Battles Over Bisphenol A

By Sarah Vogel, 4/16/08

Overview
Bisphenol A is an estrogenic chemical primarily used in the production of two major plastics: polycarbonate and epoxy resin.  Polycarbonate is a hard, rigid plastic used in kitchen appliances, chocolate molds, baby bottles, reusable water bottles, compact discs (CDs), digital video discs (DVDs), and water coolers. Epoxy resins are used as strong adhesives and coatings in products such as food and beverage can (including beer) liners, drum liners, paints, dental sealants, and water main filters.  Over the past decade hundreds of studies reporting developmental, reproductive, behavioral and neurological effects of low dose exposure to bisphenol A ignited a contentious debate over the chemical’s safety. [1]  Despite mounting evidence of low dose effects of bisphenol A in laboratory animals, representatives of the plastics industry and bisphenol A producers continue to maintain that bisphenol A is safe at low doses. [2]  

The stakes in the debate over bisphenol A safety are exceedingly high—economically, politically and biologically. Used commercially since the 1950s, current bisphenol A global production tops 6 billion pounds.  Bisphenol A is now a ubiquitous component of our economy, environment and bodies.  Recent biomonitoring data from the Centers for Disease Control and Prevention found detectable levels of bisphenol A in over 90% of human urine samples. [3] The chemical has also been found in human (adult and fetal) blood, placental tissue, amniotic fluid, and breast milk. [4

Two government-sponsored reviews of the extensive research on bisphenol A, conducted in the past year, reported conflicting levels of concern about the chemical’s safety, particularly in terms of its reproductive and developmental effects. The first assessment, sponsored by the National Institute of Environmental Health Sciences (NIEHS), the Environmental Protection Agency (EPA), and the non-profit organization Commonweal, brought together a select group of 38 bisphenol A or endocrine disruptor experts to evaluate over 700 low dose studies. This assessment integrated cell-based research, laboratory research, human exposure research and wildlife research. The final report, the Chapel Hill Consensus Statement, raised serious concerns about the reproductive and development effects of bisphenol A. 

The second assessment, sponsored by the Center for the Evaluation of Risks to Human Reproduction (CERHR) at the NIEHS, selected researchers who had not conducted research on bisphenol A. Allegations of a conflict of interest delayed the first meeting of the CERHR panel; the contractor hired to draft the CERHR report, Sciences International, also held contracts with several of the major bisphenol A producers.  After learning of the potential conflict of interest, the NIEHS conducted a basic audit of the CERHR process.  Based on the audit’s findings, the CERHR maintained the original draft report with a few minor corrections, and the panel met to review the document in August 2007.  In its assessment of the literature, the panel made controversial decisions about the criteria standards used to evaluate the studies, resulting in the elimination of many of the most alarming low dose papers from the report. The preliminary conclusions of the CERHR panel reported "minimal concern" about reproductive and development effects of bisphenol A and "some concern" about the effects on brain development.

In response to serious problems with the CERHR process and its conflicting findings with the Chapel Hill Consensus Statement, the CERHR staff revised the report and opened it once again to public comments.  The final report, released to the public in late November 2007, contained no substantial changes from the preliminary conclusions. On April 14, 2008, CERHR released the first draft of National Toxicology Program’s (NTP) Brief on Bisphenol A, which is currently open for public comments.  The final NTP report will combined the CERHR report, the NTP review and all public comments on reports and is expected to be released at the end of this summer.  The draft Brief on Bisphenol A, which does not reflect the final recommendations of the institute, did raise the level of concern for the reproductive effects of bisphenol A at levels of human exposure.  The NTP draft report maintained the CERHR Expert Panel’s conclusion of November 2007 of “some concern for neural and behavioral effects in fetuses, infants, and children at current human exposure,” and added that it “also has some concern for bisphenol A exposure in these populations based on effects in the prostate gland, mammary gland, and an early age for puberty in females.”  These effects on the mammary and prostate gland include pre-cancerous lesions that increase the susceptibility for tumor development later in life. They note that “because these effects in animals occur at bisphenol A exposure levels similar to those experienced by humans, the possibility that bisphenol A may alter human development cannot be dismissed.” [5

The Food and Drug Administration developed its safety standard for bisphenol A from a single, high dose study conducted on adult rats in the late 1970s. The agency currently relies on data from two studies, funded by the American Plastics Council, to uphold this standard. [6] In its recent report, the NTP stated that such high dose studies are insufficient in determining the cancer risks in “hormonally-responsive tissues such as the mammary gland.” [7]  The FDA must respond to the growing scientific consensus of bisphenol A’s threat to the public’s health, in particular its risks to the healthy development of fetuses, infants and children.  States across the country and the Canadian government are considering new limits and bans on bisphenol A, particularly in children’s products.  It is imperative that the FDA provides the necessary federal leadership on this issue by listening to independent experts and closing the door on chemical and plastics industry representatives who persistent in upholding the safety of bisphenol A despite the mounting evidence of harm.

