cigarette, the average length of time taken to smoke a cigarette
(except in the highest number of puffs category), and the taking
of more puffs at the end of the cigarette.
These findings, and those of the study of Auerbach, et al. (11),
add further support to the dose-response relationship between lung
cancer and total cigarette smoke condensate exposure.

SUMMARY AND CONCLUSIONS

1. Epidemiological evidence derived from a number of prospec-
tive and retrospective studies coupled with experimental and path-
ological evidence confirm the conclusion that cigarette smoking is
the main cause of lung cancer in men. These studies reveal that the
risk of developing lung cancer increases with the number of cigar-
ettes smoked per day, the duration of smoking, and earlier initia-
tion, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancer in women but
accounts for a smaller proportion of cases than in men. The mor-
tality rates for women who smoke, although significantly higher
than for female nonsmokers, are lower than for men who smoke.
This difference may be at least partially attributed to difference in
exposure; such as, the use of fewer cigarettes per day, the use of
filtered and low "tar" cigarettes, and lower levels of inhalation.
Nevertheless, even when women are compared with men who ap-
parently have similar levels of exposure to cigarette smoke, the
mortality ratios appear to be lower in women.

3. The risk of developing lung cancer among pipe and/or cigar
smokers is higher than for nonsmokers but significantly lower than
for cigarette smokers.

4. The risk of developing lung cancer appears to be higher among
smokers who smoke high "tar" cigarettes or smoke in such a man-
ner as to produce higher levels of "tar" in the inhaled smoke.

5. Ex-cigarette smokers have significantly lower death rates for
lung cancer than continuing smokers. There is evidence to support
the view that cessation of smoking by large numbers of cigarette
smokers would be followed by lower lung cancer death rates.

6. Increased death rates from lung cancer have been observed
among urban populations when compared with populations from
rural environments. The evidence concerning the role of air pollu-
tion in the etiology of lung cancer is presently inconclusive. Factors
such as occupational and smoking habit differences may also con-
tribute to the urban-rural difference observed. Detailed epidemio-
logic surveys have shown that the urban factor exerts a small
influence compared to the overriding effect of cigarette smoking in
the development of lung cancer.

276


7. Certain occupational exposures have been found to be asso-
ciated with an increased risk of dying from lung cancer. Cigarette
smoking interacts with these exposures in the pathogenesis of lung
cancer so as to produce very much higher lung cancer death rates
in those cigarette smokers who are also exposed to such substances.

8. Experimental studies on animals utilizing skin painting,
tracheal instillation or implantation, and inhalation of cigarette
smoke or its component compounds, have confirmed the presence of
complete carcinogens as well as tumor initiators and promoters in
tobacco smoke. Lung cancer has been found in dogs exposed to the
inhalation of cigarette smoke over a period of more than two years.

CANCEROFTHELARYNX

Cancer of the larynx is a disease which predominantly affects
males in the 55 to 70 year age group. In 1967, a total of 2,468 males
and 329 females died of laryngeal cancer in the TJnited States. With
the development and application of more effective therapy during
the past 30 years, the death rate for cancer of the larynx appears
to be dropping slightly (282, 289) ; however, the incidence con-
tinues to rise. Figures from the Connecticut Cancer Registry (88)
show that the age-adjusted incidence per 100,000 population of
cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961.

EPIDEMIOLOGIC`AL STUDIES

A number of epidemiological studies have investigated the rela-
tionship between smoking habits and the development of cancer
of the larynx. The major prospective studies, as outlined in table
20, show that smokers of cigarettes run an approximately six-to-
tenfold risk of dying from this form of cancer as compared to non-
smokers. Smokers of pipes and cigars incur a three-to-sevenfold
risk. The retrospective studies listed in table A21 uniformly show
fewer nonsmokers and more smokers among eases wit.h cancer of
the larynx than among matched controls. Table A22 summarizes
the relative risk ratios derived from the retrospective studies. The
wide variation is due to a number of factors, including type of popu-
lation and interview technique. But, in general, the magnitude of
most of these ratios is of the same order as in the prospective
studies.

Wynder, et al. (312) have distinguished between cancer of the
intrinsic and extrinsic larynx. Tumors arising on the vocal cords
are classified as intrinsic and constitute approximately 70 percent
of the lesions. The extrinsic larynx is composed of those sections of
the larynx excluding the vocal cords and may also be referred to as

277


TABLn Xl-Laryngeal cancer mortality ratios
(Actual number of deaths shown in parentheses)'
    SM = Smokers.    NS = Nonsmokers.
            -___.
          Prospective studies

Number

Author,
year,
cou"tly.
reference

Number and
type of
population

Data      FOllOW-
collection      UP
         years

Hammond
and
HOI.",
1958,
U.S.A.
(fZ0).

187.783 white
males 5c-69
years of age
in 9 states.

Questionnaire
and follow-
up of death
certificate.

Doll and
Hill,
1964,
Great
Britain
(74).

Approximately   Questionnaire     10
41,000 male     and follow-
British       up of death
physicians.     certificate.

Kahn      U.S. male      Questionnaire
(Darn).     veterans.      and follow-
1966,      2.265.674       up of death
U.S.A.      person years.    certificate.
(139).

                        ____
Hammond,   440,558 males    Interviews
1966,      562,671 fc     by ACS
U.S.A.     males 35-84     vo1u"teers.
(118).     years of age
          in 25 states.

  of
laryngeal
CanCer
deaths

Cigarettes/day

Pipes, cigars

COlIlIll~"t3

24    Cigarette smokers W/24.         Cigar    Data referring to mortality

SM . .24
NS 0

3/24
Mired
4124

l`atio included cancer of
esophagus and mouth.

   16
SM ..16
NS 0

  All smoke+8 by amount
      in gsame
NS . _. .   
1-14  1.00
15-24  __ __ __ ._ __. 1.00
>25 _. ._ _. _. ,, 7.60

Pipe and cigart  t Includes data on ex-
NS . 1.00    smokers of pipes and cigars.
SM 5.00    No NS died of laryngeo-
           tracheal cancer. therefore
            l-14 gram SM set as 1.00
            standard.
          Data combine laryngeal
            and tracheal carcinoma.

