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Citrinin (CIT), a mycotoxin known to exert nephrotoxicity, is a contaminant in food and feed. Since CIT contamination is not regularly analyzed, data on its occurrence and especially levels in food commodities are insufficient for conducting a conventional exposure assessment. Yet, human biomonitoring, i.e., an analysis of CIT and its metabolite dihydrocitrinone (DH-CIT) in urine samples allows to estimate exposure. This study investigated CIT exposure in young (2–14 years) and adult (24–61 years) residents of three federal states in Germany. A total of 179 urine samples from children and 142 from adults were collected and analyzed by a targeted LC-MS/MS based method for presence of CIT and DH-CIT. At least one of the biomarkers was detected and quantified in all urines, which indicated a widespread dietary exposure to the mycotoxin in Germany. Interestingly, the biomarker concentrations of CITtotal (sum of CIT and DH-CIT) were higher in children's urine (range 0.05–7.62 ng/mL; median of 0.54 ng/mL) than in urines from adults (range 0.04–3.5 ng/mL; median 0.3 ng/mL). The biomarker levels (CITtotal) of individual urines served to calculate the probable daily CIT intake, for comparison to a value of 0.2 µg/kg bw/day defined as 'level of no concern for nephrotoxicity' by the European Food Safety Authority. The median exposure of German adults was 0.013 µg/kg b.w., with only one urine donor exceeding this provisional tolerable daily intake (pTDI) for CIT. The median exposure of children was 0.05 µg/kg bw per day (i.e., 25% of the pTDI); however, CIT exposure in 12 individuals (6.3% of our study group) exceeded the limit value, with a maximum intake of 0.46 µg/kg b.w. per day. In conclusion, these results show evidence for non-negligible exposure to CIT in some individuals in Germany, mainly in children. Therefore, further biomonitoring studies and investigations aimed to identify the major sources of CIT exposure in food commodities are required. [ABSTRACT FROM AUTHOR]

Urinary bladder cancer, a smoking and occupation related disease, was subject of several genome-wide association studies (GWAS). However, studies on the course of the disease based on GWAS findings differentiating between muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) are rare. Thus we investigated 4 single nucleotide polymorphisms (SNPs) detected in GWAS, related to the genes coding for TACC3 (transforming, acidic coiled-coil containing protein 3), for FGFR3 (fibroblast growth factor receptor 3), for PSCA (prostate stem cell antigen) and the genes coding for CBX6 (chromobox homolog 6) and APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A). This study is based on 712 bladder cancer patients and 875 controls from 3 different case control studies in Germany. The 4 SNPs of interest (PSCA rs2294008 and rs2978974, FGFR3-TACC3 rs798766, and CBX6-APOBEC3A rs1014971) were determined by real-time polymerase chain reaction. The distribution of the 4 SNPs does not vary significantly between cases and controls in the entire study group and in the 3 local subgroups, including two former highly industrialized areas and a region without such history. Also, no significant differences in the bladder cancer subgroups of MIBC and NMIBC were observed. The 4 investigated SNPs do not noticeably contribute differently to the bladder cancer risk for the bladder cancer subgroups of MIBC and NMIBC. [ABSTRACT FROM AUTHOR]

This study was performed to investigate the frequency of bladder cancer in patients with an occupational history such as underground hard coal mining and/or painting after the structural change in the local industry. A total of 206 patients with bladder cancer and 207 controls were enlisted regarding occupational and nonoccupational bladder cancer risk factors by questionnaire. The phase II enzymesN-acetyltransferase 2 (NAT2), glutathioneS-transferases M1 (GSTM1), and T1 (GSTT1) and the single nucleotide polymorphism (SNP) rs11892031[A/C] reported to be associated with bladder cancer in genome-wide association studies were genotyped. The bladder cancer risk in varnishers and underground hard coal miners was increased as previously shown in a study in this area performed in the 1980s. The occupation of a car mechanic was associated with a significantly elevated bladder cancer risk and higher in the case of underground hard coal miners even though the mine was closed in 1987. The frequency of GSTM1 negative genotype was comparable in cases and controls (53% versus 54%). In the case of NAT2, the slow NAT2 genotype was more frequent (62% versus 58%) and ultra-slow NAT2 genotype (NAT2*6A and/or *7B alleles only) was 23% versus 15%. An occupational history of a varnisher or an underground hard coal miner remains a risk factor for bladder cancer occurrence. Data indicate that in the case of bladder cancer, GSTM1 is a susceptibility factor related to environmental and/or occupational exposure. [ABSTRACT FROM PUBLISHER]

