Quantitative structure - property relationships for predicting toxicokinetics of organic chemicals in biota

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The objective of this proposal is to develop new knowledge and tools for facilitating molecular structure-based prediction of the toxicokinetics of organic chemicals in dairy cattle, poultry and rats. More specifically, this proposal focuses on the development of two-tier approaches and quantitative structure-property relationships (QSPRs) for integration with physiological parameters to produce newer generation of toxicokinetic models for existing and emerging chemicals. The present project will facilitate the development of tiered approaches and QSPRs applicable for physiologically-based toxicokinetic (PBTK) modeling of a number of chemical classes (alkanes, alkenes, alkylenes, haloacetic acids, ketones, alcohols, ethers, volatile aromatics, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, dioxins, organophosphorous pesticides, as well as emerging contaminants) primarily found in air, food and/or water. The kinetic data and residue studies in cattle and chicken for a limited number of chemicals are available and those will be made use of, in the context of the present study, for calibrating the QSPRs and validating the PBTK models. Tier 1 approaches will involve the prediction of the parameters in a semi quantitative manner (ie., low, medium, high; decision-tree approach) whereas Tier 2 will require the use of more detailed considerations or predictive QSPRs. Based on the results of sensitive analysis of the Tier 1 model, Tier 2 will be conducted. The Tier-1 and Tier-2 approaches for partition coefficients and metabolism (clearance) parameters will lead to PBTK models that can provide screening-level or more precise predictions in dairy cattle and domestic fowls for a variety of environmental chemicals. The resulting models will not only facilitate molecular structure-based prediction of internal dose (i.e., residue level in tissues) of environmental chemicals in food-producing animals, but also lead to simulations of chemical concentrations in tissues, at the time when they are intended for human consumption.