Cancer 0

Table 4-8 (continued)

First Authori
Year       Location
f?reast (continued)

Comments

Kelsey
1981

Brisson
1984

Kidney
Wynder
1974
McLaughlin
1984

Maclure
1985 (abstr)
Goodman
1986

Asal
1985 (abstr)
Yu
1986

Endometrium
Kelsey
1982

Henderson
1983

La Vecchia
1984

U.S.

U.S.

U.S.


U.S.

U.S.


U.S.


U.S.


U.S.

U.S.


U.S.


IdY

Increased risk with BW in postmenopausal
women. Decreased risk in premenopausal
women.

Increased risk with BW in pre- and
postmenopausal women; inverse association
with height.

Greater proportion cases with RBW > 125%
in females only.

Increased risk with BMI in females. Positive
association for weight gain since age 20 in
females.

Increased risk with BMI in men and women.

Increased risk with BMI in men and women.

Increased risk with BMI in men and women.

Increased risk with BMI in men and women
independent of tobacco and other risk
factors.

Increased risk with BW and similar trend for
BMI (not presented by authors).
Increased risk with BW and similar trends
for BMI and BW at age 20.
Increased risk with BMI greater for
premenopausal than for postmenopausal

201


O Nutrition and Health

Table 4-8 (continued)

First Author/
Year       Location       Comments

Prostate

Wynder
1971

Colorectal
Wynder
1%9

Thyroid
McTieman
1985 (abstr)

Meningioma
Bellur
1983

U.S.

No significant difference in RBW between
cases and controls with no significant
difference in height.

Japan

No significant difference in RBW between
cases and controls.

U.S.

Increased risk with BW in > = 60 vs.
< = 52 kg. Only women studied.

U.S.

Increased risk for "obese" women. No
significant difference among men.

Key: BW  = body weight.
  BMI = body mass index.
  RBW = relative body weight.
   P values for test for trend, unless otherwise indicated.

Source: Adapted from Albanes 1987.

smokers but have a lower cancer risk) showed a relationship between
relative body weight and cancer death that was nearly linear (Lew and
Garfinkel 1979). In the United States, individuals greater than 40 percent
overweight have mortality ratios (observed cancer deaths divided by ex-
pected cancer deaths) higher than average-weight individuals by 33 percent
for men and 55 percent for women (Garfinkel 1985). In men, this relation-
ship was statistically significant for cancer of the colon, rectum, and
prostate, and in women, for cancer of the breast, uterus (cervix and
endometrium), ovary, and gallbladder.

Animal Studies

Restriction of caloric intake reduces the incidence of many different can-
cers and increases the lifespan of laboratory animals (Tannenbaum 1940a;
Kritchevsky and Klurfeld 1987). Some of these suggest that the greatest
reduction in cancer incidence is associated with lifelong restriction of

202


Cancer O

calories, but caloric restriction begun in adulthood may also have a protec-
tive effect (Weindruch and Walford 1982).

Total caloric intake as well as calories derived from fat affect cancer risk,
but their relative importance may vary for different tumor types
(Kritchevsky, Weber, and Khnfeld 1984). One study that has attempted to
separate the effects of calories from those of fat suggested that tumor
incidence in rats depends on energy intake, energy retention, and body size
rather than on percent of fat calories in the diet (Boissonneault, Elson, and
Pariza 1986).

Biochemical Mechanisms

While no unifying principle to explain the relationship has emerged, cur-
rent investigations in animals support the idea that overnutrition increases
cancer risk (Pariza and Boutwell 1987). One hypothesis is that chemical
carcinogens may be stored in body fat for mobilization and transport to
target tissues. A second hypothesis is that the supply of available energy is
one factor that controls cell growth (Pardee et al. 1978; Scott, Wille, and
Wier 1984), and an excess of available energy may increase cell multiplica-
tion and affect the promotion phase of carcinogenesis. Excess energy
could also shorten the latent period. A third hypothesis involves the
influences of female hormones on breast, ovarian, and uterine cancers,
with metabolism of hormones in adipose tissue possibly playing a role in
tumor formation and growth. Androstenedione from the adrenal gland can
be converted to estrogen in adipose tissue and may stimulate cell division
in the target organs of obese individuals (Siiteri 1987). Thus, although
animal studies suggest that caloric restriction might reduce cancer inci-
dence, the results of human studies are not wholly consistent (see Table
4-8). To resolve these inconsistencies, additional studies are needed to
separate the individual effects of calories, fat, and obesity (Willett 1987).

Role of Dietary Fiber in Cancer

Dietary fiber includes components of plant materials that, when eaten,
resist the action of human digestive enzymes. Dietary fiber has diverse
chemical constituents, including carbohydrate and carbohydrate-like cel-
lulose, hemicelluloses, lignin, gums, and pectins. Major food sources of
fiber are fruits, vegetables, and whole grain cereals.

In some studies, particularly correlation studies, consumption of high-fiber
foods has been correlated with lower risk of colon cancer. An important

203


Ll Nutrition and Health'

issue in human studies is the lack of information about the specific compo-
nents of dietary fiber and how they may affect cancer risk. Although rodent
studies have provided conflicting results, they do suggest that the type of
fiber is important. In those studies that showed a protective effect, wheat
bran, a source of water-insoluble fiber, was more consistently associated
with lower risk of colon cancer than other fiber sources (Pilch 1987).

Human Epidemiologic Studies

The results from 44 epidemiologic studies conducted between 1973 and
1987 are summarized in Table 4-9. Numerous correlation studies have
suggested a protective effect of dietary fiber against colon cancer (Burkitt
1980; Reddy 1982; Greenwald, Lanza, and Eddy 1987). Of the 24 correla-
tion studies, 21 identified an inverse association of dietary fiber, fiber-rich
diets, or other measures of fiber consumption with occurrence of colon
cancer; 3 showed no association; and none reported a positive association.
One international study that found an inverse association with total dietary
fiber also found a protective effect of cereal fiber, even after adjustment for
intake of fat or meat (McKeown-Eyssen and Bright-See 1985).

In some studies, correlations with other nutrients were also observed.
Thus, while patterns of eating foods high in fiber show good correlation
with low colon cancer rates, other dietary components might also be
influencing this association. It must also be noted that international cor-
relation studies (seven studies) tend to derive their food data from similar
sources.

