Estimating the cumulative human exposures to pyrethroids by combined multi-route PBPK models: Application to the French population

Human biomarkers of exposure to pyrethroid insecticides are usually urinary concentrations of metabolites that can be specific to a pyrethroid or common to several compounds. We developed a global toxicokinetic model that links the external exposure to four widely-used pyrethroids and their isomers (deltamethrin and cis and trans isomers of permethrin, cypermethrin, and cyfluthrin) to the urinary concentrations of metabolites (cis- and trans-DCCA, 3-PBA, F-PBA and DBCA). This global model includes physiologically based pharmacokinetic models for each parent compound and one-compartment models for the metabolites. Existing in vivo, in vitro and in silico data were used for model calibration, and human toxicokinetic data for model evaluation. Overall, the global model reproduced the data accurately as about 90% of predictions were inside the 3-fold error interval. A sensitivity analysis showed that the most influent parameter for each urinary metabolite concentration was the fraction of parent compound that is transformed into that metabolite. The global model was then tested with realistic exposures for the French population: the predictions were consistent with biomonitoring data. The global model is a tool that will improve the interpretation of biomonitoring data for pyrethroids.