UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C. 20460

OFFICE OF THE ADMINISTRATOR

 SCIENCE ADVISORY BOARD

March 1, 2011

The Honorable Lisa P. Jackson

Administrator

U.S. Environmental Protection Agency

1200 Pennsylvania Avenue, N.W.

Washington, DC 20460

Subject: Review Comments on EPA’s Responsiveness to SAB 2007 Recommendations

 for the Revision of Cancer Assessment of Inorganic Arsenic

Dear Administrator Jackson:

The Science Advisory Board (SAB) received a request from the Office of Research and 

Development’s National Center for Environmental Assessment to evaluate and comment on

EPA’s implementation of the SAB 2007 recommendations regarding the revision of the cancer 

assessment of inorganic arsenic. In response, a work group of the chartered SAB was convened 

to review the agency’s document entitled, “Toxicological Review of Inorganic Arsenic: In 

Support of the Summary Information on the Integrated Risk Information System (IRIS),”

(EPA/635/R-10/001), focusing on three areas: evaluation of epidemiological literature, doseresponse modeling approaches, and the sensitivity analysis of the exposure assumptions used in 

the assessment. The SAB was not asked to conduct a full peer review of the assessment, 

including EPA’s calculation of the cancer unit risk estimate. This report has been approved by 

the chartered SAB.

The SAB commends the agency on its efforts to be responsive to our previous 

recommendations. In keeping with SAB practice, public comments were considered by the SAB 

during the development of this report. The SAB has made a number of recommendations to 

improve the clarity and transparency of the 2010 draft assessment and to strengthen the scientific 

basis of EPA’s findings and conclusions. Key recommendations are highlighted below.

In 2007, the SAB recommended the use of the epidemiologic data on the Taiwanese 

population for estimating bladder and lung cancer risk in humans from exposure to inorganic 

arsenic. The SAB also suggested that the agency consider other epidemiologic studies from the 

United States and other countries, utilizing a uniform set of evaluative criteria. On the basis of 

available data, the Taiwanese data set remains the most appropriate data set for determining the 
cancer risk from exposure to inorganic arsenic. EPA’s 2010 draft assessment presents a 

comprehensive overview of the epidemiological literature on arsenic carcinogenicity up to 2007;

however, it needs to state more clearly the set of criteria that EPA used in evaluating and 

presenting the studies. Where possible, the summaries of the epidemiology studies should

include a quantitative or qualitative presentation of the relative risk point estimates and the 

associated confidence intervals. Additionally, EPA should consider including an addendum or 

appendix describing major epidemiology studies that were published since 2007 and that could

substantially impact the calculated cancer unit risk estimate.

In 2007, the SAB noted that there was a possibility of a nonlinear dose-response at low 

exposures to arsenic, but due to the lack of a complete understanding of the mode-of-action by 

which inorganic arsenic causes cancer in humans, the choice of a specific nonlinear model could 

not be justified. The SAB supports the agency’s choice of using a default linear approach given 

the complexity of the mode-of-action of arsenic. Although extensive new research has been done 

in this area, there is not enough information in the literature to fully define the multiple modesof-action for arsenic carcinogenicity. 

The SAB, in 2007, also recommended that EPA consider using alternative dose-response 

models and perform a sensitivity analysis of the Taiwanese data with different exposure metrics. 

EPA’s 2010 draft assessment uses a default linear low-dose extrapolation and evaluates the 

differences between a linear model and three non-linear models: quadratic, quadratic exponential

and linear exponential. The SAB finds that, while the sensitivity analysis did respond to the 2007 

recommendation, a more detailed description of the data sets used in the risk model is needed. 

Providing the distribution of variability of arsenic concentrations in well water and the data and 

parameters used in the modeling would help to make EPA’s document more transparent. The 

SAB notes that, while EPA’s choice of a linear approach is consistent with EPA’s risk 

assessment default procedures, it has produced a calculated upper-bound cancer risk estimate for 

arsenic that is of significant public health concern. The SAB suggests that EPA discuss, possibly 

in other EPA complete risk assessment documents, how the estimated risks for arsenic should be 

interpreted in light of current estimated bladder and lung cancer incidence for the U.S. 

population. 

In 2007, the SAB recommended that the agency conduct sensitivity analyses to determine 

the potential impact of different choices of exposure assumptions (both water and non-water 

consumption) for estimating arsenic cancer potency. The SAB finds that the agency was partially 

responsive to the previous recommendations. The SAB recommends that the agency revise its 

assessment to provide a more detailed and transparent explanation of the scientific rationale for

its choice and use of alternative exposure assumptions. The SAB has also recommended ways to 

enhance the rigor and transparency of the sensitivity analysis for the exposure assessment 

through further documentation, explanation and analyses.

The SAB appreciates the opportunity to provide advice on EPA’s inorganic arsenic 

cancer assessment. We look forward to the upcoming review of the IRIS assessment of noncancer effects from arsenic exposure. The SAB underscores the importance of developing
integrated, interdisciplinary IRIS assessments and is amenable to conducting a future review of a 

synthesized assessment of arsenic health effects, as needed.

Sincerely,

/signed/ /signed/

Dr. Deborah L. Swackhamer, Chair Dr. Elaine Faustman, Chair

EPA Science Advisory Board SAB Arsenic Cancer Workgroup
i

NOTICE

This report has been written as part of the activities of the EPA Science Advisory Board, a public 

advisory committee providing extramural scientific information and advice to the Administrator and 

other officials of the Environmental Protection Agency. The Board is structured to provide balanced, 

expert assessment of scientific matters related to problems facing the Agency. This report has not 

been reviewed for approval by the Agency and, hence, the contents of this report do not necessarily 

represent the views and policies of the Environmental Protection Agency, nor of other agencies in the 

Executive Branch of the Federal government, nor does mention of trade names or commercial 

products constitute a recommendation for use. Reports of the EPA Science Advisory Board are posted 

on the EPA Web site at: http://www.epa.gov/sab. 
ii

U.S. Environmental Protection Agency

Science Advisory Board

Arsenic Cancer Review Work Group

CHAIR

Dr. Elaine Faustman, Professor, Department of Environmental and Occupational Health 

Sciences, School of Public Health and Community Medicine, University of Washington, Seattle, 

WA

MEMBERS

Dr. Timothy Buckley, Associate Professor and Chair, Division of Environmental Health 

Sciences, College of Public Health, The Ohio State University, Columbus, OH

Dr. Thomas Burke, Professor, Department of Health Policy and Management, Johns Hopkins 

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

Dr. Deborah Cory-Slechta*, Professor, Department of Environmental Medicine, School of 

Medicine and Dentistry, University of Rochester, Rochester, NY

Dr. George Daston, Victor Mills Society Research Fellow, Product Safety and Regulatory 

Affairs, Procter & Gamble, Cincinnati, OH

Dr. Agnes Kane, Professor and Chair, Department of Pathology and Laboratory Medicine, 

Brown University, Providence, RI

Dr. Nancy K. Kim, Health Research Inc., Troy, NY

Dr. Jana Milford, Professor, Department of Mechanical Engineering, University of Colorado, 

Boulder, CO

Dr. Eileen Murphy, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ

Dr. Stephen M. Roberts, Professor, Department of Physiological Sciences, Director, Center for 

Environmental and Human Toxicology, University of Florida, Gainesville, FL

SCIENCE ADVISORY BOARD STAFF

Dr. Sue Shallal, Designated Federal Officer, U.S. Environmental Protection Agency, Science 

Advisory Board Staff Office, Washington, DC

*SAB Board member from 2003-2010
iii

U.S. Environmental Protection Agency

Science Advisory Board

CHAIR

Dr. Deborah L. Swackhamer, Professor and Charles M. Denny, Jr., Chair in Science, 

Technology and Public Policy and Co-Director of the Water Resources Center, Hubert H. 

