BPA and Health Is Any Exposure Safe?

A Continuing Professional Education Program for Nursing and Dietetic Professionals BPA and Health Is Any Exposure Safe? Speaker Moderator Justin Teeguarden, PhD, DABT Senior Scientist Pacific Northwest National Laboratory Diane Quagliani, MBA, RD Owner, Quagliani Communications, Inc. Presented in collaboration with Creative Educational Concepts and sponsored by The Coca Cola Company Beverage Institute for Health & Wellness. Toxicology Serves to Protect Human and Environmental Health Toxicology Must Distinguish Between Agents that Pose a Health Risk and those that do not. Risk = Hazard (how toxic) x Exposure 2 1

BPA and Health: Is Any Exposure Safe? Justin Teeguarden, PhD, DABT Systems Toxicology and Exposure Science-Pacific Northwest National Laboratory Department of Environmental and Molecular Toxicology-Oregon State University Joint Faculty 3 Funding and Potential Conflict of Interest Funding sources for the work I am going to show you: U.S. EPA, National Institute of Occupational Safety and Health (NIOSH). Other major funding sources during that time National Institutes of Health Current funding Same as above, but includes a research grant from the American Chemistry Council BPA producers group. 4 2

BPA is The Most Highly Reported Endocrine Disruptor 5 Number of Publications: Bisphenol A and Estrogenicity 350 "Bisphenol A and Estrogenicity" 300 2819 Total Publications 250 200 150 100 50 0 1980 1985 1990 1995 2000 2005 2010 Publication Year Why the Controversy? The U.S. EPA, the U.S. FDA, the European Food Safety Authority, the Japanese and others all conclude BPA is safe at current human exposures. However, a group of scientists claim that although high doses of BPA are safe, effects are expected and have been shown at low doses. Based on extraordinarily robust data in humans and monkeys, human blood levels of BPA are expected to be below What levels are causing Blood/Tissue effects in Concentrations animals However, In Humans more that Current 20 poorly Exposure controlled Levels? studies show much higher levels of BPA in human blood. 6 3

We will Answer the Most Critical, Most Frequently Asked Questions What is BPA and how does it interact with the body? How does BPA get into my body? Where does it come from? How much BPA is in the body of adults and children? Is there enough BPA in our bodies to cause estrogenic effects? What about the fetus, can it have more BPA than adults? What are low-dose effects and what are the implications for human health? 7 How is BPA Absorbed and How Does it Interact with your Body? 8 4

How does BPA get into our bodies? Ingestion of food, particularly packaged foods >90% of our exposure is via the oral route Multiple studies, adults and children Dermal Cash register receipts Ongoing studies suggest absorption is not significant (NIEHS Cashier study, report from a public meeting). Inhalation Insignificant 9 How Does it Interact with Mammalian Systems? 17 Estradiol (steroid hormone) Classical 1 Non-Classical 1 Bisphenol A 1/10,000 ~1 Genistein (soy isoflavone) 1/250? Genistein Eternal Woman 1000 mg x 4 per day 10 5

