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OCR for page 107
7
Effects of Excess Selenium
The poisonous nature of many selenium compounds remained more or less
a laboratory curiosity until the 1930s, when it was discovered that selenium
was the active principle in forages and grains that caused alkali disease in
livestock raised in certain areas of the American great plains. The practical
nature of this problem stimulated a great deal of research on both chronic
and acute selenosis (reviewed by Moxon and Rhian t1943] and Rosenfeld
and Beath [1964~. This chapter deals with general aspects of the toxicity
of selenium compounds to animals and humans.
SELENIU M TOXICITY IN LABORATORY ANIMALS
ACUTE TOXICITY
The minimum lethal dose of selenium as sodium selenite or selenate in
rabbits, rats, and cats was 1.5 to 3.0 mg/kg body weight regardless of
whether the salts were given orally, subcutaneously, intraperitoneally, or
intravenously (Smith et al., 1937~. Animals receiving such acute doses of
selenium compounds develop a garlicky breath odor because of the exhala-
tion of volatile methylated selenium metabolites. Dimethyl selenide, the
primary volatile metabolite, and trimethylselenonium ion, a urinary
metabolite, have relatively low orders of toxicity, their LD50 in rats being
1,600 mg and 49.4 mg selenium/kg, respectively (McConnell and Port-
man, 1952b; Obermeyer et al., 19711. However, these compounds should
not be regarded as innocuous, since they can have strong synergistic toxici
107
OCR for page 108
108
SELENIUM IN NUTRITION
ties with mercuric chloride (Parizek et al., 1971) and sodium arsenite
(Obermeyer et al., 19711. Also, male rats have been reported to be much
more sensitive to dimethyl selenide than female rats (Parizek et al., 1971),
and male rats fed diets low in selenium apparently are extremely sensitive
to the toxicity of dimethyl selenide (Parizek et al., 1980~. This susceptibil-
ity to dimethyl selenide toxicity can be largely eliminated by pretreating the
male rats with small injected doses of selenite or by increasing the prior
oral intake of dietary selenite. Elemental selenium is quite nontoxic, since
its oral LDso in rats is 6,700 mg/kg (Cummins and Kimura, 1971~.
Aside from garlicky breath odor, animals acutely poisoned with sele-
nium exhibit vomiting, dyspnea, tetanic spasms, and death from respira-
tory failure (Franke and Moxon, 1936~. Pathological changes include con-
gestion of the liver, with areas of focal necrosis; congestion of the kidney;
endocarditis; myocarditis; petechial hemorrhages of the epicardium; at-
ony of the smooth muscles of the gastrointestinal tract, gallbladder, and
urinary bladder; and erosion of the long bones, especially the tibia.
CHRONIC TOXICITY
Dietary selenium levels of 4 to 5 ppm are sufficient to cause growth inhibi-
tion in animals fed a normal diet (NRC, 1976b). However, the resistance or
susceptibility of animals to chronic selenium poisoning can be markedly
altered by a number of factors. For example, Harr et al. (1967) found that
rats fed a commercial "laboratory chow" diet were two to three times more
resistant to chronic selenium toxicity than rats fed a semipurified diet. On
the other hand, diets low in protein quality or quantity potentiated chronic
selenosis (Gortner, 1940; Lewis et al., 1940~. The growth rate of vitamin E-
deficient rats was depressed by only 1 mg selenium as sodium selenite/kg
of diet (Witting and Horwitt, 1964), and swine deficient in vitamin E and
selenium were shown to be more susceptible to acute selenium toxicity than
pigs fed diets supplemented with vitamin E and selenium (Van Vleet et al.,
1974~. Weanling rats are more susceptible to selenium toxicity than older
rats (Halverson et al., 1966), and rabbits are more sensitive to selenium
poisoning than rats (Pletnikova, 1970~. Jaffe and Mondragon (1969) ob-
tained evidence suggesting that rats can adapt somewhat to a chronic sele-
nium intake, since chronically poisoned rats from mothers previously ex-
posed to selenium stored less of the element in their livers than rats from
mothers fed a nonseleniferous stock diet.
