In this thesis factors that explain Swedish pharmaceutical export as been analyzed. The period investigated is from 1995 to 2010. The investigation is concluded through the use of a gravity model. It investigates not only the GDP and distance variable but also the effects of GDP/capita, exchange rates and the effect of being a part of the internal market of EU. The effects of having access to the ocean and if the country has English as its official language is investigated as well as the effect of sharing the same religion. The results show that only a smaller subset of countries make up for most of the pharmaceutical export. The results also shows that the pharmaceutical export can be explained by the same variables as most other goods.

Pharmaceuticals, personal care products and dissolved organic matter (OM) are introduced to soil via irrigation with reclaimed wastewater. This thesis examines the basic factors that influence sorption of these components in soil. Sorption of dissolved OM samples of varying composition to clay surfaces was examined. Results indicate that preferential sorption is dependent on clay type but not necessarily OM composition. Analysis of soils revealed aliphatic components, carbohydrates and amino acids are prevalent at the soil-water interface whereas aromatics are inaccessible at the soil-water interface. No clear relationship between sorption affinity of 17β-estradiol, sulfamethoxazole, carbamazepine and phenanthrene and soil OM aromaticity or aliphaticity was observed. A negative relationship between sorption and O-alkyl content may be due to these components blocking contaminant access to high affinity sorption sites. Therefore, application of reclaimed wastewater to soils with O-alkyl-rich OM may result in higher mobility of contaminants.

Pharmaceuticals, personal care products and dissolved organic matter (OM) are introduced to soil via irrigation with reclaimed wastewater. This thesis examines the basic factors that influence sorption of these components in soil. Sorption of dissolved OM samples of varying composition to clay surfaces was examined. Results indicate that preferential sorption is dependent on clay type but not necessarily OM composition. Analysis of soils revealed aliphatic components, carbohydrates and amino acids are prevalent at the soil-water interface whereas aromatics are inaccessible at the soil-water interface. No clear relationship between sorption affinity of 17β-estradiol, sulfamethoxazole, carbamazepine and phenanthrene and soil OM aromaticity or aliphaticity was observed. A negative relationship between sorption and O-alkyl content may be due to these components blocking contaminant access to high affinity sorption sites. Therefore, application of reclaimed wastewater to soils with O-alkyl-rich OM may result in higher mobility of contaminants.

Based on a diverse consortia of research completed within the last 15 years, it has been found that Pharmaceutical Compounds (PCs) are present in detectable levels within a variety of environmental matrices, including tap water. This is largely attributed to anthropogenic activities as humans are the majority consumer of PCs. As a result, the primary method of disposal is via wastewater pathways resulting from human excretion of ingested PCs. Based on past research into PC fate via the wastewater treatment process, only limited biotic and abiotic transformations are achieved – most PC’s are detected in the effluents of WWTP’s. This suggests that improving the removal of PCs during the wastewater treatment process provides a promising strategy for limiting the conveyance of PCs to the environment. Historically, studies regarding PC fate in WWTPs have predominantly focused on the activated sludge process. However, fixed film (biofilm) wastewater treatment technologies continue to gain popularity at full scale wastewater treatment facilities. The limited studies which investigated fixed film wastewater treatment processes have reported that improved transformation efficiencies were observed relative to activated sludge systems. Based on these previous studies, it was postulated that the more diverse bacterial consortium present within the Integrated Fixed Film Activated Sludge (IFAS) process, a novel treatment process which has recently gained popularity in North America, may lead to improved transformation efficiencies (“removals”) of these very complex compounds. Only one previous study which investigated the transformation efficiencies of the IFAS process compared to a control was found. It was therefore considered that an additional investigation into the IFAS process warrants further investigation. Four IFAS Sequencing Batch Biofilm Reactors (SBBRs) and four control Sequencing Batch Reactors (SBRs) were operated with varied experimental conditions in a 22 factorial design to investigate whether an observable difference in the level of PC transformations would result via the IFAS process when compared to a control. Experimental conditions were characterized by varying the operating Solids Retention Time (SRT) and mixed liquor temperature. For all other operational parameters, best efforts were made to ensure both reactors were operated under equivalent conditions. This permitted a true assessment of the effects of the inclusion of IFAS media. Reactors were investigated through three phases of sampling, under which the performance of the reactors was investigated through the measurement of the following parameters: • Conventional parameters (tCOD, sCOD, TAN, NO3-N) within the initial and final samples; • Operational parameters (MLSS, MLVSS, ESS); and • The transformation efficiencies achieved for 5 PC (Carbamazepine, Sulfamethoxazole, Trimethoprim, Atenolol and Acetaminophen). During all three phases of PC sampling, the pilot reactors were found to have been performing as anticipated with respect to conventional contaminant removals. Organic removals were found to be statistically similar between the IFAS and control reactors across all four experimental conditions. Full nitrification was observed for all reactors with the exception of the control SBR operated under the low SRT, low temperature condition. The IFAS SBBRs were found to demonstrate improved nitrification kinetics when compared to their respective controls operated under the same experimental conditions. This was believed to be related to the more diverse bacterial consortia present as a result of the IFAS biofilms. All reactors were generally believed to be operating at steady state and were within an acceptable range of the target operating conditions. Due to complications associated with the analysis of samples, only CBZ, TRIM, ATEN and ACE could be successfully quantitated. CBZ was found to not have been transformed to any appreciable level across all conditions investigated through either the IFAS SBBRs or control SBRs. ACE was transformed at efficiencies greater than 99% under all conditions and in both IFAS and control reactors and therefore no comparison could be made. TRIM and ATEN demonstrated improved transformation efficiencies under all conditions within the IFAS reactors. The presence of IFAS media, SRT and temperature were all found to be statistically significant effects through ANOVA using a confidence limit of 95%.

