Estimating Miotic, Severe and Lethal Toxic Effects in Gottingen Minipigs Following Inhalation, Intravenous and Subcutaneous Exposures to VX

Constriction of the pupils (miosis) is often identified as the first noticeable sign of exposure to vapor nerve agents. We have previously identified that in minipigs there is a 30-40 fold difference in vapor dosages of sarin (GB) that elicit miosis vs. those vapor dosages that are potentially lethal. The ratio for miotic vs. lethal vapor dosages ranges from 100-135 fold when cyclo-sarin (GF) is the nerve agent. Due to the extremely low volatility of VX the nerve agent’s primary hazard comes from percutaneous absorption. In laboratory settings a combination of high temperatures and airflow can be used to generate vapor VX at stable and measurable concentrations. In a field setting, the generation of VX vapor is less likely, although it is theoretically possible in extreme environments such as the inside of an armored HUMVEE in a desert. In the current studies sexually mature male Gottingen minipigs were exposed to various concentrations of VX vapor in order to determine the lethal (LCT50s) and effective concentrations (ECT50s) for miosis over exposure durations of 10, 60 and 180 minutes. In minipigs VX vapor is less potent than either GB or GF at causing pupil constriction. Additionally, the onset of pupil constriction is delayed in comparison to onset upon exposure to GB or GF. VX vapor was more potent than either GB or GF when lethality was the endpoint. However, unlike with GB or GF vapor exposures, constriction of the pupils was not the definitive first noticeable effect upon a potentially lethal VX vapor exposure. The ratio of ECT50 for miosis vs. LCT50 values for vapor VX exposures ranges from 3-6 fold. Therefore, the dosages of VX vapor that elicit pupil constriction are much closer to the dosages that result in severe toxic signs or lethality than are seen for either GB or GF vapor exposures. Male Gottingen minipigs were also exposed to liquid VX via intravenous (IV) or subcutaneous (SC) injections. Signs of nerve agent exposure were classified as lethal, severe, or moderate. Maximum likelihood estimation using a probit model was used to calculate the median effective (severe effects) and lethal doses (LD50) for IV and SC exposures. For intravenously injected VX, the LD50 was 11.8 μg/kg (9.7 – 14.5 μg/kg) and the ED50 (severe) was 6.6μg/kg (4.8 – 9.0 μg/kg). For subcutaneously injected VX, the LD50 was 16.1μg/kg (12.9 – 19.9 μg/kg) and the ED50 (severe) was 12.8μg/kg (10.1 – 16.2 μg/kg). VX was more potent than either sarin (GB) or cyclo-sarin (GF) by both routes of exposure. Hulet, S.W.; Sommerville, D.R.; Matson, K.L.; Crouse, C.L.; Scotto, J.A.; Benton, B.J.; Mioduszewski, R.J.; Thomson, S.A. (2007) Estimating Miotic, Severe and Lethal Toxic Effects in Gottingen Minipigs Following Inhalation, Intravenous and Subcutaneous Exposures to VX. In Defence against the Effects of Chemical Hazards: Toxicology, Diagnosis and Medical Countermeasures (pp. 7-1 – 7-14). Meeting Proceedings RTO-MP-HFM-149, Paper 7. Neuilly-sur-Seine, France: RTO. Available from: http://www.rto.nato.int. Estimating Miotic, Severe and Lethal Toxic Effects in Gottingen Minipigs Following Inhalation, Intravenous and Subcutaneous Exposures to VX 7 2 RTO-MP-HFM-149