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The European Human Biomonitoring Initiative (HBM4EU) is coordinating and advancing human biomonitoring (HBM). For this purpose, a network of laboratories delivering reliable analytical data on human exposure is fundamental. The analytical comparability and accuracy of laboratories analysing flame retardants (FRs) in serum and urine were investigated by a quality assurance/quality control (QA/QC) scheme comprising interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds performed from 2018 to 2020 for the determination of ten halogenated flame retardants (HFRs) represented by three congeners of polybrominated diphenyl ethers (BDE-47, BDE-153 and BDE-209), two isomers of hexabromocyclododecane (α-HBCD and γ-HBCD), two dechloranes (anti-DP and syn-DP), tetrabromobisphenol A (TBBPA), decabromodiphenylethane (DBDPE), and 2,4,6-tribromophenol (2,4,6-TBP) in serum, and four metabolites of organophosphorus flame retardants (OPFRs) in urine, at two concentration levels. The number of satisfactory results reported by laboratories increased during the four rounds. In the case of HFRs, the scope of the participating laboratories varied substantially (from two to ten) and in most cases did not cover the entire target spectrum of chemicals. The highest participation rate was reached for BDE-47 and BDE-153. The majority of participants achieved more than 70% satisfactory results for these two compounds over all rounds. For other HFRs, the percentage of successful laboratories varied from 44 to 100%. The evaluation of TBBPA, DBDPE, and 2,4,6-TBP was not possible because the number of participating laboratories was too small. Only seven laboratories participated in the ICI/EQUAS scheme for OPFR metabolites and five of them were successful for at least two biomarkers. Nevertheless, the evaluation of laboratory performance using Z-scores in the first three rounds required an alternative approach compared to HFRs because of the small number of participants and the high variability of experts' results. The obtained results within the ICI/EQUAS programme showed a significant core network of comparable European laboratories for HBM of BDE-47, BDE-153, BDE-209, α-HBCD, γ-HBCD, anti-DP, and syn-DP. On the other hand, the data revealed a critically low analytical capacity in Europe for HBM of TBBPA, DBDPE, and 2,4,6-TBP as well as for the OPFR biomarkers.
Darina Dvorakova; Jana Pulkrabova; Tomas Gramblicka; Andrea Polachova; Martina Buresova; Marta Esteban López; Argelia Castaño; Stefanie Nübler; Karin Haji-Abbas-Zarrabi; Nadine Klausner; Thomas Göen; Hans Mol; Holger M. Koch; Vincent Vaccher; Jean-Philippe Antignac; Line Småstuen Haug; Katrin Vorkamp; Jana Hajslova. Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project. Environmental Research 2021, 202, 111705 .
AMA StyleDarina Dvorakova, Jana Pulkrabova, Tomas Gramblicka, Andrea Polachova, Martina Buresova, Marta Esteban López, Argelia Castaño, Stefanie Nübler, Karin Haji-Abbas-Zarrabi, Nadine Klausner, Thomas Göen, Hans Mol, Holger M. Koch, Vincent Vaccher, Jean-Philippe Antignac, Line Småstuen Haug, Katrin Vorkamp, Jana Hajslova. Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project. Environmental Research. 2021; 202 ():111705.
Chicago/Turabian StyleDarina Dvorakova; Jana Pulkrabova; Tomas Gramblicka; Andrea Polachova; Martina Buresova; Marta Esteban López; Argelia Castaño; Stefanie Nübler; Karin Haji-Abbas-Zarrabi; Nadine Klausner; Thomas Göen; Hans Mol; Holger M. Koch; Vincent Vaccher; Jean-Philippe Antignac; Line Småstuen Haug; Katrin Vorkamp; Jana Hajslova. 2021. "Interlaboratory comparison investigations (ICIs) and external quality assurance schemes (EQUASs) for flame retardant analysis in biological matrices: Results from the HBM4EU project." Environmental Research 202, no. : 111705.
Homosalate (HMS) is an organic UV filter used in sunscreens and personal care products worldwide. It has been detected in various environmental matrices and in humans after application of HMS-containing products. However, sufficient data on the internal HMS exposure in humans is currently not available. Thus, we aimed at providing an analytical method for the sensitive determination of specific HMS metabolites in human urine. We describe the synthesis of analytical standards for the four oxidative HMS metabolites included in this method: 5-((2-hydroxybenzoyl)oxy)-3,3-dimethylcyclohexane-1-carboxylic acid (HMS-CA) and 3-hydroxy-3,5,5-trimethylcyclohexyl 2-hydroxybenzoate (3OH-HMS), as cis- and trans-isomers, respectively. After enzymatic hydrolysis, urine samples were analyzed using liquid chromatography-electrospray ionization-triple quadrupole-tandem mass spectrometry, including turbulent flow chromatography for online sample cleanup and analyte enrichment (online-SPE-LC-MS/MS). Quantification was performed by stable isotope dilution analysis, using deuterium-labeled HMS-CA as internal standards (cis and trans). Limits of quantification of 0.02–0.04 μg L−1 were sufficiently low to quantify the HMS metabolites for up to 96 h (trans-HMS-CA), 48 h (cis-HMS-CA and 3OH-trans-HMS), and 24 h (3OH-cis-HMS) after a pilot dermal application of a commercially available sunscreen in one human volunteer, showing clear elimination kinetics. Furthermore, in a German pilot population (n = 35), HMS metabolites were above the LOQ precisely in those three individuals who had applied sunscreen within the previous five days, thus corroborating the specificity of the identified metabolites as biomarkers of HMS exposure. The method is currently used in a human metabolism study and will be applied in future population-scale human biomonitoring studies.
Katharina E. Ebert; Vladimir N. Belov; Tobias Weiss; Thomas Brüning; Heiko Hayen; Holger M. Koch; Daniel Bury. Determination of Urinary Metabolites of the UV Filter Homosalate by Online-SPE-LC-MS/MS. Analytica Chimica Acta 2021, 1176, 338754 .
AMA StyleKatharina E. Ebert, Vladimir N. Belov, Tobias Weiss, Thomas Brüning, Heiko Hayen, Holger M. Koch, Daniel Bury. Determination of Urinary Metabolites of the UV Filter Homosalate by Online-SPE-LC-MS/MS. Analytica Chimica Acta. 2021; 1176 ():338754.
