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Jun Kanno,¹ Lesley Onyon,² Shyamal Peddada,³ John Ashby,⁴ Elard Jacob,⁵ and William Owens⁶

¹National Institute of Health Sciences, Tokyo, Japan; ²Environmental Health and Safety Division, Organisation for Economic Co-operation and Development, Paris, France; ³National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; ⁴Syngenta Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom; ⁵BASF Aktiengesellschaft, Ludwigshafen, Germany; ⁶Procter & Gamble Company, Cincinnati, Ohio, USA

Abstract
The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. The purpose of the validation program was to demonstrate the performance of two versions of the uterotrophic bioassay, the immature female rat and the adult ovariectomized rat, in four standardized protocols. This article reports the dose-response studies of the validation program ; the coded single-dose studies are reported in an accompanying paper. The dose-response study design used five selected weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p´-DDT. These weak agonists were administered in a prescribed series of doses to measure the performance and reproducibility of the protocols among the participating laboratories. All protocols successfully detected increases in uterine weights when the weak agonists were administered. Within each protocol, there was good agreement and reproducibility of the dose response among laboratories with each substance. Substance-specific variations were observed in the influence of the route of administration on the uterine response, the potency as related to the dose producing the first statistically significant increase in uterine weights, and the maximum increase in uterine weight. Substantive performance differences were not observed between the uterotrophic bioassay versions or among the standardized protocols, and these were judged to be qualitatively equivalent. It is noteworthy that these results were reproducible under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age) , indicating that the bioassay's performance as a screen is robust. In conclusion, both the intact, immature, and adult OVX versions, and all protocols appear to be reproducible and transferable across laboratories and are able to detect weak estrogen agonists. Key words: endocrine disruption, estrogen, rat uterus, uterotrophic. Environ Health Perspect 111:1530-1549 (2003) . doi:10.1289/ehp.5780 available via http://dx.doi.org/ [Online 23 January 2003]