Pharmaceutically active compounds (PhACs) have been found in wastewater effluents and receiving waters around the world. As yet there are no jurisdictions that regulate their release, or their impact on receiving water ecosystem health. The issue is complex due to the number of PhACs that exist, the variability in their structure and function, the variability in removal during different wastewater treatment processes, the potential for formation of metabolites and transformation products, and a lack of information on the impacts due to their presence on receiving waters. Gemfibrozil is a lipid regulating drug that is commonly found in wastewater effluents and receiving waters. It has been shown to partially degrade during biological wastewater treatment processes and has also been shown to produce reaction products through reactions with free chlorine. This thesis investigated the removal and transformation of gemfibrozil through several different wastewater treatment processes, namely biological removal and chlorination. Reactions between gemfibrozil and free chlorine led to the identification of four reaction products. The structures of three of the four reaction products were elucidated. The kinetics of formation of these reaction products were then investigated at a range of pH values, and in two wastewater matrices. One reaction product, 4’-ClGem was shown to form under conditions relevant to wastewater treatment. The impacts of gemfibrozil and 4’-ClGem presence on the abundance of suspended and biofilm bacteria in a simulated receiving water experiment were evaluated. It was shown that changes in the water matrix had more of an impact on bacterial abundance than presence of gemfibrozil or 4’-ClGem. A bacterial dose-response experiment showed a negative response at 10 mg/L exposure to 4’-ClGem, which is orders of magnitude higher then what would be found in receiving waters. In order to prevent the formation of chlorinated reaction products, it is necessary to remove gemfibrozil prior to disinfection. Recirculating biofilters (RBS), a biological technology for onsite or small-scale wastewater treatment, were explored as a potential treatment process for gemfibrozil removal. Results indicate that RBFs show promise as a robust technology to remove greater than 50% of influent gemfibrozil.

Pharmaceuticals are environmental contaminants causing steadily increasing concern due to their high usage, ubiquitous distribution in the aquatic environment, and potential to exert adverse effects on the ecosystems. After being discharged from wastewater treatment plants (WWTPs), pharmaceuticals can undergo transformation processes in surface waters, of which microbial degradation in river sediments is considered highly significant. In spite of a substantial number of studies on the occurrence of pharmaceuticals in aquatic systems, a comprehensive understanding of their environmental fate is still limited. First of all, very few consistent datasets from lab-based experiments to field studies exist to allow for a straightforward comparison of observations. Secondly, data on the identity and occurrence of transformation products (TPs) is insufficient and the relation of the behavior of TPs to that of their parent compounds (PCs) is poorly understood. In this thesis, these knowledge gaps were addressed by integrating the TP identification using suspect/non-target screening approaches and PC/TP fate determination. The overarching objective was to improve the understanding of the fate of pharmaceuticals in rivers, with a specific focus on water-sediment interactions, and formation and behavior of TPs. In paper I, 11 pharmaceutical TPs were identified in water-sediment incubation experiments using non-target screening. Bench-scale flume experiments were conducted in paper II to simultaneously investigate the behavior of PCs and TPs in both water and sediment compartments under more complex and realistic hydraulic conditions. The results illustrate that water-sediment interactions play a significant role for efficient attenuation of PCs, and demonstrate that TPs are formed in sediment and released back to surface water. In paper III the environmental behavior of PCs along stretches of four wastewater-impacted rivers was related to that of their TPs. The attenuation of PCs is highly compound and site specific. The highest attenuation rates of the PCs were observed in the river with the most efficient river water-pore water exchange. This research also indicates that WWTPs can be a major source of TPs to the receiving waters. In paper IV, suspect screening with a case-control concept was applied on water samples collected at both ends of the river stretches, which led to the identification of several key TPs formed along the stretches. The process-oriented strategies applied in this thesis provide a basis for prioritizing and identifying the critical PCs and TPs with respect to environmental relevance in future fate studies. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Manuscript.</p>

