PREVENTIVE
MEDICINE
Reduction
8,
358-368 (1979)
of Carbon
Monoxide
G~oB.Goru*
AND RICHARD
in Cigarette
Smoke’
L. ELLIS~
*National Cancer Institute, Division of Cancer Cause and Prevention, National Institutes of Health, Bethesda, Maryland 20205, and tEnviro Control Inc., Prime Contractor, NC1 Smoking and Health Program, 11300 Rockville Pike, Rockville, Maryland 20852
Many studies have documented that cigarette smoking is associated with coronary heart disease and appears to be a significant risk factor contributing to its pathogenesis, especially in young and middle-aged people (1). Some experimental evidence seems to implicate carbon monoxide (CO) in the pathogenesis of atherosclerosis and, even though this association has not been proven conclusively, there is significant cause among those dedicated to smoking and health programs to work at reducing the delivery of CO from cigarettes for those people who continue to smoke despite all the warnings. To appreciate better the problems of reducing CO delivery in cigarettes, a brief review of the process of smoke generation from a tobacco cigarette is in order. Figure 1 illustrates the overall makeup and characteristics of the cigarette (19). The tobacco column is wrapped in a gas- and vapor-permeable membrane that allows air to flow into the tobacco column during puffing and gas and vapor components to diffuse during the smoldering cycle. A permeable or perforated wrapper is often used on the tip of a filter cigarette, which reduces pressure and air flow into the burning cone of the cigarette during the puffing cycle. The burning cone is relatively impermeable; the majority of the air enters the cigarette along the cone surface near the edge of the burning wrapper. Figure 1 also outlines the three zones used to describe the overall smoke generation process, which will be discussed shortly. Figure 2 describes a typical air flow pattern (2). The bulk of the inspired air enters along the perimeter of the burning cone. Thus, during the puff, tobacco at the outer periphery of the column is largely consumed and between puffs the interior portion of the tobacco column is preferentially consumed. As a puff is taken, the bulk of the incoming air flows at the periphery of the coal at the char line. The exothermic oxidation of carbon heats the gas stream that acts as an energy source for the subsequent reactions. In this high-temperature zone the products are mainly gaseous with CO and carbon dioxide incorporating more than 50% of the oxygen from atmospheric oxygen; the pyrolytic formation of CO accounts for about 43% of total CO formed (2, 6, 12, 19). In the pyrolysis distillation zone the energy provided by the oxygen-depleted ’ Presented at a Workshop American Health Foundation October 10-12, 1978.
on Carbon Monoxide and Cardiovascular Disease, sponsored by the and the Federal Health Office, Federal Republic of Germany, Berlin,
358 0091-7435/79/030358-l l-$02.00/0 Copyright 0 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
WORKSHOP: CARBON MONOXIDE HIGH TEMPERATURE ZON
’ 1 I
F’YRoclslS DISTlLLAT0N ZONE
; , I
AND CVD
359
TEW%LWtE ZWE
FIG. I. Schematic of the burning cigarette (Osdene, 1976) (19).
hot gas stream yields the high-boiling compounds that are the main sources of particulates, CO, carbon dioxide, organic gases, and distillation products. The overall sum of the reactions in this area is endothermic so the gas stream cools rapidly. Baker and Kilburn (5) have presented a rather detailed picture of the temperature profile as well as the CO distribution within the combustion coal in Fig. 3. The oxygen contours show that the interior of the coal is an oxygen-deficient region; thus with oxygen in the air being unable to penetrate into this region of carbonized tobacco, the interior is largely a pyrolytic region. Probably, the major quantitative effect of oxygen is to produce carbon dioxide, CO, water, and heat. Examination of the contour diagram shows that CO production reaches a maximum in the high-temperature zone. Figure 4 describes CO production as a function of distance from the char line (5, 11). As a consequence of this type of analysis, Lanzillotti and Wayte (13) described a one-dimensional combustion profile as shown in Fig. 5 (2). Again, in zone 1, CO and carbon dioxide are formed by carbon oxidation. Hydrogen is liberated, and this results in a reducing atmosphere. In zone 2, air enters the rod around the coal and some CO is oxidized to carbon dioxide. In zone
FIG. 2. Probable air flow patterns into the combustion zone of a cigarette during a puff. Thickness of arrow is proportional to magnitude of air flow (Baker, 1975) (2).
360
GORI AND ELLIS TEMPERATUIE T omwl
so
0
30 LENGTH &JfW
bun)
FIG. 3. Gas concentration (% vv) contours (Baker and Kilbum) (5).
3, carbon dioxide is reduced to CO over the hot char; in zone 4, CO and carbon dioxide are formed by pyrolysis; in zone 5, the gases diffuse isothermally into and out of the cigarette rod. It should be mentioned here that several factors ultimately determine the qualitative and quantitative smoke composition. The major factors affecting the profile of the burning cigarette include the physical form (length and circumference) of the cigarette, filler materials, tobacco type or blend, width and/or type of tobacco cut, packing density, additives, moisture content, permeability of the cigarette rod and mouth-piece tipping paper, and the filter makeup (i.e., fiber material, plasticizers, additives, draw resistance, construction, and perforation) (24). Burton (8), for example, concludes that the heated cellulosic materials of tobacco are the major precursors of pyrolytic CO. More than 90% of the weight of the total mainstream smoke effluent is accounted for by the gas phase, where nitrogen and oxygen account for more than 70%. The mainstream smoke of a typical United States commercial nonfilter cigarette contains about 17.0 mg of CO (5.5 ~01%) and 60 mg of COO(14.5 ~01%) (7, 10,21). Especially low CO values have been reported for cigarettes with perforated filter tips (10). Both CO and CO, yields increase linearly with ascending puff
WORKSHOP: CARBON MONOXIDE
Distance
FIG.
