title: Investigations of putative reproductive toxicity of low-dose exposures to flutamide in Wistar rats.
abstract: The current investigation examines whether the model anti-androgenic substance flutamide is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen, which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology, and histopathological examinations. Doses were chosen to represent a clear effect level (2.5 mg/kg bw/d), a low endocrine effect level (LOAEL, 0.25 mg/kg bw/d), a NOAEL for endocrine effects (0.025 mg/kg bw/d), a further dose at 0.0025 mg/kg bw/d flutamide, as well as an "ADI" (0.00025 mg/kg bw/d or 100-fold below the NOAEL) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at LOAEL and the clear effect dose level but not at lower exposures. Nipple retention appeared to be the most sensitive measure of anti-androgenic effects, followed by age at sexual maturation, anogenital distance/anogenital index and male sex organ weights, as well as gross and histopathological findings. The results of all five doses indicate the absence of evidence for effects at very low dose levels. A non-monotonic dose-response relationship was not evident for the anti-androgenic drug flutamide.
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Karma C
authors.initials: KC
authors.lastname: Fussell
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Buesen
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Groeters
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Strauss
authors.affiliation: Product Safety, Regulations, Toxicology and Ecology, BASF SE, Ludwigshafen am Rhein, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Melching-Kollmuss
authors.affiliation: Experimental Toxicology and Ecology, BASF SE, 67056, Ludwigshafen am Rhein, Germany. bennard.ravenzwaay@basf.com.
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D012737:Sex Factors
chemical_list: D000726:Androgen Antagonists; D005485:Flutamide
keywords: Anti-androgenic; Endocrine disruptor; Flutamide; Low dose; Non-monotonic dose response