Wilbourn, Julian

Wilbourn, Julian

Address: International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08

Country: France

Phone: 33 72 738 511

Fax: 33 72 738 575

Education: BSc

Tuesday, 25 January 2011 19:15

Occupational Carcinogens

The control of occupational carcinogens is based on the critical review of scientific investigations both in humans and in experimental systems. There are several review programmes being undertaken in different countries aimed at controlling occupational exposures which could be carcinogenic to humans. The criteria used in different programmes are not entirely consistent, leading occasionally to differences in the control of agents in different countries. For example, 4,4-methylene-bis-2-chloroaniline (MOCA) was classified as an occupational carcinogen in Denmark in 1976 and in the Netherlands in 1988, but only in 1992 has a notation “suspected human carcinogen” been introduced by the American Conference of Governmental Industrial Hygienists in the United States.

 

The International Agency for Research on Cancer (IARC) has established, within the framework of its Monographs programme, a set of criteria to evaluate the evidence of the carcinogenicity of specific agents. The IARC Monographs programme represents one of the most comprehensive efforts to review systematically and consistently cancer data, is highly regarded in the scientific community and serves as the basis for the information in this article. It also has an important impact on national and international occupational cancer control activities. The evaluation scheme is given in table 1.

 


Table 1.  Evaluation of evidence of carcinogenicity in the IARC Monographs programme.

 

1. The evidence for the induction of cancer in humans, which obviously plays an important role in the identification of human carcinogens is considered. Three types of epidemiological studies contribute to an assessment of carcinogenicity in humans: cohort studies, case-control studies and correlation (or ecological) studies. Case reports of cancer in humans may also be reviewed. The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

 

  • Sufficient evidence of carcinogenicity: A causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.
  • Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
  • Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association, or no data on cancer in humans are available.
  • Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and the studied cancer at any observed level of exposure.

 

2. Studies in which experimental animals (mainly rodents) are exposed chronically to potential carcinogens and examined for evidence of cancer are reviewed and the degree of evidence of carcinogenicity is then classified into categories similar to those used for human data.

 

3. Data on biological effects in humans and experimental animals that are of particular relevance are reviewed. These may include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on structure-activity relationship are used when considered relevant to the possible mechanism of the carcinogenic action of the agent.

 

4. The body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure (see table 2).

 

 

 


 

Agents, mixtures and exposure circumstances are evaluated within the IARC Monographs if there is evidence of human exposure and data on carcinogenicity (either in humans or in experimental animals) (for IARC classification groups, see table 2).

 

Table 2.  IARC Monograph programme classification groups.

The agent, mixture or exposure circumstance is described according to the wording of one of the following categories:

Group 1— The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
Group 2A— The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
Group 2B— The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
Group 3— The agent (mixture, exposure circumstance) is not classifiable as to its carcinogenicity to humans.
Group 4— The agent (mixture, exposure circumstance) is probably not carcinogenic to humans.

 

 

Known and Suspected Occupational Carcinogens

At present, there are 22 chemicals, groups of chemicals or mixtures for which exposures are mostly occupational, without considering pesticides and drugs, which are established human carcinogens (table 3). While some agents such as asbestos, benzene and heavy metals are currently widely used in many countries, other agents have mainly an historical interest (e.g., mustard gas and 2-naphthylamine).

 

Table 3. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 1-Chemicals carcinogenic to humans1

Exposure2 Human target organ(s) Main industry/use
4-Aminobiphenyl (92-67-1) Bladder Rubber manufacture
Arsenic (7440-38-2) and arsenic compounds3 Lung, skin Glass, metals, pesticides
Asbestos (1332-21-4) Lung, pleura, peritoneum Insulation, filter material, textiles
Benzene (71-43-2) Leukaemia Solvent, fuel
Benzidine (92-87-5) Bladder Dye/pigment manufacture, laboratory agent
Beryllium (7440-41-7) and beryllium compounds Lung Aerospace industry/metals
Bis(chloromethyl)ether (542-88-11) Lung Chemical intermediate/by-product
Chloromethyl methylether (107-30-2) (technical grade) Lung Chemical intermediate/by-product
Cadmium (7440-43-9) and cadmium compounds Lung Dye/pigment manufacture
Chromium (VI) compounds Nasal cavity, lung Metal plating, dye/pigment manufacture
Coal-tar pitches (65996-93-2) Skin, lung, bladder Building material, electrodes
Coal-tars (8007-45-2) Skin, lung Fuel
Ethylene oxide (75-21-8) Leukaemia Chemical intermediate, sterilant
Mineral oils, untreated and mildly treated Skin Lubricants
Mustard gas (sulphur mustard)
(505-60-2)
Pharynx, lung War gas
2-Naphthylamine (91-59-8) Bladder Dye/pigment manufacture
Nickel compounds Nasal cavity, lung Metallurgy, alloys, catalyst
Shale-oils (68308-34-9) Skin Lubricants, fuels
Soots Skin, lung Pigments
Talc containing asbestiform fibers Lung Paper, paints
Vinyl chloride (75-01-4) Liver, lung, blood vessels Plastics, monomer
Wood dust Nasal cavity Wood industry

1 Evaluated in the IARC Monographs, Volumes 1-63 (1972-1995) (excluding pesticides and drugs).
2 CAS Registry Nos. appear between parentheses.
3 This evaluation applies to the group of chemicals as a whole and not necessarily to all individual chemicals within the group.

 

 

An additional 20 agents are classified as probably carcinogenic to humans (Group 2A); they are listed in table 4, and include exposures that are currently prevalent in many countries, such as crystalline silica, formaldehyde and 1,3-butadiene. A large number of agents are classified as possible human carcinogens (Group 2B, table 5) - for example, acetaldehyde, dichloromethane and inorganic lead compounds. For the majority of these chemicals the evidence of carcinogenicity comes from studies in experimental animals.

