DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Memorandum Date: June 6, 2014 From: Bisphenol A (BPA) Joint Emerging Science Working Group Smita Baid Abraham, M.D. ∂, M. M. Cecilia Aguila, D.V.M. ⌂, Steven Anderson, Ph.D., M.P.P.€* , Jason Aungst, Ph.D.£*, John Bowyer, Ph.D. ∞, Ronald P Brown, M.S., D.A.B.T.¥, Karim A. Calis, Pharm.D., M.P.H. ∂, Luísa Camacho, Ph.D. ∞, Jamie Carpenter, Ph.D.¥, William H. Chong, M.D. ∂, Chrissy J Cochran, Ph.D.¥, Barry Delclos, Ph.D.∞, Daniel Doerge, Ph.D.∞, Dongyi (Tony) Du, M.D., Ph.D. ¥, Sherry Ferguson, Ph.D.∞, Jeffrey Fisher, Ph.D.∞, Suzanne Fitzpatrick, Ph.D. D.A.B.T. £, Qian Graves, Ph.D.£, Yan Gu, Ph.D.£, Ji Guo, Ph.D.¥, Deborah Hansen, Ph.D. ∞, Laura Hungerford, D.V.M., Ph.D.⌂, Nathan S Ivey, Ph.D. ¥, Abigail C Jacobs, Ph.D.∂, Elizabeth Katz, Ph.D. ¥, Hyon Kwon, Pharm.D. ∂, Ifthekar Mahmood, Ph.D. ∂, Leslie McKinney, Ph.D.∂, Robert Mitkus, Ph.D., D.A.B.T.€, Gregory Noonan, Ph.D. £, Allison O’Neill, M.A. ¥, Penelope Rice, Ph.D., D.A.B.T. £, Mary Shackelford, Ph.D. £, Evi Struble, Ph.D.€, Yelizaveta Torosyan, Ph.D. ¥, Beverly Wolpert, Ph.D.£, Hong Yang, Ph.D.€, Lisa B Yanoff, M.D.∂ *Co-Chair, € Center for Biologics Evaluation & Research, £ Center for Food Safety and Applied Nutrition, ∂ Center for Drug Evaluation and Research, ¥ Center for Devices and Radiological Health, ∞ National Center for Toxicological Research, ⌂ Center for Veterinary Medicine Subject: 2014 Updated Review of Literature and Data on Bisphenol A (CAS RN 80-05-7) To: FDA Chemical and Environmental Science Council (CESC) Office of the Commissioner Attn: Stephen M. Ostroff, M.D. Acting Chief Scientist, Deputy Commissioner for Science and Public Health TABLE OF CONTENTS Executive Summary – 2 Introduction – 2 Methods – 3 Updated Literature and Data Review – 6 Pharmacokinetic Studies – 6 Neurotoxicology Studies – 27 Reproductive and Developmental Studies – 84 Carcinogenesis Studies – 112 Other Endpoint Studies – 118 Epidemiology Studies – 135 Review of NCTR GLP / NTP Technical Report E2176.01 – 183 JRWG Overall Conclusions – 196 List of Attachments – 200 Reference List – 200 1 EXECUTIVE SUMMARY The BPA joint review working group (JRWG), composed of representatives from several FDA Centers, was formed in January 2011. The JRWG performs systematic reviews of literature available on BPA using clearly defined criteria. The first interim report reviewed literature published from November 2009 through January 2011. The second interim report reviewed literature published from February 2011 through October 24, 2011. The memorandum herein constitutes the third interim review of JRWG evaluating literature available October 24, 2011 to July 23, 2013 and available NCTR studies. The charge of this group is to periodically review the updated scientific literature and data for the purposes of informing the risk assessment on BPA. This document is not a risk assessment. In addition, the group considers whether and how new scientific data (e.g., new pharmacokinetic (PK) data and models) may affect estimation of human exposure from regulated products, including modeling extrapolation/assessment of effects observed from in vitro or animal studies. No new information was identified to suggest revision of the existing safety assessment level (no observed adverse effect level (NOAEL) of 5 mg/kg body weight (bw)/day; oral exposure). Reviewed pharmacokinetic studies continue to provide information useful for age-dependent, interspecies, and route to route extrapolations. The characterized pharmacokinetic differences between primates and rodents reduce concerns about neonatal exposure that have been raised based on some rodent studies using oral and, particularly, non-oral exposures. Recent use of isotopically labeled BPA in pharmacokinetic studies and studies evaluating analytical methods and biomonitoring have provided a better understanding of the potential for and impact of contamination of study samples and inadvertent exposure of study subjects. The extent of potential contamination is much greater than previously realized and provides a possible explanation for inconsistencies in reported low-dose and nonmonotonic effects. Previous JRWG and CFSAN reviews reported hazard identification endpoints related to developmental neurotoxicity, prostate and mammary carcinogenesis, glucose homeostasis, and sperm pathology. The information reviewed herein significantly reduces concern regarding these endpoints. A FDA/NIEHS chronic toxicity study is being conducted at the NCTR for the purpose of further resolving questions related to these endpoints. BPA INTERIM REVIEW 3 INTRODUCTION The U.S. Food and Drug Administration (FDA) previously convened a panel to begin work in December 2010 to review recent emerging scientific