The chemical composition of tobacco leaf is also affected by
agricultural practice and by curing methods (161, 163). High levels of
nitrogen fertilizer increase nicotine and nitrate levels of the leaf.
Growing plants more closely together reduces the nicotine content of
the leaf. Flue-cured tobaccos are harvested, leaf by leaf, as each is ripe,
but the entire plant of burley tobacco is harvested at once. Changes
associated with leaf maturity depend on the harvesting practice.
Enzymatic degradation of leaf constituents is halted by heat during
flue curing. In contrast, burley, Maryland, and oriental tobaccos are
not heated to this extent, so that more extensive enzymatic changes
occur. As a consequence, there is a markedly lower sugar content in
burley tobacco along with a markedly higher content of pigment
polymers. Homogenized leaf curing (HLC), if commercially developed,
could permit better control over these chemical changes. Furthermore,
specific leaf constituents such as soluble proteins may be removed
during homogenized leaf processing. Cigarettes made with HLC
tobacco yielded smoke containing significantly less dimethylnitrosa-
mine and condensate having significantly less sebaceous gland sup
pression activity (165,169).

Rtmmstituted Sheet and Modi.d Tobaccos

The composition of cigarette smoke is also affected by the use of
reconstituted tobacco sheet and modified tobaccos (62, 69, 6.4, 65).
Reconstituted sheet can contain substantial amounts of the tobacco
%.em," which has a different composition from that of the leaf lamina.
The stem is noteworthy for having a low nicotine content. In addition,
the physical nature of reconstituted sheet can be controlled to change
its burning characteristics and hence the composition of the smoke.

In recent years, some cigarette tobacco has been "expanded" or
"puffed." Using this material, less tobacco is required to fill the
cigarette. The manner in which the tobacco is shredded also affects the
burning rate and therefore the composition of the smoke (47').
Cellulose-based substitutes have been used as a replacement for
tobacco (17, 35). These materials cause substantial differences in the
total yield and chemical composition of the smoke.

Additives

Humectants and flavoring agents have long been used as additives
in cigarette manufacture. The advent of reconstituted tobacco sheet
(RTS) technology expanded the possibilities for the addition of
substances to the sheet during the processing of tobacco for the
manufacture of cigarettes (174,188). It is possible to add substances to
the tobacco slung or suspension for extraction of specific constituents,
for dilution of the sheet, for burn rate acceleration or retardation, for

51


ash cohesion, and for enhancement of flavor (smoke aroma and taste)
(65,151). Additionally, one process for curing tobacco leaf calls for the
addition of exogenous enzymes to tobacco (169), and as noted above,
artificial tobacco substitutes are also available. In recent years,
cigarette manufacturers' advertisements have focused on the flavor of
new lower "tar" and nicotine cigarettes, enhanced presumably by the
addition of tobacco constituents or by the addition of new flavoring
materials, such as natural or synthetic chemicals. The identities and
amounts of the additives actually used in the manufacture of U.S.
cigarettes are not known. Systematic information has not been
published or made available on the influence of these additives on the
composition or biological activity of cigarette smoke.

Variatiom3 in Human Smoking Behavior

It does not appear possible to fully monitor smoking behavior in
humans without the subjects' knowledge. Butt lengths can be mea-
sured in a variety of settings, and puff frequency can be observed
without distorting smoking behavior. Measurement of puff volume and
duration and of intensity of inhalation, however, requires instrumenta-
tion that may lead to alteration of usual smoking behavior. Neverthe-
less, despite these limitations in objectivity, recent studies provide
better data than those available in the past.

Smoking measurements reported from England, Germany, and
Canada differ from those used for smoking-machines in the United
States (189, 141, 150). If the average American smoker, as well, is
taking larger puffs with a greater frequency than is the machine, the
absolute yields of smoke constituents are under-reported in the United
States. This is not to say that the relative yield of "tar" between
cigarettes is compromised; however, if smokers puff different types of
cigarettes in different ways, the relative yields may be grossly
distorted. For example, some smokers block the perforations in the
mouthpiece of ventilated cigarettes (102). These smokers receive
substantially more "tar," nicotine, and gas phase constituents than
would be predicted from machine-smoked cigarette yields. Because this
action would affect the yield only of ventilated filter cigarettes, the
relative ranking of cigarettes by yields would be affected. Similarly,
smokers' behavioral compensation for low nicotine delivery can affect
the relative yields of filter-tipped cigarettes (80,142).

