Tobacco Documents Online

Smoking and Mucous Gland Abnormalities ..................... Abnormalities of the Small Airways.........: ............. EXPERIMENTAL STUDIES Studies in Brctmans........................................ Studies in Animals..........~..... 111 Tll 112'. ., ........................ 116 CYTOLOGIC AND HISTOLOGIC STUDIES,....., ........................ 118 SUPfMARY OF RECENT NON-NEOPLASTIC BRONCPHOPUIMONARY FINDINGS... BRONCYiOPULMONARY REFERENCES,.......... 120 ........ 121 BRONCHOPUIiMONARYDISEASE SUPPLEM',ENTAL -FEFERENCES....,.......... List' of Figures 128 Figure l.--Prevalence of chronic nonspecific respiratory disease by cigarette smoking habits and traffic exposure........... 92 Figure 2.--Relationship between."'closing volume"'and age in 39 smokers ................................................. 94 Figure 3.--PYevalence of abnormal closing,voSumeJvital capacity ratios in nonsmokers, cigarette smokers, and. ex-smokersby age decades.............. .................. . 96 Figure4.--Comparison.of the.prevalence.o.f respiratory symptoms and pulmonary function abnormalities in male smokers according to their daily cigarette consumption......... 97 Figure5.--Comparison of the prevalence of respiratory symptomsandl pulmonary functlion,abnormalities in female smokers according,to their daily ciga~retteconsumption.......... 9'8 Figure 6.--The distribution of smokingg histories 'in men with bronchitis and/or emphysema ...................,.......... 100 Figure 7. -Chronic bronchitis in female'wool and cotton textile workers......., ............................................ 106 Figure~ 8.--Chronic bronchitis in male wool and cotton textile workers......................,...............,............. Il07 82

In a separate publication, McCarthy and Craig (BP 60)) reported that 15'.percent of. a groupp of 91 asymptomatic female smokers in.Manitoba, had abnormally high closing voIlumes (CU),, in contrast to the 72' percent of 46 male smokers in London (BP 8) who had abnormally high closing voliumes. None of the female nonsmokers had any CV'abnormalities,. The authors suggested that differencesin.pollution exposureofe theLondom and Manitoba study groupsi mi'ght„ in.part,, account for the differences in prevalence of the Ch abnormalities. Iir.a, study ofpulmonaryfuneti'on of subjects voluntarily reporting to an emphysema screening center, Buist, et al. (BP 116) reported that 6 percent of the nonsmokers, 35 percent of the current cigarette smokers, and23.percent of the ex-smokerss hadab..normall.CV/VC ratios.. In each decade from age 20 to 79', more smokers andlex-smokers had abnormal CV/VC ratios than nonsmokers (fig.ure. 3):. The daily consumption of. cigarettes: was relatedito. CV abnormalities in.a.dose-responser.elation- shi.p for men: (figure 4). Among the women, those.with a daily cons.ump:- tion of less than 10 cigarettes per day had significantly lower CV'/VC rati.oss than those smok:ing,more than this amount (P'a.05);.but overall,, noo doserresp.onserelationshipwas demonstrated (figure 5).

<.l0:cig4cettes/dayn:=.19 10-20.cig;trettes/dry n~=75100 . 20-40 dgaretteslday n,=77 80. >40 cigarettes/day m= 3 66.7 4 synptolmat e cc/ric% cvlvck FEV1 Figure 5.--Cbmparison.ofthaprevalence of respiratory symptoms and pulmonary functioniabnormali'ties in.female smokerss according.to.theirdaily cig:arettee consumptioa. CC - Closing capacity TLC - To.tal.lung capacity CV' - Closing volume VC - Vital capacity FEVI Cne:-s:econd f.orcedlexpiratory volume O E.: ~. la SOURCE: Bui'st A. S et al (BP 116). , ,. ., . CJ 9'8

Table 3.--Prevalence (percent) of cough day or night in both sexes in winter by air pollution index, social class, cigarette smoking, and history of chest illness under two years of age.* (Figures in parentheses are population.) Air pollution index History of Chest illness under cigarette 2 years of age smoking Never smoked No chest illness One or more chest illnesses P_re_s_e_n__t_ smoker No chest illness one or more chest illnesses 7-17 18-28 Social class Social class i+ 2 3+ 4 1+ 2 3+ 4 4.7 (344) 5.7 (369) 4.7 (277) 6.6 (212) 12.3 (57) 8.3 (108) 8.3 (84) 10.8 (102) 11.2 (214) 12.6 (325) 14.1 (192) 15.7 (261) 16.4 (55) 11.8 (102) 12.3 (73) 22.2 (144) *Excluding 980 persons--that is, ex-smokers and those whose history of cigarette smoking, social class, , air pollution index, chest illness under 2 years of age, and history of cough day or night not k.novn.. SOURCE: Colley, J. R. T., et al. (BP 213). G`101•94-C0

CHAPTER:3 NOM-NEOPLASTIC BRONCHOPUIk10NARY DISEASES INTRODUCT'ION.................................. .................... 84 EP'IDEMIOLOGIC STUDIES Smoking and COPD...................................... ....... 86 The Effects of Smoking:on Pulmonary FUnction in Patients~with COPD................................ ,.... 89 The Effects of Smokiag on Pulmonary Function i!n:Healthy Populations ........... ,...... ..., ................ 89 The Roles of'Smoking and Pollution in the Deve7opment of COPD.., ................................... ,,~ 90 The Relationship Between.Cigarette Smoking and Small Ai'rwavs D'isease ...... .............. ,............... ... 93 The Interactions Between Cigarette Smoking and the Genetic Susceptibility to the Development of COPD...:.... 99 The Effect of Smoking on the Development of Bulilous Disease of the Lungs .... ...., ......... ......„...,.... 103 Smoking and Post-Operative Complications............ The Influence ofC.igarette Smok.ing.on.theDevelopment of Pulmonary Disease Associatediwi'th Rheumatoid Arthritis........... ............. .,....... Occupational Diseases and Smoking Byssinosis..... . 104 . 104 . 105 Asbestosis................................................. . . . ... . .: 110 Chronic Bronchitis and Pulmonary Symptoms in Cement and Rubber Industry Workers.........,......,... 110 AUTOPSY STUDIES Ths. Effect of Smoking on the Prematurity o:f Q3rrs40r,tis Development.and. Seueratyof..COPD......................,,, 110 81

Figure 6.--The distribution of'smokiag histories in men with bronchitis and/or emphysema. Patients grouped by phenotype; Pi?M patients above, those with, intermediate AAT deficiency below. Each bar depicts the.fraction of patients reporting smoking histories Tn th.e ranges shown. SOURCE: Mittman, C'., Barbela, T., Lieberman, J. (BP 64).

Table 1.--Number, percentage., and age-standardized percentage of. chronic bronchiticsamong.5,438cigarette..smoking male volunteers for mass radiography, aged at least. 40, by amount and'methodiof smoking. C.igarettess per day D. Nunber of volunteers 60 Number of. chronic bronchitics 22' Percentage chronic bronchitics. 36.6 Age-s t anda.r diz ed''percentag.e of chronic bronchitics 33.9 1-9 10-19 20+ All N. D'. N. D. N.. D. N: 581 134 1,839 266 2„558' 460 4,978 150 56 552 113 9171 191 1,673 25.8 41.8' 30.0 42.4 37'.5' 41.5* 33.6* - 26.0 41.,1 32.1 44.1 41.1 41.6 35.1 *P <.001.D. = "drooping" cigarette smokers. N. = normal cigarette smokers. SOURCE: Rimington,, J. (SP 109). In an,analysisn of data from Bosnia and ISercegovina in Yngoslavia,.. Zarkovic (BP'214) reported.dose:-response relationships between depth of cigarexte smoke inhalation and prevalence rates for chronic bronchitis, pulmonaryemphysema., asthma, corpulmonale, and: clinical and.'lab.oratory signs of obstructive lung disease. .. Olziihutag„ et al. (BP 229)) studied the prevalence of chronicc bronchitis in Mongolia and found no association between cigarette smoking.a.nd chroniobronchitis in urban women, and'd a reverse association in.rural women. These authors found close associations between chronic bronchitis and smoking in men. The authors pointed.out that chronic bronch~itiss increased in frequency with age. 88

Hutchison,et al. (BP' 23) studied 28 patients with pulmonary emphysema„ 8 of whom.were homozygous deficient for alpha1-antitrypsin. Althoughth:e annual consuuption of tobacco up to the age of onset of dyspnea was equal in the deficient and nondeficient group of patients, total lifetime tobacco consaanption was significantly less among the AeYT deficient patients than az¢ong:the nondeficients (P <.01). All 8.AAT deficient patients were smokers. Although there was no significant difference in.the incidence or age of onset of chronic bronchitis between the two groups,, the A[iT deficient group of patients developedi exertional dyspnea 12 years earlier than the nondeficients(P <.00.1)... Thes.e data suggest a synergistic effect of cigarette smoking on the development of pulmonary emphysema in those patients with homozygous deficiency of alphal-antitrypsin. clolley„ et al. (BP 213) ) analyzed a cohort of. 3,899 persons born in the last week of March 1946 in England, Scotland, and Wales and found that irrespective of a~hilstory of lower respiratory tract illness before the age of two, the smokers had a greater prevalence of symptoms of' winter coughh at age 20 than th,enonsmokers (tab:le. 3). . Thee authors argued that cigarette smoking,, by age 20, is a far more important factor iin the development of'respiiratory disease than is a history of lower respiratory tract.illness. The results of this study are evidence against the hypothesis of a purely constitutional susceptibility to the development of respiratory: diseases independent of tobacco exposure. 101

CHAPTER 3 NON-NEOPLASTIC ERONCHOPUIt10NARY DISEASES IN2'RODUCTION. Chronic obstructive pulmonary disease (COPD) (defined here as chronic bronchitis and emphysema) accounted for approximately 2'5,000 deaths in.the United States in 1969.. In 1970, in the U.S., the combined preva~lence.ofe chronic bronchdtisfor members. of both sexess over age17'was29.5 per 1,000.population., and for emphysema: was 9.8 per 1„000'0 population. In: 1970,,persons with chronir br:onchitis lost, on the average, 1'.4,workdaysper year,, andl those with emphysema lost greater: than 5 workdhys,per year due to disability from these diseas:es. Epid'emiologSc., autopsy, and experimental data, presen~ted.in previous editions of this report (1964, 1967', 1968s 1969, '. 1971, 1972,. 1973): indicate that:ciga:rette smoking:g is.s the.pri'mary cause of chronic bronchitis and emphysema.. A summary of'that evidence is presented below: 1. Results from.numerous.prospective studiesshow a markedly increased mortality from COPD:for male smokers compared to:n:onsmokers... There is a limited'amount of data dealing with the relationship between cigarettesmoking and COPD.mortality in women. 2.. Dose-responserela.tionships between cigarette smoking' and mortality from chronic bronchitis and emphysema were demonstrated in all studies in which dose-specific mortality rates were evaluated. Heavy cigarette smokers ran relative riskss of mortality from chronic bronchitis rangi.ng.from.3'..6 to 21.2'timesthose of nonsmokers, and'' relative risks of mortality from emphysema ranging from 6.9 to 25.3. times those of nonsmokers. 3. Data from~many studies demonstrate that male and female smokers suffer fromsymptoms of COPD' (including cough,, sputum;production, and dyspnea) more frequently than do nonsmokers. 4.. Of the studies in which dose-specific.prevalence rates.were examined„ strong.doae-response relationshipsbetween cigarette smoking and symptoms of COMweregenera~lly demonstrated.. 5.. The relationship.between cigarette.smoking.and COPDmortality hasbeen demonstrated in theUnited.States, Canada, Great Britain, and!Ireland;:strong as.soci'ati.onsbetween cigarette smoking.and COPD morbidity have been shown in.the United.S!tates, Canada., England:,, Australia,,= . Finland, Sweden,, France, Belgium, Hungary, and Japan. W. Cn ~C+ C 84

and cigarette consumption ass risk factors in the development ofchronicf nonspecific respiratorydis.eases. In.an.analysisof the initial data from.a prospective stud'yof. Boston policemen, Speizer and Ferris (BP 159) found that a higher percentage of men in three of four smoking categories who worked in areas of heavy traffic had chronic nonspecific respiratory d'iseasecompared with men who worked in the, outskirtss ofBostom (figure 1)'.3 In general„ for each of the four traffic exposure categories, the prevalence of CNRD was greater among ex-smokers than nonsmokers,. and greater among curr.entt cigarette smokerss than among either ex-smo'kerss or nonsmokers (table 2). Conversely,, the prevalence of CNRD in current smokers appeared to be related to the number oflf years of traffic exposure; th~ose men with few yearss of'such exposureh~ad approximately the, same. incidence:as,those who worked in the outskiYts. In the analysis of thiss relatively homogenous group of men, it appears that "traffic polluti.on" and' cigarette.smoking may beacting,in.concert too ihcreas:ee the risk of developing chronic respiratory disease.. Criteriafor diagnosis of CNADiwer:e those established by the British Medical Research Council Bronchitis Committee (1955)., 91

