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The analytical determination of hemoglobin adducts was used as an effective biomonitoring tool after a fire outbrake at a chemical plant close to Cologne/Germany in 2008. More than 1000 people (e.g. fire-men, police officers, and workers) were potentially exposed to acrylonitrile and ethylene. Air monitoring in the surrounding was performed, and acrylonitrile was measured in concentrations up to 20 ppm, the mean value being 7 ppm (time range: 8 h). As many people were concerned about their individual body burden, biomonitoring was recommended for all people involved. 816 persons took advantage of this opportunity and came for blood sampling to the occupational health department of our company. Regarding the lifespan of erythrocytes up to 3 months, it was possible to analyze hemoglobin adducts of acrylonitrile and ethylene during and after the accident. In case of acrylonitrile the hemoglobin adduct N -(2-cyanoethyl) valine and regarding ethylene, N -(2-hydroxyethyl) valine was determined. As a result, the body burden was in nearly all cases within our internal adduct reference values (CyEtVal < 15 μg/L blood or <612 pmol/g globin; HyEtVal < 15 μg/L blood or 646 pmol/g globin). In about 1% of the cases, the adduct concentrations were slightly above these reference values. This means that the body burden measured by biomonitoring turned out to be far lower than the one expected from the air data. Therefore, following chemical incidents, in case biomonitoring is meaningful, it is highly recommended beside of air monitoring. [ABSTRACT FROM AUTHOR]

Di(2-propylheptyl) phthalate (DPHP), a high molecular weight phthalate, is primarily used as a plasticizer in polyvinyl chloride and vinyl chloride copolymers for technical applications, as a substitute for other phthalates currently being scrutinized because of endocrine disrupting effects. We determined urinary excretion fractions of three specific DPHP metabolites (mono-2-(propyl-6-hydroxy-heptyl)-phthalate (OH-MPHP), mono-2-(propyl-6-oxoheptyl)-phthalate (oxo-MPHP) and mono-2-(propyl-6-carboxy-hexyl)-phthalate (cx-MPHxP)) after oral dosing of five volunteers with 50 mg labelled DPHP-d4 and subsequent urine sampling for 48 h. These excretion fractions are used to back calculate external intakes from metabolite measurements in spot urine analysis. Following enzymatic hydrolysis to cleave possible conjugates, we determined these urinary metabolites by HPLC–NESI–MS/MS with limits of quantification (LOQ) between 0.3 and 0.5 μg/l. Maximum urinary concentrations were reached within 3–4 h post dose for all three metabolites; elimination half-lives were between 6 and 8 h. We identified oxo-MPHP as the major oxidized metabolite in urine representing 13.5 ± 4.0% of the DPHP dose as the mean of the five volunteers within 48 h post dose. 10.7 ± 3.6% of the dose was excreted as OH-DPHP and only 0.48 ± 0.13% as cx-MPHxP. Thus, within 48 h, 24.7 ± 7.6% of the DPHP dose was excreted as these three specific oxidized DPHP metabolites, with the bulk excreted within 24 h post dose (22.9 ± 7.3%). These secondary, oxidized metabolites are suitable and specific biomarkers to determine DPHP exposure. In population studies, however, chromatographic separation of these metabolites from other isomeric di-isodecyl phthalate (DIDP) metabolites is warranted (preferably by GC–MS) in order to distinguish DPHP from general DIDP exposure. Palatinol ® , Hexamoll ® and DINCH ® are registered trademarks of BASF SE, Germany. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 b-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. [ABSTRACT FROM AUTHOR]

Abstract: Pyrethrum as well as synthetic pyrethroids like allethrin, resmethrin, phenothrin, tetramethrin, cyfluthrin, cypermethrin, deltamethrin or permethrin are among the insecticides most often used worldwide. With a sensitive and valid gas-chromatographic–high resolution mass spectrometric method, it is possible to detect all pyrethrum and pyrethroid metabolites in one analytical run. Thus, for the first time a background level of trans-chrysanthemumdicarboxylic acid (CDCA) in urine (95th percentile: 0.15μg/l) as a characteristic, e.g. for a pyrethrum exposure was found. Following a pyrethrum exposure lasting 1 day, CDCA was found in 27 out of 30 subjects with concentrations going up to 54μg/l urine (mean: 1.1±4.4μg/l). To obtain information about the elimination kinetics of pyrethrum in humans, urinary excretion of CDCA was investigated in three volunteers after oral intake of 0.3mg pyrethrin I. CDCA was detected during the first 36h after intake with elimination being most rapid during the first 4h (mean elimination half-life: 4.2h). [Copyright &y& Elsevier]

In this paper, the difficulties of genetic screening of occupationally exposed subjects for the evaluation of retrospective, and prospective, health risk assessments is illustrated with reference to glutathione S-transferase (GST) function. Individual differences in the magnitude and half-life of adduct levels, derived from background and occupational exposure, are observed largely independently of genetically determined conjugator status. During detoxification, GSTs play a critical role in providing protection against electrophiles and products of oxidative stress. GSTs are a superfamily of enzymes that may have broad and overlapping substrate specificities. Deficiencies of GST isoenzymes may be compensated by the presence of other isoforms and by the use of alternative metabolic pathways. This may be one reason for the abundance of controversial data on GST polymorphisms and adverse health effects. [Copyright &y& Elsevier]

Climbazole is an antimycotic compound used in cosmetic products as a preservative or as an active ingredient in anti-dandruff (AD) formulations. In this study we provide human toxicokinetic data on climbazole. Using our previously published analytical method, we investigated the urinary excretion of two climbazole metabolites, (OH) 2 -climbazole and cx-OH-climbazole, for 48 h after oral ingestion (n = 5, 49–77 µg/kg bw) and for 72 h after dermal application of either a climbazole-containing rinse-off AD shampoo or a leave-on hair tonic (n = 2×3). In total, 23.9 % (18.0–33.4 %) of the oral dose were excreted as the two abovementioned metabolites over 48 h. In one volunteer, who used an over-the-counter phytopharmaceutical, metabolite excretion was about three times lower and we found influences on diastereoselectivity of (OH) 2 -climbazole formation using a modified analytical method. After dermal application, urinary concentration maxima occurred considerably later than after oral intake. The two different dermal exposure scenarios also revealed a relevance of exposure duration and product formulation on the systemic availability of climbazole. Back-calculated oral-dose-equivalent intakes from the dermal exposures showed a maximum climbazole intake of 18.5 µg/kg bw/d after hair tonic use, or 6.6 µg/kg bw/d after AD shampoo application. • (OH) 2 -climbazole and cx-OH-climbazole identified as suitable exposure biomarkers. • On average 24 % of the dose were recovered in form of the investigated biomarkers within 48 h. • Shifting diastereomeric ratios observed within the investigated excretion period. • Sum parameter recommended as the most robust approach for reverse dosimetry. [ABSTRACT FROM AUTHOR]