Ensia is a solutions-focused nonprofit media outlet reporting on our changing planet. Published by the Institute on the Environment.
At around 11 AM on November 4, Germaine Patterson stepped outside of her Clairton, Pennsylvania, home to exercise in the backyard. Dirty air sent her quickly retreating back inside.
"I started having heart palpitations," she told EHN. "I know it was due to the air quality."
For seven straight days in early November, air pollution levels in Allegheny County, Pennsylvania, exceeded limits set to protect public health. Unusually warm weather had triggered a hazardous temperature inversion: A low layer of cold air along with other airborne particles near the ground—vehicle exhaust, wood smoke, industrial releases—became trapped beneath a lid of warmer air.
"It was very noticeable to me," said Patterson, who lives about 30 minutes outside of Pittsburgh. Her house is less than a mile from an industrial plant—Clairton Coke Works—that converts coal into coke to manufacture steel. On at least one of those early November days, she recalled waking up in the "wee hours of the morning" to a bad stench. Throat irritation plagued her nearly every day.
Such air inversions, which are a natural weather phenomenon, are most common during winter months when the sun supplies less warmth to the Earth's surface. Valleys and basins are especially prone to inversions, as surrounding hills or mountains can act as walls to block the wind and further lock in cold air and pollutants. With the approaching winter and the lingering—in some cases, spiking—threat of COVID-19, susceptible regions such as Pennsylvania's Mon Valley, Utah's Salt Lake Valley and California's coast-to-mountains basin that includes Los Angeles, may face a double whammy: Studies suggest that poor air quality can worsen COVID-19's toll on the body as well as increase its ability to spread.
"We're now talking about two pandemics," Thomas Muenzel, a cardiologist at Johannes Gutenberg University in Mainz, Germany, told EHN. "We have a pollution pandemic, and we have the COVID pandemic."
Germaine Patterson in her backyard on November 19, 2020. (Credit: Germaine Patterson)
As Muenzel explained, both pollution particles and the novel coronavirus target the cardiovascular and respiratory systems in the body, triggering similarly dangerous inflammation and dysfunction. "There are clear signs that air pollution hugely aggravates the outcome of patients infected with COVID-19," he said.
A 2003 paper found that SARS coronavirus 1—a virus that belongs to the same family as the virus that causes COVID-19—patients from moderately polluted regions in China had an 84 percent elevated risk of dying from that virus compared to patients from regions with low levels of air pollution. A study published in November estimated that the COVID-19 death rate increased by 11 percent with an increase in the long-term average concentration of fine particulate matter of one microgram per cubic meter. Overall, approximately 15 percent of global COVID-19 deaths could be attributed to long-term exposure to air pollution, according to another paper published in December. Further studies from around the world appear to support the link.
A Salt Lake Valley winter inversion and resulting haze in 2010. (Credit: Garrett/flickr)
"Exposure to air pollution, both acutely and chronically, increases the lethality and severity of COVID infections," Brian Moench, president of Utah Physicians for a Healthy Environment, told EHN. "We can add this pandemic to all the other reasons why air pollution is a serious health hazard." He noted a November study in which researchers estimated that air pollution caused between 2,500 and 8,000 premature deaths per year in Utah.
Air pollution may also facilitate the spread of COVID-19 through a community, he told EHN. Recent studies hint at how the coronavirus may hitch rides on pollution particles. "And when you're talking about really microscopic particles, those things can stay suspended in the air for much longer—and can travel," said Moench. "That is probably one of the reasons why it doesn't appear as though the social distancing dictum of six-feet separation is enough."
Stagnant air during an inversion can rapidly worsen air quality. One study linked winter temperature inversions with an average increase of 40 percent or more in daily fine particulate matter pollution across large areas of the U.S.
Moench noted that most major cities do have worse fine particulate matter levels in the winter—at least in the absence of wildfires—due to inversions preventing pollution from dispersing both vertically and laterally. However, inversions are not a "one-size-fits-all event," he said. If there is snow on the ground, for example, that can decrease the surface temperature and intensify an inversion and resulting build-up of pollution at ground level.
Many of the communities that experience poor air quality, such as Clairton and parts of Salt Lake Valley, tend to also be less affluent and have a larger proportion of racial minorities. These same populations face greater risks from the coronavirus due to crowded housing conditions, disproportionate representation in essential work settings, inequitable health care access, and discrimination. Minority groups also have higher rates of certain underlying medical conditions that increase the risk of severe illness from COVID-19 such as asthma, obesity and diabetes. One study found that Black people were twice as likely to catch the virus than White people; another estimated that Black people were more than three times as likely to die from the infection than White people.
Hydrogen Sulfide spikes in Allegheny County, Pa., on November 3, 2020. (Credit: GASP)
"We're looking at a racial justice, or injustice, issue," said Patterson, adding that her own community lacked accessible COVID-19 testing in the early days of the pandemic.
While current forecasts paint a grim picture for the COVID-19 pandemic in the weeks, and perhaps months, ahead—holiday gatherings, experts warn, are likely to trigger more surges—a pair of promising vaccines could bring welcome relief to millions of Americans this winter.
"The problem is you can vaccinate against COVID, but you can't vaccinate against air pollution," said Muenzel. "So, when the COVID pandemic is finished, we still have the pollution pandemic."
Rachel Filippini, executive director of Group Against Smog and Pollution in Pittsburgh, underscored the point. "No one is immune to air pollution. It is not good for any of us," Filippini told EHN. "It is known to affect your respiratory system, cardiovascular system, just about every aspect of your health."
Inversions are also nothing new to vulnerable communities. In late October 1948, for example, an inversion event intensified a deadly smog in Denora, Pennsylvania. And in late December 2019, another warm front triggered an inversion in the Mon Valley, a cluster of townships outside Pittsburgh. Residents endured six days of stinky, polluted air.
Future winters could prove even worse, as research suggests climate change may be increasing both the frequency and severity of inversion events.
Rachel Filippini at a clean air event on June 20, 2019. (Credit: Mark Dixon/flickr)
Filippini is among advocates growing impatient for greater efforts to improve air quality. She has called out U.S. Steel, which runs several plants in the Pittsburgh area, including the Clairton Coke Works plant. "We know that regulations can take time to be developed and implemented," said Filippini. "So, right now, I think it is imperative that industry, such as U.S. Steel, show its commitment to the public by voluntarily curtailing their emissions during forecasted high pollution days."
In an email to EHN, U.S. Steel spokesperson Meghan Cox noted that the corporation was "already operating at a reduced level" and "made additional adjustments" to operations during the November inversion event.
"There were elevated emissions readings at monitors across the county and throughout the state during this inversion," said Cox. "This suggests region-wide issues such as mobile sources and background levels from other areas are contributing to elevated levels during inversions." She added that U.S. Steel is committed to supporting the county health department's development of "a science-based model to better predict inversions and their intensity."
Muenzel is hopeful COVID-19 has raised public awareness about air pollution. In the early days of the pandemic, as industries shut down and fewer vehicles filled the roads, the resulting cleaner air made international headlines.
"The numbers of patients with myocardial infarctions went down substantially during that first wave of infections," he said, highlighting the link between heart attacks and air pollution. "That's our next challenge: How can we keep air pollution levels down and not endanger our people?"
Banner photo: US Steel suffered a massive fire at its Clairton Coke Works facility. (Credit: Mark Dixon/flickr)
Beach sands around the world are laced with the chemical bisphenol-A (BPA), according to new research that calls attention to a less well-known source of exposure to the hormone-mimicking chemical.
Scientists from South Korea and Japan analyzed sand and seawater samples from beaches in 19 countries. They found BPA to be ubiquitous. Substantial amounts of the chemical—used in can liners, paper receipts and plastic products including food and beverage containers—littered all of the beaches, peaking at upwards of 200 milligrams of BPA per kilogram of sand in Greece. That would be equivalent to about 200 credit cards scattered across an American football field.
"The high BPA concentrations found on sandy beaches in this study should be a global concern," write the authors.
Scientists had already shown that people can be exposed to BPA through many sources including the air, food and water. "This is another study inventorying the extent of plastics contaminating our living environment," Rolf Halden, a sustainability scientist at Arizona State University, who was not involved in the study, told EHN. "It makes us aware that when we lie on the beach, we're not only lying on a bed of sand but a bed of plastics."
