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Biotransformation and ToxCast™
Citation:
MARTIN, M. T., K. A. HOUCK, R. JUDSON, R. J. KAVLOCK, D. J. DIX, AND D. J. DIX. Biotransformation and ToxCast™. Presented at ToxCast Data Analysis Summit, RTP, NC, May 14 - 15, 2009.
Impact/Purpose:
The bioactivity profiles of parent-metabolite pairs allowed us to identify assays with the potential to recognize chemical-specific biostransformation. This will be evaluated further by the selection of assays, and parent and metabolite chemicals for Phase II of ToxCast.
Description:
A major focus in toxicology research is the development of in vitro methods to predict in vivo chemical toxicity. Within the EPA ToxCast program, a broad range of in vitro biochemical and cellular assays have been deployed to profile the biological activity of 320 ToxCast Phase I chemicals. Only a limited number of these assays have metabolic capacity, and it is not feasible to test all potential metabolites in the over 500 assays of ToxCast. In order to assess the magnitude of this issue and explore practical solutions, the ToxCast Phase I chemicals include 12 parent-metabolite pairs that allow comparisons of in vitro assay results between the parents and metabolites. Clear differences in cytotoxicity across several cell lines were observed when comparing these parent-metabolite ToxCast results. Some parent chemicals tested in cell-based systems with metabolic capacity, demonstrated differential cytotoxicity dependent upon assay metabolic conditions. However, comparable responses were not seen when these same parent and metabolite cytotoxicities were evaluated independently, indicating the limitations of these cell-based assays. Biochemical assay results also yielded distinct activities for certain metabolites, relative to the complementary parent chemical, emphasizing the need for development of biochemical assays with biotransformation capacity or to account for biotransformation through other approaches. A practical solution may include metabolic simulation or prediction, along with targeted testing of metabolites. Results from the wide range of assays in ToxCast, with and without metabolic capacity, are being incorporated into the data mining and interpretive process. The bioactivity profiles of parent-metabolite pairs allowed us to identify assays with the potential to recognize chemical-specific biostransformation. This will be evaluated further by the selection of assays, and parent and metabolite chemicals for Phase II of ToxCast. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy.
URLs/Downloads:
Biotransformation and ToxCast(TM) (PDF, NA pp, 66 KB, about PDF)Biotransformation and ToxCast(TM) (slides) (PDF, NA pp, 707 KB, about PDF)