T,ong-term continuous oxygen therapy in hypoxemic patients with
chronic airwy ol&ruct.ion has been noted to have a beneficial effect
of reducing pulmonary arteriolsar resistawe (30) .

It, is lwrtinent to note at this point that there is a developing body
of experimental evidence discussed in previous Reports and in this
c1mpte.r t.hnt cigarette smoking may have acute delet-erious effe&s on
airway re.sistnnce and pulnlonnr~ vasoconstrictiSon which can be espe-
Aally hnrmful t.o the patient whose pulmonary funct,ion is already
compromised. The disordered pulmonary ventilation-perfusion rela-
tionships and pulmonary hypertension found in some patients with
severe chronic bronchitis can only be lvorsened by further broncho-
nonst,riction and possibly by pulmonary vasoconstriction caused by
continued cigarette smoking. These. can enhance cardiopulmonary
dccompcnsation and lead to heart failure from car pulmonale.

Further research is necessary to clarify more precisely t.he inter-
re.lationships between the disturbances of veiltilatioll-~rfusion clawed
by chronic obstriicti\-e ~~ro~ic~l~ropi~li~io~i~~~~y disexses ant1 cwtlio\-ascular
abnorn~nlities as they relate to cigaret,te smoking.

SIXMARY A\NT) RESJLIRCH SGGGESTTONS

AIc~dit.ion:~l evidence compiled since 1967 c,onfirms previous positive
fintlinm and estends our knowledge about, some of the. effec,ts of
cipnre,tte smoking on pulmon:lr;v function. There has been furthe.r
clnrific~;ltion of some of tlw illt.err~lntionships between chronic obstruc-
tire broncllitis n11d ;ltl\-t:rae carcliopulmon;~ry cffe.ct.s indioaling that
pulmon:~r;v hJ.pertrtlsion ant1 (*or pulrnon:~le map result from the more
se,vere fornls of vltronic ol)strllvtive l)rollc,llopnmonnry disease. Smok-
ing is :I tlwjor cxure of clironic~ l~roncliopnlmonnr~ disease and in
wlditioii nr:l\- 11:11-r pnrt.iculnrly harmful c~nrdiopulmorrary e.ffects
in t,liose lwtieiits wit11 severe chronic ol)structi\-e lwoncliitis.

Researc~h suqcst iow : ( 1) I,oilg-trrni followup studies on clinrqes in
pultnou:~ry fllwt ion aurollg wnt iuning ci,rlrettc smokers as compared
to those ~-110 11:1rr WI-PI* wloketl viqltvttrs and those who have discon-
tinrietl cnig:nrrtte 5nlokiug. (2) T~oi~gilritliu:~l studies of relxtive.ly young
I)eol)le l~rior to the initiation of snwkinp in order to conll)are pulmo-
11ary fulwtion heforv :\ntl after the taking up of smoking.

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76


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82


S41. KUEPPERS, F., BEARN, A. G. A possible experimental approach to the associa-
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S4R. LECLAIR, R. A. Recovery of culturable tobnc*co mosaic virus from sputum
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S-M. LIXDALL, A., MEDIXA, A., GRISMER. .J. T. A rr-evaluation of norrnnl lnilrno-
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848. LTJPI'. S. G.. YEIXAN. C., YELICAS. I). Sal~l~~~tlcni~-n 1~ ~mrodu vnutrilr-
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S.ifi. SADEL. .J. A.. SAI.EM, II.. TAMPLIS, I<., TOKIW~. T. Jlrchanisni of broncho-
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    I'hyxiology 20: I(i&lW, 1(X5.

S.3. S1co~.4ss. R. Iiliniuc.h-c~xltrrilllrlltf~lle Sl,n~l~rlllltltt~r~;nchungen lwi chroniwhrr
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83


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S6.5. REID, 1,. Mucous secretion and chronic bronchitis. Medicina Thoracalis 24:
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SCXI. Rmn. I,.. MILLARD. F. .J. C. Correlation hetxveen radiologi~~al diagnosis and
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SW. ROSE, R.. PIIILLS. .J. A. The immurw reaction in pnlmonary disease. Ar-
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SW. Ross. .J. C.. JXY. C. D., KKTMIIOLZ. R. A.. RAKBARI. H. A technique for
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Si3. SIMON. G. R:ltliolopy and vmphywmx  (`linic.al Radiolog 1.7 : XC%-306,
     October 1964.

ST-L S~~osssos. R. G. Clinic:\1 xnd physiological studies on chronic bronchitis.
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    257-300, 19G.

