Morita T, Asano N, Awogi T, Sasaki Y F, Sato S, Shimada H, Sutou S, Suzuki T, Wakata A, Sofuni T, Hayashi M
Tsukuba Research Laboratories, Nippon Glaxo Ltd., Japan.
Mutat Res. 1997 Feb 28;389(1):3-122. doi: 10.1016/s1383-5718(96)00070-8.
To assess the correlation between micronucleus induction and human carcinogenicity, the rodent micronucleus assay was performed on known and potential human carcinogens in the 6th MMS/CSGMT collaborative study. Approximately 100 commercially available chemicals and chemical groups on which there was little or no micronucleus assay data were selected from IARC (International Agency for Research on Cancer) Groups 1 (human carcinogen), 2A (probable human carcinogen) and 2B (possible human carcinogen). As minimum requirements for the collaborative study, 5 male mice were treated by intraperitoneal injection or oral gavage once or twice with each chemical at three dose levels, and bone marrow and/or peripheral blood was analyzed. Five positives and 2 inconclusives out of 13 Group 1 chemicals, 7 positives and 5 inconclusives of 23 Group 2A chemicals, and 26 positives and 6 inconclusives of 67 Group 2B chemicals were found. Such low positive rates were not surprising because of a test chemical selection bias, and we excluded well-known micronucleus inducers. The overall evaluation of the rodent micronucleus assay was based on the present data combined with published data on the IARC carcinogens. After merging, the positive rates for Groups 1, 2A and 2B were 68.6, 54.5 and 45.6%, respectively. Structure-activity relationship analysis suggested that the micronucleus assay is more sensitive to the genetic toxicity of some classes of chemicals. Those to which it is sensitive consist of (1) aziridines and bis(2-chloroethyl) compounds; (2) alkyl sulfonate and sulfates; (3) acyl-type N-nitroso compounds; (4) hydrazines; (5) aminobiphenyl and benzidine derivatives; and (6) azo compounds. Those to which it is less sensitive consist of (1) dialkyl type N-nitroso compounds; (2) silica and metals and their compounds; (3) aromatic amines without other functional groups; (4) halogenated compounds; and (5) steroids and other hormones. After incorporation of structure-activity relationship information, the positive rates of the rodent micronucleus assay became 90.5, 65.2 and 60.0% for IARC Groups 1, 2A and 2B, respectively. Noteworthy was the tendency of the test to be more sensitive to those carcinogens with stronger evidence human carcinogenicity.
为评估微核诱导与人类致癌性之间的相关性，在第六届MMS/CSGMT合作研究中，对已知和潜在的人类致癌物进行了啮齿动物微核试验。从国际癌症研究机构（IARC）第1组（人类致癌物）、2A组（很可能的人类致癌物）和2B组（可能的人类致癌物）中挑选了约100种几乎没有或完全没有微核试验数据的市售化学品和化学类别。作为合作研究的最低要求，用每种化学品的三个剂量水平对5只雄性小鼠进行腹腔注射或灌胃处理一次或两次，并分析骨髓和/或外周血。在13种第1组化学品中发现了5个阳性和2个不确定结果，在23种第2A组化学品中发现了7个阳性和5个不确定结果，在67种第2B组化学品中发现了26个阳性和6个不确定结果。由于受试化学品选择偏差，如此低的阳性率并不令人惊讶，并且我们排除了众所周知的微核诱导剂。啮齿动物微核试验的总体评估基于本研究数据以及已发表的关于IARC致癌物的数据。合并后，第1组、2A组和2B组的阳性率分别为68.6%、54.5%和45.6%。构效关系分析表明，微核试验对某些类别的化学品的遗传毒性更为敏感。对其敏感的化学品包括：（1）氮丙啶和双（2-氯乙基）化合物；（2）烷基磺酸盐和硫酸盐；（3）酰基型N-亚硝基化合物；（4）肼类；（5）氨基联苯和联苯胺衍生物；以及（6）偶氮化合物。对其不太敏感的化学品包括：（1）二烷基型N-亚硝基化合物；（2）二氧化硅和金属及其化合物；（3）没有其他官能团的芳香胺；（4）卤代化合物；以及（5）类固醇和其他激素。纳入构效关系信息后，IARC第1组、2A组和2B组的啮齿动物微核试验阳性率分别变为90.5%、65.2%和60.0%。值得注意的是，该试验对那些有更强人类致癌性证据的致癌物更敏感。
