The FDA just made it easier for food manufacturers to substitute ingredients and for vending machine operators to ditch calorie information.
We all are exposed daily to bisphenol-A (BPA) and other bisphenols – estrogen-like substances added to food can liners, paper receipts and plastic containers.
This is part 1 of a 4-part investigation of the science surrounding the chemical BPA and the U.S. regulatory push to discredit independent evidence of harm while favoring pro-industry science despite significant shortcomings.
University of Massachusetts-Amherst environmental health scientist Laura Vandenberg. (Credit: Umass.edu)<p>"Endocrine disruptors are harming people and we're not regulating them to any extent right now," Carol Kwiatkowski, executive director of The Endocrine Disruption Exchange, a nonprofit research institute that advocates against the production and use of chemicals that interfere with healthy hormone function, told EHN. </p><p>"A lot of endocrine scientists have been banging their heads against that wall for a long time and haven't made any progress in changing the risk assessment process."</p><p>It is clear that the FDA is not using modern science in protecting the public from potentially toxic chemicals. It is also clear that BPA and other endocrine disruptors threaten to disrupt the status quo of toxic chemical regulation. "BPA creates a tipping point," Laura Vandenberg, an environmental health researcher at the University of Massachusetts-Amherst's School of Public Health, told EHN. "If the FDA finds out that they have been wrong about BPA — or wrong about how they evaluate chemicals for safety — that means they are wrong about the 10,000 other chemicals behind BPA in line for the same sort of evaluation."</p><p>Vandenberg, who is not involved in Clarity, is among scientists skeptical that the groundbreaking effort will result in a fair assessment of BPA. The FDA, she said, has "a vested interest in not being wrong."</p>
Cheryl Rosenfeld, a biologist at the University of Missouri and another Clarity investigator. (Credit: University of Missouri)<p>Beginning in the 1950s, BPA became a key ingredient in polycarbonate plastic and epoxy resins — finding its way into everything from Tupperware to the lining of food cans. "That's where the problem starts," Ana Soto, an endocrinologist at Tufts University and another Clarity investigator, told EHN.</p><p>The FDA officially approved BPA for use in food and beverage containers in 1963. They classified it as a "generally regarded as safe" (GRAS) compound, since it had already been around for a few years and there was no obvious evidence of harm. By the late 1980s, the U.S was producing nearly a billion pounds of BPA a year. Even scientific laboratories began working with BPA-laden instruments. In 1993, endocrinologists at Stanford University discovered that BPA was leaching from polycarbonate flasks in their laboratory.</p><p>The first published studies to raise concern about BPA's low-dose health effects came a few years later, in 1997. Frederick vom Saal and his colleagues had found exposure to tiny amounts of BPA altered the prostates and reproductive systems of laboratory mice. Vom Saal, a professor of biology at the University of Missouri-Columbia and another Clarity investigator, warned viewers in a February 1998 episode of <a href="https://www.pbs.org/wgbh/pages/frontline/shows/nature/interviews/vomsaal.html" target="_blank">PBS's Frontline about the threat posed by endocrine-disrupting chemicals</a> used in plastics and other consumer products.</p><p>"We understand now, with new techniques, that, in fact, cells are extremely responsive to these chemicals," vom Saal stated on the show. "What you have now is clearly enough scientific information to warrant concern and a change in the regulatory approach to these chemicals." Concern grew, as did the body of research.</p><p><a href="https://ntp.niehs.nih.gov/ntp/ohat/bisphenol/bisphenol.pdf" target="_blank">By 2008</a>, enough evidence had accumulated that the NTP labeled the chemical as possibly harmful for babies. Canada responded by declaring BPA toxic and manufacturers across North America, including baby bottle and sippy cup makers, started phasing it out of their products. Wal-Mart, REI, Lululemon, Toys-R-Us and other retailers, too, began pulling products with BPA off their shelves. The market was soon flooded with BPA-free products — although most of the substitutes that landed in stores share similar chemistry with BPA and pose similar health concerns.</p><p>"The science is growing exponentially. We can't keep up with it," said Kwiatkowski, of The Endocrine Disruption Exchange. "And we have to take it all very seriously, because the preponderance of endocrine-related disorders in humans today is just skyrocketing."</p>
