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328


CHAPTER 6. LOW YIELD
         CIGARETTES AND
         THEIR ROLE IN
         CHRONIC
         OBSTRUCTIVE LUNG
         DISEASE

329

480-144 0 - 85 - 12


CONTENTS

Introduction

Problems of Measurement by Machine

Effect of Low Tar and Nicotine Cigarettes on Cough and
Phlegm Production and Development of Chronic
Obstructive Lung Disease
Epidemiologic Studies

Mechanisms of Lung Damage

Variation in Smoking Pattern With Switching to Low
Tar and Nicotine Cigarettes
  Smoking Behavior
Carbon Monoxide Uptake
  Nicotine Uptake
  Role of Tar Content

Variations in Pattern of Cigarette Smoke Inhalation

Use of Additives in Low Tar and Nicotine Cigarettes

Research Recommendations

Summary and Conclusions

References

331


Introduction

Following the initial reports in the early 1950s linking cigarette
smoke with lung cancer, the pathogenic role of cigarette tar content
received considerable emphasis. Because the tar fraction of the
smoke contained the bulk of the carcinogenic effect of whole smoke,
and because lung cancer risk was closely related to other measures of
total smoke exposure (number of cigarettes smoked per day, depth of
inhalation, etc.), it was suggested that risk might be related to the
amount of tar generated by different cigarettes. This prompted
health authorities to advise smokers who were unable to quite
smoking to switch to low tar cigarettes (U.S. Senate 1967; Health
Department of the United Kingdom 1976). To facilitate this process,
the Federal Trade Commission published smoking-machine assays of
the tar and nicotine yield of different cigarette brands (Pillsbury et
al. 1969). This approach to low tar and nicotine cigarettes was based
on the assumption that smoking lower yielding brands, as deter-
mined by a smoking-machine, would result in a proportional
reduction in the lung's exposure to these toxic substances. This
approach to "safer" cigarette smoking has been promoted by the
tobacco industry and apparently accepted by the smoking public, as
evidenced by the escalation in sales of low tar and nicotine
cigarettes. However, there is increasing evidence that this concept of
a "less hazardous" cigarette is misleading; although definitive
studies are still awaited, it appears that switching from regular to
low tar and nicotine cigarettes may not substantially reduce the risk
of chronic airflow obstruction.

Problems of Measurement by Machine

The first step in evaluating the relative health risks of different
cigarettes is to establish some standardized measure of the toxic
substances in different cigarettes in order to facilitate comparison.
Quantifying each of the several thousand constituents of cigarette
smoke for each brand of cigarette, and assessing the changes in these
constituents as the manufacturing and agricultural processes
change, would be a truly herculean task; therefore, a more modest
goal of quantifying tar and nicotine yields was accepted. To date, the
yields determined by the Federal Trade Commission have been the
most widely adopted. These measurements are obtained with a
laboratory smoking-machine, which consists of a syringe pump that
takes a 35 ml bell-shaped puff from a cigarette, over a 2-second
period, once per minute until a predetermined butt length is
reached, either 23 mm for nontiltered cigarettes or 3 mm longer than
the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969).
These parameters are based on observations of smoking patterns in
seven subjects in Europe in 1933 (Kozlowski 1983). Today's cigarette

333


is markedly different from that smoked in 1967 when these
parameters were established, yet the same parameters are still
employed.

Measurements obtained using these parameters indicate a marked
reduction in the tar and nicotine yield of cigarettes over the last
decade (Figure 1). In addition to the actual tar and nicotine yield of
the tobacco, the yield measured by a smoking-machine is influenced
by many factors, including cigarette length and diameter, porosity of
the cigarette paper, presence of a ventilated or an unventilated
filter, butt length, number of puffs, interpuff interval, puff volume,
puff duration, puff pressure profile, and frequency of puffing at
different stages of cigarette consumption. The number of puffs is
important in determining the tar yield of a cigarette, and the
number of puffs taken from some brands with the official smoking-
machine has significantly declined in recent years (Kozlowski 1981).
Since puffs are taken at l-minute intervals, a more rapidly burning
cigarette will have a smaller number of puffs. The burning time of
the cigarette is determined by porosity of the cigarette paper, the-
amount of tobacco in the cigarette, and the diameter of the cigarette
column. In a survey of Canadian cigarettes between 1969 and 1974,-
Kozlowski et al. (1980b) noted a significant reduction in the number-
of puffs taken in the official assays over this time period, which was
strongly correlated with a reduction in tar yield. Omission of the last-
few puffs can markedly affect tar yield, because tar delivery-
increases with each puff, and the last few puffs from a cigarette can
contain twice as much tar as the first few puffs (Wiley and Wickham
1974). Currently published yields do not indicate the number of puffs
taken, which may range from 7 to 12 and may result in a marked
variation of the tar yield.

Ventilated cigarette filters, which cause inhaled smoke to be
diluted with air, are one of the major methods of achieving low tar
yields (Gori and Lynch 1978). Cigarettes with ventilated filters
constituted about 25 percent of all cigarette sales in the United
States in 1979 (Hoffmann et al. 1980). During systematic interviews,
Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar
smokers block these filter perforations with their fingers or lips, a
feature unaccounted for by smoking-machines. This hole blocking
increased the yield of toxic products by 59 to 293 percent.

