Urban Groundwater Contamination by Non-Steroidal Anti-Inflammatory

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Article Urban Groundwater Contamination by Non-Steroidal Anti-Inﬂammatory Drugs

Anna Jurado * , Enric Vázquez-Suñé and Estanislao Pujades

Institute of Environmental Assessment & Water Research (IDAEA), CSIC, c/Jordi Girona 18-26, 08034 Barcelona, Spain; [email protected] (E.V.-S.); [email protected] (E.P.) * Correspondence: [email protected]; Tel.: +34-934006100

Abstract: Pharmaceuticals, such as non-steroidal anti-inﬂammatory drugs (NSAIDs) and their metabolites, have become a major concern due to their increasing consumption and their widespread occurrence in the environment. In this paper, we investigate the occurrence of NSAIDs and their metabolites in an urban aquifer, which may serve as a potential resource for drinking water, and propose a methodology to assess the removal of these substances in the river–groundwater interface. Then, risk quotients (RQs) are computed, in order to determine the risk posed by the single NSAIDs and their mixture to human health. To this end, six NSAIDs and two metabolites were collected from an urban aquifer located in the metropolitan area of Barcelona (NE, Spain), in which the major pollution source is a contaminated river. All of the target NSAIDs were detected in groundwater samples, where the concentrations in the aquifer were higher than those found in the river water (except for ibuprofen). Diclofenac, ketoprofen, propyphenazone and salicylic acid were detected at high mean concentrations (ranging from 91.8 ng/L to 225.2 ng/L) in the aquifer. In contrast, phenazone and mefenamic acid were found at low mean concentrations (i.e., lower than 25 ng/L) in the aquifer. According to the proposed approach, the mixing of river water recharge into the aquifer seemed to some extent to promote the removal of the NSAIDs under the sub-oxic to denitrifying Citation: Jurado, A.; Vázquez-Suñé, conditions found in the groundwater. The NSAIDs that presented higher mean removal values were E.; Pujades, E. Urban Groundwater 4OH diclofenac (0.8), ibuprofen (0.78), salicylic acid (0.35) and diclofenac (0.28), which are likely to Contamination by Non-Steroidal be naturally attenuated under the aforementioned redox conditions. Concerning human health risk Anti-Inﬂammatory Drugs. Water 2021, assessment, the NSAIDs detected in groundwater and their mixture do not pose any risk for all age 13, 720. https://doi.org/10.3390/ intervals considered, as the associated RQs were all less than 0.05. Nevertheless, this value must be w13050720 taken with caution, as many pharmaceuticals might occur simultaneously in the groundwater.

Academic Editor: Aldo Fiori Keywords: water management; urban aquifer; redox conditions; pharmaceuticals; metabolites; human health risk assessment Received: 4 February 2021 Accepted: 3 March 2021 Published: 6 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Sharp urban growth has raised several problems, which tend to endanger the envi- published maps and institutional affil- ronmental, economic, and social sustainability of cities [1]. As a result, sustaining healthy iations. living conditions in urban areas is a tremendous challenge; central to this mission is the provision of freshwater resources [2]. However, climate change is expected to have impacts on water resources—specifically in the Mediterranean region—which are already limited and often used at unsustainable rates [3]. Hence, potential water shortages have encouraged research into alternative water resources such as urban groundwater. Often, urban Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. areas must pump groundwater as strategic resource to cover demand at specific times and This article is an open access article to prevent damage to underground structures (e.g., building basements, underground car distributed under the terms and parks, and tunnels). This observation raises the question whether urban groundwater can conditions of the Creative Commons be used as tap water, as urban aquifers may contain a vast array of pollutants [4]. Attribution (CC BY) license (https:// Pharmaceuticals, such as analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), creativecommons.org/licenses/by/ and their metabolites, have become a major concern due to their high and increasing con- 4.0/). sumption [5]. NSAIDs are used for inflammatory reduction, and as painkillers and, at

Water 2021, 13, 720. https://doi.org/10.3390/w13050720 https://www.mdpi.com/journal/water Water 2021, 13, 720 2 of 18

present, they include more than one hundred compounds [6]. NSAIDs can be delivered to urban groundwater through different pollution sources. The main contamination source is excretion via urine and feces in wastewater, containing non-metabolized or conjugated and transformed forms [7,8]. In most cases, these substances are detected in the effluents of wastewater treatment plants (WWTPs) at concentrations ranging from ng/L to µg/L, and are discharged into the aquatic environment reaching groundwater systems [9,10]. Such inefficient removal of the NSAIDs in WWTPs has encouraged research into new technologies and materials, in order to improve their removal rates [11,12]. Additional pollution sources compromise leakage from sewerage [13] and drinking water supply systems [14], as well as waters used in managed aquifer recharge techniques, such as river bank filtration, infiltration ponds, and/or injection wells [15–17]. While some of these substances seem to be naturally attenuated during the sub-surface transport, others can persist in groundwater [18,19]. The prediction of pharmaceutical concentrations in groundwater requires a sound knowledge of the concentrations of these substances in the aquifer pollution sources, the dilution factor in the aquifer, the residence times and, most importantly the biogeochemical processes that might control the fate of pharmaceuticals in the sub-surface. In groundwater, the attenuation of pharmaceuticals seems to occur mainly through microbial degradation, as adsorption is reversible and only retards the transport of these contaminants [20]. Biodegradation of some microcontaminants has been described as a redox-dependent process [19,21]; however, the redox state of groundwater has not been described in many field studies. Moreover, most research has been performed at the laboratory scale [19,22–24], thus missing the complex hydrochemical conditions that are inherent to urban aquifers. In addition, transferring laboratory experiments to field conditions can be unsuccessful due to scale dependencies [25]. For instance, laboratory experiments frequently use concentrations of pharmaceuticals that are higher than naturally occurring ones, which can result in degradation rate constants that might not be representative of field conditions. In this context, considering the raising demand of secure freshwater, understanding the fate of the NSAIDs and the factors that most influence their efficient removal in urban aquifers at field scale are of paramount importance, in order to assure the adequate protection of human health and the environment. The objectives of this work were: (i) To investigate the occurrence of the NSAIDs and their metabolites in an urban aquifer recharged by a polluted river; (ii) to quantify their removal and identify the potential geochemical processes that might control their fate in groundwater and (iii) to assess the human health risk of the NSAIDs detected in groundwater. A total of 6 NSAIDs and 2 metabolites were collected from an urban aquifer located in the metropolitan area of Barcelona (NE Spain), in which the groundwater might serves as potential resource for drinking water. Then, risk quotients (RQs) were evaluated, in order to investigate the risk posed by the single NSAIDs and their mixture to human health. The main outcome of this research is a methodology that allows for quantification of the removal of the NSAIDs, contributing to the identification of processes that these substances might undergo in the sub-surface, as well as to determine the most persistent ones.

2. Materials and Methods 2.1. Study Area The Besòs basin extends approximately 1000 km2 and is a relatively ﬂat area, occupied by the alluvial deposits of the River Besòs, ending in a small delta located NE of the city of Barcelona, Spain (Figure1). The study area corresponds to the aquifers of the lower part of the Besòs River Delta (Figure1a). The climate is Mediterranean, with an important variation in average monthly temperatures: The coldest month is January with an average temperature of 7.5 ◦C, and the warmest is July with an average temperature of 23 ◦C[26]. The average annual precipitation is about 600 mm but has a great variability throughout the year, as up to 20% of the total annual precipitation can occur in certain months. Water 2021, 13, x FOR PEER REVIEW 3 of 19

The Besòs basin extends approximately 1000 km2 and is a relatively flat area, occupied by the alluvial deposits of the River Besòs, ending in a small delta located NE of the city of Barcelona, Spain (Figure 1). The study area corresponds to the aquifers of the lower part of the Besòs River Delta (Figure 1a). The climate is Mediterranean, with an important variation in average monthly temperatures: The coldest month is January with an average temperature of 7.5 °C, and the warmest is July with an average temperature of 23 °C [26]. The average annual precipitation is about 600 mm but has a great variability throughout the year, as up to 20% of the total annual precipitation can occur in certain months. From a hydrogeological point of view, the aquifers of the Besòs River Delta are assembled within Quaternary sediments that lie discordantly upon Pliocene and Paleozoic materials. In the lower valley, there is an accumulation of alluvial sands and gravels, which constitute two superposed aquifers that are separated by an aquitard composed of silts and clays. The unconfined shallow aquifer consists of sands and the main aquifer, which is the deep confined aquifer, consists of siliceous and carbonate sands. The shallow Water 2021, 13, 720 3 of 18 aquifer is hydraulically connected to the River Besòs, which is the major pollution source (Figure 1c) [27].

Figure 1. ((aa)) Location Location of of the the Besòs Besò sRiver River Delta Delta (Barcelona, (Barcelona, NE NE Spain); Spain); (b) (spatialb) spatial distribution distribution of of groundwater samplingsampling points points in in the the Plaça Plaça de de La La Vila Vila of Santof Sant Adri Adriàà del del Bes òBesòs;s; (c) Section(c) Section A–A’ A–A’ showing the screen depth of the sampling points and the major direction of groundwater ﬂow; (d) piezometric surface at the surrounding of Plaça de la Vila; and (e) mean residence time (d) distribution from the river to the parking lot. Note that the piezometric level is in meters above sea level (m a.s.l.), the pumping wells are represented with green dots and the black line in Figure1b shows the schematic cross-section in Figure 4 (section A–A’). The Catalan Water Agency (ACA) measures the river ﬂow at the Santa Coloma gauging station.

