Novel approaches to evaluate carbon nanotube health impacts

描述（由申请人提供）：本申请涉及广泛的挑战领域（13）智能生物材料-治疗诊断学和特定挑战主题13-ES-101，评估纳米材料健康和安全性的方法。碳基工程纳米材料，如单壁碳纳米管（SWCNT），由于其上级的电子，光学，机械，化学甚至生物学特性而受到关注。纳米级颗粒在呼吸道的上部和下部区域都具有潜在的高沉积效率，在肺部保留很长一段时间，并且诱导更多的氧化应激，并引起比其细尺寸等效物更大的炎症效应，所有这些都表明需要更好地了解这些颗粒对身体的影响。碳纳米管预计将在未来5年内被纳入价值数万亿美元的制成品中。有限的研究报告了暴露于单壁碳纳米管后的毒性和纤维化，这强烈表明迫切需要更充分地了解这些材料可能与生物系统相容或对生物系统有毒的情况。我们的研究计划的目标是阐明不同的粒子特性和暴露/剂量度量（例如，颗粒质量、表面积和尺寸）对生物命运和毒性的影响。我们假设吸入的单壁碳纳米管引起局部细胞损伤，并通过直接颗粒相互作用和促炎介质释放介导的氧化应激改变呼吸道的生化稳态。进一步假设，这些效应在很大程度上是由颗粒特征、化学和形态的分子相互作用驱动的（即，金属污染物、表面缺陷、悬空键、表面积、反应性官能团和尺寸）与重要的细胞结构。我们的研究计划将实施一些新的方法，用于材料合成和雾化，以及在肺部区域，细胞和分子水平上观察SWCNT-细胞相互作用。本研究计划的目的是检验以下特定假设：（1）吸入单壁碳纳米管导致暴露动物呼吸系统中的细胞损伤、氧化应激和生化稳态变化;（2）单壁碳纳米管颗粒保留模式和受损的巨噬细胞功能与细胞毒性和细胞重塑的区域模式相关;（3）颗粒物理化学，特别是铁含量、结构缺陷和形态，影响暴露于空气中的碳基纳米颗粒的动物的肺中的细胞损伤和氧化应激的程度;和（4）受损的脂质膜完整性、降低的抗氧化能力和诱导的脂质过氧化作用促成了吸入的SWCNT引起的肺内的局部细胞毒性。这项实验设计将汇集一些新的方法，以解决有关吸入工程纳米材料的潜在健康影响的关键问题。该研究计划将提供独特的新信息，以更全面地了解这些材料在工业，消费者使用和环境设置中对人类健康造成的潜在风险，以及可能导致潜在危害的选定工程纳米材料的物理和化学特性。我们的工作将提供一个更广泛的应用了解吸入超细或纳米颗粒如何通过呼吸系统和可能的其他靶器官中的物理或化学颗粒-细胞相互作用产生影响。我们设想，我们的方法可以通过物理-化学-活动模式广泛使用，以确定其他工程纳米材料的毒性机制，并将有助于根据反映最敏感健康结果和相关暴露途径的数据制定未来的职业和环境标准。实现更好地了解粒子物理化学，运输模式和细胞反应之间的动态在肺部和其他器官将提供一个未来的基础，建立毒性或生物相容性的预测措施和评估潜在的人类健康风险的框架。 公共卫生相关性：我们的工作将提供一个广泛的了解如何吸入超细或纳米颗粒的形式单壁碳纳米管（SWCNT）通过物理或化学颗粒细胞相互作用在呼吸系统和可能的其他目标器官的影响。我们设想，我们的方法与单壁碳纳米管可以被广泛用于定义物理化学活性途径，这将有助于制定未来的职业和环境标准的基础上，反映最敏感的健康结果和相关的暴露途径的数据。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (13) Smart Biomaterials - Theranostics and Specific Challenge Topic 13-ES-101, Methods to Evaluate the Health and Safety of Nanomaterials. Carbon-based engineered nanomaterials, such as single-walled carbon nanotubes (SWCNTs), have received notable attention due to their superior electronic, optical, mechanical, chemical, or even biological properties. Nanosized particles have a potentially high efficiency for deposition in both the upper and lower regions of the respiratory tract, are retained in the lungs for a long period of time, and induce more oxidative stress and cause greater inflammatory effects than their fine-sized equivalents, all of which suggest a need to better understand the impact of these particles on the body. Carbon nanotubes are projected to be incorporated into manufactured goods worth trillions of dollars in the next 5 years. Limited studies have reported toxicity and fibrosis following exposure to SWCNTs, which strongly suggests an urgent need to more fully understand the circumstances in which these materials might be compatible in or toxic to biological systems. The goal of our research plan is to elucidate the role that different particle characteristics and exposure/dose metrics (e.g., particle mass, surface area and size) of inhaled SWCNTs have on biological fate and toxicity. We hypothesize that inhaled SWCNTs cause localized cell injury and alter the biochemical homeostasis of the respiratory tract through oxidative stress that is mediated by direct particle interactions and release of pro-inflammatory mediators. It is further postulated that these effects are driven in large measure by molecular interactions of particle characteristics, chemistry, and morphology (i.e., metal contaminants, surface imperfections, dangling bonds, surface area, reactive functional groups, and size) with vital cellular structures. Our research plan will implement a number of novel approaches for material synthesis and aerosolization, as well as visualization of SWCNT-cell interactions at a regional, cellular and molecular level in the lungs. The aim of this research plan is to test the following specific hypotheses: (1) Inhalation of SWCNTs causes cellular injury, oxidative stress, and changes in biochemical homeostasis in the respiratory system of exposed animals; (2) SWCNT particle retention patterns and impaired macrophage function are associated with regional patterns of cytotoxicity and cellular remodeling; (3) Particle physicochemistry, specifically iron content, structural defects, and morphology, influences the extent of cellular injury and oxidative stress in the lungs of animals exposed to airborne carbon-based nanoparticles; and (4) Compromised lipid membrane integrity, diminished antioxidant capacity, and induced lipid peroxidation contribute to the regional cytotoxicity within the lungs caused by inhaled SWCNTs. This experimental design will bring together a number of novel approaches to address key issues regarding the potential health effects of inhaled engineered nanomaterials. This research program will provide unique and new information in offering a more complete understanding of the potential human health risks posed by these materials in industrial, consumer use, and environmental settings, as well as the physical and chemical characteristics of selected engineered nanomaterials that may drive the potential hazards. Our work will provide a more broadly applied understanding of how inhaled ultrafine or nanosized particles produce effects through physical or chemical particle-cellular interactions in the respiratory system and possibly other target organs. We envision that our approach can be broadly used through physical-chemical-activity patterns to determine the mechanisms of toxicity of other engineered nanomaterials and will aid in setting future occupational and environmental standards based on data reflective of the most sensitive health outcomes and relevant routes of exposure. Achieving a better understanding of the dynamics at play between particle physicochemistry, transport patterns, and cellular responses in the lungs and other organs will provide a future basis for establishing predictive measures of toxicity or biocompatibility and a framework for assessing potential human health risks. PUBLIC HEALTH RELEVANCE: Our work will provide a broad understanding of how inhaled ultrafine or nanosized particles in the form of single-walled carbon nanotubes (SWCNTs) produce effects through physical or chemical particle-cell interactions in the respiratory system and possibly other target organs. We envision that our approach with SWCNTs can be widely used to define physical-chemical-activity pathways that will aid in setting future occupational and environmental standards based on data reflective of the most sensitive health outcomes and relevant routes of exposure.