Selenium Supplement Cuts Cancer Death Rate in half:
An interview with Dr. Larry Clark

Part I: Clinical results

Richard A. Passwater, Ph.D.

A DIETARY SUPPLEMENT cuts the cancer death rate in half in a clinical study! Yes. a dietary supplement a pill not a diet low in something nor a diet rich in something. And furthermore, it's a dietary supplement found in health food stores and normally not found in conventional drug stores and supermarkets. Furthermore, the study is a human clinical study meeting the "gold standard" of scientific research requirements, not a laboratory animal or epidemiological (population survey) study. Individual foods and total diets vary too much in selenium content to be reliable sources, thus the only assured way to get the protective amount of selenium is to take the selenium supplements containing known amounts of the essential trace mineral selenium as used in the clinical study.

I don't know of anything more exciting than to see our principals once again confirmed in spite of the objections and resistence of those who have yet to understand that we can get better than average health by eating a variety of whole foods including plenty of fruits and vegetables, being active physically and mentally, invoking a positive mental and spiritual attitude, and the appropriate use of dietary supplements. The significant point lost on many is that dietary supplements can be the difference between being healthy according to average standards or in being optimally healthy. All of the other factors are required for the foundation of health, and we can't really be healthy without them, but dietary supplements can further reduce free radical damage and boost the immune system to achieve more of the potential health built into the genetic structure of our bodies.

Because of the importance of this study to everyone's health and because I have been doing research with selenium since 1960, it has been especially agonizing for me not to bring Dr. Clark's story to you earlier. I was informed of his unofficial preliminary results before Christmas 1995 and thought that the study was a wonderful present for the world. However, premature public disclosure jeopardizes the chances of acceptance of studies into scientific and medical peer- reviewed journals. This study is so important that it was vital to have it published in a major medical journal so that busy physicians, and even the news media, would know about it. It is hard enough to get a medical journal to accept an article that shows that a dietary supplement is beneficial, without having the additional burden of having the information already being old news circulated without appropriate scientific review in the news media. When this interview was conducted in April 1996, it was hoped that the Journal of the American Medical Society would rush out the vital information by July or August. However, the scientific review process is an exacting process that by necessity must move at a thoughtful; and deliberate pace. When Dr. Clark received word that his study was scheduled to be published in JAMA in January 1997, we decided to bring you the facts and story behind the clinical study in our February issue. Just after we sent the January issue to the printer, Dr. Clark informed us that his study was moved ahead in publication schedule and would be featured in a press conference scheduled for December 23, 1996. Well, we did get out Christmas present, as they say, "better late than never."

Since 1983, Dr. Larry C. Clark, M.P.H., Ph.D., the Director of the Arizona Cancer Center's Epidemiology Program of the University of Arizona (Tucson) has been studying about 1,300 East Coast residents and their risk for cancer. Recently, Dr. Clark has reported the results of his group's multi-centered Cancer Prevention Project involving seven clinical centers in South Carolina, North Carolina, Georgia, Florida and Connecticut to test the ability of selenium supplements to protect against cancer. The ten-year results are in! In Dr. Clark's study, selenium supplements are strongly associated with dramatic reductions in cancer incidence and cancer mortality.

Dr. Clark and his collaborators from Cornell University, Professor of Nutrition Gerald Combs, Jr., Ph.D. and Professor of Statistics Bruce Turnbull, Ph.D. chose to conduct their clinical study of residents of these states because their soils are low in selenium and four of the five states have relatively long seasons in which residents can enjoy the great outdoors and thus have increased sun exposure and risk of skin cancer. As figure 1 shows, the majority of the U. S. population lives in areas having less than optimal selenium levels in their soils. Diets considered to be well-balanced in the U. S. range between 60 and 200 micrograms of selenium per day. Residents of the Eastern Coastal Plain and the Pacific Northwest who eat well-balanced diets average 60 to 90 micrograms of selenium per day


Passwater: Congratulations on your exciting clinical study that indicates that selenium supplements greatly reduce the risk of cancer. The results are dramatic. Dr. Clark, you are no newcomer to researching selenium's protective role against cancer. I have often quoted your research and highlighted one of your studies in my 1986 booklet, "Selenium Update," and my last two editions of "Cancer Prevention and Its Nutritional Therapies." What aroused your interest in cancer research and especially selenium's role in protection against cancer?

