Abstract Background Low socioeconomic status (SES) groups showed increased lung cancer risks even after adjustment for smoking habits and other exposures to lung carcinogens. Although several biases were often indicated and discussed, only few studies quantified the impact of potential biases. Methods We conducted a bias analysis on the association of lung cancer and SES using data from the SYNERGY project, including 12 case-control studies with 18 study centres from Europe and Canada (16,550 cases, 20,147 controls). SES in quartiles was derived from the International Socio-Economic Index of occupational status (ISEI). Odds ratios (OR) with 95% confidence intervals (CI) were estimated by logistic regression adjusting for age, study centre, and smoking. In addition, we estimated natural direct SES effects and natural indirect smoking effects by inverse odds ratio weighting. In a multiple quantitative bias analysis, we considered impacts of misclassification of smoking status, selection bias, and unmeasured mediator-outcome confounding by a protective genetic factor, and created 95% simulation intervals (SI) by bootstrap. All analyses were stratified by sex. Results Adjustment for smoking as well as natural effects estimation showed that nearly half of lung cancer risks of lower SES groups in men and up to one third in women were attributable to smoking. Consideration of all types of bias reduced lung-cancer risks in the fully adjusted logistic regression models, with the strongest impact by selection bias: For the 4th versus 1st (highest) ISEI quartile OR decreased from 1.83 (1.69-1.98 CI) to 1.50 (1.30-1.73 SI) in men, and OR 1.48 (1.27-1.72 CI) to 1.20 (0.96-1.53 SI) in women. Conclusions Smoking is the main target for prevention of lung cancer, along with occupational and environmental exposures, in particular in lower SES groups. This finding remains, though our analysis revealed reduced lung-cancer risks of lower SES groups after multiple bias adjustment. Key messages • Impact of potential biases was quantified in the association of SES and lung cancer. • Lung cancer risks were partially attributable to smoking and multiple biases.

Lung cancer is the most common cancer globally, with more than 2 million new cases per year. It is also the cancer that causes most deaths, i.e. about 1.7 million annually or 18% of all cancer deaths. In the Russian Federation, lung cancer is the most common cancer among men, while still relatively rare among women. In Northern and Western Europe, lung cancer rates in men have decreased in the last 20 years, while the rates in women keep rising. These global patterns are largely influenced by the national smoking prevalence in the previous decades for respective sex. Environmental and occupational risk factors also contribute to the burden of lung cancer, but the extent of this contribution varies over time and by location. There is a large potential for preventing lung cancer development by reducing and eliminating external risk factors.

Hintergrund: Wir untersuchten die Assoziation von Lungenkrebs und beruflichem sozio-ökonomischen Status (SES) sowie Prestige unter Einbeziehung detaillierter Angaben zum Rauchverhalten im Rahmen des SYNERGY-Projektes.

