Using N‐Nitrosodiethanolamine (NDELA) and N‐Nitrosopiperidine (NPIP) Transgenic Rodent Gene Mutation Data and Quantum Mechanical Modeling to Derive Potency‐Based Acceptable Intakes for NDSRIs Lacking Robust Carcinogenicity Data DOI
Jason M. Roper,

Troy Griffin,

George E. Johnson

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

ABSTRACT Acceptable intake (AI) limits for nitrosamine drug substance related impurities (NDSRIs) that lack carcinogenicity data could be estimated from mutagenic potency relative to anchor nitrosamines with data. This approach integrates points of departure (PoDs) derived in vivo mutagenicity studies silico predictions generated by a validated quantum‐mechanical (QM) model. N ‐nitrosodiethanolamine (NDELA) and ‐nitrosopiperidine (NPIP), AIs robust data, were tested the transgenic rodent (TGR) gene mutation assay. Liver mutant frequency benchmark dose (BMD) modeling provided suitable, robust, precise PoD metric. BMD confidence intervals (CIs) calculated expanded range previously reported CIs other nitrosamines. Cancer‐protective NDSRIs can pragmatically on basis comparing their lower bound TGR model/anchor have results cancer bioassays. In was supported Computer‐Aided Discovery RE‐design (CADRE) program, QM model predicting NDSRI carcinogenic based underlying mechanism mutagenicity. CADRE distinguished between ‐nitrosodiethylamine (NDEA) ‐nitrosodimethylamine (NDMA) less potent NDELA NPIP. Scrutiny reactivity indices relevant physicochemical properties rationalized observed trend metabolic activity thus predicted potency. Leveraging vivo–in is valuable gaining proposed AIs, whereby serves as mechanistic validation results.

Language: Английский

Using N‐Nitrosodiethanolamine (NDELA) and N‐Nitrosopiperidine (NPIP) Transgenic Rodent Gene Mutation Data and Quantum Mechanical Modeling to Derive Potency‐Based Acceptable Intakes for NDSRIs Lacking Robust Carcinogenicity Data DOI
Jason M. Roper,

Troy Griffin,

George E. Johnson

et al.

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: May 8, 2025

ABSTRACT Acceptable intake (AI) limits for nitrosamine drug substance related impurities (NDSRIs) that lack carcinogenicity data could be estimated from mutagenic potency relative to anchor nitrosamines with data. This approach integrates points of departure (PoDs) derived in vivo mutagenicity studies silico predictions generated by a validated quantum‐mechanical (QM) model. N ‐nitrosodiethanolamine (NDELA) and ‐nitrosopiperidine (NPIP), AIs robust data, were tested the transgenic rodent (TGR) gene mutation assay. Liver mutant frequency benchmark dose (BMD) modeling provided suitable, robust, precise PoD metric. BMD confidence intervals (CIs) calculated expanded range previously reported CIs other nitrosamines. Cancer‐protective NDSRIs can pragmatically on basis comparing their lower bound TGR model/anchor have results cancer bioassays. In was supported Computer‐Aided Discovery RE‐design (CADRE) program, QM model predicting NDSRI carcinogenic based underlying mechanism mutagenicity. CADRE distinguished between ‐nitrosodiethylamine (NDEA) ‐nitrosodimethylamine (NDMA) less potent NDELA NPIP. Scrutiny reactivity indices relevant physicochemical properties rationalized observed trend metabolic activity thus predicted potency. Leveraging vivo–in is valuable gaining proposed AIs, whereby serves as mechanistic validation results.

Language: Английский

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