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Pestizide werden als Pflanzenschutzmittel im landwirtschaftlichen Bereich und als Biozide z. B. in der Industrie, in Haushalten und Kommunen eingesetzt. Bereits auf den behandelten Flächen und in den angrenzenden Gewässern können Pestizide Abbauprozessen durch u. a. Photolyse unterliegen. Diese Prozesse führen zur Entstehung von Transformationsprodukten (TP), deren Berücksichtigung bei der Umweltrisikobewertung für ein umfassendes Risikomanagement von großer Bedeutung ist. Doch gibt es über die in der Umwelt vorkommenden Transformationsprozesse und die dabei entstehenden TP immer noch Wissenslücken. Darüber hinaus sind die Eintragswege von TP, vor allem von Biozid-TP, in die angrenzenden Gewässer zum Teil unbekannt. Da eine Vielzahl von TP mit unterschiedlich starken ökotoxikologischen Effekten bewertet werden muss, besteht ein großer Bedarf an schnellen und umfassenden Methoden, um die stetig wachsende Anzahl an Chemikalien auf dem Markt erfassen zu können. Das Ziel der vorliegenden Arbeit ist daher, das Verhalten und den Verbleib ausgewählter Pestizid-TP in der aquatischen Umwelt zu analysieren. Zu diesem Zweck wurden unterschiedliche Phototransformationsprozesse von Pestiziden sowie der Eintrag aus Fassaden über Regenwasserversickerungsanlagen (RVA) in angrenzenden Gewässern der Stadt Freiburg untersucht. Schlussendlich erfolgte die Identifizierung der ökotoxikologischen Eigenschaften von 45 Pestizid-TP in einem mehrstufigen Ansatz durch die Kombination experimenteller und computerbasierter Methoden. Inwiefern unterschiedliche Phototransformationsprozesse zu unterschiedlichen TP führen, wurde im ersten Teil der Arbeit durch einen Vergleich der Entstehung von TP durch direkte und indirekte Photolyse der Substanzen Penconazol, Terbutryn und Mecoprop untersucht. Weiterhin wurde der Abbau durch die Bestrahlung mit unterschiedlichen Xenonlampen untersucht. Im zweiten Teil der Arbeit wurde der Eintrag von Bioziden, die in Fassadenanstrichen Anwendung finden, und deren TP über Regenwasserversickerungsanlagen in das Grundwasser untersucht. Dabei wurden qualitative und quantitative Target-Screening-Methoden zum Nachweis und zur Quantifizierung bekannter und unbekannter TP der Biozide Diuron, Terbutryn und Octhilinon (OIT) in der aquatischen Umwelt mittels Flüssigkeitschromatographie mit gekoppeltem Massenspektrometer (LC-MS) kombiniert. Die ökotoxikologischen Eigenschaften von 45 Pestizid-TP wurden im dritten Teil dieser Arbeit in einem mehrstufigen Ansatz untersucht. Insgesamt zeigte sich, dass die Berücksichtigung von TP im Rahmen von Gewässerüberwachung und Risikobewertung eine genauere Abschätzung der Risiken durch Schadstoffe ermöglicht. Die in dieser Dissertation entwickelte Vorgehensweise, bei der TP zunächst im Labor erzeugt und bewertet und anschließend in aquatischen Systemen gezielt analysiert werden, kann einen wichtigen Beitrag zur Regulatorik des Einsatzes und der Zulassung von Pestiziden leisten.
Metals fulfill crucial functions in areas as diverse as renewable energy, digitization and life style appliances, mobility, communication, or medicine. In the context of sustainability, achieving a more sustainable metal use means (i) minimizing the adverse effects associated with metal production and use and (ii) sustaining the availability of metals in a way that benefits present and future generations. Urgent need to act to avoid bottlenecks as well as meeting the challenge of possible conflicts of use among those areas of application calls for appropriate strategy making to intervene in the complex field of metal production and use that involves various, often interlinked operating levels, actors, and spatial and temporal scales. This dissertation focuses on strategies as a means to intervene in a system. It pursues the question, which design features could guide future strategy making to foster sustainability along the whole metal life cycle, and especially, how a better understanding of temporalities, i.e. understanding time in a diverse sense, could improve strategy design and help to bridge the assumed "transformation-material gap". This research converges the results from four research studies. A conceptual part explores the role of temporalities for interventions in complex and interlinked systems, which adds to the conceptual basis, on which the empirical part builds up to explore present and future interventions in metal production and use. The research revealed three essential needs that future strategies must tackle: (i) managing the complex interlinkages of processes and activities on various operational levels and spatial and temporal scales, (ii) providing clear guidance concerning the operationalization of sustainability principles, and (iii) keeping activities within the planet’s carrying capacity and embracing constant change as an inherent system characteristic. In response to these needs, the author developed three guidelines with two design features each (one relating to content, and one to the process of formulating and implementing the strategy) to guide future strategy making. The results show that time matters in this respect. If considered in close relation to space and diversely understood in the sense of temporalities, it serves to (i) understand the impact (duration and magnitude) of an intervention, (ii) recognize patterns of change that go beyond establishing linear, one-dimensional connections, and (iii) design interventions in a way that considers the resilience of a system. These findings can contribute to closer considering our understanding of transformation processes towards sustainability in future interventions in metal production and use.
Despite the great progress that has been made in the prophylaxis of oral diseases over the past decades, dental caries and periodontal diseases remain major challenges in the field of dentistry. Biofilm formation on dental hard tissues is strongly associated with the etiology of these oral diseases. Therefore, the process of bioadhesion and biofilm formation on tooth surfaces is of particular interest for dental research. The first stage of bioadhesion on dental surfaces is the formation of the pellicle layer. This mainly acellular film, composed largely of adsorbed proteins, glycoproteins, and lipids, is distinguished from the microbial biofilm (plaque). As the interface between teeth and the oral environment, the pellicle plays a key role in the maintenance of oral health and is of great physiological and pathophysiological importance. On the one hand, the pellicle shows protective properties for the underlying dental hard tissues. On the other hand, it also serves as the basis for dental plaque and therefore, for the development of oral diseases such as caries and periodontitis. Hydrophobic interactions, which are governed by lipophilic substances, are of high relevance for bacterial adherence. Therefore, pellicle lipids, which are a significant constituent of this biological structure, are an interesting target for dental research, as they could modulate oral surfaces, influence microbial interactions, and potentially impede bacterial adherence. Compared to the extensive work on the pellicle´s ultrastructure and protein/amino acid composition, little attention has been given to its lipid profile. Knowledge of the lipid composition of the pellicle may provide insight into several oral pathological states, including caries, dental erosion, and periodontal disease processes and could contribute to novel approaches in preventive dentistry. The principle aim of this thesis was the comprehensive characterization of the fatty acid (FA) profile of the in situ formed pellicle layer. This includes the influence of pellicle maturation on the FA profile as well as intra- and interindividual differences. Furthermore, investigations on the effect of rinses with edible oils on the pellicle´s FA composition were a focus of this work. For these purposes, an analytical method based on a combination of innovative specimen generation and convenient sample preparation with sensitive mass spectrometric analysis was successfully developed and comprehensively validated within this thesis. Pellicle samples were formed in situ on bovine enamel slabs mounted on individual upper jaw splints. After a comprehensive sample preparation, gas chromatography coupled with electron impact ionization mass spectrometry (GC-EI/MS) was used in order to characterize qualitatively and quantitatively a wide range of FA (C12-C24). The individual FA profiles of pellicle and saliva samples collected from ten research participants were investigated. The relative FA profiles of the pellicle samples gained from the different subjects were very similar, whereas the amount of FAs showed significant interindividual variability. Compared to the pellicle´s characteristic FA profile, higher proportions of unsaturated FAs were detected in the saliva samples, highlighting that FAs available in saliva are not adsorbed equivalently to the pellicle layer. This, in turn, shows that pellicle formation is a highly selective process that does not correlate directly with salivary composition. Additionally, pellicle samples collected after 3, 30, 60, 120, and 240 min of intraoral exposure were analyzed. It could be shown that pellicle maturation has only a minor impact on the FA composition. However, the FA content increased substantially with increasing oral exposure time. Modifying the pellicle´s lipid composition by using edible oils as a mouthwash could alter the physicochemical characteristics of the pellicle and strengthen its protective properties by delaying bacterial adhesion. Therefore, the impact of rinses with safflower oil on the pellicle´s FA composition was determined. The application of rinses with safflower oil resulted in an accumulation of its specific FAs in the pellicle, thus representing a possibility for modifying the pellicle´s lipid profile. The present work is the first to apply a validated method that combines in situ pellicle formation, sample preparation, and the comprehensive determination of FAs via a sensitive analytical method. The results provide valuable information regarding the pellicle´s FA composition which closes an existing knowledge gap in pellicle research. A broader knowledge of the lipid composition of the pellicle contributes to the understanding of oral bioadhesion processes and may help facilitate novel approaches in preventive dentistry.
