The FDA On BPA Safety
By Steve Hentges | February 28th 2014 04:30 AM| Steve Hentges

In June 2013, the U.S. Food and Drug Administration (FDA) answered the question “IsBPA safe?” with a simple and unambiguous answer – “Yes.”

In contrast, countless words have been written over many years suggesting exactly theopposite.

To get to that straightforward answer, FDA initiated an in-depth research and testing
program on bisphenol A (BPA) about five years ago.

Although there is more to come, the 15 studies publishedso far, most recently including one of the mostcomprehensive studies on BPA ever conducted, provide
strong support for that one-word answer.

C15H16O2 - bisphenol A. Credit and link: Chemspider
A Short History of the BPA Controversy
It’s well known that the common chemical BPA is weakly estrogenic with potency about
4-5 orders of magnitude lower than estradiol as measured in various in vitro studies(e.g., cell culture studies). The key question is whether that biological characteristic
has any in vivohealth significance for people exposed to BPA, in particular could BPAexposure cause adverse human health effects? Controversy about the potential for
BPA to cause health effects goes back to the late 1990’s when several small-scalestudies on laboratory animals reported effects from relatively low doses of BPA.

Since those initial studies, research on BPA has grown exponentially from a cottage

industry into a full-scale endeavor with researchers around the world conducting anincreasingly diverse array of studies.

By 2008, after more than 10 years and thousands of studies, scientific debate
continued and FDA’s National Center for Toxicological Research (NCTR) took
on the issue. Beginning in 2008, NCTR scientists working in conjunction withthe U.S. National Toxicology Program (NTP) designed a program of “in-depthstudies to answer key questions and clarify uncertainties about the risks ofBPA.”
The results from that well-designed program have now gone a long way towards
answering the key question. To date, NCTR scientists have published 15 papers in thepeer-reviewed scientific literature, with more to come.

Although 15 papers may seem like a small drop in the ocean of research on BPA (arecent PubMed search on ‘bisphenol A’ identified 8,108 citations), the quality of thedata speaks volumes.
Potential Toxicity of BPA Dictated by Its Pharmacokinetic Properties
For any substance, the potential to cause toxicity (or for a drug to provide beneficial
therapeutic effects) is substantially impacted by its pharmacokineticproperties. Pharmacokinetic data describe how a substance is absorbed into the body,
how it’s distributed and in what form (e.g., parent compound or metabolites), how longit lasts in the body, and how it’s eliminated.

Data of this type is quite useful for the design and interpretation of toxicity studies, andcan also be used to construct physiologically based pharmacokinetic (PBPK) modelsto
evaluate exposure scenarios beyond the specific doses studied experimentally.

Accordingly, pharmacokinetic data is particularly useful in evaluating the safety of achemical.

Building on earlier pharmacokinetic studies, FDA designed a coherent set of in-depth
studies to confirm and refine existing knowledge, as well as to specifically examine
several important and contentious issues. In general, these studies
in rodents and non-human primates confirm that BPA is rapidly metabolized andeliminated from the body by adult animals. It does not accumulate in the body and, inparticular, does not accumulate in fat.
Whereas BPA itself is weakly estrogenic, in the body it is metabolized primarily to BPAglucuronide, which is readily excreted in urine and, importantly,is not estrogenic. Since
BPA is efficiently metabolized in the gastrointestinal tract and in the liver, systemic
exposure to BPA through the bloodstream is extremely low after oral exposure, whichis how we are typically exposed to BPA through the diet. Recently a research teamfrom FDA and the Pacific Northwest National Laboratory analyzed systemic exposure
to BPA and concluded that BPA has “limited or no potential for estrogenicity inhumans.”
Much of the controversy about BPA has focused on the potential for health effects fromexposure during developmental stages, including gestation, infancy andchildhood. FDA’s research found that fetal exposure to BPA is limited by efficientmaternal metabolism while fetal capability to metabolize BPA increases throughoutgestation. In addition, the placenta has been shown to be metabolically active with noevidence for conversion of BPA-glucuronide back to BPA.

In contrast to rodents, non-human primates just after birth have the capability tometabolize BPA similar to adults.
Taken together, these results predict that typical human exposure to BPA is unlikely tocause adverse health effects at any age, including infants and young children. As ahypothesis, that prediction is now being tested experimentally by FDA researchers.

Credit and link: Fooducate.
Predicted Low Toxicity Confirmed in Large-Scale Study
Most recently, FDA researchers published the results of what may be the largestscale toxicity study ever conducted on BPA. In this study rats were exposed to BPA
during gestation and continuing through 90 days after birth, which covers all
developmental stages. The study examined seven low doses of BPA, which were theprimary focus of the study, along with two high doses of BPA, two doses of a known
estrogen (ethinyl estradiol, or EE2), and a negative control.

Notably, no effects were found at any of the seven low doses, which are of mostimportance for evaluating the safety of BPA.
Previous studies in the same laboratory have shown that the specific strain of rat usedin this study is sensitive to estrogenic effects. As expected, the two EE2 doses did
induce multiple effects that are consistent with the previous studies. The two highdoses of BPA also induced effects of the type reported in earlier studies on BPA,
indicating that the strain of rat is also sensitive to BPA. The observed and expected
effects from EE2 and the high doses of BPA validate that the study was sensitive andresponsive to BPA and estrogenic effects.

The toxicity study also included extensive measurements of the blood levels of BPA,
EE2 and endogenous estradiol in the test animals. These data provide strong support
for the biological plausibility of the observed effects from EE2 and the high doses ofBPA and, most importantly, the lack of effects at the low doses of BPA. Only EE2 andthe two high doses of BPA provided sufficient estrogenicity for potential health effects,
as was observed. Conversely, the level of BPA in blood at the low doses would have
low potential to cause estrogenic effects, also as observed.
So what does it all mean? Overall, the results “both support and extend the conclusionfrom the U.S. Food and Drug Administration that BPA is safe as currently used,” said
Daniel Doerge, one of the key FDA scientists conducting the studies at NCTR, ina recent interview with NPR's Jon Hamilton.
There’s More to Come
The FDA/NTP research program continues with several important studies now
underway. As a follow-up to the subchronic study just published, FDA is now
conducting a chronic study that examines five low doses of BPA with exposure startingin pregnancy and continuing for approximately two years. Similar to thepharmacokinetic studies conducted in laboratory animals by FDA, NTP is now
conducting pharmacokinetic studies on human volunteers.

These studies will provide important information to bring closure to the ongoing
controversy about the safety of BPA.
For the time being though, the extensive data published so far provides strong
support for FDA’s current perspective: “Is BPA safe? Yes.”