Historical Overview of Occupational Cancer Research

Abstract

Occupational carcinogens occupy a special place among the different classes of modifiable risk factors for cancer. The occupational environment has been a most fruitful one for investigating the pathogenesis of human cancer. Indeed, nearly half of all recognized human carcinogens are occupational carcinogens. Although it is important to discover occupational carcinogens for the sake of preventing occupational cancer, the potential benefit of such discoveries goes beyond the factory walls since most occupational exposures find their way into the general environment, sometimes at higher concentrations than in the workplace and, for some agents, with more people exposed in the general environment than in the workplace.

Full text

1
S. Anttila, P. Boffetta (eds.), Occupational Cancers,
DOI 10.1007/978-1-4471-2825-0_1, © Springer-Verlag London 2014
Occupational carcinogens occupy a special place among the
different classes of modifi able risk factors for cancer. The
occupational environment has been a most fruitful one for
investigating the pathogenesis of human cancer. Indeed,
nearly half of all recognized human carcinogens are occupa-
tional carcinogens. Although it is important to discover
occupational carcinogens for the sake of preventing occupa-
tional cancer, the potential benefi t of such discoveries goes
beyond the factory walls since most occupational exposures
fi nd their way into the general environment, sometimes at
higher concentrations than in the workplace and, for some
agents, with more people exposed in the general environ-
ment than in the workplace.
Early Discoveries
In 1775, Sir Percivall Pott, one of the leading British sur-
geons of the day, described some cases of cancer of the scro-
tum among English chimney sweeps. He ascribed this
condition, which was known in the trade as “soot wart,” to
the chimney sweeps’ pitifully dirty working conditions and
to the “lodgment of soot in the rugae of scrotum” [ 1 ]. In the
ensuing century, the syndrome became widely known, but it
remained the only recognized occupationally caused cancer
until the latter part of the nineteenth century. In 1875,
Volkmann described a syndrome identical to “chimney
sweeps cancer” of the scrotum among a group of coal tar and
paraffi n workers [ 2 ]. Apparent clusters of scrotal cancer
were thereafter reported among shale oil workers [ 3 ] and
mule spinners in the cotton textile industry [ 4 , 5 ]. By 1907
the belief in the carcinogenicity of “pitch, tar, and tarry sub-
stances” was widespread enough that skin cancers among
exposed workers were offi cially recognized as compensable
in the UK. Other types of cancer were also implicated as
occupationally induced. In the late nineteenth century, fol-
lowing several centuries of informal observations of unusu-
ally high incidence of lung tumors in residents of
Joachimsthal, Czechoslovakia, and Schneeberg, Germany, it
was shown that these risks were related to work in local
metal mines [ 6 – 8 ]. At about the same time, Rehn [ 9 ] reported
a striking cluster of bladder cancer cases among workers
from a German plant which produced dyestuffs from coal tar.
Following the accumulation of several of these clinical
case reports of high-risk occupations, the scientifi c investiga-
tion of cancer etiology began in earnest at the beginning of
the twentieth century with experimental animal research.
A major breakthrough came with the experiments of
Yamagiwa and Ichikawa [ 10 ], in which they succeeded in
inducing skin tumors in rabbit ears by applying coal tar.
Several important experimental discoveries were made in the
next 20 years, particularly by an English group led by
Kennaway. In a series of experiments, they managed to
isolate dibenz(a,h)anthracene and benzo(a)pyrene, both
polycyclic aromatic hydrocarbons (PAHs) and active ingre-
dients in coal tar [
11 – 13 ]. These compounds may have been
responsible for many of the excess risks of scrotal cancer in
various groups exposed to soot and oils [
14 ]. Several other
PAHs were subsequently shown to be carcinogenic to labora-
tory animals, but so were substances of many other chemical
families. For instance, 2-naphthylamine was shown to cause
Historical Overview of Occupational
Cancer Research
Jack Siemiatycki
1
J. Siemiatycki , PhD
Social and Preventive Medicine , University of Montreal ,
850 St.-Denis St. , Montreal , QC H2X OA9 , Canada
e-mail: j.siemiatycki@umontreal.ca
Keywords
Occupational cancer • Occupational carcinogens • History • Listing carcinogens •
Discovering carcinogens

2
bladder tumors in dogs, and this was thought to explain the
bladder cancers seen earlier among dyestuffs workers.
During the fi rst half of the twentieth century, there were
additional reports of high-risk occupation groups. Respiratory
cancer risks were reported in such diverse occupational set-
tings as nickel refi neries [ 15 ], coal carbonization processes
[
16 ], chromate manufacture [ 17 ], manufacture of sheep-dip
containing inorganic arsenicals [ 18 ], and asbestos products
manufacture [ 19 ]. This occurred before the smoking-induced
epidemic of lung cancer was at its peak, when the back-
ground risks of lung cancer were low.
The era of modern cancer epidemiology began around
1950 with several studies of smoking and lung cancer. In
the fi eld of occupational cancer epidemiology, this era saw
the conduct of some important studies of gas workers [ 20 ],
asbestos workers [ 21 ], and workers producing dyestuffs in
the chemical industry [
22 ]. The fi ndings of these early stud-
ies were important in highlighting signifi cant workplace
hazards, and the methods that these pioneering investiga-
tors developed for studying occupational cohorts have
strongly infl uenced the conduct of occupational cancer
research.
Subsequently, and especially with the fl owering of “envi-
ronmentalism” in the 1960s as a component of social con-
sciousness, there was a sharp increase in the amount of
research aimed at investigating links between the environ-
ment and cancer. Particular attention was paid to the occupa-
tional environment for several reasons. Most of the historic
observations of environmental cancer risks were discovered
in occupationally exposed populations. As diffi cult as it is to
characterize and study groups of workers, it is much harder
to study groups of people who share other characteristics,
such as diet or general environmental pollution. Not only are
working populations easier to delineate but, often, company
personnel and industrial hygiene records permit some, albeit
crude, form of quantifi cation of individual workers’ expo-
sure to workplace substances. Also, the pressure of orga-
nized labor was an important force in attracting attention to
the workplace. Finally, the workplace is a setting where
people have been exposed to high levels of many substances
which could potentially be harmful. Nonetheless, since many
occupational exposures can also occur in the general
environment, the cancer risks borne by workers have impli-
cations well beyond the workplace.
The burst of epidemiologic research on cancer and envi-
ronment was accompanied by extensive experimental work
aimed at testing the carcinogenic potential of different sub-
stances. Whereas this was carried out in an uncoordinated
fashion in the early years, national bodies, most notably the
National Toxicology Program in the USA, have imple-
mented systematic strategies to test large numbers of sub-
stances with standardized state-of-the-art long-term animal
studies [
23 ].
How Evidence Has Been Accumulated
on Selected Associations
Table 1.1 shows the evolution of evidence regarding ten
recognized occupational risk factors [
56 ]. For each asso-
ciation, the table indicates when the fi rst suspicions were
published and some of the signifi cant pieces of evidence
that came into play subsequently. The tables also give
some synthetic information about the nature of the epide-
miologic fi ndings. Typically, the association was fi rst sus-
pected on the basis of a clinical observation, which was
followed up by suggestive but inconclusive cohort studies
and then by more rigorous and more persuasive cohort
studies.
For most recognized carcinogens, the interval between
the fi rst clinical report and the general acceptance of the
association was measured in decades. The length of the inter-
val was great in the early period, in part because of the lack
of expertise in epidemiologic research and resources to con-
duct such studies. For three more recent “discoveries,” those
relating asbestos to mesothelioma, vinyl chloride to angio-
sarcoma of the liver, and chloroethers to lung cancer, the
interval between the fi rst publication of a suspicious cluster
and the general acceptance of a causal association was only
a matter of a few years. As a rule, early reports tended to
manifest higher relative risk estimates than more recent
reports. This is likely due to several reasons, including the
greater likelihood that outlier results will get noticed and
reported and real improvements in the industrial hygiene
conditions that have indeed had the effect of decreasing risks
of cancer.
While it is instructive to study the history of the evolu-
tion of knowledge for recognized carcinogens, it is just as
useful to understand that the trajectories of suspicion and
recognition are not necessarily monotonic. That is, there
are also examples of associations that have been considered
possible or likely in the past that are now considered as
unlikely. One such example concerns the risk of prostate
cancer following exposure to cadmium. Early studies
hinted at an association [ 57 – 60 ], but more recent and stron-
ger studies have tended to refute the hypothesis [ 61 – 63 ].
For the possible association between man-made mineral
fi bers (MMMF) and lung cancer, the impetus and suspicion
came from the similarity in physical characteristics between
MMMF and asbestos. But large American and European
cohort studies have failed to demonstrate an excess risk
[ 64 – 66 ]. Still, the absolute exposure levels to MMMF have
been so much lower than they have been to asbestos, that it
may justly be asked whether the differential evidence of
lung carcinogenicity between asbestos and MMMF is likely
due to exposure levels rather than to inherent carcinogenic
properties of the two classes of fi bers. A third example is
that of ethylene oxide and leukemia. There were reports
J. Siemiatycki

