Occupational solar exposure and basal cell carcinoma. A review of the epidemiologic literature with meta-analysis focusing on particular methodological aspects.

BACKGROUND: Numerous epidemiologic studies and a few systematic reviews have investigated the association between occupational solar exposure and basal cell carcinoma (BCC). However, previous reviews have several deficits with regard to included and excluded studies/risk estimates and the assessment of risk of selection bias (RoSB). Our aim was to review epidemiologic studies with a focus on these deficits and to use meta-(regression) analyses to summarize risk estimates. METHODS: We systematically searched PubMed (including MEDLINE) and Embase for epidemiologic studies. Study evaluation considered four main aspects of risk of bias assessments, i.e. Selection of subjects (selection bias); Exposure variables; Outcome variables; Data analysis. RESULTS: Of 56 identified references, 32 were used for meta-(regression) analyses. The overall pooled risk estimate for BCC comparing high/present vs. low/absent occupational solar exposure was 1.20 (95% CI 1.02-1.43); among studies without major deficits regarding data analysis, it was 1.10 (95% CI 0.91-1.33). Studies with low and high RoSB had pooled risk estimates of 0.83 (95% CI 0.73-0.93) and 1.95 (95% CI 1.42-2.67), respectively. The definitions of exposure and outcome variables were not correlated with study risk estimates. Studies with low RoSB in populations with the same latitude or lower than Germany had a pooled risk estimate of 1.01 (95% CI 0.88-1.15). CONCLUSION: Due to the different associations between occupational solar exposure and BCC among studies with low and high RoSB, we reason that the current epidemiologic evidence base does not permit the conclusion that regular outdoor workers have an increased risk of BCC.

Effects of occupational exposure to respirable quartz dust on acute myocardial infarction.

OBJECTIVES: The aim of this study is to investigate the effects of occupational exposure to respirable quartz (RQ) on first acute myocardial infarction (AMI). RQ causes pulmonary diseases like silicosis and has also been linked to cardiovascular diseases. Inflammation is hypothesised as the underlying pathway. METHODS: We performed a 1:3 matched case-control study nested in a cohort of male uranium miners. We included cases (identified from hospital records and validated according to WHO criteria) who had suffered their first AMI while still employed and <65 years of age. Controls were matched by date of birth and Wismut recruitment era. RQ exposure was derived from a job-exposure matrix. We performed a conditional logistic regression adjusted for smoking, metabolic syndrome and baseline erythrocyte sedimentation rate. Subgroups by date of birth and Wismut recruitment era were analysed to minimise the impact of pre-exposures. RESULTS: The study base comprised 292 matched sets. The cumulative exposure ranged from 0 to 38.9 mg/m3-years RQ. The adjusted OR of the highest RQ tertile (>14.62 mg/m3-years) was 1.27 (95% CI 0.82 to 1.98). However, for miners born after 1928 and hired in the earliest recruitment era (1946-1954), a significantly elevated risk was seen in the highest RQ tertile (OR=6.47 [95% CI 1.33 to 31.5]; 50 matched sets). CONCLUSIONS: An impact of quartz dust on first AMI was observed only in a small subgroup that had virtually no pre-exposure to RQ. Further studies on the basis of complete occupational history are required to substantiate this finding.

The Diesel Exhaust in Miners Study provides no evidence for an increase in risk for lung cancer in miners exposed to diesel engine emissions.

The Diesel Exhaust in Miners Study is unquestionably the most suitable data material to date to examine a possible link between diesel engine emissions and lung cancer risk. But the results do not appear to be consistent in themselves. The crucial methodological problem in this study, however, has yet to be discovered, to which the lack of any description of age related information (year of birth, year of hire, year of first exposure, year of death) for the cohort as well as for the cases might have contributed. This information is important to understand the flaws in the analysis. It turns out that the year of birth is associated with the exposure, i.e. with the chance to be exposed over a certain period of time as well as with the chance to be an ever-smoker. A further important issue for the interpretation of the results is the validity of the data on smoking, which are mainly obtained from next of kin for decedents up to 50 years after death. Taking all these aspects into account, it can be concluded that only the SMR-analysis can be considered from all published results.

A critical review of the relationship between occupational exposure to diesel emissions and lung cancer risk.

