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! I I I I I I I I I I I I I I I I I #41 AUTHOR(S); HAKIM, T.S., M. KING, 0.(3. WANG, AND M. CO$10 DATE: 1985 TITLE: EFFECT OF CHRONIC CIGARETTE SMOKE EXPOSURE ON PULMONARY VASOMOT1ON IN BEAGLE DOGS CITATION: J. Appl. Physiol. 59(6); 1815-1822 (1985) STUDY DESIGN: The arterial and venous occlusion technique was used to determine whether the site and magnitude of pulmonary vasoconstriction are altered by chronic cigarette smoke exposure. 12 control beagles and 5 beagles whole had smoke cigarettes (50 cigarettes/week for 40 weeks) were perfused in situ to measure the vascular pressure-flow relationship and the resistance of the three vascular segments with the arterial and venous occlusion technique. RESULTS/FINDINGS: In the control subjects the vascular resistance in the arterial, middle and venous segments was 23, 36, and 41% of the total, respectively. The segmental distribution of vascular resistance was not significantly different in the cigarette smoke exposed dogs, despite the fact that the absolute values were 30-40% less than that of the control group. The longitudinal distribution of resistance among the three vascular segments and their response to drugs were different in beagles than was previously found in mongrels. In all beagles the veins were considerably more reactive than arteries. Vasoconstriction with serotonin (5-HT) prostaglandin F2= (PGF2=), norepinephrine, histamine, and methacholine(M) infusion occurred predominantly in the veins. The effect of PGF2= and 5-HT was totally different than that previously observed in mongrels in which the constriction was predominantly in the arteries. CONCLUSIONS/COMMENTS= Chronic cigarette smoking reduced the basal pulmonary vascular resistance and attenuated the venoconstrictor response to 5-HT and M but potentiated the hypoxic pressor response of the microvessels. I

I I I I I I I I I ! I I I I I I I I #41 AUTHOR(S): HAMMOND, I=. CUYLER, OSCAR AUI=RBACH, DAVID KIRMAN, AND LAWRENCE GARFINKEL DATE: 1970 TITLE: EFFECTS OF CIGARETTE SMOKING DOGS I. DESIGN OF EXPERIMENT, MORTALITY, AND FINDINGS IN LUNG PARENCHYMA CITATION: ARCH. ENVIRON. HEALTH 21:740-753 (1970) ABSTRACT: Tracheostomy was performed on 97 male beagles. All but eight (group N) were trained to smoke cigarettes over the first 56 days through tubing from a cigarette holder to the tracheostoma. Of the 89 smoking dogs, two died and one was withdrawn during this period. On day 57, the remaining 86 dogs were divided into four groups assigned to various smoking categories, some smoking filter-tip and others nonfilter cigarettes. Starting on day 876, all surviving dogs were killed and lung sections were examined microscopically. The lungs of the group N dogs were normal while histopathological changes were found in all smoking dogs. Greatest changes were in the lungs of dogs smoking nonfilter cigarettes most heavily. RNDINGS/RESULTS: Finding in the study indicate that smoking cigarettes equipped with efficient filters produces less pulmonary fibrosis and emphysema in male beagle dogs than smoking the same cigarettes with the filter removed, duration of smoking and number of cigarettes smoke per day being the same. Additionally in this study it was confirmed a greater degree of emphysema and fibrosis was produced by smoking a large number of nonfilter cigarettes than by smoking half that number. CONCULSIONS/COMMENTS: We conclude that findings in this study strongly suggest that smoking cigarettes with an efficient filter will produce less damage to the human lung parenchyma than smoking identical cigarettes without filters. I

