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OCR for page 162
10 Minerals
Very few epidemiological studies have been conducted to determine
the relationship between minerals and the incidence of cancer in humans.
This is due partly to the difficulty of identifying populations with
significantly different intakes of the various minerals. In contrast,
there have been numerous studies in laboratory animals. In these in-
vestigations, the carcinogenic effects of many metals, administered at
high doses to the animals parenterally, have been well established and
have been reviewed extensively (Furst, 1979; Sunderman, 1977~. However,
the results of these studies have shed little light on the potential
carcinogenic risk posed by trace elements in the amounts occurring
naturally in the diet of humans.
Very few feeding studies have been conducted to test the carcino-
genicity of trace elements in animals. The carcinogenic action of these
elements is difficult to test in animals because some of them are toxic
at levels that exceed dietary requirements, and because it is diffi-
cult to control synergistic interactions of the element under investiga-
tion with other elements that may contaminate air, diet, and drinking
water. This chapter contains an evaluation of a few of those trace
elements that are nutritionally significant and suspected of playing a
role in carcinogenesis. The committee sought evidence primarily from
those experiments in which the element was fed to the animal or from
epidemiological reports of exposure through diet. Results obtained from
laboratory experiments using other routes of exposure, or evidence from
occupational exposure of humans, are described briefly when sufficient
information about dietary exposure could not be found. The effects of
both the deficiencies as well as excessive intakes of minerals are also
discussed in this chapter.
Schroeder and his associates investigated the carcinogenicity of
trace elements in a series of large experiments extending over 15 years
(Kanisawa and Schroeder, 1967; Schroeder and Mitchener, 1971a,b, 1972;
Schroeder et al., 1964, 1965, 1968, 1970~. Animals were raised in an
environment that permitted maximum control of trace element contamina-
tion; they were fed one diet of known composition; and they were observed
for their lifetime. The following elements were studied in at least 50
mice and/or rats per treatment: fluorine, titanium, vanadium, chromium,
nickel, gallium, germanium, arsenic, selenium, yttrium, zirconium, nio-
bium, rhodium, palladium, cadmium, indium, tin, antimony, tellurium, and
lead. These elements were added to the drinking water at levels of 5
mg/liter, except for selenium (3 mg/liter) and tellurium (2 mg/liter).
These levels (approximately 100 times greater than the concentrations
present naturally in the diet) did not significantly affect growth and
survival of the animals. The interpretation of these findings of no
162
10-1
OCR for page 163
Minerals 163
effects or minimally significant effects must be cautious, in view of the
small number of animals used. Only rhodium and palladium (tested in mice
only) showed any signs of carcinogenicity, but as Schroeder and Michener
(1971a) stated, The results were at a minimally significant level of
confidence. Further studies are needed to confirm these findings.
Schroeder also reported that selenate, but not selenite, increased the
incidence of spontaneous malignant mammary and subcutaneous tumors in
rats after lifetime exposure (11 in 75 controls vs 20 in 73 selenate-fed
animals). These results were not confirmed in similar studies in mice.
(The effects of selenium on carcinogenesis are discussed in further
detail below.) None of the remaining elements examined increased tumor
incidence. A significant reduction in tumor incidence was observed in
mice fed arsenic and cadmium and in mice and rats fed lead.
SELENIUM
Signs of chronic selenium toxicity in animals have been recognized
for almost 700 years, but selenium was not identified as the responsible
agent until the 1930's. Twenty years later, the economic importance of
selenosis and selenium deficiency for animal producers became apparent.
This discovery stimulated the mapping of selenium distribution in the
soils, forages, and tissues of humans in several continents. Extreme
differences of exposure were delineated, even within individual countries.
This knowledge enabled investigators to make epidemiological correlations
of diseases, including cancer, in humans and animals and to conduct lab-
oratory experiments to test the resulting hypotheses (National Academy of
Sciences, 1971~.
