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Estrogen Receptor (ER) Expert Systems for Chemical Prioritization

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The Food Quality Protection Act of 1996 requires the US EPA to screen pesticidal actives and inert ingredients for the potential to act as endocrine disruptors. Given the significant time and money required to conduct hazard assessments for the large numbers of chemicals covered by this mandate, there is a need for a strategic approach to prioritize chemicals to be nominated to move forward into higher tiered targeted testing. One approach being taken to address this need is through decision support tools called “expert systems” that are founded on quantitative structure activity relationships (QSAR) and development of effects-based chemical categories. Expert Systems are automated rule-based decision trees that can be used to predict which chemicals have the potential to disrupt endocrine systems. This is done by testing key chemicals within a chemical class to represent others, determining what is similar about the chemical structures and properties that explain their biological activity, and writing rules that help predict the activity of similar but untested chemicals that belong to the same category. The ERES developed at MED used the OECD QSAR Validation Principles to maximize transparency and usefulness by using well-defined endpoints in well-characterized assays that are appropriate for testing the types of chemicals in the EPA EDSP Universe, and striving for a mechanistic understanding of all assay results.

The conceptual approach providing the foundation for the expert system is the description of the chemically-initiated perturbation of the ER system within the framework of an adverse outcome pathway. The ER-mediated reproductive impairment adverse outcome pathway (Schmieder et al., 2004) describes the linkage between the event that initiates the pathway (e.g., a chemical binding the ER) and measures made at successively higher and more complex levels of biological organization. The pathway progresses from the molecular initiating event, through cell and tissue level gene transcription and translation, continuing through organ effects to an adverse outcome observed in the individual or population. With a plausible pathway to an adverse outcome described, a rationale is provided for using the molecular initiating event as a basis for prioritizing chemicals for further screening with Endocrine Disruptor Screening Program (EDSP) Tier I assays, which incorporate endpoints at higher levels of biological organization.

The specific in vitro assays used at MED to develop the ER expert system are: i) measured chemical binding to the rainbow trout ER to detect the potential for a chemical to initiate the ER-mediated pathway; and ii) ER-mediated vitellogenin induction in rainbow trout liver slices to confirm that ER binding translates to an effect at a point further along the ER-mediated adverse outcome pathway (Schmieder et al., 2004). Tables summarizing the parameters of these two assays are available in this ERES Assay Parameters file - (PDF) (2pp 33k).

2009 ERES SAP

In August 2009 the ER Expert System was presented to a FIFRA Science Advisory Panel (SAP) to obtain feedback on use of the effects based chemical category approach for prioritizing chemicals for further screening.  The meeting documents and minutes can be downloaded from the following links.

2013 EDSP Chemical Prioritization SAP

In January 2013 a FIFRA SAP was convened in which the Agency sought further comment on the concepts, decision logic, and computational (in silico and in vitro) methods used to prioritize chemicals for advancement into the EDSP Tier I screening assays. The document prepared for this meeting, “Prioritization of the Endocrine Disruptor Screening Program Universe of Chemicals for an Estrogen Receptor Adverse Outcome Pathway Using Computational Toxicology Tools Exit EPA Disclaimer presented the ER Adverse Outcome Pathway and further development of the initial ER Expert System as the framework to begin to address how the Expert System and computational toxicology tools, including high throughput assays, may be used together to prioritize chemicals for screening.

A set of 295 chemicals that were tested in the ER expert system trout ER binding and live slice assays and also tested in the ER high throughput (HTP) assays were discussed in Section 7 of the EDSP Chemical Prioritization SAP document. The relative binding affinity (RBA) data for these chemicals derived from the trout ER competitive binding assay can be accessed in the following download ERES Data_SAP2013 - (zip file) (22KB). The decision process for assigning the chemicals an RBA is presented in Appendix G Exit EPA Disclaimer of the document.

The trout ER binding data and trout liver slice vitellogenin mRNA expression data for this set of 295 chemicals will be released as it becomes available in the following downloads: rtER Binding Data - (zip file) (8KB) and Trout Liver Slice Vtg mRNA Data - (zip file) (8KB). Check back regularly for updated information.

ER Expert System in the OECD (Q)SAR Toolbox

In response to the recommendations of the 2009 OECD expert consultation and the 2009 FIFRA SAP, the ER Expert System has been automated and incorporated into the OECD (Q)SAR Toolbox.  The Toolbox is a freely available software tool that can be used for assessing the hazards of chemicals for which limited or no hazard information is available.  Downloads of the OECD Toolbox containing the initial version of the ER Expert System and associated instructional materials can be accessed at the OECD QSAR Toolbox. Exit EPA Disclaimer

Background References

Schmieder, P.; Tapper, M.; Linnum, A.; Denny, J.; Kolanczyk , R.; and Johnson, R. 2000. Optimization of a precision-cut trout liver tissue slice assay as a screen for vitellogenin induction: comparison of slice incubation techniques. Aquatic Toxicology. 49, 251-268.

Schmieder, P.K., M.A. Tapper, J.S. Denny, R.C. Kolanczyk, B.R. Sheedy, T.R. Henry and G.D. Veith. 2004. Use of trout liver slices to enhance mechanistic interpretation of estrogen receptor binding for cost-effective prioritization of chemicals within large inventories. Environmental Science & Technology 38. 6333-6342.

Denny, J.S., M.A. Tapper, P.K. Schmieder, M.W. Hornung, K.M. Jensen, G.T. Ankley, and T.R. Henry. 2005. Comparison of relative binding affinities of endocrine active compounds to fathead minnow and rainbow trout estrogen receptors. Environmental Toxicology and Chemistry 24:11. 2948-2953.

Report of the Expert Consultation to Evaluate an Estrogen Receptor Binding Affinity Model for Hazard Identification. OECD, Environment Directorate, Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. 21-Aug-2009, ENV/JM/MONO(2009)33. Exit EPA Disclaimer

For further information, please contact Michael Hornung (hornung.michael@epa.gov) or Patricia Schmieder (schmieder.patricia@epa.gov).

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