representing premalignant tissue changes in the respiratory t&t
cpithelium. Esophageal epithelial cells with atypical nuclei were found
far more frequently in cigarette smokers than in nonsmokers. The Mm
"atypical nuclei" describes nuclei with an irregular distribution of
chromatin. Other abnormal changes including giant nuclei may also be
present. Basal cell hyperplasia and hyperactive glands also were found
more frequently in cigarette smokers than in nonsmok8rs. An in-
crease in frequency with amount of cigarette smoking was noted for
both epithelial cells with atypical nuclei and basal cell hyperplasia.
Atypical nuclei in epithelial cells were also more frequently found
in ex-cigaretts smokers as compared to nonsmokers. Tables 20 and 21
illustrate the frequency of these Cndiigs:

TABLE 20.-Atypical nuclei in basal ce& of qithelium of esophugw of
        mda, by smoking habits and q

Atypical nucld

A. *I& YUN

Number men- _ _____________.
Total m?tlOM 1- ____________.
No atypical nuclei -_________,
Some but <@I penxnt
atypical _--_ _-----__----_--.
60 percent or more ntypical..

1. YEN VNDUB ME SC

Number men- _ ________ _____
Total sections I- ____________
No atypIcal nuckL ________
Some bat <59 percent
atypical _-_-__-- ---___---_-
60 percent or more atypical--

C. YIN AOED SO-60

Number IMXI. -__-___--_____
Total s&Ions I- ____________
No atypical nncleL. _ ______
&me but ~50 percent
atypically__ _- _ - - _ _ _ _ _-- _ _ _
60 percent or mom atypical..

D. MEN AQED 70 OB OLDEN

Number men- _ _____________
Total sectIona L _ ___ _____ ___
No atypical nuclei.. ________
Some but <@I percent
atYpical .-------__________.
60 percent or more atypIcaL

-

-

N

--









- _.









.-
._





._
.-
._


.-
.- -

91
7a7
7a3

52
2





26
228
190


a3
.___-




u
a7c
372

  1
  I





21
181
174

11
*-__.

Per-

-

___--
00.0
98.1

a0
0.3





.___-.
100.0
35.2

14.9
.____.





.___-.
lUJ.0
93.4

1.1
0.5





_-mm-
190.0
91.9

a 1
__-e-

Current
dgerette

-


1

779
II752
157

i,ssO
I, 198

1 Sections with some epithelhun present.
80vrcE: Auerbwh, O., et al. [table Z(s)].

Per-
tat
-

.-__--
lOa
2.5

79.8
17.7





.____.
100.0
3.4


OaO
6.6





_____.
100.0
2.2


75.6
22.2





-w-s-
190.0
1.5


74.0
24.5

,-

b

.-






1

Ex+aretta

181
LM
770

763
51





26
256
56


196
  7


EI
461

452
(0





U
375
253


118
  4

-

-



.-




_.
I









_.

-

zi
-

.__-_.
100.0
49.5

43.3
3.2

i----'
LOO.0
21.7


75.6
2.7

-e-m-
laI.0
43.4


47.4
4.2





-----
199. a
57.4


31.5
1.1

-

`k-
-




89
763
5a


lB3
25





  9
77
  1

74
  2





36
310
87

ml
12





42
879
15


853
11

-

2
-

.-_-_.
100.0
3.9

89.8
a3

___-_.
lo(LO
i.a

9al
2.6

-_--_
100.0
11.9

34.2
a9

__-_-
100.0
4.0

93.1
29

-

r

other

k?
-

31
266
74


176
4

I
218
117

9a
  a

-

PSr-
cent






-__--
loo.0
37.4


ea7
1.9





,_--_-
lo(10
7.5

86.8
5.7





.____-
109.0
23.9


39.5
1.6





.__---
199.0
54.9

43.7
1.4





161


TABLE 2l.-Atypid nuclei in b&Sal Clue of epithdium of esophagus of
      mu&a, by amount of smoking and age

Ce& with atypical nualel

<I P& I Is+-
         l-2 Pwka

I I
"A?- pg-
      CMt

A. All a#ee __________________________
  Total Metions 1----_-------------
No atyphl no&l ________ __ _-me
Nonlo but <No peArcent atypica.
6Opemntormoreatyplcd~--..-
B. Men ander sge 60:

  Numk mea ___________________
  Total eectloM ' -_-_____----------
No atypical nneleL. ___________e-
8ome but CEO pfrcmt atypicaL
60 paeut or mom atypical __-_-_ __.
c. Men aged m88:

  Number men ________ ____________
  Total SsctioM f -_-____-----------
No atypkal made4 ____________ ___
&me but <60-t sty&al.-
6OpercantormomatyplcaL~~~~~
D. Men aged 70 or older:

Nnmbsrmen---------------.---
Total aectlone I__________________
No atypIcal nnclel. ___________ ___
8ome but <tHl parant at&caL-
80 pemnt or mom atypical ______ __.

01 I
   - _ -- - --,
787 lmo
7aa   82.1
I    a6
a    0-a

23 _ __ _ -- _,
22a lmo
190 85.2
an   14.8
-- - _ _ __ _ _ _ _ -

44 _ _ - - - - -
a79 `imo
an   oar
4    1.1
2   -0.6


21 _-_----
la5   lmo
170   91.9
16 a1

. _ - - - _ __ _ _ - _-

__I-

"E-   Pa- Num-
  I       Ps- Num-
     cent be?  I
               ocnt be

a

0
780
8z
85

88
am
11
286
48

-- _ - --- _   U8
rmo boa9
  6.8    m
86.8  $867
  7.4.   8a8

._------   187
imo i,s79
1.1 a9
81.6 1.001

17.4

--___- --   la2
imo  1.18
11.1    11
88.2  LOB9
  a7 6@

._-_-_--
loo.0
1.8
oL2
6.0

----_---   240  .___----
imo  236   imo
  2.8    18    QS
87.9  l.bQI   76.B
  aa    491   22.2

_--_-- --    U
imo ~4
  a4 ______-.
ma ml
14.a    8a

._------
imo
._____--
76.9
24.1

l-

449

68
467
2
s82
n


111
w8
a6
8l4
299

19
174
2
911
77

-

Per-
ceut

.----__
imo
0.4
88.0
rao

.--mm__
imo
a7
04.8
al.a

.----__
imo
Ll
64.7
44.2

* 8ectioua wtth some eplthelium preaant.
8oosct: Anerbach, 0.. et al. [table S(s)].

Because of the association noted between esophageal cancer and
alcohol consumption reported in the Surgeon General's 1964 Report,
a study (68) was undertaken to consider the possibility that the car-
cinogens known to be present in tobacco smoke could penetrate esopha-
geal tissue more readily, if dissolved in aqueous solutions of ethanol.
Mice were exposed to several compounds by intraesophageal tubation.
Tissues were then removed and studied by fluorescence microscopy.
Deeper penetration and a different distribution were found when
benzo (a) pyrene was dissolved in aqueous solution of ethanol as com-
pared to benzo (a) pyrene dissolved in olive oil. It was also found that
benz (a) anthracene and fluoranthene dissolved in ethanol solution or
aqueous caffeine solution could penetrate the epithelium of the
esophagus.

The present evidence strengthens the conclusion that a four-fold to
five-fold increased risk of dying from esophageal cancer is associated

152


with tobacco smoking. Autopsy evidence indicates that smokers have a
greater frequency of pathologic changes of the esophageal tissue, some
of which are generally considered to be premalignant. It has been
demonstrated that known carcinogens such as benzo(a)pyrene and
others can penetrab the esophageal tissue when dissolved in aqueous
ethanol or caffeine solutions. The present evidence suggests that smok-
ing may be a causal factor in the development of esophageal cancers,
but is still insufficient for a firm judgment of causality. More informa-
tion on alcohol as a confounding variable and/or interactant is vitally
needed.

The data on women for the preceding categories of buccal, pharyn-
geal, laryngeal, and esophageal cancers have not been reported due to
the relatively too few cases involved. However, Hammond has pooled
these data into one group. Table 22 shows an increased mortality ratio
in this overall combined category but the number of deaths is still too
small for significant conclusions to be drawn.

