Identifying occupational carcinogens: An update from the IARC Monographs

Abstract

The recognition of occupational carcinogens is important for primary prevention, compensation and surveillance of exposed workers, as well as identifying causes of cancer in the general population. This study updates previously published lists of known occupational carcinogens while providing additional information on cancer type, exposure scenarios and routes, and discussing trends in the identification of carcinogens over time. Data were extracted from International Agency for Research on Cancer (IARC) Monographs covering the years 1971–2017, using specific criteria to ensure occupational relevance and provide high confidence in the causality of observed exposure-disease associations. Selected agents were substances, mixtures or types of radiation classified in IARC Group 1 with ‘sufficient evidence of carcinogenicity’ in humans from studies of exposed workers and evidence of occupational exposure documented in the pertinent monograph. The number of known occupational carcinogens has increased over time: 47 agents were identified as known occupational carcinogens in 2017 compared with 28 in 2004. These estimates are conservative and likely underestimate the number of carcinogenic agents present in workplaces. Exposure to these agents causes a wide range of cancers; cancers of the lung and other respiratory sites, followed by skin, account for the largest proportion. The dominant routes of exposure are inhalation and dermal contact. Important progress has been made in identifying occupational carcinogens; nevertheless, there is an ongoing need for research on the causes of work-related cancer. Most workplace exposures have not been evaluated for their carcinogenic potential due to inadequate epidemiologic evidence and a paucity of quantitative exposure data.

Full text

1
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Identifying occupational carcinogens: an update from
the IARCMonographs
Dana Loomis, Neela Guha, Amy L Hall, Kurt Straif
Review
To cite: LoomisD,
GuhaN, HallAL, etal.
Occup Environ Med Epub
ahead of print: [please include
Day Month Year]. doi:10.1136/
oemed-2017-104944
IARC Monographs Programme,
International Agency for
Research on Cancer, Lyon,
France
Correspondence to
Professor Dana Loomis,
International Agency for
Research on Cancer, Lyon
69372, France;
dploomis@ unr. edu
Received 6 December 2017
Revised 6 April 2018
Accepted 9 April 2018
ABSTRACT
The recognition of occupational carcinogens is important
for primary prevention, compensation and surveillance
of exposed workers, as well as identifying causes of
cancer in the general population. This study updates
previously published lists of known occupational
carcinogens while providing additional information
on cancer type, exposure scenarios and routes, and
discussing trends in the identification of carcinogens
over time. Data were extracted from International Agency
for Research on Cancer (IARC) Monographs covering
the years 1971–2017, using specific criteria to ensure
occupational relevance and provide high confidence in
the causality of observed exposure-disease associations.
Selected agents were substances, mixtures or types
of radiation classified in IARC Group 1 with ’sufficient
evidence of carcinogenicity’ in humans from studies of
exposed workers and evidence of occupational exposure
documented in the pertinent monograph. The number
of known occupational carcinogens has increased over
time: 47 agents were identified as known occupational
carcinogens in 2017 compared with 28 in 2004. These
estimates are conservative and likely underestimate the
number of carcinogenic agents present in workplaces.
Exposure to these agents causes a wide range of
cancers; cancers of the lung and other respiratory sites,
followed by skin, account for the largest proportion.
The dominant routes of exposure are inhalation and
dermal contact. Important progress has been made
in identifying occupational carcinogens; nevertheless,
there is an ongoing need for research on the causes of
work-related cancer. Most workplace exposures have
not been evaluated for their carcinogenic potential due
to inadequate epidemiologic evidence and a paucity of
quantitative exposure data.
INTRODUCTION
Historically, much of what was known about
the causes of cancer was derived from studies of
workers. Indeed, an observant 18th-century physi-
cian’s conclusion that cancer of the scrotum in
young chimney sweeps was caused by their occupa-
tional exposure to soot, later found to contain poly-
cyclic aromatic hydrocarbons,1 2 is often cited as the
first clear identification of a carcinogen (eg, refs 3
4). With the notable exception of tobacco smoking,
most of the other carcinogens that were recognised
during the 19th to mid-20th centuries were discov-
ered through similar observations.5 Even after
several decades of intensive research beginning
in the mid-20th century, nearly half of the ‘estab-
lished human carcinogens’ listed in Doll and Peto’s
seminal report on the avoidable causes of cancer
were occupational in nature.3 These discoveries
have been facilitated by characteristics of the work
environment that allow cancer occurrence to be
studied, notably well-defined populations that are
exposed, often at high levels, to agents that can be
quantitatively characterised. Analytical methods
first developed to study occupational cancer have
also contributed importantly to the development of
modern epidemiology.6
Identifying occupational carcinogens is an
important research endeavour with broad rele-
vance to science and public health. Occupational
exposure to carcinogens is a major cause of death
and disability worldwide,7 with an estimated
occurrence of 666 000 fatal work-related cancers
annually.8 Knowledge of cancer hazards from occu-
pational exposure supports prevention and surveil-
lance activities, as well as compensation of exposed
workers. However, creating a list of occupational
carcinogens is not a trivial exercise, as there is
neither a consensus definition of such agents nor
a single, definitive source of all the relevant data.