Humphrey School of Public Affairs, University of Minnesota, St. Paul, MN

SAB MEMBERS

Dr. David T. Allen, Professor, Department of Chemical Engineering, University of Texas, 

Austin, TX

Dr. Claudia Benitez-Nelson, Associate Professor, Department of Earth and Ocean Sciences and 

Marine Science Program, University of South Carolina, Columbia, SC

Dr. Timothy Buckley, Associate Professor and Chair, Division of Environmental Health 

Sciences, College of Public Health, The Ohio State University, Columbus, OH

Dr. Patricia Buffler, Professor of Epidemiology and Dean Emerita, Department of 

Epidemiology, School of Public Health, University of California, Berkeley, CA

Dr. Ingrid Burke, Director, Haub School and Ruckelshaus Institute of Environment and Natural 

Resources, University of Wyoming, Laramie, WY

Dr. Thomas Burke, Professor, Department of Health Policy and Management, Johns Hopkins 

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

Dr. Terry Daniel, Professor of Psychology and Natural Resources, Department of Psychology, 

School of Natural Resources, University of Arizona, Tucson, AZ

Dr. George Daston, Victor Mills Society Research Fellow, Product Safety and Regulatory 

Affairs, Procter & Gamble, Cincinnati, OH

Dr. Costel Denson, Managing Member, Costech Technologies, LLC, Newark, DE

Dr. Otto C. Doering III, Professor, Department of Agricultural Economics, Purdue University, 

W. Lafayette, IN

Dr. David A. Dzombak, Walter J. Blenko Sr. Professor, Department of Civil and Environmental 

Engineering, College of Engineering, Carnegie Mellon University, Pittsburgh, PA

Dr. T. Taylor Eighmy, Vice President for Research, Office of the Vice President for Research, 

Texas Tech University, Lubbock, TX
iv

Dr. Elaine Faustman, Professor, Department of Environmental and Occupational Health 

Sciences, School of Public Health and Community Medicine, University of Washington, Seattle, 

WA

Dr. John P. Giesy, Professor and Canada Research Chair, Veterinary Biomedical Sciences and 

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Dr. Jeffrey Griffiths, Associate Professor, Department of Public Health and Community 

Medicine, School of Medicine, Tufts University, Boston, MA

Dr. James K. Hammitt, Professor, Center for Risk Analysis, Harvard University, Boston, MA

Dr. Bernd Kahn, Professor Emeritus and Associate Director, Environmental Radiation Center, 

School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA

Dr. Agnes Kane, Professor and Chair, Department of Pathology and Laboratory Medicine, 

Brown University, Providence, RI

Dr. Madu Khanna, Professor, Department of Agricultural and Consumer Economics, University 

of Illinois at Urbana-Champaign, Urbana, IL

Dr. Nancy K. Kim, Senior Executive, New York State Department of Health, Troy, NY

Dr. Catherine Kling, Professor, Department of Economics, Iowa State University, Ames, IA

Dr. Kai Lee, Program Officer, Conservation and Science Program, David & Lucile Packard 

Foundation, Los Altos, CA

Dr. Cecil Lue-Hing, President, Cecil Lue-Hing & Assoc. Inc., Burr Ridge, IL

Dr. Floyd Malveaux, Executive Director, Merck Childhood Asthma Network, Inc., Washington, 

DC

Dr. Lee D. McMullen, Water Resources Practice Leader, Snyder & Associates, Inc., Ankeny, IA

Dr. Judith L. Meyer, Distinguished Research Professor Emeritus, Odum School of Ecology, 

University of Georgia, Lopez Island, WA

Dr. James Mihelcic, Professor, Department of Civil and Environmental Engineering, University 

of South Florida, Tampa, FL

Dr. Jana Milford, Professor, Department of Mechanical Engineering, University of Colorado, 

Boulder, CO

Dr. Christine Moe, Eugene J. Gangarosa Professor, Hubert Department of Global Health, Rollins 

School of Public Health, Emory University, Atlanta, GA
v

Dr. Horace Moo-Young, Dean and Professor, College of Engineering, Computer Science, and 

Technology, California State University, Los Angeles, CA

Dr. Eileen Murphy, Grants Facilitator, Ernest Mario School of Pharmacy, Rutgers University, 

Piscataway, NJ

Dr. Duncan Patten, Research Professor, Department of Land Resources and Environmental 

Sciences, Montana State University, Bozeman, MT

Dr. Stephen Polasky, Fesler-Lampert Professor of Ecological/Environmental Economics, 

Department of Applied Economics, University of Minnesota, St. Paul, MN

Dr. Arden Pope, Professor, Department of Economics, Brigham Young University, Provo, UT

Dr. Stephen M. Roberts, Professor, Department of Physiological Sciences, Director, Center for 

Environmental and Human Toxicology, University of Florida, Gainesville, FL

Dr. Amanda Rodewald, Professor, School of Environment and Natural Resources, The Ohio 

State University, Columbus, OH

Dr. Jonathan M. Samet, Professor and Flora L. Thornton Chair, Department of Preventive 

Medicine, University of Southern California, Los Angeles, CA

Dr. James Sanders, Director and Professor, Skidaway Institute of Oceanography, Savannah, GA

Dr. Jerald Schnoor, Allen S. Henry Chair Professor, Department of Civil and Environmental 

Engineering, Co-Director, Center for Global and Regional Environmental Research, University of 

Iowa, Iowa City, IA

Dr. Kathleen Segerson, Professor, Department of Economics, University of Connecticut, Storrs, 

CT

Dr. Herman Taylor, Professor, School of Medicine, University of Mississippi Medical Center, 

Jackson, MS

Dr. Barton H. (Buzz) Thompson, Jr., Robert E. Paradise Professor of Natural Resources Law at 

the Stanford Law School and Perry L. McCarty Director, Woods Institute for the Environment, 

Stanford University, Stanford, CA

Dr. Paige Tolbert, Professor and Chair, Department of Environmental Health, Rollins School of 

Public Health, Emory University, Atlanta, GA

Dr. John Vena, Professor and Department Head, Department of Epidemiology and Biostatistics, 

College of Public Health, University of Georgia, Athens, GA
vi

Dr. Thomas S. Wallsten, Professor and Chair, Department of Psychology, University of 

Maryland, College Park, MD

Dr. Robert Watts, Professor of Mechanical Engineering Emeritus, Tulane University, Annapolis, 

MD

Dr. R. Thomas Zoeller, Professor, Department of Biology, University of Massachusetts, 

Amherst, MA

SCIENCE ADVISORY BOARD STAFF

Dr. Angela Nugent, Designated Federal Officer, U.S. Environmental Protection Agency, 

Washington, DC
1

Table of Contents

EXECUTIVE SUMMARY ............................................................................................................ 2

Evaluation of epidemiological data ............................................................................................ 2

Mode-of-action and sensitivity analysis of dose-response modeling ......................................... 2

Exposure assessment and sensitivity analysis ............................................................................ 3

BACKGROUND ............................................................................................................................ 5

RESPONSES TO EPA’S CHARGE QUESTIONS ....................................................................... 6

Charge Question 1: ..................................................................................................................... 6

Response:.................................................................................................................................... 6