AND CVD
361
from char line in cm
4. Smoothed concentration curve for carbon monoxide (Lanzillotti and Wayte, 1975(13).
number. It should be mentioned also that leaves from the lower stalk positions generate significantly less CO and CO, than do leaves from the upper stalk positions of the same tobacco plant (7). The amount of tobacco consumed during puffing and during smoldering depends on the static burning temperature and on the same parameters that help determine the mainstream smoke formation and composition. Generally, however, the mainstream smoke effluent of a cigarette smoked to a 30-mm butt length amounts to about 500 mg. The interrelationships involved in cigarette smoke may be described by the general equation shown in Table 1 (9). From this material balance, one can suggest that reducing the pyrolytic and distillation effects and increasing the efficiency of complete combustion would decrease the yield of total particulate matter and increase the weight of the gas phase. However, to be effective in reducing the CO levels, carbon dioxide should be the carbon oxide produced. Baker (2, 5) has studied this approach and has found that the CO yield is dependent on the heating rate, although the total yield of carbon oxides is a constant; thus, an increase in carbon dioxide would result in a decreased CO level. We believe that technology generally is available to reduce substantially the delivery of the 20 gas vapor cigarette smoke components judged as health hazards, and of CO in particular. Tigglebeck (23) has commented, however, that the 3-6 ~01% CO in delivered cigarette smoke has proven to be a greater challenge to cigarette designers than have other vapor-phase components. For example, attacking CO by filtration of filter catalysis is an exercise in futility. Catalytic oxidation to carbon dioxide is limited by several factors including catalyst contact time, mild temperature and pressure conditions, and catalyst poisoning. Using adsor-
3
I -1
fhfance FIG.
0
from
1
2
3
4
.
5
char hne m cm
5. Combustion profile (Lanzillotti and Wayte) (13).
362
GORI AND ELLIS TABLE 1 THE INTERRELATIONSHIPS
INVOLVED
IN CIGARETTE
SMOKE
Weight of ash produced during puffs +Mainstream TPM weight +Mainstream gas phase weight -Mainstream entrained gas weight -Mainstream combustion oxygen weight = Weight of cigarette burned during puffs
bants such as bovine hemoglobin seems impractical from the standpoint of the large quantity necessary. There are approaches, however, which are feasible-principally air dilution filtration. Reduction of heating rates is another technique. For example, at low heating rates, the yield of CO is almost half that at high rates (2). The quantities produced are consistent with that expected by the oxidation mechanism and estimated from the oxygen isotope studies. Since the oxidative formation of CO is dependent on heating rate, it may be suggested that this mechanism might be utilized to decrease the CO yield of a cigarette. Mikami et al. (16) have also reported that the CO/CO, ratio found in smoke is a function of the rate at which air is drawn over the burning cone surface during puffing. Their data on varying puff volume at constant duration are shown in Table 2. The data illustrate that the concentration of CO increases at a faster rate than the concentration of carbon dioxide on increased puff volume. Of course, puff volume, in this case, is directly proportional to volume of air flowing over the cone surface per unit time. The same phenomenon may be observed when the air flow rate over the cone surface is changed by the amount of air entering through the wrapper. In the simplest case, there is less air flow over the cone surface on the first puff of a cigarette than the last puff. Brunnemann and Hoffmann (7) recently reported the sequential per-puff yields of CO and carbon dioxide. Although both components rise in a linear fashion with puff number, due to decreasing air dilution as the wrapper is consumed, CO rises at a faster rate than carbon dioxide with increasing
TABLE 2 EFFECT
Puff volume 10 14 20 25 30 35 45 ” Mikami et al. (16).
OF PUFF VOLUME
ON CO/CO,”
co/co*
(v/v)
0.28 0.25 0.40 0.39 0.39 0.50 0.50
WORKSHOP: CARBON MONOXIDE
363
AND CVD
puff number. CO increases 2.1 times from puffs 1 to 10, whereas carbon dioxide increases only 1.5 times. Highly permeable paper also creates a different thermal profile: It changes the oxygen concentration and flow in the fire cone region, altering the combustion process; it creates an opportunity for entry of puff-diluting air and diffusion of CO out of the cigarette rod. Tigglebeck suggests that the diffusion contribution diminishes as the cigarette burns shorter but that dilution may remain fairly constant due to a slightly decreasing tobacco resistance, although there is not uniform agreement on this point. Condensation may increase the tobacco-rod resistance, diminishing the effect of the shorter cigarette rod. However, with increasing air dilution, carbon monoxide is selectively reduced compared with tar and carbon dioxide (18, 20, 23). Rickards and Owens (20) also have observed the same relationships with lineperforated cigarette paper, a tobacco wrapper with minute perforations along the length of the cigarette rod. A representative sampling of data, using various techniques of air dilution, is shown in Table 3. The estimated degree of ventilation is determined by comparing the CO delivery with that of an appropriate control cigarette. The control cigarettes in this study were all made with a cigarette wrapper of similar porosity and permeability. This also allows one to make comparisons between the three different air-dilution techniques. As the table shows, the reduction in CO delivery is greater than the decrease in tobacco burned during puffing, due to the particular air-dilution technique. For example, where the ventilation of a cigarette is 52%, the CO reduction is 67%. The effect on carbon dioxide delivery however is not as clear-cut. It is possible that a decrease in CO may arise from both the decrease in tobacco
TABLE 3 REPRESENTATIVE
DATA
OBTAINED
BY USING
VARIOUS
TECHNIQUES
OF AIR DILUTION
Ventilation (%)
co (mfd
co* (mg)
Filter cigarette A perforated tip Filter cigarette A unperforated Percentage of unventilated
22
10.6
35.1
13.6
43.5
79
81
Cigarette B with open perforated tip Cigarette B unperforated Percentage of unventilated
43
Cigarette C with lineperforated paper Cigarette C without line perforations Percentage of unventilated
52
Sample
8.7
30.7
17.2
52.3
50.6
58.8
5.6
30.4
17.1
57.4
33
51.3
364
GORI AND ELLIS
burned during puffing and the decrease in pyrolytically formed CO associated with a decreased air flow rate over the surface of the burning cone and a corresponding reduced rate of heating in the oxidation of the carbonaceous residue. The tobacco wrapper also can affect the CO yield by a mechanism not directly attributable to the ventilation effects. That is, it can be manipulated to affect the amount of tobacco burned during puffing by its influence on static bum rate. Figure 6, reproduced from a paper by Mattina and Selke (IS), describes the effects of the various paper treatments on CO yield. With the citrate additive, the expected trend is increased yield of CO per puff with increased static burn or tobacco consumed per puff. As shown in the figure the increased number of puffs at the lower static bum rates causes a general increase on a per-cigarette basis. The unusual finding in this study is the rapid increase in CO yield on increasing phosphate additives in the paper. Although the authors do not suggest a mechanism for the high yield of CO from such treated paper, it is possible that the phosphatetreated paper results in an interference by phosphate in the air oxidation of the carbonaceous residue to carbon dioxide. The combined increase of CO + CO, is on the order of IO%, in line with the decrease in burn rate of the cigarette. Recent studies by Baker and co-workers (3, 4) examined the effects of paper permeability. As a result of these studies, a better understanding of the diffusion process was obtained. Specifically, they concluded that diffusion is a dynamic three-stage process: radial diffusion through the tobacco rod, diffusion through the paper cover, and diffusion away from the outer surface of the paper. By measuring the diffusion rates, they concluded that the diffusion rate through the paper was about twice that of diffusion through the cigarette rod. In addition, they noted that the gas composition at any given position inside the cigarette is dependent on the net chemical production of the gas and the net rate of diffusive and convective flow through any particular region.
