Title
Intravenous toxicokinetics of sulfur mustard and its DNA-adducts in the hairless guinea pig and marmoset
Author
Langenberg, J.P.
Spruit, W.E.T.
Kuijpers, W.C.
Mars, R.H.
van Helden, H.P.M.
van der Schans, G.P.
Benschop, H.P.
TNO Defensie en Veiligheid
Publication year
2009
Abstract
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.
Subject
Toxicokinetics
Mustard agents
DNA - Deoxyribonucleic acids
Guinea pigs
Therapy
Skin (anatomy)
Respiration
To reference this document use:
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TNO identifier
518846
Source
Prophylaxis and Therapy against Chemical Agents. Final report of the HFM-04/TG-004 for the Period 1999 to 2005
Document type
bookPart