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Pharmaceuticals: a threat to drinking water?
Opinion
TRENDS in Biotechnology
Vol.23 No.4 April 2005
Pharmaceuticals: a threat to drinking water? Oliver A. Jones, John N. Lester and Nick Voulvoulis Department of Environmental Science and Technology, Faculty of Life Sciences, Imperial College, London, SW7 2BP, UK
Recently, considerable interest has developed regarding the presence of pharmaceuticals in the environment, but there has been comparatively little study on the potential of these substances to enter potable supplies. This is surprising because drinking water would provide a direct route into the body for any drugs that might be present. Although many countries employ advanced treatments, such as granular activated carbon, membrane technologies, ozonation and ultraviolet radiation, for treating water intended for human consumption, some compounds have been shown to be unaffected by such processes. Here, we examine the levels of drug substances reported in drinking water around the world. The possible implications of the presence of these compounds are highlighted and assessed, and recommendations are made for further research. Introduction During the past three decades, research on the impact of chemical pollution has focused almost exclusively on the conventional ‘priority’ pollutants [i.e. persistent organic pollutants (POPs)] and this has been extensively reviewed recently [1]. Today, these compounds are less relevant for many first world countries because emissions have been substantially reduced through the adoption of appropriate legal measures and the elimination of many of the dominant pollution sources. The focus has consequently switched to compounds present in lower concentrations but which nevertheless might have the ability to cause harm [2]. One of the interesting characteristics of many of the chemicals that might cause this type of pollution is that they do not need to be persistent in the environment to cause negative effects [3]. This is because their high transformation and removal rates can be offset by their continuous introduction into the environment, often through sewage treatment works [4]. This is one reason why there is an increasingly widespread consensus that this kind of contamination might require legislative action sooner rather than later [5,6]. The problem of pharmaceutical pollution The issue of pharmaceuticals (and their metabolites) in the environment, notably the aquatic compartment, has been a growth area in environmental chemistry for several years [7]. To date, most of the published literature has addressed the occurrence of drugs in sewage effluent and Corresponding author: Lester, J.N. ( [email protected]).
receiving waters. However, although the risks associated with exposure to drugs are probably most significant with regard to the natural environment, the public’s concern is understandably more focused on human exposure. This is especially important in areas that practise indirect water reuse, where sewage effluent is released to streams and rivers that are in turn used as a source of raw water for the production of potable supplies for communities living downstream [8]. Unfortunately, there are extremely few data available (as of January 2005) on the occurrence of pharmaceutical products in point-of-use drinking waters (that is, tap water at the sink). This is probably partly related to the difficulty of analysis of pollutants at very low, sub parts per billion (mg lK1) or parts per trillion (ng lK1) concentrations, and partly related to the belief that modern treatment processes will remove pharmaceutical compounds from potable supplies. For instance, the view of the Drinking Water Inspectorate, which regulates public water supplies in England and Wales, is that pharmaceutical residues will not be detectable in tap water in the UK (http://www.dwi.gov.uk/ consumer/concerns/Drugs&EDs.htm). Their rationale is based on the fact that technologies such as ozone and granular activated carbon (GAC) treatment are now installed at many waterworks in England and Wales to remove compounds such as pesticides. Because these technologies are also effective against a wide range of other trace organic substances that might be present in source waters, including some pharmaceuticals [9,10], they reason that no drugs will be found in UK drinking water. However, they do not reference any peer-reviewed studies to back up the position. In fact, whereas studies of the susceptibility of endocrine disruptors and pharmaceutical residues to removal technologies used during water treatment processes are being performed under the auspices of the European Union (EU) Poseidon initiative [11] (http://www.eu-poseidon. com/), ozone and GAC treatments are not present at all UK waterworks. There are also several drug compounds that have been shown to be resistant to both these treatments (probably as a result of physicochemical properties such as high water solubility and/or poor degradability). These include the anti-epileptic drugs carbamazepine and primidone, and the lipid regulators clofibric acid and gemfibrozil [12–16]. The purpose of this article is therefore to draw attention to this area of pharmaceutical pollution. For simplicity, metabolites of drug compounds are not covered in this work. In addition, both natural and
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synthetic hormones are excluded. Although these compounds are an important subgroup of pharmaceuticals, there is already an abundance of work available in the literature on this topic [17]. What has been found? There is currently no regulatory requirement for the monitoring of pharmaceuticals in drinking water. On the basis of the limited dataset (Table 1), human pharmaceuticals have only occasionally been detected in drinking water, with concentrations generally being in the ng lK1 range [18]. Veterinary medicines might also have the potential to enter water sources, even in upland areas, through leaching from fields used to graze stock that are treated with drugs, or disposal of manure from stock so treated [19]. Again, there is little research in this area. To date, only the macrolide antibiotic tylosin, which is often used as a growth promoter in veterinary medicine, has been reported in drinking water [20]. Heberer and Stan [15] found clofibric acid and the drug metabolite N-(phenylsulfonyl)-sarcosine in the majority of drinking water samples collected from the 14 waterworks in the Berlin area, with the maximum concentrations in drinking water samples being 270 ng lK1. This related well with the percentage values of artificial groundwater enrichment and bank filtrate used by the water treatment plants in drinking water production. Thus, it can be assumed that both contaminants were not eliminated by the treatment used by the Berlin waterworks. In a separate study, Heberer and Stan [21] also quantified a Table 1. Concentrations of drug compounds found in finished drinking water worldwide Compound
Therapeutic group
Bezafibrate Bleomycin Clofibric acid