! I I I I I ! I I I I I I I i I i I #43 AUTHOR(S): HARADA, T., A. ENOMOTO, T. KITAZAWA, K. MALTA, AND Y SHIRUASU DATE: 1987 TITLE: ORAL LEUKOPLAKIA AND COSTOCHONDRAL HYPERPLASIA INDUCED BY DIETHYLNITROSAMINE IN HAMSTERS EXPOSED TO CIGARETTE SMOKE WITH OR WITHOUT DIETARY VITAMIN C. CITATION: VET. PATHOL 24:257-264 (1987) STUDY DESIGN: Male Syrian golden hamsters receiving 12 weekly subcutaneous injections of diethylnitrosamine (DEN) were subjected to cigarette smoke inhalation (twice a day, 5 days per week in a Hamburg II smoking machine) and fed a diet with or without 1% vitamin C supplement for a period of 58 weeks. Another group was sham-smoked control and was not fed vitamin C. Tissues of the oral cavity and costal cartilage were examined by light and./or scanning electron microscopy. RNDINGS/RESULTS: Oral leukoplakia and costochondral hyperplasia occurred with high frequency in all groups treated with DEN. Leukoplakic lesions were found in the palate, tongue, and pharynx; the early change was focal erosion with mild epithelial hyperplasia and inflammatory ceil infiltration. Advanced lesions had marked mucosal thickening due to acanthosis, parakeratosis, hyperkeratosis, and submucosal infiltration of lymphocytes and plasma cells. Precancerous lesionswere noted in tongue and pharynx. Scanning electron microscopy of tongues revealed destruction of filiform papillae, The incidence of leukoplakic lesions was higher in smoke- exposed hamsteres than in controls, but the incidence in vitamin C-supplemented hamsters was low when compared with the smoke-exposed hamsters without vitamin C. Costochondral hyperplasia was initiated by thickening of the perichondrium followed by proliferation of chondocytes. Costochondral hyperplasia appeared earlier, and the incidence was higher in the vitamin C-supplemented hamsters. I could not be determined whether costochondral hyperplasia was the primary lesion induced by DEN or secondary change. CONCLUSIONS/COMMENTS: The significant increased incidence of the oral leukoplakic lesions in the smoke-exposed hamsters with DEN indicated that cigarette smoke exposure might promote the induction of oral leukoplakia by DEN, In this study, precancerous lesions which could be regarded as carcinoma in situ were occasionally seen, but the frequency was higher in the smoke-exposed hamsters than in the sham-smoked controls. This suggest the cigarette smoking may enhance the propensity of oral leukoplakic lesions to become malignant.

i I I I I I I I I I I I I I I I #44 AUTHOR(S): RUSSO PATRIZIA, MAURO PALA, SILVIO PARODI, CARLA GHIARA, NICOLETTA FERRARI, AND GIORGIO VIDALI DATE: t984 TITLE: EFFECTS OF VITAMIN E ON LIVER DNA CITATION: CANCER LETTERS, 25:163-170 (1984) SUMMARY: The study was designed to investigate the effect of vitamin E on rat liver DNA using the alkaline elutior~ technique. Vitamin E, both in the form of dk~-tocopherol and d/-r~-tocopheryl acetate, was capable of inducing an increased alkaline elution rate of liver DNA from rats (Sprague- Dawley) treated i.p, with the vitamin. This activity was clearly both dose and time-dependent. A statistically significant effect was observed at dosages (1.25-5.0 mg/kg) that are in the range of biological activity of the vitamin in the rat. Moreover, the effect was observed at dosages that are clearly not toxic. An increased alkaline elution rate of DNA is usually interpreted as suggestive of DNA damage, however recent observations seem to indicate that functional modifications of chromatin packaging can also affect the elution rate of DNA. I

I i I I I I I I I I I I I I I I I I #45 AUTHOR(S): HARADA, TAKAMORI, KEIZO MALTA, NOBUAKI NAKASHIMA, YOSHITSUGU ODANAKA, AND YASUHIKO SHIRASU DATE: 1983 TITLE: QUANTITATIVE STUDIES OF BIOLOGICAL RESPONSES IN HAMSTERS EXPOSED TO TOBACCO SMOKE AND EFFECTS OF VITAMIN C SUPPLEMENT ON SMOKE INHALATION TOXICITY CITATION: JPN. J. VET. SCI., 45(5), 613-626 (1983) STUDY DESIGN= Male Sydan golden hamsters were exposed to smoke from 10, 20, or 30 cigarettes twice a day, 5 days a week, in a Hamburg II type smoking machine for quantitative evaluation of biological responses. An additional group received 1% dietary vitamin C supplement and was exposed to smoke from 30 cigarettes in the same manner as the other smoke exposed groups to study the effect of vitamin C on smoke inhalation toxicity. These hamsters were killed by design after 4,13, and 53 weeks of exposure. RNDING/RESULTS: The smoke exposed hamsters exhibited decreased body weight gain and food efficiency depending on the dose of cigarettes and showed various tobacco-related histological changes in the respiratory tract. Histometrical evaluation revealed that smoke exposure enhanced alveolar macrophage mobilization and thickening of the laryngeal mucosa relating to the dose of cigarettes and duration of exposure. While the vitamin C-supplemented group showed slightly improved body weight gain and food efficiency, significantly lower incidences of rhinitis, focal bronchial epithelial hyperplasia and bronchiolar adenomatoid lesion, and depressed alveolar macrophage mobilization as compared with those in the smoke-exposed group at the same dose of cigarettes. CONCLUSIONS/COMMENTS: These results indicate that measurement of alveolar macrophage count and thickness of the laryngeal mucosa may be most useful in rating the biological damage elicited by cigarette smoke in hamsters. In addition, it is assumed that vitamin C may have a protective effect in some part on smoke inhalation to×icity. I

! I I I I I I I I I I I I I I I I I #46 AUTHOR(S): HARADA, TAKAMORI, KEIZO MALTA, YOSHITSUGU ODANAKA, AND YASUHIKO SHIRASU DATE: 1984 TITLE: EFFECTS OF QUERCETIN AND BUTYLATED HYDROXYTOLUENE ON CIGARETTE SMOKE INHALATION TOXICITY IN SYRIAN GOLDEN HAMSTERS CITATION: JPN. J. VET. SCI., 46(4), 527-532 (1984) STUDY DESIGN: Male Syrian golden hamsters were divided into 5 groups of 10 animals each: Group 1 was cage controls, group II were subjected to sham smoking, group III, IV, and V exposed to cigarette smoke for 6 minutes, twice a day and 5 days a week in a Hamburg 11 type smoking machine for a period of 13 weeks., Group III was smoke exposed control for Groups IV and V. Groups IV and V were fed the basal diet mixed with quercetin and butylated hydroxytoluene (BHT) respectively. RNDINGS/RESULTS: In comparison with the smoke-exposed controls, the quercetin-supplemented hamsters showed slightly improved body weight gain and food efficiency and a significant inhibition of thickening of the laryngeal mucosa, whereas BH'I" treatment resulted in marked growth retardation and significant depletion of liver vitamin A level. CONCLUSIONS/COMMENTS: These results indicate that quercetin but not BHT may have some ameliorative effects on the biological damage elicited by cigarette smoke.

! I I I I I I I i l I I I I i I I I #47 AUTHOR(S): HARRIS, R.J.C., G. NEGRONI, SUSAM LUDGATE, C.R. PICK, F.C. CHESTERMAN, AND B.J. MAIDMENT DATE: 1974 TITLE: THE INCIDENCE OF LUNG TUMOUR IN C57BL MICE EXPOSED TO CIGARETTE SMOKE:AIR MIXTURES FOR PROLONGED PERIODS CITATION: INT, J, CANCER 14, 130-136 (1974) ABSTRACT/SUMMARY: C57BI mice, allowed to breathe a cigarette smoke:air (vapor phase - they used a Cambridge filter prior to inhalation chamber) for short periods and at frequent intervals throughout their lives, develop a higher incidence of lung cancers, adenomas and carcinomas, than untreated control animals. Smoke from the cigarettes made from a. flue-cured tobacco (T2) was more toxic and elicited cancers more quickly than that form cigarettes made from air-dried tobacco (T3) of the same crop, Filtered smoke:air from T2 and unfiltered smoke gave similar yields of lung tumours.

i I I I I I I I I I I I I I I i I I #48 AUTHOR(S): HECHT, STEPHEN S., JOHN D. ADAMS, SATOSHI NUMOTO, AND DIETRICH HOFFMANN DATE: 1983 TITLE: INDUCTION OF RESPIRATORY TRACT TUMORS IN SYRIAN GOLDEN HAMSTERS BY A SINGLE DOSE OF 4-(METHYLNITROSAMINO)-I-(3-PYRIDYL)-I-BUTANONE (NNK) AND THE EFFECT OF SMOKE INHALATION. CITATION: CARCINOGENESIS 4(10) 1287-1290 (1983) STUDY DESIGN: Experiment was designed to determine the effects on Syrian golden hamsters of a single s.c. dose of NNK, followed by treatment with smoke or sham smoking. Four groups of 10 male and female Syrian golden hamsters were given single s.c. injections of either 0.3 ml trioctanoin or of 0.3 ml of trioctanoin containing either 1.0 mg, 3.3 mg, or 10 mg of NNK. These hamsters were then exposed to diluted smoke of 30 cigarettes twice daily for 72 weeks. Four control groups received the same injections of NNK or trioctanoin but were treated by sham smoking. RESULTS/FINDINGS: Hamsters exposed to smoke generally have a longer survival rate than the sham smoke animals. The target tissues for NNK in the Syrian golden hamster were the lung, nasal mucosa, and trachea. No tumors were observed in these tissues in control animals. Basal cell hyperplasia was observed in 54% of the larynges of the hamsters exposed to smoke, compared with 9% in the sham exposed animals. The incidence of lung tumors in the females treated with 3.3 mg of NNK and smoke was significantly higher (p<O.01) than in the females treated with 3.3 mg of NNK and sham smoking. No other significant differences in respiratory tract tumor incidences were observed between the hamsters treated with smoke or sham treated. The incidences of lung tumors in the males and females treated with 10 mg of NNK and smoke and in females treated with 3.3 mg of NNK and smoke were significant (p<O,05) compared with animals treated with trioctanoin. The total numbers of animals with respiratory tract tumors were significantly higher in several of the groups treated with NNK than in the corresponding groups treated with trioctanoin. The combined numbers of males and females with respiratory tract tumors were significantly higher In several of the groups treated with NNK and smoke compared with those treated with trloctanoin and smoke. The combined incidences of respiratory tract tumors in males andd females treated with 1 o0 mg NNK and sham smoking or 10 mg NNK and sham smoking were also significantly higher than in the corresponding animals treated with trioctanoin. CONCLUSIONS/COMMENTS: These results demonstrate that even a single dose of NNK can induce respiratory tract tumors in Syrian golden hamsters. Smoke inhalation did not result in an increase in respiratory tract tumor incidence in most of the NNK treated groups. I

