COMPLEX MIXTURE MODELING ORGANOPHOSPHATE PESTICIDES

说明： 这项研究项目将建立一个评估潜在健康状况的战略 接触复杂的有机磷混合物的影响 (OP)杀虫剂。有机磷杀虫剂被广泛用于各种 存在大量职业暴露的应用和潜力。这个 目前，混合化学品暴露对健康的影响很差。 明白了，因为这种复杂混合物的毒理学特征 由于有许多潜在的组合，这是不现实的。 为了解决这一化学混合物问题，提出了一种综合方法。 涉及基于生理的药代动力学的应用/ 结合体内/体内聚焦的药效学(PBPK/PD)建模 体外研究。这个项目的目标是提供一个量化的 了解生物系统内复杂的化学相互作用， 评估组织剂量学，并量化药效学反应(即 酯酶抑制)。这种方法合理地应用了 用于生成可用于以下目的的数据的资源有限(即时间和资金 评估职业性暴露于重要农产品的人体健康风险 化学制品。 具体研究目标包括：建立二氮磷(DZN)的PBPK/PD模型 在大鼠体内；在大鼠体内进行有重点的体外实验，以量化 毒死蜱(CPF)与DZN混配的临界代谢作用 可以很容易地合并到二元混合物PBPK/PD模型中；在 CPF和DZN混合物的PBPK/PD模型相互作用的活体评价 并对人体组织进行集中的体外实验，以 量化关键的代谢相互作用，并开发出人类DZN和二元 OP混合物PBPK/PD模型。

DESCRIPTION: This research project will establish a strategy to evaluate potential health implications resulting from exposure to complex mixtures of organophosphate (OP) insecticides. OP insecticides are widely utilized in a variety of applications and potential exists for significant occupational exposure. The health implications of mixed chemical exposures are currently poorly understood, since the toxicological characterization of such complex mixtures is not practical due to the numerous potential combinations. To address this chemical mixture issue, an integrated approach is proposed involving the application of physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) modeling in conjunction with focused in vivo/ in vitro studies. The goal of this project is to provide a quantitative understanding of complex chemical interactions within biological systems, estimate tissue dosimetry, and quantitate pharmacodynamic response (i.e. esterase inhibition). This approach represents a reasonable application of limited resources (i.e. time and funding) to generate data which can be used to evaluate human health risk from occupational exposure to important agricultural chemicals. Specific research aims include: to develop a PBPK/PD model for diazinon (DZN) in the rat; to conduct focused in vitro experiments in rats to quantify critical metabolic interactions for mixtures of chlorpyrifos (CPF) and DZN that can readily be incorporated into a binary mixture PBPK/PD model; to conduct in vivo evaluations of the PBPK/PD model interactions for mixtures of CPF and DZN in the rat and to conduct focused in vitro experiments with human tissues to quantify critical metabolic interactions and to develop a human DZN and binary OP mixture PBPK/PD model.