title: 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.
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.
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Takamori
authors: T
authors: Miyaguchi
authors: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
authors: Hiroshi
authors: H
authors: Suemizu
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Makiko
authors: M
authors: Shimizu
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Satomi
authors: S
authors: Shida
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Sayako
authors: S
authors: Nishiyama
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan; Fujitsu Kyusyu Systems, Fukuoka 814-8589, Japan.
authors: Ryohji
authors: R
authors: Takano
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Norie
authors: N
authors: Murayama
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors: Hiroshi
authors: H
authors: Yamazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D002678:Chimera / Q000097:blood* / Q000378:metabolism / Q000652:urine*; D020719:Glucuronides / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D014481:United States; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D020719:Glucuronides; D010636:Phenols; C512161:bisphenol A glucuronide; D000098826:Bisphenol A Compounds; C006780:bisphenol A
keywords: Allometric scaling; Bisphenol A glucuronide; Humanized-liver mouse; PK modeling; Semi-physiologicalpharmacokinetic modeling; Species difference; Urinary excretion