Tobacco Documents Online

In summary, if an increased risk of CnPD' 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 kind'sofexposure may in~teract toincrease, the total effect beyond that contributed by each exposure. SMOKING AND OCCUPATIONAL DISEASE' Fri'edtnan„ et al. (BP 31)i,, in a study of 70,289 men and women who had. had Kaiser-Permanente multiphasi'c health checkups,,noted that smokers were more likely to report occupational exposure on alquestionnaire (Table 3) than nonsmokers. The differences are small but statistically significant and need to be considered'when investigating 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 andisensitivity to occupational exposure. Severa7l recent studies have confirmed' previous findings that 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 clarifyy the risk in certain occupational groups. Mill Workers - Byssinosis Berry, et al. (BP 41),, in a study of 595' workers in the Lancashire cotton mills over a 3'-year period, found that the decline in foxced~ expiratory volume in one second' (FEV'1) was 19 ml/'year greater in smokers thamin nonsmokers(59m1/year compared! to4'0ml/year) ,, but they could not demonstrate a dose-response relationship. Firemen Sidbr and P'eters (,BP' 94, BP 9'5)1, in al cross-sectiional 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-sectional study because firemen who develope&COPD were. no longer capable of ineeting the physical demands of the job and had retired,. thus removi'ng,them from the study population. They were able, however, to show a higher incidence of COPD'i'n 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 beenihired. SMOKING AND' PULXONARY FUNCTION TESTS It is recognized that smokers as a group have poorer pulmonary functi!on tests than nonsmokers. The standard pulmonary function tests generally on"Ly ~ . W ~ . ~ 7 1 N ~ O~

TABLE 3. - Ageadjusted p8, _ntage of cigarette sinokers and norisrxrokers i( ch race-sex group responding positively to exposure ro' chemicals, fumes, sprays, and' d'usrs Whites Dlacks Yellows Ezpasure Time periodl Smoking,srthtus . % .. %. '~ %'% i % . % Men Wnrrten, Men Women Men Women Chemicals, cleaning Before 1 year ago Smokers 24.0' 6.4 26.01 11.8 I 16.7 4.1 fluid's or sollvents (or Nonsmokers 18.9 5.1 19.2 6.7 12.9 5.11 chemical sprays)2 Inithe past year Smokers 12.1' 3.0 14.2 5'.1 13.1' 3.5' Nonsmokers 9:7 2.6 111.6 4.5' 9.4 3'.8' Insect or plant sprays Before 1 y,ear, ago Smokers 4.0' 1.0 6,6' 2'.1' 3.8 0.3'. Nonsmokers' I 3.5 0:9 5.1' 1!.9' 2.5 1'.0. . In the past year Smokers 2.9 2.1 I 4.8 2.9 3.0' 1.3' Nonsmokers 2.9 1.8 4!8 3.01 3.6 1.8 Ammonia, chlorine, Before 1i year ago Smokers 7.9 2:3' 103 4':8' 6.2 0199 ozone or nitrous gases Nonsmokers 6.2 1.9' 7.01 3:2 4.5 1.7 (nitrous oxides or other irritating gases)2' In the past year' Smokers 5.4 11.9' 7.6 3,9 8.0 0:5. Nonsmokers 3,7 1.5 5.8 3:1 3.5' 1.7, Engine or exhaust fumes Before L year ago~ Smokers 11.8 1.0 17.6 1.9 I 4 0' 0:0' (more than 2'hours a Nonsmokers 6.9 U 13.1 0.6 I 3.6 0.1 d'ay)2 ln the past' year Smokers 8.7 03 17.6 1.0 ' 4.3' 0.5 Nonsmokers 5.2 0.5 ' ' ' L 2 13.3 3.9 0.2 Plastic or resin fumes Before 1' year'ago Smokers 5.1 1.1 3.3 1.2 3.1 0.1 Nonsmokers 3.5' 0.8' 3.0 0.6 2.2 0'.3' In the past year Smokers 3.3 0.8' 3:9' 0.9 3.0' 0.1 Nonsmokers 2.5' 0.6' 4:3 0.6 Lead fumes or metal Before: 1 year ago Smokers 8.2' 0:9 9! 1' 1L5 4'.1' 0.1 fumes (leaded sprays: Nonsmokers 4:3 0:5 5:8 0.6 2.6 0.1 or paint sprays)2 In the past year Smokers 5:5 0.7 7.7 1.3' 3:3 0.5 N'onsmokers 3.1 0.5 6,8 0;8 . 2.4 0.4 Asbestos, cement or Before 1' year, ago . . Smokers 7.1 0.6 11.5' 11.2' 2.7 0.0 grain (or flbur) dusts2 Nonsmokers 4L4 0.3 8.8' 0.8 1 1.6 0.1 In the pascyear Smokers 2.8 0.4 7.5 1.0 2.7' 0:1 Nonsmnkers 1.8 0l3 6.2' 0'.8 0.3' 0.8 Silica„ sandblasting„ Before l year aga Smokers . 6.9' 0'.6 10.5' 1.3 3!.5 0.3 grinding or rock drill1 Nonsmokers 4.0 0l5' 6.8' 0L7 2.9 0.0 irtgdust (sandor coal)2 Iln the past year Smokers 3.9' 0.5 8.0' 1l0 3.3' 0.4 Nonsmokers 2'.3' 0'.4' 6.6 0.9 3.5 0_4, Total number of subjects Smokers 14,485 16.059, 2,609 2.869 65''4 446 Nonsmokers 8,282 18,526 1'„11'6' 3,218 712 1,313' tWith a few slight'variations, the questions were worded as follows: Before 1' yearago• "Before t year ago have you ever worked'in a place,where you were often ordaity araund_ ln the past year: "tn, the past', year have you worked inia place where you were,ofben or, daily around 24faterial in pa;entheses appears in "past year"'questionbut not in "before 11 year ago^'question:, Source: Friedman, G.D., tt' all (BP' 31'):