Research Needs

Many gaps in our assessment of the pharmac ological properties of
cigarette smoke can be filled by a coordinated, welldirect.ed research
program. In comparison with the economic and medical costs of
cigarette smoking, the size of the required program is modest.
Resources sufficient for implementation of a meaningful program are

52


available. For example, except for assays of "tar," nicotine, and carbon
monoxide yield, new types of cigarettes are not being monitored
regularly for the delivery of potentially harmful smoke constituents.
Scientists currently conducting sophisticated assays of cigarette deliv-
ery of various smoke constituents could serve as resource personnel in
the design of an appropriate approach to assays of new cigarettes for
suspected toxic agents. Other scientists are investigating short-term
end points indicative of long-term risk from many diseases. These
laboratories could assist in modifying these procedures specifically for
cigarette smoke and its constituents.

Surveillance of New Cigarettes

The chief research need for the study of reduced "tar" and nicotine
cigarettes is the routine and frequent surveillance of current and new
cigarettes for specific chemical constituents and biological activity.
The chemical constituents should include nicotine, be&a]pyrene,
phenols, catechols, nitrosamines, carbon monoxide, nitrogen oxides,
volatile aldehydes, and radionuclides. The biological assays should
include sebaceous gland suppression assays, mutagenesis assays,
studies of the effects of smoke on airway and ciliary function and on
the increase of urinary metabolites related to the activity of elastase,
and such other biological assays as may appear predictive of human
disease in the future.

Inherent in this recommendation is the use of quantitative short-
term end points for various conditions associated with human disease.
We do not have proven animal models for quantitative evaluation of
risks of chronic obstructive pulmonary disease, sudden death due to
cardiovascular disease, or complications of pregnancy and infancy.
Emphasis should be given to developing short- and long-term bioassays
aimed particularly at these diseases.

Determination of Parameters of Human Cigarette Smoking

Smokers may smoke different types of cigarettes differently with
respect to puff volume, duration, and frequency, inhalation profiles,
and the manner in which the cigarette is held by the fingers and in the
mouth. To conduct meaningful assays of cigarette yields and of the
biological activity of cigarette smoke, it is important to know how
smokers consume each type of commercial cigarette. Only when this
information is available can smoking-machines be designed to yield the
most accurate estimate of human dose. We must know both the
average and the range of variation in smoking pattern.
The available studies compare smokers' behavior with commercial
cigarettes found to deliver different amounts of "tar" or nicotine.
Other changes that occur in the product are often unknown. A second
type of study should use prototype cigarettes specifically designed to
deliver a wide range of concentrations of a desired constituent; for

53


example, with high or low nicotine to "tar" ratios. Such a study would
define the behavior of smokers of new types of cigarettes before or as
they are marketed. These studies, however, would require a particular
resource that is not accessible to most investigators. There are a large
number of experimental cigarettes differing widely in several respects
(6.9, 69, 64, 65). Unfortunately, they were developed without concern
for smoker acceptability and cannot be used to evaluate human
response to design changes. A coordinated program should be eatab
lished to develop a series of clinically acceptable experimental eiga-
rettes that resemble a "reference standard" as closely as possible,
differing only in one or two well-defined characteristics. These should
then be made available to appropriate investigators for the study of
human smoking behavior.

