Causal Agent-Cancer Links in Haz-Map

The chemical-disease links in Haz-Map regarding occupational cancer are based on Cancer Epidemiology and Prevention, 3rd Edition. See Table 18-3 "Substances and Mixtures That Have Been Evaluated by IARC as Definite (Group 1) Human Carcinogens and Are Occupational Exposures." This book was last published in 2006. There are 153 contributors to the 3rd edition. Chapter 18 on "Occupation" includes eight pages of references (approximately 400 references). Most of the references were published in scientific journals since 1990 with the most recent articles published in 2004. The authors of the chapter on Occupation are Jack Siemiatycki, PhD,  Lesley Richardson, MSc, and Paolo Boffetta, MD, MPH. Dr. Siemiatycki's book, Risk Factors for Cancer in the Workplace, describes decades of research in Montreal of nearly 300 occupational exposures and 20 types of cancer in which detailed job exposure information was collected in case control studies. The author of the chapter on "Ionizing Radiation" is John D. Boice, Jr. who has master's degrees in Nuclear Engineering and Medical Physics and a doctoral degree in Epidemiology at Harvard.

The Intersection of Epidemiology and Toxicology

Please read this paper published in the summer of 2011, a beautiful analysis of what it takes to translate the enormous amount of toxicological and epidemiological information into a rational method for determining the causes of occupational cancer. "The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causality." [Toxicology and epidemiology: improving the science with a framework for combining toxicological and epidemiological evidence to establish causal inference]

If a Chemical Causes Cancer in Animals, Does It Also Cause Cancer in Humans?

"Phenobarbital increased the incidence of liver tumors in long-term rodent bioassays by a mode of action that would be plausible in humans. Biological plausibility would be considered high for phenobarbital. However, epidemiological studies have found no evidence of liver tumors in patients on lifetime anti-epilepsy treatment with phenobarbital. Without epidemiological evidence, the categorization would be Likely or Uncertain, but with sufficient epidemiological evidence for an absence of an effect in humans, the categorization would be Unlikely." The same authors also write, ". . . animal studies require a greater degree of evidence relative to epidemiology. Animal studies are surrogates for actual human data and as such require higher levels of evidence." [Toxicology and epidemiology]

"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 to maximize the sensitivity of the test to detect animal carcinogens. 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 implantation) and the controlled and limited pattern of co-exposures is unlike the human situation." [Siemiatycki, Cancer Epidemiology and Prevention. p. 323]

Assessing Causation in Epidemiologic Studies: Some Quotations

"It is emphasized that not all epidemiological studies are equally informative or of equal quality. Some have low statistical power and provide little information on risks; others are so susceptible to potential or actual biases that findings have little or no validity. It is important to consider methodological issues when interpreting the evidence from different studies, and it is the consistency of findings in different studies conducted by different investigators in different parts of the world that is most informative." [John Boice. "Ionizing Radiation" in Cancer Epidemiology and Prevention]

"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 refinery workers experienced excess risks of nasal cancer does not imply that all workers in all nickel refineries 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 refinery but not in another or in one historic era but not in another. [Siemiatycki et al. "Occupation" in Cancer Epidemiology and Prevention]

"Simply observing a difference in the probability of an outcome between two groups that differ on X is not sufficient condition for causation because it does not distinguish between causation and spurious or indirect association, produced by "confounders" or ancillary causes. The notion of "causation" requires that the cause somehow actively "produce" its effect, which is captured operationally by the requirement that active manipulation of the cause should produce a change in the probability of the outcome. For example, if one saw that students with poor visual acuity typically sat closer to the front of a classroom, one would not call the seating arrangement a "cause" of their poor eyesight unless it could be shown that seating them farther back improved it." [Steven Goodman and Jonathan Samet. "Cause and Cancer Epidemiology" in Cancer Epidemiology and Prevention]

The identification of a true occupational cause of cancer by workers who are currently exposed to carcinogenic levels is an opportunity to prevent this disease. On the other hand, an association is just an observation, e.g., that the children with poorer vision are sitting closer to the front of the classroom.

"Precaution does not mean taking limited evidence and calling it sufficient. Precaution means that risk management officials are prepared to act on less than sufficient evidence when warranted." [Vincent James Cogliano. The IARC Mongraphs: a resource for precaution and prevention. [PMID 17704200]

"Making causal inferences from observational data, in combination with other relevant forms of data, can be a challenging task that requires expert judgment regarding the likely sources and magnitude of confounding, together with judgment about how well the existing constellation of study designs, results, and analyses address this potential threat to inferential validity. This judgment also needs to incorporate a broader assessment of the evidence, evaluating whether a causal effect has support in the existing knowledge of the underlying biologic process." [Steven Goodman and Jonathan Samet. "Cause and Cancer Epidemiology" in Cancer Epidemiology and Prevention]

The best example that " active manipulation of the cause should produce a change in the probability of the outcome" is the causal link between cigarette smoking and lung cancer. In the year 2000, 90-95% of lung cancer cases in men living in Europe and North America were caused by smoking. [Schottenfeld, p. 109] Trends in lung cancer incidence reflect the stage of the tobacco epidemic with a 20 to 30 year lag, and rates are currently dropping in many Western countries because of a reduction in male smoking. [Global Cancer Facts & Figures 2007, p. 14]

