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OCR for page 114
8
Selenium and Human Health
Since both selenium toxicities and deficiencies have been demonstrated in
animals under practical conditions, concerns have been expressed about
the possible impact on human health of either excessive selenium exposure
or suboptimal selenium intake. This chapter discusses various attempts
that have been made to link human health problems with either too high
an exposure or too low an intake of selenium, either by extrapolating
results from animal models to man or by making statistical associations
between the presumed selenium status of the general population and the
incidence of various human diseases.
HIGH SELENIUM EXPOSURE
CAN C ER
The concept that high levels of selenium might be carcinogenic was derived
from early work by Nelson et al. (1943), who fed groups of 18 female rats
a low-protein diet supplemented with 0, 5, 7, or 10 ppm selenium as sele-
niferous corn or wheat or 10 mg selenium/kg as a mixed inorganic sele-
nide containing ammonium potassium selenide and ammonium potassium
sulfide. Of the 73 selenium-treated rats that died or were killed before
18 months, none had any tumors or advanced adenomatoid hyperplasia.
Of the 53 selenium-treated rats that lived 18 to 24 months, 43 developed
cirrhosis and 11 had liver cell adenoma or low-grade carcinoma without
metastasis in cirrhotic livers. No tumors appeared in any of the 18- to 24
114
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Selenium and Human Health
115
month old rats that had no cirrhosis. The incidence of spontaneous hepatic
adenoma and low-grade carcinoma was low in the nonexposed control
rats, and the incidence of spontaneous hepatic tumors in the rat colony was
less than 1 percent in rats 18 to 24 months of age. The interpretation of this
experiment is complicated by the fact that hepatic tumors were observed
only in the presence of liver cirrhosis, and histological differentation be-
tween neoplasia and possible regenerative hyperplasia in sections of such
damaged organs is difficult.
Klug and Hendrick (1954) fed 35 young adult male rats a diet containing
19 ppm of selenium as seleniferous wheat for 16 months. A group of 15 con-
trol rats received the same diet, except that nonseleniferous wheat was sub-
stituted for the seleniferous wheat. No evidence of lung tumors due to sele-
nium was obtained in this experiment. These rats were not examined for
liver tumors.
Preliminary studies by Volgarev and Tscherkes (1967) suggested that
feeding 4.3 mg selenium as sodium selenate/kg in a low-protein diet
caused an increased incidence of tumors in rats, but follow-up experiments
did not reproduce these results. Also, the experimental design used in this
work was flawed in that control rats not exposed to added selenium were
not included.
An increased incidence of tumors was reported in rats given 2 ppm
selenium as sodium selenate in drinking water for 52 weeks, followed by
3 ppm until death (Schroeder and Mitchener, 1971~. However, the
increased tumor incidence in the selenate-treated rats may have been due
to the longer life span of the exposed animals. Moreover, this study is
difficult to evaluate because there appeared to be no systematic histological
search of the organs and tissues of the experimental animals.
Schroeder and Mitchener (1972) carried out two experiments in which
mice were given either O or 3 ppm selenium as either sodium selenite or
selenate in drinking water during their entire lifetime. Sections were
prepared from 119 of 180 control mice and 88 of 176 selenium-exposed
mice autopsied from both experiments. Of the controls sectioned, tumors
were found in 23 (19 percent), and 10 (43 percent) of the tumors were
malignant. Of the selenium-exposed mice sectioned, tumors were found in
13 (15 percent) and all tumors were malignant. It was concluded that
selenium as selenite or selenate had little tumorigenic or carcinogenic
effect in mice, but when tumors did appear they were all malignant.
Tinsley et al. (1967) and Harr et al. (1967) reported on an extensive
study in which 1,437 rats were fed either a commercial laboratory chow-
type diet or a semipurified diet containing either 12 or 22 percent casein.
These diets were supplemented with O to 16 mg selenium/kg fed as so-
dium selenite or sodium selenate. Most of the rats fed the semipurified
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116
S ELENIUM IN NUTRITI O N
diets supplemented with more than 2 mg/kg were dead within 100 days,
and almost all died before 2 years. However, no hepatic tumors were seen
in the 71 rats fed 0.5 to 2.0 mg/kg that survived 2 years or more.
Three studies have shown carcinogenic effects that seem due more to an
effect of a particular compound that contains selenium than to an effect of
selenium per se. For example, Seifter et al. (1946) found adenomatous
hepatic hyperplasia and multiple thyroid adenomas in rats fed 0.05 per-
cent bis-4-acetamino-phenyl-selenium dihydroxide for 105 days. Innes et al.
(1969) demonstrated an increased incidence of hepatomas, lymphomas, and
pulmonary tumors in mice given the maximal tolerated dose of selenium
diethyldithiocarbamate (ethyl selenac) for 82 weeks. The dose used was
10 mg/kg body weight via stomach tube starting at 1 week of age, followed
by 26 mg mixed directly into each kilogram of diet after 4 weeks of age.
A recent study carried out under contract for the National Cancer
Institute Carcinogenesis Testing Program indicates that high levels of
selenium sulfide, the active component of certain antidandruff shampoos,
is carcinogenic for rats and mice (NCI, 19791. Groups of 100 rats or mice
(50 males and 50 females) were given one of four treatments for 103 weeks:
untreated control, vehicle control (received volumes of 0.5 percent aqueous
carboxymethylcellulose equal to those of the test solutions administered),
and low- or high-dose groups (received stated dose of selenium sulfide
suspended in 0.5 percent aqueous carboxymethylcellulose). The dosing
schedule for the rats was 3 and 15 mg selenium sulfide/kg of body weight
given 5 days per week by gavage in the low- and high-dose groups, respec-
tively, whereas the mice received 20 and 100 mg/kg of body weight by the
same route and schedule in the low- and high-dose groups. These doses
were chosen on the basis of preliminary subchronic toxicity studies, which
indicated the highest dose of selenium sulfide that these animals would be
likely to tolerate in long-term experiments. The incidence of hepatocellular
carcinomas in the rats was 29 and 42 percent in the high-dose males and
females, respectively, while none of the other treatment groups exhibited a
tumor incidence greater than 2 percent. In the mouse study the high-dose
females had a 45 percent incidence of hepatocellular carcinoma, in contrast
to 4 percent or less in any other female treatment group. The high-dose
females also had an elevated incidence of alveolar/bronchiolar carcinomas.