TABLE 22.-Mortaht3,1 ratios and age-standardized death rates for cancer
     in uromen aged 46-64 by site and amount smoked

Buccal cavity, pharynx, larynx,
and e8OphfbgU8- __ ___ ___ _ __ _ _     2      3
Lung'-------_-______________     7     15
Pancreas- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _     6      11

~Bmoked2oormomcl r tteu
day. and begm smoHng     a day regardlw of
            fore age 25.    afe,boganmokingommokod10ormomcigerottess
                   1 E~olading raobea, pleura.
Some: Hammond, E. C. [table 26 (@)I.

Table 22 also shows the dosage effect of smoking on women, for dif-
ferent cancer sites-an increased amount of smoking being reflected
in an increased mortality ratio.

CANCER OF THE URINARY BLADDER

The Surgeon General's 1964 Report concluded: "Available data
suggest an association between cigarette smoking and urinary blad-
der cancer in the male but are not sutlicient to support judgment. on the
causal significance of this association."
The National Center for Health Statistics (84) reports that there
has been no change in the death rata from cancer of the bladder and
other urinary organs during the period 1950-64. For 1964, the male


death rate from this cause was 5.8 deaths per 166,600 population, and
the female death rate was 2.6 deaths per 166,606 population.
The mortality data from the large prospective studies are presented
below. The Hammond study reports the following mortality ratios and
death rates for cancer of the bladder and other urinary tract sites, for
males, by history of regular smoking :
TABLE ,23.-Hudd-er cuncer rnmtdty doe and age-&ndurdized
dath rate8 for mu.+% cigar& tvnokers, by sped&d age group8

                                     cfgamtte smokem

                                    Am-     Am 6S-79


Mortslityratioe_______________-----------____-_      200
Deathratee--___-------------------------------    ' (417  (1%

`Nnmbppsinpsrentheaeaindiostedsath~for~w~hr~never~kedregalsrly.
Sonncr: H ammond, E. C. [table 24 (@)I.
The Canadian Pensioners study (8) included bladder cancer in
t-he general category of genitourinary cancer.
TABLE 24.-l&&tuutirucry cancer mortu&y ratio8 for Canadian vet-saw
        by age and amount smoked

          Mortnllty ratioa             Number of dg8mttm emoked per day


                                     14       10-20      2l+


Allage. -------__----------------------.- 1.33     l.44      L 43
Age 70+ ________________-___------------     L 10     2 24      2. 43


80umx: Canadiau jmn&nere atudv [table 83 (e)].

The Dorn study of U.S. veterans (.@) reports the following mor-
tality ratios and death rates for males by quantity of cigarettes
smoked per day and by pipe and/or cigar smoking:

TABLE 25.-Bladdm and other urinary tract tamer nzortu@ ratios and
deuth ratm .for U.S. vetmam, by age, type and amouni smoked

Number of c&amt.tee smoked pw day

Mortality ratios- 1. 00
Death rates:

1. 10   1. 93   a 20   2 52 1.09

Age45-54 ______ - __________ 13    18    - - - - - - - - - - - - _
Age 55-64-m- 8                    20
Age 65-74-m 22 2: :: : 45 ::
Age 75-84-_- 89    _________--_____---------__-_-____

80~~1: U.S. veternne atady @pp. table A (ro)].
154

`aam pm


--

a 94 1.20


_----_ m---e
1s 14
9 28
_----- ---- l-


The Doll and Hill survey of British physicians ($38) reports the
following standardized death rates for cancer of the urinary bladder :

TABLE 26.-Death rates fat cancer of urinary bZu&?w by type of m&kg

-

Nonsmokers                   Type of mlokklg


             All smokers    cfgarette smokera   Mfred mnokm Pfpeorcigammokera


   17         11         13         12          7


8owcr: Study of British phyaicha [table 14 (!?@I.

TABLE 27.-Death rates for mncer of urinal b,!ad,&r by amount smoked

Amount of tobecco mloked d8uY (e.)'

   I-14          1624          25+


   10         11         13



k 1 g.- 1 cigamtte/d8y- $440~ to~~w~.
Souncr: Btudy of Brltfsb &`skhm ttable IIl (#@I.