Charge Question 2: ..................................................................................................................... 8

Response:.................................................................................................................................... 9

Mode-of-action and dose-response modeling......................................................................... 9

Sensitivity Analysis................................................................................................................ 10

Charge Question 3: ................................................................................................................... 11

Response:.................................................................................................................................. 12

Other Comments ................................................................................................................... 17

REFERENCES ............................................................................................................................. 18

APPENDIX A - Minor edits......................................................................................................... 20
2

EXECUTIVE SUMMARY

Various committees have evaluated the assessment of cancer risk associated with 

exposure to inorganic arsenic. They include two National Research Council (NRC) committees 

(1999, 2001) and the EPA Science Advisory Board (SAB) in 2007. In 2010, EPA’s National 

Center of Environment Assessment (NCEA) within the Office of Research and Development 

(ORD) requested the SAB evaluate and comment on the agency’s implementation of the SAB 

recommendations in 2007 regarding EPA’s revision of the cancer assessment of inorganic 

arsenic. In response, a workgroup of the chartered Board reviewed EPA’s draft document 

entitled, “Toxicological Review of Inorganic Arsenic: In Support of the Summary Information on 

the Integrated Risk Information System (IRIS),” (EPA/635/R-10/001) and was asked to comment 

on three areas: evaluation of epidemiological literature; dose-response modeling approaches; and 

the sensitivity analysis of the exposure assumptions used in the risk assessment. The SAB was 

not asked to conduct a full peer review of the assessment, including EPA’s calculation of the 

cancer risk estimate. A summary of the SAB responses to EPA’s charge questions follows with 

further details included in the body of the report.

Evaluation of epidemiological data

The NRC in 1999 and 2001 concluded that ecological studies from the arsenic endemic 

area of Taiwan provide the best available empirical human data and are appropriate for use in 

dose-response assessment of arsenic in drinking water. In 2007, the SAB also supported the use 

of the epidemiologic data on the Taiwanese population for estimating human cancer risk for 

inorganic arsenic, especially to identify the potential range of responses of human populations. 

The SAB agrees with these previous findings and the draft 2010 assessment that, based 

on the current data, the Taiwanese data set remains the most appropriate data set for determining 

the population risk of cancer from exposure to inorganic arsenic. The SAB also notes that the 

EPA’s draft 2010 assessment includes a comprehensive listing of the epidemiological literature 

on arsenic and cancer up to 2007; however, the set of criteria that were used in evaluating the 

studies needs to be better presented. The SAB recommends that, where possible, the summaries 

of the epidemiology studies should include a quantitative or qualitative presentation of the 

relative risk point estimates for a specific exposure comparison and the associated confidence 

intervals. Furthermore, the SAB suggests that EPA consider including an addendum or appendix 

describing major epidemiology studies published since 2007 that could substantially impact the 

calculated cancer risk estimate.

Mode-of-action and sensitivity analysis of dose-response modeling

The NRC in 1999 and 2001 concluded that the available mode-of-action data on arsenic 

did not provide a biological basis for using either a linear or nonlinear extrapolation. In 2007, the 

SAB concluded that inorganic arsenic has the potential for a highly complex mode-of-action and 

until more was learned about the complex pharmacokinetic and pharmacodynamic properties of 
3

inorganic arsenic and its metabolites, there was insufficient justification for the choice of a 

specific nonlinear form of the dose-response relationship. 

The SAB concludes that there are multiple potential mechanisms for arsenic 

carcinogenicity and potential target tissues. The SAB notes that although a large amount of 

research is available on arsenic’s mode-of-action, the exact nature of the carcinogenic action of 

arsenic is not yet clear. Therefore, there is not enough information in the literature to define a 

mode-of-action for all of the relevant cancer endpoints for this assessment. The SAB 

recommends that this complexity and limited understanding of the mode-of-action of arsenic 

should be openly acknowledged in the 2010 draft assessment. 

In 2007, the SAB recommended that EPA consider using alternative dose-response 

models and perform a sensitivity analysis of the Taiwanese data with different exposure metrics, 

with the subgroup of villages with more than one well measurement and using a multiplicative 

model that includes a quadratic term for dose. The SAB finds that the sensitivity analysis of 

dose-response modeling presented in the 2010 draft assessment was responsive to the SAB 

previous recommendations. The SAB agrees with the conclusion that none of the alternative 

models (i.e., quadratic, quadratic exponential and linear exponential) evaluated by EPA 

materially changed the estimated risk levels versus use of a linear model. EPA also evaluated 

whether the models were inordinately affected by the high end of the dose-response curve and 

found that they were not. However, the SAB believes that more transparency and a better 

scientific rationale for the agency’s selection process are needed. To improve the clarity and 

transparency of the draft assessment, a number of aspects of the sensitivity analysis should be 

described in greater detail. They include the need for a more detailed description of the 

Taiwanese data sets used in developing the risk model; a better description of the distribution of 

well water arsenic concentrations across and within the 42 exposed villages; and a further 

explanation of the sensitivity displayed for female bladder cancer risks. The SAB notes that, 

while EPA’s choice of a linear approach is consistent with EPA’s risk assessment procedures, it 

has produced a calculated upper-bound cancer risk estimate for arsenic that is of significant 

public health concern. The SAB suggests that EPA discuss, possibly in other EPA complete risk 

assessment documents, how the estimated risks for arsenic should be interpreted in light of 

current estimated bladder and lung cancer incidence for the U.S. population. 

Exposure assessment and sensitivity analysis

The 1999 NRC report noted that the assessment of arsenic exposure via drinking water is 

often based on the measurements of arsenic concentrations in drinking water and assumptions 

regarding the amount of water consumed. The 2001 NRC report added that the method used to 

characterize arsenic dose in a study is a source of uncertainty in arsenic dose-response 

assessment. Furthermore, the NRC report noted that the choice of the dose measurement affects 

the interpretation of an epidemiological study and the choice of the dose-response model. The 

2007 SAB agreed that water consumption (via drinking water, in beverages, or in cooking water) 

assumptions could have an impact on the assessment of arsenic’s risk. However, the 2007 SAB 

did not recommend specific values for EPA to use in evaluating dose-response in the Taiwanese 

study nor for levels of exposure in the U.S. population risk estimates. It instead recommended
4

that uncertainty in exposure parameters be evaluated for both the Taiwanese study population 

and the U.S. populations through sensitivity analyses. The 2007 SAB recommended that EPA 

evaluate the drinking water consumption rate assumptions used with regard to highly exposed 

and sensitive subpopulations. Additionally, the NRC (2001) recommended that EPA consider the 

background dietary intake of inorganic arsenic and incorporate the adjustment values. The 2007 

SAB also concluded that arsenic levels in food are important considerations for EPA’s 

assessment of lung and bladder cancer risk associated with exposures to arsenic in drinking 

water. The 2007 SAB stated that a range of total arsenic food intake values should be included in 

the sensitivity analyses.

The SAB finds EPA’s revisions to the IRIS assessment to be partially responsive to SAB’s 

2007 recommendations regarding the exposure assumptions. The SAB provides two primary 

general suggestions for improving the responsiveness of the assessment; they include, making 

more transparent the scientific basis of the exposure assumptions used; and enhancing the rigor 

and transparency of the sensitivity analysis. The basic approach to the sensitivity analysis is 

adequate for meeting the minimum requirements for the intended purpose, and is responsive to 

the SAB recommendation in that the impact of choice of assumptions is shown in terms of 

specific cancer risks (lung and bladder, males and females). There are sufficient data to support 

development of variability and/or uncertainty distributions for some inputs, such as drinking 

water consumption rates in the United States, but the data are not available to assign 

corresponding distributions for the Taiwanese populations. 

