Sequential changes in the development of the pancreatic lesion of zinc toxicosis in sheep

Forty-two 10-month-old castrated male sheep were dosed with zinc oxide to study the pathogenesis of the pancreatic lesion. For 4 weeks, the sheep were dosed three times per week with 240 mg Zn (as ZnO)/kg body weight/dose, and seven groups of six sheep each were necropsied at 4, 7, 14, 21, 28, 56, and 112 days after the start of dosing. Plasma zinc concentrations rose rapidly to 2.0-2.5 micrograms Zn/ml over the dosing period and fell rapidly to less than 1 microgram Zn/ml within 2 weeks after dosing ceased. Organ zinc levels in liver, kidney, and pancreas fell from concentrations above 800 micrograms Zn/g (dry matter basis) to less than 200 micrograms/g within 4 weeks after dosing ceased. Although no animals showed any clinical signs of zinc toxicity, many sheep dosed with zinc oxide developed pancreatic lesions. Pancreatic lesions took up to 4 weeks to develop fully. The early pancreatic lesions involved necrosis of the pancreatic duct epithelium, periductular inflammation, and interlobular fat necrosis, all evident at 7 days but not at 4 days. These early lesions were followed by edema, lobular cystic change, atrophy, fibrosis, and a ductular hyperplasia. The initial lesion of the pancreas was ductular injury, and the subsequent pancreatic lesions may have developed in those lobules whose excretory ducts were obstructed by inflammatory debris.