WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

TOBACCO: A MAJOR INTERNATIONAL

HEALTH HAZARD Proceedings of an International Meeting organized by the IARC

and co-sponsored by the All-Union Cancer Research Centre of the Academy of Medical Sciences of the USSR, Moscow, USSR

held in Moscow, 4-6 June 1985

EDITORS

D. G. ZARIDZE R. PETO

IARC Scientific Publications No. 74

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER LYON

1986

INFLUENCE OF CIGARETIE YIELD ON RISK OF CORONARY HEART DISEASE

AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

S.D. STELLMAN

American Cancer Society, Inc. 4 West 35th Street,

New York, NY 10001, USA

Il\TRODL'CTION

There is good reason to expect cigarette smoke to be toxic to the cardiovascular system. ~icotine produces numerous pharmacological effects, including increases in blood pressure and heart rate, increases in free fatty acids and catecholamines. and stimulation of the central nervous system. Carbon monoxide reduces the amount of oxygen available to heart muscle. The gas phase of cigarette smoke also contains numerous ciliatoxic chemi­cals, leading one to expect an effect on the respiratory system as well (US Department of Health and Human Services, 1984).

Therefore, there is some reason to expect that a lowering of the concentration of toxic agents in cigarette smoke inhaled by the smoker should lead to a reduction in the risk of diseases of the cardiovascular and respiratory systems. However, the situation is not so clearcut as for cancer risk in relation to tar yield (Stellman, this volume 1). While lower nicotine yields (as determined with automatic smoking machines) are attributable in some measure to more efficient filtration, use of filter cigarettes may not necessarily lead to reduced risk of disease, especially if the role of carbon monoxide is comparable to that of nicotine. Whereas tar and nicotine yields are generally correlated with each other, carbon monoxide yield is correlated with neither, and in fact has been found to be higher in some filter cigarettes than in nonfilter cigarettes (Borland et a/., 1983).

In this paper we examine the epidemiological evidence relating to the risk of coronary heart disease (CHD) and chronic obstructive pulmonary disease (COPD) in smokers of cigarettes of varying yields. In spite of a fairly large number of published studies, the case for risk reduction is not a strong one. This is due to a number of design and methodological problems, as well as to problems in interpretation of results. For one thing, the literature

:Seep, 197.

-237-

238 STELLMAN

on CHD and COPD contains numerous cross-sectional studies, that is, studies of preva­lence of specific symptoms among smokers of different types of cigarettes. While preva­lence studies are useful in assessing the health status of different groups of individuals, they are notoriously difficult to interpret in etiological terms, because one can never be certain whether the disease has influenced the risk factor.

Estimation of dosage for the purpose of constructing dose-response relationships is difficult because of the uncertainty surrounding the choice of which smoke component to use. Some studies have used cigarette carbon monoxide yield, some have used serum carboxy haemoglobin, some nicotine yield, and some have expressed exposure in terms of only filter versus nonfilter cigarette smoking.

Choice of endpoints to describe 'disease status' is also problematical. Some of the studies were designed to obtain incidence or death rates in large groups over a period of many years, while others examined only changes in lung function and various respiratory symptoms over a fairly short period. In many studies described below, health data were collected by questionnaire only, without clinical examination or other source of verifica­tion. Subjects in some of those studies have been classified as having 'possible angina' or 'possible claudication', but such rubrics lack the rig our attained in studies \vhere uniform clinical examinations were conducted, and make it hard to compare different studies with each other.

Another difficulty which arises in attempting to reconcile the findings of the various studies with each other is the lack of uniformity with which rates are reported. Few of the follow-up studies were analysed according to the standard life-table type of procedures. In some, 'mortality' was calculated as nothing more than number dead over initial number alive, irrespective of when deaths occurred, or the length of the follow-up period. This makes it practically impossible to compare rates between studies.

A final methodological difficulty occurs particularly for CHD studies, where other major risk factors for CHD, such as blood pressure and serum lipids, have not always been measured, leading to the possibility of confounding or other biases.

