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

Abstract

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 d(16)-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. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-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 d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (approximately 800 nM) were measured 80 min after oral administration of d(16)-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.

Urinary bisphenol-A concentration in infertile Japanese women and its association with endometriosis: A cross-sectional study

“…Based on this, endometriosis probably represents a sensitive detector of the effect of xenoestrogens in humans. However, two recent human experimental studies showing that orally administered BPA is quickly recovered in urine suggest that accurate exposure assessment based on urinary excretion is problematic, because it likely reflects recent rather than cumulative or long-term exposure (16,17). The probable importance of chronic over recent exposure may partly explain our finding of the lack of association between BPA exposure and endometriosis, and future investigation should focus on the measurement of cumulative exposure to BPA.…”

“…Because urinary conjugated BPAs were enzymatically deconjugated to the free form, MW dosed /MW excreted is equal to 1. For BPA, f = 1 was also assumed on the basis of the results of two studies of BPA oral administration in humans (16,17). Daily urinary BPA excretion is considered as average daily BPA intake (3,10).…”

Bisphenol A and Obesity in Children and Adolescents

“…Bisphenol A has a water solubility of 120 to 300 mg/L (practically insoluble in water). 2,3 On the other hand, phenols as a group have a great range in solubility. For example, phenol is soluble in water at 83 g/L.…”

“…For example, phenol is soluble in water at 83 g/L. 3 The authors do not discuss the solubility of the other phenol compounds, which would have to be comparably lipophilic to draw the conclusion that the association is specific. In addition, the study was limited by only measuring urine concentrations of BPA, which may not reflect the serum level.…”

“…After dietary ingestion, BPA undergoes first-pass glycosylation in the liver, a process that increases its urinary excretion as water-soluble glucuronide conjugates. 3 The NHANES analytic method used to measure BPA quantifies total (conjugated and unconjugated) BPA. 4 The lipophilicity of BPA compared with the other environmental phenols can be evaluated by comparing the chemicals' octanol and water partition coefficients-the higher the coefficient, the more lipophilic the compound.…”