From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

中文翻译：

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DNA修复和破坏反应途径对烷化剂非线性遗传毒性反应的贡献。

从风险评估的角度来看，通常认为DNA反应剂在所有暴露水平下均具有遗传毒性风险，因此对低剂量反应采用线性外推法。此处讨论的新方法，包括评估DNA损伤和DNA修复的更多样化和灵敏的方法，强烈支持存在可测量区域，在该区域中，剂量增加的遗传毒性反应相对于对照而言微不足道。模型单功能烷基化剂具有适合确定遗传毒性作用的出发点（PoD）的体外和体内数据集。在2013年毒理学学会会议上的一次会议提供了一个机会，以调查在了解根据经验观察到的DNA烷基化剂PoD的生物学基础方面的进展。连同自那时以来发表的文献，这篇综述讨论了由内源性和外源性烷基化DNA损伤激活的细胞途径。细胞已经进化出保守的过程，可以监视并抵消DNA损伤的自发稳态水平。DNA修复途径无处不在的网络是清除DNA损伤和防止突变的第一道防线。在此讨论的被遗传毒性应激激活的其他生物途径包括翻译后激活的细胞周期网络和转录网络，用于细胞凋亡/细胞死亡。各种DNA修复和DNA损伤反应途径的相互作用为遗传毒性化合物所观察到的PoD行为提供了生物学基础。因此，在形成DNA加合物之后，细胞途径的激活可以导致避免诱变结果。