CIGARETIE YIELD AND CORONARY HEART DISEASE

We have reviewed three cross-sectional studies which dealt with prevalence of athero­sclerotic conditions, such as angina, four follow-up studies, and one case-control study of myocardial infarction.

Cross-sectional studies of CHD

In 1974, Heliovaara and colleagues examined 1068 Finnish men, aged 59-74 years, who had initially been enrolled in 1959 in a follow-up study of CHD. As shown in Table 1, the relative prevalence ofthree conditions, claudication, chest-pain attack, and definite CHD, was greater in men whose carboxyhaemoglobin ( COHb) levels exceeded 0.5%, compared to men with COHb levels of0.5% and below. A dose response was observed for claudica­tion (Heliovaara et al., 1978).

In 1969, Wald et al. (1973) examined 1085 male and female Danish workers, and found blood COHb levels significantly associated with the prevalence of ischaemic heart disease

wo filt po

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an thl sm G<

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srr

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INFLUENCE OF CIGARETIE YIELD ON CHD A.ND COPD

Table 1. Prevalence odds rat1os among 789 Firr1sh men for definite occurrence of three cardiovascular conditions relative to unaffected men a

Prevalence odds ra!i0

Cond1hon Carboxyhaemcg'obm {0/o)

BelowO 0.6-2 0 0 4 1 +

Claud cal1on '.00 1.42 2.54 5.75 Chest-pain attacK 1.00 2.36 2.32 2.86 Definite CHD 1.00 1.42 1.59 1.58

239

and intermittent claudication. In the age group 30-69 years, a person with a COHb level of 5% or more was 21 times as likely to be affected as a person of the same age and sex, with similar smoking history, but with a level of less than 3%.

On the other hand, in home interviews conducted in 1972 in the UK with 12 736 men and women aged 37-67 years. Dean et at. (1978) observed no differences between smokers of filter and nonfilter cigarettes in the prevalence of angina, possible claudication and possible infarction.

Follow-up studies of CHD

Four studies of CHD incidence or mortality have been reported, and one very large study is now in progress in the USA.

The American Cancer Society enrolled over one million men and women aged 40 years and over, in 25 states, in a prospective study in 1959. Follow-ups were conducted annually through 1966, and again in 1971 and 1972. Analyses of CHD death rates in relation to smoking habits were previously published by Hammond (1966) and by Hammond and Garfinkel ( 1969).

Hammond et at. (1976, 1977) also presented evidence from this study showing that smokers of 'low tar-nicotine' cigarettes had CHD mortality rates 81-93% of those of smokers of 'high tar-nicotine' cigarettes, using a matched group analysis which permitted adjustment for many variables at once, including age, race, number of cigarettes smoked per day, age smoking began, urbanirural residence, education, job exposure to chemicals, X-rays. or other toxicants, history of prior illness, and calendar period.

For the present review we have re-calculated the standard mortality ratios (SMRs) according to quantity smoked daily by current smokers and by tar yield of at baseline, for CHD death in men during 1960--1966, the six years when annual follow-up was done. Calculations were also restricted to this period to minimize effects of changes in smoking habits.

Results are shown in Figure 1. There were 6050 deaths from CHD during this period. For statistical convenience, the reference population is the largest subgroup, namely, smokers of 'medium tar-nicotine' cigarettes, who smoked 20 cigarettes per day. For all other tar-nicotine and quantity categories of smokers, as well as for exsmokers and non-

240 STELLMAN

Fig :. Standard;zed mortality ratios ~or coronary heart disease in males, among nonsmokers, exsmokers ana current smokers of low-, medium- and hlgh-tar/nicctine cigarettes (defined by Hammond et ai., 1976). The groJp was enrolled in 1959, and followed up throt;gh 1966.