Epidemiological Evidence
Selenium has been reported as having a possible protective effect
against cancer. Shamberger and colleagues correlated selenium levels
in forage crops (grouped into high, medium, and low categories) with
cancer mortality by state in the United States (Shamberger and Frost,
1969; Shamberger and Willis, 1971; Shamberger et al., 1976~. They
found an inverse relationship in both males and females, especially
for cancers of the gastrointestinal and genitourinary tracts. In other
studies, Schrauzer and coworkers correlated per capita intake with cancer
mortality rates in more than 20 countries (Schrauzer, 1976; Schrauzer et
al., 1977a,b). The consumption estimates were based on international
food disappearance data for major food sources (e.g., cereals, meat, and
seafoods) to which the investigators attributed plausible mean selenium
values. They found an inverse relationship between selenium intake and
leukemia as well as with cancers of the colon, rectum, pancreas, breast,
ovary, prostate, bladder, lung (males), and skin. Using-pooled blood
samples from healthy donors in 19 U.S. states and 22 countries, they also
correlated blood levels of selenium with corresponding cancer mortality
rates. They found significant inverse relationships for most of these
same sites.
10-2
OCR for page 164
164 DIET, NUTRITION, AND CANCER
Shamberger et al. (1973) compared the blood selenium levels in
more than 100 cancer patients with those in 48 normal subjects attend-
ing a clinic. The levels in patients with gastrointestinal cancers
and Hodgkin's disease were significantly lower than those in the normal
subjects, but there were no differences between the normal subjects and
patients with cancers at other sites, such as the breast. It is not
clear from this study whether the observed difference in the selenium
levels was the result or the cause of the cancers.
Jansson _ al. (1975, 1978) examined cancer mortality rates in the
United States by county. They compared the rates in the northeastern
part of the country with corresponding levels of selenium in the water
supply. In contrast to other investigators, they reported a direct
correlation between mortality from colorectal cancer and selenium levels
in the drinking water.
Experimental Evidence
Carcinogenicity. During the past 40 years selenium has been alter-
nately described as a carcinogen and an anticarcinogen, on the basis of
experiments on animals. Because studies conducted during the 1940's
showed that high levels of selenium induced or enhanced tumor formation,
the Food and Drug Administration until recently prohibited the enrichment
of animal feeds with selenium, even in areas with established selenium
deficiency. In contrast to the results of the earlier investigations,
more recent studies by several independent investigators have established
that dietary selenium has a protective effect against tumors induced by a
variety of chemical carcinogens or at least one viral agent.
A critical review of the experimental conditions suggests that the
earlier studies demonstrating carcinogenic or promoting properties of
selenium can be faulted on the basis of experimental design. Nelson et
al. (1943) fed a 12% protein diet to 18 control rats and to 126 rats
whose diet was enriched with selenium (5, hand 10 Agog) as seleniferous
grain or selenides. Fifty-three of the test animals and 14 of the con-
trols survived to an age of 1.5 to 2 years. The livers of the control
rats were normal, but all animals fed the high selenium diet had liver
cirrhosis. Of these, 11 had developed nonmetastasizing adenomas and the
rest showed hyperplasia. These findings can be attributed to a combina-
tion of two insults: the near toxic levels of selenium and the marginal
protein content of the diet.
Harr et al. (1967) investigated the effect of selenium on tumor
formation in 1,437 rats fed a range of selenium levels for as long as 30
months. Eighty-eight rats were also fed 2-acetylaminofluorene (2-AAF)
along with selenium. The experimental design also included a repetition
of the earlier experiment by Nelson et al. (1943), i.e., a marginal pro-
tein diet was supplemented with selenium as selenate at 0.5, 2.4, or 8
Agog. As expected, diets containing selenium in concentrations
10-3
OCR for page 165
Minerals 165
higher than 8 Agog were toxic and killed the rats within the first
month. The rats fed the two lower levels survived for more than a year.
Autopsies and histological examinations performed on 1,123 of the rats on
various dietary treatments provided no evidence for a carcinogenic effect
of selenium. Forty-three tumors occurred in 88 of the rats fed 50 or
100 ~g/g of AAF diet without added selenium; the rest of the autopsied
animals exibited 20 neoplasms, randomly distributed, regardless of the
level of dietary selenium. Although there were no hepatic tumors in any
autopsied animals that did not receive the carcinogen, approximately half
of the selenium-supplemented rats that survived for more than 9 months
had hyperplastic lesions in the liver, whereas none occurred in the
controls.
In another series of studies, Volgarev and Tscherkes (1967) measured
the effect of selenium in 200 rats, but they did not use a selenium-
free control group. In the first experiment, 40 rats were fed selenium
as selenate at 4.3 to 8.6 ~g/g of diet. All animals developed liver cirr-
hosis, 10 had neoplastic tumors, 4 had precancerous lesions, and 9 were
unaffected. In a second experiment, only 5 neoplasms were observed among
60 rats. The third experiment failed to produce any tumors in 100
animals.
