2. The risk of developing esophageal cancer with the use of other
forms of tobacco, such as pipe and cigar smoking, is about the same
order of magnitude as that for cigarette smokers.
3. Epidemiological studies also indicate a synergistic relationship
between the use of alcohol and tobacco and the development of cancer
of the esophagus.

4. Experimental studies show that chemical compounds found in
cigarette smoke are capable of inducing carcinoma of the esophagus in
experimental animals. In some experimental models, esophageal
carcinogenesis is enhanced if the carcinogen is dissolved in a dilute
alcohol solution.

Cancer of the Urinary Bladder and Kidney
Bladder Cancer

Most cancers of the urinary bladder are transitional or squamous cell
carcinomas which appear either alone or in combination. Unless these
produce hematuria or obstruct the bladder outlet, they remain
undiagnosed until quite late, making a cure unlikely. For patients
diagnosed with bladder cancer from 1960 to 1973, the 5-year survival
rate was approximately 60 percent for whites and 30 percent for
nonwhites (240). The average annual incidence for males is about three
times that for females, but this ratio may change as the larger
proportion of women who are now smoking reach the age where
bladder cancer rates are high (38).

The National Center for Health Statistics reported that there were
9,673 deaths from bladder cancer in the United States in 1976. There
were 6,759 deaths among males, and 2,914 deaths among females (150).
It is estimated that 9,909 people died of bladder cancer in 1978 (4).

Qidemidogical Studies

Epidemiological data on the relationship between smoking and cancer
of the urinary bladder have been accumulating for well over 20 years.
Bladder cancer mortality ratios from the larger prospective epidemic
logical studies are summarized in Table 19. On the average, cigarette
smokers are about twice as likely to die from cancer of the bladder as
nonsmokers.
There have been numerous retrospective studies of the effect of
smoking on cancer of the bladder (5, 36, 38, 41, 55, 101, 102, 124, 125,
117, 186, 295, 207, 240, 251, 253, 255). Several of these studies show a
Positive dose-response relationship between the number of cigarettes
smoked per day, the duration of cigarette smoking or the lifetime
number of cigarettes smoked, and an increased risk of developing
bladder cancer.

5-45


TABLE lg.-Bladder cancer mortality ratios- prospective
       studies

Population

Study       NOW
size       smokers

All
cigarette
smokers

Comments

ACS
Males in
9-State Study(M)

British
doctors(47a)

1.00



1.00



1.00
1.00



1.00

Canadian
Veterans(Z0)

ACS
25 State Study&%)

U.S. Veterans(90)

California
Males in 9
occupations@%?)

Japanese
study( 77a,80)

Swedish
Study(SP)

187,783
White
M&S

1.00

200

Smokers of l&Xl cigarette3
Includes all urinary
tract ca"ceA.
IncIudea Prostate.

w@J
Male
Doctors


78,ooo
M&S

l,~,~
Males and
Females


2265,@Jo
PeEDa-
YeaR

2.11

    Canitourinary caneem
1.40   considered 89 a group



2.00 (Males 45-M)
296 (Females &79)



2.15

68,158
Males         1.00      289

265,118
Males and
Females


5.wJo
Males and
Females

1.00
1.00



1.00
1.00

1.36 (Males)
271 (Females-P. 0.05)


1.80 (Males)    Bladder +
1.60 (FernsI=)  other urinary
          organs

Wynder and Goldsmith (240) reported that the risk of developing
bladder cancer decreased among ex-smokers and approached that of
nonsmokers about 7 years after quitting smoking.

Several authors have calculated the percentage of bladder cancers
which can conservatively be attributed to the cigarette smoking habit.
Wynder and Goldsmith (240) estimated that 40 percent of male bladder
cancers and 31 percent of female bladder cancers may be attributed to
smoking cigarettes. This is in agreement with the estimates by Cole, et
al. (38) of 39 percent in males and 29 percent in females.

