100: Selenium

Selenium was discovered by Jöns Berzelius in 1817 as a contaminant in sulfuric acid vats that caused illness in Swedish factory workers. He originally believed it to be the element tellurium (from the Latin tellus, meaning “earth”); however, on finding it to be an entirely new, yet similar, element, he named it from the Greek selene, meaning “moon.” Selenium has unusual light-sensitive electrical conductive properties, leading to its widespread use in industry. The long-term health benefits and risks of selenium are the subject of much recent investigation. It is both an essential component of the human diet and a poison.

In the 1970s, the role of selenium as an essential cofactor of the enzyme glutathione peroxidase was discovered. Keshan disease, an endemic cardiomyopathy, was described in 1979 in Chinese women and children who chronically consumed a selenium-poor diet.¹¹ Kashin-Beck disease, a disease causing shortened stature from chondrocyte necrosis, is described in young children in Russia, China, and Korea; although other etiologies are also likely responsible, partial improvement results from selenium supplementation.^3,18 Selenium is currently being investigated for the prevention and treatment of a myriad of conditions, including autoimmune thyroiditis, cancer, Alzheimer disease, depression, and tropical leishmaniasis.³⁸­However, it is becoming more evident that “the moon” has two faces, as reports emerge that selenium supplementation may increase the risk of diabetes, amyotrophic lateral sclerosis, and some forms of malignancy.^20,46

The recommended daily allowance (RDA) in the United States of selenium for adults was established in 1980 at 55 μg/d. This was determined based on the degree of supplementation required to achieve optimal glutathione peroxidase activity in selenium-deficient study populations, and the amounts required to cause overt toxicity. Deficiency occurs when daily intake falls below 20 μg/d.¹¹

Chronic selenium toxicity, or selenosis, was first described in animals. It manifested as the acute syndrome of “blind staggers,” and the more chronic “alkali disease” affected livestock eating plants grown in highly seleniferous soil. Findings included blindness, walking in circles, anorexia, weight loss, ataxia, and dystrophic hooves. Humans in seleniferous areas of China and Venezuela develop similar integumentary symptoms (dermatitis, hair loss, and nail changes) at an intake of approximately 6000 μg/d.^5,41 In recent years, there have been several outbreaks of chronic selenium toxicity related to improperly formulated dietary supplements.^7,14,47

Selenium is widely distributed throughout the Earth’s crust, usually substituting for sulfur in sulfide ores such as marcasite (FeS₂), arsenopyrite (FeAsS), and chalcopyrite (CuFeS₂). It is found in the soil where it has leeched from bedrock, in groundwater, and in volcanic gas. The highest soil concentrations of selenium in the United States are in the Midwest and the West, specifically areas of the Dakotas, Wyoming, Nebraska, Kansas, Utah, Colorado, Arizona, and New Mexico.³ Dietary selenium is easily obtained through meats, grains, and cereals. Brazil nuts, grown in the foothills of the highly seleniferous Andes Mountains, contain the highest concentration measured in food, but chronic selenium toxicity from Brazil nuts has not been reported.^3,22

In industry, selenium is generated primarily as a byproduct of electrolytic copper refining and in the combustion of rubber, paper, municipal waste, and fossil fuels. Selenium compounds are used in glass manufacture and coloring, photography, xerography, rubber vulcanization, and as insecticides and fungicides. Selenium sulfide is the active ingredient in many antidandruff shampoos. Gun bluing solution, used in the care of firearms to restore the natural color to the gun barrel, is composed of selenious acid in combination with cupric sulfate in hydrochloric acid, nitric acid, copper nitrate, or methanol. Tables 100–1 and 100–2 list features and regulatory standards of common selenium compounds.

