Chowdhury Aparajita, Arnold Lora L, Wang Zemin, Pennington Karen L, Dodmane Puttappa, Farragut-Cardoso Ana Paula, Klaunig James E, Cros Daniel, Creppy Edmond E, Cohen Samuel M
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-3135, United States.
Department of Environmental Health, Indiana University, Bloomington, IN 47408, United States.
Toxicol Lett. 2018 Mar 15;285:94-103. doi: 10.1016/j.toxlet.2017.12.032. Epub 2018 Jan 2.
Polyhexamethylene biguanide (PHMB), an amphiphilic polymeric biocide, increased liver tumor incidence in male and female rats at 1000 and 1500 mg/L in drinking water, but not at 500 mg/L in previous studies. In another study, PHMB administered in diet at 4000 mg/kg was negative for hepatocellular tumors. The present studies evaluated bioavailability and distribution of PHMB administered in drinking water and diet and possible modes of action (MOA). PHMB in drinking water was unpalatable during the first 3 days, resulting in markedly decreased food consumption and decreased body weight. Ki-67 labeling index was increased in hepatocytes and endothelial cells dose responsively with PHMB administered in drinking water but not diet. Vitamin E had no effect on this. There was no cytotoxicity by histopathology or serum enzymes, and no increase in cytokines TNFα, IL-1α or NF-κB. Focal iron deposition in sinusoidal lining cells was detected. Microarray analyses were non-contributory. No effect on CAR or PPARα activation was detected. C-PHMB administered at 500, 1000, or 1500 mg/L in the drinking water or 4000 mg/kg in the diet was nearly completely absorbed and excreted in urine, with some fecal excretion. The hypothesized MOA for liver tumors induced by PHMB in drinking water is: 1) severe dehydration and starvation because of unpalatability, followed by ingestion with rapid absorption and urinary excretion; 2) increased hepatocyte proliferation; and 3) induction of hepatocellular foci and tumors. The PHMB-induced rat hepatocellular tumors are unlikely to pose a human cancer risk. However, the actual MOA has not been determined.
聚六亚甲基双胍（PHMB）是一种两亲性聚合物杀菌剂，在先前的研究中，饮用水中浓度为1000和1500mg/L时，雄性和雌性大鼠的肝脏肿瘤发生率增加，但500mg/L时未出现此情况。在另一项研究中，饮食中给予4000mg/kg的PHMB对肝细胞肿瘤呈阴性。本研究评估了饮用水和饮食中给予PHMB后的生物利用度和分布以及可能的作用模式（MOA）。饮用水中的PHMB在前3天味道不佳，导致食物摄入量显著减少和体重下降。饮用水中给予PHMB后，肝细胞和内皮细胞中的Ki-67标记指数呈剂量依赖性增加，而饮食中给予则无此现象。维生素E对此无影响。组织病理学或血清酶检测未发现细胞毒性，细胞因子TNFα、IL-1α或NF-κB也未增加。检测到窦状隙衬里细胞中有局灶性铁沉积。微阵列分析无贡献。未检测到对CAR或PPARα激活的影响。饮用水中给予500、1000或1500mg/L或饮食中给予4000mg/kg的C-PHMB几乎完全被吸收并经尿液排泄，有一些经粪便排泄。饮用水中PHMB诱导肝脏肿瘤的假设作用模式为：1）因味道不佳导致严重脱水和饥饿，随后摄入并快速吸收和经尿液排泄；2）肝细胞增殖增加；3）诱导肝细胞灶和肿瘤。PHMB诱导的大鼠肝细胞肿瘤不太可能构成人类癌症风险。然而，实际的作用模式尚未确定。
