The Health Consequences of SMOKING 1975 U.S.DEPARTMENTOFHEALTH,EDUCATION,ANDWELFARE PUBLIC HEALTH SERVICE Center for Disease Control Atlanta, Georgia 30333 July 23, 197.5 Honorable Carl Albert Speaker of the House of Representatives Washington, D.C. 205 15 Dear Mr. Speaker: As required by Section 8(a) of the Public Health Cigarette Smoking Act of 1969, enclosed is the 1975 report on the health consequences of smoking. The recent scientific information reviewed in the report reaffirms the previous evidence that cigarette smoking is a serious public health problem. It is a major contributor to the development of cardiovascular disease, various types of cancer, and respiratory disease. Its toll in illness and premature death is needless and preventable. The recent literature further refines our understanding of the mechanisms by which smoking influences these disease states. Under this Act, I am also required to submit to you such recommendations for legislation as I deem appropriate. This Department has previously taken a position in support of legislation which would authorize the regulation of cigarettes through the power to ban the manufacture and sale of cigarettes exceeding what are considered excessively hazardous levels of tar, nicotine, carbon monoxide, and other ingredients shown to be injurious to health. The extent to which the cigarette smoking public has over the years spontaneously moved towards this kind of self protection suggests that it would welcome the additional protection such legislation would bring. This Department, therefore, recommends to the Congress that it consider legislation providing this Department or some other appropriate agency with the authority to set maximum permissible levels of hazardous ingredients in cigarettes. With kindest regards. Sincerely, Caspar W. Weinberger Secretary Enclosure For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402 - PREFACE Each year the Public Health Service reviews the scientific data related to the health consequences of smoking and submits its review to the Congress. This report, the ninth in the series. summarizes recent research in four major areas: cardiovascular disease. cancer. respiratory disease, and the effects of smoking on the nonsmoker , who shares the environment of those who smoke. As has been the case with each of the previous reports in the series, the research summarized herein further confirms the relation- ships between cigarette smoking and disease and premature death and refines our understanding of the mechanisms underlying these relationships. Cigarette smoking remains the largest single unnecessary and preventable cause of illness and early death. In the eleven years since the report of the Advisory Committee to the Surgeon General in 1964, there has been progress toward reducing this toll. Millions of Americans have stopped smoking cigarettes, and millions more have not taken up smoking. Even for those who continue to smoke, there has been a striking reduction in the "tar" and nicotine content of cigarettes used by the vast majority. At the same time, however, counter-balancing these gains. there has been an increase in cigarette smoking by women and young people. especially teen-age girls. To eliminate the needless death and disability attributable to cigarette smoking, the Public Health Service remains committed today, as in the past, to increasing the knowledge about the health consequences of smoking and to educating the American people as to the nature and extent of the hazards of smoking. This is a task, not for government alone, but for the great institutions of society as a whole ~ the family, the schools, the health care system. Through concerted effort, a climate of respect for our own health and that of others can be created. Such a climate must certainly be conducive to reducing and eventually eliminating the needless burden of disease and premature death imposed by cigarette smoking. +cfii%dLe Assistallt Secretary for Health June 1975 . 111 TABLE OF CONTENTS Page Preface _............................................. iii Table of Contents . . . . . . . . . . . . . . . v Reparation of the Report and Acknowledgments . . . . . . . . . vii INTRODUCTION: Overview - The Health Consequences of Smoking . . . . . . . . . . . . . . . . 1 CHAPTER 1. Cardiovascular Diseases . . . . _ . . . . . . . . 9 CHAPTER 2. CHAPTER 3. CHAPTER 4. Cancer ................................ 39 Non-Neoplastic Bronchopulmonary Diseases ...... 57 Involuntary Smoking ...................... 83 Index1975 ......................................... ..I1 3 Index (Cumulative 1964-l 975) .............................. 118 PREPARATION OF THE REPORT AND ACKNOWLEDGMENTS Previous Reports Reviews of the scientific evidence linking smoking to health effects began in 1964 with Smokilq alrtl Health. Report of the Advisor). Committee to the Swgeorl General of` the Public Health Senvice or as subsequently referred to "the Surgeon General's Report." After this report. Public Law 89-92 was passed requiring supplemental reports to Congress on this subject. In compliance. three reports were submitted: 1. The Health Comequences of Smoking, A Public Health Service Review: I96 7. 2. The Ilealth Comequeuces of S~noki~~g. I965 Supplement to the I96 7 PHS Review. 3. The Health Corlseqnerlces of Smoking, I969 Srtpplemelzt to the 196 7 PHS Review. In April 1970. Public Law 91-122 amended the previous law and called for an updated report on the health effects of smoking no later than January 1. 1971, with annual reports thereafter. The Healtll Conse~lrellct~s of S~lol 150 and diastolic > 95) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic heart disease study by Kahn, et al. (34) raise additional questions about Seltzer's data. Kahn followed 10,000 Israeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 16 TABLE 1. - Age-standardized blood pressure changes (mm Hg)' at followup for continuing cigarette smokers and quitters according to weight changes Smoking Class Mean systolic BP changes: Continuing smokers Quitters Mean diastolic BP changes: Continuing smokers Quitters I Weight Change (LB) Significant wt Loss lb No. -25 to -5 32 -4.00 13 1.77 32 -3.28 13 -0.31 No Significant Wt Change lb No. -4 to +4 84 -1.52 27 2.22 84 -~ 2.04 27 -1.96 `Standardized on basis of age distribution of current cigarette smokers. Source: Seltzer, CC. (55). Moderate Significant Wt Gain Wt Gain No. 1 +5 ::+I2 71 2.85 24 1.50 27 4.04 32 3.69 71 0.73 24 0.04 27 4.30 32 3.94 I lb No. +13 to +30 TABLE 2. - Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters Blood pressure levels Systolic blood pressure 150+ Systolic blood pressure 160+ Diastolic blood pressure 95+ Source: Seltzer, CC. (55). Continuing cigarette smokers Quitters Number Percent Number Percent 6 2.8 9 8.7 2 0.9 5 4.8 3 1.4 5 4.8 data on the incidence of hypertension in nonsmokers, and the age distribution for his group of smokers (the original source of the quitters) is heavily weighted toward younger age groups (with only 33 of 214 men age 50 years or over). According to Kahn's data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (12) recently reported a correlation between coffee drinking (2 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,104 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those tiho were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 19 The Framingham Study (18) recently published data on coffee drinking based on a 12-year followup of 5,209 men and women ages 30-62. An increased risk of death from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smoking. No association between coffee drinking and myocardial infarction or between coffee drinking and the development of CHD, stroke, or intermittent claudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Ventricular Premature Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69), in a study of 793 men in Goteborg, Sweden, examined the frequency of rhythm and conduction disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rest or during exercise. CARBON MONOXIDE Introduction Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15 to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoxide (65, 66, 67, 68). Carbon monoxide is present in concentrations of 1 to 5 percent of the gaseous phase of cigarette smoke (II, 45). The concentration varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to 15 percent depending on the amount smoked, degree of inhalation. and the time elapsed since smoking the last cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemoglobin, impairs oxygen transportation in at least two ways: 20 First, it competes with oxygen for hemoglobin binding sites. Second, it increases the affinity of the remaining hemoglobin for oxygen, thereby requiring a larger gradient in Po2 between the blood and tissue to deliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig- ments, most notably myoglobin, for which it has even a greater affinity than for hemoglobin under conditions of low Po2. The significance of this binding is unclear. but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon Monoxide Exposure and Human Absorption Several researchers (13, 32, 35, 57, 60, 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors, determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .78 percent. Cigarette smokers, on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industrial exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However, in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to automobile exhaust - London taxi drivers (32) and garage and service station operators (13) - have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO; cigarette smokers still maintained much higher COHb levels (5.0 1 percent) than nonsmokers (2.93 percent) (8). 21 TABLE 3. