Lena Palmberg

Lung development starts in utero and continues during childhood, and can be altered by several host and environmental factors during the life-course. A range of lung function trajectories exist in the population and sub-normal trajectories are associated with several health outcomes, including respiratory (such as asthma and COPD) and cardiovascular disease.Here we propose that lung function charts could be used both for children and adults to monitor lung health status across the life-course. To this end, we have recently introduced our freely available online “Lung Function Tracker” tool.Going forward, we hypothesize in this project thatlung function trajectory modelling and long-term risk prediction of chronic airway disease be improved by incorporating individual-level clinical, lifestyle and environmental expsure data in the modelsSystemic biomarkers measured early in life provide prognostic values for long-term disease risk up to adulthoodGenetics and upper airway methylation and gene expression data will give insight into mechanisms related to onset and progression of chronic airway diseaseThe expected outcomes of the project are 1) a new prediction tool that reliably may predict long-term individual lung function trajectory and asthma/COPD risk

2) exploration of new mechanisms of airway disease and identification of novel targets for early disease detection and 3) key genes and pathways for impaired lung function and asthma/pre-COPD will be identified.

Research problem and specific questions: Cleaning and disinfection agents are widely used in various occupational settings and a growing body of evidence from observational studies shows this results in lung function impairments. However, mechanisms a behind these effects are yet unclear. This project aims to clarify the risks of lung disease posed by the mixtures in cleaning agents and evaluate the adequacy of applicable regulations. Specifically:Which biomarkers of cell membrane integrity inflammation, toxicity and cell death are activated in in vitro advanced lung mucosa models by cleaning agent exposure?How do responses compare between alveolar and bronchial mucosa models?How do responses compare between exposures to mixtures and ingredients one by one?What are the implications of potential mixture effects for regulatory hazard assessments?Data and method: We will employ systematic literature search strategies and new approach methodologies (NAMs), including advanced multicellular lung mucosa in vitro models and adverse outcome pathways (AOPs). The AOPs will be used to organise existing knowledge and translate experimental findings, such as molecular mechanisms and cellular reactions in vitro, to a human in vivo setting.Plan for project realisation: The project will start with a scoping review to connect mechanistic data to adverse respiratory tract outcomes and map out a tentative AOP network and identify mechanisms, or key events, of particular relevance to pursue experimentally. Next, experimental work on fully formulated products will be performed in multi-cellular human bronchial and alveolar models. To start untangling the mixture effects the third substudy concerns experimental work on single substance exposures. Finally, we will perform case-studies on mixture risk assessment inhalation exposure to cleaning agents.Relevance: The wide-spread use of cleaning agents makes it a chemical risk factor for a broad part of the workforce. A mechanistic understanding is essential for regulatory risk assessment, as are further studies of cleaning agents’ mixture effects and their role in lung disease. Our project is a step in identifying problematic substances and substance combinations in mixtures and lays the foundation for knowledge that can lead to reformulation of cleaning agents into safer alternatives. Our project also contributes to the field of mixture risk assessment, where inhalation exposure of mixtures is under-researched field.

The development of novel renewable fuels is paramount for reducing carbon emissions and mitigating climate change. Biofuels, such as biodiesel and lignin-based fuels could play an important role for this endeavour, particularly in Sweden. However, particles generated from combustion of such fuels could have a negative impact on human health, similar to traditionally used fuel. Knowledge on these aspects is scarce. The aim of this project is to evaluate lung toxicity of particles generated from combustion of novel biofuels such as ‘new generation’ biodiesel and lignin-based fuels that are originating from raw forest material. To this end the project will use advanced 3D in vitro models of the human lungs and experimental setups that resemble human exposure, i.e. acute and chronic exposure (3 months) at low, realistic doses. Traditional toxicological endpoints (e.g. inflammation, DNA damage) will be combined with RNA-sequencing in order to gain deep insight into potential mechanisms of toxicity and generate new hypotheses. We will also use 3D models representative of vulnerable populations such as individuals with asthma. The 3D models will be co-cultured with immune cells to evaluate the influence of the immune component for toxicity. Diesel exhaust particles will be used as reference particles for benchmarking. Overall, this project will provide relevant information on the toxicity of novel fuels that is of critical value for risk assessment and sustainable development.