Early uses and research
In the mid 1930s, not long before the first epoxy resins were created, Sir Edward Charles Dodds, a British medical researcher, identified the estrogenic properties of bisphenol A.  In his search for the first synthetic estrogen, Dodds identified the estrogenicity of a number of chemicals with similar two-dimensional structures, including diethylstilbestrol (DES) and bisphenol A.  Beginning in the 1940s, doctors prescribed the potent synthetic estrogen, DES, to millions of pregnant women to prevent miscarriages and other reproductive ‘problems,’ and meat producers injected it into livestock to increase meat production. Diethystilbestrol remained on the drug market for thirty years until it was banned in the early 1970s when the first epidemiological studies reported rare vaginal cancers in young women exposed to DES while in their mothers’ wombs—evidence that confirmed DES’s carcinogenicity. [8]

A weaker estrogen, bisphenol A, never found use as a drug; its future was in plastics.  Several years after Dodds published his research on synthetic estrogens, chemists in the U.S. and Switzerland synthesized the first epoxy resins using bisphenol A.  Commercial production of epoxy resins began in the early 1950s.  In 1957, chemists discovered another use for bisphenol A—when polymerized (linked together in long chains), it forms a hard plastic, polycarbonate.  In response to expanding markets for plastics, the production of bisphenol A took off in the 1960s and 1970s.  U.S. production of bisphenol A tripled in the 1970s to reach just under a billion pounds by the early 1980s. [9]  

The dramatic increase in production brought the chemical to the attention of researchers at the National Cancer Institute (NCI) and the National Toxicology Program (NTP).  In the late 1970s, a two-year carcinogenesis study of bisphenol A was initiated by the National Cancer Institute and conducted by Litton-Bionectics, a subcontractor working with Tractor-Jitco, the main contractor for NCI at the time.  During the time period of the bisphenol A study, the U.S. General Accounting Office released a report that documented very poor laboratory conditions at this facility. [10] Despite these findings, the bisphenol A bioassay was completed in 1979 and a draft report prepared by the main contractor Tractor-Jitco.  In 1982, after the NCI’s carcinogenesis program was transferred to the newly established National Toxicology Program, the bisphenol A study was released to the public.  The NTP’s carcinogenesis bioassay (initiated at NCI in the late 1970s) reported “no convincing evidence of carcinogenicity;” however, the committee qualified this statement

to reflect the facts that leukemia in male rats showed a significant positive trend, that leukemia incidence in high-dose male rats was considered not significant only on the basis of the Bonferroni criteria, that leukemia incidence was also elevated in female rats and male mice, and that the significance of interstitial-cell tumors of the testes in rats was dismissed on the basis of historical control data. [11

The NTP’s reproductive toxicity study reported that bisphenol A was a “reproductive toxicant” that “caused a reduction in the number of live pups born in the F0 [parent] generations, and reduced sperm motility and weight of some male reproductive organs in both the F0 and F1 [first] generation, and reduced postnatal survival of the F1 generations.” However, because the study also reported liver and kidney toxicity, the authors concluded that reproductive toxicity may be secondary to more generalized toxic effects. [12]

The reference dose and presumptions of bisphenol A safety
In the late 1980s, the EPA set the first safety standard, a reference dose, for bisphenol A at 50 µg/kg.  This continues to be the safety standard used by the Food and Drug Administration (FDA) today. The EPA calculated the reference dose by dividing the lowest observed adverse effect level (LOAEL) reported in the NTP carcinogenesis bioassay (50 mg/kg) by an uncertainty factor of 1000.  The assumption of safety at levels of exposure below the standard is just that, an assumption.  The NTP carcinogenesis study followed the standard toxicology study design of the time—they used adult mice and rats and exposed them to very high levels of bisphenol A. High dose adult animal studies, considered the cornerstone of toxicology, assume that if a chemical can cause cancer, death or mutation, the effect will more likely be seen at high doses.  Therefore, the presumption of bisphenol A’s safety below 50 µg/kg rests on data from a single high dose study conducted on adult animals, potentially under poor laboratory conditions.

In the past ten years, in response to rising concerns about the transgenerational effects of endocrine disruptors, researchers from disciplines outside toxicology began exposing developing animals (in utero or neonatally) to very low doses of bisphenol A and other endocrine disrupting chemicals and found effects on hormonally sensitive endpoints.  The first of these low dose studies on bisphenol A was published in 1997 by a team of researchers at the University of Missouri-Columbia, led by Fred vom Saal.  Trained as a developmental biologist, in the 1980s vom Saal studied behavioral and physiological effects of very subtle hormonal changes during fetal development.  This early work contributed to a growing hypothesis that mice and rat fetuses are exquisitely sensitive to minute changes in their hormonal environment. [13] In 1997 and 1998, vom Saal’s team published two studies that found increased prostate weights and other effects on the male reproductive system (including seminal vesicles, epidydmis, and sperm efficiency) in the mice exposed to levels of bisphenol A below the safety standard (2 and 20 ug/kg). [14

The publication of these studies set off a storm of controversy about the safety of bisphenol A at low doses.  The plastics and chemical industries responded swiftly.  The Society of the Plastics Industry Bisphenol A Task Group and the European Chemical Industry Council (CEFIC) sponsored two studies to replicate vom Saal’s findings. [15] The first study, conducted by John Ashby of AstraZeneca, reported no effects of bisphenol A exposure on prostate weight or sperm count. In addition, Ashby found no effects of exposure from DES, used in the study as a positive control. [16] Researchers at Shell Chemical Corporation, Dow Chemical Company, General Electric, and Bayer Corporation, all bisphenol A producers, conducted the second study, which also failed to replicate bisphenol A effects on male reproductive development reported in vom Saal’s study. [17] The lack of replication, according to the industry, reaffirmed the safety of bisphenol A.  But the intense scrutiny of vom Saal’s work only brought the issue of low dose effects under greater scientific scrutiny. 