Doll and Peto3 provided a table of ‘established occu-
pational causes of cancer,’ but did not specify the
methodology by which they were identified. Some
20 years later, Siemiatycki and coauthors9 devel-
oped a list of ‘definite occupational carcinogens’,
drawing on data from the IARC Monographs on
Carcinogenic Risks to Humans published through
2003 and other sources. The International Agency
for Research on Cancer (IARC) Monographs have
been updated since then: more than 120 additional
agents have been evaluated in 36 new volumes;
furthermore, the methodology for evaluating the
evidence base has been updated,10 11 and a re-eval-
uation of the agents classified as ‘carcinogenic to
humans’ in the first 99 volumes has been completed
with additional target organ sites identified in the
process.12
Here we provide an updated listing of occu-
pational carcinogens that includes data through
volume 120 of the IARC Monographs corre-
sponding to the years 1971–2017. We also provide
additional information on tumour type, exposure
scenarios and exposure routes, identify method-
ological challenges in compiling such a list from
available data sources, and discuss trends in the
identification of carcinogens over time.
METHODS
As a primary source of data, we used the IARC
Monographs on Carcinogenic Risks to Humans, the
world’s most comprehensive encyclopaedia of eval-
uations of carcinogenicity, comprising over 1000
entries.13 The review and evaluation methods used
to develop the IARC Monographs are documented
in the IARC Monographs Preamble.10
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

2 LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Briefly, agents are selected for review based on evidence of
human exposure and published scientific data suggestive of
carcinogenicity. For each agent evaluated, systematic reviews of
the available scientific evidence concerning the carcinogenicity
of the agent in humans and experimental animals are conducted
by an international working group of independent experts.
Each line of evidence is evaluated according to ordered catego-
ries that reflect the strength of the evidence of carcinogenicity.
The highest category of ‘sufficient evidence of carcinogenicity’
in humans or animals means that a causal relationship between
exposure to the agent and development of cancer has been estab-
lished. For epidemiological data, ‘sufficient evidence of carcino-
genicity’ is typically based on results from several well-designed,
well-conducted studies where chance, bias and confounding
could be ruled out with reasonable confidence; the conclusion is
unlikely to be altered by future studies. Data on human exposure
to the agent and toxicological data on pertinent mechanisms of
carcinogenesis are also reviewed.
An overall evaluation integrating epidemiological and exper-
imental data is derived according to a structured process that
accounts for the strength of evidence for carcinogenicity in
humans, animals and mechanistic evidence, most notably in
exposed humans. Agents with ‘sufficient evidence of carcinoge-
nicity’ in humans are assigned by default to the highest category,
‘carcinogenic to humans’ (IARC Group 1) whereas the catego-
ries of ‘probably’ (Group 2A) or ‘possibly’ (Group 2B) carcino-
genic to humans, or ‘not classifiable as to its carcinogenicity
to humans’ (Group 3) are assigned according to the combined
strength of the human, animal and mechanistic evidence. Evalu-
ations may be upgraded to a higher category when the evidence
for a relevant mechanism of carcinogenesis is sufficiently strong.
From the initiation of the IARC Monographs programme in
1971 to date, 119 agents have been classified in Group 1, 81 in
Group 2A and 299 in Group 2B. These classifications refer to
the strength of the evidence for a cancer hazard, rather than to
the level of cancer risk.
Definitions
In the absence of a consensus definition of an occupational
carcinogen, we developed the following criteria:
1. The agent is a defined substance, a mixture, or a type or
source of radiation.
2. The agent is classified in IARC Group 1 with ‘sufficient
evidence of carcinogenicity’ in humans (to ensure that
observed exposure-disease associations are causal).
3. ‘Sufficient evidence of carcinogenicity’ in humans is obtained
entirely or in part from epidemiologic studies of exposed
workers (to ensure that the carcinogen has documented
occupational exposure); the occurrence of exposure in
workers is documented in the pertinent monograph.
Evaluations based on an occupational title, industry or
production process without specification of causal agents were
also recorded, but were considered separately since they are
qualitatively different from the other classes of agents and
afford limited opportunities for prevention. Furthermore, such
evaluations are time sensitive given that processes, materials
and exposures change over time. Infectious agents and phar-
maceutical preparations, including botanicals, hormones and
antineoplastic agents, were effectively excluded because the
pertinent monographs did not provide information indicating
occupational exposure. These exclusions also facilitate compar-
ison with previous reviews by Doll and Peto3 and Siemiatycki
et al.9
Review and data extraction
Two of us (NG and DL) independently reviewed data for all
of the 120 agents classified in Group 1 through October 2017
in volumes 1–120 of the IARC Monographs to identify entries
that met the criteria defined above. These determinations were
reviewed by a third person (KS) and any discrepancies were
resolved by discussion. For each included agent, we extracted
data on the cancer sites for which the human evidence was
classified as sufficient, where the classification was established
on the basis of epidemiologic studies of workers, and where
the occurrence of exposure in workers was documented in the
monograph.
We also summarised agents across six broad classes adapted
from Cogliano et al12: chemicals; chemical mixtures; metals
and metal compounds; airborne particles; airborne complex
mixtures, and radiation and radionuclides. We grouped arsenic
with the metals, although it is now considered to be a metalloid,
to avoid creating of class containing a single agent.
Information on settings where occupational exposure is
likely to occur, as described in the pertinent monograph, was
extracted. Primary routes of exposure were also recorded for
agents in categories other than radiation and radionuclides. If
the monograph did not provide this information, we consulted
other sources, most often the NIOSH Pocket Guide to Chemical
Hazards.14
RESULTS AND DISCUSSION
Counting occupational carcinogens
Among the 120 agents classified in IARC Group 1, 70 included
mention of occupational exposures in the monographs (figure 1).