The SAB notes that much of the documentation addressing the scientific basis of the 

exposure assumptions is available through separate documents (e.g. EPA Issues Paper, 2005d) 

that, if incorporated within the agency’s draft IRIS assessment, will help address the SAB’s 

concerns. The SAB recommends that relevant information from these documents be integrated 

within the current document as appropriate with the goal of enhancing transparency and 

scientific credibility. The SAB has provided specific suggestions, within the body of the report,

for making the scientific basis of the exposure assumptions used more transparent and for 

enhancing the rigor, and transparency, of the sensitivity analyses. 
5

BACKGROUND

Arsenic is a naturally occurring element that is found throughout the environment. 

Exposure to inorganic arsenic can result in different health outcomes depending upon the route 

of exposure. Arsenic compounds are used as a mordant in the textile industry, for preserving 

hides, as medicinals, pesticides, pigments, and wood preservatives. EPA’s health effects 

assessment for inorganic arsenic was first made available on the Integrated Risk Information 

System (IRIS) database in 1988. Various committees have reviewed aspects of the EPA’s revised 

assessment of cancer risk associated with exposure to inorganic arsenic. They include two

National Research Council (NRC) committees (1999, 2001) that concluded that the cancer risk 

for inorganic arsenic should be based on internal cancers (lung and bladder) instead of skin 

cancers. In 2005, the SAB was asked to review several EPA documents including:

• Office of Pesticide Programs’ (OPP) Draft Science Issue Paper: Mode-of-action for 

Cacodylic Acid (Dimethylarsinic Acid) and Recommendations for Dose Response 

Extrapolation (U.S. EPA OPP, 2005a) 

• Office of Research and Development (ORD) Issue Paper Cancer Risk Assessment for 

Organic Arsenical Herbicides: Comments on Mode of Action, Human Relevance and 

Implications for Quantitative Dose-Response Assessment (Appendix E of U.S. EPA OPP, 

2005, USEPA ORD, 2005b). 

• Office of Water’s (OW) Draft Toxicologic Review of Inorganic Arsenic (U.S. EPA OW, 

2005c). 

At that time, the SAB convened a panel of experts to provide advice on the metabolism, 

mode of action, dose-response, and approaches to low-dose extrapolation of cancer risk for 

Dimethylarsinic Acid (DMAV

) and inorganic arsenic (iAs). The SAB review report (EPA-SAB07-008) was issued in June 2007 and is available at 

http://yosemite.epa.gov/sab/sabproduct.nsf/02ad90b136fc21ef85256eba00436459/EADABBF40

DED2A0885257308006741EF/$File/sab-07-008.pdf.

In 2010, ORD’s National Center for Environmental Assessment (NCEA) requested the 

SAB evaluate and comment on EPA’s implementation of SAB (2007) key recommendations in 

the 2010 draft assessment entitled, “Toxicological Review of Inorganic Arsenic: In Support of the 

Summary Information on the Integrated Risk Information System (IRIS),” (EPA/635/R-10/001). 

In response to this request, the SAB convened a workgroup of the chartered Board to comment 

on the agency’s charge questions that focused on three areas: evaluation of epidemiological 

literature, dose-response modeling approaches, and the sensitivity analysis of the exposure 

assumptions used in the risk assessment. The SAB was not asked to conduct a full peer review of 

the assessment, including EPA’s calculation of the cancer risk estimate. The SAB workgroup 

held a public face-to-face meeting, on April 6-7, 2010, to discuss and deliberate on its responses 

to EPA’s charge questions. The chartered Board conducted a quality review of the work group’s

draft report (May 13, 2010) at a public teleconference on June 16, 2010 and a revised draft was 

again reviewed on November 22, 2010. The final SAB report incorporates the SAB quality 

review comments and public comments, both written and oral, which were received throughout 

the advisory process. 
6

RESPONSES TO EPA’S CHARGE QUESTIONS

Charge Question 1: 

The SAB concluded that the Taiwanese data set (Wu 1989; Chen et al., 1988, 1992) 

remains the most appropriate data set to determine carcinogenic risk due to exposure to iAs. 

They recommended that EPA should evaluate other published epidemiology studies using a 

uniform set of criteria and document these findings in the assessment. They also stated that if one 

or more studies provide potential utility, comparisons should be provided in the assessment. 

EPA agreed that the Taiwanese data were the best available for determining the 

carcinogenic risk due to exposure to iAs. In response to SAB’s recommendation, an extensive 

review and evaluation of all available human studies for iAs using the criteria suggested by the 

SAB was performed by EPA and is summarized in Section 4.1 of the draft IRIS assessment and 

included in tabular format in Appendix B. EPA concluded in the 2010 draft IRIS assessment that 

there were no additional epidemiological studies that had comparable utility to the Taiwanese 

data set (Wu 1989; Chen et al., 1988, 1992). 

Please comment on EPA’s response to the recommendations and the conclusions of the 

SAB (2007) Arsenic panel regarding the evaluation of the epidemiological literature.

Response:

In 1999, the NRC concluded that ecological studies from the arsenic endemic area of 

Taiwan provide the best available empirical human data for assessing the risks of arsenicinduced cancer. The 2001 NRC report also concluded that the data from southwestern Taiwan 

remain appropriate for use in dose-response assessment of arsenic in drinking water. In 2007, the 

SAB supported the use of the epidemiologic data on the Taiwanese population for estimating 

human cancer risk for inorganic arsenic especially to identify the potential range of responses of 

human populations. The 2007 SAB urged the agency to consider other epidemiologic studies 

from the United States and other countries, utilizing a uniform set of evaluative criteria, as they 

develop their risk assessment. The 2007 SAB recommended consideration of the following 

additional factors when reviewing the studies:

1. Estimates of the level of exposure misclassification; 

2. Temporal variability in assigning past arsenic levels from recent measurements; 

3. The extent of reliance on imputed exposure levels; 

4. The number of persons exposed at various estimated levels of waterborne arsenic; 

5. Study response/participation rates; 

6. Estimates of exposure variability; 

7. Control selection methods in case-control studies; and 

8. The resulting influence of these factors on the magnitude and statistical stability of risk 

estimates.
7

The SAB concludes that EPA has been responsive to the 2007 SAB recommendations in 

evaluating the epidemiology studies published through 2007. The 2010 draft IRIS assessment

presents a well organized and very comprehensive overview of the epidemiological literature on 

arsenic and cancer through 2007. The SAB recognizes that there are limitations that are inherent 

in the design of environmental epidemiological investigations, particularly regarding 

reconstruction of past exposure levels. EPA has described the limitations of each study in 

Section 4.1 of the draft IRIS assessment, and presented a summary of study strengths and 

limitations in the tables of Appendix B. The systematic review of the literature, however, needs 

to more clearly state the set of criteria that were used in evaluating the studies. Additional 

clarification and documentation on how various study design factors were considered and 

weighted in the evaluation are needed. In addition, there are aspects of studies that are discussed 

in Section 4.1 narrative that are not included in the summary table of Appendix B. The SAB

recommends that the tables in Appendix B be reformatted to present the study summaries more 

clearly and in a more consistent format including adding any essential information from 

references into the text for clarity.

