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Über dieses Buch

When the first green wave appeared in the mid and late 1960s, it was considered a fea­ sible task to solve pollution problems. The visible problems were mostly limited to point sources, and a comprehensive "end of the pipe technology" (= environmental technology) was available. It was even seriously discussed in the US that what was called "zero dis­ charge" could be attained by 1985. It became clear in the early 1970S that zero discharge would be too expensive, and that we should also rely on the self purification ability of ecosystems. That called for the development of environmental and ecological models to assess the self purifica­ tion capacity of ecosystems and to set up emission standards, considering the rela­ tionship between impacts and effects in the ecosystems. This idea is illustrated in Fig. 0.1. A model is used to relate an emission to its effect on the ecosystem and its components. The relationship is applied to select a good solution to environmental problems by application of environmental technology.





Chapter 1. Pharmaceuticals in the Environment — Scope of the Book and Introduction

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 β-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).

K. Kümmerer

Chapter 2. Special Characteristics of Pharmaceuticals Related to Environmental Fate

An important consideration when assessing the environmental fate of pharmaceutical compounds is that, as a class, they generally possess characteristics that make them different than conventional industrial chemical pollutants. Some of these attributes include the following: tendency of the parent neutral compound and associated salts to form polymorphic solid states;introduced into the environment subsequent to human metabolism;large, chemically complex molecular structure;generally ionisable with multiple ionisation sites spread throughout the molecule.

V. L. Cunningham

Use and Occurence of Pharmaceuticals in the Environment


Chapter 3. Emissions from Medical Care Units

After administration, pharmaceuticals are excreted and released into the aquatic environment via wastewater effluent. Unused drugs are sometimes disposed of down drains, and, unless they are biodegraded or eliminated during sewage treatment, traces may enter the aquatic environment and eventually reach drinking water. It is also hypothesised that antibiotics and disinfectants disturb the wastewater treatment process and the microbial ecology in surface waters. Furthermore, resistant bacteria may be selected in the aeration tanks of STPs by the antibiotic substances present.

K. Kümmerer

Chapter 4. Pharmaceuticals in the Environment: Changes in the Presence and Concentrations of Pharmaceuticals for Human Use in Italy

Until recently information on pharmaceuticals emitted in the environment was scanty. In the last two decades, pharmaceuticals such as clofibrate, analgesics, antibiotics and antineoplastics have been found in the effluent of sewage treatment plants (STP) (Halling-Sørensen et al.1998; Kümmerer 2001). Some of these compounds were not readily biodegradable and were also detectable in surface water and groundwater (Oilers et al. 2001; Sacher et al. 2001). Several pharmaceuticals have been detected in the µg l−1 range in wastewaters throughout Europe, and some have been measured at ng l−1 concentrations in rivers and drinking water (Halling-Sørensen et al. 1998; Kümmerer 2001; Ollers et al. 2001; Sacher et al. 2001; Zuccato et al. 2000).

E. Zuccato, S. Castiglioni, R. Fanelli, R. Bagnati, D. Calamari

Chapter 5. Environmental Exposure of Antibiotics in Wastewaters, Sewage Sludges and Surface Waters in Switzerland

Human-use pharmaceuticals enter sewage effluents via urine and faeces and by improper disposal. These pharmaceuticals are discharged from private households and from hospitals. In Switzerland and many developed countries sewage effluents mainly reach wastewater treatment plants (WWTPs) (Fig. 5.1). However, direct inputs into natural waters are also possible through storm water overflow and leaks in the sewer system. In wastewater treatment plants the antibiotics are only partially eliminated and residual amounts can reach ambient waters or groundwater. Most pharmaceuticals are found in natural waters in only very low concentrations. Despite this general finding, the question arises what risks these traces of pharmaceuticals pose for aquatic ecosystems. Antibiotics are of particular interest because we do not currently know whether their presence in natural waters contributes to the spread of antibiotic resistance of microorganisms.

