Lise Charuaud
email: lise.charuaud@ehesp.fr

Emilie Jarde

Anne Jaffrezic

Marie-Florence Thomas

Barbara Le Bot

Veterinary pharmaceutical residues from natural water to tap water: Sales, occurrence and fate

Keywords: Veterinary pharmaceuticals VPRs: Veterinary pharmaceutical residues Veterinary drugs, antibiotics, animal husbandry, drinking water treatment plant, removal rates

 Worldwide, tetracyclines are the most sold veterinary pharmaceuticals  Photolysis is the main degradation pathway of veterinary residues in surface waters  Veterinary drugs concentrations in natural waters range from 1ng.L -1 to 255µg.L -1  Overall removal rates in drinking water treatment plants generally exceed 90%  11 studies on the occurrence of veterinary pharmaceutical residues in tap water

ABSTRACT

Veterinary pharmaceuticals (VPs) increasingly used in animal husbandry have led to their presence in aquatic environments -surface water (SW) or groundwater (GW)and even in tap water. This review focuses on studies from 2007 to 2017. Sixty-eight different veterinary pharmaceutical residues (VPRs) have been quantified worldwide in natural waters at concentrations ranging from nanograms per liter (ng.L -1 ) to several micrograms per liter (µg.L -1 ). An extensive up-to-date on sales and tonnages of VPs worldwide has been performed. Tetracyclines (TCs) antibiotics are the most sold veterinary pharmaceuticals worldwide. An overview of VPRs degradation pathways in natural waters is provided. VPRs can be degraded or transformed by biodegradation, hydrolysis or photolysis. Photodegradation appears to be the major degradation pathway in SW. This review then reports occurrences of VPRs found in tap water, and presents data on VPRs removal in drinking water treatment plants (DWTPs) at each step of the process. VPRs have been quantified in tap water at ng.L -1 concentration levels in four studies of the eleven studies dealing with VPRs occurrence in tap water. Overall removals of VPRs in DWTPs generally exceed 90% and advanced treatment processes (oxidation processes, adsorption on activated carbon, membrane filtration) greatly contribute to these removals. However, studies performed on full-scale DWTPs are scarce. A large majority of fate studies in DWTPs have been conducted under laboratory at environmentally irrelevant conditions (high concentration of VPRs (mg. L -1 ), use of deionized water instead of natural water, high concentration of oxidant, high contact time. etc.). Also, studies on VPRs occurrence and fate in tap water focus on antibiotics. There is a scientific gap on the occurrence and fate of antiparatic drugs in tap waters.

As the human population is growing, animal production is also rapidly expanding to feed this population [START_REF] Van Boeckel | Global trends in antimicrobial use in food animals[END_REF]. This leads to intensive agricultural practices, with confined animal feeding operations (CAFOs) [START_REF] Bartelt-Hunt | Occurrence of steroid hormones and antibiotics in shallow groundwater impacted by livestock waste control facilities[END_REF][START_REF] Obimakinde | Veterinary pharmaceuticals in aqueous systems and associated effects: an update[END_REF]. In CAFOs, it is a common practice to use veterinary pharmaceuticals (VPs) not only for curative ends, but also prophylactic purposes [START_REF] Van Boeckel | Global trends in antimicrobial use in food animals[END_REF][START_REF] Kumar | Fate, occurrence, and toxicity of veterinary antibiotics in environment[END_REF][START_REF] Van Epps | Antibiotic Residues in Animal Waste: Occurrence and Degradation in Conventional Agricultural Waste Management Practices[END_REF].VPs have also been widely used for growth promotion [START_REF] Kumar | Fate, occurrence, and toxicity of veterinary antibiotics in environment[END_REF], even if this practice has begun to be restricted or even banned, for example in the European Union (EU) [START_REF] Du | Occurrence, fate, and ecotoxicity of antibiotics in agro-ecosystems. A review[END_REF][START_REF] Kim | Occurrence and Environmental Fate of Veterinary Antibiotics in the Terrestrial Environment[END_REF]. Nowadays, more than 2000 veterinary pharmaceuticals products are available on the market worldwide [START_REF] Tasho | Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: A review[END_REF]. VPRs can be released into the environment either directly with urine and feces of animals in pastures or during aquaculture activities, or indirectly during the spreading of contaminated manure and slurry [START_REF] Kim | Occurrence and Environmental Fate of Veterinary Antibiotics in the Terrestrial Environment[END_REF][START_REF] Kools | A ranking of European veterinary medicines based on environmental risks[END_REF][START_REF] Boxall | Veterinary Medicines and the Environment[END_REF][START_REF] Jeon | Reactions and Behavior Relevant to Chemical and Physical Properties of Various Veterinary Antibiotics in Soil[END_REF][START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. Because of their continuous use, veterinary pharmaceutical residues (VPRs) represent a diffuse and pseudo-persistent pollution in the environment. Among other emerging contaminants, VPRs have been quantified worldwide in aquatic environment, with progresses in analytical methods [START_REF] Boxall | Veterinary Medicines and the Environment[END_REF][START_REF] Iglesias | Detection and quantitative analysis of 21 veterinary drugs in river water using high-pressure liquid chromatography coupled to tandem mass spectrometry[END_REF][START_REF] Iglesias | Detection of veterinary drug residues in surface waters collected nearby farming areas in Galicia, North of Spain[END_REF]. As tap water is produced worldwide from natural waters (SW or GW), it is important to review the occurrence of VPRs in natural waters and the factors affecting this occurrence. Indeed VPRs occurring in natural waters may reach DWTPs which produce tap water. A public health concern is that if these compounds are not fully removed and/or transformated in DWTPs, the human population could be chronically exposed to these compounds. This continuous exposure may represent a risk as VPs are designed to exert biological effects on animals at low doses (as for antibiotic which are active at mg of drug per kg of animal weight) or very low doses (hormones which are active at µg of drug per kg of animal weight) [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. VPR may also interact together or with other organic contaminants present in drinking water, resulting in addition or synergistic effects [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. Moreover, chronic exposure of pathogens, commensal or environmental bacteria to veterinary antibiotics can lead to cross-resistance to antibiotics through the development and selection of more harmful bacteria [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF][START_REF] Xie | Antibiotics and antibiotic resistance from animal manures to soil: a review: Antibiotics and antibiotic resistance[END_REF]. It is a crucial issue as no new class of antibiotics has been discovered since 1987 [START_REF] Tasho | Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: A review[END_REF]. However, data on VPRs fate in DWTPs as well as on their occurrence in tap water are scarce and deserve more attention as it is not known if those micropollutants are removed during the applied treatment processes. Lastly, transformation products (TPs) of VPRs should also be considered. Subsequent compounds generated after the transformation process of a certain "parent compound" are considered as TPs. TPs can be generated by natural processes such as metabolization in the treated animals [START_REF] Kim | Occurrence and Environmental Fate of Veterinary Antibiotics in the Terrestrial Environment[END_REF][START_REF] Jeon | Reactions and Behavior Relevant to Chemical and Physical Properties of Various Veterinary Antibiotics in Soil[END_REF][START_REF] Kemper | Veterinary antibiotics in the aquatic and terrestrial environment[END_REF] or via hydrolysis or photolysis in the environment [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF][START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF]. They can also be derived from engineering processes, for example during agricultural waste management practices (i.e. digestion, composting, etc.,) [START_REF] Van Epps | Antibiotic Residues in Animal Waste: Occurrence and Degradation in Conventional Agricultural Waste Management Practices[END_REF][START_REF] Youngquist | Fate of Antibiotics and Antibiotic Resistance during Digestion and Composting: A Review[END_REF] or in DWTPs during oxidation steps [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF][START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF][START_REF] Dong | Degradation of chloramphenicol by UV/chlorine treatment: Kinetics, mechanism and enhanced formation of halonitromethanes[END_REF]. These TPs can retain a biological activity [START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF][START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF][START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF] which may pose risks towards aquatic ecosystems or human health. Ciprofloxacin is the main metabolite of the veterinary antibiotic enrofloxacin, and it is also a pharmaceutical used in human medicine. Both compounds have been proved to exert a negative impact on amphibian larvae growth and development at concentrations greater than or equal to 10µg.L -1 [START_REF] Peltzer | Ecotoxicity of veterinary enrofloxacin and ciprofloxacin antibiotics on anuran amphibian larvae[END_REF]. Photo-transformation products of the antibiotic tetracycline exhibit a higher toxicity towards luminescent bacteria V. fischeri than tetracycline [START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF] and photoproducts of the hormone altrenogest seem to possess significant androgenic activity according to in vitro tests performed by Wammer et al. [START_REF] Wammer | Direct photochemistry of three fluoroquinolone antibacterials: Norfloxacin, ofloxacin, and enrofloxacin[END_REF]. Thus aquatic ecosystems can be negatively impacted by TPs generated by VPRs. When considering TPs produced during tap water production, TPs can gain toxicity during oxidation processes [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF][START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF]. TPs of nitroimidazoles compounds generated during ozonation process were more toxic to V. fischeri than the initial nitro-imidazoles [START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF]. In Leavey-Roback et al. [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF], chloramination disinfection of veterinary antiobiotics such as tetracyclines or macrolides induces the formation of the carcenogenic disinfection product N-nitrosodimethylamine. Thus, these TPs may threat human health.