Currently, there is no established occupational risk factor for prostate cancer. However, in the 1980s, a hospital-based case-control study in the greater Dortmund area showed an elevated risk for hard coal miners and, based on few cases, for painters and varnishers. Therefore, approximately 10 yr later, a similar study regarding prostate cancer was performed in this area. In total, 292 patients with prostate cancer who underwent radical prostatectomy and 313 controls who underwent transurethral resection of a benign prostatic hyperplasia were investigated by questionnaire. All of them were operated on between 1995 and 1999. This study showed a decreased risk for prostate cancer in hard coal miners (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.44–1.03). Occupational exposures related to an elevated risk for prostate cancer were exposures to combustion products (20% cases vs. 11% controls), colorants and dyes (19 vs. 13%), and cutting fluids (8 vs. 6%). The different prostate cancer risks for underground coal miners in two studies with a time interval of approximately 10 yr are striking. Factors to be discussed are the introduction of prostate-specific antigen (PSA) screening for prostate cancer and investigation of cases that underwent radical prostatectomy, where the disease in general is locally confined. Working conditions in the local underground coal mines improved over time but did not change markedly in the period of interest. In essence, the present study does not corroborate an elevated prostate cancer risk in former underground hard coal miners from the greater Dortmund area. [ABSTRACT FROM AUTHOR]

Long-term follow-ups on bladder cancer patients from highly industrialized areas are rare. Therefore, we present a follow-up of bladder cancer patients from the greater area Lutherstadt Wittenberg, a center of the chemical industry of the former German Democratic Republic. Relapse-free survival times of 213 confirmed bladder cancer cases from the greater area Lutherstadt Wittenberg were collected between 2008 and 2009. Data on lifestyle and occupational exposure to potential carcinogens was recorded by questionnaire. Genotypes of N-acetyltransferase 2 (NAT2), glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), rs710521, and rs9642880 were determined by standard methods. Cox models were used to evaluate differences in relapse-free survival. Clear differences in relapse-free survival could be observed for the number of relapses, multilocular tumor growth, and relapses with higher staging or grading than the primary tumor, as well as GSTT1. None of the other investigated polymorphisms showed significant impact on prognosis. This is the first study on two recently detected single-nucleotide polymorphisms (SNPs) showing that these polymorphisms may also contribute to shorter relapse-free times. [ABSTRACT FROM PUBLISHER]

Chronic inhalation of quartz-containing dust produces reversible inflammatory changes in lungs resulting in irreversible fibrotic changes termed pneumoconiosis. Due to the inflammatory process in the lungs, highly reactive substances are released that may be detoxified by glutathione S-transferases. Therefore, 90 hard coal miners with pneumoconiosis as a recognized occupational disease (in Germany: Berufskrankheit BK 4101) were genotyped for glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) according to standard methods. Furthermore, occupational exposure and smoking habits were assessed by questionnaire. Changes in a chest x-ray were classified according to ILO classification 2000. Of the investigated hard coal miners 43% were GSTM1 negative whereas 57% were GSTM1 positive. The arithmetic mean of the age at time of investigation was 74.2 yr (range: 42–87 yr). Seventy-four percent of the hard coal miners reported being ever smokers, while 26% denied smoking. All hard coal miners provided pneumoconiosis-related changes in the chest x-ray. The observed frequency of GSTM1 negative hard coal miners was not different from frequencies reported for general Caucasian populations and in agreement with findings reported for Chinese coal miners. In contrast, in a former study, 16 of 19 German hard coal miners (84%) with urinary bladder cancer displayed a GSTM1 negative genotype. The outcome of this study provides evidence that severely occupationally exposed Caucasian hard coal miners do not present an elevated level of GSTM1 negative individuals. [ABSTRACT FROM AUTHOR]