The response of the male mice was less clear, perhaps because of a higher
rate of spontaneous tumor formation or a greater resistance to the effects of
the test chemical. The increased incidence of liver tumors in rats and mice
given selenium sulfide differs from the studies with selenium compounds
discussed above in that the hepatic tumors were seen in animals that had not
developed cirrhotic livers.
There are few studies that have specifically investigated any possible
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Selenium and Human Health
117
relationship between overexposure to selenium and the increased inci-
dence of cancer in humans. However, Glover (1967) commented that the
death rate due to malignant neoplasms observed among workers in a sele-
nium rectifier plant in West England was about the same as that expected
for the general population of England and Wales. Moreover, studies that
have compared death rates due to cancer in different geographical areas
with blood selenium levels in the general population are not consistent with
the concept that high selenium intakes contribute to an overall increased
human cancer mortality (see the section on cancer under the heading,
"Low Selenium Exposures.
It was concluded for regulatory purposes that selenium can cause hepa-
tomas, but only in the presence of severe hepatotoxic phenomena. As a
result it was felt that selenium could not properly be classified as carcino-
genic because of its capacity to induce liver damage (and consequent
hepatomas) when abused by being consumed at high levels (Gardner,
1973~. However, this concept may have to be reexamined in light of the fact
that selenium sulfide can cause liver cancer in rats without producing liver
damage (NCI, 1979~. On the other hand, van Houweling (1979) concluded
that there must be a no-effect level for carcinogenicity for an essential trace
nutrient such as selenium.
DENTAL CARIE S
As discussed in Chapter 7, poor dental health was observed in persons
living in seleniferous areas of South Dakota (Smith et al., 1937) or in chil-
dren residing in seleniferous zones of Venezuela (Jaffe, 19761. Attempts to
produce caries experimentally in laboratory animals with high levels of
selenium have generally failed if the selenium was given posteruptively
(reviewed by Shearer and Johnson, 1980~. On the other hand, if high levels
of selenium were given during tooth development, some effect on dental
caries was obtained. For example, Buttner (1963) fed a caries-susceptible
strain of female rats a cariogenic diet and gave 0, 5, or 10 ppm sodium
selenite in the drinking water during mating, pregnancy, and lactation.
These high levels of selenium impaired reproduction so that the number of
pups born in these groups was 31, 20, and 7, respectively. The pups were
continued on the same levels of sodium selenite in the water for 120 days.
The mean number of carious lesions was increased by 36 and 62 percent in
the groups receiving 5 and 10 ppm selenite in their water, respectively, but
growth was significantly depressed in both these groups. Bowen (1972) fed
monkeys a cariogenic diet and gave one group 2 mg selenium as sodium
selenate/liter of drinking water for 15 months, followed by 1 mg/liter for
another 45 months. The dose of selenium had to be reduced because of
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118
SELENIUM IN NUTRITION
greenish malodorous stools in the selenium-treated animals. Selenium treat-
ment had no effect on the first permanent molars, which had already formed
before the start of the experiment, but the second permanent molars had a
yellow chalky appearance in the selenium-treated monkeys and carious
lesions developed more rapidly in these teeth in the selenium-exposed group.
Britton et al. (1980) gave 10-day pregnant rats either distilled drinking water
or water containing 0.8 or 2.4 ppm selenium as sodium selenite or
selenomethionine until the pups were weaned at 19 days of age. The weaned
pups received a high sucrose diet and oral inoculations of Streptococcus
mutans. No change in caries status was seen in the groups receiving 2.4 ppm
in the water, but there was a significantly reduced incidence of caries in the
groups getting 0.8 ppm. Thus, under certain conditions high levels of
selenium in the drinking water can increase caries when administered
preemptively to experimental animals, whereas moderately high selenium
levels appear to have some cariostatic effect (cariostatic effect confirmed by
Johnson and Shearer, 19811. At any rate no studies have been carried out
which indicate that selenium has any cariogenic activity when given to
animals at the lower levels likely to be encountered by people.
Several epidemiological studies have been conducted by Hadjimarkos
and associates who noted a relationship between the prevalence of dental
caries and the intake of selenium as reflected by its urinary excretion
(Hadjimarkos et al., 1952; Hadjimarkos and Bonhorst, 19581. On the
other hand, a survey undertaken by Ludwig and Bibby (1969) to determine
geographic variations in the prevalence of dental caries in the United
States indicated that caries prevalence in high-selenium areas was the
same or less than it was in New England, which is known to be a selenium-
deficient area. Cadell and Cousins (1960) also found no relationship
between urinary selenium and dental caries in children in New Zealand,
but Hadjimarkos (1960) argued that these urinary selenium levels were too
low to expect any elevation in dental caries. Schwarz (1967) criticized the
work of Hadjimarkos by pointing out that various socioeconomic factors
that might influence caries incidence were ignored and that, at any rate,
the amounts of selenium excreted into the urine were well within the limits
of those seen in normal people not exposed to excessive selenium. Suchkov
et al. (1973) reported that people living in a mountainous region of the
Ukraine had a high level of selenium in their teeth and a high incidence of
caries, while people living in a forest-steppe area had a low level of
selenium in their teeth and a low incidence of caries. But the drinking
water in the mountainous region was softer and contained lower levels of
fluoride, so these possible confounding factors cannot be ruled out.
