3.6.2.1.For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional considerations (weight of evidence). In certain instances, route-specific classification may be warranted, if it can be conclusively proved that no other route of exposure exhibits the hazard.
Table 3.6.1
Hazard categories for carcinogens
Categories
Criteria
CATEGORY 1:
Known or presumed human carcinogens
A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:
Category 1A:
Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or
Category 1B:
Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.
The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:
— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or
— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).
In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.
CATEGORY 2:
Suspected human carcinogens
The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.
3.6.2.2.Specific considerations for classification of substances as carcinogens
3.6.2.2.1.Classification as a carcinogen is made on the basis of evidence from reliable and acceptable studies and is intended to be used for substances which have an intrinsic property to cause cancer. The evaluations shall be based on all existing data, peer-reviewed published studies and additional acceptable data.
3.6.2.2.2.Classification of a substance as a carcinogen is a process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.
3.6.2.2.3.Strength of evidence involves the enumeration of tumours in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the substance and an increased incidence of tumours. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. The terms ‘sufficient’ and ‘limited’ have been used here as they have been defined by the International Agency for Research on Cancer (IARC) and read as follows:
(a)Carcinogenicity in humans
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 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 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.
(b)Carcinogenicity in experimental animals
Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:
—sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex 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, or when there are strong findings of tumours at multiple sites;
—limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.
3.6.2.2.4.Additional considerations (as part of the weight of evidence approach (see 1.1.1)). Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors need to be considered that influence the overall likelihood that a substance poses a carcinogenic hazard in humans. The full list of factors that influence this determination would be very lengthy, but some of the more important ones are considered here.
3.6.2.2.5.The factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumour findings and the other factors in a case-by-case manner.
3.6.2.2.6.Some important factors which may be taken into consideration, when assessing the overall level of concern are:
(j)the possibility of a confounding effect of excessive toxicity at test doses;
(k)mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity.
Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.
3.6.2.2.7.A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g. for benzidine congener dyes.
3.6.2.2.8.The classification shall take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumours at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.
3.6.2.2.9.It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e. structure activity relationship, is taken into consideration when undertaking classification.