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SK.Ti. Trsr. G., WOLFE. IV.. FAILAT. I<., S.UXL .I. I<olv rbf Oi nncl (`( b1 in rt~v+?rt;al
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    October 1967.

SW. ZANEI., S., Tor~ss~.~. H. H., I'MME. F. J, .\irway resistanc,e ;rlld lwak e's-
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    1238, June 8,196.X
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S90. ZWI, S., SLUIS-CREMER, G. K., Du PREEZ, I,. -4 survey of pulmonary func-
   tion in male office workers. Medical Proceedings 13( 23) : 369-554, So-
    vember 11, 1967.

85


CHAPTER 3

Smoking and Cancer

Contents

Introduction_-__--______-________________-___-___-_-__-
  Conclusions of the 1964 Report- - _ _ - _ _ _ _ - _ _ _ - - _ _ _ _ - _ -
  Highlights of the 1967 Report_--_--__---___----------
General Aspects of Carcinogenesis-____~-___--___--__------
  N-Nitrosamines_--_~-------____---_~---_---__---__-~
  Polonium-210_-------____________________--~--~~-~~
  Selenium---___---_-----~--.____~-__~--___~-__~-----
  Tobacco Pesticides and Growth Inhibitors- - - _ _ _ - - - - -
  Possible Fungal Contamination of Tobacco - _ _ - - _ _ - - - - -
Experimental Aspects of Carcinogenesis- - - - - - - - - _ - - - _ _
  Passive Inhalation of Tobacco Smoke- - - - - _ - - - - _ - - - _
  Active Inhalation of Tobacco Smoke- _ _ _ _ _ - - - - _ - - - _ _ - -
I~ungCancer--__-__--__----__--___---_---_----__--___-~
  Illortality-__-__~-_----_--_-__--------_---~__- ______
  Retrospect'ive Studies ______ -_----_--~__- _____ ~__~___
  Prospective Studies- _______ -__--------~----__--_____
Lung Cancer Relat#ionships in Women- _ - - _ _ - - - - - _ - - - -
  Additional Considerations and Conclusions_ _ - - - - - - - - _
Cancer of the Oral Cavity____--__-_~--_--_-_---~_----_--
Cancer of the Larynx-_---~__-_---~---~---------~~-~~~~~~
Cancer of the Esophagus---~_-_~~-_~~--________________
Cancer of the Pancreas ______ -~---~-~--~----_--~__-~ _____
Genito-urinary Cancer__----_-_~--~~---_______________
  Cancerof theBladder------__~ __.____ ~-_~--__---~_--
  Cancer of the Kidney ________ -------------___- ______
Cited References-__-------____________________~.~~~~~
Supplemental Cancer References-_-~--~__--~_________

Page

89
89
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90
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92
92
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93
93
93
94
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94
96
97
97
99
101
102
103
104
104
105
106
112

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INTRODUCTIOS

The pri.mary purpose of the 1968 Supl~lemental Report is t.o re\-ien
the pertinent literature that has become a\-ailable subsequent to the
1967 Report. Brief mention of the, conclusions of the lS6-f Report and
the hiph1ight.s of the 1967 Report is made to facilitate an understand-
ing of the significance of the most recent information.
The current, research findings should beg considered in the perspec-
t,ive of the B?Sf2i\ITll cGtlencr previoiisly reported in tlw lS64 ($1) and
lSG7 (92) Reports.

1. Cigarette smoking is causally related to lung cancer in men: t,he
magnitude of the effect, of cigarette smoking far outweighs all other
factors. The data for n-omen, though less estensive, point in t,he same
direction.

2. The risk of developing lung cancer increases wit,h duration of
smoking and the number of cigarettes smoked per day, and is dimin-
ished by discontinuing smoking.
.3. Tie risk of developing cancer of the lung for the combine41 group
of pipe smokers, cigar smokers, and pipe and cigar smokers is pwater
than for nonsmokers. but much less than for cigarette smokers. The
data are insufficient. to warrant a conclusion for each group
individually.
Ornl Cancfv

1. The causal relationship of the smoking of pipes to the develop-
ment of cancer of the lip appears to be est.nblished.
2. Although there are suggestions of relationships between cancer
of other specific sites of the oral cavity and the several forms of tobaxo
use, their causal implications cannot at prese.nt be stated.
Laryngeal Cancer

E~aluntion of the evitlrncc Icads to ilp ,jutlpnwilt thilt, c*iprrtte
smoking is a significant factor in. the causation of laryngeal cancer
in the male.
Esoplbag~al Guncc7~

The evidence on the tobacco-esol)ha~eal cancer relatlonshlp supports
the belief tilat an association exists. However, the dat,a are not ade-
quate to decide nliet.her the relationship is c.nnsa,l.
i'unciv of Urin.ary B?ad&r

Xvailable data suggest an association bet.ween cigarette smoking and
urinary bladder cancer in the male but, are not sufficient to support,
judgment on the causal significance of `this a.ssoc,int.ion.

