Selenium (Se)

March 11, 2019 John Bumpus

Over 200 years ago, Jöns Jacob Berzelius discovered the element selenium, which he named after the goddess of the moon, Selene. Aside from its industrial applications, selenium is an essential trace nutrient. A deficiency in selenium is a severe obstacle in areas of the world where the soil contains little selenium such as the case in the United Kingdom, Australia, New Zealand (source) and some areas of China (source) among others. It has been estimated that over 1 billion people have a low selenium status.

Supplementing doses above the RDA (40 to 70 μg) is required to inhibit genetic damage and cancer (>100 μg). The most recent revision of the RDA for selenium is based on the estimated average requirement (EAR) required to maximise the antioxidant enzyme glutathione peroxidase (GPx) activity in plasma (source) and not necessarily for selenium’s anticarcinogenic effects. Excessive doses of selenium may cause oxidative damage leading to genomic instability which raises the question, how much is enough? In this article, I try and find clarity regarding this question and bring transparency to selenium and its supplementation.

Americans have been advised that supplementation is not needed on the basis of the EAR and their serum concentrations being met according to the National Health and Nutrition Examination Survey (NHANES III) (source). However, selenium intake is on the decline in many areas of the world due to the effect of sulphur-based fertilisers on crops such as wheat (source).

Worldwide, up to one in seven people have been estimated to have low dietary selenium intake. Using moderate climate change projections, it has been predicted that future soil selenium losses from 58% (between the year 2080–2099). Predicted losses from croplands were even higher, with 66% of farmlands predicted to lose 8.7% selenium. These losses could increase the worldwide prevalence of selenium deficiency (source).

Selenium has a protective effect against some forms of cancer and may enhance male fertility, decrease cardiovascular disease mortality, and regulate inflammatory mediators in asthma (source). It has also been proposed that optimal selenium levels may potentially be useful for reducing the risk of atherosclerosis, cataracts, emphysema, inflammatory-immune disease, senile dementia, aging, and rheumatoid arthritis.

Selenium prevents cellular and sub-cellular lipids and fats from being peroxidised, which means it prevents body fats from going rancid (seen externally as “age spots” or “liver spots” called ceroid lipofuscin). Iron chelators such as desferrioxamine and antioxidants such as vitamin E, glutathione, and selenium may slow lipofuscin accumulation (source). An exclusive and indispensable role of selenium noted in that it is required to prevent hydroperoxide-induced ferroptosis, preventing fatal epileptic seizures and protecting the brain (source). A sub-clinical selenium deficiency seems to be associated with reduced immunocompetence, depression, thyroid imbalances and reproduction difficulties in both sexes.

Mechanism of action:

Selenium is essential for the amino acid Selenocysteine, the 21st essential amino acid (source). Selenium exerts various biological functions which are found in at least 25 selenoproteins. Selenoproteins are involved in diverse roles such as stabilising the integrity of the sperm flagella and are essential for thyroid hormone metabolism aiding conversion of thyroxine (T4) to the active thyroid hormone, 3,3′5-triiodothyronine (T3). Selenium is a vital component of several significant metabolic pathways such as protection from neurodegeneration, maintaining lens cell viability, and reducing oxidative damage during aging. (source, source).

Selenium is a significant contribution to the anti-oxidant system. As a component of glutathione peroxidase, selenium acts as an antioxidant and has a sparing effect on vitamin E. Glutathione peroxidase blocks the generation of free radicals that destroy polyunsaturated fatty acids in cell membranes. Cellular and plasma glutathione peroxidase is the functional parameter used for the assessment of selenium status in the body, though hair and nails are also valuable and accurate. Selenium enhances the enzyme required for the detoxification of xenobiotic chemicals in the liver, glucuronyl transferase, and is involved in the regulation of prostaglandin synthesis and the degradation of intracellular peroxides.

