https://www.ehn.org/bpa-impact-on-human-health-2641134273.html
[video, images and links in online article]
Nov 15, 2019
Exposed: A scientific stalemate leaves our hormones and health at risk
American industry, aided by federal regulators, is conducting a
large-scale, consequential experiment with our hormones and the
developing brains and reproductive systems of our children.
This is part 1 of a 4-part investigation of the science surrounding
the chemical BPA and the U.S. regulatory push to discredit independent
evidence of harm while favoring pro-industry science despite significant
shortcomings.
SEATTLE — Bisphenol A is likely coursing through your body right now.
Every day, you're inadvertently consuming and absorbing trace amounts as
it migrates from can and bottle linings into your food and drink, and
from thermal paper receipts onto your skin.
Scientists have found BPA in more than 90 percent of Americans tested.
Yet whether exposures to such small amounts of the common chemical pose
any real health hazard remains highly controversial. On one side of a
deep rift are academics who are adamant about the adverse effects; on
the other side are U.S. Food and Drug Administration scientists who
declare there are no dangers. Only one side has any control over what
actually makes its way into your body.
"This is a chasm that is not going to be breached," Daniel Doerge, a
biochemical toxicologist with the FDA for nearly 30 years, said during a
panel at the European Food Safety Authority (EFSA) conference in Parma,
Italy, last September.
Doerge and other federal scientists were attending the conference to
share details of an unprecedented multimillion-dollar project co-led by
the FDA, the Consortium Linking Academic and Regulatory Insights on BPA
Toxicity, or Clarity for short. The effort aims to settle the
long-standing dispute between government and academic scientists over
the health effects of BPA.
Yet Doerge's words did not indicate any hope for such a reconciliation.
He wore a green polo shirt, dark glasses and a grey mustache. And he
exuded frustration — if not also a bit of arrogance — as he spoke.
"Tribal dynamics," he said, are at play among the academics. Doerge
alleged they were creating their "own narrative," and "staying in a
bubble that turns into an echo chamber."
The struggle has been fermenting below the surface for years: Academics
with modern methods and a sophisticated understanding of human
physiology versus government and industry scientists who lean on
decades-old established science in their evaluation of industrial
chemicals. The suite of traditional toxicology tests recommended by the
FDA for assessing a chemical's health risks hasn't been meaningfully
updated since the early 1980s, before Doerge took his job and well
before scientists began to understand how minuscule concentrations of
certain chemicals common in consumer products, such as BPA, could mimic
and mess with hormones in the body.
Scientists have long known that a tiny change in a natural hormone
concentration — the equivalent of one drop of water in 20 Olympic-sized
swimming pools — is enough to trigger instructions via the human
endocrine system that impact growth, metabolism, sleep, reproduction and
other critical functions of the body.
Related: See our comic strip version of this story, "Clouded in Clarity"
BPA is just the tip of the iceberg. Tens of thousands of manufactured
chemicals are on the market; hundreds are believed to be endocrine
disruptors — capable of scrambling hormone signals and, therefore,
raising risks of health problems such as cancer, diabetes, obesity,
infertility and behavioral problems. Other pervasive hormone imposters
include phthalates, which are found in plastic food containers and
personal care products, and per- and polyfluoroalkyl substances (PFAS),
which are added to nonstick cookware and other goods to repel oil and
water. Also on the list are flame retardants and pesticides such as DDT,
glyphosate and chlorpyrifos. Even bisphenol S and dozens of other BPA
replacements have been found to tinker with hormones.
Yet the FDA has remained reluctant to accept new science and independent
evidence of harm. While the agency clings to the claim that BPA poses no
health risks in the amounts it is used, thousands of peer-reviewed
studies from academics suggest otherwise: Absorbing or ingesting the
ubiquitous chemical may harm people at doses 20,000 times lower than
what the FDA says is safe, comparable to levels at which most of us are
exposed.
Even back in 1982, a scientific committee established by the FDA had
warned of the potential for very low concentrations of chemicals to bind
to hormone receptors and that technology in the future might find this
interference alters the endocrine system's influential messages. The
agency continues to miss opportunities to keep pace with scientific
developments, noted Maricel Maffini, an independent consultant based in
Germantown, Maryland. Instead, she told EHN, they primarily rely on
tests devised decades ago that aren't designed to detect some
significant effects that chemicals can have on our health.