89


So relationship ha.s been established bet,ween tobacco use and
stomach cancer.

HIGHLIGHTS OF TITE 19S7 REPORT (92)

1. -\ditional epidemiological, pathological, and experime.ntal data
uot, onlv confirm the conclusions of the Surgeon Gneral's 1964 Repovt
regartlicq lung cancer iii men l)llt stwngthen the causal relationship
of smoking to lung cancer in women.

2. Cessation of cigarette smoking sharply reduces the risk of dying
from lung cancer rrlatiw to the risk of those who c.ontinue,.

R. ,1lthough additional experimental studies substantiate previous
experimental data, ntltlitiou:~l resenrc9~ is needed to specify the tumor-
initiating and tnmor-l)ro"`otiil,v agents in tobacco smoke and to eluci-
date the basic mechanisms of t.he pathogenesis of lung cancer.
La~ryngca7 Can.rc,

The. conclusion of the Surgeon General's 1964 Repent that cigarette
wiokinp is a. siqlificallt factor in the causation of laryllgeal cancer
iu the male is supported 1)~ additional e.piclemiological evidence.
Other Cancer8

Additional evidence supports the conclusions of t,he Surgeon Gen-
eral's 1964 Report and indicates a strong association between various
forms of smoking and cancers of the bucal cavity, pharynx, and esoph-
agus. In tlic absriic~~ of f1irthe.r information concerning the interaction
of smoking Stli other facto15 known or snspectacl as causative agents,
further cowlasiolls canntrt be made at this time, although a causative
relntionsliip seems likely.

Aidditionnl [,I'itlt~nliolopical? clinical, and experimental data
strengthen the asswint ion between cigarette smoking and cancer of the
urinary bl:~dtlcr~ but the presently :~vailnble data are insufficient, to
infer that the relationship is causal.

Since the IN7 report. recent nclrances iii the tobacco chemistry field
were revieIved in Tao articles (65,8.%`). The chnracteriza,tion of tobacco
smoke by gas chronlntc~~ral,hv and digital comp\~ter opened a new
areniie for the csploratiol 1 of tobacco smoke. Thr first. preliminary
data indicate the l)resence of several thousands of compounds in to-
I);~tw sn10ke. `I`lli 1i111i11wi~ f:ti. rswcds thil 700-x00 compounds pres-
ently identified ($3).

The 1067 Reljort discuswd the major concepts of experimental to-
bacco carcinogensis. Al recent nlo~lo~rapl~ 1,~ n'ynder and Hoffmann
(10-j) tlioroiiglilv describes and :~nnl~zes experimental carcinogencsis
as it relates to tobacco and tobarco smoking. The reduction of tumori-
genicity is of particular concwn. This can be accomplished by : (1)
iwluc't ioii of total "tar" wnteut, and (2) reduction of specific tuniori-

90


genie agents. It has been well established that experimental tumor
production is close-related to the amount of "tar'* in cigarette smoke
condensate (7). The a.mount of "tar!' yield varies with parameters
xwh as: (1) type of tobacco, (2') curiiqg and l~iwccssing. and (3) fil-
tration. It, has been demonstrated that by selecting. curing and blending
as we.11 as by using specific filter mx~terials and cigarette pal)erl one can
significantly reduce the "tar" yield of mainstream cigarette smoke
(39: 83,88).
Over the, past. 15 years there, has been a general decrease in the
amount of `%ar" and nicot.inc content of cigarettes (97. 1O.j). One. rea-
son probably is the decreased nicotine ant1 ?ar" content in the
"lighter" tobaccos now being grown . ,Inotlier is the increased public
de.mand for "filtered" cigarettes.

Increased nitrate content of tol)ncco and the addition of nitrate to
cigarettes has been reported t.o reduce the tumor yield in cslwriniental
animals ( 10-i). kSniokc from air-curccl tol~~cco is less tumorigrnic than
flue or sun-cured tobacco (,W. I0.j ) and cigarettes using more sheets
and st.ems rather than whole leaf have been shonn to be less tumori-
genie (64,104).

