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The Health Consequences Of Smoking CHRONIC OBSTRUCTIVE LUNG DISEASE cI 11,port oJ r11(' Sirrgeon Gefieral 1984 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES P(OUc HoMth Swvice Oftfc* on Smokkq and 1NsUh RockvlUe• Marylend 20857 Fur snle by I hr SuIK•nn(endrn~ 01 Ikxumen(a. U S C,nernn,rm Pnntu,g qllkr Kh.Mugion.I)(' YuluY •OVE009t0g

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MM mmmm on ~ mmm mmm ~ me M"Im CONTENTS Introduction Problems of Measurement by Machine Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Epidemiologic Studies Mechanisms of Lung Damage Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Smoking Behavior Carbon Monoxide Uptake Nicotine Uptake Role of Tar Content Variations in Pattern of Cigarette Smoke Inhalation Use of Additives in Low Tar and Nicotine Cigarettes Research Recommendations Summary and Conclusions References 331 ztE00t9t4z

W M M uumm~ was MIMIM Introduction Following the initial reports in the early 1950s linking cigarette smoke with lung cancer, the pathogenic role of cigarette tar content received considerable emphasis. Because the tar fraction of the smoke contained the bulk of the carcinogenic effect of whole smoke, and because lung cancer risk was closely related to other measures of total smoke exposure (number of cigarettes smoked per day, depth of inhalation, etc.), it was suggested that risk might be related to the amount of tar generated by different cigarettes. This prompted health authorities to advise smokers who were unable to quite smoking to switch to low tar cigarettes (U.S. Senate 1967; Health Department of the United Kingdom 1976). To facilitate this process, the Federal Trade Commission published smoking-machine assays of the tar and nicotine yield of different cigarette brands (Pillsbury et al. 1969). This approach to low tar and nicotine cigarettes was based on the assumption that smoking lower yielding brands, as deter- mined by a smoking-machine, would result in a proportional reduction in the lung's exposure to these toxic substances. This approach to "safer" cigarette smoking has been promoted by the tobacco industry and apparently accepted by the smoking public, as evidenced by the escalation in sales of low tar and nicot.ine cigarettes. However, there is increasing evidence that this concept of a "less hazardous" cigarette is misleading; although definitive studies are still awaited, it appears that switching from regular to low tar and nicotine cigarettes may not substantially reduce the risk of chronic airflow obstruction. Problems of Measurement by Machine The first step in evaluating the relative health risks of different cigarettes is to establish some standardized measure of the toxic substances in different cigarettes in order to facilitate comparison. Quantifying each of the several thousand constituents of cigarette smoke for each brand of cigarette, and assessing the changes in these constituents as the manufacturing and agricultural processes change, would be a truly herculean task; therefore, a more modest goal of quantifying tar and nicotine yields was accepted. To date, the yields determined by the Federal Trade Commission have been the most widely adopted. These measurements are obtained with a laboratory smoking-machine, which consists of a syringe pump that takes a 35 ml bell-shaped puff from a cigarette, over a 2-second period, once per minute until a predetermined butt length is reached, either 23 mm for nonfiltered cigarettes or 3 mm longer than the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969). These parameters are based on observations of smoking patterns in seven subjects in Europe in 1933 (Kozlowski 1983). Today's cigarette 333 . E V G Q V 1' a/ fog

W W M M M .40 M ou Sn M an M M 'm as ift M Im 4W is markedly different from that smoked in 1967 when these parameters were established, yet the same parameters are still employed. Measurements obtained using these parameters indicate a marked reduction in the tar and nicotine yield of cigarettes over the last decade (Figure 1). In addition to the actual tar and nicotine yield of the tobacco, the yield measured by a smoking-machine is influenced by many factors, including cigarette length and diameter, porosity of the cigarette paper, presence of a ventilated or an unventilated filter, butt length, number of puffs, interpuff interval, puff volume, puff duration, puff pressure profile, and frequency of puffing at different stages of cigarette consumption. The number of puffs is important in determining the tar yield of a cigarette, and the number of puffs taken from some brands with the official smoking- machine has significantly declined in recent years (Kozlowski 1981). Since puffs are taken at 1-minute intervals, a more rapidly burning cigarette will have a smaller number of puffs. The burning time of the cigarette is determined by porosity of the cigarette paper, the amount of tobacco in the cigarette, and the diameter of the cigarette column. In a survey of Canadian cigarettes between 