If a person smokes a cigarette in a manner identical to the
smoking-machine, the delivery of tar and nicotine to the mouth will
be the same as that estimated by the machine. Human smoking
patterns are diverse, however, and show considerable variation from
the machine parameters; puff volumes range from less than 20 ml to
more than 90 ml (Tobin and Sackner 19821, compared with the fixed
35 ml volume employed by the machine. Differences in puff profile
from the bell-shaped puff used by the machine also alter cigarette

334


Tar mg

100 -'









  1950     1955     1960     1965     1970     1975     1980

FIGURE l.-U.S. sales-weighted average tar and nicotine
       yields

SOCRCE Amencan Cancer Scaety 11981 I

yield. Numerous studies indicate that smokers compensate for lower
yielding cigarettes by altering their style of smoking. For each
different cigarette brand, smokers may have a different smoking
oattern. To provide more meaningful information, smoking-ma-
:hines should be designed to reproduce variations in the manner of
smoking each cigarette brand, and their assays should provide both
m average and a range of tar and nicotine yields depending on the
ndividual pattern of smoking (USDHHS 1981).
Many investigators have examined the relationship between the
nachine-determined nicotine yield of a cigarette and the concentra-
ion of nicotine or its metabolites in blood or urine. A fair correlation
vas observed in some studies (Goldfarb et al. 1976; Herning et al.
9831, but most studies have revealed a poor correlation (Russell et
-1. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983).
Jachinedetermined nicotine yield accounts for only from 4 (Russell
t al. 1980) to 25 percent (Herning et al. 1983) of the variation in
lood nicotine concentration, whereas 50 to 60 percent of the
ifferences in blood nicotine levels are attributable to individual


smoking behavior. The overriding importance of the pattern of
smoking in determining nicotine delivery from a cigarette was
underlined in a recent study demonstrating that the nicotine content
of the unburned tobacco was similar for cigarettes with high and low
nicotine yields determined by smoking-machine assays (Benowitz et
al. 1983).

The concept of providing the smoker with information on cigarette
yield need not be abandoned. Smoking-machines can be designed to
control the puff number, puff volume, puff pressure profile, puff
duration, puff interval, butt length, position of the cigarette during
and between puffs, and "restricted" or "free" smoking, i.e., whether
the butt end is closed or open Kreighton and Lewis (1978a, b). These
parameters should be determined and used to obtain an average and
a range of yields for each brand. Measurement of cigarette yield
should include assays not only of tar and nicotine but also of carbon
monoxide and other toxic substances, because compensatory smok-
ing behavior may alter the exposure to each substance beyond that
expected on the basis of tar and nicotine delivery.

Effect of Low Tar and Nicotine Cigarettes on Cough and
Phlegm Production and Development of Chronic Obstructive
Lung Disease

Cigarette smokers account for the vast majority of deaths from
chronic obstructive lung disease (COLD) (Peto et al. 1983), and the
relative risk for the effects of smoking on mortality from COLD is
even greater than that for lung cancer (see the chapter on Mortality
in this Report). Chronic obstructive lung disease in smokers may
take the following three forms: (1) cough and mucus hypersecretion,
(2) airway obstruction, and (3) emphysema. Frequently the three
components coexist, as all are related to cigarette smoking, but the
agents in cigarette smoke responsible for each type of lung injury
may be different. Over the past 25 years, considerable progress has
been made in our understanding of the role of cigarette smoking in
the pathogenesis and natural history of COLD, but most of the
available data have not related lung function to cigarette yield.

Epidemiologic Studies

The cardinal importance of cigarette smoking in the pathogenesis
of COLD has been repeatedly documented, and generally the
severity of disease increases with increasing cigarette consumption
(Ferris et al. 1976). Because of this dose-response relationship, it has
been hoped that a reduction in cigarette yield by filtration or other
means would reduce the risk of disease (Gori 1976). Available
epidemiologic studies of the effect of low yield cigarettes on the
development of COLD have shown variable results, which reflects

336


marked differences between the studies in terms of the population
studied, sample size, variation in cigarette brands, reference period
of the study, criteria of respiratory involvement, and type of
statistical analysis, and whether the study was of a cross-sectional or
a longitudinal design. Separating the studies by the three compo-
nents of smoking-induced COLD indicates that there is a growing
body of data on the effect of cigarette yield on the development of
mucus hypersecretion and airway obstruction, but currently no
information on the development of emphysema.

