Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers
 
 

 

vom Saal, FS, SM Belcher, LJ Guillette, R Hauser, JP Myers, GS Prins, WV Welshons, JJ Heindel et al. 2007. Chapel Hill Bisphenol A Expert Panel Consensus Statement: Integration of mechanisms, effects in animals and potential impact to human health at current exposure levels. Reproductive Toxicology, in press [PDF].

 

 

Thirty-eight of the world's leading scientific experts on bisphenol A have warned policymakers of potential adverse health effects of exposure to the widespread plastic. The consensus statement, published in August 2007, emerged from a workshop sponsored by the National Institute of Environmental Health Sciences, held in Chapel Hill, NC, in November 2006.

They conclude that average levels in people are above those that cause harm to animals in laboratory experiments. And they calculate that average serum levels in people can only be explained by assuming that exposures today are above the level that EPA considers safe (the reference dose).

 
Assortment of BPA-based containers for liquid
These polycarbonate bottles and cups are made from BPA. Measureable amounts will leach into the contained liquid, especially if they are heated or worn.
Close-up of NOLS bottle
A close-up of the old gray bottle above shows it has changed from transparent to milky. Leaching will be much more rapid.

This calculation rests upon observations that most of the BPA that people digest is quickly metabolized and excreted. It also assumes that human and animal rates of metabolism of BPA are roughly similar. Some data suggest that humans metabolize BPA more rapidly than animals. If that is the case, then daily human exposure must be even higher.

EPA's reference dose is based upon measurements made in the 1980s, and therefore does not reflect observations of BPA effects in animals at low doses that have been reported many times over the past decade. Were the reference dose recalculated using the conclusions of this document, many commercial uses of BPA would no longer be possible, including virtually all uses that entail contact with food or liquids.

What did they do? The meeting of BPA specialists took place in late November 2006.  Over a 6-month period prior to the meeting, 5 panels of the experts prepared extensive working documents reviewing different aspects of the BPA literature, covering in all over 700 published studies.  These documents formed the basis of discussion at the meeting.  During the meeting, these working documents were discussed among the experts working in that area and summaries of the data were prepared for discussion later in the meeting. Panels were then re-organized into four breakout groups with expertise from each of the working groups, each of which assessed levels of scientific confidence about scientific findings on BPA that were translational in nature i.e., cut across the areas of focus of the working groups.

Those assessments were then integrated into the Consensus Statement, which categorizes them with respect to three levels of scientific confidence: 
We are confident of the following:
We believe the following to be likely but require confirmation
Areas of uncertainty and suggestions for future research

Context: While first synthesized before 1900, large-scale commercial use of BPA began slowly only in the 1950s, after polymer chemists discovered that it could be polymerized into polycarbonate plastic and epoxy resins. Now, over 6 billion pounds of BPA are produced each year, making it one of the highest production volume plastics in the world. It is used in a wide array of consumer and industrial products, including polycarbonate bottles for liquids, e.g., 'sports' and baby bottles, epoxy resins to line food cans and wine/beer fermentation vats, and dental sealants to protect against cavities. Human exposure in the developed world is ubiquitous. People in the US, Europe and Japan average 1-2 parts per billion in serum.

Scientific studies with laboratory animals over the past 10 years have identified a series of adverse effects that implicate low-level exposure to BPA in a range of human health problems, including breast cancer, prostate cancer, attention deficit hyperactivity disorder, spontaneous miscarriage, type 2 diabetes and obesity. Although over 90% of government-funded studies of BPA at low levels find adverse effects, no industry-funded studies have been able to replicate the academic research. Government policy-makers have used the industry results to justify taking no action on BPA.

In 2006 the US National Toxicology Program, part of the National Institute of Environmental Health Sciences, began a review of BPA within its Center for Environmental Risks to Human Reproduction (CERHR). CERHR convened a panel of scientists who were chosen explicitly because they were not experts on BPA. In March 2007, it was discovered that CERHR had outsourced drafting of the initial document for the scientists to a company whose private sector clients included a trade association for the chemical industry, the American Chemistry Council (known formerly as the Chemical Manufactureres Association) and several BPA producers. That company was fired, but its draft continued to be the basis for the panel's work. During the spring and summer of 2007, the panel applied a series of selection criteria to the scientific literature that excluded many academic studies from consideration. Public comment by BPA specialists, available on the web, accused the panel of bias in its selection procedures.