The SAB supports the 2007 SAB conclusion that the Taiwanese data set (Wu 1989; Chen 

et al., 1988, 1992) remains the most appropriate data set for determining the population risk of 

cancer to exposure to inorganic arsenic. The limitations of the Taiwanese studies are well 

presented, particularly regarding the ecologic study design, use of death certificates, and 

assumptions regarding lifetime individual arsenic exposure. The strengths of these studies 

include availability of community drinking water exposure levels, large populations and personyears of follow-up, and consideration of important potential confounders including 

socioeconomic status, lifestyle, dietary patterns, and medical care. The SAB acknowledges the 

concerns expressed regarding the limitations of the Taiwanese data set; however given the 

fundamental mission of EPA to protect public health, these well conducted and extensively 

reviewed studies remain the most appropriate critical studies. 

The SAB received public comments that suggested when comparing the large number of 

epidemiological studies that demonstrate varying results the power calculations for the studies 

can provide important insights and should be taken into consideration. The power of an 

epidemiological study is the probability of detecting an association of a specified strength 

between exposure and disease if one exists. For example, in studies where statistical significance 

is not achieved, failure to identify an association may be a reflection of a limitation of the power 

of the study. The SAB, however, notes that while the relative power of various studies is important 

to convey, this should not be done by presenting only power calculations. Power calculations are 

useful in planning a study, but after the study is completed, the most informative presentation of 

epidemiologic findings that combines both the observed results and reflects the power of the study is 

the relative risk (RR) point estimates for a specified exposure comparison and the associated 

confidence intervals. Furthermore, systematic presentation of numbers of individuals in each 

exposure stratum provides the reader with a sense of relevant sample size within strata and the 

robustness of the exposure contrast. While a restricted range of exposure within a study population 

will limit estimation, it is also likely that studies carried out at a lower-level of exposure will be 

estimating an effect smaller than that at higher levels for a categorical comparison of higher-exposed 

to lower-exposed. For instance, the required sample size should be larger when a smaller range of 

exposures is observed (e.g., the U.S. studies), since the expected magnitude of the RR for low-level 

exposure is lower. The SAB also recognizes that many published arsenic studies may not present 
8

specific power calculations or RR and that a detailed quantitative comparison is difficult. Where 

possible, the summaries of the epidemiology studies should include a quantitative or qualitative 

presentation of the relative risk point estimates for a specific exposure comparison and the 

associated confidence intervals. This should be included both in the study descriptions in Section 

4.1 and in the table of studies in Appendix B.

As noted by public comments, the SAB agrees that failure to control potential 

confounders or misclassification of study population exposure levels may bias study results. In 

the presentation of one of the critical epidemiology studies (Chen et al. 1992), the IRIS 

assessment (p.38) states, “a weakness of the study is the assumption that an individual’s arsenic 

intake remained constant from birth to the end of the follow-up period; this flaw possibly led to 

the underestimation of risk.” Other epidemiological studies also had similar issues. Indirect 

measures of individual exposure were used to estimate population exposure levels for all of the 

epidemiology studies. In Section 4.1, the narrative presenting the epidemiology studies should 

include a more detailed discussion of bias including literature citations addressing the potential 

for bias, both underestimating and overestimating of risk, due to confounders or limitations in 

exposure estimation. While the existence of bias can usually be proposed with some certainty, the 

key issue is whether the quantitative consequences of bias are of sufficient magnitude to be of 

concern. Methods are available for this purpose (see, for example: Lash, Fox, and Fink: Applying 

Quantitative Bias Analysis to Epidemiological Data, Springer, 2009). The SAB suggests that the 

IRIS assessment include a simple table that identifies potential biases (misclassification of 

exposure, misclassification of disease, omitting potential confounders, etc.) and the potential 

magnitude and direction of bias in inferences that are drawn from the study data. A simple 

summary could then relate these sources of bias to their impact in the data and methods used in the 

IRIS assessment.

The IRIS 2010 assessment includes an extensive review of published epidemiology 

studies up to and including the year 2007. The SAB recognizes that the assessment cannot be 

continually updated with every newly published paper and it is not the purpose of IRIS to 

provide real time summaries of advancing science. However, given the large amount of ongoing 

research on the health effects of arsenic, the SAB has concerns about the 2007 cutoff. In order to 

ascertain if new studies will impact the 2010 assessment, EPA should consider including an 

addendum or appendix describing major epidemiology studies published since 2007 (i.e., those 

studies that can influence the dose-response assessment due to large sample size or effect estimate 

that is substantially different from that estimated by Chen et al. (1988, 1992).

Charge Question 2: 

The SAB noted the possibility of a nonlinear dose-response at low exposures, but due to 

uncertainty in the mode-of-action (including pharmacokinetics and dynamics) the use of a linear 

low dose extrapolation approach to determine the cancer risk for iAs was recommended using 

cancer incidence from the Taiwanese data set. In addition, the SAB stated that EPA should 

perform a sensitivity analysis for the variables in the cancer modeling with respect to the 

Taiwanese data set (i.e., exposure metrics, subgroup of villages with more than one well 

measurement, and a multiplicative model that includes a quadratic term for dose). The SAB 
9

concluded that overall, EPA had implemented the recommended modeling by NRC (2001). Also, 

the SAB made recommendations to perform a sensitivity analysis regarding the robustness of the 

model and alternative formulations. 

Consistent with the SAB recommendations, EPA used a linear low-dose extrapolation 

approach and conducted a sensitivity analysis of nonlinear forms of the dose-response in the 

2010 draft IRIS assessment. EPA also explored nonlinear forms of the dose-response from the 

Taiwanese data set (Wu 1989; Chen et al., 1988, 1992). Sensitivity analyses using alternative 

dose-response models produced potency estimates similar to the linear approach. 

Please comment on EPA’s response to the SAB’s recommendations and conclusions 

regarding the approach to modeling inorganic arsenic cancer risks and the corresponding 

sensitivity analyses. 

Response:

Mode-of-action and dose-response modeling

The 1999 NRC Committee concluded that the mechanism or mode-of-action by which 

inorganic arsenic causes toxicity, including cancer, is not well established. This conclusion was 

again supported by the NRC in 2001 which noted that although a large amount of research is 

available on arsenic’s mode-of-action, the exact nature of the carcinogenic action of arsenic is 

not yet clear. Therefore, the 2001 NRC report concluded that the available mode-of-action data 

on arsenic did not provide a biological basis for using either a linear or nonlinear extrapolation.

In 2007, the SAB concluded that inorganic arsenic has the potential for a highly complex 

mode-of-action and until more is learned about the complex pharmacokinetic and 

pharmacodynamic properties of inorganic arsenic and its metabolites, there is not sufficient 

justification for the choice of a specific nonlinear form of the dose-response relationship. The

NRC (2001) concluded that the most appropriate approach was to base risk assessments on a 

linear dose response model that includes the Southwestern Taiwan population as a comparison 

group.

The SAB agrees that there are multiple potential mechanisms for arsenic carcinogenicity 

and potential target tissues which make it very difficult to do a single risk assessment model. 