A. C. Alder, C. S. McArdell, E. M. Golet, H.-P. E. Kohler, E. Molnar, N. Anh Pham Thi, H. Siegrist, M. J.-F. Suter, W. Giger

Chapter 6. Pharmaceuticals in the Canadian Environment

One of the first reports of the release of pharmaceutically active compounds (PhACs) into the environment was a study conducted in Canada on the concentrations of selected drugs in the effluent from a Vancouver sewage treatment. Two analgesic/antiinflammatory drugs, ibuprofen and naproxen were identified in the municipal wastewater from Vancouver (Rogers et al. 1986). Since that study, the issue of the release of PhACs into the environment has developed into an area of emerging interest (Halling-Sørensen et al. 1998; Daughton and Ternes 1999; Servos et al. 2001, 2002; Heberer 2002a,b). Most of these drugs or their metabolites are excreted or are discarded into urban wastewaters and eventually make their way to wastewater treatment plants (WWTPs). Within WWTPs, drugs may be rapidly degraded and mineralised, or these substances (or their metabolites) may be relatively persistent. Hydrophilic compounds that are resistant to degradation may remain dissolved in the aqueous phase of the WWTP effluent, or more hydrophobic substance may bind to WWTP biosolids (i.e. “sludge”). Thus, these compounds may enter the environment through the discharge of WWTP effluents into receiving waters, or they may enter the environment in association with biosolids that are deposited in landfills or spread on agricultural land for soil amendment. PhACs bound to biosolids may leach into underlying groundwater, which may be used as a source of potable water (Heberer 2002a,b; Sacher et al. 2001). PhACs applied to agricultural fields may also be transported by runoff into the surrounding surface water. PhACs discharged into surface water have the potential to contaminate sources of drinking water (Heberer et al.1997, 2001).

C. Metcalfe, X.-S. Miao, W. Hua, R. Letcher, M. Servos

Chapter 7. Occurrence of Human Pharmaceuticals in Water Resources of the United States: A Review

The widespread environmental presence of some pharmaceuticals and other organic wastewater compounds has been documented globally (e.g. Buser et al. 1998; Ternes 1998; Stumpf et al.1999; Heberer et al. 2001; Kümmerer 2001; Ternes et al. 2001; Scheytt et al. 2001; Golet et al. 2002; Kolpin et al. 2002; Boyd et al. 2003; Metcalf et al. 2003). Recently, there have been several literature reviews and summary studies of the occurrence, fate, transport, and treatment of targeted human pharmaceuticals in wastewater effluent and associated environmental waters across the globe (e.g. Daughton and Ternes 1999; Sedlak et al. 2000; Suter and Giger 2000; Daughton and Jones-Lepp 2001; Jones et al. 2001; Heberer 2002; and Drewes et al. 2002). The occurrence of pharmaceutical compounds in water resources is explained by their ubiquitous use, excretion of large percentages of the mass consumed, and incomplete removal during wastewater treatment (Stumpf et al.1999). The recent increase in detection of trace concentrations (typically less than a part per billion) of pharmaceuticals in water resources across the globe reflects improvements in laboratory analytical methods (Sedlak et al. 2000) and the associated increases in field surveys. The detection of pharmaceutical compounds in large rivers in Europe and in the North Sea (Buser et al. 1998; Ternes 1998; Stumpf et al. 1999) highlighted the fact that highly soluble, trace organic compounds, such as pharmaceuticals, may escape removal in wastewater treatment, and the mixing and concentration of wastewaters through conventional wastewater treatment processes could provide a means of delivering these chemicals to environmental waters in a manner that would contaminate water resources on a large scale at trace levels (Richardson and Bowron 1985). In the United States, some of the first detections of a limited number of pharmaceutically active compounds or their transformation products were found in waters associated with landfill leachates or sewage effluent (Tabak and Bunch 1970; Garrison et al. 1976; Hignite and Azarnoff 1977; Bouwer et al. 1982; Eckel et al. 1991) decades ago. At the time of these studies, other industrial contaminants were the focus of regulatory and scientific interest; therefore, further studies on the environmental occurrence and transport of pharmaceutical compounds were rare.

M. J. Focazio, D. W. Kolpin, E. T. Furlong

Chapter 8. Strategies for Selecting Pharmaceuticals to Assess Attenuation During Indirect Potable Water Reuse

During the past decade, it has become apparent that wastewater-derived contaminants such as pharmaceuticals, steroid hormones, detergent metabolites and disinfection by products often are present in surface and groundwater (see Daughton and Ternes 1999; Kümmerer 2001; Heberer 2002; Snyder et al. 2003a for reviews). Most of the initial scientific attention related to this topic focused on the potential for certain compounds to interact with the endocrine systems of aquatic organisms (e.g. Desbrow et al. 1998, Routledge et al. 1998, Pickering and Sumpter 2003). More recently, concerns have been raised about the potential for wastewater-derived contaminants to cause other ecological effects, such as the inhibition of primary productivity (Orvos et al. 2002; Wilson et al. 2003) and the alteration of chemical communication (Kolodziej et al. 2003). The presence of pharmaceuticals in drinking water supplies also has raised concerns among water suppliers (Snyder et al. 2003a). In particular, projects that involve intentional indirect potable water reuse have received new scrutiny due to public perception of health threats posed by pharmaceuticals.

