Chromosomal alterations in exfoliated urothelial cells from bladder cancer cases and healthy men: a prospective screening study.

BACKGROUND: Chromosomal instability in exfoliated urothelial cells has been associated with the development of bladder cancer. Here, we analyzed the accumulation of copy number variations (CNVs) using fluorescence in situ hybridization in cancer cases and explored factors associated with the detection of CNVs in tumor-free men. METHODS: The prospective UroScreen study was designed to investigate the performance of UroVysion™ and other tumor tests for the early detection of bladder cancer in chemical workers from 2003-2010. We analyzed a database compiling CNVs of chromosomes 3, 7, and 17 and at 9p21 that were detected in 191,434 exfoliated urothelial cells from 1,595 men. We assessed the accumulation of CNVs in 1,400 cells isolated from serial samples that were collected from 18 cancer cases up to the time of diagnosis. A generalized estimating equation model was applied to evaluate the influence of age, smoking, and urine status on CNVs in cells from tumor-free men. RESULTS: Tetrasomy of chromosomes 3, 7 and 17, and DNA loss at 9p21 were the most frequently observed forms of CNV. In bladder cancer cases, we observed an accumulation of CNVs that started approximately three years before diagnosis. During the year prior to diagnosis, cells from men with high-grade bladder cancer accumulated more CNVs than those obtained from cases with low-grade cancer (CNV < 2: 7.5% vs. 1.1%, CNV > 2: 16-17% vs. 9-11%). About 1% of cells from tumor-free men showed polysomy of chromosomes 3, 7, or 17 or DNA loss at 9p21. Men aged ≥50 years had 1.3-fold more cells with CNVs than younger men; however, we observed no further age-related accumulation of CNVs in tumor-free men. Significantly more cells with CNVs were detected in samples with low creatinine concentrations. CONCLUSIONS: We found an accumulation of CNVs during the development of bladder cancer starting three years before diagnosis, with more altered cells identified in high-grade tumors. Also, a small fraction of cells with CNVs were exfoliated into urine of tumor-free men, mainly exhibiting tetraploidy or DNA loss at 9p21. Whether these cells are preferentially cleared from the urothelium or are artifacts needs further exploration.

A retrospective cohort study of shift work and risk of cancer-specific mortality in German male chemical workers.

OBJECTIVES: Human evidence of carcinogenicity concerning shift work is inconsistent. In a previous study, we observed no elevated risk of total mortality in shift workers followed up until the end of 2006. The present study aimed to investigate cancer-specific mortality, relative to shift work. METHODS: The cohort consisted of male production workers (14,038 shift work and 17,105 day work), employed at BASF Ludwigshafen for at least 1 year between 1995 and 2005. Vital status was followed from 2000 to 2009. Cause-specific mortality was obtained from death certificates. Exposure to shift work was measured both as a dichotomous and continuous variable. While lifetime job history was not available, job duration in the company was derived from personal data, which was then categorized at the quartiles. Cox proportional hazard model was used to adjust for potential confounders, in which job duration was treated as a time-dependent covariate. RESULTS: Between 2000 and 2009, there were 513 and 549 deaths among rotating shift and day work employees, respectively. Risks of total and cancer-specific mortalities were marginally lower among shift workers when taking age at entry and job level into consideration and were statistically significantly lower when cigarette smoking, alcohol intake, job duration, and chronic disease prevalence at entry to follow-up were included as explanatory factors. With respect to mortality risks in relation to exposure duration, no increased risks were found in any of the exposure groups after full adjustment and there was no apparent trend suggesting an exposure-response relation with duration of shift work. CONCLUSIONS: The present analysis extends and confirms our previous finding of no excess risk of mortality associated with work in the shift system employed at BASF Ludwigshafen. More specifically, there is also no indication of an increased risk of mortality due to cancer.

Shift work and risk of non-cancer mortality in a cohort of German male chemical workers.

