二甲雙胍是台灣最常用的第二型糖尿病藥物，2020年在台灣的年使用量約為 761 噸。本研究於台灣南部地區鹽水溪流域表面水及生活污水共69個樣品調查中顯示二甲雙胍濃度介於 ND ~ 81726 ng/L，檢出頻率高達89.9%，顯示其在水環境中無處不在，且其含有疑似N-nitroso dimethylamine (NDMA) 的前驅物Dimethylacetamide (DMA) 結構，對人類健康可能有潛在風險，因此本研究深入探討二甲雙胍的氯化機制，以了解其在加氯消毒的過程中是否有生成氯化副產物或是含氮消毒副產物的可能。
我們以二級反應評估二甲雙胍與氯之間的反應動力學，發現在酸性條件下有較快的降解效果。本研究以LC-MS/MS分析降解產物，檢測到四項結合氯產物和六項氯化降解產物，依產物出現順序推論二甲雙胍有兩個位置 (N3和N7) 易被氯取代，首先生成兩種一氯取代結構，緊接著生成二氯取代結構，之後伴隨HCl的生成產生三種環狀中間產物，最後生成四項未知產物(三項不含氯，一項含氯)。本研究亦使用HS-SPME-GC/MS檢測是否有含氮消毒副產物生成，分析結果顯示起始濃度30 g/L之二甲雙胍氯化後沒有檢測到NDMA生成，但N-nitrosodiethylamine (NDEA) 和N-nitrosopyrrolidine (NPyr) 的莫爾生成率分別為 0.14% 和 0.18%，顯示環境中存在的二甲雙胍加氯消毒後可能生成NDEA 與 Npyr。本研究之研究結果讓我們更了解二甲雙胍在水環境中氯化的反應性和去除效果，因此我們應該減少二甲雙胍排放於環境中，避免後續氯化副產物和亞硝胺類產物的形成。

Metformin (MET) is the most commonly used medication for type 2 diabetes, and the usage of MET was around 761 tons in the year 2020 in Taiwan. In this study, we detected 69 samples in Tainan Yanshuei River and domestic wastewater. The MET concentration ranged from ND ~ 81726 ng/L, and the detected frequency was 89.9%, indicating that MET is ubiquitous in the aqueous environment. MET contains the suspected precursor, Dimethylacetamide (DMA) of N-nitroso dimethylamine (NDMA), which causes a higher potential risk to human health. Therefore, this study will deeply discuss the chlorination mechanisms of MET to understand whether it may generate chlorinated products or nitrosamines disinfection by-products in the process of chlorination.
In this study, the reaction of MET with chlorine was evaluated by a second-order reaction, presenting faster degradation under acid conditions. According to the structure of MET, we suspected two sites (N3 and N7) would easily substitute for chlorine. The LC-MS/MS analysis results confirmed that four combined chlorine and six chlorinated degradation products were detected. Two combined chlorine products with one Cl substituted will form in the beginning, followed by the two Cl substituted products. After that, combined chlorine products released HCl to generate three cyclic intermediates and finally form four structures whose exact chemical structures we still don’t understand. The only information was one of the unknown structures contained Cl. In this study, we also used HS-SPME-GC/MS to detect whether the nitrosamines will generate or not. The results presented that we did not detect NDMA from the initial concentration of 30 μg/L MET, but the molar yields of N-nitrosodiethylamine (NDEA) and N-nitrosopyrrolidine (NPyr) were 0.14% and 0.18%, respectively, indicating when MET was present in the environment, it may generate NDEA and Npyr after chlorination. Therefore, we should reduce the discharge of MET into the environment to avoid the formation of subsequent chlorinated products and nitrosamines; at the same time, this study also gives a helpful light on the reactivities and removal effects of MET in the chlorination of a water system.

ADAMS, Z. Q. C. D. (2004). Determination of Monochloramine Formation Rate Constants with
Stopped-Flow Spectrophotometry.