After being administrated to humans or animals, pharmaceuticals may be metabolized by a variety of mechanisms and pathways within the body. Once these compounds and/or their metabolites are excreted, they may undergo degradation in the aquatic environment. Unfortunately, a rapid and complete mineralization cannot always be guaranteed, whereas relatively stable transformation products (TPs) may be formed. The largest part of older studies focused on investigation of the elimination kinetics of parent compounds without considering the amount and chemical structure of individual TPs. Only recently, there is an increasing trend to deliver such information. Nevertheless, since drugs are defined as significant environmental pollutants, it is not only important to elucidate their TPs, but also necessary to investigate whether these formed compounds preserve the same mode of action as the parent compound or are even more toxic. Thus, two main objectives of this thesis can be formulated. Firstly, to highlight the concern originated by metabolites and transformation products of pharmaceuticals that contaminate the environment. Hereby, the already-published knowledge on TPs within a certain selection of drugs is assessed to exemplify the number and quality of the existing information on their TPs. Secondly, to particularly investigate the fate of the antibiotic ciprofloxacin (CIP). This is done by (a) evaluating the suitability and sustainability of the photolytic decomposition as an advanced water treatment technique, (b) monitoring the course of genotoxicity of the irradiated mixtures using a battery of genotoxicity and cytoxicity in vitro assays, and (c) considering the potential genotoxicity for CIP´s individual TPs by the employment of in silico approaches using quantitative structure activity relationships (QSAR) models. This thesis based on the results and conclusions of five articles, which can be found in the appendix. A systematic literature review was conducted on the current state of knowledge on pharmaceuticals and its derivatives in the environment. Two groups, namely antibiotics and anticancer drugs, were considered more closely with respect to the availability of chemical structures for their TPs. Furthermore, the photodegradation of CIP as well as a preliminary toxicity assessment of its identified TPs were investigated in three research papers. An extensive review with a table at its core shows the existing data on 158 TPs, which already have an assigned registry number in chemical abstracts service (CAS-RN), was presented. In total, 294 TPs, identified with chemical structures in the literature, were found for 15 compounds out of the 21 that were selected as target compounds. Eleven TPs, created from CIP, were identified by high-performance liquid chromatography/high-resolution multiple-stage mass spectrometry. It was detected that the transformation of CIP mainly occurred through substitution of fluorine, defluorination, hydroxylation of the quinolone core and the breakdown of the piperazine ring. Some of the identified TPs of CIP were predicted as genotoxic by QSAR analysis, while the experimental testing for a few genotoxic and cytotoxic endpoints showed that the potential of the resultant mixtures could be primarily dependent on the concentration of residual CIP. In contrast, irradiation mixtures were neither mutagenic in the Ames Test nor genotoxic in the in vitro Micronucleus Test. It is possible that the effect of the TPs was masked by antagonistic mixture interactions and/or they were not formed at effectively concentrations. Nevertheless, all of the identified TPs of CIP still retained the core quinolone moiety, which is responsible for the biological activity. Thus, a more comprehensive assessment, encompassing more genotoxic endpoints, chemical analysis characterization and exposure analyses, needs to be conducted. Information available on TPs demonstrates that already slight changes in treatment conditions and processes result in the formation of different TPs. Nevertheless, most of the transformation products could neither be identified nor fully assessed regarding their toxicity. This, in turn, presents a major challenge for the identification and assessment of TPs. Hence, from a practical and sustainability point of view, limiting the input of pharmaceuticals into effluents as well as improving their (bio)degradability and elimination behavior, instead of only relying on advanced effluent treatments, is urgently needed. Solutions that focus on this
Siliziumorganische Substanzen sind aus dem Alltag kaum wegzudenken. Sie kommen in vielfältiger Form vor und finden durch ihre Stabilität in vielen Produkten des Haushalts und der Industrie Anwendung. Eine Freisetzung in die Umwelt ist unvermeidbar. Siliziumorganische Substanzen konnten bereits in allen Umweltkompartimenten (Luft, Wasser, Boden) analytisch nachgewiesen werden. Welche Risiken von dieser Stoffgruppe ausgehen, ist noch nicht abschließend geklärt. Dennoch gibt es Hinweise auf negative Auswirkungen auf Mensch und Umwelt. Deshalb sollten Strukturen in siliziumorganischen Substanzen untersucht werden, die einen Abbau in der Umwelt begünstigen, um die Akkumulation dieser Stoffe in der Umwelt zu verringern. Dafür wurden diverse biotische und abiotische Abbautests mit unterschiedlichen siliziumorganischen Substanzen durchgeführt. Der Fokus der vorliegenden Arbeit lag vor allem in der biologischen Abbaubarkeit der Substanzen. Es wurden die Organisation for Economic Co-operation and Development (OECD)-konformen Tests Closed-Bottle-Test (CBT, OECD 301D) und Manometrischer Respirationstest (MRT, OECD 301F) durchgeführt. Die Hydrolysierbarkeit wurde mithilfe des Hydrolysetests OECD 111 bei unterschiedlichen pH-Werten untersucht. Bei bestimmten Substanzgruppen ohne biologischen Abbau wurde das Verhalten der Substanzen bei Bestrahlung mit verschiedenen Bestrahlungsquellen untersucht. Die Analyse der Primärelimination der siliziumorganischen Substanzen erfolgte je nach Substanzeigenschaften mithilfe der Hochleistungsflüssigkeitschromatografie gekoppelt mit einem Spektrometer mit ultraviolettem und sichtbarem Licht (HPLC-UV/Vis) oder der Gaschromatografie gekoppelt mit einem Massenspektrometer (GC-MS). Die Transformationsprodukte wurden hingegen mithilfe der Flüssigkeitschromatografie gekoppelt mit einem Mehrfach-Massenspektrometer (LC-MSn) analysiert. Für eine umfassende Bewertung des biologischen Abbaus von siliziumorganischen Substanzen wurden ein Vergleich mit analogen Kohlenstoffverbindungen und eine Aufstockung mit Daten aus der Datenbank der Europäischen Chemikalien Agentur (ECHA) durchgeführt. Die Gruppierung der Substanzen nach ihren Strukturmerkmalen wurde hinzugezogen, um Rückschlüsse auf die Abbaubarkeit zu ziehen. Eine besser biologisch abbaubare Grundstruktur brachte für die Benzenderivate keine Verbesserung der biologischen Abbaubarkeit. Dennoch hatte die Einführung von +M-Gruppen am Aromaten einen positiven Einfluss auf die Geschwindigkeit und den Grad des photolytischen Abbaus. Die Bestrahlungsquelle hatte ebenfalls einen deutlichen Einfluss auf die Eliminierungsrate während des Photolyseexperiments. Mit einer Veränderung der Wellenlängen in den kurzwelligen Bereich und der daraus resultierenden energiereicheren Strahlung konnten die Substanzen schneller und teilweise vollständig primär eliminiert werden. Bei allen Abbaupfaden hatte die Hydrolyse eine entscheidende Rolle und wurde als einer der Hauptabbauprozesse charakterisiert. Bei einer Verbindung wurde im Nachgang an die biotischen und abiotischen Abbautests eine ausführliche Aufklärung der elf gebildeten Transformationsprodukte vorgenommen. Um den Einfluss von Silizium in organischen Substanzen auf die biologische Abbaubarkeit zu untersuchen, wurde der direkte Vergleich von siliziumorganischen Substanzen und deren Kohlenstoffanaloga im CBT durchgeführt. Dabei hat sich gezeigt, dass drei von fünf Kohlenstoffverbindungen und keine siliziumorganische Verbindung als leicht biologisch abbaubar eingestuft werden konnten. In allen bis auf einen Fall konnten für die Kohlenstoffverbindungen höhere Abbauraten im CBT beobachtet werden. Die Hydrolyse wurde als erforderlicher Schritt vor dem biologischen Abbau von siliziumorganischen Substanzen identifiziert. Das siliziumfreie Produkt der Hydrolyse bestimmte den Grad des biologischen Abbaus. Die gute biologische Abbaubarkeit der einen siliziumorganischen Verbindung resultierte aus der leicht hydrolysierbaren Silizium-Stickstoff-Bindung und der leichten biologischen Abbaubarkeit des siliziumfreien Hydrolyseproduktes. Die siliziumhaltigen Reaktionsprodukte der Hydrolyse waren nicht biologisch abbaubar. Bioabbaudaten aus eigenen Experimenten, aus vorhergehenden in der Arbeitsgruppe durchgeführten analogen Arbeiten und aus der ECHA-Datenbank wurden zusammengetragen, um einen Datensatz zu generieren. Die 182 Substanzen des Datensatzes wurden hinsichtlich ihrer Struktur gruppiert, um allgemeine Erkenntnisse für die biologische Abbaubarkeit von siliziumorganischen Verbindungen abzuleiten. Es gab Gruppen mit Substanzen, die überhaupt nicht biologisch abbaubar waren (z. B. zyklische, lineare und verzweigte Siloxane). Gruppen, die Substanzen mit Ethern, Estern, Oximen, Aminen und Amiden enthielten, waren hydrolyseanfällig, sodass auch leicht biologisch abbaubare Zwischenprodukte gebildet werden konnten. Die siliziumfreien Hydrolyseprodukte waren meist biologisch abbaubar, während die siliziumhaltigen Hydrolyseprodukte persistent waren. Allgemein hat sich gezeigt, dass Modifikationen am Molekül einen positiven Einfluss auf die Abbaubarkeit haben können. Beispielsweise können Heteroatome eine Veränderung der Polarität bzw. der Elektronendichte hervorrufen, was die Photolyse- und Hydrolysefähigkeit und folglich auch den Bioabbau zum Positiven verändern kann. Das Einführen solcher Heteroatome oder funktioneller Gruppen in Polysiloxanketten kann demnach ein vielversprechender Ansatz für leichter abbaubare siliziumorganische Verbindungen sein. Nicht abbaubare Stoffe sollten vermieden werden, wenn sie nach ihrer Verwendung in die Umwelt gelangen.