Several epidemiologic studies that include biochemical markers have cor-
related cancer rates to measures of stool weights, fecal bile acids, enzymes
from colonic bacteria, and fecal mutagens. Comparison of rural Finns (who
have low rates of colon cancer) to their urban counterparts shows that
intake of calories and fat is similar for both groups, but the rural Finns have
a higher intake of dietary fiber, a greater stool weight, and a lower level of
fecal bile acids than urban Finns (Englyst et al. 1982; Cummings and
Branch 1982; Jensen, MacLennan, and Wahrendorf 1982; Bingham et al.
1982).

The importance of these observations derives in part from the fact that
secondary bile acids, formed by bacterial degradation of primary bile acids
in the intestine, have been shown to promote tumors in animals (Wynder
and Reddy 1983), may be mutagenic (Wilpart et al. 1983), and are directly
correlated with population incidence of colon cancer (Hill 1983). Fecal
mutagens are also correlated with the incidence of colon cancer in popula-


Cancer 0

          Table 4-9
Summary of Epidemiologic Studies Examining
   Dietary Fiber and Colon Cancer

Authors            Year

         Vege-  High Fiber/
Fiber   Cereals   tables   Low Fat

International
Correlation Studies

Drasar & Irving
Irving & Drasar
Armstrong & Doll
Howell
Knox
Liu et al.
McKeown-Eyssen
& Bright-See

1973
1973
1975
1975
1977
1979

0
     - (a)
     - (a)

      -
- (a)

1985

Within-Country
Correlation Studies

Malhotra           1977
Lyon & Sorenson      1978
Enstrom            1980
Rozen et al.          1981
Maisto & Bremner      1981
Jensen             1983
Bingham et al.        1985

-(b)
0

-(b)
-09
-

Metabolic
Correlation Studies

MacLennan et al.       1978
Reddy et al.          1978
Reddy et al.         1980
Jensen et al.          1982
Reddy et al.          1983
Nair et al.           1984
Walker et al.          1986

0

Time Trend
Correlation Studies

McMichael et al.       1979   - (b)
Helms et al.          1982     -
Powles & Williams     1984        - (a)

-

-(b)

205


O Nutrition and Health

Table 4-9 (continued)

Authors            Year

Fiber

Cereals

Vege-  High Fiber/
tables   Low Fat

Case-Control Studies

Haenszel et al.        1973
Bjelke              1974a
Bjelke             1974b
Phillifis             1975
Modan et al.          1975
Graham et al.         1978
Dales et al.          1978
Moskowitz et al.        1979
Haenszel et al.        1980
Hunter et al.          1980
Jain et al.            1980
Martinez et al.        1981
Manousos et al.        1983
Pickle et al.          1984
Potter & McMichael     1986
Tuyns              1986
Macquar%-Moulin       1986
Lyon et al.          1987
Kune et al.         .I987

Cohort Studies

Hirayama

1981

0

-(b)
0
+

0
+ (a)

- (4
- (b>

+
        -

+ (a)
        -

Key: 0 = No association.

- = Inverse association (decreased risk).
+ = Direct association' (increased risk).
(a) = Adjustment for other food conlponents removes the association.
(b) = No test for significance or not statistically significant.

tions (Wilkins and Van Tassel1 1983), although no-such correlations have
been observed for individuals (Correa 1981). Recently, fecal mutagens
have been shown to be modulated by dietary fiber (Reddy et al. 1987). In
addition, fermehtation of fiber in the colon by intestinal bacteria results in
the release of short-chain fatty acids, which may directly influence colonic
mucosal cells (Reddy 1982). Further research is needed to elucidate the
role of fecal mutagens in colon cancer and the influence of v@ous dietary
fibers (Pilch 1987).                              .

Additional support for generating the fiber/cancer hypothesis comes from
time-trend correlation studies. Long-term trends in colon cancer for sev-
eral population groups also offer insights into the role of dietary fiber. In

206


Cancer 0

Denmark, the decrease in dietary fiber consumption from 1927 to 1977 has
been correlated to the rise in prevalence of colon cancer (Helms et al. 1982).
In seven other countries, changes in flour milling practices during World
War II led to increased consumption of total fiber, which correlated with a
reduced mortality of colon cancer in those countries 15 years later (Powles
and Williams 1984). Other wartime lifestyle changes, such as decreased fat
or meat consumption, however, could have also influenced mortality.

To date, 19 case-control studies have assessed the role of fiber-containing
foods in colon cancer: 3 of these studies found no effect (Moskowitz et al.
1979; Jain et al. 1980; Pickle et al. 1984). 3 found an increased risk
(Haenszel et al. 1973; Martinez et al. 1981; Potter and McMichael 19861,
and 13 observed a protective effect of fiber-containing foods, especially
vegetables. Protective effects have been found in two case-control studies
that examined the relative risk for a high-fat, low-fiber diet (Dales et al.
1978; Manousos et al. 1983). Overall, case-control studies present mixed
results. Some show fiber and fiber-containing foods to be protective: others
do not.

Animal Studies

Animal studies of dietary fiber and colon cancer have provided inconsistent
results due to a number of factors, including differences in the nature of the
carcinogen used, variations in composition of the diet, qualitative and
quantitative differences in the fibers fed, animal strain, or duration of the
experiment (Reddy 1986; Pilch 1987). In the past decade, a number of
studies have been conducted on laboratory rats fed diets of various fiber
sources and levels and exposed to certain known colonic carcinogens:
DMH, AOM, DMAB, and methylnitrosurea (MNU). When wheat bran was
used as the source of dietary fiber, a protective effect was seen in the
majority (Reddy 1982; Barbolt and Abraham 1978) but not all studies
(Bauer et al. 1979; Jacobs 1983). A protective effect against colon cancer
was found in studies of chemical carcinogens requiring microsomal activa-
tion (DMH, AOM, DMAB) but not in one study with MNU, a direct-acting
carcinogen. Other studies reported were less suggestive of protection.
Although two-thirds of studies showed that dietary cellulose was protective
for rats exposed to DMH and AOM, no effect was observed for the rest.
Studies of the effect of corn bran, rice bran, oat bran, pectin, and guar gum
must be considered indeterminant, with some showing a protective effect,
more showing an enhancing effect, and others showing no effect (Pilch
1987). The relevance of these animal models to human cancer needs to be
determined.

207


O Nutrition and Health

Biochemical Mechanisms

The means by which fiber may exert its protective action are not under-
stood. Several possibilities have been advanced: Fiber may act to reduce
transit time in the bowel and therefore decrease the time for exposure to
potential carcinogens; through its hydrophilic nature, it can dilute the
concentration of carcinogens in the colon; it can affect the production of
bile acids and other potential carcinogens in the stool; it can alter the nature
of fecal bile acids by virtue of its influence on the composition and meta-
bolic activity of fecal flora; and it can reduce colonic pH by increasing
fermentation and short-chain fatty acid production (NRC 1982; Eastwood,
McKay, and Brydon 1986).

