Synergistic Role of Alcohol for Esophageal Cancer

Numerous investigators have found a synergistic relationship
between the use of tobacco in various forms, alcohol consumption,
and the development of cancer of the esophagus (119, 132, 143, 241,
243, 263, 299, 307, 323). Some investigators report that tobacco is a
more important carcinogen than alcohol, but others report that the
reverse is true. Most of the studies report a synergism with the
combined use of tobacco and alcohol, resulting in higher rates of
cancer of the esophagus than would be observed by the addition of
the two exposures. The mechanisms by which these two factors
interact are not known. Alcohol may act as a solvent for carcinogenic
hydrocarbons in the tobacco smoke or may alter microsomal
enzymes in the mucosal cells of the esophagus (306). This hypothesis
has received support from experimental observations (150). It has
been noted, however, that alcoholism may be accompanied by severe
nutritional deficiencies, which also may predispose an individual to
certain diseases (271).

Experimental Studies

There is experimental evidence that benzo[a]pyrene is able to
penetrate the cell membranes of the esophageal epithelium, produc-
ing papillomas and squamous cell carcinoma. These studies and
others are presented in the Part of this Report on mechanisms of
carcinogenesis.

Conclusion

1. Cigarette smoking is a major cause of esophageal cancer in the
United States. Cigar and pipe smokers experience a risk of
esophageal cancer similar to that of cigarette smokers.

2. The risk of esophageal cancer increases with increased smoke
exposure, as measured by the number of cigarettes smoked
daily, and is diminished by discontinuing the habit.

3. The use of alcohol in combination with smoking acts synergisti-
cally to greatly increase the risk for esophageal cancer
mortality.

Cancer of the Urinary Bladder
introduction

It is estimated that in 1982 in the United States there will be
37,100 new cases and 10,600 deaths from cancer of the bladder (2).
The average annual incidence for males is almost three times that
for females.

101
Cancer of the bladder resulted in 6,401 deaths in 1950 and 9,812
deaths in 1977 in the United States. The age-adjusted rate fell from
3.7 to 2.9 per 100,000.

The age-adjusted mortality rate fell in all four color-sex groups
(Figure 39). The rate for white males, who had the highest mortality
from this disease, decreased by 5.7 percent between 1950 and 1977.
Among other than white males, who had the second highest
mortality rate from this disease, mortality declined by 2.6 percent. In
contrast, the age-adjusted death rate for white females decreased by
36.4 percent, and that of other than white females fell 25.9 percent.

White males between 45 and 74 years of age had lower death rates
from cancer of the bladder in 1977 than in 1960, but older males had
higher mortality. Among white females 45 years of age and older,
mortality decreased over the study period. The death rate increased
in other than white males 65 years of age or older and in other than
white females 75 years of age or older (Figures 40 and 41).

The age-specific death rates show no significant increases in either
white males or white females when plotted on a three-dimensional
graph for the period 1950-1977 (Figures 42 and 43).

Most cancers of the bladder are transitional or squamous cell
carcinomas. Unless these produce hematuria or obstruct the bladder
outlet, they remain undiagnosed until quite late, making cure less
likely. Five-year survival rates range from 4 percent for individuals
with distant metastasis, to 21 percent for individuals with regional
involvement, and to 72 percent with localized disease (2). For
patients diagnosed with bladder cancer from 1960 to 1973, the
overall 5-year survival rate was approximately 60 percent for whites
and 30 percent for other than white (313).

Certain occupational exposures are associated with an elevated
risk for bladder cancer. Many of these are related to the exposure to
certain aromatic amines in the work place. The first report of an
association between cigarette smoking and human bladder cancer in
the United States was based on a retrospective study of 321 men with
bladder cancer (157). In the ensuing 35 years, other epidemiological
and experimental data have established an association between
cigarette smoking and bladder cancer.

Several authors have conservatively calculated the percentage of
bladder cancers that can be attributed to cigarette smoking. One
study (313) estimated that 40 percent of male bladder cancers and 31
percent of female bladder cancers in the United States may be
attributed to smoking cigarettes. This is in agreement with the
estimate by Cole et al. (48) of 39 percent in males and 29 percent in
females. A Canadian study reported a population-attributable risk of
bladder cancer due to cigarette smoking of 61 percent in males and
26 percent in females (129).

