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! I I I I I I I I I I I I I I I I I #1 AUTHOR(s): AHMED, S. SULTAN., CHRISTOS B. MOSCHOS, MICHAEL M. LYONS, HENRY OLDEWURTEL, RICHARD J. COUMBISS, TIMOTHY J. REGAN, AND BESS JENKINS. DATE: 1976 TITLE: CARDIOVASCULAR EFFECTS OF LONG-TERM CIGARETTE SMOKING AND NICOTINE ADMINISTRATION CITATION: THE AMERICAN JOURANL OF CARDIOLOGY 37: 33-40(1976) STUDY DESIGN: To compare the relative effects of long-term smoking and nicotine administration on the cardiovascular system, 18 month old beagles were prepared with a permanent tracheostomy. The were divided into three groups: I, seven control dogs; II, nine dogs that smoked seven cigarettes/day; and III, eight dogs that received an equivalent amount of nicotine. After a period of up to 22 months, the animals were catheterized under anesthesia for assessment of left ventricular function and volumes by indicator-dilution technique. RNDINGS/RESULTS: Heart rate, stroke volume, left ventricular end-diastolic pressure and volume and intraventricular conduction times did not differently significantly in the three groups. Left ventricular ejection fraction was 44 -+ 3% in the control group, 35 + 3 % in the dogs that smoked cigarettes and 27 _+ 3 % in those given nicotine (P <0.01)despite similar values for end-diastolic variable in the three groups, The first derivative of left ventricular pressure (dP/dt) normalized for pre and afterload was 2.4 + 0.2 crWsec "~ in the control group, 1.41 _+ 0.12 in the cigarette smoking group (p<0.005) and 1.34 :t: 0.08 in nicotine group (p <0,01). Mean aortic pressure was significantly elevated in both the smoking (127 + 5 mm Hg) and nicotine (127 +_ 10 mm Hg) groups, there was no significant correlation with the contractililtly indexes. Reduction of afterload to normal levels did not affect the abnormal ventricular performance. Hypertrophy, inflammation and abnormalities of cell ultrastructures were not present, and myocardial lipid and cation composition were normal. Since interstitial fibrosis was evident in both experimental groups, an alteration of elastic elements may be operative. These cardiovascular abnormalities appear to be predominantly dependent on the nicotine of cigarettes. CONCLUSIONS/COMMENTS: Since clinically evident heart disease was not observed in these animals, the conclusions of an epidemtologic study that cardiac risks of long-term smoking are only evidenced when associated with other risk factory may be well founded.

! I I I I I I I I I I I I I I I I I #~ AUTHOR(s); AHMED, S. SULTAN., CHRISTOS B. MOSCHOS, HENRY OLDEWURTEL, and TIMOTHY J. REGAN DATE: 1980 TITLE; MYOCARDIAL EFFECTS OF LONG-TERM CIGARETTE SMOKING: RELATIVE ROLES OF CARBON MONOXIDE AND NICOTINE. CITATION= THE AMERICAN JOURNAL OF CARDIOLOGY 46=593-598 (1980) STUDY DESIGN= Because controversy has existed as to whether nicotine or carbon monoxide is the major pathogenetic agent in cigarette smoking, 18 adult male beagles with chronic trachestomy were placed in three groups of six dogs each: Group 1 served as a control group; group2 received 7 cigarettes of low nicotine content (0.2 rag/cigarette), which effected a peak carboxyhemoglobin level approximating 5/100ml, similar to that of regular cigarettes; and group 3 received nicotine twice daily intramuscularly in an amount equivalent to seven cigarettes/day. RNDINGS/RESULTS: In the intact anesthetized state, heart rate, left ventricular end-diastolic pressure and volume (indicator dilution) did not differ among the three groups. To assess relative myocardial wall stiffness, saline solution was infused into the left ventricular chamber. A significantly higher end-diastolic pressure and tensions were elicited in group 3, suggesting a decrease in left ventricular compliance. No such change was observed in either group 1 or 2. Only long-term nicotine use was associated with increased hydroxyproline content in the left ventricular myocardium, suggesting a basis for enhanced stiffness, An index of left ventricular contractility was derived from the peak rate of rise of left ventricular pressure (dP/dt), normalized for preload and afterload. Groups 1 and 2 showed no difference in this index (2.18 + 0.3 versus 2.15 _.+ 0.18 muscle lengths/s per cm) at similar levels of aortic pressure, but the index was significantly lower (1.28 _+ 0.12, p < 0.01) in group 3. CONCLUSIONS/COMMENTS: The effects of long-term cigarette use on the myocardium appear to be predominantly dependent on nicotine rather than on carbon monoxide, i

