Lessons learned from evaluating defined chemical mixtures in a high-throughput estrogen receptor assay system
Fred Parham1, Kristin M Eccles1, Cynthia V Rider1
1Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Summary
This study assessed chemical mixture hazards using Tox21 estrogen receptor (ER) assays. The full-length endogenous ER model (ER-luc) proved more accurate than the transfected ligand-binding domain model (ER-bla) for high-throughput mixture analysis.
Area of Science:
- Toxicology
- Environmental Health
- Biochemistry
Background:
- The U.S. Tox21 program screens chemicals for toxicity.
- Assessing the hazard of chemical mixtures is complex.
- Estrogen receptor (ER) assays are used to evaluate endocrine disruption.
Purpose of the Study:
- To evaluate the utility of Tox21 high-throughput screening for chemical mixture hazard assessment.
- To compare two different estrogen receptor (ER) assays for mixture analysis.
- To assess the predictive accuracy of mixture modeling.
Main Methods:
- Used a subset of Tox21 Phase I chemicals to create mixtures.
- Tested individual chemicals and mixtures in ER alpha (ERα) β-lactamase (ER-bla) and MCF7 ER-luc assays.
- Predicted mixture joint effects using concentration-response data and compared with observed data.
Main Results:
- Mixture responses were overpredicted by models in the ER-bla assay.
- Predictions were closer to observed responses in the ER-luc assay.
- The full-length endogenous ER (ER-luc) model showed better performance for mixture analysis.
Conclusions:
- A full-length endogenous estrogen receptor (ER) model is preferred for high-throughput mixture hazard assessment.
- Consistent experimental paradigms and robust data handling are crucial for accurate mixture predictions.
- Further development is needed for handling incomplete data and identifying inactive chemicals in mixture assessments.
Keywords:
Tox21estrogen receptor agonistsgeneralized concentration additionhigh-throughput screeningindependent actionmixturesMore Related Videos
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