Environmental Science and Pollution Research

, Volume 22, Issue 1, pp 508–515 | Cite as

Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation

  • Angela Yu-Chen LinEmail author
  • Julia Han-Fang Hsueh
  • P. K. Andy Hong
Research Article


We investigated the ozonation of the antineoplastic drugs cyclophosphamide (CP), ifosfamide (IF), and 5-fluorouracil (5-FU) and of the vasodilator pentoxifylline (PEN) in distilled water, in pharmaceutical wastewater, and in hospital effluent at pH 5–11. Under an alkaline pH of 11, all of the target compounds rapidly degraded through the attack of hydroxyl radicals, which resulted in their complete removal within 5 min at an ozone supply rate of 3 g O3/h. Under acidic pH conditions, such as pH 5.6, CP and IF exhibited slower removal rates; however, compounds with unsaturated C-C bonds, such as 5-FU and PEN, were still removed at rapid rates under acidic conditions. Although the parent compounds were removed within minutes, the resulting ozonation byproducts were resistant to further ozonation and possessed increased Microtox acute toxicity. In distilled water, the resulting ozonation products exhibited minimal mineralization but high acute toxicity, whereas in naturally buffered pharmaceutical and hospital effluents, the byproducts were more amenable to removal and detoxification.


Antineoplastic drugs Ozonation Pentoxifylline Toxicity 

Supplementary material

11356_2014_3288_MOESM1_ESM.docx (18 kb)
ESM 1 (DOCX 17 kb)
11356_2014_3288_MOESM2_ESM.docx (17 kb)
ESM 2 (DOCX 17 kb)
11356_2014_3288_MOESM3_ESM.docx (18 kb)
ESM 3 (DOCX 17 kb)
11356_2014_3288_MOESM4_ESM.docx (18 kb)
ESM 4 (DOCX 17 kb)
11356_2014_3288_MOESM5_ESM.docx (67 kb)
ESM 5 (DOCX 66 kb)


