High Nutrient Intakes—The Toxicologist's View

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Abstract
At sufficiently high intake all substances, including essential nutrients, can be toxic. Toxicity may be described by characteristics of the symptoms (identity, severity and degree of persistence) and by the dose-response relationship (threshold, slope, limit, susceptibility to modulation by other substances and tendency to bioaccumulate). Some nutrient toxicities are deleterious exaggerations of essential functions, whereas others are not. The therapeutic indices for nutrients should be defined as the ratio of the lowest toxic dose to the recommended intake, the ratio of the medians of the effective and the toxic doses commonly used in pharmacology. For infant formulas, a ratio of the lowest toxic concentration to the maximum concentration allowed is an analogous ratio. Nutrients with low therapeutic indices and small physical size of a toxic dose require special caution to avoid excessive intake. Modulation of absorption, metabolism or excretion, as well as the physiological state of the exposed individual, may alter the minimum toxic intake of a nutrient and hence alter the risk of toxicity. Extrapolation to estimate the toxic dose can be made on the basis of body weight, body surface area or food intake. Nutrient minimums and maximums in infant formula are set on a 100-kcal basis and thus are related to heat loss and surface area. Evaluation of vitamin A toxicity cases on a dose per 100-kcal basis suggest that the current maximum in infant formula is appropriate. Extrapolation from toxicity data in adults can be made on the dose per 100-kcal basis to estimate appropriate infant formula maximums for nutrients for which maximums have not been set.