Several studies have examined the effect of cigarette yield on
respiratory symptoms and have observed a relationship between
reduction in cigarette yield and the prevalence of cough (Comstock et
al. 1970: Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et
al. 1978; Schenker et al. 1982) and phlegm production (Comstock et
al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et
al. 1980b). Tar yield was not defined in some of these earlier studies
(Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne
and Fry 19781, but instead a comparison was made between smokers
of plain cigarettes and smokers of filter-tipped cigarettes. The tar
yield was specified in some studies: in the recent study by Schenker
et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman
and Fletcher (19761, from 17 to 20 mg; and in the studies by
Higenbottam et al. (1980b1, from 18 to more than 33 mg, higher than
that observed in many of today's cigarettes. In a cross-sectional
survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial
effect of low tar cigarettes on phlegm production was lost when
subjects smoked 20 or more cigarettes per day, as their prevalence of
phlegm production increased to that observed in higher tar cigarette
smokers. In contrast, in another cross-sectional study of 5,686
women (Schenker et al. 19821, cigarette tar content was a significant
risk factor for chronic cough and of borderline significance for
phlegm production; this effect of cigarette tar content was indepen-
dent of the number of cigarettes smoked per day. Chronic cough or
phlegm production was approximately twice as common in smokers
of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10
mg) smokers. In the latter study, however, multiple logistic regres-
sion analysis indicated that the risk of chronic cough and phlegm
production is more strongly affected by daily cigarette consumption
than by tar content: these symptoms were 4.5 times more common in
smokers of 25 or more cigarettes per day than in smokers of less than
15 cigarettes per day.

A small number of studies have examined the importance of
cigarette yield on change in pulmonary function. In a prospective
study of 680 men, Comstock et al. (1970) noted that smokers of plain
cigarettes, compared with smokers of filter-tipped cigarettes, had a
lower FEV, at entry into the study. Followup measurements showed

337


I a23   24-27   2E32    .33

Tar per cigarette Prv$

FIGURE 2.-Relationship between mean FEVI of
      asymptomatic smokers (adjusted for height and
       weight) and tar yield of cigarettes, by number
      of cigarettes smoked per day
SOURCE: Hlgenbottam et al rlS&Wbi.

a greater mean reduction of FEVl in users of filter-tips, so that the
reduction was similar in the two groups after 5 to 6 years of followup.
Unfortunately, the variance of the data was not stated, and tests of
statistical significance were not performed. In another longitudinal
survey of 1,355 men, Sparrow et al. (1983) determined the effect of
cigarette tar content, which ranged from less than 16 mg to more
than 22 mg, on pulmonary function. Multiple regression analysis
indicated that tar content did not significantly influence baseline
spirometry or repeat measurements after 5 years of followup. Cross-
sectional epidemiologic surveys also indicate no relationship be-
tween abnormal pulmonary function and the use of filter-tipped
versus plain cigarettes (Beck et al. 1981) or cigarette tar content
(Higenbottam et al. 1980b) (Figure 2).

Interpretation of these studies as evidence that cigarette tar and
nicotine yield is not an important factor in the development of COLD
is premature. First, cross-sectional studies are limited in their
capability of defining the natural history of a disease. Second, COLD
has a very slow progress, and Fletcher et al. (19761 suggest that a
span of approximately 8 years is necessary to establish rates of
change of spirometric values with sufficient confidence even to
distinguish between smokers and nonsmokers. Third, we have no
information on the baseline pulmonary function of smokers at the
time they choose between high or low tar and nicotine cigarettes.
Significant differences in pulmonary function have been observed
between young adults who decide to smoke and those who avoid
cigarette smoking (Tashkin et al. 19831, and it is possible that similar

338


function differences may exist in subjects who choose between high
or low tar and nicotine cigarettes. Fourth, the yield of tar and
nicotine used in many of these studies does not lie in the same range
as that produced by many of today's cigarettes.

However, the possibility that cigarette tar content is related to the
development of cough and phlegm, but not of dyspnea or airflow
obstruction, is consistent with current concepts of COLD. In a study
of 792 men followed over an g-year period, Fletcher et al. (1976)
observed that cigarette smokers were susceptible to two distinct
chronic lung diseases-mucus hypersecretion and chronic airflow
obstruction. This has recently been confirmed in a large prospective
study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years,
which showed that the risk of death from COLD was strongly
correlated with initial degree of airflow obstruction, but bore no
relationship to initial mucus hypersecretion.

Given the evidence that mucus hypersecretion may depend on the
tar fraction of cigarette smoke, while development of airflow
obstruction is more closely linked to the ilumber of cigarettes
smoked, Higenbottam et al. (1980b) reasoned that these differences
might be due to a reduction in the particulate phase products,
without a decrease in the gas phase products, in the low tar
cigarettes. They hypothesized that tar droplets and soluble gases,
such as sulfur dioxide and hydrogen cyanide, are more likely to be
deposited or absorbed in the large airways where mucus is produced.
The smaller airways, the earliest site of airflow obstruction, are
exposed to a lower concentration of tar, but to a full concentration of
insoluble gases such as nitrogen dioxide and ozone.

This line of reasoning is in agreement with several studies showing
a reduction in lung cancer with the use of low tar and nicotine
cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington
1981; Hammond et al. 1976). The tar fraction is the component of
cigarette smoke particularly linked with the development of both
lung cancer and mucus hypersecretion. Although clinicians have
long linked chronic bronchitis (mucus hypersecretion) with emphyse-
ma, recent evidence indicates that mucus hypersecretion is not
predictive of airflow obstruction, but is significantly greater in those
smokers who develop lung cancer (Pete et al. 1983).

