As presented in the Research Plan (Table 5-2, p. 8), the specific objectives are (1) to characterize concentration-time (Ct) relationships for low-level, longer time CWA vapor exposure by conducting in vivo inhalation studies; (2) to identify alternative, but physiologically significant, toxicologic end points resulting from low-level CWA exposures using end points indicative of performance decrements, mechanisms of toxicity, and potential for persistent or delayed health effects (e.g., neurobehavior effects, changes in gene expression); and (3) to conduct appropriate integration studies linking experimental data sets with predictive human health effect assessments using cross-species/cross-route data, toxicokinetic modeling, and biomarkers.
The DOD Research Plan states that the nerve agents (G-series agents tabun [GA], sarin [GB], soman [GD], and cyclosarin [GF], and VX) are being, or are going to be, studied alone and in combination with other CWAs after single and multiple exposures by the inhalation route. The highest research priority, as indicated in presentations made by DOD personnel during the committee meetings, is to evaluate the effects of single nerve agents. DOD notes that the dose-response relationships for nerve agent effects studied to date are extremely steep and therefore require a revision of the default uncertainty-factor approach to identify exposure levels that are just under threshold levels. For example, in typical noncarcinogenic risk assessments, a no-observed-adverse-effect level is divided by an uncertainty factor (generally by a factor of 10) to account for variability in sensitivity for intraspecies or interspecies extrapolations. Thus, considering the markedly steep nature of the dose-response curves for effects elicited by these agents, it may be possible to incorporate smaller uncertainty factors (e.g., 3) that would still adequately account for susceptibility differences. The data obtained from the proposed research are to be evaluated for the ability to contribute materially toward quantitative refinement of the human health risk assessments for exposure to low levels of CWAs.
The Research Plan consists of three major research thrusts, with each of the major thrusts subdivided into subthrusts. Subthrusts are further divided into research tasks.