Position statement - Selenium and cancer prevention

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Obesity > Position statement - Selenium and cancer prevention

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Position statement - Selenium and cancer prevention


Key messages

  • Selenium helps to prevent tissue damage caused by free radicals. Selenium is found in cereals, meat and fish. Cereals provide about 50% of dietary selenium. The selenium content of plant foods varies with the selenium content of the soil.
  • Cancer Council supports the National Health and Medical Research Council recommended dietary intake of 70 μg/day for men and 60 μg/day for women with an upper intake limit of 400 μg/day (six times the recommended dietary intake). Selenium is safe if taken in moderation. However selenium supplements are toxic if taken in high doses.
  • Although some observational studies suggest that selenium may reduce the risk of prostate cancer, randomised controlled trials have not confirmed these findings.
  • Cancer Council does not support the use of health claims on food labels that suggest selenium protects against the development of cancer.

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Rationale

As the food industry has proposed health claims be permitted on food labels about selenium and cancer, it is important for Cancer Council to have a clear position on the protective effects of selenium against cancer.

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Background

Selenium is found in cereals, meat, poultry, seafood, and eggs[1]. Cereals may provide about 50% of dietary selenium, however data on the selenium content of Australian foods is limited. The selenium content of plant foods varies with the selenium content of the soil.

Selenium acts as an antioxidant and helps protect the body against the damaging effects of free radicals. Selenium is essential for the activity of glutathione peroxidase, an enzyme that protects against reactive oxygen species and subsequent cell membrane damage[1].

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Views on selenium in cancer prevention reports

In 2003, the World Health Organization concluded that the strength of evidence for the role of selenium in decreasing the risk of cancer was possible/insufficient, and the evidence from randomised controlled trials suggested that selenium might have a protective role in prostate cancer development[2].

The World Cancer Research Fund found in 2007 that there was probable evidence that selenium and selenium supplements reduced the risk of prostate cancer, and limited suggestive evidence that they reduced the risk of lung and bowel[3]. Selenium was also linked to a limited suggestive lower risk of stomach cancer, and selenium supplements to a limited suggestive increased risk of skin cancer[3].

A more recent review by the World Cancer Research Fund in 2014 concluded that links between prostate cancer risk and selenium supplements have been downgraded from strong evidence of a decreased risk to no conclusion possible[4].While there was evidence of a non-linear dose-response relationship showing an inverse relationship between plasma selenium and prostate cancer at low plasma concentrations, no conclusion could be drawn for selenium supplements.

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Epidemiological evidence

A meta-analysis of nine randomised controlled trials investigating the link between antioxidant supplements and cancer risk found that selenium supplementation was found to have an overall preventive effect on cancer incidence (RR= 0.76, 95% CI= 0.58-0.99). The effect was strongest in people who had low baseline levels of selenium[5].

Another meta-analysis of four randomised controlled trials found that selenium supplementation was associated with reduced cancer incidence in men (RR= 0.77, 95% CI= 0.64-0.92), but not in women (RR= 1.00, 95% CI= 0.89-1.13)[6].

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Prostate cancer

In 2012, the WCRF published a meta-analysis of twelve studies analysing the link between plasma/serum or toenail selenium and prostate cancer as part of the Continuous Update Project[7]. The study found that prostate cancer risk decreased with increasing plasma/serum selenium up to 170 ng/mL; higher levels of toenail selenium (0.85 to 0.94 μg/g) were associated with a reduced risk of prostate cancer (relative risk 0.29; 95% confidence interval (CI)= 0.14-0.6)[7].

A 2005 meta-analysis of eleven cohort studies and five case-control studies found that any intake of selenium was associated with a reduced risk of prostate cancer in cohort studies (RR= 0.72, 95% CI= 0.61-0.84), but not in case-control studies (RR= 0.74, 95% CI=0.61-1.39)[8].

The Selenium and Vitamin E Cancer Prevention Trial (SELECT), sponsored by the National Cancer Institute, began in August 2001[9]. The randomised controlled trial aimed to determine if these two dietary supplements can protect against prostate cancer. Over 35,500 participants were randomised to receive daily supplements of either: selenium (200 μg/day) and placebo; vitamin E (400 IU/d alpha-tocopherol) and placebo; selenium and vitamin E; or two placebos. Participants stopped taking the study supplements in October 2008 and were followed-up for another three years.

Results from the SELECT trial were published in 2009[9], and again in 2011[10]. The most recent results show that selenium does not prevent prostate cancer (hazard ratio (HR)= 1.09; 99% CI= 0.93-1.27), the same was true for selenium plus vitamin E (HR= 1.05; 99% CI= 0.89-1.22)[10]. Conversely, the preliminary results from this study indicated that vitamin E supplementation alone resulted in a significant increase in prostate cancer incidence (HR= 1.17; 99% CI= 1.004-1.36)[10].

