ArticleArchives of toxicology2026
Mutagenic and carcinogenic potency determinations for NDMA support the cumulative dose assumption underpinning the less-than-lifetime Threshold of Toxicological Concern.
Article in Archives of toxicology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The management of N-nitrosamine impurities challenges pharmaceutical development and regulation worldwide. Because most medicinal exposures are shorter than lifetime and absolute impurity exclusion is impossible, reliable approaches to define duration-specific intake limits are essential. On the premise that carcinogenic risk is proportional to cumulative dose, the 'Less-Than-Lifetime' (LTL) Threshold of Toxicological Concern (TTC) framework defines progressively lower intake limits for mutagenic impurities over longer exposures. However, N-nitrosamines are currently treated as a 'cohort of concern', necessitating compound-specific evaluation placing reliance on in vivo mutagenicity assays for impurity qualifications. To better understand durational potency relationships and the application domain of the LTL-TTC, we applied benchmark dose (BMD) modelling to cumulative-dose-scaled transgenic rodent (TGR), error-corrected sequencing and rodent carcinogenicity datasets for N-nitrosodimethylamine (NDMA) obtained from the published literature. For TGR, cumulative-dose scaling better resolved liver as the most sensitive organ and reduced interstudy variability: liver BMDs spanned ~ 80-fold in daily-dose units but only ~ 20-fold when scaled to cumulative dose. Among closely-matched mouse liver gavage studies, cumulative-dose BMDs only varied by ~ 2.5-fold across 1 to 28-day treatment regimens. Error-corrected sequencing also demonstrated parity, with acute-dose regimens producing mutation burdens near-identical (< 1.2-fold) to those cumulated from 28-day repeat-dose regimens. Comparable results were obtained from carcinogenicity datasets confirming proportionality-of-effect to cumulative dose. These findings empirically support the validity of the LTL-TTC concept. More broadly, they demonstrate that short-term in vivo mutagenicity assays can serve as reliable surrogates for lifetime carcinogenicity studies, strengthening the scientific and regulatory basis for duration-adjusted acceptable intakes for N-nitrosamine impurities.
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