Risk zyxwvutsrqponmlkjih Analysis, Vol. 16, No. 6, I996 zyxwvutsrqp Interspecies Extrapolation of Physiological Pharmacokinetic Parameter Distributions Karen H. Watanabe' and FrCdCric Y. Bois2$ Received September zyxwvutsr 21. 1994; revised July 30, I996 zyxwvu Three methods (multiplicative, additive, and allometric) were developed to extrapolate physiolog- ical model parameter distributions across species, specifically from rats zyx to humans. In the multi- plicative approach, the rat model parameters are multiplied by the ratio of the mean values between humans and rats. Additive scaling of the distributions is defined by adding the difference between the average human value and the average rat value to each rat value. Finally, allometric scaling relies on established extrapolation relationships using power functions of body weight. A physio- logically-based pharmacokinetic model was fitted independently to rat and human benzene dis- position data. Human model parameters obtained by extrapolation and by fitting were used to predict the total bone marrow exposure to benzene and the quantity of metabolites produced in bone marrow. We found that extrapolations poorly predict the human data relative to the human model. In addition, the prediction performance depends largely on the quantity of interest. The extrapolated models underpredict bone marrow exposure to benzene relative to the human model. Yet, predictions of the quantity of metabolite produced in bone marrow are closer to the human model predictions. These results indicate that the multiplicative and allometric techniques were able to extrapolate the model parameter distributions, but also that rats do not provide a good kinetic model of benzene disposition in humans. KEY WORDS: Benzene; interspecies extrapolation; physiologically-based pharmacokinetics; Monte Carlo parameterization. 1. INTRODUCTION Therefore, techniques accommodating population varia- bility are needed when performing model extrapolations for risk assessment. The results of drug toxicity studies are often ex- trapolated from animals to humans to establish starting doses in clinical trials.(') Cancer risk assessments of en- vironmental toxicants also use standard methods of ex- trapolation. Two approaches are currently used in pharmacology and toxicology: allometric scaling and physiologically-based model extrapolations.(8) The allometric approach relates the quantity of in- Chemical risk assessment has motivated the use of physiologically-based pharmacokinetic (PBPK) models to improve estimates of target tissue exposures across species. Models fitted to animal data have been extrap- olated to represent humans by replacing the physiologic, biochemical, and kinetic parameters with average human values.(14)Yet, risk assessment is concerned with risks to a population, not to a hypothetical average individual. zyxwvu ' Department of Mechanical Engineering, University of California at terest, (e*g*, a tissue dose), to a power function Of body Berkeley, Berkeley, California 94720. Lawrence Berkeley National Laboratory, Berkeley, California 94720. To zyxwvutsrqp whom all correspondence should be addressed at Indoor Envi- ronment Program, mail stop 90-3058, Lawrence Berkeley Labora- tory, Berkeley, California 94720. weight, fitted across species. Y=AbwS (1) where, bw is body weight and A is a species independent 74 1 0272-4332/%/12oOa741S09.50/1 0 19% Society for Risk Analysis