D. L. Sedlak, C.-H. Huang, K. Pinkston

Chapter 9. Residues of Clofibric Acid, Ibuprofen and Diclofenac in the Aquatic Environment and their Elimination in Sewage Treatment and Drinking Water Production

Pharmaceuticals belong to the emerging issues in environmental chemistry. They are produced and administered for human and animal medical care. Due to the amount and type of application pharmaceuticals can reach the aquatic environment, in particular the ones used for medicine and veterinary drugs (Halling-Sørensen et al.1998). Being produced and applied with the aim of causing a biological effect, their occurrence in the environment is of ecotoxicological interest. In particular this is of importance for the antibiotics, but also for antineoplastics, hormones (compounds with endocrinic effects) and for various compounds and metabolites that have already been detected in sewage plant effluents and surface water in considerable concentrations (e.g. bezafibrate, clofibric acid, ibuprofen, carbamazepine, iopamidol) (Heberer 2002a; Ternes 2001; Kümmerer 2001; Ternes and Hirsch 2000; Stumpf et al.1999; Hirsch et al. 1999). More than 80 compounds, pharmaceuticals and several metabolites, have been detected in the aquatic environment in nine different countries of Europe, in Brazil, the US and Canada.

C. Zwiener, F. H. Frimmel

Chapter 10. Drugs in Municipal Landfills and Landfill Leachates

Drugs and drug metabolites are a new class of organic micropollutants which have been found in low concentrations (ng 1−1 to µg 1−1) in wastewater, ground and surface water (Hailing-Sørensen et al. 1997; Heberer 2002; Kümmerer 2001; Sacher et al. 2002; Spengler et al. 2001). Recent monitoring studies indicate that in many cases the main route for human drugs entering the aquatic environment is via treated or untreated sewage effluent (Sacher et al. 2002; Heberer 2002). Because it is common (and — with the exception of e.g. cytostatics — legal) practice in many countries to discard expired and unwanted drugs, household waste and landfills can also be expected to be a source of pharmaceutical products. Since many of the disposal sites are still open dumps without protective barriers and leachate collection systems, there is a danger of infiltration of contaminated leachates into the soil influencing the quality of groundwater near landfills. The present article gives an overview on the presence of drugs in municipal landfills and landfill leachates as found in the few publications available so far.

J. W. Metzger

Chapter 11. Antibiotics in Soil: Routes of Entry, Environmental Concentrations, Fate and Possible Effects

During the past decade pharmaceuticals have been recognised as a new class of ubiquitously occurring persistent contaminants (Halling-Sørensen et al. 1998; Daughton and Ternes 1999; Kämmerer 2001; Boxall et al. 2003; Diaz-Cruz et al. 2003; Thiele-Bruhn 2003). A large number of drugs are used extensively in both human and veterinary medicine. Antibiotics are one of the most important substance classes with a possible environmental impact. Estimations of the European Federation of Animal Health (FEDESA) revealed that approximately 8500 tons of antibiotics were used in human medicine and 4700 tons in veterinary medicine in the European Union (including Switzerland) in 1999 (Anonymous 2001).

G. Hamscher, H. T. Pawelzick, H. Höper, H. Nau

Chapter 12. Use of Veterinary Pharmaceuticals in the United States

Veterinary pharmaceuticals are widely used in the United States for food-producing animals and for pet or companion animals The purpose of this chapter is to briefly familiarise the reader with the range of veterinary pharmaceuticals available for use in livestock species in the United States. These compounds include, but are not limited to, a variety of antibacterial and antimicrobial agents, reproductive aids, growth promoters, anthelmintics and antiparasiticides.Veterinary pharmaceuticals are administered at therapeutic levels for disease treatment and prevention purposes and for increased milk production. Administration at nontherapeutic levels is usually for disease prophylaxis, growth promotion, and increased feed efficiency.

