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than on total intake. The effects of nutrients from fortified foods or supplements may differ from those of naturally occurring constituents of foods because of the chemical form of the nutrient, the timing of the intake and amount consumed in a single bolus dose, the matrix supplied by the food, and the relation of the nutrient to the other constituents of the diet. Nutrient requirements and food intake are related to the metabolizing body mass, which is also at least an indirect measure of the space in which the nutrients are distributed. This relation between food intake and space of distribution supports homeostasis, which maintains nutrient concentrations in that space within a range compatible with health. However, excessive intake of a single nutrient from supplements or fortificants may compromise this homeostatic mechanism. Such elevations alone may pose risk of adverse effects, and imbalances among the vitamins or other nutrients may also be possible. Thus, assessment of risk from high nutrient intake includes the form and pattern of consumption, when applicable.

Consideration of Variability in Sensitivity

This risk assessment model must consider variability in the sensitivity of individuals to adverse effects of nutrients. Physiological changes and common conditions associated with growth and maturation that occur during an individual’s lifespan may influence sensitivity to nutrient toxicity. For example, sensitivity increases with declines in lean body mass and with declines in renal and liver function that occur with aging; sensitivity changes in direct relation to intestinal absorption or intestinal synthesis of nutrients; in the newborn infant sensitivity is also increased because of rapid brain growth and limited ability to secrete or biotransform toxicants; and sensitivity increases with decreases in the rate of metabolism of nutrients. During pregnancy the increase in total body water and glomerular filtration results in lower blood levels of water-soluble vitamins for a given dose and therefore in reduced susceptibility to potential adverse effects. However, this effect may be offset by active placental transfer to the unborn fetus, accumulation of certain nutrients in the amniotic fluid, and rapid development of the fetal brain. There are no data to suggest increased or reduced susceptibility to adverse effects from high intake of B vitamins and choline during lactation. For the B vitamins and choline, different ULs are developed for some life stage groups, but the ULs for adults apply equally to pregnant and lactating women. For the B vitamins and choline, the ULs for infants were judged not determinable because



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