OBJECTIVES: Shift work is widely considered to be a health risk. In a previous study, we observed no elevated risk of total mortality in BASF shift workers followed up until the end of 2006. The present study aims to investigate non-cancer mortality, especially mortality caused by ischaemic heart disease (IHD), relative to shift work. METHODS: The cohort consisted of 14,038 male shift and 17,105 male day workers from manufacturing plants, who were employed for at least 1 year between 1995 and 2005. Vital status was followed from 2000 to 2009. Cause-specific mortality was obtained from death certificates. Non-cancer mortality as well as mortality specific to diagnoses from I20.0 to I25.9 according to International Classification of Disease version 10 was compared between the two working-time systems. To estimate the impact of shift work on the outcome of interest, Cox proportional hazard model was used to adjust for potential confounders such as age, smoking, alcohol consumption, job level, and disease status at baseline. The effect estimates were then given as hazard ratio (HR) with 95 % confidence interval (CI). RESULTS: Between 2000 and 2009, a total of 1,062 deaths occurred in the cohort: 513 (3.6 %) in shift and 549 (3.2 %) in day workers. Among them were 122 deaths resulting from IHD, 55 (0.39 %) and 67 (0.39 %), respectively. After adjustment for age at entry and job level, no increased risk of non-cancer mortality (HR 0.94; 95 % CI 0.77-1.15) as well as of IHD-caused mortality was found among shift workers (HR 0.77; 95 % CI 0.52-1.14). The risk estimates were robust after further adjustment for more factors in all models and consistently tended to be in favour of shift workers. Considering the duration of exposure to shift, no dose-response relationship was found. CONCLUSION: The present analysis does not find strong evidence for an increased mortality risk due to non-cancer disease and, more specifically, IHD-caused mortality associated with this shift system. Initial selection based on health criteria as well as ongoing health surveillance and health promotion is likely to have contributed to this result. Shift work over 34 years may lead to a loss of this initial selection advantage over time, but the respective risk estimates lacked statistical precision.

Screening for bladder cancer with urinary tumor markers in chemical workers with exposure to aromatic amines.

PURPOSE: To validate urinary markers for the early detection of bladder cancer (BC) in chemical workers. METHODS: UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of the German Social Accident Insurance for active or retired workers with former exposure to aromatic amines. From 2003 to 2010, 1,609 men took part in voluntary annual screens. Cytology, the quantitative NMP22(®) assay, and UroVysion™ were applied to 7,091 urine samples. RESULTS: Fifteen out of 21 tumors were detected following test positivity. The UroVysion/NMP22 panel detected 14 out of 21 tumors versus 8 tumors with cytology alone (sensitivity 66.7 vs. 44.4 %, specificity 94.5 vs. 98.5 %). The sensitivity of the panel increased to 85.7 % in samples collected ≤12 months before diagnosis and when papillomas were excluded, compared to 58.3 % with cytology. About 3 % of NMP22 tests were false-positive. UroVysion results overlapped with cytology due to the preselection of atypical cells. NMP22 was less and UroVysion more frequently positive in diluted urine samples. Leukocytes confounded NMP22 but not UroVysion. The low incidence of BC in this study population yielded low positive predictive values of the markers and high costs per tumor detected with screening. CONCLUSIONS: UroVysion in combination with NMP22 detected more cases than cytology alone, at the expense of a lower specificity. High costs per detected case resulted from a lower BC incidence than in the past when levels of occupational exposure to aromatic amines were higher. Currently, it cannot be recommended to apply these markers for screening in asymptomatic workers. The increase in sensitivity is not balanced by the high costs of UroVysion and the false-positive tests of NMP22.

Chromosomal instability and bladder cancer: the UroVysion(TM) test in the UroScreen study.

