Carbon Nanotube Structure-Activity Relationships for Predictive Toxicology

项目摘要 在理解碳纳米管（CNT）的物理化学性质如何方面存在根本性的差距 导致肺部产生危害。如果没有这些知识，就很难评估CNT在环境中的安全性。 预测和负担得起的方式。我们的多学科方法的长期目标是开发一个 CNT安全性评估的预测毒理学方法，其中物理化学性质导致 纳米/生物界面的有害相互作用可以用来理解材料的促炎性 和促纤维化作用。本申请的总体目标是开发一系列单- 壁（SW）和多壁碳纳米管（MWCNT）文库，其可以通过稳健的细胞测定筛选， 建立定量构效关系（SAR）和管道潜在的危险等级， 导致肺损伤。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、电子性质和纯度在制备纳米颗粒中起关键作用。 启动巨噬细胞和上皮细胞成分中的协同细胞相互作用， 间充质营养单位，这是关键的发展，肺部炎症的发展， 纤维化拟议研究的基本原理是，一旦具体的定量贡献 如果已知其物理化学特性对危害产生的影响，则可以使用预测毒理学 加速CNT安全评估的方法以及它们更安全的设计。以强有力的初步指导 数据，这一假设将通过追求三个具体目标进行测试：目标1：制定危险等级， 将充分制备和表征的MWCNT和SWCNT库的性质与机械性质联系起来。 上皮细胞和巨噬细胞中的毒理学反应，以建立定量结构- 活性关系（SAR），预测体内损伤潜力。目标2：开发和验证预测 良好表征的商业和纯化CNT的肺部危害潜力的毒理学范例， 使用基于体外SAR的危险等级和材料分组，也可用于分层风险 评估方法。目的3：使用共价和非共价表面改性来证明 使用预测毒理学方法，对碳纳米管的安全设计方法进行可行性研究。我们的做法是 创新，因为它代表了对现状的实质性偏离，即使用纯化和良好的- 根据预测体内毒性的稳健毒理学机制研究制备的CNT， 毒理学结果。拟议的研究很重要，因为：（i）它解决了如何 使用强大的定量科学平台进行CNT安全评估;（ii）建立 基于CNT属性分组的强大安全平台，可用于控制绑定和读取， （三）研究将建立一个负担得起的合理的科学平台， 监管决策和产品批准走向市场。

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.