The selenium gold mine

In this exclusive Q&A with leading experts in the field of selenium, Mark J. Tallon, PhD, helps unearth the latest research and applications of mineral supplementation and functional food fortification

With the 8th International Symposium on Selenium in Biology and Medicine in July in the US, this is a perfect time to give an update on an intriguing corner of our industry. Selenium (Se) is an essential trace element with biological properties like no other. Its fundamental place in the nutraceutical armory can be underlined by its essential role in maintaining antioxidant status and thyroid function.1

Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development and virulence of HIV progression to AIDS.2 It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states.

The largest study to date on selenium — the SELECT study — is currently under way
Currently the largest ever selenium study to date is underway, involving more than 35,000 men from a variety of ethnic groups in the United States, Puerto Rico and Canada. The SELECT study will assess if a combination of selenium (200mcg/day) and/or vitamin E (400IU/day) can prevent prostate cancer. Although the SELECT study may not release any data until 2008 — 2013, the body of evidence in this area is expanding rapidly, including recent findings of new human antioxidant enzymes.

Because the future for selenium could expand rapidly following positive SELECT study results, the widescale importance and applications within the functional/fortified and nutraceutical field should not be underestimated. As such I dedicate this issue to a roundtable discussion with the world's leading researchers in selenium supplementation in a bid to bring the industry to the cusp of current knowledge and market opportunities regarding this potential gold mine.

The four panelists include Robert DiSilvestro, PhD, professor of nutrition at Ohio State University and a specialist on selenium and antioxidant actions; Dr Lea Zibrik is research asociate in the division of metabolic and cellular medicine at Liverpool University in the UK, specifically investigating selenium, immune status and viral handling; John W Finley, PhD, is chief technical officer at the AM Todd Company; he has published more than 80 peer-reviewed articles regarding the physiological problems and opportunities associated with increasing the selenium content of plant foods; Dr Junxuan (Johnny) Lu is associate professor at the Cancer Biology Section Hormel Institute in the University of Minnesota and a researcher in the field of selenium and cancer.

FFN: In recent studies such as SELECT, vitamin E seems to be a factor exacerbating the low level of selenium intake. However, the mechanism of effect between vitamin E and selenium is not completely understood. Can you expand on this and is there a synergistic role in human health?

JF: We do not have any data from SELECT at present, so there is no way to know if vitamin E is a factor; the first data from SELECT will not be available for at least five years. In animal deficiency diseases, vitamin E and Se work equally well for preventing deficiency diseases such as white muscle disease.3 But results obtained in deficient animals are not directly applicable to humans.

JL: The premise of the SELECT is that these two nutrients can spare each other and may offer synergy for protecting against oxidation.

RD: Vitamin E and selenium were linked together early in the research history of selenium as a nutrient. The reason was that both nutrients exert antioxidant effects, though by different mechanisms. One idea that arose was that vitamin E stops free radical-initiated oxidant reactions, while selenium, via the enzyme glutathione peroxidase, prevents certain radicals from forming (by eliminating hydrogen peroxide, which can produce radicals). At the time these ideas were emerging, it was not yet well appreciated that antioxidant effects also derive from a number of other nutrients, as well many phytochemicals. Thus, selenium's antioxidant actions are actually linked not just with vitamin E, but also with many other agents. Still, some people maintain more awareness of the selenium-vitamin E link due to the early history of studying the two nutrients together.

FFN: What is your view on the use of low molecular weight selenium compounds such as methylseleninic acid and their application in disease treatment or therapy?

JF: The work is experimental only, and done by only a very few labs in limited animal and cell culture studies. The work is interesting and should be watched, but in the absence of human efficacy studies and animal toxicity studies, it should not be used as a basis for producing or consuming supplemental selenium.

LZ: There is good basic evidence that low molecular weight Se compounds can induce apoptosis [programmed cell death, good against cancer cells] in vitro, but in vivo studies need to be carried out to confirm this.