data on Bisphenol A (BPA) as part of the BPA Joint Emerging Science Working Group (of the FDA Chemical and Environmental Science Council, CESC) through the Office of the Commissioner. Expertise for this group has been drawn from many FDA Centers to assist in the review. Specifically, this group was tasked with addressing the following questions: 2 • what hazards should be added or removed from FDA’s continuing review/research evaluation; • what dose/response level for a specific effect/endpoint should be changed and to what level; and • how new exposure data or improved assessments should be incorporated into risk assessment. The function of the working group was strictly limited to performing a review of the updated data for the purposes of informing the risk assessment on BPA. In addition, the group considered whether and how new scientific data (e.g., new PK data and models) may affect estimation of exposure from regulated products, including modeling extrapolation or assessment of effects observed from in vitro or animal studies. Based on the literature reviewed in the previous working group memoranda, the group previously provided the following conclusions in response to the charge questions and previous FDA assessments: 1) With regard to hazard identification, data available maintained the previously identified endpoints. a) Developmental neurotoxicity related to anxiety, learning and memory (between sexes), and molecular or neuroanatomical endpoints with varying routes of administration. b) Developmental changes to prostate with non-oral administration. c) Mammary gland predisposition to cancer with non-oral administration. d) Cardiovascular disease-related factors based on human epidemiology studies. e) Perturbations in glucose homeostasis based on limited supporting evidence. f) Sperm/testicular/hormone related parameters based on occupational exposure epidemiology and very limited supporting data in rodents. 2) The available information supported maintaining the existing NOAEL (5 mg/kg bw/day). 3) Physiologically-based pharmacokinetic (PBPK) models were available and contributed to the improvement of the BPA risk assessment by clarifying the PK activities related to BPA metabolism and distribution and by estimating internal exposures of both the conjugated and unconjugated forms of BPA. The memorandum herein constitutes the third review update from the BPA Joint Emerging Science Working Group as part of FDA’s on-going assessment of BPA. The conclusions of the working group are meant to update the conclusions stated above from the previous review memoranda. The current conclusions to the charge are based on the third review of the scientific literature and data available between October 24, 2011 and July 23, 2013. The working group continued to adhere to the review methodology and criteria as defined previously. METHODS The methods employed by the group were identical to those used in the first BPA Joint Emerging Science Working Group memorandum dated May 24, 2011. This weight-of-evidence review was conducted in a three-tiered fashion: (1) literature search inclusion criteria, (2) hazard identification inclusion criteria, and (3) risk assessment inclusion criteria. Hazard identification and risk assessment criteria used for review of toxicology/physiology studies were defined in the 3 previous memorandum. Separate criteria for review of epidemiology and pharmacokinetic studies were also defined in the previous memorandum. Each study was reviewed by an FDA expert followed by a secondary review by another FDA expert. FDA experts contributing to research studies reviewed herein and in previous memoranda were not involved with the review of their own studies for this Working Group. Literature Search For the current review, PubMed and Web of Science/Embase were searched for publications (including those in-press) using the term “bisphenol” from October 24, 2011 through July 23, 2013. Studies were limited to English language reports, human epidemiology and animal studies with direct dosing to mammals (in vivo, direct dosing), which included doses of ≤ 5 mg/kg bw/day. The CAS RN (80-05-7) or Bisphenol A and various limiting terms were used in this search. FDA also considered any non-published data submitted directly to FDA. Risk Assessment (RA) The criteria for risk assessment are briefly described below and were derived from guideline study foundations of Redbook, Organisation for Economic Co-operation and Development (OECD), and the Environmental Protection Agency (EPA). For expanded discussion, see 1 previous workgroup memoranda and ‘low dose’ review memoranda. • Route of Administration: studies using direct dosing (oral, subcutaneous (SC), intraperitoneal (IP), intravenous (IV) as well