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Use of Toxicogenomic Data at the US EPA to Inform the Cancer Asessment of the Fungicide Propiconazole
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 at the US EPA to Inform the Cancer Asessment of the Fungicide Propiconazole. Presented at Symposium on Toxicity Pathway-Based Risk Assessment, Washington DC, DC, May 11 - 13, 2009.
Impact/Purpose:
presentation at meeting
Description:
The Office of Pesticide Programs’ (OPP) routinely utilizes mode of action (MOA) data when available for pesticide cancer risk assessment. A MOA analysis incorporates data from required toxicology studies and supplemental mechanistic data. These data are evaluated to identify a set of key events, quantifiable and critical steps, in the pathway to tumor development. The U. S. EPA has considered genomic data as part of the weight-of-the-evidence (WOE) in support of a MOA. However, to expand this effort, standard approaches are being developed for the inclusion of toxicogenomic data, and other new technologies, into the risk assessment process. Conazoles are antifungal pesticides used for the protection of fruit, vegetable and cereal crops and as pharmaceuticals for the treatment of fungal infections. Antifungal activity is exerted through inhibition of a specific cytochrome, CYP51, a critical step in the biosynthesis of ergosterol, a steroid required for formation of fungal cell walls. Many conazoles induce hepatotoxicity and liver tumors. A toxicogenomic dataset has been developed for the mouse liver tumorigen, propiconazole. The objective of this study was to determine how toxicogenomic data could inform MOA analysis and the interpretation of human relevance. 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 include, nuclear receptor activation, CYP induction, cholesterol inhibition, oxidative stress, altered retinoic acid and mevalonic acid levels, and in vivo mutagenicity. These key events were organized into an hypothesized MOA that explains the tumorigenic response of propiconazole. The U. S. EPA Cancer Risk Assessment Guidance was used as the process whereby genomic data was integrated into the risk assessment. This study shows how toxicogenomic data can inform our understanding of cancer and increase the efficiency and accuracy of a risk assessment. The views expressed in this abstract do not necessarily reflect those of the U.S. EPA.