Correlation Between Carcinogenic Potency and the Maximum Tolerated Dose: Implications for Risk Assessment
Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD50 as well as unit risk factors such as q*/1 for predicting low dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD50 values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents.
Carcinogen bioassay is an important source of information on the potential carcinogenic effects of chemicals. Current practice involves the exposure of animals at doses up to the maximum tolerated dose
(MTD), defined as that dose which can be administered to rodents over the course of a lifetime without appreciably altering body weight or survival other than as a result of tumor occurrence (Munro, 1977). High doses such as the MTD are used to enhance tumor response rates, thereby increasing the likelihood of observing elevated tumor occurrence rates in a small sample of experimental animals. In this regard, Haseman (1985) has shown that more than two-thirds of the carcinogenic effects detected in feeding studies conducted under the U.S. National Toxicology Program (NTP) would have been missed if the highest dose had been restricted to one-half of the MTD.
The use of such high doses in animal cancer tests has been the subject of considerable debate (cf. McConnell, 1989). In particular, it has been argued that biochemical and physiological distortions occurring at high doses may lead to toxicity-induced carcinogenic effects that might not be expected to occur at lower doses (Carr & Kolbye, 1991; Clayson et al., 1992). Ames & Gold (1990) have suggested that high dose stimulation of mitogenesis will enhance mutagenesis, leading to the identification of rodent carcinogens that may not present a human health risk. Apostolou (1990) questioned the necessity of using the MTD in animal cancer tests on the grounds that many human carcinogens can be identified in animal tests at doses of one-half of the MTD or less.
Suggestions for redefining the high dose to be used in animal cancer tests to circumvent these issues have been made (Apostolou, 1990; Carr & Kolbye, 1991). Clayson et al. (1992) considered such proposals, but recommended retaining the MTD, while recognizing that nongenotoxic carcinogens that appear to be effective in animals only at high doses may not present a risk to humans exposed to much lower doses (cf. Butter-worth, 1990). Since the definition of the maximum dose to be used in animal cancer tests is of secondary importance for our present purposes, we make no attempt to resolve this issue here. Instead, the reader is referred to the recent report by the National Research Council (1992), which considers the definition of the maximum dose to be used in detail.
The completion of several hundred bioassays over the past two decades has resulted in the availability of a large data base that may be used in global analyses of bioassay data. Recent analyses have revealed that the MTD is highly correlated with quantitative measures of carcinogenic potency such as the TD50 (Bernstein et al., 1985; Reith and Starr, 1989a), defined as the dose that reduces the proportion of tumor-free animals by 50% (Peto et al., 1984).