In 2012, a working group of the International Agency for Research on Cancer classified diesel exhaust (DE) as a human carcinogen (Group 1). This decision was primarily based on the findings of the Diesel Exhaust in Miners Study (DEMS). The disparity between the results of various methodological approaches applied to the DEMS led to several critical commentaries. An expert panel was subsequently set up by the Health Effects Institute to evaluate the DEMS results, together with a large study in the trucking industry. The panel concluded that both studies provided a useful basis for quantitative risk assessments (QRAs) of DE exposure. However, the results of both studies were non-definitive as the studies suffer from several methodological shortcomings. We conducted a critical review of the studies used by the International Agency for Research on Cancer (IARC) working group to evaluate the relationship between DE and lung cancer. The aim was to assess whether the available studies support the statement of a causal relationship and, secondarily if they could be used for QRA. Our review highlights several methodological flaws in the studies, amongst them overadjustment bias, selection bias, and confounding bias. The conclusion from our review is that the currently published studies provide little evidence for a definite causal link between DE exposure and lung cancer risk. Based on two studies in miners, the DEMS and the German Potash Miners study, QRA may be conducted. However, the DEMS data should be reanalyzed in advance to avoid bias that affects the presently published risk estimates.

Occupational exposure to respirable crystalline silica and chronic non-malignant renal disease: systematic review and meta-analysis.

BACKGROUND: While occupational exposure to respirable silica is known to lead to lung disease, most notably silicosis, its association with chronic kidney disease is unclear. OBJECTIVES: This review explores the association between occupational exposure to respirable silica and chronic non-malignant renal disease such as glomerulonephritis. The evidence has been collected and compiled. Possible sources of bias are thoroughly discussed. METHODS: Cohort studies with silica exposure and case-control studies of renal disease were searched in PubMed until January 2015. Two authors independently abstracted data; any disagreement was resolved by consulting a third reviewer. A meta-analysis was performed to evaluate the association to silica exposure. RESULTS: A total of 23 cohort and four case-control studies were included in the analysis. The meta-analysis of cohort studies yielded elevated overall SMRs for renal disease. Some studies, however, included dose-response analyses, most of which did not show a positive trend. The approaches and results of the case-control studies were very heterogeneous. CONCLUSIONS: While the studies of cohorts exposed to silica found elevated SMRs for renal disease, no clear evidence of a dose-response relationship emerged. The elevated risk may be attributed to diagnostic and methodological issues. In order to permit a reliable estimation of a possible causal link, exposed cohorts should be monitored for renal disease, as the information from mortality studies is hardly reliable in this field.

An approach to adjust standardized mortality ratios for competing cause of death in cohort studies.

PURPOSE: The calculation of standardized mortality ratios (SMRs) is a standard tool for the estimation of health risks in occupational epidemiology. An increasing number of studies deal with the analysis of the mortality in employees suffering from an occupational disease like silicosis or coal-worker pneumoconiosis (CWP). Their focus lies not on the mortality risk due to the occupational disease itself, but on other diseases such as lung cancer or heart diseases. Using population-based reference rates in these studies can cause misleading results because mortality rates of the general population do not reflect the elevated mortality due to the occupational disease investigated. Hence, the purpose of the present paper is to develop an approach to adjust the risk estimates for other causes of death with respect to the effect of an occupational disease as a competing cause of death in occupational mortality cohort studies. METHODS: To overcome the problems associated with SMRs, the paper makes use of proportional mortality ratios (PMR), which are a further approach for the estimation of health risks in occupational epidemiology. The cause-specific SMR can be rewritten as a product of PMR times the overall SMR. The PMR can be adjusted by ignoring the competing cause of death. Hence, an adjusted cause-specific SMR can be derived by multiplying this adjusted PMR with the overall SMR. This approach is applied to studies concerning lung cancer risk in coal miners suffering from CWP. RESULTS AND CONCLUSIONS: The usual approach for calculating SMRs leads to an underestimation of the real lung cancer risk in subgroups of miners suffering from CWP. The same effect can be observed in workers exposed to respirable silica already suffering from silicosis. The presented approach results in more realistic risk estimation in mortality cohort studies of employees suffering from an occupational disease. It is easily calculable on the basis of usually published values of observed cases and the corresponding cause-specific SMR.

Dinitrotoluene exposure in the copper mining industry and renal cancer: a case-cohort study.

