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CoMPARA: Collaborative Modeling Project for Androgen Receptor Activity
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2020 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 128, no 2, p. 1-17, article id 027002Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling.

OBJECTIVES: In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP).

METHODS: The CoMPARA list of screened chemicals built on CERAPP's list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast (TM) metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast (TM)/Tox21 HTS in vitro assays.

RESULTS: The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set.

DISCUSSION: The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of similar to 875,000 chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program's Integrated Chemical Environment.

Place, publisher, year, edition, pages
2020. Vol. 128, no 2, p. 1-17, article id 027002
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-169387DOI: 10.1289/EHP5580ISI: 000518589800006PubMedID: 32074470Scopus ID: 2-s2.0-85079531920OAI: oai:DiVA.org:umu-169387DiVA, id: diva2:1420904
Available from: 2020-04-01 Created: 2020-04-01 Last updated: 2023-03-24Bibliographically approved
In thesis
1. Improving alternatives assessment of plastic additives: exploring in silico tools to identify less hazardous flame retardants
Open this publication in new window or tab >>Improving alternatives assessment of plastic additives: exploring in silico tools to identify less hazardous flame retardants
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alternatives assessment is applied for replacing hazardous chemicals with viable, safer substitutes. High quality experimental hazard data, however, are usually unavailable for this purpose, and obtaining in silico data is the only approach to fill in data gaps. In silico tools also have the advantage of providing a large amount of data with much lower cost and time requirements.

The aim of this PhD project was to explore the use of in silico tools for alternatives assessment, and develop practical tools for alternatives assessment of organic plastic additives. For this purpose, flame retardants were used as case chemicals. The major results were:

1. Quantitative structure-activity relationship (QSAR) models for endocrine disruption were developed and explored (Paper I and II). These developed models were able to identify chemical properties that impact the binding affinities of brominated organic chemicals with estrogen-related receptor γ (Paper I), and to predict the androgen receptor activity of several organic chemicals, including flame retardants (Paper II);

2. A hazard ranking tool was developed for alternatives assessment based on the hazard properties of persistence (P), bioaccumulation (B), mobility in the aquatic environment (M) and toxicity (T). The flame retardant decabromodiphenyl ether (decaBDE) and 16 of its alternatives were taken as case chemicals to develop the tool. From a comparison of experimental and in silico data for these case chemicals, hazard data predicted by in silico tools were identified as the more suitable data source for the hazard ranking tool as the experimental data were confounded by large data gaps (Paper III);

3. The inclusion of chemical transformation products for the hazard ranking tool were studied with the case of decaBDE and its alternatives. Several in silico tools were used to predict transformation products, and a strategy for prioritizing chemical transformations with high occurrence potential in the environment was developed (Paper IV);

4. Multicriteria decision analysis (MCDA) tools were used to evaluate diverse P, B, M and T endpoints of parent compounds (Paper III) and their transformation products (Paper IV) simultaneously based on in silico data. Three different MCDA methods were explored, and one of them was developed to include the consideration of uncertainties of in silico data;

5. In the studied case of decaBDE alternatives, the three different MCDA methods generally agreed on the most and least hazardous alternatives. With the consideration of hazard for the studied flame retardants and their in silico predicted transformation products, two alternatives, melamine and bis(2-ethylhexyl) tetrabromophthalate, were identified as the least hazardous of considered alternatives for decaBDE (Paper III and IV);

6. It is critical for the exposure aspect of alternatives assessment to identify the key properties that influence the emission process. For this, a fast measuring method for the emission of polymer additives was developed based on a Quartz Crystal Microbalance (QCM). Empirical linear models were applied to describe the emission patterns (Weibull model) to better understand the chemical mechanism behind the emissions of organophosphate flame retardants from various polymers. The results showed that the octanol-water partitioning coefficient and molecular size are key parameters for the emission process, but also showed that the emission process is complex and is likely driven by a combination of both polymer and additive properties, as well as their interactions (Paper V).

This research shows how alternatives assessment can make more effective use of in silico tools. and it also highlights current challenges in the use of these in silico tools that require further development. The next steps to make a holistic alternatives assessment would include an exposure assessment procedure based on the work in Paper V, and combining this with the hazard ranking tools (developed in Paper III and IV), including information on technical feasibilities, economic feasibilities, and also life cycle impacts. The MCDA methods for hazard ranking in Paper III and IV can be further adapted for the decision component of such a more complete alternatives assessment for specific uses of chemicals.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2021. p. 51
Keywords
Chemical alternatives assessment, plastic additives, flame retardants, hazard, emission, in silico, modeling, quantitative structure-activity relationship (QSAR), multi-criteria decision analysis (MCDA)
National Category
Organic Chemistry Environmental Sciences
Research subject
environmental science; Organic Chemistry; Ecotoxicology; Toxicology
Identifiers
urn:nbn:se:umu:diva-182073 (URN)978-91-7855-475-1 (ISBN)978-91-7855-476-8 (ISBN)
Public defence
2021-05-06, Glasburen, KBC-huset, Linnaeus väg 6, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council Formas, 942-2015-672
Available from: 2021-04-15 Created: 2021-04-08 Last updated: 2021-05-04Bibliographically approved

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Andersson, Patrik L.Zheng, Ziye

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