Curzon (1981) analyzed 362 samples of enamel prepared from first
permanent maxillary premolars from 12- to 19-year-old lifelong residents
OCR for page 119
Selenium and Human Health
119
from various parts of the United States and New Zealand and found a
weak but significant negative relationship between individual enamel
selenium levels and individual caries scores. A recent evaluation of the
relationship between dental caries and human selenium intake (NRC,
1976a) concluded that there seems no reason to suspect that selenium is
important to cariogenesis in man, and this subcommittee uncovered no
new evidence to contradict that view.
REPRODUCTION
Sublethal doses of sodium selenite caused no embryonic malformations
when injected into pregnant hamsters (Holmberg and Ferm, 19691. In
fact, sodium selenite protected partially against the teratogenic effect of
injected sodium arsenate or cadmium sulfate. On the other hand, sele-
nium compounds have long been known to cause embryonic abnormalities
when injected into the eggs of chickens (Palmer et al., 1973~.
Old anecdotal reports from Colombia, South America, claimed that
women living in seleniferous areas gave birth to malformed infants (Rosen-
feld and Beath, 19641. More recently, one probable and four certain preg-
nancies among six women formulating microbiological media containing
sodium selenite were reported to terminate in abortions, except one, which
was born with bilateral club foot (Robertson, 19701. However, a survey of
other laboratories doing similar work revealed no pattern of such trouble,
and no difference in urinary selenium levels was noted between the affected
group of women and a control group residing nearby. On the basis of pub-
lished health statistics, no correlation could be seen between the incidence
of infant mortality due to congenital malformations and the level of sele-
nium in the urine of school children in different states of Venezuela (Jaffe
and Valez, 19731. Jaffe (1973) concluded that no modern evidence has
been presented for the teratogenicity of dietary selenium in humans. A
preliminary report that urinary selenium excretion was related to miscar-
riage (Tsongas and Ferguson, 1977) was not confirmed (T. A. Tsongas,
University of Pennsylvania, Philadelphia, personal communication, 1978~.
AMYOTROPHIC LATERAL SCLEROSIS
Kilness and Hochberg (1977) suggested that selenium might be an
environmental factor predisposing to amyotrophic lateral sclerosis (ALS)
since they observed an unusual cluster of four cases of this disease in male
farmers residing in a seleniferous area. But Schwarz (1977) pointed out
that the frequency of ALS is as high if not higher in low-selenium areas as
in moderate- or high-selenium areas. Norris and Sang (1978) concluded
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120
SELENIUM IN NUTRITION
that exposure to selenium is not related to ALS, since 19 of 20 cases had
urinary selenium levels lower than the mean for unexposed persons.
Kurland (1977) maintained that the cluster observed by Kilness and
Hochberg (1977) was probably due to chance rather than a new etiologic
clue in ALS.
CONCLUSIONS
Certain specific compounds containing selenium, i.e., bis-4-acetamino-
phenyl-selenium dihydroxide, selenium diethyldithiocarbamate, and sele-
nium sulfide, are capable of causing cancer in rats when administered at
high levels for prolonged periods. However, it is not possible on the basis of
these results to generalize about the carcinogenicity of different selenium
compounds. For example, attempts to produce cancer in rodents by giving
oxyanions of selenium such as selenite or selenate, the forms of selenium
currently used as additives to animal feeds, were either unsuccessful or
seriously flawed in experimental design.
An early report, which started the controversy regarding the carcino-
genicity of selenium compounds, used either seleniferous grain or a mixed
inorganic selenide as a source for feeding high levels of selenium to rats.
Histological evaluation suggested that these forms of selenium produced
hepatic tumors, but the interpretation of the results was complicated by the
fact that tumors occurred only in those rats that developed liver cirrhosis. A
later study in which rats were fed high levels of selenium as seleniferous
wheat did not find any lung tumors due to the selenium exposure.
Aside from the two above reports involving seleniferous grain, there
have been no animal studies that have investigated the carcinogenic
potential of the forms of selenium that occur naturally in human foods.
However, a comparison of public health statistics from various parts of the
United States reveals that, if anything, the cancer death rate is lower in
those areas of the country in which consumption of locally produced foods
could result in an increased dietary selenium intake.
A limited number of observations on workers industrially exposed to
selenium gives no indication that cancer rates are any higher in such
workers than in the general population.
Although preeruptive administration of high levels of selenium can
cause an increased incidence of dental caries in experimental animals,
there is no evidence to suggest that typical levels of exposure result in
increased caries in humans.
In contrast to old anecdotal reports, recent analyses of public health
data indicate no correlation between congenital malformations in infants
and excessive exposure to selenium.
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Selenium and Human Health
121
The notion that amyotrophic lateral sclerosis is related to selenium
overexposure has not been substantiated.
LOW SELENIUM EXPOSURE
CANCER
Clayton and Baumann (1949) first observed that high levels of dietary sele-
nium had a protective effect against chemically-induced cancer in rats.
These workers fed two groups of 15 rats a basal diet containing 0.064 per-
cent 3 '-methyl-4-dimethylaminoazobenzene for 4 weeks. During the next
4 weeks neither group received the azo dye, but one group was fed the basal
diet supplemented with 5 mg/kg selenium as sodium selenite. Then both
groups were given the basal diet plus 0.048 percent of the azo dye but no
supplemental selenium for another 4 weeks. Finally, the rats were given
the basal diet with neither azo dye nor selenium for an additional 8 weeks.
Of 9 surviving rats that were given selenium, 2 developed liver tumors,
whereas 4 of 10 survivors in the unsupplemented group had liver tumors.
