Experimental reproduction of itai-itai disease, a chronic cadmium poisoning of humans, in rats and monkeys.
To establish a useful animal model of Itai-Itai disease (IID) of humans, we conducted the following experiments. Experiment 1: Toxic effects of Cd were compared between ovariectomized (OX) and non-OX rats after daily, intravenous injection of cadmium (Cd) chloride for 14 days. In this experiment, we demonstrated that OX rats were more susceptible to Cd-induced nephrotoxicity and hepatotoxicity than non-OX rats. Experiment 2: OX rats were injected with Cd at doses of 1.0 and 2.0 mg/kg, 5 days a week, for 13 weeks. The bone Cd content was gradually increased for 13 weeks in a dose-dependent manner. Calcium and phosphorus contents in the bone and serum levels of parathyroid hormone and osteocalcin were not significantly different between Cd-treated and control rats. Mild osteomalacic lesions in the cortical bones of the midshaft haversian canals as well as chronic nephropathy appeared in the rats of the 2.0 mg/kg group. Experiment 3: OX rats were treated with Cd at doses of 0.5 and 0.05 mg/kg for 70 weeks. The rats of the 0.05 mg/kg group showed slight anemia and mild degeneration of tubular epithelium after 50 weeks of treatment. In the 0.5 mg/kg group, the rats showed definite osteomalacia of bones and nephrosclerosis. The Cd concentration in the bones increased for the first 25 weeks, but was replaced gradually with iron at from 50 to 70 weeks of the administration period. Iron deficiency anemia appeared in the 0.5 mg/kg group at from 12 to 25 weeks, and changed to renal anemia after 50 weeks of administration. The anemia at 50 and 70 weeks was normocytic and normochromic, and serum erythropoietin levels were not elevated in response to the decrease of hemoglobin concentrations of red blood cells. Experiment 4: Ten, OX cynomolgus monkeys were given intravenous injections of 0, 1.0 or 2.5 mg/kg/day Cd, 2 or 3 days per week, for 13 to 15 months. Normocytic and normochromic anemia, renal lesions characterized by tubular atrophy and interstitial fibrosis (Cd nephropathy), and bone lesions characterized by an increase of osteoid and osteopenia (Cd osteopathy) were induced in the monkeys treated with Cd. These results demonstrated that chronic cadmium toxicosis similar to IID of humans was reproducible in rats and monkeys by repeated intravenous injection of Cd and that a disease entity closely resembling IID of humans could be induced in experimental animals by chronic Cd toxicosis without participation of malnutrition, vitamin D deficiency, impaired absorption at the intestinal mucosa or multiparous birth.
Umemura
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Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. umemura@vetmed.hokudai.ac.jp
D000818:Animals; D002104:Cadmium / Q000008:administration & dosage; D002105:Cadmium Poisoning / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008252:Macaca fascicularis; D008854:Microscopy, Electron; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002104:Cadmium