toxicological review of inorganic arsenic

429 Pages·2010·3.06 MB·English

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TOXICOLOGICAL REVIEW

OF

INORGANIC ARSENIC

(CAS No. 7440-38-2)

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

March 2009

NOTICE

This document is a final draft. This information is distributed solely for the purpose of pre-
dissemination peer review under applicable information quality guidelines. It has not been
formally disseminated by EPA. It does not represent and should not be construed to represent
any Agency determination or policy. It is being circulated for review of its technical accuracy
and science policy implications.
.

U.S. Environmental Protection Agency
Washington, DC
DISCLAIMER

This document is a final draft for review purposes only. This information is distributed solely
for the purpose of pre-dissemination peer review under applicable information quality
guidelines. It has not been formally disseminated by EPA. It does not represent and should not
be construed to represent any Agency determination or policy. Mention of trade names or
commercial products does not constitute endorsement or recommendation for use.

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TABLE OF CONTENTS – TOXICOLOGICAL REVIEW for INORGANIC ARSENIC
(CAS No. 7440-38-2)
1. INTRODUCTION ................................................................................................................. 1
2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS 3
2.1 PROPERTIES .............................................................................................................. 3
2.2 USES ............................................................................................................................ 4
2.3 OCCURRENCE ........................................................................................................... 4
2.4 ENVIRONMENTAL FATE ........................................................................................ 4
3. TOXICOKINETICS ............................................................................................................. 4
3.1 ABSORPTION ............................................................................................................ 5
3.2 DISTRIBUTION .......................................................................................................... 7
3.2.1 Transport in Blood ............................................................................................. 7
3.2.2 Tissue Distribution ............................................................................................ 9
3.2.3 Cellular Uptake, Distribution, and Transport .................................................. 11
3.3 METABOLISM ......................................................................................................... 13
3.3.1 Reduction ......................................................................................................... 16
3.3.2 Arsenic Methylation ........................................................................................ 17
3.3.3 Species Differences in the Methylation of Arsenic ......................................... 20
3.3.4 Thioarsenical Metabolites ............................................................................... 21
3.4 ELIMINATION ......................................................................................................... 22
3.5 PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS ............................... 23
4. HAZARD IDENTIFICATION .......................................................................................... 26
4.1 STUDIES IN HUMANS ............................................................................................ 26
4.2 PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN
ANIMALS—ORAL .................................................................................................. 52
4.2.1 Prechronic and Chronic Studies ...................................................................... 52
4.2.2 Cancer Bioassays ............................................................................................. 52
4.3 REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL ................................. 56
4.4 OTHER STUDIES ..................................................................................................... 56
4.4.1 Possible Modes of Action (MOAs) and Key Events of Possible Importance . 56

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4.5 SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS ......... 79
4.6 WEIGHT-OF-EVIDENCE EVALUATION AND CANCER
CHARACTERIZATION ........................................................................................... 79
4.6.1 Summary of Overall Weight-of-Evidence....................................................... 79
4.6.2 Synthesis of Human, Animal, and Other Supporting Evidence ...................... 80
4.6.3 Mode of Action Information ........................................................................... 84
4.7 SUSCEPTIBLE POPULATIONS AND LIFE STAGES .......................................... 87
4.7.1 Possible Childhood Susceptibility ................................................................... 87
4.7.2 Possible Gender Differences ........................................................................... 89
4.7.3 Other ................................................................................................................ 90
5. DOSE-RESPONSE ASSESSMENTS ................................................................................ 95
5.1 ORAL REFERENCE DOSE (RfD) ........................................................................... 95
5.2 INHALATION REFERENCE CONCENTRATION (RfC) ...................................... 95
5.3 CANCER ASSESSMENT (Oral Exposure) .............................................................. 95
5.3.1 Background: History of Cancer Risk Assessments for Arsenic .................... 95
5.3.2 Choice of Study/Data, Estimation Approach, and Input Assumptions ......... 104
5.3.3 Dose-Response Model Selection for Cancer Mortality in Taiwan ............... 104
5.3.4 Selection of Cancer Endpoints and Estimation of Risks for U.S. Populations
................................................................................................................................. 106
5.3.5 Non-Water Arsenic Intake and Drinking Water Consumption ...................... 107
5.3.6 Dose-Response Data ...................................................................................... 109
5.3.7 Risk Assessment Methodology ..................................................................... 110
5.3.8 Results ........................................................................................................... 114
5.4 CANCER ASSESSMENT (Inhalation Exposure) ................................................... 126
6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND
DOSE RESPONSE .................................................................................................................... 126
6.1 HUMAN HAZARD POTENTIAL .......................................................................... 126
6.2 DOSE RESPONSE .................................................................................................. 128
6.2.1 Choice of Models .......................................................................................... 130
6.2.2 Dose Metric ................................................................................................... 131
6.2.3 Human Population Variability ....................................................................... 131
7. REFERENCES .................................................................................................................. 133
APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC
COMMENTS AND DISPOSITION ........................................................................................ 173

