Carbon Nanotube Structure-Activity Relationships for Predictive Toxicology

项目摘要 在理解碳纳米管(CNT)的物理化学性质方面存在着根本的差距。 有助于在肺部产生危险。如果没有这些知识，很难评估碳纳米管的安全性 预测和负担得起的方式。我们多学科方法的长期目标是开发一种 预测毒理学方法在碳纳米管安全性评价中的应用 纳米/生物界面上的有害相互作用可以用来理解材料的促炎作用 以及在肺中的促纤维化作用。此应用程序的总体目标是开发一系列单一的- 壁(SW)和多壁碳纳米管(MWCNT)文库，可以通过强大的细胞检测进行筛选，以 建立定量结构活性关系(SARS)和管子潜在的危险等级 导致肺损伤。我们的中心假设是管子的尺寸(包括长度、直径和 长宽比)、分散状态、催化表面化学、电子性质和纯度 在巨噬细胞和来自上皮细胞的细胞元件中启动协同细胞相互作用- 间充质营养单位，这是发展的关键，肺部炎症和 纤维化症。提出这项研究的理由是，一旦特定的 物理化学性质对危害的产生是已知的，将有可能使用一种预测性毒理学 加快碳纳米管安全评估的方法及其更安全的设计。以强劲的前期工作为指导 数据，这一假设将通过追求三个具体目标来检验：目标1：制定风险排名 将精心准备和表征的MWCNT和SWCNT文库的属性与机械性 上皮细胞和巨噬细胞的毒理学反应，以期发展定量结构- 活动性关系(SARS)预测体内损伤的可能性。目标2：开发和验证预测性 具有良好特征的商业和纯化碳纳米管的潜在肺危害的毒理学范式， 使用基于体外合成孔径雷达的危险分级和对也可用于分级风险的材料进行分组 评估方法。目的3：用共价和非共价的表面修饰来演示 碳纳米管安全设计方法的可行性，使用预测性毒理学方法。我们的方法是 创新，因为它代表了对现状的实质性偏离，即使用净化的和良好的- 制备的碳纳米管根据强大的毒理学机制进行研究，预测体内的 毒理学结果。拟议的研究具有重要意义，因为：(I)它解决了人们对如何 使用稳健、量化的科学平台进行CNT安全评估；(2)建立 基于CNT属性分组的健壮安全平台，可用于控制捆绑和读取 跨风险评估；(3)研究将开发一个负担得起的合理的科学平台 针对市场的监管决策和产品审批。

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.