Human urine and plasma concentrations of bisphenol A extrapolated from pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and semi-physiological pharmacokinetic modeling

Regul Toxicol Pharmacol. 2015 Jun;72(1):71-6. doi: 10.1016/j.yrtph.2015.03.010. Epub 2015 Mar 21.


The aim of this study was to extrapolate to humans the pharmacokinetics of estrogen analog bisphenol A determined in chimeric mice transplanted with human hepatocytes. Higher plasma concentrations and urinary excretions of bisphenol A glucuronide (a primary metabolite of bisphenol A) were observed in chimeric mice than in control mice after oral administrations, presumably because of enterohepatic circulation of bisphenol A glucuronide in control mice. Bisphenol A glucuronidation was faster in mouse liver microsomes than in human liver microsomes. These findings suggest a predominantly urinary excretion route of bisphenol A glucuronide in chimeric mice with humanized liver. Reported human plasma and urine data for bisphenol A glucuronide after single oral administration of 0.1mg/kg bisphenol A were reasonably estimated using the current semi-physiological pharmacokinetic model extrapolated from humanized mice data using algometric scaling. The reported geometric mean urinary bisphenol A concentration in the U.S. population of 2.64μg/L underwent reverse dosimetry modeling with the current human semi-physiological pharmacokinetic model. This yielded an estimated exposure of 0.024μg/kg/day, which was less than the daily tolerable intake of bisphenol A (50μg/kg/day), implying little risk to humans. Semi-physiological pharmacokinetic modeling will likely prove useful for determining the species-dependent toxicological risk of bisphenol A.

Keywords: Allometric scaling; Bisphenol A glucuronide; Humanized-liver mouse; PK modeling; Semi-physiologicalpharmacokinetic modeling; Species difference; Urinary excretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Benzhydryl Compounds / blood*
  • Benzhydryl Compounds / pharmacokinetics
  • Benzhydryl Compounds / urine*
  • Chimera / blood*
  • Chimera / metabolism
  • Chimera / urine*
  • Glucuronides / blood
  • Glucuronides / pharmacokinetics
  • Glucuronides / urine
  • Hepatocytes / metabolism
  • Humans
  • Liver / metabolism*
  • Mice
  • Microsomes, Liver / metabolism
  • Phenols / blood*
  • Phenols / pharmacokinetics
  • Phenols / urine*
  • United States


  • Benzhydryl Compounds
  • Glucuronides
  • Phenols
  • bisphenol A glucuronide
  • bisphenol A