3
from Sweden among producers and some users of ethylene
oxide that hinted at excess risks of leukemia [ 67 , 68 ]. But
larger American studies have subsequently shown no such
risk [ 69 , 70 ]. A fourth example is that concerning acryloni-
trile and lung cancer. Some American and British studies
published in the early 1980s indicated possible excess risks
[ 71 – 73 ]. But a series of large studies from Europe and the
USA subsequently failed to demonstrate any risk of lung
cancer. Finally, suspicions have been voiced for a long time
about the possible association between formaldehyde and
lung cancer. But a series of large studies have failed to
demonstrate such an effect [ 74 – 78 ].
It is certainly clear that reports of case clusters or sus-
picions based on experimental findings or individual epi-
demiologic studies are not sufficient to predict the
ultimate judgment regarding an association. Since ran-
dom chance and error, supplemented by publication bias,
will inevitably lead to the publication of some false-pos-
itive results, it is important to seek replication of
findings.
Table 1.1 Selected milestone publications illustrating the development of information in humans on selected well-established occupational
cancers
Material/cancer Reference Location Study population Study type Evidence of effect
Radon/lung Härting and Hesse [
6 ] Germany Miners Case series Moderate
Peller [ 8 ] Czechoslovakia Miners Cohort Moderate
Archer et al. [
24 ] USA Uranium miners Cohort Strong
Archer et al. [
25 ] USA Uranium miners Cohort Strong
Howe et al. [
26 ] Canada Uranium miners Cohort Strong
Benzidine/bladder Rehn [ 9 ] Germany Dye workers Case series Weak
Scott [ 27 ] England Dye workers Case series Moderate
Case et al. [
22 ] Great Britain Dye workers PMR Strong
Meigs et al. [
28 ] Connecticut Benzidine makers Cohort Strong
Nickel and nickel
Compounds/nasal Annual Report [ 29 ] Wales Nickel refi neries Case series Moderate
Doll [ 30 ] Wales Nickel refi neries PMR Strong
Kaldor et al. [
31 ] Wales Nickel refi neries Cohort Strong
Arsenic/
respiratory
Henry [ 32 ] England Sheep-dip makers Case series Weak
Hill and Faning [
18 ] England Arsenical packers PMR Moderate
Lee and Fraumeni [
33 ] Montana Smelter workers Cohort Strong
Lee-Feldstein [ 34 ] Montana Smelter workers Cohort Strong
Pinto et al. [
35 ] Washington Smelter workers (urine index) Cohort Strong
Enterline et al. [
36 ] Washington Smelter workers (air index) Cohort Strong
Asbestos/lung Lynch and Smith [
37 ] South Carolina Asbestos textile workers Single case Weak
Doll [ 21 ] England Asbestos workers Cohort Weak
Selikoff et al. [
38 ] USA Insulation workers Cohort Moderate
McDonald et al. [
39 ] Canada Chrysotile miners Cohort Strong
Dement et al. [
40 ] USA Asbestos textile workers Cohort Strong
Seidman et al. [
41 ] USA Amosite workers Cohort Strong
Benzene/leukemia Mallory et al. [
42 ] UK Various occupations Case series Weak
Vigliani and Saita [
43 ] Italy Various occupations Case series Weak
Ishimaru et al. [
44 ] Japan Various occupations Case series Moderate
Aksoy et al. [
45 ] Turkey Shoemakers Case series Moderate
Infante et al. [
46 ] Ohio Pliofi lm makers Cohort Moderate
Rinsky et al. [
47 ] Ohio Pliofi lm makers Cohort Strong
Yin et al. [
48 ] China Benzene producers Cohort Strong
Chloroethers/lung Figueroa et al. [
49 ] Philadelphia Chemical workers Case series Moderate
DeFonso and Kelton [
50 ] Philadelphia Chemical workers Cohort Moderate
McCallum et al. [
51 ] UK Chloroether makers Cohort Strong
Vinyl chloride/
liver angiosarcoma
Creech and Johnson [
52 ] Kentucky PVC makers Case series Weak
Monson et al. [
53 ] Kentucky PVC makers PMR Strong
Waxweiler et al. [
54 ] USA PVC makers Cohort Strong
Fox and Collier [
55 ] Great Britain PVC makers Cohort Moderate
From Siemiatycki et al. [
56 ]. By permission of Oxford University Press, USA
1 Historical Overview of Occupational Cancer Research

4
Sources of Evidence on Risk to Humans
Due to Chemicals
Direct evidence concerning carcinogenicity of a substance
can come from epidemiologic studies among humans or
from experimental studies of animals (usually rodents).
Additional evidence comes from the results of studies
of chemical structure-activity analysis, pharmacokinet-
ics, mutagenicity, cytotoxicology, and other aspects of
toxicology.
Epidemiology
Epidemiologic research provides the most relevant data for
identifying occupational carcinogens and characterizing
their effects in humans. It can also contribute to the under-
standing of the mechanism of action of occupational car-
cinogens. Such research requires the juxtaposition of
information on illness or death due to cancer among work-
ers and information on their past occupations, industries,
and/or occupational conditions. A third, optional data set
which would improve the validity of inferences drawn from
that juxtaposition is the set of concomitant risk factors
which may confound the association between occupation
and disease.
Because of long induction periods for most cancers, cur-
rent epidemiologic studies would not provide direct evi-
dence on carcinogenic risk that might be caused by recently
introduced industrial agents. Even for substances which
have been with us for a long time, there are obstacles. Each
human experiences, over his or her lifetime, an idiosyncratic
and bewildering pattern of exposures. Not only is it impos-
sible to completely and accurately characterize the lifetime
exposure profi le of an individual, but even if we could, it is
a daunting statistical task to tease out the effects of a myriad
of specifi c substances. The ascertainment of valid cancer
diagnoses is also problematic since subjects are often traced
via routine record sources (notably, death certifi cates),
which may be error prone or in which cancers with long
survival are poorly represented. Confounding by factors
other than the one under investigation is of course an issue
in occupational cancer epidemiology, as it is in other areas
of epidemiology. But the problem is sometimes particularly
acute in occupational epidemiology because of some highly
correlated co- exposures in the occupational environment.
The number of subjects available for epidemiologic study is
often limited, and this compromises the statistical power to
detect hazards. Despite these challenges, epidemiology has
made signifi cant contributions to our knowledge of occupa-
tional carcinogens.
Animal Experimentation
Partly in consequence of the diffi culty of generating ade-
quate data among humans and partly because of the benefi ts
of the experimental approach, great efforts have been devoted
to studying the effects of substances in controlled animal
experiments. Results generated by animal studies do bear on
carcinogenicity among humans. Certain fundamental genetic
and cellular characteristics are similar among all mammalian
species. Most recognized human carcinogens have been
reported to be carcinogenic in one or more animal species;
and there is some correlation between species in the target
organs affected and in the carcinogenic potency [ 79 – 87 ].
Still, there are several reasons for caution in extrapolating
from animal evidence to humans. The animal experiment is
designed not to emulate the human experience but rather to
maximize the sensitivity of the test to detect animal carcino-
gens. Doses administered are usually orders of magnitude
higher than levels to which humans are exposed. The route of
exposure is sometimes unrealistic (e.g., injection or implanta-
tion), and the controlled and limited pattern of co- exposures
is unlike the human situation. The “lifestyle” of the experi-
mental animal is not only different from that of humans, but it
is unlike that of its species in the wild. Animals used are typi-
cally from pure genetic strains and susceptibility to carcino-
gens may be higher in such populations than in genetically
heterogeneous human populations. Metabolism, immunol-
ogy, DNA repair systems, life spans, and other physiologic
characteristics differ between species. Tumors seen in ani-
mals often occur at sites that do not have a counterpart among
humans (e.g., forestomach or Zymbal’s glands) or that are
much more rarely affected among humans (e.g., pituitary
gland). The behavior of many tumors generated in experi-
mental animals does not mimic that of malignant neoplasms
in humans, and the malignant phenotype is sometimes
unclear. Quantitative extrapolation of effects from rodents to
humans depends on unverifi able mathematical assumptions
concerning dose equivalents, dose-response curves, safety
factors, etc. Different reasonable assumptions can lead to
wildly divergent estimates. Some experimental carcinogens
operate via mechanisms which may not be relevant to humans.
A case in point is that of kidney tumors in male rats following
exposure to various organic chemicals and mixtures includ-
ing gasoline; these tumors are apparently caused by precipita-
tion of α
2 -microglobulin, a gender- and species-specifi c
protein [ 88 ]. Gold et al. [ 89 ] have shown that even between
two species as close on the phylogenetic scale as mice and
rats, the predictive value of carcinogenicity is only in the
range of 75 %.
Despite efforts to investigate the scientifi c basis for inter-
species extrapolation and despite resources that have been
J. Siemiatycki

