A Human Physiologically Based Pharmacokinetic Model for Trichloroethylene and Its Metabolites, Trichloroacetic Acid and Free Trichloroethanol

Abstract

Nine male and eight female healthy volunteers were exposed to 50 or 100 ppm trichloroethylene vapors for 4 h. Blood, urine, and exhaled breath samples were collected for development of a physiologically based pharmacokinetic (PBPK) model for trichloroethylene and its two major P450-mediated metabolites, trichloroacetic acid and free trichloroethanol. Blood and urine were analyzed for trichloroethylene, chloral hydrate, free trichloroethanol and trichloroethanol glucuronide, and trichloroacetic acid. Plasma was analyzed for dichloroacetic acid. Trichloroethylene was also measured in exhaled breath samples. Trichloroethylene, free trichloroethanol, and trichloroacetic acid were found in blood samples of all volunteers and only trace amounts of dichloroacetic acid (4–12 ppb) were found in plasma samples from a few volunteers. Trichloroethanol glucuronide and trichloroacetic acid were found in urine of all volunteers. No chloral hydrate was detected in the volunteers. Gender-specific PBPK models were developed with fitted urinary rate constant values for each individual trichloroethylene exposure to describe urinary excretion of trichloroethanol glucuronide and trichloroacetic acid. Individual urinary excretion rate constants were necessary to account for the variability in the measured cumulative amount of metabolites excreted in the urine. However, the average amount of trichloroacetic acid and trichloroethanol glucuronide excreted in urine for each gender was predicted using mean urinary excretion rate constant values for each sex. A four-compartment physiological flow model was used for the metabolites (lung, liver, kidney, and body) and a six-compartment physiological flow model was used for trichloroethylene (lung, liver, kidney, fat, and slowly and rapidly perfused tissues). Metabolic capacity (Vmaxc) for oxidation of trichloroethylene was estimated to be 4 mg/kg/h in males and 5 mg/kg/h in females. Metabolized trichloroethylene was assumed to be converted to either free trichloroethanol (90%) or trichloroacetic acid (10%). Free trichloroethanol was glucuronidated forming trichloroethanol glucuronide or converted to trichloroacetic acid via back conversion of trichloroethanol to chloral (trichloroacetaldehyde). Trichloroethanol glucuronide and trichloroacetic acid were then excreted in urine. Gender-related pharmacokinetic differences in the uptake and metabolism of trichloroethylene were minor, but apparent. In general, the PBPK models for the male and female volunteers provided adequate predictions of the uptake of trichloroethylene and distribution of trichloroethylene and its metabolites, trichloroacetic acid and free trichloroethanol. The PBPK models for males and females consistently overpredicted exhaled breath concentrations of trichloroethylene immediately following the TCE exposure for a 2- to 4-h period. Further research is needed to better understand the biological determinants responsible for the observed variability in urinary excretion of trichloroethanol glucuronide and trichloroacetic acid and the metabolic pathway resulting in formation of dichloroacetic acid.