Microsoft word - 03-carcinogenic chemicals-18_04_2010

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“Carcinogenic Chemicals: Classification and Evaluation of Carcinogenic
Risk to Humans by International Organizations and the European Union”
Prof. A. Valavanidis & Dr. Thomais Vlachogianni
Department of Chemistry, University of Athens, University Campus Zografou, 15784 Athens, Greece E-mail: [email protected] & [email protected]
Abstract
People are continuously exposed to varying amounts of chemicals that have been shown to have
carcinogenic or mutagenic properties in experimental systems. Chemical carcinogens can occur
exogenously or endogenously in living organisms (aerobic metabolic processes, hormonal
changes, oxygen uptake and distribution, pathophysiologic states such as inflammation, genetic
factors, etc.). Exogenous exposure to carcinogens can occur through food consumption, air,
occupational exposure and drinking water. It has been estimated that exposure to extrinsic or environmental carcinogens may contribute significantly to the causation of a sizable fraction of human cancers, estimated to the range of 75-80%. Epidemiological studies provide evidence that lifestyle causes of cancer such as diet, tobacco smoking, obesity, alcohol, etc., are the major contributors to human malignant neoplasms. Carcinogenesis is a multistep process that affects to a great extent old age. The carcinogenic risk to chemical carcinogens is a composite of its effects on multiple genetic and epigenetic processes. International and national organizations, such as the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP) and other health and safety agencies, evaluate the carcinogenic risks of various chemicals,
physical and biological agents. The European Commission through the Directive 67/548/EEC and
93/101/EEC on Chemical Carcinogens and Mutagens, has collected experimental data and risk
assessment studies on chemical carcinogens. Also, numerous scientific studies evaluated the
carcinogenic potential through in vivo studies on experimental animals and in vitro studies in cell
lines. These organizations also set the limits of exposure (especially in the working environment)
and legislate to restrict the use of chemical carcinogens in other applications.
Keywords: carcinogenic chemicals, classification of risks, IARC, REACH.
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Introduction: Chemical Carcinogens, Molecular Mechanisms of Carcinogenesis and Risks to
Humans
Chemical carcinogens are substances or mixtures which have the potential to induce cancer to
humans under certain conditions and for prolonged or excessive periods of exposure. Chemical
carcinogens can be natural chemicals, synthetic compounds or mixtures of both, that are
produced or used for industrial, agricultural or commercial purposes. Carcinogens can cause
cancer by direct action in the cellular DNA or through mechanisms that generate chemical
species (such as free radicals, reactive oxygen species, carcinogenic metabolites) which enter
the cell nucleous causing mutations to cellular DNA. Chemically-induced cancer generally develops many years after exposure to a carcinogenic agent. A latency period of as much as thirty years has been observed between exposure to asbestos fibres (a known carcinogenic agent), for example, and incidence of lung cancer.1,2 Carcinogenesis is a multistep process that proceeds through multiple discernible stages, including initiation, promotion, and progression. The transition between these stages is driven by different environmental and endogenous factors and involves different mechanisms and genetic elements. Several types of chemicals initiate the carcinogenic process by yielding highly reactive species that bind covalently to cellular DNA. These carcinogenic agents distort the conformation of DNA and its functions during DNA replication and transcription. These changes have implications with respect to oncogene activation, DNA amplification, gene transposition and chromosome translocation. Carcinogenic chemicals may influence the carcinogenic process by mutational activation of protooncogenes and/or inactivation of tumor suppression genes. In addition, chemical carcinogens may act on non-mutational processes such as the clonal expansion of premalignant cells. The carcinogenic risk of specific chemical carcinogens is a composite of its effects on multiple genetic and epigenetic processes.3,4 Exogenous chemical carcinogenesis is an extremely complex multi-factorial process during which gene-environment