materials are applied late in the process. The flavorings normally used
(whether natural or chemically compounded) are usually selected from
substances generally considered safe to humans even though such
definitions do not guarantee that subsequent pyrolytically-produced
materials are safe.

Tobacco blends can also be mechanically processed in different ways.
For example, leaf tobacco can be shredded to various widths and
lengths to control density, burning rates, puff resistance, and other
related properties (15). This alteration in tobacco blends produces a
cigarette or cigar with a modified chemical composition in both the
tobacco product and the resulting smoke as has been described earlier
in this chapter.

Cigarette paper can also be manufactured with a variety of additives
and with different porosities in order to control burning qualities. High
porosity citrate paper used with a standard tobacco blend delivered less
tar, but the same nicotine, as a control cigarette. Acetaldehyde,
acrolein, formaldehyde, carbon monoxide, and hydrogen cyanide were
reduced, but the pH of the smoke was elevated slightly. Low porosity
phosphate paper used with the same blend delivered greater quantities
of tar and nicotine than did the control cigarettes. Increases were also
found for the deliveries of acetaldehyde, acrolein, formaldehyde,
carbon monoxide, and hydrogen cyanide, while the pH remained
unchanged (E-18).

Most modern cigarettes use filters of various kinds. Over 80 percent
of the cigarettes sold in 197'7 were filtered, using charcoal filters,
mentholated filters, special baffled filters, cellulose acetate, and
combination filters. Charcoal filtration reduces some of the toxic gas
components; cellulose with absorptive additiv ,s tends to remove acidic
constituents; and magnesium silicate (when used) removes some of the
aldehydes and organic vapors from smoke. Perforating the filter to
allow air dilution further reduces the concentration of gas phase
components of smoke (10,11,22).

Many modifications of cigarettes are possible and the precise
ingredients and variations thereof are usually proprietary to manufac-
turers. However, experimental cigarettes have been prepared using a
number of modifications, such as variation of the width of tobacco cut,
the use of different parts of the tobacco itself (leaf, stems, fines, etc.), a
selection of additives, and different paper porosities. These experimen-
tal cigarettes have been prepared by different methods, smoked on
smoking machines under standard conditions, and the condensate
collected. Subsequent mouse dermal bioassays showed such trends as
the following (15-17): (1) Reconstituted tobacco sheets generally
resulted in condensates less tumorigenic than standard control
cigarettes. (2) High relative paper porosity seemed to decrease
carcinogenic activity of condensate on mouse skin. (3) The addition of
nitrates to aid combustion did not reduce condensate carcinogenicity as

14-29


was originally anticipated. (4) Different shred widths of tobacco did
not appear to affect the carcinogenicity of condensate for mouse skin.
(5) Cigarettes made from 100 percent tobacco stems resulted in
condensate with the lowest carcinogenic activity for mouse skin. (6) In
two cases, cigarettes made solely of tobacco leaves produced conden-
sates so toxic that they caused the death of experimental mice before
carcinogenicity could be ascertained. (7) The relative petroleum ether
solubles in tobacco correlated with condensate carcinogenicity for
mouse skin.

Several special processes are also possible in treating tobacco blends;
for example, puffing or expanding (adding air or COZ) and freeze
drying. These methods can affect the cigarette weight, puff resistance,
nicotine delivery, and in fact, the delivery of many components such as
acetaldehyde and acrolein. Since puffing or expanding processes
introduce air and effectively reduce the density of the cigarette, they
constitute a form of dilution and tend to reduce the output of some
substances. The burning rate is also affected, which in turn will change
the yield and composition of some pyrolysis products. Freeze drying,
for example, reduced nicotine and phenol& significantly in the
experimental blend used, but produced about the same amounts of
acetaldehyde, acrolein, and formaldehyde as did control blend ciga-
rettes (15-17).

Possible approaches that plant scientists can take to modify tobacco
leaf have been reviewed by Tso (26). The main objective of such
research is to acquire the desired characteristics which will meet with
acceptance of smokers and at the same time produce a less harmful
tobacco (25). Modification may involve genetic and cultural modifica-
tion, nitrogen fertilization technology, leaf and plant population, the
physiological stage of topping, and pesticide treatments. Post-harvest
modification is also possible, as leaf composition is markedly affected
by the curing process, aging, or other treatment of cured leaves.

Other Tobacco Products

In contrast to cigarettes (see discussion on types and classes of tobacco)
cigars are normally made of filler tobacco (bulk of cigar), binder
tobacco (used to hold the shape), and wrapper tobacco (the outside
layer or covering) (30). Wrappers are now being made increasingly
from reconstituted tobacco products. Cigar tobaccos are generally air-
cured, aged, and fermented. Pipe tobacco may be pure Burley or a
blend of Burley with other tobaccos. A considerable amount of
sweeteners and other additives is used to create a pleasing aroma and
taste. Chewing tobacco is made of tobacco leaf (usually Burley, cigar,
and bright) and is heavily sweetened. Snuff is powdered and flavored
tobacco (usually dark air-cured and fire-cured).

14-30


Summary

Tobacco has been cultivated and consumed in the civilized world for
more than 300 years. It is an important economic crop and demands
high production inputs, including energy. The United States is well
known for its high quality tobacco and the application of modern
technology to tobacco production. Extensive knowledge in tobacco
science has been accumulated by intensive research effort, especially
during the past 20 years. Recent advances in various areas of research
related to tobacco and tobacco smoke have provided adequate basic
information for improvement of production.

In plant research, there are means available for genetic, cultural,
and post-harvest modification. Also, a new homogenized leaf curing
process makes it possible to extract soluble proteins and to improve the
smoking material at the same time.

14-31


The Cigarette: Composition and Construction: References

(1) BRUECKNER, H. Die Biochemie des Tabaks und der Tabakverarbeitung.
  Berlin, Verlagsbuchhandlung Paul Parey, 1936, pp. 280330.
(9) DARKIS, F.R., HACKNEY, E.J. Range of chemical composition of tobacco
  being used in cigarettes. In: Wynder, E.L., Hoffmann, D. (Editors). Tobacco
  and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York,
  Academic Press, 1967, p. 42.

(8) DAWSON, R.F., OSDENE, T.S. A speculative view of tobacco alkaloid
  biosynthesis. In: Runeckles, V.C., Tso, T.C. (Editors). Structural and Function-
  al Aspects of Phytochemistry. Recent Advances in Phytochemistry. Volume 5.
  New York, Academic Press, 1972, pp. 317-333.
(4) DEJONG, D.W., LAM, J., LOWE, R., YODER, E., TSG, T.C. Homogenized leaf
  curing. II. Bright tobacco. Beitraege zur Tabakfomchung 3(2): 93-101, May
   1975.