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race Total Sample Male Female Total Sample Nonsmokers Smoked No. x+s;T No. x+sj; No. x * sjz 16,649 2.30 +_ 0.02 lO.lS7 0.85 +_ 0.01 6,492 4.58 + 0.03 10,542 2.66 + 0.03 5,888 1.00f0.01 4,654 4.76 * 0.04 6,107 1.68 + 0.03 4,269 0.64 + 0.01 1,838 4.10 + 0.06 White 15,167 2.28 + 0.02 9,474 Male 9,669 2.65 * 0.03 5,508 Female 5.498 1.63 kO.03 3,966 Black I.429 2.59 + 0.06 641 Male 829 2.91 * 0.10 347 Female 600 2.15 * 0.09 294 `Smokers are defined as those who smoked on the day of giving blood. NOTE. - f7 = mean percent: SK= standard error of mean percent. Source: Kahn, A., et al. (35). 0.85 + 0.01 5,693 4.66 + 0.04 1.00 + 0.01 4,161 4.83 + 0.04 0.64 f 0.01 1,532 4.19 2 0.06 0.86 * 0.03 788 4.00 * 0.08 1.07 + 0.05 482 4.24 + 0.10 0.62 + 0.04 306 3.63 + 0.12 TABLE 4. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status Persons employed Classed as industrial workers1 Classed as workers other than industrial Nonsmokers I No. xis$ 8,478 0.89 * 0.01 1,523 1.38 + 0.04 6,955 0.78 * 0.01 Smokers' No. Xi& 5,962 4.6 1 * 0.03 1,738 5.01 f 0.06 4,224 4.44 * 0.04 Persons not employed 1,678 0.63 +_ 0.02 531 4.24kO.11 `Industrial workers are employed in either durable or nondurable goods manufacturing (craftsmen, operatives, or laborers). Smokers are defined as those who smoked on the day of giving blood. NOTE. - g = mean percent; S,- = standard error of mean percent. Source: Kahn, A., et al. (35). 13 P TABLE 5. - Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for smokers and nonsmokers by location Location Anchorage Chicago Denver Detroit Honolulu Houston Los Angeles Miami Milwaukee New Orleans New York Phoenix St. Louis Salt Lake City San Francisco Seattle Vermont, New Hampshire Washington, DC Source: Stewart, R.D., et al. (57). Cigarette Smokers Nonsmokers Median Range Median Range 4.7 0.9 - 9.5 5.8 2.0 - 9.9 5.5 2.0 - 9.8 5.6 1.6 - 10.4 4.9 1.6 - 9.0 3.2 1.0 - 7.8 6.2 2.0 - 10.3 5.0 1.2 - 9.7 4.2 1.0 - 8.9 5.5 2.0 - 9.6 4.8 1.2 ~ 9.1 4.1 0.9 - 8.7 5.1 1.7 ~ 9.2 5.1 1.5 ~ 9.5 5.4 1.6 ~ 9.8 5.7 1.7 - 9.6 1.5 0.6 ~ 3.2 1.7 1.0 - 3.2 2.0 0.9 - 3.7 1.6 0.7 - 2.7 1.4 0.7 ~ 2.5 1.2 0.6 ~ 3.5 1.8 1.0 - 3.0 1.2 0.4 - 3.0 1.2 0.5 - 2.5 1.6 1.0 ~ 3.0 1.2 0.6 ~ 2.5 1.2 0.5 - 2.5 1.4 0.9 - 2.1 1.2 0.6 - 2.5 1.5 0.8 - 2.7 1.5 0.8 - 2.7 4.8 1.4 - 9.0 4.9 1.2 - 8.4 1.2 0.8 - 2.1 1.2 0.6 - 2.5 TABLE 6. - Mean percent carboxyhemoglobin (COHb) saturation in cigarette smokers I hour after last cigarette Location Nonsmoker Packs of Cigarettes Smoked Per day Milwaukee New Hampshire, Vermont New York City Washington, DC Los Angeles Chicago 1.3 3.0 4.2 5.3 6.2 4.7 1.4 3.3 4.4 5.7 6.7 5.3 1.4 3.1 4.3 4.7 5.8 6.3 1.4 3.8 4.6 5.2 5.8 6.6 2.0 4.0 5.2 6.0 7.4 1.5 2.0 4.8 5.4 6.3 7.1 1.7 Source: Stewart, R.D., et al. (57). Studies on the CO burden of each cigarette have determined the body burden of CO per cigarette to be 7.10-8.66 ml (40), and the increase in COHb level produced by smoking one cigarette to be .94 to 1.6 percent after 12 hours of abstinence (40, 53). The half-life for the washout of CO in healthy college smokers (40) was calculated to be from 3 to 5 hours. Effects on Healthy Individuals Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COHb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5Z), in a study of young men exposed during exercise on a treadmill to 50 ppm CO (COHb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25" C. In a similar experiment conducted at 35" C by the same researchers (20), there was a decrease in maximum aerobic capacity in nonsmokers exposed to 50 ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of 1.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb levels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and 18 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity P50 and ATP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smoking. The authors interpret these data as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a blood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokers; this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times as great as those in the 26 simultaneously measured blood of the mother. Fetal blood was exposed to carbon monoxide in vitro, and fetal hemoglobin was found to have a shift of the oxyhemoglobin disassociation curve to the left as occurs with adult hemoglobin. The higher fetal COHb levels were attributed to the lower fetal Po2 and a resultant decrease in the ability of oxygen to compete for the fetal hemoglobin. It was felt by the authors that the high COHb levels may be responsible for the lower birth weight of infants born to mothers who smoke. Effects on Persons with Atherosclerotic Cardiovascular Disease Aronow and Isbell (5) and Anderson, et al. (I) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of systolic blood pressure times heart rate (a measure of cardiac work) were all significantly lower at onset of angina pectoris. In a continuation of this work, Aronow, et al. (2, 3) studied eight patients during two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during which each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the fist catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and coronary sinus, arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period, or cardiac index, and decreases were found in stroke index and coronary sinus, arterial, and venous Po2 . When carbon monoxide was inhaled, increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus, arterial, and venous Po2 were found. These data suggest that carbon monoxide has a negative inotropic effect on myocardial tissue resulting in the decrease in contractility (dp/dt) and stroke index. When the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. In the heart with 27 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to SO ppm CO (6). Studies on the Pathogenesis of Cardiovascular Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to 170 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 340 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 12 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at 10 and 16 percent oxygen had 3 to 3.5 times the aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol accumulation. Theodore, et al. (58) studied the aortas of monkeys, baboons, dogs, rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 weeks, there were local areas in their hearts of partial or total necrosis of myofibrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the luminal coats showed pronounced changes characterized by severe edematous reaction with extensive swelling and formation of subendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indistinguishable from early atherosclerosis. 28 Evidence that this mechanism may occur in humans is provided by the findings of Parving (50) who showed an increased trans- capillary escape rate for 131 I- labeled albumin in humans exposed to .43 percent CO (COHb 20 percent) for 3 to 5 hours, but not in those made hypoxic to an altitude of 4300 meters (hemoglobin 75 percent saturated). By exposing rabbits to different concentrations of carbon monoxide (SO, 100, and 180 ppm) for varying periods (.S. 2. 4. 8, 24, and 48 hours), Thomsen and Kjeldsen (59) were able to show a threshold of 100 ppm of CO for myocardial damage. The demonstra- tion of damage at this level of CO (COHb 8-10 percent) is possibly explained by the ratio of carboxymyoglobin to carboxyhemoglobin which is about 3 to 1 in myocardium at ambient POZ. Thus, a COHb level of 10 percent would be accompanied by a carboxymyo- globin level of 30 percent in heart muscle. This ratio is even greater under hypoxic conditions with a ratio of 6 to 1 when the arterial Po2 is below 40 mm Hg (1.5). Nicotine In a study of the effects of smoking cigarettes with low and high nicotine content, Hill and Wynder (30) noted increasing serum epinephrine levels with increasing nicotine content of the smoke, but serum norepinephrine levels were unchanged. However, increasing serum epinephrine levels with increasing number of low nicotine content cigarettes smoked were also noted. Acrolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significant increase in blood pressure and heart rate in rats. CEREBROVASCULAR DISEASE There has been conflicting evidence on whether there is an increased risk of cerebrovascular disease due to smoking (61, 62, 63, 64, 65, 66, 67, 68). A prospective study by Paffenbarger, et al. (48) of 3,991 longshoremen followed for 18 years showed no correlation between fatal strokes and smoking. However, both the Dorn study of 29 U.S. veterans (33) and Hammond's study of one million men and women (25) showed a small but significant increase in the death rates from cerebrovascular disease among cigarette smokers. The Framing- ham 18-year followup of men ages 45 to 54 (42) and Paffenbarger's study of men who entered Harvard between 19 16 and 1940 (49) also showed an excess risk of cerebrovascular disease associated with cigarette smoking. Two recent studies provided more data on this topic. Ostfeld, et al. (46, 47), in a study of 2,748 people ages 65-74 receiving old age assistance in Cook County, Illinois, were unable to find any relation between cigarette smoking habits at the start of the study and incidence of new strokes or prevalence of transient ischemic attacks. Nomura, et al. (44), in a study of the population of Washington County, Maryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. Nomura noted that "in atherosclerotic strokes the Framingham study and Paffenbarger's investigation of former college students included a great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking and atherosclerotic strokes and the present study did not, it may be that the association is age-dependent." Hammond (25) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7), indicating that the excess death rates associated with cigarette smoking increase with advancing age. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with age, reflecting the fact that cerebrovascular disease death rates attributable to other causes increase with age more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk factor for-stroke at all ages, but other causes of strokes become proportionally so important in older age groups that in studies not based on very large populations the risk due to cigarette smoking is masked by the large total number of strokes due to other causes. 