Project 2: Relating ENM Physicochemical Properties to Mechanism-Based Pulmonary T

开发一种预测性毒性范例来评估因吸入工程纳米材料(ENM)而导致的ENM肺毒性危害的重要性取决于这些材料允许扰乱肺内生物分子和生物分子过程的独特的物理化学性质。{1}我们将纳米生物界面定义为ENM表面的相互作用，这些相互作用由ENM表面的固有材料性质以及环境介质对这些性质的动态修改而形成，包括蛋白质、DNA、膜、脂类、细胞表面、细胞内通路、细胞内细胞器、胞浆、细胞核、生物液、{2}{1}虽然纳米复合材料、表面涂层和电子电路等基于ENM的产品不太可能对肺部构成直接风险，但以纳米颗粒的形式生产的ENM、纳米颗粒或由纳米结构材料组成的颗粒的凝聚体更有可能对肺部构成危害。尽管理论上可以对每一种以独立颗粒形式生产的新材料进行严格的动物吸入毒性测试，但从生产新ENM的速度来看，这在逻辑上是不可行的，包括成本和动物使用考虑。 这限制了可以在动物身上研究的不同材料成分的数量，以及评估可以工程到一种材料中的所有物理化学性质的能力，包括尺寸、表面积、形状、结晶度、表面电荷、活性表面基团、溶解、聚集或分散状态等。我们认为，关于ENM危害的知识概述必须考虑补充动物试验的其他方法。 在这项建议中，我们建议实施预测性毒理学范式，其定义是基于体外和计算机方法对ENM的体内毒性潜力进行评估。{3}预测性毒理学是成功开发药物的必要工具，因为毒性是产品的主要原因之一 药物开发过程中的失败。在开发过程中尽早识别和排除安全性不佳的候选新药是至关重要的。预测毒理学最近也被引入到工业化学毒性中。美国国家毒理学计划和美国国家科学院(NAS)的国家研究委员会(NRC)都建议，21世纪的毒理学测试应该从疾病特定模型水平上的主要观察性科学发展到侧重于广泛纳入靶标特定的、基于机制的生物学观察的预测性科学模型。{4-6}进一步建议生物测试基于强大的科学范例，可用于在一次FIME中筛选多种毒物，而不是昂贵的动物实验在一种FIME中观察一种毒物。2008年发表了一份报告，概述了美国联邦政府对NRC文件的反应，这份报告促使NIEHS、美国环保局和国家卫生研究院化学基因组中心签署了一项协议，合作开发和评估快速和大量的筛选方法，以：(I)优先考虑进行更全面的毒理学检测的物质，(Ii)确定用于进一步研究的作用机制，(Iii)为毒理学数据不足或根本不存在的商业化学品的体内生物反应监测开发预测模型。 尽管毒理学评估理念的这种变化在毒理学家、监管者和公众之间引发了一场健康而激烈的辩论，但我们的观点是，考虑采用类似的方法进行ENM危害评估是恰当的。重要的是，我们不建议取消动物实验，但我们主张使用毒理学或机械性损伤途径来建立体外性质与活性的关系，这种关系可用于动物实验的知识生成和合理规划。 项目2将确定通过精心选择和特征良好的成分和组合ENM文库来探索属性-活性重新定位是否可以帮助我们了解导致肺部炎症、细胞毒性和纤维化的材料属性。理解这些属性的一个组成部分是开发剂量学模型的能力，该模型以剂量量化而不是质量来考虑生物危害。{2}

The importance of developing a predictive toxicity paradigm to assess ENM hazard in the lung Pulmonary toxicity as a result of inhaling engineered nanomaterials (ENM) depends on the unique physicochemical properties that allow these materials to perturb bio-molecules and bio-molecular processes in the lung.{1} We define the nano-bio interface as the interacfion of ENM surfaces, which are shaped by intrinsic material properties as well as the dynamic modificafion of those properties by environmental media, with proteins, DNA, membranes, lipids, cell surfaces, endocytic pathways, intracellular organelles, cytosol, nucleus, biological fluids, fissue and organs.{2} {1}While ENM-based products such as nanocomposites, surface coafings and electronic circuits are unlikely to pose a direct risk to the lung, ENM that are being produced as nanoparticles, agglomerates of nanoparticles or particles comprised of nanostructured materials are more likely to pose a hazard to the lung.^ While it is theorefically possible to subject every new material that is being produced as an unattached particle to rigorous inhalafion toxicity testing in animals, this is logisfically unfeasible at the rates at whicti new ENM are being produced, including cost and animal use considerafions. This limits the number of different material composifions that can be studied in animals as well as the ability to assess all the physicochemical properties that can be engineered into one material, including size, surface area, shape, crystallinity, surface charge, reactive surface groups, dissolufion, state of aggregation or dispersal etc. It is our opinion that knowledge generafion about ENM hazard has to consider additional approaches that complement animal testing.{3} In this proposal, we recommend the implementation of a predictive toxicological paradigm, which is defined as the assessment of in vivo toxic potential of ENM based on in vitro and in silico methods.{3} Predictive toxicology is an essential tool for successful drug development because toxicity is one of the major reasons for product failure in the drug development process. It is essential to identify and exclude new drug candidates with unfavorable safety profiles as early as possible in the development process. Predictive toxicology has recently also being introduced to industrial chemical toxicity. Both the Nafional Toxicology Program as well as the Nafional Research Council (NRC) in the US Nafional Academy of Sciences (NAS) have recommended that toxicological testing in the 21st-century evolve from a predominanfiy observafional science at the level of disease-specific models to predictive science models focused on broad inclusion of target-specific, mechanism-based biological observations.{4-6} It is further recommended that the biological testing be based on robust scientific paradigms that can be used to screen mulfiple toxicants at one fime instead of costly animal experiments looking at a single toxicant at one fime. A report outlining the US Federal Government response to the NRC document was published in 2008 and prompted NIEHS, EPA and the National Institute of Health Chemical Genomics Center to sign an agreement to collaborate on the development and evaluation of a rapid and high volume screening methodologies to: (i) prioritize substances for more comprehensive toxicological tesfing, (ii) identify mechanisms of acfion for further invesfigafion, and (iii) develop predictive models for in vivo biological response monitoring for commercial chemicals with inadequate or nonexistent toxicological data. Although this change in toxicological assessment philosophy has catalyzed a healthy and rigorous debate among toxicologists, regulators and the public, our opinion is that it is fimely to consider an analogous approach for ENM hazard assessment. Importanfiy, we do not recommend doing away with animal experiments but we advocate the use of toxicological or mechanistic injury pathways to establish in vitro property-activity relafionships that can be used for knowledge generafion and logical planning of animal testing. Project 2 will determine whether the property-activity relafionships to be explored by carefully chosen and wellcharacterized compositional and combinatorial ENM libraries can help us understand the material properties leading to pulmonary inflammation, cytotoxicity and fibrosis. Integral to understanding these properties is the ability to develop dosimetry models that consider biological hazard in dose quantifies other than mass.{2}