OBJECTIVES: To evaluate the association between dinitrotoluene (DNT) exposure and renal cancer in a case-cohort study. METHODS: This case-cohort study was conducted among men born between 1920 and 1974 (n=16 441) who were gainfully employed between 1953 and 1990 in one of two copper mines in Mansfeld, Saxony-Anhalt, former German Democratic Republic, and followed up till 31 December 2006. The study included 109 cases with renal cancer identified by record linkage with the Common Cancer Registry of the New Federal States of Germany (GKR) or by a network of pathology institutes. A comparison subcohort of 999 cohort members was selected at random from the total cohort. Duration and intensity of inhalation and dermal exposure to DNT were assessed on the basis of a job exposure matrix. A time-dependent Cox proportional hazards model modified for case-cohort design was used to assess the relationship between cumulative inhalation and dermal DNT exposure and renal cancer. RESULTS: Elevated risks were found for medium (HR=2.73; 95% CI 1.00 to 7.42) and high (HR=1.81; 95% CI 0.75 to 4.33) dermal exposure to DNT. Relative risks for medium inhalation exposure to DNT were not increased (HR=0.93; 95% CI 0.48 to 1.79) while relative risks for high inhalation exposure to DNT were elevated to 1.36 (95% CI 0.84 to 2.21). We found a statistically significant HR of 2.12 (95% CI 1.03 to 4.37) for combined medium or high inhalation and medium or high dermal exposure to DNT. CONCLUSIONS: According to our case-cohort study, dermal and inhalation exposure to DNT is associated with increased renal cancer risk.

Cancer incidence among workers occupationally exposed to dinitrotoluene in the copper mining industry.

PURPOSE: Epidemiological and toxicological studies point to a potential carcinogenic effect of dinitrotoluene (DNT), particularly with respect to renal and urothelial cancer. METHODS: The cohort comprised all men born between 1920 and 1974 (n = 16,441) who were gainfully employed between 1953 and 1990 in one of two underground copper mines in Mansfeld, Saxony-Anhalt, former German Democratic Republic, and who were followed up for cancer incidence, 1961-2005. Incident cancer cases were identified by record linkage with the Common Cancer Registry of the New Laender. Standardized incidence ratios (SIR) were calculated with the general population of Saxony-Anhalt as the reference. RESULTS: Standardized incidence ratios for all cancers were not significantly elevated in the cohort (SIR = 1.04; 95 % confidence intervals (CI) 0.96-1.14). We found an increase in lung cancer (SIR = 1.29; 1.13-1.46), but not in kidney cancer (SIR = 1.01; 95 % CI 0.79-1.27) or bladder cancer (SIR = 1.04; 95 % CI 0.82-1.30). Standardized incidence ratios stratified by duration of employment with DNT exposure indicated moderately increased risks for kidney and bladder cancer in cohort members with longer exposure. CONCLUSIONS: The SIR analysis of workers in the copper mining industry in comparison with the general population of Saxony-Anhalt overall did not indicate increased risks for renal or bladder cancer. However, results by years of exposure to DNT suggested weakly increased risks for outcomes of a priori interest, bladder and kidney cancer. A subsequent case-cohort analysis including expert assessment of DNT exposure and identification of additional cancer cases from a network of pathology institutes will provide further insight into a potential etiologic role of DNT in renal and urothelial cancer.

Diesel motor exhaust and lung cancer mortality: reanalysis of a cohort study in potash miners.

The aim of the reanalysis is to reassess lung cancer risk associated with occupational exposure to diesel motor exhaust in potash miners, while controlling for potential confounders such as smoking and previous occupational history. Our investigation is based on a cohort study of nearly 6,000 German potash miners, who were followed up from 1970 to 2001. The reanalysis also takes into account the employment periods before potash mining, in particular uranium mining. Different approaches (nested case-control study and Cox model) were used to adjust for confounding. The exposure estimates were recalculated, lagging the exposure by 5 years. Exposure groups were defined by tertiles of cumulative respirable elemental carbon (REC) exposure estimates and occupational categories, where exposure was estimated originally by representative measurements of total carbon for different occupations. The highest REC concentration was measured for production workers, about twice as much as for other occupations. The reanalysis revealed that while about 4 % of all study subjects had worked earlier in uranium mines, 10.3 % of later lung cancer cases did so. Although their absolute number was small, the corresponding relative risk estimator was significantly elevated. Our analysis did not show any notable association between cumulative REC exposure and lung cancer risk. Introducing cumulative REC exposure as a continuous variable into the conditional logistic regression model yielded an odds ratio of OR = 1.04 [0.70-1.53]95 % adjusted for smoking and previous employment. The study results give no evidence for an association between REC exposure and lung cancer risk. Only for very high cumulative dose, corresponding to at least 20 years of exposure in the production area, some weak hints for a possible risk increase could be detected. The study underlines the importance of assessing the entire occupational history in occupational studies, especially if the supposed dose-response-relationship is weak.

Chronic obstructive pulmonary disease and longitudinal changes in pulmonary function due to occupational exposure to respirable quartz.

