review every combination of antioxidants that might have been tested, but to give a flavor of the potential benefits of this class of compounds when used in combination.

VITAMIN E (ALPHA-TOCOPHEROL)

Introduction

Vitamin E is a family of fat-soluble α-, β-, γ-, and δ-tocopherols and corresponding four tocotrienols. The α-tocopherol has been the most studied, as it is the form preferentially absorbed and transported to tissues in humans. For example, the U.S. dietary requirements have been developed considering mainly this form. Although vitamin E is an antioxidant that stops the production of ROS formed when fat undergoes oxidation, its in vivo roles are not well understood. The level of alpha-tocopherol is high in the brain, and its concentration is normally regulated (Spector and Johanson, 2007).

The consumption of vitamin E beyond the requirement levels cited in the Dietary Reference Intakes (DRIs) has been studied extensively from 1990 through 2010. Early observational studies and animal studies suggested that vitamin E’s antioxidant properties would protect the body against devastating chronic diseases having oxidative stress as part of their pathobiology, such as cardiovascular diseases and cancer; however, results from observational studies are mixed, and have not resulted in a clear association between intake of vitamin E and reduction of chronic disease (Hirvonen et al., 2000; Mezzetti et al., 2001; Watkins et al., 2000; Yochum et al., 2000). Large human trials conducted since 2000 have also failed to demonstrate such benefits. The reader is referred to the numerous discussions that can be found on this topic and on the potential reasons for the disappointing findings (Fletcher and Fairfield, 2002; Huang et al., 2006; Lichtenstein, 2009; Pryor, 2000; Steinberg, 2000). Table 7-1 lists large human trials that have evaluated the association of vitamin E with cardiovascular diseases, as well as a recent study on TBI presented at a conference (Razmkon et al., 2010). The occurrence or absence of adverse effects in humans is included if reported by the authors. The 2006 IOM report Nutrient Composition of Rations for Shortterm, High-Intensity Combat Operations reviewed vitamin E in the context of preventing oxidative damage from exhausting physical exercise in the military. That report showed no clear benefit either in reducing muscle injury due to exercise or in improving performance, and therefore no recommendation was offered to increase intake of vitamin E (IOM, 2006). That report did not review evidence on vitamin E and potential benefits for TBI.

Uses and Safety

The Recommended Dietary Allowance (RDA) for vitamin E (as alpha-tocopherol) is set at 15 mg for men 19–50 years of age. This requirement was based on maintaining plasma tocopherol concentration at a level that limited hemolysis in red blood cells resulting from peroxide exposure to less than 12 percent.

A comparison of U.S. dietary intake from National Health and Nutrition Examination Survey (NHANES) 2001–2002 data with the Estimated Average Requirements (EARs) of alpha-tocopherol (see Table 5-2 in Chapter 5) suggests that 89 percent of males and 97 percent of females older than 19 years of age consume far less vitamin E than the recommended EAR. However, overt signs of vitamin E deficiency occur very rarely in humans and have not been reported as a result of low dietary intakes, except in conjunction with moderate to severe malnutrition.

The Tolerable Upper Intake Level (UL) of vitamin E was established at 1,000 mg, based



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