Of these 70 Group 1 agents, 63 had sufficient evidence in humans
(figure 1). The other seven had indications of occupational
exposure but had been upgraded to Group 1 based on mech-
anistic evidence when the human evidence was less than ‘suffi-
cient’. These agents were therefore excluded from our count of
occupational carcinogens: ethylene oxide, dyes metabolised to
benzidine, neutron radiation, benzo(a)pyrene, 2,3,4,7,8-penta-
chlorodibenzofuran, 4,4′-methylenebis(2-chloroaniline) and
dioxin-like polychlorinated biphenyls.
Of the 63 Group 1 agents with ‘sufficient evidence of carcino-
genicity’ in humans, 59 evaluations were based at least in part
on studies of exposed workers (figure 1). The other four agents
(aflatoxins, the asbestos-like fibres erionite and fluoroedenite
and fission products including Strontium-90) were excluded
since occurrence of occupational exposure was noted but no
occupational epidemiology data were reported.
Among these 59 retained agents, 47 were individual
substances, mixtures or types of radiation and 12 were occu-
pations, industries or processes (figure 1). Although the IARC
Monographs aim to identify and evaluate specific agents, some
processes, industries and occupations have been classified in
Group 1 with ‘sufficient evidence of carcinogenicity’ in humans
(table 1). These evaluations were typically produced at a time
when the available data provided a clear indication of increased
cancer risk in an occupational group, but not enough infor-
mation to identify a causal agent. While such broadly defined
carcinogenic agents can lead to general industrial hygiene inter-
ventions, provide support to compensate exposed workers and
stimulate research to identify specific causes, they have limited
utility for informing specific prevention activities and may be
affected by changes in processes, materials and exposure levels
over time.
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

3
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
The 47 specific substances, mixtures and types of radiation
defined as occupational carcinogens are listed in table 2, with the
cancer sites for which sufficient evidence was obtained.
Our working definition of an occupational carcinogen was
developed with high specificity to ensure confidence that the
observed associations between exposure and cancer were causal
Figure 1 Defining occupational carcinogens from the International Agency for Research on Cancer (IARC) Monographs (1971–2017).
Table 1 Group 1 agents evaluated in the IARC Monographs Volumes 1–120, excluded from primary list of occupational carcinogens
Agent Volume (a) Year (a) Cancers with sufficient evidence in humans (b)
Reason for Exclusion: Group 1 classification based on mechanistic upgrade
Ethylene oxide 60 1994 N/A
2,3,4,7,8-Pentachlorodibenzofuran 100F 2012 N/A
3,4,5,3’,4’-Pentachlorobiphenyl (PCB-126) 100F 2012 N/A
4,4'-Methylenebis(2-chloroaniline) (MOCA) 99 2010 N/A
Benzidine, dyes metabolized to 99 2010 N/A
Benzo(a)pyrene 92 2010 N/A
Neutron radiation 75 2000 N/A
Reason for Exclusion: Evaluation did not include occupational epidemiology data
Aflatoxins Sup 7 1987 Liver
Erionite Sup 7 1987 Mesothelioma
Fission products, including strontium-90 100D 2012 Salivary gland, oesophagus, stomach, colon, lung, bone,
basal cell of the skin, female breast, kidney, urinary
bladder, brain and CNS, thyroid, leukaemia
Fluoro-edenite fibrous amphibole 111 2017 Mesothelioma
Reason for Exclusion: Group 1 classification is for an occupation, industry, or process
Acheson process, occupational exposure associated with 111 2017 Lung
Aluminium production Sup 7 1987 Lung, bladder
Auramine production Sup 7 1987 Bladder
Coal gasification Sup 7 1987 Lung
Coal-tar distillation 92 2010 Skin
Coke production Sup 7 1987 Lung
Haematite mining (underground, with exposure to radon)(c) Sup 7 1987 Lung
Iron and steel founding (occupational exposure during) Sup 7 1987 Lung
Isopropyl alcohol manufacture using strong acids Sup 7 1987 Nasal cavity
Magenta production Sup 7 1987 Bladder
Painter (occupational exposure as a) 47 1989 Lung, mesothelioma, bladder
Rubber manufacturing industry (occupational exposures in) Sup 7 1987 Leukaemia, lymphoma, lung, stomach, bladder
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

4 LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Table 2 Occupational carcinogens evaluated in the IARC Monographs volumes 1–120 and comparison with two previous published listings
Agent Volume† Year†
Primary exposure routes‡
Human cancers with
sufficient evidence§
Quantitative exposure-
response data
available
Included in
Siemiatycki et al9
Included in Doll
and Peto3
Occupational exposure
settings¶ ClassIngestion Inhalation Dermal contact
1,2-Dichloropropane 110 2017 x Biliary tract Manufacture of plastic
products, paints and
other chemicals; printing;
carpainting
Chemicals
1,3-Butadiene 97 2008 x Haematolymphatic
organs
x Manufacture of industrial
chemicals, rubber products
and plastic products;
petroleum refining and
petrochemical industries;
building construction
Chemicals
2-Naphthylamine 4 1973 x x Urinary bladder x x Manufacture of industrial
chemicals and dyes
Chemicals
2,3,7,8-Tetrachlorodibenzo-
para-dioxin
69 1997 x x x All cancers combined x x Manufacture of chemicals;
herbicide handling and
spraying; waste incineration
Chemicals
4-Aminobiphenyl 1 1972 x x Urinary bladder x x Manufacture of chemicals
and rubber
Chemicals
Acid mists, strong inorganic 54 1992 x x x Larynx x Manufacture of soaps and
detergents, phosphate
fertilisers, lead batteries and
other chemicals;
electroplating and pickling
Airborne
particles
Arsenic and inorganic arsenic
