An examination of the association between maximum-tolerated dose and carcinogenicity in 326 long-term studies in rats and mice.

The association between rodent carcinogenicity and maximum-tolerated dose (MTD) was evaluated in 326 long-term carcinogenicity studies in mice and rats. Others investigating this association have focused primarily on positive studies, but our investigation considered all experimental outcomes. We found that chemicals with low MTDs were somewhat more likely to be rodent carcinogens than chemicals with high MTDs, but this association was limited primarily to gavage studies. Overall, the MTD was not a reliable predictor of whether or not a chemical would be a rodent carcinogen. Our investigation confirms that comparisons of carcinogenic potencies based only on positive studies may result in artifactually elevated estimates of the underlying association between chemical toxicity and rodent carcinogenicity and thus may also inflate the estimated interspecies correlation in carcinogenic response. Nevertheless, the results of our study are consistent with the frequently cited 75% concordance in carcinogenicity outcome between rats and mice. This concordance is quite high, particularly since 80% is approximately the maximum level of observable interspecies concordance achievable for a set of chemicals with relatively low carcinogenic potency, because of the variability in observed tumor responses that can induce false negative or false positive outcomes in either of the two species. Thus, the underlying qualitative interspecies correlation in carcinogenic response between rats and mice may be greater than is commonly recognized.