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Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity

Abstract

Anticancer drugs (ADs) have been detected in the environment and represent a risk to aquatic organisms, necessitating AD removal in drinking water and wastewater treatment. In this study, ozonation of the most commonly used antimetabolite ADs, namely 5-fluorouracil (5-FU) and its prodrug capecitabine (CAP), was investigated to determine reaction kinetics, oxidation mechanisms, and residual toxicity. The specific second-order rate constants between aqueous ozone and 5-FU, 5-FU, 5-FU2−, CAP, and CAP were determined to be 7.07(±0.11)×104 M−1·s−1, 1.36(±0.06)×106 M−1·s−1, 2.62(±0.17)×107 M−1·s−1, 9.69(±0.08)×103 M−1·s−1, and 4.28(±0.07)×105 M−1·s−1, respectively; furthermore, the second-order rate constants for OH reaction with 5-FU and CAP at pH 7 were determined to be 1.85(±0.20)×109 M−1·s−1 and 9.95(±0.26)×109 M−1·s−1, respectively. Density functional theory was used to predict the main ozone reaction sites of 5-FU (olefin) and CAP (olefin and deprotonated secondary amine), and these mechanisms were supported by the identified transformation products. Carboxylic acids constituted a majority of the residual organic matter for 5-FU ozonation; however, carboxylic acids and aldehydes were important components of the residual organic matter generated by CAP. Ozone removed the toxicity of 5-FU to Vibrio fischeri, but the residual toxicity of ozonated CAP solutions exhibited an initial increase before subsequent removal. Ultimately, these results suggest that ozone is a suitable technology for treatment of 5-FU and CAP, although the residual toxicity of transformation products must be carefully considered.

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References

  • Azuma T, Ishiuchi H, Inoyama T, Teranishi Y, Yamaoka M, Sato T, Mino Y (2015). Occurrence and fate of selected anticancer, antimicrobial, and psychotropic pharmaceuticals in an urban river in a subcatchment of the Yodo River basin, Japan. Environmental Science and Pollution Research International, 22(23): 18676–18686

    Article  CAS  Google Scholar 

  • Bao Y, Deng S, Jiang X, Qu Y, He Y, Liu L, Chai Q, Mumtaz M, Huang J, Cagnetta G, Yu G (2018). Degradation of PFOA substitute: GenX (HFPO–DA Ammonium Salt): Oxidation with UV/Persulfate or reduction with UV/Sulfite? Environmental Science & Technology, 52(20): 11728–11734

    CAS  Google Scholar 

  • Beltrán F J, Aguinaco A, García-Araya J F (2009). Mechanism and kinetics of sulfamethoxazole photocatalytic ozonation in water. Water Research, 43(5): 1359–1369

    Article  CAS  Google Scholar 

  • Besse J P, Latour J F, Garric J (2012). Anticancer drugs in surface waters: What can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs? Environment International, 39(1): 73–86

    Article  CAS  Google Scholar 

  • Blaney L, Lawler D F, Katz L E (2019). Transformation kinetics of cyclophosphamide and ifosfamide by ozone and hydroxyl radicals using continuous oxidant addition reactors. Journal of Hazardous Materials, 364: 752–761

    Article  CAS  Google Scholar 

  • Blicharska B, Kupka T (2002). Theoretical DFT and experimental NMR studies on uracil and 5-fluorouracil. Journal of Molecular Structure, 613(1–3): 153–166

    Article  CAS  Google Scholar 

  • Booker V, Halsall C, Llewellyn N, Johnson A, Williams R (2014). Prioritising anticancer drugs for environmental monitoring and risk assessment purposes. Science of the Total Environment, 473–474: 159–170

    Article  CAS  Google Scholar 

  • Bui X T, Vo T P, Ngo H H, Guo W S, Nguyen T T (2016). Multicriteria assessment of advanced treatment technologies for micropollutants removal at large-scale applications. Science of the Total Environment, 563–564: 1050–1067