Chicago/Turabian StyleKatharina E. Ebert; Vladimir N. Belov; Tobias Weiss; Thomas Brüning; Heiko Hayen; Holger M. Koch; Daniel Bury. 2021. "Determination of Urinary Metabolites of the UV Filter Homosalate by Online-SPE-LC-MS/MS." Analytica Chimica Acta 1176, no. : 338754.
The population is constantly exposed to potentially harmful substances present in the environment, including inter alia food and drinking water, consumer products, and indoor air. Human biomonitoring (HBM) is a valuable tool to determine the integral, internal exposure of the general population, including vulnerable subgroups, to provide the basis for risk assessment and policy advice. The German HBM system comprises of five pillars: (1) the development of suitable analytical methods for new substances of concern, (2) cross-sectional population-representative German Environmental Surveys (GerES), (3) time trend analyses using archived samples from the Environmental Specimen Bank (ESB), (4) the derivation of health-based guidance values as a risk assessment tool, and (5) transfer of data into the European cooperation network HBM4EU. The goal of this paper is to present the complementary elements of the German HBM system and to show its strengths and limitations on the example of plasticizers. Plasticizers have been identified by EU services and HBM4EU partners as priority substances for chemical policy at EU level. Using the complementary elements of the German HBM system, the internal exposure to classical phthalates and novel alternative plasticizers can be reliably monitored. It is shown that market changes, due to regulation of certain phthalates and the rise of substitutes, are rapidly reflected in the internal exposure of the population. It was shown that exposure to DEHP, DiBP, DnBP, and BBzP decreased considerably, whereas exposure to the novel substitutes such as DPHP, DEHTP, and Hexamoll®DINCH has increased significantly. While health-based guidance values for several phthalates (esp. DnBP, DiBP, DEHP) were exceeded quite often at the turn of the millennium, exceedances today have become rarer. Still, also the latest GerES reveals the ubiquitous and concurrent exposures to many plasticizers. Of concern is that the youngest children showed the highest exposures to most of the investigated plasticizers and in some cases their levels of DiBP and DnBP still exceeded health-based guidance values. Over the last years, mixture exposures are increasingly recognized as relevant, especially if the toxicological modes of action are similar. This is supported by a cumulative risk assessment for four endocrine active phthalates which confirms the still concerning cumulative exposure in many young children. Given the adverse health effects of some phthalates and the limited toxicological knowledge of substitutes, exposure reduction and surveillance are needed on German and EU-level. Substitutes need to be monitored, to intervene if exposures are threatening to exceed acceptable levels, or if new toxicological data question their appropriateness. It is strongly recommended to reconsider the use of plastics and plasticizers.
Nora Lemke; Aline Murawski; Rosa Lange; Till Weber; Petra Apel; Małgorzata Dębiak; Holger M. Koch; Marike Kolossa-Gehring. Substitutes mimic the exposure behaviour of REACH regulated phthalates – A review of the German HBM system on the example of plasticizers. International Journal of Hygiene and Environmental Health 2021, 236, 113780 .
AMA StyleNora Lemke, Aline Murawski, Rosa Lange, Till Weber, Petra Apel, Małgorzata Dębiak, Holger M. Koch, Marike Kolossa-Gehring. Substitutes mimic the exposure behaviour of REACH regulated phthalates – A review of the German HBM system on the example of plasticizers. International Journal of Hygiene and Environmental Health. 2021; 236 ():113780.
Chicago/Turabian StyleNora Lemke; Aline Murawski; Rosa Lange; Till Weber; Petra Apel; Małgorzata Dębiak; Holger M. Koch; Marike Kolossa-Gehring. 2021. "Substitutes mimic the exposure behaviour of REACH regulated phthalates – A review of the German HBM system on the example of plasticizers." International Journal of Hygiene and Environmental Health 236, no. : 113780.
Nonylphenol (NP) is an endocrine disrupting and ecotoxic substance that has been detected in a variety of environmental matrices. It is utilized for the production of non-ionic nonylphenol ethoxylate (NPEO) detergents and other high production volume chemicals. Human biomonitoring data are scarce and mostly limited to the non-oxidized NP, which is ubiquitous in the (laboratory) environment and susceptible to external contamination. Here, we describe a sensitive, precise, accurate and rugged analytical method for the determination of OH-NP and oxo-NP, two potential alkyl-chain-oxidized metabolites of NP in human urine. We used single isomer standards, obtained by custom synthesis, for the quantification of the sum of the respective isomers. After enzymatic hydrolysis of potential urinary phase II conjugates, urine samples were analyzed by online turbulent flow chromatography for analyte enrichment and matrix depletion coupled to reversed phase liquid chromatography with negative electrospray-ionization triple quadrupole tandem mass spectrometry detection (online-SPE-LC-MS/MS). Quantification was performed by stable isotope dilution analysis. Limits of quantification in urinary matrix were 0.5 µg/L for OH-NP and 0.25 µg/L for oxo-NP. Mean relative recoveries were 101–105% (OH-NP) and 112–117% (oxo-NP) and the method imprecision (CV) in matrix was below 5%. In spite of extensive use restrictions in the EU since 2003, we could quantify OH-NP and oxo-NP in 94% and 47% of spot urine samples from the general German population (n = 32) collected in 2014. Thus, both metabolites seem suitable as sensitive and specific urinary biomarkers of NP exposure for future human biomonitoring population studies. Currently this method is used to quantitatively investigate human NP metabolism and to derive urinary metabolite excretion fractions that can be used to calculate external doses based on urinary biomarker concentrations.
Benedikt Ringbeck; Daniel Bury; Heiko Hayen; Tobias Weiss; Thomas Brüning; Holger M. Koch. Determination of specific urinary nonylphenol metabolites by online-SPE-LC-MS/MS as novel human exposure biomarkers. Journal of Chromatography B 2021, 1177, 122794 .
AMA StyleBenedikt Ringbeck, Daniel Bury, Heiko Hayen, Tobias Weiss, Thomas Brüning, Holger M. Koch. Determination of specific urinary nonylphenol metabolites by online-SPE-LC-MS/MS as novel human exposure biomarkers. Journal of Chromatography B. 2021; 1177 ():122794.
Chicago/Turabian StyleBenedikt Ringbeck; Daniel Bury; Heiko Hayen; Tobias Weiss; Thomas Brüning; Holger M. Koch. 2021. "Determination of specific urinary nonylphenol metabolites by online-SPE-LC-MS/MS as novel human exposure biomarkers." Journal of Chromatography B 1177, no. : 122794.