This complexity and limited understanding of the mode-of-action of arsenic should be openly 

acknowledged in the 2010 draft IRIS assessment. While there is an ever increasing literature on 

arsenic, there is not enough information in the literature to define a mode-of-action for all of the 

relevant cancer endpoints for this assessment. The SAB notes that it is a reasonable hypothesis 

that bladder cancer is the result of repeated cell injury, cell death and compensatory proliferation;

but there is not enough specific data at this point to confirm the hypothesis, nor are there 

hypotheses to explain the role of arsenic in lung cancer. For these reasons, the SAB concurs with

EPA’s rationale for choosing a linear default approach for risk assessment.
10

Sensitivity Analysis

The 2007 SAB recommended that EPA perform a sensitivity analysis of the Taiwanese 

data with different exposure metrics, with the subgroup of villages with more than one well 

measurement and using a multiplicative model that includes a quadratic term for dose. The SAB

finds that the sensitivity analysis of dose-response modeling presented in the 2010 IRIS 

assessment was responsive to the previous 2007 SAB recommendations. Specifically, EPA was 

asked to evaluate a model using a quadratic term for dose. EPA evaluated the differences 

between a linear model and three non-linear models: quadratic, quadratic exponential and linear 

exponential. Results are described on p. 143, which concludes that “within the range of 

exposures covered by the epidemiological data, the alternative forms predict very similar risks.” 

It would be very helpful if the results could be shown graphically, e.g., by showing the doseresponse data and model dose-response curves for selected endpoints and age and gender classes. 

The SAB agrees with the conclusion that none of the alternative models materially changed the 

estimated risk levels versus use of a linear model. EPA also evaluated whether the models were 

inordinately affected by the high end of the dose-response curve. They were not. This was 

evaluated by running the models without the highest exposure group. EPA evaluated whether 

exclusion of a reference population influenced the dose-response curve. Results of this analysis 

(see Fig. 5-2) suggest that exclusion of the reference population did have an effect on risk 

estimates. EPA evaluated the pros and cons of including a comparison population in a 2005 

issues paper (Issue Paper: Inorganic Arsenic Cancer Slope Factor, Final Draft, July 23, 2005). 

The SAB recommends that the rationale from the issue paper be included in the draft IRIS 

assessment, and the reference population described in greater detail. This will provide more 

transparency and strengthen the scientific rationale for the agency’s selection process.

To improve the clarity and transparency of the draft IRIS assessment, there are a number 

of aspects of the sensitivity analysis that should be described in greater detail. They include:

• More detailed description of underlying data. The assessment would benefit from a 

more detailed description of the Taiwanese data sets used in developing the risk model. 

The data sets are briefly described in section 4.1.1 as part of the review of the Chen et al. 

1988a, 1992 and Wu et al., 1989 studies, and key features are summarized in Table B-1. 

However, readers are required to piece together this information on their own in order to 

understand the basis for the risk modeling presented in section 5.3. 

• Variability of well water arsenic concentrations. The distribution of well water arsenic 

concentrations across and within the 42 exposed villages is not adequately described. 

Only medians and ranges across the whole set of villages are presented in Table B-1. 

While the assessment mentions that the number ranged from 2 – 47 measurements, the 

variability of measurements both within and across wells within a given village is not 

provided. This information needs to be presented to assist in understanding the results of 

the sensitivity analysis the 2007 SAB requested. It would also be helpful to see a more 

quantitative characterization of how the 1974-1976 well water re-testing results differed 

from the results of tests conducted in 1962-1964, on which the risk modeling relied. 

Table B-1 indicates the results were “similar”; however, it is not clear how to interpret 

this. 
11

• Upper and lower limits in water concentration. EPA responded to SAB’s request for 

sensitivity analysis or Monte Carlo analysis with respect to well water concentrations in 

the villages with more than a single measurement by re-estimating the model using 

minimum and maximum values of the concentrations for each village. Table 5-10 

indicates the effect (in terms of estimated cancer incidence) is up to about a ± 30% 

change. Although EPA used upper and lower limits, rather than low and high percentile 

values or Monte Carlo analysis as SAB had suggested, the sensitivity analysis responds 

adequately to the recommendation. As noted above, however, more information on the 

variability in the underlying water concentration data is needed to substantiate the 

reported models and results.

 

• Modeling data and parameters. The SAB suggests that EPA publish the data and 

parameter tables used in its modeling analysis. As requested by the 2007 SAB report, this 

would strengthen the scientific credibility and transparency in the assessment.

• Selection of a reference population. EPA has tested the sensitivity of the risk model 

with respect to the choice of reference population (southwest Taiwan, all Taiwan, or no 

reference population) and to the value of non-water arsenic intake (i.e., in accordance 

with EPA’s document, this refers to food intake) for both reference and exposed 

populations. Results indicate that the cancer incidence risks are fairly robust, with the 

exception of female bladder cancer risks. The sensitivity displayed for female bladder 

cancer risks seems to warrant further explanation – the result is described, but not 

explained, in the accompanying text (pp. 141-2). Additionally, EPA should examine

whether any combinations of these parameter variations will affect the assessment– e.g., 

using different non-water intake values in combination with a different reference 

population.

The SAB notes that there is tremendous interest in the risk associated with consumption 

of water that is contaminated with inorganic arsenic and suggests that EPA discuss how their 

results should be interpreted in light of existing population-level data on bladder and lung cancer 

risk for exposure levels that are relevant for U.S. populations. The idea of providing a “reality 

check” on the estimated risk levels was discussed. The SAB recognizes that IRIS toxicological 

reviews are not intended to provide a complete risk assessment but rather a summary and 

synthesis of the toxicological evidence that supports risk assessment. Hence, an estimation of 

risk attributable to arsenic in drinking water in U.S. populations versus the observed incidence of 

cancer is not appropriate within the purview of this document. The SAB considers this as a 

difficult but important exercise and recognizes that this is probably better suited for inclusion in 

other risk assessment and characterization documents developed by the agency.

Charge Question 3: 

The SAB did not recommend specific values for the exposure assumptions or parameters 

used in the cancer model. They did, however, recommend evaluating the impact on the cancer 
12

risk of using a range of values, assessing the variability, and conducting a sensitivity analysis for 

exposure parameters (e.g., water intake, background dietary exposure). 

EPA evaluated the impact on the estimated cancer risk of using a range of exposure 

parameter values (e.g., water intake, background dietary exposure), assessed variability, and 

conducted a sensitivity analysis. After the completion of these analyses, values were chosen for 

exposure assumptions based upon the best available science taking into account the NRC (2001) 

recommendations. 

Please comment on EPA’s sensitivity analyses and choice of the exposure assumptions used 

in modeling cancer risk as recommended by the SAB (2007) Arsenic panel. 

Response: 

The 1999 NRC report noted that assessment of arsenic exposure via drinking water is 

often based on the measurements of arsenic concentrations in drinking water and assumptions 

regarding the amount of water consumed. Such data are estimates, the uncertainty of which will 

depend on the method used. The 2001 NRC report added that the method used to characterize 

arsenic dose in a study is a source of uncertainty in arsenic dose-response assessment. 

Furthermore, the NRC report noted that the choice of the dose measurement affects the 

interpretation of an epidemiological study and the choice of the dose-response model.

The 2007 SAB agreed that water consumption (via drinking as water, in beverages, or in 

cooking water) assumptions have a substantial impact on the assessment of arsenic’s risk. 

However, the 2007 SAB did not recommend specific values for EPA to use in evaluating doseresponse in the Taiwanese study nor for levels of exposure in the U.S. population risk estimates. 

It did recommend that uncertainty in this parameter be evaluated for both the Taiwanese study 

population and the U.S. populations at risk. The 2007 SAB recommended that EPA should: 

1) Evaluate the impact of drinking water consumption rates associated with more highly 

exposed population groups with differing exposures and susceptibilities (e.g., children, 

pregnant women); 

2) Incorporate variability parameters for individual water consumption into their analysis for 

dose-response in the Taiwanese population as they have done for the U.S. population; 

3) Conduct sensitivity analyses of the impact of using a range of consumption values for the 

Taiwanese population; 

4) Provide a better justification for assuming different consumption levels by gender or in the 

absence of such a justification, conduct additional sensitivity analyses to examine the impact 

of equalizing the gender-specific consumption level; 

5) More fully articulate and document how different sources of water intake, as well as 

variability, are incorporated into the risk model (e.g. data for intake from beverages and 

cooking water). 

