Chapter 1

Pharmaceuticals in the Environment Scope of the Book and Introduction

K. Kmmerer

1.1

Pharmaceuticals A Highly Diverse Group of Chemicals with Special Properties

Pharmaceutically active compounds are complex molecules with different functionalities, physicochemical and biological properties. They are developed and used because of their more or less specific biological activity and are most notably characterised by their ionic nature. Their molecular weights range typically from 300 to 1 000. Under environmental conditions molecules can be neutral, cationic, anionic, or zwitterionic. They also often have basic or acidic functionalities. Pharmaceuticals can be classified according to their effects, but also crosswise according to their chemical structure. Normally, pharmaceuticals and disinfectants are classified according to their therapeutical purpose (e.g. antibiotics, analgesics, antineoplastics, anti-inflammatory substances, antibiotics, antihistaminic agents, contrast media, etc.). Classification according to chemical structure is used mainly for the sub-groups of the active substances, e.g. within a group of antibiotics such as -lactams, cephalosporins, penicillins or quinolones. In such cases, some of the compounds can be treated as groups and one or the other compound can be used as a general example for this group. A closely related chemical structure may be accompanied by an identical or at least a similar mode of action (e.g. antibiotics). However, as the example of antineoplastics shows, it might also be very different: alkylating, antimetabolic, mitosis inhibiting or intercalating substances belong to different classes of chemicals. In other words, compared to most bulk chemicals, pharmaceutically active compounds are often complex molecules with special properties e.g. dependence of log Kow on pH (see Chap. 2). Besides the active substances, formulations may also incorporate adjuvants and in some instances pigments and dyes are also drug components which are of minor importance in terms of significance for the environment. Many pharmaceuticals are biotransformed in the body. Biodegradation modifies the chemical structure of their active molecules, which in turn often results in a change in their physicochemical and pharmaceutical properties. Metabolism may lower activity or enhance water solubility; however, metabolism is frequently incomplete. Excretion rates range from 0 to 100%. There are two important pathways of metabolism. Phase I metabolites result from the modification of the active compound itself by hydrolysis (e.g. of ester bonds), oxidation, reduction, alkylation and dealkylation. Phase II metabolites (e.g. hydroxylated compounds) are Phase I metabolites which have been modified by glucuronation or sulfatation (coupling reactions) to enhance excretion. Not only are pharmaceuticals in the environment of special interest with respect to the compounds themselves, but also because of the differences in their occurrence,

K. Kmmerer

their fate and their effects on humans or other target organisms on the one hand, and on target and non-target organisms in the environment on the other. This can be illustrated by using the term pharmacology and eco-pharmacology (Table 1.1). 1.2

Use and Input into the Environment

Pharmaceuticals may be administered orally or intravenously, depending on the compound itself and the medical circumstances. This also has an impact on their metabolism. The diffuse input after use of pharmaceuticals, disinfectants, diagnostics and personal care products into the environment is the normal case. They are used in hospitals and are also ingested in the home. Disinfectants are widely used by the food and glue industries, as well as in medical sectors. They may enter the environment by different routes (Fig. 1.1). Because of the Good Manufacturing Practice regulations (GMPs) used by producers and the frequently high cost of the active substances, emissions during manufacturing are probably low in Europe and the United States. Only in the case of accidents may high emissions occur locally. To the authors best knowledge, no data are available on emissions during transport and storage. Point sources for the emissions are likely to be only of minor importance. The consumption and application of pharmaceuticals may vary considerably from country to country. After application, some drugs are largely metabolised before they are excreted, while others are only moderately or poorly metabolised and others yet again, such as contrast media, are excreted completely intact. Pharmaceuticals used in medicine and their metabolites enter municipal sewage and sewage treatment plants. If the drugs and their metabolites are not eliminated during sewage treatment, they may enter the aquatic environment and eventually reach drinking water (Fig. 1.1). Also, after administration, diagnostic agents and disinfectants sometimes reach wastewater and/or liquid manure i.e. soil in the form of residual quantities. It has been shown that some diagnostic agents such as iodinaredd X-ray contrast media, e.g. Gd-containing MRI contrast media and other active compounds such as caffeine and clofibrate are persistent in the envi-

