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52


CHAPTER 3

Smoking and Cancer

Contents

Summary _______________________ - _______ ----__-_----_--
Epidemiological Studies- _________________ -----__-_-------
  Lung Cancer- ___________._______ ------_---------_--
  Oral Cancer- _____________ - ______ ------------- ______
  Laryngeal Cancer- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Cancer of the Urinary Bladder and Kidney------..------
  Cancer of the Pancreas ________________ - ____ ---_-----
General Aspects of Carcinogenicity- __ _ _ _ __ _ _ _ _- _ __ _ __ __ _ _-
  Tobacco Alkaloids __________________ --___------- _____
  Nickel__________________________________-----------
Experimental Aspects of Carcinogenesis- _ _ _ _ _ - - - _ _ _ _ _ _ - - - - -
  Retention of Smoke Constituents- _ _ _ _ _ _ _ _ ___ __ __ _ ___ _
Changes in Cell Cultures Induced by Cigarette Smoke- - -
Experimental Studies of Bronchogenic Carcinoma in
   Animals_________________------______________-_-_-
Experimental Aspects of Cancer of the Bladder and
   Eidney__________-______________________---------
Cited References_--__-_--_____________________----------
Cancer Supplemental Bibliography- _ _ _ _ _ _ _ _ _ _ _ - _ _ _ - _ - - - - - -

Pane
55

55
55
58
58
60
60
61
61
62

62
62
62

63

64
65
69

53


          SMOKING AND CANCER

                 SlJadMARY
Previous reports (59,60,61) have presented the evidence that ciga-
rette smoking is a major cause of lung cancer and that cessation of
cigarette smoking sharply reduces the risk of dying from lungcancer
as compared to the risk taken by those who continue to smoke. Ciga-
rette smoking was also shown to be a significant factor in the causa-
tion of cancer of the larynx. A strong association between various forms
of smoking and cancers of the buccal cavity, pharynx, and esophagus
was also shown. Data were presented which indicated that cigarette
smoking was associated with cancer of the urinary bladder. Data were
aiso presented which suggested that cancer of the kidney and pancreas
may be related to cigarette smoking.
During the past year, both population studies and laboratory studies
from various countries have added to the weight of the evidence
linking smoking and cancer. A major study of histological changes
in the larynx has demonstrated the higher risk of premalignant
changes among smokers. More studies have been done to identify those
substances in tobacco smoke which take part in carcinogenesis. New
animal models for the experimental study of respiratory cancer, which
may be helpful in elucidating the mechanisms of respiratory tract
carcinogenesis, have been developed and refined.

            EPIDEMIOLOGICAL STUDIES
It is interesting to note that; epidemiological information on ciga-
rette smoking and lung cancer, similar to that which has been collected
in the United States and Western European countries, is now being re-
ported from Eastern Europe an.d Africa as well.
Lung Cancer
In Norway, a study of histologically proven cases of lung cancer
by Kreyberg demonstrated t.hu low frequency of lung cancer among
nonsmokers. The cases were collected between 1950 and 1964 from two
hospitals and a diagnostic laboratory which service all parts of Nor-
way, The author states that the population represented in this study
is most probably geographically representative of the whole country.
In comparing his results in Norway with those in other European

                                           55
    36CLQ28 -4


countries, Kreyberg stated that a nonsmoking Norwegian population
today should present lung cancer cases in the same number, with the
same sex ratio, and with the same representation of histological types
as prevailed in Norway 40 years ago, and in Europe in general at the
beginning of this century ($4, 2%). The risks of developing various
histological types of lung cancers among smokers, as contrasted to
nonsmokers, are presented in table 1. Two facts are strikingly apparent
from the table. First, the preponderance of the higher risk of lung
cancer in smokers lies in the categories of epidermoid carcinoma and
anaplastic small cell carcinoma. Second, while female smokers have a
higher risk of developing lung cancer than female nonsmokers, the
relative risks are smaller than those for males. At least part of this
difference may be accounted for by differences in smoking habits be-
tween men and women. Women tend to smoke fewer cigarettes, to
smoke brands lower in tar and nicotine, inhale less and smoke less of
each cigarette than do men ; therefore, women have lower exposure to
cigarette smoke.

