evidence from studies3 which
their personal experiences by relating them to a broader pat- explored the processes by which employees come to recog-
tern of assumptions and expectations. This broader pattern, nize adverse experiences at work as health problems and
according to Wainwright and Calnan,3 might be referred to the extent to which they turn to medicalized solutions for
as the ‘discourse of work stress’, and it acts almost as a guide dealing with these problems, suggest that the stress dis-
to action, or at least as a pre-existing framework within course is salient to workers (both men and women) when
which experiences can be made sense of and decisions about they are discussing adverse experiences at work, and that it
future action can be taken. The discourse of work stress is an is used to make sense of a wide range of experiences, from
informal body of social knowledge built on a mixture of lay low morale and low job satisfaction, through to embodied
experience, professional and academic opinion and media manifestations, including physiological signs and symp-
representations. It tends to reflect current social and struc- toms. Moreover, the assumption that workers passively
tural arrangements and is, therefore, historically specific.3 accept medical solutions, such as medication and coun-
This argument, however, has a further dimension in that it selling, was shown to be inaccurate and consultation was a
suggests that work stress is not entirely mediated at the level way of getting sickness absence rather than treatment (for
of consciousness or cognition.3 Over the life course, social example, Ref. 3).
experiences become embodied or as Wainwright and
Calnan propose ‘become written on the body’ in the form of . . . he (the doctor) said, ‘there are two ways of han-
learned emotional and physiological responses which can dling this, we can either give you some time off work,
later be triggered independently of conscious assessment. or, I can give you some medication, something to
Unaware that these reactions have been ‘learned’ since take.’ And I said, ‘I didn’t want to take anything,’ so he
childhood, it is taken for granted that they represent a ‘nat- signed me off work for a week. And he said; ‘come and
ural’ limit on the body’s capacity for endurance and see me in a week and we’ll see how it goes (p. 185).
resilience, further reinforcing the belief that work stress is
basically a biomedical reaction to the excessive demands And
and strains of working in the current cultural context.
The work-stress discourse can be interpreted as an the doctor was just a means to an end to get a sick note
example of the medicalization of a social problem,4,5 i.e. because I wasn’t fit enough to work. I didn’t feel that
that adverse experiences at work which were previously the doctor herself actually talked to me and helped me.
seen as political or industrial relations issues are increas- At the time I couldn’t continue to work (p. 181).
ingly falling into the domain of medical jurisdiction.
Medicalization operates at a number of different levels4–7 While some workers adhered to medical labels and fol-
with varying degrees of medical professional involvement. lowed an illness pathway which led to exit from the labour
The work-stress discourse provides a conceptual frame- market through early retirement on medical grounds,
work for defining and understanding the problem in med- others contested the medicalization process and resisted
ical terms. Yet this medicalization process may also be seeking professional medical help. The value attached to
evident at the institutional level where doctors can control personal resilience coupled with the reluctance to adopt
access to and legitimate sickness absence and benefits and the self-identity of a work stress ‘victim’ appears to be an
at the interactional level where they treat and diagnose important factor in determining resistance to the medical-
those who consult them for work-related problems. ization process (for example, Ref. 3):
There is a range of different approaches to medicaliza-
tion, but the more recent ones5,8 have emphasized the way Interviewer: How did you feel about going to the
medical discourse might influence self-identity in a posi- doctor with that kind of problem?
tive rather than a repressive way. Thus, the new self-
identity of the work-stress victim might offer an accessible Pathetic basically, you should be able to cope with
framework for making sense of and responding to, not just life, shouldn’t you, be stronger willed and get on with
adverse experiences at work, but what appear to be their everything (p. 183).
806 Work, stress and sickness absence: a psychosocial perspective
. . . you feel you’re letting yourself down because you on those whose problems appear so incapacitating that
haven’t been able to cope. You feel that you have an they are physically or mentally unable to carry on working
image that you have to maintain. I’ve told a few close and thus have little choice but to seek sickness absence.
friends and the rest you tend not to talk to about it However, the thesis of this chapter is that much work
(p. 183). stress-related sickness absence is a form of resistance,
when the employee, feeling weak and powerless in the face
A range of alternative strategies for addressing prob- of perceived oppressive managerial practices, begins to
lems at work was identified, including informal mecha- interpret their subjective emotional reaction in terms
nisms of support, ‘emotion work’ and informal relaxation of psychophysiological dysfunction and disorder. As
techniques. In a related study of arm pain,9 contrary to Fineman10 concludes (p. 126), resistance to organizational
expectations, informants rarely invoked work and its effect change arises from both the disruption of the moral/polit-
on them as a cause of their problems and as a consequence ical order that binds the employee to the organization and
did not always feel it was appropriate or possible to alert their from the apprehension and uncertainty caused to their
work colleagues and employers to their condition. Some sense of identity, security and self-worth. Sickness absence
of this reticence stemmed from a fear of being seen as a on the grounds of work-related stress is interpreted here
trouble maker and others, who felt unable to discuss their as an oblique form of resistance, a covert acting out of
condition at work, were more likely to feel this way because indignation and anger. This, as the previous theoretical
of the ‘age factor’: discussion suggested, is no easy or lightly taken option
given the moral imperative to be resilient, to be able to
I'm just very conscious of my age and I work with a lot cope and continue to work.
of young people, and I just don’t take time off of work We would argue that paradoxically the new identity
… I’ve got a TENS machine for my back and I sit and reinforced with a medical label (disorder or ‘syndrome’)
work with my TENS machine on (A1217). can become a strategic tool to redress the balance for those
employees who feel undervalued, exploited or discarded.
Why was there opposition or resistance to medicaliza- The quest for a diagnostic label and the performance of a
tion? Wainwright and Calnan3 suggest that the answer culturally standardized sequence of events and actions
seems to lie in the extent to which becoming a work- has the characteristics of a ‘culture-bound syndrome’.11
stress victim entails relinquishing control over one’s The necessary conditions for a culture-bound syndrome
mental life. Agency, or the ability to actively engage with are a specific configuration of social expectations and a
the world as a conscious actor, depends fundamentally template of how to behave when oppressed. Culture-
upon mental competence. To be unable to cope with the bound syndromes are local patterns of time-limited behav-
demands of a stressful job and to seek medical advice, is iour, specific to a particular culture, which while regarded
to give up one’s identity as an independent social actor as undesirable, have a problem-solving function for the
where being able to work is a fundamental part of social dislocated individual who is not held to be aware or
identity. The ability to cope with stressful life events responsible in the everyday sense (p. 290).12
without using medical therapy has traditionally been In the workplace, the employee who feels humiliated,
viewed as a positive personal trait, but the negative side whose dignity has been affronted or who feels that his
of valuing the capacity to withstand pressure is that those work is over-controlled, is denied what Scott calls ‘the
who fail to cope are stigmatized as weak or inadequate. ordinary luxury of negative reciprocity: trading a slap for a
Hence, the reluctance among the informants to change slap, an insult for an insult’ (p. 23).13 Being treated with
from being a person who is suffering work stress but cop- respect and dignity might be more important at work than
ing with the pressure, to someone who cannot cope with- financial reward (p. xii).13 When an individual is wronged
out clinical support. Thus, it is argued3 that for many by a person of inferior status they feel contempt, when the
experiencing work stress, the choice of consulting a doc- offender is of the same rank the victim becomes angry, but
tor or coping alone is still available and consultation when a person is treated badly by a superior they feel
remains something to be struggled against or lapsed into. bitterness and resentment,14 which can become the state
It also reflects the tension between the social benefits of chronic embitterment recently described by Tom
and disadvantages of the different statuses of ‘health’ and Sensky.15
‘illness’. In his monograph, Happiness and Unhappiness in the
Workplace, Warr14 has defined the key characteristics of
any job which lead to greater well-being and self-validation.
SICKNESS ABSENCE AS A FORM OF These include opportunities for personal control, skills
RESISTANCE use, variety, clarity of role, social interaction, status, sup-
port, security and equity, as well as amount of pay.16
This perspective on the construction of work stress and These ingredients are perceived to be lacking in the
the response to it will be used to frame the approach taken modern workplace, as in Franz Kafka’s description of a
here, although the emphasis is rather different as it focuses large open-plan office:
Susto and the sick role: a way out? 807
People were criss-crossing the middle of the floor, in ‘I would prefer not to’. ‘Nothing so aggravates an earnest
all directions, at great speed. No-one offered a person as a passive resistance … mortified as I was at his
greeting, greetings had been abolished, each one fell behaviour, and resolved as I had been to dismiss him when
into the tracks of the man ahead of him and kept his he entered my office, nevertheless I felt some superstitious
eyes on the floor, across which he walked to make as knocking at my heart, forbidding me to carry out my
rapid progress as possible (p. 34). purpose and denouncing me for a villain if I dared
Kafka17 to breathe one bitter word against this forlornest of
mankind’ (pp. 17–26).22
Employees’ complaints about stress often reflect feeling
undervalued and powerless within an organization.18
Subjective well-being is undermined by a perception of SUSTO AND THE SICK ROLE: A WAY OUT?
organizational injustice and where there is thought to be a
breach of the psychological contract. (This is defined as a set From a sociological perspective, the resort to sickness
of expectations specifying what the individual and the absence by employees with seemingly minor symptoms
employer expect to give and receive from each other in and distress is an example of both strategic manoeuvring
terms of rights, privileges, duties and obligations) (p. 149).19 and of illness behaviour. Taking sick leave is one of those
Pinder20 found that ‘systemic injustice’, i.e. the per- conditions identified by Robert Edgerton which are ‘cul-
ception of unfairness within the organizational context, turally recognized and named as brief periods during
tends to induce fear, resentment, hopelessness and sad- which the temporarily ill, intoxicated, bereaved or pos-
ness (p. 122). Anger and hatred towards superiors were sessed person is expected to behave in ways that would
common in employees who felt they had been treated ordinarily be prohibited’ (p. 49).23 In advanced industrial
unfairly, especially if there had been an element of public societies, being on sick leave starts off as a temporary status
humiliation (p. 123). ‘Employees who feel locked into which exempts people from their ordinary obligation of
their jobs have limited constructive means for dealing economic productivity (p. 6).23 When the powerless indi-
with their frustration and, as a result, are more likely to vidual is enmeshed in a situation that he cannot control,
resort to either aggression or displaced aggression in their the passive appeal of helplessness affords room for
jobs’ (p. 125). manoeuvre and negotiation with management.24
Pinder20 (p. 277) describes what job dissatisfaction feels As Brown25 has asserted (p. 39), ‘some people with the
like: ‘It often carries feelings of gloom and despair, some- same symptoms and conditions as others choose widely
times anger and resentment, sometimes futility’. He adds disparate ways of dealing with their symptoms or condi-
that ‘withdrawal in response to job dissatisfaction can take tions’. Susto is an example of the well-known ‘sick role’ as
the form of tardiness, absenteeism and turnover, as well as defined by Parsons and Fox26 which provides a socially
passive compliance and minimal effort’ (p. 278) and that sanctioned exemption from the challenge of everyday
the ‘perception of unfair or unjust treatment by employers responsibility and which is fashioned in accordance with
is a major cause of theft, sabotage, violence at work, absen- the ‘dominant social elements of medical knowledge’
teeism and lateness’ (p. 313). (p. 37).25 As with stress in the West, susto is a culturally
When the subordinate takes sick leave because of a shaped idiom of distress.27 Medical anthropology recog-
breach of the psychological contract, they might be adopt- nizes that bodily and psychological complaints are used as
ing a political strategy to redress the imbalance in the metaphors of personal, social or occupational stress,
power relationship between employer and employee, by ‘which give the sufferer a little more leverage in negotiating
embodying a ‘hidden transcript of the weak’ (p. xii),13 for a less difficult work situation …’ (p. 27).27 Sometimes
which covertly expresses their resentment and frustration’. these temporary conditions can become long term, and
‘Oh my Lord’, he thought, ‘If only I didn’t have to follow evolve into eligibility for incapacity benefits and eventually
such an exhausting profession! On the road, day in, day early retirement on the grounds of ill health.
out. The work is so much more strenuous than it would be Among the Zapotec of the Oaxaca Valley of Mexico,
in head office, and then there’s the additional ordeal of susto (‘fright sickness’)28 exempts the afflicted person from
travelling, worries about train connections, the irregular onerous duties for a limited period of time, before resump-
meals, bad food, new people all the time, no continuity, no tion of normal responsibilities. The ‘clinical presentation’
affection. Devil take it!’ (p. 88).21 of susto includes unrefreshing sleep, low mood, lack of
Historically, subordinates have disguised their resentful drive, energy and motivation, poor appetite and neglecting
opposition by resorting to tactics such as foot-dragging one’s appearance, together with feeling overwhelmed
and dissimulation which Scott describes as the ‘infrapoli- by routine tasks and non-specific aches and pains. This
tics of the powerless’ (p.xiii),13 ‘a substitute for an act of amalgam of complaints is found throughout rural Latin
assertion directly in the face of power’ (p. 155).13 America and is attributed to ‘soul loss’ in which the
In his novella about Bartleby, the indolent scrivener, person’s spiritual element departs from their body.29 The
Herman Melville describes the predicament of the benign victim has generally felt powerless and trapped in a stress-
employer in the face of his employee’s repeated refrain: ful situation where they cannot meet social or personal
808 Work, stress and sickness absence: a psychosocial perspective
obligations. Susto provides a socially respectable escape tree spirits. These vengeful spirits were now possessing and
hatch from intolerable circumstances, by affording respite punishing the factory workers.
from normal social responsibilities. Some possession cases proved to be refractory to
Becoming an asustado appears to be a more or less con- priestly intervention and so company medical officers were
scious choice. Its potency in mobilizing privileges derives invited to examine the afflicted workers. They made a diag-
from the folk belief that susto, like hypertension and even nosis of mass hysteria and prescribed psychiatric drugs,
stress in the West, is potentially fatal.30 The status of asus- mainly benzodiazepine tranquillizers. These biomedical
tado is arrived at through group negotiation, with cues interventions were only partially effective and some of the
provided by neighbours. Entitlement is sometimes chal- possessed women, after further episodes, were dismissed
lenged because not all temporary conditions that have the on medical grounds and returned to their villages.
potential to provide exemption actually have clear criteria In a foreign-owned factory in Malacca manufacturing
for entitlement and the claim for exemption has to be trainers, there were 40 outbreaks of ‘mass hysteria’ in
negotiated (p. 49).23 As Edgerton points out (p. 74), 1977–78 among poorly educated, badly paid female work-
exempting conditions such as grief, illness, intoxication ers.33 The hysterical behaviour included convulsions,
and spirit possession ‘can be readily exaggerated, pro- aggression and apparent loss of consciousness. This behav-
longed or faked altogether’. He asks, ‘Was someone really iour was attributed by the employees to spirit possession
possessed, truly drunk, honestly grief-stricken?’ In our due to violation of moral codes. Management labelled this
society, a sceptical benefits gate-keeper might ask, ‘Is this as ‘hysteria due to superstition’. Again they encouraged
person genuinely sick and disabled?’ or is this a case of local traditional healers to carry out exorcisms at the fac-
‘strategic opportunism?’ (p. 53).23 tory water tanks. Private interviews with an anthropologist
revealed a number of grievances: resentment about low
wages, lack of subsidies for bus fares, strict and closely
WORK STRESS AS A CULTURE-BOUND supervised work regimes, restricted leave and alleged
SYNDROME harassment by male supervisors. The women expressed
feelings of powerlessness, exploitation and job insecurity.
The culture-bound nature of workplace stress reactions is Their wish to join a union had been thwarted.
illustrated by the epidemic of possession states described in In both cases, the Malay cultural disapproval of open
Malaysian factories in the 1970s. display of anger prevented these workers from verbalizing
In one ethnographic account,31 foreign-owned electron- their grievances and their resistance to management took
ics factories enlisted single Muslim women from village com- an oblique form.34
munities. They lived in hostels at some distance from their Chew35 who was director of the industrial health
rural homes. These young women were closely supervised on department in the Ministry of Labour in Singapore dis-
the factory floor by male managers from a different ethnic cusses the management of outbreaks of hysteria among
background. Their electronic assembly work was repetitive factory workers in Malaysia. ‘These mass hysteria episodes
and monotonous and caused eye strain. The employees were were treated like an epidemic disease of bacteriological
motivated to work in these factories by the prospect of earn- origin. (p. 50)’ Control of contagion was attempted by iso-
ing enough money to send to their families and to pay for lating the identifiable cases from the general factory popu-
their own further education. This was an attractive alterna- lation and injecting them with chlorpromazine. Isolation
tive career to traditional arduous physical labour in the rice was required since they were considered to be ‘infectious’.
fields. However, despite the attraction of regular wages and a It was recognized that psychological factors were impor-
degree of independence from the constraints of traditional tant and it was also concluded that as a long-term preven-
village life, there were sporadic outbreaks of possession. tative measure ‘a key factor seems to be education and
These dramatic, but generally short-lived, episodes were raising the level of immunity in the susceptible community
characterized by sudden screaming and falling to the ground by “inculcating” the right notions and giving basic facts to
with violent convulsive movements. eliminate superstitious beliefs’ (p. 53).35 There is no refer-
A common theme was having a vision, while in the lava- ence to conflict in the workplace. In this public health
tory and especially when menstruating, of a Tamil male approach which was based on the principles of containing
supervisor peering at the employee (both the toilet zone a microbial epidemic, tranquillizers were administered to
and menstruation are liminal and associated with pollu- control the activity of the disease in the victims.
tion).32 Several fellow workers would typically then see the In Ackerman and Lee’s study33 of a spirit possession event
same vision, collapse and make violent movements with at a shoe factory in Malaysia, the authors emphasize the fac-
their limbs. Work on the assembly line would be halted tory’s policy of strong anti-unionism. The managing director
and production targets sabotaged. had instructed management to listen for rumblings of dis-
At first, management called in bomohs, traditional content and indications of collective organization among the
healers, to exorcise the possessing spirit. The local interpre- workers, whose leaders were to be identified and dismissed
tation of these bouts was that the factories had been built immediately to deter any would-be organizers. They describe
on virgin forest land which had offended and displaced episodes of violent convulsions, loss of consciousness,
Benign surveillance 809
incoherent mumblings and aggressive behaviour among ● Malaise due to the demands of working in an electronic
groups of Malay female workers which were interpreted as assembly plant and a shoe factory provoking a sequence
spirit possession. Fellow workers attempted to hold them of ‘symptoms’ followed by traditional folk labelling and
down, applying cooling agents to their foreheads and accom- exorcism has parallels in the West, where the therapeu-
panying them home after they had calmed down. Other tic quest for relief from work-induced medically unex-
workers were afraid to approach them in case the behaviour plained symptoms often shifts from the biomedical
was contagious. The afflicted workers were all female. The to New Age methods: acupuncture, reiki, bioenergy,
managers had few complaints about the female production amygdala retraining, ‘healing’, Chinese herbal medica-
workers’ job performance and discipline, but the male tion, multivitamins, reflexology, natural food remedies,
workers presented continual problems of insubordination Light Bath, vibration therapy, geodetic force analysis,
and theft. Management were perplexed by the outbreaks of massage and cranial osteopathy.
possession and did not hold these women workers respon-
sible for their disruptive behaviour which on occasion led
to the closure of the factory. The authors elicited antago- BENIGN SURVEILLANCE
nism towards management and both male and female
workers’ dissatisfaction with the incentive system and work The tension between productivity and employees’ subjec-
conditions, but this antagonism was not perceived by tive well-being has been a core issue of industrial psychol-
either the workers or the management as a significant causal ogy and psychiatry since the early twentieth century.40
factor in the occurrence of possession. Thus, the assumed ‘Alex’, the Daily Telegraph business pages strip cartoon
supernatural influences in the factory were not explicitly for July 28, 2008, provides a good example of the stress
linked with the workers’ grievances, i.e. the outbreaks of discourse. A senior executive at Megabank asks the bank’s
mass spirit possession and the resentment of the workers stress counsellor if anybody from his department has con-
were perceived as two unrelated domains.33 sulted him recently. The stress counsellor replies that
From the perspective of medical anthropology, these although his services are paid for by the bank, the names of
outbreaks of possession in factories in the industrializing the employees who consult him and the matters discussed
world can be interpreted as follows: have to remain strictly confidential. The executive replies,
‘But I have decisions to make about the running of my
● As with other culture-bound syndromes,36 the stylized department and I need to be forewarned if any of my team
behaviour has a shared meaning which articulates a is cracking up or losing the plot …’. He adds, ‘I mean
personal predicament and represents a conflict, in this I wouldn’t want to fire a guy and waste a payoff on him if
case the opposition between employer and employee. he was already planning to quit …’. The stress counsellor
● The culturally shaped resistance to pressure from man- refuses to breach professional confidentiality and a day or
agers has both a personal expressive meaning for the two later he himself is made redundant.
individual and an instrumental function. Close surveillance in the workplace is familiar in the
● The resistance draws on locally available beliefs in West40 and even extends to toilet breaks. Thus, Gillian
possession which mainly afflicts non-dominant people, Howard in the Law Society Manual on drafting employ-
i.e. women of low status. As in other situations of frus- ment contracts writes, ‘When you take lavatory breaks
tration, ‘the principal is able to adjust his or her situation during the course of your working day, you are required to
by recourse to mystical pressure’.37 ‘Such spiritual afflic- report to central office at the time of starting and finishing
tions … are to be found in circumstances where other the break. This is required for safety reasons so that man-
secular means of ventilating grievances or pursuing vital agement knows where you can be located in the case of any
interests are blocked, or very restricted’ (p. 89).38 This emergency or safety issue’ (p. 127).41 According to an
sideways recourse to transcendental action mobilizes the American Postal Workers’ Union official, supervisors have
‘power of the weak’,39 invoking supernatural (or bio- the right to order emergency psychiatric examinations for
medical) pressure which permits personal adjustment of employees who have ‘increased bathroom use’ or become
the situation and reduces frustration. ‘argumentative’.42 In these cases, the surveillance aspect is
● Possession tends to occur during a visit to the factory mitigated by the expressed concern for health and safety.
lavatory. This is a liminal place invested with potency Psychological interpretations of sickness absence have
because of the contrast between purity and dirt. A inspired a number of management solutions over the past
woman’s vulnerability in the toilet is enhanced if she is 100 years or so.40 These approaches have attempted to
menstruating which is also associated with notions of work on the subjective experience of the private self, i.e. to
pollution and danger. socially organize and manage thoughts. Under the French
● Furthermore, the recurrent theme of being spied on by insurance company AXA’s ‘My Budget Day’ initiative,
hallucinated foreign male apparitions reflects the sub- employees are given an hour off during a working day to
ordinate position of the female workers who are under check their financial planning and use the company’s web-
close surveillance by male supervisors of a different site to contact brokers, consultants and advisers to develop
ethnicity. personal budget plans. The scheme was introduced by
810 Work, stress and sickness absence: a psychosocial perspective
AXA to improve relations with staff and to raise morale. dissatisfaction (pp. 14–15).49 Psychological and psychoso-
The programme, interestingly, also helps managers to matic ‘symptoms’ develop as a reaction to a taxing social
check whether money worries are affecting staff (the group environment, such as problems in the workplace, but
human resources director describes the scheme as an these symptoms are often appropriate flight or fight
employer’s financial web-based ‘health check tool’). This responses of the autonomic nervous system to challenge or
initiative is included in the employee’s benefit programme threat, rather than evidence of specific disease entities or
(Daily Telegraph Business, Appointments section October of an underlying mental disorder (p. 14).47 Psychological
30, 2008, https://mybudgetday.axa.co.uk). symptoms of distress overlap across many diagnoses and lie
The programme has helped morale and reduced absen- on a spectrum of abnormality. As Kirmayer50 writes
teeism and staff turnover and managers have reported an (p. 331), ‘Some milder forms of distress are coterminous
improvement in performance when employees were less with everyday emotions …’. Anxiety is on a continuum
worried about their personal finances. After the ‘My with worry and apprehension, and depression merges with
Budget Day’ in 2007, employee turnover rates fell from grief and a sense of loss. It can be difficult to distinguish
12.8 to 11 per cent, while absenteeism which AXA uses as a demoralization from depression. Demoralization often
‘stress indicator’, fell by 10 per cent to just over 3 per cent. stems from lack of a sense of personal control in jobs where
there is close supervision, reduced autonomy and little
participation in decision-making (pp. 184–5).51
DEFINING ENTITLEMENT Entitlement can be falsely claimed. ‘Someone skilled at
strategic manipulation of the rules may successfully exag-
The sick role concept has long been criticized for having gerate the extent to which he is ill, emotionally distressed or
limited explanatory power for accounting for the social intoxicated in order to claim the exemptions from respon-
position of chronically sick people as it applies mainly to sibility that these conditions provide’ (p. 53).23 Psychiatric
acute, physical short-term illness. Of more relevance is the labels are a readily available source of mitigation and excul-
way it might be used to control deviance by providing a set pation.52 Clinical decisions about the presence of psychi-
of rules, responsibilities and obligations which circum- atric disorder are somewhat subjective and are prone to
scribe eligibility and access. influence by the social context, despite the ‘technical
The Employment Appeals Tribunal in the case of rationality of the standard diagnostic systems’ (p. 220).53
Morgan v Staffordshire University furnished practical
guidance on the type of evidence needed to ‘prove’ that an
individual is suffering from a mental impairment. For Case 1
organizational and legal purposes, ‘stress’ is often too neb-
ulous a concept and there is a requirement to produce a A commercial property surveyor threatened a colleague in
more focused diagnosis using WHO ICD-10 categories their office whom he suspected of making suggestive
(Morgan v Staffordshire University43 cited in D’Auria remarks to his girlfriend. He stormed out of the office,
et al;44 see also Jamdar and Byford45). called at his doctor’s surgery on his way home and was
A diagnosis involves reified definitions of disease into given a certificate for ‘work-related stress’. Subsequently, a
which professionals fit their observations. This implies private psychiatrist submitted a report that he was suffer-
legal endorsement for medically ‘organizing’ a mishmash ing from mixed anxiety and depressive disorder (ICD-10,
of disparate feelings, emotions and complaints to create F41.2)54 and was not fit to attend a disciplinary hearing. It
a coherent entity46 by a process of mapping reported was this specialist’s opinion that his patient was ‘unlikely to
symptoms onto available cultural models of illness and recover from his anxiety with depression unless the disci-
healing.47,48 As Brown observes ‘… physicians are con- plinary charges are withdrawn’.
fronted with what is often an “unorganized illness” and a
conglomeration of complaints and symptoms which may
be unclear, unconnected and mysterious. Their job is to INCAPACITY BENEFIT CLAIMS
understand and interpret that material in order to arrive at AND SICK NOTES
an “organized” illness’ (p. 39).25
However, although employment tribunals require Doctors are more minded to provide certificates to
specific medical diagnoses, categorical diagnostic classifica- patients with a psychological problem.55 The Health and
tions such as depressive disorder or anxiety states obscure Safety Executive has reported that work-related stress is now
the cultural shaping of symptoms. As Horwitz49 points out, the most common cause of working days lost as a result of
the basic assumption of the diagnostic framework is that the occupational injury and ill health.56 The American anthro-
presence of sufficient particular symptoms, regardless of pologist, Allan Young, has commented that, ‘When faced
their cause, indicates an underlying disease. In reality, dis- with a diagnosis for which he has equally convincing rea-
tress takes the form of generalized and non-specific symp- sons to believe that either his client is sick or he is not sick,
toms which reflect expected reactions to challenging the physician finds that the professional and legal risks are
situations, unhappiness, frustration, demoralization and less if he accepts the hypothesis of sickness’ (p. 15).57
Adverse workplace events and trauma 811
Doctors have acted as gate-keepers to the benefit system which the patient enacts a pas de deux with the doctor’
since the 1911 National Insurance Act. They control access (p. 316),12 such as requests for sick notes on the grounds of
to the Department for Work and Pensions.58,59 Sick leave is work-related stress.
discussed with between one and six patients per doctor ses- Employers might suspend the disciplinary hearing
sion,60 but only a proportion may be regarded as genuinely because of fear of litigation and failure in their duty of care.
unfit for work on medical grounds.61 Family practitioners In the case of Deadman v Bristol City Council,66 the Court
find consultations about sick notes problematic because of of Appeal decided that an employer is liable for stress
the threat to the doctor–patient relationship from a per- caused to the employee during a grievance or disciplinary
ceived conflict of roles and a suspicion that patients will investigation if it is reasonably foreseeable that the investi-
‘doctor-shop’ to obtain a sick note. Doctors might feel gation might cause personal injury (Howard, personal
coerced into writing sick notes.62 Many doctors issue cer- communication, 2008).
tificates on demand, either on the grounds of speed or of Nevertheless, in most cases, employees should be able to
acting as the patient’s advocate,63 believing that their participate in disciplinary hearings, unless they are effec-
responsibilities to the Department for Work and Pensions tively unfit to plead. Fitness to attend disciplinary hearing
are outweighed by their commitment to their patient. requires answers to the following questions which are
In a qualitative study of 19 primary care patients’ per- based on standard fitness to plead criteria:
spective in South Wales, there was an expressed need to
prove that they were genuinely disabled. This validation of ● Does the employee have the ability to understand the
their sick role was required for work, for family and for allegations made against him or her?
their community.64 Only a quarter of the 19 participants ● Does the employee have the ability to distinguish right
wanted a passive role in the decision-making process, i.e. from wrong?