Table 1.1. Pharmacology and eco-pharmacology

CHAPTER 1 Pharmaceuticals in the Environment Scope of the Book and Introduction

Fig. 1.1. Sources, distribution and sinks of pharmaceuticals in the environment

ronment. They therefore serve as possible tracers in hydrology for human impact on the aquatic environment (Mller et al. 2000; Buerge et al. 2003). Outdated medicines or their remains are sometimes disposed of down household drains. In accordance with EU-legislation, the discarding of unused drugs via household waste has been permitted since 1994 (EG 1993). It is reported that approximately one third of the total volume of pharmaceuticals sold in Germany (Greiner and Rnnefahrt 2003) and about 25% of that sold in Austria (Sattelberger 1999) is disposed of with household waste or down the drain. They enter the environment intact. If disposed of with household waste, compounds end up on land fill sites where they will enter the landfill effluent. Antimicrobials used in animals are amongst the most widely used pharmaceutical compounds for animals (Boxall et al. 2003a,b). Drugs used in animal husbandry. for veterinary purposes or as growth promoters (particularly in large-scale animal farming and intensive livestock treatment) and their metabolites are excreted with manure. Farmers use manure and sewage sludge to fertilise fields, thus the drug residues are introduced into the soil. Veterinary pharmaceuticals may reach surface water as runoff from the soil after heavy rain. The wash off from topical treatment may enter soil or ambient waters directly. Application of pharmaceuticals in aquaculture results in direct input into water and sediments. Some antibiotics such as streptomycins are used in fruit growing, while others are used in bee-keeping. Again, the situation may vary from country to country. The heavy

K. Kmmerer

use of streptomycins in fruit growing in the US is being discussed as a possible reason for the high resistance of pathogenic bacteria against these compounds. In Germany use of these antibiotics for this purpose has been banned. It is estimated that worldwide consumption of active compounds amounts to some 100 000 tons or more per annum. Use may vary from country to country. In 2001, about 50 000 different drugs were registered in Germany, 2 700 of which accounted for 90% of the total consumption and which, in turn, contained about 900 different active substances or correspondingly 38 000 t of active compounds (Greiner and Rnnefahrt 2003) (see Chaps. 58 for figures from different countries; for Austria see Sattelberger 1999). 6 0007 000 t a1 active substances are of potential environmental concern in Germany. 110 compounds are used in amounts greater than 5 t yr1, which correlates to a specific per capita consumption of of 60 g yr1. According to WHO figures, 0.4% of Japanese women of reproductive age take a contraceptive pill containing ethinyloestradiol as the main active compound, compared to 16% in North America. Antibiotics are sold over the counter without prescription in some countries, while in others they are only available on prescription. 1.3

Occurrence and Fate in the Environment

Reviews of the present international state of knowledge have recently been compiled by Halling-Srensen et al. (1998), Heberer (2002), Thiele-Bruhn (2003) and Kmmerer (2001a,b, 2003). Pharmaceuticals in the environment namely hormones first became a focus of scientific interest and public awareness in the 1970s (Tabak and Bunch 1970; Norpoth et al. 1973). The most frequent conclusion was that these hormones are not easily biodegraded. The subject generated little interest during the 1980s. Some investigations to prove the existence of drugs in the effluent of sewage treatment plants (STPs) were carried out in the mid eighties, mainly in Great Britain (Richardson and Bowron 1985; Aherne et al. 1990). Other substances of environmental relevance such as heavy metals, polycyclic aromatic hydrocarbons or chlorinated dioxins and furans, as well as pesticides and detergents were the subject of extensive investigation during this period. Awareness of the effects of pharmaceuticals in the environment has grown since the mid nineties of the last century. At the same time, a discussion started about endocrine disrupting substances (EDS) sometimes also called endocrine modulating substances and non-hormone pharmaceuticals such as lipid lowering agents (e.g. fibrates), pain killers and other substances (e.g. Stan and Linkerhgner 1992). Since then, quite a lot of activities started for the EDS beginning in the USA. In case of pharmaceuticals awareness and research started in Europe. These reports triggered further more detailed investigations into the occurrence, fate and effects of pharmaceuticals in the environment in Europe, the US and Canada. Meanwhile there is high awareness for both topics all over the world. Most of the studies conducted up till now describe the occurrence of the compounds in environmental compartments (see Chaps. 3, ). Medical substances have been detected in the effluent from medical care units, sewage, and the effluent of sewage treatment plants, in surface water, groundwater, and in drinking water. Pharmaceuticals have also been detected in the effluent from landfill sites (Holm et al. 1995; Chap. 10).

