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HARDBACK
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Integrative Evaluation

As with all six ingredients selected as prototypes, data on saw palmetto was reviewed in a manner analogous to a proactive integrative evaluation, despite the lower level of concern about the original signal that prompted its selection. This integrative evaluation was relatively broad based in that all information deemed to possibly have anything to do with toxicity was collected in the initial data search.

The impact of a data collection strategy is illustrated in the saw palmetto example. If the data collection had been limited in scope to concerns raised by human data, and the consideration of animal and in vitro data had been limited to data from traditional animal toxicity studies and validated in vitro studies, testosterone pathway concerns would probably have been overlooked. This is because the information that raised concerns was from mechanistic types of in vitro studies and from animal studies that were not classical toxicity studies. In summary, considering data from studies other than animal toxicology and validated in vitro studies was useful because the available animal studies were too limited in scope (lacking reproductive toxicology) to detect safety issues.

Shark Cartilage

Presumed Signals

Shark cartilage was flagged because of a case report of hepatitis following ingestion. Another signal of concern could have been information suggesting that shark cartilage had antiangiogenic activity, a mechanism that raises concerns with drugs.

Initial Review: Considering the Nature of the Evidence

Five clinical case reports of adverse liver effects were considered. One SN/AEMS report was confounded by concomitant ingestion of a supplement containing known hepatotoxins. There was not a consistent pattern in the other reports sufficient to overcome the lack of adequate information regarding confounders. Consideration of the limited animal data—summaries of unpublished animal toxicology available in the published literature—did not suggest reason for specific concerns given that no overt signs of toxicity were reported. In summary, a lower level of concern would have resulted from an initial review of shark cartilage’s liver effects.

As described above, shark cartilage’s purported antiangiogenic mechanism could also have triggered an initial review. An initial review of data relevant to this signal would have uncovered reports of antiangiogenic activity in animal models (non-oral administration) and in vitro models



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