Διερεύνηση της μεταβολικής τύχης των φαρμακευτικών ενώσεων στο υδάτινο περιβάλλον

Abstract

Στην παρούσα μεταπτυχιακή εργασία γίνεται διερεύνηση της μεταβολικής τύχης φαρμακευτικών ουσιών στο υδάτινο περιβάλλον. Πιο συγκεκριμένα, εξετάζονται 66 φαρμακευτικές ενώσεις (acetaminophen, acetylsalicylic acid, diclofenac, fenoprofen, ibuprofen, indomethacine, ketoprofen, mefenamic acid, naproxen, propyphenazone, salicylic acid, amoxicillin, chloremphenicol, clarithromycin, enrofloxacin, erythromycin, lincomycin, macrolides, monensin Na, metronidazole, norfloxacin, ofloxacin, penicillin V, roxithromycin, sulfamethazine, sulfamethoxazole, sulfonamide, tetracycline, trimethoprim, tylosin, atrovastatin, bezafibrate, clofibric acid, fenofibrate, gemfibrozil, pravastatin, diltiazem, enalapril, furosemide, hydrochlorothiazide, glibenclamide, atenolol, metoprolol, propranolol, sotalol, bisphenol A, 17β- estradiol, estriol, estrone, 17α- ethinylestradiol, 4-nonylphenol, 4-pktylphenol, androstenedione, testosterone, dihpenhydramin, cimetidine, famotidine, loratidine, ranitidine, carbamazepine, diazepam, fluoxetine, lorazepam, salbutamol, triclosan, galaxolide, tonalide, caffeine και oxybenzone) που ανήκουν σε 13 διαφορετικές θεραπευτικές κατηγορίες, οι οποίες εντοπίστηκαν στη γραμμή επεξεργασίας των αστικών λυμάτων, καθώς και στη γραμμή επεξεργασίας του πόσιμου νερού. Τα στοιχεία αφορούν για τις εγκαταστάσεις επεξεργασίας λυμάτων (ΕΕΛ) το συμβατικό σύστημα της ενεργού ιλύος, το σύστημα MBR, το σύστημα SBR σε λίγες περιπτώσεις, καθώς και πλήθος περιπτώσεων όπου διαθέτουν έργα τριτοβάθμιας επεξεργασίας, ενώ στις εγκαταστάσεις επεξεργασίας νερού (ΕΕΝ) αφορούν στο συμβατικό σύστημα, καθώς και σε προχωρημένες μεθόδους επεξεργασίας αυτού. Οι κατηγορίες των φαρμακευτικών ενώσεων είναι τα αναλγητικά/ αντιφλεγμονώδη φάρμακα, τα αντιβιοτικά, τα αντιϊσταμινικά, τα διουρητικά, ρυθμιστές λιπιδίων του αίματος, αντιδιαβητικά, β-αναστολείς, ορμόνες, ψυχιατρικά, β-παρεμποδιστές, αντισηπτικά, καλλυντικά, κ.ά.. Ακολούθως τα στοιχεία αυτά αναλύονται και παρατηρούνται τα ποσοστά απομάκρυνσης, καθώς και το εύρος διακύμανσης για κάθε φαρμακευτική ένωση. Έτσι πραγματοποιείται σύγκριση και ταξινόμηση της αποτελεσματικότητας της απομάκρυνσης της κάθε ουσίας, όπου συμπεραίνεται ότι το σύνολο των φαρμακευτικών ενώσεων, ανεξαρτήτως της κατηγορίας που ανήκουν, παρουσιάζουν ένα μεγάλο εύρος στα ποσοστά απομάκρυνσης από τις εγκαταστάσεις επεξεργασίας λυμάτων και νερού, τόσο μεταξύ των επιμέρους εγκαταστάσεων, όσο και μεταξύ των διαφόρων σταδίων/ διεργασιών/ βαθμίδων επεξεργασίας. Η παραπάνω ανάλυση δείχνει επίσης ότι οι υψηλότερες ποσότητες