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S C CURRENT DIGES] of Scientific Papers Relating to Tobacco Use (Compiled and Described for Informational Purposes Only for The Council for Tobacco Research-U.S.A., Inc. The Summaries Are Not Intended to be Complete Scientific Abstracts.) Vol. 28, No. 3 March 1983 Contents Page 1. Heart and Circulation 1 2. Lung Cancer 2 3. Other Respiratory Conditions 5 4. Pregnancy 7 5. GastroentePology 11 6. Oral Conditions 14 7. Other Systemic Conditions 15 8. Statistics 18 9. Nicotine 19 10. Smoke Condensate and Constituents 22 11. Psychology 27 12. Briefs from Meetings 28 13. Additional References 32 1. HEART AND CIRCULATION C BADEN, L., WEISS, S.T., THOMAS, E.H. & SPARROW, D., VA Outpatient Clinic, Harvard Medical School & Boston University Medical Center, Boston, Massachusetts O "Smoking status and the electrocardiogram: A cross-sectional and ~~ ~ longitudinal study." (Archives of Environmental Health 37/6: 365-90~ November-December 1982) CO." "Previous cross-sectional studies have shown age trends in ~ electrocardiographic wave patterns, including leftward shift in frontal plane axis and decreases in R, S, and T wave amplitudes with age. The effects of smoking on electrocardiographic measurements have also been examined. Findings of several studies vary and in- clude possible smoking-induced changes in T wave amplitude and frontal plane axis measurements. To examine both cross-sectionally and longitudinally the effects of cigarette smoking on electrocar- diographic measurements, serial recordings obtained 5 yr apart were taken from 702 healthy male participants of the Normative Aging Study, who were 23-74 yr of age at their first examination. These men were classified as current smokers (at both baseline and follow- up examinations, _N = 291), former smokers (men who stopped smoking prior to the baseline examination, N_ = 203), or never smokers (at any time, N=208). At baseline, P-R interval duration was shorter in current smokers than in former or never smokers. Longitudinal results indicated that R, S, and T wave amplitudes decreased at greater rates in smokers than in nonsmokers. These findings suggest that changes in the electrocardiogram attributed to aging may be modified by smoking."

2. KUZNETSOV, G.P. & PEREPELKINA, N.B., USSR "The influence of smoking on certain cardiohaemodynamic parameters in patients with angina pectoris and in healthy individuals." (Kardiologiya 22/11: 41-4, 1982: Authors' English summary) "Instrumental examination of 47 patients with angina pectoris and of 48 healthy individuals, including polycardiography and tetrapolar rheography was used to study the influence of smoking on the cardiovascular system. Individual reactions to smoking are described as well as the influence of chronic smoking. Changes of cardiohaemodynamic parameters before and after physical exercise showed that the myocardium needs more oxygen. Differences in the influence of smoking on the healthy persons and the patients are due to chronic ischaemic heart disease and myocardial ischaemia." 2. LUNG CANCER WELCH, K., HIGGINS, I., OH, M. & BURCHFIEL, C., The University of Michigan, Ann Arbor, Michigan "Arsenic exposure, smoking, and respiratory cancer in copper smelter workers." (Archives of Environmental Health 37/6: 325-35, November-December 1982) ~ "A report by Lee and Fraumeni in 1969 linked exposure to ~ arsenic and other contaminants to a threefold excess of respiratory cancer among 8,047 employees at the Anaconda copper smelter. We established vital status through December 1977 for a sample of 1,800 men from the original cohort. Average arsenic concentrations were estimated for each smelter department based on industrial hygiene measurements made from 1943 to 1965. Departments with similar concentrations were combined into four categories of exposure: 1) low (< 100 Ag/m3), 2) medium (100-499 jLg/m3), 3) high (500- 4,999 µg/m3) and 4) very high (>_ 5,000 ,µg/m3). Three indices of O individual arsenic exposure were developed; time-weighted average, ~, 30-day ceiling, and cumulative. Exposures to sulfur dioxide and ~j asbestos were also examined. Smoking habits were obtained by G: questionnaire. Mortality was compared to that of men in the State ~ of Montana using the modified lifetable method. A clear dose- ~ response relationship between arsenic exposure and respiratory can- cer was demonstrated. Men in the highest exposure category had a sevenfold excess. Those in the low and medium categories had a risk close to that expected. Ceiling arsenic exposure appeared to be more important than did time-weighted average exposure. Sulfur dioxide and asbestos did not appear to be important in the excess of respiratory cancer, although sulfur dioxide and arsenic ex- posures could not be separated completely. Smoking did not appear to be as important as arsenic exposure. Our findings suggest that had men worked only in departments with low or medium arsenic ex- posures (i.e., < 500 ttg/m3) there would have been little excess ~ respiratory cancer. Since the estimates of arsenic exposure were based on department averages rather than on concentrations for in- dividual jobs, these results must be interpreted with caution....

