Toxicity Profiles
Toxicity Summary for SELENIUM
NOTE:
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- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
MARCH 1993
Prepared by: Dennis M. Opresko, Ph.D, Chemical Hazard Evaluation Group, Biomedical
Environmental Information Analysis Section, Health and Safety Research Division, Oak Ridge
National Laboratory*, Oak Ridge, Tennessee.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under
Contract No. DE-AC05-84OR21400.
EXECUTIVE SUMMARY
Selenium is an essential trace element important in many biochemical and physiological
processes including the biosynthesis of coenzyme Q (a component of mitochondrial electron
transport systems), regulation of ion fluxes across membranes, maintenance of the integrity of
keratins, stimulation of antibody synthesis, and activation of glutathione peroxidase (an enzyme
involved in preventing oxidative damage to cells). Recommended human dietary allowances
(average daily intake) for selenium are as follows: infants up to 1 year,
10-15 µg; children 1-10 years, 20-30 µg; adult males 11-51+ years, 40-70 µg; adult females 11-51+ years, 45-55 µg;
pregnant or lactating women, 65-75 µg. There appears to be a relatively narrow range between
levels of selenium intake resulting in deficiency and those causing toxicity.
Selenium occurs in several valence states: -2 (hydrogen selenide, sodium selenide, dimethyl
selenium, trimethyl selenium, and selenoamino acids such as selenomethionine; 0 (elemental
selenium); +4 (selenium dioxide, selenious acid, and sodium selenite); and +6 (selenic acid and
sodium selenate). Toxicity of selenium varies with valence state and water solubility of the
compound in which it occurs. The latter can affect gastrointestinal absorption rates.
Gastrointestinal absorption in animals and humans for various selenium compounds ranges
from about 44% to 95% of the ingested dose (Thomson and Stewart, 1974; Bopp et al., 1982;
Thomson, 1974). Respiratory tract absorption rates of 97% and 94% for aerosols of selenious acid
have been reported for dogs and rats, respectively (Weissman et al., 1983; Medinsky et al., 1981).
Selenium is found in all tissues of the body; highest concentrations occur in the kidney, liver, spleen,
and pancreas (Schroeder and Mitchener, 1971a; Schroeder and Mitchener, 1972; Jacobs and Forst,
1981a; Julius et al., 1983; Shamberger, 1984; Echevarria et al., 1988). Excretion is primarily via
the urine (0-15 µg/L); however, excretory products can also be found in the feces, sweat, and in
expired air.
In humans, acute oral exposures can result in excessive salivation, garlic odor to the breath,
shallow breathing, diarrhea, pulmonary edema, and death (Civil and McDonald, 1978; Carter, 1966;
Koppel et al., 1986). Other reported signs and symptoms of acute selenosis include tachycardia,
nausea, vomiting, abdominal pain, abnormal liver function, muscle aches and pains, irritability,
chills, and tremors. Acute toxic effects observed in animals include pulmonary congestion,
hemorrhages and edema, convulsions, altered blood chemistry (increased hemoglobin and
hematocrit); liver congestion; and congestion and hemorrhage of the kidneys (Smith et al., 1937;
Anderson and Moxon, 1942; Hopper et al., 1985).
General signs and symptoms of chronic selenosis in humans include loss of hair and nails,
acropachia (clubbing of the fingers), skin lesions (redness, swelling, blistering, and ulcerations),
tooth decay (mottling, erosion and pitting), and nervous system abnormalities attributed to
polyneuritis (peripheral anesthesia, acroparaethesia, pain in the extremities, hyperreflexia of the
tendon, numbness, convulsions, paralysis, motor disturbances, and hemiplegia). In domesticated
animals, subchronic and chronic oral exposures can result in loss of hair, malformed hooves, rough
hair coat, and nervous system abnormalities (impaired vision and paralysis). Damage to the liver
and kidneys and impaired immune responses have been reported to occur in rodents following
subchronic and/or chronic oral exposures (Ganther and Baumann, 1962; Beems and van Beek, 1985;
NCI, 1980a; Tinsley et al., 1967; Harr et al., 1967; Schroeder, 1967).
Selenium is teratogenic in birds and possibly also in domesticated animals (pigs, sheep, and
cattle), but evidence of teratogenicity in humans and laboratory animals is lacking (ASTDR, 1989).
However, adverse reproductive and developmental effects (decreased rates of conception, increased
rates of fetal resorption, and reduced fetal body weights) have been reported for domesticated and
laboratory animals (Harr and Muth, 1972: Wahlstrom and Olson, 1959; Schroeder and Mitchener,
1971b).
The Reference Dose (RfD) for chronic oral exposures is 0.005 mg/kg/day for both selenium
and selenious acid (U.S. EPA, 1992a, 1992b). The subchronic RfDs for these compounds are the
same as the chronic RfDs (U.S. EPA, 1992c).