Also, more porous cigarette palmer (TO), and the atldition of nitrate,
citrate, or phosphate to cigarette pper increases tlw burning rate of
the cigarette, t.hereby lowering the number of p11tl.5 taken l)er itnit of
cigarette (104).

Filtration \Till decrease the total "tar" yield ((il. 67. 96. 104). but
except for the phenolic component, conunerical filters do not, selec-
tively filter specific carcinogenic components from the "tar".

It has been shown that. "tars" of tobacco extracts have increasing
carcinogenic proper&s in direct, relationship to the. teml)erature of
pyrolysis (lU.$) .

It is important to note that tobacco extract itself contains relatively
high amounts of tumor promot,ers. The tumor promoting activity of
tobacco extracts is of the same magnitude as thnt of tobacco smoke
condensate (104) but so far no clear tumoripcnic relationship is evi-
dent between them (6).

Despit,e recent publications on the presence. of N-nitrosamines in
tobacco (76) a.nd cigarette smoke (55)) the l)resent el.idcnce must be
regarded as insufficient. because of the high lnobnbility that this is arti-
fact,ual (66). The studies described so far hare failed to identify these
a.gent.s in fresh tobacco smoke ($5. C6). However, since sercral of the
N-nitrosamines are strong carcinogens (58) and tobacco smoke con
tains several dozen secondary amines and oxides of nitrogen which
may be precursors for nit,rosnmines (6~. 76. 80, I&T), tobacco smoke
should be regarded as a potential source of S-nitrosamines.

91


POLONIUM-210

Kew data. on polonium-210 in t,obacco leaf and cigarette smoke have
originated from various countries (8: 13,26,.%`7, ~38~ 51: 52,68,89). The
polonium-210 values vary between l-50 picocuries per 1.0 g. tobacco;
3-50 percent of it is recovera.ble, in the mainstream smoke of ciga-
ret.tcs without filter tips, Using speci~al filter material, up to 90 percent
of the polonium-210 can be filtered out of the mainstream smoke (8).
One major source for polonium-210 in tobacco was reported to be
phosphate fertilizer (89). Analyses of human tissues demonstrated
that. lung, blood, and liver of smokers contain higher concentrat.ions
of polonium-210 than t.he corresponding organs of nonsmokers (B7,@,
41. 57. 68). Rajewsky et. al. (68)estimate a daily polonium-210 inhala-
tion rate of 2 picocuries for a. smoker of 20 cigarettes per clay. Their
autopsy studies indicate an alpha dose exposure for the basal cells of
the subsegmental and twminal bronchi of 41 mrem and 79 mrem per
year, respectively, in smokers of 20 cigarettes per day. In view of the
fact, that, Jacobi (44) calculated a dose rate in these same basal cells of
l-2 rem per year from the deca.y of naturally occuring radon and
thoron in the air, Rajewsky, et al. (68) consider it. unlikely that cancer
is caused by the inhalation of polonium-210, in tobacco smoke. In
a review of the role of radioactive substances on the effect of smoking,
Casarett, was of a similar opinion (Id).

SELENIUM

At, present, there is still no substantial evidence implicating selenium
as a respiratory carcinogen, although this is still somewhat disputed
(29,lUO. 101).

Tor~\c:co PESTICIDES AM GROWTH INHIBITORS

The most widely used sucker growth inhibitor is maleic hydrazide.
This agent was recently reported-to be carcinogenic (25). Tobacco leaf
and ciyare.ttc smoke are known to contain organic pesticides (32, 104).
The first identified carcinogenic pesticide in tobacco and cigarette
smoke is l,l-dichloro-2- (o-chlorophenyl) -2- (p-cholorophenyl) ethane
(o,p'-DDD) ($3. X), whicli is it technical by-1)roduct of the commer-
cial insecticide p,p'-DDD. At present there is no known evidence of
chlorinated insecticides contributing to tobacco carcinogenesis.

POSSIBLE FUNGAL CONTAMINATION OF TOBACCO

The mold Aspergi77aus fEnz*us is knownto synthesize the carcinogens
of the afla.toxin group (17). However, a recent. investigation reported

92


the absence of these agents in tobacco and cigarette smoke (9U). h'ever-
tIleless, further studies are indicated to evaluate the possibility that,
some tobaccos may be contaminated with carcinogens produced by
fungi.

