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This document is a summary statement of the outcome from the meeting: “Bisphenol A: An Examination of the Relevance of Ecological, In vitro and Laboratory Animal Studies for Assessing Risks to Human Health” sponsored by both the NIEHS and NIDCR at NIH/DHHS, as well as the US-EPA and Commonweal on the estrogenic environmental chemical bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl)propane; CAS# 80-05-7). The meeting was held in Chapel Hill, NC, 28–30 November 2006 due to concerns about the potential for a relationship between BPA and negative trends in human health that have occurred in recent decades. Examples include increases in abnormal penile/urethra development in males, early sexual maturation in females, an increase in neurobehavioral problems such as attention deficit hyperactivity disorder (ADHD) and autism, an increase in childhood and adult obesity and type 2 diabetes, a regional decrease in sperm count, and an increase in hormonally mediated cancers, such as prostate and breast cancers. Concern has been elevated by published studies reporting a relationship between treatment with “low doses” of BPA and many of theses negative health outcomes in experimental studies in laboratory animals as well as in vitro studies identifying plausible molecular mechanisms that could mediate such effects. Importantly, much evidence suggests that these adverse effects are occurring in animals within the range of exposure to BPA of the typical human living in a developed country, where virtually everyone has measurable blood, tissue and urine levels of BPA that exceed the levels produced by doses used in the “low dose” animal experiments.
Issues relating to BPA were extensively discussed by five panels of experts prior to and during the meeting, and are summarized in five reports included in this issue: (1) human exposure to bisphenol A (BPA) ; (2) in vitro molecular mechanisms of bisphenol A action ; (3) in vivo effects of bisphenol A in laboratory animals ; (4) an ecological assessment of bisphenol A: evidence from comparative biology ; (5) an evaluation of evidence for the carcinogenic activity of bisphenol A . Further discussion occurred at the meeting where participants from the panels were reorganized into four breakout groups. The consensus statements from the meeting are presented below.
The definition of “low dose” of BPA at this meeting used the same two criteria established at a prior NIH meeting concerning the low dose endocrine disruptor issue : (1) for laboratory animal studies “low doses” involved administration of doses below those used in traditional toxicological studies conducted for risk assessment purposes. For BPA the lowest dose previously examined for risk assessment purposes was 50 mg (kg−1 day−1) in studies with rats and mice. The 50 mg (kg−1 day−1) dose is the currently accepted lowest adverse effect level (LOAEL) that was used to calculate the current US-EPA reference dose (the daily dose that EPA calculates is safe for humans over the life-time) of 50 µg (kg−1 day−1). The current reference dose is thus based on “high dose” experiments conducted in the 1980s . (2) “Low dose” also refers to doses within the range of typical human exposure (excluding occupational exposures). For purposes of this meeting, the published literature that was reviewed met both of these criteria for being considered within the “low dose” range.
Hundreds of in vitro and in vivo studies regarding the mechanisms and effects of low doses of BPA, as well as studies of biomonitoring and sources of exposure, have been published in peer reviewed journals over the last 10 years, since the first “low dose” BPA in vivo studies were published [8–10]. The meeting was convened specifically to integrate this relatively new information. This task required the combined expertise of scientists from many different disciplines, and care was taken to ensure that participants covered these diverse areas.
BPA is a high-volume (>6 billion pounds per year) production chemical used to make resins and polycarbonate plastic . Of particular concern is the use of BPA in food and beverage plastic storage and heating containers and to line metal cans. In addition, potential environmental sources of BPA contamination are due to use in dental fillings and sealants , losses at the production site , leaching from landfill [14,15], and presence in indoors air .
