Early pulmonary responses to inhalation of a sublethal dose of toluene-diisocyanate (26471625) (TDI) were examined in rats to determine whether induction of nitric-oxide synthesis played a part in the early pulmonary responses to TDI. Adult male Sprague-Dawley- rats were exposed to 0 or 2 parts per million TDI fumes for 4 hours (hr). Breathing rate (fB), tidal volume (TV), maximum flow/total expiratory time (Tme/Te), and peak expiratory plethysmograph flow (Vp/Vrms) were measured before and 0 and 18hr after exposure. The animals were killed 20hr after exposure and the lungs were removed and lavaged. Lavagate cellularity was determined. Cell free lavage fluid samples were analyzed for nitrate plus nitrite (NOx), protein, and lactate-dehydrogenase. The lavagate cells were harvested. Production of nitric-oxide-synthase (NOS) dependent reactive species by alveolar macrophages (AMs) was evaluated by determining the level of N-omega-nitro-L-arginine-methyl-ester (L-NAME) inhibitable chemiluminescence following stimulation with unopsonized zymosan. RNA was extracted from some cells and the extent of expression of inducible NOS mRNA was determined by Northern blotting. Significant increases in fB, TV, and Vp/Vrms and decreases in Tme/Te were seen immediately after TDI exposure ended. Except for Tme/Te which had returned to the baseline value, these changes were still present at the 18hr sampling point. TDI exposure caused significant increases in the number of lavagate AMs, lymphocytes, and polymorphonuclear leukocytes, NOx levels, and production of NOS dependent reactive species by AMs. The level of expression of inducible NOS mRNA was also increased by TDI. The authors conclude that acute exposure of rats to TDI fumes is associated with changes in pulmonary function and evidence of airway inflammation. These effects are also associated with increases in inducible nitric-oxide production.