Tao Luo

Jing Xu

Wei Cheng

Lian Zhou

Ré Mi Marsac

Feng Wu

Jean-Franç Ois Boily

Khalil Hanna
email: khalil.hanna@ensc-rennes.fr

Interactions of anti-inflammatory and antibiotic drugs at mineral surfaces can control environmental fate and transport

Keywords: pharmaceutical compounds, mobility, cooperative binding, transport, modeling

Various pharmaceutical compounds often coexist in contaminated soils, yet little is known about how their interactions impact their mobility. We here show that two typical antibiotic and anti-inflammatory agents (nalidixic acid (NA) and niflumic acid (NFA)) commonly form dimers at several representative soil-and sediment-building minerals of contrasting composition and structure. Co-binding occurs in the form of a NFA-NA dimer stabilized by hydrogen bonding and van der Waals interactions. Using dynamic column experiments containing goethite-coated sand, we then demonstrated that pre-sorbed NA effectively captured the otherwise weakly-binding NFA from solution. Simultaneously injecting NA and NFA to pre-sorbed NA enhanced even further both NA and NFA loadings, thereby altering their transport under flow-through conditions. We also showed that environmental level amounts of natural organic matter can reduce the overall retention in column experiments, yet it does not suppress dimer formation. These environmentally relevant scenarios can be predicted using a new transport model that accounts for kinetics and co-binding reactions of NFA onto NA bound to goethite through metal bonded, hydrogen-bonded and an outer-sphere complexes. These findings have important implications on assessing the fate of co-existing pharmaceutical compounds under dynamic flow conditions in contaminated soils.

Introduction

Pharmaceutical and personal care products often co-exist in aquatic systems at levels as high as several hundred ng per L [START_REF] Fatta-Kassinos | Pharmaceutical Residues in Environmental Waters and Wastewater: Current State of Knowledge and Future Research[END_REF][START_REF] Dȩbska | Fate and Analysis of Pharmaceutical Residues in the Aquatic Environment[END_REF][START_REF] Heberer | Occurrence, Fate, and Removal of Pharmaceutical Residues in the Aquatic Environment: A Review of Recent Research Data[END_REF][START_REF] Wu | Adsorption of the Quinolone Antibiotic Nalidixic Acid onto Montmorillonite and Kaolinite[END_REF] . Recently, antibacterial and anti-inflammatory agents have emerged as aqueous micropollutants in surface waters, groundwaters and soils [START_REF] Dȩbska | Fate and Analysis of Pharmaceutical Residues in the Aquatic Environment[END_REF][START_REF] Khetan | Human Pharmaceuticals in the Aquatic Environment: A Challenge to Green Chemisty[END_REF] . The transport and mobility of these emerging contaminants in the environment are strongly related to the nature and relative abundance of the mineral phases (e.g. metal oxides and clays) commonly found in the Earth's near-surface environment [START_REF] Linker | Adsorption of Novel Insensitive Munitions Compounds at Clay Mineral and Metal Oxide Surfaces[END_REF][START_REF] Figueroa | Sorption of Oxytetracycline to Iron Oxides and Iron Oxide-Rich Soils[END_REF][START_REF] Han | A Critical Review of Clay-Based Composites with Enhanced Adsorption Performance for Metal and Organic Pollutants[END_REF] . For this reason, several studies have focused on interactions of organic compounds with metal-oxyhydroxides and clays [START_REF] Han | A Critical Review of Clay-Based Composites with Enhanced Adsorption Performance for Metal and Organic Pollutants[END_REF][START_REF] Nayak | Removal of Phenol from Aqueous Solutions by Pharmaceutical Compounds at Mineral Surfaces: Mechanistic Modeling of Binding and Cobinding of Nalidixic Acid and Niflumic Acid at Goethite Surfaces[END_REF][10][11][12] . Still, much remains to be learned on their fate and transport mechanisms in oxide-rich environments, and particularly in multicomponent systems. In such systems, adsorption, through competitive or synergistic interactions at mineral surfaces, is key to determine the fate of pollutant mixtures [13][14][15] .

Recent spectroscopic, chromatographic and theoretical investigations have improved the description of quinolones and fluoroquinolones adsorption to Fe-oxides by identifying ligands that are (i) metal-bonded (MB; inner-sphere (IS)), (ii) hydrogen-bonded (HB; direct H-bond to surface (hydr)oxo group) or (iii) bound as outer-sphere (OS; separated by at least one hydration sheath) species. The relative importance of these species is affected by pH, ionic strength, as well as mineral surface and ligand structures [16][17][18][START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] . More particularly, we have shown that the spatial disposition functional groups of niflumic acid (NFA, a non-steroidal anti-inflammatory) favor HB over MB species at goethite (α-FeOOH) surfaces over a broad range of pH values 18,[START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] . In contrast, the keto group and carboxylate groups of nalidixic acid (NA, a quinolone antibiotic) favor MB species. [START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF][START_REF] Cheng | Effects of Organic Matter-Goethite Interactions on Reactive Transport of Nalidixic Acid: Column Study and Modeling[END_REF] Here, MB species dominate under acidic conditions, while HB/OS coexists under circumneutral to alkaline conditions.

Because most traditional environmental models are based on a single/individual contaminant basis, little is known on their transport in mixture contaminant systems, and underlying reaction mechanisms remain elusive. In addition, much of the knowledge that currently exists concerns the reactivity of environmental mineral surfaces in suspensions or slurry systems, and under equilibrium conditions [START_REF] Figueroa | Sorption of Oxytetracycline to Iron Oxides and Iron Oxide-Rich Soils[END_REF]10,[START_REF] Gu | Sorption of the Antimicrobial Ciprofloxacin to Aluminum and Iron Hydrous Oxides[END_REF][START_REF] Haderlein | Specific Adsorption of Nitroaromatic Explosives and Pesticides to Clay Minerals[END_REF][START_REF] Yang | Molecular-Scale Study of Salicylate Adsorption and Competition with Catechol at Goethite/Aqueous Solution Interface[END_REF] .

Fewer investigations have been performed on the impact of water flow on the interfacial processes, and much less in flow-through system where non-equilibrium prevails. Moreover, non-equilibrium sorption under dynamic flow conditions is particularly relevant when competitive or cooperative process in presence or absence of natural organic matter (NOM) concurrently impact the mobility of target compounds [START_REF] Wu | Adsorption of the Quinolone Antibiotic Nalidixic Acid onto Montmorillonite and Kaolinite[END_REF][START_REF] Shakiba | Dynamic Intermolecular Interactions Control Adsorption from Mixtures of Natural Organic Matter and Protein onto Titanium Dioxide Nanoparticles[END_REF][START_REF] Kretzschmar | Influence of Natural Organic Matter on Colloid Transport through Saprolite[END_REF] .

In this work, we assessed the ability of NA and NFA to co-bind at minerals surfaces. To identify the mineralogical controls on NA and NFA co-binding we monitored their uptake by batch adsorption on seven nanominerals of contrasting composition and structure (goethite, magnetite, hematite, gibbsite, kaolinite, bentonite and titanium dioxide). These natural constituents of soils and sediments are the most reactive minerals in the environment, and play an important role in controlling the fate, mobility and toxicity of contaminants. Then, to emulate contaminant migration in natural environments, such as in aquifers and sediments, we monitored NA and NFA transport in column experiments using goethite-coated quartz sand particles. Goethite, a widespread mineral in aquatic and terrestrial systems, is one of the most thermodynamically stable iron oxide with a high surface area [START_REF] Cornell | The Iron Oxides: Structure, Properties, Reactions, Occurrences and Uses[END_REF] . Furthermore, goethite is often forming coatings on less soluble soil particles such as silica sand, and thus goethite-coated sand material is generally used as a structurally stable and hydraulically conductive porous medium to mimic natural mineral assemblages [START_REF] Rusch | Coating of Quartz Silica with Iron Oxides: Characterization and Surface Reactivity of Iron Coating Phases[END_REF][START_REF] Hanna | Sorption of Phthalic Acid at Goethite Surfaces under Flow-Through Conditions[END_REF] .