In humans, inhalation of selenium or selenium compounds primarily affects the respiratory
system. Dusts of elemental selenium and selenium dioxide can cause irritation of the skin and
mucous membranes of the nose and throat, coughing, nosebleed, loss of sense of smell, dyspnea,
bronchial spasms, bronchitis, and chemical pneumonia (Clinton, 1947; Hamilton, 1949). Other signs
and symptoms following acute inhalation exposures include lacrimation, irritation and redness of
the eyes, gastrointestinal distress (nausea and vomiting), depressed blood pressure, elevated pulse
rate, headaches, dizziness, and malaise (ATSDR, 1989). In animals, acute inhalation exposures also
result in severe respiratory effects including edema, hemorrhage, and interstitial pneumonitis (Hall
et al., 1951; Dudley and Miller, 1937) as well as in splenic damage (congestion, fissuring red pulp,
and increased polymorphonuclear leukocytes) and liver congestion and mild central atrophy (Hall
et al., 1951). Information on toxicity of selenium in humans and animals following chronic
inhalation exposures is not available, and subchronic and chronic inhalation Reference
Concentrations have not been derived.
Epidemiologic studies in humans havation between chronic oral exposures to selenium and
an increased incidence of death due to neoplasms. Some studies have indicated that selenium may
have anti-neoplastic properties (see Whanger, 1983; Hocman, 1988). In studies on laboratory
animals, selenites or selenates have not been found to be carcinogenic; however, selenium sulfide
produced a significant increase in the incidence of hepatocellular carcinomas in male and female rats
and in female mice and a significant increase in alveolar/bronchiolar carcinomas and adenomas in
female mice following chronic oral exposures (NCI, 1980c). EPA has placed selenium and
selenious acid in Group D, not classifiable as to carcinogenicity in humans (U.S. EPA, 1992a and
1992b), while selenium sulfide is placed in Group B2, probable human carcinogen (U.S. EPA,
1992d). Quantitative data are, however, insufficient to derive a slope factor for selenium sulfide.
Pertinent data regarding the potential carcinogenicity of selenium by the inhalation route in humans
or animals were not located in the available literature.
1. INTRODUCTION
Selenium is an essential trace element important in many biochemical and physiological
processes including the biosynthesis of coenzyme Q (a component of mitochondrial electron
transport systems), regulation of ion fluxes across membranes, maintenance of the integrity of
keratins, stimulation of antibody synthesis, and activation of glutathione peroxidase (an enzyme
involved in preventing oxidative damage to cells) (Hammond and Beliles, 1980). Animal studies
indicate that deficiencies in selenium can result in damage to the liver, heart, kidneys, skeletal
muscle, and testes (Hammond and Beliles, 1980). Recommended human dietary allowances
(average daily intake) for selenium are as follows: infants up to 1 year,
10-15 µg; children 1-10 years, 20-30 µg; adult males 11-51+ years, 40-70 µg; adult females 11-51+ years, 45-55 µg;
pregnant or lactating women, 65-75 µg. The primary dietary sources of selenium are seafoods,
kidney and liver meats, and grains and cereals (NRC, 1989).
Selenium occurs in several oxidation states: -2 (hydrogen selenide, sodium selenide, dimethyl
selenium, trimethyl selenium, and selenoamino acids such as selenomethionine; 0 (elemental
selenium); +4 (selenium dioxide, selenious acid, and sodium selenite); and +6 (selenic acid and
sodium selenate).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Gastrointestinal absorption in humans for various selenium compounds ranges from about
44% to 95% of the ingested dose (Thomson and Stewart, 1974; Bopp et al., 1982; Thomson, 1974).
Absorption is highest when the compound is administered in solution and lowest when it is
administered as a solid. Absorption is also more efficient after a single dose than after repetitive
daily doses.
In studies on rats, mice and dogs, gastrointestinal absorption rates of 87% or more have been
reported for [75Se]-selenite (selenious acid) (Bopp et al., 1982; U.S. EPA, 1989: Furchner et
al.,1975). Absorption is highest following gavage administration, but may be only 50% when the
compound is administered in feed (Weissmann et al., 1983).
Respiratory tract absorption rates of 97% and 94% for aerosols of [75Se]-selenite (selenious
acid) have been reported for dogs and rats, respectively (Weissman et al., 1983; Medinsky et al.,
1981).
2.2. DISTRIBUTION
Selenium is found in all tissues at concentrations that vary with the amount ingested in the diet
and the type of tissue. Highest concentrations occur in the kidney, liver, spleen, and pancreas
(Schroeder and Mitchener, 1971a; Schroeder and Mitchener, 1972; Jacobs and Forst, 1981a; Julius
et al., 1983; Shamberger, 1984; Echevarria et al., 1988). Selenium is also concentrated in
erythrocytes relative to the amount in blood plasma (Butler et al., 1990). As a result of occupational
exposures, high concentrations can also be found in peribronchial nodes, lung, hair, and nails (Diskin
et al., 1979).
2.3. METABOLISM
Two major metabolic products of selenite have been identified, dimethyl selenide and trimethylselenonium ion (Palmer et al., 1969, 1970; Nakamuro et al., 1977; Jiang et al., 1983). In the
formation of dimethyl selenide, selenite (H2SeO3) is first reduced nonenzymatically to the stable
selenotrisulfide (GSSeSG) by four glutathione molecules. An NADPH-dependent reduction
involving glutathione reductase converts GSSeSG to the very unstable selenopersulfide (GSSeH),
and a further reduction by NADPH and glutathione reductase converts GSSeH to hydrogen selenide
(H2Se). Methyl groups donated by S-adenosylmethionine are transferred by a methyltransferase to
hydrogen selenide to form dimethyl selenide (Ganther, 1979; see also Whiting et al., 1980 and Bopp
et al., 1982). The reactions involved in the metabolism of selenite to trimethylselenonium are not
known; however, according to Bopp et al. (1982), it is not a simple transfer of an additional methyl
group to dimethyl selenide.