Lipid regulator Anti-neoplastic Lipid regulator
Carbamazepine
Anti-epileptic
Diazepam
Psychiatric drug
Diclofenac
Analgesic and anti-pyretic Lipid regulator Analgesic and anti-pyretic Analgesic and anti-pyretic Analgesic and anti-pyretic Macrolide antibiotic, used as a growth promoter for livestock
Gemfibrozil Ibuprofen Phenazone Propylphenazone Tylosin
www.sciencedirect.com
Country
Refs
Germany UK UK
[46] [47] [48]
Germany Germany Germany Germany Italy Canada USA UK
[46] [16] [25] [21] [20] [14] [49] [50]
23.5 6
Italy Germany
[20] [46]
70 3
Canada Germany
[14] [46]
250 400 80 120 1.7
Germany Germany Germany Germany Italy
[23] [22] [23] [22] [20]
Maximum concentration detected (ng lK1) 27 13 Positive identification 70 165 270 170 5.3 24 258 10
Vol.23 No.4 April 2005
maximum of up to 170 ng lK1 in drinking water samples taken from one of 14 waterworks in Germany. For drinking water taken from the remaining 13 waterworks, values were below 75 ng lK1, with samples from two waterworks being below the level of detection of 1 ng lK1. The analgesic and antipyretic drugs phenazone and propylphenazone were also found in Berlin drinking water in two separate studies by Reddersen et al. [22] and Zu¨hlke et al. [23], again at the ng lK1 level. However, it is of note that the source of most of the pharmaceutical pollution in Berlin drinking waters is thought to be from the use of groundwater contaminated with sewage as a water source (a practise that is known to present a wide spectrum of technical and health challenges [24]). For example, Heberer et al. [25] established that clofibric acid, phenazone, propylphenazone, diclofenac, ibuprofen and fenofibrate can all leach from contaminated surface water through the subsoil into the ground water of some waterworks through bank filtration. The problem is also mainly confined to the east of the city (where there is a more basic water treatment system built under communist rule) and is not considered a general problem in Germany as a whole [26–28]. For instance, Jux et al. [29] looked for the drugs gemfibrozil, clofibric acid, diclofenac, ibuprofen, ketoprofen, indomethacin and fenoprofen in river, pond and tap water from Cologne (west Germany) and the surrounding area. Whereas diclofenac (the drug present in the highest amount in the environment) could be detected in 10 out of 27 water samples at concentrations of up to 15 mg lK1, none of the pharmaceuticals investigated was present in any of the drinking water samples taken. However, as mentioned previously, even advanced water treatment does not always remove all drugs. For instance, a report by Tauber [14] found detectable concentrations of both carbamazepine and gemfibrozil in four out of the ten Canadian cities tested that all used advanced water treatment such as ozone or GAC (CTV: Quantitative Analysis of Pharmaceuticals in Drinking Water From Ten Canadian Cities; http://www.ctv.ca/ servlet/ArticleNews/story/CTVNews/1044053088271_ 39462288/?hubZSciTech). Although this report was not published in the peer-reviewed literature, but rather was commissioned by two Canadian news broadcasters (CTV News and The Globe and Mail), the results make interesting reading. Whereas only three of the 440 analyte–sample combinations gave detectable levels for carbamazepine, and only one gave detectable levels for gemfibrozil, the results show that there is a clear possibility that drug compounds can pass through even modern, advanced water treatment facilities. Potential for human health risks Research has shown that significant amounts of drugs are released from sewage treatment plants to the environment. Therefore, there is a risk that humans might be exposed to drugs through potable water drawn from contaminated supplies. Although this risk is likely to be relatively minor, the increasing demands on the freshwater supplies of the world will probably lead to greater incidences of indirect and direct water-reuse situations as the spatial and temporal distances between wastewater
Opinion
TRENDS in Biotechnology
and drinking water become further reduced. The potential for adverse effects should therefore not be overlooked, especially because little is known regarding the environmental or human health hazards that might be posed by chronic, sub-therapeutic levels of pharmaceutical substances or their transformation products. In addition, regardless of the absence of any proven risks, drinking water will always be a major focus of consumer concern because it is a direct route to the human body for any drug compounds that might be present [30]. Other (indirect) pathways include bodily interaction (bathing or showering in waters containing effluent) or ingestion (eating crops irrigated with effluent or grown on sewage-sludge-amended soil). The presence of pharmaceuticals in drinking water, however small, is also likely to increase the general public’s already negative attitude to water reuse [31]. Nevertheless, it should be stressed that several studies have been performed demonstrating that the likelihood of any form of acute (short-term) human health risk originating from the presence of low concentrations of pharmaceuticals in drinking water is extremely low [30,32,33]. In fact, even drinking two litres of the tainted water every day over a lifetime would not cumulatively deliver the equivalent of a single prescribed dose of any of the compounds present. This does not rule out long-term effects that might go unnoticed, and it is of course impossible to prove that the risk of any pollutant is zero. The presence of antibiotics is likely to be of most concern because it could lead to the development of resistant pathogens. Christensen [33] and Webb et al. [30] have also identified sensitization, or the development of an allergenic response to antibiotics, as being of concern. A search of the literature indicated that there has been only one case of an antibiotic (the previously mentioned veterinary drug tylosin) in drinking water reported thus far [20]. However, bacteria with antibiotic resistance genes have been found in biofilms inoculated with drinking water bacteria in Germany [34]. This indicates possible gene transfer, perhaps from surface and/or wastewater, to the drinking water distribution network. This certainly could also be a cause for concern as regards human health if it were a widespread occurrence [35]. Another facet to this problem is that of the synergistic effects of mixtures of compounds [36]. Although concentrations of individual substances might be low, it is unknown what effects, if any, exposure to repeated doses of a mixture of sub-therapeutic amounts of drugs and other chemicals (such as endocrine disruptors) could have on human health. Minor side effects to medications given at prescription doses are common but are usually outweighed by the health benefits of the medication. This would not be the case with unintended, routine exposure to the drugs or mixture of drugs that could, potentially, be found in drinking water. If drugs are present in drinking water, then potential health concerns will need to focus on individual, synergistic/antagonistic and possible mixture effects over an extended period of time (w80 years or more) [37]. Possible interactions with other medications (or even illegal drug substances) that individuals might be taking will also need to be considered [25]. For instance, ibuprofen has been demonstrated to interfere with the www.sciencedirect.com
