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Use of toxicogenomic data by the US EPA Office of Pesticide Programs Cancer Assessment Reivew Committee
Citation:
MCCARROLL, N., E. REAVES, M. MANIBUSAN, D. C. WOLF, S. D. HESTER, J. W. ALLEN, S. Y. THAI, J. A. ROSS, Y. GE, W. M. WINNIK, L. C. KING, C. F. BLACKMAN, W. O. WARD, AND S. NESNOW. Use of toxicogenomic data by the US EPA Office of Pesticide Programs Cancer Assessment Reivew Committee. Presented at Society of Toxicology, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
The Office of Pesticide Programs’ (OPP), Cancer Assessment Review Committee (CARC) routinely utilizes mode of action (MOA) data when available for pesticides whose cancer risk assessment is being considered. Typically, an MOA analysis incorporates data from required toxicology studies and supplemental mechanistic data. The CARC has considered genomic data in the weight-of-the-evidence (WOE) for support of an MOA. As part of this effort, standard approaches are being developed for the inclusion of toxicogenomic data, and other new technologies, into the risk assessment process. The Office of Research and Development has developed toxicogenomic datasets for several regulated conazoles. Members of this class of fungicides induce mouse liver tumors via an undetermined MOA. Toxicogenomic data, supplemental tissue response information, molecular and biochemical studies, and traditional registration studies were used to determine the value of applying genomic data to the MOA analysis. Postulated key events based on genomic and experimental studies are: nuclear receptor activation, CYP induction, cholesterol inhibition, oxidative stress, effects on retinoic acid and mevalonic acid levels, and in vivo mutagenicity. These key events are being synthesized into MOAs that help to explain the toxicological effects of conazoles. EPA Cancer Risk Assessment Guidance approaches will be used to develop a process whereby genomic data can be integrated into our risk assessments. The CARC sees this as an opportunity to bring new approaches that inform our understanding of cancer and increase the efficiency and accuracy of our risk assessment process. The views expressed in this abstract do not necessarily reflect those of the U.S. EPA.
Description:
Poster at meeting