. "3 Outline of the Overall Process for Evaluation of Dietary Supplement Ingredients." Proposed Framework for Evaluating the Safety of Dietary Supplements -- For Comment. Washington, DC: The National Academies Press, 2002.
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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements
have equivalent safety profiles. As discussed in the following paragraphs, differences in safety profiles may exist because the products contain different amounts of an ingredient, there are differences in bioavailability (the degree to which a substance becomes available to the target tissue after administration), there are differences in the amounts or presence of other substances (including contaminants), or the products are sold in combination with different ingredients.
Substantial variation can exist among the different brands of products purportedly containing a given dietary supplement ingredient (Foreman, 2000; Howe, 2000) due to lack of standardization. Products labels may claim that products are standardized to contain a particular amount of a substance. Several reports of product analyses, however, suggest that product labels may be inaccurate—that products may contain significantly higher or lower amounts of substances than indicated on the label (Green et al., 2001; Hamilton-Miller et al., 1999; Kamber et al., 2001). While a number of reports have suggested that substances do not contain the substances purported on the label, reports of labeling discrepancies with several botanicals have been disputed on the basis that laboratories used different analytical methods or measured different chemical markers that may not be relevant (Betz et al., 1995; Marrone, 1999). The eventual development of standards may address this problem.
In addition to differences in the amount of a substance contained in a product, significant variation may exist in bioavailability. Variability in bioavailability may result from differences in manufacturing and formulation that affect how much of a substance is absorbed. For example, dissolution maybe incomplete, or even if the ingredient’s dissolution is complete, absorption may be incomplete if it is degraded in the intestinal fluid or it does not undergo active or passive transportation out of the intestinal mucosa. Dietary supplements may be delivered in matrices (tablets, capsules, etc.) that impact dissolution and absorption, or they may contain ingredients that change absorption and other aspects of bioavailability (Chambliss, 2001).
Quality control guidelines for many ingested substances are described by current Good Manufacturing Practices (GMPs). As described in Chapter 1, FDA has not yet published proposed or final GMPs for the dietary supplement industry. Quality control variables that can impact the safety of dietary supplement products include, but are not limited to, contamination by heavy metals, contamination by harmful microorganisms, contamination by pesticides, misidentification of raw plant ingredients, and improper storage. GMPs should provide guidance in a number of these areas (CFSAN, 2000; FDA, 1997).
In addition to variations in products containing a particular supplement ingredient, many products sold today are “combination products” that are mixtures of more than one dietary supplement ingredient. These products raise another set of safety concerns because mixtures can have safety profiles different than the summed effect of discrete ingredients. There is a potential for interaction among ingredients, and even mixtures containing the same dietary supplements may differ in dose and ratio of components. Although combination products can produce effects distinct from the individual ingredients, a first approximation of a combination product’s safety can come from examining the safety of the component ingredients. A combination product containing ingredients that individually are not considered safe is likely to demonstrate some of the same safety concerns as the individual ingredients.
Even if no single ingredient raises safety concerns, MedWatch and other information sources should be monitored for clusters of serious adverse events and other possible indicators of problems related to specific combination products. For example, when data suggest that interactions between individual supplement ingredients may be associated with adverse effects, combination products that contain these interacting ingredients warrant particular attention. If