Chemical, Structural, and Superstructural Determinants of Nanocarbon Toxicity

描述(由申请人提供) 职业和环境暴露于纳米材料对人类健康造成的不利影响是一个主要问题，也是对纳米材料成功商业化和生物医学应用的潜在威胁。实现它们的商业潜力将需要更好地了解纳米材料与生物系统的相互作用，并制定新的战略来管理人类健康风险。制造的碳纳米材料在化学和物理性质、聚集状态和纯度方面有很大的变化。迫切需要毒理学筛选来确定潜在的危险纳米材料；然而，它们广泛的变异性和独特的性质使传统的体外和体内毒性测试变得复杂。布朗大学的一个跨学科研究团队，包括一名材料科学家、一名毒理学病理学家和一名分子生物学家，已经开发出一系列新颖的纳米材料和创新方法，用于纳米毒理学检测。这一模型纳米材料小组将扩大到包括经过严格表征词汇学相关材料特性的选定商业材料。该团队将开发和验证一个独特的平台，用于三维培养中的细胞分析，使用肉芽肿的形成、持续的巨噬细胞激活和纤维化作为病理终点(特定目标3)。该平台将结合纳米材料暴露后的特征，同时进行无细胞测试，以评估模拟细胞内环境中的生物持久性和聚集状态(特定目标4)。将开发一个细胞因子表达谱来预测碳纳米材料相对于标准参考材料的毒性(特定目标5)。预计这种有效的毒理学筛选试验将以较低的成本和减轻动物试验的负担提供一种替代慢性啮齿动物吸入试验的方法。识别导致细胞毒性的纳米材料的特定化学和物理性质，将有助于开发制造方法和后处理步骤，以消除固有毒性。

DESCRIPTION (provided by applicant) Adverse human health effects due to occupational and environmental exposure to nanomaterials are a major concern and a potential threat to their successful commercialization and biomedical applications. Realization of their commercial potential will require a better understanding of the interactions of nanomaterials with biological systems and the development of new strategies to manage human health risk. Manufactured carbon nanomaterials are highly variable with respect to chemical and physical properties, state of aggregation, and purity. Toxicological screening is urgently needed to identify potentially hazardous nanomaterials; however, their wide variability and unique properties complicate interpretation of traditional in vitro and in vivo toxicity assays. An interdisciplinary research team at Brown University including a materials scientist, a toxicologic pathologist, and a molecular biologist has developed a panel of novel nanomaterials and innovative approaches for nanotoxicology assays. This panel of model nanomaterials will be expanded to include selected commercial materials subjected to rigorous characterization of lexicologically relevant materials properties. Novel synthesis and characterization methods will be used to carry out systematic studies (Specific Aims 1 and 2) that reveal the chemical (surface state, metals bioavailability, biopersistence), structural (size, shape, elasticity), and superstructural (aggregate size and shape) basis of carbon nanomaterial toxicity. This team will develop and validate a unique platform for cellular assays in 3- dimensional culture using formation of granulomas, persistent macrophage activation, and fibrosis as pathologic endpoints (Specific Aim 3). This platform will incorporate post-exposure characterization of nanomaterials in parallel with an acellular assay to assess biopersistence and aggregation state in simulated intracellular environments (Specific Aim 4). A cytokine expression profile will be developed to predict toxicity of carbon nanomaterials relative to standard reference materials (Specific Aim 5). It is anticipated that this validated toxicologic screening assay will provide an alternative to chronic rodent inhalation assays at lower cost and reduced burden of animal testing. Identification of specific chemical and physical properties of nanomaterials responsible for cellular toxicity will enable development of manufacturing methods and post processing steps to eliminate intrinsic toxicity.