30 I ABLE 7. - Age-smn&rdized dearbs rores and morroltty mrios for cerebral mscutar tesrons for men and women by rype of smoking (lifetime history) and age at start of study Type of Smoking Men Age Groups 45-54 55-64 65-74 75-84 CVL Death Rates per 100,000 Person-Years Never smoked regularly 28 92 349 1,358 Pipe, cigar 25 100 369 1,371 Cigarette and other 28 129 361 990 Cigarette only 42 130 477 1,168 Total 1.272 Women Never smoked regularly 18 57 228 1,082 Cigarette 38 88 315 1,277 Total I 25 64 238 1,091 CVL Mortality Ratios Men Never smoked regularly 1.00 1 .oo 1.00 1.00 Pipe, cigar 0.89 1.09 1.06 1 .o 1 Cigarette and other 1.00 1.40 I .03 0.73 Cigarette only 1.50 1.41 1.37 0.86 w Never smoked regularly Cigarette NOTE. - CVL = Cerebral vascular lesions. Source: Hammond, E.C. (25). 1 .oo 1.00 1.00 1.00 2.11 1.54 1.38 1.18 EFFECTS OF SMOKING ON THE COAGULATION SYSTEM Several studies have contributed to an understanding of the role of smoking in thrombogenesis. Levine (41), in a controlled double blind study, showed that smoking a single cigarette increased the platelet's response to a standard aggregating stimulus (ADP). This phenomenon did not occur when lettuce leaf cigarettes were smoked and was independent of a rise in free fatty acids in the plasma. The author postulates that this may be due to increasing epinephrine levels. These data may have relevance for two other studies. In the clinical trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, England, (19) it was found that cigarette smokers were at increased risk of sudden death. This increased risk was not present in smokers treated with clofibrate. However, the researchers were unable to relate this reduction in risk to any effect of clofibrate on serum lipids. Recently Carvalho, et al. (14) evaluated 29 patients with familial hyperbetalipoproteinemia and noted that their platelets had an increased sensitivity to aggregating stimuli (ADP). Treatment with clofibrate returned the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction in the excess risk of sudden death could be due to a clofibrate induced reversal of increased sensitivity to aggregating stimuli produced by smoking. 32 SUMMARY OF RECENT CARDIOVASCULAR FINDINGS 1. Data from one recent incidence study suggest that cigarette smokers are more likely to develop hypertension than are nonsmokers. There is some evidence that suggests that stopping smoking may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major source of elevated carboxyhemoglobin levels, with occupational exposure and air pollution being far less important in most circumstances. Carboxyhemoglobin levels in cigarette smokers are two to three times the levels in nonsmokers and increase with the amounts smoked. 3. Elevated carboxyhemoglobin levels have been shown to decrease maximal oxygen uptake in healthy people as well as to decrease the exercise tolerance of persons with angina pectoris and intermittent claudication. The carboxyhemoglobin levels at which these effects take place are well within the range produced by cigarette smoking. 4. Carbon monoxide at levels of exposure commonly reached by cigarette smokers has been shown to decrease cardiac contractility in persons with coronary heart disease. 5. Carbon monoxide has been shown to produce changes like those of early atherosclerosis in the aortas of rabbits. 33 BIBLIOGRAPHY ANDERSON, E. W., ANDELMAN, R. J., STRAUCH, J. 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Archives of Environmental Health 29(3): 136-142, September 1974. 38 CHAPTER 2 Cancer CHAPTER 2 Cancer CONTENTS Introduction .......................................... 43 Lung Cancer .......................................... 44 Epidemiologic Studies ................................ 4.4 Smoking and Air Pollution ............................. 4.4 Exfoliative Cytology ................................. 47 Experimental Carcinogenicity ............................... 48 Carcinogens in Cigarette Smoke ......................... 48 Asbestos ......................................... 49 Infection and Carcinogenicity ........................... 49 Other Cancers ......................................... 50 Oral and Laryngeal Cancer ............................. 50 Genitourinary Cancer ................................ 50 Nasopharyngeal Cancer ............................... 50 Aryl Hydrocarbon Hydroxylase (AHH) ........................ 50 Summary of Recent Cancer Findings .......................... 54 Bibliography .......................................... 55 List of Figures Page Figure 1 .-Production of aryl hydrocarbon hydroxylase (AHH) in macrophages from one person in response to cigarette smoking . . . . . . . . . . . . . . . . . . . _ . . . . . . . . . . . . . . 52 List of Tables Page Table 1 .-Distribution by type of lung cancers in a composite series of nonsmokers and a representative hospital series . _ . . . . . . . _ . . . . . . . . . . . . . . . . . _ . . _ . . . . . _ .45 Table 2.-Distribution by type of lung cancer in populations with specific occupational exposures . . . . . . . _ . . . . . . . . . . . . _ . . . _ . . . . . . . . . . . . . . . . 46 Table 3.-Aryl hydrocarbon hydroxylase (AHH) inducibility in patients with lung cancer, with other tumors, and in healthy controls . . . . . . . . . . . . _ . . . . _ . . . . . . . . . . . . . . . . . 53 INTRODUCTION The major relationships between smoking and various cancers have been documented in previous reports on the health consequences of smoking (18, 19, 20, 21, 22, 23, 24, 25). Based on evaluations of detailed epidemiologic, clinical, autopsy, and experimental data accumulated over the last 30 years, cigarette smoking has been clearly identified as a causative factor for lung cancer. The risk of developing lung cancer increases directly with increasing cigarette smoke exposure as measured by number of cigarettes smoked per day, total lifetime number of cigarettes smoked, number of years of smoking, age at initiation of smoking, and depth of inhalation. Lung cancer death rates for women are lower than for men but have increased dramatically over the last 15 years coincident with the increasing number of women smokers. This increase has occurred in spite of the fact that women smokers use fewer cigarettes per day, more frequently choose cigarettes with filter tips and low tar and nicotine delivery, and tend to inhale less than men. A person who stops smoking has a decreased risk of developing lung cancer compared to the continuing smoker, but the risk remains greater than the nonsmoker's for as long as 10 to 15 years after the person stops smoking. Cigarette smoking is a significant etiologic factor in the development of cancer of the larynx, oral cavity, pharynx, esophagus, and urinary bladder and is associated with cancer of the pancreas. Certain occupational exposures have been found to be associated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these exposures to produce a greater risk of developing lung cancer than from occupational exposure alone. Uranium mining and the asbestos industries are occupations which have only slightly increased lung cancer rates for nonsmokers but dramatically elevated rates for cigarette smokers. Pipe and cigar smokers experience mortality rates from cancer of the oral cavity, larynx, pharynx, and esophagus approximately equal to those of cigarette smokers. Their risk of developing cancer of the lung is lower than the risk of cigarette smokers, but it is significantly above that of nonsmokers. This is probably due to the 43 fact that pipe, cigar, and cigarette smokers experience similar smoke exposure of the upper respiratory tract, while cigarette smokers (due to their greater tendency to inhale) have a greater exposure of their lungs to smoke than pipe or cigar smokers. The bronchial epithelium of smokers often shows premalignant changes such as squamous metaplasia, atypical squamous metaplasia, and carcinoma in situ. The pathogenesis of these changes is related to the various carcinogenic and co-carcinogenic substances in cigarette smoke; the exact mechanism of these carcinogens remains under investigation. LUNG CANCER Epidemiologic Studies Harris (3) has reviewed the reports of lung cancer in nonsmokers and compared them to a representative hospital series and has shown marked differences in the pathological types between the two groups (Table 1). When only nonsmokers are examined, the excess of squamous and oat cell carcinoma in men compared to women is not observed. Adenocarcinoma is by far the most common type of lung cancer in nonsmokers while squamous cell is by far the most common when smokers are included. The strength of the relationship between smoking and the development of lung cancer differs markedly with the type of lung tumor. Squamous and oat cell carcinoma are very closely related to smoking behavior while, according to this study, bronchiolar carcinoma shows no excess risk attributable to smoking. Harris also presented the percentages of different histologic types of cancer found in several industrial exposures (Table 2); these percent distribution patterns resembled those found in smokers far more closely than those found in nonsmokers. Wynder, et al. (26) in a retrospective study of 350 lung cancer patients and hospitalized controls, noted that the relative risk of developing lung cancer was far less in those smokers who had smoked filter cigarettes for more than 10 years than in smokers of plain cigarettes (26.8 and 46.2, respectively). Even with smokers of filter cigarettes, the risk increased with increasing number of cigarettes smoked and was significantly greater than the risk of nonsmokers. Smoking and Air Pollution Because of the magnitude of the association between smoking and the development of epidermoid lung cancer, it is difficult to 44 TABLE 1. - Distribution by type of lung cancers in a composite series of nonsmokers and a representative hospital series Type of cancer Distribution (Percent) Nonsmokers All Patients Men Women Men Women Squamous cell carcinoma 14 12 Oat cell carcinoma 4 4 Bronchiolar carcinoma - 5 Adenocarcinoma 51 54 Large cell anaplastic carcinoma 8 8 Carcinoid 14 16 Other specific types - < 1 Undifferentiated1 4 2 41 22 17 11 8 23 10 20 17 19 0.6 4 1 2 - - Total number of cases 51 `Includes oat cell carcinoma and large cell anaplastic carcinoma. Source: Harris. C.C. (3). 