1969 and 1974, Kozlowski et al. (1980b) noted a significant reduction in the number of puffs taken in the official assays over this time period, which was strongly correlated with a reduction in tar yield. Omission of the last few puffs can markedly affect tar yield, because tar delivery increases with each puff, and the last few puffs from a cigarette can contain twice as much tar as the first few puffs (Wiley and Wickham 1974). Currently published yields do not indicate the number of puffs taken, which may range from 7 to 12 and may result in a marked variation of the tar yield. Ventilated cigarette filters, which cause inhaled smoke to be diluted with air, are one of the major methods of achieving low tar yields (Gori and Lynch 1978). Cigarettes with ventilated filters constituted about 25 percent of all cigarette sales in the United States in 1979 (Hoffmann et al. 1980). During systematic interviews, Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar smokers block these filter perforations with their fingers or lips, a feature unaccounted for by smoking-machines. This hole blocking increased the yield of toxic products by 59 to 293 percent. If a person smokes a cigarette in a manner identical to the smoking-machine, the delivery of tar and nicotine to the mouth will be the same as that estimated by the machine. Human smoking patterns are diverse, however, and show considerable variation from the machine parameters; puff volumes range from less than 20 ml to more than 90 ml (Tobin and Sackner 1982), compared with the fixed 35 ml volume employed by the machine. Differences in puff profile from the bell-shaped puff used by the machine also alter cigarette 3:34 I iar mg 400 350 300 250 200 150 100 50 00 1950 1955 I 1960 v 1965 I 1970 1975 NiCo6oe m9 V 40 35 30 25 20 15 10 05 00 1980 FIGURE 1.-U.S. sales-weighted average tar and nicotine yields SOIIRCE Amrri.nn l'nnror tiriclr119fl1U yield. Numerous studies indicate that smokers compensate for lower yielding cigarettes by altering their style of smoking. For each different cigarette brand, smokers may have a different smoking pattern. To provide more meaningful information, smoking-ma- chines should be designed to reproduce variations in the manner of smoking each cigarette brand, and their assays should provide both an average and a range of tar and nicotine yields depending on the individual pattern of smoking (USDHHS 1981). Many investigators have examined the relationship between the machine-determined nicotine yield of a cigarette and the concentra- tion of nicotine or its metabolites in blood or urine. A fair correlation was observed in some studies (Goldfarb et al. 1976; Herning et al. 1983), but most studies have revealed a poor correlation (Russell et al. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983). Machine-determined nicotine yield accounts for only from 4 (Russell et al. 1980) to 25 percent (Herning et al. 1983) of the variation in blood nicotine concentration, whereas 50 to 60 percent of the differences in blood nicotine levels are attributable to individual 335 • PfE4af9toz

W W ~ ng ior." ovem,g iM rnc*Whe OW n AM Ing rn c eterrnrning nicotine delivery from a cigarette was underlined in a recent. study demonstrating that the nicotine content of the unburned tobacco was similar for cigarettes with high and low nicotine yields determined by smoking-machine assays (Benowitz et al. 1983). The concept of providing the smoker with information on cigarette yield need not be abandoned. Smoking-machines can be designed to control the puff number, puff volume, puff pressure profile, puff duration, puff interval, butt length, position of the cigarette during and between puffs, and "restricted" or "free" smoking, i.e., whether the butt end is closed or open (Creighton and Lewis (1978a, b). These parameters should be determined and used to obtain an average and a range of yields for each brand. Measurement of cigarette yield should include assays not only of tar and nicotine but also of carbon monoxide and other toxic substances, because compensatory smok- ing behavior may alter the exposure to each substance beyond that expected on the basis of tar and nicotine delivery. Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Cigarette smokers account for the vast majority of deaths from chronic obstructive lung disease (COLD) (Peto et al. 1983), and the relative risk for the effects of smoking on mortality from COLD is even greater than that for lung cancer (see the chapter on Mortality in this Report). Chronic obstructive lung disease in smokers may take the following three forms: (1) cough and mucus hypersecretion, (2) airway obstruction, and (3) emphysema. Frequently the three components coexist, as all are related to cigarette smoking, but the agents in cigarette smoke responsible for each type of lung injury may be different. Over the past 25 years, considerable progress has been made in our understanding of the role of cigarette smoking in the pathogenesis and natural history of COLD, but most of the available data have not related