Hepatic metabolism of chlorinated derivatives of bisphenol A (Cl x BPA) and interspecies differences between rats and humans.

During chlorination treatments of drinking water, aqueous bisphenol A (BPA) can react with chlorine to form chlorinated derivatives of BPA (mono, di, tri and tetra-chlorinated derivatives) or Cl x BPA. These emerging substances are endocrine disruptors associated with obesity, type II diabetes (TD2M) and myocardial infarction. Cl x BPA are present in different human biological matrices but their toxicokinetics remain unknown. The aim of this study was to measure and compare the metabolic kinetics in the liver of four Cl x BPA (ClBPA, Cl 2 BPA, Cl 3 BPA and Cl 4 BPA) between compounds and between species (Sprague-Dawley rats vs humans). To estimate their metabolic constants (V max , K m , Intrinsic clearance), metabolic assays were performed in hepatocyte suspensions. Assays revealed that metabolic constants of Cl x BPA can greatly vary depending on substances and species. While ClBPA and Cl 2 BPA show similar unbound intrinsic clearances (ClintU) in rat incubation media, values for Cl 3 BPA and Cl 4 BPA are very different (3.109 and 0.684 mL/min/106 hepatocytes, respectively). Unlike in rats, human results are quite different as Cl 3 BPA and Cl 4 BPA have similar unbound intrinsic clearances, while ClBPA and Cl 2 BPA diverge (0.350 and 1.363 mL/min/106 hepatocytes, respectively). In both species, Cl 2 BPA and Cl3BPA have relatively similar clearances, and ClBPA is very different from Cl 4 BPA. Although we quantified the proportion of sulfo- and glucurono-metabolites, other metabolites may have been formed (e.g., glutathione, disulfate, or oxidative metabolites). This study showed that chlorination had an impact on hepatic intrinsic clearance of Cl x BPA in rats and humans and measured values will be valuable for the development of PBPK models for use in exposure assessment.