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ELIZABETH JACKSON/U OF MINNESOTA
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BISPHENOL A A rift persists between SAFETY ASSESSMENTS of the man-made estrogen mimic STEPHEN K. RITTER, C&EN WASHINGTON
REGULAR EXPOSURE to bisphenol A
from food, drink, and other sources means that the commodity chemical shows up at low levels in the urine of essentially everyone. That fact has created a lot of concern about how toxic BPA might be. But assessing the risk the chemical poses has turned out to be not so simple. Primarily employed as a building block to make polymers, BPA has been used in an array of consumer goods since the 1950s. It’s a primary component of polycarbonate hard plastics found in reusable drink containers, DVDs, cell phones, eyeglass lenses, automobile parts, and sports safety equipment. The chemical is also a key component of epoxy resins that provide a protective layer inside food and drink cans. It’s found in dental sealants and in cashregister receipts as well. That BPA has estrogenic activity—the ability to simulate the activity of the primary female sex hormones—is old news, dating back to about 1930. At one point decades ago, it was even considered for use as an estrogen replacement drug until better mimics were discovered. More recently, however, hundreds of an-
imal and cell-culture research studies have linked the chemical’s low-level estrogenic activity to obesity, diabetes, attention deficit hyperactivity disorder, reproductive health problems, heart disease, and breast and prostate cancer. Yet BPA’s safety status is in limbo because regulators think that the methods used in many of those studies haven’t been fully validated. Instead, regulators continue to rely more heavily on a few larger-scale industry-funded studies that used older, standardized assays and
CONTENTS TOXICITY DEBATE, 14 The precautionary principle frames arguments over BPA safety. MULTIPLE EXPOSURES, 20 People face many sources of endocrine disrupters in everyday life. BPA-FREE REPLACEMENTS, cenm.ag/4 Chemists struggle to find alternatives that match BPA’s cost and performance. BPA CHRONOLOGY, cenm.ag/5 Dozens of C&EN articles published since 2007 have covered the BPA story.
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reported minimal ill effects at human exposure levels. It would be easy enough to test the effects of BPA directly on people and settle the issue. That’s naturally out of the question because it’s unethical. So although the ubiquitous chemical is known to prompt some harmful effects, it remains just beyond science’s grasp to provide a definitive assessment of BPA’s safety. This confounding situation has led to a vigorous debate about what to do with BPA: ban it, restrict its use, or leave it alone. As this debate has unfolded, the public has been bombarded with a steady flow of studies, reports, claims, counterclaims, conflicts of interest, lawsuits, and congressional inquiries regarding BPA. Both sides of the debate have been active in promoting their views to the media and the public. And both sides accuse each other of using spin tactics to create uncertainty about BPA, not unlike the socioscientific debates that have unfolded over cigarette smoking and climate change. In a series of articles both in print and online, C&EN takes a broad look at the ongoing bisphenol A story.
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DEBATING BPA’S TOXICITY The PRECAUTIONARY PRINCIPLE serves as a dividing line in arguments over the safety of bisphenol A STEPHEN K. RITTER, C&EN WASHINGTON
INDUSTRY LIVELIHOOD and modern
conveniences versus uncompromised human and environmental health advocacy have framed what remains an open-ended debate over the safety of the widely used chemical bisphenol A. Given mounting knowledge of BPA’s estrogen-mimicking properties and possible toxic effects, decisions have to be made on whether it should continue to be freely used, restricted for some uses, or banned completely. There are no simple answers. On one side of this debate, consumer and environmental advocacy groups who emphasize potential health problems stemming from steady, low-level exposure to BPA support their position by invoking the precautionary principle, which holds that even in the absence of scientific consensus it’s prudent to act as though a potentially harmful substance is, in fact, harmful. They argue that there is already enough scientific evidence of BPA’s toxicity to warrant a ban and that the general population shouldn’t have to be human guinea pigs while waiting for more compelling evidence. On the other side of the debate, manufacturers and chemical industry groups out to protect a multi-billion-dollar market from regulation are defending BPA as safe. They say the problem with applying the precautionary principle is that it could lead to a ban on a useful chemical that poses no actual danger. Scientists have played leading roles throughout the debate and tend to align with one side or the other. At times, they have let their emotions drive arguments over experimental design and interpretation of research results. These scientific disagreements may arise because the researchers hail from different disciplines such as endocrinology, toxicology, epidemiology, and chemistry, and because they work in different cultures such as academia, industry, government, and environmental advocacy.