Schroeder and Mitchener (1971b, 1972) studied the effect of se-
lenium supplementation (2 to 3 mg/liter in drinking water as selenate
or selenite) in lifetime experiments with rats and mice. Neither form
of selenium affected the incidence of tumors in mice, and selenite had
no effect in rats. Specifically, no hepatic cirrhosis was observed.
However, following an epidemic of pneumonia in the rat colonies, there
were 30 tumors in 73 animals in the selenate group, but only 20 in 75
animals in the controls.
Antitumorigenic Effects. A large accumulation of evidence indicates
that supplementation of the diet or drinking water with selenium protects
against tumors induced by a variety of chemical carcinogens and at least
one viral agent (Table 10-1~. Although most investigators found that
tumor incidence in the selenium-supplemented animals was approximately
one-half that of the control animals, Schrauzer et al. (1978) reported
that spontaneous breast tumors in female C3H mice were reduced from 82%
in controls to 10% in the selenium-supplemented animals. In all but two
of the experiments, comparisons were made between controls receiving
diets with nutritionally adequate selenium levels and test animals fed
diets supplemented with selenium levels 20 to 50 times higher than the
animal's requirements. In the remaining two experiments, Barr et al.
(1972) and Ip and Sinha (1981) used selenium-deficient diets and demon-
strated beneficial effects of selenium supplementation at levels close to
the physiological requirement. Of special nutritional importance is
their finding that the incidence of tumors induced by 7,12-dimethyl-
benz~ajanthracene (DMBA) was enhanced by diets high in polyunsaturated
fatty acids and by dietary deficiency of selenium. Supplementation with
physiological levels of selenium (0.1 ~g/g diet) resulted in protection
against tumor formation (Ip and Sinha, 1981~.
10-4
OCR for page 166
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OCR for page 167
Minerals 167
Although these data indicate that selenium has an antitumorigenic
effect, they provide no information on the mechanism of action or on the
stage of tumor development during which selenium might exert its protec-
tive action. In at least two studies, selenium was introduced only after
the carcinogen was applied and led to a reduction in tumor incidence.
Schrauzer _ al. (1978) stated that the selenium levels in the recipient
animals do not influence the fate of transplanted tumor cells; others
observed a strong reduction in the growth of inoculated Ehrlich ascites
cells in recipient animals injected with high doses of selenium compounds
for 3 weeks after the inoculation (Greeder and Milner, 1980~.
Mutagenicity. In vitro studies have not shed much light on the
mechanisms of action of selenium. On the one hand, selenium concentra-
tions from 0.1 to 40 mM exert antimutagenic effects against a variety of
mutagens In vitro, including the naturally occurring mutagen malonal-
dehyde (Jacobs _ al., 1977; Shamberger et al., 1978~. On the other_ _
hand, similar concentrations of selenium have been reported to increase
DNA fragmentation and chromosome aberrations in human and microbial cell
cultures (Lo et al., 1978; Nakamuro et al., 1976~. These contrasting
reports cannot be reconciled.
Potential Mechanisms of Action. There are data suggesting that
selenium _ vitro and in viva may decrease the activity of hydrox-
ylating enzymes that activate procarcinogens and may increase a detoxi-
fying enzyme--glucuronyl transferase (Griffin, 1979~. These results
suggest that selenium acts during the early stages of initiation.
The best known functions of selenium at nutritionally adequate,
but not at excessive, levels are its role as a part of the enzyme glu-
tathione peroxidase and its interaction with heavy metals. Glutathione
peroxidase destroys hydroperoxides and lipoperoxides, thereby protecting
the constituents of the cells against free radical damage. Ip and Sinha
(1981) have shown that selenium, through its function in glutathione
peroxidase, could well be involved in protecting against cancer induced
by high intakes of fat, especially polyunsaturated fatty acids. Gluta-
thione peroxidase activity in human blood increases with increasing
selenium intakes, but reaches a plateau at intakes well below those
customary in the United States (Thomson and Robinson, 1980~. Thus, if
the antitumorigenic effect of selenium is mediated through its function
in glutathione peroxidase, attempts to increase the enzyme activity by
selenium supplementation, superimposed on an adequate diet in the United
States, would not be successful.