In a cohort analysis of men and women in the United States,
Denmark, England, and Wales, Hoover and Cole (87) examined the
strength of the association between cigarette smoking, the develop-
ment of bladder cancer, and successive birth cohorts. Increasing rates
of bladder cancer were observed in populations characterized by an

546


increase in cigarette smoking among successive birth cohorts. The
association was consistent in both men and women and was also found
for different nationalities and for urban and rural groups. These
findings are consistent with a causal role for cigarette smoking in the
development of bladder cancer. It is interesting that the cohort
analysis for bladder cancer is similar to and parallels that of cancer of
the pancreas.

Other Risk Factors

Certain occupational exposures are associated with an increased risk of
developing bladder cancer. Those who work with dyestuffs, rubber,
leather, print, paint, petroleum, and other organic chemicals are
particularly at risk. The common denominator appears to be aromatic
amines. A number of specific carcinogens for the human bladder have
heen identified, including aminobiphenyl, 2-naphthylamine, benzidine,
1-naphthylamine, and bnitrobiphenyl (35). Some of these compounds
are found in cigarette smoke. The relationship between cigarette
smoking and occupational exposure is complex. It is likely that
cigarette smoking can act as a sole agent in the development of
bladder cancer; however, there may also be synergistic interactions
between cigarette smoking and occupational exposures.

Animal Studies

Numerous experiments have been undertaken to examine the relation-
ship of tobacco smoking to bladder carcinogenesis. The areas of major
concern have centered upon aromatic amines, nitrosamines, tryptophan
metabolism (109 and, more recently, non-nutritive sweetness, as in
saccharin and cyclamates. The effect of these classes of compounds on
the etiology of bladder cancer in experimental animals has been
extensively reviewed in the literature.

Khhey Cancer

For 1978, the estimated incidence of kidney and other urinary cancers,
exclusive of cancer of the bladder, was 9,409 for males and 5,709 for
females. The estimated number of deaths for these same cancers was
4690 in males and 2,809 in females (4). The 5-year survival rate
following the diagnosis of kidney cancer is 40 to 50 percent (151).

In most of the prospective studies, cancer of the kidney refers to
tumors arising from the renal parenchyma as well as tumors in the
renal pelvis and ureter. In some of the retrospective investigations,
tumors at these various sites are considered separately in relationship
to cigarette smoking. In several of the large prospective epidemiologi-
ml studies, an association was found between cigarette smoking and

5-47


TABLE 20.-Kidney cancer mortality, ratios and relative risks:

sfh&d oromedive an
I------- r---r---- - ~.~- d retrospective studies

Population _

^ .
Study SW?
and twe

Number of  Mortality ratio or
      relative risk ratio
kidney                  Comments
cancer    Non   cigarette

-1

deaths   smokers   smokers

ACS        440,558 males.
25 state      Prospective
Study(65)      study

U.S.
Veterans@)

G355,~
perso" years.
Prospective
study

California
Males in
9 Occupations@&Q)

Japanese
study( 774

Bennington,
L.auhscher(fGa.17J

Schmauz
C&(1 SO)

Armstrong(B)

Wynder
et al.(l43a)

68,153 males.
Prospective
study

122~1
males.
Prospective
study

Retrospective
study of
renal adenocarcinoma.
loo casea
190 controls

Retrospective
study.
43 cases of renal
pelvis or ureter.
451 controls

Retrospective
study.
106 adencarcinoma
of kidney.
30 carcinoma of
renal pelvis.
139 controls

Retrospective study
202 adenocarcinoma
of kidney.
394 controls.

104

141

27

30

100

18

106



30

1.00





1.00






1.00

1.00

1.00








1.00








1.00



1.00







1.00


1.00

1.45

2.46

1.20

5.1

Riik ratio for
Pipe - 10.3
Cigar - 12.9

10.0

For smoke= of
more than 2 l/2
pks/W

1.06

1.80

2.00     WW


1.59     (Females)

cancer of the kidney. The mortality ratios for all cigarette smokers
varied from 1.42 to 2.46, compared to nonsmokers. The results of these
studies are summarized in Table `20.