Armbruster, D., Happel, O., Scheurer, M., Harms, K., Schmidt, T. C., & Brauch, H. J. (2015). Emerging nitrogenous disinfection byproducts: Transformation of the antidiabetic drug metformin during chlorine disinfection of water. Water Res, 79, 104-118. doi: 10.1016/j.watres.2015.04.020
Asami, M., Oya, M., & Kosaka, K. (2009). A nationwide survey of NDMA in raw and drinking water in Japan. Sci Total Environ, 407(11), 3540-3545. doi: 10.1016/j.scitotenv.2009.02.014
Ayoub, B. M., & Mowaka, S. (2017). LC-MS/MS Determination of Empagliflozin and Metformin. J Chromatogr Sci, 55(7), 742-747. doi: 10.1093/chromsci/bmx030
Badran, I., Manasrah, A. D., & Nassar, Nashaat N. (2019). A combined experimental and density functional theory study of metformin oxy-cracking for pharmaceutical wastewater treatment. RSC Advances, 9(24), 13403-13413. doi: 10.1039/c9ra01641d
Behera, S. K., Kim, H. W., Oh, J. E., & Park, H. S. (2011). Occurrence and removal of antibiotics, hormones and several other pharmaceuticals in wastewater treatment plants of the largest industrial city of Korea. Sci Total Environ, 409(20), 4351-4360. doi: 10.1016/j.scitotenv.2011.07.015
Bond, T., Templeton, M. R., & Graham, N. (2012). Precursors of nitrogenous disinfection by-products in drinking water--a critical review and analysis. J Hazard Mater, 235-236, 1-16. doi: 10.1016/j.jhazmat.2012.07.017
Bound, J. P., & Voulvoulis, N. (2005). Household disposal of pharmaceuticals as a pathway for aquatic contamination in the United kingdom. Environ Health Perspect, 113(12), 1705-1711. doi: 10.1289/ehp.8315
Briones, R. M., Sarmah, A. K., & Padhye, L. P. (2016). A global perspective on the use, occurrence, fate and effects of anti-diabetic drug metformin in natural and engineered ecosystems. Environ Pollut, 219, 1007-1020. doi: 10.1016/j.envpol.2016.07.040
Cetin, M., & Sahin, S. (2016). Microparticulate and nanoparticulate drug delivery systems for metformin hydrochloride. Drug Deliv, 23(8), 2796-2805. doi: 10.3109/10717544.2015.1089957
Chen, W. H., Wang, Y. H., & Hsu, T. H. (2021). The competitive effect of different chlorination disinfection methods and additional inorganic nitrogen on nitrosamine formation from aromatic and heterocyclic amine-containing pharmaceuticals. Chemosphere, 267, 128922. doi: 10.1016/j.chemosphere.2020.128922
Chen, Y. T., Chen, W. R., Liu, Z. Q., & Lin, T. F. (2017). Reaction Pathways and Kinetics of a Cyanobacterial Neurotoxin beta-N-Methylamino-L-Alanine (BMAA) during Chlorination. Environ Sci Technol, 51(3), 1303-1311. doi: 10.1021/acs.est.6b03553
Choi, J., & Valentine, R. L. (2002). Formation of N-nitrosodimethylamine (NDMA) from reaction of monochloramine: a new disinfection by-product. Water Research, 36(4), 817-824. doi: https://doi.org/10.1016/S0043-1354(01)00303-7
Chu, W. H., Gao, N. Y., Deng, Y., & Dong, B. Z. (2009). Formation of chloroform during chlorination of alanine in drinking water. Chemosphere, 77(10), 1346-1351. doi: 10.1016/j.chemosphere.2009.09.030
Deborde, M., & von Gunten, U. (2008). Reactions of chlorine with inorganic and organic compounds during water treatment-Kinetics and mechanisms: a critical review. Water Res, 42(1-2), 13-51. doi: 10.1016/j.watres.2007.07.025
Dotson, A., Westerhoff, P., & Krasner, S. W. (2009). Nitrogen enriched dissolved organic matter (DOM) isolates and their affinity to form emerging disinfection by-products. Water Sci Technol, 60(1), 135-143. doi: 10.2166/wst.2009.333
E. Marco Aieta, P. T. R., and Margarita Hernandez. (1984). Determination of chlorine dioxide, chlorine, chlorite, and chlorate in water. American Water Works Association.