Selenium is a nonmetal element of group VIA of the periodic table along with oxygen, sulfur, tellurium, and polonium. Selenium exists in elemental, organic, and inorganic forms, with four important oxidation states: selenide (Se^2–), elemental (Se⁰), selenite (Se⁺⁴), and selenate (Se⁺⁶). Water solubility generally increases with oxidation state. Selenium behaves similarly to sulfur in its tendency to form compounds and in biologic systems³ and is both photovoltaic (able to convert light to electricity) and photoconductive (conducts electricity faster in bright light), which has led to its use in photography, xerography, and solar cells.

At least three solid allotropes of elemental selenium are described, including “grey selenium,” which predominates at room temperature, red crystalline selenium, and a red amorphous powder.³ In general, toxicity from elemental selenium is rare and only occurs from long-term exposure. Hydrogen selenide (H₂Se) is formed from the reaction of water or acids with metal selenides or from the reaction of hydrogen with soluble selenium compounds; at room temperature, it exists in gaseous form and results in industrial inhalation exposures. The organic alkyl selenides (dimethylselenide, trimethylselenide) are the least toxic and are byproducts of endogenous selenium detoxification (methylation). Inorganic salts and acids are responsible for all cases of acute toxicity. Selenious acid (H₂SeO₃), generated from the reaction of selenium dioxide with water, is the most toxic form of selenium; ingestion of selenious acid is often fatal.

Selenium exists in one of three forms in the body. First, selenoproteins contain selenocysteine residues and play specific selenium-dependent roles primarily in oxidation–reduction reactions. Second, nonspecific plasma proteins bind and may aid in transport of selenium; they may directly bind selenium (albumin, globulins) or contain it as selenocysteine or selenomethionine in place of cysteine and methionine, respectively. Third, there are several inorganic forms of selenium in transit throughout the body, such as selenate, alkyl selenides, and elemental selenium (Se°).

There are at least 25 selenoproteins—which include glutathione peroxidases, iodothyronine 5-deiodinases, and thioredoxin reductase—each of which contain a selenocysteine or selenomethionine residue at the active site.³⁸ The most studied of these is glutathione peroxidase I, which is responsible for detoxification of reactive oxygen species. Using reduced glutathione (GSH) as a substrate, glutathione peroxidase catalyses the reduction of hydrogen peroxide to water and oxidized glutathione (GSSG, or glutathione disulfide); the reaction occurs by concomitant oxidation of the selenocysteine unit on the enzyme.^4,37 Other selenocysteine-containing proteins, such as thioredoxin reductase, have antioxidant properties. The selenocysteine-containing thyroid hormone deiodinases are responsible for the conversion of thyroxine (T₄) to the active triiodothyronine (T₃) form (Chap. 56).

In selenium deficiency, glutathione peroxidase activity is decreased, and GSH and glutathione S-transferases are increased.³⁷ Consequently, selenium-deficient rats are more resistant to substances detoxified by ­glutathione S-transferase, such as acetaminophen and aflatoxin B,⁶ and less resistant to other prooxidants, such as nitrofurantoin, diquat, and paraquat.⁶ In animal studies of metal toxicity, selenium also appears to modify the effects of silver, cadmium, arsenic, copper, zinc, mercury, and fluoride; conversely, vanadium, tellurium, and arsenic modify the effects of selenium deficiency or excess.^16,19,33,41 Although it is proposed that this is accomplished through the formation of insoluble selenium–metal complexes, these relationships are not entirely understood.¹³

Less is known about the biochemical mechanism of selenium toxicity, and what is known is generally from in vitro data. Paradoxically, excess selenium causes oxidative stress, presumably as a result of prooxidant selenide (R-Se^–) anions. In addition, the replacement of selenium for sulfur in enzymes of cellular respiration may cause mitochondrial disruption, and the substitution of selenomethionine in place of methionine may interfere with protein synthesis. Integumentary effects are also most likely a result of selenium interpolation into disulfide bridges of structural proteins such as keratin.⁴⁵

