Ashby J, Beije B
Mutat Res. 1985 Jun-Jul;150(1-2):383-92. doi: 10.1016/0027-5107(85)90135-6.
Oral dosing of between 5-30 mg/kg of cyclophosphamide (CP) to Alderley Park rats induced micronuclei in the bone marrow between 12 and 36 h after dosing, but failed to induce unscheduled DNA synthesis (UDS) in the liver at similar dose levels and treatment periods. Dose levels of greater than 30 mg/kg were toxic to the liver. In contrast, 2-acetylaminofluorene (2AAF) induced UDS in the rat liver between 4-36 h after dosing, but gave only a weak response in the bone marrow assay at dose levels between 0.5 and 2 g/kg. Selected observations were made for each chemical using both tissues of the same test animal. It is concluded that an assessment of the genotoxicity in vivo of chemicals defined as genotoxic in vitro will contribute to an assessment of their possible mammalian carcinogenicity, and that these should involve assays conducted using both the bone marrow and the liver of rodents. Due to its relative ease of commission, the bone marrow micronucleus assay will usually be conducted first; in the case of negative results it is recommended that a liver genotoxicity assay should be conducted. The case for employing in vivo short-term genotoxicity tests to predict the possible organotropic carcinogenicity or germ cell mutagenicity of a new in vitro genotoxin is discussed.
给奥尔德利公园大鼠口服5 - 30毫克/千克的环磷酰胺（CP），给药后12至36小时可诱导骨髓出现微核，但在相似剂量水平和处理时间段内未能诱导肝脏出现非程序性DNA合成（UDS）。剂量大于30毫克/千克对肝脏有毒性。相比之下，2 - 乙酰氨基芴（2AAF）给药后4至36小时可诱导大鼠肝脏出现UDS，但在0.5至2克/千克的剂量水平下，骨髓试验仅出现微弱反应。对每种化学物质，使用同一试验动物的两种组织进行了选定的观察。得出的结论是，对在体外被定义为具有遗传毒性的化学物质进行体内遗传毒性评估，将有助于评估其可能的哺乳动物致癌性，并且这些评估应包括使用啮齿动物的骨髓和肝脏进行的试验。由于骨髓微核试验相对易于实施，通常应首先进行；如果结果为阴性，建议进行肝脏遗传毒性试验。本文讨论了采用体内短期遗传毒性试验来预测新的体外遗传毒素可能的器官特异性致癌性或生殖细胞致突变性的情况。