From a hydrogeological point of view, the aquifers of the Besòs River Delta are assembled within Quaternary sediments that lie discordantly upon Pliocene and Paleozoic materials. In the lower valley, there is an accumulation of alluvial sands and gravels, which constitute two superposed aquifers that are separated by an aquitard composed of silts and clays. The unconfined shallow aquifer consists of sands and the main aquifer, which is the deep confined aquifer, consists of siliceous and carbonate sands. The shallow aquifer is hydraulically connected to the River Besòs, which is the major pollution source (Figure1c) [27]. From a hydrological point of view, the Besòs is a Mediterranean river and its flow is characterized by high variability, which is controlled by seasonal rainfall. The average streamflow measured at the Santa Coloma gauging station varies from 2 to 4 m3/s but it Water 2021, 13, 720 4 of 18

has reached 100 m3/s after heavy rain events (Figure1a). The Bes òs River controls the chemical characteristics of the unconfined shallow aquifer, due to its hydraulic connection. A previous study concluded that three river end-members are necessary to explain the chemical variability of the river: The wet end-member (W1), which is necessary to describe the intense but short rain events and two dry end-members (D1 and D2), which are used to explain the absence of rain or the low rain events that occur throughout most of the year, especially in summer [28]. In the conducted sampling campaign, the major contributor to the resident water of the shallow aquifer was the dry end-member D2, followed by W1, being on average 57.9% and 41.1%, respectively [28]. D1 represented less than 1% of the total groundwater recharge and, thus, it was not considered for further calculations in this study (see Sections 2.3 and 3.2). Figure1d shows the piezometric surface when three wells of the drainage system— which consists of four wells (ADPM, ADPQ, ADPR, and ADPW)—are pumping. This intensive pumping induced a drainage divide, where the groundwater flow around the parking is practically radial and only linear near the river (Figure1d). Groundwater flows from the river to a parking lot with short residence times (i.e., about 1 month), due to the intensive pumping in the surroundings of the parking area [27] (Figure1e). There is also a monitoring network of 16 observation points, along with the four pumping wells, that are used to monitor the piezometric head oscillations and to assess the groundwater quality. The 13 sampling points considered in this study were the four pumping wells and the piezometers of the series SAP-n (located close to the river) and ADS-n (Figure1b,c). The screen depth intervals for the observation points are 9.5–11.5 m for SAP-1, SAP-2, and SAP-3; 4.5–6.5 m for SAP-2b and SAP-4; and 3–15 m for ADS-6n and ADS-7 (Figure1c).

2.2. Sampling and Analytical Methods One river water and 13 groundwater grab samples were collected for the analysis of NSAIDs, some redox indicators, and major ions, in May 2010. Groundwater samples were purged by pumping three well volumes to remove the stagnant water and collected, wear- ing globes, after the stabilization of the field parameters (i.e., dissolved oxygen; electrical conductivity (EC); pH; and temperature), which were measured within a flow cell. Water samples for chemical analyses were collected in high-density polyethylene bottles (25 mL for anion and 50 mL for cation samples). A volume of 30 mL was collected for Total organic carbon (TOC) analysis in glass bottles which had been previously muffled. Water samples collected for the NSAID analyses were gathered in 1 L pre-cleaned amber glass bottles, as this material has been recommended to avoid adsorption and photodegradation [29]. Water samples were stored in a portable refrigerator and shipped to the laboratory at the end of the day. Finally, water samples for the analysis of the NSAIDs were vacuum filtered at the laboratory using 1 µm glass fiber filters and 0.45 µm nylon membrane filters. Afterwards, they were stored at −20 ◦C in the dark until further analysis. For the analysis of cations, samples were filtered, acidified with 1% (v/v) HNO3, and centrifuged at 3500 rpm prior to the analysis, which was performed using the Inductively Coupled Plasma Mass Spectrometry method (ICP-MS). Anions were analyzed using ion chromatography (IC). TOC was measured using the 680 ◦C combustion catalytic oxidation method using a non-dispersive infra-red detector. Ammonium was quantified through spectrophotometry, based on the indophenol blue method. The analysis of the NSAIDs was performed by on-online Solid Phase Extraction–Liquid Chromatography–Electrospray– Tandem Mass Spectrometry (SPE–LC–ESI–MS/MS), following the methodology previously described by López-Serna et al. [30,31]. Samples, which were spiked with surrogate standards, and aqueous calibration solutions were analyzed in a fully online automated manner using a Symbiosis Pico system (Spark Holland, Emmen, The Netherlands) coupled to the LC–MS/MS system. The analytical procedure consisted of two sample injections (2.5 mL each) in the negative and positive ESI modes (ESI (-) and ESI (+), respectively). In each injection, the sample was pre-concentrated onto previously conditioned polymeric HySphere Resin GP cartridges from Spark Holland (Emmen, The Netherlands). Afterwards, the Water 2021, 13, 720 5 of 18

cartridges were washed with HPLC water and the retained compounds were eluted to the LC-MS/MS system with the chromatographic mobile phase, with a gradient of acetonitrile (0.1%) in formic acid for ESI (+) and an acetonitrile:methanol (1:1, v/v)/water gradient for ESI (-). The chromatographic separation was performed using a Purospher® STAR RP-18 ec (125 × 2 mm, 5 µm) column, preceded by a pre-column of the same composition material. MS/MS detection was performed using a 4000 Q TRAPTM from Applied Biosystems-Sciex (Foster City, California, USA) and operated under selected reaction monitoring (SRM), registering the two most intense transitions. Quantiﬁcation of all the target substances was carried out from the most intense SRM transition by the internal standard calibration approach, using the most suitable isotopically labeled compound for each analyte. This method allows for determining the target substances at concentrations ranging from 0.62–3.2 ng/L (i.e., the quantiﬁcation limits) to 500 ng/L accurately.

2.3. Removal of the NSAIDs in Groundwater The removal of the NSAIDs in groundwater was calculated as follows: ! cgw−M Rabs = 1 − (1) cgw−Riv

where Rabs is the absolute removal of a given NSAID, cgw-M is the measured groundwater concentration of the NSAIDs (ng/L), and cgw-Riv is the computed groundwater concentration by the mixing of the River Besòs (ng/L). The removal efﬁciency was divided into three categories: efﬁcient (>0.8), moderate (0.3–0.8), and poor (<0.3) [32]. The expected concentrations of the NSAIDs in the end-members W1 and D2 were evaluated using the code MIX, which allows for computing the mixing ratios and the compositions of the end-members [33]. Further details on the code and the steps followed to evaluate the concentrations of the NSAIDs in the river end-members are given in S1 (Supplementary Material).

2.4. Human Health Risk Assessment The maximum concentrations of the NSAIDs in groundwater samples were used to assess the RQs for human health, in order to determine the “worst-case” scenario. The RQs were evaluated, for different age intervals, as follows: c RQ = max (2) DWEL

where cmax is the maximum concentration of a given NSAID in groundwater samples and DWEL is the corresponding age-dependent drinking water equivalent level. DWELs were computed using Equation (3) [34]:

ng ADI × BW × HQ DWEL = , (3) L DWI × AB × FOE where ADI is the Acceptable Daily Intake (µg/kg day), which were obtained from literature (Table S4); BW represents the 50th percentile values of body weight for the different life stages (kg); and DWI is the daily water ingestion rate (L/day), which is an age-speciﬁc value set by the European Food Safety Authority [35]. Values of BW and DWI for each life-stage considered are shown in Table S5. HQ is the hazard quotient, which was assumed to be 1 in this evaluation; generally, an HQ greater than 1 is likely to be toxic, whereas less than 1 is not toxic. AB is the gastrointestinal absorption, the value of which was taken to be 1, meaning that the adsorption rate was 100; while FOE is the frequency of exposure, which was assumed to be 0.96 (350 days over 365 days) [34]. Finally, the health risk posed by the mixture of detected NSAIDs in groundwater was evaluated by summing the individual RQs, as these substances were detected simultaneously in groundwater samples. The follow risk ranking criteria was applied for the Water 2021, 13, 720 6 of 18

evaluated RQs: Substances with RQ lower than 0.1 indicate no risk, substances with RQ between 0.1 and 1 indicate median risk, and substances with RQ value higher than 1 can affect human health [36].

3. Results and Discussion 3.1. Hydrochemistry in the River Groundwater-Interface 3.1.1. General Hydrochemistry and Redox Conditions

The major ion composition of the shallow aquifer was classiﬁed as Cl-SO4-Ca-Mg type, while the river water was of HCO3-Ca-Mg type (Figure S1). The average major ion concentrations in groundwater were higher than those of the river for most of the tracers (Table S6; 195.8 vs. 96.9 mg/L for chloride, 147.9 vs. 90 mg/L for sulphate, 402.4 vs. 345.1 mg/L for bicarbonate, 125.9 vs. 96.7 mg/L for calcium, 27.5 vs. 24.7 mg/L for magnesium, 157 vs. 70.8 for sodium, and 17.9 vs. 11.4 mg/L for potassium). Only nitrate presented higher concentrations in river water than in groundwater, being 15.6 mg/L and 3.3 mg/L, respectively. The redox state of groundwater has profound implications for the mobility and persistence of contaminants of emerging concern (CECs) in groundwater and, thus, it may serve as an important factor in determining the vulnerability of urban groundwater to contamination. The Besòs was in oxidizing conditions, as shown by the presence of dissolved oxygen and nitrate at concentrations of 8 mg/L and 15.6 mg/L, respectively. The electron donor (TOC) levels were 6.6 mg/L in the river. The average concentration of electron acceptors and donors in groundwater were lower than those of the river, being 1.5 mg/L for dissolved oxygen, 1.2 mg/L for nitrate (excluding the ADS-2 sampling point), and 3.1 mg/L for TOC (Table S6). This observation suggests the occurrence of redox reactions, such as aerobic respiration and denitriﬁcation, when river water mixed with the groundwater of the shallow aquifer. Consequently, the prevalent redox state of groundwater was a reducing environment, as also indicated by higher ammonium concentrations in the aquifer (average concentrations in the river and groundwater were 2 mg/L and 4.2 mg/L, respectively).