CARBON
MONOXIDE
DELIVERY vs. FREE BURN TIME
I
2.40 2.60 t
o.-L
d
0 e 0 0 V A
CITRATE PHOSPHATE UNTREATED ALUMlNUl CHLORIDE UREA &AMINO ACIOS
y MINUTES
?
0
1p
1:
l?
PER 40 MM
FIG. 6. Carbon monoxide delivery vs free burn time (Mattina and Selke, 1975)(IS).
WORKSHOP: CARBON MONOXIDE
365
AND CVD
The extent to which air can infiltrate the paper or channel between the burning cone and the paper also seems to be a significant factor affecting the combustion products (22). Terre11 and Schultz noted that changing the permeability of the paper, changing the effective length of the cigarette, or re-orienting the packing of the tobacco within the cigarette, provides the means for regulating this channeling effect. Perforation holes, either in the paper wrapper or in the filter of a filtered cigarette, accomplishes a similar effect; less air is drawn through the combustion zone, thereby lowering the average burn temperature as well as providing a greater number of puffs. Thus, recent studies have shown that the mainstream CO yield is a function of the amount of tobacco burned during pufftng, the concentration of the pyrolytic precursors, the heating rate of the tobacco during puffing, and the permeability of the wrapper toward outward diffusion of CO. Modification of these parameters may lead to reduced yields of CO. Condensation or adsorption of the gas on the filter or unburned tobacco column does not occur to any significant degree and is not a variable affecting the CO yield. With good reason, one might ask how effectively these studies have been reduced to practice. Using the technology available, cigarette yields of tar, as well as CO, of less than 10 mg tar and 10 ml CO have been obtained in several cigarette brands. Interestingly, there seems to be a remarkably good linear correlation between tar yield and CO yield. This may be graphically demonstrated in Fig. 7 in which CO yield is plotted against tar yield. Thus, as tar yields of manufactured cigarettes have been declining in the last decade, CO levels appear to have declined as well. What effects these reduced yields may have regarding smokingrelated diseases is still speculative; however, based simply on a policy of prudence , it is an encouraging trend. The National Cancer Institute has prepared and analyzed approximately 94
Y
l
(I
+
01X
co r+ I
n-
2.SSSSS375171 B6.749942940425
+1.!N
R-SQUARE 6.916566612526 RES ERROR 1.84471943351 llAX> 3.16564208124
+;.ee
x
+e.se
,
Ie.ee
te.se
ti.00
*i.se
.+z.ee TAR -
. E *I
,
FIG. 7. Correlation of tar yield and CO emission in a sample of commercial cigarettes.
366
GORI AND
ELLIS
cigarette variations in four separate studies to define characteristics of less hazardous cigarettes. In these four sets of experimental cigarettes, a standard experimental blend cigarette (SEB) was used for comparative purposes; its composition was based on the 1970 sales-weighted averages of various tobacco types including reconstituted tobacco sheet (RTS). In each experiment, the tobaccos used for preparing the SEB cigarettes were from that year’s crop. Table 4 describes those experimental cigarettes with at least a 25% reduction in CO delivery, compared with the SEB delivery, on a per-puff basis. In Series III, we have three examples where very high porosity paper and/or an air-dilution filter have reduced CO yield. You may also note that the combined effect is greater than either that of the very high porosity paper or the air-dilution filter. In Series IV, two experimental blends, composed of 27% reconstituted sheet with 60% calcium carbonate filler and 13% additive, gave reduced delivery of CO, literally due to a reduction in the amount of fuel per cigarette. Three artificial tobacco substitutes in Series IV also gave reduced CO yields comparable to the deliveries shown in Series II and III experiments. What about trends in the future? Paper permeability technology is likely to be as important in the future as it has been to date. If dilution air flow through permeable cigarette paper can be increased suffrciently, there may be a tendency to increase the proportion of outward diffusion through the same porous openings. Since this outward diffusion of CO as well as other gases should have no effect on smoker acceptance of the product, it might be useful to provide a major part of the total dilution through conventional filter perforations, and then to experiment with papers of greater and greater permeability, produced to retain mechanical strength by using either electrical or laser technology, to generate the perforated paper (23). The goal would be to maximize the diffusion portion of the diffusion:dilution process along the tobacco column, TABLE 4 EXPERIMENTAL
Series
Delivery/puff (ml)
I II III
0.60
1.23 1.22 0.88
0.64
IV
0.83 0.52 0.49 1.21 1.22 0.62 1.04
1.11
CIGARETTES
WITH
Low
CO DELIVERY
Description SEB I, flue-cured laminae only Artificial tobacco substitute SEB III, very high porosity paper SEB III, with dilution filter SEB III, with dilution filter and very high porosity paper ATS-A and SEB III, 30/70, dilution filter ATS-B SEB IV, RTS (27%), 60% CaCO,, 13% additives, IPA-H,O azeotrope Bright leaf with full return of stems Burley leaf with full return of stems SEB IV, RTS (27%), 60% CaCO, Pesticide-free treated tobacco (Virginia 115) Pesticide-treated tobacco (Virginia 115)
WORKSHOP: CARBON MONOXIDE
AND CVD
367