BPA-containing plastics break down over time into tiny pieces, known as microplastics and nanoplastics, often with the help of the sea, surf and sand. The sand samples tested by the researchers included these fragments mixed with sand, as well as sand particles on which BPA and other chemicals have hitched a ride. They discovered that BPA concentrations were significantly higher in the sand than in seawater, and varied widely between beaches. A factor of nearly 10,000 separated levels in sands sampled from Greece and Slovenia, for example. Samples from six U.S. beaches ranged between 0.4 and 45 milligrams per kilogram, or parts per million.
The BPA concentrations uncovered in the new study surprised Thomas Zoeller, a biologist at the University of Massachusetts Amherst. "Parts per million quantities, in many of these places, is pretty outrageous," Zoeller, who was not involved in the study, told EHN.
Zoeller noted that exposure to such highly contaminated sand could be enough to cause health effects. However, he also cautioned that the study faced some significant limitations. "It's difficult to extrapolate from these numbers. They don't represent some average for a country, or even a single beach," he said. "Still, everywhere they looked they found it."
In a statement to EHN, Steven G. Hentges, senior director of the Polycarbonate/BPA Global Group at the American Chemistry Council, an industry trade group, said that "government agencies around the world consider BPA to have a low potential to accumulate to any appreciable extent in organisms that come into contact with it in the environment." BPA is "one of the most widely studied chemicals in the world, and government scientists around the globe have found that it does not pose a health risk at typical exposure level," he stated.
Thousands of peer-reviewed studies from academics, however, have concluded that absorbing or ingesting BPA may harm people at doses 20,000 times lower than what the U.S. Food and Drug Administration (FDA) says is safe—doses comparable to levels at which most of us are exposed. In November 2019, EHN published a year-long investigation which found U.S. regulators were willfully ignoring research that increasingly links low-dose BPA exposures to harmful health impacts ranging from birth defects to cancer.
"This is a chemical people should not be exposed to," Frederick vom Saal, a professor of biology at the University of Missouri-Columbia, told EHN. He lamented the lack of progress in the U.S. on regulating BPA. "There are other parts of the world that are taking this seriously," said vom Saal, who was not involved in the new study. France banned the use of the chemical in food and beverage packaging and utensils after an assessment by the French Agency for Food, Environmental Health and Safety determined that it is hazardous at much lower levels than the FDA considers hazardous.
Beachgoers may be particularly at risk due to the use of sunscreen and other oils and lotions. Vom Saal published a study in 2014 that found chemical mixtures used in a variety of personal care products facilitate the movement of BPA and other chemicals through the skin. More than 300 different chemicals can act as permeation enhancers. The use of hand sanitizer before handling receipts can increase BPA absorption through the skin by up to 200-fold, according to vom Saal's study. Beachgoers today, amidst a pandemic, may well be lathering up with sanitizer, too.
"BPA is a very sticky chemical," said vom Saal. "So, would it stick to sand? Absolutely. And if you're using sunscreen or skin lotions or hand sanitizer, then this stuff goes right through your skin."
Meanwhile, Halden's research team has detected BPA and other molecules from commonly used plastics in liver and fat of all 47 human tissue samples investigated.
"These are materials we're using on a tremendous scale without thinking about their afterlife and the consequences they pose to our health," said Halden.
Bum Gun Kwon from Chosun College of Science and Technology in South Korea, and author on the study, expressed the same concern. "Although there may be differences in degrees, large amounts of discarded plastic are too common," he told EHN in an email.
"Strict new rules for the use of sandy beaches should be set and followed," said Kwon. "For example, rules restricting the use of plastic materials derived from petroleum."
Banner photo: Brian Yurasits/Unsplash
Exposure to minuscule amounts of bisphenol-A can cause a multitude of health problems, including effects on the developing brain, heart, and ovaries, according to a paper published on Thursday that integrates data from several animal studies.
The findings build on a body of evidence that absorbing or ingesting the ubiquitous chemical may harm people at doses 20,000 times lower than what the U.S. Food and Drug Administration (FDA) says is safe — doses comparable to levels at which most of us are exposed.
"This should change how the FDA and other people look at the safety of BPA," Jerry Heindel, former health scientist administrator at the National Institute of Environmental Health Sciences and a co-author on the new paper, told EHN.
The studies were part of an unprecedented $30 million-dollar project co-led by the FDA called the Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or Clarity for short. Launched in 2012, Clarity combines a traditional regulatory guideline study from the government and investigational studies from academics with the aim of reconciling a long-standing dispute over data and conclusions on the health effects of BPA.
Academic scientists for decades have linked the chemical—found in plastic containers, food can liners, and paper receipts—to a wide array of health problems including cancer, diabetes, obesity, infertility, and behavioral problems. BPA does its damage, in large part, by mimicking and messing with hormones in the body. And it is just one of hundreds of such endocrine-disrupting chemicals we encounter every day.
However, despite this mounting evidence of harm, the FDA has maintained BPA's safety and dismissed findings from independent scientists that BPA can harm people at very low doses—even when relatively high doses prove innocuous.
"Guideline studies have not provided much evidence of harm. But academics are finding harm all over the place," Pat Hunt, a geneticist at Washington State University in Pullman, Wash., who was not involved in Clarity, told EHN.
So far, the Clarity effort has fallen well short of its goal to bridge that gap.
Cheryl Rosenfeld, a biologist at the University of Missouri, author of the new paper, and a Clarity investigator. (Credit: University of Missouri)
In November 2019, EHN published a year-long investigation of the FDA's handling of BPA science, including Clarity. It found a "willing blindness" among U.S. regulators to modern science on endocrine-disruptors, and concluded that they may be operating on the fringes of scientific integrity, possibly with the intent to keep the current testing and regulatory regime intact.
The FDA's traditional targets for tests, such as weighing organs and looking for overt signs of toxicity, are generally insensitive to the unique and often subtle effects of BPA and other endocrine disruptors, such as behavioral changes or infertility years down the road.
"The difference in regulation that would be required to account for this low-dose effect is huge. I'm not sure the FDA has the courage to do that," Thomas Zoeller, a biologist at the University of Massachusetts Amherst, and an author on the new paper, told EHN. "BPA is big money. The FDA is sensitive to that."
The FDA released its Clarity Core study, a comprehensive report from the government's side of the project, in 2018. But no comparable publication has combined the academics' independently published findings. A government-led integrated report that pulls together findings from both the government and academic scientists was scheduled for completion by the end of 2019. It has yet to be released.
"We felt we needed to make our own report, to be sure our voices would be heard," Cheryl Rosenfeld, a biologist at the University of Missouri, Clarity investigator, and an author on the new paper, told EHN.
Eight of the 10 academics who have published studies as part of Clarity contributed to the new paper. Because all of the Clarity investigators shared tissues from the same rats and followed the same study protocols, much of the noise that typically makes comparisons between studies difficult was eliminated. The team leveraged this opportunity to apply a novel statistical approach to look for patterns across different datasets generated in the laboratories of multiple investigators using organs from the same animals.
"We combined everyone's data to see what the picture showed," said Rosenfeld. "It's correlation, not causation. But, ultimately, we were able to show that low doses of BPA don't just target one system, they go after multiple systems." If there was a low-dose effect on the mammary glands, for example, there was likely also a low-dose effect on the spleen in the same animals.
In all, the new paper links BPA to interrelated impacts on the brain, prostate, urethra, mammary gland, uterus, ovary, spleen, heart, and body fat.
In an emailed response, an FDA spokesperson said the agency "along with other global food safety authorities, has extensively evaluated the totality of available evidence on the safety of BPA. The weight of the evidence shows that BPA is safe for its authorized uses in food packaging."
The spokesperson said the agency has not reviewed the new study but "will continue to monitor scientific developments and take steps as appropriate to protect public health."
Hunt and others said the new study should be a red flag for the FDA.
"It's easy for a regulator to dismiss a study or handful of studies. But when you have this series of studies of the same animals and see correlations across the studies, that gives you much more confidence," said Hunt. "This strengthens the conclusion that these low dose effects are real, and can't be dismissed as spurious."
Most effects across the studies appeared at the lowest dose tested in Clarity: 2.5 micrograms per kilogram of body weight per day, which falls in the upper range of what an average person is believed to be exposed to.
However, human biomonitoring studies may underestimate actual exposures. Hunt co-authored a paper published in December that found the tests used by federal agencies to estimate exposure to BPA are woefully inaccurate. "If we are being exposed to much higher levels than we think we are, and if these animal studies are finding effects at increasingly lower doses," she said, "then that suggests we have a real need to reconsider the safety issues here."