I I I I I I I I I I ! I I I I ! I AUTHOR(s)= ANDO, KIYOSHI AND TOMOJI YANAGITA DATE: 1981 TITLE; CIGARETTE SMOKING IN RHESUS MONKEYS CITATION= PSYCHOPHARMACOLOGY 72:117-127 (1981) ABSTRACT; In the present pilot study, an attempt was made to shape and maintain cigarette smoking behavior in rhesus monkeys both with and without the simultaneous use of other reinforcers. Initially, 14 monkeys were trained to suck air and puff on cigarettes using sweetened liquid reinforcer. After smoking had been established, the sweetened liquid reinforcement was removed. Smoking without this reinforcement, referred to as 'voluntary smoking' was then observed during 20-h daily sessions. Of the 14 monkeys studied, 2 have engaged in voluntary smoking for 2 years or longer. The maximum figures recorded for any single 20-h session were 3,271 puffs (20 cigarettes) in one monkey and 16,384 puffs (47 cigarettes) in the other. Although the baseline variability of smoking by these monkeys was quite high, low-nicotine and nicotine free cigarettes seem to lead to a clear decrease in smoking. In 2 other monkeys that did not perform voluntary smoking, smoking was reestablished under a random-time or tandem schedule for sweetened liquid reinforcement. Within this situation ('Schedule-controlled smoking") schedule manipulations also led to changes in intake of cigarette smoke. The voluntary smoking model described in the present paper should be useful for studying the factors involved in initiating and maintaining smoking behavior and for studying the psychopharmacological effects of smoking, while the schedule-controlled smoking model should be useful for studying the physiological effects of smoking and for studying the relationship of smoking with various disease entities. I

I I I I I I I I I I I I I I I I I AUTHOR(s): AOYAMA, MITSUKO, HIROSHI FUJISE AND NORIHIDE TACHI DATE: 1981 TITLE: EXPERIMENTAL STUDIES ON THE EFFECT OF CIGARETTE SMOKE ON THE PHYSIOLOGICAL GROWTH, LIFE-SPAN, AND SPERMATOGENESIS IN MALE MICE CITATION: NAGOYA MEDICAL JOURNAL 25:259-264 (1981) STUDY DESIGN: 45 male ddY mice used in this study were divided into three groups (each 15): Group A, Group B and the control. The smoke exposure experiments were performed in a chamber filled with smoke from 5 cigarettes (filter cigarette, Hi-lite Japanese brand) by the aid of an inhalation apparatus. Group A was exposed once a day for 50 minutes and group B for 25 minutes. The control group was manipulated in the similar manner for 25 minutes without smoke. The experiment was carried out for 360 consecutive days. The levels of carbon monoxide measured in the chamber was usually 400-500 ppm, while carbon dioxide was -5500-6000 ppm, and the smoke dust was - 120 mg/m3' Tissue preparations for microscopical analysis were made from the testes of the mice which survived until the end of the experiment, RNDINGS/RESULTS: The effect of cigarette on the life span of the mice is indicated by their survival rates. Mice exposed for 50 minutes a day began to die from the 60th day of exposure, and the final survival rate was 13.3%. Mice exposed for 25 min. began to die also on the 60th day, and had a final survival rate of 20%. The control group on the other hand did not start to die until the 150th day, and the final survival rate was 53.3%. The death rate between the control and exposed groups was significantly different. Physiological increase in the body weight of the exposed mice was considerably more retarded than that of the control mice. In the histological observations of the testes one of the two surviving mice in Group A on the 306th day of the experiment displayed azoospermia and two of the three surviving mice in Group B showed oligo- or azoospermia. CONCLUSIONS/COMMENTS: The marked inhlbition of spermatogensis at the end of this experiment clearly indicates that a certain component in the smoke must have a toxic effect on spermatogensis.

