Product identification and toxicity change during oxidation of methotrexate by ferrate and permanganate in water

Shengqi Zhang, Chengsong Ye, Wenjun Zhao, Lili An, Xin Yu, Lei Zhang, Hongjie Sun, Mingbao Feng

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Front. Environ. Sci. Eng. ›› 2022, Vol. 16 ›› Issue (7) : 93. DOI: 10.1007/s11783-021-1501-8
RESEARCH ARTICLE

Product identification and toxicity change during oxidation of methotrexate by ferrate and permanganate in water

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Highlights

• Oxidation of methotrexate by high-valent metal-oxo species was first explored.

• Fe(VI) presented a higher reactivity to MTX than Mn(VII) at pH 8.0.

• Ketonization and cleavage of peptide bond were two initial reaction pathways.

• Products of MTX were not genotoxic, neurotoxic, or endocrine-disrupting chemicals.

• The less biodegradable products exhibited developmental and acute/chronic toxicity.

Abstract

Accompanying an annual increase in cancer incidence, the global use of anticancer drugs has remarkably increased with their worldwide environmental prevalence and ecological risks. In this study, the oxidation of methotrexate (MTX), a typical anticancer drug with ubiquitous occurrence and multi-endpoint toxicity, by ferrate(VI) (Fe(VI)) and permanganate (Mn(VII))) was investigated in water. Fe(VI) exhibited a higher reactivity with MTX (93.34 M−1 s−1) than Mn(VII) (3.01 M−1 s−1) at pH 8.0. The introduction of Cu(II) and Fe(III) at 1.0 mM improved the removal efficiency of 5.0 μM MTX by 100.0 μM Fe(VI) from 80% to 95% and 100% after 4 min, respectively. Seven oxidized products (OPs) were identified during oxidative treatments, while OP-191 and OP-205 were characterized as specific products for Fe(VI) oxidation. Initial ketonization of the L-glutamic acid moiety and cleavage of the peptide bond of MTX were proposed. Additionally, a multi-endpoint toxicity evaluation indicated no genotoxicity, neurotoxicity, or endocrine-disrupting effects of MTX and its OPs. Particularly, serious developmental toxicity in zebrafish larvae was observed in the treated MTX solutions. Based on the acute and chronic aquatic toxicity prediction, OP-190, OP-192, OP-206, and OP-208 were deemed toxic or very toxic compared to harmful MTX. Furthermore, the reduced biodegradability index from 0.15 (MTX) to −0.5 to −0.2 (OP-192, OP-206, and OP-468) indicated the formation of lower biodegradable OPs. Overall, this study suggests that Fe(VI) and Mn(VII) oxidation are promising treatments for remediating anticancer drug-contaminated water. However, the environmental risks associated with these treatments should be considered in the evaluation of water safety.

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Keywords

Anticancer drugs / High-valent metal-oxo species / Oxidation kinetics / Reaction mechanisms / Multi-endpoint toxicity

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Shengqi Zhang, Chengsong Ye, Wenjun Zhao, Lili An, Xin Yu, Lei Zhang, Hongjie Sun, Mingbao Feng. Product identification and toxicity change during oxidation of methotrexate by ferrate and permanganate in water. Front. Environ. Sci. Eng., 2022, 16(7): 93 https://doi.org/10.1007/s11783-021-1501-8