5-48


TABLE %I.-Kidney cancer mortality ratios, by amount smoked:
       U.S. Veterans Study

Cigarettes
smoked
per &Y

Mortality              Number of
ratice                deaths

Nonsmokm                      1.00                  39
l-9                          0.97                   4
lo-19                          1.34                  21
z&39                          1.68                  16
40+                          2.75                   5

All cigarette smokers

1.45                  46

SOURCE: Kahn, HA. (SO]

Earlier retrospective reports of the association of renal adenocarci-
noma with smoking reported a relative risk ratio of about 5.0 for
cigarette smokers compared to nonsmokers (16, 17'). They did find a
positive association between cigarette smoking and cancer of the renal
pelvis, as had Schmauz and Cole (180). Wynder, et al. (248) reported a
moderate but significant association between cigarette smoking and
renal adenocarcinoma for both males and females. There were positive
dose-response relationships with the number of cigarettes smoked per
day. The results of these studies are summarized in Table 20. A dose-
response relationship with the number of cigarettes smoked per day
was also found in the study of U.S. veterans (Table 21).

Conclusions

1. Epidemiological studies demonstrate a significant association
between cigarette smoking and cancer of the urinary bladder in both
men and women. Supporting evidence from other disciplines supports
the conclusion that cigarette smoking is one of the causes of cancer of
the urinary bladder.
2. Epidemiologic studies show a positive dose-response relationship
for developing bladder cancer with increases in the number of
cigarettes smoked per day.
3. Cigarette smoking acts independently as a cause of bladder cancer
and probably a& synergistically with other risk factors for bladder
Cancer, such as occupational exposure to certain aromatic amines.
4. Epidemiological studies have demonstrated an association of
$!PM.te smoking with cancer of the kidney among men. There is some
evidence of a dose-response relationship with the number of cigarettes
smoked per day in the development of kidney cancer.

549


Cancer of the Pancreas

The National Center for Health Statistics reported that there were
19,738 deaths from cancer of the pancreas among men and women in
the United States in 1976 (150). Deaths from cancer of the pancreas
were expected to exceed 20,090 in the United States during 1978 (4).
The incidence of cancer of the pancreas has increased threefold since
1930 (100, III), and it now ranks fourth in frequency among fatal
neoplastic diseases (187).

The most common form of pancreatic cancer in humans is
adenocarcinoma, which originates from the epithelial duct cells of the
pancreas. Acinar and islet cell tumors are relatively rare. Because of an
extensive venous and lymphatic drainage system, metastases can occur
relatively early in the course of the disease, contributing to the poor 3-
year survival rate of 2 percent (15.2). Morgan and Wormsley (149) have
reported that most studies have shown a mean survival time after
diagnosis of less than 6 months.

Pancreatic cancer is more common among men than women in the
United States, but the male-to-female ratio has been decreasing
steadily from 1.6:1 during the period of 1940 to 1949 to 1.3:1 observed
from 1965 to 1969 (152).

Epidemiological Studies

Several prospective epidemiologic investigations (20, 32, 65, 79, 80, 90,
228) have reported mortality ratios for cigarette smokers of approxi-
mately 2.0, compared to nonsmokers. These data are presented in Table
22. Not all of these investigations demonstrate a dose-response
relationship with the number of cigarettes smoked per day; this is
probably due to the small number of deaths in each smoking category.
In a retrospective case control study with 81 cases of cancer of the
pancreas, Wynder, et al. (248) showed a definite dose-response
relationship with a relative risk of 5.0 for males smoking more than
two packs of cigarettes a day. These data are presented in Figure 8.
The dose-response data from the Swedish study are presented in Table
23.