2.4. EXCRETION
Within certain physiological limits trace amounts of selenium are retained in the body while
excessive amounts are excreted (Hammond and Beliles, 1980). Excretion is primarily in the urine;
however, excretory products can also be found in the feces, sweat, and in expired air. At high
dietary levels a significant fraction of the dose is eliminated in expired air, but at low dietary levels
the amount in expired air is insignificant. Only a small fraction of the amount absorbed through the
gastrointestinal tract is excreted in the feces; however, for selenium compounds that are not readily
absorbed 33-58% of the dose may appear in the feces (Bopp et al., 1982; Shamberger, 1984;
Thomson and Stewart, 1974).
Urinary excretion of selenium in humans varies with dose and frequency of administration.
According to Bopp et al. (1982), urinary excretion after ingestion of trace amounts seldom exceeds
10-15%. Thomson and Stewart (1974) reported that only 10% of a 10 µg ingested dose of [75Se]-selenite was excreted in urine within 14 days; however, urinary excretion was 41-54% following a
single 0.1-mg dose, 72-77% after a single 1-mg dose, and 36% after five 1-mg daily doses (by day
9) (Thomson et al., 1978). The elimination curve for selenium in humans is triphasic and the
terminal half-life for selenite is about 4 months (Bopp et al., 1982).
Excretion of selenium in expired air of occupationally exposed individuals is very low to
undetectable. Among individuals exposed to high acute levels a garlic-like odor to the breath is
indicative of the presence of dimethylselenide.
Excretion of selenium in animals follows a pattern similar to that in humans. In tests on rats
maintained on a diet supplemented with 1 ppm selenium, up to 67% was excreted in the urine but
only 10% in the feces (Burk et al., 1972). Mean half-times of excretion ranged from 19.5 days for
animals on a 0.1 ppm selenium diet to 1.2 days for animals on a 1 ppm diet. Elimination of selenium
by way of the respiratory tract was usually <10% (Burk et al., 1972).
3. NONCARCINOGENIC HEALTH EFFECTS
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Several cases of selenium poisoning in humans have been reported. A 3-yr-old boy died 1.5
hours after ingesting an undetermined amount of selenious acid (Carter 1966), and a 15-yr-old girl
survived after ingesting an estimated 22.3 mg Se/kg as sodium selenate (Civil and MacDonald,
1978). Clinical signs included excessive salivation, garlic odor to the breath, shallow breathing, and
diarrhea. Pulmonary edema and lung lesions have been reported in cases of acute lethal exposures
(Carter, 1966; Koppel et al., 1986). Other reported signs and symptoms of acute selenosis include
tachycardia, nausea, vomiting, abdominal pain, abnormal liver function, muscle aches and pains,
irritability, chills, and tremors.
3.1.1.2. Animal
The acute oral toxicity of selenium varies with the solubility of the chemical compound in
which it occurs; the more soluble compounds such as sodium selenite and sodium selenate are more
toxic than the less soluble elemental selenium, selenium sulfide and selenium disulfide (ATSDR,
1989). Oral LD50 values for sodium selenite range from 1 to 7 mg Se/kg (rats, rabbits, mice, and
guinea pigs), whereas an LD50 of 138 mg/kg has been reported for selenium disulfide, and a 10-d
LD50 of 6,700 mg Se/kg has been reported for elemental selenium administered to rats (Cummins
and Kimura, 1971; Pletnikova, 1970).
Respiratory effects in laboratory animals following acute oral exposures are similar to those
occurring in humans and include pulmonary congestion, hemorrhages and edema, labored
respiration, muscular weakness, and asphyxial convulsions (Smith et al., 1937). Acute exposures
can also result in altered blood chemistry (increased hemoglobin and hematocrit in dogs); liver
congestion; and congestion and hemorrhage of the kidneys (Anderson and Moxon, 1942; Hopper
et al., 1985).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
A 62-year old man ingesting 2 mg of sodium selenite daily (0.9 mg Se/day) for 2 years
developed thickened and fragile nails and had a garlic-like odor to his perspiration (Yang et al.,
1983). A 57-year old woman who had ingested an estimated 2,387 mg selenium over 77 days
exhibited almost total alopecia, brittleness and loss of fingernails, sour-milk breath, nausea, vomiting
and fatigue (CDC, 1984).
Listlessness, lack of mental alertness, and other symptoms of selenosis were observed in
members of a family exposed to high levels of selenium in well water for about 3 months (Rosenfeld
and Beath, 1964). The well water contained 9 mg Se/L and daily intake from drinking water was
estimated to be 0.26 mg Se/kg/day. Dietary intake of selenium was not reported.
3.1.2.2. Animal
Livestock grazing on plants having a high selenium content develop a condition called "alkali
disease", which is characterized by loss of hair, inflammation of the coronary band followed by
cracked or malformed hooves, rough hair coat, impaired vision, aimless wandering behavior,
reduced consumption of food and water, and paralysis (ATSDR, 1989). Symmetrical focal
poliomyelomalacia has been observed in pigs exposed to selenium (Goehring et al., 1984; Harrison
et al., 1983; Wilson and Drake, 1982), and in laboratory studies this syndrome was reproduced in
pigs receiving 50 mg Se per kg of food for 20-40 days (Wilson et al., 1983). The estimated dose was
1.5 mg Se/kg body weight (ATSDR, 1989). Doses of 0.6 and 1.1 mg/kg/day to steers resulted in
trembling and neural degeneration of the cerebral and cerebellar cortices (Maag et al., 1960).
