Person: Apel, Petra
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Veröffentlichung Concurrent assessment of Phthalates/HEXAMOLL ® DINCH Exposure and Wechsler intelligence scale for children performance in three European cohorts of the HBM4EU aligned studies(2022) Rosolen, Valentina; Apel, Petra; Giordani, Elisa; Mariuz, Marika; Kolossa-Gehring, Marike; Lange, RosaInformation about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL® DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL® DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL® DINCH biomarkers. The relation between phthalates/HEXAMOLL® DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 +/- 11 (NAC-II), 98 +/- 12 (OCC), and 81 +/- 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 5OH-MEHP+5oxo-MEHP (beta=2.56; 95% CI 0.58-4.55; N=270), 5OH-MEHP+5cx-MEPP (beta=2.48; 95% CI 0.47-4.49; N=270) and 5OH-MEHP (beta=2.58; 95% CI 0.65-4.51; N=270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value >/= 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL® DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children. © 2022 by the authorsVeröffentlichung 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 Time trend of exposure to the phthalate plasticizer substitute DINCH in Germany from 1999 to 2017: Biomonitoring data on young adults from the Environmental Specimen Bank (ESB)(2019) Kasper-Sonnenberg, Monika; Apel, Petra; Koch, Holger M.; Kolossa-Gehring, Marike; Rüther, MariaDINCH (cyclohexane-1,2-dicarboxylic acid-diisononyl ester) is a phthalate plasticizer substitute introduced into the market in 2002. It is increasingly used especially in the production of toys, food contact materials and medical devices. In this measurement campaign on 24-h urine samples of young adults (20-29 years) from the German Environmental Specimen Bank (ESB) collected in 2010, 2011, 2013, 2015 and 2017 (in total 300 samples, 60 samples/year) we analyzed three specific, oxidized DINCH metabolites (OH-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester; cx-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(carboxy-isooctyl) ester, oxo-MINCH: cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester). We merged these data with earlier data of the ESB from the years 1999-2012 and are now able to report levels and time trends of internal DINCH exposure from 1999 to 2017. After first detections of the major oxidized DINCH metabolite OH-MINCH in 2006 (6.7%) detection rates rapidly increased to 43.3% in 2009, 80% in 2010 and 98.3% in 2011 and 2012. From the year 2013 on we could detect OH-MINCH in every urine sample analyzed. The median concentrations of OH-MINCH rapidly increased from 0.15 (Mü)g/L in 2010 to twice the concentration in 2011 (0.31 (Mü)g/L) with further increases in 2013 (0.37 (Mü)g/L), 2015 (0.59 (Mü)g/L) and 2017 (0.70 (Mü)g/L). Similar increases, albeit at lower detection rates and concentration levels, could be observed for cx-MINCH and oxo-MINCH. All metabolites strongly correlate with each other. For the ESB study population, DINCH exposures are still far below health based guidance values such as the German Human Biomonitoring Value (HBM-I; 4,500 (Mü)g/L for the sum of OH-MINCH and cx-MINCH) or the tolerable daily intake (TDI) of EFSA (1mg/kg/bw/d). The median daily DINCH intake (DI) calculated for 2017 was 0.23 (Mü)g/kg bw/d, thus 4,310-times lower than the TDI. The maximum DI calculated for one individual in 2012 (42.60 (Mü)g/kg bw/d) was a factor of more than 20 below the TDI. The ongoing increase in DINCH exposure needs to be closely monitored in the future, including populations with potentially higher exposures such as children. This close monitoring will enable timely exposure and risk reduction measures if exposures reached critical levels, or if new toxicological data lead to lower health based guidance values. DINCH belongs to the European Human Biomonitoring Initiative (HBM4EU) priority substances for which policy relevant questions still have to be answered. © 2019 Elsevier GmbH. All rights reserved.Veröffentlichung The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values for selected phthalates and a substitute plasticizer(2021) Apel, Petra; Kolossa-Gehring, Marike; Rousselle, Christophe; Lange, RosaUbiquitous use of plasticizers has led to a widespread internal exposure of the European population. Until today, metabolites are detected in almost every urine sample analysed. This raised the urgent need for a toxicological interpretation of the internal exposure levels. The European Human Biomonitoring Initiative (HBM4EU) contributes substantially to the knowledge on the actual exposure of European citizens to chemicals prioritised within HBM4EU, on their potential impact on health and on the interpretation of these data to improve policy making. On that account, human biomonitoring guidance values (HBM-GVs) are derived for the general population and the occupationally exposed population agreed at HBM4EU consortium level. These values can be used to assess phthalate exposure levels measured in HBM studies in a health risk assessment context. HBM-GVs were derived for five phthalates (DEHP, DnBP, DiBP, BBzP and DPHP) and for the non-phthalate substitute Hexamoll® DINCH. For the adult general population, the HBM-GVs for the specific metabolite(s) of the respective parent compounds in urine are the following: 0.5 mg/L for the sum of 5-oxo-MEHP and 5-OH-MEHP; 0.19 mg/L for MnBP, 0.23 mg/L for MiBP; 3 mg/L for MBzP; 0.5 mg/L for the sum of oxo-MPHP and OH-MPHP and 4.5 mg/L for the sum of OH-MINCH and cx-MINCH. The present paper further specifies HBM-GVs for children and for workers. Quelle: © 2021 The Author(s)