Bacterial-mammalian mutagenesis correlations: mechanistic significance for carcinogenesis

Chemicals evaluated for their carcinogenic potential in the IARC Monographs (Supplement 4 to volumes 1-29)2 are used to compare their response in bacterial and mammalian cell mutagenicity assays in vitro. Simultaneous positive and negative test results in both systems showed a high degree of parallelism. Several carcinogens active in animals/humans, however, were not detected in either assay. The possibility of a quantitative extrapolation of bacterial mutagenesis data to processes occurring in intact mammals was further examined. Published covalent binding indices in rat liver DNA for 36 compounds were found to be correlated with their mutagenic effects in the Salmonella/liver-microsome test; several compounds deviated from this proportionality. The quantitative relationship between carcinogenicity in rodents (TD50) and mutagenicity was examined, using 10 alkylating agents. Mutagenicity in S. typhimurium TA100 strain (plate and liquid assays) showed no correlation with carcinogenic potency. However, there was a positive relationship between TD50 values and the initial ratio of N-7-alkyl/O6-alkyl guanine formed (predicted) after reaction with double-stranded DNA in vitro.