compounds†
2 1973 x x Lung, skin, bladder x x x Manufacture of glass,
pesticides and other
chemicals; agricultural
settings; mining, smelting and
refining of metals; medical
and veterinary procedures
Metals
and metal
compounds
Asbestos (all forms,
including actinolite, amosite,
anthophyllite, chrysotile,
crocidolite, tremolite)
2 1973 x Lung, mesothelioma,
larynx, ovary
x x x Mining, processing,
transportation and handling
of asbestos; work in
shipyards; manufacture and
use of asbestos-containing
products
Airborne
particles
Benzene 7 1974 x x Leukaemia (acute
myeloid)
x x x Manufacture and use of
paints, rubber products, glues
and other chemicals;
distribution and handling of
petrol; shoe manufacturing
and repair
Chemicals
Benzidine 1 1972 x x Bladder x x Manufacture of chemicals,
dyes, rubbers and plastics
Chemicals
continued
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

5
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Agent Volume† Year†
Primary exposure routes‡
Human cancers with
sufficient evidence§
Quantitative exposure-
response data
available
Included in
Siemiatycki et al9
Included in Doll
and Peto3
Occupational exposure
settings¶ ClassIngestion Inhalation Dermal contact
Beryllium and beryllium
compounds
58 1993 x x Lung x x Beryllium extraction,
processing and fabrication;
manufacture of electrical
equipment, electronic
components, aerospace
materials; dental laboratory
procedures
Metals
and metal
compounds
Bis(chloromethyl)ether;
chloromethyl methyl ether
(technicalgrade)
4 1974 x Lung x Yes Manufacture of chemicals;
laboratory procedures
Chemicals
Cadmium and cadmium
compounds
58 1993 x Lung x x Production, refining, and
processing of cadmium and
its alloys; manufacture of
batteries and pigments
Metals
and metal
compounds
Chromium (VI) compounds Sup 7 1987 x Lung x x Yes Production and use of
chromate pigments and
paints; chrome plating;
work in chrome-alloy
foundries
Metals
and metal
compounds
Coal-tar pitch 35 1985 x x Lung, skin x Production of coal-tar
products; roofing and surface
coating activities
Chemical
mixtures
Engine exhaust, diesel 105 2013 x Lung x Rail, truck, and bus operation
and mechanical maintenance;
mining; firefighting
Airborne
complex
mixtures
Formaldehyde 88 2006 x x Nasopharynx,
leukaemia
x Manufacture of formaldehyde
and other chemicals;
histopathology and anatomy
dissections; hospital
disinfection; embalming
Chemicals
Ionising radiation (all
types)**
100D 2012 None specified x x x Outdoor work involving
sun exposure; nuclear fuel
production and use; air travel;
mining; human and veterinary
medicine
Radiation and
radionuclides
Leather dust 25 1981 x Nasal cavity and
paranasal sinus
Manufacture, processing and
repair of leather, boots and
shoes
Airborne
particles
Lindane (see also
hexachlorocyclohexanes)
113 2015* x x Non-Hodgkin's
lymphoma
x Manufacture of lindane;
treatment of wood and
wooden structures;
agricultural application on
livestock and crops
Chemicals
Table 2 continued
continued
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

6 LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Agent Volume† Year†
Primary exposure routes‡
Human cancers with
sufficient evidence§
Quantitative exposure-
response data
available
Included in
Siemiatycki et al9
Included in Doll
and Peto3
Occupational exposure
settings¶ ClassIngestion Inhalation Dermal contact
Mineral oils, untreated or
mildly treated
3 1973 x x Skin x Paraffin processing;
manufacture of metal
products; metal working
Chemical
mixtures
Nickel compounds 49 1990 x x x Lung, nasal cavity and
paranasal sinuses
x x x Mining, smelting and refining
of nickel; production of nickel
alloys, stainless steel and
batteries; electroplating; paint
production and use
Metals
and metal
compounds
ortho-Toluidine 99 2010 x x Urinary bladder Manufacture of ortho-
toluidine and dyes, pigments,
and some rubber chemicals;
clinical and pathological
laboratories
Chemicals
Outdoor air pollution** 109 2016 x Lung x Where majority of working
time is spent in polluted
outdoor environments
(eg, urban traffic police,
professional drivers, street
vendors)
Airborne
particles
Particulate matter in outdoor
air pollution
109 2016 x Lung x Airborne
particles
Pentachlorophenol 117 2016* x x Non-Hodgkin's
lymphoma
x Manufacture of PCP and
other chemicals; agricultural
settings; treatment of wood
products; waste incineration
Chemicals
Plutonium 78 2001 Bone, liver, lung x Nuclear industry workers Radiation and
radionuclides
Polychlorinated biphenyls 107 2016 x x Malignant melanoma x Manufacture of PCB
capacitors; manufacture and
repair of transformers; waste
incineration and recycling;
firefighting
Chemical
mixtures
Radioiodines, including
iodine-131††
78 2001 Thyroid x Workers involved in nuclear
accident clean-up
Radiation and
radionuclides
Radionuclides, alpha-
particleemitting, internally
deposited**
78 2001 None specified x Mining and processing of
uranium and other minerals;
nuclear industry workers;
human and veterinary
medicine
Radiation and
radionuclides
Radionuclides, beta-
particleemitting, internally
deposited**
78 2001 None specified x Radiation and
radionuclides
Radium-224 and its decay
products§
78 2001 Bone Luminising industries Radiation and
radionuclides
Radium-226 and its decay
products
78 2001 Bone, mastoid process,
paranasal sinus
Radiation and
radionuclides
Radium-228 and its decay
products
78 2001 Bone, mastoid process,
paranasal sinus
Radiation and
radionuclides
Table 2 continued
continued
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

7
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Agent Volume† Year†
Primary exposure routes‡
Human cancers with
