Abstract
Rats were exposed to [1,2-14C] vinyl chloride in a closed system at initial concentrations below 100 ppm. When the system was occupied by 3 rats, a half-life of vinyl chloride in the system's atmosphere of 1.13 ± 0.12 h was observed. The volume of the system was 10.3 l. Calculation of the clearance of vinyl chloride from the system revealed that about 40% of inspired vinyl chloride is absorbed by lung. Therefore, changes in respiration did not influence uptake of vinyl chloride.
Uptake of vinyl chloride by the rats was completely blocked by acute pretreatment with potent inhibitors of cytochrome-P-450-dependent microsomal drug metabolism (i.e., by 35 mg/kg 3-bromophenyl-4(5)-imidazole or 50 mg/kg 6-nitro-1,2,3-benzothiadiazole in 0.6 ml/kg DMSO). A weaker inhibition was observed after dosing SKF 525 A or 5,6-dimethyl-1,2,3-benzothiadiazole (50 mg/kg in 0.6 ml/kg DMSO). Metyrapone did not cause inhibition.
Uptake of vinyl chloride was increased by pretreatment with DDT and, to a lesser extent, with clotrimazol. No significant stimulation of uptake was observed after pretreatment with phenobarbital, 3-methylcholanthrene, rifampicin, or chronic ethanol treatment.
Immediately after exposure, highest radioactivity levels were observed in liver and kidney. The radioactive metabolites of 14C-vinyl chloride were rapidly excreted, largely by the kidneys. Excretion of radioactivity in the urine was 69.4 ± 2.6% within 24 h.
Zusammenfassung
In einem geschlossenen System wurden Ratten initialen Konzentrationen an [1,2-14C] Vinylchlorid von unter 100 ppm ausgesetzt. Bei einer Besetzung des Systems durch 3 Ratten wurde in der Atmosphäre eine Halbwertszeit des gasförmigen Vinylchlorid von 1,13 ± 0,12 Std gemessen. Bei einem Volumen des Systems von 10,3 l ergab die Berechnung der Vinylchlorid Clearance, daß nur ca. 40% des von den Ratten eingeatmeten Vinylchlorid resorbiert wurde. Aus diesem Grunde führten Änderungen der Atemtätigkeit nicht zu Änderungen der Aufnahmegeschwindigkeit von Vinylchlorid.
Durch sehr wirksame Inhibitoren von Cytochrom-P-450-abhängigen mikrosomalen Oxidationen (3-Bromphenyl-4(5)-imidazol und 6-Nitro-1,2,3-benzothiadiazol) konnte die Aufnahme von Vinylchlorid vollständig verhindert werden. SKF 525 A und 5,6-Dimethyl-1,2,3-benzothiadiazol waren in dieser Hinsicht weit weniger wirksam.
Durch Vorbehandlung der Ratten mit DDT und, zum geringeren Maße, mit Clotrimazol wurde die Aufnahme von Vinylchlorid gesteigert. Keine signifikante Steigerung trat auf nach Vorbehandlung mit Phenobarbital, 3-Methylcholanthren, Rifampicin und nach chronischer Alkoholgabe.
Unmittelbar nach Beendigung der Exposition wurden die höchsten Radioaktivitätswerte in Leber und Niere festgestellt. Die Metabolite von 14C-Vinylchlorid wurden sehr schnell ausgeschieden. Bereits nach 24 Std wurden im Urin 69,4±2,6% der inkorporierten Radioaktivität gemessen.
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Bolt, H.M., Kappus, H., Buchter, A. et al. Disposition of [1,2-14C] vinyl chloride in the rat. Arch. Toxicol. 35, 153–162 (1976). https://doi.org/10.1007/BF00293562
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DOI: https://doi.org/10.1007/BF00293562
Key words
- Vinylchloride
- 3-Bromophenyl-4(5)-imidazole
- 6-Nitro-1,2,3-benzothiadiazole
- Inhibition of vinyl chloride metabolism
- Induction of vinyl chloride metabolism