In a repeat experiment, the incidence of liver tumors was 4 of 13 and 8 of
13 in the selenium-supplemented and unsupplemented groups, respec-
tively. Similar results were obtained more recently by Griffin and Jacobs
(1977) who fed three groups of 15 rats 0.05 percent 3'-methyl-4-dimethyl-
aminoazobenzene in a basal diet of laboratory chow and gave the supple-
mented groups either 6 mg selenium as sodium selenite/liter of drinking
water or 6 mg selenium as high-selenium yeast/kg of diet. The incidence
of liver tumors in the surviving rats was 11 of 12, 7 of 15, and 9 of 14 in
the unsupplemented, selenite-supplemented, and selenium yeast-sup-
plemented groups, respectively. Shamberger (1970) showed that selenium
applied dermally or given in the diet decreased the number of papillomas
in mice painted with various carcinogenic polycyclic hydrocarbons. For ex-
ample, the incidence of papillomas was 87 percent in mice painted daily
with 0.25 ml of a solution containing 0.01 percent 3-methylcholanthrene
for 19 weeks and 68 percent in mice painted with the same solution contain-
ing 0.0005 percent sodium selenide. In groups of mice fed a torula yeast diet
supplemented with 0, 0.1, or 1.0 mg selenium as sodium selenite/kg, the
incidence of papillomas in mice painted with 0.25 ml of 0.03 percent to`]
pyrene for 27 weeks was 14 of 35, 22 of 36, and 8 of 33, respectively.
Jacobs et al. (1977) injected two groups of 15 young male rats with 20 mg
sym,-dimethylhydrazine dihydrochloride/kg of body weight weekly for
18 weeks. The incidence of colon tumors was 6 of 15 in a group receiving
4 ppm selenium as sodium selenite in the drinking water, whereas the inci-
dence was 13 of 15 in rats not treated with selenium. The total number of
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122
SELENIUM IN NUTRITION
colon tumors was 11 and 39 in the selenium-treated and untreated groups,
respectively.
Harr et al. (1972) fed four groups of 20 weanling female rats a torula
yeast diet that contained 150 mg 2-acetylaminofluorene (AAF)/kg and was
supplemented with various levels of selenium as sodium selenite. The num-
ber of rats that had developed either hepatic or mammary cancer after
200 days was 12, 12, 2, and 0 in the groups fed the torula diet supple-
mented with 0, 0.1, 0.5, and 1.0 mg selenium/kg, respectively. However,
by the end of the experiment (320 days) the number of tumors was similar
in all groups, so these workers felt that it was not possible to conclude
"whether the observed effects of added selenite represented a prevention of
carcinogenesis or a modification of the rate of induction." Two subsequent
trials failed to confirm the protective effects of selenite against AAF-
induced tumors (P. D. Whanger, Oregon State University, Corvallis, per-
sonal communication, 19801. This discrepancy may be explained on the
basis of the degree of depletion of selenium in the rats. The original experi-
ment used rats that were depleted of selenium through two generations for
the groups receiving 0 or 0.1 ppm supplemental selenium, whereas the
follow-up studies used rats depleted only through a single generation.
Marshall et al. (1979) fed two groups of 15 adult male rats a laboratory
chow diet that contained 0.03 percent AAF for 14 weeks followed by
5 weeks of carcinogen-free diet. One group received 4 ppm of selenium as
sodium selenite in the drinking water, which was started 1 week prior to
carcinogen feeding and continued throughout the experiment. The inci-
dence of liver tumors was 4 of 14 and 9 of 13 in the selenium-treated and
untreated groups, respectively.
Ip and Sinha (1981) have recently shown that selenium-deficient rats fed
a high polyunsaturated fat diet (25 percent corn oil) had a greater inci-
dence of mammary tumors following treatment with dimethylbenz (o`) an-
thracene than did rats fed the same diet supplemented with 0.1 ppm sele-
nium. On the other hand, no difference in tumor incidence was observed
between the selenium-deficient and selenium-supplemented groups if the
diets were either low fat (1 percent or 5 percent corn oil) or high in satu-
rated fat (1 percent corn oil plus 24 percent coconut oil).
The mechanisms by which selenium diminishes the potency of these
various carcinogens is not known. However, Marshall et al. (1979) found
that liver microsomes prepared from 3-methylcholanthrene-induced rats
supplemented with 4 ppm selenium as sodium selenite in their drinking
water produced less of the highly carcinogenic metabolite, N-hydroxy-2-
acetylaminofluorene (N-OH-AAF), than did microsomes from unsupple-
mented rats. Thus, at least in this case, selenium presumably could act by
shifting carcinogen metabolism toward detoxification pathways. In other
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Selenium and Human Health
123
experiments, pretreatment of rats with 4 ppm selenium as sodium selenite
in the water increased hepatic N-OH-AAF glucoronyl transferase activity
and decreased p-nitrophenol-sulfotransferase activity but had no effect on
AAF-deacylase activity (Daoud and Griffin, 19781. Such selenium pre-
treatment also lowered hepatic levels of AAF and N-OH-AAF and de-
creased the binding of these carcinogens or their metabolites to hepatic
DNA and tRNA. Griffin (1979) has also suggested that the inhibition of
carcinogenesis by selenium may be due to protection of cellular mem-
branes against aberrant oxidations via its role in GSH-Px (see Chapter 5~.
