PhD thesis defense - Paul Quindroit

Date de publication : Nov 15, 2019 9:55:40 AM

Abstract:

Pyrethroids are ubiquitous insecticides used in many sectors. Human populations are likely to be exposed by several environmental media (air, soil, food, products; etc.), which enter the human system through various routes (inhalation, ingestion and skin contact). While some compounds are more toxic that others, parent compounds are suspected of inducing neuronal and hormonal disturbances in humans. Urinary concentrations of pyrethroid metabolites, which can be common to several pyrethroids, are often the only biomarkers of exposure. These concentrations must then be compared with the external exposure doses, which are used as the reference values for regulatory thresholds. This project develops an approach to analyze measurements of biomarkers in urineand estimate global exposure to pyrethroids based on PBPK modeling of pyrethroids. First, a global PBPK model was developed to link the external exposure of four pyrethroids (permethrin, cypermethrin, cyfluthrin and deltamethrin) and their isomers to urinary concentrations of metabolites (cis- and trans-DCCA, 3-PBA, F-PBA and DBCA). The model simulates aggregate cumulative exposures by multiple pathways (inhalation, ingestion, and skin contact). The global model was evaluated with human toxicokinetic data and tested with realistic exposures for the French population. The global model was then used to estimate the exposures of the French general population to pyrethroids from biomarkers, as measured by the ENNS study conducted by Santé Publique France. To address the problem of nonuniqueness of inverse solutions related to cypermethrin and permethrin (i.e. share two common metabolites but no specific one), we proposed a methodology based on food consumption questionnaires. This thesis demonstrates the viability of generic PBPK modeling for pyrethroids and the potential of such a model to improve the interpretation of pyrethroid exposure biomarkers.