Evaluating endocrine disrupting chemicals: A perspective on the novel assessments in CLARITY‐BPA

Abstract

BackgroundThe Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY‐BPA) was a collaborative research effort to better link academic research with governmental guideline studies. This review explores the secondary goal of CLARITY‐BPA: to identify endpoints or technologies from CLARITY‐BPA and prior/concurrent literature from these laboratories that may enhance the capacity of rodent toxicity studies to detect endocrine disrupting chemicals (EDCs).MethodsA systematic literature search was conducted with search terms for BPA and the CLARITY‐BPA participants. Relevant studies employed a laboratory rodent model and reported results on 1 of the 10 organs/organ systems evaluated in CLARITY‐BPA (brain and behavior, cardiac, immune, mammary gland, ovary, penile function, prostate gland and urethra, testis and epididymis, thyroid hormone and metabolism, and uterus). Study design and findings were summarized, and a risk‐of‐bias assessment was conducted.ResultsSeveral endpoints and methods were identified as potentially helpful to detect effects of EDCs. For example, molecular and quantitative morphological approaches were sensitive in detecting alterations in early postnatal development of the brain, ovary, and mammary glands. Hormone challenge studies mimicking human aging reported increased susceptibility of the prostate to disease following developmental BPA exposure. Statistical analyses for nonmonotonic dose responses, and computational approaches assessing multiple treatment‐related outcomes concurrently in linked hormone‐sensitive organ systems, reported effects at low BPA doses.ConclusionsThis review provided an opportunity to evaluate the unique insights provided by nontraditional assessments in CLARITY‐BPA to identify technologies and endpoints to enhance detection of EDCs in future studies.

The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA)

“…The EFSA-CEP recognized the value of the combined guideline and academic investigator findings from the CLARITY-BPA project, which unequivocally demonstrated statistically significant adverse effects at levels of BPA below the previous TDI. 26 , 54 , 55 Critically, the FDA rejected the nonguideline findings from CLARITY-BPA. 111 Our proposal is that CLARITY-BPA should serve as a model for integrating 21st century academic research into a hybrid and pluralistic regulatory assessment process for identifying hazards posed by chemicals, as initially envisioned by administrators at the NIEHS and NTP.…”

“… 26 The NTP final report states 112 : “This report does not attempt to integrate the findings or offer interpretation of reported findings.” However, this integration of core guideline and academic hypothesis-driven findings was a primary reason NIEHS initiated CLARITY-BPA, and so it was up to the academic investigators, under the leadership of Dr. Jerrold Heindel, 26 to publish a “data integration” review; CLARITY-BPA has also been reviewed by others. 54 , 55 …”

“…The former FDA Center for Food Safety and Applied Nutrition (CFSAN), along with the EFSA, have in the past taken a very traditional approach in assessing the risks posed by BPA and other EDCs in food and cosmetics. 11 , 55 In contrast to the EFSA-CEP approach in revising the TDI for BPA, the FDA-CFSAN chose to reject inclusion of nonguideline study findings in its assessment of the risks posed by BPA or any other chemical of concern in food, food packaging, or personal care products. 111 , 135 , 143 , 144 As such, FDA-CFSAN rejected the use of all data generated through grants from the US National Institutes of Health (NIH) when the guideline portion of CLARITY-BPA was completed, 144 although NIH-funded research findings are heavily relied on by the FDA Center for Drug Evaluation and Research (FDA-CDER).…”

“…We are concerned that commercial laboratories hired to conduct hazard identifications generally do not have the required expertise to conduct 21st century sophisticated research, which is thus absent from guideline protocols. 55 , 152 It is also not practical for one contract lab to be expected to save all tissues for more detailed molecular analysis using the many techniques available today. This leads us to conclude that the collaborative program based on the CLARITY-BPA model should be accepted as the best approach to incorporate 21st century science into chemical hazard identification.…”

“…Recruiting a number of individual academic investigators, each with extensive expertise studying a specific issue of interest, and many with an advanced knowledge of statistical approaches needed to analyze complex data sets, 26 , 105 to conduct (blinded to treatment) one component of the hazard identification could greatly enhance both hazard and dose–response evaluation. 26 , 55 , 103 …”