Introduction to the special issue on environmental risk assessment of pharmaceuticals

The widespread detection of a large variety of pharmaceuticals in the environment has raised concern in the European Union (EU) and elsewhere about the potential impact of these bioactive substances on the environment (Halling-Sørensen et al. 1998; Daughton and Ternes 1999; Zuccato 2000; Jones et al. 2001; Heberer 2002; Kolpin et al. 2002; Santos et al. 2010). At present, the approvals for new human and veterinary pharmaceutical products in the EU require an assessment of potential environmental risks related to their use, in addition to the evaluation of health and safety aspects, efficacy, and quality of products (Laenge et al. 2006; Koschorreck and Hickmann 2008). The current guidance by the European Medicines Agency (EMEA) describes the risk assessment for both human and veterinary pharmaceutical products as a 2-tiered assessment involving predictions based on various environmental exposure scenarios and subsequent environmental fate and effects testing (EMEA/CHMP 2006; EMEA/CVMP 2008). During the past few years, our understanding of the fate and effects of pharmaceuticals in the environment has progressed significantly (Kümmerer 2008; Crane et al. 2009). However, there are a number of uncertainties concerning the assessment of potential exposure and the effects of pharmaceuticals on organisms in the environment that have to be addressed before risks can be fully evaluated. For example, the potentially important exposure routes for veterinary drugs from pasture animals and pharmaceuticals for human use through the application of sewage sludge to land have hardly been studied. Furthermore, most ecotoxicity studies with human and veterinary pharmaceuticals have focused on short-term assays with single species, despite the fact that for many pharmaceuticals, a long-term, low-level exposure situation is more realistic. Thus, there is a need to further investigate and in a systematic manner the effects of pharmaceuticals on individual species, communities, and ecosystems. The focus of this special issue of Integrated Environmental Assessment and Management (IEAM) is to communicate to the scientific and regulatory community some key results of the project Environmental Risk Assessment of Pharmaceuticals (ERAPharm) that was funded within the Sixth Framework Programme of the European Union (project SSPI-CT-2003-511135) between October, 2004, and September, 2007. The objective of the ERAPharm project was to advance existing knowledge and methods for evaluating the potential risks that human and veterinary pharmaceuticals pose to the environment and to provide recommendations on how to improve environmental risk assessment procedures for human and veterinary pharmaceuticals. The ERAPharm consortium included representatives from the regulatory authorities (Federal Environment Agency, Germany), the pharmaceutical industry (AstraZeneca UK Ltd., United Kingdom), national research institutes (Federal Institute of Hydrology, Germany; Cemagref, France; Eawag, Switzerland; INIA, Spain), universities (Aarhus University, Denmark; Brunel University, United Kingdom; Copenhagen University, Denmark; University of York, United Kingdom; Utrecht University, The Netherlands), the Canadian Water Network, and small and medium-sized enterprises (Geotechnisches Institut AG, Switzerland; ECT Oekotoxikologie GmbH, Germany). In addition, representatives from 10 stakeholders participated in ERAPharm meetings and contributed to the project: Novartis Pharma (Switzerland), The Danish Medicines Agency, Bayer Schering Pharma (Germany), Commission des Toxiques, Ministère de l'Agriculture (France), Stockholm County Council and Health Care Without Harm (Sweden), F. Hoffmann-La Roche (Switzerland), Environment Agency (United Kingdom), Veterinary Medicines Directorate (United Kingdom), Institute for Veterinary Medicinal Products (Hungary), and Health Canada. The work addressing the specific objectives of ERAPharm was organized into 8 work packages dealing with environmental fate processes, fate and exposure models, bioanalytical screening assays, effects of pharmaceuticals on microorganisms, effects on terrestrial and aquatic invertebrates and fish, and environmental risk assessment. A considerable amount of work within the project focused on 3 case studies; 2 focused on human pharmaceuticals, the β-blocker atenolol (Küster et al. 2010) and the antidepressant fluoxetine (Oakes et al. 2010), and the third on a veterinary parasiticide, ivermectin (Liebig et al. 2010). For these 3 compounds, environmental risk assessments were performed to evaluate and highlight the strengths and weaknesses of the existing European guidelines on environmental risk assessment of pharmaceuticals. Küster et al. (2010) demonstrated that the β-adrenergic receptor blocker atenolol did not reveal any unacceptable risk to the environment when applying the assessment rules according to the European guideline (EMEA/CHMP 2006). Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm, which confirmed the outcome of the standard environmental risk assessment. However, atenolol should not be considered as representative for other β-blockers, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Oakes et al. (2010) showed that there was considerable uncertainty in the exposure assessment for the serotonin reuptake inhibitor fluoxetine, insofar as a large proportion of this compound may be present in the cationic form at the pH of natural waters, and the methods for determining the partition coefficients (e.g., KOW, KOC), on which the exposure assessment heavily relies, have been developed primarily for nonionic compounds. Nonetheless, the risk assessment showed a possible risk to aquatic organisms chronically exposed to this antidepressant. Working with the veterinary parasiticide ivermectin, Liebig et al. (2010) identified unacceptable risks for all investigated environmental compartments