In the U.S., what the government considers a safe exposure level for BPA — 50 micrograms of BPA per day per kilogram of body weight — has remained untouched for more than 30 years. Europe dropped its safety limit to 4 micrograms of BPA per kilogram of body weight per day in 2015.
The FDA generally assumes an increasing-dose-increasing-harm relationship in its evaluation of chemicals. A dose-response curve should therefore always be monotonic, according to the agency, which means it will never change direction from positive to negative, or vice versa.
Researcher Pat Hunt with lab mice in her Washington State University lab. (Credit: Lynne Peeples)
When they deem a dose of a chemical safe, their investigation typically follows an efficient, seemingly common-sense method. They start by exposing lab animals to extremely high doses of the chemical, incrementally drop the doses until they no longer detect obvious harm, then cut that last number down by a margin of safety to create a "safe" exposure limit. As a result, they may not necessarily have tested health effects at that dose — or at any lower doses.
"How many additional studies will be required for all chemicals since we haven't been going low enough?" Bernard Robaire, a reproductive toxicologist at McGill University in Montreal, who was not involved in Clarity, told EHN. His own research dating back to the 1970s identified effects of hormones and hormone mimics that were not monotonic. "Non-monotonicity is not new," he said. Robaire suggested that the new findings do lend credence to the growing concerns about the health effects of BPA and other endocrine disruptors.
Laura Vandenberg, an environmental health researcher at the University of Massachusetts Amherst's School of Public Health, who was not involved in Clarity, also noted the agency's reluctance to accept new science and independent evidence of harm. "The FDA has suggested that all the effects that occur at lowest dose — whether in the academic studies or in their Core study — are spurious effects," she told EHN. "This analysis would suggest that they can't just hold their nose and pretend something is not real."
BPA is also just the tip of a very large iceberg. Many other endocrine-disrupting chemicals, including BPA replacements such as bisphenol-S (BPS), may raise the risk of health problems. Evidence suggests that these chemicals may even be exacerbating the effects of COVID-19. The people at most risk from the virus have underlying conditions such as obesity or diabetes.
"We can't say endocrine disruptors are why people are getting fatter or have diabetes," said Hunt. "But we can see from animal models that this is what we would predict from exposure."
It remains unclear as to how the new paper will play into the final Clarity report, or if the government will respond with any changes in how they assess the safety and regulation of endocrine-disrupting chemicals.
"We need to hear from the FDA," said Vandenberg. "If they are going to decide that the academic work was not helpful, I want them to explain why."
Banner photo: BPA testing in the lab of Cheryl Rosenfeld, a University of Missouri researcher. (Credit: Cheryl Rosenfeld)
Bisphenol A and its substitute chemicals—pervasive in food and beverage containers, canned goods and store receipts—are showing up in mothers' wombs at "unexpectedly high levels," according to a new study published in the journal Environmental Science and Technology.
The study builds on previous evidence that BPA and its common replacement BPS can pass through a mother's placenta and is the first to show the same for a range of other replacements, suggesting that fetuses are being exposed to a cocktail of chemicals linked to behavioral and reproductive disorders, among other health problems.
"We are very clearly seeing these compounds going straight to the baby at totally unacceptable concentrations," Terrence Collins, a green chemist at Carnegie Mellon University, who was not involved in the study, told EHN.
The study, published in March, looked for 15 different bisphenols—including a BPA, BPS and other popular substitutes—in 60 pairs of maternal plasma, cord plasma and placenta samples from pregnant women in South China. Four bisphenols were frequently detected in all three samples: BPA, BPS, BPAF and BPE.
BPSIP, a relatively new compound commonly used in thermal paper for store receipts, appeared at high levels in all maternal plasma samples. The researchers note that BPSIP "exhibits a similar estrogenic potency and greater reproductive toxicity than BPA."
"This is another shriek from nature, 'Stop throwing BPA, or things like it, at me,'" added Collins.
The study is concerning as BPA is a known endocrine disruptor, meaning it is capable of scrambling hormone signals, and has been linked to cancer, diabetes and infertility. In-utero BPA exposure has been shown to derail the normal growth of the brain and other organs and manifest later in life as early puberty or an increase in anxiety-related behaviors or attention deficit hyperactivity disorder (ADHD). Some replacements have been tied to similar issues including obesity and reproductive problems. The new study linked BPAF concentrations in cord plasma with both premature birth and low birth weight.
Most BPA replacements are created by tweaking the BPA molecule to form similar compounds. As a result, most pose similar health concerns. A 2017 study found that six substitutes used in products promoted as BPA-free had as much, if not more, of an estrogen-mimicking effect on human breast cancer cells as BPA.
Pat Hunt, a geneticist at Washington State University in Pullman, Wash., suggested that the latest BPSIP finding reflects an ongoing pattern of regrettable replacements.
"Oh great, another one. When is this going to end?" she told EHN. "We need to worry about all these new players that come onto the scene."
BPA still made up the highest concentrations detected in the new research. Despite thousands of studies that highlight its health effects, the global BPA market continues to increase at about 3 percent per year and is projected to top seven million tons by the end of 2023.
"They are still expanding BPA into every imaginable product," said Collins. "BPA should not be produced. Period."
Meanwhile, the U.S. Food and Drug Administration maintains that the chemical poses no harm at levels to which people are exposed.
In November 2019, EHN published a year-long investigation of the FDA's handling of BPA science. It found that U.S. regulators have stacked the deck against findings from independent scientists that BPA, as well as many BPA substitutes, can harm people at very low doses.
Cheryl Rosenfeld, a biologist at the University of Missouri, published a study of mice in February that found both BPA and BPS exposure lowered serotonin production in the placenta, the primary source of the critical neurotransmitter for developing offspring. The effect could have "dramatic consequences" on brain development, Rosenfeld told EHN.
The bisphenol concentrations that the researchers found in the placenta and cord blood are both troubling, she said, as impacts may come through the placenta or by directly affecting the brain itself. "Yes, it can cross the placenta and that's important because it tells you that whatever mom is exposed to can reach the developing fetus," said Rosenfeld. "But we're even seeing effects before it gets there."
Still, not all bisphenols necessarily behave the same way. For example, BPAF crossed the placenta more readily than other bisphenols highlighted in the new study. "We can't assume that what we know about BPA will translate to the other bisphenols," said Hunt.
Valspar cans. (Credit Lynne Peeples)
One newly developed bisphenol might prove a welcome change from its chemical cousins. Valspar, recently acquired by Sherwin-Williams, has created a replacement for food and beverage can linings historically made with BPA.
Rather than just slightly tweaking the chemical structure of BPA, they assessed safety alongside functionality throughout the process. They enlisted academic scientists to test the compound, tetramethyl bisphenol F (TMBPF), for a range of endocrine disruptive activities. "The evidence is very encouraging," said Collins.
"Endocrine disruptors are having a dreadful impact on civilization," he added. "We need to give Valspar its due. But we also need to know more."
Congresswoman Grace Meng (D-NY) was pregnant with her second child when she became concerned about the toxic chemicals that she and her kids — and nearly all of us — encounter every day.
It was 2009, and she had recently been elected to the New York State Legislature as it considered a bill prohibiting bisphenol-A (BPA) from infant and children's products sold in the state. She voted yes on the bill, which passed in 2010.
Now she wants to see similar action on the national level.
"The FDA needs to be more transparent about what additives and chemicals are in our foods and products and how they could potentially impact us — just as we do for cigarettes," Meng told EHN.
Meng, who has since co-introduced federal legislation to ban BPA from food and beverage containers, is among policymakers who have reacted to a four-part series published in November 2019 by EHN. The year-long investigation found that the U.S. Food and Drug Administration has stacked the deck against findings from independent scientists that BPA, as well as many compounds used in "BPA-free" products, can harm people at very low doses.
EHN contacted 18 policymakers for comment after publication of the series. Despite numerous requests, eight did not respond at all, and seven failed to follow up or declined to comment. The three policymakers that shared their reactions expressed concern about FDA's behavior with regard to the testing and regulation of BPA, among other toxic chemicals.
We reached out due to an outcry from scientists and advocates after our investigation who say the FDA seems to be willfully ignoring science that shows BPA is harming our health and the health of our children.
The stakes are high. The chemical is used in the production of goods that pervade our lives and the manufacturing of BPA remains on the rise. The global BPA market is increasing about 3 percent per year, and is projected to reach $22.5 billion by 2022 and top 7 million tons by the end of 2023.