5
devoted to testing chemicals in animal systems, there remain
serious disagreements about the predictive value of animal
experimentation [
23 , 87 , 90 – 97 ].
Short-Term Tests and Structure-Activity
Relationships
To mitigate the lengthy and costly process of animal carcino-
genesis testing, a number of rapid, inexpensive, and inge-
nious tests have been developed, to detect presumed
correlates of or predictors of carcinogenicity [ 82 , 98 – 101 ].
However, neither alone nor in combination have these
approaches proven to be consistently predictive of animal
carcinogenicity, much less human carcinogenicity [ 99 , 102 –
104 ]. Their role is in screening chemicals for animal testing
and in complementing the results of animal experiments.
Listing Occupational Carcinogens
Although it seems like a simple enough task, it is very diffi -
cult to draw up an unambiguous list of occupational carcino-
gens. The fi rst source of ambiguity concerns the defi nition of
an occupational carcinogen. Most occupational exposures
are also found in the general environment and/or in con-
sumer products; most general environmental exposures and
consumer products, including medications, foods, and oth-
ers, are found in some occupational environments. The dis-
tinctions can be quite arbitrary. For instance, while tobacco
smoke, sunlight, and immunosuppressive medications are
not primarily considered to be occupational exposures, there
certainly are workers whose occupations bring them into
contact with these agents. Also, while asbestos, benzene, and
radon gas are considered to be occupational carcinogens,
they are also found widely among the general population,
and indeed it is likely that many more people are exposed to
these substances outside than inside the occupational envi-
ronment. There is no simple rule to earmark “occupational”
carcinogens as opposed to “nonoccupational” ones. Further,
some carcinogens are chemicals that are used for research
purposes and to which few people would ever be exposed,
whether occupationally or nonoccupationally.
A second source of ambiguity derives from the rather idio-
syncratic nature of the evidence. In some instances, we know
that an occupational or industrial group is at excess risk of
cancer, and we have a good idea of the causative agent (e.g.,
scrotal cancer among chimney sweeps and PAHs in soot [ 14 ];
lung cancer among asbestos miners and asbestos fi bers [ 63 ]) .
In some instances, we know that a group experienced excess
risk, but the causative agent is unknown or at least unproven
(e.g., lung cancer among painters [
105 ]; bladder cancer
among workers in the aluminum industry [
105 ]) . The strength
of the evidence for an association can vary. For some associa-
tions, the evidence of excess risk seems incontrovertible (e.g.,
liver angiosarcoma and vinyl chloride monomer [ 105 ]; blad-
der cancer and benzidine [
105 ]). For some associations, the
evidence is suggestive (e.g., breast cancer and shift work
[
106 ]; bladder cancer and employment as a painter [ 105 ]).
Among the many substances in the industrial environment for
which there are no human data concerning carcinogenicity,
there are hundreds that have been shown to be carcinogenic in
some animal species and thousands that have been shown to
have some effect in assays of mutagenicity or genotoxicity.
These considerations complicate the attempt to devise a list of
occupational carcinogens.
IARC Monographs
One of the key sources of information for listing occupa-
tional carcinogens is the Monograph Programme of the
International Agency for Research on Cancer (IARC) –
Evaluation of the Carcinogenic Risk of Chemicals to
Humans. The objective of the IARC Programme, which has
been operating since 1971, is to publish critical reviews of
epidemiological and experimental data on carcinogenicity
for chemicals, groups of chemicals, industrial processes,
other complex mixtures, physical agents, and biological
agents to which humans are known to be exposed and to
evaluate the data in terms of human risk.
IARC evaluations are carried out during specially con-
vened meetings that typically last a week. The meetings may
evaluate only one agent, such as silica, they may address a
set of related agents, or they may even address exposure cir-
cumstances such as an occupation or an industry. For each
such meeting, and there have typically been three per year,
IARC convenes an international working group, usually
involving from 15 to 30 experts on the topic(s) being evalu-
ated from four perspectives: (1) exposure and occurrence of
the substances being evaluated, (2) human evidence of can-
cer risk (i.e., epidemiology), (3) animal carcinogenesis, and
(4) other data relevant to the evaluation of carcinogenicity
and its mechanisms. The working group is asked to review
all of the literature relevant to an assessment of carcinogenic-
ity. In the fi rst part of the meeting, four subgroups (based on
the four perspectives mentioned above) review and revise
drafts prepared by members of the subgroup, and each sub-
group develops a joint review and evaluation of the evidence
on which they have focused. Subsequently, the entire work-
ing group convenes in plenary and proceeds to derive a joint
text. They determine whether the epidemiological evidence
1 Historical Overview of Occupational Cancer Research

6
supports the hypothesis that the substance causes cancer and,
separately, whether the animal evidence supports the hypoth-
esis that the substance causes cancer. The judgments are not
simply dichotomous (yes/no), but rather they allow the work-
ing group to express a range of opinions on each of the
dimensions evaluated. Table 1.2 shows the categories into
which the working groups are asked to classify each sub-
stance, when examining only the epidemiological evidence
and when examining only the animal experimental evidence
[ 56 ]. The operational criteria for making these decisions
leave room for interpretation, and the scientifi c evidence
itself is open to interpretation. It is not surprising then that
the evaluations are sometimes diffi cult and contentious.
The overall evaluation of human carcinogenicity is based
on the epidemiological and animal evidence of carcinogenic-
ity, plus any other relevant evidence on genotoxicity, muta-
genicity, metabolism, mechanisms, or others. Epidemiological
evidence, where it exists, is given greatest weight. Direct
animal evidence of carcinogenicity is next in importance,
with increasing attention paid to mechanistic evidence that
can inform the relevance of the animal evidence for human
risk assessment.
Table 1.3 shows the categories for the overall evaluation
and how they are derived from human, animal, and other
evidence [ 56 ]. Each substance is classifi ed into one of the
following classes (which IARC refers to as “groups”: carci-
nogenic (Group 1), probably carcinogenic (Group 2A), pos-
sibly carcinogenic (Group 2B), not classifi able (Group 3),
and probably not carcinogenic (Group 4). However, the algo-
rithm implied by Table 1.3 is only indicative, and the work-
ing group may derive an overall evaluation that departs from
the strict interpretation of the algorithm. For example, neu-
trons have been classifi ed as human carcinogens (Group 1)
despite the absence of epidemiological data, because of over-
whelming experimental evidence and mechanistic consider-
ations [ 108 ]. The IARC process relies on consensus, and this
is usually achieved, but sometimes, differing opinions among
experts lead to split decisions. In the end, the published eval-
uations refl ect the views of at least a majority of participating
experts. The results of IARC evaluations are published in
readily available and user-friendly volumes, and summaries
are published on a website [ 109 ].
There are some limitations to bear in mind. First, IARC
does not provide any explicit indication as to whether the
substance evaluated should be considered as an “occupa-
tional” exposure. Second, the evaluations are anchored in the
time that the working group met and reviewed the evidence;
it is possible that evidence that appeared after the IARC
review could change the evaluation. Siemiatycki et al. [ 110 ]
provided a consolidation of occupational carcinogens
Table 1.2 Classifi cations used in the IARC monographs to characterize evidence of carcinogenicity
Category of evidence In humans In animals
Suffi cient evidence of
carcinogenicity
A causal relationship has been established between
exposure to the agent, mixture, or exposure
circumstance and human cancer. That is, a positive
relationship has been observed between the exposure
and cancer in studies in which chance, bias, and
confounding could be ruled out with reasonable
confi dence
A causal relationship has been established between the agent
or mixture and an increased incidence of malignant neoplasms
or of an appropriate combination of benign and malignant
neoplasms in (a) two or more species of animals or (b) in two
or more independent studies in one species carried out at
different times or in different laboratories or under different
protocols
Limited evidence of
carcinogenicity
A positive association has been observed between
exposure to the agent, mixture, or exposure
circumstance and cancer for which a causal
interpretation is considered to be credible, but
chance, bias, or confounding could not be ruled out
with reasonable confi dence
The data suggest a carcinogenic effect but are limited for
making a defi nitive evaluation because, e.g., (a) the evidence
of carcinogenicity is restricted to a single experiment; (b) there
are unresolved questions regarding the adequacy of the design,
conduct, or interpretation of the study; or (c) the agent or
mixture increases the incidence only of benign neoplasms or
lesions of uncertain neoplastic potential or of certain
neoplasms which may occur spontaneously in high incidences
in certain strains
Inadequate evidence of
carcinogenicity
The available studies are of insuffi cient quality,
consistency, or statistical power to permit a
conclusion regarding the presence or absence of a
causal association between exposure and cancer, or
no data on cancer in humans are available
The studies cannot be interpreted as showing either the
presence or absence of a carcinogenic effect because of major
qualitative or quantitative limitations, or no data on cancer in
experimental animals are available
Evidence suggesting
lack of carcinogenicity
There are several adequate studies covering the full
range of levels of exposure that human beings are
known to encounter, which are mutually consistent
in not showing a positive association between
exposure to the agent, mixture, or exposure
circumstance and any studied cancer at any observed
level of exposure
Adequate studies involving at least two species are available
which show that, within the limits of the tests used, the agent
or mixture is not carcinogenic
From Siemiatycki et al. [
56 ]. By permission of Oxford University Press, USA
J. Siemiatycki

