Re-evaluation of the first synthetic estrogen, 1-keto-1,2,3,4-tetrahydrophenanthrene, and bisphenol A, using both the ovariectomised rat model used in 1933 and additional assays

1-Keto-1,2,3,4-tetrahydrophenanthrene (THP-1) was reported by Cook et al. i n 1933 as the first synthetic estrogen. Estrogenic activity was assessed by the induction of vaginal cornification in ovariectomised rats. The corresp onding 4-isomer (THP-4) was shown to be inactive. Both chemicals have been re-synthesised and assessed for hormonal activity. Each chemical bound weak ly and to the same extent to isolated estrogen receptors, but only at high concentrations. However, they each lacked estrogenic or anti-estrogenic act ivity when evaluated in vitro using a yeast hER assay, and both failed to i nduce vaginal cornification or uterotrophic effects in ovariectomised rats. THP-I, and to a lesser extent THP-4, were shown to possess weak androgenic and anti-androgenic activity in vitro when evaluated using an hAR yeast as say. Estrogenic activity for bisphenol A (BPA) was subsequently demonstrate d by [Dodds and Lawson. Synthetic, oestrogenic agents without the phenanthr ene nucleus, Nature 137, (1936)1 using the same ovariectomised rat protocol , and this activity has been confirmed and supplemented by positive uterotr ophic effects for BPA in the same bioassays. The present results illustrate the complexity of deriving conclusions regarding the hormonal activities o f chemicals. First, some activities observed in isolated hormonal receptor binding assays may not be expressed in functional hormonal assays. This ind icates the need for functional hormonal assays in any screening programme. Second, that activities observed for a chemical in one hormonal assay may n ot be reflected in related hormonal assays. This indicates the need to defi ne assay protocols with some precision when incorporating them into screeni ng batteries. Finally, that some literature reports of hormonal activity fo r chemicals may not be capable of independent confirmation under apparently identical conditions of test. This illustrates the need to use lists of ho rmonally active chemicals with care. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.