Description: Das Projekt "Vergleich des Stoffwechsels von Tetrachlorethylen in Ratten und Menschen: ein Versuch zur verbesserten Bestimmung der Risiken einer Tetrachlorethylenexposition fuer den Menschen" wird vom Umweltbundesamt gefördert und von Universität Würzburg, Institut für Pharmakologie und Toxikologie durchgeführt. Tetrachloroethylene (TETRA) is a widely used solvent and, due to its volatility and resistance to degradation, a widely distributed environmental contaminant. TETRA shows only low acute toxicity, but was found to be tumorigenic in rodents causing liver tumors in mice and kidney tumors in male rats. The chronic toxicity of TETRA is due to bioactivation reactions. Two different bioactivation pathways of TETRA have been elucidated. TETRA is oxidized by cytochrome P-450 or conjugated with glutathione by glutathione S-transferases. Oxalic acid and trichloroacetic acid are stable metabolites formed by oxidation with cytochrome P450 and represents the major urinary metabolite of TETRA in rats and in humans. Reduction of trichloroacetic acid yields trichloroethanol, which may be excreted by glucuronic acid conjugation and has been identified as urinary metabolite in rats. The bioactivation mechanisms likely responsible for TETRA nephrotoxicity, which may also be involved in renal tumor formation in rats have been elucidated. The formation of S-(1,2,2-trichlorovinyl)glutathione (TCVG) in the liver is catalysed by glutathione S- transferases. TCVG is excreted with bile and further metabolized by gamma-glutamyltransferase and dipeptidases to S- (1 ,2,2-trichlorovinyl)-L-cysteine (TCVC), which is acetylated after reabsorption to give N acetyl-S-(1,2,2-trichloro- vinyl)-L-cysteine (N-Ac-TCVC). This S-conjugate is accumulated in the kidney and may be excreted in the urine. N- Ac-TCVC is a metabolite of TETRA found in rats. No information on the biosynthesis and excretion of S-conjugates in TETRA metabolism in humans in vivo is available; one study in in vitro subcellular fractions of one human liver failed to demonstrate the formation of TCVG. TCVC is mutagenic in several strains of Salmonella typhimurium induces unscheduled DNA-synthesis in cultured renal cells and is toxic to rat kidney cells. It is cleaved by cysteine conjugate beta-lyase, which is present in human renal epithelial cells, to yield pyruvate, ammonia, and dichlorothio- ketene. Dichlorothioketene is presumed to be the ultimate metabolite responsible for the mutagenic and nephro- toxic effects of TETRA by reaction with macromolecules. To obtain information about the formation of mercapturic acids and its relevancy for his use as biomarker for TETRA exposure, controlled exposures of humans and rats were planned. The formation and excretion of N-Ac-TCVC, trichloroacetic acid, trichloroethanol and dichloroacetic acid was quantified after exposure of rats and humans to 10, 20 and 40 ppm TETRA for 6 h by inhalation to simulate occupational exposure. The concentrations used were lower than the limit for occupational TETRA exposure in the German MAK-list. Experiments under the same exposure conditions with male and female rats permit a comparison on the relative excretion of these metabolites in humans and rats and are thus a basis for risk comparisons. The result of these studies will be published in
Types:
SupportProgram
Origin: /Bund/UBA/UFORDAT
Tags: Nagetier ? Oxalsäure ? Tetrachlorethen ? Trichloressigsäure ? Tierhaltungsanlage ? Gesundheitsgefährdung ? Inhalation ? Ammoniak ? Biomarker ? Gesundheitsschaden ? Urin ? Lösungsmittel ? Pflanzensamen ? Schadstoffwirkung ? Cytochrom ? Arbeitsmedizin ? Maus ? Pharmakologie ? Ratte ? Schadstoffexposition ? Stoffwechselprodukt ? Akute Toxizität ? Chronische Toxizität ? Vinylchlorid ? Tumor ? Kausalzusammenhang ? Krebserkrankung ? Oxidation ? Studie ? Toxikologie ? Toxikologische Bewertung ? Berufsgruppe ? Biosynthese ? Medizin ? Risikoanalyse ? Volatilität ? Salmonellen ? Mensch ? Exkretion ? Stoffbewertung ? Stoffwechsel ? Risiko ?
Region: Bayern
Bounding box: 12.53381° .. 12.53381° x 47.795° .. 47.795°
License: cc-by-nc-nd/4.0
Language: Deutsch
Time ranges: 1995-07-01 - 1998-06-30
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