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

项目 2：将 ENM 理化特性与基于机制的肺 T 联系起来

• 批准号: 8067631
• 负责人: Andre Elias Nel
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067631
• 关键词: Academy; Advocate; Aerosols; Agreement; Animal Experiments; Animal Testing; Animals; Antioxidants; Area; Biochemical; Biological; Biological Availability; Biological Markers; Biological Testing; Breathing; Bronchoalveolar Lavage; Carbon Black; Cell Nucleus; Cell surface; Charge; Chemicals; Chemistry; Complement; Computer Simulation; Cytosol; DNA; Data; Development; Disease; Dose; Electronics; Engineering; Evaluation; Failure; Federal Government; Fibrosis; Genomics; Goals; Hazard Assessment; Health; Histology; Impairment; In Vitro; Inflammation; Inflammatory; Inhalation Exposure; Injury; Ions; Iron; Knockout Mice; Knowledge; Libraries; Library Materials; Lipids; Liquid substance; Lung; Membrane; Metals; Methodology; Methods; Modeling; Molecular; Monitor; Mus; National Institute of Environmental Health Sciences; Organ; Organelles; Outcome; Oxidants; Oxidative Stress; Pathway interactions; Performance; Phase; Philosophy; Pneumonia; Polymers; Process; Property; Proteins; Publishing; Rattus; Reporting; Research; Risk; Rodent; Role; Safety; Science; Screening procedure; Series; Shapes; Silicon Dioxide; Solubility; Surface; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; United States National Institutes of Health; Variant; base; cell injury; combinatorial; comparative; cost; cytotoxicity; dosimetry; drug candidate; drug development; hazard; in vivo; interest; metal oxide; nano; nanocomposite; nanomaterials; nanoparticle; nanoscale; nanostructured; neutrophil; particle; predictive modeling; programs; research study; response; response to injury; silanol; tool; toxicant; uptake

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}

开发预测毒性范例来评估 ENM 对肺部危害的重要性吸入工程纳米材料 (ENM) 导致的肺部毒性取决于独特的理化性质，这些材料可以扰乱肺部的生物分子和生物分子过程。{1}我们将纳米生物界面定义为 ENM 的相互作用 表面由内在材料特性以及环境介质对这些特性的动态修改所塑造，其中包括蛋白质、DNA、膜、脂质、细胞表面、内吞途径、细胞内细胞器、细胞质、细胞核、生物体液、组织和器官。{2} {1}而基于 ENM 的产品，例如 纳米复合材料、表面涂层和电子电路不太可能对肺部造成直接风险，但以纳米颗粒、纳米颗粒团聚体或由纳米结构材料组成的颗粒形式生产的 ENM 更有可能对肺部造成危害。^ 虽然理论上可以对以独立颗粒形式生产的每一种新材料进行严格的吸入 动物毒性测试，以新 ENM 的生产速度（包括成本和动物使用考虑）而言，这在逻辑上是不可行的。 这限制了可在动物身上研究的不同材料成分的数量，以及评估可设计成一种材料的所有物理化学特性的能力，包括尺寸、表面积、形状、结晶度、表面电荷、反应性表面基团、溶解、聚集或分散状态等。我们认为，有关 ENM 危害的知识生成必须考虑补充动物测试的其他方法。{3} 在本提案中，我们建议实施预测毒理学范式，其定义为基于体外和计算机模拟方法评估 ENM 的体内潜在毒性。{3}预测毒理学是成功药物开发的重要工具，因为毒性是产品的主要原因之一 药物研发过程中的失败。在开发过程中尽早识别和排除具有不利安全性的新候选药物至关重要。预测毒理学最近也被引入工业化学毒性。国家毒理学计划以及美国国家科学院 (NAS) 的国家研究委员会 (NRC) 均建议 21 世纪的毒理学测试从疾病特异性模型层面的占主导地位的观察科学发展为侧重于广泛包含特定目标、基于机制的生物学观察的预测科学模型。{4-6}还进一步建议 生物测试应基于强大的科学范式，可用于一次性筛选多种毒物，而不是一次性检查单一毒物的昂贵动物实验。 2008 年发布了一份报告，概述了美国联邦政府对 NRC 文件的回应，并促使 NIEHS、EPA 和美国国立卫生研究院化学基因组学中心签署了一项协议，合作开发和评估快速、大批量的筛选方法，以：(i) 优先考虑物质进行更全面的毒理学测试，(ii) 确定作用机制以进行进一步研究，以及 (iii) 制定预测性方法 用于毒理学数据不足或不存在的商业化学品的体内生物反应监测模型。 尽管毒理学评估理念的这一变化在毒理学家、监管机构和公众之间引发了一场健康而严格的辩论，但我们认为，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损伤途径来建立体外属性-活性关系，可用于动物测试的知识生成和逻辑规划。 项目 2 将确定通过精心选择和充分表征的成分和组合 ENM 库探索的特性-活性关系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特性。了解这些特性的关键是能够开发剂量测定模型，该模型考虑剂量量化而非质量的生物危害。{2}