Background The Asbest chrysotile cohort was set up in Asbest town, Sverdlovsk oblast, Russian Federation, among the current and former workforce of the world's largest operating chrysotile mine and its processing mills, to investigate cancer risk in relation to occupational exposure to chrysotile. Objectives The cohort of 35,837 people was followed-up for mortality using cause-of-death information from official death certificates issued by the Civil Act Registration Office (ZAGS) of Sverdlovsk oblast from 1976 to 2015. Data were also retrieved from the electronic cause-of-death registry of the Medical Information Analytical Centre (MIAC) of Sverdlovsk oblast, which was launched in 1990 and operates independently of ZAGS. The objectives were to compare the completeness of record linkage (RL) with ZAGS and with MIAC, and to compare the agreement of cause-of-death information obtained from ZAGS and from MIAC, with a focus on malignant neoplasms. Methods RL completeness of identifying cohort members in ZAGS and in MIAC was compared for the period 1990 to 2015. In the next step, for the comparison of the retrieved cause-of-death information, 5,463 deaths (1,009 from cancer) were used that were registered in 2002 to 2015, when causes of death were coded using International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) nomenclature by MIAC. For ZAGS, original cause-of-death text from the death certificates was obtained and then coded according to ICD-10 by the International Agency for Research on Cancer/World Health Organization (IARC/WHO). Agreement was evaluated at various levels of detail, and reasons for any disagreements between the MIAC and the IARC/WHO ICD-10-coded cancer diagnosis were systematically explored. Results A total of 10,886 deaths were obtained from all avenues of follow-up for the period 1990 to 2015 in the cohort; 10,816 (99.4%) of these were found in ZAGS. This percentage was 88.3% if only automated deterministic RL was used and 99.4% when deterministic RL was complemented with manual searches of cohort members. Comparison of the cause-of-death information showed agreement of 97.9% at the ICD-10 main group level between ZAGS (coded by IARC/WHO) and MIAC. Of 1,009 cancer deaths, 679 (67.3%) cases had identical coding, 258 (25.6%) cases corresponded at the three-character ICD-10 level, 36 (3.6%) had codes that were within the same anatomical or morphological cluster, and for only 36 (3.6%) cases were major discrepancies identified. Altogether, the agreement between IARC/WHO coding of cause-of-death information from ZAGS and MIAC coding of malignant neoplasms was therefore 96.4%. Conclusions RL completeness and agreement of cause-of-death information obtained from ZAGS and from MIAC were both very high. This is reassuring for the quality of cancer mortality follow-up of the Asbest chrysotile cohort. For future epidemiological studies in the Russian Federation, ZAGS appears to be a reliable information source for mortality follow-up, if the automated RL is complemented with manual searches of cohort members. MIAC is a good resource for prospective studies.

Hintergrund: Ein Zusammenhang zwischen sozio-ökonomischem Status (SES) und Lungenkrebs ist in vielen Studien beobachtet worden, die häufig das Rauchverhalten nicht ausreichend berücksichtigten. Wir untersuchten die Assoziation von Lungenkrebs und beruflichem SES unter Einbeziehung der detaillierten Rauchbiografien im Rahmen des SYNERGY-Projektes. Methoden: Elf Fall-Kontrollstudien aus Europa und Kanada wurden in die Analyse eingeschlossen. Der SES wurde über den International Socio-Economic Index of Occupational Status (ISEI) und die European Socio-economic Classification (ESeC, mit 3 und 5 Klassen) gemessen. Hierzu wurde der Wertebereich des ISEI geviertelt. Im Rahmen von Sensitivitätsanalysen wurden zudem vier Expositionskategorien basierend auf den Quartilen der ISEI-Verteilung in der Kontrollgruppe gebildet. Wir berechneten Odds Ratios (OR) und 95% Konfidenzintervalle (KI), adjustiert für Alter, Geschlecht, Studie und das Rauchverhalten über unbedingte logistische Regressionsmodelle. Stratifizierte Analysen nach Geschlecht, Alter, Studienregion, histologischem Subtyp und Sensitivitätsanalysen, die einzelne Studien bzw. Subgruppen von Studienteilnehmern ausschlossen, wurden durchgeführt. Ergebnisse: Die Analyse umfasste 17.021 Lungenkrebsfälle und 20.885 Kontrollpersonen. Die OR für den Vergleich von niedrigster und höchster SES-Kategorie für den längsten ausgeübten Beruf betrugen 1,80 (95% KI 1,61 – 2,02) bei ISEI, 1,50 (95% KI 1,42 – 1,59) bei ESeC mit 3 Klassen und 1,55 (95% KI 1,46 – 1,64) mit 5 Klassen. Der Zusammenhang zwischen beruflichem SES und Lungenkrebs zeigte einen sozialen Gradienten, z.B. für ISEI (nach absteigendem SES): OR 1,19 (95% KI 1,07 – 1,33), OR 1,71 (95% KI 1,54 – 1,90) und OR 1,80 (95% KI 1,61 – 2,02). Die SES-Differenzen hinsichtlich des Lungenkrebsrisikos waren bei Männern stärker als bei Frauen ausgeprägt (z.B. niedrigste vs. höchste ISEI-Kategorie Männer: OR 1,84 (95% KI 1,61 – 2,09), Frauen: 1,54 (95% KI 1,20 – 1,98)). Nach Adjustierung für das Rauchverhalten reduzierte sich das Lungenkrebsrisiko um bis zu 50%. Auch zusätzliche Adjustierung für Schulbildung führte zu einer Reduktion der Risiken. Schlussfolgerung: SES blieb nach Adjustierung für das Rauchverhalten besonders bei Männern ein Risikofaktor für Lungenkrebs.