Pancreatic cancer mortality in the United States was examined by
cohort analysis for the period 1939 to 1969 by Bernarde and Weiss (16).
White men were found to be at greater risk of developing pancreatic
cancer than white women, and the same relationship existed for
nonwhites. With the passage of time, there was a shift of the cohort
mortality rate curve by age toward younger groups. These data appear
to be compatible with an hypothesis which relates environmental
factors to the etiology of pancreatic cancer. Air and water pollution,
ionizing radiation, and improved diagnosis are unlikely to explain the
observed differences, because these factors would be expected to
influence both race and sexes more or less equally. Cigarette smoking,

5-50


TABLE 22.-Pancreatic cancer mortality ratios-
      prospective studies
study              Size of              Nonsmokers
population         population

Canadian
WteranS           78,ocQ
WI               males                  1.00

All cigarette
smokers




1.96

A.C.S. .Z5-
St&
Study
($5)

woo0
males

239,~
males

JapawSe
study
(77a,80)

122ooo
males
143,Mw
females

1.00

1.00

1.00


1.00

2.69

1.34

1.41 males

1.94 females

California
WCUpatiOnS          6v@J
NW              males                  1.00          243

Swedish           ~poo
study              males and
W)               females

1.00
1.00

3.1 male3
25 females

high risk occupations, and dietary practices are more likely to explain
these differences. Cigarette smoking is an exposure which is closely
related to cohort and sex difference.

Other Risk, Factors

There is epidemiologic evidence which links pancreatic cancer with
increased dietary fat and protein intake (80, 228). An increased
incidence of pancreatic cancer has been observed in chemists and
industrial workers exposed to beta naphthylamine (131). A survey of
death certificates of member chemists of the American Chemical
hiety indicates an increased relative frequency of pancreatic cancer
(1.20). However, specific chemical exposures could not be traced.

bnal Studies

There are relatively limited numbers of experimental laboratory
studies concerning cigarette smoking and cancer of the pancreas. Pour,
et al. (112, 166), using a nitrosamine compound, induced pancreatic
neoplasms in hamsters which were histologically similar to those in
humans. Although the particular nitrosamine used in these experi-

5-51


   5






   4





:! 3
P
.
2
6
2
   2






   1






   0

N=Care
  ContraI

    13
   G
-- l-7 ---

-u
    Never
   Smoked

11-20       2140

Cigarattapw Day

FIGURE 8.-Relative risk of pancreatic cancer in males, by number
of cigarettes smoked
SOURCE: Wynder. EL (248)

TABLE 23.-Mortality ratios for cancer of the pancreas among
     Swedish subjects, aged 18-69, by sex and amount
       smoked

Number of
cigarettes
wr dav

Males                Female

Nonsmokers                       1.0                  1.0
l-7                           1.6                  24
8-1.5                          3.4                  2.5
15+                           5.9                  3.0
All cigarette
smokers                         3.1                  2.5

SOURCE: Cederlof. R. (32)

ments is not found in tobacco smoke, a number of other nitrosamine
compounds, such as dimethyl nitrosamine and methylethylnitrosamine,

5-52


have been found in cigarette smoke (81). This points to a class of
compounds which should be investigated for their carcinogenic
potential in cancer of the pancreas.

Konturek, et al. (108) has reported that nicotine inhibits pancreatic
bicarbonate secretion in the dog by direct action on the organ. This has
led to speculation that inhibition of duct cell secretion of bicarbonate
could lead to intracellular pH changes and subsequently play a role in
carcinogenesis.

Conclusions

1. Epidemiological data from prospective and retrospective investi-
gations have demonstrated a significant association between cigarette
smoking and cancer of the pancreas.
2. Several epidemiological studies contain evidence of a dose-
response relationship for the number of cigarettes smoked per day. The
relative risk of developing cancer of the pancreas is about five times
greater for a two-pack-a-day smoker than for a nonsmoker.

Mechanisms of Carcinogenesis
Smoke Composition

Cigarette smoke for use in experimental studies is usually separated
into a gas phase and a particulate phase by passing whole smoke
through an appropriate filter. The compounds retained by the filter
constitute the particulate phase and are referred to as "tar." More than
2,000 compounds have been identified in cigarette tar. The gas phase,
which makes up more than 90 percent of the volume of whole smoke,
contains a much smaller number of compounds. The particulate phase
can be subdivided into categories based on the solubility of the
compounds in acid, neutral, or basic solvents. Most of the chemical
compounds which participate in the induction and maintenance of the
malignant process are contained in the neutral portion of the
Particulate phase. A detailed analysis of the components of cigarette
smoke is presented in the Chapter on the Constituents of Tobacco
Smoke. This subject has also been reviewed in detail by Hoffmann and
Wynder (83).

