A dozen years ago, on Christmas day December 25, 1996, great joy emanated from a clinical trial showing that suffering and death could be cut in half simply by taking a selenium supplement.
Yet, in spite of this study and other human clinical trials along with considerable mechanistic and laboratory animal evidence that selenium-containing nutrients reduce the risk of cancer in humans, on October 28, 2008, the National Cancer Institute (NCI) announced that it was prematurely halting the Selenium and Vitamin E Cancer Prevention Trial (SELECT) which was to look at this relationship over 13 years. What was their thinking? The pronouncement that the study did not show evidence of effectiveness against prostate cancer is contrary to previous NCI trial results in which high-selenium yeast was used as the selenium source. The SELECT study was designed to end in 2013. Why did they halt it prematurely? Was the study designed properly? Why did it use selenomethionine for which there are no published human clinical studies of its anticancer effect instead of selenium-yeast which was shown to have dramatic anticancer effects in a five-year study of 13,000 people? Did NCI choose the wrong form of selenium nutrient for cancer research or did they choose an inappropriate timeframe for the form that they did choose?
I will try to produce an exoteric synthesis of the complex information involving this issue. Important considerations are:
• The NCI SELECT trial did not use high-selenium yeast, a form of selenium supplementation that has been shown to be
very effective in reducing cancer incidence and mortality in an earlier NCI-sponsored clinical trial.
• The NCI SELECT trial investigated selenomethionine, a nutrient form of selenium that is readily incorporated into body proteins without forming anticancer selenium compounds. While selenomethionine is an appropriate selenium nutrient and has some anticancer properties, these properties are not as strong as many other selenium compounds and they take longer for these anticancer properties to take effect due to its removal of active selenium by its incorporation into general body proteins rather than being available for anti-cancer activity.
• Other published studies continue to demonstrate the anticancer effect of several selenium-containing nutrients.
• Selenium-containing compounds differ over a 1,000-fold in their ability to prevent cancers.
• Published studies have compared the two forms of selenium-containing nutrients—selenium yeast and selenomethionine—and have found that selenium yeast is far more effective against prostate cancer.
• The SELECT trial was prematurely terminated without scientific cause after only five years instead of running to 2013 as designed and required to observe the anticancer benefits.
• The wrong form of vitamin E was used, synthetic d,l alpha tocopheryl acetate which has little anti-cancer synergism with selenium compounds, instead of d-alpha tocopheryl succinate or gamma-tocopherol which are more synergistic with selenium compounds regarding anti-cancer activity (Passwater and Olson, U.S. Patent #6,090,414 and Regan-Shaw et al., Prostate 68:1624–1634,2008).
• No harm was demonstrated by either selenomethionine or vitamin E. There was no evidence of statistical significance of any health problem.
The SELECT trial was prompted by the findings from the Nutritional Prevention of Cancer (NPC) Trial, which found that the risk for prostate cancer was reduced by more than one-half for those taking selenium-yeast supplements. According to NCI’s Web site, “The National Cancer Institute (NCI) designed a study that it called the Selenium and Vitamin E Cancer Prevention Trial (SELECT) to test for the efficacy of daily use of a-tocopherol (and/or selenium) supplements in the primary prevention of prostate cancer in 32,400 men. The SELECT trial is expected to be published in 2013.” I winced every time someone told me they were in the SELECT trial, but they were taking extra selenium and vitamin E “just to be sure” in the event they were in a placebo group. These selfish men wanted the free medical care given to the volunteers, but they sabotaged the study results, wasted tax-payer money and ruined the study designed to find scientific answers to help all men by taking their own extra supplements. If these men wanted the protection of taking supplements, then they shouldn’t have participated in the study and ruined the protocol. There were no countermeasures in the design of the SELECT trial.
What value is the control-group data when much of the control group (placebo) is taking the same investigational supplements as the experimental (active ingredient) group? Or, if these men were actually in the experimental group, and then they were getting double the recommended dosage which may be detrimental, especially with selenium.
Also according to the NCI Web site, “SELECT began enrolling patients on August 22, 2001, and closed enrollment on June 24, 2004, with 35,534 participants. There are 435 SELECT sites throughout the United States, Puerto Rico, and Canada.”
