STATS ARTICLES 2010
Is BPA the new MMR? Debate in top scientific journal exposes flawed science
Trevor Butterworth, April 7, 2010
Britain’s top endocrine disruptor expert says governments are wasting “tens, probably hundreds, of millions of dollars” on pointless research on BPA's safety. EPA scientists detail scores of flaws in critics of chemical's case.
War has broken out on the pages of the world’s top scientific journal in toxicology – Toxicological Sciences – and for those watching it unfold, the intense combat, drawing in world leaders in their fields, has produced a clear and remarkable outcome: The panic over the chemical bisphenol A (BPA) is not only unjustified, it has reached a point where the failure to accept basic, rational principles in scientific research is damaging toxicology itself, wasting taxpayers money and undermining scientific progress.
Hostilities began with the publication of an expensive, three-year study by scientists at the Environmental Protection Agency: “In Utero and Lactational Exposure to Bisphenol A, in contrast to Ethinyl Estradiol, Does not Alter Sexually Dimorphic Behavior, Puberty, Fertility and Anatomy of Female LE Rats” (Ryan et al.).
They fed one group of pregnant rats a range of doses of BPA and another group a range of doses of the synthetic estrogen used in birth control pills – ethinyl estradiol (EE2). The LE Rats demonstrated significant sensitivity to estradiol and the researchers reported reduced body weights, genital malformations and defeminization in pups whose mothers were gavaged (fed by tube) with the hormone. The pregnant rats gavaged with BPA showed no effects. The findings built on a previous EPA study by which found similar results, as well as other multigenerational reproductive toxicity studies. In short, the study provided the strongest evidence yet that BPA did not cause endocrine disruption – or adverse effects of any sort.
Ryan et al. immediately came under attack from the small group of scientists who have maintained the position that BPA is dangerous to human health. In a February letter to Toxicological Sciences, “Flawed Experimental Design Reveals the Need for Guidelines Requiring Appropriate Positive Controls in Endocrine Disruption Research” vom Saal et al. decried the study and others like it.
“A review of the results of the positive control doses makes it clear that the experiment cannot adequately assess the consequences of low-dose exposure to BPA because the animal model is insensitive to low doses of the positive control estrogen. Therefore conclusions being drawn from this experiment about low dose responses to any estrogen are invalid, including that of “no harm” from the low doses of BPA that were tested. However, the experiment is important because it highlights the need to apply basic principles of study design, long known and accepted in studies of hormones and hormonally active drugs, to toxicological studies of chemicals with hormonal activity.”
If this seemed like a devastating criticism of the EPA’s work, it was unpersuasive to Richard Sharpe, one of Britain’s top experts on reproductive endocrinology, who is both the principal investigator for Britain’s Medical Research Council Human Reproductive Sciences Unit and the chairman of the UK Society for Endocrinology’s Expert Group on Endocrine Disruptors. Though nationally funded, the Medical Research Council is wholly independent of government, and is one of the world’s leading medical research organizations; among the achievements it has sponsored include the discoveries of penicillin, the structure of DNA, and the link between smoking and lung cancer.
Sharpe is hardly a scientist who can be described as unsympathetic to the idea or the science that environmental chemicals affect human reproduction and development (as his key overview of the state of the research on phthalates shows), and his positions testify to his stature and influence in both Britain and the fields of endocrinology and reproductive toxicology. Far from endorsing vom Saal et al.’s charge that the EPA’s studies on BPA were flawed due to failures in basic experimental design, Sharpe came to the opposite conclusion, which he framed in a broad indictment of the portrayal of BPA by its critics, both inside and outside science.
As he wrote in the rhetorically titled “Is It Time to End Concerns over the Estrogenic Effects of Bisphenol A?” a highlight on Ryan et al. for the March edition of Toxicological Sciences, “If, like me, you are uninvolved in bisphenol A research, you may be puzzled by the seemingly never-ending controversy, as the scientific process usually sorts out what is right, given time.” Why, he asks, has this not happened with BPA?