Clark: By way of background. My stepfather, Dr. William Bat, directed a cancer research foundation where some of the original work on diet and its influence on cancer and longevity was done. That sort of gave me a unique perspective; I grew up thinking that diet was related to cancer which was a rather avant garde idea at the time.

I became interested in selenium in particular because I had been doing a study in North Carolina looking at patterns of cancer mortality in the southeast and how they related to pesticide use. I saw a pattern of excess cancer mortality that followed the geology of the southeast.

We had decided that was probably related to something that we call "insect pressure" and how much pesticide you have to use and I showed this map to Dr. Andre M. van Rij from the University of Otago in Dunedin, New Zealand who was visiting and he said that it looks an awful lot like these geographic distributions in the southeast because it fits the fault lines between the Piedmont and Gulf Plains. At that time, we were very interested in arsenic which was what we thought was explaining the elevated risks of lung cancer in the southeast. We wondered if the arsenic in pesticides could increase the risk of cancer. When we did our next study which was the skin care control study, we were really focusing on arsenic and vitamin A. We also were looking at the carotenoids as provitamin A and selenium as the metabolic antagonist of arsenic as was suggested by Dr. Orville Levander. We expected to find that the more selenium present in the soil and foods, the less arsenic was absorbed and thus the lower the risk of cancer.

In the study it was selenium that showed a strong dose response relationship with the risk of skin cancer and arsenic levels were too low to show a relationship either independent or dependent with selenium. I finished my dissertation at the end of 1981 and the study was published in early 1984.


Passwater: Did you ever publish the maps comparing the distribution of soil selenium and the incidence of cancer?

Clark: We did. That was in the Archives of Environmental Health in 1992. There we looked at cancer patterns by county. We had Dr. Alloway at Cornell who was with the soil lab (actually he had retired by that time that he worked with us, but he had done the original work on the selenium distribution of the US with Dr. J. Kubota). He took their broad maps that covered multi-state areas and then classified every county in the U.S. as to whether it was in a low, intermediate or high area through detailed information from almost 3,000 forage samples. Then we looked at the patterns of cancer incidence and found a very distinct pattern just as reported by Dr. Gerhard Schrauzer and others before that showed that individuals who lived in the low selenium counties had about a ten percent excess mortality from cancer.


Passwater: Dr. Ray Shamberger did similar ecologic studies comparing the selenium content of soils and in the food supply from about twenty small regions to cancer rates. In my 1980 book, "Selenium as food and medicine," (Keats Publ. Inc.), I published, side by side, a 1967 United Sates map by the J. Kubota of the USDA (Tech. Bull. No. 758) crudely showing soil selenium content, and a 1959 cancer incidence by state map compiled by Dr. Gerhard Schrauzer. The visual impact is striking, although the data did not match perfectly.

The low selenium areas not only have more cancer, they have more heart disease and stroke. But, that's another story!

Clark: We used the most detailed geographic level which was the county rather than the state and we used the 20-year cancer data. So we used the best available information and techniques and essentially we were able to replicate what earlier investigators had found. We felt that the earlier works weren't really taken completely seriously because of methodological issues that posed alternative interpretations.


Passwater: You were looking at soil arsenic levels and arsenic exposure, and as is often the case in science, you saw something else that was even more interesting. Without setting out to examine selenium as a direct variable, you found that selenium correlated better with cancer incidence than any other variable or combination of variables that you considered..

