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: 8274476
• 负责人: Andre Elias Nel
• 金额: $ 27.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8274476
• 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; Liquid substance; Lung; Membrane Lipids; 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; Pulmonary Fibrosis; 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; nanobiology; 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}

开发预测毒性范例以评估吸入工程纳米材料（ENM）的肺毒性危害的重要性取决于这些材料独特的物理化学性质，这些性质允许这些材料干扰肺中的生物分子和生物分子过程。我们将纳米生物界面定义为ENM表面与蛋白质、DNA、膜、脂质、细胞表面、内吞途径、细胞内细胞器、细胞质、细胞核、生物液体、组织和器官的相互作用。ENM表面是由材料的固有特性以及环境介质对这些特性的动态修饰而形成的。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、纳米颗粒团块或由纳米结构材料组成的颗粒形式生产的ENM更有可能对肺部构成危害。^虽然理论上可以对每一种作为独立颗粒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，包括成本和动物使用方面的考虑，这在后勤上是不可行的。