EXPERIMENTAT, ASPECTS OF CARCIKOGENESIS

PASSIYE INIT.UATIOK OF TOBACCO SNOHE

In attempting to reproduce lung cancer in experimental animals,
the limitations of presently arailnblc bioassnys? mninl~ passive inhala-
tion studies, I~:I.IY I)ew cliwlssctl in tllv pre\.ious Rel)orts (91. 92).
T,argc scale studies in whirl1 :I variety of animals have been exposed
to the passi\-e inhnlntion of tobnccw smoke have essentially failed in
producing squan~oas ccl1 cancer of the lung (204).

The dificultics wit11 I)assive illh;llation studies ill animals relate in
part to the tosivity of (`ill'l)Oll nlonositlc and nicwtine. The defensive
"filtri~tiOl1" cnpal)ilities of the nasal l)nssngc5 alId the epithelium of the
1lpJm respirator? tract, necessitate rclntively higIl exposure kdSy
which in the case of tobacco smoke cannot adequately be accomplished
by passive inhalation methodologies.

Some laboratory studies failed to produce squamous cell cancer in
(`5'7 black mice even though some of the animals were previously
inoc.ulated wit.h Swine influenza virus (10(i). Harris and Srgroni (&),
in experiments with C57 black mice, some of which were inoculated
with viruses, achic\-ed sonic enlJ:~JJcenleJl~ of ildCllO~RI'CiJ10JJl~l~ hit did
not. produce :ms pr0wn sqnanwus wll caners.

T,ong-term cigarette smoke exposures in hamsters led only occa-
sionally to tracheal papillomas and not to squamous cancer (20).
However, one could sensitize these animals with diethylnitrosamine
and enhance the tumor production initiated by this carcinogen by a
variety of volatile irritants including tobacco smoke.

Active tobacco smoke inhalation studies as reported in the 1W
Report. (92) have shown that hyperplastic and metaplastic changes
can be produced in the lungs of dogs. These studies are expensire and
ic is difficult to keep the dogs alire long enough to permit the expected
development of ncoplastic transformation. Auerbach, et al. (4) in
continuing experiments with "smoking* clogs, have shown all the
bronchial epithelial changes including tlysplasial n+i& is the most
advanced stage of prc-mali~~nnt change. More research is needed to
elucidate the biomechanisms involved in the pathogenesis of lung
cancer caused by tobacco smoking.

93


LUNG CANCER

MORTALITY

The annual number of deaths in the United States from cancer of
the lung (ICD Code 162, 163) increased from 18,313 deaths in 1950
to 48,483 in 1965 (95). During the same period of time the crude
death rate rose from 12.2 deaths per 100,000 population to 25.0 deaths
per 100,000 population. The lung cancer age-adjusted mortality rate
for males increased from 18.5 per 100,000 population in 1950 to 39.2
per 100,t)OO 1)opulation in 1965: while in the females, the age-adjusted
rates increased from 3.9 to 6.4 per 100,000 population over the same
period.

The age-specific death rates for males show an increase with age up
to the 65 to 74 year age group, and then a decline. On the other hand,
the female lung cancer death rates show a relatively steady increase
with age, averaging approximately 7 additional deaths per 100,000
population between each ten year age group. As a result, the male to
female mortality ratio varies from a low of 2.0 for the 25 to 34 year age
age group, to a high of 8.5 for the 65 to 74 year age group.

TABLE l.-Death rates per 100,000 population for lung cancer, by age

-i-

                and sex, 1965


       3%         2634   35-44   lb54 5H.4     6674
                 years   Yem   YKUS    YCWS     years
                                __~
           -i- ~
Males--------~~.~...   1. 2  13. 2 ~ 58. 2 159.2   269. 3
Females-.----------.   0. 6   4. 4 / 13. 7 22. 1    31. 6
Ratio M/F--_----...   2. 0   3. 0   4. 2 1 7.2 ~    8. 5
                         I     I

/ -

7.wu   85 years
years   and over
~-

226. 4  152. 7
36. 5   45. 6
6. 2    3. 3

SOURCE: Satioml Center for Health Statistics (95).

RETROSPEXTICE STUDIES

Studies in Iceland uniquely support the evidence that t.he increase in
lung cancer is related to the increase in cigarette consumption. Iceland
is a small country with a total popukion of about 200,000. There is
relatively lit,tle air pollution, due mainly to the use of hot water springs
instead of the combustion of fuel <as a source of heating. Dungal (21)
in 1950 noted a beginning rise in lung cancer in Iceland, associated
with the rise in cigarette consumption during and after World War II.
He predicted t,hnt if the cigarette consumption continued to rise, t.he 20
to 30 year lag in lung cancer death rates would begin to become ap-
parent during the decade 1960-1970. Thorarinsson, et al. (81) reported
a large increase in the lung cancer incidence in Iceland from 1931 to

94


1964, corresponding to a marked increase in per capita cigwette sales.
The average annual incidence of lung cancer during the lo-year pe-
riod, 1955-1964, was 12.1 in men and 6.5 in women per 100,000 popula-
tion. However, comparing the first and second 5-year intervals, there
was a 30 percent inwease in lung cancer incidence in men and a 52 per-
cent increase in women (table 2) .