enhanced by the slower actual smoke flow rate produced by filter dilution, but still not exceeding a level of dilution beyond consumer acceptability. It can be seen that certain methods available to reduce CO yields may influence the levels of carbon dioxide while others may not. Methods of converting monoxide to dioxide chemically obviously produce an inverse relationship, while diffusion and dilution would likely produce changes in the delivered portions of both oxides and could reduce both. However, the selection of methodology, such as a judgment on the relative importance of each oxide or its effects on other smoke components such as pH, must be made. Morie (17) has reported very recently on a cigarette equipped with a vented filter that gave lower CO levels than predicted by air dilution alone. The decrease in CO levels resulted primarily from increased CO diffusion through the cigarette wrapper paper as the linear velocity of the mainstream smoke was lowered by vents in the filter. Thus, the use of a vented filter and permeable paper may be an excellent combination for decreasing the CO concentration in smoke. Paper treatment is another alternative (14). The best CO:tar ratio is likely obtained through chemically untreated wrapper paper although this paper gives an unappealing ash (see Fig. 6). Alternatives may be found to overcome this drawback. Furthermore, alternative wrappers may bring about the specific reduction of CO by modifying the combustion process. Inorganic fillers for reconstituted tobacco sheet or other types of tobacco leaf may be possible, having advantageous properties compared with the presently preferred inorganic fillers such as bentonite-hydrated clays or calcium carbonate. We must not look back on our achievements to date. Methods should continue to be developed for improving the tobacco, modifying tobacco sheet technology, and developing improved high-permeability paper; improvement of smokedilution devices and better fillers also should be encouraged. Technological achievements have been encouraging in reducing CO levels in cigarette smoke and they provide us with a sound foundation on which to build future improvements. Clearly, although the specific role of CO in the pathogenesis of atherosclerosis is not precisely defined, the reduction of this acutely toxic smoke component seems to be a desirable and prudent objective. REFERENCES I. Aronow, W. S., Introduction to smoking and cardiovascular disease, in “Proceedings of the Third World Conference on Smoking and Health, Vol. 1, New York, June 2-5, 1976” (E. L. Wynder, D. Hoffmann, and G. B. Gori, Eds.), pp. 231-236. DHEW Publication No. (NIH) 76-1221, 1976. 2. Baker, R. R., Formation of the oxides of carbon by the pyrolysis of tobacco. Eeitr. Tabakforsch. 8, 16 (1975). 3. Baker, R. R., Combustion and thermal decomposition regions inside a burning cigarette. Combust. Flame 30, 21-32 (1977). 4. Baker, R. R., and Crellin, R. A., The diffusion of CO out of cigarettes. Be&. Tabakforsch. 91, 131-140 (1977). 5. Baker, R. R., and Kilbum, K. D., The distribution of gases within the combustion coal of a cigarette. Eeirr. Tabakforsch. 7, 79 (1973). 6. Baxter, J. E., and Hobbs, M. E., Cigarette smoking studies using oxygen isotopes. I. CO* and CO produced by combustion. Tob. Sci. 11, 65 (1967).
368
GORI AND
ELLIS
7. Brunnemann, K. D., and Hoffmann, D., Chemical studies on tobacco smoke. XXIV. A quantitative method for carbon monoxide and carbon dioxide in cigarette and cigar smoke. J. Chron. sci. 12, 70-75 (1974).
8. Burton, H. R., Thermal decomposition of tobacco. V. Influence of temperature on the formation of carbon monoxide and carbon dioxide. E&r. Tnbakforsch. 8,78 (1975). 9. Gori, G. B., Reduction of TPM in smoke, in “Proceedings of the Third World Conference on Smoking and Health, Vol. I, New York, June 2-5, 1975” (E. L. Wynder, D. Hoffmann, and G. B. Gori, Eds.), pp. 451-461. DHEW Publication No. (NIH) 76-1221, 1976. IO. Greist, W. M., Quincy, R. B., and Guerin, M. R., “Selected Constituents in the Smoke of Domestic Low Tar Cigarettes,” p. 20. Report ORNL/TM-6144/Pl, Oak Ridge National Laboratory, December, 1977. II. Johnson W. R. The pyrogenesis and physicochemical nature of tobacco smoke, in, “Tobacco Smoke. Its Formation and Composition.” 31st Tobacco Chemists’ Research Conference, Greensboro, North Carolina, October 5-7, 1977. 12. Johnson, W. R., Powell, D. H., Hole, R. W., and Komfeld, R. A., Incorporation of atmosphere oxygen into components of cigarette smoke. Chem. Ind. 12, 521 (1975). 13. Lanzillotti, H. V. and Wayte, A. R., One dimensional gas concentration profiles within a burning cigarette during a puff. Beirr. Tubakforsch. 8, 219-224 (1975). 14. Mattina, C. F., Personal communication, October, 1978. 15. Mattina, C. F., and Selke, W. A., “The Influence of the Cigarette Wrapper on the Delivery of Oxides of Carbon in Mainstream Smoke.” Presented at 29th Tobacco Chemists’ Research Conference, College Park, Maryland, October, 1975. 16. Mikami, Y., Narto, N., and Kaburaki, Y., Effects of some factors on carbon monoxide concentration in the mainstream of smoke. Japan Monopoly Corp. Central Res. Znsf. 113, 99 (1971). 17. Morie, G. P., Some factors that affect the diffusion of carbon monoxide out of cigarettes. Tob. Sci. 20, I74- 176 (1976). 18. Norman, V., The effects of perforated tipping paper on the yield of various smoke components. Beitr. Tabakforsch. 7, 282-287 (1974). 19. Osdene, T. S. Reaction mechanisms on the burning cigarette, in “The Recent Chemistry of Natural Products Including Tobacco. Proceedings of the Second Philip Morris Science Symposium” (N. J. Fina, Ed.) Philip Morris, Inc., New York, 1976. 20. Rickards, J. C., and Owens, W. J., “Effect of Porous Cigarette Papers on the Yield of the Major Vapor Phase and Certain Particulate Phase Components of Cigarette Smoke,” p. 25. Presented at the 20th Tobacco Chemists’ Research Conference, Winston-Salem, North Carolina, November I-3, 1966. 21. Ross, W. S., Poison gases in your cigarette: Carbon monoxide. Reader’s Digest, 115-I I8 (October, 1976). 22. Terrell, J. H., and Schmeltz, I., Alteration of cigarette smoke composition. II. Influence of cigarette design. Tob. Sci. 14, 82-85 (1970). 23. Tigglebeck, D., Vapor phase smoke modification-an under utilized technology, in. “Proceedings of the Third World Conference on Smoking and Health, Vol. I, New York, June 2-5, 1975” (E. L. Wynder, D. Hoffmann and G. B. Gori, Eds.), pp. 507-514. DHEW Publication No. (NIH) 76-1221, 1976. 24. U.S. Public Health Service. “The Health Consequences of Smoking, 1979. Cigarette Smoke.” U.S. Department of Health, Education and Welfare, Washington D.C., in press.