R IL

54

NS ..__.....__. 1.00 (3)

Pipe

Refers to current cigarette

I_
     SM .51    l-9 ..__._._..... 3.27 (1)   NS 1.00 (3)  smokers only.
     NS 3    l&20  8.45(10)   SM .10.33 (6)
             21-39  .13.62(11)    Pipe and cigar
             >39 ,............ 18.85 (3)   NS 1.00 (3)
              All  ,. 9.95(25)   SM .._. 7.28(11)

4         57    NS ._..__._... 1.00 (3)    Pipe and cigar  Male data only.
     SM ..54    SM (age 45-64)  6.09(32)   NS  1.00 (3) Pipe and cigar data refer to
     NS 3    SM (age 65-79)  8.99(18)   SM 3.37 (4)  males 55-84 years of age.


TABLE ZO.-Loyi~~gcnl cmccr 7nwtalitjj ratios (cont.)
    (Actual number of deaths shown in parentheses)'
       SM - Smokes.     NS = Nonsmokers.

              I'rosyective studies

Author,
year,
country,
reference

Number and
type of
population

Data
collection

Number
  of
lawngeal
caneel
deaths

Cigawttrslday         Pipes, cigars          C""l"lZ?"tS

Wrir and
Dunn,
1970,
U.S.A.
(906).

68,153 males     Questionnaire      5-8        11    NS            -
                                                             No nonsmokers died of
in various      and follow-            SM ..ll    *lo  1.00                  Inryn~.eal carcinoma,
occupations     up of death            NS 0    220  ., . 5.00                  therefore -cl0 smoker set
in California.    certificnt~.                    >30  5.84                  as 1.00 standard.
                                                                   NS includes pipe and cigar
                                                                      smokers.
                                                                     SM includes ex-smokers.

' Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion
of either occasional, miscellaneous, mixed, 01' ex-smokers.


t.he hypopharynx. These authors noted that the percentage of heavy
smokers among the patients with cancer of both the extrinsic and
intrinsic larynx was significantly greater than that among controls.
However, it is of interest that the excess risk of laryngeal cancer
among cigar and pipe smokers in this study could be attributed to
the extrinsic laryngeal group.

As in studies of oral cancer, it appears that alcohol consumption
should also be taken into account in studies of laryngeal cancer.
Wynder, et al. (872) reported a significantly increased risk of
extrinsic cancer among those with alcohol intake above 7 ounces of
whiskey per day. With less than this amount, no increased risk wa,s
evident. Schwartz, et al. (&8), noted no effect in relation to alcohol
intake. Further research into the interaction of these two variables
is necessary.

Auerbach, et al. (9) studied histological changes in the larynges
of 942 men, age 21 to 95, who were autopsied at a single hospital
between 1964 and 1967. Cases of primary cancer of the larynx were
excluded from the study. Smoking histories for all cases were
obtained from family members of the deceased by trained inter-
viewers. The randomized histological sections were graded by one
observer. Tables A23 and A21 summarize the findings in the true
vocal cord. Of the men who never smoked, 7.5 percent had no cells
with atypical nuclei, only -1.3 percent had sections with areas con-
taining 60 to 69 percent of cells lvith atypical nuclei, and none had
a higher percentage. The 116 ex-smokers had laryngeal histology
similar to that of the nonsmokers, as far as atypical nuclei were
concerned. HoLvever, disintegrating nuclei \vere found in JO.5 per-
cent of the ex-cigarette smokers and in only ()..I percent of the
remaining cases. Only one of the 9 1 cigar and or pipe smokers had
no atypical cells. Three had carcinoma irl sitrc, and one case had a
section showing early invasive primary carcinoma.

The highest percentage of atypical cells IVWS found among the
cigarette smokers. The proportion of cases with a high degree of
cellular change increased with increased daily smoking. None of
the pack-or-more-a-day smokers n-as free of atypical nuclei in the
laryngeal epithelium. Of those ivho smoked t\vo or more packs per
day, 85 percent had 1eGons xvith 60 percent or more atypical cells
as compared to -1 percent of the nonsmokers. Between 10 and 18
percent of the cigarette smokers had areas of carcinoma irz sitl(,
and .I of the 64-I cases showed early microscopic invasion. The
thickness of the basal level of the true vocal cord was also directl!
related to the amount smoked.

280


EXPERIMESTAL STUDY

Dontenwill (76) has recently reported the development of an
effective and practicable method 1)~ n-hi& small rodents (ham-
sters. rats? mice) can be exposed to long-term passive inhalation of
cigarette smoke in a mannel' nhich circumvents the fatal effects of
acute toxicity. which ruincc! earlie:, attempts but allows for a dosage
of smoke great enough to induce the development of chronic patho-
logical changes. The SJ.rian Golden hamster was found to be the
most suitable species for such inhalation experiments for several
reasons : its resistance to pulmonar!- infections, its resistance to the
effects of nicotine a.5 compared to that of rats or certain strains of
mice, and, especially, its susceptibility to develop tracheobronchial
cancers after treatment nith carcinogens, in contrast to its almost
total freedom from the spontaneous development of these tumors.

Dontenwill demonstl*atecl that the concentration of deposited
cigarette smoke uas greatest in the hamster's larynx as compared
to the other portions of the exposed respiratory tract (table 25))
and that the lar\-ngeal epithelium was the tissue which underwent
the greatest smoke-induced histological changes.

In studying the changes in the larynx, the author differentiated
five stages of epithelial change, using as his reference the Atlas of
Tumor Pathology of the Armed Forces Institute of Pathology (5).
Table 26, quoted by Dontenwill, describes the five types of change.
They range from benign. such as epithelial hyperplasia, to pre-
malignant. exemplified by pseudoepitheliomatous leukoplakia.

The results of the inhalation experiment are presented in figure
-1 in which a dosage-related increase in the severity of the epithelial
changes is represented in graphic form. The author also reported,
and depicted with photomicrographs, the finding of an early inva-
sive squamous cell carcinoma. This form of cancer is the predomi-
nant type involving the human larynx.

SUMMARY AND CONCLUSIONS

1. Epidemiological, experimental, and pathological studies sup-
port the conclusion that cigarette smoking is a significant factor in
the causation of cancer of the larynx. The risk of developing
laryngeal cancer among cigarette smokers as well as pipe and/or
cigar smokers is significantly higher than among nonsmokers. The
magnitude of the risk for pipe and cigar smokers is about the same
ol.cler as that for cigarette smokers, or possibly slightly lower.

