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Apel, Petra

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  • Veröffentlichung
    Human Biomonitoring Guidance Values (HBM-GVs) for bisphenol S and assessment of the risk due to the exposure to bisphenols A and S, in Europe
    (2022) Meslin, Matthieu; Apel, Petra; Beausoleil, Claire; Zeman, Florence Anna; Kolossa-Gehring, Marike
    Within the European Joint Programme HBM4EU, Human Biomonitoring Guidance Values (HBM-GVs) were derived for several prioritised substances. In this paper, the derivation of HBM-GVs for the general population (HBM-GVGenPop) and workers (HBM-GVworker) referring to bisphenol S (BPS) is presented. For the general population, this resulted in an estimation of the total urinary concentration of BPS of 1.0 Ìg/L assuming a 24 h continuous exposure to BPS. For workers, the modelling was refined in order to reflect continuous exposure during the working day, leading to a total urinary concentration of BPS of 3.0 Ìg/L. The usefulness for risk assessment of the HBM-GVs derived for BPS and bisphenol A (BPA) is illustrated. Risk Characterisation Ratios (RCRs) were calculated leading to a clear difference between risk assessments performed for both bisphenols, with a very low RCR regarding exposure to BPA., contrary to that obtained for BPS. This may be due to the endocrine mediated endpoints selected to derive the HBM-GVs for BPS, whereas the values calculated for BPA are based on the temporary Tolerable Daily Intake (t-TDI) from EFSA set in 2015. A comparison with the revised TDI recently opened for comments by EFSA is also discussed. Regarding the occupational field, results indicate that the risk from occupational exposure to both bisphenols cannot be disregarded. © 2022 by the authors
  • Veröffentlichung
    Human Biomonitoring Initiative (HBM4EU): Human Biomonitoring Guidance Values Ddived for dmethylformamide
    (2022) Lamkarkach, Farida; Apel, Petra; Meslin, Matthieu; Kolossa-Gehring, Marike
    Within the European Joint Program on Human Biomonitoring HBM4EU, human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) or for occupationally exposed adults (HBM-GVWorker) are derived for prioritized substances including dimethylformamide (DMF). The methodology to derive these values that was agreed upon within the HBM4EU project was applied. A large database on DMF exposure from studies conducted at workplaces provided dose-response relationships between biomarker concentrations and health effects. The hepatotoxicity of DMF has been identified as having the most sensitive effect, with increased liver enzyme concentrations serving as biomarkers of the effect. Out of the available biomarkers of DMF exposure studied in this paper, the following were selected to derive HBM-GVWorker: total N-methylformamide (tNMF) (sum of N-hydroxymethyl-N-methylformamide and NMF) and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) in urine. The proposed HBM-GVWorker is 10 mgL-1 or 10 mgg-1 creatinine for both biomarkers. Due to their different half-lives, tNMF (representative of the exposure of the day) and AMCC (representative of the preceding days' exposure) are complementary for the biological monitoring of workers exposed to DMF. The levels of confidence for these HBM-GVWorker are set to "high" for tNMF and "medium-low" for AMCC. Therefore, further investigations are required for the consolidation of the health-based HBM-GV for AMCC in urine. © 2022 by the authors
  • Veröffentlichung
    Substitutes mimic the exposure behaviour of REACH regulated phthalates
    (2021) Apel, Petra; Kolossa-Gehring, Marike; Lange, Rosa; Lemke, Nora; Debiak, Malgorzata; Murawski, Aline; Weber, Till
    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. © 2021 Published by Elsevier GmbH.