Mechanisms of Lung Damage

Studies of the mechanism of cigarette-smoke-induced lung damage
have contributed significantly to the present understanding of
COLD. Cigarette smoke may initiate and aggavate lung injury by a
number of mechanisms and may also interfere with the lungs'
defense responses.

These mechanisms include the prot.ease-ir$$bit,or imbalance theo-
ry for the pathogenesis of emphysema whereby alveolar wall

339


digestion results from an excess of proteases, a deficiency of their
inhibitors, or a combination of both factors (see the chapter on
Mechanisms in this Report). The sources of endogenous proteases
include polymorphonuclear neutrophils and alveolar macrophages,
both of which are found in increased number in the lungs of cigarette
smokers. Protease release from both macrophages and neutrophils is
increased in the presence of cigarette smoke (Rodriquez et al. 1977;
Blue and Janoff 1978). In health, proteases are continually inhibited
by al-antitrypsin, whereas proteases cause unimpeded digestion of
lung tissue in patients with al-antitrypsin deficiency, with a
markedly increased risk of emphysema. In addition to increasing the
protease burden, cigarette smoke causes a functional inhibition of al-
antitrypsin through the action of oxidants in cigarette smoke (Janoff
et al. 19791.

The relative potency of smoke from cigarettes of varying tar and
nicotine yields in stimulating protease production and release and in
inhibiting al-antitrypsin has received scant scientific investigation.
Travis et al. (1980) tested the effect of both filtered and unfiltered
cigarette smoke on the elastase inhibitory activity of al-antitrypsin.
Filtered smoke reduced elastase inhibitory activity by 3 percent, and
a 19 percent reduction was observed with unfiltered smoke; the tar
content of the respective smokes was not stated. The researchers
reasoned that this small in vitro effect would be greatly magnified by
in vivo conditions in the lung, particularly through its huge surface
area. In addition to examining the effect of filters, Cohen and James
(1982) recently examined the effect of tar and nicotine content on the
elastase inhibitory capacity of al-antitrypsin. The oxidant capacity of
cigarette smoke was also examined using a chromogenic electron
donor. Aqueous condensates of cigarette smoke were obtained from a
variety of brands ranging in tar content from about 1 mg to more
than 20 mg. Reported tar and nicotine content correlated well with
the amount of measured oxidants and the ability of a brand to reduce
the elastase inhibitory capacity of al-antitrypsin. Filters were found
to remove 73 percent of the oxidants from the aqueous smoke
solutions. While these findings suggest that low tar and nicotine or
filter-tipped cigarettes could reduce a smoker's predisposition to
enzymatic lung damage and consequent COLD, it should be noted
that neither study examined the effect of lower yield cigarettes on
protease production. Morosco and Gueringer (1979) demonstrated a
greater increase in elastase in dogs exposed to high nicotine cigarette
smoke compared with low nicotine cigarette smoke. More important,
these studies have not taken into account the compensatory changes
in smoking pattern likely to result with lower yield cigarettes.

The airway response to acute exposure to cigarette smoke has been
examined by several investigators employing spirometry (Da Silva
and Hamosh 19811, body plethysmograph (Nadel and Comroe 1961j.I

340


and breathing pattern analysis (Tobin et al. 1982a). Airway narrow-
ing has been consistently observed by some investigators (Nadel and
Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a
variable response (Higenbottam et al. 1980a; Rees et al. 1982). In
some studies, the acute airway response was unrelated to cigarette
yield (Higenbottam et al. 1980a), but in most investigations (Robert-
son et al. 1969; Tobin et al. 1982a; Rees et al. 1982), smoking a low tar
or filter-tipped cigarette induced less acute bronchoconstriction. The
acute airway response is probably localized to the larger airways, as
acute cigarette exposure resulted in no change in the nitrogen
washout test of small airway function (Da Silva and Hamosh 1973;
Tobin et al. 1982al. These observations on the relative bronchocon-
strictor response of various types of cigarettes may be important in
our understanding of why some smoking novitiates persist with the
habit despite the initial unpleasant reactions (Tashkin et al. 1983),
but it is unlikely that repeated episodes of smoking-induced acute
airway narrowing finally result in COLD.

Future studies examining the mechanism of smoking-induced lung
injury must not only take into account the range of cigarette yields,
as determined by a smoking-machine, but also consider variations in
smoking behavior. Puff volumes may vary considerably with nomin-
al cigarette tar and nicotine content, thus altering the relative
amount of various toxic substances yielded by different cigarettes.
Similarly, inhalation profiles are of a diverse nature (Tobin et al.
1982b) and are likely to significantly alter the distribution, penetra-
tion, and retention of cigarette smoke constituents in the lungs.

