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Degradation of polychlorinated biphenyls (PCBs) is initiated by cytochrome P450 (CYP) enzymes and includes PCB oxidation to OH-metabolites, which often display a higher toxicity than their parental compounds. In search of an animal model reflecting PCB metabolism and toxicity, we tested Drosophila melanogaster, a well-known model system for genetics and human disease. Feeding Drosophila with lower chlorinated (LC) PCB congeners 28, 52 or 101 resulted in the detection of a human-like pattern of respective OH-metabolites in fly lysates. Feeding flies high PCB 28 concentrations caused lethality. Thus we silenced selected CYPs via RNA interference and analyzed the effect on PCB 28-derived metabolite formation by assaying 3-OH-2′,4,4′-trichlorobiphenyl (3-OHCB 28) and 3′-OH-4′,4,6′-trichlorobiphenyl (3′-OHCB 28) in fly lysates. We identified several drosophila CYPs (dCYPs) whose knockdown reduced PCB 28-derived OH-metabolites and suppressed PCB 28 induced lethality including dCYP1A2. Following in vitro analysis using a liver-like CYP-cocktail, containing human orthologues of dCYP1A2, we confirm human CYP1A2 as a PCB 28 metabolizing enzyme. PCB 28-induced mortality in flies was accompanied by locomotor impairment, a common phenotype of neurodegenerative disorders. Along this line, we show PCB 28-initiated caspase activation in differentiated fly neurons. This suggested the loss of neurons through apoptosis. Our findings in flies are congruent with observation in human exposed to high PCB levels. In plasma samples of PCB exposed humans, levels of the neurofilament light chain increase after LC-PCB exposure, indicating neuronal damage. In summary our findings demonstrate parallels between Drosophila and the human systems with respect to CYP mediated metabolism and PCB mediated neurotoxicity.

Environ Sci Pollut Res Int (2022). doi:10.1007/s11356-022-23632-2, Published by Springer, Berlin ; Heidelberg

Archives of toxicology 95(8), 2659-2665 (2021). doi:10.1007/s00204-021-03100-5, Published by Springer, Berlin

Methylisothiazolinone and the reaction mixture of chloromethylisothiazolinone/methylisothiazolinone (MCI/MI, 3 : 1) are broadly used biocides that are contained in many products of everyday life (e.g. cosmetics, wet wipes, etc.). As MI and MCI are able to sensitize (and penetrate) the skin, their application in cosmetic products is of concern. In previous work, we have revealed a background exposure of the general population to MI and/or MCI/MI (3 : 1) by the determination of urinary N-methylmalonamic acid (NMMA) as the main human metabolite. To corroborate these findings, we have now developed a two-dimensional LC/MS/MS method for the quantification of a mercapturic acid metabolite of MI and MCI ((acetylamino){[3-(methylamino)-1-(methylthio)-3-oxopropyl]thio}acetic acid or shortly “M-12”) in human urine. This analyte is enriched online using a Strata-X-column and stripped from the urinary matrix. Then, the analyte is back flushed to the analytical column (Phenomenex C18(2), 150 × 4.6 mm) and finally quantified by tandem mass spectrometry with the use of isotopically labelled M-12 as the internal standard. The LOQ for M-12 was 0.2 ng mL−1 urine and sufficient to quantify urinary background levels. Precision within and between series for M-12 in urine at concentrations varying from 0.2 to 5 ng mL−1 ranged from 2.1 to 23.9% and accuracy ranged from 86.3 to 101.8%. Mean accuracy for M-12 in individual urine samples was 94.3% (range: 89.7–102.9%). We applied this method to previously collected 24 h urine samples of 60 persons with no specific exposure to MI and/or MCI/MI (3 : 1). The metabolite M-12 could be quantified in each urine sample. The median and 95th percentile levels for urinary M-12 were determined to be 0.62 and 2.26 ng mL−1, respectively. In these urine samples, the concentrations of the previously determined metabolite NMMA and M-12 correlated well. In the future, we will apply this method to urine samples of a previously conducted human exposure study to explore the additional value of M-12 as a biomarker of exposure to MI and MCI.