BPA has become a chemical of “high concern” only in recent years, even though BPA was shown to stimulate the reproductive system in female rats and thus to be an “environmental estrogen” in 1936 , long before it was used as the monomer to synthesize polycarbonate plastic and resins in the early 1950s. However, more recent evidence has shown that BPA also exhibits other modes of endocrine disruption in addition to binding to estrogen receptors, such as alterations in endogenous hormone synthesis, hormone metabolism and hormone concentrations in blood. BPA also results in changes in tissue enzymes and hormone receptors, and interacts with other hormone-response systems, such as the androgen and thyroid hormone receptor signaling systems. While BPA was initially considered to be a “weak” estrogen based on a lower affinity for estrogen receptor alpha relative to estradiol , research shows that BPA is equipotent with estradiol in its ability to activate responses via recently discovered estrogen receptors associated with the cell membrane [19–22]. It is through these receptors that BPA stimulates rapid physiological responses at low picogram per ml (parts per trillion) concentrations.
To address the strength of the evidence regarding the published BPA research, an organizing committee was formed, and five panels of experts from different disciplines were established. Each panel had a chair or co-chairs and included a scientist who agreed to be primarily responsible, along with the chair, for preparing a preliminary draft of the panel’s report. A web site was established on which all of the available electronic files of articles concerning BPA were posted, along with other pertinent information relating to the meeting. Prior to the meeting, the panel members began working on draft reports and communicated via electronic media and telephone conference calls. The resulting preliminary report from each panel was posted on the web site and distributed at the meeting for all participants to read. After the meeting, each panel completed a manuscript that is a part of this meeting report. These five panel reports were peer reviewed using the normal manuscript submission process to Reproductive Toxicology.The following specific concerns about BPA led to the five expert panels being established:
The five panels each addressed a different topic related to their specific area of expertise with BPA and prepared a panel report that included documentation of the relevant published studies:
The purpose of the 3-day meeting was to provide an opportunity for members of the different panels to interact with each other to integrate information from different disciplines concerning low dose effects of BPA after each panel of experts had prepared a report in its specific area. The agenda of the meeting was designed to allow the members of the five panels to have time to discuss the information in their panel reports and finalize statements about the strength of the evidence for the literature that the panel had reviewed.
For the second part of the meeting the focus was on integrating the information from each of the panel reports. This was accomplished by assigning panel members to one of four breakout groups. The four replicate breakout groups were established using the following criteria, such that each breakout group should have
The charge to the replicate breakout groups was to individually integrate the information relating to the following four issues:
The reports from the breakout groups are presented below. The four breakout groups conducted a critical examination of the published research on BPA in relation to the four topics described above. Each of the breakout groups identified areas of knowledge and research gaps and made suggestions for future directions of research. In addition, each group identified which of the following two categories applied to specific outcomes:
The responses from the four different breakout groups were integrated together and organized based on levels of confidence. The criterion for a statement being included in a category was that there had to be consensus among all four of the breakout groups about the statement.
The published scientific literature on human and animal exposure to low doses of BPA in relation to in vitro mechanistic studies reveals that human exposure to BPA is within the range that is predicted to be biologically active in over 95% of people sampled. The wide range of adverse effects of low doses of BPA in laboratory animals exposed both during development and in adulthood is a great cause for concern with regard to the potential for similar adverse effects in humans. Recent trends in human diseases relate to adverse effects observed in experimental animals exposed to low doses of BPA. Specific examples include: the increase in prostate and breast cancer, uro-genital abnormalities in male babies, a decline in semen quality in men, early onset of puberty in girls, metabolic disorders including insulin resistant (type 2) diabetes and obesity, and neurobehavioral problems such as attention deficit hyperactivity disorder (ADHD).
There is extensive evidence that outcomes may not become apparent until long after BPA exposure during development has occurred. The issue of a very long latency for effects in utero to be observed is referred to as the developmental origins of adult health and disease (DOHaD) hypothesis. These developmental effects are irreversible and can occur due to low dose exposure during brief sensitive periods in development, even though no BPA may be detected when the damage or disease is expressed. However, this does not diminish our concern for adult exposure, where many adverse outcomes are observed while exposure is occurring. Concern regarding exposure throughout life is based on evidence that there is chronic, low level exposure of virtually everyone in developed countries to BPA. These findings indicate that acute studies in animals, particularly traditional toxicological studies that only involve the use of high doses of BPA, do not reflect the situation in humans.
