BPA Pharmacokinetics in the Adult and Perinatal Periods in Experimental Animals

Saturday, February 16, 2013
Room 302 (Hynes Convention Center)
Daniel R. Doerge , National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR
Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for food can liners.  The reliance on experimental animal toxicity data to determine the public health consequences of human exposure to BPA underscores the importance of validating internal dosimetry in animal models.  The unique susceptibility of developing fetuses and infants to environmental chemicals is well-recognized to arise from both the potential to interfere with normal developmental programming and immature metabolic detoxication leading to elevated internal exposures.  Indeed, much of the concern surrounding BPA is based on putative effects in developing animals.  Here we report the age-related differences (i.e., adult vs. neonatal) in pharmacokinetics of orally and parenterally administered BPA in Sprague-Dawley rats, rhesus monkeys, CD-1 mice, and distribution of unconjugated (bioactive) and conjugated (inactive) BPA into rat fetuses of different gestational ages and late-term fetal rhesus monkeys.  In adult animal models, similar serum BPA concentration-time profiles are observed for rodents and monkeys and oral clearance values scale allometrically with the corresponding predicted human value.  Low oral bioavailability (ca. 1%) of unconjugated BPA is consistently observed across adult rodent and primate species resulting from extensive presystemic Phase II conjugation in the GI tract and liver.  Neonatal rodents are characterized by immature Phase II metabolic capacity for BPA, which leads to substantially higher internal exposures than in the corresponding adults from oral BPA.  To the contrary, newborn monkeys have adequate Phase II capacity for BPA and internal exposures to unconjugated BPA are similar to adults.  While placental transfer of BPA is observed in rats and monkeys, fetal levels of unconjugated BPA are similar to maternal tissues and do not accumulate.  In addition to maternal metabolism, placental and fetal Phase II metabolism serves to decrease fetal exposures.  The ultimate utility for these data is a physiologically based pharmacokinetic model to reduce the uncertainty in risk assessments through comparisons of levels of bioactive BPA in any plausible target tissue between appropriate animal models and human fetuses, infants, or adults related to exposures through food, medical devices, and other environmental sources.