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Complementarity of genotoxic and nongenotoxic predictors of rodent carcinogenicity
K T Kitchin1, J L Brown, A P Kulkarni
1Carcinogenesis and Metabolism Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Abstract:
Twenty-one chemicals carcinogenic in rodent bioassays were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The 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 seven cancer predictors published by others [the Ames test (AMES), mutation in Salmonella typhimurium TA 1537 (TA 1537), structural alerts (SA), mutation in mouse lymphoma cells (MOLY), chromosomal aberrations in Chinese hamster ovary cells (ABS), sister chromatid 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. From the resulting 111 (chemicals) by 11 (individual cancer predictors) data matrix, the five operational characteristics (sensitivity, specificity, positive predictivity, negative predictivity, and concordance) of each of the 11 individual cancer predictors (four biochemical parameters of this study and seven cancer predictors of others) are presented. Two examples of complementarity or synergy of composite cancer predictors were found. To obtain maximum concordance it was necessary to combine both genotoxic and nongenotoxic cancer predictors. The composite cancer predictor (DD or [ODC and P450] or [ODC and ALT]) had higher concordance than did any of the four individual cancer predictors from which it was constructed. Similarly, the composite cancer predictor (TA 1537 or DD or [ODC and P450] or [ODC and ALT]) had higher concordance than any of its five individual constituent cancer predictors. Complementarity or synergy has been demonstrated both 1) among genotoxic cancer predictors (DD and TA 1537) and 2) between nongenotoxic (ODC, P450, and ALT) and genotoxic cancer predictors (TA 1537 and DD).
Insights
Combining genotoxic and nongenotoxic cancer predictors enhances accuracy. Composite predictors like DNA damage (DD) or ornithine decarboxylase (ODC) with cytochrome P450 (P450) show improved concordance for chemical carcinogen identification.
Area of Science:
- Toxicology
- Biochemistry
- Genetics
Background:
- Rodent bioassays identify chemical carcinogens.
- Predictive models for carcinogenicity are crucial for risk assessment.
- Evaluating multiple biomarkers is key to improving predictive accuracy.
Purpose of the Study:
- To assess the performance of individual and combined biochemical and genotoxicity assays in predicting chemical carcinogenicity.
- To investigate the complementarity and synergy of various cancer predictor assays.
Main Methods:
- Administered 21 known carcinogens to rats at two dose levels.
- Measured four biochemical assays: hepatic DNA damage (DD), ornithine decarboxylase (ODC), alanine aminotransferase (ALT), and cytochrome P450 (P450).
- Compiled data from seven established cancer predictors and the four new assays for 111 chemicals.
Main Results:
- Evaluated operational characteristics (sensitivity, specificity, predictivity, concordance) for 11 predictors.
- Demonstrated complementarity between genotoxic predictors (DD, TA 1537).
- Showed synergy between nongenotoxic (ODC, P450, ALT) and genotoxic predictors, with composite models outperforming individual assays.
Conclusions:
- Combining genotoxic and nongenotoxic predictors maximizes predictive concordance for chemical carcinogens.
- Composite predictors like (DD or [ODC and P450] or [ODC and ALT]) and (TA 1537 or DD or [ODC and P450] or [ODC and ALT]) show enhanced performance.
- Synergistic interactions between different assay types improve the reliability of carcinogenicity prediction.