MEDICINE
Reduction
8,
358-368 (1979)
of Carbon
Monoxide
G~oB.Goru*
AND RICHARD
in Cigarette
Smoke’
L. ELLIS~
*National Cancer Institute, Division of Cancer Cause and Prevention, National Institutes of Health, Bethesda, Maryland 20205, and tEnviro Control Inc., Prime Contractor, NC1 Smoking and Health Program, 11300 Rockville Pike, Rockville, Maryland 20852
Many studies have documented that cigarette smoking is associated with coronary heart disease and appears to be a significant risk factor contributing to its pathogenesis, especially in young and middle-aged people (1). Some experimental evidence seems to implicate carbon monoxide (CO) in the pathogenesis of atherosclerosis and, even though this association has not been proven conclusively, there is significant cause among those dedicated to smoking and health programs to work at reducing the delivery of CO from cigarettes for those people who continue to smoke despite all the warnings. To appreciate better the problems of reducing CO delivery in cigarettes, a brief review of the process of smoke generation from a tobacco cigarette is in order. Figure 1 illustrates the overall makeup and characteristics of the cigarette (19). The tobacco column is wrapped in a gas- and vapor-permeable membrane that allows air to flow into the tobacco column during puffing and gas and vapor components to diffuse during the smoldering cycle. A permeable or perforated wrapper is often used on the tip of a filter cigarette, which reduces pressure and air flow into the burning cone of the cigarette during the puffing cycle. The burning cone is relatively impermeable; the majority of the air enters the cigarette along the cone surface near the edge of the burning wrapper. Figure 1 also outlines the three zones used to describe the overall smoke generation process, which will be discussed shortly. Figure 2 describes a typical air flow pattern (2). The bulk of the inspired air enters along the perimeter of the burning cone. Thus, during the puff, tobacco at the outer periphery of the column is largely consumed and between puffs the interior portion of the tobacco column is preferentially consumed. As a puff is taken, the bulk of the incoming air flows at the periphery of the coal at the char line. The exothermic oxidation of carbon heats the gas stream that acts as an energy source for the subsequent reactions. In this high-temperature zone the products are mainly gaseous with CO and carbon dioxide incorporating more than 50% of the oxygen from atmospheric oxygen; the pyrolytic formation of CO accounts for about 43% of total CO formed (2, 6, 12, 19). In the pyrolysis distillation zone the energy provided by the oxygen-depleted ’ Presented at a Workshop American Health Foundation October 10-12, 1978.
on Carbon Monoxide and Cardiovascular Disease, sponsored by the and the Federal Health Office, Federal Republic of Germany, Berlin,
358 0091-7435/79/030358-l l-$02.00/0 Copyright 0 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
WORKSHOP: CARBON MONOXIDE HIGH TEMPERATURE ZON
’ 1 I
F’YRoclslS DISTlLLAT0N ZONE
; , I
AND CVD
359
TEW%LWtE ZWE
FIG. I. Schematic of the burning cigarette (Osdene, 1976) (19).
hot gas stream yields the high-boiling compounds that are the main sources of particulates, CO, carbon dioxide, organic gases, and distillation products. The overall sum of the reactions in this area is endothermic so the gas stream cools rapidly. Baker and Kilburn (5) have presented a rather detailed picture of the temperature profile as well as the CO distribution within the combustion coal in Fig. 3. The oxygen contours show that the interior of the coal is an oxygen-deficient region; thus with oxygen in the air being unable to penetrate into this region of carbonized tobacco, the interior is largely a pyrolytic region. Probably, the major quantitative effect of oxygen is to produce carbon dioxide, CO, water, and heat. Examination of the contour diagram shows that CO production reaches a maximum in the high-temperature zone. Figure 4 describes CO production as a function of distance from the char line (5, 11). As a consequence of this type of analysis, Lanzillotti and Wayte (13) described a one-dimensional combustion profile as shown in Fig. 5 (2). Again, in zone 1, CO and carbon dioxide are formed by carbon oxidation. Hydrogen is liberated, and this results in a reducing atmosphere. In zone 2, air enters the rod around the coal and some CO is oxidized to carbon dioxide. In zone
FIG. 2. Probable air flow patterns into the combustion zone of a cigarette during a puff. Thickness of arrow is proportional to magnitude of air flow (Baker, 1975) (2).
360
GORI AND ELLIS TEMPERATUIE T omwl
so
0
30 LENGTH &JfW
bun)
FIG. 3. Gas concentration (% vv) contours (Baker and Kilbum) (5).
3, carbon dioxide is reduced to CO over the hot char; in zone 4, CO and carbon dioxide are formed by pyrolysis; in zone 5, the gases diffuse isothermally into and out of the cigarette rod. It should be mentioned here that several factors ultimately determine the qualitative and quantitative smoke composition. The major factors affecting the profile of the burning cigarette include the physical form (length and circumference) of the cigarette, filler materials, tobacco type or blend, width and/or type of tobacco cut, packing density, additives, moisture content, permeability of the cigarette rod and mouth-piece tipping paper, and the filter makeup (i.e., fiber material, plasticizers, additives, draw resistance, construction, and perforation) (24). Burton (8), for example, concludes that the heated cellulosic materials of tobacco are the major precursors of pyrolytic CO. More than 90% of the weight of the total mainstream smoke effluent is accounted for by the gas phase, where nitrogen and oxygen account for more than 70%. The mainstream smoke of a typical United States commercial nonfilter cigarette contains about 17.0 mg of CO (5.5 ~01%) and 60 mg of COO(14.5 ~01%) (7, 10,21). Especially low CO values have been reported for cigarettes with perforated filter tips (10). Both CO and CO, yields increase linearly with ascending puff
WORKSHOP: CARBON MONOXIDE
Distance
FIG.