274 1.903 315 P TABLE 2. - Distribution by type of lung cancer in populations with specific occupational exposures Type of cancer Squamous cell carcinoma Oat cell carcinoma Adenocarcinoma Oat cell or anaplaatic carcinoma Anaplastic Distribution (%) in populations with exposure to- Nickel Chromium Hematite 51 48 33 43 16 60 - 24 - 12 I Asbestos 44 6 25 24 1 Source: Harris, C.C. (3). evaluate the effects of other possible causes of lung cancer such as air pollution. Higgins (4) recently analyzed respiratory cancer mortality in Great Britain and the United States. In the United States, although the age-specific death rates for males continued to increase, the rate of increase was not as great as in the past. Female lung cancer mortality rates, by contrast, have increased steadily since about 1955. If these increases continue, the American Cancer Society estimates that lung cancer among women will move from fourth to third place in 1975 as the site responsible for the greatest number of deaths due to cancer among women (I). In England and Wales, Higgins noted that between 1940 and 1969 lung.cancer rates for men declined in the age group under 55 and increased only in men over 65. After adjusting for cigarette smoking, an independent effect of air pollution was sought. It was found that the lung cancer death rates for men ages 25-64 in greater London decreased more than the rates in the rest of the country; he attributed this decrease to the greater decline in smoke pollution in London than elsewhere. Exfoliative Cytology Microscopic examination of respiratory epithelial cells shed into the sputum has become a useful aid in the diagnosis of lung cancer and has been employed in many lung cancer screening programs for selected high risk groups. Saccomanno, et al. (II) have conducted periodic cytologic examinations of the sputum of uranium miners and a group of nonmining controls. Many of these individuals developed abnormal squamous cell metaplasia that progressed in several cases to become invasive carcinoma. Both cigarette smoking and radiation exposure from uranium mining were associated with an increased prevalence of these cytologic changes. Of the two factors, cigarette smoking was noted to be the more important (in both miners and nonminers) for the development of atypia and carcinoma in situ. Neither cigarette smoking nor uranium mining could be correlated with the length of time it took for these changes to ' progress from one pathologic stage to the next. Schreiber, et al. (15) studied exfoliative cytology of the lungs of hamsters treated with intratracheal injection of the carcinogen henzo(a)pyrene. They noted progression from mild atypia to squamous metaplasia, to moderate and marked atypia, to changes indicative of cancer. These cytologic changes in animals exposed to carcinogens are comparable to those found in humans who smoke cigarettes. 47 EXPERIMENTAL CARCINOGENICITY Carcinogens in Cigarette Smoke A great deal of effort has been expended to identify those substances in cigarette smoke that cause malignant changes. The hope is that, if these carcinogenic substances can be identified and removed from cigarette smoke, the risk of developing lung cancer as a result of smoking can be reduced. Carcinogenic substances which act as tumor initiators, accelerators, and promoters in experimental animal systems have been identified in cigarette smoke. Hoffman and Wynder (6) conducted an extensive analysis of the tumorigenicity of tobacco smoke. Using the gas phase of cigarette smoke, they identified certain known carcinogens but were unable to induce carcinoma in the respiratory tract of experimental animals. They interpreted these results as indicating that the levels of carcinogens present in the gas phase alone are below the concentrations necessary for tumor activity. In the same study, Hoffmann and Wynder examined the particulate phase of tobacco and identified several carcinogens. The majority of tumor initiators in the particulate phase were polynuclear aromatic hydrocarbons and alkylated polynuclear aromatic hydrocarbons. They found that a significant inhibition of pyrosynthesis of these substances leads to a significant reduction of the tumorigenicity of tobacco smoke. They also identified several tumor accelerators - substances which accelerate the carcinogenicity and tumor initiating activity of the polycyclic aromatic hydro- carbons. The tumor accelerators found were trans-4, 4'-dichloro- stilbene, N-alkyl indoles, and N-alkyl carbazoles. They also reported that the tumor promoters in cigarette smoke occur in the acidic portion of the particulate matter but did not further characterize them. Hoffmann, et al. (5) reported identifying the nitrosamine, N'-nitrosonomicotine, in concentrations of 1.9 to 6.6 micrograms per gram in unburned tobacco and levels of 88.6 pg/g in one sample of finely cut chewing tobacco. This is one of the highest concentrations of an environmental nitrosamine (a family of compounds containing several organic carcinogens) yet identified; concentrations in food and drink rarely exceed 0.1 pg/g. This substance is readily extractable from tobacco by water and so would be present in high concentrations in the saliva of persons who chew 48 tobacco. As yet, N'-nitrosonornicotine has not been established as carcinogenic, and even the known carcinogenic nitrosamines are not felt to act topically. Asbestos The combination of cigarette smoking and asbestos exposure has been shown to result in a particularly high risk of developing lung cancer. Selikoff, et al. (16) have shown that asbestos workers who smoke have 90 times greater risk of developing lung cancer than nonsmoking, nonexposed people. Shabad, et al. (I 7) recently studied the possible causes of the synergistic effect of cigarette smoke and asbestos. They studied the carcinogenic activity of different types of asbestos in the U.S.S.R. and noted that all samples of chrysotile asbestos had traces of benzo(a)pyrene (a polycyclic aromatic hydrocarbon carcinogen found in cigarette smoke). In addition, they noted that chrysotile asbestos had a high adsorption activity for benzo(a)pyrene. This was not found in the other types of asbestos tested (anthophyllite and magnesiaarfvedsonite). In these animal studies, 20 percent of the rats exposed to chrysotile asbestos developed precancerous lesions; inhalation of chrysotile plus benzo(a)pyrene or of chrysotile plus cigarette smoke increased the frequency of the lesions to 57 and 38 percent, respectively. The synergism between asbestos and smoking may be the result of the adsorption of carcinogens onto asbestos, therefore prolonging their retention in the lung. Infection and Carcinogenicity There has been some discussion concerning the association between lung cancer and chronic bronchitis. Both diseases can be caused by cigarette smoking; however, chronic bronchitis may also influence the development of lung cancer by some independent mechanism. Schreiber, et al. (14) administered N-nitrosoheptamethy- leneimine to germfree rats, specific-pathogen-free rats, and rats with chronic murine pneumonia. The incidence of lung neoplasms was 17 percent in germfree males, 37 percent in specific pathogen-free males, and 83 percent in infected males. An incidence of 90 to 100 percent occurred among females in all three experimental groups. They concluded that chronic respiratory infection may enhance the neoplastic response of the lungs to a systemic carcinogen. 49 OTHER CANCERS Oral and Laryngeal Cancer Schottenfeld, et al. (13) have studied the role of smoking on the development of multiple primary cancers of the upper digestive system, larynx, and lung. They followed 733 patients surviving a first primary epidermoid cancer of the oral cavity, pharynx, or larynx for 5 years. The average annual incidence for a second primary was higher in men (18.2/1000) than in women (15.4/1000). Both men and women who developed a second primary tumor had heavier tobacco exposure prior to their first cancer than those who did not develop a second malignancy. The authors were unable to show a significant relationship between smoking habits after removal of the first primary and development of a second primary. They postulate that this failure to show an association is due to the long induction period between presence of a carcinogen and occurrence of the cancer, and they expect that a relationship, if present, may become apparent after 7 or 8 years of followup. Genitourinary Cancer Schmauz and Cole (12) studied 43 persons with cancer of the renal pelvis or ureter and noted that smoking was only a risk factor at very high levels of consumption (over 2% packs per day), despite its being related to cancer of the bladder at all levels of smoking. They postulate that, due to the rapid transit of urine through the renal pelvis and ureter, very high levels of exposure are required to have any effect whereas the bladder stores urine for some time and even small amounts of carcinogens in the urine may be sufficient to influence the bladder epithelium. Nasophary ngeal Cancer Lin, et al. (IO), in a retrospective study of nasopharyngeal cancer in Taiwan using neighborhood controls, found smoking to be significantly associated with the development of nasopharyngeal carcinoma. A person smoking over 20 cigarettes per day had twice the risk of a nonsmoker of developing nasopharyngeal cancer. ARYL HYDROCARBON HYDROXYLASE (AHH) Due to the great variation in the amount of smoking