TABLE l.-Tumor prevalence among males and females 36-69 years of
     age, by type of tumor and smoking category

[Smokers canstltuted E5 percent of populations studied]

Males:
  Epidermoid carcinoma- - _ ______  434    431     3   17. 0     25. 4
  Small cell anaplaatic carcinoma--  117    116      1    5. 7     20. 4
  Adenocarcinoma ___________ ____   88     83      5   28. 3      2. 9
  Bronchiole-alveolar carcinoma--- __ __    _ _-_    _ _ __ _ __ __ _    _ _ -_
  Carcinoid _________-__________ _   46     39      7   39. 7      1. 0
Bronchial gland tumor-- _ ___ ___ -___    ____    -___ ______    _ ___

   Total ____________________ -_  685    669     16   90. 7     7. 4

Females :
  Epidermoid carcinoma- _ _ ____ __   12      9      3
Small cell anaplastic carcinoma--   8     5     3  : ;:    12. 0
                                         6.6
  Adenocarcinoma ___---- ___ _____   56     14     42   10. 5      1. 3
  Bronchiole-alveolar carcinoma---   _ _ _ _    _ _ - _    _ _ - -   _ _ - _ _ _    _ _ _ -
  Carcinoid _____________________   32     7     25   6.3      1. 1
  Bronchial gland tumor- _ _ _ _ __ _ _   __ _ _    _ _ _-    __ __   _ ___ _ _    __ __

Total- _ ________________ ____  108     35     73   18. 3      1. 9

' NW&I that would be expected if incidenca rate among smokers WBS equal to that of nonsmokers.
sowcx Kreyherg, L. (B4).


Brett, et al. (8) found that the mortality rate for lung cancer in
smokers in England was especially high for the smokers who
"drooped" the cigarettes off the lip while they smoked, a habit which
may result in the delivery of a greater dose of smoke f'rom each
cigarette.
Gelfand, et al. (19) in a study of lung cancer in Rhodesian Africans,
reported a preponderance of smokers among the lung cancer patients
as compared to a control group. The authors express the opinion that
air pollution does not play a role in respiratory cancer in Rh0desi.a.
In the 1967 Health Consequences Report (GO), it was pointed out
that the lung cancer risk of ex-smokers declined, relative to those who
continued to smoke. It equalled that of nonsmokers about 10 years
after stopping smoking, and the rate of decline depended on the num-
ber of cigarettes previously smoked and the duration of smoking.
Brass, et al. (10) reported that the risk of developing lung cancer is
lower among filter cigarette smokers than nonfilter cigarette smokers.
Since filter cigarettes are generally lower in tar content than nonfilter
cigarettes, this study supports the inference that the tar content of
cigarettes is a meaningful measure of exposure to risk.
In view of the fact that practically all lung cancer patients started
to smoke nonfilter cigarettes and have smoked filter cigarettes only in
recent years and for a variable length of time, a more exact comparison
of the risks run by smokers of filter and nonfilter cigarettes must await
further studies (N) .
The relationship of smoking to lung cancer in women is an area of
continuing concern, since we may expect a continued increase of lung
cancer in women with the increase in cigarette smoking among them
since World War II. Lombard, et al. (39) show a relationship of
cigarette smoking to epidermoid lung cancer in women but not to
adenocarcinoma. It is generally agreed that the contribution of ciga-
rette smoking to the development of epidermoid and oat-cell lung
cancer (Kreyberg Group I) in males is significantly greater than t,o
the development of adenocarcinoma (Kreyberg Group II).
An association of other diseases to cancer of the lung is found in
a report by Salzer, et al. (.@) . Salzer and his colleagues have reported
in an autopsy study that lung cancer and scars from stomach ulcers
are statistically associated and suggested that cigarette smoking may
have contributed to both conditions. A study by Stamler, et al. (53)
indicated that male cigarette smokers with elevated cholesterol levels
had higher rates of lung cancer than those with lower cholesterol
levels. Additional studies are needed to confirm and elucidate these
observations.
Programs have been recently established to perform cytological
examinations on the sputum of smokers, since they represent
a population at a high risk for the development of carcinoma of

                                         57


the lung. These programs have detected individuals with atypical or
frankly malignant cells in their sputum before a shadow has appeared
in the lung fields of x-ray (18, &?) . Valaitis, et al. (6~3) reported that
some degree of cytological abnormality was found in the sputum of
4.8 percent of the smokers and 0.9 percent of the nonsmokers.