And, in the face of these major financial implications, the FDA keeps relying on industry studies to maintain BPA's safety — though plastic manufactures and others industries that are reliant on BPA have obvious reasons to mount a strong defense of its safety.
"We can see that there have been, to some extent, inconsistencies or lack of transparency in the information that the average American consumer is able to obtain on BPA. Obviously, that is just one chemical," said Meng, who is currently revising her BPA bill for reintroduction this year. The bill had previously stalled out in committee.
She is also pursuing federal legislation on food additives, such as Yellow 5 and Red 40, as well as potentially harmful ingredients in feminine pads and tampons.
The EHN investigation took a close look at an unprecedented $30 million-dollar project co-led by the FDA, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or Clarity for short.
The ongoing effort aims to reconcile the long-standing dispute between government and academic scientists over the health effects of BPA, which is used in the production of goods that pervade our lives — from reusable water bottles and food containers to store receipts and dental sealants. While the FDA claims that BPA poses no risks in the amounts it is used, thousands of peer-reviewed studies from academics suggest otherwise: Absorbing or ingesting the ubiquitous chemical may harm people at doses 20,000 times lower than what the agency says is safe, comparable to levels at which most of us are exposed. An integrated report that pulls together findings from both the government and academic scientists, who based their studies on the same population of rats, is currently being prepared.
The project — originally scheduled for completion by the end of 2019 but yet to be released — has so far fallen short of its goal.
Through interviews and emails obtained via Freedom of Information Act requests, EHN uncovered various deficiencies in the FDA's science on BPA and its handling of Clarity. While each sign alone could be considered a red flag, viewed as a whole, they suggest that the FDA is missing some big warning signs about BPA and, therefore, likely misleading the public in its insistence that the common chemical poses no real health hazard.
BPA research in the lab of University of Missouri researcher and professor Cheryl Rosenfeld, who was a participating Clarity project scientist. (Credit: Cheryl Rosenfeld)
"It's disconcerting that the FDA is defending a position that doesn't reflect the newest science," David Michaels, a professor of environmental and occupational health at The George Washington University, told EHN. "At a minimum, they should be acknowledging the tremendous difference among scientists. Instead they are digging in and rejecting thousands of studies that aren't consistent with their position."
So, why the discrepancies, doubt and denial? For one thing, if the FDA were to acknowledge the low-dose health effects of BPA it could open a Pandora's box. Tens of thousands of manufactured chemicals are on the market, with hundreds such as BPA suspected to be endocrine disruptors, capable of scrambling hormone signals and, therefore, raising risks of health problems such as cancer, diabetes, obesity, infertility and behavioral problems. "It would force the agency to reevaluate its past work and would raise tremendous challenges to its work in the future," added Michaels.
The agency's behavior, he said, mirrors what he witnessed while serving as the U.S. Assistant Secretary of Labor for Occupational Safety and Health Administration between 2009 and 2017. "In general, the FDA often takes positions which are consistent with those demanded by industry," said Michaels.
The regulation of mercury levels in fish is one example highlighted by Michaels. While earlier consumption recommendations from the U.S. Environmental Protection Agency had reflected the newest scientific literature at the time, acknowledging that very low levels of organic mercury can affect the neurodevelopment of fetuses and young children exposed to contaminated fish, the FDA's position for many years was "much more consistent with the fossil fuel and fuel-burning industries responsible for much of the mercury that gets in the food chain," he said.
Further, while addressing issues related to cosmetics and beauty care products during his tenure with OSHA, Michaels recalled how hesitant the FDA was to "make any effort to control exposures to formaldehyde, which arises from exposure to Brazilian blowout," a hair-smoothing chemical treatment.
"We generally found FDA to be less responsive to public health concerns than we would have expected," he added.
The FDA declined to comment for this story. The agency was also reluctant to comment during "Exposed" reporting, frequently delaying responses and answering only select questions.
BPA is used in food can linings.
Wendy Wagner, a professor of law at the University of Texas at Austin who studies the use of science by policymakers, cheered the Clarity concept, but lamented its execution. The project may just be "round one of an experiment that needs more tweaking," she told EHN.
Wagner emphasized the need to "break open the black box" and take a "hard look" at the process by which the FDA does science. On multiple occasions over the last few decades, she said, the government has manipulated the synthesis of the science.
"I've seen dozens of reported incidences of that kind of political meddling," said Wagner. "It's usually not at the bench research stage, but in the literature stage — in the synthesizing for a report." EHN's reporting, too, found hints of how the FDA may spin results across studies. Of 36 studies identified as related to neurological endpoints in a 2014 risk assessment of BPA, for example, the agency chose to only include one. That study was funded by industry.
Genna Reed, lead science and policy analyst in the Center for Science and Democracy at the Union of Concerned Scientists, echoed the same hope and concern. "It's important not just to fund these efforts but be thoughtful about the process by which these efforts are implemented and guided," she told EHN.
Reed's team conducted a survey in 2018 that found FDA employees generally felt the agency adhered to its scientific integrity policies. However, they expressed feelings that it could "better insulate scientists from undue influence from political and business interests."
The survey highlighted several issues regarding the agency's science-based decision-making processes, including evidence of the improper influence of political leadership and constraints resulting from workforce reductions.
The Union of Concerned Scientists has also looked at the agency's Good Laboratory Practice regulations. While the guidelines were designed in an effort to reduce industry misconduct, Reed argued that studies following these practices "should not be given preferential weight over studies validated by other scientific review processes." Again, in the case of BPA, the FDA has excluded from its risk assessments a large body of studies from academics, who validate their studies through different means such as peer review.
"We see so much BPA-free packaging all the time," said Reed. "The more questions that are raised by the public about these chemicals that are in our bodies and in the environment, and why they aren't being regulated by our government, the more likely it is for members of Congress in some key committees to take up this issue and figure out what the next steps are."
Sen. Tom Udall, (D-N.M.) "The FDA should be using the best available tools, including expert career staff and scientific findings, to protect public health," he told EHN. (Credit: Senate Democrats)
Some political movement is underway.
Senator Tom Udall (D-NM) stated in an email to EHN that "Congress needs to provide strong oversight to ensure that the executive branch is serving the public good – and we must assert ourselves as a co-equal branch to ensure the public interest is the first priority in every decision that is made."
"The FDA should be using the best available tools, including expert career staff and scientific findings, to protect public health. However, under this administration we've seen agencies including the FDA and EPA do the bidding of special interests – at the expense of the public interest," he said. "As a member of the appropriations committee and as the ranking member of the Senate Appropriations Subcommittee on the Interior, Environment and Related Agencies, I will continue to provide oversight to ensure that our federal agencies are serving the American people."
Udall's spokesperson added that his team "will look into this issue more to see if there are actions Congress can take to better protect public health."
Senator Patty Murray (D-WA). "I hope the FDA and all agencies involved will continue working to evaluate and take appropriate action to address any risks associated with BPA," Murray told EHN. (Credit: Peter Stevens/flickr)
Senator Patty Murray (D-WA), too, noted that she was "closely monitoring the situation regarding the regulation of chemicals like BPA."
"I encourage the FDA to follow the best available science and data to help ensure public health and safety," she told EHN in a statement. "I hope the FDA and all agencies involved will continue working to evaluate and take appropriate action to address any risks associated with BPA."
Meng's BPA bill, as previously drafted, would outlaw the use of BPA from food packaging and require BPA alternatives to undergo extensive review to avoid replacing one chemical with another that may pose similar health risks.
Meanwhile, several states are adopting bills that ban BPA, popular BPA substitutes and other endocrine-disrupting chemicals from a range of products, including receipt paper and nail polish.
While an oversight hearing might not drive change overnight, Michaels underscored its potential usefulness in "raising issues to the public and alerting the leadership of agencies that these controversies really do need to be addressed." Tobacco hearings led by Representative Henry Waxman (D-CA) in 1994 did just that, as did a series of hearings beginning in 2009 on the damage from brain injuries among NFL players.
"Up until that point, the NFL minimized the neurological effects of repeated brain hits," said Michaels. "After that hearing, the commissioner of the NFL changed his position and the league took the problem much more seriously."
He urged the same to be done for Americans exposed to toxic chemicals. "The mindless clinging to outdated science is detrimental to public health and to the development of good science and to the progress of science," said Michaels.
