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   aggravated atherosclerosis in the squirrel monkey. Experimental and Molecu-
   lar Pathology 13: 36-59,1970.

(149) WEINBLA'IT, E., FRANK, C.W., SHAPIRO, S., SAGER, RV. Prognostic
   factor in angina pector%-A prospective study. Journal of Chronic Diseases
   21: 231-245, July 1963.

(1.50) WEINBLATT, E., SHAPIRO, S., FRANK, C.W., SAGER, R.V. Prognosis of
   men after first myocardial infarction: Mortality and fit recurrence in
   relation to aelected parameters. American Journal of Public Health 53(a):
   1329-1347, August 1966.
(151) WEINROTH, LA., HERZSTEIN, J. Relation of tobacco smoking to arteriosclc-
    rosis obliterans in diabetes mellitus. Journal of the American Medical
   Association 131(3): #)5#)9, May 1946.
(Isa) WEISS, N.S. Cigarette smoking and arteriosclerosis obliterans: An epidemiolog-
   ic approach. American Journal of Epidemiology 95(l): 17-26,1972
(153) WESSLER, S., MING, S.-C., GUREWICH, V., FREIMAN, D.G. A critical
   evaluation of thromboangiitis obliterans. The case against Buerger's disease.
   New England Journal of Medicine 262(23): 115&1169, June 9,1969.
(154) WILHELMSEN, L. Recent studies on smoking and CVD epidemiology:
   Scandinavia and some other Western European countries. In: Steinfeld, J.,
   Griffiths, W., Ball, K., Taylor, RM. (Editors). Proceedings of the Third World
   Conference on Smoking and Health, New York, June 2-5, 1975. Volume II.
   Health Consequences, Education, Cessation Activities and Social Action. U.S.
   Department of Health, Education, and Welfare, Public Health Service,
   National Institutes of Health, National Cancer Institute, DHEW Publication
   No. (NIH) 77-1413,1977, pp. 171-177.

(155) WISSLER, R-W., VESSELINOVITCH, D., GETZ, G.S. Abnormalities of the
   arterial wall and ita metabolism in atherogenesis. Progrem in Cardiovascular
   Diseases 13(5): 341369, March/April 1976.

4-76


(156) WOLINSKY, H. A new look at atherosclem&. Cardiovascular Medicine: 41-54,
   September 1976.
(1.57) WRAY, R, DEX'ALMA, RG., HUBAY, C.H. Late occlusion of aortofemord
   bypass grafta: Influence of cigarette emoking. Surgery 70(6): !36&973,
    December 1971.


5. CANCER.

National Cancer institute


CONTENTS

Introduction .............................................................. 9

Lung Cancer ............................................................. 9
Trends in Lung Cancer Mortality ........................... 10
Epidemiological Studies ........................................ 11
Dose-Response Relationships .................................. I2
   Number of Cigarettes Smoked Per Day.. ........ .12
    Age at Which Smoking Began.. ...................... I3
     Inhalation of Cigarette Smoke ........................ 14
    Tar and Nicotine Content of Cigarettes.. ........ .15
  Lung Cancer in Women ....................................... 16
   Trends in Cigarette Consumption
     among Females ......................................... 16
    Epidemiological Studies ................................. .20
    Dose-Response Relationships ........................... 21
     Patterns of Cigarette Use.. ........................... .21
  Twins ................................................................ 23
Lung Cancer and the Use of Other Forms
   of Tobacco ...................................................... 23
  Histology of Lung Cancer.. .................................. .23
  Cessation of Smoking ........................................... 24
  Lung Cancer and Air Pollution.. ........................... .25
  Lung Cancer and Occupational Factors.. ................ .2'7
     Asbestos ...................................................... 28
    Uranium Mining ........................................... 2x3
     Nickel ......................................................... 23
    Chloromethyl Ethers ..................................... 29
  Animal Studies ................................................... 29
   Skin Painting and Subcutaneous Injections ...... .2!9
   Tracheobronchial Implantation and Instillation .. .29
    Inhalation Carcinogenesis ............................... 30
     Nitrosamines ............................................... .30
    Phagocytosis ............................................... .31
  Conclusions ........................................................ .31