Eggen, T., & Lillo, C. (2012). Antidiabetic II drug metformin in plants: uptake and translocation to edible parts of cereals, oily seeds, beans, tomato, squash, carrots, and potatoes. J Agric Food Chem, 60(28), 6929-6935. doi: 10.1021/jf301267c
Fan, C. C., & Lin, T. F. (2018). N-nitrosamines in drinking water and beer: Detection and risk assessment. Chemosphere, 200, 48-56. doi: 10.1016/j.chemosphere.2018.02.025
Gardner, M., Comber, S., Scrimshaw, M. D., Cartmell, E., Lester, J., & Ellor, B. (2012). The significance of hazardous chemicals in wastewater treatment works effluents. Sci Total Environ, 437, 363-372. doi: 10.1016/j.scitotenv.2012.07.086
Gartiser, S., Hafner, C., Kronenberger-Schafer, K., Happel, O., Trautwein, C., & Kummerer, K. (2012). Approach for detecting mutagenicity of biodegraded and ozonated pharmaceuticals, metabolites and transformation products from a drinking water perspective. Environ Sci Pollut Res Int, 19(8), 3597-3609. doi: 10.1007/s11356-012-0925-x
Ghoshdastidar, A. J., Fox, S., & Tong, A. Z. (2015). The presence of the top prescribed pharmaceuticals in treated sewage effluents and receiving waters in Southwest Nova Scotia, Canada. Environ Sci Pollut Res Int, 22(1), 689-700. doi: 10.1007/s11356-014-3400-z
Houtman, C. J., ten Broek, R., de Jong, K., Pieterse, B., & Kroesbergen, J. (2013). A multicomponent snapshot of pharmaceuticals and pesticides in the river Meuse basin. Environ Toxicol Chem, 32(11), 2449-2459. doi: 10.1002/etc.2351
IRIS, E. (2017). N-nitrosodimethylamine: CASRN 62-75-9. Integrated Risk Information System. US Environmental ….
Kim, M., Guerra, P., Shah, A., Parsa, M., Alaee, M., & Smyth, S. A. (2014). Removal of pharmaceuticals and personal care products in a membrane bioreactor wastewater treatment plant. Water Sci Technol, 69(11), 2221-2229. doi: 10.2166/wst.2014.145
Kinani, S., Richard, B., Souissi, Y., & Bouchonnet, S. (2012). Analysis of inorganic chloramines in water. TrAC Trends in Analytical Chemistry, 33, 55-67. doi: 10.1016/j.trac.2011.10.006
Kong, L., Kadokami, K., Wang, S., Duong, H. T., & Chau, H. T. C. (2015). Monitoring of 1300 organic micro-pollutants in surface waters from Tianjin, North China. Chemosphere, 122, 125-130. doi: 10.1016/j.chemosphere.2014.11.025
Kontaxaki, M. (2013). Review Study on Fate and Degradation of Organic Micropollutants.
