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04 - MASS BALANCE MODELLING OF PHARMACEUTICALS CONSUMPTION USING WATER Yuliya Vystavna1, Volodymyr Grynenko2 , Frédéric Huneau1 , Philippe le Costumer1 1Université de Bordeaux, GHYMAC Géosciences Hydrosciences, B18 avenue des Facultés, 33405 Talence, France 2National Academy of Municipal Economy at Kharkiv, Department of Environmental Engineering and Management, vul. Revolutsii 12, Kharkiv, 61002, Ukraine ABSTRACT Pharmaceuticals enter sewage works and natural water as parent compound or metabolites with human and animal excretion. The data on the drug consumption can be useful for the prediction of the water pollution by pharmaceuticals, environmental and health risks assessment, but also for the socio-economic analysis and market research. Unfortunately, these data are scarce or not available because of the large amount of not prescription drugs and their unpredicted distribution on the market. The mass balance modeling of pharmaceuticals based on water monitoring data was proposed for the determination of the drug consumption rate in regions. The model has been used for the calculation of the theoretical consumption rate of selected pharmaceuticals in regions of Ukraine and France and their comparison with available reported data. The mass balance model includes the drug excretion rate and efficiency of drug removal at the wastewater treatment plant. The water monitoring data were obtained from a series of sampling campaigns in the Jalle d’Eysines River, Bordeaux region, France and in the Udy River, Kharkiv region, Ukraine. Using the passive sampling technique, the concentrations of caffeine, carbamazepine, diclofenac and ketoprofen have been estimated for the each river in two contrasted seasons. The results show that the drug consumption is significantly higher in France (in more than 10 times) for all components. Also, the consumption of all targeted pharmaceuticals was significantly higher in winter than in summer period in both studied regions. The comparison of available data on the consumption of carbamazepine in France indicates that the calculated and reported consumption values were at the same magnitude. Thus, the strategy of mass balance modeling can be used for the approximate estimation of the drug consumption rate, especially in regions with a high volume of non-prescription drugs on the market and chaotic use of medicaments by the population. The mass balance model should be developed using data on the degradation of pharmaceuticals. Also continuous monitoring of water is necessary to obtain more data and verify the model. INTRODUCTION With the development of the analytical chemistry techniques and protocols, more and more pharmaceutical products (PPs) have been detected in various natural media such as fresh surface waters (Bendz et al, 2005), drinking and tap water (Heberer, 2002; Kuster et al, 2006), ground water (Barnes et al, 2008), marine and ocean waters and some aquatic organisms (Comeau et al, 2008) in different countries. The presence of these compounds in the environment are generally linked to the consumption of medicaments and effluent of non-metabolized and unused pharmaceuticals into natural waters through the wastewater treatment facilities that are considered as the main source of PPs pollutants (Togola and Budzinski, 2007). But because of the large amount of not prescription drugs and their distribution on the market, the data on the consumption of the medicaments by the population are scarce or unavailable and one of the way to get these data is mass balance modelling of pharmaceuticals (Khan and Ongerth, 2004; ter Laak et al, 2010) using water monitoring data (Kasprzyk-Hordern et al, 2009). Our study was focus on the evaluation of use pharmaceuticals as socio-economic indicators. The general tasks of the research are: (1) identify the characteristics of pharmaceuticals as socio-economic indicators; (2) propose the mass balance approach for the estimation of drug consumption and pharmaceuticals market development based on the water monitoring data. This study is a part of the research on “Trace metals and pharmaceuticals in the rivers of Eastern Ukraine”. The practical implementation of the proposed tasks has been done in the Kharkiv region of Eastern Ukraine and Bordeaux region of South –West France. STUDY AREA The Jalle d’Eysines River, Bordeaux agglomeration, France and the Udy River, Kharkiv region, Ukraine, have been selected to represent pollution status of basins with quite similar hydrological characteristics (length, width, depth, water flow etc.) and water use (wastewaters discharge, irrigation, etc) but