Thompson Chad M, Suh Mina, Proctor Deborah M, Haws Laurie C, Harris Mark A
ToxStrategies, Inc., Katy, TX, United States.
ToxStrategies, Inc., Mission Viejo, CA, United States.
Mutat Res Genet Toxicol Environ Mutagen. 2017 Nov;823:45-57. doi: 10.1016/j.mrgentox.2017.08.004. Epub 2017 Sep 12.
The determination of whether a chemical induces a specific cancer through a mutagenic or non-mutagenic mode of action (MOA) plays an important role in choosing between linear and nonlinear low-dose extrapolation to derive toxicity criteria. There is no formal framework from the U.S. EPA for determining whether environmental chemicals act through a mutagenic or non-mutagenic MOA; consequently, most such determinations are made on an ad hoc basis. Eastmond [Mutat Res 751 (2012)] recently conducted a systematic investigation of MOA determinations by U.S. and international regulatory agencies and organizations, and identified ten major factors that influence them, including toxicokinetics, in vivo genotoxicity in target organs, data quality, and evidence for alternative MOAs. We have used these ten factors to evaluate mutagenic vs. non-mutagenic MOA for gastrointestinal tumors induced by oral exposure to hexavalent chromium [Cr(VI)]. We also highlight similarities between Cr(VI) and other intestinal carcinogens previously determined to have non-genotoxic MOAs. Based on these analyses, we conclude that the MOA for Cr(VI) induced gastrointestinal tumors is non-mutagenic and that threshold risk assessment approaches are appropriate.
确定一种化学物质是通过诱变还是非诱变作用模式（MOA）诱发特定癌症，在选择线性和非线性低剂量外推法以得出毒性标准方面起着重要作用。美国环境保护局（EPA）没有用于确定环境化学物质是通过诱变还是非诱变MOA起作用的正式框架；因此，大多数此类确定都是临时做出的。伊斯特蒙德[《突变研究》751（2012）]最近对美国和国际监管机构及组织进行的MOA确定进行了系统调查，并确定了影响这些确定的十个主要因素，包括毒代动力学、靶器官的体内遗传毒性、数据质量以及替代MOA的证据。我们利用这十个因素评估了经口接触六价铬[Cr(VI)]诱发胃肠道肿瘤的诱变与非诱变MOA。我们还强调了Cr(VI)与先前确定具有非遗传毒性MOA的其他肠道致癌物之间的相似性。基于这些分析，我们得出结论，Cr(VI)诱发胃肠道肿瘤的MOA是非诱变的，阈值风险评估方法是合适的。
