The Genetic Toxicology Association (GTA) recently held a successful annual meeting in Newark, Delaware. Instem was delighted to participate in this fruitful meeting that brought attention to the latest advancements in the evaluation of genetic toxicants. The utility of Error Corrected Next Generation Sequencing (ecNGS) and the enhanced Ames test were discussed. Instem was pleased to contribute towards the success of this meeting.
Platform Presentations
Dr. Kevin Cross presented an update on the European Medicine’s Agency Mutamind project investigating nitrosamine potency where he described three contracts where Instem is participating. The aims of each contract are:
- Investigate metabolic activation, DNA adduct formation and DNA repair mechanisms to distinguish nitrosamine classes with distinct mutagenic potency.
- To optimize Ames test conditions for mutagenicity testing of nitrosamines and to evaluate the in vitro alkaline Comet assay with liver cell models (HepG2 cells, primary rat, mouse, and human hepatocytes) for detection of carcinogenic nitrosamines.
- To investigate the impact of physiological conditions on the endogenous formation of nitrosamines from APIs, specifically, direct introduction of the nitroso group into the API molecule.
The Mutamind project is led by Fraunhofer ITEM and is funded by the European Medicine’s Agency1.
Poster presentations
Dr. Kevin Cross presented a poster on the use of structure activity relationships (SAR) of N-Nitrosamides and N-Nitrosoureas to determine their carcinogenic potential. This work examined the potential for SAR considerations used in the CPCA rules as a potential extension to categorize the carcinogenicity potency of other N-nitroso compounds. Variations in the chemical reactivity of N-Nitrosamides and N-Nitrosoureas were examined by considering differences and similarities of the nitrosamines CPCA features as compared to the other N-nitroso compounds.
Dr. Candice Johnson discussed the use of direct reactivity assessments as a proxy for small molecule interactions with biomolecular pharmaceutical ingredients. In this project, direct acting mutagenicity alerts were identified based upon statistical analysis of all strains with and without rat liver-derived S9 fraction and an assessment of available literature. These alerts, together with reaction domain profiling and a model to assess direct peptide reactivity were used to assess the prevalence of potentially reactive leachables with biomolecule active pharmaceutical ingredients.
Please contact info@instem.com for copies of the posters or for more information about the projects discussed.
Authors: Candice Johnson, PhD, Senior Research Scientist for Instem & Kevin Cross, PhD, VP of Regulatory Science at Instem
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