different socio-economic conditions in terms of population density, economic activities, incomes, etc. The alluvial Jalle d’Eysines River is a right tributary of the Garonne River with 34 km of length, with depth from 0.8 to 2.5 m, and 3 m3s-1 of average water debit, located on the north from Bordeaux city, France. The river has mostly pluvial feeding, runs through residential suburban and rural areas and receives effluents from the two major municipal wastewater treatment facilities of the Bordeaux suburbs, serving greater than 100,000 people, and one local treatment works in the military area. The Udy River is alluvial transboundary river that is used for the recreation, drinking water supply, irrigation and fishing in the Kharkiv region of Ukraine (c.a. 3,000,000 inhabitants). The total length of the Udy River is about 164 km and depth ranges from 0.4 to 2.3 m, the flow of the river is regulated by several dams constructed along the watercourses. The mean annual discharge of the Udy River is 6.8 m3 s-1 in winter and 2.5 m3 s-1 in summer in the site located upstream of the Kharkiv city (Vasenko et al, 2006). River is partly covered by ice from the end of November to the end of March. The major land use categories on the watershed are agriculture (40 %), urban lands (50%) and water reservoirs (10%). The Udy River receives the mixed the municipal and industrial wastewaters (about 800,000 m3 per day) from the Kharkiv city and its suburbs. Surface water in both rivers was sampled in sites located upstream and downstream of the WWTPs. Two sites on the Jalle d’Eysines River: site 1- locates approximately 1 km downstream of the WWTP (served c.a. 50,000 people) and site 2 locates approximately 0.5 km downstream of this WWTP. Also two sites have been chosen for the sampling on the Udy River: site 1 – locates in the city centre, but approximately 0.5 km upstream of the wastewater discharges; site 2– locates approximately 0.7 km downstream of the wastewater discharge from the two WWTPs (served c.a. 1,500,000 people) of the Ukrainian region. The sampling campaigns have been done in May 2009 and December 2009 on the both rivers. MATERIALS AND METHOD The passive samplers – polar organic chemical integrated samplers (POCIS) with the Oasis HLB sorbent produced by Exposmeter Ltd. Tavelsjö, Sweden have been used for the water characterization The POCIS preparation and analysis have been performed in the ISM CNRS UMR Laboratory of University of Bordeaux 1, France. The extraction and analytical procedures for POCIS were based on previously developed methods (Togola and Budzinski, 2007). Blanks were performed in the laboratory and corrections were made in the data. Recovery rates of the POCIS samples were determined by the spike samples. The recoveries of extraction of analytes from POCIS vary from 79 to 97 % of spiked amount for all chemicals. The limit of the detection was from 0.05 to 0.1 ng L-1. Uptake rates have been calculated according to Togola and Budzinski, 2007 and Budzinski et al, 2009. The 5 pharmaceuticals of different therapeutic groups (analgesics: paracetamol (PARA), anti-inflammatories: ketoprofen (KETO) and diclofenac (DICLO), psychiatric drugs: carbamazepine (CBZ) and diazepam (DZP) and 1 stimulants (caffeine - CAF) have been chosen based on the frequency of detection (Vystavna et al, 2009; Vystavna et al, 2010) and the medicaments consumption data (Ministry of Health Protection, Ukraine: www.moz.gov.ua). In our study, the calculation of the theoretical consumption rate of selected pharmaceuticals in regions of Ukraine and France has been done using the previously proposed mass balanced model approaches (Vystavna, 2005; Kaspzyk-Hordern et al, 2009; Khan and Ogerth, 2004; Coetsier et al, 2009; ter Laak et al, 2010) with application of the water monitoring data. RESULTS Specificity of pharmaceuticals The specificity was accessed based on physic-chemical properties of the compounds (e.g. persistence (half life in the soil, days); water solubility (mgL-1), bioaccumulation (using octanol-water partition coefficient Kow or bioconcentration factor (BCF)) (Girard, 2005; Chemicals Profile by U.S. Environmental Protection Agency: www.pbtprofiler.net; Kasprzyk-Hordern et al, 2009). These chemical properties are generally known and vary between different compounds (Beausse, 2004). According to the specificity, the targeted pharmaceuticals were divided into three principle groups (Table 1): Group A – non conservative pharmaceuticals: caffeine (CAF) and paracetamol (PAR). Pharmaceuticals of this group have a high water solubility (more than 10,000 mgL-1), low accumulation (less than 0.5, estimated by