The Decreasing Fraction of Cancer Attributable to Occupation

In developed countries, 30% of cancers are attributed to diet or nutrition, 16% to tobacco, 8% to infections, 5% to occupational exposures, 2% to environmental pollution, and 39% to other causes. [Global Cancer Facts & Figures 2007, p. 4] "Of course, the major exposure to carcinogens is not through variations in the external environment (e.g., air, water, radiation) so much as in differences in lifestyle (e.g., reproduction, diet, tobacco use)." [Schottenfeld, p. 105] "With commitment from all stakeholders, it is possible that by 2025 exposure to known occupational chemical carcinogens could be essentially eliminated in Great Britain." [Exposure to Occupational Carcinogens in Great Britain, 2007] "Due to the long latent interval of many carcinogens, our estimates of current burden are based on past exposures, many of which would have been considerably higher than today; there is evidence of continuing downward trends in the United Kingdom in many exposures. A comprehensive analysis of published exposure data, particularly in Western Europe and North America, has shown similar patterns of decreasing exposure patterns across a wide range of industries and substances." [Occupation and Cancer in Britain, 2010]

In countries where industrial hygienists and safety professionals work hard to recognize and prevent hazardous job tasks, occupational toxicology is becoming "historical." Here is an example. "HL" refers to Hodgkin lymphoma. "It is unlikely that there will be further revealing studies of the wood dust-HL association for several reasons. First, the production of wood products has undergone major changes, at least in developed countries, with much cleaner workplaces (and lower exposures) for both economic and industrial hygiene reasons." [Schottenfeld, p. 885]

Causal Links to Occupation for Specific Cancers

The following cancers have been associated with occupational exposures. Established causal links, if any, are shown in the bulleted list following each specific cancer.

Bladder Cancer

A sentinel health event (occupational) associated with rubber and dye workers who were exposed to benzidine, alpha- and beta-naphthylamine, magenta, auramine, 4-aminobiphenyl, and 4-nitrophenyl; [Mullan] Beta-naphthylamine, benzidine, 4-aminobiphenyl were discontinued from industrial production and use. Suspected bladder carcinogens still in use include benzidine-based dyes, o-toluidine, 4-chloro-o-toluidine, and MBOCA. [Ward, p. 127] Other occupational exposures associated with bladder cancer include PAHs (aluminum production, coal gasification, coal-tar pitches, and diesel exhaust), and hair dyes (hairdresser or barber). Diesel exhaust had a positive association in many case-control studies, but was negative in cohort studies of transportation workers. "An open question is whether occupational exposures in industries identified in the past as high risk can still be linked to an excess risk of bladder cancer." [Adami, p. 456-8] Occupational carcinogens with strong evidence include 4-aminobiphenyl, benzidine, and 2-naphthylamine, aluminum production, coal gasification, magenta manufacture, and the rubber industry. [Siemiatycki, p. 334] Ingestion of arsenic contaminated drinking water is linked to bladder cancer. [IARC 2012: Arsenic, p. 49-50] Previously classified as 2A, MBOCA was reclassified by IARC as Group 1 in 2012. [IARC: MBOCA] I removed the link between 4,4'-Methylene Bis(2-chloroaniline) (101-14-4) and Bladder cancer in October 2019. See "Identifying occupational carcinogens: an update from the IARC Monographs, published in 2017. The full-text article is available on PubMed (PMID: 29769352). See Table 1. The reason for the exclusion of this agent as an occupational carcinogen is that, "Group 1 classification based on mechanistic upgrade." In the 2019 Supplement to ACGIH Documentation of TLVs and BEIs, MBOCA is classified as A2 (suspected human carcinogen). "Data indicative of bladder cancer in workers exposed to MBOCA were inconclusive." [ACGIH] "There is sufficient evidence in humans for the carcinogenicity of ortho-toluidine. ortho-Toluidine causes cancer of the urinary bladder." [IARC 2012: ortho-Toluidine] "There is a lack of clear and consistent evidence from epidemiological studies that dyes metabolized to benzidine cause cancer in humans. . . . Dyes metabolized to benzidine are carcinogenic to humans (Group 1)." [Dyes Metabolized to Benzidine] For painting, see IARC 2012 Changes.

Bone Cancer

A sentinel health event (occupational) associated with radium exposure by radium chemists, processors, and dial painters; [Mullan] Documented causes of radiation-induced bone cancer in humans include 226,228-radium, 224-radium, plutonium, Thorotrast (thorium oxide), and radiotherapy. "Radiation-induced bone cancer appears, it seems, only at very high doses, and it is rarely reported at doses under 5 Gy." [Schottenfeld, p. 946-52] There was strong evidence of work-related bone cancer in radium dial painters and a "meaningful association" in Mayak workers who had very high exposure to plutonium. [Boice, p. 261]

Brain Cancer

Ionizing radiation, at high doses well above background levels, is the only established environmental cause of brain cancer. Some epidemiological studies have found an increased risk of brain cancer associated with petrochemical workers, rubber and tire workers, electrical workers, health professionals, farmers, and workers with exposures to vinyl chloride and polychlorinated biphenyls. [Adami, p. 494-7] Brain cancer after radiation treatment is "occasionally associated with robust risk estimates." It is seen mainly after high-dose irradiation in childhood, e.g., an estimated dose of 1.5 Gy for treatment of ringworm of the scalp. Brain cancer was not associated with radiation in studies of Japanese A-bomb survivors, radium dial painters, radiologists, underground miners, nuclear workers, and uranium processors. [Boice, p. 260-263] There is suggestive evidence that non-arsenical insecticides and petroleum refining are occupational carcinogens. There is no strong evidence that occupational exposure to ionizing radiation is associated with brain cancer. [Siemiatycki, p. 334]

