Toxicokinetics of Sulfur Mustard and Its DNA-Adducts in the Hairless Guinea Pig - DNA-Adducts as a Measure for Epithelial Damage

摘要

The toxicokinetics of sulfur mustard (SM) as well as of its major DNA-adduct were studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. The study comprised measurement of the concentration-time course of SM in blood and measurement of the concentrations of intact SM and its DNA-adduct in various tissues at several time points after administration of, or exposure to SM. SM was analyzed in blood and tissues by gas chromatography with large volume injection and mass-spectrometric or pulsed- flame photometric dejection. DNA-adducts were measured via an immunoslotblot assay or immunofluorescence microscopy. The intravenous toxicokinetics of SM are characterized by a very rapid distribution phase and a very slow elimination phase. SM partitions strongly to various organs. The toxicokinetics are non- linear with dose. The respiratory toxicity of SM appears to be of a local, rather than a systemic nature, since concentrations of SM in blood could only be found during and after nose-only exposure to 3 LCt50 (2,400 mg.min./m). SM could also be measured in blood during and after percutaneous exposure to 1 LCt50 (10, 000 mg.min./m, estimated). Pretreatment of hairless guinea pigs with the potential scavengers N-acetyl cysteine or cysteine isopropyl ester did not significantly increase the LCt50-value for nose-only exposure to SM vapor. Topical skin protectants 1511 and 2701 protected very well against skin damage resulting from exposure to SM vapor or liquid.