2. Experimental exposure to the passive inhalation of cigarette
smoke has been observed to produce premalignant and malignant
changes in the larynx of hamsters.

281


TABLE 25.~Deposition of `"C-lubeled smoke pwticies
  in particular regions of the respimtoq tract'

Organ

Traced
radio-
activity   01-g?in
CnCi)

Head and palate 6.11  Head. palate

Tongue

0.41  Oral cavity
     in total.

Larynx      (r 39
Trachea     0.26
Lungs       6.35 1
   Total     14.12

Eitimated    Deposition
radio-       of
activity     particles
(nCi)       ( % 1

         Traced
Proportional depwsition
area of the  in relatirm
respiratory    to the
tract   ProPortional

j-3

1.6

          0.1-0.3   X561-187
1   ,Zl.i       0.6      X62.3
           1000     Xl

  1~11).0

282


TABLE 26.-Classification of the five registeredstages of epithelial charzgcs at the lwynx'.'

stage

-.-__~  --__~  __--   ~- ~.-. . ~~      - ..--. .~
                                        Drskerntosis (we-
                                           mature atypical
Acanthosis (thickm-    H, ,,erkr,xt<&     Pnrakeratosis (in-      cornification
  ing of stratum       increased      complete cornifica-     changes in the    Mitosis
  spinosum multi-      cornificntion      tion of nuclei in     nucleus prolifern-
  cellular layer)     (stratum corneum)   the stratum corneum)    tion of the basal

1. t'nchvdwmia (epithelial hywrplasia)        +             +              t              t         t

2. Leuroplakin          +             +-              1              r         t

4. t'apillrnnntou~ kwruplakia          +             t              t             +it        f


                                               TOTAL  146

  34    35    8    6    10    7    11    4    5    17    4    5
                   .    .    . . . .  .    . .    .    . . . . .
5

                     .    . . . . . .
  4

                 . .        . .             . . . .
  3

2            . . . . .    . . . . .    . .    .
52
c
"  ,I                      I             I   I

2    4    6    8    10 12 14 16    18 20   22-28
            SMOKE EXPOSURE, months

      . ZONE ANIMAL    &=ANIMAL LIVING     O=LARYNX CANNIBALIZED

FIGURE 4.-Effects of chronic cigarette smoke inhalation on the hamster larynx.
Review of the results of the inhalation experiments: number of smoke-ex-
posed animals with and without changes in the larynx, duration of smoke
exposure, and number of animals still alive.
SOURCE: Dontenwill, W. (7G).

ORAL CANCER

The cancers included in this category are those of the lips, tongue,
floor of the mouth, hard and soft palate, gingiva, alveolar mucosa,
buccal mucosa, and oropharyns. It is estimated that 15,000 of these
cancers will be diagnosed in the United States in 1970, accounting
for about 2.5 percent of the estimated 600,000 malignant neo-
plasms reported (289). A variety of histological types of malig-
nant neoplasms can affect these tissues, but squamous cell car-
cinoma is by far the predominant type, accounting for about 90
percent of the cancers.

The incidence of and mortality from oral cancers has remained
steady over the past 20 to 30 years. The Connecticut Cancer Reg-
istry (88)) which is a fairly reliable index of incidence, noted that
the incidence among males remained between 15.8 and 16.3 per
100,000 population during the years from 1950-1961. Examination
of mortality rates over the past 20 to 30 years (882, 289) reveals
a similar constancy.

The apparent lack of change in mortality from oral cancer in

284


contrast to the sharp increase that took place in lung cancer rates
in those years is probably due to serreral of the following factors.
First, pipe and cigar smoking are both significantly related to can-
cer of the oral cavity, and the increase in cigarette smoking among
men, noted between 193r and 1955, has been, to a large degree,
accompanied by corresponding l,eduetions in the use of pipe.; and
cigars. Second, aside from the V:CYiOUS changes which the Interna-
tional Classification of Diseases (ICD) had undergone during t.hat
period, the diseases discussed above are recorded in ICD Codes
140-148 which include some neoplwms not found to he related to
the use of tobacco. The various sites of cancer themselves do not
contribute equally to the o\~e~all 1,atc and are subject to nidely dif-
ferent cure rates, so that their contl.i1)ution. to the total incidence
rate is different from their colltri~Jiltil~ll to the c~vt>rall mortality
rate from oral cancer. Although more than 31,000 cancers of the
oral cavit)- were estimated ;1~ nelvl:- di:cyno.& ill 1967, the total
number of individual5 rcco~~ierl ;is tlJ,ing front oral wncer during
that year was only 6,71 x (~8:)).

Oral cancer occurs predominantly in people of the middle and
older age groups. More than 90 percent of all oral cancers occur in
persons over age -15, with the average age at time of diagnosis
approximating 60. Although the majority of oral cancers occur in
men, there is recent evidence that the ratio of males affected to
females affected is decreasing (2.57).

~EPII,E?~~IOI,~)GIC.L\L STUDIES

The use of tobacco in various forms has been associated with the
development of cancer of the oral cavity and pharynx. The studies
in this area of concer1, at-t' ?rul~- international, many having been
carried out in Asian :" :ll~ns as well as in the M'est.
The major pr(J~im,: ; t' u!~i:lumic~logic~~l htudies have found in-
creased rates of fhcw .`::I "`.:rs for cigarette smokers as well as for
pipe and cigar sni:)kei~:: (see table 27). Pipe smoking, per se, has
long been recognizt:cl :~s a cause (Jf lip cancer (?!I1 ) . The methodol-
ogy and results of the numerous retrospective studies are sum-
marized in tal,lti:.i X28 ar:d AZ&. These studies almost uniformly
show significant relalionships between the various forms of tobacco
use and )`.' `::"-c'-: 1,; -1 P c:`.:: ;:t\-ity and pharynx.

