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Veröffentlichung Human biomonitoring in health risk assessment in Europe: Current practices and recommendations for the future(2019) Louro, Henriqueta; Heinälä, Milla; Bessems, Jos; Kolossa-Gehring, MarikeHuman biomonitoring (HBM) is an important tool to survey the internal exposure of humans which represents the real life chemical body burden to chemicals and/or their metabolites. It results from total exposure to chemical substances from different sources and via different routes. These substances may be regulated under different legislative frameworks on chemicals (e.g., environmental, occupational, food safety etc). In occupational health, HBM has long traditions to control the exposures at workplaces. By providing accurate data on internal exposure, HBM data can improve human health risk assessment (RA) for both the general population and workers. Although the past few years have shown good examples on the use of HBM in the RA of chemicals, there is still quite some work to be done to improve its use in a regulatory RA. Under the scope of the European Human Biomonitoring Initiative (project HBM4EU, 2017-2021), the current study reviews the state-of-the-art of HBM use in chemicals RA with a special focus in Europe, and attempts to identify hurdles and challenges faced by regulators. To gather information on the use of HBM, including the availability of guidance on how to use it in RA, the RA schemes applied by different European or international organizations were analysed. Examples of such use were identified for a few selected groups of chemicals of concern for human health. In addition, we present the results of a survey, aimed at collecting information from national regulatory risk assessors on their day-to-day RA practices, the use of HBM data, and the obstacles and challenges related to their use. The results evidenced and explained some of the current obstacles of using HBM data in RA. These included the lack of HBM guidance values or biomonitoring equivalents (BEs), limited toxicokinetic information to support the interpretation of HBM data and, in the occupational health and safety (OSH) field, the lack of legal enforcement. Therefore, to support the integration of HBM in regulatory RA, we recommend, on one hand, the elaboration of a EU level guidance on the use of HBM in RA and, on the other hand, the continuation of research efforts to integrate HBM with new RA approaches using in vitro/in silico data and Adverse Outcome Pathways (AOPs). © 2019 The Authors. Published by Elsevier GmbH.Veröffentlichung Advancing human health risk assessment(2019) Lanzoni, Anna; Castoldi, Anna F.; Kass, George EN; Kolossa-Gehring, MarikeThe current/traditional human health risk assessment paradigm is challenged by recent scientific and technical advances, and ethical demands. The current approach is considered too resource intensive, is not always reliable, can raise issues of reproducibility, is mostly animal based and does not necessarily provide an understanding of the underlying mechanisms of toxicity. From an ethical and scientific viewpoint, a paradigm shift is required to deliver testing strategies that enable reliable, animal-free hazard and risk assessments, which are based on a mechanistic understanding of chemical toxicity and make use of exposure science and epidemiological data. This shift will require a new philosophy, new data, multidisciplinary expertise and more flexible regulations. Re-engineering of available data is also deemed necessary as data should be accessible, readable, interpretable and usable. Dedicated training to build the capacity in terms of expertise is necessary, together with practical resources allocated to education. The dialogue between risk assessors, risk managers, academia and stakeholders should be promoted further to understand scientific and societal needs. Genuine interest in taking risk assessment forward should drive the change and should be supported by flexible funding. This publication builds upon presentations made and discussions held during the break-out session 'Advancing risk assessment science - Human health' at EFSA's third Scientific Conference 'Science, Food and Society' (Parma, Italy, 18ââą Ì21 September 2018). © 2019 European Food Safety AuthorityVeröffentlichung Human biomonitoring initiative (HBM4EU) - Strategy to derive human biomonitoring guidance values (HBM-GVs) for health risk assessment(2020) Apel, Petra; Rouselle, Christophe; Kolossa-Gehring, Marike; Lange, RosaThe European Joint Program "HBM4EU" is a joint effort of 30 countries and the European Environment Agency, co-funded under the European Commission's Horizon 2020 program, for advancing and implementing human biomonitoring (HBM) on a European scale and for providing scientific evidence for chemical policy making. One important outcome will be a Europe-wide improvement and harmonization of health risk assessment following the coordinated derivation or update of health-related guidance values referring to the internal body burden. These guidance values - named HBM guidance values or HBM-GVs - can directly be compared with HBM data. They are derived within HBM4EU for priority substances identified by the HBM4EU chemicals prioritization strategy based on existing needs to answer policy relevant questions as raised by national and EU policy makers. HBM-GVs refer to both the general population and occupationally exposed adults. Reports including the detailed reasoning for the values' proposals are subjected to a consultation process within all partner countries of the consortium to reach a broad scientific