Researchers Fred vom Saal and Wade Welshons at their University of Missouri lab. (Credit: Brian Bienkowski)<p> Jennifer Sass, a senior scientist with the Natural Resources Defense Council, said that the guidelines are "a good starting point to see if there's evidence of harm," and "allow regulators from Japan to Sweden to North Africa to look at data the same way." However, she added, these guidelines "should not be used to eliminate evidence of harm." </p><p> Such standardized studies can also be pricey to conduct, often beyond the budgets of academics. And the FDA's traditional targets for tests, such as weighing organs and looking for other overt signs of toxicity, generally do not consider the unique effects of endocrine-disrupting chemicals — some of which can be subtle such as behavioral changes or infertility years down the road. </p><p> "You can't weigh a brain to find out what is going on in there," Soto said. </p><p> In 2001, the <a href="https://ntp.niehs.nih.gov/ntp/pressctr/mtgs_wkshps/2000/lowdosepeerfinalrpt.pdf" target="_blank">NTP appeared to agree</a>. They concluded in a report that published studies had provided evidence for the effects of BPA exposure at or below the safety standard set by the FDA. And they recommended a reconsideration of the current testing paradigm. </p><iframe src="https://e.infogram.com/e9cd60bd-fe58-4634-b91c-668d293885aa?src=embed" title="BPA swimming pool" width="700" height="273" scrolling="no" frameborder="0" style="border:none;" allowfullscreen="allowfullscreen"></iframe><p> The plastics industry pushed back, funding the Harvard Center for Risk Analysis, a group that had received financial support from chemical companies in the past, to do a separate review of the literature on BPA. That assessment determined that only two large studies—both funded by industry—were relevant and reliable enough to consider. Both studies would go on to make regular appearances in subsequent FDA reports. </p><p> Doerge was a co-author on FDA's most recent safety assessment of BPA, released in 2014, which reaffirmed its position that the chemical is safe at levels of exposure from food contact uses. "No new information was identified to suggest revision of the existing safety assessment level," <a href="https://www.fda.gov/media/90582/download" target="_blank"> wrote the authors</a>. </p><p> The report was an update of the agency's <a href="http://docplayer.net/102806848-Scientific-peer-review-of-the-draft-assessment-of-bisphenol-a-for-use-in-food-contact-applications.html" target="_blank">2008 assessment</a>, for which the FDA relied heavily on the same two industry-funded guideline studies considered in the Harvard group's analysis and discarded hundreds of non-GLP studies published by academics that nonetheless found low-dose effects of BPA. </p><p> An external <a href="https://www.researchgate.net/publication/237734993_Scientific_peer-review_of_the_draft_assessment_of_bisphenol_A_for_use_in_food_contact_applications" target="_blank">FDA committee had even reviewed the 2008 report and disagreed</a> with the agency's decision to exclude those other peer-reviewed papers. "The draft FDA report does not articulate reasonable and appropriate scientific support for the criteria applied to select data for use in the assessment," they wrote. "Specifically, the Subcommittee does not agree that the large number of non-GLP studies should be excluded from use in the safety assessment." </p><iframe src="https://e.infogram.com/f013adea-774f-4e13-86e8-8408f9cdcd61?src=embed" title="Annual health costs" width="700" height="676" scrolling="no" frameborder="0" style="border:none;" allowfullscreen="allowfullscreen"></iframe><p> Of note: A <a href="https://www.ncbi.nlm.nih.gov/pubmed/16256977" target="_blank">2006 analysis</a> found that 11 out of 11 industry-funded studies found BPA had no significant action, while 109 of 119 studies that had no industry funding did find effects of BPA. </p><p> Yet those industry-funded studies tend to use more expensive GLP protocols and qualify as guideline studies. "The non-guideline studies are basically ignored. To me, that's like wearing blinders," said Birnbaum. "Science has continued to advance, and I think there are questions that we really