CanCer of the Larynx.. ............................................. .32
Epidemiological Studies ....................................... .33
  Asbestos ........................................................... .u
  Animal Studies ................................................... 34

5-3


  Conclusions ......................................................... 36

Oral Cancer ............................................................ .39
  Epidemiological Studies ....................................... .39
  Other Fcmns of Tobacco.. .................................... .4fl
  Other Risk Factors.. ........................................... .&I
  Leukoplakia ........................................................ 41
  Animal Studies ................................................... 41
  Conclusions ......................................................... 42

Caner of the Esophagus ........................................... .42
  Epidemiological Studies ....................................... .a
  Other Forms of Tobacco Use ................................ 43
  Other Risk Factms ............................................. .43
  Autopsy Studies ................................................. .44
  Animal Studies .................................................. .bi
  Conclusions ........................................................ .44

Cancer of the Urinary Bladder and Kidney.. ................ .45
   Bladder Cancer ................................................... 45
    Epidemiological Studies ................................. .45
      Other Risk Factors.. .................................... .47
     Animal Studies ............................................ .4'7
  Kidney Cancer.. ....................... .I ........................ .4?
    Epidemiological Data .................................... .47
  Conclusions ........................................................ .49

Cancer of the Pancreas ............................................. .59
  Epidemiological Studies ....................................... .50
   Other Risk Factors.. ........................................... .51
   Animal Studies ................................................... 51
   Conclusions ........................................................ .53

Mechanisms of Carcinogenesis .................................... .53
  Smoke Composition ............................................. .53
  Experimental Models.. ......................................... .53
  Concepts of Carcinogenesis ................................... .54
  Aryl Hydrocarbon Hydroxylase ............................. .57
  Multi-Stage Model of Carcinogenesis ...................... .58

References .............................................................. .59

5-4


LIST OF FIGURES

Figure l.-Relative risk of lung cancer for males, by
number of cigarettes smoked per day and long-term use
of filter (F) and nonfilter (NF) cigarettes . . . . . . . . . . . . . . . . . . 18

Figure 2.-Relative risk of lung cancer for females, by
number of cigarettes smoked per day and long-term use
of filter (F) and nonfilter (NF) cigarettes . . . . . . . . . . . . . . . . . . 19

Figure 3.-Lung cancer mortality in continuing cigarette
smokers and nonsmokers as a percentage of the rate
among ex-cigarette smokers at the time they stopped
smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Figure 4.--Relative risk of developing larynx cancer for
males, by number of cigarettes smoked per day and use
of filter and nonfilter cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5

Figure 5.--Relative risk of developing larynx cancer for
females, by number of cigarettes smoked per day and
use of filter and nonfilter cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . 36

Figure 6.-Relative risk of developing larynx cancer for
male ex-smokers, by years of smoking cessation . . . . . . . . . . 37

Figure `I.-Relative risk of developing larynx cancer for
female ex-smokers, by years of smoking cessation . . . . . . . 33

Figure 8.--Relative risk of pancreatic cancer in males, by
number of cigarettes smoked . . . . . . . . . . . . . . . . ..*....*.........*. 52

LIST OF TdsLES

Table I.-Lung cancer mortality ratios-prospective
studies.. . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

5-5


Table Z.-Lung cancer mortality ratios for males, by
current number of cigarettes smoked per day, from
selected prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Table 3.-Lung cancer mortality ratios for males, by age
began smoking, from selected prospective studies . . . . . . . . 14

Table $.-Lung cancer mortality ratios for males, by
degree of inhalation, from selected prospective
studies . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .I.. . ,... 15

