Bradford Hill Criteria and the Case for γ‐Tocopherol as an Essential Dietary Nutrient in the Prevention of Nitrogen Oxide‐mediated Cellular Damage and Associated Chronic Diseases of Aging.

Abstract

The nutrition field is awash with recommendations for the benefits of “antioxidants” for the prevention of chronic diseases of aging, e.g. cancer, yet evidence of efficacy in humans for individual antioxidants is limited to cell culture, animal studies, or to epidemiologic associations. Indeed, large clinical trials with relatively high doses of the most promising antioxidant agents, β‐carotene and α‐tocopherol, have paradoxically demonstrated pro‐carcinogenic effects in humans. γ‐Tocopherol is an ubiquitous dietary antioxidant which is typically found at micromolar levels in humans. It possesses unique antioxidant properties that specifically target nitrogen oxide species capable of damaging DNA in cells. Data from published studies of the chemistry of γ‐tocopherol, its biology, its epidemiology, its effects on animal models of disease and clinical effects of decreased levels in humans are assessed in light of the Bradford Hill criteria for causality in order to establish a prima facie case for the essentiallity of γ‐tocopherol in human nutrition. While the epidemiology of γ‐tocopherol is uniquely complex, its coherence with fundamental studies of γ‐tocopherol and the plausibility provided by our understanding of its chemical mechanism of action and unique biological effects add considerable weight to epidemiological and clinical observations of its associations with chronic diseases of aging. Taken together, the evidence supports a beneficial effect of and possible requirement for moderate intake of γ‐tocopherol in the diet, however, it is unlikely that significantly higher intake beyond levels found in the typical American diet would offer additional benefit.