An update on the research showing that selenium reduces cancer incidence:
An interview with Drs. Larry Clark and Lon Baugh.
Part 1: The basics
Richard A. Passwater, Ph.D.
News from the selenium research front and supplement front will be of interest to you. On the research front, there is a lot happening in selenium research resulting in considerable excitement among scientists. At the Sixth International Symposium on the Uses of Selenium & Tellurium held in Scottsdale, Arizona in May, Dr. Larry Clark of the University of Arizona Cancer Center spoke of "changing the world with selenium." However, the general population is still hard put to explain what selenium is and what it does.
In December 1996, most of the TV network evening news broadcasts led off with the spectacular announcement that selenium supplements cut the cancer death rate in half in a large clinical study. One might think that virtually everyone would start taking selenium supplements to lower his or her own risk of getting cancer. Although there was an increased demand for the supplements for awhile -- it even outpaced the limited quantities on store shelves – the message did not sink in for the average person.
Today, if you go out on the street and ask passersby if they are taking selenium supplements, most will say something like, "Selenium? What’s that?"
What do we have to do to get the message across? Part of the answer is to do even more research, while another part is to help spread the word about selenium to the general population.
Also, on the supplement front, there is a critical change in the way to identify the only form of selenium supplements that has been tested in human cancer prevention trials. Selenium supplements are available in different forms. Some forms are single compounds, while others provide an array of different selenium compounds. As an example, high-selenium yeasts are available that differ in the quantities of selenium-containing amino acids such as selenomethionine and companion selenium-containing compounds such as selenopeptides, selenolipids and even selenides.
After the dramatic announcement that the clinical trial conducted by Dr. Clark and his colleagues reduced the incidence of cancer and cut the cancer death rate in half, we were told if we wanted to be sure to use the only supplement proven to work, we had to look for a specific trademark on labels. Other selenium supplements may work as well, but we don’t know because they haven’t been studied in clinical trials. Now, we have been informed, the company that owns the trademark that we were told to look for no longer provides the same form of selenium that Dr. Clark used.. The new trademark that now identifies the specific high-selenium yeast used in all of Dr. Clark’s trials is "SelenoPrecise™ ."
SelenoPrecise™ is available from several tablet manufacturers, but what concerns many manufacturers now are is the question of how to inform consumers who want to take the form of selenium used in Dr. Clark’s studies that they must look for the new trademark.
This matter of trademark is not trivial. It is not the same as ordering a Coca Cola® and being served a Pepsi Cola®. This type of switch merely affects taste. In the case of selenium supplements, however, we are dealing with cancer prevention.
It should be understood that selenium supplements are not "selenium." Selenium is an element, actually a "metal" that is not absorbed by the body. In order for selenium to be of use in the body, it must be converted to a selenium salt or organic compound. It is important to understand that we are not merely talking about differences in absorption among the selenium compounds, but about different selenium compounds having different actions and pathways in the body.
As a comparison, we don’t speak of "carbon" supplements when we take vitamins or amino acids or hormones. They all contain carbon, but the rest of their molecular structures are vastly different. Similarly, sodium selenite is vastly different from selenomethionine, which is different from diallyl diselenide or triphenyl phosphine selenide. By the way, if you are not familiar with the last compound, I patented it as the most effective anti-cancer compound in 1997, but it is not available as a dietary supplement (EP 750911, CA126(10)135612s). Selenium compounds such as diallyl diselenide and methylselenocysteine are found in garlic. There can be a thousand-fold difference between the most effective and least effective forms of selenium in preventing cancer.
It is possible that the mechanism(s) through which selenium compounds protect against cancer are not the normal selenium nutritional pathways. Different forms of selenium may work through different mechanisms. It is important to provide forms of selenium intended for cancer protection that have a long half-life in the blood stream and are not readily converted to dimethyl selenide and excreted via the lungs or converted into selenonium ion and excreted in the urine or significantly incorporated into structural proteins. This is an outgrowth of the research on my earlier patents in 1972 (US 39140, US 97011) showing that selenium compounds including seleno-amino acids and other selenium-containing compounds protect against cancer when taken with a synergistic combination of antioxidants.
