The common groundwater contaminant trichloroethylene (TCE), when given by oral gavage, can produce free radical species during metabolism. Furthermore, TCE end-stage metabolites, trichloroacetic acid and dichloroacetic acid, cause lipid peroxidation in mouse liver. The time courses of lipid peroxidation, free radical generation, and 8-hydroxydeoxyguanosine (8OHdG) formation were used to assess the level of oxidative stress in the liver of B6C3F1 mice dosed orally once daily, 5 days a week for 8 weeks at 0, 400, 800, and 1200 mg/kg TCE in corn oil. Peroxisomal proliferation, cell proliferation, and apoptosis were evaluated at selected times during the study. Lipid peroxidation, as measured by thiobarbituric acid-reactive substances (TBARS), was significantly elevated at the two highest dose levels of TCE on days 6 through 14 of the study. 8OHdG levels were statistically significant in the 1200 mg/kg/day group on days 2, 3, 10, 28, 49, and 56 only. The highest measured free radical load, 307% of oil control, occurred at day 6. A significant increase in cell and peroxisomal proliferation was observed during the same time period in the 1200 mg/kg/day group. Necrosis or an increase in apoptosis was not observed at any dose. The temporal relationship between oxidative stress and cellular response of proliferation, both of which occur and resolve within the same relative time period, suggests that TCE-induced mitogenesis may result from alteration in the liver microenvironment which offers a selective advantage for certain hepatocyte subpopulations.

A 7-year-old spayed female Cocker Spaniel was hospitalized with a history of chronic vomiting, anorexia, and weight loss. Laboratory abnormalities included leukocytosis, metabolic alkalosis, hypoglycemia, hypoproteinemia, and hyperinsulinemia. Gastroscopy and ultrasonography revealed multiple gastric masses and a possible pancreatic mass, respectively. Examination of tissues obtained at necropsy showed a pancreatic adenocarcinoma with hepatic metastasis, gastric hypertrophy, and multiple duodenal ulcers. Immunocytochemical staining of the neoplasia was positive for pancreatic polypeptide (PP) and insulin and negative for gastrin, calcitonin, adrenocorticotropic hormone (ACTH), serotonin, L-enkephalin, chromagranin, glucagon, and somatostatin. Subsequent serum gastrin and PP assays showed a fasting hypergastrinemia with a normal response of gastrin to provocative testing and extremely increased PP values. The high PP values may have resulted in the vomiting and gastrointestinal ulceration. A PP-secreting tumor has not previously been reported in the dog.

Chloropentafluorobenzene (CPFB) has been identified as a can didate simulant for nonpersistent chemical warfare agents. Acute toxicity studies have shown that CPFB has limited adverse ef fects on laboratory animals. A 21-day inhalation study of rats and mice to 2.5, 0.8, and 0.25 mg CPFB/liter resulted in re duced weight gain in male and female rats exposed at the high concentration only and identified the liver as a potential target organ. This multiconcentration inhalation study was designed to detect a no-observable-effect level associated with repeated expo sure to CPFB. Male and female rats and mice were exposed to 250, 50, or 10 mg CPFB/m3 (0.25, 0.05, or 0.01 mg CPFB/li ter) for 13 weeks. No treatment-related effects on body weight, clinical chemistries, mortality, absolute or relative organ weight or histopathology were noted.

The common groundwater contaminant trichloroethylene (TCE), when given by oral gavage, can produce free radical species during metabolism. Furthermore, TCE end-stage metabolites, trichloroacetic acid and dichloroacetic acid, cause lipid peroxidation in mouse liver. The time courses of lipid peroxidation, free radical generation, and 8-hydroxydeoxyguanosine (8OHdG) formation were used to assess the level of oxidative stress in the liver of B6C3F1 mice dosed orally once daily, 5 days a week for 8 weeks at 0, 400, 800, and 1200 mg/kg TCE in corn oil. Peroxisomal proliferation, cell proliferation, and apoptosis were evaluated at selected times during the study. Lipid peroxidation, as measured by thiobarbituric acid-reactive substances (TBARS), was significantly elevated at the two highest dose levels of TCE on days 6 through 14 of the study. 8OHdG levels were statistically significant in the 1200 mg/kg/day group on days 2, 3, 10, 28, 49, and 56 only. The highest measured free radical load, 307% of oil control, occurred at day 6. A significant increase in cell and peroxisomal proliferation was observed during the same time period in the 1200 mg/kg/day group. Necrosis or an increase in apoptosis was not observed at any dose. The temporal relationship between oxidative stress and cellular response of proliferation, both of which occur and resolve within the same relative time period, suggests that TCE-induced mitogenesis may result from alteration in the liver microenvironment which offers a selective advantage for certain hepatocyte subpopulations.

Pancreatic endocrine tumors in dogs are usually associated with hyperinsulinism and hypoglycemia.5 Gastrin-secreting tumors have been reported in a few dogs with a ZollingerEllison-like syndrome.' Multiple polypeptide hormones have been reported in a majority of human pancreatic endocrine tumors and recently in canine pancreatic endocrine tumors.8. 10 We report a pancreatic endocrine tumor with immunoreactivity for pancreatic polypeptide and insulin in a dog with a hypertrophic gastropathy and multiple duodenal ulcers.A 7-year-old7 spayed female cocker spaniel dog was presented with a history of frequent vomiting, inappetence, and severe weight loss. Clinicopathologic studies revealed hypoproteinemia (total protein, 3.2 g/dl), leukocytosis (44,400 celldpl), hypoglycemia (74 mg/dl), and metabolic alkalosis (pH 7.53, HCO, 27 mEq/liter). At necropsy, six round to oval, well-encapsulated nodules ranging in size from 0.5 to 2.0 cm were in the cranial lobe of the pancreas. Cut surface was white, firm, and partially lobulated. Mucosa of the pyloric region of the stomach contained numerous small raised nodules from 2 to 3 mm in diameter. Nineteen round to oval ulcers that eroded deep into the muscle layers were in the duodenum and were from 5 to 10 mm in diameter. Ulcers extended from the pylorus to the distal duodenum. In the liver there were multiple, round, white, circumscribed nodules scattered randomly throughout the parenchyma.Tissues for light microscopy were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 5 pm, and stained with hematoxylin and eosin (HE). Tissues selected for transmission electron microscopy were fixed in 3% glutaraldehyde, washed with phosphate buffer, and transferred to 1.0% osmium tetroxide, dehydrated in a graded series of alcohol solutions, and embedded in plastic blocks. Ultrathin sections were cut with a diamond knife, stained with uranyl acetate and lead citrate, and examined electron microscopically.Immunohistochemical analysis was done on formalin-fixed, paraffin-embedded tissues. Five-micron sections were placed on glass microslides with 15% white casein glue and dried overnight. Sections were deparaffinized with two changes of xylene followed by 100% ethanol and repeated for 2 minutes each, followed by a 2-minute rinse in distilled water and 30 minutes in 3% hydrogen peroxide-methanol to block endogenous peroxidase activity. Sections were rinsed three times with 0.0 1 M phosphate buffer solution (PBS) containing 0.15 M NaCl, pH 7.4 and placed overnight at 4 C in 10% normal serum-PBS derived from the same species as the bridge (secondary) antibody to reduce nonimmunologic binding of antiserum.For detection of polypeptides, sections were flooded with primary rabbit antiserum for 30 minutes at room temperature in a humidity chamber followed by immunoperoxidase staining utilizing the peroxidase-anti-peroxidase method. For detection of chromogranin, sections were flooded with primary mouse antiserum followed by reagents in the avidinbiotin peroxidase complex me...