  • 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, Rosa
    Information 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 authors
  • Veröffentlichung
    Phthalate und der Ersatzstoff DINCH - die wichtigsten Ergebnisse aus HBM4EU
    (2023) Gerofke, Antje; Apel, Petra; Kolossa-Gehring, Marike; Lange, Rosa; Schmidt, Philipp; Vogel, Nina; Weber, Till
    Im Rahmen der europäischen HumanBiomonitoringInitiative (HBM4EU) wurden aktuelle harmonisierte Daten zur körperlichen Belastung von Kindern und Jugendlichen mit Phthalat-Weichmachern und dem alternativen Weichmacher DINCH in Europa gewonnen. Zwischen den Ländern und europäischen Regionen wurden Unterschiede in der Belastung festgestellt. Ein Vergleich der HBM-Ergebnisse mit im Projekt abgeleiteten toxikologischen Beurteilungswerten zeigt, dass die Belastung trotz bestehender Regulierungen immer noch zu hoch ist. Bei Betrachtung der gleichzeitigen Belastung mit verschiedenen Phthalaten konnte für 17 rozent der Teilnehmenden ein gesundheitliches Risiko nicht mit ausreichender Sicherheit ausgeschlossen werden. Weitere Meilensteine von HBM4EU waren der Aufbau eines Labornetzwerks zur Analytik der Stoffe, eine Zeittrendanalyse, die Identifizierung von Expositionsquellen sowie Effektbiomarkern und die Untersuchung beruflich Exponierter. Die Ergebnisse ermöglichen die Beantwortung politikberatungsrelevanter Fragen sowie eine Einschätzung der Effektivität bestehender Regulierungen. Quelle: UMID : Umwelt und Mensch - Informationsdienst ; Umwelt & Gesundheit, Umweltmedizin, Verbraucherschutz / Boden- und Lufthygiene (Berlin) Institut für Wasser- - (2023), Heft 1, Seite 25
  • Veröffentlichung
    Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021)
    (2023) Govarts, Eva; Apel, Petra; Gilles, Liese; Rodriguez Martin, Laura; Kolossa-Gehring, Marike; Lange, Rosa; Lemke, Nora; Murawski, Aline; Rüther, Maria; Vogel, Nina; Weber, Till; Zimmermann, Philipp
    As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Summe (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures. © 2023 The Authors
  • Veröffentlichung
    Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A
    (2021) Ougier, Eva; Zeman, Florence; Apel, Petra; Antignac, Jean-Philippe; Kolossa-Gehring, Marike; Lange, Rosa
    The "European Human Biomonitoring Initiative" (HBM4EU) derives human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) and/or for occupationally exposed adults (HBM-GVWorker) for several priority substances and substance groups as identified by policy makers, scientists and stakeholders at EU and national level, including bisphenol A (BPA). Human exposure to BPA is widespread and of particular concern because of its known endocrine-disrupting properties. Unlike the conjugated forms of BPA circulating in the body, free BPA is known to interact with the nuclear estrogen receptors. Because free BPA is considered to be more toxicologically active than the conjugated forms (e.g. BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S)), its measurement in blood provides the superior surrogate of the biologically effective dose. However, considering the difficulty of implementing blood sampling in large HBM cohorts, as well as the current analytical capacities complying with the quality assurance (QA)/quality control (QC) schemes, total BPA in urine (i.e. the sum of free and conjugated forms of BPA measured after an hydrolysis of phase II metabolites) was retained as the relevant exposure biomarker for BPA. HBM-GVGenPop for total BPA in urine of 230 (my)g/L and 135 (my)g/L for adults and children, respectively, were developed on the basis of toxicological data. To derive these values, the concentrations of urinary total BPA consistent with a steady-state exposure to the temporary Tolerable Daily Intake (t-TDI) of 4 my/kg bw/day set in 2015 by the European Food Safety Authority (EFSA) were estimated. The BPA human physiologically-based pharmacokinetic (PBPK) model developed by Karrer et al. (2018) was used, assuming an oral exposure to BPA at the t-TDI level averaged over 24 h. Dermal uptake of BPA is suspected to contribute substantially to the total BPA body burden, which in comparison with the oral route, is generating a higher ratio of free BPA to total BPA in blood. Therefore, an alternative approach for calculating the HBM-GVGenPop according to the estimated relative contributions of both the oral and dermal routes to the global BPA exposure is also discussed. Regarding BPA exposure at the workplace, the steady-state concentration of urinary total BPA was estimated after a dermal uptake of BPA that would generate the same concentration of free BPA in plasma (considered as the bioactive form) as would a 24 h-averaged intake to the European Chemicals Agency (ECHA)'s oral DNEL of 8 (my)g BPA/kg bw/day set for workers. The predicted concentration of urinary total BPA at steady-state is equivalent to, or exceeds the 95th percentile of total BPA in urine measured in different European HBM studies conducted in the general population. Thus, no HBM-GVWorker was proposed, as the high background level of BPA coming from environmental exposure - mostly through food intake - is making the discrimination with the occupational exposure to BPA difficult. © 2021 The Author(s)