102
 

 

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RATES/100.000

FIGURE 39.—Age-adjusted* mortality rates for cancer of
the bladder and other urinary glands, by
race and sex, United States, 1950-1977

* This graph is age-adjusted to the U.S. population as enumerated in 1970; all rates cited within the text of the
Report, however, are adjusted to the population as enumerated in 1940.
SOURCE: National Cancer Institute (298).

103
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FIGURE 42.—Age-specific mortality rates by 5-year age
groups for cancer of the bladder and other
urinary glands for white males, United States,
1950-1977

SOURCE: National Cancer Institute (798).

Causal Significance of the Association
Consistency, Strength, and Specificity of the Association

There have been numerous retrospective studies of the relation-
ship between smoking and bladder cancer (3, 46, 48, 55, 75, 139, 141,
157, 159, 188, 247, 253, 267, 313, 325, 327, 330). Almost all of these
studies have found an association between smoking and cancer of the

106
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FIGURE 43.—Age-specific mortality rates by 5-year age
groups for cancer of the bladder and other
urinary glands for white females, United
States, 1950-1977

SOURCE: National Cancer Institute (798).

bladder with relative risk ratios for the smoker averaging two to
three times that of the nonsmoker (Table 31). A retrospective
population-based study of 470 confirmed cases of transitional cell or
squamous cell cancers of the bladder found a positive relationship
between cigarette smoking and bladder cancer (48). A dose-response

107

377-310 0 - 62 - 9
relationship was demonstrated for both the number of cigarettes
smoked per day and different degrees of inhalation.

In the TNCS study (299), a significant association was found
between cigarette smoking and bladder cancer. The Hawaiian study
of five ethnic groups (113) also disclosed a positive association
between smoking and bladder cancer. In a Canadian population-
based retrospective study of 632 case-controlled pairs (129), the
relative risk for developing bladder cancer for those who had ever
used cigarettes versus those who had never used cigarettes was 3.9
for males and 2.4 for females. A dose-response relationship was
demonstrated, and reduced risk was associated with the use of filter
cigarettes as compared with the use of nonfilter cigarettes. Several of
the retrospective studies found a dose-response relationship of
cigarette smoking for bladder cancer, with the risk increasing with
increased number of cigarettes smoked per day, duration of cigarette
smoking, or lifetime number of cigarettes. Further, a study of
successive birth cohorts in four countries, including the United
States, found increasing rates of bladder cancer with increasing
smoking exposure, for both males and females (128).

Several of the large prospective epidemiological studies have
examined the relationship between cigarette smoking and bladder
cancer and are summarized in Table 32.‘On the average, cigarette
smokers are twice as likely to die from cancer of the bladder as are
nonsmokers. Several of these studies also show a moderate dose-
response relationship; however, this relationship is not as strong as
that noted between smoking and lung, laryngeal, oral, and esopha-
geal cancers (Table 33). Comparisons of mortality ratios for selected
causes of disease suggest that the specificity of the association is not
as great as that noted for the above cancers (Appendix Tables A and
B). The American Cancer Society 25-State Study (155) reported a
reduced risk for bladder cancer among smokers of lower tar and
nicotine cigarettes, a reduction which was statistically significant
among females but not among males.

The lower order of strength and specificity for bladder cancer than
for cancers of the lung, larynx, oral cavity, or esophagus suggests
that factors other than smoking may also be associated etiologically
with bladder cancer.

Bladder Cancer Mortality and Cessation of Smoking

Wynder and Stellman (326) reported that the risk of bladder
cancer decreased almost to the level of nonsmokers after about 7
years of cessation (Figure 44). More recent data from the USS.
Veterans and British Physicians prospective studies show bladder
cancer mortality ratios for ex-smokers only half those for continuing
smokers (68, 224).