Table 4. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 2A—Probably carcinogenic to humans1

Exposure2 Suspected human target organ(s) Main industry/use
Acrylonitrile (107-13-1) Lung, prostate, lymphoma Plastics, rubber, textiles, monomer
Benzidine-based dyes Paper, leather, textile dyes
1,3-Butadiene (106-99-0) Leukaemia, lymphoma Plastics, rubber, monomer
p-Chloro-o-toluidine (95-69-2) and its strong acid salts Bladder Dye/pigment manufacture, textiles
Creosotes (8001-58-9) Skin Wood preservation
Diethyl sulphate (64-67-5) Chemical intermediate
Dimethylcarbamoyl chloride (79-44-7) Chemical intermediate
Dimethyl sulphate (77-78-1) Chemical intermediate
Epichlorohydrin (106-89-8) Plastics/resins monomer
Ethylene dibromide (106-93-4) Chemical intermediate, fumigant, fuels
Formaldehyde (50-0-0) Nasopharynx Plastics, textiles, laboratory agent
4,4´-Methylene- bis-2-chloroaniline (MOCA)
(101-14-4)
Bladder Rubber manufacture
Polychlorinated biphenyls (1336-36-3) Liver, bile ducts, leukaemia, lymphoma Electrical components
Silica (14808-60-7), crystalline Lung Stone cutting, mining, glass, paper
Styrene oxide (96-09-3) Plastics, chemical intermediate
Tetrachloroethylene
(127-18-4)
Oesophagus, lymphoma Solvent, dry cleaning
Trichloroethylene (79-01-6) Liver, lymphoma Solvent, dry cleaning, metal
Tris(2,3-dibromopropylphosphate
(126-72-7)
Plastics, textiles, flame retardant
Vinyl bromide (593-60-2) Plastics, textiles, monomer
Vinyl fluoride (75-02-5) Chemical intermediate

1 Evaluated in the IARC Monographs, Volumes 1-63 (1972-1995) (excluding pesticides and drugs).
2 CAS Registry Nos. appear between parentheses.

 

Table 5. Chemicals, groups of chemicals or mixtures for which exposures are mostly occupational (excluding pesticides and drugs).
Group 2B—Possibly carcinogenic to humans1

Exposure2 Main industry/use
Acetaldehyde (75-07-0) Plastics manufacture, flavors
Acetamide (60-35-5) Solvent, chemical intermediate
Acrylamide (79-06-1) Plastics, grouting agent
p-Aminoazotoluene (60-09-3) Dye/pigment manufacture
o-Aminoazotoluene (97-56-3) Dyes/pigments, textiles
o-Anisidine (90-04-0) Dye/pigment manufacture
Antimony trioxide (1309-64-4) Flame retardant, glass, pigments
Auramine (492-80-8) (technical-grade) Dyes/pigments
Benzyl violet 4B (1694-09-3) Dyes/pigments
Bitumens (8052-42-4), extracts of
steam-refined and air-refined
Building material
Bromodichloromethane (75-27-4) Chemical intermediate
b-Butyrolactone (3068-88-0) Chemical intermediate
Carbon-black extracts Printing inks
Carbon tetrachloride (56-23-5) Solvent
Ceramic fibers Plastics, textiles, aerospace
Chlorendic acid (115-28-6) Flame retardant
Chlorinated paraffins of average carbon chain length C12 and average degree of chlorination approximately 60% Flame retardant
a-Chlorinated toluenes Dye/pigment manufacture, chemical intermediate
p-Chloroaniline (106-47-8) Dye/pigment manufacture
Chloroform (67-66-3) Solvent
4-Chloro-o-phenylenediamine (95-83-9) Dyes/pigments, hair dyes
CI Acid Red 114 (6459-94-5) Dyes/pigments, textiles, leather
CI Basic Red 9 (569-61-9) Dyes/pigments, inks
CI Direct Blue 15 (2429-74-5) Dyes/pigments, textiles, paper
Cobalt (7440-48-4)and cobalt compounds Glass, paints, alloys
p-Cresidine (120-71-8) Dye/pigment manufacture
N,N´-Diacetylbenzidine (613-35-4) Dye/pigment manufacture
2,4-Diaminoanisole (615-05-4) Dye/pigment manufacture, hair dyes
4,4´-Diaminodiphenyl ether (101-80-4) Plastics manufacture
2,4-Diaminotoluene (95-80-7) Dye/pigment manufacture, hair dyes
p-Dichlorobenzene (106-46-7) Chemical intermediate
3,3´-Dichlorobenzidine (91-94-1) Dye/pigment manufacture
3,3´-Dichloro-4,4´-diaminodiphenyl ether (28434-86-8) Not used
1,2-Dichloroethane (107-06-2) Solvent, fuels
Dichloromethane (75-09-2) Solvent
Diepoxybutane (1464-53-5) Plastics/resins
Diesel fuel, marine Fuel
Di(2-ethylhexyl)phthalate (117-81-7) Plastics, textiles
1,2-Diethylhydrazine (1615-80-1) Laboratory reagent
Diglycidyl resorcinol ether (101-90-6) Plastics/resins
Diisopropyl sulphate (29973-10-6) Contaminant
3,3´-Dimethoxybenzidine (o-Dianisidine)
(119-90-4)
Dye/pigment manufacture
p-Dimethylaminoazobenzene (60-11-7) Dyes/pigments
2,6-Dimethylaniline (2,6-Xylidine)(87-62-7) Chemical intermediate
3,3´-Dimethylbenzidine (o-Tolidine)(119-93-7) Dye/pigment manufacture
Dimethylformamide (68-12-2) Solvent
1,1-Dimethylhydrazine (57-14-7) Rocket fuel
1,2-Dimethylhydrazine (540-73-8) Research chemical
1,4-Dioxane (123-91-1) Solvent
Disperse Blue 1 (2475-45-8) Dyes/pigments, hair dyes
Ethyl acrylate (140-88-5) Plastics, adhesives, monomer
Ethylene thiourea (96-45-7) Rubber chemical
Fuel oils, residual (heavy) Fuel
Furan (110-00-9) Chemical intermediate
Gasoline Fuel
Glasswool Insulation
Glycidaldehyde (765-34-4) Textile, leather manufacture
HC Blue No. 1 (2784-94-3) Hair dyes
Hexamethylphosphoramide (680-31-9) Solvent, plastics
Hydrazine (302-01-2) Rocket fuel, chemical intermediate
Lead (7439-92-1) and lead compounds, inorganic Paints, fuels
2-Methylaziridine(75-55-8) Dyes, paper, plastics manufacture
4,4’-Methylene-bis-2-methylaniline (838-88-0) Dye/pigment manufacture
4,4’-Methylenedianiline(101-77-9) Plastics/resins, dye/pigment manufacture
Methylmercury compounds Pesticide manufacture
2-Methyl-1-nitroanthraquinone (129-15-7) (uncertain purity) Dye/pigment manufacture
Nickel, metallic (7440-02-0) Catalyst
Nitrilotriacetic acid (139-13-9) and its salts Chelating agent, detergent
5-Nitroacenaphthene (602-87-9) Dye/pigment manufacture
2-Nitropropane (79-46-9) Solvent
N-Nitrosodiethanolamine (1116-54-7) Cutting fluids, impurity
Oil Orange SS (2646-17-5) Dyes/pigments
Phenyl glycidyl ether (122-60-1) Plastics/adhesives/resins
Polybrominated biphenyls (Firemaster BP-6) (59536-65-1) Flame retardant
Ponceau MX (3761-53-3) Dyes/pigments, textiles
Ponceau 3R (3564-09-8) Dyes/pigments, textiles
1,3-Propane sulphone (1120-71-4) Dye/pigment manufacture
b-Propiolactone (57-57-8) Chemical intermediate; plastics manufacture
Propylene oxide (75-56-9) Chemical intermediate
Rockwool Insulation
Slagwool Insulation
Styrene (100-42-5) Plastics
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (1746-01-6) Contaminant
Thioacetamide (62-55-5) Textile, paper, leather, rubber manufacture
4,4’-Thiodianiline (139-65-1) Dye/pigment manufacture
Thiourea (62-56-6) Textile, rubber ingredient
Toluene diisocyanates (26471-62-5) Plastics
o-Toluidine (95-53-4) Dye/pigment manufacture
Trypan blue (72-57-1) Dyes/pigments
Vinyl acetate (108-05-4) Chemical intermediate
Welding fumes Metallurgy

