Himmelstein Matthew W, Carpenter Steven C, Evans Marina V, Hinderliter Paul M, Kenyon Elaina M
E.I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road, Newark, Delaware 19711, USA.
Toxicol Sci. 2004 May;79(1):28-37. doi: 10.1093/toxsci/kfh096. Epub 2004 Feb 19.
beta-Chloroprene (2-chloro-1,3-butadiene; CD), which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance of the bioassay lung tumor findings to human health risk by developing a physiologically based toxicokinetic (PBTK) model and exploring a tissue specific exposure-dose-response relationship. Key steps included identification of the plausible genotoxic mode of action, experimental quantification of tissue-to-air partition coefficients, scaling of in vitro parameters of CD metabolism for input into the PBTK model, comparing the model with in vivo experimental gas uptake data, selecting an appropriate tissue dosimetric, and predicting a corresponding human exposure concentration. The total daily milligram amount of CD metabolized per gram of lung was compared with the animal bioassay response data, specifically combined bronchiolar adenoma/carcinoma. The faster rate of metabolism in mouse lung agreed with the markedly greater incidence of lung tumors compared with the other rodent species. A lung tissue dose was predicted for the combined rodent lung tumor bioassay data at a 10% benchmark response. A human version of the PBTK model predicted that the lung tissue dose in humans would be equivalent to continuous lifetime daily exposure of 23 ppm CD. PBTK model sensitivity analysis indicated greater dependence of model predictions of dosimetry on physiological than biochemical parameters. The combined analysis of lung tumor response across species using the PBTK-derived internal dose provides an improved alternative to default pharmacokinetic interspecies adjustments for application to human health risk assessment.
β-氯丁二烯（2-氯-1,3-丁二烯；CD）用于合成聚氯丁二烯，在B6C3F1小鼠和Fischer大鼠中引发了多种肿瘤类型的高发病率，但在Wistar大鼠或叙利亚仓鼠中未出现这种情况。本项目通过建立基于生理学的毒代动力学（PBTK）模型并探索组织特异性暴露-剂量-反应关系，研究生物测定肺肿瘤结果与人类健康风险的相关性。关键步骤包括确定合理的遗传毒性作用模式、实验量化组织与空气的分配系数、按比例缩放CD代谢的体外参数以输入PBTK模型、将模型与体内实验气体摄取数据进行比较、选择合适的组织剂量测定方法以及预测相应的人类暴露浓度。将每克肺组织中CD代谢的每日毫克总量与动物生物测定反应数据进行比较，特别是合并的细支气管腺瘤/癌。小鼠肺中更快的代谢速率与其他啮齿动物相比明显更高的肺肿瘤发病率一致。针对合并的啮齿动物肺肿瘤生物测定数据，预测了10%基准反应时的肺组织剂量。PBTK模型的人类版本预测，人类的肺组织剂量相当于每天持续终生暴露于23 ppm的CD。PBTK模型敏感性分析表明，剂量测定的模型预测对生理学参数的依赖性大于对生化参数的依赖性。使用PBTK推导的内部剂量对跨物种肺肿瘤反应进行联合分析，为应用于人类健康风险评估的默认药代动力学种间调整提供了一种改进的替代方法。