A pooled analysis of the SELECT study and one other trial found no association between selenium supplementation and prostate cancer incidence (RR= 0.78, 95% CI= 0.41-1.48)[11].

Secondary end-point analyses of the Nutritional Prevention of Cancer Trial showed a significant protective effect of selenium supplementation on the incidence of prostate cancer, although the effect was restricted to those with lower baseline prostate specific antigen (PSA) and plasma selenium concentrations[12][13]. The protective effects of selenium were not apparent for all groups of subjects. In the case of total cancer incidence, selenium treatment produced significant reductions only in males (males represented 75% of the total sample).

The Health Professionals Follow-Up Study showed a strongly inverse association of toenail selenium content and prostate cancer incidence[14].

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Skin cancer

The Nutritional Prevention of Cancer Trial, a randomised controlled trial with 1,312 subjects, was conducted to test whether selenium supplements (200 μg/day) would reduce basal and squamous cell carcinomas in the USA[15]. It is interesting to note that the trial showed that selenium treatment did not protect against the development of basal or squamous cell carcinomas of the skin,[15] and subsequent analysis of the Nutritional Prevention of Cancer Trial actually found that selenium supplementation increased the risk of squamous cell carcinoma and total non-melanoma skin cancer (result was statistically significant)[16].

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Bowel cancer

A pooled analysis of three other randomised controlled trials, the Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Study, showed an inverse relationship between higher blood selenium concentration and adenoma risk[17]. It is important to note that none of these three trials was specifically testing selenium as an intervention for adenoma protection. However these results suggest that selenium may have a protective effect on the development of bowel cancer, which warrants further investigation[17].

Observational studies have been mixed with some showing a statistically significant or suggestive protective association and some showing a null or harmful association between selenium and bowel adenomas or cancer[18].

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Potential mechanisms of action

Animal studies have consistently shown that selenium treatment can reduce tumour yields, inhibit cell growth and angiogenesis, stimulate apoptosis, protect against oxidative damage, and increase immune function[19][20][21].

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Toxicity and recommended dietary intake

The Recommended Dietary Intake (RDI) of selenium for men is 70 μg/day and 60 μg/day for women[1]. The upper dietary intake limit for adults has been proposed at 400 μg/day, based on no adverse effect levels seen in some of the Chinese randomised controlled trials. There is limited data about selenium toxicity in humans but the most common side effects include: hair and nail brittleness and loss, gastrointestinal disturbances, skin rash, fatigue, irritability and nervous system disturbances[1].

Selenium supplements sold in Australia warn that selenium is toxic in high doses and a daily dose of 100 μg/day from all sources other than food should not be exceeded. Selenium containing supplements are not recommended for children under the age of 15 years.

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Current level of intake in Australia

There is limited data on the selenium status of Australians, with one study showing that the mean plasma selenium concentration of a group of 834 South Australians was relatively high by European standards[22]. The study questioned if Australians are getting enough selenium to achieve optimal enzymatic activity of glutathione peroxidase, even though plasma selenium concentrations were above those reported for most other countries[22].

Selenium deficiency is rare in Australia. In areas of China with low soil selenium, deficiency is manifested as Keshan Disease, a form of fatal cardiomyopathy[1]. Selenium deficiency has also been reported to increase the risk of cretinism in conjunction with iodine-deficiency[1].

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Health claims

The effects of selenium are related to the specific compounds and breakdown products of selenium present in the food[23]. Therefore considerations of health claims must be related to the presence of these specific selenium compounds in the food.

The Food and Drug Administration (FDA) in the USA has permitted a qualified health claim for selenium and cancer. A qualified health claim is when there is less scientific evidence for a substance-disease relationship and the claim therefore requires qualifying language such as “FDA has determined that the evidence is limited and not conclusive”[24]. It is noteworthy that foods and natural products are regulated under different rules to pharmaceutical compounds, not having to meet the stringent criteria for demonstrated efficacy and safety.

Future research

Because of the metabolic complexity of selenium, research studies are required on what selenium dose and biologic form may be the most effective for chemoprevention. Methods are needed to characterise the specific forms of selenium present in food. A better understanding is required of the selenium dose (chemical form and amount) that would be both safe and effective in reducing cancer risk[23].

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Position statement details

The original position statement was reviewed and approved by the Public Health Committee May 2006 and updated November 2012 and June 2015.