SENSE OF SCALE 6,500,000 µg/kg
Lethal oral dose (LD50) in other mammalsa
2,400,000 µg/kg
Lethal oral dose (LD50) in micea
50,000 µg/kg/day
500 µg/kg/day
EPA no adverse effect levelb Estimated adult exposure levelc
Low-dose adverse effects observed
100 µg/kg/day
Highest estimated occupational exposuresd
50 µg/kg/day
EPA safety threshold
Up to 13 µg/kg/day
Formula-fed U.S. infant exposure leveld
Up to 1.5 µg/kg/day
U.S. adult exposure leveld
Up to 1.0 µg/kg/day
Breast-fed U.S. infant exposure leveld
0.025 µg/kg/day 0.01 µg/kg/day
Suggested safety thresholde
a Acute toxicity, where a single dose is lethal to half of the animals treated. b EPA estimate of lowest toxicity; the safety threshold is set 1,000 times lower than this value. c Daily intake determined by some endocrinology researchers. d National Toxicology Program estimated daily intake; formula-fed infant value assumes using polycarbonate baby bottles and formula packaging containing BPA, which have now been phased out. e Tolerable daily intake suggested by a group of endocrinologists.
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Meanwhile, a consumer revolt is in full swing to remove BPA from food and drink packaging. Since 2008, manufacturers have voluntarily been replacing BPA-containing polycarbonate as the plastic of choice for essentially all baby bottles and toddler sippy cups. Most reusable water bottles are also now BPA-free (see cenm.ag/4). BPA-based epoxy resin food- and beverage-can liners, however, are still widely used. Most manufacturers maintain that there are few viable alternatives for canliner applications that match the cost and shelf-life performance of current epoxy resins. CHEMICAL COMPANIES and trade groups
aren’t willing to divulge numbers, but market analyst reports estimate global annual BPA demand at up to 12 billion lb and growing at about 5% per year. Polycarbonate makes up 74% of BPA use, and epoxy resins consume about 20% of production. But the baby bottle and food-can applications combined accounted for less than 5% of BPA consumption. That means the phaseouts haven’t put a big dent in overall BPA use. The BPA debate’s ultimate outcome is still to be decided by government regulatory agencies. These authorities have treaded carefully in assessing the available information. In the U.S. they officially advocate staying on the current course of exercising caution, recommending ways to reduce exposure, and doing more research. According to the Environmental Protection Agency, people can safely be exposed to up to 50 µg of BPA per kg of body weight per day. It is that number, set in 1988, that keeps the debate alive: The chemical industry is satisfied with it, but many endocrinologists and toxicologists, and by extension environmental health and safety advocates, think it is too high. One set of 38 scientists came to the latter conclusion while attending a National Institute of Environmental Health Sciences (NIEHS) workshop on BPA in November 2006. Studies dating from the 1990s had reported that amounts of BPA at or below the 50 µg/kg/day safety threshold could cause developmental disorders in lab animals. The findings suggested that low doses of BPA and other endocrine disrupters can lead to adverse health effects, whereas higher doses short of acutely toxic levels might result in no observed effects. In reviewing hundreds of animal and cell-culture studies, the workshop scientists
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concluded that human exposure to BPA is likely in the range that had been observed to cause the low-dose effects in animals. At about the same time, a panel established by the National Toxicology Program (NTP), an interagency program administered by NIEHS, was also evaluating many of the same studies. The panel estimated that formula-fed infants up to a year old ingest up to 13 µg/kg/day of BPA; the levels were lower for breast-fed babies. For adults, NTP estimated BPA intake was up to 1.5 µg/kg/day. In its final report, issued in September 2008 and taking the NIEHS workshop findings into consideration, the NTP panel stated that it had “some concern” regarding BPA effects on the brain, behavior, and prostate gland in fetuses, infants, and children. “Some concern” represents the middle level of NTP’s five-level concern scale, which ranges from “serious” to “negligible.”
