Relationship of Respiratory Symptoms and Pulmonary Function to Tar, Nicotine, and Carbon Monoxide Yield of Cigarettes1-3

MICHAL KRZYZANOWSKI,4 DUANE L. SHERRILL, PAOLO PAOLETTI, and MICHAEL D. LEBOWITZ

Introduction

The role of cigarette smoking as a strong risk factor in chronic obstructive lung disease is well established (1-3). In an attempt to make smoking less hazardous cigarettes have been produced with reduced yields of tar and nicotine. Epidemiologic studies have shown that the risk of a variety of cancers due to smoking may indeed be reduced in smokers of cigarettes with low yields of tar (4, 5). Further, other studies found respiratory morbidity (6) and prevalence rates of cough and phlegm (7, 8) lower in subjects smoking such cigarettes than in other smokers. However, results concerning the relation of yields of contents from cigarette smoke to lung function have not been uniform (9, 10),and further studies in this area are necessary (11). From the analysis of data from the seventh survey of the Thcson Epidemiologic Study (12), conducted in 1981-1983, it was found that there was a decreased prevalence of phlegm in smokers of lower tar cigarettes and a negative correlation between lung function and estimated cumulative tar exposure (13). This paper presents longitudinal analysis of the data set from that survey and data collected in two follow-up surveys conducted in the same population over a 6-yr period. In this analysis the possible effects of tar, nicotine, and carbon monoxide (CO) contents of cigarettes were studied separately in an attempt to select the component that was best related to the prevalence and incidence of respiratory symptoms, as wellas to levelsof pulmonary function. To minimize errors in the estimation of the yield of cigarettes related to recall bias (14, 15), we used data on smoking at the time of the surveys only, not, as it was done in the previous analysis, utilizing the recalled history of smoking. The longitudinal data enabled us to examine the effects of cigarettes smoked in the past, as well as the re308

SUMMARY The data from consecutive surveys of the llIcson Epidemiologic Study (1981-1988) were used to evaluate the relationship In cigarette smokers of respiratory symptoms and pulmonary function to tar, nicotine, and carbon monoxide (CO) yields of the cigarette. There were 890 subjects who reported smoking regularly In at least one surwy, over .e15. After adjustment for Intensity and duration of smoking and for depth of Inhalation, the risk of chronic phlegm, cough, and dyspnea were not related to the tar and nicotine yields. In 414 subjects with pulmonary function tested In at least one of the three surveys the spirometric Indices used were significantly related to the dally dose of tar, nicotine, and CO (product of the cigarette yield and dally number of cigarettes smoked). The effects were more pronounced for past than for current do..s. However, the differentiation of pulmonary function due to .rlous yields of cigarettes was sman In comparison to the difference In pulmonary function between smokers and nonsmokers. AM REV RESPIR DIS 1991; 143:306-311

sponses to the current tobacco smoke exposures. Methods The detailed description of the design and methods of data collection in the Thcson Epidemiologic Study of Airway Obstructive Disease have been reported previously (12, 13, 16). The population in this study is a random stratified cluster sample of households in Tucson, Arizona enrolled in 1972-1973. The questions on brand name, size, and type of cigarettes smoked currently were included in the self-completion questionnaires in survey 7, conducted in 1981-1983, and surveys 9 (1984-1985) and 10(1986-1988). This enabled us to estimate the tar, nicotine, and carbon monoxide yields of the currently smoked cigarette based on Federal Trade Commission List of 1981 (for survey 7) and of 1985 (surveys 9 and 10) (17, 18). Consequently, the amount of tar, nicotine, and CO per cigarette is used as a unit yield in this analysis. In this analysis we included the data collected in 690 subjects (aged over 15 yr) who were current smokers in at least one of these surveys. Current smokers were defined as those subjects who reported currently smoking at least one cigarette/day regularly. There were 251 subjects reporting current smoking in all three surveys, 208 in two, and 231 currently smoking in one survey only, providing a total of 1400person-surveys of data. However, the data necessary to estimate the tar yield of the cigarettes was available only in 1169 (83.5070) cases, the nicotine yield in 83.2070, and CO content in 81.9070. The remaining questionnaires did not provide sufficient

information on the brand or type of the cigarettes smoked, or the data for the reported cigarette was not listed. The information on the number of cigarettes smoked currentlywas collected in all surveys considered. Questions on age of starting regular smoking and on depth of inhalation were asked in survey 7 but not in 9 or 10. Therefore, for subjects smoking in survey 9 or 10 but with this data missing in survey 7, we supplemented this information using similar questions from survey 8, when it was available. Questionnaire responses in each survey were used to define the symptoms: chronic cough and phlegm (symptom present on most days for at least 3 months of the year), wheeze (apart from colds), and exertional dyspnea (when walking with other people of same age on level ground). Pulmonary function tests were performed in 452 smokers (66070). Testing methodology,