interactions involving chronic exposure to chemical carcinogens and polymorphisms of cancer susceptibility genes add further complexity. These exogenous chemical carcinogens could be major contributors to human cancer.5 Chemicals related to environmental pollution appear to be of critical importance in inducing cancer, such as occupational cancers. Scientists have established that outdoor air pollution (suspended particulate matter associated with PAHs and other carcinogenic chemicals), indoor air pollution (environmental tobacco smoke, formaldehyde, VOCs such as benzene and 1,3- butadiene), food pollution (food additives, pesticide residues, dioxins, organochlorines) and other chemical pollutants (such as metals, metalloids, pharmaceutical medicines, cosmetics, etc) may contribute to malignant neoplasms in humans.6 In recent years, epidemiologists and cancer specialists agree that environmental factors play an important part in carcinogenesis. But, it is evident to them that especially lifestyle factors (tobacco smoking, diet, alcohol consumption, obesity, sedentary life and other known lifestyle factors (excessive exposure to sunlight, viruses, sexual life, hormonal changes, etc) are contributing to a major proportion of human cancers.7 Occupational cancers are known to cause, approximately, 4-5% of human cancers, but in recent years new health and safety regulations in
the working environment and the substitution and/or restriction of many known chemical
carcinogens reduced substantially the risk of exposure to workers.8,9
International Agency for Research on Cancer (IARC): Classification and Evaluation of
Carcinogenic Agents
There are many international and national organizations that collect information, scientific
studies and toxicological data which help to classify and regulate chemical carcinogens, complex
mixtures, occupational exposures, physical agents and lifestyle factors. The most prominent is the International Agency for Research on Cancer (IARC, Lyon, France, http://www.iarc.fr ), an international scientific organization of the World Health Organization (WHO). IARC has Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

international teams of toxicologists, cancer biologists, epidemiologist of cancer and experts.
These teams (Working Groups) since 1971 collected data on more than 900 agents and evaluated
the carcinogenicity of approximately 400, especially their carcinogenic potential to humans and
the risk to cause cancers under certain environmental conditions.10
IARC established criteria for the classification of carcinogenic agents and evaluated their risks to
humans. Until now IARC (2009) has published a series of 97 Monographs on the Evaluation of
Carcinogenic Risks to Humans. Also, IARC has published more than 150 related Scientific
Publications on cancer, carcinogenic risk and carcinogenesis by well known independent experts
and research scientists from all over the world.11 Each monograph consists of a brief description, data on chemical and physical properties, methods of production, use and occurrence, relevant epidemiological studies, evidence of carcinogenicity, toxicity and genetic effects. These monographs are used worldwide by research scientists, public health authorities and international regulatory agencies. IARC classifies carcinogenic agents as follows: – Group 1: the agent is carcinogenic to humans (number 108 agents) (sufficient evidence
of carcinogenicity to humans, epidemiologic evidence, occupational exposure, and animal studies. Strong evidence that the agent acts through relevant mechanisms of carcinogenicity to humans). – Group 2A: The agent is probably carcinogenic to humans (number of agents 66)
(limited evidence of carcinogenicity to humans. Sufficient evidence of carcinogenicity in experimental animals. Strong evidence that the carcinogenesis is mediated by mechanisms that are laso operate in humans) – Group 2B: The agent is possibly carcinogenic to humans (number of agents 248)
(limited evidence in humans. Less than sufficient evidence in experimental animals. Inadequate evidence in humans but sufficient or limited in experimental animals). – Group 3: The agent is not classifiable as to its carcinogenicity to humans (number of
agents 515) (Inadequate evidence in humans. Inadequate or limited to experimental animals. Mechanisms of carcinogenesis in animals does not operate in humans). – Group 4: The agent is probably not carcinogenic to humans (group 4 is not used,
negative evidence of carcinogenicity, contains only one chemical, caprolactam).
