The OECD Program to Validate the Rat Hershberger Bioassay to Screen Compounds for in Vivo Androgen and Antiandrogen Responses. Phase 1: Use of a Potent Agonist and a Potent Antagonist to Test the Standardized Protocol

摘要

The Organisation for Economic Cooperation and Development (OECD) has completedphase 1 of the Hershberger validation intended to identify in vivo activity of suspected androgens and anti-androgens. Seventeen laboratoriesfrom 7 countries participated in phase 1, and results were collatedand evaluated by the OECD with the support of an international committeeof experts. Five androgen-responsive tissues (ventral prostate, pairedseminal vesicles and coagulating glands, levator ani and bulbocavernosusmuscles, glans penis, and paired Cowper’s or bulbourethralglands) were evaluated. The standardized protocols used selecteddoses of a reference androgen, testosterone propionate (TP), and anantiandrogen, flutamide (FLU). All laboratories successfully detectedTP-stimulated increases in androgen-responsive tissue weight and decreasesin TP-stimulated tissue weights when FLU was co-administered. Thestandardized protocols performed well under a variety of conditions (e.g., strain, diet, housing protocol, bedding). There was good agreementamong laboratories with regard to the TP doses inducing significantincreases in tissue weights and the FLU doses decreasing TP-stimulatedtissue weights. Several additional procedures (e.g., weighing of thedorsolateral prostate and fixation of tissues before weighing) and serumcomponent measurements (e.g., luteinizing hormone) were also includedby some laboratories to assess their potential utility. The resultsindicated that the OECD Hershberger protocol was robust, reproducible, andtransferable across laboratories. Based on this phase 1 validationstudy, the protocols have been refined, and the next phase of theOECD validation program will test the protocol with selected doses ofweak androgen agonists, androgen antagonists, a 5α-reductase inhibitor, andchemicals having no androgenic activity.