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our carcinogenicity assessment committee, which evaluates all carcinogenicity studies that come into the Center for study conduct and results review, including a report received last week from an international company that had an unlicensed product. For their dose range finding study, the available general toxicology studies had been done in Japan, and the carcinogenicity study had been done in the United States. For their animals, they had gone to the same global supplier, which had two different colonies of animals—one in Japan and one in the United States. In the Japanese studies that were submitted, there was a phenotypic response in the animals to the drug that was unmistakable. Females lost about 100 g/kg or up to 20% of their body weight. Males were not affected. Thus, the effect that occurred in the dose range finding studies at 3 months (and later, in a separate study, at 6 months) were persistent and obviously drug related. However, in the carcinogenicity study, with the same dose levels as in the other studies and with animals from the US source, there was no effect on body weight at any time during the study.

The question is whether this difference is one of genetics, the source of animals, or the source of feed. It could be caused by many things. We are still wondering why this happened, and the issue may require 2 or 3 years and $1 to $2 million to resolve.


Another area from the regulatory view (although we are not really regulating in this area) is that of microarray technology. In the pharmaceutical arena of this technology, we are beginning to look for better ways to interpret study results—possibly to understand mechanisms for responses and to eliminate the conduct of some studies. Using this technology will be a learning experience.

Currently, I participate in an International Life Sciences Institute group, which collects and attempts to compare across market-ready platforms in an effort to characterize platform responses. The purpose of this effort is to gain a similar experience base and even, in fact, build a standard response library to enable an understanding of what kind of toxic insult might reveal a predictable pattern. It will be years before this database is built.

One of my questions is what animals will be used when specialists validate or characterize this microarray platform response data set. During our last meeting, we discussed whether we should use SD or Wistar rats when trying to compare the response with a single chemical at multiple test sites, to compare platforms. That comparison can be carried farther, and there may be data to address this issue. Differences in the source of animals should be considered, even if you get what can be called a particular strain.

Finally, it is important to determine a course of action for studies in a different strain or source of animal that result in a different signal with an unknown chemical. We need to know with certainty that a different response is due to a

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