Date:  Nov. 7, 2013




New Report Recommends Data-Driven Approach Over Default Practices for Assessing Multiple Health Effects of Inorganic Arsenic


WASHINGTON – A draft plan by the U.S. Environmental Protection Agency that describes how the agency will assess the potential health effects of oral exposure to inorganic arsenic should take greater advantage of the robust data that exists on the chemical in order to reach the best evidence-based conclusions, says a new report from the National Research Council.  While EPA's draft assessment plan includes improved approaches for evaluating evidence and conducting analyses, the Research Council report recommends alternative statistical approaches over EPA's current default methods for estimating risk.


EPA's Integrated Risk Information System (IRIS) assessments identify disease hazards and characterize associations with adverse health outcomes for a wide variety of chemicals.  EPA asked the Research Council to review its draft plan for carrying out the IRIS assessment of inorganic arsenic and evaluate critical scientific issues in assessing the potential health effects of oral exposure to the chemical.  The new Research Council report recommends how these issues could be addressed in an IRIS assessment; a second report will review the draft IRIS assessment, expected to be performed by EPA in 2014.


EPA's draft plan for carrying out the IRIS assessment includes a framework for categorizing different adverse health effects according to how strongly the evidence supports or suggests a causal relationship with inorganic arsenic exposure.  The Research Council committee that wrote the report largely agreed with this approach and offered a starting point for prioritizing these health outcomes.  The report lists lung, skin, and bladder cancer, ischemic heart disease, and skin lesions as priority outcomes for EPA to evaluate, followed by prostate and renal cancer, diabetes, non-malignant respiratory disease, pregnancy outcomes, and immune effects.


For adverse health effects with evidence of a causal or likely to be causal relationship with inorganic arsenic, EPA will conduct mode-of-action analyses, which describe the pathways that connect exposure with events that occur at the cellular level and then with a measureable adverse health outcome.  These analyses in turn help to inform dose-response analyses, which describe the relationship between different levels of exposure and the resulting health effects.  The committee supported EPA's plan to conduct dose-response analyses for all health end points deemed to have a clear or likely causal relationship with inorganic arsenic, in contrast to previous assessments that only addressed cancer end points. 


While much of the older epidemiologic data are derived from populations exposed to relatively high exposures of inorganic arsenic, the Research Council committee believes that newer studies of exposures in the low to moderate range deserve considerable attention.  A key objective of the EPA assessment should be to better characterize risk at lower exposures.  Focusing on whether the data for levels at or near background concentrations of inorganic arsenic are adequate for dose-response modeling will be an important part of the assessment process, the report says.


The committee recommended that EPA develop risk estimates for both cancer and noncancer effects on which there is adequate epidemiologic evidence and then derive risk-specific doses -- estimates of the level of exposure associated with a given degree of risk.  For those health effects where the data are inadequate for modeling at low levels, extrapolation down to lower levels of exposure will be necessary. 


EPA proposed to use linear extrapolation as the default approach for modeling the dose-response curve below the range of observation.  The committee instead proposed a data-driven strategy, where a model would be fit to the observed data and then used to extrapolate to a limited extent below the range of observation to estimate a potential dose response at lower levels.  Fitting multiple models to the data could help improve the accuracy of the extrapolation and provide greater confidence in the risk estimate.


The committee also identified several factors that could affect susceptibility to inorganic arsenic, including life stage when exposure occurs, genetic factors, sex, nutritional deficiencies, health status, smoking or alcohol consumption, or exposures to mixtures of chemicals.  Based on the degree of evidence concerning these vulnerability factors, consideration should be given to whether dose-response analyses should focus on the population as a whole or involve separate assessments for the susceptible groups, the report says.  In particular, consideration should also be given to early-life exposure and the risk of adverse health effects later in life, the report adds.  EPA’s current approach of assessing partial-lifetime exposures by prorating the risk equally regardless of age needs to be critically evaluated to determine whether it is appropriate for assessing inorganic arsenic.


The report's recommendations for improving EPA's plan for carrying out the assessment are specific to inorganic arsenic and may not be applicable to the assessment of other chemicals.  Moreover, the report focuses only on health outcomes from oral exposure and does not consider inhalation or dermal exposure. 


The study was sponsored by the U.S. Environmental Protection Agency.  The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.  They are private, independent nonprofit institutions that provide science, technology, and health policy advice under a congressional charter granted to NAS in 1863.  The Research Council is the principal operating agency of the National Academy of Sciences and the National Academy of Engineering.  For more information, visit  A committee roster follows.



Lauren Rugani, Media Relations Officer

Rachel Brody, Media Relations Associate

Office of News and Public Information

202-334-2138; e-mail


Additional resources:

Full Report

Report in Brief


Pre-publication copies of Critical Aspects of EPA's IRIS Assessment of Inorganic Arsenic: Interim Report are available from the National Academies Press on the Internet at or by calling tel. 202-334-3313 or 1-800-624-6242.  Reporters may obtain a copy from the Office of News and Public Information (contacts listed above).


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Division on Earth and Life Studies

Board on Environmental Studies and Toxicology


Committee on Inorganic Arsenic

Joseph H. Graziano (chair)

Department of Environmental Health Sciences

Mailman School of Public Health

Columbia University

New York City


Habibul Ahsan

Louis Block Professor of Health Studies
Department of Health Studies

University of Chicago



Sandra J.S. Baird

Environmental Analyst
Office of Research and Standards

Massachusetts Department of Environmental Protection



Aaron Barchowsky

Department of Environmental and Occupational Health
Graduate School of Public Health

University of Pittsburgh



Hugh A. Barton

Associate Research Fellow

Pfizer Inc.

Groton, Conn.


Gary P. Carlson

Professor Emeritus of Health Sciences

Purdue University

West Lafayette, Ind.


Mary E. Davis

Department of Physiology and Pharmacology

West Virginia University

Morgantown, W.V.


Yvonne P. Dragan

Associate Director

Safety Assessment

AstraZeneca Pharmaceuticals

Waltham, Mass.


Rebecca C. Fry

Assistant Professor
Department of Environmental Sciences and Engineering

University of North Carolina

Chapel Hill


Chris Gennings

Professor of Biostatistics
Department of Biostatistics

Virginia Commonwealth University



Gary L. Ginsberg

Senior Toxicologist
Division of Environmental and Occupational

Health Assessment

Connecticut Department of Public Health


Margaret Karagas


Department of Community and Family Medicine

Geisel School of Medicine

Dartmouth College

Lebanon, N.H.


James S. MacDonald


Chrysalis Pharma Consulting LLC

Chester, N.J.


Ana Navas-Acien

Associate Professor
Department of Environmental Health Sciences

Bloomberg School of Public Health

Johns Hopkins University



Marie E. Vahter

National Institute of Environmental Medicine

Karolinska Institutet

Stockholm, Sweden


Robert O. Wright

Professor of Preventive Medicine

Mount Sinai School of Medicine

New York City




Susan N.J. Martel

Study Director