There are other design flaws in the SELECT trial including that it permitted a high rate of “drop-ins” and also that the drug finasteride is being given to some of the participants. These flaws are not the subject of this discussion. I am also concerned that NCI chose both the wrong form of selenium and/or an inappropriate timeframe for the form. The NPC study, which demonstrated that selenium was effective against cancer, used selenium-yeast. The SELECT study used selenomethionine. They are not interchangeable. Selenium yeast contains more than 20 selenium-containing nutrients. Any one or more of these selenium forms may be responsible for its strong anticancer effect. Some of the selenium-containing compounds found in selenium yeast are small molecular- weight compounds that have a direct effect on DNA repair and apoptosis. Other selenium-containing compounds in yeast can be incorporated into selenoproteins, proteins specifically under genetic control to fight cancer and perform the other duties of selenium. My research indicates that several of the smaller selenium-containing compounds can directly interact with DNA epoxides and repair them and that also, several of these smaller selenium-compounds can destroy cancer cells via apoptosis. Seleno-methylselenocysteine is an example of the latter. Selenomethionine is merely one form of selenium compound that is largely diverted into protein formation rather than anticancer activity (although it definitely has anticancer activity).
What is even more surprising is that NCI knew of the greater anticancer effectiveness of the selenium yeast. One example was shown by a study in which the two forms were compared. Dr. David Waters at Purdue University, using the canine prostate as a scientific model, found that high-selenium yeast was more effective in the reduction of DNA damage of canine prostate cells than selenomethionine (J. Nat. Cancer Inst. 2003; 95:237–240).
An earlier study also cast doubt on the selection used by NCI. Dr. David McCormick at the Experimental Toxicology and Carcinogenesis Division, IIT Research Institute in Chicago found no effects with selenomethionine supplementation on the prevention of prostate cancer in rats (Eur. Urol. 1999; 35:464–467). Such negative findings are not the case with other selenium-containing nutrients.
In addition, NCI knew that “the anticarcinogenic activity of selenomethionine is severely compromised in a situation in which it is preferentially compartmentalized into tissue proteins instead of entering the metabolic pathway” (J. Nutr. 1998; 128, 1845–1854). While selenomethionine is a fine nutritional source of the essential micronutrient selenium and it has consistently demonstrated a moderate degree of anti-cancer activity, selenomethionine is the exception in dietary selenium forms in that it follows a non-regulated biochemical pathway (Toxic. Appl. Pharmacol. 1998; 152: 309–331). The body cannot distinguish between methionine and selenomethionine. The body can distinguish between all other forms of selenium due to the nature of the bonds. Selenomethionine is the only form of dietary selenium that can be unintentionally or accidently incorporated into ordinary body proteins in place of methionine. In fact, the body preferentially incorporates selenomethionine into proteins over methionine, unless there is more than one gram of free methionine simultaneously available (Passwater and Olson). The removal of available selenium when it is unintentionally incorporated into general body proteins other than selenoproteins reduces the available selenium pool that could be used to produce anti-cancer compounds, both small molecules that revert DNA epoxides back to normal DNA and also various selenoproteins that have direct anti-cancer activity.
Prostate cancer develops over decades and grows very slowly. NCI should not expect to see an effect from a dietary component with only moderate anti-cancer action within five years. It was remarkable that selenium yeast cut the cancer incidence in half within five years, but selenium yeast has stronger anti-cancer activity than selenomethionine. NCI should have stayed with selenomethionine for the scheduled timeframe which was selected to detect a 25% reduction in prostate cancer or NCI should have selected a stronger anti-cancer selenium nutrient such as selenium yeast or even seleno-methylselenocysteine. 
Let me explain. I have been conducting research since 1959 with various forms of selenium compounds and how they are protective against various forms of cancer. When I began my selenium research essentially 50 years ago, selenium was not recognized as being an essential nutrient in animals, let alone in humans. Human essentiality was established in 1973 by Dr. J. T. Rotruck and colleagues when he identified selenium as being part of the antioxidant enzyme glutathione peroxidase. The first RDA for selenium was published in 1980. Selenocysteine is now recognized as the 21st amino acid in human proteins. My original research was conducted using selenocysteine as the selenium-containing compound.
