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, 72 (1), 71-6

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

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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

Takamori Miyaguchi et al. Regul Toxicol Pharmacol.

Abstract

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.

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