Studir5 !I; .`$-. :!: ,t' 1;~: h:~~e examined the prevalence or inci-
dence of pl'enliijJ~J:,.!.. :i~n& , ,G;lrch as oral lettkoplakia, as well as
that of cancer of the oral cavitp. In many of thwe studies, forms of
tobacco use not prevalent in lyestern countries have been investi-
gated, including reverse smoking (in which the lighted end of t.he
cigarette is kept in the mouth close to the palate) and the chewing

285


TABLE 27.-Oral cancer mortality ratios-prospective studies

Author
year.
country,
reference

Number and
type of
population

Data
collection

   (Actual number of deaths shown in parentheses)
     SM= Smokers.    NS = Nonsmokers.

FOllOW-   Number
UP Years     of           Cigarettes
       deaths

Pipes, cigars

Comments

Hammond  187.783 white    Questionnaire      3 $6                   20/56         Pipe    MiXCd   Data referring to mortality
and      males in 9      and follow-up                                      5/M     21/56    ratio do not include cancer of
HOlYI,     states 50-69     of death             NS ..3                          Cigar        larynx and esophagus.
195R,      years of aEe.    certificate.                                           6/66       t Excludes two occasional
U.S.A.                                                                           only smokers.
(110).

Doll nnd    Approximately   Questionnaire      10         19     All smokera by amount      Pipe and cigar    No NS died of oral CBIICCI',
Hill,      41,000 male     and follow-up          SM   .19         in gram.9        NS  ....... 1.00      therefore 1-14 gram
1964.      British        of death             NS  .. .   NS            -
                                               ..............        SM  ....... 1.00      smoker set as 1.00
Great     physicians.     certificate.                    1-4  ............. 1.00                    standard.
Britain                                        15-24  ............ 0.25
(74).                                         >25  ............. 5.25
                                       - .... ..-- .
Kahn     U.S. male      Questionnaire      Xl/,        61   NS  .............. l.OO(ll)       Pipe       Data do not include pharynx.
(Darn),    wternns.      and follow-up          SM   .50   tCias/day 1-9  .... 0.86 (1) NS  ....... l.OO(ll)  t Refers to current cigarette
1966,      2.265.674      of death             NS   .ll   lo-20  ............ 2.93(13) SM  ....... 3.12 (4)   smokers only.
U.S.A.     ,:cI`:ioll YCBTS.    cel~tifirnte.                   21-39  ............ 7.34(20)       Cigar
(139).                                        >39  ............. 5.73 (3) NS  ....... l.OO(ll)
                                            All  .............. 4.09(37) SM  ........ 4.11 (9)

H~~IllOlld.  410,65;: males    Interviews by      4         95   NS  .............. 1.00 (`7)  t Pipeand/or      t Male data only. Pipe and
1966,      T,C2,1;71 females   ACS volunteers         SM   .33  SM (age 45-64)  ... 9.90(63)   cigar.            cigar data refer to males
U.S.A.     :ii-' I ycnrs "f                     NS  .. .  SM (sge65-`79)  .. 2.!33(25) NS  ....... 1.00 (7)   55-84 years of age.
(118).     apt ill 25 states.                                              SM  ....... 4.94(15)

Weir and   FR,lS:i lN.ales    Questionnaire      5-R        19   NS  .............. 1.00                   SM includes ex-smokers.
Dunn,     in vat ious      and follow-up                 -10  ............. 3.69                    NS includes pipe and
1970,      occupations     of death                     -t20  ............. 1.17                    cigar smokers.
U.S.A.     in California.    certificate.                   >3n  ............. 6.62
(.W(i).                                        All  .............. 2.76


of "pan" or "Nass," which are mixtures of tobacco with either betel
nut or lime ash, and other ingredients (241, 2.55, 256). Snuff
dipping, a habit in which snuff is placed in the gum and ret.ained
there for prolonged periods, has also been associated with the
development of oral cancer (1118, 210)) as has the chewing of
tobacco (124, 193,211,298).

The risk of developing a second primary mouth or throat cancer,
after the recognition of the first primary cancer, has been found
to be greater in continuing smokers than in those who quit smok-
ing. All of the patients studied by Moore (190) were asymptomatic
for at least three years following the treatment of the first cancer.
Of the 117 patients with adequate smoking histories, only 4 of 33
(9 percent) who quit smoking developed a new primary cancer.
On the other hand, 27 of 74 (36 percent) who continued to smoke
developed a second primary cancer.

However, a study by Castigliano (53) of patients treated fol
oral cancer did not show a greater risk of a second primary among
continuing smokers. In this study, 5 of 26 (19 percent) of those
patients who did not quit smoking developed a second primary
cancer as compared to 9 of 51 (18 percent) of those who did quit.
The rate of quitting smoking in the two studies is markedly dif-
ferent (36 percent in the Moore study and 62 percent in the Casti-
gliano study). From the data presented in the two papers, it is not
possible to evaluate the other significant ways in which the pop-
ulations may have differed.

Keller (1~0) studied 408 males with histologically confirmed
squamous cell cancer of the mouth or pharynx. This author dealt
with the question of recurrent tumors in a somewhat different
manner. The patients were observed for the development of a sec-
ond or third primary cancer at an anatomically discrete site of
the mouth and pharynx within a median period of three years after
the first cancer. He found that a second or third cancer (termed a
coexisting cancer) developed in 28 of the 408 cases. Among these
23 cases with 32 coexisting neoplasms, 21.7 percent were heavy
smokers, but among their matched controls, there were no heavy
smokers. Coexisting cancers were most commonly found on the soft
Palate, an anatomical site that is in direct contact with the main-
stream of tobacco smoke.

More recently, Wynder, et al. (S1S) studied 62 male and 23
female patients with multiple primary cancers of the mouth and
pharynx. They observed that heavy smoking prior to the develop-
ment of the oral cancer was associated with a greater likelihood
of developing a second primary. Also, continued smoking after t.he
fil'st primary was found to have a significant association with the
occurrence of a second primary.

287


With or without smoking, use of alcohol appears to contribute
to the development of oral cancer (124, lJ0, 183, 2.97, 322). In a
study of male veterans, Keller (110) found that heavy smoking
and heavy drinking were associated with cancer of the mouth and
pharynx. X:0 studies are presently available which determine the
relative contributions and possible interactions of heavy smoking,
heavy drinking, and concurrent nutritional deficiencies in the etiol-
ogy of these cancers.

