Drug toxicokinetics: scope and limitations that arise from species differences in pharmacodynamic and carcinogenic responses

Toxicokinetics describes the concentration and time course of a xenobiotic in the circulation under the conditions of a toxicology study. However, the fundamental challenge to the toxicologist, of extrapolating the findings in animals to a risk assessment in humans, requires knowledge and understanding of both the pharmacokinetics and pharmacodynamic responses in each species. This paper exemplifies situations where measurement of plasma concentrations may provide information useful in the design and interpretation of the toxicity observed in a given species; it also illustrates how intrinsic interspecies differences in pharmacodynamic response limit the extrapolation of toxicity data across species. The special case of the multistage cumulative phenomenon of carcinogenicity, with the implications of daily dose, duration of dosing, and species differences in response, is also discussed.