A 41-48% depression in body weight gain (during the initial 4 weeks of treatment) was
observed in male Holtzman rats maintained for 42-180 days on a diet containing 5 ppm Se (0.25 mg
Se/kg/day) (Ganther and Baumann, 1962). By week 6, the relative weight of the spleen was
increased twofold. Gross liver lesions, consisting of hobnailed or pebbled appearance, severe
cirrhosis and necrosis, were also observed in the treated animals.
When administered to male Syrian hamsters for 42 days, sodium selenite, at a dietary level
of 18 ppm Se (1.21 mg Se/kg/day), caused an 18% reduction in body weight gain and a 13%
reduction in food intake (Beems and van Beek, 1985). Although no treatment-related gross lesions
were seen, histopathological evaluation revealed oval cell proliferation in the periportal areas of the
liver, enlargement of hepatocytes and their nuclei in the centrilobular area, focal necrosis, necrosis
of individual cells, and pigment accumulation (lipofuscin and hemosiderin) in periportal macrophages (Beems and van Beek, 1985). No adverse effects occurred in animals receiving selenium
at a dietary level of 9 ppm (0.61 mg Se/kg bw/day).
Focal coagulation necrosis occurred in the liver of rats dosed with 31.6 mg selenium
sulfide/kg/day by gavage for 13 weeks, but not in rats receiving 17.8 mg selenium sulfide/kg/day
(NCI, 1980a). A mixture of selenium sulfide and selenium disulfide, equivalent to a dose of 464
mg/kg/day, did not cause hepatic effects in mice treated by gavage for 13 weeks; however, the
incidence and severity of interstitial nephritis increased compared to controls (NCI, 1980a). Renal
effects did not occur in mice dosed with 216 mg/kg/day.
Reduced humoral antibody (IgC) production and reduced prostaglandin synthesis were
observed in rats dosed for 10 weeks with 0.75 mg Se/kg/day (as sodium selenite in drinking water)
(Koller et al., 1986). Lower doses (0.075 and 0.28 mg/kg/day) increased natural killer cell (NKC)
cytotoxicity, enhancing the immune response to antigen stimulation; however, delayed-type
hypersensitivity (DTH) and prostaglandin E2 activity were significantly reduced.
Ingestion of organic seleniferous wheat by young rats for six weeks resulted in a reduction in
hemoglobin and the death of 1 of 8 animals receiving 0.68 mg Se/kg/day (Halverson et al., 1966).
Growth was reduced 20% at 0.55 mg Se/kg/day, and the maximum reported NOAEL was 0.42 mg
Se/kg/day.
3.1.3. Chronic Toxicity
3.1.3.1. Human
Selenium has been identified as the cause of the adverse health effects exhibited by the
inhabitants of several villages in China in a region where coal with a high selenium content is used
for cooking and also is burned in fields as a source of plant fertilizer (Yang et al., 1983). General
signs and symptoms of selenosis included loss of hair and nails, acropachia (clubbing of the fingers),
skin lesions (redness, swelling, blistering and ulcerations), tooth decay (mottling, erosion, and
pitting), and nervous system abnormalities (peripheral anesthesia, acroparaethesia, pain in the
extremities, hyperreflexia of the tendon, numbness, convulsions, paralysis, motor disturbances, and
hemiplegia). The nervous system abnormalities were attributed to polyneuritis caused by exposure
to selenium (Yang et al., 1983).
The daily selenium intake in the exposed population was
estimated to be 4.99 mg (range = 3.2-6.69 mg/day). Selenium levels in hair,
blood, and urine were 32.2 µg/g, 3.2 µg/mL and 2.68 µg/mL,
respectively. For residents in a control area, selenium intake was 0.116 mg/day, and average
concentrations in hair, blood, and urine were 0.36 µg/g, 0.095
µg/mL, and 0.026 µg/mL,
respectively. Whanger (1989) suggested that selenosis in the endemic area may have been due, in
part, to food contamination during cooking with seleniferous coal or from inhalation of volatilized
selenium. Yang et al. (1983), however, did not consider inhalation of selenium as a contributing
factor. The drinking water in the endemic area contained 54 µg Se/L.
Yang et al. (1989a,b) reevaluated the dietary intake of selenium using a larger group of
subjects from low, medium, and high selenium areas. The daily selenium intake (mean±SE) for
adults was as follows: males, 70.5±4.8 (low), 194.7±22.9 (medium), and
1438.2±76.4 µg/day
(high); females, 62.0±3.6 (low), 198.1±23.8 (medium), 1238.5±64.6 µg/day (high). Selenium
concentration in drinking water, 0.37, 1.72, and 12.27 µg/L for low, medium, and high areas,
respectively, represented 3% or less of the daily intake (based on consumption of 3 L of water per
day).
Blood selenium levels were obtained for five subjects presenting distinct and persisting
clinical signs of selenosis; the levels ranged from 1.054-1.854 mg/L of blood, with a mean of 1.35
mg/L. Based on regression analysis [i.e., logSeblood = 0.767 logSeintake 2.248], the daily selenium
intake corresponding to a blood level of 1.35 mg/L was 1,261 µg/day. Toxic signs of selenosis
occurred most often in subjects with a previous history of selenosis. About 97% of the cases were
adults older than 18 years and no cases occurred in children younger than 12 years, although children
often had daily intakes and blood levels exceeding those of the adults. Clinical chemistry studies
indicated a 44% increase in prothrombin time and a 19% reduction in whole blood glutathione at
blood levels above 1 mg/L (850 µg/day). The white blood cell counts were also elevated in subjects
from the high selenium area.