Human biomonitoring (HBM) of cadmium is essential to assess and prevent toxic exposure. Generally, low cadmium levels in urine and blood of the general population place particularly high demands on quality assurance and control measures (QA/QC) for cadmium determination. One of the aims of the HBM4EU project is to harmonize and advance HBM in Europe. Cadmium is one of the chemicals selected as a priority substance for HBM implementation in the 30 European countries under HBM4EU. For this purpose, analytical comparability and accuracy of the analytical laboratories of participating countries was investigated in a QA/QC programme comprising interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS). This paper presents the evaluation process and discusses the results of four ICI/EQUAS rounds for the determination of cadmium in urine and blood. The majority of the 43 participating laboratories achieved satisfactory results, although low limits of quantification were required to quantify Cd concentrations at general population exposure levels. The relative standard deviation of the participants’ results obtained from all ICI and EQUAS runs ranged from 8 to 36% for cadmium in urine and 8–28% for cadmium in blood. Applying inductively-coupled plasma mass spectrometry (ICP-MS), using an internal standard, and eliminating molybdenum oxide interferences was favourable for the accurate determination of cadmium in urine and blood. Furthermore, the analysis of cadmium in urine was found to have a critical point at approximately 0.05 μg/l, below which variability increased and laboratory proficiency decreased. This QA/QC programme succeeded in establishing a network of laboratories with high analytical comparability and accuracy for the analysis of cadmium across 20 European countries.
Stefanie Nübler; Marta Esteban López; Argelia Castaño; Hans Mol; Moritz Schäfer; Karin Haji-Abbas-Zarrabi; Daniel Bury; Holger M. Koch; Vincent Vaccher; Jean-Philippe Antignac; Darina Dvorakova; Jana Hajslova; Cathrine Thomsen; Katrin Vorkamp; Thomas Göen. Interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for cadmium in urine and blood: Results from the HBM4EU project. International Journal of Hygiene and Environmental Health 2021, 234, 113711 .
AMA StyleStefanie Nübler, Marta Esteban López, Argelia Castaño, Hans Mol, Moritz Schäfer, Karin Haji-Abbas-Zarrabi, Daniel Bury, Holger M. Koch, Vincent Vaccher, Jean-Philippe Antignac, Darina Dvorakova, Jana Hajslova, Cathrine Thomsen, Katrin Vorkamp, Thomas Göen. Interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for cadmium in urine and blood: Results from the HBM4EU project. International Journal of Hygiene and Environmental Health. 2021; 234 ():113711.
Chicago/Turabian StyleStefanie Nübler; Marta Esteban López; Argelia Castaño; Hans Mol; Moritz Schäfer; Karin Haji-Abbas-Zarrabi; Daniel Bury; Holger M. Koch; Vincent Vaccher; Jean-Philippe Antignac; Darina Dvorakova; Jana Hajslova; Cathrine Thomsen; Katrin Vorkamp; Thomas Göen. 2021. "Interlaboratory comparison investigations (ICI) and external quality assurance schemes (EQUAS) for cadmium in urine and blood: Results from the HBM4EU project." International Journal of Hygiene and Environmental Health 234, no. : 113711.
Di-n-butyl adipate (DnBA) is used as a plasticizer and in various consumer products (e.g. personal care products) replacing, in part, the endocrine disruptor di-n-butyl phthalate (DnBP). We provide quantitative in vivo data on human DnBA metabolism and excretion after oral dose (105−185 μg/kg bw) and dermal application to three volunteers each as a tool for exposure and risk assessment. Complete and consecutive urine samples were collected for two (oral) and four days (dermal), respectively, and analyzed for the metabolites mono-n-butyl adipate (MnBA), 3- and tentative 4-hydroxy-mono-n-butyl adipate (3OH-MnBA, 4OH-MnBA), and 3-carboxy-mono-n-propyl adipate (3cx-MnPrA), as well as the hydrolysis product adipic acid (AA) using stable isotope dilution quantification. Metabolites were excreted within 24 h after oral dose with one or two concentration maxima at 0.8–3.0 h (n = 3) and 4.8−6.3 h (n = 2). AA was the major but unspecific metabolite with urinary excretion fractions (FUEs) of 14−26 %. Mean FUEs (range) of 3cx-MnPrA, MnBA, 3OH-MnBA, and tentative 4OH-MnBA were low, but consistent between volunteers (0.47 % (0.35−0.63 %), 0.079 % (0.065−0.091 %), 0.012 % (0.006−0.016 %), and 0.005 % (0.002−0.009 %), respectively). MnBA and 3OH-MnBA seem to be suitable, specific exposure biomarkers for DnBA, whereas 3cx-MnPrA and 4OH-MnBA seem to originate also from other, unknown sources not related to DnBA. Compared to the oral study, metabolite excretion in the dermal study was delayed and MnBA excretion was somewhat higher compared to the oxidized metabolites. Based on urinary concentrations and the above excretion fractions, calculated uptakes in the dermal study did not exceed the adipate ester ADI of 5 mg/(kg bw*day).
Benedikt Ringbeck; Daniel Bury; Alexandra Gotthardt; Heiko Hayen; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. Human metabolism and urinary excretion kinetics of di-n-butyl adipate (DnBA) after oral and dermal administration in three volunteers. Toxicology Letters 2021, 343, 11 -20.
AMA StyleBenedikt Ringbeck, Daniel Bury, Alexandra Gotthardt, Heiko Hayen, Rainer Otter, Tobias Weiss, Thomas Brüning, Holger M. Koch. Human metabolism and urinary excretion kinetics of di-n-butyl adipate (DnBA) after oral and dermal administration in three volunteers. Toxicology Letters. 2021; 343 ():11-20.
Chicago/Turabian StyleBenedikt Ringbeck; Daniel Bury; Alexandra Gotthardt; Heiko Hayen; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. 2021. "Human metabolism and urinary excretion kinetics of di-n-butyl adipate (DnBA) after oral and dermal administration in three volunteers." Toxicology Letters 343, no. : 11-20.