didn't know about 30, 40, 50 years back that people are asking today." </p><p> "If you don't ask the question, you're not going to get the answer," she added. </p><p> Jerry Heindel, the health scientist administrator at the National Institute for Environmental Health Sciences (NIEHS) when Clarity was initiated, agreed. "Maybe these guideline studies aren't as gold standard and terrific as people have thought," he told EHN. "Problem is, the endpoints are so simplistic and old-fashioned." </p><p> But he and other scientists also acknowledge that the FDA has an extremely high bar to justify adoption of new approaches, let alone bans on a chemical. Regulatory agencies are in a tight spot and have to first ensure they can't be sued, added Heindel, who retired from NIEHS in 2016 and founded Commonweal's Healthy Environment and Endocrine Disruptor Strategy (HEEDS), a hub for scientists working on endocrine disruptors. "If they come out and say a chemical is toxic and we need to ban it," he said, "then they have to feel confident they have the data that will stand up in the court of law." </p>
Gail Prins, a researcher at the University of Illinois at Chicago and Clarity investigator (right). (Credit: uic.edu)<p> On February 23, 2018, upon completion of the draft version of the government's Clarity Core Study, <a href="https://www.fda.gov/news-events/press-announcements/statement-stephen-ostroff-md-deputy-commissioner-foods-and-veterinary-medicine-national-toxicology" target="_blank" rel="noopener noreferrer">the FDA released a public statement</a>, suggesting that the findings supported its position that "currently authorized uses of BPA continue to be safe for consumers." </p><p> The move stirred significant press, mostly reassurances to the public of the chemical's safety; FDA's collaborators were not pleased. Some suggested that the very agency responsible for ensuring our safety is actively working to avoid dealing with a massive experiment that is disrupting our hormones from birth. </p><p> "I smell a big fat rat here," Gail Prins, a researcher at the University of Illinois at Chicago and Clarity investigator, wrote in an email to Nigel Walker of NIEHS after learning of the statement. "The FDA is not playing fair." </p><p> Walker, a toxicologist who helped lead Clarity, responded by sending a scathing email to officials at the FDA. Members of that agency's upper management, he wrote, were "reneging on their own values in regulatory science," and "using the Clarity core study as a quasi-definitive human risk assessment document to affirm the current FDA policy on safety of BPA." In additional emails obtained by EHN, Walker went on over subsequent days to write of FDA officials' "shenanigans," calling their actions "disingenuous" and "disrespectful." He referred to himself as "peeved." </p><p> He also made a point to state that he had no conflicts of interest himself: "I don't have a horse in this race," wrote Walker. </p><p> The FDA declined to comment on the statement, or on the subsequent criticisms from collaborators. A culture clash of sorts continues between the FDA and NIEHS. Multiple scientists with the latter agency shared similar sentiments about the FDA's conduct in Clarity. Walker declined a phone interview but stated in an email to EHN that "there may from time to time be disagreements on various issues or topics." </p><p> Birnbaum said that while she was not surprised by the FDA's conclusions from the government's portion of Clarity — it was, after all, consistent with their historic stance on the chemical's safety — she did not share their opinion. "I think we reserve the right to disagree, respectfully," she said. And Bucher of the NIEHS and NTP offered his take: "The FDA conclusions are the FDA's view of how they look at data from these kinds of studies... To us, it would be more valuable to try to integrate this information and then come up with statements as to interpretations." </p><p> In September 2018, the government released the final version of its Core Study report. The FDA also advertised and hosted a webinar to detail their findings, which was preempted by outside academics who held their own webinar to present contrasting conclusions. The academic webinar was organized and moderated by Myers of Environmental Health Sciences.</p>
This is part 2 of a 4-part investigation of the science surrounding the chemical BPA and the U.S. regulatory push to discredit independent evidence of harm while favoring pro-industry science despite significant shortcomings.
