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Kinetics, Mechanisms and Stereoselective Metabolism of 1,2,4-Triazole Fungicides and the Implications for Human Health and Ecological Risk Assessment
Citation:
KENNEKE, J. F., C. S. MAZUR, W. M. HENDERSON, A. W. GARRISON, S. E. Ritger, T. J. Sack, C. C. Brown, AND J. K. Avants. Kinetics, Mechanisms and Stereoselective Metabolism of 1,2,4-Triazole Fungicides and the Implications for Human Health and Ecological Risk Assessment. Presented at 238th ACS National Meeting & Exposition, Washington, DC, August 16 - 20, 2009.
Impact/Purpose:
Our research objective is to develop and apply innovative techniques for elucidating the kinetics and mechanisms of xenobiotic metabolism, and apply these techniques to the understanding and modeling of chemical exposure for informing human health and ecological risk assessment.
Description:
A major uncertainty in risk assessment is determining the exposure of a chemical stressor to a target organism; a confounding issue is the transformation of the chemical inside the target organism. Increasingly, physiologically based pharmacokinetic (PBPK) models are becoming the preferred tool to describe the fate of xenobiotics in physiological systems. These models can be used to evaluate target tissue dose relative to route of exposure and extrapolate results between species. One obstacle preventing full implementation of PBPK models for risk assessment is the lack of xenobiotic metabolism data for a majority of organic chemicals of concern. We have utilized specific enzyme inhibitors, human CYPs, stable isotopes, stereoselective transformations, molecular docking and in silica modeling to elucidate the mechanisms and kinetics of conazole metabolism in numerous vertebrate and invertebrate species, including humans. The entire paradigm, from delineating the kinetics and mechanisms of xenobiotic transformations to PBPK model development, has been used to improve human health and ecological risk assessment. Results will be presented that illustrate the different approaches and techniques used for studying xenobiotic transformations in biological systems and how experimental results are used to improve risk assessment while reducing the reliance upon in vivo animal tests.