Bisphenol A is Almost Entirely Inactivated before it Reaches our Blood Outside the Body Inside the Body 99.7% of and Oral Dose Extensive Metabolism Bisphenol A (Active) BPA-Glucuronide BPA-Sulfate (Inactive) (1% or less of an Oral Dose) 11 Citations for Extensive Metabolism of BPA: Rats, Mice, Monkeys, Humans, during Pregnancy, and in the Fetus 1. Chapin RE, Adams J, Boekelheide K, et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A. Birth Defects Res B Dev Reprod Toxicol. Jun 2008;83(3):157-395. 2. Corbel T, Gayrard V, Viguie C, et al. Bisphenol A Disposition in the Sheep Maternal-Placental-Fetal Unit: Mechanisms Determining Fetal Internal Exposure. Biol Reprod. May 22 2013. 3. Doerge DR, Twaddle NC, Vanlandingham M, Brown RP, Fisher JW. Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague-Dawley rats. Toxicol Appl Pharmacol. Sep 15 2011;255(3):261-270. 4. Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW. Pharmacokinetics of bisphenol A in neonatal and adult Sprague-Dawley rats. Toxicol Appl Pharmacol. Sep 1 2010;247(2):158-165. 5. Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW. Pharmacokinetics of bisphenol A in neonatal and adult CD-1 mice: inter-species comparisons with Sprague- Dawley rats and rhesus monkeys. Toxicol Lett. Dec 15 2011;207(3):298-305. 6. Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW. Pharmacokinetics of bisphenol A in neonatal and adult CD-1 mice: inter-species comparisons with Sprague- Dawley rats and rhesus monkeys. Toxicol Lett. Dec 15 2011;207(3):298-305. 7. Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW. Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice. Toxicol Lett. Jun 1 2012;211(2):114-119. 8. Doerge DR, Twaddle NC, Woodling KA, Fisher JW. Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys. Toxicol Appl Pharmacol. Oct 1 2010;248(1):1-11. 9. Doerge DR, Vanlandingham M, Twaddle NC, Delclos KB. Lactational Transfer of Bisphenol a in Sprague-Dawley Rats. Toxicol Lett. Oct 5 2010. 10. Fisher JW, Twaddle NC, Vanlandingham M, Doerge DR. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans. Toxicol Appl Pharmacol. Sep 2 2011. 11. Kurebayashi H, Harada R, Stewart RK, Numata H, Ohno Y. Disposition of a low dose of bisphenol a in male and female cynomolgus monkeys. Toxicol Sci. Jul 2002;68(1):32-42. 12. Negishi T, Tominaga T, Ishii Y, et al. Comparative study on toxicokinetics of bisphenol A in F344 rats, monkeys (Macaca fascicularis), and chimpanzees (Pan troglodytes). Exp Anim. Jul 2004;53(4):391-394. 13. Taylor JA, Vom Saal FS, Welshons WV, et al. Similarity of bisphenol A pharmacokinetics in rhesus monkeys and mice: relevance for human exposure. Environ Health Perspect. Apr 2011;119(4):422-430. 14. Teeguarden JG, Calafat AM, Ye X, et al. Twenty-Four Hour Human Urine and Serum Profiles of Bisphenol A during High-Dietary Exposure. Toxicol Sci. Sep 2011;123(1):48-57. 15. Twaddle NC, Churchwell MI, Vanlandingham M, Doerge DR. Quantification of deuterated bisphenol A in serum, tissues, and excreta from adult Sprague-Dawley rats using liquid chromatography with tandem mass spectrometry. Rapid Commun Mass Spectrom. Oct 30 2010;24(20):3011-3020. 16. Völkel W, Bittner N, Dekant W. Quantitation of bisphenol A and bisphenol A glucuronide in biological samples by high performance liquid chromatography-tandem mass spectrometry. Drug Metab Dispos. Nov 2005;33(11):1748-1757. 17. Völkel W, Kiranoglu M, Fromme H. Determination of free and total bisphenol A in human urine to assess daily uptake as a basis for a valid risk assessment. Toxicol Lett. Jul 10 2008;179(3):155-162. 18. Völkel W, Kiranoglu M, Fromme H. Determination of free and total bisphenol A in urine of infants. Environ Res. Oct 21 2011;111:143-148. 19. Yang X, Doerge DR, Fisher JW. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model. Toxicol Appl Pharmacol. Apr 6 2013. 12 6

Is BPA Toxic? There are some animal and in vitro studies that show toxicity and there are epidemiology studies that show associations between disease and BPA exposure For BPA or any chemical, the answer to this question alone is not useful. The right question is: Does BPA Exposure Present a Risk to my Health? 13 Response is Related to Concentrations at the Site of Action (Basic Pharmacology) What Blood/Tissue Concentrations Cause Adverse Effects in Test Species? What Blood/Tissue Concentrations of UC-BPA Cause Adverse Effects in Test Species? Similar? Potential for a public health problem. What are Blood/Tissue Concentrations UC-BPA In Humans at Current Exposure Levels? What are Blood/Tissue Concentrations In Humans at Current Exposure Levels? 14 7