ουσιών που απορρίπτονται αφορούν στα αντιυπερτασικά, βήτα- αναστολείς και αναλγητικά / αντιφλεγμονώδη, ενώ ο υψηλότερος κίνδυνος είναι από τα αντιβιοτικά, τα ψυχιατρικά φάρμακα, όπως και τα αναλγητικά / αντιφλεγμονώδη. Αυτά τα αποτελέσματα που προκύπτουν μπορούν να βοηθήσουν επιστήμονες και διοικητικούς υπαλλήλους στο σχεδιασμό μέτρων με στόχο τη μείωση των επιπτώσεων των επεξεργασμένων αστικών λυμάτων που απορρίπτονται στα επιφανειακά ύδατα, αλλά και των επιπτώσεων από την επεξεργασία του πόσιμου νερού που καταναλώνεται από τους ανθρώπους. Στη συνέχεια πραγματοποιείται μία μελέτη περίπτωσης, όπου λαμβάνονται δεδομένα από τον όμιλο ΠΡΟΣΥΦΑΠΕ, ως προς την κατανάλωση (μηνιαία και ετήσια) συγκεκριμένων δραστικών ενώσεων, που είναι η ibuprofen, η naproxen και η ketoprofen και γίνεται σύγκριση με τις τιμές των συγκεντρώσεων των ουσιών που έχουν προσδιοριστεί από επί τόπου μετρήσεις (Πανεπιστήμιο Αθηνών, 2011). Ακόμα, για τις τρεις αυτές ουσίες γίνεται εκτίμηση της απομάκρυνσης των συγκεντρώσεών τους στα επιμέρους στάδια επεξεργασίας της εγκατάστασης επεξεργασίας λυμάτων Ψυτάλλεια και εξάγεται το συμπέρασμα ότι οι συγκεντρώσεις στα ανεπεξέργαστα λύματα της εγκατάστασης για τις ουσίες αυτές είναι 0,07-3,8 (ανάλογα με το ποσοστό απέκκρισης από τον ανθρώπινο οργανισμό), 0,21 και 0,08 ppb (μg/L) αντίστοιχα. Επιπρόσθετα, για κάθε δραστική ένωση γίνεται εκτίμηση της ποσότητας που εξέρχεται από τα έργα πρωτοβάθμιας και δευτεροβάθμιας επεξεργασίας της εγκατάστασης, μέσω των βαθμών απομάκρυνσης που έχουν εξαχθεί κατά την βιβλιογραφική ανασκόπηση για κάθε ένωση και έχουν προκύπτει σε ένα μέσο όρο αυτών. Συμπερασματικά και ενδεικτικά, οι ποσότητες (kg/έτος) της ibuprofen, naproxen και ketoprofen εξέρχονται από την εγκατάσταση με δευτεροβάθμια επεξεργασία (συμβατικό σύστημα ενεργού ιλύος) είναι 0,2-14,5 (ανάλογα το ποσοστό απέκκρισης), 3,4 και 1,9, αντίστοιχα. Η παρούσα μεταπτυχιακή εργασία περιλαμβάνει επίσης μία βάση δεδομένων, μέσω της οποίας μπορεί να γίνει μία προκαταρκτική εκτίμηση του βαθμού απομάκρυνσης και κατά επέκταση της συγκέντρωσης που θα προκύψει στο τέλος των έργων επεξεργασίας λυμάτων και νερού, ανάλογα με τις φαρμακευτικές ενώσεις που επιθυμεί ο χρήστης να παρακολουθήσει. Επισημαίνεται ότι ο βαθμός απομάκρυνσης που έχει καταχωριθεί στη βάση δεδομένων για κάθε φαρμακευτική ένωση προκύπτει από το μέσο όρο όλων των βαθμών απομάκρυνσης που έχουν καταγραφεί κατά τη βιβλιογραφική ανασκόπηση για την κάθε φαρμακευτική ένωση και για την κάθε μέθοδο επεξεργασίας, σε κάθε στάδιο επεξεργασίας (πρωτοβάθμια, δευτεροβάθμια, τριτοβάθμια έργα επεξεργασίας) στις εγκαταστάσεις επεξεργασίας λυμάτων και πόσιμου νερού.