BPA At A Glance Official name: 4,4´-(1-Methylethylidene)bisphenol First synthesized: 1888 BPA applicationsa Key uses: Otherb ■ Polycarbonate hard plastics for 6% drink containers, DVDs, cell phones, Epoxy resins 20% Polycarbonate eyeglass lenses, automobile parts, 74% sports safety equipment ■ Epoxy resins for food- and drinkcan liners, paints and coatings, adhesives, composite materials a Based on Environmental Protection Agency information. b Flame retardants and other polymers. c SRI Consulting estimate before baby bottle and water bottle phaseouts.
in the safety of BPA in all its multiple uses.” BPA critics took the finding the opposite way, emphasizing the panel’s concern about prenatal and early childhood exposures. The Environmental Working Group, a nonprofit THE PANEL ALSO had “some” or lesser advocacy organization, said in a statement concern for other outcomes, including an that the NTP report “raised concerns that earlier age for puberty in girls; fetal or neoexposure to BPA during pregnancy and natal mortality, birth defects, or reduced childhood could impact the developing birth weight; reproductive effects in nonbreast and prostate, hasten puberty, and afoccupationally exposed adults; and ill effect behavior in American children.” fects in workers exposed to higher levels in Some of the endocrinologists and toxioccupational settings. The panel based its cologists who were part of the NIEHS workdecision on the fact that shop, including Frederick although there was credS. vom Saal and John PeterSTRUCTURAL MIMIC ible evidence for the lowson Myers, criticized the BPA’s phenol rings and dose BPA developmental NTP assessment and EPA’s bridging isopropylidene effects, the experimental safety threshold in journal group are reminiscent of results weren’t consistent. commentaries. They faultthe multiring steroidal The NTP panel’s analyed the panel for several structure of estradiol and sis was interpreted as runreasons, but overall for not other estrogens. ning counter to the NIEHS giving sufficient weight to workshop’s conclusions, their low-dose results. Vom causing what had been Saal is an award-winning a simmering debate to endocrine-disruption speHO OH boil over. Members of the cialist at the University of Bisphenol A NIEHS workshop charged Missouri, Columbia. Myers OH that the NTP panel was is founder of Environbiased by industry influmental Health Sciences, a H ences and had wrongly nonprofit environmental discounted the imporadvocacy organization. tance of the low-dose data Vom Saal and Myers H H HO in its analysis. point out that current U.S. Estradiol The response that folhealth standards for exlowed was as expected. posure to toxic chemicals “The NTP report did not say BPA is bad; rest upon the assumption that high-dose it said there is some concern. You can make testing procedures used in regulatory toxithat statement about anything,” said Jack cology adequately predict potential lowN. Gerard, then-chief executive officer of dose effects. But that prediction doesn’t the American Chemistry Council (ACC), hold for BPA and other endocrine disruptthe chemical industry’s trade organization ers, they say. and lobby group. “That gives us confidence BPA binds weakly to the primary estroWWW.CEN-ONLINE.ORG
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2011 global demand = 12 billion lbc
gen receptor in people, which is bound more strongly by estrogen hormones as well as natural estrogen-like compounds in foods—so-called phytoestrogens (see page 20). BPA binds more strongly to alternative estrogen receptors, and its physiological effects are thought to be mediated by these alternative pathways. At high BPA doses—some thousands to millions of micrograms per kilogram of body weight—the chemical displays acute toxicity. But at low doses—from about 0.025 µg/kg/day up to 500 µg/kg/day— things aren’t so cut and dried. As the dose increases, it changes the suite of genes that are expressed by BPA’s action on estrogen receptors, vom Saal says, which means the impact at low doses, or at doses in between, can’t be predicted from high-dose experiments. This disrupted