Carefully Controlled Clinical Exposure Studies are one Approach to Determining How much BPA is in our Blood 15 Clinical Bisphenol A Biomonitoring Study Teeguarden JG, Calafat AM, Ye X, et al. Twenty-Four Hour Human Urine and Serum Profiles of Bisphenol A during High-Dietary Exposure. Toxicol Sci. Sep 2011;123(1):48-57. Volunteers 10 males, 10 female, non-smoking 18-54 years old No liver or kidney function deficits No use of drugs affecting liver or kidney function Protocol Highlights Volunteers ate 100% of defined meals: breakfast, lunch, dinner Urine samples ~ hourly, blood hourly from 7 am to 10 pm and a first morning void @ 24 hours. Field blanks: blood, urine, water through blood collection system, and urine collection material, water (all were below detection limit) Urine and selected blood samples analyzed for total BPA at the CDC by Dr. Antonia Calafat (LOD 0.1-0.4 ng/ml) 16 8

All Samples were Below the Limit of Detection for BPA even at Exposures that Exceeded the 95 th Percentile of Human Exposure Our Exposures were beyond the 95 th percentile Mean urine concentration nearly three times higher than the in the general population (NHANES) The 95th percentile BPA urinary concentration was more than twice the values in the general population 18 9

What are human blood concentrations if you use other methods for determining them? 19 Approaches for Estimating Human Blood Bioactive BPA Concentrations Daily External Exposure (μg) Pharmacokinetic Model Peak Blood [nm ] Exposure ( g/kg) Total BPA In Serum 0.1% Bioactive Bioactive BPA In Serum Urine Concentrations 1 42 Directly Measured Total BPA Directly Measured BPA 20 10

Human Experimental Data and Models Support Calculations of Serum BPA Concentrations Unconjugated fraction Völkel et al. (2002): upper bound:0.1% NIEHS human oral PK study: 0.2% Human PBPK modeling: ~0.1% PBPK 2 human oral-route PK studies, monkey I.V. and oral PK studies Urine:Blood BPA concentration ratio: Teeguarden et al. (2011): GM, 42 NIEHS human oral-route PK study: GM, 62 Ratio of Peak Blood Concentration to Total Exposure: Teeguarden et al. (2011): 17 nm/μg/kg NIEHS human oral-route PK study: 20 nm/μg/kg 21 Demographics for Exposure Assessment Urine-Based Teeguarden J, Hanson-Drury S, Fisher JW, Doerge DR. Are typical human serum BPA concentrations measureable and sufficient to be estrogenic in the general population? Food Chem Toxicol. Aug 17 2013. Total Serum BPA Direct Measures 22 11

Convergence of Methods: Mean Serum BPA Concentrations are in the Sub pm range Exposure = 4x U.S. 95 th Percentile Fetal Blood Concentration are Lower than Maternal BPA Blood Concentrations Patterson TA, Twaddle NC, Roegge CS, Callicott RJ, Fisher JW, Doerge DR. Concurrent determination of bisphenol A pharmacokinetics in maternal and fetal rhesus monkeys. Toxicol Appl Pharmacol. Feb 15 2013;267(1):41-48. 12

Are Serum BPA Concentrations Sufficient to Cause Estrogenic/Endocrine Disruptor Effects? Receptor Occupancy of Less than 0.001 % in Infants and Women of Child Bearing Age 13