lung function to cigarette yield. Epidemiologic Studies The cardinal importance of cigarette smoking in the pathogenesis of COLD has been repeatedly documented, and generally the severity of disease increases with increasing cigarette consumption (Ferris et al. 1976). Because of this dose-response relationship, it has been hoped that a reduction in cigarette yield by filtration or other means would reduce the risk of disease (Gori 1976). Available epidemiologic studies of the effect of low yield cigarettes on the development of COLD have shown variable results, which reflects 336 OW Wked 1WznccWeer1Wstuaft. terr thef=:atiJM studied, sample size, variation in cigarette brands, reference perioi of the study, criteria of respiratory involvement, and type of statistical analysis, and whether the study was of a cross-sectional or a longitudinal design. Separating the studies by the three comPo- nents of smoking-induced COLD indicates that there is a growing body of data on the effect of cigarette yield on the development of mucus hypersecretion and airway obstruction, but currently no information on the development of emphysema. Several studies have examined the effect of cigarette yield on respiratory symptoms and have observed a relationship between reduction in cigarette yield and the prevalence of cough (Comstock et al. 1970; Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et al. 1978; Schenker et al. 1982) and phlegm production (Comstock et al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et al. 1980b). Tar yield was not defined in some of these earlier studies (Comstock et al. 1970; Rimington 1972; I)ean et al. 1978; Hawthorne and Fry 1978), but instead a comparison was made between smokers of plain cigarettes and smokers of filter-tipped cigarettes. The tar yield was specified in some studies: in the recent study by Schenker et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman and Fletcher (1976), from 17 to 20 mg; and in the studies by Higenbottam et al. (1980b), from 18 to more than 33 rng, higher than that observed in many of today's cigarettes. In a cross-sectional survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial effect of low tar cigarettes on phlegm production was lost when subjects smoked 20 or more cigarettes per day, as their prevalence of phlegm production increased to that observed in higher tar cigarette smokers. In contrast, in another cross-sectional study of 5,686 women (Schenker et al. 1982), cigarette tar content was a significant risk factor for chronic cough and of borderline significance for phlegm production; this effect of cigarette tar content was indepen- dent of the number of cigarettes smoked per day. Chronic cough or phlegm production was approximately twice as common in smokers of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10 mg) smokers. In the latter study, however, multiple logistic regres- sion analysis indicated that the risk of chronic cough and phlegm production is more strongly affected by daily cigarette consumption than by tar content; these symptoms were 4.5 times more common in smokers of 25 or more cigarettes per day than in smokers of less than 15 cigarettes per day. A small number of studies have examined the importance of cigarette yield on change in pulmonary function. In a prospective study of 680 men, Comstock et al. (1970) noted that smokers of plain cigarettes, compared with smokers of filter-tipped cigarettes, had a lower FEV i at entry into the study. Followup measurements showed 337 MUUta7Yo(f

i M i M ~ am ili i MM M MM M MM M~W > LL 35-t 30- 25-{ 20 1-9 1 ('iKnrrtles 10-19 lar pet cgatelle (m9) 18-23 24-27 28-32 20 l 33 smokeA ppi dav FIGURE 2.-Relationship between mean FEVI of asymptomatic smokers (adjusted for height and weight) and tar yield of cigarettes, by number of cigarettes smoked per day SOURCE.Higenlwttametel tI1MMN+t a greater mean reduction of FEVI in users of filter-tips, so that the reduction was similar in the two groups after 5 to 6 years of followup. Unfortunately, the variance of the data was not stated, and tests of statistical significance were not performed. In another longitudinal survey of 1,355 men, Sparrow et al. (1983) determined the effect of cigarette tar content, which ranged from less than 16 mg to more than 22 mg, on pulmonary function. Multiple regression analysis indicated that tar content did not significantly influence baseline spirometry or repeat measurements after 5 years of followup. Cross- sectional epidemiologic surveys also indicate no relationship be- tween abnormal pulmonary function and the use of filter-tipped versus plain cigarettes (Beck et al. 1981) or cigarette tar content (Higenbottam et al. 1980b) (Figure 2). Interpretation of these studies as evidence that cigarette tar and nicotine yield is not an important factor in the development of COLD is premature. First, cross-sectional studies are limited in their capability of defining the natural history of a disease. Second, COLD has a very slow progress, and Fletcher et al. (1976) suggest that a span of approximately 