‘the doctor knows best’, while an equal number said they ● Is the employee able to instruct a friend or a lawyer to
would not work regardless of the doctor’s opinion. The represent their interests?
remainder were less committed to the sick role. ● Does the employee have the ability to understand and
A study of sickness certification by 67 doctors in follow the proceedings, if necessary with extra time and
Scotland63 found that the system was largely patient-led written explanation?
and most of them wanted a ‘sick certificate on demand
system’ (p. 91).63 The doctors themselves showed resist- It is recognized that a protracted delay in attending a
ance to participation in a perceived flawed bureaucratic disciplinary hearing is likely to increase the probability of a
system. ‘There seemed to be a code or language of sick lines normal reaction to stressful events (anxiety, low mood,
developed by general practitioners’ which fulfilled three insomnia and diminished concentration) becoming more
purposes: to preserve patient confidentiality, to communi- severe (Staley, personal communication, 2009).
cate with other agencies, and to deliberately misuse or If necessary the hearing can be held at a neutral location
sabotage the system by the use of vague diagnoses. or the employee can provide written submissions to be
Participants described writing “malaise”, “debility”, and considered in their absence or send their representative
TALOIA (“there’s a lot of it about”), producing meaning- to speak for them or ask their representative to read out
less statistics’ (p. 89).63 The authors comment that the their statements. Alternatively, they could attend a tele-
gate-keeping role is effectively sabotaged by the strategy of phone or video conference from their home with the
acquiescence to every patient. Doctors do not wish to jeop- hearing taking place in the office (Howard, personal
ardize the doctor–patient relationship by confronting communication, 2008).
patients over sick note requests (p. 89).63
The chief medical officer to the Department for
Work and Pensions has challenged the view that doctors ADVERSE WORKPLACE EVENTS AND TRAUMA
‘should simply accede to the patient’s wishes without any
negotiation’ (p. 461).65 Fraudulent or exaggerated claims to be suffering from an
exemption condition are only likely to be successful when
there are widespread examples of genuine disability to act as
FITNESS TO ATTEND DISCIPLINARY HEARINGS a template.67 Post-traumatic stress disorder (PTSD) is a
well-known model which provides the litigant with a spe-
Medical support for a claim of unfitness on mental health cific incident as the cause of emotional distress (see Ref. 68,
grounds to attend a disciplinary hearing is not uncommon. for incontrovertible work-related examples). Alexander lists
‘Withdrawal from everyday social responsibilities is made the circumstances which foster the inclusion of ‘imaginary
socially acceptable through some means of exculpation and/or deceitful’ complaints in the illness category.69 These
usually through mechanisms of biophysical determinism’ include ‘monetary gain from disability insurance, work-
(p. 298).12 ‘The mystical power of biomedicine as “external” men’s compensation, private medical insurance and litiga-
justification for individual action, and the negotiated tion; interpersonal gain – sympathy, attention, assurance of
“space” it affords seem relevant to those other situations in personal importance, excuse for inept or unsuccessful
812 Work, stress and sickness absence: a psychosocial perspective
It is a mistake to conceptualize normality and mental For the anthropologist and psychiatrist Arthur
illness as dichotomous, i.e. as states of mind which are not Kleinman, the increasing articulation of life problems as
distributed along a continuum. ‘Depression’ is a pervasive mental health conditions leads to a ‘misguided search for
term which is applied to a variety of states of unhappiness magic bullets for complex social problems’ (p. 38).27
and misery, including grief at a loss, demoralization, frustra- Kleinman also refers to the ideological influence of the
tion, low self-esteem, disillusionment and finally a depres- modern medical scientific and technological programme
sive illness which is assumed to have a biological basis. which tends to convert suffering into a technical problem:
In terms of DSM-IV, a distressed individual achieves ‘Suffering is “euphemized” and distress is “medicalized” as
‘caseness’ if they experience more than the minimum num- a psychiatric condition, thereby transforming an inher-
ber of symptoms in specific categories. The arbitrary nature ently moral category into a technical one’ (p. 35). He adds
of this diagnostic system is most apparent in the distinction that psychiatric diagnostic systems provide far-reaching
between a severe reaction to bereavement and depressive administrative and legal definitions of ‘what is a problem
illness. As Arthur Kleinman shows in Rethinking psychiatry: and how it should be treated’ (p. 39).27
From cultural category to personal experience,77 ‘An anthro- In their critique of DSM-III and its successors, Kirk and
pological sensibility regarding the cultural assumptions and Kutchins53 write, ‘The precise nature of a client’s trouble is
social uses of the diagnostic process can be an effective frequently ambiguous, its causes obscured by a lifetime
check on its potential misuses and abuses’ (p. 17). of personal experiences, environmental stresses and
The widespread belief that depression is under- psychological confusion’ (p. 226).53 However, psychiatrists
recognized at the primary care level (prompted by the may feel compelled to construe suffering in terms of a
Royal Colleges of Psychiatrists and General Practitioners distinct nosological category rather than an existential
Defeat Depression Campaign)78 has led doctors to pre- response.
scribe more readily. However, there is now evidence that The symptoms of depression, of anxiety and of post-
there is almost no difference between the effects of drug traumatic stress disorder are mostly subjective and they
treatment and placebo at moderate levels of depression.79 can be recited in a checklist fashion in the context of
As a study of psychiatric drug advertisements has sickness absence, disciplinary hearings, applications for
shown, advertisements tend to individualize negative reac- early retirement and litigation for compensation. These
tions to the workplace by ignoring the situation which pro- conditions are now amazingly common, with one in six of
voked the distress.80 Messages in these advertisements the adult population of the United Kingdom currently
reinforce the view of distress that there must be pathology suffering from ‘crippling depression’ and chronic anxiety,
within the individual. The advertisements imply that the according to the Depression Report published by the
work context is either irrelevant or is an unchangeable sit- London School of Economics, Centre for Economic
uation to which the afflicted person must accommodate. Performance.83 One million people are in receipt of inca-
Psychotropic medication is presented as the panacea for pacity benefit because of mental illness, which accounts for
the problems of adjustment to a stressful work environ- 40 per cent of all disability, both physical and mental.83
ment.80 Moving emotional distress out of the context of According to this report, poverty is a less significant cause
work and into the employee’s neurochemistry diverts of unhappiness than mental health problems. To address
attention from factors in the workplace that might require this problem, the proposed expanded psychological ther-
challenge and alteration. With the current emphasis on apy service requires an extra 10 000 therapists to treat
cognitive-behavioural therapy as an alternative cure-all, 800 000 people a year.
the identification of ‘faulty cognitions’ and ‘dysfunctional There is an increasing tendency for the normal and
attitudes’ can amplify the ‘decontextualization’ described expectable consequences of stressful circumstances, which
by Kleinman and Cohen80 so that a person’s problems are include low mood and worry, and which are a universal
defined as internal rather than external, individual rather response to unpleasant situations, to be defined as mental
than environmental, ‘psycho’ rather than ‘social’, with the illness. A low threshold for diagnosing clinical depression
option of adding antidepressants as a ‘bio’ solution if both leads to the labelling of normal emotional states as illness.
belt and braces are required.81 As Parker points out, ‘The gravitas of the term “major
Adjustment disorder is a disputed diagnosis because of depression” gave it a cachet with clinicians … and helped
the blurred distinction between the varied manifestations of patients get medical insurance cover’ (p. 328).84
adjustment disorder and normal adaptive reactions.82 Regier et al.85 warn that patients might receive a label of
Casey et al. point out that ‘transient depressive responses to depression when in fact they are having ‘appropriate home-
stressful events are increasingly regarded as illness requiring ostatic responses which are neither pathological nor in need
specific intervention’. Furthermore, ‘a low threshold for of treatment’. For Crossley,86 ‘Mental distress is predefined
making a diagnosis of depression propels an individual in western culture by the discourses of psychiatry whose
towards a specific therapeutic approach. Distress and disor- reach has extended beyond the realms of professional
der remain conflated in clinical practice, and among the cliques into the domains of everyday discourse. Psychiatric
research communities we continue to medicalize the emo- schemas and practices enjoy widely taken-for-granted
tional vagaries of the human condition’ (p. 480). status. As such, they shape perceptions/conceptions of the
814 Work, stress and sickness absence: a psychosocial perspective
lay public, some of whom will experience psychological dif- not from a myriad other sources encountered in life’
ficulties first hand in relation to either self or significant (p. 85).90 Dr Henry Field has written that it is virtually
others and may thus categorize self and others from the impossible nowadays to study a medicolegal report prepared
psychiatric point of view (p. 162).’ by a psychiatrist or psychologist instructed on behalf of the
In theory, to qualify for ‘caseness’, these psychological dif- plaintiff in personal injury litigation where it is not con-
ficulties have to be disproportionate to the trigger in terms of cluded that he or she is suffering from PTSD.91
intensity and duration after the causative stressors have dis- The fact that litigation might be based on a trivial inci-
appeared, but as Horwitz points out (p. 31):49 ‘disproportion dent is an affront to the survivors of truly horrific experi-
can only be defined according to social judgements of the ences, such as rape, torture or terrorist attacks. DSM-IV
normal range of responses to various stressors in particular rightly requires the victim to have experienced intense
contexts’. In practice, the widespread use of psychiatric horror, fear or helplessness in a life-threatening incident
nomenclature to describe common reactions to personal and any allegedly traumatic event that does not meet this
problems in specific social contexts has contributed to the criterion must be discounted. In the occupational health
escalating number of people claiming incapacity benefits on setting, one meets employees who claim to be suffering
the grounds of stress-related illness. The ready availability of from intrusive imagery, avoidance behaviour and symp-
these scientific-sounding diagnostic categories (which neces- toms of autonomic arousal in the absence of a single acute
sarily lack confirmatory laboratory and imaging evidence) overwhelming life-threatening trauma.48
contributes to ‘the technological process of transforming a The possibility of benefits or of compensation can
person with an ambiguous complaint into a client with a have a pathoplastic effect after relatively minor injuries or
defined mental disorder’ (p. 222).51 disabilities. Allan Young in Harmony of illusions (p. 17)92
Furedi87 describes the pervasive influence of the thera- cites Herbert Page, consulting physician to the London and
peutic culture, and the ever-expanding medicalization of Western Railway Company whose monograph on railway
adverse emotional experience, while Dalrymple laments accidents identified a proportion of victims with minimal
the replacement of the concept of unhappiness in modern or invisible injuries whose recovery is retarded: ‘The
life by the word ‘depression’. ‘Of the thousands of patients knowledge of compensation … seems almost from the first
I have seen, only two or three have ever claimed to be moment of illness to colour the course and aspect of the
unhappy, all the rest have said they were depressed. This case, with each successive day to become part and parcel of
shift is deeply significant, for it implies that dissatisfaction the injury in the patient’s mind, and unwittingly to affect
with life is itself pathological, a medical condition, which it his feelings towards and his impressions of the sufferings
is the responsibility of the doctor to alleviate by medical he must undergo …’ (pp. 255–6, 261).93,94
means … A marvellous pas de deux between doctor and
patient ensues: the patient pretends to be ill and the doctor
pretends to cure him (p. 9).’88 Case 4
In the encounter between client and traditional healer
in francophone creole society, the patient resorts to an A bus driver who had been rebuked by his line manager
explanatory system which absolves him of personal threatened to deliberately crash his vehicle. He claimed
responsibility by identifying an external cause for his bad that he was suffering from PTSD after seeing a friend being
behaviour. The anthropologist Massé questions whether decapitated by a roadside bombing in Iraq. It transpired
the afflicted person is ‘lying’ when he proposes to the that he had never actually served in a war zone.
healer that he is the victim of a hostile spirit, while the The diagnostic entity of PTSD was invented in 1980 by
highly paid quimboiseur actively colludes with this miti- advocates for veterans of the war in Vietnam working
gating interpretation.89 As Kirmayer50 writes (p. 335), with anti-war psychiatrists. Ben Shephard, the military
‘The microdynamics of the negotiated encounter of historian, rebukes psychiatrists for medicalizing the
patient and practitioner are embedded in larger political human response to stressful situations and for creating
and economic systems that sanction some forms of dis- a culture of trauma which is undermining resilience
tress while others are punished, suppressed or even made (p. 57).95 Shephard decries the unitary concept of trauma
unthinkable’. which groups together under a common label a very wide
range of stressors. ‘Any unit of classification that simulta-
neously encompasses the experience of surviving
POST-TRAUMATIC STRESS DISORDER Auschwitz and that of being told rude jokes at work must,
by any reasonable lay standard, be a nonsense, a patent
The choice of the diagnosis of post-traumatic stress disorder absurdity’ (p. 57).95
(PTSD) as a cause of emotional distress has strategic advan- In a comprehensive review of the unreliability of the
tages over the diagnosis of depression. With depression PTSD diagnosis, Rosen and Davison warn about the trivi-
there may be a series of causes for the individual’s distress, alization of PTSD by ‘criterion creep’, the fallibility of self-
whereas the diagnosis of PTSD implies that all the litigant’s reporting in the context of litigation, the routine use of
psychological problems arise from one specific incident ‘and checklists and of coaching by legal advisers, and ‘parroting’
Work overload, distress and sickness absence 815
as yet’. The non-medical obstacles to his return to work had diagnosis of depression and he was prescribed various
not yet been addressed and he continued to experience antidepressants and saw three different psychiatrists. He
understandable feelings of apprehension, worry and uncer- was reluctant to return to his job. A professional mediator
tainty about his future with some loss of self-confidence, attempted to work out a reconciliation, but it emerged
pessimism and distractibility because of the challenging that there was a financial disincentive to return to work
prospect of finding a new job in the present economic and the company was not prepared to take him back until
climate. his doctor reported that he was completely symptom-free.
By that time, he was taking out a compensation claim
against his employer for causing his work stress-related
COUNSELLING IS NOT A SUBSTITUTE FOR illness. The principal precipitating and maintaining
MEDIATION factors were his grievance against his employers. He felt
overwhelmed by anger and resentment, but his doctor
It is important not to medicalize these common emotions described him as suffering from anxiety with depression.
and attitudes which are entirely understandable in the cir- He was referred for cognitive-behavioural therapy, but the
cumstances of work overload but which do not in them- therapist felt that because of the unresolved conflict with
selves constitute a disease. Furthermore, it is essential to his employer he would not be able to return to work for
address the causative problems in the workplace and the the foreseeable future. (Organizational injustice increases
provision of personal counselling is not a legally sanctioned the effects of psychosocial health risks on sickness
substitute for this. absence.105) He became entrenched in the sick role and
both he and his medical advisers interpreted his frustra-
tion and anger in medical terms. He consulted his solicitor
Case 8 who felt that following the case of Barlow v Borough of
Broxbourne,106 he would find it difficult to establish that
Mrs Daw was a pay roll integration analyst with 13 years of the employer had been in breach of its duty to take reason-
outstanding service, employed by Intel. She developed a able care to ensure that he did not suffer psychiatric injury
depressive illness which was attributed to her excessive as a result of work-related stress, because it had not been
workload. Her reporting lines were confused and it was foreseeable that he would suffer such an injury. He had
difficult to prioritize the demands of her different man- previously coped perfectly well with his workload, the
agers. She eventually won an award for personal injury instances of swearing were not numerous and he had
caused by stress at work, but her employer appealed on the never reported ‘symptoms of stress’ and had not used the
grounds that she had failed to use their external confiden- employer’s counselling service.
tial counselling facility. The Court of Appeal103 concluded
that the counselling would not have attenuated the risk of
her breakdown since it would not have reduced her work- RESENTMENT AND SICKNESS ABSENCE
load, which was the only way the employer could provide a
safe working environment. The Court of Appeal held that The interpretations that employees make of their working
the provision of counselling was no substitute for putting conditions have a crucial role in determining psychological
in place measures to reduce Mrs Daw’s workload (Howard, well-being.107,108
personal communication, 2008).
Case 10
INCIVILITY IN THE WORKPLACE
A middle-aged executive had a very public falling out with
The targets of incivility often feel alienated and become less her chief executive officer. She went off sick with a diagno-
committed to the employing organization.104 sis of stress-induced depression. She was noted to have loss
of self-esteem combined with anger and resentment at the
way she had been treated. Her doctor elicited mild depres-
Case 9 sive symptoms, but over the following months she devel-
oped fatigue and lack of physical and mental energy.
A plumber went off sick from work with ‘stress-related She had a long course of acupuncture with a Chinese med-
depression’ after finding that his managers were giving icine practitioner, who had identified a weak pulse and
him more work than he could cope with and imposing prescribed adrenal gland extract. She had also had reiki
unrealistic deadlines. He had been rebuked by his line healing, reflexology and cranial osteopathy. This individ-
manager who had sworn at him in front of colleagues. ual had excellent qualifications and an outstanding profes-
He presented to his doctor with feelings of humiliation, sional track record, but so far no attempt had been made
anger and ideas of taking revenge. The doctor made a to encourage her to resume her career with another
Government policy on incapacity benefit and getting back to work 817
employer. There was no objective evidence that she had When employees return to work they are given a care-
been treated unfairly and her perception that she had been fully graded re-entry and are provided with support and
victimized would be insufficient for successful litigation on regular two-way appraisals focusing on the employee’s
the grounds of work-related stress, since the judgement in adjustment and their work priorities. The incidence of
Ian Richard Paterson v Surrey Police Authority.109 In that work-related psychological ill health was reduced by 63 per
case of a demoralized estate manager, the court concluded cent over the three years following the introduction of this
that the cause of his anxiety and depression was how he programme. This innovative round-table approach is in
considered that he had been treated by his employer, rather line with the Institute for Employment Studies’ conclusion
than any breach of duty by the employing authority. that ‘improved communication, co-operation and com-
During the trial, he evinced a strong sense of grievance mon agreed goals between employers, employees, occupa-
about a perceived challenge to his personal worth to the tional health providers, and primary care professionals can
organization, for which he had worked conscientiously for result in faster recovery, less re-occurrence of ill health and
26 years. less time out of work overall’.111
The success of this company’s programme also shows
the importance of the employer, the doctor and the
THE POSITIVE ROLE OF MEDIATION occupational health professional asking, ‘What are the
barriers to recovery and return to work that this person
The powerless individual enmeshed in an uncontrollable is experiencing?’ (p. 291).76
situation at work is afforded room for manoeuvre by the Unfortunately, there has been no published system-
dominant biomedical symbolism of ‘work stress’ with its atic assessment of the mediation/round-table model –
passive but potent appeal of helplessness.12 The mystical see for example, Workplace interventions for people with
power of biomedicine affords negotiating space to the common mental health problems112 and What works at
disaffected employee. work?111
However, long-term sick leave is demoralizing and
stigmatizing and it induces its own morbidity.59 A large
power company, EDF, has developed a constructive way GOVERNMENT POLICY ON INCAPACITY
of redressing the imbalance which might otherwise push BENEFIT AND GETTING BACK TO WORK
employees into the psychodrama of protracted sickness
absence. They provide a negotiating forum, the facilitated In recent years, there have been a number of UK
round-table meeting, which employees with stress are Government policy initiatives,113–117 aimed at getting peo-
invited to attend within a couple of weeks of going off sick. ple back to work. These policies are linked to a concern
The participants include the employee and their represen- with the high level of uptake of Incapacity Benefit (IB)
tative, their line manager, together with representatives which appears to relate to the period between 1979 and
from human resources and occupational health. 1995 when the number of recipients of Invalidity Benefit
The agenda is to ascertain the obstacles to a return to (IB) rose dramatically. However, the number has begun to
work and to negotiate practical solutions to the familiar pre- fall of late at the latter period of economic growth since
cipitating problems of work overload, conflicting demands, the 1990s recession.59 Men are more likely to be claiming
lack of control over work, poor social support, ambiguity in incapacity benefit than women and these male claimants
management and work role, conflict with colleagues and have been characterized116 as almost all having some kind
tension between work and the demands of the family.110 of health limitations; only a quarter say they cannot do any
The round-table meetings take place in a supportive work; half would like a job, but fewer than one-in-ten are
environment which helps the employee and the manager looking; health was the main reason for job loss in only half
to understand each other’s interpretation of the particular of all cases, although age, skills and qualifications would
work issue and to agree a way forward. There is construc- anyway expose them to unemployment. However, there is
tive discussion about rehabilitation and agreement to also evidence of a rising number of women claimants and
reasonable adjustments that are acceptable to all parties. the explanation for this increase is similar to that of men,
The round-table system is one ingredient of a compre- i.e. hidden unemployment, those who could be expected to
hensive intervention which is primarily educational and have been in employment in a fully employed economy.117
avoids medicalization and which has significantly reduced Other reasons for the marked increase in the uptake of IB
both sickness absence and early retirement on medical might include the political need, at least at that time, to
grounds. The programme is proactive and the aim is to keep the number of registered unemployed at a low level.
create a risk-free way in which an employee can seek help The concern for policymakers is not just that IB rates are
when they feel under pressure or develop the psychophysi- high and therefore costly, but that the benefit might be
ological feelings of distress. The company has circulated all being used by those whose intention is to malinger and
the employees with information leaflets on the early iden- avoid work, rather than by those who are genuinely
tification of these ‘symptoms’. incapacitated by health problems.58 There is thus a moral
818 Work, stress and sickness absence: a psychosocial perspective
element (a kind of ‘moral hazard’) to this policy of trying programme a new, more stringent assessment, the Work
to ensure that IB is only available to those who are deserv- Capability Assessment (WCA), was introduced in 2008 for
ing of it. new IB claimants, to assess their eligibility for the
The Pathways to Work programme, which was imple- Employment and Support Allowance (ESA) which will
mented throughout the country in 2008, is central to the replace IB. Again, this aims to distinguish between appli-
government’s IB reforms, which distinguish between those cants according to their capacity for work, with the less
with severe health problems who are incapable of work and impaired assigned to the work-related activity group who
those with less severe problems who, with appropriate will be expected to prepare for return to work, while the
help, have the propentity to return to work.113–115 This more severely disabled will receive a higher rate of benefit,
programme requires all new IB claimants to attend a work- but will still be able to volunteer for back-to-work support.
focused interview (WFI) with an IB personal adviser. These new initiatives, like the previous ones, combine
Those with severe medical conditions or deemed likely to ‘stick and carrot’ measures with pragmatic policies which
return to work without support are exempt from further intend to address some of the psychosocial barriers which
WFIs, others must attend up to five more WFIs. The other hinder people returning to work.
elements of the Pathways programme are optional and A more recent White Paper, building on this policy, has
according to recent reports not well used.115 They com- been published115 on the reform of the benefit system
prise the Choices package – a range of interventions aiming where the expectation is that most people on out-of-work
to improve labour market readiness and opportunities, benefits, such as ESA, will look for work and the proposal
including the New Deal for Disabled People and the is for all existing IB claimants will be reassessed using the
Condition Management Programme; the Return to Work WCA. Early evidence117 suggests that the vast majority
Credit; In-Work Support, and the Advisers’ Discretionary (two thirds) of new applicants for benefits such as the ESA
Fund. are being rejected at the WCA stage, although it is not
The Pathways programme has been introduced to clear what the consequences of this have been and if this
promote employment, and to address psychosocial obsta- has led to higher levels of those returning to or retaining
cles to return to work by therapeutic means. Those who employment.
refuse to participate in WFIs face benefit sanctions, while
those who return to work receive the Return to Work
Credit. Interventions, such as mentoring and job coaching, SUMMARY AND CONCLUSION
appear to aim to try to address the harm of being on long-
term benefits to personal and social identity. This chapter has attempted to show how emotional dis-
These proposals are the outcome of policy deliberations tress is often translated into an idiom of suffering which is
about the inappropriate uptake of IB which has led the used to empower the employee who feels helpless.
government to set a target of one million IB recipients The cultural and social construction of grievance in
returned to work by 2015,114 although this target figure the workplace organizes negative feelings into psychiatric
appears to have increased in more recent policy docu- diagnoses. However, diagnosis is an imperfect means of
ments.115 These IB reform policies aim not only to reduce representing psychological distress, disaffection and
the number of new people applying for benefit, but also demoralization. The sociologists Mirowsky and Ross chal-
tries to encourage long-term recipients to go off benefits lenge this medicalization of distress. ‘Psychological prob-
and back into paid employment. lems are real but are not entities. They are not discrete.