But whatever the mechanism by which selenium acts, it does not appear
to be effective against all types of chemical carcinogenesis, since dietary
selenium had no effect on the induction of tracheal cancer by 1-methyl-1-
nitrosourea (MNU) in hamsters (Thompson and Becci, 1979~. In this
study, groups of 35 hamsters were fed a torula yeast diet supplemented
with 0, 1, or 5 ppm selenium as sodium selenite/kg for 2 weeks. Then they
were continued on the diets and given weekly intratracheal instillations
with a 0.5 percent MNU solution for 12 weeks. All hamsters were killed
195 days after the first instillation, and the incidence of tracheal carcino-
mas was 9 of 34, 8 of 33 and 10 of 31 in the groups receiving 0, 1, and 5
ppm dietary selenium, respectively. If selenium is an anticarcinogen by
virtue of its effects in altering the metabolism of carcinogens, then no ef-
fect of selenium against MNU would be expected since it is a direct alkylat-
ing agent and does not require metabolic activation for its carcinogenic
properties to be exerted.
High levels of selenium have also been shown to have a protective effect
against the development of spontaneous mammary tumors in certain strains
of mice normally having an elevated incidence of spontaneous mammary
adenocarcinomas that are thought to be of viral origin. Schranzer and
Ishmael (1974) fed two groups of 30 virgin 4- to 6-week-old female C3H/St
mice a basal diet containing 0.15 ppm selenium. After 16 months, the inci-
dence of mammary adenocarcinoma in a group that received 2 mg selenium
as selenium dioxide/liter of drinking water was 10 percent, whereas 82 per-
cent of the mice given drinking water without added selenium had tumors.
In another experiment, four groups of 30 female C3H/St mice were fed a
basal diet that contained 0.45 ppm selenium and were given 0, 0. 1, 0.5, or
1.0 mg selenium/liter of drinking water. The incidence of spontaneous
mammary tumors in these groups was 42, 25, 19, and 10 percent, respec-
tively (Schrauzer et al., 19781. Medina and Shepherd (1980) found that 2
and 6 mg selenium as selenium dioxide/liter of drinking water decreased
the incidence of mammary tumors in BALB/cfC3H mice fed a laboratory
chow-type diet from 82 percent in the untreated controls to 48 percent and
12 percent, respectively. However, similar levels of selenium in the water
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124
SELENIUM IN NUTRITION
had no effect on the growth rate of primary tumors transplanted subcutane-
ously into BALB/c mice, and 4 mg of selenium as selenium dioxide/liter of
water had no effect on the rate of tumor formation in three of four different
preneoplastic mammary outgrowth lines transplanted into the mammary
gland-free fat pads of syngeneic mice. Schrauzer and Ishmael (1974) also
reported that selenium did not inhibit the growth of advanced spontaneous
or transplanted mammary tumors. Thus, selenium may act by inhibiting
chemical or viral transformation of normal cells or by inhibiting expression
of initially transformed cells. On the other hand, Poirier and Milner (1979)
found that intraperitoneal injection of 1 mg selenium as sodium selenite/kg
of body weight inhibited tumor development in mice previously inoculated
with Ehrlich ascites tumor cells.
Shamberger and Frost (1969) first called attention to an inverse relation-
ship between blood selenium levels of the general population and cancer
death rates in various areas of the United States. Later work indicated that
there was a particularly low mortality due to gastrointestinal and urogeni-
tal types of cancer in those states located in high-selenium regions of the
country (Shamberger and Willis, 1971; Shamberger et al., 1976~. How-
ever, Allaway (1972) has criticized these associations between cancer mor-
tality and the geographic distribution of selenium as lacking strength, con-
sistency, and selectivity.
Based on food consumption data from 17 countries, Schrauzer (1976)
concluded that the mortality due to cancer of the large intestine, rectum,
and breast was directly correlated with the intake of meat, eggs, milk, fat,
and sugar and was inversely correlated with the intake of high-selenium
foods such as cereals and fish. Just the opposite correlations were found for
hepatic and gastric cancer. The apparent dietary selenium intake, calcu-
lated assuming that the same average concentration of selenium was
present in the foods consumed in all countries, was highest in those coun-
tries that had the lowest mortality due to cancer of the large intestine, rec-
tum, and breast (Schrauzer et al., 1977~. However, Jansson et al. (1978)
pointed out that the same statistical associations that suggested a protec-
tive effect of dietary selenium against colon, rectal, and breast cancer also
suggested an increased risk of hepatic and gastric cancer due to selenium.
Blood selenium levels lower than normal were reported in patients with
colon or gastric cancer, but normal levels were seen in patients with rectal
and breast cancer (Shamberger et al., 19731. In fact, Capel and Williams
(1979) showed that erythrocyte selenium levels and GSH-Px activities were
higher in breast cancer patients than in controls, although plasma sele-
nium levels were depressed (the latter was also observed by McConnell et
al., 1979a). Thus, patients with rectal and breast cancer, supposedly re-
lated to low selenium intake, had normal if not elevated blood or erythro
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Selenium and Human Health
125
cyte selenium levels, whereas patients with gastric cancer, thought to be
linked to a high selenium intake, had subnormal blood selenium levels.
Broghamer et al. (1979) noted that wide variation was encountered in se-
rum selenium concentrations of carcinoma patients, and there appeared to
be an apparent relationship between the serum concentration and the ex-
tent of tumor involvement in terms of metastasis, patient survival time, the
incidence of tumor recurrence, and the occurrence of multiple primary ne-
oplasms. No difference in the blood selenium levels of New Zealand surgi-
cal patients with and without cancer was observed by Robinson et al.
(1978a) or van Rij et al. (1978~. Although these findings might be partially
explained by the generally low selenium levels seen in that country, the
selenium levels in the patients studied were all influenced by their nutri-
tional status, age, and severity and duration of disease, and lowered sele-
nium levels were not characteristic for the cancer patients. Therefore, it
was suggested that the low-selenium status of cancer patients was more
likely a consequence of their illness rather than the cause of the cancer.