108
TABLE 31.—Review of literature on smoking and bladder cancer reported since 1963—retrospective

 

 

studies
Relative risk
Years of smokers: Number of subjects
Country study Authors nonsmokers Cases Controls Study population
U.S.A. 1957-60 Wynder et al. (325) 3.58 300 300 Male patients
USA. 1951-61 Cobb and Ansell (46) 7,38 131 120 Male VA hospital
patients
Poland 1958-64 Staszewski (253) 2.7 150 750 Male patients
USA. 1958-64 Dunham et al. (75) 1.49 334 350 Male patients
1.28 159 177 Female patients
UK. 1958-67 Anthony and Thomas (4) <1 381 275 Male patients
US.A. 1967-68 Cole et al. (48) 19 360 381 Male patients
2.0 108 117 Female patients
USA. 1965-71 Simon et al. (41) 16 135 390 Female patients
Egypt 1966-71 Makhyoun (157) 1,38 278 278 Bilharzial male patients
17 87 87 Nonbilharzial male
patients
Canada 1972-73 Morgan and Jain (188) 6.4» 158 158 Male patients
4.4> 74 74 Female patients
Austria 1972-75 Flamm et al. (84) 16 150 _— Male patients; Austrian
population controls
3.0 40 — Female patients;

Austrian
population controls

 

*Recalculated from author’s data.

» Heavy smokers ( > 25 cigarettes per day) compared with nonsmokers.

SOURCE: Wynder and Goldsmith (313).

60T
TABLE 32.—Bladder cancer mortality ratios—prospective

 

 

studies
Alt
Population Study vs cigarette Comments
sie smokers
ACS 187,783 Smokers of 10-20 cigarettes
Males in White Includes all urinary
9-State Study Males 1.00 2.00 tract cancers.
Includes Prostate.

British 34,000
Physicians Male

Doctors 1.00 211
Canadian 78,000 Genitourinary cancers
Veterans Males 1.00 1.40 considered as a group
Acs 358,000
% State Study Males and 1.00 2.55

483,000 1,00 2.80

Females
U.S. Veterans 2,265,000

Person- 1.00 215

Years
California 68,153
Males in 9 Males 100 2.89
occupations
Japanese 265,118
study Males and 1.00 2.00 (Males)

Females 1.00 2.55 (Females)
Swedish 55,000
Study Males and 1.00 1.80 (Males) Bladder +

Females 1.00 1.60 (Females) _ other urinary

organs

 

For male ex-smokers, the risk after 15 years of not smoking was
less than one-half that of current male smokers (129).

Temporal Relationship of the Association

Evidence for the temporal relationship of the association is
provided by the prospective studies in which populations of initially
disease-free subjects were followed for the development of bladder
cancer. Reliable histological studies of bladder epithelium in smok-
ers compared with nonsmokers have not been reported.

110
TABLE 33.—Bladder cancer mortality ratios by amount
smoked—prospective studies

 

 

 

Amount
Smoked
Study Population per Day Ratio Comments
US. Veterans 290,000 Nonsmoker 1.00
1-9 1.22 * Based on
10-20 2.18 less than
21-39 2.78 20 deaths
> 40° 2.29
British Physicians 34,000 Nonsmoker 1.00 Grams of
males 1-14 2.20 tobacco
15-24 2.20 per day
25 + 1.40
California males 68,000 Nonsmoker 1.00
in 9 occupations males about °/. pk 1.52
about I pk 2.81
about 11% pk 5.41
Males Females
Swedish Study 55,000
males NS 1.00 NS 1.00
and 1-7 gm/day 1.50 17) 1.20
females 8-15 1.60 815 2.10
16 + 2.70 16+ 080

 

 

N= 541

 

 

 

 

“FS

a:
x
:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PRESENT 1-3 4-6 7-10 11-15 16+ NON-
SMOKERS SMOKERS

FIGURE 44.—Relative risk of male ex-smokers for cancer
of the bladder by years since quitting

smoking
SOURCE: Wynder and Stellman (326).

Coherence of the Association

Dose-Response Relationship

The finding of a dose-response relationship in both retrospective

111
and prospective studies (see page 106-107) strengthens the coherence
of the association of smoking and bladder cancer.

Correlation of Sex Differences in Bladder Cancer With Different
Smoking Habits

Two investigators (128, 185), reporting 10 years apart, found an
association between time trends in smoking patterns and bladder
cancer mortality among both males and females. Each found an
increasing risk of bladder cancer with increasing smoking exposure.

