Role of time and concentration on carbon tetrachloride toxicity in rats

Summary The hepatotoxic effect of different exposure schemes to carbon tetrachloride (CCl₄) was studied in inhalation experiments in rats. The duration of exposures at different concentrations of (CCl₄) vapours in air was changed in such a way as to give a constant product of concentration and time (CT). The animals were exposed for 4 successive days a week.A concentration of 1,625 mg/m³ (250 ppm) (CCl₄) for 72 min (CT = 300 ppm × h) caused a higher increase in SGPT activity than the exposure to 325 mg/m³ (50 ppm) for 6h (CT = 300); the effect of 6,500 mg/m³ (1,000 ppm) for 3 min six times at 1-h intervals (CT = 300) had a much smaller effect than the exposure to 6,500 mg/m³ (1,000 ppm) for 18 min (again CT = 300) (1 ppm (CCl₄) = 6.5 mg/m³). Similar results were obtained at other concentrations and by increasing the number of exposures up to 18; the effects were also confirmed by other biochemical changes in blood serum and liver and by histological examination of the liver.The results indicate that the severity of liver lesions is more influenced by the concentration of (CCl₄) in the inhaled air (and accordingly in the blood entering the liver) than by the total inhaled (and absorbed) amount of (CCl₄). This also explains the differences between the two types of exposure in the concentration of 6,500 mg/m³ (1,000 ppm): blood cannot be saturated with (CCl₄) to the same level within 3 min as within 18 min of exposure.     

Thirteen-week inhalation toxicity of carbon tetrachloride in rats and mice

Subchronic toxicity of carbon tetrachloride (CCl4) was examined by inhalation exposure of F344 rats and BDF1 mice of both sexes to 0, 10, 30, 90, 270 or 810 ppm (v/v) CCl4 vapor for 13 wk (6 h/d and 5 d/wk). In the high exposure levels at 270 and 810 ppm, altered cell foci in the livers of both rats and mice, and fibrosis and cirrhosis in the rat liver were observed. Hematoxylin and eosin-stained altered cell foci of rats were recognized as glutathione-S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of hepatocarcinogenesis. The most sensitive endpoint of CCl4-induced toxicity was fatty change with large droplets in rats of both sexes and male mice, and cytoplasmic globules in male mice, as well as increased relative liver weight in male rats. Those endpoints were manifested at 10 ppm and the LOAEL was determined as 10 ppm for the hepatic endpoints in rats and mice. Enhanced cytolytic release of liver transaminases into plasma in rats and mice and its close association with hepatic collapse in mice were observed at medium and high levels of inhalation exposure. Both CCl4-induced hematotoxicity and nephrotoxicity were observed in both rats and mice, but those toxicities were manifested at higher exposure concentrations than hepatotoxicity. The LOAEL for the hepatic endpoint and the GST-P-stained altered cell foci provide relevant animal data for reconsidering the occupational exposure limit val1ue of 5 ppm for CCl4 and strengthen the evidence of CCl4-induced hepatocarcinogenicity which is used in its carcinogenicity classification.     

Influence of protein deficiency on cadmium toxicity in rats

The effects of a low protein diet on the body uptake and retention of cadmium, levels of essential trace elements, and cadmium-induced biochemical alterations in liver and kidneys of the rat were investigated. Low dietary protein disturbs cadmium induced alterations in carbohydrate metabolism, essential trace elements metabolism and offsets the hepatic and renal process of cadmium detoxification. Protein malnutrition enhances the susceptibility to cadmium intoxication.     

Influence of dietary protein deficiency on lead-copper interaction in rats

The influence of dietary protein deficiency on the effects of exposure to lead or its combination with copper was investigated in rats. The administration of lead (100 ppm in drinking water) inhibited the activity of blood delta-aminolevulinic acid dehydratase; decreased hemoglobin, brain dopamine, and 5-hydroxytryptamine; and increased urinary excretion of delta-aminolevulinic acid, blood zinc protoporphyrin, and tissue accumulation of lead more markedly in animals fed a protein-deficient diet (10% casein) than in those fed a normal diet (21% casein). The simultaneous supplementation of copper (100 ppm in diet) reduced some of the lead-induced alterations and body uptake of lead more efficiently in animals fed a normal diet than in those fed a protein-deficient diet, which shows that the beneficial effects of copper in lead toxicity are adversely affected by low dietary protein.     

Role of dietary calcium and calcium binding protein in cadmium toxicity in rats.

