Frederick vom Saal
BISPHENOL A
Updated April, 2012
This information was prepared by:
Frederick S. vom Saal, Ph.D.
Curators’ Professor of Biology
and
Davide Ponzi, Ph.D.
Research Associate
Division of Biological Sciences
University of Missouri-Columbia
Columbia, Missouri 65211 USA
NOTE: This document provides references from the published scientific literature concerning bisphenol A, focusing on “low dose” in vivo effects, molecular mechanisms based primarily on in vitro studies, sources of exposure and pharmacokinetics. None of these reference lists should be considered to be comprehensive.
This is posted on the web at:
TABLE OF CONTENTS
I. BISPHENOL A: LOAEL AND REFERENCE DOSE
II. GOVERNMENT REPORTS ON BPA
III. REVIEW ARTICLES CONCERNING BISPHENOL A
IV.REPORT IN 1936 THAT BISPHENOL A HAD FULL ESTROGENIC ACTIVITY IN A STUDY OF ESTROGENIC CHEMICALS, AND THEN IN 1938, REPORT ON THE SYNTHESIS OF A SIMILAR MOLEDULE, DES
V. DEFINITION OF “LOW DOSE”
VI. EPIDEMIOLOGICAL STUDIES OF THE RELATIONSHIP BETWEEN BISPHENOL A AND DISEASE IN HUMANS
VII. IN VIVO STUDIES PUBLISHED IN PEER-REVIEWED JOURNALSREPORTING THAT BISPHENOL A CAUSES SIGNIFICANT EFFECTS IN ANIMALSWITH DOSES BELOW THE PUBLISHED LOAEL OF 50 mg/kg/day. INCLUDED ARE SIGNIFICANT EFFECTS AT DOSES IN THE PART PER BILLION(PPB) RANGE FOR AQUATIC ANIMALS
VIII. 44 FINDINGS OF SIGNIFICANT EFFECTS FROM THE ABOVE LIST USING DOSES AT AND BELOW THE REFERENCE DOSE OF 50 µg/kg/day
IX. INVERTED-U DOSE-RESPONSE CURVES REPORTED FOR BISPHENOL A
X. DES SHOWS SAME IN VIVO EFFECTS AS BISPHENOL A
XI. INSENSITIVITY OF THE UTEROTROPHIC ASSAY (SPECIFICALLY AN INCREASE IN UTERINE SIZE) TO LOW DOSES OF BISPHENOL A WHEN USING SOME STRAINS OF RATS AND MICE
XII. CHEMICAL INDUSTRY FUNDED STUDY OF BISPHENOL A WITH POSITIVE RESULTS (DETERMINED BY A NTP REVIEW PANEL) BUT REPORTED TO THE US-EPA AND THE PUBLIC AS NEGATIVE RESULTS
XIII. CHEMICAL INDUSTRY FUNDED STUDIES INCORRECTLY DESCRIBED AS REPLICATING PROCEDURES BY VOM SAAL (DIFFERENT FEED WAS USED) THAT REPORTED NEGATTIVE RESULTS FOR BOTH BISPHENOL A AND THE POSITIVE CONTROL CHEMICAL, DES
XIV. STUDIES REPORTING NO IN VIVO EFFECTS OF LOW DOSES OF BISPHENOL THAT USED AN INSENSITIVE RAT, THE CHARLES RIVER SPRAGUE-DAWLEY (CD-SD) RAT
XV. FINDINGS OF NO SIGNIFICANT EFFECTS IN EXPERIMENTAL ANIMALS AT DOSES OF BISPHENOL A BELOW 50 MG/KG/DAY OR AT PPB DOSES IN AQUATIC ANIMALS (INCLUDING STUDIES WITH CD-SD RATS)
XVI. IN VITRO STUDIES OF MOLECULAR MECHANISMS
XVII. BISPHENOL A BINDING AND RESPONSES WITH ER-alpha AND ER-beta
XVIII. EXPOSURE LEVELS IN HUMAN ADULTS, CHILDREN AND FETUSES
XIX. BISPHENOL A METABOLISM STUDIES IN MICE AND RATS, INCLUDING EXPOSURE DURING POSTNATAL LIFE AND OF FETUSES AFTER MATERNAL EXPOSURE
XX. EXPOSURE AND METABOLISM OF BISPHENOL A IN OTHER SPECIES
XXI. ENVIRONMENTAL MONITORING AND ANALYTICAL METHODS
XXII. LEACHING OF BISPHENOL A FROM PRODUCTS
XXIII. ESTROGENIC ACTIVITY OF BISPHENOL A DIMETHACRYLATE (BIS-DMA), BISPHENOL A GLYCEROLATE DIMETHACRYLATE (BIS-GMA) AND BISPHENOL A DIGLYCIDYL ETHER (BADGE), WHICH IS A PPAR GAMMA-SELECTIVE ANTAGONIST,IN DENTAL SEALANTS AND CAN LINING (BADGE)
XXIV. BISPHENOL A AND CANCER
XXV. BISPHENOL A AND METABOLIC SYNDROME
XXVI. BROMINATED BISPHENOL A (FLAME RETARDANT)
XXVII. BISPHENOL A EFFECTS IN PLANTS
I. BISPHENOL A: LOAEL AND REFERENCE DOSE
CASRN (80-05-7)
1 nM = 228 ppt (molecular weight = 228)
LOAEL = 50 mg/kg/day, Based on studies in the 1980s that used only very high doses, the lowest dose that was examined (50 mg/kg/day) caused adverse effects, and this is termed the LOAEL
Acceptable Daily Intake level (also called the Reference Dose) = 50 µg/kg/day. The amount that is predicted based on models to be safe for humans is calculated by dividing the LOAEL by 1000 (see IRIS, US-EPA). Until the 1990’s the assumption that 50 µg/kg/day bisphenol A was safe was not challenged by directly examining this dose to see if it actually caused effects.
