The relationship between use of the maximum tolerated dose and study sensitivity for detecting rodent carcinogenicity

The relationship between maximum tolerated dose (MTD) and study sensitivity for detecting rodent carcinogenicity was evaluated for 216 chemicals found to be carcinogens in laboratory animal studies conducted by the National Cancer Institute (NCI) and the National Toxicology Program (NTP). Approximately two-thirds of these rodent carcinogens would have been detected even without the top dose (estimated MTD), but in many of these studies, some site-specific carcinogenic effects would have been missed. Among the remaining one-third of the rodent carcinogens that required the top dose for statistical significance, approximately 80% had numerically elevated rates of the same site-specific tumors at lower doses as well. Only 13 of the NCI/NTP rodent carcinogens had increased tumor rates limited to the top dose for all sites of carcinogenicity. Alternatively, of the 838 site-specific carcinogenic effects observed in the NCI/NTP studies, 447 (53%) would have been detected even without the top dose. Of the remaining effects, 75% (294/391) showed numerically elevated site-specific tumor rates at lower doses. Our evaluation indicates that most carcinogenic effects observed at the top dose in rodent studies are also present (with reduced incidence that might or might not be statistically significant) at the lower doses typically employed (1/2MTD, 1/4MTD).