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

该提案的目的是开发新的知识和工具，以促进基于分子结构的有机化学品在奶牛，家禽和大鼠中的毒代动力学预测。更具体地说，该提案侧重于开发两层方法和定量结构-性质关系（QSPR），用于与生理参数集成，以产生新一代现有和新兴化学品的毒代动力学模型。本项目将促进制定适用于主要存在于空气、食物和/或水中的若干化学类别（烷烃、烯烃、亚烷基、卤代乙酸、酮、醇、醚、挥发性芳烃、多环芳烃、多氯联苯、二恶英、有机磷农药以及新出现的污染物）的基于生理的毒代动力学建模的分层方法和快速反应程序。现有数量有限的化学品在牛和鸡中的动力学数据和残留研究，在本研究中，将利用这些数据和研究来校准QSPR和验证PBTK模型。第1层方法将涉及以半定量方式预测参数（即，低、中、高;决策树方法），而第2层将需要使用更详细的考虑因素或预测性QSPR。根据第1层模型的敏感性分析结果，将进行第2层分析。第1层和第2层的分配系数和代谢（清除）参数的方法将导致PBTK模型，可以提供筛选水平或更精确的预测，在奶牛和家禽的各种环境化学品。所得到的模型将不仅有利于基于分子结构的内部剂量预测（即，组织中的残留水平），而且还导致模拟供人类食用时组织中的化学品浓度。

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.