Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) <0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95%CI = 0.89-0.95, and P = 1.03 × 10-5 for rs3769201; OR = 0.91, 95%CI = 0.88-0.95, and P = 2.03 × 10-6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.

Functional variants in DCAF4 associated with lung cancer risk in European populations.

Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4.

Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

PURPOSE: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. EXPERIMENTAL DESIGN: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. RESULTS: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc.

Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies.

BACKGROUND: Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. METHODS: We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. RESULTS: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. CONCLUSIONS: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.).

Prices of over-the-counter drugs used by 15-year-old adolescents in Germany and their association with socioeconomic background.

BACKGROUND: In Germany, over-the-counter (OTC) drugs are normally reimbursed up to the age of 12 years only. The aim of this study was to analyse prices of over-the-counter drugs used by adolescents in Germany and their association with socioeconomic factors. METHODS: Based on the German GINIplus and LISAplus birth cohorts, data on drug utilization among 15-year-old adolescents (n = 4677) were collected using a self-administered questionnaire. The reported drugs were subdivided into prescription drugs and OTC drugs. The drugs' prices were tracked by the pharmaceutical identification numbers. RESULTS: Overall, 1499 OTC drugs with clearly identifiable prices were eligible for analysis. Their mean price was €9.75 (95% confidence interval: €9.27-10.22). About 75% of the OTC drugs cost less than €10. Higher mean prices were associated with residing in Munich (€10.74; 95% confidence interval: €9.97-11.52) and with higher paternal education (e.g. highest education level: €10.17; 95% confidence interval: €9.47-10.86). Adolescents residing in Munich (in comparison with the less wealthy region of Wesel) and adolescents with higher educated fathers were also significantly more likely to use OTC drugs costing ≥ €10 or ≥ €25, respectively. CONCLUSIONS: The price of €10 for non-reimbursable OTC drugs may represent a (psychological) threshold. Higher prices could discourage especially adolescents from a lower socioeconomic background from taking medically advisable but non-reimbursable OTC drugs.

Informed genome-wide association analysis with family history as a secondary phenotype identifies novel loci of lung cancer.

Lung cancer is the leading cause of cancer death worldwide. Although several genetic variants associated with lung cancer have been identified in the past, stringent selection criteria of genome-wide association studies (GWAS) can lead to missed variants. The objective of this study was to uncover missed variants by using the known association between lung cancer and first-degree family history of lung cancer to enrich the variant prioritization for lung cancer susceptibility regions. In this two-stage GWAS study, we first selected a list of variants associated with both lung cancer and family history of lung cancer in four GWAS (3,953 cases, 4,730 controls), then replicated our findings for 30 variants in a meta-analysis of four additional studies (7,510 cases, 7,476 controls). The top ranked genetic variant rs12415204 in chr10q23.33 encoding FFAR4 in the Discovery set was validated in the Replication set with an overall OR of 1.09 (95% CI=1.04, 1.14, P=1.63×10(-4)). When combining the two stages of the study, the strongest association was found in rs1158970 at Ch4p15.2 encoding KCNIP4 with an OR of 0.89 (95% CI=0.85, 0.94, P=9.64×10(-6)). We performed a stratified analysis of rs12415204 and rs1158970 across all eight studies by age, gender, smoking status, and histology, and found consistent results across strata. Four of the 30 replicated variants act as expression quantitative trait loci (eQTL) sites in 1,111 nontumor lung tissues and meet the genome-wide 10% FDR threshold.

Occupational prestige, social mobility and the association with lung cancer in men.

BACKGROUND: The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. METHODS: We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitivity analyses to assess the robustness of our results. RESULTS: We observed increased lung cancer risk estimates for men with medium (OR = 1.23; 95 % CI 1.13-1.33) and low occupational prestige (OR = 1.44; 95 % CI 1.32-1.57). Although adjustment for smoking and education reduced the associations between occupational prestige and lung cancer, they did not explain the association entirely. Traditional occupational exposures reduced the associations only slightly. We observed small associations with downward prestige trajectories, with ORs of 1.13, 95 % CI 0.88-1.46 for high to low, and 1.24; 95 % CI 1.08-1.41 for medium to low trajectories. CONCLUSIONS: Our results indicate that occupational prestige is independently associated with lung cancer among men.