3.0

0

fi a: >-1-:J 2.0

~ a: 0 :::!: 0 LLJ N 25 a: 1.0 <{ NON-0 SMOKERS z ~ U)

HIGH

MEDIUM

LOW

0.0'----'-·--------'--0 10 20 30

CIGARETTES SMOKED PER DAY

40 45

smokers, expected numbers of deaths were computed by multiplying age-calendar-year­specific rates of CHD death in the reference population by the person-years of exposure to risk of dying in the target group, and summing over age-calendar-year strata. The SMR is the number of observed divided by expected deaths. Data were renormalized to give lifetime nonsmokers an SMR of 1.0.

At each tar-nicotine level, the SMR increased with quantity smoked, in an approxi­mately linear dose-response relationship. For current smokers, at each value of daily quantity smoked, the SMR for the 'high tar-nicotine' cigarette smokers exceeded that for the 'medium' group, which in turn exceeded that for the 'low' group, except at 30 cigarettes per day. Lifetime nonsmokers had death rates well below any of the current smokers, irrespective of cigarette yield for the latter.

We have recently begun a new prospective study of 1.2 million men and women in all 50 states, to examine, among other hypotheses, the effect on mortality from various causes of smoking the much lower-yield cigarettes now available in the USA (Stellman & Garfinkel, 1986). Follow-up is being conducted biennially through 1988.

Castelli et al. (1981) analysed the Framingham study data by classifying men according to their smoking habits at the seventh examination (1963-1964), and gave incidence rates as of the fourteenth examination (that is, follow-up through 1977). The 14-year CHD incidence was not lower in filter smokers than in nonfilter cigarette smokers, even after

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INF~UENCE OF CIGARETIE YIELD ON CHC AND COPD 241

adjustment for age, blood pressure, and serum cholesterol. There were no differences between filter and nonfilter cigarette smokers in rates of new myocardial infarction or total deaths.

Hawthorne and Fry (1978) followed up over 18 000 Scottish men and women aged 45-64 years between 1965 and 1977. There were 793 deaths reported among the 11 295 men, of which 360 were from ischaemic heart disease and 56 were from cerebrovascular disease. Comparing 'relative mortality' between smokers of filter versus nonfilter cigarettes, they reported no differences in men for deaths from all causes, ischaemic heart disease or cerebrovascular disease, or from all causes in women. (There were only 132 deaths among the 7491 women followed, which was apparently considered too few to analyse for specific causes of death by cigarette type.)

In the Whitehall study, ten-year CHD mortality rates were computed for 17 475 male civil servants aged 40-64 years, for whom smoking data (including tar yield, quantity, and inhalation) were available (Higenbottam et al., 1982). There were 147 CHD deaths among male smokers who said they inhaled, and 26 among those who said they did not. Among inhalers, there was a marked increase in risk with increasing tar yield at 1-9 cigarettes per day but no clear trends with respect to tar yield at higher consumption levels (see Table 2). No relation to tar yield was seen in noninhalers. With a few minor exceptions, the CHD rates for both inhalers and noninhalers were higher than for nonsmokers.

A separate analysis of the same data with respect to cigarette carbon monoxide yields (Borland et al., 1983) showed a ten-year mortality rate significantly lower in smokers of high-yield cigarettes: relative risk for CHD (adjusted for age, grade of employment, cigarettes per day and tar yield) was 0.68 among smokers of cigarettes yielding over 20 mg of carbon monoxide, compared with smokers of cigarettes yielding 18 mg or less. An inverse dose-response with respect to carbon monoxide yield was observed among men who inhaled (Table 2).