UNLABELLED: What's known on the subject? and what does the study add?: UroVysion™ is a multicolour fluorescence in situ hybridisation assay that detects DNA gain at chromosomes 3, 7 and 17 and loss at the 9p21 locus in exfoliated urothelial cells. This cell-based test is time-consuming and costly compared with voided urine cytology or other molecular markers for the early detection of bladder cancer. We determined copy number changes at chromosomes 3, 7 and 17 and at the 9p21 locus with UroVysion in a prospective screening study among chemical workers. Strong correlations between DNA gains yield a similar performance in detecting bladder cancer with just one of the probes for chromosomes 3, 7 or 17 instead of all, supporting the development of a simpler and cheaper assay. OBJECTIVE: To explore changes at chromosomes 3, 7, 17 and 9p21 in order to assess associations with bladder cancer for possible improvements of the UroVysion™ assay regarding screening. SUBJECTS AND METHODS: In all, 1609 men took part in the prospective study UroScreen. Annual screening for bladder cancer was offered to male chemical workers with former exposure to aromatic amines as a voluntary surveillance programme between 2003 and 2010. In all, 191 434 cells in 6517 UroVysion tests were analysed for copy number variations (CNV) at chromosome 3, 7, 17 (gains) and 9p21 (deletions) in 1595 men. We assessed CNVs at single or multiple loci using polysomy indices (PIs, called multiple PI and PI 3, PI 7 and PI 17). We calculated Spearman's rank correlation coefficients (rs ) between these PIs and receiver operating characteristic (ROC) curves with areas under the curves (AUCs). We applied Cox regression to estimate hazard ratios (HRs) to assess the risk of developing bladder cancer. RESULTS: Nine out of 21 bladder tumours detected in 20 participants ('cases') had a positive UroVysion test, including seven high-grade carcinomas and seven overlapping results with a positive cytology. Four cases with negative test results did not attend screening annually. No case was found because of a complete loss of 9p21 in at least 12 cells. There were strong correlations between pairwise combinations of gains at chromosome 3, 7 or 17, ranging between rs = 0.98 and rs = 0.99 in cases and between rs = 0.84 and rs = 0.88 in non-cases (P < 0.001). Associations were less pronounced with CNVs at 9p21 among cases and were lacking in non-cases. Estimates of the relative risk of DNA gain for developing a bladder tumour assessed with PIs (threshold 10% of cells) were 47.7 (95% confidence interval [CI] 18.3-124.1) for the multiple PI, 44.5 (95%CI 16.5-119.9) for PI 3, 34.7 (95%CI 13.1-92.1) for PI 7 and 52.4 (95%CI 20.7-132.6) for PI 17, as well as 7.9 (95%CI 3.0-20.6) for a complete loss of 9p21 (threshold 2.5% of cells), respectively. ROC analyses showed similar AUCs for multiple PI compared with PIs of single chromosomes 3, 7 and 17 (all AUCs between 0.79 and 0.80) and a lower AUC for a homozygous loss of 9p21 (AUC 0.72). CONCLUSIONS: The UroVysion assay showed a reasonable performance in detecting bladder cancer in the present study population and shared positive test results with cytology, which is much cheaper. A simpler, faster and cheaper version of the UroVysion assay might rely on the very strong correlations between gains at chromosomes 3, 7 and 17, resulting in a similar performance in detecting bladder cancer with single-probe PIs compared with the full set of these probes. Loss of 9p21 was less predictive for developing bladder cancer in UroScreen.

Nuclear matrix protein-22: a prospective evaluation in a population at risk for bladder cancer. Results from the UroScreen study.

UNLABELLED: What's known on the subject? and What does the study add? The prognosis of bladder cancer significantly depends on tumour stage and time of diagnosis so early diagnosis is desirable to decrease mortality and treatment costs. The NMP22 test is approved for clinical application by the Food and Drug Administration (FDA) of the US. Previous studies have reported values of 47-100% for sensitivity and 58-91% for specificity with this test, but there is no new data on the predictive value of NMP22 for screening bladder cancer (BC). The most important risk factor for BC is the tobacco consumption but occupational exposure to carcinogenic substances, especially aromatic amines, is regarded as another risk factor. The UroScreen study is a prospective longitudinal study for the early detection of BC. To our knowledge, it is the largest prospective validation study conducted over the longest period of time. The study results led us to conclude that, based on the currently available data, NMP22 should not be regarded as an alternative to endoscopy, and we could not make a general recommendation for screening or follow-up. The UroScreen results indicate that urine-based molecular markers could be a suitable addition to urine cytology and the detection of microhaematuria. OBJECTIVE: To evaluate the value of nuclear matrix protein-22 (NMP22) in bladder cancer (BC) screening, and its effect on variables in a prospective study in a high-risk population. PATIENTS AND METHODS: A total of 1772 chemical workers (mean age 62 years) exposed to carcinogenic aromatic amines were enrolled in the study. In all, 7091 screening check-ups in 1609 subjects were performed. Urine samples were collected for a quantitative NMP22 immunoassay, urine analysis and creatinine concentration assessment. Cystoscopy and subsequent transurethral resection were performed where there were suspicious findings. RESULTS: Histopathological analysis found three papillary urothelial neoplasms of low malignant potential, five recurrent BCs and 13 primary BCs. Three tumours were at a muscle-invasive stage (pT2, pT3a or pT3b). We found higher NMP22 concentrations (>10 U/mL) in 224 patients, which correctly predicted BC in six cases (sensitivity 97.29%, specificity 28.57%; negative predictive value 99.04%, positive predictive value 12.24%). Gross haematuria affected NMP22 results (odd ratio [OR] 3.49, 95% confidence interval [CI] 1.81-6.73). Infection also affected NMP22 results (OR 4.13, 95% CI 2.31-7.35). NMP22 was more frequently positive in urine with creatinine concentration >2.5 g/L (OR 1.61, 95% CI 0.91-2.86). CONCLUSIONS: NMP22 outcomes are affected by haematuria, infection and concentrated urine. NMP22 alone cannot be recommended for primary screening in a high-risk population nor as an alternative to cystoscopy during follow-up. A NMP22 test might be a useful adjunct to urine cytology.