Recent analysis suggests that these target figures may They are not something that is entirely present or entirely
be untenable as there are marked geographical variations absent without shades in between. They are not alien
in the distribution of incapacity claimants and thus things that enter a person and wreak havoc. Nevertheless,
attainment of these targets depends on an accelerated psychiatrists often speak of depression and other psycho-
revival in the economies of the North, Scotland and logical problems as if they are discrete entities entering the
Wales.118 bodies or souls of hapless victims. An imagery of detection
Is the programme effective? The limited evidence follows from such language of discrete entities. The psy-
currently available suggest it might have some advantages chiatrist detects the presence of an entity, determines its
for new IB claimants,119 although the impact of the species and selects an appropriate weapon against it. This
Pathways programme on existing IB recipients appears to categorical language is the legacy of nineteenth century
be small.120 However, further evidence is needed before the epidemiology and microbiology. A person is diseased or
effectiveness of the Pathways initiative of returning long- not. The disease is malaria or not, cholera or not, schisto-
term IB recipients to work can be fully assessed. somiasis or not. A language of categories fits some realities
More recent policy has been less influenced by concerns better than others; it fits the reality of psychological prob-
with rising levels of unemployment and more with reduc- lems poorly (p. 11).’51
ing those on IB, although this may change in the current It is increasingly clear that psychiatric assessment in
economic climate. Thus, following on from the Pathways these cases should be taking into account the problem of
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65
Mental health at work: psychological interventions
ADRIAN NEAL
health problems, such as panic disorder, adjustment disor- cognitive behavioural in their theoretical orientation,
der, complex grief, agoraphobia, generalized anxiety disor- with many having an integrated approach, there is wide
der, health anxiety, social phobia, obsessive compulsive acknowledgement that the process of case formulation is
disorder, eating disorders and phobias. The treatments central to understanding an individual’s problems and
currently practised, depending upon the condition, are thus developing effective interventions.
interpersonal therapy, cognitive analytic therapy, dialecti-
cal behaviour therapy, eye movement desensitization and
reprocessing, and brief psychodynamic therapy. Evidence A formulation framework
is also emerging to indicate that mindfulness-based cogni-
tive therapy can be helpful for people who experience Formulation begins as soon as the clinician receives infor-
reoccurring moderate clinical depression.3 Psychological mation about their potential client(s). From this point, it
therapies can also contribute in the management of patients may be helpful to use a simple framework to guide and
with complex mental health problems, including borderline organize information. The five P model7 is a widely used
personality disorder, psychosis and non-chronic bipolar generic cognitive behavioural formulation framework use-
disorder. ful in all clinical areas. The framework requires informa-
It is reasonable to suppose, in the light of these recom- tion to be organized around five key areas, namely:
mendations in the general population, that some of these presenting issues, precipitating issues, predisposing prob-
methods may be applicable to the mental health problems lems, perpetuating factors and protective factors, which are
that arise in the workplace. However, before it is possible to described in more detail below. The five P framework facil-
recommend psychological therapy in this context, caution itates the identification of a wide range of information,
is needed to ensure a tailored approach, including an allowing the clinician and client to develop a current and
acknowledgement of the potential role of the work envi- working conceptualization of the key problems, and thus
ronment and employer. Interestingly, it is this ability to begin to see hypothetically how they may be best addressed.
tailor psychological interventions to the individual that
makes them so potentially useful in a range of settings. PRESENTING ISSUES
temperament, cognitive structures (beliefs), emotions and construct and its role as a protective factor. In their review,
relationships. For many people, it is often helpful to the authors identify a number of characteristics considered
explore their past to find related factors and events which to be protective. These include having purpose, pragma-
can help give some meaning to their current distress. tism, being able to goal plan, optimism, hope, good self-
esteem, perceived control, flexibility and distress tolerance.
PERPETUATING FACTORS The authors urge caution and add that this list is not
exhaustive and other factors, such as biological, and chance
A useful way of understanding these is to consider the rela- are probably also important in making a person resilient.
tionship between the factors which maintain and perpetu-
ate the cycle of distress, and which can be internal or
external to the individual, or a combination of both. Of all Overview of the formulation process
the perpetuating factors, the ‘experiential avoidance’ of
distress8 seems to be the most commonly identified across The process of formulation, particularly if guided by the
most mental health problems. Put simply, if an individual five P model, can offer an invaluable resource for both
tries to avoid distress, or any experience that for them client and clinician. In addition to being useful in creating
triggers distress, they are likely to experience a negative a framework to understand a problem and plan for inter-
reinforcement of the problem. vention, there is an emerging literature looking at the
For example, a woman felt highly fearful following an impact of the formulation process itself on outcome.
experience of breathing difficulty and believed she was at Although early, there is a growing recognition that formu-
increased risk of choking, thus possibly dying, if she had lation is an important process as it helps form a collabora-
any future breathing difficulties. If she were to experience tive therapeutic alliance.13 Indeed, for some individuals the
being short of breath, she may well perceive this as the formulation process is all the intervention they require.
beginning of another choking episode, become fearful and Another aspect to consider and include in a formulation
then try to avoid any situation that triggers similar physical process are the accepted attributions that form part of
feelings. Over time, she successfully avoids ‘risky’ situa- the social and workplace milieu. These will differ from one
tions, but her fear actually increases. work environment to the next and may differ between
In this example, avoidance-based coping plays the pri- the type of work undertaken, e.g. information technology,
mary perpetuating factor in the person’s catastrophic medical, research, manufacturing, construction, etc.
beliefs and predictions. Likewise, problems can also be in Attribution style based on attribution theory14 is signifi-
part maintained by external factors, such as financial diffi- cant as it forms the basis of the individual’s expectations
culties, issues with family, friends, workplace and other of his employer and colleagues, and points to why the
environmental factors over which they may have minimal employee might have different values and expectations to
control. their employer. An attribution style will help determine
Within the cognitive behavioural literature, there are personal responsibility, role, and what an individual thinks
disorder-specific maintenance patterns, particularly in they deserve. Formal industrial action, ongoing antagonis-
anxiety problems.9 For example, with panic disorder and tic relationships, sabotage, conflicts and bullying between
health anxiety, there is a characteristic over-vigilance for employer and employee will be linked to the attributions of
bodily changes,10 and for post-traumatic stress disorder, those involved.
there is an active avoidance of stimuli that trigger distress.11
Although traditional psychotherapeutic models tend to anxiety, fear, guilt, concern, shame). What appeared to
focus on working directly with one adult, there are a num- have developed, however, was a number of distress main-
ber that allow for working with the individual indirectly. taining patterns that seemed to have evolved as a conse-
Systemic models often encourage teamwork and working quence of how he had tried to cope with his distressing
with more than one individual (e.g. a family) and are com- emotions. Alan had experienced marked anticipatory anx-
monly seen in child and adolescent mental health services. iety at the thought of running into colleagues who might
More recently, traditional one-to-one models have been know about the incident, so he had tried to cope by avoid-
broadened to integrate systemic ideas, allowing the psy- ing situations he considered to be ‘risky’. As a result he
chologist to work towards helping an individual through changed his route to work, worried about the journey
others within the system. In occupational settings, this may beforehand and arrived at work anxious. This anxious state
involve working with human resources, occupational triggered further anxiety as he worried that he might make
health services, general practitioners, managers and even a mistake, or that his anxiety would be seen by a colleague
colleagues where necessary. As with traditional direct who might comment critically. The worries he had about
methods, indirect methods need to be based on a clear being viewed negatively by others steadily increased, as did
understanding of the problems, and have a formulation his efforts to cope until he felt he needed help.
anchored in psychological theory. Based on the formulation, a self-directed behavioural
Before embarking on a psychological intervention, it is exposure programme was devised, and anxiety-based
important to consider, in the formulation process, what psychoeducation recommended. He later reported that the
the aims are to be, how achievable they are and whether formulation process had allowed him to see his main prob-
they are compatible with the needs of the referrer. This is lems more objectively, and to then feel able to address the
a particular issue for occupational health services as self-maintaining mechanism of his anxiety, which he learnt
returning an individual back to health in order that they were both understandable and changeable.
return to work may not, in some instances, be ethical or
indeed realistic, particularly if the work environment has
in some way played an active part in the development or Case 2
maintenance of their problem. Psychological interven-
tions are more likely to be of help if these issues can be Heather was a 43-year-old woman with 25 years’ experi-
acknowledged early on. ence of working for her employers. She had recently taken
The following case studies illustrate effective direct and a new role as team leader, a role she was well experienced in
indirect psychological interventions within different occu- and qualified for, but she was struggling. Heather was
pational health settings. referred by the occupational health department who
explained in a referral letter that ‘she was low in mood, felt
on edge and unable to cope’.
Case 1 During assessment, Heather explained that she was
experiencing a ‘crisis of confidence’ and marked low
Alan, a 48-year-old medical doctor, was referred by the mood, as well as other symptoms of moderate clinical
occupational health service of the hospital where he prac- depression. She explained that she had felt this way in the
tised. Alan reported feeling highly anxious, self-conscious, past, but had recovered quickly. She had been feeling this
lacking in confidence and low in mood, although he was way for ‘too long’ and it was impacting on her ability to
not apparently clinically depressed. All of these symptoms perform. Heather stressed how important it was that she
impacted on him negatively at work and he worried about should do her job well and explained that as a woman in a
them leading to a reduction in performance. His symptoms predominantly male work environment she could not
seemed to have developed over a period of a few months afford to ‘slack’. In addition to her low mood, she reported
following an incident at work where he had made an error feeling marginalized and unfairly treated which is why she,
during a surgical procedure. The error was identified and in her eyes, had had angry outbursts.
corrected; however, Alan was temporarily suspended from Heather’s low mood seems to have been initially trig-
surgical duties until an internal investigation had been gered following an undermining comment from a col-
carried out. Alan reported experiencing regular and dis- league. This comment had suggested that Heather’s team
tressing flashbacks to the events surrounding this incident were underperforming. It was Heather’s perception that
and seemed to be stuck in a pattern of rumination. this colleague wanted her role and that she was vulnerable.
The referral had asked for an assessment with treatment Normally, she would have been able to cope, but Heather
recommendations; however, it soon became evident that explained that she was feeling increasingly vulnerable as
formal treatment was not necessary and that an extended the project the team were tasked with was simply too com-
assessment with an active formulation would be sufficient. plex to do well. She felt a sense of failure in spite of the
The generic cognitive behavioural formulation identi- impossibility of the task.
fied that most of Alan’s distressing emotions were, at least Heather admitted that she was a perfectionist and that
to begin with, normal reactions to a difficult event (e.g. things had to be just right or she felt uncomfortable.
Formulation-based pragmatism: direct and indirect psychological interventions 827
She had a reputation at work of being a hard worker, and The formulation further indicated that she was experi-
always seemed to succeed. Faced with a task that was encing heightened social/performance anxiety under-
impossible, she began to feel low and vulnerable. The for- pinned by the belief that others would be critical and that
mulation identified, along with her protective factors she could not cope alone. Julia also explained that as a child
(determination, creativity, drive and confidence) that she her stepfather had been highly critical of her. It seems that
was also dependent upon success to support her self- these old experiences had had a direct effect on her devel-
worth. Thus, failing to maintain her standards posed grave oping self-worth and had also played a role in the forma-
risks to her self-worth. We also recognized that her perfec- tion of her beliefs about the criticalness of others.
tionism seemed to have its origins early in life. She experi- Following the annual appraisal, and to cope with feeling
enced many physical problems as a child, but she was able vulnerable due to a fear of further negative evaluation,
to excel academically. She had also learnt that to be Julia isolated herself, slowly disconnected from her social
favourably viewed by those around her, she had to succeed. network, and reduced her assertiveness at work. Over time,
Thus, not to succeed was both unfamiliar and, from her her sleep deteriorated and she began to feel ashamed and
perspective, highly frightening. highly self-conscious, and avoided more aggressively. In
The intervention was highly pragmatic and aimed pri- addition, she began to feel hopelessness having realized
marily at helping her cope with her day-to-day, work- that she would probably struggle to find another job.
related distress, and slowly she started to recover from her Although Julia struggled with the assessment, she was
depression. Based on direct cognitive behavioural-based offered a cognitive behavioural-based intervention for her
work, the focus was on identifying and adapting beliefs social anxiety. Her aims were to feel ‘stronger’ and return
that underpinned her drive to be perfect (e.g. ‘If I can’t to work, and also to be able to make an active choice about
succeed I am a failure, no one likes a failure’), activity staying in her current job. The intervention also involved
scheduling, increasing her distress tolerance, and being close liaison with occupational health professionals and
more able to directly communicate her emotions to others, her line manager in planning her return to work. The
rather than waiting until she felt uncontrollably angry. She intervention focused on helping her to feel more confident
was also helped to link present emotions, beliefs and in identifying and challenging her primary negative predic-
behaviours to relevant past experiences. The collaborative tions around negative social evaluation.
relationship was vital as she felt a deep sense of shame for We used the formulation process, then behavioral
appearing to fail. experiments, to do this over a number of weeks. At the
Later, it transpired that she had been right and her col- same time, we developed a graded exposure hierarchy
league had been trying to take her role, which was curi- combined with activity scheduling to increase her out of
ously reassuring to her as she no longer felt threatened, but work positive experience. Julia kept records of her work
consoled herself that at least she could still judge human and successes as evidence of progress and as a basis for sup-
nature. porting more compassionate self-beliefs. Julia also became
aware that she was responding defensively to perceived and
not necessarily actual threats. However, it was vital she
Case 3 accepted that at one time in her life she had needed to pro-
tect herself from actual threats. This was an important
Julia was a 34-year-old woman who worked as an adminis- message to convey as it helped her feel less ashamed of her
trator in a university records department. She reported lifelong avoidant behaviour, which was once highly adap-
experiencing high levels of anxiety at work which impaired tive and protective, even if it acted to maintain her anxiety.
her ability to function. She also reported feeling low in After 14 sessions, Julia successfully improved her
mood. Julia was referred from the occupational health understanding and management of her anxiety, increased
service, and during the initial assessment presented as her social network and confidence. She returned to work
highly distressed, she struggled to make eye contact and and finally resigned some months later with the confidence
reported that she felt unable to cope and she believed that that she could find another job.
colleagues wanted to get rid of her. It seemed that Julia’s
anxiety had been getting worse over the past few months
and that she had, in her opinion ‘always been sensitive to Case 4
criticism’. Following a critical annual appraisal, Julia had
found her anxiety increasing, her capacity to cope reduced, Mary was a 35-year-old computer programmer referred
and had eventually gone off work sick. from the occupational health department for help in deal-
The formulation process suggested that she had a pre- ing with anger at work, depressed mood and generally
disposition to feeling negatively evaluated, and although struggling to cope. She also had a history of self-harm and
never having felt this scared before, she had often felt had recently been to Accident and Emergency having
uncomfortable with others. Compounding matters fur- deeply cut one of her wrists with a broken wine glass.
ther, she had also experienced severe stress-related alopecia During the assessment, Mary struggled to recognize any
that had further increased her self-consciousness. thoughts or feelings that might shed light on her problems
828 Mental health at work
from a cognitive behavioural perspective. She also reported Before going off work, Tim had had been ill with a car-
long-standing problems with obsessional behaviour, diac problem and was undergoing tests. Psychological
restrictive eating and drinking alcohol. It quickly became assessment revealed that Tim had been feeling increasingly
clear that alcohol consumption preceded her risk behav- stressed at work for at least four or five years. He reported
iour, particularly at weekends. Mary identified her anger as changes in the work environment, management structure
a key problem and also explained she felt powerful feelings and job description that had left him feeling unsupported
of guilt. These problems seem to permeate all parts of her and at times unclear as to what his role involved. He added
life and negatively impacted on work, as there was a risk of that his job used to be very important to him, as it provided
her being disciplined and possibly made redundant. structure and predictability, as well as enjoyment and a
In order to understand Mary’s problems, the formula- sense of achievement. He also explained that his wife was
tion needed to expand to include the cognitive analytic now ill and that he was very worried about her.
therapy (CAT) model.15 The CAT model is a time-limited, Much to his doctor’s surprise, Tim’s problems seemed
integrative model incorporating cognitive, behavioural and to have worsened while off work. Rather than having time
psychodynamic components. CAT has been found to be a to recover and regain his confidence, his anxiety had deep-
useful model for problems which have a chronic dysfunc- ened and he had become clinically depressed. It also
tional relationship component and where strong emotions became clear that he had stopped all forms of exercise for
are regularly activated. The evolving reformulation (CAT fear of setting off a ‘heart attack’. He had subsequently
uses the idea of a reformulation, as opposed to formulation) invested a great deal of energy in trying to ‘think himself
suggested that Mary’s overwhelming negative emotions better’ in the form of ruminations, checking (scanning his
(anger and guilt) were connected to her relationship with body regularly for signs of danger, e.g. increased pulse rate)
her parents, particularly her father. Interestingly, she also and he avoided anything that reminded him of his work or
relied on her father to give her a lift into work each morning which triggered increased anxiety/low mood.
and described ‘starting the day on edge’. The reformulation In addition, before going off work, Tim had been
also suggested that she drank to avoid feeling strong emo- assessed for an autistic spectrum disorder, and been given
tions, but that it was also an indirect way of punishing her a diagnosis of high functioning autism. While this diagno-
parents. This strategy, however, simply promoted conflict sis made sense to him and his doctor, it seemed to add to
and critical behaviour in the family. Mary also explained his sense of feeling overwhelmed, particularly as his work
that she hated going to her parents for a meal on Sunday, colleagues upon hearing the news had started to treat him
but felt compelled to. It was at these dinners that she would differently.
often drink too much, return home and self-harm. Following the assessment and early formulation, Tim
The reformulation guided the 16-week long direct was offered a cognitive behavioural-based intervention
intervention in a number of ways. First, it allowed Mary to and realistic goals were planned. These included: develop-
observe her unhelpful patterns and see how they were ing new ways of understanding and managing his anxieties,
maintaining her very serious problems and distress. feeling more pleasure and less overwhelmed, and finally
Second, it seems to have given her permission to make returning to work. The formulation suggested that he had
some simple behavioural changes, such as getting the bus gradually grown to feel increasingly overwhelmed at work
to work, and becoming more assertive with her parents, so as he had struggled to manage organizational changes. This
she began to politely decline her parents’ offer of a Sunday was perhaps linked to his autism and the fact that he had
meal, thus avoiding becoming angry and feeling guilty. done the same job for so long. Feeling overwhelmed meant
Mary also began to accept that she could not change her he struggled to cope with the daily worries which soon
parents, but that she had a choice to change how she became too much. His heart problems were just the final
reacted. At work, her mood improved. The anger outbursts stressor and triggered an acute stress reaction. The time
decreased and she was generally happier – as were her spent off work seems to have led to an avoidance (and
managers. hypervigilance) based maintaining cycle, which had led to
a worsening of his distress.
The intervention focused on both direct and indirect
Case 5 work. Working directly with Tim using a cognitive behav-
ioural framework, he was able to understand that his anxi-
Tim was a 56-year-old laboratory technician who had ety and depression was based on catastrophic predictions
worked for a university engineering department for 26 years. about his health and ability to cope in general. He also
Tim was referred from the occupational health department found that his avoidant coping style, i.e. rumination, active
having been off work for six months with ‘stress’. avoidance and hypervigilance were making him worse.
At assessment, Tim reported high levels of anxiety, This led to a graded exercise exposure programme under
mostly around feeling overwhelmed and physically weak, advice from his doctor, who was liaising with the cardiol-
and not being able to cope with the demands of the job or ogy department. Working with occupational health, a
indeed those of his day-to-day life. He reported that these carefully graded return to work was planned and a clearer
symptoms had been getting worse since going off work sick. job description was negotiated. Occupational health also
Acknowledgements 829
established an effective line of communication between what is in the best interest of the employee, both ethically
Tim and his line manager which allowed Tim to feel lis- and clinically.
tened to and more in control. He eventually returned to Where a work environment is psychologically toxic
work successfully and negotiated a new role in his old and thus part of the identified problem, the health profes-
department after being off for nearly nine months. sional should raise the issue under the duty of care of the
employer. Occupational health practitioners have an
important role here, but as advisers they may have limited
Case studies: A summary ability to change the work set-up if the employer resists. In
these cases, there is an ethical responsibility to raise the
These five case studies draw attention to the importance of issue with the client and help them make the best informed
systematically formulating an individual’s psychological choice they can: in Julia’s situation (case 3) one of the aims
needs before embarking on a treatment plan. They also was to help her regain her confidence so she could leave the
highlight the individual nature of mental illness. Most job. It is important to be as open and pragmatic with
importantly, these cases illustrate the potential helpfulness clients as possible in order to facilitate their recovery and
of both formulation and psychological interventions, par- alleviate their distress.
ticularly when carried out in transparent coordination Finally, it is important to raise the limitations of
with other professional carers, and those working on psychological therapies. Therapies should be chosen for a
behalf of the employer. specific purpose by individuals who are competent in their
ability and knowledge base. Psychological therapies and
techniques have the potential to cause harm if used inap-
CONCLUSIONS propriately. Referrers to psychologists should be aware that
choosing a specific type of therapy, planning its individual-
As mentioned previously in this chapter, there is not ized structure and ensuring quality is complex and often
always a clear or even helpful relationship between only possible after specialized training and ongoing super-
employer, occupational health provider, psychologist and vision. Likewise, even CBT, in its many forms, can cause
employee. It is important, therefore, to include these fac- harm in the hands of an incompetent practitioner. It is
tors into any formulation process as they may have direct important for practitioners and referrers to be aware of the
impact on the aims and outcome of any intervention and contraindications to therapy, ongoing risk factors and the
may also impact on client confidentiality. realistic limitations of psychological treatment so as not to
Formulations are hypothesis based and remain ‘work in give false hope to those in distress.
progress’ with no absolute declarations or truths. At best,
they are helpful hypotheses which help individuals make
sense of their problems, at worst they are a rigid, reduc-
tionist and patronizing list of a person’s problems and do Key points
not contribute to recovery. However limited a poor formu-
lation might be, it at least does not have the same stigma- ● Mental ill health, including ‘work stress’, can be
tizing potential as some psychiatric diagnoses, e.g. conceptualized as being on a continuum of
schizophrenia or borderline personality disorder. The emotional distress ranging from mild to severe
potential normalizing effect of the distress-focused biopsy- and enduring.
chosocial formulation can help engage those individuals ● A biopsychosocial model of emotional distress is
who feel stigmatized by the thought that they may have a highly relevant in the workplace, given the range
mental illness and therefore avoid seeking help. of diverse factors that may have an influence in
It is not hard to imagine a situation where an employer any one case.
sends an anxious or depressed employee to occupational ● A problem-focused formulation can inform
health, who then discovers that aspects of the work psychological, systemic and medical
environment are directly linked to the individual’s dis- interventions in order to reduce emotional
tress. This was similar to Heather’s (case 2) experience. distress in the workplace.
The formulation may reveal that there is little that can ● Psychological interventions need to be pragmatic,
be done to change the individual and what is recom- realistic and supported by collaborative
mended is to change the environment. This can be very relationships between invested parties.
frustrating for all involved, especially if the employer
disagrees or is actively attributing blame to the employee.
This is a particularly difficult situation if the core problem
is linked to ongoing bullying, harassment, disputes or rela- ACKNOWLEDGEMENTS
tionship problems in the workplace. In these instances,
there needs to be clear communication between profes- The author would like to thank Dr Julie Highfield for her
sional carers involving the client, and an agreement about support, ideas and for proof-reading.
830 Mental health at work
or threatening clients in public services, through to more organizations, and lower rates in plant operatives and
consistent job characteristics, e.g. physical discomfort, health-associated professions, and few changes over the
both overly onerous and overly undemanding roles, social seven years between national surveys (Table 66.1).17
support, perceptions of organizational injustice and imbal- Other sources of routinely collected data have shown
ances between the efforts expended and the reward similar results – staff in certain public service occupations
received. Some of these may be related to particular occu- having higher levels of psychiatric disorders. Similar stud-
pations, organizations or types of work, others to actual or ies from Norway have also identified farmers at particular
perceived experience and all are impacted by a range of risk for anxiety and depression.18 In Canada, a study using
factors operating outside work. one simple question of self-reported mental health19 sug-
gested that risky occupations were concentrated in four of
the ten major occupational groupings: (1) health; (2) sales
Objectively assessed occupational risks and service; (3) trades, transportation and equipment
operators and related occupations; (4) occupations unique
OCCUPATION to processing, manufacturing and utilities. Nevertheless, as
the authors point out, ‘the extent of the specific contribu-
Surveys of occupations which would seem to carry a high tion of occupations in explaining variations in worker
chance of exposure to stressful events and violence, reporting of poorer mental health is rather low …’. This
unsociable hours, shift work and many other features con- would also appear to have informed Lady Justice Hale’s
sidered to constitute a ‘toxic’ working environment, con- determination that no occupation is inherently psycholog-
sistently report levels of about one-quarter to one-third of ically toxic when she said, ‘The notion that some occupa-
respondents meeting criteria for psychiatric disorder. tions are in themselves dangerous to mental health is not
These levels have been determined, most usually, through borne out by the literature to which we have already
studies in which respondents have reached a cut-off point referred: it is not the job, but the interaction between the
on a screening tool. Examples of such studies include individual and the job which causes the harm’.20 A more
front-line ambulance staff and paramedics,8–10 police,11,12 important observation in the literature, and in the above
doctors,13 other hospital staff,14 and veterinary practition- landmark judgement, appears to be the effect of being
ers.15 In such studies, the prevalence of ‘stress’ in members lower within the organizational hierarchy within each
of the occupational group are compared to the prevalence occupational grouping. The effect of occupational group-
of psychiatric disorder, ascertained through interview in a ing virtually disappears when individual factors, such as
rigorously sampled population-based study, such as the personality and family strains, were included.21 As shown
National Psychiatric Morbidity Survey in the United below, it is aspects of the job rather than occupation per se
Kingdom or the National Comorbidity Survey in the which is important for mental health.
