Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide.
Toxicology and carcinogenesis studies of hydrochlorothiazide, a benzothiadiazide diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 15-day, 13-week and 2-year studies. No rats died during the 15-day or 13-week studies at dietary concentrations of up to 50,000 ppm. Deaths of male mice in the top dose group in the 13-week study were likely to be related to chemical administration. In the prechronic studies, increased nephrosis and mineralization at the kidney corticomedullary junction were the primary toxic effects of hydrochlorothiazide observed in rats. In mice, chemical-related effects included nephrosis and calculi, inflammation and epithelial hyperplasia in the urinary bladder. In 2-year studies using dietary concentrations of 0, 250, 500 and 2000 ppm in rats and 0, 2500 and 5000 ppm in mice, survival of dosed and control groups of rats and mice was similar, as were body weights of mice. Dosed groups of male and female rats were uniformly lighter than controls (up to 25%) throughout the studies. Severe chronic renal disease with secondary parathyroid hyperplasia and fibrous osteodystrophy of the bone were attributed to chemical administration in rats. No neoplasms in rats or female mice or non-neoplastic lesions in mice were associated with hydrochlorothiazide. In high-dose male mice, liver neoplasms were increased but were not considered to be related to hydrochlorothiazide administration because of an unusually low incidence in the control group relative to historical controls.
Bucher
J R
JR
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Huff
J
J
Haseman
J K
JK
Eustis
S L
SL
Elwell
M R
MR
Davis
W E
WE
Meierhenry
E F
EF
D000232:Adenofibroma / Q000139:chemically induced; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000139:chemically induced; D004032:Diet; D004232:Diuretics / Q000633:toxicity*; D004435:Eating / Q000187:drug effects; D005260:Female; D006852:Hydrochlorothiazide / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D051379:Mice; D008815:Mice, Inbred Strains; D010282:Parathyroid Neoplasms / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004232:Diuretics; D006852:Hydrochlorothiazide