Diisononyl adipate (DINA) is a plasticizer used in PVC products as an alternative for restricted phthalate plasticizers. With this study, we provide first data on human DINA metabolism and excretion. We postulated mono(hydroxy-isononyl) adipate (OH-MINA), mono(oxo-isononyl) adipate (oxo-MINA), and mono(carboxy-isooctyl) adipate (cx-MIOA) as specific DINA metabolites based on the known human metabolism of structurally similar adipates and phthalates. Urinary excretion was quantitatively investigated after a single oral dose (113 to 145 µg/kg body weight) to three healthy volunteers using a newly developed online-SPE-LC-MS/MS method with isotope dilution and LOQs between 0.3 - 0.6 µg/L. OH-MINA turned out to be the major of the three metabolites with consistent urinary excretion fractions (FUEs) of 0.020-0.023 % among all volunteers. Oxo-MINA and cx-MIOA were excreted with lower shares (mean: 0.003 % and 0.009 %, respectively). For all three metabolites, urinary concentrations peaked quickly between 1.4 and 2.3 h post dose with maximum concentrations of 23.1 (OH-MINA), 2.87 (oxo-MINA) and 9.83 µg/L (cx-MIOA). Thus, FUEs and urinary concentrations were rather low for these specific metabolites, with the major share of the dose presumably being excreted as non-specific metabolites such as adipic acid. In a pilot population (n=35) of German adults without known DINA exposure, we could not detect any of the three metabolites, contrary to the dosage study, indicating to population exposures lower than 50 µg/kg body weight/day. The new HBM method in conjunction with the new FUEs can be used for objective DINA exposure and risk assessment especially in populations with potentially higher DINA exposures.
Alexandra Gotthardt; Daniel Bury; Hans-Willi Kling; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. Quantitative investigation of the urinary excretion of three specific monoester metabolites of the plasticizer diisononyl adipate (DINA). 2021, 20, 412 -425.
AMA StyleAlexandra Gotthardt, Daniel Bury, Hans-Willi Kling, Rainer Otter, Tobias Weiss, Thomas Brüning, Holger M. Koch. Quantitative investigation of the urinary excretion of three specific monoester metabolites of the plasticizer diisononyl adipate (DINA). . 2021; 20 ():412-425.
Chicago/Turabian StyleAlexandra Gotthardt; Daniel Bury; Hans-Willi Kling; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. 2021. "Quantitative investigation of the urinary excretion of three specific monoester metabolites of the plasticizer diisononyl adipate (DINA)." 20, no. : 412-425.
Heiko U. Käfferlein; Holger M. Koch; Daniel Bury; Sonja A. Wrobel; Hans-Detlev Gilsing; Maria Ospina; Samuel E. Baker. Comment on “Urinary Metabolites of Neonicotinoid Insecticides: Levels and Recommendations for Future Biomonitoring Studies in China”: Quantification of 5-Hydroxyimidacloprid and Biomonitoring. Environmental Science & Technology 2021, 55, 2163 -2164.
AMA StyleHeiko U. Käfferlein, Holger M. Koch, Daniel Bury, Sonja A. Wrobel, Hans-Detlev Gilsing, Maria Ospina, Samuel E. Baker. Comment on “Urinary Metabolites of Neonicotinoid Insecticides: Levels and Recommendations for Future Biomonitoring Studies in China”: Quantification of 5-Hydroxyimidacloprid and Biomonitoring. Environmental Science & Technology. 2021; 55 (3):2163-2164.
Chicago/Turabian StyleHeiko U. Käfferlein; Holger M. Koch; Daniel Bury; Sonja A. Wrobel; Hans-Detlev Gilsing; Maria Ospina; Samuel E. Baker. 2021. "Comment on “Urinary Metabolites of Neonicotinoid Insecticides: Levels and Recommendations for Future Biomonitoring Studies in China”: Quantification of 5-Hydroxyimidacloprid and Biomonitoring." Environmental Science & Technology 55, no. 3: 2163-2164.
The major purpose of human biomonitoring is the mapping and assessment of human exposure to chemicals. The European initiative HBM4EU has prioritized seven substance groups and two metals relevant for human exposure: Phthalates and substitutes (1,2-cyclohexane dicarboxylic acid diisononyl ester, DINCH), bisphenols, per- and polyfluoroalkyl substances (PFASs), halogenated and organophosphorous flame retardants (HFRs and OPFRs), polycyclic aromatic hydrocarbons (PAHs), arylamines, cadmium and chromium. As a first step towards comparable European-wide data, the most suitable biomarkers, human matrices and analytical methods for each substance group or metal were selected from the scientific literature, based on a set of selection criteria. The biomarkers included parent compounds of PFASs and HFRs in serum, of bisphenols and arylamines in urine, metabolites of phthalates, DINCH, OPFRs and PAHs in urine as well as metals in blood and urine, with a preference to measure Cr in erythrocytes representing Cr (VI) exposure. High performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was the method of choice for bisphenols, PFASs, the HFR hexabromocyclododecane (HBCDD), phenolic HFRs as well as the metabolites of phthalates, DINCH, OPFRs and PAHs in urine. Gas chromatographic (GC) methods were selected for the remaining compounds, e.g. GC-low resolution MS with electron capture negative ionization (ECNI) for HFRs. Both GC–MS and LC-MS/MS were suitable for arylamines. New developments towards increased applications of GC–MS/MS may offer alternatives to GC–MS or LC-MS/MS approaches, e.g. for bisphenols. The metals were best determined by inductively coupled plasma (ICP)-MS, with the particular challenge of avoiding interferences in the Cd determination in urine. The evaluation process revealed research needs towards higher sensitivity and non-invasive sampling as well as a need for more stringent quality assurance/quality control applications and assessments.
Katrin Vorkamp; Argelia Castaño; Jean-Philippe Antignac; Luis D. Boada; Enrique Cequier; Adrian Covaci; Marta Esteban López; Line S. Haug; Monika Kasper-Sonnenberg; Holger M. Koch; Octavio Pérez Luzardo; Agnese Osīte; Loïc Rambaud; Maria-Teresa Pinorini; Gabriele Sabbioni; Cathrine Thomsen. Biomarkers, matrices and analytical methods targeting human exposure to chemicals selected for a European human biomonitoring initiative. Environment International 2020, 146, 106082 .
AMA StyleKatrin Vorkamp, Argelia Castaño, Jean-Philippe Antignac, Luis D. Boada, Enrique Cequier, Adrian Covaci, Marta Esteban López, Line S. Haug, Monika Kasper-Sonnenberg, Holger M. Koch, Octavio Pérez Luzardo, Agnese Osīte, Loïc Rambaud, Maria-Teresa Pinorini, Gabriele Sabbioni, Cathrine Thomsen. Biomarkers, matrices and analytical methods targeting human exposure to chemicals selected for a European human biomonitoring initiative. Environment International. 2020; 146 ():106082.
