Toxicokinetics of topical sulfur mustard penetration, disposition, and vascular toxicity in isolated perfused porcine skin.
Sulfur mustard bis(2-chloroethyl) sulfide (HD) is a bifunctional alkylating agent that causes cutaneous vesication. The isolated perfused porcine skin flap is an in vitro model that has been used to study this toxic response. The purpose of this study was to formulate a toxicokinetic model of HD penetration and cutaneous disposition as an aid in correlating critical steps in the pathogenesis of vesication to HD concentrations in different regions of skin. [14C]HD was dosed topically in ethanol at 10.0 mg/ml in a 7.5-cm2 dosing site and venous efflux samples were collected over 2, 4, or 8 hr. At the termination of the experiment, stratum corneum tape strips, core biopsies for serial sections, and the entire skin flap were collected for radioassay. Peak 14C-radiolabel flux occurred within 5 to 60 min in all skin flaps, much earlier than signs of HD-induced toxicity. A toxicokinetic model was used to quantitate the time profile of HD disposition in different skin compartments. Estimates of vascular and extracellular volume changes due to topical HD toxicity were estimated using radiolabeled albumin and inulin infusions. A second toxicokinetic model, with a time-variant distribution rate, was used to simulate volume changes. In order to accurately predict HD disposition, it was necessary to add another compartment as a reservoir for slowly released metabolites of HD. This model provides a quantitative profile of the time course of HD (or metabolites) disposition within skin which would aid in the interpretation of mechanistic studies of vesication as well as in designing interventive antivesicant drug strategies.
D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D003879:Dermatologic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D066298:In Vitro Techniques; D008954:Models, Biological; D009151:Mustard Gas / Q000493:pharmacokinetics* / Q000633:toxicity*; D010477:Perfusion; D012867:Skin / Q000098:blood supply* / Q000187:drug effects*; D012869:Skin Absorption / Q000187:drug effects*; D013552:Swine
D003879:Dermatologic Agents; D009151:Mustard Gas