Chlolangiocarcinoma

"There is sufficient evidence in humans for the carcinogenicity of 1,2-dichloropropane. 1,2-Dichloropropane causes cancer of the biliary tract (confirmed as cholangiocarcinoma). . . . However, a minority of the Working Group concluded that the association between 1,2-dichloropropane and cancer of the biliary tract was credible, but the role of exposure to other agents, principally dichloromethane, could not be separated with complete confidence, and noted that most of the evidence came from studies in a single plant." [IARC 2016]

Colorectal Cancer

Studies showing an association with asbestos exposure are inconsistent. Increased colorectal cancer has been reported in workers exposed to mineral oils in the operation of printing, typesetting, and textile processing machines. There was an association between rectal cancer and machinists exposed to mineral-based metalworking fluids. [Ward, p. 173-4] Colon cancer is increased in white-collar workers who have sedentary jobs. Some studies have shown a small excess risk for workers exposed to asbestos. [Adami, p. 202]  Colon cancer was not associated with ionizing radiation exposure in studies of radiologists, underground miners, nuclear workers, or uranium processors. There was a "meaningful association" in Japanese A-bomb survivors. [Boice, p. 261]

Esophagus Cancer

Information relating to occupational causes of esophageal cancer is limited. It is not known what proportion of esophageal cancer today is linked to workplace exposures. Some studies suggest associations with occupational exposures to perchloroethylene, mustard gas, silica dust, metal dust, asbestos, combustion products, sulfuric acid, carbon black, and ionizing radiation. [Ward, p. 195] Many of these studies have inadequate adjustment for the main confounders, smoking and alcohol use. Based on heavier exposure levels that existed in the past, two groups that showed higher risks for cancer of the esophagus were workers who vulcanized rubber and those who assembled automobiles. [Adami, p. 152-3] There is suggestive evidence that occupational exposure to soots and tetrachloroethylene cause esophageal cancer. [Siemiatycki, p. 334] Studies of radiologists, underground miners, and nuclear workers have found negative associations. "Meaningful associations" were found for Japanese A-bomb survivors and patients with spondylitis treated with medical radiation. [Boice, p. 261] 

Kidney Cancer

"Renal cell cancer is not generally considered an occupationally associated tumor. . . . Considerable interest has recently been focused on the solvent trichloroethylene (TCE), largely as a result of bioassay findings in animals and of three studies conducted in the same area of Germany, which were initiated in response to clusters of renal cell cancer cases and which reported strikingly elevated relative risks for renal cell cancer associated with TCE exposure. These findings contrast starkly with results from other investigations, and several serious methodological shortcomings of these studies have been noted." [Schottenfeld, p. 1092-3] "Extensive epidemiologic cohort studies of TCE-exposed workers do not indicate significant increases in cancer incidence, but case-control studies suggest that prolonged exposure to high concentrations of TCE (hundreds to thousands of ppm) can increase the incidence of renal cancer." [ACGIH] "As in the rat studies, kidney toxicity is believed to be a prerequisite for the development of renal cancer in humans following exposure to trichloroethylene." [PMID 15031388] The high levels of exposure have been documented for the various types of degreasing processes by Bakke, Stewart, and Waters [PMID 17454505] and also by Fevotte et al. [PMID 16840434] TCE was classified as carcinogenic to humans (Group 1) by the Working Group in October 2012. [PMID 23323277] In the 2013 Hansen et al. paper on the Nordic Cohort Studies, the authors mention the IARC decision in 2012 to link TCE to occupational kidney cancer. In explaining why their study found no association between TCE and kidney cancer, the authors write, "Duration of exposure, as well as exposure levels of TCE, have in general been relatively low in Finland, Sweden, and Denmark, and if TCE is a risk factor for kidney cancer only at extremely high levels of TCE-exposure, this may explain in part our overall null finding for this cancer." [PMID 23723420]

Laryngeal Cancer

Cancer of the larynx in western countries is for the most part attributable to smoking tobacco and drinking alcohol. Possible occupational risks include exposure to nickel, asbestos, and ionizing radiation. [Adami, p. 271] Studies of cohorts from past decades have found strong associations between laryngeal cancer and occupational exposures to mustard gas manufacturing, nickel refining, and metalworking with mineral-based oils. [Ward, p. 296] Risk factors for laryngeal cancer include smoking, drinking alcohol, and asbestos exposure. Possible risk factors are leather workers, textile workers, and exposure to gasoline, diesel oil, and mineral oil. [LaDou, p. 312] There is strong evidence that the following are occupational carcinogens: isopropanol manufacture, strong acid process; inorganic acid mists containing sulfuric acid; and mustard gas. There is suggestive evidence that exposure to asbestos and the rubber industry are associated with an increased risk of work-related laryngeal cancer. [Siemiatycki, p. 334] "The committee concluded that the evidence is sufficient to infer a causal relationship between asbestos exposure and laryngeal cancer." [National Academy of Sciences. Asbestos: Selected Cancers. 2006] Established occupational causes of laryngeal cancer are "acid mists, strong inorganic" and asbestos. [IARC 2012: List of Classifications by Cancer Sites]