“Anyone involved in biomedical research knows that scientific "facts" that remain untouched by the ravages of further research are a rare commodity. Usually, most facts change their form with time (evolve), and their meaning, and probably their importance, also will change. Disappointing as this may be for our scientific egos, it represents something far more important—scientific progress. It is inevitable that scientific progress, in the form of new facts, will trample over our bright ideas, hypotheses, and even over our results. This apparently destructive process is in fact constructive, and as scientists, we have to embrace this evolution and to accept that the sacrifice of our initial beliefs (and our precious results and our interpretations) is part and parcel of advancing understanding. I spout this scientific philosophy as it seems to me that research on bisphenol A has been trying to go through this process but has become literally bogged down in the mire of controversy, much of which stems from the earliest findings and seems to have little to do with the current state of the science. The study by Ryan et al. (2009) can be considered as another attempt to release bisphenol A research from the grip of the mire back into the normal pathway of scientific evolution.
The results from Ryan et al. (2009) are unequivocal and robust and are based on a valid and rational scientific foundation. They tell us that, in vivo in female rats, bisphenol A is an extremely weak estrogen—so weak that even at levels of exposure 4000-fold higher than the maximum exposure of humans in the general population there are no discernible adverse effects, whereas the potent estrogen ethinyl estradiol (EE; the positive control) caused major adverse effects at doses used in earlier contraceptive pills and that were associated with increased risk of thromboembolism in women.”
Ryan et al also confirms previous findings “from studies involving large numbers of animals… conducted by recognized world expert groups,” wrote Sharpe. “Yet, to judge from correspondence in the wider (nonscientific) media (blogs and environmental websites)… this research is flawed and incorrect…”
Sharpe went on to take each of the major arguments against BPA – such as the charges by vom Saal et al that the rat strain used was insensitive to the control estrogen, and said they were fallacious or not supported by the best science that has been conducted around the world. Taken in combination, these similarly detailed studies “more or less close the door on the possibility that bisphenol A is an environmental chemical to be concerned about because of its ER-mediated estrogenic activity” [emphasis added]. He concluded:
“I recognize that this statement will run counter to the strong convictions of some, but I base it on objective, scientific principles of evaluation. Bisphenol A research has put one of these principles firmly under the spotlight, namely, the almost complete inability for different laboratories to reproduce the same results, although much of this may be explained by use of different routes of exposure (and therefore different levels of target tissue exposure). If an earlier result cannot be reproduced in a huge study conducted in a scientifically rigorous manner, as exemplified by Ryan et al. (2009), then the original result fails one of the golden rules that govern scientific research. When this happens repeatedly, as is the case with bisphenol A, then there can be no logical, scientifically based reason for continuing to espouse that the original results are the only ones that are correct, rather the converse.
Fundamental, repetitive work on bisphenol A has sucked in tens, probably hundreds, of millions of dollars from government bodies and industry which, at a time when research money is thin on the ground, looks increasingly like an investment with a nil return. All it has done is to show that there is a huge price to pay when initial studies are adhered to as being correct when the second phase of scientific peer review, namely, the inability of other laboratories to repeat the initial studies, says otherwise.”
The key point is that you cannot keep failing to replicate original research with more detailed statistically robust experiments and continue to maintain that the original research is correct and everyone else is “incompetent” or in hock to the chemical industry, as the key anti-BPA campaigners have maintained through years of ad hominem attacks (Sharpe told STATS that the repeated assaults on the integrity of scientists who disputed the low dose theory of BPA led him to take on this issue). At this point, there are three mouse studies and at least 10 rat studies that have failed to replicate the low dose hypothesis. Some studies have cost over a million dollars and have been supervised by scientists from the European Union agency tasked with determining consumer risk (Tyl et al.); all are statistically and methodologically superior to the basic studies claiming to have found adverse effects.
Sharpe was, in turn, attacked by Sarah Vogel, a historian who wrote her Ph.D. dissertation on the controversies over BPA. She accused him of being “simple-minded” and “theological,” and she praised vom Saal et al. for not taking offense at what he had written. Her critique, published on a public health site was a variation of the argument used by vom Saal et al to discredit Ryan et al, namely, that the rats were insensitive to EE2, which thus failed as a positive control.
