Van Birgelen A P, Van der Kolk J, Fase K M, Bol I, Poiger H, Brouwer A, Van den Berg M
Research Institute of Toxicology, University of Utrecht, The Netherlands.
Toxicol Appl Pharmacol. 1995 May;132(1):1-13. doi: 10.1006/taap.1995.1080.
Toxic and biochemical potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in a 13-week feeding study in female Sprague-Dawley rats. The diets were supplemented with 0, 0.2, 0.4, 0.7, 5, or 20 micrograms TCDD/kg diet. The estimated daily intakes were calculated to be 0, 14, 26, 47, 320, or 1024 ng TCDD/kg body wt/day. At the end of the study, TCDD concentrations were measured in liver and adipose tissue. The lowest estimated daily intake that caused an increase in liver weight was 320 ng TCDD/kg/day, while an intake of 47 ng TCDD/kg/day resulted in a decrease in plasma thyroid hormone concentrations and a decrease in body weight gain. Decreases in relative thymus weights, loss of hepatic retinoids, and induction of CYP1A1 and CYP1A2 activities were already found at 14 ng/kg/day, the lowest dose used. Therefore, 95% confidence limits for the no-effect levels (CNELs) were calculated from the corresponding dose-response relationships by using sigmoidal curve fittings (Hill, Weibull, and a Logistic model) and a probability level of p < 0.05. For increases in CYP1A1 and CYP1A2 activities, the right critical values for the CNELs ranged from 0.7 to 4 ng TCDD/kg/day (Hill and Weibull). Based on hepatic TCDD residue levels, these right critical values for the CNELs ranged from 0.06 to 0.4 ng TCDD/g liver (wet weight) (Hill and Weibull). The CNELs in this study agree very well with the no-observed-adverse-effects levels as reported before in chronic, carcinogenicity, and reproductive studies with rats and TCDD, i.e., 1 ng/kg/day.
在一项针对雌性斯普拉格-道利大鼠的为期13周的喂养研究中，对2,3,7,8-四氯二苯并-对-二恶英（TCDD）的毒性和生化效力进行了研究。在饮食中分别添加0、0.2、0.4、0.7、5或20微克TCDD/千克饮食。计算得出的每日估计摄入量分别为0、14、26、47、320或1024纳克TCDD/千克体重/天。在研究结束时，测量了肝脏和脂肪组织中的TCDD浓度。导致肝脏重量增加的最低每日估计摄入量为320纳克TCDD/千克/天，而47纳克TCDD/千克/天的摄入量导致血浆甲状腺激素浓度降低和体重增加减少。在所用的最低剂量14纳克/千克/天就已发现相对胸腺重量降低、肝脏类视黄醇损失以及CYP1A1和CYP1A2活性诱导。因此，通过使用S形曲线拟合（希尔、韦布尔和逻辑模型）以及p<0.05的概率水平，从相应的剂量反应关系中计算出无效应水平（CNELs）的95%置信限。对于CYP1A1和CYP1A2活性增加，CNELs的右侧临界值范围为0.7至4纳克TCDD/千克/天（希尔和韦布尔）。基于肝脏TCDD残留水平，这些CNELs的右侧临界值范围为0.06至0.4纳克TCDD/克肝脏（湿重）（希尔和韦布尔）。本研究中的CNELs与之前在大鼠和TCDD的慢性、致癌性和生殖研究中报告的未观察到不良反应水平非常一致，即1纳克/千克/天。
