Quantitative relationship between mutagenic potency in the Ara test of Salmonella typhimurium and carcinogenic potency in rodents. A study of 11 direct-acting monofunctional alkylating agents.

This work attempted to derive a quantitative relationship between mutagenicity and carcinogenicity by examining the association between mutagenic potency in the Ara test of Salmonella typhimurium and carcinogenic potency in rodents. Mutagenesis was monitored by selecting forward mutations to L-arabinose resistance. Lethality was measured at equivalent experimental conditions to those of mutant yield by using a mixed population of a pair of isogenic strains distinguished by their differential nutritional requirements. The study was carried out with a group of 11 direct-acting monofunctional alkylating agents, which failed to show any quantitative correlation in the histidine reverse-mutation test. Our data suggest that the mutagenic efficiency of the compounds is directly proportional to the magnitude of the maximum yield of L-arabinose resistance mutants and inversely proportional to the dose and the number of lethal hits at which the maximum yield occurs. A highly significant correlation (r10 = 0.86, P less than 0.01) was found between the mutagenic efficiencies of the compounds in the Ara test and their carcinogenic potencies in rodents, expressed as TD50 ('tumor dose' 50) values. The result suggests that the Ara forward-mutation test of S. typhimurium might be capable of reflecting the relative potency of animal carcinogens, at least when confined to particular chemical classes. A more generic and definitive conclusion about the predictive value of the Ara test would require this analysis to be extended to other types of genotoxic carcinogens.