This presentation provides examples of the use publicly available tools to for rapid estimation of Margin of Exposure for chemical prioritization. Presented at NURA: Integrated Approaches to Testing and Assessment, Houston, TX, December 2020
Use of mutants in understanding seedling development.pptx
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.