The clearance of inhaled Tc-99m DTPA aerosol from the lungs is used as an index of lung epithelial permeability. Using the radioaerosol method, we investigated the effects of long-term "crack" (free-base cocaine) inhalation on lung permeability in 23 subjects. Eighteen control subjects (12 nonsmokers and 6 cigarette smokers) with no history of drug use were also studied. Subjects inhaled approximately 150-mu-Ci (approximately 5.6 MBq) of Tc-99m DTPA aerosol and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 minutes. Regions of interest (ROIs) were selected to include the following: (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. Tc-99m DTPA lung clearance was determined from the slopes of the respective time-activity plots for the different ROIs. Radioaerosol clearance half-times (T1/2) for the seven nonsmoking crack users (61.5 +/- 18.3 minutes) were longer than for the seven cigarette-smoking crack users (27.9 +/- 16.9 minutes) and nine cigarette-smoking crack plus marijuana users (33.5 +/- 21.6 minutes). T1/2 for the nonsmoking crack users was significantly shorter (p < 0.001) than for the nonsmoking control group (123.8 +/- 28.7 minutes). T1/2 for the cigarette-smoking drug users was similar to that of the cigarette-smoking control group (33.1 +/- 17.8 minutes), suggesting a similar mechanism of damage from the smoke of crack and tobacco. From these groups, one nonsmoker and 11 cigarette smokers displayed biexponential Tc-99m DTPA clearances, indicative of greater lung injury than found in the usual cases of monoexponential clearance. The upper lungs of all crack user groups cleared faster than the lower lungs. The faster and biexponential clearance properties of inhaled Tc-99m DTPA aerosol were the principal functional abnormalities found in all the drug users. In contrast, 19 of 23 crack users had normal spirometry and gas exchange. These results indicate that Tc-99m DTPA may provide a sensitive and useful assay to evaluate the physiologic effects of cocaine inhalation in the lung.