A C C E P T E D

M A N U S C R I P T
Many reviews have been published on veterinary pharmaceutical residues in the environment [START_REF] Kumar | Fate, occurrence, and toxicity of veterinary antibiotics in environment[END_REF][START_REF] Du | Occurrence, fate, and ecotoxicity of antibiotics in agro-ecosystems. A review[END_REF][START_REF] Kim | Occurrence and Environmental Fate of Veterinary Antibiotics in the Terrestrial Environment[END_REF][START_REF] Tasho | Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: A review[END_REF][START_REF] Kools | A ranking of European veterinary medicines based on environmental risks[END_REF][START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF][START_REF] Xie | Antibiotics and antibiotic resistance from animal manures to soil: a review: Antibiotics and antibiotic resistance[END_REF][START_REF] Kemper | Veterinary antibiotics in the aquatic and terrestrial environment[END_REF][START_REF] Aga | Challenges in the Measurement of Antibiotics and in Evaluating Their Impacts in Agroecosystems: A Critical Review[END_REF][START_REF] Boxall | Are veterinary medicines causing environmental risks?[END_REF][START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Kaczala | The Occurrence of Veterinary Pharmaceuticals in the Environment: A Review[END_REF][START_REF] Khan | Chemical contaminants in feedlot wastes: Concentrations, effects and attenuation[END_REF][START_REF] Kümmerer | Antibiotics in the aquatic environment -A review -Part I[END_REF][START_REF] Kümmerer | Antibiotics in the aquatic environment -A review -Part II[END_REF][START_REF] Lumaret | A review on the toxicity and non-target effects of macrocyclic lactones in terrestrial and aquatic environments[END_REF][START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF][START_REF] Slana | Environmental Risk Assessment of antimicrobials applied in veterinary medicine-A field study and laboratory approach[END_REF][START_REF] Snow | Detection, Occurrence and Fate of Pharmaceuticals and Steroid Hormones in Agricultural Environments[END_REF][START_REF] Thiele-Bruhn | Pharmaceutical antibiotic compounds in soils -a review[END_REF][START_REF] Tolls | Sorption of veterinary pharmaceuticals in soils: a review[END_REF][START_REF] Van Den Brink | The use of terrestrial and aquatic microcosms and mesocosms for the ecological risk assessment of veterinary medicinal products[END_REF][START_REF] Wegst-Uhrich | Assessing antibiotic sorption in soil: a literature review and new case studies on sulfonamides and macrolides[END_REF]. In those reviews, veterinary pharmaceutical residues occurrence and fate in soil have been largely studied, as mobility from soil to water. But only few reviews have been published on occurrence and fate in natural waters (sorption and degradation) and tap water. This review provides an update on research performed from 2007 to 2017 on [START_REF] Van Boeckel | Global trends in antimicrobial use in food animals[END_REF] the occurrence of 65 VPRs (i.e. antibiotics, antiparasitic drugs, anti-inflammatory drugs) in natural waters (surface water and groundwater; 38 studies) related to (2) their uses and their fate. An extensive up-to-date on sales data worldwide, ten years after Sarmah et al., publication [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF] is provided, as sales and usages are critical factors impacting environmental occurrence of VPRs [START_REF] Li | The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases[END_REF][START_REF] Yao | Seasonal variation of antibiotics concentration in the aquatic environment: a case study at Jianghan Plain, central China[END_REF][START_REF] Yao | Occurrence and risk assessment of antibiotics in surface water and groundwater from different depths of aquifers: A case study at Jianghan Plain, central China[END_REF]. Sales trends over the past decade are presented for countries where they are available in the public domain. It is also mention when there is no available sales information for countries which are likely to be significant consumers of VPRs. In 2009, Kümmerer [START_REF] Kümmerer | Antibiotics in the aquatic environment -A review -Part I[END_REF] reported a lack of information on VPRs degradation pathways, especially on photolysis, with comparison between direct and indirect photolysis. To fill this gap, a complete and up-to-date overview of degradation pathways by chemical family is provided (38 studies). Afterwards, this review focus on (3) VPRs occurrence in tap water (11 studies) consequently to (4) their behaviour during drinking water treatment plant processes (28 studies). Few reviews address VPRs behaviour in DWTPs, and deal with pharmaceuticals and personal care products with great emphasis on human pharmaceuticals [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF][START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF] or with antibiotics used both in human and veterinary medicine [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Ahmed | Adsorption of quinolone, tetracycline, and penicillin antibiotics from aqueous solution using activated carbons: Review[END_REF]. To our knowledge, this review is the first to gather all available data on VPRs removals rates and fate in DWTPs.

OCCURRENCE OF VPRs IN NATURAL WATERS

The occurrences of VPRs (since 2007) in surface water and groundwater are presented in Figure 1 and Figure 2. Figure 1 focuses on VPRs that have been searched in more than one hundred samples (all studies included). The minimum and maximum quantified concentrations of VPRs in each study are shown on the graphic. Figure 2 focuses on VPRs searched in less than one hundred samples and shows minimum and maximum concentrations quantified in each study. VPRs that were investigated but not detected have not been reported in Figures 1 and2, for example coccidiostat toltrazuril and its metabolites [START_REF] Olsen | Development of an analytical methodology for the determination of the antiparasitic drug toltrazuril and its two metabolites in surface water, soil and animal manure[END_REF], avermectins [START_REF] Thompson | Large volume injection for the direct analysis of ionophores and avermectins in surface water by liquid chromatography-electrospray ionization tandem mass spectrometry[END_REF] or some corticosteroids [START_REF] Iglesias | Detection and quantitative analysis of 21 veterinary drugs in river water using high-pressure liquid chromatography coupled to tandem mass spectrometry[END_REF][START_REF] Iglesias | Detection of veterinary drug residues in surface waters collected nearby farming areas in Galicia, North of Spain[END_REF]. In the 38 studies considered [START_REF] Bartelt-Hunt | Occurrence of steroid hormones and antibiotics in shallow groundwater impacted by livestock waste control facilities[END_REF][START_REF] Iglesias | Detection and quantitative analysis of 21 veterinary drugs in river water using high-pressure liquid chromatography coupled to tandem mass spectrometry[END_REF][START_REF] Iglesias | Detection of veterinary drug residues in surface waters collected nearby farming areas in Galicia, North of Spain[END_REF][START_REF] Li | The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases[END_REF][START_REF] Yao | Seasonal variation of antibiotics concentration in the aquatic environment: a case study at Jianghan Plain, central China[END_REF][START_REF] Yao | Occurrence and risk assessment of antibiotics in surface water and groundwater from different depths of aquifers: A case study at Jianghan Plain, central China[END_REF], sampling was carried out near husbandry facilities or crops in rural watersheds, once or several times at different seasons of the year.

[Figure 1] [Figure 2] As reported in Figure 1 and 2, 64 different VPRs were detected in surface waters, especially rivers [START_REF] Burke | Occurrence of Antibiotics in Surface and Groundwater of a Drinking Water Catchment Area in Germany[END_REF][START_REF] Ok | Monitoring of selected veterinary antibiotics in environmental compartments near a composting facility in Gangwon Province, Korea[END_REF][START_REF] Kim | Effect of runoff discharge on the environmental levels of 13 veterinary antibiotics: A case study of Han River and Kyungahn Stream, South Korea[END_REF][START_REF] Zhang | Prevalence of Veterinary Antibiotics and Antibiotic-Resistant Escherichia coli in the Surface Water of a Livestock Production Region in Northern China[END_REF] but also lakes [START_REF] Tong | Analysis of veterinary antibiotic residues in swine wastewater and environmental water samples using optimized SPE-LC/MS/MS[END_REF][START_REF] Jiang | Contamination of Surface Water with Veterinary Antibiotics in Tiaoxi River Basin, East China[END_REF], at concentrations ranging from <1 ng.L -1 [START_REF] Jiang | Contamination of Surface Water with Veterinary Antibiotics in Tiaoxi River Basin, East China[END_REF][START_REF] Murata | Nationwide monitoring of selected antibiotics: Distribution and sources of sulfonamides, trimethoprim, and macrolides in Japanese rivers[END_REF][START_REF] Zrnčić | Analysis of anthelmintics in surface water by ultra high performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry[END_REF] to 255 microgram.L -1 (µg.L -1 ) (tetracycline [START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF]; out-of-scale value in Figure 1). High levels of concentrations depend on the study location and of the veterinarian prescriptions in the corresponding area. For example, the highest concentration level (tetracyline; 255 µg.L -1 ) was quantified in a sampling site that was assumed to be affected by the discharge of veterinary pharmaceuticals from a swine manure composting facility [START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF]. Sulfapyridine, sulfamethazine, sulfamethoxypyridazine and sulfadiazine were quantified in the Llobregat river in Spain at 12 µg.L -1 ; 6192 ng.L -1 ; 3704 ng.L -1 and 2312 ng.L -1 , respectively. Similarly, many agricultural areas were located upstream the sampling site [START_REF] Díaz-Cruz | Highly sensitive simultaneous determination of sulfonamide antibiotics and one metabolite in environmental waters by liquid chromatography-quadrupole linear ion trap-mass spectrometry[END_REF]. In the 11 studies considered in groundwater, 47 VPRs were quantified with concentrations ranging from <1 ng.L -1 [START_REF] Hu | Determination of 26 veterinary antibiotics residues in water matrices by lyophilization in combination with LC-MS/MS[END_REF] to 3.461 µg.L -1 for sulfacetamide [START_REF] García-Galán | Simultaneous occurrence of nitrates and sulfonamide antibiotics in two ground water bodies of Catalonia (Spain)[END_REF]. Sulfonamides (SAs)

A C C E P T E D M A N U S C R I P T
constitute the most detected chemical family but also the most studied (28 studies on 38 studies considered) so there may be a bias. Surface water can be a source of contamination for groundwater through artificial or natural exchanges between the two resources [START_REF] Yao | Seasonal variation of antibiotics concentration in the aquatic environment: a case study at Jianghan Plain, central China[END_REF][START_REF] Burke | Occurrence of Antibiotics in Surface and Groundwater of a Drinking Water Catchment Area in Germany[END_REF][START_REF] Lapworth | Emerging organic contaminants in groundwater: A review of sources, fate and occurrence[END_REF].

FACTORS IMPACTING THE OCCURRENCE OF VPRs IN NATURAL WATERS

Sales and uses of VPs worldwide

Uses of VPs strongly differ between countries, because of the different animal species (i.e. swine, cattle, sheep, etc.), animal farming methods and climate conditions [START_REF] Kools | A ranking of European veterinary medicines based on environmental risks[END_REF][START_REF] Wei | Occurrence of veterinary antibiotics in animal wastewater and surface water around farms in Jiangsu Province, China[END_REF]. However, the therapeutic classes most often used are antibiotics, antiparasitics (endo-and ectoparasitics) and steroidal hormones [START_REF] Kools | A ranking of European veterinary medicines based on environmental risks[END_REF][START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. Antibiotics represent 70% of all consumed drugs that are approved for animal medicine worldwide [START_REF] Jeon | Reactions and Behavior Relevant to Chemical and Physical Properties of Various Veterinary Antibiotics in Soil[END_REF]. Other therapeutic classes used in veterinary medicine include non-steroidal anti-inflammatory drugs, anxiolytics and sedatives such as benzodiazepines, beta-agonists agents, anesthetics, euthanasia products, antacids, diuretics, emetics, etc. [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. In 2006, [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF] provided an international overview of veterinary antibiotics sales by compiling available information at that time. Based on this previous work, an up-to-date of the sales was performed in order to show new trends in these uses and determine evolutions in data availability. In 2006, sales data were not available in the United States of America (USA) and only a few European countries (Sweden, Denmark, Finland, and Netherlands) were publishing their antibiotic sales in the public domain [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF]. Current available sales data, i.e. about ten years after [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF], are presented below. Tables 1; 2 and 3 report the latest available sales amounts for USA (2016), Europe (2015), France (2016), Japan (2015), Korea (2015), New Zealand (2014) and Australia (2010). According to the tables 1; 2 and 3, the most frequently used antibiotics worldwide for veterinary purposes are tetracyclines (TCs), SAs, penicillins (PENs) and macrolides (MLs).