During these many years, I, and others including the colleagues of Dr. Clemet Ip of the Roswell Park Cancer Institute in Buffalo, have found that the ability of various selenium compounds to protect against cancer varies over a greater than 1,000-fold. Because the critical component of these various selenium compounds is selenium, an element that is classified as a “mineral,” nutritionists and many other scientists have mentally lumped all selenium-containing compounds into a single category of which they think of as “selenium.”
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. Can I paraphrase Billy Shakespeare one more time? Selenium is not selenium is not selenium, meaning of course, that selenium compound A is not the same as selenium compound B which is also not the same as selenium compound C!
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, my colleague, Dave Olson, and I patented it as the most effective anticancer compound in 1997, but it is not yet available as a dietary supplement (EP 750911, CA126(10)135612s). Selenium compounds such as diallyl diselenide and methylselenocysteine (which is available as a dietary supplement) are found in garlic. There can be more than a 1,000-fold difference between the most effective and least effective forms of selenium in preventing cancer.
There is evidence that all selenium-containing compounds have some degree of anticancer activity, however, some require higher dietary levels and longer timeframes of intake to exert their anticancer activity. Conversely, the more effective selenium-containing anticancer nutrients work very quickly and at lower dietary levels. Dietary selenium-rich yeast has been shown in the five-year NPC human clinical study to reduce cancer incidence by 50%. (L.C. Clark et al., JAMA 1996; 276: 1957–1963.) We have discussed this study in this column with Dr. Larry Clark, the lead investigator of this study (see WholeFoods Magazine February and March 1997 or visit www.drpasswater.com/nutrition_library/Clark1.html, www.drpasswater.com/nutrition_library/seleniumcancer.html).
The U.S. Food and Drug Administration (FDA) granted Qualified Health Claim status for selenium and certain cancers on April 28, 2003. Claim 1 is, “Selenium may reduce the risk of certain cancers. Some scientific evidence suggests that consumption of selenium may reduce the risk of certain forms of cancer. However, FDA has determined that this evidence is limited and not conclusive.” And claim 2 says, “Selenium may produce anticarcinogenic effects in the body. Some scientific evidence suggests that consumption of selenium may produce anticarcinogenic effects in the body. However, FDA has determined that this evidence is limited and not conclusive.”
In December 2007, the FDA invited public comment regarding the re-evaluation of evidence for selenium and cancer. My 52-page response is listed as “Exhibit II: Passwater Report” and is online on the FDA documents Web site (http://www.regulations.gov/fdmspublic/component
/main?main=DocketDetail&d=FDA-2008-Q-0323)
Indeed, new studies have been published since the issuance of the qualified health claims by the FDA for selenium in 2003. The additional studies suggest that the existing health claims be expanded to include specific cancers. These studies include intervention studies as well as prospective and mechanistic studies. All new studies provide additional support of the original qualified health claims for selenium against cancer. None contradict the supportive evidence and all provide credible evidence supportive of the proposed new site-specific claims. I will discuss some of the newer studies in this column and address additional research findings in future columns.
New Intervention Trials
Two additional intervention studies have been published since the issuance of the qualified health claim for selenium and cancer. They provide additional support for the original claims and offer, together with the pre-existing evidence, credible evidence for the additional site-specific claims. The original NPC trial has been updated to include the longer length of time passed since the original reported findings. This trial tests selenium against cancer. A second trial, the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) French study, tests the anticancer effects of selenium in combination with other antioxidant nutrients.
NPC Trial. The seminal NPC Trial was an important consideration in determining the 2003 selenium and certain cancers health claim. The NPC Trial tested selenium against various cancers. Now, additional studies have included extended data and analysis of the original report.
As noted in the FDA’s Final Decision Letter for the existing qualified health claim for selenium and certain cancers, Dr. Clark and his colleagues published their large, gold-standard prospective, randomized, placebo-controlled, double-blind NPC trial in the Journal of the American Medical Association in 1996. As we discussed here in an interview with Dr. Clark in February 1997, that study found that daily supplementation of diets with 200 µg of selenium reduced cancer mortality 50% (P = 0.002).
