Tobacco Documents Online

CHAPTER 3: NON-NEOPLASTIC BRONCHOPW'LM0I3ARY D'ISEASES'

\.

Contents Page Introduction.. . . . . . . .. . . . . . . .1 . . .1 . . . . . . .65. Smoking and Respiratory Morbidity! . . . . . . . . . . . . . . 66 Smoking, and Air Pollution. . . . . .1 . . . . . . ., . . . . . • 66. Smoking,and'0'ccupational Disease., . . . . . . . . . . . . . .71 Mill Workers - Byssinosis.. . . . . . . . « . . . . . .71 Firemen. . . . . . . . . . .. . . . . . i . . . . . . . . . 7'1 Smoking, and!Pulmonary Function,Tests. . . . . . . . . . . . .71. .? 1-Antitrypsin. . . . . . . .i . . . . . . . . . . . . . . 74 Autopsy and Pathophysiologic Studies . . . . . . . . . . . . .7'6 Autopsy Studies. . . .i . . « . .. . . . . . . . . . . . .76 Pathophysiologic Studies: ih:Humans. . . . . .i . . . . . 80 Pathophysiologic Studies in Animals .. . . . . . . . . .80, Summary of Recent Bronchopulmonary FindingS. . . . . . . . . 83 Bibliogzaphy . . . . . . . . . . . . . .i . . . . . . . ., . . . 84

List of Figures Fi'gure. 1.--Respi'ratory bronchioli'tis in smok,ers and control g'roups. . . . . . . . . . .1 ., . . . . . . . List of Tables Tab~~Ie~ 1.~--Leve~l's~ of sulfur~ dioxi'~de~ (~S~~02)~~ and total suspended particulates (TS~P)~ in four Utah~ communities, 1971, and in five Rocky Mountain communities, 19'70. . . . . . . . . . . . . .I . . . . . Table 2'.--Mean annuall levels of sulfur dioxide (802,) and' totah suspended particulates (TBP):in four areas. . . . . . . . . . . . . . . . . . . . . . . . Table 3'.--Age-adjusted~percentage~of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to.chemi'cals, fumes, sprays, and' dusts. . . . . . . ., . . . .. .. . . ., . . . . . . Tabile 4. -The T '1.-anti'trypsin levels.and'frequency of pr~otea~s~e~~ inhibitor~ (Pi)~ phenotypes in~ h~ealthy, populations. . ., . . . . ... . . . . . . . . . . . . Table 5--Means of the numerical values.g,iven lung sections at autopsy of male current smokers and non- smokers, standardized for age.. . . . . . . . . . . . . Table 61.--Means of the: numerical values gi'ven, lung sections at autopsy of female current smokers and nonsmokers,, standardized' for age . . . . . . . . . . . . . . . . . Table 7.--Nieans of the numerical values given lung, sections at autopsy of male former cigarette smokers, standardiaed1for age . . . . . . . . . . . . . Page' . 81 . 681 . . 69' . 72 . .75 . 7'7 78' . 79 64

C INTRQDUCT ION' Chronic non-neoplastic lung diseases are major causes of permanent and temporary disability in the United States. Chronic obstructive pulmonary disease (COPD) is the largest subgroup of these diseases and in this report refers to chronic bronchitis and/'or emphysema. Relationships between smoking, and non-neoplastic lung diseases have been reviewed in previous reports on the health consequences of smoking (HCS 1, 2, 3, A, 5, 6,, Z, 8). Cigarette smoking, is the most important cause of COPD. Cigarette smokers have higher death rates from chronic bronchitis and emphysema, more frequentlyreport symptoms of pulmonary disease, and have poorer performance on pulmonary functionitests thanido nonsmokers. These differences become even more marked as the number of cigarettes smoked increases. The relationship between cigarette smoking and COPD has been demonstrated in many different national and ethnic groups, and is more stri.king,in men than in women. Pipe and cigar smokers have higher morbidity and mortality rates from COPDD than do nonsmokers but are at lower risk than cigarette smokers. Cessation of cigarette smoking results~in improvedipu'lmonary function tests, decreased pulmonary symptoms, and'reduced COPD mortali'ty rates., In additionto an increased risk of CC1PD~„ cigarette smokers are more frequently subject to and require longer convalescence from other respiratory infections than nonsmokers. Also,, if they require surgery, they are:more likely to develop postoperative respiratory complications. The relative importance of air pollution in the development of COPD remains controversial,, but is clearly less significant under most circumstances than cigarette smoking. The combination of cigarette smoking and polluted air, however,,may prod'uce higher rates of COPD' than either factor alone. Several occupational exposure groxips incur an increased risk of COPD, and cigarette smoking adds~significantly to this risk. In particu2ar, exposure to cotton fiber and coal dust appears to act in concert with. cigarette smoking to promote the development of pulmonary disease. Autopsy studies have demonstrated a dose-related effect of cigarette smokinQon the severity. of macroscopic emphysemal.Increased goblet cell density, alveolar septal rupture, thickened bronchial epithelium,, and mucous gland hypertrophy are more commonly!found in the lungs of smokers than in those of nonsmokers. Many pathophys3'.ologilc mech~anismsbywhichismoking, may cause COPD,hav!e been proposed'.. Decreased overall pulmonary clearance, reduced'1ciliary motion,, and impaired alveolar macrophage functions have all been related'to cigaret~tesmoking and probably play a role in the development of COPD. The exact mechanisms whereby cigarette smoking contributes to the development o£ COPD, O howevzr,. remain only parti'a1Tyunderstood-. ~. ~ O Ilk 65

SMOKING AND RESPIRATORY MORBIDITY An increased prevalence of respiratory symptoms in smokers from early teens to those past the age of 801has been well established. Bewleyr„ et al. (BP' 33), in a study in Derbyshire County, EngTand, extended these findings to include younger children. In alquestionnaire study of 7,115' school- children ages 10 to 11-1/2 years,, he foundd that 6.9 percent of the boys and 2.61percent of the girls smoked more than one cigarette per day. The boys who smoked reported more morning, cough (21.5% to 6,.,1%) „ cough during, the ) day or night (48.0% to 20%), and cough of 3-months duration (18'.0Z to 4.1%) than their nonsmoki!ng,schoolmates. The percentages for the girls were similar although based on smaller numbers of smokers., As in manystud'ies of'this type, it was impossible to control for air pollution, social class, or smoking,habits of the parents; nevertheless, the results suggest that cigarette smoking,even in this young age group produces respiratory symptoms. Fridy, et al. (BP 171), in alsomewhat older population (average age 25 years), examined' the effect of'smoking on airway function during,mild' viral illness. They measured' closing volumes for 22 subjects (9' cigarette smokers - average age 29.1, and 13 nonsmokers - average age 251.7) before onset andlat weekly intervals from the beginning,of a mild respiratory illness until all symptoms had subsided. The closing vollumes for smokers prior to illness were higher than those for nonsmokers, but the difference was not statistically significant. In the tests done during, the illness, the smokers had a statistically significant increase in the closing volumes (from 37.0 to! 45.8 percent of their total lung capacity, while nonsmokers hadino change 32.7 and 31.7 percent). Smokers remained symptomatic more thanitwice as long as nonsmokers (35.7'and 16.5' days, respectively), and the mean d'urationn d of pulmonary function abnormalities in smokers was 29.7 days. Nonsmokers had no change in pulmonary function tests during,ilTness.. SMOKING AND' AIR P'OLLUTION The relationships among air'po1!lution, smoking, and'COPD remain .controversial. Reasons for this controversy include difficulties in controlling such variables as socioeconomi'c class, degree of crowding, ethnic differences,, and age distribution as well as determining the exact type and amount~of individual pollution exposure. Measuri'ngind'ivi'.d'ual pollution exposure even withina small area is d'ifficult since both amount and type camvary dramatically from street to street (e.g., proximity of a street to a heavily traveled expressway). In an effort to control as many of these variables as possible, two basicap~proachesin~ studyd'esign have been,tried., Thefi'rst approach is to find areas where pollution levels have been well measured and then to select study populations that are as similar as possible in areas with different pollution levels. Thus, effects on a population in a.low pollution area can be compared to those on a similar population in a high pollution area. The secon&approach is to select a population that is as uniform as possible, for example, twins„ and then measure individual responses to different pollution exposure. Both approaches have drawbacks as will be evident from the following studies. 66

C Using, the first approach, the Community Eealth and' Environmental Surveillance System of the Environmental Protection~Agency (BP 29, BP' 14)) has conducted surveys in areas with different types and levels oTpMution in four different parts of the United States (Chicago,, New York City, the Salt Lake Basin, and1the Rocky Mountain area). Within each part of' the country, the researchers i'dentified commun3!ties of similar socioeconomic status but different pollution levels. They then administeredia questionnaire through the school systems to determine the frequency of lower respiratory tract infecti'onlin thechildren and their famil'ies:.Theyreported an increased incidence of lower respiratory tract illness in childrenlin high pollution communities compared to children in low pollution communities. This d'iffereince was demonstrable only in chil'dren1whosefamilies hadi lived in~ the high pollution communities for more than 3 years. They also reported an i'ncreased'prevalence of chronic bronchitis in parents who lived in highipollution communi!tiess compared tolparents from low pollution communities. They calculatedithe excess risk of chronicbr~onchitis prod'ucedbyairpo9!lution, to be one-thirdlof that produced by smoking but to be additive with smoking. Several major problems in these surveys make it difficult to evaluate the results. The authors describe the areas as having different kinds of polluti'on. The Salt Lake Basin and Rocky Mountain areas were felt to be high in sulfur dioxide (S©2) and'low in total suspended particles (TiSP), while New York and Chicago were high in both these pollutants. As a result,, in the Salt LakeB~asiniand Rocky Mountain areas, communiti'.eswere separated iinto lowand high pollution communities only on the basis of their SO2 levels.M'any communities classified as low pollution communities on the basis of their S02 levels had higher levels of total suspended particles than the communities classifiedias hi.gh pollution communities by SO level (Table 1). In fact, the average total suspended particles level for tie low pollution communities in the Salt Lake Basin was higher than that for the hligh pollution communities (Table 2) in the Salt Lake Basin. These differences exemplify the difficulties of using,only one pollutant as a marker of, total pollution exposure. Additional problems with these studies were the differences in socioeconomic class measurements between low and!high pollution communities in some of'the regions. In the Rocky Mountain area, the percentage of fathers who completed high school varied from 91 percent in one of the low communities to 58 percent in one of the high~pollution communities. There were also major differences between high and low pollution communities in the percentage of families with more than one person per.room in the Salt Lake Basin(59'.6% to,51.2Y)'~ , Rocky: Mountain area(',87'.,0% ' to68.0%') , and. New York (85.0%' to 72.0%). Residential stability (percentage of' families li'ving, in the community for more than 3 years) was different in the high and low pollution communities in New York (58.0T' to 36.Q%)', and Chicago (56.(1y' to. 46.0%). The percentage of parents who currently smoke also differed'for high and low pollution communities, iniNewY'ork (53% to45%'forthe fathers and 47% to 37% for the mothers). These differences rai'se questions as to whether b7