Fire plays an important role in the earth system by influencing ecosystems and climate, but climate in turn also influences fire. The system became more complex when humans started using fire as a tool. Understanding the interaction between humans, fire and climate is the major aim of paleofire research. Understanding changes in these three aspects in the past will help predicting future climate, fire and human interactions. The use of lake sediment cores as natural archives for reconstructing past fire activity by counting charcoal particles is well established. This present dissertation is dedicated to the evaluation and application of specific organic molecular markers for biomass burning: levoglucosan, mannosan and galactosan were used as proxies for reconstructing past fire activity in lake sediments thorough the entire Holocene. First, a new analytical method was developed using high-performance anion exchange chromatography combined with mass spectrometry to separate and detect these three monosaccharide anhydrides in lake sediments. The suitability of this analytical method was proven by comparing the levoglucosan, mannosan and galactosan results in selected lake sediment samples from Lake Kirkpatrick, New Zealand and by correlating the results with macroscopic charcoal. Furthermore, the method was successfully applied to a lake sediment core from Lake Petén Itzá, Guatemala to reconstruct regional Holocene fire history. The analyses of levoglucosan were combined with fecal sterols to reconstruct late Holocene human fire interactions at Lake Trasimeno, Italy, demonstrating low fire activity during the Roman period. This combination of studies proves that these molecular markers are valid fire proxies in sediments from multiple locations around the globe. Comparison of levoglucosan, mannosan and galactosan concentrations with macroscopic charcoal trends in Lake Kirkpatrick and Lake Petén Itzá, suggests that the molecular markers represent more regional fire history and low temperature fires in contrast to macroscopic charcoal, which is a local fire proxy. In addition, vegetation changes (Lake Kirkpatrick and Lake Petén Itzá) and charcoal morphotypes (Lake Petén Itzá) were compared to the levoglucosan/mannosan and levoglucosan/(mannosan+galactosan) ratios suggesting that these ratios may be a suitable tool to track burned fuel. Biodegradation tests demonstrate the potential degradation of levoglucosan, mannosan and galactosan if dissolved in water, but findings in ancient sediment samples suggest that particle-bound levoglucosan, mannosan and galactosan can be buried in sediments over millennial time scales. Although uncertainties still exist, the results of this research suggests that organic molecular markers are a suitable regional fire proxy and isomer ratios may help understand changes in burned vegetation.
Among all attenuation processes, biodegradation plays one of the most important role and is one of the most desirable processes in the environment. To assess biodegradation, a variety of biodegradation test procedures have been developed by several international organizations. OECD guidelines for ready biodegradability testing represent one of the most prominent group of internationally used screening biodegradation tests (series 301A-F). These tests are usually very simple in their designs and allow for the fast and cheap screening of biodegradability. However, because of their stringency, the test conditions are not close to simulating environmental conditions and may lead to unrealistic results. To overcome these limitations, OECD introduced simulation tests which are designed to investigate the behavior of chemicals in specified environmentally relevant compartments. Despite the fact that simulation tests give more insight into the fate of chemicals in the environment, they are not applied frequently as they are often tedious, time consuming and expensive. Consequently, there is a need to provide a new biodegradation testing method that would combine complex testing environment as in simulation tests, easiness in handling and good data repeatability as in screening biodegradation tests. Another challenge is an adaption of the existing biodegradation testing methods to new types of samples, i.e. mixtures of transformation products (TPs). The research on the presence of pharmaceuticals in the environment gained momentum in the 1990s; since then, it has been growing. Their presence in the environment is a wellestablished fact. A wide range of pharmaceuticals is continuously detected in many environmental compartments such as surface waters, soils, sediments, or ground waters. After pharmaceuticals reach the natural aquatic environment they may undergo a number of processes such as: photolysis (under direct sunlight), hydrolysis, oxidation and reduction reactions, sorption, biodegradation (by bacteria of fungi), and bioaccumulation. These processes, may cause their elimination from aquatic environment, if reaction is complete, or creation of new compounds i.e., transformation products (TPs). What is more, processes, like chlorination and advanced oxidation processes (AOPs), such as H2O2/UV, O3/UV, TiO2/UV, Fenton, and photo-Fenton, or UV treatment which might be applied in water or wastewater treatment, may also lead to the TPs introduction into aquatic environment. The research on the TPs brings many new challenges. From one side, there is a constant need for the the development of a sensitive and reliable analytical separation, detection, and structure elucidation methods. Additionally, there is a need for the preparation of appropriate assays for the investigation of properties of new compounds, especially those answering the question if TPs pose a higher risk to the aquatic ecosystems than their parent compounds. Among numerous groups of pharmaceuticals, two are of great importance: antibiotics since they might promote emergence and maintenance of antimicrobial resistance in the aquatic environment; and cytostatic drugs. Cytostatic drugs can exert carcinogenic, mutagenic and/or teratogenic effects in animals and humans. The challenges of biodegradation testing presented in this thesis, encompasses these different areas of interest and was divided into three objectives: 1) Identification of the knowledge gaps and data distribution of the two groups of pharmaceuticals antibiotics and cytostatic drugs (article I); 2) Increasing the knowledge on biodegradation of cytostatic drugs and their TPs (articles II, III, and IV) and 3) Establishment of a biodegradation test with closer to simulation tests conditions, that could be affordable and to support better understanding on processes in water sediment interface construction - screening water-sediment test. Further validation of the test with an insight into sorption and desorption processes (articles V and VI).