Gastrointestinal (GI) absorption varies with the type of selenium, and human data are limited. Elemental selenium is the least bioavailable (≤ 50%), followed by inorganic selenite and selenate salts (75%)²⁸; selenious acid is well absorbed from the lungs and GI tract (~ 85% in animal studies⁹). Organic selenium compounds are the best absorbed (~ 90%) as determined by isotope tracers in human studies.^3,24 A breastfed infant developed selenosis exclusively from maternal overexposure, suggesting transmission through breastmilk.⁴⁸

Inhalational absorption was reported in a group of workers exposed to selenium dioxide and hydrogen selenide gas,^3,15 but quantitative inhalation studies in humans are not available. Dermal absorption is limited. Selenium disulfide shampoos are not systemically absorbed as measured by urinary selenium concentrations⁹ except in cases of repeated use on excoriated skin.³⁶

The toxic dose of selenium varies widely between selenium compounds, as demonstrated by LD₅₀ (median lethal dose for test subjects: 50%) animal studies,⁴¹ making milligram per kilogram exposure estimates difficult to interpret. Elemental selenium has no reported adverse effects in acute overdose, although long-term overexposure is harmful. The selenium salts, particularly selenite, are more acutely toxic, as is selenium oxide (SeO₂) through its conversion to selenious acid in the presence of water. Selenious acid may be lethal in children following ingestion of as little as a tablespoon of 4% solution in children.

Metabolic conversion of all forms of selenium to the selenide anion occurs through various means (Fig. 100–1), after which the selenide ion undergoes one of three fates: (1) incorporation into selenoproteins such as glutathione peroxidase and triiodothyronine, (2) binding by nonspecific plasma proteins such as albumin or globulins, or (3) hepatic methylation into nontoxic, excretable metabolites. Trimethylselenide is the primary metabolite and is excreted by the kidneys, the major elimination pathway for selenium. Fecal elimination also occurs. Dimethylselenide production is usually minor but increases with exposure; this compound is volatilized through exhalation and sweat and is responsible for the garlic odor of patients exposed to excess selenium. The remaining selenium in the body is greater than 95% protein bound within 24 hours.^1,41 Toxicokinetic data are limited and vary by compound.

Acute

Dermal and Ophthalmic Exposure.

Dermal exposure to selenious acid or to selenium dioxide (which is converted to selenious acid) and to selenium oxychloride (a vesicant hydrolyzed to hydrochloric acid) causes painful caustic burns.¹² Excruciating pain may result from accumulation under fingernails. Corneal injury with severe pain, lacrimation, and conjunctival edema is reported after exposure to selenium dioxide sprayed unintentionally into the face.²⁹ In chronic exposures, “rose eye,” a red discoloration of eyelids with palpebral conjunctivitis, is also described.

Inhalational Exposure.

When inhaled, all selenium compounds have the potential to be respiratory irritants, although inhaled elemental selenium dusts are less injurious than those compounds that can be converted to selenious acid. Toxicity from hydrogen selenide inhalation is reported throughout the industrial literature.⁸ Hydrogen selenide is oxidized to elemental selenium, so acute toxic exposures are limited to confined spaces where the hazardous gas may accumulate; however, similar to hydrogen sulfide (H₂S), its ability to cause olfactory fatigue, rendering the exposed persons anosmic to the toxic fumes, may pose significant hazard (Chap. 26).⁸ Acute exposure to high concentrations of hydrogen selenide gas produces respiratory and mucosal irritation which may persist for years as residual restrictive and obstructive disease.³⁹

By contrast, selenium dioxide and selenium oxide fumes cause more injury through conversion to selenious acid in the presence of water in the respiratory tract. Twenty-eight workers in a selenium rectifier plant who were inadvertently exposed to smoke and high concentrations of selenium oxide in an enclosed area developed upper respiratory irritation, bronchospasm, and transient hemodynamic instability.⁴⁹ Some developed chemical pneumonitis, fever, chills, headache, vomiting, and diarrhea. Five patients required hospitalization for respiratory support, with fever, leukocytosis, and bilateral infiltrates. All patients recovered without sequelae.

