Metabolism of trichloroethylene

Ikeda, Mikiko; Miyake, Yuichiro; Ogata, Masana; Ohmori, Shinji

doi:10.1016/0006-2952(80)90048-9

Cited by 47 publications

(15 citation statements)

References 21 publications

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“…We observed metabolism of CH to TCE-OH and TCA in rat hepatocytes in agreement with the findings of others using rats or in vitro systems (Ikeda et al, 1980;Miller and Guengerich, 1983;Elcombe, 1985;Davidson, and Beliles, 1991;Lipscomb et al, 1996;Elfarra et al, 1998;DeSmet et al, 2000;Bloemen et al, 2001). Rat hepatocytes readily metabolised CH to TCE-OH with an apparent Km of 1.2 ± 0.2mM and Vmax of 1.45 ± 0.09nmol/min/ 10 6 cells.…”

Section: Discussionsupporting

confidence: 90%

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

et al. 2007

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The industrial solvent trichloroethylene (TCE) and its major metabolites have been shown to cause formic aciduria in male rats. We have examined whether chloral hydrate (CH) and trichloroacetic acid (TCA), known metabolites of TCE, produce an increase in formic acid in vitro in cultures of rat hepatocytes or human renal proximal tubule cells (HRPTC). The metabolism and cytotoxicity of CH was also examined to establish that the cells were metabolically active and not compromised by toxicity. Rat hepatocytes and HRPTC were cultured in serum-free medium and then treated with 0.3-3mM CH for 3 days or 0.03-3mM CH for 10 days respectively and formic acid production, metabolism to trichloroethanol (TCE-OH) and TCA and cytotoxicity determined. No increase in formic acid production in rat hepatocytes or HRPTC exposed to CH was observed over and above that due to chemical degradation, neither was formic acid production observed in rat hepatocytes exposed to TCA. HRPTC metabolised CH to TCE-OH and TCA with a 12-fold greater capacity to form TCE-OH versus TCA. Rat hepatocytes exhibited a 1.6-fold and 3-fold greater capacity than HRPTC to form TCE-OH and TCA respectively. CH and TCA were not cytotoxic to rat hepatocytes at concentrations up to 3mM/day for 3 days. With HRPTC, one sample showed no cytotoxicity to CH at concentrations up to 3mM/day for 10 days, while in another cytotoxicity was seen at 1mM/ day for 3 days. In summary, increased formic acid production was not observed in rat hepatocytes or HRPTC exposed to TCE metabolites, suggesting that the in vivo response cannot be modelled in vitro. CH was toxic to HRPTC at millimolar concentrations/day over 10 days, while glutathione derived metabolites of TCE were toxic at micromolar concentrations/day over 10 days supporting the view that glutathione derived metabolites are likely to be responsible for nephrotoxicity.

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Section: Discussionsupporting

confidence: 90%

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

et al. 2007

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“…93 CHL is not stable in vivo, and circulating concentrations are relatively low compared to its breakdown products, TCA and TCOH. 90 Within a few hours of the administration of 50 mg/kg chloral hydrate to a child, the rapid initial clearance of CHL was essentially complete, with subsequent blood concentrations paralleling the time course for TCOH but approximately an order of magnitude lower, suggesting a continuing production of CHL from TCOH.…”

Section: A Oxidative Metabolismmentioning

confidence: 97%

“…The principal oxidative metabolite formed in vitro is CHL (in its hydrated form, chloral hydrate), 93,94,97 which is subsequently reduced to TCOH in the cytosol or oxidized to TCA in either the cytosol or mitochondria. 93 CHL is not stable in vivo, and circulating concentrations are relatively low compared to its breakdown products, TCA and TCOH.…”

Section: A Oxidative Metabolismmentioning

confidence: 99%

Applying Mode-of-Action and Pharmacokinetic Considerations in Contemporary Cancer Risk Assessments: An Example with Trichloroethylene

Clewell

Andersen

2004

Critical Reviews in Toxicology

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The guidelines for carcinogen risk assessment recently proposed by the U.S. Environmental Protection Agency (U.S. EPA) provide an increased opportunity for the consideration of pharmacokinetic and mechanistic data in the risk assessment process. However, the greater flexibility of the new guidelines can also make their actual implementation for a particular chemical highly problematic. To illuminate the process of performing a cancer risk assessment under the new guidelines, the rationale for a state-of-the-science risk assessment for trichloroethylene (TCE) is presented. For TCE, there is evidence of increased cell proliferation due to receptor interaction or cytotoxicity in every instance in which tumors are observed, and most tumors represent an increase in the incidence of a commonly observed, species-specific lesion. A physiologically based pharmacokinetic (PBPK) model was applied to estimate target tissue doses for the three principal animal tumors associated with TCE exposure: liver, lung, and kidney. The lowest points of departure (lower bound estimates of the exposure associated with 10% tumor incidence) for lifetime human exposure to TCE were obtained for mouse liver tumors, assuming a mode of action primarily involving the mitogenicity of the metabolite trichloroacetic acid (TCA). The associated linear unit risk estimates for mouse liver tumors are 1.5 x 10(-6) for lifetime exposure to 1 microg TCE per cubic meter in air and 0.4 x 10(-6) for lifetime exposure to 1 microg TCE per liter in drinking water. However, these risk estimates ignore the evidence that the human is likely to be much less responsive than the mouse to the carcinogenic effects of TCA in the liver and that the carcinogenic effects of TCE are unlikely to occur at low environmental exposures. Based on consideration of the most plausible carcinogenic modes of action of TCE, a margin-of-exposure (MOE) approach would appear to be more appropriate. Applying an MOE of 1000, environmental exposures below 66 microg TCE per cubic meter in air and 265 microg TCE per liter in drinking water are considered unlikely to present a carcinogenic hazard to human health.

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“…The primary route of metabolism for TCE, shown on the right side of the diagram in Figure 1, is oxidation via the microsomal mixed-function oxidase (MFO) system, now referred to as cytochrome P450, or CYP (96)(97)(98)(99)(100)(101)(102). A minor pathway for TCE metabolism involving conjugation with glutathione (GSH) by glutathione transferase (GST) has also been observed (103).…”

Section: Metabolism Oftcementioning

confidence: 99%

“…The principal oxidative metabolite formed in vitro is CHL (96,97,100), which is subsequently reduced to TCOH in the cytosol or oxidized to TCA in either the cytosol or mitochondria (96). CHL is not stable in vivo, and circulating concentrations are relatively low compared to its breakdown products, TCA and TCOH (50).…”

Section: Metabolism Oftcementioning

confidence: 99%

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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Metabolism of trichloroethylene

Cited by 47 publications

References 21 publications

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

Lack of formic acid production in rat hepatocytes and human renal proximal tubule cells exposed to chloral hydrate or trichloroacetic acid

Applying Mode-of-Action and Pharmacokinetic Considerations in Contemporary Cancer Risk Assessments: An Example with Trichloroethylene

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

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