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Veröffentlichung Entering markets and bodies: increasing levels of the novel plasticizer Hexamoll® DINCH® in 24 hr urine samples from the German Environmental Specimen Bank(2014)DINCH (diisononylcyclohexane-1,2-dicarboxylate) was introduced into the world market in 2002 as a non-aromatic plasticizer and phthalate substitute. We analyzed 300 urine samples (24 h voids) of the German Environmental Specimen Bank (ESB for Human tissues, ESB Hum) for specific DINCH metabolites by on-line HPLC-MS/MS with isotope dilution quantification. Urine samples of the ESB Hum were from the years 1999, 2003, 2006, 2009 and 2012, chosen to investigate the appearance and a possible trend of DINCH exposure since its market introduction. No DINCH metabolites were detected in the 1999 and 2003 samples. From 2006 on, the percentage of samples with DINCH metabolites above the LOQ increased significantly over the years (7% in 2006, 43% in 2009 and 98% in 2012). The cyclohexane-1,2-dicarboxylicacid-mono(hydroxy-isononyl) ester (OH-MINCH) was the predominant metabolite. Median (and 95th percentile) concentrations (in ìg/L) increased from 0.75, p < 0.001). The median (95th percentile) DINCH intake in 2012 was calculated to be 0.14 (1.07) ìg/kg body weight/day which is considerably below daily intakes currently deemed tolerable. DINCH is regarded to have a preferred toxicological profile over certain anti-androgenic phthalates. The continuation of DINCH measurements in the ESB Hum and other human biomonitoring studies like the German Environmental Survey (GerES) allows tracking the development of DINCH body burdens, the distribution of exposure levels and daily intakes, providing basic data for future toxicological assessment and further epidemiological studies.
Quelle: http://www.sciencedirect.comVeröffentlichung Development of a multi-compartment pharmacokinetic model to characterize the exposure to Hexamoll® DINCH®(2015) Schütze, Andre; Apel, Petra; Lorber, Matthew; Gawrych, Katarzyna; Kolossa-Gehring, Marike; Brüning, Thomas; Koch, Holger MartinWe developed and calibrated a multi compartment pharmacokinetic (PK) model to predict urinary concentrations after oral exposure of four specific DINCH metabolites: MINCH, OH-MINCH, cx-MINCH, and oxo-MINCH. This descriptive model has 4 compartments: a "stomachŁ (SC) compartment, a "holdingŁ (HC) compartment, a "bloodŁ (BC) compartment and a "bladderŁ (BLC) compartment. DINCH is assumed to first deposit into the SC, with transfer split between the HC and the BC. Unmetabolized DINCH from the HC then transfers to the BC. The DINCH metabolism is assumed to occur in the BC before excretion via the BLC. At each urination event, all the metabolite mass in the BLC is excreted. The model was calibrated using published urine metabolite data from 3 different male volunteers, each orally dosed with 50 mg DINCH. Full urine voids were taken for 48 h after dosage. The predicted values showed a good agreement with the observed urinary DINCH metabolite concentrations, with a Spearman correlation coefficient exceeding 0.7 for all oxidized metabolites. We showed the importance of a holding reservoir. Without it, a good agreement could not be found. We applied the model to a set of 24-h general population samples measured for DINCH metabolites. The model was unable to duplicate the ratio of metabolites seen in the 24-h samples. Two possibilities were offered to explain the difference: the exposure pattern in the general population did not match the oral exposure in the dosing experiments, or the long-term toxicokinetics of DINCH was not captured in the 48-h controlled dosing experiments.Quelle: http://www.sciencedirect.comVeröffentlichung Bis-(2-propylheptyl)phthalate (DPHP) metabolites emerging in 24 h urine samples from the German Environmental Specimen Bank (1999-2012)(2015)Bis-(2-propylheptyl)-phthalate (DPHP) has been introduced as a substitute for other high molecular weight phthalates primarily used in high temperature applications (e.g. cable wires, roofing membranes). The aim of this study was to investigate how the increased usage of DPHP is reflected in urine samples collected over the last 14 years and to evaluate the current extent of exposure.
