COMPLEX MIXTURE MODELING ORGANOPHOSPHATE PESTICIDES

产品说明： 这项研究项目将建立一个战略，以评估潜在的健康 暴露于有机磷酸盐的复杂混合物的影响 (OP)杀虫剂OP杀虫剂广泛用于各种 应用和潜在的重大职业接触。的 目前，混合化学品接触对健康的影响不大， 理解，因为这种复杂混合物的毒理学表征 由于许多可能的组合，这是不实际的。 为了解决这种化学混合物的问题，提出了一种综合方法 包括应用基于生理学的药代动力学/ 药效学（PBPK/PD）建模结合重点体内/体内 体外研究。该项目的目标是提供一个定量的 了解生物系统中复杂的化学相互作用， 估计组织剂量，并定量药效学反应（即， 酯酶抑制）。这种方法是对 有限的资源（即时间和资金）来生成可用于 评价职业性接触重要农产品的人类健康风险 化学品 具体研究目标包括：建立二嗪农（DZN）的PBPK/PD模型 在大鼠中进行集中的体外实验， 毒死蜱（CPF）和DZN的混合物的关键代谢相互作用， 可以很容易地纳入一个二元混合PBPK/PD模型;进行 CPF和DZN混合物的PBPK/PD模型相互作用的体内评价 并对人体组织进行集中的体外实验， 量化关键的代谢相互作用，并开发人类DZN和二元 OP混合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.