James E. Oldfield
Oregon State University
Corvallis, OR 97331-6702.
It is both a privilege and a personal pleasure for me to participate in this Symposium, which honors Dr. A. L. Moxon, who is truly one of the most productive figures in selenium research.
One of the fascinating things about our knowledge of selenium has been its roller-coaster development, alternating between lows of discoveries generating fears of its toxicity and highs emphasizing its beneficial roles, culminating in its acceptance as an essential micronutrient. It is also interesting that much of this knowledge has been gained serendipitously (Oldfield, 1995).
In this context the development of our understanding of selenium began at a low point. The great Swedish chemist, Jons Jakob Berzelius, was asked to investigate worker illnesses in a sulphuric acid plant in Gripsholm. The occurrence of the problem fit a time-frame in which the company had switched from use of imported pyrites to locally-produced ones, and Berzelius speculated, correctly, that some impurity in this sulphur source was causing the trouble. Berzelius suspected that the impurity might be arsenic, whose toxic properties were well-known, or tellurium, an element which he had recently discovered. However, as he analyzed the sludge in the acid vats, he found he had identified a new element which he named selenium, in 1817.
In retrospect, it is possible to identify occurrences of selenium much earlier, which had not led to its discovery because of the insensitivity of analytical technologies at the time. An Italian scholar, Arnold of Villanova, in the 13th Century wrote of "red sulphur", which may have been similar to the deposit Berzelius investigated 500 years later (Reilly, 1996). Marco Polo, in his travels about the same time, may have encountered selenium-bearing range plants in his travels (Polo, 1967). Neither Polo nor Villanova had the expertise or equipment needed to isolate this new element; in fact, its discovery by Berzelius was a remarkable achievement in the 19th century.
Undoubtedly, selenium's discovery was delayed by the very small quantities in which it occurred in animal or plant tissues, or in the soil. The problem was eased considerably by the discovery of some remarkable plants in the range areas of the north-central United States, which had the ability to concentrate soil selenium, and became known as selenium-accumulators. Whereas most plants, even when grown on seleniferous soils, have selenium contents of around 10 ppm or less, those of the selenium-accumulators are almost unbelievably high. Beath et al. (1937) at the University of Wyoming reported a selenium level of 14,990 ppm in a sample of Astragalus racemosus. They classified these plants as primary selenium indicators, because they could only grow in seleniferous soils. Other plants that also accumulate selenium but can grow on non-seleniferous soils are called secondary selenium indicators. The primary indicators seem largely confined to North America, although one, Morinda reticulata, has been reported from high-selenium areas of Queensland, Australia (Knott and McCray, 1959).
Concern about selenium's toxicity was revived in observations of conditions variously called "alkali disease" and "blind staggers" in the Dakotas and Wyoming in the 1930's (Moxon, 1937). The names reflected cause and symptoms: "alkali disease" linked the problem to drinking from alkaline ponds (later disproved), while "blind staggers" described the unsteady gait of affected animals. These were not isolated incidents, but problems that threatened the future of range livestock production in the affected areas: more than 15,000 sheep were lost from selenium poisoning in one year in Wyoming (Wyoming State Board of Sheep Commissioners, 1908).
The selenium roller-coaster began its ascent with the surprising revelation in 1957 that selenium in minute quantities was actually a dietary necessity for laboratory animals (Schwarz and Folz, 1957). This came about, serendipitously, through investigations in Germany, through the use of brewer's yeast as a human dietary protein source. When Schwarz fed torula (brewer's) yeast to laboratory rats, he found that they developed liver necrosis, which could be avoided if bakers yeast (saccharomyces) was used instead. He proposed that a nutrient essential, which he called "Factor 3", was deficient in torula but present in baker's yeast. After a good deal of very exacting research, he was able to demonstrate that the active, preventative factor present in Factor 3 was, in fact, selenium.
Remarkable was how quickly this observation, made with laboratory animals, was translated into applications with large, food-animals, and how widespread areas of deficiency of this trace element proved to be. We found selenium protected against white muscle disease (Figure 1), and in short order, a number of livestock problems for which no cure was then available, were shown to be selenium-responsive (Table 1).
| Figure 1. Cross section of lamb leg, showing lesions of white muscle disease, at right. |
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| Table 1. Selenium responsive ailments of livestock.1 | ||
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| Ailment | Species affected | Tissues involved |
| Myopathy (white muscle, 'stiff-lamb' disease) | Cattle, sheep, goats, pigs, horses, chickens, ducks, turkeys, rabbits, mink | Skeletal muscle, heart muscle, gizzard muscle |
| Liver necrosis | Pigs | Liver |
| Pancreatic necrosis | Chickens | Pancreas |
| Stillbirth, embryonic resorption | Sheep | Embryos |
| Esophagogastric ulcers | Pigs | Esophagus, stomach |
| Exudative diathesis | Chickens, ducks, turkeys | Capillaries |
| Loss of sperm motility | Sheep | Sperm |
| 1 Oldfield, 1997. | ||
Beyond these specific ailments which it could prevent or cure, selenium was found essential for the fundamental biological processes of reproduction and growth, so that selenium supplementation became an established livestock production practice virtually worldwide.