Total cancer incidence was reduced 37% (P = 0.001) and total carcinoma incidence was reduced 45%. In addition, the three leading sites of cancer had significantly lower incidence: lung cancer incidence was reduced 46% (P = 0.04), prostate cancer incidence was reduced 63% (P = 0.002) and colon cancer incidence was reduced 58% (P = 0.03). There was a 17% reduction in all cause mortality (P = 0.14), which when adjusted for sex, current smoking and age yielded a 21% reduction in deaths from all causes (P = 0.07).
The NPC trial results, as first reported were for the first 10 years of the trial (September 15, 1983 to December 31, 1993). However, analyses of the complete trial results were presented only after the time of submission of the petition for health claims in July 2002 (26–30). The newer data provide an average of 7.9 years of follow-up/patient, which provides greater statistical precision than was available for the original analyses at which time only 6.4 years of follow-up/patient had been achieved. The analyses of the complete data support the strongest protective effects previously detected (i.e., selenium supplementation was associated with reduced risks to total cancer incidence [relative risk {RR} = 0.63] and incidences of carcinomas of the prostate [RR = 0.51] and colorectal [RR= 0.46]).
Dr. Jerry Combs has reviewed the NPC trial with emphasis on findings published since the original publication discussed in the July 2002 petition for selenium health claims. Dr. Combs points out, “The robustness of the NPC findings were tested for the strongest observed effect, protection against prostate cancer. That effect was not weakened by excluding cases not supported by elevated PSA [prostate-specific antigen] levels. It was observed in each calendar year after year one, and in each year after subject randomization after year two, across all seven participating clinics. The findings would suggest the absence of a confounding variable because it would be unlikely for such to operate over all clinics in multiple study years.”
Dr. Combs also points out, “Dr. Vinceti et al. suggested that because the complete trial was only 25 months longer than the portion originally analyzed, the relatively weaker treatment effects apparent in the complete data set compared with the original one must indicate that any cancer protection by selenium occurs only in the short term. Clearly, that point does not hold with respect to the incidences of total cancers or cancers of the prostate and colon-rectum, all of which showed comparable responses to selenium supplementation in the two periods of follow-up. One must also consider the effects of the increasing number of patients that were lost to follow-up over that period of time. Although none were lost to vital follow-up (for a total of 9,301 person-year), by the end of the 13-year blinded period, only 36% of patients were still receiving treatment. Under the “intention to treat” paradigm of analysis, this effect could be expected to mitigate detectable treatment effects despite the statistical gains achieved by additional months of follow-up.”
The complete NPC trial data for prostate cancer incidence showed that for men with plasma PSA concentrations <4 ng/mL, selenium supplementation was associated with a 65% reduction in prostate cancer risk (P= 0.01). For men entering the trial with PSA <4 µg/mL, there was no significant effect of treatment (RR = 0.88, P = 0.86), nor did selenium treatment reduce elevated PSA values or affect the clinical stage or incidence of advanced prostate cancers. These findings are consistent with a nontreatment, cancer risk reduction from selenium. There was no indication that selenium supplementation affected the stage of prostate disease among men with that diagnosis.
Many people do not obtain optimal amounts of selenium in their diets. This will be discussed more fully in a future article. Another consideration is that many people have disadvantaged genes (single nucleotide polymorphisms or SNPs) that alter their selenium biochemistry and increase their dietary needs for selenium.