Since we haven’t really identified which dietary selenium compound(s) may protect against cancer, nor have we elucidated the mechanism(s) through which they act, many feel that it is extremely important to stick with the exact supplement that has been proven effective in clinical trials. In this instance, that means staying with products that are now identified as SelenoPrecise™.
This is the first of two articles examining both the new research and clarifying the change in name that identifies the actual selenium material used in the clinical studies. My guests are Drs. Larry Clark and Lon Baugh.
Dr. Larry C. Clark, M.P.H., Ph.D., is an Associate Professor of Epidemiology at the Arizona Cancer Center at the University of Arizona (Tucson). He received his B.S. degree in Biology from Alma College in 1970, his M.P.H. in Epidemiology from the University of Michigan in 1974, and his Ph.D. in Epidemiology from the University of North Carolina, Chapel Hill in 1982. Dr. Clark was an Assistant Professor of Epidemiology in the College of Agriculture and Life Sciences, Biometrics Unit at Cornell University. He is the principal investigator for the Nutritional Prevention of Cancer Project using selenium, in which a strong association between selenium supplementation and decreased total cancer incidence was found. In October of 1997, he was honored with the "Pioneer Science Award" from the Cancer Treatment Research Foundation for research on selenium and human cancer. Dr. Larry Clark last chatted with us in the February and March, 1997 issues of Whole Foods.
Dr. Lon C. Baugh received his B.S. from Oklahoma Baptist University in 1967, his M.S. from Oklahoma University in 1968, and his Ph.D. from The University of Texas in 1974. He did Post Doctoral research at the University of California at Berkeley and has been granted Fellowships from the National Science Foundation and the National Institutes of Health. He has had extensive experience in using, developing and producing yeast products. He has been the Technical Director at Fleischmann’s Yeast, Brew Master at Miller Brewing Company, Vice President at Dixie Yeast, Production Manager at Phillips Petroleum Company (Provesta), Vice President of American Yeast, Vice President of Lallemand International (a manufacturer of yeast products) and is now President of Fermentation Consulting in Vian, Oklahoma and Technical Consultant for Cypress Systems, Inc., Fresno, CA.
Passwater: Dr. Clark, it’s been almost two years since your dramatic study that showed supplementing diets with 200 micrograms of selenium yeast daily dramatically reduced the incidence of cancer. Let’s review those sensational findings once again in case some of our readers missed the study.
Clark: The initial report that we made in the Journal of the American Medical Association (JAMA) reported a 37 percent decrease incidence of cancer among patients who are assigned a selenium supplement. We also observed a 50 percent decrease in cancer mortality in those people on the selenium supplement. In addition, we saw a dramatic decrease in the incidence of lung, prostate, and colorectal cancer.
What we can say is important about this is that this is really the first study in a western population that has shown that a nutrient given as a supplement can reduce the incidence and mortality of cancer.
Passwater: I thought that those results would immediately cause a paradigm shift in the way nutritionists and physicians looked upon supplements. The paradigm shift is occurring, but it took folate and birth defects, B6 and heart disease (via homocysteine) and vitamin E and heart disease (via oxidized-LDL) all together to finally get the point across. In April, even the Institute of Medicine which through its Food and Nutrition Board unit, finally urged most Americans (all women of childbearing age and all adults over fifty) to take supplements.
However, few of the people who need to take selenium supplements have heard of selenium. Even when you speak with practicing physicians about selenium, few know about it. What have you found two years later about the impact of your seminal study?
Clark: I think the study has had a very profound impact in a number of ways, but we are not finished with the process. We have to do more. I think that it started a paradigm shift or was a manifestation of the paradigm shift that is happening. The fact that JAMA, the leading journal of American physicians chose our study as their lead article on Christmas Day in 1996 is important. But, as you see, it takes a while for this to be incorporated into practices by individuals and physicians.
Passwater: For the benefit of those who are not familiar with selenium, please briefly review the basics of this essential trace mineral.
Clark: Selenium is an essential nutrient that we all require in our diet for optimal health. What we have shown is that 200 micrograms of selenium per day is the level that provides more optimal health than the amount of selenium that is available in a normal diet, is about 90-100 micrograms a day. So that suggests that a total intake of around 300 micrograms may be optimal for health.