Recent studies have confirmed that the aquatic ecosystem is being polluted with an unknown cocktail of pharmaceuticals, their metabolites and/or their transformation products (TPs). Although individual pharmaceuticals are typically present at low concentrations, their continuous input into the aquatic ecosystem and their toxic and persistent presence are the major environmental concerns. Therefore, it is necessary to assess the environmental risk caused by these aquatic pollutants. Data on exposure are required for quantitative risk assessment of parent compounds and their transformation products (TPs) and/or metabolites. Such data are mostly missing, especially for TPs, because of the non-availability of TPs and very often metabolites for experimental testing. Therefore, the application of different in silico tools for qualitative risk assessment can be used. Also, the presence of these micro-pollutants (active pharmaceutical ingredients, APIs) in the aquatic cycle are increasingly seen as a challenge to the sustainable management of water resources worldwide due to ineffective effluent treatment and other measures for their input prevention. Given the poor prognosis for effluent treatment (‘end of the pipe’ approach) for input prevention of APIs in the environment, it is necessary to focus on the ‘beginning of the pipe’ strategy. The very beginning of the pipe is the molecules themselves. Therefore, novel approaches are needed like designing greener pharmaceuticals, i.e. better biodegradable ones in the aquatic environment after their release. Therefore, the present research work focused on two important topics a) assessment of the environmental risk associated with the presence of highly prescribed drugs and their TPs; b) demonstrating the feasibility of the ‘benign by design’ concept for designing biodegradable drug derivatives, which will have the better biodegradability in the environment after their release. The present thesis includes four research articles (1-4) which address these approaches. The first article is about the qualitative environmental risk assessment using the example of transformation products formed during photolysis (photo-TPs) of Diatrizoic acid (DIAT). Photolysis is the chemical reaction in which the compound is broken down by photons and often in combination with hydroxyl radicals. Photolysis is the most common abatement process of micro-pollutants in the environment. The qualitative risk assessment of DIAT and selected photo-TPs was performed by the PBT approach (i.e. Persistence, Bioaccumulation and Toxicity), using chemical analysis, experimental biodegradation test assays, QSAR models with several different toxicological endpoints and in silico read-across approaches. The second article addresses a tiered approach of implementing green and sustainable chemistry principles for theoretically designing better biodegradable and pharmacologically potent pharmaceuticals derivatives. Photodegradation process coupled with LC-MSn analysis, biodegradability testing and in silico tools such as quantitative structure-activity relationships (QSAR) analysis and molecular docking proved to be a very significant approach for the preliminary stages of designing chemical structures that would fit into the ´benign by design´ concept in the direction of green and sustainable pharmacy. Metoprolol (MTL) was used as an example. The third article was also the conceptual framework to get new drug derivatives that are biodegradable in order to tackle the global challenge of micro-pollutants in the aquatic cycle. This study increased the knowledge about the role of the attachment of certain functionalities to the parent drug molecule for its biodegradability whilst conserving drug-likeness. This approach was in the past a totally neglected issue within drug development. Atenolol (ATL), a selective β1 blocker, was selected as an example to incorporate the additional attribute such as biodegradability into its molecular structure while conserving its substructures responsible for β adrenergic receptor blocker activity. In fourth article, the concept of designing green biodegradable pharmaceuticals has been proven through expanded experimental analysis setting out from the experiences collected as described in article two and three. This study could be considered as a more extensive feasibility study of rational design of green drug derivatives. The non-selective β-blocker Propranolol (PPL) was used as an example. The risk assessment study (Article #1) contributes in enhancing the existing knowledge about the life cycle and behavior (fate) of pharmaceuticals with a special focus on photo-TPs which are generally formed during advanced effluent treatment and enter as such into the environment. Based on the obtained results, the application of the in silico tools for qualitative risk assessment analysis increased knowledge space about the environmental fate of TPs in case of their non-availability for experimental testing. The benign by design studies (Article #2-4) were based on the knowledge and experience collected during the work on DIAT. It demonstrated the feasibility of a novel approach of designing comparatively better degradable and pharmacological potent derivatives through the implementation of ´green chemistry´ principles. However, the present approach is in the juvenile stage and further knowledge has to be collected beforehand for the full implementation of this approach into drug development.
Organophosphorus flame retardants and plasticizers (OPEs) have been utilized for decades as plasticizers and, to a lesser extent, as flame retardants in various consumer products to improve their material properties. The research presented in this thesis investigated the occurrence, distribution and transport of OPEs with a focus on the coastal and estuarine environment. Due to the wide range of physicochemical properties of OPEs, the environmental fate and behaviour of OPEs was investigated over a range of compartments, starting from the atmospheric occurrence to the aquatic phase and the behaviour in sediments. The aim was to gather information on the OPE contamination situation in the coastal and estuarine environments, to identify specific contamination patterns for source assessment and to investigate the distribution behaviour of OPEs between gas- and particle-phases to evaluate their environmental transport mechanism. To achieve these scientific goals, sensitive and robust chemical analytical methods for the detection and quantification of OPEs in a variety of environmental samples using gas-chromatography coupled with tandem mass spectrometry were developed. Water samples were removed along the Elbe and Rhine Rivers to test the hypothesis of whether specific point sources, such as wastewater treatment plants, are the major input pathways for OPE contamination in rivers. A total of 65 water samples, including an intensive measurement campaign during the flood event in 2013 at the Elbe, was taken and analysed for OPEs. No obvious point sources were identified along either of the rivers analysed. No significant increase or decrease in the OPE concentrations or a change in patterns were observed over a transect of over 300 km at the Elbe, with an increase in water discharge of 2.5. This finding suggested that the OPE input in large rivers is primarily driven by diffuse sources, such as surface runoff, or by minor point sources rather than local point sources. To examine the specific pattern of OPE contamination in individual rivers and estuaries, 37 sediment samples from 8 rivers in Europe and China were analysed. With this analytical data, a fingerprint analysis of the OPE patterns identified could be conducted. All the rivers investigated in Europe displayed a very similar fingerprint. In contrast, the fingerprint from China differed significantly from the one in Europe. For example, in China, the OPE restricted in Europe, Tris(2-chloroethly)phosphate, was found to be one of the major OPE components, while Tris(2-butoxyethyl) phosphate, a major compound in Europe, was negligible in China. The investigation showed that the fingerprinting analysis is a useful tool to identify different regions or characterize specific rivers regarding their OPE contamination. In addition, it could be shown that legislative restriction and processes have an impact on local or even EU-wide contamination patterns. At a coastal site next to the German city of Büsum, 58 air samples were taken over one year. Using the newly developed analytical method, it was possible to analyse the gas, as well as the particle phase, of the samples collected with very low detection limits for OPEs. In contrast to expectations, no annual trend in OPE concentrations, phase distributions or patterns was observed, but the investigation of the phase distribution challenged the previous scientific consensus that OPEs occur as primarily bound to particles in the atmosphere. Several compounds were detected in significant amounts in the gas phase. To validate these novel results, a model analysis based on the chemical properties of OPEs was conducted using three different phase distribution models. The results from the environmental data were strongly supported by the simulations, and the formal knowledge could be refuted. Consequently, the atmospheric transport assumptions and estimations about the long-range transport of OPEs have to be reassessed because compounds in the gas phase undergo other types of transport degradation and elimination mechanisms than particle-boundones. The novel findings presented in this thesis challenged an important aspect regarding the perceived scientific knowledge about the behaviour of OPEs in the environment and call on the scientific community to reassess the environmental behaviour of OPEs. The insights presented on the patterns highlight the impact of environmental policies and regulatory mechanisms to work towards the final goal of a good environmental status and the avoidance of adverse effects of discarded chemicals on humans and the environment.