Another factor that can influence the interpretation of chronic selenium
toxicity experiments is the criterion used to assess the degree of response to
a given dose of selenium. As indicated above, the most commonly used
criteria in the past were growth inhibition and mortality. Other criteria
OCR for page 109
Effects of Excess Selenium
109
used include liver damage, splenomegaly, pancreatic enlargement, ane-
mia, and elevated serum bilirubin levels (e.g., see Halverson et al., 1966~.
Jaffe et al. (1972b) reported that excess selenium intake in rats decreased
fibrinogen levels and prothrombin activities and elevated serum alkaline
phosphatase and glutamic-pyruvic or glutamic-oxaloacetic transaminase
activities. However, all these effects were observed only at selenium intakes
that also depressed growth rate.
Pletnikova (1970) measured various biochemical indices in rabbits and
rats that were given low doses of sodium selenite in aqueous solution for
long periods of time. In this experiment, 32 rabbits and 16 rats were di-
vided into 4 groups and given daily peroral doses of 0, 5.0, 0.5, and 0.05 fig
selenium/kg body weight for 7~/~ months and 6 months, respectively.
There was a significant increase in the concentration of oxidized glu-
tathione in the blood of the rabbits given 5 ,ug/kg for 2 months, and he-
patic sulfobromophthalein excretion and succinic dehydrogenase activ-
ity decreased after 7 months. Fewer and less-pronounced changes were
caused by 0.5 ,ug/kg, while 0.05 ~g/kg weakened the capacity for forming
new conditioned reflexes. Although these responses were considered harm-
ful effects of selenium, the level of selenium given perorally to rats at a dose
of 5 ~g/kg is roughly equivalent to the intake provided by a diet containing
0.063 ppm. Since this level of dietary selenium intake is clearly within the
nutritional range, the interpretation of this experiment is open to question.
Most biologists would regard responses to selenium in the doses used by
Pletnikova (1970) as physiological rather than pharmacological or toxico-
logical effects.
SELENIUM TOXICITY IN FARM ANIMALS
Rosenfeld and Beath (1964) classified three distinct forms of selenium poi-
soning in livestock: (a) acute, (b) chronic of the blind-staggers type, and
(c) chronic of the alkali-disease type.
In the field, acute selenium poisoning is caused by the ingestion of a
large quantity of highly seleniferous accumulator plants in a short period
of time. The experimental or accidental administration of selenium com-
pounds has also produced acute poisoning in farm animals (NRC, 1976b).
Signs of severe distress include labored breathing, abnormal movement
and posture, and prostration and diarrhea, and are followed by death in a
few hours. Acute selenosis is generally not a practical problem because
livestock usually avoid the accumulator plants except when other pasture
is not available.
Rosenfeld and Beath (1964) stated that blind staggers occurs in animals
that consume a limited amount of selenium accumulator plants over a pe
OCR for page 110
110
S ELK NIUM IN NUTRITI O N
riod of weeks or months, but this disease has not been produced in animals
by the administration of pure selenium compounds. However, blind stag-
gers can be mimicked experimentally by giving aqueous extracts of accu-
mulator plants, so Maag and Glenn (1967) and Van Kampen and James
(1978) suggested that alkaloids or other toxic substances in the accumula-
tors may play a role in this syndrome. The affected animals have impaired
vision, and they wander, stumble, and finally succumb to respiratory failure.
Animals that consume grains containing 5 to 40 mg selenium/kg over a
period of several weeks or months suffer from chronic selenosis, known as
alkali disease. Signs include liver cirrhosis, lameness, hoof malformations,
loss of hair, and emaciation. Although Maag and Glenn (1967) were not
able to demonstrate alkali disease experimentally in cattle given inorganic
selenium, Olson (1978) cited several studies indicating that the disease is
associated with the consumption of seleniferous grains or grasses and
could be produced experimentally by feeding inorganic selenium salts.