3.1.2. NSAIDs NSAIDs and their metabolites have frequently been detected in groundwater samples of the Besòs River Delta. Six compounds—namely, ketoprofen, diclofenac, mefenamic acid, propyphenazone phenazone, and the metabolite salicylic acid—were ubiquitous in the aquifer. The detection frequencies of ibuprofen and the metabolite 4OH diclofenac were 92% and 77%, respectively. Figure2 shows the box-plots of the NSAIDs and metabolites in groundwater samples. Several substances, such as diclofenac, ketoprofen, propyphenazone, and salicylic acid, were found at high mean concentrations (from 91.8 ng/L for propyphenazone to 225.2 ng/L for diclofenac). Conversely, phenazone and mefenamic acid were detected at low mean concentrations (11.1 ng/L and 24.1 ng/L, respectively). Gener- ally, the highest concentrations of most NSAIDs were detected in the shallower sampling points located near the river (SAP-2b and SAP-4); for example, diclofenac and its metabolite 4OH diclofenac exceeded concentrations of 300 ng/L and 140 ng/L, respectively, at these sampling points. The maximum concentrations were, in descending order, observed for salicylic acid (620 ng/L at ADPQ), diclofenac (380 ng/L in SAP-2b), and ibuprofen (379 ng/L at SAP-4). Moreover, there were many NSAIDs that exceeded the concentration of 100 ng/L at different sampling points (77% for diclofenac, 54% for ketoprofen, 30% for propyphenazone, and 15% for ibuprofen, 4OH diclofenac, and salicylic acid). Water 2021, 13, x FOR PEER REVIEW 7 of 19

shallower sampling points located near the river (SAP-2b and SAP-4); for example, diclofenac and its metabolite 4OH diclofenac exceeded concentrations of 300 ng/L and 140 ng/L, respectively, at these sampling points. The maximum concentrations were, in descending order, observed for salicylic acid (620 ng/L at ADPQ), diclofenac (380 ng/L in SAP-2b), and ibuprofen (379 ng/L at SAP-4). Moreover, there were many NSAIDs that exceeded the concentration of 100 ng/L at different sampling points (77% for diclofenac, Water 2021, 13, 720 54% for ketoprofen, 30% for propyphenazone, and 15% for ibuprofen, 4OH diclofenac, 7 of 18 and salicylic acid).

Figure 2. BoxplotsFigure showing2. Boxplots the showing concentration the concentration of the NSAIDs of the and NSAIDs their metabolites and their metabolites (ng/L) in groundwater (ng/L) in (GW, n = 13), including thegroundwater non-detected (GW, values. n = 13), The includin dots representg the non-detected the outliers andvalues. the The black dots crosses represent indicate the theoutliers mean. and There is one outlier not displayed,the black forcrosses SA (620 indicate ng/L). the Metabolites mean. There are is highlightedone outlier not in bold. displayed, DCF, diclofenac;for SA (620 4OH ng/L). DCF, Metabo- 4OH diclofenac; IBU, ibuprofen;lites KET, are highlighted ketoprofen; in MEF, bold. mefenamic DCF, diclofenac; acid; PPZ, 4OH propyphenazone; DCF, 4OH diclofenac; PZ, phenazone; IBU, ibuprofen; SA, salicylic KET, acid. ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid. Concerning the presence of the NSAIDs in the River Besòs, all substances were Concerningdetected, the presence except 4OHof the diclofenac NSAIDs (Tablein the1 River (a)). These Besòs, substances all substances were were found de- in a wide range tected, exceptof 4OH concentrations, diclofenac (Table ranging 1 (a)). from These 9.3 ng/L substances for ketoprofen were found to 293 in ng/L a wide for range ibuprofen. Salicylic of concentrations,acid andranging diclofenac from 9.3 were ng/L detected for ketoprofen at concentrations to 293 ng/L near for to 110 ibuprofen. ng/L, while Sali- the remaining cylic acid andcompounds diclofenac were were detected detected at at co concentrationsncentrations near below to 30110 ng/L. ng/L, When while comparingthe re- the mean maining compoundsconcentrations were detected in groundwater at concen samplestrations withbelow those 30 ng/L. in the When river comparing water, mefenamic acid, the mean concentrationsphenazone, and in salicylicgroundwater acid presented samples similarwith those concentrations in the river in both water, aqueous matrices, mefenamic acid,while phenazone, diclofenac, and 4OH salicylic diclofenac, acid presented ketoprofen, similar and concentrations propyphenazone in both presented higher aqueous matrices,concentrations while diclofenac, in groundwater. 4OH di Inclofenac, contrast, ketoprofen, the mean concentration and propyphenazone of ibuprofen was higher presented higherin the concentrations river water than in groundwate in groundwater.r. In Suchcontrast, distinct the behaviormean concentration of the NSAIDs of suggests that ibuprofen wasthey higher may in be the affected river water by different than in processes, groundwater. such asSuch redox distinct and sorptionbehavior processes, of when the NSAIDs suggestsriver water that inﬁltrates they may thebe affected aquifer. by Nevertheless, different processes, the concentrations such as redox reported and in the river sorption processes,water mightwhen river not be water representative, infiltrates the due aquifer. to the irregular Nevertheless, ﬂow pattern the concentra- of the Besòs River. tions reported in the river water might not be representative, due to the irregular flow Table 1. (a) Measured and computed concentrations of the NSAIDs (ng/L) in the River Besòs and (b) computed concentra- pattern of the Besòs River. tions in the end-members W1 and D2. Metabolites are highlighted in bold. DCF, diclofenac; 4OH DCF, 4OH diclofenac; IBU, ibuprofen; KET,Table ketoprofen; 1. (a) Measured MEF, mefenamic and computed acid; concentrations PPZ, propyphenazone; of the NSAIDs PZ, phenazone; (ng/L) in the SA, River salicylic Besòs acid. and (b) computed concentrations in the end-members W1 and D2. Metabolites are highlighted in bold. Concentration of the NSAIDs (ng/L) (a) Besòs RiverDCF, diclofenac; 4OH DCF, 4OH diclofenac; IBU, ibuprofen; KET, ketoprofen; MEF, mefenamic acid; PPZ,KET propyphenazone; IBF PZ, phenazone; DCF SA, salicylic 4OH DCF acid. MEF SA PPZ PP Measured 9.3 293 113 0 9.5 110 28 15.7 Concentration of the NSAIDs (ng/L) Computed(a) Besòs 60.8 River 83.6 254.0 91.0 9.1 65.2 29.0 11.4 KET IBF DCF 4OH DCF MEF SA PPZ PP Concentration of the NSAIDs (ng/L) (b) Besòs River KET IBF DCF 4OH DCF MEF SA PPZ PP End-member W1 41.9 72.6 197.8 74.4 8.1 53.7 14.4 4.6 End-member D2 133.3 125.8 469.4 154.5 13.0 109.4 84.8 37.4 WaterWaterWaterWater 2021 20212021 2021, ,13, 1313, ,13 ,x, xx ,FOR FORxFOR FOR PEER PEERPEER PEER REVIEW REVIEWREVIEW REVIEW 88 8 of 8ofof of 19 1919 19

WaterWaterWater 2021 2021 2021, ,,13 ,13 13, ,,x ,xx xFOR FORFOR FOR PEER PEERPEER PEER REVIEW REVIEWREVIEW REVIEW 88 8 of ofof 19 1919

