Kasper-Sonnenberg, Monika; Pälmke, Claudia; Wrobel, Sonja; Brüning, Thomas; Murawski, Aline; Apel, Petra; Weber, Till; Kolossa-Gehring, Marike; Koch, Holger M. Environ Int 195 (2025), 109-190, online: 12. Dezember 2024 The German Environmental Specimen Bank (ESB) annually archives 24-h urine samples since the early 1980s. In this study, we analyzed 420 of these samples from the years 2014 to 2022 for metabolites of 18 phthalates and two substitutes. We merged the new data with the data from previous measurement campaigns to a combined dataset of 1825 samples covering a 35-year period from 1988 to 2022 to investigate time trends, calculate daily intakes and perform an anti-androgenic mixture risk assessment. With the extended set of 41 biomarkers, we are now able to monitor the exposure to all EU-labelled reprotoxic phthalates. Most phthalate exposures continued to decrease since first measurements in the 80s, with biggest drops for DnBP (96.6 %) and DEHP (90.9 %). DiNP and DiDP, seen on the rise in earlier campaigns, now declined. Exposures to the newly included, reprotoxic phthalates were generally negligible. Regarding mixture risk, 5 % of the highly exposed still exceeded the Hazard Index (HI) of 1 in 2009. In the current measurement campaign only three individuals (0.7 %) exceeded the HI of 1 (with exceedances still driven by DEHP and DnBP).In 2022, 20 % of the individuals still had an HI > 0.2, which we propose as a benchmark for interpreting phthalate mixture risk, considering concurrent exposures to other anti-androgens. Exposure to the substitutes DINCH and DEHTP continues to increase, with daily intakes of DEHTP exceeding those of DEHP since 2018. Compared with the United States (US) National Health and Nutrition Examination Survey (NHANES) phthalate exposures seem to align, except for DEHTP with up to ten times higher levels in the US. Human biomonitoring (HBM) is the ideal tool to capture actual mixture exposures per individual, integrating all external exposure sources and pathways, thus we will continue to use HBM in exposure and risk assessment of phthalates and other (anti-androgenic) chemicals. doi: 10.1016/j.envint.2024.109190
Anzahl der Proben: 75 Gemessener Parameter: Mono(4-methyl-7-oxo-octyl)phthalat ist ein oxydierter Metabolit von DiNP mit funktioneller oxo-Gruppe. Probenart: 24h-Sammelurin Eine ideale Matrix für das Human-Biomonitoring, weil mit dem Urin Chemikalien und/oder deren Metabolite ausgeschiedenen werden, die zuvor in direktem Kontakt mit dem Organismus standen. Messungen im Urin können somit zuverlässige Aussagen über die interne Belastung des Menschen liefern. Probenahmegebiet: Münster Bedeutende Universitätsstadt sowie Dienstleistungs- und Verwaltungszentrum in Nordrhein-Westfalen.
Anzahl der Proben: 75 Gemessener Parameter: Mono(4-methyl-7-hydroxyoctyl)phthalat ist ein oxydierter Metabolit von DiNP mit funktioneller OH-Gruppe. Probenart: 24h-Sammelurin Eine ideale Matrix für das Human-Biomonitoring, weil mit dem Urin Chemikalien und/oder deren Metabolite ausgeschiedenen werden, die zuvor in direktem Kontakt mit dem Organismus standen. Messungen im Urin können somit zuverlässige Aussagen über die interne Belastung des Menschen liefern. Probenahmegebiet: Münster Bedeutende Universitätsstadt sowie Dienstleistungs- und Verwaltungszentrum in Nordrhein-Westfalen.