The second function of selenium is to protect against acute and
chronic toxicity of certain heavy metals. Although selenium is known to
interact with cadmium and mercury, the mechanism of action is not known.
Selenium does not cause an increased elimination of the toxic elements,
but, rather, an increased accumulation in some nontoxic form (National
Academy of Sciences, 1971~. It is conceivable that carcinogenic effects
of these, and perhaps other heavy metals, could be counteracted by
selenium, in a manner similar to its protection against their general
toxicity.
10-6
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168 DIET, NUTRITION,AND CANCER
Summary
Epidemiological Evidence. The epidemiological evidence pertaining
to the relationship between selenium and cancer is derived from a limited
number of geographical correlation studies in which the risk of cancer
was correlated with estimates of per capita selenium intake, with the
selenium levels in blood specimens, or with selenium concentrations in
water supplies. Although these studies generally demonstrated an in-
verse relationship between the level of selenium and the risk of cancer,
it is not clear whether this relationship applies to all cancer sites or
only to specific cancer sites, such as those in the gastrointestinal
tract. There are as yet no data from case-control or cohort studies.
Experimental Studies. Numerous experiments in animals have demon-
strated an antitumorigenic effect of selenium. The relevance of most
of these studies to the risk of cancer for humans is not apparent since
the levels of selenium used far exceeded dietary requirements and often
bordered on levels that might be toxic. However, one experiment has
demonstrated increased susceptibility to DMBA-induced tumors when se-
lenium deficiency was aggravated by high dietary levels of polyunsatu-
rated fatty acids, and protection by a physiological supplement of se-
lenium (0.1 ~g/g) to the diet (Ip and Sinha, 1981~. The interpretation
of these results is further complicated because of the varied protocols
used in these experiments and the knowledge that selenium interacts with
many other nutrients, such as heavy metals in the diet.
The minimum requirement for selenium in mammalian species is 0.05
agog of diet, one-hundredth of the levels used in many studies of car-
cinogenesis. A level of 4 or 5 Gig may not be acutely or even chroni-
cally toxic when fed along with a well-balanced, nutritious diet, but it
becomes chronically toxic when the quality of the diet is lowered, for
example when the protein content is reduced. At least two experiments
have demonstrated that selenium deficiency enhances carcinogenesis and
that physiological amounts of selenium have a significant protective
effect. The effectiveness of doses in the wide range between the
nutritionally adequate and the higher, effective level used in many
antitumorigenic studies has not yet been adequately investigated. The
data on the mutagenicity of selenium compounds are also contradictory.
However, these experiments provide sufficient evidence to suggest that
the antitumorigenic effect of selenium should be investigated further.
Recent data do not support the earlier reports that selenium per se is
carcinogenic.
Conclusion
Both the epidemiological and laboratory studies suggest that
selenium may offer some protection against the risk of cancer. However,
firm conclusions cannot be drawn on the basis of the present limited
evidence. Increasing the selenium intake to more than 200 ~g/day (the
10-7
OCR for page 169
Minerals 169
upper limit of the range of Safe and Adequate Daily Dietary Intakes
published in the Recommended Dietary Allowances [National Academy of
Sciences, 1980b]) by the use of supplements has not been shown to con-
fer health benefits exceeding those derived from the consumption of a
balanced diet.
ZINC
Zinc is an essential constituent of more than 100 enzymes and is
essential for life. Through its function in nucleic acid polymerases,
zinc plays a predominant role in nucleic acid metabolism, cell replica-
tion, tissue repair, and growth (Prasad, 1978~. Severe zinc deficiency
in humans has been known for 20 years; more moderate forms have been
linked to protein-energy malnutrition. Marginal zinc deficiency is
suspected to occur in a substantial number of infants and older children
in the United States (Prasad, 1978~.
Pronounced zinc deficiency in animals and humans results in depressed
immune functions. Both tissue-mediated and humoral responses are
affected. Golden _ al. (1978) have observed that impairment of delayed
hypersensitivity reactions to Candida albicans antigen in malnourished
children can be normalized by topically applied zinc preparations, but it
is not known whether or to what degree immunocompetence is impaired
by marginal zinc deficiency.
