with increases in cigarette smoking. Es-cigarette smokers tended to
have results similar. to those of nonsmokers. The authors found that
the mebrxne component, did not show any consistent change wit 11 in-
cwased current cigar&te smoking. n-lIr~wa the volume of blood in the
lung capillaries decreased markedly with increased cigarette consump-
tion, and slightly with age. The \-alue of this vascular component in
alale 1~oIm1101wrs WIS 7.FG. This tlecreased to 49.1 in males who smoked
25 or more cigarettes a day (I'<O.Ol). The figures for won~en were
77.2 and 50.7 for nonsmokers and smokers. respect.irely (1'<0.05).

Acetaldeh~de is fou~id in cigarette s~fiokc~ and is a known ciliatoxic
agent,. The single-breath retention of acctnldrlr~de vapor b- the respi-
ratory tract of human subjects was measured by Egle (I(;) who found
a direct relat.ionship between the volume inhaled and the percent taken
up. Up to 90 percent of the inhaled acetaldehytie was removed in a
single breath.

Stanescu (79) studied the single-breath oxygen test, in 38 male
smokers and 68 male ~Io~IsmOkers who were in excellent, health. -4 sig-
nificant, difference (P<O.OOl ) in t.he slope of the nitrogen gradient
between smokers and nonsmokers was found.
Teculescu (8.1) performed single-breath determinations of total lung
capacity in 89 males aged 19 through 67 \\-ho had normal chest, X-rays
and no history of respiratory disease. So significant. differences \vere
found with age or smoking habits.

Studies in Man

`rracheobronchial clearance rates were studied in nine pairs of mono-
zygotic ant1 nine pairs of djzygotic twins bv (`aniner. (4 al. (Is). A test
~osol of radioactively taggc(l tcHon 1xI&1es 6 to 7 microns in diam-
Wr was inhaled and `external measurements of radioactivity in t.he
Il111gs were made. The (alearance patterns within pairs of monozygotic
t&s were similar? more so than clearance patterns within pairs of
`(izYgotic tjvins, indicating that tl.aclleobroIlcllial clearance rates may
to &1e extcllt. be constitutiollalIv determined. Onlv one individual had
`wl a I~egular cigarette smoker.
( `:II~cI. alld I'hilipson (I(/) also studied tracheobronchial clearance
,`I S"loking-discoI,daIlt twins. using the same techniques as in the pre-
`j~s study : 10 pairs of Jllonozygotic. twins cliscordant with r~parll to
' `E:lNtcl snlokjIlg IT(`I'~~ studied. ,111 the smokers had usd 10 to 20
"l:`:lWttes a dav f(~l. 111()1'(~ tll:lIl "0 J-CRI'S. `~r~aclleobt~oliclii:~~ clearance
"W. 011 the, a~leragc. sjpific:~~~tly `( 1'<0.02) SloweI~ in the snlokers
   ~!I<L(l2fi o--;:j-. ~~ .r,                                        51


t,han in the nonsmokers. Although the basic rate of mucociliary trans.
port may be constitutionally determined, it is evident that cigarette.
smoking decreases the etrecctiveness of this physiologic mechanism.

The regional deposition of inhaled aerosols in man was studied by
Lippmann, et al. (SO), who used a monodisperse ferric oxide aerosol
tapgcd with a radioisotope. Partic.les were deposited in the pharynx,
trachea. bronchi, and alveoli. Measurements were made in 65 adults
including 14 nonsmokers, 2!1 current cigarette smokers. six elderly
bronchitic patients, and one young asthmatic. Larger particles Were
deposited in the upper airways by turbulent, precipitation with only
the small particles of 011~' to five micron size reaching the lower air-
ways. The cigarette smokers. bronchitics. and the asthmatic had a
higher proportion of palticlrs deposited in the tracheobronchial area
than nonsmokers. ,is a result, fewer particles reached the alveoli in
these patients. These findings may be the result of a decrease in the
diameter of the small bronchioles due to inflammation, mucus, or
bronchoconstriction.

hlbert.. et al. (3) studied the effects of cigarette smoking on the
kinetics of bronc.hial clearance in a group of volunteers most of whom
also participated in the previous study. X two-phase clearance pattern
was described for many subjects. The first, a short, rapid clearance
phase, was completed within a few hours and probably represented
cle.arance of the upper airways. The second phase varied in durat.ion
from a few hours to 1 dal: and represented clearance of particles
deposited in the distal portions of the bronchial tree. The average
clearance time was 126 minutes in 18 nonsmokers, 170 minutes in 19 of
the smokers, and 288 minutes in the six patients with bronchitis, most
of whom hat1 been heal-y cigarette smokers for many years. Much vari-
ation in clearance rates was found among smoke.rs. Cigarette smoking
resultrtl in diminislletl pulmotlary clearance in the upper airways first.
-1s a result. mucus cleared from the lowr airways accumulated in the
larger airways where stasis occurred. In severe cases, stasis was more
generalized throughout the bronchial tree.

Snnchis, et al. (7'4) also studied lung cle,arance mechanisms in nine
adult, females who had smoked more. than 1.5 cigarettes a day fol..more
than 5 years a.nd who had no evidence of bronchitis or respiratory
disease. ,\ group of nonsmoking females matched for age served as
controls. A heterodisperse aerosol of 113' tagged human albumin was
inhaled by the volunteers. and measurements of radioactivity were
made over three crcscentic areas of the right lung which corresponded
to large ciliated airways. intrrrnrtliatr bronchi. and nonciliated periph-
eral airways and alveoli. (`igarcttt> snlokers exhibited a slowing of the
rapid c~lcarance phase of the la1.g~ ciliated airwl>-s and also a relative
acceleration in the swond c*le:irnnc~e pliasc resulting in an accuniula-
t,ion of activity at the hilar area. (`oml)aring the clearance among

52


smokers and nonsmokers, the authors found that the nonsmokers re-
tained tv,-ice as much activity in the lung at the end of 2-Z hours as did
the smokers. This finding resulted from the, deposition of much more
of the aerosol distal to the ciliated airways in nonsmokers t,han in
smokers suggesting that seemingly health\- smokers may have obstruc-
t.ion of the small airways.

Camne.r, et al. (II) examined the short-term effects of heavy cigar-
&e smoking on mucocilary transport using the ,same methods as in his
previous studies (10. /A?). The subjects weie 13 men aged ~27 to 38 1~110
had been habitual srnok(~rs for several )-cilrs. Raselinr clearance rates
\vere measured after refrainin p from cigarette smoking for 1 hour.
The subjects t.hen repented t.he test but were instructed to "chain smoke"
by inhaling the smoke as deeply and as frequent,ly as possible, but
Ivithout coughing. Subjects snlokcd much more intensely than under
normal circumst~ancrs. The speed of mucocilary transport was sig-
Iiificantly higher durin, (r intensive cigaret,te smoking than when tlley
nere not smoking (P<O.Ol). These results differ from the results of
odier investigat.ors. The effect of the deep regular inhalation patterns
used during the period of heavy- smoking on clearance rates remains
uncertain.

Studies in Animals

Rylander (7~) studied the effect, of cigaret,te smoke on the clearance
of radioactively tagged particles and viable bacteria in t.he lungs of
111 experimental and control guinea pigs. The cle.arance of particles
lllPasures mucus transport whereas the clearance of viable bacteria is a
Ilartial indicator of phagwyt.ic a.ct,ivitJ. Inhalation of smoke from
l.igarett,es \yith varying levels of "tar" resulted in similar decreases in
ibotb the mechanical and bactericidal clearance. In each case, t,he me-
~,hical clearance appeared to be affected earlier t.han t,he bactericidal
I'learance. Jvhen phenylmethyloxadiazole (PMO) was added to the
~~~~Mcc.o~ neither the mechanical nor bact.ericidal clearance was affected
`5' cigarette smoke.

1)alhamn and Ry1ande.r (14) also reported that phenylvinyloxadia-
zok (PVO) and phrn~lmethyloxadiazole. (I'MO) , when added to
`Ol)WCO, were effective in reducing the ciliotoxic effects of cigarette
-llloke in in viva c,at trachea. preparat.ions.