TABll.E~ 1'i. -~ bevels~of sulfur~ dioxide~(S(12) , and~to~tal suspended particulates~(T'91')~ in four i'l'tah communities, 19 71', and' iir five Rocky Mountain communities, 1970, ~ Atea Community' Pollu tion Pollution levels imu8/im3 Classdfi cation S02 TSP Utah (Salt Lake Basin). Low 8' 78 Intermediate 1 15' 81 Intermediate 2' 22 45 High, 62 66 Rocky Mountain Area Low 1. 1'0' S0 Low 2 26' 6'8' Low 3 46' 110. E$igh, ll 109 43 '. High 2 186' 102 SourcerChapman. R.S,, et al. (BP2A).' 68

TABLE 2. - Mean annual' leuels of sulfur dioxide (SO2)'and total suspended pareiculates (T'SP) in four areas Pollution lev els i n µg/m~' Area SOZ2 TSP ' During Study Low High~ Decade Preceding Study Low High During Study Low High Decade Preceding$tudy. Low High Five Rocky Mountain ~Areas~ 10 275 110' 263 45 110 50 1'01l Salt Lake Basin 9 65 < 20' 144 78 66 82 62 New York. 2'3 63' <'30' 431 34104 4'0, 2'01 Chicago 57 106 109 2S0 111 1'5'1 121 1i65 N'OTE., - Area includes, highest- and lowest-pollurtedlcommurrities. , Sourca: French, I1G., et ali (EP I4) ,

the high and low poll'ution communities were really similar enough populations to justify the claim that differences in incidence of respiratory tract illness could be attributable to differences in air pollution. Increased prevalence of'COPD has also been d'emonstrated in areas off high pollution in the Netherlands (BP 119), yokkaichi,, Japan (BP 78), , and' Cracow, Poland (;BP'112). Again, however,,these studies were poorly controlled for socioeconomic status. Several recently published studies have used the second major method of investigating the relationship between smoki'ng,, air pollution, and'COPD', i.e., to select a uniform:population and then to measure individual differences to poll'ution exposure. Comstock, et al. (BP' 13), in an attemptt to control for occupational exposure and socioeconomic class,,studied threeseparate,unsform populationsoftel!ephone workers and used as a measureoft pollution the location of'the place of work and residence. The populations studied were telephone installers and repairmen in~B'altimore~,, Newl'ork City, Washington, D.C.,, and rural fTTestchester County in 1962 (survey 1')' and in 19'67' (survey 2)'„ and telephone installers and'repairmen in Tokyo in 19'67 (survey 3). They were unable to find any relation between pulmonary symptoms andidegree of urbanization of place of work or place of residence (ei:ther current or past). They were:, however, able to establish alstrong correlation between smoking habits and' pulmonary symptoms. Given the crude estimation of pollution exposure used in this study (all workers in each city were treated, as th:oughthey:received the same:exposure),, a small d:Ifference, inisymptomss due to air pollution could have been missed,, whereas the difference due to smoking could be detected both because it was larger and'because it was possible to determine individual exposure more exactl:y. Hrubec, et al. (BP' 12), in a study of twins from the U.S. Veterans Registry, were unable to show a difference in respiratory symptoms either between individuals with different exposure to air pollution or between members of twin pairs with different air pollutiomexposures. However,, they too used a.crude measure of air pollution exposure (by each aip code area), and so . could have missed a small difference due to air pollution despite being, able to relate respiratory symptoms to smoking,,, socioeconoanicstaflus,,; and alcohol intake. Colley, et al. (BP 2321), in a study of 3,899 persons (',20-year-olds born during the last week of March 1946 in the United Kingdom)', were also unablee to show a relation between COPD and air pollution. They used as their esti'mates of air pollution exposure the domestic'coal consumption inithe towns where the subjects lived. This method' of estimating air pollution exposure is subject to the same limitation cited'for the previous two studies-limited sensitivitytoismall risks d'ueto,air pollu~tion. W

In summary, if an increased risk of CnPD' due to air pollution exists, it is small compared'to that due to cigarette smoking under conditions of air pollution to which the average person is exposed'. The possibility remains that the two different kind'sofexposure may in~teract toincrease, the total effect beyond that contributed by each exposure. SMOKING AND OCCUPATIONAL DISEASE' Fri'edtnan„ et al. (BP 31)i,, in a study of 70,289 men and women who had. had Kaiser-Permanente multiphasi'c health checkups,,noted that smokers were more likely to report occupational exposure on alquestionnaire (Table 3) than nonsmokers. The differences are small but statistically significant and need to be considered'when investigating the relationship'of smoking to occupational diseases. They were not able to determine whether smokers' responses reflect•actual differences in exposure or an increased awareness of andisensitivity to occupational exposure. Severa7l recent studies have confirmed' previous findings that exposure to coal and' granite dust and cotton fiber carries an increased' risk of COPD. This risk is further increased by cigarette smoking. Other new data have been published which clarifyy the risk in certain occupational groups. Mill Workers - Byssinosis Berry, et al. (BP 41),, in a study of 595' workers in the Lancashire cotton mills over a 3'-year period, found that the decline in foxced~ expiratory volume in one second' (FEV'1) was 19 ml/'year greater in smokers thamin nonsmokers(59m1/year compared! to4'0ml/year) ,, but they could not demonstrate a dose-response relationship. Firemen Sidbr and P'eters (,BP' 94, BP 9'5)1, in al cross-sectiional study of 1,,768 Boston firemen, were unable to show a significant relationship between severity of fire exposure and impairment of pulmonary function tests or prevalence of COPD; there was a clear harmful effect of' cigarette smoking, on both. They postulate that they were unable to show an increased prevalence of COPD in this cross-sectional study because firemen who develope&COPD were. no longer capable of ineeting the physical demands of the job and had retired,. thus removi'ng,them from the study population. They were able, however, to show a higher incidence of COPD'i'n men under the age of 35 years who had been on the force more than 6 months when compared to persons of the same age who had just beenihired. SMOKING AND' PULXONARY FUNCTION TESTS It is recognized that smokers as a group have poorer pulmonary functi!on tests than nonsmokers. The standard pulmonary function tests generally on"Ly ~ . W ~ . ~ 7 1 N ~ O~

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

become abnormal late in the patholog~c process of COPD and usually only after irreversible ch~anges~ inth~e lungs have occurred.: As aresult„ tests areneed'ed that will id'entifypersonsat risk of d!eveloping,CaPDbeforethey have irreversible loss of lung function. Standard tests of pulmonary resistancee are inadequate for this purpose because they measure predominately resistance in the large airways while the first changes of'COPD occur in bronchioles that are 2'mm and smaller. Small airway resistence may be measured through evaluating f requency dependent compliance „ but this is of ten cumbersome to perform. Closing volume and maximum expiratory flow rates at 25 and 50' percent of Vital capacity have the advantage of being relatively easy to perform, yet are still able to measure changes in the small airways. Closing volume is the lung,volume at which~ the alveoli in the dependent portions of the lung begin to close, and it is usually expressed' as a percent of vital capacity. Bl:evated closing volume is cons3:deredlevid~ence of small airway disfunction.. Maximum expiratory flow rates at 25 and 50 percent of vital capacity measure air flow at low lung volumes where the resistance of the small airways makes up a much larger proportion of the measured resistanc . Several recently published studies contain data on small airway disfunction in smokers. Lim (BP 19) studied 50 smoking and 50 nonsmoking;high school students and found in smokersa stati'sticallysigp~ificant reductionin the forced exp3ratory volume in one second when the test was started at normal end expiration low lung volumes). . S'tanescu„ et al.(BP 58)' noted elevated closing,volumes in 16 healthy asymptomatic smokers whenicomparedito 16 nonsmokers,; but was unable to show any difference in maximum expiratory flow ratesat 25 and 5:0 percent vital capacity. Ruff, et a1.(BP~ 73) stud'ied~ 50 subjects ages 18 to 82' and showe&increasing, closing volumes wi'th age and smoking. Martin, et al. (BP 285), in a study of 50 subjects ages 12 to 68, found.that 25 percent of'the smokers had abnormal closing volumes, and Oxhoj, et al. (BP 307) noted el'evated' closing volumes for 50'-year-old' smokers compared to nonsmokers. Dirksen,, et al. ('BP'306)' reported higher closing volumes in smokers and notedino change with cessation of smoking. Hoeppner, et al. (B'P 244) also showedi elevated closing volumes in healthy smokers ages 16 to 61, but found these to be closely related to diecreases in the static transpulmonary pressure. They postulate that the elevated closing volumes may be xelated to decreased elastic recoil rather than changes in small airway resistance. The data have established'the fact that a greater percentage of smokers than nonsmokers have elevated closing,volumes, but the number of smokers with elevated closing,volumes who will develop COPD remains to be determined. Stebbings (BP49)',, i'n a further analysis of Densen's data (BP 86) on the ch:anges,in pulmonary function test values in malepostal'workErs,and:tr:ansit workers in New York City, noted significantly less decline in FEV1 among,Black smokers when compared to White smokers. This difference persisted even when corrections were made for differences in amount smoked, 73'

age at which smoking began, inhalation,patterns, and smaller initial lung volumes in Blacks. Black and White nonsmokers did'not differ in the rate of decline in FEV . By age 60 years, Blacks who smoked one pack per day hadia- .34 liter smaTler cumulative decrease in FEU'1 than Whites who smoked the same amount. Cf 1-ArPTTTRYPSIN It would' be useful tolid'entifythepopulationsatexcessive~ risk of developing COPDI £rom smoking,. They then might be made aware of the hazard before they develop symptomatic lung,disease. Persons with Of'1-antitrypsin deficiency may be such a population. Of -antitrypsin deficiency is a rare homozygous recessive genetic defect wAich occurs in approximately one out of every 3,600 people and results in an increased susceptibility to and premature development of' COPD. There is some evidence that smoking hastens the development of COPD,in these people. The heterozygous state (producing intermediate levels of the q''1-antitrypsfin in serum) is far more common than the homozygous state and is found in approximately ]i0' percent of the popul!ation. It is uncertain whether the heterozygous defi'ciency state predisposes to COPD. C/11-antitrypsin inheritance patterns suggest multiple codominant alleles at one gene locus, some of which (most notablY the S and Z'alleles)'Z produce lower serum protease levels than the normal M-allele (Table 4). The pathophysi~ologicmechanism,of the deficiency stateisfelt to~be theinabilityto inhibit tlie~ proteasEs found in thegranulocytes,and pulmonarymacrophages which go on to damag;e essential constituents of lung tissue. Several recent reviews of the enzyme and the clinical syndrome produced'by its deficiency have been published ($P 318'r BP 227, BP 16'5). In most studies of patients with COP'D,, investigators have found' an increased prevalence of the partially deficient heterozygote phenotypes when compared' to healthy control populations. In the few studies not finding this relationship,, only (yl-antitrypsin levels were measuredi. Because 1 antitrypsin is an acute phase protein and increases withlinfection, it i'~difficuTt to separate out the partially deficient heterozygote phenotypesy by measuring only ,A'1-antitrypsin levels. It is necessary to identify the products of eac~ allele electrophoretically iin order to identify the deficient phenotypes. Two recent studies using this technique showed anli'ncrea ediprevalence of deficient phenotypes in patients with COPD but not among control populations. Mittman, et al. (BP 93) studied 240 patients'with COPD' admitted to LaVina Hospital in Altadena, California, and'found that 19.1 percent had deficient phenotypes compared to only 7.1 percent of alcontrol 74