MeasuredMeasuredMeasuredMeasured 9.39.39.39.3 293293293293 113113113113 000 0 9.59.59.59.5 110110110110 28282828 15.715.715.715.7 ComputedComputedComputedComputed 60.860.860.860.8 83.683.683.683.6 254.0254.0254.0254.0 91.091.091.091.0 9.19.19.19.1 65.265.265.265.2 29.029.029.029.0 11.411.411.411.4 MeasuredMeasuredMeasured 9.39.39.3 293293293 113113113 00 0 9.59.59.5 110110110 282828 15.715.715.7 Measured 9.3 293Concentration ConcentrationConcentrationConcentration113 of ofof0 ofthe thethe the NSAIDs NSAIDsNSAIDs NSAIDs9.5 (ng/L) (ng/L)(ng/L)110 (ng/L) 28 15.7 (b)(b)(b)(b) ComputedBesòs Computed BesòsComputedBesòs Besòs River RiverRiver River 60.860.860.8 83.683.683.6 254.0254.0254.0 91.091.091.0 9.19.19.1 65.265.265.2 29.029.029.0 11.411.411.4 KETKETKETKET IBFIBFIBFIBF DCFDCFDCFDCF 4OH4OH4OH4OH DCF DCFDCF DCF MEFMEFMEFMEF SASASASA PPZPPZPPZPPZ PPPPPPPP ConcentrationConcentrationConcentration ofof of thethe the NSAIDsNSAIDs NSAIDs (ng/L)(ng/L) (ng/L) End-memberEnd-memberEnd-member(b)(b)End-member(b) BesòsBesòs Besòs RiverRiver River W1 W1W1 W1 41.941.941.941.9 72.672.672.672.6 197.8197.8197.8197.8 74.474.474.474.4 8.18.18.18.1 53.753.753.753.7 14.414.414.414.4 4.64.64.64.6 KETKETKET IBFIBFIBF DCFDCFDCF 4OH4OH4OH DCFDCF DCF MEFMEFMEF SASASA PPZPPZPPZ PPPPPP End-memberEnd-memberEnd-memberEnd-member D2 D2D2 D2 133.3133.3133.3KET133.3 125.8125.8125.8125.8IBF 469.4469.4469.4DCF469.4 4OH154.5154.5154.5154.5 DCF 13.013.0MEF13.013.0 109.4109.4109.4109.4SA 84.884.884.8PPZ84.8 37.437.437.4PP37.4 End-memberEnd-memberEnd-member W1W1 W1 41.941.941.9 72.672.672.6 197.8197.8197.8 74.474.474.4 8.18.18.1 53.753.753.7 14.414.414.4 4.64.64.6 Water 2021, 13, 720 End-member W1 41.9 72.6 197.8 74.4 8.1 53.7 14.4 8 of4.6 18 3.2.3.2.3.2.3.2. End-memberFate End-member FateEnd-memberFate Fate of ofof ofthe thethe the NSAIDs NSAIDsNSAIDs NSAIDs D2D2 D2 in inin 133.3inGroundwater 133.3 Groundwater133.3Groundwater Groundwater 125.8125.8125.8 469.4469.4469.4 154.5154.5154.5 13.013.013.0 109.4109.4109.4 84.884.884.8 37.437.437.4 3.2.1.3.2.1.3.2.1.3.2.1. Physicochemical PhysicochemicalPhysicochemical Physicochemical Properties PropertiesProperties Properties 3.2.3.2.3.2. FateFate Fate ofof of thethe the NSAIDsNSAIDs NSAIDs inin in GroundwaterGroundwater Groundwater 3.2. FateTheTheTheThe of physicochemical physicochemicalphysicochemical the physicochemical NSAIDs in Groundwater properties propertiesproperties properties of ofof of the thethe the ta tata rgettargetrgetrget NSAIDs NSAIDsNSAIDs NSAIDs are areare are summarized summarizedsummarized summarized in inin in Table TableTable Table 2. 2.2. 2. 3.2.1.3.2.1.3.2.1. PhysicochemicalPhysicochemical Physicochemical PropertiesProperties Properties 3.2.1.TheseTheseTheseThese Physicochemical properties propertiesproperties properties are areare are used used Propertiesused used for forfor for scoring scoringscoring scoring the thethe the mo momo mobilitybilitybilitybility of ofof of these thesethese these substa substasubsta substancesncesncesnces in inin in groundwater groundwatergroundwater groundwater TheTheThe physicochemical physicochemicalphysicochemical properties propertiesproperties of ofof the thethe ta tatargetrgetrget NSAIDs NSAIDsNSAIDs are areare summarized summarizedsummarized in inin Table TableTable 2. 2.2. [37].[37].[37].[37]. For ForForThe For instance, instance,instance, physicochemicalinstance, the thethe the octanol–water octanol–wateroctanol–water octanol–water properties partition partitionpartition partitionof the ta coefficient coefficientcoefficient rgetcoefficient NSAIDs (expressed (expressed(expressed (expressed are summarized as asas as log loglog log K KKow owKow)ow) ) isin is)is is used usedTableused used to to to 2. to TheseTheseTheseThe properties propertiesproperties physicochemical are areare used usedused properties for forfor scoring scoringscoring of the the thethe mo mo targetmobilitybilitybility NSAIDs of ofof these thesethese are substa substasubsta summarizedncesncesnces in inin groundwater groundwatergroundwater in Table2. predictpredictpredictThesepredict theproperties thethe the hydrophobicity hydrophobicityhydrophobicity hydrophobicity are used of offorof of the the the scoringthe micropollu micropollumicropollu micropollu the motants.tants.tants.bilitytants. In InIn of In general, general,general, thesegeneral, substa substances substancessubstances substancesnces in with withwith withgroundwater a aa log aloglog log K KK owowKow ow These properties are used for scoring the mobility of these substances in groundwater [37]. (i.e.,(i.e.,[37].(i.e.,[37].[37].(i.e., less less lessForFor Forless than than instance,thaninstance, instance,than 1) 1)1) 1)are areare are the thehighly the highlyhighly highly octanol–wateroctanol–water octanol–water hydrophilic hydrophilichydrophilic hydrophilic partitionpartition partition and andand and are areare are coefficientlikelycoefficient likelycoefficientlikely likely to toto tobe bebe (expressedbe(expressed mobile, (expressed mobile,mobile, mobile, while whilewhile while asas as loglog logsubstances substancessubstances substances KK Kowowow)) ) isis is usedused used with withwith with toto to For instance, the octanol–water partition coefﬁcient (expressed as log K ) is used to predictpredictpredict the thethe hydrophobicity hydrophobicityhydrophobicity of ofof the thethe micropollu micropollumicropollutants.tants.tants. In InIn general, general,general, substances substancessubstancesow with withwith a a a log loglog K KKowowow apredict alog log K owowKow theow above above hydrophobicity 4 4are are classified classified of the as as micropollulow-mobility low-mobilitytants. substances. substances. In general, Intermediate Intermediate substances logwith log K ow owKowa ow logvalues values Kow predictaa loglog KK theaboveabove hydrophobicity 44 areare classifiedclassified of the asas micropollutants. low-mobilitylow-mobility substances.substances. In general, IntermediateIntermediate substances with loglog K aK logvaluesvaluesK (i.e.,(i.e.,(i.e., lessless less thanthan than 1)1) 1) areare are highlyhighly highly hydrophilichydrophilic hydrophilic andand and areare are likelylikely likely toto to bebe be mobile,mobile, mobile, whilewhile while substancessubstances substances withwith withow ((i.e.,i.e.,(i.e.,(i.e.,(i.e., less 1 11 to 1toto thanto 4) 4)4) 4) are areare 1are) ranked arerankedranked ranked highly as asas as medium hydrophilicmediummedium medium mobility mobilitymobility mobility and are substances substancessubstances substances likely to be [37]. [37].[37]. [37]. mobile, However, However,However, However, while log log substanceslog log K KK owowKow ow may maymay may with only onlyonly only representrepresentarepresenta arepresent log loglog K KKowowow abovethe abovethe theabove the hydrophobicity hydrophobicityhydrophobicity hydrophobicity 4 4 4 are areare classified classifiedclassified of ofof ofas asneutral neutralasneutral neutrallow-mobility low-mobilitylow-mobility substances substancessubstances substances substances. substances.substances. but butbut but most mostmost most Intermediate Intermediate Intermediateof ofof of the thethe the target targettarget target log log NSAIDs logNSAIDsNSAIDs NSAIDs K KKowowow values values values are areare are a log Kow above 4 are classiﬁed as low-mobility substances. Intermediate log Kow values (i.e.,(i.e.,(i.e., 11 1 to toto 4) 4)4) areare are ranked rankedranked as asas mediummedium medium mobility mobilitymobility substancessubstances substances [37]. [37].[37]. However, However,However, log loglog KK Kowowow may maymay only onlyonly (i.e.,ionizableionizableionizableionizable 1 to 4) substances substancessubstances aresubstances ranked and, and,and, asand, medium thus, thus,thus, thus, the thethe the mobility log loglog log D DD owDowow,ow , substances, which which,which which is isis is the thethe [the37 pH-dependent pH-dependentpH-dependent]. pH-dependent However, log n-octanol–water n-octanol–watern-octanol–water Kn-octanol–watermay only representrepresentrepresent the thethe hydrophobicity hydrophobicityhydrophobicity of ofof neutral neutralneutral substances substancessubstances but butbut most mostmost of ofof the thethe target targettargetow NSAIDs NSAIDsNSAIDs are areare representdistribution,distribution,distribution,distribution, the is is hydrophobicityis is more moremore more appropriate appropriateappropriate appropriate of neutral for forfor for ascertaining ascertainingascertaining ascertaining substances the thethe the but mobility mobilitymobility mobility most of of ofof theof the thethe the target ionized ionizedionized ionized NSAIDs substances substancessubstances substances are ionizableionizableionizable substancessubstances substances and, and,and, thus, thus,thus, the thethe loglog log D DDowowow,, ,which whichwhich is isis thethe the pH-dependent pH-dependentpH-dependent n-octanol–water n-octanol–watern-octanol–water ionizableininin ingroundwater groundwatergroundwater groundwater substances [38]. [38].[38]. [38]. and, thus, the log D , which is the pH-dependent n-octanol–water distribution,distribution,distribution, is isis more moremore appropriate appropriateappropriate for forfor ascertaining ascertainingascertainingow the thethe mobility mobilitymobility of ofof the thethe ionized ionizedionized substances substancessubstances distribution, is more appropriate for ascertaining the mobility of the ionized substances in ininin groundwatergroundwater groundwaterccc c[38].[38]. [38]. groundwaterTableTableTableTable 2. 2.2. Physico 2. PhysicoPhysico Physico [38hemical].hemicalhemicalhemical properties propertiesproperties properties of ofof ofthe thethe the target targettarget target NSAIDs NSAIDsNSAIDs NSAIDs. ..These TheseThese. These properties propertiesproperties properties are areare are from fromfrom from ChemAxon ChemAxonChemAxon ChemAxon (©(©(©(© 1998 19981998 1998–––2021,2021,2021,–2021, Budapest, Budapest,Budapest, Budapest, Hungary). Hungary).Hungary). Hungary). Note NoteNote Note that thatthat that log loglog log D DDow Dowow is ow isis evaluated is evaluatedevaluated evaluated at atat atpH pHpH pH = == 7.3. 7.3.=7.3. 7.3. pK pKpK pKa,aa ,,acid aacidacid, acid dissociation dissociationdissociation dissociation constant;constant;Tableconstant;TableTableconstant; 2.2. 2. Physico(a), Physico(a), (a),Physico (a), Strongest StrongestStrongest Strongestcchemicalchemicalhemical acidic acidicacidic acidic propertiesproperties properties pK pKpK pKa;aa ;;(b), a(b),(b),; (b), ofStrongest of StrongestofStrongest theStrongestthe the targettarget target basic basicbasic NSAIDsbasicNSAIDs NSAIDs pK pKpK pKa.aa ..Metabolites aMetabolites.Metabolites. . These .TheseMetabolitesThese These properties propertiesproperties properties are areare are highlighted highlightedhighlighted highlighted are are are fromfrom from ChemAxonin ChemAxonin inChemAxon inbold. bold.bold. bold. Table 2. Physicochemical properties of the target NSAIDs. These properties are from ChemAxon (© (©(©(© 19981998 1998––2021,–2021,2021, Budapest, Budapest, Budapest, Hungary). Hungary). Hungary). NoteNote Note thatthat that loglog log DD Dowowow is isis is evaluated evaluatedevaluated evaluated at atat at pH pHpH pH = == = 7.3. 7.3.7.3. 7.3. pKpK pKaa,, ,a acid ,acidacid acid dissociation dissociationdissociation dissociation 1998–2021, Budapest, Hungary). Note that log Dow is evaluated at pH = 7.3. pKa, acid dissociation constant;constant;constant;NSAIDsNSAIDsNSAIDsNSAIDs (a),(a), (a), Strongest Strongest StrongestDiclofenacDiclofenacDiclofenacDiclofenac acidicacidic acidic pKpK pK a a; ; ;a (b), ; (b),(b), (b), Strongest Strongest4OHStrongest 4OHStrongest4OH4OH Diclofenac DiclofenacDiclofenac Diclofenac basic basicbasic basic pK pK pKaa. . .a Metabolites .MetabolitesMetabolites Metabolites IbuprofenIbuprofenIbuprofenIbuprofen are areare are highlighted highlightedhighlighted highlightedKetoprofenKetoprofenKetoprofenKetoprofen in inin in bold. bold.bold. bold. constant;MolecularMolecularMolecularMolecular (a), Strongest acidic pKa; (b), Strongest basic pKa. Metabolites are highlighted in bold. NSAIDsNSAIDsNSAIDs CCC14CDiclofenac1414DiclofenacHDiclofenacH14H11H1111ClCl11ClCl22NO2NONO2NO 2 2 2 2 4OH4OHC4OHCC14C1414HH14H Diclofenac11HDiclofenac 1111DiclofenacClCl11ClCl22NO2NONO2NO33 3 3 CIbuprofenIbuprofenCCIbuprofen13C1313HH13H18H1818OO18O2O2 2 2 KetoprofenKetoprofenCKetoprofenCC16C1616HH16H14H1414OO14O3O3 3 3 formulaformulaformulaNSAIDsformula Diclofenac 4OH Diclofenac Ibuprofen Ketoprofen MolecularMolecularMolecularNSAIDs Diclofenac 4OH Diclofenac Ibuprofen Ketoprofen Molecular formulaCCC14 C1414HHHH111111ClClClCl22NONO2NO22 2 CCCC141414HHH111111ClClCl2NO2NONO2NO33 3 CCCC131313HHH1818O18OOO22 2 CCC161616HHHH141414OOO33 3 ChemicalChemicalChemicalformulaformulaChemicalformula 14 11 2 2 14 11 2 3 13 18 2 16 14 3 structurestructurestructurestructure and andand and ChemicalChemicalChemical Chemicalmolecularmolecularmolecularmolecular structure structurestructurestructure andand and weightweightweightweightand molecular (g/mol) (g/mol)(g/mol) (g/mol) 296.15296.15296.15296.15 weightmolecularmolecularmolecular (g/mol) 312.15312.15312.15312.15 206.29206.29206.29206.29 254.28254.28254.28254.28

