Carbon Nanotube Structure-Activity Relationships for Predictive Toxicology

预测毒理学的碳纳米管结构-活性关系

• 批准号: 8632498
• 负责人: Mark C. Hersam
• 金额: $ 42.96万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-09 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632498
• 关键词: Address; Biological; Biological Availability; Breathing; Caliber; Carbon Nanotubes; Categories; Cells; Cellular Assay; Characteristics; Chemistry; Collaborations; Data; Decision Making; Defect; Development; Dimensions; Disease; Electronics; Elements; Epithelial; Epithelial Cells; Evaluation; Fiber; Fibrosis; Generations; Goals; Granulomatous; Grouping; Growth Factor; Hazardous Substances; Human; In Vitro; Inflammation; Inflammatory; Injury; Knowledge; Length; Libraries; Lung; Mesenchymal; Mission; Modification; Mus; Occupational Safety; Organ; Organelles; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Play; Pneumonia; Polymers; Product Approvals; Production; Property; Public Health; Pulmonary Fibrosis; Quantitative Structure-Activity Relationship; Reading; Regulation; Research; Risk Assessment; Role; Safety; Series; Structure-Activity Relationship; Surface; Technology; Testing; Toxicology; Tube; Work; Workplace; base; biological adaptation to stress; design; disability; hazard; in vivo; innovation; interdisciplinary approach; macrophage; multi walled carbon nanotube; nano; nanotherapeutic; new technology; novel; protective effect; public health relevance; response; screening

Project Summary There is a fundamental gap in understanding how the physicochemical properties of carbon nanotubes (CNTs) contribute to hazard generation in the lung. Without this knowledge, it is difficult to evaluate CNT safety in a predictive and affordable manner. The long-term goal of our multidisciplinary approach is to develop a predictive toxicological approach for CNT safety assessment in which the physicochemical properties leading to hazardous interactions at the nano/bio interface can be used to understand the materials' pro-inflammatory and pro-fibrogenic effects in the lung. The overall objective of this application is to develop a series of single- wall (SW) and multi-wall carbon nanotube (MWCNT) libraries that can be screened by robust cellular assays to establish quantitative structure activity relationships (SARs) and hazard ranking of the tubes' potential to induce pulmonary damage. Our central hypothesis is that tube dimensions (including length, diameter and aspect ratio), state of dispersion, catalytic surface chemistry, electronic properties and purity play key roles in initiating cooperative cellular interactions in macrophages and cellular elements from the epithelial- mesenchymal trophic unit, which are key to the development of development of pulmonary inflammation and fibrosis. The rationale for the proposed research is that once the quantitative contributions of specific physicochemical properties to hazard generation is known, it will be possible to use a predictive toxicology approach for expedited safety assessment of CNTs as well as their safer design. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1: To develop hazard ranking that relates the properties of well-prepared and characterized MWCNT and SWCNT libraries to mechanistic toxicological responses in epithelial cells and macrophages, with a view to develop quantitative structure- activity relationships (SARs) that predict in vivo injury potential. Aim 2: To develop and validate a predictive toxicological paradigm for pulmonary hazard potential of well-characterized commercial and purified CNTs, using in vitro SAR-based hazard ranking and grouping of materials that can also be used towards a tiered risk assessment approach. Aim 3: To use covalent and non-covalent surface modification to demonstrate the feasibility of safe-by-design approaches for CNTs, using a predictive toxicological approach. Our approach is innovative, because it represents a substantive departure from the status quo, namely the use of purified and well- prepared CNTs that are investigated according to robust toxicological mechanisms that predict the in vivo toxicological outcome. The proposed research is significant because: (i) it addresses the concern of how to perform CNT safety assessment using a robust, quantitative scientific platform; (ii) the establishment of a robust safety platform based on grouping of CNT properties that can be used for control banding and read- across risk assessment; (iii) the research will develop an affordable and rational scientific platform for regulatory decision-making and product approval towards the marketplace.

项目概要 对碳纳米管 (CNT) 物理化学性质的理解存在根本性差距 有助于肺部危险的产生。如果没有这些知识，就很难评估碳纳米管的安全性 具有预测性且经济实惠的方式。我们多学科方法的长期目标是开发 碳纳米管安全评估的预测毒理学方法，其中理化性质主导 纳米/生物界面上的危险相互作用可用于了解材料的促炎作用 以及肺部的促纤维化作用。该应用程序的总体目标是开发一系列单 壁（SW）和多壁碳纳米管（MWCNT）库，可以通过强大的细胞测定进行筛选 建立定量结构活动关系 (SAR) 和管子潜在的危险等级 诱发肺部损伤。我们的中心假设是管尺寸（包括长度、直径和 纵横比）、分散状态、催化表面化学、电子性能和纯度起着关键作用 启动巨噬细胞和上皮细胞成分之间的协同细胞相互作用 间充质营养单位，是肺部炎症发展的关键 纤维化。拟议研究的基本原理是，一旦特定的定量贡献 危害产生的物理化学特性已知，可以使用预测毒理学 加速碳纳米管安全评估及其更安全设计的方法。强有力的前期引导 数据，该假设将通过追求三个具体目标来检验： 目标 1：制定危险排名 将精心准备和表征的 MWCNT 和 SWCNT 库的特性与机械性能联系起来 上皮细胞和巨噬细胞的毒理学反应，以开发定量结构- 预测体内潜在损伤的活动关系（SAR）。目标 2：开发并验证预测 充分表征的商业和纯化碳纳米管的肺部危险潜力的毒理学范例， 使用基于体外 SAR 的危险排名和材料分组，也可用于分级风险 评估方法。目标 3：使用共价和非共价表面修饰来证明 使用预测毒理学方法，研究碳纳米管安全设计方法的可行性。我们的方法是 创新，因为它代表了对现状的实质性背离，即使用纯化和良好的 制备的碳纳米管根据预测体内毒理学机制进行研究 毒理学结果。拟议的研究意义重大，因为：（i）它解决了如何 使用强大的定量科学平台进行碳纳米管安全评估； (二) 设立一个 基于 CNT 属性分组的强大安全平台，可用于控制条带和读取 跨风险评估； (iii) 该研究将为以下领域开发一个负担得起且合理的科学平台： 监管决策和产品上市批准。