EXPERIMENTAL STUDIES

In 1964, the Advisory Committee to the Surgeon General on
Smoking and Health (291) reported that cigarette smoke and ciga-
rette smoke condensates had failed to produce cancer when applied
to the oral cavity of mice and rabbits or to the palate of hamsters
and t.hat the oral mucosa appears to be resistant in general to can-
cer induction even when highly active carcinogens such as benzo-
[alpyrene are applied. Some of the difficulties in experimental de-
sign were attributed to the fact that mechanical factors, such as
secretion of saliva, interfere with the retention of applied carcino-
genic agents on the tissues of the oral cavity and pharynx. Positive
results with certain carcinogens have, however, been obtained in
the hamster cheek pouch, but it has also been pointed out that the
cheek pouch lacks salivary glands and that its structure and func-
tion differ from those of the oral mucosa. The majority of these
studies are outlined in table AZ9.

Although cigarette smoke condensate acts as a complete carcino-
gen on mouse skin, the work of several authors (319) supports the
concept that cigarette smoke contains cancer promoters that may
be of special importance, particularly in oral carcinogenesis. Elzay
(90) has reported that whole cigarette smoke is a promoting agent
for the hamster cheek pouch. More importantly, regarding the
chewing of tobacco, Bock, et al. (27. .30), Van Duuren, et al. (.Z!1$),
and Wynder and Hoffmann ($21) have shown that unburned to-
bacco products contain tumor promoters that might contribute to
the promoting activity of the smoke.

Roth, et al. (d?li , ~27) have shown that the dye-binding capacity
of the DNA of oral epithelial cells is significantly enhanced in
cigarette smokers in contrast to nonsmokers, probably reflecting
an increase in the DXA content of oral epithelial cells in smokers.
Smokers had values of dye-binding capacity intermediate between
nonsmokers and "1 patients with proven oral cancer. Those smok-
ers who refrained from smoking for up to six months showed a
significant decrease toward more normal values.


SUMMARYANDCONCLUSIONS

1. Epidemiological and experimental studies contribute to the
conclusion that smoking is a significant factor in the development
of cancer of the oral cavity and that pipe smoking, alone or in
conjunction with other forms of tobacco use, is causally related to
cancer of the lip.

2. Experimental studies suggest that tobacco extracts and
tobacco smoke contain initiators and promoters of cancerous
changes in the oral cavity.

CANCER OF THE ESOPHAGUS

Esophageal cancer accounted for 4,306 deaths among American
males in 1967 and 1,321 deaths among females. The death rate
from esophageal cancer has remained relatively constant since
1939.

EPIDEMIOLOGICAL STUDIES

The major prospective epidemiological studies (table 30) have
indicated a significant relationship between smoking and esopha-
gea! cancer. Overall mortality ratios for male cigarette smokers
range from 1.74 to 6.17. There are insufficient data concerning
females for establishing firm conclusions.

A number of retrospective studies concerning the relationship
of smoking and esophageal cancer are outlined in table A31 and
&la. Smokers incur risk ratios ranging from 1.3 to 6.6 when
compared with nonsmokers.

As in studies of oral cancer, the effect of alcohol consumption
must be taken into account in studies of esophageal cancer. Because
a relationship between alcohol consumption and tobacco use is
kno1v-n to exist, Wynder and Bross (310) analyzed the association
between tobacco consumption and esophageal cancer after adjust-
ing for alcohol intake. They found that in the absence of alcohol
consumption, there was no association between the use of tobacco
and esophageal cancer but that in the presence of alcohol consump-
tion, an increasing relative risk with increasing number of ciga-
rettes smoked was apparent, as well as an association between
cigar and pipe smoking and esophageal cancer.

More recently, Takano, et al. (Z'6), in a retrospective study of
`?(I0 patients with esophageal carcinoma, found an increased risk
mith smoking which was magnified by increased alcohol consump-
tion. Martinez ( 183) analyzed the association of tobacco usage
and esophageal cancer after controlling fol. age, sex, and alcohol
consumption. Increasing relative risks with increasing tobacco use

209


TABLE 30.-Esophageal cancer mortu& ratios-prospective studies

(Actual number of deaths shown in parentheses)'
   SM = Smokers.     NS = Nonsmokers.

Author,
year,
countrY,
reference

Number and
type of
population

Data       Follow-
collection     up years

Number of
esophageal
cancer
deaths

Cigarettes/day

pipes, cigars        Commmts

Hammond
and
HOlTl,
1958.
U.S.A.
(120).

1X7.783 white
males in 9
states EDIM!,
yenrs of age.

Questionnaire
and follow-up
of death
certificate.

3%

     34    Cigarette smokers        Pipe    Mticd      Data referring to
NS ___ 1     15/33.             2/33    cigarette      mortality ratios
SM . ..33                    Cigar   smokers       included cancer
                           2/3.1    13/33        of mouth
                                            and larynx.

Doll and

Approximately

Questionnaire

10

29

All smokers bu amount

tl'ipe and cigar

t Includes ex-

Hill,       41,000 mnlc       and follow-up                        in grama        NS 1.00         smokers of pipe
1964,       British          of death                         NS  , ._ 1.00        SM 2.00         and cigars.
Great      physicians.       certificate.                        1-14 2.00
Britain                                               15-24 3.60
(74).                                                >25 5.00
                                                    All  3.00
-____-      __
Katm      U.S. male        Questionnaire      8 `A          111    NS  l.OO(tl)         Pipe         t Refers to
(Darn),     veterans         and follow-up            NS 11   t1-9 1.76 (2)         1.99 (3)         cigarette
1966.       2,265,674        of death               SM . ..lOO    10-19 4.71(18)          Cigar          smoking
U.S.A.      person years.      certificate.                     20-39 .11.50(24)         5.33(12)         OdY.
(139).                                                >25  7.65 (3)
                                                    All  6.17(47)

Hammond,   440.sj5X malrs      Interviews by       4            46    NS  1.00 (6)       Pipe and Cigar
1966.       562,671 females   ACS volunteers.            NS . 6    SM (age             NS 1.00
U.S.A.     35 a4 years of                         SM 40     45-64) 4.1'7(32)      SM 3.97(14)
(118).      age in 25 States.                                 SM (age
                                                  65-79) 1.74 (8)


(Actual number of deaths shown in parentheses)
  SM= Smokers.     NS = Nonsmokers.
              .

