Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

描述(申请人提供)：工程纳米材料(ENM)因其独特的性能而有可能给日常生活带来革命性的变化，这些独特的性能导致了电子学、材料科学和药物输送的进步。许多类型的ENM是以每年公吨为单位生产的，因此，在职业和环境环境中暴露是可能的。在这样的暴露环境中，呼吸道是ENM的主要进入途径。最近的体外和体内研究表明，ENM能够诱导氧化应激、炎症和促纤维化介质的释放以及病理学。然而，在人体中暴露在实际浓度下的ENM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/或在不现实的条件下进行的。该项目的目的是描述现实中人类暴露于新城疫的风险。研究计划：我们假设吸入ENM通过其与其反应表面特性相关的氧化应激诱导潜力在肺部引起炎症，随后的肺炎症反应增强了对次要靶点的移位和影响，如胸膜和中枢神经系统。此外，我们假设可以开发出预测短期和长期健康结果的快速筛查分析，如果它们与实际剂量下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后果的可预测性，并使用多学科分级测试方法量化实际吸入暴露后二次组织中与ENM移位相关的影响。检验这一假说的目标将满足四个具体目标：1)评估工作场所ENM暴露；2)使用非细胞系统评估ENM的特征和氧化反应性；3)使用新型雾化系统在现实条件下比较大鼠单一和重复呼吸道暴露后ENM的肺和继发性组织反应及其生物动力学；以及4)使用来自体内吸入ENM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ENM的剂量-反应关系。将进行广泛的相关性分析，以测试响应指标的新概念，该指标可用于可靠地比较不同短期测试的结果衡量标准。预期结果：我们预计ENM活性的非细胞和细胞检测将与体内靶细胞炎症反应、肺部炎症反应和继发性器官反应相关并可预测。这些结果以及关于工作场所暴露水平和ENM在肺部和次级目标组织中持久性的信息，可用于与ENM暴露相关的长期不利人类健康后果的初步风险估计，并作为更广泛的风险评估的基础。 与公共健康相关：在消费品中使用工程纳米材料(ENM)引起了人们对释放到工作场所或环境中后对人类健康的风险的担忧，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、非细胞ENM功能特征、体外培养目标细胞效应测试，以及啮齿动物体内效应和物质分布研究，以评估真实吸入ENM后在肺、胸膜和中枢神经系统中的剂量相关影响，这些影响是在天然状态下传递的，而不需要额外的表面修饰。这些结果将用于开发和验证短期测试，这些测试可用于评估ENM暴露后的潜在人类风险。

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.