Leukemia

Leukemias represent 3% of all malignant neoplasms. Ionizing radiation, benzene, and cytotoxic drugs are known causes of acute leukemia. In atomic bomb survivors, the incidence of acute leukemias peaked at 2 to 5 years and declined after 10 years. After chemotherapy, the incidence peaks at 5 to 8 years. Acute lymphocytic leukemia (ALL) is limited mainly to the first 2 decades of life. It is associated with several congenital disorders characterized by chromosomal abnormalities. Since a majority of patients with these congenital syndromes do not develop ALL, an environmental cause is suspected. (Rosenstock, p. 746-7) There is strong evidence for associations between the following and occupational leukemia: boot and shoe manufacture and repair, benzene, ionizing radiation, and ethylene oxide. [Siemiatycki, p. 334] In the chapter "Historical Overview of Occupational Cancer Research," Siemiatycki says, "There were reports from Sweden among producers and some users of ethylene oxide that hinted at excess risks of leukemia. But larger American studies have subsequently shown no such risk." [Occupational Cancers, p. 3] In studies of ionizing radiation and leukemia, strong associations were found for Japanese A-bomb survivors, radiation treatments for spondylitis, and use of Thorotrast as a contrast agent. Meaningful associations were found for radiologists working in past decades and Mayak workers. Negative associations were found for radium dial painters, underground miners, uranium processors, and  Chernobyl cleanup workers. For nuclear workers the association is "suggested but unconfirmed or questionable association." Ionizing radiation increases risks for acute lymphocytic and acute myeloid leukemias and chronic myeloid leukemia, but not for chronic lymphocytic leukemia. [Boice, p. 261, 268] "There is limited evidence in humans for a causal association of ethylene oxide with lymphatic and haematopoietic cancers (specifically lymphoid tumours, i.e. NHL, MM and CLL), and breast cancer." [IARC 2012: Ethylene Oxide] "There is sufficient evidence in humans for a causal association of formaldehyde with leukemia." [IARC 2012: Formaldehyde] "Studies from the styrene-butadiene industry show an excess of leukaemia, and a dose-response relationship with cumulative exposure to butadiene, while studies from the monomer industry show an excess of haematolymphatic malignancies in general, attributable both to leukaemia and malignant lymphoma." [IARC 2012: 1,3-Butadiene]

Liver Cancer

There were negative associations that ionizing radiation caused liver cancer in studies of radium dial painters, radiologists, underground miners, nuclear workers, uranium processors, and Mayak workers. There was strong evidence that Thorotrast (Th-232) caused liver cancer when used as a radiographic contrast agent between 1928 and 1955. [Boice, p. 261, 271] Hepatocellular carcinomas (HCC) comprise about 75% to 90% of liver cancers. "Eighty to 95% of HCCs are associated with chronic infection of hepatocytes with either of two viruses, hepatitis B virus (HBV) or hepatitis C virus (HCV)." Increased risk of angiosarcoma of the liver (ASL) was found in workers exposed to vinyl chloride while cleaning reactor vessels for the production of polyvinyl chloride. There is suggestive evidence that German vineyard workers exposed to arsenic in the 1930s and 1940s had increased incidence of angiosarcoma of the liver. [Schottenfeld, p. 763, 773] “There is compelling evidence that exposure to vinyl chloride is associated with angiosarcoma of the liver, and strong evidence that it is associated with hepatocellular carcinoma. Together with the observation that vinyl chloride increases the risk for liver cirrhosis, which is a known risk factor for hepatocellular carcinoma, the findings from two large multicentre cohort studies provide convincing evidence that vinyl chloride causes hepatocellular carcinoma as well as angiosarcoma of the liver.” [IARC Monograph 100F]

Lung Cancer

Processes strongly associated with occupational lung cancer: aluminum production, coke production, coal gasification, underground hematite mining (radon), iron and steel founding, nickel refining (nickel oxides and sulfides), painters, and passive smoking. Agents (IARC Group 1) strongly associated with occupational lung cancer: arsenic compounds, hexavalent chromium compounds, asbestos, beryllium, cadmium compounds, ionizing radiation, crystalline silica, soots, and talc containing asbestiform fibers. Bis(chloromethyl)ether and chloromethyl methyl ether (technical grade) were strongly associated with lung (oat cell) cancer. [Siemiatycki, p. 334] "There is sufficient evidence in humans for the carcinogenicity of coal-tar pitch as encountered in paving and roofing. Coal-tar pitch as encountered in paving and roofing causes cancer of the lung." [IARC 2012: Coal-tar pitch] For painting, see IARC 2012 Changes. Ionizing radiation was strongly associated with lung cancer in studies of Japanese A-bomb survivors, patients treated with radiation for Hodgkin's disease, underground miners, and Mayak workers with heavy exposure to plutonium. Negative associations were found in studies of radiologists, nuclear workers, uranium workers, and populations exposed to background radiation. [Boice, p. 261] IARC announced that diesel exhaust had been reclassified as a Group 1 carcinogen and that the evidence was sufficient for lung cancer. [IARC 2012: Diesel Exhaust] "Welders are exposed to many known and suspected carcinogens. An excess lung cancer risk among welders is well established, but whether this is attributable to welding fumes is unclear. . . . Studies that are able to disentangle welding effects from smoking and asbestos exposure are needed." [PMID 28951802] "There is sufficient evidence in humans for the carcinogenicity of welding fumes. Welding fumes cause cancer of the lung." [IARC Monograph 118]