8 years is necessary to establish rates of change of spirometric values with sufficient confidence even to distinguish between smokers and nonsmokers. Third, we have no information on the baseline pulmonary function of smokers at the time they choose between high or low tar and nicotine cigarettes. Significant differences in pulmonary function have been observed between young adults who decide to smoke and those who avoid cigarette smoking (Tashkin et al. 1983), and it is possible that similar 338 t function differences may exist in subjects who choose between high or low tar and nicotine cigarettes. Fourth, the yield of tar and nicotine used in many of these studies does not lie in the same range as that produced by many of tcday's cigarettes. However, the possibility that cigarette tar content is related to the development of cough and phlegm, but not of dyspnea or airflow obstruction, is consistent with current concepts of COLD. In a study of 792 men followed over an 8-year period, Fletcher et al. (1976) observed that cigarette smokers were susceptible to two distinct chronic lung diseases-mucus hypersecretion and chronic airflow obstruction. This has recently been confirmed in a large prospective study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years, which showed that the risk of death from COLD was strongly correlated with initial degree of airflow obstruction, hut bore no relationship to initial mucus hypersecretion. Given the evidence that mucus hypersecretion may depend on tile tar fraction of cigarette smoke, while development of airflow obstruction is more closely linked to the ;tumber of cigarettes smoked, IIigenbottam et. al. (1980b) reasoned that these differences might be due to a reduction in the particulate phase products, without a decrease in the gas phase• products, in the low tar cigFU•ettes. '1'hey hypothesized that tar droplets and soluble gases, such as sulfur dioxide and hydrogen cyanide, are more likely to be deposited or absorbed in the large airways where mucus is produced. The smaller airways, the earliest site of airflow obstruction, are exposed to a lower concentration of tar, but to a full concentration of insoluble gases such as nitrogen dioxide and ozone. This line of reasoning is in agreement with several studies showing a reduction in lung cancer with the use of low tar and nicotine cigarettes (Wynder et al. 1970;, Lee and Garfinkel 1981; Rimington 1981; Ilammond et al. 1976). The tar fraction is the component of cigarette smoke particularly linked with the development of both lung cancer and mucus hypersecretion. Although clinicians have long linked chronic bronchitis (mucus hypersecretion) with emphyse- ma, recent evidence indicates that mucus hypersecretion is not predictive of airflow obstruction, but is significantly greater in those smokers who develop lung cancer (Peto et at 1983). Mechanisms of Lung Damage Studies of the mechanism of cigarette-smoke-induced lung darnage have contributed significantly to the present understauding of COLD. ('iKarette smoke may initiate and aggravate lung injury by a number of mechanisms and may also interfere with the lungs' defense responses. These mechanisms include the protease-inhibitor imbalance theo- ry for the pathogenesis of emphysema whereby alveolar wall 3:{9 9fc00v9fJg

.. .. s.. rr r.r. arr. ... r+r. ti di l f d i ges on resu ts rom an excess of proteases, a efic ency of their inhibitors, or a combination of both factors (see the chapter on Mechanisms in this Report). The sources of endogenous proteases include polymorphonuclear neutrophils and alveolar macrophages, both of which are found in increased number in the lungs of cigarette smokers. Protease release from both macrophages and neutrophils is increased in the presence of cigarette smoke (Rodriquez et al. 1977; Blue and Janoff 1978). In health, proteases are continually inhibited by at-antitrypsin, whereas proteases cause unimpeded digestion of lung tissue in patients with ar-antitrypsin deficiency, with a markedly increased risk of emphysema. In addition to increasing the protease burden, cigarette smoke causes a functional inhibition of a,- antitrypsin through t he action of oxidants in cigarette smoke (Janoff et al. 1979). The relative potency of smoke from cigarettes of varying tar and nicotine yields in stimulating protease production and release and in inhibiting a,-antitrypsin has received scant scientific investigation. Travis et al. (1980) tested the effect of both filtered and unfiltered cigarette smoke on the elastase inhibitory activity of arantitrypsin. Filtered smoke reduced elastase inhibitory activity by 3 percent, and a 19 percent. reduction was observed with unfiltered smoke; the tar content of the respective smokes was not stated. The researchers reasoned that this small in vitro effect would be greatly magnified by in vivo conditions in the lung, particularly through its huge surface area. In addition to examining the effect of filters, Cohen and James (1982) recently examined the effect of tar and nicotine content on the elastase