Hepatocellular hypertrophy

Metofluthrin (I) The committee determined that the new data were sufficient to support a mitogenic mode of action for the development of liver tumors in rats exposed to metofluthrin in the carcinogenicity study. The report summarized mode of action study data that characterized effects such as increased P450 enzyme levels, increased smooth endoplasmic reticulum, hepatocellular hypertrophy, hepatocellular proliferation, and inhibition of intracellular communication, which were described as steps leading to tumor development via a nongenotoxic mechanism (i.e., mitogenicity). Some of these studies used sodium phenobarbital as a positive control,... 

Chronic inhalation exposure to 0, 75, 250 or 750 ppm [0, 0.32, 1.1 or 3.3 g/m ] ethylbenzene for 6 h per day on five days per week for 104 weeks caused an increased incidence of renal tubule h erplasia in male Fischer 344/N rats and increased severity of spontaneous, age-related chronic progressive nephropathy in males and females. Male B6C3Fi mice developed an increased incidence of alveolar epithelial metaplasia, syncytial alterations of hepatocytes, hepatocellular hypertrophy, hepatocyte necrosis and thyroid gland follicular-cell h erplasia. Exposure to ethylbenzene also caused an... 

Groups of 78 male and 78 female Crl CD-I (ICR) BR mice, 55 days old, were administered dimethylformamide (purity, 99.9%) at 0, 25, 100 or 400 ppm [0, 75, 300 or 1200 ing/ni ] in air by whole-body vapour exposure for 6 h per day on five days a week for 18 months. Five males and five females per group were killed at 2 weeks, 3 months and 12 months. No compound-related effect on survival was evident. At tennination, the 100- and 400-ppm males and 400-ppm females had higher liver weights. In both sexes, at the two highest exposures, centrilobular hepatocellular hypertrophy and hepatic singlecell necrosis were increased. No increased tumour incidence was observed (Malley et al., 1994). 

TCDD. Necrosis, peripheral fibrosis, and bile duct proliferation were observed in rabbits acutely exposed to 2,3,7,8-TCDD on the ear surface (Kimbrough et al. 1977). Increased liver/body weight ratio and hepatocellular hypertrophy were seen in HRS/J hairless mice topically exposed to 0.0025 g... 

Toxicity and health effects Laboratory rats exposed to 2-nitropropane in high concentrations (207 ppm) developed adverse liver changes like hepatocellular hypertrophy, hyperplasia, necrosis, and liver carcinoma. It has been reported that prolonged exposure to concentrations of 20-45 ppm of 2-nitropropane caused nausea, vomiting, diarrhea, anorexia, and severe headaches among workers. Industrial workers handling 2-nitropropane for the application of epoxy resins to the walls of a nuclear power plant developed toxic hepatitis. - ... 

In subchronic toxicity studies with mice, a dose-related decrease in white blood cells was noted as well as an increase in the incidence of centrilobular hepatocellular hypertrophy in mice receiving up to 5000 mg kg in the diet. 

Subchronic studies of the dearomatized petroleum streams in rats were conducted on C9-C12 and C10-C13 dearomatized aliphatic mixtures containing branched, straight, and cyclic alkanes, and a Cn-C17 isoparaffinic solvent containing branched and cyclic alkanes. Two of these studies reported male rat nephropathy. All three studies reported hepatic effects including hepatocellular hypertrophy and increased liver weight. Developmental toxicity was not seen at the same doses in a study of a similar mixture in rats. These unpublished subchronic studies were used as the basis for RfDs by the TPHCWG (1997c). 

LOEL 250 mg/kg/day (mice) 125 mg/kg/day [10, 11] (rats) hepatocellular hypertrophy NOEL 10 mg/kg/day increases in liver and [1] kidney weights, increases in the incidence of hepatocellular hypertrophy, increases in thyroidparathyroid weights, hypertrophy and hyperplasia of the thyroid high incidences of trace-to-mild chronic nephritis in kidneys of male rats and increased pigmentation of the renal tubules in female rats LOAEL = 312 mg/kg/day (rats) 125 mg/kg/day [10, 11] (mice) hepatocellular neoplasms and adenomas or adenocarcinomas of the liver mononuclear cell leukemia adenomas or hyperplasia of the renal tubular cells in exposed male rats follicular cell adenomas or carcinomas of the thyroid in exposed female rats and female mice alveolar/bronchiolar adenomas or carcinomas in male mice 52 mg/kg Paroil intestinal activities of aryl [13] hydrocarbon hydroxylase (increase), UDP-glucuronosyltransferase (decrease) and epoxide hydrolase (increased)... 

F344 rats C22-26 70% Cl 14 day diet NOEL 1,715 mg/kg/day no clinical signs or effects on organ weights or in tissues examined microscopically LOEL 3,750 mg/kg/day hepatocellular hypertrophy and cytoplasmic fat vacuolation in liver and increases in semm hepatic enzymes [1, 20, 21]... 

Another inhalation study in mice and rats correlated light microscopic and ultrastructural liver effects with liver levels of cyanide-insensitive palmitoyl CoA oxidase, a marker for peroxisomal -oxidation (Odum et al. 1988). Animals were exposed to 200 ppm of tetrachloroethylene for 28 days or 400 ppm for 14,21, or 28 days. Centrilobular hepatocellular vacuolization was induced in mice by tetrachloroethylene exposure. Electron microscopy revealed that this effect corresponded to lipid accumulation. Centrilobular hepatocytes with cytoplasmic eosinophilia on light microscopy had marked proliferation of cytoplasmic peroxisomes at the ultrastructural level, and there was a significant increase in the marker enzyme. These changes occurred in mice at both doses and all exposures and were most pronounced in male mice. Exposed male rats in both dose groups and female rats exposed to 400 ppm developed centrilobular hepatocellular hypertrophy, which ultrastructurally consisted of proliferation of smooth endoplasmic reticulum. There was no increase in peroxisomes (Odum et al. 1988). 

This derivation was based on the NOAEL of 0.1 mg/m for liver effects in rats exposed intermittently for 90 days (Khasawinah et al. 1989 Velsicol Chemical Co. 1984). Similar exposure to 1.0 mg/m was associated with hepatocellular hypertrophy, and exposure to 10 mg/m was associated with increased liver weight. Hepatocellular hypertrophy was the most sensitive end point in animals exposed by inhalation. 

This derivation is based on a NOAEL of 0.055 mg/kg/day for hepatic effects in rats given chlordane in the diet for 30 months (Khasawinah and Grutsch 1989a Velsicol Chemical Co. 1983a). The LOAEL was 0.273 mg/kg/day, at which an increased incidence of hepatocellular hypertrophy was observed in female rats. 

Khasawinah et al. (1989) and Velsicol Chemical Co. (1984). The LOAEL was 1.0 mg/m rats had hepatocellular hypertrophy and increased cytochrome R-450 content. 

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