"This should change how the FDA and other people look at the safety of BPA."
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."
Low doses matter
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)