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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents
(LOAEL) of VX was 3 µg per day in a subchronic toxicity study in which female sheep were fed VX daily for 55 days (Rice et al. 1971). The LOAEL was weight-normalized by dividing it by 52.7 kg (the average weight of the sheep) to yield a dose of 0.06 µg/kg per day. The RfD for VX was calculated to be 6 × 10-7 mg/kg per day by dividing the adjusted LOAEL by 90, the product of the uncertainty factors and the modifying factor selected by ORNL.
APPROPRIATENESS OF THE CRITICAL STUDY
The critical study used by ORNL for deriving the RfD for VX was a subchronic toxicity study with yearling sheep (Rice et al. 1971). Five females per group were hand-fed pellets treated with VX at doses of 3, 9, and 15 µg for 55 days. The control group comprised 10 sheep. Whole-blood-ChE determinations were made before dosing and 16 times during the exposure period. Significant depression of ChE was observed in all dose groups by day 21, and there were no signs of toxicity. ChE concentrations stabilized at about 60% of baseline values (measurements taken before exposure) by day 31 and remained at that level for the remainder of the testing period. ORNL considered the lowest dose of 3 µg per day to be the LOAEL for the study. As described earlier, that value was weight-adjusted to 0.06 µg/kg per day.
The subcommittee noted several weaknesses in the Rice et al. (1971) study, the most notable being the uncertainties about whether sheep are at least as susceptible as humans to VX. Sheep lack plasma-ChE and have lower red-blood-cell (RBC)-acetylcholinesterase (AChE) activity than humans (Ellin 1981); therefore, they might be more susceptible to VX toxicity than humans. In addition, sheep are ruminants, which means that ingested materials remain in their rumens and are later regurgitated for cud-chewing. It is unclear what effect this digestive process has on the absorption of VX. It is possible that VX is destroyed in the rumen, thereby decreasing the amount available for absorption. However, in vitro studies by Cook (1957) indicate that thiol isomers of organophosphate agents are not destroyed by rumen fluid; VX possesses a thiol group, suggesting that it would not be destroyed in the rumen. If that is the case, retention of VX in the rumen might allow increased absorption of VX through the epithelial surface of the rumen. However, there is no good evidence that shows that sheep are more sensitive than humans to VX.