Problems and opportunities in toxicity testing arising from species differences in xenobiotic metabolism

The processes of metabolism and disposition have a major bearing upon the biological properties of xenobiotics, determining both the chemical natures and target concentrations of the compound-derived materials in the body. The occurrence of major quantitative and qualitative differences between animal species in the metabolism of xenobiotics is well documented. Interspecies differences in metabolism represent a major complication in toxicity testing, being responsible for important differences both in the nature and magnitude of toxic responses. As such, they may be both help and hindrance and this presentation will illustrate both these possibilities with appropriate examples. In particular, these differences represent probably the single greatest complicating factor in the use of animal toxicity data as an indication of potential human hazard. Although it is considered desirable to identify a species which metabolizes the test compound like man, this ideal is generally not attainable. While metabolic and toxicokinetic data should be used in the selection of animal species, in reality the choices are constrained by other major factors such as availability, background pathological knowledge and regulatory acceptability. On the other hand, species differences in metabolism may present exploitable opportunities for insights into mechanisms of toxicity and with appropriate supporting data may thereby increase confidence in the animal-to-human extrapolation. The application of the new technologies of transgenesis to the creation of animals expressing the genes for human drug metabolizing enzymes offers the promise of increasing the opportunities and minimizing the problems presented by species differences in xenobiotic metabolism.