Table 5.-Age-adjusted lung cancer mortality ratios for
males and females, by tar and nicotine in cigarettes
smoked.. . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Table 6.-Age-adjusted lung cancer mortality ratios for
males and females, comparing those who smoked a few
high T/N cigarettes with those who smoked many low
T/N cigarettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Table `I.-Mortality rates for lung cancer and cancer of
the respiratory tract for white females in the United
States per 100,000 population for selected years: 1940 to
1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Table %-Percent of adult population who were current
cigarette smokers in selected years in the
United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Table 9.-Percent of teenagers who were current cigarette
smokers in selected years in the United States . . . . . . . . . . . 21

Table lO.-Lung cancer mortality ratios for women-
prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Table Il.-Lung cancer mortality ratios for females, by
number of cigarettes smoked per day: A.C.S. 25-State
Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Table 12.-Lung cancer mortality ratios for females, by
number of cigarettes smoked per day: Haenszel and
Taeuber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Table 13.-Lung cancer mortality ratios for females, by
duration of smoking: Swedish Study . . . . . . . . . . . . . . . . . . . . . . . . . 22

5-6


Table 14.-Lung cancer mortality ratios for females, by
degree of inhalation: A.C.S. 25-State Study . . . . . . . . . . . . . . . . 22

Table E-Lung cancer mortality ratios in ex-cigarette
smokers, by number of years stopped smoking . . . . . . . . . . . . 25

Table 16.-Mortality ratios for cancer of the larynx-
prospective studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Table 1'7.-Mortality ratios for cancer of the oral cavity-
prospective studies.. . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Table 18.-Mortality ratios for cancer of the esophagu-
prospective studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Table lg.-Bladder cancer mortality ratios-prospective
studies.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46

Table 20.-Kidney cancer mortality, ratios and relative
risks: selected prospective and retrospective studies . . . . .48

Table 21.-Kidney cancer mortality ratios, by amount
smoked: U. S. Veterans Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Table 22.--Pancreatic cancer mortality ratios-prospective
studies... . . . . ,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .., . . . . 51

Table 23.-Mortality ratios for cancer of the pancreas
among Swedish subjects, aged 1869, by sex and
amount smoked.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52

Table 24-Carcinogenic, promoting, and ciliatoxic agents
in the gas phase of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Table 25.-Carcinogenic agents in the particulate phase
of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Table 26.-Tumor promoters and co-carcinogens in the
particulate pha& of tobacco smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

5-7


Introduction

Cancer has been the second leading cause of death in the United States
since 1937. There were an estimated 390,000 deaths from cancer in 1978
(4). The association between tobacco smoking and the development of
lung cancer was first suggested in the 1920's and early 1930's (159,
2~). In the early 1950's, more than a dozen retrospective studies were
published which first generally alerted the medical and scientific
community to the health hazards associated with cigarette smoking.
The public was informed of the results of these studies, and as a
consequence there was a significant, but brief, dip in the per capita
consumption of cigarettes. The next decade brought an intensive
worldwide investigation into the various diseases associated with
cigarette smoking. The first official statement on smoking and health
by the U.S. Government was contained in the Report of the Advisory
Committee to the Surgeon General of the U.S. Public Health Service,
which was released 15 years ago. The evidence available at that time
warranted the conclusion 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 women, though
less extensive, point in the same direction. The risk cf developing lung
cancer increases with the duration of smoking and the number of
cigarettes smoked per day, and is diminished by discontinuing
smoking" (2133. In the 15 years since the 1964 Surgeon General's
Report was published, these conclusions have been confirmed by
numerous investigations in many countries. Cigarette smoking has also
been implicated as a significant cause of cancer of the larynx, oral
cavity, esophagus, urinary bladder, kidney, and pancreas. As data
concerning the relationship of smoking to the development of cancer at
various sites became available, they were summarized and published in
the annual issues of the Health Consequences of Smoking (209, 210,
211,212,212a,213,214,215,216).
This chapter reviews the epidemiological and experimental data for
each of the cancer sites associated with cigarette smoking. Discussions
of the specific cancers are presented sequentially, based on the
strength of the association with cigarette smoking: cancer of the lung,
larynx, oral cavity, esophagus, urinary bladder, kidney, and pancreas.

