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: 8067632
• 负责人: Donatello Telesca
• 金额: $ 20.11万
• 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 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067632
• 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; Fibrosis; 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; 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; 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.

开发基于ENM特性与ENM毒性谱关联的预测性纳米毒理学框架的重要性。关于开发预测毒理学范例来评估ENM安全性的重要性的全面讨论已包括在总体研究计划的B部分中。在这项建议中，我们为肺中ENM的定量预测毒理学范例奠定了基础。我们的方法建立在细胞中快速吞吐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。体外结构-活性关系然后被我们的电子方法用来执行危险排序和对体内毒理学进行预测。 在啮齿动物肺部的结果。科学核心提供的ENM文库已被选中，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，因此可用于预测，可能导致细胞和 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在细胞氧化剂损伤、细胞毒性、炎症、信号通路激活和膜裂解，假设这与ENM的组成、大小、尺寸分布、分散状态、电荷、形状、表面反应性、金属离子的溶解、脱落以及诱导非生物和生物产生氧自由基的能力有关。这些特性将反映在不同的材料组成以及特定特性的变化中，这些特性将通过毒理学损伤、细胞摄取和 亚细胞处理。更具体地说，我们将利用低溶解度金属和金属氧化物文库来比较定义假定的低(Ti02，CeOg，Al_2O_3，Au)和高活性(Co，Ag，Cu)金属和金属氧化物纳米粒子的ENM性质，特别强调从表面角度解释响应产生 金属离子的表面积、表面反应性、ROS的生成和脱落。表面积和表面反应性的贡献将通过使用尺寸和形状变化的组合变化以及 改变材料的物相。第二组文库材料将用于探索不同二氧化硅相的作用以及将被合成以显示不同硅醇的纳米石英颗粒的表面反应性。 表面的化学物质。这些材料将被用来剖析众所周知的结晶二氧化硅诱发严重肺部炎症和纤维化的倾向。我们还将使用金属释放二氧化硅纳米颗粒和包覆阳离子聚合物的介孔二氧化硅颗粒来分析细胞内金属释放的作用。 和阳离子电荷作为危险材料的性质。最后，我们将利用纳米氧化锌以及铁掺杂的氧化锌来剖析一种高度溶解的ENM的细胞和肺毒性，这种ENM在偶然接触焊工时会引发金属烟雾热。对指导考虑这些ENM图书馆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。有关ENM组成及其特征的具体信息发表在《科学核心》杂志上。