Liver effect

Liver Effects. In 1980 a 2-year feeding study carried out as part of the NTP/NCI Bioassay Program in the United States (38,39) indicated that DEHP causes increased incidence of Hver tumors in rats and mice and that DEHA had a similar effect in mice but not rats. In these studies the levels of plasticizers fed were very high, this being possible only because of thek low acute toxicity. 

Pernicious anaemia was a fatal disease first reported in 1880. It was not until 1926 that it was discovered that eating raw liver effected a remission. The active principle was later isolated and called vitamin B or cyanocobalamin. It was initially obtained... 

In contrast to mice, male rats treated with trichloroethylene by com oil gavage at 1,100 mg/kg/day for 3 weeks failed to exhibit histopathology in the liver, although enhanced hepatic DNA synthesis (175% of control) was detected (Stott et al. 1982). No treatment-related nonneoplastic lesions of the liver were described for male or female rats treated with 1,000 mg/kg/day trichloroethylene for 2 years (NTP 1988, 1990), with 1,097 mg/kg/day for 78 weeks (NCI 1976), or with 250 mg/kg/day for 52 weeks (Maltoni et al. 1986). Except for enlarged livers, liver effects were not reported in mice treated by gavage with trichloroethylene in com oil for 18 months at a dose of 1,978 mg/kg/day for males and 1,483 mg/kg/day for females (Henschler et al. 1984). Hepatic effects were not reported in mice treated by gavage with trichloroethylene in com oil at doses up to 1,739 mg/kg/day for 78 weeks (NCI 1976) or at 1,000 mg/kg/day for 103 weeks (NTP 1990). 

As discussed imder dermal effects, people can develop hypersensitivity to trichloroethylene. The effects observed in hypersensitive individuals include skin effects (Conde-Salazar et al. 1983 Nakayama et al. 1988 Phoon et al. 1984 Waller et al. 1994) and liver effects (Phoon et al. 1984). Dermal sensitivity was confirmed with patch testing in only two cases (Conde-Salazar et al. 1983 Nakayama et al. 1988). The woman described by Conde-Salazaer et al. (1983) reacted positively to both vapor exposure and a dermal application of 5% trichloroethylene in olive oil. 

Liver effects including blood and urine indices of liver function, and enlarged livers, have been reported in persons occupationally exposed to trichloroethylene (Bauer and Rabens 1974 Capellini and Grisler 1958 Graovac-Leposavic et al. 1964 Phoon et al. 1984 Schattner and Malnick 1990 Schuttmann 1970). 

No gross or histological hepatic alterations were observed in rabbits exposed to <480 mg/kg/day or chickens exposed to up to 720 mg/kg/day, respectively, of Cellulube 220 for an acute duration (Carpenter et al. 1959). No hepatic effects were reported in rats exposed to 50 mg/kg/day of Pydraul 90E for an intermediate duration (Monsanto 1979). Several intermediate-exposure rat studies showed liver effects for organophosphate esters. Liver weight increases were shown for tributyl phosphate at 250 mg/kg/day (Laham et al. 1985 Oishi et al. 1982), trioctyl phosphate at 250 mg/kg/day (Oishi et al. 1982),... 

Animal data suggest that renal and liver effects may occur in humans exposed to high doses of hexachloroethane. Kidney and liver effects are not specific to hexachloroethane. Lesions of the kidney (nephropathy, linear mineralization, and hyperplasia) were reported at 10 mg/kg/day or greater in male rats (NTP 1989). Urinalysis also revealed granular and cellular casts in rats exposed to hexachloroethane (47 mg/kg/day or greater) for 13 weeks (NTP 1989). Because other compounds cause similar effects and because some of these effects are unique to male rats, they are not valuable as biomarkers for human hexachloroethane exposure. 

Carlson J, Abraham R. 1985. Nuclear ploidy of neonatal rat livers Effects of two hepatic carcinogens (mirex and dimethylnitrosamine). J Toxicol Environ Health 15(5) 551-559. 

