ArticlePloS one2014
Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Evaluating the Endocrine-Disrupting and Oxidative Stress Potential of a 50-Component Human-Relevant Complex Chemical Mixture Using In Vitro Tests.Journal of applied toxicology : JAT · 2026Article
- Quantitative neurotoxic effects of heavy metals and glutamate in mouse hippocampal neuronal cells.Environmental analysis, health and toxicology · 2025Article
- Lessons learned from evaluating defined chemical mixtures in a high-throughput estrogen receptor assay system.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Breast cancer risk and prevention in 2024: An overview from the Breast Cancer UK - Breast Cancer Prevention Conference.Cancer medicine · 2024Review
- Reflected generalized concentration addition and Bayesian hierarchical models to improve chemical mixture prediction.PloS one · 2024Article
- A geospatial modeling approach to quantifying the risk of exposure to environmental chemical mixtures via a common molecular target.The Science of the total environment · 2023Article
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- Transcriptome-Wide Prediction and Measurement of Combined Effects Induced by Chemical Mixture Exposure in Zebrafish Embryos.Environmental health perspectives · 2021Article
- Transthyretin-Binding Activity of Complex Mixtures Representing the Composition of Thyroid-Hormone Disrupting Contaminants in House Dust and Human Serum.Environmental health perspectives · 2020Article
- Generalized concentration addition for ligands that bind to homodimers.Mathematical biosciences · 2019Article
- Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Pesticides With Potential Thyroid Hormone-Disrupting Effects: A Review of Recent Data.Frontiers in endocrinology · 2019Review
- BIGL: Biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonism.Scientific reports · 2017Article
- Mathematical modeling for estrogenic activity prediction of 17β-estradiol and 17α-ethynylestradiol mixtures in wastewater treatment plants effluent.Ecotoxicology (London, England) · 2017Article
- Total Effective Xenoestrogen Burden in Serum Samples and Risk for Breast Cancer in a Population-Based Multicase-Control Study in Spain.Environmental health perspectives · 2016Article
- Generalized Concentration Addition Modeling Predicts Mixture Effects of Environmental PPARγ Agonists.Toxicological sciences : an official journal of the Society of Toxicology · 2016Article
- Defining an additivity framework for mixture research in inducible whole-cell biosensors.Scientific reports · 2015Article
- Additivity and Interactions in Ecotoxicity of Pollutant Mixtures: Some Patterns, Conclusions, and Open Questions.Toxics · 2015Review
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Corrections and comments
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Authors and funding
3 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past.
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