R. A. Bloom

Chapter 13. Use and Environmental Occurrence of Veterinary Pharmaceuticals in United States Agriculture

The purpose of this chapter is to familiarise the reader with the range of veterinary pharmaceuticals used in agriculture in the United States and to provide examples of the environmental occurrence of selected veterinary pharmaceuticals. A 1998 survey conducted by the Animal Health Institute (AHI) reported that there were 109 million cattle, 7.5 billion chickens, 92 million swine, and 292 million turkeys in the United States (AHI 2002). In comparison, a 2002 survey conducted by the National Agricultural Statistics Service (NASS) reported 104 million cattle, 8.6 billion chickens, 60 million swine, and 275 million turkeys in the United States (NASS 2002). To increase the efficiency of food production and maintain economic viability, animal agribusinesses began contracting with cooperative farmers, which lead to a proliferation of large animal-feeding operations (AFOs) over the last decade. Because of the close proximity of the large numbers of animals at these facilities and the potential for the rapid spread of disease, use of pharmaceuticals is important to maintain their operations.

M. T. Meyer

Chapter 14. Fate of Veterinary Medicines Applied to Soils

Veterinary medicines are used widely to treat disease and protect the health of animals. Following administration, veterinary medicines may be metabolised and then released along with any metabolites either directly to the environment (as is the case with pasture animals) or indirectly during the application of manure or slurry.

A. B. A. Boxall, P. Kay, P. A. Blackwell, L. A. Fogg

Fate and Effects of Pharmaceuticals in the Environment


Chapter 15. Pharmaceuticals as Environmental Contaminants: Modelling Distribution and Fate

Concern is growing over the environmental consequences of the use of drugs for human and animal health. Long term treatments for several illnesses are a common mass practice in human health care (e.g. diuretics, beta blockers, antibiotics), a number of females are taking daily hormones to prevent unwanted pregnancies, modern life stress is handled very frequently through sedatives and tranquillizers, moreover there is in animal farming a general trend towards the intensification of production methods and production gains based on greater reliance on pharmaceuticals, feed additives, hormones and potent parasiticides (Halling-Sørensen et al. 1998).

A. Di Guardo, D. Calamari, E. Benfenati, B. Halling-Sørensen, E. Zuccato, R. Fanelli

Chapter 16. Effects of Pharmaceuticals on Aquatic Invertebrates — The Example of Carbamazepine and Clofibric Acid

Pharmaceuticals and their metabolites are widely distributed in the aquatic environment (Kümpel et al. 2001; Tixier et al. 2003). Concerns about potential ecological effects have been raised because these compounds are usually highly active, with the example of ethinyloestradiol and other oestrogens demonstrating that such compounds may cause effects already at concentrations between ı and ıo ng l−1 (Routledge et al. 1998). Though many data about the occurrence have been collected, not much is known in fact about possible impact on aquatic wildlife.

G. Nentwig, M. Oetken, J. Oehlmann

Chapter 17. What Do We Know about Antibiotics in the Environment?

Antibiotics are used extensively in human and veterinary medicine as well as in aquaculture for the purpose of preventing or treating microbial infections, while in livestock farming they are used to promote the growth of animals. Some antibiotics are also used in fruit growing and in bee keeping. Antibiotics are only partially eliminated in sewage treatment plants and residual amounts can reach surface waters, groundwater or sediments. In natural waters, most pharmaceuticals are only found in the μg l−1 range. Since biocidal substances are designed to cause a biological effect, when reaching the environment they may affect bacteria and other water and soil-dwelling organisms. It is only in recent years that a more complex investigation of antibiotic substances has been undertaken in order to permit an assessment of the environmental risks they may pose.

