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Genetic

The current NTP genetic toxicity testing program evolved from a broader testing initiative originally developed as a potential predictor of rodent carcinogenicity based on structure-activity relationships and chemical-induced mechanisms of DNA damage. Analysis of the early, multi-test database revealed that positive results for a chemical in the Salmonella gene mutation assay were highly correlated with carcinogenicity in multiple species/sexes of rodents and at multiple tissue sites (Ashby and Tennant, 1991); data from additional tests did not improve the correlation. Subsequently, studies of the correlation between mutagenicity test data and rodent carcinogenicity showed a strong association between clearly positive results in long-term mouse peripheral blood micronucleus tests and rodent carcinogenicity (Witt et al., 2000). The importance of genetic toxicity test data in assessing exposure hazard for NTP chemicals is underscored by the fact that most organic chemicals (other than hormones) identified by the International Agency for Research on Cancer as human carcinogens are genotoxic, and the vast majority of these are detected by both the Salmonella assay and rodent micronucleus tests (Shelby, 1988; Shelby and Zeiger, 1990). Additional assays may be conducted with certain chemicals to gain further insight into the types of DNA and chromosomal damage induced by a chemical.

References:

Ashby, J., and Tennant, R.W. (1991). Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. 257, 229-306.

Shelby, M.D. (1988). The genetic toxicity of human carcinogens and its implications. Mutat. Res. 204, 3-15.

Shelby, M.D., and Zeiger, E. (1990). Activity of human carcinogens in the Salmonella and rodent bone-marrow cytogenetics tests. Mutat. Res. 234, 257-261.

Witt, K.L., Knapton, A., Wehr, C.M., Hook, G.J., Mirsalis, J., Shelby, M.D., and MacGregor, J.T. (2000). Micronucleated erythrocyte frequency in peripheral blood of B6C3F1 mice from short-term, prechronic, and chronic studies of the NTP Carcinogenesis Bioassay Program. Environ. Mol. Mutagen. 36, 163-194.