Verbräuche von Arzneistoffen, die auf das menschliche Nervensystem wirken (Neurologika), unterliegen aufgrund der auf dem Markt befindlichen Arzneistoffvielfalt einem ständigen Wandel. Zudem waren die Haupteintragspfade für Neurologika in die aquatische Umwelt bisher nicht eindeutig geklärt. Haushalte (diffuser Eintrag) und Einrichtungen des Gesundheitswesens (punktueller Eintrag), wie psychiatrische Fachkliniken oder Pflegeheime, wurden als maßgebliche Eintragspfade diskutiert. Ziel dieser Arbeit war es deshalb, Arzneimittelverbräuche und damit verbundene Arzneistoffemissionen durch Haushalte und Einrichtungen des Gesundheitswesens mit Hilfe einer neu entwickelten Methode abzuschätzen. Bei dieser Methode wurde das jeweilige Ausmaß der Emissionen durch die Kalkulation von Abwasserkonzentrationen und den Vergleich von Verbrauchsmengen an Arzneistoffen bestimmt. Im Ergebnis konnte gezeigt werden, dass sich Arzneimittelverbrauchsmuster in psychiatrischen Fachkliniken und Pflegeheimen von denen in allgemeinen Krankenhäusern und Haushalten unterscheiden. Außerdem konnte mit dieser Methode deren jeweiliger Beitrag am gesamten Arzneistoffeintrag in das kommunale Abwasser eingeschätzt und in hohen Mengen in das Abwasser eingetragene Arzneistoffe identifiziert werden. Durch Haushalte wurde das hinsichtlich des Umweltverbleibs und -verhaltens wenig untersuchte Antiepileptikum Gabapentin in hohen Mengen in das Abwasser eingetragen. Die Bedeutung von Einrichtungen des Gesundheitswesens am Arzneimitteleintrag in das kommunale Abwasser konnte für alle untersuchten Einrichtungstypen im Vergleich zu Haushalten als gering eingestuft werden. Bestimmte einrichtungstypische Arzneistoffe, insbesondere Neurologika, können bei regionaler Betrachtung jedoch eine größere Rolle spielen. Insbesondere Quetiapin wurde in psychiatrischen Fachkliniken und Pflegeheimen als Substanz mit hohen Verbrauchsmengen und hohem Emissionspotential identifiziert. Ausgehend von diesen Erkenntnissen wurden Gabapentin und Quetiapin tiefergehend hinsichtlich ihres Verbleibs und ihres Verhaltens in der aquatischen Umwelt charakterisiert. Beide Arzneistoffe wurden bei verschiedenen Startkonzentrationen zur Simulation eines technischen Behandlungsverfahrens mit UV-Licht bestrahlt. Im weiteren Verlauf wurden Gabapentin und Quetiapin und die jeweilige Muttersubstanz im Gemisch mit gebildeten Phototransformationsprodukten hinsichtlich biologischer Abbaubarkeit im Closed Bottle Test und im Manometrischen Respirationstest nach OECD-Richtlinien und hinsichtlich toxischer Eigenschaften im Leuchtbakterientest und im Umu-Test beurteilt. Die Strukturaufklärung von Photo- und Biotransformationsprodukten erfolgte mittels hochauflösender Massenspektrometrie. Im Ergebnis konnten weder Gabapentin noch Quetiapin bei hohen Startkonzentrationen durch Photolyse über 128 min mineralisiert oder vollständig eliminiert werden. Identische Phototransformationsprodukte wurden bei unterschiedlichen Startkonzentrationen für die UVBehandlung gebildet. Die Arzneistoffe Gabapentin und Quetiapin waren nach OECD-Richtlinien im Closed Bottle Test nicht leicht biologisch abbaubar. Die photolytischen Gemische von Gabapentin sind nicht besser als Gabapentin selbst abbaubar und die Phototransformationsprodukte wurden im Closed Bottle Test ebenfalls nicht eliminiert. Auch das photolytische Gemisch von Quetiapin im Closed Bottle Test war nicht besser biologisch abbaubar als Quetiapin selbst. Die Phototransformationsprodukte von Quetiapin und Quetiapin selbst unterlagen beim Closed Bottle Test und im Manometrischen Respirationstest verschiedenen biologischen Transformationsprozessen und führten zur Bildung von verschiedenen Biotransformationprodukten. Das in biologischen Abbautests von Quetiapin maßgeblich gebildete Biotransformationprodukt BTP 398 konnte in diversen Flusswasserproben nachgewiesen werden. Dies lässt sich höchstwahrscheinlich damit erklären, dass BTP 398 unter anderem auch beim humanen Metabolismus gebildet wird. Die Langzeit-Leuchthemmung und die Zellvermehrungshemmung im Leuchtbakterientest stiegen im Verlauf der Photolyse von Gabapentin durch Bildung von Phototransformationsprodukten. Dies deutet auf eine erhöhte Toxizität der Phototransformationsprodukte im Vergleich zu Gabapentin hin. Bei Quetiapin war unter Photolyse keine Abnahme der schon vorhandenen Toxizität beim Leuchtbakterientest zu erkennen. Gabapentin, Quetiapin und deren Phototransformationsprodukte wiesen im Umu-Test keine Genotoxizität auf. …
The emission of anthropogenic trace substances into the aquatic environment continuously poses challenges to water suppliers. The contamination of raw waters with organic trace substances requires complex water treatment processes to secure drinking water quality. The routine monitoring of these raw waters as well as the behavior and fate of organic trace substances during different treatment processes is of great interest to recognize and counter potential dangers at an early stage. Non-target screening using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) allows the detection of thousands of compounds within a single run and covers known as well as unknown substances. Compared to the established analytical techniques, this is a decisive advantage for the monitoring of raw and process waters during water treatment. While the analytical technique LC-HRMS has undergone significant developments in recent years, the algorithms for data processing reveal clear weaknesses. This dissertation therefore deals with reliable processing strategies for LC-HRMS data. The first part of this work seeks to highlight the problematics of false positive and false negative findings. Based on repeated measurements, various strategies of data processing were assessed with regard to the repeatability of the results. To ensure that real peaks were barely or not removed by the filtering procedure, samples were spiked with isotope-labeled standards. The results emphasize that the processing of sample triplicates results in sufficient repeatability and that the signal fluctuation across the triplicates emerged as a powerful filtering criteria. The number of false positives and false negatives could be significantly reduced by the developed strategies which consequently improve the validity of the data. The second part of this thesis addresses the development of processing strategies particularly aimed at assessing water treatment processes. The detected signals were tracked across the treatment process and classified based on their fold changes. A more reliable signal classification was achieved by implementing a recursive integration approach. Special integration algorithms allow a reliable signal classification even though the signal to be compared was below the intensity threshold. Different combinations of replicates of process influents and effluents were processed for evaluating the repeatability. The good repeatability was indicated by the results of both the plausibility checks and the ozonation process (ozonation of pretreated river water) and thus points to high reliability. The applicability of the developed strategies to real world applications is demonstrated in the last part of this work. Besides the prioritization of the generated results, the main focus was the identification of recognized compounds. The developed strategies clearly improve the validity of the underlying data. The combination of LC-HRMS analysis with reliable processing strategies opens up multiple possibilities for a more comprehensive monitoring of water resources and for the assessment of water treatment processes. The processing strategies and validation concepts may be easily transferred to other research fields.
As modern society progresses, waste treatment becomes a pressing issue. Not only are global waste amounts increasing, but there is also an unmet demand for sustainable materials (e.g. bioplastics). By identifying and developing processes, which efficiently treat waste while simultaneously generating sustainable materials, potentially both these issues might be alleviated. Following this line of thought, this dissertation focuses on procedures for treatment of the organic fraction of waste. Organic waste is a suitable starting material for microbial fermentation, where carbohydrates are converted to smaller molecules, such as ethanol, acetic acid, and lactic acid. Being the monomer of the thermoplastic poly-lactic acid, lactic acid is of particular interest with regard to bioplastics production and was selected as target compound for this dissertation. Organic waste acted as substrate for non-sterile batch and continuous fermentations. Fermentations were initiated with inoculum of Streptococcus sp. or with indigenous consortium alone. During batch mode, concentration, yield, and productivity reached maximum values of 50 g L−1, 63%, and 2.93 g L−1 h −1. During continuous operation at a dilution rate of 0.44 d−1, concentration and yield were increased to 69 g L−1 and 86%, respectively, while productivity was lowered to 1.27 g L−1 h −1 . To fully exploit the nutrients present in organic waste, phosphate recovery was analyzed using seashells as adsorbent. Furthermore, the pattern of the indigenous consortium was monitored. Evidently, a very efficient Enterococcus strain tended to dominate the indigenous consortium during fermentation. The isolation and cultivation of this consortium gave a very potent inoculum. In comparison to the non-inoculated fermentation of a different organic waste batch, addition of this inoculum lead to an improved fermentation performance. Lactic acid yield, concentration, and molar selectivity could be increased from 38% to 51%, 49 g L−1 to 65 g L−1, and 46% to 86%, respectively. Eventually, fermentation process data was used to perform techno-economic analysis proposing a waste treatment plant with different catchment area sizes ranging from 50,000 to 1,000,000 people. Economically profitable scenarios for both batch and continuous operation could be identified for a community with as few as 100,000 inhabitants. With the experimental data, as well as techno-economic calculations presented in this dissertation, a profound contribution to sustainable waste treatment and material production was made.
The principle of this thesis was to study the environmental fate of three highly used psychotropic drugs and this achieved through: 1) examining the biodegradability of TMI, DMI and CPTX, 2) studying the behaviour of TMP, DMI and CPTX in photodegradation tests using Xe and UV lamps with studying the effect of different environmental conditions on their UV-photodegradation behaviour, 3) monitoring the primary elimination of TMP, DMI and CPTX during photodegradation and biodegradation tests using HPLC, and measuring their degree of mineralization by means of dissolved organic carbon analyser (DOC), 4) elucidating the structures of the transformation products (TPs) which formed during the degradation of TMI, DMI and CPTX by using LC-MS/MS analysis, 5) analysing the biodegradability of their TPs by laboratory tests and in-silico assessments in order to determine the fate and persistence of these TPs in the aquatic environment, 6) conducting in-silico toxicity predictions for the selected psychotropic drugs and their TPs in human (carcinogenicity, genotoxicity and mutagenicity) and in eco-system (toxicity to microorganisms and toxicity in rainbow trouts). As an overall conclusion, the present work demonstrates that a combination of laboratory simulation tests, LC-MS/MS analysis and in-silico tools result in valuable new information regarding environmental fate of three important psychotropic drugs and their TPs. This dissertation also highlights that different environmental conditions such as temperature, initial drug concentration and pH can differently affect the degradation behaviour of pharmaceuticals even when they are highly structurally related. Therefore, one cannot conclude from one pharmaceutical to another but each one needs to be investigated individually and this present a great challenge for risk assessment kinetics of chemicals in the aquatic environment. The results presented here showed that the investigated pharmaceuticals and their TPs can negatively affect the environment which may be harmful to the ecosystem as they might have been present for decades in the aquatic environment without any knowledge of their environmental fate or connected risk. Therefore, further work needs to be done including analysis of environmental samples (e.g., surface waters), as well as laboratory toxicity tests to further expand knowledge on their exact environmental impact.
