Nitrosamines Research Program

The Nitrosamines research activities exist under the umbrella of the HESI GTTC MGRA working group as a “case study” to demonstrate the usefulness of innovative, mechanism-based testing approaches.

GTTC: The mission of the Genetic Toxicology Technical Committee (GTTC) is to improve the scientific basis of the interpretation of results from genetic toxicology tests for purposes of more accurate hazard identification and assessment of human risk; to develop follow-up strategies for determining the relevance of test results to human health; to provide a framework for integration of testing results into a risk-based assessment of the effects of chemical exposures on human health; to promote the integration and use of new techniques and scientific knowledge in the evaluation of genetic toxicology; and to monitor and promote the development of innovative tests and testing strategies.

MGRA working group: The Mechanism-based Genotoxicity Risk Assessment (MGRA) working group aimed to develop a new mechanism-based risk assessment paradigm for genotoxicity that uses a genetic toxicology testing strategy designed from a “clean slate”, incorporating new science and technology to allow for a greater diversity of genomic damage to be addressed, and uses genotoxicity Adverse Outcome Pathways (AOP)s.

Subteams & Goals

  • Ames Optimization (Goal 1)

    Goal: Develop an optimized Ames protocol that is predictive for the carcinogenic potential of nitrosamines.

    Workplan:

    • Multi-site study aimed at characterizing the sensitivity and specificity of the Ames study under a variety of test conditions (including solvent optimization).
    • 32 nitrosamine compounds tested in duplicate across 16 laboratories (public and private)
    • FDA grant support for compound procurement (Award number 3U01FD006676-03S2)

    Leadership: Anthony Lynch (GSK), Joel Bercu (Gilead)

  • In Vitro Test Strategy (Goal 2)

    Goal: Identification and verification of in vitro assays to assist in nitrosamine risk identification

    Workplan: Working group launched in October 2023. Details are still under discussion, but several research objectives were identified following the FDA/HESI Research Roadmap Planning on Hazard and Risk Assessment on Nitrosamine Impurities in Drugs that the committee plans to undertake, including:

    • Identifying alternative in vitro approaches to the Ames in the identification of nitrosamines
    • Identifying in vitro assays that can be used as follow-up to the Ames

    Leadership: Xiaowen Sun (Pfizer) and Xiaoqing (Carol) Guo (US FDA/NCTR)

  • In Vivo Ames Follow-Up (Goal 3)

    Goal: Develop an in vivo strategy to verify Ames data within the frame of ICH M7

    Workplan: Working group launched in October 2023. Details are still under discussion, but several research objectives were identified following the FDA/HESI Research Roadmap Planning on Hazard and Risk Assessment on Nitrosamine Impurities in Drugs that the committee plans to undertake, including:

    • Comparison of in vitro/in vivo mutagenicity testing for NDSRIs for hazard identification
    • Comparison of in vivo mutagenicity and carcinogenicity for nitrosamines
    • Less-than-lifetime literature analysis and in vivo mutagenicity analysis
    • Comet prediction to carcinogenicity outcomes for hazard identification

    Leadership: Joel Bercu (Gilead), Robert Jolly (Eli Lilly), Sheroy Minocherhomji (Eli Lilly), Timothy McGovern (US FDA)

  • (Q)SAR (Goal 4)

    Goal: Refine and extend the CPCA using (Q)SAR and QM for more predictive and accurate predictions

    Workplan: Details of the short- and long-term goals are still under discussion, but work is set to launch in early 2024. The work will revolve around the research objectives identified following the FDA/HESI Research Roadmap Planning on Hazard and Risk Assessment on Nitrosamine Impurities in Drugs, including:

    • Development of (Q)SAR/SAR models sufficiently robust for prediction of NAs/NDSRI mutagenicity hazards
    • Refinement/enhancement of the CPCA with more structural features based on new NA/NDSRI data
    • Development of an interface from hazard ID to quantify mutagenic/carcinogenic risk beyond CPCA or read across
    • Generation of data needed to define role of QM modeling given time/resource intensive nature

    Leadership: TBD

Participating Organizations

 

Government/Regulatory Academic Industry Other
BfArM NY Medical College AbbVie Merck FSTox Consulting
EMA St. George’s Medical School, University of London AstraZeneca Merck kGA
Health Canada Swansea University BASF MultiCASE
INRA Boehringer Ingelheim Novartis
RIVM Bristol Myers Squibb PepsiCo
Swissmedic Charles River Laboratories Pfizer
US FDA/CDER/OND Corteva Proctor & Gamble
US FDA/NCTR Eli Lilly Roche
Gilead Sanofi
GSK Teva Pharmaceuticals
Inotiv Xenometrix
Janssen
Labcorp
Leadscope
Litron Laboratories
Lhasa Limited

 

HESI Staff

Leadership Team

  • Andreas Czich, PhD

    Sanofi

  • Tetyana Cheairs, PhD

    New York Medical College

Committee Events

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