Assessment of Cardiac End Points in the CLARITY-BPA Study

描述（由申请人提供）：双酚 A (BPA) 是一种内分泌干扰物和大批量生产化学品，广泛用于各种消费品和食品包装。单体 BPA 是一种普遍存在的污染物，人类广泛接触。大量研究表明，BPA 可能对健康和疾病产生影响。然而，仍然存在大量数据差距和相互矛盾的结果，引发了人们对双酚 A 有毒威胁的争议和担忧。我们最近发表的研究和本申请中提供的初步数据表明，环境相关浓度的 BPA 对小鼠和大鼠的心脏功能有直接损害。目前尚无数据可直接评估大型符合 GLP 的 BPA 毒性研究对心脏特定终点的影响。因此，迫切需要考虑心脏特定终点来确定 BPA 暴露的健康风险。 2010 年，NIEHS/国家毒理学计划 (NTP) 和 FDA 之间以联盟为基础的合作成立了“将 BPA 毒性的学术和监管见解联系起来的联盟”(CLARITY-BPA)，以对 BPA 毒性进行全面的符合 GLP 要求的 2 年慢性暴露研究，并通过包含假设驱动和通常在标准毒理学评估中不评估的疾病特异性顶端终点来增强研究。目前，CLARITY-BPA 研究设计缺乏与 BPA 暴露引起的心血管影响具体相关的终点。这是一个重大且关键的数据缺口。如果获奖，拟议的研究将消除这种符合 GLP 的 BPA 毒性综合评估中严重缺乏心脏特异性终点的问题。在此过程中，拟议分析的结果将：1）填补否则将无法解决的关键数据空白； 2) 提供原本无法用于风险评估和监管流程的关键信息。本申请中提出的研究的具体目标是将评估 BPA 对心脏组织病理学影响的心脏特定终点添加到调查 BPA 毒性的综合性 GLP 合规 2 年 CLARITY-BPA 慢性暴露研究中。该具体目标将通过确保从符合 GLP 标准的 CLARITY-BPA 为期 2 年的口服 BPA 毒性慢性研究中正确分离和利用心脏组织来实现，用于组织学和细胞形态测量方法，并评估每个研究组心脏的肥大、重塑和纤维化。从每个性别的心中，LV壁厚；将评估肌细胞的大小和体积以及纤维化程度并与对照进行比较。在正在进行的符合 GLP 标准的 2 年 CLARITY-BPA 毒性研究中添加心脏特定终点将增加风险评估和监管过程中无法获得的关键信息。在 CLARITY-BPA 研究中纳入对拟议心脏终点的分析，将提供更明智的监管决策过程，从而改善全球人类健康。

DESCRIPTION (provided by applicant): Bisphenol A (BPA) is an endocrine disruptor and high volume production chemical used extensively in a wide- variety of consumer products and food packaging. Monomeric BPA is a pervasive pollutant to which there is wide-spread human exposure. Numerous studies have demonstrated that BPA may have effects on health and disease. However, there remain numerous data gaps and conflicting results that have fueled controversy and concern about the toxic threat of BPA. Our recently published studies and preliminary data presented in this application, establish that environmentally relevant concentrations of BPA are directly harmful to cardiac function in both mice and rats. There are currently no data available directly assessing impacts on cardiac specific endpoints from large GLP compliant studies of BPA toxicity. As a result, there is a pressing need to consider cardiac specific endpoints for establishing the health risks of BPA exposure. In 2010, a consortium-based collaboration between the NIEHS/National Toxicology Program (NTP) and the FDA was established the "Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY- BPA) to perform a comprehensive GLP-compliant 2 year chronic exposure study of the toxicity of BPA augmented by inclusion of hypothesis driven and disease-specific apical endpoints not typically assessed in standard toxicological assessment. Currently, the CLARITY-BPA study design lacks endpoints specifically related to cardiovascular effects resulting from BPA exposure. This is a major and critical data gap. If awarded, the proposed studies will eliminate the critical absence of cardiac specific endpoints from this comprehensive GLP-compliant assessment of BPA toxicity. In so doing, the results from the proposed analysis will: 1) fill a critical data gap that would otherwise remain unaddressed; and 2) contribute critical information that would otherwise not be available for the risk assessment and regulatory process. The Specific AIM of the studies proposed in this application is to add cardiac specific end points assessing the impact of BPA on cardiac histopathology to the comprehensive GLP-compliant 2-year CLARITY-BPA chronic exposure study investigating the toxicity of BPA. That Specific Aim will be addressed by ensuring proper isolation and utilization of cardiac tissue from the GLP compliant CLARITY-BPA 2-year chronic study of oral BPA toxicity for histological and cellular morphometric approaches and to assess hypertrophy, remodeling and fibrosis of hearts from each study group. From hearts of each sex, LV wall thickness; myocyte size and volume, and degree of fibrosis will be assessed and compared to controls. The addition of cardiac specific endpoints to the on-going GLP-compliant 2-year CLARITY-BPA toxicity study will add critical information that would otherwise not be available for the risk assessment and regulatory process. Including analysis of the proposed cardiac endpoints in the CLARITY-BPA study will afford a more informed regulatory decision-making process that will result in improved global human health.