In this work is investigated the fate of pharmaceuticals in the aquatic environment. More specifically, it examined 66 pharmaceutical compounds (acetaminophen, acetylsalicylic acid, diclofenac, fenoprofen, ibuprofen, indomethacine, ketoprofen, mefenamic acid, naproxen, propyphenazone, salicylic acid, amoxicillin, chloremphenicol, clarithromycin, enrofloxacin, erythromycin, lincomycin, macrolides, monensin Na, metronidazole, norfloxacin, ofloxacin, penicillin V, roxithromycin, sulfamethazine, sulfamethoxazole, sulfonamide, tetracycline, trimethoprim, tylosin, atrovastatin, bezafibrate, clofibric acid, fenofibrate, gemfibrozil, pravastatin, diltiazem, enalapril, furosemide, hydrochlorothiazide, glibenclamide, atenolol, metoprolol, propranolol, sotalol, bisphenol A, 17b-estradiol, estriol, estrone, 17thethinylestradiol, 4-nonylphenol, 4-pktylphenol, androstenedione, testosterone, dihpenhydramin, cimetidine, famotidine, loratidine, ranitidine, carbamazepine, diazepam, fluoxetine, lorazepam, salbutamol , triclosan, galaxolide, tonalide, caffeine and oxybenzone) belonging to a large number of classes of drugs such as analgesics / anti-inflammatory drugs, antibiotics, antihistamines, diuretics, blood lipid regulators, anti-diabetes, beta-blockers, hormones, psychiatric, betaagonists, antiseptics, cosmetics, etc.. The total number of pharmaceutical compounds, regardless of the category they belong, have a wide range in rates of their removal from sewage treatment plants and water treatment plants, both among individual plants as also the various processing stages. Then, this work place a case study, where consuming data (monthly and annually) is received from the group PROSYFAPE, of specific active compounds, which are ibuprofen, naproxen and ketoprofen. For the above substances is simulated the removal of their concentrations in various stages of processing of sewage treatment plant and concludes that the concentrations at the influent to the facility for these substances are 7.6, 4.2 and 0,9 ppb (mg/L) respectively. Additionally, for each active compound is estimated the quantity that enters (from excretion rate) and leave the WWTP, using the removal rates that is extracted in the literature review for each compound and are resulting in an average value of these. In conclusion, the quantities (kg/year) of ibuprofen, naproxen and ketoprofen entering and exiting the facility with secondary treatment (conventional system of activated sludge) is 127.9-241.7 to 7.6-14.5, 13.8 to 3.4 and 5.8 to 1.9, respectively for the compounds, while the outputs of tertiary treatment is 0.07-0.1, <0.3 and <0.5, respectively, for most of the techniques / processes of tertiary treatment. Finally, this work contains a database through to make the first assessment of the removal rate which will occur at the end of the sewage treatment works and water, depending on the works that the user wishes to know. It is noted that the removal rate which is registered in the database for each pharmaceutical compound resulting from the average of all grades removal recorded in the literature review for each pharmaceutical compound and for each processing method in each stage (primary, secondary, tertiary treatment projects) in sewage treatment plants and drinking water treatment plants. Introduction The pharmaceutical compounds (Pharmaceutical and Personal Care Products, PPCPs) are synthetic or natural chemicals and they are a class of emerging environmental contaminants that are extensively and increasingly being used in human and veterinary medicine. All pharmaceutical compounds containing C (carbon) and H (hydrogen). The majority of these contain N (nitrogen) and / or O (oxygen). People and animals that received by any treatment, specific pharmaceutical compounds, are the main source of pollution of water resources, which if divided into different paths depending on whether patients are in private rooms in homes, hospitals or other places (eg schools, boarding schools) define qualitative, quantitative, spatial and temporal variability and loads of these compounds which are charged to the aquatic environment. Presence of pharmaceutical compounds in aquatic environment The global average annual per capita consumption of pharmaceutical compounds is at 15 g, while the consumption in developed countries is three to ten times higher (50-150 g) (Zhang et al., 2008). Due to the high consumption of pharmaceutical compounds, there is great potential these have been deposited in the environment in significant quantities. For instance, in 1983 it has revealed the presence of various antibiotics (erythromycin, tetracycline and sulfamethoxazole) in water samples from rivers (Watts et al., 1983). More recent studies in the 1990's in Germany, it has demonstrated the existence of clofibric acid at concentrations above 165 ng/L in rivers and groundwater (Stan and Linkerhager, 1994). According to Ternes (1998) it has revealed the presence of more than 20 drugs in small rivers in Germany at concentrations above 6 mg/L, while in larger rivers like the Rhine at lower values