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量生产化学品，广泛用于各种消费品和食品包装。单体双酚A是一种普遍存在的污染物，人类对其有广泛的接触。大量研究表明，双酚A可能对健康和疾病有影响。然而，仍然存在大量的数据差距和相互矛盾的结果，这引发了人们对BPA有毒威胁的争议和担忧。我们最近发表的研究和在本申请中提供的初步数据表明，与环境相关的BPA浓度对小鼠和大鼠的心脏功能都有直接损害。目前还没有直接评估符合GLP标准的大型BPA毒性研究对心脏特定终点的影响的数据。因此，迫切需要考虑心脏特定的终点，以确定双酚A暴露的健康风险。2010年，NIEHS/国家毒理学计划(NTP)和FDA之间的一个基于联盟的合作建立了“连接学术和监管对BPA毒性的见解”(Clarity-BPA)，对BPA的毒性进行了一项符合GLP的为期2年的综合慢性暴露研究，并纳入了标准毒理学评估中通常不评估的假说驱动和疾病特异性顶端终点。目前，Clarity-BPA研究设计缺乏与双酚A暴露引起的心血管效应特别相关的终点。这是一个重大而关键的数据缺口。如果获奖，拟议的研究将消除这项符合GLP标准的双酚A毒性综合评估中心脏特定终点的严重缺失。在这样做时，拟议分析的结果将：1)填补一个关键的数据缺口，否则将一直得不到解决；以及2)提供原本无法用于风险评估和监管过程的关键信息。本申请中提出的研究的具体目的是将评估BPA对心脏组织病理学影响的心脏特定终点添加到全面的符合GLP标准的Clarity-BPA慢性暴露研究中，该研究调查了BPA的毒性。这一具体目标将通过确保从符合GLP的Clarity-BPA为期两年的口服BPA毒性的组织学和细胞形态计量学方法的长期研究中适当分离和利用心脏组织来实现，并评估每个研究组的心脏肥大、重塑和纤维化。对来自不同性别的心脏的左室壁厚度、心肌细胞大小和体积以及纤维化程度进行评估，并与对照组进行比较。正在进行的符合GLP标准的为期两年的Clarity-BPA毒性研究增加了心脏特定终点，这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研究中包括对建议的心脏终点的分析，将提供一个更知情的监管决策过程，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.