IRIS (1988). Bisphenol A. (CASRN 80-05-7), US-EPA Integrated Risk Information System Substance file. Accessed, 2002.
In 2002, the European Food Safety Agency (EFSA) set a Specific Migration Limit (SML) of 3 mg BPA per kg food (3 ppm).
II. GOVERNMENT REPORTS ON BPA
NTP (US National Toxicology Program). 2001. Endocrine Disruptors Low Dose Peer Review, Raleigh, NC. Accessed October, 2009.
NTP. September 2008. NTP Final Report on Bisphenol A.
Environment Canada. 2008. Draft Screening Assessment for The Challenge Phenol, 4,4' -(1-methylethylidene)bis- (Bisphenol A). Chemical Abstracts Service Registry Number 80-05-7.
ADD
FDA REPORTS
EFSA
ANSES
III. REVIEW ARTICLES CONCERNING BISPHENOL A
Report of the Berkeley Plastics Task Force on the Manufacture and Recycling of Plastics. The Berkeley Ecology Center, Berkeley, California.
Bailin, P.D., Byrne, M. Lewis, S. Liroff, R. (2008) Public awareness drives market for safer alternatives: bisphenol A market analysis report. September 15, 2008, Investor Environmental Health Network. Accessed November 3, 2009.
In 2008, based on scientific studies showing potential health harms from low dose exposure to bisphenol A, some government agencies for the first time acknowledged potential hazards from food and water contact uses of this chemical. In a few short weeks, the chemical bisphenol A (BPA) went from being a rarely discussed, ubiquitously used substance, to becoming a chemical whose hazards were highlighted in mainstream news, driving consumer demand for alternatives that in turn invigorated retailers and manufacturers. Despite the continuing debates regarding the interpretation of the scientific data, consumers and many manufacturers and retailers erred on the side of caution – choosing to reduce exposure. This analysis reviews these marketplace dynamics, both to understand the manner in which BPA and its alternatives are being treated by market decision makers, and to understand the broader implications for investors and for public policy on chemicals. Recent estimates of the size of the global market for BPA include 2.8 million tons in 2002 (Chemical Market Associates, Inc), and approximately 3 million metric tons in 2003 (SRI Consulting). The global market grew 5.7% annually from the 1990s through 2003. Global consumption increased at an average annual rate of almost 10% from 2003 to 2006, suggesting a 2006 market of about 4.0 million metric tons. Prior to the recent health scare, demand was projected to exceed 5.5 million metric tons by 2011.
Ballesteros-Gomez, A., Rubio, S., and Perez-Bendito, D. (2009). Analytical methods for the determination of bisphenol A in food. J Chromatogr A 1216, 449-469.
Food constitutes the primary route for human exposure to bisphenol A (BPA), one of the highest volume chemicals produced worldwide. The estrogenic properties of BPA, its wide dispersive use and the recent extensive literature describing low-dose BPA effects in animals, have raised concerns about its possible adverse effects on human health. A reliable health risk assessment of BPA relies basically on its unambiguous identification and accurate quantification in food, and the aim of the present review is to give an overview of the analytical methods reported so far for the determination of BPA in these matrices. Emphasis is placed on the main strategies developed for sample treatment, which usually consists of several laborious and time-consuming steps in order to achieve the required sensitivity and selectivity. Separation, identification and quantitation of BPA is today reliably made with mass spectrometric methods, namely liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), and thus main attention is devoted to these techniques, but other methods using LC coupled to fluorescence or electrochemical detection, as well as immunochemical methods are also covered. Recent and expected future developments are discussed.