All amowltd       CMtfOll


  12          8

The Hammond and the Dorn studies report mortality ratios of
more than 2.00 in smokers of more than 20 cigarettes per day. The
Canadian study reports the same for men over 70 years, who smoke
more than 10 cigarettes per day. The Doll and Hill survey is incon-
sistent with those pre%iously mentioned in that it shows no association
between type of smoking or amount smoked and bladder cancer.
However, this survey consists of but 38 deaths due to bladder cancer.
Two controlled retrospective studies of bladder cancer patients
have been reported since the Surgeon General's 1964 Report. In both
studies these patients had a significantly greater percentage of smok-
ers, the majority of whom were cigarette smokers, as compared with
controls. The first study (18) reported 94 percent smokers in the
patient group and 74 percent in the control group. When analyzed
by the amount smoked, the patient group had 80 percent heavy smokers
(greater than one pack per day for 30 years) as compared to only 45
percent heavy smokers in the control group. The second study (89)
reported 93 percent smokers in the patient group and 34 percent in
the control group. However, when compared by the amount smoked,
there was a much larger diflerence between the two groups; there being
86 percent of the patient group with a high "smoking index" (amount
smoked X duration of smoking) as' &&pared to only 66 percent in
the control group. The latter study also reported a greater frequency
of inhalation and "cigarette only" smoking in the patient versus
controls groups.

155


A~PSY STUDIES

There have been no reported studies analyzing changes in the
bladder tissue of smokers compared with nonsmokers. Studies of this
type would be helpful to determine if smoking is associated with
pathologic changes commonly thought to be premalignant in other
types of tissue.
           EXPERIMENTAL CARCIN~GENESIS

Cigarette smoke condensate ae well as several tobacco smoke con-
stituents were implanted with chol&erol directly into the bladder
of mice (26). Only hydroquinone produced a significant number of
bladder tumors.

METABOLIC STUDIES OF ENIWGENOUS CABGINOQENIC SUBEJTANCE~ IN B&N

Certain ortho-aminophenols and aryl hydroxylamines are lznown
to be carcinogenic (16). Three normal intermediate metabolites of
tryptophan are ortho-aminophenols (3-hydroxyanthranilic acid, 3-
hydroxy-2-amino-acetophenone, 3-hydroxykynurenine) and are known
to induce cancer when placed in the bladder of mice (lb).
Kerr, et al. (61,5!8), performed metabolic studies on six men, three
smokers and three nonsmokers. He found that the three nonsmokers
had substantially increased urinary excretion values of 3-hydroxyan-
thranilic acid and 3-hydroxykynurenine, after having smoked for 5
weeks, with a concomitant decrease in the excretion of N'-methylnico-
tinamide, a normal end product of tryptuphan metabolism. After hav-
ing stopped smoking for 5 weeks, the three smokers showed decreased
urinary excretion of these same intermediate metabolites and an in-
cream in N'-methylnicotinamide excretion.

The carcinogenic metabolites increased an average of 50 percent
while the normal end metabolite decreased an average of 34 percent
in response to cigarette smoking. A reversal was noted after the men
stopped smoking. These studies suggest that cigarette smoking changes
the normal metabolic pattern of tryptophan, leading to the accumula-
tion of carcinogenic metabolites in the urine. Further studies are
needed to confirm these findings.
Another study, designed to detect abnormalities of tryptophan (6)
in patients with various neoplastic or nonneoplastic conditions of the
urinary tract, showed that 29 of 201 bladder cancer patient,s had both
kynurenine and 3-hydroxykynurenine, in contrast to eight of 167 pa-
tients with other urinary traot diseases, neoplastic and nonneoplastic.
However, more renal cancer patients had 3-hydroxyanthranilic acid
than bladder cancer patients. This study did not include data concern-
ing current smoking habits of the patients studied.

156


The additional epidemiological, clinical, and experimental data
strengthen the association between cigarette smoking and cancer of
the urinary bladder, but are still insufficient to infer that the relation-
ship is causal.

CANCER OF THE STOMACH

The Surgeon General's 1964 Report stated that no relationship has
been established between tobacco use and stomach cancer. No new
evidence refutes this statement.