Clark: At that time, when I was designing that first case control study and as I continued to study selenium it became obvious to me that this might be a really good test for the hypothesis. All the studies up to that time were case control studies and as you are aware cancer patients tend to have low levels of selenium or develop lower levels as their disease progresses. Thus you could not be sure if selenium was part of the etiology or a consequence of the cancer. You could never be sure whether you were observing a true relationship or whether it was biased by this metabolic phenomenon. So we thought skin cancer patients would be a really good group to study because the cancer is never large enough to really affect their metabolism. So that was the other motivation for looking at skin cancer and selenium. Since that time there has been a number of cohort studies that have looked at it.


Passwater: Many of our readers may not be familiar with the differences between the various types of studies. Epidemiology studies do not prove cause and effect, they merely point out a possible association between parameters. Umbrellas are associated with rainy days, but umbrellas do not cause rain.

Case control studies are a special type of epidemiological analytic study that eliminates many confusing variables of the descriptive epidemiological studies. Case control studies match a group of affected individuals with a group of similar healthy persons usually of the same age, sex, race, lifestyle, and many other factors, hoping to prevent those factors from confounding or masking the true factor that is associated with the disease.

Cohort studies are another special type of epidemiological analytic study that examine specific sub-populations or groups that all share a common factor. The study then compares various cohorts in terms of their exposure or absence of exposure to a possible risk factor for the disease over a period of time.

All of the above have weaknesses. They are purely observational. The only widely accepted "proof" that a nutrient or drug reduces disease is a clinical intervention trial. A clinical intervention trial is a randomized, double-blind, placebo controlled clinical trial in which the differences in disease rates between the control group taking the placebo and the experimental (treated) group taking the active compound is so large that the difference can not be due to chance. A placebo is a "dummy" pill that looks like the real pill but has only inert ingredients. "Double-blind" means that neither the volunteers nor the study researchers know which volunteers are getting the placebo and which are getting the active compound that is being studied. An independent person, usually a pharmacist, not directly involved with the volunteers or study researchers, keeps track of who gets which. Only after the study is completed and the data complied, is the code broken so that the researchers learn which volunteer received which pill.

Your study certainly meets these requirements.

Clark: Yes, our study was a randomized, double-blind, placebo-controlled clinical intervention prevention trial using a nutritional dose of selenium, 200 micrograms of selenium per day from high-selenium brewers yeast. The placebo was an equal amount of normal brewers yeast identical in color and smell.


Passwater: Now one more time for all of the dieticians and physicians who are opposed to the principle of dietary supplements and feel that you can get all of any nutrient that you need from a "well-balanced" diet (whatever that is). If the soil that plant foods are grown in are totally lacking selenium, the plant foods will grow fine as edible grains, nuts, fruits and vegetables do not need selenium. In the case of animal products, if the animals were fed plant foods that were low in selenium, the animals, all of which do need selenium, may grow enough to be used for meat although they too are selenium deficient. The result of selenium deficiency in animals is usually observed as muscle diseases, heart disease and cancer, which may go undetected during the short lifespans required for them to become market-ready. In an April 27, 1973 news release, the FDA stated that "selenium levels found in animal feed vary widely depending on the soils in which the feed crops were grown."

Earlier, we spoke of the selenium-distribution maps prepared by Dr. Kubota in 1967. He found that over 80 percent of the U. S. Corn Belt had selenium-deficient soils (containing less than 0.1 part selenium per million). In 1969, Dr. Oscar Olson confirmed that selenium levels ranged from 0.01 parts per million in Indiana to 2.03 parts per million in South Dakota. That's a 200-fold variation in the same crop. Even within a small area, the selenium content of corn are highly variable. Near Gregory, South Dakota, samples varied from 0.14 to 2.0 and near Rushford, MN, from 0.02 to 0.29 part per million. Seventy percent of the corn had less than 0.05 and only three percent had more than 0.15 part per million.

Wheat grown in the Midwest can contain up to 100 parts per million of selenium, whereas wheat grown in the State of Washington may have less than 0.1 part per million. This is a variation of 1,000 fold in a single food item.

