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.