Lymphoma, Non-Hodgkin

The evidence for increased risk of non-Hodgkin lymphoma in exposed workers is "suggestive" for the following agents: non-arsenical insecticides, TCDD, tetrachloroethylene, and trichloroethylene. The evidence is also suggestive for hairdressers and barbers. [Siemiatycki, p. 334] "Patients who have received immunosuppressive therapy and/or organ transplants are at increased risk for non-Hodgkin's lymphoma, suggesting that there may be a combination of chemical immunosuppression and viral infection resulting in lymphomas in some individuals." [APHA, p. 331] "Our results support previously reported increased risks among farmers, printers, medical professionals, electronic workers, and leather workers." [PMID 18805886] "The Working Group concluded that there is sufficient evidence of excess malignant lymphoma among rubber workers." [IARC 2012: Occupational Exposures in the Rubber-Manufacturing Industry] "Studies from the styrene-butadiene industry show an excess of leukaemia, and a dose-response relationship with cumulative exposure to butadiene, while studies from the monomer industry show an excess of haematolymphatic malignancies in general, attributable both to leukaemia and malignant lymphoma." [IARC 2012: 1,3-Butadiene] Data on the carcinogenicity of butadiene in humans derive essentially from studies conducted 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." [Siemiatycki, p. 338] After thoroughly reviewing the latest available scientific literature, a Working Group of 26 experts from 13 countries convened by the IARC Monographs Programme classified the insecticide lindane as carcinogenic to humans (Group 1). There was sufficient evidence in humans for the carcinogenicity of lindane for non-Hodgkin lymphoma (NHL)." [IARC Press Release 23 June 2015] "PCP was classified by the Working Group as carcinogenic to humans (Group 1) based on sufficient evidence that PCP causes non-Hodgkin lymphoma in humans. In all of the available epidemiological studies, exposure to PCP was positively associated with non-Hodgkin lymphoma." [IARC News Release, 24 October 2016] 

Melanoma

Solar radiation is a known carcinogen of skin cancer and melanoma in outdoor workers. [Siemiatycki, p. 326] "Two observations from epidemiological studies may help explain the paradox of the lack of association of melanoma with chronic sun exposure. First, outdoor workers are not at a substantially increased risk of melanoma; second, outdoor workers tend to have a higher-than-average ability to develop a tan. Outdoor workers tend to be constitutionally protected from solar skin damage and at a lower risk of skin cancer than workers in other occupations because of self-selection based on skin pigmentation." [IARC 2012: Solar and Ultraviolet Radiation] See "Skin Cancer, Melanoma, and Exposure to Ultraviolet Light." In IARC Monograph 107 published in 2016, polychlorinated biphenyls were classified as a known human carcinogen (Group 1) causing malignant melanoma (MM). However, Boffetta et al. published a meta-analysis in January 2018 showing that workers exposed to PCBs do not have an increased risk of melanoma. “These results do not support the hypothesis of an association between PCB exposure and the risk of MM. . . . in our meta-analysis, the summary risk estimates for MM are close to one in both general-population studies and occupational cohorts.” [https://www.ncbi.nlm.nih.gov/pubmed/27749494]

Mesothelioma, Peritoneal

A sentinel health event (occupational) associated with asbestos exposure; [Mullan] 

Mesothelioma, Pleural

A sentinel health event (occupational) associated with asbestos exposure; [Mullan] Seventy percent of patients with pleural mesothelioma reported in Denmark around 1980 were excess cases due to occupational asbestos exposure assuming a baseline incidence rate for women in rural areas. [Skov T, Mikkelsen S, Svane O, Lynge E. Reporting of occupational cancer in Denmark. Scand J Work Environ Health 1990;16:401-5] For painting, se "During 1999–2015, the mesothelioma age-adjusted death rate decreased 21.7% from 13.96 per million population (1999) to 10.93 (2015) . . . it was estimated that the number of mesothelioma cases among males would peak during 2000–2004 (approximately 2,000 cases) and after that period, the number of mesothelioma cases was expected to decline and return to background levels by 2055." [MMWR March 2017]

Multiple Myeloma

"Multiple myeloma (MM) is an incurable plasma cell malignancy with a poorly understood etiology. . . . We found associations between the risk of MM and employment in several manufacturing and service-related occupations and industries." [PMID 20623662] The evidence is "suggestive" that workers exposed in the past to "non-arsenical insecticides" had an increased risk of multiple myeloma. [Siemiatycki, p. 334] "Multiple studies have provided evidence that agricultural work is associated with myeloma risk. Pesticide use may account for part of the association of agricultural work with myeloma, but there is also some evidence that other agricultural exposures including exposure to animals, may increase risk. Unfortunately, there are few data concerning the specific pesticides that should be targeted for further investigation. There is fairly consistent evidence that exposures in paint-related occupations increase myeloma risk. Whether this increased risk results from dyes and pigments, or from solvents used in paint formulations, has not been discerned." [Schottenfeld, p. 939]

Nasal Sinus Cancer

Agents associated with sino-nasal cancer include cigarette smoking, wood and leather dust, nickel refining, chromates, mustard gas manufacturing, isopropanol manufacturing (sulfuric acid mists), and possibly formaldehyde and welding. [LaDou, p. 312] Softwood dust is associated with squamous cell carcinoma, and hardwood dust is associated with adenocarcinoma of the nasal cavity. An increased risk exists for sawmill workers, furniture workers, wood products workers, and carpenters. No increased risk exists for workers in forestry, logging, or paper and pulp. [Dement J. Wood Dust. In: Bingham E, Cohrssen B, Powell C, eds. Patty's Toxicology, 5th ed. New York: John Wiley & Sons; 2001:619-49] Seventy percent of patients with sinonasal adenocarcinoma reported in Denmark between 1965 and 1974 had worked for many years in wood-working jobs. [Skov T, Mikkelsen S, Svane O, Lynge E. Reporting of occupational cancer in Denmark. Scand J Work Environ Health 1990;16:401-5] Sino-nasal cancer is associated with occupational exposure to nickel (refining), wood dusts (furniture making), boot and shoe dusts (manufacturing), hexavalent chromium (pigment manufacturing), and radium (dial painting). [Ward, p. 366] Strong evidence: Boot and shoe manufacture and repair; furniture and cabinet making; isopropanol manufacture, strong acid process (sulfuric acid); nickel refining (nickel oxides and sulfides); and wood dust. Suggestive evidence: chromium compounds, hexavalent; formaldehyde; and mineral oils, untreated and mildly treated. [Siemiatycki, p. 334] "There is sufficient evidence in humans for the carcinogenicity of leather dust. Leather dust causes cancer of the nasal cavity and paranasal sinuses." [IARC 2012: Leather Dust]

