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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents
EVALUATION OF THE ARMY'S INTERIM RFD
DERIVATION OF THE ARMY'S INTERIM RFD
The Army's interim RfD for sulfur mustard is 7 × 10-6 mg/kg per day. ORNL (1998) calculated that value on the basis of the lowest oral dose of sulfur mustard that produced forestomach lesions (epithelial acanthosis, which is an increase in the thickness of the stratum spinosum of the epithelial tissue of the forestomach) in rats. The lowest-observed-adverse-effect level (LOAEL) for that effect was 0.03 mg/kg per day in a two-generation reproductive study (Sasser et al. 1989a). In that study, male and female rats were administered sulfur mustard for 5 days per week for 15 weeks, daily for 3 weeks, and 4 days per week for 3 weeks. Because of this discontinuous dosing protocol, ORNL adjusted the LOAEL (LOAELadj) to calculate the doses for continuous exposures. That adjustment was done by calculating the total dose administered during the different exposure protocols:
0.03 mg/kg per day × 5 days × 15 weeks = 2.25 mg/kg.
0.03 mg/kg per day × 7 days × 3 weeks = 0.63 mg/kg.
0.03 mg/kg per day × 4 days × 3 weeks = 0.36 mg/kg.
The combined dose over the 21-week exposure period was 3.24 mg/kg. That value was divided by the total number of days (147 days) during the exposure period to yield a LOAELadj of 0.022 mg/kg per day. The RfD for sulfur mustard was calculated to be 7 × 10-6 mg/kg per day by dividing the LOAELadj by 3,000, 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 sulfur mustard was a two-generation reproductive study (Sasser et al. 1989a) in which Sprague-Dawley rats (20 males and 27 females per group) were intragastrically intubated with sulfur mustard dissolved in sesame oil at concentrations of 0.03, 0.1, and 0.4 mg/kg per day. Males and females were dosed for 5 days per week for 15 weeks, including 13 weeks before