In 2000, at the request of the EPA, which at the time was developing a testing and screening process for endocrine disruptors (as promulgated by the 1996 Food Quality Protection Act and Safe Drinking Water Act), the NTP held a workshop on low dose effects of endocrine disruptors.  In its assessment of the bisphenol A literature, the report concluded:

... there is credible evidence that low doses of BPA [bisphenol A] can cause effects on specific endpoints. However, due to the inability of other credible studies in several different laboratories to observe low dose effects of BPA, and the consistency of these negative studies, the Subpanel is not persuaded that a low dose effect of BPA has been established as a general or reproducible finding. [18]

As to the general finding of low dose effects, the NTP concluded with greater certainty that “low-dose effects were clearly demonstrated for estradiol [naturally occurring estrogen] and several other estrogenic compounds.” They also concluded

that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see if changes are needed regarding dose selection, animal model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents. [19]

Despite the NTP’s conclusions on low dose effects, the EPA announced in 2002 that it would not include low dose considerations in the testing and screening protocols for endocrine disruptors.  In its announcement, the EPA declared that because of scientific uncertainty, it would be “premature to require routine testing of substances for low dose effects in the Endocrine Disruptor Screening Program.”  [20] In effect, the EPA took the position that in the face of uncertainty the lack of absolute evidence of harm meant no evidence of harm; rather than taking a preventative or precautious position, the EPA called for more research.  Over the next seven years the number of peer-reviewed published literature on low dose effects of bisphenol A rose from a little over twenty studies in 2000 to hundreds of papers by 2007. [21]

This enormous body of research on bisphenol A provides extensive evidence of adverse, developmental effects of low doses, and challenges the presumption of the chemical’s “weak” estrogenicity.  Bisphenol A appears to elicit different estrogenic effects depending on the target tissue, classifying it as a Selective Estrogen Receptor Modulator (SERM), similar to the drug tamoxifen.  Vom Saal’s research demonstrates that low binding affinity to sex-hormone binding globulin—the protein that binds estradiol and renders it unavailable for binding to the receptor—makes bisphenol A more readily available (free) to bind to estrogen receptors. [22] Research from other laboratories also indicates that when bisphenol A acts through estrogen receptors on the cell membrane, as opposed to the nuclear estrogen receptors, its estrogenic effect is as potent as natural estrogen. [23]

The latest health effects from exposure to bisphenol A
In response to new evidence of low dose effects and mechanisms of action of bisphenol A, representatives of the plastics and chemical industry have argued that reported low dose effects, including increased prostate weight, increased body weight, altered estrus cyclicity and reduced sperm production, do not represent traditionally defined adverse toxicological endpoints (death, malformation or cancer). In public comments to the NTP, the American Plastics Council contended that the low dose effects had “unclear biological relevance.”  [24]  Several years ago, the NIEHS’s Extramural Division of Research began funding multi-year studies aimed at supporting research that examined whether low dose exposure to bisphenol A, estrogen, DES or other endocrine disruptors during early development resulted in definitive adverse effects (defined as chronic diseases in the human population) in matured animals.  The program aimed to expand research on the fetal basis of disease, a theory that argues critical changes during fetal development can alter developmental programming, resulting in an increased risk of chronic disease in adult life. [25]  Recently published work on bisphenol A, funded by this program, includes studies from Ana Soto and Carlos Sonnenschein’s laboratory at Tufts University that found an increase of mammary gland tumors, [26] and Gail Prin’s laboratory at University of Illinois-Chicago that reported an increase of precancerous lesions in prostates of neonatally exposed animals. [27] Both of these studies correlate bisphenol A exposure to well defined adverse endpoints.

This appears to be the latest direction in bisphenol A research.  Retha Newbold, a leading expert on DES at NIEHS, recently published a study that found an increase of cystic ovaries and cystic endometrial hyperplasia in mice neonatally exposed to low doses of bisphenol A. [28] One of the most startling recent findings came from the laboratory of Pat Hunt at Carnegie Mellon University.  Her team exposed mice to low doses of bisphenol A during pregnancy and reported very high rates of aneuploidy, chromosomal damage resulting in extra or missing chromosomes (resulting from meiotic disruption) in the eggs of the exposed female mice, in the offspring of the exposed population, and in the pups of those exposed offspring, suggestive of bisphenol A’s transgenerational effect. [29]

A growing number of low dose studies of bisphenol A indicate that exposure during critical periods of development can result in unequivocally adverse effects.  These include increased risk of cancer in the mammary gland and prostate gland, polycystic ovarian disease, obesity, insulin resistant (type II) diabetes[30] and aneuploidy.  None of these effects would have been predicted by traditional high dose toxicological studies.  Collectively, this research challenges the long held assumption that bisphenol A’s “weak” estrogenicity poses little risk to human health, and raises serious questions about the presumed safety of the reference dose.

Two panels, two different conclusions
In response to the tremendous growth in research on bisphenol A, the NIEHS organized two very distinct panels to review the scientific literature.  In November 2006, bisphenol A researchers from around the world met in Chapel Hill, North Carolina, and in 2007, the Center for the Evaluation of Risks to Human Reproduction (CERHR) gathered a group of researchers outside of Washington D.C. The two expert panels reached conflicting conclusions about the safety and risks of bisphenol A.