The CERHR panel issued its draft conclusions on 8 August. They found scientific reasons for concern about BPA's impact on neurodevelopment in fetuses and newborns--within the range of current human exposure--, but little concern about reproductive effects. This is the first government panel in any country to conclude that BPA is not safe. The chair of the panel, Dr. Robert Chapin (an employee of the pharmaceutical company Pfizer) was quoted in Science Magazine: "This might be a time for the application
of the precautionary principle."

In the months after the workshop, the consensus statement and five major reviews addressing different aspects of the BPA scientific literature were finalized and submitted for publication in the peer-reviewed journal Reproductive Toxicology.

What did they find? Among the conclusions in the consensus:

We are confident of the following:
• "Human exposure to BPA is widespread."
• "Commonly reported circulating levels in humans exceed the circulating levels extrapolated from acute exposure studies in laboratory animals." This is a key finding: levels causing adverse effects in animals are lower than what is already in people.
• "BPA levels in the fetal mouse exposed to BPA by maternal delivery of 25 microgram/kg, a dose that has produced adverse effects in multiple experiments, are well within the range of unconjugated BPA levels observed in human fetal blood."
• "BPA alters “epigenetic programming” of genes in experimental animals and wildlife that results in persistent effects that are expressed later in life. ... Specifically, prenatal and/or neonatal exposure to low doses of BPA results in organizational changes in the prostate, breast, testis, mammary glands, body size, brain structure and chemistry, and behavior of laboratory animals."
• “Adult exposure studies cannot be presumed to predict the results of exposure during development.”
• “Actions mediated by membrane associated receptor signaling may underlie much of the low-dose BPA phenomena (effects have been reported at doses as low as 1 pM [picomolar] or 0.23 ppt [parts per trillion]).”

We believe the following to be likely but require confirmation
• “Exposure to BPA during different life stages differentially influences reproductive cancer etiology and progression, and exposure during sensitive periods in organogenesis may increase susceptibility to development of cancers in some organs, such as the prostate and mammary glands.”
• “Early life exposure to environmentally relevant BPA doses may result in persistent adverse effects in humans.”
• “The function of the immune system can be altered following adult exposure to BPA.”

Areas of uncertainty and suggestions for future research:
• “Studies should determine if amplification of BPA through the food chain occurs, particularly under anaerobic or hypoxic conditions due to the lack of microbial or photodegradation.”
• “Even though there have been attempts to estimate daily human intake of BPA, these estimates require many assumptions. … Known sources of human exposure to BPA do not appear sufficient to explain levels measured in human tissues and fluids.”
• “Measurement of BPA levels in serum and other body fluids suggests that either BPA intake is much higher than accounted for, or that BPA can bioaccumulate in some conditions such as pregnancy, or both.”
• “There is a need for epidemiological studies relating health outcomes to BPA exposure particularly during sensitive periods in development. These studies should be based on hypotheses from findings in experimental animals.”
• “Epigenetics should be examined as a potential mechanism mediating developmental effects as well as the trans-generational effects of BPA and other contaminants. Potential effects of adult exposures also need to be examined in relation to disruption of epigenetic changes that occur normally during aging.”

What does it mean? This consensus statement was written by the world's leading researchers on bisphenol A, reviewing all published literature. In their judgment, current levels in people, which average 1-2 nanograms/ml, are higher than what is needed to cause harm in animals. They make no regulatory recommendations in their document, but the implications are clear: The 'safe dose' level currently used by the EPA needs to be lowered to reflect research that has accumulated since the mid-1980s, when this level was last set. Based on published studies that show adverse effects at levels 25 to 250 times beneath the current reference dose, and cellular studies showing large in vitro effects down to 0.23 parts per trillion, it is highly unlikely that uses of BPA in polycarbonate food and liquid containers, or in epoxy can linings, will be consistent with a modernized reference dose.

This finding has implications that go well beyond regulatory standards for bisphenol A. Fully addressing BPA will require acknowledging that current standards have been structured using an assumption that is violated by endocrine-disrupting compounds like BPA: High dose experiments with hormones and hormone-disruptors cannot be used to predict low-dose results because the effects of hormonal exposure can differ-- even be opposite-- at different concentrations. Dose-response curves with this character are called 'non-monotonic.' Several decades of regulatory testing have been blind to this possibility. Many standards are thus likely to be far too weak to protect public health. No wonder opposition to a careful look at BPA has been so fierce.