(Received in original form January 29, 1990 and in revised form August 24, 1990) 1 From the National Institute of Hygiene,Department of Medical Statistics, Warsaw, Poland, the University of Arizona, Division of Respiratory Sciences,Tucson, and the Instituto Fisiologia Clinica CNR, Pisa, Italy. 1 Supported by the National Heart, Lung, and Blood Institute under the Thcson SCOR Grant No. HL-14136. 3 Correspondence and requests for reprints should be addressed to Dr. Duane L. Sherrill, Division of Respiratory Sciences, University of Arizona College of Medicine, Tucson, AZ 85724. .. Supported by the International Fogarty Fellowship No. I-F05-TW03940.

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PULMONARY FUNCTION AND CIGARETTE YIELDS

conforming to ATS-Snowbird criteria (19), was described previously (20). For those tested we considered FVC, FEV 1, and the flow rate at 50070 of the expired FVC (V maxso). The pulmonary function data were available on 414, 413, and 409 subjects with information on, respectively, tar, nicotine, or CO yield. Tests were available for 108 of these subjects from two surveys and for 81 subjects from all three surveys. We used logistic regression to analyze the relationship of the prevalence rates of the symptoms to tar, nicotine, and CO yields of the cigarettes in the first survey available for each subject (81070 of the subjects had the relevant data from survey 7). This analysis was expanded to include information from all available surveys for each individual. To adjust for multiple observations per subject we used regressive logistic models (21). In these models the outcome (here: presence of a given symptom) is a function of that outcome in preceding surveys. The variables corresponding to the past outcome were equal to 1 if the outcome (symptom) was reported in the preceding survey, to 0 if it was reported as absent, and to -1 if the preceding study was missing. The estimated coefficients of the model are adjusted for possible confounding or interacting effects of other factors. The odds ratios are calculated as exponents of the coefficients (or their combinations), similar to logistic regression models. The computer packages SPSS/PC (22)and BMDP (23) (program LR) were used to perform calculations, separately for each symptom. The longitudinal pulmonary function data were analyzed using a two-stage randomeffect model with modifications described by Jones (24, 25). These modifications allow the analysis of longitudinal data with an unequal number of observations per subject, and the observations can be made at different times for different subjects. The model can include a first-order autoregressive component of the within-subject observations. In this analysis both the between- and within-subject changes in lung function with age wereadequately described using first-degree linear equations. The complete model included height, sex, depth of inhalation, and age of starting smoking as constant covariates and current cigarette yields and number of cigarettes smoked currently as time-dependent covariates. Because of the high correlation of tar, nicotine, and CO yields the models were estimated separately for each of these smoke compounds. The correlation coefficients between tar and nicotine yields were as high as 0.97, and the smallest correlation was between tar and CO yields (0.88).

Results

The distributions oftar, nicotine, and CO yields in cigarettes smoked at the time of all three surveys were quite similar (table 1). The correlation of the cigarette yields exceeded 0.57 (between surveys 7

TABLE 1 TAR, NICOTINE, AND CARBON MONOXIDE (CO) YIELDS OF CIGARETTES SMOKED CURRENTLY* Survey 7

9

10

Tar

N Median 01 04 Max-min

483 12.1 8.3 16.1 0.6-26.3

356 10.2 8.3 16.1 0.6-25.1

339 11.5 8.4 16.1 1.0-25.7

Nicotine

N Median 01 04 Max-min

482 0.88 0.66 1.07 0.05-1.67

354 0.80 0.66 1.06 0.05-1.59

339 0.83 0.66 1.06 0.07-1.59

CO

N Median 01 04 Min-max

469 13.1 9.5 15.0 0.9-20.4

348 11.2 9.6 14.7 1.5-20.4

337 11.7 9.7 14.8 1.5-20.4

Definition of abbreviations: 01,04 = 1st and 4th quintiles, respectively. * Milligram per one cigarette.

