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who reported taking chaparral but no other supplements or drugs, suggesting that the adverse events were not due to concomitantly consumed substances. Reported liver problems were clinically documented. In the case report of jaundice and toxic liver disease, the individual elected to rechallenge and the symptoms recurred. Recurrence of symptoms after rechallenge is considered a convincing factor in assessing strength of association. Thus, the adverse event reports are most consistent with the description of higher concern in the right column in Table 4-1: “Describes a well-documented serious adverse event, with plasma levels at a relevant range (if available) and demonstrates dechallenge and rechallenge (if possible), temporality, and strong attribution.”

In addition to the human safety data, there were also indications that persons with pre-existing liver disease might consume chaparral.3 The fact that the very persons most susceptible to liver problems might be using chaparral should raise the concern level even higher, consistent with the discussion of particularly susceptible subpopulations in Chapter 9.

Given the high level of concern about the human data on liver problems and the additional concern about particularly susceptible subpopulations, the Framework directs FDA to proceed with an integrative evaluation of all available data about chaparral (i.e., other human data, animal data, in vitro data, and data about the safety of related substances). In this case, FDA could instead elect to do a focused monograph on the risk of liver adverse effects from chaparral consumption because the evidence available at this point indicates the greatest concern is for liver damage (see discussion of a focused monograph, later in this chapter).

Integrative Evaluation

Although FDA could have chosen to focus its efforts on liver problems, the prototype chaparral integrative evaluation was conducted with a more broad-based strategy. Studies focused on the safety of chaparral were limited in number and value, so the literature search included a search for information about safety problems associated with nordihydroguaiaretic acid (NDGA), a component of chaparral.

The human data considered included information about hepatic adverse events reported to FDA and published as case reports (as discussed in the previous section). Anecdotal information about the traditional use of chaparral as a tea was also considered. This information was only considered relevant to chaparral use as a tea, because as described in the mono-

3  

For specifics, see discussion of conditions of use (Section B) in prototype monograph, available at www.iom.edu/fnb.



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