Toxicity of carbon tetrachloride

Le Page, KN., Cheeseman, K.H., Osman, N. and Slater, T.F. (1988). Lipid peroxidation in purified plasma membrane fractions of rat liver in relation to the toxicity of carbon tetrachloride. Cell Biochem. Function 6, 87-99. 

Mehendale HM, Ray SD, Cai Z. 1991. Paradoxical toxicity of carbon tetrachloride in isolated hepatocytes from chlordecone, phenobarbital and mirex pretreated rats. In Vitro Toxicology 4(3) 187-196. 

A number of substances including ethanol, isopropyl alcohol, polybrominated biphenyls, phenobarbital, and benzo( )pyrene have been shown to synergistically affect carbon tetrachloride toxicity." Alcohol has been a concomitant factor in many of the human cases of poisoning, especially in cases in which severe liver and kidney damage have occurred. Some substances such as chlordecone greatly potentiate the toxicity of carbon tetrachloride at... 

When absorbed, isopropyl alcohol is oxidized in the liver at the hydroxyl moiety and converted to acetone." Occupational exposure to isopropyl alcohol can be biomonitored by means of urinalysis for acetone after exposures as low as 70ppm." The acetone metabolite may also be responsible for the enhanced toxicity of carbon tetrachloride following pretreatment of animals with isopropyl alcohol. Extra caution is in order when isopropyl alcohol is... 

As noted above, persons who are moderate to heavy drinkers are at greatly increased risk of liver and/or kidney injury following ingestion or inhalation of carbon tetrachloride. Occupational exposure to isopropanol has also been reported to markedly potentiate the hepatorenal toxicity of carbon tetrachloride in men and women (Folland et al. 1976). This report and numerous animal studies indicate that primary, secondary, and tertiary alcohols, as well as their ketone analogues, can substantially enhance the toxic potency of carbon tetrachloride. Substantial exposures to alcohols and ketones may occur in occupational settings or in certain instances in the use of household products containing these chemicals. 

Influence of ethanol on metabolism and toxicity of carbon tetrachloride in lung, and interaction with other xenobiotics. 

Concentration and time dependence of carbon tetrachloride-induced injury to proximal tubule mechanism of action role of metabolism in renal toxicity of carbon tetrachloride. 

Adams EM, Spencer HC, Rowe VK, et al. 1952. Vapor toxicity of carbon tetrachloride determined by experiments on laboratory animals. Arch Ind Hyg Occup Med 6 50-66. 

Bogers M, Appelman LM, Feron VJ, et al. 1987. Effects of the exposure profile on the inhalation toxicity of carbon tetrachloride in male rats. J AppI Toxicol 7 185-191. 

Bruckner JV, MaKenzie WF, Muralidhara S, et al. 1986. Oral toxicity of carbon tetrachloride acute, subacute and subchronic studies in rats. Fund AppI Toxicol 6 16-34. 

Cai Z, Mehendale HM. 1991b. Prestimulation of hepatocellular regeneration by partial hepatectomy decreases toxicity of carbon tetrachloride in gerbils. Biochem pharmacol 42 633-644. 

Shimizu Y, Nagase C, Kawai K. 1973. Accumulation and toxicity of carbon tetrachloride after repeated inhalation in rats. Ind. Health 11 48-54. 

Simko V, Michael S, Katz J, et al. 1992. Protective effect of oral acetylcysteine against the hepatorenal toxicity of carbon tetrachloride potentiated by ethyl alcohol. Alcoholism Clinical and Experimental Research 16 795-799. 

Smyth FIF, Smyth FIF Jr., Carpenter CP. 1936. The chronic toxicity of carbon tetrachloride animal exposure and field studies. Journal of Industrial Flygiene and Toxicology 18 277-298. 

Tezuka M, Momiyama K, Edano T, et al. 1991b. Protective effect of chromium(lll) on acute lethal toxicity of carbon tetrachloride in rats and mice. J Inorganic Biochem 42 1-8. 

