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The New Zealand Medical Journal

 Journal of the New Zealand Medical Association, 18-June-2004, Vol 117 No 1196

Nutritional supplements: friend or foe?
Cheryl Krone, John Ely, Louis Harms
Dietary supplements are of interest to many New Zealanders, including health professionals. Although frequent use of nutritional supplements is common in New Zealand (circa 20% of persons aged from the 20s to 70s consume supplements),1,2 reliable data from human studies on the appropriateness of supplementation is insufficient for many nutrients.
Recognised benefits for specific populations (such as pregnant women) have been identified. Folate and iron supplements for females prior to and during pregnancy can help prevent birth defects in offspring and anaemia in the mothers.3 However, such supplements may not be advantageous for everyone.
An excess of iron has been associated with poor outcome in stroke and has been implicated in the development of cardiovascular disease4—this has led to the recommendation that iron supplements should only be prescribed when there is a clear deficiency state.4
Recently, a large prospective cohort study found that zinc intake of greater than 100 mg/day, as well as long term (ie, more than 10 years) use of supplemental zinc, was associated with an increased risk of advanced prostate cancer.5 As an illustration of some of the complexities surrounding supplement usage, this viewpoint article focuses on prostate cancer versus diet and nutrition; specifically zinc supplements.

Prostate cancer and chemopreventive agents

Prostate cancer is one of the most common malignancies in affluent nations. In New Zealand, it is the third-most common cause of cancer-related death in men after lung and bowel cancer. Although debate continues around the benefits and risks of prostate cancer screening,6,7 the control of prostate cancer is based on early detection and treatment. This is due primarily to the non-modifiable nature of the known risk factors for carcinoma of the prostate (eg, increasing age, family history, ethnicity).
However, evidence is accumulating that environmental factors (notably diet and nutrition) may impact on the risk of prostate cancer.8 For example, levels and types of dietary fat appear to be influential. High animal-fat consumption is associated with an increased risk,8 while New Zealand studies have suggested that diets high in fish oils, or in vegetable oils rich in mono-unsaturated fatty acids such as canola or olive oil, may provide a protective effect.2,9
Other potentially valuable chemopreventive agents have been identified. These include vitamin E (alpha-tocopherol), selenium, zinc, and lycopene as dietary supplements.8,10,11
The most powerful evidence for a protective effect of alpha-tocopherol comes from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC)12—a large randomised controlled trial. This study was designed to examine the influence of alpha-tocopherol on lung cancer prevention, but found an unexpected 30% reduction in prostate cancer incidence in subjects who received 50 mg alpha-tocopherol (compared to controls). Another randomised controlled trial that tested 100 µg of organic selenium for protection against skin cancer revealed an unforeseen 60% decrease in prostate cancer in the participants receiving selenium.13 An extension of this trial using 200 µg daily confirmed the potent beneficial selenium effect.14
In a large population-based case-control study of middle-aged men, individual supplements of zinc, vitamins C and E (but not multivitamins) were associated with protection against prostate cancer.15 A borderline statistically-significant 45% reduction in prostate cancer risk was found among men using zinc supplements daily. There was a significant test for trend—ie, more frequent use was associated with decreased risk.

Zinc and prostate health

The highest human soft tissue zinc concentration occurs in the normal prostate. The ability to accumulate zinc is retained in benign prostatic hyperplasia. However, the zinc level in prostate adenocarcinoma is significantly decreased.16 A protective effect of supplemental zinc found by Kristal et al15 is consistent with these observations and with studies that associate zinc with suppression of prostate cancer cell growth17 and inhibition of prostate tumour cell invasion.18 Uzzo et al19 have provided strong evidence of a protective role for zinc in the development and progression of prostate malignancy. Physiological levels of zinc were shown to suppress activity of nuclear factor-kappa-B. This inactivation sensitises human prostate cancer cells to apoptosis, and inhibits the tumourigenic and metastatic properties of prostate tumour cells.20
However, other findings suggest that very high intraprostatic zinc levels could increase the activity of telomerase, an enzyme believed to cause proliferation of tumour cells.21 In prostate cancer, telomerase activity is increased. Moreover, other evidence, not specifically linked to prostate cancer, suggests that high zinc intake can have systemic effects that adversely impact metabolic processes related to cancer. These effects include immune dysfunction, impaired antioxidant defence, and elevated insulin-like growth factor-1 and testosterone; the latter two are growth factors directly related to prostate carcinogenesis.
Recent analysis (by Leitzmann et al)5 of data from the Health Professionals Follow-Up Study of nearly 47,000 males lends support to the possible deleterious effects of excess zinc intake. An increased risk of advanced prostate cancer was associated with zinc intake of greater than 100 mg/day. Use of supplemental zinc for more than 10 years was also linked to an increased risk.5 No strong evidence could be identified in support of any specific mechanisms for the observed association.