The export of e-waste from industrialized to developing countries has led to the formation of a large-scale informal e-waste recycling sector in Accra, Ghana. During recycling processes, workers are exposed to several hazardous substances, such as heavy metals. As a common component of e-waste, inorganic arsenic can be released during e-waste recycling processes. The aim of this study was to assess the exposure to inorganic arsenic species in e-waste workers compared to a control group. N = 84 e-waste workers and n = 94 control subjects were included in this analysis. Inorganic arsenic species were determined in urine samples using HPLC-ICP-MS. E-waste workers showed higher median concentrations of As(III), As(V), MMA, DMA and the sum of inorganic arsenic in comparison to the control group. More than 80% of the e-waste workers exceeded the acceptable concentration (14 μg/L), which was significantly higher in comparison to the control group (70%). The tolerable concentration (40 μg/L) was exceeded in 17.2% of the participants, meaning a statistically relevant risk of developing cancer due to arsenic exposure throughout their (working) life. In conclusion, the exposure to inorganic arsenic is not only a problem of informal e-waste recycling, but a major public health concern that needs further investigation.

After centuries of mining in the district of Euskirchen, that is, in the communities of Mechernich and Kall, the lead concentration in the soil remains high, often exceeding regulatory guidelines. To clarify the lead body burden among residents in the region, a human biomonitoring study on a voluntary basis was initiated in which the blood lead level (BLL) was assessed. A questionnaire was distributed to evaluate lead exposure routes and confounders. Overall, 506 volunteers participated in the study, of whom 7.5% were children and adolescents, 71.9% were adults from 18 to 69 years, and 19.4% were residents 70 years or older. While the BLLs in the adult population were inconspicuous, among the children and adolescents investigated, 16.7% of the children between 3 and 17 years had BLLs above the recently revised German reference values for BLL in children. These results point towards a higher lead exposure in children living in the region. The hierarchical regression analysis based on the BLL and the questionnaire revealed the significant influence of the factors age, sex, smoking, construction age of the real estate, occupancy, and intensive contact with soil on the BLL. Measures to reduce lead exposure include a focus on improved personal and domestic hygiene to minimize lead intake.

International journal of hygiene and environmental health 227, 113511 (2020). doi:10.1016/j.ijheh.2020.113511, Published by Elsevier, München

Polychlorinated biphenyls&rsquo, (PCB) exposure has been reported to be associated with depressive symptoms, which is correlated to lower dopamine- (DA) and thyroxine-concentrations (T4). T4 is necessary for DA-synthesis and it binds to transthyretin (TTR) being transported into the brain. PCBs can displace T4 by binding to TTR itself, being transported into the brain and disturbing DA-synthesis, where depressive symptoms might occur. Consequently, the free T4-concentration (fT4) increases when PCBs bind to TTR. The interaction of PCBs with fT4 and its associations with the main DA metabolite, homovanillic acid (HVA), and depressive symptoms were investigated. In total, 116 participants (91.6% men) were investigated, who took part in three annual examinations (t1&ndash, t3) of the HELPcB health surveillance program. Blood was collected for measuring PCBs, hydroxy PCBs (OH-PCBs), and fT4 and urine for HVA. Depressive Symptoms were assessed with a standardized questionnaire. Interactions were tested cross-sectionally with multiple hierarchical regressions and longitudinally with mixed effect models. Related to HVA, an interaction was cross-sectionally found for lower-chlorinated PCBs (LPCBs) and dioxin-like PCBs (dlPCBs), longitudinally only for LPCBs. Related to depressive symptoms, the interaction was found for LPCBs, dlPCBs, and OH-PCBs, longitudinally again only for LPCBs. The results give first hints that a physiological process involving the thyroid and DA system is responsible for depressive symptoms after PCB exposure.

Methylisothiazolinone and the mixture of chloromethylisothiazolinone/methylisothiazolinone (MCI/MI, 3:1) are widespread biocides used in cosmetic and household products. Due to their skin permeability, they might be taken up by the general population via use of products containing these biocides. As both compounds are known skin sensitizers, the use of these products is under discussion by regulatory agencies. In order to evaluate the possible uptake of MI and/or MCI/MI by human biomonitoring, we have developed and validated a highly sensitive and specific GC/MS/MS-method for the quantification of N-methylmalonamic acid (NMMA), a known metabolite of MI and MCI in urine of rats. After freeze-drying of urine, the analyte is derivatised with pentafluorobenzyl bromide in anhydrous solution and the PFB-derivative is extracted into n-hexane. After concentration, the derivative is finally quantified by GC/MS/MS in EI-mode using 13C3-NMMA as internal standard. The limit of quantification for NMMA was 0.5 ng mL−1 urine. Precision within and between-series was determined to range between 3.7–10.9% using native and spiked quality control samples. Accuracy ranged between 89 and 114%. In a pilot study we applied this method to spot urine samples of 63 persons not knowingly exposed to MI and/or MCI/MI. NMMA was quantifiable in every urine sample analysed, with no significant difference in urinary levels between male and female participants. The median (95th percentile) levels for urinary NMMA were 3.6 (7.4) ng mg−1 creatinine and 2.9 (9.1) ng mg−1 creatinine for males (n = 32) and females (n = 31), respectively. In a volunteer experiment, a relation of exposure to MI and/or MCI/MI and subsequent NMMA-excretion was shown. Our method is the first to report human urinary background levels of NMMA. However, the possibility of formation and urinary excretion of NMMA within physiological processes cannot be ruled out.