Lung Cancer

This year more people in the United States will die from lung cancer
than from any other malignant disease. In 1950, when the nation first
became generally` aware that there was an association between
smoking and lung cancer, there were 18,313 lmg cancer deaths. In
l96% there were 45,838 deaths from lung cancer. The National Center
for Health Stat' t'
      IS its reported that in 1976 there were 86,267 deaths
from lung cancer in the United States (150). It is estimated that there

5-9


were 92,400 deaths from lung cancer in 1978 (4). For every preventable
death from highway accidents, there were approximately two deaths
from lung cancer which could have been prevented if the individual
had not smoked cigarettes. There are about 230 deaths from lung
cancer each day in the United States.

This epidemic increase in lung cancer is reflected in rapidly changing
mortality rates in both men and women. The mortality rate for men in
1950 was 19.9/1OO,OOO/year. This rose to 41.4 in 1964, and to 63.0 in
1976. The comparable figures for white females were 4.7 in 1950 and
8.0 in 1965, and climbing rapidly to 19.5 in 1976 (Table 7).

According to results from the National Cancer Institute's Surveil-
lance, Epidemiology, and End Results (SEER) Program, the mortality
rates for black males and females are higher than for whites. In 1976,
the lung cancer mortality rate for black males was 93.0, for black
females it was 17.4 (154). Due to recent increases in death rates among
females, the ratio of male to female mortality for lung cancer has
dropped from 7:l to less than 4:l.

While recent years have seen dramatic increases in relative survival
rates for acute leukemias in children, Hodgkin's disease, multiple
myeloma, and certain other malignancies, there has been little increase
in survival rates for lung cancer. The 5-year survival rate for lung
cancer in all states is 8 percent for males and 12 percent for females
(151). The difference in survival rates between males and females can
be explained by sex-specific differences in histology or stage of the
disease.

Trends in Lung Cancer Mortality

In the United States there has been in the past few years a significant
reduction in the percent of males and females who smoke cigarettes.
As yet, there has not been a decline in the age-adjusted tot& mortality
rates for lung cancer. When the lung cancer mortality rates by age are
examined from 1950 through 1975, there is a continuining increase in
older age groups for both males and females. This is probably due to
the elevated risk experienced by older persons who use nonfiltered,
high tar and nicotine cigarettes and who have done so for the majority
of their lives. However, for female cohorts born in 1950-54 and male
cohorts born in 193539 and 194044, the age-.speci& lung cancer
mortality rates are below those of previous cohorts. This probably
results from the reductions in cigarette consumption which have
occurred in these groups.

There has been a change in the epidemic of lung cancer in England
and Wales, as summarized by the International Union Against Cancer
(UICC) workshop on the biology of cancer (Z.&?):
In England and Wales, lung cancer mortality stopped increasing in
men under the age of 50 years during the 1950's and more recently
has fallen in men under the age of 60 years. The death rate from

5-10


lung cancer in women ages 40 years and over has continued to rise,
but has leveled, or fallen in younger women since the 196O's...The fall
in lung cancer mortality among men under the age of 60 years is
likely to be due to their reduced consumption since the end of the
Second World War, and to the reduction in the tar yield of cigarettes
since 1955; particularly with the change to filter cigarettes.
Although lung cancer mortality in women over 40 years has
continued to increase along with their cigarette consumption, it is
unlikely that the incidence of lung cancer will ever reach the high
levels recorded in men, because the increasing cigarette consumption
by women has been, and is continuing to be compensated for by a
decrease in tar yield.

