Hepatocyte necrosis

F (centrilobuiar hepatocyte necrosis and severe diffuse vacuolar degeneration of midzonal and periportal hepatocytes)... 

F (increased relative liver weights hepatocyte lipid vacuolization scattered individual hepatocyte necrosis significant increase in hepatic LI)... 

At necropsy, livers were removed, weighed, examined macroscopically, and prepared for microscopic evaluation. Exposure to 90 ppm chloroform resulted in increased relative liver weights. Female mice exposed to chloroform for 4 days experienced a dose-dependent mild response of uniform hepatocyte lipid vacuolization. Scattered individual hepatocyte necrosis also occurred in a dose-dependent manner. 

The MRL was based on a hepatic NOAEL of 3 ppm chloroform administered for 6 hours a day for 7 consecutive days to mice (Larson et al. 1994c). Female mice exposed to 100 or 300 ppm exhibited centrilobular hepatocyte necrosis and severe diffuse vacuolar degeneration of midzonal and periportal hepatocytes, while exposure to 10 or 30 ppm resulted in mild-to-moderate vacuolar changes in centrilobular hepatocytes. Decreased eosinophilia of the centrilobular and midzonal hepatocyte cytoplasm relative to periportal hepatocytes was observed at 30 ppm. Livers of mice in the 1 and 3 ppm groups did not differ significantly from control animals and were considered to be NOAELs for liver effects. The NOAEL of 3 ppm was converted to the Human Equivalent Concentration (HEC) as described in Equation 4-10 in Interim Methods for Development of Inhalation Reference Concentrations (ERA 1990b). This calculation resulted in a NOAEL hec] of 3 ppm. An uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability) was applied to the NOAEL hec] value, which resulted in an MRL of 0.1 ppm. 

The MRL was based on a NOAEL of 26 mg/kg/day in the drinking water for 4 days for hepatic effects in mice (Larson et al. 1994b). The NOAEL of 26.4 mg/kg/day was divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) to arrive at the MRL of 0.3 mg/kg/day. A study performed by Moore et al. (1982) found renal effects in CFLP Swiss mice dosed at 65.5 mg/kg/day by gavage in oil. Another study by Larson et al. (1993) found both hepatic (elevated SDH, ALT and AST, hepatocyte necrosis) and renal (proximal tubule necrosis) lesions in Fischer 344 rats and hepatic lesions only in B6C3Fj mice induced by chloroform administered at 34 mg/kg/day once by gavage in oil. Lesions in the Larson et al. (1993) study were ranked as less serious LOAELs. 

No acute, intermediate, or chronic oral MRLs were derived for fuel oils because available data were not suitable for MRL derivation. Studies that report lethality at the lowest dose tested cannot be used for MRL determinations. Hepatocyte necrosis reported by Parker et al. (1981) occurred at a dose greater than dose levels at which serious effects occurred in other studies, making these data unsuitable for derivation of an MRL. 

Inhalation exposure of rats and mice (10-25ppm over 2 weeks or 5-50ppm over 13 weeks) caused methemoglobinemia, encephalopathy, and lesions in the liver (hepatocyte necrosis and hepatomegaly), kidney (hyalin nephrosis), and spleen (extramedullary... 

Cottrell et al. (1996) reported that a single oral dose of coumarin produced liver necrosis in mice 200 mg/kg bw coumarin was hepatotoxic to both C3H/He and DBA/2 mice. Hepatotoxicity was characterized by an increase in plasma aminotransferase activity, mild subcapsular linear hepatocyte necrosis and, in some C3H/He mice, centrilobular necrosis. Mice were pretreated with (3-naphthoflavone (80 mg/kg bw), Aroclor 1254 (54, 125 or 162 mg/kg bw) or vehicle alone by intraperitoneal injection for three consecutive days. Twenty-four hours later, a single dose of coumarin (200 mg/kg bw) or vehicle was administered by gavage. Pretreatment with... 

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... 

Carbon tetrachloride causes centrilobular liver necrosis and steatosis after acute exposure, and liver cirrhosis, liver tumors, and kidney damage after chronic administration. The mechanism underlying the acute toxicity to the liver involves metabolic activation by cytochrome P-450 to yield a free radical (trichloromethyl free radical). This reacts with unsaturated fatty acids in the membranes of organelles and leads to toxic products of lipid peroxidation including malondialdehyde and hydroxynonenal. This results in hepatocyte necrosis and inhibition of various metabolic processes including protein synthesis. The latter leads to steatosis as a result of inhibition of the synthesis of lipoproteins required for triglyceride export. 

TheTNF-a-dependent models are mostly characterized by the apoptotic cell death of hepatocy te at the early stage of liver injury. In these models, a large number of hepatocytes undergoing apoptosis can represent a stimulus for primed neutrophils in sinusoids to transmigrate and activate, leading to hepatic inflammation and massive hepatocyte necrosis. This... 

Serum glutamate dehydrogenase as a marker of hepatocyte necrosis in alcoholic liver disease. Brit. Med. J. 1981 283 754-755... 

A 19-year-old woman developed severe acute hepatitis and peripheral eosinophilia during oral trovafloxacin therapy for recurrent sinusitis (9). Liver biopsy showed extensive centrilobular hepatocyte necrosis, probably causing veno-occlusive disease. Clinical and laboratory abnormalities resolved completely after prolonged treatment with steroids. 

Van Puijenbroek EP, Metselaar HJ, Berghuis PH, et al. [Acute hepatocytic necrosis during ketoconazole therapy for treatment of onychomycosis. National Foundation for Registry and Evaluation of Adverse Effects.] Ned Tijdschr Geneeskd 1998 142 2416-2418. 

Hepatic 0.2 F (hepatocyte necrosis, gall bladder and biliary duct hypertrophy)... 

Liver lesions reported in animal studies include hepatocyte necrosis in male Sprague-Dawley (CD) rats exposed to nitrobenzene at 35 ppm for 2 weeks (Medinsky and Irons 1985) and increased liver weight, hepatocyte hyperplasia, and multinucleated hepatocytes in male B6C3F1 mice exposed to nitrobenzene at 16 ppm for 90 days (Hamm 1984). 

Liver effects have been reported in both humans and animals exposed to nitrobenzene. Hepatic enlargement and tenderness, jaundice, and altered serum chemistries were reported in a 47-year-old woman who had been occupationally exposed to nitrobenzene for 17 months (Ikeda and Kita 1964). The authors considered these changes to be related to increased destruction of hemoglobin and enlargement of the spleen. Liver effects observed in animals following nitrobenzene exposure are hepatocyte necrosis in rats (Medinsky and Irons 1985) and increased liver weight, hepatocyte hyperplasia, and multinucleated hepatocytes in mice (Hamm 1984). Hepatic effects have not been reported in oral studies. Dermal painting studies in mice resulted in diffuse necrosis in the outer two- thirds of the lobules of the liver (Shimkin 1939). 

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