| Accurate Prediction of the Response of Freshwater Fish to a Mixture of Estrogenic Chemicals Jayne V. Brian,1 Catherine A. Harris,1 Martin Scholze,2 Thomas Backhaus,3 Petra Booy,4 Marja Lamoree,4 Giulio Pojana,5 Niels Jonkers,5 Tamsin Runnalls,1 Angela Bonfà,5 Antonio Marcomini,5 and John P. Sumpter1 1Institute for the Environment, Brunel University, Uxbridge, Middlesex, United Kingdom; 2Centre for Toxicology, School of Pharmacy, London, United Kingdom; 3Department of Biology and Chemistry, University of Bremen, Bremen, Germany; 4Institute for Environmental Studies, Vrije Universiteit, The Netherlands; 5Department of Environmental Sciences, University of Venice, Venice, Italy Abstract
Existing environmental risk assessment procedures are limited in their ability to evaluate the combined effects of chemical mixtures. We investigated the implications of this by analyzing the combined effects of a multicomponent mixture of five estrogenic chemicals using vitellogenin induction in male fathead minnows as an end point. The mixture consisted of estradiol, ethynylestradiol, nonylphenol, octylphenol, and bisphenol A. We determined concentration-response curves for each of the chemicals individually. The chemicals were then combined at equipotent concentrations and the mixture tested using fixed-ratio design. The effects of the mixture were compared with those predicted by the model of concentration addition using biomathematical methods, which revealed that there was no deviation between the observed and predicted effects of the mixture. These findings demonstrate that estrogenic chemicals have the capacity to act together in an additive manner and that their combined effects can be accurately predicted by concentration addition. We also explored the potential for mixture effects at low concentrations by exposing the fish to each chemical at one-fifth of its median effective concentration (EC50) . Individually, the chemicals did not induce a significant response, although their combined effects were consistent with the predictions of concentration addition. This demonstrates the potential for estrogenic chemicals to act additively at environmentally relevant concentrations. These findings highlight the potential for existing environmental risk assessment procedures to underestimate the hazard posed by mixtures of chemicals that act via a similar mode of action, thereby leading to erroneous conclusions of absence of risk. Key words: concentration addition, estrogen, estrogen mimic, fathead minnow, mixture effects, Pimephales promelas, prediction. Environ Health Perspect 113: 721-728 (2005) . doi:10.1289/ehp.7598 available via http://dx.doi.org/ [Online 14 March 2005]
Address correspondence to J.V. Brian, Institute for the Environment, Brunel University, Uxbridge, Middlesex, UB8 3PH, United Kingdom. Telephone: 44-1895-266-264. Fax: 44-1895-269-761. E-mail: jayne.brian@brunel.ac.uk The research presented here is part of the ACE (Analysing combination effects of mixtures of estrogenic chemicals in marine and freshwater organisms) project, which is funded by the European Commission under the 5th Framework Programme (contract EVK1-2001-00091) . The authors declare they have no competing financial interests. Received 23 September 2004 ; accepted 14 March 2005.
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