Intravenous toxicokinetics of sulfur mustard and its DNA-adducts in the hairless guinea pig and marmoset
bookPart
ln order to provide a quantitative basis for pretreatment and therapy of intoxications with sulfur mustard the toxicokinetics of this agent as well as its major DNA-adducts are being studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. A highly sensitive method for bioanalysis of the intact agent in blood and tissues was developed, involving gas chromatography with automated thermodesorption injection and mass-spectrometric detection. Deuterated sulfur mustard is used as the internal standard. The absolute detection limit is 700 fg for sulfur mustard, which corresponds with a detection limit in blood of ca. 5 pg/ml.
DNA-adducts are measured via the previously developed immuno-slot-blot method, using antibodies directed against the adduct of sulfur mustard to guanine. The intravenous 96-h LD50 of sulfur mustard in the hairless guinea pig was determined and appeared to be 8.2 mg/kg. The intravenous toxicokinetics of this dose in the hairless guinea pig are characterized by a very rapid distribution phase and a very slow elimination phase. A rapid adduct formation occurs in blood and lung, and subsequently in other organs. The adduct levels in lung were remarkably high. A considerable repair of the adducts is observed within 6 h. However, at 2 days after administration of sulfur mustard adducts are still detectable in most of the organs studied. The intravenous toxicokinetics of sulfur mustard were also studied in the marmoset at a dose corresponding with 1 LD50 in the hairless guinea pig. The results obtained sofar will be discussed.
DNA-adducts are measured via the previously developed immuno-slot-blot method, using antibodies directed against the adduct of sulfur mustard to guanine. The intravenous 96-h LD50 of sulfur mustard in the hairless guinea pig was determined and appeared to be 8.2 mg/kg. The intravenous toxicokinetics of this dose in the hairless guinea pig are characterized by a very rapid distribution phase and a very slow elimination phase. A rapid adduct formation occurs in blood and lung, and subsequently in other organs. The adduct levels in lung were remarkably high. A considerable repair of the adducts is observed within 6 h. However, at 2 days after administration of sulfur mustard adducts are still detectable in most of the organs studied. The intravenous toxicokinetics of sulfur mustard were also studied in the marmoset at a dose corresponding with 1 LD50 in the hairless guinea pig. The results obtained sofar will be discussed.
Topics
TNO Identifier
518846
Source title
Prophylaxis and Therapy against Chemical Agents. Final report of the HFM-04/TG-004 for the Period 1999 to 2005
Collation
24 p.
Files
To receive the publication files, please send an e-mail request to TNO Repository.