CARDIOVASCULAR DISEASE
Swine fed diets deficient in both selenium and vitamin E develop a charac-
teristic cardiomyopathy (Van Vleet et al., 1977a,b; see also Chapter 6),
and rats and lambs fed diets deficient in selenium and vitamin E develop
electrocardiographic changes that can be prevented by selenium supple-
mentation (Godwin, 1965; Godwin and Fraser, 1966~. Using an approach
similar to that outlined above for cancer, Shamberger et al. (1975, 1978,
1979) concluded that age-specific heart disease mortality was lower in
those states of the United States or countries of the world with high sele-
nium intakes than in those states or countries with low selenium intakes.
However, Masironi and Parr (1976) reported no difference in tissue sele-
nium concentrations between patients who died with or without myocar-
dial infarction. Westermarck (1977) found that blood selenium levels of
patients with acute myocardial infarction were lower than those of healthy
adults, but no difference was observed in heart or liver selenium levels of
patients who died of myocardial infarction and those who died from other
diseases. Shamberger (1978) found no difference in the kidney selenium
levels of autopsy specimens taken from patients who died from atheroscle-
rosis and hypertension, compared to those who died from a variety of other
diseases. Thomson et al. (1978b) showed that blood selenium concentra-
tions of New Zealand hypertensives, with or without atheroma, were no
lower than those of normotensives. On the other hand, a recent epidemio-
logical study from Finland suggests that low serum-selenium levels may be
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SELENIUM IN NUTRITION
associated with an increased risk of cardiovascular death and myocardial
infarction (Salonen et al., 19821.
Since human blood platelets were reported to contain high levels of sele-
nium, Kasperek et al. (1979) suggested that low selenium intake might
increase the risk of thrombotic episodes, and indeed the GSH-Px activity
of platelets was shown to be depressed in patients with acute myocardial
infarction (Wang et al., 19814. Platelet GSH-Px activity is decreased in
selenium-deficient rats (Bryant and Bailey, 1980~. A biochemical rationale
for a possible role of selenium in heart disease is provided by the recent
observation that prostacyclin synthesis is decreased in aortic rings from
selenium-deficient rats (Burt et al., 1981~. Fatty acid hydroperoxides in-
hibit prostacyclin synthetase (Moncada and Vane, 1979), so it is possible
that selenium deficiency, via depressed GSH-Px activity, could inhibit the
production of prostacyclin, the arachidonic acid metabolite that decreases
platelet aggregation (Gryglewski, 1980~. Despite the inability of some
workers to relate the selenium concentrations of human tissues to the inci-
dence of cardiovascular disease, the recent report from the People's Re-
public of China describing a cardiomyopathy in children severely deficient
in selenium (so-called Keshan disease, see Chapter 6) suggests that sele-
nium may have a role in proper heart function at very low levels of dietary
intake. However, the amount of dietary selenium needed to prevent car-
diomyopathy in humans apparently is very small, since blood selenium lev-
els in children with Keshan disease were only about one-sixth of those re-
ported in New Zealand, a country of known low selenium intake, and only
about one-twentieth of those observed in the United States. It should also
be emphasized that the pathology of Keshan disease is totally different
from that characteristic of the degenerative heart conditions typical in the
West.
REPRODUCTION AND NEONATAL HEALTH
Selenium deficiency causes decreased sperm motility in rats (Wu et al.,
1979), and a variety of reproductive problems have been associated with
selenium deficiency in animals (see Chapter 61. Also, selenium has been
shown to be associated with a number of incompletely characterized pro-
teins found in testicular cytosol (McConnell and Burton, 1981) or sperma-
tozoa (Calvin et al., 1981~. Using an approach similar to that employed by
Shamberger to relate selenium status to cancer or cardiovascular disease,
Cowgill (1976) found that the birthrate in the continental United States is
lower in those regions where the selenium concentration in forage crops is
low than in those where the concentration of selenium is high. Shamberger
(1971) noted higher neonatal death rates on a population basis in low-sele
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Selenium and Human Health
127
nium areas of the United States than in high-selenium areas, but Cowgill
(1976), concerned that couples in low-selenium areas were taking selenium
to prevent neonatal death, pointed out that comparisons of neonatal death
rates should be made on the basis of live births. When expressed on this
basis, no differences in neonatal death rates were observed between high-
and low-selenium regions. Money (1970) suggested that selenium may play
a role in the etiology of the sudden infant death syndrome (SIDS), but
Rhead et al. (1972) found no difference in the blood or plasma selenium
levels between normal infants and those that had died of SIDS. In a later
paper, Money (1978) suggested that somewhat elevated iron intake might
precipitate SIDS in infants of marginal selenium and vitamin E status, but
no definitive role for any of these nutrients has been established in this
condition.
INFECTIOUS DISEASES
Mice fed a chow diet supplemented with 0.7 ppm and 2.8 ppm selenium as
sodium selenite had approximately 7 times and 30 times greater antibody
titers, respectively, after challenge with sheep red blood cells than did mice
fed the unsupplemented chow diet (Spallholz et al., 1973~. The primary
immune response to sheep red blood cells can also be increased by inject-
ing mice intraperitoneally with 3,ug to 5,ug of selenium as sodium selenite,
although the increase is greatest when the selenium is given prior to or
simultaneously with the antigen (Spallholz et al., 1975~. Toxic levels of
dietary selenium decreased the immune response of mice to sheep red
blood cells (Spallholz et al., 1973) and increased the susceptibility of
chicks to infection with Salmonella gallinarum (Hill, 1979~. Although the
mechanism by which selenium enhances the immune response is not
known (Martin and Spallholz, 1976), the lipid peroxide-destroying activity
of GSH-Px may be involved, since vitamin E and synthetic antioxidants
also stimulate the immune response under certain conditions (Nockels,
1979~.
