In 1992, Dr. David Feldman almost accidentally discovered that bisphenol A had migrated from his polycarbonate test tubes into a test specimen and appeared to be mimicking estrogen. In the years since, and especially recently with a new series of bans, BPA, and the PC it’s contained in, has sparked a debate on the chemical’s safety.
Studying estrogen action in the early 1990s, David Feldman, a medical doctor, and his team were surprised to see estrogenic activity that developed in cultures of yeast without added hormone or precursors. After a series of experiments, the researchers discovered that the estrogenic activity wasn’t coming from the yeast that they were testing but rather from the polycarbonate (PC) flasks that they were using to grow the yeast.
The first researcher to identify and call attention to the possible impact of low levels of PC component bisphenol A on human health, Feldman shares his viewpoint on his discovery some 20 years on, followed by an industry defense of the chemical from Steven Hentges, executive director of the American Chemistry Council’s Polycarbonate/BPA Global Group.
David Feldman: Yes—well, really, it was an accident or a serendipitous finding. We certainly weren’t looking for bisphenol A. The accidental finding was that we discovered what looked like an estrogenic molecule when we were growing yeast in these plastic flasks. It turned out it was not the yeast synthesizing the estrogen, but rather it was leaching from the plastic. Then we got clever enough to do a critical experiment without having the yeast in the flask, and sure enough there was still this estrogenic molecule in the medium. We then tracked it down and found it was coming from the plastic flask and was not present when we did the experiment in glass flasks.
With mass spectroscopy performed by my colleague Laszlo Tokas, we were able to identify the estrogenic substance as bisphenol A and then we used authentic BPA that we purchased to study why it behaved like an estrogen. It turned out BPA binds to the estrogen receptor, although not nearly as well as estradiol does—about 1000- to 2000-fold less. In other experiments, BPA acted like an estrogen, inducing the expression of target genes that were classically stimulated by estradiol.
MPW: At that point, were you even aware that these were PC flasks, and PC had bisphenol A in it?
DF: That’s when we started investigating and reading. We knew that we had used polycarbonate flasks; we knew it was BPA that was the estrogen; we looked at the structure of polycarbonate; and there’s BPA as a crucial component. If I remember this correctly, I was in touch with people at the Lexan plastic company [formerly GE Plastics, now Sabic Innovative Plastics, maker of Lexan PC], which I think at the time was the largest producer of PC, and they had a scientific group that knew a lot about the chemistry of plastics.
They [gave] me some insight into the plastic problem and this potential leaching problem. They were already aware that BPA could leach out of plastic containers. We sent them our samples, where we had this liquid from PC flasks that we could detect estrogenic activity in by its biological activity. By the methods they were using, they could not detect BPA in the liquid. So they told me, “There’s nothing here,” but we could see that there was estrogenic activity there. It showed us that at least at that time, the biological assay was more sensitive than the chemical assay that they were using.
MPW: Are you still looking at BPA in your current research or have you moved on?
DF: I’ve moved on. I am still asked (and you’re one example) to talk about it all the time, and I’m still very interested in the subject, so I carefully follow the literature. For example, I’ve just come back from the Endocrine Society meeting, and there were many sessions dealing with endocrine disruptors. It’s become a large field, studying BPA and other endocrine disruptors from plastics and other sources.
We wrote about this subject about 18 years ago, and at that time, that paper kind of pioneered the field of BPA acting as an estrogen and affecting people as a new area of study. Now there are many laboratories studying it so we have made progress in that sense. But there still is a large variety of PC containers in the marketplace used to package food and drinks. I think it is potentially a very serious health problem that is still underappreciated, and the extent of the problem is not known.
MPW: From your viewpoint, has the science of this been settled, in terms of BPA as a health risk?
DF: I think BPA is a health risk, although definitive proof in people is still not compelling. We can’t very well administer BPA to people to do the critical experiment. But we do have a lot of evidence. First, we know that BPA has estrogenic activity, and we now know, from all sorts of studies, that it is a modifier of the epigenetics of cells. I don’t want to get too scientific about that, but in other words, the changes that BPA induces can be inherited and the model is based on findings from diethylstilbestrol (DES).
DES is very structurally similar to BPA. They’re both biphenolic molecules, originally synthesized as part of the same series of derivatives. Many years ago, DES was used as a substitute for estrogens in women. One use was to administer DES to pregnant women who were thought to be close to a miscarriage. The DES was given to provide extra estrogens to bolster and maintain the pregnancy. DES worked to maintain the pregnancies, so it was used frequently in this setting for the purpose of stabilizing a threatened miscarriage.
The babies who were in utero at the time of DES administration seemed fine, but 20-30 years later, these “DES babies” developed an increased risk for vaginal cancer. Remember, the mother received the treatment; the baby was developing in the uterus; and years later, that baby gets a cancer that was otherwise rare. One doctor in particular recognized this, and he went back and looked for the common denominator. He found that the mothers of the young women who developed vaginal cancer had received DES during the pregnancy. Obviously the use of DES in pregnancy has been discontinued because of its carcinogenic effects.