  • Veröffentlichung
    Pentachlorophenol and nine other chlorophenols in urine of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V)
    (2021) Apel, Petra; Kolossa-Gehring, Marike; Schmidt, Lukas; Murawski, Aline; Rucic, Enrico; Schmied-Tobies, Maria Irene Hilde; Schwedler, Gerda
    Chlorophenols comprise of a large group of chemicals used inter alia for the production of biocides, pharmaceuticals, other industrial products and are used e.g. as antiseptics or wood preservatives due to their biocidal properties. Several of them are classified as toxic to aquatic life and harmful to humans by ingestion, inhalation, or dermal contact, causing skin and eye irritation. Moreover, chlorophenols are possibly carcinogenic to humans. The most prominent chlorophenol - pentachlorophenol - is carcinogenic to humans, was banned in Germany in 1989 and further regulated by the European Commission in 2006 and included in the Stockholm Convention in 2017. Some chlorophenols are persistent in the environment and are also biodegradation products of precursor substances. To evaluate the health-relevance of recent exposure and monitor the effectiveness of regulatory measures, chlorophenols were analysed in the population-representative German Environmental Survey on Children and Adolescents 2014-2017 (GerES V). First-morning void urine samples of 485 3-17-year-old children and adolescents were analysed for ten chlorophenols. Pentachlorophenol was still quantified in 87% of the children and adolescents with a geometric mean (GM) concentration of 0.19 (my)g/L (0.16 (my)g/gcrea) and a maximum concentration of 6.7 (my)g/L (5.4 (my)g/gcrea). The maximum concentration was well below the health-based guidance value HBM-I of 25 (my)g/L (20 (my)g/gcrea). 4-Monochlorophenol was quantified in all samples with a GM concentration of 1.38 (my)g/L (1.14 (my)g/gcrea). 2-Monochlorophenol, 2,4-dichlorophenol, and 2,5-dichlorophenol were quantified in 97%, 98%, and 95% of the samples, with GMs of 0.26 (my)g/L (0.21 (my)g/gcrea), 0.24 (my)g/L (0.20 (my)g/gcrea), and 0.26 (my)g/L (0.21 (my)g/gcrea). 2,6-dichlorophenol, 2,3,4-trichlorophenol, and 2,4,5-trichlorophenol were quantified in 17-25% of the samples with GMs below the limit of quantification (LOQ) of 0.1 (my)g/L 2,4,6-trichlorophenol was quantified in 72% of the samples (GM: 0.13 (my)g/L, 0.11 (my)g/gcrea), 2,3,4,6-tetrachlorophenol in 44% of the samples (GM < LOQ). Comparison to previous cycles of GerES revealed substantially lower exposure to most of the chlorophenols in GerES V. Exposure levels found in Germany were comparatively low in contrast to North American results. © 2021 Published by Elsevier Inc.
  • Veröffentlichung
    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, Maria
    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 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
    How to use human biomonitoring in chemical risk assessment: methodological aspects, recommendations, and lessons learned from HBM4EU
    (2023) Santonen, Tiina; Mahiout, Selma; Apel, Petra; Alvito, Paula; Kolossa-Gehring, Marike; Gerofke, Antje; Lange, Rosa
    One of the aims of the European Human Biomonitoring Initiative, HBM4EU, was to provide examples of and good practices for the effective use of human biomonitoring (HBM) data in human health risk assessment (RA). The need for such information is pressing, as previous research has indicated that regulatory risk assessors generally lack knowledge and experience of the use of HBM data in RA. By recognising this gap in expertise, as well as the added value of incorporating HBM data into RA, this paper aims to support the integration of HBM into regulatory RA. Based on the work of the HBM4EU, we provide examples of different approaches to including HBM in RA and in estimations of the environmental burden of disease (EBoD), the benefits and pitfalls involved, information on the important methodological aspects to consider, and recommendations on how to overcome obstacles. The examples are derived from RAs or EBoD estimations made under the HBM4EU for the following HBM4EU priority substances: acrylamide, o-toluidine of the aniline family, aprotic solvents, arsenic, bisphenols, cadmium, diisocyanates, flame retardants, hexavalent chromium [Cr(VI)], lead, mercury, mixture of per-/poly-fluorinated compounds, mixture of pesticides, mixture of phthalates, mycotoxins, polycyclic aromatic hydrocarbons (PAHs), and the UV-filter benzophenone-3. Although the RA and EBoD work presented here is not intended to have direct regulatory implications, the results can be useful for raising awareness of possibly needed policy actions, as newly generated HBM data from HBM4EU on the current exposure of the EU population has been used in many RAs and EBoD estimations. © 2023 The Author(s)