From the WebMD Archives

Oct. 4, 2018 -- A large government study has found that low doses of the chemical bisphenol A, or BPA, appear to cause biological changes in lab animals -- including an increase in breast cancers.

The finding is important because the FDA has ruled for years -- most recently in 2014 -- that BPA is safe in the small amounts people are exposed to in their everyday lives. The new finding also backs up scores of independent studies that have linked low doses of BPA to the development of breast cancer and other ills.

But the FDA is dismissing its own results, infuriating academic scientists who have been trying to convince the agency for years that BPA can cause harm even in tiny amounts.

In an ongoing study, the CDC has measured BPA in the urine of more than 90% of Americans they have tested, indicating widespread exposure. BPA is used in the production of hard, polycarbonate plastics like those used in some reusable water bottles and food storage containers, to line food cans, and in dental sealants. It also coats some kinds of cash register receipts.

Because of safety concerns, France has banned BPA in food packaging. California lists BPA as being toxic to the female reproductive tract under its Proposition 65 rule that requires manufacturers to warn consumers if certain chemicals are in their products.

The results come from a 2-year FDA study of nearly 4,000 rats that were force-fed one of five different doses of BPA.

The experiment was part of a $30 million project that was meant to reconcile conflicting scientific conclusions about the safety of BPA. In addition to the FDA’s core study, the project also funded 13 carefully selected experiments conducted by independent academic researchers. Results from these additional studies will be published by next year.

Big Study, Little Agreement

The project is called Consortium Linking Academic and Regulatory Insights on BPA Toxicology, or CLARITY. But instead of clearing the air, it has laid bare a long-simmering schism in science -- over the idea that certain chemicals may act more like hormones than classic poisons, causing a different type of harm to the body in tiny amounts than they do in large amounts.

“The whole idea was to bring the FDA scientists and academic scientists together, have them design an experiment together, have them discuss the results together, and come to some joint conclusions,” says Jerrold Heindel, PhD, who was an architect of the project when he was a program director at the National Institute of Environmental Health Sciences (NIEHS). “That part hasn’t happened, and it’s unclear whether it will happen,” says Heindel, who is now semi-retired and serving as the director of endocrine disruption strategies for the nonprofit Commonweal.

Classical toxicologists believe that anything, even water, can be harmful or harmless, depending on amount. “All things are poison and nothing is without poison; only the dose makes the poison,” according to Paracelsus, a 16th century Swiss physician who is considered the father of toxicology.

Some toxicologists feel that the effects of exposure to a chemical become more pronounced in direct relation to the amount of it that people are exposed to -- something called a dose response.

Chemical regulators, then, try to determine the level at which a chemical begins to become harmful, and to set safety levels well below that.

Many endocrinologists and pharmacologists, on the other hand, say certain chemicals can have harmful effects at very low doses if they interfere with the body’s ability to recognize or respond to its own hormones.

Though the evidence supporting the existence of low-dose effects for certain chemicals has been growing over the last decade, the FDA and other regulatory agencies have largely dismissed these studies, as well as the theory behind them.

Government regulators say studies that show low-dose effects are hard to replicate and are often too small to reliably identify problems.

But independent scientists think the FDA’s skepticism is self-serving.

“If low-dose effects exist and they acknowledge it, then what they’ve been doing this whole time is wrong -- and not just for BPA. It’s wrong for dozens, if not hundreds, of other chemicals,” says Laura Vandenberg, PhD, an associate professor of public health at the University of Massachusetts Amherst.

“It’s a house of cards,” she says.

How the Studies Were Done

All the researchers agreed to use the same strain of rat -- Sprague Dawley -- raised in FDA labs. They also agreed to follow a rigorous set of record keeping protocols called “good laboratory practices,” which are rules meant to prevent fraud. 

This kind of large study using rodents is a classic type of toxicology study.  Animals are still used to study toxic effects of chemicals because such a large, comprehensive study using people would be considered unethical.

For the FDA’s core study, the experiments ran for 2 years and involved nearly 4,000 rats that were force-fed one of five doses of BPA, two doses of estrogen, or a control liquid. All the groups were dosed before birth. Some continued to be dosed throughout their lives, while others were only dosed until they were no longer nursing.

The lowest BPA dose fed to the rats -- 2.5 micrograms per kilogram of body weight per day -- was designed to be within the range that humans are exposed to in their everyday lives. The highest dose --25,000 micrograms per kilogram per day -- is known to be toxic.

In the study, young rats fed the lowest dose of BPA until they were weaned had significantly more breast cancers than the control group -- 12 out of 50 animals got breast cancers, compared with 4 out of 50.