Passwater: One problem is that people can’t really determine how much selenium they are getting in their diet because the amount in any given food depends on the amount of selenium in the soil a plant is grown in or in the feed of the animal.
And when will the critics of dietary supplements stop saying that if the soil is deficient, the plant won’t grow as much, so therefore the nutrient content will not vary much. They fail to understand that selenium, chromium and iodine are not required by the foods that we eat, and thus these plants grow independent of the quantities of these minerals in the soil. The selenium content of foods vary dramatically, and book values are meaningless as we have discussed in earlier chats.
Clark: That is one of the problems. It is almost impossible for the average person to know how much is in the diet because foods vary in their content depending upon where they come from, and that is why the use of supplements is warranted in the case of selenium where it might not be warranted with other nutrients where nutritionists would say eat a good diet and you get plenty of nutrient X. With selenium they can’t say that.
Passwater: How can people be certain they are getting the optimal amount of selenium?
Clark: By taking a selenium supplement with a measured amount of selenium in it.
Passwater: Why did you choose selenium yeast as the supplement of choice in all of your studies?
Clark: I think it was a philosophical decision really at first. The choices were between an inorganic form of selenium which we don’t consume normally in our diet and an organic form that we do. Since I am an epidemiologist and concerned with what people normally do, I felt that an organic form found in high-selenium yeast would most approximate the natural situation.
Passwater: What selenium compounds are in this complex of selenium compounds found in high-selenium yeast? Would these same compounds be in other selenium supplements?
Clark: In relationship to the selenium yeast, I looked at the full complex of nutrients available in the yeast. The yeast has a measured level of organically bound selenium and additionally, it has the full complement of amino acids, the lipids, and the carbohydrates. So I selected a food source that has the capacity in a living state to organically bind the selenium in measured amounts and still give the full composition of other nutrients. Nutritional research differs from drug-oriented research wherein researchers look at single components. Nutrients often need accessory factors, therefore I wanted the full complex of nutrients found in yeast.
Passwater: Have you elucidated the mechanism or mechanisms through which selenium is acting to prevent and reduce the death rate of cancer?
Clark: I think we are in the process of actively elucidating the mechanism. As you said, there is likely to be more than one mechanism, and even when we find the primary mechanism, such as apoptosis (programmed cell death), which clearly is involved in selenium’s effect on cancer, the question then becomes how does selenium induce apoptosis? So there is always a mechanist question behind the question that you are able to answer.
Passwater: Many of our readers are not biochemists and may not be too familiar with apoptosis. This is a mechanism by which the body destroys imperfect cells. During the cell cycle, a cell can become damaged, and rather than let this cell continue to divide into additional imperfect cells, the apoptosis mechanism simply destroys the imperfect cell. The are two popular pronunciations; ap-o-to’sis and ap’op-to’sis. A more technical definition is that apoptosis is the single deletion of scattered cells by fragmentation into membrane-bound particles which are phagocytosed by other cells; believed to be due to programmed cell death. The word is derived from the Greek words "apo" meaning "off" and "ptosis" meaning "a falling."
An important point about apoptosis is that in apoptosis, the targeted cells quickly shrink and shed tiny vesicles that are ingested and destroyed by neighboring cells without leaving a mess to cause inflammation. In this orderly and efficient process, the cell materials can be disassembled and the building block used over again. The apoptosis process takes only a few minutes which markedly contrasts with cell necrosis, which is cell death resulting from injury or poisoning. In cell necrosis, the cells swell over a period of several hours until they burst, spilling their contents over neighboring cells eliciting an inflammatory response.
Now the question becomes which selenium compound or compounds would be most effective in regards to apoptosis or other possible mechanisms?
Clark: Let’s go back and ask what is the best dietary source? And as a supplement, I think that a high-selenium yeast is the best source because it is a high selenium food. When you get to mechanistic levels you are then talking about downstream metabolic products that really aren’t available over the counter and probably shouldn’t be available over the counter.
Passwater: Since we don’t yet know how selenium acts to reduce cancer incidence and mortality, and we don’t know which form or forms of selenium are used in this process or processes, you originally decided to go with a complex of selenium compounds in a natural food form. Have you now decided to change the supplement form you will use in your continuing cancer studies?