We compared NA and NFA binding (1) in isolated vs. mixed systems, and (2) in settings emulating stagnant vs. flowing groundwater containing Leonardite humic acid (LHA), a representative NOM. The NOM concentration range (5-10 mg/L) corresponds to the dissolved organic carbon typical of shallow groundwater, soil pore waters and surface waters [START_REF] Mcknlght | Sorption of Dissolved Organic Carbon by Hydrous Aluminum and Iron Oxides Occurring at the Confluence of Deer Creek with the Snake River, Summit County, Colorado[END_REF][START_REF] Helbling | Photochemistry of Chromophoric Dissolved Organic Matter in Natural Waters[END_REF] . Breakthrough curves (BTCs) of NA and NFA determined under different water velocities and residence times showed that co-binding of NA/NFA significantly altered the mobility of each compound. Although we have used an inflow concentration of NA or NFA higher than the level amounts of pharmaceuticals commonly detected in environmental systems (several hundred of ng per L) [START_REF] Fatta-Kassinos | Pharmaceutical Residues in Environmental Waters and Wastewater: Current State of Knowledge and Future Research[END_REF][START_REF] Dȩbska | Fate and Analysis of Pharmaceutical Residues in the Aquatic Environment[END_REF][START_REF] Heberer | Occurrence, Fate, and Removal of Pharmaceutical Residues in the Aquatic Environment: A Review of Recent Research Data[END_REF][START_REF] Wu | Adsorption of the Quinolone Antibiotic Nalidixic Acid onto Montmorillonite and Kaolinite[END_REF] , previous experimental and computational quantum findings showed that the formation of NFA-NA dimer at the surface of AlO(OH) or FeO(OH), is thermodynamically favorable, and can even occur for the very low concentration range [START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] . In addition, dynamic breakthrough experiments provide a high solid-to-liquid ratio, i.e. a small volume flowing through the porous media in packed bed columns, and therefore a total contaminant loading more representative of environmental settings 17,18 .

Multisite complexation model (MUSIC) was also established to describe the co-binding results of NA and NFA onto goethite, and predictions of BTC have been developed from surface complexation modeling parameters combined with a new kinetics term. This chemical kinetic/transport coupling was required to accurately describe the mobility of NA and NFA in the different scenarios considered in this study. These efforts helped identify conditions under which drug co-binding is likely to prevail in the environment, and highlight the importance of coupled flow and water chemistry in controlling the mobility of pharmaceutical compounds in complex environmental media.

Materials and Methods

Chemicals

Nalidixic acid (NA), Niflumic acid (NFA), ferric nitrate nonahydrate (Fe(NO3)3•9H2O), sodium chloride (NaCl), sodium hydroxide (NaOH), hydrochloric acid (HCl) and potassium bromide (KBr) were provided by Sigma Aldrich and were of analytical grade or better, and used without further purification. All solutions were prepared with ultrapure water. Leonardite Humic Acid Standard (1S104H) was purchased from the International Humic Substance Society. A LHA stock solution (2 g/L, 1276 mg C/L) was prepared by dissolving 2 g LHA in 100 mL of 1 M NaOH, then diluted to 1 L with ultrapure water. Fontainebleau quartz sand (150-300 μm) was purchased from VWR Prolabo (France). Ultrapure water was used in all experiments.

Synthesis and characterization of minerals

Goethite, hematite, magnetite, gibbsite were synthesized using published methods, and described in the SI. Commercial TiO2 Millennium PC-500 (> 99% of anatase), Georgia kaolinite (KGa-1) and Bentonite (Na-montmorillonite) were used as received. More information about synthesis and characterization are given in the Supporting information (SI).

Goethite coated sand (GCS) was obtained by mixing 500 g of Fontainebleau sand with an excess of goethite (~10 g) in 1L of 10 mM NaCl solution. Before coating, the quartz sand was cleaned with HCl, then with H2O2, and rinsed with pure water.

The resulting goethite-sand suspension was adjusted to pH 5 and then shaken for 24 h.

After that, the coated sand was washed with ultrapure water until the runoff was clear, and then it was dried in oven at 60 o C for 24 h. The final GCS was stored at ambient temperature. Acid digestion followed by measurements of total dissolved iron using Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP/AES), has permitted to determine the coating degree. For GCS, we found 0.9 g goethite per 100 g of coated sand. Previous studies from our group 17,[START_REF] Cheng | Effects of Organic Matter-Goethite Interactions on Reactive Transport of Nalidixic Acid: Column Study and Modeling[END_REF] confirmed that the coating procedure did not alter the reactivity of goethite particles.

The possible dissolution of the used quartz sand was also checked in sand suspensions with two solid loadings, 1 or 10 g/L, aged for one month and at various equilibrium pH (4-10), in pure water or 0.01 M NaCl. In both cases were dissolved silicate concentrations below the detection limits of the molybdenum blue spectrophotometric method (detection limit 1µM) and of ICP/AES analyses (detection limit 0.2 µM)).

Batch experiments

Batch adsorption experiments were conducted in 10 mL suspensions of minerals in polypropylene tubes at a wide range of pH and in 10 mM NaCl to assess the NA/NFA co-binding on different types of minerals. The investigated pH range was adapted for each mineral to avoid mineral dissolution at very low or high pH values.

All experiments were carried out under an atmosphere of N2(g) in order to avoid contributions from dissolved CO2. Suspensions were mixed for a period of 24 h by end-over-end shaking, which is largely sufficient to reach equilibrium based on preliminary kinetic study 18 . Aliquots of the resulting suspensions were thereafter sampled and filtered (0.2 µm) for analysis. NA and NFA co-binding to goethite were also investigated at pH 5 ± 0.1 in presence of various LHA concentrations. All batch adsorption experiments were performed in triplicates, with a reproducibility of 5 % for NA and 7 % for NFA. Results for the LHA-free systems are in the SI only.

NA and NFA concentrations in the aqueous solution were determined using a high performance liquid chromatography (HPLC) system. This was equipped with an auto sampler (Waters 717 plus) using a C18 column (250 mm×4.6 mm i.d., 5 μm), and a UV detector operating at 258 nm and 283 nm (Waters UV). The mobile phase was a mixture of water/acetonitrile (60:40 v/v) containing 0.1% of formic acid. The flow rate of the mobile phase was set at 1 mL/min in isocratic mode.

Continuous flow experiments

Breakthrough column experiments were conducted in a glass chromatographic column (1.6 cm internal diameter). The porous bed had a length of 4.9 cm and a dry mass of 15 g. After packing to a uniform bulk density (1.52 g/cm 3 ), the column was wetted upward with a background electrolyte solution (NaCl, 10 mM) at a constant flow rate for at least 24 h until the column was saturated and each parameter (pH, conductivity) became constant. After water saturation, 1 pore volume of 10 mM KBr LHA. In all four approaches, influent solutions were prepared at pHin 5 ± 0.1 and contained 10 mM of NaCl. Continuous on-line pH measurement was performed using pre-calibrated pH flow through sensor. In addition, the pH of collected fractions was often checked using a pH-meter (HI2210, HANNA ® ). The breakthrough curves (BTCs) were expressed as the relative aqueous concentration of solute against the number of pore volumes (V/Vp), where Vp represents the pore volume of column. The adsorbed amounts of NA and NFA were determined by integrating the area above the entire breakthrough curve of each compound, as previously reported [START_REF] Hanna | Sorption of Phthalic Acid at Goethite Surfaces under Flow-Through Conditions[END_REF][START_REF] Pokharel | Water Flow and Dissolved Mn(II) Alter Transformation of Pipemidic Acid by Manganese Oxide[END_REF] . The mass balance was further confirmed by carrying out solid-phase extraction on GCS, as described in previous work [START_REF] Zhou | Water Flow Variability Affects Adsorption and Oxidation of Ciprofloxacin onto Hematite[END_REF] . Briefly, the solid from packed column was transferred into an aqueous solution and then pH was adjusted to 11, and the suspension was stirred for 1h. The average extraction recovery derived from several desorption tests lied at 97.9 ± 3.5%, confirming that only adsorption took place in the GCS column, and that molecule breakdown by, for example, oxidation, did not occur under the experimental conditions of this study. The aqueous concentrations of NA and/or NFA in the outflow were determined by HPLC. In all the column experiments, the leaching iron from GCS column was negligible. All experiments were conducted in duplicates, and the estimated error lied at 5% for NA and NFA.

Surface complexation modeling combined with kinetics

A surface complexation model (SCM) was used to predict adsorption under equilibrium condition. However, non-equilibrium may predominate in the dynamic column experiments, and thus implementation of kinetics in surface complexation reactions is crucial to accurately describe the mobility behavior. It was reported that a fast formation of outer sphere complexes is a prerequisite for inner sphere (IS) complexes formation, which is a rate-limiting process [START_REF] Yiacoumi | Modeling Adsorption of Metal Ions from Aqueous Solutions. I. Reaction-Controlled Cases[END_REF][START_REF] Axe | Time-Dependent Surface Speciation of Oxalate at the Water-Boehmite (γ-AIOOOH) Interface: Implications for Dissolution[END_REF] . According to a previous spectroscopic study [START_REF] Axe | Time-Dependent Surface Speciation of Oxalate at the Water-Boehmite (γ-AIOOOH) Interface: Implications for Dissolution[END_REF] showing that the conversion of hydrogen-bonded organic

2H + + 2≡FeOH -0.5 + NA - (≡FeOH2)2 + ‧‧‧NA -(OS) (1)
2H + + 2≡FeOH -0.5 + NA - (≡FeOH2)2 + ‧‧‧NA -(HB) (2)

2H + + 2≡FeOH -0.5 + NA - (≡Fe)2(NA 0 )+2H2O (MB) (3)
All modeling parameters are provided in Table S2.

