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 heritable manner the expressional integrity of DNA. This usually involves measurement of the ability of a chemical to induce chromosomal aberrations or gene mutations in cultured cells, coupled to confirmation of genetic toxicity in rodents. The results of such assays, coupled to assessment of the chemical structure of the agent for sites of actual or potential electrophilicity, provide a major and primary input to estimation of whether a rodent carcinogen is operating by a genotoxic or a non-genotoxic mechanism. The extent and sites of carcinogenesis also contribute to this decision. In cases where the mechanism of action of a carcinogen is to be studied in detail, additional assessments of genetic toxicity can be made in the species/gender/tissue subject to carcinogenesis. Suitable assays include measurements of DNA adducts (e.g., 32P 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 and taxol are discussed to illustrate these concepts. The present need is 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 carcinogenic action.
Ashby
J
J
Zeneca Central Toxicology Laboratory, Nr Macclesfield, Cheshire, UK.
D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D017239:Paclitaxel / Q000633:toxicity; D011956:Receptors, Cell Surface / Q000502:physiology*
D000814:Aniline Compounds; D002273:Carcinogens; D009153:Mutagens; D011956:Receptors, Cell Surface; D005047:Etoposide; C003898:2-anisidine; D017239:Paclitaxel