become abnormal late in the patholog~c process of COPD and usually only after irreversible ch~anges~ inth~e lungs have occurred.: As aresult„ tests areneed'ed that will id'entifypersonsat risk of d!eveloping,CaPDbeforethey have irreversible loss of lung function. Standard tests of pulmonary resistancee 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 resistence may be measured through evaluating f requency dependent compliance „ but this is of ten 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. Bl:evated closing volume is cons3:deredlevid~ence of small airway disfunction.. 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 resistanc . Several recently published studies contain data on small airway disfunction in smokers. Lim (BP 19) studied 50 smoking and 50 nonsmoking;high school students and found in smokersa stati'sticallysigp~ificant reductionin the forced exp3ratory volume in one second when the test was started at normal end expiration low lung volumes). . S'tanescu„ et al.(BP 58)' noted elevated closing,volumes in 16 healthy asymptomatic smokers whenicomparedito 16 nonsmokers,; but was unable to show any difference in maximum expiratory flow ratesat 25 and 5:0 percent vital capacity. Ruff, et a1.(BP~ 73) stud'ied~ 50 subjects ages 18 to 82' and showe&increasing, closing volumes wi'th age and smoking. Martin, et al. (BP 285), 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. (BP 307) noted el'evated' closing volumes for 50'-year-old' smokers compared to nonsmokers. Dirksen,, et al. ('BP'306)' reported higher closing volumes in smokers and notedino change with cessation of smoking. Hoeppner, et al. (B'P 244) also showedi elevated closing volumes in healthy smokers ages 16 to 61, but found these to be closely related to diecreases in the static transpulmonary pressure. They postulate that the elevated closing volumes may be xelated to decreased elastic recoil rather than changes in small airway resistance. 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 (BP49)',, i'n a further analysis of Densen's data (BP 86) on the ch:anges,in pulmonary function test values in malepostal'workErs,and:tr:ansit workers in New York City, noted significantly less decline in FEV1 among,Black smokers when compared to White smokers. This difference persisted even when corrections were made for differences in amount smoked, 73'

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 FEV . By age 60 years, Blacks who smoked one pack per day hadia- .34 liter smaTler cumulative decrease in FEU'1 than Whites who smoked the same amount. Cf 1-ArPTTTRYPSIN It would' be useful tolid'entifythepopulationsatexcessive~ risk of developing COPDI £rom smoking,. They then might be made aware of the hazard before they develop symptomatic lung,disease. Persons with Of'1-antitrypsin deficiency may be such a population. Of -antitrypsin deficiency is a rare homozygous recessive genetic defect wAich occurs in approximately one out of every 3,600 people and results in an increased susceptibility to and premature development of' COPD. There is some evidence that smoking hastens the development of COPD,in these people. The heterozygous state (producing intermediate levels of the q''1-antitrypsfin in serum) is far more common than the homozygous state and is found in approximately ]i0' percent of the popul!ation. It is uncertain whether the heterozygous defi'ciency state predisposes to COPD. C/11-antitrypsin inheritance patterns suggest multiple codominant alleles at one gene locus, some of which (most notablY the S and Z'alleles)'Z produce lower serum protease levels than the normal M-allele (Table 4). The pathophysi~ologicmechanism,of the deficiency stateisfelt to~be theinabilityto inhibit tlie~ proteasEs found in thegranulocytes,and pulmonarymacrophages which go on to damag;e essential constituents of lung tissue. Several recent reviews of the enzyme and the clinical syndrome produced'by its deficiency have been published ($P 318'r BP 227, BP 16'5). In most studies of patients with COP'D,, 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 (yl-antitrypsin levels were measuredi. Because 1 antitrypsin is an acute phase protein and increases withlinfection, it i'~difficuTt to separate out the partially deficient heterozygote phenotypesy by measuring only ,A'1-antitrypsin levels. It is necessary to identify the products of eac~ allele electrophoretically iin order to identify the deficient phenotypes. Two recent studies using this technique showed anli'ncrea ediprevalence of deficient phenotypes in patients with COPD but not among control populations. Mittman, et al. (BP 93) 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 alcontrol 74

