Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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Appendix C Trichloroethylene Metabolism
Appendix C Trichloroethylene Metabolism
Pages 390-405
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From page 390... ...
appendix C Trichloroethylene Metabolism Knowledge of trichloroethylene metabolism is critical for determining susceptibility, target organ specificity, and gender and species differences and for extrapolating animal data to humans.
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Species differences exist in the fraction of administered dose of trichloroethylene that becomes available for conversion to toxic metabolites in the target organs because of differences in blood flow and overall metabolic rate. For example, blood concentrations of the three metabolites of trichloroethylene -- chloral hydrate, trichloroethanol, and trichloroacetic acid-over time after administration of an oral dose of trichloroethylene at 1,000 mg/kg to male Osborne-Mendel rats and male B6C3F1 mice were markedly higher in mice than in rats, whereas concentrations for trichloroethylene were higher in rats than in mice, indicating more rapid metabolism and elimination of trichloroethylene (Prout et al.
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32 APPENDIX C of trichloroethylene by metabolism was inversely related to dose and was nonlinear, suggesting that trace amounts of trichloroethylene in the drinking water might not enter the systemic circulation. Trichloroethylene enters the systemic circulation rapidly after inhalation exposure (Fisher et al.
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34 APPENDIX C FIGURE C-1 Metabolism of trichloroethylene. Metabolites marked with u are known urinary metabolites.
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APPENDIX C 3 TABLE C-2 Kinetic Constants for Total Oxidative Metabolite Formation from Trichloroethylenea Species Vmax (nmol/mg/min)
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36 APPENDIX C Chloral hydrate is further metabolized to either trichloroethanol or trichloroacetic acid, both of which can be further oxidized to dichloroacetic acid. Some formation of dichloroacetic acid directly from trichloroacetic acid has been observed (Abbas et al.
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APPENDIX C 3 Dichloroacetic acid formation (Figure C-1) , particularly in humans, has been a controversial issue.
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38 APPENDIX C sex- and sPeCies-dePendent oxidative metaBolism Trichloroethylene metabolism differs considerably among species (Lipscomb et al. 1997; Verma and Rana 2003)
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APPENDIX C 3 gate is a critical step for subsequent formation of cytotoxic or carcinogenic metabolites. Metabolism of S-(1,2-Dichlorovinyl)
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Glutathione-Dependent Metabolism: Tissue, Sex, and Species Differences The liver and kidneys are the major sites of glutathione conjugation. Because trichloroethylene undergoes glutathione conjugation and is translocated to the kidneys for further metabolism, most glutathione conjugation is thought to occur in the liver.
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APPENDIX C 401 TABLE C-3 Summary of Metabolism of Trichloroethylene by Glutathione Conjugation in Kidney and Liver Subcellular Fractions from Male and Female F344 Rats and B6C3F1 Micea S-(1,2-Dichlorovinyl) glutathione Formation (nmol/mg of protein or 106 cells per 60 min)
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402 APPENDIX C trichloroethylene. Trichloroethanol glucuronide can undergo enterohepatic recirculation and regenerate trichloroethanol.
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APPENDIX C 403 sPeCies diffeRenCes CYP-Dependent Metabolism of Trichloroethylene In vitro data on metabolite parameters for the oxidative metabolism of trichloroethylene are presented in Table C-5. The data show that humans are less capable than rodents of metabolizing trichloroethylene and chloral hydrate.
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404 APPENDIX C TABLE C-6 Overall Kinetics of Trichloroethylene Metabolism to Chloral Hydrate and Trichloroethanol Species Km (µM trichloroethylene) Vmax (pmol/min/mg)
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APPENDIX C 40 More trichloroethanol was produced in rat and mouse blood than in human blood. However, trichloroacetic acid production in lysed human blood was significantly greater than production in rat blood and slightly higher than in mouse blood.
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