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A total of 63 chemicals were tested for mutagenicity in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, and Escherichia coli WP2 uvrA in a four-laboratory study. Sixty of the chemicals had been tested for carcinogenicity by the National Cancer Institute or the National Toxicology Program. All chemicals were tested for mutagenicity without metabolic activation and with liver S-9 preparations from uninduced and Aroclor 1254-induced F344 rats, B6C3F1 mice, and Syrian hamsters. The intra- and interlaboratory reproducibility of the Salmonella assay with regard to the overall judgment of mutagenic or nonmutagenic was good. The results in the E coli strain, however, exhibited a high degree of variability between laboratories. With one or two exceptions, the mutagens were detected with S-9 preparations from all three species. The uninduced liver S-9 preparations did not activate any chemicals to mutagens that were not also activated by induced S-9, but some chemicals were detected as mutagens only when induced S-9 was used. A positive mutagenic response in Salmonella was predictive of carcinogenicity 69% of the time; when equivocal carcinogens and borderline mutagens were included, the predictivity increased to 83%. Conversely, 76% of the carcinogens were mutagens. When the equivocal carcinogens were included, the proportion dropped to 75%. Relatively few chemicals (18%) were mutagenic in E coli. Not all the carcinogens induced tumors in both rats and mice, and the species-specific carcinogenicity could not be predicted from the S-9-specific mutagenicity.

No abstract

We have previously described a very sensitive and efficient bacteria] test designed to detect chemical carcinogens as mutagens. Chloroacetaldehyde is mutagenic in this system and is of interest because it is a possible metabolite in mammals of the large volume industrial chemicals 1,2dichloroethane (ethylene dichloride)(3.5 billion kg/ yr, U.S.) and vinyl chloride (2.5 billion kg/yr, U.S.), and of the antineoplastic agent cyclophosphamide. Chloroacetaldehyde reverts a new Salmoneira bacterial tester strain (TAlOO). Chloroacetaldehyde is shown to be hundreds of times more effective in reversion of TA100 than is chloroethanol (ethylene chlorohydrin), a known metabolic precursor of chloroacetaldehyde and a possible metabolite of dichloroethane and vinyl chloride, or than vinyl chloride, which is itself mutagenic for TAIOO. Chloroethanol is shown to be activated by rat (or human) liver homogenates to a more highly mutagenic form with reversion properties similar to chloroacetaldehyde. Reversion jwperties of cyclophosphamide after in vitro metabolic activation suggest that chloroacetaldehyde is not the active mutagenic form of this antineoplastic drug. We have previously described a rapid, sensitive bacterial test designed to detect chemical carcinogens as mutagens (1-7). The test utilizes a special set of histidine mutants of Salmonella typhimurium for reversion, and a rat (or human) microsomal system for metabolic conversion of carcinogens to their active forms. The standard bacterial tester strains have been described in detail (1, 3, 5) and contain histidine missense (TA1535) or frameshift (TA1537, TA1538) mutations. The strains also contain uvrB and rfa (deep rough) mutations which greatly increase their sensitivity to reversion by a variety of carcinogens: uvrB causes loss of the excision repair system and rfa causes loss of the lipopolysaccharide permeability barrier. The compound to be tested, the bacterial tester strain, and when required rat (or human) liver microsomal enzymes, are combined on a petri dish and after incubation at 370 for 2 days histidine revertants are scored.Hundreds of carcinogens and noncarcinogens have been tested using the Salmonella/mammalian-microsome bacterial test system in this laboratory (1-13) and in many laboratories throughout the world. We (J.M. and B.N.A.) are currently preparing a compilation of these results, and so far about 85% of the known carcinogens tested have been detected as mutagens in the test, and very few (<10%) noncarcinogens (many close relatives of carcinogens have been tested) are positive. This and other evidence showing that a high percentage of carcinogens are mutagens is most easily explained if carcinogens cause cancer by somatic mutation (4). We believe there is a high probability that chemicals found to be mutagens in the Salmonella test will turn out to be carcinogens.We have recently introduced two new tester strains (TA100 and TA98) which were constructed by transferring to our standard tester strains TA1535 and TA1538 respectively, a res...