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Dietary Supplements: A Framework for Evaluating Safety
exist between an ingredient and a substance known to be dangerous, there is scientific merit in considering whether similar adverse health effects might also occur. This is especially true if the ingredient or its relevant metabolites are bioavailable at the target site.
Although the actual data for such consideration will fall into the categories of data described in the previous chapters (in vitro, animal, or human data), the consideration of functional relatedness is described here rather than in the other chapters because (1) the concept applies to all types of data and (2) because the concept is similar to the concept of considering substances related in other ways (either structurally or, for botanicals, taxonomically). That is, a safety evaluation should consider the relationship between the dietary supplement ingredient in question and compounds known to be toxic. This type of information may be most useful in assessing the safety of a dietary supplement ingredient for which chemical constituents are not known or, for botanicals, when not much is known about the plant genus.
Functionally related substances may have similar actions in vitro, such as genetic effects or effects on cellular processes (e.g., enzymatic effects, effects on intracellular cell signaling). One example of such functional relatedness illustrated in Chapter 11 is saw palmetto and the drug finasteride. Finasteride is considered unsafe for consumption during pregnancy because of effects on male genitalia development (Bowman et al., 2003; Clark et al., 1990, 1993; Kurzrock et al., 2000). This effect is due to inhibition of the 5-α-reductase enzyme, which is important in testosterone production (Anderson and Clark, 1990; Prahalada et al., 1997). Saw palmetto also inhibits 5-α-reductase, as shown in in vitro experiments (Bayne et al., 1999), and thus would be considered as functionally related to finasteride. Thus, in the absence of mitigating data suggesting that saw palmetto does not also lead to male genitalia development problems, it would be scientifically appropriate to consider saw palmetto as a risk for consumption by pregnant women.
When considering which substances a given dietary supplement may be functionally related to, the purported mechanism of action of the ingredient should be considered. For example, shark cartilage has been referred to as an angiogenesis inhibitor. If angiogenesis inhibition is considered as dangerous, or angiogenesis inhibiting drugs are only used with caution by pregnant women because of this mechanism, then it would be appropriate to consider whether shark cartilage is indeed a risk for the same reason.
When evaluating whether functional relatedness to other chemicals provides helpful information about the safety of a dietary supplement ingredient, it is very important to consider that overt expression of toxicity is dependent on exposure (i.e., amount ingested or dose). When animal or human data do not exhibit the toxic effects predicted based on functional relatedness, then it is necessary to consider whether the possible effects