and 9 or 10) and 0.72 (between surveys 9 and 10).Also, the number of cigarettes smoked daily did not change: the mean ranged from 20.9 cigarettes/day in survey 10to 22.0 in survey 9. Males smoked more than females (the greatest difference between the means was in survey 10: . 22.6 versus 19.2cigarettes/day, p < 0.01). In addition, the mean yields of cigarettes smoked by males was greater than females: the maximum difference for tar yield was 1.6 mg (p < 0.01), for nicotine 0.07 mg (p < 0.05), and for CO 1.0 mg (p < 0.01). The correlation of the number of cigarettes smoked and the yields of these cigarettes were below 0.04 in survey 7 and below 0.12 in survey 9 but were a little higher in survey 10:0.16 (p < 0.01) for tar and 0.17 for nicotine and CO (p < 0.001).

In the first survey in which each subject had data on cigarette yields, the prevalence rates of each symptom slightly increased with tar, nicotine, or CO contents after adjustment for age and number of cigarettes smoked currently. However, only for chronic phlegm was this increase significant: the highest odds ratio estimated in logistic regression was 2.42 per 1 mg nicotine (95070 confidence interval 1.01 to 5.85; p < 0.05). The prevalence of chronic cough, chronic phelgm, and dyspnea was significantly increased in subjects who started to smoke regularly at an earlier age. Chronic cough, wheeze, and dyspnea were also related to depth of inhalation. After adjustment for these factors the increase in prevalence rates due to the cigarette yields markedly decreased and was not signifi-

TABLE 2 REGRESSIVE LOGISTIC MODELS FOR WHEEZE Model with Tar Factor Tar, mg/cigarette Nicotine, mglcigarette Cigarettes/day Tar, * cigarettes/day Nicotine, * cigarettes/day Deep inhalation (yes = 1) Wheeze previouslyt Z1

Z2

Model with Nicotine Coefficient

SE

1.191 0.050

0.579 0.021

-0.044* 0.247

0.024

0.084 0.107 0.181

0.876 0.796

0.107 0.181

Coefficient

SE

0.065

0.033

0.400 -0.0023*

0.018 0.0013

0.244 0.885 0.789

* 0.05 < p < 0.10; for other coefficients p < 0.05. t Z1 _ 0 for observations from survey 7; for observations

0.084

from surveys 9 or 10: Z1 == - 1 if no wheeze in survey 7; 0 if no data from survey 7; 1 if wheeze in survey 7. Z2 • 0 for observations from survey 7 or 9; for observations from survey 10: Z2 • - 1 if no wheeze in survey 9; 0 if no data from survey 9; 1 if wheeze in survey 9.

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KRZYZANOWSKI, SHERRILL, PAOLETn, AND LEBOWITZ

TABLE 3 ODDS RATIOS (AND 95% CONFIDENCE INTERVALS) FOR SYMPTOMS DUE TO TAR, NICOTINE, AND CARBON MONOXIDE (CO) CONTENT IN CIGARETIES SMOKED CURRENTLY, ESTIMATED IN REGRESSIVE LOGISTICS MODELS· Cigarette Smoke Componentt Tar (per 10 mglCigarene)

Nicotine (per 1 mgICigarene)

Wheeze Component

CO (per 10 mgICigarene)

1.17 (0.81-1.69)

In smoking 5 cigarettes/day

1.70 (1.01-2.88)

2.64 (1.04-6.69)

In smoking 15 cigarettes/day

1.35 (0.97-1.90)

1.69 (0.94-3.05)

Cigarettes/day (per 10 cigarettes)

1.49 (1.05-2.11)

1.65 (1.08-2.50)

1.12 (0.99-1.26)

1.14 (0.85-1.54)

1.33 (0.79-2.24)

1.01 (0.68-1.50)

1.27 (1.11-1.45)

1.28 (1.12-1.46)

1.28 (1.12-1.46)

1.05 (0.n-1.43)

1.10 (0.64-1.90)

(0.70-1.60)

1.17 (1.02-1.34)

1.17 (1.02-1.33)

1.14 (0.99-1.31)

1.16 (0.75-1.79)

1.10 (0.53-2.29)

1.04 (0.59-1.81)

1032

1030

1010

Chronic cough Component Cigarettes/day (per 10 cigarettes) Chronic phlegm Component Cigarettes/day (per 10 cigarettes) Dyspnea Component Number of observations