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

Scandanavian po~pulation~., Keuppers and Donhardt('BP 170) found, prevalencerates fQr deficient phenotypes of 3'.5 percent in healthy controls,, 12'.9 percenr in persons retired from work because of COPD,,, and 15.7'percent in patients hospitalized for COPD. Additional population studies have been done to determine the effect oftheheterozygpusstate on theAesvelopmentof COPD'., Webb,, et a1., (BP18)i studied,5100 persons visfi.ti'ng, a multiphasic screening clinic in Monroe County, New York, and'found that 11.6 percent had deficient phenotypes. He was unable to show differences in symptoms or in pulmonary function test values between persons withinormal and deficient phenotypes. In a study of 45]1 randomly selected adults from the same county (BP 128), pulmonary function studies were done on 40 deficient heterozygote phenotypes (20MS':and 2GNIZ), andi on normal phenotype (WE),i control,smatched for age, sex, and smoking habits. When total pulmonary resistance was measured!by a forcedloscillometric technique, the nonsmoking MZ subjects had significant impairment compared to thei'r normal phenotype controls. All cigarette smokers, regardless of phenotype, had abnormal values. Although the data are still inconclusive, it may well be that heterozygousd'eficient persons are agr~oup~at excessive risk of developing COPD especially if they smoke. AUTOPSY AND PATHOPHYSIOLOGIC STUDIES A'utopsy Studies. Auerbach, et al. (Ref. 1): have previously shown dose-related macro- scopic emphysematous changes in the lungs of smokers. Now in an autopsy study (BP' 105)',of1„582' men and,38~8~ women,, theyhave~ examined'microscopiclung,parenchymal changes in relation to cigarette smoking. They were able toishow that rupture of alveolar septa (emphysema), and fibrosis and'' thickening of the small arteries and arterioles are far greater in smokers thamno:nsmokers,ande increase wfith, increasing amount smoked (Tables5and~ 6). When these researchers examined'former cigarette smokers, they found' that those who hadistopped more than ]i0'years prior to death had fewer pathologic changes than those who had stopped less than 10 years before: death. But even in those who had stopped for more than,10 years, there was a greater degree of pathologic change in those wholhad been smoking more than one pack per day than in those who had been smoking less than one pack per day (Table 7). Niewoehner, et al. (BP' 322), in anlautopsy study of 39 men who died, suddenly from various causes and who were below 40 years of age (201non- smokers and 19 smokers), observed a respiratory bronchiolitis associated 76

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

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

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

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

• .P C IFtGURE' 1i. (R'esptratory broncWi'otitia iin, srnokett and control group 5, 0 •. - NONSM'OKERS' r (N•.r..M. .aMi.1. 1 i i SMOKERS NOTE.-The position of, each symbol represents the number of sections per case in which ibronchiolitis was identified. Source: Nievwoehner„ D.E., et al. (8P 322). 81

l. Tracheal mucous velocityr has been shown to be decreased in purebred beagle dog,s~ (BP' 56)~ exposed to 100 ciga~reztes, per week forT3 , 5 ffionths,. In donkeys (BP 297) low level exposure to whole cigarette smoke accelerated' tracheobronchial clearance, whereas at intermediate and'high levelis of exposure, clearance was decreased'. At high exposure levels whole cigarette szaokehad' twicetheeffe~ct of' filtered smoke in,decreas,ingcl'earance., 8'2

1 SU,%MRY OF RECENT' BRONCHOFIJ~~LMON;ARY F'IND'INGS' l. Cigarette smokers with mild viral respiratory illnesses have been shown to develop abnormal but reversible changes in certain pulmonary function tests while nonsmokers show no changes in these tests. Cigarette smokers have also been shown to have a significantly longer duration of respiratory symptoms following mild viral illness than nonsmokers.. 2'. Cigarette smoking is more cl'osely related to COPD' than is air pollution under the conditions of air pollution encountered by the average person. The possibility remains that the two kinds of exposure may interact. to increase the total effect beyond that contributed by each exposure. 3. Cigarette smokers without respiratory symptoms have evidence of' small airway disfunction (',elevated closing,vol!umes) more frequently than do nonsmokers without respiratory symptoms. 4. Autopsy studies have shown a dose-response relationship between cigarette smoking and the microscopic changes of COPD.. Data from one study indicate that bronchiolitis may be a far more common finding in cigarette smokers than in nonsmokers. 5'. Pulmonary macrophages from cigarette smokers' Iungs have a decreased ability to respond to in vitro antigenic stimuli. 83'.

BIBLIOGRAPI'IY (BP' 297) ALBERT, R., E. , BERGER, J. , SAfiIBORIV', k. , LIPPHANN'„ Iyf. Effectsf of cigarette smoke components.on bronchial clearance in thee donkey. Archives of Environmental Health 29(2): 96-101, August 19'71. (',BP 105) AUERBACIi,, 0~.,, GARFINKEL, L., HAMMOND, E. C. Relati'on~ of smoking,and age to findings' in lung parenchXma: a micro- scopi'c study., Chest 65(,1): 29-35, Janua~ry~ 1974.~ (Ref . 1) AUERBACIi',, 0. , HAMtSOND„ E. C., GARFINKEL, L., BENANTE, C. Relation of smoking and aoe to emphysema: whole-lung section study. The New England Journal of Medicine 286 (16): 853-857, April 201, 19Z2'. (BP' 41) BERRY,, G. , McKERROW, C. B':. , MOLYNEUX, M. K. B., ROSSITER, C. E. , TO.riBLESW, J. B. L. A studylof' the acute and chronic changes in ventilatory capacity of workers in Lancashire cotton mills. British ,Tournal of Industrial Medicine 30!: 2'5-36 ,, January 19 73' . ($P' 33')BET,dLEY',, B~.~ R., HALIL,, T.,,, SNA~~ITH~, A. 11111. Smoking~ by p~~rima~,ry~ sch~oolch~ildren--preva~llenceandlassociated resp~~iratory: symptoms. British J'ournal of'P'r.eventive and' Social Medicine 27'(3): 150"153, August 1973. . (BP 29'), CHAPMAN,, R'., S. ,, SIIY,, C. M'. „ FINKLEA, J. F'., IiOUSE,, D. E.. , GOLDBERG, H'. E., HAYES',,C. G. Chronic respiratory disease in military inductees and'parents of school- children. Archives of Environmental! Iiealth 27'(,3): 138-142, September 19'73'.. (BP 232) COLLEY, J. R. T., DOUGLAS,, J. W. 8., REIDi„ D., D. Respiratory disease in young adults: influence of early childhood d lower respiratory tract illness, social class, air pollution,, and smoking. British Medical Journal 3(5873)1: 195-198, July 28, 1973, Eng,lish,., (BP 13)! COMSTOCK', G. W., STONE, R. W.„ SAKAI!„ Y., MATSUYA,, T., TO'NASCZA,,J'. A.Respiratoryfind'ings and'urban living. Archives of Environmental Health 27: 143-150, September 1973. (BP' 86) DENSEN,, P. M. ,, JONES,, E. W. , BASS, H. E. , BREUER,, J., REED:,, E. A survey of respiratory disease among N'ew York City postal and'transit workers. 2. Ventilatory function test results. Environmental Research 2(4): 277-296, July 1969~. 84 lW N W

(BP' 306) DIRKSEN, H. , JANZON, L.,, LINDELL, SI. E. Influence of smoking and cessation of smoking on lung function. Scandinavian Journal of Respiratory Diseases (Supp1!ementum~85): 266-274,, 19'74. (BP 14) FRENCH, J. G.,; LOWRIMORE, G., NELSON', W. C., FINICLEA, J. F., ENGLISH, T.„ HERTZ, M. The effect of sulfur dioxide andd suspended'sulfates on acute respiratory disease. Archives of Environmental Health 27: 129-133, September 197'3'. (BP' 171) FRIDY, W. W. , Jir., INGRAM, R. Hi. „ Jr.„ HIERHOLZER, J. C., COLEMAN, M. T. A~irwaysfunction duringmil&vi'ra1 respiratory! illnesses~. The effect of rhinovirus infectionlin cigarette smokers. Annals of Internal Medicine 80(2)': 150-155, February 1974.. (BP' 31) FRIEDMAN, G. D'., SIEGELAUB, A. A.,,. SELTZER, C. C. Cigarette smoking and exposure to occupational hazard's. Ameri!can Journal of Epidemiology 9'8(',3) r 175-183, September 19'73'. (B'P' 244)~ HOEPPNER, V., H., COOPER, D. IWI!.,,ZAMEL„ N., BRyAN',A.C'., LEV'IS0N',, H'. Relationship between elastic recoil and closing volume,in smokers and nornsmokers,., American Review of Respiratory Disease 109 (l) : 81-8'6',, January 1974. (13P 12')' HRUBEC, Z'. , CEDERII.OF', R., FRIBERG, L., HORTON'„ R.,, 0'Z'OLIN'S, G, Respiratory symptoms in twins. Archives of Environmental Health 27':189-195,S'eptember1973'. QP' 227) HUTCHISON,, D. C. S. Alpha-l-antitrypsin deficiency andi puhonary emphysema: the role of proteolytic enzymes and their inhibitors. BritishiJournal of'Diseases of' the Chest 67(3): 171-196, July 1971. (BP' 165) KfJEPPERS,, F'. q 1-antitrypsi'n. American Journal of Human Genetics 25 (6 ) : 677-686 ,, 1973. (BP' 318) KUEPPERS, F.,, BLACK, L. F. 4 1-antitrypsin and its deficiency. American R'eviewofRespiratory Disease 110(2): 176'-194,August 19'74. (BP 170')MJEPPERS,F.,DONHA'RDT„ A.ObstructiveIung~disease in hetero- zygotes for aliphal-antitrypsin deficiency. Annals of Internal Medicine 80(2): 209-212',, February 19'74.