weightweightweight (g/mol)(g/mol) (g/mol) CASCASCASCAS 15307-86-515307-86-515307-86-515307-86-5296.15296.15296.15296.15 64118-84-964118-84-964118-84-964118-84-9 15687-27-115687-27-115687-27-115687-27-1 22071-15-422071-15-422071-15-422071-15-4 312.15312.15312.15 206.29206.29206.29 254.28254.28254.28254.28 SSS (mg/L) S (mg/L)(mg/L) (mg/L) 15151515 42424242 206.2959595959 254.2836363636 CASCASCASCAS 15307-86-515307-86-515307-86-5 15307-86-5 64118-84-964118-84-9 64118-84-9 15687-27-115687-27-1 15687-27-1 22071-15-422071-15-422071-15-4 LogLogLogLog K KKow owKow ow 4.264.264.264.26 3.963.963.963.96 3.843.843.843.84 3.613.613.613.61 SSSS (mg/L)(mg/L) (mg/L) 151515 15 424242 595959 36 3636 pppKaSKapKa (mg/L)Ka (a,b) (a,b)(a,b) (a,b) 444 (a) 4(a)15(a) (a) 3.763.763.763.76 (a), (a),(a), (a), 428.61 8.618.61 8.61 (a) (a)(a) (a) 4.854.854.854.8559 (a) (a)(a) (a) 3.883.883.883.8836 (a) (a)(a) (a) LogLogLogLog KK owKowowow 4.264.264.264.26 3.963.963.96 3.84 3.843.843.84 3.613.61 3.61 LogLogLogLog D DD owDowow (pHow (pH (pH (pH = == = pppKaKaKa (a,b)(a,b)(a,b) (a,b) 1.1641.161.164 41.16 (a)4(a) (a) 3.763.76 3.76 (a),(a), 0.7(a),0.70.7 0.78.61 8.618.61 8.61 (a) (a)(a) (a) 4.85 4.851.434.851.431.431.43 (a)(a) (a) (a) 3.883.88 3.880.443.880.440.440.44 (a) (a) (a) pKa7.3)7.3)7.3)7.3) (a,b) 4 (a) 3.76 (a), 8.61 (a) 4.85 (a) 3.88 (a) LogLogLogLogD DowD Dowow(pHow (pH (pH (pH = 7.3) == = 1.16 0.7 1.43 0.44 NSAIDsNSAIDsNSAIDsNSAIDs MefenamicMefenamicMefenamicMefenamic1.161.161.16 acid acidacid acid PropyphenazonePropyphenazonePropyphenazonePropyphenazone0.70.70.7 PhenazonePhenazonePhenazonePhenazone1.431.431.43 SalicylicSalicylicSalicylicSalicylic0.440.440.44 acid acid acid acid 7.3)7.3)7.3) MolecularMolecularMolecularMolecularNSAIDs7.3) Mefenamic acid Propyphenazone Phenazone Salicylic acid NSAIDsNSAIDsNSAIDs MefenamicMefenamicMefenamicCCC15C1515HH15H15H1515NONO15NONO acid2acid2 2acid 2 PropyphenazonePropyphenazonePropyphenazoneCCC14C1414HH14H18H1818NN18N2N2O2OO2 O CPhenazoneCCPhenazone11PhenazoneC1111HH11H12H1212NN12N2N2O2OO2 O SalicylicSalicylicSalicylicCCC7C7H7HH76H6O6OO6 3 acidO3 acid3 acid 3 MolecularformulaformulaformulaNSAIDsformula formula Mefenamic C15H15NO acid2 PropyphenazoneC14H18N2OC Phenazone11H12N2OC Salicylic7H6O 3acid MolecularMolecularMolecular CCC151515HHH151515NONONO22 2 CCC141414HHH181818NNN22OO2O CCC111111HHH121212NNN22OO2O CCC77HH7H66OO6O33 3 ChemicalChemicalChemicalformulaformulaChemicalformula structureChemicalstructurestructurestructure structure and andand and andChemicalChemicalChemical molecular weightmolecularmolecularmolecularmolecular (g/mol) structurestructurestructure andand and weightweightweightstructureweight (g/mol) (g/mol)(g/mol) (g/mol) and 188.23188.23188.23188.23188.23 molecularmolecularmolecular 241.29241.29241.29241.29241.29 230.31230.31230.31230.31 138.12138.12138.12138.12138.12 weightweightweightCASCASCASCASCAS (g/mol)(g/mol) (g/mol) 61-68-761-68-761-68-761-68-7 61-68-7 479-92-5479-92-5479-92-5 479-92-5 60-80-060-80-060-80-0188.23 60-80-0188.2360-80-0188.23 69-72-769-72-769-72-7 69-72-769-72-7 241.29241.29241.29 230.31230.31230.31 138.12138.12138.12 SSS S(mg/L) S (mg/L)(mg/L)(mg/L) (mg/L) 21212121 403403 403403 49114911 49114911 11,73411,73411,734 11,73411,734 CASCASCAS 61-68-761-68-761-68-7 479-92-5479-92-5479-92-5 60-80-060-80-060-80-0 69-72-769-72-769-72-7 LogLogLogLogLog K KKow owowKow ow 5.45.45.45.4 2.352.35 2.352.35 1.221.221.22 1.22 1.981.981.98 1.981.98 SSS (mg/L)(mg/L) (mg/L) 212121 403403403 491149114911 11,73411,73411,734 pKa (a,b) 3.89 (a) 0.87 (b) 0.49 (b) 2.79 (a), 13.23 (a) LogLogLog KK Kowowow 5.45.45.4 2.352.352.35 1.221.221.22 1.981.981.98 Log Dow (pH = 7.3) 2.23 2.35 1.22 −1.51

The NSAIDs propyphenazone and phenazone are neutral substances at the average pH of 7.3 of the shallow aquifer of the Besòs River Delta; further, their log Kow and log Dow values are equivalent (Table2 ). These two NSAIDs are therefore moderate mobility substances. The remaining NSAIDs are negatively charged substances at pH 7.3 and, consequently, different values of log Kow were observed, with respect to log Dow (Table2 ). Diclofenac, ibuprofen, and mefenamic acid can be classiﬁed as moderate mobility substances (log Dow ranging from 1.16 to 2.23), whereas 4OH dicofenac, ketoprofen, and sal- Water 2021, 13, 720 9 of 18

icylic acid presented high mobility, as their log Dow values were lower than 1. Concerning the solubility in water (S) values (Table2), the NSAIDs were considered to have medium to high solubility. The NSAIDS with high solubility were propyphenazone (403 mg/L), phenazone (4911 mg/L), and salicylic acid (11,734 mg/L). In summary, NSAIDs are substances with moderate to high mobility based on their physicochemical properties (Table2); however, the local environmental conditions ( i.e., redox conditions of the aquifer, potential aquifer pollution sources and groundwater residence time, among others) must also be considered, in order to gain reliable insight into the fate of these substances in groundwater.