Nasopharynx Cancer

There is suggestive evidence that mustard gas and formaldehyde can cause occupational nasopharyngeal cancer. [Siemiatycki, p. 334] Formaldehyde is a Group 1 carcinogen with sufficient evidence that it caused nasopharyngeal cancer in humans. [IARC Vol.: 88 (2006)] Formaldehyde is a Group 1 carcinogen with sufficient evidence that it caused nasopharyngeal cancer in humans. "There is sufficient evidence in humans for the carcinogenicity of wood dust. Wood dust causes cancer of the nasal cavity and paranasal sinuses and of the nasopharynx." [IARC 2012] In conjunction with earlier studies, a pooled analysis involving close to 29,000 wood workers in Britain and the United States (Demers et al., 1995), and two recent large-scale case-control studies in separate Chinese populations (Armstrong et al., 2000; Hildesheim et al., 2001) have yielded strong evidence that intense exposure to wood dust (as occurs under occupational settings) is associated with a duration-dependent, increased risk of NPC." [Schottenfeld, p. 624]

Ovarian Cancer

"The single well-established risk factor for ovarian cancer is a family history of either ovarian or early-onset breast cancer, which appears to account for approximately 5 to 15% of all cases of the malignancy." [Cecil, p. 1319] See "Do we know what causes ovarian cancer?" on the website of the American Cancer Society. (Asbestos not mentioned.) "Occupational cohort studies have suggested that asbestos increases the risk and mortality of ovarian cancer. However, studies have had limited ability to control for confounding by factors other than age. . . . Supporting an association, asbestos fibers have been found in ovarian tissue." [Schottenfeld, p. 1018] "The Working Group carefully considered the possibility that cases of peritoneal mesothelioma may have been misdiagnosed as ovarian cancer, and that these contributed to observed excesses. Contravening that possibility is the finding that three of the studies cited here specifically examined the possibility that there were misdiagnosed cases of peritoneal mesothelioma, and all failed to find sufficient numbers of misclassified cases. The Working Group noted that the possibility of diagnostic misclassification had probably diminished in recent years because of the development of new immunohistochemical diagnostic techniques." [IARC Volume 100C (2012): Asbestos]

Pancreatic Cancer

For pancreatic cancer, occupation is not a major causal factor and probably accounts for less than 5% of all cases. There is a weak association with chlorinated hydrocarbons in epidemiological studies. [Lowenfels AB, Maisonneuve P. Epidemiologic and etiologic factors of pancreatic cancer. Hematol Oncol Clin North Am 2002;16:1-16.] Increased risk of pancreatic cancer was associated with working as a dry cleaner. There is inconclusive evidence that workers exposed to cadmium, asbestos, and ionizing radiation have increased risk. [Ward, p. 374-5] There is suggestive evidence that acrylamide can cause pancreatic cancer. [Siemiatycki, p. 334]

Prostate Cancer

Prostate cancer is not listed in Table 18-7: "Definite or Probable Occupational Carcinogens and Carcinogenic Circumstances, Categorized by Site." [Siemiatycki, p. 334] "Cadmium can be found in some insecticides and fertilizers, and exposure can occur in several workplaces such as those of smelters, nickel-cadmium battery operations, mines, metal construction sites, and rubber production. Other sources include diet and tobacco smoke. Following some early epidemiologic reports of excess risk of prostate cancer among cadmium-exposed workers, mainly in battery production or smelting operations, more recent and larger studies failed to confirm those early reports. The cumulative epidemiologic evidence does not support the hypothesis." [PMID 11588838] Table 15-1 shows "no significant association found" between increased risk for prostate cancer and the following occupations: Radiologists, Underground Miners, Nuclear Workers, and Uranium Processors. [Boice, p. 261]

Skin Cancer

The major risk for outdoor workers is exposure to ultraviolet light. Other agents carcinogenic to the skin include: PAHs (coal tar, shale oil, or mineral oils); arsenic (pesticide manufacturing; sheep dip; copper, lead or zinc smelting); and ionizing radiation (radiologists); [LaDou, p. 260-3] Arsenic exposure is associated with an increased risk of basal cell cancer after a long latency. Sun exposure increases risk for basal cell cancer, squamous cell cancer, and melanoma. [Adami, p. 290-1] Chronic arsenic poisoning causes keratoses of palms and soles, patchy hyperpigmentation, and skin cancer (squamous and basal cell). [LaDou, p. 261, 434, 302] The evidence is strong for associations between the following agents or processes and occupational skin cancer: arsenic and compounds; coal tars and pitches; coal gasification; coke production; dibenz[a,h]anthracene; mineral oils, untreated and mildly treated; shale oils or shale-derived lubricants; solar radiation; and soots. [Siemiatycki, p. 334] Studies of ionizing radiation and skin cancer have found "meaningful associations" for Japanese A-bomb survivors, tinea capitis patients treated with radiation, and radiologists working in earlier decades. [Boice, p. 260]