[Table 1] In the USA, the amount of antibiotics sold for veterinary purposes equals 70% of total antibiotics sales [START_REF] Van Boeckel | Global trends in antimicrobial use in food animals[END_REF][START_REF] Obimakinde | Veterinary pharmaceuticals in aqueous systems and associated effects: an update[END_REF][START_REF] Du | Occurrence, fate, and ecotoxicity of antibiotics in agro-ecosystems. A review[END_REF][START_REF] Snow | Detection, Occurrence and Fate of Emerging Contaminants in Agricultural Environments[END_REF]. An increase of 11% in total annual sales amount was reported between 2009 and 2016, but sales decreased by 10% between 2015 and 2016 [START_REF]Food and Drug Administration (FDA), Summary report on antimicrobials sold or distributed for use in food-producing animal[END_REF]. Sales of lincosamides and cephalosporins increased by more than 50% between 2009 and 2016 [START_REF]Food and Drug Administration (FDA), Summary report on antimicrobials sold or distributed for use in food-producing animal[END_REF]. Total amount of antibiotics for veterinary use was estimated at almost 13 983 tons in 2016 [START_REF]Food and Drug Administration (FDA), Summary report on antimicrobials sold or distributed for use in food-producing animal[END_REF], perhaps the world's largest (or second behind China [START_REF] Obimakinde | Veterinary pharmaceuticals in aqueous systems and associated effects: an update[END_REF][START_REF] Hu | Health risk from veterinary antimicrobial use in China's food animal production and its reduction[END_REF]). These high amounts are not only due to the presence of large numbers of livestock, but also to the authorized use of antibiotics as growth promoters [START_REF] Bártíková | Veterinary drugs in the environment and their toxicity to plants[END_REF]. High use of ionophores is largely responsible for quantification of monensin in surface water (300 to 5130 ng.L -1 ; [START_REF] Kurwadkar | Preliminary studies on occurrence of monensin antibiotic in Bosque River Watershed[END_REF][START_REF] Sun | Detection and quantification of ionophore antibiotics in runoff, soil and poultry litter[END_REF]), salinomycine (9022 ng.L -1 ; [START_REF] Sun | Detection and quantification of ionophore antibiotics in runoff, soil and poultry litter[END_REF]) and narasin (348 ng.L -1 ; [START_REF] Sun | Detection and quantification of ionophore antibiotics in runoff, soil and poultry litter[END_REF]) but also in groundwater (monensin, 20 to 2950 ng.L -1 ; [START_REF] Bartelt-Hunt | Occurrence of steroid hormones and antibiotics in shallow groundwater impacted by livestock waste control facilities[END_REF][START_REF] Watanabe | Environmental Occurrence and Shallow Ground Water Detection of the Antibiotic Monensin from Dairy Farms[END_REF]). Canada also has a large and dynamic animal food production industry [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF] and is reported to have a widespread use of veterinary antibiotics [START_REF] Snow | Detection, Occurrence and Fate of Emerging Contaminants in Agricultural Environments[END_REF]. However, data on veterinary pharmaceuticals sales in Canada are still not available in the public domain. Since 2010, the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) releases an annual report of antimicrobials sales, currently including data from 30 European countries, including France. Total antimicrobials sales were 8 361 tons in 2015 according to [START_REF]Sales of veterinary antimicrobial agents in 30 European countries in 2015[END_REF]. Prevalent families differ from those in the USA. However, ionophores, which constitute the second most sold family of compounds in the USA, are not included in the ESVAC report. Indeed, in Europe these compounds are no longer used as feed additives because growth promoters have been banned since 2006 [START_REF]the European Parliament and of the Council of 22 September 2003 on Additives for Use in Animal Nutrition[END_REF]. This may explain the differences observed between Europe and USA sales. In 2015, the highest antimicrobial sales were reported for Spain with 3030 tons, Italy with 1310 tons and Germany with 858 tons [START_REF]Sales of veterinary antimicrobial agents in 30 European countries in 2015[END_REF]. Between 2011 and 2015, the general trend was a 13% decrease in veterinary antibiotics sales in Europe (25 countries included). Some countries included in the ESVAC report also publish individual detailed annual reports of their antibiotics sales such as France [START_REF] Méheust | Suivi des ventes de médicaments vétérinaires contenant des antibiotiques en France en[END_REF] or United-Kingdom [92].

A C C E P T E D M A N U S C R I P T the latest report
In 2006 [START_REF] Sarmah | A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment[END_REF], sales amounts of veterinary pharmaceuticals were lacking in Asia. Ten years later, even though veterinary antibiotics uses are regulated in China, there is currently no official governmental report on sales amounts [START_REF] Hu | Health risk from veterinary antimicrobial use in China's food animal production and its reduction[END_REF][START_REF] Collignon | China, what antibiotics and what volumes are used in food production animals?[END_REF], while some previous studies suggest that China may be the first consumer of veterinary antibiotics in the world [START_REF] Van Boeckel | Global trends in antimicrobial use in food animals[END_REF][START_REF] Obimakinde | Veterinary pharmaceuticals in aqueous systems and associated effects: an update[END_REF][START_REF] Du | Occurrence, fate, and ecotoxicity of antibiotics in agro-ecosystems. A review[END_REF]. Nevertheless, limited available data suggest 210,000 tons of antibiotics are produced annually, with 46% of this tonnage used for food-producing animals [START_REF] Collignon | China, what antibiotics and what volumes are used in food production animals?[END_REF][START_REF] Mo | Application of veterinary antibiotics in China's aquaculture industry and their potential human health risks[END_REF]. Furthermore, to our knowledge, India, Indonesia or Thailand are still neither reporting any information on veterinary pharmaceutical types or amounts used.

[Table 2] On the other hand, as shown in Table 2, reports have been released in South Korea [START_REF]Monitoring and characterization of antimicrobial resistance of bacteria from livestock products[END_REF], and in Japan [START_REF]Sales Amounts and Sales Volumes (Active Substance) of Antibiotics, Synthetic Antibacterials, Antihelmintics and Antiprotozoals[END_REF]. To our knowledge, Japan is the only country worldwide reporting the sales of antiparasitic drugs (antihelmintics and antiprotozoals). The most sold antiparasitic drugs are fenbendazole and praziquantel with about 3 tons, ranking 22 nd and 23 rd in veterinary sales amounts. Between 2007 and 2015, VPs sales in Japan decreased by 11%, with 879 tons in 2007 [START_REF]Sales Amounts and Sales Volumes (Active Substance) of Antibiotics, Synthetic Antibacterials, Antihelmintics and Antiprotozoals[END_REF] and 788 tons in 2015 [START_REF]Sales Amounts and Sales Volumes (Active Substance) of Antibiotics, Synthetic Antibacterials, Antihelmintics and Antiprotozoals[END_REF]. In Korea, overall sales of antibiotics (including anticoccidians) have also gradually decreased, with 1527 tons sold in 2007 and 910 tons in 2015 [START_REF]Monitoring and characterization of antimicrobial resistance of bacteria from livestock products[END_REF]. However, phenicols and cephalosporins sales have been multiplied by 3 and 5, respectively [START_REF]Monitoring and characterization of antimicrobial resistance of bacteria from livestock products[END_REF]. Occurrence of oxytetracycline (390 to 1410 ng.L -1 , [START_REF] Ok | Monitoring of selected veterinary antibiotics in environmental compartments near a composting facility in Gangwon Province, Korea[END_REF]), chlortetracycline (13 to 793 ng.L -1 , [START_REF] Ok | Monitoring of selected veterinary antibiotics in environmental compartments near a composting facility in Gangwon Province, Korea[END_REF][START_REF] Kim | Effect of runoff discharge on the environmental levels of 13 veterinary antibiotics: A case study of Han River and Kyungahn Stream, South Korea[END_REF]), tylosin (230 to 2190 ng.L -1 , Ok et al., 2011), florfenicol (17 to 340 ng.L -1 ; [START_REF] Kim | Effect of runoff discharge on the environmental levels of 13 veterinary antibiotics: A case study of Han River and Kyungahn Stream, South Korea[END_REF]) and enrofloxacin (10 to 133 ng.L -1 , [START_REF] Kim | Effect of runoff discharge on the environmental levels of 13 veterinary antibiotics: A case study of Han River and Kyungahn Stream, South Korea[END_REF]) in Korean surface waters can be explained by the fact that those compounds are among the top ten sellers in the country. On the contrary, tetracycline, which has been quantified at 255 µg.L -1 [START_REF] Awad | Veterinary antibiotics contamination in water, sediment, and soil near a swine manure composting facility[END_REF], is not included in the top ten sellers of Korea. In Japan, oxytetracycline, the most sold compound, was quantified at 68 000 ng.L -1 [START_REF] Matsui | Occurrence of a veterinary antibiotic in streams in a small catchment area with livestock farms[END_REF].

[Table 3] New Zealand and Australia both reported zinc bacitracin as the most sold compound. Zinc bacitracin is used for the treatment and prevention of necrotic enteritis in poultry, and is administered in the feed. In Australia, there were no significant change in the total amount of antibiotics sold between 2005 and 2010. Growth promotants accounted for 4% to 7% of total antimicrobials sold for use in food animals [START_REF]Australian Pesticides and Veterinary Medicines Authority (APVMA), Quantity of antimicrobial products sold for veterinary use in Australia 2005-2010[END_REF]. In New Zealand, antibiotic sales increased by 13% between 2010 and 2014. Sales of TCs and cephalosporins increased by 57% and 36%, respectively [START_REF][END_REF]. It has to be considered that tonnages may not be an adequate parameter to assess the actual use pattern of VPs. In addition, increasing or decreasing sales trends over time may reflect usage changes, but it may also be representative of changes in animal populations across the country. To eliminate of this bias, a population correction unit [START_REF]Sales of veterinary antimicrobial agents in 30 European countries in 2015[END_REF] is used or a ratio of the active ingredient sold (mg) per kilogram of animal bodyweight is applied [START_REF] Méheust | Suivi des ventes de médicaments vétérinaires contenant des antibiotiques en France en[END_REF]92]. Within a country, uses of VPRs vary throughout the year. In winter, livestock tend to be more sensitive to pathogens and prophylactic treatments are increased to prevent respiratory

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diseases or other epidemics in herds [START_REF] Matsui | Occurrence of a veterinary antibiotic in streams in a small catchment area with livestock farms[END_REF]. Some exceptions may be noted, such as a common indication of SAs for bacterial or protozoal infections occurring in summer.

Fate of VPRs in natural waters

This part of the review considers the behaviour of VPRs in natural waters-transfer and sorption to sediment, and degradation pathwayswhich will affect concentration levels in natural water. Beyond sorption and degradation, climate and weather strongly influence VPRs concentrations in natural waters with heavy rainfall resulting in higher flow rate and significant dilution of VPRs in the waterbodies [START_REF] Tong | Occurrence of antibiotics in the aquatic environment of Jianghan Plain, central China[END_REF][START_REF] Luo | Occurrence and Transport of Tetracycline, Sulfonamide, Quinolone, and Macrolide Antibiotics in the Haihe River Basin, China[END_REF].