3.2.2. Concentration of the NSAIDs in the Recharge Sources The main contamination source of the shallow aquifer is the River Besòs, which represents 91% of the total resident water [39]. However, the sample of the River Besòs may not has been representative, as it was collected after a rainy period and, so, it is expected that the dilution capacity of the river was increased, reducing the concentrations of the NSAIDs in the collected sample (Table1 (a)). Water quality changes in the river water clearly inﬂuence the groundwater quality [27] and, therefore, it was required to assess the compositions of the River Besòs end-members (W1 and D2) using Mix Code [33](Table S1), because there was a lack of previous data concerning these substances in the River Besòs. Nonetheless, the River Besòs has some similarities with the River Llobregat, which is located in SW Barcelona, with its mouth about 15 km from the study area. Both rivers have been impacted by anthropogenic pressure (i.e., discharges coming from WWTPs) and are characterized as having irregular ﬂow regimes controlled by rainfall events. Hence, the NSAIDs concentrations might be similar in both rivers; furthermore, some previous studies reported the presence of the NSAIDs in the Llobregat (Table S3). The evaluated concentrations of the NSAIDs in the River Besòs end-members are summarized in Table1 (b). The concentrations in W1 were always lower than those in D2 for all of the substances. There were some substances, such as diclofenac and its metabolite 4OH diclofenac, ibuprofen, ketoprofen, and salicylic acid, that exceeded the threshold of 100 ng/L in the river end-member D2. The highest concentrations corresponded to diclofenac and its metabolite, which were 469.4 ng/L and 154.5 ng/L, respectively. The D2 concentrations of mefenamic acid and phenazone were low (13 ng/L and 37.4 ng/L, respectively), compared to the other NSAIDs. Concerning the NSAID concentrations in the river end-member W1, only diclofenac presented a concentration close to 200 ng/L and 4OH diclofenac and ibuprofen exceeded the threshold of 70 ng/L. The remaining compounds presented concentrations for this end-member that were below 55 ng/L (Table1 (b)). The evaluated concentrations of the River Besòs end-members were on the same order of magnitude as those reported in the lower part of the Llobregat River Basin (Table S3). Overall, mean concentrations of the NSAIDs did not exceed 100 ng/L, but some substances were detected at high concentrations; for example, ibuprofen and diclofenac were detected at maximum concentrations of 502.9 ng/L and 442.6 ng/L, respectively, in the River Llobregat [40]. Similarly, López-Serna et al. [41] have reported a wide range of NSAID concentrations in the lower section of the River Llobregat, salicylic acid being the one detected at a maximum concentration of 676 ng/L, while ketoprofen and mefenamic acid were found at concentrations close to 10 ng/L (Table S3).

were detected at maximum concentrations of 502.9 ng/L and 442.6 ng/L, respectively, in the River Llobregat [40]. Similarly, López-Serna et al. [41] have reported a wide range of NSAID concentrations in the lower section of the River Llobregat, salicylic acid being the one detected at a maximum concentration of 676 ng/L, while ketoprofen and mefenamic acid were found at concentrations close to 10 ng/L (Table S3).

3.2.3. Removal of the NSAIDs in the Aquifer The presented methodology allows for evaluating the percentage of the target NSAIDs that could be naturally removed in the river–groundwater interface. First of all, it was necessary to evaluate the concentrations of the NSAIDs in the river water and groundwater using mixing ratios. The shallow aquifer is mainly recharged by the river, in which the flow rate and hydrochemistry vary greatly over time. Thus, the integration Water 2021, 13, 720 of the River Besòs end-members W1 and D2 was necessary to explain the composition10 of of 18 NSAIDs in the aquifer (Table 1 (b)). The major contributor to the groundwater recharge was the D2 end-member, representing 59% of the total recharge on average; however, W1 alsoend-member, had an important representing contribution 59% of the to total the resident recharge water on average; of the however,aquifer, comprising W1 also had the an remainingimportant 41%. contribution Finally, tothe the computed resident waterconcentrations of the aquifer, were comprisingcompared with the remaining the measured 41%. concentrationsFinally, the computed in groundwater concentrations samples were using compared the term with Rabs the (Figure measured 3). Most concentrations of the target in NSAIDs presented Rabs values above 0 (Figure 3), meaning that the measured concentra- groundwater samples using the term Rabs (Figure3). Most of the target NSAIDs presented tions were lower than those computed in groundwater by river water mixing. Some Rabs values above 0 (Figure3 ), meaning that the measured concentrations were lower than NSAIDsthose computed were easily in groundwater and moderately by riverremoved water when mixing. river Some water NSAIDs infiltrated were the easily aquifer; and namely,moderately 4OH removed diclofenac, when ibuprofen, river water and inﬁltratedsalicylic acid, the aquifer;with median namely, Rabs 4OH values diclofenac, of 0.80, 0.74, and 0.35, respectively. This observation might indicate that the reducing conditions ibuprofen, and salicylic acid, with median Rabs values of 0.80, 0.74, and 0.35, respectively. ofThis the observationgroundwater might might indicate favor the that natural the reducing attenuation, conditions to some of extent, the groundwater of these NSAIDs might infavor the theaquifer. natural Median attenuation, removals to for some diclofenac, extent, of mefenamic these NSAIDs acid, in and the phenazone aquifer. Median were poorremovals (Rabs < for 0.3; diclofenac, Figure 3). mefenamic However, the acid, median and phenazone Rabs values were were poor negative (Rabs

Figure 3. Boxplots showing the removal (Rabs, Equation (1)) of the NSAIDs and their metabolites Figurein groundwater 3. Boxplots (GW, showing n = 13). the Theremoval dots represent(Rabs, Eq. (1)) the of outliers; the NSAIDs there and are twotheir outliers metabolites which in are not groundwaterdisplayed for (GW, SA (− n6.04) = 13). and The IBF dots (−3.01). represent DCF, the diclofenac; outliers; 4OH there DCF, are 4OHtwo outliers diclofenac; which IBU, are ibuprofen; not KET, ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid.

One of the most important results of this research was the removal quantiﬁcation of

the NSAIDs at each groundwater sampling point (Table S7). As an example, Figure4 shows the spatial distribution of the Rabs values for three NSAIDs with high (4OH diclofenac), moderate (salicylic acid), and low (mefenamic acid) median removals. The extent of the removal differed in the groundwater sampling points and the following observations can be made: • The shallow sampling points located close to the river (SAP-2b and SAP-4; Figure4) presented negative Rabs values for almost all of the target NSAIDs (except for salicylic acid in SAP-4; Figure4 and Table S7). Plausible reasons for the negative Rabs values are that: (i) The concentrations of the NSAIDs in the shallow sampling points were usually higher than those of the River Besòs; and (ii) the estimated river end-member concentrations for the NSAIDs were low, as the river sample was collected during rain events and, thus, the dilution capacity of the river was increased. Water 2021, 13, 720 11 of 18

• The deep sampling points located close to the river (SAP-1, SAP-2 and SAP-3) displayed the highest Rabs values for ibuprofen, diclofenac and 4OH diclofenac, and salicylic acid. Salicylic acid presented Rabs values ranging from 0.43 to 0.52, whereas the other three substances had Rabs values above 0.90 at these sampling points (Figure4 and Table S7). The Rabs values for these NSAIDs were somewhat low in the sampling points located in the surroundings of the parking area (Figure4 and Table S7). • Rabs values for ketoprofen, propyphenazone, and phenazone were negative at many groundwater sampling points (Table S7). This observation suggests that the computed

Water 2021, 13, x FOR PEER REVIEW concentrations for these substances by river water mixing were underestimated,12 of 19 likely as some rain events occurred during the sampling campaign.