To distinguish the two-step reactions in PHREEQC-2, we have applied the previously published approach [START_REF] Zhou | Silicate Surface Coverage Controls Quinolone Transport in Saturated Porous Media[END_REF] . Briefly, we defined one intermediate ('in') 'NA in ' and one equilibrium 'NA' species. Here, 'NA in ' is an intermediate complex first in the form of a OS species:

2H + + 2≡FeOH -0.5 + NA in- (≡FeOH2)2 + ‧‧‧NA in- (OS formation) (4)
This OS species then converts to a HB species:

(≡FeOH2)2 + ‧‧‧NA in-(OS) (≡FeOH2)2 + ‧‧‧NA in-(HB formation) ( 5
)
This conversion is a fast process, whereas the resulting HB species converts to a MB species through the following rate-limiting process:

(≡FeOH2)2 + ‧‧‧NA in-(HB) (≡Fe)2(NA 0 ) + 2H2O (MB formation) (6)
Here, kf and kb are forward and backward rate coefficients (T -1 ) respectively, which could be obtained by curve fitting, as previously reported. [START_REF] Zhou | Silicate Surface Coverage Controls Quinolone Transport in Saturated Porous Media[END_REF][START_REF] Nkedi-Kizza | Sorption Kinetics and Equilibria of Organic Pesticides in Carbonatic Soils from South Florida[END_REF] . Preliminary fitting procedures allowed us to set forward rate constant kf and backward rate constant kb to 0.050 and 0.009, respectively.

The three plane model (TPM) was employed to describe the charge of the goethite/water interface, which requires two capacitances for the 0-(C1 = 2.3 F/m 2 )

and the 1-plane (C2 = 1.07 F/m 2 ). Then multi-site complexation (MUSIC) model and PHREEQC-2 was used for modelling the species transport in the GCS-packed column.

Though singly ( ≡ FeOH -0.5 ), doubly ( ≡ Fe2OH) and triply ( ≡ Fe3O -0.5 and ≡ Fe3OH +0.5 ) coordinated oxygens exist at the goethite surface, we assumed that NA and NFA trend to bind to reactive ≡FeOH -0.5 sites of goethite through HB, OS and even MB (only for NA) complexes based on our studies 18,[START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] . The reactive site density is given as detailed in our previous work: [≡FeOH -0.5 ] = 3.12 sites/nm² and [≡Fe3O -0.5 ] = 3.12 sites/nm² on (001)/(101) planes (90% of the surface area), and [≡FeOH -0.5 ] = 7.4

sites/nm² on (210)/(010) plane (10% of the surface area).

Our modeling strategy is described as follows. Surface hydrolysis and surface complexation reactions including NA/NFA dimer formation were taken from our previous batch sorption study 18 . For the column system, NA and NFA adsorption were first modeled in their respective single systems. The corresponding surface complexation constants were then used to predict binding in the binary system, and the NA-NFA dimer formation constant was calibrated from the experimental data. The column system was described by 1D transport, with p successive equal width cells (Δz = L/p, L is the total column length, in this study p = 20). Solution transported between pn and pn+1 in time steps Δt and at the defined flow rate and dispersion through the specific transport procedure implemented into PHREEQC-2. After each time step, this procedure is coupled with the geochemical code for each cell [START_REF] David | User's Guide to PHREEQC (Version 2)-A Computer Program for Speciation, Batch-Reaction, One-Dimensional Transport, and Inverse Geochemical Calculations[END_REF] . All parameters used for transport modeling are provided in Table S2.

Results and discussion

Our previous works 18, [START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] showed that enhancement in NFA binding, which is otherwise considerable weaker than NA, results from the intermolecular interactions with the goethite-bound NA. We ascribed this enhancement to a NFA-NA dimer whose energetically favored formation (-0.5 eV compared to free molecules) is predominantly driven by van der Waals interactions [START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] . For reference, at pH 5, which will be focused in our transport work, NA loadings on goethite (0.33 mol/m 2 ; 0.20 NA/nm 2 ) are more than 3 times larger than NFA (~0.10 mol/m 2 ; 0.06 NFA/nm 2 ) (Fig. S2). Dimer formation in mixed NA and NFA solutions can enhance, in turn, NFA loadings by a factor of ~2.5 (~0.10 → ~0.25 mol/m 2 ) and NA loadings by ~1.2 (0.33 → ~0.40 mol/m 2 ) (Fig. S2).

Comparison of this enhancement effect with a suite of other minerals (SI) of contrasting composition and structure shows that NFA binding in the binary system was greatest on goethite. Namely, it followed the order: goethite (2.5-fold) > TiO2

(2-fold) > magnetite (1.8-fold) > gibbsite (1.5-fold, pH 6) ≈ kaolinite (1.5-fold) > bentonite (1.3-fold) ≈ hematite (1.3-fold). See the SI for a more detailed discussions of these results where we explain that NA-NFA dimer formation is greater on nanominerals typically with homogeneous distributions of reactive -OH functional groups (goethite, TiO2, magnetite), than those typically, with -OH limited to edges of platy minerals with unreactive basal faces (kaolinite, bentonite, hematite). For this reason, we focused our work on the effects of water flow and natural organic matter on NA-NFA interactions using goethite.

NA-NFA dimer formation under water flow

To explore the propensity of NA-NFA dimer formation under flow-through conditions, we performed dynamic flow experiments (Figs. 1, and2) with columns filled with goethite-coated sand (GCS). First, we find that injection of a mixed solution of NA+NFA after total breakthrough of NFA (Fig. 1a) decreased NFA outlet concentrations due to NA-NFA dimer formation on the goethite surface. This started at ~27 V/Vp, reached a plateau at ~29.5 V/Vp, then it gradually increased to a complete breakthrough at ~1200 V/Vp. In contrast, injecting a mixed solution of NA+NFA after total breakthrough of NA (Fig. 1b) pushed the breakthrough point of NFA to ~25 V/Vp (insert of Fig. 1b) compared to 2.3 V/Vp in the single system (Fig. S3). The BTC of NFA then tailed extensively before reaching a total breakthrough, thus adopting a classical sigmoidal shape akin to that of NA. Here, NA loadings increased from 0.68 μmol/m 2 in the single system to 0.90 μmol/m 2 in the binary system (Fig. S4), a consequence of the pre-loaded NFA (Fig. 1). Simultaneously injecting NA and NFA after total breakthrough of NA increased both NA and NFA loadings (0.90 μmol NA/m 2 ; 0.33 μmol NFA/m 2 ), however at levels close to the values obtained where NFA was first injected (Fig. 1). As a result, we find that NA and NFA exert a mutual effect on their breakthrough behavior under flow and this is basically explained from NA-NFA dimer formation at the goethite surface. The solid lines represent modelling results.

Irrespective of the injection scenario, NA exhibits an extended tailing suggesting kinetic limitations under the experimental conditions of this study. Because all of our bromide tracer experiments (Figs. S1 and S5) were well described using the CDE model, the tailing could not be explained by physical non-equilibrium effects, water regionalization into mobile/immobile zones or diffusion limitations between two water zones [START_REF] Brusseau | Simulating Solute Transport in an Aggregated Soil with the Dual-Porosity Model: Measured and Optimized Parameter Values[END_REF][START_REF] Šimůnek | Modeling Nonequilibrium Flow and Transport Processes Using HYDRUS[END_REF] . Moreover, the BTCs of NA and NFA in single systems were compared by normalizing the curves by their retardation factor to that of the bromide tracer (Fig. S6). For NFA, the steepness of BTC showed coincidence with that of bromide, and only a short tail was observed. However, the normalized BTC of NA exhibits a significant difference in steepness and shape with respect to that of bromide.

This discrepancy suggests the occurrence of chemical kinetic limitations or rate-controlled sorption processes under flow-through conditions. This is particularly the case for transport of the more strongly binding NA. This was confirmed further by results (Fig. S7) revealing greater NA loadings under conditions of lower flow rate (0.1 mL/min) that promotes higher residence times.

To check for the occurrence of kinetic limitations, SCM modeling with or without kinetics were compared for the BTC of NA (Fig. S8). These results confirmed that only kinetics implemented with SCM could describe the mobility behavior. In contrast, the equilibrium SCM seems sufficient for NFA, likely because of weaker and faster adsorption of NFA mainly through HB and OS complexes 18 (the first stage of Fig. 1a). However, as NFA adsorption on goethite was strongly related to kinetically limited NA adsorption, an extended tailing of NFA in the second stage was observed.