Experimental Models

Cigarette smoke, whole tobacco tars, the gas phase of cigarette smoke,
various tobacco condensate subfractions, and single or multiple
compounds known to be present in tobacco smoke have been used in
studying the mechanisms of carcinogenesis in experimental animals.
h% mice, hamsters, guinea pigs, rabbits, dogs, monkeys, donkeys,
chickens, and other animals have been used in studying the carcinogen-
ic Properties of tobacco smoke.

5-53


It has not been possible to duplicate the same conditions of smoke
inhalation in experimental animals as are found in humans. Many
animals are obligate nose breathers, and under these circumstances
turbulent precipitation of smoke particles in the nasal passages
prevents most of the active compounds from reaching the lungs. A
variety of alternate approaches have been used. The painting of shaved
mouse skin with whole tobacco tar and various chemical constituents
haa been widely used. Other investigators have used subcutaneous
injection, intratracheal instillation, implantation, and feeding. Tissue
and organ cultures have also been used to study carcinogenesis.
Chapter 14 contains a more complete discussion of this subject.

Concepts of Carcinogenesis

Carcinogenesis is a complex process involving multiple steps and
various compounds operating at different points in the sequence.
Chemical compounds have been classified as to the respective roles
they play in the process of carcinogenesis. Cigarette smoke and tobacco
tar act as complete carcinogens, since no additional compounds or steps
are necessary to induce malignant changes in a variety of animal
systems. When individual chemical compounds and subfractions are
examined, however, the process of carcinogenesis becomes increasingly
complex. Chemicals which can induce the first steps of malignant
transformation are known as carcinogens or tumor initiators. Tumor
promoters are compounds which continue the process of tumor
formation when they are applied to tissue following initial treatment
with a chemical carcinogen (23). Compounds known as co-carcinogens
exert their effects when administered simultaneously with carcinogens
or tumor initiators. Compounds which act as co-carcinogens do not
necessarily have tumor-promoting properties. Mouse skin is frequently
used for identifying co-carcinogens as well aa promoters (85). Catechol
is a potent co-carcinogen but is inactive as a tumor promoter. On the
other hand, phenol, a tumor promoter, has no known co-carcinogenic
activity (219). Data such as these support the idea that tumor
promotion and co-carcinogenesis are independent phenomena with
distinct mechanisms of action. Both promoters and co-carcinogens play
an important role in tumor induction by tobacco products (161).

Additionally, Hoffmann and Wynder (8.2, 2.44) have described the
property of tumor acceleration possessed by N-alkylated carbazoles
and certain other compounds. These compounds are inactive as
complete carcinogens, initiators, or promoters but accelerate. the
initiator-promoter activity of polynuclear aromatic hydrocarbons.

The carcinogens, tumor promoters, and ciliatoxic agents which have
been identified in the gas phase of tobacco smoke are listed in Table 24.
The major carcinogenic agents which have been identified in the
particulate phase of tobacco smoke are listed in Table 25. The first part
of Table 25 lists the 1'7 agents which are identified as tumor initiators;

5-54


TABLE 24.-Carcinogenic, promoting, and ciliatoxic agents in the
      gas Dhase of tobacco smoke*

Smoke compounds

   Amount in
smoke of one cigarette

I. Cminogenst

R `N-NO
R/

I
NO

I
NO

H&-NH2
I%-CHCI

II. Tumor promoters
HCHO

III. Ciliatoxic agents
HCN
HCHO
HoC-CH-CHO
II&-CHO

Dimethylnitrosamine            .%lSOn~*

Dialkylnitmsamines
(4 compounds)

Nitmsopyrrolidine

Hydrazine
Vinyl chloride

Formaldehyde

Hydrogen cyanide
Formaldehyde
Awolein
Acetaldehyde

ILllOng

CUhg"'

24-43w
Cl6ng

`List is hmcd only on publications with unambiguous identifications of tumorigenic smoke annpounds.
tlbhem smoke is suspected of also containing Ii& (amine). Ni(CO). (nickel mrbonyl) and pmsibly other volatile
cbloriMted olefi~ than vinylchloride and nitm4efina.
`.w - lorg
***#g - lorg
~UftCE: Wynder. EL (PU)

the second part contains a list of organ-specific carcinogens. The tumor
Promoters and co-carcinogens found in the particulate phase of tobacco
smoke are listed in Table 26.
Many chemical carcinogens or initiators must be partially metabo-
lized before they can exert their carcinogenic effects. Of the chemical
Carcinogens present in cigarette smoke, the metabolism of the
Polyaromatic hydrocarbons (PAH), in particular benzo(a)pyrene, has
been most widely studied. The enzyme, aryl hydrocarbon hydroxylase
(AHH), is responsible for the conversion of PAH into a number of
hydroxylated derivatives (60,91,191).

5-55


TABLE 25.-Carcinogenic agents in the particulate phase of
       tobacco smoke1

Smoke compounds

Tumor Initiators*

Biol. AcL2

   Amount in
smoke of one cigarette

Bm&lpyrene
bhlethylchrysene
Diben&hJanthracene
Benzo(b)fluoranthene
fjeasc(j)fluoranthene
Dibenz+,h)pyrene
Dibew&i)pyreoe
Diben&j)acridine
Indeno(l&+ed)py~oe
Benz(a)anthmcene
Chrysene
Methylchrysenes
Methylfluoranthenes
Dihft~a,c)anthracene
Dibenz@,h)acridine
Dibenz&g)wbazole
Benzc@phenanthrene

Organ specific carcinogens3

A. Esophagus
  N'-Nitrosonornimtine
Nitrosopiperidine
Nitrosopyrrolidine
  Unknown Nitrosamines
B. Lung
  Polonium-210
Nickel compounds
Cadmium compounds
  Unknowns
C. Pancreas
  Nitrosamines
  Unknowns
D. Kidney and Bladder
&Naphthylamine
  xdminofluorene
  x-Amincetilbene
  c-Toluidine
  Unknown Aromatic Amines
  o-Nitrotoluene
Unknown Nitm compounds
Di-n-butylnitrosamine
  Unknown nitrosamines

(+++)
c+++j
(++)
(++)
(++I
(++I
(++)
(++)
  (+)
  (+)
  (+)
I:;
  (+)
  (+)
  (+)
  (+)

  18ng
  5ong
present
O.lng
  O.lng

1%
Wng
I-llong
  ?

O.O%l.BpW
Wnfx
9-70ng
   ?

present
present
   -

2biT
1
0.3ng
?

1% far with certainty identified.
ZBiol. Act. - &latjve -inogenie activity on mow skin. + + + highly active; + + ~~Iode~telY tiVe; + Weakly
active.

~~ese cz3minogens also may act on other target organs
*pCi - pioocurie, lF%rie
SOURCE: Wynder. E.L. (W)

5-56


TABLE 26.-Tumor promoters and co-carcinogens in the
     particulate phase of tobacco smoke'

Smoke compounds

Tumor promoters

   Amount in
smoke of one cigarette

Volatile phenols
Unknown weakly acidic com~unds
Unknown neutral compounds

47ene
Methylpyrenes
Fhmranthene
Methylfluoranthenes
Benzo(ghi)perylene
kWe)pyrene
Other PAH
Napthalenes
IYethylindoles
kbfethylcarbazoles
4,4'-Dichlorostilbene
Other neutral compounds
Catecho
4Alkylartechol
Other acidic compounds