1 Evaluated in the IARC Monographs, Volumes 1-63 (1972-1995) (excluding pesticides and drugs).
2 CAS Registry Nos. appear between parentheses.

 

Occupational exposures may also occur during the production and use of some pesticides and drugs. Table 6 presents an evaluation of the carcinogenicity of pesticides; two of them, captafol and ethylene dibromide, are classified as probable human carcinogens, while a total of 20 others, including DDT, atrazine and chlorophenols, are classified as possible human carcinogens.

 

Table 6. Pesticides evaluated in IARC Monographs, Volumes 1-63(1972-1995)

IARC Group Pesticide1
2A—Probably carcinogenic to humans Captafol (2425-06-1) Ethylene dibromide (106-93-4)
2B—Possibly carcinogenic to humans Amitrole (61-82-5) Atrazine (1912-24-9) Chlordane (57-74-9) Chlordecone (Kepone) (143-50-0) Chlorophenols Chlorophenoxy herbicides DDT (50-29-3) 1,2-Dibromo-3-chloropropane (96-12-8) 1,3-Dichloropropene (542-75-6) (technical-grade) Dichlorvos (62-73-7) Heptachlor (76-44-8) Hexachlorobenzene (118-74-1) Hexachlorocyclohexanes (HCH) Mirex (2385-85-5) Nitrofen (1836-75-5), technical-grade Pentachlorophenol (87-86-5) Sodium o-phenylphenate (132-27-4) Sulphallate (95-06-7) Toxaphene (Polychlorinated camphenes) (8001-35-2)

1 CAS Registry Nos. appear between parentheses.

 

Several drugs are human carcinogens (table 9): they are mainly alkylating agents and hormones; 12 more drugs, including chloramphenicol, cisplatine and phenacetin, are classified as probable human carcinogens (Group 2A). Occupational exposure to these known or suspected carcinogens, used mainly in chemotherapy, can occur in pharmacies and during their administration by nursing staff.

 

Table 7. Drugs evaluated in IARC Monographs, Volumes 1-63 (1972-1995).

Drug1 Target organ2
IARC GROUP 1—Carcinogenic to humans
Analgesic mixtures containing phenacetin Kidney, bladder
Azathioprine (446-86-6) Lymphoma, hepatobiliary system, skin
N,N-Bis(2-chloroethyl)- b-naphthylamine (Chlornaphazine) (494-03-1) Bladder
1,4-Butanediol dimethanesulphonate (Myleran)
(55-98-1)
Leukaemia
Chlorambucil (305-03-3) Leukaemia
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU) (13909-09-6) Leukaemia
Cyclosporin (79217-60-0) Lymphoma, skin
Cyclophosphamide (50-18-0) (6055-19-2) Leukaemia, bladder
Diethylstilboestrol (56-53-1) Cervix, vagina, breast
Melphalan (148-82-3) Leukaemia
8-Methoxypsoralen (Methoxsalen) (298-81-7) plus ultraviolet A radiation Skin
MOPP and other combined chemotherapy including alkylating agents Leukaemia
Oestrogen replacement therapy Uterus
Oestrogens, nonsteroidal Cervix, vagina, breast
Oestrogens, steroidal Uterus
Oral contraceptives, combined Liver
Oral contraceptives, sequential Uterus
Thiotepa (52-24-4) Leukaemia
Treosulfan (299-75-2) Leukaemia

 

