A 7‐Day Mouse Model to Assess Protection from Sulfur Mustard (SM) Skin Injury

The mouse ear vesicant model (MEVM) is a screening tool used to identify protective compounds against acute sulfur mustard (SM)‐induced skin injury. It provides endpoints of edema and histopathology 24 h following a topical SM exposure to assess protection against inflammation and tissue damage. To further evaluate successful compounds, the MEVM was modified for use as a 7‐day model. Dose response studies were conducted with SM to select an optimal challenge dose for the new model. Due to severity of SM‐induced tissue damage by Day 7, edema and histopathology were determined unreliable endpoints. Therefore, a modified Draize scoring system (no damage to extensive necrosis) was incorporated as an endpoint to evaluate tissue damage out to Day 7. To aid in optimal SM dose selection, retro synthetic capsaicin (RSCAP), a protective compound in the MEVM, was evaluated as a treatment 15 min before exposure to 0.06, 0.08, and 0.16 mg SM. The RSCAP compound provided similar significant protection at Day 7 against the 0.06‐ (42% reduction) and 0.08‐mg doses (32% reduction), but was not effective against the severely necrotizing 0.16‐mg SM dose. Based on these results, an optimum SM dose of 0.08 mg was selected. Retro synthetic capsaicin and two pharmacologically inactive analogs were tested as topical treatments 15 min prior to SM challenge. The RSCAP compound significantly reduced injury, whereas the inactive analogs had no protective effect. The RSCAP also significantly reduced SM injury when administered topically 10 min after SM challenge. These data support the use of the 7‐day mouse ear vesicant treatment model (MEVTM) in evaluating candidate antivesicant compounds.