3. C "Table 12 shows mortality for respiratory cancer and ischemic heart disease by smoking and arsenic categories. This table should be interpreted with caution, however, because of the small numbers of nonsmokers, which resulted in many categories hav- ing too few men to provide meaningful results. Respiratory cancer mortality for smokers was very similar to that for the whole sample for both the TWA and ceiling analyses. The SMRs for nonsmokers were not very much less than those for smokers in any category. The ratio of SMRs for smokers to that for nonsmokers ranged from 1.25 to 3.5 in most categories. The pattern of mortality from ischemic heart disease for smokers was also very similar to that observed for the whole cohort. There was again very little difference in the SMRs for smokers vs. nonsmokers." MAGNUS, K., ANDERSEN, A. & HOGETVEIT, A.C., Kristiansand S, Norway "Cancer of respiratory organs among workers at a nickel refinery in Norway." (International Journal of Cancer 30/5: 681-5, December 1982) "In a previous report an excess risk of respiratory cancer among Norwegian nickel workers was demonstrated. The number of cancer cases was relatively small for the study of temporal changes in exposure. In this report the number of cancer cases increased by 70% through an extended follow-up to 1979, and the results published previously were confirmed. Data on smoking habits of the employees at the nickel refinery have now become available. The interaction between smoking and occupational nickel exposure is assessed by comparing the excess risk of lung cancer caused by smok- ing in the study group and in a sample of the general population. It is shown that the interaction is closer to being additive than multiplicative. This observation has methodological implications for studying temporal changes in occupational exposure. These implications are discussed. No substantial reduction in occupation- al exposure at the nickel refinery can be observed as far as lung cancer is concerned. For nasal cancer, however, the risk is much smaller among those employed around 1960 than among those employed around 1930. The difference in trend of occupational risk for the two types of cancer cannot be explained by the data presented.... "The incidence of lung cancer among non-smokers and smokers is shown in Table V. The follow-up of the general population sample was based on the calendar years 1966-1977. The data for the employees at the nickel refinery are therefore tabulated in Table V for the same period as well as for the total observation period 1953-1979. The two estimates of the risk ratio smokers/ non-smokers among the employees of the plant are lower than that of the general population sample, and the last column of the Table C indicates that the interaction between smoking and occupational Li nickel exposure is closer to being additive than mulitplicative." Q; [N=2,247]. ~ !-~ ~

4. WEISS, W., The Hahnemann Medical College & Hospital, Philadelphia, Pennsylvania "Epidemic curve of respiratory cancer due to chloromethyl ethers." (Journal of the National Cancer Institute 69/6: 1265-70, December 1982) "In 1962, suspicion arose that an excess of lung cancers was developing in a chemical plant. A prospective cohort study of 125 male workers was begun, and the group was followed from January 1963 to the end of 1979. A small epidemic of respiratory cancer evolved, including 14 cases of lung cancer (13 were the small cell type) and 2 cases of laryngeal cancer among 91 men ex- posed to chloromethyl ethers in the 17-year period, as compared to 2 cases of lung cancer among 34 unexposed men. The lung cancer epidemic peaked 15-19 years after onset of exposure and began to subside thereafter.... "The smoking factor was examined by the building in which the men were exposed to CME (table 1). While the proportion of nonsmokers was higher among the 13 men in buildings A 1 and 2 than among the 45 men in building B, the numbers of men were so small that this factor had no discernible effect on the crude respiratory cancer risk in the 2 groups. Table 1 shows that the crude 17- year cancer incidence was about twice as high among