I I I I I I I I I AUTHOR(s)= AUERBACH, OSCAR, AND LAWRENCE GARFINKEL DATE= 1970 TITLE= EFFECT OF CIGARETTE SMOKING ON DOGS. II. PULMONARY NEOPLASMS CITATION; ARCH ENVIRON HEALTH 21; 754-768 (1970) STUDY DESIGN= Of 86 male beagle does trained to smoke through a tracheostoma, 12 dogs (group F) smoke filter-tip, 24 (group H) and 38 (group h) smoked non-filter cigarettes and 12 (group L), half as many non filter cigarettes. Eight dogs (group N) never smoked. RNDINGS/RESULTS= By day 875, none of the N dogs, 2 F dogs, 2 L dogs, 12 H dogs, and 12 h dogs had died, and the remaining N,F,L, and H dogs were killed. Noninvasive brochiolo-alveolar tumors were found in dogs of all five groups. Invasive bronchiolo-alveolar tumors were found only in H and h dogs; in two of 12 group h and group H dogs, respectively, which died, and eight of 12 group H dogs which were killed. One extended to and four into the pleura. Early invasive squamous cell carcinoma was found in bronchi of two of 12 group H dogs which were killed. CONCLUSIONS/COMMENTS: The smoking of cigarettes greatly increases the probability of development of noninvasive bronchiolo-alveolar tumors in male beagle dogs and that smoke from filter-tip cigarettes of the type used in this study is less potent in regard to tumor production than smoke from non-filter cigarettes of the type used. No invasive tumors were found in the nonsmoking dogs, dogs smoking filter-tip cigarettes, and dogs which smoked half as many nonfilter cigarettes as were smoked by other smoking dogs. However, these types of tumors were found in 4 of 24 dogs that died after 626 to 753 days of smoking many nonfilter cigarettes and in eight of 12 dogs killed after 875 days of smoking nonfilter cigarettes. We conclude that the smoking of a large number of nonfilter cigarettes daily over two years can lead to the development of invasive bronchiolo-alveolar tumor in male beagles, I

! I I I I I I I I I I I I I I I I I AUTHOR(s): AVIADO, DOMINGO M. AND TETSUYA WATANABE DATE: 1974 TITLE: FUNCTIONAL AND BIOCHEMICAL EFFECTS ON THE LUNG FOLLOWING INHALATION OF CIGARETTE SMOKE AND CONSTITUENTS. I. HIGH- AND LOW- NICOTINE CIGARETTES IN MICE CITATION: TOXICOLOGY AND APPLIED PHARMACOLOGY 30, 185-200 (1974) STUDY DESIGN: Two strains of male mice (Swiss and ICR) were exposed to smoke twice a day, daily for either 5 or 10 weeks using a Walton horizontal smoke-exposure machine. Study was designed to examine the effects of the length of exposure (5 or 10 weeks), the nicotine content of the cigarettes (University of Kentucky 1R 1 or 1A1 cigarettes), and the presence or exclusion of smoke particulate matter using Cambridge Filters on pulmonary function. RESULTS/FINDINGS: Daily inhalation of cigarette smoke for 5 or 10 wk elicited the following effects: (1) increase in pulmonary resistance; (2) decrease in functional residual capacity; (3) decrease in pulmonary compliance; (4) decrease in tidal volume; (5) no change in phospholipid content of the lung; and (6) increase in wet weight of the lung relative to body weight which was reduced. The increase in pulmonary resistance and the decrease in functional residual capacity were elicited by nonfiltered smoke as well as by the vapor phase, and their appearance was related to the nicotine content of the cigarettes and the duration of exposure. The decrease in pulmonary compliance was elicited by inhalation of nonfiltered smoke but not by the vapor phase. The decrease in tidal volume as well as the increase in pulmonary resistance, or bronchospasm, occurred more readily in ICT mice than in the Swiss mice. Both strains developed tolerance to bronchospasm after 10 wk of exposure. There was no increase in functional residual capacity and, hence, no functional sign of pulmonary emphysema in mice that had been exposed to cigarette smoke for 5 or 10 weeks. CONCLUSIONS/COMMENTS: The results indicate that the effects observed with pulmonary resistance and functional residual capacity are elicited by a combination of nicotine contained in particulate material and constituents of the vapor phase. The effect of smoke on pulmonary compliance indicates that the causative factor is in the particulate matter, probably nicotine, because the appearance of decreased compliance depended on the nicotine content of the cigarette. The ICR mice strain had a greater sensitivity to cigarette smoke compared to the Swiss strain. The phospholipid content of the lung remained unchanged in all of the mice, no matter the treatment. This suggest that chronic exposure to smoke does not reduce surfactant activity under the experimental conditions of this study. I