Figure 4. Spatial distribution of Rabs (Equation (1)) for three selected NSAIDs with (a) high (4OH Figure 4. Spatial distribution of Rabs (Equation (1)) for three selected NSAIDs with (a) high (4OH di- diclofenac), (b) moderate (salicylic acid), and (c) poor (mefenamic acid) Rabs. The removal concen- trationclofenac), (ng/L) (b of) moderatethese NSAIDs (salicylic is also shown acid), (in and red). (c) poor (mefenamic acid) Rabs. The removal concentration (ng/L) of these NSAIDs is also shown (in red). The potential natural removal of the NSAIDs was further explored by comparing the concentrations at SAP-2b and ADPW, as the flow regime between these two points was linear (Figure 1b,d). To this purpose, firstly, the mean degradation velocity for the NSAIDs was calculated using the decreases in concentrations between ADPW and SAP-2b and the mean residence time distribution shown in Figure 1e. Note that SAP-2b

Water 2021, 13, 720 12 of 18

The potential natural removal of the NSAIDs was further explored by comparing the concentrations at SAP-2b and ADPW, as the flow regime between these two points was Water 2021, 13, x FOR PEER REVIEW 13 of 19 linear (Figure1b,d). To this purpose, firstly, the mean degradation velocity for the NSAIDs was calculated using the decreases in concentrations between ADPW and SAP-2b and the mean residence time distribution shown in Figure1e. Note that SAP-2b was selected as it was selected as it had the highest concentration for the target NSAIDs (except for had the highest concentration for the target NSAIDs (except for propyphenazone). The propyphenazone). The mean residence time distribution was obtained from a steady-statemean residence groundwater time distribution numerical wasmodel obtained [42]. Afterwards, from a steady-state the computed groundwater mean deg- numerical radationmodel [velocity42]. Afterwards, was used to the calculate computed the Rabs mean distribution degradation along the velocity linear wasgroundwater used to calculate flowthe pathRabs distributionbetween the river along and the thelinear parking groundwater area. As an example, flow path Figure between 5 shows the the river Rabs and the forparking 4OH diclofenac, area. As andiclofenac, example, and Figure phenazone5 shows from the theRabs riverfor to 4OH the parking diclofenac, area. diclofenac, Note and that,phenazone in the absence from theof representative river to the parkingriver concentrations, area. Note that,a Rabs inof the0 was absence assumed of in representative the riverriver (Figure concentrations, 5). a Rabs of 0 was assumed in the river (Figure5).

Figure 5. Graphical distribution of the Rabs values for (a) 4OH diclofenac, (b) diclofenac and (c) phenazone from the river Figure 5. Graphical distribution of the Rabs values for (a) 4OH diclofenac, (b) diclofenac and (c) to the parking area. Rabs was evaluated using the mean degradation velocity using the decrease in the concentrations phenazone from the river to the parking area. R was evaluated using the mean degradation between ADPW and SAP-2b and the mean residence time distribution shown in Figureabs 1e. Note that, in the absence of representative river concentrations,velocity it usingwas assumed the decrease that R inabs = the 0 in concentrations the river. between ADPW and SAP-2b and the mean residence time distribution shown in Figure1e. Note that, in the absence of representative river concentrations,

it wasAll assumed of the NSAIDs that Rabs were= 0 removed, in the river. to some extent, from groundwater points SAP-2b to ADPW, ranging from 0.30 for phenazone and 0.83 for 4OH diclofenac (Figures 5 and S2). InAll Figure of the S2, NSAIDsRabs values were are evaluated, removed, comparing to some extent,the NSAID from concentrations groundwater at pointssam- SAP-2b plingto ADPW, points rangingSAP-1, SAP-2, from ADS-6n, 0.30 for ADS7, phenazone and ADPW and 0.83 with for these 4OH at diclofenacSAP-2b. It is (Figure im- 5 and portant to mention that the removal in the sampling points SAP-1 and SAP-2 for diclo- Figure S2). In Figure S2, Rabs values are evaluated, comparing the NSAID concentrations fenac,at sampling 4OH diclofenac, points SAP-1,and ibuprofen SAP-2, did ADS-6n, not follow ADS7, a linear and decay, ADPW aswith their theseRabs values at SAP-2b. It variedis important from 0.9 toto 1 mention (Figure S2a that vs. the Figure removal 5). High in values the sampling of Rabs were points also SAP-1evaluated and for SAP-2 for salicylic acid, being above 0.7 at these sampling points (Figure S2a). This observation diclofenac, 4OH diclofenac, and ibuprofen did not follow a linear decay, as their R values suggests that some processes may occur that deplete these NSAIDs at these sampling abs points,varied which from deserves 0.9 to 1 (Figurefurther investigation. S2a vs. Figure Ketoprofen5). High presented values of removalRabs were rates also that evaluated increasedfor salicylic from acid, the points being abovelocated 0.7to the at these river samplingto the parking points area, (Figure whereas S2a). phenazone This observation andsuggests mefenamic that acid some had processes similar removal may occurefficiencies that (Figure deplete S2b). these NSAIDs at these sampling points, which deserves further investigation. Ketoprofen presented removal rates that

Water 2021, 13, 720 13 of 18

increased from the points located to the river to the parking area, whereas phenazone and mefenamic acid had similar removal efficiencies (Figure S2b). All the NSAIDs seemed to be partially attenuated under the sub-oxic and nitrate reducing conditions of the groundwater resulting from the mixing of oxic river water recharged into the aquifer, driving redox reactions such as denitrification and aerobic respiration [43]. Presumably, this may be the case for diclofenac, 4OH diclofenac, and ibuprofen and, to a lesser extent, for salicylic acid, mefenamic acid, and phenazone. This observation was supported by the positive correlation (R2) of these substances with two redox indicators—ammonium and TOC (Figures S3 and S4)—and the lack of correlation with dissolved oxygen (Figure S5). Previous studies have suggested that ibuprofen is biodegradable under oxic conditions in groundwater [44]; however, Carr et al. [45] found that the most efficient biological degradation occurred under reduced oxygen conditions (half-life of 41.2 days vs. 121.9 days in aerobic soils). No retardation was observed in column and field experiments for ibuprofen [17,46]. In contrast, high retardation values of diclofenac and 4OH diclofenac have been observed at a bank filtration site in Berlin, Germany, reaching values of up to 80.3 and 13.3, respectively [47,48]. The strong sorption of diclofenac has also been reported in other German river bank filtration systems in the Flehe—Rhine River (aerobic to denitrifying conditions) and Torgau-Elbe River (denitrifying conditions) [49]. Moreover, diclofenac also appeared to biodegrade at the bank filtration site in Berlin, with a half-life of 36 days. Concerning phenazone, previous studies have reported that redox conditions in groundwater have an influence on its degradation [50], as it was found to be highly degradable under the presence of oxygen [19,47]. However, this substance may also degrade under sub-oxic conditions, as Sanz-Prat et al. [48] reported a decline of concentration along the flow path at low dissolved oxygen concentrations in a river bank filtration site in Berlin, Germany. Retardation of phenazone was observed neither in field [48] nor laboratory experiments [51]. In this study, a negative correlation was observed among propyphenazone and ammonium and TOC and no correlation with dissolved oxygen (Figures S3–S5) was observed. Previous studies have reported that the natural attenuation of propyphenazone was enhanced under oxic conditions in groundwater at field scale [52]; whereas, in this study, it was also observed under sub-oxic conditions (average dissolved oxygen concentration 1.5 mg/L). To conclude, when surface water infiltrates through the soil, the aquifer sediments act as a natural filter and the concentrations of most of the NSAIDs were partly reduced, likely due to physical and chemical processes such as sorption, mixing, and biodegradation, which may provide substantial improvements in water quality. The redox state of the shallow aquifer of the Besòs River Delta has to be regarded as the key factor driving the removal of the target NSAIDs, as the residence time from the river to the parking area is somewhat short (about a month; Figure1e).

3.3. Human Health Risk Assessment The occurrence of pharmaceuticals in urban aquifers has raised many questions about their risk to human health, as groundwater is the main source of drinking water in many European countries. In this study, the quantiﬁcation of threat that the NSAIDs pose to human health was assessed by comparing the highest concentration of individual NSAIDs in groundwater to DWEL values. The DWEL values were always at least two or three orders of magnitude higher than the highest concentration of each individual NSAID in groundwater (Table S8). Consequently, these substances do not pose any risk to human health, in the case that the groundwater of the shallow aquifer of the Besòs River Delta is used as drinking water, as life-stage RQs for the 8 age intervals ranged from 0.027 to 0.000038. The NSAIDs that had the highest RQs were diclofenac followed, by ketoprofen. Among the assessed life stages, infants (6 to 12 months) and children (age 1 to 3 years) were the age intervals that presented the highest RQs (Figure6). This observation suggests that early life stages are the most sensitive to exposure to NSAIDs from groundwater, as Water 2021, 13, x FOR PEER REVIEW 15 of 19

Water 2021, 13, 720 14 of 18 The evaluation of the risk of individual NSAIDs might have been underestimated, as these substances were detected simultaneously in groundwater samples. Thus, it was considered important to compute the RQ for the mixture of these substances (Figure 6). Thethey mixture ingest of a higherNSAIDs amount seemed of to waterrepresent per a body minimal weight. risk to One human limitation health, of as the the assessmentRQs of forRQs all wasage intervals that there considered exists no were information far less than on 0.1. the DWI and BW of the inhabitants of Spain.