consensus on the derivation approach and on the derived values. The final HBM-GVs should be applied first within the HBM4EU project, but may also be useful for regulators and risk assessors outside this project. The subsequent adoption of derived HBM-GVs at EU-level needs to be discussed and decided within the responsible EU bodies. Nevertheless, the establishment of HBM-GVs as part of HBM4EU is already a step forward in strengthening HBM-based policy efforts for public and occupational health. The strategy for deriving HBM-GVs which is based on already existing approaches from the German HBM Commission, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) as well as from the US-based scientific consultant Summit Toxicology, the allocation of a level of confidence to the derived values, and the consultation process within the project are comprehensively described to enlighten the work accomplished under the HBM4EU initiative. © 2020 The Author(s).Veröffentlichung Risk assessment for irritating chemicals - derivation of extrapolation factors(2021) Mangelsdorf, Inge; Schröder, Katrin; Escher, Sylvia E.; Kolossa-Gehring, Marike; Debiak, MalgorzataIrritation of the eyes and the upper respiratory tract are important endpoints for setting guide values for chemicals. To optimize the use of the often-limited data, we analysed controlled human exposure studies (CHS) with 1-4 h inhalation of the test substance, repeated dose inhalation studies in rodents, and Alarie-Tests and derived extrapolation factors (EF) for exposure duration, inter- and intraspecies differences. For the endpoint irritating effects in the respiratory tract in rodents, geometric mean (GM) values of 1.9 were obtained for the EF for subacute ->subchronic (n = 16), 2.1 for subchronic -> chronic (n = 40), and 2.9 for subacute -> chronic (n = 10) extrapolation. Based on these data we suggest an EF of 2 for subchronic -> chronic and of 4 for subacute -> chronic extrapolation. In CHS, exposure concentration determines the effects rather than exposure duration. Slight reversible effects during 4 h exposure indicate that an EF of 1 can be considered for assessing chronic exposures. To assess species extrapolation, 10 chemicals were identified with both, reliable rat inhalation studies and CHS. The GM of the ratio between the No Observed Adverse Effect Concentration (NOAEC) in rats and humans was 2.3 and increased to 3.6 when expanding the dataset to all available EF (n = 25). Based on these analyses, an EF of 3 is suggested to extrapolate from a NOAEC in a chronic rat study to a NOAEC in a CHS. The analysis of EFs for the extrapolation from a 50% decrease in respiratory frequency in the Alarie test in mice (RD50) to a NOAEC in a CHS resulted in a GM of 40, for both, the reliable (n = 11) and the overall dataset (n = 19). We propose to use the RD50 from the Alarie test for setting guide values and to use 40 as EF. Efs for intraspecies differences in the human population must account for susceptible persons, most importantly for persons with chemical intolerance (CI), who show subjective signs of irritation at low concentrations. The limited data available do not justify to deviate from an EF of 10 - 20 as currently used in different regulatory settings. © 2020 The Authors.Veröffentlichung Bisphenol A and six other environmental phenols in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V)(2021) Tschersich, Carolin; Kolossa-Gehring, Marike; Murawski, Aline; Rucic, Enrico; Schwedler, GerdaExposure to environmental phenols such as bisphenol A, benzophenones, 2-phenylphenol, triclosan, and triclocarban is of concern, because of their endocrine disrupting properties and broad application in consumer products. The current body burden of the 3-17-year-old population in Germany to these substances was assessed in first-morning void urine samples (N = 515-516) collected within the population-representative German Environmental Survey for Children and Adolescents 2014-2017 (GerES V). Bisphenol A was the most prominent phenol analysed here, ubiquitously found in almost all samples with a geometric mean (GM) concentration of 1.905 (my)g/L (1.669 (my)g/gcreatinine) and a maximum (MAX) urinary concentration of 399 (my)g/L. Benzophenone-3 and benzophenone-1 were quantified in 35% and 41% of the samples. GM was below the limit of quantification (LOQ) for benzophenone-3 and 0.559 (my)g/L (0.489 (my)g/gcrea) for benzophenone-1, MAX concentrations were 845 (my)g/L and 202 (my)g/L, respectively. In 16% of the samples triclosan was found in quantifiable amounts resulting in a GM below LOQ and a MAX concentration of 801 (my)g/L. Benzophenone-8, 2-phenylphenol and triclocarban were quantified in none or only 1% of the samples. Benzophenone-1 and -3 concentrations were found to be associated with frequent application of personal care products. A comparison with the previous cycle of the survey, GerES IV (2003-2006), showed a decrease of urinary bisphenol A concentrations, mainly in young children. Despite this decrease, the concentration of bisphenol A exceeded the human biomonitoring (HBM) value HBM-I of 0.1 mg/L in 0.11% of the samples. For triclosan, all urinary concentrations were well below the HBM-I value of 2 mg/L. To minimise environmental health risks, it is therefore necessary to maintain a further declining trend for bisphenol A and continue monitoring the exposure to environmental phenols, as well as to monitor substitutes such as bisphenol F and S. © 2020 Published by Elsevier B.V.