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6roncnms O Grade I E3 Grade 2' 13 Grade 3 Mo~ 55 38: 40~~. 35 63~ 211 26 25 Age~. <A0, 40•~<40~~ 40•~ <401 40• <40 40•~ Expo3Lre~. Wool.~~ CUIIOn wool conon $makrng nonM1lmokeri~ smokeri Figure ].--Chronic.b.ronchitiis in female wool and cotton textile work.ers.. SOURCE: Kilburn, K. H.,, et al. (HP' 166). 106

Traffic = = Outskirt . . . . . : Stalioni r Nonsmokers: 1-24••- 25'» Ex-smokers.. Current,No. of Cigarettes Smoked Daily Figure 1. -PrevaIlence of chronic nonspecific respiratory disease by cigarette smoking habits and'trafffic exposure. SOURCE: Speizer, F. E.,, Ferris, B. Cs.,, Jr. (BP 159). Table 2. -Prevalence'of chronic nonspecific respiratory disease grouped by current cigarette categories and traffic exposure. ~- ~ TiotatlNo..Men Never tn Traffic~. .. 1+4i0 Imrramc ~ 1~~1•20 p 20+ Neversmo+eJ 45" 11.5. 1'1.1 25.01 16J~~ ge-smoker 86 30.3~~ 27.3 19.0'. 28.6 Currcnt~.ogarette~ smoker 137 . 492'~ 44.1 57.7' 64.3, Total 268 76.1: ' 3512 79.2'. ~ 39.0 - •NeverfnwYe6ca'tegoryinclu0es 112'meniwno.kavCSmokeODiDeanocigdry SOURCE: Speizer,, P. E., Ferris, B. C., Jr., (BP 159). .. - r .'. ... . _... 1 1' .' `.. 1 _.. ,.r,,. .. .. :".{,

®ronchilis 'O Grade. 1, O'Ciade. 2 [: Grade 3 No, 30 41 47' 16 88 36'. 103 57 A7e' . <40 40•'<4'0. 40+<4040+ <40 4oiExposure wool cottortn wool ¢otton Smokinp.g non-smokers smokers Figure 8.--Chronic bronchitis in male wool and cotton textile workers. SOl7RCE: Kilburn,, K. H:.,, et al. (BP 166). r In a cr.oss se¢tional surovey of 1,140 cotton workers in England, Fox, et al. (BP 100) found,,by regression analysis,,thaC for each level of dust exposure (mg. yrs./m.3)' smokers and ex-smokers had 1'ower FEW'1 observed/predicted percent than nonsmokers.Tihe differences in the slopes of these lines were not significant (figure 9). The authors also reported that the percentage of smokers with.bysainosi's was, hiigher than that for nonsma&ers at'each level of exposure, the slopes ofthe lines being si'gnificantly different (P <.001) (fi'gure 10)1. 6 107

Figure 9.--Effect of smokingong pulmonaryventilation.aty different levels of time-weighted dust exposure.....,.... 108 Figure 1&.,--Effect of smoking on prevalence of byssinosis at different time-weighted dust.exposure levels............ 109 Figure 11.--A freq;uency distribution curve of the internal diameters of the small airways in an autopsy population of nonemphysematous patients with and without histories of chronic bronchitis.................. 12 Figure 12.--Mean clearance curves for normal subjects,, subjects with airway obstruction, and.restrictiveimpairment of the lungs ...... ............. ...... .................. . 114 Figure 13'„--M'ean clearance curves for`smokers,.ex-smokers, and nonsmokers in the healthy group and the group with respiratory impairment ...............,.................. 115 Figure 14.--Effectsof aqueous cigarette.smoke extract on initial oxqgen uptake, final oxygen.uptake;n and celll viability of':puSmonary macrophages..................... 119 ,List of Tables Table 1.--Number; percentlage,, and age-standardized'percentage of chronic bronchitics among 5,438 cigarette smoking male volunteers for mass radiography, aged.at least 40, by amount and method of smoking ..................... 1 88 Table 2.--Prevalence of chronic nonspecific respiratory disease grouped by current cigarette categoxies and traffic exposure.......... ......................... ............. . 92 Table 3.--P'revalence (percent) of cough day or night in both sexes in winter by air pollution.index, social class, cigarette smoking, and'hi'story of chest illness under 2 years ofage.......... ...I .........,....I ...,......,............ 102 Table 4.--E'stima~~ted ratess ofbullous diseas..eofe the lung.per 1,000. ~ men by age, race, and cigarette smoking habi'ts.......... C 103 ::. Table 5.--Estimated rates of bullous disease of the lung,per. 1,000' m men with no demonstrable occupational hazard (class 1),.. 10:4 83