References

[1]
Barışçı S, Turkay O, Ulusoy E, Şeker M G, Yüksel E, Dimoglo A (2018). Electro-oxidation of cytostatic drugs: Experimental and theoretical identification of by-products and evaluation of ecotoxicological effects. Chemical Engineering Journal, 334: 1820–1827
CrossRef Google scholar
[2]
Calza P, Medana C, Sarro M, Rosato V, Aigotti R, Baiocchi C, Minero C (2014). Photocatalytic degradation of selected anticancer drugs and identification of their transformation products in water by liquid chromatography-high resolution mass spectrometry. Journal of Chromatography. A, 1362: 135–144
CrossRef Pubmed Google scholar
[3]
Chen J, Qi Y, Pan X, Wu N, Zuo J, Li C, Qu R, Wang Z, Chen Z (2019). Mechanistic insights into the reactivity of Ferrate(VI) with phenolic compounds and the formation of coupling products. Water Research, 158: 338–349
CrossRef Pubmed Google scholar
[4]
Chen J, Wu N, Xu X, Qu R, Li C, Pan X, Wei Z, Wang Z (2018). Fe(VI)-mediated single-electron coupling processes for the removal of chlorophene: A combined experimental and computational study. Environmental Science & Technology, 52(21): 12592–12601
CrossRef Pubmed Google scholar
[5]
Della-Flora A, Wilde M L, Pinto I D F, Lima É C, Sirtori C (2020). Degradation of the anticancer drug flutamide by solar photo-Fenton treatment at near-neutral pH: Identification of transformation products and in silico (Q)SAR risk assessment. Environmental Research, 183: 109223
CrossRef Pubmed Google scholar
[6]
Evgenidou E, Ofrydopoulou A, Malesic-Eleftheriadou N, Nannou C, Ainali N M, Christodoulou E, Bikiaris D N, Kyzas G Z, Lambropoulou D A (2020). New insights into transformation pathways of a mixture of cytostatic drugs using Polyester-TiO2 films: Identification of intermediates and toxicity assessment. Science of the Total Environment, 741: 140394
CrossRef Pubmed Google scholar
[7]
Feng M, Qu R, Zhang X, Sun P, Sui Y, Wang L, Wang Z (2015). Degradation of flumequine in aqueous solution by persulfate activated with common methods and polyhydroquinone-coated magnetite/multi-walled carbon nanotubes catalysts. Water Research, 85: 1–10
CrossRef Pubmed Google scholar
[8]
Feng M, Wang X, Chen J, Qu R, Sui Y, Cizmas L, Wang Z, Sharma V K (2016). Degradation of fluoroquinolone antibiotics by ferrate(VI): Effects of water constituents and oxidized products. Water Research, 103: 48–57
CrossRef Pubmed Google scholar
[9]
Feng Y, Qing W, Kong L, Li H, Wu D, Fan Y, Lee P H, Shih K (2019). Factors and mechanisms that influence the reactivity of trivalent copper: A novel oxidant for selective degradation of antibiotics. Water Research, 149: 1–8
CrossRef Pubmed Google scholar
[10]
Gao Y, Zhou Y, Pang S Y, Jiang J, Yang Z, Shen Y, Wang Z, Wang P X, Wang L H (2019). New insights into the combination of permanganate and bisulfite as a novel advanced oxidation process: Importance of high valent manganese-oxo species and sulfate radical. Environmental Science & Technology, 53(7): 3689–3696
CrossRef Pubmed Google scholar
[11]
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(11): 1056–1063
CrossRef Pubmed Google scholar
[12]
Haddad T, Baginska E, Kümmerer K (2015). Transformation products of antibiotic and cytostatic drugs in the aquatic cycle that result from effluent treatment and abiotic/biotic reactions in the environment: An increasing challenge calling for higher emphasis on measures at the beginning of the pipe. Water Research, 72: 75–126
CrossRef Pubmed Google scholar
[13]
Hsu M H, Tsai C J, Lin A Y C (2019). Mechanism and pathways underlying the self-sensitized photodegradation of methotrexate under simulated solar irradiation. Journal of Hazardous Materials, 373: 468–475
CrossRef Pubmed Google scholar
[14]
Hu L, Martin H M, Arce-Bulted O, Sugihara M N, Keating K A, Strathmann T I (2009). Oxidation of carbamazepine by Mn(VII) and Fe(VI): Reaction kinetics and mechanism. Environmental Science & Technology, 43(2): 509–515
CrossRef Pubmed Google scholar
[15]