With regards to those not receiving adequate dietary selenium, Dr. Combs has noted, “Protection by selenium supplementation was significant only for subjects who entered the trial with relatively low baseline plasma selenium levels. Those with plasma selenium <106 µg/L (1.35 µmol/L), i.e., in the lowest tertile of that cohort, showed the strongest effect of Se-treatment (RR = 0.14, P = 0.002) in reducing the risk of being diagnosed with prostate cancers over the subsequent years of follow-up. Subjects in the middle tertile of plasma selenium, 107–123 µg/L (1.37–1.58 µmol/L), showed a more modest, but still protective effect of selenium supplementation (RR = 0.39, P = 0.03); however, subjects in the highest tertile of plasma selenium (>123 µg/L, or >1.58 µmol/L) showed no significant treatment effect (RR = 1.20, P = 0.66). To explore the possibility of a diagnostic bias, Dr. Duffield-Lillico et al. simulated results based on the diagnoses they projected on the basis of comparable biopsy rates between selenium and placebo treatment groups; despite a generally attenuated cancer incidence, their analyses showed significant protection by selenium in the lowest plasma selenium tertile group.” Dr. Combs continues, “It is important to note that with baseline plasma selenium levels of 114 ± 23 µg/L, the subjects in the NPC trial did not have nutritionally subadequate selenium status. In fact, only two subjects had levels <80 µg/L, which we’ve found to be the level above which healthy adults show no further increases in selenium-dependent glutathione peroxidase when supplemented with selenium. In fact, these levels suggest an average daily intake of at least 85 µg selenium/day, or at least 155% of the RDA for reducing cancer risk. Subjects entering the trial with plasma selenium levels <120 µg/L showed the greatest risks of subsequent cancer as well as the strongest protective effects of selenium-yeast supplementation.”
The SU.VI.MAX Trial. A 2004 French intervention trial, the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX), studied 13,017 French adults in the general population which gives additional support to the NPC trial.
The SU.VI.MAX study tested selenium plus other antioxidants against cancer. This study incorporated 100 µg of selenium as selenomethionine in its regimen that also included vitamins C and E, beta-carotene and zinc. The amount of selenium used was only half the amount used in the NPC trial.
It is not scientifically valid to argue that intervention trials using multiple nutrients including selenium necessarily do not apply to selenium alone and thus cannot be included in the total body of scientific evidence. The anticancer effect of selenium would be demonstrated in trials of multiple nutrients provided that sufficient selenium was used. The other nutrients may or may not have additional anticancer effects. It cannot be validly argued that the trial results do not necessarily apply to each nutrient separately and thus, in turn, arbitrarily eliminate the anticancer effect of each separate nutrient individually. The fallacy being that to do so ignores the demonstrated anticancer effect. Trials finding anticancer effects that include selenium along with other nutrients must be considered supportive, but not conclusive, of an anticancer effect of selenium.
During the median follow-up period of 7.54 years, there were 98 deaths in the placebo group compared with 76 in the intervention group (P = 0.09). Overall mortality decreased by 37% in males (63 men in the placebo group versus 40 men in the intervention group) (P = 0.02).
Sex differences in selenium biochemistry plus lifestyle differences in the eating habits of the genders can account for sex differences in the results. Estrogen appears to up-regulate some selenoproteins and, also, young French women tend to eat more salads, fruits and vegetables than the older French men in the study.
Total cancer incidence was significantly (P = 0.008) lower in men by 31%, but not in women. An important observation is that the divergence between the placebo and intervention groups continued to broaden with time, suggesting that the reduction in cancer becomes greater over time. Extending the slopes of cancer incidence of the intervention and placebo groups suggests a 60% reduction in cancer within the next seven years.
The significant reductions in cancer incidence were widespread in cancer type including thyroid, urinary tract, skin, respiratory tract, digestive tract and oral cavity cancers. Only hematological and genital cancer incidences were not significantly reduced.
Drs. F. Meyer et al. interpret the results as supporting the hypothesis that chemoprevention of prostate cancer can be achieved with nutritional doses of antioxidant vitamins and minerals.
The AHRQ Review
A report based on research conducted by The Johns Hopkins University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0018) adds more information. The information in this report is intended to help clinicians, employers, policymakers and others make informed decisions about the provision of health care services.
The AHRQ report adds more information about a clinical study of selenium and cancer conducted in China called the “Linxian Trial.” The AHRQ report notes, “the reductions in gastric cancer incidence (relative risk [RR] 0.84, 95% confidence interval [CI] [0.711.00]), cancer mortality (RR 0.87, 95% CI 0.75–1.00), especially stomach cancer mortality (RR 0.79, 95% CI 0.64–0.99) in the groups receiving 30 ‚ß-carotene, vitamin E and selenium compared to the groups receiving other vitamin/mineral combinations.” Additionally, the AHRQ report comments, “reduction in cancer mortality was greater in women than in men and among those of age less than 55 years in this trial (RR 0.79, 95% CI 0.64–0.98) vs. RR 0.93, 95% CI 0.77–1.12), and (RR 0.71, 95% CI 0.55–0.92) vs. RR 0.94, 95% CI 0.80–1.11), respectively).”
