title: Urinary physiologic and chemical metabolic effects on the urothelial cytotoxicity and potential DNA adducts of o-phenylphenol in male rats.
abstract: ortho-Phenylphenol (OPP), a fungicide and antibacterial agent with food residues, is carcinogenic to rat bladder. The present studies provide information on changes in urinary composition and urinary metabolites, urothelial cytotoxicity and regenerative hyperplasia, and DNA adducts in male F344 rats fed OPP. An initial experiment evaluated dietary doses of 0, 1,000, 4,000, and 12,500 ppm OPP fed for 13 weeks. There was no evidence of urinary calculi, microcrystalluria, or calcium phosphate-containing precipitate, but urothelial cytotoxicity and hyperplasia occurred at the highest dose only. In a second experiment, rats were fed dietary OPP levels of 0, 800, 4,000, 8,000, and 12,500 ppm. Urinary pH was > 7 in all groups. Urinary volume was increased at the 2 highest doses with consequent decreases in osmolality, creatinine, and other solutes. Total urinary OPP metabolite excretions were increased, mostly excreted as conjugates of OPP and of phenylhydroquinone. Free OPP or free metabolites accounted for less than 2% excreted in the urine without a dose response. Urothelial toxicity and hyperplasia occurred only at doses of 8,000 and 12,500 ppm. OPP-DNA adducts were not detected in the urothelium at any dose. In summary, OPP produces cytotoxicity and proliferation of the urothelium at dietary doses > or = 8,000 ppm without formation of urinary solids. The paucity of unconjugated metabolites and the lack of OPP-DNA adducts suggests that OPP is acting as a bladder carcinogen in male rats by inducing cytotoxicity and hyperplasia without it or its metabolites directly binding to DNA.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.forename: W R
authors.initials: WR
authors.lastname: Christenson
authors.forename: M J
authors.initials: MJ
authors.lastname: Bartels
authors.forename: L L
authors.initials: LL
authors.lastname: Arnold
authors.forename: M K
authors.initials: MK
authors.lastname: St John
authors.forename: M
authors.initials: M
authors.lastname: Cano
authors.forename: E M
authors.initials: EM
authors.lastname: Garland
authors.forename: S G
authors.initials: SG
authors.lastname: Lake
authors.forename: B S
authors.initials: BS
authors.lastname: Wahle
authors.forename: D A
authors.initials: DA
authors.lastname: McNett
authors.forename: S M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000648:ultrastructure; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D006965:Hyperplasia / Q000139:chemically induced; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D001713:Biphenyl Compounds; D002273:Carcinogens; D018736:DNA Adducts; D005659:Fungicides, Industrial; C004369:2-phenylphenol