Longnecker et al. (1991) studied the selenium intake and health of 142 subjects living in
western South Dakota and eastern Wyoming, a region where the soil has a high selenium content.
Mean selenium intake was estimated to be 3.04 µmol/day (240 µg/day) with a range of 0.86-9.20
µmol/day (68-730 µg/day). No adverse health effects that might be associated with exposure to
selenium were found in the study population.
3.1.3.2. Animal
The chronic oral toxicity of sodium selenite has been evaluated in several laboratory species.
In one study, male and female Wistar rats were given dietary sodium selenite at concentrations of
0, 0.5, and 2.0 ppm in a semipurified high-protein diet for an entire lifetime (Tinsley et al., 1967;
Harr et al., 1967). The maximum body weight was reduced by 9-10% in male and female rats
receiving the 0.5-ppm diet and by 28% in rats receiving the 2-ppm diet. Histopathological effects
consisted of hepatic parenchymal lesions and interstitial nephritis; both conditions were less severe
and occurred less frequently in animals given sodium selenite than in those given sodium selenate.
Myocarditis was more severe and occurred more frequently in animals given sodium selenite.
In a study conducted by Schroeder (1967), female Long-Evans strain rats were administered
sodium selenite in drinking water for 24 months. The time-weighted-average (TWA) dose for the
entire period was 0.173 mg Se/kg/day (0.379 mg sodium selenite/kg/day). Statistically significant
reductions were observed in mean body weight (14% at 24 mo), mean heart weight at death, and
survival rates (51%) of animals 9 months of age. Gross lesions observed in treated animals dying
before 9 months of age were atrophy and irregular areas of fatty degeneration in the liver. Among
those rats surviving until termination, one rat had focal cirrhosis of the liver. No other organs were
affected (Schroeder, 1967; Schroeder and Mitchener, 1971a).
Schroeder (1967) also conducted a drinking water study using male and female Charles River
CD mice exposed to sodium selenite from 20-22 days of age until 15 months of age. Concentrations
in drinking water were 2 µg Se/mL [the weight-normalized dose was estimated to be 0.38 mg
Se/kg/day (0.83 mg sodium selenite/kg/day)]. Gross lesions (not otherwise specified) were seen in
the liver of 15 of 35 mice (sex not specified).
In another study, Schroeder and Mitchener (1972) administered 3 ppm of selenium (sodium
selenite) in drinking water to male and female Charles River CD mice for their entire lifetime.
Based on water consumption of 19% of body weight (U.S. EPA, 1986), the weight-normalized dose
was 0.57 mg Se/kg/day (1.25 mg sodium selenite/kg/day). Treated mice were less active, in poor
health, and shortly before death their extremities became edematous. Growth and longevity were
enhanced in treated males but depressed in females. Amyloidosis of the kidney, heart, adrenal, liver,
spleen, and lung was seen in 58% of the selenium-treated mice, but also in 30% of the controls.
Jacobs and Forst (1981a) administered 0 or 4 ppm of selenium (sodium selenite) to male
Sprague-Dawley rats in their drinking water for 1 or 2 years. The estimated weight-normalized dose
was 0.56 mg Se/kg/day (1.23 mg sodium selenite/kg/day). No treatment-related gross or histopathologic effects occurred in either treated group. Hepatic glutathione peroxidase activity was
reduced by 50% in rats given selenium for only 1 year. In a related study, Jacobs and Forst (1981b)
exposed female Swiss albino mice to selenium as sodium selenite (0, 1, 4, 8 ppm) in drinking water
for 50 weeks. Based on data provided by the authors, weight-normalized doses were 0, 0.27, 0.84
and 1.41 mg Se/kg/day (0, 0.59, 1.83 and 3.09 mg sodium selenite/kg/day). The only reported
treatment-related effect was a 50% reduction in weight gain in the mice receiving 8 ppm. Hepatic
glutathione peroxidase activity was increased.
3.1.4. Developmental and Reproductive Toxicity
3.1.4.1. Human
There is no clinical or epidemiologic evidence that selenium is teratogenic in humans, and in
one epidemiologic study of a population in which the incidence of selenosis was high, no selenium-associated reproductive or developmental effects were reported (Yang et al., 1989b).
3.1.4.2. Animal
Selenium is teratogenic in birds and possibly also in domesticated animals (pigs, sheep, and
cattle), but evidence of teratogenicity in laboratory animals is lacking (ASTDR, 1989). Adverse
developmental and reproductive effects have been reported in both domesticated and laboratory
animals.
Decreased rates of conception and increased rates of fetal resorption have been reported in
cattle, sheep, and horses fed diets high in organic selenium (25-50 mg/kg diet) (Harr and Muth,
1972). Similar effects on conception rates have been observed in pigs maintained on a diet
containing the equivalent of 0.41 mg Se/kg/day (as sodium selenite) (Wahlstrom and Olson, 1959).
In 3-generation studies conducted on mice by Schroeder and Mitchener (1971b), sodium
selenate (0.42 mg Se/kg/day in drinking water) had no adverse effects on reproduction, while sodium
selenite (0.42 mg Se/kg/day) adversely affected breeding in 50% of the treated pairs.