Limited information is available on the types of dietary fiber that might
protect against cancer. Research will have to define the importance of
various fiber compounds relative to the risk for specific cancers. The term
fiber embraces a broad range of food components whose primary com-
monality is their relative indigestibility. Different types of fiber have very
different qualities. Some are classified as soluble, others insoluble. Some,
but not all, appear to affect gastric emptying. Some affect absorption of
certain nutrients, others do not. Animal studies suggest that different types
of fiber work differently with respect to the occurrence of colon cancer. As
noted earlier, wheat bran, which decreases gastrointestinal transit time and
increases stool weight, appears to more consistently reduce the frequency
of colon tumors in animals than other types of fiber (Pilch 1987). However,
until better methods for analyzing the fiber content of foods are developed,
the influence of fiber components such as pentosan fractions (Bingham et
al. 1979). uranic acids (pectins), or cellulose (Bingham, Williams, and
Cummings 1985) must be considered uncertain.

In humans, a sudden change from a low-fiber to a high-fiber diet may
provoke symptoms of gastrointestinal distress, although effects are not
generally seen with gradual increases. The most frequently suggested
adverse effect of high fiber intake is mineral imbalance. While the evidence
is mixed, a recent review suggested that consumption of diets containing
about 20 to 25 g of insoluble fiber from foods per day does not appear to
pose a problem relative to mineral availability (Pilch 1987). This amount
translates to approximately 30 to 35 g of total dietary fiber from a mixed
adult diet and is consistent with current recommendations of the National
Cancer Institute (20 to 30 g daily from a variety of food sources, including
vegetables, fruits, and whole grain cereals).

208


Cancer O

Role of Vitamin A and Carotenoids in Cancer

A large body of evidence suggests that foods high in vitamin A and car-
otenoids are protective against a variety of epithelial cancers (Mettlin 1984;
Kummet, Moon, and Meyskens 1983; Bertram, Kolonel, and Meyskens
1987; Palgi 1984).

Vitamin A in foods occurs in two forms: (1) preformed vitamin A (retinol
and retinol esters) from animal foods and (2) provitamin A (carotenoids that
the body can convert to vitamin A) from plant foods. Hundreds of other
carotenoid compounds in fruits and vegetables seem to have no vitamin A
activity. Beta-carotene-containing foods have been extensively studied in
cancer epidemiology (Peto et al. 1981). Although beta-carotene is most
efficiently converted (Linder 1985), it still has only one-sixth the biologic
activity of retinol. Many reports on the effects of vitamin A do not specify
whether they are studying preformed vitamin A, carotenoids in general,
retinoid analogs of vitamin A, or beta-carotene alone (NRC 1982). This
chapter uses the term vitamin A to include all of the above unless otherwise
specified.

Epidemiologic studies have used food intake records to analyze the intake
of beta-carotene, carotenoids, and retinol, or a "vitamin A index" that
combines these. A methodological difftculty is that foods such as green and
orange-yellow vegetables may contain protective factors in addition to
carotenoids (Mettlin 1984). Other complications are presented because
inverse correlations between blood levels of beta-carotene and retinol and
risk for cancer have been identified in some but not all studies (Willett and
MacMahon 1984a). Future studies that better distinguish the individual
effects of beta-carotene, carotenoids, retinol, and other food components
will require improved dietary assessment methods (Russell-Briefel, Cag-
giula, and Kuller 1985).

Human Epidemiologic Studies

Low levels of vitamin A (or retinol) in blood have been associated with an
increased risk for cancer in some (Wald, Idle, and Boreham 1980; Kark et
al. 1981) but not all (Wald et al. 1984; Willett et al. 1984; Nomuraet al. 1985;
Salonen et al. 1985) studies. Low levels of beta-carotene in stored blood
also have been associated with an increased risk for cancer in some
(Nomura et al. 1985; Stahelin et al. 1984) but not all (Willett et al. 1984;
Menkes and Comstock 1984) studies. There are problems, however, in
relating blood levels to cancer risk. Blood retinol remains unchanged
across a wide range of dietary intakes because of homeostatic mechanisms.


O Nutrition and Health

Thus, increased vitamin A is unlikely to result in increased serum retinol,
except during vitamin A depletion. Consequently, the association between
serum retinol and cancer may be due to factors that regulate serum retinol
rather than to dietary vitamin A itself. In contrast, serum carotenoids may
better reflect dietary carotenoids, and the relationship between dietary
carotenoids (or the foods that contain them) and cancer may be more direct
than that between serum retinol and cancer. A major weakness of these
studies is that blood levels of vitamin A or carotenoids observed at the time
of diagnosis may be different from those present when the disease began.

One prospective cohort study on the older population in Massachusetts has
shown that the risk for all cancers decreases with increasing intake of
carotenoid-containing vegetables (Colditz et al. 1985). Foods containing
vitamin A may be protective against cancer of the oropharynx (Ibrahim,
Jafarey, and Zuberi 1977), larynx (Graham et al. 1981), breast (Grahamet al.
1982), stomach (Stehr et al. 198% cervix (La Vecchia et'al. 1984), colon
(Modan, Cuckle, and Lubin 1981), and bladder (Mettlin, Graham, and
Swanson 1979). Results for cancer of the prostate have been mixed, how-
ever, with one study showing a protective effect (Schuman et al. 1982), two
studies showing the opposite (Graham et al. 1983; Heshmat et al. 1985), and
one showing no effect (Whelan, Walker, and Kelleher 1983).

Lung Cancer. The strongest evidence for the role of vitamin A in preven-
tion of human cancer comes from epidemiologic studies that correlate
consumption of carotenoid-containing vegetables or foods with a high
vitamin A index to protection against cancer of the lung (Shekelle et al.
1981; Kvale, Bjelke, and Gart 1983). These studies are summarized in
Table 4-10. The Western Electric Study of 1,984 middle-aged men, for
example, found a protective effect with provitamin A (beta-carotene) but
not preformed vitamin A (Shekelle et al. 1981). A case-control study of lung
cancer in white males in New Jersey showed a 30 percent greater risk of
cancer for men in the lowest quartile of carotenoid intake but no increased
risk for a low consumption of retinol or total vitamin A intake (Ziegler et al.
1986). The Western New York Diet Study showed a protective effect for
both total vitamin A and vitamin A from fruits and vegetables in men but
not in women (Byers et al. 1987).

