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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
The presence of pharmaceutical drugs and their by-products as environmental organic contaminants in a variety of eco-systems and their potential environmental impacts is a well-known aspect and has been raised in recent years. Studying the transformation of pharmaceutical drugs in the aquatic system is very important as it can lead to the formation of many new transformation products (TPs) that can have different properties (e.g. more mobile, toxic or present at higher concentrations) and this can enable them to reach the environmental compartments not affected by their parent compounds. Yet, many of the pharmaceutical drugs are not well regulated or controlled and they can cause a lot of adverse ecological and/or human health effects. In addition, impact of the continuous change in the environmental conditions such as pH, temperature and initial concentration on the transformation behaviour of pharmaceuticals is overlooked in many researches although it is of high interest.
Psychotropic drugs are among the pharmaceuticals which their potential hazards including environmental fate and behaviour is still not well understood compared to other drugs such as antibiotics. Psychotropic drugs are highly used, and their worldwide consumption has been increasing nowadays especially in developed countries such as Europe and the United States. Furthermore, they are highly found in different environmental compartments and can cause a lot of toxicological problems. Trimipramine (TMP), Desipramine (DMI) and Chlorprothixene (CPTX) are three psychotropic drugs with closely related chemical structures and they are selected to be studied in this thesis as they are among the worldwide commonly prescribed psychotropic drugs and data available on their environmental fate (e.g., degradation or transformation and fate of the TPs) is lacking in the environmental researches.
To investigate the ecological impact of the pharmaceuticals on water organisms and to study their fate in the aquatic system, laboratory biodegradation and photodegradation tests are recommended. The use of LC-MS/MS analysis with the combination of photolysis and biodegradation tests to identify the formed TPs and to study the biodegradability and the persistence of the TPs is a helpful new insight into the environmental behaviour of contaminants and their TPs. Different environmental conditions can affect the fate of pharmaceuticals in the environment, therefore answering the question how different variables such as temperature, pH and initial concentration could affect the degradation pattern of pharmaceuticals can provide valuable information regarding their environmental fate. Toxicity assessments of contaminants and their TPs using in-silico software based on quantitative structure activity relationship (QSAR) models can be a good choice especially in case of TPs because the TPs are mostly not available commercially and II
are usually only formed in low concentrations within complex matrices so that isolation and purification are very difficult.
Accordingly, 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 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).
TMP, DMI and CPTX were found to be not readily biodegradable in Closed Bottle test (CBT), and in Manometric Respiratory test (MRT). They did not show any significant elimination or mineralization within 128 minutes of irradiation using a xenon Lamp. In UV-photodegradation samples, LC-MS/MS results showed elimination of the three psychotropic drugs with corresponding comparatively lower degrees of mineralization indicating formation of abundant photo-TPs.
From the UV-photolysis tests, which were carried out under different environmental conditions, it can be concluded that the degradation rates of TMP, DMI and CPTX decreased when their initial concentrations increased. pH affected the photodegradation behaviour of TMP, DMI and CPTX with different pattern depending on many factors such as solubility, molar absorption coefficient (ɛ), ionisation form and chemical structure. Temperature elevation showed non-significant effect on the photodegradation performance of DMI and CPTX, while showed an enhanced effect on the photodegradation performance of TMP. This could be because the molecules of DMP and CPTX can reach the sufficient energy required for degradation at low temperature. While TMP`s molecules still require some more energy to undergo degradation and temperature helps them to reach easily these required activation energy.
Elucidating the TPs and studying the degradation pathways for TMP, DMI and CPTX during UV irradiation indicated that hydroxylation is the most abundant pathway followed by oxidation and isomerization. De-chlorination pathway was observed during the UV-transformation of CPTX.
III
Deamination and loss of the aliphatic side chain were observed only during the UV-transformation of TMP, while not observed during DMI and CPTX transformation. This indicates that the bond between the amino- group and the aliphatic side chain in DMI and CPTX can be more resistant to photodegradation compared to the same bond in TMP. This could be due to the presence of extra methyl groups in TMP molecule which can decrease the previously mentioned bond strength.
Biodegradation tests performed for photodegradation mixtures, which contain the psychotropic drugs and their TPs, showed low biodegradation results. Despite that, elimination of some TPs was observed in the LC-MS/MS analysis at the end of these biodegradation tests. This indicates the probability of biodegradation ability for some TPs and this ability was hindered by the predominant effect of other non-biodegradable compounds. In-silico predictions showed that for many endpoints, photo-transformation might lead to an increased toxicity in humans and to water organisms compared with the parent compound.
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.
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. With the restriction and ban of the widely used brominated diphenyl ethers (PBDEs) by, ultimately, the Stockholm Convention due to their adverse effects on humans and the environment, the use of OPEs as replacements has increased rapidly. However, the potential adverse properties, environmental distribution and fate of OPEs are insufficiently understood. 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, which can be explained by the common European market with consistent legislative regulations. 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.