Growing male rats were fed a purified diet containing 0.6% Ca (two groups) or 0.1% Ca (two groups) for 8 weeks. One 0.6% Ca group and one 0.1% Ca group received 25 ppm Cd (as CdC12) in the drinking water. Diets were fed on an equalized basis with the 0.1% Ca + Cd group determining the amount of diet fed to the other groups. Water was provided ad libitum. Terminal body weights were not different among the four groups. Packed cell volumes were depressed in the Cd-exposed groups, especially the 0.1% Ca + Cd group. The highest concentrations of Cd were found in the lungs, liver, and kidneys of the 0.1% Ca + Cd group. More Cd was bound to low molecular weight proteins of the intestinal mucosa from the 0.1% Ca + Cd group than the 0.6% Ca + Cd group. Rats fed the 0.1% Ca diet appeared to have a greater capacity to absorb either Ca or Cd than rats fed the 0.6% Ca diet, as shown by an enhanced binding of 45Ca and 115mCd to intestinal calcium-binding protein (CaBP) in the rats fed the low calcium diet. A portion of the mucosal Cd was accounted for as Cd bound to metallothionein. It was concluded, based upon these experiments, that cadmium retention and signs of toxicity are enhanced by feeding low Ca diet and that the increased CaBP activity due to Ca restrictions is responsible for the increased Cd uptake observed.     

甲基维生素B_（12）、维生素B_（12）降低甲基汞含量及免疫与行为毒性作用的研究

研究发现２．０～３．０ｍｇ／ｋｇ甲基维生素Ｂ_（１２）、维生素Ｂ_（１２）均可使孕鼠脑、肝、肾中甲基汞含量明显低于甲基汞组，而对胎仔脑及胎盘中甲基汞含量有明显减少。甲基维生素Ｂ_（１２）、维生素Ｂ_（１２）并可增强机体特异性细胞免疫功能与机体非特异性免疫功能，可改善动物多种行为不良作用。     

Influence of magnesium deficiency on liver collagen after carbon tetrachloride or ethanol administration to rats

The effects of magnesium deficiency on liver collagen after the administration of a hepatotoxic substance were investigated. Rats, fed a control or magnesium-deficient diet (0.040 g/kg), received six CCl4 or mineral oil injections administered at 2-d intervals starting from the first day of diet treatment. They were killed 3 or 12 d after the last injection. Between postinjection d 3 and 12, no change of magnesium concentration in liver was observed in the deficient rats. Three days after the end of treatment liver calcium in the magnesium-deficient CCl4-treated rats was higher than in any other group. Liver collagen of untreated control rats and untreated magnesium-deficient rats was not significantly different. In control and magnesium-deficient animals receiving CCl4 treatment, the liver collagen levels were significantly higher than in untreated rats. The magnesium-deficient rats receiving CCl4 have higher liver collagen than the controls receiving CCl4. In a second experiment the effect of suboptimum intake of magnesium (0.120 g/kg) combined with the ingestion of ethanol was studied in rats given a solution of ethanol in water for 55 d as their only source of fluid. Mortality occurred in the magnesium-deficient rats receiving ethanol, and body weights of these rats were lower than those of animals in the other three groups. The collagen concentration in liver was higher in magnesium-deficient rats consuming ethanol than in any other group. The synergistic action between magnesium deficiency and ethanol therefore appears to be analogous to that observed with CCl4.     

Effects of trichloroethylene, 1,1,1-trichloroethane and carbon tetrachloride on plasma lipoproteins of rats

Effects of single intraperitoneal administration of trichloroethylene, 1,1,1-trichloroethane, and carbon tetrachloride (positive control) on the plasma contents of lipoproteins were investigated in rats. Plasma was fractionated to VLDL, LDL, and HDL by sequential ultracentrifugation. On the administration of carbon tetrachloride at 30 to 1000 mg/kg, VLDL and HDL were reduced dose-dependently, but the reduction in LDL was not dose-dependent. With trichloroethylene at 30 to 300 mg/kg, the lipid contents of VLDL and LDL fractions were decreased. At 1000 mg/kg, VLDL and LDL was increased by the trichloroethylene. The HDL was decreased with increasing doses of trichloroethylene at 30 to 1000 mg/kg. With 1,1,1-trichloroethane at 100 to 300 mg/kg, VLDL and LDL were increased. The HDL levels rose at 100 mg/kg but fell at 1000 mg/kg. Thus trichloroethylene impairs VLDL formation at low doses. 1,1,1-Trichloroethane stimulates the VLDL synthesis at low doses and inhibits it at high doses. The decreases in HDL at high doses of trichloroethylene and 1,1,1-trichloroethane resulted from the inhibition of HDL synthesis. Liver-to-body weight ratios were raised with increasing doses of carbon tetrachloride, trichloroethylene, and 1,1,1-trichloroethane. Plasma GOT and GPT activities rose at much higher doses of solvents than dose levels which produce the changes in lipoproteins and the increases in liver weights. The liver enlargement appeared to be a sensitive marker of hepatotoxicity related to the changes in lipoproteins, the profile of which was different in three solvents.