! I I I I I I I I I I I I I I I I I ALITHOR(s)= AYRE, D.J., D. KEAST, AND J.M. PAPADIMITRIOU DATE: 1981 TITLE= EFFECT OF TOBACCO SMOKE EXPOSURE ON SPLENIC ARCHITECTURE AND WEIGHT, DURING THE PRIMARY IMMUNE RESPONSE OF BALB/c MICE CITATION: JOURNAL OF PATHOLOGY 133:53-59 (1981) STUDY DESIGN: Female mice BALB/c, 8-12 weeks of age were exposed once daily on weekdays to smoke of 30 cigarettes in a Hamburg II Small Animal Smoking Machine. High-tar, filtered cigarettes (16.0 mg tar, 1.1 mg nicotine/cigarette) were used in this study. Mice were exposed to smoke for 3days, or 18 or 28 weeks, prior to SRBC inoculation. Spleen weight changes were monitored 0, 1, 8 and 12 days post inoculation. RNDINGSIRESULTS: Mice exposed to tobacco smoke (TS) for 3 days or 18 or 28 weeks, prior to SRBC inoculation subsequently displayed less pronounced and/or "shorter-lived" splenomegaly than age matched controls. In addition mice exposed to TS for three days or 18 weeks displayed a reduction in both the magnitude and duration of the primary immune response as evidenced by the pattern of expansions of splenic white pulp and "RNA-rich" white pulp volumes. In contrast mice exposed to TS for 28 weeks, prior to inoculation, displayed white pulp and "RNA-rich" white pulp volumes similar to those of control mice. CONCLUSIONS/RESULTS: Cigarette exposed mice consistently exhibit a reduced splenomegaly following primary i.v. inoculation with SRBC. Similarly significant alteration of splenic architecture may be detected following both acute and chronic TS-exposure.

! I I I I I I I I I I I I I I I I I AUTHOR(s): BAZIN, R., H. TURCOI-FE, R. LAGACE AND M. BOUTET DATE: 1981 TITLE: EFFETS CARDIOVASCULAIRES DE LA FUME~E DE CIGARETTE CHEZ LE RAT CITATION: REV. CAND. BIOL 40:263-276 (1981) STUDY DESIGN: Seventy-two Sprague-Dawley rats were subjected to cigarette smoke for 1 day (acute effects), 2 weeks (sub-acute) and 15 weeks (chronic effects) and were sacrificed 5 minutes or 8 hours after smoking and the permeability of aortic endothelium and myocardial capillaries were examined using the diffusion tracer peroxidase. RNDINGS/RESULTS: Peroxydase was not generally Present at the sub-endothelial level in the aortic endothelium of control animals and sham-smokers. However, in smokers, the increase in peroxidase permeability is proportional to the smoking period. Moreover, in these smokers we observed junctional and subendothelial vacuolar dilatations which correspond to degenerative morphologic changes. Cigarette smoke has a different effect on the right ventricle. Endothelial permeability of the myocardial capillaries increases in animals subjected to cigarette smoke for 1 day and those who smoked for 2 weeks sacrificed 5 minutes after smoking. This increase in permeability is not related to the significant morphologic changes observed in the myocardium and endothelial capillaries. However, the myocardial endothelial capillaries, the sub-endothelial space and the adjacent interstitial space were generally free of peroxidase in animals subjected to smoke for 15 weeks and those smoking 2 weeks sacrificed 8 hours later. CONCLUSIONS/COMMENTS: An adaptive phenomenon to the effects of cigarette smoke appears to exist in the myocardial endothelium capillaries contrary to that which is observed in the thoracic aorta. i