which ranged between 0,05 to 0,3 mg/L. Also, Holm et al. (1995) have reported the presence in groundwater of organic compounds from pharmaceutical waste. These compounds include sulfonamides, propylphenazone and barbituric acid, compounds which used by people at decades from 1940 to 1970 as a kind of treatment. Numerous researchers (Alexandra Titz and Petra Doll (2009), Ternes (2000) and S. Mompelat et al. (2009)) argue that the pharmaceutical compounds, leading in surface water or groundwater from any use and from there to pumping performed for drinking water. The majority of studies from the literature indicate the general presence of pharmaceutical compounds in water bodies at concentrations of ng/L to several mg/L, and more rare, but essential for human health, drinking water, indicating the main therapeutic categories, nonsteroidal anti-inflammatory drugs and antibiotics. Given the fate of pharmaceutical compounds, their concentration decreases from wastewater on the environment. For example, ofloxacin, a fluoroquinolone antibiotic, was detected in the effluent of hospitals at 35,5 mg/L in Albuquerque (New Mexico, USA), while the influent and effluent of STP was determined at a concentration 410 ng/L and 110 ng/L, respectively, representing no more than 77% of the rate of removal of the WWTP, and subsequently has not been detected in surface waters notably the Rio Grande River (Brown et al., 2006 Nonsteroidal anti-inflammatory drugs (NSAIDs) have the highest concentrations were recorded, ranging between 0,4 ng/L to 15 mg/L. Some of them are diclofenac, paracetamol and ibuprofen (Jux et al., 2002, Moder et al., 2007). Other major compounds is caffeine, with a maximum concentration of 6 mg/L, the antibiotic sulfamethoxazole with 1,9 mg/L in the U.S. (Kolpin et al., 2002), the antiepileptic carbamazepine to 1,3 mg/L in Germany (Zühlke et al., 2004) and Canada (Hua et al., 2006), the lipid regulator gemfibrozil up to 790 ng/L (Kolpin et al., 2002 ), anti-oxic ranitidine up to 580 ng/L (Kolpin et al., 2002), a betablocker atenolol with 241 ng/L in Italy (Zuccato et al., 2005) or less in the United Kingdom (Kasprzyk-Hordern et al., 2007) and antidiabetic metformin up to 150 ng/L (Kolpin et al., 2002). Other substances such as paracetamol was detected in 211 ng/L in French wells (Rabiet et al., 2006), carbamazepine (up to 465 ng/L between 5 and 10 m below the ground, Heberer et al. (2004)) and clofibric acid in Germany at 125 ng/L (Heberer et al., 2004). The presence of ibuprofen, salicylic acid, gemfibrozil, naproxen, indomethacine and bezafibrate was found in effluent from septic tanks located in Ontario, Canada at concentrations up to 2150, 480, 430, 300, 4 and 12 ng/L, respectively, some of which are still found up to 10 to 20 m downstream of the land until a few micrograms / L (Carrara et al., 2008). Metabolites of these compounds are often detected at entrances and in wastewater treatment plants, but not systematically in natural waters. Among the different pollution profiles, carbamazepine is of great interest as it can be used as a tracer in order to emphasize the anthropogenic contribution in the transport and distribution of substances, and hence the metabolic fate in groundwater (Reinstorf et al., 2008, Osenbrück et al., 2007). One study gathered the five products of carbamazepine (10,11-dihydro-10 ,11-epoxycarbamazepine, 10,11-dihydro-10, 11 - dihydroxy-carbamazepine, 2 hydroxycarbamazepine, 3- hydroxycarbamazepine and 10.11-dihydro-10 - hydroxycarbamazepine), in a treatment plant in Peterborough, Canada, and has identified relevant concentrations of 426, 52, 1325, 132 and 9 ng/L respectively, while carbamazepine and 10.11-dihydro-10,11-dihydroxycarbamazepine was detected only at 0,7 and 2,2 ng/L, respectively (Miao and Metcalfe, 2003). It should be noted that these results are in agreement with the very low rate of excretion of carbamazepine. Despite the low rate of excretion, however, several studies, show high concentrations in the order of mg/L (Zühlke et al., 2004). Therefore, the resistance of degradation of carbamazepine, may be the result of the inability of microorganisms (Pérez and Barceló, 2007) or transport of metabolites into the environment bound form, and therefore hardly degradable and assimilate them microorganisms (Lai et al., 2002). Fate of pharmaceutical compounds in the environment Regardless of the course to enter the environment, the concentration of a pharmaceutical substance and its resistance to aqueous systems is determined by various physicochemical processes. The fate of these can be divided into three categories: • transport / dispersion / dilution, • the sortion and • degradation. The transport is the category in which the concentration of pharmaceutical substances affected by dilution at the point of entry. The extra dispersion and dilution of the influent water (eg rivers) and turbulent mixing can further reduce the concentration of these substances. The next category is the sorption of pharmaceutical substances in the aquatic environment itself. These processes are performed