  1. Adams CD, Cozzens RA, Kim BJ (1997) Effects of ozonation on the biodegradability of substituted phenols. Water Res 31:2655–2663CrossRefGoogle Scholar
  2. Andreozzi R, Canterino M, Marotta R, Paxeus N (2005) Antibiotic removal from wastewaters: the ozonation of amoxicillin. J Hazard Mater 122:243–250CrossRefGoogle Scholar
  3. Andreozzi R, Canterino M, Giudice RL, Marotta R, Pinto G, Pollio A (2006) Lincomycin solar photodegradation, algal toxicity and removal from wastewaters by means of ozonation. Water Res 40:630–638CrossRefGoogle Scholar
  4. Boluda R, Quintanilla JF, Bonilla JA, Sáez E, Gamón M (2002) Application of the Microtox® test and pollution indices to the study of water toxicity in the Albufera Natural Park (Valencia, Spain). Chemosphere 46:355–369CrossRefGoogle Scholar
  5. Brooke S, Newcombe G, Nicholson B, Klass G (2006) Decrease in toxicity of microcystins LA and LR in drinking water by ozonation. Toxicon 48:1054–1059CrossRefGoogle Scholar
  6. Buerge IJ, Buser H-R, Poiger T, Müller MD (2006) Occurrence and fate of the cytostatic drugs cyclophosphamide and Ifosfamide in wastewater and surface waters. Environ Sci Technol 40:7242–7250CrossRefGoogle Scholar
  7. Clara M, Strenn B, Gans O, Martinez E, Kreuzinger N, Kroiss H (2005) Removal of selected pharmaceuticals, fragrances and endocrine disrupting compounds in a membrane bioreactor and conventional wastewater treatment plants. Water Res 39:4797–4807CrossRefGoogle Scholar
  8. Dantas RF, Canterino M, Marotta R, Sans C, Esplugas S, Andreozzi R (2007) Bezafibrate removal by means of ozonation: primary intermediates, kinetics, and toxicity assessment. Water Res 41:2525–2532CrossRefGoogle Scholar
  9. David Yao CC, Haag WR (1991) Rate constants for direct reactions of ozone with several drinking water contaminants. Water Res 25:761–773CrossRefGoogle Scholar
  10. Dewhurst RE, Wheeler JR, Chummun KS, Mather JD, Callaghan A, Crane M (2002) The comparison of rapid bioassays for the assessment of urban groundwater quality. Chemosphere 47:547–554CrossRefGoogle Scholar
  11. Dowideit P, von Sonntag C (1998) Reaction of ozone with ethene and its methyl- and chlorine-substituted derivatives in aqueous solution. Environ Sci Technol 32:1112–1119CrossRefGoogle Scholar
  12. Garcia-Ac A, Broséus R, Vincent S, Barbeau B, Prévost M, Sauvé S (2010) Oxidation kinetics of cyclophosphamide and methotrexate by ozone in drinking water. Chemosphere 79:1056–1063CrossRefGoogle Scholar
  13. Haag WR, Yao CCD (1992) Rate constants for reaction of hydroxyl radicals with several drinking water contaminants. Environ Sci Technol 26:1005–1013CrossRefGoogle Scholar
  14. Hao OJ, Shin C-J, Lin C-F, Jeng F-T, Chen Z-C (1996) Use of microtox tests for screening industrial wastewater toxicity. Water Sci Technol 34:43–50CrossRefGoogle Scholar
  15. Hengstler JG, Fuchs J, Oesch F (1992) DNA strand breaks and DNA cross-links in peripheral mononuclear blood cells of ovarian cancer patients during chemotherapy with cyclophosphamide/carboplatin. Cancer Res 52:5622–5626Google Scholar
  16. Hoigné J, Bader H (1976) The role of hydroxyl radical reactions in ozonation processes in aqueous solutions. Water Res 10:377–386CrossRefGoogle Scholar
  17. Hoigne J, Bader H (1979) Ozonation of water: selectivity and rate of oxidation of solutes. Ozone Sci Eng 1:73–85CrossRefGoogle Scholar
  18. Hua WY, Bennett ER, Maio X-S, Metcalfe CD, Letcher RJ (2006) Seasonality effects on pharmaceuticals and s-triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit River. Environ Toxicol Chem 25:2356–2365CrossRefGoogle Scholar
  19. Inaba M, Mitsuhashi J, Sawada H, Miike N, Naoe Y, Daimon A, Koizumi K, Tsujimoto H, Fukushima M (1996) Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells. Cancer Sci 87:212–220CrossRefGoogle Scholar
