title: Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A.
abstract: A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States. Electronic address: xiaoxia.yang@fda.hhs.gov.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.affiliation: Health Effects and Exposure Science, Pacific Northwest National Laboratory, Richland, WA 99352, United States; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, United States.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Teeguarden
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Fisher
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000395:Air Pollutants, Occupational / Q000097:blood* / Q000493:pharmacokinetics*; D001559:Benzhydryl Compounds / Q000097:blood* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D010636:Phenols / Q000097:blood* / Q000493:pharmacokinetics*; D013045:Species Specificity; D014018:Tissue Distribution; D055815:Young Adult; D000098826:Bisphenol A Compounds
chemical_list: D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: BPA; Bisphenol A; Human; PBPK; Physiologically based pharmacokinetic model