Correlation of carcinogenic potency with mouse-skin 32P-postlabeling and muta-Rmouse lac Z- mutation data for DMBA and its K-region sulphur isostere: comparison with activities observed in standard genotoxicity assays.

Abstract The genotoxicities in vitro and in vivo of the mouse-skin carcinogen 7,12-dimethylbenz[ a ]anthracene (DMBA) have been compared with those of its weakly carcinogenic 4,5-sulphyr analogue, 6,11-dimethylbenzo[ b ]naphtho-[2,3- d ]thiophene (S-DMBA). The only datasets that correlated with the relative carcinogenicity of these agents to the skin were those conducted using topically exposed mouse skin. Thus, both chemicals induced lacZ − mutations in the skin of lacZ + transgenic mice, and both produced DNA adducts on mouse-skin DNA as assessed using the 32 P-postlabeling technique. In each case, DMBA gave a stronger response than did S-DMBA. In contrast to these responses, only DMBA was active in the mouse bone-marrow micronucleus assay and in the C3H10T1/2 in vitro cell transformation assay. Both chemicals were mutagenic to Salmonella and of approximately equal potency. The molecular geometry of DMBA and S-DMBA are compared, and divergent CASE predictions of activity in the Salmonella assay and skin-painting bioassay are discussed. The importance of conducting predictive genotoxicity assays in systems close to those in which carcinogenicity is to be assessed is emphasized by these data.