Selenium hexafluoride is a caustic gas used in industrial settings as an electrical insulator. Its caustic properties are derived from its conversion to elemental selenium and hydrofluoric acid in the presence of water. Severe pain and burning of the eyes, skin, and respiratory tract similar to that seen with hydrofluoric acid exposure can occur after inhalation of selenium hexafluoride (Chap. 107).

Oral Exposure.

Acute fulminant selenium toxicity occurs after ingestion of inorganic selenium compounds, the most toxic of which is selenious acid in the form of gun bluing solution. Similar toxicity may result from selenium oxide and dioxide, which are converted to selenious acid as well as sodium selenite and selenate. The underlying mechanism for this often fatal syndrome is not well understood but may stem from a multifocal disruption of cellular oxidative processes and antioxidant defense mechanisms. Elemental selenium and organic selenium compounds do not cause acute toxicity.

Some authors have proposed a “triphasic” course of acute inorganic selenium toxicity, with GI, myopathic, and circulatory symptoms as the toxic effects progress.⁴⁴ In reality, acute inorganic selenium poisoning is often rapid and fulminant, with onset of symptoms within minutes and, in some cases, death within one hour of ingestion. GI symptoms are the most commonly described and the first to occur and include abdominal pain, diarrhea, nausea, and vomiting. This may be partly caused by caus­tic esophageal and gastric burns but does not occur in all cases. Patients may have a garlic odor. The myopathic phase is characterized by weak­ness, hyporeflexia, myoclonus, fasciculations, and elevated creatine phosphokinase concentrations with normal myocardial band (MB) fraction. Acute kidney injury is also reported and presumably results from myoglobinuria and hemolysis. More severely poisoned patients may exhibit lethargy, delirium, and coma.

Circulatory failure is the hallmark of serious inorganic selenium toxicity. Patients present with dyspnea, chest pain, tachycardia, and hypotension. Initial electrocardiography (ECG) may demonstrate ST elevation, a prolonged QT interval, and T-wave inversions. Refractory hypotension occurs as a combined product of decreased contractility from toxic cardiomyopathy and decreased peripheral vascular resistance. Pulmonary edema, ventricular dysrhythmias, myocardial and mesenteric infarction, and metabolic acidosis all contribute to poor outcome in these patients.^30,34,49 Death results from circulatory collapse in the setting of pump failure, hypotension, and ventricular dysrhythmias, often within 4 hours of ingestion.^17,21,35,43 Other less frequent abnormalities include hypokalemia, hyperkalemia, coagulopathy, leukocytosis, hemolysis, thrombocytopenia, and metabolic acidosis with elevated lactate.^40,44

Chronic

Chronic elemental selenium toxicity, or selenosis, has received recent attention because of reports of improperly formulated selenium-containing dietary supplements. In 2008, at least 200 people developed painful skin lesions, diarrhea, alopecia, fever, fatigue, memory loss, and nail deformities after use of the errant supplement.^2,27,47 The manufacturer voluntarily recalled the product, and a US Food and Drug Administration investigation revealed that the liquid supplement contained approximately 200 times the concentration stated on the packaging.¹⁰ The patients consumed approximately 40,000 μg/d while taking the supplement, or 1000 times the US RDA.² A similar outbreak occurred from a super-potent supplement in 1983, affecting at least 13 patients, all of whom recovered after discontinuation of the supplement.^7,14

