Objective: To evaluate the short term associations between nitrogen dioxide (NO ₂ ) and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide, using a uniform analytical protocol. Design: Two stage, time series approach, with overdispersed generalised linear models and multilevel meta-analysis. Setting: 398 cities in 22 low to high income countries/regions. Main outcome measures: Daily deaths from total (62.8 million), cardiovascular (19.7 million), and respiratory (5.5 million) causes between 1973 and 2018. Results: On average, a 10 μg/m ³ increase in NO ₂ concentration on lag 1 day (previous day) was associated with 0.46% (95% confidence interval 0.36% to 0.57%), 0.37% (0.22% to 0.51%), and 0.47% (0.21% to 0.72%) increases in total, cardiovascular, and respiratory mortality, respectively. These associations remained robust after adjusting for co-pollutants (particulate matter with aerodynamic diameter ≤10 μm or ≤2.5 μm (PM ₁₀ and PM _2.5 , respectively), ozone, sulfur dioxide, and carbon monoxide). The pooled concentration-response curves for all three causes were almost linear without discernible thresholds. The proportion of deaths attributable to NO ₂ concentration above the counterfactual zero level was 1.23% (95% confidence interval 0.96% to 1.51%) across the 398 cities. Conclusions: This multilocation study provides key evidence on the independent and linear associations between short term exposure to NO ₂ and increased risk of total, cardiovascular, and respiratory mortality, suggesting that health benefits would be achieved by tightening the guidelines and regulatory limits of NO ₂ .

Objective: To assess short term mortality risks and excess mortality associated with exposure to ozone in several cities worldwide. Design: Two stage time series analysis. Setting: 406 cities in 20 countries, with overlapping periods between 1985 and 2015, collected from the database of Multi-City Multi-Country Collaborative Research Network. Population: Deaths for all causes or for external causes only registered in each city within the study period . Main outcome measures: Daily total mortality (all or non-external causes only). Results: A total of 45 165 171 deaths were analysed in the 406 cities. On average, a 10 µg/m ³ increase in ozone during the current and previous day was associated with an overall relative risk of mortality of 1.0018 (95% confidence interval 1.0012 to 1.0024). Some heterogeneity was found across countries, with estimates ranging from greater than 1.0020 in the United Kingdom, South Africa, Estonia, and Canada to less than 1.0008 in Mexico and Spain. Short term excess mortality in association with exposure to ozone higher than maximum background levels (70 µg/m ³ ) was 0.26% (95% confidence interval 0.24% to 0.28%), corresponding to 8203 annual excess deaths (95% confidence interval 3525 to 12 840) across the 406 cities studied. The excess remained at 0.20% (0.18% to 0.22%) when restricting to days above the WHO guideline (100 µg/m ³ ), corresponding to 6262 annual excess deaths (1413 to 11 065). Above more lenient thresholds for air quality standards in Europe, America, and China, excess mortality was 0.14%, 0.09%, and 0.05%, respectively. Conclusions: Results suggest that ozone related mortality could be potentially reduced under stricter air quality standards. These findings have relevance for the implementation of efficient clean air interventions and mitigation strategies designed within national and international climate policies.

Objective: To investigate potential interactive effects of fine particulate matter (PM _2.5 ) and ozone (O ₃ ) on daily mortality at global level. Design: Two stage time series analysis. Setting: 372 cities across 19 countries and regions. Population: Daily counts of deaths from all causes, cardiovascular disease, and respiratory disease. Main outcome measure: Daily mortality data during 1994-2020. Stratified analyses by co-pollutant exposures and synergy index (>1 denotes the combined effect of pollutants is greater than individual effects) were applied to explore the interaction between PM _2.5 and O ₃ in association with mortality. Results: During the study period across the 372 cities, 19.3 million deaths were attributable to all causes, 5.3 million to cardiovascular disease, and 1.9 million to respiratory disease. The risk of total mortality for a 10 μg/m ³ increment in PM _2.5 (lag 0-1 days) ranged from 0.47% (95% confidence interval 0.26% to 0.67%) to 1.25% (1.02% to 1.48%) from the lowest to highest fourths of O ₃ concentration; and for a 10 μg/m ³ increase in O ₃ ranged from 0.04% (−0.09% to 0.16%) to 0.29% (0.18% to 0.39%) from the lowest to highest fourths of PM _2.5 concentration, with significant differences between strata (P for interaction <0.001). A significant synergistic interaction was also identified between PM _2.5 and O ₃ for total mortality, with a synergy index of 1.93 (95% confidence interval 1.47 to 3.34). Subgroup analyses showed that interactions between PM _2.5 and O ₃ on all three mortality endpoints were more prominent in high latitude regions and during cold seasons. Conclusion: The findings of this study suggest a synergistic effect of PM _2.5 and O ₃ on total, cardiovascular, and respiratory mortality, indicating the benefit of coordinated control strategies for both pollutants.

