Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8456463 | Mutation Research/Genetic Toxicology and Environmental Mutagenesis | 2014 | 16 Pages |
Abstract
For the in vitro chromosomal aberration (CA) test, the proposed top-concentration limit will be reduced to '10Â mM or 2Â mg/mL' (whichever is lower) in the draft revised OECD (r-OECD) test guideline (TG) 473, down from '10Â mM or 5Â mg/mL' in the current OECD TG, which was adopted in 1997 (1997-OECD). It was previously reduced to 1Â mM or 0.5Â mg/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.
Keywords
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Cancer Research
Authors
Takeshi Morita, Atsuko Miyajima, Akiko Hatano, Masamitsu Honma,