ABSTRACT

A physiologically based pharmacokinetic (PBPK) model was developed to described uptake, disposition and clearance of bromate in the rat using published experimental data in rat. The rodent bromate model was extrapolated to human using species-specific physiological parameters and standard interspecies scaling of rate constants. The bromate model is kinetically linear (i.e. AUC and Cmax) across the range of drinking water concentrations used in the cancer bioassays (15 to 500 ppm). This is likely the result of the poor oral bioavailability of bromate due to high reduction rates in the intestinal tract. The bromate PBPK model was used to assess the human equivalent drinking water concentration (HEC) consistent with average plasma concentrations in the rodent bioassays. At drinking water concentrations <500 mg/L, the predicted HEC was two to three fold lower than the bioassay concentration and was dependent on the reported drinking water intake reported in the bioassay.

摘要

开发了基于生理学的药代动力学 (PBPK) 模型，以使用已发表的大鼠实验数据来描述大鼠中溴酸盐的摄取、处置和清除。使用物种特异性生理参数和速率常数的标准种间标度，将啮齿动物溴酸盐模型外推到人类。溴酸盐模型在癌症生物测定中使用的饮用水浓度范围内（15 至 500 ppm）呈动力学线性（即 AUC 和 Cmax）。这可能是由于肠道中的高还原率导致溴酸盐口服生物利用度差的结果。溴酸盐 PBPK 模型用于评估与啮齿动物生物测定中的平均血浆浓度一致的人类等效饮用水浓度 (HEC)。在饮用水浓度 <500 mg/L 时，