Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Health Canada Tunney's Pasture, Ottawa, Ontario, Canada.
Reprod Toxicol. 2022 Jan;107:123-139. doi: 10.1016/j.reprotox.2021.09.012. Epub 2021 Sep 21.
The toxicity of PCB-156 (2,3,3',4,4',5-hexachlorobiphenyl) was investigated in rats following subchronic dietary exposure. Groups of 10 male and female Sprague-Dawley rats were administered PCB-156 in the diet at 0, 0.01, 0.1, 1 or 10 ppm for 90 days. Dose-dependent increases were detected for the liver, lung and kidney weights, as well as for the liver EROD, PROD and UDPGT enzyme activities and liver uroporphyrin concentration. Dose-dependent decreases were observed in final body weight, body weight gain, and thymus weight. Apolar retinoid concentrations were decreased in the liver and lungs and increased in the kidneys. Histopathological examination of the liver, thyroid, and thymus showed mild to moderate dose-related changes. A LOAEL of 0.01 ppm was established, based on reduced apolar liver retinoid concentration. Benchmark dose-modelling corroborated the sensitivity of liver retinoid endpoints. The lower confidence limits (BMDL) for a 5% decrease in apolar liver retinoid concentrations were 0.0009 and 0.0007 ppm, respectively, in males and females, corresponding to a daily dose of 0.06 μg PCB-156 per kg body weight. Organizing dose-response data for the individual hepatic endpoints along the PCB-156 dosing scale revealed a sequence of events compatible with a causal link between depletion of apolar retinoids and the other liver biochemistry and pathology findings. Taken together, data suggest that the retinoid endpoints should be further evaluated for a causal relationship to PCB-induced liver toxicity and that retinoid system endpoints are identified and characterized to support health risk assessment in the emerging research fields of endocrine disruption and mixture toxicology.
研究人员用大鼠进行了亚慢性饮食暴露实验，研究多氯联苯-156（2,3,3',4,4',5-六氯联苯）的毒性。实验将 10 只雄性和雌性 Sprague-Dawley 大鼠分为 5 组，分别喂食含 0、0.01、0.1、1 或 10ppm 多氯联苯-156 的饲料 90 天。结果显示，大鼠的肝、肺和肾重量，肝 EROD、PROD 和 UDPGT 酶活性以及肝卟啉浓度均呈剂量依赖性增加，而终体重、体重增加和胸腺重量呈剂量依赖性降低。肝和肺中非极性视黄醇浓度降低，而肾中非极性视黄醇浓度升高。肝脏、甲状腺和胸腺的组织病理学检查显示出与剂量相关的轻度至中度变化。基于降低的非极性肝视黄醇浓度，确定 0.01ppm 为无可见作用水平。基于视黄醇终点的基准剂量建模证实了其敏感性。雄性和雌性大鼠非极性肝视黄醇浓度分别降低 5%时的下限置信区间（BMDL）分别为 0.0009 和 0.0007ppm，相当于每天每公斤体重摄入 0.06μg 多氯联苯-156。沿着多氯联苯-156 给药剂量范围组织肝内各终点的剂量-反应数据，揭示了一系列与非极性视黄醇耗竭和其他肝生物化学和病理学发现之间因果关系相一致的事件。综上所述，数据表明，视黄醇终点应进一步评估其与多氯联苯诱导的肝毒性之间的因果关系，并且应确定和表征视黄醇系统终点，以支持内分泌干扰和混合物毒理学等新兴研究领域的健康风险评估。
