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

点击翻译按钮获取中文摘要

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.