| 研究生: |
陳柏均 Chen, Bo-Jyun |
|---|---|
| 論文名稱: |
污水廠中內分泌干擾活性及藥物之檢測和藥物氯化衍生物之活性變化 Endocrine disrupting activity and concentrations of pharmaceuticals in wastewater treatment plants and endocrine disrupting activity of pharmaceutical chlorinated derivatives |
| 指導教授: |
周佩欣
Chou, Pei-Hsin |
| 學位類別: |
碩士 Master |
| 系所名稱: |
工學院 - 環境工程學系 Department of Environmental Engineering |
| 論文出版年: | 2018 |
| 畢業學年度: | 106 |
| 語文別: | 中文 |
| 論文頁數: | 122 |
| 中文關鍵詞: | 藥物與個人保健用藥 、污水處理廠 、內分泌干擾活性 、報導基因生物試驗法 、氯化衍生物 、液相層析串聯式質譜儀 、風險商數 |
| 外文關鍵詞: | Pharmaceuticals and personal care products, Endocrine disrupting activities, Wastewater treatment plants, Yeast-based reporter gene assays, Liquid chromatography tandem mass spectrometry, Chlorinated derivatives |
| 相關次數: | 點閱:101 下載:6 |
| 分享至: |
| 查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
隨著醫藥的普及,人們使用量與日俱增,而醫藥的濫用與隨意棄置,使之成為環境中之新興污染物。某些藥物具有可能影響生物內分泌系統之作用,進而影響環境生態,然而這些藥物通常無法透過污水處理流程而完全去除。在污水處理流程中的消毒程序同時也可能與藥物反應而生成氯化衍生物,無論是母物質或氯化衍生物,對於環境之影響須審慎評估。
本研究選定南部地區四座民生污水處理廠與兩座醫院污水處理廠中不同處理單元進行樣本採集,利用報導基因酵母菌之生物試驗法與液相層析串聯式質譜儀,分析樣本中之內分泌干擾活性與六種環境中常見的個人保健用藥濃度,同時也鑑定藥物及其氯化衍生產物是否仍具有內分泌干擾活性。
藥物之內分泌干擾活性試驗中,非類固醇類止痛藥具有干擾甲狀腺激素受體、糖皮質激素受體、鹽皮質激素受體之能力,而咖啡因與乙醯氨酚則不具有測試的內分泌干擾活性。此外,待克菲那 (Diclofenac)之氯化衍生物可能具有抗甲狀腺激素與抗糖皮質激素活性,那普洛辛 (Naproxen)之氯化衍生物則可能具有抗糖皮質激素活性。針對污水廠樣本中內分泌干擾活性之檢測,抗甲狀腺激素活性僅在三座污水處理廠中測得,而抗糖皮質激素活性與抗鹽皮質激素活性則在六座污水處理廠中皆有測得,且醫院污水處理廠進流水中之抗糖皮質激素與抗鹽皮質激素活性皆高於民生污水處理廠。
以液相層析串聯式質譜儀檢測污水廠樣本中藥物濃度之結果顯示,藥物主要存在於水相中,進流水中乙醯氨酚 (Acetaminophen) (6.3~159.2 µg/L)與咖啡因 (Caffeine) (14.9~119.5 µg/L)具有相當高的濃度,而非類固醇類藥物各為可多普洛芬 (Ketoprofen) (20~305 ng/L)、待克菲那 (169~3818 ng/L)、異布洛芬 (Ibuprofen) (318~7040 ng/L)、那普洛辛 (195~6075 ng/L)。除了可多普洛芬,其餘藥物之最高濃度皆在醫院污水處理廠樣本中測得。比較藥物於污水廠中之去除率時,易生物降解之乙醯氨酚、咖啡因、異布洛芬、那普洛辛各為40-99%、36-99%、45-93%、-21-94%,而不易生物降解之待克菲那與可多普洛芬各為-179-50%、-674-100%。此外,將樣本中內分泌干擾物質之濃度轉換為內分泌干擾活性標準品當量濃度,並與生物試驗測得之活性比較,其結果顯示生物試驗所得之當量濃度遠高於由儀器分析濃度換算之活性,原因可能為環境樣本複雜而造成的協同作用或還有許多未被選定之內分泌干擾物質所致。
比較污水廠各單元間拮抗活性之變化可得知,污水廠中內分泌干擾活性大多能透過生物處理程序得到有效的去除,而由藥物在出流水中殘餘濃度,計算風險商數後發現那普洛辛、異布洛芬及待克菲那皆為中度風險及高風險,對此需要更高級的處理流程才能完善的去除,達到保護環境之功用。
The presence of pharmaceuticals and personal care products (PPCPs) in the environment has received a lot of attention in recent years. The waste streams from hospitals and wastewater treatment plants (WWTPs) have been identified as major contributors to environmental contamination with human-derived medications. Chlorination is a common disinfection process in sewage treatment. During the chlorination process, chlorinated derivatives of drugs may be produced, and there is a lack of sufficient toxicological information for these chlorination by-products.
