Inferring Toxicological Similarity with Multidimensional Relational Analysis

Ginkgo biloba extract (GBE; CASRN 90045-36-6) is a commonly used herbal supplement. A comprehensive toxicological assessment by the NTP identified GBE as hepatotoxic. The constituents of GBE can vary across lots, hence the question arises as to how representative the lot tested by NTP is of other lots of GBE and by extension to what degree the results of the NTP hazard characterization are more broadly applicable to the various GBEs on the market. In order to get a detailed fingerprint of the biological activity of five chemically distinct lots of GBE, extracts were administered at multiple dose levels to rats for five days after which global liver gene expression was examined. Genomic bench mark dose modeling was performed to provide detailed quantitative and qualitative description of the biological effects of the test articles. The GBE tested by NTP in its initial toxicological characterization had the overall largest and most potent effect on gene expression in the liver. A variety of multidimensional relational metrics found that two lots of GBE were similar in their biological effects to the lot used by NTP for their toxicological assessment. The two lots showing the greatest degree of multidimensional biological similarity also showed the highest degree of chemical fingerprint similarity, suggesting that in this case study chemical fingerprint similarity provides good approximation of biological similarity and can likely be used to identify lots of GBE that would be forecasted to have similar toxicological properties to the lot that has gone through comprehensive toxicological testing by the NTP.