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Considering the Amount Ingested

Some reports of adverse events are based on intakes that exceed the amount specified on the particular dietary supplement label for “intended use.” A number of factors make it difficult, if not impossible, to determine the contribution of dose to the effects reported. The lack of adequate premarketing data to establish the validity of labeled dosing for many dietary supplements is coupled with significant variability in the amount of the particular dietary supplement constituents in different preparations. Known pharmacokinetic variability among individuals also makes it difficult, if not impossible, to determine the contribution of dose to the effects reported. However, in conclusion, if an adverse event report provides credible evidence that a serious adverse event is associated with a dietary supplement ingredient (see criteria in the earlier section), its utility in establishing a level of concern should not be discounted simply because the intake (resulting in adverse events) exceeds that specified in current dietary supplement labeling.

Summary of Spontaneous Report Use

In summary, higher concern is warranted in situations where one or more well-documented serious adverse events manifests positive temporality, and other factors (e.g., positive dechallenge, biological plausibility, or laboratory results) combine to strengthen the perceived association between the dietary supplement ingested and the adverse event in question. Given the inherent limitations of spontaneous reports (including report quality) in general, and those concerning dietary supplement ingredients in particular, not all of this information will be available in many cases.

Tables 4-1 and 4-2 illustrate the relative spectra of concern. The columns on the right describe situations that warrant higher concern because the greatest risk to public health exists, while situations described on the left are of lower concern. The level of concern increases in proportion to the completeness of information provided and the likelihood of confounding decreasing. However, with serious, unexpected adverse events, possible confounding in the associated reports should not automatically lessen the level of concern, but rather heighten the attempt to obtain more reports of the highest possible quality to maximize the signaling function of spontaneous report systems. In addition, the nature of the serious adverse event itself and its potential for significant harm should stimulate appropriate heightened concern.

The great utility of spontaneous reports lies in the generation of hypotheses about relationships between supplement ingredients and untoward effects, thus highlighting potential problems and signals that the agency may want to explore in greater depth. Evaluation of signals from



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