Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints.

IF 2.3 4区 医学 Q3 ENVIRONMENTAL SCIENCES
Paul A White, Guangchao Chen, Nikolai Chepelev, Madison A Bell, Lauren R Gallant, George E Johnson, Andreas Zeller, Marc A Beal, Alexandra S Long
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Abstract

The benchmark dose (BMD) approach constitutes the most effective and pragmatic strategy for the derivation of a point of departure (PoD) for comparative potency analysis, risk assessment, and regulatory decision-making. There is considerable controversy regarding the most appropriate benchmark response (BMR) for genotoxicity endpoints. This work employed the Slob (2017) Effect Size (ES) theory to define robust BMR values for the in vivo transgenic rodent (TGR) and Pig-a mutagenicity endpoints. An extensive database of dose-response data was prepared and curated; BMD analyses were used to determine endpoint-specific maxima (i.e., parameter c) and within-group variance (i.e., var). Detailed analyses investigated the dependence of var on experimental factors such as tissue, administration route, treatment duration, and post-exposure tissue sampling time. The overall lack of influence of these experimental factors on var permitted the determination of typical values for the endpoints investigated. Typical var for the TGR endpoint is 0.19; the value for the Pig-a endpoint is 0.29. Endpoint-specific var values were used to calculate endpoint-specific BMR values; the values are 47% for TGR and 60% for Pig-a. Endpoint-specific BMR values were also calculated using the trimmed distribution of study-specific standard deviation (SD) values for concurrent controls. Those analyses yielded endpoint-specific BMR values for the TGR and Pig-a endpoints of 33% and 58%, respectively. Considering the results obtained, and the in vivo genetic toxicity BMR values noted in the literature, we recommend a BMR of 50% for in vivo mutagenicity endpoints. The value can be employed to interpret mutagenicity dose-response data in a risk assessment context.

体内诱变终点的基准反应(BMR)值。
基准剂量(BMD)方法是推导起始点(PoD)以进行比较效力分析、风险评估和监管决策的最有效和实用的策略。关于遗传毒性终点的最合适基准反应(BMR)存在相当大的争议。本研究采用Slob(2017)效应大小(ES)理论定义了体内转基因啮齿动物(TGR)和猪-a致突变性终点的稳健BMR值。编制和管理了一个广泛的剂量-反应数据数据库;骨密度分析用于确定终点特定最大值(即参数c)和组内方差(即var)。详细分析了var对实验因素的依赖性,如组织、给药途径、治疗持续时间和暴露后组织采样时间。这些实验因素对var总体上没有影响,因此可以确定所研究的终点的典型值。TGR终点的典型var为0.19;Pig-a端点的值为0.29。终点特异性var值用于计算终点特异性BMR值;TGR为47%,Pig-a为60%。终点特异性BMR值也使用研究特异性标准差(SD)值的修剪分布计算。这些分析得出TGR和Pig-a的终点特异性BMR值分别为33%和58%。考虑到获得的结果,以及文献中提到的体内遗传毒性BMR值,我们建议体内诱变终点的BMR为50%。该值可用于解释风险评估背景下的致突变性剂量-反应数据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.40
自引率
10.70%
发文量
52
审稿时长
12-24 weeks
期刊介绍: Environmental and Molecular Mutagenesis publishes original research manuscripts, reviews and commentaries on topics related to six general areas, with an emphasis on subject matter most suited for the readership of EMM as outlined below. The journal is intended for investigators in fields such as molecular biology, biochemistry, microbiology, genetics and epigenetics, genomics and epigenomics, cancer research, neurobiology, heritable mutation, radiation biology, toxicology, and molecular & environmental epidemiology.
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