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range at the site of action are worthy of further consideration, because of the potential for their activities to be adverse.

Having determined whether an ingredient is likely to be absorbed from the gut at a concentration that could alter cellular, biochemical, or biological activities, the next issue to consider is whether the compound is readily metabolized or degraded to an inactive metabolite. For example, effects on endpoint cells and tissues are unlikely if there are efficient mechanisms for metabolizing these compounds into inactive compounds.

Sensitivity of the target system to variation in the endogenous substance: An important question to ask about endogenous substances is whether a homeostatic regulatory system would attenuate biological effects that could otherwise occur. If the target system is one that is not tightly regulated by feedback or other mechanisms to maintain homeostasis, then there is greater likelihood of potential risk.


Hormones are an illustrative example for how some ingredients related to endogenous substances can be evaluated. Exogenous hormones can be potent substances often used clinically as pharmaceuticals to treat specific deficiency states (e.g., insulin to treat diabetes, thyroid stimulating hormone to treat hypothyroidism, human growth hormone to treat dwarfism) in order to achieve physiological homeostasis. Use of dietary supplements containing hormones, hormone precursors, or hormone mimetics known to be highly potent raises the possibility of significant and substantial harm unless there is demonstrated hormonal insufficiency.


GUIDING PRINCIPLE: When data (i.e., in vitro or animal data) suggest that a dietary supplement constituent targets a receptor, enzyme, or other biological target in a manner similar to a compound known to be toxic, concern is warranted, especially if the dietary supplement constituent is known to reach the biological target in a relevant concentration.

Compounds that appear to be structurally dissimilar may nonetheless affect the same biological targets or have the same mechanism of action and thus result in the same downstream adverse health effect. Thus, if data strongly suggest that similar biological activity or mechanisms of action

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