Beate Pesch

The role of occupational exposures in agricultural and industrial settings has been addressed in several breast cancer studies. Recently, the influence of shift work in nurses added as an occupational hazard that has been intensively discussed. Here, we investigate the association of job tasks in the industrial and health sector and breast cancer in a large case-control study. The population-based case-control study Gene-ENvironment Interaction and Breast CAncer (GENICA) was conducted in the Greater Region of Bonn, Germany. Occupational history and job task information were collected in computer-assisted interviews. Thirty pre-defined job tasks were assessed for 1143 cases and 1155 controls in addition to the occupational history. Risk estimates were calculated as odds ratios (ORs) with 95% confidence intervals (CIs) conditional on age and adjusted for potential confounders. First preliminary results indicate an increased age-adjusted risk for women who ever worked in anaesthesia (O...

Siderosis due to excessive iron exposure is a rare disease in welders. Less is known about the effect of inhaled iron on systemic iron status in welders. Here we present the association between exposure to iron as major constituent of the welding fume and the iron status in German welders. In this analysis we included 192 welders from the German WELDOX study not wearing respirators. Respirable welding fume was measured during one shift and analysed for its metal content. Iron status was assessed with different measures, including serum iron, serum ferritin (SF), transferrin, and prohepcidin. High iron stores were classified according to international standards. The influence of exposure to iron and other factors on the iron status was analysed with multiple regression models. Median shift exposure to respirable iron was 88 µg/m³ (interquartile range 13-690 µg/m³). For the overall study population the prevalence of high iron stores (SF > 200 µg/L) was 31.3%. A lower prevalence was...

To assess level and trend of exposure to hexavalent chromium (Cr(VI)) in chromium-exposed occupations for the estimation of lung cancer risks in community-based studies. This analysis was based on 3666 personal measurements and auxiliary data compiled in the German MEGA database from 1988-2009. Cr(VI) was determined spectrophotometrically at 540 nm after reaction with diphenylcarbazide. We assigned jobs tasks with known Cr(VI) exposure using coded and textual information about the workplaces. Measurements below the limit of quantification (LOQ) were multiply imputed according to their distribution above LOQ. Statistical modelling was performed to the log-transformed Cr(VI) concentrations to adjust for duration and reason of sampling. Cr(VI) exposure could be assessed for eight out of 30 jobs tasks with known Cr(VI) exposure. The majority of measurements (53%) were collected in welders (N = 1930), which we further detailed by welding technique. Spray painting and the welding of stain...

This article describes the principles of marker research with prospective studies along with examples for diagnostic tumor markers. A plethora of biomarkers have been claimed as useful for the early detection of cancer. However, disappointingly few biomarkers were approved for the detection of unrecognized disease, and even approved markers may lack a sound validation phase. Prospective studies aimed at the early detection of cancer are costly and long-lasting and therefore the bottleneck in marker research. They enroll a large number of clinically asymptomatic subjects and follow-up on incident cases. As invasive procedures cannot be applied to collect tissue samples from the target organ, biomarkers can only be determined in easily accessible body fluids. Marker levels increase during cancer development, with samples collected closer to the occurrence of symptoms or a clinical diagnosis being more informative than earlier samples. Only prospective designs allow the serial collecti...

Exposure to crystalline silica ranks among the most frequent occupational exposures to an established human carcinogen. Health-based occupational exposure limits can only be derived from a reliable dose–response relationship. Although quartz dust seems to be a well-measurable agent, several uncertainties in the quantification of exposure to crystalline silica can bias the risk estimates in epidemiological studies. This review describes the

A coal-burning power station in the Nitra Valley in central Slovakia annually emitted large quantities of arsenic (up to 200 tonnes) between 1953 and 1989. Since then, pollution-control measures have reduced arsenic emissions to less than 2 tonnes a year. However, the power station was still a source of airborne arsenic pollution. As part of an EU-funded study on exposure to arsenic and cancer risk in central and Eastern Europe we carried out a study of environmental levels of arsenic in the homes and gardens of residents of the district. Garden soil samples (n=210), house dust samples (n=210) and composite house dust samples (n=109) were collected and analysed using inductively coupled plasma atomic absorption spectroscopy (ICP-AES) at Imperial College. The mean arsenic content of coal and ash in samples taken from the plant was 519 microg/g (n=19) and 863 microg/g (n=22), respectively. The geometric mean (GM) arsenic concentration of garden soils was 26 microg/g (range 8.8-139.0 microg/g), for house dust 11.6 microg/g (range 2.1-170 microg/g) and for composite house dust 9.4 microg/g (range 2.3-61.5 microg/g). The correlation between the arsenic levels in soil and in house dust was 0.3 (P<0.01), in soil and composite house dust 0.4 and house dust and composite house dust 0.4 (P<0.01 for both), i.e., were moderate. Arsenic levels in both house dust and soil decreased with distance from the power station. Overall, levels in both fell by half 5 km from the point source. Weak correlations were seen between the total urinary arsenic concentrations and arsenic concentrations in composite house dust.

