| Autor: |
Zhang, Shaofei, Coffing, Stephanie L., Gunther, William C., Homiski, Michael L., Spellman, Richard A., Van, Phu, Schuler, Maik |
| Předmět: |
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| Zdroj: |
Environmental & Molecular Mutagenesis; Jul2024, Vol. 65, p190-202, 13p |
| Abstrakt: |
The detection of N‐nitrosamines in drug products has raised global regulatory interest in recent years due to the carcinogenic potential of some nitrosamines in animals and a need to identify a testing strategy has emerged. Ideally, methods used would allow for the use of quantitative analysis of dose–response data from in vivo genotoxicity assays to determine a compound‐specific acceptable intake for novel nitrosamines without sufficient carcinogenicity data. In a previous study we compared the dose–response relationships of N‐nitrosodiethylamine (NDEA) in three in vivo genotoxicity endpoints in rats. Here we report a comparison of NDEA's genotoxicity profile in mice. Big Blue® mice were administered NDEA at doses of 0.001, 0.01, 0.1, 1 and 3 mg/kg/day by oral gavage for 28 days followed by 3 days of expression. Statistically significant increases in the NDEA induced mutations were detected by both the transgenic rodent mutation assay (TGR) using the cII endpoint and by duplex sequencing in the liver but not bone marrow of mice. In addition, administration of NDEA for two consecutive days in male C57BL/6N mice caused elevated DNA damage levels in the liver as measured by % tail DNA in comet assay. The benchmark dose (BMD) analysis shows a BMDL50 of 0.03, 0.04 and 0.72 mg/kg/day for TGR, duplex sequencing and comet endpoints, respectively. Overall, this study demonstrated a similar genotoxicity profile of NDEA between mice and rats and provides a reference that can be used to compare the potential potency of other novel nitrosamines for the induction of gene mutations. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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