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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research 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 Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.
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
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
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 effects. 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 information 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 invited 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 perspectives 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 comments 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 process. 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 Pastoor, 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 David 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 institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the author committee and the institution.
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 assistant; 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
Contents
Recommendations from Previous National Research Council Committees
The Environmental Protection Agency’s Draft Plans
Natural and Anthropogenic Sources
Absorption, Distribution, Metabolism, and Elimination
3 IRIS ASSESSMENT DEVELOPMENT PLANS: EVIDENCE EVALUATION, SYSTEMATIC REVIEW, AND META-ANALYSIS
Systematic Review and Meta-Analysis
Effects on Liver, Prostate, and Pancreas
Genetics of Arsenic Metabolism and Toxicity
Sex Differences in Arsenic Metabolism and Health Effects
Important Aspects of Mode-of-Action Analysis
Potential Modes of Action of Arsenic
Dose–Response Analysis for Noncancer and Cancer End Points
Sensitive Populations and Life Stages
A BIOSKETCHES OF THE COMMITTEE ON INORGANIC ARSENIC
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
2 Hierarchy of Health End Points of Concern for Inorganic Arsenic
4 Examples of Research Questions about Epidemiologic and Experimental Data
5 Concentration Descriptors Used in This Report
6 Steps of Mode-of-Action Analysis
7 Illustration of Proposed Strategy for Estimating Risk at Low Doses
FIGURES
1 Steps of the toxicologic assessment of inorganic arsenic
2 Arsenic metabolism: Inorganic arsenate (AsV) can be reduced by glutathione (GSH) or other reductants to yield inorganic arsenite (AsIII) and glutathione disulfide (GSSG)
3 Potential interaction between chemical exposure and disease process
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
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
2 Urinary Arsenic Concentrations in Studies of Neurotoxicity
3 Most Sensitive Neurodevelopmental End Points in Human Studies
4 Recent Studies of Diabetes and Arsenic Measured at the Individual Level That Reported Two or More Arsenic Categories