If we followed the academics' science, BPA and its close relatives would
effectively have to be banned, not reduced, in order to protect our
health. "Really, if you look at the data, we shouldn't be making these
compounds, period," Terrence Collins, a green chemist at Carnegie Mellon
University, told EHN.
An investigation by EHN has uncovered a pattern of dissonance between
academic scientists and federal agencies, as well as between the
agencies themselves, regarding the evaluation and regulation of BPA and
other endocrine disruptors. No one smoking gun surfaced. Yet putting
together all the pieces creates a persuasive picture of willful
blindness. Based on hundreds of emails obtained via Freedom of
Information Act requests — along with dozens of studies and reports, and
more than 50 conversations with scientists, regulators and other
stakeholders — evidence suggests 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's findings include:
●Insistence by the FDA on a study design that limited Clarity's
robustness to reveal health effects, including the use of a strain of
animal that had been shown to be insensitive to hormone disruptors, the
choice of a stressful means to deliver BPA to the animals, and the
allocation of small numbers of animals provided to some of the
participating academic scientists.
●Potential BPA contamination of the control animals, which may have
further masked true differences in health effects between control
animals and animals receiving administered doses of BPA.
●Statistical approaches in the government's side of Clarity, a
traditional regulatory toxicology study dubbed the Core Study, that set
a high bar to detect differences and disregarded patterns in the data
that did not fit outdated assumptions on the relationship between a dose
of an endocrine-disrupting chemical and its health effects.
●Framing of the government's Clarity Core Study draft report and
corresponding press release that downplayed the health effects that did
emerge in the data.
●Hints of potential industry influence, such as the FDA's reliance on
industry-funded studies.
Clarity, the intended remedy for the government-academics impasse, was
launched in 2012 by the FDA, the National Institute of Environmental
Health Sciences (NIEHS) and the National Toxicology Program (NTP). The
effort combines a traditional regulatory toxicology study from the
government and investigational studies from academics.
The FDA took the lead on raising and treating the study animals and on
performing the Core Study, which was published under the auspices of the
NTP. The NIEHS awarded grants to participating academics and worked with
the NTP to coordinate the study. The government and most of the 14
participating academic scientists completed their respective studies for
the collaborative project in the months preceding the September 2018
EFSA conference in Italy.
Everyone used the same breed of lab rats, and followed
government-approved standards as they investigated possible health
impacts. To prevent bias, all Clarity scientists were blinded to the BPA
exposure levels of the animals and tissues that they received for study.
Earlier in the Italy meeting, Doerge and his federal colleagues
presented the government's Core Study. Once again, they relayed results
that they said generally absolved BPA. They did not discuss findings
from the participating academics. In fact, during the panel, Doerge
seems to dismiss those studies, many of which challenged BPA's safety.
"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," he said. (The FDA did not make Doerge available for an interview.)
Sitting in the audience in Italy was Heather Patisaul, a biologist at
North Carolina State University and one of the academics participating
in the massive BPA study. "I was screaming in my chair," she told EHN.
"He said it so smugly."
An integrated report that pulls all of the Clarity studies together is
underway, co-authored by the FDA and other participants. John Bucher, a
senior scientist with NTP and NIEHS, told EHN that he expects the report
to be completed by the end of this year. It will then be up to the FDA
whether or not those results will spur any reshaping of U.S. regulations.
Several of the academic scientists are concurrently working on their own
independent review of the Clarity data. Cheryl Rosenfeld, a biologist at
the University of Missouri and another Clarity investigator, is among
the co-authors on that report. "Many of us are not happy with the FDA,"
she told EHN, adding that she and others are skeptical of what will end
up in the official integrated report and if it will have any impact on
policy.
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, leaving us all exposed daily
to the chemical. Meanwhile, other countries represented at the EFSA
meeting have begun reaching agreements and acting on BPA.
France has enacted the strictest regulations, banning the use of the
chemical in all food and beverage packaging and utensils after an
assessment by the French Agency for Food, Environmental Health and
Safety determined that it is hazardous at much lower doses than the FDA
considers hazardous. A Danish Food Institute Clarity-like study, too,
recognized effects at low doses.
