| The OECD Program to Validate the Rat Uterotrophic Bioassay to Screen Compounds for in Vivo Estrogenic Responses: Phase 1 Jun Kanno,1 Lesley Onyon,2 Joseph Haseman,3 Penelope Fenner-Crisp,4 John Ashby,5 and William Owens6 1National Institute of Health Sciences, Tokyo, Japan
2Environment, Health and Safety Division, OECD, Paris, France
3National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
4U.S. Environmental Protection Agency, Washington, DC, USA
5Syngenta Central Toxicology Laboratory, Macclesfield, Cheshire, UK
6Procter & Gamble, Cincinnati, Ohio, USA Abstract
The Organisation for Economic Co-operation and Development has completed the first phase of an international validation program for the rodent uterotrophic bioassay. This uterotrophic bioassay is intended to identify the in vivo activity of compounds that are suspected agonists or antagonists of estrogen. This information could, for example, be used to help prioritize positive compounds for further testing. Using draft protocols, we tested and compared two model systems, the immature female rat and the adult ovariectomized rat. Data from 19 participating laboratories using a high-potency reference agonist, ethinyl estradiol (EE) , and an antagonist, ZM 189,154, indicate no substantive performance differences between models. All laboratories and all protocols successfully detected increases in uterine weights using EE in phase 1. These significant uterine weight increases were achieved under a variety of experimental conditions (e.g., strain, diet, housing protocol, bedding, vehicle) . For each protocol, there was generally good agreement among laboratories with regard to the actual EE doses both in producing the first significant increase in uterine weights and achieving the maximum uterine response. Furthermore, the Hill equation appears to model the dose response satisfactorily and indicates general agreement based on calculated effective dose (ED) 10 and ED50 within and among laboratories. The feasibility of an antagonist assay was also successfully demonstrated. Therefore, both models appear robust, reproducible, and transferable across laboratories for high-potency estrogen agonists such as EE. For the next phase of the OECD validation program, both models will be tested against a battery of weak, partial estrogen agonists. Key words: endocrine disruption, estrogen, rat uterus, uterotrophic. Environ Health Perspect 109:785-794 (2001) . [Online 3 August 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p785-794kanno/ abstract.html
Address correspondance to J.W. Owens, Human & Environmental Safety, The Procter & Gamble Company, PO Box 538707, Cincinnati, OH 45253-8707 USA. Telephone: (513) 627-1385. Fax: (513) 627-1208. E-mail: owens.jw@pg.com Address any correspondence or questions about the OECD Programme and OECD documents to L. Onyon, Environment Health and Safety Division, OECD, 2 rue André Pascal, 75775 Paris Cedex 16, France. Telephone: 33-1-45-24-0840. Fax: 33-1-45-24-1675. E-mail: lesley.onyon@oecd.org We acknowledge the dedicated efforts and work of the participating labs in generating these data: the Chemical Evaluation and Research Institute, Japan ; the Food Drug Safety Centre, Japan ; the Institute of Environmental Toxicology, Japan ; Mitsubishi Chemical Safety Institute, Japan ; Japan Bioassay Research Centre, Japan ; Sumitomo Chemical Company, Japan ; AstraZeneca Toxicology Laboratory (now Syngenta Central Toxicology Laboratory) , UK ; TNO, the Netherlands ; Research Institute of Chemical Technology, Korea ; WIL Research Laboratories, USA ; BASF, Germany ; BAYER-AG, Germany ; CIT, France ; Rhone-Poulenc, France ; Exxon Biomedical Sciences Inc., USA ; Free University of Berlin, Germany ; National Institute of Toxicological Research, Korea ; Huntingdon Life Sciences, UK ; Institute of Food Safety and Toxicology, Denmark. We also acknowledge E. Vindimian for suggesting and performing examples of the effective dose calculations based on the Hill equation, and especially Schering and AstraZeneca for donation of the reference chemicals. We thank H.B.W.M. Koëter of the OECD Secretariat and responsible manager of the Test Guidelines Programme for reviewing the manuscript. This paper represents the opinions of the authors and may not reflect the official policy of the OECD member countries or official U.S. Environmental Protection Agency policy. Received 10 January 2001 ; accepted 13 February 2001.
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