Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

描述（由申请人提供）：工程纳米材料 (ENM) 因其独特的特性而有可能彻底改变日常生活，这些特性促进了电子、材料科学和药物输送领域的进步。许多类型的 ENM 每年产生数吨，因此可能会在职业和环境环境中暴露。在此类暴露环境中，呼吸道是 ENM 进入的主要途径。最近的体外和体内研究表明，ENM 具有诱导氧化应激、炎症和促纤维化介质释放以及病理学的能力。然而，人类实际浓度的 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/或不切实际的条件下进行的。该项目旨在描述人类实际暴露于 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（与其反应性表面特性相关）诱导肺部炎症，并且随后的肺部炎症反应增强了胸膜和中枢神经系统等次要目标部位的易位和影响。此外，我们假设，如果与实际剂量下的相关毒性机制相关，可以开发出可预测短期和长期健康结果的快速筛查方法。我们的目标是评估短期非细胞、细胞体外和体内检测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生组织中 ENM 易位相关的影响。检验假设的目标将通过四个具体目标来实现：1）评估工作场所 ENM 暴露； 2）利用非细胞系统评估ENM的特性和氧化反应性； 3) 使用新型雾化系统，在真实条件下比较大鼠单次和重复呼吸道暴露后 ENM 的肺和继发组织反应和生物动力学； 4) 使用源自吸入 ENM 体内生物动力学研究的剂量评估培养的初级和次级器官靶细胞中的 ENM 剂量反应关系。将进行广泛的相关分析来测试响应指标的新概念，该概念可用于可靠地比较不同短期测试的结果测量。预期结果：我们预计 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。这些结果以及有关工作场所暴露水平以及有关 ENM 在肺和次要目标组织中持续存在的信息，可用于对与 ENM 暴露相关的长期不良人类健康结果进行初步风险评估，并作为更广泛风险评估的基础。 公共健康相关性：工程纳米材料 (ENM) 在消费品中的使用引起了人们对释放到工作场所或环境中后对人类健康造成风险的担忧，最近的一些研究描述了体外和体内暴露后的不良后果。我们将进行全面的研究，包括工作场所暴露特征、无细胞 ENM 功能特征、培养靶细胞效应的体外测试，以及啮齿类动物的体内效应和材料分布研究，以评估真实吸入暴露于天然状态且无需额外表面修饰的 ENM 后对肺、胸膜和中枢神经系统的剂量相关影响。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。

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.