Absorption, elimination and metabolism of trichloroethylene: a quantitative comparison between rats and mice

Dekant, W.; Schulz, Arthur R.; Metzler, Manfred; Henschler, D.

doi:10.3109/00498258609043517

Cited by 73 publications

(29 citation statements)

References 14 publications

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“…As shown in Table 8, the predicted ratio of TCOH:TCA is 10 to 20, depending on species. These predictions agree well with the observed urinary elimination of TCOH and TCA in mice and rats exposed to 200 mg TCE/kg (53,54) and with initial (0-1 hr) plasma levels of metabolites observed in CH-exposed humans, where the levels of TCOH were slightly higher than plasma levels (79,80). Figure 1, the other possible fate of TCE besides oxidative metabolism is conjugation with GSH, which is catalyzed by the GSTs.…”

Section: Variations Among Humanssupporting

confidence: 78%

Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

246

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A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex-and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ,B Iyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from in vitro studies, can be extrapolated to humans for risk assessment.

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Section: Variations Among Humanssupporting

confidence: 78%

Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

246

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“…The low fecal excretion is apparently associated to some extent with enterohepatic recirculation of TCOH (i.e., biliary excretion of the glucuronide, followed by hydrolysis and reabsorption of TCOH), which has also been suggested to occur in rats (119). DCA has been identified as a minor urinary metabolite of TCE (on the order of 1%) in both rats and mice (114,115,117,120), whereas MCA appears to be present at less than 0.1% (114) (124). Significantly, the clearance in humans appears to be much more rapid than would be expected from allometric scaling of animal data.…”

Section: Metabolism Oftcementioning

confidence: 82%

“…The relative proportion of the major metabolites does not appear to be a strong function of dose. However, repeated dosing does appear to increase the production of TCA at the expense of TCOH (114), and the relative production of CO2 increases with increasing dose in mice (115 (117). A study of TCE metabolism in nonhuman primates (118) found that TCA was partially excreted as the glucuronide, particularly at longer times after dosing.…”

Section: Metabolism Oftcementioning

confidence: 99%

“…An alternative mechanism was proposed, in which direct conjugation of TCE with GSH in the liver was followed by further metabolism in the kidney to a cysteine conjugate that could then be cleaved to a reactive intermediate in the kidney tubular cells (131). The cysteine conjugate formed from TCE, DCVC, has been shown to be highly nephrotoxic (78) and mutagenic in the Ames test (115).…”

Section: Dose Metric Sdection Uncertaintymentioning

confidence: 99%

“…To apply these approaches to (100). Sex, pregnancy, and age-related differences in metabolism can result from normal variations in CYP 2E1 content (101); increased metabolism can result from the inducibility of CYP 1A1/2 (e.g., by aromatics), 2B1 (e.g., by phenobarbital), or 2E1 (e.g., by ethanol) (102,115). Studies of human populations have shown that the activity of the CYP enzymes can vary by more than a factor of 10 between individuals (152,174,175), and that there is a genetic difference (polymorphism) between individuals with high activity and low activity that is associated with a different susceptibility to cancer (176).…”

Section: Dose Metric Sdection Uncertaintymentioning

confidence: 99%

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Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Covington¹,

Clewell²,

Fisher³

2004

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A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating crossspecies differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

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