The NRC (2001) recommended that EPA consider the background dietary intake of 

inorganic arsenic and incorporate the adjustment values of 0, 10, 30, and 50 μg per day into the 
13

cancer risk calculations. The 2007 SAB also agreed that arsenic levels in food are important 

considerations for EPA’s assessment of lung and bladder cancer risk associated with exposures 

to arsenic in drinking water. However, the 2007 SAB once again did not recommend a specific 

value for EPA to use in its base risk assessment. It did recommend a range of values for 

consideration by EPA in its sensitivity analysis and the 2007 SAB offered suggestions to EPA 

for additional analytical steps to clarify the impact of food levels of arsenic on dose-response and 

exposure as it revises its risk estimates. The 2007 SAB recommended that EPA should: 

1) Conduct sensitivity analyses using a range of total arsenic food intake values from at least 

50 to 100 μg per day to perhaps as high as 200 μg per day to assess the impact of this range 

of dietary intakes on risk of lung and bladder cancer from exposure via drinking water in the 

Taiwan cohort; 

2) Not assume that the control population has an intake value of zero arsenic from food; 

3) Apply greater rigor in their discussions of data used in these assessments (e.g., sources, 

methodological and analytical issues, bioavailability); and 

4) Give immediate research attention to the issue of arsenic bioavailability.

The SAB finds EPA’s revisions to the IRIS assessment to be partially responsive to the 

2007 SAB recommendations regarding the sensitivity analyses and choice of the exposure 

assumptions used in modeling cancer risk. The SAB provides two primary general suggestions

for improving the responsiveness of the assessment. They include, making more transparent the 

scientific basis of the exposure assumptions used and enhancing the rigor and transparency of the 

sensitivity analysis. 

The basic approach to the sensitivity analysis is adequate for meeting the minimum 

requirements for the intended purpose, and is responsive to the 2007 SAB recommendation in 

that the impact of choice of assumptions is shown in terms of specific cancer risks (lung and 

bladder, males and females). In evaluating the consequences of choices regarding modeling 

assumptions and intake values, the IRIS assessment states, “The agency felt that the currently 

available data were insufficient to support detailed probabilistic uncertainty and variability 

estimation.” The SAB agrees with this conclusion. There are sufficient data to support 

development of variability and/or uncertainty distributions for some inputs, such as drinking 

water consumption rates in the United States, but the data are not available to assign 

corresponding distributions for the Taiwanese populations.

The SAB notes that much of the documentation addressing the scientific basis of the 

exposure assumptions was available through separate documents (e.g. EPA Issues Paper, 2005d) 

that if incorporated within the current assessment, will help address the SAB’s concerns. The 

SAB recommends that relevant information from these documents be integrated within the 

current document as appropriate with the goal of enhancing transparency and scientific 

credibility.

The SAB is providing the following specific suggestions for making the scientific basis 

of the exposure assumptions used more transparent and enhancing the rigor and transparency of 

the sensitivity analysis. 
14

• Better explanation of what the sensitivity analysis shows. The sensitivity analyses 

presented offer insight as to how the cancer potency estimates change as drinking water 

consumption and non-water arsenic intake assumptions change. The various non-water 

arsenic intake rate assumptions produced modest changes in risk, with the exception of 

bladder cancer risk in females. This calculated risk was very sensitive to the non-water 

intake rate assumption. The assessment and this analysis will be strengthened by 

providing a short explanation for why this is the case. 

• Need for better justified default assumptions. Despite some effort to discuss drinking 

water consumption rates and sources of information for non-water arsenic intake rates, 

the reasons for some of the specific values chosen to be included in the sensitivity 

analyses are not clearly justified. For example, the “default” drinking water consumption 

rate for Taiwanese males is 3.5 L/day, citing precedent from U.S. EPA (1988), Chen et 

al. (1992), and NRC (1999 and 2001). For the sensitivity analysis, alternative values of 

2.75, 3.0, and 5.1 L/day were evaluated [along with alternative values for Taiwanese 

females]. No rationale is provided for these specific numbers, other than they are thought 

by the agency to span a “reasonable range of values” (see page A-6). To enhance

transparency in this example, it would be helpful to know the scientific basis for selecting

the lowest and highest numbers (defining the range). Also, if the intent was to illustrate 

effects at the boundaries of the range of drinking water consumption rates, it is unclear 

why the lowest estimate for males (2.75 L/day) was not consistent with the lowest 

estimate for females (2.0 L/day) (see Table 5-10), especially given the SAB’s request to 

justify different consumption values for men and women. Furthermore, no values for 

drinking water consumption rates for Taiwanese women were evaluated below the 

“default” rate of 2.0 L/day, suggesting that the value selected by the agency is at the limit 

of the range of reasonable values for this parameter. The effects on risk were determined 

based on assumptions that both the reference and exposed populations had non-water 

intake rates of 0, 30, and 50 μg/day arsenic. Although compliant with SAB’s 2007 

recommendations, better discussion of dietary intake of inorganic arsenic would help the 

reader understand whether the various values included in the analysis represent different 

interpretations of the existing data, bounding estimates, or something else.

• Consider additional permutations of gender-specific water consumption. The 2007 

SAB recommended: “Because data on gender differences in consumption in Taiwan are 

limited, a better justification for assuming different consumption levels by gender is 

needed, particularly given the lack of sex difference in consumption in United States and 

observed in studies from other countries (Watanabe et al., 2004). In the absence of such a 

justification, the SAB recommends an additional sensitivity analysis to examine the 

impact of equalizing the gender-specific consumption level.” The agency complied with 

this recommendation to some extent, evaluating the effect on risk of setting the drinking 

water consumption rate for both Taiwanese males and females at 2.75 L/day in the 

sensitivity analysis. However, the basis for the choice of this particular drinking water 

consumption rate is not explained. Also, by examining a single drinking water 

consumption rate for both sexes, the influence of selection of different rates on resulting 

risk is not illustrated. In order to be responsive to the 2007 SAB recommendation, 
15

discussion of the impact of using a single drinking water consumption rate for males and 

females for the Taiwanese populations needs to be justified and expanded. 

• Need to clearly delineate the basis for water concentration assumptions. Based on the 

data in tables 5-10 and 5-11, it isn’t clear if EPA has completed the calculations that the 

SAB requested. Those tables noted that the sensitivity analyses used minimum and 

maximum village water arsenic concentration values. It isn’t clear if only the villages 

with more than one well measurement were used or if all the villages were used. EPA 

needs to clarify the water concentration assumptions. This recommendation is also 

consistent with recommendations under charge question #2. 

• Need to address water consumption rates of susceptible groups. The 2007 SAB 

recommended that the “EPA should evaluate the impact of drinking water consumption 

rates associated with more highly exposed population groups with potentially different 

exposures and susceptibilities (e.g. children, pregnant women) in its arsenic exposure 

estimates as the agency determines the overall effects of drinking water consumption 

rates on arsenic risk.” In the current 2010 draft IRIS assessment, the impact of drinking 

water consumption rates associated with more highly exposed population groups with 

potentially different exposures and susceptibilities (e.g. children, pregnant women) in its 

arsenic exposure estimates has not been evaluated. During the April meeting, the agency

indicated that including these populations in the sensitivity analysis would be difficult 

and of limited value. So that the response to this 2007 SAB comment is clear, an 

explanation of why this aspect of the sensitivity analysis was not conducted should be 

included in Appendix A.