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

, 230. OSMAN',. H. A.,,WAHDAN„PY.. H.,.NOWEDR, M. H. Health.problemsresult.ing, from prolonged eneposure too ch.emicall agents in rubber indus.try.. Journal of the Egyptian Public Heal'xh Association 47(5)~: 290-311, 1972. 2'37. SHERMAN, J., WOLFE, S., HRICKO, A., METS, M. A Health Research Group Study on Diseas.eAmong Work.ersin.the' AutoIndustry.. Hzalth.ReseaVch Croup, Washington, D. C. September 7, 1973. 43 pp. 240. WOOLCOCK,, A. J., COLMAN, M. H., BLACKBURN„ C. R. B. Chronic lung diseaseim Papua.NewGui!nea.and Australian populations. Papua NewGuinea.Medical Journal 16(1): 29'-35„ M'arch~ 1973'. 241. MITTMAN, C.,. BARBELA, T.,LIiEBERMAN, J. Antitrypsin deficiency and abnormal proteas.einhib.itor phenoiype&. Archives of. Einviorn-mental Health 27(3): 201-206, September 19'73. 127

lfrumholz and Hedrick (BP 79)~ studied pulmonary function in.91! eigarettesmoking:and.136e nonsmok.ing,"healthy" male executives„ ag.ed! 35 to 64. They found significant impairment in the smokers for VC! (P' <.01),. FEV1 (P<.001),. FEV7,(P<.001):,, FEVZ5 7q ~ (P <.00.1!), Raw (airway resistance) (P <.05), MVV' (P' <,05)„ RV/TLC. (P <.05)„ C0 diffusion (P «..001), and'.D1C0/TLCY,. (P'<.001)~. Mean Lungg voluses were the sameitu the two groups except for RV/TLG. The methodsof's selection of patientsfor this study were.not detailed. Brooks and Waller (BP'42)',,in a study of 2,,703 people attending, a public health.exhibition.,,found' a nonsignificant difference in peak floa rates between smokers and'nonsmokers ag,e 45 and over; no differences were.demonstrated for the younger than 45 age groups. The authors pointedi out a ntunher of bia's.eswhichlimdt the.conclusions which may be drawn from these d'ata.. Coleman, et al. (BP192) investigated the.maximal oxygen consumption (physica~l work capacity); of 78 members of the Texas Tech. University faculty and.found no difference in~this value between smokers andd nonsmokers. However,.astheauthorspointed omt,., the mean age of the smokers: wass.even yearss less than. that o.f the nonsmoker:s, andd the daily activity level ofth~e smokers was also g.reater: than that of the nonsmokers... The' combination of these two effects may havepartially accounted for. thelack of difference.in maximal physical work.capacity between the smokers and nonsmokers in this study population. In a cross-s,ectional study of men and women fromm th.e Western. Hlghlands: District.and Trobriand Islands in.New Guinea, Woolcock„ et al. (BP9'3)'fo.und, a greater decrease.of FVC.,, FEV1,.and PEF with~ age in men who smoked', compared to nonsmokers'(no P value reported). No such differences were found'for women for FEVl and, PEF. The authorsstated that most of the smokers used home-grown: tobacco smoked as cigars. Woolcock, et al. (BP 2'40) also reported that in this same.group of New Guineans smoking.g wasnot strongly associated with.coughh on a.single.examination in.theWestern Highlands District (WHD) population,, but wass strongly associated in the. Trobriand Islands. (TI) population... The authors stated, though,, that the TIpopulation smoked westernn cigarettes, whereas the WHDpopulation smoked predominantly home-grown tobacco rolled' in newspaper., The Roles of Smoking an&Pollution.im th.e.Development.ofCOPD Ciga:rette.smoking is the predominant factor in the development of chronic nonspecific respiratory disease (ChRD):, but there have been.few prospective studies, on.th~e interaction b..etween.air pollu.tion. 90'

80 4 96 . 12 0 0 0 2 ,~I ; •I 7~ 7 3 43 8~1 20 . . <20~ . : 20-29~ PQonsmok.:cs ('2 84) Smokets(524) Ex-smol:ers (268) 0' 10 21 15 ~` is 30 8 2' ' 3049 e 18 '46 19 I r.rq 36 2 18 ~1:If,ll0 3 7049~. =. 80~. S r - Figure 3.--Preva]ience of abnormal closing volume/vital capacity ratios iin nonsmokers, cigarette smokers, and ex,-smokers by age decades. SOURCE: Buist,. A. S., et aL: (BP'1Il6). '

-' Tim.•weiy,hted duut meusurement (imqf,eure/mI/ - ~- ~ 0 10 70 JO~~i 40 50 60 70~. -~ 100 nnn.,~nle`47ap. as i `N©n.smokcrs':'. .. FEV,.. (Obsewed) ' j i : . . . ~ ~ . FL=Y,,, (Lxpccicd) ~ ~~99-,00r 0MS x (TWmM):~. '~ . 1 'Smokcrs ' ffEV,.e (oesorved) i . . ~~, : ..~ t:v. ~. _ F[P,.. (fspccrod)i 34'86,- 0033'~. x~ Q1RV@kt}:~ ffigure 9, -Effect of'smoking on pulmonary ventilation (FEV1) at diffferent"lsuels of time-weighted dust exposure. SOURCE: Fox, A. J., et.al. (BP 100) . a 9

Ashestosis Chew, et al. (BP 157) examined 112 asbestos workers in Singapore and found only s.light.differences in mean.FEYls.between smokersand nonsmokers (2.73 L and' 2'.79 L, respectively). Chronic,Bronchitis and Pulmonary Symptoms in Cement and!RubfiberIndustry Workers In a cross-sectional study of 847 cement workers in Yugoslavia, KalaciE ($P 54„ 55) found that nonsmokers had a higher prevalence of. cough.,, sputum pr.od'uction, exertional dyspnea„ and chronic bronchitis than controls with other occupations., Within the group of cement workers, cigarette smokers had higher prevalence rates of cough., sputum production, exertional dyspnea „ wheezing, and chronic bronchitis than nonsmokers regardless of' th,e number of years of exposure in; the cement plants. No significant differences in FVC or FEV% were observed between cigarette smoking andinonsmoking, cement workers:. Osman, et al. (BP 230) studied 230 rubber iindustry employees in Egypt andfound a higher prevalencee of upper.respiratory tract irritation„ acute bronchitis, and chronic bronchitis in smokers; compared to nonsmokers (NS). There was a lower prevalence of these three conditions among control smokers compared with smokers exposed to these industrial fumes, thereby suggesting a synergistic action of cigarette consumption and exposure to rubber industry fumes. AUTOPSYSTUDIES The Effect of Smoking on.thePrematurity of Development and Severity of COPD' Spain, et al.(BP 1]13)) evaluated'the degree of emphysema in whole lung mountss of134 victims of accidents,., suidice, homicid'e, or sudden coronary death.autopsiedat theoffice.of the Medical Examiner of Westchester County (85men and149 women),.. Degree of emphysema.was graded.from 0 to 100., In men, 3'' of 30 nonsmokers had grades of'20 or higher (10 percent), while 16' of 41 heavysmokers had grades of 200 orr higher (39,percent)!. Thiss difference.was.significant (P'<.01). The highest grade which the nonsmokers reached was 20, whereas several of'the.heavy smokers reached.gFades of' 50 (precise data not given). Themean..agese of' the nonsmokers, light smokers, and'heavy smokers with grades 20 or greater were.66, 62', and 52, respectively. The mean grade of emphysema in all the heavy smokers was 1'4,, compared to 11 in the lighter smokers and' 8 in the nonsmokers. Among 21 nonsmoking women, there were no cases of grade 20 or greater,, while in the heavy smokers 5 of 22'cases had grade 20': or greater. The mean age of' this Q group of smokers was 40. For the women, as in the men, the mean grade C.: of emphysema rose with the intensity of smoking.. The authors attributed Q the differences in degrees of emphysema solely to smoking. ,t,. ~ 110 j, ,,

These authors also measuredpulmonary fungtion in this cohort of policemen (BP 160) and found.correlations between impairment of FEV1 and lifetime,cigarette smoking for all the men (P <.00.1). S!tatistiically significant correlations between impairment of flow volume relationships at 50'0 and 25 percent,lung volume and current cigarette consumption (P <.05 and <„001), and lifetime cigarette consumption (P <.01 and <.001) were found for the outskirt station officers, but not for the traffic officers,, although the heavier smokers.amongthem did demonstrate impairment of these parameters comparred.to the nonsmokers and ex-smokers. The data also revealed that'th.e heavier smokers with the longest exposure to:traffic had the greatest.impairme.nt of flo.a-volumerelations.hips at 50. percent (and,25lpercent) vital capacity„ again suggesting the synergistic:action.ofc air pollution andl cigarette smoking in producing ob.structive.pu.lmonary disease. The Relationship Betcueen Cigarette Smoking.and Small Airways Disease The role of small airwaysdiseas.e in the patthogenesisof COPD has comeunder closescrutiny in recent years. Resu.ltsfrom s.everall s.tudiess indicate that.th:e resistancee of airwaysl'essthan 2mm.2 internal diameter contributes little to the total measurable pulmonary resistance, and that considerableobs.truction of.f these small airways may be present before changes in theto:tal pulmonary resistance are recorded (BP10):. Several techniquess have been developed to detect the presence of small a.irways.disease, but.some of 'th.ese.are technically difficult, expensive„ and impractical for large-scale screening. The measurement off dynamic compliance was on.e ofthe first techniques used to demonstrate disease of the small airways (BP 143). Patients with small airways disease demonstrate frequency dependent decreases'in dynamic compliance compared to controls. More recently, the measurement of closing volume (CU) has been used as a technically easier and less expensive method for the assessment of small airways.function. The theoretical basis of these:methods in the assessment of small airways disease is described in many recent publications (BP 8, 10', 12, 31, 61,, 105, 116, 119„ 143„ 144,, 147, 150, 151,, 15:3', 155, 177, 206). it is currently unclear whether those subjects withh evidence of small airways disease are particularly susceptibleto:th~e development of clinically identifiable forms. of COPD. a37G4058 IHcCarthy„ et al. (BP 8)') measured closing volumesin.112 subjects by the single-breath argon gas:bolusmethod..Clos.ing,volume increased inn a.linear..fashion with respect to age.Of the 66 nonsmokers.,: no: subjiects.had closing volumes greater or less than 2 SDs.from the mean. normal values,, whereas 266 of 39 cigarette smokers (7 smokers were excluded because of grossly abnormal ventilation distribution as measured by the argon.technique) had closing volumes.greater than.2lSDs. abovee the mean (figure 2'.)... This diffierence in.closing vol[m e.washi'ghlysignificant. (P'<.,001). and indicated a higherr prevalence of small airways 93