Correlation of Bladder Cancer Among Populations With Different
Tobacco Consumption

Coherence of the association is also illustrated by data showing a
low prevalence of this disease in groups with small proportions of
smokers (e.g., Mormons and Seventh Day Adventists) (79, 165, 166,
211, 294),

Bladder Cancer Mortality and Cessation of Smoking

Cessation of smoking decreases the risk of bladder cancer com-
pared to that of continuing smokers. A study of male ex-smokers
(129) found a risk of less than one-half that of continuing smokers 15
years after quitting smoking; a similar finding was observed in two
of the major prospective studies (68, 224).

Bladder Cancer and Non-Cigarette Tobacco Use

Two prospective studies have noted a relationship between pipe
and cigar smoking and cancer of the bladder (68, 131). In the British
Physicians Study, a mortality ratio of 1.5 was observed for the
combined category of Pipe/cigar smokers, whereas in the US.
Veterans Study, a relationship was noted only for pipe smokers
(ratio 1.20).

Synergistic Role of Other Substances for Bladder Cancer

The relationship between cigarette smoking and occupational
exposure(s) is complex and has not been clearly elucidated. A
number of carcinogens specific for the human bladder have been
identified (45). Some of these compounds are found in cigarette
smoke in very low concentrations. Cigarette smoking probably acts
as an independent agent in the development of bladder cancer;
however, there may also be additive or synergistic interactions
between cigarette smoking and substances present in the work place.

Those who work with dye stuffs, rubber, leather, print, paint,
petroleum, and other Organic chemicals are at higher risk for
bladder cancer than workers not exposed. ,

112
Conclusion

1. Cigarette smoking is a contributory factor in the development
of bladder cancer in the United States. This relationship is not
as strong as that noted for the association between smoking
and cancers of the lung, larynx, oral cavity, and esophagus. The
term “contributory factor” by no means excludes the possibili-
ty of a causal role for smoking in cancers at this site.

Cancer of the Kidney
Introduction

Over the period 1950-1977, the age-adjusted mortality rate for
kidney cancer rose from 2.2 to 2.6. The annual number of deaths due
to cancer of the kidney increased from 3,643 to 7,373. It is estimated
that in 1982 there will be 18,100 new cases and 8,300 deaths due to
kidney and other urinary tract cancers in the United States (other
than bladder cancer) (2).

The death rate of white males was higher than that of the other
three color-sex groups (Figure 45). While age-adjusted death rates
increased, although at a decelerating pace, among white males
throughout this period, rates among other than white males actually
decreased slightly after 1967. Among white females, the age-adjusted
rate increased between 1950 and 1957, when it stabilized. Among
other than white females, who had the lowest age-adjusted rate of
death from this disease, mortality rose from 1.2 to 1.4 per 100,000.

In the white population, the mortality sex ratio (male/female)
increased from 1.75 in 1950 to 2.24 in 1977, reflecting the rise in the
male death rate and the relative stability of the female rate. In the
other than white populations, the mortality sex ratio was slightly
lower during the 28-year period.

White males and white females were at greater risk from this
disease than were their counterparts, although the white to other-
than-white differential narrowed throughout the study period. In all
four color-sex groups, death rates moved generally upward in the
population between 45 and 84 years of age (Figures 46 and 47). In
1977, both white and other than white males had higher death rates
from this disease than did white and other than white females in the
10-year age group from 35 to 44.

The age-specific death rates for cancer of the kidney show an
upward trend in the older age groups, without a significant increase
in the rates for the younger age groups when plotted on a three-
dimensional graph for the period 1950-1977 (Figures 48 and 49).

There are four primary histological types of kidney cancer: (1)
renal cell carcinoma, (2) nephroblastoma (Wilm’s tumor), (3) sarco-

113
 

 

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RATES/ 100.000

FIGURE 45.—Age-adjusted* mortality rates for cancer of
the kidney, by race and sex, United States,
1950-1977

* This graph is age-adjusted to the U.S. population as enumerated in 1970; all rates cited within the text of the
Report, however, are adjusted to the population as enumerated in 1940.
SOURCE: National Cancer Institute (198).