R. Alexy, A. Schöll, T. Kümpel, K. Kümmerer

Chapter 18. Resistance in the Environment

There has been growing concern about antimicrobial resistance for some years now. A vast amount of literature is available on the emergence of resistance and the use of antimicrobials in medicine, veterinary medicine and animal husbandry. Resistance genes and resistant bacteria have been detected in environmental compartments such as sewage, surface water, oceans, sediments, sewage sludge and soil (for a more detailed review of antibiotic resistance in the environment see Kümmerer, to be published). The most prominent medical examples are vancomycin resistant enterococci (VRE), methicillin resistant Staphylococcus aureus (MRSA), and multi-resistant pseudomonades. The selection pressure due to the presence of antibiotics above a certain concentration against the microbial biocoenosis is an important factor in the selection and spread of resistant bacteria. Transfer of resistance genes as well as the already resistant bacteria themselves is favored particularly by the presence of antibiotics over a long period and in sub-therapeutic concentrations. Exposure of bacteria to such sub-therapeutic antimicrobial concentrations is thought to increase the speed with which resistant bacterial strains are selected, e.g. if antibiotics are used as growth promoters or by improper use in veterinary medicine and medicine. The development of resistance through the input of antibiotics into the environment is a new issue in this discussion.

K. Kümmerer

Chapter 19. Effects of Ethinyloestradiol and Methyltestosterone in Prosobranch Snails

Recent reports have shown that a number of pharmaceuticals do occur not only in raw sewage but also in effluents of sewage treatment works, sewage sludge and receiving surface waters (Daughton and Ternes 1999; Kümmerer 2001). The list of pharmaceuticals detected in aquatic ecosystems is steadily increasing while almost nothing is known regarding their potential effects on aquatic wildlife. Although concentrations of pharmaceuticals in the aquatic environment are generally in the lower ng l−1 and μg l−1 range, it has to be considered that these compounds were developed to exhibit a high biological activity, often associated with a high stability so that they are not readily biodegradable. Therefore, concerns have been raised regarding the potential impact from such compounds on aquatic wildlife even at the low reported environmental concentrations because of unknown safety factors and because accumulating compounds may attain much higher concentrations in organisms than in the water phase.

U. Schulte-Oehlmann, M. Oetken, J. Bachmann, J. Oehlmann

Risk Assessment and Risk Management


Chapter 20. Risk Assessment of Organic Xenobiotics in the Environment

It seems appropriate to begin this paper with a brief presentation of some definitions that will clarify this discussion, taking into account the possible absence of background of some readers in risk assessment. These definitions will present the different steps necessary for performing risk assessment, the activity of collective expertise, and finally the role of risk managers which has to be perfectly differentiated from the assessment process.

P. Hartemann

Chapter 21. Environmental Risk Assessment of Medicinal Products for Human Use: Aspects of Its Regulations in the European Union, Canada and United States

In this chapter we describe aspects of the regulations which relate to the environmental risk assessment of those risks to the environment arising from use, storage and disposal of a medicinal product (Fig. 21.1).

K. Olejniczak, P. Spindler

Chapter 22. Environmental Risk Assessment of Pharmaceuticals in the EU — A Regulatory Perspective

The authors report on the progress made in the development of regulatory guidance documents on environmental risk assessment (ERA) procedures of human as well as veterinary medicinal products. The elaboration of an EU Note for Guidance (NfG) document on the ERA of human pharmaceuticals began more than a decade ago. Seven years have passed since a multi-lateral process has been initiated aiming at the development of a new guidance paper on the ERA of veterinary medicinal products. At present, both documents are still in a draft stage but have been released for a six-month public consultation period (human pharmaceuticals: July 2003-January 2004; veterinary pharmaceuticals: October 2003-April 2004). Both guidance documents are expected to be implemented with changes possible in the EU in 2004/05.

J. Koschorreck, J. de Knecht

Chapter 23. The ECO-SHADOW Concept — A New Way of Following Environmental Impacts of Antimicrobials

Microorganisms are the dominating part in all ecological systems (ecosystems) and it is well recognised that antimicrobial agents (for convenience, later called antibiotics) are Mother Nature’s own weapons for establishment and maintenance of all microbial ecosystems. Consequently, antibiotic resistance is a natural part of the regulatory factors in any ecosystem, and genes coding for resistance have existed as long as microbes have been around. However, during our increased use of antibiotics over half a century, we have selected more and more bad genes in more and more microbial communities. We got what we have asked for and what we have deserved.

T. Midtvedt

Chapter 24. A Data-based Perspective on the Environmental Risk Assessment of Human Pharmaceuticals I — Collation of Available Ecotoxicity Data

There is a growing literature relating to observations of human pharmaceuticals in the environment. Discussions about the environmental consequences of the presence of such compounds have taken place in the general absence of a systematic analysis of the potential risk. This can partly be attributed to the lack of public domain information relating to the ecotoxicity of pharmaceuticals. The lack of such an analysis means that to date, decisions concerning environmental risk assessment criteria and/or regulatory thresholds have been somewhat arbitrary or based upon inappropriate groups of industrial chemicals such as pesticides. This study attempts to address that deficiency and collates examples of data relating to the ecotoxicity of existing human pharmaceuticals. The intention is to provide perspective that will prove useful during the further development of assessment criteria. The database may also prove useful in the context of the risk assessment of individual substances.