  20. Indrayanto G, Syahrani A, Moegihardjo, Soeharyono, Lianawati T, Wahyuningsih I, Aditama L, Brittain HG (1998) Pentoxifylline. In: Harry GB (Editor), Analytical profiles of drug substances and excipients. Academic, pp. 295-339Google Scholar
  21. Johnstone EC, Lind MJ, Griffin MJ, Boddy AV (2000) Ifosfamide metabolism and DNA damage in tumour and peripheral blood lymphocytes of breast cancer patients. Cancer Chemother Pharm 46:433–441CrossRefGoogle Scholar
  22. Kaiser K (1998) Correlations of Vibrio fischeri bacteria test data with bioassay data for other organisms. Environ Health Perspect 106:583CrossRefGoogle Scholar
  23. Kang C-S (2012) Photodegradation of pentoxifylline in aquatic environments. Graduate Institute of Environment Engineering, National Taiwan University Master ThesisGoogle Scholar
  24. Kim SD, Cho J, Kim IS, Vanderford BJ, Snyder SA (2007) Occurrence and removal of pharmaceuticals and endocrine disruptors in South Korean surface, drinking, and waste waters. Water Res 41:1013–1021CrossRefGoogle Scholar
  25. Krasner SW, Weinberg HS, Richardson SD, Pastor SJ, Chinn R, Sclimenti MJ, Onstad GD, Thruston AD (2006) Occurrence of a new generation of disinfection byproducts. Environ Sci Technol 40:7175–7185CrossRefGoogle Scholar
  26. Kümmerer K, Steger-Hartmann T, Meyer M (1997) Biodegradability of the anti-tumour agent ifosfamide and its occurrence in hospital effluents and communal sewage. Water Res 31:2705–2710CrossRefGoogle Scholar
  27. Leonhardt H, Grigoleit H-G (1977) Effects of pentoxifylline on red blood cell deformability and blood viscosity under hyperosmolar conditions. Naunyn-Schmiedeberg’s Arch Pharmacol 299:197–200CrossRefGoogle Scholar
  28. Li K, Yediler A, Yang M, Schulte-Hostede S, Wong MH (2008) Ozonation of oxytetracycline and toxicological assessment of its oxidation by-products. Chemosphere 72:473–478CrossRefGoogle Scholar
  29. Lin AY-C, Yu T-H, Lin C-F (2008) Pharmaceutical contamination in residential, industrial, and agricultural waste streams: risk to aqueous environments in Taiwan. Chemosphere 74:131–141CrossRefGoogle Scholar
  30. Mahnik SN, Rizovski B, Fuerhacker M, Mader RM (2004) Determination of 5-fluorouracil in hospital effluents. Anal Bioanal Chem 380:31–35Google Scholar
  31. Mahnik SN, Lenz K, Weissenbacher N, Mader R, Fuerhacker M (2007) Fate of 5-fluorouracil, doxorubicin, epirubicin, and daunorubicin in hospital wastewater and their elimination by activated sludge and treatment in a membrane-bio-reactor system. Chemosphere 66:30–37CrossRefGoogle Scholar
  32. Martin N, Benezet-Toulze M, Laplace C, Faivre M, Langlais B (1992) Design and efficiency of ozone contactors for disinfection. Ozone Sci Eng 14:391–405CrossRefGoogle Scholar
  33. McDowell DC, Huber MM, Wagner M, von Gunten U, Ternes TA (2005) Ozonation of carbamazepine in drinking water: identification and kinetic study of major oxidation products. Environ Sci Technol 39:8014–8022CrossRefGoogle Scholar
  34. Metcalfe CD, Koenig BG, Bennie DT, Servos M, Ternes TA, Hirsch R (2003) Occurrence of neutral and acidic drugs in the effluents of Canadian sewage treatment plants. Environ Toxicol Chem 22:2872–2880CrossRefGoogle Scholar
  35. Moldovan Z (2006) Occurrences of pharmaceutical and personal care products as micropollutants in rivers from Romania. Chemosphere 64:1808–1817CrossRefGoogle Scholar
  36. Mone MK, Chandrasekhar KB (2010) Degradation studies of pentoxifylline: isolation and characterization of a novel gem-dihydroperoxide derivative as major oxidative degradation product. J Pharm Biomed Anal 53:335–342CrossRefGoogle Scholar
  37. Mullot J-U, Karolak S, Fontova A, Huart B, Levi Y (2009) Development and validation of a sensitive and selective method using GC/MS-MS for quantification of 5-fluorouracil in hospital wastewater. Anal Bioanal Chem 394:2203–2212CrossRefGoogle Scholar
