Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: A dose-effect study

Buben, John A.; O’Flaherty, Ellen J.

doi:10.1016/0041-008x(85)90310-2

Cited by 107 publications

(64 citation statements)

References 29 publications

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“…Therefore, only a short summary of the rationale for the selection of noncancer dose metrics is included here. The relationship of various noncancer dose metrics across species is shown in Table 9 (73) have demonstrated that the relationship between the acute hepatotoxicity of TCE and the total production of urinary metabolites is linear, and it has been suggested that this result is consistent with the hypothesis that the toxicity is produced by reactive intermediates (13). Based on this assumption, the most reasonable dose metric for the hepatic toxicity of TCE would be the total amount of metabolism divided by the volume of the liver (18).…”

Section: Dose Metric Sdection Uncertaintysupporting

confidence: 70%

“…Several target tissues have also been identified for the noncancer toxicity of TCE, including the liver (73), kidney (65,66), CNS (74), immune system (75,76), and developing fetus (77). As in the case of the carcinogenicity of TCE, several of these noncancer end points appear to be associated with exposure to the metabolites of TCE rather than to the parent chemical itself (73,78).…”

Section: Introductionmentioning

confidence: 99%

“…As in the case of the carcinogenicity of TCE, several of these noncancer end points appear to be associated with exposure to the metabolites of TCE rather than to the parent chemical itself (73,78). In addition to the metabolites mentioned above with regard to the carcinogenicity of TCE, it was felt (43) that a PBPK model developed to support a noncancer risk assessment for TCE should also include a description of the kinetics of trichloroethanol (TCOH), a major metabolite of TCE that has been suggested to be responsible for the observed neurological effects of chloral hydrate (79).…”

Section: Introductionmentioning

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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Section: Dose Metric Sdection Uncertaintysupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…The effects on liver was further confirmed in recent reports of animal experiments with a single i.p. dose of <1000 mg/kg to mice (Rouisse and Chakrabarti 1986), or repeated oral dose of 1600 mg kg (Buben and O'Flaherty 1985) or supply of feed containing TRI by 4.41% to rats (Melnick et al 1987) ; all resulted in the liver damage as evidenced by elevated levels of GOT and GPT in serum or liver necrosis.…”

Section: Discussionmentioning

confidence: 99%

Increased subjective symptom prevalence among workers exposed to trichloroethylene at sub-OEL levels.

Liu

Jin

Chen

et al. 1988

Tohoku J. Exp. Med.

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Over 100 workers exposed to trichloroethylene (TRI) mostly at less than 50 ppm during the production or vapor degreasing operation and about an equal number of the non-exposed control workers were examined for subjective symptoms, hematology, serum biochemistry, and sugar, protein and occult blood in urine. Essentially all the clinico-laboratory tests stayed normal, and there was no significant difference in the findings between the exposed and the controls. Thus, no clinically significant effects of TRI exposure were found in the blood and liver functions among the exposed workers as compared with the controls. The prevalence of the subjective symptoms was, however, significantly higher in the exposed group than in the controls, and dose-response relationship could be established in some selected symptoms such as nausea, heavy feeling in the head, forgetfulness, tremor in extremities, cramp in extremities and dry mouth, although the exposure was low. The findings warrant further attention to the effects of TRI especially on the central nervous system at the concentration lower than, e.g., 50 ppm.

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“…It is a icity of these chemicals appears to be common and persistent environmental enhanced by their metabolism catalyzed by pollutant, and has been found in over one-liver cytochrome P450 (CYP) enzymes, third of hazardous waste sites and in 10% of which produce multiple reactive and/or groundwater sources (1). Exposure to TCE toxic metabolites (3). These metabolites and related chlorinated hydrocarbons is may act, at least in part, via peroxisome Abbreviations used: ADIOL-S, 5-androstene-3,, 17p-diol 3p-sulfate; CYP, cytochrome P450; DCA, dichloroacetic acid; DHEA, dehydroepiandrosterone; DHEA-S, DHEA 3,Bsulfate; DMEM, Dulbecco's modified Eagle's medium; PPAR, peroxisome proliferator-activated receptor; PPARa knockout mice, (-/-), PPARa wild-type mice, (+); RXR, retinoid X receptor; TCA, trichloroacetic acid; TCE, trichloroethylene; Wy-14,643, pirinixic acid.…”

Section: Introductionmentioning

confidence: 99%

Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids.

Zhou

Waxman

1998

Environ Health Perspect

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Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: A dose-effect study

Cited by 107 publications

References 29 publications

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

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

Increased subjective symptom prevalence among workers exposed to trichloroethylene at sub-OEL levels.

Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids.

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