United States. These studies get good publicity and are Studies evaluating the role of occupation in suicide in
popular with the respective professional groups and high income countries have shown two consistent pat-
unions, yet frequently suffer from poor response rates, terns. First, not having a job is worse than having any
different methods of determining disorder (self-report type of job,22–24 although less so in a period of high
measures often derive higher prevalence rates than inter- unemployment.25 This was confirmed recently in a pan-
view-based studies) and little information on the context European study.26 Second, suicide registers consistently
that may lead to response bias. For instance, it is quite pos- suggest that healthcare workers27 are the only occupational
sible that the answers to a ‘stress’ survey may differ from groups consistently associated with raised suicide rates
identical questions asked in a ‘well-being’ survey. It is after adjusting for other known risk factors. For instance,
important to remember that prevalence estimates obtained among those who have previously been admitted with
in different groups using different study designs cannot be psychiatric disorders, minimal associations between occu-
directly compared. Therefore, such studies are unlikely to pation and suicide are observed except for doctors, who are
provide a valid answer to the question of whether one at almost four-fold greater risk. This presumably reflects
group has a higher prevalence of psychiatric disorder access to the means of suicide (drugs) and knowledge of
compared to other occupational groups. how to use them. Some have suggested knowledge of the
Attempts have been made to use broader based surveys consequences of chronic illness or the effect of having
to identify occupations in which employees are more or people so dependent upon them as explanations.27 In
less likely to develop common psychiatric disorders. Using others, the risk may be due to economic factors, such as
a large self-reported database, ambulance workers, teach- the transient nature of some occupations predisposing
ers, social services, customer services (call centres), prison to periods of being unemployed and being in receipt of
officers and police reported poorer than average scores on low income. Within such groups, however, the same risk
psychological well-being and job satisfaction measures.16 factors operate for being vulnerable to suicide as in the
More robust data come from population-based data in the rest of the population – psychiatric or personality disor-
UK where higher rates of psychiatric disorders are found der and previous deliberate self-harm being the most
among teachers, sales staff and managers in government prominent.28
Effect of work upon the development of psychiatric symptoms and disorder 835
Table 66.1 The prevalence of psychological disorder by standard occupational classification group
(reproduced with permission from Stansfeld et al.17).
The oft-quoted association of suicide with another large POSITION IN THE ORGANIZATION
group with access to lethal means, farmers and farm work-
ers, is less consistent with both positive and null associa- Within many workplaces or jobs, there is a hierarchy
tions, although veterinarians have high levels, presumably between higher and lower grades. A consistent finding is
for similar reasons to other health professionals.29 Groups that those in lower status jobs have higher levels of psycho-
such as the police and other front-line public sector work- logical distress. In the Whitehall II study, this association
ers have similar rates to the rest of the population. Much of was not explained by poorer mental health leading to
the apparently high suicide rates in certain occupations are employment grade changes (social causation), but rather
due to lower death rates from other causes.29 Beyond this, supporting a selection into certain grades by factors that
it is difficult to make out a common job pattern, although are also risks for psychiatric disorder.31 The association
Sanne et al.18 suggest a strong effect of low skill use occupa- with workplace position in fact appears stronger than
tions being associated with depression in men suggesting broader objective measures of socioeconomic position in
job selection. Certain people are drawn to certain jobs, for society as a whole.32 Subjective measures of socioeconomic
example, there is a stronger relationship between a simple status also have a strong effect,33 bolstering the idea that
global measure of intelligence with future occupational workplaces perceived to have flatter hierarchies may be less
level than the multitude of specific aptitudes often tested in likely to engender negative health effects.
the psychological selection processes used by many organ-
izations.30 Late adolescent personality characteristics also HOURS WORKED
play a strong role in determining future occupation and
attainment, with ‘alienated and hostile adolescent’s … per- Long hours and overtime have also been linked to psychi-
sonality dispositions leading them to work experiences that atric disorder in some studies (e.g. Ref. 34), which can
undermine their ability to make a successful and rewarding receive media attention. However, the most compre-
transition into the adult world’.31 hensive literature review in the area35 showed that fewer
836 Work and psychiatric disorder
than half of all longitudinal studies demonstrated any neg- was determined using a validated interview. The two
ative impact of long hours, indicating a need for more studies assessing demands provided conflicting results
understanding and better determination of what long of no or a strong association. There was no association of
hours mean rather than a simplistic ‘more work bad’ decision latitude on its own. The combined measure of
approach. high job strain (high demand and low control) did pro-
duce an effect, particularly in men, with a relative risk in
the 1.5–2.5 range. A second systematic review in the same
PSYCHOSOCIAL WORK ENVIRONMENT year44 with the same objectives identified a slightly dif-
ferent, but generally overlapping, set of studies. This
Job strain and effort–reward imbalance review concluded that there were consistent effects of job
demands upon the development of depression with rela-
Men are disturbed not by things, but by the view tive risks around 2.0, but conflicting results with respect to
which they take of them decision latitude. Social support at work was associated
Epictetus (AD55–135) with a decrease in risk for future depression, as all four
studies identified showed that high social support reduced
Two major models have emerged to describe the psychoso- the risk of future depression. Both of these latter reviews
cial work environment – both are determined by an indi- suggested less of a gender difference. One important point
vidual’s perception of their environment. In the ‘job strain’ was the observation of a ‘very strong’ publication bias with
model the ‘demands’ of work are contrasted with the level only one negative study published which was attributed to
of control (‘decision latitude’) an individual has over how a positive secondary outcome.
they work.36 ‘Job strain’ is said to occur when high Another recent study across 11 large companies has
demands are associated with low decision latitude. Later, a bolstered the observation of the deleterious effects of peo-
third dimension was added to the model, namely, per- ple reporting either high strain or so-called ‘passive’ (low
ceived social support at work, and was combined with the demand, low control) work stress patterns leading to later
other two dimensions. Hence, a high-strain job in the con- onset of prolonged sick leave for depression, particularly
text of low social support should produce the worst effects for men, a negative effect of low control for both genders,45
on health. This situation created the ‘demand–control– but failed to show any protective effect of social support. A
support’ or ‘iso-strain’ model. The second model is the young birth cohort showed that higher levels of psycholog-
‘effort–reward imbalance’, in which stress responses are ical, but not physical, job demands, poor support and low
believed to occur when effort expended at work is not decision latitude (high strain) were associated with a recent
matched by rewards in terms of pay, self-esteem and sense onset of well-defined major depressive disorder and gener-
of achievement.37 Both job strain and effort–reward imbal- alized anxiety disorder in 32 year olds.46 Previous studies
ance were shown to be associated with psychiatric disorder have highlighted the importance of adjusting for prior dis-
in numerous cross-sectional studies, e.g. Ref. 38. When order given the social causation effect. Finally, recent
objective, rather than self-reported, assessments of work Canadian work has shown that those exposed to chronic
demands are included, the association between the psy- high job strain developed depression at twice the rate (8
chosocial work environment and psychological morbidity per cent) as those with consistently low strain (4 per cent)
is attenuated.39 Adversely perceived changes in these stres- and those who reported a change from high to low job
sors, particularly control, are associated with future strain had a risk of major depression similar to those
increased and longer spells of absenteeism.40,41 exposed to persistently low job strain.47 This would rein-
A meta-analysis of prospective studies from both force the idea that reducing an individual’s perception of
Europe and North America42 showed that there was strain may have a positive impact on the risk of depression.
consistent evidence for similar effects of job strain (sum- While the study of the perceived psychosocial work
mary OR 1.8 (95 per cent CI 1.1–3.1)) and effort–reward environment has deepened our understanding of the
imbalance (summary OR 1.8 (95 per cent CI 1.4–2.3)), in nature of the relationship between the individual and his
predicting later psychological symptoms, termed ‘com- work, the models have limitations. The reliance upon self-
mon mental disorder’, that was not explained by response reported data is either a hindrance or the ‘core of the issue’
bias (the tendency for certain individuals to report things depending upon the viewpoint as it incorporates beliefs,
more negatively). The individual components of these perceptions and attitudes to work. More work is needed on
models, i.e. demands, decision authority and support, validating methods of assessing work demands and the
showed smaller but still significant effects of increasing the way in which the perceptions of demands and decision
likelihood of later psychological distress by about 1.3 latitude are filtered or modified by individual factors, such
times. The effects were less strong generally among women as personality, temperament and previous experience.
than men. The literature has concentrated upon depression and
When the outcome of a clinically defined diagnosis of depressive symptoms with little emphasis upon anxiety.
depression is used, the evidence is less convincing. Bonde43 Bonde’s review demonstrated that not one of the 16 papers
identified seven studies where the risk of later depression accounted for all common potential confounders of
Psychosocial work environment 837
demography, life events/family demands, personality, pre- reflecting the gender-segregated composition of many
vious disorder, chronic disease and family history. The work environments. In the only cohort study, less than half
similar findings of associations across widely varying meas- of those reporting bullying did so over the two-year time
urements of both stressor and psychiatric disorder, with no period, but this group had much poorer outcomes, being
apparent trend towards greater effect of early versus late four times more likely to develop depressive symptoms.48
onset (unlike other life event work), and the huge variation Bullying has also been associated with insomnia57 and
in outcome prevalence, led him to suggest that much of the a range of other health indices, although once again ham-
association may represent bias and confounding. pered by tautologous definitions and cross-sectional study
Other specific elements of the psychosocial work envi- designs with their inherent biases. One interesting observa-
ronment have attracted research attention and seem tion is that people who report observation of the bullying
important clinically. of others have poorer mental health themselves, which
may suggest either the presence of wide organizational
issues or support the view that those with low mood per-
Bullying (mobbing) ceive actions and workplaces in a less favourable light.58
exposed to dead bodies and physical danger and who gave looked at more recent operations found that among UK
assistance to survivors in disaster situations. The study troops, about 4 per cent of the force, whether deployed or
observed the rescue workers for one year and found a three- not, reported symptoms of probable PTSD, although troops
fold increase in the risk of developing depression of 3.5. engaged on combat duties reported higher rates (6 per
A significant critique of the field in ascribing PTSD to cent),70 suggesting that increased ‘toxic’ exposure may well
an occupational cause, has been that the occurrence of ‘a have a significant, albeit small, effect upon PTSD rates.
stressful event or situation of an exceptionally threatening A primary source of traumatic events outside the emer-
nature, which is likely to cause pervasive distress in almost gency services is violence at work which is more common
anyone’ (the criterion A event necessary for a diagnosis) is in those working in the public sector: health and social
common. The proportion of adults who report having work professionals. According to the British crime survey,
experienced at least one such traumatic event includes the 0.9 per cent of employees had been physically assaulted
majority of people in the United States (61 per cent of men, while they were working, a similar number threatened and
51 per cent of women),60 such that many have suggested it 0.5 per cent of workers said that worrying about workplace
does not provide a specific aetiology for a disorder.61 The violence had a ‘great deal’ of impact on their health, and
association between exposure to trauma and the develop- 2 per cent said that it affected their health ‘quite a bit’.
ment of symptoms of post-traumatic stress is not fully Despite increasing attention, the reported rates in this fre-
understood. It involves a complex interplay between quently repeated survey have actually been falling since
factors related to the trauma, neurobiology and psychoso- 1995.
cial influences. All of these determine an individual’s vul- A major issue besets the field of post-traumatic distress
nerability or resilience to developing PTSD as a result of disorder and violence in medicolegal settings. If two peo-
exposure to a traumatic event. Certain sociodemographic ple experience the same DSM-IV or ICD-10 criterion A
factors, such as sex, age, ethnicity and income, have also event, yet only one goes on to develop a disorder, only this
been shown to be associated with vulnerability to develop- person is compensated for this experience with sickness
ing PTSD.62 absence, pension or some other form of social recom-
The majority of studies addressing work-related trau- pense. There has long been a suggestion that the presence
matic events has focused on specific occupational groups of compensation claims can prolong the course of the dis-
that obviously carry a much higher risk of experiencing order as seems to be the general pattern following a range
such events, i.e. military, ambulance, fire and police staff. of injuries.71 The United States veterans’ review suggested
Surveys of emergency service personnel find a sizeable that compensation was not a barrier to help seeking, but
minority of fully operational employees who screen posi- did not address the issue of whether it was a disincentive to
tive or meet criteria for PTSD. For example, in UK ambu- recovery. However, as shown by the rates of PTSD specific
lance personnel between 5 and 20 per cent of paramedics to trauma experienced at work in occupational groups, the
still working screen positive for PTSD.8,63,64 There is an presence of such a disorder does not preclude employment
extensive literature which suggests that many employees even in front-line operational posts. Work into the factors
experience horrendous events but do not develop PTSD. preventing the onset of PTSD72 and enabling well-trained
Our survey of London ambulance staff in the aftermath of people to continue being gainfully employed, e.g. by tack-
the July 2005 London bombings63 suggested that the ling the stigma associated with help seeking,73 are major
prevalence of PTSD as found on a screening tool was simi- foci of attention in the area.
lar to that in the general population (2–3 per cent), with a Given the apparent lack of specificity of a traumatic
higher prevalence of 6 per cent in those involved in the event as a cause, the numerous vulnerability and resilience
bombings directly. The failure to find substantially raised factors and the role that compensation and other benefits
levels in emergency services59 suggests either that affected play in the development and persistence of symptoms
staff rapidly leave the service or that people joining such of PTSD (and other disorders), the disorder can be a
organizations self-select for resilience.65 medicolegal minefield. Future research may help to clarify
In the field of military operations, there are extensive matters, although with more and more experiences being
texts best referred to, such as the PTSD Compensation and considered as potentially traumatic (www.hcp.med
Military Service report.66 Cohort studies of military per- .harvard.edu/wmhcidi/instruments_papi.php) the thresh-
sonnel deployed in Iraq and Afghanistan suggest a three- old for traumatic events is likely to be lowered, making this
fold elevated incidence of PTSD among those reporting group far more heterogenous.
combat exposures of around 8 per cent.67 As above, there
are vulnerability factors – those with poor physical and
mental health prior to deployment being the most likely to Downsizing and job insecurity
develop PTSD for any given level of combat exposure.68 In
United Kingdom, Gulf War veterans of low rank and leav- In the Stansfeld meta-analysis,42 job insecurity appeared to
ing the service were the strongest determinants of poor have a moderate effect on increasing the risk of future psy-
mental health, with little effect of either pre-deployment chiatric disorder, primarily in men (OR 1.3) in the two
training or post-deployment leave.69 Studies which have studies that assessed this, both by simply asking a yes/no
Psychosocial work environment 839
question.74,75 As with many of these psychosocial risks, the The effect of the recent economic downturn is likely to be
effect seems stronger in cross-sectional surveys. The effect felt most acutely in this group.
of current job insecurity seems stronger in men51,76 and
uncommonly observed in women21 in population-based
studies. The Finnish study also followed up those who left Stigma and discrimination
the workplace showing that for those who found employ-
ment elsewhere, their mental health improved and was in People with psychiatric disorders are among the stigma-
fact better on average than those who stayed, particularly tized and the workplace is an important source of discrim-
after major restructuring. ination.85 The ‘concealability’, attribution of blame and
Job insecurity is noted in two main areas: first when perceived unpredictability are key components of this
organizations are downsizing, retrenching or rightsizing work-placed risk.86 Individuals with psychiatric disorders
(‘making people redundant’ as it used to be called). are less likely to enter the job market and, if they do, they
Although there are some studies from the mid-1990s sug- are more likely to be underemployed, employed in low
gesting positive health benefits during downsizing (e.g. status or poorly remunerated jobs, or employed in roles
Parker et al.77) in general, the remaining workforce appears which are not commensurate with their skills or level of
to be consistently and negatively affected. One interesting education.87 Many more have entered employment over
observation is that the perception of job insecurity medi- the past few years of economic growth, but often in contin-
ates the relationship between actual likelihood of being laid gent and flexible roles.88 They then become harder to iden-
off, e.g. being given warning notices or having members of tify and study, and are overlooked in reports where only
one’s team laid off, and psychological problems.78 This has data from the primary labour market are analysed. The
also been suggested to be mediated through longer hours flexible and short-term nature of these positions may be
and work intensification across a range of countries and attractive to those returning to the workforce following a
industries and occurs despite the observation that those prolonged absence, but this comes at a price. Positions in
still employed tend to be a healthier group than those who the secondary labour market are often unstable, poorly
lose their jobs.79 Chronic job insecurity seems to have a remunerated or open to exploitation. Short-term employ-
particularly strong effect.80 In a large Scandinavian study ees have weaker legal protection, and poorer opportunities
group, the 4783 employees who worked in organizations for training and career development.89 They frequently
undergoing change, but kept their jobs after downsizing, report being denied opportunities for training, promotion
were at a higher risk of being prescribed psychotropic or transfer. Others have been dismissed or forced to resign.
drugs (rate ratio 1.49, 95 per cent CI 1.10 to 2.02 in men Baldwin and Marcus identified over 5 per cent of workers
and 1.12, 95 per cent CI 1.00 to 1.27 in women) than the with a psychiatric disorder who had been laid off, fired
17 600 not exposed to downsizing.81 The association of or told to resign because this fact became known.90
downsizing was strongest with hypnotics among the men Furthermore, those returning to work following a psychi-
and with anxiolytics among the women. Older workers, atric disorder come under far greater scrutiny, such as vig-
those more committed to their employer and potentially ilance for, or overinterpretation of, symptoms,91 or more
male gender were identified as riskier groups for the psy- requests for further information from doctors than those
chological effects of downsizing. Others have identified returning after an apparently physical disorder.92 There
racial factors potentially indicating forms of discrimina- is, however, a spectrum of views – depression is better
tion or stigma.82 tolerated than psychosis, and individuals are viewed more
The other major area of job insecurity occurs in what is charitably if they are taking medication, better still if they
called ‘contingent’ or ‘precarious’ employment.83 This are not currently ill.93
term reflects the growth of flexible workers, such as fixed- When it comes to disclosure of a mental illness to
term employees and workers without an employment con- an employer, most high-income countries have anti-
tract in many OECD countries. These employees are more discrimination policies and laws obliging employers to
likely to have health problems on recruitment, particularly accommodate people despite health problems. The presence
poorer mental health, and also to develop health problems of such laws has made people aware of these processes, but
later.84 This effect is not explained by part-time, as covert discrimination is hard to detect and tackle.94 As
opposed to full-time work, but rather contract type. In such, a challenge for those with psychiatric illness is if, how
many OECD countries, contract workers constitute a size- and when to disclose this to an employer.95 Many patients
able minority of the workforce. As this practice spreads, are reluctant to disclose their psychiatric history96 fearing
there will be more work on this area of insecure employ- being treated differently or having their job offer with-
ment and the broader impacts on health both within drawn, often with good reason. The Shaw Trust, a UK dis-
organizations and society.6 Although some have suggested ability charity, recently conducted telephone interviews
that increased focus on performance has reduced the toler- with CEOs, directors and human resources officers in 500
ance of staff with health problems, the job market over businesses of different sizes. A huge majority (89 per cent)
the early part of this millennium was such that many believed that they did not have anyone with a diagnosis of
with mental health problems re-entered employment. mental illness working in their organization at present.
840 Work and psychiatric disorder
Furthermore, 80 per cent believed that ‘potential employ- returning to work on mortality seen over the first few years
ees should disclose mental health problems prior to was reversed by year four. Any effect of job stressors on the
recruitment’, but when asked if they would employ some- health of women with cardiovascular disease has yet to be
one with mental health problems, only one-third reported shown convincingly, although it has been examined.111
that they would (compared with 62 per cent for physical The potential pathways by which occupational stressors
health disability).97 In terms of what drives these discrimi- lead to physical disease are legion. Some have suggested
nating views, work with human resources managers sug- that any effect of work stressors on cardiovascular health
gested these were based less on an expectation that those may be mediated by psychiatric disorder. Depression, for
with a history of psychiatric disorder would take more time instance, has an independent effect upon the development
off, rather that they would be worse at their jobs.92 of cardiovascular disease in otherwise healthy people112
Disclosure is therefore often delayed until a ‘good impres- and for poorer outcome, in particular recurrent depressive
sion’ has been made.98 In trying to keep problems secret, episodes, after a cardiac event.113 The psychiatric disorder
employees may be less likely to seek appropriate support may mediate this through health behaviours and poor
from occupational health,87 be reluctant to be seen taking adherence, social exclusion or reduced support. Cognitive
medication or to seek time off for hospital or therapy models of harm avoidance, coping and self-efficacy appear
sessions. useful in understanding work-related illness in pain condi-
tions.114 The Whitehall II study suggested that a combina-
tion of adverse health behaviours and the development of
Emerging concepts metabolic syndrome explained a significant part of the link
between work stressors and cardiovascular disease.115
There has been a slew of very recent studies examining Alternatively, linked (pro-) inflammatory and immune
other psychosocial risks. Initial results suggest that employ- responses and hypothalamic–pituitary–adrenal axis dys-
ees with low workplace social capital, both vertical (lack of function are being explored as either common determi-
respectful and trusting relationships across power differen- nants of psychiatric and physical disorders or as the
tials at work) and horizontal components (lack of trust and mediating paths between psychosocial risks and disease.116
reciprocity between employees at the same hierarchical There are whole textbooks in this emerging field of psy-
level) increase the odds for newly diagnosed depression and choneuroimmunology, but a useful introduction can be
antidepressant treatment by 30–50 per cent compared to found in Ref. 117.
their counterparts with high social capital at work.99 Poor One emerging avenue is the impact of many of these
team climate and other group level indictors can also occupational stressors, such as the effort–reward imbal-
impact upon the mental health of employees,100 as can per- ance in men,118 long hours119 and organizational injus-
ceptions of organizational injustice101 and unfairness. tice,120 on sleep disturbance and insomnia. Given that
similar inflammatory and oxidative stress markers are
apparent in people with sleep disturbance as in mood dis-
Psychosocial risk factors at work and physical orders and cardiovascular disease,121 sleep disturbance
disorders may be one of the mediating paths by which health is
affected.122
The contribution of many of these psychosocial occupa-
tional risks to more physical disorders has been addressed.
There are a number of reviews in pain conditions which Toxic exposures and medically
generally show a tendency for higher job strain to be asso- unexplained syndromes
ciated with development of back pain and neck/upper limb
pain.102 Working longer hours is associated with a range Another important consequence of working in high threat
of adverse physical health outcomes.103 Recent evidence locations is the potential for personnel who do so to
suggests that long hours also make cognitive function develop a ‘syndrome’ of physical symptoms which lack a
decline faster in middle age.104 Organizational injustice consistent pathophysiological base. Such syndromes are
and unfairness at work has been linked to cardiovascular categorized in ICD-10 as somatoform disorders and also
disease105 and heavy drinking.106 known as functional somatic syndromes or medically
Work stressors are entrenched in the public’s percep- unexplained symptoms.123 Probably the best known of
tion as a cause of heart attacks, although the evidence is not these conditions afflicted, and continues to afflict, military
consistent, e.g. Kivimaki et al.107 and Eaker et al.108 This has personnel who served in the 1991 Gulf War.124 Although it
led to observations that it is the accumulated impact of is not clear who first coined the term, initial media reports
chronic work-related stressors that are important.109 described so-called ‘Gulf War Syndrome’ (GWS) as being
Certainly, chronic job strain was shown to increase the risk clusters of either unusual illnesses in veterans or their fam-
of recurrent myocardial infarction110 in a predominantly ilies, such as cancers in previously fit veterans, or birth
male cohort, independent of any demographic or medical defects in veterans’ children. Soon, however, the term cov-
risk factors. This was to the extent that the positive effect of ered virtually any physical or psychological symptom,
Psychosocial work environment 841
alone or in combination, occurring in anyone who had associated with low level exposure to a variety of industrial
served in the region. Troops from almost all coalition substances, such as smoke, pesticides, plastics, synthetic
nations, including the United States, United Kingdom, fabrics, scented products, petroleum products and paints.