the nonsmokers as among the smokers in each group, but the overall crude incidence in each group was about the same." CLARY, C.F., MICHEL, R.P., WANG, N-S & HANSON, R.E., Royal Victoria Hospital & McGill University, Montreal, Quebec, Canada C C "Metastatic carcinoma. The lung as the site for the clinically undiagnosed primary." (Cancer 51/2: 362-6, January 15, 1983) "Of 387 patients who died with lung cancer, 28 cases were reviewed (7.2%) which were clinically undiagnosed. The male: female ratio was 3.6 and mean age was 64 years in the males, 47 years in the females. The most frequent presenting symptoms were neurologic. Prior to death, 21 patients had known or suspected metastatic disease (biopsy-proven in 12), while a malignant diagnosis was not considered in seven patients. Mean survival was 3.5 months. Despite a mean tumor size of 2.8 cm, most of the chest x-rays were not diagnostic even in retrospect. At autopsy, 65% of the tumors were adenocarcinomas (compared to 32% in the other 359 patients); 53% of these showed vascular and lymphatic invasion around the primary tumor, explaining their wide dissemination. In patients with small cell carcinomas (25% of the cases reviewed) or with solitary metastases (14% of the cases reviewed) therapeutic in- W tervention could possibly have been beneficial." ~ ~ N M~

5. C 3. OTHER RESPIRATORY CONDITIONS BEECKMAN, P., DEMEDTS, M., CLARYSSE, I. & VANCLOOSTER, R., Vrije University, Brussels,Belgium "Radiographic evaluation of the influence of age and smoking on thoracic and regional pulmonary dimensions." (Lung 161/1: 39-46, 1983) "Chest roentgenograms were taken at full inspiration (TLC) and expiration (RV) in healthy, nonsmoking and smoking, young and old subjects in the upright posture. Linear distances (D) were measured in apicodiaphragmatic and transverse thoracic directions and extensions [(DTLC-DRV)DTLC and (DTLC-DRV)/DRV] and volumes were calculated. In the apico-diaphragmatic direction a subdivision was made into an apico-fissural (A-F) distance and a fissuro-diaphragmatic (F-D) distance by means of the minor fissure. Overall volumes at TLC were identical in the four groups but differences were present in distances, extensions and volumes above and below the fissure. Aging caused mainly an increase in D(A-F) and a decrease in D(F-D) at TLC as well as at RV, indicating hyperinflation and airtrapping of the upper zone and hypoinflation and flattening of the lower zone. Smoking caused an increase in D(F-D) at RV, indicating airtrapping in the lower zone. In both groups E(F-DR) was reduced but in old subjects this was due to a decrease in regional TLC and in young smokers to an increase in regional RV. In old, smoking subjects a combination of the effects of aging and smoking was present." [N= 58] RAMAN, A.S., SWINBURNE, A.J. & FEDULLO, A.J., University of Rochester at Rochester General Hospital, New York "Pneumococcal adherence to the buccal epithelial cells of cigarette smokers." (Chest 83/1: 23-7, January 1983) of nonsmokers' cells with smoker's saliva resulted in increased "Adherence to mucosal surfaces is necessary for bacterial colonization. The in-vitro adherence of type 25 Streptococcus pneumoniae to buccal epithelial cells was studied in 15 smokers, 15 nonsmokers, and 21 exsmokers. Background adherence in smokers and nonsmokers was similar, but smokers had a markedly increased pneumococcal adherence compared to nonsmokers (12.3+6.9 vs 0.7 + 0.4). This increase was not related to subject age or duration of cigarette use. Pneumococcal adherence in some exsmokers remained elevated for up to three years after smoking cessation. Incubation