TABLE' 4L - The a t-antitrypsiir I'evels andfrequency of protease inhibitor (Pi) phenotypes in healthy populations HlealtByr populat'ions Protease inhibitor. (!Pi)' type n 1-antitrypsin ooncentration (9a normal) Expected frequency of Pi'types (per 1,000 people)'. MM 1i00 898 (FM„FF,I':N,Iu1V~,MX) 1100 28 MW 80 _a MP 80 1' M8 80 41: ' (FS;IS) 80 1 MZ 60 29 (FZ) 60 1 SS 55 1 SZ' 40, 1 ZZ. 1 S' <I a Seert rarely in Spanish populations. Source: Mittman, C.,, Lieberman, J!.,(8P 2'64)~ 75

Scandanavian po~pulation~., Keuppers and Donhardt('BP 170) found, prevalencerates fQr deficient phenotypes of 3'.5 percent in healthy controls,, 12'.9 percenr in persons retired from work because of COPD,,, and 15.7'percent in patients hospitalized for COPD. Additional population studies have been done to determine the effect oftheheterozygpusstate on theAesvelopmentof COPD'., Webb,, et a1., (BP18)i studied,5100 persons visfi.ti'ng, 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 withinormal and deficient phenotypes. In a study of 45]1 randomly selected adults from the same county (BP 128), pulmonary function studies were done on 40 deficient heterozygote phenotypes (20MS':and 2GNIZ), andi on normal phenotype (WE),i control,smatched for age, sex, and smoking habits. When total pulmonary resistance was measured!by a forcedloscillometric technique, the nonsmoking MZ subjects had significant impairment compared to thei'r normal phenotype controls. All cigarette smokers, regardless of phenotype, had abnormal values. Although the data are still inconclusive, it may well be that heterozygousd'eficient persons are agr~oup~at excessive risk of developing COPD especially if they smoke. AUTOPSY AND PATHOPHYSIOLOGIC STUDIES A'utopsy Studies. Auerbach, et al. (Ref. 1): have previously shown dose-related macro- scopic emphysematous changes in the lungs of smokers. Now in an autopsy study (BP' 105)',of1„582' men and,38~8~ women,, theyhave~ examined'microscopiclung,parenchymal changes in relation to cigarette smoking. They were able toishow that rupture of alveolar septa (emphysema), and fibrosis and'' thickening of the small arteries and arterioles are far greater in smokers thamno:nsmokers,ande increase wfith, increasing amount smoked (Tables5and~ 6). When these researchers examined'former cigarette smokers, they found' that those who hadistopped more than ]i0'years prior to death had fewer pathologic changes than those who had stopped less than 10 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 wholhad 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. (BP' 322), in anlautopsy study of 39 men who died, suddenly from various causes and who were below 40 years of age (201non- smokers and 19 smokers), observed a respiratory bronchiolitis associated 76

ti TABLE 5. - Means of the numerical values given lung sections at autopsy of male current.smokers and'nonsrnokers, standardized for age. Subjects Who Neve Stnoked Current Pipe Cig o r Current Cigarette Smokers r Regularly r a Smokers <,5 .5-1 1-2 > 2' Pk. Pk. Pk. Pk. lvumber of' Subjects 175 141 66 115 440 216 Emphysema 0.09 0.90 1.43 1.92' 2:17' 2~:27' Fibrosis 0.4'0, 1'.88' 2.78 3.73' 4':06, 4!28' Thickening,of arterioles 0'.110 1'.1T 1'.35' 1.66' 1.82' 1.89, Thickening of arteries 0.02 0.23' 0.42' ' 0:68 0:83' 0.90 NOTE. - IYumerical values were determined by raring' each,lung section, on scales of 0-4 for em,physemaiand't'hickening,of arterioles; 0-7 for fibrosis„and 0-3 for thickening of the arteries. Source: A;uerbachi„O., et at., (BP 103):, 77

