Animal extrapolation and the challenge of human heterogeneity

The capacity of animal models to predict the responses of humans to carcinogenic agents in light of the occurrence of human heterogeneity is assessed in this paper. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. At the same time, it is believed that the conventional rodent models, which are usually highly inbred and reared in standard ways, display a very homogeneous response to toxic agents, including carcinogens. The question then becomes, To which narrow band of the broad spectrum of human responses can specific animal models likely be extrapolated? First, the occurrence of human heterogeneity is examined with respect to a broad range of biological characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, glutathione S-transferase activity, beta-glucuronidase activity, debrisoquine hydroxylation, and DNA adduct formation), with particular emphasis on those which affect responses to carcinogens. Second, the occurrence of heterogeneity for selected animal models for these characteristics is assessed and the outcomes are related to the spectrum of human responses noted above.