exposure before the development of lung cancer, attempts have been made to 50 identify groups of people who may have a greater sensitivity to the carcinogenic effect of cigarette smoke. Interest has developed in the possibility that aryl hydrocarbon hydroxylase (AHH) may be a genetically determined enzyme that mediates such increased susceptibility to certain environmental carcinogens. AHH is an enzyme system which metabolizes polycyclic aromatic hydrocarbons; some of the resulting metabolites are carcinogenic. It has been postulated that persons with high levels of this enzyme may be at greater risk of developing cancer from exposure to the polycyclic hydrocarbons in cigarette smoke than those with low levels. The amount of AHH produced in response to an inducing stimulus can be used to separate a population into three groups (those capable of being induced to produce high, medium, and low levels of AHH). Keller-man, et al. (8) studied the induction of AHH activity in 353 healthy subjects (67 families with 165 children). They felt that the enzyme was controlled by a single gene locus with two alleles (one able to be induced to produce high AHH levels with a gene frequency of .283 and one, to produce low levels with a gene frequency of .7 17). All six possible crossmatings were found in the families studied, and no deviations from the expected phenotypes were found in the children. Cantrell, et al. (2), studied 19 healthy volunteers and found that cigarette smokers had higher levels of AHH in their pulmonary aveolar macrophages than nonsmokers. In one subject they showed an increase in AHH activity starting 1 week after he began to smoke 10 to 15 cigarettes per day (2, Fig. 1). Holt and Keast (7) also showed increased levels of AHH activity in homogenates of lung tissue from mice exposed to cigarette smoke. Kellermann (9) also studied the inducibility of AHH in the lymphocytes of 50 patients with bronchogenic carcinoma and compared them to a healthy white population and to a group of patients with nonrespiratory malignancies (Table 3). They found that lung cancer patients had a statistically significant, higher percentage of persons homozygous for the high allele, i.e., able to be induced to high AHH levels, than either the healthy or tumor controls. They postulated that the reason for the greater frequency of persons homozygous for the high AHH inducibility allele in the lung cancer group was that this group was more susceptible to lung cancer due to their increased ability to convert polycyclic aromatic hydrocarbons into carcinogenic metabolites. The incidence of lung cancer, 51 however, does not show a markedly familial occurrence pattern; therefore, a single genetic locus can not be the major factor determining susceptibility. Persons with increased ability to metabolize polycyclic aromatic hydrocarbons may well be a group at increased risk of developing lung cancer if they smoke; however, prospective studies of random populations controlled for smoking and environmental factors will be necessary before this genetic susceptibility can be confirmed. FIGURE I.-Production of aryl hydrocarbon hydroxylase (AHHI in macrophages from one person in response to cigarette smoking 0.05 - B c" 8 0.04 - b E (D 0 0.03 _ l- b P VI C 5 0.02 _ : 0.01 _ . . . . . . . . ...*..... . . . . . ..*....*.... I., ~~~--~-=`,--`1 I I I I I 1 -115 0 10 20 30 40 50 60 70 80 90 DAYS NOTE.-Shaded bar indicates duration of smoking; the vertical lines indicate the range of duplicate determinations at each time period. Source: Cantrell, E.T., et al. (2). 52 TABLE 3. - Aryl hydrocarbon hydroxylase (AHH) inducibility in patients with lung cancer, with other tumors, and in healthy controls GROUP NUMBER IN DISTRIBUTION OF GENE FREQUENCIES GROUP GENOTYPES ( PERCENT)' OF A AND B ALLELES I I I AA AB BB A B Healthy control 85 44.7 45.9 9.4 0.676 0.324 Tumor control 46 43.5 45.6 10.9 0.663 0.337 Lung cancer 50 4.0 66.0 30.0 0.370 0.630 `AA = low inducibility;AB = intermediate inducibility; BB = high inducibility Source: Kellerman. G.. et al. (9). SUMMARY OF RECENT CANCER FINDINGS 1. Filter cigarette smokers have a lower risk of developing lung cancer than nonfilter cigarette smokers, but that risk is still greater than the risk to nonsmokers and increases with increasing number of filtered cigarettes smoked. 2. Cigarette smoking and exposure to radioactivity by uranium mining have been related to cytologic changes in the respiratory tract epithelium including carcinoma in situ. Cigarette smoking has been more strongly related to these changes than mining exposure. 3. Crysotile asbestos has been shown to contain traces of the carcinogen benzo(a)pyrene, and the combination of the two has been shown to be a more potent carcinogen in rats than either alone. 4. Heavy smoking prior to a first primary oral or respiratory cancer has been shown to be related to the development of a second primary in the respiratory tract or oral cavity. 5. Results from one study have shown a greater proportion of lung cancer patients having high levels of aryl hydrocarbon hydroxylase activity than among either healthy persons or persons with other cancers. Persons with high levels of AHH may be a group which has a genetically determined increased risk of lung cancer if they smoke, but no excess risk if they do not smoke. 54 2 10 11 12 13 AMERICAN CANCER SOCITY. `75 Cancer Facts and Figures. New York, N.Y., 1974, 31 PP. CANTRELL, E. T., MARTIN. R. R., WARR, G. A., BUSBEE, D. L., KELLERMANN, G., SHAW, C. Induction of aryl hydrocarbon hydroxylase in human pulmonary alveolar macrophages by cigarette smoking. Transactions of the Association of American Physicians, 86th Session, Atlantic City, New Jersey, May l-2. 1973. 86: 121-130. HARRIS, C. C. The epidemiology of different histologic types of bronchogenic carcinoma. Cancer Chemotherapy Reports 4(2, Part 3): 59-61, March 1973. HIGGINS, I. T. T. Trends in respiratory cancer mortality: In the United States and in England and Wales. Archives of Environmental Health 28(3): 121-129, March 1974. HOFFMANN, D., HECHT, S. S., ORNAF, R. M., WYNDER, E. L. M-nitrosonor- nicotine in tobacco. Science 186(4160): 265-267, October 18, 1974. HOFFMANN, D., WYNDER, E. L. Chemical composition and tumorigenicity of tobacco smoke. In: Schmeltz, 1. (Editor). The chemistry of tobacco and tobacco smoke. Proceedings of the symposium on the chemical composition of tobacco and tobacco smoke held during the 162nd National Meeting of the American Chemical Society in Washington, DC., September 12-17, 1971. Plenum Press, New York, 1972, pp. 123-147. HOLT, P. G., KEAST, D. induction of aryl hydrocarbon hydroxylase in the lungs of mice in response to cigarette smoke. Experientia 29: 1004, August 15, 1973. KELLERMANN, G., LUYTEN-KELLERMANN, M., SHAW, C. R. Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes. American Journal of Human Genetics 25: 327-331, 1973. KELLERMANN, G., SHAW, C. R., LUYTEN-KELLERMANN, M. Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. New England Journal of Medicine 289(18): 934-937, November 1, 1973. LIN, T. M., CHEN, K. P., LIN, C. C., HSU. M. M., TU, S. M., CHIANG, T. C., JUNG, P. F., HIRAYAMA, T. Retrospective study on nasopharyngeal carcinoma. Journal of the National Cancer Institute Sl(5): 1403-1408, November 1973. SACCOMANNO, G., ARCHER, V. E., AUERBACH, O., SAUNDERS, R. P., BRENNAN, L. M. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 33(l): 256-270, January 1974. SCHMAUZ, R., COLE, P. Epidemiology of cancer of the renal pelvis and ureter. Journal of the National Cancer Institute 52(5): 1431-1434, May 1974. SCHOTTENFELD, D., GANlT, R. C., WYNDER, E. L. The role of alcohol and tobacco in multiple primary cancers of the upper digestive system, larynx. and lung: A prospective study. Preventive Medicine 3(2): 277-293, June 1974. 55 14 SCHREIBER, H., NETTESHEIM, P., LIJINSKY, W., RICHTER, C. B., WALBURG, H. E., Jr. Induction of lung cancer in germ-free specific-pathogen-free, and infected rats by N-nitrosoheptamethyleneimine: Enhancement by respiratory infection. Journal of the National Cancer Institute 49(4): 1107-1114, October 1972. 15 SCHREIBER, H., SACCOMANNO, G., MARTIN .D. H., BRENNAN, L. Sequential cytological changes during development of respiratory tract tumors induced in hamsters by benzo(a)pyrene-ferric oxide. Cancer Research 34(4): 689-698, April 1974. 16 SELIKOFF, 1. J., HAMMOND, E. C., CHURG, J. Mortality experiences of asbestos insulation workers 1943-1968. Pneumoconiosis. Proceedings of the International Conference on Pneumoconiosis, 3d, Johannesburg, 1969. Oxford University Press, New York, 1970. Pp. 180-186. 17 SHABAD, L. M., PYLEV, L. N., KRIVOSHEEVA, L. V., KULAGINA, T. F., NEMENKO, B. A. Experimental studies on asbestos carcinogenicity. Journal of the National Cancer Institute 52(4): 1175-l 187, April 1974. 18 U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103, 1964, 387 pp. 19 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Public Health' Service Review: 1967. U.S. Department of Health, Education, and Welfare. Washington, Public Health Service Publication No. 1696, Revised January 1968,227 pp. 20 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1968. Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Public Health Service Publication 1696, 1968, 117 pp. 21 US PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1969. Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington, Public Health Service Publication 1696-2, 1969, 98 pp. 22 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 71-7513, 1971,458 pp. 23 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: A Report of the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 72-6516, 1972, 158 pp. 24 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1973. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 73-8704, 1973, 249 pp. 25 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1974. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (CDC) 74-8704, 1974, 124 pp. 26 WYNDER, E. L., MABUCHI, K., BEATTIE, E. J., Jr. The epidemiology of lung cancer. Journal of the American Medical Association 213(13): 2221-2228, September 28, 1970. 56 CHAPTER 3 Non-Neoplastic Bronchopulmonary Diseases CHAPTER 3 Non-Neoplastic Bronchopulmonary Diseases Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1 Smoking and Respiratory Morbidity .......................... 62 Smoking and Air Pollution ................................. 63 Smoking and Occupational Disease ........................... 68 Mill Workers - Byssinosis .............................. 68 Firemen ......................................... 68 Smoking and Pulmonary Function Tests ........................ 7 1 a, -Antitrypsin ..................................... 72 Autopsy and Pathophysiologic Studies ......................... Autopsy Studies .................................... `7:: Pathophysiologic Studies in Humans Pathophysiologic Studies in Animals ............................................ GF Summary of Recent Bronchopulmonary Findings .................. 78 Bibliography .......................................... 79 List of Figures Figure 1 .-Respiratory bronchiolitis in smokers and control groups . . . . . . . . . . . . . . . . . . . . . . _ . _ . List of Tables Table 1 .-Levels of sulfur dioxide (SO,) and total suspended particulates (TSP) in four Utah communities, 197 1, and in five Rocky Mountain communities, 1970 . . . . . _ . . . . . . . . . . . . . . . . . . Table 2.-Mean annual levels of sulfur dioxide (SO,) and total suspended particulates (TSP) in four areas . . . . . . . . . . . . . . _.................. Table 3.-Age-adjusted percentage of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to chemicals, fumes, sprays, and dusts . . . . . . . . . . . . . _ . . . . . . . _ . . . _ . . . . Table 4.-The aI -antitrypsin levels and frequency of protease inhibitor (Pi) phenotypes in healthy populations _ . . . . . . . . . . . . . . . . . . . _ . . . . _ . . . Table 5.-Means of the numerical values given lung sections at autopsy of male current smokers and non- smokers, standardized for age _ . . . . . . _ . . . . _ . . . . Table 6.-Means of the numerical values given lung sections at autopsy of female current smokers and nonsmokers, Page Page . . . . . . . . 65 . . . . . . . . 66 ...... 69-70 . . . . . . . . 75 7F standardized for age . . . . . . . . . . . . . . . _ . . . . . . . . . . . . . . . . . , _. Table 7.-Means of the numerical values given lung sections at autopsy of male former cigarette smokers, standardized for age . . . :. . . . . . . . . . . . . . . . . . . . . . . 76 INTRODUCTION Chronic non-neoplastic lung diseases are major causes of permanent and temporary disability in the United States. Chronic obstructive pulmonary disease (COPD) is the largest subgroup of these diseases and in this report refers to chronic bronchitis and/or emphysema. Relationships between smoking and non-neoplastic lung diseases have been reviewed in previous reports on the health consequences of smoking (36, 37, 38, 39, 40. 41, 42, 43). Cigarette smoking is the most important cause of COPD. Cigarette smokers have higher death rates from chronic bronchitis and emphysema, more frequently report symptoms of pulmonary disease, and have poorer performance on pulmonary function tests than do nonsmokers. These differences become even more marked as the number of cigarettes smoked increases. The relationship between cigarette smoking and COPD has been demonstrated in many different national and ethnic groups and is more striking in men than in women. Pipe and cigar smokers have higher morbidity and mortality rates from COPD than do nonsmokers but are at lower risk than cigarette smokers. Cessation of cigarette smoking often results in improved pulmonary function tests, decreased pulmonary symp toms, and reduced COPD mortality rates. In addition to an increased risk of COPD, cigarette smokers are more frequently subject to and require longer convalescence from other respiratory infections than nonsmokers. Also, if they require surgery, they are more likely to develop postoperative respiratory complications. The relative importance of air pollution in the development of COPD remains controversial, but it is clearly less significant under most circumstances than cigarette smoking. The combination of cigarette smoking and polluted air, however, may produce higher rates of COPD than either factor alone. Several occupational exposure groups incur an increased risk of COPD, and cigarette smoking adds significantly to this risk. In particular, exposure to cotton fiber and coal dust appears to act in concert with cigarette smoking to promote the development of pulmonary disease. 61 Autopsy studies have demonstrated a dose-related effect of cigarette smoking on the severity of macroscopic emphysema. Increased goblet cell density, alveolar septal rupture, bronchial epithelial thickening, and mucous gland hypertrophy are more commonly found in the lungs of smokers than in those of nonsmokers. Many pathophysiologic mechanisms by which smoking may cause COPD have been proposed. Decreased overall pulmonary clearance, reduced ciliary motion, and impaired alveolar macrophage functions have all been related to cigarette smoking and probably play a role in the development of COPD. The exact mechanisms whereby cigarette smoking contributes to the development of COPD, however, remain only partially understood. SMOKING AND RESPIRATORY MORBIDITY An increased prevalence of respiratory symptoms in smokers from early teens to those past the age of 80 has been well established. Bewley, et al. (5), in a study in Derbyshire County, England, extended these findings to include younger children. In a questionnaire study of 7,l 15 schoolchildren ages 10 to 11% years, he found that 6.9 percent of the boys and 2.6 percent of the girls smoked more than one cigarette per day. The boys who smoked reported more morning cough (2 1.5% to 6.1%), cough during the day or night (48.0% to 20%), and cough of 3-months duration (18.0% to 4.1%) than their nonsmoking schoolmates. The percentages for the girls were similar although based on smaller numbers of smokers. As in many studies of this type, it was impossible to control for air pollution, social class, or smoking habits of the parents; nevertheless, the results suggest that cigarette smoking even in this young age group produces respiratory symptoms. Fridy, et al. (12), in a somewhat older population (average age 25 years), examined the effect of smoking on airway function during mild viral illness. They measured closing volumes for 22 subjects (9 cigarette smokers - average age 29.1, and 13 nonsmokers - average age 25.7) before onset and at weekly intervals from the beginning of a mild respiratory illness until all symptoms had subsided. The closing volumes for smokers prior to illness were higher than those for nonsmokers, but the difference was not statistically significant. In the tests done during the illness, the smokers had a statistically significant increase in the closing volumes (from 37.0 to 45.8 percent of their total lung capacity, while nonsmokers had no change,32.`7 62 and 31.7 percent). Smokers remained symptomatic more than twice as long as nonsmokers (35.7 and 16.5 days, respectively), and the mean duration of pulmonary function abnormalities in smokers was 29.7 days. Nonsmokers had no change in pulmonary function tests during illness. SMOKING AND AIR POLLUTION The relationships among air pollution, smoking, and COPD remain controversial. Reasons for this controversy include difficulties in controlling such variables as socioeconomic class, degree of crowding, ethnic differences, and age distribution as well as determining the exact type and amount of individual pollution exposure. Measuring individual pollution exposure even within a small area is difficult since both amount and type can vary dramatically from street to street (e.g., proximity of a street to a heavily traveled expressway). In an effort to control as many of these variables as possible, two basic approaches in study design have been tried. The first approach is to find areas where pollution levels have been well measured and then to select study populations that are as similar as possible in areas with different pollution levels. Thus, effects on a population in a low pollution area can be compared to those on a similar population in a high pollution area. The second approach is to select a population that is as uniform as possible, for example, twins, and then measure individual responses to different pollution expo- sures. Both approaches have drawbacks as will be evident from the following studies. Using the first approach, the Community Health and Environ- mental Surveillance System of the Environmental Protection Agency (6, II), has conducted surveys in areas with different types and levels of pollution in four different parts of the United States (Chicago, New York City, the Salt Lake Basin, and the Rocky Mountain area). Within each part of the country, the researchers identified communi- ties of similar socioeconomic status but different pollution levels. They then administered a questionnaire through the school systems to determine the frequency of lower respiratory tract infection in the children and their families. They reported an increased incidence of lower respiratory tract illness in children in high pollution communi- ties compared to children in low pollution communities. This difference was demonstrable only in children whose families had lived in the high pollution communities for more than 3 years. They also reported an increased prevalence of chronic bronchitis in parents 63 who lived in high pollution communities compared to parents from low pollution communities. They calculated the excess risk of chronic bronchitis produced by air pollution to be one-third of that produced by smoking but to be additive with smoking. Several major problems in these surveys make it difficult to evaluate the results. The authors describe the areas as having