by bioconcentration, adsorption and deposition in particles. On the other hand chemicals can return in the aquatic environment through the degradation of aquatic life, erosion of sediments, and recovering from the atmosphere during the deposition of particles or gas exchange. The procedures by which it is possible to reduce the concentration of chemical substances include photolysis, biodegradation and hydrolysis. Investigations on the fate of pharmaceutical substances have begun by the mid of 80's. The expected paths of pharmaceutical compounds in the environment shown in Figure 1, depending on their type. These substances are used for two main reasons: a) for human treatment (F1) or b) veterinary medicinal products (F2). Veterinary substances also subdivided into those which act as accelerators of development, therapeutic substances or coccidiostats in domestic production units (F3) as therapeutic substances in production facilities in the countryside (F4) and lastly, as food additives in fish farms (F5) . On the other hand, drugs used for humans, resulting through urine and stool (F6) the sewer system and from there to biological wastewater treatment plants (F7). Also an unknown percentage of the pharmaceuticals leads to the sewer system as surplus (Zimmer et al., 1992) (F8). The fate of pharmaceutical compounds in the path of aquatic environment can be divided into three main cases: a) the substance to undergo full conversion to CO2 and water b) if the structure is lipophilic and difficult biodegradable this implies that it remains in the sludge (F9) c) the substance can be metabolized to a more hydrophilic form but remain resilient and passes through the treatment of waste water (F10) and result in the aquatic environment (F11), possibly impacting on aquatic organisms For the same reasons, medicinal substances used in farming lead to soil either directly through urine and stool (F12), or indirectly through the deposition of manure for domestic plants (F13). The drugs used in fish farms are exposed directly to aquatic environment because their use in fish is by providing them as supplements to their diet. However, any quantity of food is not eaten by fish, it is deposited and accumulated on the seabed (Jacobsen and Berglind, 1998). Removal of pharmaceuticals compounds In terms of levels / stages of processing in a WWTP, pharmaceutical compounds are not uncommon organic chemicals and removal rates are reasonably predictable based on physical and chemical properties of these compounds. The biological treatment system, in a conversional treatment plant, such as activated sludge and bio membrane reactor (MBR), shown several times removing significant amounts of pharmaceutical compounds that are biodegradable or can readily be associated with microorganisms (Ternes et al., 1999, Joss et al., 2005, Kim et al., 2007). However, the removal rates for pharmaceutical compounds can vary within and between studies (Kasprzyk- Hordern, Dinsdale and Guwy, 2009, Wick et al., 2009), depending on various factors such as age of the sludge, the temperature of water sludge tank, the hydraulic residence time, etc.. For example, the removal of diclofenac from an activated sludge system ranges from 21% to 50%, but this can be optimized by the process that the facility operates a sludge age of eight days or more (Ziylan & Ince, 2011). Advanced processing of liquid waste, such as membranes, advanced oxidation processes (tertiary treatment), etc, have shown high efficiency removal of pharmaceutical compounds (e.g. advanced oxidation processes can achieve up to 100% removal of diclofenac, Klavarioti, Mantzavinos & Kassinos, 2009). However, the conventional method of treatment is usually sufficient to meet regulatory requirements, and capital-intensive advanced treatments are not always acceptable for wastewater treatment (Spellman, 2010). Conventional methods of treatment with flocculation, filtration and chlorination can remove approximately 50% of these compounds, while the advanced treatment methods such as ozonation, advanced oxidation, charcoal and membrane processes (e.g. reverse osmosis, nanofiltration ), can achieve higher rates of removal. Reverse osmosis, for example, can remove over 99% of large pharmaceutical molecules (WHO, 2011). Removal in a water treatment facility For conventional treatment of drinking water, bench-scale studies have shown that the flocculation (with or without softening by the addition of chemicals) are largely ineffective for the removal of pharmaceutical compounds (Westerhoff et al., 2005, Yoon et al., 2006 , Snyder et al., 2007). The free chlorine was found to oxidize about half of pharmaceutical compounds and chloramines are less effective. In contrast, antibiotics such as sulfamethoxazole, trimethoprim and erythromycin are one of the compounds showed high removal of free chlorine (Khiari, 2007). Advanced water treatment processes (tertiary treatment) such as ozonation, advanced oxidation, charcoal and membrane processes (nanofiltration, reverse osmosis), were shown to achieve higher removal rates (over 99%) for specific pharmaceutical compounds in various published studies. However, advanced oxidation processes may lead to secondary degradation products, such as metabolites, and for this reason, future research could examine the value and feasibility of the formation and the effect of these metabolites (Celiz, Tso & Aga, 2009 ). Conclusions and further work Pharmaceutical compounds are used in large quantities in humans and in veterinary medicine, thus reaching the aquatic environment mainly through sewage treatment systems, where concentrations may be found in the levels of milligrams liter (mg/L). Although we can make some predictions based on physical and chemical properties, for the fate of pharmaceutical compounds in the aquatic environment, these generally characterized by different metabolic fate and behavior, so that the efficiency of their removal during wastewater treatment are not clear. Pharmaceutical compounds are usually present in the influent wastewater at concentrations of about 100mg/L and even more, so the majority of STPs is unable to effectively remove all of these compounds. The published literature and individual studies have shown that concentrations of pharmaceutical compounds in surface and ground waters affected by discharges and are typically less than 0,1mg/L (or 100ng/L), and concentrations in treated drinking water is usually below 0,05mg/L (or 50ng/L). Additionally, it was observed that the efficiency of removal of pharmaceutical compounds vary in a wide range of different compounds, and for the same substance, the removal depend on physical and chemical properties of pharmaceutical compounds and operating conditions (mainly aerobic, anaerobic, anoxic conditions, the residence time of solids, pH and temperature), as discussed throughout the study. The operated MBR system showed ensure higher returns removal for most compounds which results in a better quality of effluent water from the WWTP. This paper also shows the fact that the occurrence of certain pharmaceutical compounds in wastewater after secondary treatment, it works discharged to surface waters a medium to high risk to aquatic life. In addition, many other pharmaceutical compounds, even if their concentration was found to be low, the daily discharge at high loads, could contribute to the adverse effects on aquatic organisms in the long run because of chronic toxicity. It is prudent to note that advanced and expensive water treatment technologies will not be able to completely remove all of these compounds. Therefore, it is imperative to examine the toxicological significance of these various compounds in the appreciable risks to human health. Increased or rapidly changing exposure resulting from the specific local conditions such as increasing the concentration of pharmaceutical compounds in surface waters from unregulated disposal of sewage should also be investigated. For these reasons, it would be wiser to start a program to monitoring the concentrations of the most commonly occurring medicinal compounds, and those with the highest environmental risk, such as antibiotics (including erythromycin, ofloxacin, sulfamethoxazole, clarithromycin, amoxicillin , tetracycline and azithromycin), psychiatric medicines (such as fluoxetine, diazepam and carbamazepine), analgesics / anti-inflammatories (ibuprofen, mefenamic acid, naproxen, diclofenac and ketoprofen) and regulators of lipid (fainofivriko acid, fenofibrate and gemfibrozil). On the part of the legislation is very important to note that the instructions concerning the protection of the aquatic environment and related agencies are Framework Directive 2000/60/EC (WFD), Directive 2006/118/EC (GWD) to protect groundwater and Directive 2008/105/EC (PSD), stating the list of priority substances (also known as Annex X of WFD) for surface waters and related Environmental Quality Standards (EQS). Despite the fact that the increasing research activities in wastewater and water treatment, there is still a great need for future research and further investigation to assess the importance of the residues of pharmaceutical compounds in terms of endurance / resistance, and potential environmental impacts that may result. The development of indicators for the contamination of sewage and surface water by pharmaceutical compounds would also be useful in this direction, as well as the parallel registration of bibliographic and experimental data and data on hazards, biodegradability and metabolic fate of pharmaceutical compounds, regardless of their use. The specific criteria relating to the toxicity and biodegradation can be defined for the compounds tend to enter the WWTP and DWTP, and restrictions could be imposed even on the production and use of compounds, if these criteria are not met. Any changes in the parameters of the wastewater and water should be taken into account, as well as the financial cost. Similarly, restrictions or uses of drugs should be weighed against the possible loss / benefit human health and / or the environment resulting from the administration of these drugs.