Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
Arch Toxicol. 2021 May;95(5):1573-1593. doi: 10.1007/s00204-021-03015-1. Epub 2021 Mar 14.
The present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration-response curves for AChE inhibition obtained in the current study to predicted in vivo dose-response curves. The predicted dose-response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL values) were in line with the reported BMDL values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.
本研究采用基于生理的动力学（PBK）建模辅助反向剂量学方法，预测了在体人类和大鼠红细胞（RBC）乙酰胆碱酯酶（AChE）在敌敌畏（DZN）暴露下的抑制情况。由于 DZN 和其氧化代谢物敌敌畏（DZO）均可抑制 AChE，因此在预测体内 AChE 抑制时，PBK 模型中纳入了毒性等效因子（TEF），以综合 DZN 和 DZO 的效应。PBK 模型基于从大鼠和人肝部分或血浆的体外孵育中得出的动力学常数来定义，并用于将当前研究中获得的体外 AChE 抑制浓度-反应曲线转化为预测的体内剂量-反应曲线。预测的大鼠体内剂量-反应曲线与现有的 AChE 抑制体内数据相匹配，10%抑制的基准剂量下限置信区间（BMDL 值）与报告的 BMDL 值一致。人类对 AChE 抑制的敏感性比大鼠高 6 倍，主要是因为毒代动力学的种间差异。结论是，编码 TEF 的 DZN PBK 模型结合定量体外到体内外推（QIVIVE）为预测急性口服 DZN 暴露后 RBC AChE 抑制提供了一种充分的方法，并可为风险评估中推导起始点（POD）提供替代测试策略。