Chicago/Turabian StyleKatrin Vorkamp; Argelia Castaño; Jean-Philippe Antignac; Luis D. Boada; Enrique Cequier; Adrian Covaci; Marta Esteban López; Line S. Haug; Monika Kasper-Sonnenberg; Holger M. Koch; Octavio Pérez Luzardo; Agnese Osīte; Loïc Rambaud; Maria-Teresa Pinorini; Gabriele Sabbioni; Cathrine Thomsen. 2020. "Biomarkers, matrices and analytical methods targeting human exposure to chemicals selected for a European human biomonitoring initiative." Environment International 146, no. : 106082.
Glyphosate is the highest volume herbicide used worldwide, and its main biodegradation product is aminomethylphosphonic acid (AMPA), both are listed as priority substances in the Human Biomonitoring for Europe (HBM4EU) initiative which aims at improving policy by filling knowledge gaps by targeted research. The objective of the current study was to advance the sensitivity of an existing gas chromatography-tandem mass spectrometry analytical method to measure environmental population exposures. A 50% lower limit of quantification of 0.05 µg/L was achieved for both analytes by slight modifications in sample work-up, and use of another isotope labelled internal standard. In a pilot study, 41 urine samples from the general German population were analysed, of which glyphosate and AMPA could be quantified in 66% and 90% of the samples respectively, which is sufficient to reliably describe distributions of urinary concentrations in the non-occupationally exposed population.
Alison Connolly; Stephan Koslitz; Daniel Bury; Thomas Brüning; André Conrad; Marike Kolossa-Gehring; Marie A. Coggins; Holger Martin Koch. Sensitive and selective quantification of glyphosate and aminomethylphosphonic acid (AMPA) in urine of the general population by gas chromatography-tandem mass spectrometry. Journal of Chromatography B 2020, 1158, 122348 .
AMA StyleAlison Connolly, Stephan Koslitz, Daniel Bury, Thomas Brüning, André Conrad, Marike Kolossa-Gehring, Marie A. Coggins, Holger Martin Koch. Sensitive and selective quantification of glyphosate and aminomethylphosphonic acid (AMPA) in urine of the general population by gas chromatography-tandem mass spectrometry. Journal of Chromatography B. 2020; 1158 ():122348.
Chicago/Turabian StyleAlison Connolly; Stephan Koslitz; Daniel Bury; Thomas Brüning; André Conrad; Marike Kolossa-Gehring; Marie A. Coggins; Holger Martin Koch. 2020. "Sensitive and selective quantification of glyphosate and aminomethylphosphonic acid (AMPA) in urine of the general population by gas chromatography-tandem mass spectrometry." Journal of Chromatography B 1158, no. : 122348.
Metabolites 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 μg/L, with highest levels in the mg/L range. The GM for the other metabolites were 0.55 μg/L for 5OH-MEHTP, 0.54 μg/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.
Gerda Schwedler; Enrico Rucic; Holger M. Koch; Frederik Lessmann; Thomas Brüning; André Conrad; Maria I.H. Schmied-Tobies; Marike Kolossa-Gehring. 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. International Journal of Hygiene and Environmental Health 2020, 230, 113589 .
AMA StyleGerda Schwedler, Enrico Rucic, Holger M. Koch, Frederik Lessmann, Thomas Brüning, André Conrad, Maria I.H. Schmied-Tobies, Marike Kolossa-Gehring. 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. International Journal of Hygiene and Environmental Health. 2020; 230 ():113589.
Chicago/Turabian StyleGerda Schwedler; Enrico Rucic; Holger M. Koch; Frederik Lessmann; Thomas Brüning; André Conrad; Maria I.H. Schmied-Tobies; Marike Kolossa-Gehring. 2020. "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." International Journal of Hygiene and Environmental Health 230, no. : 113589.
Glyphosate continues to attract controversial debate following the International Agency for Research on Cancer carcinogenicity classification in 2015. Despite its ubiquitous presence in our environment, there remains a dearth of data on human exposure to both glyphosate and its main biodegradation product aminomethylphosphonic (AMPA). Herein, we reviewed and compared results from 21 studies that use human biomonitoring (HBM) to measure urinary glyphosate and AMPA. Elucidation of the level and range of exposure was complicated by differences in sampling strategy, analytical methods, and data presentation. Exposure data is required to enable a more robust regulatory risk assessment, and these studies included higher occupational exposures, environmental exposures, and vulnerable groups such as children. There was also considerable uncertainty regarding the absorption and excretion pattern of glyphosate and AMPA in humans. This information is required to back-calculate exposure doses from urinary levels and thus, compared with health-based guidance values. Back-calculations based on animal-derived excretion rates suggested that there were no health concerns in relation to glyphosate exposure (when compared with EFSA acceptable daily intake (ADI)). However, recent human metabolism data has reported as low as a 1% urinary excretion rate of glyphosate. Human exposures extrapolated from urinary glyphosate concentrations found that upper-bound levels may be much closer to the ADI than previously reported.
Alison Connolly; Marie A. Coggins; Holger M. Koch. Human Biomonitoring of Glyphosate Exposures: State-of-the-Art and Future Research Challenges. Toxics 2020, 8, 60 .
AMA StyleAlison Connolly, Marie A. Coggins, Holger M. Koch. Human Biomonitoring of Glyphosate Exposures: State-of-the-Art and Future Research Challenges. Toxics. 2020; 8 (3):60.
Chicago/Turabian StyleAlison Connolly; Marie A. Coggins; Holger M. Koch. 2020. "Human Biomonitoring of Glyphosate Exposures: State-of-the-Art and Future Research Challenges." Toxics 8, no. 3: 60.
