Long-term exposure to NO₂ and O₃ and all-cause and respiratory mortality: A systematic review and meta-analysis

WHO has published several volumes of Global Air Quality Guidelines to provide guidance on the health risks associated with exposure to outdoor air pollution. As new scientific evidence is generated, air quality guidelines need to be periodically revised and, where necessary, updated.

The aims of the study were 1) to summarise the available evidence on the effect of long-term exposure to ozone (O₃) and nitrogen dioxide (NO₂) on mortality; 2) and to assess concentration response functions (CRF), their shape and the minimum level of exposures measured in studies to support WHO's update of the global air quality guidelines.

We conducted a systematic literature search of the Medline, Embase and Web of Science databases following a protocol proposed by WHO and applied Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines for reporting our results.

Cohort studies in human populations (including sub-groups at risk) exposed to long-term concentrations of NO₂ and O₃. Outcomes assessed were all-cause, respiratory, Chronic Obstructive Pulmonary Disease (COPD) and Acute Lower Respiratory Infection (ALRI) mortality.

Studies included in the meta-analyses were assessed using a new Risk of Bias instrument developed by a group of experts convened by WHO. Study results are presented in forest plots and quantitative meta-analyses were conducted using random effects models. The certainty of evidence was assessed using a newly developed adaptation of GRADE.

The review identified 2068 studies of which 95 were subject to full-text review with 45 meeting the inclusion criteria. An update in September 2018 identified 159 studies with 1 meeting the inclusion criteria. Of the 46 included studies, 41 reported results for NO₂ and 20 for O₃. The majority of studies were from the USA and Europe with the remainder from Canada, China and Japan. Forty-two studies reported results for all-cause mortality and 22 for respiratory mortality. Associations for NO₂ and mortality were positive; random-effects summary relative risks (RR) were 1.02 (95% CI: 1.01, 1.04), 1.03 (1.00, 1.05), 1.03 (1.01, 1.04) and 1.06 (1.02, 1.10) per 10 μg/m³ for all-cause (24 cohorts), respiratory (15 cohorts), COPD (9 cohorts) and ALRI (5 cohorts) mortality respectively. The review identified high levels of heterogeneity for all causes of death except COPD. A small number of studies investigated the shape of the concentration-response relationship and generally found little evidence to reject the assumption of linearity across the concentration range. Studies of O₃ using annual metrics showed the associations with all-cause and respiratory mortality were 0.97 (0.93, 1.02) and 0.99 (0.89, 1.11) per 10 μg/m³ respectively. For studies using peak O₃ metrics, the association with all-cause mortality was 1.01 (1.00, 1.02) and for respiratory mortality 1.02 (0.99, 1.05), each per 10 μg/m³. The review identified high levels of heterogeneity. Few studies investigated the shape of the concentration-response relationship. Certainty in the associations (adapted GRADE) with mortality was rated low to moderate for each exposure-outcome pair, except for NO₂ and COPD mortality which was rated high.

The substantial heterogeneity for most outcomes in the review requires explanation. The evidence base is limited in terms of the geographical spread of the study populations and, for some outcomes, the small number of independent cohorts for meta-analysis precludes meaningful meta-regression to explore causes of heterogeneity. Relatively few studies assessed specifically the shape of the CRF or multi-pollutant models.

The short-comings in the existing literature base makes determining the precise nature (magnitude and linearity) of the associations challenging. Certainty of evidence assessments were moderate or low for both NO₂ and O₃ for all causes of mortality except for NO₂ and COPD mortality where the certainty of the evidence was judged as high.