The chronic toxicity of bromovinyldeoxyuridine in beagle dogs.
Bromovinyldeoxyuridine (BVDU), a substituted pyrimidine analog with antiviral activity, was given orally to beagle dogs (6/sex/dosage) at dosages of 0, 5, 12, and 30 mg/kg/day for 52 weeks. Complete physical examinations, including ECG recordings and rectal temperature measurements, and clinical laboratory determinations were performed every 13 weeks. At the end of the dosing period, 4 dogs/sex/dosage were sacrificed and complete gross and microscopic examinations performed. The remaining 2 dogs/sex/dosage were sacrificed following a 13-week recovery period. BVDU had no effect on feed consumption, respiration, body temperature, or heart rate. At 30 mg/kg, males gained less weight than controls. At 12 mg/kg (males) and 30 mg/kg (both sexes) there were slight, but statistically significant decreases in mean corpuscular volume, but no changes in red blood cell (RBC) count, hematocrit, or hemoglobin, and no evidence of reticulocytosis. In males dosed at 30 mg/kg, during the last 6 months of dosing, partial thromboplastin times, serum alanine aminotransferase, and alkaline phosphatase increased, and cholesterol decreased. Histologically, bile ductule hyperplasia and gall bladder epithelial hyperplasia were present at 12 and 30 mg/kg in both sexes at the end of both the dosing and recovery periods. At 30 mg/kg, bone marrow hypocellularity and testicular germ cell atrophy were also present in males. Thus, the liver and gall bladder are the major target organs of chronically administered BVDU in dogs. BVDU causes degenerative and proliferative hepatobiliary damage, and secondarily causes changes in clinical chemical parameters. At higher dosages, there are hypoplastic and degenerative changes in the bone marrow and testes.
Chengelis
C P
CP
Department of Product Safety Assessment, G.D. Searle Research & Development, Skokie, Illinois 60077.
Port
C D
CD
Dickie
B C
BC
D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D005260:Female; D008099:Liver / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D012737:Sex Factors; D013997:Time Factors
D000998:Antiviral Agents; C020235:brivudine; D001973:Bromodeoxyuridine