Tobacco Documents Online

....-7,wA c-,- -- - 6. Aerosol Ht1012110'9 a. Title: INDUCTION Of ORNITHINE DECARBOXYLASE (ODC) BY 12--0-TETRADECANOYL-PHORBOL-13- ACETATE (TPA) IN PULMONARY TISSUE: A MODEL SYSTEM FOR TUMOR PROMOTION IN MOUSE LUNGS Authors: M. Dinowitz, R. Nims, B. Bhooshan, R.E. Kouri, and C.J. Henry SUMMARY i A model system is under investigation in our laboratory for studying two stage initiation-promotion carcinogenesis in lung tissue. We have used ODC induction as a biochemical marker for promotion and have established conditions to optimize detec- tion of pulmonary ODC activity whereby low levels of ODC could be detected following exposure to a tumor promoter. A collision nebulizer has been modified to generate an aerosol of respirable particles of TPA in ethanol with an estimated mass median dia- meter of 0.4 microns. C5761/6 Cum mice were exposed to aerosoli- zed TPA resulting in exposure to the lungs of controlled doses ranging from 25 to 400 ng. Our dosimetry studies have shown that greater than 80% of the aerosolized TPA is found in the lungs of mice immediately after exposure. Induction of ODC activity was dose-dependent, with 400 ng TPA resulting in the highest specific activity of ODC, 600 pmoles CO /mg protein/20 min, compared to the specific activity of ODC in2lungs of control mice of <10. Increased ODC activity as low as 20-•50 pmole/mg protein/20 min is detectable within 3 nours after exposure to TPA. The time of appearance of induced ODC activity was Inversely related to dose with the lowest doses, 25 and 50 ng TPA, reaching meximum activity by 6 hours and lungs exposed to 100, 200 and 400 ng reaching maximum ODC activity at 8, 9 and 12 hours, respectavely. At all dose levels, ODC activi- ly declined rapidly after reaching peak activity and returned to control levels with 24 hours after exposure. Status: Abstract, Proc. Amer. Assoc. Cancer Res., 20: 242, 1979, first draft sche- duled for 11/81. i ~!

HTM0121110 b. Title: PULMONARY DEPOSITION OF TETRAG:•:ONYL- PHORBOL-13-ACETATE (TPA) IN BC3F1/CUM MICE AFTER AEROSOL EXPOSURE Authors: K.K. Hwang, B. Bhooshan, D.R. Dansie, L.A. Breth, K.K. Kangalingam, R.E. Kouri, and C.J. Henry SUMMARY Aerosols of 3H-TPA were generated by nebulization of a 0.2% ethanolic solution over a 6 minute period. The particle size of the aerosolized material was found to be 0.4 microns, mass median diameter. BC3F1/Cum nice were exposed to aerosols of 3H-TPA using a"nose-only" exposure -system, in which the animals breathe the aerosol from a flowing stream and where minimal aero- sol deposition occurs on the fur of the animal. Mice were killed at 0.5 min, 30 min and 1, 4, 8 and 24 hours after exposure to 3H-TPA aerosols. Distribution of radio- activity in seven tissues was examined. Approximately 50-60% of the radiolabeled material inhaled by the mouse was found in the lungs immediately after exposure, with about 75% found in the respiratory tract. Results indicate that TPA is rapidly cleared from the lung, with a half-life of -20 minutes. This rapid clearance of radiolabeled material from the lung is associated with a concomitant redistribution to the stomach, hide and re- mains. The half-life of TPA from the wnole 5ody was -10 hours. Status; First d•raft scheduled 1/82.