inhibitory capacity of ai-antitrypsin. The oxidant capacity of cigarette smoke was also examined using a chromogenic electron donor. Aqueous condensates of cigarette smoke were obtained from a variety of brands ranging in tar content from about 1 mg to more than 20 mg. Reporled tar and nicotine content correlated well with the amount of measured oxidants and the ability of a brand to reduce the elastase inhibitory capacity of ai-antitrypsin. Filters were found to remove 73 percent of the oxidants from the aqueous smoke solutions. While these findings suggest that low tar and nicotine or filter-tipped cigarettes could reduce a smoker's predisposition to enzymatic lung damage and consequent COLD, it should be noted that neither study examined the effect of lower yield cigarettes on protease production. Morosco and Gueringer (1979) demonstrated a greater increase in elastase in dogs exposed to high nicotine cigarette smoke compared with low nicotine cigarette smoke. More important, these studies have not taken into account the compensatory changes in smoking pattern likely to result with lower yield cigarettes. The airway response to acute exposure to cigarette smoke has been examined by several investigators employing spirometry (Da Silva and Hamosh 19811, body plethysmograph (Nadel and Comroe 1961), 340 r.. M M M M ... +ra W and breathing pattern analysis (Tobin et al. 1982a). Airway narrow- ing has been consistently observed by some investigators (Nadel and Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a variable response (Higenbottam et al. 1980a; Rees et al. 1982). In some studies, the acute airway response was unrelated to cigarette yield (Higenbottam et al. 1980a), but in most investigations (Robert- son et al. 1969; Tobin et al. 1982a; Rees et al. 1982), smoking a low tar or filter-tipped cigarette induced less acute bronchoconstriction. The acute airway response is probably localized to the larger airways, as acute cigarette exposure resulted in no change in the nitrogen washout test of small airway function (Da Silva and Hamosh 1973; Tobin et al. 1982a). These observations on the relative bronchocon- strictor response of various types of cigarettes may be important in our understanding of why some smoking novitiates persist with the habit despite the initial unpleasant reactions (Tashkin et al. 1983), but it is unlikely that repeated episodes of smoking-induced acute airway narrowing finally result in COLD. Future studies examining the mechanism of smoking-induced lung injury must not only take into account the range of cigarette yields, as determined by a smoking-machine, but also consider variations in smoking behavior. Puff volumes may vary considerably with nominr al cigarette tar and nicotine content, thus altering the relative amount of various toxic substances yielded by different cigarettes. Similarly, inhalation profiles are of a diverse nature (Tobin et al. 1982b) and are likely to significantly alter the distribution, penetra- tion, and retention of cigarette smoke constituents in the lungs. Variation In Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Low tar and nicotine cigarettes have gained considerable populari- ty among the smoking public, partly on the premise that a reduction in the nominal tar and nicotine yield results in a proportional reduction in the health hazards of cigarette smoking. The validity of this approach to cigarette smoking is contingent on the accuracy of smoking-machines in reflecting the actual manner of puffing and also on the smoker not altering smoking behavior to compensate for variations in nominal tar and nicotine content. Should smokers develop compensatory alterations in their smoking behavior, this would not only reduce the relevance of the smoking-niachitie assays but might also alter the proportionate delivery of the different toxic substances in cigarette smoke and expose the smoker to concentra- tions beyond those predicted by the smoking-machine. 341 4r40of' a7M' l,lg

W M M = ~ M M M = Smoking Behavior Nearly 40 years ago, Finnegan et at. (1945) studied the effect of alterations in cigarette nicotine content on smoking behavior and noted no change in cigarette consumption. It is only in the last decade, with the increasing popularity of low tar and nicotine cigarettes, however, that this question has attracted significant interest. The results of 38 studies examining alterations in smoking behavior with a reduction in cigarette yield are shown in Table 1. Considerable differences can be observed between the studies, partly reflecting variations in the level of cigarette yield reduction, alterations in other cigarette constituents, type and duration of switching procedure, parameters evaluated, and techniques used in their measurement. Most studies agree that smokers rarely increase their daily cigarette consumption upon switching from higher to lower yield brands. Reports are almost equally divided as to whether a smoker increases the number of puffs per cigarette or shows no change on switching to a lower yielding brand. There is an almost