Data concerning the irritative effects of current exposure to fumes of bitumen on the airways in humans are limited. To assess the effects of fumes of bitumen on the airways a cross-shift study was conducted with monitoring of inflammatory process in upper and lower airways of workers exposed to fumes of bitumen and a reference group. All workers were examined

For the detection of malignant mesothelioma no single biomarker with reasonable sensitivity and specificity has been described so far. Mesothelin, the most prominent blood-based biomarker, is characterized by high specificity but low sensitivity. It might be reasonable to combine biomarkers of different molecular classes in order to improve the overall performance. The aim of this study was to assess the performance of the combination of mesothelin and miR-103a-3p as blood-based biomarker for mesothelioma. Mesothelin concentration in plasma and miR-103a-3p levels in the cellular blood fraction were analyzed in 43 male mesothelioma patients and 52 male controls formerly exposed to asbestos. For the discrimination of epithelioid and biphasic mesothelioma from asbestos-exposed controls mesothelin and miR-103a-3p showed 74% and 89% sensitivity and 85% and 63% specificity, respectively. For the combination of mesothelin and miR-103a-3p a sensitivity of 95% and a specificity of 81% were c...

The development of head and neck squamous cell cancer (HNSCC) is known to be strongly associated with tobacco use. One of the main enzymes for bioactivation of tobacco-related substances is the cytochrome 450 (CYP)2E1, of which different genetic variants are described. Analyzing a correlation between certain neoplasia and alteration of the CYP2E1 gene, most studies focus on the polymorphisms -1053C>T and 7632T>A, but recently another polymorphism, named -71G>T, with enhanced transcriptional activity, has been identified. In the current case-control study we investigate the putative association of the mentioned CYP2E1 polymorphisms on the risk of HNSCC. Comparing 312 German individuals with HNSCC to 299 controls we found a significantly enhanced risk for the development of that neoplasia in smoking carriers of -71G>T heterozygosity, while in -1053C>T and 7632T>A polymorphisms a corresponding correlation was absent. Since a coincidence of an aberrant p53 gene and CYP2E1 mutations has been described, we choose a subgroup of 140 patients with HNSCC for analyzing an association of mutations in these two genes. However, no such association could be found in either of the mentioned polymorphisms. Further studies have to focus on the -71G>T polymorphism and its possible linkage to cancers, in which smoking is a known risk-factor, as well as its functional relevance concerning the bioactivation of tobacco-related substances.

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.

In order to investigate possible associations of genetic variants in genes of xenobiotic metabolism with longevity, we compared allele frequencies and genotype distributions of polymorphic genes between 205 octogenarians and a non-cancer reference group of 294 persons aged less than 80 years. We analyzed common sequence variations in the cytochrome P-450 genes CYP1A1 T461N, 3801 T > C and CYP1B1 V432L, and in the glutathione S-transferase genes GSTM1 (deletion), GSTT1 (deletion), and GSTP1 (I105V). In octogenarians, the CYP1B1 432L allele was less prevalent than in the reference group (allele frequency 0.49 versus 0.60; odds ratio, OR, 0.63, 95% confidence limits (CI) 0.40-1.00). Octogenarians turned out to have marginally significant more GSTM1 negatives (frequency 0.56 versus 0.48; OR 1.41, 95% CI 0.97-2.05), but less GSTT1 deficient genotypes (frequency 0.14 versus 0.21; OR 0.64; 95% CI 0.38-1.06). In octogenarians without cancer, GSTT1 negative carriers were less prevalent than in the aged with cancer (frequency 0.12 versus 0.27; OR 2.81; 95% CI 1.00-7.38). Polymorphic metabolic susceptibility genes could become relevant for processes of aging when toxic defense mechanisms decline.

A power station in central Slovakia emitted arsenic (As) in large quantities for over 30 years as a result of burning As-rich brown coal. Nowadays emissions of As are low. Over the lifetime of the plant's operation over 3000 tonne of As have been emitted into the environment. This paper aims to examine the concentrations of As in the soil around the power station, and also to investigate whether the coal burnt in the plant, and consequently the emissions from it, contained raised levels of six further heavy metals. Soil concentrations were compared to ground level air As concentrations predicted by an air dispersion model. Coal samples were taken from the power station and analysed to determine concentrations of As, Zn, Pb, Cu, Cr, Ni and Cd. Soil samples (n=113) were taken up to 12 km from the plant along a transect designed to follow the valley floor in which the power station is situated. Soil samples were analysed for concentrations of those elements for which coal was tested. Concentrations of As in coal were high (AM 518 mug/g). Those of other heavy metals were, in general, low. Concentrations of soil As were substantially raised in the near vicinity of the plant but decreased within 5 km to concentrations similar to those in the rest of the district. Overall, levels within 10 km of the plant were slightly above those recommended for residential levels in the UK. Soil concentrations of other heavy metals were higher in the vicinity of the plant but none, overall was raised. Comparison of results from a previous air dispersion model of ground level air arsenic concentrations showed a moderate correlation (r=0.6) between modelled and measured values. Over its period of operation the power plant has contributed to raised levels of soil As in the local soils, though not substantially of other elements. Though now airborne As emissions are controlled, concern remains regarding soil arsenic concentrations and fugitive emissions from the plant that could be contributing to exposure of the local population and of the workforce.

