EVALUATION OF THE DOSE-RESPONSE AND INUTERO EXPOSURE TO SACCHARIN IN THE RAT
EVALUATION OF THE DOSE-RESPONSE AND INUTERO EXPOSURE TO SACCHARIN IN THE RAT
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DOI：
10.1016/0278-6915(85)90142-5
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发表时间：
1985-01-01
影响因子：
4.3
通讯作者：
CARLBORG, FW
中科院分区：
文献类型：
--
作者：
SCHOENIG, GP;GOLDENTHAL, EI;CARLBORG, FW
设计了糖精钠（NaS）的2代生物测定，涉及2500只第2代雄性大鼠，以确定雄性大鼠膀胱肿瘤的剂量反应，并评价可能与肿瘤发生有关的其他变化。六个处理组（125-700只大鼠/组）饲喂1.0- 7.5%的NaS饮食水平。为了评价子宫内暴露的作用，另外2个组仅在妊娠期间通过饲喂含5.0% NaS的饲料的母鼠暴露于NaS，或从出生开始暴露于单代NaS。在后一组中，哺乳母鼠在分娩后立即接受NaS饮食，其后代断奶后接受含5.0% NaS的饮食。第三组，包括评估的特异性NaS和过量的钠在膀胱肿瘤的发生中的作用，饲料中含有马尿酸钠（NaH）2代，5.0%NaH的第1代和第2至8周龄，随后3.0%，因为意外的毒性。在第二代中观察到膀胱肿瘤的明确剂量反应。NaS处理的雄性大鼠。剂量-反应曲线的陡峭斜率表明肿瘤发生率随剂量降低而迅速下降。1.0%的饮食水平（喂养700只大鼠）被认为是膀胱肿瘤的无效水平。唯一的其他给药相关病理学变化是饲喂≥ 100 mg/kg的大鼠膀胱重量增加。3.0%，肾脏矿化增加≥1.0%。在NaS处理组中观察到几种生理效应，显示膀胱肿瘤增加（即，那些被喂食的3.0%）。一些变化（例如生长抑制和饮水量增加）表明这些大鼠存在一般性紊乱，但体重、摄食量、化合物消耗量和饮水量数据分析显示，在任何剂量组内，这些定量数据与膀胱肿瘤的发生之间均无相关性。指示喂食高饮食水平NaS的大鼠状况受损的其他变化包括喂食5.0%或7.5%的断奶大鼠的贫血以及饮食水平下窝仔数的减少。百分之三尿量和尿渗透压的变化与膀胱肿瘤的发生密切相关。仅在妊娠期间暴露于NaS的大鼠的膀胱肿瘤发病率与未处理的对照组相当，并且从出生开始暴露于NaS的大鼠的膀胱肿瘤发病率与喂食含5.0%NaS的饮食的大鼠的膀胱肿瘤发病率相似。膀胱肿瘤的发病率没有增加，在大鼠喂养NaH的2代，但需要降低饮食水平从5.0至3.0%，在研究过程中减少了这组的值比较生理效应和肿瘤发病率后NaH治疗与NaS治疗的大鼠。
A 2-generation bioassay on sodium saccharin (NaS), involving 2500 2nd generation male rats, was designed to determine the dose response for urinary bladder tumors in male rats and to evaluate other changes possibly related to the occurrence of the tumors. Six treatment groups (125-700 rats/group) were fed dietary levels of NaS ranging from 1.0-7.5%. To evaluate the role of in utero exposure, 2 additional groups were exposed to NaS only during gestation via dams fed diet containing 5.0% NaS or for a single generation beginning at birth. In the latter group, the nursing dams were placed on an NaS diet immediately after giving birth and their offspring were weaned onto diets containing 5.0% NaS. A 3rd additional group, included to evaluate the specificity of NaS and the role of excess Na in the occurrence of urinary bladder tumors, was fed diet containing sodium hippurate (NaH) for 2 generations, 5.0% NaH to the 1st generation and to the 2nd until 8 wk old, and subsequently 3.0% because of unexpected toxicity. A clear dose response for urinary bladder tumors was observed in the 2nd generation. NaS-treated male rats. The steep slope of the dose-response curve indicated a rapid decline in tumor incidence with decreasing dose. the 1.0% dietary level (fed to 700 rats) was considered to be a no-effect level for bladder tumors. The only other treatment-related pathological changes were an increase in urinary bladder weight in rats fed .gtoreq. 3.0% and an increase in mineralization of the kidneys with .gtoreq. 1.0%. Several physiological effects were seen in the NaS-treated groups showing an increase in bladder tumors (i.e., those fed .gtoreq. 3.0%). Some changes, e.g depressed growth and increased water consumption, were indicative of a general disturbance of these rats, but analysis of body weight, food consumption, compound consumption and water consumption data revealed no correlation within any dose group between these quantitative data and the occurrence of bladder tumors. Other changes indicative of the compromised situation of the rats fed high dietary levels of NaS were anemia in weanling rats fed 5.0 or 7.5% and a reduction in litter size at dietarry levels .gtoreq. 3.0%. Changes in urine volume and urine osmolality were highly correlated with the occurrence of the urinary bladder tumors. The bladder tumor incidence in rats exposed to NaS only during gestation was comparable to that of the untreated controls, and that in rats exposed to NaS from birth for a single generation was similar to that of rats fed diets containing 5.0% NaS for 2 generations. Bladder tumor incidence was not increased in rats fed NaH for 2 generations, but the need to lower the dietary level from 5.0 to 3.0% during the study reduced the value of this group for comparing the physiological effects and tumor incidence following NaH treatment with those in NaS-treated rats.