By Wei Kun, CNCIC
Dr. Steven Hentges is the Executive Director of the Polycarbonate/BPA Global Group of the American Chemistry Council (ACC) and has been deeply involved with the science on health & environment aspects of bisphenol A for almost 20 years.
CCR: Could you give us a brief introduction on what the US and EU authorities have done to clarify the safety of BPA?
Steven: Bisphenol A (BPA) has been a hot topic for almost 20 years, primarily because some scientists claim that BPA is harmful to our health, even at the very low levels of exposure that we may experience as consumers. Large-scale studies that follow internationally accepted testing guidelines, conducted by government agencies and industry, consistently show that BPA has low toxicity and is not likely to be harmful.
In contrast, a diverse range of small-scale, exploratory studies conducted by academic scientists suggest that BPA may cause health effects at low doses. However, these studies do not follow accepted testing guidelines and generally report inconsistent results.
In response, many regulatory agencies around the world have conducted safety assessments that include comprehensive reviews of all relevant studies. Based on their reviews, most regulatory agencies support the safety of BPA, in particular at current very low exposure levels.
For example, on its website the U.S. Food and Drug Administration (FDA) summarizes the conclusion of its assessment with the question “Is BPA safe?” and an unambiguous answer – “Yes.” Similar conclusions have been reached by other agencies around the world. Nevertheless, the controversy has continued. To finally resolve the controversy, FDA scientists developed a comprehensive research program to answer open questions and resolve uncertainties about the safety of BPA. All of this research was government funded and conducted by government scientists.
CCR: Could you give us some details on government funded research?
Steven: The FDA scientists realized that research in two areas was needed to reach a clear conclusion on the safety of BPA. First is information on how BPA is processed in the body, including both humans and rodents, which are used for toxicity studies. This information is needed to quantitatively compare doses of BPA across species, at different dose levels and routes of exposure. To reach this goal, FDA scientists have now conducted a wide range of pharmacokinetic studies of BPA with results all published in the scientific literature. Included are studies in rodents, non-human primates and even in human volunteers. From these studies we know that BPA is efficiently converted to an inactive metabolite, which is rapidly eliminated from the body. This information supports the prediction that BPA is not likely to be harmful, in particular at low doses.
To test this prediction, FDA needed reliable information on the toxicity of BPA. Toxicity studies must meet FDA’s rigorous standards for use in making regulatory decisions and must be capable of addressing claims that BPA acts as a synthetic hormone. A series of studies have now been conducted, most notably a large-scale subchronic toxicity study in rats that involved exposure of rats to BPA during their developmental period, from pregnancy to 90 days after birth. This study confirmed the prediction that BPA is not harmful at low doses.
To complete the research program, a final study known as CLARITY-BPA was conducted.
CCR: What is it CLARITY-BPA?
Steven: The name CLARITY is an acronym that refers to a consortium of scientists from FDA, the U.S. National Toxicology Program, the U.S. National Institute of Environmental Health Sciences and a group of academic scientists. This consortium designed a lifetime toxicity study of BPA in rats similar to the subchronic study with exposure to BPA beginning during pregnancy, but with exposure then continuing through the lifetime of the offspring.
The CLARITY Core Study was conducted by FDA scientists and followed accepted testing guidelines. In addition, the academic scientists were given grants to conduct additional studies on animals from the Core Study, similar to smaller scale studies they had previously conducted. The overall objective was to determine in a single high-quality study if these additional academic studies provide critical information beyond what was provided in the Core Study.
A study of this scope and magnitude has never been conducted before for BPA. Since the study was first announced about five years ago, regulatory agencies around the world have been waiting for the results to reach final conclusions on the safety of BPA.
CCR: Why is CLARITY-BPA so important?
Steven: Nothing like the CLARITY-BPA study has ever been conducted. Not only does it include a large-scale study conducted according to internationally accepted testing guidelines and with Good Laboratory Practices (GLP), but it also includes additional studies conducted by academic scientist according to their practices.
The overall study was designed by a large consortium of government and academic scientists. Most of the academic scientists have been critics of the safety of BPA. The combination of the guideline and academic components all in the same study will bridge between these two types of research and allow a final, definitive conclusion on the safety of BPA.
