Regulatory agencies currently rely on rodent carcinogenicity bioassay data to predict whether or not a given chemical poses a carcinogenic threat to humans. We argue that it is always more useful to know a chemical's carcinogenic potency (with confidence limits) than to be able to say only qualitatively that it has been found to be a carcinogen. In a typical bioassay, a chemical is administered to groups of 50 to 100 rodents at the highest feasible level (the maximum tolerated dose) and rarely at less than 1/10 this dose in order to maximize the statistical significance ofany increase in tumors that might result. Recently, much experimental work has focused on the mechani by which site-specific toxicity arising from chronic administration at the maximum tolerated dose may lead to carcinogencity. Extrapolation ofhigh-dose results to low doses does not take into consideration the possibility ofa threshold dose, below which the carcuiogenic potency is much lower or even zero. Threshold dose-response phenomena may be much more relevant to the etiology of cancer in the rodent bioassays than was earlier realized; if so, there is an even greater need for establishing dose-dependent potency estimates. The emphasis of this review is on the interspecies comparison of high-dose potencies. The qualitative and quantitative comparison ofcarcinogenicities between mice and rts and between rodents and humans isreviewed and discussed.We conclude that there is a good qualitative (yes/no) correlation for both the rat/mouse and the rodent/human comparison. There is also a good correlation of the carcinogenic potencies between rats and mice, and the upper limits on potencies in humans are consistent with rodent potencies for those chemicals for which human exposure data are available. For the rodent/human comparison, the best estimate ofthe interspecies potency factor is lognormally distributed around 1 when the potencies in both species are measured in units of (mg/kg-day) -'.

Regulatory agencies currently rely on rodent carcinogenicity bioassay data to predict whether or not a given chemical poses a carcinogenic threat to humans. We argue that it is always more useful to know a chemical's carcinogenic potency (with confidence limits) than to be able to say only qualitatively that it has been found to be a carcinogen. In a typical bioassay, a chemical is administered to groups of 50 to 100 rodents at the highest feasible level (the maximum tolerated dose) and rarely at less than 1/10 this dose in order to maximize the statistical significance of any increase in tumors that might result. Recently, much experimental work has focused on the mechanisms by which site-specific toxicity arising from chronic administration at the maximum tolerated dose may lead to carcinogenicity. Extrapolation of high-dose results to low doses does not take into consideration the possibility of a threshold dose, below which the carcinogenic potency is much lower or even zero. Threshold dose-response phenomena may be much more relevant to the etiology of cancer in the rodent bioassays than was earlier realized; if so, there is an even greater need for establishing dose-dependent potency estimates. The emphasis of this review is on the interspecies comparison of high-dose potencies. The qualitative and quantitative comparison of carcinogenicities between mice and rats and between rodents and humans is reviewed and discussed. We conclude that there is a good qualitative (yes/no) correlation for both the rat/mouse and the rodent/human comparison. There is also a good correlation of the carcinogenic potencies between rats and mice, and the upper limits on potencies in humans are consistent with rodent potencies for those chemicals for which human exposure data are available. For the rodent/human comparison, the best estimate of the interspecies potency factor is lognormally distributed around 1 when the potencies in both species are measured in units of (mg/kg-day)-1.

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Wartenberg and Gallo(') find fault with Ames et ~l . (~) for using the rank order of rodent TD5,s to predict the rank order of carcinogen hazards to humans when exposures are at much lower levels than the doses typically used in the rodent bioassays. This is certainly a topic that merits serious investigation, but Wartenberg and Gallo do not offer any new perspectives or much analysis of existing information. Rather than provide a thorough investigation of the problem, their sole purpose seems to have been to refute a paper that they apparently did not read carefully enough.The authors call Ames et al. (2) to task for proposing "a new model" in which the rodent TD50 is used as the basis for evaluating human carcinogenic hazards. But the TD50 or a similar high-dose measure of potency is already widely used for risk assessment, and Ames et ~l . (~) are quick to point out that this is an inadequate, if sometimes expedient, approach: