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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents
depression in plasma cholinesterase (ChE) activity in rats. The no-observed-adverse-effect level (NOAEL) of GA was 28.13 µg/kg per day in a subchronic toxicity study (Bucci et al. 1992). In that study, male and female rats were injected i.p. with GA 5 days a week for 13 weeks. To estimate the equivalent oral NOAEL from the i.p. NOAEL, ORNL compared the oral and i.p. LD50 (lethal dose to 50% of test animals) values for the rat and assumed that the same ratio would apply for longer-term exposures. Rat studies reported an oral LD50 of 3,700 µg/kg (RTECS 1995) and i.p. LD50 of 490 µg/kg (RTECS 1995) and 800 µg/kg (U.S. Department of the Army 1974) (average 645 µg/kg). Thus, the equivalent oral NOAEL was calculated as follows:
Because of the discontinuous exposure regimen, ORNL adjusted the equivalent oral NOAELadj for continuous exposures by multiplying 161 µg/kg per day by a factor of 5/7 (i.e., 5 days/7days) to yield a NOAELadj of 115 µg/kg per day (or 0.115 mg/kg per day). The RfD for GA was calculated to be 4 × 10-5 mg/kg per day by dividing the NOAELadj 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 GA was a subchronic toxicity study (Bucci et al. 1992) in which Caesarian-derived Sprague-Dawley rats (12 males and 12 females per group) were injected i.p. with GA at doses of 28.13, 56.25, and 112.50 µg/kg per day for 5 days per week for 13 weeks and then sacrificed and necropsied. PlasmaChE and red-blood-cell (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. Considerable variability was observed in RBC-AChE concentrations. Significant depression in RBC AChE was observed in female rats in the mid-and high-dose groups at weeks 7 and 3, respectively, compared with control values and in male rats at all doses at week 1. Bucci et al. (1992) reported that mean baseline values (measurements taken before exposure) for RBC AChE