BACKGROUND: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents. OBJECTIVES: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking. METHODS: In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI). RESULTS: All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; p = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8). DISCUSSION: Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

Boston College Chestnut Hill Massachusetts USA

Cancer Epidemiology Unit Department of Medical Sciences University of Turin Turin Italy

Center for Research in Epidemiology and Population Health Team Exposome and Heredity U1018 Inserm University Paris Saclay University Paris Cité Villejuif France

Comprehensive Pneumology Center Munich Munich Germany

Dalla Lana School of Public Health University of Toronto Toronto Canada

Department of Cancer Epidemiology and Prevention N N Blokhin National Research Centre of Oncology Moscow Russia

Department of Environmental Epidemiology The Nofer Institute of Occupational Medicine Lodz Poland

Department of Epidemiology ASL Roma E Rome Italy

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Social and Preventive Medicine University of Montreal Montreal Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Bethesda Maryland USA

Epidemiology Unit Department of Cancer Epidemiology and Prevention M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Epidemiology Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Faculty of Health Catholic University Ružomberok Slovakia

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Faculty of Mathematics and Computer Science Institute of Statistics University of Bremen Bremen Germany

Health Research Institute of Asturias University of Oviedo ISPA and CIBERESP Oviedo Spain

Institut für Medizinische Informatik Biometrie Epidemiologie Ludwig Maximilians University Munich Germany

Institute and Clinic for Occupational Social and Environmental Medicine University Hospital LMU Munich Munich Germany

Institute for Medical Informatics Biometry and Epidemiology University Hospital Essen Essen Germany

Institute for Prevention and Occupational Medicine of the German Social Accident Insurance Institute of the Ruhr University Bochum Germany

Institute for Risk Assessment Sciences Utrecht University Utrecht The Netherlands

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

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

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

International Agency for Research on Cancer Lyon France

ISGlobal Barcelona Spain

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany

Masaryk Memorial Cancer Institute Brno Czech Republic

National Institute of Public Health Bucharest Romania

National Public Health Center Budapest Hungary

Occupational Cancer Research Centre Ontario Health Toronto Canada

Regional Authority of Public Health Banská Bystrica Slovakia

Roy Castle Lung Cancer Research Programme Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool UK

Stony Brook Cancer Center Stony Brook University Stony Brook New York USA

University Rennes Inserm EHESP Irset UMR_S 1085 Pointe à Pitre France

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