The lab of Cheryl Rosenfeld, a biologist at the University of Missouri and another Clarity investigator. (Credit: Cheryl Rosenfeld)<p> Ila has just returned from her first puppy training class as I arrive at Hunt's home in Moscow, Idaho. Labradoodles are known to have a lot of energy, and Ila's bouncy greeting of this newcomer corroborated that reputation. Hunt tells me she is surprised Ila has yet to hurdle the childproof gate that separates the mudroom from the dining room. "I keep thinking she could hop over it so easily, but she just never does," says Hunt. </p><p> Other dog breeds may be calmer, but Hunt and her husband had good reason to go with a labradoodle: The breed sheds less fur and other allergy-triggering substances than other breeds. "We had a lab once before and the hair was everywhere, and our allergies were terrible," she says. Sure enough, I made it out of her house without any of Ila's dark brown fur. </p><p> Like dogs, lab animals can be diverse in their behavior and biology. </p><p> To determine the impact of a chemical, scientists track various changes, called endpoints, in an animal such as organ weight, tumor development, changes in behavior or insulin levels. Different strains of different rodents are often used in different studies. Hunt and many others who investigate the impacts of hormones and hormone mimics often opt for strains of mice. For one, the animals can be more practical — they eat less and take up less space than rats. Certain strains of mice are also known to be particularly sensitive to hormone changes. </p><p> "If your animal model can't respond to your experimental manipulation, then you can never determine if the manipulation does anything, ever," Scott Belcher, a biologist at North Carolina State University, and a Clarity investigator, told EHN. </p><p> Belcher, too, tends to use mice in his studies of impacts on the heart. "Rats and mice aren't the same things," he said. </p><p> The FDA's go-to animals for chemical toxicity testing are Sprague-Dawley rats bred at the FDA's National Center for Toxicological Research in Jefferson, Arkansas. These were the animals chosen for Clarity, despite objections from some academic investigators. The rats <a href="https://academic.oup.com/biolreprod/article/89/5/108,%201-10/2513941" target="_blank">have long been used</a> in government regulatory studies, and they have long been known to have low sensitivity to BPA. </p><h3><em>Related: Want this story in comic strip form? Check out <a href="https://www.ehn.org/test-comic-post-2640636344.html" target="_blank" rel="noopener noreferrer">"Clouded in Clarity"</a></em></h3><p> Jerry Heindel, the health scientist administrator at NIEHS when Clarity was initiated, noted one particularly unusual characteristic of the rats. "Estrogen stimulates puberty in a female animal. You can generally make puberty come up two, three days earlier by giving an animal extra estrogen," he told EHN. "But in this animal, you can't." A couple days early is relatively significant for an animal that, on average, hits puberty at 38 days. </p><p> "So some endpoints are going to be insensitive or much less sensitive. There's no getting around that," said Heindel. (The FDA did not respond when asked about the choice of study animal.) </p><p> Of course, animal studies all have their limitations. The only way to be relatively sure of a chemical's effect in humans would be to study the effect of that chemical in humans. In a first-of-its-kind study published in 2018, <a href="https://www.ehn.org/bpa-linked-to-diabetes-2604258226.html" target="_blank">researchers exposed a small group of people to a very small amount of BPA</a> and saw a link to a precursor of type 2 diabetes. The researchers first lowered participants' BPA levels and then brought those levels back up to the normal range. (Myers was an author on the paper.) Still, to knowingly expose people to something suspected of being harmful can raise some ethical concerns. Epidemiological studies do the next best thing — they take advantage of the natural experiment currently underway by estimating levels of exposure and health outcomes in people and then determining if and how the measures might be related. </p><p>In his epidemiological studies, John Meeker, an environmental health scientist at the University of Michigan School of Public Health, has uncovered evidence that BPA may alter circulating levels of hormones and birth outcomes. He laments how regulators have remained reliant on animal toxicology studies. "We need more harmonization of animal and human research in the regulatory setting," he told EHN.</p><p>Both research methods have their place. Toxicology studies allow scientists to directly compare exposed and unexposed animals, control the experimental environment and precisely measure outcomes. Meeker noted that his epidemiological findings do not always match up with toxicology studies. "When they do match up, it gives you more confidence," he said. "When they don't, it could be due to chance in human studies or due to species differences in their responses to exposure."</p>