log Kow) and high efficiency of treatment (more than 60% of removal) on the conventional wastewater treatment plant (active sludge). Group B – conservative pharmaceuticals: diazepam (DZP) and carbamazepine (CBZ). Pharmaceuticals of this group have low water solubility (less than 1,000 mgL-1), high accumulation (more than 2.5, estimated by log Kow) and low efficiency of treatment (less than 30% of removal) on the conventional wastewater treatment plant (active sludge). Due to their properties (Table 1), they are able to accumulate in the natural environment. Group C – pharmaceuticals with mixed properties: diclofenac (DICLO) and ketoprofen (KETO). These pharmaceuticals have different physic-chemical properties. For example, diclofenac and ketoprofen have low water solubility less than (1,000 mgL-1), high accumulation, but the treatment efficiency of these compounds are relatively good (40-60% of removal from raw wastewaters on the conventional wastewater treatment plant). Possibly, other additional factors, e.g. photodegradation, impact on the presence of these compounds in the natural environment. Table 1. Physico-chemical property of pharmaceuticals a – according to the U.S. EPA http://www.pbtprofiler.net/ b – according to Miege et al, 2009 c – KNAPPE, 2008 These physico-chemical properties of pharmaceuticals were taken into account for the mass balanced modelling. Mass balanced model The following mass balanced model was applied for the estimation of the medicaments consumption rates (Eq. 1). Mc - drug consumption rate in a studied settlement, which is served by sewage system, (g d-1); K1 – drug excretion rate (a part of a pharmaceutical component which enters a sewerage system in unchanged form with human excretion), (g g-1). Pharmacokinetics represents a very complex process and depends on the metabolism, age, activity etc. In this study we used previously reported data on the drugs excretion (Khan and Ongerth, 2004; Kasprzyk- Hordern et al, 2009; Froehner et al, 2010). Metabolites of targeted pharmaceuticals have not been included in the research. K2 – the efficiency of wastewater treatment processes, that was estimated a part of a pharmaceuticals what are removed during the treatment, (g g-1). The efficiency has been used from previously published works for selected substances with taking into account the type of the treatment processes (Table 1). Cu – the concentration of the pharmaceuticals in the upstream part, (g m-3) (Table 2). Table 2. The concentration of pharmaceuticals in the Jalle d’Eysines and Udy Rivers, (ngL-1, ±S.D., n=3) Qw, Qu– the water flow rate in the river, downstream and upstream of the WWTPs The daily drug consumption rate per person (D) was estimated as Eq. 2: where P – is the number of people using the sewage system, inhabitants. Thus, for the conservative substances (carbamazepine and diazepam) and for diclofenac as the compound with high accumulative ability, we took into the account the upstream influent, for non conservative pharmaceuticals (caffeine and paracetamol), we considered only downstream concentrations. For ketoprofen, the upstream inputs were taken in to account only for the winter season, as potentially the photodegradation (Nakada et al, 2008) is low during this season and KETO behaves as the conservative substance. A limitation of the used approach is that the veterinary consumption was not taken into account, as wastewater from veterinarian hospitals and excrements of domestic animals can also enter the sewage systems. Environmental degradation and sorption was not included because of the absence of relevant data. The calculated consumption rates of targeted pharmaceuticals presented in the Table 3. Table 3. The calculated consumption rate of pharmaceuticals in Bordeaux region, France and Kharkiv region, Ukraine It was found that consumption rates of caffeine, paracetamol and ketoprofen in Ukraine are significantly lower than in France. The consumption of caffeine in Ukraine and France exhibits high seasonal variation (R.S.D. > 70%), that possibly relates to the higher consumption of drinks during the cold winter season. But the estimated consumption of carbamazepine and diclofenac were close to these data in France. It should be noted that in spite of the lower consumption rate of drugs in Ukraine compare to French data, the concentration of these chemicals were found higher in the Udy River than in the Jalle d’Eysines River. It shows, that non sufficient dilution and treatment of wastewaters, but also discharge of untreated and uncontrolled inputs in water bodies impact on the contamination of the river by emerging pollutants together with the