JL: In a recent review, we summarised why methyl Se should be better than other forms of selenium for cancer prevention and treatment.4 In most animal models, Se-met is inferior to selenite, which is in turn less than or about equal to methylseleninic acid or methylselenocysteine.

RD: I think that it is way too early to ascribe special anti-cancer properties to compounds such as methylseleninic acid. A lot of the attention to this compound versus selenomethionine derives from studies in cell cultures. In cultured cells, there can be limited ability to convert one selenium compound into another. In contrast, this may become a non-factor in vivo (in intact animals or people). It should be noted that in a review article, Dr Whanger notes that differences between the two aforementioned compounds in cultured cells do not occur in some studies done in vivo.5

FFN: Seleno-compounds are potentially toxic and based on the wider view of the literature the therapeutic index seems to be rather small. What issues should be talked about before we can give firm recommendations for dietary supplementation as some healthy individuals, like athletes, are under levels of free radical production rivaling those of disease states?

JF: There are several issues here; first, the clear guidelines are in the DRI's: a recommendation of 55 micrograms Se per day for adults, not to exceed 400 micrograms per day. This is well within the safety window. The issue is that in that absence of an athlete being deficient in Se (as diagnosed by a doctor) there is absolutely no data suggesting that increased intakes of Se will benefit oxidative stress. Intakes of Se beyond the dietary requirement have only been demonstrated to reduce the risk of cancer; there are no other benefits documented for humans.

LZ: It has been shown that there is an upper threshold level of Se supplementation above which no additional benefits are seen. Therefore, maximum effects are likely to be seen in a relatively narrow range (=200mcg/day). As regards to recommendations for Se supplementation to athletes, one should be careful in reasoning. Athletes do produce more free radicals; however, they also produce more antioxidant enzymes, therefore they are in the redox balance, negating the need for extra supplementation.

JL: Dosage and forms of Se are critical issues. Work by us and others have shown high levels of selenite and selenium compounds that metabolise to hydrogen selenide-induced DNA damage. Methyl Se, which are precursors to methylselenol, appear to lack such genotoxicity. I must emphasise that these claims have yet to be been tested in animal and human trials.

It appears that 200mcg/day or less provides protection, so any supplement or food should not exceed this limit
RD: We still don't know enough in this area. It seems that 200mcg selenium per day is the lower end of what has been generally used in human supplementation studies. So far, I don't see any strong evidence that this level is toxic. So, this dose would seem to be a safe starting point.

FFN: During increased viral loads, it has been suggested GPX1 (selenoprotein) is integral in providing cellular protection. How important is selenium intake at this time and do you feel there is a need for supraphysiological intakes during viral loading including exposure to illness such as the common cold?

LZ: Viral mutations may be driven by oxidative damage. It has been shown in the past that GPX1 plays a protective role in minimising the viral oxidative damage and hence mutations. Furthermore, it has been shown in mice that other antioxidants cannot compensate for the lack of GPX1, making it vital in viral infections.

A study done in our laboratory (Prof. MJ Jackson) showed that selenium-supplemented subjects cleared poliovirus from the body faster than the non-supplemented subjects.6 It was also shown that fewer mutations of the poliovirus were found in the faecal samples recovered from Se-supplemented subjects. A study has also shown that selenite has a direct antiviral activity (in cell culture).7 Further study is currently underway in our laboratory to determine the nature and effect of the viral mutations in Se supplemented and non-supplemented subjects. We will also look at the effect of direct elimination of virus by high concentrations of local Se.

FFN: At present testicular selenium levels seem to be implicated in some forms of infertility. However, selenium supplementation does not seem to impact these levels even when given at supraphysiological doses. Do you feel supplementation or dietary fortification with other more bioavailable forms of selenium may be effective or is it simply an issue relating to SeIP receptor activity?

JF: The idea of SelP as a transporter is not widely accepted. In general the brain and testis both have strong barriers that maintain a strong homeostatic control over substances entering or leaving. Again, excess Se would only be important in deficiency, and that seems to be almost impossible to get in the testes.