The National Toxicology Program (USA) for Long-term Cancer Studies of Suspected Chemicals
The National Toxicology Program (NTP) was established in 1978 by the Secretary of Health and
Human Services (U.S.A.) to coordinate toxicology research and testing of potential hazardous
chemicals. The NTP supports national public health programmes by initiating research designed
to understand the physiological, metabolic and genetic basis of chemical toxicity. Among the
responsibilities of NTP are in vitro and in vivo toxicity testing of suspected chemical carcinogens,
broadening the spectrum of toxicological information on known hazardous chemicals, developing
and validating toxicologic assay systems and rapidly communicating test results to government
agencies with regulatory responsibilities as well as to medical and scientific communities.12
The concept of testing chemical carcinogens in experimental animals as a surrogate for human
risk was formulated in 1960 by the National Cancer Institute (Director Dr. K. Endicott). The NTP
tumor bioassay system in rats and mice has become the universally accepted standard for rodent
toxicity tests. Also, the NTP has added numerous in vivo non-cancer assays, both chronic and
sub-chronic, to the toxicological evaluation including metabolic fate of the chemical, tissue
distribution, specific organ toxicity, neurotoxicity, reproductive failure and teratology. The
growth of molecular genetics has stimulated the NTP to initiate efforts into development of
potentially new assays based upon transgenic technology that will extent understanding of the
metabolic mechanisms of chemical toxicity down to the level of the gene.12 Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

The National Toxicology Program started publishing the Reports of Carcinogens in 1980, and the
last one is the 11th Report (January 2005). The 11th Report has a total of 246 entries, of which 58
are known to be human carcinogens and 188 reasonably anticipated to be human carcinogens.13
(http://ntp.niehs.nih.gov/?objectid=47B37760-F1F6-975E7C150022B9C93B5A6 )
The criteria used by the NTP for listing an agent, substance, mixture, or exposure circumstance
in the Reports of Carcinogens (RoC) are as follows:
1. Known To Be Human Carcinogen: There is sufficient evidence of carcinogenicity from
studies in humans, which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer. 2. Reasonably Anticipated To Be Human Carcinogen: There is limited evidence of
carcinogenicity from studies in humans which indicates that causal interpretation is
credible, but that alternative explanations, such as chance, bias, or confounding factors,
could not adequately be excluded,
2a. there is sufficient evidence of carcinogenicity from studies in experimental
animals, which indicates there is an increased incidence of malignant and/or a
combination of malignant and benign tumors (1) in multiple species or at multiple tissue
sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to
incidence, site, or type of tumor, or age at onset
2b. there is less than sufficient evidence of carcinogenicity in humans or laboratory
animals; however, the agent, substance, or mixture belongs to a well-defined,
structurally related class of substances whose members are listed in a previous Report on
Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a
human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans. The NTP considers that its studies, regarding carcinogenicity to humans or experimental animals, are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms which
do not operate in humans and would therefore not reasonably be anticipated to cause cancer in
humans. This evidence can include traditional cancer epidemiology studies, data from clinical
studies, and/or data derived from the study of tissues or cells from humans exposed to the
substance in question that can be useful for evaluating whether a relevant cancer mechanism is
operating in people.13
Other Organizations and Systems for Classification and Evaluation of Chemical Carcinogens
The Globally Harmonized System of Classification and labeling of Chemicals (GHS) is a United
Nations (UN) initiative to attempt to harmonize the different systems of assessing chemical risk
which currently exist (as of March 2009) around the world. It classifies carcinogens into two
categories, of which the first may be divided again into subcategories if so desired by the
competent regulatory authority:
– Category 1: known or presumed to have carcinogenic potential for humans
– Category 1A: the assessment is based primarily on human evidence
– Category 1B: the assessment is based primarily on animal evidence
– Category 2: suspected human carcinogens
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The Revised third edition of Globally Harmonized System of Classification and Labelling of
Chemicals (GHS) was published in July 2009.