There is no effective way to counteract selenium toxicity in livestock ex-
cept to remove the animals from the areas with high selenium soils and
close these areas to livestock production. Grains or grasses grown in these
areas, however, can still be used if they are blended with crops from areas
with lower selenium soils.
SELENIUM OVEREXPOSURE IN HUMANS
The public health aspects of excess selenium exposure first became of con-
cern after the discovery that selenium caused alkali disease in livestock,
since it was quickly realized that selenium from grains or vegetables grown
on seleniferous soils could also enter the human food chain. Smith et al.
(1936) surveyed rural farming and ranching families living in the Great
Plains area of the United States known to have a history of alkali disease in
livestock. No symptoms pathognomonic of human selenium poisoning
were found, and no serious illness definitely attributable to selenium toxic-
ity was observed. Vague symptoms of anorexia, indigestion, general pal-
lor, and malnutrition were reported, and more pronounced disease states
such as bad teeth, yellowish discoloration of the skin, skin eruptions,
chronic arthritis, diseased nails, and subcutaneous edema were seen.
Since the results of this preliminary study were not clear, a second, more
complete survey was carried out to delineate more exactly the symptoma-
tology of human selenosis and its possible relationship to urinary selenium
excretion (Smith and Westfall, 1937~. To increase the probability of de-
tecting effects of selenium overexposure, 100 subjects were selected from
the earlier survey who had high levels of selenium in their urine. Once
again it was concluded that none of the symptoms observed could be con
OCR for page 111
Effects of Excess Selenium
111
sidered specific for selenium poisoning. However, numerous complaints of
gastrointestinal disturbance were considered significant, and a high inci-
dence of icteroid skin discoloration was thought perhaps to be related to
liver dysfunction possibly caused by selenium ingestion. Bad teeth were
also seen in 27 percent of the individuals surveyed. Other symptoms were
reported so rarely that they did not appear to be associated with selenium.
Jaffe (1976) conducted a survey in Venezuela and compared children
from a high-selenium region (Villa Bruzual) with those from Caracas. Av-
erage hemoglobin and hematocrit values were depressed in Villa Bruzual,
but no correlation between blood and urine selenium levels and hemoglo-
bin or hematocrit values was observed in specific individuals. Any differ-
ences in hemoglobin were thought to be more likely due to differences in
nutritional or parasitological status rather than to differences in selenium
intake (Jaffe et al., 1972a). Prothrombin and serum alkaline phosphatase
and transaminase activities were normal in all children, and no correlation
with blood selenium levels was found. Dermatitis, loose hair, and patho-
logical nails were more common in children from the high-selenium re-
gion, and the clinical signs of nausea and pathological nails seemed to
correlate with serum and urine selenium levels. But it was doubted that
selenium was responsible for the increased incidence of those clinical signs
since no differences attributable to selenium were seen in the various bio-
chemical tests carried out (Jaffe et al., 1972a).
Nine cases of acute selenium intoxication were described by Kerdel-
Vegas (1966) in persons who had consumed nuts of the "Coco de Mono
tree" (Lecythys ollaria) from a seleniferous area in Venezuela. In most
cases, nausea, vomiting, and diarrhea occurred a few hours after eating
the nuts, followed by hair loss and nail changes a few weeks after the initial
episode. Most patients appeared to make a satisfactory recovery, with
eventual regrowth of hair and nails; but a 2-year-old boy died due to severe
dehydration. Samples of Brazil nuts marketed in Great Britain contained
an average of 22 ppm of selenium (Thorn et al., 1978), and Chavez (1966)
reported signs of selenium toxicity in rats fed diets that included defatted
Brazil nut flour containing 51 ppm of selenium. Brazil nuts marketed in
the United States also are high in selenium, with 6 percent of one sample
containing 100 ppm or more (Palmer et al., 1982~.
