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Veröffentlichung A pilot study on the feasibility of European harmonized Human Biomonitoring: Strategies towards a common approach, challenges and opportunities(2015) Casteleyn, Ludwine; Dumez, Birgit; Becker, Kerstin; Den Hond, Elly; Schoeters, Greet; Castaño, Argelia; Koch, Holger Martin; Angerer, Jürgen; Esteban, Marta; Exley, Karen; Sepai, Ovnair; Bloemen, Louis; Fiddicke, Ulrike; Horvath, Milena; Knudsen, Lisbeth E.; Joas, Anke; Joas, Reinhard; Biot, Pierre; Koppen, C.; Dewolf, M.-C.; Katsonouri, Andromachi; Hadjipanayis, Adamos; Cerna, Milena; Krskova, A.; Kolossa-Gehring, Marike; Nielsen, Jeanette K.S.; Jensen, J.F.; Rudnai, Peter; Közepesy, S.; Mulcahy, M.F.R.; Mannion, R.; Gutleb, Arno C.; Fischer, M.E.; Ligocka, Danuta; Jakubowski, M.; Reis, M.Fátima; Namorado, S.; Lupsa, Ioana-Rodica; Schwedler, Gerda; Gurzau, Anca ElenaIn 2004theEuropeanCommissionandMemberStatesinitiatedactivitiestowardsaharmonizedap-
proach forHumanBiomonitoringsurveysthroughoutEurope.Themainobjectivewastosustainen-
vironmental healthpolicybybuildingacoherentandsustainableframeworkandbyincreasingthe
comparability ofdataacrosscountries.Apilotstudy totestcommonguidelinesforsettingupsurveys
wasconsideredakeystepinthisprocess.Throughabottom-upapproachthatincludedallstakeholders,
a jointstudyprotocolwaselaborated.
FromSeptember2011tillFebruary2012,17Europeancountriescollecteddatafrom1844mother-
child pairsintheframeofDEMOnstrationofastudytoCoordinateandPerformHumanBiomonitoring
on aEuropeanScale(DEMOCOPHES). Mercury inhairandurinarycadmiumandcotininewereselected
as biomarkersofexposurecoveredbysufficient analyticalexperience.PhthalatemetabolitesandBi-
sphenol Ainurinewereaddedtotakeintoaccountincreasingpublicandpoliticalawarenessfor
emerging typesofcontaminantsandtotestlessadvancedmarkers/markerscoveredbylessanalytical
experience.Extensiveeffortstowardschemo-analyticalcomparabilitywereincluded.
The pilotstudyshowed thatcommonapproachescanbefoundinacontextofconsiderablediffer-
ences withrespecttoexperienceandexpertize,socio-culturalbackground,economicsituationandna-
tional priorities.ItalsoevidencedthatcomparableHumanBiomonitoringresultscanbeobtainedinsuch
context.AEuropeannetworkwasbuilt,exchanging information,expertise andexperiences,andpro-
viding trainingonallaspectsofasurvey.Akeychallengewas finding therightbalancebetweenarigid
structure allowingmaximalcomparabilityanda flexibleapproachincreasingfeasibilityandcapacity
building. NextstepsinEuropeanharmonizationinHumanBiomonitoringsurveysincludetheestab-
lishment ofajointprocessforprioritizationofsubstancestocoverandbiomarkerstodevelop,linking
biomonitoring surveyswithhealthexaminationsurveysandwithresearch,andcopingwiththediverse
implementations ofEUregulationsandinternationalguidelineswithrespecttoethicsandprivacy.
©2014ElsevierInc.Allrightsreserved.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 Time course of phthalate cumulative risks to male developmental health over a 27-year period: Biomonitoring samples of the German Environmental Specimen Bank(2020) Apel, Petra; Kortenkamp, Andreas; Conrad, André; Koch, Holger Martin; Kolossa-Gehring, Marike; Rüther, MariaIn several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates' developmental toxicity. The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subjectâ€Ìs combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 - 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures. © 2020 The Authors.Veröffentlichung Metabolites of the substitute plasticiser Di-(2-ethylhexyl) terephthalate (DEHTP) in urine of children and adolescents investigated in the German Environmental Survey GerES V, 2014-2017(2020) Conrad, André; Koch, Holger Martin; Kolossa-Gehring, Marike; Rucic, Enrico; Schmied-Tobies, Maria Irene Hilde; Schwedler, GerdaMetabolites of di-(2-ethylhexyl) terephthalate (DEHTP), a substitute for ortho-based phthalate plasticisers like di-(2-ethylhexyl) phthalate (DEHP), were analysed in 2112 first-morning void urine samples from children and adolescents aged 3-17 years, participating in the population representative German Environmental Survey on Children and Adolescents, GerES V 2014-2017. The major metabolite 5cx-MEPTP was detected in all urine samples with a geometric mean (GM) of 7.39 (my)g/L, with highest levels in the mg/L range. The GM for the other metabolites were 0.55 (my)g/L for 5OH-MEHTP, 0.54 (my)g/L for 5oxo-MEHTP and below the limit of quantification (LOQ) for 2cx-MMHTP. As already observed for other plasticisers and their substitutes, the youngest children (3-5 years) had 2-2.5-fold higher urinary DEHTP metabolite levels compared to 14-17 years old adolescents. High urinary levels of DEHTP metabolites were associated with high DEHTP concentrations in house dust. None of the samples analysed exceeded the toxicologically derived German human biomonitoring guidance value (HBM-I-Value) of 1.8 mg/L for 5cx-MEPTP. Comparison with DEHTP levels reported in other HBM studies worldwide confirmed a widespread exposure of children, adolescents and adults, with considerably higher exposures (2.6-7 fold) reported in the United States. In GerES V, exposure data for 12 different phthalates and the phthalate substitute DINCH were generated as well. Together with the data for DEHTP presented in this manuscript, GerES V allows a current and comprehensive overview on the concurrent exposure of German children and adolescents to common plasticisers. Further evaluation of aggregate exposure characteristics shall support efforts to reduce chemical hazard burden from plasticisers in Germany and beyond. © 2020 The Author(s).