C (BP 19) LIM, T. P. K. Airway obstruction among high school students. American Review of Respiratory Disease 108(4): 985-988, October 1973'. (BP' 285)i MARTIN, R. R. , LEMELIX„ 0'. , ZUTTER, M. ,, ANTHONISEN, N. R. Measurementof"closing, volume/R1:~ application,and d limitations. Bulletin de Phys3o-Pathologie Respiratoire 9: : 979-995, July-August 1973. (BP 264) MITTMAN, C., LIEBERMAN,, Ji. Screening, for Of 1-antitrypsin deficiency. Israel Journal of Medical Science9:. 13'11-131&, September-October 1973'. (BP 93) MITTM'AN,, C., LIEBERMAN, J., RU:wtSFELD, J. P'revalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung d3sease. American Review of Respiratory Disease 10.9'(2) : 295-296, February 1974. (BP' 322) NIEWOEHNER, D. E. „ KLEINERMAN, J.,, RICE,, D. B. Pathologic changes in the peripheral airways of young cigarette smokers. New Englan&Journal of Medicine 291(15):. 755-758, October 10, 1974. ~ ($P' 78) OSHIMA, H. , IMAI, M., KAWAGISHI, T. Effects of air pollution on the respiratory symptoms in Yokkaichi, Central Japan. a'i'e Igaku 16 (1)1: 25-29 , June 19'72'. (BP~~ 307)' OXHG,-#~~,, H~.,,, BAKE, B.~,~ WILHELMSEN, L. Closing volume in 50- and 60-year-old'men. A preliminary report. Scand'inavi'an Journal of Respiratory Diseases (Supplementum 85) :.'.59-2'65, . 1974. (BP' 4T)' ROSZrsA-N„ T'. L., RUGERSI, A. S. The immunosuppressive potential of products derl".ved fromicigarette smoke. AmericaniR'eview, of' Respiratory Disease 108(5)': 1158'-1163, November 1973'. (BP' 73), R'UFF, F.,, SALEM, A., BUSY, F.,, de VERNEJOUL, P. ,, EV'ENi P'. , BROUET, G. La fermeture des voi'es aeriennes peripheriques. Sonlaugmentation chez les fumeurs. (',Closing, of the peripheral airways. Its increase in smokers.) Revue d'e Tuberculose et de Pneumologie 36(2): 308'-311,, March 19'72'. (,BP 48) RYLANDER, R. Toxicity of cigarette smoke components: free lung, ce711 response in acute exposures. American Revieww of Respiratory Disease 108'S): 1279-1282, November 1973'. 86

(BP' 112')i SAWICKI, F'., Air pollution ande prevalenceofchronic nonspecific respiratory diseases. In: Brzezinski, Z., Kopczynski, J.i, Sawicki, F. (Editor),. Ecology of chronic nonspecific respiratory diseases, International Sumposium, September 7-8, 1971,W'arsaw, P'oland,PanstwowyZaklad WydawnictwLekarskich,. Warsaw, 1972, pp. 3-13. (8P 128) SCHWARTZ,, R. H. Alpha-l-antitrypsin deficiency and chronic respiratory disease. Annual Report June 28', 1972'- Jiune 20, 19'73'. Unfiversity of Rochester,, Rochester, N. Y. Prepared for Respiratory Diseases Branch,, National Heart and Lung Institute, National Institutes of Health, Bethesd'a,, Maryland. (BP' 95)' SIDOR, R'., PETERS, J., M. Fire fighting and pulmonary functi'on. An epid'emiologic study. American Review of Respiratory Disease, 109~(2)!: 249-254, February1974. (BP 94) SIDOR, R'.„ PETERS, J. M. Prevalence rates of chronic nonspecific respiratory disease in fire fighters. American Review of Respiratory Disease 109(2): 255-261, February 1974. (BP' 58) STANESCU, D. C, , VERITER, C. , FBAN',S,; A., BRASSEUR, L. Maximal expiratory flow rates and "'closing vol:ume"' in asymptomatic healthy smokers.Scandi'navian Journal of Respiratory Diseases 54: 264-2'71, 1973.. (BP'49') STEBB'INGSI, J. H., JR. A survey of respiratory disease among New~ York City postal andd transit wo~~r~ker~s~~., IV. Racial differences in the FEVli. Environmental Research 6: 147=1L.58!, June 1973'. (HCS~1)1 U.S. PUBLIC HEALTH SERVICE. Smoking, and Health. Report of' the Advisory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Department of'Health, Education,, andWelfare, Public Health Service Publication IV1o. 1103, 1964, . 387 pp. (HCS 2), U'. S. PUBLIC' HEALTH SERVICE. The Health Consequences of Smoking,. A P'ublic Health Service Review: 1967. U. S. Department of Health, Education, andiWelfare. Washington, Public Health Service Publication No. 1696,, Revised January 1968, 222' pp. 0)

(HCS 3) U.S. PUBLIC HEALTH SERVICE. The Health,Consequences of Smoking. 1968. Supplement to the 1967Public Health Service Review. U.S. Department of Health, Education, and Welfare. Washington,, Public Health Service Publication 1696, 1968, 117 pp. (HCS4) U.S. PtlB.hICHEAI.TH SERVICE. The Health~ Consequences ofSmoking,.1969.Supplement to the 1967Public Health Service Review. U.S. Department of Health, Educationi, and Welfare. Washington, Public Health Service Publication 1696-2, 1969, 98 pp. (HCS~ 5), U.S. PUBLIGHEALTR SERVICE. The Health Cor-sequencesof Smoking. A Report of the Surgeon General: 1971. U.S. Department of Health, Education, and Wel!fare., Washington,, DHEGZ Pub,lication! No. (HSM) 71-7513, 19'71, 45&pp. (HCS 6) U.S'. PUBLIGHEALTH SERVICE.The Health,Consequences,of Smoking. A Report of the Surge=General: 1972. U.S. Department of Health, Education, and Welfare., Washington, D'HEGJ~ Publicati'on; No. (HSM) 72-6516, 1972, 158 pp. (HCS 7), U.,S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1973. U'.S. Department~ of Health, Ed!ucation,,, and Welfare., WashingZon„ DHEW Publication No. (H2,f) 73-8704, 1973, 249' pp. (HCS 8) U.S., PUBLIC' HEALTHSERVICE. TheHealth Consequences of Smoking; 1974. U.S. Department of Health, E~ducationi, and Welfare. Washington, DHEW Publication No. (CDC) 74-8704. ($P 119) VAN DER LEITDE, R., DE KROON, J. P. M., T?.Ml`ELING, G. J.„ VISSER, B. F. , DE VRIES,, K., WEVER-HESS, J., ORIE, N. G. H. PYevalence of chronic nonspecific lunddisease in a,non- polluted,and an air-polluted area.of theNetherlands. In: Brzezinski, Z., KopczynsKi, J., Sawcki, F'. (Editors). Ecology of chronic nonspecific respiratory diseases, International Symposium, September 7-8, 1971, Warsaw, Poland, Panstwowy Zaklad Wydawnictw Lekarskich, Warsaw, 1972, pp. 27-33. (BP 56) WANhER, A., HIRSCH, J. A,, GREENELTCH, D. E., SWENSJV, E'. W., FORE, T. T'racheal mucous velocity in beagles after chronic exposure to cigarette smoke. Archives of Environmental Health 27(6) : 370'-371, December 1973. (BP 217')' WARR, G. A., MARTIN, R. R. In vitro migration of human alveolar macrophag,es,: effects of cigarette suioking., Infectipn and Iuununity 8(2) : 222-227, August 1973. 88

(BP1!8)'k1EB'B,D.R. , HYDE, R. W., SCHWARTZ,, R. H., HAI:.L,W., J., COND .F~~tI, J. J., TOWNES, P. L. Serum 1-antitrypsin variants. Prevalence and clinical spirometry. American Review of Respiratory Disease 108(4) : 918-925, October 1973. (BP 303) YEAGER„ H., JR., Z'I2O1ET, S. M., SCHWARTZ,, S. L. Pinocytosis by human alveolar macroph,ages~., Comparison of'smokers and nonsmokers. Journal of Clinical Investigattion 54(2'): 247-251, August 1974. i 89

CNAPTER' 4 INVOLUNTARY SMOKING

Contents Pa e Introdtiction.. . . . . . . . . . . « . . . . . . . . . . . 95 Constituents of Tobacco Smoke« . . . . . . . . « . . . . . 96'. Carbon M'onoxide. . . . . . . . « . . . . . . . . . . . 96 Nicotine . . . . . . . . . . . . . . ... . . . . . . . 101 Other Substances.., . . . . . . . ., . . . . . . . . . 102 Effects of Exposure to Cigarette Smoke. . . . . . . . . . 102 Cardiovascular Effects of Involuntary Smoking. .... 102 Effects of Carbon Monoxide on Psychomotor Tests. ..« 103 Pathologic Effects of Exposure to Cigarette Smoke. . . 103 Summary of Involuntary Smoking,Find'ings. . . . . ., . . ., . 111 Bib] iogzaphy. . . . . . . .1 . . . . . . .. . « . . . . . . . 112 List of Tables Page Tab1e 1.--Comparison of mainstream and sidestream cigarette smoke. . . . . . . . . . . .. . « . . Table 2.--Measurements of constituents released by the combustionof tobacco~ products in various s ituations . . . . . . . . . . . . . « . . . . . . 97 . ., ., . 9'.8 Table 3!.--Effects of carbon monoxide on psychomotor functions . . . . . . . . . . . . . . « . . . . . . Table 4.--Admission rates (per 100 infants)by diagnosis, birth weight, and maternal smoking. . . . . . . . . . . . . . . « . . . . « . « . 1014 Table 5.--P'rieumonia and bronchitis in the first 5 years of life by parents" smoking habitt and' morning. phlegTn. « . . . . . . . . . . . . . . . . .109~ 93'

0 w ~ ~ ~ N GJ W

C 1 INTRODUCTION The effects of smoking, on the smoker have been extensively studied, but the effects of tobacco smoke on nonsmokers have received much less attention. Ttie 1972 Health Consequences of Smoking (IS 38)' reviewed the effects of public exposure to the~air pollution resulting,from tobacco smoke. This exposure has been called "passiivesmoking'°by: many!authorities~, but will be referred to in this report as "Involuntary Smoking." The term involuntary smoking will be used to mean the inhalation of tobacco!combustion products from smoke-filSed atmospheres by the nonsmoker. This type of exposure is, iM a sense, "''smoking"'because it provides exposure to many of the same constituents of tobacco smoke that voluntary smokers experience. It is also "invol!untary"' because the exposure occurs as an unavoidable consequence:of breathing in a smoke-filledienvironment. Tihe~ chemical constituents found in~ an atmosphere filled with tobaccoo smoke are derived from two sources-mainstream and sidestream smoke. Main- stream smoke emerg;es from the tobacco product after being drawnithrough the tobacco during puffing,. Sid'estream smoke rises from the burning, cone of tobacco. 1°tainstream and sidestream smoke contribute different concentrations of many substances to the atmosphere for several reasons: Different amounts. of tobacco are consumed in the production of mainstream and side3tream smoke; the temperature of'combustion differs for tobacco during,puffing,or while smoul'dering; and certain substances are partially absorbed from.the mainstream smoke by the.smoker., The amount of a substance absorbed by the smoker depends arn the characteri!stics of the substance and the depth of inhalation bythe smoker. As discussed in the 19'72'Report,, when the smoker do~esnot inhalethe smoke intohislungs,, the smoke he exhales contains lessthan half its original amount of water-soluble volatile compound's, four-fifths of the original nonwater-solubile compounds and particulate matter, andialmost all of the carbon monoxide (',IS 15). Wfienithe smoker inhales the mainstream smoke, he exhales into the atmosphere less thanione-seventh olf the amount of volatile and particulate substances that were originally presentt in the smoke and also reduces the exhaledi C01to less than half' its original concentration (IS 14). As alresu3t,, vastly different concentrations of substances Are found in exhaled mainstream smoke depending on the tobacco .product, compositionof the tobacco, and degree of inhalation by the smoker. Several minor symptoms: (conjunctival irritation., dry throat,, etc.) are caused byLevels of cigarette smoke encounteredlin everyd'ay life,,and'iserious allergic-like reactions to cigarette smoke may occur in some sensitive individuals. A major conce~rni, however, about atmosphericcontam~ination byrcigarette smoke has been due:to the producti'on!of significant levels of carbon monoxide. Cigarette smoking in poorly ventilated enclosed spaces