35. MIL.NE, J. S.., WILLIA,'HSON:,,J. Respiratory symptoms and smoking habits in older peoplewith age andlsex.differences. Respiration 29(4): 359-370, 1972. 42. BROOKS, A. G.. F'., WALLER„ R. E. Peak flow measurements among, visitors to a public health exhibition. Thorax 27(5): 557-562, September 1972. 44. CAIRD„ F. I.,„ AKHTAR, A. J. Chronic respira..torydisease in thee elderly. Thorax 27(6): 764r768, November 1972. 54:. KAI,ACTC, I.. Chronic nonspecific lung disease in cement work.ers:.. Archives of Environmental Health 26(2): 78-83,. February 1973. 55. KAZACIC, I. Venti'liatory lung function in.cement workers. Archives of Environmental Health. 26(2): 84-85', February 1973. 56. THCMSON, M. L,, PAVIA„ D.Long-term tobacco.smoking and muco.ciliary clearance.. Archives of Environmental Health 26(2): 86-89, February 1973. 57. CA,`!INER, P., PHILIPSON, K.,,ARVIDSSON, T. Withdrawal of cigarette smoking. A study on tracheobronchiall elearance. Archives of EnvLronmental Health 26(2)r, 90-92, February 19:73, 60!. McCARTHY, D. S.,, CRAIG:„ D...B. Why the difference in closing volume? (Letter). Lancet 2(7790.):: 1321, December 16, 1972. 61. CLARK, T. J. H., Assessment of airway closure usingg theclios..ing volume method. Proceedings of the Royal Society of Medicine 64(12): 1245-12:46,. December 1971. 64. MITTPL4.'!, C.,, BARB'ELA, T.,. LIEBERTIAN„ J.A1ph.a1-antitrypsin deficiencyy as.s an indicator of susceptibil'ity'toy pulmonarydis:ease. Journal of Occupational Medicine 1S(1)': 33-38, January 1973. 66. BINN'S, R.,, CLARK,,G. C. An experimental model for the assessment of the effects of cigarette:sm.oke:inhal'ation on pulmonary physiology. Annals of Occupational Hygiene 15:(2-4,): 237-247, November 19.72., 67. FREEMAN, G.,,CRANE, S. C.,, FURIOSI, N. J., STEPHENS', R.. J., EVANS, Nf. J..., MOORE, W,. D. Covert reduction in ventilatorysurface in rats during, prolonged exposure to subacute nitrogen dioxide. American Review of Respolratory Disease 106(4): 563~5'79,. October C 1972. ~ 68. GIORDANO, A. M., MORROW, P'. E. Chronic low-level nitrogen dioxide C exposure an6mucociliary clearance. Health 25(6): 443-449, December 1972'. Archives of EnvironmentaD y -Q 122- -

of 62'and'90, living in Edinburgh and registered with a practicing physician,, Milne and williamson (BP19', 35) reported that over 73 percent of the women hadinever smoked compared with 7.9 percent of the men; 62 percent of the men were current smokers (71 percent of wham ilnhaled):, while only 18'percent of the women werecurrent smokers (50 percent inhalers). In both men and women, a higher percentage of smokers had persistent coagh and sputum production than nonsmok.ers(P <.001 for men and P<..Ol.for women), li.ut.twice the proportion of male smokers had these symptoms than women smokers. A dbse-response relationship was. demonstrated, since a.higher percentage of heavy smokers had these symptoms than lighter smokers(P<.01). In men,. 12.4 percent of the'smokers had persistent cough, sputum„ and a recent chest illness; none of the nonsmokers had this combination.. For men, significant differences in histories of wheezing and dyspneawere found between smokers and nonsmokers.For women, a significant difference between smokers and nonsmokers was demonstratedionly for wheezing (P <.05). The authors found that the FEU% (NEV/VC) was below 60 in 32'percent of the men who smoked compared to 6.7 percent of the nonsmokers (P'<.05).For women„ the figures were 9.4 percent and 3.9 percent. This differencewase not statisticayly significant. In a cross-sectional study of 300 men and'women aged'65 and over in Glasgow„ Scotland, Caird'and Akhtar (BP 44) found that chronic bronchitis in women was reported by 11 percent of the nonsmokers, 13 percent of the light smokers., and by 50 percent.ofthe heavy smokers.. For men,. a d'ose-response relation was shown for lightt and h.eavysmokers,:y but the small nvmb.ersof nonsmokers (5' no.nsmokers; 2 with¢hronic bronchitis): . limit the conclusions which can.be.drawn from the data. In a.retrospective study of 5,348 men aged 40. and over who were current smokers, Rimington (BP' 109)') examined the relationship between the pattern of smoking and the prevalence of chronic bronchitis. lie foundlthat for eachh level of daily consumption.of cigarettes, chronic bronchitis was more prevalent among those smokers who kept the.cigarette in their mouths dur.ing:.the entire.per:iod of smoking (,'°droopers") than among those smokers who removed the cigarette from.th.eir mouths between puffs (normals) (table1). For: all levels of consumption, there wasa significantly higher prevalence of chronic bronchitis among droopers tha.n among normal smokers (P' <.001). When these values were age-standardized, (thiss was: necessary tiecause there.was both a higher incidence of bronchitiss and a higher percentage of droopers in men over 60: yearsof age),. there wass still a.high:er prevalence of chronie.bronchitis amongthe droopers than among the.normals, but the.sta~ti'stical.signif.ican:ceof this difference was not presented„ nor could it be calculated from C the dota gLven. W. .I ~. Xap' C^ t~l 87'

YS disease in the.group of smokers. Of 14 smokers with abnormalities of standard: pulmonary function tests,,'13 were symptomatic and all but one had abnormal closing, voSumes:``Of note was,that of 17 asymptomatic smokers, 9 had abnormally high closing,volumes.' a4lthough.none of the smokers had'.sought medical attention, 29 of the 46 smokers had: cfironic bronchitis„ and had, on the whole, higher closing,volumes than the asymptomatic smokers. 50 .?Oio• ! : . , ..n+nrem.fte o..rm.c~omanc 10~. <O , 50 60. _ 70 ~ ' AGE (Years) . . . . y ~:, t; . . ;Ll. . ' . - . ,. . .. - . ~ . , . . - . . . . ~ - ~Figure 2---Relationship between "closing vo,lume^~ and age in..39,smo~.kers~.. (Thirty-two smokers~~ with normal conventional~ lung. . ~. , ,. . - ~ ~ ~.dunc6ion data and sevea smokers. (Cases 8-14~, Table I)~. ,. . ~~ ,~ . whose dat'a~ are~ identiiied' by numbersa~. Average~~e relation. . ~ . ships~_-L2 SD betSvecn. "closing~volume^'and age in sixty+- - _ six nonsmokers are~ alsoo shown:. Solid ciicles indicate .. .~ ~ smokers who, according~, to the questionnaire used;~. had~ ~. ..~ simple chronic~c bronchitis; and~ open circles indicate~ ~ smokers who~ were~ dsymptomatic. Note~e tha[~ in nine. esymptomaticc smokers~ the "closing volume!' was above~ . ... V. . . .' the normai lrmits~• ..:.. .. ~ _ ± ~..~ •~ .., .~ •.:~: ... ~ . ~ . ... . ..~ . ~: ,. ~Q~ " . _ ~... . ~ ... ~ . ~ ~ ~ ~' ~ ~ ~.. . . SOU.RCE: McCarthy, D. S., et al. (EP' 8). ~ skAOKEaS SEATED O-.. 10 20 94 ia ~ e., ..«.,,.:,A;a .:w:

Table 5.--EsIlimatedrates ofbulllous diseaseofthe l:ung'. per 1,000 men with nodemonstrable occupational hazard (class 1). Pace„SOn Aqe.yr IYOnsmoYer<1P*cM/Day IPacYi/Day 25r44 0 0 0 45} 0 4.0 2.2 NWM' 25-44 0 2.0 5.4 45+ 0 4.6 7.7 Talall 05.2. 4.9 SOJRCE: Stoloff, I. L., Victor, S. B. (BP'25). Smoking and Post-Operative Complications Laszlo, et al. (BP 199) studied the incidence of post-operative pulmonary complications in 52 bronchitic and 88 nonbronchitic patients undergoing elective surgery in London. They found:that a significantly higher percentage of, current nonbronchitic smokers (53 percent) developed post-operative pulmonary complications than.nonbrpnchitic nonsmokers (22 percent) (P'<.02)'. In patients with~no~history of chronic'bronchitis, there was a dose-response gradient of post-operative bronchitis and/or pneumonia from nonsmokers through ex-, light, and heavy smokers. The presence of bronchitis did not seem to influence the effects of smoking;: thebronchiticand'nornbronchitic sankers hadi an equal.incidlence of'pulmonary complications. Of the six cases of severe post-operative bronchitis, five occurred in smokers. The authors noted that the threepaYients'whodeve'loped severe purulent bronchitis after minor surgk'ry wereaQl smokers ofmore than one packper. day. The Influenceof Cigarette Smokinon.the Development of Pulmonary Disease Associated.with Rfieumatoid Arthritis Frank, et al.. (BP 167) investigated 14 memand 27 women with classical rheumatoid arthritis:and.evaluated the presence or absence C of pulmonary dysfunction in.this group. They reported the presence of pulmonary function abnormalities in 57 percent of the men and 33 percent.of the women. The men with abnormal pulmonary function tests ,~.. 7 ~. 104

The Effect of Smoking on the Development of Bullous Disease of'the Lun s Stoloff' and Victor (BP'25). revieweil 44,887 outpatient photo f luorograms seen in the Philadelphia Central Mass X-ray Unit from 1969 to 1970, and found',59: men and one woman witli bullous di'wease of tfle lung. Smoktng information was availab.le',on 51 of the.men. There w:er.eno nonsmokers among the 51 cases (P <.,00.L). In.nonwhiteand white'men under age'45 and in nonwhites greater than 45 years old„ the rates of this disease increased for each.progressively higher level of daily cigarette.consannption (table' 4). When men without known.possiblen or probable, occupational hazards were studied, dose-response relationships were again demonstrated in the.nonwhite population., inclusive of alll agee groups (table 5). The absence of dose-respons.e relations in whites older than 45 may be at least partially explained,by the small numbers of cases of bu]llous disease of the lung found in whites (19 of the. 51 cases). The authors stated'.that the data °are.consistent with', the hypothesis that eigarette smoke is capable of causing alveolar septal rupture..." and, hence, bullous disease of the lung. Table 4.--E'stiimated rates of bullous disease of the lung per 1,000 men by age, race, and cigarette smoking habits. Raue;Sea Ag,e,.yr Nonsmoker <1Pack/@ey 1Pe[k}/Oby. WM' 25,44 0 1.0 45+ 4.5 219' NWM 25+ 4.3 919 45+ 4.1 1310 SOURCEa Stoloff,.I.: L., Victor, S. B. ($P 25)., 103

72. SCHWARTZ„ S:.. L..,,EVANS, D:. E., LUNDIN,. J.E., BONDq. J'.C.. Inhibi- tion of pinocytosis by nicotine. Journal of Pharmacology and Experimental Therapeutics 183(2); 370-3J7,, November 1972. 78. KASS„ I., 0"BRSEN„ L. E., ZAMEL„ N., IDYKSTERHUIS, J. E. Lack of correlati!on between.clinical backgr.ound" and pulmonary function tests in patients with chronic obstructive pulmonary diseases. Aretrospective study of 140 cases. American~Review of Respiratory Disease 107(1)': 64-69, January 1973., 79. KRUMHOLZ', R. A., HEDRICK., E. C., Pulmonary function differences in normal smoking,and nonsmoking,. middle-aged, white-collar workers.. American Review of R'espiratory Disease 107(2): 225-230, February 1973. 90. GOLDSTEIN, E!.,, EAGLE, M. C.,, HOEPRICH',, P'. D. Effect of nitrogen dioxide on pulmonary bacterial defense mechanisms. Archives of Environmental Health 2'6'(4)I: 202-204,. Apri1.1973.. 93. WOOLCOCK, A... J.,.COLMAN,. M. H., BLACKBURN', C. R. B. Factors affecting normal values for ventilatory lung function. American Review of Respiratory Dise:ase10.6:(5): 69.2-709:,. November 1972.. ' 95. SCOTT, K. W. M. An autopsy study of bsonchial mucous gland hyper- trophyin.Glasgow. American Review of Respiratory Disease 107(2):, 239-245, February 1973. 97. MATSUBA, K.,, THURL'BECK, W. M.. Disease of the small airways in chroni'c.bronchitlis. American Review of Respiratory Disease 107(4): 552-558, April 1973. 100. FOX, A.. J'.„ TOMBLESON,. J. B. L., WATT,, A., WrLKIE„ A., G. A survey of respfiratory disease in cotton operatives. Part II. Symptoms, dust estimati'ons., and the effect of' smoking habit. British Journal of Industrial Medicine 30(1): 48-53',,January 1973. I105. GELB„ A. F., ZAMEL, N. Simplified diagnosis of small-airway obstruction. New England Journal of Medicine 288(8): 395-398,, February 22', 1'973'. 109. RIMINGGON'; J'. Chronia bronchitis: Method of cigarette smoking. British Medical Journal 1(5856): 776-778,,March 31„ 1973. 110. DA SILVA, A.. M. T.., HAMOSH, P. Effect of sumoking a single cigarette on the: "small airways". Journall ofApp.lied Physiology 34(3): 361-365', March 1973'. 123

t. ,. - . i' .- . < 10 dgarettes/day . - n=21. ~1o-"G0 czgarettes/day, ~ n = 136! ~69«6~ ~. ~ 20-40dgarettes/day~ n=175~ 84 ~ ~'> ~4o~dgaretres/day n=~19'. : 80 .. .. . . . ~. r ~,. 72.1 68. 7k"..;`r ;._ r, ... .~~ , ymptomatic. b7.9 49.7 37.5 ..~33.,3 47:4 ' 38.3 34,6 , ~ 3'3.3~. a. .~.. ~ 13.2 0 I i 26.s V Figure 4..--Comparison of the prevalence of respiratory symptoms and - pulmonary function: abnormalities in maiesmokers according to their daily cigarette consumption.. CC - Closing, capacity TLC - Total lung capacity CV - Cliosing, volvme VC. - Vital capacity F6V1- One-second forced'expiratory volume SOURCE: Buist.,,A. S., et al. (BP'11'6).