IARC GROUP 2A—Probably carcinogenic to humans
Adriamycin (23214-92-8)
Androgenic (anabolic) steroids (Liver)
Azacitidine (320-67-2)
Bischloroethyl nitrosourea (BCNU) (154-93-8) (Leukaemia)
Chloramphenicol (56-75-7) (Leukaemia)
1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) (13010-47-4)
Chlorozotocine (54749-90-5)
Cisplatin (15663-27-1)
5-Methoxypsoralen (484-20-8)
Nitrogen mustard (51-75-2) (Skin)
Phenacetin (62-44-2) (Kidney, bladder)
Procarbazine hydrochloride (366-70-1)

1 CAS Registry Nos. appear between parentheses.
2 Suspected target organs are given in parentheses.

 

Several environmental agents are known or suspected causes of cancer in humans and are listed in table 8; although exposure to such agents is not primarily occupational, there are groups of individuals exposed to them because of their work: examples are uranium miners exposed to radon decay products, hospital workers exposed to hepatitis B virus, food processors exposed to aflatoxins from contaminated foods, outdoor workers exposed to ultraviolet radiation or diesel engine exhaust, and bar staff or waiters exposed to environmental tobacco smoke.

The IARC Monograph programme has covered most of the known or suspected causes of cancer; there are, however, some important groups of agents that have not been evaluated by IARC—namely, ionizing radiation and electrical and magnetic fields.

 

Table 8. Environmental agents/exposures known or suspected to cause cancer in humans.1

Agent/exposure Target organ2 Strength of evidence3
Air pollutants
Erionite Lung, pleura 1
Asbestos Lung, pleura 1
Polycyclic aromatic hydrocarbons4 (Lung, bladder) S
Water pollutants
Arsenic Skin 1
Chlorination by-products (Bladder) S
Nitrate and nitrite (Oesophagus, stomach) S
Radiation
Radon and its decay products Lung 1
Radium, thorium Bone E
Other X-irradiation Leukaemia, breast, thyroid, others E
Solar radiation Skin 1
Ultraviolet radiation A (Skin) 2A
Ultraviolet radiation B (Skin) 2A
Ultraviolet radiation C (Skin) 2A
Use of sunlamps and sunbeds (Skin) 2A
Electric and magnetic fields (Leukaemia) S
Biological agents
Chronic infection with hepatitis B virus Liver 1
Chronic infection with hepatitis C virus Liver 1
Infection with Helicobacter pylori Stomach 1
Infection with Opistorchis viverrini Bile ducts 1
Infection with Chlonorchis sinensis (Liver) 2A
Human Papilloma virus types 16 and18 Cervix 1
Human Papilloma virus types 31 and 33 (Cervix) 2A
Human Papilloma virus types other than 16, 18, 31 and 33 (Cervix) 2B
Infection with Schistosoma haematobium Bladder 1
Infection with Schistosoma japonicum (Liver, colon) 2B
Tobacco, alcohol and related substances
Alcoholic beverages Mouth, pharynx, oesophagus, liver, larynx 1
Tobacco smoke Lip, mouth, pharynx, oesophagus, pancreas, larynx, lung, kidney, bladder, (others) 1
Smokeless tobacco products Mouth 1
Betel quid with tobacco Mouth 1
Dietary factors
Aflatoxins Liver 1
Aflatoxin M1 (Liver) 2B
Ochratoxin A (Kidney) 2B
Toxins derived from Fusarium moniliforme (Oesophagus) 2B
Chinese style salted fish Nasopharynx 1
Pickled vegetables (traditional in Asia) (Oesophagus, stomach) 2B
Bracken fern (Oesophagus) 2B
Safrole 2B
Coffee (Bladder) 2B
Caffeic acid 2B
Hot mate (Oesophagus) 2A
Fresh fruits and vegetables (protective) Mouth, oesophagus, stomach, colon, rectum, larynx, lung (others) E
Fat (Colon, breast, endometrium) S
Fiber (protective) (Colon, rectum) S
Nitrate and nitrite (Oesophagus, stomach) S
Salt (Stomach) S
Vitamin A, b-carotene (protective) (Mouth, oesophagus, lung, others) S
Vitamin C (protective) (Oesophagus, stomach) S
IQ (Stomach, colon, rectum) 2A
MeIQ 2B
MeIQx 2B
PhIP 2B
Reproductive and sexual behavior
Late age at first pregnancy Breast E
Low parity Breast, ovary, corpus uteri E
Early age at first intercourse Cervix E
Number of sexual partners Cervix E

1 Agents and exposures, as well as medicines, occurring mainly in the occupational setting are excluded.

2 Suspected target organs are given in parentheses.

3 IARC Monograph evaluation reported wherever available (1: human carcinogen; 2A: probable human carcinogen; 2B: possible human carcinogen); otherwise E: established carcinogen; S: suspected carcinogen.

4 Human exposure to polycyclic aromatic hydrocarbons occurs in mixtures, such as engine emissions, combustion fumes and soots. Several mixtures and individual hydrocarbons have been evaluated by IARC.

 

Industries and Occupations

Current understanding of the relationship between occupational exposures and cancer is far from complete; in fact, only 22 individual agents are established occupational carcinogens (table 9), and for many more experimental carcinogens no definitive evidence is available based on exposed workers. In many cases, there is considerable evidence of increased risks associated with particular industries and occupations, although no specific agents can be identified as aetiological factors. Table 10 present lists of industries and occupations associated with excess carcinogenic risks, together with the relevant cancer sites and the known (or suspected) causative agent(s).

 

Table 9. Industries, occupations and exposures recognized as presenting a carcinogenic risk.

