Chronic dietary toxicity and carcinogenicity study with potassium perfluorooctanesulfonate in Sprague Dawley rats
Chronic dietary toxicity and carcinogenicity study with potassium perfluorooctanesulfonate in Sprague Dawley rats
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DOI：
10.1016/j.tox.2012.01.003
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发表时间：
2012-03-11
期刊：
影响因子：
4.5
通讯作者：
Thomford, Peter J.
中科院分区：
文献类型：
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作者：
Butenhoff, John L.;Chang, Shu-Ching;Thomford, Peter J.
为了研究长期接触全氟辛烷磺酸盐（PFOS）的毒性和致癌潜力，对雄性和雌性Sprague道利大鼠进行了为期两年的毒性和致癌生物测定，通过饮食接触标称浓度为0、0.5、2、5和20微克/克（ppm）的全氟辛烷磺酸钾（K+PFOS），持续104周。其他组在前52周喂食20 ppm饲料，之后在研究结束时喂食对照饲料（20 ppm恢复组）。在第4、14和53周进行计划的中期处死，在第103和106周之间进行终末处死。钾+全氟辛烷磺酸似乎耐受性良好，在某些研究期间，与对照组相比，接受治疗的大鼠体重有所减轻。在两个最高给药水平下，雄性大鼠的死亡率呈统计学显著性下降趋势，至足月存活率显著增加。血清总胆固醇降低（尤其是雄性）和血清尿素氮升高是一致的临床化学观察结果，与给药明显相关。与钾+全氟辛烷磺酸接触相关的主要非肿瘤效应发生在雄性和雌性的肝脏中，包括肝细胞肥大、内质网增生、空泡化和细胞质嗜酸性粒细胞增多。在20 ppm给药组的雄性（p=0.046）和雌性（p=0.039）中观察到肝细胞腺瘤统计学显著性增加，并且在存活至终末处死的大鼠中观察到所有这些肿瘤。在20 ppm剂量组雌性动物中观察到唯一的肝细胞癌。在研究结束时，喂食钾+全氟辛烷磺酸的大鼠的甲状腺组织中没有发现与治疗相关的结果;然而，20 ppm恢复组的雄性大鼠甲状腺滤泡细胞腺瘤在统计学上显著增加，这被认为是假的。没有证据表明对肾脏或膀胱有影响。在大鼠中，两种性别大鼠肝肿瘤增加10%的基准剂量的95%置信下限估计饮食剂量为8 ppm。最近的机制研究表明，在本两年研究中观察到的肝肿瘤的作用模式是PPAR α/CAR/PXR介导的。(c)2012爱思唯尔爱尔兰有限公司保留所有权利。
To investigate toxicity and neoplastic potential from chronic exposure to perfluorooctanesulfonate (PFOS), a two-year toxicity and cancer bioassay was conducted with potassium PFOS (K+PFOS) in male and female Sprague Dawley rats via dietary exposure at nominal K+PFOS concentrations of 0, 0.5, 2, 5, and 20 mu g/g (ppm) diet for up to 104 weeks. Additional groups were fed 20 ppm for the first 52 weeks, after which they were fed control diet through study termination (20 ppm Recovery groups). Scheduled interim sacrifices occurred on Weeks 4, 14, and 53, with terminal sacrifice between Weeks 103 and 106. K+PFOS appeared to be well-tolerated, with some reductions in body weight occurring in treated rats relative to controls over certain study periods. Male rats experienced a statistically significant decreased trend in mortality with significantly increased survival to term at the two highest treatment levels. Decreased serum total cholesterol, especially in males, and increased serum urea nitrogen were consistent clinical chemistry observations that were clearly related to treatment. The principal non-neoplastic effect associated with K+PFOS exposure was in livers of males and females and included hepatocellular hypertrophy, with proliferation of endoplasmic reticulum, vacuolation, and increased eosinophilic granulation of the cytoplasm. Statistically significant increases in hepatocellular adenoma were observed in males (p=0.046) and females (p=0.039) of the 20 ppm treatment group, and all of these tumors were observed in rats surviving to terminal sacrifice. The only hepatocellular carcinoma observed was in a 20 ppm dose group female. There were no treatment-related findings for thyroid tissue in rats fed K+PFOS through study termination; however, male rats in the 20 ppm Recovery group had statistically significantly increased thyroid follicular cell adenoma, which was considered spurious. There was no evidence of kidney or bladder effects. In rats, the dietary dose estimated as the lower 95% confidence limit of the benchmark dose for a 10% increase in hepatic tumors was 8 ppm for both sexes. Recent mechanistic studies suggest a PPAR alpha/CAR/PXR-mediated mode of action for the liver tumors observed in the present two-year study. (c) 2012 Elsevier Ireland Ltd. All rights reserved.