(http://www.unece.org/thans/danger/publi/ghs/ghs_rev03/03files_e.html )
The American Conference of Governmental Industrial Hygienists (ACGIH)
The ACGIH is a private organization in the United States, best known for its publication of
threshold limit values (TLVs) for occupational exposure and monographs on workplace chemical
hazards. The ACGIH assesses carcinogenicity as part of wider assessment of the occupational
hazards of chemicals. The ACGIH has the following classification (http://www.acgih.org). – Group A1: Confirmed human carcinogen
– Group A2: Suspected human carcinogen
– Group A3: Confirmed animal carcinogen with unknown relevance to humans
– Group A4: Not classifiable as a human carcinogen
– Group A5: Not suspected as a human carcinogen

The European Union on Classification and Evaluation of Chemical Carcinogens
The European Union has its own classification of carcinogens which is part of the Directive for
Dangerous Substances and the Dangerous Preparations Directive. It consists of three categories
of carcinogenic agents:
Directive 67/548/EEC on approximation of laws, regulations and administrative provisions
relating to the classification, packaging and labeling of dangerous substances, Directive
2001/59/EC adapting to technical progress for the 28th time Council Directive 67/548/EEC “on
the approximation of the laws, regulations and administrative provisions relating to the
classification, packaging and labelling of dangerous substances”, (Offic J Eur Commun
21.8.2001.L.225/1). The EU collected computerized data on chemical carcinogens and their evaluation followed the IARC list for legislative purposes.15-19 The new regulations about dangerous chemicals in the European Union have changed with the new regulation of REACH (Registration, Evaluation and Authorization of Chemicals, 2006). Hazard assessment of carcinogens for the REACH system can follow various techniques, including QSARs (Quantitative Structure-Activity Relationships), transgenic mouse assays and other alternative methodologies. 20-22 There are recent developments and parallel discussions of how to assess carcinogenicity of chemicals in Europe. The European center for Ecotoxicology and Toxicology of Chemicals (ECETOX) and the European Environmental Mutagen Society (EEMS) discussed new concepts of thresholds in mutagenesis and carcinogenesis within the EUROTOX Congress (Budapest, Sept. 2002) and in other recent conferences.23, 24 The classification of carcinogens, according to the EU, consists of three categories of carcinogenic agents: – Category 1: Substances known to be carcinogenic to humans.
– Category 2: Substances which should be regarded as if they are carcinogenic to humans.
– Category 3: Substances which cause concern for humans, owing to possible carcinogenic
effects but in respect of which the available information is not adequate for making a satisfactory assessment. This assessment scheme of the European Union is being phased out in favor of the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations, to which it is very close in category definitions. Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

The Carcinogenic Potency Project (CPDB)
The Carcinogenic Potency Project started in 1980 by Professors Bruce Ames and Lois Swirsku
Gold (Berkeley, University of California). The project publishes regular updates of their results.
The CPDB has contacted 6540 chronic animal cancer tests on 1547 chemicals for their
carcinogenic potency, expressed as TD50, and its statistical significance in rats, mice, hamsters,
dogs, and nonhuman primates. (http://potency.berkeley.edu )
Scandinavian Countries and Carcinogen Classification
Scandinavian countries are very active for decades in setting standards for carcinogenic agents
in the working environment aiming for the protection of workers. Carcinogen classification
approaches and risk assessment methodologies differ between countries.25
In Europe, differences between countries and organizations exist in terms of how chemical
carcinogenicity is evaluated, how risk assessments are performed and how occupational
exposure limits (OELs) are established.26 Differences in cancer classification exist in part due to
differences in the ultimate purpose of classification and to the relative importance of different
types of data. For example, there are differences in how some scientists extrapolate
carcinogenic data from animal studies to human data, or interpret mechanistic data, or characterize benign and malignant tumour. But the various groups of experts tend to agree on classification of chemicals with good evidence of carcinogenicity in humans, and agree less on classification or limited evidence in humans. Most distinguish between genotoxic and non-genotoixc chemicals when conducting risk assessment. Also, risk assessment approaches include other factors and selection criteria, such as health vs technology-based exposure limits, technology feasibility and socio-economic factors.27-30 The differences on carcinogenic classification of certain chemicals (acrylonitrile, asbestos, benzene, chloroform, cadmium, etc) among IARC, European Union. Germany, Netherlands,
Sweden and Norway are presented in the following Table 1.
