臺灣博碩士論文加值系統

過去以來，許多藥物不斷在環境水體中被檢出，環境水體中的殘留藥物對生態系統具潛在性危害。文獻已證實這些常用藥物無法完全被傳統污水處理及飲用水處理系統去除，且藥物目前非屬放流水標準等相關法規管制項目，導致醫院廢水成為環境中殘留藥物最重要來源之一，然而廢水中殘留藥物對於環境影響之研究卻非常有限。因此，本研究目標包括（一）探討醫院廢水藥物濃度及生態毒性效應評估：利用生物急毒性測試探討醫院放流水毒性、藥物混合毒性及自然光解前後毒性變化等。除了常見藥物外，本研究特別選用非法濫用、環境中經常檢測出且不易自然分解之精神性藥物-氯胺酮（K他命）進行研究目標（二）探討氯胺酮在環境中真實濃度之生態毒性，首先建立生物急毒性資料並探討氯胺酮在混合及光解毒性上之變化，再利用慢毒性試驗評估氯胺酮在環境真實濃度下造成繁殖毒性影響進行深入探討。本研究各目標及重點成果簡列如下：
於「探討醫院廢水藥物濃度及生態毒性效應評估」目標，本研究先證明環境承受水體中藥物濃度明顯會受到醫院放流水影響而增加。利用四種生物急毒性試驗方法（鯉魚、羅漢魚、米蝦及水蚤）評估放流水及環境水體生物急毒性，結果顯示原廢水對於兩種脊椎生物皆具有明顯急毒性，而鯉魚(Cyprinus carpio)為脊椎生物中最敏感且急毒性較為顯著（半致死濃度LC50約59%）。藥物在放流水及環境水體中皆呈現混合存在，故本研究選定19種 (sulfamethoxazole, tetracycline, caffeine, pentoxifylline, acetaminophen, ciprofloxacin, ofloxacin, cephalexin, cephradine, cephapirin, cefazolin, naproxen, ketoprofen, diclofenac, piroxicam, gemfibrozil, salbutamol, propranolol and atenolol) 醫院放流水中較高濃度藥物並利用鯉魚作為試驗生物評估混合藥物毒性之變化，研究結果19種混合毒性之LC50為60.19 mg/L (每一種藥物3.19 mg/L)；而19種藥物在單一狀況(3.19 mg/L)皆不具急毒性，結果證明藥物在混合狀態下會造成毒性增強效應。另外，本研究進一步證明藥物毒性會隨著自然光解作用而增加；混合藥物在自然光照1~5天後，對鯉魚造成的急毒性明顯增加；除了急毒性死亡率增加外，更導致許多不正常行為及後遺症（如翻肚游、魚鰓變紅、瞳孔放大及厭食症狀等）。然而接觸試驗藥物樣品倖存的鯉魚，即使回到無藥物存在的環境，也無法正常地延續生命；透過28天連續觀察，最終仍造成約四成的死亡率。因此殘留在生物體內的藥物可能會不斷產生後遺症，結果顯示殘留藥物對環境生態影響非常值得持續進行研究。
於「探討氯胺酮在環境中真實濃度之生態毒性」目標，氯胺酮為重要非法及濫用之藥物且被證實無法被傳統污水處理系統去除，許多文獻在環境及廢水中檢測出高濃度的氯胺酮，但環境中生態毒性卻未被明確定義。因此，本研究建立氯胺酮及其主要代謝產物去甲基氯胺酮(norketamine)之水蚤急毒性及慢毒性範圍，並測試許多不同環境情境氯胺酮及去甲基氯胺酮混合毒性變化。另外，本研究更探討氯胺酮光解毒性之變化及光解產物。研究結果發現，在48小時暴露下，氯胺酮和去甲基氯胺酮水蚤急毒性半致死濃度分別為30.93 及 25.35 mg/L。照光後毒性明顯會增強；氯胺酮(20 mg/L)照光兩小時後死亡率由0%急速增加至100%，在光解過程中新的去甲基氯胺酮光解副產物(M.W. 241)初次被發現。研究成果首度證實氯胺酮在環境真實濃度(5 μg/L-100 μg/L)下對水蚤造成顯著性的繁殖抑制，繁殖量減少33.6-49.8% (p < 0.05)。本研究結果顯示，氯胺酮在環境相關濃度下具環境危害之風險，但造成毒性之原因尚未無法完全釐清。因此除氯胺酮之外，醫院放流水中更含有數百種已知或尚未被檢出之殘留藥物及其代謝產物，造成的環境風險不但充滿未知數且不容被忽視，值得未來持續探討及評估。