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, TillThe 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 The European Human Biomonitoring Initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) for the aprotic solvents N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP)(2021) Apel, Petra; Gerofke, Antje; David, Madlen; Kolossa-Gehring, Marike; Lange, RosaToxicologically and/or epidemiologically derived guidance values referring to the internal exposure of humans are a prerequisite for an easy to use health-based interpretation of human biomonitoring (HBM) results. The European Joint Programme HBM4EU derives such values, named human biomonitoring guidance values (HBM-GVs), for priority substances which could be of regulatory relevance for policy makers and have been identified by experts of the participating countries, ministries, agencies and stakeholders at EU and national level. NMP and NEP are such substances for which unresolved policy relevant issues should be clarified by targeted research. Since widespread exposure of the general population in Germany to NMP and NEP was shown for the age groups 3-17 years and 20-29 years, further investigations on exposure to NMP and NEP in other European countries are warranted. The HBM-GVs derived for both solvents focus on developmental toxicity as decisive endpoint. They amount for the sum of the two specific urinary NMP metabolites 5-HNMP and 2-HMSI and likewise of the two specific urinary NEP metabolites 5-HNEP and 2-HESI to 10 mg/L for children and 15 mg/L for adolescents/adults. The values were determined following a consultation process on the value proposals within HBM4EU. A health-based risk assessment was performed using the newly derived HBM-GVGenPop and exposure data from two recent studies from Germany. The risk assessment revealed that even when considering the combined exposure to both substances by applying the Hazard Index approach, the measured concentrations are below the HBM-GVGenPop in all cases investigated (i.e., children, adolescents and young adults). © 2021 The Authors. Published by Elsevier GmbH.Veröffentlichung Corrigendum to "Substitutes mimic the exposure behaviour of REACH regulated phthalates - A review of the German HBM system on the example of plasticizers"(2022) Apel, Petra; Kolossa-Gehring, Marike; Lange, Rosa; Lemke, Nora; Debiak, Malgorzata; Murawski, Aline; Weber, TillVeröffentlichung Concept for the evaluation of carcinogenic substances in population-based human biomonitoring(2022) Wollin, Klaus-Michael; Apel, Petra; Chovolou, Yvonni; Kolossa-Gehring, Marike; Deutschland. Umweltbundesamt. Kommission Human-BiomonitoringThe Human Biomonitoring (HBM) Commission at the German Environment Agency holds the opinion that for environmental carcinogens for which no exposure levels can be assumed and are harmless to health, health-based guidance values corresponding to the classical definition of the HBM-I or HBM-II value cannot be established. Therefore, only reference values have been derived so far for genotoxic carcinogens from exposure data of the general population or subpopulations. The concept presented here opens up the possibility of performing health risk assessments of carcinogenic substances in human biomonitoring, and thus goes decisively beyond the purely descriptive statistical reference value concept. Using the presented method, quantitative dose descriptors of internal exposure can be derived from those of external exposure, provided that sufficient toxicokinetic information is available. Dose descriptors of internal exposure then allow the simple estimate of additional lifetime cancer risks for measured biomarker concentrations or, conversely, of equivalent concentrations for selected risks, such as those considered as tolerable for the general population. HBM data of chronic exposures to genotoxic carcinogens can thus be used to assess the additional lifetime cancer risk referring to the general population and to justify and prioritize risk management measures. © 2022 by the authorsVeröffentlichung Human-Biomonitoring für Europa (HBM4EU) - erste Einblicke in die Ergebnisse der Initiative(2022) Apel, Petra; Kolossa-Gehring, Marike; Weise, PhilippBeim Human-Biomonitoring wird die innere Schadstoffbelastung des Menschen aus verschiedenen Quellen wie Nahrung, Alltagsgegenständen oder Atemluft erfasst, indem z.B. Blut und Urin analysiert werden. Um das Human-Biomonitoring in Europa zu fördern und zu koordinieren, wurde 2017 das Projekt "Human-Biomonitoring für Europa" (HBM4EU) begonnen, an dem sich 30 Länder, die Europäische Umweltagentur und die Europäische Kommission beteiligt haben. Im Juni 2022 wurde das Projekt abgeschlossen. Vergleichbare und zuverlässige Belastungsdaten konnten für eine breite Palette von Umweltchemikalien erfasst und einheitlich bewertet werden. Weitere wichtige Erfolge der Initiative waren die Etablierung eines Kontrollprogramms zur Qualitätssicherung, ein Konzept zur Vereinheitlichung zukünftiger HBM-Studien, eine gemeinsame Strategie zur Ableitung von gesundheitsbezogenen Beurteilungswerten (HBM Guidance Values - HBM-GVs) und die Einrichtung nationaler Gremien. Die gewonnenen Belastungsdaten sind über die Informationsplattform für die Überwachung von Chemikalien (IPCHEM) und das EU HBM-Dashboard zugänglich. Publikationen sind über die HBM4EU-Onlinebibliothek frei verfügbar. Insgesamt zeigen die Ergebnisse, dass die Belastungen der EU-Bevölkerung für viele Chemikalien wie etwa Phthalate und perfluorierte Alkylsubstanzen (PFAS) zu hoch sind und weiterhin Handlungsbedarf seitens der Politik besteht. Das im Projekt HBM4EU generierte Wissen kann die politischen Entscheidungsträger:innen bei der Verbesserung der Chemikalienââą Ì, Umwelt- und Gesundheitspolitik unterstützen. © Der/die Autor(en) 2022