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性的衡量指标。流行病学方法一直在努力解开这个质量中PM成分的相对危害，以及共污染气体，如NO2，导致所有PM2.5成分必须被视为对人类健康同样有害的争论。这在毒理学上没有什么意义。缺乏PM成分和共同排放气体的相对危害等级意味着政策重点是基于污染物浓度总体降低的生硬战略，而不是对健康相关来源和成分的精细关注。这带来了意外后果的风险，例如，专注于PM2.5的最大贡献者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提供预期的健康益处。在室外空气中，这一问题20多年来一直没有得到解决，但在完整的暴露情况下，必须考虑异质室内环境带来的进一步复杂性。为了解决这一重大的知识差距，英国需要整合和重点的毒理学资源方法，以确定室内和室外PM的最危险的部分，并阐明因果关系的途径，有助于疾病的发展和恶化。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的公认专业知识，开展世界领先的跨学科合作，以建立空气污染危害识别平台。该平台将提供对来自不同来源的特定污染物混合物进行受控和特征化暴露的能力，用于体外，体内动物和人类毒理学研究。我们将使用曼彻斯特大学的大型大气模拟室进行实验，将人类志愿者暴露于柴油废气，木材烟雾，烹饪排放物，二次有机气溶胶和NOx增强混合物中，所有这些都处于环境大气水平。这些被选中是因为它们对室内和室外空气污染的重大贡献。试验箱暴露将用作参考，这些实验将用于提供PM的过滤样本，供合作机构进行体外和转基因动物暴露。将为所有一级和二级污染物混合物开发可参考的便携式污染源装置，确定其特征并部署用于体外和动物暴露于全部气体和颗粒混合物。在该提案中，我们将展示该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，尽管该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的可能直接和间接机制，确定与细胞活化相关的分子途径。使用一组独特的转基因应激报告小鼠品系，将在体内以组织和细胞特异性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，该等级可与体外分子特征相关。对易患阿尔茨海默氏病的小鼠进行重复实验，将检查这些应激反应的变化。将在靶组织中检查表观遗传DNA特征。一组具有痴呆风险增加家族史的健康老年人受试者将提供生物样本，并接受暴露于不同混合物的认知测试，进一步使其危险等级与体外和动物研究相关。将使用候选驱动生物标志物和非靶向代谢组学和表观遗传学研究探索动物和人体暴露反应之间的机制联系。

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.