Hazard Identification Platform to Assess the Health Impacts from Indoor and Outdoor Air Pollutant Exposures, through Mechanistic Toxicology

英国空气质量政策对颗粒物（PM2.5）质量减少的关注反映了监管合规的衡量标准。流行病学方法一直在努力理清这一质量中PM成分的相对危害，以及共同污染气体，如二氧化氮，导致人们认为所有PM2.5成分都必须被视为对人类健康同样有害。这在毒理学上说不通。由于缺乏对可吸入颗粒物成分和共同排放气体的相对危害排名，政策侧重于基于总体减少污染物浓度的生硬战略，而不是侧重于与健康有关的来源和成分。这可能会带来意想不到的后果，例如，关注PM2.5的最大贡献者以遵守法规，而不是最有害的部分，可能无法为我们社会中最脆弱的成员带来预期的健康益处。在室外空气中，这个问题20多年来一直没有得到解决，但室内环境的异质性带来了进一步的复杂性，这必须在一个完整的暴露图中加以考虑。为了解决这一重大知识差距，英国需要整合和关注毒理学资源方法，以确定室内和室外PM中最危险的部分，并阐明导致疾病发展和恶化的因果途径。我们提议的联盟汇集了英国在大气科学、毒理学和生物医学科学方面公认的专业知识，以世界领先的跨学科合作建立一个空气污染危害识别平台。该平台将提供对来自不同来源的确定污染物混合物进行受控和特征暴露的能力，用于体外、体内动物和人体毒理学研究。我们将利用曼彻斯特大学的大型大气模拟室进行实验，将人类志愿者暴露在柴油废气、柴烟、烹饪废气、二次有机气溶胶和氮氧化物增强混合物中，所有这些都是在环境大气水平下进行的。这些被选中是因为它们对室内和室外空气污染做出了公认的重大贡献。室内暴露将作为参考，这些实验将用于为伙伴机构的体外和转基因动物暴露提供PM的过滤样品。将开发可用于所有主要和次要污染物混合物的可参考便携式源单元，对其进行表征，并用于体外和动物接触完整的气体和颗粒混合物。在提案中，我们将展示平台阐明空气污染对神经系统影响所涉及的毒理学机制的能力，尽管平台可以获得任何健康结果。体外研究将用于探索神经炎症和损伤可能的直接和间接机制，确定与细胞激活相关的分子途径。使用一组独特的转基因应激报告小鼠系，将在体内以组织和细胞特异性的方式跟踪暴露于各种污染物的应激反应，并提供污染物的危害等级，这些污染物可以与体外分子特征联系起来。对易患阿尔茨海默病的小鼠进行重复实验，将检验这些应激反应的变化。将在靶组织中检查表观遗传DNA特征。一组有痴呆风险增加家族史的健康老年人类受试者将提供生物样本，并接受接触不同混合物的认知测试，进一步使其危害排名与体外和动物研究相关联。动物和人类暴露反应之间的机制联系将通过候选驱动的生物标志物和非靶向代谢组学和表观遗传学研究来探索。

The focus on particulate matter (PM2.5) mass reductions in UK air quality policy reflects the metrics measured for regulatory compliance. Epidemiological approaches have struggled to untangle the relative hazard of PM constituents within this mass, as well as co-pollutant gases, such as NO2, leading to the contention that all PM2.5 components must be treated as being equally harmful to human health. This makes little toxicological sense. The lack of a relative hazard ranking of PM constituents and co-emitted gases means that policy focuses on blunt strategies based on overall reductions in pollutant concentrations, rather than a refined focus on health relevant sources and components. This poses risks of unintended consequences, e.g. focusing on the largest contributors to PM2.5 for regulatory compliance, rather than the most harmful fractions, may fail to deliver predicted health benefits to the most vulnerable members of our society. In outdoor air this has remained unresolved for over 20-years, but further complexity is introduced by the heterogeneous indoor environment which must be considered in a complete picture of exposure. To address this major knowledge gap, the UK requires integration and focus of toxicological resource methodologies to identify the most hazardous fractions of indoor and outdoor PM and to elucidate the causal pathways contributing to disease development and exacerbation. Our proposed consortium brings together recognised UK expertise in atmospheric sciences, toxicology and biomedical sciences in a world-leading interdisciplinary collaboration to build an Air Pollution Hazard Identification Platform. This platform will deliver the capability to conduct controlled and characterised exposures to defined pollutant mixtures from different sources for in vitro, in vivo animal and human toxicological studies. We will use the large atmospheric simulation chamber at the University of Manchester to conduct experiments exposing human volunteers to diesel exhaust, woodsmoke, cooking emissions, secondary organic aerosol and NOx-enhanced mixtures, all at ambient atmospheric levels. These have been selected for their recognised substantial contributions to indoor and outdoor air pollution. The chamber exposures will be used as a reference and these experiments will be used to provide filtered samples of the PM for in vitro and transgenic animal exposures at the partner Institutions. Referenceable portable source units for all primary and secondary pollutant mixtures will be developed, characterised and deployed for in vitro and animal exposures to the full gas and particle mixture. Within the proposal, we will demonstrate the capability of the platform to elucidate the toxicological mechanisms involved in the neurological impacts of air pollution, though any health outcomes are accessible to the platform. The in vitro studies will be used to explore possible direct and indirect mechanisms for neuroinflammation and injury, identifying the molecular pathways associated with cellular activation. Using a unique panel of transgenic stress-reporter mouse lines, the stress response on exposure to the various pollutants will be tracked in a tissue and cell specific manner in vivo and provide a hazard ranking of the pollutants that can be related back to the in vitro molecular signatures. Repeat experiments with mouse lines susceptible to Alzheimer's disease will examine changes in these stress responses. Epigenetic DNA signatures will be examined in target tissues. A panel of healthy aged human subjects with a family history of increased dementia risk will provide biosamples and be subjected to cognitive tests on exposure to the different mixtures, further enabling their hazard ranking for correlation with the in vitro and animal studies. The mechanistic linkages between the animal and human exposure responses will be explored using candidate driven biomarker and untargeted metabolomic and epigenetic studies.