Les substances pharmaceutiques sont classées comme contaminants environnementaux émergents et suscitent une attention croissante du fait de leurs effets potentiellement néfastes sur les écosystèmes. Après excrétion ou élimination inappropriée, les médicaments vont se retrouver dans les eaux de surface, souterraines voire de consommation. De nombreuses études écotoxicologiques ont pour objet la mesure de leurs impacts sur les écosystèmes. Pour autant, ces études portent essentiellement sur le médicament lui-même alors que nombre d'entre eux sont susceptibles de se transformer dans l'environnement selon des processus biotiques (microorganismes) et/ou abiotiques (traitements chimiques, photodégradation). Les produits de transformations (PTs) ainsi formés vont d'une part, progressivement remplacer le médicament parent dans l'environnement, et d'autre part y exprimer une écotoxicité potentielle. Face à ce problème, nous nous proposons à partir d'un médicament largement utilisé, de procéder à la synthèse de ses PTs plausibles et à la mise au point de méthode de détection dans des matrices complexes. L'accès aux PTs suivra une approche pluridisciplinaire faisant appel à la bioconversion, l'électro-Fenton et l'oxydation électrochimique. L'analyse comparative des composés obtenus par ces différentes approches permettra de sélectionner les PTs les plus probables / Pharmaceuticals as well as personal care products are classified as emerging pollutants of increasing concern due to possible negative impacts on ecosystems. They are constantly introduced in sewage treatment plants either through excretion, or disposal by flushing of unused or expired medication, or directly within the sewage effluents of plants or hospitals. They end up in surface and ground waters and can even be found in drinking water. Many studies report on adverse effects on terrestrial and aquatic organisms. Pharmaceuticals have complex chemical structures capable of reacting in an aqueous medium under the action of chemical, biological or physical agents. Thus, the transformation products (TPs) gradually replace the parent drug in the environment. In addition these transformation products constitute markers of past or current presence of the drug in the environment. Faced with this problem, we believe it is necessary to synthesize the transformation products of the parent compounds to development their detection. The proposed method consists, firstly, to prepare the largest number of (TPs) of a particular drug using three complementary approaches : bioconversion, electro-Fenton and electrochemical oxidation. A second step is to identify the structures which are the most likely present in the environment. Expected advances are the development of a predictive methodology applicable to the study of any molecule involved in environmental risk

For bioactive chemical classes, it is often assumed that environmental transformation eliminates associated ecosystem risks. However, for endocrine-active steroid hormones, modest changes in structure can have a significant influence on biological activity and thus, subtle environmental transformations can yield products with conserved, enhanced, or activity across different biological endpoints. The aim of this work was to explore the environmental fate of high potency, endocrine-active steroid hormones during natural or engineered water processes in order to test the hypothesis that steroid transformation products generated during these processes are likely to contribute to residual bioactivity often reported in water resources. Specifically, laboratory experiments were used to simulate chemical disinfection (e.g., chlorination) or natural processes (e.g., photolysis) to: (i) determine the rate and extent of steroid transformation, (ii) isolate and identify products that are formed, and (iii) evaluate products or product mixtures for biological activity. These experimental results can be used to help guide occurrence studies for any products of concern in the environment and also guide computational predictions or rationalizations of chemical reactivity. Ultimately, the goal is to expand upon our awareness and understanding of how these potent endocrine ligands behave in the environment and how they potentially affect ecosystem health. Chapter 2 discusses the reaction of glucocorticoids (GC)s with aqueous chlorine (effectively, HOCl) to simulate their fate during engineered drinking water and wastewater chemical disinfection. Numerous transformation pathways were unveiled, including interconversion of GCs (e.g., endogenous cortisol to synthetic prednisolone), production of known androgens in the adrenosterone class, and chlorination of GCs (e.g., formation of 9-chloro-prednisone). We also showed that other advanced processes (e.g., oxidation via ozonation) result in more complete degradation of such pollutants, and may be better alternatives to chemical disinfection at eliminating bioactive steroidal product formation. In Chapter 3, results of the direct photolysis of dienogest (DNG), a widely prescribed oral contraceptive agent, are presented to simulate its fate in natural sunlit surface waters and engineered photochemical treatment systems (e.g., UV disinfection systems). The major products (~ 80% of the converted mass in neutral aqueous solutions) were identified to be photohydrates resulting from photochemical-induced incorporation of water into parent DNG. These products were found to be prone to dehydration in the dark, and thus, a source of substantial DNG regeneration (~ 65% after 72 h in neutral solutions). Other minor, non-revertible products were also identified, including two known estrogens. Although minor in initial yield, these estrogens are likely to accumulate over time through repeated cycling between DNG and its photohydrates, and thus, dominate DNG long-term fate. It was also found that DNG undergoes an unusual photochemical rearrangement to produce a minor product with a novel tetracyclic ring system--the subject of Chapter 4. Further, the generality of this unique photorearrangement process was explored through extension to the photolysis of two other dienone pharmaceutical steroids (e.g., the androgens methyldienolone and dienedione). Surprisingly, despite the significant change in core steroidal structure, the rearrangement products retain some progesterone receptor (PR) and androgen receptor (AR) bioactivity (i.e., low-µM to sub-nm EC50 values). Again, these represent other non-revertible, minor products that are likely to accumulate over time, with likely adverse ecological consequences. Chapter 5 covers results arising from the direct photolysis of trenbolone acetate (TBA) metabolites in the presence of model nucleophiles (e.g., sodium azide, sodium thiosulfate, ammonium hydroxide, hydroxylamine, and humic acid), some of which would be expected to be present, along with TBA metabolites, in agriculturally-impacted water resources. Previous studies by our group revealed that TBA metabolites undergo photohydration-thermal dehydration cycling, like that described above for DNG photolysis. The objective of this study was to determine if other nucleophiles would outcompete water for photochemical incorporation across the TBA metabolite extended conjugation system. It was found that TBA metabolite photolysis results in photochemical (and at times thermal) addition of the nucleophile to the TBA metabolites. It was also found that the addition products undergo thermal elimination in the dark and contribute to TBA metabolite regeneration, and therefore, are expected to increase TBA metabolite persistence in water resources. Finally, Chapter 6 discusses the reactions of various trienone and dienone steroids with aqueous chlorine to simulate their fate during engineered drinking water and wastewater chemical disinfection. Single-step transformation pathways were unveiled for each steroid class, including 4-chlorination (trienones) and 9,10-epoxidation (dienones). Chlorination at position C-4 is known to enhance anabolic potency of androgenic steroids and the 9,10-epoxy products were found to undergo acid- or base-catalyzed ring-opening and aromatization to yield known estrogenic products. In addition, Chapter 7 provides conclusions and future directions, while Chapter 8 details the experimental methods and procedures used throughout this thesis. Collectively, the results presented herein confirm our overall hypothesis that steroid transformation products would be expected to contribute to residual biological activity often detected in water resources. Furthermore, the results indicate that the transformation of high potency pharmaceuticals does not automatically equate with reduction or elimination of hazards to exposed organisms, especially in cases where such compounds have potential to form products exhibiting diverse biological endpoints. More holistic approaches to risk assessment of such high potency environmental contaminants are needed in order to accurately assess the fate and effects of such emerging pollutant classes and their bioactive transformation products.

