title: A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data.
abstract: To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.
authors.affiliation: Département de santé environnementale et santé au travail, Chaire d'analyse et de gestion des risques toxicologiques and Institut de recherche en santé publique de l'Université de Montréal (IRSPUM), Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Côté
authors.affiliation: Environmental Health Program, Health Canada, Longueuil, Quebec, Canada.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Bonvalot
authors.affiliation: Département de santé environnementale et santé au travail, Chaire d'analyse et de gestion des risques toxicologiques and Institut de recherche en santé publique de l'Université de Montréal (IRSPUM), Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Gaétan
authors.initials: G
authors.lastname: Carrier
authors.affiliation: Environmental Health Program, Health Canada, Longueuil, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lapointe
authors.affiliation: Department of Pharmacology, University of Cologne, Clinical Pharmacology Unit, Köln, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
authors.affiliation: Department of Pharmacology, University of Cologne, Clinical Pharmacology Unit, Köln, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Tomalik-Scharte
authors.affiliation: Infectopharm Arzneimittel und Consilium GmbH, Heppenheim, Germany.
authors.forename: Bertil
authors.initials: B
authors.lastname: Wachall
authors.affiliation: Département de santé environnementale et santé au travail, Chaire d'analyse et de gestion des risques toxicologiques and Institut de recherche en santé publique de l'Université de Montréal (IRSPUM), Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Michèle
authors.initials: M
authors.lastname: Bouchard
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics* / Q000633:toxicity; D026023:Permethrin / Q000493:pharmacokinetics* / Q000633:toxicity; D011722:Pyrethrins / Q000493:pharmacokinetics* / Q000633:toxicity; D066007:Toxicokinetics
chemical_list: D015415:Biomarkers; D007306:Insecticides; D011722:Pyrethrins; C017160:cypermethrin; D026023:Permethrin