IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk
IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk
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DOI：
10.1016/j.mrgentox.2014.10.008
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发表时间：
2015-05-01
影响因子：
1.9
通讯作者：
Thybaud, Veronique
中科院分区：
文献类型：
--
作者：
MacGregor, James T.;Froetschl, Roland;Thybaud, Veronique
这是国际基因毒性测试研讨会 (IWGT) 遗传毒理学风险评估定量方法工作组 (QWG) 两份报告中的第二份。第一份报告总结了 QWG 的讨论和建议，涉及遗传毒理学数据定量剂量反应分析的必要性、阈值反应的存在和适当评估、分析暴露-反应关系的方法以及得出可确定可接受暴露水平的出发点 (PoD)。本报告总结了 QWG 关于评估与暴露相关的基因毒性损害风险的适当方法的讨论和建议，包括在确定的 PoD 下以及跨测试系统和物种的外推。建议包括选择适当的遗传终点和目标组织、要考虑的不确定因素和外推方法、作用方式、毒代动力学、代谢和暴露生物标志物信息的重要性和使用，当使用定量暴露-反应数据来确定人群中可接受的暴露水平或评估与已知或预期暴露相关的风险时。还检查了动物模型中遗传损伤（突变和染色体畸变）与癌症之间的经验关系。结论是，对于被认为通过基因毒性机制起作用的药物，癌症诱导与致突变和/或致断裂损伤之间存在一般相关性，但由于在直接可比较的途径和实验方案下暴露的相同物种和菌株的相同靶组织中以足够数量的剂量可以比较突变和癌症的病例数量不足，因此这种相关性是有限的。 (C) 2014 年作者。由 Elsevier B.V. 出版
This is the second of two reports from the International Workshops on Genotoxicity Testing (IWGT) Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment (the QWG). The first report summarized the discussions and recommendations of the QWG related to the need for quantitative dose-response analysis of genetic toxicology data, the existence and appropriate evaluation of threshold responses, and methods to analyze exposure-response relationships and derive points of departure (PoDs) from which acceptable exposure levels could be determined. This report summarizes the QWG discussions and recommendations regarding appropriate approaches to evaluate exposure-related risks of genotoxic damage, including extrapolation below identified PoDs and across test systems and species. Recommendations include the selection of appropriate genetic endpoints and target tissues, uncertainty factors and extrapolation methods to be considered, the importance and use of information on mode of action, toxicokinetics, metabolism, and exposure biomarkers when using quantitative exposure-response data to determine acceptable exposure levels in human populations or to assess the risk associated with known or anticipated exposures. The empirical relationship between genetic damage (mutation and chromosomal aberration) and cancer in animal models was also examined. It was concluded that there is a general correlation between cancer induction and mutagenic and/or clastogenic damage for agents thought to act via a genotoxic mechanism, but that the correlation is limited due to an inadequate number of cases in which mutation and cancer can be compared at a sufficient number of doses in the same target tissues of the same species and strain exposed under directly comparable routes and experimental protocols. (C) 2014 The Authors. Published by Elsevier B.V.