A longitudinal comparison of drug use among 10-year-old children and 15-year-old adolescents from the German GINIplus and LISAplus birth cohorts.

PURPOSE: The purpose of this study was to compare longitudinal data on drug utilization between 10-year-old children and 15-year-old adolescents and to analyse the association of drug use at the age of 15 years with drug use at the age of 10 years. METHODS: Based on the German GINIplus (German infant study on the Influence of Nutrition Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influence of lifestyle factors on the immune system and allergies in East and West Germany plus the influence of traffic emissions and genetics) birth cohorts, data on drug utilization (past 4 weeks) were collected using a self-administered questionnaire for 3642 children (10-year follow-up) and 4677 adolescents (15-year follow-up). The drugs were classified by therapeutic categories (conventional drugs, homeopathic drugs, etc.) and by codes according to the anatomical therapeutic chemical (ATC) classification system. Associations of adolescents' drug use with gender, study area, maternal education, parental income, presence of chronic conditions, and prior drug use at the age of 10 years were analysed using a logistic regression model. RESULTS: The 4-week prevalence rates of overall drug use were similar for adolescents (41.1%) and children (42.3%). However, adolescents used noticeably more anti-inflammatory drugs, analgesics, and systemic antihistamines. Exactly 3194 children/adolescents participated in both follow-ups. Adolescents' use of anti-inflammatory drugs was predicted (OR = 3.37) by use of anti-inflammatory drugs as a child. In summary, the strongest predictor of adolescents' use of specific therapeutic categories or ATC groups was the previous use of the same therapeutic drug category or ATC group as a 10-year-old child. CONCLUSIONS: Despite similar prevalence rates of overall drug utilization among both age groups, there is a noticeable difference concerning the use of drugs from specific ATC groups. Drug use as a child may partly determine what they use as an adolescent.

Neighbourhood and physical activity in German adolescents: GINIplus and LISAplus.

INTRODUCTION: Impact of neighbourhood on physical activity (PA) is under-investigated in European adolescents, and few studies have used objective data on both exposures and outcomes. Therefore we investigated the association between objectively measured neighbourhood characteristics and PA in 15-year-old German adolescents. METHODS: Study populations comprised of 688 adolescents residing in the urban Munich area and 504 from the rural Wesel area from the GINIplus and LISAplus birth cohorts. Neighbourhood was defined as a circular 500-m buffer around the residence. Greenness was calculated 1) as the mean Normalized Difference Vegetation Index (NDVI), and 2) as percent tree cover. Neighbourhood green spaces and sport and leisure facilities were defined as present or absent in a neighbourhood (data only available for Munich). Data on PA were collected from one-week triaxial accelerometry (hip-worn ActiGraph GT3X). Minutes of PA were classified into moderate-to-vigorous (MVPA), light and sedentary using Romanzini's et al. triaxial cutoffs, and averaged over the recording period. Activity diaries were used for differentiation between school and leisure (total minus school) PA. Area-specific associations were assessed by adjusted negative binomial regressions. RESULTS: In the Wesel area, residing in a neighbourhood with higher NDVI was associated with 9% more leisure MVPA among females and with 8% more leisure MVPA in rural dwellers. In the Munich area, residing in a neighbourhood with sport facilities was associated with 9% more leisure MVPA. The latter association was only significant in urban dwellers while neighbourhood leisure facilities increased MVPA in rural dwellers. Estimates were very similar when total MVPA was considered rather than solely leisure. CONCLUSION: There is indication that neighbourhood features could be associated with MVPA in German adolescents. However, different features seem to be important across sexes and in rural/urban settings, which need to be specifically addressed in future studies.

Modeling Lung Carcinogenesis in Radon-Exposed Miner Cohorts: Accounting for Missing Information on Smoking.

Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955-1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.

Lung cancer risk among bricklayers in a pooled analysis of case-control studies.