Cadmium in zinc supplements

One possible explanation for these findings is the presence of the carcinogenic metal cadmium in some zinc supplements.22 Zinc and cadmium invariably occur together in nature because of their very similar chemical properties.
All commercially available zinc supplements that we analysed contained detectable cadmium.22 However, the amount varied by almost 40-fold when based on a fixed amount of zinc (eg, 12 mg zinc, the New Zealand Recommended Dietary Intake). In Leitzmann's5 high intake group, the median daily supplemental zinc intake was 143 mg. This group exhibited a relative risk of advanced prostate cancer of 2.29 compared to nonusers of zinc supplements. Consuming this amount of zinc using the product we analysed (that contained the highest cadmium-to-zinc ratio) would yield a cadmium dose circa 19 µg. This is nearly double the total mean daily lifetime exposure to cadmium from foods, excluding shellfish, as estimated in the US Food and Drug Administration's Total Diet Study (ie, 10 µg cadmium/person/day).
Food is the major route of cadmium uptake for the non-occupationally exposed general public. Human tissues, including the prostate, accumulate cadmium with age. The biological half-life of cadmium is on the order of decades. It has been suggested that even small repeated low doses could accumulate and mimic zinc, leading to the adverse effects observed for cadmium on the prostate.23
Satarug et al recently summarised the data on cadmium in soils, foods, human tissues, etc in Australia, and related them to the burden on health of non-occupational cadmium exposure.24 A long-term chronic total intake of 30–50 µg cadmium/day was associated with adverse health effects—including renal dysfunction, especially in regard to hypertension. Thus, it is advisable to avoid any unnecessary cadmium intake.
Cadmium has been implicated epidemiologically and experimentally in causation of prostate cancer.25 Malignant transformation of normal human prostate epithelial cells in vitro was demonstrated using a cadmium concentration at the low end of the concentration range found in human prostates of men without occupational cadmium exposure.23 These malignant cells showed increased secretion of active metalloproteinases, which are associated with prostate cancer invasion and are typical of aggressive tumours.26 When the transformed cells were injected into mice, they rapidly produced poorly differentiated invasive adenocarcinomas.23
Furthermore, cadmium has been shown to replace zinc in the tumour-suppressor protein, p53, thereby impairing p53's DNA binding activity. This impairment can decrease the ability of cells to respond to DNA damage.27