Oral Cancer
In the Soviet Union, Orlovskiy has shown an association between
cigarette smoking and lung cancer, as well as an association between
the use of %as" (a mixture of tobacco and ashes) and the development
of cancer of the oral cavity (37). Other studies of interest from around
the world include one by Pindborg, et al. (39) on the epidemiology
and histology of oral leukoplakia and leukoedema among Papuans
and New Guineans. They report that smoking may be more closely
associated with these conditions than is the chewing of betel nut
which previously was considered the obviously associated habit. A
study by Wahi (6.4) reports on the relationship of tobacco chewing
to oral and oropharyngeal cancer ,in a district in India. Pindborg also
presents evidence from India indicating that oral submucous fibrosis
(38) may be associated with tobacco use and may result in an oral
cpithelium more susceptible to the carcinogenic substances in tobacco.
In a study of oral malignancies indexed in a large tumor registry in
California, Chierici, et al. (IS) found that 88 percent of the cancer
patients were smokers. The proportion of smokers ranged from 81 to
83 percent for cancers of the gingival and alveolar mucosa, buccal
mucosa, bard palate, and lip, to 94 percent or more for cancers of the
floor of the mouth, soft palate, tonsil, or oropharynx. Unfortunately,
comparable percentages of smokers in a control population are not
presented. No new studies have appeared which clarify the relative
contributions of other environmental risk factors for oral cancer,
such as alcohol consumption, nutritional problems, fand poor oral
hygiene.
Larynged Cancer
Auerbach, et al. (1) studied the histology of the larynx of 942 men,
aged 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 interviewers. The numerous ran-
domized histological sections were graded by one observer. Table 2
shows the percentage of cells with atypical nuclei found in the true
vocal cord. Of the men who never smoked, 75 percent had no cells with
atypical nuclei, only 4.5 percent had sections with areas containing
60 to 69 percent of cells with atypical nuclei, and none had a higher
percentage.

58


TABLE 2.-Number and percent distribuiion by relative frequency of
atypical nuclei among true vocal cord cells, of men classi$ed by smoking
category

[lo0 per cent atypical cells defined 84 carcinoma]

Total-....
     -

None. ___ _ ___ _ __
LeesthanSQ...-
so-39 _ - - _ _ _ _ _ _ _ _
w-69 _ _ _ _ - _ _ _ _ _ _
79-79 - _ _ - _ - _ _ - _ _
w-69 _---_-- ____
QO-QQ ___- _ --____
lOlIZ

88 lQQ.0   116 loo.0    94 lw.0   126 100.0   329 loo.0   190 loo.0

66  75.0    86  74.1     1   1.1     1   .8    0 __-__    0  _____
8   9.1    14  12.1    4   4.3    23  20.0    4 1.2    0  __-__
10  11.4    13  112    50  63.0    34  43.2    872a.4    29   15.3
4   4.6    1   .Q    23  246    21  16.8   116 35.3    76   39.4
0  ---__    2   1.7    9   9.6    9   7.2    44 13.4    38   20.0
0  ---__    0  ---__    2   21    2   1.6    19 5.8    11   6.8
0  -____    0  _-___    1   1.1    0  _____    5 1.5    0  _.___

0  --___    0  _____    3   3.2    13  10.4    52  15.8    35   18.4

0  _____    0  ---__    1   1.1    0  -_-__    2   .I3    2   1. 1

SOURCE: Auerbach, O., et al. (I).

The 116 ex-smokers had laryngeal histology similar to that of the
nonsmokers, as far as ,atypical nuclei were concerned. However, dis-
integrating nuclei were found in 40.5 percent of )the ex-cigarette
smokers and in only 0.4 percent of the remaining cases. Only one of
the 94 cigar and/or pipe smokers had no atypical cells. Three had car-
cinoma in situ and one case had a section showing early invasive pri-
mary carcinoma. The highest percentage of atypical cells was found
among the cigarette smokers. The proportion of cases with a high de-
gree of cellular change increased with increased daily smoking. None
of the pack-or-more-a-day smokers was free of atypical nuclei. Of
those who smoked two or more packs per day, 85 percent had lesions
wi,th 60 percent or more atypical cells as compared to 4 percent of the
nonsmokers. Between 10 and 18 percent of the cigarette smokers had
areas of carcinoma in situ, and four of the 644 cases showed early
microscopic invasion. The thickness of the basal level of the true vocal
cord was also directly related to the amount smoked (table 3).

