Toxicokinetics of Sulfur Mustard and its Dna-Adducts in the Hairless Guinea Pig

Abstract

In order to provide a quantitative basis for pretreatment and therapy of intoxications with sulfur mustard (SM) the toxicokinetics of this agent as well as 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 adduct to guanine 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 automated thermodesorption injection and mass-spectrometric detection. DNA-adducts were measured via an immuno-slot-blot method. In contrast with nerve agents of the phosphofluoridate type, SM partitions strongly to various organs, especially the lung, spleen, liver and bone marrow. The respiratory toxicity of SM appears to be local, rather than systemic. Surprisingly, the maximum concentration of SM in blood upon percutaneous exposure to 1 LCt50 (10,000 mg.min.m-3, estimated) is approximately 6-fold higher than that for nose--only exposure to 3 LCt50 (2,400 mg.min.m-3). 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.

Inhalation and Percutaneous Toxicokinetics of Sulfur Mustard and Its adducts in Hairless Guinea Pigs and Marmosets. Efficacy of Nasal Scavengers

“…As already stated above, we observed a strikingly similar phenomenon in the concentration-time profiles of sulfur mustard in blood for percutaneous and respiratory exposure (Langenberg et al 1998). As in the case of inhalation toxicokinetics, the percutaneous toxicokinetics of sulfur mustard in the hairless guinea pig appeared to be characterized by the existence of two absorption phases, one relatively rapid and one relatively slow.…”

“…LIST OF TABLES Page Table 1. The concentration of sulfur mustard vapor to which the individual animals were exposed 22 In 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-adduct (N7-HETE-gua) were studied for the intravenous, respiratory and percutaneous routes, within the framework of Cooperative Agreement DAMD17-94-V-4009 (Langenberg et al 1998). The experiments were performed in the hairless guinea pig, which is considered to be a suitable animal model in studies of sulfur mustard since the thickness of the epidermis and the effect of sulfur mustard on the skin is reasonably comparable to that in man (Mershon et al 1990).…”

“…In the Final Report of Cooperative Agreement DAMD17-94-V-4009 we have made some speculations with respect to the toxicologically relevant level of sulfur mustard in blood and/or tissues and the time course thereof (Langenberg et al 1998). Obviously, the strategy of (pre)treatment of intoxication with sulfur mustard would benefit from definition of such a time period.…”

“…The concentration-time course of sulfur mustard in blood will be determined, and the concentrations of intact sulfur mustard and N7-HETE-gua in blood and tissues will be measured at various time points after ending the nose-only exposure. Furthermore, the distribution of N7-HETE-gua within the respiratory tract of the marmoset will be studied, and the tract will be examined histopathologically, as was previously performed for hairless guinea pigs (Langenberg et al 1998). …”

“…The apparatus for controlled generation of SM vapor in air is described in detail elsewhere (Langenberg et al 1998). …”