(5) DONG, M. SCHMELTZ, I., JACOBS, E., HOFFMANN, D. Asa-arenes in
  tobacco smoke. Journal of Analytical Toxicology 2: 21-25,1973.
(6) FORGACS, J., CARLL, W.T. Mycotoxicoses: Toxic fungi in tobaccos. Science
   152: 1634-1635, June 1966.
(7) FRANKENBURG, W.G. Chemical changes in the harvested tobacco leaf, Part I.
  Chemical and ensymic conversions during the curing process. In: Nord, F.F.
  (Editor). Advances in Enzymology and Related Subjects of Biochemistry,
  Volume 6. New York, Interscience Publishers, 1946, pp. 399337.
(8) HARLAN, W.R., MOSELEY, J.M. Tobacco. In: Encyclopedia of Chemical
  Technology, Volume 14. New' York, Interscience Encyclopedia, Inc., 1955, pp.
    242-261.
(9) HARLEY, N.H., COHEN, B.S., TSO, T.C. Polonium-210 in tobacco. Presented at
  the Symposium on Public Health Aspects of Radioactivity in Consumer
  Products, Atlanta, Georgia, February 2-4, 1977. Symposium Summaries
  published by the Nuclear Regulatory Commission.
(10) KEITH, C.H. Filtration as a means of reduction of tar and nicotine levels in
   tobacco smoke. In: Wynder, E.L., Hoffmann, D., Gori, G.B. (Editors).
  Proceedings of the Third World Conferenm on Smoking and Health, New
  York, June 2-5, 1975. Volume I. Modifying the Risk for the Smoker. U.S.
  Department of Health, Education, and Welfare, Public Health Service,
  National Institutes of Health, National Cancer Institute, DHEW Publication
   No. (NIH) 761221,1976, pp. 49-55.

(II) KIEFER, J.E., TOUEY, G.P. Filtration of tobacco smoke particulatea In:
  Wynder, E.L., Hoffmann, D. (Editors). Tobacco and Tobacco Smoke. Studies in
  Experimental Carcinogenesis. New York, Academic Press, 1967, pp. 545575.
(12) LOWE, R.H. Crystallization of fraction 1 protein from tobacco by a simplified
   procedure. FEBS Letters 73(l): 93-166, June 1977.
(IS) MATTINA, C.F., SELKE, W.A. Reconstituted tobacco sheets. In: Wynder, E.L.,
  Hoffmann, D., Gori, G.B. (Editors). Proceedings of the Third World Confer-
  ence on Smoking and Health, New York, June %5,1975. Volume I. Modifying
  the Risk for the Smoker. U.S. Department of Health, Education, and Welfare,
  Public Health Service, National Institutes of Health, National Cancer
  Institute, DHEW Publication No. (NIH) 78I221,1976, pp. 67-72.
(14) MOSHY, R.J. Reconstituted tobacco sheet. In: Wynder, E.L., Hoffmann, D.
  (Editors). Tobacco and Tobacco Smoke. Studies in Experimental Carcinogen*
  sis. New York, Academic Press, 1967, pp. 4733.

(15) NATIONAL CANCER INSTITUTE, SMOKING AND HEALTH PROGRAM.
  Report No. 1. Toward Less Hazardous Cigarettes. The First Set of Experimen-
  tal Cigarettes. U.S. Department of Health, Education, and Welfare, Public
  Health Service, National Institutes of Health, National Cancer Institute,
  DHEW Publication No. (NIH) 76995,1976,143 pp.

14-32


(16) NATIONAL CANCER INSTITUTE, SMOKING AND HEALTH PROGRAM.
  Report No. 2. Toward Less Hazardous Cigarettes. The Second Set of
  Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
   Public Health Service, National Institutes of Health, National Cancer
   Institute, DHEW Publication No. (NIH) 761111,1976,153 pp,
(17) NATIONAL CANCER INSTITUTE, SMOKING AND HEALTH PROGRAM.
  Report No. 3. Toward Less Hazardous Cigarettes. The Third Set of
  Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
   Public Health Service, National Institutes of Health, National Cancer
   Institute, DHEW Publication No. (NIH) 77-l239,1977,152 pp.
(18) NATIONAL CANCER INSTITUTE, SMOKING AND HEALTH PROGRAM.
  Report No. 4. Toward Less Hazardous Cigarettes. The Fourth Set of
  Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
   Public Health Service, National Institutes of Health, National Cancer
   Institute. (Unpublished preliminary results)

(19) RADFORD, E.P., JR., HUNT, V.R. Polonium-210: A volatile radioelement in
  cigarettes. Science 143(3693): 247-249, January 17,1964.
(20) RATHKAMP, G., TSO, T.C., HOFFMANN, D. Chemical studies on tobacco
  smoke. XX: Smoke analysis of cigarettes made from bright tobaccos differing
  in variety and stalk positions. Beitraege zur Tabakforschung 7(3): 179-139,
   November 1973.

(21) SUGAWARA, S., ISHIZU, I., KOBASHI, U. Studies on casing effects on
  cigarettes. I. Change in chemical composition with casing additives. Scientific
  papers of the Central Research Institute, Japan Monopoly Corporation 195:
   203-207,1963.
(.%a) TIGGELBACK, D. Vapor phase modification-an under-utilized technology. In:
  Wynder, EL., Hoffmann, D., Gori, G.B. (Editors). Proceedings of the Third
  World Conference on Smoking and Health, New York, June 2-5,1975. Volume
  I. Modifying the Risk for the Smoker. U.S. Department of Health, Education,
  and Welfare, Public Health Service, National Institutes of Health, National
   Cancer Institute. DHEW Publication No. (NIH) 761221, 1976, pp. 597514.
(28) TSO, T.C. Manipulation of leaf characte&tics through production-role of
   agriculture in health-related tobacco research. Journal of the National Cancer
   Institute, 43(6): 1811-1819, June 1972.

(24) TSO, T.C. Physiology and Biochemistry of Tobacco Plants. Stroudsburg,
  Pennsylvania, Dowden, Hutchinson & Ross, Inc., 1977, pp. 53,91-99.
(a) TSO, T.C. The potential for producing safer cigarette tobacco. Agricultural
   Science Review lo(3): l-10,1972.

(86) TSO, T.C. Production, phytochemistry and modification of tobacco. In: Minutes
  of the Smoking and Health Contractors Conference, National Cancer Institute,
  Savannah, Georgia, March 11-14, 1979) (Minutes to be published, May 1979)
(27) TSO, T.C. Tobacco. In: Standen, A. (Editor). Encyclopedia of Chemical
   Technology, Volume 29,2nd edition. New York, John Wiley & Sons, 1969, pp.
(2%) TE:l Tobacco and tobacco smoke. In: Childers W F Russo G.M. (Editors).
Nightshades and Health. Somerville, New Jersei, Ho&ultuAl Publications,
   Somerset Press, 1975, pp. 93-121.

(29) TSO, T.C. Tobacoo as potential food source and smoke material. Beitraege zur
   Tabakforschung 9(2): 6366, June 1977.

