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}

由于吸入工程的纳米材料（ENM）而产生预测毒性范式来评估肺肺毒性中的ENM危害的重要性取决于这些材料的独特物理化学特性，这些特性允许这些材料摄取生物性生物分子和生物分子的过程，而nNAN的界面则是nino的。表面是由固有材料特性以及通过环境介质对这些特性的动态化塑料形成的，蛋白质，DNA，膜，膜，脂质，细胞表面，细胞内细胞器，内细胞内器官，细胞内细胞器，细胞质，细胞质，核，生物流体，fissue，fissue和insure and insure and Iners and Iner and Iner and Iner ins of Ins and Ins and Ins and Ins and Ins。纳米复合材料，表面旋转和电子电路不太可能对肺部构成直接风险，作为纳米颗粒，纳米颗粒或纳米结构材料组成的纳米颗粒的聚集物或颗粒所产生的元素更有可能对肺部造成危害的材料，虽然是在某种材料中构成的，但它是在其造成的，虽然它是在某种程度上构成的。在动物中进行毒性测试，这是在Whicti New Enm的逻辑上不可行的，包括成本和动物使用考虑。 这限制了可以在动物中研究的不同材料组合的数量，以及可以评估所有可以设计成一种材料的物理化学特性的能力，包括尺寸，表面积，形状，形状，结晶度，表面电荷，反应性表面组，散布状态，聚集状态或分散等。我们的意见是我们对ENMHAZARD的认识进行了预测，以预言其他方法。 在该提案中，我们建议实施预测毒理学范式，该范式定义为基于体外和计算机方法的ENM的体内毒性潜力的评估。{3}预测毒理学是成功药物开发的重要工具，因为毒性是毒性的主要原因之一 药物开发过程中的失败。在开发过程中，尽早识别和排除具有不利安全概况的新药候选者至关重要。最近还将预测毒理学引入工业化学毒性。 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生物测试是基于可靠的科学范式基于的，可用于在一个唱片中筛选毛ulfiple有毒物质，而不是在一个弹药处观察单一有毒物质的昂贵动物实验。 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体内生物响应的模型监测商业化学物质的毒理学数据不足或不存在的模型。 尽管毒理学评估理念的这种变化促进了毒理学家，监管机构和公众之间的健康和严格的辩论，但我们的看法是，考虑到ENM危害评估的一种类似方法是合适的。 eximentanfiy，我们不建议取消动物实验，而是主张使用毒理学或机械损伤途径来建立可以用于知识的体外财产活性恢复物，并用于知识传播和动物测试的逻辑规划。 项目2将确定是否通过精心挑选的和良好的成分和组合ENM库来探索财产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特性。理解这些特性不可或缺的是开发考虑剂量生物学危害的剂量测定模型的能力，可以量化质量以外的其他。{2}