"Historically, many out-of-date scientific paradigms are overturned or disappear only over time, as the scientists who cling closely to them retire and new scientists take over their positions," he added. "But, given the importance of protecting the public from endocrine-disrupting chemicals, it would be a great shame if we have to wait decades for that change to occur."
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.
SEATTLE — Bisphenol A is likely coursing through your body right now. Every day, you're inadvertently consuming and absorbing trace amounts as it migrates from can and bottle linings into your food and drink, and from thermal paper receipts onto your skin.
Scientists have found BPA in more than 90 percent of Americans tested. Yet whether exposures to such small amounts of the common chemical pose any real health hazard remains highly controversial. On one side of a deep rift are academics who are adamant about the adverse effects; on the other side are U.S. Food and Drug Administration scientists who declare there are no dangers. Only one side has any control over what actually makes its way into your body.
"This is a chasm that is not going to be breached," Daniel Doerge, a biochemical toxicologist with the FDA for nearly 30 years, said during a panel at the European Food Safety Authority (EFSA) conference in Parma, Italy, last September.
Doerge and other federal scientists were attending the conference to share details of an unprecedented multimillion-dollar project co-led by the FDA, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or Clarity for short. The effort aims to settle the long-standing dispute between government and academic scientists over the health effects of BPA.
Yet Doerge's words did not indicate any hope for such a reconciliation. He wore a green polo shirt, dark glasses and a grey mustache. And he exuded frustration — if not also a bit of arrogance — as he spoke. "Tribal dynamics," he said, are at play among the academics. Doerge alleged they were creating their "own narrative," and "staying in a bubble that turns into an echo chamber."
The struggle has been fermenting below the surface for years: Academics with modern methods and a sophisticated understanding of human physiology versus government and industry scientists who lean on decades-old established science in their evaluation of industrial chemicals. The suite of traditional toxicology tests recommended by the FDA for assessing a chemical's health risks hasn't been meaningfully updated since the early 1980s, before Doerge took his job and well before scientists began to understand how minuscule concentrations of certain chemicals common in consumer products, such as BPA, could mimic and mess with hormones in the body.
Scientists have long known that a tiny change in a natural hormone concentration — the equivalent of one drop of water in 20 Olympic-sized swimming pools — is enough to trigger instructions via the human endocrine system that impact growth, metabolism, sleep, reproduction and other critical functions of the body.
BPA is just the tip of the iceberg. Tens of thousands of manufactured chemicals are on the market; hundreds are believed to be endocrine disruptors — capable of scrambling hormone signals and, therefore, raising risks of health problems such as cancer, diabetes, obesity, infertility and behavioral problems. Other pervasive hormone imposters include phthalates, which are found in plastic food containers and personal care products, and per- and polyfluoroalkyl substances (PFAS), which are added to nonstick cookware and other goods to repel oil and water. Also on the list are flame retardants and pesticides such as DDT, glyphosate and chlorpyrifos. Even bisphenol S and dozens of other BPA replacements have been found to tinker with hormones.
Yet the FDA has remained reluctant to accept new science and independent evidence of harm. While the agency clings to the claim that BPA poses no health risks in the amounts it is used, thousands of peer-reviewed studies from academics suggest otherwise: Absorbing or ingesting the ubiquitous chemical may harm people at doses 20,000 times lower than what the FDA says is safe, comparable to levels at which most of us are exposed.
Even back in 1982, a scientific committee established by the FDA had warned of the potential for very low concentrations of chemicals to bind to hormone receptors and that technology in the future might find this interference alters the endocrine system's influential messages. The agency continues to miss opportunities to keep pace with scientific developments, noted Maricel Maffini, an independent consultant based in Germantown, Maryland. Instead, she told EHN, they primarily rely on tests devised decades ago that aren't designed to detect some significant effects that chemicals can have on our health.
If we followed the academics' science, BPA and its close relatives would effectively have to be banned, not reduced, in order to protect our health. "Really, if you look at the data, we shouldn't be making these compounds, period," Terrence Collins, a green chemist at Carnegie Mellon University, told EHN.
An investigation by EHN has uncovered a pattern of dissonance between academic scientists and federal agencies, as well as between the agencies themselves, regarding the evaluation and regulation of BPA and other endocrine disruptors. No one smoking gun surfaced. Yet putting together all the pieces creates a persuasive picture of willful blindness. Based on hundreds of emails obtained via Freedom of Information Act requests — along with dozens of studies and reports, and more than 50 conversations with scientists, regulators and other stakeholders — evidence suggests that regulators may be operating at the fringes of scientific integrity, possibly with the intent to keep the current testing and regulatory regime intact and to avoid scrutiny. EHN's findings include:
●Insistence by the FDA on a study design that limited Clarity's robustness to reveal health effects, including the use of a strain of animal that had been shown to be insensitive to hormone disruptors, the choice of a stressful means to deliver BPA to the animals, and the allocation of small numbers of animals provided to some of the participating academic scientists.
●Potential BPA contamination of the control animals, which may have further masked true differences in health effects between control animals and animals receiving administered doses of BPA.
●Statistical approaches in the government's side of Clarity, a traditional regulatory toxicology study dubbed the Core Study, that set a high bar to detect differences and disregarded patterns in the data that did not fit outdated assumptions on the relationship between a dose of an endocrine-disrupting chemical and its health effects.
●Framing of the government's Clarity Core Study draft report and corresponding press release that downplayed the health effects that did emerge in the data.
●Hints of potential industry influence, such as the FDA's reliance on industry-funded studies.
Clarity, the intended remedy for the government-academics impasse, was launched in 2012 by the FDA, the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP). The effort combines a traditional regulatory toxicology study from the government and investigational studies from academics.
The FDA took the lead on raising and treating the study animals and on performing the Core Study, which was published under the auspices of the NTP. The NIEHS awarded grants to participating academics and worked with the NTP to coordinate the study. The government and most of the 14 participating academic scientists completed their respective studies for the collaborative project in the months preceding the September 2018 EFSA conference in Italy.
Everyone used the same breed of lab rats, and followed government-approved standards as they investigated possible health impacts. To prevent bias, all Clarity scientists were blinded to the BPA exposure levels of the animals and tissues that they received for study.
Earlier in the Italy meeting, Doerge and his federal colleagues presented the government's Core Study. Once again, they relayed results that they said generally absolved BPA. They did not discuss findings from the participating academics. In fact, during the panel, Doerge seems to dismiss those studies, many of which challenged BPA's safety. "I don't see a lot of advantages in, so far anyway, in what the extramural research funding initiative has brought into the Clarity project," he said. (The FDA did not make Doerge available for an interview.)
Sitting in the audience in Italy was Heather Patisaul, a biologist at North Carolina State University and one of the academics participating in the massive BPA study. "I was screaming in my chair," she told EHN. "He said it so smugly."
An integrated report that pulls all of the Clarity studies together is underway, co-authored by the FDA and other participants. John Bucher, a senior scientist with NTP and NIEHS, told EHN that he expects the report to be completed by the end of this year. It will then be up to the FDA whether or not those results will spur any reshaping of U.S. regulations.
Several of the academic scientists are concurrently working on their own independent review of the Clarity data. Cheryl Rosenfeld, a biologist at the University of Missouri and another Clarity investigator, is among the co-authors on that report. "Many of us are not happy with the FDA," she told EHN, adding that she and others are skeptical of what will end up in the official integrated report and if it will have any impact on policy.
In the U.S., what the government considers a safe exposure level for BPA — 50 micrograms of BPA per day per kilogram of body weight — has remained untouched for more than 30 years, leaving us all exposed daily to the chemical. Meanwhile, other countries represented at the EFSA meeting have begun reaching agreements and acting on BPA.
France has enacted the strictest regulations, banning the use of the chemical in all food and beverage packaging and utensils after an assessment by the French Agency for Food, Environmental Health and Safety determined that it is hazardous at much lower doses than the FDA considers hazardous. A Danish Food Institute Clarity-like study, too, recognized effects at low doses.
Many more countries are keeping a close eye on Clarity. EFSA, which is funded by the European Union to conduct risk assessment but not to create policy, told EHN that it will consider the results as part of its ongoing evaluation of BPA. In January 2015, based on the latest information, EFSA dropped its safety limit from 50 to 4 micrograms of BPA per day per kilogram of body weight.