Stomach Cancer

In the list of industrial processes associated with human cancer, only work in the rubber industry is a possible cause of stomach cancer. [LaDou, p. 238-9] Populations exposed to high-dose radiation from the atomic bomb and from radiotherapy for ankylosing spondylitis had increased risk for stomach cancer. "Because the large literature on occupational exposures and gastric cancer risk is not strikingly consistent, the data need cautious interpretation." For the following chemicals, the evidence is weak for a causal relationship: asbestos, silica, wood dust, chlorophenols. Many studies show a positive association between gastric cancer and occupational exposure to mineral/metal dusts, nitrosamines, and some metalworking fluids. [Adami, p. 180-1] Substantial evidence exists for a causal association between heavy exposure to asbestos and stomach cancer. Strong evidence exists for coal miners, and some evidence exists for ethylene oxide production, painters, and exposure to sulfates and sulfites in the pulp and paper industry. [Ward, p. 462-3] There was suggestive evidence of increased occupational stomach cancer in painters and workers in the rubber industry. [Siemiatycki, p. 334] Negative associations were found in studies of ionizing radiation and stomach cancer in radiologists, underground miners, nuclear workers, and uranium processors. There was a suggested but unconfirmed or questionable association between Mayak workers heavily exposed to plutonium and stomach cancer. [Boice, p. 261] "Occupational exposures in the rubber-manufacturing industry cause leukemia, lymphoma, and cancers of the urinary bladder, lung, and stomach." [IARC 2012: Occupational Exposures in the Rubber-Manufacturing Industry]

Thyroid Cancer

Thyroid cancer was strongly associated with exposure to ionizing radiation in Japanese A-bomb survivors, patients treated with radiation to the head and neck (tinea capitis, thymus, and hemangiomas); and children exposed to Chernobyl fallout. Negative associations have been found in studies of nuclear workers, uranium processors, Chernobyl cleanup workers, and populations exposed to background radiation. A negative association means that "no significant association found, although study was reasonably powerful." [Boice, p. 261]

According to the "Thyroid Cancer" chapter in Cancer Epidemiology and Prevention, 3rd Edition, "Although the studies employed different methodologies and included populations from many countries exposed to a broad range of doses, all have demonstrated significantly increased risks of thyroid carcinomas following radiation exposure during childhood. In contrast, exposure during adulthood, to either external radiation or internal ¹³¹I, has not been linked convincingly to thyroid cancer." [Schottenfeld, p. 983]

Thyroid cancer was not included in the list of SHE(O)s published by NIOSH in 1992. [Mullan]

*These are industrial exposures that were added to the agents table and linked to the associated diseases. For example, see Aluminum production.

Redrawing Haz-Map Based on the New IARC Changes

Prior to the 2012 IARC changes, the map of occupational cancer in Haz-Map was based on the "Occupation" chapter in Cancer Epidemiology and Prevention, 3rd Edition. New studies and new interpretations from IARC are now available. The following excerpts demonstrate some of the complexity of this issue:

For Painting, "There is little information on specific work settings. . . . Data from studies carried out since the previous evaluations of painters still involve primarily painters who were exposed in the 1960s and the 1970s before many changes in paint components had taken effect." [IARC 2012: Occupational Exposure as a Painter]

For MBOCA, "There is inadequate evidence in humans for the carcinogenicity of 4,4'-methylenebis(2-chlorobenzenamine)." However, "Particularly compelling data on the genotoxicity of MOCA include the higher micronucleus frequencies measured in exfoliated bladder epithelial cells and in peripheral lymphocytes of exposed workers." and "The genotoxicity of 4,4′-methylenebis(2-chlorobenzenamine) is well documented and its toxicological profile is similar to that of orthotoluidine, thus indicating a common mode of action." Also, see: http://www.ncbi.nlm.nih.gov/pubmed/19564173 and http://www.ncbi.nlm.nih.gov/pubmed/722185

"No epidemiological data on benzo[a]pyrene alone were available to the Working Group. . . . Based on the best available, consistent and strong experimental and human mechanistic evidence it is concluded that benzo[a]pyrene contributes to the genotoxic and carcinogenic effects resulting from occupational exposure to complex PAH mixtures that contain benzo[a]pyrene." Benzo(a)pyrene is a biomarker of polycyclic aromatic hydrocarbon (PAH) exposure as occurs in aluminum production and coal gasification, two processes which are carcinogenic to humans. [Benzo[a]pyrene]

"There is a lack of clear and consistent evidence from epidemiological studies that dyes metabolized to benzidine cause cancer in humans. . . . Dyes metabolized to benzidine are carcinogenic to humans (Group 1)." [Dyes Metabolized to Benzidine]

For 2,3,4,7,8-Pentachlorodibenzofuran and 3,3',4,4',5-Pentachlorobiphenyl (PCB-126), there is strong evidence for an aryl hydrocarbon receptor-mediated mechanism but no epidemiological evidence. [2,3,4,7,8-PeCDF; PCB-126]

Haz-Map Changes Resulting from 2012 IARC Changes to Group 1 Carcinogens

    Published in September 2012; Scheduled to be published at end of 2012;

    IARC: Agents Classified by the IARC Monographs, Volumes 1–105, by Cancer Site

    PubMed: Preventable exposures associated with human cancers.