Many more countries are keeping a close eye on Clarity. EFSA, which is
funded by the European Union to conduct risk assessment but not to
create policy, told EHN that it will consider the results as part of its
ongoing evaluation of BPA. In January 2015, based on the latest
information, EFSA dropped its safety limit from 50 to 4 micrograms of
BPA per day per kilogram of body weight.
The scientific, economic and political stakes are high. For decades,
modern commerce across the Western world has depended on BPA. The
chemical is used in the production of goods that pervade our lives:
reusable water bottles, food containers, canned goods, store receipts,
medical devices and dental sealants. And despite growing concerns, the
manufacturing of BPA remains on the rise. The global BPA market is
increasing about 3 percent per year, and is projected to reach $22.5
billion by 2022 and top 7 million tons by the end of 2023.
"BPA is very cheap to make," said Collins. "I believe the regulatory
bodies of the country are locked up by the monetary implications of
addressing endocrine disruption."
While the clash continues over how endocrine-disrupting chemicals are
tested and thereby regulated, irreversible changes to our bodies and
health may be happening now. Collins pointed to declining sperm counts
and rising rates of endometriosis, which he suggested could be a
consequence of these exposures given that the chemicals have been shown
to induce such effects in animals.
"Endocrine disruptors are harming people and we're not regulating them
to any extent right now," Carol Kwiatkowski, executive director of The
Endocrine Disruption Exchange, a nonprofit research institute that
advocates against the production and use of chemicals that interfere
with healthy hormone function, told EHN.
"A lot of endocrine scientists have been banging their heads against
that wall for a long time and haven't made any progress in changing the
risk assessment process."
It is clear that the FDA is not using modern science in protecting the
public from potentially toxic chemicals. It is also clear that BPA and
other endocrine disruptors threaten to disrupt the status quo of toxic
chemical regulation. "BPA creates a tipping point," Laura Vandenberg, an
environmental health researcher at the University of
Massachusetts-Amherst's School of Public Health, told EHN. "If the FDA
finds out that they have been wrong about BPA — or wrong about how they
evaluate chemicals for safety — that means they are wrong about the
10,000 other chemicals behind BPA in line for the same sort of evaluation."
Vandenberg, who is not involved in Clarity, is among scientists
skeptical that the groundbreaking effort will result in a fair
assessment of BPA. The FDA, she said, has "a vested interest in not
being wrong."
Imposter's poster child
In the 1930s, a British medical researcher discovered that BPA could
mimic the activity of estrogen — a female sex hormone — in the human
body. The chemical was briefly considered for use as a pharmacological
hormone but ultimately lost to another synthetic estrogen,
diethylstilbestrol (DES). While DES was prescribed to millions of
pregnant women over the next 30 years before its own health risks became
known, BPA was never turned into a drug.
Its future would instead be in the chemical industry.
Beginning in the 1950s, BPA became a key ingredient in polycarbonate
plastic and epoxy resins — finding its way into everything from
Tupperware to the lining of food cans. "That's where the problem
starts," Ana Soto, an endocrinologist at Tufts University and another
Clarity investigator, told EHN.
The FDA officially approved BPA for use in food and beverage containers
in 1963. They classified it as a "generally regarded as safe" (GRAS)
compound, since it had already been around for a few years and there was
no obvious evidence of harm. By the late 1980s, the U.S was producing
nearly a billion pounds of BPA a year. Even scientific laboratories
began working with BPA-laden instruments. In 1993, endocrinologists at
Stanford University discovered that BPA was leaching from polycarbonate
flasks in their laboratory.
The first published studies to raise concern about BPA's low-dose health
effects came a few years later, in 1997. Frederick vom Saal and his
colleagues had found exposure to tiny amounts of BPA altered the
prostates and reproductive systems of laboratory mice. Vom Saal, a
professor of biology at the University of Missouri-Columbia and another
Clarity investigator, warned viewers in a February 1998 episode of PBS's
Frontline about the threat posed by endocrine-disrupting chemicals used
in plastics and other consumer products.
"We understand now, with new techniques, that, in fact, cells are
extremely responsive to these chemicals," vom Saal stated on the show.
"What you have now is clearly enough scientific information to warrant
concern and a change in the regulatory approach to these chemicals."
Concern grew, as did the body of research.
