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EDSP SAP Whitepaper Draft

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EDSP SAP Whitepaper Draft Continuing Development of Alternative High- Throughput Screens to Determine Endocrine Disruption, Focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways U.S. Environmental Protection Agency Endocrine Disruptor Screening Program Jointly developed by: U.S. EPA Office of Chemical Safety and Pollution Prevention (OCSPP) U.S. EPA Office of Research and Development (ORD) U.S. EPA Office of Water (OW) NIH National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) FIFRA SAP, November 28-30, 2017 Table of Contents 1. Background ........................................................................................................................................... 1 1.1 Statutory Mandate and History of the Endocrine Disruptor Screening Program (EDSP) ............ 1 1.2 Testing Under the EDSP and the Importance of High-Throughput Screening ............................ 1 1.3 Summary of Previous EDSP21 SAPs ........................................................................................... 5 1.4 Comments from the SAP of December 2014 and Agency Responses ....................................... 12 1.4.1 ER Bioactivity ................................................................................................................... 12 1.4.2 AR Bioactivity .................................................................................................................. 14 1.4.3 IBER Approach ................................................................................................................. 14 1.5 Performance-Based Approach to Establishing Confidence ........................................................ 15 1.6 Computational and Pathway Models to Integrate High-Throughput Assay Data ...................... 17 1.7 Scientific Issues for this FIFRA SAP Meeting ........................................................................... 18 2. Androgen Receptor (AR) Pathway Activity ..................................................................................... 19 2.1 Introduction ................................................................................................................................ 19 2.1.1 Assay Data ........................................................................................................................ 20 2.1.2 Overall Approach .............................................................................................................. 21 2.2 Methods ...................................................................................................................................... 22 2.2.1 High-Throughput Screening Data ..................................................................................... 22 2.2.2 AR Pathway Model ........................................................................................................... 23 2.2.3 Mathematical Representation of the Pathway Model ....................................................... 26 2.2.4 Cytotoxicity Filter ............................................................................................................. 27 2.2.5 Cell Stress Flags ................................................................................................................ 28 2.2.6 Confirmation Flags ........................................................................................................... 28 2.2.7 Uncertainty Quantification................................................................................................ 29 2.2.8 Systematic Literature Review for Reference Chemical Identification ............................. 29 2.2.9 Reference Chemical Criteria ............................................................................................. 30 2.3 Results ........................................................................................................................................ 31 2.3.1 Activity in the AR Pathway Model Across the ToxCast Library ..................................... 31 2.3.2 Systematic Literature Review Search Results .................................................................. 33 2.3.3 Potency of Transactivation Agonists ................................................................................ 36 2.3.4 Potency of Transactivation Antagonists ........................................................................... 38 2.3.5 AR Pathway In Vitro Reference Chemicals ...................................................................... 40 2.3.6 AR Pathway Model Performance ..................................................................................... 41 2.3.7 Distinguishing Antagonism and Cell Stress ..................................................................... 47 2.3.8 Antagonism Confirmation Assay Results ......................................................................... 48 2.3.9 Antagonist Activity Confidence Scoring .......................................................................... 49 2.3.10 Comparison with EPA EDSP Tier 1 AR Binding Assay .................................................. 50 2.4 Discussion................................................................................................................................... 53 2.5 Responses to the Recommendations Noted in the December 2014 FIFRA SAP ....................... 56 2.5.1 Introduction ....................................................................................................................... 56 2.5.2 Response to Comments ..................................................................................................... 56 2.6 Limitations of the current model and future refinements ........................................................... 59 2.6.1 Metabolic Capacity ........................................................................................................... 59 2.6.2 Chemical Library Restrictions .......................................................................................... 59 2.7 Future Use of the AR Pathway Model ........................................................................................ 60 2.7.1 Alternative to Other EDSP Tier 1 Assays ......................................................................... 60 2.7.2 Prioritization and Risk Assessment .................................................................................. 60 2.8 Performance-Based Approach to Establishing Confidence: Considerations & Conclusions for the AR Pathway Model .................................................................................... 61 i 2.8.1 The Performance-Based Approach ................................................................................... 61 2.8.2 Summary and Conclusions ............................................................................................... 63 2.9 Supplemental File ....................................................................................................................... 64 3. Steroidogenesis Pathway Activity ..................................................................................................... 65 3.1 Introduction ................................................................................................................................ 65 3.1.1 Current EDSP Tier 1 In Vitro Approach for Screening for Perturbation of Steroid Biosynthesis ...................................................................................................................... 65 3.1.2 Objectives ......................................................................................................................... 65 3.1.3 Background on the OECD-Validated H295R Assay and the ToxCast HT H295R Assay ................................................................................................................................. 66 3.1.4 Analysis Approach for the HT H295R Data ..................................................................... 67 3.2 Methods ...................................................................................................................................... 68 3.2.1 Chemical Library .............................................................................................................. 68 3.2.2 HT H295R Assay and Quantification of Steroid Hormones ............................................. 69 3.2.3 Data analysis ..................................................................................................................... 73 3.2.4 Computation of the Mean Mahalanobis Distance to Derive a Maximum Mean Mahalanobis Distance by Chemical .................................................................................. 76 3.2.5 MANOVA and Computation of the Covariance Matrix ................................................... 79 3.2.6 Comparison Methodology for HT H295R to OECD Reference Chemicals ..................... 80 3.3 Results ........................................................................................................................................ 83 3.3.1 Analysis of HT H295R Data by ANOVA and Post-Hoc Dunnett’s Test ......................... 84 3.3.2 Pathway-Based Results Using the Mahalanobis Distance Approach ............................... 87 3.3.3 Comparison and Evaluation of the ANOVA and maxmMd Results ................................ 92 3.4 Discussion................................................................................................................................. 103 3.5 Limitations of the
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