biochemistry triggers changes in hormone concentration, enzyme function, protein synthesis, and more, which are of greatest concern for developing fetuses and newborns. Scientists propose that such changes stay with a person over a lifetime and play a key role in the development of diseases. Overlooking low-dose effects creates the strong likelihood that some health standards currently used to set exposure limits for the American public are too weak, vom Saal and Myers assert. They suggest that based on low-dose research findings, no level of BPA might be safe. In extrapolating the current safety threshold to the level where low-dose effects are observed, they say, the safety threshold should be some 5,000 times lower—0.01 µg/kg/day instead of 50 µg/kg/day. That level would likely require eliminating BPA from all types of products, including
CDs, eyeglasses, and football helmets. ty threshold is based on GLP-compliant found microgram-per-liter levels of BPA in In response to the low-dose findings, the animal studies. the urine of 93% of the hundreds of people chemical industry commissioned its own Critics of BPA’s continued use state that tested. large-scale low-dose BPA studies. Among the standardized assays used in GLP studThe Melzer study revealed that people the most influential of these were two ies are outdated because they are incapable with higher urine concentrations of BPA studies led by Rochelle W. Tyl and coworkof detecting the types of low-dose effects are at greater risk for heart disease, type ers of the North Carolina-based Research that state-of-the-art techniques and ex2 diabetes, and increases in liver enzyme Triangle Institute (now RTI International), perimental designs show (Environ. Health activity (J. Am. Med. Assoc., DOI: 10.1001/ an international independent research Perspect., DOI: 10.1289/ehp.0800173). jama.300.11.1303). The researchers coninstitute. cluded that “these findings add to the In 2002, with funding from the Society “THE TOOLS we have been dependent evidence suggesting adverse effects of lowof the Plastics Industry, Tyl and coworkers on to assess risk are largely blind to these dose BPA in animals.” monitored three generations of rats dosed endocrine-disrupter effects,” Myers says. Last year, when NHANES data were with different levels of BPA and found no “We haven’t done a good job advancing released for 2005–06, Melzer and coworkadverse effects at low doses. But those restandardized assays at a pace that can keep ers repeated their analysis. The newer data sults were called into question by vom Saal, up with new scientific observations.” showed lower levels of BPA in U.S. adults Myers, and 34 other leading BPA scientists. Nevertheless, low-dose methods and compared with the earlier data, but the Among other reasons, they noted the data aren’t yet being considered concrete heart disease and liver enzyme associastudy used a strain of rats that some scienenough to be used for BPA risk assessments tions were replicated; the diabetes associatists believe is insensitive to low doses of and regulatory decision making, to the contion was not apparent in the 2005–06 data estrogen-like compounds (PLoS One, DOI: 10.1371/ such as BPA. Using those journal.pone.0008673). CHEMICAL LINCHPIN Bisphenol A is a commodity chemical and animals makes it impossible To be fair, the researchessential component of two classes of polymers. to adequately assess the ers show an association beconsequences of low-dose tween BPA and the humanOH BPA exposure, they say. health conditions, not proof O Tyl led a follow-up ACCof causation. Nevertheless, + 2 + H2 O funded study in 2008 that Melzer tells C&EN that he HO OH used mice instead of the believes these associated Acetone Phenol Bisphenol A rats. It also found no adeffects shown by analyzO O verse effects from low-dose ing independent data sets Cl Cl Cl BPA. In this case, the study “should be taken seriously.” Epichlorohydrin Phosgene was criticized for, among Because testing the efother reasons, problems fects of BPA directly in peowith the animal chow fed ple is unethical, scientists O to the mice—phytoestrolooking