By 2008, enough evidence had accumulated that the NTP labeled the
chemical as possibly harmful for babies. Canada responded by declaring
BPA toxic and manufacturers across North America, including baby bottle
and sippy cup makers, started phasing it out of their products.
Wal-Mart, REI, Lululemon, Toys-R-Us and other retailers, too, began
pulling products with BPA off their shelves. The market was soon flooded
with BPA-free products — although most of the substitutes that landed in
stores share similar chemistry with BPA and pose similar health concerns.
"The science is growing exponentially. We can't keep up with it," said
Kwiatkowski, of The Endocrine Disruption Exchange. "And we have to take
it all very seriously, because the preponderance of endocrine-related
disorders in humans today is just skyrocketing."
Pregnant women, infants and young children face the greatest risks, as a
healthy functioning endocrine system is especially critical during
development. "If you perturb it, it is not going to be reversible,"
Linda Birnbaum, former director of the NIEHS and the NTP, told EHN.
"Whatever happens, it is done."
In-utero BPA exposure, for example, may derail the normal growth of the
brain and other organs and manifest later in life as early puberty or an
increase in anxiety-related behaviors or attention deficit hyperactivity
disorder (ADHD).
And, again, BPA is just one of many chemical threats to our hormones. We
are exposed daily to a cocktail of stuff suspected of altering our
endocrine system. "When we talk about endocrine-disrupting chemicals, it
might be that the real story is in the mixture," Chris Gennings, the
director of biostatistics and an environmental medicine researcher at
the Icahn School of Medicine at Mount Sinai in New York, told EHN. While
the level of exposure to any single chemical might not surpass a safety
threshold, she explained, "if you put all of them together, then the
mixture can reach a level of concern."
It is not only the potential health consequences that are leading many
scientists to urge a more substantial overhaul of the testing and
oversight of endocrine-disrupting chemicals. There are economic
concerns: In 2014, researchers conservatively estimated that just the
cases of childhood obesity and adult heart disease attributable to BPA
cost the U.S. $3 billion annually. A 2016 study that considered a few
endocrine-disrupting chemicals and a few specific diseases calculated an
annual $340 billion in U.S. health costs and lost wages — or about 2.3
percent of the GDP. (Editor's note: Pete Myers, CEO and chief scientist
of Environmental Health Sciences, was a co-author on the paper. He is
also the founder of EHN, though the publication is editorially independent.)
"This is an underestimate of an underestimate of an underestimate," Dr.
Leonardo Trasande, a researcher at New York University, author of the
book, Sicker, Fatter, Poorer, and an author on both studies, told EHN.
Trasande noted his initial hope that Clarity would result in "progress
toward a consensus" on methods to evaluate BPA. But the FDA, he said,
"has taken the approach that its science and its mindset are superior to
that which has been published in peer-reviewed scientific literature."
Maurice Whelan, head of the Chemical Safety and Alternative Methods
Unit of the Directorate for Health, Consumers and Reference Materials of
the European Commission's Joint Research Center, shared similar thoughts
while sitting next Doerge on the panel in Italy. Clarity was
"institutionally biased," he said, with "the science strategy dictated"
and a "very clear mindset about how to go about this."
Recipe for a poison
Core to the discord is a historical assumption about toxic chemicals.
Nearly 500 years ago, Swiss physician and chemist Paracelsus coined an
adage that would become a basic principle of toxicology: "The dose makes
the poison." In other words, the higher the concentration of a toxic
chemical, the more toxic it is.
The FDA generally assumes this increasing-dose-increasing-harm
relationship in its evaluation of chemicals that come into contact with
food, whether directly or indirectly through production, processing,
packaging and distribution. A dose-response curve should therefore
always be monotonic, according to the agency, meaning it will never
change direction from positive to negative, or vice versa.
As a result, when the agency deems a dose of a chemical safe, their
investigation has not necessarily tested health effects at that dose —
or at any lower doses. Rather, industry and government scientists
typically follow 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
conservatively "safe" exposure limit.
