To the best of our knowledge, this is the first national perspective cohort study investigating mortality effects of long-term exposure to ambient NO2 in China. By involving 30,000 + adult participants ages 16–110 years, our study provided robust longitudinal evidence for raised death risk associated with NO2 exposure in Chinese general population. Stratified analyses revealed potential heterogeneities in NO2-mortality associations between subpopulations, suggesting significantly greater vulnerability among men.
In accordance with the up-to-date evidence synthesized from epidemiologic studies, our cohort study identified a significantly positive association between NO2 exposure and all-cause mortality. Several toxicological mechanisms may possibly interpret NO2-induced hazards. Exposure to ambient NO2 could promote a systemic vascular oxidative stress reaction[43, 44], and cause endothelial dysfunction, monocyte activation, and certain pro-atherosclerotic changes in lipoproteins, thereby initiating plaque formation, exacerbating disease, and increasing mortality. For a 10-ppb rise in NO2 exposure, a recent meta-analysis of 28 cohorts estimated a pooled risk of 1.06 (95% CI: 1.04–1.08) in all-cause mortality, whereas substantial heterogeneities existed across studies (HRs ranging between 0.95–1.91). By enrolling a national cohort of 30,843 adults in mainland China, this study associated an excessive death risk of 27.8% (8.8–50.2%) with a 10-ppb increase in annual NO2 exposure. However, two prior Chinese investigations reported an insignificant or opposite NO2-mortality association in Hong Kong elderly and northern residents. Sources of huge heterogeneity between existing studies still remain not well clarified, but could possibly be related to great diversity in exposure assessment methods (e.g., fixed monitor, land use regression, and satellite-based retrievals), study demographics (e.g., age structure, locations, and NO2 exposure levels), methodological strategies (e.g., sample size, confounding adjustment, and statistical analysis).
Using time series data from 398 cities in 22 low to high income countries/regions, Meng and colleagues provided strong evidence for the linear associations between short-term NO2 exposure and daily total, cardiovascular, and respiratory mortality. In terms of long-term assessments, most international studies failed to investigate the dose-response curve and reported estimates by assuming a linear relation. Our study did not identify evidence (p = 0.273) for the nonlinear effect of NO2 exposure on all-cause death at a concentration range of 6.9–57.4 µg/m3. The Dutch Environmental Longitudinal Study (DUELS) reported a consistent finding (p = 0.37 for nonlinearity) in associations of NO2 with non-accidental deaths, but found a strongly superlinear relation (p < 0.005) with deaths due to circulatory diseases. Owing to limited longitudinal evidence available for C-R associations between NO2 and mortality outcomes, the state-of-art global burden of disease (GBD) studies only provided comparative estimates of deaths attributable to ambient PM2.5 and ozone, irrespective of the potential contribution from NO2. Using a counterfactual analytic framework adopted by GBD, we attributed 1.65 million deaths to NO2 exposure in China for the year 2018 only, accounting for 112% of GBD 2019 estimate (1.47 million) due to ambient PM2.5 and ozone for Chinese population. NO2-mortality cohort studies focusing on C-R analyses are thus warranted across the world, particularly in developing countries, so as to facilitate more comprehensive GBD estimation of disease burden attributable to ambient air pollution.
Our study observed an elevated death risk associated with NO2 among adult men only, showing a significant effect modification by sex. This finding could be partially explained by great differences in biological heredity between sex and intensity of work-related exposures to outdoor air pollution. Stronger NO2-mortality associations were also estimated for men in two European cohorts, while DUELS reported significantly greater vulnerability among women when assessing mortality causes of respiratory disease and lung cancer. We found a tendency for higher NO2-related HR in younger age groups (16–59 years), which was in agreement with evidence of effect modification by age as highlighted in two large cohorts (over 1 million participants) in Rome and Netherlands for nonaccidental deaths. As demonstrated in our stratified analyses by behavioral factors, only ever/current smokers and alcohol drinkers were at greater death risks induced by NO2 exposure, whereas no clear evidence for modifying effects was identified in our study population. In addition, we estimated highly comparable NO2-associated hazards between those having and not having regular physical activity. Combined effects of air pollution and physical activity on mortality raised great research interest but remained not yet fully understood. In several existing large cohorts of US women (n = 104,990), middle-aged Danish adults (n = 52,061), and Hong Kong elderly (n = 66,820), no significant interactions between NO2/PM2.5 exposure and physical activity were reported in associations with total and cardiovascular mortality.
This study has several strengths. First, this cohort investigation provided the first nationwide epidemiologic evidence for long-term association between NO2 exposure and adult mortality in mainland China. Second, exposure assessment in our analysis was based on high-resolution NO2 prediction models, through taking advantages of satellite retrieved estimates and machine learning methods. This novel advance in methodology could largely reduce exposure errors as compared to the majority of prior cohort studies relying on measurements from fixed-site monitors or estimates derived from geospatial statistical methods and chemistry transport models. Additionally, our analyses took into account a rich set of confounders including individual lifestyles and provided robust NO2-mortality evidence by including high-resolution PM2.5/O3 for additional adjustment.
Some limitations of our analyses should also be noted. First, participants’ NO2 exposures were assessed at the county level rather than assigned based on residential addresses, which may result in some inevitable exposure misclassifications. Second, high-quality NO2 estimates at finer spatial-temporal scales were still of wide lack globally and regionally, which has hampered the comparative analyses using various exposure datasets. Third, owing to data unavailability, we failed to account for residential mobility of study participants in CFPS follow-up surveys during 2012–2018. Finally, cause-specific analyses for NO2-mortality associations were not performed due to a relative high proportion of indeterminable causes of death in the CFPS database. This limitation may introduce some difficulty in direct comparison of estimates of NO2-attributable deaths between our calculation based on all-cause deaths and assessments through summing up cause-specific contributions.