Theme III - Biomarkers of exposure and effect
Theme III will use a 'whole systems' approach to study the mechanistic pathways linking ambient air pollution exposure to disease outcomes. This Theme will involve metabolic phenotyping technologies (metabolomics) that are powerful tools to capture information on a range of toxicological and disease processes. As exhaust emission controls take effect, non-exhaust emissions from brakes and tyres are drawing increasing attention. Research on the health impacts of these emissions will provide information requested by the Committee on the Medical Effectives of Air Pollutants (COMEAP). Our work on asthma aims to identify the components and sources of ambient PM that contribute most to negative impacts in this condition. Finally, our work on e-cigarettes will fulfil the UK Health Security Agency requirements in this important area.
Theme III Projects
Project outline: There is an incomplete understanding of the initial biochemical and physiological disturbances related to pollutant exposure that drive the causal pathways to disease and disease exacerbation. These pathway data are necessary to strengthen the causal basis for the epidemiological findings of an association between air pollution and disease outcomes and disease interventions. We will use multivariate metabolic phenotyping to discover novel blood-based markers of air pollution exposures and discern causal pathways (asbestos, diesel exhaust, wood smoke).
Project outline: Changes in the traffic fleet are leading to alterations in the types of airborne particles. To date, the major public health focus has been on exhaust particles. As these exhaust particles decrease, focus is changing to particles from tyre, brake, and road wear. These particles are generated from both electric and combustion vehicles and they have a different composition from combustion particles and thus may have different health effects. This project will use in vitro models to examine the effects of non-exhaust particles on pulmonary immunity, with focus on macrophage and dendritic cell function.
Project outline: To build on work from the previous HPRU, and link with other projects to test a range of PM samples for their effects in humans to understand components that drive inappropriate inflammatory responses. This will be associated with PM compositional data in order to identify relevant signalling pathways and explore potential mediators that may mitigate detrimental PM effects.
Project outline: Knowledge gaps exist around the toxicity of e-cigarette components, especially around flavour chemicals that are considered as safe based only on oral toxicology data. Toxicity to human airway cells will be investigated by combining air-liquid interface exposure and high-throughput toxicity screening assays. This work will be undertaken by a NIHP-funded PhD student. Additional studies will evaluate the contributions of e-cigarette device characteristics (coil age, temperature settings, coil resistance etc.) and ageing to aerosol characteristics. Characterisation will include analysis of aerosol (number concentration and size distribution) and determining the concentrations of nicotine, VOCs, metals and flavour compounds in air and deposited on surfaces. Using these analyses estimate theoretical quantities and location of aerosol deposited within the lung.
Project outline: Build on previous HPRU networks, capitalising on the novel systems developed in the toxicological assessment of particulates and in vitro cell systems to investigate the mechanistic basis of the adverse health effects of combustion derived particulates and NO2, that are currently ill-understood and difficult to separate in epidemiological studies. These novel systems have many advantages in terms of achieving more realistic exposure modalities (e.g. ALI aerosol exposure) and biological relevance (e.g. co-culture models). Comparative toxicology using these approaches will allow measured/considered judgement on the plausibility and likely size of possible mechanistic effects, to include lung inflammation, oxidative stress, aging, carcinogenicity potential and innate immunity governing adaptive immune responses to allergens. The initial part of this project will focus on establishing, characterising and validating the laboratory conditions for such combinatorial experiments to take place.
Project outline: Uncertainties remain about the potential health impact of nanomaterials and other advanced materials, especially at environmentally relevant levels. This work commenced in the previous HPRU and the intention is to extend this. Using established cellular models and exposure systems further advanced under Project 5, the size of possible mechanistic effects, to include lung inflammation, oxidative stress, aging, carcinogenicity potential and innate immunity governing adaptive immune responses to allergens, in response to a number of relevant materials will be evaluated. Attempts to classify materials into response type groups will be made to assist in supporting future read-across approaches for regulatory control. With its focus on mechanistic toxicity and inhaled materials the project has many synergies with projects in Theme III and will have useful input on materials and exposure levels from Theme I project 4.