Antioxidants are compounds that inhibit oxidation. Oxidation is a chemical reaction that can produce free radicals, thereby leading to chain reactions that may damage the cells of organisms. Antioxidants such as thiols or ascorbic acid (vitamin C) terminate these chain reactions. To balance the oxidative stress, plants and animals maintain complex systems of overlapping antioxidants, such as glutathione and enzymes (e.g., catalase and superoxide dismutase), produced internally, or the dietary antioxidants vitamin C and vitamin E. The term 'antioxidant' is mostly used for two entirely different groups of substances: industrial chemicals that are added to products to prevent oxidation, and naturally occurring compounds that are present in foods and tissue. The former, industrial antioxidants, have diverse uses: acting as preservatives in food and cosmetics, and being oxidation-inhibitors in fuels. Antioxidant dietary supplements have not been shown to improve health in humans, or to be effective at preventing disease. Supplements of beta-carotene, vitamin A, and vitamin E have no positive effect on mortality rate or cancer risk. Additionally, supplementation with selenium or vitamin E does not reduce the risk of cardiovascular disease. Although certain levels of antioxidant vitamins in the diet are required for good health, there is still considerable debate on whether antioxidant-rich foods or supplements have anti-disease activity. Moreover, if they are actually beneficial, it is unknown which antioxidants are health-promoting in the diet and in what amounts beyond typical dietary intake. Some authors dispute the hypothesis that antioxidant vitamins could prevent chronic diseases, and others declare that the hypothesis is unproven and misguided. Polyphenols, which have antioxidant properties in vitro, have unknown antioxidant activity in vivo due to extensive metabolism following digestion and little clinical evidence of efficacy. Although dietary antioxidants have been investigated for potential effects on neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, the studies had poor design and there was no evidence of effect, except for maintaining normal levels of vitamin C to lower the risk of cognitive deficits during aging. Common pharmaceuticals (and supplements) with antioxidant properties may interfere with the efficacy of certain anticancer medication and radiation. A 2016 systematic review examined allopurinol and acetylcysteine as possible add-on treatments for schizophrenia. Tirilazad, a steroid derivative that inhibits lipid peroxidation, was shown in human trials to have no effect on mortality or other outcomes in subarachnoid haemorrhage and worsened results in ischemic stroke. Relatively strong reducing acids can have antinutrient effects by binding to dietary minerals such as iron and zinc in the gastrointestinal tract and preventing them from being absorbed. Examples are oxalic acid, tannins and phytic acid, which are high in plant-based diets. Calcium and iron deficiencies are not uncommon in diets in developing countries where less meat is eaten and there is high consumption of phytic acid from beans and unleavened whole grain bread. High doses of some antioxidants may have harmful long-term effects. The beta-carotene and Retinol Efficacy Trial (CARET) study of lung cancer patients found that smokers given supplements containing beta-carotene and vitamin A had increased rates of lung cancer. Subsequent studies confirmed these adverse effects. These harmful effects may also be seen in non-smokers, as one meta-analysis including data from approximately 230,000 patients showed that β-carotene, vitamin A or vitamin E supplementation is associated with increased mortality, but saw no significant effect from vitamin C. No health risk was seen when all the randomized controlled studies were examined together, but an increase in mortality was detected when only high-quality and low-bias risk trials were examined separately. As the majority of these low-bias trials dealt with either elderly people, or people with disease, these results may not apply to the general population. This meta-analysis was later repeated and extended by the same authors, with the new analysis published by the Cochrane Collaboration; this analysis confirmed the previous results. These two publications are consistent with some previous meta-analyzes that also suggested that Vitamin E supplementation increased mortality, and that antioxidant supplements increased the risk of colon cancer. Beta-carotene may also increase lung cancer. Overall, the large number of clinical trials carried out on antioxidant supplements suggest that either these products have no effect on health, or that they cause a small increase in mortality in elderly or vulnerable populations.