Carbon tetrachloride exposure

No other studies of interactions of hexachloroethane with other chemicals were identified in the published literature. However, the primary metabolites of hexachloroethane (tetrachloroethene and pentachloroethane) are themselves toxic and would be expected to exacerbate hexachloroethane toxicity if they were present in a mixture with hexachloroethane. Concurrent carbon tetrachloride exposure would also be expected to exacerbate hexachloroethane toxicity. Both hexachloroethane and carbon tetrachloride are processed by microsomes to generate free radicals, and carbon tetrachloride also forms endogenous hexachloroethane in the liver (Fowler 1969a). 

Many reported cases of carbon tetrachloride toxicity are associated with drinking alcohol. The frequent drinking of alcoholic beverages increases the danger from carbon tetrachloride exposure. 

Dermal/Ocular Effects. Very few reports mention any effect of carbon tetrachloride inhalation on the skin. Inhalation exposure to carbon tetrachloride for several days in the workplace caused a blotchy, macular rash in one man (but not in six others) (McGuire 1932). Similarly, a hemorrhagic rash occurred in a woman exposed to carbon tetrachloride fumes for several days in the workplace (Gordon 1944), and black and blue marks were seen in a patient exposed intermittently to carbon tetrachloride vapors for several years (Straus 1954). Because observations of dermal effects are so sporadic, it is difficult to judge whether these effects are related to carbon tetrachloride exposure, or are incidental. Conceivably, they may have been secondary to reduced synthesis of blood coagulation factors resulting from carbon tetrachloride-induced hepatotoxicity. No studies were located regarding ocular effects in humans or animals after inhalation exposure to carbon tetrachloride. 

Death Many cases of human fatalities have occurred as the result of carbon tetrachloride exposure, both by ingestion and inhalation (Norwood et al. 1950 Umiker and Pearce 1953 von Oettingen 1964). Most fatal cases of carbon tetrachloride toxicity involve individuals with a history of alcohol consumption, while nondrinkers are considerably less susceptible. 

Although central nervous system depression is often a prominent effect of carbon tetrachloride exposure, it is rarely the cause of death in humans. Rather, death is usually due to renal and/or hepatic injury and the sequelae thereof. The lowest inhalation exposure reported to cause death in humans was that in an alcoholic who inhaled 250 ppm for 15 minutes (Norwood et al. 1950), which corresponds to an absorbed dose of approximately 100-200 mg/kg. This is consistent with the range of minimum oral doses (40-320 mg/kg) reported to have caused death in humans (Lamson et al. 1928 Umiker and Pearce 1953 von Oettingen 1964). Due to restrictions in the use of carbon tetrachloride, opportunities for acute exposure to lethal amounts of carbon tetrachloride (either orally or by inhalation) are now quite rare. 

Cardiovascular Effects. Inhalation and oral studies in humans and animals have not revealed any treatment-related histopathological lesions of heart tissue, or impairment of cardiac functions, even at dose levels causing severe liver and kidney damage (Adams et al. 1952 Stewart et al. 1961 Umiker and Pearce 1953). It is possible that high-level carbon tetrachloride exposure may produce cardiac arrhythmias by sensitization of the heart to catecholamines (Reinhardt et al. 1971). Accordingly, there is some concern for cardiovascular toxicity following substantial exposure to carbon tetrachloride. 

Since these liver, kidney, and central nervous system effects also occur following exposure to other chemicals, they are not specific for carbon tetrachloride exposure. No other biomarkers have been identified to characterize effects associated with exposure. 

Ethanol. Alcohol (ethanol) ingestion has repeatedly been associated with potentiation of carbon tetrachloride-induced hepatic and renal injury in humans. In two cases in which men cleaned furniture and draperies with carbon tetrachloride, one man, a heavy drinker, became ill and died (Smetana 1939). His coworker, a nondrinker, suffered a headache and nausea but recovered quickly after breathing fresh air. Both men were subjected to the same carbon tetrachloride exposure, as they had been working in the same room for the same amount of time. In 19 cases of acute renal failure due to carbon tetrachloride inhalation or ingestion, 17 of 19 patients had been drinking alcoholic beverages at about the time of their carbon tetrachloride exposure (New et al. 