CHAPTER 1 Pharmaceuticals in the Environment Scope of the Book and Introduction

Systematic studies of the occurrence of pharmaceuticals in the environment are now available for Italy, the US, Canada and other countries (see Chaps. 39). Meanwhile, there is evidence of the occurrence of some 80 different drugs in STP effluent, surface water and groundwater and even in drinking water. Polar compounds such as ibuprofen, carbamazepine, and the fibrates, which are relatively easy to measure, are generally among the compounds analysed in most detail (e.g. Ternes 1998) and used for environmental fate investigations. Another important group frequently measured are the antibiotics (Hirsch et al. 1999). This is because not only are they an important group in terms of the amounts used, but also because their use is associated with the emergence of resistance (see Chap. 18). The concentrations in surface waters and effluent from STPs have been shown to lie in the ng l1 to g l1 range (Sacher et al. 2001; Chaps. 39). Drugs applied in veterinary medicine, livestock farming and aquaculture for therapeutic purposes, prevention, and as growth promoters have been analysed in manure and soil (see Chaps. 11, 13 and 14). Evidence of a wide variety of different active substances in the aquatic environment, in liquid manure, and in the soil also shows that the active substances are at the very least not completely eliminated during sewage treatment nor are they biodegraded in the environment. A limited number of investigations deal explicitly with sources (e.g. Kmmerer 2001a; Kmmerer and Henninger 2003), fate i.e. (bio)degradation, and the effects of the active compounds on the environment (Kmmerer 2001b; Boxall et al. 2003a; Chaps. 3 and 4). The predominant fate processes for pharmaceuticals in the different environmental compartments are sorption (e.g. tetracyclines and quinolones) and (bio)degradation. Photodegradation and hydrolysis (e.g. for quinolones and some -lactams, respectively) can also be significant. Sorption of pharmaceuticals depends on the extent of neutral and ionic species present and the characteristics of the target particles. Sorption may have an impact on the spread and (bio)availability of pharmaceuticals in the environment (particle bound transport) and their removal during wastewater treatment. 1.4

Effects
The active ingredients of medications have been selected or designed because of their activity against organisms. Thus it is to be expected that the following properties will be crucial for their environmental impact effective against bacteria effective against fungi effective against (non) target higher organisms sometimes persistent

Little information is available on the effects of the active substances on organisms in the aquatic and terrestrial environment. High concentrations of some compounds, i.e. in the mg per litre range have been found to produce effects in environmental organisms. However, an effect on Daphnia, algae and bacteria has also been demonstrated using low

K. Kmmerer

concentrations in chronic tests. Most often these studies covered antibiotics (HoltenLtzhft et al. 1999; Halling-Srensen 2000a,b; Backhaus and Grimme 1999; Al-Ahmad et al. 1999; Kmmerer and Al-Ahmad 1999; Kmmerer et al. 2000; Boxall et al. 2003a). 1.5

Resistance
According to our current knowledge, it often appears that bacteria are unaffected by the presence of antibiotics in standardised tests, if the toxicity of the antibiotics is checked as well as the size of the biomass in the test systems described in the ISO or OECD guidelines (Halling-Srensen 2000b; Kmmerer et al. 2004). It is known that antibiotics in sub-inhibitory concentrations can have an impact on cell functions and change the genetic expression of virulence factors or the transfer of antibiotic resistance (Ohlsen et al. 1998; Salyers et al. 1995). Antimicrobials exhibit different activity spectra and mechanisms of action. Therefore, different bacterial populations may be affected in different ways and to a different extent. In vitro experiments have shown that gentamicin in a concentration of 100 g per litre increased the transfer rate of resistance in staphylococci but did not select resistant bacteria. Other substances, such as macrolides, quinolones or vancomycin did not have such an impact (Ohlsen et al. 2004). When a complex mixture of bacteria is exposed to antibiotics, increased activity can be observed in some cases (Halling-Srensen 2000; Alexy et al. 2001). The significance of antibiotics in the environment is not yet clear. 1.6