Apart from genetics, nutrition, and environment, occupational factors also play an important role in colon and rectal cancer development. The aim of this study was to examine these cancer types in an area of former coal, iron, and steel industries, which was found to display an increased incidence of colon cancer mortality. N-Acetyltransferase 2 (NAT2) and glutathione S-transferase M1 (GSTM1) genotypes were investigated in 108 colon cancer cases, 80 rectum cancer cases, and 188 controls (suffering from nonmalignant diseases). Further, in a pilot study, 28 colorectal cancer patients were NAT2 phenotyped by the caffeine test. Possible occupational and nonoccupational risk factors were investigated by a personal interview. The frequency of rapid NAT2 genotype was 35% in colon cancer cases, 47% in rectal cancer cases, and 42% in controls (GSTM1 0/0 genotype: 53, 46, and 47%, respectively). In the 29 patients with cancer in the ascending colon, 10% were of the rapid NAT2 genotype. In the pilot study the frequency of the rapid NAT2 phenotype was 49%. The only major professional group with an elevated risk was painters (colon cancer OR 2.48, 95% CI 0.4–15.23; rectal cancer OR 5.65, 95% CI 1.06–30.21). In contrast to early studies, in the present study the slow NAT2 status is overrepresented. As colorectal cancer is associated with nutrition and physical activity, present findings may be due to excessive physical heavy work and the resulting nutrition in this area. [ABSTRACT FROM AUTHOR]

In the 1990s, an uncommonly high percentage of glutathione S-transferase M1 (GSTM1) negative bladder cancer cases (70%) was reported in the greater Dortmund area. The question arose as to whether this uncommonly high percentage of GSTM1 negative bladder cancer cases was due to environmental and/or occupational exposure decades ago. Thus, 15 years later, another study on bladder cancer was performed in the same area after the coal, iron, and steel industries had finally closed in the 1990s. In total 196 bladder cancer patients from the St.-Josefs-Hospital Dortmund-Hörde and 235 controls with benign urological diseases were assessed by questionnaire and genotyped for GSTM1, glutathione S-transferase T1 (GSTT1), and the N-acetyltransferase 2 (NAT2) tag SNP rs1495741. The frequency of the GSTM1 negative genotype was 52% in bladder cancer cases and thus lower compared to a previous study performed from 1992 to 1995 in the same area (70%). NAT2 genotypes were distributed equally among cases and controls (63% slow acetylators). Fewer GSTT1 negative genotypes were present in cases (17%) than in controls (20%). [ABSTRACT FROM AUTHOR]

Information about several topics discussed at the 16th EUROTOX Training and Discussion Session in Dortmund, Germany is presented. The meeting covered areas of recent developments in industrial and occupational toxicology, toxicogenomics, mycotoxins, lead, asbestos, boron, bitumen, deletions polymorphisms and single nucleotide polymorphisms (SNPs) interactions. Moreover, the occasion was part of the retirement of Professor Hermann M. Bolt, former president of EUROTOX.

Information about several papers discussed at "Environmental Toxicology in North Rhine-Westphalia, Germany—Interdisciplinary Research Activities in Toxicology, Statistics, Hygiene and Medicine" symposium in Dortmund, Germany in May 2011 on environmental toxicology is presented. Topics include polychlorinated biphenyls exposure, toxicogenomics and neurotoxicity, and environmental toxicology. The symposium featured participants and scientists from interdisciplinary environmental research.

