Associations of long-term nitrogen dioxide exposure with a wide spectrum of diseases: a prospective cohort study of 0·5 million Chinese adults

Abstract

Background: Little evidence is available on the long-term health effects of nitrogen dioxide (NO₂) in low-income and middle-income populations. We investigated the associations of long-term NO₂ exposure with the incidence of a wide spectrum of disease outcomes, based on data from the China Kadoorie Biobank.

Methods: This prospective cohort study involved 512 724 Chinese adults aged 30-79 years recruited from ten areas of China during 2004-08. Time-varying Cox regression models yielded adjusted hazard ratios (HRs) for the associations of long-term NO₂ exposure with aggregated disease incidence endpoints classified by 14 ICD-10 chapters, and incidences of 12 specific diseases selected from three key ICD-10 chapters (cardiovascular, respiratory, and musculoskeletal diseases) found to be robustly associated with NO₂ in the analyses of aggregated endpoints. All models were stratified by age-at-risk (in 1-year scale), study area, and sex, and were adjusted for education, household income, smoking status, alcohol intake, cooking fuel type, heating fuel type, self-reported health status, BMI, physical activity level, temperature, and relative humidity.

Findings: The analysis of 512 709 participants (mean baseline age 52·0 years [SD 10·7]; 59·0% female and 41·0% male) included approximately 6·5 million person-years of follow-up. Between 5285 and 144 852 incident events were recorded for each of the 14 aggregated endpoints. Each 10 μg/m³ higher annual average NO₂ exposure was associated with higher risks of chapter-specific endpoints, especially cardiovascular (n=144 852; HR 1·04 [95% CI 1·02-1·05]), respiratory (n=73 232; 1·03 [1·01-1·05]), musculoskeletal (n=54 409; 1·11 [1·09-1·14]), and mental and behavioural (n=5361; 1·12 [1·05-1·21]) disorders. Further in-depth analyses on specific diseases found significant positive supra-linear associations with hypertensive disease (1·08 [1·05-1·11]), lower respiratory tract infection (1·03 [1·01-1·06]), arthrosis (1·15 [1·09-1·21]), intervertebral disc disorders (1·13 [1·09-1·17]), and spondylopathies (1·05 [1·01-1·10]), and linear associations with ischaemic heart disease (1·03 [1·00-1·05]), ischaemic stroke (1·08 [1·06-1·11]), and asthma (1·15 [1·04-1·27]), whereas intracerebral haemorrhage (1·00 [0·95-1·06]), other cerebrovascular disease (0·98 [0·96-1·01]), acute upper respiratory infection (1·03 [0·96-1·09]), and chronic lower respiratory disease (0·98 [0·95-1·02]) showed no significant association. NO₂ exposure showed robust null association with external causes (n=32 907; 0·98 [0·95-1·02]) as a negative control.

Interpretation: In China, long-term NO₂ exposure was associated with a range of diseases, particularly cardiovascular, respiratory, and musculoskeletal diseases. These associations underscore the pressing need to implement the recently tightened WHO air quality guidelines.

Funding: Wellcome Trust, UK Medical Research Council, Cancer Research UK, British Heart Foundation, National Natural Science Foundation of China, National Key Research and Development Program of China, Sino-British Fellowship Trust, and Kadoorie Charitable Foundation.

Figure 1

Annual average ambient NO₂ concentration (A) and area-specific distribution of NO₂ concentrations (B) from 2005 to 2018 across ten study areas In panel B, study areas are ranked in descending order of annual average NO₂ levels in 2005. In the box plots, horizontal bolded lines represent medians across the whole 2005–18 period and the edges of the boxes represent IQRs. Vertical lines indicate 1·5 times the IQR. Black dots indicate outliers. NO₂=nitrogen dioxide.

Figure 2

Exposure–response relationships of long-term NO₂ exposure with disease incidence across 14 ICD-10 chapter-based endpoints in the main models Solid lines represent HRs and the shaded areas represent 95% CIs. All models were stratified by age-at-risk (in 1-year scale), ten study areas, and sex, and were adjusted for education, household income, smoking status, alcohol intake, cooking fuel type, heating fuel type, self-reported health status, BMI, physical activity level, temperature, and relative humidity. The bottom right panel shows the number of incident cases recorded for each aggregated endpoint during the follow-up period. HR=hazard ratio. NO₂=nitrogen dioxide.

Figure 3

Hazard of 14 ICD-10 chapter-based endpoints per 10 μg/m³ higher annual NO₂ exposure in the main models The solid boxes represent HRs, with the size inversely proportional to the variance of the logarithm of the HR, and the horizontal lines represent 95% CIs. All models were stratified by age-at-risk (in 1-year scale), ten study areas, and sex, and were adjusted for education, household income, smoking status, alcohol intake, cooking fuel type, heating fuel type, self-reported health status, BMI, physical activity level, temperature, and relative humidity. The models fit from the 1st to 99th percentiles of NO₂ concentration. HR=hazard ratio. NO₂=nitrogen dioxide.

Figure 4

Exposure-response relationships of long-term NO₂ exposure with 12 specific causes of disease incidence in the main models Solid lines represent HRs and shaded areas represent 95% CIs. All models were stratified by age-at-risk (in 1-year scale), ten study areas, and sex, and were adjusted for education, household income, smoking status, alcohol intake, cooking fuel type, heating fuel type, self-reported health status, BMI, physical activity level, temperature, and relative humidity. The bottom panel shows the number of incident cases of the 12 specific endpoints across three ICD-10 chapters. HR=hazard ratio. NO₂=nitrogen dioxide.

Figure 5

Hazard of 12 specific causes per 10 μg/m higher annual NO₂ exposure in the main models The solid boxes represent HRs, with the size inversely proportional to the variance of the logarithm of the HR, and the horizontal lines represent 95% CIs. All models were stratified by age-at-risk (in 1-year scale), ten study areas, and sex, and were adjusted for education, household income, smoking status, alcohol intake, cooking fuel type, heating fuel type, self-reported health status, BMI, physical activity level, temperature, and relative humidity. The models fit from the 1st to 99th percentiles of NO₂ concentration. HR=hazard ratio. NO₂=nitrogen dioxide.