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APPENDIX B: TABULAR DATA ON CANCER EPIDEMIOLOGY STUDIES............. 180
APPENDIX C. TABLES FOR STUDIES ON POSSIBLE MODE OF ACTION FOR
INORGANIC ARSENIC .......................................................................................................... 214
APPENDIX D. IMMUNOTOXICITY ................................................................................... 395
APPENDIX E. QUANTITATIVE ISSUES IN THE CANCER RISK ASSESSMENT FOR
INORGANIC ARSENIC .......................................................................................................... 401
E.1 Cancer Risk Assessment for the Taiwanese Population ......................................... 401
E.1.1 MLE Estimation of Dose-Response Parameters ........................................... 402
E.1.2 Estimation of Upper Confidence Limits (UCLs) on the Arsenic Dose-
Response Parameters ............................................................................................... 402
E.2 Estimation of Risk for U.S. Populations Exposed to Arsenic in Drinking Water ... 403
APPENDIX F. RISK ASSESSMENT FOR TOWNSHIPS AND LOW-EXPOSURE
TAIWANESE POPULATIONS ............................................................................................. 405
F.1 Recent Studies of the Taiwanese Populations that Do Not Find Consistent Exposure-
Response Relationships ........................................................................................... 405
F.2 Limitations of the Recent Studies ........................................................................... 406
F.3 Calculations of Risks for Township Groups ........................................................... 407
F.4 Calculation of Arsenic-Related Cancer Risks for Low-Exposure Villages ............ 409

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LIST OF TABLES

Table 2–1. Chemical and Physical Properties of Arsenic and Selected Inorganic Arsenic
Compounds (ATSDR, 2000; Merck Index, 1989) .................................................. 3
Table 4-1. Summary of Number of Rows Derived from Peer-reviewed Publications for
Different Hypothesized Key Events* ................................................................... 60
Table 5-1. Historical Summary of Arsenic Risk Assessment Efforts .................................... 98
Table 5-2. Cancer Mortality Data used in the Arsenic Risk Assessment ............................ 110
Table 5-3. Cancer Incidence Risk Estimates for Lung and Bladder Cancers in Males and
Femalesa .............................................................................................................. 115
Table 5-4. Combined Lung and Bladder Cancer Incidence Risk Estimate for the U.S.
Population (Males and Females) ......................................................................... 116
Table 5-5. Comparison of ED and LED a Estimates From Past Studiesb with Those from
01 01
the Current Analysis ........................................................................................... 117
Table 5-6. Comparison of Cancer Risk Assessment Results with Estimates from NRC
(2001), and U.S. EPA (2005c) ............................................................................ 119
Table 5-7. Drinking Water Intake and Body Weight Assumptions in Recent Arsenic Risk
Assessments ........................................................................................................ 119
Table 5-8. Sensitivity Analysis of Estimated Cancer Incidence Risks Associated with 10
μg/L to Changes in Modeling Assumptions and Inputs ...................................... 121
Table 5-9. Proportional Changes in Cancer Risks at 10 µg/L Associated with Changes in
Modeling Inputs and Assumptions ..................................................................... 122
Table B-1. Taiwan Cancer Studies ....................................................................................... 183
Table B-2. Japan Cancer Studies .......................................................................................... 197
Table B-3. South America Cancer Studies ........................................................................... 198
Table B-4. North America Cancer Studies ........................................................................... 203
Table B-5. China Cancer Studies .......................................................................................... 209
Table B-6. Finland Cancer Studies ....................................................................................... 210
Table B-7. Denmark Cancer Studies..................................................................................... 212
Table B-8. Australia Cancer Studies ..................................................................................... 213
Table C-1. In Vivo Human Studies Related to Possible Modes of Action of Arsenic in the
Development of Cancer ...................................................................................... 232
Table C-2. In Vivo Experiments on Laboratory Animals Related to Possible Modes of Action
of Arsenic in the Development of Cancer— Only Oral Exposures ................... 242
Table C-3. In Vitro Studies Related to Possible Modes of Action of Arsenic in the
Development of Cancer ...................................................................................... 267
Table D-1. Lymphocyte Counts and Labeling, Mitotic, and Replication Indexes (Mean ± SE)
in the Peripheral Blood Lymphocytes in Populations Exposed to Low (Control)
and High (Exposed) Levels of Arsenic (Gonsebatt et al., 1994) ........................ 396
Table F-1. Coefficients from Linear Regressions of Age-Adjusted Cancer Risk versus
Arsenic Doses for Townships Identified by Lamm et al. (2006) ........................ 409
Table F-2. Arsenic Dose Coefficients for Study Populations with Median Well Water
Arsenic Concentrations Less than 127 ppb ......................................................... 410