• More complete and graphical analysis. EPA has responded to the 2007 SAB’s 

suggested sensitivity analysis with the development of Tables 5-10 and 5-11 along with 

Figure 5-2 showing the influence of various exposure assumptions including water 

arsenic concentration, non-water arsenic intake, and water consumption on various cancer 

endpoint risks. The tables and figure are efficient in providing a “snapshot” of their 

influence for various assumed point estimates; however, a more complete description of 

their influence can be shown by graphing across the range of plausible values. 

Admittedly, the graphical representation will be less efficient (i.e., require more space) 

but will provide a more complete depiction. To the extent possible, it would be useful to 

illustrate on these graphs the various historically and currently “assumed” values. 

• Testing the effects of layered assumptions. To further respond to the 2007 SAB’s 

recommendation, EPA tested the effects of changing assumptions one at a time. This 

approach is necessary to clearly show how individual values potentially affect cancer 

potency and risk. This approach does not, however, indicate how changes in assumptions 

might interact to produce overall changes in potency and risk. Testing all of the various 

permutations of changes in assumptions in a sensitivity analysis would be arduous and of 

dubious value. Nevertheless, it may be instructive to examine selected sets of exposure 

assumptions and their effect on cancer potency. This would provide an indication of the 

extent to which a reasonable range of exposure assumptions in the aggregate has the 

potential to affect cancer potency estimation.
16

• Clarification of what the exposure assumptions are intended to represent. It is often 

unclear in the assessment whether the exposure assumptions (e.g., drinking water 

consumption rate) selected are intended to represent best estimates of the mean for the 

exposed population, upper confidence estimates of the mean, upper percentile values, 

upper confidence limit estimates of an upper percentile value, or something else. This 

should be specified in the IRIS assessment. During the April meeting, the agency

indicated that different types of assumptions may be appropriate for different values. The 

rationale for why a particular value is used should be provided in the IRIS assessment. 

For example, why an upper percentile drinking water ingestion rate is appropriate for the 

U.S. population, while an average (or upper bound average) assumption is used for the 

Taiwanese population. 

• The bases for the exposure assumptions selected are not adequately described. The 

SAB in 2007 stated, “Much greater rigor needs to be applied in discussing and presenting 

documented data sources and making clear the basis on which assumptions are being 

made and the relative strength of those assumptions.” That criticism applies to the 2010 

version of the IRIS assessment as well. Some examples include:

o For non-water arsenic intake, EPA has selected an assumed intake value of 10 μg/day. 

Discussion in support of this selection occurs on pgs. 123-124 of the revised 

assessment and is based on six references including US EPA (1989), Schoof et al. 

(1998), Yost et al. (1998), NRC (1999), NRC (2001), and EPA (2005c). Of these, 

there are only two references that relate to the peer-reviewed primary literature, 

reflecting the scarcity of data from which to base this estimate. Although EPA does a 

reasonable job of discussing these reports, the current assessment lacks a specific 

rationale or justification for the selected value. It appears that the US EPA 1989 

reference supporting an intake range of 2 μg/day to 16 μg/day may provide the 

rationale for this selection. Since this reference is not easily available, the SAB 

recommends that within the IRIS assessment a more complete discussion of data and 

evidence supporting this intake range be provided in a manner similar to what has

been provided for Schoof et al. 1998 and Yost et al. 1998. In the current assessment, 

it is unclear what the 2 to 16 μg/day estimate is based on. Moreover, the current 

assessment does not provide a specific justification or rationale for this selection, but 

rather makes a broad statement “Based on available information, EPA selected 10 μg

/day as the best estimate for non-water arsenic intake (food sources) in baseline 

calculations.” The selection of this value can be strengthened by: 1) elaborating on 

the lack of data or evidence upon which to base this estimate; 2) distinguishing 

between evidence that is primary (i.e., peer-reviewed with data collection) and reports 

that provide expert assessment, and 3) providing specific and scientific justification 

for the selected value that can be traced to the primary literature. Again, because of 

the effect this parameter has on the risk estimates, providing support for the values 

chosen for this parameter is important.

o The current dose-response assessment is based on an assumed water intake value of 

3.5 and 2.0 L/day for men and women, respectively. As with the assumed values for 
17

non-water intake above, justification for these values can be strengthened by 

establishing a clear link to data within the primary literature where possible. The 

specific relevant findings from Chen et al. 1992 and Chowdhury et al. 2001 should be 

provided in relation to the selected values. In the current assessment, it appears that 

EPA justified the selected values largely based on precedent (e.g., EPA and NRC 

reports) rather than on the data reported in the primary literature. It is unclear why 

EPA did not base their estimate on the data of Chowdhury et al. 2001 since it is 

unique and relevant. No discussion is provided of the data available from Chen et al. 

1992. To the extent that EPA relies on previous EPA and NRC assessments, the link 

to the primary data (if available) should be maintained. The problem illustrated by the 

2010 assessment is that these assumed values take on a life of their own and the 

evidence upon which they are based is lost, i.e., the scientific basis for the 

assumptions is no longer discernible.

• The reason for limiting non-water intake to dietary sources is not explained. Nonwater exposure is currently assumed to consist entirely of arsenic in the diet. For 

completeness and transparency, EPA should provide a short description of alternate 

routes of exposure (e.g. inhalation, non-dietary ingestion, dermal absorption) from other 

media such as soil and include arsenic intake estimates using EPA's routine exposure 

assumptions for both the Taiwan and the U.S. populations; EPA should provide 

justification for why these other exposures were not considered in the current doseresponse assessment. If the reason is that other pathways are assumed to be minor relative 

to arsenic intake from diet, some illustration of this should be provided as justification.

Other Comments

• More clear delineation of organic vs. inorganic exposure assumptions. It would be 

helpful to provide a paragraph for IRIS users explaining why the organic arsenic 

compounds do not affect the risk estimates for inorganic arsenic. The explanation will 

probably be fairly straight forward for the seafood organic arsenic compounds. This may 

not be as straight forward for any organic arsenic compound in produce (e.g. rice, etc.). 

As a related comment, when discussing non-water arsenic intake care should be taken to

distinguish between inorganic and organic or total arsenic in food. The current draft 

assessment is in some places ambiguous, referring simply to “arsenic.” (see pages 123-

124).

• Value in identifying research gaps. Given the importance and scarcity of data for 

purposes of estimating exposure, the SAB suggests that EPA provide a short paragraph 

describing the research needs along with suggested designs to produce credible estimates 

for water and non-water intake rates. The research needs are not only to provide point 

estimates, but data for distribution analysis to support the more credible stochastic 

approaches to risk estimation. Maybe 10 years from now, we will not find ourselves in 

the position that we are in now of relying on largely the same sparse/inadequate data for 

risk estimation that we were in 10 years ago. 
18

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19

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20

APPENDIX A - Minor edits

• Pages 139 and 140: Providing some information in these tables about the range in village 

water arsenic concentrations would be useful.

• Type in footnote for Table 5-11. Table 5-8 should probably be Table 5-10.

• Page 141, line 27. Tables 5-6 and 5-9 should be Tables 5-10 and 5-11

• Page 142 – line 3. Should both increased and decreased be there?