7
identifi ed by the IARC Monographs up to 2003, including
identifi cation of target organs. We use their operational defi -
nition of occupational agents. In 2008 and 2009, a series of
IARC Monograph meetings were held to reevaluate evidence
regarding agents that had previously been considered to be
Group 1 carcinogens. The evidence of carcinogenicity was
reevaluated, and where appropriate the target organs were
identifi ed.
D e fi nite and Probable Occupational Risk
Factors for Cancer
Table 1.4 shows a list of 32 agents which have been classifi ed
as Group 1 (i.e., defi nite) causes of cancer and which we
consider to be occupational exposures. It shows the target
organs at risk, and it shows the main occupations or indus-
tries in which the agents are found. The table also shows 11
occupations and industries which have been found to be at
risk, but for which the responsible agent has not been
identifi ed.
Some of these carcinogens are naturally occurring sub-
stances or agents (e.g., asbestos, wood dust, solar radiation),
while some are man-made (e.g., mineral oils, TCDD, vinyl
chloride). Some are well-defi ned chemical compounds (e.g.,
benzene, trichloroethylene), while others are families of
compounds which may include some carcinogens and some
noncarcinogens (e.g., nickel compounds, acid mists, wood
dust), while yet others are mixtures of varying chemical
composition (e.g., diesel engine emissions, mineral oils).
Among the 11 high-risk occupations and industries shown
in Table 1.3 , most are industries in which the number of
workers is quite small, in developed countries at least. But
one occupation group, painters, stands out as an occupation
group which is quite prevalent on a population basis, and for
which the agent responsible for the excess risk has not been
clearly identifi ed. It may be reasonably speculated that aro-
matic amines such as benzidine and 2-nathphalymine may be
responsible for some of the excess bladder cancer risk, but it
is not obvious what the cause of lung cancer might be [ 111 ].
Table 1.5 shows a list of 27 occupational agents which
have been classifi ed as Group 2A (i.e., probable) causes of
cancer. The table also shows 5 occupations and industries
which have been found to be probably at risk, but for which
a cause has not been identifi ed, and another type of occupa-
tional circumstance – shift work. Some of these are agents
for which there is a body of epidemiologic evidence, but that
body of evidence does not permit a clear-cut determination
of carcinogenicity (e.g., lead compounds, creosotes); but
most agents in this table are defi nite animal carcinogens with
little or no epidemiologic evidence to confi rm or contradict
the animal evidence. Most agents listed in Table 1.5 have
fewer workers exposed than the agents in Table 1.4 .
The Evolution of Knowledge
Table 1.6 shows how current occupational carcinogens were
considered in two earlier times. The lists of agents in
Tables
1.4 and 1.5 were compared with lists of carcinogens
Table 1.3 Classifi cations and guidelines used by IARC working groups in evaluating human carcinogenicity based on the synthesis of epidemio-
logical, animal, and other evidence
Combinations which fi t in this class
Group Description of group Epidemiological evidence Animal evidence Other evidence
1 The agent, mixture, or exposure
circumstance is carcinogenic to
humans
Suffi cient Any Any
Less than suffi cient Suffi cient Strongly positive
2A The agent, mixture, or exposure
circumstance is probably
carcinogenic to humans
Limited Suffi cient Less than strongly positive
Inadequate or not available Suffi cient Strongly positive
2B The agent, mixture, or exposure
circumstance is possibly
carcinogenic to humans
Limited Less than suffi cient Any
Inadequate or not available Suffi cient Less than strongly positive
Inadequate or not available Limited Strongly positive
3 The agent, mixture, or exposure
circumstance is not classifi able as
to its carcinogenicity to humans
Inadequate or not available Limited Less than strongly positive
Not elsewhere classifi ed
4 The agent, mixture, or exposure
circumstance is probably not
carcinogenic to humans
Suggesting lack of
carcinogenicity
Suggesting lack of carcinogenicity Any
Inadequate or not available Suggesting lack of carcinogenicity Strongly negative
This table shows our interpretation of the IARC guidelines used by the working groups to derive the overall evaluation from the combined epide-
miological, animal, and other evidence. However, the working group can, under exceptional circumstances, depart from these guidelines in deriv-
ing the overall evaluation. For example, the overall evaluation can be downgraded if there is less than suffi cient evidence in humans and strong
evidence that the mechanism operating in animals is not relevant to humans. For details of the guidelines, refer to the Preamble of the IARC
Monographs [
107 ] From Siemiatycki et al. [ 56 ]. By permission of Oxford University Press, USA
1 Historical Overview of Occupational Cancer Research

8
Table 1.4 Occupational exposures, occupations, industries, and occupational circumstances classifi ed as defi nite carcinogenic exposures (Group 1)
by the IARC Monographs , Volumes 1–106
Agent, occupation, or industry Target organ Main industry or use
Chemical agents
Acid mists, strong inorganic Larynx Chemical
4-Aminobiphenyl Bladder Rubber
Arsenic and inorganic arsenic compounds Lung, skin, bladder Glass, metals, pesticides
Asbestos (all forms) Larynx, lung, mesothelium, ovary Insulation, construction, renovation
Benzene Leukemia Starter and intermediate in chemical
production, solvent
Benzidine Bladder Pigments
Benzo[ a ]pyrene Lung, skin (suspected) Coal liquefaction and gasifi cation, coke
production, coke ovens, coal tar distillation,
roofi ng, paving, aluminum production
Beryllium and beryllium compounds Lung Aerospace, metals
Bis(chloromethyl)ether, chloromethyl methyl ether Lung Chemical
1,3-Butadiene Leukemia and/or lymphoma Plastics, rubber
Cadmium and cadmium compounds Lung Pigments, battery
Chromium (VI) compounds Lung Metal plating, pigments
Coal tar pitch Lung, skin Construction, electrodes
Engine exhaust, diesel Lung Transport, mining
Ethylene oxide – Chemical, sterilizing agent
Formaldehyde Nasopharynx, leukemia Plastic, textile
Ionizing radiation (including radon-222 progeny) Thyroid leukemia, salivary gland, lung,
bone, esophagus, stomach, colon, rectum,
skin, breast, kidney, bladder, brain
Radiology, nuclear industry, underground
mining
Leather dust Nasal cavity Shoe manufacture and repair
4,4′-Methylenebis(2-chloroaniline) (MOCA) – Rubber
Mineral oils, untreated or mildly treated Skin Lubricant
2-Naphthylamine Bladder Pigment
Nickel compounds Nasal cavity, lung Metal alloy
Shale oils Skin Lubricant, fuel
Silica dust, crystalline, in the form of quartz or
cristobalite
Lung Construction, mining
Solar radiation Skin Outdoor work
Soot Lung, skin Chimney sweeps, masons, fi refi ghters
2,3,7,8-Tetrachlorodibenzo- para -dioxin (TCDD) – Chemical
Tobacco smoke, secondhand Lung Bars, restaurants, offi ces
ortho -Toluidine Bladder Pigments
Trichloroethylene Kidney Solvent, dry cleaning
Vinyl chloride Liver Plastics
Wood dust Nasal cavity Furniture
Occupation or industry without specifi cation of the responsible agent
Aluminum production Lung, bladder –
Auramine production Bladder –
Coal gasifi cation Lung –
Coal tar distillation Skin –
Coke production Lung –
Hematite mining (underground) Lung –
Iron and steel founding Lung –
Isopropyl alcohol manufacture using strong acids Nasal cavity –
Magenta production Bladder –
Painter Bladder, lung, mesothelium –
Rubber manufacture Stomach, lung, bladder, leukemia –
J. Siemiatycki