Table 1. Differences on carcinogenic classification of certain chemicals in various countries,
IARC and the European Union.
European
Netherlands Sweden
nc: not classified. Acetonitrile and 1,2-Dichloroethylene are classified as dangerous, but not carcinogenic, by the EU and Sweden. Source: ACGIH 1996, DFG 1999, IARCH 1999, SNCI 1999. Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

Conclusions
Identification, classification and risk assessment of carcinogenic chemicals by international
organizations and national agencies of health and safety in the working environment, have been
advanced in recent years. Despite the differences in interpreting the results of carcinogenic
studies, there are general agreements on the classification of most chemicals and preventative
actions to restrict or avoid completely the use or exposure to carcinogens in the natural
environment and especially under occupational condition in the workplaces.
References
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their implications for cancer prevention and treatment. Cancer Res 48: 4135-4143, 1988. 2. Barrett JC, Wiseman RW. Cellular and molecular mechanisms of multistep carcinogenesis: relevance to carcinogen risk assessment. Environ Health Perspect 76: 65-70, 1987. 3. Barrett JC, Shelby MD. Mechanisms of human carcinogens. Progr Clin Res 374: 415-434, 4. Wogan GN, Hecht SS, Felton JS,. Conney AH, Loeb LA. Environmental and chemical carcinogenesis. Semin Cancer Biol 14: 473-486, 2004. 5. Irigaray P, Belpomme D. Basic properties and molecular mechanisms of exogenous chemical carcinogens. Carcinogenesis 2009 [Epub ahead of print]. 6. Belpomme D, Irigaray P, Hardell L, Clapp R, Montagnier L, Epstein S, Sasco AJ. The multitude and diversity of environmental carcinogens. Environ Res 105: 414-429, 2007. 7. Irigaray P, Newby JA, Clapp R, Hardell L, Howard V, Montagnier L, Epstein S, Belpomme D. Lifestyle-related factors and environmental agents causing cancer: an overview. Biomed Pharmacother 61: 640-658, 2007. 8. Clapp RW, Jacobs MM, Loechler EL. Environmental and occupational causes of cancer: new evidence 2005-2007. Rev Environ Health 23: 1-37, 2008. 9. Montesano R, Hall J. Environmental causes of human cancer. Eur J cancer 37: 67-87, 2001. 10. International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vols 1-97 (until 2009). IARC publications, Lyon, France (http://monographs.iarc.fr ). 11. IARC. Preamble to the IARC Monographs and Related Publications (http://monographs.iarc.fr/ENG/Preamble/currenta1background0706.php) 12. National Toxicology Program. Compendium of abstracts form the long-term cancer studies reported by the National Toxicology Program from 1976 to 1992. Environ Health Perspect 101 (Suppl. 1): 1-294, 1993. 13. Hoenerhoff MJ, Hong HH, Ton TV, Lahouse SA, Sills RC. A review of the molecular mechanisms of chemically induced neoplasia in rat and mouse models in National Toxicology Program Bioassays and their relevance to human cancer. Toxicol Pathol 2009 [Epub ahead of print]. 14. National Toxicology Program. 11th Report on Carcinogens. U.S. Department of Health and human Services, Public Health Service, NTP, January 2005. 15. Bourdeau P, Ott H, Haigh R. The approach of the European communities to the assessment of the carcinogenic risk of environmental chemicals, in particular artificial colouring. IARC Sci Publs, 1979 (25):101-109, 1979. 16. Skov T, Hermind B, Lynge E. Legislation by the European Community on carcinogens. Pharmacol Toxicol 72 (Suppl. 1): 155-160, 1993. 17. Terracini B. Cancer hazard identification and qualitative risk assessment. Sci Total Environ 18. Soulat JM, Pujol M. Development of the occupational carcinogen legislation in he European Community. Bull Cancer 84: 199-205, 1997 (in French). 19. Pratt JS, Barron T. Regulatory recognition of indirect genotoxicity mechanisms in the European Union. Toxicol Lett 140: 53-62, 2003. Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