Epidemiological evidence does not show a significant relationship
between smoking and stomach cancer. The overall mortality ratios,
although greater than for nonsmokers, are smaller than for any other
disease related to smoking. There is also no gradient with the amount
of tobacco smoked.

TABLE 28.-Male mortality ratios and death rates for cancer of stumah
         by spec$ed age groups

                                   apsra-sr     &wm-7Q


Mortality ratios- ___ ___ ___ __ _ __ _ ____ -_ __ ______ __      1.42      1.26
Death rates------------------------------------ 1(11) 16    (57) 72

1 Numbers In psmntheaaa indicate death rates of persons who had never smoked cbrettea regalarly.
SOUSCE: Hammond, E. C. [table 24 (lo)].

TABLE 29.-Mortuiity ratios and d&h rates for cancer of stomach
    by age, type, and amount smoked, in U.S. wteram

Mortality ratio
(tohI) - - - - - - - - - - - _
Death rate:
  Age 45 to 54----
  Age 55 to64----
  Age 65 to 74-e-e
  Age 75 to 84----

0     1-Q   lo-#) n-a9 40+
-----

1.00 2.17 1.61 1.35 1.87

10 __----    7  - - - _ - - - - - - -
13 27 21 24 53
28 68 48 58 46
87 ___________________-___.

~OWCE: U.8. Veterans study [app. table A Wll.

157


TABLE

%I.-Death ratm for cancer of tttmach by type and amount
    moked, in British phy8Gam

Although cigarette smokers appear to have slightly higher death
rates from cancer of the stomach, the differences am small and do
not bear any consistent relationship with amount smoked.

CANCER OF TFIE PANCREAS

The Surgeon General's 1964 Report did not report on cancer of
the psncreas.
The more recent epidemiologic evidence shows an increase in the
death rates and mortalit
cigarette smokers (@,@ 3 ratios for  creatic cancer among male
          . Comparab y elevated ratios are noted for
           $"
females but not to the extent noted for males (@) (see tables 22,31,
32,33). Both theU.S. veterans study (M) and the Canadian pensioners
study (8) reveal a gradient of mortelity risk increasing with the
amount of cigarettes smoked. Data are ins&Gent to draw any con-
clusions for pipe and/or cigar smokers.

TABLE 3l.-Mon!u.&y 9~ztio8 an& d&h rata for cu?m~ of paweua
    by 8ex and epec+ age group8 in cigarette smokers

&o lb-79

                                           F-ale      Mob


Mortality ratio- _ __ _ __ _ _ __ _ ____                   ' 1.41     2. 17
Death rate ______- ______-__-___             * (32) 46   ' (31) 66



*Corn  tedkomap .tf4bie19.
~Nnmeralnpmen saa8indloabdaathrUesd~W~~nsosr~~desretteareeulerly.
  Pp &
louucr: Hammond, E. C. [tabled 24,28, and apt. tfatde 19 (@)I.

168


TABLE 32.-Mortality ratios and death Tales for cancer of pancreaa
     by age, type, and amount smoked, in U.S. veterans

                     C@rette3/daY         Mor cfgar
                    *I?        Pipe

                  0                       c&ars
                       l-9    1lMO   21-&l 40-k
                --------

Mortality ratio
(t&al)-. ---------- 1.00   . 87 1.93 2.18 1.87 1.13 1.52 .74
Death rate:
  Age45to54---------------- 9    21 __--__   26 ---------_--
  Age55to64---- 13 15 24   '26 21 19 21    22
  Age65to74---- 29 29 50 56 27 38 58 19
  Age 75 to &I----  109 ______ ________-_________ 32 33    68


sOwcr: U.S. vetemna study [app. table A (4@1.

TABLE X3.-Male mort&ty ratios for cancer of pawem of cuxrd
      cigarette smoker8 by amount mkeo?


                                  CWettsddsr


                            0        1-9       10-20       21+


Mortality ratio ________________     1. 00     1. 40     1. 96      2. 37


SOWQ: Cauadlan pensi~mra study [table 8.2 (8%

                RfisUlU5

An association between cigarette smoking and pancreatic cancar
is implied, but in the absence of data on other possible causal factors,
confounding variables and interactants, the signikance of this `BSSD-
ciation is not clear.


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