Anzahl der Proben: 48 Gemessener Parameter: Mono(4-methyl-7-carboxyheptyl)phthalat ist ein oxydierter Metabolit von DiNP mit funktioneller Carboxyl-Gruppe. Probenart: 24h-Sammelurin Eine ideale Matrix für das Human-Biomonitoring, weil mit dem Urin Chemikalien und/oder deren Metabolite ausgeschiedenen werden, die zuvor in direktem Kontakt mit dem Organismus standen. Messungen im Urin können somit zuverlässige Aussagen über die interne Belastung des Menschen liefern. Probenahmegebiet: Münster Bedeutende Universitätsstadt sowie Dienstleistungs- und Verwaltungszentrum in Nordrhein-Westfalen.
Over the last twenty-five years it has become evident that exposure to several phthalates can have adverse effects on human health, such as endocrine disruption. This led to a series of EU regulations that resulted in a decrease in the production volumes of the restricted phthalates and an increased production of substitutes. The current study describes the impact of regulations and changes in production and use of phthalates and their substitutes on internal exposure patterns in two European populations since the beginning of the 2000'ies. Using harmonised data from young adults in Denmark (Danish Young Men Study, n = 1,063, spot urine) and Germany (Environmental Specimen Bank, n = 878, 24-h urine) with repeated cross-sectional design (3-11 cycles per biomarker) we applied Locally Estimated Scatterplot Smoothing (LOESS) and Generalized Linear Models (GLMs) to estimate time trends and the role of covariates on the trend (e.g. age, BMI). Time trends of daily excretion (mikrog/24h) are comparable between the two samples for the regulated (DEHP, BBzP, DiNP, DnBP, DiBP, DiDP/DPHP) as well as the non-regulated substances (DMP, DEP, DINCH, DEHTP) although the rate of change differ for some of the compounds. GLM results indicate that the daily excretion of the most regulated phthalates has decreased over time (DEHP yearly about 12-16%, BBzP 5%, DnBP 0.3-17%, and DiBP 4-12%). Interestingly, also the non-regulated phthalates DMP and DEP decreased by 6-18% per year. In sharp contrast, the phthalate substitutes DINCH and DEHTP show very steep annual increases (~10-68% and ~100%, respectively) between 2009 and 2017. We did not find an effect of age, sex, BMI, or education on the time trend. The present study provides comparable insights into how exposure to phthalates and two of their substitutes have changed over the last two decades in Germany and Denmark. © 2022 The Authors
Phthalates are mainly used as plasticizers for polyvinyl chloride (PVC). Exposure to several phthalates is associated with different adverse effects most prominently on the development of reproductive functions. The HBM4EU Aligned Studies (2014-2021) have investigated current European exposure to ten phthalates (DEP, BBzP, DiBP, DnBP, DCHP, DnPeP, DEHP, DiNP, DiDP, DnOP) and the substitute DINCH to answer the open policy relevant questions which were defined by HBM4EU partner countries and EU institutions as the starting point of the programme. The exposure dataset includes ~5,600 children (6-11 years) and adolescents (12-18 years) from up to 12 countries per age group and covering the North, East, South and West European regions. Study data from participating studies were harmonised with respect to sample size and selection of participants, selection of biomarkers, and quality and comparability of analytical results to provide a comparable perspective of European exposure. Phthalate and DINCH exposure were deduced from urinary excretions of metabolites, where concentrations were expressed as their key descriptor geometric mean (GM) and 95th percentile (P95). This study aims at reporting current exposure levels and differences in these between European studies and regions, as well as comparisons to human biomonitoring guidance values (HBM-GVs). GMs for children were highest for total-DEHP metabolites (33.6 mikrog/L), MiBP (26.6 mikrog/L), and MEP (24.4 mikrog/L) and lowest for total-DiDP metabolites (1.91 mikrog/L) and total-DINCH metabolites (3.57 mikrog/L). In adolescents highest GMs were found for MEP (43.3 mikrog/L), total-DEHP metabolites (28.8 mikrog/L), and MiBP (25.6 mikrog/L) and lowest for total-DiDP metabolites (= 2.02 mikrog/L) and total-DINCH metabolites (2.51 mikrog/L). In addition, GMs and P95 stratified by European region, sex, household education level, and degree of urbanization are presented. Differences in average biomarker concentrations between sampling sites (data collections) ranged from factor 2 to 9. Compared to the European average, children in the sampling sites OCC (Denmark), InAirQ (Hungary), and SPECIMEn (The Netherlands) had the lowest concentrations across all metabolites and ESTEBAN (France), NAC II (Italy), and CROME (Greece) the highest. For adolescents, comparably higher metabolite concentrations were found in NEB II (Norway), PCB cohort (Slovakia), and ESTEBAN (France), and lower concentrations in POLAES (Poland), FLEHS IV (Belgium), and GerES V-sub (Germany). Multivariate analyses (Survey Generalized Linear Models) indicate compound-specific differences in average metabolite concentrations between the four European regions. Comparison of individual levels with HBM-GVs revealed highest rates of exceedances for DnBP and DiBP, with up to 3 and 5%, respectively, in children and adolescents. No exceedances were observed for DEP and DINCH. With our results we provide current, detailed, and comparable data on exposure to phthalates in children and - for the first time - in adolescents, and - for the first time - on DINCH in children and adolescents of all four regions of Europe which are particularly suited to inform exposure and risk assessment and answer open policy relevant questions. © 2023 The Authors.
Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe - as comparably as possible - the EU-wide general population's internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies. © 2023 by the authors
Vogel, Nina; Lange, Rosa; Schmidt, Phillipp; Rodriguez Martin, Laura; Remy, Sylvie; Springer, Andrea; Puklová, Vladimíra; Černá, Milena; Rudnai, Péter; Középesy, Szilvia; Janasik, Beata; Ligocka, Danuta; Fábelová, Lucia; Kolena, Branislav; Petrovicova, Ida; Jajcaj, Michal; Eštóková, Milada; Esteban-Lopez, Marta; Castaño, Argelia; Tratnik, Janja Snoj; Stajnko, Anja; Knudsen, Lisbeth E.; Toppari, Jorma; Main, Katharina M.; Juul, Anders; Andersson, Anna-Maria; Jørgensen, Niels; Frederiksen, Hanne; Thomsen, Cathrine; Sakhi, Amrit Kaur; Åkesson, Agneta; Hartmann, Christina; Dewolf, Marie Christine; Koppen, Gudrun; Biot, Pierre; Den Hond, Elly; Voorspoels, Stefan; Gilles, Liese; Govarts, Eva; Murawski, Aline; Gerofke, Antje; Weber, Till; Rüther, Maria; Gutleb, Arno C.; Guignard, Cedric; Berman, Tamar; Koch, Holger M.; Kolossa-Gehring, Marike Toxics 11 (2023), 241; online: 4 März 2023 Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe—as comparably as possible—the EU-wide general population’s internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.
Vogel, Nina; Frederiksen, Hanne; Lange, Rosa; Jorgensen, Niels; Koch, Holger M.; Weber, Till; Andersson, Anna-Maria; Kolossa-Gehring, Marike Int J Hyg Environ Health 248 (2023), 114080; online: 17 Januar 2023 Over the last twenty-five years it has become evident that exposure to several phthalates can have adverse effects on human health, such as endocrine disruption. This led to a series of EU regulations that resulted in a decrease in the production volumes of the restricted phthalates and an increased production of substitutes. The current study describes the impact of regulations and changes in production and use of phthalates and their substitutes on internal exposure patterns in two European populations since the beginning of the 2000'ies. Using harmonised data from young adults in Denmark (Danish Young Men Study, n = 1,063, spot urine) and Germany (Environmental Specimen Bank, n = 878, 24-h urine) with repeated cross-sectional design (3-11 cycles per biomarker) we applied Locally Estimated Scatterplot Smoothing (LOESS) and Generalized Linear Models (GLMs) to estimate time trends and the role of covariates on the trend (e.g. age, BMI). Time trends of daily excretion (mug/24h) are comparable between the two samples for the regulated (DEHP, BBzP, DiNP, DnBP, DiBP, DiDP/DPHP) as well as the non-regulated substances (DMP, DEP, DINCH, DEHTP) although the rate of change differ for some of the compounds. GLM results indicate that the daily excretion of the most regulated phthalates has decreased over time (DEHP yearly about 12-16%, BBzP 5%, DnBP 0.3-17%, and DiBP 4-12%). Interestingly, also the non-regulated phthalates DMP and DEP decreased by 6-18% per year. In sharp contrast, the phthalate substitutes DINCH and DEHTP show very steep annual increases ( approximately 10-68% and approximately 100%, respectively) between 2009 and 2017. We did not find an effect of age, sex, BMI, or education on the time trend. The present study provides comparable insights into how exposure to phthalates and two of their substitutes have changed over the last two decades in Germany and Denmark. doi: 10.1016/j.ijheh.2022.114080
