A METHOD TO QUANTITATE THE RELATIVE INITIATING AND PROMOTING POTENCIES OF HEPATOCARCINOGENIC AGENTS IN THEIR DOSE-RESPONSE RELATIONSHIPS TO ALTERED HEPATIC FOCI
A METHOD TO QUANTITATE THE RELATIVE INITIATING AND PROMOTING POTENCIES OF HEPATOCARCINOGENIC AGENTS IN THEIR DOSE-RESPONSE RELATIONSHIPS TO ALTERED HEPATIC FOCI
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DOI：
10.1093/carcin/8.10.1491
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发表时间：
1987-10-01
期刊：
影响因子：
4.7
通讯作者：
CAMPBELL, HA
中科院分区：
文献类型：
--
作者：
PITOT, HC;GOLDSWORTHY, TL;CAMPBELL, HA
在存在和不存在促进剂苯巴比妥的情况下，通过定量体视学方法研究了 Sprague-Dawley 和 Fischer 344 (F-344) 品系成年雌性大鼠肝脏中对不同起始剂量的二乙基亚硝胺 (DEN) 和二甲基苯并[a]蒽诱导改变的肝病灶 (AHF) 的数量和大小（肝脏体积％）的相对反应（PB，饮食中 0.05%）。在所有情况下，即使在采用的最低剂量下，也获得了与剂量相对线性的反应，但最高剂量 DEN (30 mg/kg) 下的 AHF 数量除外，与 F-344 雌性大鼠中 10 mg/kg 剂量下的 AHF 数量没有显着差异。在 70% 肝切除术后 24 小时开始使用 DEN (10 mg/kg) 后，在 F-344 雌性大鼠的肝脏中，两种有效促进肝癌发生的促进剂 PB 和 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的不同剂量获得了类似的剂量反应数据。对这些试剂的反应表现出阈值水平，低于该阈值，数量或体积不会增加。与未用促进剂处理的动物的肝脏相比，记录AHF肝脏的百分比。在几个阈下剂量的 PB 和 TCDD 下，观察到 AHF 形成和生长（以肝脏体积％测量）的抑制。基于定量立体学计算，已经建立了用于估计化学品作为引发剂或促进剂的相对效力的参数。这些定义为：起始索引=否。诱发灶数。次。肝脏-1.次。 [mmol/kg体重]-1，促进指数=Vf/Vc×。 mmol-1.倍第 1 周，其中 Vf 是用测试药物治疗的大鼠肝脏中 AHF 所占的总体积分数 (%)，Vc 是刚刚启动的对照动物中 AHF 的总体积。这些参数是根据文献中公布的数据和本文报告的数据计算出许多试剂的。根据本文的数据，这两个参数均不会随引发剂的剂量发生显着变化。促进指数的范围扩大了超过八个数量级，而启动指数的变化则小得多。这些参数可用作肝癌剂效力的定量估计，这些值具有潜在应用于风险估计的价值。
The relative response to various initiating doses of diethylnitrosamine (DEN) and dimethylbenz[a]anthracene of the induction of numbers and size (vol. % of liver) of altered hepatic foci (AHF) in livers of adult female rats of the Sprague-Dawley and Fischer 344 (F-344) strains was studied by methods of quantitative stereology in the presence and absence of the promoting agent, phenobarbital (PB, 0.05% in the diet). In all cases, a relatively linear response with dose, even at the lowest doses employed, was obtained except for the numbers of AHF at the highest dose of DEN (30 mg/kg), which was not significantly different from that at a dose of 10 mg/kg in F-344 female rats. Similar dose-response data were obtained at various doses of two promoting agents effective in hepatocarcinogenesis, PB and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in livers of F-344 female rats following initiation with DEN (10 mg/kg) 24 h post-70% hepatectomy. The response to these agents exhibited threshold levels below which no increase in number or vol. % of liver of AHF was noted in comparison with that in livers of animals not treated with the promoting agents. At several subthreshold doses of both PB and TCDD an inhibition of AHF formation and growth (measured as vol. % of liver) was observed. Based on quantitative stereologic calculations, parameters for the estimation for the relative potency of chemicals as initiating or promoting agents have been established. These are defined as: initiation index = no. of foci induced .times. liver-1 .times. [mmol/kg body wt]-1 and promotion index = Vf/Vc .times. mmol-1 .times. weeks-1, where Vf is the total volume fraction (%) occupied by AHF in the livers of rats treated with the test agent and Vc is the total volume of AHF in control animals which have only been initiated. These parameters were calculated for a number of agents based on data published in the literature and from those reported herein. Neither parameter varied significantly with the dose of the initiating agent based on the data in this paper. The range of promotion indices extended over more than eight orders of magnitude, whereas that of initiation indices was much less variable. Such parameters may be useful as quantitative estimates of the potency of hepatocarcinogenic agents, such values having potential application to risk estimations.