Evaluation of Health Effects of Nicotine

Nicotine has pharmacological significance for man and animals (92).
The alkaloid is suspected of playing a role in sudden death due to
cardiovascular disease, to the complications of pregnancy and infancy,
and possibly to chronic obstructive pulmonary disease. Nicotine in
cigarettes leads to the formation of tobacco-specific nitrosamines in
the smoke. These are potent carcinogens. Nicotine itself is a significant
cocarcinogen in mouse skin carcinogenesis assays of smoke condensate.
It is important to determine whether nicotine acts as a cocarcinogen
under the conditions of dosage achieved by cigarette smokers and
whether the levels of nicotine-derived nitrosamines play a role in
human malignant disease. Resources for such study are available and
should be employed in a comprehensive evaluation of the potential
carcinogenic effects of new types of cigarettes.
Nicotine should be tested alone, and in the presence of other noxious
agents such as carbon monoxide, in animal systems designed to serve
as models for nonmalignant diseases associated with cigarette smoke.
Experimental cigarettes with a range of nicotine content have been
produced for studies of carcinogenesis. Many of these cigarettes are
still available. Those experimental cigarettes that might be needed for
pharmacological studies of nicotine should be identified and distributed
to appropriate laboratories as the need develops.

The Effecta of Smoking-Machiie Parame ters on Relative ad
Ab~~lute Yields of Smoke Components F'rom Various Types of
Cigarettes

Smoking-machine assays of cigarettes fulfill two needs. The FTC
ratings of "tar" and nicotine yields measure an implied risk to the
smoker. Smoking-machine data guide experimenters in elucidating the
mechanisms of induction of smoking-related disease. Absolute levels of
smoke constituents may be very important for experiments, so the
experimenter must have reliable information about the comparability


of machine and human smoking. The use of machine data to monitor
risk has somewhat different requirements. If the relative yields of
different cigarettes are not greatly affected by smoking conditions,
present smoking-machine standards will be adequate to indicate
relative risk of new cigarettes. We know, however, that the relative
yield of many constituents is affected by butt length, puff frequency,
and degree of ventilation. We need to determine how the variations in
these smoking parameters affect relative yields of the several sub
stances in smoke that are of toxicological interest.

Influence of Raw Product Modification on the Pharmacology of
Cigarette Smokfz

The composition of smoke is determined by the physical and chemical
properties of leaf tobacco. Modification of the raw product therefore
changes the pharmacology of cigarette smoke. The diversity of
available tobacco germplasm along with known genetic techniques
permits reduction of hazards in cigarettes through plant breeding and
selection. Cultural and curing practices are constantly changing in
response to market demands and the needs of farmers. Pesticides
currently registered for use on tobacco have been tested as contribu-
tors to the carcinogenic activity of cigarette smoke condensates. When
used as directed, these materials caused no significant change in
biological activity (65, 166). However, the pesticides used in tobacco
farming change from time to time in response to the occurrence of new
plant pests; for example, the recent spread of blue mold in tobacco-
growing regions has led to the use of a new pesticide. It is not known
whether the use of such materials may result in changes in the hazards
of cigarette smoke.

Present tobacco curing processes .may vary somewhat from farm to
farm. Furthermore, marked differences in agricultural practices such
as close spacing of tobacco plants, bulk curing, and homogenized leaf
curing might be introduced in the future. We need to determine the
consequences of changes (genetic, cultural, and curing methodologies)
on both the chemical composition and the biological effect of cigarette
smoke.

PhysicaI and Chemical F'roperties of Smoke From Cigar&tea
Delivering Less Than 10 mg of `Tar"

In the past few years, cigarettes delivering less than 10 mg of "tar"
by FTC test have been placed on the market. These cigarettes
apparently employ efficient filters together with various degrees of
smoke dilution. The extreme reduction of "tar" and nicotine delivery
by these cigarettes suggests significant differences in combustion
processes. Substantial differences in the chemical nature of both
mainstream and sidestream smoke might result from such changes.

55


Some or all of the new lower "tar" and nicotine cigarettes are
manufactured by processes that involve the use of chemicals or flavor
additives to improve consumer acceptability. The nature of these
additives, and their combustion products, that are currently used in
marketed cigarettes is not available to the public or to the Govern-
ment. Likewise, there are no published data on the biologic effects of
these additives or their combustion products.