2.2.1. Partitioning and sorption VPRs are found in different fractions of water: soluble fraction, colloidal fraction or particular fraction [START_REF] Li | The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases[END_REF][START_REF] Dong | Antibiotics in water and sediments from Liao River in Jilin Province, China: occurrence, distribution, and risk assessment[END_REF][START_REF] Cheng | Influence of the natural colloids on the multi-phase distributions of antibiotics in the surface water from the largest lake in North China[END_REF]. Ionic and hydrophobic interactions known to occur between VPRs and soil [START_REF] Kim | Occurrence and Environmental Fate of Veterinary Antibiotics in the Terrestrial Environment[END_REF][START_REF] Tasho | Veterinary antibiotics in animal waste, its distribution in soil and uptake by plants: A review[END_REF][START_REF] Boxall | Veterinary Medicines and the Environment[END_REF][START_REF] Jeon | Reactions and Behavior Relevant to Chemical and Physical Properties of Various Veterinary Antibiotics in Soil[END_REF][START_REF] Kemper | Veterinary antibiotics in the aquatic and terrestrial environment[END_REF][START_REF] Kümmerer | Antibiotics in the aquatic environment -A review -Part I[END_REF][START_REF] Wegst-Uhrich | Assessing antibiotic sorption in soil: a literature review and new case studies on sulfonamides and macrolides[END_REF][START_REF] Schauss | Analysis, fate and effects of the antibiotic sulfadiazine in soil ecosystems[END_REF][START_REF] Jechalke | Fate and effects of veterinary antibiotics in soil[END_REF] will apply for the partitioning between VPRs and the different fractions: colloids, solid particulate matter (SPM) and sediment. To determine the partitioning behaviour and the dynamics of VPRs between the different phases (i.e. soluble, colloidal, SPM, sediment), the calculation of a pseudo-partition coefficient (P-PC) is useful [START_REF] Li | Distribution and Risk Assessment of Antibiotics in a Typical River in North China Plain[END_REF][START_REF] Yang | Simultaneous determination of four classes of antibiotics in sediments of the Pearl Rivers using RRLC-MS/MS[END_REF]. (P-PC) is calculated as the ratio of the VPR concentration in the studied solid phase (either colloidal, SPM or sediment) to the corresponding concentration in the water phase (soluble). Calculated P-PCs between water and SPM are presented in table 4 [START_REF] Li | The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases[END_REF][START_REF] Cheng | Influence of the natural colloids on the multi-phase distributions of antibiotics in the surface water from the largest lake in North China[END_REF], and table 5 identified some of the P-PC between sediment and water phase calculated for veterinary antibiotics [START_REF] Li | The distribution of veterinary antibiotics in the river system in a livestock-producing region and interactions between different phases[END_REF][START_REF] Zhou | Occurrence, spatiotemporal distribution, mass balance and ecological risks of antibiotics in the subtropical shallow Lake Taihu, China[END_REF][START_REF] Luo | Occurrence and Transport of Tetracycline, Sulfonamide, Quinolone, and Macrolide Antibiotics in the Haihe River Basin, China[END_REF][START_REF] Li | Distribution and Risk Assessment of Antibiotics in a Typical River in North China Plain[END_REF][START_REF] Yang | Simultaneous determination of four classes of antibiotics in sediments of the Pearl Rivers using RRLC-MS/MS[END_REF][START_REF] Kim | Temporal and spatial trends in the occurrence of human and veterinary antibiotics in aqueous and river sediment matrices[END_REF][START_REF] Liang | The distribution and partitioning of common antibiotics in water and sediment of the Pearl River Estuary, South China[END_REF][START_REF] Cheng | Seasonal variation and sedimentwater exchange of antibiotics in a shallower large lake in North China[END_REF] .

[Table 4] [Table 5] Table 4 and 5 show that means P-PCs water -SPM and P-PCs water-sediment for antibiotics increase in the following order: SAs and MLs (10 2 order) < TCs (up to 10 3 ) < fluoroquinolones (FQs) (up to 10 4 ). As expected, TCs and FQs have a stronger binding capacity to solid fractions (sediments and SPM) than SAs [START_REF] Dong | Antibiotics in water and sediments from Liao River in Jilin Province, China: occurrence, distribution, and risk assessment[END_REF][START_REF] Cheng | Influence of the natural colloids on the multi-phase distributions of antibiotics in the surface water from the largest lake in North China[END_REF][START_REF] Kim | Temporal and spatial trends in the occurrence of human and veterinary antibiotics in aqueous and river sediment matrices[END_REF][START_REF] Liang | The distribution and partitioning of common antibiotics in water and sediment of the Pearl River Estuary, South China[END_REF], as in soils. FQs tend to be more persistent than MLs once in sediments [START_REF] Dong | Antibiotics in water and sediments from Liao River in Jilin Province, China: occurrence, distribution, and risk assessment[END_REF] and have a higher tendency to accumulate in sediments than TCs [START_REF] Cheng | Seasonal variation and sedimentwater exchange of antibiotics in a shallower large lake in North China[END_REF]. As SAs, trimethoprim, lincomycin and florfenicol tend to be distributed only in the aqueous phase [START_REF] Zhou | Trends in the occurrence of human and veterinary antibiotics in the sediments of the Yellow River, Hai River and Liao River in northern China[END_REF]. Thus, sediment constitute an important sink but also a potential secondary source for VPRs, which can be released in water through sorption-desorption and re-suspension processes [START_REF] Zhou | Occurrence, spatiotemporal distribution, mass balance and ecological risks of antibiotics in the subtropical shallow Lake Taihu, China[END_REF][START_REF] Yang | Simultaneous determination of four classes of antibiotics in sediments of the Pearl Rivers using RRLC-MS/MS[END_REF][START_REF] Kim | Temporal and spatial trends in the occurrence of human and veterinary antibiotics in aqueous and river sediment matrices[END_REF][START_REF] Cheng | Seasonal variation and sedimentwater exchange of antibiotics in a shallower large lake in North China[END_REF][START_REF] Zhou | Trends in the occurrence of human and veterinary antibiotics in the sediments of the Yellow River, Hai River and Liao River in northern China[END_REF]. However, no significant seasonal variations of SAs, MLs, TCs and FQs concentrations in the sediment were reported in [START_REF] Dong | Antibiotics in water and sediments from Liao River in Jilin Province, China: occurrence, distribution, and risk assessment[END_REF][START_REF] Liang | The distribution and partitioning of common antibiotics in water and sediment of the Pearl River Estuary, South China[END_REF]. Sorption will also influence VPRs transport into groundwaters. As VPRs are mostly ampholytic compounds, a retardation of their transport in groundwaters can be expected because of ion sorption dominated by electrostatical interactions [START_REF] Schaffer | A framework for assessing the retardation of organic molecules in groundwater: Implications of the species distribution for the sorption-influenced transport[END_REF].

Degradation in water

In water, VPRs can be degraded and/or transformed through biotic (biodegradation) or abiotic (hydrolysis or photolysis) processes. These degradation mechanisms are more efficient during dry seasons, as a rise in temperature promotes microbial activity and photolysis [START_REF] Yao | Seasonal variation of antibiotics concentration in the aquatic environment: a case study at Jianghan Plain, central China[END_REF][START_REF] Yao | Occurrence and risk assessment of antibiotics in surface water and groundwater from different depths of aquifers: A case study at Jianghan Plain, central China[END_REF][START_REF] Tong | Analysis of veterinary antibiotic residues in swine wastewater and environmental water samples using optimized SPE-LC/MS/MS[END_REF]. Photolysis is an important degradation pathway of VPRs in surface water [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF][START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF]. VPRs can undergo direct photolysis with direct absorbance of photons [START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF] if there is an overlap between the irradiation spectrum and the absorption spectra of the molecule [START_REF] Li | Photochemical Transformation of Aminoglycoside Antibiotics in Simulated Natural Waters[END_REF]. VPRs that

