Investigations of dose, age, and duration of administration on the hepatorenal damage induced in mice by cultural products of Penicillium viridicatum

The following studies were completed in mice fed rice cultures of P. viridicatum: the approximate LD50-14 days, age susceptibility, life span, and pathogenesis of hepatorenal damage. Mice were fed the dried, ground rice culture mixed with a purified diet at concentrations from 2.5 to 30%. Diets producing mortalities closest to 50% were those containing 10 and 15% concentrations of the rice culture. In the age susceptibility study, mice of ages 2–18 wk were fed a diet containing 50% rice culture of P. viridicatum. Although mortality was not great in groups older than 6 wk of age, weight loss, and lowering of packed cell volume occurred in all groups fed the fungal diets. Older mice did not become resistant to the toxic effects of P. viridicatum because hepatic and renal lesions were observed in mice of ages 8, 10, 14, and 18 wk. These hepatic lesions were centered in the biliary system and included necrotizing cholangitis, bile duct proliferation, periductal fibrosis, and ductal ectasia. Hepatic cell changes included marked variation in size and shape of nuclei, bizarre mitotic figures, and multinucleated cells. To provide data on the life span of test mice, mice were fed rice cultures at a 7.5% concentration in the diet. Clinical signs of toxicity included anemia, jaundice, and high mortality. None survived beyond 9 wk of feeding. Most of the mice had hepatic focal necrosis and bile duct proliferation. Tubular necrosis was present in most of the kidneys. The development of the hepatorenal lesions was followed in mice fed 5% P. viridicatum diets and killed after 1–24 wk of feeding. Most of the mice presented signs of toxicity such as roughened hair coats early and many were anemic after 7 wk of feeding. Body weights of test groups were always less than controls. Hepatic changes progressed from perilobular, hydropic, and fatty degeneration of hepatocytes to necrotizing cholangitis followed by hepatic cell necrosis. In more chronically fed mice, proliferation of bile duct cells was accompanied by bile duct hyperplasia and periductal fibrosis, and these changes were followed by bile duct ectasia with loss of hepatic parenchyma. The nuclear alterations in hepatocytes were similar to those described in mice of the age susceptibility study.