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Veröffentlichung Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences(2016) Mangerich, Aswin; Debiak, Malgorzata; Birtel, Matthias; Ponath, Viviane; Balszuweit, Frank; Lex, Kirsten; Martello, Rita; Burckhardt-Boer, Waltraud; Strobelt, Romano; Siegert, Markus; Thiermann, Horst; Steinritz, Dirk; Schmidt, Annette; Bürkle, AlexanderMustard agents are potent DNA alkylating agents with mutagenic, cytotoxic and vesicant properties. They include bi-functional agents, such as sulfur mustard (SM) or nitrogen mustard (mustine, HN2), as well as mono-functional agents, such as "half mustardŁ (CEES). Whereas SM has been used as a chemical warfare agent, several nitrogen mustard derivatives, such as chlorambucil and cyclophosphamide, are being used as established chemotherapeutics. Upon induction of specific forms of genotoxic stimuli, several poly(ADP-ribose) polymerases (PARPs) synthesize the nucleic acid-like biopolymer poly(ADP-ribose) (PAR) by using NAD+ as a substrate. Previously, it was shown that SM triggers cellular poly(ADP-ribosyl) ation (PARylation), but so far this phenomenon is poorly characterized. In view of the protective effects of PARP inhibitors, the latter have been proposed as a treatment option of SM-exposed victims. In an accompanying article (Debiak et al., 2016), we have provided an optimized protocol for the analysis of the CEES-induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to further analyze mustard-induced PARylation and its functional consequences, in general. Thus, in the present study, we performed a comprehensive characterization of the PARylation response in HaCaT cells after treatment with four different mustard agents, i.e., SM, CEES, HN2, and chlorambucil, on a qualitative, quantitative and functional level. In particular, we recorded substance-specific as well as dose- and time-dependent PARylation responses using independent bioanalytical methods based on single-cell immuno-fluorescence microscopy and quantitative isotope dilution mass spectrometry. Furthermore, we analyzed if and how PARylation contributes to mustard-induced toxicity by treating HaCaT cells with CEES, SM, and HN2 in combination with the clinically relevant PARP inhibitor ABT888. As evaluated by a novel immunofluorescence-based protocol for the detection of N7-ETE-guanine DNA adducts, the excision rate of CEES-induced DNA adducts was not affected by PARP inhibition. Furthermore, while CEES induced moderate changes in cellular NAD+ levels, annexin V/PI flow cytometry analysis revealed that these changes did not affect CEES-induced short-term cytotoxicity 24 h after treatment. In contrast, PARP inhibition impaired cell proliferation and clonogenic survival, and potentiated micronuclei formation of HaCaT cells upon CEES treatment. Similarly, PARP inhibition affected clonogenic survival of cells treated with bi-functional mustards such as SM and HN2. In conclusion, we demonstrate that PARylation plays a functional role in mustard-induced cellular stress response with substance-specific differences. Since PARP inhibitors exhibit therapeutic potential to treat SM-related pathologies and to sensitize cancer cells for mustard-based chemotherapy, potential long-term effects of PARP inhibition on genomic stability and carcinogenesis should be carefully considered when pursuing such a strategy.Quelle: http://www.sciencedirect.comVeröffentlichung Schadstoffe im Innenraum - aktuelle Handlungsfelder(2018) Birmili, Wolfram; Kolossa-Gehring, Marike; Debiak, Malgorzata; Salthammer, Tunga; Valtanen, KerttuVeröffentlichung Integration von Geschlecht in die Forschung zu umweltbezogener Gesundheit. Ergebnisse des interdisziplinären Forschungsnetzwerks Geschlecht - Umwelt - Gesundheit (GeUmGe-NET)(2018) Bolte, Gabriele; David, Madlen; Debiak, Malgorzata; Kolossa-Gehring, MarikeDie umfassende Berücksichtigung von Geschlecht (biologische und soziale Dimensionen) in der Gesundheitsforschung ist essenziell, um Relevanz und Validität der Forschungsergebnisse zu erhöhen. Im Unterschied zu anderen Bereichen der Gesundheitsforschung fehlt bislang eine systematische Aufarbeitung des Forschungsstandes zur Bedeutung von Geschlecht bei umweltbezogener Gesundheit. In dem interdisziplinären