the hormone replacement therapy randomized control trial designed to look at benefits of the therapy over time (Rossouw et al., 2002).

Epidemiologists tend to agree on characteristics of epidemiological studies that suggest an increasingly strong association between an adverse effect and an ingested substance, describing this in terms of establishing “causality” between a substance and an effect (Hennekens et al., 1987; Hill, 1971; Rothman and Greenland, 1998; Sackett et al., 1991). While these characteristics can certainly be used to demonstrate whether the threshold of causality has been met, meeting such a threshold is less important for dietary supplements for which it is only necessary to determine whether an unreasonable or significant risk exists.

For a dietary supplement ingredient studied in epidemiological studies, concern increases as more of the following criteria are met: large relative risk; consistency of findings in different studies or in different populations; association that “makes sense” because other plausible causes are ruled out and results are consistent with current knowledge of cause and effect in humans, animals, and cells in vitro; association that is limited to a single potential cause and a single type of adverse event;⁸ a dose-response relationship⁹ and temporality (i.e., the adverse event occurs after a dietary supplement is ingested). In the evaluation of safety of dietary supplements, one high-quality epidemiological study alone can cause a high level of concern, as shown on the right side of Table 4-5. Epidemiological studies that do not meet these criteria may be used to form hypotheses about safety or to strengthen or generalize the results from RCTs or other data.

As described in the guiding principles, a credible report or study finding of a serious adverse event in humans that is associated with use of a dietary supplement ingredient raises concern about the ingredient’s safety. While historical use should not be used as prima facie evidence that the ingredient does not cause harm, it may be appropriate to give considerable weight to a lack of adverse events in large, high-quality, randomized clinical trials or