We established and validated a specific and sensitive analytical method for the determination of 1-vinyl-2-pyrrolidone (VP) as 1-vinyl-2-pyrrolidone-mercapturic acid (VPMA) in urine using an electrospray liquid chromatography tandem mass spectrometry (ESI-LC/MS/MS) column switching method. An online solid phase extraction (SPE) for sample cleanup was performed by column switching to a restricted access material and back-flushing to the analytical column. A Phenomenex Luna C8 column was used for sample separation (150mm; ID 4,6mm; 3μm). D4-VPMA served as an isotope labeled internal standard and was detected in negative multiple-reaction monitoring (MRM) mode. The Limit of quantification (LOQ) for VPMA was 1.5μg/L, the intra-day precision of three concentrations (2μg/L, 75μg/L and 400μg/L) of spiked urine samples ranged from 2.7 to 7.3%, the inter-day precision from 3.4 to 14.4%. The accuracy ranged from 6.2 to 9.0%, for the intra-day experiments and from 0.3 to 6.9% for the inter-day experiments. The method was applied to urines of Sprague-Dawley rats exposed to VP as a proof of principle of VPMA as a potential biomarker.

Informal e-waste recycling leads to a contamination of the workers with several hazardous substances, in particular heavy metals and persistent organic pollutants (POPs). Polychlorinated biphenyls (PCBs) belong to the group of POPs and are suspected to be associated with adverse health effects. In particular lower chlorinated PCBs, such as the congeners PCB 28 and PCB 52 are a marker of occupational exposure. The aim of our study was to assess the occupational PCB exposure in e-waste workers in relation to their specific recycling task (e.g. dismantling, burning). Altogether, n = 88 e-waste workers and n = 196 control subjects have been included in this study. All plasma participant's samples were evaluated for the PCB congeners PCB 28, 52, 101, 138, 153, 180 and sum of NDL-indicator congeners by human biomonitoring. A significant difference could be detected for the lower chlorinated PCB congeners (PCB 28, 52, and 101) for e-waste workers in comparison to the control group. Analyzing specific recycling tasks, workers who dismantle and those who burn e-waste showed the highest plasma levels of PCB 28 and 52. In conclusion, e-waste workers showed occupational related elevated PCB levels. Although those levels did not exceed the BAT value, workers were contaminated with PCBs during their task. Occupational health and safety measure are therefore necessary to protect the worker's health.

Hair analysis has been increasingly used to establish long-term biomarkers of exposure to both endogenous and exogenous substances, with a special emphasis on steroidal hormones. Hair cortisol and cortisone have been associated to physiological and psychological strains, anxiety and depression. Hair is a very complex matrix, which might jeopardize analyte detection at low concentrations. A new, highly selective and sensitive method based on fragments of second order, MS(3) (MS/MS/MS), was developed and validated for the analysis of hair cortisol and cortisone. An online solid phase extraction was performed on a C8 restricted access material (RAM) phase following by separation on a reversed-phase C18 column using methanol and 0.02% ammonium hydroxide as mobile phase. The developed method required minimal sample preparation and the injection of only 50 µL of sample leading to a LOQ of 2 pg mg(-1). Good linear responses were observed in the range 2-200 pg mg(-1) (R(2)0.99) and extraction recoveries ranged between 77-125% and 70-123% for cortisol and cortisone, respectively. Intra- and inter-assay coefficients of variation were between 1.4 and 14%. In order to evaluate the applicability of the method, preliminary tests (N=33) were conducted in 3 cm hair samples (close to scalp) of healthy volunteers with an age range of 4-63. Average concentrations in hair were 12.7±14 pg mg(-1) and 41.6±42 pg mg(-1) for cortisol and cortisone, respectively. Further investigations on cortisol and cortisone as biomarkers for chronic psychological strain will be assessed as a next step.