Hua Z, Li D, Wu Z, Wang D, Cui Y, Huang X, Fang J, An T (2021). DBP formation and toxicity alteration during UV/chlorine treatment of wastewater and the effects of ammonia and bromide. Water Research, 188: 116549
CrossRef Pubmed Google scholar
[16]
Jeong T Y, Simpson M J (2019). Daphnia magna metabolic profiling as a promising water quality parameter for the biological early warning system. Water Research, 166: 115033
CrossRef Pubmed Google scholar
[17]
Jiang W, Chen L, Batchu S R, Gardinali P R, Jasa L, Marsalek B, Zboril R, Dionysiou D D, O’Shea K E, Sharma V K (2014). Oxidation of microcystin-LR by ferrate(VI): kinetics, degradation pathways, and toxicity assessments. Environmental Science & Technology, 48(20): 12164–12172
CrossRef Pubmed Google scholar
[18]
Jiang X, Song D, Wang D, Zhang R, Fang Q, Sun H, Kong F (2020). Eliminating imidacloprid and its toxicity by permanganate via highly selective partial oxidation. Ecotoxicology and Environmental Safety, 191: 110234
CrossRef Pubmed Google scholar
[19]
Jureczko M, Kalka J (2020). Cytostatic pharmaceuticals as water contaminants. European Journal of Pharmacology, 866: 172816
CrossRef Pubmed Google scholar
[20]
Kanjal M I, Muneer M, Abdelhaleem A, Chu W (2020). Degradation of methotrexate by UV/peroxymonosulfate: Kinetics, effect of operational parameters and mechanism. Chinese Journal of Chemical Engineering, 28(10): 2658–2667
CrossRef Google scholar
[21]
Kinch C D, Ibhazehiebo K, Jeong J H, Habibi H R, Kurrasch D M (2015). Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 112(5): 1475–1480
CrossRef Pubmed Google scholar
[22]
Laera G, Cassano D, Lopez A, Pinto A, Pollice A, Ricco G, Mascolo G (2012). Removal of organics and degradation products from industrial wastewater by a membrane bioreactor integrated with ozone or UV/H2O2 treatment. Environmental Science & Technology, 46(2): 1010–1018
CrossRef Pubmed Google scholar
[23]
Lai W W P, Chuang Y C, Lin A Y C (2017a). The effects and the toxicity increases caused by bicarbonate, chloride, and other water components during the UV/TiO2 degradation of oxazaphosphorine drugs. Environmental Science and Pollution Research International, 24(17): 14595–14604
CrossRef Pubmed Google scholar
[24]
Lai W W P, Hsu M H, Lin A Y C (2017b). The role of bicarbonate anions in methotrexate degradation via UV/TiO2: Mechanisms, reactivity and increased toxicity. Water Research, 112: 157–166
CrossRef Pubmed Google scholar
[25]
Li D, Chen H, Liu H, Schlenk D, Mu J, Lacorte S, Ying G G, Xie L (2021). Anticancer drugs in the aquatic ecosystem: Environmental occurrence, ecotoxicological effect and risk assessment. Environment International, 153: 106543
CrossRef Pubmed Google scholar
[26]
Li J, Jiang J, Pang S Y, Gao Y, Sun S, Wang Z, Wang P, Wang L, Zhou Y (2019). Transformation of bisphenol AF and bisphenol S by permanganate in the absence/presence of iodide: Kinetics and products. Chemosphere, 217: 402–410
CrossRef Pubmed Google scholar
[27]
Lutterbeck C A, Baginska E, Machado Ê L, Kümmerer K (2015a). Removal of the anti-cancer drug methotrexate from water by advanced oxidation processes: Aerobic biodegradation and toxicity studies after treatment. Chemosphere, 141: 290–296
CrossRef Pubmed Google scholar
[28]
Lutterbeck C A, Wilde M L, Baginska E, Leder C, Machado Ê L, Kümmerer K (2015b). Degradation of 5-FU by means of advanced (photo)oxidation processes: UV/H2O2, UV/Fe2+/H2O2 and UV/TiO2-Comparison of transformation products, ready biodegradability and toxicity. Science of The Total Environment, 527-528: 232–245
CrossRef Pubmed Google scholar
[29]
Meng Y, Liu W, Fiedler H, Zhang J, Wei X, Liu X, Peng M, Zhang T (2021). Fate and risk assessment of emerging contaminants in reclaimed water production processes. Frontiers of Environmental Science & Engineering, 15(5): 104
CrossRef Google scholar
[30]
Mišík M, Filipic M, Nersesyan A, Kundi M, Isidori M, Knasmueller S (2019). Environmental risk assessment of widely used anticancer drugs (5-fluorouracil, cisplatin, etoposide, imatinib mesylate). Water Research, 164: 114953
CrossRef Pubmed Google scholar