20. Louekari K, Sihvonen K, Kuittinen M, Somnes V. In vitro tests within the REACH information
strategies. Altern Lab Anim 34: 377-386, 2006. 21. Combes R, Grindon C, Cronin MT, et al. Integrated decision-tree testing strategies for mutagenicity and carcinogenicity with respect to the requirements of the EU REACH legislation. Altern Lab Anim 36(Suppl. 1): 43-63, 2008. 22. Wells MY, Williams ES. The transgenic mouse assay as an alternative test method for regulatory carcinogenicity studies- implications for REACH. Regul Toxiol Pharmacol 53:150-155, 2009. 23. Bolt HM, Degen GH. Human carcinogenic risk evaluation, Part II: Contributions of the EUROTOX Specialty Section for Carcinogenesis. Toxicol Sci 81: 3-6, 2004. 24. Bolt HM, Foth H, Hengstler JG, Degen GH. Carcinogenicity categorization of chemicals: New aspects to be considered in a European perspective. Toxicol Lett 151: 29-41, 2004. 25. Norseth T. Regulatory aspects of carcinogens at work in the Scandinavian countries. Med Lav 26. Seeley MR, Tonner-Navarro LE, Beck BD, Deskin R, Feron VJ, Johanson G, Bolt HM. Procedures for health risk assessment in Europe. Regul Toxicol Pharmacol 34: 153-169, 2001. 27. Whysner J, Williams GM. International cancer risk assessment: the impact of biological mechanisms. Regul Toxicol Pharmacol 15: 41-50, 1992. 28. Sanner T, Dybing E, Kroese D, Roelfzema H, Hardeng S. Carcinogen classification systems: Similarities and differences. Regul Toxicol Pharmacol 23: 128-138, 1996. 29. Moolenaar RJ. Default assumptions in carcinogen risk assessment used by regulatory agencies. Regul Toxicol Pharmacol 20: S135-S141, 1994. 30. Health Council of the Netherlands (HCN). Risk assessment of carcinogenic chemicals in the Netherlands. Regul Toxicol Pharmacol 19:14-30, 1994. Science advances on Environment, Toxicology & Ecotoxicology issues (www.chem-tox-ecotox.org)

APPENDIX
IARC Overall Evaluations of Carcinogenicity to Humans
Group 1: Carcinogenic to humans
Agents and groups of agents (108 agents up to 2009)

4-Aminobiphenyl [CAS No.: 92-67-1]
Aristolochic acid
(NB: Overall evaluation upgraded from 2A to 1 based on mechanistic and other relevant data)
Arsenic [7440-38-2]
(NB: This evaluation applies to the group of compounds as a whole and not necessarily to all
individual compounds within the group)
Asbestos [1332-21-4]
Azathioprine [446-86-6]
Benzene [71-43-2]
Benzidine [92-87-5]
Benzo[a]pyrene [50-32-8]
(NB: Overall evaluation upgraded from 2B to 1 based on mechanistic and other relevant data)
Beryllium [7440-41-7] and beryllium compounds
N,N-Bis(2-chloroethyl)-2-naphthylamine (Chlornaphazine) [494-03-1]
Bis(chloromethyl)ether [542-88-1] and chloromethyl methyl ether [107-30-2] (technical-grade)
1,3-Butadiene [106-99-0]
1,4-Butanediol dimethanesulfonate (Busulphan; Myleran) [55-98-1]
Cadmium [7440-43-9] and cadmium compounds
Chlorambucil [305-03-3]
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU; Semustine) [13909-09-
6]
Chromium[VI]
Cyclophosphamide [50-18-0] [6055-19-2]
Cyclosporine [79217-60-0]
Diethylstilboestrol [56-53-1]
Dyes metabolized to benzidine
(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)
Epstein-Barr virus
Erionite [66733-21-9]
Estrogen-progestogen menopausal therapy (combined)
Estrogen-progestogen oral contraceptives (combined)
(NB: There is also convincing evidence in humans that these agents confer a protective effect
