Toxicokinetics of Sulphur-Adducts in the Hairless Guinea Pig - DNA-Adducts as a Measure for Epithelial Damage. Midterm Report.
PRINS MAURITS LABORATORIUM TNO RIJSWIJK(NETHERLANDS)
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In order to provide a quantitative basis for pretreatment and therapy of intoxication with sulphur mustard SM the toxicokinetics of this agent as well as its major DNA-adduct, 7-SM-guanine, are studied in male hairless guinea pigs for the intravenous i.v., respiratory and percutaneous routes. A highly sensitive method for bio-analysis of the intact agent in blood and tissues was developed, involving gas chromatography with mass-spectrometric detection. Deuterated sulphur mustard D8-SM is used as the internal standard. 7-SM-guanine is measured with an immuno-slot-blot assay. In this midterm report, the first results on the i.v. toxicokinetics of SM and 7-SM-guanine in hairless guinea pigs are presented. The 96-h i.v. LD50 appeared to be 8.2 mgkg 95 confidence interval 7.1-8.8 mgkg. The i.v. toxicokinetics of SM for a dose corresponding with 1 LD50 are characterized by a very rapid distribution phase and very slow elimination phase, with half-lives of 0.77 and 107 min, respectively. Three mins after i.v. administration of 1 LD50 SM, 7-SM-guanine was already present in blood, lung, spleen, bone marrow, liver and small intestine. The highest initial adduct levels were found in lung. Whereas most of the adducts had disappeared within 6 h of SM administration, significant adduct levels were still present in most tissues 48 h after administration.
- Medicine and Medical Research
- Chemical, Biological and Radiological Warfare