The NIEHS Bisphenol A Expert Panel in Chapel Hill, composed of the world’s leading bisphenol A experts, reviewed over 700 low dose bisphenol A studies (in vitro, in vivo, wildlife, and human exposure studies).  The final conclusions of the panel, the Chapel Hill Consensus Statement (published as a peer-reviewed article in the August 2007 issue of Reproductive Toxicology), stated with certainty that bisphenol A presents a risk to reproductive, neurological, behavioral, and metabolic development, particularly when the exposure occurs during critical windows of development (i.e., in utero or neonatally). The experts also concluded with certainty that humans are currently exposed to levels of bisphenol A found to cause adverse effects in laboratory animals, and exposure to low doses of bisphenol A results in “organizational changes in the prostate, breast, testis, mammary glands, body size, brain structure and chemistry, and behavior of laboratory animals.” [31]

In contrast, the Center for the Evaluation of Risks to Human Reproduction's expert panel included a mix of university, government and industry researchers, none of whom worked with or published on bisphenol A.  The logic behind the decision to exclude bisphenol A researchers from the expert panel assumed that the expertise would bias the report.  This approach contrasts with the Chapel Hill meeting as well as scientific reviews conducted by the International Agency for Research on Cancer (IARC) and the NTP’s Low Dose review. 

Excluded from the panel meetings, bisphenol A experts used the public comment period to respond to what they saw as a flawed draft report.  Researchers at Tufts University submitted a 60-page response paper (12 pages of written comments and 48 pages of references) that raised six major critiques of the report, including: arbitrary setting of criteria standards for evaluating studies; setting of standards not established a priori; misrepresentation of the data; inconsistency of application of some criteria; and bias in funding source for data included in the review.[32]

The preliminary conclusions drawn by the CERHR panel expressed more limited concerns about bisphenol A safety compared to the Chapel Hill Consensus Statement.  The panel concluded that they had “some concern” about behavioral and neural development, but “minimal” and “negligible concern” about reproductive toxicity, birth defects and malformations. 

CERHR’s weakness
The first meeting of the CERHR panel, scheduled to be held in March of 2007, was unexpectedly delayed after the Environmental Working Group (EWG) raised allegations of a serious conflict of interest of the private contractor Sciences International hired by the NTP to draft the CERHR report.  The Los Angeles Times reported that Sciences International also held contracts with major chemical companies, including bisphenol A producers Dow and BASF.  In response to a request for a briefing on the allegations from Representative Henry Waxman and Senator Barbara Boxer’s office, the NIEHS cancelled its contract with Sciences International and conducted an audit of the contractor’s report.

The audit consisted of a simple comparison of the number of published studies on bisphenol A found in the open literature with the number of studies included in the Sciences International draft report. Next, the auditors counted the number of recommendations made by the CERHR panel incorporated in Sciences International’s report.  Based on these two comparative figures, the auditors found no consistent irregularities.  The NTP’s audit report concluded:

The audit provides assurance that the draft BPA expert panel reports include considerations of all relevant references and reliably include changes requested by the expert panel members.  NTP concludes that the draft expert panel reports are useful for the CERHR evaluation of BPA.[33]

CERHR retained the original draft report with a few minor additions. While the NTP’s audit cleared Sciences International of any overt biases, it fell short in addressing two serious questions raised in this debate: first, is there sufficient and transparent oversight of private contractors at the NTP/NIEHS; and second, what is the process for selecting criteria standards for evaluating studies and how do these standards influence the conclusions drawn.

One of the criteria standards for evaluating the adequacy of a given study in the CERHR report was oral exposure to bisphenol A.  The committee reasoned that this method of administration more closely mimics human exposure. Exposing animals via injection or subcutaneous pump, the panel members argued, bypasses metabolic processes that may reduce the toxicity of the chemical.  While the pharmacokinetics of bisphenol A represents an important factor in determining a more accurate internal dose, this criteria standard effectively gave preference to route of exposure over the dose level or timing of exposure, both of which are critically important variables in determining effect.

Researchers using injections or pumps contend that such methods provide better control for delivering an exact dose to the animal, since animals often avoid contaminated food, and the alternative, force feeding or gavage, stresses the animal.  Moreover, very low dose injections replicate documented levels of bisphenol A in amniotic fluid and breast milk.  This is of particular concern in studies examining the effects of fetal exposure to bisphenol A.  The fetus may be exposed orally to bisphenol A in amniotic fluid; additionally, bisphenol A in maternal serum may also be available to the fetus since the chemical can cross the placental barrier. 

Finally, the oral criteria standard also failed to take into account several studies, reviewed by participants of the Chapel Hill meeting, that report similar metabolic patterns in neonatal animals exposed orally and by injection. [34] In an effort to further explore the metabolic difference in exposure routes, vom Saal’s laboratory recently conducted a study comparing the blood levels of neonatal animals exposed orally with those exposed by injection.  Their findings found similar blood levels of bisphenol A in the two dosing groups. [35] These results further support the hypothesis that neonatal animals and fetuses do not have the same ability to metabolize bisphenol A as adults.  As such, this research upholds the credibility of low dose studies that use injections and pumps and calls into question the CERHR’s reasons for excluding such studies from their assessment.

