title: PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marie-Emilie
authors.initials: ME
authors.lastname: Willemin
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Toxicologie Expérimentale (TOXI), Parc ALATA BP2, 60550, Verneuil en Halatte, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Desmots
authors.affiliation: Centre Hospitalo-Universitaire de Limoges, Service de Pharmacologie et de Toxicologie - Pharmacovigilance, 2, avenue Martin Luther King, 87042 Limoges, France.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Le Grand
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Innovation pour la Mesure (NOVA), Parc ALATA BP2, 60550, Verneuil en Halatte, France.
authors.forename: François
authors.initials: F
authors.lastname: Lestremau
authors.affiliation: 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.
authors.forename: Florence A
authors.initials: FA
authors.lastname: Zeman
authors.affiliation: Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338 Biomechanics and Bioengineering, Centre de recherche Royallieu CS 60319,60203 Compiègnee Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Leclerc
authors.affiliation: Centre Hospitalo-Universitaire de Limoges, Service de Pharmacologie et de Toxicologie - Pharmacovigilance, 2, avenue Martin Luther King, 87042 Limoges, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Moesch
authors.affiliation: 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. Electronic address: celine.brochot@ineris.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Brochot
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001499:Bayes Theorem; D007306:Insecticides / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D008099:Liver / Q000378:metabolism; D008297:Male; D026023:Permethrin / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014018:Tissue Distribution; D066007:Toxicokinetics
chemical_list: D007306:Insecticides; D026023:Permethrin
keywords: 3-Phenoxybenzoic acid; Bayesian calibration; Metabolites; PBPK model; cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid; cis/trans-Permethrin