AND CVD
361
from char line in cm
4. Smoothed concentration curve for carbon monoxide (Lanzillotti and Wayte, 1975(13).
number. It should be mentioned also that leaves from the lower stalk positions generate significantly less CO and CO, than do leaves from the upper stalk positions of the same tobacco plant (7). The amount of tobacco consumed during puffing and during smoldering depends on the static burning temperature and on the same parameters that help determine the mainstream smoke formation and composition. Generally, however, the mainstream smoke effluent of a cigarette smoked to a 30-mm butt length amounts to about 500 mg. The interrelationships involved in cigarette smoke may be described by the general equation shown in Table 1 (9). From this material balance, one can suggest that reducing the pyrolytic and distillation effects and increasing the efficiency of complete combustion would decrease the yield of total particulate matter and increase the weight of the gas phase. However, to be effective in reducing the CO levels, carbon dioxide should be the carbon oxide produced. Baker (2, 5) has studied this approach and has found that the CO yield is dependent on the heating rate, although the total yield of carbon oxides is a constant; thus, an increase in carbon dioxide would result in a decreased CO level. We believe that technology generally is available to reduce substantially the delivery of the 20 gas vapor cigarette smoke components judged as health hazards, and of CO in particular. Tigglebeck (23) has commented, however, that the 3-6 ~01% CO in delivered cigarette smoke has proven to be a greater challenge to cigarette designers than have other vapor-phase components. For example, attacking CO by filtration of filter catalysis is an exercise in futility. Catalytic oxidation to carbon dioxide is limited by several factors including catalyst contact time, mild temperature and pressure conditions, and catalyst poisoning. Using adsor-
3
I -1
fhfance FIG.
0
from
1
2
3
4
.
5
char hne m cm
5. Combustion profile (Lanzillotti and Wayte) (13).
362
GORI AND ELLIS TABLE 1 THE INTERRELATIONSHIPS
INVOLVED
IN CIGARETTE
SMOKE
Weight of ash produced during puffs +Mainstream TPM weight +Mainstream gas phase weight -Mainstream entrained gas weight -Mainstream combustion oxygen weight = Weight of cigarette burned during puffs
bants such as bovine hemoglobin seems impractical from the standpoint of the large quantity necessary. There are approaches, however, which are feasible-principally air dilution filtration. Reduction of heating rates is another technique. For example, at low heating rates, the yield of CO is almost half that at high rates (2). The quantities produced are consistent with that expected by the oxidation mechanism and estimated from the oxygen isotope studies. Since the oxidative formation of CO is dependent on heating rate, it may be suggested that this mechanism might be utilized to decrease the CO yield of a cigarette. Mikami et al. (16) have also reported that the CO/CO, ratio found in smoke is a function of the rate at which air is drawn over the burning cone surface during puffing. Their data on varying puff volume at constant duration are shown in Table 2. The data illustrate that the concentration of CO increases at a faster rate than the concentration of carbon dioxide on increased puff volume. Of course, puff volume, in this case, is directly proportional to volume of air flowing over the cone surface per unit time. The same phenomenon may be observed when the air flow rate over the cone surface is changed by the amount of air entering through the wrapper. In the simplest case, there is less air flow over the cone surface on the first puff of a cigarette than the last puff. Brunnemann and Hoffmann (7) recently reported the sequential per-puff yields of CO and carbon dioxide. Although both components rise in a linear fashion with puff number, due to decreasing air dilution as the wrapper is consumed, CO rises at a faster rate than carbon dioxide with increasing
TABLE 2 EFFECT
Puff volume 10 14 20 25 30 35 45 ” Mikami et al. (16).
OF PUFF VOLUME
ON CO/CO,”
co/co*
(v/v)
0.28 0.25 0.40 0.39 0.39 0.50 0.50
WORKSHOP: CARBON MONOXIDE
363
AND CVD
puff number. CO increases 2.1 times from puffs 1 to 10, whereas carbon dioxide increases only 1.5 times. Highly permeable paper also creates a different thermal profile: It changes the oxygen concentration and flow in the fire cone region, altering the combustion process; it creates an opportunity for entry of puff-diluting air and diffusion of CO out of the cigarette rod. Tigglebeck suggests that the diffusion contribution diminishes as the cigarette burns shorter but that dilution may remain fairly constant due to a slightly decreasing tobacco resistance, although there is not uniform agreement on this point. Condensation may increase the tobacco-rod resistance, diminishing the effect of the shorter cigarette rod. However, with increasing air dilution, carbon monoxide is selectively reduced compared with tar and carbon dioxide (18, 20, 23). Rickards and Owens (20) also have observed the same relationships with lineperforated cigarette paper, a tobacco wrapper with minute perforations along the length of the cigarette rod. A representative sampling of data, using various techniques of air dilution, is shown in Table 3. The estimated degree of ventilation is determined by comparing the CO delivery with that of an appropriate control cigarette. The control cigarettes in this study were all made with a cigarette wrapper of similar porosity and permeability. This also allows one to make comparisons between the three different air-dilution techniques. As the table shows, the reduction in CO delivery is greater than the decrease in tobacco burned during puffing, due to the particular air-dilution technique. For example, where the ventilation of a cigarette is 52%, the CO reduction is 67%. The effect on carbon dioxide delivery however is not as clear-cut. It is possible that a decrease in CO may arise from both the decrease in tobacco
TABLE 3 REPRESENTATIVE
DATA
OBTAINED
BY USING
VARIOUS
TECHNIQUES
OF AIR DILUTION
Ventilation (%)
co (mfd
co* (mg)
Filter cigarette A perforated tip Filter cigarette A unperforated Percentage of unventilated
22
10.6
35.1
13.6
43.5
79
81
Cigarette B with open perforated tip Cigarette B unperforated Percentage of unventilated
43
Cigarette C with lineperforated paper Cigarette C without line perforations Percentage of unventilated
52
Sample
8.7
30.7
17.2
52.3
50.6
58.8
5.6
30.4
17.1
57.4
33
51.3
364
GORI AND ELLIS
burned during puffing and the decrease in pyrolytically formed CO associated with a decreased air flow rate over the surface of the burning cone and a corresponding reduced rate of heating in the oxidation of the carbonaceous residue. The tobacco wrapper also can affect the CO yield by a mechanism not directly attributable to the ventilation effects. That is, it can be manipulated to affect the amount of tobacco burned during puffing by its influence on static bum rate. Figure 6, reproduced from a paper by Mattina and Selke (IS), describes the effects of the various paper treatments on CO yield. With the citrate additive, the expected trend is increased yield of CO per puff with increased static burn or tobacco consumed per puff. As shown in the figure the increased number of puffs at the lower static bum rates causes a general increase on a per-cigarette basis. The unusual finding in this study is the rapid increase in CO yield on increasing phosphate additives in the paper. Although the authors do not suggest a mechanism for the high yield of CO from such treated paper, it is possible that the phosphatetreated paper results in an interference by phosphate in the air oxidation of the carbonaceous residue to carbon dioxide. The combined increase of CO + CO, is on the order of IO%, in line with the decrease in burn rate of the cigarette. Recent studies by Baker and co-workers (3, 4) examined the effects of paper permeability. As a result of these studies, a better understanding of the diffusion process was obtained. Specifically, they concluded that diffusion is a dynamic three-stage process: radial diffusion through the tobacco rod, diffusion through the paper cover, and diffusion away from the outer surface of the paper. By measuring the diffusion rates, they concluded that the diffusion rate through the paper was about twice that of diffusion through the cigarette rod. In addition, they noted that the gas composition at any given position inside the cigarette is dependent on the net chemical production of the gas and the net rate of diffusive and convective flow through any particular region.