An important question in each of these studies is whether the protective
effects attributed to vitamin A activity, as discussed above, are truly
attributable to vitamin A or whether they are due to some other factor that
may be present in the foods. For example, epidemiologic studies have
shown an inverse association between the consumption of cruciferous
vegetables such as cabbage, broccoli, Brussels sprouts, or cauliflower and

210


         Table 4-10
Dietary Vitamin A and Lung Cancer Risk:
  A Summary of Previous Studies

                    No. of                                    Findings
                   Cases:                                    (Approxi-
                   Controls                                         mate %
                       or                    No. of                Nutrient    of Study     Relative
   Reference (location)      Cohort Size     Sex        Foods    Nutrient       Level     Group)      Risk

   Cuse-Conrrol Studies

   MacLennan et al.       233:300       Males and     loo     Green, leafy     Low      (NW       2.2
    1978                        females           vegetables     High      (NW        I.0
   (Singapore)
   Mettlin et al. 1979       292:801        Males       33      Vitamin A      Low       (49)        1.7
N
E   (New York)                                                  Medium     (27)        I.5
                                                 High      (24)        I.0

   Gregor et al. 1980       78:llO        Males        IO      Vitamin A       Low      02)        2.5
   t England)                                                    Medium     (46)        2.8
                                                 High      (22)         I.0

    Hinds et al. 1984       364:627       Males and     85      Carotene       Lowest I    (25)         I.6
   (Hawaii)                       females                             2    125)        1.2
                                                                      3    (25)        I.1
                                                  Highest 4    (25)        I.0

   Ziegler et al. 1986       763900       Males        44      Carotene       Low      (25)        1.3
   (New Jersey)                                                   Medium     (SO)        1.3
                                                 High      cm         I.0

    &met et al. 1985        342: 546       Males and     55      Carotene       Low       (33)        I.5
   (New Mexico)       (Angles only)    females                          Medium     (33)        I.5
                                                 High      (33)         I.0

D
R
2

0


Table 4-10 (continued)

0
z

Wu et al. 1985
(Los Angeles)
Adenocarcinoma

Squamous cell

Byers et al. 1987
(New York)

   Prospective Studies
E   Bjelke 1975
   (Norway)
   Hirayama 1979
   (Japan)
   Shekelle et al. 1981
   (Chicago)

Kvale et al. 1983
(Norway)

149: 149        Females      21      Carotene

71:71


450902

Females


Males and
females

8,278


265.1 I8


3.102

Males


Males and
females

Males

16.713        Males and     50      Vitamin A

21


129

Carotene


Fat, vits.
A, C, E,
fiber,
protein

50


1


26

Vitamin A


Green-yellow
vegetables
Carotene

Lowest I    (25)
    2    (25)
     3    (25)
Highest 4    (25)

LOW      (50)
High      (50)

Lowest I    (2%
    2    (25)
    3    (25)
Highest 4    (23

Low      (32)
High      w
Lowa      (NP)
Highb      (NP)

Lowest I    (25)
    2    (25)
     3    (25)
Highest 4    (25)

Low      (35)
Medium     (2%
High      (36)

2.5
1.3
0.8
1.0

1.5
1.0

1.8
I.8
I.0

1.0
(fruits/vegs.)

2.6
1.0

1.8
1.0

7.2
5.5
3.0
1.0

1.4
1.2
1.0

BNP = Not presentea.

aFor Hirayama, low = not daily; high = daily.
Source: Byers, T.E.; Graham, S.; Haughey, B.P.; Marshall, JR.; and Swanson, M.K. 1987. Diet and lung cancer risk: findings from the Western New
  York Diet Study. American Journal of Epiderniobgy 125:351-63. Reprinted with permission.

E


Cancer 0

cancers of the alimentary tract (Hirayama 1977; Haenszel et al. 1976) and
large bowel (Graham et al. 1978). A study of lungcanceramong New Jersey
white males showed a protective effect for fruits and vegetables that was
greatest for dark yellow-orange and green vegetables, but no statistically
significant effect for retinol, carotenoids, or vitamin A activity (Zeigler et
al. 1986). The protective effect could have been due to unmeasured car-
otenoids, vitamin C, indoles, or other unknown components present in
these foods (Wattenberg and Loub 1978; NRC 1982). The lack of associa-
tion for vitamin A or carotenoids might also be due to problems in calculat-
ing vitamin A and carotenoid intake from food composition tables based on
dietary records (Beecher and Khachik 1984).

Animal Studies

Vitamin A and synthetic retinoids protect against epithelial cancers of the
skin, lung, bladder, and breast in animals (Spom 1980). High doses sup-
press induction of cancers of the cervix, vagina, colon, skin, forestomach,
tracheobronchi, pancreas, and liver (Welsch, Zile, and Cullum 1986).
Retinoids have also been shown to reverse the effects of carcinogens in
mouse prostate organ cultures (Lasnitzki and Goodman 1974). Although
beta-carotene is protective against skin cancer in animals, it has not re-
ceived as much attention as vitamin A or retinoids because beta-carotene is
poorly absorbed in animals. Synthetic analogs may have greater effects,
greater site specificity, and less toxicity than natural vitamin A (Spom and
Roberts 1984).

Biochemical Mechanisms

Because retinoids are required for normal cell differentiation, their de%
ciency leads to improper differentiation of stem cells in epithelial tissue. In
animals, retinoids may inhibit initiation and promotion stages of carcino-
genesis (Welsch, Zile, and Cullurn 1986). Retinoids may also have a role in
reversing cancerous changes, as has been demonstrated in mouse prostate
organ cultures @porn 1980).

Antioxidant chemicals are thought to protect against certain promoters of
carcinogenesis (Ames 1983). Foods containing vitamin A have been shown
to protect against the formation of oxygen radicals and lipid peroxidation
(Welsch, Zile, and Cullum 1986), and beta-carotene is a very efficient
neutralizer of oxygen radicals (Foote 1976). Vitamin A, along with vitamin
C, vitamin E, and selenium, may neutralize peroxidation effects and mini-
mize carcinogenesis (Ames 1983), although these hypotheses remain to be
confirmed.