[31]
Mukherjee S, Mehta D, Dhangar K, Kumar M (2021). Environmental fate, distribution and state-of-the-art removal of antineoplastic drugs: A comprehensive insight. Chemical Engineering Journal, 407: 127184
CrossRef Google scholar
[32]
Oller I, Malato S, Sánchez-Pérez J A (2011). Combination of Advanced Oxidation Processes and biological treatments for wastewater decontamination: A review. Science of the Total Environment, 409(20): 4141–4166
CrossRef Pubmed Google scholar
[33]
Pieczyńska A, Fiszka Borzyszkowska A, Ofiarska A, Siedlecka E M (2017). Removal of cytostatic drugs by AOPs: A review of applied processes in the context of green technology. Critical Reviews in Environmental Science and Technology, 47(14): 1282–1335
CrossRef Google scholar
[34]
Roig B, Marquenet B, Delpla I, Bessonneau V, Sellier A, Leder C, Thomas O, Bolek R, Kummerer K (2014). Monitoring of methotrexate chlorination in water. Water Research, 57: 67–75
CrossRef Pubmed Google scholar
[35]
Sanabria P, Scunderlick D, Wilde M L, Lüdtke D S, Sirtori C (2021). Solar photo-Fenton treatment of the anti-cancer drug anastrozole in different aqueous matrices at near-neutral pH: Transformation products identification, pathways proposal, and in silico (Q)SAR risk assessment. Science of the Total Environment, 754: 142300
CrossRef Pubmed Google scholar
[36]
Selderslaghs I W T, Blust R, Witters H E (2012). Feasibility study of the zebrafish assay as an alternative method to screen for developmental toxicity and embryotoxicity using a training set of 27 compounds. Reproductive Toxicology (Elmsford, N.Y.), 33(2): 142–154
CrossRef Pubmed Google scholar
[37]
Shao B, Dong H, Sun B, Guan X (2019a). Role of ferrate(IV) and ferrate(V) in activating ferrate(VI) by calcium sulfite for enhanced oxidation of organic contaminants. Environmental Science & Technology, 53(2): 894–902
CrossRef Pubmed Google scholar
[38]
Shao B, Qiao J, Zhao Z, Guan X (2019b). Advances in contaminants abatement by ferrate(VI). Chinese Science Bulletin, 64: 3401–3411
[39]
Sharma V K, Zboril R, Varma R S (2015). Ferrates: Greener oxidants with multimodal action in water treatment technologies. Accounts of Chemical Research, 48(2): 182–191
CrossRef Pubmed Google scholar
[40]
Siedlecka E M, Ofiarska A, Borzyszkowska A F, Białk-Bielińska A, Stepnowski P, Pieczyńska A (2018). Cytostatic drug removal using electrochemical oxidation with BDD electrode: Degradation pathway and toxicity. Water Research, 144: 235–245
CrossRef Pubmed Google scholar
[41]
Slade D, Eustermann S (2020). Tuning drug binding. Science, 368(6486): 30–31
CrossRef Pubmed Google scholar
[42]
Song Y, Jiang J, Qin W, Li J, Zhou Y, Gao Y (2021). Enhanced transformation of organic pollutants by mild oxidants in the presence of synthetic or natural redox mediators: A review. Water Research, 189: 116667
CrossRef Pubmed Google scholar
[43]
Sun H J, Zhang Y, Zhang J Y, Lin H, Chen J, Hong H (2019). The toxicity of 2,6-dichlorobenzoquinone on the early life stage of zebrafish: A survey on the endpoints at developmental toxicity, oxidative stress, genotoxicity and cytotoxicity. Environmental pollution, 245: 719–724
CrossRef Pubmed Google scholar
[44]
Sun S, Gui Y, Wang Y, Qian L, Liu X, Jiang Q, Song H (2009). Effects of methotrexate on the developments of heart and vessel in zebrafish. Acta Biochimica et Biophysica Sinica, 41(1): 86–96
CrossRef Pubmed Google scholar
[45]
Tkaczyk A, Bownik A, Dudka J, Kowal K, Ślaska B (2021). Daphnia magna model in the toxicity assessment of pharmaceuticals: A review. Science of the Total Environment, 763: 143038
CrossRef Pubmed Google scholar
[46]
Toolaram A P, Kümmerer K, Schneider M (2014). Environmental risk assessment of anti-cancer drugs and their transformation products: A focus on their genotoxicity characterization-state of knowledge and short comings. Mutation research. Reviews in mutation research, 760: 18–35
CrossRef Pubmed Google scholar
[47]