Selenium is believed to encourage the immune system (source) and has been postulated to reduce the risk of cancer by a variety of mechanisms (source, source). Though, the potential benefits of selenium supplementation in tumour patients are undeniable (source). By enhancing the stability of the genome inhibiting carcinogen-induced covalent DNA adduct formation, selenium may also reduce the risk of cancer, retard oxidative damage to DNA, lipids, and proteins, retarding angiogenesis, and modulating cellular events critical in cell growth inhibition. Laboratory studies that have demonstrated oxidative stress induced by sodium selenite at high concentrations in both acute and chronic treatments of prostate cancer cells have proposed different mechanisms were involved (source). After acute exposure to selenite, cells presented mitochondrial injury and cell death, mainly by apoptosis while chronic exposure of selenium exerted its effects on human prostate cancer cells by altering the intracellular redox state, subsequently blocking the cell cycle.

Food Sources:

The selenium content of foods is mostly dependent on soil levels. It can generally be found in brewers yeast, whole grains, meat, kelp, seaweed, fish and other seafood (e.g. tuna, oysters, herring), brazil nuts, garlic, milk, eggs, and kidneys that are grown or raised on selenium-rich soil.

Dose:

The RDA for selenium is 55 μg for healthy adult males and 55 to 75 μg for healthy females. The RDA for children starts at 15 μg and increases to 40 μg by the age of 9 years. The therapeutic dose range is 200 to 800 μg/day and does not lead to toxicity (source). Selenium has a narrow safety margin, with clinical toxicity reported on daily doses of 1000 to 2000 μg over a month. The dose for long-term use is believed to range between 100 to 400 μg. Extrapolation from animal experiments suggests that 400 to 700 μg/day may be needed for cancer protection. Since 400 μg daily is probably the upper limit of safety, daily doses of 100 to 200 μg may be more realistic and safe objectives for inhibiting genetic damage and carcinogenesis in humans(source, source). Such recommendations are contrary to the traditional nutritional essentiality paradigm; however, as such advice is consistent with a better health outcome, perhaps it is time that the paradigm is reviewed (source, source).

One of the safest selenium supplements is selenium organically bound to yeast. Yeast-based selenium is approximately 40% selenomethionine, 20% other amino acid conjugates (e.g., selenocysteine, methylselenocysteine), and 40% unidentified selenopeptides (source). Doses of 500 to 1000 μg have been observed to be well tolerated. Another safe form of organic selenium is selenomethionine at doses of 200mcg (source). Selenomethionine appears more effective at increasing selenium status; while selenite and selenate are more bioavailable than selenomethionine. In one animal study, co-administration of vitamin C suppressed the chemopreventive effect of inorganic selenium (selenite), but not those of selenomethionine.

Animal studies have established that the dose and form of selenium compounds are critical factors regarding circumscribing cellular responses, inorganic selenium at doses up to 10 μmol, and organic selenium compounds at doses equal to or greater than 10 μmol achieve distinctly different cellular responses (source). Animal studies using multiple different tumorigenesis models have mainly found that selenium has notable chemopreventive activity.

Clinical Uses:

Biochemical changes produced by selenium deficiency predisposes people who experience additional stresses to develop certain illnesses (source). Insufficient selenium intake has been estimated to affect up to 1 billion people worldwide (source). Selenium has cancer-protective effects (source, source, source, source). In a placebo-controlled human trial, supplementation of 200 μg selenium from 0.5 g brewer’s yeast has been determined to decrease the incidence of several types of cancers (source). This prospective study found that a daily supplement of 200 μg selenium over an average of 4.5 years revealed no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin. However, the selenium-treated group did have substantial reductions in the incidence of prostate cancer and total cancer incidence and mortality(source). This dose is three or four times the RDA.