Phagocytosi.3

R!lander (7%) studied the effect of acute and chronic exposure to
I r:\Wte smoke 011 the numt>er* of alveolar ~~uxroplqges in the guinea
i"rI. .\cute exposure to t.he smoke of five or more cipatMes. re&ted in

53


a significant (P~0.05) reduction in the number of alveolar macro-
phages. With more prolonged exposure to c,igarette smoke, an increase
occurred in the number of alveolar macrophages over control values.

The effect of nitrogen dioxide (KO,), a compound found in cigar-
ette smoke, on alveolar macrophapes in rabbits was studied by Acton
and Myrvik (I). Phagoc-ytir: activity and virus-induced resistance to
rabbit.pox virus were suppressed by esposure to 15 p.p.m. of NO, over
a a-hour period.

Bacterial a,nd Mycological Xtudies

The prevalence of fungi in the t,hroat was examined by Martin, et al,
(567 in a populat.ion of 365 male and 103 female European patients in
South Africa who were hospitalized for a variety of conditions. Throat,
swabs were taken shortly after admission and plated on appropriate
culture media. The yeasts isolated were Rhodotorula mucilaginosa.
Torulopsis glabrata. and seven species of Candida. h seasonal varia-
tion in prevalence. was noted with a decline in the winter and with
peaks in t.he spring and summer. Smokers of more than 30 cigarettes a
da.y had a higher prevalence of pharyngeal fungi than nonsmokers or
those smoking less than this amount. So effect of age or disease category
on the prevalence of pharyqeal fungi was found.

The bact,erial flora in respiratory tree secretions obtained at bron-
rhoscopg from `20'i patients with chronic lung disease and 48 controls
were characterized by Dobisova, et al. in a study from Germany (15).
So relationship was found between smoking or severity of respiratory
symptoms and the composition of the bacterial flora. They also reported
that smokers comprised 84.6 percent of those with chronic cough hut
only 58.3 percent. of the cont,rols.

The effects of nitrogen dioxide and cigarette smoke. on t.he retention
of inhaled bacteria wcreinvrstig~ted by IIenry, et al. (52). Male goldw
hamsters were exposed to an wrosol of Kle.bsiclla prwumoniar follow-
ing exposure to SO? and/or cigarette smoke. AI control group was ex-
posed to the pathogen without pretreatment. .Icutc rxposurc to ritlwl
SO, or cigarette smoke rcslllted in an increased mortality and de-
c~reascd survival time from Iilebsirlla infections. E:sposuw to both NO:
and cigaret.te smoke reduced the rate of clearance. of viable bacterin
from thr lungs to a greater extent than exposure to either substance
alone, The increase in lethal effects of Klebsiella exposure may hare
rcslllted from inhibition of the mucociliar~ transport system or reduc-
tion of phagocytic cal)acity of the alveolar macrophages.

54


The Surfactant System

Finley and Ladman (80) measured pulmonary surfactant in ciga-
rette smokers and nonsmokers. The surfactant was recovered after en-
dobronchial lavage. The lipid cont.ent of surfactant in smokers and
nonsmoke.rs was qualitatively similar; however smokers had on t,he
average only 14.5 percent of the surfactant levels found in nonsmokers.
Their levels of su.rfact.ant returned promptly to levels found in non-
smokers following cessation of smoking. Cigaret.te smoking may re-
duce the quantity of surface a&\-e material lining the alveolar walls
through either decreased production, an increased removal, or a dilu,-
tion wit,h mucus from the airways.

Summary of Recent Nonneoplastic Bronchopulmonary
           Findings

In addition to the summary presented in the introduction of this
r,hapter, based on previous reports of the health consequences of smok-.
itig, the following statements are made to emphasize the recent develop-
ments in the field :

1. Epidemiological and clinical studies from several countries con-
firm that cigarette smoking by both men and women is associated
with an increased prevalence of respiratory symptoms and de-
creased pulmonary function compared to nonsmokers.
2. The regular use of filter cigarettes is associated with less cough
and sputum production compared with the regular use of non-
filter cigarettes.

3. Cigarette smoking in combination with certain occupational ex-
posures is associa.ted with a higher prevalence of respiratory
symptoms and COPD than is observed with either cigarette
smoking or occupational exposure alone. Byssinosis is found more
frequently in cotton mill employees who smoke cigarettes than
in nonsmoking workers.

-j. Recent autopsy studies confirm that pulmonary emphysema is
much more frequent and severe in cigarette smokers than in
nonsmokers.

:. Several recent investigations have confirmed that cigarette smok-
ing exerts adverse effects on pulmonary clearance and macro-
phage. funct,ion.

55


Bronchopulmonary References

(I) AGPON, J. D., MYBVIK, Q. 2;. Nitrogen dioxide effects on alveolar macro-
   phages. Archiv-es of Environmental Health 24(l) : 48-52, January 1972.
(2) AKQ~~N, S., Cizotixt$ H. Smoking and lung function measurements, Aeta
   Medica Turcica 8 (1) : 3444, 1971.

(3) ALBERT, R. E., LIPPMANN, M., PETERSON. H. T., Jr. The effects of cigaret.te
   smoking on the kinetics of bronchial clearance in humans and donkeys,
   In: Walton, W. H. (Editor). Inhaled Particles III. Proceedings of an
   International Symposium organized by the British Occupational Hygiene
   Society, London, Sept. 14-23, 1970. Surres. England. Unwin Brothers,
   Ltd.;-The Gresham Press, 1970, pp. 165182.

(4) AUERBACH,~~., Hallr~ox~, I;. C., GARFINKEL, L., BENANTE, 0. Relation of
:- -  smoking and age to emph.vsema. Whole-lung section study. New England
    Journal of Medicine 2% ( 16) : K%`!-857, Apr. 20,1972.
(5) BATAWI, M. -4. EL Health problems of industrial workers in Egypt. In-
    dustrial Medicine and Sllrgery 41(2) : 1323, February 1972.
(6) BECKLAKE, M. R., FOURNIER-MASSEY. G.. ROSSITER, C. E., MCDONALD, J. C.
    Lung function in chrysotile asbestos mine and mill workers of Quebec.
    Archives of Environmental Health 24(6) : 401409, June 19'72.
(7) BLORMKE, M., DEPSER, R., GR~~NTZIG, A., KOSCHORRECK, B.. STEIZER, 0.
    Uber Unterschiede in der HemLungenfunktion und Befindiichkeit bei
    Miinnern mit verschiedenen Rauchgewohnheiter. (On differences in the
    heart-and-lung function and feeling healthy in men with different smok-
    ing habits.) Zeitschrift fiir Praventivmedizin 14(4) : 235-242, July-
    August 1969.

(8) BOUHUYS, A., WOLFXON, R. I,.. HORNER, D. TV.. BRAIN, J. D., ZUGKIN, E.
   Byssinosis in cotton textile workers. Respiratory survey of a mill with
   rapid labor turnover. Annals of Internal Medicine 71(2) : 257-269, Au-
   gust 1969.

(9) BBOWNINQ, W. H. Deleteriotm effects of cigarette smoking and 100 percent
   oxygen on aircrew members in high-performance aircraft. Aerospace
   ,Medicine 41(l) : 3942, January 1970.

(10) CAMNER. P., PJIILIPSOX, K. Trachetrbronchial clearance in smoking-discord-
   ant twins. Archives of Fmvironmental Health 25(l) : 6963, July 1972.
(II) CAMNER, P., PHILIPSON, K., L\~~~~~~~~, T. Cigarette smoking in man. Short-
   term effect on mucociliary transport. Srchives of Environmental Health
    23(6) : 421426, December 1971.
(1.9) CAMNER, P.. PIIILIPSON, K., FRIBERG,  I,. Traclieol)roncbial clearance in
    twins. Srchives of Environmental Health W(2) : 82287, February 1972.
(IS) COUDRAY, P., SERISE. Jl., FREOUR, P. Recherche epidemiologique sur les
   bronchites rhroniques et Ies insufb.sances respiratoires. etude de pi+
    valence dans un echantillrm de femmes de 30 a 70 ans. (Epidemiologic
   study of chronic bronchiti?; and rrspirator~ insufficiency. Prevalence in
    a sample of women 30 to 70 years of age.) Revue de Tnberculose et de
   Pneumologie 33 (6) : iGDSi80, September-October 1969.
