From The March 1999 Issue of Nutrition Science News
By Stephanie Briggs, Ph.D.
The mineral selenium has been gaining household recognition and respect in recent years by virtue of its addition to the list of nutritional antioxidants--substances that offer protection against our most dreaded diseases and aging. Indeed, selenium, as a component of several enzymes, does help rid the body of destructive oxidation products.
In the 1950s, when selenium (Se) was recognized as an essential nutrient, it was also identified as the mysterious factor in certain yeast strains that were capable of overcoming liver necrosis in vitamin Edeficient rats. Subsequently, it was recognized that certain livestock diseases--white muscle disease in lambs and cattle, mulberry heart in pigs, muscle dystrophy in horses, infertility in ewes, reproductive disorders in cattle--were associated with low selenium intake. Parallels in humans were not recognized until the late 1970s.
At that time, a type of human juvenile cardiomyopathy known as Keshan disease was associated with severe selenium deficiency. Keshan disease afflicts primarily children between the ages of 2 and 10. It is characterized by heart enlargement, pulmonary edema (fluid in the lungs), cardiac arrhythmias and cardiac insufficiency. Its onset can be sudden, and it is often fatal. The disease is named after the Chinese county in the Heilongjiang Province where it was first described. Keshan County lies in a geographical band stretching from northeastern to south-central China, wherein the topsoil contains low amounts of selenium, and little of the existing selenium is in a water-soluble form. Thus, the plants grown there take up little selenium (selenium is not thought to be essential for plants) and as a result the livestock and human populations manifest selenium deficiencies.
|A little-known mineral contained in grain offers powerful protection against many different diseases.|
Residents in areas with high rates of Keshan disease have the lowest tissue levels of selenium of any population in the world.  Their blood selenium levels are half those of Finns and New Zealanders, whose countries have notably low
selenium levels in their soil. Residents of China's Keshan disease area also have borderline vitamin E deficiencies, a link in the etiology of the condition.
In 1973, when selenium was discovered to be a constituent of the enzyme glutathione peroxidase (hence the enzyme's abbreviation, SeGPx), it became a little clearer why many conditions that are helped by selenium occur only when both selenium and vitamin E are deficient. Both molecules have an antioxidant function. SeGPx prevents free radical formation by breaking peroxide into harmless water; without that pathway, peroxide can be converted to an initiator of free radical formation, which can lead to the undesirable peroxidation of lipids and other molecules. Normally, fat-soluble vitamin E quenches free radicals. If vitamin E--or possibly some other as yet undetermined antioxidant--is not there to do the quenching, and the population of free radicals enlarges because of insufficient SeGPx to break down peroxide, molecular mayhem ensues.
Although the etiology of Keshan disease is not completely understood, it seemed reasonable that selenium repletion might reduce the onset of the disease, since the map of its occurrence is an almost exact overlay of the map of areas with low soil selenium levels. And, in fact, several intervention studies that provided sodium selenite in table salt or in tablet form showed that selenium supplementation could reduce the incidence of Keshan disease.  The results were so impressive that the studies' control groups were abolished and given supplementation as well. However, selenium supplementation did not eliminate new cases of Keshan disease entirely, suggesting that the cause of Keshan disease is more complex than simple selenium deficiency. Because Keshan disease outbreaks have a seasonal pattern, some researchers suggest a virus may also be involved.
Selenium has other viral connections as well. Research done in the 1980s and 1990s showed that selenium deficiency might allow certain viruses to be more virulent. A Coxsackie virus, which causes heart lesions, was isolated from Keshan disease victims and injected into mice fed a low-selenium diet where it caused extensive damage.  Supplementing the mice with selenium before inoculation reduced the severity of the lesions. Mice thought to be genetically resistant to Coxsackie-induced myocarditis have been rendered susceptible by feeding them a diet deficient in both selenium and vitamin E.  So it is possible that to get Keshan disease, the victim must become infected with the virus while deficient in selenium. Whether concurrent vitamin E deficiency has an effect was not studied.
|Although selenium was associated with significant reductions in lung, colorectal and prostate cancers, it was also linked to increased risk of breast cancer.|
Selenium's exact biochemical role in all situations in which it appears to have an effect is not known. One area of interest is selenium's protective role against cancer. Selenium intervention studies conducted in China show selenium supplementation programs are associated with significant drops in liver and esophageal cancer rates.  (Some of these programs supplemented with more than just selenium.) While these results are impressive, they cannot be extrapolated to suggest similar results in the United States and other places where selenium deficiency is not thought to exist. Frank selenium deficiency doesn't occur in the United States because Americans' food sources and varied diet provide enough selenium to prevent deficiencies--even in low-selenium areas of the country.