Canada, Australia and Denmark, reported suffering from However, blinded trials show that in fact those who are
the condition.125 Numerous studies investigating GWS said to suffer with this condition do not react to chemi-
have repeatedly failed to find any definitive evidence of a cals.134 A detailed review of 37 provocation studies con-
syndrome that is specific to Gulf War service. Instead, cluded that ‘persons with MCS do react to chemical
studies repeatedly showed that personnel, who had served challenges; however, these responses occur when they can
in the 1991 Gulf War, report two to three times more discern differences between active and sham substances,
symptoms than those who did not, but the pattern of suggesting that the mechanism of action is not specific to
symptom reporting is the same irrespective of deployment the chemical itself and might be related to expectations and
to the Gulf in 1991. prior beliefs’.135
Although there is no consistent evidence for a causative Another important occupational consideration in these
agent for GWS, medically unexplained symptoms were conditions is that they have a relatively poor prognosis. For
experienced by some 17 per cent of UK service personnel instance, the UK’s Health and Safety Executive suggests
who served in the Gulf War.126 Furthermore, those who that while 40 per cent of those who suffer from chronic
suffer from the condition remain adamant that their work fatigue syndrome may improve with treatment, only few
was the direct cause of their symptoms and disability. The recover fully.136 Once these syndromes are established,
suggested candidates for causative agents are legion and occupational outcomes tend to be even poorer.137
include pesticides, oil fires and vaccinations. One particu- Psychiatric medication, usually antidepressants, is gener-
lar substance, depleted uranium (DU), has been frequently ally not effective at treating these conditions, although
linked to the development of GWS. However, studies of comorbid depression and anxiety, which may be present in
military personnel who have been injured with DU frag- up to 50 per cent of cases, should respond to pharmacolog-
ments, and thus indisputably exposed, have not shown ical approaches. However, there is evidence that cognitive
them to have suffered higher levels of adverse health conse- behavioural therapy (CBT) is effective in some cases.138
quences to date.127 Evidence from the 2003 Iraq War has A 2007 meta-analysis of five CBT randomized controlled
also failed to link exposure to DU with health problems in trials of chronic fatigue and chronic fatigue syndrome
coalition forces.128 Another putative cause was pyridostig- (CFS) reported 33–73 per cent of the patients improved to
mine bromide (PB), which was used, in tablet form, as a the point of no longer being clinically fatigued.139
prophylactic against the possible effects of some chemical However, in keeping with the controversial nature of these
weapons. However, Canada sent three ships to the Gulf, disorders, the use of CBT has often been criticized by
the personnel of only two of which used PB prophylaxis, patients. For instance, a survey (n 285) of CFS sufferers
yet the rate of illness was the same in all three ships.129 conducted by ‘Action for ME’ found that only 7 per cent of
In summary then, although multiple unexplained respondents reported CBT to be helpful, while 26 per cent
symptoms have been found to afflict substantial numbers reported that it made their condition worse.140
of veterans of the 1991 Gulf War, those symptoms did In summary, such medically unexplained symptoms
not cluster in any particular pattern, nor has it been and the associated syndromes are generally difficult to
possible to demonstrate any definitive links with possible manage in the occupational environment because of con-
toxic, causative agents. The GWS legacy continues though, troversy about their causation, their impairing effects on
with a four-year follow up of UK veterans showing that function and the poor response to treatment, particularly
the majority of those who had originally reported GWS when the cause is perceived to be the workplace.
symptoms remained unwell.130 Although GWS is perhaps
the most well known of the military somatization disor-
ders, it is noteworthy that similar patterns of symptoms Future for psychosocial risk evaluation
have been found in military personnel after many other
conflicts.131,132 Whereas the models of job strain and effort–reward imbal-
Moreover, the military is not the only occupation to be ance have merits, the other psychosocial working condi-
associated with an increased risk of controversial somatiza- tions identified above have uncommonly been investigated
tion disorders. Although these disorders go by many in epidemiologic studies, with the exception of responses to
names, such as chronic fatigue syndrome, multiple chemi- traumatic events. In future research, more precise meas-
cal sensitivity or fibromyalgia, the constellation of symp- ures of risk and exposure are needed including duration or
toms, including fatigue, joint pain or dizziness, reported by the intensity of a given exposure. Such evaluation cannot
those who suffer from them are similar, as are the frequent be obtained by means of postal or Internet-based question-
disagreements about what causes them.133 These condi- naires alone. In addition, standardized in-depth interviews
tions tend to affect people of working age (between 20 and can be applied in order to gather more information on the
50 years) and are more commonly seen in women. quality and quantity of occupational risks. These observa-
Multiple chemical sensitivity, for instance, is said to be tions will need to be replicated in different countries and
842 Work and psychiatric disorder
organizations and the relative effects of these versus other None of these
risks determined in well-conducted cohort studies that take 25%
Illness 3%
the full range of mediators and confounders into account.
not appear to be any work characteristics which predict the retirement and disability pensioning.2,180 This rise has not
length of sick leave, although lower education and, surpris- occurred due to a fall in the prevalence of musculoskeletal
ingly, being the main breadwinner, do seem to be associ- disorders – they have just increased more quickly.
ated with longer leave.174 Furthermore, this rise in benefit claims for symptom-
related disorders does not reflect a similar rise in the inci-
dence of such disorders in the population which have
Returning to work remained fairly static over the same period, suggesting a
lowering of the severity at which retirement is awarded.
A successful return to work is the desired outcome for most More research is needed to discover what lies behind this
episodes of sick leave due to psychiatric disorder; however, discrepancy, but it seems probable that it has been brought
there has been little research on how best to ensure that about by a greater acceptance of psychiatric disorders on
personnel do indeed return to work. The longer someone is the part of claimants and their doctors. Even then, the true
off sick the less likely they are to return to work. This is impact of psychiatric symptoms may be underestimated. A
partly due to factors related to the initial difficulties sur- large prospective study found that anxiety and depression
rounding the decision to take time off, but also relates to were strong predictors of ill health retirement awarded for
obstacles implementing a return to work. Fear-avoidant physical disorders.181 The same was found for insomnia,
and catastrophizing coping strategies175 impact on the which only in rare cases is denoted as a cause for disability
decision to leave work and are also likely to play a role in pensions.182
decisions on returning to work, particularly in workers The evidence about the health impact of ill health
who believe that their work has either caused their health retirement is mixed – some studies show an improvement
problem or made it worse.176 A commonly used technique over time.183 However, this apparent improvement might
to overcome some of these problems is a phased return to instead be a return to normal after a temporarily increased
work. The employee starts back to work initially part-time level of symptoms around the time of being awarded the
and gradually builds up the hours and/or days over several disability pension.184 Given the potential harmful social
weeks. While being apparently sensible, there is little evi- and individual effects, it is surprising that many who are
dence to suggest whether such an approach is the best one awarded ill health retirement for psychiatric illness report
to use and, if so, in which circumstances. not having received treatment for it.185 Nonetheless, sev-
Decisions about when to return to work are made more eral studies, most notably of health service employees in
difficult by issues of timing – when is someone who has the UK, identify that a large minority of people supposedly
been off work with a psychiatric disorder ready to go back retired for a (semi-) permanent incapacity are back in
to work? Although obtaining reports from treating physi- work a year later.186
cians is common practice, the only study of liaison between
the employer and the employee’s treating physicians found
that doing so actually increased the time to return to work Burnout
in those with psychiatric disorder, although communica-
tion between employer and employee only, had a positive Burnout is defined as a ‘prolonged response to chronic
effect.177 There is also no standard way in which an individ- emotional and interpersonal stressors on the job’ and is a
ual moves through the ‘stages’ or ‘phases’. Should the widely used term in occupational psychology and even a
employee increase his hours in a preordained fashion qualifying ‘diagnosis’ for accessing social welfare benefits
decided at the start or should the increase depend on how in some countries, such as Sweden.187 The concept is
well he is performing, or his level of symptoms? In many almost universally measured by one or other version of the
physical disorders, where the natural history of this aspect originator’s assessment: the Maslach Burnout Inventory
of recovery is relatively well understood, these dilemmas (MBI), the primary version of which has 22 items. The
may be less important, but recovery from psychiatric dis- three key dimensions, as postulated by Maslach, are of
orders is less predictable, and might not fit into a rigid ‘overwhelming exhaustion’, ‘feelings of cynicism and
protocol. The attitudes of the individual’s co-workers and detachment from the job’ and ‘reduced effectiveness/
resentment over covering their work or perceived under- accomplishment’. There is an extensive literature associat-
performance might also play a role in making the return to ing burnout as an outcome of a range of negatively per-
work a success.178 These effects appear even greater in those ceived work experiences. However, Wieclaw has identified
from minorities, compounding the discrimination.179 conceptual and measurement difficulties with this concept,
including the challenging issue, from an occupational
health and preventive perspective, of providing convincing
Ill health retirement and disability pensioning evidence of the relationship between burnout and specific
occupational exposures.188 There are strong correlations
In both the United Kingdom and many OECD countries, of burnout with psychiatric disorders, such as depression
psychiatric disorders have now overtaken musculoskeletal and anxiety, and personality traits like neuroticism and job
disorders as the most common cause of ill health satisfaction (from 0.40 to 0.75). The questions in the
What influences the interface of occupational risks and psychiatric disorder? 845
measure itself ask the respondent to attribute their sickness absence: a psychosocial prespective (p. 804), a host
response to their job which, it is argued, establishes that of contextual factors plays a role in shaping these influ-
‘burnout is a problem that is specific to the work context, ences. More recent work has demonstrated the proximal
in contrast to depression which tends to pervade every effects of an individual’s cognitive processes as the media-
domain of a persons life’,187 regardless of conflicting evi- tor between external factors and occupational dysfunction.
dence showing the substantial contribution of non-work Karasek and Theorell,36 Marmot197 and Stansfeld et al.39
factors if assessed, e.g. life events.189 This study of medical have all alluded to the role of such individual perceptions,
students also highlights problems with the term being used which have been extensively studied in the field of muscu-
as an end point. Nearly 50 per cent of the medical students loskeletal disorders, but less so in psychiatric disorders.
were already classified as ‘burnt out’ yet the vast majority What might influence such perceptions is difficult to
will go on to long and productive careers in the same study, but a range of related personal factors are important
area. Recent work has shown that once labelled burnt out, determinants of psychiatric disorder and are candidates for
someone has a greater risk of permanent disability in mediating the effects of work upon mental health.
Finland even accounting for baseline diagnosable disor- Job satisfaction is strongly associated with mental
ders.190 While burnout is not a psychiatric disorder, and health in meta-analyses,198 as are many aspects of percep-
unlikely to become so in DSM-V or ICD-11, establishing tion and personality.199 These derive from a combination
the concept’s utility and validity as potentially a mediator of temperament, mainly genetic, and a range of early expe-
of work-related stressors and disorder is warranted. riences. Using lifecourse data, Henderson et al.200 have
shown that teachers’ ratings of temperament in childhood
and even whether the child’s father was off sick were also
Comorbidity of physical and psychiatric strongly predictive of work disability in adult life, over and
disorders above accepted predictors such as IQ and education. This
suggests there are early life influences upon health behav-
Psychiatric disorders are often comorbid with physical ill- iours which affect the likelihood of an individual to take
ness. Attributing sickness absence to a single physical sick leave.
‘cause’ ignores the multiple factors that contribute to the Individual perceptions on work functioning are influ-
process. The propensity for those with psychiatric disor- enced by a number of other contextual factors, the most
ders to have periods of absence ‘… not necessarily the type notable being balancing demands between work and other
diagnosed as nervous’, has been recognized for at least aspects of life. Appreciation of this by researchers (lagging
80 years.191 Many cross-sectional studies have shown behind clinicians) has shown that such factors as perceiv-
higher unemployment or poorer occupational functioning ing an imbalance between work and family/personal lives
in people who have comorbid depression and anxiety. For was strongly associated with current mood problems in
instance, the presence of a comorbid depression192 and both genders and in anxiety in women, even making
anxiety193 is associated with greater degrees of work dis- allowances for standard work stress measures,201 a gender
ability across all pain-related conditions. effect seen elsewhere.202 In some cases, a specific home life
For those who are employed and experience an episode pressure actually makes some people more likely to come
of physical illness, even accounting for the physical impair- to work.165
ment arising from that condition, the presence of mental The interaction between work factors, the individual
ill health, usually defined by some cut-off point on a scale, and their psychiatric disorder can best be understood using
has a deleterious impact upon returning to the workplace. a dynamic model whereby individuals are seen as active
Glozier et al.194 showed that for the 20–25 per cent of agents making decisions about their status along a ‘sickness
people who have a stroke while of working age, over half journey’ as shown below. This accords with what is called
return to work by six months. However, those with mental the ‘voluntaristic’ aspect of sickness behaviour in an occu-
ill health were less than half as likely to return, even after pational setting.203 It provides a framework for thinking
adjusting for levels of physical disability and other factors. about how to manage an individual with psychiatric symp-
Similar findings have been shown after myocardial toms in a specific context as there will be a host of influ-
infarction.195,196 ences on the cognitive factors underlying each decision.
Certainly tackling the cognitions that determine these
decisions has been shown to improve such occupational
WHAT INFLUENCES THE INTERFACE OF disability as return to work after myocardial infarction.204
OCCUPATIONAL RISKS AND PSYCHIATRIC This dynamic model (Figure 66.2) suggests that an
DISORDER? employee’s perception of their symptoms and health
occurs in a specific context leading to the person actively
Most research into the effect of work characteristics upon making a decision about their work status. The journey
the development or exacerbation of psychiatric disorder starts with perceiving sensations or feelings as symptoms of
has focused either on the nature of the work or the nature illness that may or may not have an effect upon function.
of the disorder. As shown in Chapter 64, Work, stress and Any reduced function can be expressed as either taking
846 Work and psychiatric disorder
Asymptomatic worker
Drivers of
mental ill health:
– occupational
factors
– external demands
– physical illness
– substance use
– individual
Symptomatic worker
resilience/vulnerability
– employer/union
responses
– cultural factors
Fear of stigma and
– insurance and
discrimination
1 legal framework
Sickness benefits,
workers‘ compensation
and disability policies
4
Figure 66.2 Decisions made by employees during their sickness pathway and potential influences.
leave from work or presenteeism. The decision (point 1) required. The decision to seek (point 2): this is also multi-
on which of these two options to take will, as shown above, factorial and includes such factors as ease of access, benefit
be affected by a range of factors, e.g. personality (conscien- systems and perception of how likely the doctor is to
tiousness, for instance), background culture of working, concur with the patient. After a period of time on some
organizational (team structure or flexibility) and social form of sickness benefit, a decision has to be made upon
characteristics (level of unemployment), as well as per- returning to work – of either the original role in some
ceived severity. Most countries allow some period of self- form – full or modified (point 4) or of moving to another
certified absence after which a doctor’s confirmation is role, or seeking the more permanent support of a disability
What can be done in the workplace? 847
pension (point 3). These time periods, ease of access, level intensive 40-hour programme did appear to have a benefi-
of support, etc., vary dramatically across countries, as do cial effect,207 suggesting a major commitment was needed
even the diagnoses allowable for compensation. It is the to make an impact.
understanding of this sickness pathway that underpins
much of what professionals in the field do (Figure 66.2).
Primary and indicated prevention through
individually focused interventions
WHAT CAN BE DONE IN THE WORKPLACE?
Alternative approaches have focused on the individual
While it is clear that workplace factors have a moderate role worker, rather than the work environment, with interven-
in the development and perpetuation of psychiatric disor- tions aimed at increasing an individual’s ability to cope
ders, and that the public health impact of psychiatric symp- with stressful work situations. Two separate systematic
toms on occupational outcomes is enormous, it is unclear reviews have concluded that the heterogeneity of individu-
how governments, insurers, employers and health services ally focused prevention programmes and the limited
should respond. The most striking feature of the research methodological quality prevent any definite recommenda-
to date is the paucity of high quality studies addressing tions being made.207,213 Nevertheless, both reviews
these questions.205 There are also differing views from reported that the majority of stress management pro-
reviews of the same literature, potentially dependent upon grammes have a modest or short-term impact on a range
the views of the authors and the rigor of the review criteria of variables associated with individual distress. Other
which make any recommendations difficult. reviews have concluded that interventions which reduce
psychological distress among workers will also reduce
levels of sickness absence.214 A meta-analysis of 48 experi-
Primary and indicated prevention through mental studies agreed that individually focused interven-
organizational interventions tions designed to reduce or prevent psychological
consequences of occupational stress tended to be more
A common conclusion from the epidemiological studies of effective than organizational interventions,215 and that
psychosocial risk factors is that one or more of the identi- cognitive behavioural therapy had the best evidence for
fied factors should be tackled to prevent later psychiatric effectiveness.213,215 New linked interventions, such as
disorder. While there have been some examples of simple acceptance and commitment therapy (ACT) may have a
changes in the workplace, such as in the pattern of shift role in reducing psychiatric disorders in employees via
work, leading to lower levels of distress,206 a recent system- increasing their acceptance of undesirable thoughts and
atic review concluded that there was currently insufficient feelings.216 A similar review in healthcare workers sug-
evidence to judge the effectiveness of any specific organi- gested a positive effect of individual interventions, gener-
zational changes.207 Graveling et al.207 identified a range of ally cognitive and behaviourally based, on ‘stress and
participatory approaches to changing organizational prac- burnout’.217
tices in 11 studies, fewer than half of which showed a pos- A number of employers have instigated general ‘healthy
itive benefit upon ‘mental well-being’. A systematic review lifestyle’ programmes to improve employee health and,
of organizational interventions to improve employee con- presumably, occupational performance. Undertaking reg-
trol could not identify a single randomized controlled trial ular exercise and maintaining a healthy weight may help
(RCT) in this field of study.208 A small majority of the prevent psychiatric disorders,218 but no reliable studies
studies showed some benefit and two studies which ran have been able to demonstrate that exercise programmes
concurrently with redundancies reported worsening in the workplace reduce levels of psychiatric illness.213
health. An interesting observation from a second review by There is, however, some evidence from observational stud-
this team209 suggested that task-restructuring interven- ies that workers in sedentary jobs who engage in regular
tions increasing team working had minimal or no effect strenuous leisure-time physical activity outside the work
and that working in autonomous groups in fact caused environment, have a lower risk of sickness absence due to
deterioration in the psychosocial work environment, with psychological complaints.219
resulting health effects. Interventions that did manage
to improve employee control appear to have a positive
effect, but the processes by which this is achieved have not Screening and treatment of established cases
been identified, making any replication of the study very of psychiatric disorder
difficult.210
Educating and training individual managers about Health screening is an established part of risk management
psychiatric illness and the potential importance of job in many larger organizations. A large trial220 demonstrated
strain through web-based or more traditional formats, that screening for depression in the workplace, followed by
although attractive, does not seem to reduce either job a systematic programme of telephone outreach and care
strain or psychiatric illness when evaluated.211,212 One management (encouraging employees to enter appropriate
848 Work and psychiatric disorder
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SECTION THREE
Substance abuse
JONATHAN D CHICK
WORKPLACE PROBLEMS RELATED Although heavy drinkers are most at risk of accidents at
TO ALCOHOL work, it is moderate drinkers who, because they are more
numerous, account for most of the cases; hence ‘the pre-
Work competence and safety ventive paradox’.1 Harm at work will be reduced if all
employees reduce their alcohol consumption, not only the
The acute effects of alcohol are chiefly those of a central heaviest drinkers. When a port authority reduced availabil-
nervous system depressant, leading to impairment of ity of alcohol at lunchtime, it removed a peak of accidents
reasoning, perception, reaction time, balance and co- in dock employees in the afternoon and reduced the
ordination. In some drinkers, in the appropriate social overall rate of accidents.
setting, a transient disinhibition gives the feeling of
enhanced interpersonal communication and well-being. Chronic use of alcohol and performance
This is partly due to culturally defined expectations.
However, in this state, decision-making, operating machin- Light drinking of up to 4 units/day in middle age and above
ery, driving and other skilled activities are compromised. is associated with better cognitive functioning than absti-
Even before the burgeoning of UK alcohol consump- nence, even after adjusting for basic educational attain-
tion in the late 1900s, surveys found that 24 per cent of ment, social and health confounders.8–10 It is suspected
company executives in a variety of organizations and that there are inefficiencies of cognition in those drinking
14 per cent of manual workers in alcohol production between 8 and 16 units/day, while above 16 units/day
industries admitted to occasional impaired work efficiency impairments of the degree seen in alcohol treatment clinics
due to drinking in the preceding six months.1 The dose- will sometimes occur, the early signs being impaired prob-
related effects of alcohol on motor/perceptual skills and lem-solving, rigidity of thought, impaired recent memory
judgement have been shown in American drivers.2 A blood and difficulty with spatial tasks.11
alcohol level of 60 mg/dL (produced by approximately two
consecutive pints of 3.5 per cent alcohol by volume beer,
i.e. 4 UK units, where 1 unit contains 8 g ethanol) doubled
Epilepsy
the risk of involvement in an accident compared with driv-
‘Rum fits’ were well known in the British Navy, usually
ers with no alcohol in the blood; levels of 100 mg/dL (con-
occurring two to three days after the ship left port. An anal-
sumption of 7 units) and of 150 mg/dL (consumption of
ogous situation occurs now in oil rig workers. Oil rigs are
10 units) were associated with increased risk of six and
alcohol-free zones to which workers return after two weeks
25 times, respectively. Laboratory experiments show that
on shore. In drinkers who develop chemical dependence,
risk-taking increases and perceptual decision-making
an epileptic seizure can occur when alcohol consumption
skills begin to decline at blood alcohol levels as low as
is reduced or ceases. Although this may be an immediate
25–50 mg/dL. After a major train accident in California, a
indication for a change of job if machinery is involved,
survey of drinking among railroad workers revealed that
clinical experience shows that affected individuals do not
more than 33 per cent of employees reported seeing a
have recurrence of fits if they maintain long-term absti-
co-worker drinking on duty in the preceding year and
nence from alcohol (or if, after some months of abstinence,
20 per cent reported seeing a colleague too drunk to work.3
they eventually resume drinking but keep consumption
Workers seeking medical attention after an accident
below, say, 10 units per week).
often refuse a blood alcohol test. Thus, estimates of the role
This may be the first presentation of alcohol depend-
of alcohol in industrial accidents are very approximate.
ence. Investigations might be necessary to exclude other
In an autopsy study of cases where the death certificate
causes of late onset of fits. The electroencephalogram in
recorded ‘injury at work’, 9.2 per cent were found to have a
alcohol dependence does not show epileptic foci.
blood alcohol level of over 100 mg/dL; workers in the
transport industry were the most commonly affected.
Diazepam was detected in 15.6 per cent of cases, although Absenteeism
the extent of its use in the local population of working age
was not available for comparison.4 An autopsy study of General practitioners are sometimes asked by drug or alco-
fatal occupational injuries in Maryland found that 11 per hol users for medical certificates to cover absence from work
cent of cases had a blood alcohol concentration of at least actually spent seeking drugs or drinking, or recovering from
80 mg/dL.5 Since alcohol continues to be metabolized after the effects thereof. Clinicians should be aware of the typical
death, these rates might underestimate the true prevalence. pattern. Where weekend drinking is the culture, Monday
Laboratory studies of ‘hangover’ have examined cogni- morning is the most common day for alcohol-related
tive function the next day after a ‘normal’ evening’s drink- absenteeism, usually because of hangover or gastrointestinal
ing by university students, when the blood alcohol level upset. If pay day is on Thursday rather than Friday for the
has returned to zero. They find that performance is weekly paid staff, some drinkers will not appear for work on
impaired on tests of vigilance and reaction time, and Friday. Such absenteeism is common even among those
possibly memory.6,7 whose alcohol-related problems are not severe.
Identification of the problem drinker/drug addict 861
The study of Scottish company executives/alcohol pro- have a higher average intake of alcohol at recruitment than
duction workers, mentioned above,1 found that 4 per cent biscuit factory workers, but the brewery workers also
of the executives and 23 per cent of the workers admitted increased their consumption to a greater extent during the
to being off work because of alcohol in the two-year period next two years.19 Thus, both selective recruitment and
before the survey interview. A higher than average medical exposure contribute to the alcohol-related risks in the
consultation rate was noted in the ten years that preceded a brewing industry. Both may also be important in seamen
diagnosis of alcoholism in a sample of US Navy person- (officers and crew) and fishermen, who have mortality
nel.12 Drinkers whose problems are sufficient to lead to rates for hepatic cirrhosis three or four times the average.
attendance at an alcohol problem clinic have twice the Absence from home and family, and lack of a normal social
sickness absenteeism rate of the general population.13,14 and sexual life, are clear risk factors; they may also con-
Sickness absence certificates covering alcohol-related tribute to the higher rates of cirrhosis in the armed services
absenteeism span a wide range of diagnoses, including and the construction industry. In the latter occupation in
gastritis, anxiety state, nervous disability and injuries.13 England, recruitment of labourers from Ireland and
In the New South Wales police force, heavy drinkers were Scotland is also relevant, because among them there is a
found to have more sickness absenteeism.14 higher proportion of heavy drinkers than among indige-
nous labourers.
Professions with higher risks include insurance, finance,
Mortality law and journalism. In the most recent decennial report,
UK doctors were for the first time in 40 years no longer
The famous J-shaped curve of alcohol consumption versus showing an increased mortality from alcohol-related
mortality is only seen above age 35.15 This is presumably causes.20 Freedom from supervision at work, high incomes
because deaths from accidents begin to occur in young and the emotionally demanding nature of their work have
people whose average consumption is low, and when they been proposed as reasons why these professions have
drink heavily they lack tolerance, as well as being inexperi- increased rates of alcoholism. The culture at work presum-
enced drivers. The contribution of alcohol has been dis- ably explains some of the journalists’ problems, just as the
cussed above. Among new conscripts to the Swedish army business lunch routine and the after-business wine bar
(aged 18), those who admitted to drinking over 250 g of have contributed to alcoholism among executives.
alcohol per week (30 units) had a mortality rate over the
subsequent 15 years five times greater than the remainder.16
The risks of several cancers are increased in drinkers: Other contributing factors
cancer of the mouth, pharynx, larynx and oesophagus,
colorectum and breast cancer in women.17 Rates of death Clinicians assessing individual patients with alcohol and
among heavy drinkers are increased for haemorrhagic drug problems must consider the following factors outside
stroke, liver disease, suicide and violence. This increased the occupational sphere: other psychiatric disorder to
mortality commences with consumption as low as 4 units which substance misuse is secondary, such as anxiety,
per day. However, after middle age, abstainers have a phobic or panic disorder, and depressive illness; family
higher mortality than light drinkers. Thus, the mortality history of alcohol or drug misuse (alcohol problems are
risk curve for alcohol consumption is J-shaped. Care has to highly heritable); living alone; or death of a spouse.
be taken in interpreting these data because the group of Divorce or legal separation from a spouse can, of course, be
‘abstainers’ may include ex-drinkers (and often ex-smokers) a cause or consequence of substance misuse.
who have commenced abstaining because of diagnosed
illnesses such as heart disease, rather than being life-long
abstainers. Moderate drinkers (1–3 units/day) may be peo- IDENTIFICATION OF THE PROBLEM
ple with better social adjustment and a healthier lifestyle DRINKER/DRUG ADDICT
than either abstainers or heavy drinkers, but even taking
this into account the evidence is increasingly persuasive The workplace is often where an alcohol or drug problem
that moderate ethanol consumption in those over four is first identified. Accidents, illnesses or a drink/drive
years of age protects against coronary artery disease and conviction may make the diagnosis clear. Unreliable time-
possibly ischaemic stroke.18 keeping, coming to work smelling of alcohol and (or)
arguments with colleagues are earlier signs, but are often
missed. ‘Denial’ of the contribution of alcohol or drugs to
WORK FACTORS CONTRIBUTING TO such difficulties is common and such overt signs as shaky
ALCOHOL-RELATED PROBLEMS hands in the morning might wrongly be attributed to
‘stress of the morning business meeting’. The individual
Mortality rates from hepatic cirrhosis vary with occupa- may evade any discussion that could implicate alcohol as
tional group and are highest in the alcohol manufacturing the cause of his difficulties. The drinker or drug user is
and retailing industries. Brewery workers were found to likely to perceive any discussion of his habit as one of
862 Substance abuse and the workplace
Only answer the following questions if your answer above is monthly or less
How often in the last year have Never Less than Monthly Weekly Daily or
you not been able to remember monthly almost
what happened when drinking daily
the night before?