Uranine (sodium fluorescein, UR) has been routinely used in hydrological research to monitor surface and subsurface water flow, transport and mixing processes since the end of nineteenth century. Based on such obtained data, further conclusions can be drawn on the spread and behavior of pollutants (partly on models). Use of UR for qualitative (visual) studies of underground contamination is common, however data available on its environmental behavior (e.g., conversion, degradation or formation and fate of the transformation products, TPs) are incomplete or not readily comparable. UR observations of biodegradation are still speculative. S-metolachlor (SM) is a popular worldwide chloroacetamide herbicide, which highly correspond to the global pesticide use. It is offered on the French market as an effective multicrop herbicide against annual grasses and certain broadleaf weeds under the trade name Mercantor Gold (MG). Photodegradation contributes to the fate of SM in the aquatic environment. TPs were already found in surface and groundwater. However, further fate and assessment of the TPs was not done. Moreover, adjuvants in MG´s formula can affect the solubility, biodegradation, photolysis and sorption properties of the active compound SM. TPs can have different properties (e.g. more mobile, toxic or present at higher concentrations) that enable them to reach the environmental compartments not affected by the parent compound (PC) itself. To assess the ecological impact of pesticides, tracers, and their respective TPs on water organisms, their behavior can be investigated in laboratory screening biodegradation tests. Yet, incomplete data was available on SM, MG and UR transformation or their photo- TPs´ fate in surface and water-sediment systems. The combination of photolysis with aerobic biodegradation in order to identify persistent photo-TPs could provide new insight into the environmental behavior of the selected compounds. Therefore, principle of this thesis was to 1) identify the impact of MG´s adjuvants on the biodegradation, photolysis (Xe lamp) and sorption compared to the SM alone, 2) examine the photolysis and biodegradability of UR 3) monitor the primary elimination (photolysis) of the PCs by HPLC (-UV, -FLD) and measure the degree of mineralization by means of nonpurgeable organic carbon (NPOC) 4) elucidate the photo-TPs of SM, MG and UR by using LCMS/ MS 5) analyze biodegradability of the photo-TPs in order to determine their fate and persistence in aquatic environment 6) conduct in silico toxicity predictions (pesticides) in human (carcinogenicity, genotoxicity and mutagenicity) and eco-toxicity (microtoxicity, bioconcentration factor and toxicity in rainbow trouts). SM, MG and UR were found not readily biodegradable in Closed Bottle test (CBT), Manometric Respiratory test (MRT) and in water-sediment test (WST). Chemical analysis of photolysis samples showed higher elimination of SM in MG compared to SM alone whereas UR displayed high primary elimination rate in general. The overall low degree of mineralization indicated that abundant photo-TPs were formed. Furthermore, the photo-TPs were found not biodegradable in performed biodegradation tests. Only small degradation rates for UR could be observed in the CBT and WST. Additionally, in the MRT and WST new bio-TPs were generated from the photo-TPs of SM and SM in MG. Obtained results suggest that the MG formulation did not significantly affect the biodegradation, however it influenced the diffusion of the active substance (SM) to sediment and potentially affected the photolysis efficiency, which might result in faster formation of photo-TPs in the environment. In silico predictions showed that for many endpoints, biotransformation might lead to an increased toxicity in humans and to water organisms compared with the parent compound SM. No indications were found for UR toxicity. Still, target-oriented investigations on long term impacts of photo-TPs from UR are warranted. The present work demonstrates that a combination of laboratory tests, analytical analysis and in silico tools result in valuable information regarding environmental fate of the TPs from selected compounds. Furthermore, it was shown that photo-TPs formed in the aquatic environment should be taken into account not only the parent compound and its decay.
Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been widely used since 1950 in various consumer products as well as in industrial applications owing to their unique properties, e.g. being hydrophobic and lipophobic at the same time. Nowadays, some of these persistent and man-made PFASs can ubiquitously be found in humans, wildlife and various environmental media. One prominent representative of concern, belonging to the subgroup of perfluorocarboxylates (PFCs) and their conjugate acids (PFCAs), is perfluorooctanoat (PFO) and its conjugate acid (PFOA). Because of its adverse effects on human health and its persistency in the environment industry has started to replace PFO(A) and related long chain chemicals (with seven and more fully fluorinated carbon atoms) with so-called short chain PFASs (less than seven fully fluorinated carbon atoms), including precursors of PFC(A)s. Also these short chain PFC(A)s are persistent and can already be found in humans, ground- and drinking water and in remote regions. However, knowledge gaps exist in understanding the partitioning and the resulting mobility of short chain PFC(A)s in the environment. This is due to the fact that partitioning data of PFC(A)s from standardised experiments can easily be biased by various artefacts, e.g. self-aggregation of the molecules. Therefore, the objectives of this thesis are (i) to quantify the partitioning of PFC(A)s into mobile environmental media, (ii) to show how results from non-standard tests can be used to assess substance properties of concern and (iii) to conclude on whether the environmental exposure to short chain PFC(A)s is of concern from a regulatory point of view. In the first part of this thesis, the environmental mobility of short chain C4-7-PFC(A)s was investigated by quantifying their partitioning under non-standardised semi-environmental conditions into mobile environmental media, focusing on water and air, and comparing it to long chain PFC(A)s. Results are: Partitioning between water and particles in the aeration tank, primary and secondary clarifier of a wastewater treatment plant (WWTP) showed no distinct differences for short chain PFC(A)s compared to their long chain homologues (Paper 1). In a water-saturated sandy sediment column short chain PFC(A)s were not retarded, whereas long chain homologues were retarded by sorption to the sediment (Paper 2). Atmospheric particle-gas partitioning showed a lower fraction sorbed to particles for short chain PFC(A)s compared to long chain ones in samples from a WWTP (Paper 3). Air-water concentration ratios based on samples from the tanks of a WWTP were found to be higher for short chain PFC(A)s compared to long chain PFC(A)s (Paper 1). Additionally, in a newly developed experimental set-up the water to air transfer was used to derive that the pKa of C4-11-PFCAs must be <1.6 instead of up to 3.8 as reported in the literature (Paper 4). Overall, in the investigated systems short chain PFC(A)s showed a higher mobility due to a more pronounced partitioning into mobile environmental media compared to long chain PFC(A)s. In the second part of the thesis it was shown how PFO(A) - owing to its persistent, bioaccumulative and toxic (PBT-)properties – was in the context of this thesis successfully assessed as a substance of very high concern according to the criteria of the European REACH Regulation (EC No 1907/2006) by using data from non-standard tests (Paper 5). In conclusion, based on the knowledge of the high environmental mobility of short chain PFC(A)s and taking into account the argumentation of the PBT-concern of PFO(A), environmental exposure to short chain PFC(A)s is of concern and existing knowledge is already sufficient to initiate measures to prevent emissions of short chain PFC(A)s and their precursors into the environment.