Bernal, A.J., Jirtle, R.L., 2010. Epigenomic disruption: the effects of early developmental exposures. Birth Defects Res A Clin Mol Teratol 88, 938-944.
Through DNA methylation, histone modifications, and small regulatory RNAs the epigenome systematically controls gene expression during development, both in utero and throughout life. The epigenome is also a very reactive system; its labile nature allows it to sense and respond to environmental perturbations to ensure survival during fetal growth. This pliability can lead to aberrant epigenetic modifications that persist into later life and induce numerous disease states. Endocrine-disrupting compounds (EDCs) are ubiquitous chemicals that interfere with growth and development. Several EDCs also interfere with epigenetic programming. The investigation of the epigenotoxic effects of bisphenol A (BPA), an EDC used in the production of plastics and resins, has further raised concern over the impact of EDCs on the epigenome. Using the Agouti viable yellow (A(vy)) mouse model, dietary BPA exposure was shown to hypomethylate both the A(vy) and the Cabp(IAP) metastable epialleles. This hypomethylating effect was counteracted with dietary supplementation of methyl donors or genistein. These results are consistent with reports of BPA and other EDCs causing epigenetic effects. Epigenotoxicity could lead to numerous developmental, metabolic, and behavioral disorders in exposed populations. The heritable nature of epigenetic changes also increases the risk for transgenerational inheritance of phenotypes. Thus, epigenotoxicity must be considered when assessing these compounds for safety.
Brown, J. S., Jr. (2009). Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia. Schizophr Bull 35, 256-278.
In recent years, numerous substances have been identified as so-called "endocrine disruptors" because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.
Alonso-Magdalena, P., Ropero, A. B., Soriano, S., Quesada, I., and Nadal, A. (2010). Bisphenol-A: a new diabetogenic factor? Hormones (Athens) 9, 118-126.
The aim of this review was to analyze the potential effects of environmental chemicals on homeostatic control related to glycemia and energy balance. Many of the environmental chemicals can mimic or interfere with the action of hormones and are generally referred to as "endocrine disruptors". Among these compounds, polychlorinated biphenyls, dioxins, phthalates and bisphenol-A have been correlated with alterations in blood glucose homeostasis in humans. In rodents it has been demonstrated that small doses of bisphenol-A have profound effects on glucose metabolism. Therefore, this altered blood glucose homeostasis may enhance the development of type 2 diabetes.
Alonso-Magdalena P, Ropero AB, Soriano S, Garcia-Arevalo M, Ripoll C, Fuentes E, Quesada I, Nadal A (2011). Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways. Mol Cell Endocrinol.
Bisphenol-A (BPA) is an estrogenic monomer commonly used in the manufacture of numerous consumer products such as food and beverage containers. Widespread human exposure to significant doses of this compound has been reported. Traditionally, BPA has been considered a weak estrogen, based on its lower binding affinity to the nuclear estrogen receptors (ERs) compared to 17-beta estradiol (E2) as well as its low transcriptional activity after ERs activation. However, in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood. In addition, mounting evidence suggests a variety of pathways through which BPA can elicit cellular responses at very low concentrations with the same or even higher efficiency than E2. Thus, the purpose of the present review is to analyze with substantiated scientific evidence the strong estrogenic activity of BPA when it acts through alternative mechanisms of action at least in certain cell types.
Arnich, N., Canivenc-Lavier, M. C., Kolf-Clauw, M., Coffigny, H., Cravedi, J. P., Grob, K., Macherey, A. C., Masset, D., Maximilien, R., Narbonne, J. F., et al. Conclusions of the French Food Safety Agency on the toxicity of bisphenol A. Int J Hyg Environ Health 214, 271-275.
Since more than 10 years, risk assessment of bisphenol A (BPA) is debated at the international level. In 2008, the U.S. National Toxicology Program (NTP) expressed some concern for adverse effects, at current level of exposure to BPA, on developmental toxicity. In this context, the French Food Safety Agency (AFSSA) decided to review the toxicity data on BPA with a special focus on this endpoint at doses below 5mg/kg bw/day (the no observed adverse effect level set by different regulatory bodies). This paper summarizes the conclusions of a collective assessment conducted by an expert Working Group from AFSSA. Studies were classified into 3 groups: (i) finding no toxicity, (ii) reporting results not considered to be of concern and (iii) indicating warning signals. The term "warning signal" means that no formal conclusion can be drawn regarding the establishment of a health based guidance value but the study raises some questions about the toxicity of BPA at low doses. It was concluded that studies are needed to ascertain the significance for human health of these warning signals and to be able to propose new methodologies for assessing the risks associated with low doses of BPA and more generally of endocrine disruptors.