Clark: No! Only the trademark name has changed. The high-selenium yeast that I have used in all of my clinical studies, as well as that being used in the studies that will get underway shortly, is now called SelenoPrecise™. The selenium that we used is our trial was produced by Cypress Systems of Fresno, California. This company continues to produce it by the precise method previously used and it continues to achieve the same high-quality product. The product is then distributed to companies that formulate it and market it under their individual brand names. I do not know. However, the use of that trademark certainly would help the consumer identify which product we used in our trial.
Passwater: The most predominant compound in high-selenium yeast is selenomethionine. Is selenomethionine the most active cancer-preventing compound in yeast or are other organic selenium compounds in yeast more effective?
Clark: Selenomethionine has clearly been shown to be anti-carcinogenic in animals, so there is no question about that. Given its long half-life I suspect that there are other compounds in the yeast that are also very biologically active and we are hoping to identify those in the near future.
Remember that many of these nutrients have accessory factors which can work together to produce greater activity. It’s quite possible that although selenomethionine is a major selenium compound found in high-selenium yeast, it utilizes other minor compounds to facilitate its activity.
Passwater: Are you counting on selenium yeast to provide some compounds such as selenopeptides that are quick-acting and other compounds such as selenomethionine that are longer-acting? Or are you counting on a complex of selenium compounds to follow different pathways to give greater efficiency of protection?
Clark: I think selenium yeast does both. I think it gives you immediately available selenium for the body’s selenium pool for selenium prevention. Or these selenopeptides might actually have specific effects that we are currently unaware of. And long term, the selenomethionine gives you good stability in your selenium status so that if you miss a pill one day it really is of very little consequence.
Passwater: Years ago brewers’ yeast was a beloved dietary supplement. Then because of some unfavorable publicity for one specific, unrelated yeast, candida, yeast supplements were shunned. Dr. Baugh, please tell us a little about the basics of yeast supplements. Please begin by explaining the difference between baker’s yeast and brewer’s yeast.
Baugh: In the early ‘50s and ‘60s, brewer’s yeast was introduced to the supplement market primarily because of huge volumes of the brewer’s yeast coming from the waste stream of breweries in the United States, Canada and Mexico.
The brewer’s yeast is used to ferment seven to ten batches of beer. By the time it has been used for about ten fermentations, it is discarded for one reason only. That is because of high levels of contamination with bacteria and other wild yeasts. Because of the huge volumes and because it has some protein, it was introduced into the health food or supplement markets. The problem being that during the ‘50s and ‘60s, the drying process used for that yeast was not effective in terms of killing everything that was in the liquid yeast. Therefore, some of the bacterial contaminants, yeast and many of the wild yeast strains survived live and made it through into the finished dried product. This made it unacceptable for many of the people who would consume it.
No one today recommends the consumption of live yeast because it is a voracious scavenger of B vitamins. Many of the people who would consume live yeast would end up developing symptoms of B-vitamin deficiencies. The contamination with wild yeast in waste brewer’s yeast also presented a potential pathogenic problem with species such as the Candida. In the 70s, baker’s yeast was accepted as a much, much better substitute for nutritional supplementation because it was grown as a primary culture, i.e., not a waste stream from an industrial process and it could be grown in much cleaner, pure cultures. In addition, the pasteurization or sterilization processes prior to drying were highly developed by baker’s yeast manufacturers. This process assured that a very sterile, clean product could be made, and an uncontaminated product could be produced which is completely dead in the finished dry material.
Baker’s yeast is different from brewer’s yeast -- as different as a horse is from a donkey. Both are mammals, and you can ride both of them, they even share genetic backgrounds. But physically, biochemically and physiologically, they are different. Baker’s yeast and brewer’s yeast have this broad range of differences, not only structurally and physically, but physiologically as well.
The classic brewer’s yeast was classified as Saccharomyces uvarum or Saccharomyces carbergenis. Many folks now classify them all as Saccharomyces cerevisiae, which I am not sure is wise. But, they have. Now industrially we are seeing as many as a hundred different strains or "races" of Saccharomyces cerevisiae and they are distinguishable primarily by the way they react to certain sugars and by the way they react to an aerobic environment versus an anaerobic environment. So when we talk about the differences between baker’s yeast and brewer’s yeast, there are some very real concrete genetic and physiological differences.
