QUANTITATION OF BISPHENOL A AND BISPHENOL A GLUCURONIDE IN BIOLOGICAL SAMPLES BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY-TANDEM MASS SPECTROMETRY

Bisphenol A (BPA) is a weak estrogen. Pharmacokinetic studies of BPA have demonstrated a rapid and extensive metabolism of BPA to the nonestrogenic BPA-monoglucuronide (BPA-gluc). Some investigators have reported that BPA was found at parts per billion concentrations in the tissues or urine of humans without known exposure to BPA. This work developed a rapid and sensitive method for the determination of BPA and BPA-gluc in plasma and urine based on liquid chromatography-tandem mass spectrometry. The liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitation of BPA and BPA-gluc uses stable isotope-labeled internal standards. A linear ion trap mass spectrometer permits identification and quantitation of BPA-gluc and BPA without sample workup. Development of separation conditions reduced the BPA-background in solvent samples to below 2.5 pmol/ml for BPA. Limit of quantitation (LOQ) for BPA in control urine was 15 pmol/ml; LOQ for BPA-gluc was 65 pmol/ml. Application of the method to urine samples from human subjects (n = 6) after administration of 25 μg of BPA/person (estimated maximum human daily intake) permitted the determination of excretion kinetics for BPA-gluc; BPA was below the LOD in all except two of the samples. In urine or blood samples of human subjects (n = 19) without intentional exposure to BPA, BPA concentrations were always below the limit of detection (≈2.5 pmol/ml) with or without prior glucuronidase treatment. The results show that care is required for analysis of BPA and its major metabolite BPA-gluc. The LOD obtained and the absence of detectable levels of BPA in samples from individuals suggests that general exposure of humans to BPA is much lower than the worst-case exposure scenario developed.

[1]  P. Perez,et al.  Bisphenol A diglycidyl ether as a potential metabolic source of bisphenol A. , 1998, Environmental health perspectives.

[2]  W. Dekant,et al.  Disposition and biotransformation of the estrogenic isoflavone daidzein in rats. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[3]  R. Ito,et al.  Stir bar sorptive extraction with in situ derivatization and thermal desorption-gas chromatography--mass spectrometry for measurement of phenolic xenoestrogens in human urine samples. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[4]  J. Yoshinaga,et al.  Daily urinary excretion of bisphenol A , 2004, Environmental health and preventive medicine.

[5]  A. Heredia,et al.  Resveratrol glucuronides as the metabolites of resveratrol in humans: characterization, synthesis, and anti-HIV activity. , 2004, Journal of pharmaceutical sciences.

[6]  K A Thayer,et al.  Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  T. Fennell,et al.  Metabolism and disposition of bisphenol A in female rats. , 2000, Toxicology and applied pharmacology.

[8]  S Z Cagen,et al.  The relative bioavailability and metabolism of bisphenol A in rats is dependent upon the route of administration. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  P. Cooke,et al.  A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and Behavior , 1998, Toxicology and industrial health.

[10]  H. Nakazawa,et al.  Application of liquid chromatography-mass spectrometry to the quantification of bisphenol A in human semen. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[11]  Y. Taketani,et al.  Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. , 2002, Human reproduction.

[12]  Masatoshi Morita,et al.  Bisphenol A levels in human urine. , 2002, Environmental health perspectives.

[13]  H. Yokota,et al.  Bisphenol a glucuronide, a major metabolite in rat bile after liver perfusion. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[14]  Samuel P. Caudill,et al.  Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population , 2004, Environmental health perspectives.

[15]  Frederick S vom Saal,et al.  Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  I. Chahoud,et al.  Parent bisphenol A accumulation in the human maternal-fetal-placental unit. , 2002, Environmental health perspectives.

[17]  W. Dekant,et al.  Biotransformation and kinetics of excretion of methyl-tert-butyl ether in rats and humans. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[18]  K. Nephew,et al.  Effects of the Xenoestrogen Bisphenol a on Expression of Vascular Endothelial Growth Factor (VEGF) in the Rat , 2001, Experimental biology and medicine.

[19]  C. Sonnenschein,et al.  Prenatal Exposure to Low Doses of Bisphenol A Alters the Periductal Stroma and Glandular Cell Function in the Rat Ventral Prostate1 , 2001, Biology of reproduction.

[20]  R. Kishi,et al.  Maternal serum and amniotic fluid bisphenol A concentrations in the early second trimester. , 2002, Reproductive toxicology.

[21]  A. Calafat,et al.  Simultaneous measurement of urinary bisphenol A and alkylphenols by automated solid-phase extractive derivatization gas chromatography/mass spectrometry. , 2003, Analytical chemistry.

[22]  L. R. Harris,et al.  Normal reproductive organ development in Wistar rats exposed to bisphenol A in the drinking water. , 1999, Regulatory toxicology and pharmacology : RTP.

[23]  M. Ema,et al.  Rat two-generation reproductive toxicity study of bisphenol A. , 2001, Reproductive toxicology.

[24]  O. Tsutsumi,et al.  Serum bisphenol a concentrations showed gender differences, possibly linked to androgen levels. , 2002, Biochemical and biophysical research communications.

[25]  Wolfgang Völkel,et al.  Metabolism and kinetics of bisphenol a in humans at low doses following oral administration. , 2002, Chemical research in toxicology.

[26]  B. Burchell,et al.  UDP-glucuronosyltransferases: a family of detoxifying enzymes. , 1990, Trends in pharmacological sciences.

[27]  Y. Taketani,et al.  Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. , 2004, Endocrine journal.

[28]  K. Ballschmiter,et al.  Determination of endocrine-disrupting phenolic compounds and estrogens in surface and drinking water by HRGC-(NCI)-MS in the picogram per liter range. , 2001, Environmental science & technology.

[29]  J Ashby,et al.  Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero. , 1999, Regulatory toxicology and pharmacology : RTP.

[30]  B. Shin,et al.  Pharmacokinetic disposition and tissue distribution of bisphenol A in rats after intravenous administration. , 2000, Journal of toxicology and environmental health. Part A.

[31]  D. Feldman,et al.  Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. , 1993, Endocrinology.

[32]  S. Oishi,et al.  Disposition of orally administered 2,2-Bis(4-hydroxyphenyl)propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses. , 2000, Environmental health perspectives.

[33]  M. Pyo,et al.  Gender differences in the levels of bisphenol A metabolites in urine. , 2003, Biochemical and biophysical research communications.

[34]  Chengjun Sun,et al.  Determination of environmental estrogens in human urine by high performance liquid chromatography after fluorescent derivatization with p-nitrobenzoyl chloride , 2004 .

[35]  T. Zacharewski,et al.  In Vitro and in Vivo Interactions of Bisphenol A and Its Metabolite, Bisphenol A Glucuronide, with Estrogen Receptors α and β , 2001 .

[36]  C Siew,et al.  Pharmacokinetics of bisphenol A released from a dental sealant. , 2000, Journal of the American Dental Association.

[37]  T. Kawamoto,et al.  Biological Monitoring of Bisphenol A in a Korean Population , 2003, Archives of environmental contamination and toxicology.

[38]  W. Dekant,et al.  Biotransformation and kinetics of excretion of ethyl tert-butyl ether in rats and humans. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  Shaw Watanabe,et al.  Measurement of bisphenol A in human urine using liquid chromatography with multi-channel coulometric electrochemical detection. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.