Author
year.
country.
reference

Number and
type of
population

Data       Follow-
collection     up years

HirElYalIla,   265,118 male      Trained PHS       II/&     SM . ..21    NS  l.OO(p<O.Ol)
1867,       and female       nurse inter-                       SM  2.47(21)
Japan      adults 40         view and
(125).      years of age      follow-up
          and older.        of death
                       certificate.

Weir and    6X,153 males      Questionnaire       S-R           32    NS ._ _. 1.00
DUllll,      in various       and follow-up                      *lo 1.27
1970.      occupations       of death                         -czo 1.69
U.S.A.      in California.      ccrtilicate.                        >30 l.f?2
(SUB).                                                All  1.82

' Unless otherwise specified,  disparities between the total number of
deaths and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellnncous, mixed, or ex-smokers.

Comments

Refers to all
forms of
smoking.

NS includes pipe
and cigar
smokers.


were noted. The consumption of very hot beverages was also found
to be related to the development of esophageal cancer.

PATHOLOGICALSTUDY

Autopsy studies of smokers as compared with nonsmokers, spe-
cifically observing the pathological changes in esophageal tissue,
have been performed by Auerbach, et al. (15). A microscopic study
was made of 12,598 sections of esophageal autopsy tissue from
1,268 men who died from causes other than esophageal cancer. The
findings were strikingly similar to the abnormalities generally ac-
cepted as representing premalignant tissue changes in the respira-
tory tract epithelium. Esophageal epithelial cells with atypical
nuclei (having an irregular distribution of chromatin) were found
far more frequently in cigarette smokers than in nonsmokers. Basal
cell hyperplasia and hyperactive glands were also found more fre-
quently in cigarette smokers than in nonsmokers. An increase in
frequency with amount of cigarette smoking was noted for both
epithelial cells with atypical nuclei and basal cell hyperplasia.
Tables A32 and A33 summarize these findings.

EXPERIMENTALSTUDIES

Kuratsune, et al. (156) investigated the possibility that the car-
cinogens known to be present in tobacco smoke could penetrate the
esophageal epithelium more readily if dissolved in aqueous ethanol.
Mice were exposed to several compounds by esophageal intubation.
Tissues were then removed and studied by fluorescence microscopy.
Deeper penetration and a different distribution were found when
B[a]P was dissolved in aqueous ethanol as compared to B[a]P in
olive oil. It was also found that benzo[a]anthracene and fluoran-
thene dissolved in ethanol solution or aqueous caffeine solution
could penetrate the epithelium of the esophagus.

Horie, et al. (132) reported on the development of 10 papillomas
and one squamous cell carcinoma of the esophagus in a group of
63 mice periodically forced to drink a solution of benzo[a]pyrene
dissolved in diluted ethanol. Twenty-six papillomas and one squam-
ous cell carcinoma also developed in a group of 63 mice to which
4nitroquinoline l-oxide was administered in the same way. None
of the 67 control animals given only diluted ethanol developed
neoplasms.

Several other authors have reported nitrosamine-induced esopha-
geal cancer in experimental animals (56, 79, 80, 81) . As noted
above, the presence of nitrosamines in cigarette smoke is still a
subject of debate.

292


SUMMARY AND CONCLUSIONS

1. Epidemiological studies have demonstrated that cigarette
smoking is associated with the development of cancer of the esopha-
gus. The risk of developing esophageal cancer among pipe and/or
cigar smokers is greater than that for nonsmokers and of about
the same order of magnitude as for cigarette smokers, or perhaps
slightly lower.

2. Epidemiological studies have also indicated an association be-
tween esophageal cancer and alcohol consumption and tthat alcohol
consumption may interact with cigarette smoking. This combina-
tion of exposures is associated with especially high rates of cancer
of the esophagus.

CANCER OF THE URINARY BLADDER AND KIDNEY

EPIDEMIOLOGICAL STUDIES (BLADDER)

Cancer of the urinary bladder accounted for 6,019 deaths among
American males and 2,743 deaths among American females in 1967
(289). Incidence rates have increased from 1949 to 1962 (88)) but
the death rates from bladder cancer have remained relatively
stable during that period. Improvements in early diagnosis and
therapy may have masked the increasing incidence of this disease.

A number of epidemiological studies have indicated that smokers
have an increased risk of contracting or of dying from bladder
cancer (see tables 34 and A35). Certain of these studies include
kidney cancer mortality in the results. The major prospective stud-
ies, with the exception of that of British physicians, have shown
bladder cancer mortality ratios among cigarette smokers ranging
from 1.40 to 2.89. Smokers of more than 1 pack per day were shown
to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 7'5)
of British physicians, on the other hand, reports death rates for
smokers to be lower than those of nonsmokers based on 38 bladder
cancer deaths. The mortality ratios for pipe or cigar smokers are
substantially lower than those among cigarette smokers. Pipe
smokers were shown by both Hammond and Horn (120) and Kahn
(139) to incur ratios approximating 1.20.
Retrospective studies (table A35a) have also shown an increased
proportion of smokers among bladder cancer patients when com-
pared with matched controls. Relative risk ratios for bladder can-
cer among smokers range from 1.0 to 7.3 among all smokers and
up to 10.3 among heavy smokers of all types.

293


TABLE 34.-Kidney and urinary bladder cancer--prospective studies-Mortality ratios
               (Actual number of deaths shown in parentheses)'
                   SM = Smokers.     NS = Nonsmokers.

Author,
  yen=.    Number ar.d     Data     Follow-   Number
country,     type of     collection   up years     of      Cigarette/day                Kidney     Bladder         Comments
reference   population                    deaths                Pipe. cigar

Hammond  187,783 white   Questionnaire    3 I/(?

and
Horn,
1958.
U.S.A.
(120).

males in 9     and
states.       intrrview.

   287 NS 1.00(383      Pipe
       <lO 2.00(14) NS ..1.00(38)
SM .249  lo-20 X00(42) SM t, .1.17(21)
NS 38  >20 3.42(41)      Cigar
                   NS .1.00(38)
                   SM .1.06(19)

Data include patients
dying of prostatic
carcinoma.
Data refer to
microscopically
PlW"Wl
carcinomas.