Studies to determine whether selenium supplementation affects cancer incidence in a supposedly selenium-adequate population have been attempted. In a double-blind, randomized, placebo-controlled study of more than 1,300 patients in seven low-selenium areas of the United States during a 10-year period, investigators hypothesized that selenium supplements would protect against the recurrence of skin cancer.  They found that it did not. To their surprise, however, selenium supplementation was associated with significant reductions in the occurrence of lung, colorectal and prostate cancers and with an increased risk of breast cancer. The selenium dosage in this study was 200 mcg per day, given as a half-gram, high-selenium brewer's yeast tablet.
Does this mean these Americans were selenium deficient? It's difficult to say, because even experimentally achieving selenium deficiency is difficult. But the U.S. cancer study suggests that the selenium intakes of some Americans may not be enough to prevent diseases such as lung, colorectal and prostate cancers.
Although the incidence of certain cancers was reduced, the relative breast cancer risk in the selenium-supplemented group was nearly three times that of the placebo group. The number of cases was small, and the difference in incidence between the two groups was not statistically significant. However, until these results are refuted or confirmed by another controlled, blinded study, it is unclear if selenium supplementation for women is a good idea.
Dosages and Sources
How much selenium is optimal? We don't know. Researchers are looking for a marker of selenium status; after the discovery of SeGPx, the activity of SeGPx became a new way to measure selenium status. Selenium could be fed in different forms and different amounts, and the change of SeGPx activity could be observed in red blood cells. The correlation between selenium and SeGPx levels in red blood cells is good up to a certain selenium intake level. At higher levels, SeGPx activity does not increase at the same rate as the selenium concentration. So, is optimal selenium intake that which is sufficient to maximize SeGPx activity? Maybe. It is not known, for instance, whether SeGPx provides selenium's protective effect in certain cancers. For now, SeGPx reamins an important indicator of selenium status.
Among the richest dietary sources of selenium are organ meats and Brazil nuts. But the most important sources, based on quantities consumed, are cereal grains, meat and fish. The selenium content of foods grown in different parts of the world varies greatly. Even the United States has regions where the wheat grown contains less than 0.3 mg/kg selenium and others where it contains more than 3 mg/kg. Cereal products in the store, however, are made of grain blends from different regions; therefore, cereal products eaten in a low-selenium region may not differ greatly in selenium content from those eaten in a high-selenium region.
The authors of The Role of Selenium in Nutrition (Academic Press, 1986) took a sample, Western-style menu (a day's meals) and calculated its selenium content if prepared from foods grown in various countries. (See chart, page 148.) As can be seen, the selenium variations between regions in a country and the countries themselves are tremedous, ranging as low as 13 mcg to as high as 3,945 mcg.
Fifty to 100 mcg selenium per day is thought to be sufficient to prevent deficiencies. This estimate is based on nutritional intake observations in areas where there are no signs of nutritional deficiency. However, selenium may provide protective effects at levels higher than those necessary to prevent an overt deficiency. The more accurate range of safe intake is probably 50 to 750 mcg per day.
However, high dosages of selenium can be toxic. This is evident in instances of commercial overexposure, such as fumes in copper smelting plants; in people and animals living in the high-selenium regions of China; and at the Kesterson National Wildlife Refuge in California, where agricultural drainage contributed to selenium levels in the waters high-enough to poison ducks and other birds. Typical signs of selenium toxicity in humans and animals are hair and nail loss, brittle nails or hooves, and gastrointestinal disturbances. In the northern Great Plains of the United States, the highest selenium area of the country, cattle and horses can develop "blind staggers," a debilitating hoof disease caused by eating high-selenium grains and selenium-accumulator plants such as locoweed.
In humans, a total intake of 1,000 mcg selenium per day on a regular basis may lead to toxicity, as reported in one Chinese village.  That is by no means a firm number, as individual intakes were calculated from averages, and the individual with toxicosis may have had an intake greater than 1,000 mcg per day. However, a 750 mcg/day upper limit seems prudent. The amounts used in cancer intervention studies ranged from 50 to 200 mcg selenium (as high-selenium yeast) daily.
Does the form of selenium supplement matter? Different selenium forms have different degrees of bioavailability. The form used in the Keshan disease intervention study was a carbonless, inorganic type called sodium selenite, used in most laboratory animal studies, given as a 500-mcg or 1,000-mcg tablet once a week. The form of selenium most commonly found in food is selenomethionine--the amino acid methionine with selenium substituted for the sulfur atom. It is the dominant form of selenium in high-selenium yeast, which was used in the cancer intervention studies. Carbon-containing forms of selenium are less toxic than inorganic forms of the mineral.
Until recently, selenium supplementation for Americans was considered unnecessary. However, in light of the findings about selenium and U.S. cancer incidence, that thinking is changing. When the results of the American selenium and cancer study are confirmed by other studies and when the mechanism of selenium's protective effect against cancer is discovered, we will be closer to knowing what the optimal selenium intake is.
Stephanie Briggs, Ph.D. (formerly SB Combs), a nutritional biochemist, spent six months in China as part of a selenium research team. She is co-author of The Role of Selenium in Nutrition (Academic Press, 1986).
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