University of Missouri - Columbia, Division of Biological Sciences, Columbia, Missouri.
University of Massachusetts - Amherst, Department of Environmental Health Sciences, Amherst, Massachusetts.
Endocrinology. 2021 Mar 1;162(3). doi: 10.1210/endocr/bqaa171.
In 1997, the first in vivo bisphenol A (BPA) study by endocrinologists reported that feeding BPA to pregnant mice induced adverse reproductive effects in male offspring at the low dose of 2 µg/kg/day. Since then, thousands of studies have reported adverse effects in animals administered low doses of BPA. Despite more than 100 epidemiological studies suggesting associations between BPA and disease/dysfunction also reported in animal studies, regulatory agencies continue to assert that BPA exposures are safe. To address this disagreement, the CLARITY-BPA study was designed to evaluate traditional endpoints of toxicity and modern hypothesis-driven, disease-relevant outcomes in the same set of animals. A wide range of adverse effects was reported in both the toxicity and the mechanistic endpoints at the lowest dose tested (2.5 µg/kg/day), leading independent experts to call for the lowest observed adverse effect level (LOAEL) to be dropped 20 000-fold from the current outdated LOAEL of 50 000 µg/kg/day. Despite criticism by members of the Endocrine Society that the Food and Drug Administration (FDA)'s assumptions violate basic principles of endocrinology, the FDA rejected all low-dose data as not biologically plausible. Their decisions rely on 4 incorrect assumptions: dose responses must be monotonic, there exists a threshold below which there are no effects, both sexes must respond similarly, and only toxicological guideline studies are valid. This review details more than 20 years of BPA studies and addresses the divide that exists between regulatory approaches and endocrine science. Ultimately, CLARITY-BPA has shed light on why traditional methods of evaluating toxicity are insufficient to evaluate endocrine disrupting chemicals.
1997 年，内分泌学家进行的首例体内双酚 A（BPA）研究报告称，以 2μg/kg/天的低剂量给怀孕小鼠喂食 BPA，会导致雄性后代出现不良生殖效应。从那时起，数千项研究报告称，低剂量 BPA 会对动物产生不良影响。尽管有 100 多项流行病学研究表明 BPA 与疾病/功能障碍之间存在关联，这些研究也在动物研究中得到了报道，但监管机构仍坚称 BPA 暴露是安全的。为了解决这一分歧，CLARITY-BPA 研究旨在评估同一组动物中传统毒性终点和现代基于假设的、与疾病相关的结果。在测试的最低剂量（2.5μg/kg/天）下，毒性和机制终点都报告了广泛的不良影响，这导致独立专家呼吁将最低观察到的不良效应水平（LOAEL）从目前过时的 50000μg/kg/天的 LOAEL 降低 20000 倍。尽管内分泌学会的成员批评食品和药物管理局（FDA）的假设违反了内分泌学的基本原则，但 FDA 拒绝了所有低剂量数据，认为这些数据在生物学上是不合理的。他们的决定依赖于 4 个不正确的假设：剂量反应必须是单调的，低于某个阈值就不会有影响，两性必须有相似的反应，只有毒理学指导方针研究是有效的。本综述详细介绍了 20 多年来的 BPA 研究，并阐述了监管方法和内分泌科学之间存在的分歧。最终，CLARITY-BPA 揭示了为什么传统的毒性评估方法不足以评估内分泌干扰化学物质。