    Article  CAS  Google Scholar 

  • Buxton G V, Greenstock C L, Helman W P, Ross A B (1988). Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (·OH/·O) in aqueous solution. Journal of Physical and Chemical Reference Data, 17(2): 513–886

    Article  CAS  Google Scholar 

  • Chang J, Chen Z L, Wang Z, Shen J M, Chen Q, Kang J, Yang L, Liu X W, Nie C X (2014). Ozonation degradation of microcystin-LR in aqueous solution: intermediates, byproducts and pathways. Water Research, 63: 52–61

    Article  CAS  Google Scholar 

  • Chen P, Wang F, Chen Z, Zhang Q, Su Y, Shen L, Yao K, Liu Y, Cai Z, Lv W, Liu G (2017). Study on the photocatalytic mechanism and detoxicity of gemfibrozil by a sunlight-driven TiO2/carbon dots photocatalyst: The significant roles of reactive oxygen species. Applied Catalysis B: Environmental, 204: 250–259

    Article  CAS  Google Scholar 

  • Cruz-Alcalde A, Sans C, Esplugas S (2017). Priority pesticides abatement by advanced water technologies: The case of acetamiprid removal by ozonation. Science of the Total Environment, 599–600: 1454–1461

    Article  CAS  Google Scholar 

  • Deanna N (2018). Global Oncology Trends 2018. Parsippany: IQVIA Institute for Human Data Science

    Google Scholar 

  • Deborde M, Rabouan S, Duguet J P, Legube B (2005). Kinetics of aqueous ozone-induced oxidation of some endocrine disruptors. Environmental Science & Technology, 39(16): 6086–6092

    Article  CAS  Google Scholar 

  • Elovitz M S, Shemer H, Peller J R, Vinodgopal K, Sivaganesan M, Linden K G (2008). Hydroxyl radical rate constants: comparing UV/H2O2 and pulse radiolysis for environmental pollutants. Journal of Water Supply: Research & Technology-Aqua, 57(6): 391–401

    Article  CAS  Google Scholar 

  • Elovitz M S, von Gunten U, Kaiser H (2000). Hydroxyl radical/ozone ratios during ozonation processes. II. The effect of temperature, pH, alkalinity, and DOM properties. Ozone Science and Engineering, 22(2): 123–150

    Article  CAS  Google Scholar 

  • Faria P C C, Órfão J J M, Pereira M F R (2008). Activated carbon catalytic ozonation of oxamic and oxalic acids. Applied Catalysis B: Environmental, 79(3): 237–243

    Article  CAS  Google Scholar 

  • Ferre-Aracil J, Valcárcel Y, Negreira N, de Alda M L, Barceló D, Cardona S C, Navarro-Laboulais J (2016). Ozonation of hospital raw wastewaters for cytostatic compounds removal. Kinetic modelling and economic assessment of the process. Science of the Total Environment, 556: 70–79

    Article  CAS  Google Scholar 

  • Flyunt R, Theruvathu J A, Leitzke A, von Sonntag C (2002). The reactions of thymine and thymidine with ozone. Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry, 9: 1572–1582

    Article  CAS  Google Scholar 

  • Franquet-Griell H, Gómez-Canela C, Ventura F, Lacorte S (2015). Predicting concentrations of cytostatic drugs in sewage effluents and surface waters of Catalonia (NE Spain). Environmental Research, 138: 161–172

    Article  CAS  Google Scholar 

  • Franquet-Griell H, Medina A, Sans C, Lacorte S (2017). Biological and photochemical degradation of cytostatic drugs under laboratory conditions. Journal of Hazardous Materials, 323(Pt A): 319–328

    Article  CAS  Google Scholar 

  • Fu R, Tian L, Chen F (2014). Comparing methods for predicting the reactive site of electrophilic substitution. Wuli Huaxue Xuebao, 30(04): 628–639 (in Chinese)

