Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals

Abstract

The effectiveness of four in vitro short-term tests (STT) for genetic toxicity, induction of mutations in Salmonella (SAL) and mouse lymphoma L5178Y cells (MLA), and induction of sister chromatid exchanges (SCE) and chromosome aberrations (ABS) in Chinese hamster ovary cells that are used for predicting rodent carcinogenicity were examined. The in vitro results were compared with the results from 41 rodent carcinogenicity studies performed by the National Toxicology Program. The predictive values of, and interrelationships among, the STT for these 41 chemicals were similar to those previously reported for 73 chemicals and confirm those earlier results [Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R (1987): Science 236:933-941]. Because of this similarity among the two datasets, the chemicals were combined into a single dataset of 114. The results with 114 chemicals show that SAL had the lowest sensitivity (.48) and the highest specificity (.91), whereas MLA had the highest sensitivity (.72) and the lowest specificity (.40). The concordances of the test results with rodent carcinogenicity were .66, .61, .59, and .59, for SAL, ABS, SCE, and MLA, respectively. Salmonella was the most predictive for carcinogenicity; 89% of the chemicals mutagenic in SAL were carcinogenic in rodents, however a negative result in any or all of the STT was not indicative of noncarcinogenicity. The STT results reported here show good agreement with the potential electrophilicity of the chemicals, and the majority of carcinogens that are undetected by the STT do not have an electrophilic structure. There was no complementarity among the tests and no combination of the four tests was more effective than any single test for predicting carcinogenicity.