We analyzed 300 urine samples (24 h voids) from the German Environmental Specimen Bank collected in the years 1999, 2003, 2006, 2009 and 2012, 60 samples per year, from 30 male and 30 female volunteers (age: 20-30 years) for three specific, secondary oxidized DPHP metabolites (with hydroxy, oxo and carboxy modifications of the alkyl side chain). We determined DPHP metabolites with a previously developed GC-HRMS method, enabling us to unambiguously distinguish DPHP metabolites from co-eluting, structurally isomeric di-iso-decyl phthalate (DIDP) metabolites. All samples were blinded before analysis.
We detected no DPHP metabolites in urine samples from the years 1999, 2003 and 2006. Thereafter, detection rates increased from 3.3% in 2009 to 21.7% in 2012. Mono-oxo-propylheptylphthalate (oxo-MPHP) was the most abundant metabolite, with concentrations between Our results show that the general German population is increasingly exposed to DPHP. However, exposure is considerably lower than for DIDP or other high molecular weight phthalates. Future measurements will enable us to monitor the development of DPHP exposure and advise risk management steps, if warranted.© 2015 Elsevier GmbH. All rights reserved.Veröffentlichung Pesticide exposure assessment for surface waters in the EU(2016) Bach, Martin; Diesner, Mirjam; Großmann, Dietlinde; Müller, Alexander; Priegnitz, JanIn 2001, the European Commission introduced a risk assessment project known as FOCUS (FOrum for the Coordination of pesticide fate models and their USe) for the surface water risk assessment of active substances in the European Union. Even for the national authorisation of plant protection products (PPPs), the vast majority of EU member states still refer to the four runoff and six drainage scenarios selected by the FOCUS Surface Water Workgroup. However, our study, as well as the European Food Safety Authority (EFSA), has stated the need for various improvements. Current developments in pesticide exposure assessment mainly relate to two processes. Firstly, predicted environmental concentrations (PECs) of pesticides are calculated by introducing model input variables such as weather conditions, soil properties and substance fate parameters that have a probabilistic nature. Secondly, spatially distributed PECs for soilŃclimate scenarios are derived on the basis of an analysis of geodata. Such approaches facilitate the calculation of a spatiotemporal cumulative distribution function (CDF) of PECs for a given area of interest and are subsequently used to determine an exposure concentration endpoint as a given percentile of the CDF. For national PPP authorisation, we propose that, in the future, exposure endpoints should be determined from the overall known statistical PEC population for an area of interest, and derived for soil and climate conditions specific to the particular member state. © 2016 Society of Chemical IndustryVeröffentlichung Comparison of dilution factors for German wastewater treatment plant effluents in receiving streams to the fixed dilution factor from chemical risk assessment(2017) Link., Moritz; Voß, Katharina; von der Ohe, Peter C.; Schäfer, Ralf B.Veröffentlichung Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014(2018) Ulrich, Nadin; Bury, Daniel; Koch, Holger Martin; Kolossa-Gehring, Marike; Rüther, Maria; Weber, TillPurpose The aim of this study was to get a first overview of the exposure to the solvents and reproductive toxicants N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) in Germany. NMP and NEP metabolite concentrations were determined in 540 24-h urine samples of the German Environmental Specimen Bank collected from 1991 to 2014. With these data we were able to investigate NMP/NEP exposures over time and to evaluate associated risks. Methods NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) and NEP metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were determined by stable isotope dilution analysis using solid phase extraction followed by derivatization (silylation) and GCâ€ÌEIâ€ÌMS/MS. Results We were able to quantify 5-HNMP and 2-HMSI in 98.0 and 99.6% and 5-HNEP and 2-HESI in 34.8 and 75.7% of the samples. Metabolite concentrations were rather steady over the timeframe investigated, even for NEP which has been introduced as an NMP