Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months
Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months
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DOI：
10.1093/toxsci/69.1.244
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发表时间：
2002-09-01
影响因子：
3.8
通讯作者：
Thomford, P
中科院分区：
文献类型：
--
作者：
Butenhoff, J;Costa, G;Thomford, P
全氟辛酸铵（APFO）是生产含氟聚合物的加工助剂，已被证明在人体血液中具有较长的半衰期。为了解灵长类动物的潜在毒理学反应，雄性食蟹猴组每日经口（胶囊）给予0、3、10或30（降低至20）mg/kg/天剂量，持续26周。末次给药后，观察对照组和10 mg/kg/天剂量组各2只猴90天。监测临床观察、临床化学、关键激素测定、大体和显微病理学、细胞增殖、过氧化物酶体增殖、胆汁酸测定以及血清和肝脏全氟辛酸（PFOA）浓度。在研究早期，在30 mg/kg/天剂量下观察到毒性，包括体重减轻和摄食量减少;因此，将剂量降至20 mg/kg/天。在20 mg/kg/天剂量组的3只猴中出现了相同的毒性体征，之后这些猴停止给药。1只30/20 mg/kg/天组猴出现上述毒性体征和可能的给药损伤，该猴在第29天濒死状态下被处死。3 mg/kg/天剂量组猴在第137天因濒死状态被处死，原因与APFO给药无明显相关性。在所有APFO给药组中，由于线粒体增殖导致肝脏重量呈剂量依赖性增加。在3或10 mg/kg/天剂量下均未观察到肝损伤的组织学证据。在最高剂量组濒死状态下处死的猴中观察到肝损伤证据。在30/20 mg/kg剂量下，体重降低。血清和肝脏中的PFOA浓度变化很大，与剂量不成线性比例，并在末次给药后90天内清除至背景水平。本研究中未确定无可观察到的作用水平，基于肝脏重量增加和导致第137天1只低剂量猴濒死处死的病因不确定性，认为3 mg/kg/天的低剂量为最低可观察到的作用水平。除上述情况外，无APFO相关肉眼或显微镜变化、临床化学、激素或尿分析变化或血液学影响。特别是，在本研究中未观察到与大鼠胰腺和睾丸毒性发展相关的效应。
Ammonium perfluorooctanoate (APFO) is a processing aid in the production of fluoropolymers that has been shown to have a long half-life in human blood. To understand the potential toxicological response of primates, groups of male cynomolgus monkeys were given daily po (capsule) doses of either 0, 3, 10, or 30 (reduced to 20) mg/kg/day for 26 weeks. Two monkeys from each of the control and 10 mg/kg/day dose groups were observed for 90 days after the last dose. Clinical observations, clinical chemistry, determination of key hormones, gross and microscopic pathology, cell proliferation, peroxisomal proliferation, bile-acid determination, and serum and liver perfluorooctanoate (PFOA) concentrations were monitored. Toxicity, including weight loss and reduced food consumption, was noted early in the study at the 30 mg/kg/day dose; therefore, the dose was reduced to 20 mg/kg/day. The same signs of toxicity developed in 3 monkeys at 20 mg/kg/day, after which treatment of these monkeys was discontinued. One 30/20 mg/kg/day monkey developed the signs of toxicity noted above and a possible dosing injury, and this monkey was sacrificed in extremis on Day 29. A 3 mg/kg/day dose-group monkey was sacrificed in extremis on Day 137 for reasons not clearly related to APFO treatment. Dose-dependent increases in liver weight as a result of mitochondrial proliferation occurred in all APFO-treated groups. Histopathologic evidence of liver injury was not observed at either 3 or 10 mg/kg/day. Evidence of liver damage was seen in the monkey sacrificed in moribund condition at the highest dose. Body weights were decreased at 30/20 mg/kg. PFOA concentrations in serum and liver were highly variable, were not linearly proportional to dose, and cleared to background levels within 90 days after the last dose. A no observable effect level was not established in this study, and the low dose of 3 mg/kg/day was considered the lowest observable effect level based on increased liver weight and uncertainty as to the etiology leading to the moribund sacrifice of one low-dose monkey on Day 137. Other than those noted above, there were no APFO-related macroscopic or microscopic changes, changes in clinical chemistry, hormones, or urinalysis, or hematological effects. In particular, effects that have been associated with the development of pancreatic and testicular toxicity in rats were not observed in this study.