sufficient evidence§
Quantitative exposure-
response data
available
Included in
Siemiatycki et al9
Included in Doll
and Peto3
Occupational exposure
settings¶ ClassIngestion Inhalation Dermal contact
Radon-222 and its decay
products
43 1988 Lung x Mining and other
underground work; mineral
processing
Radiation and
radionuclides
Shale oils 35 1985 x Skin x Mining and production of
shale oils and products;
manufacturing of
cottontextiles
Chemical
mixtures
Silica dust, crystalline, in the
form of quartz or cristobalite
68 1997 x Lung x x Mining and quarrying
operations; foundries;
ceramics, cement and glass
industries; construction
activities
Airborne
particles
Solar radiation** 55 1992 Skin (basal cell
carcinoma, squamous
cell carcinoma,
melanoma)
x Outdoor work with sun
exposure
Radiation and
radionuclides
Soot 3 1973 x x Lung, skin x x Industries and tasks with
exposure to combustion
products (eg, coke-
making, chimney cleaning,
incineration)
Airborne
particles
Sulfur mustard (see also
mustard gas)
9 1975 x Lung x x Manufacture of mustard gas;
military service in WWI
Chemicals
Tobacco smoke,
secondhand**
83 2004 x Lung Work in public settings
where smoking occurs (eg,
restaurants, bars, casinos,
planes)
Airborne
complex
mixtures
Trichloroethylene 106 2014 x x Kidney Manufacture of metals and
plastic products; printing;
textilefurnishing; dry
cleaning; construction
Chemicals
Ultraviolet radiation** 118 2017* Eye, skin x x Various work environments
where welding is performed
Radiation and
radionuclides
Vinyl chloride 7 1974 x Liver (angiosarcoma,
hepatocellular
carcinoma)
x x x Manufacture of polyvinyl
chloride
Chemicals
Welding fumes 118 2017* x Lung x Various work environments
where welding is performed
Airborne
particles
Wood dust 62 1995 x Nasal cavity and
paranasal sinus,
nasopharynx
x x Forestry and logging;
sawmilling; manufacture of
wood products; carpentry;
construction
Airborne
particles
Table 2 continued
continued
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

8 LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
and substance specific. The number of occupational carcinogens
estimated using these criteria consequently represents a lower
limit. The definition of an occupational carcinogen could be
expanded to include the 12 occupations and industries with
sufficient evidence in humans, the seven agents with less than
sufficient evidence of carcinogenicity in humans that were
upgraded to Group 1 on mechanistic grounds, or the four agents
with evidence of occupational exposure but no contributing data
from occupational epidemiology studies. Similarly, occupational
exposures to some biological agents and pharmaceuticals have
been documented elsewhere in the literature, and those with
sufficient evidence in humans could be considered as occupa-
tional carcinogens.
The number of carcinogens in the workplace may be substan-
tially larger for additional reasons. New substances are intro-
duced into workplace and environmental settings faster than
information on potential health effects can be generated. For
example, over 80 000 chemicals are currently registered for
use in the USA alone, but only a small fraction have ever been
evaluated for carcinogenicity.15 Because of limited resources, no
carcinogen evaluation programme is able to evaluate all agents
of potential interest. Accordingly, the IARC Monographs give
higher priority to evaluating agents for which there are indi-
cations of human exposure and scientific data suggestive of
carcinogenicity. Nevertheless, among the approximately 1000
agents IARC has evaluated, the evidence on cancer in humans
has been judged to be inadequate for the majority. This determi-
nation is often reached when no relevant epidemiological studies
have been done, the number of studies available is too small to
be conclusive, the studies are of low quality, or the findings are
inconsistent across studies.
Cancer sites, agents and exposure routes
Twenty-three different types of cancer are causally associated
with the 47 specific occupational carcinogens identified in this
paper (table 3). Some cancers (eg, lung, urinary bladder, skin) are
associated with multiple agents, and some agents are associated
with more than one type of cancer. Among these, lung cancer
was the most common, representing nearly a quarter (23%)
of all agent-cancer associations. Other cancers that occurred
frequently were skin cancer (10%), bone cancer (9%), bladder
cancer (7%) and cancers of the nasal cavity and paranasal sinuses
(6%) (table 3).
While the patterns of frequently occurring cancers are clear,
the exact numbers are subject to interpretation because the
reporting of cancer sites in the monographs necessarily depends
on the data available at the time of the evaluation. Some of the
tumour sites listed in table 3 could justifiably be combined,
resulting in higher counts for certain cancers, such as the aggre-
gate of tumours of lymphatic and haematopoietic tissues (9%),
but with a corresponding loss of detail. The number of cancer
sites associated with an agent can also increase over time if new
data become available. This was the case, for example, with
asbestos: the original evaluation was based only on mesothe-
lioma and lung cancer, but cancers of the larynx and ovary have
been added in subsequent evaluations.16
Patterns relating the type of agent, routes of exposure and
occurrence of cancer by organ site are also evident. Inhalation
and skin absorption are the principal routes of exposure for most
cancer sites (table 2). Not surprisingly, inhaled agents are associ-
ated primarily with lung, nasal and sinus cancers (figure 2).