Many other cases of carbon tetrachloride-induced hepatic and/or renal injury associated with ethanol ingestion have been described in the medical literature (Durden and Chipman 1967 Guild et al. 1958 Jennings 1955 Lamson et al. 1928 Markham 1967 Tracey and Sherlock 1968). These clinical reports establish that occasional or frequent ingestion of alcoholic beverages can increase the danger from relatively moderate carbon tetrachloride exposure. As ethanol is known to induce microsomal mixed-function oxidase activity in man (Rubin and Lieber 1968), the mechanism of potentiation may involve ethanol-induced enhancement of the metabolic activation of carbon tetrachloride. 

Influence of acute carbon tetrachloride exposure on transcription of liver-specific versus general cellular genes relationship between chronic carbon tetrachloride exposure and collagen synthesis and hepatic fi brosi s. 

Food Chain Bioaccumulation. Limited data indicate that carbon tetrachloride has a low tendency to bioconcentrate in the food chain, even though it is a lipophilic compound (Neeley et al. 1974 Pearson and McConnell 1975). The lack of bioconcentration is mainly due to the volatility of carbon tetrachloride, which facilities clearance from exposed organisms. Nevertheless, carbon tetrachloride does tend to become concentrated in fatty tissues, and further studies on the levels of carbon tetrachloride in the fat of fish would help evaluate the risk of carbon tetrachloride exposure by this pathway. No data are available on the bioconcentration in plants. Additional studies would be useful in assessing potential for human exposure from ingestion of plant foodstuff. Data are also needed on the biomagnification of the compound in the aquatic and terrestrial food chain. These data would be useful in assessing food chain bioaccumulation as a potential human exposure pathway. 

The effects of chromium(III) chloride and sodium chromate(VI) on the hepatotoxicity of carbon tetrachloride exposure to mouse hepatocytes were examined by Tezuka et al. (1995). Primary cultures of mouse hepatocytes were pretreated with 10 or 100 pM chromium for 24 hours followed by exposure to 1-5 mM carbon tetrachloride for up to 1 hour. Chromium(VI) pretreatment significantly reduced the cell toxicity as well as lipid peroxidation caused by carbon tetrachloride. Chromium(III) pretreatment did not have any effect on cell toxicity. About 50% of chromium(VI) was taken up and reduced in the cells by 90% to chromium(III) within 10 minutes. The initial uptake rate of chromium(HI) into cells was greater than 500-fold less than chromium(VI), and only about 5% was absorbed. The protection against carbon tetrachloride damage by chromium(VI) was attributed to its rapid uptake and conversion to chromium(III), and it was determined that chromium(III) acts as a radical scavenger for the free radicals generated by carbon tetrachloride within the cell. Furthermore, chromium(VI) pretreatment reduced the activity of NADPH cytochrome c reductase which metabolizes carbon tetrachloride to reactive species. 

Tezuka M, Sadanobu S, Gomi K, et al. 1995. In vitro effect of chromium and other trace metals on mouse hepatotoxicity induced by carbon tetrachloride exposure. Biol Pharm Bull 18(2) 25 6-261. 

Chronic carbon tetrachloride exposures have produced liver tumors in several rodent species, with the tumor types including hepatocellular carcinoma and adenoma, and adrenal pheochromocytoma. 

Benzene and carbon tetrachloride Exposure scores normalized to... 

Luton EF. Carbon tetrachloride exposure during anticoagulant therapy. Dangerous enhancement of hypoprothrombinemic effect. JAMA (1965) 194, 1386-7. 

The hepatotoxic effects of carbon tetrachloride are more severe in the setting of alcohol consumption. Animal studies demonstrate that the temporal relationship between ethanol ingestion and carbon tetrachloride exposure determines the severity of toxicity. Maximal hepatotoxieity is derived from ethanol ingested eighteen hours preceding exposure to carbon tetrachloride, - whereas exposure to ethanol three hours prior to carbon tetrachloride exposure leads to minimal hepatotoxieity. The mechanism for this interaction is... 

---