In their Correspondence in The Lancet Diabetes & Endocrinology, Roy Gerona and colleauges1Gerona R Vom Saal FS Hunt PA BPA: have flawed analytical techniques compromised risk assessments?.Lancet Diabetes Endocrinol. 2020; 8: 11-13Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar asserted that indirect measurement of bisphenol A (BPA) metabolites in urine underestimates exposure to BPA in human biomonitoring studies. The indirect method quantifies levels of total BPA in a two-step procedure (enzymatic deconjugation and extraction), whereas the direct method eliminates the enzymatic deconjugation but requires concurrent determination of three species: BPA glucuronide, BPA sulfate, and free BPA. Both human pharmacokinetic and laboratory studies have shown the validity of the indirect method, the approach used by most laboratories routinely measuring BPA. Human pharmacokinetic and laboratory studies have good agreement regarding levels of BPA and its conjugates, including studies in humans that compared levels using direct and indirect methods.2Teeguarden JG Twaddle NC Churchwell MI et al.24-hour human urine and serum profiles of bisphenol A: evidence against sublingual absorption following ingestion in soup.Toxicol Appl Pharmacol. 2015; 288: 131-142Crossref PubMed Scopus (45) Google Scholar Pharmacokinetic studies from several laboratories using controlled dosing with isotopically labeled BPA agree with each other, showing that BPA in the body is conjugated and eliminated quantitatively (84–109% of total administered dose) in urine, mainly as BPA-glucuronide.2Teeguarden JG Twaddle NC Churchwell MI et al.24-hour human urine and serum profiles of bisphenol A: evidence against sublingual absorption following ingestion in soup.Toxicol Appl Pharmacol. 2015; 288: 131-142Crossref PubMed Scopus (45) Google Scholar, 3Thayer KA Doerge DR Hunt D et al.Pharmacokinetics of bisphenol A in humans following a single oral administration.Environ Int. 2015; 83: 107-115Crossref PubMed Scopus (105) Google Scholar, 4Völkel W Colnot T Csanády GA Filser JG Dekant W Metabolism and kinetics of bisphenol A in humans at low doses following oral administration.Chem Res Toxicol. 2002; 15: 1281-1287Crossref PubMed Scopus (575) Google Scholar Laboratory experiments also show distribution of concentrations of BPA metabolites similar to those in human pharmacokinetic studies: more BPA glucuronide than BPA sulfate, and more BPA sulfate than free BPA.2Teeguarden JG Twaddle NC Churchwell MI et al.24-hour human urine and serum profiles of bisphenol A: evidence against sublingual absorption following ingestion in soup.Toxicol Appl Pharmacol. 2015; 288: 131-142Crossref PubMed Scopus (45) Google Scholar, 5Buscher B van de Lagemaat D Gries W et al.Quantitative analysis of unconjugated and total bisphenol A in human urine using solid-phase extraction and UPLC-MS/MS: method implementation, method qualification and troubleshooting.J Chromatogr B Analyt Technol Biomed Life Sci. 2015; 1005: 30-38Crossref Scopus (8) Google Scholar, 6Lacroix MZ Puel S Collet SH et al.Simultaneous quantification of bisphenol A and its glucuronide metabolite (BPA-G) in plasma and urine: applicability to toxicokinetic investigations.Talanta. 2011; 85: 2053-2059Crossref Scopus (40) Google Scholar, 7Provencher G Bérubé R Dumas P et al.Determination of bisphenol A, triclosan and their metabolites in human urine using isotope-dilution liquid chromatography-tandem mass spectrometry.J Chromatogr A. 2014; 1348: 97-104Crossref PubMed Scopus (51) Google Scholar, 8Völkel W Bittner N Dekant W Quantitation of bisphenol A and bisphenol A glucuronide in biological samples by high performance liquid chromatography-tandem mass spectrometry.Drug Metab Dispos. 2005; 33: 1748-1757Crossref PubMed Scopus (175) Google Scholar
Antonia M Calafat; Holger Martin Koch; Ss Andra; Jp Antignac; A Castaño; K Choi; A Covaci; W Dekant; Doerge; H Frederiksen; T Göen; M Kolossa-Gehring; A Leblanc; Jf Mueller; Sf Nakayama; J Nassif; A St-Amand; W Völkel; Ms Wolff. BPA and risk assessment. The Lancet Diabetes & Endocrinology 2020, 8, 269 -270.
AMA StyleAntonia M Calafat, Holger Martin Koch, Ss Andra, Jp Antignac, A Castaño, K Choi, A Covaci, W Dekant, Doerge, H Frederiksen, T Göen, M Kolossa-Gehring, A Leblanc, Jf Mueller, Sf Nakayama, J Nassif, A St-Amand, W Völkel, Ms Wolff. BPA and risk assessment. The Lancet Diabetes & Endocrinology. 2020; 8 (4):269-270.
Chicago/Turabian StyleAntonia M Calafat; Holger Martin Koch; Ss Andra; Jp Antignac; A Castaño; K Choi; A Covaci; W Dekant; Doerge; H Frederiksen; T Göen; M Kolossa-Gehring; A Leblanc; Jf Mueller; Sf Nakayama; J Nassif; A St-Amand; W Völkel; Ms Wolff. 2020. "BPA and risk assessment." The Lancet Diabetes & Endocrinology 8, no. 4: 269-270.
Di-n-butyl adipate (DnBA) is an alternative to the anti-androgenic and strictly regulated di-n-butyl phthalate (DnBP) used as a cosmetic ingredient, plasticizer, and in various articles of everyday life. Hence, exposures of the general population have to be expected. Currently, biomarkers of DnBA exposure and methods for their determination are not available. Here, we describe a sensitive, rugged and precise analytical method for the determination of the DnBA monoester metabolite mono-n-butyl adipate (MnBA), as well as its potential downstream metabolites 3-hydroxy-mono-n-butyl adipate (3OH-MnBA) and 3-carboxy-mono-n-propyl adipate (3cx-MnPrA) in human urine. Glucuronic acid conjugates present in urine were deconjugated using a pure β-glucuronidase. The metabolites were then analyzed by liquid chromatography on a C18 column with superficially porous particles coupled to electrospray ionization-triple quadrupole-tandem mass spectrometry, applying online turbulent flow chromatography for analyte enrichment and matrix depletion (online-SPE-LC-MS/MS). The metabolites were quantified using stable isotope dilution analysis with limits of quantification of 0.05 µg/L (MnBA), 0.1 µg/L (3OH-MnBA), and 0.5 µg/L (3cx-MnPrA). Method imprecision in urinary matrix was below 7% (coefficient of variation) for all analytes. Mean relative recoveries were between 93% and 107%. The suitability of the DnBA metabolites as biomarkers of exposure was demonstrated after dermal application of a commercially available sunscreen containing DnBA. Maximum concentrations were reached 6.5 h after dose (219 µg/L 3cx-MnPrA, 91 µg/L MnBA, and 3.9 µg/L 3OH-MnBA). Elimination kinetics were similar for all three metabolites. We were able to quantify 3cx-MnPrA and MnBA until 4 d after sunscreen application. In a sample set of 35 urine samples from the general German population, 3cx-MnPrA was quantified in 94% (median 2.54 µg/L, maximum 78.3 µg/L) and MnBA in 3% (median < LOQ, maximum 0.18 µg/L) of the samples. The method will be applied in future human metabolism and human biomonitoring population studies.
