The Poison Paradigm

No Clarity with CLARITY

By: Franklynn Bartol

BPA, the poster-child of endocrine disruptors, became a media sensation in the 2000s, after decades of research found the chemical could have serious health effects, even at minimal doses.

But the FDA refused to acknowledge much of the mounting evidence against BPA, claiming the methodology didn’t live up to their standards.

The FDA’s “gold standard” is based on strict study criteria from the 1980s, called the ‘guideline’ criteria— which regulated the calculation of safe doses of chemicals for humans.

This meant that FDA reviews rejected much of the academic evidence, relying instead on industry-funded studies that met the FDA’s criteria. Meanwhile, academics continued to point to inadequacies in these ‘guideline’ methods, since they are based on a monotonic dose-response model, which endocrine disruptors do not follow. Regulation was impossible without a resolution to this divide.

In an attempt to bridge the divide, the US FDA, the  National Toxicology Program and the National Institute of Environmental Health Sciences established:
“ The Consortium Linking Academic and Regulatory Insights on BPA Toxicity” -- also known as CLARITY-BPA.

The 7-year, $30 million program was supposed to have academics and FDA scientists collaborate in an effort to “cut through the confusion” around BPAs.

The FDA would look at studies that met its existing guidelines that looked at BPA toxicity across dose levels-- thjis was known as the Core Study.
Independent research groups, run by academics, took on 14 independent studies looking at a matter of specific impacts of BPA (such as on the heart or brain). There were called the Grantee studies.

While it was hoped that the design of CLARITY BPA would settle the debate on BPA’s safety, the results of the studies have been mired in controversy and debate. The main issue is that the ‘core’ and ‘grantee’ studies’ conclusions conflict.

In February 2018, the FDA made a public statement announcing the results of the guideline-compliant core study. It stated there were “minimal effects” in the BPA-exposed rodents, supporting the FDA’s continuing stance that current levels of BPA exposure in humans is safe.

This was met with harsh criticism from the scientific community, particularly endocrinologists and the academics working on CLARITY-BPA’s independent studies. The FDA’s early publication and statement on BPA—before the grantee studies were considered—went against CLARITY-BPA’s stated intent to merge independent and FDA data before drawing conclusions.

In fact, Daniel Doerge, an FDA scientist presenting at the EFSA conference, dismissed inquiries into those studies’ findings saying “"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” (video of conference available).

In addition to ‘jumping the gun’, critics say the FDA’s conclusion ignores its own study’s significant findings of increased risk of breast tumours, kidney disease, and prostate inflammation in rats with low levels of exposure to BPA; these effects were dismissed as ‘irrelevant’ because they were not seen at higher doses.

The response was swift: a panelist sitting next to Doerge at the EFSA conference, Maurice Whelan, head of the Chemical Safety and Alternative Methods Unit of the European Commission's Joint Research Center, immediately critiqued CLARITY BPA as “institutionally-biased”.

Just weeks after the FDA’s statement, the Endocrine Society held a webinar for the media in which Laura Vandenberg, PhD and Heather Patisaul, PhD explained their deep concerns about the FDA’s methodology and conclusions.

Patisaul, who participated as a grantee in the CLARITY-BPA, said of the FDA’s statements: “FDA has put a stake in the ground, they’ve said that BPA is safe, and they’re very reluctant to back away from this stake.”

As one group of CLARITY grantee researchers noted in their own study’s publication, despite the “well-characterized estrogenic activity of BPA and over eight thousand published studies by independent academic investigators reporting a wide range of adverse health effects...the FDA has deemed BPA to be safe at current levels of exposure. The basis for this difference is the absence of the application of the precautionary principle in the USA as opposed to countries in Europe” where some regulations of BPA have been instituted in food and baby products (Uchtmann et al., 2020).

They further note that the FDA is ignoring statistically significant CLARITY results.

Indeed, since the FDA’s premature statement, results of the independent grantee studies have been flowing in, with all but two finding harmful ‘low-dose’ effects of BPA that are ‘non-monotonic’ (i.e. occur at low but not high doses) for a range of health outcomes, including alterations in brain development and increased risk of prostate cancer.

Researchers are also critiquing the FDA study’s ‘guideline’ methodology — which hasn’t been meaningfully updated since 1982 but is still touted as a ‘gold standard’ by the FDA (EHN, 2019)—as outdated and inappropriate for detecting these effects (vom Saal, 2019).

One recent article critiqued the FDA’s use of “cherry picked” historical control data that make EDCs seem less harmful (Vandenburg et al., 2019).

At the Endocrine Society’s webinar, Vandenburg pointed to discrepancies between the effects of the control substance (a synthetic hormone) in the current study and the FDA’s previous studies.

Others pointed out that the mice receiving BPA had undergone significant stress from the study’s invasive methods of administering the substance, which would alter hormone levels.

In 2019, a  landmark article “BPA: have flawed analytical techniques compromised risk assessments?”  showed that levels of BPA, and likely its replacements, in humans is vastly underestimated by current (FDA) accepted methods of measurement.

Actual levels in humans are estimated to be 44 greater than previously thought, totally undermining the FDA’s argument that exposure is negligible.

Importantly, this finding is relevant for currently widespread and accepted methods of detecting other EDCs, such as other phenols, phthalates, and the bisphenols often used to replace BPA.

The disagreement is being described as not only between the FDA and academic scientists, but between disciplines.

As Gail Prinds, a CLARITY-BPA grantee researcher whose own findings support adverse low-dose effects, notes: “These are toxicologists, they are not endocrinologists, and they don’t understand that effects at a low dose but no effects at high dose are very biologically plausible.” (as quoted in The Scientist, 2018)

Indeed, Daniel Doerge, a biochemical toxicologist with the FDA for more than 30 years, expressed strong views about the divide while reporting on the FDA’s CLARITY-BPA findings at the September 2018 European Food Safety Authority conference:

"This is a chasm that is not going to be breached”, he said, “"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." (quoted in EHN, 2019).

Other toxicologists, such as Steve Hentges of the American Chemistry Council, have come out in support of the FDA’s conclusions.

In November 2019, amidst these ongoing academic debates, Environmental Health News—a publication of the U.S non-profit organization Environmental Health Sciences—released a four-part series of articles detailing issues with the FDA’s planning, execution, and interpretation of the BPA studies.

Its investigation found little collaboration. “No one smoking gun surfaced. Yet putting together all the pieces creates a persuasive picture of willful blindness. (EHN, Nov 2019).

It went on to find, through Freedom of Information Act requests, evidence 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, Nov 2019).

In sum, their investigation revealed: multiple methodological and statistical choices that would reduce the likelihood of finding BPA effects, such as choosing a control animal species known to be insensitive to hormone disruptors and sending inadequate sample sizes to grantee researchers; potential BPA contamination of control animals, which was known by the FDA but unreported; public downplaying of health impacts that were found statistically significant; and potential industry influence, given the FDA’s reliance on industry-funded studies.

The NTP is expected to publish a report in spring of 2020 overviewing the CLARITY BPA findings.  While the debate continues, some researchers, such as reproductive biologist Patricia Hunt, say that the focus should no longer be BPA, since it’s gradually being removed from many plastics products, but instead BPA’s replacements.

With over 50 BPA replacement chemicals, one has to wonder how decades-long scientific and political debates that take a chemical-by-chemical approach can keep up with our regulatory needs.