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practicalities of how to make such comparisons in a systematic way and the limitations inherent in systematic prediction software may limit the usefulness of this approach, as may the important fact that small changes in chemical structure can result in major changes in physiological activity.

CONSIDERATION OF SUBSTANCES RELATED TO ENDOGENOUS SUBSTANCES

GUIDING PRINCIPLE: Dietary supplement ingredients that are endogenous substances or may be structurally or functionally related to endogenous substances should be evaluated to determine if their activities are likely to lead to serious effects. Considerations should include the ingredient’s ability to raise the steady-state concentration of biologically active metabolites in tissues and whether the effect of such increases is linked to a serious health effect.

A number of dietary supplement ingredients may be structurally or functionally related to endogenous substances. Such substances include hormones, metabolites and their precursors, and ingredients created as mimetics of these substances (see Table 6-2 for examples). Any safety issues of ingredients related to endogenous substances are based on the extent to which the ingredient’s similarity to an endogenous substance alters homeostasis. Concern about one of these ingredients is warranted when certain characteristics or qualities are present, as discussed below.

Relevant Characteristics

Physiologically relevant amount of ingredient ingested: It is important to consider whether the ingredient is delivered to potential sites of action at a concentration that is physiologically relevant. For example, a supplement ingredient ingested at an amount that is clearly a small fraction of the amount typically provided in the diet is less likely to pose a risk because the likelihood of physiological impact is low.

Concentration at the site of action that can cause harm: The next consideration is whether the substance reaches the site of action at a concentration that can cause harm, which is largely determined by the substance’s bioavailability, rate of metabolism, and excretion. For example, dietary supplement ingredients for which evidence suggests negligible uptake from the gastrointestinal tract would be unlikely to pose a risk beyond local effects, such as gastrointestinal upset. In contrast, ingredients that may result in concentrations of endogenous substances above the normal



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