Margaret P. Rayman

The importance of selenium to human health

The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.

Selenium and human health

Selenium is incorporated into selenoproteins that have a wide range of pleiotropic effects, ranging from antioxidant and anti-inflammatory effects to the production of active thyroid hormone. In the past 10 years, the discovery of disease-associated polymorphisms in selenoprotein genes has drawn attention to the relevance of selenoproteins to health. Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline. Higher selenium status or selenium supplementation has antiviral effects, is essential for successful male and female reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a nutrient is inadequate. Supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefit people with low status, those with adequate-to-high status might be affected adversely and should not take selenium supplements.

Selenium in cancer prevention: a review of the evidence and mechanism of action

Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCys-insertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from gamma-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.

Food-chain selenium and human health: emphasis on intake

Following the publication of the landmark trial of Clark et al. in 1996 that appeared to show that Se could reduce the risk of cancer, awareness of the importance of Se to human health has markedly increased. As a result, there is now much more aggressive marketing of Se supplements and functional foods, even in situations where additional consumption of Se is inappropriate. The present review addresses how Se gets into the food chain, the wide variability in Se content of foods and the very different levels of intake between countries and regions. Though it is clear that there are adverse consequences for health of both deficient and excessive intake, health effects at intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which depends on a large number of factors, such as which functions of Se are most relevant to a particular disease state, which species of Se is most prominent in the Se source, which health condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. These complexities need to be understood, particularly by policy makers, in order to make informed judgments. Potential solutions for increasing Se intake, where required, include agronomic biofortification and genetic biofortification or, for individuals, increased intake of naturally Se-rich foods, functional foods or supplements. The difficulties of balancing the risks and benefits in relation to Se intake are highlighted.

The use of high-selenium yeast to raise selenium status: how does it measure up?

Selenium-enriched yeast (Se-yeast) is a common form of Se used to supplement the dietary intake of this important trace mineral. However, its availability within the European Union is under threat, owing to concerns expressed by the European Community (EC) Scientific Committee on Food that Se-yeast supplements are poorly characterised and could potentially cause the build up of Se in tissues to toxic levels. The present review examines the validity of these concerns. Diagrams of the biosynthesis and metabolism of Se compounds show which species can be expected to occur in Se-yeast preparations. Se-yeast manufacture is described together with quality-control measures applied by reputable manufacturers. The way in which speciation of Se-yeast is achieved is explained and results on amounts of Se species in various commercial products are tabulated. In all cases described, selenomethionine is the largest single species, accounting for 54-74 % of total Se. Se-yeast is capable of increasing the activity of the selenoenzymes and its bioavailability has been found to be higher than that of inorganic Se sources in all but one study. Intervention studies with Se-yeast have shown the benefit of this form in cancer prevention, on the immune response and on HIV infection. Of about one dozen supplementation studies, none has shown evidence of toxicity even up to an intake level of 800 microg Se/d over a period of years. It is concluded that Se-yeast from reputable manufacturers is adequately characterised, of reproducible quality, and that there is no evidence of toxicity even at levels far above the EC tolerable upper intake level of 300 microg/d.

The argument for increasing selenium intake.

The essential trace mineral, Se, is of fundamental importance to human health. As a constituent of selenoproteins it plays both structural and enzymic roles, in the latter context being best known as an antioxidant and catalyst for the production of active thyroid hormone. While Se-deficiency diseases have been recognised for some time, evidence is mounting that less-overt deficiency can also cause adverse health effects and furthermore, that supra-nutritional levels of Se may give additional protection from disease. In the context of these effects, low or diminishing Se status in some parts of the world, notably in some European countries such as the UK, is giving cause for concern. While deficiency has an adverse effect on immunocompetence, Se supplementation appears to enhance the immune response. Se appears to be a key nutrient in counteracting certain viral infections; thus, in a Se-deficient host the benign coxsackie virus becomes virulent, causing heart damage, the influenza virus causes more serious lung pathology and HIV infection progresses more rapidly to AIDS. Long recognised as essential for successful animal reproduction, Se is required for human sperm maturation and sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking Se to cardiovascular disease risk, although other conditions involving oxidative stress and inflammation have shown some association with Se status. There is growing evidence that higher Se intakes are associated with reduced cancer risk. While persuasive evidence already exists to suggest that additional Se would be beneficial in some health conditions, results from intervention trials underway or planned have the potential to reinforce or refute the argument for increasing Se intake.