As only the sorption kinetics of NA were considered here, we anticipate that this could affect the adsorption of NFA through co-binding reactions (cf. Table S2). Under such conditions, our combined SCM and kinetics reproduced the mobility of both NA and NFA (Fig. 1).

To provide further evidence for the co-dependency of NA and NFA binding to GCS, we investigate the transport of the compounds under conditions where both NA and NFA were injected simultaneously (Fig. 2) to a clean column. This revealed two-step breakthrough behavior in the form of two fronts and of two plateaus in the outlet concentration of NFA. This contrasts with the cases of where NFA was injected before (Fig. 1a) or simultaneously with NA (Fig. 2). NFA sorption in the binary system increased sharply to 0.34 µmol/m 2 , compared to that in the single system, yet, they still kept the same breakthrough point at 2.3 V/Vp (insert of Fig. 2). In conclusion, although NA and NFA adopted contrasting BTCs from different injection schemes (NFA/(NFA+NA), NA/(NFA+NA), and (NFA+NA)), their surface loadings after total breakthrough were largely comparable (see Table S3). Here, NA and NFA loadings both increased in the binary compound systems, 1.3 times for NA and 16-19 times for NFA compared to the single system. As such, although NA and NFA transport processes depend on the injection methodology, because of the high-affinity NA to goethite, the injection order has almost no effect on NA and NFA loadings and in the co-binding behavior in the binary systems.

Finally, we confirmed these co-binding effects in experiments conducted at a lower flow rate (0.1 mL/min; Fig. S7), where an extended tailing for NA or NFA was also revealed. As a result, the same model previously used in sequential injection has adequately described the behavior of NA and NFA in simultaneous injection approach (Fig. 2).

Altered fate of NA and NFA transport by natural organic matter

Building upon these results, we evaluated how NOM altered the fate of NA and NFA interactions. We used LHA as a representative NOM at loadings of up to ~ 1 mg C/m 2 (~ 50 C atoms/nm 2 ) at pH 5 on goethite. From batch adsorption experiments (Fig. 3) we find that LHA binding effectively decreased, yet did not completely suppress, NA loadings. At the same time, we find that LHA fully suppressed NFA co-binding at LHA loadings above ~ 0.2 mg C/m 2 (∼10 C/nm 2 ). Based on previous work from our group [START_REF] Cheng | Water Vapor Binding on Organic Matter-Coated Minerals[END_REF] , the goethite surface still exposed unreacted -OH groups at this loading, and is therefore not entirely covered by LHA. Still, bound LHA was sufficiently effective to prevent binding NFA to the near-interfacial region of goethite for NA/NFA dimer formation. One possible explanation is that LHA altered the interfacial hydration environment and the surface charge of goethite, and thus the potential energy landscape for the NFA diffusion across the goethite/water interface and onto goethite-bound NA. It is also interesting to note that LHA offer no possibilities for NFA binding via, for example, van der Waals π-π electron coupling interactions. The enhanced uptake of NFA with NA is therefore driven by a very specific steric control between these two molecules. Experiments under flow (Fig. 4), again using GCS, showed that LHA at two environmentally-relevant concentrations for groundwater and surface waters [START_REF] Mcknlght | Sorption of Dissolved Organic Carbon by Hydrous Aluminum and Iron Oxides Occurring at the Confluence of Deer Creek with the Snake River, Summit County, Colorado[END_REF][START_REF] Helbling | Photochemistry of Chromophoric Dissolved Organic Matter in Natural Waters[END_REF] (5 and 10 mg/L) also affected NA and NFA mobility. Despite the competitive binding with LHA, co-binding and a two-step breakthrough behavior were still observed (Fig. 4a,b). Small breakthrough times and shorter tailing (steeper BTC) likely resulted from the consumption of adsorption sites by LHA. At relatively low LHA loadings, both NA and LHA compounds bound to goethite surface sites through ligand-exchange and hydrogen bonding, in turn altering the breakthrough behavior of NA. This competitive binding between NA and carboxylic/aromatics compounds of LHA may occur at the first step, followed probably by further adsorption of NA to LHA covered goethite.

NFA enhanced adsorption could be clearly observed (from 0.02 to 0.17 μmol/m 2 at 5 mg/L LHA), though this increase was reduced with increasing in LHA amount (from 0.02 to 0.04 μmol/m 2 at 10 mg/L LHA), likely because of the decrease in NA sorption as a result from LHA competitive binding (cf. Table S3). Based on previous studies [START_REF] Cheng | Effects of Organic Matter-Goethite Interactions on Reactive Transport of Nalidixic Acid: Column Study and Modeling[END_REF][START_REF] Kleber | A Conceptual Model of Organo-Mineral Interactions in Soils: Self-Assembly of Organic Molecular Fragments into Zonal Structures on Mineral Surfaces[END_REF][START_REF] Coward | Direct Evidence for Temporal Molecular Fractionation of Dissolved Organic Matter at the Iron Oxyhydroxide Interface[END_REF] we can expect that LHA binding results in a molecular fractionation caused by selective adsorption of heterogeneous LHA components. Lower molecular weight fractions of LHA with higher aromaticity could have primarily, and preferentially, bound to goethite in the first adsorption stage [START_REF] Coward | Direct Evidence for Temporal Molecular Fractionation of Dissolved Organic Matter at the Iron Oxyhydroxide Interface[END_REF] .

The higher molecular weight fractions, such as lignin-like and aliphatic compounds, could have, in turn, bound in the following stage [START_REF] Coward | Direct Evidence for Temporal Molecular Fractionation of Dissolved Organic Matter at the Iron Oxyhydroxide Interface[END_REF] . This view falls in line with the breakthrough behavior of LHA in GCS column, particularly in terms of the discrepancy between TOC and UV, which we report in Fig. S9 of the SI. In essence, higher TOC values with respect to UV absorbance at 254 nm were observed during the first adsorption stage. This aligns with the concept that LHA compounds of smaller molecular weight were preferentially adsorbed and successively replaced those of higher weight, as previously reported [START_REF] David | User's Guide to PHREEQC (Version 2)-A Computer Program for Speciation, Batch-Reaction, One-Dimensional Transport, and Inverse Geochemical Calculations[END_REF] . The same behavior was previously observed when only LHA was injected in GCS column [START_REF] Cheng | Effects of Organic Matter-Goethite Interactions on Reactive Transport of Nalidixic Acid: Column Study and Modeling[END_REF] , suggesting that the presence of NA and NFA did not significantly affect the binding of LHA components in column.

As NOM consists of a polydisperse mixture of organic molecules of varying molecular size, incorporation of complex binding reactions of the LHA components in TLM model is not straightforward. To simplify the model, we only considered sites consumed by LHA components. Then we reduced the available goethite site density (i.e. 15 % reduction for 5 mg/L LHA; 60% reduction for 10 mg/L LHA) to describe the modification of NA and NFA BTC in presence of LHA. These results could suggest that changes in site density were not linearly correlated to LHA loadings, and this could be explained by LHA fractionation and complex interactions with goethite.

We have also slightly adjusted the surface NA-NFA dimer formation constant of NA and NFA (Table S2) (24.4 → 23.8 for 5 mg/L LHA; 24.4 → 23 for 10 mg/L LHA) to improve the fit to the data, as the presence of LHA likely alters the formation of NA-NFA dimer. Because of the functional (e.g. carboxylates) groups of LHA, the complexation constant of NA on goethite by HB (Table S2) was also modified (20.4

→ 20.6 for 5 mg/L LHA; 20.4 → 21 for 10 mg/L LHA). These slight adjustments improved the fit of our model to the experimental data (Fig. 4), and thus our ability to predict multicomponent transport in complex systems. This consequently adds further confidence to the ability of our proposed model to account for NA and NFA (co)-binding under real-world conditions.

Environmental implications for environmental fate of pollutant mixtures

Emerging contaminants such as pharmaceutical compounds in the environment often occur in mixtures rather than as individual entities. The increasing occurrence of multiply contaminated aquatic ecosystems worldwide require efforts to predict synergistic and antagonistic effects affecting the transport of toxic agents in nature.

This study contributes to mounting evidence showing that mobility of pollutant mixtures cannot be predicted based on single-compound based adsorption data. More particularly, we showed that mineral-bound antibiotics can be new adsorption sites for other contaminants at mineral surfaces. Since this cooperative phenomenon is strongly dependent on the molecular structure of target compound (e.g., possibility of Van der Waals interactions and/or hydrogen bonding), it cannot be generalizable to all pharmaceutical compounds. Indeed, a parallel set of efforts showed that no co-binding occurred with sulfamethoxazole (SMX) neither with NA nor NFA, because of the lack of molecular interactions of SMX with co-existing compounds and goethite surfaces.