An MRL of 3 mg/kg/day has been derived for acute oral exposure to di-M-octylphthalatc. This MRL is based on liver effects observed in rats administered di- -octylphthalate via gavage at a dose of 1,000 mg/kg/day (Lake et al. 1986). The hepatic effects consisted of a statistically significant (p<0.01) 17% increase in relative liver weight and a statistically significant (p<0.05) reduction in enzyme (7-ethoxycoumarin 0-deethylase) activities. The LOAEL was divided by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from animals to humans, and... 

Disulfoton induced the liver MFO system in animals (Stevens et al. 1973). In the same study, exposure to disulfoton orally for 3 days also increased ethylmorphine N-demethylase and NADPH oxidase activities, but had no effect on NADPH cytochrome c reductase. Thus, the induction of the MFO system required repeated dosing with relatively high doses. Furthermore, these changes are not specific for disulfoton exposure, and these subtle liver effects require invasive techniques in humans to obtain liver tissue for performance of these enzyme assays. 

Hepatic Effects. Serum markers of liver effects, bilirubin, glucose, cholesterol, and aspartate aminotransferase were not affected in 39 persons exposed to phenol in the drinking water at an estimated dose of 0.14-3.4 mg/kg/day for several weeks (Baker et al. 1978). Because these examinations were completed 7 months after the spill, this study does not provide conclusive evidence that there was no reversible liver damage. 

Hepatic Effects. An increase in serum iron, which may reflect an adverse liver effect, was observed in workers exposed for 6 months to phenol in a wood treatment liquid (Baj et al. 1994). Elevated concentrations of hepatic enzymes in serum, and an enlarged and tender liver suggestive of liver injury, were reported in an individual who had been exposed repeatedly to phenol vapor for 13.5 years (Merliss 1972). Since phenol was also spilled on his clothes resulting in skin irritation, dermal and inhalation exposures were involved. A 2-fold increase in serum bilirubin was observed in a man who was accidentally splashed with a phenol solution over his face, chest wall, hand, and both arms (Horch et al. 1994). Changes in liver enzymes were not observed in persons exposed to phenol in drinking water for several weeks after an accidental spill (Baker et al. 1978). This study is not conclusive because the measurements were completed 7 months after the exposure. 

Phenol can result in hemolytic anemia. Therefore, red blood cell counts may serve as a useful biomarker of effect following exposure to phenol. Measurement of liver enzymes in the serum following phenol exposure would also be useful to determine if liver effects have occurred. 

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. 

As discussed in Section 2.3.3, the mechanism of chloroform-induced liver toxicity may involve metabolism to the reactive intermediate, phosgene, which binds to lipids and proteins of the endoplasmic reticulum, lipid peroxidation, or depletion of GSH by reactive intermediates. Because liver toxicity has been observed in humans exposed to chloroform levels as low as 2 ppm in the workplace and in several animal species after inhalation and oral exposure, it is possible that liver effects could occur in humans exposed to environmental levels, to levels in drinking water, or to levels found at hazardous waste sites. 

An intermediate-duration oral MRL was derived based on liver effects in dogs (Heywood et al. 1979). An intermediate-duration inhalation MRL was derived based on toxic hepatitis which occurred in humans (Phoon et al. 1983). Pharmaeokinetie data regarding dermal exposure to chloroform are limited, but it is known that ehloroform can be absorbed through the skin. Intermediate-duration dermal studies in animals would provide information about ehloroform toxieity via this exposure route. The information would be... 

An MRL of 0.1 mg/kg/day has been derived for intermediate-duration oral exposure to ehloroform. The MRL is based on a NOAEL of 15 mg/kg/day for liver effects (increased SGPT) in dogs exposed to chloroform in toothpaste for >6 weeks (Heywood et al. 1979). 

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