The potential mechanisms that link night-shift work with breast cancer have been extensively discussed. Exposure to light at night (LAN) depletes melatonin that has oncostatic and anti-estrogenic properties and may lead to a modified expression of estrogen receptor (ER) α. Here, we explored the association between shift work and breast cancer in subgroups of patients with ER-positive and -negative tumors. GENICA (Gene-ENvironment Interaction and breast CAncer) is a population-based case-control study on breast cancer with detailed information on shift work from 857 breast cancer cases and 892 controls. ER status was assessed by immunohistochemical staining. Associations between night-shift work and ER-positive and -negative breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders. ER status was assessed for 827 cases and was positive in 653 and negative in 174 breast tumors. Overall, 49 cases and 54 controls were "ever employed" in shift work including night shifts for ≥ 1 year. In total, "ever shift work" and "ever night work" were not associated with an elevated risk of ER-positive or -negative breast tumors. Night work for ≥ 20 years was associated with a significantly elevated risk of ER-negative breast cancer [odds ratio (OR) 4.73, 95% confidence interval (95% CI) 1.22-18.36]. Our case-control study suggests that long-term night-shift work is associated with an increased risk of ER-negative breast cancers. Further studies on histological subtypes and the analysis of other potentially relevant factors are crucial for discovering putative mechanisms.

To validate urinary markers for the early detection of bladder cancer (BC) in chemical workers. 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. 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. 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.

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. 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. 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. 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). 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.

Study Type - Diagnostic (validating cohort). 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. • 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. • 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. • 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) . • 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.

Technical advances to analyze biological markers have generated a plethora of promising new marker candidates for early detection of cancer. However, in subsequent analyses only few could be successfully validated as being predictive, clinically useful, or effective. This failure is partially due to rapid publication of results that were detected in early stages of biomarker research. Methodological considerations are a major concern when carrying out molecular epidemiological studies of diagnostic markers to avoid errors that increase the potential for bias. Although guidelines for conducting studies and reporting of results have been published to improve the quality of marker studies, their planning and execution still need to be improved. We will discuss different sources of bias in study design, handling of specimens, and statistical analysis to illustrate possible pitfalls associated with marker research, and present legal, ethical, and technical considerations associated with storage and handling of specimens. This article presents a guide to epidemiological standards in marker research using bladder cancer as an example. Because of the possibility to detect early cancer stages due to leakage of molecular markers from the target organ or exfoliation of tumor cells into the urine, bladder cancer is particularly useful to study diagnostic markers. To improve the overall quality of marker research, future developments should focus on networks of studies and tissue banks according to uniform legal, ethical, methodological, and technical standards. This article is part of a Special Issue entitled: Computational Proteomics in the Post-Identification Era. Guest Editors: Martin Eisenacher and Christian Stephan.

Irritative effects caused by vapours and aerosols of bitumen were assessed by non-invasive methods including spirometry, nasal lavage fluid (NALF) and induced sputum (IS) in a cross-shift study comparing 320 bitumen-exposed workers with 118 road construction workers as the reference group. Lung function parameters, forced vital capacity (FVC) and forced expiratory volume in one second (FEV(1)) were within normal ranges in both the reference and the bitumen-exposed groups pre- and post-shift with marginally lower values in smokers of both groups. During the shift, a slight decline in FEV(1) and FVC was observed in the bitumen-exposed group independent of their smoking habits, whereas in the non-smoking reference group, the decline in FEV(1) was not observed. No significant differences between bitumen-exposed workers and the reference group and no significant shift effect were observed on the upper airways using NALF analysis. The IS concentrations of interleukin (IL)-8, total protein and matrix metalloproteinase-9 were significantly higher in bitumen-exposed workers than in the reference group. However, the concentration of these three biomarkers in the IS samples, which are indicators of inflammatory effects on the lower airways of bitumen-exposed workers, was already higher in exposed workers before shift and did not show an increase during the shift. Therefore, the key finding of this aspect of the Human Bitumen Study is the detection of potentially (sub-) chronic irritative inflammatory effects in the lower airways of bitumen-exposed workers.