(24) DALHAMN, T., RYLAXDER. R. Reduction of cigarette smoke ciliotoxicitg ly
   certain tobacco additives, American Review of Respiratory Disease
    103(6) : 355-35i, June 1971.

(15) DOBISOVA, ,\I., TRXKA, L., FISEX, F., TOXASEK. A. Ahbiingigkeit der mikro-
    biellen Flora im Bronchh~lbaum van der Bronchialsrkretion und den
   hustens~mpttnnen bei chronisch Lungenkranken. (Dependence of the
   bronchial secretion and cough symptoms on the microbial flora in the

56


bronchial tree of chronic lung disease patients.) Praxis der Pneumologie
25(5) : 249-254, May 1971.

(16) EGLE, J. L. Single-breath retention of acetaldehgde in man. .4rchives of
   Environmental Health 23(6) : 427133, December 1971.
(17) ELLEFSEN, P., Tos, M. Goblet cells in the human trachea. Quantitative
   studies of a pathological biopsy material. Srchives of Otolar~ngologS
   95(6) : 517-555. *June 1972.

(18) EVANS, >I. a.. STEPHENJB, R. J.. CABRAL, I,. J., FREEMAN, G. Cell renewal
   in the lungs of rats exposed to low levels of SO?. Archives of Enriron-

  .-.  mental.He~lth 24 (3) : lt?&188, March 1972.
<(.I&) FINGERLA~~, 3, HUSAK. T.. BENDLOYA. J. Cflntribution to the inwstiga-
    tion of the effect of cigarette smoking. Shomik Vedeckych Praci Le-
   karskr FiIkUltS KarloTT University v Hradci Kralove 14(2) : 221-233,
     1971.

110) FINLEY, T. fi., LADA~AN, A. J. Low yield of pulmonan surfactant in Ciga-
   rette smokers. New England Journal of Medicine 286(5) : 223-227,
   Feb. 3, 1972.

ief) FOURNIER. E.. ZIVY, P. Poumon et tabae. (Lung and tobacco.) Poumon
   et le Coeur 26(H) : 1109-1125, 1970.

18) FREEDMAX, S., FLEWHEX, C. M., FIELD, G. B. Effects of smoking modified
   cigarettes on respiratory symptoms and vrntilatorr capacity. Journal
   of the National Cancer Institute 48(6) : 1805-1810, June 1972.
`2.7) FICEOUR, P., COUDRAY, P. Le probleme des bronchites chroniques a Bordeaux
   et en Gironde. Etudes epidemiologiques. (The problem of chronic bron-
   chitis at Bordeaux and at Gironde. Epidemiological studies.) Bordeaux
   Medical 3( ?h ) : 1745-1779, July-August 1970.
`24) G~LLI, V. Etude epidemiologique des bronchopathies non specifiques.
   (Epidemiological  study of nonspecific bronchopathies.) Branches
   a(5) : 313-330, September-October 1970.
`25) GOLLI, V., L'Influence de l'usage du tabac et de l'emoussi6rage sur la
   ftiquence des bronchites chroniques. (The effect of the use of tobacco
   and the inhalation of dust on the frequency of chronic bronchitis.) La
   Presse MCdicale 78: 1542-1543, July 2EcAug. 1, 1970.
`?6) GOLLI Jr. STEF.~NIN, E., ST.0, R.. TURNESCU, B. Etude sur la prevalence
       7 I
   actuelle de la bronchite chronique dans une population urbaine. (Study
   of current prevalence of chronic bronchitis in an urban population.)
   Acta Tuberculosea et Pneumologica Belgica 60(5) : 714-725, September-
    October 1969.

`?:) GRACZYK, J., BUKALSKA, Z. Przewlekle zapalenie oskrzeli i ocena
   \vSdolnosci oddechowej u ozdrowiencow z gruzlicy. (Chronic bronchitis
   and assessment of respiratory function in convalescents after tuber-
   culosis.) Gruzlica i Chorohy Pluc 39( 7) : 61W15, .July X971.
""I GREGORY, J. A study of 340 cases of chronic bronchitis. Archives of En-
   vironmental Health 22(4) : 42.%4%, April X971.
.`!`I 1IAaER. J.. HORVATII, R., KISHIXDI KISS, K., PAL, I., SI~ION. Z., ZIB~TWS, H.
   h dohanyzas es felso leguti hurut koroki szerepe a Pecsi szenbangaszok
   kronikns bronchitiseben. (Smoking and upper airway catarrh as factors
   causing chronic bronchitis in coal miners from the city of Pers.) Orvosi
   Hetilap 112(233) : 13441:&R, .June 6, 1971.
"" ~~AOERUP, L., LARSEX, &!I. Tobaksrygning og respiratoriskr syml?tomer i en
  Dansk populatiou. Fra 50 ars undersogelseu i Glostrup. (Tobacco smok-
  lflg and rwl)iratory symptoms in a Wtnish prqmhtion. From R .-X-year
   stlldy in Glostmlx) I'geskrift for Larger 1X3(27) : l~W2-1Xs(wi. Jnly 9.
   1971.

57


($1) HABRIE, T. R., MERCHAXT, J. A.. KILBC'RN, K. H., HAMILTON, J. D. Byssino-
    sis and respiratory diseases of cotton mill workers. Journal of Occupa-
     tional Medicine 14 (3) : 199296. March 1972.
(8.3) HENBY, M. C., SPANGLER, J., FINDLAY, J., EHRLICH, R. Effects of nitrogen
      dioxide and tobacco smoke on retention of inhaled bacteria. In: Wal-
     ton, W. H. (Editor). Inhaled Particles III. Proceedings of an Inter-
    national Symposium organized by the British Occupational Hygiene
     Society, London, Sept. 14-23, 1970. Surrey, England, Unwin Brothers,
     Ltd., The Gresham Press, .1970, pp. 527533.
($8) HUNTER, M. B. Symptomatology. In: Key, M. M., Kerr, L. E., Bundy, M.
     (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Experi-
     ence, New York, Academic Press, 1971, pp. 57-69.
(84) H~TTEMAN, T., OSWALD, P., LODE, H., HVCKAUF, H. Veriinderungen der
     Lungenfunktion Jugendlicher als Folge langjiihrigen ZigareMenrau-
    chens. (Changes in pulmonary function of young people as a result of
     cigarette smoking over many years.) Deutsche Medizinische Wochen-
._-..- -.@h&ft 96 (46) : 1791-1793. Nov. 12, 1971.
( (35) INQBAM; R. H., Jr., O'CAIN. C. F. Frequency dependence of compliance in
`- ,---

    apparently healthy smokers versus nonsmokers. Bulletin de Physio-
   Pathologie Respiration 7 : 195-212, January-February 1971.
($6) JANCIK, E. Pneumopathies rhroniques non specifiques: Enquate epidemio-
   logique a Brno. Rapport prelminaire. (Chronic nonspecific lung diseases :
   Epidemiological investigation ; at Brno. Preliminary report.) Branches
   lS(2) : 185-199, Alarch-April 1969.

(37) JANCIK, E. Quelques don&es et correlations provenant dune Qtude epi-
    demilogique sur l'incidence des symptomes caracteristiques des maladies
    respiratoires chroniques non speciilques. (Some facts and correlations
    from an epidemiologic study on the incidence of symptoms character-
    istic to chronic nonspecfic lung diseases.) Revue de Tuberculose et de
    Pneumologie 34(5) : 749-752, July-August 1970.
(38) JANCIK, E.,  JANCIK-11~~. 11. Chronische unspezifische Lungenerkrankun-
    gen. (Chronic nonspecific I ung diseases. ) Praxis der Pneumologie vere-
    inigt mit "Der Tuberkulosrarzt" 2 6( 2) : 6981, February 1972.
($9) JONES, R., BOLDUC, P., REJU, L. Protection of rat bronchial epithelium
    against tobacco smoke. British 1Iedical Journal 2(5806) : 142-144, Apr.
    15, 1972.

(40) KEY, M. M., KERR, L. E., BXTNDY, >I. (Editors). Pulmonary Reactions to
   Coal Dust. .4 Review of U.S. Experience. Environmental Science Series.
   Sew York, Academic Prrss. 1971. 215 pp.