In this study, recombinant yeast bioassays and liquid chromatography–mass spectrometry (LC-MS/MS) were used to investigate the endocrine disrupting activities and concentrations of selected PPCPs, including naproxen, diclofenac, ketoprofen, ibuprofen, acetaminophen, caffeine in Taiwanese WWTPs. The endocrine disrupting activities of chlorinated derivatives were also examined. Our results showed that nonsteroidal anti-inflammatory drugs are potential endocrine disrupting chemicals, which elicited thyroid receptor hormone antagonistic activities, glucocorticoid receptor antagonistic activities and mineralocorticoid receptor antagonistic activities. Also, WWTP water samples showed thyroid hormone receptor antagonistic activities, glucocorticoid receptor antagonistic activities and mineralocorticoid receptor antagonistic activities. The concentrations of PPCPs were often detected at ng/L to µg/L levels. In addition, chlorinated derivatives of naproxen and diclofenac showed endocrine disrupting activities.
Ammann, A. A., Macikova, P., Groh, K. J., Schirmer, K., & Suter, M. J. LC-MS/MS determination of potential endocrine disruptors. Analytical and Bioanalytical Chemistry, 406(29), pp. 7653-7665. (2014).
Anderson, F. D., Gibbons, W., & Portman, D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception, 73(3), pp. 229-234. (2006).
Asensio, L., González, I., García, T., & Martín, R. Determination of food authenticity by enzyme-linked immunosorbent assay (ELISA). Food Control, 19(1), pp. 1-8. (2008).
Ashfaq, M., Li, Y., Wang, Y., Chen, W., Wang, H., & Chen, X. Occurrence, fate, and mass balance of different classes of pharmaceuticals and personal care products in an anaerobic-anoxicoxic wastewater treatment plant in Xiamen, China. Water Research, 123, pp. 655-667. (2017).
Behera, S. K., Kim, H. W., Oh, J.-E., & Park, H.-S. Occurrence and removal of antibiotics, hormones and several other pharmaceuticals in wastewater treatment plants of the largest industrial city of Korea. Science of the Total Environment, 409, pp. 4351-4360. (2011).
Behera, S. K., Kim, H. W., Oh, J.-E., & Park, H.-S. Occurrence and removal of antibiotics, hormones and several other pharmaceuticals in wastewater treatment plants of the largest industrial city of Korea. Science of the Total Environment, 409(20), pp. 4351-4360. (2011).
Bellet, V., Hernandez-Raquet, G., Dagnino, S., Seree, L., Pardon, P., Bancon-Montiny, C., & Fenet, H. Occurrence of androgens in sewage treatment plants influents. Water Research, 46(6), pp. 1912-1922. (2012).
Bender, M., & MacCrehan, W. A. Transformation of Acetaminophen by Chlorination Produces the Toxicants 1,4-Benzoquinone and N-Acetyl-p-benzoquinone Imine. Environmental Science & Technology, 40(2), pp. 516-522. (2006).
Berkowitz, A. B., H.Tarver, J., & SydneySpector. Release of norepinephrine in the central nervous system by theophylline and caffeine. European Journal of Pharmacology, 10(1), pp. 64-71. (1970).
