Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.

Cancer Epidemiology Unit Department of Medical Sciences University of Turin and CPO Piemonte Torino Italy

Center for Research in Epidemiology and Population Health Team Exposome and Heredity Inserm Unit 1018 University Paris Saclay Villejuif France

Comprehensive Pneumology Center Munich Member of the German Center for Lung Research Munich Neuherberg Germany

Consiglio Nazionale delle Ricerche Istituto per la Ricerca e l'Innovazione Biomedica Palermo Italy

Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Faculty of Health Catholic University Ružomberok Slovakia

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Inserm Unit 1018 Villejuif France

Institut für Epidemiologie Deutsches Forschungszentrum für Gesundheit und Umwelt Neuherberg Germany; and

Institut für Medizinische Informatik Biometrie Epidemiologie Ludwig Maximilians Universität Munich Germany

Institute and Outpatient Clinic for Occupational Social and Environmental Medicine Inner City Clinic University Hospital of Munich and

Institute for Medical Informatics Biometry and Epidemiology University of Duisburg 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 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

Leibniz Institute for Prevention Research and Epidemiology Bremen Institute for Prevention Research and Social Medicine Bremen Germany

Masaryk Memorial Cancer Institute Brno Czech Republic

National Cancer Institute Bethesda Maryland

National Institute of Public Health Bucharest Romania

National Public Health Center Budapest Hungary

Occupational Cancer Research Centre Cancer Care Ontario Toronto Ontario Canada

Regional Authority of Public Health Banská Bystrica Slovakia

Roy Castle Lung Cancer Research Programme Cancer Research Centre University of Liverpool Liverpool United Kingdom

Russian Cancer Research Centre Moscow Russia

Spanish Consortium for Research on Epidemiology and Public Health Faculty of Medicine University of Oviedo Oviedo Spain

The Institute of Environmental Medicine Karolinska Institute Stockholm Sweden

The M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

The National Institute for Public Health and Environmental Protection Bilthoven the Netherlands

The Nofer Institute of Occupational Medicine Lodz Poland

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York

Unità di epidemiologia Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Université de Rennes 1 Inserm Unit 1085 École des hautes études en santé publique Pointe à Pitre France

University of Montreal Hospital Research Centre University of Montreal Montreal Quebec Canada

Am J Respir Crit Care Med. 2020 Aug 1;202(3):317-319. doi: 10.1164/rccm.202004-1404ED. PubMed

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