The scientific, economic and political stakes are high. For decades, modern commerce across the Western world has depended on BPA. The chemical is used in the production of goods that pervade our lives: reusable water bottles, food containers, canned goods, store receipts, medical devices and dental sealants. And despite growing concerns, the manufacturing of BPA remains on the rise. The global BPA market is increasing about 3 percent per year, and is projected to reach $22.5 billion by 2022 and top 7 million tons by the end of 2023.
"BPA is very cheap to make," said Collins. "I believe the regulatory bodies of the country are locked up by the monetary implications of addressing endocrine disruption."
While the clash continues over how endocrine-disrupting chemicals are tested and thereby regulated, irreversible changes to our bodies and health may be happening now. Collins pointed to declining sperm counts and rising rates of endometriosis, which he suggested could be a consequence of these exposures given that the chemicals have been shown to induce such effects in animals.
University of Massachusetts-Amherst environmental health scientist Laura Vandenberg. (Credit: Umass.edu)
"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.
"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."
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."
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."
In the 1930s, a British medical researcher discovered that BPA could mimic the activity of estrogen — a female sex hormone — in the human body. The chemical was briefly considered for use as a pharmacological hormone but ultimately lost to another synthetic estrogen, diethylstilbestrol (DES). While DES was prescribed to millions of pregnant women over the next 30 years before its own health risks became known, BPA was never turned into a drug.
Its future would instead be in the chemical industry.
Cheryl Rosenfeld, a biologist at the University of Missouri and another Clarity investigator. (Credit: University of Missouri)
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.
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.
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 PBS's Frontline about the threat posed by endocrine-disrupting chemicals used in plastics and other consumer products.
"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.
By 2008, 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.
"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."
Pregnant women, infants and young children face the greatest risks, as a healthy functioning endocrine system is especially critical during development. "If you perturb it, it is not going to be reversible," Linda Birnbaum, former director of the NIEHS and the NTP, told EHN. "Whatever happens, it is done."
In-utero BPA exposure, for example, may derail the normal growth of the brain and other organs and manifest later in life as early puberty or an increase in anxiety-related behaviors or attention deficit hyperactivity disorder (ADHD).
And, again, BPA is just one of many chemical threats to our hormones. We are exposed daily to a cocktail of stuff suspected of altering our endocrine system. "When we talk about endocrine-disrupting chemicals, it might be that the real story is in the mixture," Chris Gennings, the director of biostatistics and an environmental medicine researcher at the Icahn School of Medicine at Mount Sinai in New York, told EHN. While the level of exposure to any single chemical might not surpass a safety threshold, she explained, "if you put all of them together, then the mixture can reach a level of concern."
It is not only the potential health consequences that are leading many scientists to urge a more substantial overhaul of the testing and oversight of endocrine-disrupting chemicals. There are economic concerns: In 2014, researchers conservatively estimated that just the cases of childhood obesity and adult heart disease attributable to BPA cost the U.S. $3 billion annually. A 2016 study that considered a few endocrine-disrupting chemicals and a few specific diseases calculated an annual $340 billion in U.S. health costs and lost wages — or about 2.3 percent of the GDP. (Editor's note: Pete Myers, CEO and chief scientist of Environmental Health Sciences, was a co-author on the paper. He is also the founder of EHN, though the publication is editorially independent.)
"This is an underestimate of an underestimate of an underestimate," Dr. Leonardo Trasande, a researcher at New York University, author of the book, Sicker, Fatter, Poorer, and an author on both studies, told EHN.
Trasande noted his initial hope that Clarity would result in "progress toward a consensus" on methods to evaluate BPA. But the FDA, he said, "has taken the approach that its science and its mindset are superior to that which has been published in peer-reviewed scientific literature."
Maurice Whelan, head of the Chemical Safety and Alternative Methods Unit of the Directorate for Health, Consumers and Reference Materials of the European Commission's Joint Research Center, shared similar thoughts while sitting next Doerge on the panel in Italy. Clarity was "institutionally biased," he said, with "the science strategy dictated" and a "very clear mindset about how to go about this."
Core to the discord is a historical assumption about toxic chemicals. Nearly 500 years ago, Swiss physician and chemist Paracelsus coined an adage that would become a basic principle of toxicology: "The dose makes the poison." In other words, the higher the concentration of a toxic chemical, the more toxic it is.
The FDA generally assumes this increasing-dose-increasing-harm relationship in its evaluation of chemicals that come into contact with food, whether directly or indirectly through production, processing, packaging and distribution. A dose-response curve should therefore always be monotonic, according to the agency, meaning it will never change direction from positive to negative, or vice versa.
As a result, when the agency deems a dose of a chemical safe, their investigation has not necessarily tested health effects at that dose — or at any lower doses. Rather, industry and government scientists typically follow an efficient, seemingly common-sense method. They start by exposing lab animals to extremely high doses of the chemical, incrementally drop the doses until they no longer detect obvious harm, then cut that last number down by a margin of safety to create a conservatively "safe" exposure limit.
Endocrinologists, on the other hand, expect craziness in their data. At least for hormone-mimicking chemicals, a relatively high dose might prove innocuous while a far lower dose wreaks havoc on the body. And they've observed that different doses can cause different effects. Such a non-monotonic dose-response curve might take the shape of a "U" or a bell. Take, for example, a 1997 paper co-authored by vom Saal. At 200 nanograms of DES per gram of body weight per day, the prostates of the mice in his study were significantly smaller than prostates in the control mice and prostates in mice receiving other doses.
At a mid-range of 20 nanograms of DES, no effect was seen. And that, under traditional toxicology, is where regulators would stop testing. But drop the dose further, to 2.0, 0.2 and 0.02 nanograms, and vom Saal found prostates were significantly larger than prostates in all of the other animals. The resulting dose-response relationship resembled a bell.
"What we've learned from literally tens of thousands of papers, is that endocrine activity is stimulated by very tiny quantities of endocrine hormones," said Collins, the green chemist. "If you raise the concentrations, you turn the effect off."
His guess as to why: "Nature has decided it doesn't want to have an overreaction to an endocrine hormone."
Birnbaum compared the phenomenon to the body's response to vitamins and minerals, where "too little is a problem and too much is a problem." And scientists have identified potential biological mechanisms for non-monotonic dose-responses, such as opposing effects from multiple hormone receptors.
Still, others push back on the notion of non-monotonicity. "It's illogical. It flies in the face of every mechanism we know in science," Patrick McKnight, a measurement scientist at George Mason University in Fairfax, Virginia, told EHN. "In toxicology you really have to demonstrate that there's an effect of some sort, and I think a lot of these investigators are searching for these effects." (McKnight is on the advisory board at Sense About Science USA, formerly the Statistical Assessment Service, which has industry ties and a record of downplaying the dangers of products.)
Steven G. Hentges, senior director of the Polycarbonate/BPA Global Group at the American Chemistry Council, an industry trade group, stated that "experimental evidence" to support non-monotonic dose-response has been "limited." He pointed to a recent European review that supported that view. Of 179 datasets evaluated in the paper, the authors concluded that only 10 met criteria for a non-monotonic dose response. They acknowledged difficulty in identifying relevant studies and applied strict rules for inclusion in the review, including a requirement that studies include at least five dose groups. This is rare. Even guidelines for traditional regulatory toxicology studies recommend just three dose groups.
The FDA, meanwhile, has stuck to its guns, repeatedly dismissing data on low-dose effects or non-monotonicity. Marianna Naum, an FDA spokesperson, told EHN in an email that the FDA and other federal agencies have determined that non-monotonicity "is not often found in toxicology of the endocrine system," and that "current regulatory testing methods are sufficient" to pick it up. (EHN tried for months through multiple emails and phone calls to arrange a phone interview with someone at the FDA. The agency repeatedly ignored and denied those requests.)
The agency also has a history of brushing off study results because they did not fit its strict study criteria adopted in the 1980s to calculate doses of chemicals that are expected to be safe for humans. These traditional "guideline" studies, as they are called, follow validated "good laboratory practice" (or GLP) protocols. Together, the rigorous study guidelines and lab rules dictate the number and type of animal used, levels of exposure to the chemical of interest, the outcomes to evaluate and record-keeping methods, among other details. And these studies remain the evidence preferred by the FDA, because they "provide risk assessors and risk managers with reproducible results upon which science-based decisions and policy may be based," Naum stated in the email.
Researchers Fred vom Saal and Wade Welshons at their University of Missouri lab. (Credit: Brian Bienkowski)
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."
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.
"You can't weigh a brain to find out what is going on in there," Soto said.
