Hematological profile of the euthymic hairless guinea pig following sulfur mustard vesicant exposure.

Sulfur mustard (HD) is a potent vesicating agent of military importance, with known radiomimetic properties. The euthymic hairless guinea pig (EHGP) (Cavia porcellus) is emerging as the animal model of choice for cutaneous HD study. With elucidation of the systemic effects, we may better utilize this animal for all HD toxicity work. To this end, studies were conducted to determine the definitive median lethal dose (MLD) of subcutaneously applied sulfur mustard (HD) in the EHGP, and to correlate the induced hematological changes. Eight groups of two animals each were dosed at 0.3 log intervals from an extrapolated expected dose, deriving a tentative mean around which five groups of six animals each were dosed at 0.1 log intervals, resulting in a definitive MLD of 48.17 mg kg(-1). Sulfur mustard was then administered to seven groups of six animals each at a dose of 30 mg kg(-1) and hematology performed. Significant leukocyte count suppression was found to occur on days 4, 5 and 6, following a leukocyte elevation on day 1 after exposure. Serum potassium levels were found to be elevated all 7 days after HD exposure. Establishing the MLD for subcutaneously applied HD and the pattern of induced leukocyte suppression allows for more definitive evaluation of successful toxicity counter-measures.

Topical anesthetic-induced methemoglobinemia and sulfhemoglobinemia in macaques: a comparison of benzocaine and lidocaine.

Benzocaine (BNZ) and lidocaine (LC) are commonly used topical (spray) anesthetics approved for use in humans. Benzocaine has structural similarities to methemoglobin (MHb)-forming drugs that are current candidates for cyanide prophylaxis, while LC has been reported to increase MHb in man. In this study, we compared MHb and sulfhemoglobin (SHb) production in three groups of Macaques (Chinese rhesus and Indian rhesus (Macaca mulatta) and pig-tailed macaques (Macaca nemestrina)) after exposure to BNZ and LC. Formation of SHb, unlike MHb, is not thought to be reversible and therefore is considered to be of greater toxic significance. Both MHb and SHb levels were measured periodically on a CO-Oximeter. All rhesus macaques (n = 8) were administered an intratracheal/intranasal) dose of 56 mg (low dose) or 280 mg (high dose) of BNZ or 40 mg of LC in a randomized cross-over design (all animals received all three treatments). Pig-tailed macaques (n = 6) were given an intranasal dose of 56 mg of BNZ and 40 mg of LC. As no differences in the peak MHb or time to peak (mean +/- SD) were observed among the three macaque subspecies, the data were pooled. Lidocaine did not cause MHb or SHb formation above baseline in any monkey. In contrast, all monkeys (n = 14) had a significant elevation in peak MHb formation after 56 mg of BNZ, which ranged from 4.0% to 19.4% with an average of 8.6 +/- 4.0% (mean +/- SD), with peak MHb levels reached at 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Protection of rhesus monkeys against soman and prevention of performance decrement by pretreatment with acetylcholinesterase.

The ability of acetylcholinesterase from fetal bovine serum (FBS AChE) to protect against soman, a highly toxic organophosphorus (OP) compound, was tested in rhesus monkeys. Intravenous administration of FBS AChE produced a minimal behavioral effect on the serial probe recognition task, a sensitive test of cognitive function and short-term memory. Pharmacokinetic studies of injected FBS AChE indicated a plasma half-life of 40 hr for FBS AChE in monkeys. Both in vitro and in vivo titration of FBS AChE with soman produced a 1:1 stoichiometry between organophosphate-inhibited FBS AChE and the cumulative dose of the toxic stereoisomers of soman. Administration of FBS AChE protected monkeys against the lethal effects of up to 2.7 LD50 of soman and prevented any signs of organophosphate intoxication, e.g., excessive secretions, respiratory depression, muscle fasciculations, or convulsions. In addition, monkeys pretreated with FBS AChE were devoid of any behavioral incapacitation after soman challenge, as measured by the serial probe recognition task. Compared to the current multicomponent drug treatment against soman, which does not prevent the signs or the behavioral deficits resulting from OP intoxication, use of FBS AChE as a single pretreatment drug provides significantly effective protection against both the lethal and the behavioral effects of soman.

The characterization of hereditary abnormalities of keratin: Clouston's ectodermal dysplasia.

Ectodermal dysplasia of the Clouston type is a disease caused by a single dose of an autosomal dominant gene. It appears to involve only the skin and its appendages. An investigation of the physical and chemical abnormalities of the hair protein in this disease is beginning to throw some light on the action of the gene involved.