Ames concordance with the in vivo transgenic rodent (TGR) gene mutation assay for NDSRIs and relative in vivo TGR potency with nitrosamines with robust dose-response carcinogenicity data

The HESI Global Genetic Toxicology Technical Committee (GTTC) is pleased to announce a new open-access publication that advances how the scientific and regulatory community evaluates nitrosamine drug substance-related impurities (NDSRIs), a challenging class of impurities that can pose mutagenic and carcinogenic risk if not appropriately assessed and controlled.

Why this matters: For many structurally complex NDSRIs, compound-specific data are limited. This can increase uncertainty when setting health-based limits and may affect supply decisions while patient safety remains the priority.

What HESI Global helped solve: This multi-sector collaboration compiles and compares mutagenicity datasets for NDSRIs across in vitro Ames testing and the in vivo transgenic rodent (TGR) gene mutation assay. Across 33 NDSRIs, the analysis found 79% concordance in overall mutagenic calls, providing practical evidence on when these approaches align for hazard identification.

The paper also supports the use of quantitative in vivo mutation data for risk assessment. For select nitrosamines with robust carcinogenicity dose-response data, TGR mutagenic potency (BMDL50) strongly correlated with carcinogenic potency (TD50) (r² = 0.95), reinforcing the value of TGR data to inform acceptable intake (AI) determinations using quantitative approaches.

Aligned with HESI Global’s mission to collaboratively develop science-based solutions for global health challenges, this publication helps improve consistency, transparency, and confidence in nitrosamine risk evaluation.

Read the full article here: Jolly et al., 2026. Ames concordance with the in vivo transgenic rodent (TGR) gene mutation assay for NDSRIs and relative in vivo TGR potency with nitrosamines with robust dose-response carcinogenicity data. Regulatory Toxicology and Pharmacology. https://doi.org/10.1016/j.yrtph.2026.106051.

Learn more about the Nitrosamines Research Program