GENETIC TOXICITY IN RELATION TO RECEPTOR-MEDIATED CARCINOGENESIS

There is growing agreement on the types and number of assays required to assess the ability of a chemical to mutate or to affect in a herita ble manner the expressional integrity of DNA. This usually involves me asurement of the ability of a chemical to induce chromosomal aberratio ns or gene mutations in cultured cells, coupled to confirmation of gen etic toxicity in rodents. The results of such assays, coupled to asses sment of the chemical structure of the agent for sites of actual or po tential electrophilicity, provide a major and primary input to estimat ion of whether a rodent carcinogen is operating by a genotoxic or a no n-genotoxic mechanism. The extent and sites of carcinogenesis also con tribute to this decision. In cases where the mechanism of action of a carcinogen is to be studied in detail, additional assessments of genet ic toxicity can be made in the species/gender/tissue subject to carcin ogenesis. Suitable assays include measurements of DNA adducts (e.g., P -32 post-labelling), assessment of DNA damage using, for example, the single-cell gel electrophoresis (Comet) assay, or the determination of transgenic mutation frequencies in appropriate rodent model systems. The genetic toxicity of o-anisidine, methyl clophenipate, etoposide an d taxol are discussed to illustrate these concepts. The present need i s for high quality genetic toxicity data to be derived and integrated with other relevant toxicological data on a new carcinogen in order to provide an informed estimate its most likely mechanisms of carcinogen ic action.