Epidemiological Studies

The first comprehensive reviews of the effects of smoking on lung
cancer were published in 1962 and 1964 by the Royal College of
Surgeons of London and the Surgeon General of the United States,
respectively (171, 217). They included data from studies on epidemiolo-
gy, profiles of the consumption of tobacco, the composition and
carcinogenicity of components of tobacco smoke, the effects of smoke
on experimental animals, and the pathological changes observed in
humans and animals. The conclusions reached in these assessments and
by all of the periodic reviews that have followed at regular intervals
(209, 210, 211, 212, 212q 213, 214, 215, 216) are impressively uniform
and consistent. So much so that it has been observed that the results of
any one of the major studies might be taken to represent all of them.
There have been at least nine major prospective epidemiological
studies which have examined the relationship between cigarette
smoking and mortality from various causes. The results of eight of
these studies are related to cigarette smoking and lung cancer and are
presented in Table 1. The lowest mortality ratios are experienced by
female smokers. The mortality ratios for male cigarette smokers are as
low as 3.35 for Japanese males and as high as 14.0 for British doctors
and Canadian veterans. Combining the data from the largest studies
allows the conclusion that cigarette smokers on the average are 10
times as likely to develop lung cancer as nonsmokers. The mortality
ratios are much higher for heavy cigarette smokers. This will be
detailed in the section on dose-response relationships.
In the past 30 years, more than 50 retrospective studies on the
relationship between cigarette smoking and lung cancer have been
Published. These data are too extensive for convenient summarization;
they have been reviewed in recent issues of the Health Consequences
*f Smoking (212,212a, 213,214,215).

5-11


TABLE l.-Lung cancer mortality ratios-prospective studies

Population

sii

Number
of deaths

Nonsmokers

Cigamtte
SmdterS

British
doctms(b?a)

Swedish
study@?)

Japanese
study( 77a,78)

A.C.S. 26-
State Study(65)

U.S. veterans(90)

34,000 males

27,000 males
23,060 females

122,066 males
143,060 females

440,000 males
562,lXUl females

239,000 males

Canadian
veterans(~)

A.C.S. 9-
State Study@@

California male3
in 9 owupa-
tions(228)

78,CdlO male3

188,oM) males

68,qoO males

441          1.00          14.0

55          1.60          8.2
  8          1.66          4.5

590          1.06          3.76
148          1.60          203

1,159          1.00          920
133          1.00          2.20

1zsS          1.00         1214

331

448

368          1.00          7.61

1.00         14.2

1.06          10.73

Dose-Response Relationships

An important factor in the causal relationship betwe& smoking and
lung cancer. is the demonstration of dose-response relationships. In
most epidemiological studies, dosage has been measured by the number
of cigarettes smoked per day at the time of entry into the study. Other
dose variables which have been examined include the maximum
number of cigarettes smoked per day, the age an individual began
smoking, the degree of inhalation-of tobacco smoke, the total number
of years an individual has .smoked, the total lifetime number of
cigarettes smoked, tar and nicotine levels of the brand of cigarettes
used, the number of puffs per cigarette, the length of the unburned
portion of the cigarette, and combinations of these variables into
"dosage" scores. All of these variables have been shown- in one study or
another to contribute to the risk of developing lung cancer. Only a few
representative samples of dosage variables as related to lung cancer
mortality are examined in this section.

Number Of Cigarettes Smoked Per Day

`rhe risk of developing lung cancer increases with the number of
cigarettes smoked per day. In the U.S. and British populations, the risk
of developing lung cancer for individuals smoking more than two packs

5-E


TABLE 2.-Lung cancer mortality ratios for males, by current
     number of cigarettes smoked per day, from selected
     prospective studies

smoked
per day

Mortality
ratio

A.C.S. 25-
state study(65)

Nonsmoker                1.00
  l-9                  4.62
lo-19                  8.62
2039                 14.69
40+                  18.77

