Exposure-response effects of inhaled sulfur mustard in a large porcine model: a 6-h study.

CONTEXT: Inhalation of sulfur mustard (HD) vapor can cause life-threatening lung injury for which there is no specific treatment. A reproducible, characterized in vivo model is required to investigate novel therapies targeting HD-induced lung injury. MATERIALS AND METHODS: Anesthetized, spontaneously breathing large white pigs (~50 kg) were exposed directly to the lung to HD vapor at 60, 100, or 150 µg/kg, or to air, for ~10 min, and monitored for 6 h. Cardiovascular and respiratory parameters were recorded. Blood and bronchoalveolar lavage fluid (BALF) were collected to allow blood gas analysis, hematology, and to assay for lung inflammatory cells and mediators. Urine was collected and analyzed for HD metabolites. Histopathology samples were taken postmortem (PM). RESULTS: Air-exposed animals maintained normal lung physiology whilst lying supine and spontaneously breathing. There was a statistically significant increase in shunt fraction across all three HD-exposed groups when compared with air controls at 3-6 h post-exposure. Animals were increasingly hypoxemic with respiratory acidosis. The monosulfoxide ß-lyase metabolite of HD (1-methylsulfinyl-2-[2(methylthio)ethylsulfonyl)ethane], MSMTESE), was detected in urine from 2 h post-exposure. Pathological examination revealed necrosis and erosion of the tracheal epithelium in medium and high HD-exposed groups. CONCLUSION: These findings are consistent with those seen in the early stages of acute lung injury (ALI).

Liquid chromatography tandem mass spectrometry applied to quantitation of the organophosphorus nerve agent VX in microdialysates from blood probes.

VX (O-ethyl-S-[2(di-isopropylamino)ethyl] methylphosphonothiolate) is a low volatility organophosphorus (OP) nerve agent and therefore the most likely route of exposure is via percutaneous absorption. Microdialysis has been used as a tool to study percutaneous poisoning by VX in the anesthetised guinea pig. A liquid chromatography tandem mass spectrometry (LC-MS-MS) method using positive electrospray ionisation (ESI) was used to quantitate VX in microdialysate samples collected from microdialysis probes, implanted into a blood vessel of anesthetised guinea pigs. The method resulted from modification of a LC-MS-MS method previously developed for the analysis of dermal microdialysates. Modification increased the sensitivity of the method, allowing quantitation of the trace levels of VX in blood microdialysates, over the range 0.002-1 ng/ml, with linear calibration. Quantitative results have been used to determine the time course of VX concentrations in the blood of guinea pigs following percutaneous poisoning.