A growing public awareness of the benefits of a healthy lifestyle has been accompanied by an explosive use of nutraceuticals over the past decade. This has afforded the opportunity for increased historical and planned trials of the benefits and risks involved in taking supplements. In particular, emphasis has been placed on the anti-oxidant arsenal, which is an area that has been well studied but ambiguous. A great many studies have been conducted on the effects of anti-oxidant consumption after absorption at the molecular level (for example in blood), but critically most have overlooked the initial deleterious effects on the GI Tract.

Recently, vigorous debate has ensued regarding the toxic side-effects of nutraceutical self-administration. The health advantages of vitamin C have been widely reported. Vitamin C has been shown to exhibit anti-oxidant effects at low doses but conversely at high doses it becomes a pro-oxidant 1. Studies have shown that vitamin C intake above the RDA frequently occurs and is attributed to the increase in supplementation in addition to dietary sources. A recent report gave vitamin C intake levels with 1524% RDA (50 mg) in supplement users however even in non-supplement users the recommended levels were exceeded with an average intake of 210% 2.

A daily intake exceeding the RDA was also found for other key nutrients such as iron. The daily intake of iron was found to be 1874% of the published Korean RDA (18 mg) for supplement users in comparison to 62% RDA for non-supplement users. This dramatic finding pertained to some one third of the population. Elevated ingestion of ferrous iron leads to the generation of reactive oxygen and nitrogen species (RONS), lipid peroxidation and oxidative stress 3. High tissue concentrations of iron are associated with a number of pathologies including some cancers, inflammation, diabetes, liver and heart disease 4.

Despite these alarming figures, iron supplementation is very common. It is often taken in conjunction with vitamin C to aid absorption. The damaging effects of a high intake of either iron salts or vitamin C alone warrants serious consideration. However, in tandem this cocktail is potent. Uncontrolled interaction between vitamin C and iron salts leads to oxidative stress. Many patients suffering from diseases of the GI tract such as Crohn's disease and ulcerative colitis often also present with iron deficiency anaemia requiring co-supplementation of vitamin C and iron. A great deal of interest has been shown in the effects of iron supplementation on gastric function in patients suffering from inflammatory diseases and in healthy individuals. Numerous studies have demonstrated iron-induced increases in oxidative damage and disease severity in animal models of gastric inflammation 567. In particular, studies have highlighted the induction of gastric ulcers in rats by the injection of ferrous iron and ascorbic acid 8. However, ferrous iron or ascorbic acid, when injected alone into the gastric wall did not produce penetrating ulcers. The authors propose that lipid peroxidation mediated by oxygen radicals plays a critical role in ulcer pathogenesis as treatment with superoxide dismutase significantly decreased ulceration in tandem with peroxidation. In a long-term study, an iron enriched diet affected an increase in colorectal carcinoma in induced colitis in mice 7.

In humans, a single clinical dose of ferrous sulfate has been shown to induce oxidative damage in healthy individuals 9. This study extends previous reports showing iron induces enhanced lipid peroxidation in rats 8. Using a double-lumen perfusion tube, perfusion with saline containing ferrous sulphate resulted in some fifty fold increases in lipid peroxidation as measured by thiobarbituric acid reactive substances. Intriguingly, antioxidant capacity increased some three-fold with iron administration. In patients with Crohn's disease, treatment with ferrous sulphate (120 mg for 7 days), increased clinical symptoms of disease activity 10. These results clearly indicate that the unnatural concentration of iron salts in a bolus dose accompanied by excess reducing vitamin C can seriously compromise the epithelial lining of the GI tract.

Ascorbic acid has a number of known interactions with metal ions. These interactions involve redox reactions including i) activation of molecular oxygen leading to oxidation of endogenous aromatic moieties [Udenfriend's system] 1112, ii) the reduction reactions of Fe(III) to Fe(II) facilitating their involvement in the activation of peroxides [the Fenton reaction] 13, iii) metal ion catalysis of the oxidation of ascorbic acid with concomitant formation of hydrogen peroxide (H₂O₂) and potential hydroxyl radical (^•OH) generation [from Weissberger et al.] 141516.

Co-supplementation of ferrous salts with vitamin C exacerbates oxidative stress in the gastrointestinal tract, predisposing individuals to ulceration, inflammatory disorders, and exacerbation of existing chronic disorders and may cause cancer.

Iron and ascorbic acid form a potentially toxic cocktail. Ascorbic acid has been shown to exhibit both anti-oxidant and pro-oxidant effects in a dose related fashion. The chemical mechanisms given above have been established demonstrating the potential for these compounds to interact and oxidatively damage surrounding tissues. Even in healthy subjects a positive or negative deviation from the optimal plasma ascorbic acid level results in oxidative damage 23. The detrimental effects of large quantities of ascorbic acid and iron in healthy subjects and patients with GI inflammatory diseases warrant further investigation. In addition dietary supplements containing iron and ascorbic acid may be deleterious as these components do not naturally come in concentrated form (as in supplementation tablets).

The evidence for inflammation resulting from the interaction of ferrous ions and ascorbate in animals already exists. These studies can be extended to humans by exploiting some of the many studies undertaken on vitamin and mineral supplementation. A recent study conducted by the Food Standards Agency (UK) is the largest to date and could be exploited in a follow up to assess the long term effects of iron and ascorbic acid co-supplementation 24. As iron uptake in the GI tract is regulated by plasma iron levels 25, analysis of plasma iron should dictate the requirement for iron and vitamin C supplementation to avoid residual iron damaging the GI tract.

None declared.

The authors contributed equally to this work.