Exhibitor-hosted session on March 13, 10:30 a.m. - 11:30 a.m., SOT Annual Meeting 2024

N-nitrosamines (NAs) are potentially human carcinogens frequently occurring as impurities in drugs or through endogenous formation in the human organism. The MUTAMIND project, funded by the European Medicine Agency (EMA) investigated the ability of a set of structurally divers NAs to induce genotoxic effects by testing (and optimizing) in-vitro approaches including comet assay and AMES tests, investigating their metabolic activation as well as repair processes. This work contributes to the development of structural activity relationships, that can be applied to predict the genotoxic potential of untested NAs.

Dr. Sylvia Escher, Anke Londenberg and Max Spänig (Fraunhofer ITEM) together with Dr. Kevin Cross (Instem) will present recent results from the EMA funded MUTAMIND project, which investigated the genotoxicity of NAs derived from active pharmaceutical ingredients.

Dr. Sylvia Escher coordinated the project and will provide an overview. Anke Londenberg will give further insights into the benchmark modelling approach used to rank NAs based on results from AMES test. Max Spänig will highlight the ability of secondary amines to from NAs under physiological conditions in the human organism and the use of physiologically based kinetic modelling to address interspecies differences as well as potential bioaccumulation in the liver. Finally, Dr. Kevin Cross will outline the grouping as well as structure activity approach followed in this project. 

Dr. Sylvia Escher is head of the Department of In-silico Toxicolgy at Fraunhofer ITEM. The main focus of her work is on the improvement on chemical risk assessment methodologies. She is experienced in the integration of data and data mining using toxicological databases. She analyzed in-vivo animal data to gain further insights into regulatory questions like development of read-across approaches, TTC and extrapolation factors. In the ongoing NC3R project “virtual dog” as well as the recently finished eTRANSAFE project, her group is contributing to the development of virtual control groups. Further a special focus of her work is the replacement of in-vivo animal studies by new approach methods (NAM) starting with read-across approaches (EUTOXRISK, CEFIC LRI ZET-O-MAP and EXITOX) and in ongoing projects on ab initio risk assessments (RISK-HUNT3R, ZeroPM, PARC).

Recently, Sylvia Escher also led the EFSA project on the “Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment”, which analyzed data and knowledge gaps in the area of NAM based hazard and risk assessment and identified research needs. The Department of In-silico Toxicology has a lot of expertise in transcriptome analyses and PBK modelling. Sylvia Escher coordinated several (inter)national projects like EFSA NAM Roadmap, EFSA Read-Across Workflow, CEFIC LRI ZET-O-MAP. She also is engaged as work package leader (RiskHunt3r, PARC WP5.3.4) and leads several multi-disciplinary case studies on the development of IATAs (RiskHunt3r, ZeroPM, EUTOXRISK).
 

At SOT 2024 Dr. Sylvia Escher will also give the following lectures:

Symposium Sessions:

Integration of Metabolite Data into Read-Across Assessments
Session: New Approach Methodology and Kinetic Modeling Approaches to Support Read-Across; Talk 1111
Tuesday, March 12, 8:35 a.m. - 9:05 a.m., Grand Ballroom E‚ Salt Palace Convention Center

Modeling of Bioavailable Concentration of N-Nitrosamines Built via Endogenous Mechanisms
Session: Nitrosamines: Mechanistic Evidence to Support Subclasses with Varying Mutagenic Potency; Talk 1209
Tuesday, March 12, 4:50 p.m. - 5:10 p.m., Grand Ballroom A‚ Salt Palace Convention Center

Round table session:

Evaluation of Clinical Chemistry Parameters: Which Factors Have an Impact?
Session: Is Less More? Reduction of Animal Use through Virtual Control Groups
Wednesday, March 13, 11:25 noon - 11:35 a.m., Room 250 A‚ Salt Palace Convention Center
 

Dr. Sylvia Escher is also involved in the following poster discussions:
 

Mutamind: Benchmark Dose Modeling of N-Nitrosamines based on comet and enhanced Ames assay data

Poster 3106/P210; Session: Genotoxicity/DNA Repair
Monday, March 11, 2024, 11:45 a.m. - 1:45 p.m.
Authors: A. Londenberg, S. Chang, M. A. Djuari, K. P. Cross, G. Johnson, M. Schulz, C. Ziemann, and S. Escher

ZET-O-MAP: Identify molecular drivers of teratogenic toxicants in time-resolved NAM data

Poster 3848/P351; Session: Developmental and Juvenile Toxicology
Tuesday, March 12, 2024, 11:45 a.m. - 1:45 p.m.
Authors: M. M. Wehr, B. Schultz, H. Witters, S. Remy, K. Hollanders, M. Jacobs, and S. Escher

Evaluating the deviation of the inhalTTC group's assessment on NOAEC/LOAEC values from those of the study authors

Poster 3617/P118; Session: Risk Assessment II
Tuesday, March 12, 2024, 11:45 a.m. - 1:45 p.m.
Authors: M. Schwarz-Zocher, A. M. Api, K. Joshi, S. Collins, G. Patlewicz, A. M. Bowden, F. Boislève, M. Singal, A. Giusti, N. Sadekar, and S. E. Escher

Physiological based kinetic modelling to assess the distribution of nitrosamine formed under physiological conditions

Poster 4430/P218; Session: Mathematical Modeling
Wednesday, March 13, 2024, 2:15 p.m. - 4:15 p.m.
Authors: M. Spänig, M. Vogel, T. Hansen, U. Deppenmeier, and S. Escher

Anke Londenberg's focus is on benchmark dose (BMD) modelling, databases and structural analysis of N-nitrosamines. She is writing her doctoral thesis at Fraunhofer ITEM and is involved in all three MUTAMIND projects.
 

Anke Londenberg is also involved in the following poster discussion:
 

Mutamind: Benchmark Dose Modeling of N-Nitrosamines based on comet and enhanced Ames assay data

Poster 3106/P210; Session: Genotoxicity/DNA Repair
Monday, March 11, 2024, 11:45 a.m. - 1:45 p.m.
Authors: A. Londenberg, S. Chang, M. A. Djuari, K. P. Cross, G. Johnson, M. Schulz, C. Ziemann, and S. Escher

Max Spänig specializes in physiologically based kinetic (PBK) modelling of the human organism. He is currently writing his PhD thesis at Fraunhofer ITEM and is involved in various projects, including the MUTAMIND (Q)SAR project.
 

Max Spänig is also involved in the following poster discussion:
 

Physiological based kinetic modelling to assess the distribution of nitrosamine formed under physiological conditions

Poster 4430/P218; Session: Mathematical Modeling
Wednesday, March 13, 2024, 2:15 p.m. - 4:15 p.m.
Authors: M. Spänig, M. Vogel, T. Hansen, U. Deppenmeier, and S. Escher

Kevin P. Cross, Ph.D., is the Vice-President of Regulatory Science at Instem where he is Principal Investigator of U.S. FDA/instem research collaborations. He completed a Ph.D. in chemistry from Michigan State University in 1985 and joined Leadscope (later purchased by Instem) in 1999. He has been developing chemoinformatics tools and products for over 40 years. He is involved in several collaborative efforts creating in-silico protocols and procedures for performing chemical hazard and risk assessments for regulatory purposes as well as developing and assessing the performance of QSAR models.

Currently he is participating on 2 EMA contracts studying nitrosamines, and a HESI GTTC sub-team investigating nitrosamine Structure-Activity Relationships and in-vitro testing. He has published over 45 papers and 3 book chapters.