Morita Takeshi, Miyajima Atsuko, Hatano Akiko, Honma Masamitsu
Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Division of Medical Devices, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
Mutat Res Genet Toxicol Environ Mutagen. 2014 Jul 15;769:34-49. doi: 10.1016/j.mrgentox.2014.04.018. Epub 2014 May 13.
For the in vitro chromosomal aberration (CA) test, the proposed top-concentration limit will be reduced to '10mM or 2mg/mL' (whichever is lower) in the draft revised OECD (r-OECD) test guideline (TG) 473, down from '10mM or 5mg/mL' in the current OECD TG, which was adopted in 1997 (1997-OECD). It was previously reduced to 1mM or 0.5mg/mL in the International Conference of Harmonization (ICH) S2 (R1) guideline for pharmaceuticals. Reduction of the top-concentration limit is expected to reduce the number of false or misleading positives. However, this reduction may affect the sensitivity or specificity to predict rodent carcinogenicity. Thus, the effect of a reduction in the top-concentration limit on sensitivity and specificity was investigated by use of a dataset on 435 chemicals obtained from the 'Carcinogenicity and Genotoxicity eXperience' (CGX) database (267 CA-positives and 168 CA-negatives; 317 carcinogens and 118 non-carcinogens) where three TGs (i.e., 1997-OECD, r-OECD and ICH) were applied. The application of the r-OECD TG did not affect the sensitivity (63.1%) or specificity (59.3%) against carcinogenicity, compared with the 1997-OECD TG (sensitivity 63.1%, specificity 59.3%). However, the application of the ICH TG had certain effects, i.e., a decrease in sensitivity (45.4%) and an increase in specificity (72.9%). A change in the number of CA-positives by the application of each TG was also investigated by use of 124 CA-positives from the Japanese Existing Chemical (JEC) database. The application of r-OECD TG showed a small reduction in CA-positives, but the ICH TG reduced this number by approximately half. More than half of the CA-positives had a molecular weight <200. These results suggest that the r-OECD TG will not affect the sensitivity or specificity for the detection of rodent carcinogens, indicating the usefulness of the guideline. However, nearly no improvement with respect to a reduction in the number of false positives should be expected.
在体外染色体畸变（CA）试验中，经合组织（OECD）修订草案（r - OECD）试验指南（TG）473中提议的最高浓度限值将从当前1997年采用的经合组织试验指南（1997 - OECD）中的“10mM或5mg/mL”（取较低值）降至“10mM或2mg/mL”（取较低值）。在国际人用药品注册技术协调会（ICH）S2（R1）药品指南中，该限值先前已降至1mM或0.5mg/mL。降低最高浓度限值有望减少假阳性或误导性阳性的数量。然而，这种降低可能会影响预测啮齿动物致癌性的敏感性或特异性。因此，利用从“致癌性和遗传毒性经验”（CGX）数据库获得的435种化学物质的数据集（267种CA阳性和168种CA阴性；317种致癌物和118种非致癌物），研究了最高浓度限值降低对敏感性和特异性的影响，其中应用了三种试验指南（即1997 - OECD、r - OECD和ICH）。与1997 - OECD试验指南（敏感性63.1%，特异性59.3%）相比，应用r - OECD试验指南对致癌性的敏感性（63.1%）或特异性（59.3%）没有影响。然而，应用ICH试验指南有一定影响，即敏感性降低（45.4%）和特异性增加（72.9%）。还利用日本现有化学品（JEC）数据库中的124种CA阳性物质，研究了每种试验指南的应用对CA阳性数量的变化。应用r - OECD试验指南显示CA阳性数量略有减少，但ICH试验指南使该数量减少了约一半。超过一半的CA阳性物质分子量<200。这些结果表明，r - OECD试验指南不会影响检测啮齿动物致癌物的敏感性或特异性，表明该指南有用。然而，预计在减少假阳性数量方面几乎没有改善。