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do not absorb light at λ > 290 nm do not undergo direct photolysis [START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF][START_REF] Li | Photochemical Transformation of Aminoglycoside Antibiotics in Simulated Natural Waters[END_REF]. VPRs can also be subjected to indirect photolysis or even self-sensitized photo-oxidation [START_REF] Ge | Aquatic Photochemistry of Fluoroquinolone Antibiotics: Kinetics, Pathways, and Multivariate Effects of Main Water Constituents[END_REF]. Indirect photolysis is induced by light absorption of components from dissolved organic matter (DOM) or nitrates [START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF][START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF]. The components will generate various reactive species of oxygen (ROS), such as light excited DOM, hydroxyl radical, peroxyl radicals, singlet oxygen, and superoxide [START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF]. ROS can react with VPRs and increase their degradation [START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF]. However, DOM can also prevent photolysis of VPRs by screening sunlight [START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Babić | Photolytic degradation of norfloxacin, enrofloxacin and ciprofloxacin in various aqueous media[END_REF], by competitive absorption of solar radiations [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF], by quenching ROS [START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF], or by adsorbing VPRs themselves [START_REF] Li | Photochemical Transformation of Aminoglycoside Antibiotics in Simulated Natural Waters[END_REF]. In the end, indirect photolysis of VPRs will depends of the balance of each opposite contribution of DOM (i.e. photosensitizing and/or inhibiting photolysis) [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF]. Selfsensitized photo-oxidation is a process in which photo-sensitized organic compounds may produce reactive singlet oxygen via the energy transfer from the light-excited triplet state of the molecule to ground state.The reactive singlet oxygen will then transform and/or degrade the organic compound by oxidation [START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF]. TCs, ionophores and phenicol antibiotics, are subjected to self-sensitization photo-oxidation [START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF][START_REF] Chen | Photodegradation of tetracycline and formation of reactive oxygen species in aqueous tetracycline solution under simulated sunlight irradiation[END_REF]. For phenicols, the photooxidation occurs on the carbon atoms and generate isomers of the parent compounds [START_REF] Ge | Light-Source-Dependent Effects of Main Water Constituents on Photodegradation of Phenicol Antibiotics: Mechanism and Kinetics[END_REF]. Table S3 presents the photolysis tests performed under experimental conditions close to environmental conditions. For example, experiments performed in freshwater are preferred to experiments performed in deionized water. Likewise, experiments performed under sunlight are preferred to experiments performed in artificial light. When the study is performed on deionized water, only direct photolysis is estimated. Both direct and indirect photolysis is evaluated on freshwater, due to the presence of DOM. Several parameters will influence the photolysis rate of VPRs such as VPR concentration levels [START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF][START_REF] Babić | Photolytic degradation of norfloxacin, enrofloxacin and ciprofloxacin in various aqueous media[END_REF][START_REF] Prabhakaran | Photolysis of difloxacin and sarafloxacin in aqueous systems[END_REF], water pH [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF][START_REF] Wammer | Direct photochemistry of three fluoroquinolone antibacterials: Norfloxacin, ofloxacin, and enrofloxacin[END_REF][START_REF] Prabhakaran | Photolysis of difloxacin and sarafloxacin in aqueous systems[END_REF][START_REF] Li | Photolysis of Enrofloxacin in aqueous systems under simulated sunlight irradiation: Kinetics, mechanism and toxicity of photolysis products[END_REF][START_REF] Sturini | Photodegradation of fluoroquinolones in surface water and antimicrobial activity of the photoproducts[END_REF], ionic species (i.e. nitrates, phosphates, divalent cations as Ca 2+ ) [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF][START_REF] Ge | Aquatic Photochemistry of Fluoroquinolone Antibiotics: Kinetics, Pathways, and Multivariate Effects of Main Water Constituents[END_REF][START_REF] Prabhakaran | Photolysis of difloxacin and sarafloxacin in aqueous systems[END_REF][START_REF] Li | Effects of nitrate and humic acid on enrofloxacin photolysis in an aqueous system under three light conditions: kinetics and mechanism[END_REF][START_REF] Xuan | Hydrolysis and photolysis of oxytetracycline in aqueous solution[END_REF], composition and concentration of DOM [START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF][START_REF] Bahnmüller | Sunlight-induced transformation of sulfadiazine and sulfamethoxazole in surface waters and wastewater effluents[END_REF], light intensity [START_REF] Prabhakaran | Photolysis of difloxacin and sarafloxacin in aqueous systems[END_REF] and depth of natural waters [START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF]. Besides, VPRs can be biodegraded and/or biotransformed by bacteria [START_REF] Xu | Sulfamethoxazole biodegradation and biotransformation in the water-sediment system of a natural river[END_REF][START_REF] Radke | Fate of the Antibiotic Sulfamethoxazole and Its Two Major Human Metabolites in a Water Sediment Test[END_REF][START_REF] Su | Biodegradation of sulfamethoxazole phototransformation products in a water/sediment test[END_REF][START_REF] Adamek | Assessment of the biodegradability of selected sulfa drugs in two polluted rivers in Poland: Effects of seasonal variations, accidental contamination, turbidity and salinity[END_REF] or fungi present in water. However, fungi do not usually have a great role in degradation of pharmaceuticals in the aquatic environment [START_REF] Kümmerer | Pharmaceuticals in the environment: sources, fate, effects and risks ; with 62 tables[END_REF]. Concerning steroidal hormones, although data are lacking, it has been suggested that they are subjected to biodegradation [START_REF] Khan | Chemical contaminants in feedlot wastes: Concentrations, effects and attenuation[END_REF], and biodegradation of antiparasitic drugs in soil has been reported [START_REF] Khan | Chemical contaminants in feedlot wastes: Concentrations, effects and attenuation[END_REF]. Thus, it can be assumed that biodegradation is also likely to occur in aquatic environment. Hydrolysis is also a common reaction leading to abiotic degradation of substances in the aquatic environment [START_REF] Białk-Bielińska | Hydrolysis of sulphonamides in aqueous solutions[END_REF]. VPRs may either be stable in water or rapidly hydrolyzed. Table 6 summarizes the degradation pathways reported by literature for the studied chemical families. These studies focus on degradation pathways of antibiotics including ionophores. Data on the environmental behaviour of antiparasitic drugs in water is missing in the literature.

[Table 6] According to Table 6, only SAs are reported to be subjected to biodegradation, while hydrolysis has been observed for PENs, cephalosporins and TCs. Photolysis appears to be the major degradation/transformation pathway of VPRs in natural waters. Moreover, according to the half-lives reported in Table 6, photolysis degradation of VPRs is also occurring faster than hydrolysis and biodegradation of VPRs. Multiple transformation products can be generated during the degradation of parent compounds [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF][START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Xuan | Hydrolysis and photolysis of oxytetracycline in aqueous solution[END_REF][START_REF] García-Galán | Kinetic studies and characterization of photolytic products of sulfamethazine, sulfapyridine and their acetylated metabolites in water under simulated solar irradiation[END_REF]. Photolysis of fluoroquinolones leads to the formation of 5 and 2 photo-transformation products for enrofloxacin and marbofloxacin respectively [START_REF] Sturini | Photochemical degradation of marbofloxacin and enrofloxacin in natural waters[END_REF], while photolysis of the SAs sulfadimethoxine, sulfamethazine and sulfamethoxypyridazine generated 11, 8 and 6 transformation products, respectively [START_REF] Guerard | Photochemical fate of sulfadimethoxine in aquaculture waters[END_REF][START_REF] García-Galán | Kinetic studies and characterization of photolytic products of sulfamethazine, sulfapyridine and their acetylated metabolites in water under simulated solar irradiation[END_REF][START_REF] Khaleel | Photolysis of sulfamethoxypyridazine in various aqueous media: Aerobic biodegradation and identification of photoproducts by LC-UV-MS/MS[END_REF]. These TPs can be more stable than the parent compounds as it was observed with sulfamethoxypyridazine and

A C C E P T E D M A N U S C R I P T
sulfathiazole photo-degradation products for example [START_REF] Khaleel | Photolysis of sulfamethoxypyridazine in various aqueous media: Aerobic biodegradation and identification of photoproducts by LC-UV-MS/MS[END_REF][START_REF] Niu | Photodegradation of sulfathiazole under simulated sunlight: Kinetics, photo-induced structural rearrangement, and antimicrobial activities of photoproducts[END_REF]. Also TPs may still exercise a biological activity or even be more toxic to the ecosystems than the parent compound [START_REF] Jiao | Aqueous photolysis of tetracycline and toxicity of photolytic products to luminescent bacteria[END_REF][START_REF] Li | Effects of nitrate and humic acid on enrofloxacin photolysis in an aqueous system under three light conditions: kinetics and mechanism[END_REF][START_REF] García-Galán | Kinetic studies and characterization of photolytic products of sulfamethazine, sulfapyridine and their acetylated metabolites in water under simulated solar irradiation[END_REF]. The antimicrobial-active transformation products 4-Epi-, α-apo-, and β-apooxytetracycline were identified during hydrolysis of oxytetracycline [START_REF] Xuan | Hydrolysis and photolysis of oxytetracycline in aqueous solution[END_REF]. Altrenogest photoproducts exhibit an androgenic activity comparable to that of altrenogest [START_REF] Wammer | Environmental Photochemistry of Altrenogest: Photoisomerization to a Bioactive Product with Increased Environmental Persistence via Reversible Photohydration[END_REF]. However TPs can also be inactive, as TPs generated during the photolysis of the ionophore salinomycine or the aminoglycoside streptomycin [START_REF] Sun | Photodegradation of Veterinary Ionophore Antibiotics under UV and Solar Irradiation[END_REF][START_REF] Li | Photochemical Transformation of Aminoglycoside Antibiotics in Simulated Natural Waters[END_REF].

OCCURRENCE OF VPRs IN TAP WATER

There is an evident lack of data on the occurrence of VPRs in tap water, as shown in table 7, which includes only four studies from 2007 to 2017 [START_REF]Campagne nationale d'occurrence des résidus de medicaments dans les eaux destinées à la consummation humaine[END_REF][START_REF] Ye | Trace Analysis of Trimethoprim and Sulfonamide, Macrolide, Quinolone, and Tetracycline Antibiotics in Chlorinated Drinking Water Using Liquid Chromatography Electrospray Tandem Mass Spectrometry[END_REF][START_REF] Leung | Pharmaceuticals in Tap Water: Human Health Risk Assessment and Proposed Monitoring Framework in China[END_REF][START_REF] Li | Veterinary antibiotics in food, drinking water, and the urine of preschool children in Hong Kong[END_REF].

[Table 7] Due to this limited number of studies on VPRs in tap water (11 studies), the studies locations are not specifically rural areas with livestock activities nearby. All studies analyzing at least one VPR in tap water were taken into account. Neverthless, VPRs have been quantified in tap water at lower concentrations than in water resources (both SW and GW), from 2 ng.L -1 [START_REF] Ye | Trace Analysis of Trimethoprim and Sulfonamide, Macrolide, Quinolone, and Tetracycline Antibiotics in Chlorinated Drinking Water Using Liquid Chromatography Electrospray Tandem Mass Spectrometry[END_REF] to a maximum of 104 ng.L -1 [START_REF] Leung | Pharmaceuticals in Tap Water: Human Health Risk Assessment and Proposed Monitoring Framework in China[END_REF]. In China, 6 VPRs were quantified in the 113 tap waters sampled in 13 cities, up to 104 ng.L -1 for thiamphenicol [START_REF] Leung | Pharmaceuticals in Tap Water: Human Health Risk Assessment and Proposed Monitoring Framework in China[END_REF]. During a national survey conducted in France on 285 samples, only 3 of the 12 investigated compounds were detected [START_REF]Campagne nationale d'occurrence des résidus de medicaments dans les eaux destinées à la consummation humaine[END_REF]. Besides the studies mentioned in table 7, a few other studies have investigated VPRs in tap water but without detecting any [START_REF] Boleda | Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments[END_REF][START_REF] Cimetiere | Standard addition method for the determination of pharmaceutical residues in drinking water by SPE-LC-MS/MS[END_REF][START_REF] Gros | Fast and comprehensive multi-residue analysis of a broad range of human and veterinary pharmaceuticals and some of their metabolites in surface and treated waters by ultra-high-performance liquid chromatography coupled to quadrupolelinear ion trap tandem mass spectrometry[END_REF][START_REF] Qiao | Occurrence and fate of pharmaceuticals and personal care products in drinking water in southern China[END_REF][START_REF] Vulliet | Occurrence of pharmaceuticals and hormones in drinking water treated from surface waters[END_REF][START_REF] Paíga | Development of a multi-residue method for the determination of human and veterinary pharmaceuticals and some of their metabolites in aqueous environmental matrices by SPE-UHPLC-MS/MS[END_REF][START_REF] Castillo-García | Determination of veterinary penicillin antibiotics by fast high-resolution liquid chromatography and luminescence detection[END_REF].