Thomas Zoeller, a biologist at the University of Massachusetts, Amherst, and Clarity investigator in his lab. (Credit: Umass.edu)<p>Thomas Zoeller, a biologist at the University of Massachusetts, Amherst, suggested such species differences resulted in what he called "unprecedented" findings in his Clarity study. "This is a very odd strain of animal," he told EHN.</p><p>For a century, explained Zoeller, researchers including himself have studied the impact of thyroid hormone insufficiency on brain development in animal models. "Nobody sees a lack of effect," he said. Zoeller treated some of his Clarity rats with a medication used for hyperthyroidism, propylthiouracil, that suppresses thyroid activity. And while it did succeed in altering thyroid hormone levels, as expected, the brains of his rats appeared almost unfazed.</p><p>"The data that we have show that these animals are different," added Zoeller. "They may just be different with respect to the thyroid system. But I doubt that." He suggested that because the strain was selectively bred to be prolific breeders over many generations, other changes likely accompanied the increased fecundity.</p><p>The impact of species differences can go both ways, explained Patrick McKnight, a measurement scientist at George Mason University in Fairfax, Virginia. Using a model animal that is overly sensitive to the agent of interest can artificially inflate the size of an effect, he told EHN.</p><p>Still, Linda Birnbaum, former director of the NIEHS and the NTP, shared the academics' concerns. "When we started this study, I remember having nightmares thinking, 'What happens if we don't find anything?' Because we really didn't have much data on using this strain of rat and BPA," she told EHN. "In retrospect, if I were to do this study again, I probably would've done it in mice and I probably would've used a strain which had been reported to have clear effects."</p><p>Vandenberg added her worries. "Why are we using this strain to test all chemicals if we now have evidence that it is not the right strain?" she added. "Have we made a mistake on everything?"</p>
Linda Birnbaum, former director of the NIEHS and the NTP, speaking at Northeastern University's Our Environment, Our Health event in 2016. (Credit: Matthew Modoono/Northeastern University)<p>Even when assuming a chosen animal is a reasonable model to test a chemical of interest, the next critical factor for a successful study is enlisting a large enough number of those animals to detect health effects if there are effects to be detected. The more animals, the more so-called statistical power a study has to reveal the true effects of a chemical. </p><p> Prins believes that the FDA shortchanged her on animal numbers. She had determined prior to the study that she would need at least 18 animals per treatment group to have adequate power to detect differences between the groups. Yet for one of her treatment groups she received just four animals. "When you get that number of animals, you can't get a significant effect," Prins told EHN. "I would go out on a limb and say this was done intentionally." </p><p> In a 2008 federal review of the evidence on BPA, the FDA excluded a study of hers from their risk assessment because, in part, her study didn't include enough animals. That FDA assessment, which ended up relying on just two studies — both funded by industry — restated the agency's stance that BPA is safe. </p><p> "The FDA wants to tell a story," said Prins. "They want to tell the story that BPA is fine. And it's not." </p><p> Another Clarity researcher, Jodi Flaws, struggled with a similar power problem in her Clarity research. She ended up with just three animals in one of her treatment groups, Flaws told EHN, because the tissue sent to her by the government was not collected on the same day of the animals' menstrual cycle — a critical detail that she had requested. </p><p> Her team still managed to publish a paper with their results, which indicated that BPA exposure at some doses altered hormone production and the number of developing eggs in female rats. But she told EHN that the small number of animals underpowered them to see the stronger results in Clarity that they had seen in their prior studies. </p><p> "There was no way to make sense of anything," said Flaws, who studies genetic and environmental factors that affect the female reproductive system at the University of Illinois at Urbana-Champaign. (The FDA did not respond to a question regarding the number of study animals provided some researchers.) </p><p> John Bucher, a senior scientist with NTP and NIEHS, and one of the Clarity leads, acknowledged this shortcoming of Clarity. "We recognize that some of the investigators didn't get as many samples as they would have liked. And that's regrettable," he told EHN. "This was an enormously complicated study and we tried to accommodate as many requests as possible.... We probably overpromised." </p>