Industry (ISIC code) Occupation/process Cancer site/type Known or suspected causative agent
Agriculture, forestry and fishing (1) Vineyard workers using arsenic insecticides Fishermen Lung, skin Skin, lip Arsenic compounds Ultraviolet radiation
Mining and quarrying (2) Arsenic mining Iron ore (haematite) mining Asbestos mining Uranium mining Talc mining and milling Lung, skin Lung Lung, pleural and peritoneal mesothelioma Lung Lung Arsenic compounds Radon decay products Asbestos Radon decay products Talc containing asbestiform fibers
Chemical (35) Bis(chloromethyl) ether (BCME) and chloromethyl-methyl ether (CMME) production workers and users Vinyl chloride production Isopropyl alcohol manufacture (strong-acid process) Pigment chromate production Dye manufacturers and users Auramine manufacture p-chloro-o-toluidine production Lung (oat-cell carcinoma) Liver angiosarcoma Sinonasal Lung, sinonasal Bladder Bladder Bladder BCME, CMME Vinyl chloride monomer Not identified Chromium (VI) compounds Benzidine, 2-naphthylamine, 4-aminobiphenyl Auramine and other aromatic amines used in the process p-chloro-o-toluidine and its strong acid salts
Leather (324) Boot and shoe manufacture Sinonasal, leukaemia Leather dust, benzene
Wood and wood products (33) Furniture and cabinet makers Sinonasal Wood dust
Pesticides and herbicides production (3512) Arsenical insecticides production and packaging Lung Arsenic compounds
Rubber industry (355) Rubber manufacture Calendering, tyre curing, tyre building Millers, mixers Synthetic latex production, tyre curing, calender operatives, reclaim, cable makers Rubber film production Leukaemia Bladder Leukaemia Bladder Bladder Leukaemia Benzene Aromatic amines Benzene Aromatic amines Aromatic amines Benzene
Asbestos production (3699) Insulated material production (pipes, sheeting, textile, clothes, masks, asbestos cement products) Lung, pleural and peritoneal mesothelioma Asbestos
Metals (37) Aluminum production Copper smelting Chromate production, chromium plating Iron and steel founding Nickel refining Pickling operations Cadmium production and refining; nickel-cadmium battery manufacture; cadmium pigment manufacture; cadmium alloy production; electroplating; zinc smelters; brazing and polyvinyl chloride compounding Beryllium refining and machining; production of beryllium-containing products Lung, bladder Lung Lung, sinonasal Lung Sinonasal, lung Larynx, lung Lung Lung Polycyclic aromatic hydrocarbons, tar Arsenic compounds Chromium (VI) compounds Not identified Nickel compounds Inorganic acid mists containing sulphuric acid Cadmium and cadmium compounds Beryllium and beryllium compounds
Shipbuilding, motor vehicle and railroad equipment manufacture (385) Shipyard and dockyard, motor vehicle and railroad manufacture workers Lung, pleural and peritoneal mesothelioma Asbestos
Gas (4) Coke plant workers Gas workers Gas-retort house workers Lung Lung, bladder, scrotum Bladder Benzo(a)pyrene Coal carbonization products, 2-naphthylamine Aromatic amines
Construction (5) Insulators and pipe coverers Roofers, asphalt workers Lung, pleural and peritoneal mesothelioma Lung Asbestos Polycyclic aromatic hydrocarbons
Other Medical personnel (9331) Painters (construction, automotive industry and other users) Skin, leukaemia Lung Ionizing radiation Not identified


 

Table 10.  Industries, occupations and exposures reported to present a cancer excess but for which the assessment of the carcinogenic risk is not definitive.