The role of haematuria in bladder cancer screening among men with former occupational exposure to aromatic amines.

UNLABELLED: Study Type - Diagnostic (validating cohort). LEVEL OF EVIDENCE: 1b. What's known on the subject? and What does the study add? Microscopic haematuria (µH) is frequently detected in elderly adults. The American Urological Association recommends the follow-up of subjects with µH on bladder cancer. Whereas gross haematuria is considered an important sign of the presence of bladder cancer, the disease-predictive value of µH is less clear. No association of µH with the development of bladder tumours in a prospective screening cohort of chemical workers was observed. The positive predictive value of µH for bladder cancer was as low as 1.2%. Haematuria interfered with NMP22 but not with cytology and UroVysion(TM) test results. OBJECTIVE: • To assess the positive predictive value (PPV) of microhaematuria (µH) and gross haematuria (GH) in bladder cancer screening and the influence of haematuria on tumour tests in a prospective study. PATIENTS AND METHODS: • From September 2003 to January 2010, 1323 men took part in an annual voluntary bladder cancer screening programme for chemical workers with former exposure to aromatic amines. • In 5315 urine samples haematuria was determined with a dipstick, followed by a microscopic blood cell count in the sediment. Haematuria was categorized into traces, µH and GH. • Urinary leukocytes and other factors were investigated as potential predictors of haematuria using a generalized estimating equation model for repeated urinalysis. The risk of haematuria for positive tumour tests was analysed correspondingly. • The bladder cancer risk was estimated for the highest degree of haematuria occurring during the study with Poisson regression. RESULTS: • As of July 2010, 15 bladder tumours were detected in 14 participants. • GH was found in four out of nine high-grade tumours and associated with a rate ratio of 3.82, 95% confidence interval (CI) 0.50-29.15 for the development of bladder lesions. • The PPV of GH was 11.4%, but only 1.2% for µH. µH occurred in 18.8% of urine samples and was not associated with bladder cancer [rate ratio (RR) 0.72, 95% CI 0.11-4.78]. • Abundant urinary leukocytes were associated with µH [odds ratio (OR) 8.34, 95% CI 2.26-30.69] and even stronger with GH (OR 22.25, 95% CI 6.42-77.06). • Haematuria and leukocytes influenced NMP22 positivity (µH: OR 1.63, 95% CI 1.06-2.51, abundant leukocytes: OR 8.90, 95% CI 1.58-50.16), but not test results for urine cytology and UroVysion(TM) . CONCLUSION: • While the PPV of µH for bladder cancer was low, there was a strong influence of haematuria and leukocytes on the protein-based tumour test NMP22®. • Erythrocytes and leukocytes should be determined at least semi-quantitatively for the interpretation of positive NMP22 test results. • In addition, a panel of tumour tests that includes methods not affected by the presence of erythrocytes or leukocytes such as cytology and UroVysion(TM) would improve bladder cancer screening.

Medical program for shift workers--impacts on chronic disease and mortality outcomes.