Variation in Smoking Pattern With Switching to Low Tar and
Nicotine Cigarettes

Low tar and nicotine cigarettes have gained considerable populari-
ty among the smoking public, partly on the premise that a reduction
in the nominal tar and nicotine yield results in a proportional
reduction in the health hazards of cigarette smoking. The validity of
this approach to cigarette smoking is contingent on the accuracy of
smoking-machines in reflecting the actual manner of puffing and
also on the smoker not altering smoking behavior to compensate for
variations in nominal tar and nicotine content. Should smokers
develop compensatory alterations in their smoking behavior, this
would not only reduce the relevance of the smoking-machine assays
but might also alter the proportionate delivery of the different toxic
substances in cigarette smoke and expose the smoker to concentra-
tions beyond those predicted by the smoking-machine.

341


Smoking Behavior

Nearly 40 years ago, Finnegan et al. (1945) studied the effect of
alterations in cigarette nicotine content on smoking behavior and
noted no change in cigarette consumption. It is only in the last
decade, with the increasing popularity of low tar and nicotine
cigarettes, however, that this question has attracted signEcant
interest. The results of 38 studies examining alterations in smoking
behavior with a reduction in cigarette yield are shown in Table 1.
Considerable differences can be observed between the studies, partly
reflecting variations in the level of cigarette yield reduction,
alterations in other cigarette constituents, type and duration of
switching procedure, parameters evaluated, and techniques used in
their measurement.

Most studies agree that smokers rarely increase their daily
cigarette consumption upon switching from higher to lower yield
brands. Reports are almost equally divided as to whether a smoker
increases the number of puffs per cigarette or shows no change on
switching to a lower yielding brand. There is an almost unanimous
consensus that smokers take a larger puff volume from a lower
yielding brand. Studies of puff volume also indicate huge variation
between individual subjects (Guillerm and Radziszewski 1978; Hern-
ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and
that considerable increases in puff volume may occur on switching
from a higher to a lower yielding brand, with certain subjects
increasing their puff volume by up to 75 percent (Tobin and Sackner
19821. This compensatory increase in puff volume may be observed
within a single experimental session (Tobin and Sackner 1982) and
maintained over several weeks Rawbone et al. 1978; Stepney 1981).
Full compensation for a lower yielding cigarette is generally not
achieved by smokers taking a large puff volume (Rawbone et al.
1978; Herning et al. 1981; Tobin and Sackner 1982).

Instrumentation is required to quantitatively assess the pattern of
smoking, but it is important to realize that such instrumentation
may, in itself, alter usual smoking behavior. Puff volume has been
almost universally measured by using a specialized cigarette holder
incorporating different flowmeter designs (Frith 1971; Adams 1977;
Rawbone et al. 1978). These devices consist of two tubes connected to
a pressure transducer that measures the pressure drop across a
small resistance (a filter insert) in the holder; the flow measured is
integrated to obtain volume. Use of a cigarette holder has been
shown to increase the rate of puffing and puff volume, compared
with measurements made with the cheek inductive plethysmogra-
phy coil (Tobin and Sackner 1982).

Unlike the compensatory increases in puff volume, measurements
of the subsequent inhalation volume-which includes the volume of
smoke mixed with air inhaled into the lung-have shown no change

342


TABLE l.-Effect of smoking low yield cigarettes on smoking pattern

                                                (`0 paramrters           Nlcotme parameters ~____
                        Number Number        Volume   Durat Km           Relationship    Nlcotinr'rotlninr  Mouth Relationship
      Reference Expenmental of cigs of     Puff     of       of        Expwd     to          level      CCpOS"W    LO
First author    year     de@   smoked puffs/cig volume mhalatmn  mhalatlon  C'OHb   (`0  nominal yield   tblood!ur~ne/salw;i)  Index normal yield

F1llIIegaIl      I945
Ashton       1970
Fnth        1971
(bhen        1971
Rwssell       1973
Turner       1974
Russell       1975
Coldfarb      1976
FO&8       I976
Adams       1977
Wald        1977
Sutton        I978
R&s&one      1976
Schulz        197X
(`wghtnn     1978a.b
Adams       1978
(;udlerm      1978
clamk        1978
Ashton       1979
tiarfinkrl      1979
HI11         19fUl
RobInson      I980
Russell       1980
Hrnnmgtield    1980
Wald        19&I

cl3      NC
VCF
CS
CS
cs      t
CS
cs       I
CS      f
CS
cs      NC
svs
VCF      NC
C'S
CS      NC
s
CS
cs
CS
CS      NC
svs      NC
cs
svs
svs
VCF      NC
svs

NC
1 /1N(

NC     NC

                         I
NC     i      N(

t     t
1     NC     NC

t                         t     NC

PcKJr
(hod
PO0 I

1      POW


E   TABLE I.-Continued
Dr-                                                      CO paramrten           Nicotme parameters

                             NUdW  NUdW        Volume   rhmitml           Belatlonshlp   Nwtmeicotinme  Mouth Belatlonship
           Reference Experimental of CITY    of     Puff     of       of        EXPlWd     to          level      exposure    t4,
    Fwst author    year     design   smoked puffs/cig volume lnhaletwn lnhalatlon  COHb (`0  nominal yleld   ibloodod/urme/saliva~ Index  normal yield