(41) KHOSLA, T. Indices of vmtilatory measurements, British Journal of Pre
   ventive and Social Jledirinc 25(4) : 203-209, Sorember 1971.
(@) KIRCHKNOPF, M., YOVAGO. 11. AZ idiilt. hiirghurut elofordulasa az Ozdi

   kohaszati iizemrk flnombrngrrmili dolgowi kiireben. (The incidence rate
   of chronic bronchitis among the precision calendering workers at the
   foundry of Ozd.) Orrosi Hetilal) llO( 44) : 258+2586, Nov. 2, 1969.
(4.3) KORNITZER, >I., DE~IEESTER, M. La symptomatologie respiratoire en epi+
    demiologio. Resultats de l'enquett~ effectuee dans une banque Bruxelloise.
    (Respiratory symlrtomatology in epidemiology. Results from a survey
   effected in a bank in Brussels.) Acta Tuberculosea et Pneumologica
   Belgica 61(5/6) : -iSl-566, September-December 1970.
(44) LAINHART. W. Y., MORGAN, \V. K. C. Extent and distribution of respira-
   tory effects. In: Key, 11. M., Kerr, L. E., Bundy. M. (Editors). Pulmonary
    Reactions to Coal Dust. A Review of U.S. ExlErience. New York. Aca-
   demic Press, 1971. B[J. 29-56.


145) LA~YGLASDS. .r. H. >I.. WALLACE. I\`. F. .\I., ~IxPSON, Jf. .I. f?. hSllkitiOII
   workers in Belfast. 2. Morbidity in men still at. work. British Journal of
    Industrial .\Iedicine %(3) : 217-25, .July 1971.
(4s) Law, S. L., HAXKISSOS, J. I,., BURGESS. D. B., O'BRIEX, R. Changes in
    rentilatory function in coal miners after a work shift. Archives of En-
    vironmental Health 24(3) : 26-208, March 1972.
I',;) LAPP. S. I,.. SEATOS, A., KAPL~S, K. C., HUSSAKEK, 11. R., MORG~S, TV. K. C.
   Pulmonaq- hemodynamics in s.vmptomatic coal miners. American Re-
   view of Respiratory Disease 104 (3) : 41s-LPO. September 1971.
($8) LATIMER, R. G., I)ICKM.~S. 11.. Dal-. I\`. c`.. GI-SS, JI. I,., SCIIJIIDT, f!. D.

7-enti1ator.v 1)attrms and 1mImonar.v wmplications after upper ahdomi-
nal surgery determined 1,s ltreoperative illlfl lmstolwratire computerized
spir0metr.v and 1110~~~ gas anal.vsis. American Journal of Surgery 122 i 5) :
622-632. Sorenlller 1971.

($9) LEE. D. H. K. Etiology. Iw: Key. 31. AI.. Kerr, I,. E., Bund~. AI. (Editors).
   Pu1monar.r Reactions to Coal Dust. A Review of U.S. Esperience. New
   Tork, Academic Press, 1971. 1)p. lS9-195.

(50) LIPPMANS, XI.. ALBERT. R. E.. PETERSOS, H. T., Jr. The regional deposition
    of inlialH1 aerosols in man. 171: Walton, W. II. (Editor), 1nh:~letl Par-
    ticles III. Proceedings of an International Sgtnl)nsium organized br the
    British OccuI~ational Hygiene Societ.v. Tmdrm. Sept. l&23. l!X'O. Surrey,
   England, Unwin Brothers, Ltd.. The Gresham Press, 1970. pp. 103-122.
(51) LOWE, C. R., KIIOSLA, T. Chronic bronchitis in es-coal miners working in
    the steel industry. British dournal of Industrial Medicine 29( 1) : 4%I9.
     1972.

(52) LYOSS, J. P., RYUER, R.. CAMPBELL. H., GOLWH. J. Pulmonary disabi1it.r in
    coal workers' pneumoconiosis. British Medical .Journal 1(5X02) : 713-
   716, Mar. 18, 1972.

(58) MCDONALD, J. c., BECKLAKE, 11. R.. FOURSIER-lIASSEY, G.. ROSSITER. C. E.
    Respiratory symptoms in chrysolite asbestos mine and mill workers of
    Quebec. Archives of Environmental Health 24(s) : 3W-363, Mar 1972.
(54) MCKERROW, (1. B., QCHILLIS~, R. S. F. A pilot enquiv- into bsssinosis in
    two cotton mills in the United States. Journal of the American Medical
   Association iii (12) : 85X+53, Sept. 23, 1961.
!s.i) JIANU, P.. DUMITRIU, >I., GIIISE, O., ConrasEscr. (`. (`ercetari el)idrmio-
   logice privind bronsita cronica la un lot din populatia generala a orasului
    Bucuresti. (Epidemiological studies on chronic bronchitis in a sample of
    the general population of Bucharest.) JIedicina Jnterna 22(!)1 : 1123-
    1134. September 1970.

(-56) ~IAKTIS. I'.. K~SAREK. D.. ZWI. S., Born, A. V.. K~ORSHOF, H. .T. The inci-
    dence of fungi in the throat. Mgcolmthologia et JIYcologia A%l)l)lic:ita 45
    (2) : 16~187, oet. 13, 1!)71.

(X' I J~A\~I~ESLEY-`~HO~~AS, I,. E.. HEALXY, I'., B.~RHY, D. II. Experimental hron-
    chitis in animals due to sullmur dioside and cigarette smol~e. An auto-
    mated quantitative studs. In: Walton. I\`. H. (Editor I Inhaled Particles
    III. Proceedings of an International S~ml)osium organized by the British
    ( Wupational Hygiene Society. I~~ndon. Sept. l-L-23, 1970. Surrey, Eng-
    land. J~nwin Brr)thers, I,ttl.. The Gresham Press. 1970. lq). 509526.
`.;h') lIERC'EI.4ST. J. Ai., IiII,HYRS. Ii. II., O'FALLOS. I\`. 31.. IhMILTOS. .J. D.,
    LU.\~SIXS. J. C. B.vssinosis and chronic Inwrmhitis amc)ilg cotton textile
    worlirrs. AtlllilIS of Internal Medicine X(3) : &X3--133. March 1972.
`.;9) lIlLLE:R. G. .J., i\SII(%OFT. 1I. T. A\ comnlunit~ surrf~y of rrsl)ir:rttrr~ disease
    among East Intlian ant1 .\friwn adults iii (:uay;)na. Thorax %( 3) : X31-
    338. Nay 1971.

59


(60) MITCHELL R. S.. MAISEL. J. C.. DART, G. A.. SILVEHS, G. TV. The nwura~p
    of the death certifiwte in reliorting cnusr of death in iIdllltS. with special
    reference to chronic bronchitis :tntl eml)hysema. American Review of
    ResDir;Story Disease 1M Cfi) : X+-X50, Dewmlwr 1971.
trill ;\IORGAN. 1V. K. C'., HVKQ~:SS. I). JS.. LAPP. N. I,.. SEATOS. A\.. REOER, R. R,
   Hyperlnflation of the lungs in NI:II miners. Thorax L%(J) : 5h.%590,
    Septemltier l!)Tl.

(62) NAEYE. R. J,. Structural features in Alq)alnchinn con1 workers, Zn: Key.
    AL. 11.. Kerr, I,. E., ~undy. 11. (Editors I. Pulmowr;\ Keartions to (`oal
    Dust. A Review of U.S. E:sl~erirnce. Sew York. Academic Press. 1971,
    -pp.93-110.

, (/C'S) NAEYE, R. I,., DELHSGER. `W'. S. Pulmonary nrtrrial ch::nges with z~pe and
-.

   smoking. Lirrhires of Pathology *`L(4) : 2X1-%%, October 1971.
(64) ~WSINSKI. 6.. .JANu~, 'l`.. MYSTIK, AI. Wystgwwanie l~rzemleklych nies-
    woistych choroh nkladu oddechowego (IJ.n.ch.u.r). ) wrod l~racownikoa
    zaklatlu przemgslu giDso\vego "Dolin? Uidv" w Gnckaclr. (Occurrence
                                 c- .
    of chronic unsI)ecific diseases of the resI)iratory sgstrm among workers
    in the plaster works at "Dolinn i%idy" in Garki.) Przeglad J,ekarski 2~
    (i) : 17C%SO. 1971.