The supplement conundrum

Zinc is an essential nutrient that must be continually obtained in the diet. A deficiency of this element ranks among the top ten leading causes of death in developing countries.28 An estimated 800,000 annual deaths worldwide could be prevented by correcting zinc deficiency. Certain populations in developed counties also are at risk for poor health linked to inadequate zinc intake.
New Zealand infants had intakes of less than the reference values at ages under 18 months.29 Many adolescent females and young women in New Zealand, have inadequate dietary zinc intake and or low plasma zinc levels.30,31 Indeed, in a group of New Zealand rheumatoid arthritis patients, less than 10% reached the necessary dietary intake for zinc.32 The recommended treatment for moderate zinc deficiency is supplementation.30–32
Our results suggest that safe zinc supplements with relatively low cadmium levels can be produced (eg, supplements containing the gluconate form of zinc uniformly had lower levels of cadmium than those containing zinc sulfate or zinc as an amino acid chelate).22
Regardless of whether it is proven that cadmium in zinc supplements presents a health hazard in high-zinc consumers, or whether zinc contributes to the observed increase in advanced prostate cancer, the findings point out that caution in adopting supplement regimens is necessary—as there can be undetected or unknown concomitant chemicals in supplements. In addition to cadmium in zinc supplements, 25% of 70 brands of calcium supplements contained potentially hazardous levels of lead.33
Furthermore, the action of pure dietary components at pharmacologic doses does not always produce the expected effects. An example of this is the ATBC trial in which an unanticipated and undesirable increase in lung cancers was observed among the cigarette smokers given pharmacologic doses of beta-carotene.12
Yet, for correction of zinc deficiency states in several at-risk populations, zinc supplements are very effective. Also, for prostate cancer, the large randomised controlled studies mentioned earlier have indicated benefit from alpha-tocopherol and selenium supplementation12,13, as did the large population-based case-control study find utility from zinc, alpha-tocopherol and ascorbic acid (AA) supplementation.15
In two prospective studies, dietary intake of AA was not associated with a reduced risk of prostate cancer.34,35 However, there was a non-significant reduction in relative risk for supplement users,35 and 30-year overall survival was positively associated with AA intake.34
Two other prospective studies measuring plasma levels of AA have not revealed differences between cases with prostate cancer and controls.36,37 However, few of the study participants supplemented AA (less than 2%) and the mean plasma levels of AA were quite low (ie, below the renal threshold for AA). A small number of prospective studies have found a reduced risk of other cancers associated with increased AA intake, or (in some cases) increased plasma AA levels.38 In the older British population (ages 75–84 years), low blood AA levels are strongly predictive of mortality.39
A major limitation in the above studies of AA is the relatively low AA intake (below 400 mg/day). This is much lower than the AA produced endogenously by any one of the circa 4000 AA-synthesising mammals—or the amounts that have been found necessary in the diet for optimum health in the very few mammals that are not AA-synthesisers, such as the primates (ie, ~50 mg/kg body weight or about 3.5 g for a 70 kg human). These amounts (eg, ~3 g/day) appear necessary and are safe for humans, who are also non-AA-synthesisers. Recently, a randomised prospective study of critically ill surgical patients given 1 g ascorbate (intravenously) three times daily (along with oral alpha-tocopherol) found significantly decreased pulmonary morbidity, incidence of organ failure, and length of ICU stay.40

Conclusions

Consumption of nutritional supplements is reasonably common in New Zealand. In older males (mean age 69 years) who served as controls for studies of dietary factors and prostate cancer, about 20% reported regular use of dietary supplements.2 The prevalence of supplement use is about 17% in young New Zealanders age 26 years.1 Twenty-four percent of a large US probability sample of the general population reported daily use of supplements.41
Although the possibility of adverse effects from supplements exists, few individuals consume these nutrients in amounts considered toxic.42 For example, of the nearly 47,000 participants in the American Health Professionals Follow-up Study, only 412 were supplementing more than 100 mg zinc daily.5
Thus, current levels of vitamin and mineral supplementation do not appear to pose a health risk for most of the population.42 Furthermore, there are important roles for supplements in treating deficiency states. Conceivably, supplements could form the basis for inexpensive and easy methods for preventing various disorders, including malignancies. These potential benefits of dietary supplements deserve further study. For use in prostate cancer prevention, this is particularly true because of the non-modifiable nature of the known risk factors.
However, confirmation of the beneficial effects of nutritional factors should be a priority before public health recommendations regarding dietary changes or supplemental nutrients are made.
Author information: Cheryl A. Krone, Senior Research Scientist, Applied Research Institute, Palmerston North; John T.A. Ely, Research Associate Professor Emeritus, Radiation Studies, University of Washington, Seattle, Washington, USA; Louis C. Harms, Registered Professional Engineer, Evanston, Illinois, USA
Correspondence: Cheryl A. Krone, Applied Research Institute, PO Box 1969, Palmerston North. Fax (06) 353 1012; email: cakrone@xtra.co.nz
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