1,1,2-trichloroethylene metabolism

Soucek and Vlachova 1960 Vesterberg and Astrand 1976). None of these studies provided evidence of saturation of trichloroethylene metabolism in humans. The data of Nomiyama and Nomiyama (1977) and of Ikeda (1977) indicated that the liver s capacity for metabolizing inhaled doses of trichloroethylene is... 

Saturation of trichloroethylene metabolism in mice occurs at higher dose levels than in rats (Dallas et al. 

Differential saturation of trichloroethylene metabolism by rats and mice has also been demonstrated using oral exposure regimens (Buben and O Flaherty 1985 Prout et al. 1985). Trichloroethylene metabolism... 

Excretion data show that saturability of trichloroethylene metabolism occurs at lower exposure levels for rats than for mice (Dekant et al. 1986b Prout et al. 1985). In mice receiving a single oral dose of 10, 500, 1,000, or 2,000 mg/kg trichloroethylene, urinary TCA and exhaled carbon dioxide over a 24-hour period were... 

Sato et al. (1991) expanded their earlier PBPK model to account for differences in body weight, body fat content, and sex and applied it to predicting the effect of these factors on trichloroethylene metabolism and excretion. Their model consisted of seven compartments (lung, vessel rich tissue, vessel poor tissue, muscle, fat tissue, gastrointestinal system, and hepatic system) and made various assumptions about the metabolic pathways considered. First-order Michaelis-Menten kinetics were assumed for simplicity, and the first metabolic product was assumed to be chloral hydrate, which was then converted to TCA and trichloroethanol. Further assumptions were that metabolism was limited to the hepatic compartment and that tissue and organ volumes were related to body weight. The metabolic parameters, (the scaling constant for the maximum rate of metabolism) and (the Michaelis constant), were those determined for trichloroethylene in a study by Koizumi (1989) and are presented in Table 2-3. 

Although trichloroethylene itself may not be genotoxic, several of its metabolites are reactive and potentially genotoxic compounds (Miller and Guengerich 1982). Several isomers of 1,2-dichlorovinyl-cysteine, a product of trichloroethylene metabolism in the kidney, are mutagenic in the in vitro Ames assay... 

Animal studies indicate that trichloroethylene can sensitize the heart to epinephrine-induced arrhythmias. Other chemicals can affect these epinephrine-induced cardiac arrhythmias in animals exposed to trichloroethylene. Phenobarbital treatment, which increases the metabolism of trichloroethylene, has been shown to reduce the trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1979), whereas high concentrations of ethanol, which inhibits trichloroethylene metabolism, have been found to potentiate trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1981). These results indicate that trichloroethylene itself and not a metabolite is responsible for the epinephrine-induced arrhythmias. In addition, caffeine has also been found to increase the incidence of epinephrine-induced arrhythmias in rabbits exposed to trichloroethylene (White and Carlson 1982). 

Trichloroethylene is exhaled following inhalation and oral exposures (Dallas et al. 1991 Koizumi et al. 1986 Stewart et al. 1970), whereas metabolites are mainly excreted in the urine (Fernandez et al. 1977 Koizumi et al. 1986 Monster etal. 1979 Sato et al. 1977). Based on the knowledge of trichloroethylene metabolism and excretion, potential methods for reducing the body burden are presented. These methods have not been used in persons or animals exposed to trichloroethylene and should be researched further before being applied. 

Attempts to diminish the overall metabolism of trichloroethylene might be useful (e.g., hypothermia, mixed-function oxidase inhibitors, competitive inhibitors of trichloroethylene metabolism [i.e., P-450 substrates]), if instituted soon enough after trichloroethylene exposure. Catecholamines (especially beta agonists) act in concert with trichloroethylene, increasing the risk of cardiac arrhythmias. Hence, catecholamines should be administered to patients only in the lowest efficacious doses and for certain limited presentations of trichloroethylene poisoning. Ethanol should also be avoided because concurrent exposure to trichloroethylene and ethanol can cause vasodilation and malaise and may potentiate central nervous system depression at high dosage levels of either compound. 

Bardodej Z, Vyskocil J. 1956. The problem of trichloroethylene in occupational medicine trichloroethylene metabolism and its effect on the nervous system evaluated as a means of hygienic control. AMA Arch Ind Health 56 581-592. 

Ensley BD. 1991. Biochemical diversity of trichloroethylene metabolism. Annu Rev Microbiol 45 283-299. 

Nakajima T, Wang RS, Murayama N, et al. 1990b. Three forms of trichloroethylene-metabolizing enzymes in rat liver induced by ethanol, phenobarbital, and 3-methylcholanthrene. Toxicol Appl Pharmacol 102 546-552. 

Nelson MJK, Montgomery SO, Pritchard PH. 1988. Trichloroethylene metabolism by microorganisms that degrade aromatic compounds. Appl Environ Microbiol 54 604-606. 

Seiji K, Inoue O, Jin C, et al. 1989. Dose-excretion relationship in tetrachloroethylene-exposed workers and the effect of tetrachloroethylene co-exposure on trichloroethylene metabolism. Am J Ind Med 16 675-684. 

Lipscomb, J.C., J.W. Fisher, P.D. Confer, and J.Z. Byczkowski. 1998. In vitro to in vivo extrapolation for trichloroethylene metabolism in humans. Toxicol. Appl. Pharmacol. 

The symptoms of poisoning from oral intake of trichloroethylene are nausea, vomiting, diarrhea, and gastric disturbances. The acute oral toxicity, however, is low. The oral LD50 value in mice is in the range 2500 mg/kg. Trichloroethylene metabolizes to trichloroacetic acid, which is excreted in the urine. 

Uncertain. One suggested mechanism is a disulfiram-like inhibition of acetaldehyde metabolism by trichloroethylene (see Alcohol + Disulfiram , p.61). Another suggested mechanism is inhibition of trichloroethylene metabolism in the presence of alcohol, resulting in increased plasma levels and possibly an accumulation of trichloroethylene in the CNS. ... 

The toxieity of triehloroethylene is dependent upon metabolism and induction of cytochrome P450. Triehloroethylene is metabolized through chloral hydrate to compounds including trichloroacetic acid and dichloroacetic acid which alter intercellular communication, induce peroxisome proliferation and may promote tumor production. Significant variability in trichloroethylene metabolism in 23 human haptic microsomal samples was reported by Lipscomb et al. It was also demonstrated that the trichloroethylene metabolism is dependent on enzymatic activities of the cytochrome system, and they conclude that their data indicates that humans are not uniform in their capacity for CPY dependent metabolism of trichloroethylene and increased activity may increase susceptibility to trichloroethylene induced toxicity in humans. These observations are compatible with the variability reaction which is depending on nutritional factors, enzyme induction factors, hormonal factors and interaction with other environmental chemicals, prescription medications and general health conditions, and explains the variable reports as far as trichloroethylene and level of liver toxicity in the various individuals studied. 

Lipscomb JC, Fisher JW, Confer PD, Byczkowski JZ (1998) In vitro to in vivo extrapolation for trichloroethylene metabolism in humans. Toxicol Appl Pharmacol 152 376-387 Liu HX, Yao XJ, Zhang RS, Liu MC, Hu ZD, Fan BT (2005a) Prediction of the tissue/blood partition coefficients of organic compounds based on the molecular structure using least-squares support vector machines. J Comput Aided Mol Des 19 499-508... 

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