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首页> 外文期刊>Dose-response >Mechanistic models fit to ED001 data on 40, 000 trout exposed to dibenzo[A, L]pyrene indicate mutations do not drive increased tumor risk
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Mechanistic models fit to ED001 data on 40, 000 trout exposed to dibenzo[A, L]pyrene indicate mutations do not drive increased tumor risk

机译：机理模型符合ED001数据，即> 40，000鳟鱼暴露于二苯并[A，L] re表明突变不会驱动增加的肿瘤风险

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摘要

ED001-study data on increased liver and stomach tumor risks in 40, 000 trout fed dibenzo[a, l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED001tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2-stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model's assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.
机译：ED001的研究数据表明，> 40，000鳟鱼喂养的二苯并[a，l] py（DBP）是已知的最具致突变性的化学致癌物之一，肝和胃肿瘤风险增加，提供了最大的低剂量剂量反应分辨率迄今为止任何实验性诱导的肿瘤数据集。尽管多阶段体细胞突变/克隆扩增癌症理论预测，遗传毒性致癌物以线性无阈值随低剂量剂量增加肿瘤风险，但ED001tumor数据奇怪地显示出低剂量非线性。为了探索非遗传毒性机制可能产生这种非线性的作用，肝和胃肿瘤数据集分别由两个模型拟合，这两个模型均假设有遗传毒性和非遗传毒性途径可增加肿瘤风险：随机2期（MVK）癌症模型，以及实施最新的肿瘤发生失调的适应性增生（DAH）理论的模型。数据集的MVK和DAH拟合均非常好，但出乎意料的是，每个MVK拟合都暗示DBP通过完全非诱变的机制来增加肿瘤风险。鉴于DBP是一种有效的诱变剂，因此获得的MVK模型拟合似乎在生物学上是不可行的，而DAH模型拟合则反映了该模型的假设，即化学诱导的肿瘤发生通常是由修复细胞数量的增加而不是突变本身引起的。

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