may generate carbon monoxide levels above the acceptable 8-hour industrial exposure limits (50' ppm)--set by the American Conference of Government Industrial Hyg,ienists (IS' 1)'. Exposure to this level of carbon monoxidee even for short period's of time has been shown to reduce significantly the exercise tolerance of some persons with symptomatic cardiovascular disease. There is also some evidence that prolonged exposure to this level of' carbommonoxide in combination with a high cholesterol diet can enhance experimental atherosclerosis in animals (Chapter 1, Cardiovascular Diseases). In the present chapter, the effects of cigarette smoke on the environment and on the nonsmoker in that environment will be examinediby reviewing data on (1) the constituents of cigarette smoke measured under various conditions and (2)' the physiologic effects of this "involuntary smoking"' on individuals. CONSTITiJENTS OF' TOBACCO S:fOKE In a recent workshop on the effects of environmental tobaccoismoke on the nonsmoker (IS 49)', Corn (IS' 41) presented a compilation ad'apted' ~/ from Hoegg (IS 47)i of some of the substances in mainstream cigarette smoke and the ratio of sidestream to mainstream levels for some of'these substances (Table 1)'. Many-of these substances including, nicotine and carbonimonox~ide:are found inimuchihigher concentrations in sidestream smoke than in mainstream smoke, establishing that the smoke exposure of the involuntary smoker differs qualitatively as wel1 as quantitatively from the smoke exposure of' the voluntary smoker. A more comprehensive recent _ review of the constituents of mainstream and'sid'estreamismoke has also been provided by Schmeitz, et al. (IIS' 32). w A number of other researchers have attempted to measure the levels of some of the substances in cigarette smoke encountered in everyday V situations (Table 2). They have alsoitried to determine the factors controlling the atmospheric concentrations of these substances as well as the amount absorbed by nonsmokers under these conditions. Carbon monoxide, nicotiney bienzol(a)pyrene, acrolein, and acetaldehyde have been of particular concern. Carbon Monoxid'e. Levels of'carbon monoxide (CO), a major product of tobacco combustion, have been studied in a variety of situations, and concentrations ranging from 2 to 11fJ ppm have been measured (Table 2) . The major determinants of the COlevels in these situations are size of the space in which the smoking occurs (dilution of CO), the number and type of tobacco products smoked (CO production), and the amount and effectiveness of ventilation (CO' removal). ! 96

C TABLE ' D. - eomparison of mainstrearn and'sid'estream cigarette sntoJce ",2i Compound Mainstream (mg/cig) Sidestream (rng/cig) Ratio Sidestreamf' Mainstream A General characteristics Duration of smoke production 20'sec SS0isec 2'7' 'fobacco burnt' 347 411 1.2' Par'tiiculat'es, no. per cigarette 11.0S X 1011 3'.S X 1i01' 2 3.3 B Particulate phase 2Tar (chloroform extract) 20•$ 44'.1 2'.1 10! 2 343 3'.4I Nicotine 0:92' 1'.6'9 1' 8! 0.46 1'.27' 2'.8' Benza(a~)Pyrene~~ 3:5~~ X~1Iq"s~~ 13!5~~ X~l0 ~ IT Pyrene 13' X 1I0-s' 3;9 X 1,0-s' 3~ 0! Total phenols 0.228 0:603 2.6 Cadmium 12:5 X 1Qi 4'S X 10-s 3 6 C Gases and vapors Water 7:5 298' 39.7' Ammonia 0:16' 7.41 46 Carbon monoxide 31.41 148' 4.7. Carbon dioxide 63.5' 79.5' 1.3. Nrtrous oxides 0.0i1'4' 0:05'11 16 Comment Filter cigarette Filter cigarette 3:S' mg of Mainstream and! S'.5 mg of Sidestream in particulate phase, tesCin vapor phase t Adapted from Hoegg, U.R'., (IS 46, 47) 2For 3S':mI pufff volumay 2' sec puff'diirzt',ion„ona puff per minute and 23 or 30 mm, butt' length, and 10 per'cent, tobacco mouture. Source: Corn, RMI. (IS 4I')L 0 9'7

TABLE 2. - Measurements of constituents released by the combustion of tobacco products tit various situations [Cig = cigarettes; -= unknown; TPM = total particulate matter] Reference, I.ocation, and Dimensions If Known Harke, H.-e., et ai. (IS 44) Mid-size European car, engine off, In wind tunnel at 50 krn/hr wind speed Ventilation Amount of Tobacco Burned Constituents None AIr jets open & blower off 9 cig 6 cig AirJEtsoptnd: 6cig blower on 30 ppm CO 20 ppm CO 10 ppm CO 110 ppm CO Mid-size European car, None 9 cig engine off, in wind ~ tunnel at zero kmfhr None 6 cig wind speed 90 ppm CO Air jEts open dc -6 cig 8-10 pptn CO blower on 'Harke, H.-P., Peters, H. (IS 43) Car in traffic None 4 cig 21.4 ppm CO Srch, M. (IS 35) Car, engine off-. None 10 cig in 1 hr 90 ppm CO, Smokers 5-1096 COHb 2.09 m3 Nonsmokers 2-5% COHb S_e_Iff, H.E. (IS 34) Intercity buses 15 air changes per hr 23 cig 33 ppm CO (at driver's scat) (burning continuously) ~ 3 cig (burning continuously) 18 ppm CO (at driver's scat) U.S. Dept. 3'ransportation, et al. (lS.ll) Airplane flights: Overseas-100% filled 15-20 air changes per hr - 2-5 ppm CO, <. 120 mg/m3 TPM Domestic-6696 filled do. - <2 ppm CO, <.12U mg/n13 TPIM 4iCZV94C0

TABLE 2. - Measurements of constituents released by the combustion of tobacco products In various situations - Continued [Cis = cigarettes; -= unknown; TPM =_ total particulate matter] Reference, Location, and Dimenaions If Known Cano, J.P., et al. (IS 12) Submarines-66 m3 Godin, G„ et al. (IS 20) Ferry boat compartments: Smoking Nonsmoking T-heater: Foy er Auditorium Bridge, D.P., Corn, M. (IS 9) Party rooms: 145 m3 101 m3 Harke, H.-P., et al. (IS 24) Room-38.2 m3 Harke, H.-P. (IS 50) Office Bldg Office Bldg Room-78.3 m3 SM94c0 Amount of Ventilation Tobacco Burned Constituents Yes 157 cig per day <40 ppm CO, 32 µg/m3 Nicotine 94-103 cig per day <40 ppm CQ, 15-35 µg/rn3 Nicotine ' 18.4 t8.7 ppm CO 3.012.4 ppm CO 3.4t0.8 ppm CO 1.4±0.8 ppm CO 7 air changes per hr 50 cig & 17 cigars in 1.5 hr 7 ppm CO 10.6 air changes per hr 63 cig & 10 cigars in 1.5 hr 9 ppm CO None 30 cig per 13 min (by machine) 64 ppm CO, 510 Ng/m3 Nicotine .46 m%/m3 Acrolcin 6.5 mg/rrt3 Acetaldehyde 5 cig per 13 min (by machine) 11.5 ppm CO, 60 µg/m3 Nicotine, .07 mg/m3 Acrolein, 1.3 mg/m3 Acetaldchyde Air conditioned - <5 ppm CO Not air conditioned -. <S-ppm CO - -- - - - 3 smokers 15.6 ppm CO

TABLE 2. -Measurements of constituents released by the combustion of tobacco products in various situations -(.1ontinued [Cig = cigarettes; -=. unknown; TPM = total particulate matter] I Reference, Location, and Dimensions If Known Harke, H.-P., (IS 22) Room-57 m3 Room-.170 m3 Anderson, G., Dalhamn, T. (IS 2) Room-80 m3 Ventilation None 7.2 air changes per hr 8.4 air changes per hr None 7.2 air changes per hr None 7.2 air changes per hr None 1.2 air changes per hr 2.3 air changes per hr 6.4 air changes per hr Amount of Tobacco Burned 42 cig 42 cig 42 cig 9 cigars 9 cigars 9 pipes 9 pipes 105 cig 107 cig 101 cig 46 cig & 3 pipcfuls Constituents 50 ppm CO, 530 Mg/m3 Nicotine 10 ppm CO, 120 µg/m3 Nicotine <10 ppm C0, <100 µg/m3 Nicotine 60 ppm CO. 1040 ug/m3 Nicotine 20 ppm CO, 420 µg/m3 Nicotine 10 ppm CO, 520 µg/rn3 Nicotine <10 ppm C(), <100 vg/m3 Nicotine 30 ppm CO. Smokers 7.5% COIIb Nonsmokers 2.1%COHb S ppm CO, Smokers 5.8%COHb Nonsmokers 1.3% COHb 75 ppm C_O_ , Smokers 5.0% COlib Nonsmokers 1.6% COHb 4.5 ppm CO, 377 ; g/m3 Nicotine, 3.0 mg/m TPM Russell, M.A.H., et al. (IS 31) Room-43 m3 None 80 cig & 2 cigars per hr 38 ppm CO, Smokers 9.6% COHb Nonsmokers 2.6% COHb Harmsen, H., Effenberger, E. (IS 4S) Room-93 m3 None 62 cig in 2 hrs 80 ppm CO, 52100 µg/m3 Nicotine Hoegg, U. R. (IS 46, 4 T-) 3 Scaled test chambcr-.25 m3 None 4 cig TPM 12.2 ppm ( (). :'.28 mg/rn 8 cig 25.6 ppm CO, 5.39 mg/m3 TPM 16 cig 47.0 ppm CO, 11.41 mg/mTTPM 24 cig 69.8 ppm CO, 16.65 mg/m8 TPM 6M94c©

The' type of tobacco product smoked as a ae'terminant of C0 exposure . ~:5 ..+T 'J ... important because'it has been found' that mainstream smoke from regular and small cigars contains more CO' per puff and per gram of tobac¢o' burned', l4 ' n f1 than fi]itered or unfiltered cigarettes (,IS 40) . This g,reater production1P of CO by cigars was confirmed by Harke (IS 22). He measured the CO produced by 42' cigarettes, 9' cigars,, and 9 pipefuls of tobacco, each product evaluated separately' but under the same room conditions.' . 7Phe cigars produced the highest C0 level .(60' ppm). }. '' ..{* ' In additionto ttle' effect of type, of tobacco' product on C0 leuels, , . data on the effects of room size, amount of tobacco burned, and ventilation 1. are included in Table 2. Only underconditions of unusually heavy smoking and poor ventilation did CO levels exceed' the' maximum pe'rm3ssible, 8'-liour .: .industrial exposure limit of 50 ppm CO (IS 1); however, even in cases .r1 where the ventilation was adequate, the measured C0 levels did exceed I j~,. ~,st ~~ the~ maximuml acceptable ambient level of~~ 9 ppm (YS~ 17). ~ One must~ be careful k'when using the levels recorded in Table 2 as measures of individual exposure because the' CO levels were usually measured at points several feet from hkdbbld' h b hifi te neares t smoer an proaly wouaveeenger if measured at as. . to the pasi'tiom of a person sitting next to the smok points corresponding,er ,; r; ~ ZS' 16)'. In addition, it is the CO absorbed by the body that causes the' harmful 4 Ci: ,.effects and not that which is' measured' in the atmosphere._ This absorption can vary from individual to individual, depending on factors such as duration of exposure,, volume of air breathed per minute, and card;:o-re'spiratory function. Several investigators have tried to de'termine the amount of carbon,`y._. ,~., monoxide absorbed' in involuntary smok3n;, situations by measuring ch'anges : in carboxyhemoglobin levels in nonsmokers exposed to ci'garette smoke-filled environments. Anderson and Dalhamn (IS 2) were unable' to find any change in the COh-b levels of nonsmokers in a well ventilated roon where the ., . CO level was 4.5 ppm. When Harke (IS 22) studied nonsmokers under similar ;, conditions (good venti]iationand less than 5' ppm CO)' ,, he was able , to show an F increase in COIIb level fromi1.1 to 1.6 percent; without ventilation the '' CO levels rose to 30 ppm and!the COHb level increased from .9 to 2'.1 percent ~ .aY.. in 2 hours. Russell, et al. (IS 31) also found that COHb levels i'ncreased ,, from 1.6 to 2.6 percent in nonsmokers exposed to a smoke-filLed room where the CO level was measured at 3!8'ppm; however, he cautioned that 1nearly all p'ersons in the room felt that the conditions were'worse than those experien'ced in most social situations. The levels of COHb measured by both Harke and Russell, et al. (IS 22', IS 31) are well within 'the range' that has been shown to decrease the exercise tolerance of patients with angina pectoris (IS 3,, 4, 5, 6, 7,--Chapter' 1, Cardiovascular Diseases)!._ Nicotine Nicotine in the atmosphere'differs from CO'in that it'tends to' settle. out of the ain with or without ventilation (thereby decreasing,its

