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.
Subject(s)
Benzhydryl Compounds/toxicity , Ecotoxicology/standards , Endocrine Disruptors/toxicity , Environmental Pollutants/toxicity , Phenols/toxicity , Prenatal Exposure Delayed Effects/prevention & control , Animals , Congresses as Topic , Disease Models, Animal , Ecotoxicology/methods , Environmental Exposure/adverse effects , Female , Fetal Development/drug effects , Guidelines as Topic , Humans , National Institute of Environmental Health Sciences (U.S.)/standards , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Rats, Sprague-Dawley , Risk Assessment/methods , Risk Assessment/standards , Toxicity Tests/methods , Toxicity Tests/standards , United States , United States Food and Drug Administration/standardsABSTRACT
The Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) involved the Food and Drug Administration, the National Toxicology Program and 14 academic investigators funded by the National Institute of Environmental Health Sciences. Two key questions to be answered by CLARITY-BPA were as follows: (1) Would the academic investigator studies show effects at low doses of bisphenol A (BPA) while the core guideline study conducted by the FDA only showed toxic effects at high doses? (2) Would the academic investigators be able to replicate their numerous prior studies with animals raised and treated in the FDA's toxicology centre? Several flaws in the design and execution of CLARITY-BPA biased the experiment towards not finding significant results (Type 2 error): (1) use of the oestrogen-insensitive NCTR CD-SD rat, (2) use of a stressful daily gavage BPA administration procedure throughout life, (3) lack of inclusion of non-gavaged negative controls and (4) lack of a comprehensive examination of animals for BPA contamination. In spite of these flaws, in some of the experiments conducted by CLARITY-BPA academic investigators, and also in the FDA's core study, there were significant low-dose effects, but these were ignored by the FDA. Thus, immediately after releasing the results from their core portion of CLARITY-BPA, the FDA issued a statement concluding BPA was "safe," and they ignored non-monotonic dose-response relationships. The FDA should not base its BPA risk assessment only on outdated guideline studies, but instead on the vast (~8000) number of publications documenting the similar health hazards BPA poses to animals and humans.
Subject(s)
Benzhydryl Compounds/toxicity , Disease Models, Animal , Endocrine Disruptors/toxicity , Environmental Pollutants/toxicity , Phenols/toxicity , Research Design , Animals , Ecotoxicology/methods , Ecotoxicology/standards , Environmental Exposure/adverse effects , Female , Fetal Development/drug effects , Guidelines as Topic , Humans , National Institute of Environmental Health Sciences (U.S.)/standards , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/prevention & control , Rats, Sprague-Dawley , Risk Assessment/methods , Risk Assessment/standards , Toxicity Tests/methods , Toxicity Tests/standards , United States , United States Food and Drug Administration/standardsABSTRACT
Animal models serve an important role in assessing preclinical safety and efficacy of new medicines and vaccines; however, such assessments can involve significant pain and distress and large numbers of animals. Best practice approaches seek to enhance animal well-being, minimize or avoid pain and distress, and use fewer animals. Advances in science and technology are providing opportunities for improved mechanism-based models and integrated safety assessments that will support improved animal welfare and reduce animal use.