    CAS  Google Scholar 

  • Gómez-Canela C, Bolivar-Subirats G, Tauler R, Lacorte S (2017). Powerful combination of analytical and chemometric methods for the photodegradation of 5-Fluorouracil. Journal of Pharmaceutical and Biomedical Analysis, 137: 33–41

    Article  CAS  Google Scholar 

  • Gómez-Canela C, Ventura F, Caixach J, Lacorte S (2014). Occurrence of cytostatic compounds in hospital effluents and wastewaters, determined by liquid chromatography coupled to high-resolution mass spectrometry. Analytical and Bioanalytical Chemistry, 406(16): 3801–3814

    Article  CAS  Google Scholar 

  • Gómez-Ramos M M, Mezcua M, Agüera A, Fernández-Alba A R, Gonzalo S, Rodríguez A, Rosal R (2011). Chemical and toxicological evolution of the antibiotic sulfamethoxazole under ozone treatment in water solution. Journal of Hazardous Materials, 192(1): 18–25

    Google Scholar 

  • Governo M, Santos M S F, Alves A, Madeira L M (2017). Degradation of the cytostatic 5-Fluorouracil in water by Fenton and photo-assisted oxidation processes. Environmental Science and Pollution Research International, 24(1): 844–854

    Article  CAS  Google Scholar 

  • Guo R, Zheng F, Chen J (2015). Evaluation of the aquatic toxic effect varied during the degradation of capecitabine under the environmental abiotic and biotic processes. RSC Advances, 5(94): 76772–76778

    Article  CAS  Google Scholar 

  • Heath E, Filipič M, Kosjek T, Isidori M (2016). Fate and effects of the residues of anticancer drugs in the environment. Environmental Science and Pollution Research International, 23(15): 14687–14691

    Article  Google Scholar 

  • Hopkins Z R, Blaney L (2014). A novel approach to modeling the reaction kinetics of tetracycline antibiotics with aqueous ozone. Science of the Total Environment, 468–469: 337–344

    Article  CAS  Google Scholar 

  • Hopkins Z R, Snowberger S, Blaney L (2017). Ozonation of the oxybenzone, octinoxate, and octocrylene UV-filters: Reaction kinetics, absorbance characteristics, and transformation products. Journal of Hazardous Materials, 338: 23–32

    Article  CAS  Google Scholar 

  • Jin L, Lü M, Zhao C, Min S, Zhang T, Zhang Q (2017). The reactivity of the 5-formylcytosine with hydroxyl radical: A theoretical perspective. Journal of Physical Organic Chemistry, 30(11): e3691

    Article  CAS  Google Scholar 

  • Jin X, Peldszus S, Huck P M (2012). Reaction kinetics of selected micropollutants in ozonation and advanced oxidation processes. Water Research, 46(19): 6519–6530

    Article  CAS  Google Scholar 

  • Kosjek T, Heath E (2011). Occurrence, fate and determination of cytostatic pharmaceuticals in the environment. TrAC Trends in Analytical Chemistry, 30(7): 1065–1087

    Article  CAS  Google Scholar 

  • Kosjek T, Perko S, Žigon D, Heath E (2013). Fluorouracil in the environment: Analysis, occurrence, degradation and transformation. Journal of Chromatography. A, 1290: 62–72

    Article  CAS  Google Scholar 

  • Kovalova L (2009). Cytostatics in the aquatic environment: Analysis, occurrence, and possibilities for removal. Dissertation for the Doctoral Degree. Aachen: RWTH Aachen University

    Google Scholar 

  • Kuang J, Huang J, Wang B, Cao Q, Deng S, Yu G (2013). Ozonation of trimethoprim in aqueous solution: identification of reaction products and their toxicity. Water Research, 47(8): 2863–2872