RATIONALE The monomer 1-vinyl-2-pyrrolidone (VP) is a substance with excellent solvent features. It is used in a wide variety of pharmaceutical, cosmetic, food industrial or technical applications and produced in industrial scale. Since VP has caused adenocarcinoma of the nasal cavity and liver cell carcinoma in long term experiments with rats, a human biomarker would be appreciated for risk assessment. METHODS A sensitive analytical electron ionization GCMSMS method for the determination of six possible biomarkers for VP in urine was established and validated. Two isotope labeled internal standards (ISTD) were used for quantification. A simple and easy to use freeze drying step was performed prior to derivatization with N-tert-butyldimethylsilyl-N-methyltrifluoracetamide (MTBSTFA) and following sample extraction for cleanup purposes. RESULTS A calibration curve with 6 calibration standards ranging from 50 μg/L to 2000 μg/L (10 fold higher for H-OPAA) in urine was prepared. Validation results were satisfying with recoveries ranging from 88.2 to 110.2 % with two exceptions for the lowest quality control for two substances without ISTD (126.4 % and 139.3 %). Three of the substances could be identified as VP metabolites in an exposure study with Sprague-Dawley (SD) rats. CONCLUSIONS The paper provided describes a quick and easy to use method of six target molecules investigated for better understanding of the VP metabolization. Two of three substances identified as metabolites of VP might serve as a nonspecific human biomarker for a VP exposure as shown with an excerpt of an exposure study performed in SD rats.

// Sarah Urnauer 1 , Andrea M. Muller 1 , Christina Schug 1 , Kathrin A. Schmohl 1 , Mariella Tutter 1 , Nathalie Schwenk 1 , Wolfgang Rodl 2 , Stephan Morys 2 , Michael Ingrisch 3 , Jens Bertram 4 , Peter Bartenstein 5 , Dirk-Andre Clevert 3 , Ernst Wagner 2 and Christine Spitzweg 1 1 Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany 2 Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany 3 Department of Clinical Radiology, University Hospital of Munich, LMU Munich, Munich, Germany 4 Department of Nuclear Medicine, Radiopharmacy, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany 5 Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany Correspondence to: Christine Spitzweg, email: Christine.Spitzweg@med.uni-muenchen.de Keywords: sodium iodide symporter, gene therapy, theranostic application, nonviral EGFR-targeted gene transfer, colon cancer metastases Received: April 26, 2017 Accepted: August 04, 2017 Published: September 16, 2017 ABSTRACT Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131 I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18 F-tetrafluoroborate ( 18 F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18 F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131 I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.

The ambiguity of query terms is a major obstacle for performance in information retrieval. Clarity or ambiguity scores measure how often terms appear together with different other terms by applying the Kullback-Leibler Divergence. These scores have been used to predict the performance of queries. We calculated the clarity scores within a large patent collection and compared the ambiguity of terms selected form claims and description within the same and within the other field.

Enterprise apps on mobile devices typically need to communicate with other system components by consuming web services. Since most of the current mobile device platforms (such as Android) do not provide built-in features for consuming SOAP services, extensions have to be designed. Additionally in order to accommodate the typical enhanced security requirements of enterprise apps, it is important to be able to deal with SOAP web service security extensions on client side. In this article we show that neither the built-in SOAP capabilities for Android web service clients are sufficient for enterprise apps nor are the necessary security features supported by the platform as is. After discussing different existing extensions making Android devices SOAP capable we explain why none of them is really satisfactory in an enterprise context. Then we present our own solution which accommodates not only SOAP but also the WS-Security features on top of SOAP. Our solution heavily relies on code generation in order to keep the flexibility benefits of SOAP on one hand while still keeping the development effort manageable for software development. Our approach provides a good foundation for the implementation of other SOAP extensions apart from security on the Android platform as well. In addition our solution based on the gSOAP framework may be used for other mobile platforms in a similar manner.

Objective Emissions from a particular welding process, metal inert gas brazing of zinc-coated steel, induce an increase in C-reactive protein. In this study, it was investigated whether inflammatory effects could also be observed for other welding procedures. Methods Twelve male subjects were separately exposed to (1) manual metal arc welding fumes, (2) filtered air, and (3) metal active gas welding fumes for 6 hours. Inflammatory markers were measured in serum before, and directly, 1 and 7 days after exposure. Results Although C-reactive protein concentrations remained unchanged, neutrophil concentrations increased directly after exposure to manual metal arc welding fumes, and endothelin-1 concentrations increased directly and 24 hours after exposure. After exposure to metal active gas and filtered air, endothelin-1 concentrations decreased. Conclusions The increase in the concentrations of neutrophils and endothelin-1 may characterize a subclinical inflammatory reaction, whereas the decrease of endothelin-1 may indicate stress reduction.