OBJECTIVE: In 1983, global chemical company BASF SE implemented a supplemental health protection program to help its employees cope with the stressors associated with shift work. The program included comprehensive medical examinations and health promotion activities targeted at shift workers. METHODS: To assess the possible long-term health impacts of the program, cohorts of 14,128 male rotating shift and 17,218 male day wage employees were established via electronic job history searches. Health examination and mortality records were linked to job histories and studied over an 11-year period. RESULTS: Between 1996 and 2006, there were 414 and 463 deaths among rotating shift and day work employees, respectively. Mortality risks were marginally lower among shift working employees when taking age and job level into consideration, and remained so when cigarette smoking, alcohol intake, and existing chronic disease conditions were included as explanatory factors. The incidence of obesity, diabetes, and diseases of the circulatory and digestive system, as diagnosed or reported during health examinations, was higher among shift work employees, possibly as a consequence of enhanced medical surveillance or a direct effect of shift work. CONCLUSION: Incorporation of extensive occupational medical examinations, health seminars, and other intervention programs may help mitigate the long-term health consequences of shift work.

Pregnancy protection program in a large chemical company: design and initial survey results.

OBJECTIVES: To describe the BASF pregnancy protection program and provide initial results regarding selected pregnancy outcomes. METHODS: Pregnancies (n=1148) occurring between 1997 and 2002 were identified and outcomes were documented by questionnaires administered after the pregnancy announcement, end of pregnancy, and one year later. Potential maternal exposures were assessed via job histories, workplace inspections, and questionnaire. RESULTS: Participation was 90% overall and was consistently high across employee subgroups. Pregnancy losses (11.5%) did not differ significantly by type of work. Among pregnancy symptoms vaginal bleeding was weakly associated with two exposure measures. Preterm births (8.7%) were in agreement with general population norms and did not vary by maternal exposure category. CONCLUSIONS: High participation rates and a structured approach to employee education and documentation of reproductive outcomes may be of value in addressing reproductive health issues in the workplace.

Pregnancy protection program in a large chemical company: infant outcomes.

OBJECTIVES: The purpose of this study was to investigate reproductive outcomes in infants relative to maternal exposures in the chemical industry. METHODS: Via questionnaires administered after the pregnancy announcement, end of pregnancy, and 1 year later, infant outcomes were documented for 1147 live births. Maternal exposure factors were evaluated relative to birth height and weight, sex ratio, Apgar score at 5 minutes, and major malformations. RESULTS: Birth height and weight, sex ratio, and Apgar score did not differ by maternal work area or chemical hazard categories. Major malformations (3.1%) and organ-specific anomalies were consistent with the experience of a regional birth defects registry. Rates of malformation were marginally higher in infants born to women assigned to chemical versus office jobs. CONCLUSIONS: Infant outcomes to date have been consistent with comparable findings from population-based studies. Longer-term observation will be needed to assess trends for low-frequency outcomes and more specific maternal exposures.

Pesticides and childhood cancer: an update.

OBJECTIVES: Epidemiological studies have reported associations between childhood cancer and either parental or child exposure to pesticides. Reviews have been published in 1997, 1998 and 2006 where the evidence was found suggestive but not conclusive. The present review is an extended update of the latter one. METHODS: The PubMed database was searched to identify published studies on this topic issued between 1998 and 2006. RESULTS: Thirty-six new studies have been identified for this review. Some cohort studies and the majority of the case-control studies suggest an increased risk for the cancer types studied, associated with exposure to pesticides in at least one of a large variety of exposure categories. However, the evidence is conflicting with regard to cancer types as well as to causative factors across studies. The major shortcomings concern exposure assessment, where, e. g., "farming" is treated equal to "exposure to pesticides", disregarding other possible exposures, e.g., to biological or infectious agents, and hitherto unidentified lifestyle factors. Also, many exposure categories used, mainly in case-control studies, lack chemical or toxicological plausibility. In most studies exposures were categorized as "ever vs. never", with little regard of exposure intensity or duration. CONCLUSIONS: The available literature does not allow firm conclusions with regard to pesticides and any type of childhood cancer. But even if the reported associations were true, exposure to pesticides could not explain the vast majority of childhood cancer cases. Investing in the acquisition and critical review of exposure information appears to be the crucial step for causal assessment in future research. However, focusing on the presence of pesticides, and not asking the question why they were used, might mask relevant associations to other causative agents.