S. F. Webb

Chapter 25. A Data Based Perspective on the Environmental Risk Assessment of Human Pharmaceuticals Il — Aquatic Risk Characterisation

Environmental risk assessment (ERA) evaluates the likelihood that adverse ecological effects result from exposure to a substance. It therefore requires a consideration of both exposure and effects in relevant environmental compartments. The exposure assessment considers the fate of a substance released to the environment and predicts the environmental concentration or PEC (“predicted environmental concentration”). The effects assessment considers data relating to the effects of the substance upon representative biota and uses such data to predict the no-effect concentration or PNEC (“predicted no-effect concentration”) for the various environmental compartments (i.e. surface waters, sediment, soil, etc.). The PEC and PNEC are combined in order to characterise the risk, i.e. calculation of the PEC/PNEC ratio (see Fig. 25.1). Decisions regarding the safety of the substance depend upon the value of this quotient.

S. F. Webb

Chapter 26. A Data Based Perspective on the Environmental Risk Assessment of Human Pharmaceuticals III — Indirect Human Exposure

Concerns have previously been expressed over the possibility of adverse human effects arising from indirect exposure to pharmaceuticals via drinking water supplies (e.g. Richardson and Bowron 1985; Christensen 1998). This follows numerous observations of pharmaceuticals (or their metabolites) as contaminants in wastewater, surface water and groundwater following normal usage (e.g. Rurainski et al. 1977; Aherne et al.1985; Aherne and Briggs 1989; Aherne et al. 1990; Stan et al.1994; Stumpf et al. 1996; Ternes 1998; Hirsch et al. 1999). At present there is no regulatory guidance as to how the significance of the potential presence of pharmaceuticals at trace concentrations in drinking water supplies may be assessed. Risk assessment of pharmaceuticals for marketing authorisation purposes within both the United States and European Union do not address this point (Olejniczak 1995; FDA-CDER 1998). In order to provide some perspective on this issue, quantitative estimates of potential worse case indirect exposure to pharmaceuticals via drinking water have been undertaken. Potential effects endpoints against which to benchmark such exposure include daily therapeutic dosage.

S. F. Webb

Chapter 27. Plasma Concentrations of Human Pharmaceuticals as Predictors of Pharmacological Responses in Fish

Pharmaceuticals typically have specific enzyme and receptor-based modes of action, which are extensively studied in mammals during drug development. Based on the considerable evidence of enzyme/receptor conservation across species, a predictive model has been developed that links therapeutic mammalian plasma levels to pharmacological responses in fish. In this model, a measured human therapeutic plasma concentration (HTPC) is compared to a predicted steady state plasma concentration (FssPC) in fish, which results in an effect ratio (ER = HTPC/FssPC) being computed. The lower the ER, the greater the potential for a pharmacological response in fish. The model was applied to twenty-eight drugs representing 15 therapeutic classes. ER values ranged from ≤ 1 to ≥ 10 000, with the category that represented an ER ≥ 10 000 containing the largest number of compounds (12 of 28). The two compounds with an ER ≤ 1 (17β-oestradiol and 17α-ethinyloestradiol) have previously been identified in chronic ecotoxicity evaluations as being active in fish. To begin to validate this model, rainbow trout were exposed for 96 h to 900 ng ml−1 ibuprofen or 200 ng ml−1 carbamazepine. These exposures resulted in measurable levels of these two compounds in trout plasma. These data indicate that pharmaceuticals may partition from water into fish plasma. While additional model refinement is needed, the model can provide a framework and prioritisation tool for considering pharmaceutical responses in fish.

