Cross species extrapolation in neurotoxicology: neurophysiological and neurobehavioral aspects

The theory of phylogenetic continuity of animal species is the basis of any comparative or extrapolative endeavour (Calabrese, 1983). Cross species extrapolation is also a prerequisite for hazard identification in general and developmental neurotoxicology. Two steps must be distinguished: The first step is endpoint-based or qualitative, whereas the second is dose-based or quantitative. Comparison of different species, typically rodents, nonhuman primates and humans, in terms of endpoints is preferentially done within a framework of broad functional categories, such as sensory, motivational, cognitive, motor, and social variables. Within each category specific neurobehavioral as well as electrophysiological measures need to be considered; typically the degree of comparability is higher for electrophysiological than for most behavioral measures. For some frequently used behavioral endpoints in human neurotoxicology, such as psychometric IQ, there is no direct animal counterpart. Once the neural substrate of a particular neurotoxic effect has been identified, as is true for several chemicals such as the pyrethroid insecticides, the organophosphates, most nerve gases or MPTP, or if interspecies comparability in terms of endpoints has proven satisfactory, an effort towards quantitative, dose-based extrapolation is needed. Here species-specific differences in toxicokinetics and metabolism must be taken into consideration in order to arrive at valid translations of dose-response contingencies. If at all possible internal rather than external doses should serve as the frame of reference here. Neurotoxic chemicals of environmental concern for which an adequate data base is available for comparative purposes include alcohol, carbon monoxide, lead, methylmercury and polychlorinated biphenyls (PCB). Principles of cross species extrapolation in neurotoxicology will be illustrated by means of representative neurobehavioral and electrophysiological findings.