    The Lancet Oncology: A review of human carcinogens—Part F: Chemical agents and related occupations

Links to Agents in Haz-Map on the NLM Website

MBOCA

o-Toluidine

Formaldehyde

1,3-Butadiene

Sulfur mustard (mustard gas)

Coal tar pitch volatiles

Leather dust

Rubber production industry
Occupational exposure as a painter

Iron and steel founding

Soot (as found in occupational exposure of chimney sweeps)

Mineral oils, untreated and mildly treated

Links to Documents on the IARC Website

Volume 100C (2012)

A Review of Human Carcinogens: Arsenic, Metals, Fibres, and Dusts

(501 pages)

Volume 100F (2012)

A Review of Human Carcinogens: Chemical Agents and Related Occupations

(599 pages)

IARC Changes in 2017

See the "List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 117." Also, see a 36-page table called "Agents Classified by the IARC Monographs, Volumes 1-117." Both tables are available from http://monographs.iarc.fr/ENG/Classification/: "Cancer site" (the first table) and "Alphabetical order" (the second table).

There are several agent-disease links that will be updated in Haz-Map:

Comments on IARC Changes

1. Polychlorinated biphenyls in Haz-Map:

Chlorodiphenyl (42% chlorine); Chlorodiphenyl (54% chlorine); 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB 153); 2,3',4,4',5,5'-Hexachlorobiphenyl (PCB 167); 3,3',4,4',5,5'-Hexachlorobiphenyl (PCB 169); 3,3',4,4'-Tetrachlorobiphenyl (PCB 77); Polychlorinated biphenyls; 3,4,5,3',4'-Pentachlorobiphenyl (PCB 126); 2,2',3-Trichlorobiphenyl (PCB 16);

2. In the "Occupation" chapter in Cancer Epidemiology and Prevention, 3rd ed., polychlorinated biphenyl exposure during production or electrical capacitor manufacturing is listed in table 18-4 showing the Suppl. 7 (1987) IARC designation of 2A for the cancer site "Liver and biliary tract." In table 18-7 in the same chapter, melanoma is linked to solar radiation (strong evidence) and UV light from artificial sources (suggestive evidence). In the chapter on melanoma, the authors cite the Loomis et al. study, "It found an overall relative risk of melanoma of 1.29 (95% CI: 0.84-1.98). . . . Exposure to PCBs probably does increase risk of melanoma." [Schottenfeld, p. 328, 334, 1209]

3. No mention of a link between PCBs and melanoma was found in Cecil Medicine, Preventing Occupational Disease and Injury, or Textbook of Clinical Occupational and Environmental Medicine. [Cecil, APHA, Rosenstock] Likewise, no mention was made in the following abstracts:

Occupational exposure to polychlorinated biphenyls and cancer risk

A cohort study of Swedish capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs)

Weight of evidence evaluation of potential human cancer risks from exposure to polychlorinated biphenyls: an update based on studies published since 2003

Polychlorinated biphenyls and cancer: an epidemiological assessment

A case-control study of cancer mortality at a transformer-assembly facility

Cancer Incidence and mortality in workers employed at a transformer manufacturing plant: update to a cohort study

Update of the mortality study of workers exposed to polychlorinated biphenyls (Pcbs) in two Italian capacitor manufacturing plants

4. See the page on PCBs and Melanoma.

IARC Changes in 2018

1. See "Identifying occupational carcinogens: an update from the IARC Monographs." This 2018 document from IARC provides three important tables: Table 1.) Group 1 agents excluded from occupational carcinogens; Table 2.) List of Group 1 agents showing which ones were included in Siemiatycki et al.; and Table 3.) List of Group 1 agents sorted by occupational disease. 

2. Agents are considered causal of occupational cancers in Haz-Map when they are Group 1 based on occupational epidemiology.

3. The occupational carcinogens in Haz-Map, shown in the list above by type of cancer, conform to the ones shown in Table 3 with a few exceptions.

4. Outdoor air pollution is not listed in Haz-Map as an occupational carcinogen.

5. As shown in the following table from "Ionizing Radiation" by John D. Boice, Jr. in Cancer Epidemiology and Prevention, 3rd Ed., workers are not considered to be at risk for certain cancers (breast, thyroid, brain, colon, kidney, esophagus, salivary gland, stomach, and bladder) caused by exposure to ionizing radiation.

Derived from: Figure 15-1. Distribution of various types of cancer associated with radiation in different populations

+ = suggested but unconfirmed or questionable association; - = no significant association found, although study reasonable powerful;

Blank = no or minimal data; U. = underground; W. = workers; P. = processors; C = cleanup; 

6. Haz-Map shows that workers are at risk for the following cancers after exposure to high doses of ionizing radiation: leukemia, bone, lung, and skin.

7. "The observed association between exposure in arsenic in drinking-water [not an occupational exposure] and bladder cancer cannot be attributed to chance or bias. There is evidence of dose-response relationships within exposed populations." [IARC Monograph 100C] Note that arsenic is not listed as an occupational cause of bladder cancer in the "Occupation" chapter of Cancer Epidemiology and Prevention, 3rd Ed. See Table 18-3.

8. "Welding fumes (not otherwise specified)" are now linked to lung cancer. "Polychlorinated biphenyls" are linked to melanoma. "Acheson process, occupational exposure" is linked to lung cancer. Vinyl chloride is now linked to both Angiosarcoma of the liver and Liver cancer to comply with IARC Monograph 100F. Benzo(a)pyrene is no longer linked to cancers of the bladder, lung, skin. This is because the IARC classification is based on mechanistic data, not occupational epidemiology.

9. For questions about the IARC classifications, see the following two pages:

    Do Polychlorinated Biphenyls Cause Malignant Melanoma after Occupational Exposure?  

    Do Welding Fumes Cause Lung Cancer?

Revised: December 16, 2019

brownjay@haz-map.com