Kristina A Thayer1, Daniel R Doerge2, Dawn Hunt3, Shepherd H Schurman4, Nathan C Twaddle5, Mona I Churchwell6, Stavros Garantziotis7, Grace E Kissling8, Michael R Easterling9, John R Bucher10, Linda S Birnbaum11. 1. Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop K2-02, Research Triangle Park, NC 27709, USA. Electronic address: thayer@niehs.nih.gov. 2. Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, NCTR-53C RM204L HFT-110, 3900 NCTR Road, Jefferson, AR 72079, USA. Electronic address: daniel.doerge@fda.hhs.gov. 3. Clinical Research Unit, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop CU-01, Research Triangle Park, NC 27709, USA. Electronic address: dawnhunt2233@outlook.com. 4. Clinical Research Unit, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop CU-01, Research Triangle Park, NC 27709, USA. Electronic address: schurmansh@niehs.nih.gov. 5. Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, NCTR-53C RM204L HFT-110, 3900 NCTR Road, Jefferson, AR 72079, USA. Electronic address: Nathan.Twaddle@fda.hhs.gov. 6. Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food & Drug Administration, NCTR-53C RM204L HFT-110, 3900 NCTR Road, Jefferson, AR 72079, USA. Electronic address: Mona.Churchwell@fda.hhs.gov. 7. Clinical Research Unit, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop CU-01, Research Triangle Park, NC 27709, USA. Electronic address: garantziotis@niehs.nih.gov. 8. Biostatistics Branch, National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop A3-03, Research Triangle Park, NC 27709, USA. Electronic address: kissling@niehs.nih.gov. 9. Social & Scientific Systems, Inc., 1009 Slater Rd # 120, Durham, NC 27703, USA. Electronic address: MEasterling@s-3.com. 10. Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop K2-02, Research Triangle Park, NC 27709, USA. Electronic address: bucher@niehs.nih.gov. 11. National Cancer Institute, National Institutes of Health, Department of Health and Human Services, P.O. Box 12233, Mail Drop B2-01, Research Triangle Park, NC 27709, USA. Electronic address: birnbaumls@niehs.nih.gov.
Abstract
BACKGROUND: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. OBJECTIVE: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. METHODS: We exposed six men and eight women to 100 μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. RESULTS: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h. CONCLUSIONS: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h. Published by Elsevier Ltd.
BACKGROUND:Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. OBJECTIVE: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. METHODS: We exposed six men and eight women to 100 μg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. RESULTS: Mean serum total (unconjugated and conjugated) d6-BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 ± 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 ± 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 ± 2.0 h and 6.2 ± 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h. CONCLUSIONS: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h. Published by Elsevier Ltd.
Authors: Frederick S Vom Saal; Catherine A VandeVoort; Julia A Taylor; Wade V Welshons; Pierre-Louis Toutain; Patricia A Hunt Journal: Reprod Toxicol Date: 2014-02-25 Impact factor: 3.143
Authors: Annette M Hormann; Frederick S Vom Saal; Susan C Nagel; Richard W Stahlhut; Carol L Moyer; Mark R Ellersieck; Wade V Welshons; Pierre-Louis Toutain; Julia A Taylor Journal: PLoS One Date: 2014-10-22 Impact factor: 3.240
Authors: Antonia M Calafat; Jennifer Weuve; Xiaoyun Ye; Lily T Jia; Howard Hu; Steven Ringer; Ken Huttner; Russ Hauser Journal: Environ Health Perspect Date: 2008-12-10 Impact factor: 9.031
Authors: Antonia M Calafat; Xiaoyun Ye; Lee-Yang Wong; John A Reidy; Larry L Needham Journal: Environ Health Perspect Date: 2008-01 Impact factor: 9.031
Authors: Laura N Vandenberg; Roy R Gerona; Kurunthachalam Kannan; Julia A Taylor; Richard B van Breemen; Carrie A Dickenson; Chunyang Liao; Yang Yuan; Retha R Newbold; Vasantha Padmanabhan; Frederick S Vom Saal; Tracey J Woodruff Journal: Environ Health Date: 2014-04-01 Impact factor: 5.984
Authors: Sara E Pinney; Clementina A Mesaros; Nathaniel W Snyder; Christine M Busch; Rui Xiao; Sara Aijaz; Naila Ijaz; Ian A Blair; Jeanne M Manson Journal: Reprod Toxicol Date: 2016-11-06 Impact factor: 3.143
Authors: Yan Lin; Xinghua Qiu; Jinming Liu; Chi-Hong Tseng; Patrick Allard; Jesus A Araujo; Yifang Zhu Journal: Environ Int Date: 2020-05-08 Impact factor: 9.621
Authors: Shaina L Stacy; Melissa Eliot; Antonia M Calafat; Aimin Chen; Bruce P Lanphear; Russ Hauser; George D Papandonatos; Sheela Sathyanarayana; Xiaoyun Ye; Kimberly Yolton; Joseph M Braun Journal: Environ Sci Technol Date: 2016-05-23 Impact factor: 9.028
Authors: Cynthia J Hines; Annette L Christianson; Matthew V Jackson; Xiaoyun Ye; Jack R Pretty; James E Arnold; Antonia M Calafat Journal: Ann Work Expo Health Date: 2018-08-13 Impact factor: 2.179
Authors: Joseph M Braun; Nan Li; Tye E Arbuckle; Linda Dodds; Isabelle Massarelli; William D Fraser; Bruce P Lanphear; Gina Muckle Journal: Environ Res Date: 2019-02-26 Impact factor: 6.498