title: OECD validation of the Hershberger assay in Japan: phase 2 dose response of methyltestosterone, vinclozolin, and p,p'-DDE.
abstract: The Organisation for Economic Co-operation and Development has initiated the development of new guidelines for the screening and testing of potential endocrine disruptors. The Hershberger assay is one of the assays selected for validation based on the need for in vivo screening to detect androgen agonists or antagonists by measuring the response of five sex accessory organs and tissues of castrated juvenile male rats: the ventral prostate, the seminal vesicles with coagulating glands, the levator ani and bulbocavernosus muscle complex, the Cowper's glands, and the glans penis. The phase 1 feasibility demonstration stage of the Hershberger validation program has been successfully completed with a single androgen agonist and a single antagonist as reference substances. The phase 2 validation program employs a range of additional androgen agonists and antagonists as well as 5alpha-reductase inhibitors. Seven Japanese laboratories have contributed phase 2 validation studies of the Hershberger assay using methyltestosterone, vinclozolin, and 2,2-bis (4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE). The methyltestosterone doses were 0, 0.05, 0.5, 5, and 50 mg/kg/day, and the vinclozolin and p,p'-DDE doses were 0, 3, 10, 30, and 100 mg/kg/day. All chemicals were orally administered by gavage for 10 consecutive days. In the antagonist version of the assay using vinclozolin and p,p'-DDE, 0.2 mg/kg/day of testosterone propionate was coadministered by subcutaneous injection. All five accessory sex preproductive organs and tissues consistently responded with statistically significant changes in weight within a narrow window. Therefore, the Japanese studies support the Hershberger assay as a reliable and reproducible screening assay for the detection of androgen agonistic and antagonistic effects.
authors.affiliation: Chemicals Assessment Center, Chemicals Evaluation and Research Institute, Hita, Oita, Japan. yamasaki-kanji@ceri.jp
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Masakuni
authors.initials: M
authors.lastname: Sawaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Ohta
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okuda
authors.forename: Seiichi
authors.initials: S
authors.lastname: Katayama
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamada
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ohta
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kosaka
authors.forename: William
authors.initials: W
authors.lastname: Owens
mesh_terms: D000726:Androgen Antagonists / Q000633:toxicity*; D000818:Animals; D001681:Biological Assay / Q000592:standards*; D001835:Body Weight / Q000187:drug effects; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005835:Genitalia / Q000187:drug effects / Q000473:pathology; D007390:International Agencies; D007564:Japan; D008297:Male; D008777:Methyltestosterone / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010080:Oxazoles / Q000633:toxicity*; D051381:Rats; D015203:Reproducibility of Results
chemical_list: D000726:Androgen Antagonists; D010080:Oxazoles; D003633:Dichlorodiphenyl Dichloroethylene; C025643:vinclozolin; D008777:Methyltestosterone