different kinds of pollution. The Salt Lake Basin and Rocky Mountain areas were felt to be high in sulfur dioxide (SO2) and low in total suspended particles (TSP), while New York and Chicago were high in both these pollutants. As a result, in the Salt Lake Basin and Rocky Mountain areas, communities were separated into low and high pollution communities only on the basis of their SO2 levels. Many communities classified as low pollution communities on the basis of their SO2 levels had higher levels of total suspended particles than the communities classified as high pollution communities by SO;! level (Table 1). In fact, the average total suspended particles level for the low pollution communities in the Salt Lake Basin was higher than that for the high pollution communities (Table 2) in the Salt Lake Basin. These differences exemplify the difficulties of using only one pollutant as a marker of total pollution exposure. Additional problems with these studies were the differences in socioeconomic class measurements between low and high pollution communities in some of the regions. In the Rocky Mountain area, the percentage of fathers who completed high school varied from 91 percent in one of the low communities to 58 percent in one of the high pollution communities. There were also major differences between high and low pollution communities in the percentage of families with more than one person per room in the Salt Lake Basin (59.6% to 5 1.2%), Rocky Mountain area (87.0% to 68.00/o), and New York (85.0% to 72.0%). Residential stability (percentage of families living in the community for more than 3 years) was different in the high and low pollution communities in New York (58.0% to 36.0%) and Chicago (56.0% to 46.0%). The percentage of parents who currently smoke also differed for high and low pollution communi- ties in New York (53% to 45% for the fathers and 47% to 37% for the mothers). These differences raise questions as to whether the high and low pollution communities were really similar enough populations to justify the claim that differences in incidence of respiratory tract illness could be attributable to differences in air pollution. 64 TABLE 1. - Levels of sulfur dioxide (S02) and total suspended particulates (TSP) in four Utah' communities, I9 71, and in five Rocky Mountain communities, I9 70 Area Community Pollution Classification so2 Pollution levels in &m3 TSP Utah (Salt Lake Basin) Low 8 78 Intermediate 1 15 81 Intermediate 2 22 45' High 62 66 Rocky Mountain Area Low 1 10 50 Low 2 26 68 Low 3 46 110 High 1 IOY 43 High 2 186 102 Source: Chapman. R.S.. et al. (6). cn wl TABLE 2. - Mean annual levels of sulfur dioxide (SO2) and total suspended particulates (TSP) in four areas Pollution levels in p&n3 Area SO2 Decade During Study Preceding Study Low High Low High Five Rocky Mountain Areas 10 21s 10 263 Salt Lake Basin 9 65 < 20 144 New York 23 63 < 30 431 Chicago 51 106 109 250 NOTE. - Area includes highest- and lowest-polluted communities. Source: French, J.G., et al. (II). TSP Decade During Study Preceding Study Low High Low High 4.5 110 50 101 78 66 82 62 34 104 40 201 111 151 121 165 Increased prevalence of COPD has also been demonstrated in areas of high pollution in the Netherlands (44), Yokkaichi, Japan (25), and Cracow, Poland (30). Again, however, these studies were poorly controlled for socioeconomic status. Several recently published studies have used the second major method of investigating the relationship between smoking, air pollution, and COPD, i.e., to select a uniform population and then to measure individual differences to pollution exposure. Comstock, et al. (8), in an attempt to control for occupational exposure and socioeconomic class, studied three separate, uniform populations of telephone workers and used as a measure of pollution the location of the place of work and residence. The populations studied were telephone installers and repairmen in Baltimore, New York City, Washington, D.C., and rural Westchester County in 1962 (survey 1) and in 1967 (survey 2); and telephone installers and repairmen in Tokyo in 1967 (survey 3). They were unable to find any relation between pulmonary symptoms and degree of urbanization of place of work .or place of residence (either current or past). They were, however, able to establish a strong correlation between smoking habits and pulmonary symptoms. Given the crude estimation of pollution exposure used in this study (all workers in each city were treated as though they received the same exposure), a small difference in symptoms due to air pollution could have been missed, whereas the difference due to smoking could be detected both because it was larger and because it was possible to determine individual exposure more exactly. Hrubec, et al. (15), in a study of twins from the U.S. Veterans Registry, were unable to show a difference in respiratory symptoms either between individuals with different exposure to air pollution or between members of twin pairs with different air pollution expo- sures. However, they too used a crude measure of air pollution exposure (by each zip code area), and so could have missed a small difference due to air pollution despite being able to relate respiratory symptoms to smoking, socioeconomic status, and alcohol intake. Colley, et al. (7), in a study of 3,899 persons (20-year-olds born during the last week of March 1946 in the United Kingdom), were also unable to show a relation between COPD and air pollution. They used as their estimates of air pollution exposure the domestic coal consumption in the towns where the subjects lived. This method of estimating air pollution exposure is subject to the same limitation cited for the previous two studies - limited sensitivity to small risks due to air pollution. 67 In summary, if an increased risk of COPD due to air pollution exists, it is small compared to that due to cigarette smoking under conditions of air pollution to which the average person is exposed. The possibility remains that the two different kinds of exposure may interact to increase the total effect beyond that contributed by each exposure. SMOKING AND OCCUPATIONAL DISEASE Friedman, et al. (13), in a study of 70,289 men and women who had had Kaiser-Permanente multiphasic health checkups, noted that smokers were more likely to report occupational exposure on a questionnaire (Table 3) than nonsmokers. The differences are small but statistically significant and need to be considered when investi- gating the relationship of smoking to occupational diseases. They were not able to determine whether smokers' responses reflect actual differences in exposure or an increased awareness of and sensitivity to occupational exposure. Exposure to coal and granite dust and cotton fiber carries an increased risk of COPD. This risk is further increased by cigarette smoking. Other new data have been published which clarify the risk in certain occupational groups. Milt Workers - Byssinosis Berry, et al. (4), in a study of 595 workers in the Lancashire cotton mills over a 3-year period, found that the decline in forced expiratory volume in one second (FEVr ) was 19 ml/year greater in smokers than in nonsmokers (59 ml/year compared to 40 ml/year, P > .02) but they could not demonstrate a dose-response relationship. Firemen Sidor and Peters (32, 33), in a cross-sectional study of 1,768 Boston firemen, were unable to show a significant relationship between severity of fire exposure and impairment of pulmonary function tests or prevalence of COPD; there was a clear harmful effect of cigarette smoking on both. They postulate that they were unable to show an increased prevalence of COPD in this cross-sec- tional study because firemen who developed COPD were no longer capable of meeting the physical demands of the job and had retired, thus removing them from the study population. They were able, however, to show a higher incidence of COPD in men under the age of 35 years who had been on the force more than 6 months when compared to persons of the same age who had just been hired. 68 TABLE 3. - Ageadjusted percentage of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to chemicals, fumes, sprays, and dusts Exposure Chemicals, cleaning fluids or solvents (or chemical sprays)2 Insect or plant sprays Ammonia, chlorine, ozone or nitrous gases (nitrous oxides or other irritating gases)2 Engine or exhaust fumes (more than 2 hours a dayJ2 Time period1 Before 1 year ago In the past year Before I year ago In the past year Before 1 year ago In the past year Before 1 year ago In the past year Smoking status Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Whites Blacks % % % % Men Women Men Women 24.0 6.4 26.0 11.8 18.9 5.1 19.2 6.7 12.1 3.0 14.2 5.1 9.1 2.6 11.6 4.5 4.0 1.0 6.6 2.1 3.5 0.9 5.1 1.9 2.9 2.1 4.8 2.9 2.9 1.8 4.8 3.0 1.9 2.3 10.3 4.8 6.2 1.9 7.0 3.2 5.4 1.9 1.6 3.9 3.1 1.5 5.8 3.1 11.x 1 .o 17.6 1.9 6.9 0.5 13.1 0.6 8.7 0.7 17.6 I.0 5.2 0.5 13.3 1.2 Yellows % % Men Women 16.7 4.1 12.9 5.1 13.1 3.5 9.4 3.8 3.x 0.3 2.5 1 .o 3.0 1.3 3.6 1.x 6.2 0.9 4.5 1.7 8.0 0.5 3.5 1.7 4.0 0.0 3.6 0.1 4.3 0.5 3.9 0.2 TABLE 3. - Age-adjusted percentage of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to chemical, fumes, sprays, and dusts - Continued Exposure Time period ' Smoking Status Plastic or resin fumes Lead fumes or metal fumes (leaded sprays or paint sprays)2 Asbestos, cement or grain (or flour) dusts2 Silica, sandblasting, grinding or rock drill- ing dust (sand or coal)2 Total number of subjects Before 1 year ago In the past year Before 1 year ago In the past year Before 1 year ago In the past year Before 1 year ago In the past year Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Smokers Nonsmokers Whites Blacks Yellows % % Men Women 5.1 1.1 3.5 0.8 3.3 0.8 2.5 0.6 8.2 0.9 4.3 0.5 5.5 0.7 3.1 0.5 7.1 0.6 4.4 0.3 2.8 0.4 1.8 0.3 6.9 0.6 4.0 0.5 3.9 0.5 2.3 0.4 14,485 16,059 8,282 18,526 % % Men Women 3.3 1.2 3.0 0.6 3.9 0.9 4.3 0.6 9.1 1.5 5.8 0.6 1.7 1.3 6.8 0.8 11.5 1.2 8.8 0.8 7.5 1.0 6.2 0.8 10.5 