title: Dose-response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats.
abstract: Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a herbicide that induced urothelial tumors in the urinary bladder of Wistar rats fed 2500ppm during a long-term study. The currently suggested non-genotoxic mode of action (MOA) of diuron encompasses in succession urothelial necrosis induced by direct cytotoxicity, regenerative cell proliferation and sustained urothelial hyperplasia that increases the likelihood of neoplasia development. This study evaluated the dose-response profile of urothelial histological and ultrastructural lesions induced by diuron. Sixty male Wistar rats were fed ad libitum diuron mixed in the diet at 0, 60, 125, 500, 1250, or 2500ppm for 20 weeks. The incidences of urothelial simple hyperplasia and the cell proliferation index were significantly increased in the diuron-fed 1250 and 2500ppm groups. By scanning electron microscopy, the incidences and severity of lesions were significantly increased in the 500 and 1250ppm groups. The incidences of urothelial hyperplasia in the kidney pelvis were significantly increased in the 500, 1250 and 2500ppm groups. The present study documents the dose-response influence of diuron on the rat urothelium, with a no observed effect level (NOEL) at 125ppm; 1250ppm was as effective as 2500ppm at inducing urothelial lesions.
authors.affiliation: Center for the Evaluation of the Environmental Impact on Human Health (TOXICAM), Department of Pathology, Botucatu Medical School, UNESP - São Paulo State University, Botucatu 18618-970, São Paulo, Brazil. Electronic address: anaferragut@fmb.unesp.br.
authors.forename: Ana Paula Ferragut
authors.initials: AP
authors.lastname: Cardoso
authors.forename: Shadia Muhammad
authors.initials: SM
authors.lastname: Ihlaseh Catalano
authors.forename: Mitscheli Sanches
authors.initials: MS
authors.lastname: da Rocha
authors.forename: Merielen Garcia
authors.initials: MG
authors.lastname: Nascimento E Pontes
authors.forename: João Lauro Viana
authors.initials: JL
authors.lastname: de Camargo
authors.forename: Maria Luiza Cotrim Sartor
authors.initials: ML
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D004237:Diuron / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D008855:Microscopy, Electron, Scanning; D009092:Mucous Membrane / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure
chemical_list: D006540:Herbicides; D004237:Diuron
keywords: ANOVA; BrdU; Cell proliferation; Cytotoxicity; Diuron; Dose–response; H&E; LI; LM; LOAEL; MOA; NOAEL; NOEL; PCNA; PNH; Rat urothelial hyperplasia; SEM; SH; Scanning electron microscopy; U.S. Environmental Protection Agency; USEPA; analysis of variance; bromodeoxyuridine; hematoxylin and eosin; labeling index; light microscopy; lowest observed adverse effect level; mode of action; no observed adverse effect level; no observed effect level; papillary and nodular hyperplasia; proliferating cell nuclear antigen; scanning electron microscopy; simple hyperplasia