In contrast, ciprofloxacin (CIP) containing carboxyl and carbonyl functional groups, enhanced NFA binding, because CIP strongly binds to goethite surfaces, and may act as an attachment site for NFA. Therefore, this work raises the importance of recognizing drug co-binding, and lack of co-binding, for accurately predicting the fate of complex pharmaceutical mixtures in the environment.

Flow-through column experiments showed that co-binding caused by intermolecular interactions considerably affects the mobility and transport of NA and NFA in reactive porous media. These new findings combined with batch data and previous theoretical calculations [START_REF] Xu | Co-Binding of Pharmaceutical Compounds at Mineral Surfaces: Molecular Investigations of Dimer Formation at Goethite/Water Interfaces[END_REF] confirmed that the co-binding phenomenon takes place at the mineral surface, and over a wide range of aqueous concentration. Though the concentration in inflow solution may appear higher than the level of aqueous concentration commonly found in aquatic systems [START_REF] Fatta-Kassinos | Pharmaceutical Residues in Environmental Waters and Wastewater: Current State of Knowledge and Future Research[END_REF][START_REF] Dȩbska | Fate and Analysis of Pharmaceutical Residues in the Aquatic Environment[END_REF][START_REF] Heberer | Occurrence, Fate, and Removal of Pharmaceutical Residues in the Aquatic Environment: A Review of Recent Research Data[END_REF][START_REF] Wu | Adsorption of the Quinolone Antibiotic Nalidixic Acid onto Montmorillonite and Kaolinite[END_REF][START_REF] Khetan | Human Pharmaceuticals in the Aquatic Environment: A Challenge to Green Chemisty[END_REF] , continuous flow-through conditions offered the possibility to work with a suitable soil-aqueous phase ratio, and then monitor the effects of dispersion and nonequilibrium sorption on the transport of pollutants. This would certainly bring dynamic-flow tests closer to environmental and real-world conditions.

The presence of environmental level amounts of natural organic matter can reduce the overall retention by minerals, yet it does not suppress cooperative binding.

Taking these phenomena into account in a new SCM, which even accounts for kinetic

(

  with 10 mM NaCl, pH 5) was injected in between the NaCl background solution to determine the flow characteristics of the porous bed. The tracer BTC was recorded by ion chromatography (Fig. S1 in supporting information, SI). The classical convection dispersion equation (CDE) was applied to describe the 1D transport of a non-reactive solute under steady-state water flow in a saturated column (cf. SI for detailed description of model). The fitting parameters of the bromide elution confirmed the flow homogeneity and predominance of a convective regime in the column. The mass balance ratios calculated based on BTCs of Br -were close to 100% (Fig. θ (0.36±0.005) and dispersivity λ (242 ± 2 µm) (See SI). After the pulse tracer experiments, four sets of column experiments were performed by step-injection at the same constant flow rate of : (i) NFA/(NA+NFA): injection of 10 µM of NFA first, then 10 μM NA+10 μM NFA when the total breakthrough of NFA was achieved; (ii) NA/(NA+NFA): injection of 10 µM of NA first, then 10 μM NA+10 μM NFA when the total breakthrough of NA was achieved, (iii) (NA+NFA): simultaneous injection of 10 μM NA+10 μM NFA directly; (iv) (NA+NFA+LHA): simultaneous injection of 10 μM NA+10 μM NFA + 5/10 mg/L

Figure 1 .

 1 Figure 1. The full range of experimental breakthrough curves of NA and NFA through GCS-packed column in two successive steps at constant flow rate (0.5 ml/min). (a) Step I: injection of 10 μM NFA and 10 mM NaCl at pHin 5 ± 0.1 until the complete breakthrough of NFA. Step II: injection of mixture of 10 µM NA + 10 µM NFA and 10 mM NaCl at pHin 5 ± 0.1. The solid lines represent modelling results. (b) Step I: injection of 10 μM NA and 10 mM NaCl at pHin 5 ± 0.1 until the complete breakthrough of NA. Step II: injection of mixture of 10 µM NA + 10 µM NFA and 10 mM NaCl at pHin 5 ± 0.1. Insert is the breakthrough curve of NFA in the initial stage.

Figure 2 .

 2 Figure 2. Experimental and calculated breakthrough curves of NA and NFA in binary system at flow rate of 0.5 mL/min through GCS-packed column. Inflowing solution contains mixture of 10 μM NA and 10 μM NFA 10 and 10 mM NaCl at pHin = 5 ± 0.1. Insert is the breakthrough curves of NFA in the initial stage. The solid lines represent modelling results.

Figure 3 .

 3 Figure 3. The effect of humic acid on the adsorption of NA and NFA on 0.5 g/L goethite in single ([NA]tot = 20 μM or [NFA]tot = 20 μM) and binary ([NA]tot = [NFA]tot = 20 µM) system at pH 5 and ionic strength 10 mM (NaCl).

Figure 4 .

 4 Figure 4. Experimental and calculated breakthrough curves of NA and NFA in multicomponent system with LHA at flow rate of 0.5 mL/min through GCS-packed column. a) Inflowing solution contains mixture of 10 μM NA, 10 μM NFA and 5 mg/L of LHA and 10 mM NaCl at pHin = 5 ± 0.1. b) Inflowing solution contains mixture of 10 μM NA, 10 μM NFA and 10 mg/L of LHA and 10 mM NaCl at pHin = 5 ± 0.1. The solid lines represent modelling results.

  effects, allowed us to predict cooperative adsorption under dynamic flow and non-equilibrium conditions. This new transport model has the potential of successfully predicting the fate of pharmaceutical compounds, as NA and NFA, in various different environmentally relevant scenarios, and over a wide range of concentration including the level amounts commonly detected in environmental systems. As these co-binding mechanisms at mineral surfaces are not often considered in traditional thermodynamic modeling, our findings raise the importance of recognizing co-binding as a mechanism contributing to the migration of antibiotics and anti-inflammatory agents in complex environmental mixtures. As such, this work contributes to efforts aiming to accurately assess co-binding mechanisms at environmental surfaces, and the fate of co-existing contaminants in the environment. Supporting Information. Synthesis and characterization of minerals; tracer experiments and modeling; co-binding of NA and NFA on different nanominerals; experimental BTCs of NA or NFA with different flow rates and calculated BTCs of NA by using equilibrium and kinetic model in PHREEQC-2. Breakthrough curves of LHA at 5 and 10 mg/L.

  Sorption on Low Cost Clay. Desalination 2007, 207 (1-3), 71-79. (10) Cheng, W.; Elaheh, Lot, K.; Remi, M.; Hanna, K. Adsorption of Quinolone Antibiotics to Goethite under Seawater Conditions : Application of a Surface Complexation Model. Environ. Sci. Technol. 2019, 53, 1130-1138. (11) Gao, J.; Pedersen, J. A. Adsorption of Sulfonamide Antimicrobial Agents to Clay Minerals. Environ. Sci. Technol. 2005, 39 (24), 9509-9516. (12) Sheng, F.; Ling, J.; Wang, C.; Jin, X.; Gu, X.; Li, H.; Zhao, J.; Wang, Y.; Gu, C. Rapid Hydrolysis of Penicillin Antibiotics Mediated by Adsorbed Zinc on Goethite Surfaces. Environ. Sci. Technol. 2019, 53 (18), 10705-10713. Evanko, C. R.; Dzombak, D. A. Surface Complexation Modeling of Organic Acid Sorption to Goethite. J. Colloid Interface Sci. 1999, 206, 189-206. (17) Hanna, K.; Boily, J. F. Sorption of Two Naphthoic Acids to Goethite Surface under Flow through Conditions. Environ. Sci. Technol. 2010, 44 (23), 8863-8869.

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(13) Gu, B.; Mehlhorn, T. L.; Liang, L.; McCarthy, J. F. Competitive Adsorption, Displacement, and Transport of Organic Matter on Iron Oxide: I. Competitive Adsorption. Geochim. Cosmochim. Acta 1996, 60 (11), 1943-1950. (14) Gu, B.; Mehlhorn, T. L.; Liang, L.; Mccarthy, J. F. Competitive Adsorption , Displacement , and Transport of Organic Matter on Iron Oxide: II. Displacement and Transport. Geochim. Cosmochim. Acta 1996, 60 (16), 2977-2992. (15) Liu, S. Cooperative Adsorption on Solid Surfaces. J. Colloid Interface Sci. 2015, (18) Xu, J.; Marsac, R.; Wei, C.; Wu, F.; Boily, J. F.; Hanna, K. Cobinding of

Acknowledgements

This work was supported by the Institut Universitaire de France, the Swedish Research Council (2020-04853), the French National Research Agency via the C-FACTOR project (ANR-18-CE01-0008) and the CNRS (PICS 2018-2020). We gratefully acknowledge the Chinese Scholarship Council of PR China for providing financial support for Tao Luo to stay at the ENSCR.