59


TABLE 3.-Number and percent distribution, by highest number of cell
rows in the basal layer of the true vocal cord, of men clmsi$ed by
smoking category

                                 Current cigarette smokers

Number of cell Neversmoked E;z$kyAte
         regularly                          l-2 packs a   2 or more
   _^-"                                     day    packs a day

Total_..--   88 100.0   116 10Q.o    94 loo.0   125 100.0   329 109.0   190 100.0

30  34.1    7   6.0    4   4.3    3   2.4     1   0.3    0  _--__
23  33.0    27  23.3    20  2L3    27  21.6    33  11.6    20   10.6
8   9.1    15  12.9    15   6.0    25  20.0    61  15.4    24   12.6
6   6.8    12  10.3    18  19.1    12   9.6    36  11.6    19   10.0
8   9.1    14  121    9   9.6    13  10.4    36   9.1    23   12.1
1   11     7   6.0    7   7.4     6   4.8    26   7.9    14   7.4


6   6.8    34  29.4    21  223    39  31.2   145  44.1    96   47.4

Soumx: Auerbach, O., et al. (I).

Cancer of the Urinary Bladder and Kidney

Several studies have dealt with the relationship of smoking to can-
cer of the bladder and kidney. James, et al. (23) demonstrated that an
association existed for cancer of the bladder. The study by Fraumeni
(17) also showed epidemiological evidence for such a relationship for
bladder and kidney cancers. Bennington, et al. (3,,$) indicated an as-
sociation between all kinds of tobacco usage and adenocarcinoma of the
kidney as well as adenoma of the kidney. However, on the basis of this
study alone, the relationship between "all kinds of tobacco" and cancer
of the kidney cannot be considered ,as established in view of the small
number of cases involved. In a preliminary report of a study on the epi-
demiology of cancer of the kidney, Wynder, et al. (68) have shown a
strong association between excessive cigarette smoking and adenocar-
cinema of the kidney, and although the disease is not uncommon in non-
smokers, they considered excessive cigarette smoking to be a contribu-
tory factor. This study found no relationship to pipe smoking, and only
a very weak relationship to cigar smoking. A significant association
was found between cigarette smoking and epidermoid oancer of the
kidney, a relatively uncommon type of cancer. Further research on the
strength and mechanisms of the association between smoking and can-
cers of the urinary traot is needed.
Cancer of the Pancreas
The previously suggested association between cigarette smoking and
cancer of the pancreas was again noted in a Japanese study by Ishii, et

60


al. (22)) in which the authors reported a higher relative risk for pan-
creatic cancer among smokers than among nonsmokers.

        GENERAL ASPECTS OF CARCINOOENICITP

The mlajority of the tumorigenic agents in tobacco smoke are found
in the particulate matter "tar. " The well established carcinogenicity
of tobacco "tar" in a variety of animal species and tissues (66) was
reconfirmed recently (21,35,40,5$`, 56). A small portion of the smoke
part.iculates (0.03 percent) is made up of polynuclear aromatic hydro-
carbons (PAH) with two or more rings. A concentrate containing
polynuclear aromatic hydrocarbons and amounting to 0.6 percent of
the whole "tar" was found to be the most carcinogenic fraction of to-
bacco smoke (66). Another preparation of a PAH concentrate induced
significant cytologic changes in mouse trachea and human fetal lung
when grown in organ culture (??8,.%9). Other applications of concen-
trations of selected polynuclear aromatic hydrocarbons have produced
similar results (27).
Of the identified PAH, at least 12 are known tumor initiators. These
particular compounds have been shown to be carcinogenic, even when
applied in doses of a few micrograms (63,86). Tumor initiators induce
changes in the target cells, especially in DNA (9, 14). Tumor pro-
moters are agents which promote the neoplastic transformation of ini-
tiated cells. Although the structures of most of these tumor promoters
are still unknown, there appear <to be several different types in tobacco
smoke (5,41,59,66). Recently, Bock, et al. (6) published data which
confirmed earlier findings that whole cigarette tar, t,he neutral frac-
tion, two neutral subfractions and the weak acidic (phenolic) fraction
contain tumor promoters. One recent study indicated that "tar!' ob-
tained from tobacco stems only had essentially no tumor promoting
activity (65).
During the last year, several studies have reconfirmed the finding
that selection of tobacco and the use of tobacco sheets and filters can
lead to a significant reduction of `%a?' and PAH in cigarette smoke,
as well as to a reduction of the tumorigenicity of tobacco "tars." Simi-
lar results have also been reported. for commercial cigarettes (U,34).
Experimental studies demonstrated that with tobacco additives one
can reduce "tar," nicotine, PAH and tumorigenicity of cigarette smoke
(Id, 91). In terms of selective reduction of tobacco smoke components,
these investigations may be of practical value, as well as of academic
interest (57).
Tobacco Al?cahids
Present evidence does not indicate that tobacco alkaloids are car-
cinogenic. A possible exception may be cotinine, which was reported
to induce malignant tumors in rats [principally leukemias (58)] and

