The ability of predicted internal dose measures to reconcile tumor bioassay data for chloroform

PBPK models are developed in the hope that they will improve our ability to extrapolate from one species to another and from one exposure regime to another. Evidence that a dose measure was successful at reconciling the available animal bioassay data would be encouraging. It would give us some confidence that the dose measure (as evaluated by a PBPK model) might yield reasonable predictions for yet other species (e.g., humans) and other dose routes. We have investigated the ability of a modified version of the Corley et al. (R. A. Corley, A. L. Mendrala, F. A. Smith, D. A. Staats, M. L. Gargas, R. B. Conolly, M. E. Andersen, and R. H. Reitz, 1990, Toxicol. Appl. Pharmacol. 103, 512-527) PBPK model for chloroform to reconcile the available bioassay data. Two rate-dependent dose measures, maximal rate of metabolism in the liver, and percentage of hepatocytes killed per day performed well at reconciling the rodent liver bioassay data, while all rate-independent dose measures performed less well. In contrast, none of the PBPK dose measures were capable of reconciling the rat and mouse kidney tumor response data. Here, administered dose scaled to body surface area performed the best.