Susan Schulz

Cutaneous Uptake of 14C-Hd Vapor By The Hairless Guinea Pig

The hairless guinea pig (HGP) is used by our laboratory to model the human cutaneous response to sulfur mustard (HD), bis(2-chloroethylsulfide), exposure. We determined the HD content in the skin of HGP after a 7-min exposure to vapors saturated with a mixture of HD and 14C-HD. Concentration/time (CT) values in the range of 2 micrograms/cm2/min were determined by counting skin 14C disintegrations per min (dpm) in animals euthanized immediately after exposure. These values are similar to human penetration rates obtained by other investigators. A rate curve monitoring the reduction in skin 14C dpm was developed for animals euthanized between 0 and 24 hr post- exposure. This curve showed the greatest change after 1 hr. The epidermal (62%) to dermal (38%) ratio of 14C at 24 hr was measured for two animals. We saw no site preference for HD penetration among the 8 sites used. The 14C content of template adhesive tape was determined to follow HD distribution. These results contribute to a better understanding of the cutaneous response to HD in the HGP model.

Median lethal dose determination for percutaneous exposure to soman and VX in guinea pigs and the effectiveness of decontamination with M291 SDK or SANDIA foam.

Soman (GD) and VX are chemical warfare agents that can be absorbed through the skin. We determined the median lethal dose (MLD) for the cutaneous application of GD and VX in anesthetized haired guinea pigs and then tested the ability of a currently fielded decontamination kit, the M291 Skin Decontamination Kit (SDK), and decontaminating foam made by SANDIA Labs to decontaminate areas that have been exposed to cutaneous applications of GD and VX. The fur of guinea pigs was clipped on the left flank 24h prior to exposure. Animals were anesthetized and 5 min later neat GD or neat VX was applied. The MLD for percutaneous exposure to GD was 11.6 mg/kg, and to VX it was 0.10mg/kg. To test the ability of the M291 SDK, either GD or VX was applied and removed 1 min later with the pads of the M291 SDK clasped in a pair of forceps and wiped across the flank of the animal. The MLDs for GD and VX removed with the M291 SDK pads were 76.9 mg/kg and 0.87 mg/kg, respectively. When neat GD or neat VX was applied and removed 1 min later in the same manner with gauze soaked in SANDIA foam (MDF-100), the MLDs were 412 mg/kg and 10.4 mg/kg respectively. These data demonstrate that GD and VX are significantly less potent when applied cutaneously than previously reported for subcutaneous injections and indicate that improvement is needed on the limited protective ratio provided by the M291 SDK.

Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus Nerve Agent Poisoning

Scopolamine (SCP) is an anticholinergic drug used clinically for decades to treat motion sickness, as a surgical preanesthetic, and as a smooth muscle antispasmodic. It has also been used experimentally as a pretreatment and/or treatment adjunct to mitigate the toxic sequelae of organophosphorus (OP) nerve agent intoxication. SCP has been reported to increase survival, prevent or terminate seizures, and reduce morbidity from nerve agent intoxication in a number of animal models. The purpose of this study was to evaluate the effect of atropine dose, pyridostigmine bromide (PB) pretreatment, and oxime selection on the efficacy of SCP as an adjunctive treatment to enhance survival following lethal nerve agent exposure in guinea pigs. The results indicate that the use of an effective oxime and/or PB pretreatment was a critical factor in determining the efficacy of SCP. SCP can also reduce the dose of atropine required for survival against lethal nerve agent intoxication.

Phenidone and hydroxyurea reduce sulfur mustard-increased proteolysis in hairless guinea pig skin

AbstractIncreased proteolytic activity at the dermal-epidermal junction is postulated as being involved in sulfur-mustard-induced cutaneous injury. Homogenates of skin punch biopsy specimens from the skin of hairless guinea pig at 6, 9, 12, and 24 h after a 7 min vapor cup exposure to sulfur mustard (HD) demonstrated enhanced proteolytic activity. Homogenates from the biopsy specimens of exposed animals produced from 3 to 10 times the hydrolysis of the chromogenic peptide substrate Chromzym TH (tosyl-gly-pro-arg-p-nitranilide) and human elastase substrate N-methoxysuccinyl-ala-ala-pro-val-p-nitranilide than did the homogenates from control samples. In this study HD-increased proteolysis of the TH substrate by extracts of hairless guinea pig skin biopsies was nearly eliminated by systemic treatment with hydroxyurea and greatly reduced by topical application of the anti-inflammatory compound phenidone. Compounds that reduce HD-increased proteolytic activity, such as phenidone and hydroxyurea, can serve as p...

Application and detection of (14)c-hd in two mouse models.

The CD1-haired mouse and the SKH-hairless mouse are two animal models that have been used to evaluate sulfur mustard (HD) exposure and protection in our laboratory. In a recent study we observed that a substance P inhibitor protected the haired mouse ear against an HD solution, but the same drug was not successful in protecting the hairless mouse against HD vapor. This experiment prompted us to compare HD exposures between these models. We determined the 14C content in the skin after exposures to HD containing 14C-HD. Rate curves were generated for applications of (1) HD in methylene chloride to the haired mouse ear; (2) HD in methylene chloride to the hairless mouse dorsal skin; and (3) saturated HD vapor to the hairless mouse dorsal skin for 6 min. The curves showed a reduction in 14C disintegrations per min in animals euthanized 0 to 2 h postexposure. The largest percentage of decrease of 14C content in skin occurred within 30 min of HD challenge for all exposures. An 8-mm skin-punch biopsy and a 14-mm annular skin section surrounding the region of the 8-mm skin punch were taken from the hairless mouse dorsal skin exposed to HD in methylene chloride. The ratio of the 14C content in the 8-mm skin punch to that in the surrounding 14-mm annular skin section was 7.3, demonstrating that the HD application spreads beyond the initially biopsied site. A concentration/time value of 6.3 μg/cm2/min was determined by counting skin 14C disintegrations per minute in animals euthanized immediately after exposure to saturated HD vapor. Determinations of the amount of HD showed that similar quantities of HD, 0.4 mg, were detected on each model. These results contribute to a better quantitative understanding of HD application in the haired and hairless mouse models.