LZ: Selenium incorporated into phospholipid hydroperoxide glutathione peroxidase (PHGPx) or GPX4 can play a structural role in sperm capsule protein; hence it may not be influenced directly by intake.

JL: More research should be done with methylselenium compounds, as there is no data to render a judgment to this issue.

RD: We don't know much about how different forms of selenium may better target different parts of the body. However, I think that this is an issue worth considering.

FFN: What role may selenite and/or selenomethionine play in human nutrition as either a dietary supplement or functional fortificant to food? I understand there is some work in this area already (Ip and Colleagues on selenomethionine and gamma-glutamyl-selenocysteine supplementation).8 Could you expand?

JF: Selenium supplementation is important for one reason: Supplemental Se reduces the risk of cancer in men (it may actually increase non-melanoma skin cancer rates in women). To this end, both sources are important. In the absence of human data it is deceptive to claim any one form is better than another. It appears that 200mcg/day or less provides protection, so any supplement or food should not exceed this limit. Also, any supplement or food must be formulated so total intake (diet + supplement) does not exceed the established upper limit of 400mcg/day.

LZ: At present, selenium is available in the form of selenite-yeast as a supplement. Selenomethionine is found naturally in plants; therefore it might be the form to use in supplements, as selenite is toxic at high doses. In our laboratory a trial is underway to look at the effects and doses of selenite and selenomethionine on the immune system.

JL: For correction of nutritional Se deficiency, these forms of Se at low levels should be beneficial. For cancer prevention purposes, these may not be the best choice. Cell culture data have shown better attributes for methyl selenium in terms of affecting biochemical and cellular processes for cancer prevention and treatment.9 Selenite at high dosage can cause DNA damage like X-rays.10 Se-Met causes usually high tissue accumulation of Se due to its replacement of Met in general protein synthesis. In animal studies, methyl selenol precursor compounds outperform selenite, which is more efficacious than Se-Met.11 However, we need more animal studies and human studies to back these claims up. Therefore, I concur with Dr. Finley's comments to this question.

RD: The whole issue of bioactivity variation among different types of selenium supplements is not all that clear-cut. When I wrote a recent book on mineral supplements (Handbook of Minerals as Nutritional Supplements, CRC Press, 2005), I really struggled with a conclusion in this area. One study would say one thing while another says something else. I think that we need more head-to-head comparisons of different types of selenium supplements in humans with a wide range of endpoint evaluations.

FFN: Recent work on genetic polymorphisms (eg, sep15) implies some individuals may need greater amounts of selenium to treat some disease states. We also do not know the requirements for the optimal expression of some selenoproteins such as Selenoprotein P; what is your view on current RDI for selenium?

LZ: The RDI in UK is currently at 75mcg/day for males and 60mcg/day for females. This is set by the Se needed to saturate the GPX activity. Therefore, in order to reap the benefits of selenium for the cancer prevention etc, low molecular weight selenium compounds may be needed. These are only present when Se is in excess of GPX needs. Therefore, we feel the current RDI could be increased slightly, bearing in mind that the maximum safe intake of selenium is set at 400mcg/day as recommended by WHO.

JL: Keep current values until more research supports revision.

RD: RDAs are not intended to deal with high nutrient needs due to disease. Thus, the findings about Se in treating diseases, though tremendously important, should not shape the RDA. On the other hand, I am not totally sold on the Se RDA for another reason; the RDA is based just on one type of blood measurement of glutathione peroxidase. I think that this is a very narrow way to define an RDA. How do we know that glutathione peroxidase in every tissue saturates at the same Se intake as this blood measurement? Also, other functions of Se may show more individual variation than glutathione peroxidase.

FFN: Any final thoughts?

Se as a potential chemosensitizer for cancer therapy has attracted some attention lately
JL: The use of Se as potential chemosensitizer for cancer therapy has attracted some attention lately. 12 Again the form and dosage of Se matter very much based on cell culture studies. I concur with Dr DiSilvestro on this comment. Correction of nutritional deficiency in itself is very important in countries like China where Se is low in two-thirds of the land areas. The form of Se for this application should not matter a great deal. Fortifying salt with selenite has proven quite effective and economical in China for this purpose. Selenium toxicity is a really important concern and therefore for the applications intended for cancer prevention, the forms of Se in terms of efficacy and safety must be balanced.

