RESPONSE

PACT/Hazardexpert. However, by the rule they claim to have used (equivocal carcinogens are regarded as noncarcinogens), only ybutyrolactone is predicted correctly. Inclusion of additional related variables in the predictive method. After the carcinogenicity outcomes were known, Lewis et al. found that the predictive performance of COMPACT could be enhanced if they included an additional COMPACT prediction (C2E) and also a predictor variable ("Hazardexpert") that incorporates information about metabolism. While there is nothing inherently wrong with including additional variables in a predictive methodology, this exercise should ideally have been carried out prospectively, not retrospectively. It is much easier to find predictive variables that work once the study outcomes to be predicted are known. The important (and yet to be answered) question is, how will the authors' newly derived, multivariate predictive methodology fare for prospective predictions? Hopefully, it will be better than COMPACT's limited predictive success (56%) for the 44 NTP chemicals. The combination of COMPACT and Hazardexpert eliminated the apparent discordance for three chemicals: tris(2chloroethyl)phosphate, 2,3-dibromo-1propanol, and 1,2,3-trichloropropane, while introducing discordance for another chemical previously predicted correctly (methyl bromide). However, the authors misclassify two other chemicals: chloramine and HC Yellow 4, both of which are reported as successful predictions, but in fact were not predicted correctly (see Table 2). Including additional predictor variables (and not correcting for the misclassification of chloramine and HC Yellow 4) reduced the number of discordant predictions from 11 to 8. Inclusion of additional, apparently unrelated, variables in the predictive method. The eight chemicals that Lewis et al. conclude are not correctly predicted by COMPACT/Hazardexpert are designated in their Table 4 (p. 182). The authors then carry out further analyses to reduce the number of discordant predictions from eight to five. Frankly, it is unclear exactly how the authors achieve this reduction. It appears that the basis for eliminating the final three chemicals from "discordancy" was an appeal to "structural alert, chronic toxicity studies, and the Ames test," which correctly predicted the carcinogenicity of o-benzyl-p-chlorophenol, methylphenidate hydrochloride, and diphenylhydantoin, three chemicals "missed" by COMPACT/Hazardexpert. One other chemical (mercuric chloride) not even evaluated by COMPACT/Hazardexpert, but correctly identified by "the metal ion redox potentials for inorganic compounds," was also apparently added in as a correct prediction. The authors should justify how these additional predictions, based on apparently unrelated variables, can be meaningfully interpreted as improving the performance ofCOMPACT/ Hazardexpert. In any case, the authors include these successful predictions in their calculations and conclude that the concordance for COMPACT/ Hazardexpert when predicting rodent carcinogenicity is 86% (32/37). I leave it to the reader's judgment to determine how much confidence to place in this figure. I have no objection to the development of techniques designed to predict rodent (or more importantly, human) carcinogenicity, and I suspect that it is possible to develop methods that will be successful in this regard. However, I strongly urge caution in placing too much confidence in COMPACT or in any other predictive method that has little success when applied prospectively and seems to work only when applied retrospectively to the original data set, using extensive (and scientifically questionable) data manipulations and reanalysis.