Cell proliferation analysis is a reliable predictor of lack of carcinogenicity: Case study using the pyrethroid imiprothrin on lung tumorigenesis in mice.,Regulatory Toxicology and Pharmacology

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Cell proliferation analysis is a reliable predictor of lack of carcinogenicity: Case study using the pyrethroid imiprothrin on lung tumorigenesis in mice.
Regulatory Toxicology and Pharmacology ( IF 3.0 ) Pub Date : 2020-03-27 , DOI: 10.1016/j.yrtph.2020.104646
Kensuke Kawamoto ₁ , Keiko Ogata ₁ , Hiroyuki Asano ₁ , Kaori Miyata ₁ , Tokuo Sukata ₁ , Tooru Utsumi ₁ , Samuel M Cohen ₂ , Tomoya Yamada ₁

Affiliation

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.

中文翻译：

细胞增殖分析是缺乏致癌性的可靠预测指标：使用拟除虫菊酯亚米普罗辛对小鼠肺部肿瘤发生的案例研究。

在小鼠致癌性研究中，在雄性小鼠中以7000 ppm观察到肺腺癌的明显增加。根据毒理学，肿瘤学，病理学和统计学的总体评估，我们得出结论，肺肿瘤的明显增加与丙咪嗪的致癌性评估无关（Regul Toxicol Pharmacol，105，1-14，2019）。为了研究丙咪嗪对小鼠Club细胞是否有丝分裂作用，本研究检查了丙咪嗪在3500和7000 ppm的饮食中处理7天的雄性小鼠中Club细胞的复制DNA合成和肺组织病理学的影响。异烟肼（一种已知的小鼠肺有丝分裂原和肿瘤诱导剂）也已在饮食中以1000 ppm的浓度进行检查，作为Club细胞有丝分裂和形态变化的阳性对照。通过光学或电子显微镜观察，丙咪嗪和异烟肼均未引起肺中任何坏死性变化。丙咪嗪组中的溴脱氧尿苷（BrdU）标记指数没有增加，而异烟肼组中BrdU标记指数有统计学上的显着增加。这些发现表明，imiprothrin不会诱导小鼠Club细胞增殖或形态变化，从而支持了我们先前所述的结论。因此，imiprothrin不应分类为致癌物。此外，这项研究表明，专注于细胞增殖的短期研究可以可靠地预测测试化学品的致癌潜力。丙咪嗪组中的溴脱氧尿苷（BrdU）标记指数没有增加，而异烟肼组中BrdU标记指数有统计学上的显着增加。这些发现表明，imiprothrin不会诱导小鼠Club细胞增殖或形态变化，从而支持了我们先前所述的结论。因此，imiprothrin不应分类为致癌物。此外，这项研究表明，专注于细胞增殖的短期研究可以可靠地预测测试化学品的致癌潜力。丙咪嗪组中的溴脱氧尿苷（BrdU）标记指数没有增加，而异烟肼组中BrdU标记指数有统计学上的显着增加。这些发现表明，imiprothrin不会诱导小鼠Club细胞增殖或形态变化，从而支持了我们先前所述的结论。因此，imiprothrin不应分类为致癌物。此外，这项研究表明，专注于细胞增殖的短期研究可以可靠地预测测试化学品的致癌潜能。支持上述我们先前的结论。因此，imiprothrin不应分类为致癌物。此外，这项研究表明，专注于细胞增殖的短期研究可以可靠地预测测试化学品的致癌潜能。支持上述我们先前的结论。因此，imiprothrin不应分类为致癌物。此外，这项研究表明，专注于细胞增殖的短期研究可以可靠地预测测试化学品的致癌潜力。

更新日期：2020-03-27

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