114
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* 21967-1963
© =1964-1970
© =1971-1977

10 20 30 40 so 60 70
AGE IN YEARS (BY S-YEAR AGE GROUPS)

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FIGURE 48.—Age-specific mortality rates by 5-year age
groups for cancer of the kidney for white
males, United States, 1950-1977

SOURCE: National Cancer Institute (798).

ma, and (4) epithelial tumors of the renal pelvis. Renal cell
carcinomas comprise about 90 percent of kidney tumors and
generally affect individuals after age 40 (average 55 to 60) (197). This
tumor may be silent until far advanced. The median survival time
for kidney cancer in the adult is about 2.7 years for those aged 35 to
54 at the time of diagnosis and 1 year for those 65 or older (197).

117
 

   

   
    

     
  

    

 

 

            
  
  
  

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FIGURE 49.—Age-specific mortality rates by 5-year age
groups for cancer of the kidney for white
females, United States, 1950-1977

SOURCE: National Cancer Institute (198).

Epidemiological studies have established an association between
cigarette smoking and kidney cancer.

Causal Significance of the Association
Consistency, Strength, and Specificity of the Association

Several retrospective studies have examined the relationship
between smoking and kidney carcinoma. Data from these studies

118
(Table 34) show a positive association between smoking and kidney
cancer with relative risks ranging from 1.06 to over 5, with one study
of renal pelvis cancer reporting a tenfold risk for heavy cigarette
smokers. Other studies also reported an increasing relative risk of
renal adenocarcinoma and cancer of the renal pelvis in cigarette
smokers (20, 21, 130, 238); the increase of relative risk of renal
adenocarcinoma among cigarette smokers was found for both males
and females (320). A significant positive association between ciga-
rette smoking and renal cancer was noted in the TNCS study (299)
and in the Hawaiian Study of Five Ethnic Groups (113).

In most of the prospective studies, cancer of the kidney refers to
tumors arising from the renal parenchyma as well as to tumors in
the renal pelvis and ureter. In several of the large prospective
studies (Table 34), an association was found between cigarette
smoking and cancer of the kidney. The mortality ratios for all
cigarette smokers varied from 1.20 to almost 3, compared with
nonsmokers. Four of the prospective studies have noted a dose-
response relationship as measured by the number of cigarettes
smoked per day for kidney cancer (68, 105, 224, 290). Data from these
studies are presented in Table 35. Generally, heavy smokers have
mortality ratios two to three times greater than nonsmokers. In the
U.S. Veterans Study, Rogot and Murray observed a decline in kidney
cancer mortality among ex-cigarette smokers with a mortality ratio
of 1.21 versus 1.41 for continuing smokers. Thus, the strength of the
association of cigarette smoking related to kidney cancer risk is less
marked than that for cancer of the other sites discussed above.

Chemical elements such as lead and cadmium, hormones, ionizing
radiation, genetic susceptibilities, as well as tobacco smoke have
each been suggested as potential etiologic factors in this disease
(322). Several studies (21, 32, 130, 214) have shown that a substance
present in tobacco smoke, di-methylnitrosamine, causes kidney
tumors in rats.

Temporal Relationship

The prospective studies provide support for the temporal relation-
ship of the association.

Coherence of the Association
Dose-Response Relationship

The dose-response relationship noted in four of the prospective
studies lends support to the coherence of the association between
smoking and cancer of the kidney.

119
TABLE 34.—Kidney cancer mortality, ratios and relative
risks, prospective and selected retrospective

 

 

 

studies
Number of Morality ish satin
kidney relative risk ra Comments
Population Study size cancer Non- Cigarette
deaths smokers smokers
Prospective Studies
ACS 9-State 188,000 54 1.00 158 Based on 54
Study white males microscopically
proved cases
ACS 25-State 440,558 males 104 1.00 1.42 Age 45-64
Study 1.57 Age 65-79
U.S. 290,000 257 1.00 141
Veterans
California 68,153 males 27 1.00 2.46
males in
9 occupations
Japanese 122,261 30 1.00 1.20
Study males
British 34,000 46 1.00 2.66 All smokers
Physicians males
Retrospective Studies
Bennington renal adenocarcinoma 100 1.00 5.1 Risk ratio for
Laubscher 100 cases pipe - 10.3
(20, 21) 190 controls cigar - 12.9
Schmauz and 43 cases of renal 18 1.00 10.0 For smokers of
Cole pelvis or ureter more than 2'/,
(238) 451 controls pks/day
Armstrong 106 adenocarcinoma 106 1.00 1.06
(5a) of kidney
30 carcinoma of 30 1.00 1.80
renal pelvis
139 controls
Wynder 202 adenocarcinoma 1.00 2.00 (males)
et al. of kidney
(322) 394 controls 1.00 1.50 (females)