CARBON
MONOXIDE
DELIVERY vs. FREE BURN TIME
I
2.40 2.60 t
o.-L
d
0 e 0 0 V A
CITRATE PHOSPHATE UNTREATED ALUMlNUl CHLORIDE UREA &AMINO ACIOS
y MINUTES
?
0
1p
1:
l?
PER 40 MM
FIG. 6. Carbon monoxide delivery vs free burn time (Mattina and Selke, 1975)(IS).
WORKSHOP: CARBON MONOXIDE
365
AND CVD
The extent to which air can infiltrate the paper or channel between the burning cone and the paper also seems to be a significant factor affecting the combustion products (22). Terre11 and Schultz noted that changing the permeability of the paper, changing the effective length of the cigarette, or re-orienting the packing of the tobacco within the cigarette, provides the means for regulating this channeling effect. Perforation holes, either in the paper wrapper or in the filter of a filtered cigarette, accomplishes a similar effect; less air is drawn through the combustion zone, thereby lowering the average burn temperature as well as providing a greater number of puffs. Thus, recent studies have shown that the mainstream CO yield is a function of the amount of tobacco burned during pufftng, the concentration of the pyrolytic precursors, the heating rate of the tobacco during puffing, and the permeability of the wrapper toward outward diffusion of CO. Modification of these parameters may lead to reduced yields of CO. Condensation or adsorption of the gas on the filter or unburned tobacco column does not occur to any significant degree and is not a variable affecting the CO yield. With good reason, one might ask how effectively these studies have been reduced to practice. Using the technology available, cigarette yields of tar, as well as CO, of less than 10 mg tar and 10 ml CO have been obtained in several cigarette brands. Interestingly, there seems to be a remarkably good linear correlation between tar yield and CO yield. This may be graphically demonstrated in Fig. 7 in which CO yield is plotted against tar yield. Thus, as tar yields of manufactured cigarettes have been declining in the last decade, CO levels appear to have declined as well. What effects these reduced yields may have regarding smokingrelated diseases is still speculative; however, based simply on a policy of prudence , it is an encouraging trend. The National Cancer Institute has prepared and analyzed approximately 94
Y
l
(I
+
01X
co r+ I
n-
2.SSSSS375171 B6.749942940425
+1.!N
R-SQUARE 6.916566612526 RES ERROR 1.84471943351 llAX> 3.16564208124
+;.ee
x
+e.se
,
Ie.ee
te.se
ti.00
*i.se
.+z.ee TAR -
. E *I
,
FIG. 7. Correlation of tar yield and CO emission in a sample of commercial cigarettes.
366
GORI AND
ELLIS
cigarette variations in four separate studies to define characteristics of less hazardous cigarettes. In these four sets of experimental cigarettes, a standard experimental blend cigarette (SEB) was used for comparative purposes; its composition was based on the 1970 sales-weighted averages of various tobacco types including reconstituted tobacco sheet (RTS). In each experiment, the tobaccos used for preparing the SEB cigarettes were from that year’s crop. Table 4 describes those experimental cigarettes with at least a 25% reduction in CO delivery, compared with the SEB delivery, on a per-puff basis. In Series III, we have three examples where very high porosity paper and/or an air-dilution filter have reduced CO yield. You may also note that the combined effect is greater than either that of the very high porosity paper or the air-dilution filter. In Series IV, two experimental blends, composed of 27% reconstituted sheet with 60% calcium carbonate filler and 13% additive, gave reduced delivery of CO, literally due to a reduction in the amount of fuel per cigarette. Three artificial tobacco substitutes in Series IV also gave reduced CO yields comparable to the deliveries shown in Series II and III experiments. What about trends in the future? Paper permeability technology is likely to be as important in the future as it has been to date. If dilution air flow through permeable cigarette paper can be increased suffrciently, there may be a tendency to increase the proportion of outward diffusion through the same porous openings. Since this outward diffusion of CO as well as other gases should have no effect on smoker acceptance of the product, it might be useful to provide a major part of the total dilution through conventional filter perforations, and then to experiment with papers of greater and greater permeability, produced to retain mechanical strength by using either electrical or laser technology, to generate the perforated paper (23). The goal would be to maximize the diffusion portion of the diffusion:dilution process along the tobacco column, TABLE 4 EXPERIMENTAL
Series
Delivery/puff (ml)
I II III
0.60
1.23 1.22 0.88
0.64
IV
0.83 0.52 0.49 1.21 1.22 0.62 1.04
1.11
CIGARETTES
WITH
Low
CO DELIVERY
Description SEB I, flue-cured laminae only Artificial tobacco substitute SEB III, very high porosity paper SEB III, with dilution filter SEB III, with dilution filter and very high porosity paper ATS-A and SEB III, 30/70, dilution filter ATS-B SEB IV, RTS (27%), 60% CaCO,, 13% additives, IPA-H,O azeotrope Bright leaf with full return of stems Burley leaf with full return of stems SEB IV, RTS (27%), 60% CaCO, Pesticide-free treated tobacco (Virginia 115) Pesticide-treated tobacco (Virginia 115)
WORKSHOP: CARBON MONOXIDE
AND CVD
367