FigureFigure 6. 6. HumanHuman health health life-stage life-stage RQ profile RQ proﬁle for the for target the NSAIDs target NSAIDs and their andmixture their (sum mixture of the (sum of the target NSAIDs) in the shallow aquifer of the Besòs River Delta. DCF, diclofenac; IBU, ibuprofen; target NSAIDs) in the shallow aquifer of the Besòs River Delta. DCF, diclofenac; IBU, ibuprofen; KET, KET, ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid. ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid. 4. Conclusions The evaluation of the risk of individual NSAIDs might have been underestimated, Water scarcity has encouraged research into alternative water resources, such as as these substances were detected simultaneously in groundwater samples. Thus, it was urban groundwater; however, the continuous input of pharmaceutical compounds, such asconsidered NSAIDs, may important limit its topotential compute uses the and RQ pose for thea tremendous mixture of risk these to human substances health, (Figure 6). particularlyThe mixture if safe of NSAIDs drinking seemed water is toto representcome from a groundwater minimal risk sources. to human With health, this pur- as the RQs posefor all in agemind, intervals this study considered investigated were the faroccu lessrrence than of 0.1.NSAIDs and their metabolites in an urban aquifer, proposed a methodology to quantify the removal of these substances from4. Conclusions groundwater and, finally, demonstrated that the NSAIDs would not pose any risk to humanWater health scarcity if the has urban encouraged groundwater research was used into as alternative potential source water for resources, drinking such as water.urban A groundwater; total of six NSAIDs however, and the two continuous metabolites input were ofinvestigated pharmaceutical in river compounds, and 13 such groundwateras NSAIDs, samples, may limit coupled its potential with major uses ions and and poseredox aindicators, tremendous in an riskurban to aquifer human health, locatedparticularly in Barcelona if safe (Spain). drinking water is to come from groundwater sources. With this purpose in mind,Six of thisthe target study NSAIDs investigated were ubiquitous the occurrence (ketoprofen, of NSAIDs diclofenac, and mefenamic their metabolites acid, in an propyphenazone, phenazone, and the metabolite salicylic acid), while the remaining two urban aquifer, proposed a methodology to quantify the removal of these substances from were frequently detected (>75%) in groundwater. The highest average concentrations in thegroundwater aquifer were and, 225.2ﬁnally, ng/L for demonstrated diclofenac, 110.2 that ng/L the for NSAIDs salicylic acid, would 97.7 not ng/L pose for ke- any risk to toprofen,human health and 91.7 if the ng/L urban for propyphenazone. groundwater was Overall, used asthe potential higher concentrations source for drinking of the water. A NSAIDstotal of were six NSAIDs detected andat the two shallow metabolites sampling were points investigated located near inthe river river and(SAP-2b 13 groundwater and SAP-4).samples, The coupled maximum with individual major ionsconcentratio and redoxns were, indicators, in descending in an order: urban 620 aquifer ng/L for located in salicylicBarcelona acid (Spain). (ADPQ), 380 ng/L for diclofenac (SAP-2b), and 379 ng/L for ibuprofen (SAP-4).Six All of of the the target target NSAIDs substances were were ubiquitous detected in (ketoprofen,the River Besòs, diclofenac, except 4OH mefenamic diclo- acid, fenac,propyphenazone, with concentrations phenazone, ranging and from the 9.3 metabolite ng/L (for ketoprofen) salicylic acid), to 293 while ng/L the (for remaining ibu- two profen).were frequently The average detected concentrations (>75%) inin groundwater.groundwater samples The highest were averagehigher than concentrations those in detectedthe aquifer in river were water 225.2 for ng/Lall of the for NSAIDs, diclofenac, expect 110.2 for ibuprofen; ng/L for however, salicylic the acid, concen- 97.7 ng/L for ketoprofen, and 91.7 ng/L for propyphenazone. Overall, the higher concentrations of the NSAIDs were detected at the shallow sampling points located near the river (SAP-2b and SAP-4). The maximum individual concentrations were, in descending order: 620 ng/L for salicylic acid (ADPQ), 380 ng/L for diclofenac (SAP-2b), and 379 ng/L for ibuprofen (SAP- 4). All of the target substances were detected in the River Besòs, except 4OH diclofenac, with concentrations ranging from 9.3 ng/L (for ketoprofen) to 293 ng/L (for ibuprofen). The average concentrations in groundwater samples were higher than those detected in river water for all of the NSAIDs, expect for ibuprofen; however, the concentrations Water 2021, 13, 720 15 of 18

reported in the river water—which is the main pollution source of the aquifer—may not be representative, due to the irregular flow pattern of the River Besòs. We proposed a methodology to evaluate the percentage of the NSAIDs that were naturally removed in the river–groundwater interface by the term Rabs, which compares the expected concentrations of these substances by river water mixing in groundwater with those measured in the groundwater in the sampling campaign. Most of the NSAIDs presented Rabs above 0 and the substances that were easily and moderately removed were 4OH diclofenac, ibuprofen, and salicylic acid with median Rabs values of 0.80. 0.74 and 0.35, respectively. This observation suggests that the reducing conditions in the aquifer might favor the natural attenuation of the NSAIDs. Median removals for diclofenac, mefenamic acid, and phenazone were poor (Rabs < 0.3). The innovative aspect of the proposed approach is the quantification of the removal capacity of these substances in the subsurface at each groundwater sampling point. Finally, RQs were estimated, in order to assess the human health risks posed by the considered NSAIDs in groundwater, as this resource might serve as an alternative source for drinking water provision. Individual NSAIDs and their mixture posed a minimum risk for human health, for all life stages, as associated RQs values were all less than 0.05. Nevertheless, the evaluation of the risk posed by the sum of different pharmaceuticals should be evaluated, as these substances can be detected simultaneously in groundwater. This preliminary research can help to set groundwater quality standards for CECs, such as pharmaceuticals, as this freshwater is expected to be used as a drinking water source in semi-arid regions, such as Spain. There exist some knowledge gaps regarding the fate and risk assessment of NSAIDs in groundwater, which deserve further investigation in the near future. First, it is necessary to better understand the dynamics of the NSAIDs (and CECs in general) in groundwater over long periods of time (e.g., hydrogeological year), including a wide range of flow conditions. Moreover, it is of paramount importance to quantify the hydrochemical processes (i.e., transport and redox processes and adsorption) that control the behavior of the NSAIDs in groundwater, by means of numerical modelling. This additional research will help to better characterize the variability of the NSAID concentrations in the river water, to properly define the potential uses of urban groundwater, and to implement solutions for its management in urban areas. Secondly, as the consumption of pharmaceuticals has been increasing sharply and urban groundwater is expected to constitute a source of drinking water more frequently in the future, evaluating the human risk posed by these substances is a major issue, as their effect on human health is not yet well-understood.

Supplementary Materials: The following are available online at https://www.mdpi.com/2073 -4441/13/5/720/s1, Figure S1: Piper diagram showing major ion chemistry of the groundwater (blue triangles) and river water (green squares), Figure S2: Removal of the NSAIDs along linear groundwater ﬂow path (from SAP-2b to ADPW) for (a) diclofenac, 4OH diclofenac, ibuprofen, and salicylic acid and; (b) ketoprofen, mefenamic acid, and phenazone. The removal was evaluated as follows: 1-(CGW-Obs/CSAP-2b), where CGW-Obs and CSAP-2b are the concentrations of a given NSAID in the groundwater sampling points and at SAP-2b, respectively, Figure S3: R-squared (R2) values for the target NSAIDs (ng/L) vs. ammonium (mg/L), Figure S4: R-squared (R2) values for the target NSAIDs (ng/L) vs. total organic carbon (TOC, mg/L), Figure S5: R-squared (R2) values for the target NSAIDs (ng/L) vs. dissolved oxygen (DO, mg/L), Table S1. Details of MIX Code and steps followed for the evaluation of the concentration of the NSAIDs and the mixing ratios, Table S1: Initial concentrations of the river end-members for (a) major elements (mg/L) and EC (µS/cm) and (b) NSAIDs (ng/L). Metabolites are listed in bold. DCF, diclofenac; 4OH DCF, 4OH diclofenac; IBU, ibuprofen; KET, ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid, Table S2: Standard deviations assigned to major ions, EC, and the target NSAIDs in the river and groundwater samples. Metabolites are listed in bold. Rrw, Average concentration in River Besòs end-members; Rgw, Average concentration in groundwater sampling points; DCF, diclofenac; 4OH DCF, 4OH diclofenac; IBU, ibuprofen; KET, ketoprofen; MEF, mefenamic acid; PPZ, propyphenazone; PZ, phenazone; SA, salicylic acid, Table S3: Maximum (max.), minimum (min.), Water 2021, 13, 720 16 of 18

and mean concentrations (ng/L) in the River Llobregat. Metabolites are listed in bold. -, no data available; n.d, not detected; LOQ, Limit of quantification, Table S4: Acceptable daily intake (ADI) values of the target NSAIDs in groundwater. ADI not available. Metabolites are listed in bold, Table S5: 50th percentile body weight and Drinking Water Intake (WHO) for selected age groups, Table S6: Concentrations of major ions (mg/L) and some redox indicators (mg/L) in groundwater sampling points and river water, Table S7: Removal (Rabs) of the NSAIDs in the groundwater sampling points Metabolites are listed in bold, Table S8: (a) DWEL (µg/L) and (b) risk quotients (RQs) of the target NSAIDs in groundwater for the selected life stages. Metabolites are listed in bold. Author Contributions: Conceptualization, A.J. and E.P.; methodology, A.J. and E.P.; investigation, A.J., E.P. and E.V-S.; data curation, A.J. and E.P.; writing—original draft preparation, A.J.; writing— review and editing, A.J., E.P. and E.V-S.; visualization, A.J. and E.P.; project administration, A.J. and E.V-S.; funding acquisition, A.J. and E.V-S. All authors have read and agreed to the published version of the manuscript. Funding: IDAEA-CSIC is a Centre of Excellence Severo Ochoa (Spanish Ministry of Science and Innovation, Project CEX2018-000794-S). A. J gratefully acknowledges the support from the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia and the Marie Sklodowska-Curie COFUND of the programme H2020 (BP3, contract number 801370). The authors would like to thank the European Commission, the Spanish Foundation for Science & Technology (FECYT) and State Research Agency (AEI)) for funding in the frame of the collaborative international consortium (URBANWAT) financed under the 2018 Joint call of the WaterWorks2017 ERA-NET Cofund. This ERA-NET is an integral part of the activities developed by the Water JPI. Additionally, authors would also thank the Ministry of Science, Innovation and Universities, for funding the projects UNBIASED (Ref: RTI2018-097346-B-I00) under the 2018 call of the “Proyectos de I+D Retos Investigación” and INTEGRATE (Ref: PID2019-107945RJ-I00) under the 2019 call of the “Proyectos de I+D Retos Investigación”. Data Availability Statement: Data supporting the reported results can be found in the Supplemen- tary Materials. Acknowledgments: Thanks are given to EUSAB and the City Councils of Sant Adrià del Besòs for the technical support. Conflicts of Interest: The authors declare no conflict of interest.

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