D. B. Huggett, J. F. Ericson, J. C. Cook, R. T. Williams

Chapter 28. Using (Quantitative) Structure-Activity Relationships in Pharmaceutical Risk Assessment

Sound risk assessment depends on the availability of sufficient good quality data. To remove the shortcomings of experimental testing, for some time, attempts have been made to reduce the amount of money and time it requires. One option is to correlate the structure of a chemical or parts of its structure with a certain activity or with physicochemical properties (structure-activity relationship = SAR). Computer based expert systems are used for this purpose (“in silico testing”). Such an approach has a comparatively long tradition in the development of new drugs and is an important tool in the drug development process (Kellogg and Semus 2003; Cronin 2003). These systems are used for screening drugs and other chemicals for unwanted side effects (Polloth and Mangelsdorff 1997) and for predicting the physicochemical properties of new compounds such as water solubility and Kow. In the meantime, SAR has become an increasingly important tool in the regulatory process and has now reached the stage where some regulatory agencies such as the US Environmental Protection Agency routinely use QSAR-predicted toxicities as well as environmentally important properties for regulatory purposes (e.g. with the software suite EPISUITE (EPA 2001) which can be downloaded free of charge from the US EPA homepage). It is anticipated that such use will increase in future. The EU will probably accord QSARs greater prominence in the new technical guidance documents which form the basis for risk assessment. There is a good deal of literature describing the application and evaluation of QSAR software in ecotoxicology (for a overview: ECETOC 1998; ECVAM 1997; Boethling and Mackay 2000; Dearden 2002).

K. Kümmerer

Chapter 29. Removal of Pharmaceutical Residues from Contaminated Raw Water Sources by Membrane Filtration

In recent years, pharmaceutically active compounds (PhACs) have been recognised as persistent residues mainly being discharged via municipal sewage effluents into the aquatic environment (Halling-Sørensen et al. 1998; Daugthon and Ternes 1999; Kümmerer 2001; Heberer 2002). In the meantime, more than 70 different PhACs have been detected at concentrations up to the μg l−1 level in sewage effluents, surface waters, bank filtrate, groundwater, and in a few cases even in drinking water (Heberer 2002). Thus, PhACs have also been recognised as potential contaminants of raw water sources to be used for the generation of drinking water. Besides other purification pretreatment or treatment techniques such as bank filtration (Heberer and Stan 1997; Heberer et al. 1997, 2001, 2002a; Brauch et al. 2000; Kühn and Müller 2000; Reddersen et al. 2002; Verstraeten et al. 2002), artificial groundwater replenishment (Heberer and Stan 1997), soil aquifer treatment (SAT) (Drewes et al. 2002), slow-sand filtration (Preuß et al. 2001; Ternes et al. 2002), ozonation (Andreozzi et al. 2002; Ternes et al. 2002, 2003; Huber et al. 2003) or filtration applying granular activated carbon (Ternes et al. 2002), membrane filtration using nanofiltration (NF) or reverse osmosis (RO) membranes is one of the most promising techniques for the removal of PhACs. NF and RO are used extensively in water and wastewater treatment. Additionally, RO is also used in desalination. NF distinguishes itself from RO by only retaining multivalent ions, which makes it a very economic alternative where the retention of monovalent salts is not required (Schäfer et al. 2003). The main objective for the use NF or RO filtration in water and wastewater treatment is the removal of trace pollutants. However, the retention of such compounds is to date not well understood (Schäfer et al. 2003).

T. Heberer, D. Feldmann

Chapter 30. Potential Environmental Risks by Cleaning Hair and Skin

Eco-Label — A Possibility to Reduce Exposure to Personal Care Products

The published scientific knowledge of the impact of personal care products (PCPs) on the environment was recently summarised by Daughton and Ternes (1999) and Daughton and Jones-Lepp (2001). Specific attention has been paid to musk compounds and their occurrence in and effects on the environment (e.g. Balk and Ford 1999a,b). A very comprehensive compilation of toxicological and ecotoxicological data on household detergents and cosmetic detergent products was published by Madsen et al. (2001). Nevertheless, there is still a considerable lack of knowledge about occurrence, fate and potential effects of PCPs in the environment (Ternes et al. 2003). In this chapter, we will have a closer look at environmental effects of three related groups of PCPs: shampoos, shower gels and foam baths (SSBs).