TABLE 2.-Average annual incidence rates for cancer of the lung, by
          sex: Iceland, 1955 to 1964

                  [Rate per 100,000 population]

Males ______ -_-___-___--_-_-___-______________
Females _______ -.__-___-__-_-_-_---____________

SOURCE: Thorarinsson, H. et al. (87).

Although the total number of deat,hs was small, 88 percent of the
histologic.ally classifiable tumors were of the squamous, undifferen-
tiated, or oat-cell varieties. Ninety percent of the squamous, 82 per-
cent of the oat-cell cancers, and 33 percent of the undifferentiated or
adenocarcinomas occurred in smokers.

A small study by Guillan, et al. (31) again illustrates that cigarette
smoking is also associated \vith adenocarcinoma of lung cancer. Of
24 cases of adenocarcinoma of t.he lung in men, a smoking history could
be determined in 22 cases. Of these, 91 perce.nt were smokers.

In a large retrospective study of 1,787 lung cancer patients in Japan
by Ishikaaa (.&`), adenocarcinoms was the most frequent histologic
type noted in both males and females who did not, smoke. Squamous
cell carcinoma n-as the most frequent, histologic type in male cigarette
smokers and undifferentiated carcinoma the most frequent type in
female cigarette smokers.

Of the male and female lung cancer pat,ients, 22.6 and 2.9 percent,
respectively, were smokers of over 30 cigarettes a day. Ishikawa com-
pared this to the corresponding smoking habits of patients in a large
ongoing prospective study of Hirayama (discussed later) which
showed only 4.3 percent. of the adult males over age 40 and 0.1 percent
of the adult females over age 40 smoking 30 cigarettes a day or more.

Abelin, et al. (1) showed that the relative risk of lung cancer in
Switzerland was associa.ted with heavy cigar and pipe smoking (as
well as cigarette smoking) to a much greater degree than previously
reprte.d. Most other studies hare not, shown a high association of lung
cancer with cigar and pipe smoking. The authors suggest that their
findings might be due t,o differences in either the amount smoked and/

95


or the carcinogenicity of Swiss and German cigars as compared to
American cigars. The diflarence might also be explained by the greater
use and more frequent inhalation of small cigars in Switzerland as
compared ,to other countries where larger cigars are more commonly
smoked but rarely inhaled.

PROSPECTIVE STUDY

The major, long-term, prospective studies vere reviewed in the 1967
Report. The Doll and Hill (18? 19) study is still in progress, but no
new data have become available. Data collection for the Best, Ham-
mond, and Dorn studies (5,34,4S) are completed, but various asp&s
are still being analyzed and new information a411 appear in the future.
Preliminary data from a large scale prospective study (3'7) of
265>118 men and Jvomen in Japan show that the death rate from lung
cancer is significantly higher in cigarette smokers as compared to non-
smokers for both males and females. There is also a posit'ive correlation
between lung cancer death rates and both the amount smoked and the

I-



l-



l-



l-



)-



I-



,-



,-

BY sex and
smoking habit

             :
            : :.
            +
~
            .::
            `: ,::

Non-     Smoker

NOW    1-24    25.

smoker

           --
smoker  cigarettes per day

Number 3
studied    -346 9    J
    23350 119136 97047 17473     23350
m Male   m Female

-20    21    22--

21
36912 7    9
     16644   34769

FIGTXE l-Death rates for lung cancer, among persons age over 40 years, classi-
fied by sex and extent of cigarette smoking, and by age smoking began : Study
of 29 Health Center Districts in Japan, danuary 1966 to March 1967.

SOUBCE: Hirayama, T. (37)

96


age smoking began, but the number of deaths is too small for adequate
analysis at. this time.

LUNG CANCER RELATIONSHIPS IN WOMEN

Critics have tried to throlr- doubt on the smoking-lung cancer rela-
tionship by saying that the lung cancer death rates for u-omen have
increased only slightly as compared to the greater relative increase
in the number of women smokers.