substitute only in the last decade. Calculated median daily intakes in 2014 were 2.7 Ìg/kg bw/day for NMP and 1.1 Ìg/kg bw/day for NEP. For the combined risk assessment of NMP and NEP exposure, the hazard index based on the human biomonitoring assessment I values (HBM I values) was less than 0.1. Conclusions Based on the investigated subpopulation of the German population, individual and combined NMP and NEP exposures were within acceptable ranges in the investigated timeframe. Sources of NEP exposure in the 90s and 00s remain elusive. © Springer-Verlag GmbH Germany, part of Springer Nature 2018Veröffentlichung Internal exposure of young German adults to di(2-propylheptyl) phthalate (DPHP): Trends in 24-h urine samples from the German Environmental Specimen Bank 1999-2017(2019) Schmidtkunz, Christoph; Gries, Wolfgang; Kolossa-Gehring, Marike; Weber, TillDi(2-propylheptyl) phthalate (DPHP) is used as a substitute for high molecular weight phthalates like di(2-ethylhexyl) phthalate (DEHP) which were subjected to authorization under REACh in 2015. An earlier study on the time trend of exposure in human 24-h urine samples from the German Environmental Specimen Bank has revealed that metabolites of DPHP emerged in 2009 and 2012 (Schütze et al., 2015). In order to better assess a potential trend and the present state of exposure to DPHP, we now measured 180 urine samples from the German Environmental Specimen Bank, 60 per year, collected in 2011, 2014 and 2017, randomized and blinded before analysis. Together with the previously analyzed samples, data for a total of 480 samples covering 19 years from 1999 to 2017 was thus generated. We were able to show that DPHP exposure of the studied population, university students from Münster (Northwestern Germany), has remained essentially constant since 2011, after a rapid increase starting around 2009. Even so, urinary metabolite concentrations were always in the low ppb or sub-ppb range, indicating that DPHP exposure of the general population is substantially lower than for other modern plasticizers, and far below levels currently regarded as critical. DPHP is a plasticizer which is mostly used in non-sensitive applications with little probability of close contact to humans. Still, we observed how temporal trends of DPHP exposure largely follow trends of DPHP consumption in the Western European market. Our results hence demonstrate the potential of biomonitoring to sensitively detect the effects of industrial product strategy on the environment, even when biomarkers are present only at trace level. © 2019 Elsevier GmbH. All rights reserved.Veröffentlichung Building a European exposure science strategy(2019) Fantke, Peter; Conrad, André; Götz, Natalie von; Schlüter, UrsExposure information is a critical element in various regulatory and non-regulatory frameworks in Europe and elsewhere. Exposure science supports to ensure safe environments, reduce human health risks, and foster a sustainable future. However, increasing diversity in regulations and the lack of a professional identity as exposure scientists currently hamper developing the field and uptake into European policy. In response, we discuss trends, and identify three key needs for advancing and harmonizing exposure science and its application in Europe. We provide overarching building blocks and define six long-term activities to address the identified key needs, and to iteratively improve guidelines, tools, data, and education. More specifically, we propose creating European networks to maximize synergies with adjacent fields and identify funding opportunities, building common exposure assessment approaches across regulations, providing tiered education and training programmes, developing an aligned and integrated exposure assessment framework, offering best practices guidance, and launching an exposure information exchange platform. Dedicated working groups will further specify these activities in a consistent action plan. Together, these elements form the foundation for establishing goals and an action roadmap for successfully developing and implementing a â€ÌEuropean Exposure Science Strategyâ€Ì 2020-2030, which is aligned with advances in science and technology. Quelle: https://www.nature.comVeröffentlichung N-methylmalonamic acid (NMMA) as metabolite of