I I I I I I I I I I I I I ! I I I I #49 AUTHOR(S): HECKMAN, CAROL A. AND WALDEN E. DALBEY DATE; 1982 TITLE: PATHOGENESIS OF LESIONS INDUCED IN RAT LUNG BY CHRONIC TOBACCO SMOKE INHALATION CITATION: JNCI 69(1) 117-128 (1982) STUDY DESIGN: In this experiment, animals exposed in parallel with those for the lifetime study were killed at earlier intervals for assessment of morphologic lesions induced by smoke inhalation. SPF females F344 rats were exposed to tobacco smoke (from NCI Code 16 nonfiltered cigarettes) in the Maddox/ORNL smoking machine. Two final dose levels were used, 7 or 10 cigarettes/day, and the animals were killed at time intervals from 1 to 2 years after exposure began. Since mortality was high in the 10 cigarettes/day group, all the remaining animals in the group were killed at 1.5 years. Both untreated and sham-exposed groups were killed in parallel with the exposed animals. RNDINGS/RESULTS: Parallel lifetime exposures induced pulmonary tumors in 9% of the animals. In serially killed animals, four types of lesions were found: 1) perivascular or peribronchiolar accumulation of lymphoretlcular cells, 2) fibrotic and cellular enlargement of peribronchiolar septa, 3) type II cell hyperplasia with septal fibrosis, and 4) air-space enlargement (emphysema). However, emphysema occurred only in animals exposed to a higher dose of tobacco smoke (10 cigarettes). Ultrastructural studies showed all of the focal lesions to be infiltrated by cells typical of the inflammatory response. The type II hyperplastic and peribronchiolar alveolar lesions involved larger portions of the parenchyma in fibrotic changes but differed in structure, location, and frequency. The incidence of the peribronchiolar alveolar lesions was temporally related to tumor incidence. CONCLUSIONS/COMMENTS: Peribronchiolar lesions were dependent on the duration of exposure and/or on the age of the exposed animals.

I I I I I I I I I I I I I I I i I I #5O AUTHOR(S): HECKMAN, CAROL A. AND GERALD L. LEHMAN DATE: 1985 TITLE: ULTRASTRUCTURE AND DISTRIBUTION OF INTRACELLULAR SPICULES IN RAT LUNG FOLLOWING CHRONIC TOBACCO SMOKE EXPOSURE CITATION: JNCI 74(3) 647-657 (1985) ABSTRACT: The present studies were undertaken to determine whether the development of proliferative lesions in the respiratory airways of smoke-exposed rats was preceded by ultrastructural alterations in the epithelium. Previous studies had shown that tobacco smoke exposures of 1-2 years duration induced only one major type of lesion involving the respiratory airways, i.e. fibrotic and cellular enlargement of peribronchiolar alveolar septa. The airway epithelium in these areas was metaplastic and in some of the lesions, the airway ~ining epithelium advanced out onto the surfaces of adjacent alveoli. Epithelial cells in these lesions frequently contained elongated cytoplasmic inclusions which were oriented with their long dimensions roughly in the same plane as the long axis of the cell. Macrophages contained similar but larger inclusions. Because the composition of the inclusions could be indicative of their origin, we subjected samples of treated and control lung tissues concurrently to transmission electron microscopy and energy-dispersive X-ray fluorescence spectrometry. Spectra from inclusions of macrophages indicated the presence of the elements sulfur, phosphorus, aluminum, silicon, and iron. Spectra from type II cells, however, which did not contain inclusions, showed a different elemental composition. The results suggested that spicules were present in epithelial cells throughout the airways. Minor lesions corresponding to "microinvasion" of epithelium into the lamina propria and of capillaries into the epithelial layer were also found in the trachea.