1.06

* Other significant factors in the models: for wheeze, symptoms in all preceding surveys, deep inhalation; for chronic cough, age, symptoms in survey 9, age of starting smoking, deep inhalation; for chronic phlegm, age, symptoms in survey 9, age of starting smoking; for dyspnea, sex, age. symptoms in all preceding surveys, age of starting smoking, deep inhalation. t Yield per one cigarette.

cant. The highest estimated odds ratio was for chronic phlegm (1.89 per 1 mg nicotine, CI 0.70 to 5.13). The data from all available surveys were analyzed simultaneously using regressive logistic models. After adjustment for age, number of cigarettes smoked, sex, and symptoms in the preceding surveys the odds for chronic cough increased with the tar yield of the cigarettes smoked (odds ratio per 10 mg tar, 1.31; 95070 confidence interval 0.99 to 1.72; p < 0.10). The odds of chronic cough also increased with the nicotine contents of the cigarette (OR = 1.67per 1 mg, CI 1.01 to 2.71), but the relation to CO yield was not significant (OR = 1.15 per 10 mg, CI 0.79 to 1.66). Risk of other symptoms also increased with increasing yields, but these relationships were not significant. When these relations were adjusted in the regressive logistic models for age of starting smoking or depth of inhalation the effects of the cigarette yields on the symptoms changed considerably. The only pronounced relationships were those of wheeze to tar or nicotine yields of cig-

arettes, attenuated by a number of cigarettes smoked (table 2). The significant (p < 0.05) changes in odds were due to change in tar or nicotine yields in subjects smoking five or less cigarettes per day. These effects weresimilar in subjects reporting and not reporting the symptoms in the preceding surveys: this was verified testing significance of the interaction terms between yields, number of cigarettes, and indicator variables ZI and Z2. Further, there was no indication of a nonlinear effect of the tar yield of the cigarettes on the symptoms since the variable indicating "low-tar cigarettes" (below 5 mg/cigarette) was not significant. Table 3 shows the odds ratios for wheeze estimated from models in table 2, as well as the relevant results from the regressivelogistic models for other symptoms. The previously described associations of chronic cough to tar and nicotine were then weaker and not significant. The relationship of chronic phlegm and dyspnea to the cigarette yields remained nonsignificant, with the estimated odds ratios adjusted for depth of inhalation and age of starting smoking being smaller than

before the adjustment. Models for chronic cough and phlegm and for wheeze indicate an increased risk of symptoms in people smoking more cigarettes/day; it was not seen for dyspnea after adjustment for depth of inhalation. - The incidence rates of the symptoms during the follow-up period were determined for each symptom in smokers without the symptom in survey 7 using survey9 or 10reports. For chronic cough, chronic phlegm, and wheeze the results of regressive logistic analysis suggested an increase in the risk of the onset of the symptoms with increasing yield of cigarettes smoked in survey 7, but the estimated coefficients did not exceed their standard errors. The only significant (p < 0.10)result was obtained for the relation of dyspnea to CO yield of cigarettes smoked in survey 7, but the effect was strongly related to number of cigarettes smoked and was estimated with a relatively large standard error. The increase in dyspnea incidence due to CO yield was seen in subjects smoking a few cigarettes per day [OR = 7.6 per 10 mg CO, lower limit (LL) 90070 CI = 1.03for smoking 4 cigarettes/day], but statistical significance disappeared in subjects smoking more (OR = 3.4, LL = 0.7 for 10 cigarettes/day). The relationships of pulmonary function to the yield of cigarettes were more pronounced than for the symptoms. However, the tar, nicotine, and CO contents were important only in connection with the number of cigarettes smoked and had no independent effect on pulmonary function (table 4). The results from the random-effect models indicate that FEV 1 levels decreased with increasing tar or nicotine yield in all smokers; the difference was 2.9 ml/l0 mg tar per 1cigarette/day, which is equivalent to 87 ml for 30 cigarettes/day. The decrease in FEV 1 with CO yield significantly changed with age: no difference was seen in subjects 30 yr of age (at all levels of amount of smoking), but in subjects 60 yr of age the effects of 10 mg CO were -6 and -18 ml in smoking 10 and 30 cigarettes/day, respectively. The relationships of Vmaxso to the tar, nicotine, and CO, multiplied by number of cigarettes, were similar to those of FEV 1 , but they did not change with age. Levels of FVC were related to cigarette yields only in.females: this is shown by the significant interaction term in the model based on data for both sexes (table 4), as well as the (not shown) sex-specificanalysis. The additional effects of the number of cigarettes smoked daily on pulmonary func-