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cardioprotective properties of aspirin [38], some of the new generation of cyclooxygenase-2 inhibitors might interfere with bone healing and re-growth after fracture [39], and caffeine can enhance the effects of certain analgesics [40]. It is very doubtful that concentrations would be high enough in drinking water to cause these effects. However, continual life-long exposure to trace levels of pollutants is an unexplored area of toxicology and the many possible issues that could theoretically be involved have not been extensively studied. Thus, further research in defining the potential human health risks of pharmaceuticals in drinking water would be useful because concerns cannot realistically be ruled out completely for several reasons, as given below. † The efficiency of contaminant removal might vary both between chemicals and between water treatment plants owing to the differing processes employed. Whereas advanced technologies such as ozone and GAC remove many compounds [41], they do not eliminate all drugs, and are by no means universally applied to the treatment of potable supplies, even in developed countries. † Although primarily a sewage treatment option, there is the potential to use sequencing batch reactors and/or membrane bioreactors to remove drug compounds. A study by Clara et al. [42] compared the behaviour of selected micro-pollutants in a membrane bioreactor and an activated sludge plant operating at a very high sludge age. Each gave high removal rates for most compounds and there was no significant difference between either option in the removal efficiencies of several pharmaceutical compounds. This might be partly attributable to the low molecular size and high solubility of the compounds under investigation. † Drugs are designed to be biologically active, and it is possible that unintended effects on non-target organisms and/or receptors occur at lower concentrations than the intended therapeutic effects. † Long-term effects might occur at much lower concentrations and follow different toxicodynamic mechanisms than those extrapolated from short-term studies. † The effects of mixtures of sub-therapeutic levels of complex mixtures of drugs (and other pollutants) over perhaps 80 years or more are unknown. † Although toxicological evidence is seldom uncontroversial or unanimous, there is practically zero data for gauging the potential toxicity of chronic exposures to low doses of pharmaceutical compounds. This makes carrying out accurate risk assessments on the potential health impacts to humans of ingestion of a mixture of medicines, at many times less than the therapeutic dose, very difficult. Most probably, the presence of these compounds would be of little or no consequence in healthy adults but variations such as gender and maturation might result in different sensitivity and dose responses for the same toxicological tests [17]. Effects might therefore be more pronounced in the young or elderly (who might have a reduced ability to remove toxic compounds from their bodies) or through allergies to certain compounds or during particularly vulnerable life stages such as pregnancy. However, there
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is no proof of this because few risk assessments have been performed with regard to drinking water exposure. Those that have been carried out have generally used the comparatively high doses required for therapeutic effects, which are orders of magnitude higher than what would be required for subtle, non-therapeutic effects. What does the future hold? Although it is unlikely that a serious problem exists now, it would be prudent to apply the precautionary principle and try to reduce the levels of these compounds in drinking water before any harm is proved. Because it is impractical to assess fully the risks of every medicine and application authorized for use, one approach might be to develop a prioritisation scheme to identify those substances that might pose a risk to human health and therefore warrant further study. This is because a better understanding of risk and risk-based management could well provide for better use of resources than an exposurebased management approach. For example, one approach could be through the setting of meaningful action levels or maximum admissible concentrations (MAC-values) for drinking water [43]. However, it should be remembered that resources are finite and it might prove too costly to justify this at present. It might therefore be helpful to at least keep a watchful eye on the situation (perhaps through monitoring programs), so as to have the ability to supply an early warning of an emerging problem before it becomes significant. Some workers have suggested using advanced drinking water treatment technologies to treat sewage so as to reduce the presence of drugs in natural water sources used for potable supply. In fact, when subjected to life cycle analysis, large-scale investment into increasingly energyintensive treatments is seen to be environmentally unsustainable [44]. This is because the benefits of improved effluent quality are often outweighed by the negative effects on the wider environment when process construction and operation are looked at as a whole [45]. The occurrence of organic micro-pollutants such as pharmaceuticals in water supplies is a key issue in relation to the quality of drinking water. Although these compounds are not currently regulated, we would suggest that more research to better predict likely concentrations of drug compounds in potable water is highly desirable and would allow the assessment of potential risks and effects on human health at high-risk locations and the consequences for sustainability. Acknowledgements O.A.J. is grateful to the UK Engineering and Physical Sciences Research Council (EPSRC) for the award of a PhD scholarship.
References 1 Birkett, J.W. and Lester, J.N., eds (2002) Endocrine Disrupters in Wastewater and Sludge Treatment, IWA Publishing 2 Larsen, T.A. et al. (2004) How to avoid pharmaceuticals in the aquatic environment. J. Biotechnol. 113, 295–304 3 Ayscough, N.J. et al. (2000) Review of Human Pharmaceuticals in the Environment (P390), Environment Agency of England and Wales, Bristol, UK www.sciencedirect.com