and hence suggest that a reassessment of ivermectin-containing products is necessary, inasmuch as previously performed environmental risk assessments for this compound showed no concern for the aquatic environment and only transient effects on dung-insect populations in the terrestrial environment. Also, the case study with ivermection revealed several shortcomings of the European standard guideline (EMEA/CVMP, 2008). Supplementing the ERAPharm efforts, Straub (2010) has included an environmental risk assessment of the cytostatic human pharmaceutical 5-fluorouracil and its prodrug capecitabine in this special series of papers. The work offers another important example of the application of European guidelines to environmental risk assessment of pharmaceuticals. Straub (2010) concluded that the current use of capecitabine and 5-fluorouracil does not present any risk to the environment. An additional evaluation of persistence, bioaccumulation, and toxicity properties supports the conclusion that there is no significant environmental risk from human use of this cytostatic pharmaceutical. In addition to the case studies, several important aspects of the environmental risk assessment process were addressed by ERAPharm scientists collaborating in technical working groups. Schmitt et al. (2010) critically evaluated the concept of action limits, which stipulate that effects testing of pharmaceuticals is required only when the first step of the assessment shows that the predicted environmental concentrations are above certain threshold concentrations; the authors concluded that effects testing should be mandatory for pharmaceuticals under several circumstances, including situations in which the drug targets biological functions that are conserved across species, has a high potency or a small therapeutic margin, is from a new therapeutic class, or is structurally similar to other compounds with known effects. Taking into account that pharmaceuticals belong to the category of data-rich substances; are biologically highly active; and are relatively hydrophilic, polar, or charged compounds, Tarazona et al. (2010) presented a conceptual approach for a targeted environmental risk assessment that reduces the uncertainties of risk characterization by using the information provided in the nonenvironmental part of the regulatory dossier for pharmaceuticals. Three steps were defined for the conceptual approach: 1) collation of specific information contained in the regulatory dossiers for pharmaceuticals, 2) evaluation of this information with regard to environmental compartments likely to be exposed and organisms likely to be affected, and 3) selection of single- and/or multispecies tests to generate additional information for the ecotoxicological risk characterization of pharmaceuticals. During the 3 y of ERAPharm, partners and stakeholders contributed to intensive interdisciplinary discussions of both scientific and regulatory issues. ERAPharm members were involved in several international committees, including professional advisory groups in the Society of Environmental Toxicology and Chemistry (SETAC). Through these supplementary meetings and technical outreach efforts, ERAPharm members were able to promote and integrate the findings of the ERAPharm program into related science and policy arenas. Other efforts included the introduction of advanced test protocols for assessing the fate and effects of pharmaceuticals to the Organisation for Economic Co-operation and Development (OECD). The protocols were developed as part of the ERAPharm project. ERAPharm also recommended improvements to methods for environmental risk assessment of pharmaceuticals to working groups of the European Food Safety Authority (EFSA) and the European Medicines Agency (EMEA). Representatives of the Canadian regulatory agencies regarded their participation as helpful to the ongoing development of Canadian environmental regulations for personal care products and pharmaceuticals. The ERAPharm program culminated in the technical conference Pharmaceuticals in the Environment hosted in York, United Kingdom, by Central Science Laboratory on 19 to 21 September, 2007. Attended by more than 100 scientists and stakeholders from throughout Europe, Canada, the United States, and elsewhere, the conference highlighted the path forward for improvement of risk assessment practices and environmental studies to better understand the fate and effects of human and veterinary pharmaceuticals in the environment. Many of the results generated from the ERAPharm project have been published in numerous scientific articles and presented at technical and science policy conferences (see www.erapharm.org). As the project coordinator (Thomas Knacker), I thank the 3 scientific officers from the European Commission who supported ERAPharm at different stages of the program: Kirsi Haavisto during the contract negotiations, Jürgen Büsing during the productive technical phase of the project, and Georges Deschamps during the final reporting stage. In addition, I wish to thank all partners and stakeholders for their very enjoyable and productive interdisciplinary cooperation. Finally, it is a great pleasure for me to acknowledge the outstanding performance of my colleagues Karen Duis and Anja Coors as members of the coordination team of ERAPharm. As guest editors, Chris Metcalfe and I express our appreciation to the first and corresponding authors of the articles included in this IEAM special series. This work benefited greatly from their leadership and expertise throughout the process of completing the work and preparing papers for peer review and publication. Last but not least, we acknowledge the professional and friendly support provided by Richard Wenning, Editor-in-Chief, and Jenny Shaw, Managing Editor, at IEAM for their guidance through the submission, review, and production process of this special series of papers.

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