British
dcctors(l7a)

iNonsmoker                1.00
  1-14                 7.80
15-24                 12.70
25+                 25.10

Swedish males(9f)

Nonsmoker                !.oo
  l-7                  230
  a15                  8.89
16+                  13.99

Japanese males( 78)

Nonsmoker                1.00
  l-9                  1.99
lc-14                  3.52
lM4                  4.11
25-49                  4.57
50+                  5.78

a day is approximately 20 times that of nonsmokers (4% 65, 68, 80,
228). Data for Swedish males are of the same magnitude (32). Japanese
males who smoke 50 or more cigarettes a day experience a risk which is
5.8 times greater than for nonsmokers. Hirayama noted that the slope
of the dose-response curve for lung cancer was less in Japan than in
the United States and that this was probably due to the lower
Percentage of regular deep inhalers, a lower level of environmental
Promoting conditions, and also a higher percentage of adenocarcinoma
in Japan than in the United States (78). Table 2 presents lung cancer
mortality ratios from selected prospective studies for males by the
current number of cigarettes smoked per day.

Age at which Smoking Began

Lung cancer mortality ratios exhibit an inverse relationship with the
age of initiation of the smoking habit. Lung cancer mortality ratios for
males by age at which they began smoking are presented in Table 3.
Most cigarette smokers began the habit while in high school and are at
the greatest risk of developing lung cancer. Those who began smoking

5-13


TABLE 3.-Lung cancer mortality ratios for males, by age began
     smoking, from sele&.ed prospective studies

Age began
smoking
in years

Mortality
ratio

A.C.S. 25-
State Study(65)

Nonsmoker                1.00
25+                  4.08
ax?.4                 lO.QB
15-19                 19.69
under 15                16.77

J8paIlW
study( 78)

Nonsmoker
25+
20-24
under 20

U.S.
veterans(90)

Nonsmoker                1.00
25+                  520
20-24                  9.50
15-19                 14.40
under 15                18.70

1.00
2.37
3.35
4.44

after the age of 25 have mortality ratios which are only 4 to 5 times
greater than those of nonsmokers.

Inhal4&n of Cigarette Smoke

Inhalation of tobacco smoke is an important dosage variable. Inhala-
tion of smoke well into the lungs is the major mechanism whereby lung
tissue is exposed to the carcinogens which ultimately produce lung
cancer. Techniques for quantitating the degree of tobacco smoke
inhalation have been developed using carboxyhemoglobin levels or end
expiratory carbon monoxide levels as an index of smoke inhalation.
These objective methods of measuring inhalation have not been
applied to studies of lung cancer mortality. In most investigations, the
smoker was asked to report subjectively on his own inhalation
practices. This is subject to considerable variation but is not as
inaccurate as might be presumed. Available data show a strong dose-
response relationship between self-reported inhalation of cigarette
smoke and lung cancer mortality. Representative figures from selected
prospective studies are presented in Table 4. These data suggest that
cigarette smokers may underestimate the degree to which they inhale
cigarette smoke. Those who report that they do not inhale cigarette
smoke experience lung cancer mortality ratios which are 4 to 8 times
greater than for nonsmokers. Deep inhalation results in mortality
ratios which are as high as 17 times greater than for nonsmokers.

5-14


TABLE I.-Lung cancer mortality ratios for males, by degree of
     inhalation, from selected prospective studies
                     NT=
                            of             Mortality,

                         inhalation                ratio

A.C.S. 25
State Study(G)

Nonsmoker                1.00
None                  8.00
Slight                 8.92
Moderate                13.08
DIP                 17.00