Epidemiological Evidence
There have been few epidemiological studies of the relationship
between exposure to zinc and risk of cancer. Stocks and Davies (1964)
correlated cancer mortality with the zinc and copper content of soil in
12 districts of England and Wales. They found higher zinc levels and
higher ratios of zinc to copper in the soil of vegetable gardens near
houses in which a death from gastric cancer had occurred than in the soil
of gardens near houses in which there was a death attributed to another
cause. The levels near houses with deaths from other cancers did not
differ from those of the noncancer households. These analyses were made
only when the deceased had resided in the same house for 10 or more
years. Since the copper levels in soil varied little, the differences
could be attributed to zinc.
Schrauzer et al. (1977a,b) examined per capita food intake data in 27
countries. They found a direct correlation between estimated zinc intake
and age-adjusted mortality from leukemia and cancers of the intestine,
breast, prostate, and skin. Based on these findings and the inverse
correlation between zinc and selenium concentrations in blood, they
suggested that zinc increases cancer risk by its antagonism of selenium.
Van Rensburg (1981) observed that wheat and corn are the primary
dietary staples in many populations at high risk for esophageal cancer
10-8
OCR for page 170
170 DIET, NUTRITION, AND CANCER
around the world. In contrast, the staples in low-risk populations
include millet, cassava, yams, and peanuts. Since diets based on wheat
and corn generally contain low concentrations of zinc, magnesium,
nicotinic acid, and possibly riboflavin, he suggested that a deficiency
of one or more of these micronutrients might be etiologically related to
esophageal cancer.
A number of investigators have examined the relationship between
cancer and levels of zinc in blood and other body tissues. Schrauzer_
al. (1977b) found that mean zinc concentrations in pooled blood from
healthy donors in 19 U.S. collection sites correlated directly with
corresponding mortality rates from cancers of the large bowel, breast,
ovary, lung, bladder, and oral cavity. Zinc and selenium levels in the
blood were inversely correlated with each other. Strain et al. (1972)
compared zinc and copper levels in the serum of patients with broncho-
genic carcinoma and the levels in the serum of controls. Although zinc
levels did not differ between the two groups, the copper levels were
lower in the controls, resulting in higher ratios of zinc to copper in
the cancer patients. On the other hand, Davies et al. (1968) reported
that zinc levels in the plasma of bronchogenic carcinoma patients were
lower than those of other cancer patients and lower than normal labora-
tory values.
et
Lin_ al. (1977) examined serum, hair, and tissues from Chinese men
in Hong Kong for levels of zinc and other minerals. They found that
levels of zinc in serum and diseased esophageal tissue from esophageal
cancer patients were much lower than those in other cancer patients and
in normal subjects. Zinc levels in hair were lower in both cancer groups
than in normal subjects. The serum of esophageal cancer patients also
contained slightly elevated copper levels and much lower iron levels
than the serum of normal sub jects . Gyorkey et al . (1967 ) reported that
zinc concentrations in malignant prostatic tissue were lower than those
in normal tissue, whereas benign hypertrophied prostatic tissue contained
higher zinc levels. In all of these studies, the altered zinc levels
may have followed, rather than preceded, the onset of the cancers.
Experimental Evidence
Experiments in animals have demonstrated both enhancing and retarding
effects of zinc on tumor growth. Several reports suggest that a zinc
deficiency strongly inhibits the growth of transplanted tumors in animals
and prolongs survival time. The studies by Petering et al. (1967) with
transplanted Walker 256 carcinoma in rats were confirmed by DeWys et al.
(1970) and extended to other types of tumors, such as leukemias, Lewis
lung carcinoma (DeWys and Pories, 1972), Ehrlich ascites tumor (Barr
and Harris, 1973), P388 leukemia (Minkel et al., 1979), and plasmacy-
toma TEP C-18 3 (Fenton et al., 1980~. The results of these studies are
consistent with the knowledge that rapidly growing tumor cells require
zinc for growth; however, they do not suggest zinc deficiency as a
therapeutic modality because zinc deficiency by itself, with or with-
out concomitant malignancies, results in death of the animals.