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PULMONARY FUNCTION AND CIGARETTE YIELDS

TABLE 4 ESTIMATED EFFECTS· OF TAR, NICOTINE, AND CARBON MONOXIDE (CO) CONTENTS OF CIGARETTES SMOKED CURRENTLY ON LUNG FUNCTION (PARAMETER ± STANDARD ERROR) Cigarette Smoke Component Tar (per 10 mglCigarette) FEV h ml Component, * cigarettes/day Component, * cigarettes/day-age Cigarettes/day Cigarettes/day,· age Cigarettes/day,· sex Cigarettes/day, * sex-age Vmaxso , ml/s Component, * cigarettes/day Cigarettes/day Cigarettes/day, * age Cigarettes/day, * sex Cigarettes/day, * sex-age FVC, ml Component, * cigarettes/day Component, * cigarettes/day-sex Cigarettes/day Cigarettes/day, * age Cigarettes/day, * sex Cigarettes/day,· sex, age Number of subjects Number of observations

Nicotine (per 1 mg/Cigarette)

CO (per 10 mgICigarette)

-2.9 ± 1.2

-4.6 ± 2.2

-0.7 -0.3 1.3 0.5

± ± ± ±

2.8t 0.1 1.2t 0.1

-0.4 -0.3 1.3 0.5

± ± ± ±

3.0t 0.1 2.9t 0.1

-3.2 -0.2 -0.8 -0.05 1.3 0.5

-7.5 4.7 -0.8 -1.8 0.7

± 3.3 ± 7.2t ± 0.3 ± 7.5t ± 0.3

-9.8 3.5 -0.8 -1.2 0.7

± ± ± ± ±

5.8* 7.8t 0.3 7.6t 0.3

-7.6 4.8 -0.8 -1.9 0.7

0.4 ± 2.0t -6.6 ± 3.1 -7.7 ± 3.8 -0.2 ± O.1t 11.7 ± 5.1 0.5 ± 0.1 414 684

1.2 ± 3.8t -11.0 ± 5.4 -8.3 ± 4.4 -0.2 ± 0.1t 13.0 ± 5.8 0.5 ± 0.1 413 683

± ± ± ± ± ±

1.7t 0.1 3.1t 0.2t 2.9t 0.1

± 4.5* ± 8.0t

± 0.3 ± 7.6t ± 0.3

1.8 ± 3.5t -8.2 ± 4.4* -9.6 ± 5.1 -0.2 ± 0.1t 13.4 ± 6.2 0.5 ± 0.1 409 671

* Adjusted for age (centered to the mean = 45.0 yr), sex (males = 0, females = 1) and height in random-effect models.

t p > 0.10.

*

0.05

< p < 0.10.

For other effects in the models p

< 0.05.

tion, besides those expressed by the products of this number and the yields, were different in males and females and were related to age. Figure 1 illustrates these results, calculated from the models, for FEV 1 in subjects 30 and 60 yr of age with tar as an indicator of the yield; the patterns for expected Vmaxso and FVC, and for nicotine and CO, were similar. In 60yr-old men the overall effect was a decrease in pulmonary function with increasing cigarette consumption at all levels of cigarette yields, but in 30-yr-old men this relation was not significant. In women pulmonary function decreased with increasing daily cigarette consumption in younger women: in older subjects the changes were smaller and not significant. However, the pulmonary function of subjects smoking higher yield cigarettes was worse than in those smoking lower yield brands at all ages and levels of amount of smoking. As mentioned earlier, the tar, nicotine, and CO yields were very highly correlated, and it was not possible to estimate the effect of one substance after adjustment for the effects of the others. The fit of the models, assessed by the likelihood function, was slightly better for the models with tar than for the other substances. However, the expected changes in pulmonary function in response to

change in yields of each compound (where the unit of change is 1 standard deviation, SD) were similar. The age of smoking onset and the depth of inhalation were not related to pulmonary function (p > 0.30). The levels of FEV 1 in surveys 9 and 10were significantly related to the yields of cigarettes smoked at the time of the preceding survey (7 or 9, respectively; table 5). The effects of current exposure adjusted for past exposure were not significant. The magnitude of decrements due to past exposure was similar to the effects estimated for the current yields before adjustments for the past (presented in table 4). Similar results were also found for Vmaxso- Levels of FVC were related (p