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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents
(ChE) activity in rats. The lowest-observed-adverse-effect level (LOAEL) of GB was 0.075 mg/kg per day in a subchronic toxicity study (Bucci and Parker 1992). In that study, male and female rats were administered GB by gavage for 5 days per week for 13 weeks. Because of the discontinuous exposure regimen, ORNL adjusted the LOAEL (LOAEL adj for continuous exposures by multiplying 0.075 mg/kg per day by a factor of 5/7 (i.e., 5 days/7 days) to yield a LOAELadj of 0.054 mg/kg per day. The RfD for GB was calculated to be 2 × 10-5 mg/kg per day by dividing the LOAELadj by 2,700, 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 GB was a subchronic toxicity study (Bucci and Parker 1992) in which Caesarian-derived Sprague-Dawley rats (12 males and 12 females per group) were administered GB with diisopropylcarbodiimide as a stabilizer (type II GB) by gavage at doses of 0.075, 0.15, and 0.3 mg/kg per day 5 days per week for 13 weeks. Plasma-ChE and RBC-acetylcholinesterase (AChE) measurements, as well as several other blood measurements, were taken before dosing and at the end of weeks 1, 3, 7, and 13. Plasma-ChE values in females of the mid-dose group were reported to be significantly lower than control values at weeks 1 and 7 and in the high-dose group at weeks 1, 3, and 7. In males, significant reduction in plasma ChE was observed in the low- and mid-dose groups only at week 1. ORNL reanalyzed the data using analysis of variance (ANOVA) and Dunnett's comparison and reported significant decreases in plasma ChE in females in the high-dose group at weeks 1, 3, and 7 and in the mid-dose group at weeks 1 and 3 compared with control and baseline values. A significant decrease was also observed in the mid-dose females at week 7 compared with control but not baseline values. For males, significant depression in plasma ChE was observed in the mid- and high-dose groups compared with control but baseline values. throughout the test period. At the low dose, significant decreases in ChE were observed at week 1 and 7 compared with control but not baseline values and at weeks 3 and 13 compared with baseline but not control values.
Bucci and Parker (1992) reported significant dose-related RBC-AChE depression in female rats in the mid- and high-dose groups and in male