BRONCHOPULMONARI'' DDSEA.SE REFERENCES~ BP 3. DALIIAMN,, T.. Some factors influencing.tlie respiratory toxicity of cigarette smoke. Journal of the National Cancer Iinstitute 48'(6): 182'1-1824, June 1972. 8.. MeCARTHY , D~. S.., SPENCER, R., GREENE, R.,, MLLIC-EMILI, J. Measurement of "closing volume" as a simple and'.sensitivetes.t forear..ly detection of small airway disease. Ainerican Journal of Medicine 52 (,6) : 747-753, June 19'72'. 10.MACKLEM',,,P. T. Obstruction in small airways--a challenge to medicine. American Journal of Medicine 52'(6)',: 721-724, June 1972. 12. STANESCU,,D'. C. Age and smoking dependency of the single-breath oxygen test in healthy subjects. Pneumonologie 147(1).: 46-51, 1972. 15.LEPINE, C..,. MYRE, M.. L. L'emphysemepulmonaire. Confrontations cliiniques.et phy:siopathollogiques, avec.unereference specialee a 1'usage de la cigarette. (Pulmonary emphysema. Clinical and physiopathological comparisons with a special reference to cigarette usage.), Medecine d''Afrique Noire 17(3): 261-267, March 1970. 18.REINTJES„ M,., SWDERENGA,. J., BOGAARD,. J.. M.E.f.fect of smokingg onecigaretteone airwayresistance.. Scandinavian.-Journal of Respira- tory Diseases 53I(3)': 129-134, 1972. 19. MILNE,.J.S., WILLIAMSON, J. • The relationship of respiratory function tests to respiratory symptomss and smoking'g in older people. Respiration 29(3)': 206-213, 1972. ' 23. HUTCHISON, D. C. S.,BAR'.TER'.., C. E'.., COOK„ P. J. L., LAWS,. J. W., 4. MARTEllLI, N. A., HUGH-JONES„ P. Severe pulmonary emphysema., A comparison of patients with and without al-antitrypsin deficiency. Quarterly Journal of Medicine 41(163):: 301-315, July 1972. POWELL,, G. M..,, GREEN',, C. M. Gigarette smoke--a proposed metabolic lesion.inn alveolar macrophages. Biochemical Pharmacology 21(13): 1785-1798, July 1, 1972. 25. STOLOFF, I. ii.,. VICTOR, S. B.` Another hazard of smoking,: Bullous disease.of the lung. Archives of Environmental Health.25(;6):: 415-41i9, December 1972. C C.: ~ 31. . HEZDENDAL, G.-K., FO:ITANA, R.. S., TAUXE, W. N. Radioactive xenon .t+ pulmonary studies in the smoker. Canc'er 30(5'): 1358-1367, ~ November 1972. ' 121

401 4 1ryll }. Wii ,7 N ..-•2..•4-•G-.g'.-tD-Lp..,1.4_1.6-1.a-Z:O - '- DIAMETER OF AIRWAYS. (mmN '----,-' NO'.DRONCNITIS. NOEMPMYSEMA "~- .. CHRONIC. , . ;' .. . .. . t Figure 1L. -A frequency distribution curve of the internal diameters of '; the small ai'rt,*ayss in an autopsy population of nonemphysematous ~"'patients with and!without histories of chronic bronchitis. SOORCE: Matsuba, K.,, Thurlbeck„ W. M. E7PERIMENTAt: STUDIES Studies in Humans, Paterson, et al. (Bp' 201) measured pulmonary ffunction in a group~ that the increase in ai'rways, resistance in nonsmokers was mostly due ~j to bronchoconstriction; that seen in smokers. was thought to be a combina- ~ tion of bronchoconstriction, mucosal edema, and accumulation of.secretory ~,:-- bronchoconstrictive agent) than.the smokers. The authors suggested W 1N h. after exercise following use of'disodium chromoglycate (an anti- C No significant differences in FVO, BEVI, MMEFR, and,FRC were observedi between these two groups.before,exercise. However, after exercise.,, the smokers exhibited.a greater drop in MEFR, FEV1, and specific .. airways conductance than.the.nonsmokers, thus demonstrating that post-exercise airways narrowing was greater in the smokers. The nonsmokers demonstrated a greater improvement in all these parameters measured of 16 nonsmokers and 10 heavy cigarette smokers before and after exercise.

V-1 W iLn oxygen consumption was observed, proportional to the incubation period an& concentration: of smoke extract (figure 14). The enzymatic mechanism of the inhibition of macrophage respiration was not examined in these experiments. r 100 . 01 0.2~~ o.a . 0.6~. 0.8 1.0 ~ 1.2~. 1.4 .. ~ ..'~~Smoke 6ctraet', mI~ } Figure 1A• -Effects of aqueops cigarette smoke extract on initial'oxqgen uptake,.fiinaS oxygen uptake, and cell viability of pulmonary macrophages. . ..,ci. . . . , ... .. .. + ,.. .. . . . .. ., . .. .. . . SDURCE: York„ G'. K..,, et al. (BP'198). nicotine inhibi'ted'invertase-iinduced.pinocytosis by sucrose-laden ,.' mouse peritoneal monocytes by 29 and 18 percent, depending on the ~. .concentration of nicotine added to the medium. The contribution of C„} this type of'pinocytosis to the,bactericidal activity of these monocytes ~j ' 3chwartz,, et al. (BP 72), utilizing this test system, reported that pinocytosis by sucrose-laden mouse peritoneal macrophages (monocytes). Snvertase: placed in a med'itmm of calf's sertua results in enhanced, p . ._. . ., ..., . ;, . ~ is tmcleas a~t resent Wa iJ 4

r u pulmonary function,.smokers had:slower clearance rates,from~l to 5 hours after inhalation of the part:icles,;but these differences were not statistically significant (figures 12'and 13). Camner,, et al. (bP 57) reported on clearance rates in 17'young and middle-aged ex- ( smokers who had stopped smoking for 3'months. These workers, noted that mucociliary clearance of 6 um:'ffluorinated ethylene propylene (Teflon 120')~ particles tagged wit(tTCP9m- measured at 2 hours post- ` inhalation had improved at 3 annths post-quitting in 11 of 17 patients. Mean retention of particles was significantly higher prior to stopping smoking than at 3.months (P <.05), and also was higher at 1 week post- quitting eompared, to 3 months post-cessation (P'=.005). In this study, the volume of inhaled aerosol was not controlled. In addition, coughing, after_inhalation of the particles was reported to be conspicuously - absent or rare., whereas in the Thomson study (SP 56), ths,effect of '• coughing during the study was not discussed.:•t too r 70 ~.~ m . _: . P so x ~ 'J R~JF.. . ... .!. '+ . ~ Nbrmal (50) ~~~ .. `~'0 ~ Restrictive (ti6) 40 ~ ~ F. _ - . . . ~~ ! ~~. .. .. ~ . - `A ~ Obstructive (13)~. n- . ~ . 1 .. ~ . . . . - . F~ 0.37 &67 0.65 1.00 `0L80! 1.26. ~ 1~.993.09~. 2.40 1.92 1.88 '~. 3:06 ~ i. Not~Sipnilicant~ , 11 1' 1 r, ~' I' r N~ 1 1 2 3 4 . Time Aper~Tnhalatlorn (hr)', 0 Figure 12. -Mean clearance curves for normal subjects, subjects with ~' airway obstruction,and restrictive impairment of the. M lungs. F=:Snedecor's F'; the value required for signifi- `C.. cance here at the 5 percent.level is 3.11. C t . J J 1

72-1046.IRAVANI, J. Fli'mmeraktivitat im~ Res pirat ions t rakt nach chronischer Zigarettenrauchexposition:. (Ciliary activity in.then respiratory tract after chronic exposure.toe cigar:ettesmoke.) Rehabilitation,, Praventivmedizin, Physikalische Medizin,. Sozialmed9.zin 25(1/2):: 40-42,, 1972. 73-0415. JONES, R., BOLDUC, P'., REID, L. Coblet cell glycoprotein and. tracheal gland hypertrophy in rat airways: The effect of tobacco smoke with.or without the anti-inflammatory agent phenylmethyloxadiazole. British Journal of Experimental Pathology 54(2):: 229-239',,'April 1973. 73-0476. KANNER, R. E., KLAUBER„ M. R., SATANABE, S., RENZETTI, A. Di., Jr., BIGLER.,, A. Pathologic patterns of chronic obstructive pulmonary disease in patients with normal and deficient levels of alphal,-antitrypsin. American Journal of Medicine 54(Cf)r 706-712, June 1973,: 73-0346. ROSMIDER, S., FELUS,, E.,, WYSOCKI, J. Ocena niekt6rych h wyznacznik6w odpornosci hi®oralnej u palaczy papieros6w. (Evaluation of'some humoral resistancedeterminantse inn smokers.) Polski Tygodnik Lekarski 28(2): 47-50, January 8, 1973., 72-12,40.. LEWIS, A. J., NICHOLLS, P. J. Effect of inhaled cigarette smoke on content, release and breakdown of histamine in guinea-pig. lung. Life Sciences 11(23, Part 2): 116'7-1171„ December 8„ 1972. 73-0646.. LEWIS, C. I., McGEADY, J. C., TONG, H. S,.,, SCHULTZ, F. J'.,, SPEARS, A. W~. Cigarette smoke tracers: Gas chromatograpfiicc analysis of decarhSorobiphenyl. American Review of Respiratory Disease l08(2): 367-370, August 1973. 72'-0590:., LEWIS, C:. I., McGEADY', J. C., WAGNER, J. R., SCHULTZ,, F.Ji.,, SPEARS, A. W. Di¢hlorbenzophenone as a nonradioactive tracer for cigarette smoke-gas chromatographic analysis of tracer. - American: Review of Respiratory Disease: 106(3): 480-484, September 1972. 72-0'766.. McFADDEY, E. R'.., Jr.,, LINDEN, D'.. A. A redbcti'on in maximum C ` ' mid-expiratory flow rate. A spirographic manifestation of . . ~ small airway disease. American Journal of Medicine 52(6): 725-737, June 1972. a MACKLEM, P. J., DESPAS, P. J.,, LEROU%, M. Site of airway F C C obstruction in asthma. Chest 63(4, SuppLement):. 28S, April 1973. 0 135'