(SO) m, T.C. Tobacco composition: Potential for changes through production.
   Tobacco-The International Weekly: 69-72, April 25,1969.
(81) TSO, T.C., CHAPLIN, J.F. Simple Correlation and Multiple Regression Among
  Leaf Characteristics, Smoke Components, and Biological Responses of Bright
  Tobaccos. U.S. Department of Agriculture, Agricultural Research Service,
   Technical Bulletin 1551, May 1977,135 pp.

14-33


(32) TSO, T.C., GORI, G.B. Effect of tobacco characteristics on cigarette smoke
  composition. In: Schmeltz, I. The Chemistry of Tobacco and Tobacco Smoke.
   New York, Plenum Press, 1972, pp. 51-63.
(34 TSO, T.C., LOWE, R., DEJONG, D.W. Homogenized leaf curing. I. Theoretical
  basis and some preliminary results. Beitraege zur Tabakforschung 3(l): 44-51,
   January 1975.

(3.4 TSO, T.C., RATHKAMP, G., HOFFMANN, D. Chemical studies on tobacco
  smoke. XXI: Correlation and multiple regression among selected cigarette-
  smoke constituents and leaf characteristics of bright tobacco. Beitraege sur
  Tabakfomchung 7(3): 196-194, November 1973.
(95) U.S. DEPARTMENT OF AGRICULTURE. Agricultural Statistics, 1976. U.S.
  Department of Agriculture, 1976, pp. 96111.
(36) U.S. DEPARTMENT OF AGRICULTURE, AGRICULTURAL RESEARCH
  SERVICE. Tobacco production. U.S. Department of Agriculture, Agricultural
  Research Service, Agriculture Information Bulletin No. 245, December 1976,
   77 PP.

($7) WOLF, F.A. Tobacco production and processing. In: Wynder, E. L., Hoffmann,
  D. (Editors). Tobacco and Tobacco Smoke. Studies in Experimental Carcino-
  genesis. New York, Academic Press, 1967, pp. 5-49.

14-34


Smoke Formation

The raw material that goes into the making of a cigarette is only a
prelude to what happens when the cigarette is smoked. Indeed, the
lighted cigarette is a unique chemical factory generating more than
2,000 known compounds by a variety of processes responsive to
thermodynamic constraints. The following sections will review the
smoke generation process and the effects on smoke composition.

Physico-Chemical Nature of Cigarette Smoke

As a smoker takes a puff from a burning cigarette, he draws the
mainstream smoke that issues from the butt end. The aerosol emitted
from the burning cone during puff intervals is the sidestream smoke,
and is chemically different from mainstream smoke. That portion of
the smoke which can be retrained by a Cambridge glass fiber filter
(99.9 percent efficient for particles >O.l p) is defined as the particulate
phase, whereas the portion that passes the filter is termed the gas
phase.

Smoke aerosol is a highly concentrated aerosol of liquid particles
constituting the "tar." Each particle is composed of a large variety of
organic and inorganic chemicals that are dispersed in a gaseous media
consisting primarily of nitrogen, oxygen, hydrogen, carbon dioxide,
carbon monoxide, and a large variety of volatile and semivolatile
organic chemicals in equilibrium with the particulate phase of the
tobacco smoke. The smoke aerosol is a continuously changing entity.
Aging of the aerosol results in changes in its physical and chemical
properties (13).

In order to generate reproducible physical and chemical data for the
analysis of cigarette smoke, standard smoking conditions have been set
up baaed on observations of patterns in human smoking. In the United
States, these standard conditions prescribe 1 puff per minute, 2-second
puff duration, a puff volume of 35 ml, and a butt length of 23 mm in an
unfiltered cigarette, or the length of the filter tip, including the
overwrap plus 3mm, whichever is greater, in a filtered cigarette.
Smoking conditions for cigarettes in other countries (9) and for cigars
(46) differ somewhat from the adapted standards for U.S. cigarettes.

Temperature Profiles

Several parameters determine the qualitative and quantitative smoke
composition of mainstream and sidestream smoke. The major factors
affecting the temperature profiles of the burning cigarette include
physical form (length and circumference) of the cigarette, filler
materials, tobacco type or blend, tobacco cut, packing density,
additives, moisture content, quality of the cigarette paper (porosity,
additives), and the filter (fiber material, plasticizer, draw resistance,
construction, perforation). During puffing, temperatures in the

14-35


burning cone reach 900oC with some hot spots on the periphery of the
cigarette up to 1,050". A steep temperature gradient from 880oC to
40oC is observed away from the burning center extending over the
next 3 centimeters of the tobacco column (65,100). On the basis of this
temperature profile, three major reaction zones are defined: the high
temperature zone (90CMOOoC) which is free of oxygen (immeasurable)
and contains up to 8 volume percent of hydrogen and 15 volume
percent of carbon monoxide, the oxygendepleter pyrolysisdistillation
zone (600-lOO"C), and the low-temperature zone (<lOOoC) with up to
12 volume percent of oxygen. Within these three zones, the actual
mainstream smoke formation occurs by hydrogenation, pyrolysis,
oxidation, decarboxylation, dehydration, chemical condensation, distil-
lation, and sublimation. The exit temperature of the mainstream
smoke at the cigarette butt ranges from 25 to 5O"C, depending on the
butt length.

The sidestream smoke is generated during smoldering of the
cigarette at peak temperatures inside the glowing cone of up to 300oC
but reaches ambient temperatures at a distance of a few centimeters
from the burning cone.

Material Balance

The amount of tobacco consumed during puffing and smoldering
depends on the static burning temperature and on the same parame-
ters which determine the mainstream smoke formation. An indicator
for the release of sidestream smoke is the static burning rate between
puffs which generally ranges from 5 to 7 mm of tobacco column per
minute. It has been shown that between 55 and `70 percent of the
tobacco of a cigarette is burned between puffs and thus serves as a
source for the formation of sidestream smoke and ashes. The
mainstream smoke effluent of a cigarette smoked to a 30 mm butt
length amounts to about 500 mg (Tables 12 and 13, and reference 4 ).
Of the 55 mm tobacco column, about 300 mg is consumed for the
generation of mainstream smoke (and ashes) and about 500 mg for the
formation of sidestream smoke (and ashes).

The interrelationships involved in cigarette smoke may be described
by the general equation described recently by Gori (25).

Werght of ash pwduced during puffs
+Mainstream TPM weight
+Mainstream gas phase weight
-Mainstream entrained gas weight
-Mainstream combustion oxygen weight

=Weight of cigarette burned during puffs

14-36


TABLE 12.-Percent distribution of cigarette smoke*

Material

Weight
(mg/cigarette)

Weight of
total effluent (S)

Particulate matter (ix cond. I&O)
Nitrogen (67.2 vol St)
Oxygen (13.3 vol %)
Carbon dioxide (9.3 vol %)
Carbon monoxide (3.7 vol W)
Hydrogen (2.2 vol W)
Argon (0.3 ~01 %)
Methane (0.5 vol W)
Water vapor (relative humidity=0.6)
C&s h:dnxarbons
Carbonyls
Hydrogen cyanide
Other known gaseous materials

40.6               ~8.2
235.4             59.0
66.8            13.4
68.1               13.6
16.2                3.2
0.7                0.1
5.0                1.0
1.3                0.3
5.8                1.2
2.5                0.5
1.9                0.4
0.3                0.1
1.0                0.2

Total

Measured total effluent

505.6           101.2

500                100

`66 mm nonfilter cigarettes. 30 mm butt length, 10 puffs of 38.9 ml volume each.
SOURCE: Keith. C.H. (52).

