In view of the advanced development of new specific active pharmaceutical ingredients, the question arises as to whether the established standard procedures for the environmental risk assessment in the context of marketing authorization are still sufficient to adequately cover relevant effects on environmental organisms. The focus of this project is on specific test strategies for substances from the group of oncologicals, cardiologicals and statins, as well as their experimental verification in case studies. Studies with aquatic plants in the Lemna sp. Growth Inhibition Test ( OECD 221), the zebrafish embryo toxicity test (OECD 236) amended with sublethal endpoints and the comet assay with environmentally relevant cell types are discussed as possible adaptations, although not all of them proved to be suitable. Veröffentlicht in Texte | 21/2024.
Within the project "bioassay-based test strategy to determine risk potentials of migration waters" the German Environment Agency (UBA ) and the Association for Pipe Systems Inside Buildings (VRH) had the common aim to develop a test strategy based on established bioassays. This in vitro test strategy detects cytotoxicity, genotoxicity and estrogenic like activity of migration waters. Quelle: https://www.umweltbundesamt.de
Im Projekt "Biotestbasierte Prüfstrategie zur Erfassung von Gefährdungspotenzialen in Migrationswässern" hatten das Umweltbundesamt (UBA ) und der Verein für Rohrleitungssysteme in der Haustechnik e.V. (VRH) das Ziel eine auf Biotests basierende Prüfstrategie zu entwickeln. Diese In-vitro-Teststrategie erfasst die Zytotoxizität, die Gentoxizität und die estrogenartige Wirkung von Migrationswässern. Quelle: https://www.umweltbundesamt.de
Deutsch: Während eines Handytelefonats kann die Wange vergleichsweise starken hochfrequenten elektromagnetischen Feldern ausgesetzt sein (Exposition). Diese Studie am Menschen untersucht die Wirkung dieser Felder auf Zellen der Wangenschleimhaut unter realistischen Bedingungen. Es wurden einige zytotoxische Wirkungen, aber keine Chromosomschäden gefunden. Im Vergleich zu früheren Studien wurde die Erzeugung und Quantifizierung der Exposition sowie die Gewebeuntersuchungen methodisch verbessert, die Aussagekraft der Studie ist jedoch limitiert.
Due to their beneficial properties, the use of zinc oxide nanoparticles (ZnO NP) is constantly increasing, especially in consumer-related areas, such as food packaging and food additives, which is leading to an increased oral uptake of ZnO NP. Consequently, the aim of our study was to investigate the cellular uptake of two differently sized ZnO NP (<50 nm and <100 nm; 12-1229 (micro)mol/L) using two human intestinal cell lines (Caco-2 and LT97) and to examine the possible resulting toxic effects. ZnO NP (<50 nm and <100 nm) were internalized by both cell lines and led to intracellular changes. Both ZnO NP caused time- and dose-dependent cytotoxic effects, especially at concentrations of 614 (micro)mol/L and 1229 (micro)mol/L, which was associated with an increased rate of apoptotic and dead cells. ZnO NP < 100 nm altered the cell cycle of LT97 cells but not that of Caco-2 cells. ZnO NP < 50 nm led to the formation of micronuclei in LT97 cells. The Ames test revealed no mutagenicity for both ZnO NP. Our results indicate the potential toxicity of ZnO NP after oral exposure, which should be considered before application. © 2021 by the authors
Background<BR>At Holi festivals, originally celebrated in India but more recently all over the world, people throw coloured powder (Holi powder, Holi colour, Gulal powder) at each other. Adverse health effects, i.e. skin and ocular irritations as well as respiratory problems may be the consequences. The aim of this study was to uncover some of the underlying mechanisms.<BR>Methods<BR>We analysed four different Holi colours regarding particle size using an Electric field cell counting system. In addition, we incubated native human cells with different Holi colours and determined their potential to induce a pro-inflammatory response by quantifying the resulting cytokine production by means of ELISA (Enzyme Linked Immunosorbent Assay) and the resulting leukocyte oxidative burst by flow cytometric analysis. Moreover, we performed the XTT (2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and Propidium iodide cytotoxicity tests and we measured the endotoxin content of the Holi colour samples by means of the Limulus Amebocyte Lysate test (LAL test).<BR>Results<BR>We show here that all tested Holi colours consist to more than 40 % of particles with an aerodynamic diameter smaller than 10 ìm, so called PM10 particles (PM, particulate matter). Two of the analysed Holi powders contained even more than 75 % of PM10 particles.<BR>Furthermore we demonstrate in cell culture experiments that Holi colours can induce the production of the pro-inflammatory cytokines TNF-á(Tumor necrosis factor-á), IL-6 (Interleukine-6) and IL-1â(Interleukine-1â). Three out of the four analysed colours induced a significantly higher cytokine response in human PBMCs (Peripheral Blood Mononuclear Cells) and whole blood than corn starch, which is often used as carrier substance for Holi colours. Moreover we show that corn starch and two Holi colours contain endotoxin and that certain Holi colours display concentration dependent cytotoxic effects in higher concentration. Furthermore we reveal that in principle Holi colours and corn starch are able to generate an oxidative burst in human granulocytes and monocytes. In Holi colour 1 we detected a fungal contamination.<BR>Conclusions<BR>Some of the observed unwanted health effects of Holi colours might be explained by the high content of PM10 particles in conjunction with the possible induction of a pro-inflammatory response and an oxidative leukocyte burst.<BR>Quelle: http://occup-med.biomedcentral.com