Goldstein, et al. (BP 90),reported.on.the effects of liow.level NOZ exposure on bactericidal activity of the mouse lung. 11heyfirst infected mice with: radioactively labelled Staphylococcus; aureus and' then exposed them to different concentrations of NOZ for 4 hours. The authors then measured pulmonary radioactivity and bacterial concentra- tions. They found that.at concentrations of 7, 9.2, and'.14,.8 p.p.m. N02 the level of radioactivity was unchanged„ but bacterial counts were greater in the N02-exposed mi.ce.(P' <,05)„ and they concluded that the bactericidal activity of the N02-exposed animals wass signif.icantlyless than that of control animals at these concentrations of NOZ. In a series of experiments where mice.were first exposed to~1.0, 2.3',., and 6.6 p.p.m. N02 for 17 hours and then infected with the labelled Staphylococcus aureus, pulmonary bactericidal activity was decreased in the mice exposed to the latter two concentrations of NOZ (P' <.05 and P'<.,,01).. In $..oth~setss of experiments, thepfiysical removal rates of bacteria by the pulmonary tree (as measured by the degree of remaining radioactive label)~ was not influenced by NO'.2. Thesee experiments suggest that the retardation of'pulmonary bactericidal activity was due to dysfunction.of the: cellular elements.of.thepulmonary defense mechanism. (ii.e;, pulmonary alveolar macrophages [PAMs],) in the N02-exposed mice. Fenters, et al. (BP 195) exposed four monkeys to low dose NO2. (~ p..,p.m~..) for 156 monthss and i'nfected.these animals with influenza~ virus. Three controll monkeys were exposed to the virus, but not to the N02., The N02-exposed animals had higher hemaggliutinati;on-inhibition~ and serum neutralizing antibody responsess ag.ainst.the.virust than the nonexposed animals. Pathologic examination.of the 1'ungsof thesee animals dlemonstrated.slight to.moderate emphysema.in theN02-expos.ed, an.d virus-infected monkeys,, alongg with thicken.ing.of.thebronchial and bronchiolar epithelium,. and no such changes.in..thoseanimals whowereonlg infected with.virus. - Dalhamni(DP 3) conducted experiments~ on.40livecats, exposing them to cigarette.smoke of different chemical compositions. The cigarettesmokewasanalyzedfo.r "tar°', nicotine, pH,, acrolein., nitrogenn oxides(NO), acetaLdehyde., hydrogen:cyanide (HCN),, and carbon monoxid.e (CO). The author found an inverse.correlation between the number of puffs required to produce ciliostasiss of the trach.eobron:chial treeand the amounz ofa:crolein,. HCN„ Co, "tar", and nicotine found in: the cigarettee smoke.. The data appearedd to indicate that themafority of theeffecte was caused by the "tar" and acrolein content of the cigarette smoke. Gairola.and LU.eem (BP 140)' studied the effect of the water soluble and insoluble fractions of tobacco smoke on rat liver miitochondrial function.. These inves:ti'gators.found that.b:oth.fractionswere effective in inducing a decline in energy production by the mitochondkia, but to differing.d'egrees„ thereby s.uggesting,some diifferencein their' mechanisms of action on mitochondria. 117

SMerman.,. et al., (BP'2'37)) conducted a study in Detroit on 489 working men and women,, among whom 459'were employed in the autoo industry. All subjects were referred to one physician for evaluation for workmen's compensation, The authors concluded that their data challenged "the traditional view (held) by...much of the,medical profession that workers' lung and! heart diseases are.largely caused by cigarettes ratherr than byworkplacepoiisons." Thes.ee investigators studied various occupationall exposures.within the auto industry and found.that both~ in exposed and.unexposed.working populations„ approximately the samepercentag,esof cigarette smokers and nonsmokers suffered from bronchitis, emphysema,. and heart disease.: Imprecise smoking his:toriess and the absence off adjustment for several potentially confounding variables limit the conclusions which can be drawn from, these data.. T,'he: Effects of Smoking on Pulmonary,Function in Patients with COPD In a retrospective study of 41 hospitalized cigarette smokers with aa diagnosis ofpulmona~ry emphysema,: Lepine and Nfyre(BP 15) found dose-response relationships between.number of daily cigarettes smokedd andd years of. dyspnea, years of cough„ and impairment of the maximum expiratory flow rate (MEF). No dose-response relationships were found for the presenceofe cor pulmonale by ECG, X, rayevzdenceof cardiomegaly„ impairment of carbon monoxide diff.usion,functional residual capacity„ ar.terial.blood.gasl abnormalities, or the:ratioof residual volume to total lung capacity (ItV/TliC). In a retrospective analysis ofPFTs:of 140patients0 with emphysema,, chtonic bronchitis.,, or both, Kass, et al. (BP 78) found no correlation between the severity of impairment of pulmonary function.testsand the amount or duration of cigarette smoking.. The Effects of Sfioking on Pulmonary Function in Hea1'thy Populations Grimes and Hanes (BP' Ig8): studied 1,059' employees of a.largea insurance:company and:found that cigarette smoking,was associated d with decreases in FVC and FEVl for all age groups.iin.men. In women,,, theyoungerex, smokerss had higher valuess on pulmonary function testing than the.nonsmokers. Higgins and Keller (BP' 189),,utilizing.datag obtained'.from the.Tecumseh Study, did'note differences in FVC,.. FEV1,. FEV1/VC„ and MEF50% b:etween.smokers and nonsmokers for both.sexes and between smokers of greater than and less than 20 cigarettes per ~ day. In this study, smokersof'.either sex ha&lower mean FVC,. FEV1„ Wi FEV1[FVC'', M'&.'F50%, MME'F25:-75%> MMEF0.2'-2L.and PEF than nonsmokers„ ~ an&all these values decreasediwith increasing tobacco consumption. 4,, O CA 89.

11 7 4 ~. . 0 p~. 70~. 30 40 50 b0 70 ~Time~raiq~teQ. dvsl~m<owrement {mq Imrt)mtl . 'Nonsmokcn': ~ ~I •/, = 1•57~+~0+33 x. (TWDM): r ~ P27. . ... ~. ~ m~5-76+~030, x (IILVDM1):r ~ G23~ SOURCE: Fox,.A. J., et aT~. (BP 100). s Figure 1Q. --Effect of'smokin,g,on prevalence of byssinosis at different time-weighted dust exposure levels.

100 01 70. X 0 3 MealthyGroup ,. . . . . P P1otSignificant B . r ) - -A , Smokers 118) Nonsmokers 123)} Wealthy ` _ ExSmokers (9) ` _ Nonsmokers (6) ~z_-y Smokers (17) ~ Impaired - b Exsmokers. (6) „ 7 0.15. . .'!~ .. F 1.10. 0t16 0.16'. Oi17 0 0:12 ~.. 0:38 0:48 .,0.68 .@.32' 0~ 30, L F 2.86. 0.70 1.34 11.66 ; 1.91~ 1.54 '1.12, 0561 00111 ~`Impaired'Group 0.06 : 0.12~~ tldot. Significant . .. .,:3 ~ . ~ 4 rrTlme After Inhalation (hr)'. i Figure 13. -Meaz1 clearance 'curves for smokers„ ex-smakers, and'nonsmokers >•atn the healthy group and the group with respiratory im?air- ment. F'= Snedecor's F';.t:he values required for significance at the S percent level are 3.19 for the healthy group and 3.35 for the i;npaired guoup '. ' 1 SOURCE: Thomson, M. L.;"Yavia; ~• (BP 56). f Q The question of whether the short-term effect of cigarette smoking C 67 on et$Sam`in2 mtienaili'arv rr~namnrt ic. anari'..fie tnn rioarw+hrwrmnlrp .. Q or is due to a.nonspecifi'c reaetion of the tranheobronchial tree, ~ .ii+ was investigated by Camner„ et al. (BP 161): who found that inhalation p of inert carbon particles by 8 normal subjects, (including 2'smokers) 0) resul'tediin similar or enhanced pulmonary clearance rates compared' 0 to the control' atates. These results suggest that the increased mucocil!iary transport effected by ahort-term exposure to cigarette smoke may be a nonspecific reaction. _"_1•.., .. .

SUMMARY OF' RECENT. NON-NEOPLAS'LIC BRONCHOPIJLMONARY' FINDINGB 1. Results from epidemiologic s.tudieson eld!erly populations demonstrate an increased prevalence of respiratory symptomss and impairment of pulmonary function among smokers of both sexes.s compared'tod nonsmokers. 2. Data from several recent studies indicate that standard pulmornaryfunction: tests and physical work capacity are impaired in apgarently healthy smokers compared to:nonsmokers., 3. Recent epidemiologi';c data suggest that smokers who retain the cigarette in their mouths:cnntinuously while smoking (droopers) have a higher prevalence of. chronic bronchitis than those smokers who remove the.cigarette from.their mouths between puffs., 4. Arecent epidemiologic study confirms the observation that cigarette smoke and air pollution act synergistically in the development of symptoms of respiratory disease. 5. Results from several recent studies indicate.that cigarette smokers have a higher prevalence of.functional abnormalities of the small airways than.do nonsmokers. 6. Results from:arecent study suggest that.although aa history of lower:respiratory diseas.easan infant.isrelated to thee prevalence of cough at age 20, cigarette smoking isa.far more important factorinr the d'evelopment.ofcough in young adulthood., 7'. Data from a major retrospective study indicate that cigarette smoking is closely related to the development of bullous disease of the 1ung., 6'. Experimental studies in animals have shown that exposure to nitrogen dioxide, a eonstituent'of the.vapor phase.ofr cigarette smoke,.results in emphysema-likee changes.in the.pulmonary parenchyma, diminished mucociliary cliearance, and impairment of bactericidal activity of. alveolar macrophages. Data from.excperimental studies have demonstrated that.the filtered gas phase.of tobacco smoke may effect changes.in pulmonary alveolar macrophage metabolismthrough inhibition of the glyco3ytic pathway„ cigarette smoke may also impair oxygen consumption and pinocytic activity of pulmonary alveolar macrophages.. 120:

Snider, et.al. ($Y 218)') exposed rats to0.1 percent cadmium chloride solution by aerosol, and were able to demonstrate centrilobular emphysema in theseanimalis after 100 days.Since cadmium hass been found in cigarette smoke,, and smokersand'patientswith emphysema havebeene shown to have elevated tissue levelsofcadmiums at postmortem„ further s.tud'ies.s defini'ng.therole of cadmium~in the development of pulmonary emphys~emaa in man..would'.beuseful.. Iln, Snider's experimental protocol, animaIlss exposed to 1 percent of CdCl2 developed a.severe hemorrhagic necrotizing. chemical pneumonia, and the lower dose of CdC12 also elicited a hemorrhagic. response, aSthoughno evidence of such an,inflammatory response was evident 10 days post-exposure. CYTOLOGIC AND IHISTOLOGICSTUDIES Experimental evidence indicates that cigarette.smoke can impair the function of pulmonary alveolar macropbages (BP 24). Pulmonary macrophages appear to.beflhe primary defense against bacterial°invasion of the pulmonary parenchyma and also serve to remove particulate contami- nants from inspired'. air.. In recent experimental work.,. Powell and Green (BP 24) investigated the mechanism.of actionn of cigarette smoke on macrophage function. By using his.tochemical staining techniques, these workers found!that the filtered gas phase of.cigarette smoke (FGP) inhibited aldehyde dehydrogenase activity in rabbit pulmonary alveoliar.macrophag.es (PAMs). This effect of FGP'was inhibited by prior addition of cysteine to the medium. Th.e loss: of enzyme activity correlated'withthe Lossofpacrophagephagocytic function (which wass also.prevented by the.prior,ad'dition.of cysteime). No other enzyme was inhibited by cigarette smoke (except for C6PD in those preparations of cells which adhered:.togiass)1. Byusing crystalline glycera.ldehyde3-pho.sphate dehydrogenase, the authorsdemonstratedl that FGP~ inhibitedl activity of this enzyme, and the degree of inhibition was directly related to:the period.ofincubation..(most of the inhibition occurringg within thefirst.five..minutes).. Dbisenzymewass not inhibited by FGP in the presence of'cysteine.When enzyme activity was assayed in cell preparations, glycerald'ehyde 3-phosphate dehydrogenase activity was.reduced by FGP. This inhibition was dose-related to FGP'. FGP didlnot influence G6PDorLIDH.activity in the pulmonary alveolar macrophages. These experiments suggest that FGP inhibited the glycolytic pathway withinn the.pulmonary alveolar macrophagess concurrent with.the impairmentt of phagocytic activity of these cells.The authors postulated that FGP may act as a sulfhydryl agent (thereby explaining,the protective effect of cysteine) in the disruption of the activity of glyceraldebyde C 3-phosphate dehydrogenase., L ~ York, et.al. (BP 198) showed that incubatiion'of sheep pulmonary ~ macrophages with tobacco extract.resulted in.an initial stimulation, 7 then inhibition..of macrophagee oxygen consumption. When cigarette smoke extract was incubated witky the macrophages, a continuous decrease . ~ 1118

