Critical Aspects of EPA’s IRIS
Assessment of Inorganic Arsenic

Interim Report

Committee on Inorganic Arsenic

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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Critica al Aspeects of EPA’s I IRIS As ssessmment of f Inorgaanic Ar rsenic Interi im Repport Co ommittee on Inorgani Arsenic o ic Bo oard on En nvironmental Studies and Toxicology vision on Earth and L Studies Div Life s

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Re- search Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract EP-C-09-003 between the National Academy of Sciences and the US Envi- ronmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publica- tion are those of the author) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-29706-6 International Standard Book Number-10: 0-309-29706-0 Additional copies of this report are available for sale 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 2013 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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COMMITTEE ON INORGANIC ARSENIC Members JOSEPH H. GRAZIANO (Chair), Columbia University Mailman School of Public Health, New York, NY HABIBUL AHSAN, University of Chicago, Chicago, IL SANDRA J.S. BAIRD, Massachusetts Department of Environmental Protection, Boston, MA AARON BARCHOWSKY, University of Pittsburgh, Pittsburgh, PA HUGH A. BARTON, Pfizer, Inc., Groton, CT GARY P. CARLSON, Purdue University, West Lafayette, IN MARY E. DAVIS, West Virginia University, Morgantown, WV YVONNE P. DRAGAN, AstraZeneca Pharmaceuticals, Waltham, MA REBECCA C. FRY, University of North Carolina, Chapel Hill, NC CHRIS GENNINGS, Virginia Commonwealth University, Richmond, VA GARY L. GINSBERG, Connecticut Department of Public Health, Hartford, CT MARGARET KARAGAS, Dartmouth Geisel School of Medicine, Lebanon, NH JAMES S. MACDONALD, Chrysalis Pharma Consulting, LLC, Chester, NJ ANA NAVAS-ACIEN, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD MARIE E. VAHTER, Karolinska Institute, Stockholm, Sweden ROBERT O. WRIGHT, Mount Sinai School of Medicine, New York, NY Staff SUSAN N.J. MARTEL, Project Director KERI STOEVER, Research Associate NORMAN GROSSBLATT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects TAMARA DAWSON, Program Associate Sponsor US Environmental Protection Agency v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM PRAVEEN AMAR, Clean Air Task Force, Boston, MA MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA JONATHAN Z. CANNON, University of Virginia, Charlottesville, VA GAIL CHARNLEY, HealthRisk Strategies, Washington, DC FRANK W. DAVIS, University of California, Santa Barbara, CA CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY LYNN R. GOLDMAN, George Washington University, Washington, DC LINDA E. GREER, Natural Resources Defense Council, Washington, DC WILLIAM E. HALPERIN, University of Medicine and Dentistry of New Jersey, Newark, NJ STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY ROBERT A. HIATT, University of California, San Francisco, CA PHILIP K. HOPKE, Clarkson University, Potsdam, NY SAMUEL KACEW, University of Ottawa, Ontario, ON, Canada H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA THOMAS E. MCKONE, University of California, Berkeley, CA TERRY L. MEDLEY, E.I. du Pont de Nemours & Company, Wilmington, DE JANA MILFORD, University of Colorado at Boulder, Boulder, CO RICHARD L. POIROT, Vermont Department of Environmental Conservation, Waitsfield, VT MARK A. RATNER, Northwestern University, Evanston, IL KATHRYN G. SESSIONS, Health and Environmental Funders Network, Bethesda, MD JOYCE S. TSUJI, Exponent Environmental Group, Bellevue, WA Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies ELLEN K. MANTUS, Senior Program Officer for Risk Analysis SUSAN N.J. MARTEL, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects vi

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Preface The US Environmental Protection Agency’s Integrated Risk Information System (IRIS) program has been working for several years on updating its toxicologic assessment of inorganic arsenic. The agency released an updated draft cancer assessment of inorganic arsenic in 2010. However, in 2011, Congress mandated an independent peer review of the assessment by the National Research Council before EPA takes any action to make the assessment final. In response to that mandate, EPA withdrew its draft cancer assessment and announced plans to redo the toxicologic assessment to include cancer and noncancer ef- fects. The agency asked the National Research Council to provide a review in two phases. The first phase would involve providing EPA with guidance on key aspects of performing the toxicologic assessment (the focus of this report), and the second phase would be a review of the draft document after the agency completed its assessment. In response to EPA’s request, the National Research Council convened the Committee on Inorganic Arsenic, which prepared this report. The members of the committee were selected for their expertise in toxicology, epidemiology, carcinogenesis, mechanisms, genomics, physiologically based pharmacokinetic modeling, environmental medicine, risk assessment, and biostatistics (see Appendix A for biographic in- formation on the members). For the first phase of the project, the committee conducted a public workshop to evaluate critical scientific issues in assessing cancer and noncancer effects from oral exposure to inorganic arsenic. The workshop was held on April 4, 2013 (see agenda in Appendix B). The committee wishes to thank the in- vited speakers for their participation in the workshop and panel discussions. The workshop proceedings were used by the committee to inform its preliminary survey of the literature on inorganic arsenic. The committee’s report has been reviewed in draft form by persons chosen for their diverse perspec- tives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of the independent review is to provide candid and critical com- ments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative pro- cess. We thank the following individuals for their review of the report: Thomas Burke, Johns Hopkins Bloomberg School of Public Health; Yu Chen, New York University; David Dorman, North Carolina State University; Molly Kile, Oregon State University; Roger McClellan, Toxicology and Human Health Risk Analysis; Louise Ryan, University of Technology Sydney School of Mathematical Sciences; Timothy Pas- toor, Syngenta Crop Protection, Inc.; Craig Steinmaus, University of California, Berkeley; and Michael Waalkes, National Institute of Environmental Health Sciences. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Joan Rose, Michigan State University, and Da- vid Eaton, University of Washington. Appointed by the National Research Council, they were responsible for making certain that an independent examination of the report was carried out in accordance with institu- tional procedures and that all review comments were carefully considered. Responsibility for the final con- tent of the report rests entirely with the author committee and the institution. vii

