Project 3: Computational Processing and Quantitative Risk Assessment of ENM Toxic

项目3：ENM有毒物质的计算处理和定量风险评估

• 批准号: 8274477
• 负责人: Donatello Telesca
• 金额: $ 19.76万
• 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/8274477
• 关键词: Adopted; Adverse effects; Area; Bayesian Analysis; Binding; Biological Assay; Biological Availability; Cell physiology; Cells; Characteristics; Charge; Chemicals; Chemistry; Collaborations; Computer Simulation; Cytolysis; Data; Development; Dimensions; Dose; Engineering; Exposure to; Foundations; Generations; Hazardous Substances; Health; Health Hazards; Human; In Vitro; Injury; Ions; Iron; Joints; Lead; Learning; Libraries; Library Materials; Link; Lipid Bilayers; Lung; Maps; Markov Chains; Measures; Membrane; Meta-Analysis; Metal fever; Metals; Methodology; Methods; Modeling; Molecular; Multivariate Analysis; Outcome; Oxidants; Pathway interactions; Phase; Physics; Pneumonia; Polymers; Probability; Process; Production; Property; Protocols documentation; Pulmonary Fibrosis; Quartz; Reaction Time; Reactive Oxygen Species; Research; Risk; Risk Assessment; Rodent; Role; Safety; Sampling; Screening procedure; Series; Shapes; Signal Pathway; Silicon Dioxide; Solubility; Source; Statistical Models; Structure; Structure-Activity Relationship; Surface; Techniques; Toxic effect; Toxicology; Translating; Uncertainty; Variant; Weight; base; cell injury; combinatorial; cytotoxicity; design; dosage; experience; hazard; high throughput screening; improved; in vivo; metal oxide; nano; nanobiology; nanomaterials; nanoparticle; nanoscale; nanotoxicology; particle; research study; response; silanol; uptake

The importance of developing a predictive nano-toxicology framework, based on the association of ENM properties to ENM toxicity profiles. A comprehensive discussion about the importance of developing a predictive toxicology paradigm to assess ENM safety has been included in Section B of the Overall Research Plan. In this proposal we implement the foundation for a quantitative predictive toxicology paradigm for ENM in the lung. Our approach builds on rapid throughput screening data in cells to establish a relationship between ENM properties and cellular or bio-molecular injury pathways. The in vitro structure-activity relationships are then used by our in silico methods to perform hazard ranking and make predictions about in vivo toxicological outcomes in the rodent lung. The ENM libraries provided by the Scientific Core have been s.elected to highlight key physicochemical properties that are relevant to a number of cellular injury mechanisms that we propose may lead to pulmonary toxicity and can therefore be used for making predictions, potentially leading to cellular and molecular injury mechanisms of toxicity in the lung. The in vitro studies that will be conducted in Project #1 will concentrate on cellular oxidant injury, cytotoxicity, infiammation, signaling pathway activation and membrane lysis, which hypothetically is linked to ENM properties such as composition, size, size distribution, state of dispersal, charge, shape, surface reactivity, dissolution, shedding of metal ions and ability to induce abiotic and biotic oxygen radical production. These properties will be reflected in the different material compositions as well as the variation of specific properties that will be investigated in terms of toxicological injury, cellular uptake and subcellular processing. More specifically, we will utilize low solubility metal and metal oxides libraries to compare the ENM properties that define putative low (Ti02, CeOg, AI2O3, Au) and high reactive (Co, Ag, Cu) metal and metal oxide nanoparticles, with particular emphasis on explaining the response generation in terms of surface area, surface reactivity, ROS generation and shedding of metal ions. The contribution of surface area and surface reactivity will then be further explored by using combinatorial variations of size and shape changes as well as varying the material phase. A second group of library materials will be used to explore the role of different silica phases as well as the surface reactivity of nano-quartz particles that will be synthesized to display different silanol chemistries on the surface. These materials will be used to dissect the well known propensity of crystalline silica to induce severe pulmonary inflammation and fibrosis. We will also use metal-releasing silica nanoparticles and mesoporous silica particles coated with a cationic polymer to dissect the role of metals released intracellulariy and cationic charge as hazardous material properties. Finally, we will utilize nano-ZnO as well as iron-doped ZnO to dissect the cellular and pulmonary toxicity of a highly dissolvable ENM that in incidental exposures to welders can induce metal fume fever. A comprehensive discussion of the scientific hypothesis guiding the consideration of these ENM libraries appear in the Overall Research Plan, as well as in the Project #1 & #2 proposals. Specific information about the ENM composition and their characterization appear in the Scientific Core.

基于ENM特性与ENM毒性特征的关联，开发预测性纳米毒理学框架的重要性。在总体研究计划的第B节中纳入了关于开发预测毒理学范式以评估ENM安全性的重要性的全面讨论。在这项提案中，我们实现了定量预测毒理学范式的基础上，ENM在肺。我们的方法建立在细胞中的快速通量筛选数据的基础上，以建立ENM特性与细胞或生物分子损伤途径之间的关系。体外构效关系，然后使用我们的计算机模拟方法进行危害排名，并作出预测，在体内毒理学 啮齿动物肺部的结果。科学核心提供的ENM库已被选中，以突出与我们提出的可能导致肺毒性的许多细胞损伤机制相关的关键物理化学性质，因此可用于进行预测，可能导致细胞和细胞毒性。 肺毒性的分子损伤机制。将在项目#1中进行的体外研究将集中于细胞氧化损伤、细胞毒性、炎症、信号通路激活和膜溶解，假设其与ENM特性相关，例如组成、大小、大小分布、分散状态、电荷、形状、表面反应性、溶解、金属离子脱落以及诱导非生物和生物氧自由基产生的能力。这些特性将反映在不同的材料成分以及特定特性的变化中，这些特性将在毒理学损伤、细胞吸收和 亚细胞加工更具体地，我们将利用低溶解度金属和金属氧化物库来比较限定推定的低（TiO2、CeO2、Al2O3、Au）和高反应性（Co、Ag、Cu）金属和金属氧化物纳米颗粒的ENM性质，特别强调解释在表面活性方面的响应产生。 面积、表面反应性、ROS生成和金属离子脱落。表面积和表面反应性的贡献，然后将进一步探讨通过使用组合变化的大小和形状的变化，以及 改变材料相。第二组库材料将用于探索不同二氧化硅相的作用以及纳米石英颗粒的表面反应性，这些纳米石英颗粒将被合成以显示不同的硅烷醇。 表面的化学物质。这些材料将用于解剖众所周知的结晶二氧化硅诱导严重肺部炎症和纤维化的倾向。我们还将使用释放金属的二氧化硅纳米颗粒和涂覆有阳离子聚合物的介孔二氧化硅颗粒来剖析细胞内释放的金属的作用。 和阳离子电荷作为有害材料特性。最后，我们将利用纳米氧化锌以及铁掺杂氧化锌解剖细胞和肺毒性的高度可溶性ENM，在偶然暴露于焊工可以诱导金属烟雾热。对指导这些ENM库考虑的科学假设的全面讨论出现在总体研究计划以及项目#1和#2提案中。关于ENM组成及其特性的具体信息见科学核心。