Forschungsnetzwerk Geschlecht - Umwelt - Gesundheit (GeUmGe-NET) wurde in ausgewählten Themenfeldern der Forschungsbereiche Umwelttoxikologie, Umweltmedizin, Umweltepidemiologie und Public-Health-Forschung zu Umwelt und Gesundheit der aktuelle Stand zur Integration von Geschlechteraspekten bzw. Genderkonzepten systematisch erhoben. In allen Bereichen wurden Wissenslücken und Forschungsbedarfe identifiziert sowie Potenziale für methodische Weiterentwicklungen durch Nutzung von Genderkonzepten aufgezeigt. Mit dem Forschungsnetzwerk GeUmGe-NET wurde ein Dialog zwischen biomedizinisch bzw. Public-Health-orientierter Gesundheitsforschung und sozialwissenschaftlicher Genderforschung begonnen. Dieser Dialog ist weiterzuführen, insbesondere hinsichtlich der gemeinsamen Erprobung methodischer Innovationen bei Datenerhebung und Datenanalyse. Erkenntnisse aus dieser interdisziplinären Forschung sind relevant für die Praxisfelder umweltbezogener Gesundheitsschutz, Gesundheitsförderung, Umweltgerechtigkeit und umweltbezogene Gesundheitsberichterstattung. © Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2018Veröffentlichung The German approach to regulate indoor air contaminants(2019) Fromme, Hermann; Debiak, Malgorzata; Sagunski, Helmut; Kolossa-Gehring, MarikeIndoor air quality (IAQ) and exposure to indoor chemicals are widely discussed in terms of personal discomfort and health risks. In contrast to ambient air and working environments, legally binding regulations are only partially established for indoor contaminants, and other available European guidelines are limited. To correct these deficits, the German Committee on Indoor Guide Values (AIR), formerly known as the Ad hoc Working Group (Ad hoc AG), performed health assessments of indoor air contaminants. The main tasks were to develop toxicologically based indoor air guide values, health-based guideline values, and reference values largely based on the 95th percentile of the concentrations found in a reference population. Here, we provide a comprehensive overview of the indoor air values set in Germany and discuss the basis of their derivation. This overview includes a description of legally binding standards, indoor air guide values for 38 substances or groups, and guidelines for TVOC (total volatile organic compounds), particulate matter, and carbon dioxide as well as risk-related guidelines for carcinogenic substances.Veröffentlichung Toxic gender? The role of sex and gender in chemicals management(2019) Arning, Jürgen; Conrad, André; Debiak, Malgorzata; Kolossa-Gehring, Marike; Sauer, Arn Thorben; Steinkühler, NadjaVeröffentlichung Sex and gender approaches in environmental health research: two exemplary case studies of the German environment agency(2019) Debiak, Malgorzata; Groth, Katrin; Kolossa-Gehring, Marike; Sauer, Arn Thorben; Tobollik, Myriam; Wintermeyer, DirkEngaging with the analytical categories of sex and gender in environmental health studies remains challenging in practice but promising with regards to research excellence and scientific benefit. The German Environment Agency reports on two case studies navigating this complex interaction in the fields of health risk assessment of environmental stressors and human biomonitoring studies. It is apparent that the levels of integration of the sex/gender theories and sex/gender data are differently advanced in research. In some areas the collection of sex-disaggregated data has just begun, whereas in others research started engaging with newer gender theories such as embodiment or intersectionality. The practical applications and obstacles in incorporating sex and gender dimensions into environmental health studies are presented and discussed. Quelle: https://www.tandfonline.comVeröffentlichung Toxic gender? The role of sex and gender in chemicals management(2019) Arning, Jürgen; Conrad, André; Debiak, Malgorzata; Kolossa-Gehring, Marike; Sauer, Arn Thorben; Steinkühler, NadjaVeröffentlichung Nutzen und Grenzen von Hausstaubuntersuchungen in Innenräumen(2020) Hurraß, Julia; Birmili, Wolfram; Salthammer, Tunga; Heinzow, Birger; Debiak, Malgorzata; Kolossa-Gehring, Marike; Moriske, Heinz-JörnVeröffentlichung 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 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.