Chemicals are associated with a diverse array of cancer
sites, again with inhalation and skin absorption representing
Agent Volume† Year†
Primary exposure routes‡
Human cancers with
sufficient evidence§
Quantitative exposure-
response data
available
Included in
Siemiatycki et al9
Included in Doll
and Peto3
Occupational exposure
settings¶ ClassIngestion Inhalation Dermal contact
X-radiation and gamma-
radiation**
75 2000 Multiple, including:
breast; leukaemia;
thyroid; bone; brain
and central nervous
system; colon; kidney;
lung; oesophagus;
salivary gland; skin;
stomach; bladder
x Nuclear industry workers;
human and veterinary
medicine; workers involved in
nuclear accident clean-up
Radiation and
radionuclides
*Monographs still in press.
†Volume and year of publication correspond to the first instance of a Group 1 classification for the agent.
‡Routes not listed for radiations and radionuclides
§The cancer sites listed reflect the most recent IARC evaluation of the agent.
¶Examples of potentially exposed industries, work locations and/or occupations described in the relevant monograph; do not represent exhaustive summaries of past and present exposure scenarios.
**Occupational and non-occupational data contributed to first Group 1 evaluation.
††Occupational data contributed to subsequent Group 1 evaluation.
IARC, International Agency for Research on Cancer;PCB, polychlorinated biphenyl;PCP, pentachlorophenol;WWI, First World War.
Table 2 continued
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

9
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
the principal routes of exposure to most (table 2). Cancers
frequently associated with chemicals and chemical mixtures
include tumours of the lymphohaematopoietic system (25%),
bladder (20%), lung (15%) and skin (15%). The aggregate of
cancers of the haematopoietic and lymphatic systems, including
leukaemias and non-Hodgkin’s lymphomas, is mainly associated
with exposure to chemicals through inhalation or contact with
skin (table 2 and figure 2). To date, most chemicals are associ-
ated with only one cancer site, with the exception of formalde-
hyde, associated with leukaemia and cancer of the nasopharynx.
Dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin) is unique in
being associated most consistently with all cancers combined.17
Ionising radiation and radionuclides are associated with a
wide array of different cancers (table 2), reflecting the varied
physical properties and biological activities of these agents. X-ra-
diation and gamma-radiation penetrate the whole body and are
associated with numerous types of cancer, while radon (an inert
gas) inhaled by underground miners causes lung cancer, and
radium isotopes ingested by dial painters tend to be deposited in
bones and teeth and are associated with cancer of bony tissues.18
Solar radiation and ultraviolet (UV) radiation are associated with
several types of skin cancer (table 2). UV radiation generated in
welding is also associated with cancer of the eye.19
We examined data for the 12 agents with ‘sufficient evidence
of carcinogenicity’ for more than one cancer site, to identify
cancers that tend to co-occur. Cancers of the lung and skin most
often co-occurred together, due to exposure to coal-tar pitch,
soot, arsenic and inorganic arsenic compounds. A similar exam-
ination of agents associated with cancers with both sufficient
and limited evidence revealed combinations for cancers of the
lung and bladder or kidney (data not shown). These patterns in
cancers associated with exposure to certain carcinogens may be
explained by route of exposure and physiochemical properties
of the agents.
Table 3 Cancers caused by occupational carcinogens (n=47 agents), evaluated in IARC Monographs volumes 1–120
Cancers with sufficient evidence in
humans Agents Number of occurrences %
Lung Bis(chloromethyl)ether; chloromethyl methyl ether (technical-grade); cCoal-tar pitch; sSulfur
mustard; aArsenic and inorganic arsenic compounds; bBeryllium and beryllium compounds;
cCadmium and cadmium compounds; cChromium (VI) compounds; nNickel compounds;
aAsbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite,
tremolite); pParticulate matter in outdoor air pollution; sSilica dust, crystalline, in the form of
quartz or cristobalite; sSoot; wWelding fumes; eEngine exhaust, diesel; oOutdoor air pollution;
tTobacco smoke, second-handsecondhand; X-radiation and gGamma-rRadiation; pPlutonium;
rRadon-222 and its decay products
19 23
Skin Coal-tar pitch; mMineral oils, untreated or mildly treated; sShale oils; aArsenic and inorganic
arsenic compounds; sSoot; X-radiation and gGamma-rRadiation; sSolar radiation; uUltraviolet
radiation
8 10
Bone, including mastoid process X-radiation and gGamma-rRadiation; pPlutonium; rRadium-224 and its decay products;
rRadium-226 and its decay products; rRadium-226 and its decay products
5 6
Haematolymphatic system, including
leukaemia, NHL
1,3-Butadiene; bBenzene; cCoal-tar pitch; X-radiation and gGamma-rRadiation; fFormaldehyde;
lLindane; pPentachlorophenol
7 9
Leukaemia Benzene; cCoal-tar pitch; X-radiation and gGamma-rRadiation 3 4
Non-Hodgkin lymphomanNon-Hodgkin's
lymphoma
Formaldehyde; lLindane; pPentachlorophenol 3 4
Urinary bladder ortho-Toluidine; aArsenic and inorganic arsenic compounds; X-radiation and gGamma-
rRadiation; 2-nNaphthylamine; 4-aAminobiphenyl; bBenzidiene
6 7
Nasal cavity and paranasal sinus Acid mists, strong inorganic; cChromium (VI) compounds; lLeather dust; nNickel compounds;
wWood dust
5 6
Thyroid X-radiation and gGamma-rRadiation; rRadioiodines, including iodine-131 2 2
Breast X-radiation and gGamma-rRadiation 1 1
Kidney Trichloroethylene; X-radiation and gGamma-rRadiation 2 2
Larynx Asbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite);
aAcid mists, strong inorganic
2 2
Liver Plutonium; vVinyl chloride 2 2
Nasopharynx Formaldehyde; wWood dust 2 2
All cancers combined 2,3,7,8-Tetrachlorodibenzo-para-dioxin 1 1
Biliary tract 1,2-Dichloropropane 1 1
Brain and central nervous system X-radiation and gGamma-rRadiation 1 1
Colon X-radiation and gGamma-rRadiation 1 1
EsophagusOesophagus X-radiation and gGamma-rRadiation 1 1
Eye Ultraviolet radiation 1 1
Malignant melanoma Polychlorinated biphenyls 1 1
Mesothelioma Asbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite) 1 1
Ovary Asbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite) 1 1
Salivary gland X-radiation and gGamma-rRadiation 1 1
Stomach X-radiation and gGamma-rRadiation 1 1
Total 82 100
IARC, International Agency for Research on Cancer;NHL, non-Hodgkin lymphoma.
