Chemical carcinogen mechanisms of action and implications for testing methodology.

Chemical carcinogens are of two distinct types, DNA-reactive and epigenetic. Testing methodology can be directed toward detecting effects of both types of carcinogen. Carcinogens of the DNA-reactive type are defined by the formation of covalently bound DNA adducts. These chemicals have structures that yield electrophilic reactants either directly or after bioactivation. These agents cause genomic alteration in the structure or function of DNA in the target cell. In addition, these compounds can exert other cellular and tissue epigenetic effects, such as cell proliferation and growth promotion. Carcinogens of the epigenetic (paragenetic) type, in contrast, do not react with DNA, but rather display cellular effects such as neoplasm growth promotion, cytotoxicity, inhibition of tissue growth regulation, peroxisome proliferation, endocrine modification, immunosuppression and/or sustained tissue ischemia that can be the basis for increases in neoplasia. Their chemical structure is such that they do not give rise to a reactive electrophile. The testing methodologies to identify either type follow a Decision Point Approach designed to identify potential carcinogenicity and yield mechanistic information on the production of effects that underlie carcinogenicity. It has 5 stages focusing on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays and finally the application of the accelerated bioassay (ABA). ABA requires 40 weeks and applies the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenic process directed toward developing mechanistic information. The ABA has the potential to replace the chronic bioassay in rodents in some circumstances and can serve as an alternative to a chronic bioassay in a second species.