Bricklayers may be exposed to several lung carcinogens, including crystalline silica and asbestos. Previous studies that analyzed lung cancer risk among these workers had several study design limitations. We examined lung cancer risk among bricklayers within SYNERGY, a large international pooled analysis of case-control studies on lung cancer and the joint effects of occupational carcinogens. For men ever employed as bricklayers we estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for study center, age, lifetime smoking history and employment in occupations with exposures to known or suspected lung carcinogens. Among 15,608 cases and 18,531 controls, there were 695 cases and 469 controls who had ever worked as bricklayers (OR: 1.47; 95% CI: 1.28-1.68). In studies using population controls the OR was 1.55 (95% CI: 1.32-1.81, 540/349 cases/controls), while it was 1.24 (95% CI: 0.93-1.64, 155/120 cases/controls) in hospital-based studies. There was a clear positive trend with length of employment (p < 0.001). The relative risk was higher for squamous (OR: 1.68, 95% CI: 1.42-1.98, 309 cases) and small cell carcinomas (OR: 1.78, 95% CI: 1.44-2.20, 140 cases), than for adenocarcinoma (OR: 1.17, 95% CI: 0.95-1.43, 150 cases) (p-homogeneity: 0.0007). ORs were still elevated after additional adjustment for education and in analyses using blue collar workers as referents. This study provided robust evidence of increased lung cancer risk in bricklayers. Although non-causal explanations cannot be completely ruled out, the association is plausible in view of the potential for exposure to several carcinogens, notably crystalline silica and to a lesser extent asbestos.

Is previous respiratory disease a risk factor for lung cancer?

RATIONALE: Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously. OBJECTIVES: Investigate lung cancer risk associated with chronic bronchitis, emphysema, tuberculosis, pneumonia, and asthma. METHODS: The SYNERGY project pooled information on previous respiratory diseases from 12,739 case subjects and 14,945 control subjects from 7 case-control studies conducted in Europe and Canada. Multivariate logistic regression models were used to investigate the relationship between individual diseases adjusting for co-occurring conditions, and patterns of respiratory disease diagnoses and lung cancer. Analyses were stratified by sex, and adjusted for age, center, ever-employed in a high-risk occupation, education, smoking status, cigarette pack-years, and time since quitting smoking. MEASUREMENTS AND MAIN RESULTS: Chronic bronchitis and emphysema were positively associated with lung cancer, after accounting for other respiratory diseases and smoking (e.g., in men: odds ratio [OR], 1.33; 95% confidence interval [CI], 1.20-1.48 and OR, 1.50; 95% CI, 1.21-1.87, respectively). A positive relationship was observed between lung cancer and pneumonia diagnosed 2 years or less before lung cancer (OR, 3.31; 95% CI, 2.33-4.70 for men), but not longer. Co-occurrence of chronic bronchitis and emphysema and/or pneumonia had a stronger positive association with lung cancer than chronic bronchitis "only." Asthma had an inverse association with lung cancer, the association being stronger with an asthma diagnosis 5 years or more before lung cancer compared with shorter. CONCLUSIONS: Findings from this large international case-control consortium indicate that after accounting for co-occurring respiratory diseases, chronic bronchitis and emphysema continue to have a positive association with lung cancer.

Changes in dietary intake during puberty and their determinants: results from the GINIplus birth cohort study.

BACKGROUND: Understanding changes in dietary intake during puberty could aid the mapping of dietary interventions for primary prevention. The present study describes dietary changes from childhood to adolescence, and their associations with parental education, family income, child education, body mass index (BMI), pubertal onset and screen-time sedentary behaviour. METHODS: Dietary data (n = 1232) were obtained from food frequency questionnaires at the 10- and 15-year follow-ups of the GINIplus birth cohort study. Intakes of 17 food groups, macronutrients and antioxidant vitamins, were described by a) paired Wilcoxon rank sum tests, comparing average intakes at each time-point, and b) Cohen's kappa "tracking" coefficients, measuring stability of intakes (maintenance of relative tertile positions across time). Further, associations of changes (tertile position increase or decrease vs. tracking) with parental education, family income, child education, pubertal onset, BMI, and screen-time, were assessed by logistic regression and multinomial logistic regression models stratified by baseline intake tertile. RESULTS: Both sexes increased average intakes of water and decreased starchy vegetables, margarine and dairy. Females decreased meat and retinol intakes and increased vegetables, grains, oils and tea. Males decreased fruit and carbohydrates and increased average intakes of meat, caloric drinks, water, protein, fat, polyunsaturated fatty acids (PUFAs), vitamin C and alpha-tocopherol. Both sexes presented mainly "fair" tracking levels [κw = 0.21-0.40]. Females with high (vs. low) parental education were more likely to increase their nut intake [OR = 3.8; 95 % CI = (1.7;8.8)], and less likely to decrease vitamin C intakes [0.2 (0.1;0.5)], while males were less likely to increase egg consumption [0.2 (0.1;0.5)] and n3 PUFAs [0.2 (0.1;0.5)]. Females with a higher (vs. low) family income were more likely to maintain medium wholegrain intakes [0.2 (0.1;0.7) for decrease vs. tracking, and 0.1 (0.0;0.5) for increase vs. tracking], and were less likely to decrease vitamin C intakes [0.2 (0.1;0.6)]. Males with high education were less likely to increase sugar-sweetened foods [0.1 (0.1;0.4)]. Finally, BMI in females was negatively associated with decreasing protein intakes [0.7 (0.6;0.9)]. In males BMI was positively associated with increasing margarine [1.4 (1.1;1.6)] and vitamin C intakes [1.4 (1.1;1.6)], and negatively associated with increasing n3 PUFA. CONCLUSIONS: Average dietary intakes changed significantly, despite fair tracking levels, suggesting the presence of trends in dietary behaviour during puberty. Family income and parental education predominantly influenced intake changes. Our results support the rationale for dietary interventions targeting children, and suggest that sex-specific subpopulations, e.g. low socio-economic status, should be considered for added impact.

