Gas chromatography-tandem mass spectrometry analysis of red blood cells from Göttingen minipig following whole-body vapor exposure to VX.

A method to detect fluoride ion generated O-ethyl methylphosphonofluoridate (VX-G) in Göttingen minipig red blood cells (RBC) following whole-body exposure to VX vapor utilizing a gas chromatograph-tandem mass spectrometer (GC-MS-MS) has been developed. Dose-response curves for VX exposure were generated after applying the fluoride ion reactivation assay to the RBC fraction of serially collected whole blood samples that were taken after whole-body exposures that varied in both duration and concentration. GC-MS-MS analysis of minipig RBC samples following 180-min exposures at two different concentrations was a more precise indicator for severity of exposure than the analysis of acetylcholinesterase (AChE) inhibition for the same samples. AChE enzyme activity recovered faster than indicated by the apparent elimination rate of VX-G. GC-MS-MS analyses of RBC samples following VX exposure demonstrate this technique has both adequate sensitivity and specificity to indicate the severity of exposure.

Inhalation toxicity of Cyclosarin (GF) vapor in rats as a function of exposure concentration and duration: potency comparison to sarin (GB).

The inhalation toxicity of cyclohexyl methylphosphonofluoridate (GF) was examined in male and female Sprague-Dawley rats exposed by whole body in a dynamic 750-L chamber. The objectives of this study were to (1) generate GF vapor in a dynamic inhalation chamber system, starting in the lethal to near-lethal concentration range, (2) examine dose-response effects of inhaled GF vapor and analyze the relationship between concentration (C) and exposure duration (T) in determining probability of lethality, and (3) establish a lethal potency ratio between GF and the more volatile agent Sarin (GB). Using a syringe pump, GF vapor concentrations were generated for exposure times of 10, 60, and 240 min. Dose-response curves with associated slopes were determined for each exposure duration by the Bliss probit method. GF vapor exposures were associated with sublethal clinical signs such as tremors, convulsions, salivation, and miosis. Concentration-exposure time values for lethality in 50% of the exposed population (LCT(50)) were calculated for 24-h and 14-day postexposure periods for 10-, 60-, and 240-min exposures. In general, LCT(50) values were lower in female rats than males and increased with exposure duration; that is, CT was not constant over time. The GF LCT(50) values for female rats were 253 mg min/m(3) at 10 min, 334 mg min/m(3) at 60 min, and 533 mg min/m(3) at 240 min, while the values for males were 371, 396, and 585 mg min/m(3), respectively. The GB LCT(50) values for female rats were 235 mg min/m(3) at 10 min, 355 mg min/m(3) at 60 min, and 840 mg min/m(3) at 240 min, while the values for males were 316, 433, and 1296 mg min/m(3), respectively. At longer exposure durations, the LCT(50) for GF was less than that found for GB but at shorter exposure durations, the LCT(50) for GF was more than that found for GB. Empirical models, consisting of the toxic load model plus higher order terms, were developed and successfully fit to the data.

Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats.

Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.

Chemical and toxicological evaluation of pyrotechnically disseminated terephthalic acid smoke.

The terephthalic acid (TPA) smoke obscurants (M-83 grenade and M-8 smoke pot) were developed by the U.S. Army for training purposes to replace the more toxic hexachloroethane (HC) smoke. Inhalation toxicity testing and chemical characterization of pyrotechnically generated TPA was conducted to assess the health hazard potential of TPA and its combustion products. Fisher 344 rats were subjected to acute and repeated exposures to TPA smoke generated from the M-83 grenade. Acute exposure levels ranged from 150-1,900 mg/m3 for 30 minutes and repeated dose exposures ranged from 128-1,965 mg/m3 for 30 min/day for 5 days. Exposed and control rats were evaluated for toxic signs, and histopathologic changes. During exposure, the rats exhibited slight to moderate lacrimation, rhinorrhea, lethargy and dyspnea, which reversed within 1-hr post-exposure. No deaths occurred, even at the highest smoke concentrations. Histopathological changes were confined to exposure related nasal necrosis and inflammation in both the acute and repeated dose exposures at levels above 900 mg/m3. Chemical characterization of the M-83 grenade and the M-8 smoke pot showed that formaldehyde, benzene and carbon monoxide were the major organic vapor by-products formed. These by-products were above their respective ACGIH threshold limit values at various concentrations, but should not pose a hazard if the smoke is deployed in an open area. Overall, TPA is a safer training smoke to replace the HC smoke.