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Medical News & Perspectives
March 21, 2018

Scientists Call FDA Statement on Bisphenol A Safety Premature

JAMA. Published online March 21, 2018. doi:10.1001/jama.2018.3288

A recent US Food and Drug Administration (FDA) press release on the endocrine-disrupting chemical bisphenol A (BPA) was met with widespread criticism from scientists outside the agency.

The February statement from Stephen Ostroff, MD, the FDA deputy commissioner for foods and veterinary medicine, said a pre–peer review draft report of a 2-year study involving rats supported the agency’s prior determination that BPA is safe for currently authorized uses in food containers and packaging.

The same day the draft report and press release went out, FDA chief Scott Gottlieb, MD, tweeted, “#FDA continues to conclude BPA is safe for its currently authorized uses” and shared an NPR article with the headline, “Plastic Additive BPA Not Much Of A Threat, Government Study Finds.”

But the Endocrine Society, an international professional organization with some 18 000 members including researchers and clinicians, quickly issued a statement expressing concern with the FDA press release. The society and scientists interviewed by JAMA who study the potential health effects of BPA and other endocrine disruptors in laboratory animals and humans characterized the FDA’s statement to the media and the public as premature and incomplete.

Weighing the Methods

The FDA, which declined to comment on the press release, banned BPA in baby bottles and children’s sippy cups in 2012 and in infant formula cans the next year. The agency has specified that those rulings were based on industry abandonment of the chemical for these uses rather than on safety concerns. Although the chemical’s use has declined—particularly in plastic water bottles and plastic food containers—following public pressure on industry, it’s still found in many aluminum can liners. (It’s also in a range of other types of products including some medical and sports equipment, plastic toys, dental sealants, and store receipts.)

The new controversy centers around a research collaboration between government and academic scientists called the Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or CLARITY-BPA. The interagency National Toxicology Program (NTP), the National Institute of Environmental Health Sciences (NIEHS), and the FDA launched CLARITY-BPA early this decade to study the full range of potential health effects from BPA exposure.

The project’s final conclusions, expected in August 2019, will be based on 2 sets of results: one from a “core study” mainly of growth, organ weight, and tumor development in BPA-exposed rats conducted at the FDA’s National Center for Toxicology Research and another from 13 NIEHS-funded grantee studies at US universities looking at other end points in the same rodents, including effects on reproduction, cardiovascular disease, neurobehavior, and immunity.

The recent statement from Ostroff focused on largely null results in the core study, which also evaluated survival, estrous cycles, sperm counts, and serum profiles, among other end points. The report, released by the NTP for public comment, is scheduled to undergo external peer review at a public meeting on April 26.

The statement noted that an integrated report incorporating grantee data will be published in the future, but did not mention that 9 CLARITY-BPA articles by grantees have already been published in peer-reviewed journals. Several of these studies found harms at low-level exposures. The core study also found an increase in mammary gland tumors at the lowest exposure dose, a result that researchers said was downplayed in the FDA statement.

Scientists outside the government responding to the statement expressed deep disappointment and questioned why a regulatory official would make a public proclamation about a controversial chemical’s safety based on only half of an investigation.

“I’m speechless that the regulators can maintain a perspective about their own science that is devoid of the rest of modern science and what we know,” said endocrinologist Thomas Zoeller, PhD, of the University of Massachusetts (UMass) at Amherst, who is the principal investigator on a CLARITY-BPA study of thyroid and brain anatomy end points.

The statement was particularly troubling, he said, because CLARITY’s larger purpose is to determine if the standard toxicology tests used in regulatory and industry laboratories are adequate for determining the safety of endocrine disruptors. The concern is that toxicology studies like the CLARITY-BPA core study use end points specified in the Organisation for Economic Co-operation and Development international test guidelines that may not be sensitive enough for detecting the effects of endocrine disruptors.

“This type of toxicity testing is used to see: Do the animals die? Do they develop any gross morphological problems? Do they have any overt cancers?” said toxicologist Andrea Gore, PhD, of the University of Texas at Austin, who studies endocrine disruptors. “There’s nothing wrong with that testing, but when you’re talking about endocrine-disrupting chemicals, it is considered to be very inadequate.”

Classic toxicology testing, developed in the 1960s, ’70s, and ’80s, largely relies on comparing organ weights. But today, endocrinologists outside of the regulatory system use state-of-the-art methods to look for things like changes in gene expression or cell phenotype and their relation to specific health and behavioral outcomes.