    Article  CAS  Google Scholar 

  • Kümmerer K, Haiß A, Schuster A, Hein A, Ebert I (2016). Antineoplastic compounds in the environment-substances of special concern. Environmental Science and Pollution Research International, 23(15): 14791–14804

    Article  CAS  Google Scholar 

  • Lee Y, Kovalova L, McArdell C S, von Gunten U (2014). Prediction of micropollutant elimination during ozonation of a hospital wastewater effluent. Water Research, 64: 134–148

    Article  CAS  Google Scholar 

  • Leitzke A, Sonntag C V (2009). Ozonolysis of unsaturated acids in aqueous solution: Acrylic, methacrylic, maleic, fumaric and muconic acids. Ozone Science and Engineering, 31(4): 301–308

    Article  CAS  Google Scholar 

  • Li W, Nanaboina V, Chen F, Korshin G V (2016). Removal of polycyclic synthetic musks and antineoplastic drugs in ozonated wastewater: Quantitation based on the data of differential spectroscopy. Journal of Hazardous Materials, 304: 242–250

    Article  CAS  Google Scholar 

  • Li W, Tanumihardja J, Masuyama T, Korshin G (2015). Examination of the kinetics of degradation of the antineoplastic drug 5-fluorouracil by chlorine and bromine. Journal of Hazardous Materials, 282: 125–132

    Article  CAS  Google Scholar 

  • Lin A Y, Hsueh J H, Hong P K A (2015). Removal of antineoplastic drugs cyclophosphamide, ifosfamide, and 5-fluorouracil and a vasodilator drug pentoxifylline from wastewaters by ozonation. Environmental Science and Pollution Research International, 22(1): 508–515

    Article  CAS  Google Scholar 

  • Lin A Y, Wang X H, Lee W N (2013). Phototransformation determines the fate of 5-fluorouracil and cyclophosphamide in natural surface waters. Environmental Science & Technology, 47(9): 4104–4112

    Article  CAS  Google Scholar 

  • Lin H H, Lin A Y (2014). Photocatalytic oxidation of 5-fluorouracil and cyclophosphamide via UV/TiO2 in an aqueous environment. Water Research, 48: 559–568

    Article  CAS  Google Scholar 

  • Liu T, Yin K, Liu C, Luo J, Crittenden J, Zhang W, Luo S, He Q, Deng Y, Liu H, Zhang D (2018). The role of reactive oxygen species and carbonate radical in oxcarbazepine degradation via UV, UV/H2O2: Kinetics, mechanisms and toxicity evaluation. Water Research, 147: 204–213

    Article  CAS  Google Scholar 

  • Lutterbeck C A, Wilde M L, Baginska E, Leder C, Machado Ê L, Kümmerer K (2016). Degradation of cyclophosphamide and 5-fluorouracil by UV and simulated sunlight treatments: Assessment of the enhancement of the biodegradability and toxicity. Environmental Pollution, 208(Pt B): 467–476

    Article  CAS  Google Scholar 

  • Mahnik S N, Lenz K, Weissenbacher N, Mader R M, 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(1): 30–37

    Article  CAS  Google Scholar 

  • Mahnik S N, Rizovski B, Fuerhacker M, Mader R M (2004). Determination of 5-fluorouracil in hospital effluents. Analytical and Bioanalytical Chemistry, 380(1): 31–35

    Article  CAS  Google Scholar 

  • MarvinSketch (2018). MarvinSketch (version 18.23.0). Budapest: ChemAxon

    Google Scholar 

  • Miolo G, Marzano C, Gandin V, Palozzo A C, Dalzoppo D, Salvador A, Caffieri S (2011). Photoreactivity of 5-fluorouracil under UVB light: Photolysis and cytotoxicity studies. Chemical Research in Toxicology, 24(8): 1319–1326

    Article  CAS  Google Scholar 

  • Mohamed H S, Dahy A A, Hassan G S, Eid S M, Mahfouz R M (2017). Quantum-chemical investigation on 5-fluorouracil anticancer drug. Structural Chemistry, 28(4): 1093–1109

