There is no information on the relative role of dose, concentration, and duration of exposure in determining the magnitude of the bronchial response in subjects with isocyanate-induced asthma. Four subjects with asthma induced by toluene diisocyanate (TDI) were challenged using a recently described closed-circuit exposure chamber in which stable concentrations of TDI monomer can be generated. Each subject was challenged using various concentrations and durations of exposure on separate days. They were all exposed on three to four occasions to the same dose that had been shown to cause a 20% fall in FEV1 at a concentration of 15 ppb (DR15ppb) by varying the concentration (5, 10, 15, and 20 ppb) and durations (1 to 90 min), making sure that the total dose (concentration x duration) remained constant. They were also exposed to lower total doses by modifying the concentration and the duration on the remaining visits. Exposing subjects to the same DR15 ppb by modifying the concentration or the duration resulted in falls in FEV1 > or = 20%, except in one instance. Exposing subjects to doses lower than DR15 ppb, even at higher concentrations or for longer periods than in the challenges used for obtaining the DR15 ppb always caused falls in FEV1 < 20%. We conclude that the main determinant of bronchial responsiveness to TDI is not concentration nor duration of exposure per se but the product of both factors, that is, total dose.