Endocrine Society Experts Question FDA's Statement on BPA

Kristin Jenkins

November 01, 2018

The US Food and Drug Administration (FDA) "jumped the gun" when it recently announced that the "authorized use" of the food packaging compound bisphenol A (BPA) continues to be safe for consumers despite study findings to the contrary, scientists with the Endocrine Society say.

What's more, the regulatory agency dismissed results from its own research findings in the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) study, according to Laura N. Vandenberg, PhD, associate professor and graduate program director, School of Public Health and Health Sciences, University of Massachusetts at Amherst.

Speaking at a news conference organized by the Endocrine Society on October 23, Vandenberg said that results from the FDA's investigation revealed significant low-dose effects in more than 20% of animals exposed to BPA compared with controls.

These effects included an increased incidence of mammary adenocarcinoma, nephropathy, and prostatic inflammation at the lowest doses tested, said Vandenberg, who is also a member of the Endocrine Disruption Chemical Advisory Group of the Endocrine Society.

"The reason that we decided to organize this webinar is that the FDA has repeatedly stated that the way that BPA is used in food containers is safe for humans," she said. "The problem with that statement is that it's based on incomplete data. Even with current data interpreted by the FDA as safe, scientists still disagree. Additional data is forthcoming."

Vandenberg also expressed concerns about the agency's approach to testing BPA. She notes that when ethinyl estradiol (EE) was used as a positive control, the effects were not reproducible even in studies conducted in the same laboratory with the same rats.

"There may be a much deeper story here," Vandenberg warned. "The way that regulatory agencies have been evaluating chemicals for safety using traditional methods of evaluating toxicity may not be reproducible."

On February 23, Stephen Ostroff, MD, deputy commissioner for Foods and Veterinary Medicine at the FDA, posted an online statement about the draft report on BPA. In it, Ostroff noted that BPA is authorized for use in polycarbonate plastics and epoxy resins in certain food and beverage can linings.

"Given this interest," he wrote, "the FDA has routinely considered and evaluated the scientific evidence surrounding the use of BPA and continues to conclude that BPA is safe for the currently authorized uses in food containers and packaging."

As previously reported, CLARITY-BPA was designed to help regulators and scientists working at different universities achieve consensus about the public health impact of BPA exposure. Participants had agreed that the National Toxicology Program would integrate data from the FDA's study findings with the academic research results before the release of a single CLARITY-BPA study in the fall of 2019.

Then the FDA made its unexpected unilateral announcement. The announcement shocked the academic collaborators in CLARITY-BPA, who were conducting companion hypothesis-based research with identical BPA exposures and blinded samples supplied by the FDA.

"I share Dr Vandenberg's concern that FDA has put a stake in the ground declaring that BPA is safe," said Heather Patisaul, PhD, a CLARITY-BPA investigator and associate professor in the Department of Biological Sciences, North Carolina State University in Raleigh.

As of 2014, nearly 100 published epidemiologic studies have linked BPA to health problems, including reproductive, behavioral, and metabolic disorders, she noted.

Patisaul, who is also member of the Endocrine Disruption Chemical Advisory Group of the Endocrine Society, called the study "the most ambitious project that's ever been done to examine the effects of any chemical." However, she also emphasized that the conflicting conclusions about the safety of BPA underscore the need to "get real" about updating toxicity testing strategies.

"The significant advantage of the CLARITY-BPA program is that we really got to test drive some of the endpoints and assays we think are going to be the most sensitive. The regulators need to use that information to update their toxicology testing system. We are in desperate, desperate need."

BPA is widely used to make polycarbonate plastic found in many beverage containers and infant bottles, compact disks, plastic dinnerware, impact-resistant safety equipment, automobile parts, and toys.

BPA is used in the epoxy resins lining metal food cans, bottle tops, and water supply pipes to keep them from corroding. Thermal paper — a material formulated to change color when exposed to heat — also contains BPA and is used in adding machines, cash registers, and credit card terminals.

Data from the 2003-2004 National Health and Nutrition Examination Survey  showed that 93% of 2517 people age 6 years and older had detectable levels of BPA. Women had statistically higher BPA concentrations than men, and children had higher concentrations than adolescents or adults.

These findings led the Centers for Disease Control and Prevention to conclude that  BPA exposure in the general population is widespread.

Toxicology Data Alarming

Vandenberg explained that the FDA studies included several investigations using one of two BPA exposures: continuous or stop dose.