213


O Nutrition and Health

Clinical Trials

Recurrence of urinary bladder cancer has been shown to decrease by about
half with synthetic retinoid treatment in two clinical trials (Studer et al.
1984; Alftlan et al. 1983). Micronucleus formation, a marker for cellular
genetic damage, has been reversed by beta-carotene treatment of people
who chew betel nuts and tobacco (Stich et al. 1984). Synthetic retinoid
treatment causes regression of bronchial dysplasia (Gouveia et al. 1982).
Clinical trials are now in progress to determine the efficacy of retinoids in
the prevention and treatment of cervical cancer, malignant melanoma, and
other cancers (Meyskens 1982). The National Cancer Institute is funding a
number of trials (Table 4-l 1) to determine the effects of beta-carotene and
other antioxidant nutrients on several cancer types. These will produce
results in the early 1990's.

Large amounts of retinoids in the blood or tissues, however, can be toxic
and may cause birth defects (Kamm 1982) and adverse effects on skin,
liver, and neurologic tissue (Olson 1983). Excessive intake of preformed
vitamin A or retinoid supplements should be avoided, especially by preg-
nant women. However, increased intake of carotenoids from foods alone is
unlikely to have any adverse effects, other than skin discoloration at very
large intakes.

Role of Alcohol in Cancer

Reviews of experimental and epidemiologic data suggest an association
between alcohol consumption and human cancer that is strongest for
certain head and neck cancers (Tuyns 1982; NRC 1982). Alcohol intake and
smoking act synergistically to increase the risk for cancer of the mouth,
larynx, and esophagus (Broitman, Vitale, and Gottlieb 1983). Although
alcohol has an effect independent of smoking in increasing cancer risk, it
remains uncertain whether the responsible agent is alcohol itself or any of
the more than 400 congeners (other chemicals) identified in alcoholic
beverages (Darby 1982). Consumption of excess alcohol is often accom-
panied by poor eating habits, but the effects of alcohol and nutrition can be
distinguished (see chapter on alcohol), and poor nutritional intake and
alcohol intake appear to have separate and multiplicative effects on the
risks of esophageal cancer (Ziegler et al. 1981). Chronic alcoholism, partic-
ularly in the marginally nourished individual, can deplete various essential
nutrients (Vitale, Broitman, and Gottlieb 1981). As discussed in the chap-
ter on infections and immunity, the nutritional deficiencies produced in
alcoholics could be associated with impaired immune function, permitting
increased carcinogenesis (Watson 1984).

2l4


Cancer O

         Table 4-11
NCI-Sponsored Prevention Clinical Trials
     Related to Vitamin A

Investigator/Cancer Site/Agent       Population Under Study

Hennekenslah sites/beta-carotene,
aspirin

Greenberg/skin/beta-carotene

Luande/skin!beta-carotene

Bowen/colonfbeta-carotene

KuIIerlIungJbeta-carotene

AIbaneslIunglbeta-carotene, alpha-
tocopherol
Safailskinlbeta-carotene, vitamins
CandE

Greenberg/colon/beta-carotene,
vitamins C and E

Moon/skin/retinal

Tangrea, PecWskin/l3-cis retinoic
acid

Meyskenslskinlretinol, 13-cis
retinoic acid

Taylorlesophagusibeta-carotene

Taylor/esophagus/beta-carotene,
multiple vitamins and/or minerals

Omennihmg/retinol, beta-carotene

U.S. male physicians, 40-84 years
old. No evidence of cancer, heart
disease, or stroke.

Males and females less than 85
years of age, basal or squamous
cell carcinoma within past year.
African albinos with epidermai
atrophy, dermal hypertrophy, or
stage III solar keratoses.
Males and females with prior
adenomatous colonic polyp.
Males, 55-70 years old, moderate
to heavy cigarette smokers.
Finnish males, S(M9 years old,
cigarette smokers.
Males and females, 40-80 years
old, 2 or more prior basal cell
carcinomas.

Males and females, less than 75
years old, prior neoplastic polyp.
Males and females, 21-85 years
old, more than 10 prior actinic
keratoses.

Males and females, 40-75 years
old, 2 or more prior basal cell
carcinomas.

Males and females, 40-85 years
old, 8 or more prior basal ceU or
squamous cell carcinomas.
Males and females, 40-69 years
old, severe esophageal dysplasia,
Linxian, China.

Males and females, 40-69 years
old, general population, Linxian,
China.

Males and females, minimum age
45 years, at least 20 years since
fust exposure to asbestos,
diagnosis of asbestosis.

215


O Nutrition and Health

Table 4-11 (continued)

Investigator/Cancer Site/Agent      Population Under Study

Goodman/Iung/retinoI, beta-
carotene

McLartyilunglretinoI, beta-carotene

Schatzkin/Iung/beta-carotene,
retinal, vitamin E, selenium

Surwitlcervixltrans-retinoic acid,
retinyl acetate

Males and females, 50-67 years
old, smoking history of 20 pack
years or greater, current smokers
or those who have quit smoking
less than 6 years previously.
Males and postmenopausal
females, former asbestos workers
verified by the Tyler Asbestos
Workers Program, University of
Texas Health Center patients with
moderate or severe sputum
cytology atypia.

Tin miners active and retired, more
than 40 years of age, at least 10
years of underground experience.
l&45 years old, moderate or
severe cervical dysplasia.

An international comparison shows a correlation between intake of beer
and the incidence of colorectal cancer (Vitale, Broitman, and Gottlieb
1981). A strong association between beer intake and rectal cancer and a
weak association between wine or whiskey and lung cancer have been
found in a prospective cohort study of Japanese men in Hawaii (Pollack et
al. 1984). These associations were seen only at high intakes, and no
increased risk was observed at moderate intakes. Case-control studies
have failed to show a consistent relationship between alcohol and colon or
rectal cancers, possibly due to confounding variables, including contami-
nants in alcoholic beverages. An increased incidence of liver cancer among
alcoholic patients appears to be due to increased exposure to hepatitis B
virus rather than to alcohol itself (Brechot et al. 1982).

Although it is difficult to determine true levels of alcohol consumption,
women with breast cancer are reported to consume more alcohol than
controls (Williams and Horm 1977). A slightly greater risk for breast cancer
in women has been associated with intake of as few as three alcoholic
drinks per week (Schatzkin et al. 1987). Another recent study found
increased risk associated with an average of one drink per day in a cohort of
89,538 U.S. women (Willett et al. 1987). Results of other analytical studies
are inconsistent.

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Cancer O

Although the associations observed between alcohol and oral, esophageal,
and laryngeal cancers may be due in part to smoking, appropriate study
designs and analyses have demonstrated independent effects of alcohol
(Misslbeck and Campbell 1986). If the consumption of alcoholic beverages
is reduced, a sizeable decrease in the incidence of cancers of the buccal
cavity, pharynx, larynx, and esophagus should be possible (Tuyns 1982).