Heather Patisaul, a professor of biology at North Carolina State University and a Clarity investigator. (Credit: NCSU)<p>"The fact is, they don't know where the contamination came from and they don't know if the Clarity controls were contaminated," said Zoeller. "They didn't measure it."</p><p>"If you can't ferret it out, it's like shooting yourself in the head before you even start the study," added Hunt.</p><p>Birnbaum expressed little concern about that potential contamination. "When we deal with environmental chemicals, almost everyone — or every animal — has some exposure," she said. "Control doesn't have to mean zero — it means you know what you have and it is lower than the intentionally exposed."</p><p>Hunt still maintained that contamination with an endocrine-disrupting chemical could derail a study. "If you have contamination, you don't have a control. There's no way around it," she said. "It puts a shadow over the whole thing."</p>
Researcher Pat Hunt with lab mice. (Credit: Lynne Peeples)<p> Whenever it is wet outside, Hunt makes sure to clean off Ila's four paws before they come inside. "We pause for paws," she said. Given the puppy's high energy, it is a given that the outside mud would end up just about everywhere inside her house. Yes, Hunt is familiar with both dirty dogs and dirty data — and the struggle to keep puppies and studies under control. </p><p>Contamination is one of the ways in which a study and its results might become tainted; a lack of control is another. </p><p>Standard protocol for research on endocrine disruptors demands the inclusion of both "positive" and "negative" controls — groups of animals that researchers can then use as a baseline comparison against their exposed group of animals. A negative control is your typical study control animal that doesn't receive any exposure. (Again, in the case of Clarity, academics argue that this purity was spoiled by potential contamination.) A positive control is exposed to something with a known response. </p><p>For example, <a href="https://www.maryvillecollege.edu/media/dsx/manager/Faculty/NaturalSciences/dcrain/publications/Vom%20Saal%20et%20al%202010.pdf" target="_blank" rel="noopener noreferrer">academic studies of BPA</a> have generally included a group of animals exposed to a synthetic hormone for which effects are well known: ethinyl estradiol, the estrogen mimic in oral contraceptives. This positive control helps scientists decipher whether or not a lack of an effect in BPA-exposed rats compared to negative controls was because the experiment simply did not have the sensitivity to detect estrogen-like effects or because BPA really had no such effect. </p><p>When the government initially declared their plan not to include positive controls in Clarity, according to emails reviewed by EHN, 11 of the academic researchers pleaded for them to reconsider. In one of the emails from April 2012, Frederick vom Saal, a professor of biology at the University of Missouri-Columbia and a Clarity investigator, stated that without these controls, the experiment could "waste millions of dollars and generate uninterpretable data."</p><p>Positive controls were eventually provided and used for most, but not all, of the Clarity studies. Kim Boekleheid, a toxicologist at Brown University, was the only academic scientist not to use a positive control in his study of male reproduction. His decision ignited ire among some of his Clarity co-investigators, especially upon the release of his results. While previous academic studies have found that male reproduction is very sensitive to BPA, Boekleheid's study concluded that exposure to BPA did not harm the testes or sperm in rats. Hunt and others question how he could be so sure without a positive control. Boekleheid declined to be interviewed for this story. </p><p>An additional type of control was enlisted by the government in their Core Study. When they found higher rates of mammary cancer in rats exposed to low doses of BPA compared to negative controls, the FDA authors then also looked to a control group from a somewhat similar study conducted about a decade earlier. Turned out those non-BPA-exposed animals, considered "historical" controls, developed more mammary tumors than the non-BPA-exposed rats in the Clarity study. The government used this as one of their reasons to disregard the mammary cancers as a true BPA effect. </p><p>Outside scientists questioned their motives and noted, for example, that the animals not exposed to BPA in the old study would have been housed in plastic cages made partially of BPA. So, those rats may, too, have been inadvertently exposed to small doses of BPA. Gore added that "things change over 10 years." In work in her own lab, she has found that animals vary across generations — "even if they are the same strain, fed the same food and all animal husbandry is done the same."</p>