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4 Suter, M.J.F. and Giger, W. (2001) Trace determinants of emerging water pollutants: endocrine disruptors, pharmaceuticals, and speciality chemicals. Chimia (Aarau) 54, 13–16 5 Petrovic, M. et al. (2003) Analysis and removal of emerging contaminants in wastewater and drinking water. Trends Anal. Chem. 22, 685–696 6 Hilton, M.J. et al. (2003) Targeted Monitoring Programme for Pharmaceuticals in the Aquatic Environment (R&D Technical Report P6-012/06/TR), Environment Agency of England and Wales, Bristol, UK 7 Jones, O.A.H. et al. (2001) Human pharmaceuticals in the aquatic environment: a review. Environ. Technol. 22, 1383–1394 8 van Dijk-Looijaard, A.M. and van Genderen, J. (2000) Levels of exposure from drinking water. Food Chem. Toxicol. 38, S37–S40 9 Zwiener, C. and Frimmel, F.H. (2000) Oxidative treatment of pharmaceuticals in water. Water Res. 34, 1881–1885 10 Ternes, T.A. et al. (2002) Removal of pharmaceuticals during drinking water treatment. Environ. Sci. Technol. 36, 3855–3863 11 Betts, K.S. (2002) Keeping drugs out of drinking water. Environ. Sci. Technol. 36, 377A–378A 12 Drewes, J.E. et al. (2002) Fate of pharmaceuticals during indirect potable reuse. Water Sci. Technol. 46, 73–80 13 Heberer, T. (2002) Tracking persistent pharmaceutical residues from municipal sewage to drinking water. J. Hydrol. 266, 175–189 14 Tauber, R. (2003) Quantitative Analysis of Pharmaceuticals in Drinking Water from Ten Canadian Cities, Enviro-Test Laboratories, Xenos Division, Ontario, Canada 15 Heberer, T. and Stan, H.J. (1997) Determination of clofibric acid and N-(phenylsulfonyl)-sarcosine in sewage, river and drinking water. Int. J. Environ. Anal. Chem. 67, 113–124 16 Stan, H.J. et al. (1994) Occurrence of clofibric acid in the aquatic system – does the medical application cause contamination of surface, ground and drinking water (in German)? Vom Wasser 83, 57–68 17 Lai, K.M. et al. (2002) The effects of natural and synthetic steroid estrogens in relation to their environmental occurrence. Crit. Rev. Toxicol. 32, 113–132 18 Jones, O.A.H. et al. (2003) Analytical method development for the simultaneous determination of five human pharmaceuticals in water and wastewater samples by gas chromatography-mass spectrometry. Chromatographia 58, 471–477 19 Bila, D.M. and Dezotti, M. (2003) Pharmaceutical drugs in the environment. Quim. Nova 26, 523–530 20 Zuccato, E. et al. (2000) Presence of therapeutic drugs in the environment. Lancet 355, 1789–1790 21 Heberer, T. and Stan, H.J. (1996) Occurrence of polar organic contaminants in Berlin drinking water (in German). Vom Wasser 86, 19–31 22 Reddersen, K. et al. (2002) Identification and significance of phenazone drugs and their metabolites in ground- and drinking water. Chemosphere 49, 539–544 23 Zu¨hlke, S. et al. (2004) Detection and identification of phenazone-type drugs and their microbial metabolites in ground and drinking water applying solid-phase extraction and gas chromatography with mass spectrometric detection. J. Chromatogr. A. 1050, 201–209 24 Asano, T. and Cotruvo, J.A. (2004) Groundwater recharge with reclaimed municipal wastewater: health and regulatory considerations. Water Res. 38, 1941–1951 25 Heberer, T. et al. (1997) Detection of drugs and drug metabolites in ground water samples of a drinking water treatment plant. Fresenius Environ. Bull. 6, 438–443 26 Heberer, T. et al. (2002) From municipal sewage to drinking water: fate and removal of pharmaceutical residues in the aquatic environment in urban areas. Water Sci. Technol. 46, 81–88 27 Heberer, T. et al. (1998) Occurrence and distribution of organic contaminants in the aquatic system of Berlin. Part 1: Drug residues and other polar contaminants in Berlin surface water and groundwater. Acta Hydrochim. Hydrobiol. 26, 272–278 28 Heinzmann, B. (1998) Improvement of the surface water quality in the Berlin region. Water Sci. Technol. 38, 191–195 29 Jux, U. et al. (2002) Detection of pharmaceutical contaminations of river, pond, and tap water from Cologne (Germany) and surroundings. Int. J. Hyg. Environ. Health 205, 393–398
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30 Webb, S. et al. (2003) Indirect human exposure to pharmaceuticals via drinking water. Toxicol. Lett. 142, 157–167 31 Bridgeman, J. (2004) Public perception towards water recycling in California. Water Environ. J. 18, 150–154 32 Schulman, L.J. et al. (2002) A human health risk assessment of pharmaceuticals in the aquatic environment. Human Eco. Risk Assess. 8, 657–680 33 Christensen, F.M. (1998) Pharmaceuticals in the environment – a human risk? Regul. Toxicol. Pharmacol. 28, 212–221 34 Schwartz, T. et al. (2002) Detection of antibiotic-resistant bacteria and their resistance genes in wastewater, surface water, and drinking water biofilms. FEMS Micro. Ecol. 1470, 1–11 35 Jones, O.A.H. et al. (2003) Potential impact of pharmaceuticals on environmental health. Bull. World Health Organ. 81, 768–769 36 Jones, O.A.H. et al. (2004) Potential ecological and human health risks associated with the presence of pharmaceutically active compounds in the aquatic environment. Crit. Rev. Toxicol. 34, 335–350 37 Jones, O.A.H. et al. (2002) Aquatic environmental assessment of the top 25 English prescription pharmaceuticals. Water Res. 36, 5013–5022 38 MacDonald, T.M. and Wei, L. (2003) Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 361, 573–574 39 Simon, A.M. et al. (2002) Cyclo-oxygenase 2 function is essential for bone fracture healing. J. Bone Miner. Res. 17, 963–976 40 Buerge, I.J. et al. (2003) Caffeine, an anthropogenic marker for wastewater contamination of surface waters. Environ. Sci. Technol. 37, 691–700
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41 Boyd, G.R. et al. (2003) Pharmaceuticals and personal care products (PPCPs) in surface and treated waters of Louisiana, U. S. A. and Ontario, Canada. Sci. Total Environ. 311, 135–149 42 Clara, M. et al. (2004) Comparison of the behaviour of selected micropollutants in a membrane bioreactor and a conventional wastewater treatment plant. Water Sci. Technol. 50, 29–36 43 Reimann, C. and Banks, D. (2004) Setting action levels for drinking water: are we protecting our health or our economy (or our backs!)? Sci. Total Environ. 332, 13–21 44 Zakkour, P.D. et al. (2001) Anaerobic treatment of domestic wastewater in temperate climates: treatment plant modelling with economic considerations. Water Res. 35, 4137–4149 45 Zakkour, P.D. et al. (2002) Developing a sustainable energy strategy for a water utility. Part II: A review of potential technologies and approaches. J. Environ. Manage. 66, 115–125 46 Stumpf, M. et al. (1996) Determination of drugs in sewage treatment plants and river water (in German). Vom Wasser 86, 291–303 47 Aherne, G.W. et al. (1990) Cytotoxic drugs and the aquatic environment – estimation of Bleomycin in river and water samples. J. Pharm. Pharmacol. 42, 741–742 48 Fielding, M. et al. (1981) Organic Micro-Pollutants in Drinking Water (TR159), Water Research Council 49 Stackelberg, P.E. et al. (2004) Persistence of pharmaceutical compounds and other organic wastewater contaminants in a conventional drinking-water-treatment plant. Sci. Total Environ. 329, 99–113 50 Waggot, A. (1981) Trace organic substances in the River Lee (Great Britain). In Chemistry in Water Reuse (1st edn) (Cooper, W.J., ed.), pp. 55–99, Ann Arbour Science
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Vol.23 No.4 April 2005