Kluwe WM, Hook JB, Berstein J. 1982. Synergistic toxicity of carbon tetrachloride and several aromatic organohalide compounds. Toxicology 23 321-336. 

Measurements in vivo, such as barbiturate sleeping times, are in agreement with these findings, sleeping times being longer in protein-deficient animals. Toxicity may also be influenced by such factors as a low-protein diet. For example, the hepa to toxicity of carbon tetrachloride is markedly less in protein-deficient rats than in normal animals, and this correlates with the reduced ability to metabolize the hepato toxin in the protein-deficient animals. 

Furthermore, initiation of this repair process by prior treatment of an animal with a small sub-toxic dose will afford protection against a second, larger dose. This may be part of the mechanism underlying the tolerance to the hepa to toxicity of carbon tetrachloride as well as the destruction of cytochrome P-450 (see chap. 7). Effects on tissue repair may also be important in interactions between compounds. Thus, exposure to another agent such as phenobarbital may stimulate tissue repair and decrease the eventual toxicity of carbon tetrachloride. 

The toxicity of carbon tetrachloride has been reviewed (Recknagel et al., 1989 McGregor Lang, 1996). 

Siegers. C.P., Horn, W. Younes, M. (1985a) Effect of hypoxia on the metabolism and hepato-toxiciti of carbon tetrachloride and vinylidene chloride in rats. Acta pharmacol. toxicol., 56, 81-86... 

Lipid peroxidation has been implicated in a wide range of tissue injuries, diseases, and even in the aging process. The liver toxicity of carbon tetrachloride (CCI4) is a classic example of the destructive effects of lipid peroxidation. A very small portion of administered carbon tetrachloride is metabolized into trichloromethyl free radical (CCI3) by the action of cytochrome P450 in the liver. This radical reacts rapidly with oxygen and gives rise to the trichloro-methylperoxyl radical... 

Ethanol potentiates the toxicity of carbon tetrachloride. This phenomenon is exemplified by a report in the literature of human exposure to carbon tetrachloride. In two separate instances, acute liver and kidney poisoning ensued following exposure to carbon tetrachloride vapors from a discharged fire extinguisher. In both cases, other workers exposed to the same vapors for the same period of time showed no toxic signs or symptoms. Upon investigation, it was determined that the two injured individuals were chronic ethanol users, with daily consumptions of 120 and 250 g/day, respectively. Each of their nonaffected coworkers consumed less than 50 g of ethanol per dayJ13l... 

The renal toxicity of carbon tetrachloride is also potentiated by isopropanol (IPA), as well as by ethanol. Workers in a chemical packaging plant were exposed to a mixture of vapors of carbon tetrachloride and IPA when the spacing between two packaging lines (one for each solvent) was small enough to create a mixed vapor atmosphere. Renal failure developed in 4 of the 14 workers so exposed. The authors of the study attribute the potentiating effect of IPA on carbon tetrachloride to acetone, a metabolite of IPA. They contrast this with the potentiation of ethanol on carbon tetrachloride, where it is the contaminant (ethanol) and not the metabolite that is the cause of the potentiation. P21 This is a further example of a potentiated effect being observed from a mixture of a lipophile (carbon tetrachloride, Kqw = 2.83) and a hydrophile (acetone, Kqw = -0.24). 

Mehendale and associates have conducted a series of studies on the effects of pretreatment of Kepone (chlordecone) on the acute toxicity of carbon tetrachloride (69-79). After the discovery of the dramatic potentiation of carbon tetrachloride hepatotoxicity by pretreatment of Kepone (69), Klingensmith and Mehendale (73) and Mehendale (74) demonstrated that pretreatment of young maTe Sprague-DawTey rats with a very low level (10 ppm) of Kepone in the diet for 15 days enhanced acute toxicity of carbon tetrachloride 67-fold (Table II). 

Table II. Enhancement of Acute Toxicity of Carbon Tetrachloride by Low Level Dietary Pretreatment of Kepone...

Seawright AA, Filippich LJ, Steele DP. 1972. The effect of carbon disulfide on the toxicity of carbon tetrachloride for sheep. Aust Vet J 48 38. 

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