Table 2. Ten-year coronary neart disease mortality rates (per hurdred) among smokers (inhalers only) accoraing to cigarette tar and carbon monoxide yields in the White rail S!Ldy

~.Jo. of cioaret!es smoked

Tar yield a

18-23mg 2.68 24-32mg 3.81 33 !:lQ or more 7.42

Ratio: 33+ versus 18-23 2.77

Carbon monoxide y eld b

18 mg or less 6.12 f\.bove 18-20 mg 4.98 Above20mg 3.01

-'Fwm Higenbonam et at. (1982), no_ of deaths. 147 °F'om Bo:tJnd et (1983), no of deatlls. 200

- 1(}-19

5.63 6.57 6.47

1.15

6.60 6.23 7.84

1.19

242 STELLMAN

Other studies of CHD

A case-control study of men aged 30-54 years with new cases of nonfatal myocardial infarction (MI) in US hospitals was reported by Kaufman et al. (1983 ). Between the 502 cases and 835 controls, there were no significant differences in mean yields of nicotine, tar, or carbon monoxide, and relative risks for \11 did not vary with any of these yield parameters. It should be pointed out that the cigarette yields referred to the most recently smoked cigarette, relative to the time of the MI; historical data on smoking were not presented.

Finally, Wald eta!. (1981) measured the serum cotinine in smokers of cigarettes, pipes and cigars, and found the highest levels by far in pipe smokers. Wald argued that as pipe smokers have little excess CHD risk, nicotine cannot be responsible for CHD in cigarette smokers. This paper led to considerable contention (Mc:Nicol & Turner, 1982; Wald et al., 1982), but Wald has maintained his views.

Coronary heart disease: discussion

The evidence linking cigarette yield to increased risk of CHD and other cardiovascular diseases is not nearly as strong as the evidence for tar and lung cancer, and cannot at this time be said to be established beyond doubt. There are many possible reasons for this situation. One may be, of course, that we are looking at the wrong components of cigarette smoke, and that the factor (or factors) responsible for increasing the risk of CHD has not yet been identified. It may also be that carbon monoxide plays a more important role than we realize, and that the joint effect of carbon monoxide and nicotine (which are not correlated with each other and which in fact may go in opposite directions) may be crucial.

A second problem is how to interpret a smoker's level of serum carboxyhaemoglobin or other metabolite as measured today with respect to smoking exposures in the past, particularly since tar and nicotine yields of practically all cigarettes are now well below the levels of two or three decades ago.

A third problem is assignment of specific cigarette yield values to individuals. People, of course, do not smoke in the same fashion as the machines on which nicotine yields are measured. and smokers can inhale considerably different levels of toxicants than indicated on the cigarette package or in laboratory reports (Kozlowski. 1980).

Even if the nominal yield values are accepted, in most follow-up studies the mortality was related to yields of cigarettes at baseline, determined up to twelve years earlier, whereas average yields may have changed dramatically during the follow-up period. The usual excuse for this assignment is lack of new smoking data during the follow-up period, and the hope that the fall in yields occurred roughly in parallel in all brands, but this must surely lead to significant misclassification.

Figure 2 illustrates the difficulties encountered by the investigator who attempts to interpret data gathered from smokers followed over a long period of time. In the Figure. the calendar periods for a number of follow-up studies (and survey periods for some cross­sectional studies) have been superimposed upon a graph of the sales-weighted tar and nicotine levels in the USA. While British levels have fallen at a different rate than have American levels, the point is the same for both countries: tar and nicotine cigarette yields

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Fir fashi• stud)

INFLUENCE OF CIGARETIE YIELD ON CHD AND COPD 243

F1g. 2. Observation or survey periods for studies of coronary heart disease, chronic obstructive pulmonary d1sease, and lung cancer, 1n relation to time trends in US sales-weighted average tar and nicotine levels; (•-•). tar; (•-----•). nicot1ne

40 3.4 HELIOVAARA. 1959

l 3.2

35 HAMMOND, 1959-1972 3.0 = = .§. E Cl CASTELLI. 1963-1977 2.8 Cl _J _J L..U L..U

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recorded at the start of a follow-up study almost invariably overstate the average exposure to the smoker throughout the observation period.