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viii Preface The committee is grateful for the assistance of National Research Council staff in preparing the report. It particularly wishes to acknowledge the support of Project Director Susan Martel, who coordinated the project and contributed to the committee’s report. Other staff members who contributed to this effort are James Reisa, director of the Board on Environmental Studies and Toxicology; Keri Stoever, research assis- tant; Tamara Dawson, program associate; Norman Grossblatt, senior editor; and Mirsada Karalic- Loncarevic, manager of the Technical Information Center. Finally, I thank all the members of the committee for their efforts throughout the development of this report. Joseph H. Graziano, PhD Chair, Committee on Inorganic Arsenic

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Contents SUMMARY ......................................................................................................................................................... 3 1 INTRODUCTION ................................................................................................................................. 8 Recommendations from Previous National Research Council Committees, 9 The Environmental Protection Agency’s Draft Plans, 10 Structure of the Report, 10 2 EXPOSURE CONSIDERATIONS .................................................................................................... 11 Natural and Anthropogenic Sources, 11 Food Sources, 11 Bioavailability, 12 Absorption, Distribution, Metabolism, and Elimination, 13 Biomarkers of Exposure, 15 3 IRIS ASSESSMENT DEVELOPMENT PLANS: EVIDENCE EVALUATION, SYSTEMATIC REVIEW, AND META-ANALYSIS ...................................................................... 18 Evidence Evaluation, 18 Systematic Review and Meta-Analysis, 19 4 HAZARD IDENTIFICATION .......................................................................................................... 23 Skin Diseases, 24 Respiratory Effects, 26 Cardiovascular Disease, 29 Bladder Effects, 31 Renal Effects, 33 Pregnancy Outcomes, 36 Neurotoxicity, 38 Diabetes, 42 Effects on Liver, Prostate, and Pancreas, 45 Immune Effects, 47 Summary, 49 5 SUSCEPTIBILITY FACTORS ......................................................................................................... 51 Life Stages, 51 Genetics of Arsenic Metabolism and Toxicity, 53 Sex Differences in Arsenic Metabolism and Health Effects, 57 Nutritional Deficiencies, 58 Pre-Existing Disease, Smoking, and Alcohol Consumption, 60 Mixtures and Coexposures, 66 Summary, 68 ix

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x Contents 6 MODE OF ACTION ........................................................................................................................... 70 Important Aspects of Mode-of-Action Analysis, 70 Potential Modes of Action of Arsenic, 73 Summary, 75 7 DOSE–RESPONSE ANALYSIS ........................................................................................................ 76 Dose–Response Analysis for Noncancer and Cancer End Points, 76 Dose–Response Meta-Analysis, 81 Sensitive Populations and Life Stages, 82 IRIS Usability, 83 REFERENCES ................................................................................................................................................. 84 APPENDIXES A BIOSKETCHES OF THE COMMITTEE ON INORGANIC ARSENIC ..................................... 111 B WORKSHOP AGENDA................................................................................................................... 115 BOXES, FIGURES, AND TABLES BOXES 1 Committee’s Guidance and Recommendations for Improving Steps of the Toxicologic Assessment of Inorganic Arsenic Illustrated in Figure 1, 4 2 Hierarchy of Health End Points of Concern for Inorganic Arsenic, 5 3 Statement of Task, 9 4 Examples of Research Questions about Epidemiologic and Experimental Data, 21 5 Concentration Descriptors Used in This Report, 23 6 Steps of Mode-of-Action Analysis, 72 7 Illustration of Proposed Strategy for Estimating Risk at Low Doses, 79 FIGURES 1 Steps of the toxicologic assessment of inorganic arsenic, 4 2 Arsenic metabolism: Inorganic arsenate (AsV) can be reduced by glutathione (GSH) or other reductants to yield inorganic arsenite (AsIII) and glutathione disulfide (GSSG), 14 3 Potential interaction between chemical exposure and disease process, 61 4 Cadmium-induced shift in GFR distribution at a chronic exposure of 1 μg/kg per day relative to a 47.8-year-old female baseline, 63 TABLES 1 Large Cohort Studies of Overall Cardiovascular Disease and Arsenic Exposure Measured at the Individual Level and Reported in Two or More Arsenic Categories in Populations with Arsenic in Drinking Water at Less than 150 μg/L, 30 2 Urinary Arsenic Concentrations in Studies of Neurotoxicity, 39 3 Most Sensitive Neurodevelopmental End Points in Human Studies, 42 4 Recent Studies of Diabetes and Arsenic Measured at the Individual Level That Reported Two or More Arsenic Categories, 44