OBJECTIVE: To evaluate the short term associations between nitrogen dioxide (NO2) 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/m3 increase in NO2 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 (PM10 and PM2.5, 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 NO2 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 NO2 and increased risk of total, cardiovascular, and respiratory mortality, suggesting that health benefits would be achieved by tightening the guidelines and regulatory limits of NO2.

Air Health Science Division Health Canada Ottawa ON Canada

Center for Environmental and Respiratory Health Research University of Oulu Oulu Finland

Centre for Global Health School of Public Health Nanjing Medical University Nanjing China

Centre for Statistical Methodology London School of Hygiene and Tropical Medicine London UK

Centre on Climate Change and Planetary Health London School of Hygiene and Tropical Medicine London UK

Children's Hospital of Fudan University National Centre for Children's Health Shanghai China

CIBER of Epidemiology and Public Health Madrid Spain

Department of Earth Sciences University of Turin Turin Italy

Department of Environmental Health Harvard T H Chan School of Public Health Boston MA USA

Department of Environmental Health Portuguese National Institute of Health Porto Portugal

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Melbourne VIC Australia

Department of Global Health Policy Graduate School of Medicine University of Tokyo Tokyo Japan

Department of Hygiene Epidemiology and Medical Statistics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Public Health and Clinical Medicine Umeå University Umeå Sweden

Department of Public Health Environments and Society London School of Hygiene and Tropical Medicine London UK

Department of Public Health Science Graduate School of Public Health and Institute of Health and Environment Seoul National University Seoul South Korea

Department of Public Health Universidad de los Andes Santiago Chile

Department of Statistics and Operational Research Universitat de València València Spain

Department of Statistics Computer Science and Applications G Parenti University of Florence Florence Italy

Environmental and Occupational Medicine National Taiwan University College of Medicine and NTU Hospital Taipei Taiwan

EPIUnit Instituto de Saúde Pública Universidade do Porto Porto Portugal

Estonian Environmental Research Centre Tallinn Estonia

Faculty of Environmental Sciences Czech University of Life Sciences Prague Czech Republic

Faculty of Geography Babes Bolay University Cluj Napoca Romania

Faculty of Health and Sport Sciences University of Tsukuba Tsukuba Japan

Faculty of Medicine University of São Paulo São Paulo Brazil

Institute of Atmospheric Physics Czech Academy of Sciences Prague Czech Republic

Institute of Environmental Assessment and Water Research Spanish Council for Scientific Research Barcelona Spain

Institute of Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Family Medicine and Public Health University of Tartu Tartu Estonia

Institute of Social and Preventive Medicine University of Bern Bern Switzerland

Instituto Nacional de Salud Pública de México Cuernavaca México

Key Laboratory of Environment and Health Ministry of Education and State Key Laboratory of Environmental Health School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China

National Institute of Environmental Health Sciences National Health Research Institute Miaoli Taiwan

Oeschger Centre for Climate Change Research University of Bern Bern Switzerland

Potsdam Institute for Climate Impact Research Potsdam Germany

School of Epidemiology and Public Health University of Ottawa Ottawa ON Canada

School of Nursing and Obstetrics Universidad de los Andes Santiago Chile

School of Population Health and Environmental Sciences King's College London London UK

School of Public Health and Management Binzhou Medical University Yantai Shandong China

School of Public Health and Social Work Queensland University of Technology Brisbane QLD Australia

School of Public Health Institute of Environment and Population Health Anhui Medical University Hefei China

School of Public Health Key Laboratory of Public Health Safety of the Ministry of Education and Key Laboratory of Health Technology Assessment of the Ministry of Health Fudan University P O Box 249 130 Dong An Road Shanghai 200032 China

School of the Environment Yale University New Haven CT USA

School of Tropical Medicine and Global Health Nagasaki University Nagasaki Japan

Shanghai Children's Medical Centre Shanghai Jiao Tong University School of Medicine Shanghai China

Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention Fudan University Shanghai China

Swiss Tropical and Public Health Institute Basel Switzerland

Universidad Pablo de Olavide Department of Physical Chemical and Natural Systems Sevilla Spain

University of Basel Basel Switzerland

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