Female rats fed the lowest dose also had more changes to their livers and kidneys than the control group. Males in groups that received the lowest doses of BPA throughout their lives also had significant changes in their breast and prostate.

Disagreement Over Methods, Findings

Barry Delclos, PhD, a research toxicologist at the FDA who is one of the lead researchers on the core study, presented the agency’s findings in a Webcast last month.

Delclos acknowledged that there had been a lot of interest in the breast cancer findings, but he also said the agency’s scientists questioned the “biological relevance or plausibility” of the higher number of breast cancers in rats dosed with small amounts of BPA. 

Delclos said the breast cancer findings in females were questioned because they were observed only in rats fed the lowest dose for a short amount of time, but not in the rats that were dosed throughout their lives.

Chemicals that have effects in the womb are not unheard of. Critics point to the example of diethylstilbestrol, or DES, a synthetic estrogen drug given to women between 1938 and 1971 to prevent miscarriages and preterm labor. Adult children exposed to DES in the womb were more likely to have rare kinds of cancers than those whose mothers were not given the drug.

Delclos also pointed to the lack of a dose-response. That is, there was no increase in breast cancers in rats in the other dose groups.

Academic researchers say that’s to be expected since BPA is believed to act as a weak estrogen in the body. It may cause problems only in low doses.

“Hormones don’t act in a linear fashion. They never do,” says CLARITY researcher Tom Zoeller, PhD, who studies environmental impacts to the thyroid gland at the University of Massachusetts Amherst.

Finally, Delclos says, when the FDA looked back at other experiments that used the same kind of rats from a decade ago, the control animals in those group -- so-called historical controls -- had more breast cancers, suggesting that the number of breast cancers in control animals in this experiment were abnormally low.

It wasn’t that the low-dose group in the core study had more cancers, then; just that the control group had fewer than they’ve seen in the past.

Zoeller says it’s common for the FDA to look at control animals from other studies as a way to help interpret its research findings, but he questions whether that’s sound science.

“I don’t think that’s outside of what’s normally done, but think it’s also very concerning that it’s normally done this way,” he says.

There’s another problem with the FDA’s use of historical controls in this case, according to Zoeller’s colleague, Laura Vandenberg. Those rats were kept in polycarbonate plastic cages, meaning the control rats could have been contaminated with BPA, which could explain their higher incidence of breast cancers.

“It is truly shocking that the FDA insists that this is not relevant,” says Ana Soto, MD, a professor of integrative physiology and pathobiology at Tufts University, who was one of the academic researchers who took part in CLARITY. She’s also studying the effect of BPA on the mammary gland.

WebMD requested an interview with Delclos through the FDA’s media office. The agency declined to have him respond to verbal or written questions. Instead, it sent a statement that said, in part, “FDA looks forward to the completion and publication of CLARITY-BPA research, which will include data from the grantees and the peer-reviewed NCTR core study and will inform FDA’s continued assessment of the safety of BPA.”

In the meantime, the FDA continues to say that BPA is safe in the amounts people are exposed to every day.

But not all experts agree. In July, the American Academy of Pediatrics, citing critical weaknesses in the regulatory process, called on parents to avoid products with BPA.

Likewise, the Endocrine Society has called the FDA’s conclusions “premature” and said the government’s data “does not provide assurance of BPA’s safety.”

The National Toxicology Program says it’s planning to publish a study incorporating findings from both the core and grantee studies in the fall of 2019.

“We have this sort of impasse on how to interpret the findings now,” Heindel says.

WebMD Health News


Jerrold Heindel, PhD, director of endocrine disruption strategies, Commonweal, Bolinas, CA.

Laura Vandenberg, PhD, associate professor of public health, University of Massachusetts Amherst.

Barry Delclos, PhD, research toxicologist, FDA.

Ana Soto, MD, professor of integrative physiology and pathobiology, Tufts University, Boston.

Tom Zoeller, PhD, professor, department of biology, University of Massachusetts Amherst.

National Toxicology Program: “NTP Research Report on the CLARITY-BPA Core Study: A Perinatal and Chronic Extended-Dose-Range Study of Bisphenol A in Rats.”

FDA Grand Rounds: “Bisphenol A: Toxicology and Pharmacokinetic Data to Inform Ongoing Safety Assessments,” presented by K. Barry Delclos, Sept. 13, 2018.

Carnegie Mellon University Institute for Green Science and Environmental Health Sciences, webinar on the CLARITY findings, Sept. 12, 2018.

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