The epidemiological evidence on the interaction between heat and ambient air pollution on mortality is still inconsistent. To investigate the interaction between heat and ambient air pollution on daily mortality in a large dataset of 620 cities from 36 countries. We used daily data on all-cause mortality, air temperature, particulate matter ≤ 10 μm (PM₁₀), PM ≤ 2.5 μm (PM_2.5), nitrogen dioxide (NO₂), and ozone (O₃) from 620 cities in 36 countries in the period 1995-2020. We restricted the analysis to the six consecutive warmest months in each city. City-specific data were analysed with over-dispersed Poisson regression models, followed by a multilevel random-effects meta-analysis. The joint association between air temperature and air pollutants was modelled with product terms between non-linear functions for air temperature and linear functions for air pollutants. We analyzed 22,630,598 deaths. An increase in mean temperature from the 75^th to the 99^th percentile of city-specific distributions was associated with an average 8.9 % (95 % confidence interval: 7.1 %, 10.7 %) mortality increment, ranging between 5.3 % (3.8 %, 6.9 %) and 12.8 % (8.7 %, 17.0 %), when daily PM₁₀ was equal to 10 or 90 μg/m³, respectively. Corresponding estimates when daily O₃ concentrations were 40 or 160 μg/m³ were 2.9 % (1.1 %, 4.7 %) and 12.5 % (6.9 %, 18.5 %), respectively. Similarly, a 10 μg/m³ increment in PM₁₀ was associated with a 0.54 % (0.10 %, 0.98 %) and 1.21 % (0.69 %, 1.72 %) increase in mortality when daily air temperature was set to the 1^st and 99^th city-specific percentiles, respectively. Corresponding mortality estimate for O₃ across these temperature percentiles were 0.00 % (-0.44 %, 0.44 %) and 0.53 % (0.38 %, 0.68 %). Similar effect modification results, although slightly weaker, were found for PM_2.5 and NO₂. Suggestive evidence of effect modification between air temperature and air pollutants on mortality during the warm period was found in a global dataset of 620 cities.

Evidence on the potential interactive effects of heat and ambient air pollution on cause-specific mortality is inconclusive and limited to selected locations. We investigated the effects of heat on cardiovascular and respiratory mortality and its modification by air pollution during summer months (six consecutive hottest months) in 482 locations across 24 countries. Location-specific daily death counts and exposure data (e.g., particulate matter with diameters ≤ 2.5 µm [PM_2.5]) were obtained from 2000 to 2018. We used location-specific confounder-adjusted Quasi-Poisson regression with a tensor product between air temperature and the air pollutant. We extracted heat effects at low, medium, and high levels of pollutants, defined as the 5th, 50th, and 95th percentile of the location-specific pollutant concentrations. Country-specific and overall estimates were derived using a random-effects multilevel meta-analytical model. Heat was associated with increased cardiorespiratory mortality. Moreover, the heat effects were modified by elevated levels of all air pollutants in most locations, with stronger effects for respiratory than cardiovascular mortality. For example, the percent increase in respiratory mortality per increase in the 2-day average summer temperature from the 75th to the 99th percentile was 7.7% (95% Confidence Interval [CI] 7.6-7.7), 11.3% (95%CI 11.2-11.3), and 14.3% (95% CI 14.1-14.5) at low, medium, and high levels of PM_2.5, respectively. Similarly, cardiovascular mortality increased by 1.6 (95%CI 1.5-1.6), 5.1 (95%CI 5.1-5.2), and 8.7 (95%CI 8.7-8.8) at low, medium, and high levels of O₃, respectively. We observed considerable modification of the heat effects on cardiovascular and respiratory mortality by elevated levels of air pollutants. Therefore, mitigation measures following the new WHO Air Quality Guidelines are crucial to enhance better health and promote sustainable development.

Background: Minimum mortality temperature (MMT) is an important indicator to assess the temperature-mortality association, indicating long-term adaptation to local climate. Limited evidence about the geographical variability of the MMT is available at a global scale. Methods: We collected data from 658 communities in 43 countries under different climates. We estimated temperature-mortality associations to derive the MMT for each community using Poisson regression with distributed lag nonlinear models. We investigated the variation in MMT by climatic zone using a mixed-effects meta-analysis and explored the association with climatic and socioeconomic indicators. Results: The geographical distribution of MMTs varied considerably by country between 14.2 and 31.1 °C decreasing by latitude. For climatic zones, the MMTs increased from alpine (13.0 °C) to continental (19.3 °C), temperate (21.7 °C), arid (24.5 °C), and tropical (26.5 °C). The MMT percentiles (MMTPs) corresponding to the MMTs decreased from temperate (79.5th) to continental (75.4th), arid (68.0th), tropical (58.5th), and alpine (41.4th). The MMTs indreased by 0.8 °C for a 1 °C rise in a community’s annual mean temperature, and by 1 °C for a 1 °C rise in its SD. While the MMTP decreased by 0.3 centile points for a 1 °C rise in a community’s annual mean temperature and by 1.3 for a 1 °C rise in its SD. Conclusions: The geographical distribution of the MMTs and MMTPs is driven mainly by the mean annual temperature, which seems to be a valuable indicator of overall adaptation across populations. Our results suggest that populations have adapted to the average temperature, although there is still more room for adaptation.