6.8 8.0 6.6 1.3 0.7 1.0 0.9 2,609 2.869 1,116 3,218 -~ % % Men Women 3.1 0.1 2.2 0.3 3.0 0.1 1.3 0.3 4.1 0.1 2.6 0.1 3.3 0.5 2.4 0.4 2.7 0.0 1.6 0.1 2.1 0.1 0.3 0.8 3.5 0.3 2.9 0.0 3.3 0.4 3.5 0.4 654 446 712 1,313 `With a few slight variations, the questions were worded as follows: SMOKING AND PULMONARY FUNCTION TESTS It is recognized that smokers as a group have poorer pulmonary function tests than nonsmokers. The standard pulmonary function tests generally only become abnormal late in the pathologic process of COPD and usually only after irreversible changes in the lungs have occurred. As a result, tests are needed that will identify persons at risk of developing COPD before they have irreversible loss of lung function. Standard tests of pulmonary resistance are inadequate for this purpose because they measure predominately resistance in the large airways while the first changes of COPD occur in bronchioles that are 2 mm and smaller. Small airway resistance may be measured through evaluating frequency dependent compliance, but this is often cumbersome to perform. Closing volume and maximum expiratory flow rates at 25 and 50 percent of vital capacity have the advantage of being relatively easy to perform, yet are still able to measure changes in the small airways. Closing volume is the lung volume at which the alveoli in the dependent portions of the lung begin to close, and it is usually expressed as a percent of vital capacity. Elevated closing volume is considered evidence of small airway dysfunction. Maximum expiratory flow rates at 25 and 50 percent of vital capacity measure air flow at low lung volumes where the resistance of the small airways makes up a much larger proportion of the measured resistance. Several recently published studies contain data on small airway dysfunction in smokers. Lim (20) studied 50 smoking and 50 nonsmoking high school students and found in smokers a statistically significant reduction in the forced expiratory volume in one second when the test was started at normal end expiration (i.e , low lung volumes). Stanescu, et al. (34) noted elevated closing volumes in 16 healthy asymptomatic smokers when compared to 16 nonsmokers, but were unable to show any difference in maximum expiratory flow rates at 25 and 50 percent vital capacity. Ruff, et al. (28) studied 50 subjects ages 18 to 82 and showed increasing closing volumes with age and smoking. Martin, et al. (21), in a study of 50 subjects ages 12 to 68, found that 25 percent of the smokers had abnormal closing volumes, and Oxhoj, et al. (26) noted elevated closing volumes for 50-year-old smokers compared to nonsmokers. Dirksen, et al. (10) reported higher closing volumes in smokers and noted no change with cessation of smoking. Hoeppner, et al. (14) also showed elevated closing volumes in healthy smokers ages 16 to 6 1, but found these to be closely related to decreases in the static transpulmonary pressure. They postulate that the elevated closing volumes may be related to decreased elastic recoil rather than changes in small airway resistance. 71 The data have established the fact that a greater percentage of smokers than nonsmokers have elevated closing volumes, but the number of smokers with elevated closing volumes who will develop COPD remains to be determined. Stebbings (35), in a further analysis of Densen's data (9) on the changes in pulmonary function test values in male postal workers and transit workers in New York City, noted significantly less decline in FEVl among Black smokers when compared to White smokers. This difference persisted even when corrections were made for differences in amount smoked, age at which smoking began, inhalation patterns, and smaller initial lung volumes in Blacks. Black and White nonsmokers did not differ in the rate of decline in FEVt . By age 60 years, Blacks who smoked one pack per day had a .34 liter smaller cumulative decrease in FEVl than Whites who smoked the same amount. a I -ANTITRYPSIN It would be useful to identify the populations at excessive risk of developing COPD from smoking. They then might be made aware of the hazard before they develop symptomatic lung disease. Persons with a 1 -antitrypsin deficiency may be such a population. a 1 -antitrypsin deficiency is a rare homozygous recessive genetic defect which occurs in approximately one out of every 3,600 people and results in an increased susceptibility to and premature develop- ment of COPD. There is some evidence that smoking hastens the development of -COPD in these people. The heterozygous state (producing intermediate levels of the al -antitrypsin in serum) is far more common than the homozygous state and is found in approxi- mately 10 percent of the population. It is uncertain whether the heterozygous deficiency state predisposes to COPD. a 1 -antitrypsin inheritance patterns suggest multiple codominant alleles at one gene locus, some of which (most notably the S and Z alleles) produce lower serum protease levels than the normal M-allele (Table 4). The pathophysiologic mechanism of the deficiency state is felt to be the inability to inhibit the proteases found in the granulocytes and pulmonary macrophages which go on to damage essential constituents of lung tissue. Several recent reviews of the enzyme and the clinical syndrome produced by its deficiency have been published (26, 17, 18). 72 TABLE 4. - The a l-antitrypsin levels and frequency of protease inhibitor (Pi) phenotypes in healthy populations Protease inhibitor (PO type Healthy populauons Q 1 -antitrypsin concentration (% normal) Expected frequency of Pi types (pm 1,000 people) MM 100 898 (FM,FF,IM,MV.MX) 100 28 MW 80 -a MP 80 1 MS 80 41 FVS) 80 1 MZ 60 29 (FZ) 60 1 SS 55 1 SZ 40 1 zz 15 Cl a Seen rarely in Spanish populations. Source: Mittman, C., Lieberman, J. (22). In most studies of patients with COPD, investigators have found an increased prevalence of the partially deficient heterozygote phenotypes when compared to healthy control populations. In the few studies not finding this relationship, only al-antitrypsin levels were measured. Because a 1 -antitrypsin is an acute phase protein and increases with infection, it is difficult to separate out the partially deficient heterozygote phenotypes by measuring only al-antitrypsin levels. It is necessary to identify the products of each allele electrophoretically in order to identify the deficient phenotypes. Two recent studies using this technique showed an increased prevalence of deficient phenotypes in patients with COPD but not among control populations. Mittman, et al. (23) studied 240 patients with COPD admitted to LaVina Hospital in Altadena, California, and found that 19.1 percent had deficient phenotypes compared to only 7.1 percent of a control Scandinavian population. Keuppers and Donhardt (19) found prevalence rates for deficient phenotypes of 3.5 percent in healthy confrols, 12.9 percent in persons retired from work because of COPD, and 15.7 percent in patients hospitalized for COPD. 73 Additional population studies have been done to determine the effect of the heterozygous state on the development of COPD. Webb, et al. (47) studied 500 persons visiting a multiphasic screening clinic in Monroe County, New York, and found that 11.6 percent had deficient phenotypes. He was unable to show differences in symptoms or in pulmonary function test values between persons with normal and deficient phenotypes. In a study of 451 randomly selected adults from the same county (31), pulmonary function studies were done on 40 deficient heterozygote phenotypes (20 MS and 20 MZ) and on normal phenotype (MM) controls matched for age, sex, and smoking habits. When total pulmonary resistance was measured by a forced oscillometric technique, the nonsmoking MZ subjects had significant impairment compared to their normal phenotype controls. All cigarette smokers, regardless of phenotype, had abnormal values. Although the data are still inconclusive, it may well be that heterozygous deficient persons are a group at excessive risk of developing COPD especially if they smoke. AUTOPSY AND PATHOPHYSIOLOGIC STUDIES Autopsy Studies Auerbach, et al. (3) have previously shown dose-related macro- scopic emphysematous changes in the lungs of smokers. Now in an autopsy study (2) of 1,582 men and 388 women, they have examined microscopic lung parenchymal changes in relation to cigarette smoking. They were able to show that rupture of alveolar septa (emphysema) and fibrosis and thickening of the small arteries and arterioles are far greater in smokers than nonsmokers and increase with increasing amount smoked (Tables 5 and 6). When these researchers examined former cigarette smokers, they found that those who had stopped more than 10 years prior to death had fewer pathologic changes than those who had stopped less than IO years before death. But even in those who had stopped for more than 10 years, there was a greater degree of pathologic change in those who had been smoking more than one pack per day than in those who had been smoking less than one pack per day (Table 7). Niewoehner, et al. (24), in an autopsy study of 39 men who died suddenly from various causes and who were below 40 years of age (20 nonsmokers and 19 smokers), observed a respiratory 74 Subjects Who Current Pipe Current Cigarette Smokers Never Smoked or Cigar Regularly Smokers < .5 S-1 l-2 >2 Pk. Pk. Pk. Pk. Number of Subjects 175 141 66 115 440 216 Emphysema 0.09 0.90 1.43 1.92 2.17 2.27 Fibrosis 0.40 1.88 2.78 3.73 4.06 4.28 Thickening of arterioles 0.10 1.11 1.35 1.66 1.82 1.89 Thickening of arteries 0.02 0.23 0.42 0.68 0.83 0.90 NOTE. - Numerical values were determined by rating each lung section on scales of O-4 for emphysema and thickening of arterioles, O-7 for fibrosis, and O-3 for thickening of the arteries. Source: Auerbach, O., et al. (2). TABLE 6. - Means of the numerical values given lung sections at autopsy of female current smokers and nonsmokers, standardized for age Subjects Who Current Cigarette Never Smoked Smokers Regularly