That important finding indicated that exposing the mother to a molecule can actually affect the offspring many years later and perhaps the next generation as well. So DES exposure of the mother affects the inheritance of the offspring, increasing the risk of a rare malignancy like vaginal cancer. That’s a big worry for me, because although DES and BPA are not quite twins, they are so similar that the possibility of similar actions is very strong. New research shows that BPA also alters the epigenetic profile of animals exposed to it.
Genetics is based on the DNA code and these molecules don’t change the DNA code—they change the proteins that cover the DNA that determine which parts of the DNA get used and which parts don’t get used. That’s why it’s called epigenetics. These modifiers of epigenetics affect inheritance but they do not change the DNA code, and I’m very concerned that BPA does that just like DES.
The problem is that we may not see the risks of BPA in the diet for many years. Exposure of pregnant women and young children to BPA may perhaps cause an increased risk of breast, vaginal, uterine, or some estrogen-driven cancer down the line—that’s a major concern. And cancer is only one of many potential risks.
MPW: That’s one thing I wanted to ask about. Given that BPA is a bioaccumulative chemical, there’s some debate in industry on whether the presence of something necessarily means that it’s negative or could have a negative effect. Is there any research in that area?
DF: The endocrine system is tightly regulated, so that the mother, the developing fetus, or the young child is not supposed to have too much of the wrong hormones signaling at the wrong time. When a girl goes through puberty, the estrogens are supposed to come out; they’re not supposed to be there during development and infancy. So if you put something there that shouldn’t be present and that can cause changes that shouldn’t be induced in the baby at that time, I would say that’s a risk factor. And the risk of BPA accumulating and combining with other endocrine disruptors to magnify its actions is a real possibility. But also, DES and BPA are not just estrogenic; they are structurally very different from natural estrogens and can carry additional risky actions beyond only the simple but potentially serious problem of causing increased exposure to an estrogen at the wrong time.
I think it’s fair to say we don’t have a smoking gun. We haven’t seen evidence that BPA increases the risk of cancer in people as has been shown for DES. We know now what DES did, but we only recognized that in retrospect. We don’t know yet if that is the case for BPA. But there are enough parallels to DES that it’s very worrisome, and I think if there are alternatives to BPA that can be used, which it seems there are, that would be the safe and the prudent thing to do.
MPW: Do you track the regulatory environment at all?
DF: A little. I don’t work primarily on this subject anymore but I certainly listen and I realize that for many, many years, the EPA and FDA or whoever is making the regulation has not forced the issue to reduce the BPA exposure of the population. But the parents have done so in the case of baby bottles and perhaps in toys and other sources of exposure for their children.
I think that you can no longer go into a store in the U.S. and buy a baby bottle that has BPA in it because the market has driven plastic makers to change, rather than the regulatory agency doing it. I approve of that.
I have advised my children to be careful to limit the exposure of my grandchildren to BPA. I’ve asked them not to use plastic baby bottles, not to microwave food in plastic containers, to try not to drink beverages from plastic containers, to avoid canned foods or rinse the contents of the cans before using, and so on.
In other words, if you put a little exogenous estrogen—even if it were a normal estrogen, which BPA is not—into an adult, the body might be able to accommodate to it. So I think the main risks here are abnormal estrogens in an inappropriate place and time, especially during development or infancy. And also since a baby is a very small individual, even small doses can be more likely to cause significant effects than in a full-sized person.
But that’s another thing worth mentioning: BPA is not the only endocrine disruptor around and there are many other environmental factors that are estrogenic. So there may be a cumulative effect, and just estimating the BPA concentration may not be an adequate measure of how much endocrine disruptor exposure there is and what the cumulative impact may be.
MPW: The link between BPA and PC was initially brought up in the early 1990s, but only recently seems to have really piqued public interest. Can you attribute that to any one thing or maybe talk about how the atmosphere has changed?
Steven Hentges: I don’t know that I really understand. BPA is scientifically interesting, and it’s that science that gets the regulatory industries interested and to some extent also gets legislators interested, and then all of these things get media interest, so you’ve got a lot going on. This whole concept of endocrine disruptors has been a very interesting, popular subject in scientific circles for a number of years now, and since BPA kind of sits squarely in the middle of that, it just makes it more interesting than it might be at a different time or if it weren’t in the middle of that whole area.
MPW: Do you feel like, in some ways, the tenor of the debate has changed so that you’re now fighting more of an uphill battle to advocate on behalf of BPA?
SH: I don’t know if I’d say it was an uphill battle. I think it’s just a very busy time. A number of states have had an interest in BPA and of course federal legislators have some interest in it, and there’s a lot of regulatory interest as well.