Citrinin (CIT), a mycotoxin known to exert nephrotoxicity, is a contaminant in food and feed. Since CIT contamination is not regularly analyzed, data on its occurrence and especially levels in food commodities are insufficient for conducting a conventional exposure assessment. Yet, human biomonitoring, i.e., an analysis of CIT and its metabolite dihydrocitrinone (DH-CIT) in urine samples allows to estimate exposure. This study investigated CIT exposure in young (2-14 years) and adult (24-61 years) residents of three federal states in Germany. A total of 179 urine samples from children and 142 from adults were collected and analyzed by a targeted LC-MS/MS based method for presence of CIT and DH-CIT. At least one of the biomarkers was detected and quantified in all urines, which indicated a widespread dietary exposure to the mycotoxin in Germany. Interestingly, the biomarker concentrations of CIT total (sum of CIT and DH-CIT) were higher in children's urine (range 0.05-7.62 ng/mL; median of 0.54 ng/mL) than in urines from adults (range 0.04-3.5 ng/mL; median 0.3 ng/mL). The biomarker levels (CIT total ) of individual urines served to calculate the probable daily CIT intake, for comparison to a value of 0.2 µg/kg bw/day defined as 'level of no concern for nephrotoxicity' by the European Food Safety Authority. The median exposure of German adults was 0.013 µg/kg b.w., with only one urine donor exceeding this provisional tolerable daily intake (pTDI) for CIT. The median exposure of children was 0.05 µg/kg bw per day (i.e., 25% of the pTDI); however, CIT exposure in 12 individuals (6.3% of our study group) exceeded the limit value, with a maximum intake of 0.46 µg/kg b.w. per day. In conclusion, these results show evidence for non-negligible exposure to CIT in some individuals in Germany, mainly in children. Therefore, further biomonitoring studies and investigations aimed to identify the major sources of CIT exposure in food commodities are required.

Transfer of knowledge along the different phases of drug development is a fundamental process in pharmaceutical research. In particular, cross-species extrapolation between different laboratory animals and further on to first-in-human trials is challenging because of the uncertain comparability of physiological processes. Physiologically based pharmacokinetic (PBPK) modeling allows translation of mechanistic knowledge from one species to another by specifically considering physiological and biochemical differences in between. We here evaluated different knowledge-driven approaches for cross-species extrapolation by systematically incorporating specific model parameter domains of a target species into the PBPK model of a reference species. Altogether, 15 knowledge-driven approaches were applied to murine and human PBPK models of 10 exemplary drugs resulting in 300 different extrapolations. Statistical analysis of the quality of the different extrapolations revealed not only species-specific physiology as the key determinant in cross-species extrapolation but also identified a synergistic effect when considering both kinetic rate constants and gene expression profiles of relevant enzymes and transporters. Moreover, we show that considering species-specific physiology, plasma protein binding, enzyme and transport kinetics, as well as tissue-specific gene expression profiles in PBPK modeling increases accuracy of cross-species extrapolations and thus supports first-in-human trials based on prior preclinical knowledge., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

In Germany, more than 100 bladder tumor cases are annually recognized as occupational disease and compensated, given that medical experts regard exposure to carcinogenic aromatic amines as a likely cause of cancer. The amount of compensation is initially based on the tumor staging and grading at the time of initial diagnosis ("basic MdE") (MdE--reduction of earning capacity) and is adapted after a recurrence-free period of 2 and 5 years, respectively. In the event of treatment or tumor-related secondary conditions, the monthly compensation increases based on the severity of the objectified functional disorder. In the following article, medical experts specializing in this field provide a complete list of all known disorders, including treatment-related loss of a kidney or erectile dysfunction. In addition, the weighting of medical criteria in the assessment and calculation of the compensation is analyzed in greater detail. Since the given criteria are based on comprehensible experiences of urologists with their patients, they also provide medical experts in other countries with valuable points of reference for the calculation of the compensation.

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5-10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case-control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case-control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.