                                              61


adenomas of the bladder in mice (7). Boyland recently suggested that
one or more of the three possible nicotine-N-oxides may be present in
tobacco smoke and may be carcinogenic (7).
Tobacco alkaloids could theoretically contribute to the overall car-
cinogenicity of tobacco smoke, based on the possibility that in tobacco
smoke nornicotine and other secondary amines may react with nitro-
gen oxides to form the N-nitrosamines, of which several are known
carcinogens, especially N-nitrosonornicotine and N-nitrosoanabasine
(36). So far, however, N-nitrosamines of nornicotine and other alka-
loid N-nitrosamines have not been detected in tobacco smoke (36).

Nickel

The relationship of nickel compounds to the development of cancer
has been discussed in a recent review by ,Sunderman (55), who sug-
gests that there is a possibility that nickel carbonyl may be present
in cigarette smoke and may act as a cocarcinogen ,by inhibiting the
induction of pulmonary benzopyrene hydroxylase, an enzyme which
converts 3,4-benzpyrene to noncarcinogenic hydroxylated derivatives.

EXPERIMENTAL ASPECTS OF CARCINCXENSIS

Retention of Snwke Constituents

Studies on human smokers by Dalhamn, et al. (15) demonstrated
that about 60 percent of the volatile, water soluble compounds of
cigaret.te smoke, 20 percent of the volatile, nonwater soluble com-
pounds, and 16 percent of the particulate matter of cigarette smoke
can be retained in the mouth when the smoke is held in the mouth for
up to 2 seconds. Under conditions in which the smoke'is immediately
deeply inhaled, between 91 and 99 percent of the components of ciga-
rette smoke investigated (particulate matter, toluene, acetonitrile, ace-
tone, isoprene, acetaldehyde) were retained, with the exception of
carbon monoxide, of which 50 to 60 percent was retained (16).

C'tinges in Cekl Cdtures Induced by Cigarette Sake

Leuchtenberger, et al. (30)  h ave reported that passing cigarette
smoke through a charcoal filter prevented the damage caused by either
whole smoke, or the isolated gas phase of cigarette smoke, to cultures
of mouse kidney cells. In the same paper, they reported that the single
exposure of tissue cultures to puffs of charcoal-filtered smoke produced
a significant increase in t,he mitotic index of the kidney cells. In an-
other study, Leuchtenberger, et al. (31) reported that single exposure
to nine puffs of the gas phase from charcoal-filtered cigarette smoke
quickly stimulated the synthesis of DNA and RNA by cultures of
mouse ~fibroblasts. Repeated exposure of t,he cultures to the filtered gas
phase resulted in morphological and cytochemical changes indicative

62


of abnormal proliferation. Since the same alterations were found to be
present, to a much lesser extent, in some control cultures, the authors
considered that the filtered gas phase enhanced characteristics already
possessed by the cells. They concluded that the gas phase of unfiltered
cigarette smoke contains not only substances which inhibit cellular
metabolism, but also factors which stimulate cellular metabolism. These
latter factors may be unmasked by passing the gas phase through a
charcoal filter. The identities of the specific gases removed by the char-
coal filter and the extent to which each was removed were not reported
by the authors. Investigation of the relationship between the changes
observed in the tissue cultures and in &vo metabolism is necessary for
the interpretation of the results of these experiments.