Although data from industrial exposure to selenium are limited, Glover
(1976) has stated that "there have been no deaths or cases of irreversible
pathological conditions due to selenium or its compounds being absorbed
from industrial processes."
A detailed description of an episode of endemic human selenosis was
recently reported from the People's Republic of China (Yang et al., 19831.
The morbidity due to selenium intoxication was almost half of 248 inhabit
OCR for page 112
112
SELENIUM IN NUTRITION
ants from the 5 most heavily affected villages during the years of peak prev-
alence (1961 to 1964~. Loss of hair and nails was the most common sign of
the poisoning, but lesions of the skin, nervous system, and possibly teeth
may have been involved in the areas of high incidence. The mean urinary
selenium level found in this area of China with selenosis (2.68 Mogul) was
greater than even the maximum value (1.98,ug/ml) reported by Smith and
Westfall (1937~. The average blood selenium level in this high-selenium
region of China (3.2,ug/ml) substantially exceeded the level that Jaffe et al.
(1972a) concluded was hazardous to children (0.813,ug/ml). The selenium
content of vegetable, cereal, hair, blood, and urine samples from the sele-
nosis area was up to three orders of magnitude higher than that of corre-
sponding samples from Keshan disease (selenium-deficiency) areas. The
selenium entered the food chain from soils that had been contaminated by
weathered coal of a very high selenium content (average greater than
300 ,ug/g).
Thus, with the exception of the Chinese experience, it has not been pos-
sible to identify any specific, definitive long-term human health problem
due to selenium overexposure. This seems rather remarkable in light of the
great inherent toxicity of selenium. However, it should be pointed out that
others felt that human selenium poisoning is common, widespread, and in
certain localities of importance to public health (Lemley, 1943~. Kilness
(1973) decried the fact that no subsequent systematic survey with appro-
priate controls has been made in South Dakota since the first surveys done
over 30 years earlier. Moreover, Smith and Westfall (1937) were surprised
by the absence of definite evidence of serious injury, especially in those
subjects whose urinary selenium concentrations were markedly elevated.
Because of the lack of any well-documented selenium intake data during
excess selenium exposure, a precise figure for an intake that would be
harmful to humans cannot be given. Most of the subjects of Smith and
Westfall (1937) were thought to be absorbing between 10 and 100 ,ug/kg
body weight per day. This would be equivalent to a dietary selenium intake
of 700 to 7,000 ,ug/day by a 70 kg man, if it can be assumed that all of the
ingested selenium was absorbed. Tsongas and Ferguson (1977) could find
no difference in the health status of two populations that drank water con-
taining 50 to 125 ,ug selenium/liter or 1 to 16 ,ug selenium/liter, respec-
tively. It was not possible to estimate the daily dietary intake of selenium in
the endemic-selenosis area of China during the period of peak prevalence,
but the dietary intake some time after the peak prevalence had subsided
averaged 4.99 mg/day with a range of 3.20 to 6.69 mg/day (Yang et al.,
1983~. A tentative maximum acceptable daily selenium intake for the pro-
tection of human health of 500 fig was proposed by Sakurai and Tsuchiya
(1975~. This intake was arrived at by first estimating that the usual average
OCR for page 113
Effects of Excess Selenium
113
selenium intake by humans ranged between 50 and 150 ,ug/day. Intakes of
10 to 200 times normal were thought acceptable as an estimated range for
the safety margin within which most persons could tolerate selenium. Mul-
tiplying the lower of both estimates gave the lowest level of potentially dan-
gerous selenium intake, i.e., 50 X 10 or 500 ,ug/day.
Obviously, progress in selenium toxicology would be greatly enhanced if
a more specific and sensitive test of selenium overexposure could be devel-
oped. Perhaps with the discovery of the role of selenium in GSH-Px (see
Chapter 4) and the newly found inhibition of protein synthesis by seleno-
diglutathione (Vernie et al., 1979) such tests will be forthcoming in the
future.
Representative terms from entire chapter:
selenium toxicity