9
noted by a WHO expert panel in 1964 [ 112 ] and also with
the list accrued by the IARC Monograph Programme in 1987
[ 113 ]. One third of today’s Group 1 defi nite occupational
carcinogens were already recognized as such by 1964. Two-
thirds were considered to be defi nite or probable as of 1987.
In contrast, none of today’s Group 2A probable occupational
carcinogens had even been mentioned as of 1964, and about
one-third were mentioned as of 1987. While it is possible for
the classifi cation of agents to change over time in either
direction, in practice there have been rather few instances of
agents being “downgraded” between successive periods.
Notable counterexamples are:
• 3,3 Dichlorobenzene, which was considered a defi nite
carcinogen in 1964 and was only considered as possible
as of 1987 and as of 2002
• Acrylonitrile and propylene oxide, which were consid-
ered probable carcinogens in 1987 and only as possible in
2002
The number of occupational agents rated by IARC as
Group 1 carcinogens has tapered off since 1987, while the
proportion of Group 2B evaluations increased. This refl ects
the fact that, when the Monograph Programme began, there
was a “backlog” of agents for which strong evidence of car-
cinogenicity had accumulated, and, naturally, these were the
Table 1.5 Occupational exposures, occupations, industries, and occupational circumstances classifi ed as probable carcinogenic exposures (Group
2A) by the IARC Monographs , Volumes 1–106
Agent, occupation, or industry Suspect target organ Main industry or use
Chemical agents
Acrylamide – Plastics
Bitumens (combustion products during roofi ng) Lung Roofi ng
Captafol – Pesticide
alpha-Chlorinated toluenes (benzal chloride, benzotrichloride,
benzyl chloride) and benzoyl chloride (combined exposures)
– Pigments, chemicals
4-Chloro- ortho -toluidine Bladder Pigments, textiles
Cobalt metal with tungsten carbide Lung Hard metal production
Creosotes Skin Wood
Diethyl sulfate – Chemical
Dimethylcarbamoyl chloride – Chemical
1,2-Dimethylhydrazine – Research
Dimethyl sulfate – Chemical
Epichlorohydrin – Plastics
Ethylene dibromide – Fumigant
Glycidol – Pharmaceutical industry
Indium phosphide – Semiconductors
Lead compounds, inorganic Lung, stomach Metals, pigments
Methyl methanesulfonate – Chemical
2-Nitrotoluene – Production of dyes
Non-arsenical insecticides – Agriculture
PAHs (several apart from BaP) Lung, skin Coal liquefaction and gasifi cation, coke production, coke
ovens, coal tar distillation, roofi ng, paving, aluminum
production
Polychlorinated biphenyls – Electrical components
Styrene-7,8-oxide – Plastics
Tetrachloroethylene (perchloroethylene) – Solvent
1,2,3-Trichloropropane – Solvent
Tris(2,3-dibromopropyl) phosphate – Plastics, textiles
Vinyl bromide – Plastics, textiles
Vinyl fl uoride – Chemical
Occupation or industry without specifi cation of the responsible agent
Art glass, glass containers, and pressed ware (manufacture of) Lung, stomach –
Carbon electrode manufacture Lung –
Food frying at high temperature – –
Hairdressers or barbers Bladder, lung –
Petroleum refi ning – –
Occupation circumstance without specifi cation of the responsible agent
Shift work involving circadian disruption Breast Nursing, several others
1 Historical Overview of Occupational Cancer Research

10
agents that IARC initially selected for review. Once the
agents with strong evidence had been dealt with, IARC
started dealing with others.
Many of the recognized defi nite occupational carcinogens
were already suspected or established by the 1960s. It may
be that there were only a limited number of strong occupation-
cancer associations, and these were suffi ciently obvious that
they could produce observable clusters of cases for astute
clinicians to notice. It may be that levels of exposure to occu-
pational chemicals were so high before the 1960s as to pro-
duce high cancer risks and cancer clusters, but that
improvements in industrial hygiene in industrialized coun-
tries have indeed decreased risks to levels that are diffi cult to
detect.
While the evaluation of the hypothesis of an agent caus-
ing human cancer depends critically on epidemiological and
experimental evidence, the initial suspicion can be provoked
by epidemiological surveillance, by experimental evidence,
or by clinical cluster observations. Indeed, most defi nite
occupational carcinogens were fi rst suspected on the basis of
case reports by clinicians or pathologists [
114 ]. These dis-
coveries were usually coincidental [
115 ]. It is thus reason-
able to suspect that there may be some, perhaps many, as yet
undiscovered occupational carcinogens.
Interpreting the Lists
The determination that a substance or circumstance is carci-
nogenic depends on the strength of evidence at a given point
in time. The evidence is sometimes clear-cut, but more often
it is not. The balance of evidence can change in either direc-
tion as new data emerge.
The characterization of an occupation or industry group
as a “high-risk group” is strongly rooted in time and place.
For instance, the fact that some groups of nickel refi nery
workers experienced excess risks of nasal cancer does not
imply that all workers in all nickel refi neries will be subject
to such risks. The particular circumstances of the industrial
process, raw materials, impurities, and control measures
may produce risk in one nickel refi nery but not in another
or in one historic era but not in another. The same can be
said of rubber production facilities, aluminum refi neries,
and other industries and occupations. Labeling a chemical
substance as a carcinogen in humans is a more timeless
statement than labeling an occupation or industry as a high-
risk group. However, even such a statement requires quali-
fi cation. Different carcinogens produce different levels of
risk, and for a given carcinogen, there may be vast differ-
ences in the risks incurred by different people exposed
under different circumstances. Indeed there may also be
interactions with other factors, environmental or genetic,
that produce no risk for some exposed workers and high
risk for others.
This raises the issue of quantitative risk assessment,
which is an important tool in prevention of occupational can-
cer. While it would be valuable to have such information, for
many agents, the information base on dose-response to sup-
port such quantifi cation is fragmentary.
Illustrative Examples and Controversies
In this section, we present a few examples to illustrate some
of the diffi culties inherent in research to evaluate occupa-
tional carcinogens.
Polycyclic Aromatic Hydrocarbons (PAHs)
PAHs comprise a large family of chemical compounds which
are produced during incomplete combustion of organic mate-
rial and in particular fossil fuels. PAHs are found in many
occupations and industries, and they are found in such non-
occupational settings as vehicle roadways, homes heated by
burning fuel, barbequed foods, cigarette smoke, and many
more.
As described above, the earliest known occupational car-
cinogens were coal-derived soots, oils, and fumes that caused
skin cancers. Animal experiments showed that several of the
chemicals found in these complex mixtures were carcino-
genic. These chemicals were in the family of polycyclic
aromatic hydrocarbons. When epidemiologic evidence accu-
mulated on lung cancer risks among workers exposed to
complex mixtures derived from coal, petroleum, and wood,
it was widely felt that the responsible agents were likely to
be PAHs. Several of the complex mixtures (coal tars and
pitch, mineral oils, shale oils, soots) which are classifi ed as
IARC Group 1 carcinogens include PAHs, and several of the
Table 1.6 How current IARC Group 1 ( n = 32) and Group 2A ( n = 27)
occupational carcinogens (agents, not occupations or industries) were
rated in 1964 and 1987
Past rating Current Group 1 Current Group 2A
1964 WHO rating
Well-documented carcinogen 9 0
Suspected carcinogen 1 0
Not mentioned 22 27
Total 32 27
1987 IARC rating
Group 1 14 0
Group 2A 6 8
Group 2B 3 5
Group 3 1 0
Not rated 8 15
Total 32 27
J. Siemiatycki

