Therapeutic effects of hypothermia on Lewisite toxicity

The cytotoxicity of the arsenical vesicant Lewisite was assessed in first passage cultures of proliferating neonatal human skin keratinocytes. Both munitions grade and distilled Lewisite were extremely toxic with LC50 values in the low ng/ml range, with no significant differences between them. This similarity in toxicity was also mirrored with respect to their toxic effects on hairless guinea pig skin. Two-, 4- and 6-min vapour exposures of these agents resulted in similar and severe skin injury that was obvious by 3–5 h post-exposure and almost maximal at 24 h. The toxicity of Lewisite in culture was temperature dependent, with a >10-fold reduction in 24 h LC50 values as the incubation temperature was reduced from 37 to 25 °C. However, this cooling induced protection was not persistent. In contrast, cooling of Lewisite exposed hairless guinea pig skin at ∼10 °C for as little as 30 min post-exposure resulted in dramatic and permanent protection, with 4 h of cooling almost completely eliminating Lewisite induced skin injury. Further, significant protection was also evident even when cooling was delayed for as long as 2 h post-Lewisite exposure. In an effort to investigate whether cooling might also increase the window in which chelation therapy against this vesicant agent would be useful, we examined the protective effects of the heavy metal chelator dimercaptosuccinic acid (DMSA). Topical application to Lewisite exposed skin was extremely protective, even when delayed for 2 h after Lewisite. Cooling of Lewisite exposed skin for 2 h, followed by DMSA topical application resulted in decreased skin injury compared to either treatment in isolation. It appears that the simple and non-invasive application of cooling measures may provide not only significant therapeutic relief to Lewisite exposed skin, but that it may also increase the therapeutic window in which medical countermeasures against this vesicant agent are useful.