Kosma, C. I., Lambropoulou, D. A., & Albanis, T. A. (2015). Comprehensive study of the antidiabetic drug metformin and its transformation product guanylurea in Greek wastewaters. Water Res, 70, 436-448. doi: 10.1016/j.watres.2014.12.010
Krasner, S. W., Mitch, W. A., McCurry, D. L., Hanigan, D., & Westerhoff, P. (2013). Formation, precursors, control, and occurrence of nitrosamines in drinking water: a review. Water Res, 47(13), 4433-4450. doi: 10.1016/j.watres.2013.04.050
Lee, C., Lee, Y., Schmidt, C., Yoon, J., & Von Gunten, U. (2008). Oxidation of suspected N-nitrosodimethylamine (NDMA) precursors by ferrate (VI): kinetics and effect on the NDMA formation potential of natural waters. Water Res, 42(1-2), 433-441. doi: 10.1016/j.watres.2007.07.035
Liew, D., Linge, K. L., & Joll, C. A. (2016). Formation of nitrogenous disinfection by-products in 10 chlorinated and chloraminated drinking water supply systems. Environ Monit Assess, 188(9), 518. doi: 10.1007/s10661-016-5529-3
Lin, A. Y., Lin, C. F., Tsai, Y. T., Lin, H. H., Chen, J., Wang, X. H., & Yu, T. H. (2010). Fate of selected pharmaceuticals and personal care products after secondary wastewater treatment processes in Taiwan. Water Sci Technol, 62(10), 2450-2458. doi: 10.2166/wst.2010.476
MacCrehan, W. A., Bedner, M., & Helz, G. R. (2005). Making chlorine greener: performance of alternative dechlorination agents in wastewater. Chemosphere, 60(3), 381-388. doi: 10.1016/j.chemosphere.2004.11.075
Martin, J., Buchberger, W., Santos, J. L., Alonso, E., & Aparicio, I. (2012). High-performance liquid chromatography quadrupole time-of-flight mass spectrometry method for the analysis of antidiabetic drugs in aqueous environmental samples. J Chromatogr B Analyt Technol Biomed Life Sci, 895-896, 94-101. doi: 10.1016/j.jchromb.2012.03.023
Mitch, W. A., & Sedlak, D. L. (2002). Formation of N-Nitrosodimethylamine (NDMA) from Dimethylamine during Chlorination. Environmental Science & Technology, 36(4), 588-595. doi: 10.1021/es010684q
Mrozik, W., & Stefanska, J. (2014). Adsorption and biodegradation of antidiabetic pharmaceuticals in soils. Chemosphere, 95, 281-288. doi: 10.1016/j.chemosphere.2013.09.012
Muellner, M. G., Wagner, E. D., McCalla, K., Richardson, S. D., Woo, Y.-T., & Plewa, M. J. (2007). Haloacetonitriles vs. Regulated Haloacetic Acids:  Are Nitrogen-Containing DBPs More Toxic? Environmental Science & Technology, 41(2), 645-651. doi: 10.1021/es0617441
Nam, S. W., Jo, B. I., Yoon, Y., & Zoh, K. D. (2014). Occurrence and removal of selected micropollutants in a water treatment plant. Chemosphere, 95, 156-165. doi: 10.1016/j.chemosphere.2013.08.055
Niemuth, N. J., & Klaper, R. D. (2015). Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish. Chemosphere, 135, 38-45. doi: 10.1016/j.chemosphere.2015.03.060
Pai, C. W., Leong, D., Chen, C. Y., & Wang, G. S. (2020). Occurrences of pharmaceuticals and personal care products in the drinking water of Taiwan and their removal in conventional water treatment processes. Chemosphere, 256, 127002. doi: 10.1016/j.chemosphere.2020.127002
Piazzoli, A., Breider, F., Aquillon, C. G., Antonelli, M., & von Gunten, U. (2018). Specific and total N-nitrosamines formation potentials of nitrogenous micropollutants during chloramination. Water Res, 135, 311-321. doi: 10.1016/j.watres.2018.02.019
Scheurer, M., Michel, A., Brauch, H. J., Ruck, W., & Sacher, F. (2012). Occurrence and fate of the antidiabetic drug metformin and its metabolite guanylurea in the environment and during drinking water treatment. Water Res, 46(15), 4790-4802. doi: 10.1016/j.watres.2012.06.019
Schmalz, C., Frimmel, F. H., & Zwiener, C. (2011). Trichloramine in swimming pools--formation and mass transfer. Water Res, 45(8), 2681-2690. doi: 10.1016/j.watres.2011.02.024
Schreiber, I. M., & Mitch, W. A. (2006). Nitrosamine Formation Pathway Revisited:  The Importance of Chloramine Speciation and Dissolved Oxygen. Environmental Science & Technology, 40(19), 6007-6014. doi: 10.1021/es060978h
Sedlak, D. L., Deeb, R. A., Hawley, E. L., Mitch, W. A., Durbin, T. D., Mowbray, S., & Carr, S. (2005). Sources and fate of nitrosodimethylamine and its precursors in municipal wastewater treatment plants. Water Environment Research, 77(1), 32-39.