DeWitt et al. (1957a,b) found that torula yeast-based diets deficient in
selenium, vitamin E, and cystine decreased the resistance of mice to Schis-
tosomiasis mansoni. However, the deficient torula diet produced an unfa-
vorable in vivo growth environment for the parasites, since somatic devel-
opment was markedly impaired and, although more worms were present,
they did not attain sexual maturity. Thus, the underdeveloped worms did
not produce eggs, which in the normal infection are the major cause of
pathology.
Serfass and Ganther (1975) showed that the ability of peripheral poly-
morphonuclear neutrophils from selenium-deficient rats to kill Candida
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SELENIUM IN NUTRITION
albicans was markedly decreased, although ingestive activity was not im-
paired. Peritoneal exudate polymorphonuclear neutrophils from sele-
nium-deficient rats also tended to have decreased fungicidal activity, al-
though the changes were not statistically significant. The authors stated
that to their knowledge this was the first demonstration of impaired phago-
cytic microbicidal capacity due to the deficiency of a specific nutrient.
Later work indicated that selenium deficiency in rats caused declines in the
GSH-Px activities of peritoneal exudate polymorphonuclear neutrophils
and pulmonary alveolar and peritoneal exudate macrophages (Serfass and
Ganther, 1976~.
Chen and Anderson (1979) reported that the selenium concentrations in
the sera of 17 patients acutely ill with Legionnaire's disease were lower
than in their paired convalescent-phase sera. Such a trend was not seen in
10 similarly matched samples of serum from control patients with pneu-
monia. Although the mechanism of this effect is not known, Jaquess et al.
(1980) reported that rather high concentrations of sodium selenate (50 fig/
ml) stimulated the growth of Legionella pneumophila when grown on agar
cultures.
CYSTIC FIBROSIS
Research on cystic fibrosis in humans has been hampered by the lack of a
suitable animal model of the disease. The histopathology of the pancreatic
lesions seen in selenium-deficient chickens (discussed in Chapter 6) in
some ways resembles that of cystic fibrosis in humans, but the similarities
are superficial and are not considered to be the result of the same underly-
ing causes. Wallach (1978) noted that the histopathological changes he
observed in one sick rhesus monkey were reminiscent of certain pathologi-
cal features of cystic fibrosis in humans. This monkey had been fed a pel-
leted diet that had been soaked in "a commercial long chain polyunsatu-
rated oil supplement" in order to correct a hair coat problem. It was sug-
gested that the sickness of the monkey was due to the prooxidant stress of
the elevated intake of polyunsaturated fatty acids coupled with a presumed
marginal deficiency of selenium and/or vitamin E, but no analytical values
for these latter two nutrients in the tissues of the monkey were available.
On this basis, Wallach postulated that selenium deficiency may play a key
causative role in human cystic fibrosis, although marginal intakes of other
nutrients, including vitamin E, zinc, copper, and riboflavin, as well as an
excessive intake of polyunsaturated fat, were also thought to be involved.
To support his hypothesis, Wallach and Garmaise (1979) presented lim-
ited analytical data on the selenium content of blood and tissues from pa-
tients with cystic fibrosis. An acute case had a whole-blood selenium level
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Selenium and Human Health
129
of 0.08 ,ug/ml (the units in Wallach's original paper were ,ug/dl, but ,ug/ml
almost certainly was intended; the fluorometric analytical technique used
for selenium determination would not be sensitive enough to measure hun-
dredths of micrograms per deciliter of blood). Although this value is some-
what low in comparison to usual levels in the United States, the concentra-
tion is certainly higher than that of most native New Zealanders, who have
no known predisposition to develop cystic fibrosis. In fact, Wallach's
(1978) own figures show that the rate of cystic fibrosis in New Zealand is
only one-fifth to one-half that in the United States; the rate in Sweden,
another country thought to have rather low selenium intakes, is only one-
tenth to one-fourth that in the United States. Analysis of stabilized cases
(Wallach and Garmaise, 1979) revealed whole-blood selenium values of
0.12 to 0.30 ,ug/ml, well within the typical range in the United States.
Analysis of tissues from two deceased infants aged 4 and 7 months that had
cystic fibrosis revealed liver and kidney values of 0.19 and 0.25 ,ug per
gram and 0.54 and 0.50 ,ug/g, respectively. Although these values were
stated to be only one-tenth normal levels, this is incorrect; Wallach's anal-
yses were expressed on a wet-weight basis whereas the values he used for
comparison were on a dry-weight basis. Also, the data Wallach used for
comparative purposes were obtained from tissues taken from middle-aged
or elderly adults, and since the selenium level in tissues may vary consider-
ably with age, it is improper to compare data from infants with that from
adults. Unfortunately, data on selenium levels of tissues from infants are
even more limited than those available from adults, but Schroeder et al.
(1970) found that the level of selenium in the liver and kidney of a 9-
month-old male infant was 0.33 and 0.70 ,ug/g, respectively values which
are not that far removed from Wallach's figures. It should also be pointed
out that the levels found by Wallach in the tissues of his cystic fibrosis
patients are not particularly low in light of the levels that are found in sele-
nium-deficient animals and would not be considered indicative of selenium
deficiency in animals (see Chapter 6~. Selenium levels in serum or whole
blood of cystic fibrosis patients were not considered deficient, and whole-
blood GSH-Px activity was in the normal range (Lloyd-Still and Ganther,
1980; Castillo et al., 1981; B. A. Underwood, Massachusetts Institute of
Technology, Cambridge, personal communication, 1980~.