I think the scientific case regarding the safety of BPA is still strong, and we have found that that resonates well with both legislators and regulators. Indeed, the science of BPA has been evaluated by a number of government agencies and regulatory bodies over the last several years, and there still is a consensus amongst these regulators that BPA is safe in the way that it’s being used now.
Because of the new science developing, a lot of these are fairly new evaluations. Several of those came out this year, including one from the German Environmental Risk Assessment, which was an update of their views based on the science. They hadn’t changed their view—they are still part of that consensus on the safety of BPA. Food safety regulators in Australia and New Zealand, same thing: an update but reaffirming their previous views. The FDA’s new evaluation released at the beginning of this year was an important one in the U.S., and although it was commonly reported that the FDA changed its views on BPA, that’s not true. What it did was reaffirm its views on BPA.
As stated by Dr. Joshua Sharfstein of FDA [in a January 2010 news conference], “If we thought it was unsafe, we’d be taking strong regulatory action.” In fact, FDA is not taking or even proposing regulatory action. So it has reaffirmed its views on BPA although it, like others, including us, recognizes that additional scientific research is appropriate to resolve key scientific questions and uncertainties.
MPW: What are the scientific questions this latest research is trying to address?
SH: It’s a range of things. The research they have coming out first, and this is what I understand will be published very soon, is what’s called pharmacokinetic research. . . . it tells you what happens to BPA when it gets in the body, where it goes, what form it’s in, and if the body gets rid of it. That’s very important information because it frames or puts limits on whether BPA can or cannot be toxic and how it might be toxic.
FDA presented some of its results on this research in December at a scientific conference, and it was consistent with what other researchers have found about how BPA is processed in the body, and I think would be very strongly supportive of the safety of BPA. It tells us that when BPA enters the body it is rapidly and efficiently metabolized and then quickly eliminated from the body, so that really does put limits on whether BPA could be toxic.
MPW: Apart from what the FDA is doing, is the ACC tracking any particular legislative proposals on a national level?
SH: There’s been interest from up in Congress on BPA. That was in the form of a couple of bills that were introduced last year proposing, as all of these usually do, to ban some products containing BPA. Those bills have not moved anywhere yet, although there’s a lot of discussion about [CA Democratic] Sen. Feinstein trying to progress her bill by tacking it onto a Food Safety bill that the senate may be taking up some time in the not-too-distant future. So that’s where the discussion has really been in the Senate.
MPW: From the ACC’s perspective, is the science on BPA settled? It sounds like there are still studies under way; where does the science of it stand in terms of relative safety?
SH: I think our view would be consistent with the consensus view of the regulators: The weight of the scientific evidence continues to support the safety of BPA, including in products that contact food, whether it’s PC containers or epoxy resin can coatings. In science, of course, there’s always more that you can do, and we continue to support research ourselves. Our approach has been to closely monitor the scientific literature, so we try to keep track of what everyone else is publishing, integrate that into our knowledge base, and then look for any critical areas of uncertainty.
Science, like I said, you can research forever, but our core interest is that our products are safe. So we monitor the science and look for any uncertainties that are directly relevant to that core question. When we see things where we think there’s an uncertainty or a data gap, we assess whether we’re positioned to be able to fill that gap or address that uncertainty. We do have research under way that is aimed at those areas, and other researchers do, too. That’s basically what FDA has done as well.
MPW: Apart from scientific research, in terms of the court of public opinion, does the ACC feel that the battle is lost when you see mass exodus in certain products away from PC?
SH: I don’t think that battle is lost at all. I think these products do still have a future, and we think the science supports the safety of them. Although you’re right, certain products have migrated to other materials—baby bottles, in particular, are one that has switched over to alternatives.
Keep in mind with alternatives: You’ve got a rich scientific database for BPA; you don’t have that for any alternatives. It’s a strange situation where you have something with a lot of data—data that have been reviewed by many government agencies, all of which have concluded that the material is safe as it’s being used—and you’re comparing that with alternatives that have very little data, and they haven’t really been reviewed very thoroughly by government bodies.
David Feldman is a medical doctor and emeritus professor of medicine at the Stanford University School of Medicine’s Div. of Endocrinology. A trained endocrinologist acting as both a clinician and a scientist, Feldman was the chief of the Div. of Endocrinology for 10 years. He is currently focused on cancer research—specifically, how hormones regulate target genes, particularly the ability of Vitamin D to inhibit breast and prostate cancer.
Steven Hentges, executive director of the Polycarbonate/BPA Global Group at the American Chemistry Council (ACC; Washington, DC), has a doctorate in chemistry and has spent most of his career in health and environmental training. Hentges worked in the chemical industry for 18 years, and has been involved with BPA for more than 10 years. During that time, he has managed the ACC’s PC/BPA global group, whose members include manufacturers of BPA and PC. In addition to sponsoring scientific research, it advocates on behalf of BPA.