TABLE ' 6: - Means of the numai'caat mlhees given lung sections at autopsy of ferrraLt cNurrertt smokers and'nonsmo,kers, stand'ardized for age Subjecta /Vlio Never Smoked! Crtrent! Cigarettis Smokers R'e gtdarly <1' Pk. a1 Pk Number of Subjects 252' 33 64 Emphysema 0.05 1.37 1.70 Fibrosis 0'.37 2.89' 3.46 Thickening of arterioles 0'.06 1.26 1.57 Thickening of arteries 0.01 0.40! 0'.64'. NQTE. - Numerical values were determined by, rating each lung~ section on scalea of 0-4 for emphysema and thickenitfg of the arteriioles, 0-7 for fibrosis, and 0-3 tor thickening of the arteries: Soureer. Auerbach+ 0., et al. (B!' 1'Q5). 78 ,

t c TABLE 7. - Means of rhe nwrneaieal'ualues gi>'en lung sections at autopsy of nrate former cigarette smokers, standardized for age. Stopped Z 10 xr. Stopped <10yr. Formerly Smoked <1 Pk. Pk.. <i. Pk. Pk. Number of 9ubjects 35 66, 51 13! Emphysema~ 0.24 0.70 1'.08', 1!.69. Fibrosis 1.14 1.74' 2:4'4 3.30 Z'hickening, or arteriales 0.57 M93 1.25~ 1'.59 Thickening of arteries 0.04 0'.1I6 0!36 0.611 NOTE. - Numercial!valuex fior each finding, were determined' by rating,each lung section on scales of 0-4 for emphysema and' thickening of the arterioies; 0-7 for fibrosis, and 0-3 for thickening of'the arteries. Source: Auerbech„0., et aL (BFI'Q5). . 7 9I

with clusters of pigmented alveolar macrophages in the lungs of smokers. They foundithese changes only rarely in the lungs of nonsmokers (Fig. 1)i. The smokers were young (average age 251.7'years), were a heavy smoking _ popuLationi(average 20.1 pack years)', but did not differ significantly fromm the nonsmokers in age, sociia'class, or pollution exposure. However, 12' of' the 19 smokers had had productive cough or frequent cold'compared to only 3' of the 20 nonsmokers. These authors postulated that bronchiolitis may bee responsible for the abnormalities in the tests of small airway function of smokers. Pathophysiologic Studies in Humans Yeager, et al. (BP 3013) ) showed decreased pinocytosis in human alveolar macrophages obtained from asymptomatic cigarette smoking volunteers when compared to those obtained from nonsmoking controls. - Warr and'Martin (BP' 217) studied alveolar macrophages lavaged'from four healthy smokers and'four healthy nonsmokers. Only two members of each group^ were reactive to delayed hypersensitivity skin tests for Cand'ida alblicans. Macrophages from nonsmokers responded' to Migration I'nhibitory Factor (MIF) by a depression in migration of at least 30 percent,,whereas macrophages from smokers did not respond to MIF'. The cells from smokers were notede to migrate three times faster than those from nonsmokers. When Candida antigen was added to the medium, cells from the nonreactive subj,ects (both smokers andinonsmokers) were not inhibited, the cells fromithe reactive nonsmokers were inhibited,, but the cells from reactive smokers were not inhibited. 'fhus, macrophages from smokers did not respond normally to either MIF or antigenic challenge. Pathophysiologic Studies in Animals Roszman and Rogers (BP 47)' noted that either the nicotine or the water soluble fraction of whole cigarettes smoked' suppressed the immunoglobuhin response of lymphoid cell cultures. When concerftrations of over 200 microgarams per milliliter of nicotine of the water soluble fraction were added, they were able to completely suppress the response and to observe this suppression even imcells,exposed' for2hoursprior to the antigenic challeng~e. Guinea piga (BP 48) exposedito the smoke of five cigarettes andithen lavaged 2 hours later had fewer pulmonary macrophages and leukocytes in the lavagefluid than di'd'controls not~exposed to smoke., The d'ecreasei~n the number of macrophages was highly correlated with, acetaldehyde, tar,, nicotine, hydrogen cyanide, andiacrolein concentrations in the cigare te smoke. The decrease in ttie number of leukocytes was more closely correlated' with pH of the particulate phase and concentrations of acetaldehydie and' tar. 80