Selenosis is similar to arsenic toxicity, with the most consistent manifestations being nail and hair abnormalities. As with arsenic toxicity, nail or hair findings alone are unlikely to be the sole evidence of selenosis, but their absence makes the diagnosis unlikely. The hair becomes very brittle, breaking off easily at the scalp, with regrowth of discolored hair and the development of an exfoliative pruritic scalp eruption with acneiform papules.²⁶ The nails also break easily, with white or red ridges that can be either transverse or longitudinal; the thumb is usually involved first, and paronychia and nail loss may develop.^26,32 The skin becomes erythematous, swollen, and blistered, as well as slow to heal and has a persistent red discoloration. Increased dental caries may occur.²⁶ Neurologic manifestations include hyperreflexia, peripheral paresthesia, anesthesia, and hemiplegia. Although cardiotoxicity is described with both selenium deficiency and acute poisoning, no such cases are reported with human selenosis. Aside from one case described in endemically exposed patients in China⁵⁰ in which there were insufficient postmortem data, there have been no reported deaths from intermediate or chronic exposure.

Selenosis is implicated in a number of long-term environmental ­exposures. Many descriptions come from inhabitants of the Hubei province of China from 1961 to 1964, the majority of whom developed clinical signs after an estimated average consumption of 5000 μg/d of selenium (but as little as 910 μg/d) derived from local crops and vegetation.⁵⁰ Inhabitants of a seleniferous area of Venezuela, consuming approximately 300 to 400 μg/d of selenium, also develop symptoms of selenium excess; however, the low socioeconomic and poor dietary status of the subjects may also contribute to their symptoms. By contrast, US residents in a seleniferous area with a high selenium intake (724 μg/d) over 2 years who were compared with a control population and monitored for symptoms and laboratory abnormalities remained asymptomatic, with only a clinically insignificant elevation of hepatic aminotransferases in the high-selenium group.^22,25 Average selenium concentrations were serum, 0.215 mg/L; whole blood, 0.322 mg/L; and urine, 0.17 mg/L. A similar cohort with comparable blood concentrations was also reported in the Brazilian Amazon.²²

Selenosis is also reported in the industrial setting. Copper refinery workers develop garlic odor and GI and respiratory symptoms coincident with exposure to selenium dust and fumes.¹⁵ Long before workplace biologic monitoring took place, intense garlic odor of the breath and secretions was recognized as a reason to remove a worker from selenium exposure until the odor subsided. Neuropsychiatric findings such as fatigue, irritability, and depression are reported throughout the industrial literature and are difficult to quantify. Early reports describe the selenium factory worker who “could not stand his children about him” at the end of the day.¹²

Although carcinogenicity is suggested by a number of animal studies, in humans, the data available suggest, if anything, an inverse correlation between selenium intake and cancer risk. The International Agency for Research on Cancer does not list selenium as a known or suspected carcinogen.³ Animal studies also suggest that selenium has embryotoxic and teratogenic properties.¹³ A recent large randomized controlled trial of selenium supplementation reported an increased risk of diabetes mellitus with the ingestion of 200 μg/d of elemental selenium-fed baker’s yeast compared with placebo.^20,46

Over time, selenium is incorporated into blood and erythrocyte proteins, making serum the best measure of acute toxicity and whole blood preferable for the assessment of patients with chronic exposure. Patients with acute poisoning generally have an initial serum concentration greater than 2 mg/L, which falls below 1 mg/L within 24 hours, reflecting redistribution.³² Patients with long-term elemental exposures are reported to have serum concentrations of 0.5 to 1.0 mg/L. However, there is no predictable relationship between selenium concentrations and exposure, toxicity, or time course. Population-based studies suggest an average serum concentration of 0.126 mg/L in the United States.³¹

Urine concentrations reflect very recent exposure because urinary excretion of selenium is maximal within the first 4 hours. In addition, urine concentrations are an imperfect measure because they can be affected by the most recent meal and hydration status. However, in general, a normal urinary concentration is less than 0.03 mg/L. Freezing of urine specimens after collection is recommended to retard the enzymatic formation of difficult-to-detect volatile metabolites.³²

Hair concentrations of selenium were measured in the Hubei Chinese populations of interest and during the contaminated supplement outbreak in 2008 and may be a useful qualitative measure of chronic exposure.^26,42,50 However, the usefulness of hair selenium is limited in countries such as the United States where the use of selenium sulfide shampoos is widespread.