Benedikt Ringbeck; Daniel Bury; Heiko Hayen; Tobias Weiss; Thomas Brüning; Holger M. Koch. Determination of di-n-butyl adipate (DnBA) metabolites as possible biomarkers of exposure in human urine by online-SPE-LC-MS/MS. Journal of Chromatography B 2020, 1141, 122029 .
AMA StyleBenedikt Ringbeck, Daniel Bury, Heiko Hayen, Tobias Weiss, Thomas Brüning, Holger M. Koch. Determination of di-n-butyl adipate (DnBA) metabolites as possible biomarkers of exposure in human urine by online-SPE-LC-MS/MS. Journal of Chromatography B. 2020; 1141 ():122029.
Chicago/Turabian StyleBenedikt Ringbeck; Daniel Bury; Heiko Hayen; Tobias Weiss; Thomas Brüning; Holger M. Koch. 2020. "Determination of di-n-butyl adipate (DnBA) metabolites as possible biomarkers of exposure in human urine by online-SPE-LC-MS/MS." Journal of Chromatography B 1141, no. : 122029.
During the population representative German Environmental Survey of Children and Adolescents (GerES V, 2014–2017) 2256 first-morning void urine samples from 3 to 17 years old children and adolescents were analysed for 21 metabolites of 11 different phthalates (di-methyl phthalate (DMP), di-ethyl phthalate (DEP), butylbenzyl phthalate (BBzP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di-cyclohexyl phthalate (DCHP), di-n-pentyl phthalate (DnPeP), di-(2-ethylhexyl) phthalate (DEHP), di-iso-nonyl phthalate (DiNP), di-iso-decyl phthalate (DiDP) and di-n-octyl phthalate (DnOP)). Metabolites of DMP, DEP, BBzP, DiBP, DnBP, DEHP, DiNP and DiDP were found in 97%–100% of the participants, DCHP and DnPeP in 6%, and DnOP in none of the urine samples. Geometric means (GM) were highest for metabolites of DiBP (MiBP: 26.1 μg/L), DEP (MEP: 25.8 μg/L), DnBP (MnBP: 20.9 μg/L), and DEHP (cx-MEPP: 11.9 μg/L). For all phthalates but DEP, GMs were consistently higher in the 3–5 years old children than in the 14–17 years old adolescents. For DEHP, the age differences were most pronounced. All detectable phthalate biomarker concentrations were positively associated with the levels of the respective phthalate in house dust. In GerES V we found considerably lower phthalate biomarker levels than in the preceding GerES IV (2003–2006). GMs of biomarker levels in GerES V were only 18% (BBzP), 23% (MnBP), 23% (DEHP), 29% (MiBP) and 57% (DiNP) of those measured a decade earlier in GerES IV. However, some children and adolescents still exceeded health-based guidance values in the current GerES V. 0.38% of the participants had levels of DnBP, 0.08% levels of DEHP and 0.007% levels of DiNP which were higher than the respective health-based guidance values. Accordingly, for these persons an impact on health cannot be excluded with sufficient certainty. The ongoing and substantial exposure of vulnerable children and adolescents to many phthalates confirms the need of a continued monitoring of established phthalates, whether regulated or not, as well as of potential substitutes. With this biomonitoring approach we provide a picture of current individual and cumulative exposure developments and body burdens to phthalates, thus providing support for timely and effective chemicals policies and legislation.
Gerda Schwedler; Enrico Rucic; Rosa Lange; André Conrad; Holger Martin Koch; Claudia Pälmke; Thomas Brüning; Christine Schulz; Maria I.H. Schmied-Tobies; Anja Daniels; Marike Kolossa-Gehring. Phthalate metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014–2017. International Journal of Hygiene and Environmental Health 2020, 225, 113444 .
AMA StyleGerda Schwedler, Enrico Rucic, Rosa Lange, André Conrad, Holger Martin Koch, Claudia Pälmke, Thomas Brüning, Christine Schulz, Maria I.H. Schmied-Tobies, Anja Daniels, Marike Kolossa-Gehring. Phthalate metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014–2017. International Journal of Hygiene and Environmental Health. 2020; 225 ():113444.
Chicago/Turabian StyleGerda Schwedler; Enrico Rucic; Rosa Lange; André Conrad; Holger Martin Koch; Claudia Pälmke; Thomas Brüning; Christine Schulz; Maria I.H. Schmied-Tobies; Anja Daniels; Marike Kolossa-Gehring. 2020. "Phthalate metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014–2017." International Journal of Hygiene and Environmental Health 225, no. : 113444.
In 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 subject’s 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.
Petra Apel; Andreas Kortenkamp; Holger Martin Koch; Nina Vogel; Maria Rüther; Monika Kasper-Sonnenberg; Andre Conrad; Thomas Brüning; Marike Kolossa-Gehring. Time course of phthalate cumulative risks to male developmental health over a 27-year period: Biomonitoring samples of the German Environmental Specimen Bank. Environment International 2020, 137, 105467 .
AMA StylePetra Apel, Andreas Kortenkamp, Holger Martin Koch, Nina Vogel, Maria Rüther, Monika Kasper-Sonnenberg, Andre Conrad, Thomas Brüning, Marike Kolossa-Gehring. Time course of phthalate cumulative risks to male developmental health over a 27-year period: Biomonitoring samples of the German Environmental Specimen Bank. Environment International. 2020; 137 ():105467.
Chicago/Turabian StylePetra Apel; Andreas Kortenkamp; Holger Martin Koch; Nina Vogel; Maria Rüther; Monika Kasper-Sonnenberg; Andre Conrad; Thomas Brüning; Marike Kolossa-Gehring. 2020. "Time course of phthalate cumulative risks to male developmental health over a 27-year period: Biomonitoring samples of the German Environmental Specimen Bank." Environment International 137, no. : 105467.