6. Epidemiologic evidence from~many countriess indica.testhat„ for both sexes, symptomatic an3 asymptomatic cigarette smokers have g,reaterimpailrment of pulmonary function than do:nonsmokers.l 7'. Previous evidence.indi'cates that cessation.ofn smoking results. in lower death rates from COPD, improved pulmonary function, and a d'ecrease in the prevalence of pulmonary symptoms:. 8'. Prospective and cross-sectional analyses of data reveal that pipe and cigar smokers have higher. mortality rates from chronic bronchi'.tisand.emphysema.than doo nonsmokers, but.lower rates thann thosee ofcigaret.te smokers.. Pipe and cigar smokershave a higher prevalence of respiratory symptoms than do nonsmokers. The limited' data on pulmonary functiion studies in pipe and cigar smokers are, thus far, inconclusive. 9. Available data suggest that although air pollution may contribute to the prevalence of symptomss of respiratory disease, cigarette smokingg is far more.important in producing respiratory d'isease. Cigarette smoking and,air pollution may interact to produce higher rates of pulmonary disease than are seen with'either factor alone. 10. Certain occupational exposures result in an increased incidence of COPD',.but the relationship is not as strong asfor cigarette smoking. The combination off certain.occupational hazards and.ciga!re.ttesmokin.g has been observed,,in many studies, to result iniadditive effects. on morbidity from:COPD. Exposures too cotton fiber, asbestos, an.dd coal dust, in particular, appear to act in concert with.cigarette smoking.in.the development.of'pulmonary disease. The role cigarette smoking plays in the development of coal workers' pneumoconiosis is unclear at present. 11.. A genetically determined protease-deficiency (alphal antitrypsinn deficiency), inherited as an autosomal recessive trait, is,found as a homozygous deficiency in approximately 1/3,600 people,and as a heterozy- gous deficiency i:n approximately5,to,8'percent of the population. Dhosewith; the:homozygo.us-defi.ciency have an increased prevalence off pulmonaryy emphysema. it iss not clear whether cigarette smoking C iss an fmportant contributor to the premature development of emphysema (,,,~ in people with the homozyg.ous:orheterozygous deficiency states. ~' It iss alsoo unknown whether nonsmoking heterozygotes are at a greater Q"t+ riskk of deve.loping,g emphysema than nonsmokers or smokers:with normal O. alphal-antitrypsin activity. O 11ln these studies, the degree of the relationshipbetwe.en smoking and impairedd pulmonary function was found to be dependent on thesensitivi'ty of the particular pulmonary function.test utilized todeiect pulmonary obstruc:tiion and/or small airways disease, the age, sex, occupation, place of residence, generalistate of health, and intensity of the smoking habit of the population.examined. 85

73-0652. WARR,. G., A.,. MARTIN, R. R'..Response of human pulmonary macrophage.tomi'gration inhibition factor.. Amer.ican Review of Respiratory Disease 1!08!(2):371-373., August 1973. , ' 0 . 137

r The.Interactions Between Cigarette Smoking, and the Genetic Sus.ceptibilityto the Development of COPD Mittman, et al. (BP'6'4, 114, 241) reported on the interaction between.cigarette smoking and', the genetic susceptibility to d'evelopment of chronic obstructive pulmonary disease (the alphal-antitrypsin deficiency state). These authors described the polymorphic (multiple gene)system of protease inhibition (Pi) by alphaL-antiitrypsin (AeYT), and listed, some of the partial and severe deficiency states of this enzyme system. In a series of 170: consecutive patients with a diagnosis of, COPD admitted to the City of Hope Medical Center who had' no previously known history of AIS:T deficiency, 40 patients (24 percent). demonstratedlsome type of AltT deficiency. This was a significantly higher percentage than was found in a control group of the Mbrwegiian population, which is known to~have a high incidence of'this enzyme deficiency (P <:.©0!1). The lifetjme cigarette consumption of the population of patients with emphysema who had some degreG of AAT deficiency was significantly less than those emphysema patients with~a normal phenotype (PiMM) (P <.05) (figure 6),, suggesting a possible interaction between smoking and the.genetic abnormality. The data imply that a greater degree of exposure to tobacco was required to produce emphysema,in those. patients who did,not.have agenetic predisposition than.in: those with the genetic defect.. The authors concluded that any degree of AAT deficiency makes an individual more susceptible to the effects of smok.ing.Thesame authors have also examine& 144peoplewith.par.tial AAT deficiencies who were apparently healthy and compared them with 100 controls matched for age, sex,, and smoking,history (BP 64). They found that 25' of the 62 smokers with partial k4T deficiency (40 percent)) had abnormaIlitiess of. pulmonary function tests suggestiveofe obstruction.,, while 7 of 47 smokers in the control group (15 percent) demonstratedi such abnormalities. This difference wasstatistically significant (P <.05). 99

