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

通过机械毒理学评估室内和室外空气污染物暴露对健康的影响的危害识别平台

• 批准号: NE/W002051/1
• 负责人: Jacqueline Hamilton
• 金额: $ 52.38万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NE%2FW002051%2F1
• 关键词: Hazard; Identification; Platform; Assess; Health

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.

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衡量指标。流行病学方法一直难以理清该物质中 PM 成分以及 NO2 等共污染物气体的相对危害，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。这没有什么毒理学意义。缺乏 PM 成分和共同排放气体的相对危害排名意味着政策侧重于基于污染物浓度总体降低的生硬策略，而不是对健康相关来源和成分的精细关注。这会带来意想不到的后果的风险，例如为了遵守法规而关注 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带来预期的健康益处。在室外空气中，这个问题二十多年来一直没有得到解决，但异质的室内环境又带来了进一步的复杂性，必须在全面的暴露情况下考虑这一问题。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、毒理学和生物医学领域公认的专业知识，通过世界领先的跨学科合作建立空气污染危害识别平台。该平台将能够对不同来源的特定污染物混合物进行受控和表征暴露，以进行体外、体内动物和人类毒理学研究。我们将利用曼彻斯特大学的大型大气模拟室进行实验，让人类志愿者在环境大气水平下暴露于柴油废气、木烟、烹饪排放物、二次有机气溶胶和氮氧化物增强混合物中。这些之所以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。室暴露将用作参考，这些实验将用于为合作伙伴机构的体外和转基因动物暴露提供过滤后的 PM 样本。将开发、表征和部署所有主要和次要污染物混合物的可参考便携式源装置，以用于体外和动物暴露于完整的气体和颗粒混合物。在提案中，我们将展示该平台阐明空气污染神经系统影响所涉及的毒理学机制的能力，尽管该平台可以获取任何健康结果。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，将以组织和细胞特异性方式在体内跟踪暴露于各种污染物的应激反应，并提供可与体外相关的污染物的危害等级。分子签名。对易患阿尔茨海默病的小鼠品系进行重复实验将检查这些应激反应的变化。将在目标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，并接受接触不同混合物的认知测试，进一步使其危险排名与体外和动物研究相关。将使用候选驱动的生物标志物以及非目标代谢组学和表观遗传学研究来探索动物和人类暴露反应之间的机制联系。

项目成果

Overcoming the lack of authentic standards for the quantification of biogenic secondary organic aerosol markers

• DOI: 10.1039/d2ea00074a
• 发表时间: 2023
• 期刊: Environmental Science: Atmospheres
• 作者: D. Bryant;Alfred W. Mayhew;K. Pereira;S. Budisulistiorini;Connor Prior;W. Unsworth;D. Topping;A. Rickard;J. Hamilton