   Hernmg       1981       cs            NC'     I                         t

    Wtlld        19R1       svs      NC                            I           Poor
   Stepney       1981      cs      NC     t      f                       I      Fair         I        I
    Jaffe        1981      svs    NC/ 1                                   NC     PCXJr
    Tobin        1982      cs            NC     I      NC      NC
   Battig        1982      svs      NC           t                        NC
    Sutton        1982      svs                t                              coed                        Poor
    Griffith8      1981       CS             NC     t
    Jaffe        1982      cs     NC/ 1                                   NC     Poor
   Feyrrabend     1982      svs                                                                           Poor
   HtTWlg       1983      cs                                                                           FHIT
    Benowitz      19n3      svs

     NOTE Cs controlled swtchmg. VCF - var,able c,garette filters. SVS a~wntaneo~rs voluntary wltchw. NC = no change. T - mcreaee. ;  = dexeaee. CO - ctlrbon monvx,dr


on switching to a low yield cigarette. Likewise, in one short-term
study (Tobin and Sackner 1982), duration of inhalation showed no
relationship to nominal cigarette yield. Perhaps compensatory
changes in inhalation parameters require a longer period of time
than puff volume does.

Measurement of carboxyhemoglobin (COHb) concentration has
been proposed as an index of the pattern of inhalation (Wald et al.
1975, 1978). While COHb provides valuable information on the
amount of carbon monoxide absorbed from the lung during compen-
satory alterations in smoking behavior, it is an indirect index and
provides complementary information on cigarette smoke inhalation
rather than replacing direct measurements of the volume of
inhalation.

Carbon Monoxide Uptake

Unlike tar and nicotine, which are present in the particulate
phase, carbon monoxide (CO) is a constituent of the vapor phase of
cigarette smoke. For this reason, cigarettes purported to produce a
low tar and nicotine yield may not necessarily provide a lower yield
of carbon monoxide. Compared with tar and nicotine yield, carbon
monoxide yield is more dependent on cigarette design, including
such features as paper porosity and perforations in the filter tips.
These factors regulate the dilution of smoke with air and the
burning profile of the cigarette, and thus can significantly reduce
carbon monoxide yield. Wald (1976) showed that the carbon monox-
ide yield of filter-tipped cigarettes was 28 percent higher than that of
plain cigarettes, although the average nicotine yield was lower in the
filter-tipped cigarettes. He reasoned that smoke passing through a
cigarette is diluted by air entering through the porous cigarette
paper. However, the filter of filter-tipped cigarettes is surrounded by
relatively nonporous paper, resulting in a higher content of carbon
monoxide exiting from the proximal cigarette end. Perforations in
the filter tip circumvent this problem and significantly reduce
carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973).

Many investigators have measured COHb or carbon monoxide
concentration in expired gas following cigarette smoking and
compared the levels achieved in smoking brands with different
nominal yields (see Table 1). An increase, decrease, or no change in
carbon monoxide intake has been observed, depending on relative
differences in cigarette design and experimental procedure. As
expected,  unventilated filter-tipped cigarettes produced higher
COHb levels than those observed with unfiltered cigarettes (Wald et
al. 1977). This is in agreement with information provided by
smoking-machine assays (Wald et al. 19731, but the use of ventilated
filter-tipped cigarettes may produce COHb levels similar to those
observed with unfiltered cigarettes despite lower carbon monoxide

345


yields on smoking-machine assay (Wald et al. 1977). Comparison of
cigarettes with a marked difference in nominal carbon monoxide
yield usually results in a lower COHb level when the lower yielding
brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton
et al. 1978; Ashton et al. 1979); but over the range of different carbon
monoxide yields there is a poor correlation between levels of COHb
and measured carbon monoxide yield. Similar information has been
observed using expired carbon monoxide concentrations.

Nicotine Uptake

It has been long considered that nicotine might serve as a primary
reinforcer of cigarette smoking and that smokers might adjust their
smoking behavior to regulate their level of nicotine intake. Several
investigators have measured the blood, urinary, or salivary levels of
nicotine or its major metabolite cotinine during the smoking of
cigarettes of varying nominal nicotine yields (see Table 1). A
reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et
al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976;
Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill
and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al.
1979; Hill and Marquardt 1980) cotinine levels has generally been
observed on switching to a cigarette with a lower nominal nicotine
yield. However, smokers show variable degrees of compensation for
the lower yield, as there is generally a poor relationship between
nominal nicotine yield and measured blood nicotine levels (Russell et
al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al.
1983).

Relating nominal nicotine yield and blood nicotine levels, Ashton
et al. (1979) estimated that smokers compensated for about two-
thirds of the difference in nominal yields when they switched from
medium nicotine cigarettes to high or low nicotine brands. Using a
stepwise multiple regression analysis of nicotine yield and blood
nicotine concentration, Russell et al. (1980) observed a significant,
but very weak, correlation (r = 0.21) between the two measurements,
but the nominal nicotine yield of the cigarettes accounted for only
4.4 percent of the variability in blood nicotine concentrations. The
use of absolute rather than logarithmic analysis in this study has
been criticized (Kozlowski et al. 1982; Herning et al. 19831, and the
criticism involved the problems of trying to predict doses to
individuals rather than the dose to groups. In another study using
log-linear regression analysis (Herning et al. 19831, a better correla-
tion was observed between nominal nicotine yield and the increasing
blood nicotine after smoking (r=0.5), but this study used Kentucky
reference cigarettes rather than commercial brands, and these low
yield cigarettes have less nicotine in the unburned tobacco than
commercial low yield brands. Such a relationship still accounted for

346


only 25 percent of the individual differences in blood nicotine levels,
whereas 50 to 60 percent was accounted for by individual differences
in smoking behavior (Herning et al. 1983).

