title: Dose-response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats.
abstract: The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4-10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1mg/kg bw/day for males and <2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. goncalo.gamboa@fda.hhs.gov
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Jacob
authors.forename: Linda S
authors.initials: LS
authors.lastname: Von Tungeln
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Hasbrouck
authors.forename: Greg R
authors.initials: GR
authors.lastname: Olson
authors.forename: David G
authors.initials: DG
authors.lastname: Hattan
authors.forename: Renate
authors.initials: R
authors.lastname: Reimschuessel
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000502:physiology; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006651:Histocytochemistry; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D014227:Triazines / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D014227:Triazines; C071913:melamine cyanurate; D003404:Creatinine