Swedish

Nonsmoker
   None
Light inhalation
Deep inhalation

1.00
3.70
7.FQ
9.20

Tar and Nicotine Content of Cigarettes

The major constituents of cigarette smoke that cause lung cancer are
among the more than 2,000 different compounds found in cigarette
smoke. Cigarette filters, first introduced during the mid-1950's, have
the effect of trapping tar. Data presented by Maxwell (136) show that,
in 1976, more than 600 billion cigarettes were smoked and that 88.4
percent of these were filtered. It has been known that the risk of
developing lung cancer increased with the tar and nicotine content of
cigarettes. Until recently, however, there has not been a great deal of
evidence that individuals who switch to lower tar and nicotine
cigarettes experience less lung cancer mortality (27). It has been
argued that, if the tar and nicotine content of tobacco were reduced,
individuals might increase the number of cigarettes smoked per day
and thereby abolish any benefit that might be gained. Alternatively,
those who switch to low tar and nicotine cigarettes might inhale the
smoke more deeply than smokers of high tar and nicotine cigarettes,
and thereby exposure to tar and nicotine might not be reduced. In a
large prospective study by Hammond, et al. (67), these tar and nicotine
relationships were examined with respect to lung cancer. The 897,825
men and women in 23 States were divided into 3 tar and nicotine
categories. The high tar and nicotine (T/N) category was defined as 2.0
to 2.7 mg of nicotine and 25.8 to 35.7 mg of tar. The medium TN
ategory was defined as 1.2 to 1.9 mg of nicotine and 17.6 to 25.7 mg of
tar. The low T/N category included cigarettes containing less than 1.2
mg of nicotine and less than 17.6 mg of tar. A matched-group analysis,
similar to age standardization, was utilized. Individuals in each group
`ere alike with respect to age, race, number of cigarettes smoked per
day* age when they began to smoke cigarettes, place of residence,

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TABLE 5.-Age-adjusted lung cancer mortality ratios* for males
     and females, by tar and nicotine in cigarettes
      smoked

High T/N                       1.00                  1.00
Medium T/N                      0.95                  0.79
Law T/N                        0.81                  0.60

`The mortality ratio for the category with highest risk ~88 made 1.00 so tksl the relative reductions in risk with
the use of lower T/N cigarettes could be visudiwd.
SOURCE: Hammond. EC. (67)

occupational exposure to dust fumes, chemicals, etc., education, prior
history of lung cancer, and prior history of heart disease. Results of
this analysis are presented in Table 5. The mortality ratio for the
category with the highest risk was made 1.0 so that the relative
reduction in risk with the use of lower T/N cigarettes could be
visualized. For males smoking the same number of cigarettes per day,
there appears to be a 20 percent reduction in risk of developing lung
cancer with the use of low T/N cigarettes. For females, there was a 40
percent reduction in the risk of developing lung cancer with the use of
low T/N cigarettes, keeping the number of cigarettes smoked per day
constant. The amount of tar and nicotine taken into the body per day
depends on the number of cigarettes smoked, as well as on the tar and
nicotine content of each cigarette. Hammond conducted a second
matched-group analysis comparing subjects who smoked 1 to 19 high
T/N cigarettes per day and those who smoked 20 to 39 low T/N
cigarettes per day. These results are presented in Table 6. The number
of cigarettes smoked per day was a relatively more important variable
than the tar and nicotine content of cigarettes. The mortality ratio was
1.6 for males and 2.1 for females who smoked 20 to 39 low T/N
cigarettes a day, compared to individuals who smoked only 1 to 19 high
T/N cigarettes per day.

Wynder and Stellman (253) conducted a large retrospective study of
1,034 white males and females with histologically proved cancer of the
lung and larynx. Relative risks were consistently lower among long-
term smokers of filter cigarettes, compared to smokers of nonfilter
cigarettes. These groups were standardized for number of cigarettes
smoked, duration of smoking, inhalation, and cigarette butt length.
These dose-response relationships are presented in Figures 1 and 2.

