CLARITY‐BPA academic laboratory studies identify consistent low‐dose Bisphenol A effects on multiple organ systems

Abstract

Bisphenol A (BPA) is a high-production chemical used in a variety of applications worldwide. While BPA has been documented as an endocrine-disrupting chemical (EDC) having adverse health-related outcomes in multiple studies, risk assessment for BPA has lagged due to reliance on guideline toxicology studies over academic ones with end-points considered more sensitive and appropriate. To address current controversies on BPA safety, the United States National Institute of Environmental Health Sciences (NIEHS), the National Toxicology Program (NTP) and the Food and Drug Administration (FDA) established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) using the NCTR Sprague-Dawley rats. The goal of CLARITY-BPA is to perform a traditional regulatory toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies by academic laboratories focused on previously identified BPA-sensitive organ systems (Academic studies). Combined analysis of the data from both study types will be undertaken by the NTP with the aim of resolving uncertainties on BPA toxicity. To date, the Core study has been completed and a draft report released. Most of the academic studies have also been finalized and published in peer-reviewed journals. In light of this important milestone, the PPTOX-VI meeting held in the Faroe Islands, 27-30 May 2018 devoted a plenary session to CLARITY-BPA with presentations by multiple investigators with the purpose of highlighting key outcome. This MiniReview synthesizes the results of three academic studies presented at this plenary session, evaluates recently published findings by other CLARITY-BPA academic studies to provide an early combined overview of this emerging data and places this in the context of the Core study findings. This co-ordinated effort revealed a plethora of significant BPA effects across multiple organ systems and BPA doses with non-monotonic responses across the dose range utilized. Remarkably consistent across most studies, including the Core study, are low-dose effects (2.5, 25 and 250 μg BPA/kg body-weight). Collectively, the findings highlighted herein corroborate a significant body of evidence that documents adverse effects of BPA at doses relevant to human exposures and emphasizes the need for updated risk assessment analysis.

Flaws in design, execution and interpretation limit CLARITY‐BPA’s value for risk assessments of bisphenol A

“…Regarding the low‐dose issue, Dr. Delclos' conclusion is based on the assumption by FDA toxicologists that if an effect of BPA is found at a low dose within the range of human exposure, but the same effect is not found to consistently increase or decrease across a 10,000‐fold dose range, then the toxicological maxim “the dose makes the poison” has not been confirmed and the statistically significant low‐dose results can be declared of no biological significance. Specifically, a number of adverse effects were seen in the lowest (2.5 µg/kg/day) dose group in the FDA's guideline portion of CLARITY‐BPA, consistent with effects observed in a number of the studies conducted by the academic investigators; reviewed in Prins et al The FDA ignored their core‐experiment findings concerning mammary adenoma/adenocarcinoma, uterine stromal polyps, plus significant increases in prostatic inflammatory disease at low doses of BPA. These findings should not be ignored, nor should related findings of low‐dose effects in studies conducted by the academic investigators.…”

“…The FDA has not been willing to acknowledge the importance of these low‐dose findings to the public health . Other publications reviewing the low‐dose CLARITY‐BPA findings by the academic investigators, together with the FDA core guideline study results, discuss the implications of these findings for BPA risk assessments in more detail . However, given the design and execution flaws in CLARITY‐BPA, it is not surprising that some prior findings from studies by academic investigators, that had been conducted with appropriate animal models sensitive to environmental oestrogens, with different exposure methods and with appropriate negative controls, were not replicated in CLARITY‐BPA.…”

“…26 There also appeared to be effects on body-weight due to daily gavage in the CLARITY-BPA study. 39,40 Since the FDA restrained and gavaged all negative controls every day, there was no actual true "negative control" group in CLARITY-BPA. The stress response that daily gavage could trigger might also obscure aspects of the endocrine disrupting effects that low doses of the positive control, EE2, has repeatedly been shown to cause.…”

“…57 This declaration ignores significant findings of adverse effects at low doses of BPA in both their FDA core study 1,58 and many of the published studies from the academic collaborators. 39,40,[59][60][61][62][63][64][65][66] Given the attempt by the FDA to use their CLARITY-BPA core studies as the sole basis for assessing the safety of BPA, 57,58 the flaws identified above and discussed in detail in this review need to be considered in evaluating this FDA pronouncement of BPA safety. 57 Subsequently, in an FDA Grand Rounds webinar on 13 September 2018, the FDA official in charge of the guideline portion of CLARITY-BPA, Dr Barry Delclos, presented the position on BPA of the FDA that they have been promoting for the last decade, as if the approximately 15-million-dollar academic investigator portion of CLARITY-BPA had not occurred.…”

Development priority

“…The CLARITY‐BPA project in the United States brought together regulatory (Food and Drug Administration) and academic scientists to assess developmental and life‐time BPA exposures in rats treated at a common facility and consistent study design across a range of tissue end‐points and organ systems. However, discrepant results, weaknesses of the study protocol and disagreement on interpretation of the results make this effort a questionable success . Although this nascent collaboration may still lead to better co‐ordination between academic and agency research, a remaining issue is the focus.…”