TY - JOUR
T1 - Cell proliferation analysis is a reliable predictor of lack of carcinogenicity
T2 - Case study using the pyrethroid imiprothrin on lung tumorigenesis in mice
AU - Kawamoto, Kensuke
AU - Ogata, Keiko
AU - Asano, Hiroyuki
AU - Miyata, Kaori
AU - Sukata, Tokuo
AU - Utsumi, Tooru
AU - Cohen, Samuel M.
AU - Yamada, Tomoya
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6
Y1 - 2020/6
N2 - In the mouse carcinogenicity study, an apparent increase in lung adenocarcinoma was observed in male mice at 7000 ppm. Based on the overall evaluation of toxicology, oncology, pathology and statistics, we concluded that the apparent increase in lung tumors is not relevant for evaluation of carcinogenicity of imiprothrin (Regul Toxicol Pharmacol, 105, 1–14, 2019). To investigate whether imiprothrin has any mitogenic effect on mouse Club cells, the present study examined its effects on replicative DNA synthesis of Club cells and lung histopathology in male mice treated with imiprothrin for 7 days at 3500 and 7000 ppm in the diet. Isoniazid, a known mouse lung mitogen and tumor inducer, was also examined at 1000 ppm in the diet as a positive control of Club cell mitogenesis and morphological changes. Neither imiprothrin nor isoniazid caused any necrotic changes in lung by light or electron microscopy. There were no increases observed in the bromodeoxyuridine (BrdU) labeling index in the imiprothrin groups, while there was a statistically significant increase in the BrdU labeling index in the isoniazid group. These findings demonstrate that imiprothrin does not induce mouse Club cell proliferation or morphologic changes, supporting our previous conclusion described above. Thus, imiprothrin should not be classified as a carcinogen. Furthermore, this study indicates that short-term studies focusing on cell proliferation can be reliable for predicting a lack of carcinogenic potential of test chemicals.
AB - In the mouse carcinogenicity study, an apparent increase in lung adenocarcinoma was observed in male mice at 7000 ppm. Based on the overall evaluation of toxicology, oncology, pathology and statistics, we concluded that the apparent increase in lung tumors is not relevant for evaluation of carcinogenicity of imiprothrin (Regul Toxicol Pharmacol, 105, 1–14, 2019). To investigate whether imiprothrin has any mitogenic effect on mouse Club cells, the present study examined its effects on replicative DNA synthesis of Club cells and lung histopathology in male mice treated with imiprothrin for 7 days at 3500 and 7000 ppm in the diet. Isoniazid, a known mouse lung mitogen and tumor inducer, was also examined at 1000 ppm in the diet as a positive control of Club cell mitogenesis and morphological changes. Neither imiprothrin nor isoniazid caused any necrotic changes in lung by light or electron microscopy. There were no increases observed in the bromodeoxyuridine (BrdU) labeling index in the imiprothrin groups, while there was a statistically significant increase in the BrdU labeling index in the isoniazid group. These findings demonstrate that imiprothrin does not induce mouse Club cell proliferation or morphologic changes, supporting our previous conclusion described above. Thus, imiprothrin should not be classified as a carcinogen. Furthermore, this study indicates that short-term studies focusing on cell proliferation can be reliable for predicting a lack of carcinogenic potential of test chemicals.
KW - Carcinogenicity
KW - Club cells
KW - Isoniazid
KW - Pyrethroid
KW - Replicative DNA synthesis
KW - Short-term bioassays
UR - http://www.scopus.com/inward/record.url?scp=85082706997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082706997&partnerID=8YFLogxK
U2 - 10.1016/j.yrtph.2020.104646
DO - 10.1016/j.yrtph.2020.104646
M3 - Article
C2 - 32229244
AN - SCOPUS:85082706997
SN - 0273-2300
VL - 113
JO - Regulatory Toxicology and Pharmacology
JF - Regulatory Toxicology and Pharmacology
M1 - 104646
ER -