Development of a toxicokinetic modeling approach to estimate the cumulative exposure to pyrethroids
Résumé
Context and objective: Pyrethroids are ubiquitous insecticides used in many areas such as agriculture and human or veterinary medicine. The human biomarkers are usually the urinary concentrations of metabolites. The interpretation of these biomarkers to assess the environmental exposure of populations to a specific compound can be difficult since pyrethroids share metabolic pathways and common metabolites. In this work, we propose to develop a global model that links the external exposure to four pyrethroids (permethrin, cypermethrin, cyfluthrin and deltamethrin) to the urinary concentrations of their common metabolites (DCCA, 3-PBA, F-BPA and DBCA) and to apply this model to predict the exposure of the French population. Methods: A generic and gender-dependent physiologically based pharmacokinetic (PBPK) model was adapted to the toxicokinetics of the four pyrethroids, and onecompartment models were developed to describe the levels of metabolites in urine. The models for the parent compounds and the metabolites were connected at the level of the metabolic sites. In vivo, in vitro and in silico data were used for the model parametrization. Human toxicokinetic data were used to evaluate the model predictions. Several scenarios were tested, e.g. different pathways of exposure (oral, dermal and inhalation) or biological matrices (blood, urine). Realistic exposure scenarios were defined using food and air contamination data. The global model was then used to estimate the urinary metabolites concentration after a cumulative exposure to pyrethroids and results were compared with biomonitoring data of the French population (ENNS study). Results and conclusion: Results of the model evaluation showed a proper agreement between the model predictions and experimental data. The estimated cumulative exposure was used as input to the PBPK model. Exposure doses calculated for French population from the ingestion and inhalation of pyrethroids are similar to previous assessment. The median ratios between predictions of urinary concentrations after cumulative exposures and the data from the biomonitoring study were in a range between 0.58 and 1.5. Difficulties remain in estimating the inter-individual variability and extreme values. The global PBPK model can be used to estimate the biomarkers of internal exposure by taking into account cumulative exposure to pyrethroids.