The use of an uncertainty factor (UF) to account for interspecies variation in risk assessment procedures for noncarcinogens is well known and implemented by regulatory agencies at the federal and state levels. The approach that has been widely adopted is to assume that humans may be 10- fold more sensitive than the animal model. This factor of 10 has become routinely adopted in essentially all risk assessment procedures involving animal model data for extrapolation. Despite the long-standing use of the interspecies UF of 10, only limited biological and/or toxicological justification for the interspecies UF has ever been put forth by any regulatory agency (1) or national advisory committee (e.g., National Academy of Sciences Safe Drinking Committee). The adoption of the 10-fold factor appears to have been based on a combination of public health protection philosophy, practical/ intuitive toxicological insights based on experience, and a sense that it achieves its goal of protecting human health. The present paper offers what the authors we believe to be a toxicological and statistically defensible foundation for deriving the interspecies UF, its database requirements, and statistical procedures for its derivation. In brief, the recommended interspecies UF is defined as the 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons based on phylogenetic relatedness. More specifically, the UF is derived by determining the minimum ratio of the estimated toxicity value and its 95% upper or lower PI after back-transformation from the logarithmic expression. This paper presents the toxicological and statistical basis for this proposal and its implications for judging the reliability of current regulatory interspecies UF procedures as well as offering a fundamentally novel approach to deriving an interspecies UF.