Human Health Risk Assessment for Priority Substances

Appendix B -- Criteria for Classification of Carcinogenicity

Chemicals are classified into six categories on the basis of the following criteria⁹ (modified from those of the International Agency for Research on Cancer):

Group I -- Carcinogenic to Humans

Group I -- Data from adequate epidemiological studies indicate that there is a causal relationship between exposure to a substance and an increased incidence of cancer in humans (i.e., the observed association is unlikely to be due to bias, confounding or chance). Confidence in inferring a causal relationship is increased when the association is strong and observed in several studies, when there is a dose-response relationship, when a reduction in exposure is followed by a reduction in the incidence of cancer or when there are supporting data which indicate that the association is biologically plausible.

Group II-- Probably Carcinogenic to Humans

Group II -- Data from epidemiological studies are inadequate to assess carcinogenicity either because there are few pertinent investigations or because chance, bias or confounding cannot be excluded as a possible explanation for the results. However, there is sufficient evidence of carcinogenicity in animal species (i.e., there is an increased incidence of malignant tumours in multiple species or strains, in multiple experiments with different routes of exposure or dose levels, or the incidence, site or type of tumour or age of onset is unusual). Confidence in the sufficiency of the data from animal studies is increased when there is evidence of a dose-response relationship, supporting results from in vitro studies or a number of limited carcinogenicity bioassays, evidence of structure-activity relationships, genotoxic effects and/or supporting data on a mechanism of carcinogenicity which is operative in humans and animal species. Exceptionally, a compound for which the evidence of carcinogenicity is limited but for which there is a strong supporting dataset (on genotoxicity, for example) which indicates that the compound is likely to be carcinogenic would be included in this category.

Group III -- Possibly Carcinogenic to Humans

Group III.A -- Data from epidemiological studies indicate an association between exposure and human cancer but alternative explanations such as chance, bias or confounding cannot be excluded.

Group III.B -- Data from epidemiological studies are inadequate to assess carcinogenicity. There is some evidence of increased tumour incidence in animals but the data are limited because the studies involve a single species, strain or experiment; study design (i.e., dose levels, duration of exposure and follow-up, survival, number of animals) or reporting is inadequate; the neoplasms produced often occur spontaneously and have been difficult to classify as malignant by histological criteria alone (e.g., lung and liver tumours in mice). The weight of limited evidence indicates that the compound is genotoxic or results are mixed.

Group III.C -- Data from epidemiological studies are inadequate to assess carcinogenicity. There are sufficient data which indicate that the substance is carcinogenic in long-term animal experiments but there are data available which indicate that the aetiology of tumour induction may be epigenetic (for example, there is evidence that tumours occur only at very high doses as a result of tissue damage, that the administered compound acts as a tumour promoter perhaps by increasing the proliferation rate of pre-neoplastic cells and the weight of evidence from a variety of short-term tests indicates that it is not genotoxic).

Group III.D -- Data from experimental studies in animal species indicate that the compound is carcinogenic in one species only and there is suspicion that the results are species- specific but available data on mechanisms of toxicity are insufficient to conclude unequivocally that this is the case.

Group IV -- Unlikely to Be Carcinogenic to Humans

Group IV.A -- There is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies. There is some evidence of carcinogenicity in well-designed and well-conducted carcinogenicity bioassays in animals, but the results are limited (i.e., they are confined to a single study or single species, sex or strain of animals and/or exposure produces a non-statistically significant increase in tumour incidence, compared to unexposed controls).

Group IV.B -- There is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies; there is evidence of carcinogenicity in well-designed and well-conducted carcinogenicity bioassays in animals, but the increased tumour incidence can be confidently (but not necessarily unequivocally) ascribed to species- specific mechanisms of toxicity and/or metabolism which do not appear to be operative in humans. (Generally the weight of evidence indicates that such compounds are not genotoxic).

Group IV.C -- Data from epidemiological studies are inadequate to assess carcinogenicity; there is evidence of carcinogenicity in well-designed and well-conducted carcinogenicity bioassays in animals, but the increased tumour incidence can be confidently (but not necessarily unequivocally) ascribed to species-specific mechanisms of toxicity and/or metabolism which do not appear to be operative in humans. (Generally the weight of evidence indicates that such compounds are not genotoxic).

Group IV.D -- Data from epidemiological studies are inadequate to assess carcinogenicity; there is no evidence of carcinogenicity in well-designed and properly conducted carcinogenicity bioassays in two species of animals.

Group V -- Probably Not Carcinogenic to Humans

Group V.A -- There is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies; there is no evidence of carcinogenicity in adequate studies in two animal species and available data indicate that the compound is not genotoxic.

Group V.B -- There is no evidence of carcinogenicity in sufficiently powerful and well-designed epidemiological studies; data in animal species are inadequate.

Group V.C -- There is inadequate evidence of carcinogenicity in humans but evidence of a lack of carcinogenicity in two species of laboratory animals is strongly supported by a broad range of other relevant data.

Group VI -- Unclassifiable with Respect to Carcinogenicity in Humans

Group VI.A -- Data from epidemiological and/or animal studies are inadequate (i.e., because of major qualitative or quantitative limitations, the studies cannot be interpreted as showing either the presence or absence of carcinogenicity).

Group VI.B -- There are no data on carcinogenicity available for evaluation.

Group VI.C -- Results of epidemiological studies in human populations and experimental studies in animal species are conflicting, without an identifiable mechanistic basis.

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^9.Though criteria for several subgroups of each category are specified, they are presented as representative examples only of possible combinations of results and are not exhaustive. This does not preclude inclusion of a compound in the category for which available data do not precisely fulfil the exact criteria specified in one of the subgroups.