Selenium

What selenium does in the body

Selenium is incorporated directly into proteins as selenocysteine; 25 such selenoproteins are known in humans. The best known are the glutathione peroxidases. At least as important are the deiodinases: they turn the storage hormone T4 into the active T3. Selenium was only identified as a component of such an enzyme in the 1990s. Of all adult organs, the thyroid has the highest selenium content per gram of tissue.

A widespread statement needs correcting: selenium does not produce glutathione. The body assembles glutathione from amino acids, without selenium. Selenium only sits in the enzyme that uses up glutathione.

What supply looks like in Germany

That European soils are low in selenium is true and is stated as such by the DGE. The BfR estimates the average selenium intake of adults in EU countries at 31 to 66 µg per day, in large part therefore below the DGE estimated value.

One caveat is rarely mentioned: there are no current measured data for Germany, as selenium content is not recorded in German food consumption surveys. The talk of undersupply rests on soil data and EU estimates. What genuine deficiency looks like is shown by Keshan disease, a heart muscle disease in selenium-poor regions of China: there, selenium supplementation lowers the risk of the disease by 86 %.

The cancer protection claim and what became of it

Selenium’s reputation as cancer protection stems from a single trial. From 1983, the NPC trial gave a total of 1,312 patients with a history of skin cancer 200 µg of selenium daily. The primary endpoints were missed, whereas the secondary endpoints, defined only in 1990 after the fact, turned out spectacularly: 29 versus 57 cancer deaths, 77 versus 119 new cases. The blinded phase was ended early, and the authors themselves called for independent confirmation.

That confirmation trial was SELECT, with 35,533 men and prostate cancer as the primary endpoint. After a median of 5.46 years, the hazard ratio was 1.04, and there was no difference for any of the other prespecified cancer endpoints either. The Cochrane review draws the same line: a relative risk of 1.01 for overall cancer incidence, with high certainty.

Part of the context is what SELECT did not test: it enrolled healthy men without selection by selenium status. Below the 60th percentile of toenail selenium, selenium supplementation had no effect, and in the NPC trial the apparent protection was limited to baseline values below 123.2 ng/ml of plasma selenium. What was tested, then, was whether more selenium helps when supply is adequate.

The risk signal from the same trials

Both large selenium trials not only showed no benefit but also provided indications of harm. In the NPC follow-up analysis, 58 participants on 200 µg daily developed type 2 diabetes over a mean of 7.7 years, compared with 39 on placebo, hazard ratio 1.55. In SELECT, the signal pointed in the same direction but stayed below the threshold of significance.

The second signal concerns the endpoint that was originally at stake: in men with high selenium status, high-grade prostate cancers increased with selenium supplementation. This is exactly what is meant by the U-shaped relationship that keeps appearing with selenium.

Thyroid: the most robust part

In Hashimoto’s thyroiditis, selenium reliably lowers TPO antibodies; a reassessment of 23 trials found them significantly lower after 3, 6 and 12 months. TSH did not change. Quality of life and levothyroxine dose were not recorded at all in the trials included by Cochrane. An antibody titer is a surrogate marker, not how someone feels.

A clinical endpoint, by contrast, has been reached in mild Graves’ orbitopathy: in a trial in 159 patients, selenium improved the overall ophthalmic assessment and disease-specific quality of life over 6 months. This is the clearest positive finding on selenium, but it applies only to this condition. In newly diagnosed Graves’ disease, a trial in 430 patients found no difference.

What the studies show

SELECT: no effect on prostate cancer

Randomized, double-blind, placebo-controlled four-arm trial in 35,533 men from 427 centers, enrolled from age 50 and with a PSA of no more than 4 ng/ml. The arms received 200 µg of L-selenomethionine daily, vitamin E, both, or double placebo. The primary endpoint was prostate cancer. After a median of 5.46 years, the hazard ratio for selenium was 1.04, with 432 cases versus 416 on placebo. The endpoint was not met.

