Objective:
Complete studies on the sensitivity of blood leukocytes from different human donors to DON-induced stress activation and cytokine upregulation. Identify threshold doses of DON required for stress activation and cytokine upregulation in the mouse and corresponding DON tissue levels.

Approach:
Compare the concentration of DON required for MAPK activation and cytokine mRNA response profile in the absence and presence of specific co-stimuli. Relate data to antiproliferative effects of DON. Determine the lowest observed adverse effect level (LOAEL) and the no observed adverse effect level (NOAEL) for DON required to induce MAPK and cytokine production in the mouse in acute and chronic exposure models. Relate these thresholds to DON tissue concentrations in the exposed animals. Compare DON tissue levels corresponding to these thresholds to in vitro studies of human leukocytes and previous studies with mouse leukocytes.