Risk and Risk Management

The risk of adverse effects on humans through ingestion of pharmaceuticals contained in drinking water seems to be negligible. The maximum possible intake within a lifespan (2 litres drinking water per day over 70 years) is far below the dosages used in therapy (Christensen 1998; Kmmerer and Al-Ahmad 1998). Thus, the risks posed to humans from pharmaceuticals in the environment seem to concern environmental hygiene rather than toxicology and pharmacology. More important in terms of toxicity are the possible effects against organisms in the environment. How to extrapolate data from high dose short-term ingestion during therapy to a low dose long term ingestion i.e. medication via drinking water is still an unresolved issue in toxicology and in ecotoxicology. Furthermore, up to now risk assessments have been undertaken for single substances only and not for mixtures (see Chap. 5). Some of the compounds have carcinogenic, mutagenic or reproductive toxic effects (CMR compounds). There are no procedures to assess the risks connected with their emission into the environment. Besides the CMR compounds, the following groups of drugs and diagnostic aids may deserve special attention: cytostatic agents, because of their frequently evident carcinogenic, mutagenic or embryotoxic properties; antibiotic agents and disinfectants, because of their potential for forming resistance and their bacterial toxicity, and because of their potential to disturb environmental bacterial consortia and processes, i.e. the elemental cycles;

CHAPTER 1 Pharmaceuticals in the Environment Scope of the Book and Introduction

chlorophenols, chlorine-releasing reagents such as sodium hypochlorite, dichloroisocyanuric acid and others used as disinfectants and as bleaching agents or diagnostics such as organic iodinated X-ray contrast media because they contribute to the absorbable organic halogen compounds (AOX); and heavy metals, such as disinfectants and preservatives containing mercury, cytostatic agents containing platinum or contrast media containing gadolinium. Other groups of drugs, analgesics or sedatives for instance, are also of interest for reasons of environmental hygiene because of the volume used. Some groups of compounds such as nitro compounds (e.g. nitroglycerin, iso-sorbit dinitrate) or calcium blockers which are also heavily used and which to a large degree are mostly metabolised have not yet been studied. Besides toxicity, the element of persistence is of particular importance for the assessment of the environmental significance of substances (Kmmerer and Held 1997). Persistent compounds increase the potential for long-term and hence varied effects, and the longer the exposure lasts for multiple contamination of the ecosystem. This cannot be tested in advance with the presently available test systems (Cairns and Mount 1992). Standard tests are often used for effect assessment and biodegradability testing (e.g. according to OECD Series 200 and 300) developed for bulk chemicals. It is unclear to what extent the test systems have to be modified to obtain reliable results. In the case of antimicrobials, resistant bacteria may be selected by recalcitrant antimicrobials in the tanks of sewage treatment plants (STPs) or in other environmental compartments, such as soil (see Chap. 18). This may be one source of the growing number of pathogenic bacteria resistant to antibiotics in hospitals and may also be a reason for the increase of severe nosocomial infections. Concentrations for antibiotics have been calculated in hospital effluents and have been measured for single compounds in the range favouring the selection of resistant bacteria. The effluents are diluted by municipal sewage, but antibiotics from households are also present. There are some procedures for the risk assessment of pharmaceuticals. But it is as yet unclear which are suitable for pharmaceuticals or what the constraints are and which assessment factors should be used (Chap. 5). Adoption of the last draft of the EU guidelines on human pharmaceuticals is expected in 2004 (Chaps. 21 and 22). For risk management the treatment of STP effluent has been described using (photochemical) oxidation processes and filtration technology (e.g. Qiting and Xiheng 1988; Zwiener et al. 2001; Ravina et al. 2002; Kiffmeyer 2003; Ternes et al. 2003), filtration and reverse osmosis (Schrder 2002; Drewes et al. 2002; Chap. 29). Therefore, the technology seems to be available. The related costs are not yet established. Growth promoters will be phased out in the EU by 2005. The World Health Organisation also advises abandoning the use of antibiotics as growth promoters, as data show that there is no need to use growth promoters (Ferber 2003). 1.7

Conclusion
It should be pointed out that although new and essential knowledge has been published since the first edition of this book data are still too scarce to allow us to undertake a sound risk assessment. There is still an urgent need to close the gaps in our knowledge. The most important issues are addressed in Part IV.