By eliminating these low dose studies, the committee dismissed some of the most compelling and alarming bisphenol A studies.  These include recent work demonstrating low dose effects of altered mammary gland development and in situ carcinoma, increased risk of prostate cancer development, and chromosomal abnormalities.  In the absence of these studies, the committee, in its assessment of reproductive effects, relied on one large scale, high dose study, funded by the chemical industry, that used a relatively estrogen-insensitive rat and reported no significant effects on the reproductive system. [36] As a result, the CERHR panel’s initial conclusions presented a level of concern disturbingly out of step with the Chapel Hill Consensus Statement and in line with the major chemical and plastics trade association’s position. 

Lessons for the NIEHS
Comparing the process and content of the Chapel Hill and CERHR assessments yields important lessons for the NIEHS.  The problems that plagued the CERHR panel strongly suggest that the structure of the evaluation process needs to be reconsidered. In light of the controversy and serious problems with the CERHR review process, the following are a list of recommendations for the NIEHS:

  1. Creating an independent panel does not mean that participants should have no experience working with the chemical under review.  The CERHR should look to reviews conducted by the National Academy of Sciences, the International Agency for Research on Cancer (IARC) and other programs at the NTP (such as the 2001 Low Dose Workshop) that include experts (without financial conflicts of interest) on their panels or allow experts to present their data.  A researcher’s extensive knowledge about a chemical does not create bias; rather it defines an expert.  By excluding experts from the panel, the CERHR unsuccessfully sought to contain the very high political stakes in this debate.  However, as the panel members experienced first hand, they were no more immune to the politics of the situation than the bisphenol A experts.  With a strong conflict of interest policy, expert committees can achieve a high level of both credibility and competence.
  2. Determining conflict of interest is not simply a matter of identifying blatant biases.  The audit conducted by the NIEHS only scratched the surface of concerns regarding the development of the CERHR criteria standards.  More extensive conflict of interest policies developed by IARC may present NIEHS with possible models for the future.
  3. Public meetings should be fully open to the public.  This seems like an obvious comment, but the CERHR panel spent a vast majority of their meeting time behind closed doors, breaking briefly to inform the public that they were returning once again to closed-door sessions.  This not only frustrated the public, but allowed doubt and skepticism about the quality of the evaluation, first sown in March, to take root and grow.  
  4. Evaluating the weight of the evidence should integrate scientific research from in vitro, in vivo, human exposure, and wildlife studies as was done in the Chapel Hill assessment.  Limiting the review to only those studies that expose animals orally failed to acknowledge other critically important factors in study design, such as timing of exposure, endpoints measured, timing of the outcome measurement and definition of low dose.

NTP Draft Brief on Bisphenol A
The second step in the CERHR evaluation of bisphenol A involved an in-house review of the scientific literature by scientists at the National Toxicology Program (NTP)—the NTP Brief on Bisphenol A.  This report, released in draft form on April 14, 2008, raised the level of concern for bisphenol A exposure in fetuses, infant and children on the prostate and mammary gland, as well as early on-set of puberty.  In its draft form, the NTP concluded that there is “some concern for bisphenol A exposure in these populations [fetuses, infants and children] based on effects in the prostate gland, mammary gland, and an earlier age for puberty in females.” The NTP Brief also maintained the CERHR conclusion of “some concern for neural and behavioral effects in fetuses, infants, and children.”  Since these conclusions drew on laboratory studies at levels “similar to those experienced by humans,” the NTP declared that “the possibility that bisphenol A may alter human development cannot be dismissed.” [37] The significant change in the NTP’s draft conclusions on the risks of bisphenol A reflects a shift in the institution’s interpretation of low dose studies that use non-oral routes of exposure.  In its draft review, the NTP acknowledged that neonatal and fetal rats and mice have a reduced ability to metabolize bisphenol A when compared with adults and cites a recent study demonstrating no difference in free bisphenol A in neonatal mice exposed orally or subcutaneously. Taking into account the decreased ability of neonatal and fetal mice to metabolize bisphenol A, the NTP considered studies using subcutaneous injections or pumps to be useful when neonatal animals were exposed. These studies, as the NTP report noted, present evidence that low doses of bisphenol A during early development cause lesions in the mammary glands (“generally recognized as…pre-neoplastic lesions in the human”) and prostate glands that increase the risk of tumor development later in life. [38]

The NTP’s Brief on bisphenol A together with the Chapel Hill Consensus Statement present two rigorous reviews of the available literature that raise significant concerns about the safety of bisphenol A at levels of human exposure particularly for the developing fetus, infant and child.  The collective effort of dozens of independent scientists, working to evaluate the state of the science, stands in stark contrast to the FDA’s safety standard, which is based on the findings from a single, high dose study of the carcinogenic effects of exposure in adult animals conducted in the late 1970s. Despite the rising concerns of scientists and consumers, the FDA has persistently supported the position of the chemical and plastics industry.  In 1999, the FDA director of the division of product policy, George Pauli, in response to growing concerns about the safety of bisphenol A remarked: “Our conclusion is we should go with the track record. We have evaluated in a thorough manner, and concluded its use is safe.  We haven’t seen anything that would persuade us to change that.” [39]

It is overwhelmingly evident that much has changed over the past nine years.  Today dozens of studies point to adverse reproductive and neurological effects of extremely low doses of bisphenol A in the developing fetus, infant and young.  How does the FDA continue to justify the safety of its current standard?  It relies on two studies of bisphenol A, sponsored by the plastics industry.  Among the hundreds of studies published on bisphenol A, none of the industry-funded studies have reported any effects of bisphenol A exposure. [40]  Upholding industry-financed research as sufficient evidence to protect the public’s health strongly suggests that the FDA holds greater concern for the needs and demands of the chemical and plastics industry than the health and safety of the population at greatest risk—the developing young.