How often in the last year have Never Less than Monthly Weekly Daily or
you falled to do what was expected monthly almost
of you because of drinking? daily
Has a relative/friend/doctor/health No Yes, but Yes, Figure 67.3 The FAST Alcohol Use Disorders
worker been concerned about your not in the during the Screening Test. Score of 3 or more suggests a
drinking or advised you to cut down? last year last year
hazardous or harmful drinker.21
moral disapproval: any comment about his behaviour is management about performance and attendance. A full
seen as an insult. He/she may be practised at evasion and history, including a non-judgemental, objective enquiry
colleagues at work may be misled or afraid of upsetting the into drinking patterns and drug use, should eventually
cantankerous employee, and minimize the problem or be elicited:
cover up. Yet it is the manager at work who is well placed
to intervene when an alcohol- or drug-related problem ● What is your current main concern?
occurs. ● Help me understand how this came about.
Because alcohol has a legitimate and accepted role in ● What are the various factors in your view?
Western society, the manager who confronts an employee ● Where does your use of alcohol fit in? Have you used
about smelling of alcohol at work may be made to feel a alcohol to help with stress/insomnia?
‘killjoy’ or ‘wet blanket’. Managers may become more ● What would your partner say if he/she were here?
motivated to involve the personnel staff or occupational
physician as soon as work performance is affected if they The clinician might specifically enquire into the past seven
can be persuaded that early intervention for substance days, work and leisure time, to determine what and where
misuse can prevent later, more difficult and perhaps costly drinking (or drug use) took place. Ask about injuries at
problems which might arise when the employee is involved home, at work, on the road or at leisure, and enquire
in an incident – or long-suffering workmates finally lose about any relation to alcohol. Specifically, ask about police
their tolerance. involvement or convictions. Ideally also, information
The manager must, however, take a delicate and confi- from the family is obtained, because in this situation it is
dential approach. The manager’s role is not the diagnosis common for individuals to minimize their alcohol or drug
of alcohol or drug problems, but the assessment of work intake and the problems caused.
performance. He or she should firmly encourage the
individual to consult the occupational physician or general
practitioner, who should then deal with the patient with Clinical features
the usual care about confidentiality.
Any clinician assessing a patient with a drink or drug Intoxication with alcohol or sedatives may manifest as
problem should ask about comments or complaints from slurred speech or disinhibited behaviour. Inappropriate
colleagues and managers at work as well as from those at giggling or elation might indicate cannabis intoxication
home, and if disciplinary action has commenced, know (Figure 67.5). At physical examination, the heavy drinker
what stage has been reached. may show excessive capillarization of the conjunctivae
When a health screening opportunity arises, a useful and skin of the cheeks and nose. Close examination of
questionnaire for alcohol screening is FAST (Figure 67.3).21 the tongue may reveal the smell of alcohol on the breath.
The test identifies problems with alcohol at an early stage, In the dependent drinker, tremor of the tongue and mouth
as well as later cases of alcohol dependence. can be seen before it is visible in the outstretched fingers.
Intoxication with sedatives may cause nystagmus. Opiates
cause constriction of the pupils; there may be venepuncture
Assessment marks. The drinker may have an enlarged liver, signs of
parenchymal liver disease, cerebellar ataxia particularly
Within the confidential interview (Figure 67.4), the affecting the gait, weakness of the proximal shoulder and
clinician discusses with the employee information from pelvic girdle muscles, or evidence of peripheral neuropathy.
Identification of the problem drinker/drug addict 863
Occupational health
Consider blood tests for future monitoring Negative for alcohol problem
Positive for alcohol problem
Link with treatment agency Negative for other health problem
Figure 67.4 Managing the employee with a suspected alcohol problem. HR, Human resources/personnel manager.
Hepatomegaly Smell of alcohol; positive breath LFTs (specify GGT and AST)
signs of neuropathy or blood alcohol (laboratory to keep serum sample for later CDT) Full blood count
greater confidence to the diagnosis of alcohol abuse. work should be passed to the treatment agency if the
Clearly there are other medical conditions, and medication employee is still being dealt with under the policy.
effects which can cause false positives, obesity is associated Supervision, independent of the treating agency, with
with slight elevations of GGT. Two abnormal findings are objective testing, is recommended. (This is important
a stronger indication of heavy drinking than any single for the success of such policies, but not always
abnormality. enshrined in the policy.)
Serum carbohydrate-deficient transferrin (CDT) is a 5. If there is poor cooperation with treatment, or if
marker used by some specialists. A standard 5 mL venous treatment fails, the employer may return to the
blood sample is required. Only selected clinical chemistry disciplinary route if this were justified (i.e. the ultimate
laboratories run the test routinely. The percentage of sanctions of disciplinary action or termination of
transferrin which is deficient in its carbohydrate moiety is employment on health grounds remain when all
calculated. This is raised in some 60 per cent of those efforts at help have failed).
recently drinking above 60 g per day. It may be elevated in
primary biliary cirrhosis, but is only rarely raised in other Some large companies in North America employ staff to
non-alcoholic liver disease and is not affected by common run the alcohol and drug policy, and to make assessments
medications.22 Although sensitivity for detecting excessive of drug and alcohol problems. Elsewhere, the responsibility
drinking is only slightly greater for CDT than for GGT, for the policy is with the human resources department, the
specificity is greater (i.e. fewer false positives). It is useful health and safety team or the occupational health team, and
when the cause of a raised GGT is being explored. assessments are made by outside agencies including, in the
An indirect method of screening for people in whom it United Kingdom, by the National Health Service. Guidance
might be clinically relevant to ask about drinking, is to ask in the United Kingdom has been provided by the Health
about fractures or dislocations, head injuries, assaults or and Safety Executive.28 It is important that clinicians clar-
road traffic accidents since the age of 18. When sports ify at the first interview whether such workplace policies
injuries are excluded, it is found that people who answer exist, and especially whether point 4 (above) applies.
‘yes’ to two or more of the above, and then answer positively
to the question ‘Have you been injured after drinking alco-
holic beverages’, are likely to have an alcohol problem.27 Coercion? – ethics
had a role in their coming for treatment (see under guided by the general practitioner or nurse. Ideally, the
Helping a fellow physician, p. 867). patient is seen daily to monitor the dosage of the medica-
When treating an employed substance misuser, if his or tion (usually benzodiazepine) and to ensure that drinking
her problem is already known to the employer, it can is not continuing. Admission to hospital is appropriate if
sometimes improve the outcome of therapy to recommend this fails, or if the individual is liable to severe withdrawal
such supervision by the employer or his nominee. symptoms and lives alone. (A patient drinking 25 or more
When substance abuse has led to doubt about fitness to units per day may require 50 mg of diazepam or equivalent
work in very critical posts, for example in the airline indus- in the first 24 hours, reducing to zero over 5 days.)
try (pilots, traffic controllers) and medicine, continued Subjects can also withdraw from benzodiazepines,
supervision of compliance with abstinence, including opiates and stimulant drugs as outpatients. The socially
random monitoring of breath, sputum, urine or blood unstable young abuser often takes a very wide variety of
tests, contributes to good outcome. substances, including alcohol, and discussion during a
drug-withdrawal regimen should include strategies of
developing a different lifestyle.
INGREDIENTS OF SUCCESSFUL TREATMENT Medical aid for the opiate abuser who requests detoxifi-
cation is necessary only if chemical dependence exists –
Perhaps the most important element of treatment is for the often such abusers are only intermittent users and hope to
individual to enter a non-judgemental, objective relation- obtain more drugs (sometimes to sell) by requesting
ship in which he can weigh up the advantages and disad- detoxification. Treatment will consist of either substituting
vantages of continuing the alcohol or drug habit. Only a reducing dose of oral liquid methadone or sublingual
then is it possible for him to make a firm decision to alter buprenorphine, with controls to check other continuing
his habit and obtain support to stick to that decision. drug use, or attempting to reduce withdrawal symptoms
It was common practice in North America, to offer the with clonidine or lofexidine, perhaps with a benzodi-
employee residential treatment with an emphasis on group azepine to aid sleep. A specialist clinic should advise about
therapy lasting between four and six weeks. Controlled appropriate doses. Ultra-rapid withdrawal by giving an
studies demonstrating the advantage of such relatively opiate antagonist while the patient is unconscious under
expensive treatment over outpatient care are lacking. anaesthetic is possible, but is rarely practised because of
However, specific psychological treatments such as marital the risk of respiratory or circulatory failure. It requires
counselling, anxiety management and social skills training full intensive care facilities, an experienced addiction spe-
have been shown to be effective. cialist and an experienced anaesthetist. In such hands, the
Alcoholics Anonymous has helped thousands of alco- patient’s discharge and return home after being prescribed
holics, in many countries, and a stable fellow employee naltrexone can be achieved in a few days.
who is an AA member may be a great help in introducing a
colleague. Narcotics Anonymous (NA), for drug abusers,
Deterrent medication
can be found in some cities.
Psychotropic medication to reduce relapse may occa-
When an employee has been given his final warning, the
sionally have a place if other psychiatric disorders are treatment agency may suggest that he takes disulfiram
found to persist after the drug use has ceased.
supervised at work or at a clinic. The occupational physi-
Two compounds (naltrexone and acamprosate) are
cian or employer’s representative can request assurance
now licensed in many countries to help prevent relapse in
that the employee is complying in swallowing the medica-
newly abstaining alcoholics. Their neuropharmacological
tion as required, which might be daily, or in double doses
actions, while different from each other, are consistent
if administered three days per week. The deterrent effect
with current knowledge of the neurotransmitter basis of
of this drug is its highly unpleasant alcohol interaction and
dependence and relapse. The characteristics of patients
depends on taking it regularly in sufficient dosage.
most likely to respond are still to be specified. However, Counselling on changing lifestyle during the disulfiram-
when patients are willing to take disulfiram, in a supervised induced abstinence is important if relapse is not to occur
arrangement to improve compliance (see under Deterrent when the disciplinary period ends. Naltrexone can be used
medication), and are randomly allocated to either that in the same way with an opiate abuser. Naltrexone blocks
treatment or to supervised acamprosate or naltrexone, the rewarding mental effects of opiates, rather than causing
disulfiram has been shown to be more effective than either an aversive reaction, and, if taken regularly (perhaps three
naltrexone or acamprosate.30 times per week), greatly reduces the risk of relapse.
supports (family and job) and without impulsive personal- although studies of psychomotor performance in patients on
ities and many social problems are those who might a stable dose of methadone have not shown impairment.
succeed to control their drinking. Abstinence is the appro-
priate goal for most other alcohol and drug abusers.
Services for opiate addicts, because of the imperative of Ordinary licence – The high risk offender
reducing the spread by needles of AIDS, have emphasized scheme
‘harm reduction’ and offered substitution therapy to many
injecting opiate users. Although many opiate users state to On reapplication for an ordinary UK driving licence
research interviewers that they would like to become absti- following disqualification for drink/driving, a driver must
nent, the relapse rate among those who are helped to with- satisfy the Secretary of State for Transport’s medical advis-
draw is high. Therefore, oral methadone or buprenorphine ers that he or she is not, or never was, alcohol dependent, if
is offered, to satiate the opioid neuroreceptors and thus to (1) the blood alcohol at the time of the offence was 200 mg/L
reduce injecting, and stabilize the user’s pattern of life. or more, or (2) he or she refused the tests, or (3) he or she
Patients taking regular doses of substitute opiates may be has been disqualified more than once in ten years.
able to perform satisfactorily at work, unless they are also
using additional ad hoc street drugs, which treatment
clinics try to prevent but cannot rule out. Maintenance SUBSTANCE MISUSE AND THE MEDICAL
prescribing of benzodiazepine to benzodiazepine addicts is PROFESSION
common, and some users continue functioning effectively
at work, but should not drive vocationally or operate The annual reports of the UK regulatory authority, the
machinery because reaction time and cognitive function General Medical Council (GMC), show that alcohol and
may be impaired. drug misuse, with or without other psychiatric disorders, is
a common cause of unfitness to practise.
‘Stress’ in the medical profession was widely researched
Prognosis and discussed in the 1990s33,34 and it appears that person-
ality features may contribute both to an attraction to a
In individuals who have reached criteria for dependence medical career and to a vulnerability to stress.35 Stress can
and/or have come for treatment, a period of abstinence be a factor in substance misuse in doctors, but should not
from drugs or alcohol of less than a year has no prognostic be too readily assumed to be the central issue. For some,
value.31 Abstinence for one year begins to indicate a good addiction has simply begun as a great liking for a drug’s
outcome. Individuals do best when they still have a job and euphoric effects. Medical student life in Western countries
a close relationship. In the emerging life story of males who can involve heavy drinking. Later on, doctors not only
at some stage in their life abused alcohol, it can be seen that have sufficient income to subsidize heavy drinking, but
an abstinent period of five years is only very rarely followed they also have relatively easy access to other addictive sub-
by a relapse, but nevertheless can still occur.32 It is clearly stances. Anaesthetists are at particular risk of opiate misuse
very difficult to decide when it will be safe for a recovering (oral or injected) or misuse of anaesthetics (sniffing), and
alcohol or drug misuser to resume work, especially if when may experiment to the point of dependence. Pharmacists
the job is responsible for public safety, for example as a and veterinarians share the high risk of drug dependence
driver, pilot, ship’s captain or a doctor. Monitoring is essen- due to the availability of addictive drugs.
tial and might reasonably continue for up to five years,
although some US medical boards recommend 15 years.
Helping a fellow physician
Vocational driving licences Work colleagues may have maintained a blanket of secrecy,
so that the addiction is well advanced when help is eventu-
In the European Union and in many other countries, ally sought. Your support and understanding may be
employees with an alcohol or drug problem are not per- needed, but you may also need to take a firm stance (easier
mitted to drive large goods- or passenger-carrying vehicles. if disciplinary action is pending) to shift the misusing doc-
A minimum of several years (three years in the United tor to the point of acceptance that there is a problem to be
Kingdom) since cessation of treatment, and evidence of addressed.36,37 This requires courage and compassion, not
recovery, is required before renewal of the licence. covering up. If he or she is a work colleague, leave the treat-
The driver who develops a drug or alcohol problem ment to a specialist. If the doctor makes no attempt to seek
should declare this to the licensing authorities. Opiate addicts advice, then others who can bring some coercion to bear
maintained on oral methadone and patients receiving regu- may need to be involved, for example, the hospital man-
lar benzodiazepines may not hold vocational licences in the agers, the appropriate section of the local health authority
UK and the European Community. It is a debated point or, when none of these are relevant and fitness to practise is
whether such individuals may hold ordinary driving licences, in question, the GMC or appropriate licensing board.
868 Substance abuse and the workplace
In helping a substance-misusing doctor, the dialogue accepted, self-referrals to these programmes are rare and
should be as with an intelligent layman, without assuming managers still tend to refer only when impaired work
he or she has special knowledge. Commence with his or performance is severe or chronic.
her main concerns, using a non-judgemental style. Avoid Employee committees, when consulted about health
secrecy. Be ready to set limits and prevent too early discon- promotion they would see as relevant, tend not to mention
tinuation of treatment. Beware too ready an acceptance of drugs or alcohol. They perceive organizational stressors
the view that ‘stress’ or ‘depression’ are the main issues: the as the most important: deadlines, unrealistic expectations,
main issue may be the substance dependence itself, but this excessive supervision, inadequate supervision, poor feed-
is not yet identified/accepted by the individual. It is easy to back and harassment.43 Health promotion in the work-
collude in a way that only postpones dealing with the place should be broad and look at links between personal
dependence on the drug, that is, to making a commitment health practices (eating, smoking, exercise, weight con-
to abstinence and following methods to achieve that. trol, stress management) and factors at the workplace.
Monitor progress using objective markers such as breath, Programmes should help participants to develop or regain
blood and urine tests. If matters have reached a point a sense of control, efficacy and competence in their health
where the professional licensing board is involved, evi- practices, and to use support from family, friends and
dence will be required that treatment is being followed and fellow workers if trying to change these. Such projects are
abstinence achieved before limitations on practice are most likely to be successful when the workforce is involved
rescinded. The UK General Medical Council appoints in their development. Health promotion programmes
supervisors, separate from the treating specialist. applied in group sessions to workers have not had a strik-
Doctors who resume work tend to have a better out- ing impact.43 Didactic teaching that comes down from per-
come than other substance misusers; supervision, with sonnel departments or management is unlikely to succeed
testing, may be a helpful ingredient.38,39 Professional in individualistic Western society. It is not known whether
mutual support networks should be accessed.37 In the more success would be obtained by education projects
United Kingdom, there is the Doctors’ and Dentists’ initiated by the workforce.44
Group, c/o Medical Council on Alcoholism, Tel: 0207 487
4445. In addition, in the United Kingdom, there is the
National Counselling Service for Sick Doctors, Tel: 0207
935 5982. Key points
● Alcohol misuse and drug misuse are a cause of
PREVENTION absenteeism, inefficiency and work accidents.
● Early identification can be helped by blood tests.
Limiting the availability of alcohol in the workplace is ● Abstinence must usually be the goal.
important and can reduce accidents; similarly, regulations ● Workplace policies agreed by employer and
about the taking of psychotropic drugs or alcohol at work employee representatives are helpful.
or before coming to work can be helpful. One strategy is ● Success of an intervention can be helped by
to provide free hot lunches inside the plant to discourage sanctions and monitoring which may involve the
lunch hour and ‘parking lot’ drinking by blue-collar employer or professional regulator.
workers. ● Workplace health education around substances
Hazardous drinkers, detected opportunistically at family seems to have little effect.
practices, have been shown to respond favourably to fairly
minimal medical intervention (such as feedback about
their level of drinking or their serum GGT).40 In one four-
year follow-up study, a reduction of sickness absenteeism
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20. Baker A. Alcohol-related deaths by occupation: What do data on probation: An 8 year follow-up. Journal of the American
for England and Wales in 2001–2005 tell us about doctors’ Medical Association. 1987; 257: 2931–4.
mortality? Alcohol and Alcoholism. 2008; 43: 121–2. 40. Bertholet N, Daeppen JB, Wietlisbach V. Reduction of alcohol
21. Hodgson R, Alwyn T, John B et al. The FAST alcohol screening consumption by brief alcohol intervention in primary care:
test. Alcohol and Alcoholism. 2002; 37: 61–6. Systematic review and meta-analysis. Archives of Internal
22. Ryan J, Zwerling C, Jones M. The effectiveness of Medicine. 2005; 165: 986–95.
preemployment drug screening in the prediction of 41. Kristenson H, Ohlin H, Huttin-Nosslin MB et al. Identification
employment outcome. Journal of Occupational Medicine. and intervention of heavy drinking in middle-aged men:
1992; 34: 1057–63. Result and follow-up of 24–60 months of long term study
870 Substance abuse and the workplace
with randomised controls. Alcoholism, Clinical and other drug problems. US Dept of Health and Human Services
Experimental Research. 1983; 7: 203–9. OSAP Prevention monograph. Washington DC: US
42. Richmond R, Kehoe L, Heather N, Wodak A. Evaluation of Government Printing Office, 1990: 106–12.
a workplace brief intervention for excessive alcohol
consumption: The workscreen project. Preventive Medicine.
2000; 30: 51–63. FURTHER READING
43. Bennett JB, Patterson CR, Reynolds GS et al. Team
awareness, problem drinking, and drinking climate: Edwards G, Marshall J, Cook C. The treatment of drinking
Workplace social health promotion in a policy problems, 3rd edn. Oxford: Oxford University Press,
context. American Journal of Health Promotion. 2004; revised, 1997.
19: 103–13. Department of Health. Drug misuse and dependence: Guidelines
44. Shain M. Worksite community processes and the prevention on clinical management. London: Department of Health.
of alcohol abuse: Theory to action. In: Giesbrecht N, Conley Last accessed December 17, 2005. Available from:
P, Denniston RW et al. (eds). Research, action and the www.dh.gov.uk/en/Publicationsandstatistics/Publications/
community: Experiences in the prevention of alcohol and PublicationsPolicyAndGuidance/DH_4009665.
PART SEVEN
RESPIRATORY DISORDERS
General issues
PAUL M TAYLOR
INTRODUCTION
more energy and pass more easily through all tissues, pro-
ducing a ‘flatter’ image with less intrinsic contrast. A high
The developments in imaging technology that have occurred
kV exposure may be preferred since it produces clearer
over the last two decades have provided valuable insights
images of the mediastinum and the overlying lung.
into the body’s structure and function. Despite this, the
However, this is at the expense of clarity of the ribs and
chest radiograph remains the primary and, in many cases,
intrathoracic calcifications. The converse occurs with a
the only radiological investigation performed. The use of
lower kV exposure.
more complex imaging techniques often carries a financial
Radiographic film varies in quality. In order to reduce
and radiation penalty and these must be balanced against
radiation dose to the patient, manufacturers have deve-
the expected benefits.
loped more sensitive films which produce a similar level of
radiographic density at a lower exposure to x-rays. This
development, although desirable, is not without its draw-
CHEST RADIOGRAPHY backs and these films may produce a coarser image. This is
of particular relevance in occupational disease where sub-
Conventional radiography tle alterations in the parenchymal pattern may be signifi-
cant. The practical impact of these considerations is that in
Within a year of Roentgen’s discovery of x-rays chest radio- longitudinal studies of workers, no effort should be spared
graphy had been used as a diagnostic tool. The initial in ensuring that exposure factors and film quality vary as
images of the chest were crude, but progress was rapid and little as possible.
by the early part of the twentieth century the chest radio- Of equal importance to technical factors are patient
graph was a recognized part of clinical investigation. Its variables involved in the radiograph and before any
validity in occupational lung disease was established as a attempt is made at interpretation, the observer should con-
result of correlative radiological and pathological studies. sider the following:
The principles of chest radiography are well known. The
patient is positioned with the anterior chest placed against a ● Is the patient rotated? Rotation produces asymmetry in
cassette containing the film and the x-ray tube approxi- the size and density of the lungs. Rotation is assessed by
mately 2 metres from the film, behind the patient. The film noting the position of the medial ends of the clavicles
is exposed during maximum inspiration. Exposure factors with respect to the spinous processes of the upper thoracic
can radically alter the appearance of the resultant radio- spine.
graph. The radiographer can alter the kilo voltage (kV) of ● Has the patient achieved a satisfactory inspiration? A
the x-rays produced by the tube. Higher kV x-rays possess poor inspiration causes crowding of the basal lung
876 Imaging in occupational lung disease
Grey scale
causes the lungs to appear dark with loss of normal
vascular markings, which is often misinterpreted as
‘emphysematous lungs’. Underexposure causes the lungs
to appear pale, often misinterpreted as due to pulmonary
infiltration. Exposure is difficult to assess objectively
and depends upon body habitus. It may be necessary to
take two films at different exposures to demonstrate the
lungs and mediastinum.
White X-ray exposure
During the acquisition of a CT image, the patient lies on HRCT differs from conventional CT in two key
the examination table and the area of the body to be exam- respects:11,12
ined is positioned within the CT gantry. The CT gantry
contains the x-ray tube and an array of x-ray detectors. 1. Section thickness. In conventional CT, the sections are
These are mounted on opposite sides of a ring which sur- approximately 10 mm in thickness. In HRCT, the
rounds the patient. During the exposure, the x-ray tube sections are typically no more than 1 mm thick. The
rotates around the patient emitting a tightly collimated beneficial effect of this is that partial volume averaging
beam of x-rays. The x-rays emerging from the patient is reduced. Partial volume averaging occurs when a
strike the detectors and the data from these are fed to a structure only partially fills a voxel. When the
computer. The computer calculates the attenuation of the attenuation value for the voxel is calculated an average
beam by the patient’s body to produce a matrix (typically value is obtained lying between the true attenuation
512 512) in which the attenuation value of each cell in value of the structure and its background. As a result,
the matrix is determined. Attenuation values are measured small structures, such as peripheral pulmonary vessels
in Hounsfield units (HU). Air has a value of 1000 HU or small nodules, can be ‘lost’ because they occupy
and water 0 HU. Soft tissues in the body range in value only a small fraction of a voxel. By reducing slice
between 40 and 80 HU, their attenuation varies depending thickness, the voxels are made smaller and the
on factors such as the subject’s haemoglobin level, the percentage occupied by these small structures
amount of fat in the tissue and the presence of any calcifi- increases, thus decreasing partial volume averaging.
cation. The matrix is displayed as an image by correlating The disadvantages of thinner sections are two-fold.
the calculated attenuation values with a grey scale, in which First, if the section thickness is reduced from 10 to
the higher the attenuation value the brighter the shade of 1 mm, ten times as many sections would be required to
grey. Thus, the image consists of many thousands of pic- image the same volume of the body. In practice, this is
ture elements (pixels) each one of which represents the not a problem since the images although 1 mm thick
attenuation value of a small volume of tissue (voxel). are usually acquired at 10-mm increments rather than
Because of the wide range of calculated attenuation values contiguously. In effect only 10 per cent of the lung is
and the limited number of shades of grey detectable by the imaged and this therefore is a second sampling
human eye, it is not practicable to display each attenuation technique problem, inherent in all CT systems, that
value as a separate level of grey and the range of attenua- reducing the section thickness decreases the signal to
tion values to be displayed must be selected. The range noise ratio. This makes the images appear rather
selected can be altered by changing the window width and ‘noisy’ with variations in pixel density even in
level. The window width describes the range of attenuation homogenous body tissue. The problem can be
values that are allocated to the available levels of grey. overcome to some extent by increasing the output of
A narrow window width ensures that tissues of slightly dif- the x-ray tube, although this results in a higher
ferent attenuation are displayed as different levels of grey; radiation dose to the patient.
this is suitable for demonstrating the mediastinal struc- 2. Reconstruction algorithm. In calculating the attenuation
tures. A wider window is selected to demonstrate the lungs values of the voxels the computer has to deal with
to accommodate the large range of attenuation present. biological heterogeneity of body tissue, variation in x-ray
Attenuation values above and below the chosen range output and other factors which produce variations in
appear white and black, respectively. The window level is the calculated attenuation of ostensibly homogenous
defined as the attenuation value at the midpoint of the structures. To overcome this software used in conven-
window width. A low level is selected for predominantly tional CT smoothes these variations, reducing the
low attenuation regions, such as the lung, and a high level differences between adjacent voxels. However, in het-
for higher attenuation tissues, such as bone. erogeneous tissues, such as the lung, smoothing results
In common with other digital imaging systems, CT in loss of clarity of the margins of small structures
images can be post-processed. Post-processing procedures making them appear blurred. In HRCT, however, a
include changing algorithms to smooth or filter the image, high spatial frequency processing algorithm is used
reformatting the data in different planes and statistical which has a much reduced smoothing function.
analysis of the attenuation data.