FATE OF VPRs IN DRINKING WATER TREATMENT PLANTS

In DWTPs, the VPRs are subjected to the same or very similar processes that they face in water resources. Thus, their fate and behaviour in DWTPs depends on the same physical or chemical reactions as in the environment (i.e. adsorption, oxidation, biodegradation). Nowadays, DWTPs are not designed to treat VPRs, but because some VPRs have similar physicochemical properties (polarity, molecular weight) to other micropollutants (pesticides for example), some of them can be removed. For example, the use of membranes with molecular weight cut-off varying between 200 and 400 Da is generally appropriate for pesticides removal [START_REF] Plakas | Removal of pesticides from water by NF and RO membranes -A review[END_REF]. These results can be compared with nanofiltration removal efficiencies observed by Dolar et al. [START_REF] Dolar | Effect of water matrices on removal of veterinary pharmaceuticals by nanofiltration and reverse osmosis membranes[END_REF] for VPRs such as febantel and ciprofloxacin. For the production of tap water from surface water with high total organic carbon concentration, the average DWTP has a clarification process, preceded or followed by advanced treatment processes (i.e. activated carbon, oxidation, membranes filtration). The last step is disinfection. A scheme of a DWTP is succinctly represented in Figure 3. Each treatment step is described in details in the corresponding section below.

[Figure 3] The table 8 summarizes removal rates for some VPRs reported during the different DWTPs steps. The considered studies were mostly conducted at laboratory scale, thus the parameters used vary from one study to another (i.e. VPR concentration, oxidant concentration, contact

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time etc.) and may not be representative of full-scale DWTP conditions. The main bias in laboratory studies is the VPRs concentration. For example, in studies reported on VPRs adsorption on activated carbon, VPRs concentrations vary from 5 µg.L -1 [START_REF] Zhang | Performance evaluation of powdered activated carbon for removing 28 types of antibiotics from water[END_REF] to 600 mg.L -1 [START_REF] Rivera-Utrilla | Pharmaceuticals as emerging contaminants and their removal from water. A review[END_REF], which are not representative of environmental concentrations. To compare, in a study performed on full-scale DWTP [START_REF] Boleda | Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments[END_REF], the reported concentration of the antibiotic erythromycin in the influent prior to filtration on activated carbon was included between 0.8 and 1.4 ng.L -1 .

[Table 8]

Clarification

Clarification consists of several steps: coagulation, flocculation, sedimentation and sand filtration [START_REF] Shammas | Water engineering: hydraulics, distribution and treatment[END_REF]. Clarification aims at reducing turbidity and total organic carbon by removing particulate matter and colloids [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF]. The main parameters that control clarification process are the coagulant/floculant types and amounts, pH [START_REF] Shammas | Water engineering: hydraulics, distribution and treatment[END_REF]. As VPRs can be adsorbed onto particulate matter and colloids, they may be removed during the clarification process, depending on their physicochemical properties (log Kow and pkas) [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF]. TCs are amphoteric compounds which possess three pkas and they are known to bind on particulate matter and colloids by ionic exchanges in raw water. Coagulation of seven TCs was studied on river water at lab-scale, with aluminum polychloride as coagulant [START_REF] Choi | Removal of antibiotics by coagulation and granular activated carbon filtration[END_REF]. Coagulation was effective to remove TCs with optimum removal rates ranged between 47% and 66% for an incoming concentration of 100µg/L of TCs and 60mg/L of coagulant. However, most studies indicate that clarification steps alone poorly remove VPRs [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF][START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF][START_REF] Zhang | Performance evaluation of powdered activated carbon for removing 28 types of antibiotics from water[END_REF][START_REF] Dong | Kinetics and degradation pathway of sulfamethazine chlorination in pilot-scale water distribution systems[END_REF][START_REF] Frade | Environmental contamination by fluoroquinolones[END_REF][START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF], for any operating conditions.

Advanced treatment technologies

Oxidation processes, adsorption on activated carbon, and membrane filtration processes (ultrafiltration, nanofiltration) are classified as advanced treatment technologies and are mainly used on raw surface water [START_REF] Shammas | Water engineering: hydraulics, distribution and treatment[END_REF].

Oxidation processes

Pre-oxidation can be performed as first step of the process, using either KMnO4, chlorinederived species, or ozone (O3). The aim of pre-oxidation is to eliminate mineral compounds such as iron or manganese, which can modify the color and taste of water, but also algae [START_REF] Sun | Comparison on Permanganate and Ozone as Pre-Oxidation Agents[END_REF]. An intermediate oxidation step sometimes takes place after clarification using O3 only. Its goal is to enhance the degradation of micropollutants and residual organic matter. Finally, oxidation is performed for a third time as the last step in the whole treatment process. It is the disinfection step, which aims to eliminate all micro-organisms before distribution of the treated water. Disinfection can be performed either with O3, chlorine-derived species or ultraviolets (UV) [START_REF] Zhong | Seasonal evaluation of disinfection by-products throughout two full-scale drinking water treatment plants[END_REF]. The oxidant type impacts the process. Ben et al. [START_REF] Ben | Oxidation of sulfonamide antibiotics by chlorine dioxide in water: Kinetics and reaction pathways[END_REF] found that the reaction rates constants of SAs with chlorine dioxide at pH7 and 20°C were higher than with free chlorine, but lower than with ozone under comparable experimental conditions. Besides the oxidant type, the contact time and the dosage of the oxidant is different between preoxidation, intermediate oxidation and disinfection [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF]. VPR degradation rate during the oxidation steps will depend on those parameters, with enhanced degradation at higher oxidant doses and through longer contact time. Garoma et al. [START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF] studied the influence of ozone gas

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concentration on ozonation reaction of four sulfonamides. At 120 seconds of reaction, SAs removal ranged between 90 and 99% for 3.2 mg.L -1 of ozone gas applied. For the same reaction time, SAs removal ranged between 65 and 80% when using an ozone concentration of 2.3 mg.L -1 . Thus, results showed that the removal of all sulfonamides increased as ozone gas concentration increased [START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF].

Oxidation processes can lead to the formation of oxidation by-products that may be more toxic than the parent compound. Currently, the formation pathway, the chemical structure and the potential impacts towards human health of those transformation products are largely unknown [START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF].

KMnO4

Pre-oxidation can be performed as first step of the process, using potassium permanganate (KMnO4), chlorine-derived species, or ozone (O3). In a full-scale DWTP, up to 87% and 89% of florfenicol and flunixin, respectively, were removed during the pre-oxidation (using KMnO4) and coagulation stages (using aluminum polychloride). However, this high removal rate was probably largely due to the pre-oxidation step [START_REF] Azzouz | Influence of seasonal climate differences on the pharmaceutical, hormone and personal care product removal efficiency of a drinking water treatment plant[END_REF].

Ozonation

Ozone has an important reduction potential (E=2.07V), superior to Cl2 (E= 1.36 V). Consequently, it is a powerful oxidant [START_REF] De Oliveira | Antimicrobial activity and acute toxicity of ozonated lomefloxacin solution[END_REF]. It can interact with VPRs either directly or via hydroxyl radicals formed during ozone decomposition at pH 7 or higher [START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF][START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF][START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF][START_REF] Sui | Kinetics of Ozonation of Typical Sulfonamides in Water[END_REF]. SAs (sulfadiazine and sulfamethoxazole) antibiotics and nitroimidazole antibiotics (metronidazole, dimetridazole, tinidazole, ronidazole) had a higher degradation rate when reacting with hydroxyl radical formed during ozone decomposition than when reacting with molecular ozone [START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF][START_REF] Sui | Kinetics of Ozonation of Typical Sulfonamides in Water[END_REF]. Therefore, the ozone process is usually more efficient at alkaline pH [START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF][START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF][START_REF] De Oliveira | Antimicrobial activity and acute toxicity of ozonated lomefloxacin solution[END_REF]]. An exception was noted in [START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF], where sulfaquinoxaline degraded faster and more efficiently (99% in one minute) at acidic pH when reacting only with molecular ozone at 2.8 mg/L. The exception was explained by the greater selectivity of ozone towards sulfaquinoxaline compared to hydroxyl radicals [START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF]. At a full-scale DWTP, ozonation was the main step responsible for antibiotics degradation, with an removal rate of 65% for 1 mg/L of ozone [START_REF] Liu | Removal of typical antibiotics in the advanced treatment process of productive drinking water[END_REF]. Removal rates during ozonation may be reduced by organic matter and inorganic salts in water resources which can act as scavengers during radical reactions [START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF][START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF][START_REF] Garoma | Removal of sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfathiazole from aqueous solution by ozonation[END_REF]. The degradation products formed and their properties depend on the oxidant (ozone or hydroxyl radical) most prevalent in the process [START_REF] De Oliveira | Antimicrobial activity and acute toxicity of ozonated lomefloxacin solution[END_REF]. When antibiotics react directly with ozone, degradation products appear to be biologically inactive. However, when antibiotics react with hydroxyl radicals, toxic and persistent degradation products could be generated [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF][START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF][START_REF] Sánchez-Polo | Removal of pharmaceutical compounds, nitroimidazoles, from waters by using the ozone/carbon system[END_REF][START_REF] De Oliveira | Antimicrobial activity and acute toxicity of ozonated lomefloxacin solution[END_REF]. For example, four degradation products were identified after sulfaquinoxaline ozonation, including three highly toxic and persistent compounds [START_REF] Urbano | Influence of pH and ozone dose on sulfaquinoxaline ozonation[END_REF]. Moreover, assessing VRPs degradation pathways during ozonation is a complex task, because one VPR can lead to many by-products. For example, 27 degradation products of lomefloxacin and 9 degradation products of tetracycline have been identified after ozonation reactions [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF].

Adsorption on activated carbon

Activated carbon is used to adsorb and sometimes biologically degrade (after ozonation) organic matter and micropollutants [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF]. The adsorption level of VPRs on activated carbon depends on the nature, the surface area and the porosity of the adsorbent as well as on the properties of the VPR (i.e. size; log Kow and pKa) [START_REF] Ahmed | Adsorption of quinolone, tetracycline, and penicillin antibiotics from aqueous solution using activated carbons: Review[END_REF][START_REF] Rivera-Utrilla | Pharmaceuticals as emerging contaminants and their removal from water. A review[END_REF]. Adsorption on powder or granular activated carbon is known to remove efficiently hydrophobic pharmaceuticals from water [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF][START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF][START_REF] Ahmed | Adsorption of quinolone, tetracycline, and penicillin antibiotics from aqueous solution using activated carbons: Review[END_REF]. VPRs are not destructed but transferred to another phase [START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF][START_REF] Daghrir | Tetracycline antibiotics in the environment: a review[END_REF] thus

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avoiding the formation of transformation products [START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF], except with biological activated carbon. Biological activated carbon consists in microorganisms adsorbed on the surface of the activated carbon and forming bacteria colonies [START_REF] Rivera-Utrilla | Pharmaceuticals as emerging contaminants and their removal from water. A review[END_REF]. Thus, VPRs may be biotransformed by contact with the bacteria and generate TPs. Powder activated carbon at 20mg/L (pore size of 3.03nm, specific surface area of 853m 2 /g) showed high adsorption capacity (>85%) on antibiotics belonging to six different chemical families (SAs, TCs, phenicols, quinolones, MLs, and PENs) in surface water [START_REF] Zhang | Performance evaluation of powdered activated carbon for removing 28 types of antibiotics from water[END_REF]. FQs were also efficiently eliminated by powder activated carbon (diameter of 40 µm) in [START_REF] Fu | Activated carbon adsorption of quinolone antibiotics in water: Performance, mechanism, and modeling[END_REF], where the removal rate of five FQs reached 80-96% after 30-40 hours. Granular activated carbon filtration efficiently removed more than 68% of the seven tetracyclines studied by [START_REF] Choi | Removal of antibiotics by coagulation and granular activated carbon filtration[END_REF]. Two different carbons were used in this study, a coconut-based carbon (pore volume of 0.495 cc/g, specific surface area of 1230 m 2 /g) and a coal-based carbon (pore volume of 0.548 cc/g, specific surface area of 1110 m 2 /g). Coal-based carbon was a bit more efficient, maybe due to a larger pore volume, but it was not significantly different. Biological activated carbon filtration can also be used as in [START_REF] Liu | Removal of typical antibiotics in the advanced treatment process of productive drinking water[END_REF]. For a contact time of 15 minutes, this system accounted for 23%, 23% 20%, 19%, 17% of amoxicillin, sulfamethoxazole, oxytetracycline, sulfamethazine and tetracycline removals respectively. Even if studies number on activated carbon is limited for now (few compounds tested, and few AC types), the results tend to demonstrate that activated carbon participates to the removal of VPRs in DWTPs. Nevertheless, future work will need to assess which carbon type will be more efficient for specific VPRs.