., . ' .. . , , ;4~ - .. . . . ~ . . . . •~,• atmospherzc concentration)'', whereas the.CO level! will remain constant until the CO is removed. The concentrations of both substances are decreased '' substantially by ventilation. As can be seen from data, iu Table 2, ' under conditions ' of adequate ventilation neither exceed's the maximum `'"' threshold limit values for industrial exposure (nico'tine,, 500 Ag/m3;, CO, 501 ppm,, ('IS~~ 1)i; whereas in~~cond~itions without~~ ventilation,,~ smoking produces very high concentrations of both (nicotine, up to 5,200/t g/m3', CO!, 110, ppm) .^'-j ;`'. ~ .~Y+IT . . .,. ~ , ...,~ ., . ; . . . ' . .', - ~; Ni cotine in the enviro~ament is of concern because nicotin~ abs©rbed by cigarette smokers is felt to be one factor contributing to the development of atherosclerotic cardiovas'cular disease: Several researchers have 'attempted' to measure the' amounti of nicotine absorbed' by~ nonsmokers in' involuntar~ 'smoking situations. "'-Canol, et al. (IS' 12)i studied urinary excretion of nicotine by persons on a submarine." Despite very low levels measured in the air (15 to' 32 /Z g/m3)', nonsmokers did show a small rise in nicotine ;° excretion; however, the amount•excreted wasistill less than 1 percent of'the''' amount excreted bY smokers.``•Harke (IS'22)i measured nicotine and its `~' metabolite cotininein the urine of smolcersi and nonsmokers' exposed to a'' smoke-filled environment and'reported'that nonsmokers excreted' less than : .1' percent af' the -amount of nicotine and cotinine excreted' by smokers. -----`-:- H'e feels that' at this~ low level of absorption nic+otine is' unlikely to '; be a hazard to the }'nonsmoker.f` , l.di?~y~+'~' ~,,a. Other Substancee 4~''~J.~~~ ~ 4lr,. ;; 4~. ~f.; In two studies environmental levels of the experimental carcinogen benzo(a)pyrene were`measured. Galuskinova aS 19) found' levels'` - of benzo(a)pyren'e from'2.82 ' to 14.4 mg/m3 in smoky" restaurants, but it isnotclearhawTauchofthiis~ was dtiueto'cooking and, hoRamuch, was due to smoking, - In a study of' the concentration of benza(a)!pyrene in the atmosphere of airplanes (IS 37)'',' only a fraction of a microgram per cubic meter was detected, The effect of chronic exposure to very lowlevels o£ this carcinogen hasnot been established for ~~ I .. . . . . _ - ' ~ -. . " - . . . . ~ . . ,. - .. . Acrolein. and acetaldehydehave also-been measured in' smoke-filled rooms (IS 24, Table 2) and'may Eontribute to the•eye firritation commonly experienced in these EFF'ECTS OF' EXPOSITRE TO CIGARETTE SMOKE ' Cardiovascular Effects of Ihvo'luntary Smoking y The effects "of cigarette smoking on the'cardiovascul''ar 'system' of the smoker are well established, but vary little is known about th'e cardio- vascular response of the nonsmoker to cigarette smoke. Harke and Bleichert

s ~ (IS2'3)! studied,]18adults (11 smokers and' 7 nonsmokers) in a room 17Gm3larg,e in which 150 cigarettes were smoked or allowed to burn in ashtrays for 30' minutes. They noted'that the subjects whoismoked during thee experiment had' alsi'gnificant lowering of skin temperature and a riseM/ in blood pressure. Nonsmokers who were exposed to the same smolie- contaminated'environment showed no change in either of these parameters.. L.uqiuette, et al. (IiS' 27) performed' a similar experiment with 40 children exposed' alternately to smolte-contaminated' and clean~ atmospheres, buf' other- wise under identical experimental condi'tions.They,f~ound that exposure to the smoke caused increases in heart rate (5 beats per minute)' and in systolic (4 mm Hg)~ and diastolic (5 mm Hg) blood pressures. The d'ifferences in results between these studi'es may be d'ue,, in part, to the age of the subjects--i.e., children may be more sensitive to the cardiovascular effects,of involuntarysmokingth~an adults,, or the increase in heart rate and blood pressure may be due to a difference between chil'dren and adults in~ the psychologic response to being, in a smoke- filled atmosphere. Effects of Carbon Monoxide on P'svchomotor Tests Carbon monoxide from tobacco smoke, automobile exhaust, and' industrial poSlution is an important component of air pollution. f'iere has been some: concern over the effect of'relatively low l:evels of carbon monoxide on psychomotor functions (the ability to perceive andireact to stiznuli), especially those functions related' to driving an automobile (Table 3). Carbon monoxide levels occasionally reached' in some involuntary smoking situations result in measurable cognitive and'motor effects, but these effects generally are measurable only at thie threshold of stimuli perception. One study (Wright, et al., (IS 39) found'that the safe driving habits,measur'ed on,a driving, simulator did not improve as!much~with practice in a group exposed' to CU' as did the habits of a control group. Another study (IS' 2'8), with a different experimental design but'at the same levels of CO did not find any effect on complex psycho- motor activity such as driving,a car. Thus, thie role of CO alone in motor vehicle accidents remains unclear. The effect on judgement and reactions of COn in combination with factors such as fatigue!and alcohol, conditi'onsknown to influence judgement and' reaction time, has not been d'etermined. Paithoiogi'c Effects of Exposure to Cigarette Smoke The effect of involuntary smoking on an indi'vidual is determined not only by the qualitative and' quantitativeaspectsofthesmoke-f~illedenvironment,, but also largely by the characteristics of the individual. Reacti'ons may vary wi'thiage as well as with the sensitivity of an individual to the components of tobacco smoke. The severity of possible effects range from minor eye and throat irritations experiencediby most people in smoke-filled rooms„ to the incapacitating anginal attacks of some persons with cardiovascular d'isease. 3 101

Ti ABL,E 3~. - Effects of carbon nsonl.~ le on psychomotor functions c 0 Reference Test or Measurement CO level (ppm)' COHb tevel' (Percent) ffect . M'cFarland„R.A. Ability of'd'ri;vers to stay 6. None (IS28) between two-lane markers i11 None while being permitted only 17' None Ray, A.M., brief glimpses of the road Reaction time to 10 Prolonged! Rockwell, T.H. (IS 30) car taillights McFarland, R.A. Performance of two tasks at 700 17' None US 29) same time Dark adaptationi and glaree 7'00, 17 PVone. recovery Peripheral vision at 16' 700' 117 ' Idone and 30' Peripheral vision at' 2D` 700! 117 Decreased Depth perceptilorr, 7001 17 None, Stewart, R'.D:,, et' al. Time perception 500, 20' None (ifS 3'6) Fodor; (;,.G., Attentiveness to 50'x, 5 hrs: 2-5' Decreased Winneke, G: (iS L8) auditory stiinulil Flicker fusion 50 x 5 hrs., 2•5 hirchange Speed' of motor performance 50 x 5'hrs.. 2'-5' No change Perception of complex 50x5hn 2-5 1'mproved visual I patt'erns Cognitive function 100 5 Decreased' Schulte, I:H. US 33) Reaction time 20' No change Bender„tiV_, et all Tlnreskiold' for temporal' 100, 7.25 Raised (IS 8) resolution of visual'stimulii Manuall dexterity 100, 7.25 Decreased. Il.earning,m eaningless syllables 100' 7.25 Decreased, Retention of 10 syllables 100! 7:25 No change Gtoll-lCnapp; R:,,et'al. forlhr Attentiveness to audit'ory 50' Deterioration at (IS 2l) stimuli 100, 50 ppm, worse at 150! 100 ppm, worst' at 1'50'ppm Wright, G:,, et al. Reactionitime 6.3 Ptol'onged. US34) Glare recovery 6.3 Prolonged Careful driving habits 6.3 Failure to improve with practice 1fl4

C e The minor symptomatic irritation experienced'by nonsmokers in a smoke- filled environment is influenced by the humidity of the air as well as the concentration of irritating substances found in the atmosphere. Johansson and Ronge (IS' 48) have shown that irritation d'ue to cigarette smoke is maximal in warm, dry air and decreases with a small rise in relative humidity. A change from acceptable to unpleasant was reported at 4.7 mg/m3 of particulate matter for nonsmokers and eye irritation was noted at 9 mg/'m3 for both smokers and nonsmokers. The authors concluded that a ventilation rate of 12'm3/hr/cig was necessary to avoid' eye irritation and'50 m3/hr/cig was necessary to avoid unpleasant od'ors. Two government sponsored studies have attempted! to evaluate the degree of minor irritation due to cigarette smoke experiencediby bus and plane passengers. The U'.S'. Department of Transportation,(IS 34) studi'edi the environment on two ventilated buses--one with simulated unrestricted smoking and another with simulated smoking limited to the rear 20 percent of the seats. In one bus„ lighted cigarettes were placed at every other seat (23 cigarettes) to s3mulate a bus filled with smokers. In the other bus, cigarettes were placed only in the rear 2'0' percent of the bus (,five cigarettes) to simulate a bus where smoking,was llimited'to the rear 20 percent of the seats. When smoking,was limited, the C0 level at the driver"s seat was only ]i$ ppm compared to~the level of 33 ppm measured in the unrestricted smoking situation. Four of the six subjects seated in the bus reported eye irritation during,the unrestricted smoking simulation.. None of the six subjects reported any eye irritation in the restricted smoking situation (not even those seated in the rear 20 percent of the bus). Several Federal agencies (IS 37) cooperated to survey the symptoms experienced by travelers on both military and commercial aircraft. They distributedia questionnaire to passengers on 20 military and 8'commercial flights; 57 percent of the passengers on the military flights and 45, percent of the passengers on the commerciall flights were smokers. The planes were well ventilated, and CO levels were always below 5 ppm with low levels of'other pollutants as well. In spite of the low level of measurable pollution, over 6'01percent of the nonsmoking passengers and 15 to 22 percent of the smokers reported'being annoyed'by the other passengers' smoking. Seventy- three percent of the nonsmoking passengers on the commercial flights and 62' percent of the nonsmoking passengers on the military flights suggested that some remedial action be taken;, 84 percent of those suggesting remedial action felt that segregrating the smokers from nonsmokers would be a satisfactory solution. These feelings were even more prevalent among those nonsmokers who had ahistory of respiratory disease.. Children have been found to have a higher incidence of respiratory infections and are thought to be more sensitive to the effects of air pollution due to their greater minute ventilation per body weight than edults. Several researchers have investigated the effects of parental O. ~ d~S , - i0s , ~