! I I I I I I I I I I I I I I I I I AUTHOR(s): BENDDICT, WILLIAM F., ASHUTOSH BANERJEE, KEN K. KAGALINGAM, DAVID R. DANSIE, RICHARD E. KOURI AND CAROL J. HENRY DATE= 1984 TITLE: INCREASED SISTER-CHROMATID EXCHANGE IN BONE MARROW CELLS OF MICE EXPOSED TO WHOLE CIGARETTE SMOKE. CITATION= MUTATION RESEARCH 136 (1984) 73-80 STUDY DESIGN: BC3F1/Cum female mice were exposed nose-only to cigarette smoke using a large-capacity Smoke Exposure Machine (SEM II). Kentucky reference 2R1 and 3A1 cigarettes were used throughout these experiments, with the smoke being diluted to 10% (v/v) under the following conditions: 15 sec smoke, followed by 45 sec of air for each minute for 126 consecutive minutes on a daily basis for 1 week and up to 46 weeks. Control animals were both cage control and sham controls. Studies were scheduled so that all cytogenetic observations were made 2-3 days after the last smoke exposure. RESULTS/FINDINGS: Exposure of BC3F1/Cum mice to whole cigarette smoke significantly increased the number of SCE's in bone marrow compared to sham-exposed controls. After exposure of mice to smoke for 1 week, the number of SCE's was significantly (p<0.05) increased in 2R1 and 3A1 cigarette smoke exposed animals compared to sham-exposed animals, and this increase could be reproduced in two separate experiments. Differences between animals exposed to the two types of cigarette smoke were not significant. No increase in SCE's was observed in the sham- exposed animals relative to the untreated, shelf-control animals. Continued exposure to cigarette smoke for 4, 12, and 46 weeks showed similar significant increases in SCE in the smoke exposed mice. And again, no significant differences between mice exposed smoke from either cigarette type or between the sham-exposed and shelf-control animals were found at any of these time points. The persistence of smoke-induced increase in SCE's was examined in two groups of mice, one exposed for 1 week and a second group exposed to smoke for 46 weeks. Significant increases in SCE's persisted after cessation of smoke exposure for mice exposed to smoke for either 1 week or 46 weeks compared to sham- exposed mice. CONCLUSIONS/COMMENTS: This is the first demonstration of the induction of SCE's in laboratory animals that have been exposed to smoke in vivo. These data from this study suggest either that those cells damaged by smoke exposure are not eliminated but continue to function and turnover at normal rates, or that certain smoke constituents may be retained and continue to exert their effects. I

! I I I I I I I I I I I I I I I I I AUTHOR(s): BERNFELD, PERER, F. HOMBURGER, AND E. SOTO DATE: 1983 TITLE; SUBCHRONIC CIGARETTE SMOKE INHALATION STUDIES IN INBRED SYRIAN GOLDEN HAMSTERS THAT DEVELOP= LARYNGEAL CARCINOMA UPON CHRONIC EXPOSURE. CITATION: JNCI 71 (1983) 619-623 STUDY DESIGN= Male BIO~' 15.16 Syrian golden hamsters were exposed to smoke from each of three types of cigarettes, as well as sham smoking conditions, for total durations of 6,9,12, 15, and 20 weeks, using the modified reverse Walton smoking machine. Smoke exposure was intermittent: 27 sec of 22% cigarette smoke alternated with 33 sec of fresh air. Each hamster exposed to 12 minutes of this regimen, twice a day (4 hours between sessions), 7 days per week. The three types of experlmental cigarettes emptoyed were: 1) type A, a flue-cured, all tobacco cigarette found on the open market in the UK around 1975; 2) type B, a cigarette made of 100% Cytrel, and 3) a cigarette that consisted of 1:1 blend of the type A and B smoking materials. All cigarettes were filter-tipped, RNDINGSIRESULTS: The incidence and severity of laryngeal hyperplasia increased in these hamsters, a few (2) laryngeal papillomas appeared, alveolar macrophages became more frequent and aggregated, and hyperplasia of terminal bronchiolar epithelium occurred. This subchronic response of hamster to smoke markedly differed for the three types of cigarettes. Statistical evaluation of the data by log linear models proved these differences to be significant. At equal doses of smoke, the most severe response was caused by an all-tobacco cigarette. The weakest subchronic effects next to those seen in the negative control group, were elicited by smoke from a cellulose-derived tobacco supplement. The effects of smoke from a 1:1 blend of the two smoking materials were intermediate. The severity of the subchronic response of the respiratory tract paralled the extent of malignant transformations of the larynx previously observed in the same animal model with the same three types of cigarettes in chronic inhalation studies. CONCLUSIONS/COMMENTS: Although there is no evidence to assume that the short term phenomena observed were precancerous nature, the obvious parallelism between the subchronic and chronic response for the three types of cigarettes strongly suggest that the short term results may be of predictive nature for what will happen with a given type of cigarette upon chronic smoke exposure of hamsters.