Aquatic plants of the family Lemnaceae (e.g., duckweed) actively uptake, metabolize, and sequester pollutants in natural and engineered wetland systems. Numerous interrelated processes contribute to pollutant removal in wetlands; of these processes, interactions between organic pollutants and aquatic plants may be least understood. Research focused on (1) understanding parameters that affected uptake of fluorinated organic pollutants by Lemnaceae, (2) identifying plant processes involved in removal of wastewater-associated organic pollutants by Lemnaceae, and (3) assessing use of Lemnaceae callus cultures in understanding toxicity and metabolism of fluorinated organic pollutants by Lemnaceae. Through active plant uptake, Lemna minor rapidly removed 13 fluorinated phenols, with pseudo-first order rate constants of 0.20±0.04 d-1 to 0.84±0.07 d-1. Uptake rates depended on substituent type (i.e., trifluoromethyl- vs. fluoro-) and position, with slowest removal rates for di-ortho-substituted fluorophenols. Uptake rates decreased with increasing concentrations of fluorinated phenols; assessments of inhibition of plant oxygen production in conjugation with concentration studies indicated that concentration affected uptake rates even when Lemnaceae was not inhibited. Additionally, temperature dependencies of fluorinated phenol uptake by Lemnaceae were well represented by Arrhenius relationships; however, effects of temperature on plant activity were also observed in trends of uptake rates with temperature. Increasing uptake with decreasing concentration and increasing temperature, in addition to effects of plant inhibition, plant activity, and sorption on uptake, strongly emphasized the importance of plant metabolism in uptake of fluorinated phenols by Lemnaceae. Active plant uptake of wastewater-associated organic pollutants affected fate of fluoxetine, triclosan, and 2,4-dichlorophenoxyacetic acid, while passive plant removal processes contributed to fate of four of six wastewater derived organic pollutants. Consequently, plant-associated processes were important components of fate for over 50% of experimental wastewater-associated organic pollutants. Furthermore, assessments with Lemnaceae callus cultures indicated that callus cultures were generally more susceptible to inhibitory responses to fluorinated phenols than were Lemnaceae plants; however, metabolism of 3-trifluormethylphenol in Lemnaceae callus cultures and plants was similar, indicating that callus cultures may be valuable in plant metabolism studies. Research advances understanding of fate of organic pollutants in wetland systems, and thus has important implications for water quality, ecosystem health, and human health.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