Nevertheless, such findings are supported by epidemiologic studies, which have shown that low selenium status is associated with an increased total cancer incidence, particularly of gastrointestinal, prostate, and lung cancers (source). Surely, epidemiologic, laboratory and serendipitous results of two randomised clinical trials suggest that men with high selenium and vitamin E intake have a lower risk of prostate cancer (source). Also, a case-control study has also found that low plasma selenium is associated with a four-to-five-fold increased risk of prostate cancer (source).
It should be noted that the reduced levels of prostate-specific antigen (PSA), a commonly used marker for prostate cancer, observed with selenium supplementation are expected due to the effect of selenium on cancer cells and not because of selenium interfering with the production of PSA for any reason other than a decrease in cancer cells. A useful indicator in the disease progression in individuals is the change in serum PSA levels during selenium supplementation (source).

Since plasma selenium decreases with age, supplementation may be beneficial to older men. It appears that low selenium serum levels correlate with cancer of the head, neck (source) and lung (source). Low selenium serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis (source). Moreover, serum concentrations of selenium are significantly decreased in patients with malignant tumours (source).

While the protective effect of selenium against cancer and the low serum level of selenium is reasonably well documented, there is less clinical evidence to support the anti-inflammatory effect of selenium in arthritis. A clinical trial failed to demonstrate that selenium treatment (200 μg/day) produced any clinical benefit in the case of rheumatoid arthritis. However, when examining the quality of life, there was a significant improvement in arm movements and health feeling in selenium-treated patients (source).

The Human Immunosuppression Virus (HIV) depletes the body stores of selenium, which, in turn, cause the immune system failures manifested as Acquired Immunodeficiency Disease Syndrome (AIDS). Selenium supplementation has been shown to forestall the progression of HIV infection to developing AIDS, to reduce the symptoms of AIDS and to improve the lifespan of AIDS patients. (source, source, source)

Selenium can up-regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down-regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while influencing the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN (involved in metastasis) has been reported to be down-regulated by selenium (source)

Animal studies suggest other areas for investigation. It is possible that selenium deficiency and vitamin E deficiency can activate latent viruses such as herpes (source). Animal studies have also shown that mice on either selenium or vitamin E deficient diets developed myocarditis when exposed to coxsackievirus infection; those with adequate selenium or vitamin E status did not (source). Viral-induced neuropathy was found to abate once selenium, vitamin E, carotenoid, and riboflavin blood levels were increased. It appears that a normally avirulent viral genome may become pathogenic in a nutritionally deprived host. An experimental animal study has also found that growth retardation induced by selenium deficiency is associated with impaired bone metabolism and a reduction in bone mineral density (source).

It appears that selenium is critical for healthy sperm and may improve fertility and the chance of a successful conception for both men and women. Supplementation in the case of selenium deficiencies in the procreation period of both women and men is of utmost significance to prevent gestational complications, miscarriages and the damaging of the nervous and immune systems of the fetus as well as to promote fertility (source). 56% of subfertile men with low selenium status showed a positive response to selenium supplementation, improving sperm motility and the chance of successful conception. This study highlights the inadequate provision of this essential element in the Scottish diet (source).

Hair Tissue Mineral Analysis Notes:

There are moderate correlations between selenium levels in whole blood, serum, toenails and hair and correlate with dietary intake assessed through nutritional records and food frequency questionnaires (source, source, source, source). Thus hair mineral tissue analysis (HTMA) may be a useful tool in monitoring selenium treatment (source) or occupational exposure (source). There is a good correlation between hair and plasma selenium levels in healthy children (source)

Selenium can protect and antagonise arsenic and has the potential to mitigate arsenic toxicity (source). As well as a mutual antagonism between mercury (source), cadmium (source), silver (source), and thallium (source, source). Excess storage of iron can be produced by deficiencies of selenium, copper, zinc, and is wrongly blamed for liver cirrhosis, fibrosis of the pancreas, hypertrophic cardiomyopathy and diabetes. These diseases are not the direct result of iron excess, but rather a deficit or biounavailability of the elements listed above.