The majority of HRCT images are obtained with the
patient supine during maximum inspiration. However, in
some circumstances, it may be preferable to perform prone
HIGH-RESOLUTION COMPUTED or expiratory images.
TOMOGRAPHY Due to the greater hydrostatic pressure in the supine
position, the vessels in the posterior lung become dis-
Introduced in the mid-1980s, high-resolution computed tended and there is an increase in the extravascular fluid.
tomography (HRCT) of the lungs is now the preferred CT This produces an increase in the attenuation of the poste-
technique in the investigation of diffuse lung disease.8–10 rior lung which can obscure underlying structural change
878 Imaging in occupational lung disease
ULTRASOUND
(b)
MAGNETIC RESONANCE
Figure 68.2 (a) A CT section through the lung bases in a
patient with normal lungs demonstrating hypostatic change.
The ability of magnetic resonance (MR) to image in multi-
Note the gradation in density through the lung with the posterior
ple planes with high intrinsic soft tissue contrast without
dependent lung appearing denser and the pulmonary vessels
using ionizing radiation has made it an essential imaging
larger. (b) The same patient as has been turned to the prone
tool in many areas of the body, in particular the brain,
position, with the dependent changes now present in the
spine and skeleton.19 Within the thorax, it has established a
anterior lung.
role in cardiovascular and mediastinal imaging.20,21 Its use
in the lung is restricted for several reasons.22
(Figure 68.2a,b). This is of particular importance in 1. Magnetic resonance primarily images protons. Within
asbestosis since the posterior lung bases are the most the lung, the large amount of air produces a very low
frequently involved portions of the lung. proton density.
By turning the patient prone and repeating the sections, 2. The combination of air-containing spaces and
the hypostatic changes are repositioned anteriorly. A period interlacing vessels produces heterogeneity in the
of 5–10 minutes is required for full reversal of these magnetic field which significantly degrades the image.
changes. Failure to undertake this manoeuvre can result 3. There are physiological movements, in particular
in fibrosis being obscured by the hydrostatic changes or cardiac and respiratory motion, which produce
normal lung being misinterpreted as abnormal. artefacts.
Air trapping in the gas exchange spaces of the lungs occurs
in several conditions including extrinsic allergic alveolitis.13 Despite these problems, several studies have demonstrated
It is difficult to detect air trapping on inspiratory scans, but the ability of MR to image patients with diffuse lung dis-
expiratory sections are helpful. On expiration, the normal ease. It is likely that further developments in MR will be
Coalworker’s pneumoconiosis 879
RADIONUCLIDE STUDIES
Small opacities
Rounded
Size p Up to 1.5 mm diameter
q 1.5–3 mm diameter
r 3–10 mm diameter
Profusion 1a Few in number
2a Numerous, lung markings visible
3a Very numerous, lung markings
obscured
Irregular
Type s Fine irregular or linear
t Medium irregular
u Coarse irregular
Profusion 1a Few, lung markings visible
2a Numerous, lung markings
partially obscured
3a Very numerous, lung
markings totally obscured
Figure 68.4 A chest radiograph in a patient with Caplan’s Large opacities
syndrome demonstrating multiple nodules in both lungs. Size A 1–5 cm
B Larger than 5 cm, but smaller
than area of the right upper lobe
Complicated coalworker’s pneumoconiosis C Larger than the area of the
right upper lobe
The defining process in the development of complicated Pleural thickening Site, calcification, extent and width
CWP is the formation of areas of progressive massive fibro- Pleural calcification Site, calcification, extent and width
sis (PMF). Characteristically, the lesions occur in the mid a
Each point on the scale is subdivided, e.g. 1/2.
and upper zones of the lung and are frequently bilateral.
They are ovoid or ‘sausage’-shaped and enlarge over many
years to reach several centimetres in diameter. In advanced People with silicosis are at increased risk of tuberculosis; this
cases of PMF, there is often distortion and marked emphy- may lead to new upper lobe shadowing on serial radiographs
sema in the surrounding lung. PMF usually occurs on a and cavitation of confluent silicotic nodules.
background of nodules of simple CWP of at least category 2 HRCT demonstrates changes not appreciable on chest
profusion (see Table 68.1), but the background nodules may radiography. These include emphysema, bronchial dilata-
become less apparent as the emphysema becomes more tion and, on expiratory sections, air trapping.37
advanced. The lesions of PMF rarely cavitate and there may
be hilar lymph node enlargement. In clinical practice, the
prime differential diagnosis is bronchial carcinoma which Asbestos exposure
has an occurrence, even in miners, many times that of PMF.
With the decline in coal mining in the United Kingdom,
asbestosis is now the most frequently encountered pneu-
Silicosis moconiosis. The radiological features can be considered
under three headings: pleural disease, pulmonary diseases
The appearances of silicosis are not dissimilar to CWP.35 and extrathoracic manifestations.
However, the degree of fibrosis present in the lung is
greater and as a result the nodules are larger, more discrete, PLEURAL DISEASE
and tend to become confluent. Hilar and mediastinal node
enlargement occurs and the periphery of the nodes calcifies Pleural plaques are the most frequent radiological feature
producing an ‘eggshell’ appearance. Silicosis is now an of asbestos exposure. They form well-defined, rather angu-
uncommon condition in developed countries and sar- lar densities. These are most easily seen on the chest radio-
coidosis is a more common cause of these appearances. graph when they lie along the lateral chest wall or over the
However, silicosis remains a problem in less developed diaphragm, since in these positions they lie tangential to
countries. PMF occurs infrequently in silicosis (Figure 68.5).36 the x-ray beam rather than en face. The plaques may calcify
Coalworker’s pneumoconiosis 881
PULMONARY DISEASE in North America and Europe has meant that patients
are often investigated when the extent of pulmonary fibrosis
Asbestosis is characterized, on the chest radiograph, by the is mild, frequently before the radiographic features are
presence of fine reticular basal shadowing producing loss of visible on a standard chest radiograph and the radiological
clarity of the cardiac silhouette. Increased public awareness changes are detectable only on HRCT.
Coalworker’s pneumoconiosis 883
EXTRATHORACIC MANIFESTATIONS
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69
Work and chronic air flow limitation
DAVID J HENDRICK
Chronic air flow limitation results from a persistent diffuse Airway obstruction which responds partially, but not fully,
reduction in airway calibre relative to the degree of to treatment implies there may be an asthmatic or acute
lung inflation (i.e. airway obstruction), which cannot be bronchitic component to the disorder, of which the fixed
reversed by treatment. The fixed nature of this obstruction component alone should be identified as COPD. The fixed
is the cardinal feature, but this is shared by several patho- component may itself be a consequence of long-standing
genically distinct disorders. They are recognized collec- asthma, but more commonly it is a consequence of emphy-
tively to produce chronic obstructive pulmonary disease sema or obstructive bronchiolitis. Bronchiectasis too
(COPD). The importance of COPD lies with its tendency often leads to COPD, but is an uncommon cause of COPD
to progress and to cause a disabling, even life-threatening, overall. Whether chronic bronchitis should be considered
loss of lung function. It seems likely that 10–20 per cent of a cause depends on whether it is defined solely by a persist-
current cases can be attributed to occupational causes, but ent, otherwise unexplained, productive cough – as it usu-
the evidence to confirm this has proved to be illusive. The ally is. Many subjects with mucus hypersecretion (and
investigatory difficulties that have arisen will consequently hence chronic productive cough) have no airway obstruc-
be reviewed in some detail, as will persisting uncertainties tion, implying that when both chronic bronchitis and
and controversies. COPD do occur together, they are usually independent
It has been conventional to apply the term COPD to effects of the same inducing cause – for example, cigarette
fixed airway obstruction which develops insidiously over smoking.
many years – long before any symptoms are recognized. It is estimated that about 10 per cent of adults are
Recent experience demands an adjustment to accommodate affected by COPD globally, depending on the diagnostic
a few novel subacute causes which produce fixed airway criteria used.1 The prevalence is higher (about 14 per cent)
obstruction over a matter of weeks or months at bronchiolar in industrially developed countries,2,3 with 1–2 per cent
level (bronchiolitis obliterans). Bronchiolitis obliterans may affected severely. Although most are smokers, as many as
also arise acutely as a rare complication of toxic lung injury 3 per cent of never-smokers have COPD to some degree.
(e.g. from gassing accidents or warfare), but this has been COPD is currently the sixth leading cause of death globally
recognized for many decades and is beyond the scope of and is projected to become fourth by 2020.4 It is already
this chapter. ranked fourth in individuals aged over 45 years in Europe
890 Work and chronic air flow limitation
and the United States, and is responsible for 200–300 deaths asthma, and the curious work-related periodicity of the
per 100 000 per year in industrially developed countries. symptoms (which had been considered particularly char-
Data from the third National Health and Nutrition acteristic of byssinosis) has since been observed with other
Examination Survey (NHANES 3) suggest that 19 per cent types of occupational asthma. As with active asthma of any
of COPD in the United States overall can be attributed to aetiology, airway hyper-responsiveness can be demon-
work, while among never-smokers the percentage climbs strated to a variety of bronchoconstrictor agents at times
to 31 per cent.5 The American Thoracic Society estimates when byssinosis grade 1 or grade 2 is active. If, then, byssi-
independently that about 15 per cent of COPD in the nosis grades 1 and 2 are examples of occupational asthma,
United States is occupationally induced.6 is occupational COPD (i.e. byssinosis grade 3) simply a
The recent Global Initiative on Obstructive Lung consequence of occupational asthma? This is certainly
Disease (GOLD) adopted the commonly used value of 70 plausible, since long-standing asthma of non-occupational
per cent for the ratio of forced expired volume in 1 second origin often results in fixed airway obstruction.
(FEV1) to forced vital capacity (FVC) as the defining point The relation of byssinosis grade 3 to byssinosis grades 1
for airway obstruction – that is, the lower limit of normal- and 2 may, however, be looked at from a different view-
ity.7 It is recognized that the ratio tends to fall as a normal point to that adopted by Schilling and Bouhuys. The inves-
consequence of ageing and so this definition may lead to tigations which led to their grading classification were
the prevalence of COPD being underestimated in young cross-sectional not longitudinal in structure. Grade 1
adults, but overestimated in the elderly. byssinosis was not, in fact, observed to progress to grade 3
byssinosis, and so it is conceivable that byssinosis grade 3 is
a fundamentally different disorder from byssinosis grades
HISTORICAL BACKGROUND 1 and 2, albeit one which is also induced by occupational
exposure to cotton dust. If this is so, byssinosis grade 3
That COPD might arise as a consequence of the occupa- could be regarded as the prototype for occupational
tional environment is a matter of evolving interest and COPD, and the question arises whether it is likely that cot-
importance, and not a little controversy. The possibility of ton dust alone among occupational agents would have this
COPD of occupational origin, unassociated with compli- effect on the airways?
cated pneumoconiosis, first gained widespread acceptance Most of the cotton workers of the 1960s had been heavy
as recently as the 1960s as a result of a series of investiga- cigarette smokers for many years, and doubts were
tions in cotton workers by Schilling and Bouhuys and col- expressed subsequently whether the confounding effect of
leagues.8,9 They suggested that cotton dust-induced airway this on the development of COPD (which was barely rec-
disease (byssinosis) could be usefully classified into three ognized in the 1960s) was adequately taken into account.10
distinct clinical grades. Workers who developed chest Although recent investigations have confirmed that COPD
tightness and breathing difficulty only on the first working does arise as a consequence of occupational exposure to
day of each week were said to have byssinosis grade 1; those cotton dust independently of smoking,11,12 this relation-
who had similar symptoms on additional working days of ship remained uncertain for many years, and the
the week, but who recovered fully away from the work- confounding role of cigarette smoking came to lie at the
place, were said to have byssinosis grade 2; and those who centre of current controversies.
had symptoms of persisting respiratory disability were said
to have byssinosis grade 3. Physiological studies indicated
that byssinosis grades 1 and 2 were associated with reversible UNCERTAINTIES AND CONTROVERSIES
airways obstruction, while byssinosis grade 3 was associated
with fixed airways obstruction. It was assumed that affected The experience with the cotton industry provides invalu-
workers followed an orderly progression through these able lessons for the assessment of occupational COPD, and
escalating grades. Cotton dust was consequently a potential for evaluating today’s inevitable controversies. In essence,
cause of COPD, and byssinosis grade 3 was the first docu- they centre on whether an excess prevalence of COPD in a
mented example of occupational COPD. given working population has arisen from some other
The specific effects of cotton dust are discussed in detail cause (such as smoking or asthma), rather than the work-
in Chapter 73, Byssinosis and other cotton-related diseases, ing environment, and whether, if the workplace is respon-
and so cotton dust and byssinosis will be mentioned here sible, COPD arises independently of occupational asthma
only to provide a convenient historical focus for reviewing or as a direct consequence of it – or both (Figure 69.1).13
the claims and controversies which have arisen subse- There is a further source of confusion – regular exposure
quently from many occupational environments concerning to respirable dusts and irritant gases/vapours commonly
COPD. leads to mucus hypersecretion and to chronic productive
Many (perhaps most) authorities would now regard cough (i.e. chronic bronchitis). In an occupational setting,
byssinosis grades 1 and 2 as occupational asthma attribut- this is often termed ‘industrial bronchitis’. When chronic
able to cotton dust. The physiological correlates (acute, but bronchitis develops coincidentally alongside asthma (whether
reversible episodes of airway obstruction) are diagnostic of occupational or not), the emergence of obstructive
Cigarette smoking – confounding and interactions 891
No. Smokers
(per cent)
Asthma ? Chronic obstructive
pulmonary disease
Workers
Figure 69.1 Pathways to chronic obstructive pulmonary Low exposure 179 30
disease. From: Thorax, 1995, 50 (Suppl. 1), S16–S21, reproduced Medium exposure 219 39
with permission from the BMJ Publishing Group. High exposure 284 58
School leavers
Low exposure 53 9
symptoms (wheeze, chest tightness, undue shortness of Medium exposure 126 21
breath) is often attributed, not unreasonably, to COPD High exposure 75 36
and to the cause of the productive cough.
The possible presence of coincidental asthma (now a Data taken from Ref. 14.
common disease at all ages in the population at large) may
consequently simulate occupational COPD. This is partic- An important additional tendency is for those who are
ularly likely if industrial bronchitis or smoker’s bronchitis best able to tolerate the heaviest levels of tobacco con-
coexists. Asthma of non-occupational origin may also sim- sumption to take on jobs with the most noxious occupa-
ulate occupational asthma because it is likely to worsen tional exposures (and vice versa), or for cultural or family
transitorily in the workplace if there are respirable irritants, influences to link smoking with recruitment to particular
and in some occupational settings (e.g. cotton mills) the types of work. This inevitably confounds any potential
development of occupational asthma is as plausible as the effect of the work environment with that of smoking, and
development of occupational COPD. If it is true that there is illustrated in Table 69.1.14 Here, the smoking habits of
are substantial differences in the prevalence of asthma 15- to 16-year-old school leavers applying for a range of
from region to region, from population to population and apprenticeships associated with three levels of exposure to
from birth cohort to birth cohort, as is now suggested, noxious working environments (low, medium, high con-
formidable difficulties must be expected in allowing for centrations of welding fume) are compared with estab-
this if a given working population appears to show an lished workers aged 19–26 years in the same trade groups.
excess of COPD. The clear differences in current smoking prevalence seen
The difficulty in distinguishing between asthma and between the occupational exposure groups of the workers
COPD is compounded by the common occurrence of both can also be observed in the school leavers before any occu-
disorders in the same individual. When this does occur, pational exposure occurred, though age exerted an addi-
however, the clinical features tend to resemble those of tional effect and increased the prevalences in the older
COPD alone much more closely than asthma alone – as workers in all work-exposure categories.
pointed out in the recent American Thoracic Society state- Smoking is thus likely to be associated with the very occu-
ment, ‘Occupational contribution to the burden of airway pational environments which are themselves suspected of
disease’.6 causing COPD. This may lead not only to confounding, but
to an exaggerated survival bias. The most susceptible workers
are likely to leave the particular working environment pre-
CIGARETTE SMOKING – CONFOUNDING maturely if they develop COPD (whether from smoking,
AND INTERACTIONS occupational exposure or both), thereby producing a surviv-
ing population which is less severely affected. Investigation of
The relative effects of smoking and occupation on COPD the surviving workers will underestimate the occupational
can only be assessed from epidemiological investigations hazard involved. Furthermore, those workers who are ini-
where study populations include smokers and non-smokers, tially less able (or less willing) to tolerate noxious exposures
and workers with different levels of the relevant occupa- will avoid the relevant working environments and this will
tional exposure (some, ideally, with none). There may be exert an additional bias (healthy-worker effect) on the selec-
difficulty in finding such a balanced population, and there tion of populations who work with the risk of developing
may be difficulty in avoiding bias in the exposure histories occupational lung disease. Investigators, regulating bodies,
which are obtained. The investigation of possible occupa- employers and employees may be hard-pressed to recognize
tionally induced disease often leads to anxiety, anger and when longitudinal loss of ventilatory function in a working
claims for compensation in at least some of the study population is truly excessive once the idiosyncratic effect of
population. Once these arise, memory for the noxious cigarette smoking is taken into account. Full smoking histories
nature of former workplace environments may prove to be are consequently essential in research, and should include a
better preserved than that of former tobacco consumption. quantitative measure of cumulative consumption.
892 Work and chronic air flow limitation
(a) (b)
The issue is unduly complicated because only a bronchial inflammation is often seen, especially when
minority of smokers (15–20 per cent) appear to develop there is chronic productive cough. This is best regarded as
COPD (hence the idiosyncrasy) and because doubts over an independent phenomenon and is often unassociated
the accuracy of past smoking histories may invalidate, or at with airflow limitation. COPD is also associated with
least weaken, the statistical analyses involved. There may bronchiectasis, but the underlying mechanism is at present
be strong justification for such doubts. In a UK study of the uncertain.
population at large, it was concluded that up to 7 per cent The potential importance of obstructive bronchiolitis
of smokers and former smokers had described themselves has taken a new twist over the last few years with the recog-
incorrectly as never-smokers,15 while in an American study nition of subacute causes among workers inhaling certain
of coal miners seeking compensation, as many as 15 per food-flavouring materials, synthetic fibre flock and gar-
cent claimed to be never-smokers despite recording in ment printing dyes. Disablement occurs within a matter of
earlier assessments that they were regular smokers.16 weeks or months of exposure onset, rather than years.
been recognized by a number of investigators. Those from It depends also on the cumulative burden of all damaging
Tulane University demonstrated a more striking discrep- pulmonary insults throughout the ageing period
ancy when estimating the annual decline in FEV1 from a (Figure 69.5).
longitudinal study over five years of a normal population By using study subjects as their own controls and
of males aged 30–58 years.18 The cross-sectional data avoiding the problems which arise from mismatching in
from each survey year indicated a mean decline of cross-sectional studies (i.e. by eliminating between-worker
40–50 mL/year with increasing age, once the effect of variability), longitudinal studies are inherently more
height was taken into account, while the mean of the actual satisfactory. They are less ‘sensitive’, however, because they
longitudinal declines measured in each participant was detect change over the period of longitudinal surveillance
only 12.4 mL/year (Table 69.2). only. By contrast, cross-sectional studies quantify the
Thus cross-sectional data cannot be extrapolated to changes which have occurred throughout the lifetimes of
predict longitudinal change with any precision and should the participants. Longitudinal studies may also be more
not be compared directly with longitudinal data from vulnerable to diminishing participation rates, and this may
other investigations. Much of the discrepancy arises introduce new risks of bias. They are also lengthy and very
because subjects at the younger end of an age spectrum of, expensive.
say, 20–60 years from a current cross-sectional investiga-
tion do not necessarily have the same mean FEV1 as did
those at the older end of the spectrum some 40 years earlier Other non-occupational factors of possible
when they were of a similar young age. In fact, the cur- relevance
rently young subjects are likely to have greater values
of FEV1 at a standardized young age, partly because they The study of London transport and postal workers usefully
have larger lungs and partly because they are less likely to suggested that although intercurrent episodes of respira-
have sustained respiratory diseases (e.g. tuberculosis, tory tract viral infection (i.e. episodes of acute bronchitis,
bronchiectasis) which impair ventilatory function. The exacerbations of COPD) caused significant reductions
difference in FEV1 between younger and older subjects at in ventilatory function, the effect was only temporary.
the time of a cross-sectional study therefore exaggerates Full recoveries to former levels of ventilatory function
the true declines which were experienced by the older were noted within a few weeks, after which the rate of lon-
subjects during the preceding years. Furthermore, the gitudinal decline returned to its usual level. Repeated viral
currently young subjects are likely to encounter less lung infections do not therefore influence the assessment of
damaging insults as they age to 60 years, compared with occupational COPD from either cross-sectional or longi-
subjects who had already attained 60 years. Thus, mean tudinal studies, provided there are no acute infections at
longitudinal decline in lung function in populations is the time of study. Whether intercurrent episodes of acute
not wholly a consequence of increasing age and of cumula- bronchitis following brief exposure to toxic chemicals at
tive exposure to cigarette smoke or occupational agents. work (e.g. gassing accidents) will prove to be equally
Chronic obstructive pulmonary disease and agents known to induce asthma 895
benign is currently a matter of much speculation, concern Table 69.3 Definite and probable causes of occupational
and ongoing investigation. Major accidents which produce chronic obstructive pulmonary disease.
life-threatening pulmonary toxicity are recognized to
cause bronchiolitis obliterans in a small proportion of Agents thought to induce occupational asthma by
survivors, although the majority of survivors appear to hypersensitivity pathways
recover fully. A few develop asthma, which may persist Cotton dust Di-isocyanates
indefinitely and so pose a further pathway for the Grain dust
emergence of COPD. Farm dusts
This asthmatic complication of acute pulmonary Flour
toxicity (it may also follow a series of less toxic exposures,
Other agents
one alone having insufficient potency) has been termed
Acramin dye – Ardystil Flock (nylon, rayon,
the reactive airways dysfunction syndrome (RADS).19,20
syndrome polypropylene)
The term is unhelpful in one sense because it suggests,
Cadmium Food (popcorn)
incorrectly, that RADS is a disorder distinct from asthma.
Coal mine dust flavouring – diacetyl
However, it is helpful in another sense because it neatly
Cotton dust Silica
categorises a major subgroup of occupational asthma
cases (some 5–10 per cent overall) for which the mecha-
nism is reasonably clear. For the remaining cases, the
Table 69.4 Possible causes of occupational chronic obstructive
mechanism(s) is generally assumed to involve hypersensi-
pulmonary disease.
tivity pathways, but confirmatory evidence has been
illusive for many causal agents (particularly low molecular
Agents thought to induce occupational asthma by
weight chemicals) and with certain organic dusts (e.g.
hypersensitivity pathways
from cotton, grain, animal confinement buildings) endo-
Wood dust
toxin from contaminating Gram-negative microorgan-
isms may play a critical role in inducing asthmatic Other agents
responsiveness.6 Ammonia Printing
Age, height, race, gender, smoking and increasing body Carbon black Rubber and plastics
mass all exert important influences on the measurement of manufacture
ventilatory function, and it may be that passive smoking Concrete dust Smoke (fire fighting)
and air pollution during the course of longitudinal investi- Endotoxin Sulphur dioxide/paper
gation will also exert potentially important (adverse) pulp dust and fume
effects. The wide range of apparent individual susceptibil- Iron and steel foundry fume/dust Vanadium
ity to COPD suggests a dependence on genetic factors and Leather work Welding fume
there is supportive evidence for this especially from twin Metal ore processing and smelting Wollastonite
studies.21,22 Genetically determined atopy has not generally Nitrogen oxides Wood/biomass smoke
been found to influence COPD, but this depends on how
COPD is defined and how vigorously an asthmatic
contribution is excluded.