157. CHEW, P. K., CH:I!A,. M., CHEW, S. F.,, SUPRAMAN!IAM, J. M..J., CHAN, W., CHEW, C!., H.,, NG, Y. K., GANDEUTA,, B. Asbestos workers in Singa- pore. A clinical, functional,, and radiological survey. Archives. of Envirocmiental Health 26(6)': 290-293„ June 1971. 159. SPEIZER, &. E.,,FZr!RRIS, B. G., Jr. Exposure to automobile exhaust. L. Prevalence of respiratory symptoms and disease. Archives of Environmental Health 26(6): 313-318„ June 1973'. 160. SPEIZER,.F. E',., FERRIS, B:.. G..., Jr. Exposure to automobile exhaust. II. Pulmonary function.measurements... Archives of Environmental.Health 26(6): 319-324,,June 1973. 161. CAMNER, P., HELSTRDM, P.-A., PHILIPSCN, K. Carbon dust and mucociliary' transport. Archives of Environmental Health 26(6): 294-29b, June 1973. 166. KILBURN, K. H., MERCHANT, J..., LUMSDEN, J,., HAMILTON, J.. Chronic bronchitis in cotton textile workers. Evidence for addition.of effect of cigarette smoking and occupational exposure. IN: Brzeziinski, Z., Kopczynski, J.., Sawicki, F. of Chronic Nonspecific Respiratory Diseases. (Editors..): Ecology International Sympos:i'.um.,. Warsaw, Pol'andi„ September'7-8,. 1971. Warsaw, Panstwowy Zaklad Sydawnictw Lekarskich, 1972. 76-82. 167. FR7SNK„ S. T..,, WEG,.J. G!.,,HARKLEROAD, L. E.,, FIiTCH..,, R. F. Pulmonary dysfunc:tiom in:rheumatoid dis.ease.. Chest fi3(1):27'-34.,. January 1973. , 170. LINN, W. S., HACILNEY, J. D.. Nitrogen andlhelium "closing volumes" simultaneous measurement and reproducib.i.lity.. Applied Physiology 34(3).: 396-399, March, 1973. Journal of 173. WESTERGAARD, 0., OLSEN'„ P. Smoking and'ciliary movement in the upper respiratory tract. Archiv fur Klinische und Experimentelle Ohren. Nasen- und Kehlkopfheilkunde 203'(3): 179-1'$3, 19'73. 177. MACKLEM:, P. T., MEAD, J. Resistance'of central and' peripheral air- ~ w'ays.measurediby a retrograde catheter. Physiology 22(3): 395-401„ 1967. Journa l of Applied~. w.. C 188_ GRIMES, C. A., HANES, B. Influence of cigarette L smoking on the p apirometric evaluation of employees of a large insurance company.. American Review of Respiratory Disease 108(2): 273-282, August 1973. 189. HIGGINS, M. W., KELLER, J.. B. Seven measures of'ventilatory lung function. Population values and aco¢nparison of their ability to discriminate between persons with and without chronic respiratory symptoms and disease, Tecumseh~, Michigan. American Review of Respiratory Disease 108(2): 258-272„ August 197'3.,, . 125

Westergaard and Olsen (BP 173) studied ciliary activity in biopsy specimens from the larynx and carina in 20 patients and found that there was no ciliary activity in epithelial cells from~these sites in.the entire:g;roup of 16 moderate and heavy smokers, while in 3 nonsmokers and ]i cigar smoker normal ciliary activity was observed. Studies in Animal's Binns and Clark (BP'66) described a.new experimental model for testing the short- and long-term effects of cigarette smoke on pulmonary physiology. By using male cynomolgus.monkeys which were fitted with a specially designed smoking:g device, these authorss demonstratedd marked increases in total pulmonary resistance in animals smoking approximately 12' cigarettes per day, for 5' days per.week. These changes stabilized at about 20 weeks of exposure and extended througfi the 6-month test. period. The changes in pulmonary resistance were statistically significant (P <.001),. After.6 months, no changes. in tidal volume, respiratory rate, or dynamic compliance were noted. Histologic sections of lungs: from smoking,monkeys showed!clumping of pulmonary alveolar macrophages containing pigmented granules and foamy cytoplasm., These nonspecific cytologic changes have been observed in other animals. exposed to cigarette smoke., Previous editions of this report (1972„ 197'3)' have described experimental.l evidencee concerning.the production.of:emphysematousehanges in rat.and guinea pig: lungs by exposure to nitrogen dioxide (N02), one of the gaseous componentsf of cigarette smoke. Freeman, et al. (BP 67) described experiments whereby low (10' to.L5 p.p.m.), intermittent dosess of'.NO2. administered over the normal life span of rats resulted in more severe changes.of the pulmoriary parenchyma than those previously reported,;; these changes included fibroblastic proliferation,, epithelial hypertrophy, loss of cilia in.the respiratory bronchi'.oles, fibrosiss of alveolar ducts, destruction of alveolar walls, and enlargement of alveolar air spaces. These authors calculated a129 percent loss, of ventilatory surface in theNO~-exposed.rats,. occurring in a p.anlobularr diistribution.. The lungs of the N02-exposed rats had greater residual vo:lumes than the controls,, and these rats.s suffered fr:om hypoxemia,, hyp.ercarbia,., andiaeidosis.,, as.well as.a compensatory polycythemia. Thus, by administering,lower doses: of N02 intermuttently„ survival of these rats was prolonged,(compared with survival of rats receiving continuousN02)„ and the development of a.full-blown picture of emphysema similar to that.seen in humans was produced. The relative role of NO2 in the causation of emphysema in humans is still unknown. In another series off experiments,. Giordano and Marrow (,HP 68) studied mucocilliary clearance rates in f avale rats exposed continuously tolowo dosesof N0i2. (6 p..p.m.) over a per:iod'of: 6 weeks. They found a significantly decreased rate of clearance in rats exposed to N02 than in nonexposed!rats (P <.02). In those animals with a decrease, in mucociliary activity, the effect of N02 was reversible within.7 days following this:long-term,low dose exposure. 116 1

73'-0306'. MARTIN,, R. R. Altered morphology and increased acid hyd'rolase content of pulmonary macrophages from cigarette smokeas. American.Review of Respiratory Disease 107(4): 596-601, April 1973. MITCHELL, C. A,,, ZUSKIN„ E.,, BOUHUYS,, A. The effect of ciga- .rettesmoke andB-adrenergican.tagonis,tson small airways. American Review' of Respiratory Disease 107(6).: 1098-1099, June 1973. 72-1286. OSCHEBWITZ,,M.,, EDLAVITCH, S: A.,..BAhER, T'. R.,; JARBOE„ T. Differences in pulmonary funxitiions in various racial groups. Ame:rican..Jburnal of Epidemiology 96(5).: 319-327,, November. 19:72. 73-0423., PARKINSON, D. RI., STEPHENS„ R. J.Mlorphological surface changes in the terminal bronchiolar region of N02-exposed. rat.lun.g. Environmental Research 6(1): 37-51, March 1973.. 71-1180. RYLANDER.,, R., FYeeLung:celli studies in cigarette.smokeinhala- tion experiments. Scandinavian, Journal of Respiratory Diseases 52(2):: 121-128, 1971. 7866. SIMONSSON, B'.. G. Clinical and physiological studies on chronic bronchitis.. I.Clinical description of th,e patient,material. Acta Allergologica 20(4):': 257-300, 1965. 73-03113.STEBBINGS., J. H..,, J.r.Two observed associations betweem respiratory allergies and hypertension.in nonsmokers. American Journal of Epidemiology97'(1):! 4-15, January 1973. 73-0497. STOLOFF,, I. L. Bullous lung.dis'.ease in short order cooks. Journal of.0ccupationall Medicine 15:(,3): 202-203, March 1973. 73-07$1. TA'SHkIN„ D. P., LEVY„ S. E.,, TH0MPS0N„ J. R.., SIMMONS, Ds. H., GORDON,. B.Mi. Pulmonary effects. ofchron2c niicotineadminis- tration in.young.and.old Fischer-344:rats_Proceedings of the Western Pharmacological Society 16: 209-214„ 1973. 73-0610i. THOMAS, W., HOLT, P'. G.,, KEAST„ D. Effect of cigarette smoking on primary and.secondary hvmoral responses of mice. Nature 2'43:(5404): 240-241, May 25„ 1973. ' THURLBECK, W,, M. Small aiYways.disease. Human Pathology 4:(2): C W Q 150i152'„ June 1973. M Fy 73-0434. VASSALD.O'„ C. L., DOMM,, B. M., POE„ R. H., DUNCOMBE, Ms L., ~ 136 GEE, J'.: B.L.N02 effects on,alveolar macrophage phago.cytosis µ and'metabolism. Archives of Ehvironmental Health 26(5): 270- 274, May 1973'..

t 113. SPAIN, B. M.., SIEGEL, H., BRADESS', V. A. Emphysema in apparentDy healthy adults.. Smoki'ng., age, and sex. Journal of the American Medical Association 2'24(3)r 322-325, April 16, 1973. 114. MITTMAN, C. Chronic,obstructive lung disease: The result of the interaction of genetic and environmental factors. Heart and'.. Lung,2(2): 222-226,, March-April 1973. 116. BUIST, A. S., VAN FLEET,,D. L., ROSS, B. B'. A comparison of conventional spirometric tests and!the test of closing volume in an emphysema screening, center. American Review of Respiratory Disease 107(5): 735-743, May 1973. 1 119'. BUIST, A. S.,, ROSS, B. B'. Predicted.values for closing volumes using a mod'ified single breath nitrogen test. American Review of. Respiratory Disease 10.7(5): 744-752, May 1973. 140. GAIROLA„ C.,, ALEEM, M. 1. H,. Cigarette smoke,: Effect of aqueous an.d nonaqiueous fractions on mitochondrial.function.. Nature241(5387)~: 287-288, January 26, 1973. 143. WOOLCOCK„ A. J., VINCENT„ N. J.,,MACKLEM, P. T. Frequency dependence of compliance as a test for obstruction in the small airways. Journal of Clinical Investigation 48: 1097-1106, 1969. 144. INGRAM, R, H..., Jt'., SCHILDER'.,,D. P. Association of a decrease in dynamio.comp.liance.with a change in gasdistrib.ution. Journal of Appliied. Physiology 23(6): 911-916, December 1967. 147'.C;REEN, M., TRAVIS, D. M. A simplified closing-volume method. suitable for field use. Lancet 2'(7783): 905-906, October 28, 1972'. 150.LEBLANC, P., RUFF, F'.,, MILIC'-EMILI, J. Effects of age and body position on."airway closure" in. man. Journal of Applied Physiology 28: 448'-451,, 19'70,.. 151. . MACKLEM;, P. T., PROCTOR, D_ F'., HOGG, Ji, C. The stability off peripheral airways:. Respiration Physiology 8: 191-203, 1970. 153'. SUSSKIND, H., RICHARDS„ P., SKOLNICK, M., ATKINS„ H.. L. Detectiion of impaired pulmonary function with a mass-spectrographic tracer technique. 24th AGE.*SB, International Hotel„ Las Vegas, October' 31-November 4, 19'71. 1 p. C' ~ 155. LANCET'. Closing volume.. Lancet 2(7783): 908-910', October 281, 1972.0' . 124