11
industries in which cancer risks have been identifi ed (coal
gasifi cation, coke production, aluminum production, iron
and steel founding) are industries in which PAHs are preva-
lent. Paradoxically, however, there is only one specifi c PAH
on the Group 1 list – benzo(a)pyrene. Some others are
classed in Group 2A. This is because it is virtually impossi-
ble to epidemiologically isolate the effect of one versus
another of the components of these carcinogenic mixtures.
Because of the non-feasibility of measuring all PAHs when
they are measured for industrial hygiene purposes, benzo(a)
pyrene has typically been considered a representative marker
of PAHs. While this marker may be available for epidemio-
logic purposes, it cannot be assumed that this is the only
PAH present or how its presence is correlated with those of
other PAHs. Similar considerations apply to urinary
1-OH-pyrene, the most widely used biomarker of internal
PAH dose, whose excretion depends on the composition of
the mixture of PAH and on metabolic pathways under the
control of polymorphic genes. It is possible that biomarker
and genetic studies will provide the additional information
that would permit the determination that specifi c PAHs are
defi nite human carcinogens.
Diesel and Gasoline Engine Emissions
Engine emissions are common in many workplaces and are
ubiquitous environmental pollutants. Based in part on exper-
imental evidence and in part on epidemiologic evidence,
there has long been suspicion that emissions from diesel-
powered engines may be lung carcinogens; but, until recently,
the epidemiologic evidence was considered inconclusive
[ 116 – 118 ]. The diffi culty of drawing inferences regarding
the effect of diesel exhaust was in part due to some method-
ological limitations and in part due to the indirect nature of
the evidence. Namely, most of the studies had used certain
job titles (most often, truck driver) as proxies for occupa-
tional exposure to diesel exhaust. Few studies were able to
control for the potential confounding effect of cigarette
smoking and of other occupational exposures. Many of the
studies had low statistical power and/or insuffi cient follow-
up time. Finally, the relative risk estimates in most studies
ranged from 1.0 to 1.5, making it diffi cult to exclude the pos-
sibility of chance or bias. The number of diesel-powered
vehicles is increasing in many countries. Because of the sig-
nifi cant scientifi c and public policy implications [ 119 , 120 ],
it is important to derive more defi nitive inferences regarding
the potential human carcinogenicity of diesel emissions.
Recently some studies of diesel-exposed mine workers and
railroad workers have provided more defi nitive evidence that
the associations previously observed are probably true [ 121 –
124 ], and IARC classifi ed diesel engine emissions as a
human carcinogen [
125 ].
There is less evidence, both experimental and epidemio-
logic, for a carcinogenic effect of exposure to gasoline engine
emission than to diesel emission.
Engine emission provides an example of a common
dilemma in occupational and environmental cancer risk
assessment. A chemical analysis of both gasoline and diesel
exhaust shows the presence of many substances which are
considered carcinogenic, notably some nitro-PAHs which
are classed by IARC as 2A and 2B. Should the presence of a
carcinogen within a complex mixture automatically trigger a
labeling of the mixture as carcinogenic, irrespective of the
epidemiologic evidence on the mixture? There is no wide
consensus on this issue, but it has important consequences.
For instance, it would have meant that both diesel and gaso-
line engine emissions would have been classifi ed long ago as
probable or defi nite human carcinogens.
Asbestos
Few health issues have sparked as much public concern, con-
troversy, and expense as has asbestos-related cancer risk.
Asbestos is a term describing a family of naturally occurring
fi brous silicates which have varied chemical and physical
compositions and which have been widely used in industrial
and consumer products for over a century. The main fi ber
types are called chrysotile and amphibole. Exposure to
asbestos fi bers has occurred in many occupations, including
mining and milling, manufacture of asbestos-containing
products, and the use of these products. Currently, in devel-
oped countries, construction and maintenance workers con-
stitute the largest group of asbestos-exposed workers,
resulting from application and removal of asbestos products
and building demolition. Asbestos was one of the most ubiq-
uitous workplace exposures in the twentieth century.
Case reports linking asbestos with lung cancer started to
appear in the 1930s and 1940s [ 37 ], but the fi rst formal inves-
tigations were published in the 1950s and 1960s [
21 , 126 ]. In
the early 1960s, reports appeared linking asbestos exposure
to a hitherto unrecognized tumor of the pleura and perito-
neum called mesothelioma [
127 ]. By the mid-1960s, it was
clear that the very high and virtually uncontrolled exposure
conditions prevalent up to then could induce lung cancer and
mesothelioma.
While asbestos production and use have declined dramat-
ically in most industrialized countries since 1975, public
concern and controversy have not [ 128 – 134 ]. Asbestos fi bers
are highly persistent and widespread in the environment,
partly because of its widespread industrial use in the past and
partly because it is a natural geological component of out-
croppings in many areas of the world. Measurements carried
out in all kinds of nonoccupational settings have detected
asbestos fi bers, and it has become clear that asbestos is a
1 Historical Overview of Occupational Cancer Research

12
widespread environmental pollutant, albeit at much lower
levels than in some workplaces. Also, because of long
latency periods, we are still seeing the cancer impact of high
occupational exposure levels experienced 30–50 years ago,
and we will for some time to come. Since exposure levels are
much lower than they used to be, it is of interest to determine
the risk due to low levels of asbestos exposure. Risk assess-
ment models have been developed to extrapolate from high
to low exposure levels, but these models have not been vali-
dated [
135 ].
Many countries have banned use of asbestos, while some
others have instituted regulatory limits orders of magnitude
below levels that had been known to produce harmful effects.
The availability of alternative non-asbestos substitution prod-
ucts makes such strategies feasible. Perhaps because they are
not carcinogenic or perhaps because exposure levels to the
substitution products are much lower than that experienced
by asbestos-exposed workers in the past, there has been no
demonstrated cancer risk related to the substitution products.
While asbestos use has declined in developed countries,
its use has been increasing in some developing countries.
Cadmium and Cadmium Compounds
Cadmium has been produced and used in alloys and various
compounds for several end products including batteries, pig-
ments, electroplating, and some plastics [ 63 ]. Exposure var-
ies widely between industries in both types of cadmium
compounds and level of exposure. Following reports in a few
small cohorts of excess cases of prostate cancer among
workers in battery plants, an early IARC working group con-
cluded that there was moderately persuasive evidence of an
excess risk of prostate cancer as a result of cadmium expo-
sure [ 136 , 137 ]. They noted in passing that one of the cohorts
also reported an excess of lung cancer. In the following
decade, a number of additional cohort studies were under-
taken in cadmium-exposed workers [
138 ]. There was no
additional evidence of an increase in prostate cancer risk.
But the evidence on lung cancer, which was unremarkable in
the fi rst few studies, became much more pronounced as addi-
tional data were accumulated. By 1993, another IARC work-
ing group pronounced cadmium a Group 1 carcinogen but
solely on the basis of its association with lung cancer. Still,
the assessment of carcinogenicity of cadmium highlighted
several methodological problems. The number of long-term,
highly exposed workers was small, the historical data on
exposure to cadmium was limited, and the ability to defi ne
and examine a gradient of exposure was limited to one study.
Confounding by cigarette smoking in relation to lung cancer
was diffi cult to address. Control of the confounding effect of
co-exposure to other metals, particularly arsenic and nickel,
was limited and remains somewhat problematic.
Styrene
Styrene is one of the most important industrial chemicals.
The major uses are in plastics, latex paints and coatings,
synthetic rubbers, polyesters, and styrene-alkyd coatings
[
139 ]. These products are used in construction, packaging,
boats, automotive (tires and body parts), and household
goods (e.g., carpet backing). Nearly 18 million tons were
used worldwide in 1998. It has been estimated that as many
as one million workers in the USA may be exposed to sty-
rene, and the numbers worldwide would be much greater. In
addition, there is widespread low-level environmental
exposure.
The fi rst evidence of a possible cancer risk came from
case reports of leukemia and lymphoma among workers in
various styrene-related industries [
140 – 142 ]. A number of
cohort studies have been carried out since then in Europe
and the USA in various industries [ 143 – 147 ]. The interpre-
tation of these studies has been bedeviled by four main
problems: the different types of industries in which these
studies were carried out make it diffi cult to compare results
across studies; within most industries, styrene is only one of
several chemical exposures, and these tend to be highly cor-
related with styrene exposure; the pattern of results has been
unpersuasive, though there are a couple of hints of excess
risk of leukemia in some subgroups of some cohorts; and
fi nally, the classifi cation of hematopoietic malignancies is
complicated [ 148 ].
The substantial body of epidemiologic evidence can rea-
sonably be interpreted as showing no cancer risk, or it can be
interpreted as showing suggestions of risk of leukemia in
some subgroups of some cohorts. The IARC working group
leaned in the latter direction as they categorized the human
evidence as “limited” rather than “inadequate.” The studies
already conducted have been large, and there have been sev-
eral of them. It is not clear that another study would resolve
the issue [ 149 ].
Nor does the experimental evidence provide clear guid-
ance. The animal experimental evidence is equivocal, and
human biomarker studies show some signs of DNA adduct
formation.
1,3-Butadiene
Concern about the possible carcinogenicity of 1,3-butadiene
in humans derives from the results of animal experiments,
which showed an increased incidence of leukemia in mice
and, to a lesser extent, rats [ 150 ]. Data on the carcinogenicity
of butadiene in humans derive essentially from studies con-
ducted among workers employed in the production of the
monomer and in the production of styrene-butadiene rubber
(SBR), where high exposure levels occurred in the past.
J. Siemiatycki