The primary difference in terms of nutritional supplementation is that the baker’s yeast characteristically is approximately 55 to 56 percent protein by weight, whereas the brewer’s yeast typically is only 35 to 36 percent protein by weight. This will become even more important as we talk about selenized products.
The secondary difference is that the baker’s yeast strains have the ability in the presence of high levels of oxygen to convert almost all of their energy to the production to new cell mass or growth. Under these aerobic conditions we can generate a doubling of cell mass every three and a half hours with the baker’s yeast strains and during that time produce 55-56 percent of that cell mass as all new protein. The baker’s yeast strains are preferable because of their high quality and high levels of protein, their purity and ability to completely kill and sterilize prior to the drying of the product. Consequently, there is an absence of contaminants, pathogens and unwanted organisms in the product.
Passwater: It seems obvious that if someone were to develop a specialized high selenium yeast, it would be of a baker’s yeast variety.
Baugh: That’s exactly correct. We came to the conclusion in the late l970s that the classic baker’s yeast strains are much preferable for nutritional supplementation, but particularly true with selenium. We had major advantages in utilizing the baker’s yeast strains versus any of the other strains of Saccharomyces. We were able to find a classic baker’s yeast that achieved greater than 98% efficiency of selenium uptake, with 100% organic binding in a very high-quality protein. This is the material used by Dr. Clark in the 1996 JAMA study and is now provided exclusively as SelenoPrecise™.
Passwater: What is the difference between conventional baker’s yeast supplements and high selenium yeast?
Baugh: Many of the yeast supplements are utilizing yeast simply as a carrier. The selenium yeast, as well as the chromium yeast, is different in that it requires the active growth of the organism, not only to take up the mineral, but also to assimilate it into an organic compound. Selenium and chromium are two examples of yeast supplements which require this active metabolic process of doubling cell mass to succeed in the organic binding of this material. As an example, one very popular yeast product is a dead dried yeast that carries enrichments of B-vitamins. The baker’s yeast makes a high level of B-vitamins for itself but in the supplementation industry a higher potency was required. So we can add a B-vitamin kit to a baker’s yeast slurry and mix it thoroughly and then spray dry it to produce a very-high potency of B-vitamins utilizing yeast as simply a carrier. However, in the selenium and the chromium supplements, it is required for the yeast to be in an active state of growth to both assimilate the minerals and to bind them in organic molecules. It is not wise to use yeast as a carrier of the inorganic salts of these minerals because of concerns about toxicity and low bioavailability.
Passwater: I remember, just after the publication of my book "Supernutrition: Megavitamin Revolution" in 1975, that high-selenium yeast supplements were introduced. Were you involved in the development of high-selenium yeast?
Baugh: No. Dr. Henry Peppler, who was at that time Director of Research and Development for Universal Foods, did most of the early work in developing selenized yeast for nutritional supplements. I became involved in 1979. My role was to work with Dr. Henry Peppler in my laboratories in North Carolina to do the scale-up for the large-scale fermentation development.
In addition, I worked with Dr. Peppler to increase the potency and then be able to take it from laboratory work to a large-scale aerobic fermentation. We first produced selenized yeast by what is now known as the SelenoPrecise™ process in my North Carolina baker’s yeast factory in 1981. Cypress Systems, Inc. now owns the exclusive right to this process and uses it to create a high-selenium yeast identical to that employed by Dr. Clark in his 1996 study.
Passwater: So in order to meet the growing demand for selenium yeast, it had to go from the small batches that could be made under laboratory or pilot plant conditions to larger scale production. Is that the point at which you became involved?
Baugh: That’s correct. There is another factor too. The original work achieved potencies of
selenium that were low--under 1,000 micrograms per gram of dry weight. When Dr. Peppler came to me in North Carolina, the key issue was to increase the potency of the selenium and avoid free-selenium salt contamination. We found it necessary to select a yeast strain which produced a very high protein percentage in order to both increase the potency and maintain complete organic binding.
Passwater: I remember a few years later after the introduction of high-selenium yeast as a dietary supplement that another mock selenium yeast was introduced which was no more than a physical mixture. It was baker’s yeast mixed with reddish selenium salts. It was easy to tell the physical difference under a microscope. You could see the particles of the inorganic salts. What is the nutritional difference between this mock selenium yeast and true high-selenium yeast?