10 -9
OCR for page 171
Dineros 171
The results of these studies contradict reports indicating that zinc
deficiency enhances chemically induced carcinogenesis. For example, Fang
et al. (1978) observed that the incidence of esophageal tumors induced by
n~trosomethylbenzylamine (NMBA) was significantly higher in zinc-defi-
cient rats than in control rats. The intragastric incubation of NMBA in
a dose of 48 ~g/g body weight resulted in a 15% incidence of carcinoma in
control rats fed ad libitum and a 43% incidence in rats maintained on
zinc-deficient diets. In two consecutive experiments, lowering the dose
of NMBA to 34 ~g/g body weight produced no cancer in the control rats,
but 83% and 33Z in the zinc-deficient animals. In contrast, some studies
have indicated that zinc intake greatly exceeding nutritional requirements
suppresses carcinogenesis induced by DMBA in Syrian hamsters (Poswillo
and Cohen, 1971) or by azo dyes in rats (Duncan and Dreosti, 1975~. But
Schrauzer (1979) demonstrated that high concentrations of zinc (200 ma/
liter) in the drinking water of C3H mice countered the protective effect
of selenium against spontaneous mammary carcinoma and resulted in a
significant increase in tumor growth.
These contradictory reports are not easily reconciled. Perhaps there
are two different mechanisms of action by which zinc influences two dif-
ferent phases of carcinogenesis: Zinc, perhaps through its effect on the
immune system, may be protective during the early phases of transforma-
tion, whereas the demonstrated role of zinc in cell proliferation may
explain the protective effect of zinc deficiency against the growth of
established tumors. Furthermore, numerous interactions of zinc with
other trace elements, such as selenium, are incompletely understood.
Thus, the evidence is insufficient to determine the answer to an impor-
tant question: Does marginal zinc deficiency, believed to be widespread,
especially among children, present a risk for or provide protection
against carcinogenesis?
Summary
Epidemiological Evidence. There are few epidemiological data con-
-
cerning dietary zinc and cancer. Some studies have suggested that higher
levels of dietary zinc are associated with an increase in the incidence
of cancer at several different sites, including the breast and stomach,
and other studies have reported lower levels of zinc in the serum and
tissue of patients with esophageal, bronchogenic, and other cancers,
compared to corresponding levels in controls. However, the possibility
that the lower serum and tissue levels resulted from the cancer itself
has not been ruled out.
Experimental Evidence. Experiments in animals have shown that zinc
can either enhance or retard the growth of tumors. Zinc deficiency
appears to retard the growth of transplanted tumors, whereas it enhances
the incidence of some chemically induced cancers. In some experiments,
dietary zinc exceeding nutritional requirements has been shown to sup-
press chemically induced tumors in rats and hamsters, but when given in
10-10
OCR for page 172
172 DIET, NUTRITION, AND CANCER
drinking water it counteracts the protective effect of selenium in mice.
These data are insufficient to explain the effects of zinc and of inter-
actions between zinc and other minerals on tumorigenesis.
Conclusion
The epidemiological evidence concerning zinc is too sparse and the
results of laboratory experiments too contradictory to permit any con-
clusion to be drawn. In view of the important nutritional role of zinc
and of its many interactions with other minerals involved in carcino-
genesis, additional research is warranted to resolve the contradictory
results.
IRON
Epidemiological Evidence
Iron deficiency has been associated with cancers of the upper ali-
mentary tract including the esophagus and stomach. In epidemiological
studies conducted in Sweden, iron deficiency was associated with
Plummer-Vinson (Paterson-Kelly) syndrome, which in turn was associated
with increased risk for cancer of the upper alimentary tract (Larsson et
_., 1975; Wynder et al., 1957~. Improved nutrition, especially with_
regard to iron and vitamins in the diet, has been associated with the
virtual elimination of new cases of Plummer-Vinson disease in areas of
Sweden where it had formerly been highly endemic (Larsson et al., 1975~.
Broitman _ al. (1981) studied iron-deficient patients with ante-
cedent lesions of gastric carcinoma in an area of Colombia with high
risk for this cancer. They found that hypochlorhydria and achlorhydria,
which are associated with chronic atrophic gastritis resulting from iron
deficiency, permitted bacterial colonization of the stomach. The investi-
gators postulated that these bacteria could reduce ingested nitrate to
nitrite, leading to the formation of nitrosamines that are carcinogenic
in the stomach of laboratory animals, and are suspected of being carcin-
ogenic in humans. A similar mechanism was suggested by Ruddell et al.
(1978) to explain the increased risk of gastric cancer in patients with
· . —
pernlclous anemia.
There have been no epidemiological reports of cancer associated with
increased dietary intake of iron, although heavy inhalation exposure to
high levels of iron oxide has been related to increased risk for lung and
laryngeal cancers in miners of iron ore, metal workers, and workers in
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10-40
Representative terms from entire chapter:
drinking water