Material

TPM (wet)                                    46.6
Nitrogen                                     265.4
Oww                                     66.8
Argon                                        5.0
carbon dioxide                                  63.1
Carbon monoxide                                 16.2
Water vapor                                    5.3
C&s hydrocarbons                                2.5
Carbnyls                                      1.9
Other (gaseous)                                  3.3

TABLE lh-Typic& mainstream smoke mixture*

Weight
(mg/eigarette)

505.6

`66 mm cigarette, 90 mm butt length. 10 puffs of %X9 ml volume each.
SOURCE: Gwi, G.B. (OS).

Mainstream Smoke Aerosol
The undiluted smoke as it leaves the cigarette butt contains up to 5 x
109 heterogeneous particles per ml with round and spheric forms
ranging in diameter between 0.2 and 1.0 F and a median particle
diameter of about 0.4 p (13, 51). The smoke aerosol is slightly charged
with about 10'2 electrons per gram of smoke; about 55 percent of the
particles contain one or more charges (51). The pH of the total smoke
effluent of a cigarette is primarily determined by the tobacco. For a

14-37


blended U.S. cigarette, the pH of the mainstream smoke varies
between 5.5 and 6.2, and that of the sidestream smoke ranges between
6.5 and 7.5, depending on the puff number measured. In the case of
cigarettes made exclusively from Burley or black tobacco, or in the
case of cigars, the pH for mainstream smoke varies between 6.5 and 8.5
(highest values for last puffs) and for sidestream smoke between 7.5
and 8.8 (8). Cigarette smoke has reducing activity which increases with
puff number (79).

Chemical Composition of Tobacco Smoke
To facilitate the analysis of the tobacco smoke, the smoke is separated
into a gas phase and a particulate phase in the following way: the
particulate phase is defined as that portion of the smoke collected on a
conventional Cambridge filter pad (99.9 percent efficient for particles
more than 0.1 CL), and the gas phase is the portion that passes through
the Cambridge filter.

Gas Phase

Carbon Monoxide and Carbon Dioxide

More than 96 percent of the weight of the total mainstream smoke
effluent is given by the gas phase with nitrogen and oxygen already
comprising more than `70 percent. Of the remaining gas phase
components, carbon dioxide and especially carbon monoxide have been
studied in great detail. These compounds are primarily formed by
oxidation of the tobacco constituents in the high temperature zone and
by decarboxylation in the pyrolysis and distillation zone and in the low
temperature zone. Both CO and COZ increase linearly with ascending
puff number. Leaves from the lower stalk positions generate
significantly less CO and COZ than do leaves from the upper stalk
positions of the same tobacco plant (6). The mainstream smoke of U.S.
commercial cigarettes contains between 1.8 and 17.0 mg of CO (1.5-5.5
volume percent) and between 10 and 60 mg of COZ (8.5-14.5 volume
percent) (6, 30, 74). Especially low CO values have been reported for
cigarettes with perforated filter tips (27). A study with a limited
number of commercial cigarettes from England indicates that filter
cigarettes without perforated filter tips may contain as much, if not
slightly more, CO than nonfilter cigarettes (98). Levels of sidestream
smoke CO may be three times as high as those levels in mainstream
smoke, and COz may be up to eight times as high. The CO and COz
values for the smoke of cigars are significantly higher than those for
cigarette smoke, primarily because of the relatively unporous cigar
wrapper (6).

14-38


Nitrogen Oxides

Tobacco smoke is known to contain nitric oxide (NO) and trace
amounts of nitrogen dioxide (NOz) and nitrous oxide (N20). The alkali
nitrates in tobacco are the major precursors for the nitrogen oxides in
the smoke (100). With the possible exception of the last few puffs of a
cigarette, fresh mainstream smoke does not contain NO2 (S&z);
however, upon aging, NO in the smoke is quickly oxidized to NO2
(although the half lifetime of NO in cigarette smoke is about 10
minutes). In concentrated smoke, aging leads to the formation of
nitrites (96). Nitrogen oxides can be reduced in the mainstream smoke
of cigarettes and little cigars with the aid of charcoal-containing filter
tips (91). The concentration of NO in the smoke of U.S. commercial
cigarettes varies between 5 and 800 pg per cigarette (1,27, 72).

Ammonia

The major precursors for ammonia in the mainstream and sidestream
smoke of tobacco products are alkali nitrate and protein (48). The
nitrate in tobacco is reduced to nitrogen and ammonia in the burning
cone with a high yield in sidestream smoke. The mainstream smoke of
U.S. commercial tobacco products contains between 22 and 130 E
ammonia (as the ammonium ion) per cigarette and between 63 and 135
pg ammonia per little cigar (7, 33). The ratio of ammonia in sidestream
smoke to that in mainstream smoke ranges from 1:40 to 1:70. The
sidestream smoke of cigars is even richer in ammonia, with amounts up
to more than 1 mg per cigar.

Volatile N-Nitrosamines

Another type of compound for which the yield is largely determined by
the nitrate content of the tobacco is that of nitrosamines, many of
which are known animal carcinogens (57). To date eight volatile
nitrosamines have been identified in tobacco smoke with dimethylni-
trosamine (DMN), diethylnitrosamine (DEN) and nitrosopyrrolidine
(NPy) as the major representatives (76). The unaged (freshly
generated) smoke of three U.S. cigarettes without filter tips contained
13 to 65 ng of DMN, 15 to 50 ng of DEN, and 11 to 34 ng of NPy (11).
Cellulose acetate filter tips retain volatile nitrosamines selectively,
whereas charcoal filter tips do not exhibit such selective removal.
Unaged sidestream smoke contains 10 to 40 times higher concentra-
tions of volatile nitrosamines than the mainstream smoke of the same
cigarette.

Hydrogen Cyanide and Cyanogen

Amino acids and protein are the major precursors for hydrogen
cyanide (HCN), cyanogen, and nitriles in tobacco smoke (49). HCN is
the major ciliatoxic agent in cigarette smoke; however, its selective

14-39


reduction by charcoal filters, among other things, diminishes the
inhibition of lung clearance of the cigarette smoke to a significant
degree. The concentration of HCN in the smoke of U.S. commercial
cigarettes varies between 10 and 400 pg per cigarette with low values
for low "tar" cigarettes and cigarettes with charcoal filter tips (.27, 72).
Sidestream smoke (SS) contains significantly less HCN than main-
stream smoke (MS) with SWMS ratios between 0.006 and 0.37 (12, 49).
Tobacco smoke also contains small amounts of cyanogen (CN)2 with
concentrations varying between 10 and 20 Fg1cigarett.e (1.2). Since
(CN)2 hydrolyzes easily to cyanide and cyanate, it can contribute to the
hydrogen cyanide concentration in the smoke. In the case of cigar
smoke, this can amount to 10 to 30 percent of the measured HCN.