6. pneumococcal adherence to the nonsmokers' cells (1.1+0.9 to 8.2+4.4), suggesting mediation of pneumococcal adherence by a noncellular constituent of smokers' saliva. The increased pneumococcal adherence in cigarette smokers may promote oropharyn- geal colonization and contribute to the increased risk of respira- tory infection in cigarette smokers." FISHER, G.L., McNEILL, K.L., FINCH, G.L., WILSON, F.D. & GOLDE, D.W., Batelle Columbus Laboratories, Ohio "Functional evaluation of lung macrophages from cigarette smokers and nonsmokers." (Journal of the Reticuloendothelial Society 32/4: 311-21, 1982) ~ "The in vitro function of pulmonary alveolar macrophages (PAM) was compared for human smokers and nonsmokers. Initial studies demonstrated the feasibility of shipping lavaged cells on ice with storage up to 6 hr. Comparative studies were performed to evaluate ideal culture conditions including media composition, preincubation period, and phagocytic variables. Smokers had a six-fold enhancement in lavagable macrophages compared to non- smokers. Macrophages from smokers demonstrated a decreased phagocytic capability compared to nonsmokers. The effects of cigarette smok- ing on phagocytosis were observed over a wide range of challenge periods using either fetal or newborn bovine serum (FBS or NBS). Regardless of smoking history, enhanced phagocytosis was observed C with media containing NBS compared to FBS. No effects on in vitro viability, attachment, or adherence were observed." [N = 12] SPARROW, D., STEFOS, T., BOSSE, R. & WEISS, S.T., Harvard Medical School, Boston, Massachusetts "The relationship of tar content to decline in pulmonary function in cigarette smokers." (American Review of Respiratory Disease 127/1: 56-8, January 1983) "The impact of the tar content of cigarettes on pulmonary function was examined in 1,355 men. These men reDresented 383current cigarette smokers, 555 former cigarette smokers, and 417 never smokers enrolled in a longitudinal study of aging. Current smokers' cig- arette exposure was estimated by the number of cigarettes smoked per day and tar content twice on all subjects at analysis indicated that fluence baseline levels per a cigarette. Spirometry was performed 5-yr interval. A multiple regression tar content did not significantly in- of forced vital capacity (FVC) or forced O CJ ~ C.J -4~ C ~-A w

7. C expiratory volume in one second (FEV1), after controlling for age, height, and number of cigarettes smoked. Similarly, tar content did not significantly influence follow-up levels of FVC or FEV1, after controlling for age, height, number of cigarettes, and baseline pulmonary function. These data suggest that low tar cigarettes may not protect smokers from an increased rate of decline in pulmonary function.... "Since 1950, tobacco companies have been promoting the idea that smoking lower tar cigarettes is less harmful. However there is no evidence that the low tar cigarettes conferred any protection from reduced pulmonary function for men in the Norm- ative Aging Study. The data underline the importance of quitting smoking, because this remains the single most effective way to reduce the hazards associated with smoking." 4. PREGNANCY C HINGSON, R., GOULD, J.B., MORELOCK, S., KAYNE, H., HEEREN, T., ALPERT, J.J., ZUCKERMAN, B. & DAY, N., Boston,Massachusetts "Maternal cigarette smoking, pyschoactive substance use, and infant Apgar scores." (American Journal of Obstetrics and Gynecology 144/8: 959-66, 1982) "A study of 1,709 mother/child pairs at Boston City Hospital examined whether maternal cigarette smoking, drinking, or the use of other psychoactive substances was associated with low infant Apgar scores. The potential confounding effects of other labor and delivery risks were controlled in the analysis. In contrast to previous reports, univariate and stepwise multiple regression analyses did not identify a significant negative association be- tween cigarette smoking and 1- or 5-minute Apgar scores. None of the substance use variables was significantly associated with low infant Apgar scores at 1 and 5 minutes. Other labor and delivery risks, such as short length of gestation, abnormal delivery pre- sentation, placental abnormalities, nuchal cord, and exposure to general anesthesia during delivery, were associated with low Apgar scores.... "In this study, consistent with previous research, low Apgar scores were clearly associated with a high risk of infant death. However, in contrast to previous reports, neither this study's univariate nor multivariate analyses support the hypothesis that maternal cigarette smoking during pregnancy is associated with low 1= or S-minute Apgar scores."