unanimous consensus that smokers take a larger puff volume from a lower yielding brand. Studies of puff volume also indicate huge variation between individual subjects (Guillerm and Radziszewski 1978; Hern- ing et at. 1981; Tobin and Sackner 1982; Herning et al. 1983) and that considerable increases in puff volume may occur on switching from a higher to a lower yielding brand, with certain subjects increasing their puff volume by up to 75 percent (Tobin and Sackner 1982). This compensatory increase in puff volume may be observed within a single experimental session (Tobin and Sackner 1982) and maintained over several weeks (Rawbone et al. 1978; Stepney 1981). Full compensation for a lower yielding cigarette is generally not achieved by smokers taking a large puff volume (Rawbone et al. 1978; Herning et al. 1981; Tobin and Sackner 1982). Instrumentation is required to quantitatively assess the pattern of smoking, but it is important to realize that such instrumentation may, in itself, alter usual smoking behavior. Puff volume has been almost universally measured by using a specialized cigarette holder incorporating different flowmeter designs (Frith 1971; Adams 1977; Rawbone et at. 1978). These devices consist of two tubes connected to a pressure transducer that measures the pressure drop across a small resistance (a filter insert) in the holder; the flow measured is integrated to obtain volume. Use of a cigarette holder has been shown to increase the rate of puffing and puff volume, compared with measurements made with the cheek inductive plethysmogra- phy coil (Tobin and Sackner 1982). Unlike the compensatory increases in puff volume, -neasurements of the subsequent inhalation volume-which includes the volume of smoke mixed with air inhaled into the lung-have shown no change 342 N C ~ 0 U 0 ~ a. a U U 7 . . . . ~ U 'T. S n. U 7. U U f 7 U J !. U U U U U U U Y3>~~13~~3~~ >Y~> > rn m rn ~+ m m~rn a+ m rn m rn rn ao r rn m m m rn m a: ~+ rn am mp~ .-. _. L = H L ~ C G N- C =~-~~d>sl_~ C.4 ~ Y W`~'d ~~~ 3 L J l. L L~ l] ~ C N i~ ~c`c?xJ%t'a ~cp°a3 ~n' ~,3i: ~c~ ~ ~»a4cex3 :34:3 8fE00r0f0g

c s n Ys 8 'I. ~ ~ ~ 8 344 M MM II 8 F a U U z 7. U % U U ~ U 7, z U 7. U > 7: Of °~f OI v c E ~ x3 R HR ~ ~ x~y ai q1 ~ E G ~o > Y ugi-~iFrArn U-a4.S c~ ~ ~ ~ ~ ~ ~ on switching to a low yield ci arette. i ,, nC se, ., ie s rrn~ study (Tobin and Sackner 1982), duration of inhalation showed no relationship to nominal cigarette yield. Perhaps compensatory changes in inhalation parameters require a longer period of time than puff volume does. Measurement of carboxyhemoglobin (COHb) concentration has been proposed as an index of the pattern of inhalation (Wald et al• 1975, 1978). While COHb provides valuable information on the amount of carbon monoxide absorbed from the lung during compen- satory alterations in smoking behavior, it is an indirect index and provides complementary information on cigarette smoke inhalation rather than replacing direct measurements of the volume of inhalation. Carbon Monoxide Uptake Unlike tar and nicotine, which are present in the particulate phase, carbon monoxide (CO) is a constituent of the vapor phase of cigarette smoke. For this reason, cigarettes purported to produce a low tar and nicotine yield may not necessarily provide a lower yield of carbon monoxide. Compared with tar and nicotine yield, carbon monoxide yield is more dependent on cigarette design, including such features as paper porosity and perforations in the filter tips. These factors regulate the dilution of smoke with air and the burning profile of the cigarette, and thus can significantly reduce carbon monoxide yield. Wald (1976) showed that the carbon monox- ide yield of filter-tipped cigarettes was 28 percent higher than that of plain cigarettes, although the average nicotine yield was lower in the filter-tipped cigarettes. He reasoned that smoke passing through a cigarette is diluted by air entering through the porous cigarette paper. However, the filter of filter-tipped cigarettes is surrounded by relatively nonporous paper, resulting in a higher content of carbon monoxide exiting from the proximal cigarette end. Perforations in the filter tip circumvent this problem and significantly reduce carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973). Many investigators have measured COHb or carbon monoxide concentration in expired gas following cigarette smoking and compared the levels achieved in smoking brands with different nominal yields (see Table 1). An increase, decrease, or no change in carbon monoxide intake has been observed, depending on relative differences in cigarette design and experimental procedure. As expected, unventilated filter-tipped cigarettes produced higher COHb levels than those observed with unfiltered cigarettes (Wald et al. 1977). This is in agreement with information provided by smoking-machine assays (Wald et al. 1973), but the use of ventilated filter-tipped cigarettes may produce COHb levels similar to those observed with unfiltered cigarettes despite lower carbon monoxide 345 6VE00f9f0g