Summary of Workshop on Mixtures
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Reinhard Laenge, PhD Schering AG, Germany Henry Stemplewski Preclinical Assessor Medicines and Healthcare Products Regulatory Agency, UK
Summary of Workshop on Mixtures
THE ISSUE Concentrations of individual pharmaceutical compounds occur mainly below known effect levels. Present hazard and risk assessment procedures consider generally each compound individually. The effect of pharmaceutical mixtures with similar or different modes of (pharmacological or toxicological) action on wildlife organisms is presently unknown. Appropriate methods and models are required to determine whether mixtures represent a risk below concentrations of their individual effect thresholds. In a regulatory context, adequate guidance is needed to evaluate the potential environmental risk of pharmaceutical compounds.
GENERAL REMARKS In general, neither the exposure nor the effects of mixtures of chemicals and, especially, of human pharmaceuticals have been investigated to a great extent. Although pharmaceuticals occur only at very low concentrations in the environment, there is concern that the combination effects of those compounds may be of greater potential risk to the environment than that of individual compounds. However, the database for the assessment of those mixtures is extremely small, and validated methodology for such an assessment is not available.
Mixtures could be assessed in various ways, depending on the purpose of the assessment and the properties of the components. A widely used approach to assess mixtures with unknown constitution is the so-called whole-mixture approach, which is used under regulatory regimes for the assessment of industrial or municipal effluents (whole-effluent testing, WET). This approach is strictly effect driven; that is, the mixture (effluent) is tested for biological effects in various taxonomic groups of organisms and regardless of type of components constituting the mixture. For the further identification of compounds resulting in effects observed in WET testing, toxicity identification and evaluation techniques, including chemical analysis and biological assays, can be employed. These approaches were successfully used to identify the causes of estrogenic effects from municipal wastewater treatment plant effluents in England (1). To assess prospectively the ecotoxicity of mixtures, two basic concepts can be applied: concentration addition and independent action. The concentration addition approach is based on the assumption that the components of a mixture act in a similar way, that is, have similar targets for (eco)toxicological action. This means that even substances occurring below effects levels individually can in combination produce
Drug Information Journal, Vol. 41, pp. 211–212, 2007 • 0092-8615/2007 Printed in the USA. All rights reserved. Copyright © 2007 Drug Information Association, Inc.
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adverse effects in environmental organisms (2). This concept seems to be a feasible approach when assessing mixtures of pharmaceutical compounds with similar
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