Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)