c smoking on the health of children. Cameron, et al. conducted two telephone surveys of Detroit families to determine the relationship between children''s respiratory il:lnessandi parental smoking, habits.In th~efirst survey(IS11) they found a statistically significant relationship betweenithe prevalencee of children"s respiratory infection and parental smoking,habits only when all children under 16 were considered (not whenionly those under 9 or under 5 were considered). Inia larger survey of the same city (IS 101) they foundd a relationship between parental smoking and prevalence of respiratory illness in the 10- to 16-year age group and in the birth to 5-year age group. Neither study controlled for smoking by the children which might be a factor in the 10- to 16'-year age group or for socioeconomic status which has an effect on both, smoking habits and illness. However,, the data were consistent with a higher prevalenceof'respiratorydiseese in~familieswhiere~there aresmokers than in nonsmoking families. Colley (IS 13) also found a relationship between parental smoking, habits and the prevalence of respiratory illness in the children. He found an even stronger relationship between parental cough and phlegm production and respiratory infections in children,. He postulates this latter relation- ship toiresult from the greater infectivity of these parents due to their cough and phlegm production. The relationship between parental cigarette smoking, and respiratory infection in their children would then occur because cigarette smoking, caused the parents to cough andiproduce phlegm and would not be indicative of'a direct effect of cigarette smoke-filled air on the child'ren. Harlap and Davies CIS 25) studiedli'nfant admissions to Hadassah Hospital in West Jerusalem and found a relationship between admissions for bronchitis and pneumonia in the first year of life andimaternal smoking habits during, pregnancy. Data on maternal smoking habits after the birth of' the ckild were not obtained, but it can be assumed that most of the mothers who smoked during,pregnancy continued to smoke during,the first year of the infant"slife., A relationshipbetweenlinfant admission andimaternal smoking habits was demonstrable only between the sixth and ninth months of infant life and~was more pronounced during,the winter months (whenthe effect of cigarette smoke on the indoor environment would be greatesu;. Mothers who smoke duringg pregnancy are known to have infants with a lower average birth weight than the infants of nonsaaokfng,mothers. The relationship between maternal smoking, and their infants' admission to the hospital found in this study was greater for lowbfrthweight i.nfan~ts,but wasalso!fo~und for normal birth wej!ghtinfants(Table 4) (IS 25). Harlap, and Davies (IS 25) demonstrated' a dose-response relationship for maternal smo?cing, and infant admission for bronchitis and pneumoniai, however„ theyr also found a relationshl;p betweenimaternal smoking, O ¢a CJT,

C 0 TABLE 4:- AdmiWon rates (per 100 infants) by'diagnosis, bdrth weight, andmaternalsrnoking B'irth we;ght (g) Total IDingnosiu cs~gg; 3,p00- 3,499' 3,Spp+ (including unknown) S, (297) -NS (2',316)i S (4'15) NS (4,098) S (264) NS (3,1'95) S (986} NS' (9,686). Bronchit'i.s and pneumonia 19.2 1',2.3 9'.6 8.2 1!2'.1, 9'A 13:1 9.5' All other 22.6 19.9' 1i4'.5 14'.6 15'.2' 13.3 16.9' 15:5 T.otall 41.8 32'.2' 24.1 22.8 27.3 22'.3' 30:0 24.9' NOTE. - S=Smokars;; NS=N'onsmokers. Source:: Harlip, S:, Davies; A.M. (IS 24

` and infant admissions for poisoning and!in,juries. This may indicate a bias in the study due to relationships whi'ch may exist between smoking and'factors such~as parental neglect or socioeconomic class. •,In ad'd'ition, hospital admission rates may not: be an accurate index of infant morbidity. Colley,, et al. (IS 42) studied the incidence of pneur.ionia and'bronchitis . in2',205 chil'dren overtheFirs~t 5: years of' llifein relation to~ the smokingg habits of both parents. They found that a relationship between parental smoking habits and respiratoryinfectioninch,ildrenoccurred only during the first years of life (Table 5). They also showed a relationship between parental cough and phlegm production and infant infection (Table 5) which~was found to be independent of'the effect of parental smoking habits. The relationship betwe~en parental smoking and infant infection was greater when both parents smoked and increased with increasing number of cigarettes smoked per d'ay. The relationship persisted after social class and birth, weight had been controlled' for. Thus, respiratory infections during the first year of life are closely related to smoking,habits independent of parental symptoms, sociali class,, and birth weight. Because of the dose-response reliationship~between parental smoki'ngand':infantrespiratoryinfection established by Colley, et al. (IS 42), it is reasonable to suspect that cigarette smoke in the atmosphere of the home may be the cause of these infectionsy however, other factors such as parental neglect may also play a role. The above studies examined the effects of involuntary smoking on relatively healthy people. A substantial proportion of the U.S. population suffers from chronic cardiovascular and pulmonary diseases, however,,and they represent the segment of the population most seriously jeopardized by conditions found in involuntary smoking situations. In Chapter 1 of this report (Cardiovascular Diseases)' evidence was presented whichishowed, that levels of CO' sometimes experienced in smoke-filled environments (',50 ppm)' are capable of significantly decreasing the exercise tolerance of persons with angina pectoris and intermittent claudication. In addition, these levels of CO have been shown to decrease cardiac contractility and to raise left ventricular end-dias:tolic press~ure(~an,indi'cation:of heart faiLure)in personswi'th cardiovascular disease. Persons,w.Lth chronic bronchitis and emphysema have considerable excesss mortality under conditions of severe air pollution. In smoke-filled environments lievels of C0 and several other pollutants may be as high or higher than occur during air pollution emergencies. The effects of short- term exposure of'persons with chronic obstrucCive bronchopulmonary disease (COPD) to these condi:ti,)ns have not been evaluated!. Persons with COPD are also possibly at increased' risk to'CO exposure because of their low alveolar pp2. Due to the reduced'amount of'oxygen available to compete with the CO for hemoglobin binding sites, these persons might experience a carboxy- hemoglobin tooxyhemoglobinratiohi'gher than those in health~ysubjects

M r C Ta BLE 5. - Pneumonia and bronchitis in the,first Syears of life by parents'smoking habit and morning phlegra Atnnual!ihcidertce of pneumonia snd'~ bronchitis per 100 childiaen (Albsolu2e numbers in iparentheses)' - Both ex-unoiters • Year of I Both nonsmokers One smoker Both amoken or one ex-smolcer All FollowuR ~ om'amoking habit changed IY~ OI!B' 19~ 0YB' N O/B I+I~ Ol/B~ I N ~ 018 1 7:6' 10.3 10!4 1 4 1 15.3 23'.0' 8.2 13.2' 10:1 16'.7' (343) (29) (424) 1 , 8 ()' (339) (139) (546) (129) (1,65'2) (425). 2' 8.1 8.3' 7:~1 ~ 1'5~.5 8,7'~ 9.2~ 6.5~ ~ 10:7~ 7.4'~ ~ T1'i.3' ! (322) (36) (365)' (129)' (286) (152) (599) (159) (1,572), (4~76). 3 6.9 8.1 10.5'. 9.4 7:9 11.0 8'.2' 11.6 8.4 10.6 (305) (37) (353) ~ (107)' ~ (242): (154) ~ ('661), ~~ (173~~)~ ~~ (1,561), (47~11)~. 4 8.01 11.1 7.5' 1'0.8' 7.6 11.6 8,2' 9.1 7:91 j 10.3 (287) (36) (306) (1102)~ (2'36)1 (1211)', (69S'Y (187) (1,524) (4'46)i 5' 6.7 14':T 5.6 9:41 3.9 10.6 6.4 7.3 5'.9' 1 9.11 (285) (34) (267) I (107)~ (208): (132) (737): (219) (1,497) I (492)' NOTE. - N=neither with winter morning phlegm. A/,B:=one or both with winter morning, phlegm., 5ource: Cottey, 1lR.T., et all (IS,42) 109 i

under the same conditions of C4 exposure. The retention of Wmay also be prolonged due to both this increased bindi~ngof CO to hemoglobin underlcrw alveolar P02,and decreased ventilatory capacity to excrete C!0. In summary, the effects of cigarette smoke on healthy nonsmokers consists mainly of minor eye and throat irritation. However, people with certain heart and lung diseases (angina pectoris, COPD, allergic asthma) may suffer exacerbations of their symptoms as a result of exposure to tobacco smo&e- filLed enui'ronments. These effects are dependent on the degree of individual exposure to cigarette smoke which is d'etermined'by proximity to the source of the tobacco smoke, the type andd amount of tobacco product smoked'„ conditions of room size and ventilation as well as tiie amount of time the individuall spends in the smoke-filled environment, andihis physiologic condition at the time of exposure. 0

M 1. Tobacco smoke can be a significant source of atmospheric pollution in enclosed areas. Occasionally under conditions of heavy smoking, and poor ventilation, the:maximum limit for an 8-hour work exposure to carb=monoxide (501ppm) may be exceeded., 2. Carbon monoxide,, at levels occasionally foundiin cigarette smoke- filled environments, has been shown to produce slight deterioration in, some tests of psychomotor performance, especially attenti'venessand cognitive function. It is unclear whether these levels impair complex psychomotor activities such as driving a car. The!effects produced by CO may become important when added to.factors such as fatigue and alcohol which are knownn to have anieffect on the ability to safely operate almotor vehicle. 3., Unrestricted smoking on buses: and planes is reported tolbe annoying to the majority of nonsmoking passengers under conditions of adequrateven~tilation. 4i. Children ofparen~ts whoismoke are more, likely to~havebronchitisand pneumonia during the first year of life, and this is probably at least partly °due to their being exposed1to cigarette smoke in the atmosphere. 5. Levels of carbon monoxide couanonly found in cigarette smoke-filled environments have been shown to decrease the exercise tolerance of patients with angina pectoris and probably have an adverse affect on persons with chronic obstructive pulmonarydisease.