Background We studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as occupational prestige’s lifetime trajectory.Methods We included 11,433 male cases and 14,147 male control subjects from the international pooled SYNERGY case-control study. Each job was translated into an occupational social prestige score by applying Treiman’s …

Objectives We estimated the lung cancer risk following occupational exposure to carbon black while adjusting for smoking, and explored the effect of time-windows of carbon black exposure since recent studies have hypothesised that recent exposure is the most important time-window for carbon black exposure. Methods The multicenter case-control study on lung cancer was conducted from 1998 to 2002 in seven European countries; 2861 cases and 2936 controls were recruited. Occupational and socio-demographic information was collected through interviews. Industrial hygiene experts in each country evaluated exposure to 70 occupational agents, including carbon black. Unconditional logistic regression models were applied to calculate ORs and 95% CIs adjusting for centre, sex, other occupational exposures and tobacco smoking. Results The OR for ever exposure to carbon black was 1.64 (95% CI 1.09 to 2.46). We observed a significant dose-response trend for maximum intensity (p-value, 0.02) and average intensity (p-value, 0.03). The OR for the highest exposure category of cumulative exposure in the last 15-years was OR 3.32 (95% CI 1.22 to 9.03). Conclusions The results show an association between occupational exposure to carbon black and lung cancer risk, and a significant dose-response relationship with increasing intensity. The most recent 15 years appear to be the most relevant time of exposure.

Objectives Occupational exposure assessment is one of the major challenges for retrospective community-based epidemiological studies. Having access to workplaces where study subjects spent their working days is basically impossible. Within the SYNERGY project we set out to test the feasibility of using existing measurement databases and measurement data from research institutes to estimate quantitatively occupational exposure to five major lung carcinogens. Methods Exposure data collection started September 2007 and finished August 2010. Existing exposure databases were identified and research institutes were approached in order to identify pertinent exposure measurement data. Individual air measurements data were entered following a standardized protocol. Results ExpoSYN database currently includes almost 370 000 personal and stationary air measurements from 21 mainly European countries. Measurements are distributed as follows: respirable crystalline silica (44%), asbestos (20%), chromium (16%), nickel (14%), and polycyclic aromatic hydrocarbons (7%). Measurement data cover a time period from 1951 until present, but great majority of measurements were collected after 1975. Quality of data differed considerably between data sources and we noted that information on sampling purpose and strategy was not always available in an informative way. In addition, other exposure concentration affecting variables like sampling and analytical methods were closely linked to country of origin of measurements, and therefore hampering adequate adjustment. Conclusions We have created a unique occupational exposure database covering a time period of more than 50 years. This database is being used to develop a country-, job-, and time-period-specific quantitative job exposure matrix (SYNJEM). SYNJEM will enable data-driven quantitative exposure assessment in the SYNERGY project.

Objectives Quantitative exposure assessment in a multinational pooled-analysis of community-based lung cancer case-control studies can be reached via exposure modelling of occupational exposure measurements. We describe a modelling framework for respirable quartz exposure to create a quantitative job-exposure matrix (JEM). Methods Personal measurements of respirable quartz exposure from Europe and Canada were obtained for exposure modelling. A mixed-effects model was used, with region and job titles (ISCO 1968 coding) as random-effect terms. The fixed-effect terms included time period (years), measurement strategy (representative or worst-case), sampler device (categorical), sampling duration (minutes) and a-priori intensity expert ratings for each job from an independently developed JEM (ordinal 0–2). Results 30 393 respirable quartz exposure measurements covering the time period from 1976 to 2009 were used for modelling, showing an overall time trend of -7% per year. An effect of region was found with higher exposures in Canada and the UK and lower exposure levels in Northern and Southern Europe. The other fixed-effect variables influenced exposures in line with a-priori expectation, for example, estimates for worst-case scenarios were higher than for representative situations, samplers with PUF foam under sampled respirable quartz as compared to sampling with filters, and sampling duration was negatively associated with exposure level. Conclusions The modelling exercise showed that quantitative data can be used to derive a quantitative JEM. The presented model will allow us to predict time, job, and region specific exposure levels of respirable quartz. These predictions will be used in the SYNERGY study, an ongoing international pooled community-based case-control study on lung cancer.