Other factors related to the design and analysis of specific studies must also colour our interpretation of these results. For one thing, the influence of other risk factors of the same level of importance as smoking (such as serum lipids and blood pressure) have not often been measured, and their importance is often ignored. Secondly, the weight to be attached to prevalence studies in general must be less than for either prospective or case-control studies. An association in a cross-sectional study cannot differentiate too well between cause and effect, and smokers who survive CHD often alter their smoking habits, some­times in response to medical advice, and often out of plain fear. Thus, one does not know for certain whether a high prevalence of a particular symptom in a group of smokers is observed because smoking caused that symptom, or whether it would have been higher still except for large numbers of subjects who quit smoking because of it.

Finally, several of the follow-up studies presented mortality results in a very crude fashion, by dividing total deaths from a given cause by the number of men at the start of the study. Such analysis (or lack of it) fails to account for time periods of exposure to risk, and

244 STELLMAN

does not discriminate between deaths which may have occurred early in the follow-up period from those which occurred later, and can slight competing risks from other causes of death (and there are, of course, many for cigarette smoking).

Summary of findings for CH D

The prevalence rates of ischaemic heart disease or CHD and intermittent claudication were significantly associated with serum carboxyhaemoglobin in two studies, but not with filter versus nonfilter cigarette use in one study.

CHD death rate was associated with cigarette tar yield at all levels of daily quantity smoked in one prospective study, based on 6050 observed CHD deaths. CHD death rates increased with tar yield at low but not high daily consumption levels in another prospective study. based on 173 CHD deaths, and were inversely related to cigarette carbon monoxide yield in the same study. CHD death rates were not different in smokersoffilter versus non­filter cigarettes in two other prospective studies. The relative risk for new myocardial infarction in younger men was unrelated to cigarette tar, nicotine or carbon monoxide yield in one case-control study.

On the basis of tar-nicotine yield alone, and considering the magnitude of the American Cancer Society study, the evidence from prospective studies strongly favours a relationship between cigarette yield and risk of death from CHD. This conclusion seems at odds with the two prospective studies in which no relation was found with filter usage, as well as with the case-control study. It might be argued, however, that filter use is a less sensitive index of exposure to cardiotoxic components of cigarette smoke, especially given the wide range of tar and nicotine yields in filter cigarettes smoked by the cohorts in question. Lack of an association in the case-control study might possibly be due to its dealing with MI survivors only, who may have smoked lower yield cigarettes than those who succumbed immedi­ately. and to use as an exposure index of cigarette yields at time of MI, rather than past exposures. This is only speculation, however. Fortunately, an American Cancer Society prospective study of 1.2 million men and women, now in progress, is designed to resolve many of these issues (Stellman & Garfinkel, 1986 ).

The totality of evidence, therefore, is weakly consistent with, but does not yet conclus­ively support, a relationship between cigarette yield and subsequent death from CHD.

CIGARETTE YIELD AND CHRO~IC OBSTRUCTIVE PULMONARY DISEASE

Cross-sectional studies of COPD

Four studies were identified in which the prevalence rates of one or more respiratory symptoms were studied among smokers of various types of cigarettes. Three were con­ducted in the UK and one in the USA.

Rimington (1972) evaluated sputum production in 10 414 men aged 40 years and over who had volunteered for a mass radiographic screening programme, and found that 37.2% of those who smoked non filter cigarettes had persistent daily sputum, compared to 31.9% who smoked filter cigarettes.

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2 See

INFLUENCE OF CIGARETTE YIELD ON CHD AND COPD 245

Dean eta!. (1978) reported on a representative cross-sectional sample of 6277 men and 6459 women interviewed at home in England, Scotland and Wales in 1972. Prevalence rates of four 'respiratory' symptoms (bronchitis, morning cough, shortness of breath, wheezing) increased with the number of cigarettes smoked per day, and with inhalation, and were higher in nonfilter than in filter cigarette smokers, but differences were signifi­cant only for morning cough (men and women) and shortness of breath (women only).

Higenbottam et al. (1980) reported an analysis of respiratory symptoms and lung function measurements in the Whitehall study of 18 403 male civil servants aged 40-64 years. Phlegm production increased with tar yield of current cigarette; forced expiratory volume in one second (FEV1) did not decrease with tar yield according to the authors. but did according to a re-analysis by Lee (1980).

