Wilson D M, Goldsworthy T L, Popp J A, Butterworth B E
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Environ Mol Mutagen. 1992;19(3):209-22. doi: 10.1002/em.2850190305.
Preliminary results from the National Toxicology Program (NTP) bioassays of furan given by gavage indicate the induction of hepatocellular carcinomas in male F-344 rats and in both sexes of B6C3F1 mice, and cholangiocarcinomas in both sexes of rats. To assess the genotoxicity of furan, chemically induced unscheduled DNA synthesis was evaluated in the in vivo hepatocyte DNA repair assay. Furan did not induce unscheduled DNA synthesis in hepatocytes isolated after single gavage treatment of male F-344 rats (5, 30, and 100 mg/kg) or male B6C3F1 mice (10, 50, 100, and 200 mg/kg). Furan induced cytotoxicity and enhanced cell proliferation were evaluated in livers of rats and mice as events that also might give rise to mutations and/or drive tumor formation. The labeling index (LI, percentage of hepatocyte nuclei in S-phase) was measured histoautoradiographically following a single gavage administration of furan (30 mg/kg, male rats; 50 mg/kg, male mice) followed by an injection of 3H-thymidine 2 hr prior to sacrifice. Hepatocellular necrosis and a sharp increase in LI (23.9 for mice and 17.8 for rats vs. less than 0.5 for controls) was observed 48 hr after treatment with furan, indicative of restorative cell proliferation secondary to cytotoxicity. Hepatocyte proliferation was evaluated also at the highest NTP bioassay dose (15 mg/kg/day for mice and 8 mg/kg/day for rats, 5 days/week) by labeling with 3H-thymidine administered via a 6 day osmotic pump implanted subcutaneously. Necrosis and inflammation were observed along the subcapsular visceral surface of the left or caudate liver lobes, likely due to diffusion of furan directly through the stomach to the liver. After 6 weeks of furan administration, male and female rats, but not mice, exhibited bile duct hyperplasia as well as metaplasia in the areas of fibrosis along the subcapsular visceral surface of the left or caudate liver lobes. The fold increase in hepatocyte LI in treated animals relative to the combined controls measured at weeks 1, 3, and 6 ranged from 39 to 5 for male mice, 18 to 51 for male rats, and 12 to 19 for female rats. Taken together, these data suggest that mechanisms other than direct DNA-reactivity might explain the profile of oncogene mutations observed in the mouse liver tumors, including selective promotion of different subpopulations of preneoplastic cells and/or mutational events secondary to sustained cell proliferation or inflammation. The extensive amount of furan-induced cell proliferation subsequent to cytotoxicity likely had a significant impact on tumor development, and such data should be considered in risk evaluations for this compound.
美国国家毒理学计划（NTP）经口灌胃给予呋喃的生物测定初步结果表明，雄性F-344大鼠以及B6C3F1小鼠的雌雄两性均诱发了肝细胞癌，大鼠的雌雄两性均诱发了胆管癌。为评估呋喃的遗传毒性，在体内肝细胞DNA修复试验中对化学诱导的非程序性DNA合成进行了评价。单次经口灌胃给予雄性F-344大鼠（5、30和100mg/kg）或雄性B6C3F1小鼠（10、50、100和200mg/kg）后分离的肝细胞中，呋喃未诱导非程序性DNA合成。在大鼠和小鼠肝脏中评估了呋喃诱导的细胞毒性和增强的细胞增殖，这些事件也可能导致突变和/或推动肿瘤形成。在单次经口灌胃给予呋喃（雄性大鼠30mg/kg；雄性小鼠50mg/kg）后，于处死前2小时注射3H-胸腺嘧啶核苷，然后通过组织放射自显影法测量标记指数（LI，即S期肝细胞细胞核的百分比）。用呋喃处理48小时后，观察到肝细胞坏死以及LI急剧增加（小鼠为23.9，大鼠为17.8，而对照组小于0.5），这表明细胞毒性继发了修复性细胞增殖。还通过皮下植入的6天渗透泵给予3H-胸腺嘧啶核苷标记，在NTP生物测定的最高剂量（小鼠为15mg/kg/天，大鼠为8mg/kg/天，每周5天）下评估肝细胞增殖。在左叶或尾状叶肝脏的包膜下脏面观察到坏死和炎症，这可能是由于呋喃直接通过胃扩散到肝脏所致。给予呋喃6周后，雄性和雌性大鼠（而非小鼠）在左叶或尾状叶肝脏的包膜下脏面纤维化区域出现胆管增生以及化生。在第1、3和6周测量，处理动物肝细胞LI相对于联合对照组的增加倍数，雄性小鼠为39至5，雄性大鼠为18至51，雌性大鼠为12至19。综上所述，这些数据表明，除直接DNA反应性之外的其他机制可能解释了在小鼠肝肿瘤中观察到的癌基因突变情况，包括对不同亚群的癌前细胞的选择性促进和/或继发于持续细胞增殖或炎症的突变事件。呋喃诱导的细胞毒性后大量的细胞增殖可能对肿瘤发展产生了重大影响，在对该化合物进行风险评估时应考虑此类数据。