to clarify the BPA gens in the feed may have debate are designing studies (O ) (O ) O O masked BPA’s effects. that can ascertain toxicity OH Polycarbonate Epoxy resin Tyl, who has moved on without dosing people. to other areas of research, In one such example, a is unconvinced that BPA is harmful. The tinued frustration of the scientists designteam led by Ruthann A. Rudel of the Silent argument against BPA “now transcends ing and carrying out the studies (C&EN, Spring Institute, a nonprofit environmendata, facts, and results and is driven by an Nov. 8, 2010, page 40). tal advocacy organization, reported in unjustified fear,” she says. One sticking point has been proving that March that BPA levels in the urine of five For their part, regulatory agencies have BPA exposure is causing adverse health effamilies in San Francisco dropped on avergiven more weight to the Tyl experiments fects in people during adulthood like those age 66% when they stopped eating canned and others like them because they are seen in short-lived lab animals, when there and plastic-packaged foods for three days large-scale studies and adhered to socould be many causes. These may include and ate only freshly prepared food at home. called Good Laboratory Practice (GLP), other man-made chemicals or combinaWhen the families went back to their norwhereas most of the other hundreds of tions of chemicals coupled with high-calomal diets, their BPA levels returned to the studies showing negative effects, which rie diets and lack of exercise. original levels (Environ. Health Perspect., were smaller and in some cases considered The first major epidemiologic study to DOI: 10.1289/ehp.1003170). The researchonly screening tests, did not. make this connection came out in 2008, at ers’ conclusion: Removing BPA from food GLP is a set of federal rules for conductabout the same time as the NTP report. A packaging will significantly decrease expoing research on health effects or safety team led by David Melzer of the University sure for adults and especially children. testing of drugs and chemicals. The rules— of Exeter, in England, analyzed data from But these types of studies still don’t conwhich were established in 1978 after a spate the 2003–04 U.S. National Health & Nunect BPA exposure with ill health effects. of fraudulent toxicology studies on pestitrition Examination Survey (NHANES), In other experiments, scientists are trying cides—spell out how such studies must be which was conducted by the Centers for to connect adverse effects observed in lab executed and reported. EPA’s current safeDisease Control & Prevention. The survey mice and rats to people. Two such studies WWW.CEN-ONLINE.ORG
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Saal suggests that the results of the two studies actually are the same. FDA declined to make Doerge available for comment on the vom Saal study. FDA, TAKING into account the plethora
of scientific studies, reports, and policy statements from environmental groups, industry trade groups, independent labs, and federal agencies—including its own BPA task force—issued a statement in January 2010 in which it agreed with NTP’s analysis of “some concern” regarding BPA. But FDA did not restrict BPA. Then-FDA deputy commissioner Joshua STEVE RIT T ER/C&EN
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reported last year further fueled the BPA debate. In one study, a team led by Daniel R. Doerge of the Food & Drug Administration’s National Center for Toxicological Research dosed adult and baby rhesus monkeys with BPA (Toxicol. Appl. Pharmacol., DOI: 10.1016/j.taap.2010.07.009). The researchers reported that the monkeys metabolized BPA at rates similar to those reported for humans and that their results were “clearly different” from those reported in studies using rats. The team concluded that “any toxicological effect observed in rats in early postnatal exposures
IN THE CAN Fruit cans, such
as the peach can at left, typically don’t use an epoxy resin lining except on the lid and bottom. The tomato can at right has a thick epoxy resin liner to protect the acidic tomatoes.