13
A series of analyses examined the mortality of approxi-
mately 17,000 male workers from eight SBR-manufacturing
facilities in the USA and Canada. Although mortality from
leukemia was only slightly elevated in the most recent
updates [
151 – 153 ], large excesses of mortality from leuke-
mia were seen in workers in the most highly exposed areas of
the plants and among hourly paid workers, especially those
who had been hired in the early years and had been employed
for more than 10 years. These excesses were seen for both
chronic lymphocytic and chronic myelogenous leukemia,
with signifi cant exposure-response relationships. The analy-
ses showed that the exposure-response for butadiene and leu-
kemia was independent of exposures to benzene, styrene,
and dimethyldithiocarbamate [ 152 , 153 ]. The inferences
from these analyses are limited because of the diffi culty of
diagnosing and classifying lymphatic and hematopoietic
malignancies. There was some evidence of an association
between exposure to butadiene and non-Hodgkin lymphoma
in studies in the butadiene monomer industries [ 154 – 156 ].
Overall, the epidemiological evidence from the styrene-
butadiene and the butadiene monomer industries indicates an
increased risk for hematolymphatic malignancies. Studies
from the styrene-butadiene industry show an excess of leuke-
mia and a dose-response relationship with cumulative expo-
sure to butadiene, while studies from the monomer industry
show an excess of hematolymphatic malignancies in general
attributable both to leukemia and malignant lymphoma. It
will be diffi cult to fi nd exposed populations in which to try to
replicate these fi ndings.
Vinyl Chloride
Vinyl chloride (VC) is a large volume industrial chemical
with many practical applications. In the early 1970s, clini-
cians observed a cluster of cases of angiosarcoma of the liver
among a group of workers in a plant using VC [ 52 ]. The
tumor is so rare that they were struck by the cluster. Within a
very short time, other similar clusters were reported, and the
association was quickly accepted as causal [ 157 , 158 ]. The
discovery was facilitated by the rarity of the tumor, the
strength of the association, and the fact that there are no other
known risk factors for this tumor and thus little danger of
confounding. Early cohort studies confi rmed the strong effect
of vinyl chloride on risk of angiosarcoma of the liver and also
raised questions about a possible association with lung can-
cer. In fact the data were suggestive enough in the 1980s that
an effect on lung cancer was considered likely [ 113 , 159 ].
However, subsequent studies have failed to demonstrate such
an effect, and it is likely that the early reports were distorted
by confounding or chance [ 160 ]. While there is growing evi-
dence that lung cancer is not a target organ, it is becoming
more plausible, as a result of recent meta- analyses [
160 ], that
exposure to VC may cause hepatocellular carcinoma as well
as liver angiosarcoma. Detecting an association of moderate
strength with a fairly rare tumor which has a long latency is
diffi cult, and it will take more data to confi rm it. A further
complication is whether some of the hepatocellular carcino-
mas are in fact misdiagnosed angiosarcomas. An additional
source of potential bias and confusion derives from the obser-
vation, in the two multicenter cohort studies [
161 , 162 ], that
diagnostic misclassifi cation may occur between liver angio-
sarcoma and soft tissue sarcomas, and, given the rarity of soft
tissue sarcomas, this could artifi cially create the appearance
of an association with soft tissue sarcomas. Because of the
drastic decrease in exposure levels that took place in the vinyl
chloride industry after the discovery of its carcinogenic activ-
ity, it is unlikely that there will be new cohorts of highly
exposed workers to investigate. It is conceivable that new data
can be generated from further follow-up of existing cohorts;
however, the maximum latent period for most cancers is
likely to be approaching, and additional cancers are increas-
ingly likely to refl ect background and risk factors other than
vinyl chloride. Molecular epidemiology provides another
avenue for exploring the carcinogenic effects of VC, notably
studies of mutation in the p53 gene [ 163 – 165 ].
Radium and Radon
Radium and radon provide an interesting contrast from the
point of view of prevention strategies. Both radium and
radon gas induce tumors in exposed workers through ioniz-
ing radiation. Radium was used by dial painters and caused
osteosarcomas. Radon gas caused lung cancer in miners. The
risk due to radium was easily eliminated by, in effect, elimi-
nating the occupation of radium dial painting. Mining cannot
be eliminated, and radon gas is an inevitable exposure in
mines. The best strategy here is to fi nd a cost-effective way
to reduce exposures by engineering methods, while also
improving the epidemiologic database on dose-response
relationships. Radon also provides one of the most success-
ful examples of the use of high-dose occupational data for
the purpose of extrapolation to lower-dose environmental
exposure levels [ 166 ].
Some Methodological Considerations
The main stages in occupational cancer epidemiology are
detection/discovery of hazards, which can be broken down
into hypothesis generation and hypothesis testing, and char-
acterization of risks. This categorization is simplistic. In
reality, a given piece of research may serve two or three of
these stages, and the operational distinctions among them are
ambiguous. But it is a useful conceptual framework.
1 Historical Overview of Occupational Cancer Research

14
Before the 1950s, the generation of hypotheses relied pri-
marily on astute clinicians to notice clusters of cancer among
groups of workers, and the investigation of hypotheses was
carried out by means of industry-based historical cohort
studies. Thereafter, new approaches were introduced, includ-
ing attempts to generate hypotheses from analyses of routine
record sources (such as death certifi cates) and from case-
control studies. For testing hypotheses and characterization
of hazards, there was increasing use of case-control methods.
The various approaches that are used in occupational cancer
epidemiology can be divided in two major families:
community- based studies and industry-based studies. The
following sections describe some of the salient features of
these designs and their advantages and disadvantages in this
area.
Industry-Based Studies
In an industry-based study, the population under investiga-
tion is defi ned on the basis of belonging to a union or work-
ing for a company or some other work-related institution.
Because of the long latency of cancer, the study design typi-
cally used is a historical cohort design [ 167 ]. A given work-
force is generally exposed to a relatively narrow range of
occupational substances, and for this reason the prime role of
cohort studies has been and remains to investigate specifi c
associations (or to “test hypotheses” or characterize relation-
ships), rather than to generate hypotheses. But this is an
oversimplifi cation; a typical cohort study produces results on
possible associations between one or more exposures and
many types of cancer. Since it is often diffi cult or costly in
practice to constitute an appropriate group of unexposed sub-
jects with whom to compare the exposed and since the cohort
usually constitutes a very small fraction of the entire popula-
tion, it is expedient and often acceptable to take the disease
or death rates in the entire population (national or regional)
as a close approximation of those in the unexposed. The lat-
ter are easily available from published statistics or databases.
When the disease experience of the exposed cohort is com-
pared with that of the entire population, it is possible to take
into account such basic demographic variables as age, sex,
and race. The most common statistical approach is indirect
standardization, and the resulting parameter is called a stan-
dardized mortality ratio (SMR) or standardized incidence
ratio (SIR).
There are two signifi cant advantages of the cohort
approach, both relating to exposures of workers. The fi rst is
the opportunity it affords to focus on a group of workers with
relatively high exposure levels, thereby improving the
chances of detecting a risk. Secondly, by focusing on a single
industry or company, it is sometimes possible to derive
detailed and valid data on the exposure histories of study
subjects. It is common for companies to maintain job history
records for each worker, and these are often maintained for
decades. Depending on the nature of the industry, the com-
pany, and the relationship established between the investiga-
tor and the company, it may be possible to obtain detailed
historic exposure measurements, and these might be linkable
to the job histories of individual workers. It may also be pos-
sible to consult company hygienists or engineers or other
workers who can inform the investigator about past condi-
tions and exposure circumstances. The cooperation of
employers is usually a sine qua non to conduct such studies.
It is sometimes possible to obtain quite high-quality his-
toric exposure information and to use this in assessing and
characterizing hazards [ 167 – 169 ]. Notable examples include
studies on formaldehyde [ 75 , 170 ], asphalt workers [ 171 ],
acrylonitrile [ 172 , 173 ], and nickel compounds [ 174 ]. In
some historic examples, such as in certain cohorts of asbes-
tos workers, there were no available quantitative data on
exposure levels, but the industrial process was thought to be
so “simple” that only one substance was thought to be worth
considering as an explanation for the excess risk of the entire
cohort [ 175 ]. Such reasoning may be acceptable in a few
industries, such as the extractive industries; but most indus-
trial processes entail diverse mixtures of exposures. The suc-
cess at characterizing past exposures will depend on the skill
and resources of the investigating team and the availability of
adequate industrial hygiene data. Ingenious methods have
been brought to bear by industrial hygienists working with
epidemiologists to evaluate historic exposures to specifi c
substances in various cohorts [ 176 ].
Community-Based Case-Control Studies
In a community-based study, the population is typically
defi ned on the basis of living in a given geographic area or
falling in the catchment area of a set of health-care providers.
Questionnaire-based case-control studies provide the oppor-
tunity to collect information on lifetime occupation histories
and on other relevant cofactors directly from cancer patients
or close relatives and appropriate controls. From this, it is
possible to estimate cancer risks in relation to various occu-
pational circumstances.
Case-control studies provide the opportunity to conduct
analyses based on job titles. Analyses using job titles are use-
ful. Several associations with cancer have been discovered
by means of analyses on job titles. Such analyses are most
valid and valuable when the workers have a relatively homo-
geneous exposure profi le. Examples might include miners,
motor vehicle drivers, butchers, and cabinetmakers. Whatever
attempts are made to derive specifi c exposures in community-
based studies, it is nevertheless worthwhile to also conduct
the statistical analyses to evaluate risks by job titles. However,
J. Siemiatycki