An FDA survey found no selenium in five samples of a balanced diet. The analyses were done by activation analysis which is extremely sensitive and accurate (Hopkins and Majaj, 1967). In 1971, Dr. Douglas Frost reported on the scarcity of selenium in prepared meals. In 1973, I reported that I could not find selenium in any of the several "TV dinners" that I analyzed spectrophotofluorometrically (Fluorescence News, 1973). Several investigators have reported well-balanced diets contain 50 to 120 micrograms of selenium daily, and Dr. Orville Levander has reported that in some areas, diets contain 100 to 225 micrograms of selenium, but the point is diets do vary in selenium content even though the same food groups are eaten. This is not unlike the case with iodine. Iodine is lacking from the soils of the "goiter-belt." People living in low- iodine soil areas can not get enough iodine from their diets. The problem was alleviated with the introduction of food fortification in the form of iodized salt. It is difficult to find table salt that is not iodized, even if you live in an iodine-rich soil area.

Food processing adds another variable. Although selenium is a mineral, it is usually present in foods as organic selenium compounds which are fairly volatile. Heat, processing and cooking can diminish the selenium content of foods. The refining of grains can destroy as much as 50 to 75 percent of the selenium in whole grains. Boiling may eliminate about 45 percent of a food's selenium content.

Whatever amount of selenium the average American is eating is not enough for optimal health. In addition, the average American can not be assured of a diet that is considered to be representative of the typical American. The values are just too variable. But we do know that there are areas in this country that have very low amounts of soil selenium, and that this is a risk for these residents

Clark: This is why we were particularly concerned with the areas in which we conducted the study. They are regions in which soils are generally low in selenium.


Passwater: When you published your first information it was probably pretty hard to get funding for such a thing as selenium and cancer. Did you have to go through a series of small steps to get funding or was it relatively non-eventful.

Clark: I actually did this research while I was employed at the National Institute of Environmental Health Sciences (NIEHS) in the Research Triangle Park and the University of North Carolina. NIEHS funded the original project with a couple of small purchase orders.


Passwater: I notice that in your April 1966 FASEB abstract, "The nutritional prevention of cancer with selenium 1983-1993: A randomized trial," you began enrolling people in the study by 1983. That step, going from your observational study to a clinical intervention trial, as logical as it seems to you and me, based on the vast animal and epidemiological literature, probably seems to be a rather big step in the minds of some researchers. |

Clark: The sequence is that we did the case control study, then we followed those patients up for several years in a cohort study and found a similar association. By 1983 we felt it was time to investigate the feasibility of doing a clinical intervention trial.


Passwater: That's certainly reasonable. In spite of all the animal and epidemiological evidence, most of the medical community just will not accept any evidence that supplements prevent cancer until they see it so proven by a clinical intervention trial.

Did you have trouble getting the funding to do a clinical intervention study?

Clark: We had lots of problems getting funding.


Passwater: It seems that no agency wants to fund a study until the outcome has been guaranteed.

Clark: I find it interesting with the huge database of experimental research how difficult it has been to get people interested in it. I am amazed by the fact that we are the only people in the country doing a human clinical intervention trial considering that the experimental literature is so strong.


Passwater: Let's talk about the experimental literature. There are mechanistic studies, there are animal studies, and there are epidemiological studies and now, thanks to your research, we have a clinical intervention trial that is randomized, placebo-controlled and double-blinded, which are the gold standards of clinical studies. When you made your first observations, I am sure you decided to check the literature. What struck you at that time? What did you notice that encouraged you?

Clark: When we started our clinical trials, we had two studies involving our population the case control and the cohort study -- that suggested an effect. Also, in the 1980s, there were a lot of animal studies. The Hypertension Detection and Follow-up Program (HDFP) cohort had just been published by Dr. Walter Willett, so in my thinking, the body of literature at that time made a strong a case for selenium preventing cancer. There was a better case for selenium than for any other compound or family of compounds, especially carotenoids.