Other ancillary tests to assess selenium toxicity include ECG, thyroid function, platelet counts, hepatic aminotransferases, creatinine, and serum creatine phosphokinase concentrations. These are abnormal in some patients (eg, patients with selenious acid poisoning) and are not indicated in patients not expected to develop systemic toxicity.

Pain

Aside from standard pain management strategies, a number of topical remedies for selenium burns have been suggested historically with little evidence supporting their use. For example, a 10% sodium thiosulfate solution or ointment to reduce selenium dioxide to elemental selenium is mentioned as a potential therapy for painful skin, nail bed, or ocular burns.¹² In one series, workers exposed to selenium dioxide fumes reported similar relief from inhalation of vapor from ammonium hydroxide–soaked sponges; the mechanism of this is unclear, and further study is required before this practice can be recommended.⁴⁹

Workers exposed to selenium hexafluoride gas may be treated with calcium gluconate gel to the affected areas. This is the same treatment as in hydrofluoric acid exposures, which is discussed in Chap. 107.

Decontamination

As with any toxic exposure, prompt removal from the source is required if possible. Patients with dermal exposure should have their skin irrigated immediately. There are limited data to support the use of aggressive GI decontamination after the ingestion of most elemental selenium–­containing xenobiotics because little expected acute toxicity is present. However, in xenobiotics with the potential for producing systemic toxicity, such as the selenite salts, decontamination with gastric lavage or activated charcoal may be warranted. Although no activated charcoal adsorption data are available to guide this therapy, it should be considered in light of potential benefit until further information is available.

Special mention should be made of the ingestion of selenious acid. Given its toxicity, the judicious use of small nasogastric lavage may be indicated based on the time since ingestion, the amount and concentration ingested, the presence or absence of spontaneous emesis, the likelihood of caustic esophageal injury, and the clinical condition of the patient.

Chelation and Antidotal Therapy

There are no proven antidotes for selenium toxicity. Animal studies and scant human data suggest that chelation with dimercaprol (BAL),²⁴ edetate calcium disodium (CaNa₂EDTA), or succimer is not advised due to the formation of nephrotoxic complexes with selenium, do not speed clinical recovery and may, in fact, worsen toxicity.^23,24 Arsenical compounds appear to ameliorate selenium toxicity through enhanced biliary excretion,^8,13,15,23 but there are no studies to guide this inherently toxic therapy. Vitamin C is hypothesized to limit oxidative damage but has not been studied. Bromobenzene may accelerate urinary excretion of selenium,⁸ but its inherent toxicity limits its use, regardless of efficacy.

Extracorporeal removal techniques such as hemodialysis or hemofiltration decrease selenium concentrations in patients undergoing the procedure regularly for chronic kidney disease, so theoretically, this could be of use in lowering toxic serum selenium concentrations. However, because of extensive protein binding, this benefit may be only minor and only relevant to patients undergoing frequent dialysis. Although there are reports of using hemodialysis in patients with acute selenium poisoning, further study must occur before this can be recommended.^19,21

Supportive Care

This is the mainstay of therapy in selenium poisoning. In particular, patients with selenious acid toxicity require intensive monitoring and multisystem support to survive.

• Selenium is an essential trace element and is required in the diet of both animals and humans.

• Ingestion of selenious acid is often fatal.

• Other selenium compounds cause variable toxicity, usually following setting of occupational exposure. Topical and inhalational exposure causes burns and pulmonary irritation, respectively. Acute systemic exposure results in gastrointestinal, myopathic, and circulatory signs and symptoms.

• Long-term exposure to elemental selenium may cause selenosis, of which alopecia is the most consistent finding.

• Although it is possible to obtain blood, urine, and hair selenium concentrations to confirm exposure, no clear relationship exists between concentration and clinical outcome.

• Supportive therapy remains the standard of care.

References