PDF(Pubmed)
Abstract：
Worldwide use of organophosphate pesticides as agricultural chemicals aims to maintain a stable food supply, while their toxicity remains a major public health concern. A common mechanism of acute neurotoxicity following organophosphate pesticide exposure is the inhibition of acetylcholinesterase (AChE). To support Next Generation Risk Assessment for public health upon acute neurotoxicity induced by organophosphate pesticides, physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach was employed in this study, with fenitrothion (FNT) as an exemplary organophosphate pesticide. Rat and human PBK models were parametrized with data derived from in silico predictions and in vitro incubations. Then, PBK model-based QIVIVE was performed to convert species-specific concentration-dependent AChE inhibition obtained from in vitro blood assays to corresponding in vivo dose-response curves, from which points of departure (PODs) were derived. The obtained values for rats and humans were comparable with reported no-observed-adverse-effect levels (NOAELs). Humans were found to be more susceptible than rats toward erythrocyte AChE inhibition induced by acute FNT exposure due to interspecies differences in toxicokinetics and toxicodynamics. The described approach adequately predicts toxicokinetics and acute toxicity of FNT, providing a proof-of-principle for applying this approach in a 3R-based chemical risk assessment paradigm.
摘要：
全球范围内使用有机磷农药作为农业化学品的目的是保持稳定的食品供应，虽然它们的毒性仍然是一个主要的公共卫生问题。有机磷农药暴露后急性神经毒性的常见机制是乙酰胆碱酯酶（AChE）的抑制。为了支持下一代有机磷酸酯农药引起的急性神经毒性的公共卫生风险评估，本研究采用了基于生理学的动力学（PBK）建模促进的体外定量到体内外推（QIVIVE）方法，用杀尼特硫磷(FNT)作为示例性有机磷酸酯杀虫剂。用来自计算机模拟预测和体外孵育的数据对大鼠和人PBK模型进行参数化。然后，进行基于PBK模型的QIVIVE以将从体外血液测定获得的物种特异性浓度依赖性AChE抑制转化为相应的体内剂量反应曲线。从中得出出发点(POD)。获得的大鼠和人的值与报告的未观察到的不良反应水平（NOAEL）相当。由于毒物动力学和毒物动力学的种间差异，发现人类比大鼠更容易受到急性FNT暴露引起的红细胞AChE抑制。所描述的方法充分预测FNT的毒物动力学和急性毒性，为在基于3R的化学风险评估范式中应用这种方法提供了原理证明。