Pharmaceuticals: a threat to drinking water? Oliver A. Jones, John N. Lester and Nick Voulvoulis Department of Environmental Science and Technology, Faculty of Life Sciences, Imperial College, London, SW7 2BP, UK
Recently, considerable interest has developed regarding the presence of pharmaceuticals in the environment, but there has been comparatively little study on the potential of these substances to enter potable supplies. This is surprising because drinking water would provide a direct route into the body for any drugs that might be present. Although many countries employ advanced treatments, such as granular activated carbon, membrane technologies, ozonation and ultraviolet radiation, for treating water intended for human consumption, some compounds have been shown to be unaffected by such processes. Here, we examine the levels of drug substances reported in drinking water around the world. The possible implications of the presence of these compounds are highlighted and assessed, and recommendations are made for further research. Introduction During the past three decades, research on the impact of chemical pollution has focused almost exclusively on the conventional ‘priority’ pollutants [i.e. persistent organic pollutants (POPs)] and this has been extensively reviewed recently [1]. Today, these compounds are less relevant for many first world countries because emissions have been substantially reduced through the adoption of appropriate legal measures and the elimination of many of the dominant pollution sources. The focus has consequently switched to compounds present in lower concentrations but which nevertheless might have the ability to cause harm [2]. One of the interesting characteristics of many of the chemicals that might cause this type of pollution is that they do not need to be persistent in the environment to cause negative effects [3]. This is because their high transformation and removal rates can be offset by their continuous introduction into the environment, often through sewage treatment works [4]. This is one reason why there is an increasingly widespread consensus that this kind of contamination might require legislative action sooner rather than later [5,6]. The problem of pharmaceutical pollution The issue of pharmaceuticals (and their metabolites) in the environment, notably the aquatic compartment, has been a growth area in environmental chemistry for several years [7]. To date, most of the published literature has addressed the occurrence of drugs in sewage effluent and Corresponding author: Lester, J.N. ( [email protected]).
receiving waters. However, although the risks associated with exposure to drugs are probably most significant with regard to the natural environment, the public’s concern is understandably more focused on human exposure. This is especially important in areas that practise indirect water reuse, where sewage effluent is released to streams and rivers that are in turn used as a source of raw water for the production of potable supplies for communities living downstream [8]. Unfortunately, there are extremely few data available (as of January 2005) on the occurrence of pharmaceutical products in point-of-use drinking waters (that is, tap water at the sink). This is probably partly related to the difficulty of analysis of pollutants at very low, sub parts per billion (mg lK1) or parts per trillion (ng lK1) concentrations, and partly related to the belief that modern treatment processes will remove pharmaceutical compounds from potable supplies. For instance, the view of the Drinking Water Inspectorate, which regulates public water supplies in England and Wales, is that pharmaceutical residues will not be detectable in tap water in the UK (http://www.dwi.gov.uk/ consumer/concerns/Drugs&EDs.htm). Their rationale is based on the fact that technologies such as ozone and granular activated carbon (GAC) treatment are now installed at many waterworks in England and Wales to remove compounds such as pesticides. Because these technologies are also effective against a wide range of other trace organic substances that might be present in source waters, including some pharmaceuticals [9,10], they reason that no drugs will be found in UK drinking water. However, they do not reference any peer-reviewed studies to back up the position. In fact, whereas studies of the susceptibility of endocrine disruptors and pharmaceutical residues to removal technologies used during water treatment processes are being performed under the auspices of the European Union (EU) Poseidon initiative [11] (http://www.eu-poseidon. com/), ozone and GAC treatments are not present at all UK waterworks. There are also several drug compounds that have been shown to be resistant to both these treatments (probably as a result of physicochemical properties such as high water solubility and/or poor degradability). These include the anti-epileptic drugs carbamazepine and primidone, and the lipid regulators clofibric acid and gemfibrozil [12–16]. The purpose of this article is therefore to draw attention to this area of pharmaceutical pollution. For simplicity, metabolites of drug compounds are not covered in this work. In addition, both natural and
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TRENDS in Biotechnology
synthetic hormones are excluded. Although these compounds are an important subgroup of pharmaceuticals, there is already an abundance of work available in the literature on this topic [17]. What has been found? There is currently no regulatory requirement for the monitoring of pharmaceuticals in drinking water. On the basis of the limited dataset (Table 1), human pharmaceuticals have only occasionally been detected in drinking water, with concentrations generally being in the ng lK1 range [18]. Veterinary medicines might also have the potential to enter water sources, even in upland areas, through leaching from fields used to graze stock that are treated with drugs, or disposal of manure from stock so treated [19]. Again, there is little research in this area. To date, only the macrolide antibiotic tylosin, which is often used as a growth promoter in veterinary medicine, has been reported in drinking water [20]. Heberer and Stan [15] found clofibric acid and the drug metabolite N-(phenylsulfonyl)-sarcosine in the majority of drinking water samples collected from the 14 waterworks in the Berlin area, with the maximum concentrations in drinking water samples being 270 ng lK1. This related well with the percentage values of artificial groundwater enrichment and bank filtrate used by the water treatment plants in drinking water production. Thus, it can be assumed that both contaminants were not eliminated by the treatment used by the Berlin waterworks. In a separate study, Heberer and Stan [21] also quantified a Table 1. Concentrations of drug compounds found in finished drinking water worldwide Compound
Therapeutic group
Bezafibrate Bleomycin Clofibric acid
Lipid regulator Anti-neoplastic Lipid regulator
Carbamazepine
Anti-epileptic