Die Weichmacher können aus Plastik austreten und können in Humanproben nachgewiesen werden Unternehmen setzen Phthalate vor allem als Weichmacher in PVC ein. Die chemische Industrie in Europa produziert jährlich etwa eine Million Tonnen Phthalate. Über 90 Prozent davon gehen in die Weich-PVC Herstellung. Als Weichmacher bilden Phthalate keine festen Bindungen mit dem PVC, so kann ein Teil der Phthalate aus den Produkten, wie beispielsweise Fussböden, Tapeten oder Verpackungsmaterial, entweichen. Das Human-Biomonitoring verschiedener Länder hat gezeigt, dass die Bevölkerung industrialisierter Länder durchgehend mit Phthalaten belastet ist. In zwei retrospektiven Untersuchungen der Umweltprobenbank wurden in nahezu sämtlichen Urinproben Phthalate nachgewiesen. Dies weist auf eine ubiquitäre Belastung der deutschen Bevölkerung hin. Unter REACH sind ca. 600 Phthalate vorregistriert worden; die sechs am häufigsten verwendeten Verbindungen sind DiDP (Diisodecylphthalat), DiNP ( Diisononylphthalat ), DEHP ( Diethylhexylphthalat ), DnBP ( Di-n-butylphthalat ), DiBP ( Diisobutylphthalat ) und BBzP ( Butylbenzylphthalat ). 2011 hat die EU entschieden, dass DEHP, DnBP und BBzP zu den ersten Chemikalien gehören, deren Anwendung durch REACH umfassend geregelt wird: Der Verkauf und die Verwendung dieser Chemikalien war somit ab dem 1.1.2015 verboten. Ausnahmen gibt es nur, wenn die EU Kommission einem Unternehmen eine eigene Zulassung für die Verwendung der Phthalate erteilt. Dafür müsste das Unternehmen darlegen, dass mögliche Risiken durch entsprechende Maßnahmen adäquat begrenzt werden können oder dass der sozioökonomische Nutzen der Verwendung dieser Chemikalien die möglichen Risiken für Mensch und Umwelt überwiegt. Bereits 2005 hatten die Mitgliedsstaaten der Europäischen Union DEHP, DnBP, DiBP und BBzP als reproduktionstoxische Stoffe eingestuft. Seitdem ist die Verwendung dieser Chemikalien in Kinderspielzeug, Babyartikeln und Kosmetika verboten. Der Gebrauch dreier weiterer Phthalate - DiNP, DnOP (Di-n-octylphthalat) und DiDP - in Kleinspielzeug sowie Babyartikeln, die Kinder in den Mund nehmen können, wurde ebenfalls untersagt. Für diese Phthalate gibt es bereits seit 1999 ein Verbot entsprechender Verwendungen. Um die Belastung des Menschen zu erfassen und die Wirksamkeit der regulatorischen Maßnahmen zu überprüfen, wurden in drei retrospektiven Studien fast 1200 archivierte 24-h-Sammelurinproben der Umweltprobenbank auf Primär- und Sekundärmetabolite der Phthalate DMP (Dimethylphthalat), DEP (Diethylphthalat), BBzP, DiBP, DnBP, DCHP (Dicyclohexylphthalat), DnPeP (Di-n-pentylphthalat), DEHP, DiNP, DiDP, DPHP (Di-propyl-heptylphthalat) und DnOPuntersucht. Studierende der Universität Münster im Alter von 20 bis 29 Jahren spendeten die Proben zwischen 1998 und 2015. Die erste Messreihe umfasst die