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each category of data, by itself, may be insufficient to indicate concern, but when a pattern of mechanistically related adverse effects is observed across two or more categories in a consistent manner, this can establish biological plausibility and warrant heightened concern for potential harmful effects in humans.

Causal Models for Considering Consistency and Biological Plausibility

Synthesis is the concept or process of integrating safety data from different types of study designs and across different categories of data. Data synthesis can be facilitated, and conceptually illustrated, by the use of causal evidence models. A causal evidence model (see Figure 10-1) provides a structure to help interpret available data from a number of sources that address a specific safety question (Harris et al., 2001). The model can describe the relationship among a dietary supplement, potential adverse health outcomes (e.g., liver failure, death), and biological effects3 by depicting the relationship as linkages that are illustrated with arrows. The type of arrow illustrates the type of evidence: convincing data are depicted by solid arrows and weaker or less conclusive data are depicted by dashed arrows. A “path” between the dietary supplement ingredient and an adverse health effect illustrates a relationship. When the available information is integrated, multiple links between the dietary supplement ingredient and a given health outcome are illustrated by multiple arrows, as discussed below.

A solid arrow (Arrow A, Figure 10-1) linking the ingredient to the adverse health effect illustrates that a clear association between the ingredient and the effect has been demonstrated. An arrow (Arrow B, Figure 10-1) linking the ingredient to the biological effect illustrates a situation where the ingredient is known to cause the biological effect, whether or not the biological effect has been linked directly to the adverse health effect (Arrow C, Figure 10-1). Note that Arrow B could be present without Arrow C for many situations, but that a conclusive situation occurs when the ingredient is linked to the biological effect and the biological effect is linked to the adverse health effect, illustrated by Arrows B and C together.

Figures 10-2 through 10-4 illustrate other possible scenarios where conclusive data (human, animal, or in vitro) exist. Figure 10-2 illustrates two possible scenarios of conclusive animal data. The first diagram illustrates a situation where the dietary supplement ingredient is known to

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The term “biological effects” does not necessarily mean health effects. For example, it can include mechanistic effects, such as enzyme inhibition.



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