8. PICONE, T.A., ALLEN, L.H., SCHRAMM, M.M. & OLSEN, P.N., University C of Connecticut, Storrs "Pregnancy outcome in North American women. I. Effects of diet, cigarette smoking, and psychological stress on maternal weight gain." (The American Journal of Clinical Nutrition 36/6: 1205- 13, December 1982) "This study examined the roles of diet, cigarette smoking, and psychological stress in pregnancy weight gain. The 60 subjects were selected by defined criteria to minimize variation in anthro- pometric, socioeconomic, and medical variables which also affect weight gain. To maximize variation in weight gain, subjects were also selected on the basis of low weight gain (!~ 15 lb) and adequate weight gain (> 15 lb). Each weight gain group contained smokers and nonsmokers. Smokers consumed more calories than nonsmokers (2119 versus 1810 kcal/day, pG 0.01). For nonsmokers, differences be- tween the intakes of low weight gain (1617 kcal/day) and adequate weight gain (1905 kcal/day) women were significant (p< 0.02) and calorie intake was correlated with weight gain (r=0.44, p< 0.02). Psychological stress negatively correlated with weight gain (r = 0.37, p< 0.01) but not with calorie intake. We conclude that low weight gain is associated with a lower food intake. In contrast, smoking and stress may cause low weight gain by reducing the utilization of calories for weight gain.... "Smokers, who comprised 32 of the 60 subjects, smoked from 10 to 40 cigarettes/day. Thirteen were classified as light smokers (-.1 15 cigarettes/day), 15 as moderate smokers (15 to 30 cigarettes/ day), and four as heavy smokers, (> 30 cigarettes/day). Maternal weight gain was not affected by smoking, as anticipated from our study design." PICONE, T.A., ALLEN, L.H., OLSEN, P.N. & FERRIS, M.E., University of Connecticut, Storrs "Pregnancy outcome in North American women. II. Effects of diet, cigarette smoking, stress, and weight gain on placentas, and on neonatal physical and behavioral characteristics." (The American Journal of Clinical Nutrition 36/6: 1214-24, December 1982) "This study evaluated the effects of diet, weight gain (low - LWG.< 15 lb: adequate> 15 lb), smoking, and stress on the pregnancy outcomes of 60 women. LWG mothers, compared to adequate weight gain, had lower calorie intakes, shorter gestations (0.5 wk, Dubowitz) smaller placentas (345 + 65 versus 373 + 75 g), and in- fants with lower birth weight 2640 + 329 versus 3193 + 307 g), pon- deral indices (2.37 versus 2.62), and growth rates. Mothers who O GJ ~ 09 G: ~ N Cl1 C t

9. C C ` smoked had increased calorie intake, but showed no alterations in gestational age of infants or placenta weights. Infants of smokers weighed less than those of nonsmokers (2875 + 522 versus 3059 + 511 g), but had a normal ponderal index. LWG or smoking were associated with impaired habituation, orientation, and regulation of state (Brazelton exam). LWG (second trimester) impaired motor per- formance, visual habituation and orientation, and reflexes. Smoking adversely affected auditory habituation and orientation, and auto- nomic regulation. LWG and smoking have significant, but separate, detrimental effects on pregnancy outcome.... "Repeated measures analysis of variance (nested design) showed that smoking during pregnancy was also associated with impair- ments in infant behavior at all three test dates. Since no significant differences in cluster scores were seen among the three test dates, the mean scores for each cluster are reported (Table 8). Maternal cigarette smoking significantly affected habituation, ori- entation, and autonomic regulation of the infant. Regulation of state was impaired, although this was mediated by the lower birth weight of these infants. "When the habituation and orientation scores were divided into their auditory and visual components, there was evidence of a marked effect of smoking