Fast and complete removal of the 5-fluorouracil drug from water by electro-Fenton oxidation

Cytostatic drugs are a troublesome class of emerging pollutants in water owing to their potential effects on DNA. Here we studied the removal of 5-fluorouracil from water using the electro-Fenton process. Galvanostatic electrolyses were performed with an undivided laboratory-scale cell equipped with a boron-doped diamond anode and a carbon felt cathode. Results show that the fastest degradation and almost complete mineralization was obtained at a Fe2+ catalyst concentration of 0.2 mM. The absolute rate constant for oxidation of 5-fluorouracil by hydroxyl radicals was 1.52 × 109 M−1 s−1. Oxalic and acetic acids were initially formed as main short-chain aliphatic by-products, then were completely degraded. After 6 h the final solution mainly contained inorganic ions (NH4+, NO3− and F−) and less than 10% of residual organic carbon. Hence, electro-Fenton constitutes an interesting alternative to degrade biorefractory drugs.


Introduction
Pharmaceuticals are non-regulated trace organic emerging contaminants that are ubiquitous in the aquatic environment due to discharge of effluents from pharmaceutical industry, hospitals and municipal wastewater treatment facilities (Feng et al. 2015, Petrie et al. 2015. In most cases, these pollutants are also present in the digested sludge, potentially entailing a high ecotoxicological risk (Martín et al. 2012). In order to avoid the propagation and subsequent accumulation of pharmaceutically active compounds in water bodies, specific prevention systems should be devised at major point sources of pollution. In the case of pharmaceuticals, such locations are hospitals and production sites. Unfortunately, removal efficacy data are scarce since the vast majority of the studies only focus on their impact on pharmaceutical loads.
The most hazardous representatives among these pollutants are those with a very powerful pharmacological action. Among them, the class of cytostatic (antineoplastic) drugs, used to prevent or inhibit the growth of malignant cells or tumors, can display severe negative effects on non-target organisms including humans, like carcinogenicity, cytotoxicity, genotoxicity, mutagenicity and teratogenicity (Kosjek et al. 2013). 5-Fluorouracil ( Fig. 1A) belongs to the subclass of antimetabolites and its consumption reaches the range of tonnes in Europe. Several studies have reported its presence in natural water at concentrations ranging from ng L -1 to µg L -1 (Lutterbeck et al. 2016).
Conventional water treatment methods based on biological processes have been shown as insufficient to eliminate the majority of target pharmaceuticals because of their high recalcitrance and toxicity to bacteria (Kovalova et al. 2012). 5-Fluorouracil is not an exception and, furthermore, it has been demonstrated that photodegradation by sun is not suitable for its removal either, showing partial degradation and no mineralization (Lutterbeck et al. 2016). Therefore, it does not undergo natural attenuation in the environment and cannot be removed in traditional treatment plants.
Chemical degradation with NaClO or H 2 O 2 could be an option to face up to this troubling situation, as tested in the hospital environment (Castegnaro et al. 1997).
Alternatively, several enhanced water treatment technologies have been developed in recent years. In particular, the advanced oxidation processes (AOPs), which utilize strong reactive oxidant species like hydroxyl radicals ( • OH) generated on site, present appealing perspectives for treating biorefractory pollutants (Oturan and Aaron 2014). A relatively new group of AOPs is constituted by electrochemical methods (EAOPs) such as electro-oxidation, Fenton-based EAOPs and photoelectrocatalysis, whose great performance during the treatment of pharmaceuticals has been thoroughly reviewed (Sirés and Brillas 2012, Feng et al. 2013, Brillas and Sirés 2015. The common feature of all the EAOPs is their ability to generate reactive oxygen species (ROS), as either superoxides (MO x ) or hydroxyl radicals (M( • OH)), adsorbed on the anode (M) surface from the oxidation of water. Active anodes like Pt promote the formation of the first kind of ROS, whereas non-active anodes like boron-doped diamond (BDD) foster the second type via reaction (1). However, only the Fenton-based EAOPs like electro-Fenton (EF) process are able to produce homogeneous • OH from Fenton's reaction (2) thanks to the in situ generation of H 2 O 2 from the two-electron cathodic reduction of O 2 : The fundamentals and reactivity of EF process are well described elsewhere (Brillas et al. 2009). EF has been successfully employed for the treatment of acidic aqueous solutions containing antibiotics, antidepressants or β-blockers, among others, using , as well as Fenton and photo-Fenton processes (Governo et al. 2017;Koltsakidou et al. 2017). In this context, the aim of the present work is to optimize the key operation parameters for a fast drug decay and large mineralization of aqueous solutions of the emerging pollutant 5-fluorouracil by EF using a BDD/carbon felt cell, trying to confirm the great oxidation power of this method to treat highly (bio)recalcitrant molecules.

