Willemin Marie-Emilie, Desmots Sophie, Le Grand Rozenn, Lestremau François, Zeman Florence A, Leclerc Eric, Moesch Christian, Brochot Céline
Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Modèles pour l'Ecotoxicologie et la Toxicologie (METO), Parc ALATA BP2, 60550, Verneuil en Halatte, France; Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338 Biomechanics and Bioengineering, Centre de recherche Royallieu CS 60319,60203 Compiègnee Cedex, France.
Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Toxicologie Expérimentale (TOXI), Parc ALATA BP2, 60550, Verneuil en Halatte, France.
Toxicol Appl Pharmacol. 2016 Mar 1;294:65-77. doi: 10.1016/j.taap.2016.01.011. Epub 2016 Jan 20.
Permethrin, a pyrethroid insecticide, is suspected to induce neuronal and hormonal disturbances in humans. The widespread exposure of the populations has been confirmed by the detection of the urinary metabolites of permethrin in biomonitoring studies. Permethrin is a chiral molecule presenting two forms, the cis and the trans isomers. Because in vitro studies indicated a metabolic interaction between the trans and cis isomers of permethrin, we adapted and calibrated a PBPK model for trans- and cis-permethrin separately in rats. The model also describes the toxicokinetics of three urinary metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA), 3-phenoxybenzoic acid (3-PBA) and 4'OH-phenoxybenzoic acid (4'-OH-PBA). In vivo experiments performed in Sprague-Dawley rats were used to calibrate the PBPK model in a Bayesian framework. The model captured well the toxicokinetics of permethrin isomers and their metabolites including the rapid absorption, the accumulation in fat, the extensive metabolism of the parent compounds, and the rapid elimination of metabolites in urine. Average hepatic clearances in rats were estimated to be 2.4 and 5.7 L/h/kg for cis- and trans-permethrin, respectively. High concentrations of the metabolite 4'-OH-PBA were measured in urine compared to cis- and trans-DCCA and 3-PBA. The confidence in the extended PBPK model was then confirmed by good predictions of published experimental data obtained using the isomers mixture. The extended PBPK model could be extrapolated to humans to predict the internal dose of exposure to permethrin from biomonitoring data in urine.
氯菊酯是一种拟除虫菊酯类杀虫剂，被怀疑会引起人类神经和激素紊乱。生物监测研究中对氯菊酯尿液代谢物的检测证实了人群的广泛暴露。氯菊酯是一种手性分子，有顺式和反式两种异构体。由于体外研究表明氯菊酯的反式和顺式异构体之间存在代谢相互作用，我们分别在大鼠中对反式和顺式氯菊酯的生理药代动力学（PBPK）模型进行了调整和校准。该模型还描述了三种尿液代谢物——顺式和反式3-(2,2-二氯乙烯基)-2,2-二甲基-(1-环丙烷)羧酸（顺式和反式-DCCA）、3-苯氧基苯甲酸（3-PBA）和4'-羟基苯氧基苯甲酸（4'-OH-PBA）的毒代动力学。在斯普拉格-道利大鼠身上进行的体内实验用于在贝叶斯框架下校准PBPK模型。该模型很好地捕捉了氯菊酯异构体及其代谢物的毒代动力学，包括快速吸收、在脂肪中的蓄积、母体化合物的广泛代谢以及代谢物在尿液中的快速消除。大鼠体内顺式和反式氯菊酯的平均肝脏清除率分别估计为2.4和5.7升/小时/千克。与顺式和反式-DCCA以及3-PBA相比，尿液中检测到高浓度的代谢物4'-OH-PBA。然后，通过对使用异构体混合物获得的已发表实验数据的良好预测，证实了扩展PBPK模型的可信度。扩展的PBPK模型可以外推到人类，以根据尿液中的生物监测数据预测氯菊酯的内部暴露剂量。
