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

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.

Graphical abstract

Keywords

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

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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.

Electronic Supplementary Material

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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