to BPA could overpredict those possible in primates.” In the other study, vom Saal’s group also dosed rhesus monkeys with BPA (Environ. Health Perspect., DOI: 10.1289/ehp.1002514). But the researchers came to a completely opposite conclusion—mice and monkeys metabolize BPA at similar rates as people. As a result, they argue that it is reasonable to directly extrapolate health effect studies of BPA in mice to humans. Vom Saal and coworkers also concluded that people likely have significant BPA exposure from nondietary sources. They further confirmed earlier studies that show people might be exposed to BPA at up to 500 µg/ kg/day to achieve the levels observed in biomonitoring studies. That figure is 10 times higher than EPA’s safety threshold. In their paper, vom Saal and coworkers reanalyzed the data in the Doerge study, suggesting that those researchers made erroneous assumptions and that their data did not support their conclusions. Vom WWW.CEN-ONLINE.ORG
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M. Sharfstein, a physician, commenting on FDA’s position on the safety of BPA for pregnant women and children, said: “If we thought it was unsafe, we would be taking strong regulatory action.” In addition, in March 2010 EPA added BPA to its list of chemicals targeted for possible regulation under the Toxic Substances Control Act (TSCA) and announced it would be gathering more safety data. As part of the plan, EPA is using its Design for the Environment program to encourage manufacturers to implement green chemistry to redesign products to reduce the chemical’s presence in the environment. But EPA has not restricted BPA use. Last fall, FDA’s counterpart in Europe announced that it too had concerns about BPA safety. But in its review of some 800 research studies on BPA published since 2007, the European Food Safety Authority found no new evidence to justify lowering its tolerable daily intake value of 50 µg/kg/ day, which is the same as the U.S. level.
The European Commission, which had charged the agency with evaluating BPA safety, subsequently invoked the precautionary principle and banned BPA in baby bottles. China recently did the same. In the absence of U.S. regulatory action, Congress has toyed with the idea of superseding federal agencies by imposing legislation banning BPA. Congress has also considered revising TSCA, which both sides of the debate agree is in need of an overhaul. Indeed, some BPA critics suggest regulatory agencies haven’t acted on BPA because they do not have appropriate regulatory authority under TSCA. In effect, many people would like to see a reversal of U.S. policy: Abandoning the current approach in which chemicals can be used until proven toxic in favor of a policy more like Europe’s Registration, Evaluation, Authorization & Restriction of Chemical substances (REACH) program, in which the industry must provide data demonstrating a chemical is safe before it can be used in commerce. FOR THE MOMENT, U.S. federal regulators continue to consider BPA safe by a bare margin. But the debate is not over. New studies are addressing the earlier research design criticisms in order to test the low-dose hypothesis. NIEHS has invested some $30 million on additional BPA research by 10 leading science groups, including vom Saal’s, that will be reaching journals during the coming year. These studies might show more convincingly that the low-dose data can reliably be used to inform regulatory decisions. Or they might show that BPA is safe for continued use. “There are some experts who are passionately convinced of the counterintuitive fact that small amounts of BPA are more problematic than large amounts, and that a lot of bad things can come from it,” observes John C. Warner of the Warner Babcock Institute for Green Chemistry, in Wilmington, Mass., who has investigated BPA in cash-register receipts. “But then there are equally competent and passionate scientists who believe BPA is perfectly safe. It’s difficult to know who is wrong and who is right. Our society is so frustrated.” Warner suggests the role of scientists “should not be to come down on the side of being right or wrong, but to quantify the magnitude of the problem and let consumers make their choices, which will ultimately decide what happens in the marketplace.” ■
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ed the experiments last year (Green Chem. Lett. Rev., DOI: 10.1080/17518253. 2010.502908). The results in both studies indicate that in the Boston area about 70% of the stores had BPA in their receipts. “But more important, 30% didn’t,” Warner says. “That means there’s already a cost-effective alternative technology in the marketplace, so we don’t need to invent a new technology to solve this problem.” One “disheartening” detail about almost all of the BPA-free thermal-imaging papers, Warner cautions, is that they employ bisphenol S compounds in which an SO2 unit occupies the spot of BPA’s isopropylidene group. “From what I understand, BPS displays the same estrogenic activity as BPA,” Warner says. Warner is now helping retailers determine whether their receipts contain BPA and the best way to avoid the issue if they do, either by switching thermal-imaging paper or going to a different printing system. ON CONTACT Cash
register receipts are one source of human exposure to bisphenol A, shown in its off-white crystalline form.
