Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

吸入纳米材料暴露的危害评估和风险评估

• 批准号: 8071680
• 负责人: Alison Elder
• 金额: $ 4.71万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071680
• 关键词: Acute; Address; Aerosols; Biological Assay; Bolus Infusion; Brain; Breathing; Cells; Cellular Assay; Characteristics; Classification Scheme; Cultured Cells; Data; Deposition; Dose; Drug Delivery Systems; Electronics; Elements; Engineering; Environment; Evaluation; Exposure to; Hazard Assessment; Health; Human; Human Engineering; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhalation Exposure; Institution; Knowledge; Life; Lung; Lung Inflammation; Mediator of activation protein; Methods; Metric; Minnesota; Modification; Neuraxis; Occupational; Organ; Outcome; Outcome Measure; Oxidative Stress; Pathology; Pleura; Pleural; Population; Production; Property; Rattus; Research; Research Personnel; Respiratory System; Respiratory tract structure; Risk; Risk Assessment; Risk Estimate; Rodent; Route; Science; Screening procedure; Secondary to; Site; Surface; Surface Properties; System; Testing; Tissues; Toxic effect; Universities; Workplace; adverse outcome; base; brain cell; consumer product; design; exposed human population; hazard; in vitro Assay; in vitro testing; in vivo; in vivo Model; innovation; meetings; member; multidisciplinary; nanomaterials; novel; particle; public health relevance; response; Acute; Address; Aerosols; Biological Assay; Bolus Infusion; Brain; Breathing; Cells; Cellular Assay; Characteristics; Classification Scheme; Cultured Cells; Data; Deposition; Dose; Drug Delivery Systems; Electronics; Elements; Engineering; Environment; Evaluation; Exposure to; Hazard Assessment; Health; Human; Human Engineering; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhalation Exposure; Institution; Knowledge; Life; Lung; Lung Inflammation; Mediator of activation protein; Methods; Metric; Minnesota; Modification; Neuraxis; Occupational; Organ; Outcome; Outcome Measure; Oxidative Stress; Pathology; Pleura; Pleural; Population; Production; Property; Rattus; Research; Research Personnel; Respiratory System; Respiratory tract structure; Risk; Risk Assessment; Risk Estimate; Rodent; Route; Science; Screening procedure; Secondary to; Site; Surface; Surface Properties; System; Testing; Tissues; Toxic effect; Universities; Workplace; adverse outcome; base; brain cell; consumer product; design; exposed human population; hazard; in vitro Assay; in vitro testing; in vivo; in vivo Model; innovation; meetings; member; multidisciplinary; nanomaterials; novel; particle; public health relevance; response

DESCRIPTION (provided by applicant): Engineered nanomaterials (ENM) have the potential to revolutionize every-day life due to unique properties that have led to advances in electronics, materials science, and drug delivery. Many types of ENM are produced by the metric ton per year and, thus, exposures in occupational and environmental settings are likely. The respiratory tract is a primary route of entry for ENM in such exposure settings. Recent in vitro and in vivo studies have demonstrated the ability of ENM to induce oxidative stress, inflammatory and profibrotic mediator release, and pathology. However, the long-term consequences of ENM exposures at realistic concentrations in humans are unclear because short-term testing is often done at unreasonably high doses and/or under unrealistic conditions. This project is aimed at characterizing risk from realistic human exposures to ENM. Research Plan: We hypothesize that inhaled ENM induce inflammation in the lungs through their oxidative stress-inducing potential that is related to their reactive surface properties and that the ensuing pulmonary inflammatory response enhances translocation to and effects in secondary target sites such as pleura and central nervous system. Furthermore, we hypothesize that rapid screening assays can be developed that are predictive of short- and long-term health outcomes if they are related to relevant mechanisms of toxicity at realistic doses. Our objectives are to assess the predictability of short-term acellular, cellular in vitro, and in vivo assays for long-term adverse health outcomes in the respiratory tract and to quantitate ENM translocation- related effects in secondary tissues following realistic inhalation exposure using a multidisciplinary tiered testing approach. The objectives to test the hypothesis will be met with four Specific Aims to: 1) evaluate workplace ENM exposures; 2) use acellular systems to assess the characteristics and oxidative reactivity of ENM; 3) compare pulmonary and secondary tissue responses to and biokinetics of ENM following single and repeated respiratory tract exposures in rats under realistic conditions using a novel aerosolization system; and 4) evaluate ENM dose-response relationships in cultured primary and secondary organ target cells using doses that are derived from in vivo biokinetics studies of inhaled ENM. Extensive correlation analyses will be done to test a new concept of a response metric that can be used to reliably compare outcome measures from different short-term tests. Expected Results: We expect that acellular and cellular assays of ENM activity will correlate with and be predictive of target cell inflammatory responses, lung inflammation, and secondary organ responses in vivo. These results, as well as information about exposure levels at workplaces and about the persistence of ENM in lung and secondary target tissues, can be used for preliminary risk estimations of the long-term adverse human health outcomes related to ENM exposure and as a basis for more extensive risk assessment. PUBLIC HEALTH RELEVANCE: The use of engineered nanomaterials (ENM) in consumer products has raised concerns about risks to human health following release into workplaces or the environment and some recent studies have described adverse outcomes following in vitro and in vivo exposures. We will conduct comprehensive studies - including workplace exposure characterizations, acellular ENM functional characterizations, in vitro tests of effects in cultured target cells, and in vivo effects and material distribution studies in rodents - to assess dose-related effects in the lung, pleura, and central nervous system following realistic inhalation exposures to ENM that are delivered in their native state without additional surface modifications. These results will be used to develop and validate short-term tests that can be used for estimating potential human risk following ENM exposure.

