The intakes of Se recommended by health authorities in different countries vary between 50 and 70 ^g day-1. These values are based on the observation that such intakes should produce maximal expression of extracellular GPX
(eGPX) in plasma or cyGPX activity in red cells. Thus, the Se requirements are based on biochemical parameters and, as yet, there is no consensus as to other biochemical or physiological effects of Se status that may be used to determine optimal intake. The recognition that the anti-cancer effects of Se in humans can occur at intakes of 200 ^g day-1 or more suggests that a reappraisal of optimal Se intake may be needed.
Daily Se intakes of humans can vary across the globe from less than 5 ^g day-1 up to 3000 ^g day-1. However, these intakes represent extremes and, in most cases, Se intakes are between 30 and 200 ^g day-1. With regard to human health issues, most debate revolves around whether intakes of 30-75 ^g day-1 are associated with an increased incidence of a range of diseases, including cardiovascular disease and cancers. Low dietary Se intake has been implicated in the development of numerous health disorders in humans. These include Kashin-Beck disease, cancer, cardiovascular disease (including Keshan disease), muscular dystrophy, malaria, alopecia areata, pregnancy hypertension syndrome, altered immune function, male infertility and even AIDS (reviewed in Rayman, 2000). Patients on long-term parenteral nutrition without Se supplementation in their formulation run the risk of Se deficiency, which is manifested in myopathy and cardiomyopathy. Low Se status (low Se and erythrocyte GPX activity) in the elderly was correlated with lower tri-iodothyrinine (T3)-to-thyroxine (T4) ratios, due to raised T4 concentrations, and was seen with advancing age (Olivieri et al., 1996). Se supplementation decreased the serum T4 concentration in these patients. The age-related decline in T3 content was ascribed to the requirement for iodothyronine-5'-deiodinase, which is a selenoprotein, to catalyse the conversion of T4 to T3. A deficiency in T4-to-T3 conversion will impair general metabolism, including immunity.
In 1965, Shamberger and Rudolph demonstrated a significant reduction of skin-cancer incidence in carcinogen-treated mice given a topical application of sodium selenite. This initiated a great number of subsequent studies, using animal models, which consistently demonstrated the anti-carcinogenic nature of Se. The anti-cancer effects seem to be of two types: one is the ability to protect against DNA damage and to bolster immune effectiveness and the second is the ability of selenocompounds to cause growth inhibition and apoptosis of tumour cells, while leaving normal cells unaffected (reviewed in Combs and Clark, 1999; Ganther, 1999). Se compounds inhibit the cellular oncogene AP-1, which is required for cell growth. Other selenocompounds, such as seleno-diglutathione, do not kill normal cells, but cause apoptosis of tumour cells by inducing the tumour suppressor protein, p53, and apoptosis (Lanfear et al., 1994). For p53 to bind to DNA, thiol groups on nine critical cysteine residues must be in a reduced state, this is mediated by thioredoxin. Inactivation of thioredoxin reductase prevents activation of a functional p53 (references in McKenzie et al., 2002). Se compounds also prevent metastasis and angiogene-sis of tumours, possibly by inhibition of release of cytokines, such as IL-8.
In humans, some, but not all, epidemiological studies have suggested an inverse correlation between Se intake and the prevalence of malignancy. The most convincing evidence for Se having an anti-cancer effect in humans comes from a recent randomized, double-blind, placebo-controlled, supplementation study (Combs and Clark, 1999). In this study, 1300 subjects from the USA received 200 ^g of Se daily (given as Se-rich yeast) or a placebo for approximately 5 years. Total cancer incidence was 42% lower in the Se-supplemented group compared with the placebo group, with significant decreases in the incidence of prostate, gastric and colorectal cancers. Similarly, the total death rate from malignancy was 52% lower in the subjects who received Se supplementation when compared with the placebo group. The multicentre PRECISE trial has recently been started in the USA, Finland, Denmark, Sweden and the UK with a view to extending these observations to European populations (Rayman, 2000).
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