Neonicotinoid insecticides are widespread in surface waters across the agriculturally-intensive Midwestern US. We report for the first time the presence of three neonicotinoids in finished drinking water and demonstrate their general persistence during conventional water treatment. Periodic tap water grab samples were collected at the University of Iowa over seven weeks in 2016 (May-July) after maize/soy planting. Clothianidin, imidacloprid, and thiamethoxam were ubiquitously detected in finished water samples and ranged from 0.24-57.3 ng/L. Samples collected along the University of Iowa treatment train indicate no apparent removal of clothianidin and imidacloprid, with modest thiamethoxam removal (~50%). In contrast, the concentrations of all neonicotinoids were substantially lower in the Iowa City treatment facility finished water using granular activated carbon (GAC) filtration. Batch experiments investigated potential losses. Thiamethoxam losses are due to base-catalyzed hydrolysis at high pH conditions during lime softening. GAC rapidly and nearly completely removed all three neonicotinoids. Clothianidin, hydrolysis products of thiamethoxam and known metabolites of imidacloprid are susceptible to reaction with free chlorine and may undergo transformation during chemical disinfection via chlorination or during distribution with chlorine residual. We identify several transformation products resulting from these oxidation and hydrolysis reactions, and discuss implications for human health. Our work provides new insights into the persistence of neonicotinoids and their potential for transformation during water treatment and distribution, while also identifying GAC as a potentially effective management tool to lower neonicotinoid concentrations in finished drinking water.

Development and application of target and non-target techniques for routine analysis, identification of transformation products, and characterization of unknown compounds in water matrices using liquid-chromatography high-resolution mass spectrometry (HRMS) were explored in this dissertation. A novel analytical method based on online-SPE-LC-HRMS was developed for the detection of 18 drugs of abuse (DOAs) in raw sewage water from a college campus. Results showed the presence of 14 DOAs for which amphetamine and 11-nor-9-carcoxy-THC (THC metabolite) were the most prevalent and had the highest potential consumption rates. A second study dedicated to the identification of transformation products (TPs) generated from DOAs was conducted using a combination of HR-MS/MS and metabolic identification and structural elucidation software. Findings confirmed the presence of multiple phase I and II DOA TPs (n=35) in raw sewage influents. Concentrations of all TPs were estimated based on the parent DOAs response factors, and used to calculate the percent mole fraction contributions of each TP to the parent concentrations. High abundance and frequency (compared to the parent drug) was determined for 9 of the TPs coming from drugs like oxycodone, morphine, codeine, methadone, LSD, cocaine, and MDEA. Non-target analysis using HRMS was explored as a tool to characterize, and compare a series of interconnected water matrices along a river system. Several thousands of formulae were generated using automated heuristic rules from the full-scan acquisition at 140,000 resolution. Samples were part of a trajectory covering upstream, effluent, effluent mixing zone, downstream, drinking water intake, and treated drinking water locations. Graphical representations of the data were used to evaluate commonalities among the system. Using this approach, a total of 64 recalcitrant components were identified throughout the samples downstream of the effluent release point. Using a combination of MS/MS and computer-aid software techniques 4 out of the 64 compounds were tentatively confirmed. In addition, comparison of drinking water intake and finalized treated drinking water sites showed the presence of 1,152 chemical entities that were common to both locations; and 1,857 that were unique to the treated drinking water. Therefore, this non-target technique could be used to identify the potential formation of treatment byproducts.

No description available.

No description available.

Zugl.: Heidelberg, Universiẗat, Diss., 2008. / Includes bibliographical references (p. 313-338).

This diploma thesis will be focused on the identification and quantification of selected phytopharmaceuticals ant theri transformation products using separation and spectrometric methods available in the laboratories of ICTEP.