Bladder cancer may be produced by azo dyes due to the presence of carcinogenic aromatic amines. Nine cases of suspected occupational bladder cancer that were exposed to different crack test sprays in metal-related jobs were examined. A detailed occupational history was taken and, if possible, the N-acetyltransferase 2 (NAT2) status was determined. The first exposure to crack test sprays ranged from 1957 to 1986. Age at first exposure was between 14 and 33 yr. Age at first diagnosis of bladder cancer varied from 35 to 64 yr. Latency periods were between 17 and 45 yr. The maximal reported exposure period was 29 yr. Four of six genotyped cases were slow NAT2 acetylators. The handling of the crack test spray included spraying the red dye-containing matter on the metal body and washing off the spray with a rag. Thus, workers were exposed by dermal contact as well as by inhalation. The crack test spray, which makes the cracks visible after washing off the red testing spray compounds and applying an additional white spray, contained dyes such as solvent red 19 (Sudan red 7B, N-ethyl-1[[4-(phenylazo)phenyl]azo]-2-naphthylamine) or a mixture of p-phenylazoaniline-N-ethyl-2-naphthylamine and p-phenylazoaniline-N-ethyl-1-naphthylamine. The aromatic amine 2-naphthylamine is classified as human carcinogen by IARC and the national authorities and has been banned in many countries since the mid 1950s. Bladder cancer patients with metal-related jobs need to be explicitly asked about the use of crack test sprays.

In a chemical plant in Germany producing 3,3'-dichlorobenzidine dihydrochloride for the manufacture of colorants, blood and urine samples were taken for biological monitoring. 3,3'-Dichlorobenzidine (DBZ) was analyzed in urine by thin-layer chromatography and subsequently further combined with analysis of adducts of 3,3'-DBZ in hemoglobin. Data highlight current ranges of industrial exposure to 3,3'-DBZ in Germany and demonstrate the applicability of biological monitoring to minimize this exposure. Effective biological monitoring was achieved by a combination of monitoring hemoglobin adducts with spot samplings of urinary 3,3'-DBZ excretion in cases of reported exposure periods. Data presented might help to identify biological guidance values (BGV/BAR) for 3,3'-DBZ-exposed individuals.

In most patients with osteoarthritis (OA), therapy-resistant pain is the indication for hip or knee replacement. Glutathione S-transferases, particularly glutathione S-transferase M1 (GSTM1), are involved in metabolism of highly reactive metabolites that may be generated by inflammatory processes. In total, 148 patients with indication for hip or knee replacement and 129 patients of the same hospital without indication for joint replacement were genotyped for GSTM1 and GSTT1 and interviewed by a newly developed questionnaire for occupational and nonoccupational risk factors of hip and/or knee osteoarthritis. Mean age was 70.9 yr in OA cases and 67.4 yr in controls. The frequency of GSTM1 negative in the OA case group was (45%) in the lower range compared to values in Caucasian general population (approximately 50%), whereas the frequency in the controls was normal (51%). The frequency of GSTT1 negative genotype in OA cases and controls was normal. The normal distribution of the GSTM1 negative genotype in patients with indication for hip or knee replacement indicates that the role GSTM1 in these patients is different from that in other aseptic inflammatory diseases such as ozone-related inflammatory reactions of the respiratory tract.

Single nucleotide polymorphism (SNP) rs710521[A], located near TP63 on chromosome 3q28, was identified to be significantly associated with increased bladder cancer risk. To investigate the association of rs710521[A] and bladder cancer by new data and by meta-analysis including all published data, rs710521 was studied in 1,425 bladder cancer cases and 1,740 controls that had not been included in previous studies. Blood samples were collected from 1995 to 2010 in Germany (n = 948/1,258), Hungary (n = 262/65), Venezuela (n = 112/190) and Pakistan (n = 103/227) supplemented by a meta-analysis of 5,695 cases and 40,187 controls. Detection of a A/G substitution (rs710521) on chromosome 3q28, position 191128627 was done via fast real-time polymerase chain reaction (rt-PCR). Rs710521[A] is associated with increased risk in the unadjusted analysis (OR = 1.21; 95% Cl = 1.04-1.40; P = 0.011) and in the recessive model adjusted for age, gender, smoking habits and ethnicity (OR = 1.23; 95% Cl = 1.05-1.44; P = 0.010). No difference between individuals occupationally exposed versus not occupationally exposed to urinary bladder carcinogens was observed concerning the relevance of rs710521[A]. Similarly, rs710521[A] did not confer different susceptibility in smokers and non-smokers. Performing a meta-analysis of 5,695 cases and 40,187 controls including all published studies on rs710521, a convincing association with bladder cancer risk was obtained (OR = 1.18; 95% Cl = 1.12-1.25; P < 0.0001). However, the odds ratio is relatively small.