ROLE OF INCREASED DNA-REPLICATION IN THE CARCINOGENIC RISK OF NONMUTAGENIC CHEMICAL CARCINOGENS

DNA replication is not an error-free process; therefore induction of c ell proliferation with the requisite increase in DNA replication may b e an important mechanism by which carcinogenesis can be induced by che micals. Data presented in this overview indicate a positive associatio n between increased cell proliferation and carcinogenesis, and illustr ate the value of performing mechanistic studies such as cell prolifera tion assays in conjunction with short-term tests to further investigat e the results of cancer bioassays. Whereas chemically-induced cell pro liferation per se may not be sufficient to induce carcinogenesis, it c reates a favorable environment for tumor development. There are two ty pes of chemically-induced cell proliferation, mitogenic and cytotoxic, and they have different consequences regarding the mechanism of carci nogenesis of a chemical. Mitogenic chemical such as phenobarbital, oxa zepam, and the peroxisome proliferating agents exert a short-term cell proliferative response that may exert its primary effect in carcinoge nesis at the promotion stages. It is not clear at what stage(s) cytoto xic agents such as methapyrilene, alpha(2u)-globulin inducers or sacch arin exert their effects in carcinogenesis. A confounding factor in ev aluation of cell proliferation in risk assessments is the production o f chemical specific pleiotropic effects that may contribute to the car cinogenicity of a chemical. It is clear that mechanistic studies perfo rmed to understand the relationship of sex, species and dose in rodent carcinogenicity assays of chemicals is critical for the extrapolation of such data for human health assessments,