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Using publicly available tools for rapid MoE estimation
- 1. Rebecca Clewell 21st Century Tox Consulting NURA: Integrated Approaches to Testing and Assessment 11-12 Dec 2019 Houston, TX Rapid Risk Estimation - Using current tools for quick estimates of MoE
- 2. Bioactivity Components of a risk assessment Dosimetry Margin of Exposure (MoE) Safe Dose Estimated Exposure Blood Fat Liver Tissues
- 3. Wetmore et al. 2015. Toxicol Sci. 148(1):121-36.. Margin of Exposure (MoE) MoE
- 4. Ultra-high throughput in silico - Rapid exposure estimation – ExpoCast, etc - In silico ADME models - QSAR bioactivity models – TTC, read-across High throughput in vitro - HT-IVIVE - In vitro parent chemical clearance - In vitro screening (ToxCast/Tox21) Organotypic in vitro - Q-IVIVE - Bioactivation, metabolite ID - AOPs, organotypic in vitro models Traditional, in vivo - AEPs - PBPK models - Mode of action, targeted endpoint evaluation Throughput Confidenceinaccuracy Prioritization/compound selection - Relative potency - Margin of Exposure (MoE) Hazard ID - Putative Mode of Action (MOA)
- 10. If your compound of interest is a metabolite, you will have to specify that. Note that when you change compounds, the classification from the previous compound remains highlighted.
- 11. Updates to TCC in Kroes et al 2004. Neurotoxins – acetylcholinesterase inhibitors (organophosphates and carbamates – reduced to 0.3 mg/kg-day DNA reactive carcinogens – based on Cheeseman et al. Carcinogenic Potency Database and 1 in 1e6 lifetime cancer risk – reduced to 0.0025 https://efsa.onlinelibrary.wiley .com/doi/epdf/10.2903/j.efsa. 2019.5708
- 25. The link between these exposure and bioactivity is the dosimetry (IVIVE) The caveat is that all models are only as good as the data they are built on.