No abstract

Granular cell tumors of the reproductive tract in rodents granules with indistinct cell borders and were separated by have been reported primarily in the uterine cervix of mice collagen bundles or smooth muscle cells (Fig. 3). Scattered treated with estrogens.> Spontaneous cervical and vaginal within the mass were foci of perivascular and interstitial granular cell tumors occur rarely in the Fischer rat.' We mononuclear cell infiltrates. Both granular cell tumors were describe histopathologic, immunohistochemical, and ultra-periodic acid-Schiff positive and diastase resistant (Fig. 4) structural features of granular cell tumors in the uterine cer-and stained faintly with Alcian blue. Both tumors stained vix and vagina of two aged Wistar rats.positively for S-l 00 protein. The tumor from rat No. I had Tumor specimens were obtained from animals from a foci that stained positively for neuron-specific enolase. Nei-2-year carcinogenicity study. Rat No.1 was a 11O-week-old ther tumor stained for vim entin, desmin, or actin. Ultravehicle control female Wistar rat. Rat NO.2 was a l l O-week-structural examination of tumor tissue from rat No.2 reold female Wistar rat that had been treated intravenously vealed that cytoplasmic granules were actually large aggregates with a synthetic anticancer chemotherapeutic compound. (approximate average diameter 3 !Lm) of polymorphous maTreatment consisted of once daily dosing for 5 days, followed terial (Fig. 5a). The aggregates contained single membraneby a 23-day recovery period. This regimen was repeated for bound lysosomal bodies of various sizes (approximately 200-six dosing cycles. Vehicle consisted of N,N-dimethylacet-400 nm in diameter) and shapes, with electron-dense amoramide (DMA) in a lactic acid diluent. Neither the test sub-phous cores. Electron-dense bodies were packed together with stance nor vehicle possessed any known estrogenic proper-smaller, moderately electron-dense granular material that had ties.an approximate average diameter of 40 nm (Fig. 5b). CyTissues were fixed in 10% neutral buffered formalin, pro-toplasm also contained scattered profiles of free ribosomes, cessed for light microscopic examination, and stained with mitochondria, and mildly dilated rough endoplasmic retichematoxylin and eosin, Masson's trichrome, Alcian blue, and ulum. Nuclei were peripherally located and round to slightly periodic acid-Schiff. Three-micrometer deparaffinized sec-indented and contained dispersed euchromatin and a single tions were stained by the avidin biotin peroxidase immu-prominent nucleolus. Basal lamina were not seen; however, noperoxidase method as previously described.t' using rabbit a few poorly defined widely distributed cell junctions were polyclonal anti-bovine S-100 protein and neuron-specific observed. enolase (DAKO Corp., Carpinteria, CA), mouse monoclonal Granular cell tumors have been described in seminal vesanti-porcine vimentin (Biogenex, San Ramon, CA), anti-hu-icles and in uteri of 2-year-old untreated Naval Medical Reman desmin (DAKO Corp.), and acti...

The antihistamine methapyrilene (MP) was widely used as a component of cold, allergy and sleep-aid medications in the 1970s until it was identified as a potent rat liver carcinogen. MP does not induce positive responses in most short-term genotoxicity assays, which suggests that it is carcinogenic by a non-genotoxic mechanism. We have evaluated the potential of MP to induce unscheduled DNA synthesis (UDS), a genetic end point and S-phase synthesis (SPS), and indicator of cell proliferation, in Fischer-344 (F344) rat and B6C3F1 mouse liver. We also examined the response of MP in hepatocytes from two species treated in vitro. MP failed to induce UDS in rat or mouse liver following in vivo treatment, or in hepatocytes from rat and adult human treated in vitro. Control rats and mice yielded less than 0.3% of cells in S-phase (%S). In contrast, MP induced significant elevations in SPS both in male F344 rat (6.3%S) and female B6C3F1 mice (1.4%S). In the male rat, sorbitol dehydrogenase (SDH), bilirubin, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) showed elevations of 9-, 10-. 17- and 28-fold over controls respectively, indicating that significant hepatotoxicity was induced by MP. This was confirmed by histopathologic examination, which revealed significant periportal and focal necrosis followed by an increased presence of mitotic figures. These results indicate that MP is not genotoxic in rat liver, but is a potent inducer of hepatic cell proliferation by inducing toxicity and subsequent regeneration, which may be an important mechanism of hepatocarcinogenesis.

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.