PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats - Ineris - Institut national de l'environnement industriel et des risques Access content directly
Journal Articles Toxicology and Applied Pharmacology Year : 2016

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.
Fichier principal
Vignette du fichier
2016-001_post-print.pdf (2.15 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

ineris-01862928 , version 1 (28-08-2018)

Identifiers

Cite

Marie-Emilie Willemin, Sophie Desmots, Rozenn Le Grand, François Lestremau, Florence Anna Zeman, et al.. PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats. Toxicology and Applied Pharmacology, 2016, 294, pp.65-77. ⟨10.1016/j.taap.2016.01.011⟩. ⟨ineris-01862928⟩
102 View
516 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More