Lung Cancer in Women

Trends in Cigarette Consumption Among Females
In 1964, the Advisory Committee to the Surgeon General concluded
that cigarette smoking was causally related to cancer in men, and that

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TABLE 6.--Age-adjusted lung cancer mortality ratios* for males
     and females, comparing those who smoked a few
     high T/N cigarettes with those who smoked many
     low T/N cigarettes

Males
Females

1-19 high T/N           2039 low T/N
cigarettes/da):         cigarettes/day

   1.00                  1.6
   1.00                  2.1

*The mortality ratio for the category with lowest risk was made 1.00 90 the increase in risk with smoking more
ciguettes/dsy could be illustrated.
SOURCE: Hammond, E. C. (60

"the data for women though less extensive, point in the same
direction" (217). Today, 15 years later, the lung cancer epidemic among
women is well established. Several investigators had predicted sharp
increases in lung cancer mortality among women. In 1966, Linden (118)
examined lung cancer mortality in California women and predicted:
"One can expect to see further increase in the number of lung cancer
deaths and the death rates as the increasing proportions of women who
smoke cigarettes reach the age when lung cancer is most likely to
OCCW."

In 1964, lung cancer was the fifth leading cause of death from cancer
in women. It became the fourth leading cause in 1967 and moved to the
third leading cause of death from cancer in 1969, passing cancer of the
uterus. Projections for 1979 indicate that lung cancer is approaching
cancer of the colon and rectum as the second leading cause of death
from cancer in women. If present trends are not reversed, during the
next decade lung cancer will become the leading cause of death from
cancer in women, exceeding deaths from cancer of the breast.

In 1955, there were only 4,100 deaths from lung cancer in women. In
1976, the National Center for Health Statistics reported there were
20,455 deaths from lung cancer among females in the United States
(150); the American Cancer Society estimated that in 1978 this
increased to 21,900 deaths (4).
These increases are not due to increases in the population. Death
rates for lung cancer have been steadily rising in women, especially in
the past decade. The lung cancer mortality rate for white females in
1950 was 4.7 per 100,000; by 1976 this had risen to 19.5 per 100,000. This
is more than a fourfold increase (Table 7).
The Surveillance, Epidemiology and End Results (SEER) Program
of the National Cancer Institute recently reported that the lung cancer
death rate for black females exceeded that of white females (16.8
blacks, 15.0 whites)(154). Data from this survey are collected from 10
geographic areas in the United States and therefore do not represent

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LUNG CANCER I. MALES

126

25
62

NON    F NF     F NF    F NF    F NF     F NF
SMOKER   l-10     11-20    21-30    31-40     41+

NO. OF CIGARETTES SMOKED PER DAY

FIGURE l.-Relative risk of lung cancer for males, by number of
cigarettes smoked per day and long-term use of filter (F) or nonfilter
(NF) cigarettes
SOURCE: Wynder, E.L. (253)

national trends per se. The lung cancer mortality rate (15.0 per 100,000)
among black females in the general U.S. population is equal to that of
whites.

Increases in lung cancer mortality among females cannot be
explained by exposure to occupational carcinogens. Increases in
cigarette consumption are responsible for these trends.

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25

20

15

10

5

LUNG CANCER I. FEMALES

N:   CASES
CONTROLS

20
2955

F NF     F NF

F NF

SMOKER    l-10      11-20     21-30       31+

     NO. OF CIGARETTES SMOKED PER DAY

FIGURE L-Relative risk of lung cancer for females, by number of
cigarettes smoked per day and long-term use of filter (F) and
nonfilter (NF) cigarettes
SOURCE: Wynder. FL (S.53)
The epidemic of lung cancer in women has lagged behind that in
men, primarily because of differences in patterns of cigarette smoking.
There are fewer women smoking than men, but the gap is narrowing.
Among teenagers in several age categories, girls are smoking more
than boys (155). Table 8 shows the percentage of the U.S. adult
Population who are currently smoking cigarettes for selected years. In
1975, approximately 29 percent of adult females were smoking,
whereas 39 percent of adult males were smoking (1%). It should also
be noted that, over the past decade, there has been a 2.6 percent

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