title: Effects of lowering the proposed top-concentration limit in an in vitro chromosomal aberration test on assay sensitivity and on the reduction of the number of false positives.
abstract: 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.
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: morita-tk@nihs.go.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Morita
authors.affiliation: Division of Medical Devices, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Miyajima
authors.affiliation: Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatano
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
mesh_terms: D001681:Biological Assay / Q000592:standards*; D002273:Carcinogens / Q000494:pharmacology*; D002869:Chromosome Aberrations / Q000139:chemically induced*; D004249:DNA Damage / Q000187:drug effects*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005189:False Positive Reactions; D017408:Guidelines as Topic; D066298:In Vitro Techniques; D012680:Sensitivity and Specificity
chemical_list: D002273:Carcinogens
keywords: False positive; In vitro chromosomal aberration test; OECD test-guideline; Sensitivity; Top-concentration limit