Volatile Sulfur Compounds

This class of gas-phase compounds is of special interest because of its
high reactivity. Sulfur-containing volatiles are highly sensitive to
flame photometric detectors, and nanogram amounts of sulfur
compounds can be rapidly determined even in the presence of great
excesses of other gases. Guerin and Horton determined 23 sulfur
compounds in the gas phase of cigarette smoke (29, 4.3). Typical
cigarette deliveries of the major sulfur constituents include 85 pg of
hydrogen sulfide, 35 pg of carbonylsulfide, 2 pg of carbon disulfide, and
3 pg of sulfur dioxide (43). The authors also observed an "aging effect"
during the first 30 seconds after smoking, even when Teflon@ sampling
loops and columns were used instead of conventional stainless steel
tubes. During "aging," the composition of the mixture of the sulfur
components in the smoke shifts significantly from low molecular
compounds (such as hydrogen sulfide) toward high molecular weight
sulfur components.

Volatile Nitriles

The major precursors for volatile nitriles in tobacco are amino acids
and protein similar to those for hydrogen cyanide (50). The most widely
studied nitrile is acetonitrile (CH&N). Its concentration in the smoke
of one cigarette varies between 100 and 250 pg. So far a total of 13
aliphatic nitriles and 20 aromatic nitriles have been identified in
tobacco smoke, many of which occur in the gas phase (76). Pyridine3-
carbonitrile and possibly some aliphatic and aromatic nitriles may be
formed from nicotine and other tobacco alkaloids during smoking.
Recently one volatile smoke nitrile has been reported as carcinogenic in
the experimental animal and is considered as a possible occupational
carcinogen (64). Acetonitrile has been reported in much higher
concentration in sidestream smoke than in mainstream smoke (1:3.9).

14-40


Other N-Containing Volatile Compounds

To date, more than 600 N-containing compounds have been identified
in tobacco smoke; several of them are volatile (76). Of these, aliphatic
and aromatic nitrohydrocarbons and nitrophenols have been studied in
some detail. The concentration of the major representative, nitrometh-
ane, varies between 0.5 and 1.0 pg per cigarette and nitrobenzene
between 10 and 25 ng per cigarette. These compounds are formed
primarily from NOZ and C,H-radicals in the hot zones of burning
tobacco products; thus concentration of the nitro compounds is
governed by the nitrate content of the tobacco. Little is known about
the tumorigenic potential of nitrohydrocarbons and nitrophenols,
although it should be considered that the aromatic nitrohydrocarbons
and possibly nitrophenols are reduced in viva to the corresponding
amines, some of which are known carcinogens. Recently 2nitropropane
(0.2-2.0 pg/cigarette) has been reported to induce hepatomas in mice
(24).

Tobacco has long been known to contain aliphatic and aromatic
amines, with methylamine (4.6 CLg/cigarette) and aniline (1.2
pg/cigarette), as representative examples, present in the highest
concentrations. In the blended U.S. cigarette with a smoke pH around
6, the major portion of the volatile amines may be protonated and thus
found in the particulate phase. In recent years, several amines,
especially the volatile secondary amines including pyrrolidine, have
been discussed as precursors for carcinogenic N-nitrosamines. Since
nitrosamines as well as both types of their precursors, NOlzand amines,
have been found in much higher concentrations in the smoke of
nitrate-rich cigarettes (48), the concept of smoke amines as potential
precursors for nitrosamines has been supported. Aniline and possibly
other volatile amines are present in significantly higher concentration
in sidestream smoke than in mainstream smoke (1: > 30) (67).

Three other N-compounds with tumorigenic activity in the experi-
mental animal have been reported in tobacco smoke. These are
hydrazine (30 lug/cigarette), 1,ldimethylhydrazine (100 ng/cigarette),
and urethane (20-38 ng/cigarette). The hydrazines are not formed
from the maleic hydrazide, the major U.S. tobacco sucker growth
inhibitor, but both are transferred from tobacco during smoking and
are also pyrosynthesized. Urethane is primarily formed during
smoking. As with other compounds with the amino group (ammonia
and amines), more hydrazine is found in sidestream smoke than in
mainstream smoke (1:3).

Volatile Hydrocarbons

The highest concentration of organic compounds found in the gas
phase are the hydrocarbons (88). Methane (200-1,000 pg/cigarette),
ethane (10&600 pg/cigarette), and propane (50-300 pg/cigarette) are

1441


cigarettes accounted for less than 40 percent of the total market in
1957 and comprise nearly 90 percent of today's market, Several
parameters influence the "tar" yields of cigarettes. These include
tobacco type, use of reconstituted tobacco sheets and expanded
tobacco, packing density, cigarette paper, and filter tips. The effects of
these and other factors are discussed in the next section.

The sidestream smoke of cigarettes has been determined in specially
designed chambers which are under constant slow airflow during the
collection procedure. In this case, the particulate matter is retained and
measured on Cambridge fiber filter discs (100). For nonfilter ciga-
rettes, the "tar" ratio in mainstream and sidestream smoke varies from
1:1.4 to 1:1.2; for low "tar" filter cigarettes this ratio can shift
considerably in favor of sidestream smoke. The quantitative composi-
tions of the two "tars," however, differ widely (as noted later in this
section).

In 1972, the FTC reported "tar" yields for U.S. little cigars to range
from 16.5 to 47.8 mg (92). All cigars weighing less than 1.36 g are
considered "little cigars." When the tobacco of little cigars is wrapped
in cigarette paper, the tar yield remains the same as or only slightly
lower than that of little cigars with normal wrappers. This observation
is quite different from that made for the CO yield. Here, the paper
wrapper leads to a 30 to 50 percent CO reduction. Large cigars puffed
under standard cigar-smoking conditions generally deliver more "tar"
than cigarettes and little cigars because of their higher weight.
Compared on the basis of gram-to-gram tobacco consumed, the cigar
"tar" yield, however, is only 20 to 30 percent that of a cigarette (~5,
loo).

Nicotine and Minor Tobacco Alkaloids

Nicotine and the compounds derived from it contribute significantly to
the organoleptic nature and toxicity of tobacco smoke and are
considered a major factor in tobacco habituation. As in the case of
"tar," the FTC reports the nicotine values for the smoke of U.S.
cigarettes semiannually (0.05-2.50 mg)(23). The sales-weighted average
of nicotine in the smoke of U.S. cigarettes has decreased from 2.5 mg in
1957 to 1.1 mg in 1976 (97). Similar observations were made for
products of other countries (99). Figures 15 and 16 describe the trends
of tar and nicotine in the United States.

