Occupational exposure to chlorinated solvents and lung cancer: results of the SYNERGY case-control study.

ObjectiveThe Synergy project derived quantitative exposure-response associations for five occupational lung carcinogens (asbestos, chromium-VI, nickel, polycyclic aromatic hydrocarbons, and respirable crystalline silica) and lung cancer in a pooled analysis of...

To quantify, after extending follow-up 15 years, the relationship between occupational respirable crystalline silica (RCS) exposure and risk of silicosis diagnosis and lung cancer mortality in the German Porcelain Workers Cohort Study, and to estimate possible exposure thresholds for these. Porcelain workers enrolled between January 1, 1985, and December 31, 1987, in a mandatory medical surveillance program including triennial chest x-rays and alive at the end of the previous study follow-up (2005) were followed through December 2020, for lung cancer mortality and silicosis incidence. Cause of death was determined from death certificates. Silicosis cases were identified by re-reading x-rays of individuals remaining in the medical surveillance program or filing insurance claims for silicosis. RCS exposure was estimated for each cohort member using a job exposure matrix (JEM) based on about 8,000 historical industrial hygiene RCS measurements. Cause-specific standardized mortality ratios (SMRs) and Cox proportional hazards ratios (HRs) and their 95% confidence intervals (95% CIs) were estimated by cumulative and average exposure groups, controlling for age, sex, smoking status and employment duration. Exposure-response analyses were performed to identify possible exposure thresholds for lung cancer and silicosis risk. Total deaths increased from 1,610 (9.1%) to 4,586 (26%) over 537,129 total person-years at risk. All-cause mortality was elevated among men (SMR = 1.10, 95% CI 1.06-1.14); however, a deficit was seen among women (SMR = 0.93, 95% CI 0.89-0.98). No statistically significantly increased mortality was seen due to lung cancer, renal cancer, or non-malignant renal disease - conditions reportedly associated with RCS exposure. Lung cancer mortality was unrelated to RCS exposure level. However, for silicosis cases classified using International Labor Organization (ILO) categories ≥1/1 or 1/0, risk was strongly associated with estimated average exposure >0.10 mg/m3 and 0.15 mg/m3, and cumulative exposure >3.0 mg/m3-years and > 1.0 mg/m3-years, respectively. Despite the large number (n = 284) of lung cancer deaths and high historical RCS exposures, no excess risk and no relationship with exposure level were seen. However, RCS exposure was strongly associated with silicosis risk, with clear exposure thresholds. This study further confirms the lack of increased lung cancer risk at RCS levels historically prevalent in the German porcelain industry and that exposures exceeding estimated thresholds clearly increased silicosis risk. Occupational exposure levels in the German porcelain industry in recent decades have remained well below these thresholds; therefore, few additional silicosis cases are expected.

Authors' response to: Qualitative job-exposure matrix--a tool for the quantification of population-attributable fractions for occupational lung carcinogens?

Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 μg/m3 were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.

Occupational exposure to respirable crystalline silica (RCS) has been associated with both silicosis and lung cancer, but no systematic review (SR) specifically focused on exposure-response relationships has been published for these diseases. We conducted this SR in compliance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed searches, supplemented with Web of Science and Google Scholar searches, identified 1,007 potentially relevant articles. After applying selection criteria and removing duplicates, 65 publications were reviewed and evaluated, 20 of which presented at least semi-quantitative exposure-response results for lung cancer (n = 12) and/or silicosis (n = 10). Cumulative RCS exposure was most commonly reported. Increasing silicosis risk with increasing cumulative RCS exposure was reported in all studies, with exposure thresholds indicated, but at different cumulative exposures. For most studies defining silicosis as International Labor Organization (ILO) score ≥ 1/0, substantially increased risks were clear at or above 1 mg-/m3-yr. For lung cancer, exposure-response estimates were mixed with 4 studies reporting no statistically significantly increased relative risk of lung cancer at any cumulative RCS exposure. Three studies reported statistically significant increased risks but only for high cumulative RCS exposures. Residual confounding by smoking was not explicitly discussed in most studies. One case-control study presented an exposure-response analysis for silica and lung cancer limited to never-smokers with substantial silica exposure; risk was increased only among those in the highest RCS exposure category. Studies with more detailed smoking information generally reported risks close to background levels except at the highest cumulative RCS exposure categories. Silicosis risk clearly and consistently was increased above cumulative exposure thresholds of roughly 1 mg/m3-years across most studies. However, for lung cancer, results were heterogeneous with potential residual confounding by smoking complicating interpretation. Results suggest that lung cancer risk may not be increased at cumulative RCS exposures below the reported exposure thresholds for silicosis risk.

