Role of increased DNA replication in the carcinogenic risk of nonmutagenic chemical carcinogens

DNA replication is not an error-free process; therefore induction of cell proliferation with the requisite increase in DNA replication may be an important mechanism by which carcinogenesis can be induced by chemicals. Data presented in this overview indicate a positive association between increased cell proliferation and carcinogenesis, and illustrate the value of performing mechanistic studies such as cell proliferation assays in conjunction with short-term tests to further investigate the results of cancer bioassays. Whereas chemically-induced cell proliferation per se may not be sufficient to induce carcinogenesis, it creates a favorable environment for tumor development. There are two types of chemically-induced cell proliferation, mitogenic and cytotoxic, and they have different consequences regarding the mechanism of carcinogenesis of a chemical. Mitogenic chemical such as phenobarbital, oxazepam, and the peroxisome proliferating agents exert a short-term cell proliferative response that may exert its primary effect in carcinogenesis at the promotion stages. It is not clear at what stage(s) cytotoxic agents such as methapyrilene, alpha(2u)-globulin inducers or saccharin exert their effects in carcinogenesis. A confounding factor in evaluation of cell proliferation in risk assessments is the production of chemical specific pleiotropic effects that may contribute to the carcinogenicity of a chemical. It is clear that mechanistic studies performed 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,