Industry's bias
For decades, industry trade associations and their lawyers staved off the regulation of unsafe products like tobacco, lead and asbestos by arguing that scientific uncertainty precluded government action. [41] Similarly, the plastics and chemical industries seek to deny, delay, and dismiss the low dose research on bisphenol A.  First, industry studies failed to replicate low dose effects. When more and more studies found effects on hormone sensitive tissues and systems at doses below the safety standard, the industry argued that the reported physiological changes were irrelevant to human health.

For example, in 2000, the American Plastics Council (APC) contracted with the Harvard Center for Risk Analysis to conduct a “weight of the evidence” evaluation of bisphenol A.  The report, published in 2004 and updated in 2006 by the Gradient Corporation, concluded that low dose exposure to bisphenol A presented no significant risk to human health. [42] Both assessments used a criteria standard developed by the Annapolis Center’s Accord for the Use of Toxicology in Risk Assessment and Decision-Making that, like the CERHR report, excluded those studies that exposed animals by injection or pump. [43] The Annapolis Center, Harvard Center for Risk Analysis and the Gradient Corporation all receive funding by major plastics, chemical, petroleum, and tobacco companies and industry trade associations. [44] This industry-funded protocol for conducting weight of the evidence assessments reflects a broader strategic effort to control what constitutes “sound science.” The NIEHS and the FDA must be aware of industry-led efforts to determine legitimate, relevant, and reliable scientific research. On April 15, 2008, the American Chemistry Council issued a press release that spun the latest NTP draft Brief on Bisphenol A as further confirmation that the chemical is safe at low levels, leaving one to wonder what report they actually read. [45]

Conclusion
Political pressure to re-evaluate bisphenol A safety is mounting in response to dozens of studies demonstrating adverse effects from low dose exposure to bisphenol A.  A number of states, including California, Maryland, Minnesota and Michigan, are considering bills to ban or severely restrict bisphenol A in children’s products.  In early 2008, federal lawmakers finally began to respond to rising concerns about bisphenol A safety.  Congressmen John Dingell (D-MI) and Bart Stupak (D-MI) initiated an investigation into the presence of bisphenol A in infant formula and sent letters to the FDA noting that the agency's position on bisphenol A's safety appears to be entirely dependent on two studies funded by the American Plastics Council and requesting details about the FDA's determination of the chemical's safety. [46]  These actions of the state, however, are painfully slow when compared with consumer responses to the emerging scientific consensus on bisphenol A risks.  All across the U.S. and Canada, parents are throwing out polycarbonate baby bottles and Nalgene sports bottles, effectively making their own personal decisions about the potential risks of bisphenol A exposure.
 
While consumer demands and choices send an important message to manufacturers and lawmakers, with over 6 billion pounds produced per year, bisphenol A is critically important to the production of plastics used in hundreds if not thousands of products—not just baby bottles.  It is, therefore, critically important that lawmakers take a strong stand in protecting the public’s health.  This means stepping beyond the political debate over scientific uncertainty stirred by those with the greatest economic stakes—the chemical industry—to consider what is known about this chemical.
 
Bisphenol A binds to estrogen receptors (alpha and beta nuclear receptors and plasma-membrane bound receptors). Exposure to very low doses early in development alters the breast and prostate tissues in ways that increase the risk of developing cancer later in life, and disrupts brain development and behavior.  Low dose exposure may also increase the risk of developing insulin resistant diabetes and obesity, and disrupt chromosomal alignment, resulting in one of the most common causes of miscarriage in humans. Its estrogenicity, once considered weak, is now known to be much more potent. Most importantly, these effects are being reported at levels found in the human body.

The public should not have to wait for years for unequivocal epidemiological evidence to determine the risks of this chemical. Today there is a growing scientific consensus among independent bisphenol A experts that this chemical poses a significant public health risk at levels millions of times below the current safety standard.  The FDA’s safety standard remains conspicuously out of date.  Maintaining such a standard only serves the interests of the chemical and plastics industry, and leaves unprotected the long-term health of the developing young. If we want to prevent chronic disease and protect the public’s health, lawmakers across the U.S. and the world should support the removal of bisphenol A from our food, water, air, and bodies.

 

About the Author: Sarah Vogel is a PhD Candidate at Columbia University in the Department of Sociomedical Sciences’ Center for the History and Ethics of Public Health and Medicine. She holds master’s degrees in public health and environmental management from Yale University. Her dissertation, “Politics of Plastic: the economic, political and scientific history of bisphenol A,” will be completed in the spring of 2008.

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Notes
[1] F. S. Vom Saal et al., "Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure," Reprod Toxicol 24, no. 2 (2007), F. S. vom Saal and C. Hughes, "An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment," Environ Health Perspect 113, no. 8 (2005): 131-8.

[2] J. E. Goodman et al., "An updated weight of the evidence evaluation of reproductive and developmental effects of low doses of bisphenol A," Crit Rev Toxicol 36, no. 5 (2006): 387-457.

[3] A. M. Calafat et al., "Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population," Environ Health Perspect 113, no. 4 (2005): 391-5 and Calafat, AM, et al., “Exposure of the US population to bisphenol A and 4-tertiary-octylphenol: 2003-2004,” Environ Health Perspect 116, no. 1 (2008): 39-44.