In the discourse on pharmaceuticals in the environment, hardly any attention has been paid to anticancer drugs. Because of their none-selective modes of action, that is, because they affect both cancerous and healthy cells, these drugs are regarded as potentially carcinogenic, genotoxic, mutagenic, and teratogenic substances. It is, however, not known how and to what extent these substances affect organisms and the environment in the long run. For this reason, this dissertation evaluated, addressing several endpoints and using organisms from different trophic levels and in silico predictions, the fate (bio- and photo degradation) and ecotoxicity of these substances. Four anticancer drugs (cyclophosphamide (CP), 5-fluorouracil (5-FU), methotrexate (MTX), and imatinib (IM) were selected. None of these anticancer compounds can be classified as ´readily biodegradable,´ a classification that indicates that biodegradation will only play a minor role in the elimination of these compounds and that they cannot be removed by the conventional processes used in sewage treatment plants and will most likely remain in the water cycle. Despite the high degrees of mineralization achieved in advanced (photo)oxidation processes, it was not possible to fully mineralize the compounds, a result that indicates that transformation products were created during these reactions. The ecotoxicity assays performed with V. fischeri indicated that 5-FU was, of all the substances tested, likely to be the most toxic (very toxic), followed by MTX (toxic) and IM (toxic/harmful), whereas CP was nontoxic. MTX presented the highest phytoxicity activity in the Lactuca sativa assay, followed by 5-FU, IM, and CP. The results of the tests performed with A. cepa showed cytotoxic (5-FU, MTX, and CP) and genotoxic effects (5-FU, CP, and IM) and mutagenic activity (5-FU, MTX, CP, and IM) of the compounds. Photo transformation products (PTPs) of CP, MTX, and 5-FU were nontoxic towards V. fischeri. However, some PTPs formed during the photodegradation of 5-FU led to positive mutagenic and genotoxic alerts in several in silico models. Not one of the compounds examined in this dissertation is likely to be fully eliminated from the water cycle by (natural) photolysis and/or advanced oxidation. Moreover, some of the treatments resulted in the formation of stable intermediates that were even less biodegradable than parent compounds. This finding shows that it is not enough to focus on primary elimination because TPs are not necessarily better biodegradable than their respective parent compounds. As indicated by the genotoxic and mutagenic positive alerts presented by different in silico models, the PTPs observed here are likely to require, despite their lower toxicity in comparison to the parent compounds, screening after treatments.
Mikroalgen können bei den internationalen Bemühungen zur Begrenzung der CO2-Emissionen einen wichtigen Beitrag leisten. In der Photosynthese der Mikroalgen wird das CO2 aus der Atmosphäre in Biomasse fixiert. Im Gegensatz zu Landpflanzen können Mikroalgen zudem exponentiell wachsen, haben geringere Anforderungen an die Wasserqualität und konkurrieren nicht mit Agrarflächen, die begrenzt und für die Nahrungsmittelsicherheit der Weltbevölkerung erforderlich sind. Die produzierte Mikroalgenbiomasse kann als regenerative Ressource zu Biokraftstoffen wie Biogas und Biodiesel umgewandelt und somit als Energieträger genutzt werden. Zudem können Mikroalgen auch bei der biotechnologischen Produktion kommerziell relevanter Wertstoffe wie Pigmenten und Omega-3-Fettsäuren für die Nahrungsmittelindustrie Anwendung finden. Mit dem Ziel der Steigerung dieser Wertstoffe stand die Untersuchung des Einflusses der Kultivierungsparameter Licht und Temperatur auf das Wachstum und die Zusammensetzung der Mikroalgenbiomasse im Mittelpunkt dieser Dissertation. Insbesondere der Einfluss unterschiedlicher Lichtspektren auf das Wachstum und die Wertstoffproduktion in Mikroalgen wurde detailliert untersucht. Zusätzlich wurde überprüft, ob sich die gewonnenen Erkenntnisse auch auf Landpflanzen übertragen lassen. Im Rahmen dieser Promotion wurde erstmals systematisch der Einfluss unterschiedlicher Temperaturen und Lichtspektren im zeitlichen Verlauf der Kultivierung auf Mikroalgen untersucht. Hierbei konnten distinkte Spektralbereiche sowie Temperaturen ermittelt werden, die für eine maximale Produktion von Biomasse und Pigmenten sowie einem maximalen Desaturierungsgrad der Fettsäuren erforderlich sind. Die in dieser Arbeit gewonnenen Erkenntnisse tragen zu einem besseren Verständnis der Biochemie von photosynthetischen Organismen bei.
Biozide Wirkstoffe sind Chemikalien, die zum Schutz der menschlichen oder tierischen Gesundheit oder zum Schutz von Materialien vor Schädlingen eingesetzt werden. Monitoringergebnisse lassen vermuten, dass diese Wirkstoffe auch häufig im Innenraum von Haushalten eingesetzt werden und von dort vor allem über Abwasserleitungen und Kläranlagen in die Umwelt gelangen, wenn sie in Kläranlagen nicht eliminiert werden. Die Produkte, aus denen die Wirkstoffe aus Haushalten in das Abwasser gelangen, sind bislang jedoch nicht identifiziert worden. Aus diesem Grund konnten die daraus resultierenden Umweltbelastungen nicht eingeschätzt und keine entsprechenden Emissionsminderungsmaßnahmen umgesetzt werden. In dieser Arbeit wurde deshalb untersucht, in welchen Haushaltsprodukten biozide Wirkstoffe eingesetzt werden und in das Abwasser gelangen. Zudem sollte erforscht werden, was die Haushaltsmitglieder über Biozidprodukte wissen und wie sie mit ihnen umgehen. Ziel war es, die Anwendungen von bioziden Wirkstoffen in Haushalten zu identifizieren, von denen die höchsten Umweltbelastungen zu erwarten sind, und geeignete Emissionsminderungsmaßnahmen abzuleiten. Um die Anwendung biozider Wirkstoffe in Haushalten zu untersuchen, wurde zunächst durch eine Befragung in Haushalten eines dörflichen Wohngebietes ermittelt, was die Haushaltsmitglieder über Biozidprodukte wissen und wie sie die damit verbundenen Risiken im Vergleich zu anderen Haushaltsprodukten einschätzen. Zudem wurde für jeden der teilnehmenden Haushalte ein Inventar der vorhandenen Produkte erstellt. Dabei wurden neben den Biozidprodukten auch Wasch- und Reinigungsmittel und Körperpflegeprodukte untersucht. Ähnliche Erhebungen fanden zusätzlich in Haushalten in urbanen Gebieten statt. Die aufgrund der inventarisierten Produkte zu erwartenden Stoffe wurden im Laufe eines Jahres durch ein speziell abgestimmtes Monitoringprogramm im Abwasser des dörflichen Wohngebietes in Tages- und Stundenmischproben untersucht. Alle Proben wurden nach der Probenahme aufgearbeitet und mittels Flüssigchromatographie gekoppelt mit einem Triple-Quad-Massenspektrometer analysiert. Dabei wurden die Konzentrationen von 14 Wirkstoffen gemessen: 1,2-Benzisothiazol-3(2H)-on (BIT), C12-Benzalkoniumchlorid, Carbendazim, 5-Chlor-2-methyl-2H-isothiazol-3-on (CMIT), Dichloroctylisothiazolinon (DCOIT), N,NDiethyl-meta-toluamid (DEET), Diuron, Icaridin, 2-Octyl-2H-isothiazol-3-on (OIT), Piperonylbutoxid (PBO), Triclosan, Tebuconazol, Terbutryn und Tetramethrin. Vielen Befragten war nicht bewusst, dass sie Biozidprodukte nutzen. Der Begriff "Biozid" war oft nicht bekannt und wurde inhaltlich häufig falsch verstanden. Die Auswertungen der inventarisierten Produkte und der darin enthaltenen bioziden Wirkstoffe zeigten, dass ein Großteil der Wirkstoffe nicht aus Biozidprodukten in das Abwasser gelangt, sondern aus Körperpflegeprodukten und Wasch- und Reinigungsmitteln. Insgesamt 64 % der Anwendungen von bioziden Wirkstoffen in den inventarisierten Produkten wurden nicht unter der Umweltrisikobewertung der Verordnung (EU) 528/2012 über die Bereitstellung auf dem Markt und die Verwendung von Biozidprodukten berücksichtigt, was zu einer erheblichen Unterschätzung der Umweltrisiken führt. Die Ergebnisse der Abwasseruntersuchungen deuten ebenfalls darauf hin, dass biozide Wirkstoffe aus Wasch- und Reinigungsmitteln, Körperpflegeprodukten und Biozidprodukten gleichermaßen in das Abwasser eingetragen werden. Die Messergebnisse können gut mit den Produktinventaren in Verbindung gebracht werden. Einige Wirkstoffe scheinen maßgeblich durch Biozidprodukte eingetragen zu werden. Auch Konservierungsmittel wurden regelmäßig nachgewiesen. Für Triclosan hingegen ist gemäß den Inventaren Zahnpasta vermutlich die Produktgruppe, die in dem untersuchten Wohngebiet maßgeblich für den Eintrag ins Abwasser verantwortlich ist. Diese Arbeit zeigt zum ersten Mal, welche Produkte im Haushalt eine wichtige Quelle für biozide Wirkstoffe im Abwasser sind. Sie müssen mit einbezogen werden, wenn Emissionen an der Quelle reduziert werden sollen. Es sollten Maßnahmen ergriffen werden, die über die Produktzulassung von Biozidprodukten hinausgehen, um die Emissionen so gering wie möglich zu halten. Diese Maßnahmen sollten sich nicht darauf beschränken, die Bevölkerung über Biozidprodukte aufzuklären und zu sensibilisieren. Stattdessen sollten Maßnahmen früher in der Wertschöpfungskette ansetzen, wie zum Beispiel beim Design der Wirkstoffe oder der Formulierung der Produkte, um so Einträge biozider Wirkstoffe in die Umwelt zu verringern.
