Chairs: Giel Hendriks & Clive Roper
Genetic toxicology plays a crucial role in chemical safety assessment, identifying substances that may cause DNA damage, mutations, cancer, or hereditary diseases. Traditional genotoxicity testing follows a tiered approach, combining in vitro and in vivo assays to evaluate mutagenic potential. While widely accepted by regulatory agencies such as OECD, ICH, FDA, EMA, ECHA, and EFSA, these methods have limitations, including false positives/negatives, incomplete metabolic activation, reliance on animal testing, and limited mechanistic insight.
To address these challenges, Novel Approach Methodologies (NAMs) are emerging to improve genotoxicity assessments. Techniques such as reporter cell assays, toxicogenomics, and error-corrected next-generation sequencing (ecNGS) provide more accurate and mechanistically relevant data. Additionally, quantitative dose-response modeling using the Benchmark Dose (BMD) approach enhances risk assessment by offering a data-driven alternative to the No-Observed-Adverse-Effect Level (NOAEL). BMD modeling, combined with physiologically based pharmacokinetic (PBPK) modeling, facilitates In Vitro-to-In Vivo Extrapolation (IVIVE), improving human relevance while reducing reliance on animal testing.
Despite their advantages, NAMs face regulatory acceptance challenges due to stringent validation requirements, including multi-laboratory studies to ensure reproducibility and reliability. This session will explore the development, validation, and regulatory review of two NAMs, ToxTracker and gH2AX/H3 assays, currently under OECD evaluation. The session will also highlight the BMD approach, ToxPi visualization tool, and IVIVE applications, with case studies demonstrating the integration of NAMs in genotoxicity testing. Additionally, a novel ecNGS-based mutation detection method will be introduced as an alternative to traditional in vitro and in vivo assays.
Bringing together experts from industry, academia, and regulatory agencies, this session will showcase the latest advancements in in vitro genotoxicity testing and their potential to replace animal-based methods, enhancing the accuracy and efficiency of genetic toxicology assessments.
Speakers
- Giel Hendriks – VALIDATION AND IMPLEMENTATION OF THE TOXTRACKER ASSAY FOR MECHANISTIC GENOTOXICITY ASSESSMENT
- George Johnson – Benchmark Dose Modeling and Data Visualisation of Multiplex Data using ToxPi
- Birgit Mertens – ADVANCING GENOTOXICITY ASSESSMENT FOR REGULATORY APPLICATIONS BY INTEGRATING TRANSCRIPTOMICS WITH BMD AND IVIVE APPROACHES
- Sam Sharifi – Single-Molecule Mutation Sequencing (SMM-seq): Ultra-Sensitive Genotoxicity Profiling at Single-Nucleotide Resolution
- Marc Audebert – Development and regulatory acceptance of the gH2AX/H3 method