Very low yield cigarettes may add to present concerns with respect
to sidestream smoke (5, 157, 184). While these cigarettes may deliver
such low levels of "tar," nicotine, and gas phase constituents that
smokers cannot compensate completely, the delivery of sidestream
smoke may not be reduced. Indeed, the sidestream smoke might
contain more of some substances (e.g., pyrolytic products of flavor
additives) than does the sidestream smoke of higher yield cigarettes.
For very low yield cigarettes, the risk of the sidestream smoke may
equal that of the mainstream smoke. The chemical and physical nature
of sidestream smoke should be determined on new cigarettes.

Development and Validation of Analytical Methods

Methods for determining "tar" and nicotine yield were developed
before very low yield cigarettes were an important segment of the
market. It is questionable whether existing procedures can measure
accurately the "tar" delivery of the cigarettes yielding 0.1 mg of "tar."
Other techniques giving acceptable results must be developed. F'roce-
dures for determining "tar" yields of low magnitude through measure-
ment of fluorescence have been recommended (159). These methods
must be validated by determining intra- and inter-laboratory reprodue
ibility. Furthermore, fluorescence measurements may be compromised
by additives that interfere with fluorescence, either directly or through
the behavior of their pyrolytic products. Fluorescence measurements
may not be satisfactory for use with new commercial cigarettes.
Analytical procedures must also be validated for a number of
chemical constituents in smoke such as aldehydes, nitrogen oxides,
phenols and catechols, aromatic hydrocarbons, and nitrosamines.
Several laboratories are conducting such assays with favorable results.
However, coordinated comparisons among laboratories to measure the
degree of intra- and inter-laboratory variability have not been
reported.

Other Research Needs

A number of other research needs of lesser priority should be
addressed:

1. It is necessary to study the interaction of smoking with
occupational and environmental exposure to other noxious mate-
rials. The incidence of lung cancer is greatly increased in asbestos
workers or uranium miners who smoke cigarettes (8,70,117). The

56


risk of using contraceptive hormones is also greater in cigarette
smokers (~52,174). Laboratory models of wcarcinogenesis should
be used to measure the potential effect of combined smoking and
exposure to other environmental toxins. Animal models should be
developed to investigate the possible synergism of smoking and
the environment in causing other diseases.
2. It is necessary to determine the threshold, if any, for carbon
monoxide with respect to cardiovascular effects, pregnancy, and
psychological performance. Carbon monoxide delivery of ciga-
rettes can be controlled by ventilation (66,126). To determine the
carbon monoxide risk of lower "tar" and nicotine cigarettes, we
need to know whether thresholds for carbon monoxide activity
exist and whether these thresholds vary for individuals of
different ages, medical histories, or genetic backgrounds. Evalu-
ation of risk due to carbon monoxide must take environmental
exposure into consideration (152).
3. It is necessary to define the extent of smoker compensation for
differences in nicotine delivery of cigarettes. To the extent that
smokers compensate for lower nicotine delivery, they will
probably obtain more of other constituents from lower nicotine
than from higher nicotine cigarettes. For example, the smoker
might take more puffs to obtain the same dose of nicotine, and
thus receive a greater dose of carbon monoxide (80, 145). It
should be determined at what point smokers can no longer
compensate for lower nicotine levels and whether compensation
is a permanent behavior change of smokers who switch to lower
"tar" and nicotine cigarettes. To carry out such studies, standard-
ized noninvasive procedures to indicate smoke uptake from
cigarettes yielding various amounts of "tar," nicotine, and carbon
monoxide should be validated. Analyses of blood, urine, and
expired air have been used for these purposes (25, 179, 181).
Analysis of saliva for nicotine might also be useful. With any
procedure, inter-laboratory comparisons using standardized
methods are needed.