Nobunaga et al. (1979) studied the maternal and fetal toxicity of sodium selenite administered
in drinking water to female IVCS mice. Fourteen females received 11.4 nmol/mL (3 ppm; low dose)
and ten females received 22.8 nmol/mL (6 ppm; high dose) 30 days before mating and through day
18 of gestation. The length of the estrus cycle was changed in about 12% of mice receiving the low
dose. No significant effects were observed on the mean litter size or the numbers of implants,
resorptions, dead fetuses or gross malformations. The mean fetal weight was reduced by 7%
(p<0.01) at the high dose.
Hardin et al. (1987) dosed female CD-1 mice by gavage with sodium selenite dissolved in
water. Fifty females per group were given 0, 3.5, 5, 7 or 14 mg sodium selenite/kg/day on gestation
days 6-13 inclusive. No toxicity was observed in either dams or pups in the 3.5- to 7-mg/kg dose
groups. The 14-mg/kg dose caused 44% maternal mortality (compared with 0% in controls); 40%
reduction in maternal body weight gain; 40% reduction in the percentage of viable litters; decreased
mean birth weight and decreased mean 3-day postnatal weight gain.
Bergman et al. (1990) administered diets containing 0.15, 3.0 or 4.5 ppm of selenium (sodium
selenite) to female Sprague-Dawley rats for 8 weeks prior to mating, during mating and up to
gestation day 14. Sodium selenite did not induce toxic effects in either the dam or fetuses.
3.1.5. Reference Dose
3.1.5.1. Subchronic
ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1992c)
UNCERTAINTY FACTOR: 3
NOAEL: 0.015 mg/kg/day, humans (average body weight 55 kg).
3.1.5.2. Chronic
ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1992a)
UNCERTAINTY FACTOR: 3
NOAEL: 0.015 mg/kg/day, humans (average body weight 55 kg).
LOAEL: 0.023 mg/kg/day, humans.
CONFIDENCE:
Study: Medium
Data Base: High
RfD High
VERIFICATION DATE: 3/27/91
PRINCIPAL STUDIES: Yang et al., 1989a, 1989b
COMMENT: Based on an epidemiologic study of selenosis in humans (U.S. EPA, 1992a).
NOAEL calculated from regression analysis based upon correlation between dietary
selenium intake and blood selenium level related to clinical selenosis in adults (average
body weight 55 kg). The same chronic oral RfD of 0.005 mg/kg/day has been verified for
selenious acid (U.S. EPA, 1992b).
3.2. INHALATION EXPOSURES
Selenium compounds most likely to occur in air include elemental selenium and selenium
dioxide dusts and hydrogen selenide gas (ATSDR, 1989). Other volatile selenium compounds that
might be present are dimethyl selenide and dimethyl diselenide.
3.2.1. Acute Toxicity
3.2.1.1. Human
Inhalation of selenium or selenium compounds affects primarily the respiratory system. Dusts
of elemental selenium and selenium dioxide can cause irritation of the mucous membranes of the
nose and throat, coughing, nosebleed, loss of sense of smell, dyspnea, bronchial spasms, bronchitis
and chemical pneumonia (Clinton, 1947; Hamilton and Hardy, 1949). Concentrations of 0.007-0.05
mg Se/m3 produced tracheobronchitis in 9 of 62 exposed workers (Kinnigkeit, 1962). Hydrogen
selenide gas is also a respiratory tract irritant and acute exposures can lead to pulmonary edema,
severe bronchitis, and bronchial pneumonia (Buchan, 1947).
Other signs and symptoms following acute inhalation exposures to selenium compounds
include lacrimation, irritation and redness of the eyes, gastrointestinal distress (nausea and
vomiting), depressed blood pressure, elevated pulse rate, headaches, dizziness, and malaise
(ATSDR, 1989).
3.2.1.2. Animal
Exposure of rats for 8 hr to 30 mg Se/m3 (elemental selenium dust) resulted in severe
respiratory effects including edema, hemorrhage, and interstitial pneumonitis (Hall et al., 1951).
Diffuse bronchopneumonia and pneumonitis occurred in guinea pigs exposed to 7.8 mg Se/m3 for
4 hr (Dudley and Miller, 1937). The 4-hr LC50 was reported to be 9 mg/m3.
Splenic damage (congestion, fissuring red pulp, and increased polymorphonuclear leukocytes)
occurred in guinea pigs exposed to 31 Se mg/m3 (elemental selenium dust, 4 hr/day for 8 days); and
to the liver (mild congestion and mild central atrophy) in rats exposed to 30 mg Se (dust)/m3 for 8
hr (Hall et al., 1951).
3.2.2. Subchronic Toxicity
Information on the toxicity of selenium or selenium compounds in humans or animals
following subchronic inhalation exposures was not available.
3.2.3. Chronic Toxicity
3.2.3.1. Human
Diskin et al. (1979) reported a case study of a 71-year old man occupationally exposed to
selenium for 50 years who suffered from an acute myocardial infarction. A chest X-ray showed
bilateral basilar infiltrates indicative of congestive heart failure. Postmortem findings showed
evidence of generalized coronary atherosclerosis; severe passive congestion of the lungs, spleen, and
liver; and numerous perivascular noncaseating granulomas of the lung and some areas of fibrosis.