    Article  CAS  Google Scholar 

  • National Cancer Institute (2018). Cancer Statistics. 2018. Bethesda: National Cancer Institute

    Google Scholar 

  • Negreira N, de Alda M L, Barceló D (2014). Cytostatic drugs and metabolites in municipal and hospital wastewaters in Spain: filtration, occurrence, and environmental risk. Science of the Total Environment, 497–498: 68–77

    Article  CAS  Google Scholar 

  • Negreira N, López de Alda M, Barceló D (2013). On-line solid phase extraction-liquid chromatography-tandem mass spectrometry for the determination of 17 cytostatics and metabolites in waste, surface and ground water samples. Journal of Chromatography. A, 1280: 64–74

    Article  CAS  Google Scholar 

  • Nielsen U, Hastrup C, Klausen M M, Pedersen B M, Kristensen G H, Jansen J L C, Bak S N, Tuerk J (2013). Removal of APIs and bacteria from hospital wastewater by MBR plus O3, O3+ H2O2, PAC or ClO2. Water Science & Technology, 67(4): 854–862

    Article  CAS  Google Scholar 

  • Oldenkamp R, Huijbregts M A J, Hollander A, Versporten A, Goossens H, Ragas A M J (2013). Spatially explicit prioritization of human antibiotics and antineoplastics in Europe. Environment International, 51: 13–26

    Article  CAS  Google Scholar 

  • Parrella A, Lavorgna M, Criscuolo E, Russo C, Fiumano V, Isidori M (2014). Acute and chronic toxicity of six anticancer drugs on rotifers and crustaceans. Chemosphere, 115: 59–66

    Article  CAS  Google Scholar 

  • Qian J, Li W, Zhang Y, Yun Y, Zhang Y (2014). Degradation of anticancer drug 5-fluorouracil by Fenton and oxalic-Fenton process. Environmental Chemistry, 33(7): 1229–1234 (in Chinese)

    CAS  Google Scholar 

  • Rey R P, Padron A S, Leon L G, Pozo M M, Baluja C (1999). Ozonation of cytostatics in water medium. Nitrogen bases. Ozone Science and Engineering, 21(1): 69–77

    Article  CAS  Google Scholar 

  • Rosal R, Gonzalo M S, Boltes K, Letón P, Vaquero J J, García-Calvo E (2009). Identification of intermediates and assessment of ecotoxicity in the oxidation products generated during the ozonation of clofibric acid. Journal of Hazardous Materials, 172(2–3): 1061–1068

    Article  CAS  Google Scholar 

  • Sonntag C V, Gunten U V, Sonntag C V, Gunten U V (2012). Chemistry of Ozone in Water and Wastewater Treatment: from Basic Principles to Applications. London: Iwa Publishing

    Book  Google Scholar 

  • Straub J O (2009). Combined environmental risk assessment for 5-fluorouracil and capecitabine in Europe. Integrated Environmental Assessment and Management, 6(Suppl. 1): 540–566

    Google Scholar 

  • Tauxe-Wuersch A, De Alencastro L F, Grandjean D, Tarradellas J (2006). Trace determination of tamoxifen and 5-fluorouracil in hospital and urban wastewaters. International Journal of Environmental Analytical Chemistry, 86(7): 473–485

    Article  CAS  Google Scholar 

  • Tekle-Röttering A, Reisz E, Jewell K S, Lutze H V, Ternes T A, Schmidt W, Schmidt T C (2016). Ozonation of pyridine and other N-heterocyclic aromatic compounds: Kinetics, stoichiometry, identification of products and elucidation of pathways. Water Research, 102: 582–593

    Article  CAS  Google Scholar 

  • Theruvathu J A, Flyunt R, Aravindakumar C T, von Sonntag C (2001). Rate constants of ozone reactions with DNA, its constituents and related compounds. Journal of the Chemical Society, Perkin Transactions 2, 3: 269–274