Diazepam
Psychiatric drug
Diclofenac
Analgesic and anti-pyretic Lipid regulator Analgesic and anti-pyretic Analgesic and anti-pyretic Analgesic and anti-pyretic Macrolide antibiotic, used as a growth promoter for livestock
Gemfibrozil Ibuprofen Phenazone Propylphenazone Tylosin
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Country
Refs
Germany UK UK
[46] [47] [48]
Germany Germany Germany Germany Italy Canada USA UK
[46] [16] [25] [21] [20] [14] [49] [50]
23.5 6
Italy Germany
[20] [46]
70 3
Canada Germany
[14] [46]
250 400 80 120 1.7
Germany Germany Germany Germany Italy
[23] [22] [23] [22] [20]
Maximum concentration detected (ng lK1) 27 13 Positive identification 70 165 270 170 5.3 24 258 10
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maximum of up to 170 ng lK1 in drinking water samples taken from one of 14 waterworks in Germany. For drinking water taken from the remaining 13 waterworks, values were below 75 ng lK1, with samples from two waterworks being below the level of detection of 1 ng lK1. The analgesic and antipyretic drugs phenazone and propylphenazone were also found in Berlin drinking water in two separate studies by Reddersen et al. [22] and Zu¨hlke et al. [23], again at the ng lK1 level. However, it is of note that the source of most of the pharmaceutical pollution in Berlin drinking waters is thought to be from the use of groundwater contaminated with sewage as a water source (a practise that is known to present a wide spectrum of technical and health challenges [24]). For example, Heberer et al. [25] established that clofibric acid, phenazone, propylphenazone, diclofenac, ibuprofen and fenofibrate can all leach from contaminated surface water through the subsoil into the ground water of some waterworks through bank filtration. The problem is also mainly confined to the east of the city (where there is a more basic water treatment system built under communist rule) and is not considered a general problem in Germany as a whole [26–28]. For instance, Jux et al. [29] looked for the drugs gemfibrozil, clofibric acid, diclofenac, ibuprofen, ketoprofen, indomethacin and fenoprofen in river, pond and tap water from Cologne (west Germany) and the surrounding area. Whereas diclofenac (the drug present in the highest amount in the environment) could be detected in 10 out of 27 water samples at concentrations of up to 15 mg lK1, none of the pharmaceuticals investigated was present in any of the drinking water samples taken. However, as mentioned previously, even advanced water treatment does not always remove all drugs. For instance, a report by Tauber [14] found detectable concentrations of both carbamazepine and gemfibrozil in four out of the ten Canadian cities tested that all used advanced water treatment such as ozone or GAC (CTV: Quantitative Analysis of Pharmaceuticals in Drinking Water From Ten Canadian Cities; http://www.ctv.ca/ servlet/ArticleNews/story/CTVNews/1044053088271_ 39462288/?hubZSciTech). Although this report was not published in the peer-reviewed literature, but rather was commissioned by two Canadian news broadcasters (CTV News and The Globe and Mail), the results make interesting reading. Whereas only three of the 440 analyte–sample combinations gave detectable levels for carbamazepine, and only one gave detectable levels for gemfibrozil, the results show that there is a clear possibility that drug compounds can pass through even modern, advanced water treatment facilities. Potential for human health risks Research has shown that significant amounts of drugs are released from sewage treatment plants to the environment. Therefore, there is a risk that humans might be exposed to drugs through potable water drawn from contaminated supplies. Although this risk is likely to be relatively minor, the increasing demands on the freshwater supplies of the world will probably lead to greater incidences of indirect and direct water-reuse situations as the spatial and temporal distances between wastewater
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and drinking water become further reduced. The potential for adverse effects should therefore not be overlooked, especially because little is known regarding the environmental or human health hazards that might be posed by chronic, sub-therapeutic levels of pharmaceutical substances or their transformation products. In addition, regardless of the absence of any proven risks, drinking water will always be a major focus of consumer concern because it is a direct route to the human body for any drug compounds that might be present [30]. Other (indirect) pathways include bodily interaction (bathing or showering in waters containing effluent) or ingestion (eating crops irrigated with effluent or grown on sewage-sludge-amended soil). The presence of pharmaceuticals in drinking water, however small, is also likely to increase the general public’s already negative attitude to water reuse [31]. Nevertheless, it should be stressed that several studies have been performed demonstrating that the likelihood of any form of acute (short-term) human health risk originating from the presence of low concentrations of pharmaceuticals in drinking water is extremely low [30,32,33]. In fact, even drinking two litres of the tainted water every day over a lifetime would not cumulatively deliver the equivalent of a single prescribed dose of any of the compounds present. This does not rule out long-term effects that might go unnoticed, and it is of course impossible to prove that the risk of any pollutant is zero. The presence of antibiotics is likely to be of most concern because it could lead to the development of resistant pathogens. Christensen [33] and Webb et al. [30] have also identified sensitization, or the development of an allergenic response to antibiotics, as being of concern. A search of the literature indicated that there has been only one case of an antibiotic (the previously mentioned veterinary drug tylosin) in drinking water reported thus far [20]. However, bacteria with antibiotic resistance genes have been found in biofilms inoculated with drinking water bacteria in Germany [34]. This indicates possible gene transfer, perhaps from surface and/or wastewater, to the drinking water distribution network. This certainly could also be a cause for concern as regards human health if it were a widespread occurrence [35]. Another facet to this problem is that of the synergistic effects of mixtures of compounds [36]. Although concentrations of individual substances might be low, it is unknown what effects, if any, exposure to repeated doses of a mixture of sub-therapeutic amounts of drugs and other chemicals (such as endocrine disruptors) could have on human health. Minor side effects to medications given at prescription doses are common but are usually outweighed by the health benefits of the medication. This would not be the case with unintended, routine exposure to the drugs or mixture of drugs that could, potentially, be found in drinking water. If drugs are present in drinking water, then potential health concerns will need to focus on individual, synergistic/antagonistic and possible mixture effects over an extended period of time (w80 years or more) [37]. Possible interactions with other medications (or even illegal drug substances) that individuals might be taking will also need to be considered [25]. For instance, ibuprofen has been demonstrated to interfere with the www.sciencedirect.com
