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! I I I I I I I I I I I I i i I I I AUTHOR: KEHDRICK, J., P IqETTESHEIM, M GUERIN, J. CATON, W. DALBEY, R. GRIESEMER, I. RUBIN AND W, MADDOX _D_..~T.~; 1976 TITL~ E; TOBACCO SMOKE INHALATION STUDIES IN RATS CITATION: TOXICOLOGY AND APPLIED PHARMACOLOGY 3_Z7, 557-569 (1976) .S_ .T U D,,Y I~ES, IGN: 3.4 month old F~male Filler-344 rats used. The intermittent MMdox/ORNL smoking machine was used for exposures.drawing a 2-see. 35 cm~ l~lff into a 3~ocm; exposure ch,'unber to produce a 10% smoke ,"cresol. Smoke remained in chamber for 28 sec. ('hamher then purged with air (4000 m Umin) for 30 sec before next puff taken. Ten rats exposed at a time. with only nostrils protruding into the chamber. Experimental cigarettes (Cmies 9 and 16) supplied by NC[. delivered 29.8 and 22.7 mg TPM and 1.75 and 1.1 mg nicotine per cisarette r~spectively. A total of 160 rate were exposed to 7-10 cigarettes/day. Ninety received lifetime exposure. 20 age-controls as ",'.'ell as 30 container controls (shams). were kept for the survival study. 70 of smoke exposed rats were sacrificed ~ter 12. 18 and 24 month of exposure for extensive biochemical, physiological, and histological evaluation. Equal numbers of controls were sacrificed at each time interval Overt signs of k'~xicity during the first exposures of the clvonic study was avoided by gradually increasing the number of ci~day ~t a weel,3y rate of I cig'day over ~t 7-10 wk period. Experimental cig,'vettes were labeled with [I~C] dotriacontane as a tr.~er for smoke-particulate deposition experiments. For tl~ del~SitK~n stud,s, rats previously adapted to tobacco smoke were expo~d first to smoke from an unlabeled cigarette and then. after a 5 rain, interval, to that from a labeled cigarette. Deposition data were expressed as amount of TPM/o~an [TPM/organ-tdpm in orgaWdpm m cigJxITPMJcig)]. F1NOINGS/RESUL TS: Both tidal volume and respiratory rate were markedly reduced during smoke exposure (25%). however respiration r~turned to nomml during the 30-sec break between puffs. For the smoke de~x~sition studies: Both hamstet.'s and rats were used. Total deposition was .38 and .34 mg of TPM in mrs and hamsters respectively, amounting to about 1.4 and 1.3% of the radioactivity offered in the smoke chamber, Of Ihe organs examined, the lung contained ,27 mg TPM while the stomach contained. 12 mg TPM. indicating movement o£ the smoke particles £rom the large airways and/or nose. Only O. 1 mg TPM was observed both the lat)'nx and head. In the lung most of the particles were localized in the dN~t inferior and left lobes. A progressive increase in total radioactivity was observed with successive exposures. Carboxyhemoglobin in these rats reached 17% atler I cigmvtte, but did not inct~ease above 30% after 5 or I0 cig. Chron.ic Ex~ure to Ci_marette Smoke Studies: The mean body weights of container controls were xveil below those of the age.controls. Restraint for 8-rain periods. 7 time per day in containet.'s used for smoke exposure apparently constitutes a major stress. The mean weights of smoke exposed t,'ats were only sliN~tly less than those of tile container controls, Survival (18 month of experiment) in the group exposed to 7 ci~day is only sliN~tly below Ihnt of the control g~oups. The moriality rate in the group exposed to t0 cig/day is consider,ably above that of the control groups (53% vs 3% container controls vs 11% age controls). Of the pathological lesions observed in the histological materials available fl'om smoke exposed rats. the mtvlt significant appear to occur in the bronchioles and alveoli. Only mild focal epithelial hyperplasias were observed in the upNr airways, BronchMitis of the terminal bronchioles and marked focal ,'-dveolitis occun'ed, each nmrked by epithelial hyperplasia and pigmented macrophages. .Q,ONCL.=US_,I,ONS: The chrorfic smoke exposure studies ate ongoing, but preliminary ~vsults indicate that the mt as a model for tob~co smoke inhalalion studies xvill offer advantages such as the l~k of chronic ~vspiratory infection and longer survival expcctan,:y. This study demonstrated that the great sertsitivity of rats to smoke toxicity could be overcome by ,~t,ndual adaptation, Smoke .induced pathological changes were observed in the tvspiratory tract only.