Role of Other Dietary Constituents in Cancer

Vitamin C

Vitamin C functions as a chemical-reducing agent and antioxidant. It is
synthesized in adequate amounts by most animals but not by some pri-
mates, fish, guinea pigs, and humans (Linder 1985).

Human studies have shown a protective association between foods that
contain vitamin C and cancers of the esophagus (Aoki et al. 1982; Acker-
man, Weinstein, and Kaplan 1978), stomach (Graham, Schotz, and Mar-
tino 1972; Higginson 1%7; Kolonel, Nomura, et al. 1981), and cervix
(Wassertheil-Smaller et al. 1981). Small-scale studies have indicated that
colonic polyps regress (DeCosse et al. 1975) or decrease in area (Bussey et
al. 1982) with vitamin C therapy. Recurrence of colonic polyps after
polypectomy was reduced among patients in the treatment group of a study
with 200 subjects (McKeown-Eyssen et al. 1987). Supplements of vitamins
C and E have been shown to reduce the formation of mutagens in the feces
in one study @ion et al. 1982) but not in another (Wilkins, Lederman, and
Van Tassel1 1981). While many studies support a role of vitamin C in
reducing cancer risk (Block and Menkes 1988), no wholly consistent pic-
ture of the role of vitamin C in human cancer has been defined.

Experimental animal studies have found that animals given both precursors
of carcinogenic nitrosamines and vitamin C develop fewer tumors than
animals given these precursors alone (Mirvish et al. 1976). Vitamin C
protects hamster lung cultures from the mutagenic effects of tobacco
smoke (Leuchtenberger and Leuchtenberger 1977) and has been shown to
reduce bladder tumors induced by one carcinogen (Pipkin et al. 1969) but
not by another (Soloway et al. 1975).

Biochemical studies suggest that vitamin C blocks the formation of carcino-
genic nitrosamines from nitrates and nitrites within the digestive tract
(Weisburger et al. 1980; Mirvish et al. 1975) and prevents oxidation of
certain chemicals to active carcinogenic forms (Pipkin et al. 1%9).


cl Nutrition and Health

Because most studies demonstrating a beneficial effect of vitamin C have
not quantified its actual intake levels, associations between vitamin C and
cancer prevention are subject to the same difficulties as those discussed for
vitamin A. Amounts of vitamin C in excess of the Recommended Dietary
Allowances @DA's) may cause rare adverse effects, including gastroin-
testinal disturbances, iron overload in susceptible individuals, altered me-
tabolism of certain drugs, precipitation of calcium oxalate kidney stones,
altered absorption (both positive and negative) of several minerals, and
interference with several laboratory tests (Sestili 1983). Despite limitations
in data, the American Cancer Society guidelines recommend "foods rich in
vitamins A and C" (ACS 1984), and the National Cancer Institute suggests
eating a variety of fruits and vegetables, thus ensuring an adequate supply
of vitamin C (Butt-urn, Clifford, and Lanza 1988). There is no adequate
evidence that larger amounts of vitamin C provide any additional benefits.

Vitamin E

Studies on vitamin E and the development of cancer are complicated by its
instability in stored blood serum, its wide prevalence in the food supply,
and its multiple chemical forms. Perhaps because of these problems, there
are relatively few studies on the role of vitamin E and cancer, but the role of
vitamin E as an antioxidant justifies its further consideration as a potential
preventive agent in cancer control (Willett and MacMahon 1984a).

In human studies, no relationship has been found between vitamin E levels
and the risk for cancer when incidence rates at all sites are combined in
either prospective (Willett et al. 1984; Stahelin et al. 1984) or case-control
analyses (Salonen et al. 1985; Nomura et al. 1985). In one case-control
analysis of prospective data, serum vitamin E had no statistically signifi-
cant independent association with cancer mortality, but low vitamin E
enhanced an independent risk observed for low serum selenium levels
(Salonen et al. 1985). A protective effect of serum vitamin E against cancer
of the breast has been found in one (Wald et al. 1984) but not a second
(Willett et al. 1984) study. In the positive study, an increased risk was
associated only with the lowest 20 percent of serum vitamin E levels. Low
vitamin E levels have also been correlated with an increased risk for lung
cancer (Menkes and Comstock 1984) and intestinal cancer (Gey, Bru-
bather, and Stahelin 1987), but a recent study found no such association
with ovarian cancer (Heinonen, Koskinen, and Tuimala 1985).

Variable results have also been observed in experimental animal studies.
Vitamin E was protective in carcinogen-induced tumor systems (Sham-
berger and Rudolph 1966; Bonmasser, Dallavalle, and Guiliani 1968) or

218


Cancer 0

when administered as a dietary supplement (Haber and Wissler 1%2), but
other studies have not observed this effect (Cook and McNamara 1980;
Epstein et al. 1967). A recent review states that the animal evidence is
inconsistent but suggests a protective effect of vitamin E in carcinogen-
induced tumor systems (Newbeme and Suphakam 1983).

Biochemical studies indicate that vitamin E functions as a lipid-soluble
antioxidant and free radical scavenger. Thus, the protective role tentatively
assigned to both carotenoids and vitamin C may also apply to vitamin E and
its derivatives. Vitamin E, like vitamin C, blocks the in vitro formation of
nitrosamines. The fact that vitamin E is lipid soluble permits this action in a
lipid environment, as opposed to the water-soluble vitamin C. Knowledge
of carcinogenic mechanisms from experimental and animal studies justifies
further exploration of the vitamin E and cancer prevention hypothesis.
Some concern has been expressed that reduced fat intake would compro-
mise availability of this fat-soluble vitamin, but it has been estimated that a
reduction in fat intake to 20 to 25 percent of daily calories should not result
in adverse effects from lowered vitamin E or other fat-soluble vitamin
intake (Judd, Kelsay, and Mertz 1983).

Selenium

Selenium is present in animal and plant foods as selenate, selenocystine,
selenomethionine, and other yet unidentified forms. A suggested daily
dietary intake for selenium has been established by extrapolation from
animal studies, but the range of 50 to 200 pg per person (NRC 1980) does
not imply greater benefit at the upper limit (Diplock 1987). Well over 90
percent of selenium intake is from cereal grains, fish, meat, and poultry (Lo
and Sandi 1980).