Doll and   Approximately Questionnaire 10
Hill,      41,000 male    and follow-
1964,      British      UP of death
Cl-eat     physicians.    certificate.
Britain
(74).

Best,     Approximately Questionnaire 10
1966,      78,000 male    and follow-
Canada    Canadian     UP of death
(21).     veterans.     certificnte.

Hammond,  440,66X males   Interviews by    4
1966.     562.671       ACS
U.S.A.     females      volunteers.
(11X).     35-84 years
        of age in 25
         states.

38

NS ..l.OO
SM ..0.41

  All SM bg
amount in grams
NS . ..l.OO
l-14 .0.59
15-24 .0.65
>25 .0.76
All .0.`71

114   NS 1.00        Pipe                        Refers to
   <lO 1.33(29) NS .l.OO                        genitourinarv
   lo-20 1.44(67) SM .0.56(10)                      cancers as a
   >20 1.43(16)      Cigar                        group.
   All 1.40(10) NS ..I.00
               SM .1.16 (3)

Bladder
    138
SM ,115
NS 23
Kidney
   104
SM 82
NS 22

     Cigarettes         Cigarettes   Male data onl2/.
NS  .1.00(22)       1.00(23) Bladderincludes
SM (age 45-64)  .1.42(64)       2.00(59)   other urinary
SM (we 65-79)  .1.57(28)       2.96(S)   tract cancers.


  `I'ABLE 34.-KicOlc7!y und wimry hladdcr cancer-prospective studies--Mortality ratios (cont.)
                    (Actual number of deaths shown in parentheses)'
                           SM = Smokers.     NS = Nonsmokers.

Number and     Data     Follow-   Number
type of     collection
pom&ition            "I) Years  de:ftha    Cigarette/day    Pipe, cigar       Kidney     Bladder

comments

Kahn     U.S. malt     Questionnaire

(Darn),    vetcrnns     and folluw-
13FF,      2,265,G74     up of death
U.S.A.     person       certificate.
(138).     years.

Hirayama,  265,118 male   Trained PHS
1067,     ana female    nurse inter-
Japan     adults 40      view and
(125).    yea,? of age    follow-up
        and older.     of death
                  certificate.

Weir and   FR,lRR males   Questionnaire
DlIIlll.     in various     pnd follnw-
1070,     occupations    up of death
1J.S.A.    in California.   certificate.
(sns).

-.- .___
S'/,    Bladder               NS  _... .1.00(38)       1.00(52) Bladder includes
         224               Pipe  .1.32 (6)       1.20 (8)   other urinary
     SM ,112               Cigar  .O.W (6)       0.94 (10)   tract calleers.
     NS . 52              Ciaarettes/day:
     Kidwey                  l-9  .a.97 (4)       1.10 (6)
         141                10-19  .1.34(21)       1.93(U)
     SM ,102                20-38  l&8(16)       3.20(34)
    NS 39               >39 .2.76 (5)       2.62 (6)
                         All  . .1.45(46)      2.15(82)
                         _.--.                                -___
l',$ SM    6  NS 1.00                               Bladder cancer only.
           SM . . ..lO.OO (6)                                Refers to all
                                                    forms of smoking.

6-8

Bladder
   27
Kidney
   27

NS
a10
?20
>30
All

1.0"     NS . ..l.OO     SM include ex-

.0.&i
.3.30
.2.57
.2.46

?lO   .1.52      smokers.
520   .2.81     NS include pipe
>30   .5.41      and cigar
A11   .2.89      smokers.

' Unless otherwise specified,  disparities between the total number of
deaths and thr sum nf the individual smoking categories are due to the
exclusion of either wcasional. miscellaneous, mixed, or w-smokers.


EPIDEMIOLOGICAL STUDIES (KIDNEY)

A total of 5,894 Americans died of cancer of the kidney during
1967. A relationship between smoking and this type of cancer has
been suggested by several epidemiological studies. The three major
studies which separately examine the relationship of kidney cancer
to smoking (table 34), namely those of Hammond (II 8)) Kahn
(139), and Weir and Dunn (306)) have shown mortality ratios for
all cigarette smokers to range from 1.42 to 2.46. Retrospective
studies by Bennington, et al. (18, 19) have indicated a significant
association between all forms of smoking and renal adenoma and
adenocarcinoma.

EXPERIMENTAL STUDIES

Numerous experiments have been undertaken by many investi-
gators to elucidate the relationship of tobacco smoking to bladder
carcinogenesis. The two areas of major concern have centered upon
the presence of a known bladder carcinogen, beta naphthylamine,
in cigarette smoke and the presence of abnormal tryptophan me-
tabolism in patients with bladder cancer.

By virtue of data gathered concerning industrial exposure of
workers, beta naphthylamine has long been known as a bladder
carcinogen. Complementing such data was the work of Hueper, et
al. (136) who subjected mongrel dogs to daily subcutaneous injec-
tions and oral administration of commercial beta naphthylamine.
Thirteen of the 16 animals developed bladder papillomas and car-
cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet
containing up to 1.0 percent beta naphthylamine and observed that
18 of 39 animals developed bladder tumors, almost all typical tran-
sitional cell carcinomas. More recently, Conzelman, et al. (5.9) ad-
ministered beta naphthylamine to 24 rhesus monkeys for more
than 30 months. Transitional cell carcinomas of the urinary blad-
der were induced in 9 of the animals, and a dose-response relation-
ship was apparent.

Pailer, et al. (207') and Miller and Stedman (185) failed to find
this amine in cigarette smoke. However, more recently, Hoffmann,
et al. (127) identified it in cigarette smoke. The authors, noting
the minute quantity present in each cigarette (2.2 x l&`g), hesi-
tated to attach a biological significance to the finding.