consumption patterns. Discrepancy in drug consumption between countries can be because of the difference in the age structure and health problems of population, regulation of the medicament market and welfare. All these aspects need the additional research in order to find the relation between socio-economic and environmental data. The same approach can be applied for the other groups of emerging contaminants, but also for the illicit and regulated drugs in the community for the analysis of the market and sales of drug without prescription, identification of the disposal of drugs leading to the overestimation of usage. Other application of the environmental loads of the pharmaceuticals is the identification of the type of the human settlements (urban and rural) and presence of the animal farms (monitoring of the veterinary medicaments). COMPARISON WITH THE OFFICIAL DATA ON THE PHARMACEUTICALS CONSUMPTION The calculated data on carbamazepine and diclofenac consumption rates (Table 3) have been compared with reported data for France. For Ukraine similar data were not available, as no any official statistics on the drug consumption exist and the insurance and social security system is under development (Ministry of Health Protection, Ukraine www.moz.gov.ua) In 2006, about 22 ton of carbamazepine was used in France (63 mln inhabitants) (Coetsier et al, 2009), it is equal 0.3 g per person per year. In our calculation this is approximately 0.1 g per person per year, as there was no significant variation in seasonal use of this medicament in May and in December. So, the calculated carbamazepine consumption rate was in the same magnitude as the reported one. A good agreement between predicted environmental concentration and measured environmental concentration was found in previous research on carbamazepine in the South of France (Coetsier at al, 2009). For diclofenac the discrepancy was much higher, as we estimated an annual consumption rate of 1.7 g per person (based on the May data) and 4.3 g per person (based on the December data). The reported data (Coetsier et al, 2009) were much lower, however; approximately 0.25 g per person per year. A high discrepancy between the calculated and measured concentrations of diclofenac has been presented in research in Sweden (Bendz et al, 2005) and France (Coetsier et al, 2009). As the reported data were based on the statistics of the social security reimbursement and present only a prescribed amount, we can assume that a significant amount of diclofenac can be used without prescription. Potentially the ratio between estimated (ED) and official data (RD) can be used for the diversion drugs into different groups. For example, the first group can consists of pharmaceuticals with ED/RD ratios is less than 1, where the ratio is possibly affected by the behavior of the molecules and extent of their degradation in the environment. The other group consists of pharmaceuticals detected at concentrations higher than expected (ED/RD is higher than 1) (Calamari et al, 2003). In this group, consisting of drugs sold without prescription or for veterinary use, market justifications (sales load uncertainty) have more role than chemical properties and environmental fate to explain differences between calculated and reported data. CONCLUSIONS The results of this simple mass balance approach show that water quality monitoring can be useful for the estimation of social indicators such as the medical drug consumption rate and the illicit drug consumption rate. For further development of the approach, temporal variations, environmental degradation and other uncertainty factors can be incorporated in the mass balance model. Extensive monitoring data should be included for the verification and higher accuracy of the modelling process as well. But the simple process of mass balanced modelling can be effectively applied for the using the water quality monitoring data in the socio-economic research e.g. drug (illicit and licit) consumption level, pharmaceuticals industry and market development, etc. REFERENCES Barnes K., Kolpin D., Furlong E., Zaugg S., Meyer M., Barber L., 2008. A national reconaissance of pharmaceuticals and other organic wastewater contaminants in the United States – I) Grounwater. Sci Total Environ 402, 192-200. Beausse, J., 2004. Selected drugs in solid matrices: a review of environmental determination, occurrence and properties of principle substances. Trends in Analytical Chemistry 23, 753-761. 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Published by Stockholm International Water Institute. Sweden, 420-421.

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