Probenahmejahre 1988, 1989, 1991, 1993, 1996, 1998, 1999, 2001 und 2003. Die zweite Messreihe umfasst überlappend die Probenahmejahre 2002, 2004, 2006 und 2008; die dritte Messreihe die Jahre 2007, 2009, 2011, 2013 und 2015. In nahezu sämtlichen Urinproben wurden die Metabolite der meisten Phthalate nachgewiesen. Dies weist auf eine ubiquitäre Belastung der deutschen Bevölkerung hin. Diese Ergebnisse stimmen gut mit den Untersuchungen in anderen Industrieländern überein. Die Untersuchungen zeigen, dass die Phthalat-Belastung junger Erwachsener in Deutschland in den letzten zwanzig Jahren gesunken ist. Mitte der 1990er Jahre erreichten die Messwerte für DEHP, BBzP und DnBP ihr Maximum, anschließend sanken die Belastungen. Im Gegensatz dazu stieg die Belastung mit DiNP, das auch als Ersatzstoff für DEHP eingesetzt wird, an. Die Konzentration von DiBP sank erst während der letzten Messreihe. Alle Daten zur Ergebnisbeschreibung anzeigen In den 1980er Jahren begann die Diskussion um die Risiken der Verwendung des Weichmachers DEHP in Plastik. Wie der an Umweltprobenbank-Proben gemessene Zeittrend zeigt, stieg die Belastung der weiblichen und männlichen Probanden mit DEHP in dieser Zeit noch an. Erst Mitte der 1990er Jahre, als die Debatte um die sichere Verwendung von DEHP die breite Öffentlichkeit erreichte, endete der Anstieg der Belastung. 1997 verlangten Dänemark und Spanien von der EU Kommission eine vorsorgliche Anwendungsbeschränkung. Die EU Kommission entschied sich wenig später für die zunächst temporäre, dann unbefristete Beschränkungsregelung zum Schutz der Kinder vor DEHP. Der Zeittrend der Umweltprobenbank deutet an, dass die chemischen Unternehmen die Verwendung von DEHP neu bewertet haben, als sich die Pläne der Kommission zur Anwendungsbeschränkung abzeichneten: Die Konzentration der DEHP Metabolite in den 24-h-Sammelurin Proben begann ab 1997 kontinuierlich zu sinken. Da die Proben von jungen Erwachsenen stammen, zeigt sich deutlich, dass die Veränderung des Marktes für Weichmacher offensichtlich nicht nur Kinderspielzeug betraf, sondern vor allem auch Produkte, die zu einer Phthalat-Belastung von Lebensmitteln führen. Dies ist von besonderer Bedeutung, da die Phthalat-Belastung des Menschen in erster Linie aus kontaminierten Lebensmitteln stammt. 2008 war die Konzentration der DEHP Metabolite in den Proben junger Erwachsener aus der UPB auf die Hälfte bis ein Drittel der Messwerte der späten 1980er Jahre gesunken. Dennoch überschreiten immernoch 1% der Proben den BE Richtwert (biomonitoring equivalents). Vor diesem Hintergrund dokumentieren die Zeittrends eine positive Entwicklung, zeigen aber auch, dass die toxikologisch bedenklichen Phthalate immer noch so breit eingesetzt werden, dass weitere Regulierungsschritte sinnvoll erscheinen. Durch den aufgezeigten abnehmenden Trend der Phthalatexposition ist es von hoher Priorität, die Exposition gegenüber alternativen Weichmachern, wie beispielsweise Hexamoll DINCH, zu untersuchen. Aktualisiert am: 12.01.2022 Datenrecherche Datenrecherche Datenrecherche Datenrecherche
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