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models cannot be overruled by lesser-quality human data, such as a lack of spontaneously reported adverse events in current or historical use, less than adequate clinical or in vitro studies, or lack of structural similarities to any known poison. To justify disregarding animal observations, the event occurring in animals would need to be specifically monitored for and detectable in humans under the conditions reported. For example, a lack of cancer in humans exposed to an animal carcinogen assumes greater importance when there are data of sufficient quality and power to detect the cancer if it were to occur. Thus, even though an event such as breast cancer that occurs with some frequency in the human population would be difficult, statistically, to attribute to an ingredient used in a human study, a lack of resolving power in epidemiologic studies does not rule out a relationship between the ingredient and human cancers.

Human exposure may need to be prolonged to detect latent or chronic toxicities. Therefore, regardless of the presence of even high-quality human data suggesting no toxicity following short-term exposure, certain chronic animal toxicity or biological activity data could warrant elevated concern. In particular, animal studies that warrant special concern are those that indicate the following potential effects in humans: evidence of cancer, reproductive system effects, developmental toxicity effects including teratology, or other delayed serious toxicities (see Table 5-1).

There are only a few scientifically appropriate reasons to discount animal observations because human effects are not observed, such as the well-understood differences in pharmacokinetics and/or pharmacodynamics between humans and the experimental animal described in Chapter 5. One example is manifestation of toxic effects that depends on metabolic pathways present in animals but not in humans, thus producing animal study results that are not very applicable to human health. (A hypothetical example is an adverse effect that results because the dietary supplement ingredient blocks a pathway that humans are not dependent on.) While it is unusual in the dietary supplement field at present to have such detailed knowledge, occasionally an understanding of the pathway responsible for the toxicity can mitigate the extrapolation to humans of concerns raised in animal studies.

PROOF OF HARM

For a number of dietary supplements ingredients, decisions regarding safety must be made despite sparse data and shortcomings in the studies that are available. In making such decisions, interpretation of available data must be made by weighing it against the assumption that all dietary supplement ingredients are safe (see Chapter 1, description of DSHEA). The assumption that dietary supplement ingredients are safe is not equivalent to



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