Ben-Jonathan, N., Hugo, E. R., and Brandebourg, T. D. (2009). Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome. Mol Cell Endocrinol 304, 49-54.
Bisphenol A (BPA) is one of the most prevalent and best studied endocrine disruptors. After years of exposure to consumer products containing BPA, most individuals tested have circulating BPA at the low nanomolar levels. In addition to its well documented actions on the reproductive system, BPA exerts a wide variety of metabolic effects. This review summarizes recent findings on the ability of BPA, at environmentally relevant doses, to inhibit adiponectin and stimulate the release of inflammatory adipokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) from human adipose tissue. Expression of several classical and non-classical estrogen receptors in human adipose tissue raises the possibility of their involvement as mediators of BPA actions. The implications of these observations to the obesity-related metabolic syndrome and its sequelae are discussed.
Beronius, A., Ruden, C., Hakansson, H., and Hanberg, A. (2010). Risk to all or none? A comparative analysis of controversies in the health risk assessment of Bisphenol A. Reprod Toxicol 29, 132-146.
Bisphenol A (BPA) is an endocrine disruptor for which health risk assessment has proven controversial. Conclusions regarding health risks of BPA vary between assessments from "there is no risk to any part of the population" to "there is risk to the entire population". We have carried out a literature study investigating what might be the scientific and/or policy-related reasons for these differences. Ten risk assessments for BPA were scrutinized and several factors were compared between assessments, including estimations of exposure levels, identification of critical study and NOAEL, assessment factors and significance attributed to reports of low-dose effects. Differences in conclusions were mainly influenced by the evaluation of low-dose effects and the uncertainties surrounding the significance of these data for health risk assessment. The results illustrate the impact of differences in risk assessment policy and expert judgment on the risk assessment process and highlight the importance of transparency in this process.
Braun, J. M., and Hauser, R. (2011). Bisphenol A and children's health. Curr Opin Pediatr 23, 233-239.
Bisphenol A (BPA) is a widely used chemical that has been shown to adversely affect health outcomes in experimental animal studies, particularly following fetal or early life exposure. Despite widespread human exposure in the United States and developed countries, there are limited epidemiological studies on the association of BPA with adverse health outcomes. This review briefly summarizes the epidemiological literature with special emphasis on childhood health outcomes. RECENT FINDINGS: Several studies report correlations between urinary BPA and serum sex steroid hormone concentrations in adults. Two studies report weak associations between urinary BPA concentrations and delayed onset of breast development in girls. One study found a relationship between prenatal BPA exposure and increased hyperactivity and aggression in 2-year-old female children. SUMMARY: Additional large prospective cohort studies are needed to confirm and validate findings from animal studies. Even in the absence of epidemiological studies, concern over adverse effects of BPA is warranted given the unique vulnerability of the developing fetus and child. Healthcare providers are encouraged to practice primary prevention and counsel patients to reduce BPA exposures.
Bushnik, T., Haines, D., Levallois, P., Levesque, J., Van Oostdam, J., and Viau, C. (2011). Lead and bisphenol A concentrations in the Canadian population. Health Rep 21, 7-18.
Lead is a known toxicant that occurs naturally in the environment. Bisphenol A (BPA) is an industrial chemical used primarily in polycarbonate plastic and epoxy resins. It has been 30 years since lead exposure was measured at a national level, and it is the first time for a national assessment of BPA exposure. DATA AND METHODS: Data are from the 2007-2009 Canadian Health Measure Survey. Lead in whole blood (PbB) and urinary BPA were measured in 5319 and 5476 respondents aged 6 to 79, respectively. Geometric means (GMs) are presented by age group and sex for PbB (pg/dL), volume-based BPA (microg/L), and creatinine-standardized BPA (microg/g creatinine). Adjusted least squares geometric means (LSGMs) for PbB and BPA are presented by selected covariates. RESULTS: PbB was detected in 100% of the population, with a GM concentration of 1.34 microg/dL. Adults aged 60 to 79 and males had significantly higher GM PbB concentrations. Lower household income, being born outside Canada, living in a dwelling at least 50 years old, current or former smoking, and drinking alcohol at least once a week were associated with higher PbB concentrations. Urinary BPA was detected in 91% of the population, with a GM concentration of 1.16 microg/L (1.40 microg/g creatinine). Children aged 6 to 11 had significantly higher GM creatinine-standardized BPA concentrations than did other age groups. INTERPRETATION: Although PbB concentrations have declined dramatically since the 1970s, socio-demographic characteristics, the age of dwellings, and certain lifestyle behaviours are associated with higher levels. Given the short half-life of orally ingested BPA and the high frequency of detection, the CHMS data suggest continual widespread exposure in the Canadian population.