描述（由申请人提供）：工程纳米材料（ENM）有可能由于独特的特性而导致电子，材料科学和药物输送的独特特性彻底改变每天的生活。每年的度量公吨都会产生许多类型的ENM，因此可能在职业和环境环境中暴露。呼吸道是在这种曝光设置中ENM的主要进入途径。最近的体外和体内研究表明，ENM诱导氧化应激，炎症和纤维化介质释放以及病理学的能力。但是，在人类逼真的浓度下，ENM暴露的长期后果尚不清楚，因为短期测试通常是在不合理的高剂量和/或在不切实际的条件下进行的。该项目旨在表征现实的人类暴露于ENM的风险。研究计划：我们假设吸入的ENM通过其氧化应激诱导潜力引起肺部炎症，与其反应性表面特性相关，随之而来的肺炎症反应会增强诸如Pleura和中枢神经系统等次要靶位点的易位和影响。此外，我们假设可以开发快速筛查测定法，这些测定可以预测短期和长期健康结果，如果它们与现实剂量时毒性的相关机制有关。我们的目标是评估短期细胞，体外细胞的可预测性，以及在呼吸道中长期不良健康结果的体内测定，并使用多学科的二级测试方法对二级组织中的ENM易位 - 相关效应进行定量。检验该假设的目标将具有四个特定目的：1）评估工作场所ENM暴露； 2）使用细胞系统评估ENM的特性和氧化反应性； 3）使用新型的雾化系统在逼真的条件下，在大鼠中对ENM的肺和次要组织反应和二次组织反应和生物动力学进行比较； 4）使用从体内生物动力学研究中得出的吸入ENM的剂量来评估培养的原始和次要器官靶细胞中的ENM剂量反应关系。将进行广泛的相关分析来测试一个新的响应度量概念，该概念可用于可靠地比较不同短期测试的结果度量。预期结果：我们期望ENM活性的细胞和细胞测定将与靶细胞炎症反应，肺部炎症和体内二级器官反应相关并预测。这些结果以及有关工作场所的暴露水平以及有关肺和次要目标组织中ENM持久性的信息，可用于对与ENM暴露有关的长期不良人类健康结果的初步风险估计，并作为更广泛的风险评估的基础。 公共卫生相关性：在消费产品中使用工程纳米材料（ENM）引起了人们对在工作场所或环境中释放后对人类健康风险的担忧，并且最近的一些研究描述了体外和体内暴露后的不良结果。我们将进行全面的研究 - 包括工作场所的暴露特征，细胞ENM功能特征，体外对培养的靶细胞效应的体外测试以及啮齿动物的体内效应和材料分布研究 - 以评估肺，pleura和中枢神经系统中与剂量相关的剂量相关的作用，以及对ENM的现实性吸入状态，而无需进行现实的表面状态。这些结果将用于开发和验证短期测试，可用于估计ENM暴露后潜在的人类风险。