against cancer in the endometrium and ovary)
Estrogens, nonsteroidal
(NB: This evaluation applies to the group of compounds as a whole and not necessarily to all
individual compounds within the group)
Estrogens, steroidal
(NB: This evaluation applies to the group of compounds as a whole and not necessarily to all
individual compounds within the group)
Estrogen therapy, postmenopausal
Ethanol [64-17-5] in alcoholic beverages (Vol. 96; in preparation)
Ethylene oxide [75-21-8]
(NB: Overall evaluation upgraded from 2A to 1 based on mechanistic and other relevant data)
Etoposide [33419-42-0]
(NB: Overall evaluation upgraded from 2A to 1 based on mechanistic and other relevant data)
Etoposide in combination with cisplatin and bleomycin
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Formaldehyde [50-00-0]
Gallium arsenide [1303-00-0]
[Gamma Radiation: see X- and Gamma (g)-Radiation]
Helicobacter pylori (infection with)
Hepatitis B virus (chronic infection with)
Hepatitis C virus (chronic infection with)
Human immunodeficiency virus type 1 (infection with)
Human papillomavirus types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 an 60
(NB: The HPV types that have been classified as carcinogenic to humans can differ by an order of
magnitude in risk for cervical cancer)
Human T-cell lymphotropic virus type I
Melphalan [148-82-3]
8-Methoxypsoralen (Methoxsalen) [298-81-7] plus ultraviolet A radiation
Methylenebis(chloroaniline) (MOCA) [101-14-4]
(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)
MOPP and other combined chemotherapy including alkylating agents
Mustard gas (Sulfur mustard) [505-60-2]
2-Naphthylamine [91-59-8]
Neutrons
(NB: Overall evaluation upgraded from 2B to 1 with supporting evidence from other relevant
data)
Nickel compounds
N'-Nitrosonornicotine (NNN) [16543-55-8] and 4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-
butanone (NNK) [64091-91-4]
(NB: Overall evaluation upgraded from 2B to 1 based on mechanistic and other relevant data)
[Oestrogen: see Estrogen]
Opisthorchis viverrini (infection with)
[Oral contraceptives, combined estrogen-progestogen: see Estrogen-progestogen oral
contraceptives (combined)]
Oral contraceptives, sequential
Phenacetin [62-44-2]
(NB: Overall evaluation upgraded from 2A to 1 with supporting evidence from other relevant
data)
Phosphorus-32, as phosphate
Plutonium-239 and its decay products (may contain plutonium-240 and other isotopes), as
aerosols
Radioiodines, short-lived isotopes, including iodine-131, from atomic reactor accidents and
nuclear weapons detonation (exposure during childhood)
Radionuclides, a-particle-emitting, internally deposited
(NB: Specific radionuclides for which there is sufficient evidence for carcinogenicity to humans
are also listed individually as Group 1 agents)
Radionuclides, b-particle-emitting, internally deposited
(NB: Specific radionuclides for which there is sufficient evidence for carcinogenicity to humans
are also listed individually as Group 1 agents)
Radium-224 and its decay products
Radium-226 and its decay products
Radium-228 and its decay products
Radon-222 [10043-92-2] and its decay products
Schistosoma haematobium (infection with)
Silica [14808-60-7], crystalline (inhaled in the form of quartz or cristobalite from occupational
sources)
Solar radiation
Talc containing asbestiform fibres
Tamoxifen [10540-29-1]
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(NB: There is also conclusive evidence that tamoxifen reduces the risk of contralateral breast
cancer)
2,3,7,8-Tetrachlorodibenzo-para-dioxin [1746-01-6]
(NB: Overall evaluation upgraded from 2A to 1 with supporting evidence from other relevant