enhanced by the slower actual smoke flow rate produced by filter dilution, but still not exceeding a level of dilution beyond consumer acceptability. It can be seen that certain methods available to reduce CO yields may influence the levels of carbon dioxide while others may not. Methods of converting monoxide to dioxide chemically obviously produce an inverse relationship, while diffusion and dilution would likely produce changes in the delivered portions of both oxides and could reduce both. However, the selection of methodology, such as a judgment on the relative importance of each oxide or its effects on other smoke components such as pH, must be made. Morie (17) has reported very recently on a cigarette equipped with a vented filter that gave lower CO levels than predicted by air dilution alone. The decrease in CO levels resulted primarily from increased CO diffusion through the cigarette wrapper paper as the linear velocity of the mainstream smoke was lowered by vents in the filter. Thus, the use of a vented filter and permeable paper may be an excellent combination for decreasing the CO concentration in smoke. Paper treatment is another alternative (14). The best CO:tar ratio is likely obtained through chemically untreated wrapper paper although this paper gives an unappealing ash (see Fig. 6). Alternatives may be found to overcome this drawback. Furthermore, alternative wrappers may bring about the specific reduction of CO by modifying the combustion process. Inorganic fillers for reconstituted tobacco sheet or other types of tobacco leaf may be possible, having advantageous properties compared with the presently preferred inorganic fillers such as bentonite-hydrated clays or calcium carbonate. We must not look back on our achievements to date. Methods should continue to be developed for improving the tobacco, modifying tobacco sheet technology, and developing improved high-permeability paper; improvement of smokedilution devices and better fillers also should be encouraged. Technological achievements have been encouraging in reducing CO levels in cigarette smoke and they provide us with a sound foundation on which to build future improvements. Clearly, although the specific role of CO in the pathogenesis of atherosclerosis is not precisely defined, the reduction of this acutely toxic smoke component seems to be a desirable and prudent objective. REFERENCES I. Aronow, W. S., Introduction to smoking and cardiovascular disease, in “Proceedings of the Third World Conference on Smoking and Health, Vol. 1, New York, June 2-5, 1976” (E. L. Wynder, D. Hoffmann, and G. B. Gori, Eds.), pp. 231-236. DHEW Publication No. (NIH) 76-1221, 1976. 2. Baker, R. R., Formation of the oxides of carbon by the pyrolysis of tobacco. Eeitr. Tabakforsch. 8, 16 (1975). 3. Baker, R. R., Combustion and thermal decomposition regions inside a burning cigarette. Combust. Flame 30, 21-32 (1977). 4. Baker, R. R., and Crellin, R. A., The diffusion of CO out of cigarettes. Be&. Tabakforsch. 91, 131-140 (1977). 5. Baker, R. R., and Kilbum, K. D., The distribution of gases within the combustion coal of a cigarette. Eeirr. Tabakforsch. 7, 79 (1973). 6. Baxter, J. E., and Hobbs, M. E., Cigarette smoking studies using oxygen isotopes. I. CO* and CO produced by combustion. Tob. Sci. 11, 65 (1967).
368
GORI AND
ELLIS
7. Brunnemann, K. D., and Hoffmann, D., Chemical studies on tobacco smoke. XXIV. A quantitative method for carbon monoxide and carbon dioxide in cigarette and cigar smoke. J. Chron. sci. 12, 70-75 (1974).
8. Burton, H. R., Thermal decomposition of tobacco. V. Influence of temperature on the formation of carbon monoxide and carbon dioxide. E&r. Tnbakforsch. 8,78 (1975). 9. Gori, G. B., Reduction of TPM in smoke, in “Proceedings of the Third World Conference on Smoking and Health, Vol. I, New York, June 2-5, 1975” (E. L. Wynder, D. Hoffmann, and G. B. Gori, Eds.), pp. 451-461. DHEW Publication No. (NIH) 76-1221, 1976. IO. Greist, W. M., Quincy, R. B., and Guerin, M. R., “Selected Constituents in the Smoke of Domestic Low Tar Cigarettes,” p. 20. Report ORNL/TM-6144/Pl, Oak Ridge National Laboratory, December, 1977. II. Johnson W. R. The pyrogenesis and physicochemical nature of tobacco smoke, in, “Tobacco Smoke. Its Formation and Composition.” 31st Tobacco Chemists’ Research Conference, Greensboro, North Carolina, October 5-7, 1977. 12. Johnson, W. R., Powell, D. H., Hole, R. W., and Komfeld, R. A., Incorporation of atmosphere oxygen into components of cigarette smoke. Chem. Ind. 12, 521 (1975). 13. Lanzillotti, H. V. and Wayte, A. R., One dimensional gas concentration profiles within a burning cigarette during a puff. Beirr. Tubakforsch. 8, 219-224 (1975). 14. Mattina, C. F., Personal communication, October, 1978. 15. Mattina, C. F., and Selke, W. A., “The Influence of the Cigarette Wrapper on the Delivery of Oxides of Carbon in Mainstream Smoke.” Presented at 29th Tobacco Chemists’ Research Conference, College Park, Maryland, October, 1975. 16. Mikami, Y., Narto, N., and Kaburaki, Y., Effects of some factors on carbon monoxide concentration in the mainstream of smoke. Japan Monopoly Corp. Central Res. Znsf. 113, 99 (1971). 17. Morie, G. P., Some factors that affect the diffusion of carbon monoxide out of cigarettes. Tob. Sci. 20, I74- 176 (1976). 18. Norman, V., The effects of perforated tipping paper on the yield of various smoke components. Beitr. Tabakforsch. 7, 282-287 (1974). 19. Osdene, T. S. Reaction mechanisms on the burning cigarette, in “The Recent Chemistry of Natural Products Including Tobacco. Proceedings of the Second Philip Morris Science Symposium” (N. J. Fina, Ed.) Philip Morris, Inc., New York, 1976. 20. Rickards, J. C., and Owens, W. J., “Effect of Porous Cigarette Papers on the Yield of the Major Vapor Phase and Certain Particulate Phase Components of Cigarette Smoke,” p. 25. Presented at the 20th Tobacco Chemists’ Research Conference, Winston-Salem, North Carolina, November I-3, 1966. 21. Ross, W. S., Poison gases in your cigarette: Carbon monoxide. Reader’s Digest, 115-I I8 (October, 1976). 22. Terrell, J. H., and Schmeltz, I., Alteration of cigarette smoke composition. II. Influence of cigarette design. Tob. Sci. 14, 82-85 (1970). 23. Tigglebeck, D., Vapor phase smoke modification-an under utilized technology, in. “Proceedings of the Third World Conference on Smoking and Health, Vol. I, New York, June 2-5, 1975” (E. L. Wynder, D. Hoffmann and G. B. Gori, Eds.), pp. 507-514. DHEW Publication No. (NIH) 76-1221, 1976. 24. U.S. Public Health Service. “The Health Consequences of Smoking, 1979. Cigarette Smoke.” U.S. Department of Health, Education and Welfare, Washington D.C., in press.