In an American study, 5686 women were selected at random from Western Pennsylvania telephone directories and interviewed by telephone (Schenker et al., 1982). Tar was a significant risk factor for chronic cough (relative risk, 2.0) and chronic phlegm (relative risk, L6). but not for grade 3 dyspnoea or wheeze. The two former symptoms were more strongly affected by daily quantity smoked than by tar.

Follow-up studies of COPD

We have computed standardized mortality ratios (SMRs) for COPD deaths from the American Cancer Society study, in a fashion similar to that presented above for CHD, and in an earlier paper for lung cancer (Stellman, this volume2). A total of 322 deaths from COPD were observed during the first six years of follow-up (1960--1966). Results are shown in Figure 3. A dose-dependence of the SMR forCOPD on quantity smoked per day was observed for smokers of high- and medium-tar cigarettes only. Among smokers of 20 cigarettes per day or less, the risk were not detectably different for high-tar compared to low-tar smokers, while for smokers of even greater numbers daily, COPD risks were actually highest among medium-tar smokers.

Comstock et al. (1970), who observed a group of 670 male telephone company employ­ees for six years, found that smokers of nonfilter cigarettes had a higher initial prevalence of cough and phlegm than filter cigarette smokers, and experienced a greater increase in both symptoms. The mean FEV1 was lower in nonfilter than in filter cigarette smokers at baseline, but decreased relatively less over time in the nonfilter group.

Hawthorne and Fry (1978) reported a follow-up study in Scotland of over 18 000 men and women 45-64 years. Both male and female nonfilter cigarette smokers had a higher prevalence at baseline than did filter cigarette smokers of bronchitis symptoms, shortness of breath, wheezing and phlegm. A similar finding was obtained with tar level. The mortality rate from chronic bronchitis in men appeared to be slightly higher in non­filter than in filter cigarette smokers, but the numbers of deaths were small (28 in all), differences were not significant, and the information on mortality presented was very crude. Corresponding death rates for women were not given owing to the small numbers.

2 Seep. 197.

246 STELLMAN

Fig. 3. Standardized mortality ratios for chronic obstructive pulmonary disease in males, among ronsmokers, exsmor<ers, and current smokers of low-, medium- and high-tar/n:cotine c1garettes (deft ned by Hammond era!., 1976). The group was enro:led :n 1959, and foilowed up through 1966.

15

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CIGARETTES SMOKED PER DAY

Peto etc, relation to years. Whi was not rei airway obs be confour

In a US cigarette t< follow-up l

Summary'

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In sumn phlegm pr for an effe

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INFLUENCE OF CIGAFlETIE YIELD ON CHD AND COPD 247

Peto et al. (1983) presented some interesting and useful data on COPD death rates in relation to smoking in a cohort of2718 British men aged 25-64 years followed up for 20-25 years. While no specific data on tar or nicotine levels were presented, the COPD death rate was not related to mucous hypersecretion; the authors suggested that persons with severe airway obstruction may switch to lower-tar cigarettes, and that cross-sectional studies may be confounded by this phenomenon.

In a US study of 2144 men followed up from 1963 to 1968, Sparrow eta!. (1983) found cigarette tar yield unrelated to pulmonary function (FVC or FEV1), either at baseline or at follow-up five years later.

Summary of findings for COPD

Four cross-sectional and five prospective studies have been reviewed. Both filter use and low tar levels were consistently related to lower sputum or phlegm production in five studies, to reduced prevalence of cough in three studies, and to shortness of breath in two studies. Wheeze and dyspnoea were higher in non filter than in filter cigarette smokers in two cross-sectional analyses, but were unrelated to tar level in a third.

Lung function (as measured by FVC or FEY J was lower on average (that is, worse) in smokers of higher-tar or nonfilter cigarettes in two cross-sectional studies, but was unre­lated to tar level in one prospective study either at baseline or after five years of follow-up.