data)
Thiotepa [52-24-4]
Thorium-232 and its decay products, administered intravenously as a colloidal dispersion of
thorium-232 dioxide
ortho-Toluidine [95-53-4]
Treosulfan [299-75-2]
Vinyl chloride [75-01-4]
X- and Gamma (g)-Radiation
Mixtures
Aflatoxins (naturally occurring mixtures of) [1402-68-2]
Alcoholic beverages
Areca nut
(NB: Overall evaluation based on human data, animal data, and mechanistic and other relevant
data)
Betel quid with tobacco
Betel quid without tobacco
Coal-tar pitches
Coal-tars [8007-45-2]
Household combustion of coal, indoor emissions from
Mineral oils, untreated and mildly treated
Phenacetin, analgesic mixtures containing
Plants containing aristolochic acid
Salted fish (Chinese-style)
Shale-oils [68308-34-9]
Soots
Tobacco, smokeless
Wood dust
Exposure circumstances
Aluminium production
Arsenic in drinking-water
Auramine production
Boot and shoe manufacture and repair
Chimney sweeping
Coal gasification
Coal-tar distillation
Coke production
Furniture and cabinet making
Haematite mining (underground) with exposure to radon
Involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke)
Iron and steel founding
Isopropyl alcohol manufacture (strong-acid process)
Magenta production
Painter (occupational exposure as a)
Paving and roofing with coal-tar pitch
Rubber industry
Strong-inorganic-acid mists containing sulfuric acid (occupational exposure to)
Tobacco smoking and tobacco smoke
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IARC: Group 2A
(number of agents 66)
(http://monographs.iarc.fr/ENG/Classification/crthgr02a.php)
The agent is probably carcinogenic to humans (limited evidence of carcinogenicity to humans.
Sufficient evidence of carcinogenicity in experimental animals. Strong evidence that the
carcinogenesis is mediated by mechanisms that are also operate in humans).
Selection of chemicals
Acrylamide[79-06-1]
(NB: Overall evaluation upgraded from 2B to 2A with supporting evidence from other relevant
data)
Adriamycin[23214-92-8]
(NB: Overall evaluation upgraded from 2B to 2A with supporting evidence from other relevant
data)
Azacitidine[320-67-2]
(NB: Overall evaluation upgraded from 2B to 2A with supporting evidence from other relevant
IARC: Group 2B
(number of agents 248)
(http://monographs.iarc.fr/ENG/Classification/crthgr02b.php )
The agent is possibly carcinogenic to humans (limited evidence in humans. Less than sufficient
evidence in experimental animals. Inadequate evidence in humans but sufficient or limited in
experimental animals).
Selection of the first chemicals (Group 2B)
Acetaldehyde [75-07-0]
Acetamide [60-35-5]
Acrylonitrile [107-13-1]
AF-2 [2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide] [3688-53-7]
Aflatoxin M1 [6795-23-9]
para-Aminoazobenzene [60-09-3]
ortho-Aminoazotoluene [97-56-3]
2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole [712-68-5]
Amsacrine [51264-14-3]
ortho-Anisidine [90-04-0]
Antimony trioxide [1309-64-4],
IARC: Group 3
(number of agents 515)
(http://monographs.iarc.fr/ENG/Classification/crthgr03.php) The agent is not classifiable as to its carcinogenicity to humans (Inadequate evidence in
humans. Inadequate or limited to experimental animals. Mechanisms of carcinogenesis in
animals does not operate in humans).
Selection of first chemicals (Group 3)
Acenaphthene [83-32-9]
Acepyrene (3,4-dihydrocyclopenta[cd]pyrene) [25732-74-5]
Aciclovir [59277-89-3]
Acridine orange [494-38-2]
Acriflavinium chloride [8018-07-3]
Acrolein [107-02-8]
Acrylic acid [79-10-7]
Acrylic fibres
Actinomycin D [50-76-0], etc.

Source: http://chem-tox-ecotox.org/wp/wp-content/uploads/2010/04/03-Carcinogenic-Chemicals-18_04_2010.pdf