Der hohe Verbrauch von Antibiotika führt zu stetig steigenden Konzentrationen der Wirkstoffe und ihrer Transformationsprodukte in der Umwelt. Antibiotika in der Umwelt haben das Potential Funktionen von Ökosystemen zu stören und tragen zur Entwicklung und Selektion von resistenten Bakterien bei. Um diese negativen Auswirkungen auf Mensch und Umwelt zu reduzieren, sind vielseitige Lösungen notwendig. Benign by Design (BbD) ist ein wichtiger Baustein dafür. Daher ist es wichtig zu verstehen, inwiefern das BbD Prinzip auf verschiedene Substanzgruppen anwendbar ist und welche Limitierungen zu berücksichtigen sind. Mit dieser Arbeit soll ein Beitrag zur Entwicklung von in der Umwelt mineralisierbaren Antibiotika entsprechend des Benign by Design Konzeptes geliefert werden. Dies wurde am Beispiel der Fluorchinolonantibiotika durchgeführt, da diese sehr wichtige, aber auch sehr persistente Wirkstoffe sind. Ziel war es, zu verstehen, welche Veränderungen an der Grundstruktur vorgenommen werden können, um Derivate zu erzeugen, die während der Wirkdauer und Lagerung ausreichend stabil bleiben, aber anschließend in der Umwelt möglichst schnell und vollständig mineralisiert werden können. Im ersten Teil der Arbeit wurden die BbD Ansätze des targeted und non-targeted Re-Designs und de novo Designs, sowie die Verwendung von in silico Tools zu deren Umsetzung, untersucht. Basierend darauf wurde ein Workflow entwickelt, der eine mögliche Verwendung von computergestützten Methoden innerhalb des BbD Frameworks aufzeigt. Der Ansatz des non-targeted Re-Designs wurde für neun verschiedene Substanzen aus der Klasse der Fluorchinolone angewandt. Dafür wurden Transformationsprodukte der Muttersubstanzen mittels Photolyse und Photokatalyse erzeugt. Das resultierende Substanzgemisch wurde hinsichtlich der biologischen Abbaubarkeit und Toxizität untersucht. Es konnte gezeigt werden, dass durch die Bestrahlung mit UV-Licht eine Vielzahl an neuen Strukturen entstehen und das Gemisch oft eine gesteigerte biologische Abbaubarkeit im Vergleich zur Muttersubstanz aufweist. Das targeted Re-Design wurde am Beispiel von Fluorchinolon-Glucosamin-Derivaten untersucht. Dabei galt es zu verstehen, inwiefern Glucosamin-Substituenten die biologische Abbaubarkeit beeinflusst. Es konnte gezeigt werden, dass durch die Verwendung von acetylierten Glucosamin-Substituenten ein partieller Abbau stattfindet. Diese Erkenntnisse können zukünftig in das gezielte, fragment-basierte Design von grüneren Strukturen einfließen. Im letzten Teil der Arbeit wurden die Struktur-Bioabbau-Beziehungen von N-hetero-zyklischen Verbindungen, welche auch die Basis des Fluorchinolon-Grundgerüstes sind, untersucht und leicht biologisch abbaubare Leitstrukturen identifiziert. Dafür wurden 84 verschiedene N-Heterozyklen nach OECD 301 Richtlinien getestet. Basierend darauf wurde zum einen ein lokales 3D-QSAR Modell, insbesondere zur Visualisierung der Effekte der Substituenten im dreidimensionalen Raum, erstellt, als auch Regeln für das Design von umweltfreundlicheren Chinolonen und verwandten Strukturen abgeleitet. Weiterhin wurden abbaubare Strukturen aus der Gruppe der Chinazoline identifiziert, welche vielversprechende Leitstrukturen für das Design von Topoisomerase-Inhibitoren oder anderer Chemikalien darstellen. Insgesamt zeigen die Ergebnisse, dass die Umsetzung von BbD im Wirkstoffdesign möglich ist und wie potentielle Vorgehensweisen aussehen können. Dabei konnte gezeigt werden, dass selbst die als besonders persistent geltenden Fluorchinolonantibiotika das Potential bieten, zu besser abbaubaren Derivaten re-designt zu werden. Es wurde jedoch auch deutlich, dass es keine allgemeingültige Herangehensweise gibt und Methoden den entsprechenden Substanzklassen und Anforderungen angepasst werden müssen.
Das ubiquitäre Vorkommen von Arzneimittelrückständen ist eng mit möglichen Risiken für Mensch und Umwelt verbunden. Das übergeordnete Ziel dieser Forschungsarbeit ist die Weiterentwicklung methodischer Ansätze für die Identifizierung prioritärer Arzneimittelrückstände vor dem Hintergrund bestehender Wissens- und Regulierungslücken. Unter diesem Gesichtspunkt wurden drei aktuelle Problemfelder aus dem Themenkomplex "Arzneimittel in der Umwelt " ausgewählt und anhand konkreter Fallbeispiele betrachtet. Tierarzneimittel werden häufig mit der Ausbringung von Wirtschaftsdünger in landwirtschaftlich genutzte Böden eingetragen. Gegenstand der ersten Publikation ist die Frage, inwiefern Anwendungsschemata aus der Nutztierhaltung für die retrospektive Identifizierung prioritärer Tierarzneimittelrückstände genutzt werden können. Hierzu wurde eine spezielle Herangehensweise entwickelt und am Beispiel von Antibiotika erprobt. Die durchgeführte Eintragsabschätzung ermöglichte erstmalig eine umfassende Einschätzung der potenziellen Antibiotikabelastung in Wirtschaftsdünger und landwirtschaftlich genutzten Böden im nordwestdeutschen Raum. Die Ergebnisse deuten auf erhebliche Umwelteinträge hin, die eine Neubewertung bestehender Wirkstoffzulassungen notwendig erscheinen lassen. In der zweiten Publikation wurden am Beispiel einer Mischung aus 18 Arzneistoffen verschiedene Bewertungsansätze verfolgt, um das Risiko einer kombinierten antimikrobiellen Wirkung genauer zu charakterisieren und prioritäre Mischungsbestandteile zu identifizieren. Das Risiko einer antimikrobiellen Wirkung wurde sowohl durch eine experimentelle Prüfung der Mischung als auch durch einen komponentenbasierten Berechnungsansatz bestätigt. Der komponentenbasierte Ansatz verdeutlichte zudem die besondere Relevanz der in der Mischung enthaltenen Fluorchinolon-Antibiotika. Die notwendige Grundlage für eine belastbare Abschätzung von Kombinationseffekten sind jedoch harmonisierte Einzelstoffdaten, die bisher nicht im benötigten Umfang zur Verfügung stehen. Deshalb sollte speziell für Antibiotika eine systematische Prüfung der Wirkung auf Umweltmikroorganismen durchgeführt werden. Arzneistoffe können entlang ihres Lebenszyklus verschiedene biotische und abiotische Transformationsprozesse durchlaufen, die oft zur Bildung von unvollständig charakterisierten Transformationsprodukten (TPs) führen. Die Publikationen 3-7 leisten einen allgemeinen Beitrag zur Einschätzung des möglichen Gefahrenpotenzials von pharmazeutischen TPs im Wasserkreislauf und generieren neue methodische Erkenntnisse vor dem Hintergrund einer vorausschauenden Identifizierung von prioritären Abbauprodukten. Die durchgeführten Fallstudien bestätigten, dass photochemische Transformationsprozesse nicht nur zur Abschwächung bereits vorhandener, sondern im Gegenteil auch zur Entstehung gänzlich neuer Gefahrenpotenziale beitragen können. Es ist somit stark in Frage zu stellen, ob die alleinige Fokussierung auf bekannte Aktivitäten der Muttersubstanz für eine sichere Bewertung von TPs ausreicht.