Analysis of data from the American Multicentre Lung CHRONIC OBSTRUCTIVE PULMONARY
Health Study suggests that airway responsiveness (to DISEASE AND AGENTS KNOWN TO
methacholine) may prove to be almost as important as cig- INDUCE ASTHMA
arette smoking in exerting an adverse influence on the rate
of decline in ventilatory function.23 If it is confirmed that a Naturally occurring inducers of
measure of asthmatic activity is relevant to predicting the occupational asthma
development of COPD (a relationship enshrined in what
became known as the Dutch hypothesis of the 1970s and Respiratory disease in grain workers has been widely
1980s, but disputed thereafter), then factors of aetiological recorded since the eighteenth century and the time
relevance to asthma may also need to be taken into account of Ramazzini. Grain dust has become a particularly well-
when studying COPD.24,25 It may be useful, therefore, to recognized cause of occupational asthma, although the
consider the occupational agents (or environments) that precise causative agent (or agents) remains unclear.
have been associated with COPD in two categories – those Storage mites, microbial contaminants, pesticides and
which are also believed to cause asthma through ‘non- fungicides, and even rodent urinary proteins have all been
RADS’ pathways and those which are not. It may also be incriminated together with allergenic material derived
useful to classify them according to whether current from the grain itself. A number of investigators have pro-
evidence identifies them as ‘definite or probable’ causes duced impressive evidence that occupational exposure to
of occupational COPD (Table 69.3) or merely ‘possible’ grain dust may also lead to COPD, though none has sug-
causes (Table 69.4). gested that this is a direct consequence of occupational
896 Work and chronic air flow limitation
asthma and most have found some inconsistencies among di-isocyanate asthma continues to provide a typical exam-
their data.26,27 The uncertainty as to the precise causal ple of asthma attributable to occupational chemicals. Not
agent extends to many other settings associated with occu- unnaturally, di-isocyanate workers have provided a focus
pational COPD (and asthma), and thus Tables 69.3 and for investigations, of which there have been many, of pos-
69.4 refer either to a particular agent or to a particular sible occupational COPD. The results have been conflict-
setting. ing. A major multicentre surveillance programme in the
The experience of Chan-Yeung and colleagues28 in the United Kingdom revealed no hint of a COPD effect, while
port of Vancouver provides a useful illustrative example. study of a single di-isocyanate-producing plant in the
They followed port grain workers and control subjects United States suggested a crippling occupationally induced
working in civic centre posts between 1978 and 1990. After mean decline in FEV1 exceeding 100 mL/year.33,34 Both
six years, the annual rates for the decline in FEV1 were sig- investigations may have been flawed: the one because there
nificantly greater among the grain workers (–31 mL/year) was an implausibly low prevalence of occupational asthma
than the controls (4 mL/year), but when the smokers (and possibly a major survivor bias), the other because the
alone were studied little difference was noted between grain levels of ventilatory function observed initially were too
workers and controls (36 mL/year versus 31 mL/year). well preserved for an excessive decline of such a degree to
In this particular investigation, therefore, the grain–COPD have been occurring before the investigation commenced.
effect was seen largely in the non-smokers (in whom The five-year investigation of Diem and colleagues of
asthma was not satisfactorily excluded though atopy workers in a new toluene di-isocyanate-manufacturing plant
proved to be irrelevant) and it appeared to be of similar included an extensive series of exposure measurements, from
magnitude to the smoking–COPD effect in the control which the workforce was usefully separated into categories of
workers. Furthermore, its demonstration depended on low–average cumulative exposure (68.2 ppb-months) and
there being an unusually small annual decline in FEV1 high cumulative exposure (68.2 ppb-months).35 The high
among the controls (in fact, there was a trivial increase). exposure group showed a significantly greater annual decline
After 12 years, significant differences between grain work- in FEV1 (37 mL/year) than the non-smokers of the low
ers and controls were no longer evident, but this may have exposure group (1 mL/year), but it was not influenced by
been a consequence of survivor bias or of the greatly smoking. Smoking did, however, lead to a similar excessive
diminishing levels of grain dust exposure during the course decline in those with low levels of di-isocyanate exposure.
of the investigation. Not all investigators have found this Thus, similar excessive declines in FEV1 of modest degree
COPD effect. When it was observed, it was generally appeared to result from either di-isocyanate exposure or
clearer among the smokers than non-smokers, contrary to smoking, without there being any additive or multiplicative
the Vancouver experience. effects (Figure 69.6). These conclusions differ from the
Grain dust is also encountered by farm workers, who general consensus, which does favour an interaction between
additionally encounter other types of occupational dust smoking and the occupational environment, but they mirror
from harvesting and storing crops, hay and straw, and from those derived from the grain workers in the port of
handling and feeding livestock. Several asthmagenic agents Vancouver. Interestingly, Diem and colleagues attempted to
may contribute to their risk of COPD, which has been identify asthmatics from their study population, and showed
demonstrated from a number of studies.29 The refined no weakening of the COPD effect when these workers were
product of grain, flour, is encountered by many workers excluded from the analysis.
beyond the farming community, and has proved to be a
potent cause of allergic asthma and rhinitis. It too appears
to cause COPD, not necessarily in association with asthma. CHRONIC OBSTRUCTIVE PULMONARY
With wood dust, a further common cause of occupa- DISEASE AND AGENTS NOT KNOWN
tional asthma, evidence for a COPD effect is less strong. TO INDUCE ASTHMA
Again there is evidence that smokers may be unduly sus-
ceptible to it. This is noteworthy in view of the curious Cadmium
‘protective’ effect of smoking observed with occupational
asthma attributable to western red cedar.30 A similar pro- Cadmium-induced emphysema was first described in
tective effect in smokers, for which there are plausible 1952.36 For some years, doubts persisted as to whether the
immunological explanations, has been observed with apparently excess prevalences of COPD noted among some,
extrinsic allergic alveolitis and sarcoidosis, and so should but not all, cadmium-exposed working populations might
not be dismissed too hastily.31,32 instead be a consequence of smoking.37 More recent
investigations involving long-term surveillance have pro-
vided more convincing evidence that cadmium does indeed
Chemical inducers of occupational asthma cause emphysema. Thus, in a case–control study, Davison
and colleagues38 found radiographic and spirometric
In the United Kingdom in recent years, di-isocyanates evidence of emphysema in twice as many men manufactur-
have been a common cause of occupational asthma and ing copper–cadmium alloy for at least one year than in
Chronic obstructive pulmonary disease and agents not known to induce asthma 897
Average change in FEV1, mL/year the years in the coal mining industry and partly because of
(Controlling for mean age of 35.6 years political influence. Particularly detailed cross-sectional
and ‘FEV1 level’ above 550 mL/m3
studies from British and American coal mines both showed
excess declines in FEV1 related to estimated cumulative
never smokers current smokers levels of exposure to coal mine dust, after appropriate
1 adjustments for the effects of smoking and other potential
(n 35) confounders.48–51 Similar associations between lung func-
tion impairment and exposure were subsequently reported
from other countries. In the most heavily exposed miners,
the severity of the dust effect approached that of smoking.
The conclusion that coal mine dust causes COPD was
partly but not fully supported by subsequent longitudinal
studies – FEV1 decline during the surveillance period being
related to the cumulative (lifetime) levels of exposure,
but not exposure sustained during the actual periods of
26 surveillance.52,53 The cumulative level of exposure from
(n 64) employment onset was calculated from measured levels
during the studies together with estimates of earlier levels
37 37 using extrapolations and so could include inaccuracies. The
(n 21) (n 35) relation might also have been confounded by factors exert-
ing an accumulated effect over the years of exposure (for
Low TDI exposure, 68.2 ppb-months∗
example, air pollution, passive smoking and weight gain),
High TDI exposure, >68.2 ppb-months
for which adjustments were not made. For some, uncer-
tainty persists. It may prove to be irresolvable because expo-
Figure 69.6 Longitudinal loss of FEV1 versus toluene sure levels (hence risk) and the numbers of active coal
di-isocyanate (TDI) exposure. Compiled from data in Ref. 35.
miners (hence epidemiological power) have diminished too
*ppb-months is the net result of multiplying the mean exposure
profoundly. The optimal opportunity to demonstrate a
in parts per billion (ppb) by the number of months over which
COPD effect from coal dust may already have passed.
the exposure was sustained.
The evidence does, nevertheless, point to a COPD effect
from coal dust.54 This led to it becoming a prescribed indus-
unexposed controls with similar smoking habits, and they
trial disease in the United Kingdom in 1992 (Prescribed
identified a significant dose–response relationship linking
Disease D12: ‘Chronic bronchitis or emphysema’ in
cumulative measures of exposure to decline in gas transfer.
underground coal miners, see www.opsi.gov.uk/ si/si1993/
Although cadmium is a trace component of cigarette
Uksi_19931985_en_1.htm, for more information), pro-
smoke, cumulative exposures from smoking alone are not
viding the claimant has worked underground for at least 20
likely to approach those sustained occupationally. It seems
years and severity is sufficient to reduce the FEV1 by 1 litre
improbable that smoking-induced emphysema could be
from its predicted value. An amendment of 1996 catered
attributed to cadmium.39
for miners of short stature and benefit became payable as
soon as the FEV1 fell to or below 1 litre. The UK’s pre-
Mineral dusts scribed diseases legislation requires that the relevant occu-
pational exposure doubles, at least, the risk which already
Although airway obstruction was quickly recognized to exists within the population at large (thereby making it
be a feature of complicated pneumoconiosis and of its more likely than not in an affected individual that the
accompanying emphysema, COPD in the absence of com- disease in question would not otherwise have arisen).
plicated pneumoconiosis was until recently attributed to At present, only occupational exposure to coal mine dust is
other, coincidental, disorders. High mortality rates from considered to meet these requirements, although COPD
respiratory disease in some groups of miners led to early from occupational exposure to cotton dust or cadmium is
and intensive investigations of large numbers in many already covered by separate state legislation. A possible
countries.40–43 Although complicated pneumoconiosis and need for wider ‘prescription’ was considered by the UK’s
occupational tuberculosis were associated with excess respi- Industrial Injuries Advisory Council in 2007. It recom-
ratory mortality and morbidity, the pattern of respiratory mended that surface work with coal dust should also qualify
disease in miners seemed otherwise similar to that in their for state compensation, provided the worker has exposure
families and in suitably matched control populations.44–47 for a minimum of 40 years. This implies that two years of
It appeared to be related more to social circumstances (and surface work has roughly the same adverse effect as one
particularly to smoking) than to the working environment. year underground, and so surface and underground work
The largest investigations involved coal miners, princi- can now be aggregated to satisfy the minimum require-
pally because of the enormous populations employed over ment for cumulative exposure.
898 Work and chronic air flow limitation
Similar events were experienced in South Africa in rela- age range of 17–69 years. After allowing for age and height,
tion to exposure to respirable silica in gold mines. Although the trades associated with welding fume exposure showed a
state compensation became available there from 1952, later mean and significant overall loss in FEV1 of 250 mL com-
investigations did not provide uniformly supportive evi- pared with the unexposed trades. This effect was noted
dence of a silica-related loss of ventilatory function.55,56 only among the smokers.63 From the original study popu-
More recently, cross-sectional and longitudinal studies have lation, 487 were re-examined seven years later.64 Multiple
shown an excess of COPD in silica-exposed workers which regression analyses suggested that FEV1 was declining at an
could not be attributed to smoking, but there was no clear annual rate of 16.2 mL for a 50-year-old non-smoking
relationship with intensity of exposure.57–59 In one investi- worker without occupational exposure to welding fume.
gation, silica and smoking appeared to exert effects of simi- The additional losses attributable to smoking and welding
lar magnitude, while in another, the influence of smoking fume exposure were 17.7 and 16.4 mL/year, respectively.
on FEV1 decline was approximately twice that of silica expo- Interactions were noted between welding fume and smok-
sure. In the severe cases which led to death, an interaction ing, and between welding fume and atopy. There was no
between the two environmental factors seemed likely. effect from welding fume on gas transfer. The longitudinal
Both siliceous and non-siliceous ore is encountered in study consequently suggested that a mild COPD effect
the refining and smelting of metals generally, and exposure attributable to welding fume might also occur in non-
to a number of airborne mineral dusts is inevitable during smokers, but it confirmed that this effect was greater in
the processing of iron and steel. The dusts involved are smokers. The further enhancement of the effect in atopic
considered ‘mixed’, and in some circumstances have posed subjects provides a hint of an asthmatic component, and
excess risks for pneumoconiosis, lung cancer and COPD. the lack of any effect on gas transfer suggests that COPD
Investigation of some groups of asbestos-exposed pop- was not occurring as a consequence of emphysema. In the
ulations has suggested asbestos-induced impairment of absence of smoking and atopy, the risk of COPD was not
ventilatory function at the small airway level, thought not clearly doubled by welding fume.
of sufficient degree for asbestos to be considered a cause of
COPD.
So far there is not convincing evidence to suggest that Non-tobacco smoke
man-made (ceramic) mineral fibre poses a risk for COPD.
The issue could change, however, as fibres of increasingly Although welding fume usually contains smoke (particulate
smaller diameter are produced. Some exposed populations products of combustion) from surface coatings or contam-
have shown an excess prevalence of pleural plaques, but inants, its probable adverse respiratory effects are chiefly
this was possibly a consequence of earlier, coincidental, consequences of metal fume itself. Smoke (and oxides of
exposure to asbestos. nitrogen and sulphur) from sources other than welding and
tobacco may nevertheless contribute to COPD, whether
encountered in industrial settings, during firefighting,65 in
Welding fume polluted air generally66 or in poorly ventilated domestic
environments where biomass (e.g. wood, crop residue,
Welding fume is conveniently considered separately charcoal, dung) is used as a cooking fuel. Biomass smoke, in
from other minerals, partly because the circumstances of particular, was thought to explain the higher prevalence of
exposure are rather different, partly because a possible COPD in a rural compared with an urban area of China,
COPD effect in welders is a matter of considerable topical both in the study populations as a whole (12.0 versus
interest and partly because evidence of an additional asth- 7.4 per cent) and in the non-smoking women who did most
magenic effect is now emerging. The latter is convincing for of the cooking (7.2 versus 2.5 per cent).67 A further Chinese
stainless steel welding fume (where hypersensitivity to study demonstrated a significantly diminished relative risk
chromium is presumed), but most welders work with mild of COPD in both men (0.58) and women (0.75) when
steel or other metals, not stainless steel, and the evidence efficient chimneys were installed for cooking stoves that
for asthma here is less convincing. were previously unvented.68
Consistent with the investigation of numerous work-
forces exposed regularly to respirable irritant or noxious
dusts, vapours or fumes, many investigations of welders CHRONIC OBSTRUCTIVE PULMONARY
have demonstrated a clear excess prevalence of chronic DISEASE OF SUBACUTE ONSET
productive cough (industrial bronchitis). Until recently,
none has found convincing evidence of an excess of airway The unusual experience of observing COPD develop over
obstruction implying, perhaps, that if there is a COPD a matter of weeks or months only, has made it much easier
effect it must be of relatively small degree.60–62 to identify a number of interesting and recently emerged
A small but significant COPD effect was the conclusion causes of subacute bronchiolitis obliterans. Because of mod-
of a cross-sectional study of 607 shipyard workers carried erate or severe (even life-threatening) disablement, the iden-
out by Cotes and colleagues.63 The workforce spanned an tities of the causal agents were quickly established. Evidence
Perspective in the population at large 899
that bronchiolitis obliterans could result from inhaled pop- increasing public concern, particularly with regard to the
corn-flavouring ingredients was first published in 2002.69 Its aetiology and progression of COPD and asthma. Both dis-
recognition in eight former workers from a single American orders are clearly dependent on changing patterns of life
factory packaging popcorn for microwave use led to the within industrially developed countries and so environ-
term ‘popcorn worker’s lung’. It was sufficiently severe in four mental factors must be of great relevance. It may be that
that lung transplantation was considered. Investigations by many different respirable agents are capable of exerting an
the National Institute for Occupational Safety and Health influence and that in different individuals the measured
(NIOSH) showed that the prevalence of fixed airway COPD effects are due to different combinations of these
obstruction among continuing employees was 3.3-fold that agents (the ‘multiple hit’ hypothesis) together with inher-
expected, that bronchiolitis obliterans could be detected in ent susceptibility.
workers from four of five subsequently studied microwave Recent investigations in the former east and west regions
popcorn plants and that a prominent ingredient providing a of Germany provide interesting comparisons within the
butter taste (the oily organic chemical 2,3-butanedione developed world between, respectively, an area of high
[diacetyl]) could cause airway necrosis when inhaled by smoking prevalence and relatively high outdoor air pollu-
laboratory animals. Subsequent publications have shown tion from industrial emissions, and one of high domestic
that occupational exposure to diacetyl, as a food-flavouring affluence.76,77 It appears that COPD dominated in the for-
ingredient, has caused obstructive bronchiolitis in settings mer and asthma in the latter, although in the more affluent
other than popcorn manufacture and in countries other than societies there is greater not lesser outdoor pollution from
the United States.70,71 The Industrial Injuries Advisory Council vehicle exhausts. This is thought to be of relevance to
in the United Kingdom has recommended prescription of asthma in Los Angeles where such pollution is persistently
bronchiolitis obliterans in association with exposure to high and intermittently dramatically so, but a recent com-
diacetyl.72 parative study using measurements of airway responsive-
No evidence at present suggests that diacetyl is haz- ness between an urban area with more modest exposure to
ardous when ingested, but the possibility is not lightly dis- vehicle exhaust (Newcastle upon Tyne, UK) and a rural
missed. Inhaled diacetyl causes a relatively pure form of area with low exposure (Cumbria and the English Lake
obliterative (or constrictive) bronchiolitis as does the District) showed no difference.78 Vehicle exhausts are
ingestion, as an appetite suppressant, of leaf extracts from changing qualitatively as well as quantitatively, however,
the Asian shrub, Sauropus androgynus, in the population at and it remains to be seen whether the products of catalytic
large.73 Occupational exposures to the sprayed garment converters will pose new hazards despite eliminating those
print dye, acramin (Ardystil syndrome) and dust-containing associated with lead.
fragmented synthetic polymer fibres (flock worker’s lung), Further perspectives regarding the possible role of
carry the potential for more widespread parenchymal lung occupational exposures in the aetiology of COPD in the
disease. Some affected subjects show a lymphocytic pneu- population at large can be seen from the results of an epi-
monitis or bronchiolitis obliterans organizing pneumonia demiological investigation of urban (Bergen) and rural
(BOOP), while in others the subacute inflammatory response (Hordaland) communities in western Norway.79 A postal
is largely confined to the bronchioles.74,75 Acramin is no survey first sampled 5000 individuals from a total population
longer used as a transport chemical for the dyes used for of 250 000, and from the respondents an age-stratified
garment printing, and flock worker’s lung appears to occur sample of 1500 was invited to undertake a more detailed
only when rotary cutters (rather than guillotine cutters) investigation that included respiratory symptoms, smoking
are used to produce flock. In consequence, both diseases history, work history and spirometry. In all, 1275 individuals
should be readily controllable. It remains to be seen participated. When COPD was defined from strict spiro-
whether a suitable substitute will be found for diacetyl metric parameters alone (FEV1/FVC 70 per cent and
within the food-flavouring industry (perhaps butter itself) FEV1 80 per cent of predicted), smoking proved to be the
and whether the sporadic cases of obstructive bronchiolitis only explanatory variable of clear relevance from multiple
identified so far may prove in an epidemiological sense to regression analyses.
be tips of icebergs. In any event, physicians need to be When COPD was defined less stringently but more clini-
aware that COPD is not always an insidious disease which cally from objective spirometry (FEV1/FVC 70 per cent) or
progresses slowly over many years. Some cases, and per- subjective symptoms (chronic productive cough together
haps many, are subacute in nature and they may arise in with undue breathlessness or wheeze), the odds ratios for
unexpected settings. participants reporting specific occupational exposure to
aluminium, welding/metal fume, quartz or asbestos all
increased to significant levels; so too did the odds ratio for
PERSPECTIVE IN THE POPULATION AT LARGE heavy exposure to any source of occupational dust. An
increased prevalence of COPD was also noted in the urban
The relative risk posed to the general population by com- compared with rural communities, but this was attributa-
mon allergens, outdoor air pollution, air pollution within ble to the greater number of elderly individuals (who were
the home and respirable agents at work is a matter of affected disproportionately) living in the city of Bergen.
900 Work and chronic air flow limitation
The study population was consequently sufficiently large ● Occupational COPD will be found uncommonly
for subjective evidence of occupational productive cough
in the absence of both smoking and asthma.
to be demonstrated. However, the excess prevalences of ● Some cases of fixed airway obstruction are
strictly defined airway obstruction, which were noted
subacute rather than chronic in their
among certain groups of workers, did not reach conven-
development, and have surprising and
tional levels of statistical significance.
unexpected causes.
In its 2007 review, the UK’s Industrial Injuries Advisory
Council did not identify any further occupational causes,
other than coal mine dust, cotton dust and cadmium fume,
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●
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●
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Butterworths, 1983: 415–53.
level of the agent involved.
●
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●
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70
Health effects of ultrafine/nanoparticles
KEN DONALDSON, ROBERT J AITKEN, JON G AYRES, BRIAN G MILLER AND C LANG TRAN
Table 70.1 Different nanoparticle types, potentially exposed populations and their potential effects.
Diesel exhaust particles Drivers Exacerbation of asthma and COPD, lung cancer
Bulk manufactured nanoparticles, Workers in the carbon black, titanium Increased prevalence of productive cough
e.g. carbon black, silica, alumina dioxide industries
Welding fume Welders Metal fume fever
Bronchitis
Airway irritation
Chemical pneumonitis
Lung cancer
Nanotechnology applications, Workers in manufacture Unknown
e.g. carbon nanotubes, of carbon nanotubes
fullerenes, quantum dots
COPD, chronic obstructive pulmonary disease.
Figure 70.1 Transmission electron microscope images of nanoparticles of (a) carbon black; (b) welding fume; (c) diesel soot. Arrows
indicate individual nanoparticles, but note the occurrence of the nanoparticles commonly in the form of aggregates and chains, especially
evident in the carbon black and diesel soot. The welding fume particles are more heterogeneous in size and shape than the two carbon-
based nanoparticle samples.
the air poses a difficult problem that is being addressed in ultrafine fraction as a likely major arbiter of adverse effects,1
ongoing research (Figure 70.1). although not the only potentially harmful component of
particulate matter in air pollution.2 The ultrafine compo-
TOXICOLOGY nent of PM in urban air is dominated by combustion-
derived nanoparticles (CDNP) like diesel soot. CDNP have
Origins of concern over ultrafine/nanoparticle a number of components and properties that enable them to
exposure in the workplace be potent producers of free radicals and oxidative stress in
the environment of the lungs, leading to inflammation
PARTICULATE MATTER (Figure 70.2) (reviewed in Ref. 3). Although adverse effects
are seen in asthmatics and patients with COPD, the lead
Concern regarding the potential adverse effects of nanopar- adverse effects of PM10 are seen in patients with cardiovas-
ticles came to the fore in the 1990s when the environmental cular disease, where increases in PM10 and PM2.5 (PM2.5,
air pollution literature highlighted the importance of particles in ambient air collected using a sampling conven-
particulate matter (PM) (PM10, particles in ambient air col- tion that has 50 per cent efficiency for particles with an
lected using a sampling convention that has 50 per cent effi- aerodynamic diameter of 5 m) were found to exacerbate
ciency for particles with an aerodynamic diameter of 10 m) atherothrombosis leading to deaths and hospitalizations.
as the most potent component of the air pollution cocktail. A potential mechanistic link was made between
Adverse effects of PM10 were seen in some susceptible popu- ultrafine particles and cardiovascular effects4 that has
lations with increases of as little as 10 g/m3, suggesting developed into more generic hypotheses regarding the
that this was a potently toxic exposure. This sparked off impact of nanoparticles on atherothrombosis and heart
substantial research into which component(s) of PM10 rate variability (see under Effects of nanoparticles on
might be most important. This research highlighted the extrapulmonary sites, p. 908).
Toxicology 905
particles.10 More recently, ‘grand challenges’ for safe nano- following direct exposure of the peritoneal mesothelium in
technologies have been published.11 mice. Long and short asbestos showed exactly the same
length-dependent behaviour with ‘frustrated’ or incomplete
phagocytosis of the long fibres of either asbestos or nan-
Nanotubes and high aspect ratio nanoparticles otubes being an important underlying stimulus to inflam-
mation (Figure 70.4).
Asbestos and fibre toxicology, in general, has considerable There are a number of caveats in interpreting this work
resonance in the public and scientific mind. There is thus to mean that exposure to long nanotubes in workplaces
added concern regarding the toxicology of fibre-shaped or might lead to mesothelioma: it is not known whether nano-
high aspect ratio nanoparticles (HARN).8 Carbon nanotubes tubes are present in the air in workplaces in appreciable
(CNT) are HARN whose production is increasing dramati- numbers; it is not known whether nanotubes that deposit
cally, because of their potentially useful properties and the in the air spaces of the lung can find their way to the pleu-
fact that they can be made as very long fibrils (Figure 70.3).12 ral mesothelium in the way that asbestos does, nor whether,
Research to date has shown CNT to be highly fibrogenic even if they did, they would cause mesothelioma.17
after instillation into rodent lungs,13–16 but these were not However, these data do sound a warning bell that HARN
individual ‘fibre-shaped’ nanotube particles, but rather bun- may behave like asbestos in some ways.
dled, particulate aggregates. The question regarding whether Other types of high aspect ratio nanoparticles need to be
nanotubes can be present in the air as long thin particles has considered for their conformity with the fibre paradigm.
not been addressed at the time of writing. However, one
study17 has addressed the likely impact of such long nano-
tube fibres in relation to the ‘fibre pathogenicity paradigm’ Deliberate exposure to nanoparticles:
which includes asbestos. The current paradigm for fibre nanomedicine, cosmetics and food
pathogenicity is that fibres are pathogenic if they are thin, technology
biopersistent and longer than around 20 m.18 As regards
thinness and biopersistence, there is good evidence that nan- There are a number of scenarios where there is use of
otubes satisfy these components of the paradigm as a result nanoparticles with a high or certain likelihood of penetration
of their intrinsic structure (thinness) and being composed of into the body. They are mentioned here for completeness.
highly durable graphene (biopersistence). The study17 The use of nanoparticles in medicine is developing and
examined the third component of the paradigm, i.e. the holds out promise for therapeutics, imaging and tissue
length-dependence of pathogenicity. A direct mesothelial engineering. The types of particles used in nanomedicine
model was chosen that measured the inflammation and generally differ from the types of ‘hard’ nanoparticles dis-
granulomatous response to long and short nanotubes and cussed so far. They include liposomes, dendrimers and
relevant controls. Essentially, the results showed that carbon polymers, but carbon-based nanoparticles such as C60 and
nanotubes conformed to the length-dependent paradigm in