Oral exposure to the trichothecene deoxynivalenol (DON), a common cereal grain contaminant, adversely affects growth and immune function in experimental animals. Besides foodborne exposure, the potential exists for DON to become airborne during the harvest and handling of grains and therefore pose a risk to agricultural workers. The purpose of this study was to compare the effects of oral and intranasal exposure to DON (5mg/kg bw) on tissue distribution and proinflammatory cytokine induction in the adult female mouse. Competitive direct ELISA revealed that, regardless of exposure route, DON concentrations in plasma, spleen, liver, lung and kidney were maximal within 15-30 min and declined by 75-90% after 120 min. However, plasma and tissue DON concentrations were 1.5-3 times higher following intranasal exposure as compared to oral exposure. The functional significance of elevated DON tissue concentrations was assessed by measuring IL-1beta, IL-6, and TNF-alpha mRNA responses in spleen, liver and lung. Oral exposure to DON-induced robust proinflammatory cytokine gene expression after 60 and 120 min. In contrast, inductions of IL-1beta, IL-6 and TNF-alpha mRNAs in nasally exposed mice were 2-10, 2-5 and 2-4 times greater, respectively, than those in the tissues of orally exposed mice. Taken together, these data suggest that DON was more toxic to the mouse when nasally exposed than when orally exposed, and that this might relate to greater tissue burden of the toxin.