EXPOSURE ROUTES CONFOUND BPA DEBATE Beyond bisphenol A in food and drink containers, people face many SOURCES OF ENDOCRINE DISRUPTERS in everyday life STEPHEN K. RITTER, C&EN WASHINGTON
CONCERN OVER potentially harmful
health effects from exposure to the estrogen-mimicking compound bisphenol A initially leveled a spotlight on baby bottles and food cans. But that focus has left several other potentially important sources of estrogen mimics in the environment largely in the dark. In fact, sources of these so-called endocrine disrupters go well beyond bottles and cans. Key among them are credit card and cash register receipts that use BPA in the printing process, natural estrogenic compounds found in foods, and estrogenic compounds that leach from a wide range of plastics, not just those that contain BPA. “When it comes to BPA in the environment, the biggest exposure, in my opinion, is from cash register receipts,” says John C. Warner of the Warner Babcock Institute for Green Chemistry (WBI), in Wilmington, Mass. “Once on the fingers, BPA can be transferred to the mouth, onto food, and likely absorbed through the skin.” The BPA-receipt connection is something Warner has been thinking about for years, based on knowledge of thermal-imaging printing technology he gained as a researcher at Polaroid in the 1980s and ’90s.
In polycarbonate plastic bottles and epoxy resin food-can liners, BPA exists as a monomer unit bound in a polymer—nanograms of residual BPA might leach out, Warner explains. “But for thermal imaging,” he emphasizes, “receipt-paper manufacturers put a powdery layer containing BPA and an invisible ink on one side of the paper. In this case, BPA is a free substance coated on the paper in milligram quantities. “When pressure or heat is applied, the chemicals meld together to form an imprint,” he continues. “When you grab the receipt, your fingertips can get coated with BPA.” In the early 2000s, when he was a chemistry professor at the University of Massachusetts, Boston, Warner had students go to different retail and grocery store chains to gather receipts, bring them into the lab, and then analyze samples by mass spectrometry to quantify the amount of BPA present. With the recent upwelling of interest in BPA exposure, Warner and his team at WBI repeat-
LAST YEAR, a pair of research studies helped confirm Warner’s speculation that BPA can be readily absorbed through the skin and that people who constantly handle receipts are at risk for higher exposure (C&EN, Nov. 15, 2010, page 36). Daniel Zalko of the French National Institute for Agricultural Research, in Paris, led a team that measured significant diffusion of 14C-labeled BPA through samples of pig and human skin. Separately, Harvard University’s Joseph M. Braun and coworkers monitored the diets and analyzed BPA in urine samples of nearly 400 pregnant women, finding that cashiers had the highest BPA levels and that teachers and industrial workers had significantly lower levels. Actually, people can be exposed to BPA without directly handling receipts: A study released last December by Erika Schreder of the Washington Toxics Coalition, a nonprofit environmental advocacy organization, found that most paper currency is contaminated with small amounts of the chemical, likely originating from contact with receipts.
“When you grab the receipt, your fingertips can get coated with BPA.” WWW.CEN-ONLINE.ORG
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In addition to food and drink packaging, the food and drink itself is another important route by which humans are exposed to endocrine disrupters. People regularly ingest dozens of natural compounds in foods and beverages that are stronger estrogen mimics than BPA. One letter to the editor sent to C&EN last year by Donald R. Kelsey of Guerneville, Calif., pointed out that exposures to these so-called phytoestrogens typically far exceed the exposure levels of man-made BPA, but they have received little publicity (C&EN, April 19, 2010, page 5). One explanation for this lack of attention, Kelsey writes, “is the common but false assumption that synthetic chemicals such as BPA are suspect, but ‘natural’ chemicals are harmless.”
exposure (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0703739104). Other plastics—even BPA-free ones— may also be a source of endocrine disrupters. A recent analysis of more than 450 everyday plastic products, from plastic bags to water bottles, found that about 95% of the items tested leached chemicals that triggered a bioassay for estrogenic activity,
including most of the products labeled as BPA-free (C&EN, March 14, page 48). The plastics analysis didn’t attempt to identify the individual estrogenic compounds responsible in each case. Instead it focused on quantifying estrogenic activity, irrespective of the chemical causes, explains neurobiologist George D. Bittner of the University of Texas, Austin, who led the study.