(65) PANDE, pi. S.. MARW~I~A. R. K.. PATEL, N. .\I. Smoking :11x1 lung function.
    Indian I'rartitioner 1 (i) : 3.53-357, July 19il.
(66) RACOVEASU, C.. .\IANICATII)E. 11.. SICOLAESCI-. V. Cerwtari r~~idrniiologice
    :\supra I\ronxitei croniw in duoa zone f;lra l)olunre :ttmosferiw indus-
    trial& ( ElJidemiological study of chronic bronchitis in two regions with-
    out industrial air lwllutinn.) Studii si rerwtari dr .\Irdicin;t Interna
    X2(4) : 359-367.1971.

(67) REOAX, G. 31.. TAGQ. JL. \V.~LFORI), J.. THOMSOS. ,\I. J,. Thr relative imI)or-
    tance of ~liniral. radiological, and lmlmonnry function vurial)les in eral-
    rmting nsbestosis and chronic obstructive airway disrnsr in ;lsbestos
    workers. Clinic%1 Scienw -kl : 56~5%. 1971.

(68) REICHWI., G. Effect of air lrollution on the Prevalence of respiratory dis-
    PHSW in West (;erln;ln~. In: England. Il. 11. Beerr, W. T. (Editors).
    Proceedings of The Second Internatirrm~l (`lean Air Congress. Washing-
    ton, D.V.. Dw. e-11, 1970. Ac;tdemic Press. Sew York, 1971. 1~1~. l%-191.
(69) REICHEL. G., lT~~~~~. W. `I'., IKOS-OXIDES. S. 2. Einfliisse der Raucherge-
    wohnheiten auf die IIhdlgkeit unslwzifischer Atelii~~egserkr:lrikn!Igrn.
    III. Mitteilung. (Influence of smoking hal)its cm the inctidenre of non-
    sl)erific respiratory dist*nses.  III. (~ornmlunirntion.) Internntitmnlr
    Archir fiir Airlwitsnlrdizin 2i (l/2) : -i!biZ, Oct. 30, 1970.
(711) REID, D. D. Ilronc,hitis among the British. Israel .Journal of Medical
    Werices 7( 12) : l~i@L1572, December 1971.

(7'1) RIMIXGTOS, $1. Phlegm nrtd filters. Rritish Medical .Tournxl 2(58OS) :
    262-%A, Apr. ,"), 1972.
17.2) HYLASDEE. R. Free Iung cell studies in cigarette smoke inhalation es-
    lwriments. Scandinavian .Jwrn:ll of ReslJiratory Diseases 52(Z) : 1%
     12X. 1971.

(7.f) RYIASIJEH. R. J,r~ng (~l(~nr:~nc~e elf llarticles and bnvteria. ICffects of cigarette
    smoke eslJosure. Archirw of I*:nvirnnmental Health 23(C) : 321-326.
     ~S~~vemtwr 1!)71.

l?i I Sast 111s. .1.. Do~ovrcII. 11.. ('HALVERS, Ii., SEWIIOI~SE. 31. T. Regional
     tli*trilliltillll ;lntl lllnr 1~lt5ltxncv niwli:rnism~ in smnkvrs :ind nom
    winkers. 2~: Walton, W. 1-I. I Editor). Inlmled I'articles III. l'rweedings
    of an Interiinticbnal S.rmlwaium organized by the Uritish Occupntional

60


   Hygiene Society, London, Sept. 14-23, 1970. Surrey, England, Unwin
   Brothers, Ltd., The Gresham Press, 1970. pp. 183-191.
(75) SCHF~AG, P. E., GULLETT, A. D. Byssinosis in cotton textile mills. American
   Review of Respiratory Disease lOl(4) : 497-503, April 1970.
(76) SEATON, A., LAPP, N. L., MORGAP~, W'. K. C. Relationship of pulmonary
   impairment in simple coal workers' pneumoconiosis to type of radio-
   graphic opacity. British Journal of Industrial Medicine 29(l) : 50-55,
     1972.
(77) SHERWIN, R. P., DIBBLE, J., WEINER, J. Alveolar wall cells of the guinea
    pig. Increase in response to 2 p.p.m. nitrogen dioxide. Archives of En-
    vironmental Health 24 (1) : 4347, January 1972.
(78) SOBONYA, R. E.. KLEISERJIAN, J. Jlorl~hometric studies of bronchi in
   young smokers. American Review of Respiratory Disease 105(5) :
   768-775, Xay 1972.
(L?) STANESCU,II). C. Age and smoking dependency of the single-breath oxygen
  - - ---7--~

   test in health)- subjects. Pneumonologie l-IT(l) : 46-51, 1972.
(80) STEPHENS, R. J., FREE~~AX, G., EVASS, 11. J. Early response of lungs to
    low levels of nitrogen dioxide.  Archives of Environmental Health
    24 (3) : X0-179, March 1972.

(81) SYZGANOV, A. N., GOLO~I~, Y. A., TIWITSKAYA, T. G. 0 rliranii tabachnogo
    dyma pri kurenii na organr dgkhaniya v eksperimente. (Experiments
    on the influence of tobacco smoke on the respirators organs during
    smoking.) Eksperimental'naia  Khirurgiia i Anesteziologiia 16(6) :
    2326,1971.

(88) SZYMCZYKIEWICZ, K. E., KUSSKI, H., GIELEC, L. Clinical evaluation of the
   respiratory system in cotton workers. Bulletin of Polish Medical Science
   and History 13 (3) : 110-114, Juls 1970.

(83) TECULESCU, D. B. Validity, variabi1it.v. and reproducibility of single-
    breath total lung capacity determination in normal subjects. Bulletin
    de Phgsio-Pathologie Respiratoire 7 (3) : 645-658, IfaJ--June 1971.
(84) TF.CULESCU, D., STANESCU, D. Ventilatia si misica pulmonara la barbati
    tineri sanatosi, fumatori si nefumatori. (Pulmonary ventilation and
   distribution in young healthy males, smokers and nonsmokers.) Studdi
    si Cercetari de Medicina Interna 5 (11) : 419423,197O.
(85) TSUN~VSHI, Y., SHI~~IZU, T., TAKAHASHI, H., ICHINOS~~A, A., UEDA, M.,
  NAKAYAMA, N., YABLAGATA, Y., OHSHINO, A. Epidemiological study of
    chronic bronchitis with special reference to effect of air pollution.
    Internationales Archir fur Arbeitsmedizin 29 (1 j : l-27,1971.
(86) ULMEB, 1%`. T. Emphysema of the lung: Clinical and experimental investi-
   gations of its pathogenesis. Geriaterics : 25(5) :  161-165, 168-169,
-.zaay 1970.
($"W. T. Lung function studies in epidemiologic investigations of
    respiratory diseases. Bulletin  de Phxsio-Pathologie Respiratoire
   6 : 6&-616,1970.

(88) UL~WXR, W. T., REICHEL, G. Zur Epidemiologie der chronischen Bronchitis
   und deren Zusammenhang mit der Luftverschmutzung. (A contribution
    to the epidemologv of chronic t,ronchitis and to its relation to air
   pollution.) Deutsche Mrdizinsche Wochenschrift 95(51) : m9-2554,
    Dec. 18, 1970.

(89) ULRICII, L., ~~AI.IK, E. Chronic bronrhitis in agricultural and chemical
   workers. Arhir za Higijrnu Rada i Toksikologiju 21( 1) : 3.5-47, 1970.
'$0) U.S. DEPARTVENT OF 'TRANSPORTATION. $%X,ERAI. i\5'1,4TI(,S .~~)~~ISISTR.~TIO~.
   T!.s. I)bX'AliTlIEXl. OF Hs~1.1.11. I.:I,I~(~Al.IO~. AS,, \VEI.I.AK,:. Na',`I(,X,iI.
   INSTITI'T~: FOR Oc~cr~r.~l'~ox~r. SAFETY .4sn HEAI,TH. TIwltl, .\slwts of

61


(91)

(92)

(9.3)

(91)

(95)

(96)

(97)


(98)



(99)



( 100)

Smoking in Transport Aircraft. U.S. Department of Healt.11, Education,
and Welfare, Public Health Service. Health Services and Mental Health
Administration. Sational Institute for Occu]rational Safety and Health,
Rockville. Md., AD-73fOQ7. December 1971, 85 pp.