73r0314,. SUCIU:, Il., PRODAN, L., ILEA, E., COCARLA., A., COROIU, Mi., OPREA, V. F'actori Care Iintervin in Grabirea.sau Prelungirea Timpului de Instalaresi Evolutie a Silicozei. (F'actorss promoting, and hindering the time of apparition andievolution of siLicosis.) CL'ujul Medical 45(2'/3)': 303-307, 1972. 73'-0651., TSE, K. S.,, WARREN, P.,, JANUSZ, M., McCARTHY, D. S.,, CHERNIACK, R. M. Respiratoryab.normalitiesy in.workersexposed to grain dust. Archivesof Environmental Health 27(2): 74-77,. August 1973. 72-0222'.VAN GANSE, W. F.,, FERRIS, B. G., Jr., COTES', J. E. Cigarette smoking and pudmonary diffusing capacity (transfer factor). American Review of Respiratory Disease 1'05(1): 30-41,. January 1972. 73-0'316'., WALTON, M. Industrial a®onia.gassing. British Journal of Industrial Medicine 30(1).: 78-85, January 1973. 73-0503'. WI'LSON, R. W. conditions. March 197.3. Cigarette smoking, disability days and respiratory Journal of Occupational Medicine 15(3): 236-24'0!, 72-0663'. WY'SOCKI, M. Testy Spdrometryczne TQT i~.FEU7--Wlasciwosci i Przydatnos.c w Rozpoznawaniu PrzewleklegoZapaleniaOskrzeli., (S.pirometry tests TQT and FEV--their propertiiess and usefulness in diagnosiss of chronic bronchitis.) Gruzlica i Chorogy Pluc 40(1)I: 35-44, January 1972. Part II (Additional articles which were reviewed but not discussed in the text.)~ AILSBY„ R. L., GHADIALLY, F. N.Atypical cilia in human bronchial mucosa.. Journal of Pathology 109(',l): 75'-78,, January 1973. 73':-0047.. ALBERT„ R. E..,,LIPPMANN', M., PETERSON, H. T.., Jr.,,, BERGER,.J.,, SANBORN, K.,BORNING, D. Bronchial deposition and clearance, of aerosols. Archives of Internal Medicine 131(1):. 115-127„ January 1973. 72-0fi4.7.ASTIN'„ T. W. Reversibility of airways bronchitis. Clinical Science 4'2(6),: obstruction in chronic 725-731, 1972. 133

BRONCHOPULMONARY DISEASE SUPPLEMENTAL REFERENCES Part I (Articles:which were reviewed' but not discussed in the text, providing. data confirming well-established.relationships.between:smoking and bronahopulmonary diseas:e.) . 72-1082. ANDERSON,. J. A., DUNNILL, M. S., RYDER„ R.. C!. Dependence of the incidence of emphysema on smoking history„ age, and sex. Thorax 27(5): 547-551, September 1972. ANTHDNSSEN„ N. R., DANS!ON„ J.,, ROBERTSON, P. C., ROSS,,W. R. D. Airway closure as a function of'age. Respiration Physiology 8: 58-65, 1969-1970. 73-0048. BERARD,, J., EMONOT, A. Enquete sur li'Etiolog,ie due Pneumothorax Spontane, Dit Tdiopathiq;ue. (Survey on the etiology of so- called idiopathir spontaneous pneumothorax.) Journall de, Medeci'ne de Lyon 53: 281-284, 287-290, February 20, 1972. 73,-01'56,. BOUDIK„ F..,, ULRICH, J.,, SVEC, F.,. BOBAK, J.,, GOLDSMITH,, J. R. Prevalence of respiratory symptoms in: three areas of Bohemia with different air pollution. IN: Brzezinski, Z.., Kopczynski, J., Sawicki, F. (Eddtors)~. Ecology of Chronic Nonspecific Respiratory Diseases, International Symposium, September 7-8, 1971, Warsaw„ Poland. Warsaw, Panstowowy ZakladiWydawnictw Lekarskichy, 1972'. pp. 34-42. 72-0934. BRILLE, D. Ep:idemiologie de 1'a.bronchite chronique donn6ess actuel'lesd`apres Ies etudbs staitiques. (:Epidemiology of chronic bronchitis current.data.accordingtostaticstudies.)Evoluation Medicalle 15'(3-5):~ 287-299, 1971. 71-0611. BRILLE, D. Frequence de la bronchitee chroniquech.ezla femme. Role da tabac.. (Incidence of chronic bronchiitis.i:n.women.. The role of tobacco.) Revuede Tuberculose et dp Pneumologie33(6): 794-797, 1969. 72-1083. BRSNKLru1N',.G, L., BLOCK, D. L. Chronic bronchitis in a working, population. Journal.ofl Occupational Medicine14.(11)': 825-827, November 1'972'. 72-0648. BRINKMAN, G. L., BLOCK, D. L.,,CRESS, C. Effects of bronchitis . and occupation on pulmonary ventila:tion,overn an 11-year: period'. Journal of Occupational Medicine 14(,8): 615-620, August 1972. 128 '

192. CQLEMAN, A., E., BURFORD, C. L., KREUZER, P. Aerobic capacity of relatively sedentary males. Journal of. Occupational Medicine 15(8): 628!-6':32,, August 1973. 195. : FENTERS„ J.D., FINDLAY, J. C.,PORT', C. D., EHRLICHi,. R., COFFIN, D. L. Chronic exposure to nitrogen dioxid'e.. Immunologic„ physio- logic.,, andd pathologic effe:cts:s in virus-challenged squirrel monkeys:..Archives of Environmental Health 27'(2);: 85-89, August 1973. 198., YORK, G. K.,,ARTH', C.„ STUMBO, J. A.,, CROSS, C. E., MUSTAFA,, M'. C., Pulmonary macrophage:r:espiration as affected by cigarette smoke and tobacco extract. Archives of Environmental Health 27(2):: 96-98„ August 1973. 199.IIASZLO, G.„ ARCHER, G., G,, DARRELL., J. Hi., DAWSON,, J. M'., FLETCHER, C. M. The diagnosis and prophylaxis of' pulmonary complications of surgical operation. British Journal of Surgery60(:2:): 129-134, February 1973. 201.: 06., PhTERSON„ N. A. Mi., AEDMAD, D. „ LEFCO&„ N.M. Airways narrowin$, in exercise in normal subjects and the effect of disodium cromoglycate. British Journal of Diseases of the Chest 67: 197-20:7, July 1973. BUIST,, A. S., ROSS', B'.B'. Closing volume as a simple, sensitive test for.thsdete:ction of peripheral airway dis.ease.. Chest 63'.(4,. Supplement) : 29'5:-30S, April• 1973.. , 2'10.STONE,,D. J.,, SARKAR,, T.. K.,, KELTZ, H. Effect of ad'renergic stimula- tion and inhibition on human airways. Physiology 34(5)a 624-fi27„ May 1973. Journal of Applied 213. COLLEY:, J. R. T., DOUGLAS, J. W. B., REID, D,. D. Respiratory diseas:ein young.adults:: Inf.luence.ofearly childhoodl lower respira- tory tract Illnes.s,.social class, air pol.lution,, and smoking... British Medical Journal 3(5873): 19'5-19'8,. Ju1y 28, 1973. 214. ZARKOVIC„ G. Etiology of non-specific chronic respiratory illness and cor pulmonale in Bosnia and Hercegpvina. International Journal of Epidemiology 1(2): 167-176, 1972.: 0376,Y'Ivryl 218. SNIDER, G. L., HAY'ES„ J. A., KORTHY, A. L., LEWIS, G.P.: Centrilobular emphysema experimentally induced by cadmium chloride aerosol. American Review of Respiratory Disease 108(1): 40-48, July 1973. '' 2229. OLZIIHUTAG, A., DONDOG, H.,, BADAMTSEDEN„ B.,, CHAGNAJAV, L. The prevalence of chronic bronchitis under the conditions of Mongplia. Sante Publiq,ue; Revue Internationale 15'(2')1: 20 1-207, 19'72. 126

72'-10'92.. MARTIN, R. R.,, ANTHONISEN, N. R.,, ZUTTER, M. Flow dependence of theintrapulmonarydistri'butione of inspired b.olusess of 1 3ke in smokers and non-smokers. Clinical Science4.3'.(3)I: 319-329, September 1972. MiYRTIN„ R. R., LINDSAY„ D. L., DRSPAS', M. D., MACKLEM, P. T.,. ANTHONISEN, N. R,.. Reversible small airway obstruction associated with~cigarette smoking. Chest 63(4„ Supplement): 31S, April 1973'., 72'-1284. MATHUR, K. C., MISRA, S. N. .Incidence of pulmonary diseases among wool workers. Indian Journal of Chest Diseases 14(3):, 172-178„ July 1972. 73-0485.. MERCHANT, Ji. A., LUMSDEN, J. C., KILBURN, K. H,., 0'FALLON„ W. M.,, UJDA,J. R:.., GERMINO, V. H.,: Jr., HAMILTON, industrial study of the biological effects J. of D. An. cotton diust and cigarette smoke exposure. Journal of Occupational Medicine 15(3)e 212-221, March 1973. 73-0486., MERCHIANT,: J.. A., LUMSDEN„ Ji. C., KILBURN, K.... Hi., 0'FALLON, W. M.,, 2:-00'42.. UJDA, J. R'., GRRMINO;,V. Hi., Jr.,, HAMZLTON, J. D. Dose response.studies in cotton textile workers. Journal of Occupational Medicine 15(3): 222-230, March 1973. RISPOLI„ J., A., DeSOBEL,.N.. L.,,: SPECTOR.,, C.H., TORTI., D. Di., URQUIJO, C., MASSUN, A. L. Epidemiologic surveys on air pollution., IN: Englund, H1. M.,, Beery, W: T. (Editors)~. Proceedings of The Second.Isternational C.lean Air Congress, Washington, D. C., December 6-11, 1970. New York,. Academic Press, 1971.. pp. 2'01-209'. 72-0772.. i ROBBINS„ W..T.. Bronchial epitheDium in cigarette-smoking 772-1057. college students. Journal of'the American College Health Association 20(3):2Q9'-211, February 1972. SAKAKURA.,, Y'..., PROCTOR, D... F. The effect of various conditi'onson tracheal mucociliary transport in dogs. Proceedings of . the Society forExperimental.Bio.logy an.d Medicine 1i40(;_°~): 870-879, July 1972. 7 2-0775. SCHLESINGER, Z.,. GOLDBOURT,. U., MEDALIE,, J. H., RISS, E'., NEUFELD, H.. N., ORON, D, Pulmonary functiom andrespiratory disease among, adult male Israelis. Variations by age and birthplace.. Israel Journal of Medical Sci'ences8(7): 957-964, July 1972. 132

Using simultaneous h.eliiumbolius and: nitrogen dilution techniqueson:9 subjects, Linnn.a:nd Hackney (BP170), showed that„ with the He method., none of 4 nonsmokers had mean CV/'VC'percent greater than 15.9, whereas both the current cigarette smokers and the.oneex-smoker had CW/VC% greater than 21.3'. The one pipe smoker had a ratio of 18.9. With the nitrogen dilution technique„ the same pattern of abnormalities of' th.e.CV/VG ratioin.this groupp off subjects wass demonstrated. The highest CV/VC`/, among t}ie.nonsmo.kers was 17.4, and the.lowest:amongthe current, ex-, and pipe smokers was 18.0. Reintjes, et al.. (BP 18'): studied the acute effects of smoking, one cigarette on large airway resistance in a group of 30' young healthy male volunteers (15 smokers'and 15'non and ex-smokers)I, and found that immediately after the smoking of one nonfilter cigarette there was a significant increase in mean airway resistance for both smokers and.nonsmokers (P <.001). The FEV% did not vary after the smoking, of the cigarette in either group of'volun'teers. Da Silva and Hamosh (BP 110) reported on pulmonary function tests performed on 21 volunteers before and after smoking one nonfilter cigarette„ and found that total airway resistance (Raw) was significantly increased (p'<.001) and M50, was significantl'y d'ecreased after smoking, (P <.001)..Other measurements,,including,those used to assess smalil airways function, showed no~sdgnificant ehangesfrom the.con.troh to the post-smoking states. Stone, et al. (BP'210) conducYe&experiments on 19 volunteers.,4 of whom.had.chron:i.c bronchitis. There were:11 cigarette smokersand 8'.nonsmokers. These.authors.foundthat thee infusion of isoproterenoli increas:ed.speci'fic airwayco..nductance(SGaw) equally in smokers.,, nonsmokers,. and~patients.wiith chronic bronchitis. Likewise.,., infusion.ofpropranololn decreased' SGaw equally in.all.these groups of subjects. Alpha-adrenergic stimulation and blockadehad'no.effeck on SGaw in anyof theexperimenta~l groups. Inan.experimental study evaluating pulmonary clearance in 79 elderlysubjects., Thomson.andl Pavia (BP 5fi),, utiliz.ing,Tc99m- labelled pol'ysterene par.ticles.of 5pm.,.found no statistically significant difference in pulmonary (mucociliary) clearance of.these particlesbetween smokers and.nonsmokers with:and without evidence of obstructive and res:trictive.pullmonary disease. The volume of inha.lediparticleswas controlled in this group of e_speriments. There was. a slight diminution in mucociliary clearance of the healthy smokers compared to thenonsmokers. The group of subjects with impaired.pulmonary function had':higher clearance rates than the normals, probably owing: to the greater deposition of particles nearer the mouth. Among the subjects with subnormal 113

