Assessing the Cancer Potency of Acrylonitrile in Rats Using Internal Dosimetry. S. M. Hays, C. R. Kirman, M. L. Gargas, J. Czernec, and D. E. Strother, ChemRisk/McLaren-Hart, 5900 Landerbrook Drive, Cleveland OH 44124; BP Chemical, 4440 Warrensville Center Road, J-230A, Cleveland, OH 44128-2837
Acrylonitrile (AN) has been shown to be a multi-site tumorigen in more than ten separate rat bioassays in which AN was administered by gavage, drinking water or inhalation. Historically, cancer slope factors (CSFs) have been derived using applied dose and tumor response data from a single "key" study or by averaging CSFs from several "key" studies. The objective of this work is to explore the use of physiologically-based pharmacokinetic (PBPK) modeling to normalize internal dose measures across studies in an effort to improve tumor response characterization. The combined tumor bioassay data set for AN includes more than 4,000 rats exposed to 40 different exposure levels. All applied doses were normalized to internal dose measures, using a previously published and validated PBPK model for rats. A total of eight internal dose measures were considered, including maximum concentration (Cmax) and area-under-the-curve (AUC) for both AN and its oxide metabolite, cyanoethylene oxide (CEO), in both the blood and brain. The brain tumor dose-response database for AN in rats was best described by Cmax CEO in brain. In this exercise, the application of PBPK modeling to estimate internal doses provides a more complete description of the dose-response relationship for AN-induced brain tumors. By using a larger portion of the database to characterize dose-response, decisions regarding the selection of dose-response models and calculation of upper confidence limits can be made with higher confidence than otherwise possible when evaluating studies independently.