Synopsis

This work contributes to efforts aiming to accurately assess co-binding mechanisms and the fate of co-existing contaminants in the environment.


M.Sc Christophe Ballouard

PhD Marc Poujol

PhD Philippe Boulvais

Yannick Branquet

PhD Romain Tartèse

PhD Jean-Louis Vigneresse

PhD Jarda Dostal
email: jdostal@smu.ca

Calvin Miller
email: calvin.f.miller@vanderbilt.edu

Sasha ( Aleksandr

PhD ) Stepanov
email: sasha.stepanov@utas.edu.au

PhD Philippe Muchez
email: philippe.muchez@ees.kuleuven.be

Specialist of Nb-Ta fractionation during igneous processes

Keywords: Nb-Ta fractionation, peraluminous granites, magmatic-hydrothermal transition, mineralization-bearing granites

Nb-Ta fractionation in peraluminous granites

INTRODUCTION

In granitic systems, the magmatic-hydrothermal transition separates a purely magmatic system dominated by crystal-melt interaction from a system dominated by crystal-melt-magmatic fluid phase interaction (Halter and Webster, 2014). Hydrothermal activity in peraluminous granites can be either localized, as evidenced by pegmatites and/or quartz veins, or pervasive, leading to significant element mobility and, in the most extreme cases, to the formation of greisens [START_REF] Pirajno | Effects of Metasomatism on Mineral Systems and Their Host Rocks: Alkali Metasomatism, Skarns, Greisens, Tourmalinites, Rodingites, Black-Wall Alteration and Listevenites[END_REF]. Such alteration events occur during the sub-solidus stage of the granitic melt emplacement and may lead to the deposition of economically significant mineralization such as Sn or W.

Nb and Ta are lithophile elements considered as "geochemical twins" because they have the same charge and similar ionic radius. As a result they have similar geochemical properties and should not be fractionated during most geological processes [START_REF] Goldschmidt | The principles of distribution of chemical elements in minerals and rocks. The seventh Hugo Müller Lecture delivered before the Chemical Society on March 17th[END_REF]. However, in granitic rocks, Nb/Ta ratios are highly variable (< 2 -25;[START_REF] Green | Significance of Nb/Ta as an indicator of geochemical processes in the crustmantle system[END_REF]. Some authors have demonstrated that the Nb/Ta ratios decrease in granites during fractional crystallization (Raimbault et al. 1995;[START_REF] Linnen | Columbite solubility in granitic melts: consequences for the enrichment and fractionation of Nb and Ta in the Earth's crust[END_REF][START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF]. Other studies have suggested that Nb and Ta could be fractionated in highly evolved peraluminous granites during the interaction with late magmatic fluids [START_REF] Dostal | Contrasting behaviour of Nb/Ta and Zr/Hf ratios in a peraluminous granitic pluton[END_REF]Tartèse and Boulvais, 2010;Ballouard et al., 2015;Dostal et al., 2015).

In order to decipher the specific role of the magmatic and hydrothermal processes on the evolution of the Nb/Ta ratios, we compiled whole rock geochemical data available in the literature for peraluminous granites emplaced at different times and in various tectonic contexts.

Based on these data, we show that fractional crystallization of granitic melts alone is not sufficient to account for the Nb-Ta behavior observed in most peraluminous granites and that hydrothermal processes are necessarily involved.

PRESENT KNOWLEDGE

Magmatic behavior of Nb-Ta

In highly evolved granites and pegmatites, columbite ((Fe,Mn)Nb2O6) and tantalite ((Fe, Mn)Ta2O6) are the main mineral phases hosting Nb and Ta. Experimental studies have shown that the solubility of these two minerals in granitic melts increases with temperature, but decreases with increasing the Aluminium Saturation Index (ASI), a parameter related to the degree of polymerization of the melt [START_REF] Linnen | Columbite solubility in granitic melts: consequences for the enrichment and fractionation of Nb and Ta in the Earth's crust[END_REF][START_REF] Aseri | Effects of fluorine on the solubilities of Nb, Ta, Zr and Hf minerals in highly fluxed water-saturated haplogranitic melts[END_REF]. The Li content of granitic melts also increases the solubility of columbite and tantalite [START_REF] Linnen | The solubility of Nb-Ta-Zr-Hf-W in granitic melts with Li and Li + F; constraints for mineralization in rare metal granites and pegmatites[END_REF][START_REF] Aseri | Effects of fluorine on the solubilities of Nb, Ta, Zr and Hf minerals in highly fluxed water-saturated haplogranitic melts[END_REF].

Partial melting can produce granitic peraluminous melts with Nb/Ta ratios higher or lower than their source, depending on the temperature. Melts formed during high temperature anatexis tend to have high Nb/Ta ratios, as a result of the complete consumption of biotite and the high abundance of Ti-bearing oxides in the residue, which preferentially incorporate Ta over Nb [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF]. Conversely, low temperature partial melting generates melts with low Nb/Ta ratios because residual biotite incorporates preferentially Nb over Ta [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF]. Since biotite and Ti-bearing minerals can also be involved during differentiation of granitic melts, fractional crystallization also changes Nb/Ta ratios: Nb/Ta increases during high temperature fractional crystallization of Ti-rich melts due to the preferential saturation of Tioxide minerals over biotite, whereas Nb/Ta ratios decrease during low temperature differentiation of granitic melts due to the fractionation of biotite and/or muscovite [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF]. In the most evolved peraluminous melts, the lower solubility of manganocolumbite (MnNb2O6) compared to manganotantalite (MnTa2O6) also enhances the decrease of the Nb/Ta ratio in the melt [START_REF] Linnen | Columbite solubility in granitic melts: consequences for the enrichment and fractionation of Nb and Ta in the Earth's crust[END_REF].

Melt inclusions in Li-F granites (Orlovka massif, Eastern Transbaikalia) indicate a separation of an immiscible F-rich hydrosaline melt that can induce a decrease of the Nb and Ta contents in the residual melt [START_REF] Badanina | Composition of Li-F granite melt and its evolution during the formation of the ore-bearing Orlovka massif in Eastern Transbaikalia[END_REF].

Nb-Ta behavior in hydrothermal systems

Nb and Ta are poorly soluble in aqueous solutions, Ta being even less soluble than Nb [START_REF] Zaraisky | Experimental studies of Ta2O5 and columbite-tantalite solubility in fluoride solutions from 300 to 550°C and 50 to 100 MPa[END_REF]. Experiments with aqueous F-rich fluids and aluminosilicate melt indicate that Nb and Ta preferentially partition in the melt [START_REF] Chevychelov | Effect of melt composition and temperature on the partitioning of Ta, Nb, Mn, and F between granitic (alkaline) melt and fluorine-bearing aqueous fluid: Fractionation of Ta and Nb and conditions of ore formation in rare-metal granites[END_REF]. However, the solubility and hydrothermal transfer of Ta and Nb are greatly enhanced in F-rich solutions under reducing conditions [START_REF] Zaraisky | Experimental studies of Ta2O5 and columbite-tantalite solubility in fluoride solutions from 300 to 550°C and 50 to 100 MPa[END_REF]. These experimental results are consistent with the fact that several F-rich cupolas of greisenized peraluminous granites are significantly enriched in both Nb and Ta (e.g. Zaraisky et al., 2009).

VARIATIONS OF WHOLE ROCK NB/TA RATIOS IN PERALUMINOUS GRANITES

We compiled data for peraluminous granites (i.e., with a A/CNK ratio > 1) as well as for some greisens of different ages (Archean to Mesozoic) and emplaced in various geodynamical contexts (see Table DR1 in the GSA Data Repository).

Nb-Ta fractionation during magmatic processes

In Figure 1, the Nb/Ta ratios are highly variable between ~15 and ~0 when reported as a function of Nb and Ta, the lowest values being recorded by whole rocks displaying the highest Nb and Ta contents. Mica fractionation in granitic melt induces a decrease of the Nb/Ta ratios [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF]. In Figure 1, we modeled the evolution of a melt with an initial Ta and Nb contents of 1.5 ppm and 12 ppm (Nb/Ta = 8), respectively, undergoing fractionation of a cumulate made of 80 wt.% (quartz + feldspar) + 10 wt.% muscovite + 10wt.% biotite, using the Rayleigh distillation law and the silicate-melt partition coefficients compiled by [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF].

The modeling qualitatively reproduces the behaviors of Nb and Ta, but it requires an unrealistic rate of mineral fractionation (over 90 wt.%) to reach low Nb/Ta ratios around 2 and Nb and Ta contents around 20 and 10 ppm, respectively (Fig. 1). The addition of 0.5 wt.% Fe-Ti oxide (e.g.ilmenite or rutile) in the cumulate, in which Ta and Nb are highly compatibles [START_REF] Stepanov | The key role of mica during igneous concentration of tantalum: Contribution to Mineralogy and Petrology[END_REF], makes things even worse. Indeed, the fractionation of this cumulate causes a decrease of the Nb content (Fig. 1A), resulting in a trend opposite to the trend displayed by the peraluminous granites.