Endocrinologists, on the other hand, expect craziness in their data. At
least for hormone-mimicking chemicals, a relatively high dose might
prove innocuous while a far lower dose wreaks havoc on the body. And
they've observed that different doses can cause different effects. Such
a non-monotonic dose-response curve might take the shape of a "U" or a
bell. Take, for example, a 1997 paper co-authored by vom Saal. At 200
nanograms of DES per gram of body weight per day, the prostates of the
mice in his study were significantly smaller than prostates in the
control mice and prostates in mice receiving other doses.
At a mid-range of 20 nanograms of DES, no effect was seen. And that,
under traditional toxicology, is where regulators would stop testing.
But drop the dose further, to 2.0, 0.2 and 0.02 nanograms, and vom Saal
found prostates were significantly larger than prostates in all of the
other animals. The resulting dose-response relationship resembled a bell.
"What we've learned from literally tens of thousands of papers, is that
endocrine activity is stimulated by very tiny quantities of endocrine
hormones," said Collins, the green chemist. "If you raise the
concentrations, you turn the effect off."
His guess as to why: "Nature has decided it doesn't want to have an
overreaction to an endocrine hormone."
Birnbaum compared the phenomenon to the body's response to vitamins and
minerals, where "too little is a problem and too much is a problem." And
scientists have identified potential biological mechanisms for
non-monotonic dose-responses, such as opposing effects from multiple
hormone receptors.
Still, others push back on the notion of non-monotonicity. "It's
illogical. It flies in the face of every mechanism we know in science,"
Patrick McKnight, a measurement scientist at George Mason University in
Fairfax, Virginia, told EHN. "In toxicology you really have to
demonstrate that there's an effect of some sort, and I think a lot of
these investigators are searching for these effects." (McKnight is on
the advisory board at Sense About Science USA, formerly the Statistical
Assessment Service, which has industry ties and a record of downplaying
the dangers of products.)
Steven G. Hentges, senior director of the Polycarbonate/BPA Global Group
at the American Chemistry Council, an industry trade group, stated that
"experimental evidence" to support non-monotonic dose-response has been
"limited." He pointed to a recent European review that supported that
view. Of 179 datasets evaluated in the paper, the authors concluded that
only 10 met criteria for a non-monotonic dose response. They
acknowledged difficulty in identifying relevant studies and applied
strict rules for inclusion in the review, including a requirement that
studies include at least five dose groups. This is rare. Even guidelines
for traditional regulatory toxicology studies recommend just three dose
groups.
The FDA, meanwhile, has stuck to its guns, repeatedly dismissing data on
low-dose effects or non-monotonicity. Marianna Naum, an FDA
spokesperson, told EHN in an email that the FDA and other federal
agencies have determined that non-monotonicity "is not often found in
toxicology of the endocrine system," and that "current regulatory
testing methods are sufficient" to pick it up. (EHN tried for months
through multiple emails and phone calls to arrange a phone interview
with someone at the FDA. The agency repeatedly ignored and denied those
requests.)
The agency also has a history of brushing off study results because they
did not fit its strict study criteria adopted in the 1980s to calculate
doses of chemicals that are expected to be safe for humans. These
traditional "guideline" studies, as they are called, follow validated
"good laboratory practice" (or GLP) protocols. Together, the rigorous
study guidelines and lab rules dictate the number and type of animal
used, levels of exposure to the chemical of interest, the outcomes to
evaluate and record-keeping methods, among other details. And these
studies remain the evidence preferred by the FDA, because they "provide
risk assessors and risk managers with reproducible results upon which
science-based decisions and policy may be based," Naum stated in the email.
Jennifer Sass, a senior scientist with the Natural Resources Defense
Council, said that the guidelines are "a good starting point to see if
there's evidence of harm," and "allow regulators from Japan to Sweden to
North Africa to look at data the same way." However, she added, these
guidelines "should not be used to eliminate evidence of harm."
Such standardized studies can also be pricey to conduct, often beyond
the budgets of academics. And the FDA's traditional targets for tests,
such as weighing organs and looking for other overt signs of toxicity,
generally do not consider the unique effects of endocrine-disrupting
chemicals — some of which can be subtle such as behavioral changes or
infertility years down the road.
"You can't weigh a brain to find out what is going on in there," Soto said.
In 2001, the NTP appeared to agree. They concluded in a report that
published studies had provided evidence for the effects of BPA exposure
at or below the safety standard set by the FDA. And they recommended a
reconsideration of the current testing paradigm.
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