Interspecies Extrapolation

Interspecies extrapolation encompasses two related but distinct topic areas that are germane to quantitative extrapolation and hence computational toxicology—dose scaling and parameter scaling. Dose scaling is the process of converting a dose determined in an experimental animal to a toxicologically equivalent dose in humans using simple allometric assumptions and equations. In a hierarchy of quantitative extrapolation approaches, this option is used when minimal information is available for a chemical of interest. Parameter scaling refers to cross-species extrapolation of specific biological processes describing rates associated with pharmacokinetic (PK) or pharmacodynamic (PD) events on the basis of allometric relationships. These parameters are used in biologically based models of various types that are designed for not only cross-species extrapolation but also for exposure route (e.g., inhalation to oral) and exposure scenario (duration) extrapolation. This area also encompasses in vivo scale-up of physiological rates determined in various experimental systems. Results from in vitro metabolism studies are generally most useful for interspecies extrapolation purposes when integrated into a physiologically based pharmacokinetic (PBPK) modeling framework. This is because PBPK models allow consideration and quantitative evaluation of other physiological factors, such as binding to plasma proteins and blood flow to the liver, which may be as or more influential than metabolism in determining relevant dose metrics for risk assessment.