It is true that the lung cancer death rates for women are presently
much lower than the corresponding rates for men. Women presently
account for onl,y about one-sixth of the total deaths from lung cancer.
But since 1930 the lung cancer death rate in women has increased over
400 percent. Over the past 14 years alone this increase has been over 50
percent (94). ,Z most likely reason for the difference in male/female
lung cancer death rates is that women still have not had the same degree
of total exposure to cigarettes as haw men. For instance, as late as 1955.
only 24.5 percent of the adult female population (age 18 and over)
were regular smokers compared to 52.6 percent of the adult. male
populat.ion (33). In 1966 the figures show only 33.6 percent of the adult
females smoking (age 21 and over) as compared to 51.8 perwnt of the
adult males. Also, the female smoker's per capita consumption was
about 26 percent less than that of the male smoker in 1955, and about
20 percent less in 1966 (93). In adclition, it has been show-n that women
smoke differemly than men do (c9t9). They do not, smoke cigarettes
as far to the end, where proportionally more nicotine and "t,ars" are
inhaled than from the first part of t.he cigarett.e.. Won1e.n smoke more
filter-Cl> cigarettes than men, and smoke more "low tar and nicotine"
cigarettes than do men. They also inhale less frequently and deeply
than men. Furthermore, cigarette smoking still tends t.o be heavily
concentrated in those women under the age of 50 years, prior to the age
at, which lung cancer is mostly likely to occur.

An anlysis of the Iun g cancer death rates (94) shows that,, "Vntil
1960 the rat,io of the death rate in the male population for this cause
to the corresponding death rate in the female population continued
upward. But after 1960 this ratio leveled off, reflecting the greater
relative rise in mortality from lung cancer in the female population."

ADDITIONAL (`IoNSIDEIL~T~O~`S `IND CONCLVSIONS

Filter cigarettes, in general, have lower "tar" and nicotine ra1ue.s
than comparable non-filter cigarettes. In this respect, a study by Brass
(9), shows preliminary evidence that smokers who switched to filter
cigarettes have a decreased risk of developing lung cancer.
(;raham (3'0) studied the smoking habits of male lung cancer patients
and controls. Previously he showed, on smoking machines, that dif-

97


fcrent, patterns of cigarette smoking gave different "tar" yields. His
lung cancer patients had significantly greater high "tar?' yield cigarette
smoking patterns than the controls. The risk of lung cancer increased
with increase in : (I) the mean number of puffs per cigtwette, (2) t.he
average length of time taken to smoke a cigarette (except in the highest,
number of puffs category) and (3) taking more puffs towards the end
of the cigarette. These findings add further support to t,he dose-re-
sponse relationship between lung cancer and cigarette "tar" exposure.

As pointed out in the 1964 and 1967 Reports, there appear to be
several other factors which may also contribute to the etiology of lung
cancer, especially in the presence of cigarette smoking. However, there
has been no evidence to refute the statement in the 1964 Report. that,
"Cigarette smoking is causally related to lung cancer in men; the
magnitude of the effect of cigarette smoking far outweighs all other
factors. The data for n-omen, though less extensive, point in the same
direction."

Of particular interest are the studies of Ruell, et al. (II, 12). They
reviewed various prospective and retrospective studies which shelved
that the urban-rural differences in lung cancer death rates in non-
smokers n-ere of the range of 2 : 1 to 4.4 : 1. However, the much greater
effect. of smoking on increasing the lung cancer death rates was evident
by their statement "that smoking can act independent.ly of the urban
factor, the gradients among rural dwellers rising to as much as 10 to
15 fold for heavy smokers." TJ?th regard to the high levels of photo-
chemical air pollutants in Los ,Ingeles, they concluded: `With controls
for cigarette smoking and length of residence, the risk of pulmonary
canc.er in Los ,Inpeles, where photochemical air pollution levels are
highest, was not greater than in other major met.ropolitan areas of
California."

hlthough photochemical air pollution might not be a contributing
factor to lung cancer mortality in man, as is the "sulfur dioxide" air
pollution found in most industrial areas, it may be too early to ascer-
tain any effects. since air pollution in TAX Angeles only became a prob-
lem between 1945 and 1960.

Storks (@. 85) shows that per capita solid fuel consumption has a
positive correlation with lung cancer death rates but to a much lesser
degree than per capita cigarette consumption. He sug,mts, therefore,
that air pollution from solid fuel combustion is related to lung cancer
death rates and that this might possibly be independent of cigarette
smoki~lg. However, Stocks did not de.termine the specific smoking
histories of indiriduals ~-ho died from lung ca.ncer.