van der Velden D L, Hoes L R, van der Wijngaart H, van Berge Henegouwen J M, van Werkhoven E, Roepman P, Schilsky R L, de Leng W W J, Huitema A D R, Nuijen B, Nederlof P M, van Herpen C M L, de Groot D J A, Devriese L A, Hoeben A, de Jonge M J A, Chalabi M, Smit E F, de Langen A J, Mehra N, Labots M, Kapiteijn E, Sleijfer S, Cuppen E, Verheul H M W, Gelderblom H, Voest E E (2019). The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature, 574(7776): 127–131
CrossRef Pubmed Google scholar
[48]
Wang S, Shao B, Qiao J, Guan X (2021). Application of Fe(VI) in abating contaminants in water: State of art and knowledge gaps. Frontiers of Environmental Science & Engineering, 15(5): 80
CrossRef Google scholar
[49]
Wild CP, Weiderpass E, Stewart BW (2020). World Cancer Report: Cancer Research for Cancer Prevention. Lyon Int. Agency Research Cancer 23–33
[50]
Wormington A M, De María M, Kurita H G, Bisesi J H Jr, Denslow N D, Martyniuk C J (2020). Antineoplastic agents: Environmental prevalence and adverse outcomes in aquatic organisms. Environmental Toxicology and Chemistry, 39(5): 967–985
CrossRef Pubmed Google scholar
[51]
Wu D, Zhang F, Lou W, Li D, Chen J (2017). Chemical characterization and toxicity assessment of fine particulate matters emitted from the combustion of petrol and diesel fuels. Science of the Total Environment, 605-606: 172–179
CrossRef Pubmed Google scholar
[52]
Xu X, Chen J, Wang S, Ge J, Qu R, Feng M, Sharma V K, Wang Z (2018). Degradation kinetics and transformation products of chlorophene by aqueous permanganate. Water Research, 138: 293–300
CrossRef Pubmed Google scholar
[53]
Yang T, Wang L, Liu Y, Huang Z, He H, Wang X, Jiang J, Gao D, Ma J (2019). Comparative study on ferrate oxidation of BPS and BPAF: Kinetics, reaction mechanism, and the improvement on their biodegradability. Water Research, 148: 115–125
CrossRef Pubmed Google scholar
[54]
Yin J, Niu Y, Shao B (2017). Products of methotrexate during chlorination. Journal of Environmental Sciences (China), 55: 100–108
CrossRef Pubmed Google scholar
[55]
Yuan L, Qian L, Qian Y, Liu J, Yang K, Huang Y, Wang C, Li Y, Mu X (2019). Bisphenol F-induced neurotoxicity toward zebrafish embryos. Environmental Science & Technology, 53(24): 14638–14648
CrossRef Pubmed Google scholar
[56]
Zhang J, Sun B, Guan X (2013). Oxidative removal of bisphenol A by permanganate: Kinetics, pathways and influences of co-existing chemicals. Separation and Purification Technology, 107: 48–53
CrossRef Google scholar
[57]
Zhang T, Liu H, Zhang Y, Sun W, Ao X (2020). Comparative genotoxicity of water processed by three drinking water treatment plants with different water treatment procedures. Frontiers of Environmental Science & Engineering, 14(3): 39
CrossRef Google scholar
[58]
Zhang X, Feng M, Luo C, Nesnas N, Huang C H, Sharma V K (2021). Effect of metal ions on oxidation of micropollutants by ferrate(VI): Enhancing role of FeIV species. Environmental Science & Technology, 55(1): 623–633
CrossRef Pubmed Google scholar
[59]
Zheng Q, Wu N, Qu R, Albasher G, Cao W, Li B, Alsultan N, Wang Z (2021). Kinetics and reaction pathways for the transformation of 4-tert-butylphenol by ferrate(VI). Journal of Hazardous Materials, 401: 123405
CrossRef Pubmed Google scholar

Acknowledgments

This research was supported by the President Research Funds from Xiamen University (No. 20720210081), Singapore-China Joint Research Grant Call (NRF-NSFC 3rd Joint Grant Call-Earth Science) (No. 41861144023), Natural Science Foundation of China-Joint Fund Project (No. U2005206), Xiamen Municipal Bureau of Science and Technology (No. YDZX20203502000003). The authors want to thank the support of Nanqiang Youth Scholar program of Xiamen University. Also, we want to thank Prof. Lu Wang from Harbin Institute of Technology for providing potassium ferrate of high purity gratuitously.

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ƒSupplementary material is available in the online version of this article at https://doi.org/10.1007/s11783-021-1501-8 and is accessible for authorized users.

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