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>

Orientador: Sérgio Luís de Carvalho / Banca: Alessandro Minillo / Banca: Cristiano Poleto / Resumo: A contaminação dos ecossistemas aquáticos por compostos farmacológicos intensificou-se nos últimos anos devido ao aumento da produção e ao consumo desenfreado destas substâncias pela população. Estes compostos são encontrados em águas naturais e em efluentes de Estações de Tratamento de Esgoto (ETE), comprovando que sua presença em águas naturais é um indicativo de contaminação por águas residuárias de ETE. A presente pesquisa avaliou a ocorrência de compostos farmacológicos no Córrego da Onça, município de Três Lagoas (MS), bem como as relações específicas entre os pontos de monitoramento do corpo d'água. Assim, foram coletadas mensalmente, em um período de 12 meses amostras de água (1L) em seis pontos distintos representando diferentes seções do córrego. As amostras foram submetidas ao processo de extração em fase sólida e analisadas por cromatografia líquida de alta eficiência. Fármacos como atenolol, diclofenaco, ibuprofeno, naproxeno, paracetamol e piroxicam foram detectados nos pontos de coleta do corpo d'água. Com auxílio de uma ferramenta estatística, os pontos amostrais foram reunidos em duas classes, observando-se maior similaridade entre P1(Lagoa do Meio) e P2 (Lagoa Maior), e entre P4 (Jusante da ETE) e P5 (Novas Nascentes). Os resultados evidenciam a contaminação no córrego por compostos farmacológicos, possivelmente devido aos indícios de ligações clandestinas de esgoto sanitário e/ou não eficiência do sistema utilizado pela ETE do município de Três Lagoas. / Abstract: The contamination of aquatic ecosystems by pharmacological compounds has intensified in recent years due to increased production and consumption of these substances by population. These compounds are found in natural waters and effluents from sewage treatment plants (WTP), confirming that their presence in natural waters is indicative of contamination by wastewater from WTP. This study investigated the occurrence of pharmacological compounds in the Stream of Onça at TrêsLagoas (MS), and the specific relationships between the monitoring points of the waterbody. Water samples were collected monthly, over a period of 12 months (water samples 1L) at six different points representing different sections of the stream. The samples were subjected to the process of solid phase extraction and analyzed by high performance liquid chromatography. Drugs such as atenolol, diclofenac, ibuprofen, naproxen, paracetamol and piroxicam were detected in the sampling points of the waterbody. A statistical tool aided to divide the sites into two classes, with a greater similarity between P1 (Middle Pond) and P2 (Major Pond), and between P4 (Downstream of WTP) and P5 (New springs). The results show that the stream contamination by pharmacological compoundsis an indication of illegal connections of sanitary sewer and/or inefficiency of the system used by WTP of Três Lagoas (MS). / Mestre

Crystallising large, flexible molecules, which are becoming more common in pharmaceutical development, often presents significant challenges for chemists and particle scientists. These difficulties are sometimes attributed to the flexibility of the molecule, and the existence of multiple conformers in solution. Structurally related impurities, frequently present when crystallising these materials, can also impact on growth and habit, and both these aspects are considered in this thesis. This work considers two pharmaceutical compounds, a relatively small but nonetheless flexible molecule, ethenzamide, and a precursor of Amprenavir, a much larger molecule. Both compounds typically grow as thin needles in a wide variety of solvents, and effort was required to grow suitable crystals for structure determination. Ethenzamide has an unusual structure, the amide group being out-of-plane relative to the ring, while in all known co-crystals of the compound, including three new co-crystal structures determined in this work, it has a planar structure with an intramolecular hydrogen bond not seen in the single component crystal. Theoretical structure generation calculations suggest a second polymorph with a planar conformation may exist, though a screen has not found any further solid phases. ab initio work suggests the planar conformation is the stable arrangement in vacuo. Several structures for the Amprenavir intermediate have been determined, as an ethanol solvate, a methanol solvate and a hydrate. A phase diagram has been measured in the industrial solvent mix, and the nucleation and growth properties of this molecule, both pure and in the presence of several structurally related impurities, have been measured. The Cambridge Structural Database has been searched for similar structures, and conformational searches have been carried out for both molecules, using vacuum phase ab initio energy calculations. Infrared spectroscopy has been used to investigate solution phase structure. These theoretical and practical studies will try to relate conformational properties to crystallisation behaviour.

A number of pharmaceuticals have been shown to have adverse effects on key biological processes of aquatic organisms at low concentrations (ng/l range). Key questions for chemical risk assessment are whether such pharmaceuticals can produce adverse effects on organisms when present in the environment in combination and at low concentrations, whether these can be classified as additive, and under what circumstances can they be predicted. The main purpose of this study was to assess the potential for combination effects of a multicomponent steroid pharmaceutical mixture of dissimilarly acting compounds on an ecologically relevant end point – reproduction, using the existing predictive toxicity models Concentration Addition (CA) and Independent Action (IA). Concentrations of steroids close to those reported in the environment were shown to produce adverse effects on reproduction when present in combination with other steroids. Clear combination effects significantly larger than the effects of the individual compounds were observed when each compound was present at a concentration below the detection limit of the assay, demonstrating a ‘something from nothing’ mixture effect. Furthermore, IA predicted more pronounced effects on egg production that CA, an observation previously unreported from the literature. Actual observed effects were closer to the IA prediction. Additional biomarker and molecular endpoints were examined in subsequent studies to establish the mechanisms of disrupted reproduction in pair-breeding FHMs exposed to the steroid mixture. Results from this study indicate that reproductive impairment of fish exposed to the steroid mixture is likely due to the masculinisation of female fish due to the androgenic activity of the mixture. These results have implications for chemical risk assessment, and in particular, highlight the need for caution when using CA as a worst-case approximation of mixture effects.