This data plus data not included in the AHRQ evaluation provide convincing evidence in support of the existing and proposed health claims. Note that the actual amount of selenium used in the trial was only 50 µg per day, which is only one-fourth of the effective amount used in the NPC Trial.
The AHRQ report summarizes: “Evidence on the role of selenium in cancer prevention is limited, but suggests some benefit in prevention of total and prostate cancer, with the greatest benefit in men with a normal baseline prostate specific antigen level. Taking into consideration the quantity, quality, and consistency of evidence on the efficacy of selenium in preventing chronic disease (including cancer), we concluded that the overall strength of evidence is ‘moderate’” (AHRQ pg. 26 and Table 6).
Again, it is noted that the AHRQ report considers the category “chronic disease” to include cancer, chronic disease and condition.
Update of the Linxian Trial
The original Linxian Trial was discussed by FDA in its examination of the supportive evidence for selenium against cancer in issuing the limited health claim for selenium and cancer in 2003. The original Linxian Trial, an intervention trial involving 30,000 adult Chinese found that supplementation of selenium combined with two other antioxidants significantly decreased mortality from stomach cancer. FDA commented that “these results cannot provide clear evidence of an effect of selenium per se. The relevance of these results to the general population, which does not have the same high incidence of stomach cancer or malnutrition, is uncertain.” FDA did agree that the trial “provided some evidence that a selenium-containing supplement had some effect on lowering cancer mortality.”
In 2004, Wei et al. published a 15-year follow-up study of 1,103 participants randomly selected from the larger trial cohort. They found a significant inverse association between baseline serum selenium concentrations and death from esophageal squamous cell carcinoma and gastric cardia cancer.
New Prospective Studies
Although not intervention studies, these prospect studies add further credible scientific support to the anticancer effect of selenium. Prospective studies are not conclusive, but they provide credible evidence of the premise.
In 2002, Knekt published his review of all prospective studies of selenium and cancer. He divided all existing studies into the following categories: “all cancers; lung cancer; colorectal cancer; gastrointestinal and stomach cancers; prostate cancer; female cancers; miscellaneous cancers that included cancers of the liver, bladder, mouth, pharynx, esophagus and melanoma.” He reviewed 72 prospective studies with 50 of the studies establishing a lower risk of cancer associated with higher intake or status of selenium.
A Harvard group examined the records of physician volunteers in the Harvard Physicians Study. In this study, 586 physicians were tested in 1982 and followed for 13 years. Among other tests was a determination of plasma selenium. The median age at testing was 60 years. These authors reported “a statistically significant inverse association between prediagnostic selenium levels and the risk of advanced prostate cancer.” They also reported that men with PSA levels greater than 4 ng/mL at the beginning of the study appeared to be protected from prostate cancer by a higher plasma level of selenium. They suggest that “selenium may influence tumor progression.” These data and others suggest that selenium can play a major role in the development and progression of prostate cancer.
In 2005, a prospective study called the Etude du Vieillissement Arteriel (EVA) Study was conducted in France. The EVA study was a nine-year longitudinal study with six periods of follow-up. During the two-year period from 1991 to 1993 (EVA0), 1,389 men and women born between 1922 and 1932 were recruited. The effects of plasma selenium at baseline on mortality were determined by Cox proportional hazards regression analysis, adjusting for the following variables: sociodemographic characteristics, dietary habits, health and cognitive factors.
