氧化铝纳米颗粒暴露特征及其职业暴露所致神经毒性的关联性研究

This project aims to study the exposure characteristics of alumina nanoparticles in the workplace and their formation mechanisms that are related to particle agglomeration and production environmental factors, as well as to reveal the association between the elements of exposure characteristics and neurotoxic effects. After a particle emission model for alumina nanoparticles is established, the relationships between particle agglomeration modes (i.e. primary particles, agglomeration or combination with background particles) and periodicity of concentration variation, dynamic change in particle size and particle nature were investigated through utilizing multiple nanoparticle measurement techniques. The influence of production environmental factors (including background particles, working activities, ventilation, spatial distribution and meteorological conditions) on exposure characteristics is investigated. The exposure assessment for nanoparticles in the workplace is established based on the above two findings. Additionally, through in vitro and in vivo tests, the correlations between the elements of exposure characteristics (e.g. mass concentration, number concentration, surface area concentration, particle size and their chemical compositions) and indicators for neurotoxic effects (e.g. oxidative stress, inflammation response, cytotoxicity and genotoxicity, functions of learning and motion, neurotransmitters) are investigated. Moreover, related biomarkers are screened through an analysis of dose-effect (response). Finally, an investigation for verification in the occupational population is conducted to improve the exposure assessment method established and to confirm the biomarkers screened. These findings will accelerate the making of occupational standards for nanoparticles in the workplace, as well as the screening of biomarkers for nano-alumina, thus provide a baseline data for the health risk assessment of nanomaterials.

项目旨在研究氧化铝纳米颗粒暴露特征及其颗粒聚集、生产环境因素相关的形成机制，揭示其暴露特征要素的神经毒性效应关联性。建立氧化铝纳米颗粒排放源模型，联合应用最新纳米颗粒测量技术，研究浓度演变周期性、粒径和颗粒属性的规律变化与颗粒聚集模式（原始颗粒、自身聚集或与背景颗粒结合）关系；并分析背景颗粒、作业活动、通风、空间分布和气象条件等生产环境因素对暴露特征形成的影响。基于上述两个结果建立工作场所纳米颗粒暴露评估方法。另外，从体外、动物实验研究暴露特征要素（质量浓度、数量浓度、表面积浓度、粒径和化学组成）与神经毒性指标（氧化应激、炎症反应、细胞遗传毒性、学习运动功能、神经递质等）的关联性，通过剂量效应（反应）关系筛选相应生物标志物；最后,通过人群验证来完善已建立的暴露评估方法及确认筛选出的生物标志物。研究结果将推动我国纳米颗粒职业卫生标准制定和纳米氧化铝生物标志的筛选，为纳米材料健康风险评估奠

氧化铝纳米颗粒的暴露特征与神经毒性的关联性研究甚少。本课题研究氧化铝纳米颗粒暴露特征的颗粒聚集形成机制，揭示氧化铝纳米颗粒暴露特征基本要素的神经毒性效应相关性，建立工作场所纳米颗粒暴露评估方法和测量方法，从氧化铝纳米颗粒实验研究、体外实验、体内实验和人群验证四个维度研究。研究结果发现，氧化铝纳米颗粒有其特有的颗粒聚集模式、演变周期和粒径变化规律，数量浓度和表面积浓度相对于质量浓度更能反映纳米颗粒暴露情况,与作业活动密切相关。体外实验结果发现纳米氧化铝颗粒比大尺寸颗粒或对照纳米颗粒容易被神经元细胞摄入，导致更大细胞毒性、氧化应激反应、炎症反应，且对细胞的损伤程度随着粒径减小而加重。动物实验结果发现纳米颗粒更能导致小鼠外周血细胞DNA损伤、神经细胞凋亡及淀粉样斑块形成、动物的学习记忆功能减退等，且对动物的损伤程度随着粒径减小而加重。人群调查初步验证了氧化应激反应和内暴露负荷增加。研究结果说明，纳米颗粒产生被释放到空气中具有独特的暴露特征。氧化铝纳米颗粒比微米级颗粒能诱发更大的神经毒性效应，该效应与颗粒浓度、粒径、化学成分等暴露特征显著相关。筛选出1 组氧化铝纳米颗粒健康效应生物标志物，包括了尿铝、DNA损伤、凋亡、淀粉样斑块、学习记忆功能等；根据已有研究结果，建立了工作场所纳米颗粒暴露评估方法和测量方法，其相应的国家标准《工作场所空气中粉尘测定 第6部分： 超细颗粒、细颗粒总数量浓度》（GBZ/T192.6-2018）已经由国家卫生健康委发布，发表了11篇SCI收录的论文和4部专著，国家大会交流1次。研究结果为下一步大规模的人群流行病学调查、纳米颗粒毒作用机制研究以及工作场所纳米颗粒测量技术推广应用奠定了科学基础。