5IMOOng
-g
100-260ng
  1mg
  @w
  3fJng
   7
0.%6.3jlg
O.Qlg
0.14&q
  Id&
   ?
-P&c
  wiz
   ,

% far with certainty identified.
W&es are decreasing because of lemer use of DDT and DDD for thacm cultivation.
SOURCE: Wynder, EL (r&T)

Aryl Hydrocarbon Hydroxylase
AHH activity is present in most tissue of the body. It is induced by
treatment in wivo or in witro with a variety of PAH or related
chemicals. Tobacco smoke inhalation elevates AHH activity in
respiratory tissues of laboratory animals (2, 51, 231) and in human
peripheral lymphocytes and pulmonary alveolar macrophages (29,129).
Inducible levels of the enzyme vary both with the tissue and with the
individual (60,97,156).

Kellermann, et al. (25, 96) reported that the percentage of lung and
laryngeal cancer patients with highly inducible AHH levels was much
greater than in the normal population. On the other hand, there have
been reports in which the inducibility of AHH in lung cancer patients
either did not differ significantly from controlled populations (123) or
Was lower than in controls (17). Further research is necessary to clarify
the relationship between cigarette smoking, AHH inducibility, and the
development of cancer.

5-57


Multi-Stage Model of Carcinogenesis

One unifying hypothesis is the multi-stage model of carcinogenesis.
This model has been proposed in various forms by several scientists and
has recently heen given attention by Armitage (6), Doll (42), and Peto
(165). In the multi-stage model, carcinogenesis is considered a disease
of interactions.

  The transformation of a normal cell to a malignant one would
require two or more separate stages, each with a characteristic
probability of occurrence determined by one or more of the carcinogens
present. The initiation and development of cancer would thus be a
multi-stage, multi-causal process, in which both external and internal
factors act in a sequence of several steps before the cancer would
appear clinically. The multi-stage concept of carcinogenesis offers a
plausible explanation for some of the peculiarities of the induction of
lung cancer (such as the multiplicative effect of asbestos on cigarette
smokers and the changing risks of ex-smokers). It is likely that
development of cancer in each organ or tissue requires a different set
of factors to induce malignant changes. It should not be surprising that
cigarette smoking can induce malignant changes in as many organ
systems as it does. Evidently, among the 2,000 chemical compounds
found in cigarette smoke, there are sufficient carcinogens, tumor
initiators, co-carcinogens, and tumor promoters to induce cancer in
multiple-organ systems. Certainly, over the long time period in which
the smoker is exposed to the products of tobacco combustion, there is
sufficient time to satisfy the most complex multi-phased or multi-
causal process. Given this model, it is not surprising that tobacco

carcinogenesis is additionally influenced by a number of environmental
factors (76). This would explain the synergism for lung cancer observed
in cigarette smokers in various occupations, such as asbestos workers
and uranium miners.              .-

5-58


Cancer: References

(I) ABELIN, T., GSELL, O.R. Relative risk of pulmonary cancer in cigar and pipe
  smokers. Cancer 20 (8): 1288-1296, August 1967.
(2) ABRAMSON, RK., HUTTON, J.J. Effects of cigarette smoking on aryl
  hydrocarbon hydroxylase activity in lungs and tissues of inbred mice. Cancer
  Research 35: 23-29, January 1975.

(3) ACKERMAN, L.V., REGATO, J.A. Cancer diagnosis, treatment and prognosis.
  St. Louis, C.V. Mosby Company, 1970, p. 412.
(I) AMERICAN CANCER SOCIETY. 1978 Cancer Facts and Figures. American
  Cancer Society, Inc., New York, 1977, p. 12.
(5) ANTHONY, H.M., THOMAS, G.M. Bladder tumours and smoking. International
  Journal of Cancer 5 (2): 266-272, March X5,1970.
(6) ARMITAGE, P., DOLL, R. Stochastic models for carcinogenesis. In: Proceedings
  of the Fourth Berkeley Symposium on Mathematical Statistics and Probabili-
  ty. Biology and Problems of Health, Volume 4. Berkeley, Univemity of
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