The nicotine values for the smoke of U.S. little cigars were reported
by the FTC in 1972 to vary between 0.52 and 3.11 mg (92). In general,
the yield of nicotine in the smoke of a cigar is considerably higher than
that in the smoke of a cigarette. However, on a per-gram-tobacco-
smoked basis (or for a given smoke volume), the nicotine yield is
significantly lower for cigars (20 to 40 percent) (75, 100). When one
considers the physiological effects of nicotine, however, the comparison
of the nicotine content of cigarette smoke with that of cigar smoke can

14-44


be misleading. In cigarette smoke, with the exception of French black
tobacco cigarettes, nicotine is present in a protonated form, whereas in
cigar smoke, nicotine is partially present in the more easily absorbed
unprotonated form (2,8,34).

Depending on the Nicotiunu tabacum variety, the nicotine content of
the processed leaf can vary between 0.2 and 5.0 percent of the dry
weight. The nicotine content of smoke tobaccos, however, varies
generally between 1.0 and 2.0 percent, with values below 1.0 percent
reported for certain low "tar" cigarettes. Because of the pharmacologi-
cal effect of nicotine and its relatively high concentration in the
tobacco, it is important to study the fate of tobacco nicotine during
smoking. Studies with W-labelled nicotine have shown that, in the
case of the blended US. cigarette, 14 to 22 percent of the nicotine was
transferred unchanged into mainstream smoke and 20 to 30 percent
was found unchanged in the sidestream smoke (47, 80). Four to eight
percent of the radioactivity in the mainstream smoke particulate
matter was given by decomposition products of i4C-nicotine. The major
decomposition products identified were myosmine, bipyridyl (Figure 3),
and pyridines. Despite the high transfer rate of intact nicotine into
mainstream smoke and the low yield of (non-tumorigenic) decomposi-
tion products, one cannot exclude a contributory role of the thermal
decomposition of nicotine towards the tumorigenicity of cigarette
smoke. So far, it has been shown that nicotine may yield traces of the
carcinogenic dibenzacridines, a dibenzocarbazole (93, 100), and tobacco
specific nitrosamines (38).

The structural formulas of nicotine and of other tobacco alkaloids
and of tobacco specific nitrosamines are presented in Figure 3,
together with their concentrations in the mainstream smoke of
cigarettes.

Nonvolatile N-Nitrosamines

During curing and fermentation of tobacco, specific nitrosamines can
be formed by nitrosation of alkaloids, as was shown by identification of
N'-nitrosonornicotine (NNN), 4-(N-methyl-N-nitrosamino)-1-(3-pyri-
dyl)-1-butanone (NNK) and N'-nitrosoanatabine (NAtB) in processed
tobacco leaves. The yield of these compounds depends on the
concentration of the nitrate and alkaloids in the leaf. In the case of
cigarette tobacco, NNN and NNK were found in concentrations
between 0.3 and 7.0 ppm and 0.1 and 0.4 ppm, respectively. The
reported values for cigar tobacco were for NNN, 3 to 45 ppm, and for
NNK, 2 to 36 ppm. Since chewing of tobacco has been associated with
an increased risk of cancer of the oral cavity and esophagus, high
values of nitrosamines in chewing tobacco and snuff are of more than
academic interest (NNN 2 to 90 ppm) (35,38).

NNN, NNK, and NAtB have also been identified in the mainstream
smoke of cigarettes (NNN, 0.14 to 3.70 pg/cigarette; NNK, 0.11 to 0.42

14-45


cue
0       N
         I

  N      CH3

NlOOtll-N3
0.1-2.5 mg

o-ch
0       N    0

  N   cl!3

Cow-me
9-57 rg

   0
CP
0       N

  N

2. 3".f%py&l
7-27 fig

2'. 3' -Dehydrmtme

CP
0       N
         I
          H
  N

AWUJZ35lW
3-12 rg

t?
0   `N

  N

Myosmme
g&J

       \
(r3
0      N
         I
         H
  N-

Anatatune
3-14 rg

   NNN
N' - N~trOSOnOmotOtme
13o=600 ngkg

   NNK
4-(N-me4hyl-N-fMtfOS&-nmO)
-l-(3-pyn*lj-l-butanone
lock420 ngfag

  NAtS
N' -Nltrosanatabcw

FIGURE 3.-Common tobacco alkaloids and tobacco-specific nitro-
samines in cigarette smoke. (Numbers are values for mainstream
smoke of a cigarette).

14-46


pg/cigarette) and cigars (NNN, 3.2 to 5.5 pglcigarette; NNK, 1.9 to 4.2
pg/cigarette), as well as in the sidestream smoke of cigarettes (NNN,
1.7 to 6.1 pg; NNK, 0.41 to 0.60 pg) and cigars (NNN, 0.9 to 17.0 M;
NNK, 0.8 to 16.0 pg). Again, as for other smoke compounds depending
on the reduction of nitrogen oxides in the burning cone, tobacco-
specific nitrosamines are found in higher amounts in sidestream than
in mainstream smoke (38).

The transfer rate of W-labelled NNN into mainstream smoke was
determined for a U.S. blended nonfilter cigarette and was found to be
about 11 percent (3&z). This finding indicates that about 50 percent of
the NNN in the smoke originates by transfer from tobacco and the
other half was pyrosynthesized from nicotine during smoking. The
nonvolatile nitrosamines are of special interest because they are the
only tobacco-specific carcinogens thus far identified.

In the United States, about 70 to 80 percent of all tobaccos are
treated during cultivation with the sucker growth inhibitor, maleic
hydrazide (MH-46). Since this chemical is water-insoluble, it is
solubilized as a diethanolamine formulation. During curing, the
diethanolamine residue on tobacco is nitrosated to the carcinogenic N-
nitrosodiethanolamine (74, 76). As an alternative, the potassium salt of
MH has been used to impart water solubility. Although no data are
presently available, it is possible that residues of pesticides with amino
groups give rise to nitrosamines in tobacco and its smoke (e.g.,
carbaryl)(ZO). This area needs to be investigated.

Aromatic Amines

Aromatic amines have been discussed as one possible factor in the
association of cigarette smoking with bladder cancer (16). So far, two
known human bladder carcinogens have been identified in trace
amounts in cigarette smoke. These are j?-naphthylamine (1-2
nglcigarette) and Caminobiphenyl (0.8-2.4 nglcigarette). These
amines may serve as indicators of the concentration of other potential
carcinogens in tobacco smoke,  since most aromatic amines are
pyrosynthesized by the same mechanism and have been isolated from
tobacco smoke, although not yet fully identified (66, 67). Furthermore,
a safe level of exposure for human bladder carcinogens has not been
established (73,93). Tobacco smoke also contains a number of alkylated
o-toluidines, of which only the parent compound has been tested so far
and found to be carcinogenic in the experimental animal (73).