Abnormally high levels of selenium were found in the peribronchial nodes, lung, hair, and nails and
moderately high levels in the thyroid and kidney. The levels of selenium in the liver were within
the normal range.
3.2.3.2. Animal
Information on the toxicity of selenium or selenium compounds in animals following chronic
inhalation exposures was not available.
3.2.4. Developmental and Reproductive Toxicity
Information on the developmental and reproductive toxicity of selenium or selenium
compounds in humans or animals following inhalation exposures was not available.
3.2.5. Reference Concentration
3.2.5.1. Subchronic
A subchronic inhalation Reference Concentration for selenium and selenium compounds is
not available.
3.2.5.2 Chronic
A chronic inhalation Reference Concentration for selenium and selenium compounds is not
available.
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Dermal exposure to dusts of elemental selenium or selenium dioxide can result in skin rashes
and contact dermatitis (Clinton, 1947; Glover, 1967; Middleton, 1947; Pringle, 1942).
3.3.1.2. Animal
Information on the acute toxicity of selenium or selenium compounds in animals following
dermal exposure or other routes of exposure was not available.
3.3.2. Subchronic Toxicity
Information on the subchronic toxicity of selenium or selenium compounds in humans or
animals by dermal or other routes of exposures was not available.
3.3.3. Chronic Toxicity
Information on the chronic toxicity of selenium or selenium compounds in humans or animals
by dermal or other routes of exposures was not available.
3.3.4. Developmental and Reproductive Toxicity
3.3.4.1. Human
Information on the developmental and reproductive toxicity of selenium or selenium
compounds in humans by dermal or other routes of exposure was not available.
3.3.4.2. Animal
Subcutaneous or intravenous injection of selenium into pregnant mice or hamsters produced
no teratogenic effects even at dose levels lethal to the dam (Lee et al., 1979; Yonemoto et al., 1984;
Holmberg and Fern, 1969).
Significant testicular degeneration and atrophy was observed in male mice receiving daily
intraperitoneal injections of 0.035 mg Se/kg (as selenium dioxide) for 90 days (Chowdhury and
Venkatakrisna-Bhatt, 1983).
Ostadalova and Babicky (1980) reported a dose-related increase in eye cataracts in 10-day-old
rats receiving single subcutaneous doses of sodium selenate, DL-selenomethionine, or DL-selenocystine. Dimethyl selenide and trimethylselenonium chloride did not cause cataracts.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
3.4.1.1. Primary Target Organ(s)
1. Nervous system: Peripheral anesthesia, acroparesthesia, pain in the extremities,
hyperreflexia of the tendon, numbness, convulsions, paralysis, motor disturbances, and
hemiplegia in humans chronically exposed. Listlessness, lack of mental alertness,
irritability, chills and tremors following acute and subchronic exposures.
2. Skin and hair: Dermatitis, brittle nails, loss of hair and nails, mottled and eroded teeth
in humans chronically exposed.
3. Developmental and reproductive effects: Decreased rates of conception and increased
rates of fetal resorption in animals.
4. Liver: Severe cirrhosis and necrosis following chronic exposures in animals.
Abnormal liver function in humans following acute exposures.
3.4.1.2. Other Target Organ(s)
1. GI tract: Nausea, vomiting, abdominal pain in humans following acute exposures.
2. Immune system: Reduced humoral antibody (IgC) production and reduced
prostaglandin synthesis in animals following subchronic exposures.
3. Blood chemistry: Reduced hemoglobin levels in humans chronically exposed.
3.4.2. Inhalation Exposures
3.4.2.1. Primary Target Organ(s) (chronic exposure data not available)
1. Respiratory tract: Irritation, dyspnea, bronchial spasms, bronchitis and chemical
pneumonia in humans and animals following acute exposures.
2. GI tract: Gastrointestinal distress (nausea and vomiting) in humans following acute
exposures.
3. CNS: Headaches, dizziness, and malaise in humans following acute exposures.
3.4.2.2. Other Target Organ(s)
1. Liver: Mild congestion and mild central atrophy in animals following acute exposures;
severe cirrhosis and necrosis following chronic exposures.
2. Spleen: Congestion, fissuring red pulp, and increased polymorphonuclear leukocytes
in animals following acute exposures. No chronic exposure data.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
Epidemiologic studies in humans have failed to show a positive association between selenium
exposure and an increased incidence of death due to neoplasms. The preponderance of data
indicates that selenium has anti-neoplastic effects (see Whanger, 1983; Hocman, 1988). Several
epidemiologic studies have revealed negative correlations between selenium intake [based on direct
or indirect data on consumption (i.e., soil or plant concentration)] or selenium blood levels (based
on direct clinical measurement) and cancer incidence or mortality rates (Shamberger and Willis,
1971; Shamberger et al., 1976; Stampfer et al., 1987; Shamberger et al., 1973; Broghamer et al.,
1976; Willett et al., 1983). The anti-neoplastic activity of selenium is thought to be due to one or
more mechanisms including: (1) activation of glutathione peroxidase, a enzyme that protects cells
against oxidative damage caused by superoxide and hydroxide radicals; (2) interference with
enzymes that convert carcinogens to active metabolites; (3) enhancement of immunological
responses; (4) inhibition of the interaction of carcinogens with DNA; (5) reductions in body weight;
and (6) inhibition of cell proliferation (Hocman, 1988).