Additional information on compensatory alterations in nicotine
intake has been provided by studying the mouth exposure index,
which is calculated from analysis of cigarette butts for nicotine
content and a knowledge of the retention efficiency of the filter tip
(Ashton and Watson 1970). Because the amount of nicotine retained
by a filter is proportional to the amount that passes through, it is
possible to estimate the amount of nicotine presented to the smoker
from the nicotine content of the filter. Results using this index have
revealed a greater variation between individual studies (see Table 1)
than obsewed with blood nicotine measurements. This may be
related to the fact that filter efficiency is usually determined by a
machine, but retention of nicotine is also dependent on the way the
cigarette is smoked; therefore, the retention efficiency of the filter
may vary between smokers.

Role of Tar Content

The observations that smokers adapt their smoking behavior
according to the nicotine delivery of a cigarette and that many of the
toxic effects of smoking appear to be related to tar rather than
nicotine content has led to the suggestion that altering the tar to
nicotine ratio might produce a cigarette less hazardous to health
(Russell 1976; Stepney 1981). A cigarette with a medium nicotine,
low tar, and low carbon monoxide yield might be advantageous.
While nicotine has been the component most extensively studied, it
may not be the only substance responsible for the addictive power of
tobacco. It is not possible to separate the effects of tar and nicotine in
most studies, as their respective yields usually show a very close
correlation.

Using research cigarettes providing three different yields of
nicotine and two different yields of tar, Goldfarb et al. (1976) found
evidence of compensation for nicotine but not for tar content. The
authors urged cautious interpretation of the results because of the
limited range of tar yields examined. Examining a large number of
subjects smoking cigarettes of varying tar and nicotine yield, Wald et
al. (1981) found that both tar and nicotine were significantly related
to blood COHb, taken as an index of cigarette smoke inhalation. Two-
way analysis of variance of the data indicated that after allowing for
the effect of either tar or nicotine yield, the COHb index was no
longer significantly influenced by the other. A cross-over study of
medium tar smokers who were switched to low nicotine, low tar
cigarettes and medium nicotine, low tar cigarettes has been reported
by Stepney (1981). While the intake of carbon monoxide was least
with the medium nicotine, low tar cigarette, the mouth exposure

347


index to tar was similar among the brands. Indeed, the pattern of
smoking adopted by the subjects was more effective in reducing the
difference in tar delivery between the cigarettes than in compensat-
ing for nicotine delivery. Further evidence indicating the importance
of cigarette tar delivery in-determining smoking behavior was
reported by Sutton et al. (1982). Using multiple regression analysis,
they observed that when nicotine yield was controlled, smokers of
lower tar cigarettes had higher blood nicotine levels than smokers of
higher tar cigarettes, indicating that they inhaled a greater volume
of smoke. In contrast, when tar yield was controlled, smokers of
lower nicotine cigarettes had lower blood nicotine concentrations
than smokers of higher nicotine cigarettes, indicating that they
inhaled less smoke. These results suggest some compensation for tar
over and above any compensation for nicotine. It may be that
ncnpharmacologic, sensory stimulation by factors such as the flavor
of cigarette smoke may be more important than nicotine in
determining smoking behavior.

These new observations, especially on the role of tar delivery,
require further investigation. Most published research consists of
controlled switching experiments in which the subject smokes
cigarettes of varying yields (see Table 1). Further studies of smoking
behavior in sutjects who have voluntarily chosen cigarettes of
different yields are needed. The absence of an acceptable, palatable
"standard" research cigarette continues to be an impediment to
research in this area.

Variations in Pattern of Cigarette Smoke Inhalation

While cigarette smoking is the single most important factor in the
development of COLD, the majority of smokers never develop
clinically significant airflow obstruction (Fletcher et al. 1976).
Despite the clear dose-response relationship between number of
cigarettes smoked and death from COLD, attempts at identifying the
indi-Jidual susceptible smoker on the basis of number of cigarettes
smoked have had very limited success.

Another approach to identifying the susceptible smoker is to study
the manner of smoking, as this is probably a major determinant of
the lung's exposure to cigarette smoke. Cigarette smoking consists of
two phases: initially, the smoker takes a puff into the mouth, and
after a variable 1 to 4 second pause, the smoke mixed with air is
inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al.
1980a; Tobin and Sackner 1982). Individual differences in the
pattern of cigarette smoking such as the size of the puff volume, the
duration of holding the smoke in the oral cavity before inhalation,
and the depth and duration of inhalation are among the important
factors determining the relative concentration of smoke constituents

348


that reach the lung. Despite its significance in determining the
distribution and deposition of cigarette smoke, the mode of inhala-
tion following the puff has received scant scientific investigation.