In the continuous exposure studies, animals were given BPA by gavage, starting at day 6 of pregnancy, at doses of: 2.5 µg/kg/day, 25 µg/kg/day, 250 µg/kg/day, 2500 µg/kg/day, or 25,000 µg/kg/day. At birth, offspring were exposed to BPA continuously until euthanasia at 1 or 2 years of age.

A matched group of animals was exposed to continuous EE at two different doses (0.05 µg/kg/day and 0.5 µg/kg/day) or to vehicle.

The stop-dose studies looked at animals exposed to the same five continuous BPA dose groups from day 6 of gestation up to day 21 of life. There was an unexposed control but no group exposed to EE.

Overall, the FDA study results showed significant effects on numerous organs, including the ovary, testis, reproductive tract, mammary, liver, kidney, mammary, thyroid/parathyroid, and pituitary, in both males and females at different doses, Vandenberg said.

However, some of the very serious effects were seen at the very lowest doses of BPA (2.5 µg/kg/day) compared with controls, including the following:

  • Increases in the incidence of mammary cancer in more than 20% of animals exposed during gestational development and up to day 21 of life;

  • Inflammation of the dorsal and lateral lobes of the prostate in males exposed throughout life; and

  • Significant increases in nephropathy in females exposed throughout life.

In addition, changes were seen in the body weight of females continuously exposed to mid to lower doses of 250 µg/kg/day BPA compared with controls.

The FDA study also showed an increased incidence of mammary cancer in more than 15% of animals exposed to 2500 µg/kg/day BPA compared with controls. BPA has a nonlinear dose-response relationship shaped like an inverted U, explained Vandenberg. This is also seen with vitamins and other essential nutrients, as well as with many drugs and pharmacologic agents.

However, the FDA constructed its studies and analyzed the data based on the assumption that there is a linear dose-response relationship between BPA exposure and health effects. It looked at outcomes related to overt signs of toxicity at high doses, including extreme changes to organ weight, seizures, and changes to the number of pups born to exposed females.

Vandenberg noted that this approach doesn't fit the situation. This is appropriate for compounds that act strictly as a toxicant, but not for hormones and endocrine disruptors, she said.

In outlining results from the CLARITY-BPA academic studies, Patisaul said that most have been published and all show that at the lowest dose of 2.5 μg/kg/day, BPA exposure affects the prostate, ovary, heart, and immune system. Her three studies have been published and show low-dose effects of BPA on the brain.

"When you go back and look at available studies in the literature plus the academic studies in CLARITY-BPA, you see very clearly that there are effects on the brain, behavior, the female reproductive system, and on the cardiovascular system with low doses of BPA," she said.

"A major part of the problem has been who is reading the data, who is interpreting it, and how are they using it for decision-making," she added.

Counseling Concerned Patients

For clinicians faced with concerned patients, a general discussion about chemicals in the environment as they relate to health can help increase awareness, Patisaul said. "It's really sad to say, but just because something is on a store shelf doesn't mean it's safe. So people need to become more proactive when they go shopping."

Since BPA dissipates from the body very quickly, advising patients to shift from plastics to glass is a good way to start to controlling exposure. Avoiding canned foods, especially canned tomatoes, which are acidic, will also reduce exposure.

Patisaul finds Internet tools, such as the Healthy Living app from the Environmental Working Group, particularly helpful. She said she uses it to navigate the grocery store and find safer cosmetics, cleaning products, and personal care products.

Even when consumer products are labeled "BPA-free," however, there may be cause for concern, Vandenberg said. Many of the chemicals used to replace BPA may be just as harmful to health, but very little is known about them, she explained.

"Scientists often refer to these chemicals as 'regrettable replacements,'" she said. "How long will it take us to study all of these replacements? It's mind-boggling to think about."

In Europe, the health effects of endocrine-disrupting chemicals are estimated to cost between €157 billion and €270 billion annually. In the United States, studies show that the cost of exposures to endocrine disruptors is similar, Vandenberg said.

"Even though a 100% causal relationship between BPA exposures and health outcomes in humans has not been established, the best available evidence suggests that exposures to endocrine disruptors like BPA are costing us billions of dollars a year," she pointed out. "I think it's important to end on the idea that the decision to do nothing is a decision that costs us something."

Vandenberg and Patisaul have disclosed no relevant financial relationships.

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