U.S. PUBLIC HEALTH SEWICE. Smoking and Health. Report of the Advisory
Committee to the Surgeon General of the Public Health Service. Wash-
ington, U.S. Department of Health, Education, and Welfare, Public
Health Service Publication So. 1103, 1X%, 387 pp.
U.S. PCBLIC HEALTH SEKVICE. The Health Consequences of Smoking. A
Public Health Service Review: 1967. U.S. Department of Health, Edn-
cation, and Welfare. Washington, Public Health Service Publication
No. 1696, Revised January lQ&S, 227 pp,
U.S. PGTBLIC HEALTH SERIICE. The Health Consequences of Smoking. 196s
Supplement to the lQ67 IW1lic Health Srrviee Review. U.S. Department
of Health, Education. and Welfare. Washington, Public Health Servire
Publication 16Q6, 196x, 117 pp.
U.S. PUBLIC HEALTII S.ERWE. The Health Consequtwws of Smoking. 1989
Supplement to the lQG7 Public Health Service Review. 1i.S. Department
of Health, Eduration. and Welfare. Washington. Public Health Service
Puhlicatinn lti!W-2, l!HiQ). QX iq1.
U.S. PUBLIC HEALTH Stxvrre. The Health Consequenc~es of Smoking. A
Report of the Surgeon General: lD71. U.S. Department of Health, Edu-
cation. and Welfare. Washington, DHEW Publication So. (HSJI) 71-
7513, 1X1, 458 pl1.
U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Report of the Surgeon General: 1072. U.S. Department of Health, Edu-
cation, and Welfare. Wasl1ington. DHE\V I'ul1liration So. t HSM) 7%
&5X, 1972, 153 pp.

VALIC, F., STAHCLJ~IC, 11. B. Kronicni hronhitis U pekara. (Chronic hrnn-
chitis in Ipakers.) Lijecnic~ki Vjesnik Q3t 7) : 7329-748, 1971.
VAN GAXSE, W. F., FERRIS. Ii. G.. *Jr., COTES. J. E. Cigarette smoking and
pulmonary diffusing c.aI)acity (transfer factor). American Review of
Respiratory Disease 105(I) : R&-41. ,January lQ72.
WALKER, D. D., ARCHEL~LD, 1~. JI., ATTFIELD, M. D. Brornhitis in men
employed in the coke industry. British dournal of Industrial Medicine
t's(4) : 358-363, O(toher 7Q71.

YOKOYAMA, K., PERA, Y.. Kor~snrrrc~. T.. MAT~UMOTO. T., SAGOSHI, S..
hsaar. T., SAKAI. II., Hrw.ina, K. 1IanSei kikanshien no ekigakuteki
kenkyu. (El1idemitdogical survey of cl~rtrnic l1ronehitis.) Ir.v11 24(2) :
10.5-114, Frlumary 1970.

ZI~Y, I'. I*% l1nenn1othon1 s spontanG dea fumrurs. 1.e l1ounion tal1nglclur.

Tabaglsme alveolaire et troubles metaholiques. (Sponta11eous pneumo-
thorax of sml1kers : t1)lM(Y'O lung : alveolar nicotinism a11d 111etaI)olic
disorders.) Revue de Tuherculose et de Pneumologie 34(l) : 125-153.
1970.

62


CHAPTER 3

Cancer


Contents

Page

Introduction-_-_-------------------------------- --------    67
LungCancer__-______________________________----------- 68
Epidemiological Studies- _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ - - - _ _ _ _ _    68
Es-Smokers_- -__________________ --- ___________ - _____    71
Uranium Mining and Exposure to Radioactivity.. _ - - - _ _ _ _ _    72
Air Pollution---------------------------------------- 72
Asbestos___-________-------------------------------- 73
Autopsy and Cytological Studies------- _____ --_-_-- _____    73
OralCancer------_--------------------- ____ ---- ____ ---_    74
Cancerof theEsophagus_-- _______ ---_- _____ ---_---__-___    76
Cancer of the Larynx------------------------------------    76
Cancer of the Pancreas------------------..---------------    77
Cancer of the Kidney and Urinary Bladder------------_----    77
Experimental Carcinogenesis-_---------------------------- 78
Respiratory Tract Carcinogenesti- _ - _ - _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _    78
Experiments in Mice----- ____ ----_-- ____________-____    80
Aryl Hydrocarbon Hydroxylase (AHH)-- _ _ _ _ _ _ _ _ _ _ - - - - -    82
  Cell and Tissue Culture Studies- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - - - -    84
Binding of Polycyclic Hydrocarbons to DNA and RNA- _ _ _    86
  N-Nitrosamines in Tobacco Smoke ____ - _ __ _ _ _ _ _ _ _ _ _ - - - - -    87
Yummary of Recent Cancer Findings-------------------w--    88
References---- _______ -_-__-- _____________-_____--------    88

List of Figures

Figure l.-Standardized lung cancer mortality ratios of
Jltpanese by number of cigarettes smoked (1966-70) _ _ _ - - - -    69
Figure 2.-Lung cancer mortality ratios of Japanese by age
at initiat,ion of cigarette smoking (1966-70)--_ _-_ _ _-_ _ _-- -    69
Figure S.-The survival of ex-smokers and cont,inuing smokers
who were treat*ed for a primary cancer of the oral cavity,
pharynx,orlarynx--- ______ ----___- ____ _______-_ ----    7.5

65


List of Tables

Page

Table l.-Age-standardized lung cancer death rates of British
physicians and the population of England and Wales at
various time periods-- ______ - _________ - _____ - _____ ---__    70
Table 2.-N-dimethylnitrosamine (DANA) content of con-
densates obtained from :several tobaccos grown in both
"high" and r`lo~v" nitrogen soils_-- ___________ -_--__-_-_-    87

66


Introduction

This introduction is a brief summary of the major relationships
between smoking and cancer which have been established in previous
reports on the health consequences of smoking (91, %`,93,94,95,96).

Cigarette smoking has been clearly identified as t,he major cause of
lung cancer in the United States. This conclusion is based on detailed
apidemiological, clinical, autopsy, and experimental data which have
accumulated over a period of more than 20 years. For both men and
women, the risk of developing lung cancer is directly related to total
exposure to cigaret,te smoke as measured by the number of cigarettes
smoked per day, the total lifetime number of cigarettes smoked, the
duration of smoking in years, the age at initiation of smoking, the
depth of inhalation of tobacco smoke, and the "tar" and nicotine levels
in the cigarettes smoked, Lung cancer death rates, however, are lower
for women than they are for men, a finding due, in part, to a difference
in exposure. Women smokers use fewer cigarettes a day, choose filtered
cigarettes with lower "tar" and nicotine values, and also tend to inhale
less. However, even when women experience comparable levels of ex-
posure to cigarette smoke as men, their mortality rates for lung c,ancer
still remain somewhat lower.

Those who stop smoking experience a decline in the risk of develop-
ing lung cancer relative to continuing smokers. The air pollution
commonly found in an urban setting appears to result in elevated lung
cancer death rates; however? t,his effect is relatively small compared to
the overriding effect of cigarette smoking.

Certain occupational exposures have been found to be associated
with an increased risk of dying from lung cancer. Cigarette smoking
interacts with many of these exposures to produce much higher death
rates from lung cancer than would result from one exposure alone.
Interact.ing exposure factors may be experienced simultaneously or at
different times. The uranium mining and asbestos industries are exam-
ples of occupations in which this interaction occurs.
The bronchial epithelium of smokers often shows premalignant
changes including squamous metaplasia, atypical squamous metaplasia,
ancl carcinoma in situ.

Pipe and/or cigar smokers experience a risk of developing lung
cancer that. is higher than the risk of nonsmokers; howrver. it remains

195~(128 O-73-6

67


significantly lower than the risk of cigarette smokers. A more complete
discussion of the risks from pipe and cigar smoking is found in
another chapter of this report.

Epidemiological, e,xperimental, and aut.opsy data have demonstrated
that cigarette smoking is a significant. fact,or in the development of
cancer of the larynx, oral cavity. esophagus? and urinary bladder.
