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，人类广泛接触。大量研究表明BPA可能对健康和疾病有影响。然而，仍然存在大量的数据缺口和相互矛盾的结果，这引发了对双酚a毒性威胁的争议和担忧。我们最近发表的研究和本申请中提供的初步数据证实，环境相关浓度的BPA对小鼠和大鼠的心脏功能都有直接危害。目前还没有数据可以直接评估BPA毒性对心脏特定终点的影响。因此，迫切需要考虑确定BPA暴露的健康风险的心脏特定终点。2010年，NIEHS/国家毒理学计划（NTP）和FDA之间建立了一个以联盟为基础的合作，建立了“双酚a毒性学术和监管见解联盟”（CLARITY- BPA），以执行一项全面的符合glp的2年慢性暴露毒性研究，该研究通过纳入假设驱动和疾病特异性顶点，而不是标准毒理学评估中通常评估的。目前，CLARITY-BPA研究设计缺乏与BPA暴露引起的心血管效应相关的特定终点。这是一个重大而关键的数据缺口。如果获得批准，拟议的研究将消除BPA毒性综合glp依从性评估中心脏特异性终点的缺失。这样，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)提供关键信息，否则这些信息将无法用于风险评估和监管过程。本申请中提出的研究的具体目的是在研究BPA毒性的综合性GLP-compliant 2年CLARITY-BPA慢性暴露研究中，增加评估BPA对心脏组织病理学影响的心脏特异性终点。这一特定目标将通过确保从GLP符合CLARITY-BPA的2年口服BPA毒性慢性研究中适当分离和利用心脏组织来解决，该研究采用组织学和细胞形态计量学方法，并评估每个研究组的心脏肥大、重塑和纤维化。从心的性别，左壁厚薄；将评估心肌细胞大小、体积和纤维化程度，并与对照组进行比较。在正在进行的符合glp的2年CLARITY-BPA毒性研究中增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。包括CLARITY-BPA研究中提出的心脏终点分析，将提供一个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.