Baugh: The mock selenium yeast was produced by adding inorganic selenium salts into a liquid yeast slurry and then spray drying it. This process leaves over 95% of the selenium as the inorganic salt. There is very little incorporation of selenium into the yeast and virtually no organic binding. That product at times would have a slightly pink color and an acidic pH typically below a pH 5. Normal baker’s yeast that has been selenized organically is light tan in color and has a pH at 6 or above -- very close to neutrality -- and never having a pink color.
The key problem there is that the inorganic salt has a lower bioavailability, significantly lower than an organic bound selenium. The consumer simply doesn’t get his money’s worth. Keep in mind that it most likely is the organic selenium compounds that are the most efficient cancer-protecting compounds. Also, inorganic selenium salts are toxic at about one-third of the level of seleno-amino acids.
Passwater: How can consumers today who want to use the same high-selenium yeast that Dr. Clark has used and will be continuing to use in the upcoming studies, tell which is which? Is there a quick test that the consumer can look at or is there a label difference the consumer should look for?
Baugh: I very much hope that there will a distinct label difference in that the compositors or manufacturers of the supplements should be utilizing the trademarked SelenoPrecise™ logo on the labels of their branded products.
There also is a simple test that the manufacturer can do to determine the presence of free inorganic selenium salt. The average consumer, however, is not going to have the ability to do this test. Dr. Gerhard Schrauzer developed a selenium kit utilizing the dye methylene blue which can quickly determine the presence of a free inorganic salt of selenium. These reagent test kits are available in all microanalytical laboratories, but generally not available to consumers. So the consumer is going to have to be dependent upon the appearance of the SelenoPrecise™ logo indicating that this is the yeast used in Dr. Clark’s clinical studies.
Passwater: So let me recap this. We were speaking of a mock selenium, which was a crude mixture of yeast plus selenium salts and comparing that to high-selenium yeast. But according to your remarks there also are various levels of high-selenium yeast that could be as much as 98 percent of the product incorporating all the selenium as organo-selenium compounds. You also mentioned 78-80 percent so another grade of high-selenium yeast may have lesser amounts that are organo-selenium compounds.
Baugh: There are several manufacturers of selenized yeast currently in the United States and Canada, and of these, the only one that certifies and guarantees the organically bound selenium at a level approaching 100 percent (98-99 percent). This is the SelenoPrecise™ product.
Passwater: So this might constitute another test that the manufacturers could use. They could, as part of their certificate of analysis, ask for their guarantee of the selenium presence being organically incorporated into selenium compounds and for the absence of inorganic selenium compounds.
Baugh: Exactly. The procedure using the selenium test kits is well documented in Dr. Gerhard Schrauzer’s publications and I believe the best of the manufacturing groups, tableters, and compositors are going to be doing that analysis as a part of their quality control on raw materials. But at the very least, they should demand from the manufacturer analysis stating the organically bound properties.
Passwater: It seems that, as with all supplements, a high-selenium yeast may be of high-quality or low-quality, but, we’re not just speaking of taste or freshness. There is a nutritional difference between the two.
Baugh: The differences in the percentages of organically bound selenium are a direct consequence in of time and money invested by the manufacturer. Anyone who manufactures a quality product must spend more time and use very expensive equipment. There has to be a much more exhaustive washing of the product prior to drying. This adds considerable costs, therefore, the lower quality products are produced because they are cheaper to make and realize a higher profit margin. The production of these lesser quality products is simply a factor of greed.
Passwater: What we are looking at is not merely the loss of organic compounds that may be needed for the cancer protection but we are also adding undesirable, possibly toxic inorganic forms as well.
Baugh: Exactly. That is exactly correct.
Passwater: Obviously, it is difficult and expensive to grow yeast with an elevated content of natural selenium compounds.
Let’s give our readers a break here for now and finish our discussion of high-selenium yeast next month. At that time, we will look at the exciting new studies that Dr. Clark has underway that, hopefully, will once and for all, we will be able to prove that selenium supplements -- at least in the form tested -- drastically lower the incidence of many types of cancer, and even decrease the death rate from those cancers in persons who already have the disease.
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