The average per capita consumption of dietary selenium in 27 countries
was inversely correlated with total cancer mortality as well as deaths from
leukemia and cancers of the colon, rectum, breast, ovary, and lung
(Schrauzer, White, and Schneider 1977). Inverse correlations between
local soil and crop levels of selenium and regional cancer incidence in the
United States (Shamberger and Willis 197 1) and between the average blood
selenium concentration of residents in different regions of the United
States and the incidence of cancer of the breast, colon, rectum, and lung in
these regions (Schrauzer, White, and Schneider 1977) have been reported.
These studies must be interpreted cautiously due to the mobility of both
food supply and population.

219


0 Nutrition and Health

In several case-control studies, persons with cancer had lower blood
selenium levels than controls (Shamberger et al. 1973; McConnell et al.
1980). These studies must also be interpreted cautiously because these low
levels of blood selenium may be a consequence of illness rather than its
cause (Helzlsouer 1983).

Prospective studies can show whether low serum levels precede cancer.
One prospective study showed that risk for cancer was increased in a group
with low serum levels of selenium and vitamins A and E (Willett et al.
1983). Two other prospective studies in Finland, where selenium intake is
half that of the United States, found an increased risk for cancer at all sites
among the population with low serum levels of selenium (Salonen et al.
1984; Salonen et al. 1985). All three ofthese prospective studies as well as a
subsequent case-control study (Kok et al. 1987) support the hypothesis
that serum selenium is a risk factor for cancer death in men but not in
women. These studies are summarized in Table 4-12.

Selenium inhibits neoplastic transformation in a variety of epithelial organs
in animals (Medina 1985). Studies have demonstrated protective effects
against cancer of the liver (Daoud and G&in 1978), breast (Ip 1981), colon
(Jacobs, Matney, and Griffin 1977), and skin (Shamberger 1970) from
selenite, selenate, or organic selenium. However, the dose giving this
protective effect in most experiments is similar to the dose that may be
toxic with long-term administration (Helzlsouer 1983).

Selenium is among the most toxic essential elements (Longnecker et al.
1987). Its effects in humans have been mostly limited to occupational
hazards (Buell1973) but toxic effects have been reported among individu-
als consuming excessive selenium supplements (CDC 1984). Selenium is
present in the active site of glutathione peroxidase, an enzyme that helps to
prevent perioxidative damage to the cells. Although the molecular basis for
the function of selenium as an inhibitor of neoplastic transformation is not
understood, its enzymatic role may explain this relationship. The docu-
mented toxicity and the narrow range of safe levels of intake of this nutrient
suggest that recommendations for increasing dietary intakes are not war-
ranted.

An association between protein consumption, especially animal protein,
and the incidence of certain cancers has been observed in several human
epidemiologic studies. However, the association of cancer and protein
intake is confounded by a high correlation of protein intake to many other

220


Findings

   Cancer Site


General

Inverse relationship between
cancer rates and selenium
exposure

._~-.-_
  No. of Studies  No. of Studies
  Showing the   Not Showing    Specific Nature of the
   Association   the Association       Association

     Correlution Studies
       4              Selenium in forage crops
                  I      Selenium in forage crops;

association a direct one for
some sites

Selenium in soil and water
Dietary selenium intake
Blood selenium levels
Selenium in water;

  Lower blood selenium levels
E  in cases than in controls

Colon-rectum


General

`           I

Case-Control Studies
I

2           1

Leukemias & Lymphomas      I

                                3
Mouth & Pharynx                      1

Breast
Skin

I
I

association a direct one

Gastrointestinal tract cancers
and Hodgkin's disease
Carcinoma only
Chronic lymphocytic
leukemia only

Plasma selenium increased in
cases, but RBC selenium
and glutathione peroxidase
levels decreased

Both basal and squamous cell
types                 n

Lower prediagnostic serum
selenium levels in cases than

General

in noncases

Cohort Studies
3             Association especially
             evident in males and

smokers

Source: Adapted from &tram, Kolonel, and Meyskens 1987.


u Nutrition and Health

nutrients, including fat. Thus, it has not been possible to define an indepen-
dent effect for protein (Kolonel and Le Marchand 1986; Palmer 1986). In
one international correlational study, for example, a positive association
was observed between total protein and animal protein and breast, colon,
prostate, renal, and endometrial cancers (Armstrong and Doll 1975). Simi-
larly, a migrant study indicated an association between meat consumption
and cancer of the breast and colon (Kolonell987). In a recent case-control
study of breast cancer, the greatest positive association was with a high-
protein, high-fat, and low-fiber diet, but when these three dietary compo-
nents were assessed independently, fat had the strongest association
(Lubin, Wax, and Modan 1986). A positive association between protein
and colon cancer has been found in another study, but again, the associa-
tion with fat was stronger (Jain et al. 1980). In an Australian case-control
study on large bowel cancer, the highest risk was assigned to a high-
protein, high-energy, low-fiber diet (Potter and McMichael 1986). Studies
have also found an association between breast cancer and meat intake
(Lubin et al. 1981) and an association of meat, especially beef, with large
bowel cancer among Japanese (Haenszel et al. 1973), although a subse-
quent study found a lower risk for all cancers among Japanese who con-
sumed a higher daily intake of meat (Hirayama 1981).

In animal studies, an excessive intake of protein is not consistently associ-
ated with an increased incidence of tumors at most sites. When animals
were fed ad l&turn diets with a protein content ranging from 10 to 51
percent of calories, the total incidence of tumors was not affected (Ross and
Bras 1973; Tannenbaum and Silverstone 1949), although certain tumors
such as bladder papillomas and mammary tumors are enhanced by in-
creased protein intake (NRC 1982). These same studies reported that high-
protein diets in early life increased the incidence of tumors (Ross and Bras
1973). Because very low-protein diets have a suboptimal nutritional value,
the decreased tumor risk at very low intake is not relevant for guidelines for
human diets.

Salt-Pickled, Salt-Cured, and Smoked Foods

Methods of storage and preparation of foods vary widely in different parts
of the world, and these differences may contribute to the large international
variation in some types of cancer. Smoked and charred foods acquire
polycyclic aromatic hydrocarbons (PAH`s), some of which are known to be
carcinogenic in animals (Chu and Malmgren 1965; Ames 1983). These and
other potential carcinogenic agents may be formed within foods during
cooking in amounts that may be related to the temperature and duration of
cooking at very high temperatures (Lijinsky and Shubik 1964; Lijinsky and
Ross 1967; Weisburger, Horn, and Barnes 1983). For example, high temper-

222


Cancer 0

ature grilling and broiling with open flames produces carcinogenic PAH's
on the charred surface of foods (Sugimura 1982). Burning amino acids with
sugars during cooking results in a variety of mutagenic chemicals, some of
which may be carcinogenic (Pourie et al. 1981). Salt-cured and salt-pickled
foods contain nitrates and nitrites that can form carcinogenic nitrosamines
in the mouth and stomach (Weisburger, Barnes, and Czemiak 1986). Salt-
cured and salt-pickled foods have been linked to gastric cancer, possibly
because of effects of salt on gastric mucosa (Joossens and Geboers 1985) or
conversion of nitrates to carcinogenic nitrosamines (Weisburger, Barnes,
and Czerniak 1986). Except for a few instances, however, potential
causative agents have not been identified in cured, pickled, or smoked
foods (Palmer and Bakshi 1983).