Shift Work and Prostate Cancer Incidence in Industrial Workers: A Historical Cohort Study in a German Chemical Company.

BACKGROUND: There is inconsistent evidence for a possible carcinogenic effect of shift work. In particular, little is known about the putative association of shift work with prostate cancer. METHOD: We studied a cohort of 27,828 male industrial production workers residing in the German federal state of Rhineland-Palatinate who worked for at least one year in a chemical company in the period 1995-2005. We obtained data on shift work and potential confounders including age, occupational task, and duration of employment from personnel files and from the records of the occupational health service. New cases of cancer in the period 2000-2009 were ascertained from the state cancer registry. Differences in risk between shift workers and daytime workers were analyzed with Cox regression, stratified by stage of cancer, and adjusted for potential confounding effects. RESULTS: There were 146 new cases of prostate cancer in 12,609 rotating shift workers and 191 in 15,219 daytime workers. The median year of birth was 1960 in the first group and 1959 in the second. The shift workers did not have an elevated hazard ratio for prostate cancer in comparison to the daytime workers (HR = 0.93, 95% confidence interval [CI] 0.73-1.18). Some differences were seen depending on tumor stage. Both groups of workers had a higher incidence of prostate carcinoma than the general population (standardized incidence rate [SIR] = 1.44, 95% CI 1.22-1.70 for daytime workers; SIR = 1.51, 95% CI 1.30-1.74 for shift workers). CONCLUSION: In this well-documented, large-scale cohort study, the incidence of prostate cancer among shift workers did not differ from that among daytime workers. In the authors' opinion, further follow-up of this relatively young cohort is required.

Pilot study on prevalence of color vision dysfunction in long-term solvent-exposed painters.

Main purpose of our study was to examine whether painters with long-term exposure to mixtures of organic solvents show slight dysfunctions in color vision ability. The study population consisted of 140 men with chronic exposure to organic solvents from paint and thinners (mean duration of exposure: 26 years). We used the Lanthony Desaturated Panel-D-15 (LDP-D15) to test color vision and calculated the color confusion index (CCI). The results were compared with reference values taken from the literature. Additionally the questionnaire Q18 for solvent related neurotoxic symptoms was applied and its results compared with the CCI. Painters between 25 to 55 years old had higher median CCI values than the respective age group of the references. No statistical significant association between CCI and the actual or chronic solvent exposure was found. The results of the Q18 did also not correlate significantly with the exposure indices. We recommend further studies to explore if the color confusion index is an appropriate indicator of early neurotoxic effects in painters.

A retrospective cohort study of shift work and risk of incident cancer among German male chemical workers.

OBJECTIVE: Human evidence of carcinogenicity concerning shift work is inconsistent. This industry-based cohort study aimed to examine the relationship between working in a rotating shift and cancer incidence. METHODS: The cohort consisted of male production workers (12 609 shift and 15 219 day), employed in a large chemical industry for at least one year between 1995-2005, and residing in the German federal state of Rhineland-Palatinate. Incident cancer cases from 2000-2009 were identified through record linkage with the cancer registry of Rhineland-Palatinate. Information on exposure to shift work and potential confounders, including age, smoking status, job level, and employment duration, was extracted from the personnel and health records. Cox proportional hazard models were used to estimate hazard ratios (HR) with 95% confidence interval (95% CI) adjusted for potential confounders. RESULTS: Between 2000-2009, 518 and 555 cancer cases (excluding non-melanoma skin cancer) occurred among shift and day work employees, respectively. Compared to "never shift work", shift workers experienced an increased risk of cancers neither at all-sites (HR 1.04, 95% CI 0.89-1.21) nor for prostate cancer in particular (HR 0.93, 95% CI 0.71-1.21). The risks of leukemia and esophagus cancer were increased if smoking was not taken into account, albeit based on small numbers. However, adjusting for smoking changed the HR and the risk diminished. CONCLUSIONS: Our analyses do not provide evidence for a carcinogenic effect of the shift system under study.

Occupational stress perception and its potential impact on work ability.

