Hazard Assessment and Risk Estimation of Inhaled Nanomaterials Exposure

描述（由申请人提供）：工程纳米材料（ENM）由于其独特的特性，在电子学、材料科学和药物输送方面取得了进步，因此具有彻底改变日常生活的潜力。许多类型的ENM每年以公吨为单位产生，因此可能在职业和环境环境中暴露。在这种暴露环境下，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具有诱导氧化应激、炎症和纤维化介质释放和病理的能力。然而，人体实际浓度的ENM暴露的长期后果尚不清楚，因为短期试验经常在不合理的高剂量和/或不现实的条件下进行。该项目旨在描述人类实际接触ENM的风险。研究计划：我们假设吸入ENM通过其氧化应激诱导电位诱导肺部炎症，这与其反应性表面特性有关，随后的肺部炎症反应增强了向胸膜和中枢神经系统等次要靶点的易位和作用。此外，我们假设，如果快速筛选试验与实际剂量下的毒性相关机制相关，则可以开发出预测短期和长期健康结果的快速筛选试验。我们的目的是评估短期脱细胞、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吸入暴露后继发组织中ENM易位相关的影响。测试假设的目标将满足四个具体目标：1)评估工作场所ENM暴露；2)利用脱细胞系统评价ENM的特性和氧化反应性；3)比较现实条件下使用新型雾化系统的大鼠单次和多次呼吸道暴露对ENM的肺和继发组织反应和生物动力学；4)利用吸入ENM的体内生物动力学研究得出的剂量，评估ENM在培养的初级和次级器官靶细胞中的剂量-反应关系。将进行广泛的相关分析，以检验可用于可靠地比较不同短期试验结果测量值的反应度量的新概念。预期结果：我们预计ENM活性的非细胞和细胞分析将与靶细胞炎症反应、肺部炎症和体内继发器官反应相关并可预测。这些结果，以及关于工作场所接触水平和关于ENM在肺部和次级靶组织中持续存在的信息，可用于对与ENM接触有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。

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.