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cardioprotective properties of aspirin [38], some of the new generation of cyclooxygenase-2 inhibitors might interfere with bone healing and re-growth after fracture [39], and caffeine can enhance the effects of certain analgesics [40]. It is very doubtful that concentrations would be high enough in drinking water to cause these effects. However, continual life-long exposure to trace levels of pollutants is an unexplored area of toxicology and the many possible issues that could theoretically be involved have not been extensively studied. Thus, further research in defining the potential human health risks of pharmaceuticals in drinking water would be useful because concerns cannot realistically be ruled out completely for several reasons, as given below. † The efficiency of contaminant removal might vary both between chemicals and between water treatment plants owing to the differing processes employed. Whereas advanced technologies such as ozone and GAC remove many compounds [41], they do not eliminate all drugs, and are by no means universally applied to the treatment of potable supplies, even in developed countries. † Although primarily a sewage treatment option, there is the potential to use sequencing batch reactors and/or membrane bioreactors to remove drug compounds. A study by Clara et al. [42] compared the behaviour of selected micro-pollutants in a membrane bioreactor and an activated sludge plant operating at a very high sludge age. Each gave high removal rates for most compounds and there was no significant difference between either option in the removal efficiencies of several pharmaceutical compounds. This might be partly attributable to the low molecular size and high solubility of the compounds under investigation. † Drugs are designed to be biologically active, and it is possible that unintended effects on non-target organisms and/or receptors occur at lower concentrations than the intended therapeutic effects. † Long-term effects might occur at much lower concentrations and follow different toxicodynamic mechanisms than those extrapolated from short-term studies. † The effects of mixtures of sub-therapeutic levels of complex mixtures of drugs (and other pollutants) over perhaps 80 years or more are unknown. † Although toxicological evidence is seldom uncontroversial or unanimous, there is practically zero data for gauging the potential toxicity of chronic exposures to low doses of pharmaceutical compounds. This makes carrying out accurate risk assessments on the potential health impacts to humans of ingestion of a mixture of medicines, at many times less than the therapeutic dose, very difficult. Most probably, the presence of these compounds would be of little or no consequence in healthy adults but variations such as gender and maturation might result in different sensitivity and dose responses for the same toxicological tests [17]. Effects might therefore be more pronounced in the young or elderly (who might have a reduced ability to remove toxic compounds from their bodies) or through allergies to certain compounds or during particularly vulnerable life stages such as pregnancy. However, there
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is no proof of this because few risk assessments have been performed with regard to drinking water exposure. Those that have been carried out have generally used the comparatively high doses required for therapeutic effects, which are orders of magnitude higher than what would be required for subtle, non-therapeutic effects. What does the future hold? Although it is unlikely that a serious problem exists now, it would be prudent to apply the precautionary principle and try to reduce the levels of these compounds in drinking water before any harm is proved. Because it is impractical to assess fully the risks of every medicine and application authorized for use, one approach might be to develop a prioritisation scheme to identify those substances that might pose a risk to human health and therefore warrant further study. This is because a better understanding of risk and risk-based management could well provide for better use of resources than an exposurebased management approach. For example, one approach could be through the setting of meaningful action levels or maximum admissible concentrations (MAC-values) for drinking water [43]. However, it should be remembered that resources are finite and it might prove too costly to justify this at present. It might therefore be helpful to at least keep a watchful eye on the situation (perhaps through monitoring programs), so as to have the ability to supply an early warning of an emerging problem before it becomes significant. Some workers have suggested using advanced drinking water treatment technologies to treat sewage so as to reduce the presence of drugs in natural water sources used for potable supply. In fact, when subjected to life cycle analysis, large-scale investment into increasingly energyintensive treatments is seen to be environmentally unsustainable [44]. This is because the benefits of improved effluent quality are often outweighed by the negative effects on the wider environment when process construction and operation are looked at as a whole [45]. The occurrence of organic micro-pollutants such as pharmaceuticals in water supplies is a key issue in relation to the quality of drinking water. Although these compounds are not currently regulated, we would suggest that more research to better predict likely concentrations of drug compounds in potable water is highly desirable and would allow the assessment of potential risks and effects on human health at high-risk locations and the consequences for sustainability. Acknowledgements O.A.J. is grateful to the UK Engineering and Physical Sciences Research Council (EPSRC) for the award of a PhD scholarship.
References 1 Birkett, J.W. and Lester, J.N., eds (2002) Endocrine Disrupters in Wastewater and Sludge Treatment, IWA Publishing 2 Larsen, T.A. et al. (2004) How to avoid pharmaceuticals in the aquatic environment. J. Biotechnol. 113, 295–304 3 Ayscough, N.J. et al. (2000) Review of Human Pharmaceuticals in the Environment (P390), Environment Agency of England and Wales, Bristol, UK www.sciencedirect.com