The EVA study found a significant association between cancer-related mortality and low plasma selenium concentrations [increment = 0.2 µmol/L; RR = 1.61 (1.19 –2.13); P = 0.001]. Analysis by quartile of plasma selenium showed that mortality risk increased significantly in individuals with plasma selenium in Q1 and Q2 compared with individuals with plasma selenium in Q4 [Q1 vs. Q4: RR = 4.06 (1.51–10.92); P = 0.006; Q2 vs. Q4: RR = 2.95 (1.06–8.18); P = 0.04]. Cancer-related mortality did not differ significantly between individuals who had plasma selenium concentrations in Q3 compared with those in Q4 [Q3 vs. Q4: RR = 1.92 (0.63–5.86); P = 0.25]. The RR of cancer-related mortality associated with plasma selenium decreases in increments of 0.2 µmol/L, adjusting for all factors, was 1.79 (1.32–2.44); P= 0.0002.
New “Meta” Analyses
In 2006, a meta-analysis was undertaken to quantitatively determine if men with low selenium levels were at increased risk of prostate cancer. Twenty epidemiologic studies were selected. Mean differences were: –5.55 µg/L (–9.82; –1.27; P = 0.01), –0.01 µg/L (–0.03; 0.006; P = 0.19), –0.52 µg/L (–4.63; 3.58; P = 0.80) for serum, toenail and plasma studies, respectively. Overall, the pooled standardized mean difference between cases and controls was; –0.23 (–0.40; –0.05; P = 0.01) indicating an inverse association between selenium levels and risk of prostate cancer.
Also in 2006, a case-control study was undertaken to quantitatively determine if low selenium levels were associated with increased risk of bladder cancer. Eight epidemiological studies examined the association between serum selenium concentration and bladder cancer risk. A population case-control study in 178 cases and 362 controls was carried out to assess the relationship between bladder cancer risk and selenium serum concentrations. Unconditional logistic regression was calculated to determine odds ratios (OR) for bladder cancer occurrence with corresponding 95% confidence intervals (95% CI). Effect modification by smoking status, low fruit and vegetable intake, retinol equivalent, vitamin C, vitamin E and total antioxidant status were also assessed. The results were that serum selenium level was negatively associated with bladder cancer risk. After adjustment for sex, age, smoking and occupational exposure, the OR was 0.48 (95% CI 0.29–0.79) comparing the second with the lowest tertile (serum selenium concentration >82.40 µg/L). The adjusted OR for the highest tertile (serum selenium concentration >96.00 µcg/L), was 0.30 (95% CI 0.17–0.52) (P-trend <0.001). An increase of 10 µg/L in serum selenium concentration was associated with a significant decreased bladder cancer risk (OR: 0.76; 95% CI 0.67–0.85). The researchers concluded that this case-control study demonstrated an inverse association between serum selenium concentration and bladder cancer risk.
Summary
Credible research continues to show that selenium protects at least some people from some forms of cancer. There are still more questions than answers, but recent mechanistic studies are uncovering more and more pieces of the puzzle. Research showing the relationship of the single nucleotide polymorphism Glutathione peroxidase 1 (GPX1) variations to erythrocyte GPX activity and cancer risk is especially enlightening.
Additional research is needed to clarify which dietary forms of selenium are optimal, as well as their amounts are optimal. Which selenium compound(s) is (are) the more active anticancer compounds(s)? Are some simple selenium compounds more effective as anticancer compounds than some selenoproteins? What are the various mechanisms for selenium compounds as anticancer compounds? What are the roles of the various selenoproteins? What are the best biomarkers for selenium nutriture and cancer protection?
In the next article in this nonconsecutive series, I will present evidence that supports additional health claims for selenium against organ-specific cancers including prostate cancer, bladder and urinary tract cancers, lung and respiratory tract cancers, colon and digestive tract cancers, thyroid cancer, brain cancer, liver cancer and breast cancer.
Fortunately, there are other clinical trials of the anticancer effect of selenium underway. A list of approximately 70 clinical studies of selenium in various health conditions funded by the National Institutes of Health is given at http://clinicaltrials.gov/ct2/results?term=selenium. Many of these are cancer studies and several use selenium yeast and dietary forms of selenium other than selenomethionine. Many lives and much suffering are at stake. Hopefully, the remaining clinical trials are better designed. WF
Dr. Richard Passwater is the author of more than 40 books and 500 articles on nutrition. He is the director of research and development for Solgar Vitamin and Herb, Inc. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1985. More information is available on his Web site, www.drpasswater.com.
Published in WholeFoods Magazine, December 2008
