Hepatic lesions

Pathological changes observed in animals treated with chlorodibenzo-dioxins were inconsistent from animal to animal and species to species. Hepatic lesions were observed consistently, but the nature, degree, and distribution of the lesions were variable. Changes in organs other than the liver were sporadic and unpredictable. Gross and microscopic examination of tissues after chlorodibenzodioxin treatment did not reveal the cause of death. An in-depth evaluation of the toxicity associated with chronic exposure to the chlorodibenzodioxins is needed. 

Malins DC, MM Krahn, MS Myers, LD Rhodes, DW Brown, CA Krone, BB McCain, S-L Chan (1985) Toxic chemicals in sediments and biota from a creosote-polluted harbor relationships with hepatic neoplasms and other hepatic lesions in English sole (Parophrys vetulus). Carcinogenesis 6 1463-1469. 

Johnson, L.L., C.M. Stehr, O.P. Olson, M.S. Myers, S.M. Pierce, C.A. Wigren, B.B. McCain, and U. Varanasi. 1993. Chemical contaminants and hepatic lesions in winter flounder (Pleuronectes americanus) from the northeast coast of the United States. Environ. Sci. Technol. 27 2759-2771. 

Krahn, M.M., L.D. Rhodes, M.S. Myers L.K. Moore, W.D. MacLeod, Jr., and D.C. Malins. 1986. Associations between metabolites of aromatic compounds in bile and the occurrence of hepatic lesions in English sole (Parophrys vetulus) from Puget Sound, Washington. Arch. Environ. Contam. Toxicol. 15 61-67... 

Relative Patterns of Hepatic Enzyme Elevation versus Type of Hepatic Lesion... 

A significant disadvantage of these compounds lies in their relatively high toxicity (DL50 = 100-220 mg/kg, i.m., mice) some of them (dipiroxime) are able to form difficult-to-hydrolyze esters with OPC, whose toxicity is higher than that of the initial compounds. Severe hepatic lesions, unusual for OPC toxic effects, were described, when dipiroxime was used for a long time. 

Additional information on hepatic lesions in species other than the rat and mouse would be useful in evaluating the risk to humans for both noncarcinogenic and carcinogenic effects from hexachloroethane exposure. 

Hepatic Effects. Workers monitored for liver function had increased serum levels of liver enzymes (Hoogendam et al. 1965). Only limited conclusions should be drawn from these results as the levels returned to normal within 1 week to 3 months concurrent exposure to other chemicals and alcohol was not controlled. Diffuse degenerative hepatic lesions were observed in rabbits and mice exposed to lethal doses of endrin and in surviving animals (Treon et al. 1955). Rats, mice, guinea pigs, and hamsters administered a relatively high dose of endrin exhibited moderate hepatic histopathology (Hassan et al. 1991). 

A wide spectrum of hepatic lesions has been reported in AIDS (H4), but it is not known whether the changes are related to the presence of HIV-1. Therefore, sections from livers of autopsied patients with AIDS were examined for the presence of HIV-1 antigen p 24 (core) and gp 41 (envelope) by the avidin-biotin-peroxidase complex methods using monoclonal antibodies. The most common histologic abnormalities were steatosis, portal inflammation, Kupffer cell hyperplasia, and focal hepatocellular and bile duct damage. Immunoreactivity for HIV-1 antigens was demonstrated in 80% of cases. 

In intermediate-duration studies, no effects on clinical chemistry indices of liver toxicity and no histopathological hepatic lesions were found in rats given 0.34 mg/kg/day (males) or 0.55 mg/kg/day (females) (Klotzsche 1972) or in mice given ().63 mg/kg/day (males) or 0.71 mg/kg/day (females) (Rivett et al. 1972) in the diet for 90 days. However, a slight increase in liver weight was observed in female mice at 0.71 mg/kg/day (Rivett at al. 1972). 

Liver was not examined histologically in the subchronic study used to set concentrations for the NCI chronic gavage bioassay of 1,2-dibromoethane (NC11978). In the NCI (1978) gavage bioassay (discussed in detail in Section 2.2.2.8), a nonneoplastic hepatic lesion, peliosis hepatis, occurred in a small number of treated male and female Osborne-Mendel rats and had an equivocal relationship to... 

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. 

Animals exposed to 2100 ppm for 1-3 hours exhibited restlessness, mucous membrane irritation, and drowsiness. Rats exposed to 1500 ppm for 8 hours survived. Injection of 3 ml/kg or intragastric administration of 5 ml/ kg diacetone alcohol in rabbits caused respiratory depression, narcosis, and death. A temporary decrease in the number of erythrocytes in the blood of rats was observed for IM- days after intragastric administration of 2 ml/kg of diacetone alcohol hepatic lesions characterized by vacuolization and granulation of the parenchymal cells were noted, but recovery was complete in 7 days. ... 

Hepatic lesions (adenomas, focal nodular hyperplasia, hepatocellular carcinoma, etc) Rarely, benign and malignant hepatic adenomas have been associated with the use of hormonal contraceptives. Severe abdominal pain, shock, or death may be due to rupture and hemorrhage of a liver tumor. 

Malins, D.C., Krahn, M.M., Brown, D.W., Rhodes, L.D., Myers, M.S., McCain, B.B., Chan, S.L. (1995). Toxic chemicals in marine sediment and biota from Muldlteo, Washington Relationships with hepatic neoplasms and other hepatic lesions in EngUsh sole Parophrys vetulus). JNatl Cancer Inst 74 487 94. 

Popper, H., Selikoff, I.J., and Maltoni, C. (1977). (Comparisons of neoplastic hepatic lesions in man and experimental animals, page 1359 in Origins of Human Cancers. HlATT, H.H., WATSON, J.D., AND WiNSTEN, J.A., Eds. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York). 

Signs of methyl bromide toxicity following acute exposure include irritation of the eyes and respiratory tract, tremor, incoordination, depression of the central nervous system and convulsions. Long-term exposure induces pulmonary congestion, central nervous system effects, and renal and hepatic lesions. After oral administration to rats, hyperplasia and hyperkeratosis (and squamous-cell carcinomas) of the forestomach were observed (lARC, 1986). 

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