OBJECTIVE: To examine perceived stress across employees with different occupational status, to investigate the impact of stress on work ability and to derive conclusions regarding health promotion activities. PARTICIPANTS AND METHODS: A comprehensive survey combining questionnaire and medical examination was offered in one division in BASF Ludwigshafen. Among 867 voluntary participants, 653 returned complete questionnaires. The questions were directed at perception of safety at the workplace, self-rated health status, frequency of stress symptoms, unrealistic job demands, time pressure and maladjustment of work life balance. The outcome of interest was self-estimated health measured by the Work Ability Index (WAI). RESULTS: Occupational stressors were perceived differently across occupational status groups. Frontline operators had more health concerns due to workplace conditions, while professional and managerial staff reported higher frequencies of perceived tension, time pressure, and maladjustment of work life balance. After adjustment for occupational status, demographic and lifestyle factors, perceived stress was associated with a modest to strong decline in WAI scores. CONCLUSION: While perceived occupational stress had an apparent impact on WAI, and WAI has been demonstrated to be predictive of early retirement, more intensive and employee group-specific stress management interventions are being implemented beyond traditional strategies of routine occupational medical surveillance.

Prospective evaluation of fluorescence-in situ-hybridization to detect bladder cancer: results from the UroScreen-Study.

BACKGROUND: UroScreen is a prospective study for early diagnosis of bladder cancer (BC) in chemical workers formerly exposed to aromatic amines, aimed to assess the performance of molecular tumor markers in comparison with urinary cytology. Here we evaluate the cancer-predictive values and potential effect modifiers of fluorescence-in-situ-hybridization (FISH). SUBJECTS AND METHODS: A FISH test was performed in 7,091 urine samples from 1,609 subjects between 2007 and 2010. Cystoscopy was recommended in case of positive or suspicious findings. Logistic regression models were applied to estimate the influence of potential test confounders like urinary creatinine and hematuria on detecting BC. Receiver operating characteristic (ROC) curves for FISH were adjusted for test confounders. Cancer-predictive values were calculated from test results in the last sample before diagnosis. RESULTS: Histopathology revealed 16 incidental BCs and 5 recurrent tumors in 20 study participants. FISH was positive in 9 BC cases of which 7 were high grade. Cytology detected 8 tumors. FISH overlapped with cytology in 7 cases. Sensitivity was 45.0% and PPV (positive predictive value) was 16.4% in all and 53.85% and 13.21% in high-grade tumors. Specificity and negative predictive value (NPV) were 96.97% and 99.26% in all bladder tumors. BC detected during UroScreen was associated with an odds ratio (OR) of 6.88 (95% CI 1.72-27.44) for positive FISH and with an OR of 8.81 (95% CI 1.41-54.96) for gross hematuria. The adjusted area under the curve was 0.77 (95% CI 0.62-0.92) for all and for high-grade lesions (0.85; 95% CI 0.69-1.00). CONCLUSIONS: FISH showed a performance in detecting bladder cancer comparable to cytology but a larger number or false-positive results. It remains to be investigated if chromosomal instability can be detected earlier than morphologic changes of exfoliated bladder cancer cells.

Shift work and cancer: state of science and practical consequences.

In 2007, an expert Working Group convened by the IARC Monographs Programme concluded that shift work that involves circadian disruption is probably carcinogenic to humans (Group 2A). We scrutinised the epidemiological basis for this conclusion, with a focus on, but not limited to, breast and prostate cancers. We further considered practical consequences for shift workers in our industry against the background of new findings.We carried out a literature search including the epidemiological studies cited by IARC and newer available literature on shift work and cancer.Since the IARC assessment, eleven new studies have emerged, ten of which have already been published, with inconclusive results. Heterogeneity of exposure metrics and study outcomes and emphasis on positive but non-significant results make it difficult to draw general conclusions. Also, several reviews and commentaries, which have been published meanwhile, came to equivocal results. Published evidence is widely seen as suggestive but inconclusive for an adverse association between night work and breast cancer, and limited and inconsistent for cancers at other sites and all cancers combined.At this point in time it can not be ruled out that shift work including night work may increase the risk for some cancers in those who perform it. However, shift schedules can be organised in ways that minimise the associated health risks, and the risks may be further reduced through the implementation of structured and sustained health promotion programs specifically tailored to the needs of shift workers.

Worker protection during mercury electrolysis cell plant decommissioning.

This article brings information on how to protect worker health during the decommissioning of mercury-based electrolysis facilities. It relies on the Euro Chlor document "Health 2, Code of practice, Control of worker exposure to mercury in the chlor-alkali industry" that provides protection guidelines for both normal production and decommissioning activities, and on hands-on experience gained during chlor-alkali plant decommissioning operations.Decommissioning and dismantling of mercury-containing chlorine production plants presents challenges to industrial hygiene and health protection that are usually not present during normal operations. These involve meticulous training and enforcement of the appropriate use of personal protective equipment to prevent excessive mercury exposure.The best practice guidelines and recommendations available from Euro Chlor can help employers and occupational physicians to manage these challenges, as they provide state-of-the-art procedures. Our experience is that rigorous implementation of these procedures and worker training ensured acceptable hygiene at the workplace and prevented mercury-related adverse health effects.

Analysis of protein adducts as biomarkers of short-term exposure to ethylene oxide and results of follow-up biomonitoring.

An accidental exposure of six workers to ethylene oxide (EO) provided the rationale for a biomonitoring and follow-up study, whose aim was to analyse protein adduct kinetics and examine the differentiation between accidental and environmental exposure, e.g., from tobacco smoke. For this purpose, the decrease in the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV) was followed during a five-month period after the accident, together with N-2-cyanoethylvaline (CEV) and urinary cotinine, two well-established biomarkers for smoking. The follow-up study showed that EO adduct concentrations significantly increased after a short but presumably high exposure. Initial biomonitoring revealed HEV levels above 500 pmol g(-1) globin in all cases, with a maximum of about 2,400 pmol g(-1) globin. This compares to a German EKA value (exposure equivalent for carcinogenic substances) for a daily 8-h-exposure to 1 ppm EO of 90 µg L(-1) blood (~3,900 pmol g(-1) globin). The adduct levels dropped in accordance with the expected zero-order kinetics for a single exposure. After the five-month observation interval, the HEV concentrations in blood reflected the individual background from tobacco smoking. The results of this study show that even a short exposure to ethylene oxide may result in a significant rise in haemoglobin adduct levels. Although protein adducts and their occupational-medical assessment values are considered for long-term exposure surveillance, they can also be used for monitoring accidental exposures. In these cases, the calculation of daily 'ppm-equivalents' may provide a means for a comparison with the existing assessment values.

Performance of survivin mRNA as a biomarker for bladder cancer in the prospective study UroScreen.

BACKGROUND: Urinary biomarkers have the potential to improve the early detection of bladder cancer. Most of the various known markers, however, have only been evaluated in studies with cross-sectional design. For proper validation a longitudinal design would be preferable. We used the prospective study UroScreen to evaluate survivin, a potential biomarker that has multiple functions in carcinogenesis. METHODS/RESULTS: Survivin was analyzed in 5,716 urine samples from 1,540 chemical workers previously exposed to aromatic amines. The workers participated in a surveillance program with yearly examinations between 2003 and 2010. RNA was extracted from urinary cells and survivin was determined by Real-Time PCR. During the study, 19 bladder tumors were detected. Multivariate generalized estimation equation (GEE) models showed that ß-actin, representing RNA yield and quality, had the strongest influence on survivin positivity. Inflammation, hematuria and smoking did not confound the results. Survivin had a sensitivity of 21.1% for all and 36.4% for high-grade tumors. Specificity was 97.5%, the positive predictive value (PPV) 9.5%, and the negative predictive value (NPV) 99.0%. CONCLUSIONS: In this prospective and so far largest study on survivin, the marker showed a good NPV and specificity but a low PPV and sensitivity. This was partly due to the low number of cases, which limits the validity of the results. Compliance, urine quality, problems with the assay, and mRNA stability influenced the performance of survivin. However, most issues could be addressed with a more reliable assay in the future. One important finding is that survivin was not influenced by confounders like inflammation and exhibited a relatively low number of false-positives. Therefore, despite the low sensitivity, survivin may still be considered as a component of a multimarker panel.