This requires some explanation: In order to test the effects of a chemical, a positive control is used. As Julie Goodman, Director of Epidemiology and a board certified toxicologist at the Gradient Corporation, explains:
“When you do an experiment, if nothing happens, there are two possibilities: Either the thing you are testing really doesn't cause an effect or there is a problem with the experiment itself, in that the methods just aren't designed to see what it is you are looking for (i.e., the test is not responding as it should). The best way to see if the latter is the case is to have a positive control. A positive control is something that you know will cause a certain effect, so if your positive control ‘works,’ then you know there is not an issue with the experiment itself.”
Vom Saal et al. object to the EPA and others using rat strains that are, they argue, largely insensitive to estrogens and therefore cannot detect the effects of BPA. Specifically, vom Saal et al. criticize Ryane et al. because they found no effect from dosing rats with 0.5 µg of Ethinyl Estradiol (EE2), which means that they were not a sensitive enough model, given that this dose of EE2 causes effects such as ovulation inhibition in women.
Sharpe says this simply isn’t true. “In many respects,” says Sharpe via email, “I consider the insensitive strain/lack of positive controls argument is an attempt to divert arguments away from important issues and down a sideline. In any case… these criticisms are spurious. It is nonsense to say that humans respond to 0.5 µg E2 as Fred Vom Saal asserts because anyone who knows about the pill should know that the main effective ingredient is the progestagen, and it is this that is mainly responsible for inhibiting ovulation – precisely because the E2-alone pill needed so much E2 to do the job that the risk of (serious) side effects was too high.”
Goodman concurs: EE2, in fact, worked as a positive control in Ryan et al, “showing their experimental system is adequate for assessing whether BPA was estrogenic.”
Finally, one of the co-authors of Ryan et al., Earl Gray – the EPA’s Senior Reproductive Toxicologist and widely regarded as a world-eading authority on endocrine disruption – weighed in with a detailed rebuttal that has been accepted for publication in Toxicological Sciences and is available in advance online (for subscribers). Among the specific points (abbreviated here) that Gray et al. raise:
- The insensitive strain argument “has been used for almost a decade in some quarters to try to dismiss every well-conducted rat study that obtained negative results with BPA. It is based on a failure to recognize the basic endocrinology underlying the cellular and molecular basis for tissue-specific responses to estrogens in different strains of rats… It is evident that the degree of estrogen sensitivity varies from tissue to tissue and no single rat strain is more or less sensitive than another for all traits…”
- “Several expert panels have addressed the ‘insensitive strain’ argument and dismissed this as being without “scientific merit” (Canada 2008; Chapin et al. 2008; National Toxicology Program 2008; Scientific Panel on food additives 2007).
- The rat strain they use (Long Evans – LE) has been used as a model for studying the effects of environmental estrogens for 45 years, thus there are “validated protocols” for studying the effects of chemicals such as BPA. There are, in addition, thousands of published studies using the LE rat for behavioral observations.
- There is abundant pharmacological and toxicological data demonstrating that humans and the LE and Sprague Dawley rat strains show similar sensitivities to EE2. Research by the National Center for Toxicology Research found effects from EE2 in rats at doses similar to the lowest doses of EE2 found in contraceptive pills.
- Comparing combination birth control pills to administering EE2 alone “is like comparing apples and oranges. Oral contraceptives include not only EE2 but also five to ten fold higher doses of progestins.”
- The doses of EE2 that produce adverse effects in women when a contraceptive pill does not contain any progestins range from 2 to 100 µg /per kilogram of bodyweight per day. Ryan et al. found “statistically significant adverse effects” in maternal rats at 1.5 µg /kg/day. Other observable adverse effects were associated with doses between 2.6 and 5 µg /kg/day. These results say Gray et al., “demonstrate the LE and SD rats are the most appropriate animal models for the study of EE2 since the sensitivity to this chemical, and likely other estrogens, is similar to the human sensitivity to EE2.”