15
job titles are limited as descriptors of occupational exposures
[
115 ]. On the one hand, many job titles cover workers with
very diverse exposure profi les. On the other hand, many
exposures are found to occur across many occupation cate-
gories. In such circumstances, epidemiologic analyses by job
title may entail too much noise to allow for a signal to be
detected. Several approaches have been used to ascertain
exposures in community-based studies, including self-
reported checklist of exposures, job-exposure matrix (JEM),
and expert assessment [ 177 ].
Some Trends in Epidemiologic Research
on Occupational Cancer
Since the revolution in genetic research methods, there has
been a shift in research resources on occupational cancer
from an attempt to assess the main effects of occupations and
occupational exposures to an attempt to assess so-called
gene-environment interactions. While this is an interesting
and worthwhile pursuit, it has not yet led to a proportionate
increase in knowledge of new carcinogens. It remains the
case that almost all the knowledge that has accrued about
occupational risk factors has been gained without recourse to
genetic interactions. It is important to avoid the temptation to
shift all the “research eggs” into the basket of gene-
environment interaction studies and to keep some of the
resources in research approaches that have proven their worth.
In the past, the main focus of attention was on occupa-
tional exposures associated with “dirty” industrial environ-
ments. But over the past few decades, as “dirty” environments
have been cleaned up or eliminated, there has been increasing
attention to nonchemical agents in the work environment.
Physical agents such as radon gas and electromagnetic fi elds
have been investigated, but behavioral and ergonomic charac-
teristics such as physical activity (or sedentarism) and shift
work have come into view as potential cancer risk factors.
Industries and occupations are in constant evolution. Even
if we knew all there was to know about the cancer risks in
today’s occupational environments, which we do not, it is
important to continue to monitor cancer risks in the occupa-
tional environment because it is always changing and intro-
ducing new exposures and circumstances (e.g., nanoparticles,
radiofrequency fi elds).
While the lists of occupational risk factors in Tables 1.4
and 1.5 are lengthy, they are not complete. There are likely
many more occupational carcinogens that have not been dis-
covered or properly documented. For many if not most occu-
pational circumstances, there is no epidemiological evidence
one way or the other concerning carcinogenicity. One of the
foremost problems in occupational epidemiology is how to
uncover the hidden part of the iceberg of occupational
carcinogens.
Continued Importance of Research
on Occupational Cancer
In the 1960s and 1970s, the fi eld of occupational cancer
research was one of the most thriving areas of epidemiologi-
cal research. This was fed by the social trends which raised
the profi le of environmentalism and workers’ health and by
important discoveries of occupational carcinogens such as
asbestos. There was a perception that research on environ-
mental causes of cancer was important and that it would be
feasible to make breakthroughs. Workers’ organizations
were active and vocal in calling for improved working condi-
tions and for the research that would support such action.
Many young investigators, infl uenced by the zeitgeist of the
1960s, were ideologically drawn to a research area which
would dovetail with their political and social interests. In
contrast, today we perceive a waning of interest and enthusi-
asm. What has happened?
The reasons are complex, but may well include the fol-
lowing. The political/social climate that supported work on
occupational health has greatly changed. In western coun-
tries, the economies and workforces have shifted, and there
are fewer blue-collar industrial workers than there were
30 years ago. Union membership, especially in blue-collar
unions, has declined, and the unions have become less mili-
tant. These trends have been fostered by technology (e.g.,
computerization and robotization) and by globalization. To a
certain extent, “dirty jobs” have been eliminated or exported
from western to developing countries. The bottom line is that
a smaller fraction of the western workforce is involved in
traditional “dirty jobs.” Another factor is that, as mentioned
above, most large workplaces have become much cleaner, at
least in some industrialized countries.
Another reason for the defl ation of interest in this area is
that the expectations of some for quick and dramatic discover-
ies of “smoking guns” like asbestos did not pan out. The
expectations were unrealistic, but that was not clear at the
time. There was a widespread belief that there were many
cancer-causing hazards in the workplace and it would only be
a matter of shining some light in the right places to fi nd them.
There was much more epidemiological research in the 1970s,
1980s, and 1990s than there had been in the preceding decades.
While this research produced a large number of important
fi ndings, these were incremental in the overall scheme of
things and, for some, did not seem proportional to the effort.
In the face of these social and economic changes and the
ostensible diminishing returns from research in occupational
cancer, is this an area of investigation that should be fos-
tered? Our answer is an unambiguous “Yes!” for the follow-
ing reasons and with the following caveats:
(a) In industrialized countries, a large fraction of the work-
force still works in circumstances which bring workers
into contact with chemical agents. Even if the fraction is
1 Historical Overview of Occupational Cancer Research

16
less than it was a century ago, it is still sizeable and will
remain so for the foreseeable future. While industrial
design and hygiene have succeeded in lowering expo-
sures in many industries, there remain pockets where
exposure levels remain high.
(b) The story of occupational hygiene conditions in devel-
oping countries is less rosy. Enormous numbers of peo-
ple are now working in insalubrious conditions. As life
expectancy in these populations rises with increasing
affl uence and improved living conditions and medical
care, the numbers of cancer cases and most likely the
numbers of occupationally related cancers are steadily
increasing. There is a tremendous opportunity for epide-
miologists to investigate occupation-cancer relation-
ships in developing countries.
(c) There are many thousands of chemicals in workplaces.
Many of them are obscure and involve relatively few
workers; but many involve exposure for thousands of
workers. Of these, only a small fraction have been ade-
quately investigated with epidemiological data.
(d) The industrial environment is constantly evolving with
the introduction of new and untested chemicals. We need
to maintain a monitoring capacity to detect “new” occu-
pational carcinogens. A recent example of a suspected
carcinogen is indium phosphide in the semiconductor
industry [
178 ].
(e) The occupational environment is one that lends itself to
preventive intervention.
(f) Many chemicals in the workplace fi nd their way into the
general environment, either via industrial effl uent or via
their use in consumer products. Hazards identifi ed in the
workplace often have an importance that goes beyond
the factory walls.
(g) The discovery of occupational carcinogens is important
to understanding the principles of carcinogenesis: work-
ers represent a “natural experiment” of high exposure to
a potentially carcinogenic agent.
(h) The ability to detect hazards is increasing with improvement
of methods for exposure assessment and outcome assess-
ment, as well as the tendency to use larger study sizes.
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