Metabolism and Kinetics of Bisphenol A in Humans at Low Doses Following Oral Administration

 University of Würzburg.

 Present address:  Merck KgaA Darmstadt.

 GSF-München.

 To whom correspondence should be addressed. E-mail:  dekant@toxi.uni-wuerzburg.de. Phone:  +49-931-20148-449. Fax:  +49-931-20148-865.

Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an “endocrine disruptor”. This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d₁₆-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d₁₆-Bisphenol A glucuronide was the only metabolite of d₁₆-bisphenol A detected in urine and blood samples, and concentrations of free d₁₆-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d₁₆-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d₁₆-bisphenol A glucuronide. Maximum blood levels of d₁₆-bisphenol A glucuronide (800 nM) were measured 80 min after oral administration of d₁₆-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses.