Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

描述（由申请人提供）：工程纳米材料（ENM）具有革命性的日常生活的潜力，由于独特的性能，导致了电子，材料科学和药物输送的进步。许多类型的化学纳米材料每年都以公吨为单位生产，因此，在职业和环境环境中的接触是可能的。呼吸道是此类暴露环境中ENM的主要进入途径。最近的体外和体内研究已经证明ENM诱导氧化应激、炎症和促纤维化介质释放以及病理学的能力。然而，人体实际浓度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/或不现实的条件下进行的。该项目的目的是确定人类实际接触电磁辐射的风险。研究计划：我们假设吸入ENM通过与其反应性表面特性相关的氧化应激诱导潜力诱导肺部炎症，并且随后的肺部炎症反应增强了向次级靶位点（如胸膜和中枢神经系统）的转运和对次级靶位点的影响。此外，我们假设，快速筛查检测可以开发预测短期和长期的健康结果，如果它们与现实剂量的相关毒性机制有关。我们的目标是评估短期无细胞、细胞体外和体内试验对呼吸道长期不良健康结果的可预测性，并使用多学科分层测试方法定量真实吸入暴露后次级组织中ENM易位相关效应。检验假设的目的将通过以下四个具体目标实现：1）评价工作场所ENM暴露; 2）使用非细胞系统评估ENM的特性和氧化反应性; 3）使用新型雾化系统在现实条件下比较大鼠单次和重复呼吸道暴露后肺部和继发组织对ENM的反应和生物学代谢;和4）使用来自吸入ENM的体内生物动力学研究的剂量，评价培养的原代和次级器官靶细胞中ENM的剂量-反应关系。将进行广泛的相关性分析，以测试一个新的概念，可以用来可靠地比较结果的措施，从不同的短期测试的反应度量。预期结果：我们预期ENM活性的非细胞和细胞测定将与体内靶细胞炎症反应、肺部炎症和次级器官反应相关并可预测这些反应。这些结果，以及在工作场所的接触水平和有关的持久性ENM在肺和次要目标组织的信息，可用于初步的风险估计的长期不利的人类健康结果与ENM接触，并作为更广泛的风险评估的基础。 公共卫生相关性：在消费品中使用工程纳米材料引起了人们对释放到工作场所或环境中后对人类健康风险的担忧，最近的一些研究描述了体外和体内接触后的不良后果。我们将进行全面的研究-包括工作场所暴露表征，非细胞ENM功能表征，体外培养靶细胞效应测试，以及啮齿动物体内效应和材料分布研究-以评估现实吸入暴露于ENM后肺，胸膜和中枢神经系统中的剂量相关效应，这些ENM以其天然状态提供，无需额外的表面修饰。这些结果将用于开发和验证可用于估计ENM暴露后潜在人类风险的短期测试。

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.