Respiratory Effects of Traffic-Related Air Pollution: A Randomized, Crossover Analysis of Lung Function, Airway Metabolome, and Biomarkers of Airway Injury

BACKGROUND: Exposure to traffic-related air pollution (TRAP) has been associated with increased risks of respiratory diseases, but the biological mechanisms are not yet fully elucidated. OBJECTIVES: Our aim was to evaluate the respiratory responses and explore potential biological mechanisms of TRAP exposure in a randomized crossover trial. METHODS: We conducted a randomized crossover trial in 56 healthy adults. Each participant was exposed to high- and low-TRAP exposure sessions by walking in a park and down a road with high traffic volume for 4 h in random order. Respiratory symptoms and lung function, including forced expiratory volume in the first second ([Formula: see text]), forced vital capacity (FVC), the ratio of [Formula: see text] to FVC, and maximal mid-expiratory flow (MMEF), were measured before and after each exposure session. Markers of 8-isoprostane, tumor necrosis [Formula: see text] ([Formula: see text]), and ezrin in exhaled breath condensate (EBC), and surfactant proteins D (SP-D) in serum were also measured. We used linear mixed-effects models to estimate the associations, adjusted for age, sex, body mass index, meteorological condition, and batch (only for biomarkers). Liquid chromatography–mass spectrometry was used to profile the EBC metabolome. Untargeted metabolome-wide association study (MWAS) analysis and pathway enrichment analysis using mummichog were performed to identify critical metabolomic features and pathways associated with TRAP exposure. RESULTS: Participants had two to three times higher exposure to traffic-related air pollutants except for fine particulate matter while walking along the road compared with in the park. Compared with the low-TRAP exposure at the park, high-TRAP exposure at the road was associated with a higher score of respiratory symptoms [2.615 (95% CI: 0.605, 4.626), [Formula: see text]] and relatively lower lung function indicators [[Formula: see text] (95% CI: [Formula: see text] , [Formula: see text]), [Formula: see text]] for [Formula: see text] and [Formula: see text] (95% CI: [Formula: see text] , [Formula: see text]; [Formula: see text]) for MMEF]. Exposure to TRAP was significantly associated with changes in some, but not all, biomarkers, particularly with a [Formula: see text] (95% CI: 0.297, 0.691; [Formula: see text]) increase for serum SP-D and a [Formula: see text] (95% CI: [Formula: see text] , [Formula: see text]; [Formula: see text]) decrease for EBC ezrin. Untargeted MWAS analysis revealed that elevated TRAP exposure was significantly associated with perturbations in 23 and 32 metabolic pathways under positive- and negative-ion modes, respectively. These pathways were most related to inflammatory response, oxidative stress, and energy use metabolism. CONCLUSIONS: This study suggests that TRAP exposure might lead to lung function impairment and respiratory symptoms. Possible underlying mechanisms include lung epithelial injury, inflammation, oxidative stress, and energy metabolism disorders. https://doi.org/10.1289/EHP11139