Of more recent interest have been the metabolites of tryptophan
present in certain patients with bladder cancer. A number of nor-
mal and abnormal metabolites of tryptophan have been found to
be carcinogenic when tested by implantation in the bladders of mice.
These include 3hydroxykynurenine (OHKy), 3-hydroxyanthranilic

196


acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino-
phenols), the g-methyl ether of xanthurenic acid (CHXa) , xanthu-
renic acid (Xa) , L-kynurenine (KY), quinaldic acid, and 3-meth-
oxyanthranilic acid (3CHOA) (2, 36, 37, 39, 47, $8). OHKy and
OHA are frequently present in human urine, as is kynurenic acid
(WA).
Certain investigators have concentrated their attention on the
presence of abnormal tryptophan metabolites and increased
amounts of normal tryptophan metabolites in the urine of patients
with bladder cancer as compared with selected controls (1, 10, $6,
97, 148, 211, 2;3, 32.9). These authors have observed the increased
excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky-
nurenine in such patients. Yoshida, et al. (Jz!?), in a recent study
concerning the relationship between tryptophan metabolism and
heterotopic recurrences of human urinary bladder tumors, reported
that those patients with recurrences showed abnormal metabolfte
excretion more often than those without recurrences.

The relationship of smoking to these biochemical findings is
presently uncertain. Kerr, et al. (123)) in 30 experiments on 3
smokers and 3 nonsmokers who were given large doses of trypto-
phan, found that smoking increased the urinary excretion of OHKy
and OHA and decreased that of N'methylnicotinamide (an end
product of tryptophan metabolism). Kerr concluded that smoking
interferes with the normal metabolism of tryptophan. Recently,
Brown, et al. (is) studied 15 adults under smoking and abstinence
conditions and found that except for the basal excretion of acetylky-
nurenine, tryptophan metabolite excretion did not change with
smoking or cessation. The authors also compared 13 nonsmokers
and 17 regular cigarette smokers under basal and tryptophan-
loaded conditions. No differences were observed in the excretion of
the measured tryptophan metabolites. However, due to its instabil-
ity, OHA was not measured. The authors concluded that the rela-
tionship of smoking to urinary bladder cancer was probably not via
its effect on the kynurenine pathway of tryptophan metabolism.

Another experimental approach to the relationship of smoking
and urinary bladder cancer is reflected in the work of Schlegel, et
al. (241, 215). The authors observed an elevated concentration of
certain ortho-aminophenols in the urine of bladder cancer patients
and cigarette smokers, when compared with nonsmokers (241).
More recently (215) , the same group compared the chemilumines-
cence of the urines of smokers, nonsmokers, and bladder tumor
patients. They noted that nonsmokers showed the lowest level of
luminescence (which they relate to the presence of aromatic hydro-
carbons) and the bladder tumor patients the highest level. The
normal cigarette smokers' level was found to be intermediate.

297


TABLE 36.-Pancreatic cancer mortality ratiosqrospective studies
       (Actual number of deaths shown in parentheses)'

                                    S.M x Smokers.    NS = Nonsmokers.
       .____-
  Author.
  year,    Number and       Data      I+llOW-UP    Number                                      Comments
  country,      type of       collection      years     of deaths         Cigarettes        Pipes, cigars
reference     population
___~
Best.       Appro\imntelp  Queutionnni;~      F     SM 35    Currntt ~cigarcttes OnLY)       Pipes            --

7x.000 male
Canadian
vrternns.

and folk,w-up
of death
crrtiiicate.

NS 1.00           NS .l.OO
<lO ., 1.40 (5)       SM ..2.60 (6)
to-20 1.96 (16)           Cigars
>20 .,.. 2.37 (7)        NS .l.OO
                   SM .2.63 (1)

           -~ ~-___                                             -:
Hammond    140,55X male5    Intcrvicms b,      4           262  NS~.. 1.00 (29)                  Male data only.

19GG       St;L'.liil fcmnies   ACS                SM . ..a233   SM (age
U.S.A.      .15-x4 )Iw,w     v~,ln"tre~.s.            NS 29    45-64 )  Z.G9(158)
(IIY).      of nge in 25                              SM (age
        stntrs.                                    65-79)  2.17 (75)

Kahn
(Darn )
10 c G

          __
    344 NS 1.00 (88)         Pipes ~~~
                                     t Refers to current smokers
tSM . ..256   1-9 0x7 (8)       NS .1.00(88)    of all types.
NS X8  lo-20 1.93 (65)        SM ..0.74 (8)

1J.S.A.      per`s,," yr?ll'b.    certifiratc.                     21-39 2.18 (43)           Cigar8
( I.79 ,                                           >39 1.87 (7)       NS .l.OO(SS)
                                           All 1.84(125)        SM .1.52(27)
                                                                     Both
                                                                  NS .l.OU(RUt

                                      SM .0.93;13;
Hirasrima,   265.11~ malr     Trained PHS      111     SM 14  NS t. 1.00                                      -

l!lCi,       and femnle     nurse inter-                  1 (P<O.Ol)
                               SM . . ...15.56 (14)J

          and <,lder.      deathcertificate.
  ~-__  -~___        .~
Weir and    G'.153 maleh     Questionnaire      5-u    SM . ..-`I1  NS -1.00                      SM includes cx-smokers.

D11"",
l!liO,
U.S.A.
(.:06).

and fulloa-up
of death
cc1-tificatc.

t10 2.04
f20 2.45
>a0 1.44
All   2.43

NS includes pipe and cigar
smokers.


At present, no definite conclusions can IX: rlra\vn concerning the
interrelationships of bladder cancer, abnormal tryptophan metab-
olism, and tobacco smoking. Further study is required in this and
the other areas of bladder cancer pathophysiology.

SUMMARY AND CONCLUSIONS

1. Epidemiological studies have demonstrated an association of
cigarette smoking with cancer of the urinary bladder among men.
The association of tobacco usage and cancel' of the kidney is less
clear-cut.

2. Clinical and pathological studies have suggested that tobacco
smoking may be related to alterations in the metabolism of trypto-
phan and may in this way contribute to the development of urinary
tract cancer.

CANCER OF THE PANCREAS

Several prospective epidemiologic studies have suggested a rela-
tionship between cigarette smoking and cancer of the pancreas
(table 36). A retrospective study of 465 cases of pancreatic cancer
by Ishii, et al. (137) has shown a dose-related increased risk of
pancreatic cancer in association with smoking. Analysis of dietary
data revealed that the relative risk for pancreatic cancer from
smoking was considerably greater than from dietary factors.

No experimental studies relating to this question have been
reported.

SUMMARY AND CONCLUSIONS

Epidemiological studies have suggested an association between
cigarette smoking and cancer of the pancreas. The significance of
the relationship is not clear at this time.

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