In 2001, the NTP appeared to agree. 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.
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.
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," wrote the authors.
The report was an update of the agency's 2008 assessment, 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.
An external FDA committee had even reviewed the 2008 report and disagreed 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."
Of note: A 2006 analysis 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.
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."
"If you don't ask the question, you're not going to get the answer," she added.
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."
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."
Gail Prins, a researcher at the University of Illinois at Chicago and Clarity investigator (right). (Credit: uic.edu)
On February 23, 2018, upon completion of the draft version of the government's Clarity Core Study, the FDA released a public statement, suggesting that the findings supported its position that "currently authorized uses of BPA continue to be safe for consumers."
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.
"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."
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."
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.
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."
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."
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.
As expected, the government's report stated that exposing rodents to BPA resulted in some health effects at high doses but not at the low doses to which people are generally exposed.
Hentges, of the ACC, praised the report. "The scope and magnitude of the FDA study are unprecedented for BPA, and the results clearly show that BPA has very little potential to cause health effects, even when people are exposed to it throughout their lives," he told EHN in an email. (The ACC declined multiple requests for a phone interview.)
But that is not exactly what the government's data said, even if that sentiment was reflected in the FDA's early press release.
"They have a bunch of data that says BPA is doing something. But they're ignoring that data," Patisaul, the North Carolina State University biologist and Clarity investigator, said.
This March, Vandenberg co-authored an opinion paper with two other scientists also not involved in Clarity, to see what data the feds may be missing. After a close look at the government's Core Study results, they identified 41 endpoints with statistically significant effects. As with the academics' studies, the lowest doses were associated with the greatest number of effects, such as mammary gland cancer, kidney damage, increased body weight and altered gene expression in the brain. "There are a lot more effects at low doses than high doses. A lot more," Vandenberg said. "It's hard to ignore that and say everything is fine here. Even the FDA's own data suggests there is harm."
During another session at last September's EFSA meeting in Italy, Barry Delclos, a biochemical toxicologist with the FDA, responded to a question from Patisaul regarding these low-dose results. He answered that his team had looked to see if "consistent responses" would explain the statistically significant results they had found. "We didn't feel that was the case," he said. Delclos also stated in the September 2018 webinar that his team questioned the biological significance of findings that didn't fit a consistent dose-response relationship.
The frustrations of academics and health advocates, as well as of FDA scientists, is tangible. Patisaul argued that Delclos, Doerge and their colleagues are in their "own echo chamber," doing the "same thing they are accusing everyone else of doing," and unwilling to recognize that their science might be outdated. Doerge went on during the EFSA panel discussion: "You come to someone that has all the responsibility mandated by law to protect the public from this or that, and you're saying, 'Oh, these basic tenets that you've used to do your job for all these years is no longer valid. Dose-response doesn't exist any longer,'" he said. "This is a fundamentally unbreachable barrier, in my opinion."
In the 1998 PBS interview, vom Saal detailed a "distinct pattern" that comes with any paradigm shift in science — especially one, he said, that could impact billions of dollars of profits for chemical companies. "The first thing is absolute denial," he said. "The second is a feeling that it may be true, but it's only true in very limited circumstances. The third is, it's true but the economic consequences are so great that we can't do anything about it."
Lisette van Vliet, a senior policy coordinator with Breast Cancer Prevention Partners, a San Francisco-based nonprofit, likened it to the times of Galileo. "A bunch of scientists were saying the Earth is the center of the universe; other scientists were saying the sun is the center," she told EHN. "They were using very different ways of ascertaining reality."
"These paradigm fights tend to be long and protracted and don't always have a complete 'aha' moment," said van Vliet. "The Clarity study was as good of a stab as anyone could make… The integrated final version of the study is going to be a really important point in this discussion, but it is not going to be the end of the story. And, meanwhile, public health will suffer because of continued exposure to this harmful chemical."
In part 2 of this series, EHN details how the FDA operates on the edge of research honesty, inconspicuously misleading the public with regard to the testing and regulation of BPA.
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.
PULLMAN, Wash.—Tiny pink lab mice disappear then quickly reappear again from within a cage's hardwood chip bedding. The squirmy newborns are part of Patricia Hunt's latest series of experiments on the health impacts of industrial chemicals widely found in products we all use.
Here, in a dim basement at Washington State University, where metal shelves are stacked high with rows of plastic cages, Hunt has made multiple discoveries that call into question claims made by U.S. federal regulators about the safety of one of those chemicals: bisphenol A, or BPA.
Virtually all of us have tiny amounts of it in our blood and bodies – at least two millionths of a gram per liter of blood, the equivalent of about 14 pinches of table salt in an Olympic-sized swimming pool. The Food and Drug Administration maintains that the chemical, known to mimic and mess with natural hormones, poses no real health threat at such levels.
Hunt's results say otherwise. Since being among the first scientists to report on the harmful effects of BPA on mice in 2003, Hunt has further identified genetic abnormalities, fertility problems and other health impacts in animals at very low doses.
We encounter the chemical every day in food and beverage cans, plastic packaging and cash register receipts. And it doesn't appear to be going away anytime soon: The global BPA market is predicted to surpass $30 billion by the mid 2020s. "I'd like to vote the bisphenols off the planet. But that's not likely to happen," Hunt later tells me in an upstairs room flanked with microscopes used to view tissues from the mice. "The more immediate goal should be to change the way we do toxicity testing for these types of chemicals."
Her findings—and those of others—have implications far beyond BPA to the hundreds of other chemicals capable of wreaking similar havoc on our hormones.
Discoveries in Hunt's lab also hint at how an evaluation of a chemical can easily conclude that it is safe even if it may cause harm. Twice now, Hunt has found BPA or one of its equally troublesome replacements, such as bisphenol S, coursing through the bodies of her control mice — animals not intentionally dosed with a chemical in her experiments. The source: those plastic cages housing the mice.
Natural wear and tear of Hunt's cages and, more recently, potential cross-contamination in a shared wash area from another facility's damaged plastic cages, likely led to tiny amounts of the chemicals getting into the animals. She has had similar misadventures with contamination from phytoestrogen-laden mice chow, wildfire smoke and cleaning products. Such unplanned exposures could dilute differences in health outcomes between a study's experimental and control animals, making it difficult to detect if a chemical truly poses a health risk and, ultimately, making it all the easier for hazardous things to continue finding their way into our bodies.
Both times Hunt found bisphenol contamination, she essentially lost her experiment. "It was a whole lot of déjà vu all over again," said Hunt, who is in her mid-60s, her face framed by rimless glasses, cropped gray hair and small hoop earrings.
Hunt's repeated frustrations point to just one of the myriad ways a study's design, implementation, analysis, interpretation and presentation can diminish, obscure or even totally hide any true health effects of a chemical. The risk of such oversights may be especially high for BPA and other chemicals that interfere with the action of hormones in the body, a class called endocrine disruptors.
An investigation by Environmental Health News suggests that an ongoing multimillion-dollar project called Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or Clarity, includes a number of these potentially harm-hiding elements. Launched in 2012 by the U.S. Food and Drug Administration (FDA), the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP), Clarity combines a traditional regulatory toxicology study from the government and investigational studies from academics who wield more modern techniques. The goal is to reconcile a long-standing dispute over data and conclusions on BPA's health effects. But it's bigger than BPA—the collaboration aims to determine if the study methods used by government regulators are sufficient to determine the safety of the hundreds of chemicals suspected of being endocrine disruptors. The implications could reverberate through the entire U.S. chemical regulatory structure.
FDA officials continue to claim that concerns over low-dose effects of BPA are unfounded; academic scientists continue to publish studies that underscore risks such as altered brain development, cancer and diabetes.
Through interviews and emails obtained via Freedom of Information Act requests, EHN has uncovered various signs of deficiencies in the FDA's science on BPA and its handling of Clarity. While each sign alone could be considered a red flag, viewed as a whole, they suggest that the FDA is missing some big warning signs about BPA and, therefore, likely misleading the public about its safety.
Some of these signs can be traced back to before the study began. For example, evidence of BPA contamination emerged during a preliminary Clarity study. If the animals in the main Clarity study had been contaminated, that would dilute any true differences between exposed and unexposed groups. And during the study's design, the FDA insisted on using a specific type of rat that had been shown to be insensitive to the effects of estrogen and its mimics, including BPA. Michael Hansen, a senior scientist for Consumer Reports, compared using this rat to operating a radar gun that doesn't detect speeds under 100 mph and then concluding that no one is speeding. "It is almost as though they were trying not to find differences," Hansen told EHN.