- “Our study is certainly not the only study to find that BPA did not exhibit any estrogenic activity when administered orally. Oral treatment with BPA also failed to produce any estrogen-like reproductive effects in Wistar, Alderley-Park, SD, F344, and LE rats and CF-1 and CD-1 mice at any dose level in several large robust multigenerational and transgenerational studies. These were conducted under both GLP [Good Laboratory Practice] and non-GLP conditions by scientists from government (Ema et al. 2001; Howdeshell et al. 2008; Ryan et al. 2010), academia (Yoshino et al. 2002), industry (Ashby et al. 1999; Cagen et al. 1999a, b; Tinwell et al. 2002) and contract laboratories (Tyl 2003; Tyl et al. 2008a; Tyl et al. 2002).”
- While vom Saal et al. describe Ryan et al. as “flawed,” regulatory agencies that recently reviewed Ryan et al. did not concur – and described it as useful for risk assessment. In contrast, “a significant percentage of publications that reported effects of BPA at low dose levels were described as ‘inadequate’ for methodological or statistical reasons, ‘not replicable’, ‘extremely limited’ or of uncertain toxicity and relevance to human health risk assessment.” [Emphasis in original]
- The claim by vom Saal, “that ‘The science is clear and the findings are not just scary, they are horrific. Why you feed a baby out of a clear, hard plastic bottle, it’s like giving a baby a birth control pill’ is inaccurate…”
If this were any other field of science, Ryan et al, Sharpe and Gray et al’s criticisms would have generated a media feeding frenzy much as recent exposes of the supposed Himalayan glacier melt rate or the claim that MMR vaccine causes autism have led to punishing scrutiny. The public has been repeatedly told over the past three years that BPA is dangerous to their children’s health or, as Frederick vom Saal put it to Discover magazine, the biological equivalent of global warming.
But because most of the media coverage has framed BPA through the claims of vom Saal and his associates, too much journalistic credibility is now bound to the conclusion that BPA is dangerous and should be banned. This means that the current exchange will not be the last word on BPA. Proving it dangerous has turned into an industry that supports not only vom Saal et al. but their laboratories and post doctoral students; meanwhile, environmental activists and journalists have invested too much time and effort in, essentially, promoting this research as representating the state of the science to concede that they have, in fact, backed the wrong scientific horse
But for the majority of scientists, Ryan et al., Sharpe, and Gray et al., will surely have ended whatever debate on BPA might have been left from previous regulatory pronouncements about its safety. The reason is replication - or rather the failure to replicate original results. As Sharpe told STATS:
“…if a study is not repeatable in a second lab then it is not robust. Even if there was some substance in the arguments about sensitive strains, then please will they show me the data that says that these are more appropriate models for humans – without recourse to the fallacious contraceptive pill argument. I do not have an axe to grind with BPA and I honestly remain open to being convinced that it poses a health risk to humans – but based on the present evidence for estrogenic effects, I just don't see an issue. But I reiterate – I am completely open to being convinced otherwise, especially if any new data can at the same time explain away Earl Gray's data and that of other large (negative) studies.”
Wolfgang Dekant, one of the lead authors of the European Union’s risk assessment on BPA concurs, adding that from a toxicological perspective, the failure to model the risk of BPA through oral exposure is the fatal flaw in vom Saal’s work and one of the reasons the European Food Safety Agency has rejected the conclusions of his research along with many studies done in a similar fashion with similar results.
That the National Institutes of Environmental Health Sciences, which funded much of the earlier work by vom Saal et al., now insists that future research on BPA follow the study design and protocols used by Ryan et al is, perhaps, the final confirmation that the side the media has ignored in covering this issue was right all along.
Of course, that raises the question why the NIEHS funded so much flawed research to begin with, and why, in light of that flawed research has it directed stimulus money to vom Saal et al. to continue to do research on BPA – especially in light of comments by vom Saal in recent years that no more research was necessary. Given Sharpe’s claim that tens of millions of taxpayer dollars are going to waste, perhaps this is a key question for Congress and the states to consider before they think about any ban on a chemical vital to food safety.