Pharmaceuticals are detected frequently in aquatic environments, including surface water, ground water and drinking water; these compounds cannot be adequately removed by conventional wastewater treatment plants and drinking water treatment systems. Hospital effluents are an important source of residual drugs and other classes of pharmaceuticals in aquatic environments, but current knowledge of the environmental effects of residual drugs is limited. The first objective of this research is to evaluate the ecotoxicity and variation of residual pharmaceuticals in hospital effluents, including their biological, mixture and photolysis toxicity. Specifically, a neuro-active drug ketamine was chosen to evaluate its ecotoxicological effects at environmentally relevant concentrations and to determine its acute and chronic toxicity. The photolysis and synergistic aquatic toxicity of ketamine/norketamine was also evaluated. Environmentally relevant concentrations of ketamine were specifically examined in reproductive toxicity tests.
In the first part of this thesis, entitled “Increased acute toxicity caused by pharmaceuticals in hospital effluents”, raw wastewater from the studied hospital exhibited acute toxicity to vertebrate organisms, and Cyprinus carpio was the most sensitive organism tested (LC50~59%). A mixture of 19 commonly used pharmaceuticals (sulfamethoxazole, tetracycline, caffeine, pentoxifylline, acetaminophen, ciprofloxacin, ofloxacin, cephalexin, cephradine, cephapirin, cefazolin, naproxen, ketoprofen, diclofenac, piroxicam, gemfibrozil, salbutamol, propranolol and atenolol) caused acute toxicity to Cyprinus carpio with an LC50 value of 60.68 mg/L (3.19 mg/L for each chemical) after 96 h. This study demonstrated that irradiation for 1-5 days significantly increased the acute toxicity of the pharmaceuticals to fish, leading to increased mortality after a 2-h exposure, and approximately 40% of the surviving fish died within 28 days. The pre-irradiated pharmaceutical mixture also induced strange behaviors (including swimming belly up, the presence of red gills, mydriasis and anorexia) in the fish that survived the test. The environmental effects caused by residual drugs require in-depth investigation in future studies.
In the second part of this thesis, entitled “Ecotoxicological effect of ketamine”, one specific class of neuro-active drugs, i.e., ketamine, which is frequently detected in receiving surface waters and wastewater, was thoroughly investigated. Ketamine has been increasingly used in medicine and has the potential for abuse or illicit use around the world. Ketamine cannot be removed by conventional wastewater treatment plants. Although ketamine and its metabolite norketamine have been detected to a significant extent in effluents and aquatic environments, their ecotoxicity effects in aquatic organisms remain undefined. In this study, we investigated the acute toxicity of ketamine and its metabolite, along with the chronic reproductive toxicity of ketamine (5–100 μg/L) to Daphnia magna. Multiple environmental scenarios were also evaluated, including drug mixtures and sunlight irradiation toxicity. Ketamine and norketamine caused acute toxicity to D. magna, with half lethal concentration (LC50) values of 30.93 and 25.35 mg/L, respectively, after 48 h of exposure. Irradiated solutions of ketamine (20 mg/L) significantly increased the mortality of D. magna; pre-irradiation durations up to 2 h rapidly increased the death rate to 100%. A new photolysis byproduct (M.W. 241) of norketamine that accumulates during irradiation was identified for the first time. Environmentally relevant concentrations of ketamine produced significant reproductive toxicity effects in D. magna, as revealed by the reduction in the number of total live offspring, i.e., by 33.6-49.8% (p < 0.05). The results of this work demonstrated the hazard risks of environmentally relevant ketamine concentrations. In addition to ketamine, hundreds of compounds are present in hospital wastewaters and undergo solar photolysis in aquatic environments; therefore, potential synergistic effects of mixed pharmaceuticals on aquatic organisms cannot be ignored.

致謝 ……………………………………………………………………………………i
中文摘要 ……………………………………………………………………………ii
Abstract………………………………………………………………………………iv
Chapter 1. Introduction and framework.....1
1.1 Background/Problem statement 1
1.2 Aims and scope 3
1.3 Research framework of this study 5
1.4 Dissertation overview 7
Chapter 2. Literature Review 8
2.1 Occurrences of pharmaceuticals in hospital wastewater 8
2.2 Ecotoxicity of pharmaceuticals 9
2.2.1 Environmental impact and toxicity of pharmaceuticals 9
2.2.2 Photolysis toxicity of pharmaceuticals 10
2.3 The ecotoxicity of neuroactive drugs: Ketamine 11
Chapter 3. Materials and Methods 23
3.1 Chemicals and Standards 23
3.2 Description and water quality of the sampled hospital effluents and surface water 23
3.3 Chemical analysis of the pharmaceuticals 26
3.4 Byproducts Identification 29
3.5 Photolysis experiment 30
3.5.1 Sunlight photolysis experiment of mixture pharmaceuticals 30
3.5.2 Simulator photolysis experiments of ketamine and norketmine 30
3.6 Acute toxicity test 32
3.7 Chronic exposure (reproduction test) 35
3.8 Mixture toxicity 36
Chapter 4. Results and Discussion 37
4.1 Part I: Increased acute toxicity caused by pharmaceuticals in hospital effluents 37
4.1.1 Common pollutants and pharmaceuticals in hospital wastewater 37
4.1.2 Acute toxicity of hospital wastewater 44
4.1.3 Acute toxicity of a pharmaceutical mixture to Cyprinus carpio 49
4.1.4 Acute toxicity variation in samples pre-irradiated with sunlight 62
4.2 Part II: Ecotoxicological effect of ketamine 67
4.2.1 Acute toxicity of ketamine and norketamine to Daphnia magna 67
4.2.2 Acute toxicity variations (with different pre-irradiated times) and photolysis byproducts 69
4.2.3 Mixture toxicity of ketamine and norketamine 74
4.2.4 Reproduction test (chronic toxicity) 76
4.2.5 Environmental relevance 82
Chapter 5. Conclusions, environmental implications and Suggestions 83
5.1 Conclusions 83
5.2 Environmental implications and suggestion for future work 85
Chapter 6. References 87

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