Concurrent st,udies of cigarette smoking and air pollution, in the
same populations with precise smoking histories on individuals who
have died from lung cancer, might serve to clarify the probable inter-
action between cigarette smoking and air pollution or possible inde-

98


pendence of cigarette smoking from air pollution as they relate to the
etiology of lung cancer.

The preponderance of evidence [ 1964 Report (91). 1967 Report (5%`))
and this report] continues to indicate that most lung cancers occur in
cigarette smokers and that cigarette smoking is the major cause of
lung cancer. A majority of lung cancer cases are of the squamous cell
rnriety and most investigators are in agreement that squamous cell
carcinoma is rare in the male nonsmoker (3. 15, 103). The elimination
of cigarette smoking would in time eliminate most lung cancer. That
this is a real goal is supported by the study of British physicians (18,
2,9) reriewed in the 1967 report..

It is not, disputed that some cases of lung cancer can occur in those
people who have never smoked ciparette,s or inhaled any form of
tobacco smoke. In these cases air pollution possibly pln~s a larger role
in the cawation, but in most cases, it appears that it is the ciga.ret,te
smoker nho is especially susceptible to whatever additional risk for
lung cancer may be presented by certain types of air pollution or other
fnctors such as asbestos or uranium dust inhalatSion.

`l'he 1967 report showed that the overall death rates for oral cancer
remained about the same during the period 1950-1964. This was in-
fluenced somewhat by recent changes in the ICD Code.

It is intere&ing to note that the incidence rates of oral cancer have
also remained relatively constant over the period 19X-19&2,* in spite
of increased cigarette smoking (24). This may be explained, in part,
by the fact that the numerators of such rates often include neoplasms
coded to the International Classification of Disease, rubrics 140
through 148. These rubrics identify many oral and pharyngeal diag-
nostic sites which do not contribute equally to either the. morbidity or
mortality experience resulting from the use of tobacco, For example,
preliminary findings in an unpublished study by Keller (47) suggest
that. salivary cancers (ICD rubric 142), unlike tongue and floor of
mouth cancers, are not associated with the tobacco habit,. The fact that
pipe and cigar smoking in this country began to be replaced by cipar-
ette smoking among men born subsequent to 1900 may also be signifi-
cant, although this trend has leveled off and may even have been re-
versed since the health consequences of smoking cigarettes first came
to public attention in the mid-1950's. In the population which accounts

`There is no ntitional ctata collection on inddenw rates of ddseam. Sewral &ates have
mncer wgi&-ier whirh have information cm the incidence of caner in that particu1a.r
state. Thr data from Connecticut are generally thought to reflect the ch~ngiing patterns
of cmcer incidence throughout the I:nited States. It is realized that there might he indi-
vidual state differences. Krfcrencw to incidence rates in this chapter section are taken
from the Connecticut Dunn unless otherwise specified.

99


EUCCALCAVlTYANDPHARYNX

?        ?         ?         ?         ?         ?
1935         1940        1945         1950        1955        1960
                         YCXS

- Maler    ---Females

FIG~RF. Z-Age-adjusted rates of the iucidence of caucer of the buccal cavity aud
      pharynx, for males and females : Connecticut, 19351962.

SOURCE : Eisenberg, et al. (24).

for the bulk of oral cancer cases-men over 45-there has been a greater
change in the form in which tobacco is used than in the proportion of
men using tobacco.

Since pipe and cigar smoking is associated with oral cancer, with
mortality ratios not very different from those for cigarette smokers,
the constant incidence rates may reflect the fact that the proportion of
t,obacco users among men over 45 has been fairly stable.

A review of the recent retrospective studies shows a relationship
of oral caucer to all forms of the tobacco habit (22. 2%. .53,5$. 77, 78. 79,
98). This includes the use, in the nlucobuccal fold, of either snuff,
among n-omen (lo, 22, 71, 7.2, 81), or the betel nut quid with tobacco,
among the residents of India and Southeast Asia (~6, j$,77: 78,79,,%?).

Reddy has 1noduce.d tumors in mice by daily instillation of a "pan"
mixture with tobacco (the same mixture used for chewing) into the
vaginas of virgin mice (69) .

There is evidence that in the presence of tobacco consumption,
alcohol may also be a factor in the etiology of oral cancer (48, 4.9> 50,
97). In a recent study on male veterans, Keller concluded, "* * *
heavy smoking, heavy drinkin g and liver cirrhosis (either alone, or
as a measure of heavy drinking) are associated with cancer of the

100