10

K. Kmmerer

References
Aherne GW, Hardcastle A, Nield AH (1990) Cytotoxic drugs and the aquatic environment. Estimation of bleomycin in river and water samples. J Pharm Pharmacol 42:741742 Al-Ahmad A, Daschner FD, Kmmerer K (1999) Biodegradability of cefotiam, ciprofloxacin, meropenem, penicillin G, and sulfametohoxazole and inhibition of wastewater bacteria. Arch Environ Cont Toxicol 37:158163 Alexy R, Kmpel T, Drner M, Kmmerer K (2001) Effects of antibiotics against environmental bacteria studied with simple tests. Proceedings of the 11th Annual Meeting of SETAC Europe, Madrid, 611 May Backhaus T, Grimme LH (1999) The toxicity of antibiotic agents to the luminescent bacterium Vibrio fischeri. Chemosphere 38:32913301 Boxall ABA, Kolpin D, Halling-Srensen B, Tolls J (2003a) Are veterinary medicines causing environmental risks. Environ Sci Technol 36:286A294A Boxall ABA, Fogg LA, Kay P, Blackwell PA, Pemberton EJ, Croxford A (2003b) Veterinary medicines in the environment. Rev Environ Contam Toxicol 180:191 Buerge IJ, Poiger T, Muller MD, Buser HR (2003) Caffeine, an anthropogenic marker for wastewater contamination of surface waters. Environ Sci Technol 37:691700 Cairns J jr, Mount DI (1992) Aquatic toxicology. Envrion Sci Technol 24:154161 Christensen FM (1998) Pharmaceuticals in the environment a human risk? Reg Tox Pharm 28:212221 Drewes JE, Heberer T, Reddersen K (2002) Fate of pharmaceuticals during indirect potable use. Wat Sci Technol 46:7380 EG (1993) Richtlinie 93/39/EWG des Rates vom 14. Juni 1993 zur nderung der Richtlinien 65/65/EWG, 75/318/EWG und 75/319/EWG betreffend Arzneimittel. Amtsblatt der Europischen Gemeinschaften Nr. L 214/22 vom 24.08.93 Ferber D (2003) Antibiotic resistance. WHO advices kicking the livestock antibiotic habit. Science 301:1027 Greiner P, Rnnefahrt I (2002) Management of environmental risks in the life cycle of pharmaceuticals. European Conference on Human and Veterinary Pharmaceuticals in the Environment, Lyon, 1416 April Halling-Srensen B (2000a) Algal toxicity of antibacterial agents used in intensive fish farming. Chemosphere 40:731739 Halling-Srensen B (2000b) Inhibition of aerobic growth and nitrification of bacteria in sewage sludge by anti-bacterial agents. Arch Environ Contam Toxicol 40:451460 Halling-Srensen B, Nilesen N, Lanzky PF, Ingerslev F, Holten-Ltzhft, Jrgensen SE (1998) Occurrence, fate and effects of pharmaceutical substances in the environment a review. Chemosphere 36:357393 Heberer T (2002) Occurrence, fate, and removal of pharmaceutical residues in the aquatic environment: a review of recent research data. Toxicol Lett 131:517 Hirsch R, Ternes T, Haberer K, Kratz KL (1999) Occurrence of antibiotics in the aquatic environment. Sci Tot Environ 225:109118 Holm JV, Rugge K, Bjerg PL, Christensen TH (1995) Occurrence and distribution of pharmaceutical organic compounds in the ground water down gradient of a landfill (Grinsted, Denmark). Envrin Sci Tech 29:4151420 Holten-Ltzhft HC, Halling-Srensen B, Jrgensen SE (1999) Algal toxicity of antibacterial agents applied in Danish fish farming. Arch Environ Contam Toxicol 36:16 Kiffmeyer T (2003) Minimisation of human drug input by oxidative treatment of toilet effluents from hospital wards. European Conference on Human and Veterinary Pharmaceuticals in the Environment, Lyon, 1416 April Kmmerer K (2001a) Drugs, diagnostic agents and disinfectants in waste water and water a review. Chemosphere 45:957969 Kmmerer K (ed) (2001b) Pharmaceuticals in the environment. Sources, fate, effects and risks, 1st edn. Springer-Verlag, Heidelberg Berlin Kmmerer K, Al-Ahmad A (1998) The cancer risk for humans related to cyclophoshamide and ifosfamide excretions emitted into surface water via hospital effluents. Cancer Det Prev 22(Suppl 1):136 Kmmerer K, Al-Ahmad A (1999). Epirubicinhydrochlorid in der aquatischen Umwelt Biologische Abbaubarkeit und Wirkung auf aquatische Bakterien. 7. Nordwestdeutscher Zytostatika-Workshop, Hamburg-Harburg, 29.31.01.1999 (Proceedings, pp 1011) Kmmerer K, Held M (1997) Die Umweltwissenschaften im Kontext von Zeit Begriffe unter dem Aspekt der Zeit. UWSF Z Umweltchem kotox 9:169178 Kmmerer K, Henninger A (2003) Promoting resistance by the emission of antibiotics from hospitals and households into effluents. Clin Microbiol Inf 9:12031214