r BIBLIOGRAPHY (Is 1) A2vIER'ICAN CONFERENCE OF GpVERNi+tENT' INDUSTRIAL HYGIEN'ISTS. TLi) threshold limit values for chemical substancess in workroomiair adopted by the American conference of '. government industrial hyg~ienistsfor1973. Journal of Occupational Med'icine, 16:(',1)': 3'9-49,JanuarX19'74. (IS 3) ANDERSO~T~, E. W., ANDELMAN, R., J., STRAUCH, J. M.,, FORTUIN, N. J'. , KNELSONi„ J. H. Effect of low-level carbon monoxide exposure on onsefi and dkirata:on of' angina pectoris. A study of' tenipatients with ischemic heart disease. Annals of Internal Med'icine 79'(1): 46-50, July 19!73. (IS 2) ANDERSON',, G.„ DALHAM!1„ T. The risks to health of passive -- 8 A smoking. Lakartidningen 70: 2833'-236,ugust 15, 1973. (IS' 7) ARONOW, W. S.„ CASSIDY, J., V'ANGROW,, J. S'., MARCH, H., KERNI, J. C., GOLDSMITH',, J. R.,, EOiFMICA, M'., PAGANO, J. VAWTER, Mi. Effect of' cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics inn anginal patients. Circulation 50 (2)I : 340-347, August 19'74. (IS 5) ARONOW, W'. S., GOLD6'MITH,„ J. R.i, KERi~i', J. C., JOTNSON', L. L. Effect of smoking cigarettes on cardiovascular hemo- dynami'cs. Archives of Environmental Health 28(6): 3I30~- 332',IJLme 1974. (IS' 6) ARON'OWi, W. S'. , HARRIS, C. N. ,, ISBELL, M. W'. , ROKAW, S. N'. , IMPARATO,, B. Effect of freeway travel on angina pectoris. Annals of Internal Medicine 77(5): 669-676, November 1972. (IS 4) ARONOt+T„ W. S'. , ISBELL, M. W. Carbon monoxide effect on exercise-induced angina pectoris. Annals of Internal Medicine 79 (3) : 39'2-395, Seg `ember 1973. (IS 8) BENDER, W'. , GOTHERT, M., MALORNY,, G. Effect of low carbon monoxide concentrations on psychological functions. S~taub R~einhaStung, der Luft 32(4): 5:4-60!,April 1972., (IS 9)i BRIDGE, D. P.„ CORN, M'. Contributionito: the assessment of , exposure of nonsmokers to air pollution from cigaret~te and cigar smoke in occupied spaces. Environmental Research 5: 192-209, 1972.

t 4 (IS' 40) BRUNNEIMSANN, K. D., HOFFTTANN', D. Chemical studies on tobacco smoke. XXIV. A quantitative method for carbon monoxide andlcarbon dioxide in cigarette and cigar smoke. Journal of Chromatographic Science 12(2): 70~-75,, February 19'74. (IS 11) CAMERON, P'., KOSTIN, J. S., ZAKS, J. M~., WOLFE, J. H., TIGHE, G., OSELETT, B.,; STOCKER, R., WINTON, J. The health~of smokers" and nonsmokers' children. The Journal of Allergy 43(6): 336-341,, June 1969. (IS 10) CAMERON~„ P., ROBERTSON, D. Effect of home environment tobacco smoke on family health. Journal of Applied Psychology 57 (,2') : 142!-147, 1973I. (IS'~ 12)~ CAN'~0~~,~ J., P'.~,, CATALIN, J., BADRE,, R., DUMAS~,, C., V'IALA,~ A., GUILLERXE, R. Determination de la nicotine par chromatographie en phase gazeuse. II - Applications Annales,ph~armaceutique~s~~francaises: 28(11):~ 633-64&, 19701.. QS 13') COLLEY, J. R. T. Respiratory symptoms in children and parental smoking, and phlegm prod'uction. British Medical Journal 2:, 201-204, April 27', 19!74. (IS 42)' COLLEY, J., R. T. „ HOLLAND,, W. W'. , CORKHILL,; R. T. Influence of passive smoking, and parental phlegm on pneumonia and (IS 41) bronch~i~tis!in early~ childhood.~ Lancet~ 2'(~,7888):~~, 1031-1034, November 2', 19'74. CORN, M. Characteristics of tobacco sidestream smoke and factors influencing, its concentration and distribution in occupied spaces. Pages 21-36 in R. Rylander, ed. Environmental tobacco: smoke ef'fectson th~enon-smoker.. ScandinavianlJournal of Respiratory Diseases. Supplementum 91: 1-901, 1974. (IS 15) DALHAMN, T. ,, EDFQRS, M. , RYLANDER, R'. Mouth absorption of'various compounds in cigarette smoke. Archives of Environmental Health 16(6):831-835,, June 1965. (IS 14) DALHAMN,, T., EDF'ORS', M., RYLANDER, R., Retention of cigarette smoke components in human Iungs. Archives of Envi'ron- mental Health 17'(5): 746-748, November 1968. 113

(IS' 116) ' DUBLIiN,, W. B. Secondary smoking: a problem that deserves . attenti'on. Pathologist 26(9):244-245, September 1972. (IS 17)ENVIR©NMENTAL PROTECTION AGENCY. National primary and' secondary ambient air quality standard's. Federal Register 36 (84-Part II) :8186-82'01„ April 30, 1971. (',IS' 18') FODOR, G. G., WINNEKE, G. Effect of low CO concentrations on resistance to~monotony and on psychomotor capacity. Staub Reinha'ltung, der Luft 32(4):46-54, April 1972. (,IS']i9~Y GALUSKINOVA, V.3',4 -' Benzpyrene determination in the smoky atmosphere of social meeting,rooms and restaurants. A contribution to'the problems of so-called passive smoking. Neoplasma 11:465-4'68', 19'64. (IS20) GO~D'IN,~ GI.,,, WR'IGHT',, G., SHEPHARD, R. J. Urban exposure to carbon monoxide. Archives of Environmental Health 2'5 (S)~: 305~-313, November 1972. (IS 21) GROLL-KNAPP',, E., WAGNER, H. „ HAUCK, H'. , HA1[DER, M. E£f ects of l:ow carbon monoxide concentrations on vigilance and computer-analyzed brain potentials. Staub'Reinhaltung der Lufe 32(,4)1:64-6&, April 19'72.1 (IS' 22) HARKE, H. -P. The problem of "passive smoking." Munchener Medizinische Wochenschrift 112'(51) 2'328-2'334, _ December 18, 1970 (IS 50) ) HARKE',; H. -P'. The problem of passive smoking. I. The' influence of smoking on the Cfl, concentration in office rooms. I!nternationales Archiv fur Arbeitsmedizin 33(3)': 199-206,, 1974. ( IS! 24) HARKE, H'. -P .i„ BAARS, A., FRAHM, B'. , PETER'S, H. ,, SCHULTZ',, C.. Zum Problem des Passivrauchens (The problem of passive smoking,.). Internationales Archiv fur Arbeitsmedizin .2'9:323'-339', 197'2'. (IS'~ 2'3)~' HA'RKE~,~ H~.~ -P'., BLEICHERT, A. Zum Problem, d'es~~ Pass3Lvrauchen& (The problemlof passive smoking.) Internationales . Archiv fur' Arbeitsnedizin' 29:312-322', 1972. (IS 44) HAFtKE, H. -P'. , LTEDL„ W., DENKEbC, D. The problem of passive smoking. ITi. Investigations of C0 level in the auto- mobile after cigarette'smoking. Internationales Archiv fiir Arbeitsmedizin 33(3) :207-22'0', 1974. 114

I 0 IS 43) HAR.KE, H. -P. , PETER!S', H. The problem of: passive smoking,. III. The influence of smoking on the C0 concentration in driving automobiles. Internationales Archiv fur Arbeitsmedizin 33(3):221-2'29, 1974. (IS 25) HARLAP, S., DAVIES, A. M. Infant admissions to~ hospital and maternal smoking. Lancet 1(,7857)~:529-532, March 30, 1974. (IS 45X HARM'SEIJi, H. , EFFENBERGER, E. Tobacco smoke in transportationn vehicles, living, a.nd! working, rooms. Archiv fur Hygiene and Bakteriologic L41(5):383-400., 1957. I~ S 46) HOEGG, U. R'. The significance of'cigarette smoking in confined spaces. Thesis. University of Cincinnati, Division of Graduate Studies, Department of Environmental Health. 1972' 137 pp. IS 47) HO'EGG', U. R. Cigarette smoke in closed'spaces. Environmental Health Perspectives 117-12'8, October 1972I. (IS 48!)JOHANSSOTV', C. R.,RONGE,H~. Acuteirritati'oneffectsof tobaccoismoke in the room atmosphere. Nordiisk Hygienist Tidskrift 46:45-50, 1965. (IS 27)LUQUETTE, A. J. , II:AND'ISS, C. W., M'ERKI, D. J1. Some immediate effects of a smoking environment on children of elementary school age. The Journal of School Health 40~(10) :53'3'-536,, December 1970. (IS 28) McFARLAND~,, R. A. A study of the effects of low levels of carbon mono:aide upon humans performing driving tasks at the Harvard School of Public Health. 1973 Automotive Air Pollution Research Symposiumy Washington, D.C'., March 7-9, 1973. (IS 29) McFARLAI+ID'„ R: A. Low level exposure to carbon monoxide and , driving,perfarmance. Archives of Environmental Health 27 (6) :355-359, December 197'3'. (1[S 30)' RAY', A. M. , ROCKWELL, T. H. An exploratory study of auto- mobile driving,performance under the influence of low levels of carboxyhemoglobin. Annals N'ew York Academy of S'cilences174:396-408, October 5, 197:0. (IS' 31) RUSSELL,, M. A. H. , COLE, P. V. , BROt+IN, E. Absorption by non-smokers of carbon monoxfde fro:n~ roosn air polluted by tobacco smoke. Lancet 1(7803'):576-579, March 1!7'„ 1973.

(IS 49) RYLAND(:.,, R., Ed. Environmental tobacC smoke ef f ects on the non-smoker. Scandinavian Journal of Respiratory Diseases Supplementum 91:1-90, 1974. (IS~~ 32) SCHMELTZ~, I., HOFFMANN, D~. ,[MTDER'~, E. L.~ Th~e~~ infl!uence~ of tobacco smoke on-indoor atmospheres. I. An overview. Preventive Medicine 4:6'6-82',, 19'75. (IS 33)i SCHULTE, J. K.Effectsofraildl carbon mono~xideintoxicationi. Archives of Environmental Health 7(5) :30-3'6, November 1963. (IS 34) SEIFF, H. E. Carbon monoxide as an indicator of cigarette- caused pollution levels i'n intercity buses. U.S'. Depart- ment of T'ransportation, Federal Highway Administration, Bureau of Motor Carrier Safety„ April 19'73„ 11 pp. (IS 35) SRCH, M. Uber die Bedeutung, des Kohlenoxyds beim Z'igaretten- rauchemim Pers'onenkr~aftwageninnern.Deutsclie Zeitschriftfiir gerichtliche Medizin 60:80-89, 1967. (IS 36)' STEWART, R. D., N'EWTON, P. E. ,, HOSKO, J. J., PETERS'ON,, J. E. Effect of carbon monoxide on time perception. Archives of Environmental Health 27(3') :155'-160', September 1973. (IS 37')~ U.S. DEPA'RTMENT' OF TRANSPORTATION, FEDERAL AVIATION ADMIiNISTRA- TION, U.S. DEPAR'TMENT'OF HEALTH', EDUCATION„ AND WELFARE. NATIONAL INSTIiTUTE' FOR OCCUPATIONAL SAFETY AND~ HEALTH'.. Health aspects of smoking in transport aircraft. Rockville, Md'. AD-736097, December 1971, 85 pp. (IS 38) U.S. PUBLIC HEALTH SERVICE. The Health~ Consequences of Smoking. A Report of the Surgeon G'eneral: 19'72'. U.S. Department of Health, Education, and Welfare. Washington,, DHELJ. Publication No. (HSrT)'~ 7'2-65~16,1972, 158 pp. (IS 39) WRIGHT, G., RA,DELLa P., SHEPHARD, R. J. Carbon monoxide and driving skills. Archives of Environmental Health 27:349-354, December 1973. , r

o37~s~zs~; .w. :0

U3'76425'7

---

---