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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Review of U.S. EPA's ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. doi: 10.17226/26289.
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PREPUBLICATION COPY Review of U.S. EPA’s ORD Staff Handbook for Developing IRIS Assessments: 2020 Version Committee to Review EPA’S IRIS Assessment Handbook Board on Environmental Studies and Toxicology Division on Earth and Life Studies A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by Contract No. 68HERC19D0011 between the National Academy of Sciences and the U. S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/26289 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2021 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2021. A Review of U.S. EPA’s ORD Staff Handbook for Developing IRIS Assessments: 2020 Version. Washington, DC: The National Academies Press. https://doi.org/10.17226/26289.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

COMMITTEE TO REVIEW EPA’S IRIS ASSESSMENT HANDBOOK Members Lisa A. Bero (Chair), Colorado School of Public Health, Aurora Hugh A. Barton, Consultant, Mystic, CT Weihsueh A. Chiu, Texas A&M University, College Station Gary L. Ginsberg, New York State Department of Health, Albany Julie B. Herbstman, Columbia University, New York, NY Jessica L. Myers, Texas Commission on Environmental Quality, Austin Heather B. Patisaul, North Carolina State University, Raleigh David B. Richardson, University of North Carolina, Chapel Hill Paul Whaley, Lancaster University, Lancaster, United Kingdom Kristine L. Willett, University of Mississippi, University Corwin M. Zigler, University of Texas, Austin Staff Raymond Wassel, Scholar Clifford S. Duke, Director, Board on Environmental Studies and Toxicology Kathryn Guyton, Senior Program Officer Leslie Beauchamp, Program Assistant Melissa Franks, Senior Program Officer (until May 14, 2021) Sponsor U.S. Environmental Protection Agency Prepublication Copy v

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members William H. Farland (Chair), Colorado State University, Fort Collins Dana Boyd Barr, Emory University, Atlanta, GA Ann M. Bartuska, U.S. Department of Agriculture (retired), Washington, DC E. William Colglazier, American Association for the Advancement of Science, Washington, DC Francesca Dominici, Harvard University, Boston, MA George Gray, The George Washington University, Washington, DC R. Jeffrey Lewis, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ Germaine M. Buck Louis, George Mason University, Fairfax, VA Linsey C. Marr, Virginia Polytechnic Institute and State University, Blacksburg R. Craig Postlewaite, U.S. Department of Defense, Burke, VA Reza J. Rasoulpour, Corteva Agriscience, Indianapolis, IN Ivan Rusyn, Texas A&M University, College Station Joshua Tewksbury, Future Earth, Boulder, CO Sacoby M. Wilson, University of Maryland, College Park Staff Clifford S. Duke, Director Raymond Wassel, Scholar Kathryn Guyton, Senior Program Officer Kaley Beins, Associate Program Officer Laura Llanos, Finance Business Partner Tamara Dawson, Program Coordinator Leslie Beauchamp, Program Assistant Thomasina Lyles, Program Assistant vi Prepublication Copy

Acknowledgments This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: HARVEY CLEWELL, Ramboll US Consulting, Inc. PENNY FENNER-CRISP, private consultant SUE JINKS-ROBERTSON (NAS), Duke University JULEEN LAM, California State University East Bay JENNIFER McPARTLAND, Environmental Defense Fund MOSHE OREN (NAS/NAM), Weizmann Institute of Science KAREN ROBINSON, Johns Hopkins University ANDREW ROONEY, National Institute of Environmental Health Sciences KAN SHAO, Indiana University KIM TRUONG, California Environmental Protection Agency LAURA VANDENBERG, University of Massachusetts – Amherst Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by JOEL KAUFMAN, University of Washington and LYNN GOLDMAN (NAM), the George Washington University. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. Prepublication Copy vii

Abbreviations and Acronyms ADME Absorption, Distribution, Metabolism, Excretion BMR Benchmark Response CRO Contract Research Organization EPA U.S. Environmental Protection Agency GRADE Grading of Recommendations, Assessment, Development and Evaluation HAWC Health Assessment Workspace Collaborative IAP IRIS Assessment Plan IRIS Integrated Risk Information System KC Key Characteristics LOAEL Lowest-observed-adverse-effect Level MOA Mode of Action NAMs New Approach Methods/Methodologies OHAT Office of Health Assessment and Translation OPPT U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics ORD U.S. Environmental Protection Agency Office of Research and Development PBPK Physiologically Based Pharmacokinetic PECO Population, Exposure, Comparator, Outcome PK Pharmacokinetic PODs Points of Departure RfC Reference Concentration RfD Reference Dose ROBINS-E Risk of Bias in Non-randomized Studies of Exposures ROBINS-I Risk of Bias in Non-randomized Studies of Interventions TACIT Tool for Addressing Conflicts of Interest in Trials TK Toxicokinetics TSCA Toxic Substances Control Act Prepublication Copy ix

Contents SUMMARY ................................................................................................................................................. 1 1 INTRODUCTION .............................................................................................................................. 12 2 OVERVIEW OF ORGANIZATION AND CONTENT OF THE HANDBOOK ......................... 18 3 PLANNING ASSESSMENTS ........................................................................................................... 30 4 STUDY EVALUATION .................................................................................................................... 47 5 EVIDENCE SYNTHESIS ................................................................................................................. 57 6 EVIDENCE INTEGRATION ........................................................................................................... 63 7 HAZARD CONSIDERATIONS AND STUDY SELECTION FOR DERIVING TOXICITY VALUES......................................................................................................................... 69 REFERENCES .......................................................................................................................................... 75 APPENDIXES A COMMITTEE MEMBER BIOSKETCHES ................................................................................... 81 B 2020 IRIS HANDBOOK ORGANIZATION AND CONTENTS AND EPA QUESTIONS TO THE COMMITTEE ............................................................................................ 85 C OPEN SESSION AGENDAS............................................................................................................. 89 BOXES, FIGURES, AND TABLES BOXES S-1 Stages in the Development of IRIS Assessments Listed in the Handbook, 2 1-1 Statement of Task, 13 1-2 Considerations for Critique of Handbook Chapters, 14 FIGURES 3-1 Mapping of three stages of the IRIS planning process identified by the committee, 34 3-2 Illustration of an assessment plan, literature inventory, and assessment protocol from the IRIS planning process, 39 6-1 Example of a terminology map illustrating units of analysis, 66 Prepublication Copy xi

Contents TABLES 1-1 Mapping of Committee’s Report Chapters and EPA Questions, 16 2-1 Common Uses of Mechanistic and Toxicokinetic Evidence in IRIS Assessments, 22 3-1 Illustrative Documentation of an Assessment Plan, Literature, Inventory, and Assessment Protocol from the IRIS Planning Process, 38 xii Prepublication Copy

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The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) program develops human health assessments that focus on hazard identification and dose-response analyses for chemicals in the environment. The ORD Staff Handbook for Developing IRIS Assessments (the handbook) provides guidance to scientists who perform the IRIS assessments in order to foster consistency in the assessments and enhance transparency about the IRIS assessment process. At the request of the EPA, this report reviews the procedures and considerations for operationalizing the principles of systematic reviews and the methods described in the handbook for determining the scope of the IRIS assessments, evidence integration, extrapolation techniques, dose-response analyses, and characterization of uncertainties.

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