Clewell Harvey J, Thomas Russell S, Gentry P Robinan, Crump Kenny S, Kenyon Elaina M, El-Masri Hisham A, Yager Janice W
CIIT Centers for Health Research, Research Triangle Park, NC 27709, USA.
Toxicol Appl Pharmacol. 2007 Aug 1;222(3):388-98. doi: 10.1016/j.taap.2007.03.021. Epub 2007 Mar 30.
Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an adequate biologically based dose response (BBDR) model that could provide a quantitative basis for an alternative nonlinear approach. This paper describes elements of an ongoing collaborative research effort between the CIIT Centers for Health Research, the U.S. Environmental Protection Agency, ENVIRON International, and EPRI to develop BBDR modeling approaches that could be used to inform a nonlinear cancer dose response assessment for inorganic arsenic. These efforts are focused on: (1) the refinement of physiologically based pharmacokinetic (PBPK) models of the kinetics of inorganic arsenic and its metabolites in the mouse and human; (2) the investigation of mathematical solutions for multi-stage cancer models involving multiple pathways of cell transformation; (3) the review and evaluation of the literature on the dose response for the genomic effects of arsenic; and (4) the collection of data on the dose response for genomic changes in the urinary bladder (a human target tissue for arsenic carcinogenesis) associated with in vivo drinking water exposures in the mouse as well as in vitro exposures of both mouse and human cells. An approach is proposed for conducting a biologically based margin of exposure risk assessment for inorganic arsenic using the in vitro dose response for the expression of genes associated with the obligatory precursor events for arsenic tumorigenesis.
无机砷的癌症风险评估一直基于人类流行病学数据，假定在肿瘤观察范围以下存在线性剂量反应关系。在砷风险评估中持续采用线性方法的部分原因是缺乏一个适当的基于生物学的剂量反应（BBDR）模型，该模型可为替代的非线性方法提供定量基础。本文描述了CIIT健康研究中心、美国环境保护局、ENVIRON国际公司和电力研究所在进行的一项合作研究工作的内容，旨在开发可用于为无机砷的非线性癌症剂量反应评估提供依据的BBDR建模方法。这些工作集中于：（1）完善小鼠和人类体内无机砷及其代谢物动力学的基于生理的药代动力学（PBPK）模型；（2）研究涉及细胞转化多种途径的多阶段癌症模型的数学解决方案；（3）回顾和评估关于砷基因组效应剂量反应的文献；（4）收集与小鼠体内饮用水暴露以及小鼠和人类细胞体外暴露相关的膀胱（砷致癌作用的人类靶组织）基因组变化剂量反应的数据。本文提出了一种利用与砷致瘤必需前体事件相关基因表达的体外剂量反应，对无机砷进行基于生物学的暴露风险边际评估的方法。