B-naphthylamine, a carcinogen known to cause cancer of the urinary
bladder in humans! has been identified in cigarette smoke. There is also
an association bet,ween cigarette smoking and cancer of the pancreas.
Experimental studies with animals in which cigarette smoke or one of
its constituent compounds is administered in a variety of assays have
confirmed the presence of complete carcinogens, cocarcinogens such as
tumor initiators and tumor promoters. and tumor accelerators in
cigarette smoke.

Recently, additional epidemiological, autopsy, and experimental
studies have added bo our understanding of these relationships.

Lung Cancer

An ongoing prospective ep-idemiological study conducted in Japan
provides a unique opportunity to examine the relationship of cigarette
smoking to death rates in a populat.ion with genetic? dietary, and
other cultural differences from previously examined Western popula-
tions. Hirayama (37) has now reported 5-year followup data on
265,118 me.n and women aged 40 years and older. This represented 91 to
99 percent of the total populal-ion in the area of the 29 health districts
where the study was conducted. A total of 11,858 deaths occurred dur-
ing the 5-year period which included a total of 1,269,382 person-years
of observation. Both men anal women who smoked cigarettes expe,ri-
enced higher death rates from lung cancer than nonsmokers. Among
smokers, the lung cancer mortalitv ratio was 3.85 for men and 2.44 for
women as compared to nonsmokers (P<O.OOl) . Ijose-response relation-
ships were demonstrated for the number of cigarettes smoked per day
and the age at initiation of smoking (figs. 1 and 2). These mortality
ratios are considerably lower than those reported for the I'nitetl States.
(`anada. ant1 Great 13ritain3 and maI reflect a lower average number of
cigarettes smoked a day, au older age, at initiation of smoking. or re-
tluced inhalation of cigarette ,smoke among the Japanese. In spite of
thew tliffercnces. the overall wsults of this study. including the dose-
I'esponse relationsl~i~~s , arc similar to the results of all the other nlajor


rl~idemiological investigations. Thus, the reliabilit,y and accuracy of the
lnethods of population select,ion and analysis used in previous st.udies
based on population samples, and the conclusion that cigarette smok-
ing is t,he major cause of lung cancer are agaiu confirmed.

Figure 1 .-Standardized lung cancer mortality ratios of Japanese by number of
     cigarettes smoked (1966-1970).

9.0

8.0

7.0

6.0

5.0

4.0

3.0

L                            7.8

c            3.6

lJTzl-b
     1.0

2.0

1.0

0

          Non.
         smoker

SOURCE: Hlrayama, T. (37).

1-14     15-24    x4      Ex-
  cigarettes per day         smoker

Figure 2 .-Lung cancer mortality ratios of Japanese by age at initiation of
     cigarette smoking (1966-1970).

5.0

4.0

3.0

2.0

1.0

0

Non-      >25      ~24      <19
smoker       Age at initiation of smoking

SOURCE: Hirayama, T. (37).

69


TABLE 1 .-Age-standardized lung cancer death rates of British physicians
and the population of England and Wales at var';ous t,ime periods

Lung cancer standardized death rate per 1,ooO men per year in-

                                  Doctors        England and Wales
                            ---_I_-__ ---I_--__
Years ._........ . . . . . . .._.._......._..._ . . . . . ~... 19E3-57  19574  1961-65  1954-57  195W31  1962-65

Deathrateper 1,000._----- __... --_-. 1. 10 0.85 0.83 1.49 1.71   1. 88

Source: Doll, R., Pike, M. C. ifs).

Kennedy (45) studied primary lung cancer in 29 men and 11 women
diagnosed before the age of 40 and found a strong associat,ion between
cigarette smoking and the development of this disease.

Boucot, et al. (11) further characterized the 121 cases of lung
cancer detected in the population of the Philadelphia pulmonary
neoplasm research project,. The risk of developing lung cancer in-
creased with age, was higher in nonwhites than in whites, and increased
sharply with increased cigarette consumption.

The relationship between cigarett,e smoking and lung cancer was
investigated in a retrospective study by Ferrara (25) in La Plata,
Argentina. The smoking habi'ts of 144 lung cancer patients were con-
trasted with those of 386 controls. A dose-response relationship was
found between cigarette usage measured by the number of cigarettes
smoked per day and the duration of smoking and the risk of developing
lung cancer.

A high incidence of lung cancer is reported from the island of
Jersey in the Channel Isles compared to England and Wales. The
island has no heavy industry and only minimal levels of air pollution.

;i i-`i Cragg (16) studied 144 patients who developed lung cancer on Jersey
   during a 4-year study period. Only three nonsmokers were found
   among the 113 patients for whom histories were available.

Fingerland, et al. (.%`G) determined the prevalence of lung cancer
and certain other diseases in an autopsy series of 1,338 adults in
Czechoslovakia. Some 198 cases of primary lung cancer were identified.
In the autopsy population,, 1.4sercent of the nonsmokers? 14.1 percent
of those smoking less than ?f `I O&O00 lifetime cigarettes, and 33.3 pe.rcent
of those smoking more thaII 500,000 lifetime cigarettes had lung
cancer.           ?1 FL\
Rickard and Sampson (71) studied 94 Negro patients with lung

cancer in Washington, B.C.! and found that 57 (92 percent) of 63
patients whose smoking history was available were regular smokers.

Epidemiological studies conduct,ed in Italy (IO), Sweden (48),
Poland (46)) Russia (&), Cuba (73), Mexico (13), and the Nether-
lands (98) demonstrate an association between cigarette smoking and
lung cancer.

70


Berg, et al. (5) examined the incidence of recurrent primary cancers
following initial primary cancers of the respiratory and upper di-
gestive systems in Eew York. During 83,802 man-years of observation
in 9,415 patients with an initial squamous cell cancer, 518 second
cancers developed at other sites. Patients whose first primary cancer
was in the lung had an observed to expected relative risk ratio of 5.7
(P<O.O5) for- subsequent cancers of the respiratory or upper GI
system. Patients with the first cancer in the oral cavity or larynx
frequently developed a second cancer in the lung. Medical records
confirmed long smoking histories among almost all of these patients
do developed second cancers.

Cancer of the lung, oral cavity? larynx, and esophagus were reported
by Schmidt and De T,int (79) to be common causes of death among
6,578 men and wonwn who had received treatment for alcoholism in
Toronto. The. authors attributed this finding to the strong assocGa-
tion that, exists between alcohol and tobacco use and not to the effect of
alcohol alone.

Carcinoma of the trachea is a relatively rare condition with only
about 400 cases having been reported in thr literature. III a study of 41
patients with carcinoma of the trachea, Hajdu, et. al. (32) found an
apparent association bet.wectn cigarette smoking and the development
of epidermoid cancers of this structure.
An association betwern cigarette smoking and the development of
bronchiole-alveolar carcinoma in 71 pat ielrts w-as described by Delarue!
et al. (18).

Ex-smokers

Those who stop smoking experience a decline. in the risk of develop-
ing lung cancer relative to continuing smokers. Doll and Pike (-On")
i*onducted a study of the smoking habits and causes of death of 40,000
British physicians. Smoking habits were surveyed in 1951, 1957, and
l!KXi. I)urinp the study Iwriwl, II~OI`E than 3,;iOO physicians 1)ecanie ex-
~lokers. The a:re-stalltlar.dizrtl percentage of es-smokers anlong phy-
sicians 35 to 6-i years of age rose, from 18.1 percent in 1951 to "6.5 per-
wit in 19% and 29.5 I)ercent in l!Nti. (`oncurrently, the percentage of
physicians smoking vigawttcs fthll from 44.1 lwcrnt~ to 2~0 percent.
nhilr over t,he siinir Iwriotl estitimtrs of the per capita cigarWe con-
;mnption for the adult male Iwpulation in tbc 1-nited Kingdom sug-
Zrste(l a slight increase in cigarette con~unlI)tion. Over this l.i-year
period, the mortality f ronl lung caiicei~ among physicinnS dropped con-
5iclcrxMy while lung cancer dcatll rates among the male I)opulat.ion in
F:ngIantl and Wales incrcasetl to sonic extent (table 1 j. -ilthougIi ccr-

71


tnin limitations apply to the interpretations derived from secular data,
analysis of the study design and the magnitude of the results indi-
cate that, this stntly constitut-es important evidence of some of the bene.
tits t.hat result, f ram the cessation of cigaret.to smoking.