Development

This position statement was reviewed by:

  • Anita Tang
  • Carla Saunders
  • Graham Lyons
  • Stewart Truswell
  • Simone Lee
  • Marina Reeves
  • Dallas English
  • Craig Sinclair
  • Katrine Baghurst
  • Ingrid Flight
  • Monica Robotin


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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 National Health and Medical Research Council. Nutrient reference values for Australia and New Zealand including recommended dietary intakes. Canberra: NHMRC; 2006 Available from: http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/n35.pdf.
  2. World Health Organization, Food and Agriculture Organization. Diet, nutrition and the prevention of chronic diseases. Geneva, Switzerland: WHO; 2003. Report No.: WHO technical report series 916. Available from: http://apps.who.int/iris/bitstream/10665/42665/1/WHO_TRS_916.pdf.
  3. 3.0 3.1 World Cancer Research Fund, American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR; 2007.
  4. World Cancer Research Fund International. Continuous Update Project Report: Diet, Nutrition, Physical Activity, and Prostate Cancer. World Cancer Research Fund International; 2014 Available from: http://www.wcrf.org/sites/default/files/Prostate-Cancer-2014-Report.pdf.
  5. Lee EH, Myung SK, Jeon YJ, Kim Y, Chang YJ, Ju W, et al. Effects of selenium supplements on cancer prevention: meta-analysis of randomized controlled trials. Nutr Cancer 2011 Nov;63(8):1185-95 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22004275.
  6. Bardia A, Tleyjeh IM, Cerhan JR, Sood AK, Limburg PJ, Erwin PJ, et al. Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis. Mayo Clin Proc 2008 Jan;83(1):23-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18173999.
  7. 7.0 7.1 Hurst R, Hooper L, Norat T, Lau R, Aune D, Greenwood DC, et al. Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 2012 Jul;96(1):111-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22648711.
  8. Etminan M, FitzGerald JM, Gleave M, Chambers K. Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis. Cancer Causes Control 2005 Nov;16(9):1125-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16184479.
  9. 9.0 9.1 Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009 Jan 7;301(1):39-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19066370.
  10. 10.0 10.1 10.2 Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011 Oct 12;306(14):1549-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21990298.
  11. Jiang L, Yang KH, Tian JH, Guan QL, Yao N, Cao N, et al. Efficacy of antioxidant vitamins and selenium supplement in prostate cancer prevention: a meta-analysis of randomized controlled trials. Nutr Cancer 2010;62(6):719-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20661819.
  12. Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU Int 2003 May;91(7):608-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12699469.
  13. Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach LA, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002 Jul;11(7):630-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12101110.
  14. Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998 Aug 19;90(16):1219-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9719083.
  15. 15.0 15.1 Clark LC, Combs GF Jr, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996 Dec 25;276(24):1957-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8971064.
  16. Duffield-Lillico AJ, Slate EH, Reid ME, Turnbull BW, Wilkins PA, Combs GF Jr, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst 2003 Oct 1;95(19):1477-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14519754.
  17. 17.0 17.1 Jacobs ET, Jiang R, Alberts DS, Greenberg ER, Gunter EW, Karagas MR, et al. Selenium and colorectal adenoma: results of a pooled analysis. J Natl Cancer Inst 2004 Nov 17;96(22):1669-75 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15547179.
  18. Duffield-Lillico AJ, Shureiqi I, Lippman SM. Can selenium prevent colorectal cancer? A signpost from epidemiology. J Natl Cancer Inst 2004 Nov 17;96(22):1645-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15547171.
  19. Combs GF Jr, Gray WP. Chemopreventive agents: selenium. Pharmacol Ther 1998 Sep;79(3):179-92 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9776375.
  20. Combs GF Jr. Status of selenium in prostate cancer prevention. Br J Cancer 2004 Jul 19;91(2):195-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15213714.
  21. McKenzie RC, Rafferty TS, Beckett GJ. Selenium: an essential element for immune function. Immunol Today 1998 Aug;19(8):342-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9709500.
  22. 22.0 22.1 Lyons GH, Judson GJ, Stangoulis JC, Palmer LT, Jones JA, Graham RD. Trends in selenium status of South Australians. Med J Aust 2004 Apr 19;180(8):383-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15089727.
  23. 23.0 23.1 Combs GF Jr. Current evidence and research needs to support a health claim for selenium and cancer prevention. J Nutr 2005 Feb;135(2):343-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15671240.
  24. Trumbo PR. The level of evidence for permitting a qualified health claim: FDA's review of the evidence for selenium and cancer and vitamin E and heart disease. J Nutr 2005 Feb;135(2):354-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15671242.

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