SEDLAK, K. E. P. D. L. (2004). Transformation of Aromatic Etherand Amine-Containing Pharmaceuticals during Chlorine Disinfection.
Shalmashi, A. (2008). New Route to Metformin Hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) Synthesis. Molbank, M564.
Shen, R., & Andrews, S. A. (2011). Demonstration of 20 pharmaceuticals and personal care products (PPCPs) as nitrosamine precursors during chloramine disinfection. Water Res, 45(2), 944-952. doi: 10.1016/j.watres.2010.09.036
Shen, R., & Andrews, S. A. (2013). Formation of NDMA from ranitidine and sumatriptan: the role of pH. Water Res, 47(2), 802-810. doi: 10.1016/j.watres.2012.11.004
Sinclair, A., Saeedi, P., Kaundal, A., Karuranga, S., Malanda, B., & Williams, R. (2020). Diabetes and global ageing among 65-99-year-old adults: Findings from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract, 162, 108078. doi: 10.1016/j.diabres.2020.108078
Trautwein, C., Berset, J. D., Wolschke, H., & Kummerer, K. (2014). Occurrence of the antidiabetic drug Metformin and its ultimate transformation product Guanylurea in several compartments of the aquatic cycle. Environ Int, 70, 203-212. doi: 10.1016/j.envint.2014.05.008
VIKESLANDKENAN, P. J., & VALENTINE, O. L. (2000). MONOCHLORAMINE DECAY IN MODEL AND DISTRIBUTION SYSTEM WATERS.
Wang, X., Yang, H., Zhou, B., Wang, X., & Xie, Y. (2015). Effect of oxidation on amine-based pharmaceutical degradation and N-Nitrosodimethylamine formation. Water Res, 87, 403-411. doi: 10.1016/j.watres.2015.07.045
William A. Mitch, Jonathan O. Sharp, R. Rhodes Trussell, Richard L. Valentine, & Lisa Alvarez-Cohen, a. D. L. S., *. (2003). N-Nitrosodimethylamine (NDMA) as a Drinking Water
Contaminant: A Review. ENVIRONMENTAL ENGINEERING SCIENCE, 20.
Yan, B., Liu, Z., Liu, Y., Huang, R., Xu, Y., Liu, D., . . . Shi, W. (2020). Effects and mechanism on the removal of neurotoxin beta-N-methylamino-l-alanine (BMAA) by chlorination. Sci Total Environ, 703, 135513. doi: 10.1016/j.scitotenv.2019.135513
Zhang, A., Li, Y., Song, Y., Lv, J., & Yang, J. (2014). Characterization of pharmaceuticals and personal care products as N-nitrosodimethylamine precursors during disinfection processes using free chlorine and chlorine dioxide. Journal of Hazardous Materials, 276, 499-509. doi: https://doi.org/10.1016/j.jhazmat.2014.05.069
Zhang, R., He, Y., Yao, L., Chen, J., Zhu, S., Rao, X., . . . Wu, L. (2021). Metformin chlorination byproducts in drinking water exhibit marked toxicities of a potential health concern. Environ Int, 146, 106244. doi: 10.1016/j.envint.2020.106244
林雅婷（2012）。水中代表性化合物經氧化前處理後消毒副產物生成特性之探討。國立台灣大學。
衛生福利部中央健康保險署. (2020). 藥品使用量分析. from https://www.nhi.gov.tw/Content_List.aspx?n=5AA7CAFFF61CB16D&topn=3FC7D09599D25979
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 4091, Metformin. Retrieved April 14, 2022 from https://pubchem.ncbi.nlm.nih.gov/compound/Metformin.
International Diabetes Federation. IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021. Available at: https://www.diabetesatlas.org