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vones, coumestans, and lignans found in beans, olive oil, some fruits and vegetables, cereal grains, tea and coffee, wine and beer, and chocolate. Their phenolic structures are similar to the structures of estrogens, generally more so than BPA’s structure. Researchers have observed a mixed bag of effects with phytoestrogens. Some compounds have been shown in lab studies to act as beneficial antioxidants by trapping singlet oxygen, a reactive species that can cause cellular damage. But others exhibit adverse effects in animals and humans. For example, coumestrol and the isoflavone genistein, found in soy products such as tofu, can negatively affect fertility, pituitary function, birth weight, and puberty onset in rats. Soy protein, however, is associated with lower rates of breast cancer and other types of cancers. BPA manufacturers suggest that, given the level of exposure to phytoestrogens in the daily diet, the tiny amounts of BPA that leach from polycarbonate plastics and epoxy resins may not really matter. The counterargument is that natural estrogenics have been around for millions of years and humans have evolved with them, Warner points out. “The issue with manmade things is that we did not coevolve with them, and thus we likely lack any compensatory biochemistry,” he says. In fact, studies by Duke University epigeneticist Randy L. Jirtle and coworkers have found that some phytoestrogens can counteract BPA’s adverse effects. The researchers suggest that genistein, for example, might be useful as a dietary supplement for women during pregnancy to protect their unborn children from BPA
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“Although BPA is the most notorious chemical with estrogenic activity used in plastics, it is not the only one, nor does it have the highest biological effect,” Bittner says. Bittner believes compounds with phenolic moieties such as BPA or that are converted to or degrade to phenolic compounds during product use are the most common causes of estrogenic activity in plastics. Not all chemicals that show estrogen-like activity are necessarily toxic, he adds. But Bittner is concerned that ingesting these chemicals from plastics contributes to people’s daily load of estrogenic compounds, and he suggests that it makes sense HO OH to seek out estrogenic-activityBisphenol A free plastics, especially when the additional production cost HO O “can often be as little as a fraction of a cent per pound.” FOR NOW, manufacturers
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that have gone BPA-free have switched from polycarbonate to O O different base polymer systems, notably Eastman Chemical’s OH Tritan copolyester, glycol-modO HO ified polyethylene terephthalCoumestrol ate (also a copolyester), and clarified polypropylene, Bittner notes. “But as our data show, the switch to some new materials has not ameliorated the estrogenic activity: BPA-free does not mean estrogenic-activity-free,” he says. (See also cenm.ag/4.) Scientists involved in the BPA issue are quick to point out that the estrogenic assay study of plastics needs to be verified, in particular because Bittner has a conflict of interest in the results. The research was carried out at CertiChem and PlastiPure, a pair of contract firms cofounded by Bittner. CertiChem uses its estrogenic activity assays to test plastics, foods, chemicals, and packaging. PlastiPure designs plastic formulations so that products can be certified to be free of endocrine-disrupting activity. Bittner stands by his results, noting that the study was funded by the National Science Foundation and by the National Institute of Environmental Health Sciences, and it was published in NIEHS’s peer-reviewed journal, Environmental Health Perspectives. “Before we jump to the conclusion that all plastics are bad, some important details need to be filled in,” observes Daniel F. Schmidt, a polymeric materials chemist at the University of Massachusetts, Lowell, who reviewed the Bittner study for C&EN. “While the compositions of specific plastics formulations often are not publicly released, we know which compounds are used as additives in the plastics industry. What we don’t know is which compounds are being extracted in the Bittner research and trigger the assays, or the extent to which they constitute an important source of human exposure.” Schmidt argues that rapid progress is needed on the question of human exposure to endocrine disrupters, and that better screening of plastics under actual-use conditions will be an important part of any answer. For additional context, the significance of other sources of possible estrogenic phenolic compounds, such as paper products and phytoestrogens, should also be studied, Schmidt says, “to give ourselves a reality check and make sure we’re not missing the forest for the trees.” ■
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