Sidestream smoke of cigarettes contains significantly higher
amounts of aromatic amines than mainstream smoke. For example, the
mainstream smoke of a nonfilter cigarette was found to contain 160 ng
of o-toluidine, 1.7 ng of /3-naphthylamine, and 4.6 ng of 4-aminobiphe-
nyl. The amounts of these amines in the sidestream smoke of the same
cigarette were 3,000 ng, 67 ng and 140 ng, respectively (67). Since
tobacco smoke may also contain the highly mutagenic amino-p-

14-47


carbolines which can be pyrosynthesized from tryptophan (87'), further
studies are needed before one can evaluate the contribution of
aromatic amines to tobacco carcinogenesis.

Alkanes and Alkenes

The coating of leaves with "waxes" is an almost universal phenomenon
throughout the plant kingdom (100). The waxy layer of tobacco leaves
is primarily composed of alkanes, alkenes, terpenes, esters, phytoster-
ols, and alkaloids (85). The tobacco specific alkane fraction of the wax
layer is made up of n-, iso-, anteiso&Hsa to C&Hn, paraffin
hydrocarbons. The most abundant hydrocarbon is n-(and iso-) hentria-
contane (GlHti), which amounts to 30 to 40 percent of the total
alkanes. Trace amounts of hydrocarbons have also been found from
CZHB to &Ha. The content of the crystalline alkanes amounts to 0.24
to 0.43 percent of the dry weight of the leaves.

Mainstream smoke of nonfilter cigarettes contains between 0.7 and
1.2 mg of nonvolatile alkanes, depending on the type of tobacco leaves
used as cigarette filler. When diluents such as reconstituted tobacco
sheets, stems, or expanded tobacco are incorporated into the cigarette
blend, the content of nonvolatile alkanes decreases accordingly. These
nonvolatile hydrocarbons are retained by filter tips to the same degree
as "tar" in general.

Studies with "C-labelled ndotriacontane have shown that about 25
percent of the radioactivity is recovered in the mainstream smoke and
75 percent in the sidestream smoke. Of the radioactivity in the
mainstream smoke, about 95 percent was given by the unchanged Gz-
hydrocarbon and 0.7 percent by CO+ Co2 and the rest by Cl to GO
compounds. Ndotriacontane did not contribute in any measurable
degree to the benzo(a)pyrene content in mainstream and sidestream
smoke (47').

So far, only a limited number of studies have been concerned with
the unsaturated hydrocarbons (GO to CSZ) in the mainstream smoke
particulate matter, because they amount to less than 0.02 percent of
the "tar." It appears that the nonvolatile acids, esters, and ketones in
the leaf serve as precursors for the alkenes in the smoke.

The alkanes and alkenes appear to play no major roie in tobacco
toxicity and carcinogenesis other than to influence the resorption of
smoke carcinogens. In studies on mouse skin, this effect was seen as an
inhibition of resorption, which delayed latency of tumor development
and diminished tumor yield.

Tobacco lsoprenoids

Tobacco and its smoke contain a large spectrum of isoprenoids; many
of them can be regarded as tobacco-specific.constituents (85). They are
important because they contribute to the organoleptic nature of

14-48


tobacco smoke and thereby add to the consumer acceptability of
specific tobacco products. The increasing volume of cigarettes with
reduced and low "tar" yield and the desire to produce tobacco
substitutes have given renewed impetus to chemical research on
tobacco flavor components, especially on tobacco isoprenoids, during
the last decade.

Primarily four types of terpenoids are found in tobacco: the
carotenoids and acyclic isoprenoids; the cytoplasmic triterpenoids and
phytosterols; the diterpenoids, which are biosynthesised in the
t&homes; the glandular hair of the leaves; and the cyclic sesquiterpe-
noids and monoterpenoids (Figure 4) (85). The concentration and
nature of these terpenoids in the leaf are not just dependent on plant
genetic factors and growth conditions but also on the curing and
fermentation processes that lead to the final tobacco product.

For the details on the chemistry and organoleptic nature of
individual tobacco &penes, the reader should refer to the specific
scientific literature (21, 82, 85, 100). At present, several hundred
isoprenoids have been isolated from tobacco. During smoking, some of
these compounds, especially the more volatile ones, are transferred
partially intact and appear also in the mainstream smoke as thermally
rearranged or oxidized decomposition products. Although it has been
demonstrated that the tobacco terpenoids represent an important part
of smoke flavor, little is known about their contribution to the toxicity
or tumorigenic properties of tobacco products. Some authors have
considered it possible that certain cyclic tobacco isoprenoids may be
active as tumor promoters (S6), while others have shown that cyclic
terpenes, upon pyrolysis, form relatively high concentrations of
carcinogenic polycylic hydrocarbons (100). At best, the data at hand are
inconclusive. Therefore, intensified research is needed on the possible
contribution of isoprenoids to smoke toxicity and tumorigenicity. The
importance of such a program is underscored by the fact that, today,
flavoring agents derived from tobacco and mixtures of plant extracts
are added to tobacco in order to make low "tar" cigarettes acceptable
to the consumer.

Benzenes and Naphthalenes

During all incomplete combustions of organic matter, small amounts of
aromatic hydrocarbons are formed. Like other plant materials, tobacco
already contains a number of compounds with the benzene ring
structure, such as hemicellulose, plant phenols and polyphenols, certain
amino acids, and a few terpenes (e.g., aromatized menthanes) (82, 85,
100). In addition, benzenes are pyrosynthesized from C,H-radicals and
by diene-synthesis reactions with subsequent dehydrogenation during
burning of the tobacco. It is, therefore, not surprising that cigarette
smoke contains more than two dozen benzene hydrocarbons, with
toluene (20 to 150 ~g/cigarette) and benzene itself (10 to 100 pg) as the

1449


o- OH

Memhol

FIGURE I.-Tobacco isoprenoids.

      CH3          =+3
                 I
H -E '
   cl42 - c=cn-cl42 3 CH~C=Ct+cu2C
                 6
      salaneeol

OH

14-50


most abundant compounds of this type. Most benzene compounds are
considered to be semivolatile and thus are present in both the gaseous
and the particulate phase.

Concern has been expressed in recent years about the possible risk of
leukemia for workers who have been exposed to benzene. This wncern
has led to a standard of 10 ppm as a threshold limit for benzene in the
working atmosphere. Although some prospective and retrospective
studies have reported a somewhat higher risk of leukemia for cigarette
smokers, these data remain unconfirmed and no dose.-response
relationship has been established between death rate from leukemia
and number of cigarettes smoked.

In model studies with W-labelled precursors, Badger and his group
showed that the probability of pyrosynthesis of polycyclic aromatic
hydrocarbons decreases with the number of condensed rings (3); thus,
tobacco smoke contains less naphthalene (2.0 to 3.5 pg/cigarette) than
toluene (20 to 150 Icg/cigarette) (6, 85, 100). Other naphthalenes
identified in cigarette smoke are ethylnaphthalenes, dimethylna-
phthalenes, and trimethylnaphthalenes . Neutral tobacco smoke
condensate fractions, which contain naphthalene and methylnaphthal-
enes and are free of three-ring and higher polycyclic hydrocarbons, are
inactive as carcinogens, co-carcinogens, and tumor initiators, as are the
pure compounds (77, 78). There has been some indication that
naphthalenes may induce lymphomas in mice; however, this finding
needs confirmation.

