Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Abstract

Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5μg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically-and toxicologically-relevant.

A comprehensive review on the carcinogenic potential of bisphenol A: clues and evidence

“…A study by Prins and co-workers in 2018 using NCTR, Sprague-Dawley cesarean-derived rats, and prostate epithelial cells proposed that BPA exposure can increase the risk of aging-associated cancers such as PC (Prins et al 2018 ). To have better clarity on the CLARITY-BPA studies’ findings, Heindel and co-workers consolidated the findings of various studies (Heindel et al 2020 ). The same report proposes that BPA exposure during development can adversely affect multiple organs’ functioning (Heindel et al 2020 ).…”

“…To have better clarity on the CLARITY-BPA studies’ findings, Heindel and co-workers consolidated the findings of various studies (Heindel et al 2020 ). The same report proposes that BPA exposure during development can adversely affect multiple organs’ functioning (Heindel et al 2020 ). Besides, as per the CLARITY-BPA core study, BPA at a dose of 2.5 μg/kg/day induced adenocarcinoma of the mammary gland.…”

Scientific discrepancies in European regulatory proposals on endocrine disruptors—REACH regulation quo vadis?

“…Thus the analysis by the NTP could not confirm the low-dose NMDR hypothesis for BPA even with the most thorough repeated-dose and chronic studies ever done on BPA and analyzing a comprehensive range of classical toxicological endpoints. (ii) The laboratories testing non-guideline endpoints found mixed results, some claiming evidence of low-dose NMDR (Heindel et al 2020). The claimed NMDR occurred at different doses, depending on the endpoint, and had W-, Z-or U-forms-in most cases individual doses anywhere in the dose range showed a signal which was considered biologically relevant by the authors, although from a traditional statistical viewpoint, these curves would rather be interpreted as spurious or erratic.…”

“…(See also below about the EFSA opinion on NMDR for CLAR-ITY-BPA). Some high-level comparison to previous studies was given in Table 5 in the recent review on the studies investigating non-guideline endpoints (Heindel et al 2020), however this Table indicated whether effects at any dose on an organ were seen, not whether the same dose triggered the same effect on the same measurement parameter as observed before. Although the CLARITY-BPA study was conducted blinded, some of these assessments are post hoc analyses after un-blinding.…”

NTP Research Report on the Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA): A Compendium of Published Findings

“…In addition, Camacho et al (2019) presented a summary of the core study data but included a more expansive discussion of the FDA's conclusions. An integrated analysis of findings from eight CLARITY-BPA grantee studies has also been published (Heindel et al 2020); however, this paper is not summarized in this report.…”