, 73r-0157. CARILLI, A.D., KOTZEN, L. Mi.,,FISCHER, M. J. The.ches.t roentgenogram in smoking females. American Review of Respiratory Diseas:e 107(1): 133-136, January 1973. DAVIDSON„ F., F'., GLAZIER, JI. B'., MURRAY, J. F. The components of thealveolar.-arterial oxygen tension difference in normaLl subjects and in patients with.pneumonia and obstructive lungg disease. American Journal of Medicine 52: 754-762, 1972. 73-0583. ESBER, H. J., MENNSNGER„ F. F., Jz.,, BOGDEN, A. E., MASON, M. M. Immunological deficiency associated with cigarette smoke inhalation by mice. Primary and secondary hemagglutinin respons:e.: Archives: of. Environmental Health 27('2): 99!-104, . August 1973. 73-0128. EVANS', M. J'., CABRAL, L. J.„ STEPHENS, R. J., FREEMAN, G. Cell division of alveolar macrophages in rat,lung following - exposure to N02,.American.Jburnal of Pathology 70,(2): 199-208, February 1973. I 73-0129. EVANS, M.J., CABRAL, L. J., STEPHENS, R. J..,, FREEMAN~, C.. Renewal of alveolar epithelium in the.rat fo3lowingexposure to: N02. American Journal of Pathology 70(2): 175-198,. February 1973. 73-0474. HIRST, R., N,,Jr.,, PERRY, H. M.„ Jr. , CRUZ, t4. G.,, PIERCE, J. A. Elevated.cad'mium.concentration in emphysematouss lungs. Amer- ican Review of Respiratory Disease 108(1): 30-39., July 1973. 72-0614., HO, S,l~.,.BENTON„ M.., FUjtST, A. The clearance ofbenzo:(a.)pyreneand ferric oxide from mouse lungs.. Ptoce:edings of the Western Pharmacology Society 15: 58-60, 1972. 73-0810. HOLT', P., G,., KEAST, DLAcute effects ofcigarette.smoke.on murine macrophages. Archives of Environmental Health 26(6): 300-304, June 1973. 73-0254. HOLT, P'. G., KEAST, D. Cigarette smoke inhalation: Effects on cells.of the.immuneseries in the murine lung, Life Sciences 12(8, Part 2): 377-383', April 22, 1973.. 73-0411. HOLT', P'. G., KEAST, 11. The effect of tobacco smoke on pro- tein synthesis in macrophages. Proceedings of the Society for Experimental Biology and Medicine 142(4): 1243-1247„ 1973. TiCHIOKA,,, M. Model experimenxs on absorbability of the airway mucous membrane of S0l andl N62 gases. Biulletin of' the: Tokyo:Medi'ca1 and Dental University 19: 36I1-3!75, 1972'. 1!34

73-0643. FRAPPIER-DAVIGNON, L., ST.-PIERRE, J. E'tudp de 1"effet combine dee la. pollution atmospherique, de 1'exposition professionnelle et des habitudes de tabac dans lesaffectionsa pulmonairesobstructilves. 2. Firme d'alimentation: expositi'on profes- sionnellenulle. (A studgof the combined effectsofs atmospheric pollution in occupational exposure and smoking habdtss on obstructive pulmonary diseases... II. The.food industryr. No.occupational.exposure). L'Un.ion.Me`dicale du Canada~102(7),: 1542-1546„ July 1973. 73-0299., GpTTLIEB',,L. S.,, BALCHUM, 0. J. Course of chronic obstructive pulmonary diisease following first onset of respiratory failure. Chest 63(1): 5-8, January' 1973. 73-080!7., GREGG, L., NiIIv'N, A. J~. Peak expiratory flow in normal subj'ects. British.Medical Journal 3(587'4): 282-284, August 4,,,1923.72-1260. HEtENSZEL, W..,, HOUCEN„ A. Prevalence of respiratory symptoms in Norway. Journal of Chroniic Diseases: 25(9): 519'-544,, September 1972., 72'-1089.HUTTEM'ANN, U., OSWALD',.P., LODE, H'., HUCKAUF, H.. Ner den Einfluss langjalirigen 2lgarettenrauchens auf die Lungenfunktionn jugendlicher Normalpersonen. (Lung,function studies in young apparently healthy cigarette smokers versus nonrsmokersJ Respiration 29(3')'+: 270-287, 1972'. 73-0054.. HUTTEMANN, U., SCHUEREN, &. P. Chronisch. obstruktive Lunigenerkrankungen> Klinische Erscheinungsformen un.d ihre Korrelation aurgesLorten Atmungsfunktion. (Chronic obstructive lung,dis.ease`.ClinicaL.symptomsand their correlation to lung function disorders'..) Klinis.che Wochen- schrift 50(20'.): 944-952, October 15, 1972'. 73-0475. IM'BUS, H.R. , SUH„ M.W. Byssinosis., A study of 10,133, textile workers. Archives of Environmental Health 26(4)e 183-191„ April 1973. 73-0413. IRAVANI„ J. Effects of cigarette smoke on the ciliated respira, tory epithelium of rats:. Respiration 29(5/6):: 480-487, 1972. 72-0760'.. JAIN„ B. L.,.ABRAH7IM, E.,, KOKAN, A. R. A study of ventilatory Lung,functions in smokers from a tropical.area. Journal of Tropical Medicine and Hygiene 75'(6): 103-108, June 1972. 130

73-0301. JEDRYCH'oWSKI,. W. Badania Epidemiologiczne Wplywu Warunkow. Srodowiska Pracy na Wystepowanie Przew.le'klych Nieswoiistych ChorobUkladu Oddecliowego. (Epidemiological studies.s coacerning theilnfluence.of working conditi!onson the incidence of chronic nonspecific respiratory diseases.) Przeglad Lekarski 29(8): 737-743,, 19'72. 73-0478., 73-0303. 73-0166., KIBELSTIS,,J. A. Diffusing capacity in.bituminous coal miners. Chest 63!(4).: 501-504 „ April. 1973. KOSTBEWSKI, J. Chronic non-specific lung disease in.Krakow. Sante Publique; Revue Internationale 15(2): 209-216, 1972. KOZAREVIC,. D., ROBERTS, A., PIRC, B. Prevalence of chronic obstructive lun.g.diseases among,rural and..urban.popula- tiions.in two.different.areaso ofYugpslavia.INs. Brzezinki,. A.,Kopczynski, J'., Sawicki, F. (Editors.)'. Ecology of Chronic Nonspecific Respiratory Diseases, International. Symposium,September. 7-8, 1971, .Wars:aw„ Poland. Panstowowy Zaklad Wydawnictw Lekarskich,,Warsaw, 1972. pp. 178-184 73-0168., KUBIK, A., FEUEREISL, R., GALLAS, J., KAVAN., F., FELKEL, H., REIL, I. Air pollution and prevalence of'chronic non- specific respiratory disease in males.aged 16 and 18 years residing in Prague 7. INi:, Brzezinski„ Z.:, Kopczynski,J',, Sawicki, F. (EditorsJ Ecology of Chronic Nonspecifi'c Res- piratory diseases„ International Symposium, September 7-8, 1971, Warsaw, Poland. Panstwowy Zaklad WydawnictwLekarskich, Warsaw, 1972. pp.. 50-54. 73-0041. KUBO, R., ONO, M. Kitsue:7 no Koto Poripu ni Oyobosu Eikyo ni Tsuite.. (Influence of smoking on the development of laryngeal pol'yps.,) Jibi to Rinsho, 17(2):: 122-125, 1971. 73-0482. KUPERMAN'„ A. S., RIKER, J. B. The variable effect of smoking on pul:monary' functiou.. Chest 63(5).: fi5.5-660, May 1973'. 73-00'58., LUZ, T. P.,. BUSTAMANTE, H. T. de, SZKLO, M.,, STiROZENBERG„ A... "Complexoo deSintomas Res.pira,torios." e "R:inite Vasomotora"'. Prevalencia em Operarios da Fabril Juta:de Parintins, Amazonas;, (Junho.de.1971). ("Respiratory symptoms complex" and "bas.omotor rhindtis:." Prevalence among the jute manufacturing plant workers in Parintins, Amazonas; [June 1971].). Revista. Brasiliera de Medicina 29(4): 184-187, April 1972. 73-0038. McCALLLIS,. R. I. Respiratory disease in foundrymen. British. ~ J!ournal of Industrial Medi.cine 29(3) : 341-343, July 1972. , ~ ? ,~. n ~ 131

72'-09:79. CUNNINGHAM, D'. A:., MONTOYE, H. .I., HIGGINS, M. W., KELLER„ J.: B.Smokinghabits.,,chronic bronchitiss and shortness of breath.and physical fitness. Medicineand Science.in Sports 4(3): 138-145„ 1972. 73-0465. DELOFP„ L.,,PUDELSKI, J., OKLEK, K.,, ROZANOWICZ, A., SEDLACZEK:, A. Obraz Epidbmiologiczny Ptzewleklych Ndeswoistych Chorob P'luc u Mezczyzn Miasta Zabrza. Wplyw Palenia Papierosow i Pracy Zawodowej. (Epidemiological picture of chronic non-specific pulmonary diseases in men,, at Zabrze. The effect of smoking and' of professional work.) Gruzlica. i' Choroby Pluc 40(10): 889-896, October 19:72. 72-03601., ELLEFSEN, P.,„ TOS,. Mi., Goblet cells in the human trachea.. Quantitative studies of a pathological biopsy material. Archives of'otolaryngology 95(fi).: 547=555, June 1972. 73!-0]i60.FELKEL, H., KUBIK, A., FEUEREISL,, R.,„ GALLAS, I., REIL, I. Chronic bronchitis im manual.workers employed in the open ' ailrand in afacto:ry hall. IN: Brzezinski, Z. „ Kopczynski,, J., Sawicki„ F..(Editors)'..: Ecology ofCfironic Nonspecific Res.pi'ratoryDiseases;, International Symposium, September 7-8, Warsaw, P'oland., Warsaw, Panstwowy Zaklad! Wydawnictw Lekarskich, 1972.. pp. 114-116., 73-003.7.FERRIS, B. G., Jr., HIGGLNS.,, B. T. T., HIGGINS:,: M. W., PETERS„ J. M.Chron3c nonspecific respiratory disease in Berlin.,.. New Hampshire, 1961 to 1967. .. A folllow-up,study. American Review of Respiratory Disease 107(1)': 110-122, January 1973. FERRIS, B. G., Jr., RLINAIDIVE'., M.. V. ,. PETERS'..,, J. M., MURPHY, R.. L. H., BURGESS., W. A.,. PENDERGRASS„ H. P.PrevaIence of chronic respiratory disease. Asb'.estosisin ship repadrworkers. Archives of Environmental Health 23(3).: 220-225, September 1973'. 72-1108. FEUEREISL, R. , KRZHIVANEK, I.,,REIL„ I.,, KUBIIK, A,., FELKEL,. K.Deis:tvie Kureniya na Serd.echno-Lego.chnuyu: Funkktsiyu. (Effect . of.smoking, on..card'i'opulmonaryfunction.) Kliinicheskaya Meditsina 50(7):, 82-84,, 1972. 73-0296. FOX.,.A. J.,,TOMBLESON, J. B. L.,WATT, A.,, WILKIE, A. G. A survey of respiratory disease in cotton operatives. Part I. Symptoms and ventilation test results. British.Journal of Industrial Medicine 30(1)':42-4.7, January 1973. 129