Bernstein, L., Deapen, D., Cerhan, J. R., Schwartz, S. M., & Liff, J. Tamoxifen Therapy for Breast Cancer and Endometrial Cancer Risk. Journal of the National Cancer Institute, 91(19), pp. 1654-1622. (1999).
Bessems, J. G., & Vermeulen, N. P. Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Critical Reviews in Toxicology, 31(1), pp. 55-138. (2001).
Bishnoi, A., Carlson, H. E., Gruber, B. L., Kaufman, L. D., Bock, J. L., & Lidonnici, K. Effects of commonly prescribed nonsteroidal anti-inflammatory drugs on thyroid hormone measurements. The American Journal of Medicine, 96(3), pp. 235-238. (1994).
Carlsson, C., Johansson, A.-K., Alvan, G., Bergman, K., & Kühler, T. Are pharmaceuticals potent environmental pollutants?: Part I: Environmental risk assessments of selected active pharmaceutical ingredients. Science of The Total Environment, 364(1-3), pp. 67-87. (2006).
Cederbaum, Y. D. Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells. Journal of Pharmacology and Experimental Therapeutics, pp. 1497-1505. (1995).
Chandrasekharan, N. V., Dai, H., Roos, K. L., Evanson, N. K., Tomsik, J., Elton, T. S., & Simmons, D. L. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. PNAS, 99(21), pp. 13926-13931. (2002).
Choi, K., Kim, Y., Park, J., Park, C. K., Kim, M., Kim, H. S., & Kim, P. Seasonal variations of several pharmaceutical residues in surface water and sewage treatment plants of Han River, Korea. Science of the Total Environment, 405(1-3), pp. 120-128. (2008).
Cryer, B., & Feldman, M. Cyclooxygenase-1 and Cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. American Journal of Medicine, 104(5), pp. 413–421. (1998).
Dahlin, D. C., & Nelson, S. D. Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen. Journal of Medicinal Chemistry, 25(8), pp. 885-886. (1982).
Dave, G., & Herger, G. Determination of detoxification to Daphnia magna of four pharmaceuticals and seven surfactants by activated sludge. Chemosphere, 88(4), pp. 459-466. (2012).
Edmund, M., & Dubois, L. High dosage steroid therapy for systemic lupus erythematosus. Arthritis & Rheumatology, 5(3), pp. 250–260. (1962).
European Commission 2003. Technical Guidance Document on Risk Assessment in support of Commission Directive 93/67/EEC on Risk Assessment for new noti- fied substances. Office for Official Publications of the European Communities, Luxembourg.
Ezechiáš, M., Janochová, J., AlenaFilipová, Křesinová, Z., & Cajthaml, T. Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors. Chemosphere, 152, pp. 284-291. (2016).
Gerlier, D., & Thomasset, N. Use of MTT colorimetric assay to measure cell activation. Journal of Immunological Methods, 94(1-2), pp. 57-63. (1986).
González-Pérez, D. M., Pérez, J. I., & Gómez, M. A. Behaviour of the main nonsteroidal anti-inflammatory drugs in a membrane bioreactor treating urban wastewater at high hydraulic- and sludge-retention time. Journal of Hazardous Materials, 336, pp. 128-138. (2017).
Gracia-Lor, E., Sancho, J. V., Serrano, R., & Hernández, F. Occurrence and removal of pharmaceuticals in wastewater treatment plants at the Spanish Mediterranean area of Valencia. Chemosphere, 87(5), pp. 453-462. (2012).
Hans-Rudolf, Aerni; Bernd, Kobler; V., Rutishauser Barbara; E., Wettstein Felix; René, Fischer; Walter, Giger; Andreas, Hungerbühler; Dolores, Marazuela M.; Armin, Peter; René, Schönenberger; Marc, J.-F. A. Christiane Vögeli; L., Eggen Rik I. Combined biological and chemical assessment of estrogenic activities in wastewater treatment plant effluents. Analytical and Bioanalytical Chemistry, 378(3), pp. 688-696. (2004).
Harada, A., Komori, K., Nakada, N., Kitamura, K., & Suzuki, Y. Biological effects of PPCPs on aquatic lives and evaluation of river waters affected by different wastewater treatment levels. Water Science & Technology, 58(8), pp. 1541-1546. (2008).
