The purpose of this investigation was to determine if the variability of bronchial responsiveness to inhaled histamine in normal subjects is related to the total dose of histamine deposited in the airways. To test this possibility, we used a new method of histamine challenge that permits calculating the histamine mass deposited in the airways in an attempt to correlate it with the magnitude of the response. Using a standardized breath-holding maneuver, 10 healthy nonsmokers and 10 healthy smokers with normal spirometry inhaled an aerosol generated from a solution containing a fixed ratio of histamine and a small quantity of hematoporphyrin serving as a fluorescent tracer. The mass of histamine deposited was calculated from the measured fluorescence of the inspired and expired aerosol. Forced expiratory volume in one second (FEV1) was measured before and 10 min after inhalation challenge. There was a negative correlation between percent decrease in FEV1 (delta FEV1) and histamine mass deposited in the nonsmokers (r = -0.83, p less than 0.005) and smokers (r = -0.82, p less than 0.005) without a difference between the 2 slopes. The range of delta FEV1 was 7 to 33% and of histamine mass deposited, 0.02 to 0.18 mg in the nonsmokers. The respective values in the smokers were 2 to 30% and 0.02 to 0.17 mg. In 6 subjects in whom dose-response curves were obtained, the mean deposited histamine mass required to decrease the FEV1 by 10% was 0.11 mg.(ABSTRACT TRUNCATED AT 250 WORDS)