Membrane filtration

Membrane processes, such as ultrafiltration (UF) and nanofiltration (NF) are used to remove natural organic matter and disinfection by-product precursor matter such as humic acids [START_REF] Metsämuuronen | Natural Organic Matter Removal from Drinking Water by Membrane Technology[END_REF]. Membranes will act as physical barriers that will reject some compounds and let some other pass through, depending on the membranes pore size and molecular weight of the substances [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF]. Concerning micropollutants, results are mixed [START_REF] Ogutverici | Triclosan removal by NF from a real drinking water source -Effect of natural organic matter[END_REF], even if membrane processes prove to be highly efficient in the removal of some micropollutants ( [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Yang | Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/sewage treatment plants: A review[END_REF][START_REF] Koyuncu | Removal of hormones and antibiotics by nanofiltration membranes[END_REF]). The efficiency of VPRs rejection by membrane filtration depends on VPR properties (size, molecular weight, etc.), membrane properties (molecular weight cut-off, pore size, surface charge, etc.), matrix composition (presence and nature of organic matter, ionic strength) and temperature [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Dolar | Effect of water matrices on removal of veterinary pharmaceuticals by nanofiltration and reverse osmosis membranes[END_REF]. The main rejection mechanisms for a membrane are charge and size exclusion [START_REF] Dolar | Effect of water matrices on removal of veterinary pharmaceuticals by nanofiltration and reverse osmosis membranes[END_REF][START_REF] Koyuncu | Removal of hormones and antibiotics by nanofiltration membranes[END_REF]. Thus, an important aspect to consider with membrane filtration is the molecular weight cut-off, which reports the molecular weight (expressed in Dalton) of a hypothetical non-charged solute that is 90% rejected [START_REF] Plakas | Removal of pesticides from water by NF and RO membranes -A review[END_REF]. In [START_REF] Koyuncu | Removal of hormones and antibiotics by nanofiltration membranes[END_REF], nanofiltration rejections were higher than 95% for VPRs with a molecular weight higher than 300 g/mol. As a result, TCs antibiotics with molecular weight of around 450 g/mol were completely rejected, while sulfamethoxazole, the SAs with the lowest molecular weight (253 g/mol), had the smallest rejection rate. Therefore, only small VPRs with a molecular weight inferior to the cutoff molecular weight of the membrane will pass through membranes processes. In a laboratoryscale test, three VPRs from different therapeutic classes (ciprofloxacin, dexamethasone and febantel) present in ultrapure water were removed (> 97%) with the 4 different nanofiltration membranes (NF90, NF270, NF and HL) [START_REF] Dolar | Effect of water matrices on removal of veterinary pharmaceuticals by nanofiltration and reverse osmosis membranes[END_REF]. In some cases, like in presence of organic matter in the matrix, even small VPRs can be rejected by interacting with organic matter to form a macromolecular complex rejected by size exclusion. They can also undergo hydrophobic interactions with the membrane caused by organic matter, thus narrowing the pores and leading to a higher rejection [START_REF] Dolar | Effect of water matrices on removal of veterinary pharmaceuticals by nanofiltration and reverse osmosis membranes[END_REF]. Some studies mention that there is no generation of by-products with membranes [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF]. Nevertheless, microbial attachment and growth on membranes [START_REF] Lutskiy | A microbiologybased assay for quantification of bacterial early stage biofilm formation on reverse-osmosis and nanofiltration membranes[END_REF] may lead to the

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generation on TPs by biodegradation. Depending on their sizes and molecular weights, TPs may be rejected or pass through the membrane.

Disinfection

Disinfection is the last step in the whole treatment process. It aims to eliminate all microorganisms before distribution of the treated water. Disinfection can be performed either with O3, chlorine-derived species or ultraviolets (UV) [START_REF] Zhong | Seasonal evaluation of disinfection by-products throughout two full-scale drinking water treatment plants[END_REF].

Chlorination

Several species with chlorine are used in DWTPs to disinfect water (free chlorine, chlorine dioxide, chloramines) but also have the potential to oxidize micropollutants. Free chlorine (i.e. hypochlorite anion and hypochlorous acid) is a non-selective oxidant widely used in DWTP at the disinfection step [START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF][START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF]. In full-scale DWTPs, different behaviours of VPRs were observed when reacting with free chlorine. In [START_REF] Liu | Removal of typical antibiotics in the advanced treatment process of productive drinking water[END_REF], only 4% of all antibiotics were removed during the disinfection step. This percentage was explained by the low concentrations of antibiotics in the influent (below 10 ng.L -1 ) and the low dosage of chlorine. It can be assumed that the low amount of chlorine will be preferentially consumed by other compounds and/or micro-organisms having higher chlorine demand than antibiotics. The quinolone flumequine, which does not have a piperazine ring, does not react at all with chlorine and the FQ enrofloxacin reacts very slowly [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF]. As an explanation, organic matter may interact and form complexes with VPRs, slowing down the reaction rate with chlorine species [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF]. Other VPRs are known to react heavily with chlorine such as trimethoprim, tetracyclines and FQs like ciprofloxacin or levofloxacin [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF]. A major drawback of chlorination is the formation of disinfection by-products can retain the initial biological activity of the parent compounds, or even become more toxic than parent compounds [START_REF] Dong | Degradation of chloramphenicol by UV/chlorine treatment: Kinetics, mechanism and enhanced formation of halonitromethanes[END_REF]. Disinfection by-products of the antibiotic carbadox are believed to retain antibacterial activity as the biological active n-oxide group remains in their structures [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF]. Sulfamethazine degradation by chlorine induces the formation of trihalomethanes and haloacetic acids, which are undesirable chlorination by-products, potentially carcinogenics [START_REF] Dong | Kinetics and degradation pathway of sulfamethazine chlorination in pilot-scale water distribution systems[END_REF]. 38 disinfection by-products were generated during the chlorination of sulfamethoxazole, sulfathiazole and sulfadimethoxine [START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF]. Fifteen of these disinfection byproducts may have retain antibacterial activity as their their sulfonamide functional group was preserved. Besides, 21 disinfection by-products may have acquired negative and toxic effects by the incorporation of a chlorine atom in their chemical structure [START_REF] Wang | A non-target approach to identify disinfection byproducts of structurally similar sulfonamide antibiotics[END_REF]. Chlorine dioxide is used to replace conventional chlorine species because it does not lead to the formation of halogenated species like trihalomethanes when reacting with organic compounds [START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Frade | Environmental contamination by fluoroquinolones[END_REF][START_REF] Navalon | Reaction of chlorine dioxide with emergent water pollutants: Product study of the reaction of three β-lactam antibiotics with ClO2[END_REF][START_REF] Wang | Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation[END_REF]. Instead, chlorine dioxide induces the formation of oxygenated and hydroxylated products when reacting with TCs [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF]. In addition, chlorine dioxide is more selective than free chlorine, and does not react with aromatic, hydrocarbons, carbohydrates, primary and secondary amines, aldehydes, and ketones or piperazine ring. Consequently, the antibacterial activity of FQs remains after the disinfection step with chlorine dioxide. Chlorine dioxide reacts with phenols and tertiary amine groups or piperazine rings [START_REF] Postigo | Transformation of pharmaceuticals during oxidation/disinfection processes in drinking water treatment[END_REF][START_REF] Homem | Degradation and removal methods of antibiotics from aqueous matricesa review[END_REF][START_REF] Wang | Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation[END_REF]. This is supported by the fact that [START_REF] Wang | Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation[END_REF] noticed a chlorination of the piperazine ring of enrofloxacin and ciprofloxacin. Chloramine can also be used for disinfection in DWTPs. However, there is a concern that their reaction with micropollutants like VPRs may lead to the formation of carcinogenic N- [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF]. Indeed, some VPRs with diethylamine groups are very reactive with chloramine. Spiramycin and minocycline were transformed respectively at 3.4 and 4.9% into NDMA in [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF]. The carcinogenic effect of the resulting NDMA solutions has not been assessed in the study. However, as NMDA is classified as a carcinogenic compound at low concentration levels (ng.L -1 ) [START_REF] Leavey-Roback | Veterinary antibiotics used in animal agriculture as NDMA precursors[END_REF] it can be assumed than it can be harmful to human health.

A C C E P T E D M A N U S C R I P T nitrosodimethylamine (NDMA)

Ultraviolets (UV)

UV (254 nm) is used in DWTPs as a disinfectant, but it can also contribute to the reduction of water contamination by some chemical families of VPRs. Efficiency of VPRs removal by UV oxidation depends on the ability of the VPR to absorb at 254 nm, the UV fluence (i.e. UV dose, expressed in mJ/m 2 ) and on the irradiation time [START_REF] Snowberger | Direct Photolysis of Fluoroquinolone Antibiotics at 253.7 nm: Specific Reaction Kinetics and Formation of Equally Potent Fluoroquinolone Antibiotics[END_REF][START_REF] Yao | Kinetics and Modeling of Degradation of Ionophore Antibiotics by UV and UV/H 2 O 2[END_REF]. For twelve SAs (sulfaguanidine, sulfadiazine, sulfamerazine, sulfamethazine, sulfathiazole, sulfamethizole, sulfamethoxazole, sulfonamide, sulfisoxazole, sulfachloropyridazine, sulfamethoxydiazine, sulfadimethoxine) direct UV photolysis at 254 nm was very efficient, with removal rates between 95% and 100% after 30 minutes of irradiation. It was noticed that SAs with a fivemembered heterocycle undergo a higher removal rate than sulfonamides with a six-membered heterocycle [START_REF] Cui | Removal of trace level amounts of twelve sulfonamides from drinking water by UV-activated peroxymonosulfate[END_REF]. Four ionophores (monensin, salinomycin, nigericin and narasin) were completely degraded in 300 seconds. Faster degradation was observed for salinomycin and narasin than monensin. This difference was attributed to the extra double bonds of narasin and salinomycin [START_REF] Yao | Kinetics and Modeling of Degradation of Ionophore Antibiotics by UV and UV/H 2 O 2[END_REF]. UV photolysis can generate transformation products with equal or higher antibacterial activity. For example, the FQ enrofloxacin can be degraded into ciprofloxacin, which is also used as a pharmaceutical [START_REF] Snowberger | Direct Photolysis of Fluoroquinolone Antibiotics at 253.7 nm: Specific Reaction Kinetics and Formation of Equally Potent Fluoroquinolone Antibiotics[END_REF].