Hayashi, Masaru; Tsutamoto, Takayoshi; Wada, Atsuyuki; Tsutsui, Takashi; Ishii, Chitose; Ohno, Keijin; Fujii, Masanori; Taniguchi, Atsushi; Hamatani, Tomokazu; Nozato, Yoshitaka; Kataoka, Ken; Morigami, Naoki; Ohnishi, Masato; Kinoshita, Masahiko; Horie, Minoru. Immediate Administration of Mineralocorticoid Receptor Antagonist Spironolactone Prevents Post-Infarct Left Ventricular Remodeling Associated With Suppression of a Marker of Myocardial Collagen Synthesis in Patients With First Anterior Acute Myocardial In. Circulation, 107(20), pp. 2559-2565. (2003).
Hernandoa, Mezcuaa, M., Fernández-Albaa, A. R., & Barceló, D. Environmental risk assessment of pharmaceutical residues in wastewater effluents, surface waters and sediments. Talanta, 69(2), pp. 334-342. (2006).
Hidalgo, V. S., Silva, A. P., Undurraga, S. F., Soto, I. N., & Marinovic, M. M. Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis associated to the use of propylthiouracil. Report of four cases. Revista Medica de Chile, 134(4), pp. 475-480. (2006).
Hoeger, B., Köllner, B., Dietrich, D. R., & Hitzfeld, B. Water-borne diclofenac affects kidney and gill integrity and selected immune parameters in brown trout (Salmo trutta f. fario). Aquatic Toxicology, 75(1), pp. 53-64. (2005).
Holčapek, M., Jirásko, R., & Lísa, M. Recent developments in liquid chromatography–mass spectrometry and related techniques. Journal of Chromatography A, 1259, pp. 3-15. (2012).
Horáková, D., Rumlová, M., IvaPichová, & TomášRuml. Luminometric method for screening retroviral protease inhibitors. Analytical Biochemistry, 345(1), pp. 96-101. (2005).
Ihara, M., Ihara, M. O., Kumar, V., Narumiya, M., Hanamoto, S., Nakada, N., & Yamashita, N. Co-occurrence of Estrogenic and Antiestrogenic Activities in Wastewater: Quantitative Evaluation of Balance by in Vitro ERα Reporter Gene Assay and Chemical Analysis. Environmental Science & Technology, 48(11), pp. 6366-6373. (2017).
Isidori, M., Lavorgna, M., Nardelli, A., Parrella, A., Previtera, L., & Rubino, M. Ecotoxicity of naproxen and its phototransformation products. Science of The Total Environment, 348(1-3), pp. 93-101. (2005).
Ito-Harashima, S., Shiizaki, K., Kawanishi, M., Kakiuchi, K., Onishi, K., Yamaji, R., & Yagi, T. Construction of sensitive reporter assay yeasts for comprehensive detection of ligand activities of human corticosteroid receptors through inactivation of CWP and PDR genes. Journal of Pharmacological and Toxicological Methods, 74, pp. 41-52. (2015).
Jackson, L. M., & Hawkey, C. J. COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs. Drugs, 59(6), pp. 1207-1216. (2000).
Jandera, P. Stationary and mobile phases in hydrophilic interaction chromatography: a review. Analytica Chimica Acta, 692(1-2), pp. 1-25. (2011).
Jugan, M. L., Oziol, L., Bimbot, M., Huteau, V., Tamisier-Karolak, S., Blondeau, J. P., & Lévi, Y. In vitro assessment of thyroid and estrogenic endocrine disruptors in wastewater treatment plants, rivers and drinking water supplies in the greater Paris area (France). Science of the Total Environment, 407(11), pp. 3579-3587. (2009).
Kasprzyk-Hordern, B., Dinsdale, R. M., & Guwy, A. J. The removal of pharmaceuticals, personal care products,endocrine disruptors and illicit drugs during wastewater treatment and its impact on the quality of receiving waters. Water Research, 43(2), pp. 363-380. (2009).