Industry (ISIC code) Occupation/process Cancer site/type Known (or suspected) causative agent
Agriculture, forestry and fishing (1) Farmers, farm workers Herbicide application Insecticide application Lymphatic and haematopoietic system (leukaemia, lymphoma) Malignant lymphomas, soft-tissue sarcomas Lung, lymphoma Not identified Chlorophenoxy herbicides, chlorophenols (presumably contaminated with polychlorinated dibenzodioxins) Non-arsenical insecticides
Mining and quarrying (2) Zinc-lead mining Coal Metal mining Asbestos mining Lung Stomach Lung Gastrointestinal tract Radon decay products Coal dust Crystalline silica Asbestos
Food industry (3111) Butchers and meat workers Lung Viruses, PAH1
Beverage industry (3131) Beer brewers Upper aero-digestive tract Alcohol consumption
Textile manufacture (321) Dyers Weavers Bladder Bladder, sinonasal, mouth Dyes Dusts from fibers and yarns
Leather (323) Tanners and processors Boot and shoe manufacture and repair Bladder, pancreas, lung Sinonasal, stomach, bladder Leather dust, other chemicals, chromium Not identified
Wood and wood products (33), pulp and paper industry (341) Lumbermen and sawmill workers Pulp and papermill workers Carpenters, joiners Woodworkers, unspecified Plywood production, particle-board production Nasal cavity, Hodgkin lymphoma, skin Lymphopoietic tissue, lung Nasal cavity, Hodgkin lymphoma Lymphomas Nasopharynx, sinonasal Wood dust, chlorophenols, creosotes Not identified Wood dust, solvents Not identified Formaldehyde
Printing (342) Rotogravure workers, binders, printing pressmen, machine-room workers and other jobs Lymphocytic and haemopoietic system, oral, lung, kidney Oil mist, solvents
Chemical (35) 1,3-Butadiene production Acrylonitrile production Vinylidene chloride production Isopropyl alcohol manufacture (strong-acid process) Polychloroprene production Dimethylsulphate production Epichlorohydrin production Ethylene oxide production Ethylene dibromide production Formaldehyde production Flame retardant and plasticizer use Benzoyl chloride production Lymphocytic and haemopoietic system Lung, colon Lung Larynx Lung Lung Lung, lymphatic and haemopoietic system (leukaemia) Lymphatic and haemopoietic system (leukaemia), stomach Digestive system Nasopharynx, sinonasal Skin (melanoma) Lung 1,3-Butadiene Acrylonitrile Vinylidene chloride (mixed exposure with acrylonitrile) Not identified Chloroprene Dimethylsulphate Epichlorohydrin Ethylene oxide Ethylene dibromide Formaldehyde Polychlorinated biphenyls Benzoyl chloride
Herbicides production (3512) Chlorophenoxy herbicide production Soft-tissue sarcoma Chlorophenoxy herbicides, chlorophenols (contaminated with polychlorinated dibenzodioxins)
Petroleum (353) Petroleum refining Skin, leukaemia, brain Benzene, PAH, untreated and mildly treated mineral oils
Rubber (355) Various occupations in rubber manufacture Styrene-butadiene rubber production Lymphoma, multiple myeloma, stomach, brain, lung Lymphatic and haematopoietic system Benzene, MOCA,2 other not identified 1,3-Butadiene
Ceramic, glass and refractory brick (36) Ceramic and pottery workers Glass workers (art glass, container and pressed ware) Lung Lung Crystalline silica Arsenic and other metal oxides, silica, PAH
Asbestos production (3699) Insulation material production (pipes, sheeting, textiles, clothes, masks, asbestos cement products) Larynx, gastrointestinal tract Asbestos
Metals (37, 38) Lead smelting Cadmium production and refining; nickel-cadmium battery manufacture; cadmium pigment manufacture; cadmium alloy production; electroplating; zinc smelting; brazing and polyvinyl chloride compounding Iron and steel founding Respiratory and digestive systems Prostate Lung Lead compounds Cadmium and cadmium compounds Crystalline silica
Shipbuilding (384) Shipyard and dockyard workers Larynx, digestive system Asbestos
Motor vehicle manufacturing (3843, 9513) Mechanics, welders, etc. Lung PAH, welding fumes, engine exhaust
Electricity (4101, 9512) Generation, production, distribution, repair Leukaemia, brain tumors Liver, bile ducts Extremely low frequency magnetic fields PCBs3
Construction (5) Insulators and pipe coverers Roofers, asphalt workers Larynx, gastrointestinal tract Mouth, pharynx, larynx, oesophagus, stomach Asbestos PAH, coal tar, pitch
Transport (7) Railroad workers, filling station attendants, bus and truck drivers, operators of excavating machines Lung, bladder Leukaemia Diesel engine exhaust Extremely low frequency magnetic fields
Other Service station attendants (6200) Chemists and other laboratory workers (9331) Embalmers, medical personnel (9331) Health workers (9331) Laundry and dry cleaners (9520) Hairdressers (9591) Radium dial workers Leukaemia and lymphoma Leukaemia and lymphoma, pancreas Sinonasal, nasopharynx Liver Lung, oesophagus, bladder Bladder, leukaemia and lymphoma Breast Benzene Not identified (viruses, chemicals) Formaldehyde Hepatitis B virus Tri- and tetrachloroethylene and carbon tetrachloride Hair dyes, aromatic amines Radon

1 PAH, polycyclic aromatic hydrocarbon.

2 MOCA, 4,4’-methylene-bis-2-chloroaniline.

3 PCBs, polychlorinated biphenyls.

 

Table 9 presents industries, occupations and exposures in which the presence of a carcinogenic risk is considered to be established, whereas Table 10 shows industrial processes, occupations and exposures for which an excess cancer risk has been reported but evidence is not considered to be definitive. Also included in table 10 are some occupations and industries already listed in table 9, for which there is inconclusive evidence of association with cancers other than those mentioned in table 9. For example, the asbestos production industry is included in table 9 in relation to lung cancer and pleural and peritoneal mesothelioma, whereas the same industry is included in table 10 in relation to gastrointestinal neoplasms. A number of industries and occupations listed intables 9 and 10 have also been evaluated under the IARC Monographs programme. For example, “occupational exposure to strong inorganic acid mist containing sulphuric acid” was classified in Group 1 (carcinogenic to humans).

Constructing and interpreting such lists of chemical or physical carcinogenic agents and associating them with specific occupations and industries is complicated by a number of factors: (1) information on industrial processes and exposures is frequently poor, not allowing a complete evaluation of the importance of specific carcinogenic exposures in different occupations or industries; (2) exposures to well-known carcinogenic exposures, such as vinyl chloride and benzene, occur at different intensities in different occupational situations; (3) changes in exposure occur over time in a given occupational situation, either because identified carcinogenic agents are substituted by other agents or (more frequently) because new industrial processes or materials are introduced; (4) any list of occupational exposures can refer only to the relatively small number of chemical exposures which have been investigated with respect to the presence of a carcinogenic risk.

 

 

All of the above issues emphasize the most critical limitation of a classification of this type, and in particular its generalization to all areas of the world: the presence of a carcinogen in an occupational situation does not necessarily mean that workers are exposed to it and, in contrast, the absence of identified carcinogens does not exclude the presence of yet unidentified causes of cancer.

A particular problem in developing countries is that much of the industrial activity is fragmented and takes place in local settings. These small industries are often characterized by old machinery, unsafe buildings, employees with limited training and education, and employers with limited financial resources. Protective clothing, respirators, gloves and other safety equipment are seldom available or used. The small companies tend to be geographically scattered and inaccessible to inspections by health and safety enforcement agencies.

 

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Sunday, 16 January 2011 19:15

Approaches to Hazard Identification: IARC

The identification of carcinogenic risks to humans has been the objective of the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans since 1971. To date, 69 volumes of monographs have been published or are in press, with evaluations of carcinogenicity of 836 agents or exposure circumstances (see Appendix).

These qualitative evaluations of carcinogenic risk to humans are equivalent to the hazard identification phase in the now generally accepted scheme of risk assessment, which involves identification of hazard, dose-response assessment (including extrapolation outside the limits of observations), exposure assessment and risk characterization.