4.1.2. Animal
Studies on laboratory animals have not demonstrated a correlation between exposure to
selenites or selenates and increased tumor incidence. Although Schroeder and Mitchener (1971a)
reported a high incidence rate for tumors (62.5% vs 30.8% in controls) and malignant tumors (41.7%
vs. 16.9% in controls) in rats dosed with up to 0.42 mg Se/kg/day (as sodium selenite and sodium
selenate in drinking water for a lifetime), according to ATSDR (1989), the study was flawed because
the treated rats lived longer than the controls. By adjusting the data for differences in life span, no
significant differences in tumor incidence rates were measurable (ATSDR, 1989).
Volgarev and Tscherkes (1967) reported tumor incidence rates of 43% (10/23) and 26% (5/19)
in male rats exposed for 25 months to dietary equivalents of 0.22 mg Se/kg/day and 0.43 mg
Se/kg/day, respectively; however, no controls were used in these tests and in a third experiment no
increase in tumor incidence was observed in 100 animals maintained for 25 months on a diet
containing the equivalent of 0.22 mg Se/kg/day.
Harr et al. (1967) evaluated the development of histopathologic lesions in Wistar rats
maintained for their entire lifetime (32 months) on diets containing 0, 0.5, 2.0, 8.0 or 16.0 ppm Se
(as sodium selenite). No neoplastic lesions could be attributed to the exposure to selenium.
Schroeder and Mitchener (1972) conducted a long-term study in which Charles River CD mice
were given drinking water containing 3 ppm Se (as sodium selenite). The incidence of malignant
tumors in treated mice (15%) was not significantly different from that in the controls (8%).
Jacobs and Forst (1981a) conducted a 2-year study in which Sprague-Dawley rats were given
drinking water containing 4 ppm Se (as sodium selenite). No neoplastic lesions were reported.
Although selenite and selenate compounds have not been found to be carcinogenic in
laboratory animals, one study has demonstrated that selenium sulfide when administered orally to
rats and mice can result in significant increases in the incidence of hepatocellular carcinomas (male
and female rats and female mice) and alveolar/bronchiolar carcinomas and adenomas (female mice
only) (NCI, 1980a; U.S. EPA, 1992d). A mixture of selenium monosulfide and selenium disulfide
(in 0.5% aqueous carboxymethyl cellulose) was administered by gavage at 3 and 15 mg/kg/day to
F344 rats (50/sex/group) and at 20 or 100 mg/kg/day to B6C3F1 mice, 7 days/week for 103 weeks.
The incidence of hepatocellular carcinomas was 0/50, 0/50 and 14/49 in control, low-dose and high-dose male rats; 0/50, 0/50 and 21/50 in control, low-dose, and high-dose female rats; and 0/49, 1/50
and 22/49 in control, low-dose and high-dose female mice. The incidence of alveolar/bronchiolar
carcinomas and adenomas was 2/50, 0/49, 3/50, and 12/49 in the untreated controls, vehicle controls,
low-dose and high-dose female mice.
4.2. INHALATION EXPOSURES
Pertinent data regarding the potential carcinogenicity of selenium by the inhalation route were
not located in the available literature. There are no epidemiological data to support a causal
association between inhalation exposures and induction of cancer in humans, and no long-term
animal studies have been conducted.
4.3. OTHER ROUTES OF EXPOSURE
Information on the carcinogenicity of selenium, selenite or selenate compounds in humans or
animals by other routes of exposure was not available. The potential carcinogenicity of selenium
sulfide by the dermal route has been evaluated in ICR Swiss mice (NCI, 1980b and 1980c). In one
study a suspension of selenium sulfide in 0.5% aqueous carboxymethyl cellulose was applied to the
clipped backs of the test animals at 0, 0.5 or 1.0 mg/animal three times per week for 86 weeks (NCI,
1980b). The incidence of alveolar/bronchiolar carcinomas and adenomas (16%) in the high-dose
females was significantly greater than the vehicle controls (4%), but lower than the untreated
controls (18%). The incidence of total hemangiomas or hemangiosarcomas was significantly
elevated in female mice (1/50, 0/50, 1/50 and 4/50 for untreated, vehicle control, low-dose and high-dose groups). In a second study, ICR Swiss mice were treated with selenium sulfide-based Selsun
shampoo (0.5 mL of 25% or 50% in distilled water) using the same protocol described above. The
incidence of alveolar/bronchiolar carcinomas and adenomas was 1/49, 7/50, and 9/48 in the vehicle
controls, low- and high-dose groups. Tumors of this type are common in aged Swiss mice and
therefore a causal association with exposure to selenium sulfide could not be clearly established
(U.S. EPA, 1992d).
4.4. EPA WEIGHT-OF-EVIDENCE
Selenium and selenious acid
Classification -- D; not classifiable as to human carcinogenicity (U.S. EPA, 1992a, 1992b)
Basis -- Inadequate human data and inadequate evidence of carcinogenicity in animals.
Selenium sulfide
Classification -- B2, probable human carcinogen (U.S. EPA, 1992d)
Basis -- Based on inadequate human data and sufficient evidence of carcinogenicity in
animals.
4.5. CARCINOGENICITY SLOPE FACTORS
The calculation of slope factors for elemental selenium, selenites, and selenates is not possible
due to the lack of evidence of carcinogenicity. The calculation of a slope factor for selenium sulfide
is not possible because of lack of suitable quantitative data (U.S. EPA, 1992d).
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