The fact that very few epidemiological studies have been conducted to address the issue of the potential for BPA to impact human health is a concern, and more research is clearly needed. This also applies to wildlife, both aquatic and terrestrial. The formulation of hypotheses for the epidemiological and ecological studies can be greatly facilitated by the extensive evidence from laboratory animal studies, particularly when common mechanisms that could plausibly mediate the responses are known to be very similar in the laboratory animal models, wildlife and humans.
Meeting support was provided by NIEHS and NIDCR, NIH/DHHS, the US-EPA and Commonweal. We thank Paul French for assistance with the meeting in web site and Albert Kingman for advice during preparation of the manuscript. This manuscript does not reflect US-EPA, USGS or NIH agency policy. FvS is supported by NIH grant ES11283.
Frederick S. vom Saal, Division of Biological Sciences, University of Missouri-Columbia, 105 Lefevre Hall, Columbia, MO 65211, United States.
Benson T. Akingbemi, Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL 36849, United States.
Scott M. Belcher, Department of Pharmacology and Cell Biophysics, Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267, United States.
Linda S. Birnbaum, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709, United States.
D. Andrew Crain, Biology Department, Maryville College, Maryville, TN 37804, United States.
Marcus Eriksen, Algalita Marine Research Foundation, Los Angeles, CA 90034, United States.
Francesca Farabollini, Department of Physiology, University of Siena, 53100 Siena, Italy.
Louis J. Guillette, Jr, Department of Zoology, University of Florida, Gainesville, FL 32611, United States.
Russ Hauser, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, United States.
Jerrold J. Heindel, Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
Shuk-Mei Ho, Department of Environmental Health, University of Cincinnati Medical School, Cincinnati, OH 45267, United States.
Patricia A. Hunt, School of Molecular Biosciences, Washington State University, Pullman, WA 99164, United States.
Taisen Iguchi, National Institutes of Natural Science, Okazaki Institute For Integrative Bioscience Bioenvironmental Science, Okazaki, Aichi 444-8787, Japan.
Susan Jobling, Department of Biological Sciences, Brunel University, Uxbridge, Middlesex, UK.
Jun Kanno, Division of Cellular & Molecular Toxicology, National Institute of Health Sciences, Tokyo 158-8501, Japan.
Ruth A. Keri, Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, United States.
Karen E. Knudsen, Department of Cell and Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States.
Hans Laufer, Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States.
Gerald A. LeBlanc, Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695, United States.
Michele Marcus, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, United States.
John A. McLachlan, Center for Bioenvironmental Research, Tulane and Xavier Universities, New Orleans, LA 70112, United States.
John Peterson Myers, Environmental Health Sciences, Charlottesville, VA 22902, United States.
Angel Nadal, Instituto de Bioingeniería, Universidad Miguel Hernández, Elche 03202, Alicante, Spain.
Retha R. Newbold, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
Nicolas Olea, CIBERESP Hospital Clinico-University of Granada, 18071 Granada, Spain.
Gail S. Prins, Department of Urology, University of Illinois at Chicago, Chicago, IL 60612, United States.
Catherine A. Richter, USGS, Columbia Environmental Research Center, Columbia, MO 65201, United States.
Beverly S. Rubin, Department of Anatomy and Cellular Biology, Tufts Medical School, Boston, MA 02111, United States.
Carlos Sonnenschein, Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
Ana M. Soto, Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
Chris E. Talsness, Charité University Medical School Berlin, Campus Benjamin Franklin, Institute of Clinical Pharmacology and Toxicology, Department of Toxicology, 14195 Berlin, Germany.
John G. Vandenbergh, Department of Zoology, North Carolina State University, Raleigh, NC 27695, United States.
Laura N. Vandenberg, Tufts University Sackler School of Graduate Biomedical Sciences, Boston, MA 02111, United States.
Debby R. Walser-Kuntz, Carleton College, Department of Biology, Northfield, MN 55057, United States.
Cheryl S. Watson, Biochemistry and Molecular Biology Department, University of Texas Medical Branch, Galveston, TX 77555, United States.
Wade V. Welshons, Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, United States.
Yelena Wetherill, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, United States.
R. Thomas Zoeller, Biology Department, University of Massachusetts, Amherst, MA 01003, United States.