4种急性经口毒性试验方法的比较研究

Comparison Study on Four Acute Oral Toxicity Testing Methods

[目的]通过比较4种急性经口毒性试验方法操作性和结果一致性,分析其在化学品急性毒性评价中的应用价值及其意义。[方法]对3种已知化学物(对苯二胺、对苯二酚、硼酸)分别使用固定剂量法(FDP)、上下增减剂量法(UDP)、急性毒性分类法(ATC)3种替代方法与传统霍恩氏(Horn’s)法进行大鼠急性经口毒性试验。比较各方法判断化学物毒性分类的一致性;并对动物使用、剂量选择、观察指标进行综合分析。[结果]3种化学物分别用4种方法测定得到的全球化学品统一分类和标签系统(GHS)分类结果一致。3种替代方法均采用序贯原则,使用实验动物数量较少,但实验周期更长。FDP法和ATC法不以获得精确半数致死量(LD50)为研究目标,即不以动物死亡作为最终结果判定标准,降低了实验动物的死亡率,提高了动物福利。UDP法与Horn’s法很相似,系列剂量都有相对固定的剂量级数因子,都以动物死亡为重要的结果判断指标,都能获得确切的LD50值及其95%CI;但UDP更适合染毒后短期(48 h内)死亡的急性毒性评价。[结论]可根据受试物的性质和已知资料,选择合适的急性经口毒性替代方法代替传统Horn’s法。

[ Objective ] To evaluate the operability and results consistency among four acute oral toxicity testing methods and analyze the application value of these methods to acute oral toxicity assessment. [ Methods ] Traditional Horn＇s procedure and three alternative methods including fixed dose procedure （FDP）, up-and-down procedure （UDP）, and acute toxic class method （ATC） were applied to assess the acute oral toxicity of selected chemicals of P-phenylenediamine, hydroquinone, and boracic acid to rats. The consistency of results, manipulation of experimental animal, dose selection, and observed indicators were compared among these four procedures. [ Results ] The Globally Harmonized System （GHS） grades of the three alternative methods are consistent with those of Horn＇s. The three alternative methods with sequential principle used less experimental animals but required a longer testing period. FDP and ATC methods did not provide accurate LD50 values and not take animal death as final result judgment standards; therefore, the two methods reduced the mortality rate of experimental animals and improved animal welfare. UDP was similar with Horn＇s method in terms of relatively fixed dose progression factor, taking animal death as an important result judgment indicator, and providing exact LD50 values and corresponding confidence intervals, but UDP was more suitable for the evaluation of acute toxicity resulting in death within 45 h after exposure. [ Conclusion ] According to the properties and available data of test substances, we could adopt appropriate alternative method to replace Horn＇s method for acute oral toxicity assessment.