Experimental
The cytostatic drug 5-fluorouracil was of analytical grade (> 99% purity) from Sigma-Aldrich, and it was used as received.

Optimization of EF parameters for 5-fluorouracil removal
The catalyst content and applied current (I) are the most crucial operation parameters to be optimized in EF treatments. First, the effect of the initial Fe 2+ concentration on 5fluorouracil destruction was studied at 300 mA. The drug decay with oxidation time is represented in Fig. 1A as the ratio between the concentrations of pollutant at time t and before the electrolysis. As can be observed, the destruction of the drug was quick and complete in all cases. At 0.1 mM Fe 2+ , total disappearance is attained in only 7 min, thanks to the synergistic action of • OH formed in the bulk and BDD( • OH) adsorbed on the anode surface (Brillas et al. 2009). The oxidation is accelerated when increasing the initial Fe 2+ content to 0.2 mM, achievieng a significantly quicker decay at the early stages and an overall removal at 6 min. This enhancement can be explained by the larger production of • OH from Fenton's reaction (2) Fig. 2A. Again, a fast and total destruction is achieved, being required a shorter time as current increases. For example, the application of currents from 50 to 300 mA allows shortening the required time from 9 to 6 min. This is due to the gradually greater production of BDD( • OH) from reaction (1), as well as of • OH via reaction (2) due to the upgrading of H 2 O 2 cathodic electrogeneration. In contrast, the application of a higher current like 400 mA is detrimental, since the process becomes slower and 7 min are needed to completely remove the drug. The values of k app ranged between 0.38 and 0.60 min -1 , with a maximum of 0.74 min -1 appearing at 300 mA. As in

Mineralization of 5-fluorouracil solutions and by-products generated
The effect of Fe 2+ content and current on the mineralization ability of the EF process is shown in Fig. 3 as the percentage of TOC removal. Fig. 3A confirms that 0.2 mM Fe 2+ is also the optimal concentration for the degradation of reaction intermediates, since the removal percentage increased from 76% to 86% at 360 min. Further increase of the catalyst content to 0.5 mM was detrimental, with a slower and lower final mineralization of 82%. In order to assess the possibility of attaining larger TOC removals, current was tested from 200 to 1500 mA (Fig. 3B). As can be seen, almost overall mineralization (> 94%) was achieved at the highest current value due to the simultaneous action of hydroxyl radicals onto the parent drug and its intermediates, whereas gradually lower percentages were achieved as the applied current decreased. Depending on the energy cost, currents < 1500 mA can be chosen, still attaining > 90% mineralization at long time.
The attack of • OH and BDD( • OH) on the cyclic structure causes its hydroxylation upon attack onto nitrogen atoms and/or -CH group (Lutterbeck et al. 2016), followed by ring cleavage with formation of carboxylic acids. This is demonstrated for 5-fluorouracil in

Conclusion
The fastest destruction of cytotoxic drug 5-fluorouracil by electro-Fenton process (6 min at 300 mA) was reached at an optimum Fe 2+ concentration of 0.2 mM. Regarding the mineralization of 5-fluorouracil solutions, the application of 1500 mA ensured the abatement of > 94% TOC. The second-order rate constant (k abs ) for oxidizing this drug with hydroxyl radical was determined for the first time. Electro-Fenton process is shown as highly effective for destroying cytostatic pharmaceutical residues in water.