Objectives Several epidemiologic studies indicate an increased risk of lung cancer among cooks but it is not known whether this is caused by cigarette smoking or by occupational exposure to carcinogens. Emissions from high-temperature frying have been classified by the IARC as probably carcinogenic to humans. Methods We used data from the SYNERGY project with pooled information on lifetime work histories and tobacco smoking from 13 176 lung cancer cases and 16 129 controls from 11 case-control studies in Europe and Canada. There were 704 persons (405 men, 299 women) who had ever worked as a cook or kitchen worker (based on ISCO-68), among them 340 cases and 364 controls. ORs and 95% CIs were estimated by unconditional logistic regression, adjusted for study, age, sex, smoking, and ever employment in an occupation with established lung cancer risk. Results Occupation as a cook or kitchen worker was associated with an increased lung cancer risk before (OR 1.20, 95% CI 1.03 to 1.40) but not after (OR 1.01, 95% CI 0.86 to 1.20) controlling for smoking habits. There was no significant exposure-response relationship in terms of work duration, and no significant heterogeneity in lung cancer risk among cooks across studies. It was not possible to separate cooks from other kitchen workers. Conclusions Working as a cook or kitchen worker was not associated with an increased risk of lung cancer. However, the possible risk by cooking fumes cannot be ruled out. Misclassification of exposure may have biased our results towards the null.

Objectives SYNERGY9s primary scope is the investigation of joint effects of occupational lung carcinogens. Smoking will be explored as potential confounder and effect modifier. Methods The SYNERGY database has been developed as platform for pooling studies with detailed occupational and smoking information. Occupations and industries were coded according to international classifications. Smoking-status definitions were harmonised. We present lung cancer risk estimates for smoking for 13 169 cases and 16 010 controls. Results The database comprises 16 830 cases (13 397 men, 3 433 women) and 20 975 controls (16 309 men, 4666 women) from 13 studies (54 centres, 13 countries, recruitment 1985–2007). Among cases, 2% of men and 24% of women were never smokers. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and women but squamous cell carcinoma (SqCC) in male smokers. Current smoking was associated with an OR of 23.6 (95% CI 20.4 to 27.2) in men and 7.8 (95% CI 6.8 to 9.0) in women. ORs increased by intensity or duration of cigarette smoking more pronounced for SqCC and small cell lung cancer (SCLC) than for AdCa. Smoking cessation reduced the risks already shortly after quitting but risk in heavy smokers did not fully return to the baseline risk of never smokers. Conclusions The SYNERGY project is the largest collection of cases and controls with detailed occupational and smoking information. This database allows precise risk estimates for pulmonary carcinogens and in-depth analyses, for example, in never smokers or for the subtypes of lung cancer. Smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa.

Objectives Exploratory analyses by occupation or industry are commonly conducted in case-control studies. However, cancer risks limited to certain jobs within an industry, or to a job within a given industry, become undetectable in the overall industry or job odds-ratio. Using the SYNERGY dataset we conducted an analysis based on occupations and industries combined. Methods Data included 10 917 male cases and 13 154 male controls. Industries and jobs were coded according to ISIC Revision 2 and ISCO 1968, respectively. Odds-ratios were computed for ISCO-ISIC combinations with ≥10 study subjects, adjusting for study, age, and smoking. To allow for multiple comparisons we applied a semi-Bayes approach, shrinking towards a group mean the estimate for each ISCO-ISIC combination, previously classified as: occupation known or suspected to entail lung cancer risk, other manual workers, other non-manual workers. Results Out of 1187 evaluated ISCO-ISIC combinations, 50 had an increased odds-ratio (p<0.05). For 26 combinations the risk remained elevated after semi-Bayes shrinkage. As an example, painters in car repair, but not in other industries like car building, had an increased risk (odds-ratio after shrinkage: 1.79, 95% CI 1.04 to 3.07). Likewise, only 8 jobs had increased risk among 63 analysed within the construction industry: miners (2.05, 1.18 to 3.55), bricklayers (1.57, 1.37 to 1.80), welders (1.57, 1.08 to 2.28), earth-moving operators (1.36, 1.05 to 1.76), carpenters (1.30, 1.08 to 1.57), other workers (1.24, 1.06 to 1.44), plumbers (1.23, 1.02 to 1.49) and labourers (1.20, 1.05 to 1.36). Conclusions The use of ISCO-SIC combinations and a semi-Bayes approach identified specific jobs within specific industries with an increased lung cancer risk.