Other potential red flags popped up during the course of the study, such as the small number of animals provided to some of the academic scientists — also limiting their ability to detect differences — and a public statement on BPA's safety made by the FDA before all the data was in.
"Is it total incompetence or fraud? I don't know their thinking. But neither choice is pleasant, and it represents the waste of about $15 million in public funding," Pete Myers, CEO and chief scientist of Environmental Health Sciences, told EHN. (Editor's note: Myers is also the founder of Environmental Health News, though the publication is editorially independent.)
An integrated report that pulls together government and academic findings is in preparation and expected by the end of 2019. Eight of the 14 academic investigators have so far published 14 papers based on their findings in a scattering of different peer-reviewed journals such as Endocrinology and Toxicological Sciences. Many found health effects in rats exposed to very low levels of BPA. "There isn't one big publication coming out with the academics' results," Gail Prins, a researcher at the University of Illinois at Chicago and Clarity investigator, told EHN. "I'm afraid that significant findings across academic studies are going to be buried."
Federal regulators have also now published their part of Clarity, one big publication known as the Clarity Core Study that was widely publicized. Their results, too, reveal some effects at low doses. Yet they again concluded in their report — and in the accompanying press — that exposing rodents to BPA did not result in health effects at the low doses to which people are generally exposed.
"I think that a lot of this is failure by design," Laura Vandenberg, an environmental health researcher at the University of Massachusetts-Amherst's School of Public Health and who was not involved in Clarity, told EHN.
The lab of Cheryl Rosenfeld, a biologist at the University of Missouri and another Clarity investigator. (Credit: Cheryl Rosenfeld)
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.
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.
Like dogs, lab animals can be diverse in their behavior and biology.
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.
"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.
Belcher, too, tends to use mice in his studies of impacts on the heart. "Rats and mice aren't the same things," he said.
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 have long been used in government regulatory studies, and they have long been known to have low sensitivity to BPA.
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.
"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.)
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, researchers exposed a small group of people to a very small amount of BPA 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.
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.
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."
Thomas Zoeller, a biologist at the University of Massachusetts, Amherst, and Clarity investigator in his lab. (Credit: Umass.edu)
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.
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.
"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.
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.
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."
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?"
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)
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.
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."
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.
"The FDA wants to tell a story," said Prins. "They want to tell the story that BPA is fine. And it's not."
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.
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.
"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.)
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."
On Hunt's office wall in Pullman hangs a framed quilt made by the Sarum Quilters of Salisbury, England. The primary-color design depicts the DNA double helix, genes, eggs and sperm that have been the primary characters in her 40-plus years of research. Other genetics references fill the room — there is the thick blue Dictionary of Genetics, and the half-moon table braced by arms and a back that are shaped as x and y chromosomes.
Human-made chemicals only began to take center stage in the latter half of Hunt's research career. In fact, before 1998, Hunt knew nothing about BPA. She was simply investigating at the time how hormonal changes in mice might affect the quality of a female's eggs. Then, some unexpected data began to emerge: Abnormal eggs appeared in both her experimental and control animals. "We knew we had a problem," said Hunt, wearing a dog-fur-free blue long-sleeve t-shirt and dark blue jeans, along with a multi-colored stone pendant. "It took me a month to track down what was going on."
At first, she suspected everything — from construction project debris to pesticides sprayed nearby. Then she took a closer look at the plastic cages. As they were repeatedly washed and autoclaved, she could see that the cages were starting to degrade. Across the street from her lab was the university's polymer sciences building. She recalled running over to those scientists and learning from them that BPA was likely leaching out of her cages.
While some health effects of BPA were already suspected by the late 1990s, impacts on female eggs — and, therefore, potentially increased risks of miscarriages and birth defects — were not yet among them. Hunt spent the next three years confirming her data. Today, female reproductive problems are included with the published risks associated with BPA exposure. Hunt has continued to investigate how BPA and other endocrine disruptors might further affect genes and reproduction. And, while not a participating scientist, she is also keeping a close eye on Clarity.
In emails and PowerPoint slides obtained by EHN, FDA scientists acknowledged as far back as July 2013 that contamination occurred in a study done to determine Clarity's feasibility. During this preliminary study, which was carried out at the same facility that later housed the animals used in the large-scale Clarity study, tests had revealed that BPA levels in control rats were similar to those in the four lowest exposure groups.
That's a problem: Endocrine disruptors, like natural hormones themselves, can impact the body at extremely low levels. So, unintentionally exposing controls to a tiny dose of a chemical may result in those animals showing similar effects as experimental animals intentionally exposed. In a comparison of health effects between the control and experimental animals, any true differences between the groups would be diluted.
In January 2014, Barry Delclos, a biochemical toxicologist with the FDA, wrote in an email that, while data from the preliminary study revealed "the potential for significant effects in the low BPA dose range," the BPA contamination "confounds the interpretation of the changes observed in the lowest BPA exposure groups."
Marianna Naum, an FDA spokesperson, told EHN in an email that data suggesting contamination of the control rats might have been due to "the housing of the animals in the same room as animals treated with high BPA doses." Although Naum also noted that the agency has still not confirmed the source of contamination, and that it remains unclear to what extent any contamination might have affected the rats in Clarity. Still, the government's Core Study report asserts that contamination was not an issue.
Heather Patisaul, a professor of biology at North Carolina State University and a Clarity investigator. (Credit: NCSU)
"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."
"If you can't ferret it out, it's like shooting yourself in the head before you even start the study," added Hunt.
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."
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."
It was unlikely a pleasant experience to be a Clarity rat. Every day, while restrained, a lab technician stuck a tube down its throat and into its stomach to deliver a solution. For the experimental animals, the solution contained BPA. For the controls, it either contained a dose of ethinyl estradiol, the synthetic estrogen in oral contraceptives, or nothing. The method is called gavage.
FDA scientists argue that gavage is a better way to ensure the correct dose is getting into an animal than putting the chemical in its food. Academic scientists counter that gavage triggers chronic stress and can therefore significantly alter hormone levels — another means by which any actual differences between experimental and control animals could be artificially diminished. Because the control animals were also exposed to the stress of gavage, they argue, there was no true control group of rats in Clarity.
Heather Patisaul, a professor of biology at North Carolina State University and a Clarity investigator, co-authored a 2013 study in which she found that gavage alone was enough to change the expression of hormone receptors and other genes in areas of the brain that are known to respond to stress.
"Clearly animals gavaged and not gavaged are not the same," she told EHN.
During the planning of Clarity, the FDA made it clear that use of gavage was non-negotiable, noted Heindel, the former NIEHS health scientist administrator. The academics could accept that or simply not participate.
So, many reluctantly signed on, despite believing that gavage and other design factors dictated by the FDA would make it extra difficult to show effects that many of them had identified in their previous studies. Use of gavage was among the criteria adopted by the government decades ago for studies that evaluate the safety of chemicals. In addition to standardizing the number and type of animal used, and levels of exposure to the chemical of interest, these so-called "guideline" studies also generally focus only on traditional endpoints such as overt signs of toxicity, rather than the unique effects of endocrine-disrupting chemicals that academics tend to investigate.
Academics usually use other means of administering chemicals to animals. Prins delivers BPA into a mouse's mouth with a pipette tip. Andrea Gore, a neuroendocrinologist at the University of Texas at Austin, said her lab is starting to administer chemicals to animals via vegetable oil placed on a piece of cookie. "There is evidence that gavage is stressful," Gore, who was not involved in Clarity, told EHN. "When you're talking about low doses of endocrine-disrupting chemicals, that is extremely relevant."
Hunt, too, feeds her mice BPA via corn oil. "We gently pipette oil into the mouth and the animals actually like it," she said.
Researcher Pat Hunt with lab mice. (Credit: Lynne Peeples)
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.
Contamination is one of the ways in which a study and its results might become tainted; a lack of control is another.
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.
For example, academic studies of BPA 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.
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."
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.
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.
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."
Ana Soto, an endocrinologist at Tufts University and a Clarity investigator, with fellow Tufts researcher, Carlos Sonnenschein (Credit: Tufts University).
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."
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.
And that would have called into question the rest of their results.
"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."
Zoeller agreed. "They at least appear — by their inconsistency — to have a preconceived conclusion that they arrive at by selective logic," he said.
In part 3 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.
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