RD: We may have to think about Se intakes in two tiers. One tier may be sufficient to cover basic functions, while a higher tier may be optimal for lowering the risk of cancer. However, we need to define that higher tier since selenium toxicity can be an issue, especially in some people who may have high sensitivity.

Cutting-edge selenium applications Although this Q&A is heady in terms of novel information, this exclusive roundtable is a great opportunity to look into the crystal ball of future possibilities for the functional food, drink and nutraceutical markets. Here is what I see as the biggest insights gleaned from this expert discussion:

  • Low molecular weight selenium compounds seem to have good applications as a cancer treatment. Most effective forms are methylseleninic acid or methylselenocysteine; therefore, R&D into functional food components should begin here.
  • More work is needed to confirm the exciting in-vitro data in humans.
  • Direct precursors to methylselenol (eg, methylselenic acid) display lower genotoxicity compared to current selenium supplements (including selenite). This may be a preferable form for those wishing to promote a higher selenium intake.
  • Claims for selenium use as a thyroid aid are unfounded, although structure/function claims for selenium, such as "Selenium helps support healthy thyroid function," may be possible, based on current evidence.
  • Selenium supplementation studies are underway regarding optimising intake, which may have beneficial influence in protection against viral infections.
  • 400mcg/day seems to bring about a consensus as the upper limit of all experts (diet and supplementation combined). Those recommending or fortifying products above this dose should take note.
  • RDA/RNI levels should be increased beyond current levels as should the methods for dictating this level.

Selenium is still a relatively untapped market outside of Europe with huge opportunities in regards to IP. The fact that it already carries an FDA-qualified health claim for cancer from 2003 gives direct access to those willing to enter this up-and-coming market boomer.

Mark J Tallon, PhD, is chief science officer of OxygeniX, a London-based consultancy firm specialising in claims substantiation, product development and technical writing.
Dr Tallon is also co-founder of Cr-Technologies, a raw-ingredients supplier.
Respond: [email protected]

1. Flohe L, et al. Glutathione peroxidase: a selenoenzyme. FEBS Lett 1973;32(1):132-4.
2. Kohrle J. Selenium and the control of thyroid hormone metabolism. Thyroid 2005;15(8):841-53.
3. Ogunro PS, et al. Plasma Selenium Concentration and Glutathione Peroxidase Activity in HIV-1/AIDS Infected Patients: A Correlation with the Disease Progression. Niger Postgrad Med J 2006;13(1):1-5.
4. Lu J, Jiang C. Selenium and cancer chemoprevention: hypotheses integrating the actions of selenoproteins and selenium metabolites in epithelial and non-epithelial target cells. Antioxid Redox Signal 2005;7(11-12):1715-27.
5. Whanger PD. Selenium and its relationship to cancer: an update dagger. Br J Nutr 2004;91(1):11-28.
6. Broome CS, McArdle F, et al.An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr 2004;80(1):154-62.
7. May SW. Selenium-based pharmacological agents: an update. Expert Opin Investig Drugs 2002;11(9):1261-9.
8. Ip C, et al. Chemical speciation influences comparative activity of selenium-enriched garlic and yeast in mammary cancer prevention J Agric Food Chem 2000;48(9):4452.
9. Wycherly BJ, et al. High dietary intake of sodium selenite induces oxidative DNA damage in rat liver. Nutr Cancer 2004;48(1):78-83.
10. Rayman MP. Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc 2005;64(4):527-42.
11. Last K, et al. Activity of methylated and non-methylated selenium species in lymphoma cell lines and primary tumours. Ann Oncol 2006;17(5):773-9.
12. Wachenheim C.J. Managing the Food Chain During New Product Introduction: The Case of a High Selenium Food Product 2nd Annual World Food & Agribusiness. Chicago, USA. 2005.

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