Intravenous BPA: A Model for Non-Oral Routes of Exposure No Observable Changes in Estrogen Regulated Genes In Rat Prostate or Mammary Tissue Lower Bound BPA Method Limit of Detection Large, Chronic, Multi-Generation Animal Studies Consistently Show no Adverse Effects of BPA at Exposure Levels 1000 s of Times Higher than Human Exposure 2 or 3 generations of exposure, mice and rats (Tyl et al. 2002, 2008) Mice, rats, effects on sperm production and prostate (Ashby et al. 1999, 2003) Rats, exposed during pregnancy and development (FDA, B. Delclos). (1) Tyl RW, Myers CB, Marr MC, et al. Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice. Toxicol Sci. Aug 2008;104(2):362-384. (2) Tyl RW, Myers CB, Marr MC, et al. Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci. Jul 2002;68(1):121-146. (3) Ashby J, Tinwell H, Haseman J. Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero. Regul Toxicol Pharmacol. Oct 1999;30(2 Pt 1):156-166. (4) Ashby J, Tinwell H, Lefevre PA, Joiner R, Haseman J. The effect on sperm production in adult Sprague-Dawley rats exposed by gavage to bisphenol A between postnatal days 91-97. Toxicol Sci. Jul 2003;74(1):129-138. 14

Conclusions There is extraordinary convergence between theory, experiment and simulation Environmental, non-occupational exposures most likely lead to extremely low ( pm or sub-pm ) internal exposures to BPA in the majority of the population. high blood concentrations reported in studies and in the media are outliers, and are most likely the result of contamination*. There is no consistent evidence that BPA at these concentrations is toxic or acts as an endocrine disruptor in animals *Researchers at the Food and Drug Administration, the Centers for Disease Control and other academic researchers 1. Koch HM, Kolossa-Gehring M, Schroter-Kermani C, Angerer J, Bruning T. Bisphenol A in 24 h urine and plasma samples of the German Environmental Specimen Bank from 1995 to 2009: A retrospective exposure evaluation. J Expo Sci Environ Epidemiol2012 May 23. 2. Koch HM, Calafat AM. Human body burdens of chemicals used in plastic manufacture. Philos Trans R Soc Lond B Biol Sci2009 Jul 27;364(1526):2063-78. 3. Ye X, Zhou X, Hennings R, Kramer J, Calafat AM. Potential External Contamination with Bisphenol A and Other Ubiquitous Organic Environmental Chemicals during Biomonitoring Analysis: An Elusive Laboratory Challenge. Environ Health Perspect2013 Mar;121(3):283-6. 4. Teeguarden JG, Calafat AM, Ye X, Doerge DR, Churchwell MI, Gunawan R, et al. Twenty-Four Hour Human Urine and Serum Profiles of Bisphenol A during High-Dietary Exposure. Toxicol Sci2011 Sep;123(1):48-57. 5. Doerge DR, Twaddle NC, Vanlandingham M, Fisher JW. Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice. Toxicol Lett2012 Jun 1;211(2):114-9. I Hear that BPA causes Effects at Low Doses. What are low doses? Does the low dose data mean I am at risk? 30 15

Method Systematic review of published low dose BPA literature. All BPA toxicology papers self-referring as low dose or environmentally relevant or low concentration. Tabulated exposure levels g/kg/day for in vivo studies nm for in vitro studies No consideration for route or duration of exposure Compared to measures of human exposure External: National exposure assessments (NHANES) Internal: Median serum concentrations (analysis above) 31 Few BPA Low-Dose Studies have been Conducted in the Range of Human Exposure In Vivo 32 16

Few BPA Low-Dose Studies have been Conducted in the Range of Human Exposure In Vivo: Independent Tabulation 33 vom Saal FS, Welshons WV. Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A. Environ Res. Jan 2006;100(1):50-76. Few BPA Low-Dose Studies have been Conducted in the Range of Human Exposure In Vitro 34 17

Conclusions The term low-dose is extraordinarily non-specific. Low-dose does not describe a body of BPA toxicity studies conducted within the range of human exposures Greater care should be taken in inferring human risk from low dose studies, or reviews of low-dose studies. There is an opportunity to utilize the wealth of BPA exposure data to place all toxicity studies in the context of human exposure and to design appropriate toxicity studies. Final Conclusions Broad groups of scientists within regulatory bodies have consistently concluded BPA exposure levels do not pose a risk to human health Human internal exposure is far below levels that consistently show effects in animals and is not expected to be estrogenic. The term low dose is misleading and applied to BPA has led to tremendous confusion about the risks posed by exposure to BPA. Carefully consider your sources of information. 36 18