Kermia, A. E., Fouial-Djebbar, D., & Trari, M. Occurrence, fate and removal efficiencies of pharmaceuticals in wastewater treatment plants (WWTPs) discharging in the coastal environment of Algiers. Comptes Rendus Chimie, 19(8), pp. 963-970. (2016).
Kitamura, S., Jinno, N., Ohta, S., Kurokib, H., & Fujimoto, N. Thyroid hormonal activity of the flame retardants tetrabromobisphenol A and tetrachlorobisphenol A. Biochemical and Biophysical Research Communications, 293(1), pp. 554-559. (2002).
Komjarova, I., & Blust, R. Application of a stable isotope technique to determine the simultaneous uptake of cadmium, copper, nickel, lead, and zinc by the water flea Daphnia Magna from water and the green algae Pseudokirchneriella Subcapitata. Environmental Toxicology, 28(8), pp. 1739-1748. (2010).
Kosma, C. I., Lambropoulou, D. A., & Albanis, T. A. Investigation of PPCPs in wastewater treatment plants in Greece: Occurrence, removal and environmental risk assessment. Science of the Total Environment, 466-467, pp. 421-438. (2014).
Laska, E. M., Sunshine, A., Mueller, F., Elvers, W. B., Siegel, C., & Rubin, A. Caffeine as an Analgesic Adjuvant. The Journal of the American Medical Association, pp. 1711-1718. (1984).
Lin, A. Y.-C., Yu, T.-H., & Lin, C.-F. Pharmaceutical contamination in residential, industrial, and agricultural waste. Chemosphere, 74(1), pp. 131-141. (2008).
Linden, S. C., Heringa, M. B., Man, H.-Y., Sonneveld, E., Puijker, L. M., Brouwer, A., & Burg, B. V. Detection of multiple Hormonal Activities in Wastewater Effluents and Surface Water, Using a Panel of Steroid Receptor CALUX Bioassays. Environmental Science & Technology, 42(15), pp. 5814-5820. (2008).
Moore, M. T., Greenway, S. L., Farris, J. L., & Guerra, B. Assessing Caffeine as an Emerging Environmental Concern Using Conventional Approaches. Archives of Environmental Contamination and Toxicology, 54(1), pp. 31-35. (2008).
Mrvos, R., Reilly, P., Dean, B., & Krenzelok, E. Massive caffeine ingestion resulting in death. Veterinary and Human Toxicology, 31(6), pp. 571-572. (1989).
Myers, M. G. Caffeine and Cardiac Arrhythmias. Annals of Internal Medicine, 114(2), pp. 147-150. (1991).
Nyholm, J., Norman, A., Norrgren, L., Haglund, P., & Andersson, P. Maternal transfer of brominated flame retardants in zebrafish (Danio rerio). Chemosphere, 73(2), pp. 203-208. (2008).
Oaks, J. L., Gilbert, M., Virani, M. Z., Watson, R. T., Meteyer, C. U., & Rideout, B. A. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature, 427, pp. 630-633. (2004).
Passmore, A. P., Kondowe, G. B., & Johnston, G. D. Caffeine and Hypokalemia. Annals of Internal Medicine, 105(3), p. 468. (1986).
Petersen, K. E., Tygstrup, I., & Thamdrup, E. Familial adrenocortical hypoplasia with early clinical and biochemical signs of mineralocorticoid deficiency (hypoaldosteronism). Acta Endocrinologica, 84, pp. 605-619. (1977).
Quinn, B., Gagné, F., & Blaise, C. An investigation into the acute and chronic toxicity of eleven pharmaceuticals (and their solvents) found in wastewater effluent on the cnidarian, Hydra attenuata. Science of the Total Environment, 389(2-3), pp. 306-314. (2008).
Quintana, J. B., Rodil, R., Lo´pez-Mahı´a, P., Muniategui-Lorenzo, S., & Prada-Rodrı´guez, D. Investigating the chlorination of acidic pharmaceuticals and by-product formation aided by an experimental design methodology. Water Research, 44, pp. 243-255. (2010).
