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COMPLEMENTARITY OF GENOTOXIC AND NONGENOTOXIC PREDICTORS OF RODENT CARCINOGENICITY
Citation:
Kitchin, K., J. Brown, AND A. Kulkarni. COMPLEMENTARITY OF GENOTOXIC AND NONGENOTOXIC PREDICTORS OF RODENT CARCINOGENICITY. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/035.
Description:
Twenty-one chemicals known to be carcinogenic in rodent bioassays were selected for study. he chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. he effects of these 21 chemicals on four biochemical assays (hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450)) were determined. Available data from six cancer predictors published by others (the Ames test (AMEs), structural alerts (SA), mutation in mouse lymphoma cells (MOLY), chromosomal aberrations in Chinese hamster ovary cells (ABS), sister chromated exchange in hamster ovary cells (SCE), and the ke test (ke) were also compiled for these 21 chemical carcinogens plus 28 carcinogens and 62 noncarcinogens already published by our laboratory. rom the resulting 111 (chemicals) by 10 (cancer predictors) data matrix, the operational characteristics of each of the ten individual cancer predictors (four biochemical parameters of this study and six cancer predictors of others) were examined. Then, composite cancer predictors of various combinations of the ten individual cancer predictors were subsequently created. f the 10 individual and millions of possible composite predictors, 11 predictors with greater than 80% sensitivity, 8 predictors with greater than 80% specificity and 7 predictors with greater than 60% concordance are reported here. ensitivity (percent of rodent carcinogens which test positive) of 100% was obtained for the composite predictor (ODC or k. or AMES]. oncordance (percent of agreement between the test system and rodent carcinogenicity) of 75% was obtained for the composite predictor [[AMES and ke and SA and ABS) or [ODC and P450]]. he former composite predictor is an example of complementarity or synergy between the genotoxic parameter of (AMES and ke and SA and ABS) (concordance of 63%) and the nongenotoxic parameter [ODC and P4501] (concordance of 56%).