Polynuclear Aromatic Hydrocarbons (PAH)

Fractionation studies with tobacco "tar" have shown that only those
neutral fractions and subfractions in which the PAH are enriched
induce tumors on mouse skin and the bronchial epithelium of rats and
sarwmas in the connective tissues of rats (40, 83, 100). Minute
subfractions (<0.002 percent) of the "tar," containing only four-, five-,
and six- ring PAH, are the only fractions which show activity as tumor
initiators upon application in low doses. PAH alone, however, account
for only a small portion of the carcinogenicity of tobacco "tar." These
observations, and the fact that a significant reduction of PAH in the
smoke leads to a concomitant reduction of the tumorigenicity of the
total "tar" on mouse skin, are the major reasons for the extensive
chemical analytical studies and identification of tumorigenic PAH (83,
100). More than 100 individual four-ring and higher polycyclic
hydrocarbons have been identified to date. These include the
classical carcinogens benzo(a,)pyrene, dibenz(u,h)anthracene, and
dibenzo(a,h)pyrene as well as other PAH. The levels of carcinogenic
PAH in tobacco smoke are well below their practical threshold as
complete mouse skin carcinogens, but their role in tobacco smoke
condensate is definitely that of a tumor initiator.

14-51


Certain PAH are not active when tested as complete carcinogens,
but they are active as tumor initiators or as co-carcinogens when
applied as such. A major characteristic for a tumor initiator is that it
merely induces a dormant tumor cell, thus not eliciting tumors in
epithelial tissues unless the tissue is exposed to a promoting agent.
Promotors are active only in tissues previously treated with a tumor
initiator. A co-carcinogen is a chemical which is neither a tumor
initiator nor a complete carcinogen; it is, however, typically capable of
significantly increasing the carcinogenic response towards a low dose
of a carcinogen. Figure 5 presents the structural formulas of several
carcinogenic PAH, tumor-initiating PAH and co-carcinogenic PAH.
Table 15 lists the concentrations of some of the active PAH in cigarette
smoke. Since it has been demonstrated that most, though not all, of the
PAH are pyrosynthesized from C,H-radicals by the same mechanism
and from unspecific precursors, carcinogenic F~xP has often been used
as an indicator of the concentration of tumorigenic PAH in the smoke
of a given cigarette and cigar. The concentration of BaP in "tar" of
cigarettes made primarily from tobacco lamina has served as an
indicator of the carcinogenic potential of the smoke particulates on
mouse skin.

N-Heterocyclic Hydrocarbons (Aza-Arenes)

Although the nicotine-free basic portion of tobacco smoke is inactive as
a complete carcinogen, it contains traces of carcinogenic aza-arenes.
This group includes dibenz(a,h)acridine and dibenz(ad)acridine (Figure
6). Another aza-arene with carcinogenic activity is dibenzo(c,g)carba-
zole, which is found in the neutral portion (100). Van Duuren and
coworkers have shown in model studies that nicotine can serve as
precursor for these carcinogenic aza-arenes (94). So far, the basic
portion of tobacco smoke has not been found to be carcinogenic (40).
Mutagens thus far identified in cigarette smoke are: quinoline (MS 1.7
pg/cigarette; SS 18 pgjcigarette), all seven isomeric methylquinolines
(MS 0.7 pg/cigarette; SS 8 pg/cigarette), benzo@quinoline (MS 0.01
pg/cigarette; SS 0.1 pglcigarette), phenanthridine (MS 0.01
pg/cigarette; SS 0.01 pg/cigarette), and benzo(h)quinoline (MS 0.01
pg/cigarette; SS 0.1 pg/ cigarette) (84, 88). Quinoline induces
hepatomas when fed in high doses to rats (19,3Y, 83).

Phenols

The weakly acidic fraction of cigarette smoke condensate is active as
both a tumor promoter and co-carcinogen (13,100). It contains volatile
phenols, polyphenols, cyclopenteno!s, fatty acids, and pyridinols
(Figure 7). Among these, the catechols are of special interest as co-
carcinogens (95). At present, however, the major tumor promoters and
co-carcinogens in the weakly acidic fraction need identification.

14-52


00
6ip
00

  00
aP
00
         -43
  wh3twchrysene

0
%
00
0

FIGURE 5.-Some tumorigenic PAH in tdacco smoke.


TABLE 15.-Tumorigenic PAH in cigarette smoke'
                            Relative activity
                PAH                a9 complete
                               carcinogen*

ng/cig

hnzo(o)pyrene
5-Methylchryscne
Dihenz@,h)anthracene
Fknzo(b)fluoranthene
Benzo@fluoranthene
Dihenz&.k)pyrcne
Dihenz&~)pyrene
Indeno(1, 2, %cd)pyrcne
Ekw.o(e)phenanthrene
Bcnz(a)anthracene
Chryaene
~nzofe)pyFene
2, 3-Methylchrysene
l-, CMethylchrysene
ZMethylfluoranthene
3-Methylfluoranthene
Dihcnz@,c)anthracene

+++
+++
++
++
++
++
++
  +
  +
  +
- (+?)
- (+?)
  +

+
?
?

10-60
  0.6
40
30
60
Pfl
P@
s
4CHO
40-60
5-m
  7
10
30
40
PF'

Pyrene                                                 .FJwam
Methylpyrenes                                             rJo400
FIuoranthene                                             100-260
Eknm(g,h,i)perylene                                            60

%clative carcinogenic activity on mouse skin.
Treaent, but no quantitative data available.
SOURCE: Hoffman. D. (40).

Catechol is the phenol with the highest concentration in the smoke of
cigarettes. In the mainstream smoke of a plain cigarette it varies from
160 to 500 pg, and in the mainstream smoke of a filter cigarette it
ranges from 60 to 200 pg (10, 100). Smoke also contains a number of
alkylated catechols, hydroquinone, resorcinol, and volatile phenols. The
latter group appears to contribute only to a minor extent to the tumor-
promoting activity of the weakly acidic portion. Compared to
mainstream smoke, sidestream smoke of cigarettes contains less
catechol (SWMS 0.7-0.8) and more volatile phenols (SS/MS Z-3). It
appears that the major precursors for the smoke catechols reside in the
"wax" layer of the tobacco leaf and that the major precursors for the
smoke phenols are the tobacco carbohydrates.

Extensive investigations in several laboratories have demonstrated
highly selective filtration of semi-volatile phenols from cigarette
smoke by cellulose acetate filter tips (52, 61). Because of their low

14-54


    CM
m
00
      N

4-Melhylqunoline

Phenanlhrtdine