Mode of action

The toxicity of tetrachloroethylene is due to biologically active metabolites rather than the parent compound itself. Covalent binding to hepatic macromolecules by reactive metabolites has been demonstrated in vivo (Pegg et al., 1979; Schumann et al., 1980) and in vitro (Bonse et al., 1975). However, binding to hepatic DNA has not been observed (Schumann et al., 1980).

Liver carcinogenicity observed in B6C3F1 mice may be due to repeated cytotoxicity and exacerbation of the high incidence of liver tumours in this strain (Schumann et al., 1980), or due to trichloroacetic acid-induced hepatic peroxisome proliferation (Odum et al., 1988). Both of these hypotheses involve a non-genotoxic mechanism for carcinogenicity. Trichloroacetic acid has been shown to cause hepatocellular carcinoma in male B6C3F1 mice when administered in their drinking water (Herren-Freund et al., 1987). Trichloroacetic acid does not induce peroxisome proliferation in human hepatocytes (Elcombe, 1985) and primates do not respond to peroxisome proliferation to the same extent as rodents (Cohen and Grasso, 1981). As the metabolites are the cause of the toxic effects of tetrachloroethylene, the greater the metabolism the greater the risk of toxicity. This was demonstrated in a study comparing B6C3F1 mice and Sprague-Dawley rats. The mice metabolised more tetrachloroethylene and produced a greater quantity of active metabolites. This resulted in a greater degree of liver damage when compared to the rats (Schumann et al., 1980).

The mechanism by which tetrachloroethylene induces renal injury is unknown. The metabolite 1,2,2,-trichlorovinylcysteine can be cleaved by renal P-lyase and the products, pyruvate and ammonia, indicate that trichlorovinylthiol is produced as a third cleavage product. This compound is unstable and can react (through hydrogen chloride elimination) to form dichlorothioketene or (through molecular rearrangement) dichloroethylthionyl chloride. Both these compounds are reactive species which can cause DNA damage and renal toxicity (BUA, 1996). This pathway of glutathione conjugation is less efficient in humans compared to rodents and this would suggest that humans are at less risk of renal toxicity (Birner et al., 1996). However, low concentrations of 1,2,2-trichlorovinyl-N-acetylcysteine could indicate more efficient metabolism through the P-lyase pathway, which would mean that humans were at greater risk of renal toxicity. However, the activity of this enzyme in humans is much less than that in rats (Green et al., 1990) and this would not support the latter hypothesis (Birner et al., 1996). Renal toxicity of tetrachloroethylene may involve the formation of free radicals (Salahudeen, 1998). Depletion of glutathione (a free radical scavenger) may make cells more susceptible to free radical damage. Also, the pathway for the epoxide metabolite may involve nucleophilic attack, and reactive oxygen metabolites may also result from peroxidase proliferation.

Renal toxicity may be rare in humans because the metabolism of tetrachloroethylene may become saturated (Ikeda et al., 1972; Ikeda, 1977). As a result the kidney concentration of reactive metabolites may remain low (Solet and Robins, 1991).

The metabolites of tetrachloroethylene, like other chlorinated hydrocarbons, may interact with the tubero-infundibular dopaminergic system forming tetrahydroisoquinolones resulting in dopamine depletion (Mutti and Franchini, 1987). This may manifest as changes in neuroendocrine function and be the cause of the behavioural changes (Mutti and Franchini, 1987) and reproductive effects reported with tetrachloroethylene (Ferroni et al., 1992). 2,2,2-Trichloroethanol, a possible metabolite of tetrachloroethylene, has been shown to potentiate the GABA-activated current in CNS neurones in vitro and this may contribute to the depressant effect of this solvent (Peoples and Weight, 1994).

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