New procedures for phthalate mixture risk assessments (MRAs) focused on male developmental toxicity (anti-androgenicity) are overdue. Previous efforts suffer from several shortcomings: There is a lack of consistency in terms of the phthalates entered into the assessments, and in the choice of tolerable intakes. Many of these values do not reflect new evidence about low dose male developmental effects. Nearly all previous mixture risk assessments have focused solely on phthalates, with no regard for exposures to other chemicals that also induce male developmental toxicity, leading to underestimations of risks. Here, we address these weaknesses and inconsistencies by proposing criteria for the selection of phthalates for MRA based on structure-activity relationships. We suggest new reference doses for phthalates for use in MRA, as follows: DBP 6.7 μg/kg/d, DIBP 100 μg/kg/d, BBP 10 μg/kg/d, DEHP 10 μg/kg/d, DINP 59 μg/kg/d. We conclude that the fixation on the Hazard Index (HI) = 1 as signalling acceptable combined phthalate exposures is misguided as it ignores co-exposure to other anti-androgenic chemicals that also contribute to male developmental risks. Until more comprehensive assessments of phthalates in combination with other anti-androgens become feasible, we propose the use of a HI of 0.1–0.2 as a benchmark for interpreting phthalate mixture risk assessments.
Andreas Kortenkamp; Holger M. Koch. Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity. International Journal of Hygiene and Environmental Health 2019, 224, 113428 .
AMA StyleAndreas Kortenkamp, Holger M. Koch. Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity. International Journal of Hygiene and Environmental Health. 2019; 224 ():113428.
Chicago/Turabian StyleAndreas Kortenkamp; Holger M. Koch. 2019. "Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity." International Journal of Hygiene and Environmental Health 224, no. : 113428.
The article Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014.
Nadin Ulrich; Daniel Bury; Holger M. Koch; Maria Rüther; Till Weber; Heiko-Udo Käfferlein; Tobias Weiss; Thomas Brüning; Marike Kolossa-Gehring. Correction to: Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014. International Archives of Occupational and Environmental Health 2019, 93, 147 -147.
AMA StyleNadin Ulrich, Daniel Bury, Holger M. Koch, Maria Rüther, Till Weber, Heiko-Udo Käfferlein, Tobias Weiss, Thomas Brüning, Marike Kolossa-Gehring. Correction to: Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014. International Archives of Occupational and Environmental Health. 2019; 93 (1):147-147.
Chicago/Turabian StyleNadin Ulrich; Daniel Bury; Holger M. Koch; Maria Rüther; Till Weber; Heiko-Udo Käfferlein; Tobias Weiss; Thomas Brüning; Marike Kolossa-Gehring. 2019. "Correction to: Metabolites of the alkyl pyrrolidone solvents NMP and NEP in 24-h urine samples of the German Environmental Specimen Bank from 1991 to 2014." International Archives of Occupational and Environmental Health 93, no. 1: 147-147.
Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107−164 μg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10–40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17–0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03–0.10%) and 0.05% (0.01–0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5–2.3 h, tmax2 = 3.8–6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1–3.8 h. The majority (98–100%) of metabolites was excreted within 24 h. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 μg/kg bw/day). The highest daily intake (114 μg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.
Alexandra Nehring; Daniel Bury; Benedikt Ringbeck; Hans-Willi Kling; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose. Toxicology Letters 2019, 321, 95 -102.
AMA StyleAlexandra Nehring, Daniel Bury, Benedikt Ringbeck, Hans-Willi Kling, Rainer Otter, Tobias Weiss, Thomas Brüning, Holger M. Koch. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose. Toxicology Letters. 2019; 321 ():95-102.
Chicago/Turabian StyleAlexandra Nehring; Daniel Bury; Benedikt Ringbeck; Hans-Willi Kling; Rainer Otter; Tobias Weiss; Thomas Brüning; Holger M. Koch. 2019. "Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose." Toxicology Letters 321, no. : 95-102.
During the past two decades human exposure to bisphenol A (BPA) and phthalates such as di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP) and di-(2-ethyl-hexyl) phthalate (DEHP) has received substantial interest due to widespread population exposures and potential endocrine disrupting effects. Therefore, these chemicals have gradually been restricted and phased out through legislation. However, humans are still exposed to a wide range of other less studied phthalates, phthalate substitutes and BPA analogues as well as other polychlorinated and phenolic substances. In this study, we investigated human exposure to these chemicals over the past decade. Three hundred urine samples collected in 2009, 2013 and 2017 (100 samples each year) from young Danish men of the general population, participating in a large on-going cross-sectional study, were selected for the present time trend study. The urinary concentration of metabolites of 15 phthalates, di-2-ethylhexyl terephthalate (DEHTP) and di-iso-nonyl-cyclohexane-1,2-dicarboxylate (DINCH), seven bisphenols including BPA, bisphenol S (BPS) and bisphenol F (BPF), as well as triclosan, triclocarban, benzophenone-3, three chlorophenols and two phenylphenols were analyzed by two new sensitive LC-MS/MS methods developed and validated for the present study. A significant decrease in urinary concentrations over time was observed for the majority of the chemicals. Median concentrations of BPA and the metabolites of DiBP, DnBP, BBzP and DEHP were more than halved from 2009 to 2017. Similar decreases were observed for triclosan and the chloro- and phenylphenols. In contrast, metabolites of the two phthalate substitutes DEHTP and DINCH increased more than 20 and 2 times, respectively. The potential BPA substitutes; BPS and BPF also increased, but only slightly. Despite these new exposure patterns, the exposure to the old well-known chemicals, such as DiBP, DnBP, BBzP, DEHP and BPA was still higher in 2017 compared to the exposure level of the new substitutes such as DEHTP, DINCH, BPS and BPF. A significant decrease in internal exposure to most of the common phthalates and BPA over the past decade was observed, reflecting market changes and regulatory measures implemented in EU. Despite increasing exposures to some of the known phthalate substitutes and BPA analogues, the total amount of each measured chemical group (original and substitute analytes combined) was lower in the more recently collected samples. This indicates only partial direct substitution or substitution by chemicals not covered in this approach, or a general decline in the exposure to these chemical/product groups over the last decade.
Hanne Frederiksen; Ole Nielsen; Holger M. Koch; Niels E. Skakkebaek; Anders Juul; Niels Jørgensen; Anna-Maria Andersson. Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009–2017. International Journal of Hygiene and Environmental Health 2019, 223, 93 -105.
AMA StyleHanne Frederiksen, Ole Nielsen, Holger M. Koch, Niels E. Skakkebaek, Anders Juul, Niels Jørgensen, Anna-Maria Andersson. Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009–2017. International Journal of Hygiene and Environmental Health. 2019; 223 (1):93-105.
Chicago/Turabian StyleHanne Frederiksen; Ole Nielsen; Holger M. Koch; Niels E. Skakkebaek; Anders Juul; Niels Jørgensen; Anna-Maria Andersson. 2019. "Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009–2017." International Journal of Hygiene and Environmental Health 223, no. 1: 93-105.