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Fate of psychotropic drugs in the aquatic environment

Abbauverhalten von Psychopharmaka in der aquatischen Umwelt

  • 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.
  • I Summary 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.

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Metadaten
Author:Nareman Dahshan Henedaq Khaleel (Dr. rer. nat.)GND
URN:urn:nbn:de:gbv:luen4-opus4-11395
URL: https://pub-data.leuphana.de/frontdoor/index/index/docId/1139
Subtitle (English):Assessment of dead-end photo-degradation products generated under varying conditions by combination of experimental and "in-silico" methods
Subtitle (German):Bewertung der unter verschiedenen Bedingungen entstehenden Photoabbauprodukte durch Kombination von experimentellen und "in-Silicio"-Methoden
Advisor:Klaus Kümmerer (Prof. Dr.)
Referee:Ralf Ebinghaus (Prof. Dr.)ORCiDGND, Carolin Floeter (Prof. Dr.)
Document Type:Doctoral Thesis
Language:English
Year of Completion:2021
Date of Publication (online):2021/05/07
Date of first Publication:2021/06/02
Publishing Institution:Leuphana Universität Lüneburg, Universitätsbibliothek der Leuphana Universität Lüneburg
Granting Institution:Leuphana Universität Lüneburg
Date of final exam:2021/03/23
Release Date:2021/06/02
Note:
Das Rahmenpapier der kummulativen Dissertation enthält drei Beiträge
Institutes:Fakultät Nachhaltigkeit / Institut für Nachhaltige Chemie und Umweltchemie (INUC)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 543 Analytische Chemie
Licence (German):License LogoDeutsches Urheberrecht