Gerald P Murphy masthead

Selenium and Prostate Cancer: The Challenge
of Promoting Health in a U-Shaped World

David J. Waters, PhD, DVM
Gerald P. Murphy Cancer Foundation

The perception that is pervasive among the public is that, when it comes to taking dietary supplements, more is better. A growing body of scientific evidence, however, suggests that the dose response between DNA damage and the dietary intake of nutrients is U-shaped. Therefore more of these “good things" may not necessarily be a good thing. This concept is especially relevant to health-conscious men and women, who are ironically at highest risk for the ill-effects of oversupplementation because they are already consuming high-quality diets rich in vitamins and minerals.

When it comes to identifying the optimal selenium dose for prostate cancer risk reduction, it is not likely that more selenium will always be better. A recent meta-analysis of the dose-response between selenium and prostate cancer risk in men showed a U-shaped relationship between toenail selenium level and risk for prostate cancer [1]. Landing in the trough of the U — achieving mid-range selenium status — is better than being too low or too high. This stance is bolstered by an extensive review of the scientific literature by Rayman [2], who concluded: “The crucial factor that needs to be emphasized with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefit people with low status, those with adequate-to-high status might be affected adversely and should not take selenium supplements.”

We have observed an intriguing U-shaped dose-response relationship between toenail selenium concentration and the extent of DNA damage within the prostate of elderly dogs [3, 4]. We studied elderly dogs, because, like men, they develop naturally-occurring prostate cancer. Using the aging dog prostate to mimic the aging human prostate, we could study the effects of selenium on prostate cells in an appropriate context — amidst the complex environment of an aging prostate gland prior to the onset of cancer. We showed that the concentration of selenium in toenails that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk in several studies. The U-curve established from our dog work parallels the results of Larry Clark's selenium supplementation study, the Nutritional Prevention of Cancer Trial (NPCT). In NPCT, men with low selenium significantly lowered their prostate cancer risk with supplementation [5]. But men with highest selenium did not benefit. Further evidence for the link between low selenium and prostate cancer risk comes from cross-sectional study of men in the Netherlands study published in 2013 [6]. These investigators showed a 63% reduction in prostate cancer in men as they moved toward the optimal middle range of selenium. Further incentive for navigating the U-curve and adjusting your selenium level to an optimal middle range comes from a 2014 paper published from SELECT, showing that men with highest toenail selenium level (greater than 1.0 ppm) actually suffered a 2-fold increase in risk for prostate cancer following selenium supplementation [7].

In conclusion, promoting health in a U-shaped world poses distinctive challenges. The public craves simplified health messages. They expect large-scale interventional trials like SELECT to deliver a concrete verdict like: “Selenium is good for you.” But in a U-shaped world where more is not necessarily better, this is a meaningless, context-less statement that offers no guidance at all. Now, more than ever, we need a new approach to cancer prevention — one that is personalized. Defining the U-shaped relationship between DNA damage and cancer-protective nutrients can move us one step closer to developing personalized, cancer-reducing interventions. It follows from this understanding that not all individuals will necessarily benefit from increasing their nutrient intake. Finally, the language we use — the deep-rooted metaphor “more is better" along with our reliance on the binary thinking of “good or bad” — represents a significant obstacle to our efforts to successfully communicate life style decisions that really do promote health [8].


1. Hurst, R., Hooper, L., Norat, T., et al. (2012) Selenium and prostate cancer: Systematic review and meta-analysis. Am J Clin Nutr 96:111-122.

2. Rayman, M. P. (2012) Selenium and human health. Lancet 379:1256-1268.

3. Waters D. J., Shen, S., Glickman, L. T., et al. (2005) Prostate cancer risk and DNA damage: Translational significance of selenium supplementation in a canine model. Carcinogenesis 26:1256-1265.

4. Chiang, E. C., Shen, S., Kengeri, S. S., et al. (2010) Defining the optimal selenium dose for prostate cancer risk reduction: Insights from the U-shaped relationship between selenium status, DNA damage, and apoptosis. Dose-Response 8:285-300.

5. Duffield-Lillico, A. J., Dalkin, B. L., Reid, M. E., et al. (2003) Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: An analysis of the complete treatment period of the Nutrition Prevention of Cancer Trial. BJU Int 91:608-612.

6. Geybels, M. S., Verhage, B. A., van Schooten, F. J., et al. (2013) Advanced prostate cancer risk in relation to toenail selenium levels. J Natl Cancer Inst 105:1394-1401.

7. Kristal, A. R., Darke, A. K., Morris, J. S., et al. (2014) Baseline selenium status and effects of selenium and vitamin E supplementation on prostate cancer risk. J Natl Cancer Inst 106:djt456.

8. Waters, D. J., Chiang, E. C. (2010) It’s a U-shaped world: A Batesonian prescription for promoting public health. ETC: A Review of General Semantics 67:218-226.

  • More about "The Challenge of Promoting Health in a U-Shaped World

  • Our publications on U-shaped thinking