CHAPTER 1 Pharmaceuticals in the Environment Scope of the Book and Introduction

11

Kmmerer K, Al-Ahmad A, Mersch-Sundermann V (2000) Biodegradability of some antibiotics, elimination of their genotoxicity and affection of waste water bacteria in a simple test. Chemosphere 40:701710 Kmmerer K, Alexy R, Httig J (2004) Standardized tests fail to assess the effects of antibiotics against environmental bacteria because of delayed effects. Wat Res 38:21112116 Mller P, Dulski P, Bau M, Knappe A, Pekdeger A, Sommer-von Jarmerasted C (2000) Anthropogenic gadolinium as a conservative tracer in hydrology. J Geochem Explor 69/70:409414 Norpoth K, Nehrkorn A, Kirchner M, Holsen H, Teipel H (1973) Investigations on the problem of solubilityand stability of steroid ovulation inhibitors in water, waste water and activated sludge. Zbl Hyg I Abt Orig B 156:500511 Ohlsen K, Ziebuhr W, Koller K, Hell W, Wichelhaus TA, Hacker J (1998) Effects of sub inhibitory concentrations of antibiotics an alpha-toxon (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 42:28172823 Ohlsen K, Werner G, Ternes T, Ziebuhr W, Witte W, Hacker J (2004) Impact of antibiotics on conjugational resistance in gene transfer in Staphylococcus aureus in sewage. Environ Microbiol (to be published) Qiting J, Xiheng Z (1988) Combination process of anaerobic digestion and ozonization technology for treating wastewater from antibiotics production. Wat Treat 3:285291 Ravina M, Campanella L, Kiwi J (2002) Accelerated mineralization of the drug diclofenac via Fenton reactions in a concentric photo-reactor. Wat Res 36:35533560 Richardson ML, Bowron JM (1985) The fate of pharmaceutical chemicals in the aquatic environment. J Pharm Pharmacol 37:112 Sacher F, Lange FT, Brauch HJ, Blankenhorn I (2001) Pharmaceuticals in groundwaters analytical methods and results of a monitoring program in Baden-Wurttemberg, Germany. J Chromatogr A 938:199210 Salyers AA, Shoemaker NB, Stevens AM, Li LY (1995) Conjugative transposons: an unusual and diverse set of integrated gene transfer elements. Microbial Rev 59:579590 Sattelberger S (1999) Arzneimittelrckstnde in der Umwelt, Bestandsaufnahme und Problemstellung. Report des Umweltbundesamtes sterreich, Wien Schrder HF (2002) Mass spectrometric monitoring of the degradation and elimination efficiency for hardly eliminable and hardly biodegradable polar compounds by membrane bioreactors. Wat Sci Technol 46:5764 Stan H-J, Linkerhgner M (1992) Indentifizierung von 2-(4-Chlorphenoxy)-2-methylpropionsure im Grundwasser mittels Kapillargaschromatographie mit Atomemissionsdetektion und Massenspektrometrie. Vom Wasser 79:8588 Tabak HH, Bunch RL (1970) Steroid hormones as water pollutants. In: Developments in Industrial Microbiology, Washington, pp 367376 Ternes TA (1998) Occurence of drugs in German sewage treatment plants and rivers. Wat Res 32: 32453260 Ternes TA, Stuber J, Herrmann N, McDowell D, Ried A, Kampmann M, Teiser B (2003) Ozonation: a tool for removal of pharmaceuticals, contrast media and musk fragrances from wastewater? Wat Res 37:19761982 Thiele-Bruhn S (2003) Pharmaceutical antibiotic compounds in soils a review. J Plant Nutr Soil Sci 166:145167 Zwiener C, Gremm TJ, Frimmel FH (2001) Pharmaceutical residues in the aquatic environment and their significance for drinking water production. In: Kmmerer K (ed) Pharmaceuticals in the environment. Sources, fate, effects and risks, 1st edn. Springer-Verlag, Heidelberg Berlin, pp 8189

http://www.springer.com/978-3-540-21342-0