NPC: primary endpoint missed, secondary impressive

Randomized, double-blind trial in 1,312 patients with a history of skin cancer, 200 µg of selenium daily, mean treatment duration 4.5 years. The primary endpoints, basal cell and squamous cell carcinoma, were missed, with relative risks of 1.10 and 1.14. Only the secondary endpoints defined after the fact turned out clearly. For prostate cancer, the complete treatment phase gave a relative risk of 0.51, but only below 123.2 ng/ml of baseline plasma selenium.

Diabetes signal from the same cohort

Secondary analysis of the NPC trial in 1,202 participants without type 2 diabetes at baseline, on 200 µg of selenium daily and with a mean follow-up of 7.7 years. The endpoint was new-onset diabetes: 58 cases on selenium versus 39 on placebo, 12.6 versus 8.4 cases per 1,000 person-years, hazard ratio 1.55. In the top tertile of baseline levels, it was 2.70. Diabetes was a secondary endpoint here, and the diagnoses were mostly self-reported.

Toenail selenium: whom more selenium harms

Case-cohort analysis within SELECT with 1,739 prostate cancers, 489 of them high-grade, and 3,117 men in the random subcohort. Without supplementation, selenium status was not linked to risk. Below the 60th percentile of toenail selenium, selenium supplementation had no effect; above it, it increased the risk of high-grade cancers by 91 %.

Where the data stop

It is not established that selenium protects against cancer when supply is adequate. The finding that founded this reputation was a secondary endpoint of a trial whose primary endpoints were missed. The confirmation trial and the Cochrane review were negative. It remains open whether supplementation in proven deficiency prevents cancer; no one has tested that.

It is not established that selenium improves symptoms in Hashimoto’s: antibodies fall, TSH does not, and the endpoints that matter to those affected were not assessed. A detoxification function with a clinical endpoint is not established either. And the cancer data can hardly be transferred to women, as 88 % of participants were men.

Status, approval and legal

Selenium is an authorized nutrient for food supplements. There is no statutory maximum amount; since February 2024, the BfR has recommended 40 µg per recommended daily dose for people aged 15 and over and, for fortified foods, 12 µg per 100 g, or alternatively 24 µg per 100 g for solids and 6 µg per 100 ml for liquids. The DGE gives estimated values of 70 µg daily for men, 60 µg for women and 75 µg during breastfeeding. Six health claims are authorized in the EU, including normal thyroid function and protection of cells from oxidative stress; a claim on cancer prevention is not among them. Selenium is not on the WADA Prohibited List.

Safety

The gap between requirement and upper limit is smaller for selenium than for most micronutrients. In 2023, EFSA set the tolerable total intake at 255 µg per day, derived from an adverse-effect level of 330 µg per day at which hair loss occurred, divided by an uncertainty factor of 1.3. Excess intake shows up as selenosis: hair loss, brittle nails, garlic breath, a metallic taste, nausea and irritability. Brazil nuts are not a side issue: a single nut contains 68 to 91 µg of selenium, and EFSA names regular Brazil nut eaters, alongside users of high-dose supplements, as the groups that may exceed the limit. As a precaution, the DGE advises pregnant and breastfeeding women and children to avoid Brazil nuts entirely, because Brazil nuts accumulate radioactive substances. Anyone with a thyroid condition or receiving cisplatin should clarify their selenium intake with a physician.

Sources

• Lippman et al., JAMA 2009 (SELECT)
• Klein et al., JAMA 2011 (SELECT, extended follow-up)
• Kristal et al., J Natl Cancer Inst 2014 (baseline selenium status)
• Clark et al., JAMA 1996 (NPC trial)
• Duffield-Lillico et al., BJU Int 2003 (NPC, plasma selenium)
• Stranges et al., Ann Intern Med 2007 (type 2 diabetes)
• Vinceti et al., Cochrane Database Syst Rev 2018
• Marcocci et al., N Engl J Med 2011 (Graves’ orbitopathy)
• EFSA NDA Panel, EFSA Journal 2023 (upper limit for selenium)
• BfR, opinion 010/2024 (maximum levels for selenium)