EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

在NTP 2 - 3中使用的Fischer 344/N大鼠品系中， 2000年的毒性和致癌性研究是自发的 白血病开始于大约18个月，这减少了 检测化学性白血病的灵敏度。 的in 建立了白血病细胞移植模型， 从患有自发性白血病的大鼠体内提取脾细胞， 健康的受体大鼠。 发病后， 来自这些大鼠的白血病脾细胞再次用于 移植以在体内维持白血病细胞系。 的 器官和细胞的形态和生化反应， 移植大鼠的特征是更好地区分 年龄诱发的白血病和化学增强的白血病 肿瘤 形态学、细胞生物化学和癌基因表达， 移植病例相似，但肿瘤发生时间缩短 从18个月到2个月。 的准确度和灵敏度 预测长期致白血病潜能的移植模型 在短期试验中， （2-乙氧基乙醇，4-己基间苯二酚）减少， 增加的化学品（吡啶、敌敌畏、2，4，6- 三氯苯酚）前2年白血病患病率 毒性和致癌性研究。 与此相关的其他研究 移植模型揭示了结构与活性之间的关系 含有乙二醇醚结构的化学品 白血病

Up to 30% of the Fischer 344/N strain of rats used in the NTP 2- year toxicity and carcinogenicity studies develop spontaneous leukemia commencing at about 18 months, which reduces the sensitivity for the detection of chemical leukemogenesis. An in vivo cell transplant model was developed to transfer leukemic spleen cells from a rat with spontaneous leukemia into young, healthy recipient rats. After manifestation of the disease, leukemic spleen cells from those rats were again used for transplantation to maintain the leukemic cell line in vivo. The morphological and biochemical responses in organs and cells from the transplanted rats were characterized to better discriminate between age-induced and chemically-enhanced leukemia. The tumor morphology cellular biochemistry, and oncogenetic expressions and transplanted cases were similar, but the time to tumor was reduced from 18 months to 2 months. The accuracy and sensitivity of the transplant model for predicting the long-term leukemogenic potency of chemicals was confirmed in short-term assays with two chemicals (2-ethoxyethanol, 4-hexylresorcinol) that had decreased, and three chemicals that had increased (pyridine, dichlorvos, 2,4,6- trichlorophenol) the prevalence of leukemia in previous 2-year toxicity and carcinogenicity studies. Additional studies with this transplant model revealed structure-activity relationships between chemicals containing the glycol ether structure and the repression of leukemia.