U. Klaschka, M. Liebig, J. F. Moltmann, T. Knacker

Need for Further Research


Chapter 31. Risks Related to the Discharge of Pharmaceuticals in the Environment: Further Research Is Needed

Many pharmacologically active substances are used every year in the world for human and animal health care. Some are excreted unmetabolised or as active metabolites, escaping degradation in sewage treatment plants, and enter the environment, affecting surface waters and groundwaters (Halling-Sørensen et al. 1998). Drugs used in aquaculture are emitted directly into surface waters. Improper disposal of expired medication can contribute to this pollution. Since pharmaceuticals may have long half-lives in the environment, they can accumulate, reaching biologically active levels (Daughton and Ternes 1999). The environmental persistence of several commonly used medicinal drugs, such as erythromycin, cyclophosphamide, naproxen, sulfamethoxazole, sulfasalazine, and quinolones is longer than one year, and clofibric acid is estimated to persist for several years (Zuccato et al. 2001). This massive use of medicinal products can therefore potentially contaminate the environment, with risks for wildlife. Furthermore, resistant bacteria may be selected by persistent and accumulating antibiotics, which might be one source of the growing number of antibiotic-resistant pathogens in human medicine (Kümpel et al. 2001). Data are scant on the amounts of the different active substances emitted into wastewater, surface water or soil. Recent investigations indicated not only that several drugs are detectable in the effluent from sewage treatment plants, but also that several are not degraded and can reach ng 1−11 and μg l−1 concentrations in rivers and drinking water (Ollers et al. 2001; Zuccato et al. 2000).

E. Zuccato, S. Castiglioni, R. Fanelli, R. Bagnati, G. Reitano, D. Calamari

Chapter 32. Methodological Aspects Concerning the Environmental Risk Assessment for Medicinal Products — Research Challenges

The fate and behaviour of pharmaceuticals in the environment have been studied since several decades (Zondek and Sulman 1943; Soulides et al.1962; Tabak and Bunch 1970), and the presence and effects of residues in the environment is a concern that has been identified not long after that (Berland and Maestrini 1969; Manten 1971; Blume et al. 1976; Rurainski et al. 1977; Patten et al. 1980). More recently several reviews on use, emission, fate, occurrences and effects of pharmaceuticals have been published and at national and supra-national regulatory levels the environmental risks of pharmaceuticals are on the agenda (Roij and De Vries 1980; Römbke et al. 1996; Ternes 1999; Jørgensen and Halling-Sørensen 2000; Daughton and Jones-Lepp 2001; Kümmerer 2001; Dietrich 2002; Halling-Sørensen et al. 2002a; Boxall et al. 2004).

M. H. M. M. Montforts

Chapter 33. PPCPs in the Environment: Future Research — Beginning with the End Always in Mind

Pharmaceuticals and personal care products (PPCPs) are an extraordinarily diverse group of chemicals used in veterinary medicine, agricultural practice, and human health and cosmetic care. The various sources and origins of PPCPs as pollutants in the environment are depicted in the illustration “Origins and Fate of PPCPs” (available:ı/chemistry/pharma/images/drawing.pdf; note: all of the URLs cited in the text of this chapter are from the web site Daughton/EPA 2003a). PPCPs are ubiquitous pollutants, owing their origins in the environment to their worldwide, universal, frequent, and highly dispersed but cumulative usage by multitudes of individuals (and domestic animals) and from other uses such as pest control (e.g. seeı/chemistry/pharma/images/double-drugs.pdf). Therapeutic drugs in current use comprise more than 3 000 distinct bioactive chemical entities formulated (using a wide array of so-called inert “excipients”) into tens of thousands of registered end-use products; the definitive listings of drugs regulated in the US is maintained by the US FDA (2003). Personal care products contribute untold numbers of additional ingredients and formulations.

C. G. Daughton



Chapter 34. Conclusion

Drugs and medicines are characterised by their powerful effects and wide-ranging benefits in certain areas of application. However despite their beneficial therapeutic effects, some drugs affect organisms in the environment and ecosystems, and from the point of view of environmental hygiene, contamination of groundwater and drinking water is highly undesirable, even if the compounds involved have a low acute toxicity for humans. It is not clear whether the dynamics of bacterial population in the environment are influenced by the input of antibacterials and resistant bacteria. Our current knowledge shows that harmful effects for humans are not to be expected from the intake of pharmaceuticals with drinking water. As far as humans and organisms in the environment are concerned, the extent to which a comparison of a short-lived high dose (for diagnosis and treatment) and a long-term low dose (intake via drinking water) is permissible, is open to question, not least because of the polymorphic differences in sensitivity and the responsiveness of individual persons.

K. Kümmerer


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