methylisothiazolinone and methylchloroisothiazolinone in 24-h urine samples of the German Environmental Specimen Bank from 2000 to 2017(2020) Schettgen, Thomas; Kolossa-Gehring, Marike; Rüther, Maria; Weber, TillMethylisothiazolinone (MI) and the mixture of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI, 3:1) are widespread biocides used in cosmetics, household products, paints or as disinfectant in air-conditioning systems. Exposure to these compounds has raised concerns due to their sensitizing potential, as rates of skin sensitization were reported to increase in the last decade. We have analyzed N-methylmalonamic acid (NMMA), a common metabolite of MI and MCI in 24-h urine samples of the German Environmental Specimen Bank collected from 480 participants (240 male/240 female) between the years 2000 and 2017. Using these data, we were able to calculate the overall daily intake of MI and/or MCI/MI (3:1) of the study participants and point out time trends. NMMA was determined in all urine samples investigated above the LOQ of 0.5 (my)g/L urine. Median and 95th percentile level of NMMA in all 24-h urine samples was 4.1 (my)g/g creatinine and 8.5 (my)g/g creatinine, respectively. This would correspond to a median and 95th percentile daily intake of 0.35 (my)g/kg bw and 0.71 (my)g/kg bw for exclusive uptake of MI and 0.64 (my)g/kg bw and 1.28 (my)g/kg bw for exclusive uptake of MCI/MI (3:1). We noted only slight variations over time for median exposures, but an increasing time trend in the 95th percentile exposure between 2006 and 2011 with a decrease in recent years, probably reflecting regulatory measures on MI and MCI/MI (3:1) in cosmetic products. Increasing knowledge on determinants of exposure to MI and/or MCI/MI (3:1) would be necessary to further lower exposure to these sensitizing compounds. © 2019 Elsevier Ltd. All rights reserved.Veröffentlichung A biomonitoring study assessing the exposure of young German adults to butylated hydroxytoluene (BHT)(2020) Schmidtkunz, Christoph; Kolossa-Gehring, Marike; Küpper, Katja; Weber, TillThe antioxidant 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene, BHT) is used ubiquitously in food, cosmetics, pharmaceuticals, fuels, plastics, rubbers and many other products. Therefore, exposure of the general population to this substance is likely. We analyzed the BHT metabolite 3,5-di-tert-butyl-4-hydroxybenzoic acid ("BHT acid") in 24-h urine samples from the German Environmental Specimen Bank with the aim of gaining a better understanding of the internal burden of BHT in young nonspecifically exposed adults. The study population consisted of students between 20 and 29 years of age at the time of sampling, all from Halle/Saale in Central Germany. In total, 329 samples collected in the years 2000, 2004, 2008, 2012, 2015, and 2018 were measured by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). BHT acid was detected above the limit of quantification (0.2 My g/L) in 98% of the samples. The median of the measured concentrations was 1.06 My g/L and 1.24 My g/g creatinine respectively, the median of the daily excretion was 1.76 My g/24 h and - additionally normalized for body weight - 26.8 ng/24 h * kg bw respectively. The corresponding 90th percentiles were 3.28 My g/L, 3.91 My g/g creatinine, 5.05 My g/24 h, and 81.9 ng/24 h * kg bw. Medians of creatinine-corrected values were slightly higher in women than in men, while the opposite situation was observed for the volume concentrations and the 24-h excretion values (not corrected for body weight). Values simultaneously normalized both for 24-h excretion and body weight did not exhibit any significant differences between males and females, probably indicating a virtually identical magnitude of exposure for both genders. The background exposure of the investigated population was found to be largely constant since the year 2000, with only weak temporal trends at most. Daily intakes were estimated from excretion values and found to be largely below the acceptable daily intake (ADI) of BHT at 0.25 mg/kg bw: our worst-case estimate is a daily BHT intake of approximately 0.1 mg/kg bw at the 95th percentile level. However, these intake assessments rely on very limited quantitative data regarding human metabolism of BHT. © 2020 Elsevier GmbH. All rights reserved.