SELENIUM SUPPLEMENTS
As is readily apparent from the above discussion, numerous attempts have
now been made to associate low or suboptimal selenium intakes with a
wide variety of human diseases. For example, one investigator has ques-
tioned whether the optimal levels of dietary selenium for the postulated
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SELENIUM IN NUTRITION
nutritional requirement are the same as those needed for cancer preven-
tion (Griffin, 19791. Some workers have called for an increase in dietary
selenium intakes to protect against cancer, either by consuming selenium-
rich foods or by taking selenium supplements (Schrauzer and White,
19781. Griffin (1979), however, has stated that supplementation of sele-
nium in humans is not warranted at this time and that in fact there are
reasonable doubts that selenium may have any practical value in the pre-
vention of cancer in humans. It was concluded there must be proof that
selenium indeed is of value against human cancer before selenium supple-
mentation can be advocated in humans.
Other workers have suggested that selenium deficiency may play a role
in the etiology of heart disease (Frost and Ingvoldstad, 1975) but, again,
the usefulness of selenium supplements in such conditions must be ques-
tioned. Cardiomyopathy is seen only in animals deficient both in vitamin E
and selenium, and heart damage is not observed in uncomplicated sele-
nium deficiency. The relationship between selenium levels in human tis-
sues and various types of heart disease remains controversial. While it is
true that a cardiomyopathy in children that was thought to be related to
low selenium intake has recently been reported in the People's Republic of
China, it must be emphasized that the amounts of dietary selenium needed
to prevent this condition are very small. The Chinese noted that this dis-
ease did not occur in areas where the daily dietary intake of selenium was
30 ,ug or more. There is no evidence that any intake greater than this is of
any benefit against such heart disease. To suggest otherwise is to fall into
the common "if a little is good, then more must be better" trap of faulty
reasoning about nutritional supplementation. Also, it must again be em-
phasized that the pathology of Keshan disease is quite different from that
of cardiovascular disease commonly seen in Western cultures.
Because of the wide coverage given the hypothesis that selenium defi-
ciency may play a role in cystic fibrosis in the popular press and various lay
nutrition publications (see, for example, Shaw, 1979), it has been esti-
mated that several hundred cystic fibrosis patients in the United States
may presently be following a high-selenium diet and/or taking selenium
supplements (M. Adams, Center for Disease Control, Atlanta, personal
communication, 1979~. While it was claimed that supplementation with
selenium reversed a positive sweat test in one infant diagnosed as having
cystic fibrosis (Wallach and Garmaise, 1979), the child later died after a
short period on selenium supplements (Hubbard et al., 19801. An editorial
recommending against the use of selenium supplements for cystic fibrosis
patients has recently appeared (Hubbard et al., 19801. Thomson and
Robinson (1980) were unable to find any association between any human
disease and the low selenium intake characteristic of New Zealand and
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Selenium and Human Health
131
concluded that supplementation of the general population was not justi-
fied at present.
As was discussed in Chapter 7, the amount of selenium needed to cause
toxicity can be decreased in certain situations. Also, selenium has peculiar
metabolic interactions with other compounds; e.g., methylated selenium
metabolites that occur naturally in the body have a pronounced synergistic
toxicity with mercuric chloride and inorganic arsenic compounds. An in-
terrelationship of particular interest in the present context is the finding of
Jacobs and Griffin (1979) that combined supplementation of 1,2-dimethyl-
hydrazine-treated rats with vitamin C in the diet and selenium in the
drinking water led to an increased incidence of colon tumors as compared
to unsupplemented rats or rats supplemented with selenium or vitamin C
alone. This observation is of importance to human health because those
persons taking selenium supplements may also be taking vitamin C sup-
plements for other reasons. Therefore, in light of the inherent toxicity of
selenium and the inability to predict many of its metabolic interrelation-
ships with other dietary constituents, its use as a human dietary supple-
ment cannot be encouraged at this time.
CONCLUSIONS
Experiments with rodents have shown under a wide variety of conditions
that selenium has a protective effect against certain chemically induced
and spontaneous, presumably virally induced, tumors.
Associations have been made between the presumed selenium status of
various populations and their incidence of cancer, but such correlations
have been criticized because of their lack of strength, consistency, and se-
lectivity. Although low blood selenium levels are sometimes observed in
cancer patients, depressed blood selenium levels are not uniquely charac-
teristic of such patients and may rather reflect their lack of well being or
poor nutritional status.
Animals deficient in both vitamin E and selenium develop cardiomy-
opathy, but such a condition is not found in animals suffering from an
uncomplicated selenium deficiency.
As in the case of cancer, associations have been drawn between pre-
sumed human selenium status and the rate of heart disease but, again,
these associations are lacking strength, consistency, and selectivity.
Although a cardiomyopathy in children (Keshan disease) that is thought
to be at least partially caused by selenium deficiency has been recently re-
ported in the People's Republic of China, the disease is found only in pop-
ulations severely deficient in selenium.
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S ELENIUM IN NUTRITION
There is no evidence to suggest that inadequate selenium intake plays
any role in human reproductive failure.
Selenium at levels in excess of nutritional requirements improves the im-
mune response in mice, and selenium deficiency decreases the microbici-
dal activity of phagocytes in rats. However, there is no evidence indicating
that suboptimal selenium intake contributes to impaired resistance to in
fectious diseases in humans.
The hypothesis that cystic fibrosis is a conditioned selenium-deficiency
disease has not been substantiated.
In well-nourished populations there is no evidence to indicate that sele-
nium supplements have any prophylactic or therapeutic benefit against
human diseases such as cancer, cardiovascular disease, or cystic fibrosis.
Selenium supplements were reported to be of benefit against Keshan dis-
ease, a juvenile cardiomyopathy found in certain areas of the People's Re-
public of China, but this condition was not observed in any area where the
daily dietary intake of selenium exceeded 30 ,~Ag/day. In most parts of the
world, human diets readily furnish this quantity, and there seems little justi-
fication at this time for the general use of human selenium supplements.
Representative terms from entire chapter:
cystic fibrosis