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

10 LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
Trends
A comparison of table 2 with previously published lists of occu-
pational carcinogens suggests that progress continues to be made
in identifying these agents despite the lack of adequate epide-
miologic data for many occupational exposures. Furthermore,
despite methodological differences in approach and changes in
classification practices, the pace of identification appears to have
increased over time. The list of 28 known occupational carcin-
ogens developed by Siemiatycki et al9 included 12 more agents
than the list of 16 occupational carcinogens identified 23 years
earlier by Doll and Peto.3 Table 2 of this paper includes 24 more
agents added in the 14 years since Siemiatycki et al published
their list.
Some methodological differences between reports are worth
noting, however. Siemiatycki et al9 combined all ‘ionizing
radiation and sources thereof ’ in a single listing and include
talc-containing asbestiform fibres and erionite in their counts. In
contrast, we list each type of ionising radiation separately, as in
the monographs, and do not include asbestiform talc or erionite,
as the former is classified with asbestos and the latter did not
have occupational exposure documented in the monograph.
Although neither previous authors nor we included occupa-
tions, industries or processes in the final count of occupational
carcinogens (note: Siemiatycki et al listed them in a separate
table),9 it is noteworthy that the occurrence of such evaluations
has declined over time. A few such Group 1 evaluations have
been refined or superseded by evaluations of specific agents as
improved exposure data have become available: the historical
evaluation of ‘boot and shoe manufacturing and repair’ has been
superseded by benzene and leather dust, ‘furniture and cabinet
making’ has been replaced by wood dust and haematite mining
has been made more specific by the addition of ‘underground,
with exposure to radon.’ In contrast, only one new Group 1
classification of an occupation, industry or process (occupational
exposures in the Acheson process for producing silicon carbide)
has been added since 1989.
Improvements in the quality of epidemiologic studies may
be a contributing factor in the increasing specificity of evalua-
tions and the growth of knowledge about occupational carcino-
gens.20 Interest in identifying subtle risks, sometimes associated
with low levels of exposure, has led to increasing emphasis on
obtaining quantitative or semiquantitative exposure data. The
presentation of exposure-response data can be taken as one
marker of study quality because it requires collection of quan-
titative exposure data. Furthermore, analyses of exposure-re-
sponse associations internal to an occupational cohort are also
less susceptible to confounding and bias than comparisons to
an external referent population. Exposure-response data were
noted in the pertinent monographs for 29 occupational carcin-
ogens (table 2), most from more recent evaluations from 2010
onwards. This trend may continue if efforts to collect and
retain quantitative exposure data in occupational settings are
successful.21
The growth and diversity of available scientific information
may also contribute to the increasing numbers of occupational
carcinogens identified. Bibliometric research shows that the
number of published scientific articles, including medical and
health sciences articles, has increased exponentially since Doll
and Peto’s3 work was published.22 At the same time, science is
becoming more global, with growing numbers of publications
from outside the historical centres of Europe, the USA and
Japan.23 Similar analyses of publications related to occupational
health are not available, but statistics from the journal Occupa-
tional & Environmental Medicine suggest substantial growth and
globalisation in this field, as well.24 Studies from diverse regions
of the world are valuable for hazard identification, because they
can support findings of causality by demonstrating consistency
across populations and locations.25
Figure 2 Route of exposure to occupational carcinogens and the cancers they cause (ionising radiation not included due to the diversity of exposure
routes and cancer types).NHL, non-Hodgkin lymphoma.
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from

11
LoomisD, etal. Occup Environ Med 2018;0:1–11. doi:10.1136/oemed-2017-104944
Review
There are signs for concern amid this growth, however.
Some data indicate that since the 1990s, funding for occupa-
tional research has slowed or even declined in some high-in-
come countries.23 26 Furthermore, significant gaps in knowledge
remain concerning occupational exposures and diseases in low/
middle-income countries where high exposures to many agents
(which facilitate hazard identification) now tend to occur as a
result of globalisation and the export of hazardous industries.27 28
For instance, in the People's Republic of China, coke production
increased more than fivefold between 1970 and 1995, while
decreasing in Europe and North America.29 In several African
countries, rapid developments in agricultural production have
led to increased pesticide use, with implications for both occu-
pational exposure and health.30 31
CONCLUSIONS
Studies of workers have played a central role in identifying the
causes of human cancer. Data compiled from the IARC Mono-
graphs from its initiation in 1971 through 2017 indicate that the
number of recognised occupational carcinogens has increased
progressively in recent decades. This trend may have been
facilitated by advances in study quality, notably in quantitative
exposure assessment, and in the global growth of the scientific
literature base.
Despite notable progress, there continues to be a need for
research on the causes of work-related cancer. Epidemiologic
evidence is inadequate or entirely lacking for the majority of the
over 1000 agents evaluated by IARC; many more agents present
in workplaces have never been evaluated for carcinogenicity.