Food-chain selenium and human health: spotlight on speciation

There is a growing appreciation that it is not just the total intake of dietary Se that is important to health but that the species of Se ingested may also be important. The present review attempts to catalogue what is known about Se species in foods and supplements and the health effects in which they are implicated. The biosynthetic pathways involved in Se assimilation by plants and the way in which Se species are metabolised in animals are presented in order to give an insight into the species likely to be present in plant and animal foods. Known data on the species of Se in the food chain and in food supplements are tabulated along with their concentrations and the analytical methodology used. The latter is important, since identification that is only based on retention-time matching with authentic standards must be considered as tentative: for evidence of structural confirmation, fragmentation of the molecular ion in addition to MS data is required. Bioavailability, as normally defined, is higher for organic Se species. Health effects, both beneficial and toxic, thought to be associated with specific Se species are described. Potent anti-tumour effects have been attributed to the low-molecular-weight species, Se-methyl-selenocysteine and its gamma-glutamyl-derivative, found in a number of edible plants of the Allium and Brassica families. There remain considerable gaps in our knowledge of the forms of Se that naturally occur in foods. Without adequate knowledge of Se speciation, false conclusions may be drawn when assessing Se requirements for optimal health.

Dietary selenium: Time to act

# Dietary selenium: time to act {#article-title-2} The essential trace element, selenium, which we largely obtain from bread and cereals, fish, poultry, and meat, plays a vital part in many metabolic functions. While new research increasingly suggests its relevance to disease prevention, evidence that dietary intake is falling in some parts of the world is giving cause for concern. Selenium is a key component of a number of functional selenoproteins required for normal health. The best known of these are the antioxidant glutathione peroxidase enzymes, which remove hydrogen peroxide and damaging lipid and phospholipid hydroperoxides generated in vivo by free radicals and other oxygen derived species. If not removed, lipid hydroperoxides impair membrane structure and function1 and cause blood clotting disturbances by decreasing the production of prostacyclin while increasing the production of thromboxane.2 Furthermore, lipid hydroperoxides are not stable end products but, in the presence of transition metal ions, can decompose to give further reactive free radicals and cytotoxic aldehydes.3 Such secondary products may initiate more lipid peroxidation, promote atherosclerosis, damage DNA, and metabolically activate carcinogens.3 Selenium also plays an important role in the control of thyroid hormone metabolism. The iodothyronine deiodinases, which are responsible for the conversion of thyroxine (T4) to its active form, triiodothyronine (T3), are selenoenzymes.4 Selenium deficiency may cause reduced growth rates owing to a feedback response which …

Selenoproteins and human health: Insights from epidemiological data

Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.

Low selenium status is associated with the occurrence of the pregnancy disease preeclampsia in women from the United Kingdom

OBJECTIVE Because the trace element selenium behaves as an antioxidant and peroxynitrite scavenger when incorporated into selenoproteins, our objective was to determine whether low selenium status was associated with a greater risk of occurrence of preeclampsia. STUDY DESIGN Fifty-three preeclamptic patients and 53 matched pregnant controls at the John Radcliffe Hospital, Oxford, gave clippings of their toenails (laid down from 3-12 months previously) for selenium determination by neutron activation analysis. Clinical characteristics of the women and their infants were recorded. Statistical analysis was by Wilcoxon signed rank test and odds ratios were calculated by the ratio of discordant pairs. RESULTS Median toenail selenium concentrations in the preeclamptic subjects were significantly lower than in their matched controls (P=.001). Being in the bottom tertile of toenail selenium was associated with a 4.4-fold (95% CI 1.6-14.9) greater incidence of the condition. Within the preeclamptic group, lower selenium status was significantly associated (P=.029) with more severe expression of disease, as measured by delivery before 32 weeks. CONCLUSION In the light of the reduction in selenium status in a number of European countries in recent years, this study raises the question of whether a small increase in selenium intake might help prevent preeclampsia in susceptible women.