12. . Data.from most studies implicate cigarette smoking:as an important factor in.Increasing:the risk of dev:eloping,pos:t-aperativepulmonaty complicatiorns. 13. Some data suggest that cigarette smoking may increase th.e risk of development of spontaneous pneumothorax. 14.Da:ta:fromp:athologic and autopsy studiess have demonstrated a dose-responseeffec.te of cigarettesmoking.on the severity of. emphysema;. pipe and cigar.smokersh.ave.degrees o.fanphysema intermediate between those of nonsmokersand cigarette smokers:. 15. Goblet cell density and d3s.tention., alveolar septal rupture, thickened bronchial.epithel.ium:,l andimucous gland hypertrophy have been shown at autopsy to be more common in cigarette smokers than in nonsmokers. 16. Experimental data on.humans.have demonstrated that inhalation of cigarettee smoke results in acute impai{ment of certaimparameters of.pu]monaryfunction.. In humans, overall pulmonary clearanae,,, ciliary function., and alveolar macrophage function have been found to be impaired in smokers compared to nonsmokers.. Some recent data suggest that acute heavy cigarette smoking with deep inhalation may result in increased pulmonary clearance. 1'7. Inanimal studies„ in vivo and in vitro exposures to whole cigarette smoke (C[45) and several of its components have resulted in.impairment.in overaQl pulmonary clearance, ciliary function, and! alveolar macrophage functibn.. 18. Experimental data on humans and animals presented in the past suggestt that cigarette smoke may impair the:function.ofthepulmona~ry surfactant system. Most of the studies reviewed in the last year confirmed but did not extendthe knowledge of the.relationship between cigarette smokingg and'bronchopulmonary disease. L1listing of these studies appears in a separate.section of the Supplemental Bibliography. A number of studies extende&the knowledge of the association between ci~garettee smoking.g and bronchopuLmonary disease, and.several studiess presented data which wereei'ther.partially or wholly inconsistent with.the knownn relationships; these two types of s.tudies.are.reviewed'below. EPIDEM.IOLOGIC STUDIES Smok.ing and COPD TMerehave been relatively fewstudi'.es designed to evaluate the association between cigarette constartption: and the prevalence of chronic obstructive pulmonary disease (COPD)in'elderly populations.Iin a O' ~'. random cross-sectional study of487'men and womenr between.theages ~C+ C M+ 86

Smoking and Mucous Gland Abnormalities In~an.autopny series in Glasgow of 149 mem and women with known smoking,histories,, Scott.(BP 95) stud'ied.the degree of mucous gland hypertrophyus'.ing theReidlind'ex and point counting technique. He found'.that the mean Reid.index was significantly greater in smokers tharn nonsmokers (P <.01) and that fewer smokershad normal Reid indices than nonsmo&ers(p'=.02),. Although more smokers had! an abnormally high.Reid indexcomparedlto nonsmokers, the.difference was not statistically significant. In this autopsy series,, the R'eid!index was found to be higher in young subjects; also men were noted to have a significantly higher index than women (P<.05).. ' ` . Abnormalities of the Small Airways Maasub.a and Thurlbeek.(BF'97), in a study of posturortem lung specimens, found that in.patients with chronic bronchitis without emphysema who.died.ofnonrespiratorycauses,,there'was significant narrowing of smaLl.adirways compared to patients without.either chronic bronchitis or emphysema, as measured by the smaller average diameter of the small airways(P'<.001).. These patients had an excess of airways with 0..2'2 to.0:.6mmi. internal diameterr and a deficit of adrwayswith an internal diameter of 0.6 to 1.g.mm. (figure 11). In addition,. these workers observed more mucusin,the airways of the patients with chronic bronchitis without emphysema than in those patients without either disease. The authors concluded that both small airway narrowing and mucus plugging constitute the maj;or morphologic lesions corresponding to the functional abnormalities of small airways seen in patients withch.ronic bronchitis. . .

(spirometry and CO diffusion) had a higher mean lifetime. consumption of cigarettes than men with,normal pulmonary function tests(p'<.A'.5).; however,: the:mean.age of the abnormal group was, 55 yearsgreater than that.of the norms.l group.. The women with abnormall.values of pulmonary function tests smoked.more than those with normal values (14.44 vs. 9.72'pack years),, but the difference was not statistically significant. The group of women wjith abnormal values was also slightly older than the normal group (by 1.12 years). Occupationa:l Diseases and smoking. Byssinosis Kilburn, et a1.(BP' 166) reported on the prevalence of chronic bronchitis in wool and cotton.mill workers in North Carolina. These investigators found that in women the combination of cigarette smoking and cotton dust exposure was associated with a marked increase' in. the prevalence of chronic bronchitis (figure 7). Of the nonsmoking nonexposed employees, less than I percent had chronic bronchitis. Cotton dust exposure and cigarette smoking,alone were associated'.with prevalence rates of 8'percent and 13'.per.cent, respeetively., Both exposures in combination resulted in a prevalence rate for chronic bronchitis of'27 percent. For inen, a synergistic effect was demonstrated (figure 8), but it was not as striking as that forr women. The.authors suggested that the.dtiffzrences in prevalence of chronic bronchitis between men and women, and the differencesin.the effects of the two n.oxiousexposuwr.ess in combination.may have been due to, the fact that men were moreh:eaviEyexposede to bothcotton dust andcigarette smoke than.women. 105