[4] For a summary of exposure data, see M. V. Maffini et al., "Endocrine disruptors and reproductive health: the case of bisphenol-A," Mol Cell Endocrinol 254-255 (2006): 179-66.

[5] Draft NTP Brief on Bisphenol A [CAS NO. 80-05-7]. National Toxicology Program, National Institute of Environmental Health Sciences/National Institutes of Health/U.S. Department of Health and Human Services. April 14, 2008. p. 37.

[6] Letter from John Dingell, Chairman of the House of Representatives Committee on Energy and Commerce and Bart Stupak, Chairman of the Subcommittee on Oversight and Investigations, to Andrew von Eschenbach, MD, Commissioner of the FDA. April 4, 2008.

[7] Draft NTP Brief on Bisphenol A [CAS NO. 80-05-7]. National Toxicology Program, National Institute of Environmental Health Sciences/National Institutes of Health/U.S. Department of Health and Human Services. April 14, 2008. p. 22.

[8] A. L. Herbst, H. Ulfelder, and D. C. Poskanzer, "Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women," N Engl J Med 284, no. 15 (1971): 878-81.

[9] "Chemical Profile: Bisphenol A," Chemical Marketing Reporter, January 10 1972, 8, "Chemical Profile: Bisphenol A," Chemical Marketing Reporter, May 26 1980, p. 9.

[10] Statement of Edward A. Densmore, Deputy Director Human Resources Division Before the Senate Committee on Labor and Human Resources on Three GAO Reviews of Contract Administration by the National Cancer Institute.  U.S. General Accounting Office. Released June 2, 1981. Report to Honorable Henry A. Waxman, House of Representatives, B-164031(2), U.S. General Accounting Office. March 30, 1979.

[11] NTP, "Carcinogenesis Bioassay of Bisphenol A (CAS No. 80-0507) In F344 Rats and B6C3F1 Mice (Feed Study)," (National Toxicology Program, US Department of Health and Human Services, and National Institutes of Health, 1982).  James Huff at the NIEHS has argued that based on the categories of carcinogenesis evidence adopted by the NTP the year after the bisphenol A report was issued, evidence from this study would be considered “equivocal.” See J. Huff, "Carcinogenicity of bisphenol A revisited," Toxicol Sci 70, no. 2 (2002): 281-3.

[12] NTP, "Bisphenol A: Reproduction and Fertility Assessment in CD-1 Mice When Administered in the Feed,"  (National Toxicology Program, 1985).

[13] Howard A. Bern, "The Fragile Fetus," in Chemically-Induced Alterations in Sexual and Functional Development: The Human/Wildlife Connection, ed. Theo Colborn and Coralie Clement, Advances in Modern Environmental Toxicology, vol 21 (Princeton, New Jersey: Princeton Scientific Pub Co, 1992): 9-15.

[14] S. C. Nagel et al., "Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol," Environ Health Perspect 105, no. 1 (1997), F. S. vom Saal et al., "A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior," Toxicol Ind Health 14, no. 1-2 (1998): 70-6.

[15] "Study Finds No Danger From Bisphenol-A," Chemical Market Reporter, October 19 1998, p. 4.

[16] It is important to note that Ashby’s laboratory had no prior experience working at such low doses.  Vom Saal sent researchers in his laboratory with extensive experience working with low doses and fetal mice, to train Ashby’s technicians.  "New Study of BPA Finds No Negative Health Effects," Chemical Market Reporter, January 18 1999, 23, John Ashby, H Tinwell, and J Haseman, "Lack of Effects for Low Dose Levels of Bisphenol A and Diethylstilbestrol on the Prostate Gland of CF1 Mice Exposed in Utero," Regulatory Toxicology and Pharmacology 30 (1999): 156-66. 

[17] SZ Cagen et al., "Normal Reproductive Organ Development in Wistar Rats Exposed to Bisphenol A in the Drinking Water," Regulatory Toxicology and Pharmacology 30 (1999): 130-39.

[18] National Institute of Environmental Health Sciences. National Toxicology Program., NIH., "National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review,"  (2001).

[19] R. Melnick et al., "Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review," Environ Health Perspect 110, no. 4 (2002): 429.

[20] U.S. Environmental Protection Agency, "EPA Statement Regarding Endocrine-Disruptor Low Dose Hypothesis," (2002).

[21] According to a count conducted by The Endocrine Disruptor Exchange in September 2007 over 300 studies examining the effects of exposure to 1 part per million or lower existed in the published literature. See http://www.endocrinedisruption.com/. Accessed November 5, 2007.  The Chapel Hill Consensus Statement examined over 700 papers. These included in vitro, in vivo, exposure research, and wildlife research. 

[22] S. C. Nagel et al., "Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol," Environ Health Perspect 105, no. 1 (1997): 70-6, F. S. vom Saal et al., "A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior," Toxicol Ind Health 14, no. 1-2 (1998): 239-60.

[23] I. Quesada et al., "Low doses of the endocrine disruptor bisphenol-A and the native hormone 17beta-estradiol rapidly activate transcription factor CREB," Faseb J 16, no. 12 (2002): 1671-3.