The aim of the IARC Monographs programme has been to publish critical qualitative evaluations on the carcinogenicity to humans of agents (chemicals, groups of chemicals, complex mixtures, physical or biological factors) or exposure circumstances (occupational exposures, cultural habits) through international cooperation in the form of expert working groups. The working groups prepare monographs on a series of individual agents or exposures and each volume is published and widely distributed. Each monograph consists of a brief description of the physical and chemical properties of the agent; methods for its analysis; a description of how it is produced, how much is produced, and how it is used; data on occurrence and human exposure; summaries of case reports and epidemiological studies of cancer in humans; summaries of experimental carcinogenicity tests; a brief description of other relevant biological data, such as toxicity and genetic effects, that may indicate its possible mechanism of action; and an evaluation of its carcinogenicity. The first part of this general scheme is adjusted appropriately when dealing with agents other than chemicals or chemical mixtures.

The guiding principles for evaluating carcinogens have been drawn up by various ad-hoc groups of experts and are laid down in the Preamble to the Monographs (IARC 1994a).

Tools for Qualitative Carcinogenic Risk (Hazard) Identification

Associations are established by examining the available data from studies of exposed humans, the results of bioassays in experimental animals and studies of exposure, metabolism, toxicity and genetic effects in both humans and animals.

Studies of cancer in humans

Three types of epidemiological studies contribute to an assessment of carcinogenicity: cohort studies, case-control studies and correlation (or ecological) studies. Case reports of cancer may also be reviewed.

Cohort and case-control studies relate individual exposures under study to the occurrence of cancer in individuals and provide an estimate of relative risk (ratio of the incidence in those exposed to the incidence in those not exposed) as the main measure of association.

In correlation studies, the unit of investigation is usually whole populations (e.g., particular geographical areas) and cancer frequency is related to a summary measure of the exposure of the population to the agent. Because individual exposure is not documented, a causal relationship is less easy to infer from such studies than from cohort and case-control studies. Case reports generally arise from a suspicion, based on clinical experience, that the concurrence of two events—that is, a particular exposure and occurrence of a cancer—has happened rather more frequently than would be expected by chance. The uncertainties surrounding interpretation of case reports and correlation studies make them inadequate, except in rare cases, to form the sole basis for inferring a causal relationship.

In the interpretation of epidemiological studies, it is necessary to take into account the possible roles of bias and confounding. By bias is meant the operation of factors in study design or execution that lead erroneously to a stronger or weaker association than in fact exists between disease and an agent. By confounding is meant a situation in which the relationship with disease is made to appear stronger or weaker than it truly is as a result of an association between the apparent causal factor and another factor that is associated with either an increase or decrease in the incidence of the disease.

In the assessment of the epidemiological studies, a strong association (i.e., a large relative risk) is more likely to indicate causality than a weak association, although it is recognized that relative risks of small magnitude do not imply lack of causality and may be important if the disease is common. Associations that are replicated in several studies of the same design or using different epidemiological approaches or under different circumstances of exposure are more likely to represent a causal relationship than isolated observations from single studies. An increase in risk of cancer with increasing amounts of exposure is considered to be a strong indication of causality, although the absence of a graded response is not necessarily evidence against a causal relationship. Demonstration of a decline in risk after cessation of or reduction in exposure in individuals or in whole populations also supports a causal interpretation of the findings.

When several epidemiological studies show little or no indication of an association between an exposure and cancer, the judgement may be made that, in the aggregate, they show evidence suggesting lack of carcinogenicity. The possibility that bias, confounding or misclassification of exposure or outcome could explain the observed results must be considered and excluded with reasonable certainty. Evidence suggesting lack of carcinogenicity obtained from several epidemiological studies can apply only to those type(s) of cancer, dose levels and intervals between first exposure and observation of disease that were studied. For some human cancers, the period between first exposure and the development of clinical disease is seldom less than 20 years; latent periods substantially shorter than 30 years cannot provide evidence suggesting lack of carcinogenicity.

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

Sufficient evidence of carcinogenicity. A causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.

Limited evidence of carcinogenicity. A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding cannot be ruled out with reasonable confidence.

Inadequate evidence of carcinogenicity. The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association, or no data on cancer in humans are available.

Evidence suggesting lack of carcinogenicity. There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and the studied cancer at any observed level of exposure. A conclusion of “evidence suggesting lack of carcinogenicity” is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies.

The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on time and place. The specific exposure, process or activity considered most likely to be responsible for any excess risk should be sought and the evaluation focused as narrowly as possible. The long latent period of human cancer complicates the interpretation of epidemiological studies. A further complication is the fact that humans are exposed simultaneously to a variety of chemicals, which can interact either to increase or decrease the risk for neoplasia.

Studies on carcinogenicity in experimental animals

Studies in which experimental animals (usually mice and rats) are exposed to potential carcinogens and examined for evidence of cancer were introduced about 50 years ago with the aim of introducing a scientific approach to the study of chemical carcinogenesis and to avoid some of the disadvantages of using only epidemiological data in humans. In the IARC Monographs all available, published studies of carcinogenicity in animals are summarized, and the degree of evidence of carcinogenicity is then classified into one of the following categories:

Sufficient evidence of carcinogenicity. A causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in two or more species of animals or in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.

Limited evidence of carcinogenicity. The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, for example, (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are some unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.

Inadequate evidence of carcinogenicity. The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.

Evidence suggesting lack of carcinogenicity. Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.

Other data relevant to an evaluationof carcinogenicity

Data on biological effects in humans that are of particular relevance include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on kinetics and metabolism in experimental animals are summarized when considered relevant to the possible mechanism of the carcinogenic action of the agent. The results of tests for genetic and related effects are summarized for whole mammals including man, cultured mammalian cells and nonmammalian systems. Structure-activity relationships are mentioned when relevant.