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LIST OF FIGURES

Figure 3–1. Traditional Metabolic Pathway for Inorganic Arsenic in Humans ....................... 14
Figure 3–2. Alternative Metabolic Pathway for Inorganic Arsenic in Humans Proposed by
Hayakawa et al. (2005) ......................................................................................... 15
Figure 3-3 Thioarsenical Structures ....................................................................................... 21
Figure 4-1. Level of Significant Exposure of Adult Mice to Sodium Arsenite in Drinking
Water in ppm As ................................................................................................... 64
Figure 5-1. Estimated Oral Slope Factors for Individual and Combined Cancer Endpoints 116
Figure 5-2. Change in Arsenic-Related Unit Risk Estimates Associated with Variations in
Input Assumptions .............................................................................................. 122
Figure F-1. Lifetime Crude Total Cancer Risk (Male + Female) for the Low- and High-
Exposure Villages ............................................................................................... 408

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FOREWORD
The purpose of this Toxicological Review is to provide scientific support and rationale
for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to inorganic
arsenic. It is not intended to be a comprehensive treatise on the chemical or toxicological nature
of inorganic arsenic.
The intent of Section 6, Major Conclusions in the Characterization of Hazard and Dose
Response, is to present the major conclusions reached in the derivation of the reference dose,
reference concentration and cancer assessment, where applicable, and to characterize the overall
confidence in the quantitative and qualitative aspects of hazard and dose response by addressing
the quality of data and related uncertainties. The discussion is intended to convey the limitations
of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk
assessment process.
For other general information about this assessment or other questions relating to IRIS,
the reader is referred to EPA s IRIS Hotline at [phone] (phone), [phone] (fax), or
=
[email protected] (email address).

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER/AUTHOR

Santhini Ramasamy, Ph.D., MPH, DABT
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC

OFFICE OF RESEARCH AND DEVELOPMENT CO-LEAD/AUTHOR

Reeder Sams, Ph.D.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC

AUTHORS

Robyn B. Blain, Ph.D.
Gregory M. Blumenthal, Ph.D.
William M. Mendez, Ph.D.
Welford C. Roberts, Ph.D.
ICF International
Fairfax, VA

Paul B Selby, Ph.D., DABT
RiskMuTox
Oak Ridge, TN

Arthur W. Stange, Ph.D.
Oak Ridge Associated Universities
Arvada, CO 80005

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Susan M. Wells, MPH.
Oak Ridge Associated Universities
Oak Ridge, TN 37831-0117

CONTRIBUTORS

Elizabeth Doyle, Ph.D.
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC

Jonathan Chen, Ph. D.
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, DC

Andrew Schulman, Ph.D.
Office of Enforcement and Compliance Assurance
U.S. Environmental Protection Agency
Washington, DC

Chao Chen, Ph.D.
National Center for Environmental Assessment,
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

Paul White, M.S.
National Center for Environmental Assessment,
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

Irene Dooley
Office of Water
U.S. Environmental Protection Agency
Washington, DC

Brenda Foos, Ph.D.
Office of Children's Health Protection
U.S. Environmental Protection Agency
Washington, DC

REVIEWERS
This document has been reviewed by EPA scientists, interagency reviewers from other

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