Uranium occurs naturally in soil and rocks, and therefore where it is present in water-soluble form it also occurs naturally in groundwater as well as in drinking water obtained from groundwater. Animal studies suggest that the toxicity of uranium is mainly due to its damage to kidney tubular cells following exposure to soluble uranium compounds. The assessments of the absorption of uranium via the gastrointestinal tract vary, and this has consequences for regulation, in particular the derivation of e.g. drinking water limit values. Absorption rates vary according to the nature and solubility of the compound in which uranium is presented to the test animals and depending on the animal species used in the test. No differences for sex have been observed for absorption in either animals or humans. However, human biomonitoring data do show that boys excrete significantly more uranium than girls. In animal studies neonates took up more uranium than adults or older children. Nutritional status, and in particular the iron content of the diet, have a marked influence on absorption, and higher uranium levels in food intake also appear to increase the absorption rate. If the pointers to an absorption mechanism competing with iron are correct, these mechanisms could also explain the relatively high concentration and chemical toxicity of uranium in the kidneys. It is here (and in the duodenum) that divalent metal transporter 1 (DMT1), which is primarily responsible for the passage of iron (or uranium?) through the cell membranes, is most strongly expressed.Quelle: http://www.sciencedirect.com
Pool water is continuously circulated and reused after an extensive treatment including disinfection by chlorination, ozonation or UV treatment. In Germany, these methods are regulated by DIN standard 19643. Recently, the DIN standard has been extended by a new disinfection method using hypobromous acid as disinfectant formed by introducing ozone into water with naturally or artificially high bromide content during water treatment. In this study, we tested the disinfection efficacy of the ozone-bromine treatment in comparison to hypochlorous acid in a flow-through test rig using the bacterial indicator strains Escherichia coli, Enterococcus faecium, Pseudomonas aeruginosa, and Staphylococcus aureus and the viral indicators phage MS2 and phage PRD1. Furthermore, the formation of disinfection by-products and their potential toxic effects were investigated in eight pool water samples using different disinfection methods including the ozone-bromine treatment. Our results show that the efficacy of hypobromous acid, depending on its concentration and the tested organism, is comparable to that of hypochlorous acid. Hypobromous acid was effective against five of six tested indicator organisms. However, using Pseudomonas aeruginosa and drinking water as test water, both tested disinfectants (0.6 mg L-1 as Cl2 hypobromous acid as well as 0.3 mg L-1 as Cl2 hypochlorous acid) did not achieve a reduction of four log10 levels within 30 s, as required by DIN 19643. The formation of brominated disinfection by-products depends primarily on the bromide concentration of the filling water, with the treatment method having a smaller effect. The eight pool water samples did not show critical values in vitro for acute cytotoxicity or genotoxicity in the applied assays. In real pool water samples, the acute toxicological potential was not higher than for conventional disinfection methods. However, for a final assessment of toxicity, all single substance toxicities of known DBPs present in pool water treated by the ozone-bromine treatment have to be analyzed additionally. © 2021 The Authors
Depending on the ambient pH, ionizable substances are present in varying proportions in their neutral or charged form. The extent to which these two chemical species contribute to the pH-dependant toxicity of ionizable chemicals and whether intracellular ion trapping has a decisive influence in this context is controversially discussed. Against this background, we determined the acute toxicity of 24 ionizable substances at up to 4 different pH values on the embryonic development of the zebrafish, Danio rerio, and supplemented this dataset with additional data from the literature. The LC50 for some substances (diclofenac, propranolol, fluoxetine) differed by a factor of even >103 between pH5 and pH9. To simulate the toxicity of 12 acids and 12 bases, six models to calculate a pH-dependant logD value as a proxy for the uptake of potentially toxic molecules were created based on different premises for the trans-membrane passage and toxic action of neutral and ionic species, and their abilities to explain the real LC50 data set were assessed. Using this approach, we were able to show that both neutral and charged species are almost certainly taken up into cells according to their logD-based distribution, and that both species exert toxicity. Since two of the models that assume all intracellular molecules to be neutral overestimated the real toxicity, it must be concluded, that the toxic effect of a single charged intracellularly present molecule is, on the average, lower than that of a single neutral molecule. Furthermore, it was possible to attribute differences in toxicity at different pH values for these 24 ionizable substances to the respective deltas in logD at these pH levels with high accuracy, enabling particularly a full logD-based model on the basis of logPow as a membrane passage descriptor to be used for predicting potential toxicities in worst-case scenarios from existing experimental studies, as stipulated in the process of registration of chemicals and the definition of Environmental Quality Standards (EQS). © 2023 The Author(s).
Mustard 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.com
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