  38. Phyu YL, Warne MSJ, Lim RP (2005) Effect of river water, sediment and time on the toxicity and bioavailability of molinate to the marine bacterium Vibrio fischeri (Microtox). Water Res 39:2738–2746CrossRefGoogle Scholar
  39. Ribo JM, Kaiser KLE (1983) Effects of selected chemicals to photoluminescent bacteria and their correlations with acute and sublethal effects on other organisms. Chemosphere 12:1421–1442CrossRefGoogle Scholar
  40. Richardson SD, Thruston AD, Caughran TV, Chen PH, Collette TW, Floyd TL, Schenck KM, Lykins BW, G-r S, Majetich G (1999) Identification of new ozone disinfection byproducts in drinking water. Environ Sci Technol 33:3368–3377CrossRefGoogle Scholar
  41. Ringwood AH, DeLorenzo ME, Ross PE, Holland AF (1997) Interpretation of Microtox® solid-phase toxicity tests: the effects of sediment composition. Environ Toxicol Chem 16:1135–1140CrossRefGoogle Scholar
  42. Rowney NC, Johnson AC, Williams RJ (2009) Cytotoxic drugs in drinking water: a prediction and risk assessment exercise for the thames catchment in the United Kingdom. Environ Toxicol Chem 28:2733–2743CrossRefGoogle Scholar
  43. Sacher F, Ehmann M, Gabriel S, Graf C, Brauch H-J (2008) Pharmaceutical residues in the river Rhine—results of a one-decade monitoring programme. J Environ Monit 10:664–670CrossRefGoogle Scholar
  44. Scott AC, Zubot W, MacKinnon MD, Smith DW, Fedorak PM (2008) Ozonation of oil sands process water removes naphthenic acids and toxicity. Chemosphere 71:156–160CrossRefGoogle Scholar
  45. Snyder SA, Wert EC, Rexing DJ, Zegers RE, Drury DD (2006) Ozone oxidation of endocrine disruptors and pharmaceuticals in surface water and wastewater. Ozone Sci Eng 28:445–460CrossRefGoogle Scholar
  46. Staehelin J, Hoigne J (1982) Decomposition of ozone in water: rate of initiation by hydroxide ions and hydrogen peroxide. Environ Sci Technol 16:676–681CrossRefGoogle Scholar
  47. Steger-Hartmann T, Kümmerer K, Schecker J (1996) Trace analysis of the antineoplastics ifosfamide and cyclophosphamide in sewage water by twostep solid-phase extraction and gas chromatography-mass spectrometry. J Chromatogr A 726:179–184CrossRefGoogle Scholar
  48. Tanaka K, Abe K, Sheng CY, Hisanaga T (1992) Photocatalytic wastewater treatment combined with ozone pretreatment. Environ Sci Technol 26:2534–2536CrossRefGoogle Scholar
  49. Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Water Res 32:3245–3260CrossRefGoogle Scholar
  50. Trapido M, Veressinina J, Munter R (1994) Ozonation and AOP treatment of phenanthrene in aqueous solutions. Ozone Sci Eng 16:475–485CrossRefGoogle Scholar
  51. von Gunten U (2003) Ozonation of drinking water: part I. Oxidation kinetics and product formation. Water Res 37:1443–1467CrossRefGoogle Scholar
  52. Wang C, Yediler A, Lienert D, Wang Z, Kettrup A (2003) Ozonation of an azo dye C.I. Remazol Black 5 and toxicological assessment of its oxidation products. Chemosphere 52:1225–1232CrossRefGoogle Scholar
  53. Wolska L, Sagajdakow A, Kuczyńska A, Namieśnik J (2007) Application of ecotoxicological studies in integrated environmental monitoring: possibilities and problems. TrAC Trends Anal Chem 26:332–344CrossRefGoogle Scholar
  54. Yin J, Shao B, Zhang J, Li K (2010) A preliminary study on the occurrence of cytostatic drugs in hospital effluents in Beijing, China. Bull Environ Contam Toxicol 84:39–45CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Angela Yu-Chen Lin
    • 1
    Email author
  • Julia Han-Fang Hsueh
    • 1
  • P. K. Andy Hong
    • 2
  1. 1.Graduate Institute of Environmental EngineeringNational Taiwan UniversityTaipeiRepublic of China
  2. 2.Department of Civil and Environmental EngineeringUniversity of UtahSalt Lake CityUSA

Personalised recommendations