Rationale: Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. Objectives: We aimed to examine the relationship between occupational benzene exposure and lung cancer. Methods: Subjects from 14 case-control studies across Europe and Canada were pooled. We used a quantitative job-exposure matrix to estimate benzene exposure. Logistic regression models assessed lung cancer risk across different exposure indices. We adjusted for smoking and five main occupational lung carcinogens and stratified analyses by smoking status and lung cancer subtypes. Measurements and Main Results: Analyses included 28,048 subjects (12,329 cases, 15,719 control subjects). Lung cancer odds ratios ranged from 1.12 (95% confidence interval, 1.03-1.22) to 1.32 (95% confidence interval, 1.18-1.48) (Ptrend = 0.002) for groups with the lowest and highest cumulative occupational exposures, respectively, compared with unexposed subjects. We observed an increasing trend of lung cancer with longer duration of exposure (Ptrend < 0.001) and a decreasing trend with longer time since last exposure (Ptrend = 0.02). These effects were seen for all lung cancer subtypes, regardless of smoking status, and were not influenced by specific occupational groups, exposures, or studies. Conclusions: We found consistent and robust associations between different dimensions of occupational benzene exposure and lung cancer after adjusting for smoking and main occupational lung carcinogens. These associations were observed across different subgroups, including nonsmokers. Our findings support the hypothesis that occupational benzene exposure increases the risk of developing lung cancer. Consequently, there is a need to revisit published epidemiological and molecular data on the pulmonary carcinogenicity of benzene.

ObjectivesMining is associated with exposures to various lung carcinogens such as diesel engine exhaust (DEE) and respirable crystalline silica (RCS). We aimed to determine if lung cancer incidence was higher...

IntroductionLittle is known about joint effects between occupational carcinogens on lung cancer risk. We investigated pairwise exposure to five occupational exposures: asbestos, respirable crystalline silica, metals (i.e. nickel, chromium VI),...

The mortality of 2650 employees (93.4% males) in the mine and mill production of roofing granules at four plants was examined between 1945 and 2004. Hypotheses focused on diseases associated with exposure to silica: nonmalignant respiratory disease, lung cancer, and nonmalignant renal disease. Study eligibility required ≥ 1 year of employment by 2000. Work history and vital status were followed through 2004 with < 1% lost to follow-up. Industrial hygiene sampling data (1871 sampling measurements over a 32-year period) and professional judgment were used to construct 15 respirable crystalline silica exposure categories. A category was assigned to all plant-, department-, and time-dependent standard job titles. Cumulative respirable crystalline silica exposure (mg/m3-years) was calculated as the sum of the product of time spent and the average exposure for each plant-, department-, job-, and calendar-year combination. The cohort geometric mean was 0.17 mg/m3-years (geometric standard deviation 4.01) and differed by plant. Expected deaths were calculated using U.S. (entire cohort) and regional (each plant) mortality rates. Poisson regression was used for internal comparisons. For the entire cohort, 772 deaths (97.4% males) were identified (standardized mortality ratio 0.95, 95% CI 0.88–1.02). There were 50 deaths from nonmalignant respiratory diseases (1.14, 95% CI 0.85–1.51). Lagging exposure 15 years among the male cohort, the relative risks for nonmalignant respiratory disease were 1.00 (reference), 0.80, 1.94, and 2.03 (p value trend = 0.03) when cumulative exposure was categorized < 0.1, 0.1–<0.5, 0.5–<1.0, and ≥ 1.0 mg/m3-years, respectively. There was a total of 77 lung cancer deaths (1.11, 95% CI 0.88–1.39). Lagging exposure 15 years, the relative risks for males were 1.00 (reference), 1.83, 1.83, and 1.05 (p value trend = 0.9). There were 16 deaths from nonmalignant renal disease (1.76, 95% CI 1.01–2.86). This exposure-response trend was suggestive but imprecise. The study results are consistent with other cohorts with similar levels of exposure to respirable crystalline silica.

This study investigated associations between exposure to polycyclic aromatic hydrocarbons (PAH) and the incidence of lung, bladder, kidney, and pancreatic cancer among Norwegian aluminum plant workers. Cancer incidence was investigated from 1953 to 1996 among 11,103 men employed for more than 3 years in the industry, giving 272,554 person-years during follow-up. A job exposure matrix was constructed to estimate exposure to particulate PAH and fluorides. The observed cases of cancer were compared with expected figures calculated from national rates. Dose-response relations were investigated by internal comparisons using Poisson regression and stratified analyses for standardized incidence ratio. Potential confounding by smoking was investigated in subanalyses restricted to 3 of the plants. The study showed an overall excess for bladder cancer, standardized incidence ratio 1.3 (95% confidence interval 1.1-1.5), which increased with increasing cumulative exposure to PAH and reached a relative risk of about 2 for the upper exposure category in the analysis with 30 years of lag time. There was no association between cumulative PAH exposure and lung cancer, but there were indications of an elevated risk of kidney cancer among the most heavily PAH-exposed persons in the analyses with a lag time of 30 years. For pancreatic cancer we found a higher incidence among the PAH-exposed persons than among the unexposed ones, but no clear dose-response association was found. The study showed an association between bladder cancer and exposure to PAH, but gave no support to an association between PAH exposure and lung cancer in the primary aluminum industry.

Asbestos Exposure, Asbestosis, and Lung Cancer

IntroductionBenzene is widely present in various industries and ubiquitously in the general environment. Benzene has been classified as a known human carcinogen, but there is limited evidence linking benzene exposure...

Infectious complications

ObjectiveUsing data from the SYNERGY project, we evaluated the association between occupational exposure to polycyclic aromatic hydrocarbons (PAH) and the risk of lung cancer, adjusted for tobacco smoking. MethodsFor 16...

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.