International epidemiologic evidence suggests that populations consuming
diets high in salt-cured, salt-pickled, and smoked foods have a higher
incidence of stomach and esophageal cancers. Stomach cancer has been
linked to pickled vegetables in Japan (Haenszel et al. 1972), salted fish in
Norway (Bjelke 1978), and smoked trout and mutton in northwestern
Iceland (Dungal 1961). Nitrates, nitrites, and N-nitroso compounds in food
and water (Weisburger, Barnes, and Czerniak 1986) and salted foods
(Geboers, Joossens, and Kesteloot 1985) have been associated with gastric
cancer in several epidemiologic studies. Salt-pickled and salt-cured foods
have been associated with an increased risk for cancers of the nasopharynx
(Sasco, Hubert, and De The 1985) and esophagus (Tttyns, Riboli, and
Doombos 1985). Esophageal cancer in China has been linked to the con-
sumption of pickled vegetables and nitroso compounds (Yang 1980). Most
international epidemiologic studies have linked smoked foods to gastric or
esophageal cancers (Bjelke 1978).

Esophageal (`luyns, Riboli, and Doombos 1985) and stomach cancers
(Geboers, Joossens, and Kesteloot 1985) have been associated with poor
nutrition. In fact, almost all diet and stomach cancer studies have found a
protective effect of vegetable and fruit intake (Cordle 1986), and even the in
vitro formation of N-nitroso compounds can be minimized by antioxidants
such as vitamins E and C (Weisburger, Barnes, and Czemiak 1986).

Nevertheless, the impact of risks from salt-cured, salt-pickled, and smoked
foods in the U.S. diet appear to be small, because rates of stomach and
esophageal cancers are low compared with those in other parts of the world
and because consumption of smoked, salt-cured, and salt-pickled foods
generally is not high.

223


O Nutrition and Health

Food and Color Additives

The FDA approves (or disapproves) all new food and color additives after
detailed review of the safety, purpose, and anticipated exposure. The FDA
also monitors the food supply for chemical contaminants such as
pesticides, environmental contaminants, and heavy metals through the
annual Total Diet Study, which has been conducted since the mid-MO's
(NRC 1982). Before substances are approved for marketing, they are
evaluated for safety on the basis of experimental studies in animals and
relevant clinical studies demonstrating their suitability for their intended
use. After marketing, if new evidence on the safety of the substance is
brought to light, such evidence is reviewed in depth to determine if there
should be a change in the regulatory status of the substance. This process
should protect the U.S. population against the presence of added sub-
stances in the food supply that could involve a risk to health, including
cancer.

Implications for Public Health Policy

Dietary Guidance

General Public

The dietary factors evaluated for the possible relationship to cancer risk are
fat, calories, fiber, foods high in vitamin A and carotenoids, and alcohol.
Roles for vitamin C, vitamin E, selenium, protein, and salt-cured, salt-
pickled, and smoked foods have been proposed.

Studies of carcinogen-induced tumorigenesis in experimental animals and
international epidemiologic comparisons have provided substantial but not
conclusive evidence that dietary fat increases the risk for cancers of the
breast, colon, rectum, endometrium, and prostate. The results of epi-
demiologic investigations within more homogeneous population groups,
however, are inconsistent. Because fat contains more than twice the calo-
ries per given quantity of protein or carbohydrate, high-fat diets are gener-
ally high in calories. Despite such complications, the animal and intema-
tional epidemiologic data suggest that a decrease in fat consumption by the
general public from the current 37 percent of total caloric intake might
reduce the risk for certain cancers.

Results from animal and human studies of obesity and cancer are not
wholly consistent, perhaps because of the difficulty of separating the
effects of calories, fat, and body weight. Furthermore, the level of caloric
restriction that seems effective in preventing cancer in most animal studies

224


Cancer O

is at a food intake level not advisable for most humans. Consistent with
other health recommendations, maintenance of desirable weight is recom-
mended and may potentially decrease the risk of breast, colon, prostate,
and endometrial cancers.

Correlational epidemiologic studies suggest an association between diets
low in fiber and increased risk for colon cancer, while results from case-
control studies are mixed. Studies in experimental animals indicate that
further research is needed on the effects of different types of fiber. While
inconclusive, evidence suggests that an overall increase in intake of foods
high in fiber might decrease the risk for colorectal cancer. Despite the need
for additional evidence, this recommendation is consistent with guidance
for reducing gastrointestinal disease.

Likewise, epidemiologic studies provide suggestive evidence that con-
sumption of foods containing carotenoids, including the beta-carotene
precursor of vitamin A, protects against development of epithelial cell
cancers such as those of the oral cavity, bladder, or lung. These studies
have generally shown lower rates of cancer among individuals consuming
the highest overall levels of vitamin A, carotenoids, or fruits and vegeta-
bles. These studies have not distinguished the specific form of vitamin A
associated with protection, nor have they ruled out the possibility of
protection from as yet unidentified components of fruits and vegetables.
Until the results of clinical trials examining these relationships become
available, an increase in consumption of fruits and vegetables might benefit
persons who now consume below-average amounts of these foods. There is
no evidence that vitamin A in amounts greater than the RDA is beneficial.

Despite some difficulties in distinguishing the cancer-producing effects of
excessive alcohol intake from those of cigarette smoking, evidence sug-
gests that a reduction in alcohol intake among the portion of a population
that drinks most heavily would help to reduce the prevalence of cancers of
the mouth, esophagus, pharynx, and perhaps other sites.

Excessive selenium intake is toxic. This fact and limitations in information
about selenium intake in the general population suggest that selenium
intake should not be increased above levels now in the average diet.

Although some epidemiologic studies suggest an association between di-
etary protein and cancer incidence, these studies are limited and not
consistently supported by animal evidence. Thus, the evidence does not
justify a recommendation to the general public to decrease protein on the
basis of its relationship to cancer.

225