Effect modification of the association of cumulative exposure and cancer risk by intensity of exposure and time since exposure cessation: a flexible method applied to cigarette smoking and lung cancer in the SYNERGY Study.

The indiscriminate use of the cumulative exposure metric (the product of intensity and duration of exposure) might bias reported associations between exposure to hazardous agents and cancer risk. To assess the independent effects of duration and intensity of exposure on cancer risk, we explored effect modification of the association of cumulative exposure and cancer risk by intensity of exposure. We applied a flexible excess odds ratio model that is linear in cumulative exposure but potentially nonlinear in intensity of exposure to 15 case-control studies of cigarette smoking and lung cancer (1985-2009). Our model accommodated modification of the excess odds ratio per pack-year of cigarette smoking by time since smoking cessation among former smokers. We observed negative effect modification of the association of pack-years of cigarette smoking and lung cancer by intensity of cigarette smoke for persons who smoked more than 20-30 cigarettes per day. Patterns of effect modification were similar across individual studies and across major lung cancer subtypes. We observed strong negative effect modification by time since smoking cessation. Application of our method in this example of cigarette smoking and lung cancer demonstrated that reducing a complex exposure history to a metric such as cumulative exposure is too restrictive.

Respirable quartz dust exposure and airway obstruction: a systematic review and meta-analysis.

Studies on exposure to respirable quartz dust at the workplace and the development of chronic obstructive pulmonary disease (COPD) were selected into a systematic review and meta-analysed to obtain an overall estimate of forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) reduction. PubMed and Embase were searched from 1970 to 2010. In total, 257 cross-sectional and longitudinal studies were identified that reported on inorganic dust exposure and had available lung function data. Of the 55 publications which met our inclusion criteria, 11 reported on associations with occupational exposure to respirable quartz dust. The combined average effect estimate of respirable quartz dust on spirometric parameters was obtained using a random effects model meta-analysis. Between-study heterogeneity was assessed via the I(2) statistic. Most studies found a significant negative association of FEV1 and FEV1/FVC related to increasing exposure to crystalline quartz at the workplace. One study found an effect only for smokers, and one did not observe such an effect at all. The meta-analysis of cross-sectional studies showed that the mean ratio FEV1 to FVC was reduced and FEV1 of workers exposed to respirable quartz dust was 4.6% less than predicted compared with workers with no/low exposure. Both results showed a statistically significant difference. Occupational exposure to respirable quartz dust was associated with a statistically significant decrease in FEV1 and FEV1/FVC, revealing airway obstruction consistent with COPD.

Welding and lung cancer in a pooled analysis of case-control studies.

Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.

Lung cancer risk among hairdressers: a pooled analysis of case-control studies conducted between 1985 and 2010.

Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95% confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95% CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio = 2.66, 95% CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio = 2.20, 95% CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies.

Lung cancer risk among bakers, pastry cooks and confectionary makers: the SYNERGY study.