This could at least in part explain a big inconsistency: After laboratory cell studies first identified BPA as a chemical that mimics and disrupts hormone systems, government and industry studies of BPA-exposed laboratory animals have generally failed to reveal adverse effects, while a slew of studies from academic laboratories have shown effects at low doses.

The Research Disconnect

Academics have published hundreds of studies documenting health problems in rodents exposed to BPA during prenatal development, including effects on reproductive organs and function, the brain and neurobehavior, and metabolism, according to Laura Vandenberg, PhD, an endocrinologist and environmental health scientist at UMass Amherst and a spokesperson for the Endocrine Society.

“There are substantial animal studies from multiple independent investigators that raise serious concerns about a host of effects,” said Leonardo Trasande, MD, a pediatrician at New York University School of Medicine who studies endocrine disruptors and child health.

In addition, more than 100 epidemiological studies have shown associations between BPA exposure and disease outcomes in people, Vandenberg said. Cross-sectional studies show associations with reproductive conditions, metabolic disease, and behavioral problems, while prospective studies have begun to link early-life BPA exposure to later outcomes like increased body weight and behavioral issues similar to those found in attention deficit disorder and obsessive compulsive disorder.

Yet so-called guideline-compliant studies have led the FDA, the European Food Safety Authority, and Health Canada’s Food Directorate to conclude that dietary exposure to BPA in food packaging at current levels is safe.

“There is a large disconnect between the literature—which is voluminous—on bisphenol A, and the signals that come out of the guideline regulatory studies,” said John Bucher, PhD, an NTP senior scientist. The $30 million taxpayer-funded CLARITY-BPA program was devised to make sense of those disconnects, he said.

Asked about the FDA’s decision to put out a press release before all of the data had been collected and synthesized, Bucher said, “It would have been nice if we would have been able to have all of the grantee information available at the same time as the core study information, to be evaluated together. The process wasn’t optimal.”

Fraught From the Start

By drawing conclusions from a guideline study alone—while omitting findings from grantee studies—researchers said the FDA undercut the very premise of the research program.

“The whole point of CLARITY was to make a determination about whether or not organ weight actually is the most sensitive way of evaluating safety,” Zoeller said.

But the study was fraught from the beginning, he said. Early on, academic investigators expressed concerns about the strain of rats chosen for the study and the method used to orally dose them with BPA.

Then, in 2014, FDA scientists published an article in Toxicological Sciences on a 90-day CLARITY-BPA pilot study—a truncated version of the core study—without consulting their academic collaborators. To the academics’ chagrin, the article suggested that low-dose dietary BPA exposures were safe. The pilot study was also included in the literature and data review for the FDA’s last BPA safety assessment in 2014.

The early study revealed problems with the CLARITY-BPA experimental protocol. Rats in the control group had BPA in their blood indicating that they had been inadvertently exposed to the chemical. The source of the contamination was not identified and, according to Vandenberg, it’s unclear if the problem was resolved in the larger core study.

“They didn’t even test the blood as far as I can tell,” she said of the core study. “So they knew there was a problem in their pilot study, and now we have no evidence of whether or not that problem continued or if it was fixed.”

A Brilliant Idea

Zoeller said the FDA has more than once betrayed agreements it made with academics about how CLARITY results would be reported. He and others blame industry influence. “I have to emphasize that the FDA was in communication with industrial groups through this whole thing,” he said. “They have created a system that has kept modern science out of chemical safety determination.”

After the pilot study article, Zoeller wasn’t surprised the FDA put out a premature statement. His fear now is that the chemical industry will manipulate the raw data from the grantee studies, scheduled to be released on the NTP website in August, to their own purposes.

According to Bucher, the final integrated report due next year will undergo peer review. Grantees will be consulted to clarify their data, if needed, but it’s unclear if they will be involved in crafting or reviewing the document. “We will probably be going back to them as we delve into their papers and look at the raw data and make sure that we understand fully what they found,” Bucher said.

The effort to find the best way to test chemical toxicity has perhaps become even more urgent as BPA and other chemicals of concern have begun to be replaced with a greater number of similar agents that may be just as harmful.

Despite his disappointment and apprehension, Zoeller believes research partnerships like CLARITY are vital to understanding the safety of chemicals for the good of public health. “This collaboration between regulatory people and independent scientists seemed like a brilliant idea and an opportunity that could actually change the global scene for regulating chemicals,” he said.

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