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An Approach to Using Toxicogenomic Data in US EPA Human Health Risk DRAFT EPA/600/R-09/028A DO NOT CITE OR QUOTE May 2009 External Review Draft An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study NOTICE THIS DOCUMENT IS AN EXTERNAL REVIEW DRAFT. It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent U.S. EPA policy. It is being circulated for comment on its technical policy implications. Please note gene and protein names in this document have been standardized using information from the Rat Genome Project. National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, DC 20460 DISCLAIMER This document is a draft for review purposes only and does not constitute U.S. EPA policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This document is a draft for review purposes only and does not constitute Agency policy. ii DRAFT—DO NOT CITE OR QUOTE CONTENTS LIST OF TABLES ........................................................................................................................ vii LIST OF FIGURES ....................................................................................................................... ix LIST OF ABBREVIATIONS AND ACRONYMS ...................................................................... xi PREFACE ......................................................................................................................................xv AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................... xvi 1. EXECUTIVE SUMMARY ............................................................................................. 1-1 1.1. APPROACH ........................................................................................................ 1-1 1.2. DBP CASE STUDY ............................................................................................ 1-2 1.3 RECOMMENDATIONS ..................................................................................... 1-5 1.4. RESEARCH NEEDS ........................................................................................... 1-6 2. INTRODUCTION ........................................................................................................... 2-1 2.1. PURPOSE ............................................................................................................ 2-1 2.2. REPORT OVERVIEW ........................................................................................ 2-1 2.3. USE OF TOXICOGENOMICS IN RISK ASSESSMENT ................................. 2-3 2.3.1. Definitions................................................................................................ 2-3 2.3.2. Current Efforts to Utilize Toxicogenomic Data in Risk Assessment ...... 2-6 2.3.2.1. Toxicogenomics Informs Mode of Action (MOA) ................... 2-6 2.3.2.2. Toxicogenomics Informs Dose-Response ................................ 2-8 2.3.2.3. Toxicogenomics Informs Interspecies Extrapolations .............. 2-9 2.3.2.4. Toxicogenomics Informs Intraspecies Variability .................. 2-10 2.3.2.5. Toxicokinetic/Toxicodynamic (TK/TD) Linkages Informed by Toxicogenomic Data ......................................... 2-10 2.3.2.6. Toxicogenomic Activities at the U.S. Food and Drug Administration (U.S. FDA) .................................................... 2-11 2.3.2.7. Toxicogenomic Activities at the U.S. Environmental Protection Agency (U.S. EPA) ............................................... 2-13 2.3.2.8. Toxicogenomic Activities at Other Agencies and Institutions .............................................................................. 2-15 2.3.3. Current Challenges and Limitations of Toxicogenomic Technologies .......................................................................................... 2-16 2.4. CASE STUDY ................................................................................................... 2-17 2.4.1. Project Team .......................................................................................... 2-17 2.4.2. Chemical Selection ................................................................................ 2-18 2.4.2.1. Six Candidate Chemicals ........................................................ 2-18 2.4.2.2. DBP Selected as Case Study Chemical .................................. 2-22 2.4.3. Case Study Scope ................................................................................... 2-23 3. DBP CASE STUDY APPROACH AND EXERCISE .................................................... 3-1 3.1. EVALUATING DBP IRIS ASSESSMENT EXTERNAL REVIEW DRAFT ................................................................................................................ 3-1 3.2. CONSIDERATION OF RISK ASSESSMENT ASPECTS THAT TOXICOGENOMIC DATA MAY ADDRESS .................................................. 3-4 This document is a draft for review purposes only and does not constitute Agency policy. iii DRAFT—DO NOT CITE OR QUOTE CONTENTS (continued) 3.2.1. Informing Toxicokinetics......................................................................... 3-7 3.2.1.1. Identification of Potential Metabolic and Clearance Pathways ................................................................................... 3-7 3.2.1.2. Selection of Appropriate Dose Metrics .................................... 3-8 3.2.1.3. Intra- and Interspecies Differences in Metabolism ................... 3-8 3.2.1.4. Toxicokinetic/toxicodynamic (TK/TD) Linkages and Feedback ................................................................................... 3-9 3.2.1.5. Research Needs for Toxicogenomic Studies to Inform Toxicokinetics ........................................................................... 3-9 3.2.1.6. DBP Case Study: Do the Available Toxicogenomic Data Inform TK? ............................................................................. 3-10 3.2.2. Informing Dose-Response ..................................................................... 3-13 3.2.3. DBP Case Study: Do the Toxicogenomic Data Inform Dose- Response? .............................................................................................. 3-13 3.2.4. Informing Toxicodynamics/Mechanism and Mode of Action ............... 3-14 3.2.4.1. General Considerations: Mechanism and Mode of Action .... 3-14 3.2.4.2. DBP Case Study: MOAs for Male Reproductive Developmental Effects ............................................................ 3-16 3.3. IDENTIFYING AND SELECTING QUESTIONS TO FOCUS THE DBP CASE STUDY ................................................................................................... 3-18 4. EVALUATION OF THE REPRODUCTIVE DEVELOPMENTAL TOXICITY DATA SET FOR DBP ..................................................................................................... 4-1 4.1. CRITERIA AND RATIONALE FOR INCLUSION OF TOXICOLOGY STUDIES IN THE EVALUATION .................................................................... 4-2 4.2. REVIEW OF THE TOXICOLOGY DATA SET .............................................. 4-11 4.3. UNEXPLAINED MODES OF ACTION (MOAS) FOR DBP MALE REPRODUCTIVE TOXICITY OUTCOMES .................................................. 4-23 4.4. CONCLUSIONS ABOUT THE TOXICITY DATA SET EVALUATION: DECISIONS AND RATIONALE ..................................................................... 4-29 5. EVALUATION OF THE DBP TOXICOGENOMIC DATA SET FROM THE PUBLISHED LITERATURE................................................. 5-1 5.1. METHODS FOR ANALYSIS OF GENE EXPRESSION: DESCRIPTION OF MICROARRAY TECHNIQUES AND SEMI-QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (RT-PCR) .......................................................................... 5-1 5.1.1. Microarray Technology ........................................................................... 5-1 5.1.2. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) ............... 5-2 This document is a draft for review purposes only and does not constitute Agency policy. iv DRAFT—DO NOT CITE OR QUOTE CONTENTS (continued) 5.2. REVIEW OF THE PUBLISHED DBP TOXICOGENOMIC STUDIES ........... 5-3 5.2.1. Overview of the Toxicogenomic Studies ................................................. 5-3 5.2.2. Microarray Studies ................................................................................... 5-3 5.2.2.1. Shultz et al. (2001) .................................................................... 5-3 5.2.2.2. Bowman et al. (2005)................................................................ 5-7 5.2.2.3. Liu et al. (2005) ........................................................................ 5-8 5.2.2.4. Thompson et al. (2005) ........................................................... 5-10 5.2.2.5. Plummer et al. (2007) ............................................................. 5-12 5.2.3. Real-Time Reverse Transcription- Polymerase Chain Reaction (RT-PCR) Studies .................................................................................. 5-14 5.2.3.1. Barlow et al. (2003) ................................................................ 5-14 5.2.3.2. Lehmann et al. (2004) ............................................................. 5-15 5.2.3.3. Thompson et al. (2004) ........................................................... 5-17 5.2.3.4. Wilson et al. (2004) ...............................................................
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