Many micronutrients are currently being tested for cancer prevention activity. A short-term study recently suggested that two of these nutrients, beta-carotene and alpha-tocopherol, may have an adverse interaction, with beta-carotene supplementation leading to markedly decreased serum concentrations of alpha-tocopherol. We have analyzed the effect of beta-carotene supplementation on serum concentrations of alpha-tocopherol in 2319 participants enrolled in the Carotene and Retinol Efficacy Trial who have taken beta-carotene and vitamin A for up to 6 years. One thousand thirty-five participants enrolled in two pilot trials to the Carotene and Retinol Efficacy Trial had serum collected at yearly intervals; an additional 1284 recently recruited participants had serum collected at biennial intervals. Using standard high pressure liquid chromatography techniques, with attention to quality control, these samples were analyzed for beta-carotene and alpha-tocopherol. After up to 6 years of supplementation with beta-carotene (30 mg/day) and vitamin A (25,000 international units/day) we found a small but statistically significant increase in the serum concentration of alpha-tocopherol in participants taking the active agents. No evidence of a decrease was found in any of the subpopulations examined. We conclude that long-term supplementation with the combination of beta-carotene and vitamin A does not decrease serum concentrations of alpha-tocopherol. Our long-term trial validates results from several shorter trials conducted by others. The concept of adverse interactions between supplemental micronutrients is important. All cancer prevention trials should closely monitor serum concentrations of micronutrients, as well as the incidence of other significant disease.

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