Experimental &u&es of Brmhogenic Carcinoma in Anid

Because of the technical problems involved in inhalation experi-
ments in small animals (69,61), various animal models have been de-
veloped which do not employ the inhalation of smoke. These models
have been used to study the role played by carcinogenic substances
found in tobacco smoke in the induction of bronchogenic carcinoma.

Saffiotti (43) in a rec.ent review of experimental respiratory tract
carcinogenesis described the development of experimental models
for the induction of pulmonary tumors and discussed a method of in-
ducing bronchogenic carcinomas in Syrian golden hamsters by intra-
tracheal instillation of a finely particulated crystalline carcinogen
(e.g., benzo (a)pyrene) attached to a suspension of fine particles of
a carrier dust (e.g., ferric oxide) . This method reproduces some of the
conditions of human exposure to inhaled carcinogens and has resulted
in incidences of up to 100 percent of respiratory tumors, mostly squa-
mous cell and anaplastic carcinomas of the larger bronchi. These
tumors have been found to be invasive, metastasizing, and t.ransplant-
able. Saffiotti reported that the carrier dust particles play an essential
role in transporting the carcinogens through the bronchiolar and alveo-
lar wall int,o the lung tissues where they are phagocytized. The carcino-
gens are then eluted by the plasma and diffused into the lung tissue,
reaching up to the mucosa of the larger ,bronchi (42,44,45,46). Varia-
tions in particle size and distribution in the suspended particulate
matter affect the retent.ion rates of benzpyrene in the lungs (47). The
development. of this experimental model has led to the undertaking of
new research in many laboratories attempting to define the factors
responsible for carcinogenesis in the respiratory tract.

Two other techniques used to produce squamous cell carcinoma in
small laboratory animals are the passage of t.hreads impregnated with
carcinogenic hydrocarbons into the lung and the implantation of wire

63


mesh pellets in the bronchus. The latter technique gives a dose-response
relationship between carcinogenic hydrocarbons and squamous cell
carcinoma of the lung in rats (97). In order to overcome the traumatic
effects of the surgery involved in these procedures, two additional tech-
niques have been utilized. In one method, the carcinogen is suspended
in Freund's adj,uvant and upon tracheal instillation can lead to bron-
chial cancer (69). In this experiment, even more cancers were found
when the rats were pretreated with tubercle bacilli. Pretreatment of
the animals with tubercle bacilli produced infarcts, as well as scarring
of the lung. This finding is of interest `because earlier studies showed
that scarring of rat lung by the halogenated hydrocarbon hexachloro-
tetrafluorobutane increases their susceptibility to the development of
squamous carcinoma when exposed to carcinogenic hydrocarbons (54).
That scarring of the lung may increase the susceptibility of the lung
to carcinogens is in line with some recent observations on humans by
Bennett, et al. (g) who showed the frequent occurrence of pulmonary
scars in males with adenocarcinoma of the lung.

Experimental Aspects of Cancer of the BEadder and .lirirEny

Tobacco smoke ,appears to contain traces of several aromatic amines
which are established ,bladder carcinogens. Of these, however, only
Betanaphthylamine has thus far been identified in tobacco smoke with
2.2 x lo-* g. per cigarette ($0). At concentrations such as this, it ap-
pears unlikely that such aromatic amines can account for the increased
risk among cigarette smokers of developing kidney and bladder cancer.
A more likely correlation may exist between these types of cancers in
smokers and their elevated urinary excretion rate of carcinogenic
metabolites of tryptophan, and their oxidation products (@, 60).

Recently, the tobacco alkaloid cotinine was reported to induce ade-
nomas in the bladder of mice [16 percent (7)]. This observation needs
further testing. Cotinine is one metabolic product of nicotine and is
found in tobacco, cigarette smoke (86) and the urine of smokers (3.9).

A study by Schlegel, et al. (61) indicates an elevated concentration
of certain o-aminophenols plus their phenoxazon-oxidation products in
the urine of certain types of bladder cancer patients and cigarette
smokers, when compared to the urine of nonsmokers. Further studies
are needed on this problem.

64


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74


CHAPTER 4

Effects of Smoking
  on Pregnancy

Contents

Summary_--------------------------------------------- 77
Epidemiological Studies- _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _    77
Experimental Studies_-_-------______-_____-_------------------ 80
Cited References _______ ---_---- ______________________ ---    81

75