 

Correlation of Sex Differences in Kidney Cancer With Different
Smoking Habits

There has been an increase in the white male to female ratio of
deaths from kidney cancer. This trend does not demonstrate an

120
TABLE 35.—Kidney cancer mortality ratios by amount
smoked per day—prospective studies

 

 

Amount per Day Study/Ratio Comments
US. Veterans
Nonsmoker 1.00 “Less than
1-9 0.95 20 deaths
10-19 1.32
20-39 1.63
40+ 2.59*
All smokers 141

British Physicians**

Nonsmoker 1.00 **Grams of
1-14 2.66 tobacco
15-24 3.00 per day
254 3.00

All smokers 2.66

ACS 9-State Study***

Nonsmokers 1.00 ***Includes
1-9 1.90 genitourinary
10-20 18
21+ 2.94
All smokers 1.90

California Males in
Various Occupations

Nonsmoker 1.00
about 10 0.86
about 20 3.30
Over 30 2.57

All smokers 2.46

 

effect of the later initiation of smoking by females as evidenced so
clearly by the recent increases in female lung and laryngeal cancer
risks.

Correlation of Kidney Cancer Mortality Among Populations With
Different Tobacco Consumption

The relative risk of kidney cancer is reduced in populations with a
low proportion of smokers (79, 165, 166, 211, 294), although this
reduction is not as great as that observed for lung, larynx,
esophageal, and oral cancer.

Smoking and Histologic Changes in the Kidney

No human autopsy studies have been published which examine
histologic changes in the kidney among smokers compared to
nonsmokers.

121
Kidney Cancer and Non-Cigarette Tobacco Use

An elevated relative risk of from tenfold to twelvefold has been
reported for smokers of pipes or cigars in one study (21). The U.S.
Veterans Study noted an association for pure pipe smokers (ratio
1.32) and for mixed smokers of pipe and cigars (ratio 1.52) and kidney
cancer, but not for pure cigar smokers.

Conclusion

Cigarette smoking is a contributory factory in the development of
kidney cancer in the U.S. The term “contributory factor” by no
means excludes the possibility of a causal role for smoking in cancers
of this site.

Carcinoma of the Pancreas

Introduction

In 1982, it is estimated that there will be 24,800 new cases and
22,300 deaths from carcinoma of the pancreas in the United States
(2).

Pancreatic cancer caused the deaths of 8,953 persons in 1950 and
20,465 persons in 1977 (the data for 1977 include deaths coded under
ICD No. 157). The age-adjusted death rate rose from 5.3 per 100,000
in 1950 to a peak of 6.8 in 1968, and has remained stable since, at
about 6.7. After 1968, the age-adjusted death rate from this disease
actually decreased slightly from 6.8 to 6.7 per 100,000.

Increases in the age-adjusted rate between 1950 and 1967 resulted
from increases in the mortality rates of all four color-sex groups
(Figure 50), with white females showing the smallest increase and
other than white males showing the largest. In 1950, white males
and females had higher death rates from this disease than did males
and females of other races. By 1977, the age-adjusted rate for whites
was 22 percent lower than the rate for others.

The age-adjusted death rate of white males increased from 6.4 to
8.3 per 100,000 over the study period, and that of white females rose
slowly from 4.3 to 5.2. Rates nearly doubled in the other populations,
rising from 3.4 to 6.6 in females and from 5.3 to 10.5 in males.

Among white males 25 to 84 years of age, there was an increase in
mortality from 1950 until 1967 (Figure 51). Thereafter, this trend
was reversed, except in males 75 or older. Among other than white
males, rates rose steadily during the 1950s and early 1960s and then
leveled off or declined, except among those 55 or older, whose
mortality rates continued to increase through 1977 (Figure 52). Both
white and other females of most ages had increasingly higher
mortality rates over the entire 1950-1977 period.

Generally, the mortality sex ratio decreased with advancing age in
both the white and the other than white populations. The age-
specific death rates over time show an increase in the older age

122
       

 

 

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Report, however, are adjusted to the population as enumerated in 1940.
SOURCE: Nationel Cancer Institute (198).

123

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