There is also a need to identify the numbers of exposed workers
by geographic location and to produce quantitative exposure
data as a basis for hazard identification, exposure-response esti-
mation and risk assessment.
Contributors DL conceived the paper and wrote the first draft. NG did data
analyses. ALH compiled exposure data. All authors contributed to generating and
reviewing the data, producing tables and figures and revising the manuscript.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the
terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others
to distribute, remix, adapt and build upon this work, for commercial use, provided
the original work is properly cited. See: http:// creativecommons. org/ licenses/ by/ 4. 0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
REFERENCES
1 Brown JR, Thornton JL. Percivall Pott (1714-1788) and chimney sweepers’ cancer of
the scrotum. Br J Ind Med 1957;14:68–70.
2 Cogliano VJ. Identifying carcinogenic agents in the workplace and environment.
Lancet Oncol 2010;11:602.
3 Doll R, Peto R. The causes of cancer. Oxford, UK: Oxford University Press, 1981.
4 Checkoway H, Pearce N, Kriebel D. Research methods in occupational epidemiology.
2nd Ed. New York: Oxford University Press, 2004;5.
5 Tomatis L. Cancer: occurrence, causes and control. IARC Sci Publ, 1990;100:1–11.
6 Lynge E. From cross-sectional survey to cohort study. Occup Environ Med
2009;66:428–9.
7 Afshin A, Abajobir AA, Abate KH, et al. Global, regional, and national comparative risk
assessment of 84 behavioural, environmental and occupational, and metabolic risks
or clusters of risks, 1990-2016: a systematic analysis for the Global Burden of Disease
Study 2016. Lancet 2017;390:1345–422.
8 Takala J. Eliminating occupational cancer. Ind Health 2015;53:307–9.
9 Siemiatycki J, Richardson L, Straif K, et al. Listing occupational carcinogens. Environ
Health Perspect 2004;112:1447–59.
10 IARC. Preamble, IARC Monographs on the evaluation of carcinogenic risks to humans.
Lyon, France: IARC, 2006. http:// monographs. iarc. fr/ ENG/ Preamble/ CurrentPreamble.
pdf
11 Smith MT, Guyton KZ, Gibbons CF, et al. Key Characteristics of Carcinogens as a
Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ Health Perspect
2016;124:713–21.
12 Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated with human
cancers. J Natl Cancer Inst 2011;103:1827–39.
13 IARC. Agents classified by the IARC Monographs volumes 1-120. 2017 http://
monographs. iarc. fr/ ENG/ Classification/ index. php (accessed 19 Mar 2018).
14 NIOSH (National Institute for Occupational Safety and Health). NIOSH pocket guide to
chemical hazards. 2017 https://www. cdc. gov/ niosh/ npg/ default. html
15 Wilson MP, Schwarzman MR. Toward a new U.S. chemicals policy: rebuilding the
foundation to advance new science, green chemistry, and environmental health.
Environ Health Perspect 2009;117:1202–9.
16 IARC. A Review of Human Carcinogens, Part C: Arsenic, metals, fibres and dusts. IARC
Monographs on the Evaluation of Carcinogenics Risks to Humans 100C, 2012a.
17 IARC. A Review of Human Carcinogens, Part F: Chemical agents and related
occupations.IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
100F, 2012b.
18 IARC. A Review of Human Carcinogens, Part D: Radiation.IARC Monographs on the
Evaluation of Carcinogenics Risks to Humans 100D, 2012c.
19 Guha N, Loomis D, Guyton KZ, et al. Carcinogenicity of welding, molybdenum trioxide,
and indium tin oxide. Lancet Oncol 2017;18:581–2.
20 Loomis D. On the importance of quantification. Occup Environ Med 2012;69:609.
21 Kromhout H. Hygiene Without Numbers. Ann Occup Hyg 2016;60:403–4.
22 Bornmann L, Mutz R. Growth rates of modern science: a bibliometric analysis
based on the number of publications and cited references. J Assoc Inf Sci Technol
2015;66:2215–22.
23 Society R. Knowledge, Networks and Nations: Global scientific collaboration in the
21st century. The Royal Society, London 2011.
24 Loomis D, Sim MR. 2012: the year in review. Occup Environ Med 2013;70:287–8.
25 Hill AB. The environment and disease: association or causation? Proc R Soc Med
1965;58:295–300.
26 Mabe M, Amin M. Growth dynamics of scholarly and scientific journals. Scientometrics
2001;2001:147–62.
27 Jeyaratnam J. et alTransfer of hazardous industries. In: Pearce N, Matos E, Vainio H,
Boffetta P, Kogevinas M, . Occupational cancer in developing countries. IARC Sci Publ,
1994;129:23–9.
28 Lucchini RG, London L. Global occupational health: current challenges and the need
for urgent action. Ann Glob Health 2014;80:251–6.
29 IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some
Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures.
Lyon, France: IARC, 2010;92.
30 Ahouangninou C, Martin T, Edorh P, et al. Characterization of health and
environmental risks of pesticide use in market-gardening in the Rural City of Tori-
Bossito in Benin, West Africa. J Environ Prot 2012;03:241–8.
31 Negatu B, Kromhout H, Mekonnen Y, et al. Use of Chemical Pesticides in Ethiopia: A
Cross-Sectional Comparative Study on Knowledge, Attitude and Practice of Farmers
and Farm Workers in Three Farming Systems. Ann Occup Hyg 2016;60:551–66.
on 16 May 2018 by guest. Protected by copyright.http://oem.bmj.com/Occup Environ Med: first published as 10.1136/oemed-2017-104944 on 16 May 2018. Downloaded from