Ana Soto, an endocrinologist at Tufts University and a Clarity investigator, with fellow Tufts researcher, Carlos Sonnenschein (Credit: Tufts University).<p>Ana Soto, an endocrinologist at Tufts University and a Clarity investigator suggested that historical controls are typically only used when a difference is not seen between an experiment group and control group. "They are doing the opposite. They seem to be trying to minimize the fact that they found differences between BPA-treated and the simultaneous control," she told EHN. "That is where you start wondering whether this choice is plainly inept or disingenuous."</p><p>Vandenberg too was curious about the government's use of historical controls in guideline studies, such as the Clarity Core Study. So she took a closer look at how the government dealt with other outcomes. For example, they found a significant increase in pituitary cancer in female rats exposed to ethinyl estradiol and used that as support that the positive control worked in Clarity. However, the same historical controls the government referenced for cases of mammary cancer also had a rate of pituitary tumors comparable to the ethinyl estradiol group. "If they had applied the same logic to the ethinyl estradiol pituitary data in Clarity as they did to the BPA mammary gland data, they would have had to conclude that the positive control had no effect," she said.</p><p>And that would have called into question the rest of their results.</p><p>"When the FDA didn't like the data they got, they went back into their own lab to try to dismiss it," added Vandenberg. "But then they don't do that for the data they like. This asymmetric treatment of data is one more example of how the FDA seemed to manipulate the interpretation of the Clarity data."</p><p>Zoeller agreed. "They at least appear — by their inconsistency — to have a preconceived conclusion that they arrive at by selective logic," he said.</p><p><em>In <a href="https://www.ehn.org/bpa-science-health-2641150585.html" target="_blank">part 3</a> of this series, EHN further details critical questions surrounding how the FDA assesses the evidence and frames their conclusions on BPA, as illustrated in the agency's handling of Clarity.</em></p>
This is part 3 of a 4-part investigation of the science surrounding the chemical BPA and the U.S. regulatory push to discredit independent evidence of harm while favoring pro-industry science despite significant shortcomings.
University of Missouri researchers Fred vom Saal and Wade Welshons. (Credit: Brian Bienkowski)<p>Which is worse, deeming something as safe when it's not or saying something causes harm when it doesn't?</p><p>The two scenarios are referred to, respectively, as false negatives and false positives. "The FDA uses very, very conservative statistics with a low risk of false positives," said Patisaul. "That's always been a sticky wicket with the FDA versus academic scientists."</p><p>By applying conservative statistics throughout the Clarity Core Study that generally minimize false positives, noted Patisaul, the government increased the risk of false negatives — or the chance of deeming a chemical innocent when it was actually guilty of harm. </p><p>It is a balancing act, explained Bailer. With conservative methods, you may be less likely to see real effects. "But the counter response is: You are less likely to see false effects," he told EHN.</p><p>Even with a high bar, statistically significant effects emerged from the government's data. In tests for mammary gland cancerous growths, for example, the Core Study detected significant effects at the lowest dose of BPA in the part of the study where exposure stopped when the rats were weaned. But through the government's "weight-of-evidence approach," they discounted the finding as "unlikely" to be a "plausible BPA treatment-related lesion." </p><p>Their rationale: similar effects were not observed at the highest doses, the effect was not observed in animals exposed over their entire lifetimes and, as noted earlier, lesions were found in historical controls. (EHN gave the FDA a chance to comment, but the agency declined.)</p>
Researchers Ana Soto, Carlos Sonnenschein and Silva Krause looking at mammary glands from a BPA experiment at Tufts University. (Credit: Ana Soto)<p>Patisaul disagreed with their methods and rationale. "There are certainly cases where developmental-only exposure has different effects than lifelong exposure," she said. "Just because you don't know why something is happening doesn't mean that the phenomenon is erroneous or 'not biologically plausible.'"</p><p>"This attitude is certainly not precautionary nor protective of public health and emphasizes the lengths to which this group will go to bury potentially important outcomes," added Patisaul.</p><p>Vom Saal said he faced a particularly high bar to uncover potentially important outcomes in his Clarity study. The weights of the rats that the FDA provided him for analysis of the effects of BPA on the development of the urogenital system, he explained, ranged widely — the heaviest rat weighed at least 250 percent more than the lightest rat. To prevent bias, all Clarity scientists were blinded to the BPA exposure levels of the animals and tissues that they received for study. Once the data were unblinded, vom Saal learned that his BPA-unexposed rats also weighed significantly less than the BPA-unexposed rats in the government's Core Study.</p><p>Increased variability in weights could cause increased variability in other measures of interest. A statistical fallout of that variability can be a watering down of the differences between exposed and unexposed rats. "This was just not done correctly," said vom Saal.</p>
Mice from Pat Hunt's lab. (Credit: Lynne Peeples)