Finally, mortality from chronic bronchitis was no different in filter than in nonfilter cigarette smokers in one follow-up study, and was about the same in high-tar/nicotine smokers compared to low-tar/nicotine smokers in another extremely large study.

In summary, there is good evidence that smoking low-yield cigarettes leads to lower phlegm production, reduced cough and less shortness of breath, but conflicting evidence for an effect on lung function, and none for an effect on mortality from COPD.

REFERENCES

Borland, C., Chamberlain, A., Higenbottam, T., Shipley, M. & Rose, G. (1983) Carbon monoxide yield of cigarettes and its relation to cardiorespiratory disease. Br. med. f., 287, 1583-1586

Castelli, W.P., Dawber, T.R., Feinleib, M., Garrison, R.J., McNamara, P.M. & Kannel, W.B. (1981) The filter cigarette and coronary heart disease: The Framingham Study. Lancet, ii, 109-113

Comstock, G.W., Brownlow, W.J., Stone, R.W. & Sartwell, P.E. (1970) Cigarette smoking and changes in respiratory findings. Arch. environ. Health, 21, 50-57

Dean, G., Lee, P.N., Todd, G.F., Wicken, A.J. & Sparks, D.N. (1978) Factors related to respiratory and cardiovascular symptoms in the United Kingdom. f. Epidemiol. Com­munity Health, 32, 86-96

Hammond, E.C. (1966) Smoking in relation to the death rates of one million men and women. In: Haenszel, W., ed., Epidemiologic Approaches to the Study of Cancer and Other Chronic Diseases (National Cancer Institute Monograph No. 19), Bethesda, MD, US Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, pp. 127-204

248 STELLMAN

Hammond, E.C. & Garfinkel, L. (1969) Coronary heart disease, stroke, and aortic aneurysm. Factors in the etiology. Arch. environ. Health, 19, 167-182

Hammond, E.C., Garfinkel, L., Seidman, H. & Lew, E.A. (1976) Tar' and nicotine content of cigarette smoke in relation to death rates. Environ. Res., 12, 263-274

Hammond, E.C., Garfinkel, L., Seidman, H. & Lew, E.A. (1977) Some recent findings concerning cigarette smoking. In: Hiatt, H.H., Watson, J.D. & Winsten, J.A., eds, Origins of Human Cancer, Book A, Incidence of Cancer in Humans, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, pp. 101-112

Hawthorne, V.M. & Fry, J.S. (1978) Smoking and health: the association between smoking behaviour, total mortality, and cardiorespiratory disease in west central Scot­land. I. Epidemiol. Community Health, 32, 260-266

Heliovaara, M., Karvonen, M.J., Vilhunen, R. & Punsar, S. (1978) Smoking, carbon monoxide, and atherosclerotic diseases. Br. med. I., 1978, i, 268-270;

Higenbottam, T., Shipley, M.J., Clark, T.H.J. & Rose, G. (1980) Lung function and symptoms of cigarette smokers related to tar yield and number of cigarettes smoked. Lancet, i, 409-412

Higenbottam, T., Shipley, M.J. & Rose, G. (1982) Cigarettes, lung cancer, and coronary heart disease: the effects of inhalation and tar yield. J. Epidemiol. Community Health, 36, 113-117

Kaufman, D.W., Helmrich, S.P., Rosenberg, L., Miettinen, O.S. & Shapiro, S. (1983) Nicotine and carbon monoxide content of cigarette smoke and the risk of myocardial infarction in young men. New Engl. I. Med., 308, 409-413

Kozlowski, L.T., Frecker, R.C., Khouw, V. & Pope, M.A. (1980) The misuse of "less­hazardous" cigarettes and its detection: hole-blocking of ventilated filters. Am. I. Public Health, 70, 1202-1203

Lee, P.N. (1980) Low tar cigarette smoking, Lancet, i, 1365-1366 McNicol, M.W. & Turner, J.A.~1cM. (1982) Nicotine, carbon monoxide, and heart

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