Ra, J. S., Oh, S.-Y., Lee, B. C., & Kim, S. D. The effect of suspended particles coated by humic acid on the toxicity of pharmaceuticals, estrogens, and phenolic compounds. Environment International, 34(2), pp. 184-192. (2008).
Ragugnetti, M., Adams, M. L., Guimarães, A. T., Sponchiado, G., Vasconcelos, E. C., & Oliveira, C. M. Ibuprofen Genotoxicity in Aquatic Environment: An Experimental Model Using Oreochromis niloticus. Water, Air, & Soil Pollution, 218(1-4), pp. 361-364. (2011).
Routledge, E. J., & Sumpter, J. P. Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen. Environmental Toxicology and Chemistry, 15(3), pp. 241-248. (1996).
Saag, K. G., Criswell, L. A., Sems, K. M., Nettleman, M. D., & Kolluri, S. Low‐dose corticosteroids in rheumatoid arthritis. A meta‐analysis of their moderate‐term effectiveness. Arthritis & Rheumatology, 39(11), pp. 1818-1825.
Schleimer, R. P. (1993). An overview of glucocorticoid anti-inflammatory actions. European Journal of Clinical Pharmacology, 45, pp. 3-7. (1996).
Schurig, V. Enantiomer analysis by complexation gas chromatography : Scope, merits and limitations. Journal of Chromatography , 441(1), pp. 135-153. (1988).
Shena, O., Du, G., Sun, H., Wu, W., Jiang, Y., Song, L., & Wang, X. Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicology Letters, 191(1), pp. 9-14. (2009).
Shiizaki, K., Asai, S., Ebata, S., Kawanishi, M., & Yagi, T. Establishment of yeast reporter assay systems to detect ligands of thyroid hormone receptors α and β. Toxicology in Vitro, 24(2), pp. 638-644. (2010).
Sinha-Hikim, I., Taylor, W. E., Gonzalez-Cadavid, N. F., Zheng, W., & Bhasin, S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: Up-regulation by androgen treatment. The Journal of Clinical Endocrinology & Metabolism, 89(10), pp. 5245-5255. (2004).
Stamatis, N. K., & Konstantinou, I. K. Occurrence and removal of emerging pharmaceutical, personal care compounds and caffeine tracer in municipal sewage treatment plant in Western Greece. Journal of Environmental Science and Health, 48(9), pp. 800-813. (2013).
Sunyoung, H., Kyungho, C., Jungkon, K., Kyunghee, J., Sunmi, K., & Byeongwoo, A. Endocrine disruption and consequences of chronic exposure to ibuprofen in Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa. Aquatic Toxicology, 98(3), pp. 256-264. (2010).
Witters, H. E., Vangenechten, C., & Berckmans, P. Detection of estrogenic activity in Flemish surface waters using an in vitro recombinant assay with yeast cells. Water Science & Technology, 43(2), pp. 117-123. (2001).
Yen, P. M. Physiological and Molecular Basis of Thyroid Hormone Action. Physiological Reviews, 81(3), pp. 1097-1126. (2001).
Zarrelli, A., DellaGreca, M., Iesce, M. R., Lavorgna, M., Temussi, F., Schiavone, L., . . . Isidori, M. Ecotoxicological evaluation of caffeine and its derivatives from a simulated chlorination step. Science of the Total Environment, 470-471, pp. 453-458. (2014).
Zhang, Q., Wang, J., Zhu, J., Liu, J., & Zhao, M. Potential glucocorticoid and mineralocorticoid effects of nine organophosphate flame retardants. Environmental Science & Technology, 51(10), pp. 5803-5810. (2017).
Zhang, Y., Geißen, S.-U., & Gal, C. Carbamazepine and diclofenac: Removal in wastewater treatment plants and occurrence in water bodies. Chemosphere, 73(8). (2008).
Zloh, M., Perez-Diaz, N., Tang, L., Patel, P., & S.Mackenzie, L. Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists. Life Sciences, 146, pp. 66-72. (2016).
高雄市政府水利局。http://wrb.kcg.gov.tw/08_affair/Sewage7.asp
衛生福利部食品藥物管理署 (2017),105年度藥品使用情形一覽表。
DrugBank。https://www.drugbank.ca/
校內:2023-08-27公開