Epidemiological evidence supported by autopsy studies has estab-
lished that airborne radiation. particularly in synergistic combination
with cigarette smoking, is the major cause of the excess of respiratory
cancers among uranium miners.

Lundin, et al. (53) considered quantitative and temporal aspects
of radon daughter exposure and respiratory cancer in a report from the
Epidemiological Study of Tlnited States T-ranium Miners. They ob-
served a st,atistically signific,ant excess of respiratory cancer a1no11g
white uranium miners at each cnn~ulative radiation exposure category
down to and including 1204~9 WL1\I (working level months). The
authors noted that' although cigarette smoking alone entailed a risk of
the development of cancer o-f the respiratory tract, in miners just, as
it does in nonmincrs, cigarette smoking in combination with radon
daughter exposure appeared to result in an CVEII greater risk.

Several aut.hors (30,JJ. K?. 84. 104) continlle to report the presence
of polonium-210 or one of the thorium isotopes in tobacco leaf, tobacco
smoke, or the lungs of smokers.

Ah Pollution

Data standardized for cigarette smoking indicate the existence of an
urban factor in the development of lung cancer: it is likely that air pol-
lution, frequently part of tile city environment, is a component of the
urban fact.or.

The Kational .Icademy of >iciences published a revirw (61) of the
biolog.ical effects of utmospllrric pollution by 1)articulate polycyclir
organtc matter. Detailed epidcmiologicnl, exl)erimental, physical, and
chemical data were reviewed. It ~--as concluded that air pollution, as
commonly found in urhnn settings, was found to bc associated with in-
creased lung cancer mortality in cities. An examination of the data
presented, however, indicates that cigar&e smoking is, in most cases,
the overriding factor in the drvelopment of lung cancer. Polvcvclic
hydrocarbons and related com~)ounds which are known to cause`cancer
of the lung and other organs in experimental animals were found to

71


be present in relatively high concentrations in cigarette smoke, in large
quantities in the air of industries iu which workers have high-lung
cancer rates, and also in the air of urban communities.

Sterling and Pollack (86) reviewed the etiects of air pollution on
death rates from lung cancer. They suggested that particles resulting
from the combustion of organic fuels may br more strongly related to
the incidence of lung cancer in the population than cigarette smoking.
The cumulat,ed epidemiological data regarding cigarette smoking and
lung cancer were not. considered by the authors in this report.

Asbestos

Cigarette smoking asbestos workers havr markedly elevated lung
cancer death rates compared to nonsmoking asbestos workers. 1)err.y
(6) examined the combined effect of asljcsto-: exposure and smoking on
mortality from lung cancer among 1,400 nralr and 480 female asbestos
factory workers over a lo-year period. Tllerc was no significant in-
crease in lung cancer mortality among smoking or nonsmoking workers
with a low-to-moderate exposure to asbestos. However, among smokers
who had heavy exposure to asbestos, 32 lung cancer deaths occurred
among 663 men (9.8 expected), and there were 18 deaths among 292
women (1.4 expected). This confirms the greatly increa.sed risk of de-
veloping lung cancer among asbestos workers who smoke cigarettes.

Autopsy and Cytological Studies

The respiratory tract of cigarette smokers examined at, autopsy fre-
quently demonstrates cpithelial changes considered to be precursors of
bronchogenic carcinoma. Such changes include squamous metaplasia,
atypical squamous metaplasia, and carcinoma in situ. Herrold (35)
studied histologic types of prinlary lung cancer in 1T.S. veterans who
were subjects of the Darn study. Of a total of 2,241 white male vet-
erans who died of lung cancer over an 8-year pwiod. histologic mate-
rial was available for review in 1.177 patients. Histologic t.ypes were
grouped according to the Kreybcrg classification of Groups I and II
tumors. Group I tumors, rpidcrnloid and oat-cell carcirromas. were
prweiit, in Y7.3 pc>rccnt of the 5.; nonsmo1wrs and were prewnt in 57.1
percent of the li'2 "currout sn~ol~r~~s of cigarettes only." The ditferencr
We statisticbally signiticant (P<O.OOl). confirming tllc strong associa-
tion between (bigarrtte smoking and Iircyberg Groltl) I tumors.

73


Auerbach et al. (2) examined epithelial changes in the bronchial tree
of 456 men and 302 women who had died of a cancer other than lung
cancer. There were 72 ex-smokers among the men, all of whom had
smoked for 10 years or more but had quit smoking for at least 5 years
prior to deat,h. Atypical cells were present in 93.2 percent of the current
smokers, 6.0 percent of the ex-smokers, and 1.2 percent of the non-
smokers. Areas of epithelium composed entirely of atypical cells devoid
of cilia were found in the bronchial tree of 8 percent of the current
smokers, 0.2 percent of the ex-smokers, and none of the nonsmokers.
Unusual cells with disintegrating or fading nuclei were found exclu-
sively in 15 percent of the ex-smokers.

The prevalence of atypical cells (hyperplastic and metaplastic) in
the sputum of 122 male and 1.28 female lvorkers was examined by Rob-
bins (72). These smokers, all under the age of 19, were matched wit,h
a control group drawn from a population of college students. Atypical
cells were found in 14 percent of the smokers and 5 percent of the non-
smokers.

Oral Cancer

Data from the large Japanese prospective study by Hirayama (37)
indicate that mortality rates from cancer of the oral cavity among
males are higher in smokers than nonsmokers. A dose-response rela-
Gonship was demonstrated for the age at initiation of smoking. The
standardized mortality ratio among cigarette smokers \vas 10.0 for
men (PCO.001) and 1.22 for wonlen compared to nonsmokers. These
ratios are not stable due to the few deaths that occurred from oral can-
cer in this study.

Certain relationships be,tween cigarette smoking and cancer of the
oral cavity, pharynx, and larynx were investigated by Moore (59).
Over a IS-year period, 1,000 patients wit11 invasive squamous carci-
noma at these sites were treated in Kentucky. Of these patients, 208
had a history of cigarette smoking and had had no recurrence of
cancer for a period of ~3 years l)r more. This group was further divided
on the basis of current smoking habits. Of the 122 who continued to
smoke, -IS (10 percent) evcntllnlly de\-eloped a second cancer at. these
sites, whereas only five (6 percbent) of the 81 who stopped smoking de-
veloped a second maliplancy. This sixfold difference is statistically
significant (P<O.OOl). The survival curves for these two groups are
presented in figure 3.

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Figure 3.-The survival of ex-smokers and continuing smokers who were treated
     for a primary cancer of the oral cavity, pharynx, or larynx.
  100

80

20

10

0

o---4 Ex-smokers
- Continuing Smokers

I                                       I

3    4    5    6    7    8    9    10    11   12    13

              Follow-Up (yr)

SOURCE: Moore, c. (591.

Martinez (57) studied the relationship between smoking in various
forms and cancer of the oral cavity in a retrospective study of 153
patients with this disease. Dose-response relationships were demon-
strated for the amount smoked; the amount of alcohol consumed, and
the development of cancer of the oral cavity.
Tyldesley (90) examined the prevalence of leukoplakia among 402
English coal miners of whom 280 smoked and chewed tobacco. Tobacco
chewing was commonly found to be a substitute for smoking in under-
ground conditions where smoking was impossible. Leukoplakia \vas
found in 3.6 percent of the chewers. whereas no leukoplakia was found
among the nonchewers.

Nelson and Ship (62) determined the relative influence of eight
variable fact.ors on the development of oral cancer in relation to age
at the onset of disease in a population of 191 patients with a confirmed
diagnosis of a primary squamous cell carcinoma of the oral cavity.
The factors considered included age, sex, race, consumption of alco-
1101 and tobacco, certain systemic diseases, and oral trauma. The
Prevalence of heavy tobacco use was more common among the younger
Patients. While 91 percent of the cancer patients under the age of 45
smoked more than 20 cigarettes a day. only 59 percent of the patients
orer 65 smoked this heavily.

75