A number of epidemiologic studies have examined the relationship
between cigarette smoke inhalation, based on the smoker's subjec-
tive estimation, and the severity of pulmonary disease. Results of
these studies are conflicting; some investigators repcrted an associa-
tion between smoke inhalation and the presence of mucus hyperse-
cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and
decline in pulmonary function (Ferris et al. 1976; Bosse et al. 19?5),
and others observed no relationship between inhalation and pulmo-
nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The
inconsistencies in these epidemiologic studies may be due to the
smokers' inability to accurately describe their inhalation pattern.

There are three reports of the relationship between subjective
estimations of cigarette smoke inhalation and direct objective
measurement. Rawbone et al. (1978) found that the rating on a
visual analog scale was a good predictor of inhalation volume
(r=0.65). Conversely, Tobin et al. (1982a) noted no relationship
between inhalation volume and the smoker's perception of depth of
inhalation, indicated on a visual analog scale (i-=0.04); a similar
finding was reported by Adams et al. (1983) (i-=0.04). Standardizing
the inhaled volume for vital capacity did not improve the relation-
ship. Other investigators using measurements of COHb observed a
weak relationship between self-estimated inhalation and COHb
concentration (Stepney 1982; Wald et al. 1978). Measurements of
COHb reflect the amount of cigarette smoke absorbed by the long. In
addition to being affected by the depth of inhalation, COHb
concentration is influenced by the varying carbon monoxide yields of
different cigarettes, the number of puffs per cigarette, puff volume,
pulmonary function-particularly diffusing capacity and alveolar
ventilation-and hemoglobin concentration (Wald et al. 1978; Ric-
kert et al. 1980). Therefore, it yields valuable complementary
information, but it does not provide a direct measure of the pattern
of inhalation (Tobin et al. 1982a; Guyatt et al. 1983).

Direct measurements of the pattern of cigarette smo!ce inhalation
have been reported for a small number of smokers. Initially, the puff
from the cigarette is taken into the molrth, and after a variable
pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et. al.
1978; Higenbottam et al. 1980a; Tobin and Sackner 1982; Tobin et al.
1982a; Adams et al. 1983). Higenbot,tam et a1,(1980a) reasoned that
this pause, while holding the smoke in the mouth, minimized the
irritant qualities of cigarette smoke. In a group of five subjects who
were requested to inhale smoke directly into%eii lungs, withoslt an
intervening pause in the mouth, consistent acute airway narrowing
was observed. In contrast, smokers adopting the usual two-phase

349


smoking pattern showed a variable airway response. The authors
suggested that buccal absorption of water-soluble compounds, such
as sulfur dioxide and acrolein, together with precipitation of tar,
minimized the irritating qualities of cigarette smoke. They observed
no relationship between the acute airway response and amount of
smoke inhaled in the regular two-phase smokers, although there
appeared to be a relationship in those directly inhaling smoke into
their lungs. However, there is a marked discrepancy in the inhala-
tion volumes reported in this study compared with the values
reported in other studies of cigarette smoke inhalation, probably due
to the inaccuracy of the magnetometers employed for the measure-
ments; therefore, a statement regarding the relationship between
depth of smoke inhalation and the acute airway response may be
misleading.

The report that acute airway narrowing is uncommon after
cigarette smoking is in disagreement with the findings of several
investigators who have observed bronchoconstriction to be a common
phenomenon after acute smoke exposure (Nadel and Comroe 1961;
Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a);
however, it is certainly plausible that the response is greater in
smokers who inhale smoke directly into the lungs than in two-phase
smokers. The frequency of direct inhalation of cigarette smoke into
the lungs is unknown. In a small study of 10 smokers, Tobin and
Sackner (1982) observed 1 subject who showed an approximately 50
ml expansion of the abdominal compartment simultaneously with
taking the puff from the cigarette.

Adams et al. (1983) studied the relationship between puffing,
cigarette smoke inhalation, and partitioning of airflow between the
nose and mouth in 10 smokers. After taking the puff into the mouth,
two subjects actively exhaled 80 ml and 200 ml volumes, respective-
ly, before the subsequent inhalation. In this situation, the volumes of
smoke might be expelled from the mouth, and little, if any, would be
available for subsequent inhalation into the lungs. The frequency of
this smoking pattern was not given, but another report from the
same laboratory (Rawbone et al.  1978) indicated that it was
uncommon. There was marked intersubject variation in the parti-
tioning of airflow between the nose and mouth during smoking, with
four subjects inhaling almost exclusively through the mouth, four
inhaling predominantly through the nose, and the other two
demonstrating both patterns of inhalation. The importance of factors
in determining whether cigarette smoke is inhaled as a bolus
followed by a subsequent "chaser" of air or is evenly distributed
throughout the inhaled volume of air remains to be determined.

Considerable discrepancies exist between published reports of the
volume of air mixed with smoke that is inhaled into the lungs, with
reported mean inhalation volumes of 34 to 152 ml (Higenbottam et

350