    Article  Google Scholar 

  • Ueda Y, Saito A, Fukuoka Y, Yamashiro Y, Ikeda Y, Taki H, Yasuda T, Saikawa I (1983). Interactions of beta-lactam antibiotics and antineoplastic agents. Antimicrobial Agents and Chemotherapy, 23(3): 374–378

    Article  CAS  Google Scholar 

  • Valsania M C, Fasano F, Richardson S D, Vincenti M (2012). Investigation of the degradation of cresols in the treatments with ozone. Water Research, 46(8): 2795–2804

    Article  CAS  Google Scholar 

  • Wei X, Chen J, Xie Q, Zhang S, Ge L, Qiao X (2013). Distinct photolytic mechanisms and products for different dissociation species of ciprofloxacin. Environmental Science & Technology, 47(9): 4284–4290

    Article  CAS  Google Scholar 

  • Yin K, Deng L, Luo J, Crittenden J, Liu C, Wei Y, Wang L (2018). Destruction of phenicol antibiotics using the UV/H2O2 process: Kinetics, byproducts, toxicity evaluation and trichloromethane formation potential. Chemical Engineering Journal, 351: 867–877

    Article  CAS  Google Scholar 

  • Yu X, Zuo J, Tang X, Li R, Li Z, Zhang F (2014). Toxicity evaluation of pharmaceutical wastewaters using the alga Scenedesmus obliquus and the bacterium Vibrio fischeri. Journal of Hazardous Materials, 266: 68–74

    Article  CAS  Google Scholar 

  • Zhang G, Liu C, Chen L, Hang T, Song M (2015). Identification of related substances in capecitabine by LC-MS. Chinese Journal of New Drugs, 24(16): 1902–1910 (in Chinese)

    CAS  Google Scholar 

  • Zhang J, Chang V W, Giannis A, Wang J Y (2013). Removal of cytostatic drugs from aquatic environment: A review. Science of the Total Environment, 445–446: 281–298

    Article  CAS  Google Scholar 

  • Zhang W, Zhou S, Sun J, Meng X, Luo J, Zhou D, Crittenden J (2018). Impact of chloride ions on UV/H2O2 and UV/persulfate advanced oxidation processes. Environmental Science & Technology, 52(13): 7380–7389

    Article  CAS  Google Scholar 

  • Zhao Y, Yu G, Chen S, Zhang S, Wang B, Huang J, Deng S, Wang Y (2017). Ozonation of antidepressant fluoxetine and its metabolite product norfluoxetine: Kinetics, intermediates and toxicity. Chemical Engineering Journal, 316: 951–963

    Article  CAS  Google Scholar 

  • Zounková R, Odráska P, Dolezalová L, Hilscherová K, Marsálek B, Bláha L (2007). Ecotoxicity and genotoxicity assessment of cytostatic pharmaceuticals. Environmental Toxicology and Chemistry, 26(10): 2208–2214

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Major Science and Technology Program for Water Pollution Control and Treatment in China (No. 2017ZX07202006), and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1261).

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Correspondence to Gang Yu.

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Highlights

• Specific second-order rate constants were determined for 5-FU and CAP with ozone.

• Reaction sites were confirmed by kinetics, Fukui analysis, and products.

• The olefin moiety was the main ozone reaction site for 5-FU and CAP.

• Carboxylic acids comprised most of the residual TOC for 5-FU.

• Ozonation removed the toxicity associated with 5-FU and products but not CAP.

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Chen, S., Blaney, L., Chen, P. et al. Ozonation of the 5-fluorouracil anticancer drug and its prodrug capecitabine: Reaction kinetics, oxidation mechanisms, and residual toxicity. Front. Environ. Sci. Eng. 13, 59 (2019). https://doi.org/10.1007/s11783-019-1143-2

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  • DOI: https://doi.org/10.1007/s11783-019-1143-2

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