[24] Letter from Steven Hentges, Executive Director, Polycarbonate Business Unit, American Plastics Council to NTP Office of Liaison and Scientific Review. July 16, 2001. See Appendix C in National Institute of Environmental Health Sciences. National Toxicology Program., NIH., "National Toxicology Program's Report of the Endocrine Disruptors Low Dose Peer Review,"  (2001).

[25] J. J. Heindel, "The fetal basis of adult disease: Role of environmental exposures--introduction," Birth Defects Res A Clin Mol Teratol 73, no. 3 (2005): 131-2.

[26] L. N. Vandenberg et al., "Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland," Endocrinology 148, no. 1 (2007): 116-27.

[27]  S. M. Ho et al., "Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4," Cancer Res 66, no. 11 (2006).

[28] R. R. Newbold, W. N. Jefferson, and E. Padilla-Banks, "Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract," Reprod Toxicol 24, no. 2 (2007): 253-8.

[29] P. A. Hunt et al., "Bisphenol a exposure causes meiotic aneuploidy in the female mouse," Curr Biol 13, no. 7 (2003): 546-53, M. Susiarjo et al., "Bisphenol A exposure in utero disrupts early oogenesis in the mouse," PLoS Genet 3, no. 1 (2007): e5.

[30] In a review of the literature, participants of the Chapel Hill Consensus meeting, concluded with certainty that bisphenol A exposure at low doses affects the male reproductive system, the brain, and metabolic systems (including effects of increased body weight and insulin resistance).C. A. Richter et al., "In vivo effects of bisphenol A in laboratory rodent studies," Reprod Toxicol 24, no. 2 (2007): 199-224.

[31] F. S. Vom Saal et al., "Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure," Reprod Toxicol 24, no. 2 (2007): 131-8.

[32] Laura N. Vandenberg et al., "Response to the Interim Draft of the NTP-CERHR report on the Reproductive and Developmental Toxicity of Bisphenol A,"  (2007).

[33] National Toxicology Program, National Institute of Environmental Health Sciences., NIH., Department of Health and Human Services. "Audit of Literature Cited and Fidelity of Requested Changes to Draft Bisphenol A Expert Panel Reports." July 24, 2007.

[34] L. N. Vandenberg et al., "Human exposure to bisphenol A (BPA)," Reprod Toxicol 24, no. 2 (2007): 139-77.

[35]  J.A. Taylor et al. “No Effect of Route of Exposure (Oral; Subcutaneous) on Plasma Bisphenol A Throughout 24 hrs After Administration in Neonatal Female Mice.” Reprod Toxicol 25, no.2 (2008): 169-176.

[36] R. W. Tyl et al., "Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats," Toxicol Sci 68, no. 1 (2002): 121-46.

[37] Draft NTP Brief on Bisphenol A [CAS NO. 80-05-7]. National Toxicology Program, National Institute of Environmental Health Sciences/National Institutes of Health/U.S. Department of Health and Human Services. April 14, 2008. p. 37.

[38] Ibid. p. 20-23.

[39]  "FDA Unimpressed By Low Dose Claims," Endocrine/Estrogen Letter, May 20 1999.

[40] F. S. vom Saal and C. Hughes, "An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment," Environ Health Perspect 113, no. 8 (2005): 926-33.

[41] D. Michaels, "Doubt is their product," Sci Am 292, no. 6 (2005): 96-101. Allan M. Brandt, The cigarette century: the rise, fall and deadly persistence of the product that defined America (New York: Basic Books, a member of the Perseus Books Group, 2006), Gerald E. Markowitz and David Rosner, Deceit and denial: the deadly politics of industrial pollution (Berkeley, CA: University of California Press, 2002).

[42] Gray et al., "Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A." Human and Ecological Risk Assessment 10 (2004): 875-921.

[43]  George M. Gray et al., "The Annapolis Accords on the Use of Toxicology in Risk Assessment and Decision-Making: An Annapolis Center Workshop Report," Toxicology Methods 11 (2001): 225-31.

[44] Anne Barnard, "Group Blasts Bush Nominee For Industry-Tied Research," Boston Globe, March 13 2001, A2. Letter to Thomas J. Borelli, PhD., Director of Science and Environmental Policy, Phillip Morris Management Corp. from Richard C. Rue, Vice President of The Annapolis Center. January 29, 1998. [Phillip Morris documents, www.pmdocs.com, document # 2073684230. Accessed October 23, 2007]. Letter to John D. Graham, Harvard Center for Risk Analysis, from “Rick” Enrique J. Guardia, Vice President Scientific Relations, Kraft General Foods. August 12, 1992. [Phillip Morris documents, www.pmdocs.com, document #2025534555. Accessed October 23, 2007.]

[45] “Draft National Toxicology Program Report Supports Safety of Bisphenol A,” American Chemistry Council. April 15, 2008.

[46] "Committee to Investigate Chemical in Infant Formula Liners," Committee on Energy and Commerce, Rep. John D. Dingell, Chairman. News release. January 17, 2008. Letter from John Dingell, Chairman of the House of Representatives Committee on Energy and Commerce and Bart Stupak, Chairman of the Subcommittee on Oversight and Investigations, to Andrew von Eschenbach, MD, Commissioner of the FDA. January 17, 2008. Letter from John Dingell, Chairman of the House of Representatives Committee on Energy and Commerce and Bart Stupak, Chairman of the Subcommittee on Oversight and Investigations, to Andrew von Eschenbach, MD, Commissioner of the FDA. April 4, 2008.

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