INTRODUCTION: Some studies have suggested increased lung cancer risks among bakers, however the results overall were inconsistent. The authors studied lung cancer risks among bakers and baking-related occupations in the SYNERGY pooled case-control database from 16 countries. METHODS: Occupation in a baking-related job was identified from the subjects' job histories. ORs adjusted for log(age), study centre, smoking behaviour and ever employment in a job with known exposure to occupational lung carcinogens were calculated by unconditional logistic regression. Findings were stratified by sex, histological subtype of lung cancer and smoking status. RESULTS: 19 366 cases (15 606 men) and 23 670 control subjects (18 528 men) were included. 473 cases (415 men, 58 women) and 501 controls (437 men, 64 women) had ever worked in baking or a related job. We did not observe an increased risk for men in baking (OR 1.01; 95% CI 0.86 to 1.18). No linear trends were observed for duration of employment. Some results suggested increased lung cancer risks for women, for example, for working as a baker for >30 years and in never-smokers, but after exclusion of one study these increased risks disappeared. DISCUSSION: The findings from this study do not suggest increased lung cancer risks in baking-related professions.

Size-fractioned particulate air pollution and cardiovascular emergency room visits in Beijing, China.

BACKGROUND: Although short-term exposure to ambient particulate matter has increasingly been linked with cardiovascular diseases, it is not quite clear how physical characteristics of particles, such as particle size may be responsible for the association. This study aimed at investigating whether daily changes in number or mass concentrations of accurately size-segregated particles in the range of 3nm-10µm are associated with daily cardiovascular emergency room visits in Beijing, China. METHODS: Cardiovascular emergency room visit counts, particle size distribution data, and meteorological data were collected from Mar. 2004 to Dec. 2006. Particle size distribution data was used to calculate particle number concentration in different size fractions, which were then converted to particle mass concentration assuming spherical particles. We applied a time-series analysis approach. We evaluated lagged associations between cardiovascular emergency room visits and particulate number and mass concentration using distributed lag non-linear models up to lag 10. We calculated percentage changes of cardiovascular emergency room visits, together with 95% confidence intervals (CI), in association with an interquartile range (IQR, difference between the third and first quartile) increase of 11-day or 2-day moving average number or mass concentration of particulate matter within each size fraction, assuming linear effects. We put interaction terms between season and 11-day or 2-day average particulate concentration in the models to estimate the modification of the particle effects by season. RESULTS: We observed delayed associations between number concentration of ultrafine particles and cardiovascular emergency room visits, mainly from lag 4 to lag 10, mostly contributed by 10-30nm and 30-50nm particles. An IQR (9040cm(-3)) increase in 11-day average number concentration of ultrafine particles was associated with a 7.2% (1.1-13.7%) increase in total, and a 7.9% (0.5-15.9%) increase in severe cardiovascular emergency room visits. The delayed effects of particulate mass concentration were small. Regarding immediate effects, 2-day average number concentration of Aitken mode (30-100nm) particles had strongest effects. An IQR (2269cm(-3)) increase in 2-day average number concentration of 30-50nm particles led to a 2.4% (-1.5-6.5%) increase in total, and a 1.7% (-2.9-6.5%) increase in severe cardiovascular emergency room visits. The immediate effects of mass concentration came mainly from 1000-2500nm particles. An IQR (11.7µgm(-3)) increase in 2-day average mass concentration of 1000-2500nm particles led to an around 2.4% (0.4-4.4%) increase in total, and a 1.7% (-0.8-4.2%) increase in severe cardiovascular emergency room visits. The lagged effect curves of number and mass concentrations of 100-300nm particles or 300-1000nm particles were quite similar, indicating that using particulate number or mass concentrations seemed not to affect the cardiovascular effect (of particles within one size fraction). The effects of number concentration of ultrafine particles, sub-micrometer particles (3-1000nm) and 10-30nm particles were substantially higher in winter comparing with in summer. CONCLUSIONS: Elevated concentration levels of sub-micrometer particles were associated with increased cardiovascular morbidity. Ultrafine particles showed delayed effects, while accumulation mode (100-1000nm) particles showed immediate effects. Using number or mass concentrations did not affect the particle effects.

Cigarette smoking and lung cancer--relative risk estimates for the major histological types from a pooled analysis of case-control studies.

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8-143.2) for SqCC, 111.3 (95% CI: 69.8-177.5) for SCLC and 21.9 (95% CI: 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5-124.6), 108.6 (95% CI: 50.7-232.8) and 16.8 (95% CI: 9.2-30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.