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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues
More trichloroethanol was produced in rat and mouse blood than in human blood. However, trichloroacetic acid production in lysed human blood was significantly greater than production in rat blood and slightly higher than in mouse blood. Erythrocytes were the site of trichloroacetic acid production. Plasma is the primary site of trichloroethanol production by blood.
Dichloroacetic Acid Metabolism
Dichloroacetic acid is a trichloroethylene metabolite found in rodents but is generally not identifiable in humans. Dichloroacetic acid degradation occurs primarily in rat hepatic cytosol (Lipscomb et al. 1995). Km values for dichloroacetic acid were 350, 280, and 71 µM and Vmax values were 13.1, 11.6, and 0.37 nmol/min/mg of protein in mice, rats, and humans, respectively (Lipscomb et al. 1995). Clearance values indicate that degradation of dichloroacetic acid in liver cytosol is less efficient in humans than in rodents.
Glutathione-Dependent Metabolism of Trichloroethylene
Glutathione conjugation of trichloroethylene is much slower than CYPcatalyzed oxidation reactions. Lash et al. (1999) exposed human volunteers (n = 21) to trichloroethylene vapors at 50, 60, or 100 ppm for 4 hours and measured metabolites produced by the glutathione pathway in blood and urine samples. S-(1,2-Dichlorovinyl)glutathione was detected in blood within 30 minutes after exposure was completed, and it persisted in the blood for up to 12 hours. Concentrations of S-(1,2-dichlorovinyl)glutathione were higher in males than in females. Formation of S-(1,2-dichlorovinyl)glutathi one is the initial step in the generation of nephrotoxic metabolites and does not directly correlate with it because subsequent detoxification reactions, such as mercapturate formation, can still occur (see Chapter 3 for specific details).
The rate of glutathione conjugation has been found to vary by as much as 3.4-fold in liver cytosol obtained from 9 males and 11 females and by as much as 8.5-fold in microsomes from 5 males and 15 females (Lipscomb et al. 2003). No significant sex-dependent differences in mean activity values were found, but the degree of variation was greater in microsomes from females (7.4-fold) than in males (4.1-fold). Although the overall degree of variation in glutathione S-transferase activity is significantly less than that observed with P-450 activity, it could be another factor to account for in a human health risk assessment of trichloroethylene.