on the hearing ability of the infant (Table 9)." BOTTOMS, S.F., KUHNERT, B.R., KUHNERT, P.M. & REESE, A.L., Cleveland, Ohio "Maternal passive smoking and fetal serum thiocyanate levels., (American Journal of Obstetrics & Gynecology 144/7: 787-91, December 1, 1982) "Passive smoking, exposure of the nonsmoker to air con- taminated with tobacco smoke, has been reported to have several adverse consequences for health. However, its effects of the fetus are unknown. Detailed smoking histories and fetal SCN (thiocyanate) levels were obtained in 107 low-risk pregnancies in order to evaluate fetal exposure to this metabolic byproduct of tobacco smoke. Among nonsmokers, fetal SCN levels were increased in association with passive smoking in the home (p< 0.05). Significant differences in clinical characteristics were associated with passive smoking, but none of these differences accounted for significant increase in fetal SCN levels. These findings suggest that maternal passive smoking exposes the fetus to SCN which is reported to be an effective biochemical marker of overall exposure to smoking, and which is known to be toxic in higher doses.... a

10. "This study and other studies of passive smoking suggest the possibility that the effects of smoking may have been under- estimated by including subjects with passive exposure to smoking in control groups (nonsmokers). Finally, these findings indicate the need for further research to determine the risks of passive smoking and of relatively small increases in SCN for the fetus." ASMUSSEN, I., University of Copenhagen, Denmark "Chromatin changes of endothelial cells in umbilical arteries in smokers." (Clinical Cardiology 5/12: 653-6, 1982) "Fine granular spots within the nucleus of endothelial cells have been demonstrated in umbilical arteries from newborns. These nuclear changes were predominantly found in vessels from new borns delivered by heavy smoking mothers (> 10 cigarettes per day)x 2 = 8.28, p< 0.005. Similar nuclear changes have until now only been reported in man in relation to tumors or other pathological con- ditions. The vessels showed signs of increased cellular turnover compatible with the findings in experimental atherosclerosis. The nuclear changes thus could be interpreted as an alteration of nuclear activity." [N=52) ROWELL, P.P. & CLARK, M.J., University of Louisville School of Medicine "The effect of chronic oral nicotine administration on fetal weight and placental amino acid accumulation in mice." (Toxicology and Applied Pharmacology 66/1: 30-8, October 1982) c "Nicotine was administered to female mice by addition to the drinking water at concentrations up to 100 ,U.g/ml. The animals were given the solutions for at least 2 weeks before breeding and through- out gestation. The fetuses and placentas from all animals were examined on the 17th day of gestation. Fetuses of the nicotine- treated mice weighed up to 12% less than controls. There was no reduction in the litter size in the treated animals. Placental mince was incubated in vitro to measure the ability of the tissue to accumulate the neutral amino acid, oC-aminoisobutyric acid. Placentas from animals receiving nicotine, 100 f,tg/ml in the drinking water, or by ip injection, 1.3 mg/kg, had a decreased intracellular amino acid concentration measured at 60 min. Determinations of placental fluid parameters indicated that this decrease was not due to an effect on intracellular space. Animals receiving 100 ug/ml nicotine in the drinking water had a decrease in mean placental weight compared to control. Nicotine treatment had no effect on the placental concentrations of acetylcholine or the activities of acetylcholinesterase or acetyltransferase. The results of this investigation demonstrate that nicotine is able to decrease fetal weight and depress placental amino acid transport in mice as it does in humans." C 03663417