If crystal-melt fractionation is likely to occur during the crystallization of granitic melts in magmatic bodies [START_REF] Dufek | Quantum magmatism: Magmatic compositional gaps generated by melt-crystal dynamics[END_REF] and during the magma ascent in dykes (Tartèse and Boulvais, 2010;[START_REF] Yamato | Numerical modelling of magma transport in dykes[END_REF], numerical modeling shows that the efficiency of crystal-melt segregation is restricted to cases where crystals represent a low percentage of the total magma volume (Yamato et al., in press). Indeed, 70-75% of crystallization marks the particle locking threshold (PLT in Figure 1B, [START_REF] Vigneresse | Rheological Transitions During Partial Melting and Crystallization with Application to Felsic Magma Segregation and Transfer[END_REF] where the liquid becomes totally locked, precluding any crystal-melt segregation. The model presented here thus suggests that fractional crystallization alone is not sufficient to explain the behaviors of Nb and Ta in peraluminous granitic rocks.

Nb-Ta fractionation during magmatic-hydrothermal processes

Mineralogical markers

Secondary muscovitization and greisenization occur under sub-solidus conditions during the interaction between crystallized granites and acidic late magmatic fluids [START_REF] Pirajno | Effects of Metasomatism on Mineral Systems and Their Host Rocks: Alkali Metasomatism, Skarns, Greisens, Tourmalinites, Rodingites, Black-Wall Alteration and Listevenites[END_REF]. The Figure 2 shows that the Nb/Ta ratios of whole rock granites and greisens are anti-correlated with the average MgO/(Na2O + TiO2) ratios of the muscovite they host (a chemical marker for secondary muscovitization, [START_REF] Miller | Composition of plutonic muscovite; genetic implications[END_REF]. This observed anti-correlation suggests that the fluids involved in the secondary muscovitization processes could also be responsible for the decrease of the Nb/Ta whole-rock values. Whole rock hydrothermal enrichment of Ta during secondary muscovitization is, for example, observed in ongonites (topaz-bearing microleucogranites) from the Ongon Kairkhan (Mongolia) and this process is associated with the crystallization of late Ta-rich overgrowth on Nb-Ta oxides (Dostal et al., 2015).

Geochemical markers

The whole rock Nb/Ta ratios of peraluminous granites are anti-correlated with their Sn contents, an element highly mobilized at the magmatic-hydrothermal transition (Fig. 3A): high Sn contents above ~30 ppm are only encountered in granitic samples (or greisens) with low Nb/Ta (< 5).

These samples also display high contents in Cs, F, Li, W and Rb. Because such incompatible elements present a strong affinity for magmatic fluids, their enrichment is commonly used as a marker of a magmatic-hydrothermal alteration in highly evolved crustal granites. Indeed, increasing the abundance of highly incompatible elements, with a bulk partition coefficient Kd between the mineral phases and the melt close to 0, by two orders of magnitude, as observed in Figure 3A (from ~10 to ~1000 ppm), during fractional crystallization requires a unrealistic degree of fractional crystallization up to 99 wt.%, suggesting that hydrothermal processes are also involved. Such enrichments in highly incompatible element, attributed to interaction with magmatic fluids, have been noticed in the Erzgebirge massif [START_REF] Förster | Late-Collisional Granites in the Variscan Erzgebirge[END_REF], in the South Mountain Batholith (e.g. [START_REF] Dostal | Contrasting behaviour of Nb/Ta and Zr/Hf ratios in a peraluminous granitic pluton[END_REF], or in the French Armorican Massif (Tartèse and Boulvais, 2010;Ballouard et al., 2015).

The Nb/Ta ratios also correlate with the K/Rb ratios (Fig. 3B). Most granites with low Nb/Ta display K/Rb values lower than 150, characteristic of the pegmatite-hydrothermal evolution [START_REF] Shaw | A review of K-Rb fractionation trends by covariance analysis[END_REF]. Such a tendency is observed in the South Mountain Batholith, where it was interpreted as evidence for a magmatic-hydrothermal alteration [START_REF] Dostal | Contrasting behaviour of Nb/Ta and Zr/Hf ratios in a peraluminous granitic pluton[END_REF].

Finally, the whole rock Nb/Ta ratios can be compared with the magnitude of the tetrad effect, which corresponds to the intra-REE fractionation observed in the REE patterns of highly fractionated magmatic rocks and hydrothermal precipitates (e.g. [START_REF] Irber | The lanthanide tetrad effect and its correlation with K/Rb, Eu/Eu*, Sr/Eu, Y/Ho, and Zr/Hf of evolving peraluminous granite suites[END_REF]. Although Duc-Tin and Kepller (2015) have recently suggested that the tetrad effect could result from monazite and xenotime fractionation, most authors have argued that such REE patterns actually reflect a selective complexation of the REE during the interaction of granitic melts with F-and Cl-rich aqueous fluids (e.g. [START_REF] Bau | Controls on the fractionation of isovalent trace elements in magmatic and aqueous systems: evidence from Y/Ho, Zr/Hf, and lanthanide tetrad effect[END_REF][START_REF] Irber | The lanthanide tetrad effect and its correlation with K/Rb, Eu/Eu*, Sr/Eu, Y/Ho, and Zr/Hf of evolving peraluminous granite suites[END_REF][START_REF] Monecke | Origin of convex tetrads in rare earth element patterns of hydrothermally altered siliceous igneous rocks from the Zinnwald Sn-W deposit, Germany[END_REF]. [START_REF] Irber | The lanthanide tetrad effect and its correlation with K/Rb, Eu/Eu*, Sr/Eu, Y/Ho, and Zr/Hf of evolving peraluminous granite suites[END_REF] quantified the degree of tetrad effect (TE1-3) by determining the deviation of the first and the third tetrad of granites REE-patterns from a hypothetical tetrad effect-free REE pattern. The large majority of the samples with significant tetrad effect (TE1-3 > 1.1) are also characterized by low Nb/Ta ratios below ~5 (Fig. 3C).

Metallogenic markers

The Nb/Ta ratio is commonly compared to the Zr/Hf ratio, as the latter has been proposed as either a marker of magmatic-hydrothermal interactions [START_REF] Bau | Controls on the fractionation of isovalent trace elements in magmatic and aqueous systems: evidence from Y/Ho, Zr/Hf, and lanthanide tetrad effect[END_REF] or of fractional crystallization [START_REF] Linnen | Melt composition control of Zr/Hf fractionation in magmatic processes[END_REF][START_REF] Claiborne | Tracking magmatic processes through Zr/Hf ratios in rocks and Hf and Ti zoning in zircons: An example from the Spirit Mountain batholith[END_REF]. The Zr/Hf ratio is a geochemical indicator of the fertility of granitic rocks as a Zr/Hf ratios below ~25 (corresponding to the lower limit of the CHArge and RAdius Control range; [START_REF] Bau | Controls on the fractionation of isovalent trace elements in magmatic and aqueous systems: evidence from Y/Ho, Zr/Hf, and lanthanide tetrad effect[END_REF] are expected in granites where Sn, W, Mo, Be and Ta mineralization are described (Zaraisky et al., 2009). In a Nb/Ta vs. Zr/Hf diagram (Fig. 4), most barren granites plot in the field defined by 26 < Zr/Hf < 46 (CHARAC range of [START_REF] Bau | Controls on the fractionation of isovalent trace elements in magmatic and aqueous systems: evidence from Y/Ho, Zr/Hf, and lanthanide tetrad effect[END_REF] and by 5 < Nb/Ta < 16, whereas peraluminous granites associated with Sn, W and/or U deposits have 18 <Zr/Hf< 46 with Nb/Ta ratio lower than 5. Rare metals granites are characterized by even lower Zr/Hf ratios (< 18) with Nb/Ta ratios that are still lower than 5.

From the diagrams presented in Figures 2, 3 and4, we highlight significant mineralogical (secondary muscovitization), geochemical (Sn contents, K/Rb ratio, tetrad effect) and metallogenic (Sn-W-U and rare metal mineralization) evidence that magmatic-hydrothermal processes account for the decrease of the Nb/Ta ratio in peraluminous granites. The solubility and hydrothermal transfer of Nb and Ta are greatly enhanced, by up to three orders of magnitude, in reduced F-rich aqueous solutions [START_REF] Zaraisky | Experimental studies of Ta2O5 and columbite-tantalite solubility in fluoride solutions from 300 to 550°C and 50 to 100 MPa[END_REF]. Therefore, in peraluminous granites affected by sub-solidus alteration, the Nb/Ta ratios can be lowered by an increase of the Ta content in Ta-Nb-bearing minerals due to the lower mobility of Ta compared to Nb in aqueous solutions. As a consequence, we suggest here that the decrease of the Nb/Ta ratios to values lower than ~5 in peraluminous granites reflects the concomitant effect of fractional crystallization and sub-solidus magmatic-hydrothermal alteration, likely by F-rich acidic reduced fluids of magmatic origin.

