Response of the ke test to NCI/NTP-screened chemicals. I. Non-genotoxic carcinogens and genotoxic non-carcinogens

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Abstract
The responses of a physico-chemical carcinogen-screening test, the ke test, to 46 rodent carcinogens and 20 putative non-carcinogens that had been screened in long-term two-species bioassays by the National Cancer Institute/National Toxicology Program are reported. All of the chemicals screened are those that yield mutagenicity responses in the Ames Salmonella/microsome test that are either equivocal or contrary to the rodent carcinogenicity responses. The electron attachment rate constants, kes, of the test chemicals in cyclohexane at 21°C were measured using a pulse-conductivity technique. The kes of 27 of the 46 rodent carcinogens (59%) are equal or greater than the diffusion-controlled ke of carbon tetrachloride, which is regarded as the boundary between a positive and negative response; the kes of 8 of the 20 mutagenic non-carcinogens (40%) are less than diffusion-controlled. If the boundary between positive and negative ke responses is decreased to half the diffusion-controlled ke, six additional carcinogens yield a positive ke response which increases the ke test sensitivity to 72% while the specificity to non-carcinogens remains at 40%. Comparison of these kes with measures of the chemicals' electrophilicity that had been inferred from chemical structure indicates that ke provides a markedly different measure of electrophilicity and one that complements the Ames Salmnella assay. The use of the ke test as an analytical tool to indicate the presence of electron-attaching impurities in solvents such as benzene is discussed, as is the sensitivity of the ke test to rodent-liver carcinogens.