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Conazoles: Application of Omic Technologies to Mode of Action Evaluations

Project Purpose:
To apply state-of-the-art molecular tools supported by traditional toxicological methods and develop mechanistic data for risk assessment on this class of pesticides. To examine interspecies relationships, and to develop a model approach for the use of toxicogenomic data in the evaluation of classes of environmental agents for risk assessment.

Project Description(s):
Conazoles are triazole containing azole fungicides used to protect fruits, grains, and grasses. They have broad antifungal activity and can prevent as well as treat fungal infections. Their antifungal characteristic is due to their ability to block the synthesis of ergosterol which is an essential component of the fungal cell membrane. It is this general feature which makes this class of chemicals suitable for use in agriculture as crop protection products as well as veterinary and human medicine as antifungal drugs. The primary enzyme blocked by the conazoles is lanosterol 14-á-demethylase (CYP51), the only member of the cytochrome family present in animals, plants, fungi, and prokaryotes. This evolutionarily conserved enzyme is also important in cholesterol, Vitamin D, and sex sterol biosyntheses. In vertebrate species, conazoles have complex effects on hepatic and non-hepatic microsomal enzymes. They act as both inducers and inhibitors of cytochrome P450s depending on the tissue and specific conazole. Conazoles have been shown to affect the activity and expression of a number of P450s in the liver. In addition to altered expression and activity of cytochromes, other enzyme activities, the Phase 2 enzymes are also altered (e.g. UDPGTs and GSTs). Many conazoles are hepatotoxic and hepatocarcinogenic in mice and also induce thyroid follicular cell tumors in rats.

This Human Health Research Project seeks to uncover the modes of action of conazole induced liver tumors in mice and thyroid tumors in rats. Three conazoles were selected for study based on their different toxicological profiles: triadimefon (Bayleton®), propiconazole (Banner®), and myclobutanil (Systhane® or Eagle®). In 2-year feeding studies in rats and mice, triadimefon produced an increased incidence of hepatocellular adenomas in male and female NMRI and CF1/W74 mice, and a slightly higher incidence of thyroid follicular cell adenomas in male Wistar/Han rats. Propiconazole induced both hepatocellular adenomas and adenocarcinomas in male CD-1 mice and produced no tumors in the rat. Myclobutanil did not show any treatment-related tumorigenic effects in 2-year studies in mice or rats.

Our approach is to apply toxicogenomic and proteomic analyses to tissues from mice and rats treated with these conazoles under the experimental conditions used in their chronic bioassays. The results of these studies will lead to testable hypotheses which will be explored further using analytical chemical, biochemical, molecular, and cell biological approaches. This project directly addresses the needs to derive a commonly accepted set of principles defining how mode of action information can be used in risk assessments, particularly as it relates to extrapolation issues. Evaluating whether chemicals have a common mode of action for their multiple toxicities and the implications of that mode of action for dose-response assessment is one of the fundamental problems in harmonization of human health risk assessment approaches. This project addresses both qualitative and quantitative methods that could eventually be applied to risk assessment activities. It is envisioned that the results of these investigations will be applicable not only to these specific conazoles but to the larger class of these fungicide chemicals for use in human health risk assessment.

Project Outcomes:

L. Earl Gray, Jr. at gray.earl@epa.gov

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