Nb/Ta = 5: a critical ratio for granite petrogenesis and mineral exploration strategies

The peraluminous granite whole rock samples with Nb/Ta ratios lower than 5 show significant evidence of interaction with fluids. We suggest that Nb/Ta = 5 represents a threshold between a purely magmatic system (Nb/Ta > 5) and a magmatic-hydrothermal system (Nb/Ta < 5). Taking a cut off value of 5 for the Nb/Ta ratio as a marker of the magmatic-hydrothermal transition in peraluminous granites bears some implications for exploration strategies as it can also help to define the economic potential of these granites. Indeed, Figure 4 demonstrates that a Nb/Ta ratio of 5 can be used as a geochemical indicator to differentiate barren granites from granites spatially related to Sn-W-(U) or rare metals mineralization. Since whole rock trace element analyses (including Nb and Ta) are routinely performed in most laboratories around the world, the simple calculation of whole rock sample Nb/Ta ratios can, therefore, help exploration geologists to define potential targets for Sn-W-(U) and rare metals deposits.

CONCLUSION

The mineralogical and geochemical evidence of fluid interaction recorded in granitic whole rock samples, indicate that the value Nb/Ta = 5 is a good marker of the magmatic-hydrothermal transition in peraluminous granites. The decrease of the Nb/Ta ratio in peraluminous granites is associated with an increase of the degree of secondary muscovitization and with geochemical and metallogenic evidence of hydrothermal interactions, suggesting that sub-solidus alteration is involved in the fractionation of Nb-Ta. To further constrain the mechanisms involved in the fractionation of Nb/Ta ratios in peraluminous granites at the magmatic-hydrothermal transition, mineral-scale analyses would now be required. From an exploration point of view, and based on the large compilation of data presented in this study, the Nb/Ta ratio appears to be a good geochemical indicator to differentiate barren from ore-bearing peraluminous granites. [START_REF] Miller | Composition of plutonic muscovite; genetic implications[END_REF]. (B)

FIGURE CAPTIONS

Diagram reporting the evolution of Nb/Ta ratios for whole rock samples from different peraluminous granites against the average value of the MgO/(Na2O + TiO2) ratios of their diochtaedral micas.

Figure 3: Evolution of Nb/Ta ratios of peraluminous granites as a function of selected markers of magmatic-hydrothermal alteration. The degree of tetrad effect (TE1-3) has beencalculated using the equation of [START_REF] Irber | The lanthanide tetrad effect and its correlation with K/Rb, Eu/Eu*, Sr/Eu, Y/Ho, and Zr/Hf of evolving peraluminous granite suites[END_REF]. CC: Continental Crust composition (from [START_REF] Rudnick | Composition of the Continental Crust[END_REF].

Figure 1 .

 1 Figure 1.Nb/Ta vs. (A) Nb and (B) Ta abundances for peraluminous granites. The colored curves represent a model of evolution of Nb and Ta in a liquid L0 (Nb= 12 ppm, Ta =1.5 ppm, Nb/Ta = 8) during the fractionation of an assemblage made of 10 wt.% biotite + 10 wt.% muscovite + 80 wt.% (quartz + feldspar). The numbers above the curves indicate the amount of fractional crystallization. The black dashed line represents the same model during the fractionation of an assemblage composed of 10 wt.% biotite + 10 wt.% muscovite + 0.5 wt.% ilmenite + 79.5 wt.% (quartz + feldspar). The Kd used and presented in the table in inset in the diagram are from Stepanov et al. (2014) and reference therein. PLT: Particle Locking Threshold[START_REF] Vigneresse | Rheological Transitions During Partial Melting and Crystallization with Application to Felsic Magma Segregation and Transfer[END_REF].

Figure 2 .

 2 Figure 2. (A) Mg-Na-Ti ternary classification diagram of muscovite[START_REF] Miller | Composition of plutonic muscovite; genetic implications[END_REF]. (B)

Figure 4 .

 4 Figure 4.Nb/Ta vs.Zr/Hf diagram differentiating barren and ore-bearing peraluminous granites.

Figure 1

 1 Figure 1

Figure 2

 2 Figure 2

Figure 3

 3 Figure 3

Figure 4

 4 Figure 4

ACKNOWLEDGMENTS

We acknowledge Calvin Miller and two anonymous referees for their fruitful comments on a previous version of this manuscript.

Table DR1: Synthesis of the peraluminous granites reported in this study with their location, their age, their associated metal deposits when available and the corresponding references.

Supplemental file

Click here to download Supplemental file DR1.docx


Opinion of the actors for the planning of care for the elderly, territorial organization of the response, and mortality in the nursing homes.

An attempt at understanding covid epidemy.

.

Opinion of the actors for the planning of care for the elderly, territorial organization of the response, and mortality in the nursing homes. An attempt at understanding covid epidemy.

Alain Jourdain

To cite this version:

Alain Jourdain. Opinion of the actors for the planning of care for the elderly, territorial organization of the response, and mortality in the nursing homes. An attempt at understanding covid epidemy.. XXIX International Population Conference (IPC2021), Dec 2021, Conference held virtually, France. hal-03485363

Introduction

The 14 May 2021 there have been 26307 deaths in housing facilities for the elderly dependent or for the disabled in France. While research on the health needs of the population is conducted mainly in quantitative form, we need more qualitative analyses of the discourses of social policy stakeholders, users, professionals, elected officials and association. Our hypothesis is that social representations and health resources are of equal importance to drive planning of social care for elderly.

Method

We interviewed 23 people in 3 ideal-typic regions of France: professionals from the territorial delegations, departmental councils, municipalities and intercommunity, associations or professional federations. The discussions focused on their views and their role in the reforms as well as the contribution of the provisions of the services. We tried to categorize the discursive formations of the medico-social field with the use of textometry.

The 5 groups of social representations. The classical public administration (class 5) and the new public governance (class4), centralized, express a common interest in the territorial policies undertaken by the State, the discursive formations of the territorial actors of social care and health (classes 2 and 3) have in common their peripheral position and their expertise of the field, and finally the formations of the new public management (Class 1), present themselves as integrative forces of the medical-social sector.

Health representations

Three ideal-typical regions have been chosen to take into account the diversity of environments in which the players in the "medicosocial" sector in France.

In the Region B, the health and social sectors are independently linked to the center, the former by management the latter by health democracy.

In the region A administration and management combine, as well as health and medico social. It is only in a second step that the process of healthy democracy makes it possible to close the device.

In the region C the organization of social planning follows a linear process of management administration towards a democracy that is ultimately enriched towards health.

Health resources

Region A representative of others with healthy population, well endowed with care professionals, although under-endowed with health and social institutions and more dependent on social benefits. Region C, representing disadvantaged, in worse health and poverty, more poorly endowed with professionals. On the other hand, the rate of equipment in shortstay beds compensates for a rather unfavorable situation in terms of care provision. Region B, representative of others with poor health indicators, less affected by extreme poverty and more by low wages. It has better resources in psychiatry, for disability and the elderly in institutions.

Observation of mortality in nursing homes during the pandemics

Mortality in the nursing homes (EHPAD) was higher during the first wave of the pandemics in Region C (May 2020), but Region A was higher during the second wave (November 2020). This phenomenon continues in 2021 when Region A was affected more strongly, especially with a lower vaccination rate..

Discussion

One region has consistently experienced a lower mortality rate and has achieved a high vaccination rate. It is not the better endowed or equipped region. The construction of its social planning was done by a double approach, social administration and health democracy, the administration being in these four poles of representation.

Another region experienced a serious onset of crisis, followed by a reversal of the situation, controlling the epidemic in nursing homes, while having an average vaccination rate. This region is the poorest, its system is public. Its policy was developed from an alliance of the administration and local authorities on the theme of the social care in order to build a managerial form before completing the health dimension.

The third region was well placed at the beginning of the epidemic, it lost its advantage thereafter and did not develop a significant vaccination campaign. It was also the region with the best health workforce. Politics was built on management and medico-social as in the first, but administration and health, democracy intervenes only as a last resort.

If we consider that region B provides better management, we can analyze the two other regions from this reference .

In A the fact of linking administration and health, without democratic regulation (CRSA) may represent an obstacle because the link between governance (local democracy) and health does not work effectively.

In C, activating the social care and administration to build a management system that will support the health system is an alternative and cumbersome system to meet the requirements of the epidemic.