title: Vinclozolin: a case study on the identification of endocrine active substances in the past and a future perspective.
abstract: In the late 1980s vinclozolin was tested for prenatal developmental toxicity in rats for registration purposes in USA. At 1000mg/kgbw, 95% of all fetuses were female upon visual inspection (ano-genital distance determination). Anti-androgenic effects (AA) were also noted in a subsequent 2-generation study. These findings triggered mechanistic investigations at BASF and at US-EPA. Results published by the latter were the starting point of the endocrine disruption (ED) discussion in the 1990s. AA effects of vinclozolin are mediated by two metabolites, which have an antagonistic effect on the androgen receptor. Currently, determination of ED has become a major end-point in toxicology testing and the US-EPA has set up an elaborated testing paradigm to fulfill this requirement. Future screening for ED can be improved making use of new technologies. ED modes of action can be determined by three alternative (3R) methods. Steroid synthesis in H295R cells (1), androgen-receptor binding in modified yeast (2) and metabolomics (3). Using vinclozolin as a case study, results indicate: (1) an effect on steroid synthesis in vitro, (2) an antagonistic effect on the androgen receptor and (3) that the metabolome profile of vinclozolin is similar to that of other receptor mediated anti-androgens (e.g. flutamide).
authors.affiliation: BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
authors.forename: Susanne N
authors.initials: SN
authors.lastname: Kolle
authors.forename: Tzutzuy
authors.initials: T
authors.lastname: Ramirez
authors.forename: Hennicke G
authors.initials: HG
authors.lastname: Kamp
mesh_terms: D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D052244:Endocrine Disruptors / Q000493:pharmacokinetics / Q000633:toxicity*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D010080:Oxazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D018675:Toxicity Tests / Q000266:history* / Q000639:trends
chemical_list: D000726:Androgen Antagonists; D052244:Endocrine Disruptors; D010080:Oxazoles; C025643:vinclozolin
keywords: Endocrine; In vitro; Metabolome analysis; Strategy; Vinclozolin