Regulatory Toxicology and Pharmacology ( IF 3.0 ) Pub Date : 2023-06-03 , DOI: 10.1016/j.yrtph.2023.105428 Mark Lafranconi 1 , Janet Anderson 2 , Robert Budinsky 3 , Lisa Corey 4 , Norman Forsberg 5 , Joanna Klapacz 3 , Matthew J LeBaron 3
1,4-Dioxane is an environmental contaminant that has been shown to cause cancer in rodents after chronic high dose exposures. We reviewed and integrated information from recently published studies to update our understanding of the cancer mode of action of 1,4-dioxane. Tumor development in rodents from exposure to high doses of 1,4-dioxane is preceded by pre-neoplastic events including increased hepatic genomic signaling activity related to mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity. These events are followed by regenerative repair and proliferation and eventual development of tumors. Importantly, these events occur at doses that exceed the metabolic clearance of absorbed 1,4-dioxane in rats and mice resulting in elevated systemic levels of parent 1,4-dioxane. Consistent with previous reviews, we found no evidence of direct mutagenicity from exposure to 1,4-dioxane. We also found no evidence of CAR/PXR, AhR or PPARα activation resulting from exposure to 1,4-dioxane. This integrated assessment supports a cancer mode of action that is dependent on exceeding the metabolic clearance of absorbed 1,4-dioxane, direct mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity followed by sustained proliferation driven by regenerative repair and progression of heritable lesions to tumor development.
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啮齿动物中 1,4-二恶烷癌症作用模式和阈值反应的综合评估
1,4-二恶烷是一种环境污染物,已被证明在长期高剂量接触后会导致啮齿动物癌症。我们回顾并整合了最近发表的研究中的信息,以更新我们对 1,4-二恶烷的癌症作用模式的理解。啮齿类动物暴露于高剂量的 1,4-二恶烷后,会出现肿瘤发生之前的肿瘤前期事件,包括与有丝分裂相关的肝脏基因组信号活性增加、Cyp2E1 活性升高以及导致基因毒性和细胞毒性的氧化应激。这些事件之后是再生修复和增殖以及肿瘤的最终发展。重要的是,这些事件发生的剂量超过了大鼠和小鼠吸收的 1,4-二恶烷的代谢清除率,导致母体 1,4-二恶烷的全身水平升高。与之前的评论一致,我们没有发现接触 1,4-二恶烷会导致直接致突变的证据。我们还没有发现 CAR/PXR、AhR 或 PPARα 因暴露于 1,4-二恶烷而激活的证据。这种综合评估支持癌症作用模式,该模式依赖于超过吸收的 1,4-二恶烷的代谢清除、直接有丝分裂、Cyp2E1 活性升高和氧化应激,导致遗传毒性和细胞毒性,然后由再生修复和进展驱动持续增殖。遗传性病变对肿瘤发展的影响。