4. Many gas phase components of cigarette smoke are ciliatoxic in
the experimental setting. They may overwme physiologic de-
fense barriers against pulmonary toxins. To some extent, the
ciliatoxic agents are absorbed in the mouth and upper airways
and do not reach the deeper portions of the lung. Experimental
systems may not be capable of duplicating the anatomic and
behavioral factors that may affect human response to ciliatoxic
agents. Nevertheless, short-term sequellae of smoking can be
measured in human smokers of different types of cigarettes.
Further evaluation of these effects in man should be undertaken.
5. Attention to chemical habituation evoked by cigarette smoking is
centered on nicotine, which is the most active acute pharmacolog-

57


ic agent in cigarette smoke. It is necessary to determine whether
there may be other chemicals present in cigarette smoke that
contribute to cigarette smoking reinforcement.

6. A variety of short-term animal models with quantitative end
points predictive of the development of tobacc+aasociated dis-
easea should be developed. Fzcept for cancer, long-term animal
models suitable for quantitative comparisons of disease risk are
not adequate. Even if successful long-term animal models are
developed, the costs in time and resources may prevent the timely
evaluation of new cigarettes.
`7. It is necessary to develop methods for dissemination of informa-
tion regarding the delivery of various noxious agents by ciga-
rettes. The smoke content of "tar," niwtine, carbon monoxide,
phenolic constituents, volatile aldehydes, nitrogen oxides, are-
matic hydrocarbons, and nitrosamines may all contribute to the
risks incurred by smokers. The Federal Trade Commission
releases its findings of "tar" and niwtine yields of cigarettes and
has announced its intention to assay carbon monoxide delivery.
As additional monitoring assays are conducted, it will be
necessary to present the new information to the public and to
health professionals in a meaningful way.

8. It is neceSSBTy to evaluate the health hasard posed by passive
inhalation by nonsmokers of the sidestream smoke from new
types of cigarettes. Lower Yar" and nicotine cigarettes are
designed to reduce the mainstream smoke received by the
smoker. There is no evidence that the amount of sidestream
smoke or its quality is improved by these design changes. Indeed,
if additives are used to insure acceptability of the cigarettes by
the smoker, their pyrolytic products may occur in the side&ream
smoke. New types of cigarettes should be monitored for the
qualitative and quantitative risks they might impose on the
nonsmoker.
9. It is n ecessary to evaluate cigarettes with lower "tar" to nicotine
ratios than are currently found in the market place. Compensa-
tion by smokers of lower "tar" and nicotine cigarettes appears to
be baaed on niwtine delivery. The "tar" to nicotine ratio may
limit the delivery of smoke constituents to the smoker. A low
ratio might be a desirable strategy for lower risk cigarettes. It
should be determined whether smoke from cigarettes with
unusually low "tar" to nicotine ratios has unusual pharmacologic
or toxiwlogic properties.

10. It is necessary to develop a low "tar" and nicotine reference
cigarette. Several laboratories will need these reference ciga-
rettes as a standard for wmparisons of lower "tar" and nicotine
commercial cigarettes. Commercial products cannot serve as a
reference because design changes are made without announce-

5s


ment and because the identity of additives is not disclosed.
Without a stable reference, intra-laboratory wmparisons con-
ducted at different periods of time and many inter-laboratory
studies will be wmpromised. Reference cigarettes are available
for a limited range of "tar" and nicotine deliveries. A reference
cigarette delivering very low levels of "tar," niwtine, and gas
phase constituents is needed. To produce a reference of sufficient
quality, large numbers of cigarettes must be made. Because an
effort of this magnitude cannot be undertaken by individual
researchers, a centralized facility to provide reference cigarettes
to appropriate scientists is desirable.

Summary

1. Several thousand constituents have been identified in tobacco
and tobacw smoke. Of these, niwtine appears to be the most
important acute-acting pharmacologic agent. Nicotine's physic
logic effects include increased heart rate and blood pressure.
Nicotine also can permit the formation of tobacco-specific
nitrosamines, which are potent carcinogens, and nicotine itself
may be a significant wcarcinogen. The carcinogenic potency of
cigarette smoke condensates appears to depend on the nicotine
content of the "tar." This relationship may be due in part to the
conversion of niwtine to tobacco-specific nitrosamines or to the
coexistence of nicotine and some other unidentified carcinogen.
Whether the carcinogenic effects of niwtine as determined in
animal studies are directly applicable to humans is not known at
present.