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4 Suter, M.J.F. and Giger, W. (2001) Trace determinants of emerging water pollutants: endocrine disruptors, pharmaceuticals, and speciality chemicals. Chimia (Aarau) 54, 13–16 5 Petrovic, M. et al. (2003) Analysis and removal of emerging contaminants in wastewater and drinking water. Trends Anal. Chem. 22, 685–696 6 Hilton, M.J. et al. (2003) Targeted Monitoring Programme for Pharmaceuticals in the Aquatic Environment (R&D Technical Report P6-012/06/TR), Environment Agency of England and Wales, Bristol, UK 7 Jones, O.A.H. et al. (2001) Human pharmaceuticals in the aquatic environment: a review. Environ. Technol. 22, 1383–1394 8 van Dijk-Looijaard, A.M. and van Genderen, J. (2000) Levels of exposure from drinking water. Food Chem. Toxicol. 38, S37–S40 9 Zwiener, C. and Frimmel, F.H. (2000) Oxidative treatment of pharmaceuticals in water. Water Res. 34, 1881–1885 10 Ternes, T.A. et al. (2002) Removal of pharmaceuticals during drinking water treatment. Environ. Sci. Technol. 36, 3855–3863 11 Betts, K.S. (2002) Keeping drugs out of drinking water. Environ. Sci. Technol. 36, 377A–378A 12 Drewes, J.E. et al. (2002) Fate of pharmaceuticals during indirect potable reuse. Water Sci. Technol. 46, 73–80 13 Heberer, T. (2002) Tracking persistent pharmaceutical residues from municipal sewage to drinking water. J. Hydrol. 266, 175–189 14 Tauber, R. (2003) Quantitative Analysis of Pharmaceuticals in Drinking Water from Ten Canadian Cities, Enviro-Test Laboratories, Xenos Division, Ontario, Canada 15 Heberer, T. and Stan, H.J. (1997) Determination of clofibric acid and N-(phenylsulfonyl)-sarcosine in sewage, river and drinking water. Int. J. Environ. Anal. Chem. 67, 113–124 16 Stan, H.J. et al. (1994) Occurrence of clofibric acid in the aquatic system – does the medical application cause contamination of surface, ground and drinking water (in German)? Vom Wasser 83, 57–68 17 Lai, K.M. et al. (2002) The effects of natural and synthetic steroid estrogens in relation to their environmental occurrence. Crit. Rev. Toxicol. 32, 113–132 18 Jones, O.A.H. et al. (2003) Analytical method development for the simultaneous determination of five human pharmaceuticals in water and wastewater samples by gas chromatography-mass spectrometry. Chromatographia 58, 471–477 19 Bila, D.M. and Dezotti, M. (2003) Pharmaceutical drugs in the environment. Quim. Nova 26, 523–530 20 Zuccato, E. et al. (2000) Presence of therapeutic drugs in the environment. Lancet 355, 1789–1790 21 Heberer, T. and Stan, H.J. (1996) Occurrence of polar organic contaminants in Berlin drinking water (in German). Vom Wasser 86, 19–31 22 Reddersen, K. et al. (2002) Identification and significance of phenazone drugs and their metabolites in ground- and drinking water. Chemosphere 49, 539–544 23 Zu¨hlke, S. et al. (2004) Detection and identification of phenazone-type drugs and their microbial metabolites in ground and drinking water applying solid-phase extraction and gas chromatography with mass spectrometric detection. J. Chromatogr. A. 1050, 201–209 24 Asano, T. and Cotruvo, J.A. (2004) Groundwater recharge with reclaimed municipal wastewater: health and regulatory considerations. Water Res. 38, 1941–1951 25 Heberer, T. et al. (1997) Detection of drugs and drug metabolites in ground water samples of a drinking water treatment plant. Fresenius Environ. Bull. 6, 438–443 26 Heberer, T. et al. (2002) From municipal sewage to drinking water: fate and removal of pharmaceutical residues in the aquatic environment in urban areas. Water Sci. Technol. 46, 81–88 27 Heberer, T. et al. (1998) Occurrence and distribution of organic contaminants in the aquatic system of Berlin. Part 1: Drug residues and other polar contaminants in Berlin surface water and groundwater. Acta Hydrochim. Hydrobiol. 26, 272–278 28 Heinzmann, B. (1998) Improvement of the surface water quality in the Berlin region. Water Sci. Technol. 38, 191–195 29 Jux, U. et al. (2002) Detection of pharmaceutical contaminations of river, pond, and tap water from Cologne (Germany) and surroundings. Int. J. Hyg. Environ. Health 205, 393–398
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30 Webb, S. et al. (2003) Indirect human exposure to pharmaceuticals via drinking water. Toxicol. Lett. 142, 157–167 31 Bridgeman, J. (2004) Public perception towards water recycling in California. Water Environ. J. 18, 150–154 32 Schulman, L.J. et al. (2002) A human health risk assessment of pharmaceuticals in the aquatic environment. Human Eco. Risk Assess. 8, 657–680 33 Christensen, F.M. (1998) Pharmaceuticals in the environment – a human risk? Regul. Toxicol. Pharmacol. 28, 212–221 34 Schwartz, T. et al. (2002) Detection of antibiotic-resistant bacteria and their resistance genes in wastewater, surface water, and drinking water biofilms. FEMS Micro. Ecol. 1470, 1–11 35 Jones, O.A.H. et al. (2003) Potential impact of pharmaceuticals on environmental health. Bull. World Health Organ. 81, 768–769 36 Jones, O.A.H. et al. (2004) Potential ecological and human health risks associated with the presence of pharmaceutically active compounds in the aquatic environment. Crit. Rev. Toxicol. 34, 335–350 37 Jones, O.A.H. et al. (2002) Aquatic environmental assessment of the top 25 English prescription pharmaceuticals. Water Res. 36, 5013–5022 38 MacDonald, T.M. and Wei, L. (2003) Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 361, 573–574 39 Simon, A.M. et al. (2002) Cyclo-oxygenase 2 function is essential for bone fracture healing. J. Bone Miner. Res. 17, 963–976 40 Buerge, I.J. et al. (2003) Caffeine, an anthropogenic marker for wastewater contamination of surface waters. Environ. Sci. Technol. 37, 691–700
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41 Boyd, G.R. et al. (2003) Pharmaceuticals and personal care products (PPCPs) in surface and treated waters of Louisiana, U. S. A. and Ontario, Canada. Sci. Total Environ. 311, 135–149 42 Clara, M. et al. (2004) Comparison of the behaviour of selected micropollutants in a membrane bioreactor and a conventional wastewater treatment plant. Water Sci. Technol. 50, 29–36 43 Reimann, C. and Banks, D. (2004) Setting action levels for drinking water: are we protecting our health or our economy (or our backs!)? Sci. Total Environ. 332, 13–21 44 Zakkour, P.D. et al. (2001) Anaerobic treatment of domestic wastewater in temperate climates: treatment plant modelling with economic considerations. Water Res. 35, 4137–4149 45 Zakkour, P.D. et al. (2002) Developing a sustainable energy strategy for a water utility. Part II: A review of potential technologies and approaches. J. Environ. Manage. 66, 115–125 46 Stumpf, M. et al. (1996) Determination of drugs in sewage treatment plants and river water (in German). Vom Wasser 86, 291–303 47 Aherne, G.W. et al. (1990) Cytotoxic drugs and the aquatic environment – estimation of Bleomycin in river and water samples. J. Pharm. Pharmacol. 42, 741–742 48 Fielding, M. et al. (1981) Organic Micro-Pollutants in Drinking Water (TR159), Water Research Council 49 Stackelberg, P.E. et al. (2004) Persistence of pharmaceutical compounds and other organic wastewater contaminants in a conventional drinking-water-treatment plant. Sci. Total Environ. 329, 99–113 50 Waggot, A. (1981) Trace organic substances in the River Lee (Great Britain). In Chemistry in Water Reuse (1st edn) (Cooper, W.J., ed.), pp. 55–99, Ann Arbour Science
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