Passwater: I believe that Dr. Willett's study "Prediagnostic serum selenium and risk of cancer was published in the Lancet in July of 1983. In this case control study, blood samples had been collected in 1973 from 4,480 healthy men from fourteen regions of the United States and stored for later analyses. During the next five years, 111 cases of cancer were detected in the group. The researchers then retrieved the stored blood samples from these men and from 210 other men who were selected because they matched the newly-developed cancer patients in age, sex, race, and smoking history. The levels of several nutrients and other factors were compared between the men who developed cancer and those men who remained free of cancer. Only one difference stood out as being significant. The risk of cancer for men in the lowest quintile (fifth) of blood selenium levels was twice that of men in the highest.

That study was so interesting that I wrote to him and extended an offer from the Solgar Nutritional Research Center to fund additional research. He declined our offer, but later followed the 1983 study by looking at data provided by measuring the selenium content of toenails obtained from nurses and comparing this level to the incidence of breast cancer in the nurses. [Garland, M., et al., J. Natl. Cancer Inst. 87(7):497-505 (April 5, 1995)]

Clark: That study was difficult to interpret. On first examination, the results didn't seem to support the thesis that selenium was protective against cancer.


Passwater: The results were limited because of at least two factors. First, the nurses were consuming diet having a very narrow range in selenium. You won't find much variation in cancer incidence between diets having small differences near the lower extreme of selenium deficiency. The actual amount of selenium in the diets was not even measured. Since the amount of selenium in any given food item varies according to the amount of selenium present in the soil in which that particular plant was grown, food tables or other "book values" of selenium content are meaningless.

Secondly, there is poor correlation (0.4) between selenium in the toenails and glutathione peroxidase levels or any other selenium-containing compound in the body. Let me jump ahead. I mentioned glutathione peroxidase. We don't know really what the actual selenium-containing compound or compounds that protect against cancer is or are. Is it glutathione peroxidase, methylselenide, or other selenium-containing compounds that protect against cancer, or is it a combination of selenium-containing compounds, or a combination of one or more selenium- containing compounds with vitamin E? We don't even know precisely which mechanism or mechanisms are involved.

Clark: That's true. One other point is that when we started the study one of our rationales was to emulate the epidemiology as much as possible. Therefore we decided to use a high-selenium yeast which contains selenium methionine and other organic selenium-containing compounds, rather than a purified singular form of selenium. We felt the organic yeast would be more representative of what people were eating in their diet and inorganic selenium wouldn't be.


Passwater: It seems that all of us selenium researchers have had to get by on shoestring budgets.

Clark: The history is we had a small pilot study supported by a company that distributes high-selenium yeast with $15,000, then the American Institute for Cancer Research funded us for a total of four years. That allowed us to expand the study to three clinics. Next the American Cancer Society funded us for a number of years which allowed us to expand to the full seven clinics. When we had achieved that, the National Cancer Institute (NCI) funding finally came through. NCI has supported the project since 1987.


Passwater: OK, we have teased the readers long enough. Let's get to your study results. What was the effect of selenium supplements on cancer mortality in the population studied in your clinical study?

Clark: Cancer mortality was reduced 50 percent (p=0.002) and overall mortality was reduced 17 percent (p=0.14)


Passwater: The statistics show that there is little chance that the results were merely due to chance alone. Medical statisticians have arbitrarily agreed that a result is called "significant" if there is less than one chance in twenty (five percent) that the result is due to chance alone and that the result is consistent with the hypothesis being tested. This is expressed mathematically as the parameter, p, having a "p-value" of 0.05 or less (p<0.05).

Clark: Yes, the p values were very respectful.


Passwater: What effect did the selenium supplements have on cancer incidence?

Clark: Total cancer incidence was reduced 37 percent (p=0.001). In addition, the three leading sites of cancer had significantly lower incidence; lung cancer was reduced 46 percent (p=0.04), prostate cancer was reduced 63 percent (p=0.002) and colon cancer was reduced 38 percent (p=0.03).


Passwater: In Part II, let's discuss the details of your clinical study and more basic information about selenium as a dietary supplement.


Reprinted from Whole Foods magazine (February 1997)
Copyright 1997 by Whole Foods magazine