Objectives In order to estimate the exposure-response relation of respirable quartz and lung cancer risk, we developed a quantitative time/job/region specific job-exposure matrix (JEM) based on statistical modelling of historical exposure data. We compared the performance of this quantitative JEM (SYN-JEM) with an already available semi-quantitative general population JEM (DOM-JEM) within a study of pooled community-based lung cancer case-control studies (SYNERGY). Methods Detailed lifetime occupational and smoking history was available for 13 259 cases and 16 232 controls from 11 case-control studies from 12 European countries and Canada. Occupational histories were linked with SYN-JEM and DOM-JEM to derive estimates of cumulative exposure. ORs for lung cancer were estimated using unconditional logistic regression adjusted for age, gender, study, cigarette pack-years, time-since-quitting smoking, and ever occupational exposure to five other known lung carcinogens. Results Exposure to respirable quartz was associated with a monotonic increase in risk of lung cancer. Cumulative exposure estimates based on the quantitative SYN-JEM ranged from 0.005 to 104 mg/m3-years. Quartiles of cumulative exposure (categorised using the exposure distribution among exposed controls) showed significant elevated risks ranging from 1.16 to 1.40. SYN-JEM did not perform better than the ordinal DOM-JEM which provided similar ORs. Conclusions We found a positive exposure-response association between occupational exposure to respirable quartz and lung cancer in a large pooled community-based case-control study. A semi-quantitative approach showed similar results as the quantitative exposure assessment approach except that with the latter risk can be expressed in terms of mg/m3 quartz years, which would facilitate quantitative risk-assessment.

Introduction: Smoking is a strong risk factor for lung cancer. As part of a series of supplemental analyses of the project SYNERGY that has been designed as a pooled analysis of lung cancer studies on the interaction of occupational carcinogens the risk of smoking was estimated for histological subtypes. Materials and Methods: This dataset comprised 10,050 cases (8,403 males, 1,647 females) and 12,388 controls (10,246 males, 2,142 females) from 11 European countries. Odds ratios (ORs) and 95% confidence intervals (CIs) of smoking cigarettes for squamous cell carcinoma (SqCC), small cell lung carcinoma (SCLC), and adenocarcinoma (AdCa) were estimated with logistic regression models in men and women, conditional on study center, adjusted for smoking of any other type of tobacco (yes/no) and age (in five-year classes). Results: Only 2% males and 29% females were never smokers, with AdCa as leading subtype. In current smokers, 54% men and 35% women had a diagnosis of SqCC. Current smoking of cigarettes was associated with an OR of 45.3 (95% CI 33.3–61.6) for SqCC, 43.0 (95% CI 27.5–67.3) for SCLC, and 9.2 (95% CI 7.2–11.7) for AdCa among men. The corresponding risk estimates in women were 12.4 (95% CI 9.2–16.5) for SqCC, 17.7 (95% CI 12.4–25.3) for SCLC, and 3.2 (95% CI 2.5–4.0) for AdCa. High risks of current smoking of >30 cigarettes/day were observed for SqCC (OR 91.6; 95% CI 64.2–130.6) and SCLC (OR 84.5; 95% CI 51.2–139.6) in men and for SqCC (OR 46.9; 95% CI 17.3–127.1) and SCLC (OR 77.4; 95% CI 22.7–263.8) in women. Conclusion: Cigarette smoking in our study was associated with a considerably higher risk both for SqCC and SCLC than for AdCa. These observations corroborate findings from experimental and former epidemiological studies.