OBJECTIVES: The present study sought to examine the long-term effects of exposure to respirable quartz on pulmonary function with particular focus on chronic obstructive pulmonary disease (COPD). METHODS: The study is based on the Wismut cohort of former uranium miners. Spirometric data were ascertained together with quantitative estimates of cumulative exposure to respirable quartz for each of 1421 study subjects born between 1954 and 1956. The case definition for COPD is based on the criteria of the Global Initiative for Chronic Obstructive Lung Disease. Linear mixed regression models were fitted to identify significant determinants of longitudinal changes in lung function parameters. RESULTS: An average of five spirometries were available for each miner. It was shown that cumulative exposure to 1 mg/m(3)-year respirable quartz leads, on average, to a relative reduction in forced expiratory volume in 1 s/ orced vital capacity (FEV(1)/FVC) of 2.75% (p<0.001). A nested case-control approach demonstrated that the risk for COPD stage I increases with increasing cumulative exposure to respirable quartz (OR 1.81 per 1 mg/m(3)-year). CONCLUSIONS: This paper adds further evidence on the long-term effects of exposure to respirable quartz, which include a decline in pulmonary function parameters and an increase in the incidence of COPD.

Differences in baseline lung cancer mortality between the German uranium miners cohort and the population of the former German Democratic Republic (1960-2003).

A previous analysis of the radon-related lung cancer mortality risk, in the German uranium miners cohort, using Poisson modeling techniques, noted internal (spontaneous) rates that were higher on average than the external rates by 16.5% (95% CI: 9%; 24%). The main purpose of the present paper is to investigate the nature of, and possible reasons for, this difference by comparing patterns in spontaneous lung cancer mortality rates in a cohort of male miners involved in uranium extraction at the former Wismut mining company in East Germany with national male rates from the former German Democratic Republic. The analysis is based on miner data for 3,001 lung cancer deaths, 1.76 million person-years for the period 1960-2003, and national rates covering the same calendar-year range. Simple "age-period-cohort" graphical analyses were applied to assess the main qualitative differences between the national and cohort baseline lung cancer rates. Some differences were found to occur mainly at higher attained ages above 70 years. Although many occupational risk factors may have contributed to these observed age differences, only the effects of smoking have been assessed here by applying the Peto-Lopez indirect method for calculating smoking attributability. It is inferred that the observed age differences could be due to the greater prevalence of smoking and more mature smoking epidemic in the Wismut cohort compared to the general population of the former German Democratic Republic. In view of these observed differences between external population-based rates and internal (spontaneous) cohort baseline lung cancer rates, it is strongly recommended to apply only the internal rates in future analyses of uranium miner cohorts.

Estimation of an Exposure Threshold Value for Compensation of Silica-Induced COPD Based on Longitudinal Changes in Pulmonary Function.

(1) Background: To estimate the cumulative exposure to respirable crystalline silica (RCS) that reduces lung function to an extent corresponding with airway obstruction equivalent to chronic obstructive pulmonary disease (COPD). (2) Methods: The study is based on a miners' cohort with longitudinal data on lung function and RCS exposure. Random-effects linear regression models, allowing for a possible threshold concerning the exposure concentration were used to analyze the impact of RCS on the ratio of forced expiratory volume in 1 s and forced vital capacity (FEV1/FVC). The proposed threshold is the amount of RCS resulting in a decrease in FEV1/FVC from the expected value to the lower limit of normal. (3) Results: The analysis shows that a threshold model fits the data significantly better than the usual linear model. The estimated threshold value for the exposure concentration is 0.089 mg/m3. Using this threshold, the estimate for the corresponding reference dose for RCS is 2.33 mg/m3·y. (4) Conclusions: The analysis confirmed that RCS has a negative impact on lung function. The effect is primarily due to exposure above a concentration threshold of 0.1 mg/m3. It is recommended that COPD should be compensated as an occupational disease if cumulative exposure was at least 2 mg/m3·y above this threshold.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

New insights into the mortality risk from nasopharyngeal cancer in the national cancer institute formaldehyde worker cohort study.

BACKGROUND: Indications were found that a diagnostic bias could have contributed to the National Cancer Institute's (NCI) suggestion of a persistent increased mortality risk for nasopharyngeal cancer (NPC). METHODS: NCI provided the cohort data updated through 2004. We computed local county rate-based standardized mortality ratios (SMRs) for NPC and all other entities of the pharynx for two time periods. Moreover, SMRs were calculated for pharyngeal cancer in relation to study site by cumulative exposure to formaldehyde (FA). RESULTS: Overall, our results corroborate the indications of a diagnostic bias by strong but contrary temporal trends for NPC and pharynx, not specified. Moreover, it was shown that mortality risks were increased in the Wallingford cohort for all pharyngeal cancer combined and for pharyngeal cancer excluding NPC. In contrast, no increased risks for these categories were found in the nine other study sites combined. CONCLUSIONS: Our re-analysis provided little or no evidence to support NCI's suggestion of a persistent association between FA exposure and mortality from NPC.