among those tissues, between 6 and 7 hours (Dallas et al 1994). In poorly perfused tissues, such as fat and muscle, peak tetrachloroethylene concentrations are reached after a longer delay, which may be an hour or more than a day for adipose tissue. The elimination of tetrachloroethylene from fat is also much slower than that from other tissues and can take twice as long (Dallas et al. 1994). Because of its lipophilicity, the highest concentrations of tetrachloroethylene are found in adipose tissue (Savolainen et al. 1977; Dallas et al. 1994). In humans, the fat-to-blood concentration ratio has been estimated to be as high as 90:1 (Monster et al. 1979). Relatively high concentrations are also observed in the liver and brain (Savolainen et al. 1977). On the basis of animal studies and sparse human data, the brain concentration of tetrachloroethylene is 4-8 times the blood concentration (Dallas et al. 1994; Lukaszewski 1979).

The disposition of an absorbed dose of tetrachloroethylene occurs primarily through pulmonary excretion; metabolism is less important than for other chlorinated solvents, such as trichloroethylene. Mass-balance studies in rats with 14C-labeled tetrachloroethylene indicated that 70% or more of an oral or inhaled dose can be recovered in expired air as the parent compound (Pegg et al. 1979; Frantz and Watanabe 1983). The next most important excreted fraction occurs in urine and feces, which may collectively account for up to 23% of an administered dose. A small portion of the dose (less than 3%) may be converted to CO2 and exhaled. Most of the radioactivity recovered in urine can be attributed to formation of trichloroacetic acid, a nonvolatile metabolite of tetrachloroethylene that is excreted primarily in urine. That general pattern of disposition of tetrachloroethylene appears to be consistent after both oral and inhalation dosing (Pegg et al. 1979). However, it is important to note that the highest urinary and fecal elimination coincide with lower administered doses of tetrachloroethylene.

Despite the low overall metabolism of tetrachloroethylene compared with other chlorinated solvents, its metabolism has been studied extensively in both human volunteers and laboratory animals, using both in vivo and in vitro techniques. The studies showed that many metabolites are produced, including some known to be cytotoxic, mutagenic or both. Tetrachloroethylene metabolism can be viewed as having three pathways. The first is cytochrome P-450-mediated (CYP-mediated) oxidation. The second and third share a starting point: direct conjugation with glutathione to S-(1,2,2-trichlorovinyl)glutathione (TCVG) and then further processing to S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC). For the second pathway, β-lyase catalyzes the formation of reactive products from TCVC. The third pathway is independent of β-lyase: TCVC is processed further by acetylation and sulfoxidation reactions. Genotoxic and cytotoxic metabolites are formed by each of these pathways. The predominant metabolic pathway is the CYP path, followed by the β-lyase pathway and then the β-lyase independent pathway. The TCVC derivatives are toxicologically important but quantitatively minor metabolites. A simplified scheme is shown in Figure 2-1.



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