呋喃是一种在热加工食品中广泛存在的内源性污染物，可在食物链中快速积累，并被广泛检测出现在小麦、面包、咖啡、罐装肉类产品和婴儿食品等食物中。摄入该化学物质可能带来健康风险。国际癌症研究机构将呋喃归类为可能的2B类人类致癌物，其主要靶器官为肝脏。肝纤维化是呋喃非肿瘤有害效应中最重要的效应，也是呋喃致癌过程中的重要事件。尽管呋喃引起肝脏纤维化的具体机制还不清楚，但可能涉及氧化应激和遗传毒性，其中细胞色素P450 2E1 (CYP2E1) 的激活可能是关键事件。因此，我们在大鼠的120天体内亚慢性毒性实验中，使用综合多终点遗传毒性平台进行了研究。结果显示，CYP2E1活化的大鼠在D4表现出DNA双链断裂，在D60表现出基因突变，在D120表现出反应性氧化物种和红细胞相关因子2相关因子表达增加。肝脏中也发生了坏死、凋亡、肝星状细胞活化和纤维化，表明呋喃可以通过氧化应激和遗传毒性途径独立地影响肝脏纤维化。通过基于剂量反应曲线(BMD)方法获取了起始点 (PoD)，建立了基于健康指导值的人体等效剂量，从BMDL05得出的健康指导值的人体等效剂量为2.26 μg/kg bw/d。这些发现为呋喃的安全评估和风险评估奠定了基础，并为肝脏纤维化的不良结局途径网络的进一步构建和改进提供了数据。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

Furan is a widespread endogenous contaminant in heat-processed foods that can accumulate rapidly in the food chain and has been widely detected in foods, such as wheat, bread, coffee, canned meat products, and baby food. Dietary exposure to this chemical may bring health risk. Furan is classified as a possible category 2B human carcinogen by the International Agency for Research on Cancer, with the liver as its primary target organ. Hepatic fibrosis is the most important nontumoral harmful effect of furan and also an important event in the carcinogenesis of furan. Although the specific mechanism of furan-induced liver fibrosis is still unclear, it may involve oxidative stress and genetic toxicity, in which the activation of cytochrome P450 2E1 (CYP2E1) may be the key event. Thus, we conducted a study using an integrating multi-endpoint genotoxicity platform in 120-day in vivo subchronic toxicity test in rats. Results showed that the rats with activated CYP2E1 exhibited DNA double-strand breaks in D4, gene mutations in D60, and increased expression of reactive oxygen species and nuclear factor erythroid 2-related factor 2 in D120. Necrosis, apoptosis, hepatic stellate cell activation, and fibrosis also occurred in the liver, suggesting that furan can independently affect liver fibrosis through oxidative stress and genotoxicity pathways. Point of Departure (PoD) was obtained by benchmark-dose (BMD) method to establish health-based guidance values. The human equivalent dose of PoD derived from BMDL05 was 2.26 μg/kg bw/d. The findings laid a foundation for the safety evaluation and risk assessment of furan and provided data for the further construction and improvement of the adverse outcome pathway network in liver fibrosis.Copyright © 2023 Elsevier Ltd. All rights reserved.