 

 

Bisphenol A in the news

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This consensus statement, prepared by scientists actually engaged in research on BPA, contrasts sharply with the draft conclusions of the CERHR assessment, issued 8 August. That panel was composed of scientists chosen because they had not worked on BPA. The CERHR panel found "some concern that exposure to Bisphenol A in utero causes neural and behavioral effects," making it the first governmental assessment to conclude that BPA is not safe. But it expressed "minimal concern" that BPA causes accelerations in puberty, causes birth defects or malformations, or causes effects on the prostate.

To reach that conclusion it chose to ignore a wide array of studies, including all those from Ana Soto's lab or Frederick vom Saal's lab. These studies have been published in a wide array of peer-reviewed journals, including Nature, the Proceedings of the National Academy of Sciences, Endocrinology and Environmental Health Perspectives. It also placed heavy weight upon an industry-funded study conducted by Shelly Tyl which has not been published in the peer-reviewed literature. As noted above, no industry-funded studies have reported adverse effects of BPA at low levels, whereas over 90% of government funded studies do find adverse effects.

The criteria used to exclude studies from the CERHR's assessment included disallowing studies using routes of exposure other than oral. This was based on the fact that of the known BPA exposure for people is oral, and most of that is excreted rapidly. As pointed out in an extensive set of comments from Soto's lab, while this may be justified for adult exposures, "fetuses don't eat." According to their assessment, how BPA gets into a pregnant female is irrelevant for studying its effects on fetal development. What matters is that once it is in the pregnant mother's serum, it crosses the placenta and enters the fetus.

The new Associate Director of the National Toxicology Program, Dr. John Bucher, has repeated publicly on several occasions that the final decision from NTP will integrate both the CERHR's report as well as the Chapel Hill Consensus Statement along with new scientific results not available to either of these assessments (e.g., Newbold et al. 2007). Their decision will also be subject to peer review.

Resources:

CERHR 2007. Draft meeting summary. Expert panel evaluation of bisphenol A [PDF]. Center for the Evaluation of Risks to Human Reproduction.

Ho, S-M, W-Y Tang, J Belmonte de Frausto, and GS Prins. 2006. Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4. Cancer Research 66: 5624-5632.

Kaiser, J. 2007. Common plastic ingredient may be cause for concern. Science Magazine.

Murray, TJ, MV. Maffini, AA Ucci, C Sonnenscheinand AM. Soto. 2006. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reproductive Toxicology 23: 383-390.

Newbold, RR, WR Jefferson, and EP Banks. 2007. Long-term Adverse Effects of Neonatal Exposure to Bisphenol A on the Murine Female Reproductive Tract. Reproductive Toxicology, in press.

Richter CA, JA Taylor, RL Ruhlen, WV Welshons and FS vom Saal. 2007. Estradiol and bisphenol a stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate mesenchyme cells. Environmental Health Perspectives, in press.

Susiarjo, M, TJ Hassold, E Freeman and PA Hunt. 2007. Bisphenol A Exposure In Utero Disrupts Early Oogenesis in the Mouse. PLoS Genetics, 3(1): e5. doi:10.1371/journal.pgen.0030005.

Vandenberg, LN, MV Maffini, PR Wadia, C Sonnenschein, BS Rubin and AM Soto. 2007. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology 148(1):116-27.

Vandenberg, LN, MV Maffini, BS Rubin and AM Soto. 2007. Comments on Bisphenol A expert panel interim draft report [PDF].

vom Saal, F and W Welshons. 2006. Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A. Environmental Research 100: 50-76.

Welshons, WV, KA Thayer, BM Judy, JA Taylor, EM Curran and FS vom Saal. 2003. Large effects from small exposures. I. Mechanisms for endocrine disrupting chemicals with estrogenic activity. Environmental Health Perspectives 111:994-1006.

Wetherill, YB, JK Hess-Wilson, CES Comstock, SA Shah, CR Buncher, L Sallans, PA Limbach, S Schwemberger, GF Babcock and KE Knudsen. 2006. Bisphenol A facilitates bypass of androgen ablation therapy in prostate cancer. Molecular Cancer Therapeutics 5:3181-3190.

 

 

 

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