CCR: How was CLARITY-BPA Core Study designed and conducted?
Steven: The study was conducted in the Sprague-Dawley (SD) rat, which is a well-understood experimental animal commonly used in the FDA laboratory. Importantly the SD rat has been shown in previous studies to be sensitive to effects caused by estrogens, which is one of the key requirements initially set by FDA.
The rats were exposed to BPA beginning in pregnancy with exposure continuing throughout the lifetime of the rats, which is approximately two years. In addition to the negative control animals with no exposure, groups of rats were exposed to a wide range of five BPA doses and to two doses of a reference estrogen known as EE2 (ethinyl estradiol). The lowest BPA dose is at the upper end of potential human exposure and the highest dose is about 250 000 times higher than typical human exposure. The purpose for EE2 is to demonstrate that the SD rats in this study are in fact sensitive to estrogenic effects. This helps to validate the study for BPA, which is known to be weakly estrogenic.
All animals for the Core Study and for the academic studies were dosed and handled in exactly the same way in the same facility. The diet for all animals was monitored for BPA to be sure that the results would not be confounded by accidental BPA contamination. For the Core Study, animals were sacrificed and evaluated at the 1-year (interim) and 2-year (terminal) time points.
An important feature of the academic studies is that all animals were provided in coded form, meaning that the researchers did not know the dose group from which each animal came. Only after uploading their raw data into an NTP database were the researchers given information to identify dose groups and only at that time were the researchers able to conduct statistical evaluations of their data to determine outcomes. The purpose of this elaborate procedure was to eliminate researcher bias, which could occur based on researcher expectations of what would happen in the study.
The results of the Core Study, which was conducted by FDA scientists, were released in the form of a draft report in February 2018. The study, along with public comments on the draft report, was then peer-reviewed by a panel of six independent scientists, none of which had been involved with the study or had previously been involved with BPA.
The peer-review panel discussed their findings in a public meeting in April 2018. In general, the panel endorsed the design and execution of the study as well as FDA's interpretation of the results. Their recommendations to improve the report were then incorporated into a final CLARITY Core Study report, which was released at the end of September 2018.
CCR: What are the results and conclusions of the Core Study?
Steven: The overall conclusion of the CLARITY Core Study indicates that BPA did not cause significant effects, in particular at the low doses of most relevance for human exposure. Importantly, and in contrast to BPA, the highest dose of EE2 “elicited several estrogenic effects in females in a clearly interpretable and biologically plausible manner”. This result helps to validate the study for BPA by demonstrating that the animals were sensitive to estrogenic effects. If BPA were causing estrogenic effects, they would have been found in the study.
The results of the study were clearly interpreted by the study’s Principal Investigator:
“In the study authors’ judgment of the results from the CLARITY-BPA 2-year core toxicology study, BPA did not elicit clear, biologically plausible, adverse effects, particularly below 25 000 μg BPA/kg bw/day.”
In simple terms, BPA did not cause any significant effects at doses even remotely close to actual human exposure. This finding again confirms the prediction from pharmacokinetic studies that BPA is not likely to be harmful, and provides strong support for the safety of BPA.
These results led FDA to release a statement when the draft report was released in February. Importantly the statement came from a Deputy Commissioner, which is the highest level of FDA and indicates the significance of the study in FDA’s view.
“Our initial review supports our determination that currently authorized uses of BPA continue to be safe for consumers” (Dr. Stephen Ostroff, Deputy Commissioner for Foods and Veterinary Medicine).
CCR: Could you give us some information on the other part of CLARITY-BPA, the academic studies?
Steven: As part of the CLARITY program, 13 grants were given to academic scientists to conduct additional studies on animals from the CLARITY Core Study. Most of the grantees have previously conducted research on BPA and have been critical of the safety of BPA. To date, results from only five of the grants have been published. These results seem to be generally comparable to what FDA found in the Core Study itself.
Importantly, all raw data from the academic studies has now been released. Whether the academic scientists publish their findings or not, others will be able to download and analyze the data. In addition, NTP plans to integrate all data from the CLARITY study and issue a final report in about a year from now.