许多致癌物的风险评估涉及对动物研究所使用的剂量水平和较低的人类接触水平进行巨大的外推。1,4-二噁烷是如此，它在雄鼠和雌鼠的肝脏中都有一致的致癌作用。在某些情况下，这些数据已应用于风险评估，假设低剂量线性外推，但在其他情况下则使用非线性或阈值模型。这个选择取决于我们对1,4-二噁烷致癌机制的理解。尽管1,4-二噁烷在标准测试电池中不具有遗传毒性和非线性毒代动力学，但其致癌作用机制仍未知，并且是一个活跃的研究领域。本综述总结了该化学物质的可能作用方式，数据空缺以及应用于风险评估的情况。我们发现细胞毒性/增生和代谢饱和假说不能解释致癌反应，并且不能考虑1,4-二噁烷诱导自身代谢，导致慢性暴露期间饱和可能性降低。有证据表明存在其他机制，特别是与CYP2E1诱导和体内遗传毒性相关的氧化应激，这在体外不可见。与1,4-二噁烷致癌剂量反应的时间和剂量反应相比，需要进一步探索这些效应。另一个考虑因素是这些1,4-二噁烷作用方式可能如何增强天然存在和导致人类肝癌增长率上升的与疾病相关的过程。这些因素增加了使用非阈值线性方法对该致癌物进行低剂量外推的合理性，这与没有明确定义的作用方式的致癌物的默认方法相一致。

The risk assessment of many carcinogens involves extrapolation across large exposure differences between the dose levels used in animal studies and the much lower human exposures. This is true for 1,4-dioxane which has a consistent liver carcinogenic effect in both genders of rats and mice. These data have been applied to risk assessment assuming a linear low dose extrapolation in some cases but non-linear or threshold models have been used in others. This choice hinges on our understanding of the 1,4-dioxane cancer mechanism. While 1,4-dioxane is not genotoxic in standard test batteries and has non-linear toxicokinetics, the mechanism for its carcinogenic effect remains unknown and is an active area of research. This review summarizes the possible modes of action for this chemical, data gaps and application to risk assessment. We find that the cytotoxicity/hyperplasia and metabolic saturation hypotheses do not explain the carcinogenic response and do not take into account 1,4-dioxane's induction of its own metabolism, leading to less likelihood for saturation during chronic exposure. There is evidence for other mechanisms, especially oxidative stress associated with the induction of CYP2E1 and in vivo genotoxicity that is not seen in vitro. The dose response for these effects needs further exploration compared to the time course and dose response for 1,4-dioxane-induced carcinogenesis. An additional consideration is the manner in which these 1,4-dioxane effects may augment naturally occurring and disease-related processes that contribute to the increasing rate of human liver cancer. These factors add to the rationale for using a non-threshold linear approach for extrapolating to low dose for this carcinogen, which is consistent with the default for carcinogens which do not have a clearly defined mode of action.