Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) / Chapter Skim
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5: Evaluation of the Army
5: Evaluation of the Army
Pages 48-58
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From page 48... ...
Because there was no evidence that GD is carcinogenic, a slope factor was not derived. The Army's Surgeon General accepted ORNL's proposed RfD as an interim exposure value until an independent evaluation of the proposed RfD was conducted by the National Research Council (NRC)
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From page 49... ...
to yield a LOAELadj of 0.0125 mg/kg per day. The RfD for GD was calculated to be 4 x lo-6 mg/kg per day by dividing the LOAELadj by 2,700, the product of the uncertainty factors and the modifying factor selected by ORNL.
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From page 50... ...
The subcommittee considered other possible toxicity end points, notably neurotoxicity, associated with GD exposure. Organophosphate compounds like GD may act directly on nerve cell receptors or, by inhibiting neural AChE, interfere with neuromuscular transmission and produce delayed-onset subjunctional muscle damage.
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From page 51... ...
Provided that appropriate assays were used, the subcommittee finds no reason at this time to alter the practice of using RBC-ChE or plasma-ChE inhibition as the critical toxicity end point, and agrees with ORNE that such inhibition is the best available critical noncancer end point on which to base the calculation of the RfD for GD. APPROPRIATENESS OF UNCERTAINTY FACTORS For GD, ORNE assigned values greater than ~ to five uncertainty factors and a value of ~ to the modifying factor.
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From page 52... ...
PROTECTING SUSCEPTIBLE SUBPOPULATIONS ORNE used a factor of 10 for the uncertainty factor to protect susceptible subpopulations (UFH) because some individuals have a genetic polymorphism causing their serum-ChE activity to be abnormally low (Evans et al.
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From page 53... ...
The subcommittee agrees that a factor of 3 is appropriate. DATA-BASE ADEQUACY As noted by ORNE, the data base for GD lacks chronic oral studies in two species and reproductive and developmental toxicity studies.
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From page 54... ...
The subcommittee's recommendations are the same as those of ORNL. TABLE 5-1 Uncertainty Factors Used by ORNL and the NRC to Calculate the RfD for GD Uncertainty Factor Description ORNL NRC UFA For animal-to-human extrapolation 10 10 UFH To protect susceptible subpopulations 10 10 UF, For LOAEL-to-NOAEL extrapolation 3 3 UPS For subchronic-to-chronic extrapolation 3 3 UFD For data-base adequacy 3 3 ME Modifying factor for additional uncertainty 1 1 TOTAL UF 2,700 2,700 Abbreviations: LOAEL, lowest-observed-adverse-effect level; ME, modifying factor; NOAEL, no-observed-adverse-eKect level; NRC, National Research Council; ORNL, Oak Ridge National Laboratory; RfD, reference dose; UF, uncertainty factor
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From page 55... ...
DATA GAPS AND RESEARCH RECOMMENDATIONS The major gap in the available information on GD is the lack of an oral subchronic or chronic toxicity study that demonstrates a clear dose-response relationship between GD exposure and ChE inhibition. The absence of that type of data could be addressed by conducting a subchronic oral toxicity study that assesses anti-ChE activity in RBCs and plasma in one or preferably two species.
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From page 56... ...
U.S. Army Medical Research and Development Command, Biomedical Laboratory, Aberdeen Proving Ground, Edgewood, Md.
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From page 57... ...
Environmental Protection Agency, Washington, D.C. NRC (National Research Council)
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From page 58... ...
1984. Changes in Me Oven and Is of rat plasma chohnesterases during chronic dUsoprop~phospboroOuoddste into~cadon.
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