title: Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model.
abstract: Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Food & Drug Administration, Jefferson, AR 72079, USA. Xiaoxia.Yang@fda.hhs.gov
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Fisher
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001559:Benzhydryl Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005544:Forecasting; D008136:Longevity / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D010636:Phenols / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds