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.

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.

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.

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.

Shift-specific associations between age, chronotype and sleep duration.

The objective of this study was to examine the association of age with chronotype and sleep duration in day workers and rotating shift workers, including night shift work. Between October 2012 and February 2015, a cross-sectional study was conducted in a German chemical company. Using the "Munich ChronoType Questionnaire" (MCTQ), data about sleep onset and sleep offset during workdays and work-free days were retrieved and the chronotype was computed during regular voluntary occupational health check-ups. Associations between age and chronotype, as well as sleep duration, were assessed using linear regression analyses. Potential effect modification by the working time system was examined. Within the study period, 4,040 employees (82.3% and 17.7% were engaged in day work and rotating shift work, respectively) completed the questionnaire. Study participants were on average 41.8 years old (Min = 18.0, Max = 65.0, SD = 10.2) and predominantly male (75.4%). Mean chronotype and overall sleep duration was 03:22 (SD = 54 min) and 7.2 h (SD = 1.0 h) respectively. Older age was associated with earlier chronotype and reduced overall sleep duration in both day workers and rotating shift workers (p < 0.001 for all models). Compared to day workers, employees whom engaged in rotating shift work were later chronotypes and had overall a longer sleep duration. With older age, the difference between day and rotating shift workers regarding chronotype increased, while the difference regarding overall sleep duration decreased (pinteraction<0.005 for both models). This finding could indicate that both changes in circadian physiology and exposure to certain work schedules contribute to the age-related changes. Older rotating shift workers, with early chronotypes may have issues with night shifts, while day work and morning shifts may be best compatible to earlier chronotypes. Differences in sleep timing across age groups, might indicate that the same work hours will affect shift workers differently, dependent on their age, suggesting that more flexible and chronotype-adapted work hours could provide useful; especially for older employees. Sleep education in the form of courses and health campaigns could be a way to raise awareness of the importance of a healthy sleep pattern. This could be achieved by learning strategies to better adjust individual sleep patterns to work hours.

Metabolic syndrome in a large chemical company: prevalence in a screened worksite sample.

The metabolic syndrome (MS) leads to serious health problems like diabetes and has serious economic consequences for multinational companies. Thus, the workplace is an important setting for primary prevention. Aim of this study was to evaluate the prevalence of MS in a mixed working population to provide a basis for interventional strategies. In 2006, 1,594 employees attended a screening program at BASF Ludwigshafen, the number of employees with MS was determined and the distribution of impaired glucose tolerance (IGT), type 2 diabetes and cardiovascular disease (CVD) analyzed. The study-population consisted of 1,075 men and 519 women, aged 17-64. 374 individuals (23.5%) were classified to be affected by MS, of which 86.9% were male (prevalence MS in men 30%, in women 9.7%). Subjects with MS had higher BMI (P < 0.01), blood pressure (P < 0.01), heart rate (P < 0.01), liver enzymes (P < 0.01), uric acid (P < 0.01) and LDL (P < 0.01), while HDL was significantly lower (P < 0.01). (Pre)-Diabetes and CVD were found more frequently in subjects with MS. There were no significant differences between individuals with different types of employment ("white collar vs. blue collar" workers) or smoking status. We found a high prevalence of MS in our working population, thus interventional programmes should be implemented. The workplace-setting can be used to promote long-term prevention strategies in this adult working population.

A unique, fast-forwards rotating schedule with 12-h long shifts prevents chronic sleep debt.

Sleep debt--together with circadian misalignment--is considered a central factor for adverse health outcomes associated with shift work. Here, we describe in detail sleep-wake behavior in a fast-forward rotating 12-h shift schedule, which involves at least 24 hours off after each shift and thus allows examining the role of immediate recovery after shift-specific sleep debt. Thirty-five participants at two chemical plants in Germany were chronotyped using the Munich ChronoType Questionnaire for Shift-Workers (MCTQ(Shift)) and wore actimeters throughout the two-week study period. From these actimetry recordings, we computed sleep and nap duration, social jetlag (a measure of circadian misalignment), and the daily timing of activity and sleep (center of gravity and mid-sleep, respectively). We observed that the long off-work periods between each shift create a fast alternation between shortened (mean ± standard deviation, 5h 17min ± 56min) and extended (8h 25min ± 72min) sleep episodes resulting in immanent reductions of sleep debt. Additionally, extensive napping of early chronotypes (up to 3 hours before the night shift) statistically compensated short sleep durations after the night shift. Partial rank correlations showed chronotype-dependent patterns of sleep and activity that were similar to those previously described in 8-h schedules; however, sleep before the day shift did not differ between chronotypes. Our findings indicate that schedules preventing a build-up of chronic sleep debt may reduce detrimental effects of shift work irrespective of shift duration. Prospective studies are needed to further elucidate the relationship between sleep, the circadian system, and health and safety hazards.

Are chronotype, social jetlag and sleep duration associated with health measured by Work Ability Index?

The present study investigates the impact of chronotype, social jetlag and sleep duration on self-perceived health, measured by Work Ability Index (WAI), within an industrial setting. Between 2011 and 2013, 2474 day and shift workers participated in a health check offered by an occupational health promotion program and filled out the Munich ChronoType Questionnaire (adapted to the rotational 12-h schedule for shift workers) and the WAI. We computed sleep duration on work and free days, chronotype, and social jetlag. We used linear regression models to examine chronotype, sleep duration and social jetlag for association with the WAI sum score, and proportional odds models to estimate the combined effect of social jetlag and sleep duration. Participants reported an average daily sleep duration of 7.35 h (SD: 1.2 h), had an average chronotype of 3:08 a.m. (SD: 1 h), and the average social jetlag corresponded to 1.96 h (SD: 2.05 h). Increasing social jetlag and shorter sleep duration were independently associated with a decreasing WAI, while chronotype per se was not associated with WAI. Short sleep duration combined with high social jetlag significantly increased the risk of poor WAI (OR = 1.36; 95% CI: 1.09-1.72), while long sleep duration and high social jetlag were not associated with poor WAI (OR = 1.09; 95% CI: 0.88-1.35). Our results add to a growing body of literature, suggesting that circadian misalignment, but not chronotype per se, may be critical for health. Our results indicate that longer sleep may override the adverse effects of social jetlag on WAI.

Primary selection into shift work and change of cardiovascular risk profile.

OBJECTIVES: A potential "healthy shift worker effect" may bias the studied effect of shift work on health. The observed differences among shift and day workers in health behavior and health outcomes can be caused by: (i) primary selection, (ii) the influence from the shift work-related environment, and (iii) the impact of shift work. We aimed to study these potential sources. METHODS: A cohort of 4754 male trainees who had finished their professional training and started their career in production in a chemical company between 1995 and 2012 was identified. Among them, 1348 (28%) were involved in rotating shift work and 3406 (72%) in day work. Information on health behavior and risk factors for cardiovascular diseases was retrieved from the medical examinations. This information was then compared (i) at the beginning of training, (ii) at the end of training, and (iii) 3 years after the employment, in relation to the working time. RESULTS: At the beginning of the training, the prevalence of smokers was higher among future shift workers (26% versus 21%), from 1995 to 2012. During the training and the first three years of employment, a marginal decline of systolic blood pressure and an elevation of triglyceride were related with shift work. No difference was found with respect to other risk factors for cardiovascular diseases. CONCLUSIONS: Our findings do not support a primary selection in favor of shift workers. An impact of shift work on the risk profile of cardiovascular diseases was not indicated in the observation period.

Pregnant Employee Protection Program in a Large Chemical Company.

OBJECTIVES: To assess whether a structured employee protection program for pregnant workers at a chemical company has an impact on pregnancy outcomes. METHODS: Reported pregnancies (n = 1402) between 2003 and 2010 and their outcomes were documented using questionnaires at the time of pregnancy report, end of pregnancy, and 1 year later. Potential maternal exposures were assessed using job histories, workplace inspections, and questionnaires. RESULTS: Participation was 86% overall and was consistently high across subgroups.Pregnancy losses (10.9%), pregnancy complications, and preterm births (8.1%) were in agreement with rates in the general population and were independent of type of work and maternal exposure category. CONCLUSIONS: Pregnancy complication rates in this chemical company are not statistically elevated than that in the general population, as suggested in a previous study. The protection program may play a role in preventing complications that may have occurred.

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.

Alanine-aminotransferase levels predict impaired glucose tolerance in a worksite population.

Insulin resistance and impaired glucose tolerance precede the development of type 2 diabetes. In 2006, the BASF Occupational Medicine and Health Protection Department offered a diabetes screening program for 33,000 employees. 1,594 employees had their diabetes risk tested: 285 employees were at medium to high risk for diabetes type 2, according to the Finrisk score. Hundred and fifty-seven of these individuals underwent oral glucose tolerance testing: 22 were shown to have impaired glucose tolerance (IGT), and 5 had manifest diabetes. Thus, 18% of this worksite sample population were affected by IGT or type 2 diabetes. A total of 87% were affected by metabolic syndrome (MS) according to the International Diabetes Federation (IDF) criteria. At baseline, individuals with normal glucose tolerance and impaired glucose tolerance differed significantly with respect to fasting glucose (97 +/- 8 vs. 103 +/- 10 mg/dl, P < 0.01), HbA1c (5.5 +/- 0.3 vs. 5.7 +/- 0.4%, P < 0.01), and alanine-aminotransferase (ALT) (28 +/- 15 vs. 36 +/- 18 U/I, P < 0.05). In binary logistic regression analysis adjusted for age and gender, fasting glucose and ALT were the only independent predictors of impaired glucose tolerance (OR 4.8 [1.24-24.8] and OR 5.5 [1.2-24.8]), while age and HbA1c had only borderline significance (OR 3.9 [0.94-15.92] and OR 2.8 [0.94-8.67]). Waist circumference, BMI, triglycerides, and HDL as central components of the MS had no predictive value for impaired glucose tolerance. In summary, in this particular sample population, fasting glucose and ALT were the only significant predictors of IGT. These data point to an important role of the liver in insulin resistance and the development of impaired glucose tolerance in the relatively young and small population studied.

Health and safety protection for chemical industry employees in a rotating shift system: program design and acute injury and illness experience at work.

OBJECTIVES: To describe a comprehensive health protection program for rotating shift employees and evaluate the program effectiveness in injury and illness prevention. METHODS: For 14,128 shift and 17,218 day wage employees, occupational medical records were linked to job assignment records and studied over an 11-year period. RESULTS: Between 1995 and 2005, initiatives directed to shift employees contributed to their 59% and 100% greater participation in medical examinations and health seminar days, respectively, compared to day wage employees. Injury rates declined over time and with increasing employee age and were not elevated among rotating shift compared to day wage employees. Clinic visit rates for acute illnesses were generally higher for day than shift work employees. CONCLUSION: Coupling of active medical monitoring with additional health and safety initiatives appears to mitigate the expected adverse physiological and psychosocial stresses of shift work.

Considerations on occupational medical surveillance in employees handling nanoparticles.

OBJECTIVES: The use of engineered nanoparticles not only offers new technical perspectives but also raises questions regarding possible health aspects for producers and users. Nanoparticles may, just by virtue of their size, exert biological effects unrelated to the chemicals they are composed of. These considerations, and results from experimental animal studies suggesting that engineered nanomaterials may pose a health hazard to employees, all underscore the need for preventive measures. In this context, the need for, the feasibility, and the appropriateness of targeted occupational medical surveillance are currently subject to debate. METHODS: We compared established concepts for the development of occupational medical surveillance programs to existing knowledge on exposures in workplaces and on health effects of nanomaterials. RESULTS: A variety of potential effect parameters have been proposed for medical surveillance of exposed personnel, such as heart rate variability, blood-clotting parameters, pro-inflammatory cytokines, etc. None of these parameters are specific, most are not validated as individual health risk indicators, and some require sophisticated equipment not routinely available. Against this background, BASF currently puts specific weight on risk assessment and exposure control in workplaces. Particle emissions are primarily avoided by manufacturing in closed systems or using effective extraction systems. Appropriate personal protective equipment has been defined for such operations where an exposure potential cannot be excluded. CONCLUSIONS: While there is presently no evidence-based foundation for "nano-specific" occupational medical screening, one can perform general medical screening with methods targeted at some of the health outcomes under discussion. The results of such examinations can provide a basis for future epidemiologic studies. Therefore, the establishment of exposure registries to enable the conduct of large-scale multi-centric prospective epidemiologic studies is recommended.

Screening for pre-diabetes and diabetes in the workplace.

BACKGROUND: Diabetes is an increasingly prevalent and burdensome disease in working populations. In settings with established occupational medical programmes, there may be opportunities to intervene in a positive way to reduce the burden of this disease. AIM: To integrate diabetes screening and prevention into an existing occupational medical programme. METHODS: Screening to detect potential cases of pre-diabetes and diabetes was conducted in a large working population using differing criteria to define risk groups over a 2-year period. Classification of new cases was based on fasting plasma glucose, random plasma glucose or oral glucose tolerance test (OGTT). RESULTS: Among 13,086 employees screened via fasting or random glucose, there were 96 diabetes and 650 pre-diabetes cases detected. Among high-risk employees, 20 new cases of pre-diabetes and 8 cases of diabetes were detected in 84 employees assessed by OGTT. The percentage of employees with new findings increased with increasing age (2.3%, under age 40 compared to 11.4% for age 50 years and above) and body mass index (2.6, 6.1 and 11.4% among normal weight, overweight and obese employees, respectively). CONCLUSIONS: Given the likely magnitude of unrecognized diabetes and pre-diabetes cases, further interventions are being implemented targeting all employees and not just those who require routine occupational medical examinations.

Experimental herpes simplex virus encephalitis: a combination therapy of acyclovir and glucocorticoids reduces long-term magnetic resonance imaging abnormalities.

Despite early antiviral treatment, herpes simples virus encephalitis (HSVE) still remains a life-threatening sporadic disease with high mortality and morbidity. In patients and in experimental disease, chronic progressive magnetic resonance imaging (MRI) abnormalities have been found even after antiviral therapy. Secondary autoimmune-mediated and not directly virus-mediated mechanisms might play a key role for the outcome of disease. This study aimed to evaluate a possible beneficial effect of a therapy of acyclovir and corticosteroids versus acyclovir only. In a mouse model of HSVE (intranasal inoculation with 10(5) pfu [plaque-forming units] of HSV-1 strain F), a long-term MRI study was realized. Cranial MRI was performed serially at days 2, 7, 14, 21, 60, and 180 in different therapy groups: 1, saline; 2, acyclovir; 3, acyclovir, subsequently methylprednisolone; 4, sham-infected with saline. Brain viral load peaked at day 7 to decline thereafter to a low baseline value. Viral load in group 1 was significantly higher than in animals with antiviral therapy. In group 4, no viral DNA was detectable. Viral load did not differ significantly between acyclovir and acyclovir/corticosteroid-treated groups, suggesting that the use of corticosteroids in addition to acyclovir does not increase viral burden. MRI findings in untreated and acyclovir-treated animals revealed chronic progressive changes. In contrast, there was a significant reduction of the severity of long-term MRI abnormalities in acyclovir/corticosteroid-treated animals. With respect to abnormal MRI findings, this study demonstrates a clear beneficial effect of an acyclovir and corticosteroid therapy without influencing brain viral load.