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(54-05) Environmental Risk Assessment of Pharmaceutical Drug Substances - Conceptual Considerations. Laenge, Reinhard*,1, Dietrich, Daniel2, 1 Schering AG, Berlin, Germany2 University of Konstanz, Konstanz, Germany ABSTRACT- Drugs, active ingredients of human medicinal products, may be introduced into the environment after use in patients by sewage effluent pathways and consequently are detected at low concentrations in sewage effluents and in surface waters. Legal requirements in some geographical regions (Europe, US, Canada) demand environmental risk assessments (ERA) for new drug substances. However,those regulatory concepts of ERA are based initially on a set of short-term ecotoxicological studies in three to four different species, environmental behaviour and the application of assessment factors to correct for the ERA inherent uncertainty. Based on theoretical considerations and the experience with a very limited well investigated examples while considering that drugs are highly biologically active compounds, the appropriateness of this risk assessment procedure for all drug substances might be questioned. Indeed, e.g. long-term effects may occur at much lower concentrations and follow different toxicodynamic mechanism than extapolated from short-term studies, which thus cannot be corrected for with assessment factors. Although long-term tests with a variety of organisms would provide a complete data base for the evaluation of the environmental risks, this is inachievable for all drugs due to time, money and animal welfare constraints. In order to avoid unnecessary testing, a concept is presented, which makes use of pharmacological, toxicological, and pharmaco- and toxicokinetical and -dynamical information derived from mammals during drug substance development. Useful data for adoption in a case-by-case testing strategy can be obtained by evaluating (a) the pharmacological activity, which indicates specific targets in mammalian species and may allow for an analysis, whether a similar target is available in aquatic species; (b) the mammalian toxicity, which may indicate, which targets are most susceptible to adverse effects; (c) the difference between acute and chronic effects in mammals, since the magnitude of this difference may indicate, whether long-term effects are expected at significantly lower levels than acute effects; (d) the (pharmacologically and toxicologically) effective plasma levels in mammalian test organisms, which may be compared to the relevant exposure scenario for the environment. Key words: Environmental Risk Assessment, Pharmaceutical Drug Substances |
