EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

自发性单核细胞白血病是评估中的混杂因素 NTP 2年致癌性研究中的化学致白血病性。 一 建立了F344大鼠白血病的短期检测方法 年龄诱发的白血病和化学增强的白血病 的准确性和 移植模型预测长期移植的敏感性 化学品的致白血病效力在短期试验中得到证实， 化学物质增加或减少了白血病的患病率， 既往2年致癌性研究。 其他研究 短期分析揭示了化学品的结构-活性关系 对白血病的发展趋势有积极或消极影响。 九个不同 在短期抗白血病试验中评价了乙二醇醚 活动 其中，只有乙二醇单甲醚和乙烯 乙二醇单乙醚具有化疗潜力。 乙烯 乙二醇单甲醚是一种更有效的抗白血病药物， 单乙醚，并在无毒剂量的饮用水完全 消除了白血病的早期表现，防止了早期死亡， 肿瘤的潜伏期延长了一倍 这些数据得到了 用悬浮的白血病细胞培养物进行体外试验。 如今 的酸和醛代谢物的化学治疗潜力 乙二醇单甲醚，以及丙烯中的化学物质 乙二醇单甲基乙二醇烷基醚系列，正在评估。 通过 相反，两种含有磷酸二甲酯的化学品 （敌敌畏和敌百虫）增强了白血病在 短期试验和2年致癌性试验。 其他三 具有相同结构关系的化学品：二甲基氢 亚磷酸酯，甲基膦酸二甲酯，和 二甲基吗啉代磷酰胺还增加了白血病的发病率 在最近完成的为期两年的研究。 这些观察表明， 二甲基磷酸酯部分应被认为是结构上的 警惕白血病 目前， 对乙酰氨基酚在短期白血病移植中的应用 模型，以确认和扩展从2年的研究中获得的观察结果。

Spontaneous mononuclear cell leukemia is a confounding factor in evaluating chemical leukemogenicity in the NTP 2-year carcinogenicity studies. A short-term assay for F344 rat leukemia was developed to better discriminate between age-induced and chemically-enhanced leukemia. The accuracy and sensitivity of the transplant model for predicting the long-term leukemogenic potency of chemicals was confirmed in short-term assays with 7 chemicals that had increased or decreased the prevalence of leukemia in previous 2-year carcinogenicity studies. Additional studies with the short-term assay revealed structure-activity relationships for chemicals that were either negative or positive for leukemic trends. Nine different glycol ethers were evaluated in the short-term assay for anti-leukemic activity. Of these, only ethylene glycol monomethyl ether and ethylene glycol monoethyl ether exhibited chemotherapeutic potential. Ethylene glycol monomethyl ether was a more potent antileukemic agent than the monoethyl ether, and at non-toxic doses in drinking water completely eliminated the early manifestations of leukemia, prevented early mortality, and doubled the tumor latency period. These data were confirmed by in vitro tests with suspended leukemic cell cultures. Presently, the chemotherapeutic potential for the acid and aldehyde metabolites of ethylene glycol monomethyl ether, as well as chemicals in the propylene glycol monomethyl glycol alkyl ether series, are being evaluated. By contrast, two chemicals containing dimethyl esters of phosphoric acid (dichlorvos and trichlorfon) enhanced the expression of leukemia in the short-term assay and in 2-year carcinogenicity tests. Three other chemicals with the same structural relationship: dimethyl hydrogen phosphite, dimethyl methylphosphonate, and dimethylmorpholinophosphoramidate also increased the incidence of leukemia in recently completed 2-year studies. These observations suggest that the dimethyl phosphoric acid ester moiety should be considered a structural alert for leukemogenicity. Presently, the leukemogenic potential of acetaminophen is being evaluated in the short-term leukemia transplant model to confirm and extend the observations obtained from 2-year studies.