Overall removal efficiencies

In [START_REF] Liu | Removal of typical antibiotics in the advanced treatment process of productive drinking water[END_REF] the behavior of six veterinary antibiotics was studied in an industrial-scale DWTP including coagulation, sedimentation, sand filtration and chlorination processes, combined with an advanced treatment process composed of ozonation and biological activated carbon. 91% of total antibiotics were removed during the whole process (85% for amoxicillin; 86% for oxytetracycline; 92% for tetracycline; and complete removal for sulfamethoxazole, sulfamethazine, and erythromycin) [START_REF] Liu | Removal of typical antibiotics in the advanced treatment process of productive drinking water[END_REF]. In 2011, [START_REF] Boleda | Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments[END_REF] studied a DWTP composed of dioxychlorination, clarification and a separation of water into two parallel treatment lines. The first treatment line was a conventional one (ozonation and granular activated carbon filtration) and the second an advanced one (ultrafiltration, ultraviolets and reverse osmosis). The two different treatment lines (conventional one and advanced one) were then blended and the water was chlorinated and distributed. Reverse osmosis is not usually used for drinking water treatment, but in [START_REF] Boleda | Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments[END_REF] the raw water quality was altered by salt mine exploitations, so reverse osmosis was applied for desalination. Six veterinary antibiotics (lincomycin, sulfamethoxazole, sulfadimethoxine, sulfamethazine, trimethoprim and tylosin) were studied and efficiently eliminated with removal percentages > 99%. Lincomycin, sulfamethoxazole and trimethoprim were totally removed with both applied treatments (conventional and advanced). The conventional treatment was more effective to remove sulfadimethoxine and sulfamethazine than the advanced treatment. On the other hand, tylosin was eliminated at 99% with the advanced treatment and at 94% with the conventional treatment [START_REF] Boleda | Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments[END_REF].

A C C E P T E D

M A N U S C R I P T
Other studies reported complete removal of the studied VPRs with conventional treatments for the following compounds: lincomycin [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF][START_REF] Stackelberg | Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[END_REF], sulfamethazine [START_REF] Stackelberg | Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[END_REF], sulfadimethoxine [START_REF] Stackelberg | Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[END_REF], and sulfathiazole [START_REF] Stackelberg | Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[END_REF], tiamulin [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF], flunixin [START_REF] Azzouz | Influence of seasonal climate differences on the pharmaceutical, hormone and personal care product removal efficiency of a drinking water treatment plant[END_REF]. Influent concentration levels ranged from 4 ng.L -1 to 50 ng.L -1 [START_REF] Lin | Occurrence, removal and risk assessment of pharmaceutical and personal care products (PPCPs) in an advanced drinking water treatment plant (ADWTP) around Taihu Lake in China[END_REF][START_REF] Azzouz | Influence of seasonal climate differences on the pharmaceutical, hormone and personal care product removal efficiency of a drinking water treatment plant[END_REF][START_REF] Stackelberg | Efficiency of conventional drinking-water-treatment processes in removal of pharmaceuticals and other organic compounds[END_REF].

CONCLUSION AND WAY FORWARD

VPRs have been widely quantified in natural waters (either surface water or groundwater) between 2007 and 2017, from 1 ng.L -1 to 255µg.L -1 . This demonstrates that natural waters contamination by VPRs is still an actual issue that must be evaluated and managed. Plenty of parameters are involved in the dynamics (occurrence, mobility, persistence) of VPRs in natural water, depending on spatial aspects and temporal aspects. An emphasis is made on sales and uses of VPRs which are major factors impacting their occurrence. The update provided in this review on VPRs sales worldwide (regarding the available information) shows that sales tend to decrease in most countries with the exception of the USA and in New Zealand. TCs are the most sold veterinary antibiotics worldwide, followed by PENs, MLs and SAs. Compared to ten years ago, more countries sales data are available in the public domain which is an improvement. Indeed, sales information enables a better targeting of the compounds to be sought in the environment of specific countries. Nevertheless, sales amounts of probably important VPRs consumer countries such as China, India or Canada are not yet available. Considering fate of VPRs in natural waters, studies published over the past few years have provided knowledge on the degradation mechanisms in natural waters. VPRs can be degraded or transformed by biodegradation, hydrolysis or photolysis. Photodegradation appears to be the major degradation pathway in SW. Only few studies were published on VPRs occurrence in tap water (11 studies), as shown in section 3. Nevertheless, veterinary antibiotics have been detected from traces to 100ng.L -1 . Those concentration levels are unlikely to cause acute toxicity effects on human health [START_REF] Houtman | Human health risk assessment of the mixture of pharmaceuticals in Dutch drinking water and its sources based on frequent monitoring data[END_REF]. However there is a concern as VPRs are added to the cocktails of micropollutants already present in drinking water, such as human drug residues, pesticides, biocides, flame retardants, metals [START_REF] Bot | Exposure of children to metals via tap water ingestion at home: Contamination and exposure data from a nationwide survey in France[END_REF][START_REF] Fingler | Herbicide micropollutants in surface, ground and drinking waters within and near the area of Zagreb, Croatia[END_REF]. It is therefore important to understand fate of VPRs in DWTPs. Overall removals of VPRs in DWTPs generally exceed 90% and advanced treatment processes (oxidation processes, adsorption on activated carbon, membrane filtration) greatly contribute to these removals. However, studies in VPRs fate performed on full-scale DWTPs are scarce (6 studies). Figure 4 is focusing on studies on fate of VPRs in natural waters and fate of VPRs in DWTPs (however, studies on VPRs occurrence in natural and tap water are not considered). Among the 38 studies dealing with VPRs fate in natural waters, only 18% were conducted under environmentally relevant conditions. Conditions considered as environmentally relevant were the following: VPRs concentrations below 100µg.L -1 ; natural sunlight; natural water. Conditions considered as environmentally irrelevant were the following: VPR concentrations higher than 100 µg.L -1 , artificial sunlight, deionized water.

[Figure 4] Among the 28 selected papers on the fate of VPRs in DWTP, only 21% were performed under relevant full-scale DWTP conditions (Figure 4). Additional parameters such as concentration of the reactive used in DWTP (oxidant for example) and contact time were considered. This suggests that results of fate studies in DWTP should be considered with caution as the removal rates may be different in full-scale DWTP conditions. Although the issue of experimental conditions and experimental concentrations levels has long been emphasized in order to accurately reproduce environmental phenomena, it seems that there are still improvements to be made. Also, oxidation processes can result in the formation of oxidation by-products that may be more toxic than the parent compound. Currently the formation pathway, the chemical structure and the potential impacts of these transformation products on human health are largely unknown and need to be investigated. To finish, many VRPs have not been investigated yet. There is a scientific gap on the occurrence and fate of antiparatic drugs in natural waters and tap water (only 11 studies considered versus 105 studies on antibiotics). b All details (studies references, studies locations…) can be found in Table S1 [START_REF][END_REF] and in Australia in 2010 [START_REF]Australian Pesticides and Veterinary Medicines Authority (APVMA), Quantity of antimicrobial products sold for veterinary use in Australia 2005-2010[END_REF]

  Postal address: EHESP/LERES, 15, avenue du Pr. Léon-Bernard, CS 74 312

FIGURE 1 :b

 1 FIGURE 1: Concentration ranges (ng/L) of VPRs frequently searched in natural waters (2007-2017) (n a samples>100) b

FIGURE 2 :

 2 FIGURE 2: Concentration ranges (ng/L) of VPRs less searched in natural waters (2007-2017) (n a samples<100) b

SALES

FIGURE 3 :

 3 FIGURE 3: Representation of a drinking water treatment plant

FIGURE 4 :

 4 FIGURE 4: Number of studies dealing with fate of VPRs in natural waters and DWTPs

  and Table S2 in Supplementary Information

TABLE 1 : Sales of VPRs in France

 1 [START_REF] Méheust | Suivi des ventes de médicaments vétérinaires contenant des antibiotiques en France en[END_REF], Europe[START_REF]Sales of veterinary antimicrobial agents in 30 European countries in 2015[END_REF] and USA[START_REF]Food and Drug Administration (FDA), Summary report on antimicrobials sold or distributed for use in food-producing animal[END_REF] Sales in Europe integrate 30 european countries sales data, including France ** Others include the following: Aminocoumarins, Amphenicols, Diaminopyrimidines, Glycolipids, Orthosomycins, Pleuromutilins, Polymyxins, Polypeptides, Quinoxalines, Streptogramins Acronyms: TCs: Tetracyclines SAs: Sulfonamides PENs: Penicillins MLs: Macrolides

		SALES IN FRANCE IN 2016		SALES IN EUROPE IN 2015*	SALES IN UNITED STATES IN 2016
	Chemical family	Authorized Compounds	Sales (tons of	Chemical
		in 2016	active ingredient)	family

*

TABLE 2 :

 2 Sales of VPRs in Korea[START_REF]Monitoring and characterization of antimicrobial resistance of bacteria from livestock products[END_REF] and Japan[START_REF]Sales Amounts and Sales Volumes (Active Substance) of Antibiotics, Synthetic Antibacterials, Antihelmintics and Antiprotozoals[END_REF] in 2015

			U S C R I P
			N
		A
		M
	C C E P T E D
	A
	MOST SOLD VPs IN KOREA (2015)	MOST SOLD VPs IN JAPAN (2015)
	Chemical family	Compound	Sales of active	Chemical family	Compound	Sales of active

TABLE 3 : Sales of VPRs in New-Zealand in 2014

 3

ACKNOWLEDGMENTS

This work was supported by La Région Bretagne (COH15002), L'Agence Française de la Biodiversité (Project no. 224), EHESP (2015/539/DRH/EHESP), ARS and DREAL Bretagne (56/2016/277). Declarations of interest: none.