High Hair Selenium

High hair selenium can be due to the use of shampoos containing selenium and may indicate a loss of selenium through the hair.

Low Hair Selenium

Low hair selenium may be due to dietary deficiency, which is relatively common, especially among those who eat refined foods.

Toxicity or Drug interactions:

Selenium toxicity is increased in animals with low or depleted stores of vitamin E. Chronic ingestion of more than 0.6 mg/day can cause toxicity.

Possible Symptoms of Selenium Toxicity

Garlic breath
Paresthesia
Rough Hair
Hair loss
Nausea
Gastric disturbances
Brittle fingernails
Dermatitis
Hepatorenal damage
A metallic taste
Nervous irritability
Depression
Unusual fatigue
Vomiting
Lameness
Pain
Sloughing of skin
Erosion of joints
Liver cirrhosis
Cardiac Atrophy
Lowered conception rates
Anemia
Congenital disabilities
Muscle spasms

Clinical Caution:

Less than 11mcg selenium daily is considered to unquestionably put people at risk of selenium deficiency and genetic damage (source). An increased risk of cancer is suspected of being associated with selenium deficiency. Clinically, conclusions consistent with selenium deficiency include fingernail and skin changes, cardiomyopathy (source), and skeletal muscle fatigue, tenderness, and weakness.
Patients on monoamine inhibitors should avoid yeast-containing selenium products.
Although an adequate vitamin C status is necessary for normal selenium metabolism, megadoses of vitamin C may decrease absorption of selenium taken as sodium selenite (source).
Selenium deficiency could exacerbate iodine deficiency (source).
Smoking tends to lower selenium biomarker concentrations, even though smoking is a source of selenium exposure - a phenomenon that might be related to increased excretion of the metalloid due to interaction with cadmium or other heavy metals (source, source)

Selenium Deficiency Diseases:

HIV (AIDS) Anemia (RBC fragility)
Age Spots & Liver Spots–ceroid lipofuscin
Fatigue Muscular weakness
Myalgia (Fibromyalgia, muscle pain and soreness)
Rhabdomyolysis (breakdown of skeletal muscle cell walls following exercise)
Scoliosis
Muscular Dystrophy (MD, White Muscle Disease, Stiff Lamb Disease)
Cystic Fibrosis Cardiomyopathy (Keshan Disease, “Mulberry heart” disease)
Multiple sclerosis (MS) Blindness – cataracts, macular degeneration Heart palpitations Irregular heart beat
Liver cirrhosis
Pancreatitis
Pancreatic atrophy
Lou Gehrig’s disease (ALS)
Parkinson’s Disease
Alzheimer’s Disease
Adrenoleukodystrophy (ALD – “Lorenzo’s Oil” Syndrome)
Infertility
Low birth weight
High infant mortality
Miscarriages
Sudden Infant Death Syndrome (SIDS)
Cancer
Clinical AIDS (HIV infection)
Pathogenic viruses
Sickle-cell anemia; thalassemia
Wilson’s Syndrome (hypothyroidism)
Hyperthyroidism

Practice Tips:

Animal studies have shown selenium causes congenital disabilities when given in large doses.
Close monitoring of patients on selenium supplementation is necessary.
Vitamin E 500 IU enhances the efficacy of selenium.
Selenium and vitamin E have closely related mechanisms of action, and deficiency in one often overlaps with a deficiency in the other.
Muscular pain associated with selenium deficiency may be corrected with 200 μg daily.
Selenium modulates T lymphocyte-mediated immune responses and stimulates peripheral lymphocytes to respond to antigens.Selenium 200 μg daily combined with beta-carotene 15 mg and vitamin E 500 IU may reduce the risk of cancer.
Selenium does not protect against skin cancer, whether it be basal or squamous cell cancer.

Those with low levels of selenium before selenium supplementation had a significantly lower incidence of lung cancer due to selenium supplementation (source, source)