For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions:

  •  evidence of genotoxicity (i.e., structural changes at the level of the gene): for example, structure-activity considerations, adduct formation, mutagenicity (effect on specific genes), chromosomal mutation or aneuploidy
  •  evidence of effects on the expression of relevant genes (i.e., functional changes at the intracellular level): for example, alterations to the structure or quantity of the product of a proto-oncogene or tumour suppressor gene, alterations to metabolic activation, inactivation or DNA repair
  •  evidence of relevant effects on cell behaviour (i.e., morphological or behavioural changes at the cellular or tissue level): for example, induction of mitogenesis, compensatory cell proliferation, preneoplasia and hyperplasia, survival of premalignant or malignant cells (immortalization, immunosuppression), effects on metastatic potential
  •  evidence from dose and time relationships of carcinogenic effects and interactions between agents: for example, early versus late stage, as inferred from epidemiological studies; initiation, promotion, progression or malignant conversion, as defined in animal carcinogenicity experiments; toxicokinetics.

 

These dimensions are not mutually exclusive, and an agent may fall within more than one. Thus, for example, the action of an agent on the expression of relevant genes could be summarized under both the first and second dimension, even if it were known with reasonable certainty that those effects resulted from genotoxicity.

Overall evaluations

Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure. An evaluation may be made for a group of chemicals when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative.

The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.

Group 1

The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

Group 2

This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.

Group 2A. The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

Group 2B. The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

Group 3

The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.

Group 4

The agent (mixture) is probably not carcinogenic to humans. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group.

Classification systems made by humans are not sufficiently perfect to encompass all the complex entities of biology. They are, however, useful as guiding principles and may be modified as new knowledge of carcinogenesis becomes more firmly established. In the categorization of an agent, mixture or exposure circumstance, it is essential to rely on scientific judgements formulated by the group of experts.

Results to Date

To date, 69 volumes of IARC Monographs have been published or are in press, in which evaluations of carcinogenicity to humans have been made for 836 agents or exposure circumstances. Seventy-four agents or exposures have been evaluated as carcinogenic to humans (Group 1), 56 as probably carcinogenic to humans (Group 2A), 225 as possibly carcinogenic to humans (Group 2B) and one as probably not carcinogenic to humans (Group 4). For 480 agents or exposures, the available epidemiological and experimental data did not allow an evaluation of their carcinogenicity to humans (Group 3).

Importance of Mechanistic Data

The revised Preamble, which first appeared in volume 54 of the IARC Monographs, allows for the possibility that an agent for which epidemiological evidence of cancer is less than sufficient can be placed in Group 1 when there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity. Conversely, an agent for which there is inadequate evidence of carcinogenicity in humans together with sufficient evidence in experimental animals and strong evidence that the mechanism of carcinogenesis does not operate in humans may be placed in Group 3 instead of the normally assigned Group 2B—possibly carcinogenic to humans—category.

The use of such data on mechanisms has been discussed on three recent occasions:

While it is generally accepted that solar radiation is carcinogenic to humans (Group 1), epidemiological studies on cancer in humans for UVA and UVB radiation from sun lamps provide only limited evidence of carcinogenicity. Special tandem base substitutions (GCTTT) have been observed in p53 tumour suppression genes in squamous-cell tumours at sun-exposed sites in humans. Although UVR can induce similar transitions in some experimental systems and UVB, UVA and UVC are carcinogenic in experimental animals, the available mechanistic data were not considered strong enough to allow the working group to classify UVB, UVA and UVC higher than Group 2A (IARC 1992). In a study published after the meeting (Kress et al. 1992), CCTTT transitions in p53 have been demonstrated in UVB-induced skin tumours in mice, which might suggest that UVB should also be classified as carcinogenic to humans (Group 1).

The second case in which the possibility of placing an agent in Group 1 in the absence of sufficient epidemiological evidence was considered was 4,4´-methylene-bis(2-chloroaniline) (MOCA). MOCA is carcinogenic in dogs and rodents and is comprehensively genotoxic. It binds to DNA through reaction with N-hydroxy MOCA and the same adducts that are formed in target tissues for carcinogenicity in animals have been found in urothelial cells from a small number of exposed humans. After lengthy discussions on the possibility of an upgrading, the working group finally made an overall evaluation of Group 2A, probably carcinogenic to humans (IARC 1993).

During a recent evaluation of ethylene oxide (IARC 1994b), the available epidemiological studies provided limited evidence of carcinogenicity in humans, and studies in experimental animals provided sufficient evidence of carcinogenicity. Taking into account the other relevant data that (1) ethylene oxide induces a sensitive, persistent, dose-related increase in the frequency of chromosomal aberrations and sister chromatid exchanges in peripheral lymphocytes and micronuclei in bone-marrow cells from exposed workers; (2) it has been associated with malignancies of the lymphatic and haematopoietic system in both humans and experimental animals; (3) it induces a dose-related increase in the frequency of haemoglobin adducts in exposed humans and dose-related increases in the numbers of adducts in both DNA and haemoglobin in exposed rodents; (4) it induces gene mutations and heritable translocations in germ cells of exposed rodents; and (5) it is a powerful mutagen and clastogen at all phylogenetic levels; ethylene oxide was classified as carcinogenic to humans (Group 1).

In the case where the Preamble allows for the possibility that an agent for which there is sufficient evidence of carcinogenicity in animals can be placed in Group 3 (instead of Group 2B, in which it would normally be categorized) when there is strong evidence that the mechanism of carcinogenicity in animals does not operate in humans, this possibility has not yet been used by any working group. Such a possibility could have been envisaged in the case of d-limonene had there been sufficient evidence of its carcinogenicity in animals, since there are data suggesting that α2-microglobulin production in male rat kidney is linked to the renal tumours observed.

Among the many chemicals nominated as priorities by an ad-hoc working group in December 1993, some common postulated intrinsic mechanisms of action appeared or certain classes of agents based upon their biological properties were identified. The working group recommended that before evaluations are made on such agents as peroxisome proliferators, fibres, dusts and thyrostatic agents within the Monographs programme, special ad-hoc groups should be convened to discuss the latest state of the art on their particular mechanisms of action.

 

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Contents

Preface
Part I. The Body
Part II. Health Care
Part III. Management & Policy
Part IV. Tools and Approaches
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides