Hypochlorite solution as a decontaminant in sulfur mustard contaminated skin defects in the euthymic hairless guinea pig.

Hypochlorite solutions are thought to be efficacious when used to topically decontaminate intact skin. However, few studies have examined the efficacy of decontamination of chemically contaminated wounds. Therefore, we compared the decontamination efficacy of sodium hypochlorite (0.5% and 2.5% solutions), calcium hypochlorite (0.5% and 2.5% solutions) and sterile water to untreated controls in wounds exposed to sulfur mustard (HD). Anesthetized euthymic hairless guinea pigs (EHGP) (n = 6) were exposed to 20 mg/kg (approximately 0.4 LD50) HD in a full-thickness 8 mm surgical biopsy skin defect (i.e., wound). Each animal was subsequently decontaminated, after a two-minute intra-wound exposure to liquid HD, with nothing or one of the decontamination solutions. Decontamination efficacy was determined by the visual grading of the HD-traumatized wound lesion and by comparison of the expected HD-induced leukocyte suppression. Leukocyte suppression was inconsistent in all animals; therefore, the visual grading was the only viable evaluation method. No significant differences were observed among wounds decontaminated with any of the solutions. However, the skin surrounding non-decontaminated (but exposed) control animals showed the least visual pathology. The lesions induced following decontamination are presumed to be due to the mechanical flushing of HD onto the peri-lesional skin, or by chemical damage induced by the solution, or HD-solution interaction. Further studies are required to best delineate the optimal decontamination process for HD contaminated wounds.

Metabolite pharmacokinetics of soman, sarin and GF in rats and biological monitoring of exposure to toxic organophosphorus agents.

This study reports on the pharmacokinetics of the elimination of the metabolites of three toxic organophosphorus compounds (soman, sarin and GF). Urine, blood and lung tissue were collected from rats dosed subcutaneously at 75 micrograms kg-1. Urinary excretion of the metabolite was the major elimination route for these three compounds. The major differences among them were primarily the extent and rate of excretion. The hydrolyzed form, alkylmethylphosphonic acid, was the single major metabolite formed and excreted in urine by a non-saturable mechanism. Nearly total recoveries of the given doses for sarin and GF in metabolite form were obtained from the urine. The terminal elimination half-lives in urine were 3.7 +/- 0.1 and 9.9 +/- 0.8 h for sarin and GF, respectively. Soman metabolite showed a biphasic elimination curve with terminal half-lives of 18.5 +/- 2.7 and 3.6 +/- 2.2 h. Soman was excreted at a slower rate with a recovery of only 62%. Lung was the major organ of accumulation for soman. In blood the toxic agents were concentrated more in red blood cells than in plasma. The acid metabolites can serve as a better chemical marker for monitoring organophosphorus exposure in humans via their higher concentration and longer half-life in urine than the parent compounds.

Behavioral decrements persist in rhesus monkeys trained on a serial probe recognition task despite protection against soman lethality by butyrylcholinesterase.

Recently, it has been demonstrated that an exogenously administered enzyme such as butyrylcholinesterase (BuChE) can prevent death in rhesus monkeys exposed to multiple-lethal doses of the acetylcholinesterase inhibitor soman when the enzyme is given prior to soman exposure (3). We report that despite BuChE protecting against soman-induced lethality, behavioral effects are seen in these monkeys which last for at least 6 days as measured by performance on a serial probe recognition (SPR) task. Analyses of the serial position curves showed that performance was lower on the probe trials when the probe items were from the middle of the list than when the probe items were from the beginning or end of the list which were unaffected. BuChE given alone also produced behavioral effects, causing all animals not to respond on the probe trials until 8 h following BuChE administration. Taken together, these findings suggest that the BuChE is not completely binding all of the soman and that a concentration of soman which is capable of causing behavioral effects may be entering the CNS.

Evaluation of the toxicity, pathology, and treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rhesus monkeys.

Cyclohexylmethylphosphonofluoridate (CMPF) is an organophosphate cholinesterase inhibitor with military significance. The purpose of these studies was 1) to determine the acute toxicity of CMPF in the male rhesus monkey, 2) to evaluate the efficacy of pyridostigmine (PYR) pretreatment plus atropine and oxime (2-PAM or H16) treatment, and 3) to evaluate the pathological consequences of acute poisoning. An i.m. LD50 of CMPF was estimated using an up-and-down dose selection procedure and 12 animals. The 48-h and 7-day LD50 was 46.6 micrograms/kg, i.m. In the protection experiments, pyridostigmine (0.3-0.7 mg/kg/24 h) was administered by surgically implanted osmotic minipumps for 3-12 days resulting in 21-65% inhibition of erythrocyte acetylcholinesterase activity. Animals were challenged with 5 x L50 CMPF (233 micrograms/kg) and treated with atropine (0.4 mg/kg) and either 2-PAM (25.7 mg/kg) or HI6 (37.8 mg/kg) at the onset of signs or 1 min after challenge. Osmotic pumps were removed within 30 min after agent challenge. Pyridostigmine, atropine, and either 2-PAM or H16 were completely effective against CMPF, saving ten of ten animals in each group. In comparison, three of five animals challenged with 5 x LD50 of soman and treated with atropine and 2-PAM survived 7 days. The primary histologic lesions in the acute toxicity group were neuronal degeneration/necrosis and spinal cord hemorrhage. The CMPF treated groups (total of 20 animals) had minimal nervous system changes with no significant lesion difference resulting from the different oxime therapies. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration which occasionally progressed to necrosis and mineralization.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of metabolites of toxic alkylmethylphosphonates in biological samples.

The major metabolites and breakdown products of some toxic organophosphonates are their respective alkymethylphosphonic acids. These acids ionize at physiological pH and are not amenable to gas chromatographic analysis in their underivatized forms. Their detection in biological samples has been difficult because of their presence at only trace levels. Existing analytical methods were developed mainly for measuring these phosphonic acids in environmental samples and at higher concentrations. In this study, we devised a gas chromatographic/mass spectrometric method to provide confirmation and quantification of the organophosphonic acids of soman (GD), sarin (GB) and GF in blood and urine. This report describes the various derivatization conditions that we have studied and demonstrates the characteristic mass spectra by different ionization techniques.