2. In an important study to predict the carcinogenic activity of
cigarette smoke condensate, the amount of available nicotine
delivered to the mice was found to be a factor in every term but
one of the predictive model.
3. Polycyclic aromatic hydrocarbons and tobaccospecific nitrosa-
mines are two prominent classes of tumor initiators found in the
smoke condensates of commercial cigarettes. Of the polycyclic
aromatic hydrocarbons formed during combustion, ben-
zo[alpyrene (BaP) may be the most important and has been
studied the most extensively. A wrrelation has been found
between be@a]pyrene levels and the carcinogenic activity of
smoke condensates from several types of cigarettes, but other
studies have failed to show that carcinogenic potential is
significantly dependent on beHa]pyrene content. However, the
interaction of BaP with niwtine does appear important in
carcinogenesis.

4.The tobacco-specific nitrosamines (TSNA) are formed during
curing and fermentation of tobacco leaves and combustion of

59


cigarettes. TSNAs induce cancer in the lungs and trachea of
hamsters and may be of particular importance in the induction of
human laryngeal cancer. They may be active as contact car&+
gens, or their metabolism at distant sites may produce carcino-
gens that are then transported to a target site.
5. It is not known whether the unidentified mutagens in cigarette
smoke are an important cause of lung cancer in humans, but
added exposure to any tumor initiators probably carries an
increased risk of cancer.

6. Cigarette smoke contains oxidants that have been shown to
reduce the activity of alphal-antitrypsin in animals and man. This
inhibitory function is distinct from the effect whole smoke has on
increasing levels of elastolytic enzymes released by neutrophils
and macrophages.

7. The great variety of tobacco types makes it possible to manipu-
late the plant genetically to change the content of the constitu-
ents of the leaf. The chemical content of the leaf is also affected
by agricultural practices and curing methods. The nicotine
content of tobacco, for example, is related to the amount of
nitrate fertilizer used in cultivation. Modification of tobacco as
reconstituted sheet incorporates substantial amounts of tobacco
stems that contain less nicotine than the leaf. The physical nature
of reconstituted sheets can be controlled to change their burning
characteristics and smoke composition.
8. Vapor-phase constituents of cigarette smoke inhibit ciliary
motility and mucous flow in experimental animals.

9. Cigarette smokers metabolize several wmpounds more rapidly
than do nonsmokers. This effect is believed to be caused by the
induction of microsomal oxidases, which include aryl hydrocarbon
hydroxylase (AHH). Induction of AHH activity appears to be
caused by systemic exposure to the smoke compounds themselves
or to the metabolites of those compounds. The AHH system may
be involved in the metabolic formation of ultimate carcinogens
from procarc' inogen precursors.
10. In recent years, a number of flavoring additives or cellulose-
based tobacco substitutes may have been included in manufac-
tured cigarettes. The nature and amounts of such additives as
actually used are not known, nor is it known what influence these
additives may have on the chemical composition or subsequent
biological activity of cigarette smoke.

11. Cigarette design has a major effect on smoke composition. The
filter is the design characteristic that has the most impact on
"tar" yield; it can also selectively remove nitrosamines and
semivolatile phenols from smoke. The porosity of cigarette paper
and the presence of holes in the mouthpiece influence smoke

60


composition because ventilation reduces the quantity of "tar" and
dilutes the gas phase of smoke.

12. Because of the complexity of cigarette smoke, the total impact of
any cigarette modification on smoke composition will probably
never be fully known.

13. Many laboratory studies of the effects of smoke constituents
have been carried out using smoking machines that control puff
volume, frequency and duration, butt length, and other factors
according to standardized parameters. However, the most widely
used parameters were established in 196'7, and the type of
cigarettes generally smoked today are substantially different
with respect to length, paper porosity, "tar" and nicotine content,
and concentration of gas phase constituents. Evaluation of the
toxicological and pharmacological properties of smoke from new
types of cigarettes requires detailed knowledge of the manner in
which those cigarettes are smoked, as well as of how smoking
patterns affect smoke composition.

61


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Section 3. CANCER