Development of a Physiologically-Based Toxicokinetic Model of BPA in Fish Including Its Two Main Metabolites, Bpa-Glucuronide and Bpa-Sulfate

International audiencePhysiologically-based toxicokinetic models (PBTK) are useful tools to improve understanding of the fate of a chemical inside an organism. Recently, Grech et al. (2019) proposed a generic PBTK model for four different fish, including zebrafish (Danio rerio), threespine stickleback (Gasterosteus aculeatus), rainbow trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas). Meanwhile, bisphenol A (BPA) is considered as very high concern substance due to its endocrine disruptor function, its high production volume and its persistence in the aquatic environment. In this work, the PBTK will be adapted to accurately model the ADME processes (absorption, distribution, metabolization and excretion) of BPA. A particular effort will be carried out to predict internal concentration of its two main metabolites, BPA-monoglucuronide (BPA-g) and BPA-monosulfate (BPA-s), in various organs. In vitro data from zebrafish, rat (Sprague-Dawley) and mouse (CD-1) hepatocytes will be used to calculate Michaelis-Menten parameters related to metabolism. Moreover, TK data in zebrafish and rainbow trout for BPA, BPA-G and BPA-S in different organs will be retrieved from literature to calibrate the model. The objective will be to accurately predict TK data measured in vivo in external datasets. Further development will later add TD sub-models to predict the dynamic of biomarkers measured in organs