With firm evidence of selenium's beneficial effects on domestic animals in hand, attention was next directed toward ways of administering the necessary dosage levels, and some innovative procedures resulted. In our first studies of selenium's use in alleviating white muscle disease, we provided it by injection and orally - in the feed (Muth et al., 1958), and both these methods have continued in use. The extremely small amounts of selenium that are needed by animals make possible its administration to ruminants in heavy pellets, which were first developed in Australia as a means of providing cobalt. Kuchel and Buckley (1969) developed a heavy pellet of elemental Se and iron filings that was heavy enough to stay in the forestomach of the animals, where it slowly dispensed Se over extended periods of time. Experience with their use showed these pellets were effective for almost a year (Judson et al., 1991). Alternatives to the iron-based pellets were later developed, including soluble glass boluses, which sometimes contained other nutrient essentials in addition to Se (Telfer et al., 1983) and osmotic pumps that will accurately deliver 3 mg Se per day (Figure 2).
| Figure 2. Left, soluble glass boluses; right rear, iron-based boluses; right front, osmotic pump. |
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Our knowledge of selenium took a quantum leap forward with the discovery in 1971 that glutathione peroxidase was a selenoenzyme (Rotruck et al., 1971) and with the precise charting of selenium's position in the enzyme molecule by Flohé et al. (1973) in Germany. Although it can affect other, specific metabolic functions, it appears that its major activity is in maintaining the integrity of cell membranes and preventing oxidative damage (Oldfield, 1987).
The dramatic responses to selenium by animals naturally led to questions whether benefits might be conveyed by its supplementation in the human diet. At first, such benefits were thought unlikely, because the sources of human foods in industrialized countries are so varied that chances of deficiency seemed slight. The situation has changed, however, with findings that at slightly higher than "nutritional" levels selenium may enhance immune systems and protect against some troublesome human ailments, including coronary disease and cancer (Oldfield, 1999). This concept has been strengthened recently by some intriguing observations that selenium deficiency may provoke pathogenicity in certain, otherwise benign, viruses (Levander and Beck, 1996).
There was a brief hiatus in this state of near-euphoria when selenium was (mistakenly, it was later proved) declared to be a carcinogen (Nelson et al., 1943). The implication of this was that it put selenium under the purview of the so-called Delaney clause of the 1962 drug amendments of the Federal Food, Drug and Cosmetics Act. This, in turn, placed the Food and Drug Administration (FDA) in the difficult position of having to deny dietary supplementation with an essential nutrient when needed. The awkward situation was resolved when scientists from the FDA and the National Cancer Institute reviewed relevant data and concluded that "judicious administration of Se derivatives to domestic animals would not constitute a carcinogenic risk" (U.S. FDA, 1973).
The latent knowledge of selenium's marked toxicity in excess regained the forefront of public attention with the discovery that nesting waterfowl were dying or their chicks were malformed at the Kesterson Reservoir in the northern San Joaquin Valley in California. The situation was an interesting one. California's San Joaquin Valley is one of the most productive agricultural areas in the country, but for some years it had been plagued by problems of poor irrigation and accumulation of various salts in the topsoil. An answer seemed to be the installation of deep drains to carry off excess irrigation water before it could raise salts to the topsoil level. Such excess irrigation water, with its attendant salts, was collected in the large San Luis drain, a 188 mile, concrete channel built by the Bureau of Reclamation to carry water from some 300,000 irrigated acres of farmland. The San Luis Drain ended at the Kesterson Reservoir in a series of 12 shallow evaporation ponds, which were managed as a "wetlands" area by the U.S. Fish and Wildlife Service. The project was hailed at the time as a solution to pressing problems in both irrigated agriculture and wildlife management (Engberg, Westcot, Dalamore and Holz, 1998). In 1981, biologists noticed deaths and malformations among the nesting waterfowl and concluded they were related to the high salt content in the pond water, especially that of selenium (Ohlendorf et al., 1986). The solution finally arrived at was to seal off the San Luis Drain (Figure 3) and disperse the irrigation runoff locally. Its success was confirmed by the purchase of some of the Kesterson Reservoir lands to be used by duck clubs. There was, however, some continuing concern that excessive selenium levels might occur in California food crops and that these might be aggravated by the use of selenium supplements in livestock diets. A thorough study initiated by the Council for Agricultural Science and Technology (CAST) concluded this was not true, and that animal diet supplementation with selenium returned negligible amounts of selenium to the environment (CAST, 1994).
| Figure 3. The sealing-off of the San Luis Drain. |
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Appropriately, this paper ends on a high note concerning the extended recognition of protective effects of selenium in human health. Selenium supplementation as a means of supporting health and productivity of domestic animals has been so successful and is so well-established that it appears assured of continuance in the future. In New Zealand, concern for animal productivity, which sup-ports a major part of the economy, was strong enough that the government recommends addition of selenium to fertilizers to ensure adequate selenium levels in feeds and forages.
In Finland, on the other hand, addition of selenium to all NPK fertilizers marketed was authorized by the government in 1985 out of concerns for human health, rather than animal productivity. Before such additions, the average daily intake of selenium by the Finnish population was 25 to 50 g/day; now, 12 years later, it has risen to 70 to 80 g/day and it has been observed that, "Selenium fertilization is a convenient and safe way to increase selenium intake by animals and man...Until now there have been no measurable signs of environmentally-detrimental effects" (Kivisaari, 1998).
Among the disclosures which gave rise to the increased interest in selenium use by humans, prominent listing should be given to the discovery that a large-scale cardiomyopathy in China, called Keshan disease, was selenium-responsive (Chen et al., 1980) and more recently to the demonstration in a decade-long, double-blind, placebo-controlled study involving 1,800 elderly Americans that selenium supplementation resulted in significant reductions in total cancer incidence and specifically of cancers of the lung, colon-rectum and prostate (Clark et al., 1997). As this is being written, another very large cancer-prevention trial is being organized in Europe.
While we must always bear in mind and guard against incidences of its toxicity in excess, the future of selenium as a useful element in maintaining animal and human health seems assured.
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