Abstract

This report provides an overview of one of the fundamental problems in cancer risk assessment: extrapolation of observed experimental results between animal species and man. Lacking detailed information on interspecific differences, researchers assume that experimental results can be extrapolated between species using the first power of body weight or using surface area scaling (body weight to 2/3 power). Neither of these extrapolation procedures will be exactly correct for all compounds. However, in the absence of species-specific data, body weight or surface area extrapolations are used with the explicit knowledge that they are only approximately correct. We recommend that when a scaling metric for a specific compound is known, the scaling metric should be used in a risk assessment. When there is no prior knowledge of a chemical's pharmacokinetics or mechanism of action (the usual case in risk assessment), we recommend that the 3/4 power of body weight be used as the most appropriate interspecies scaling metric. The methods and properties used in interspecies extrapolation include allometric scaling, scaling physiological parameters (organ volumes, volume rates, partition coefficients, and biological half-life), physiological time, and physiologically-based pharmacokinetics. The extrapolation of these physiological, biochemical, and metabolic parameters across species controls interspecific extrapolation of pharmacokinetics. We analyzed clearance and half-life data for several compounds in multiple species and determined that the 3/4 power scaling law provides a more accurate estimate of a compound's true scaling metric than does the surface area scaling metric or the first power of body weight scaling metric.