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TOXICOLOGICAL REVIEW of INORGANIC ARSENIC (CAS No DRAFT—DO NOT CITE OR QUOTE EPA/635/R-10/001 www.epa.gov/iris TOXICOLOGICAL REVIEW OF INORGANIC ARSENIC (CAS No. 7440-38-2) In Support of Summary Information on the Integrated Risk Information System (IRIS) February 2010 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. ii DRAFT—DO NOT CITE OR QUOTE TABLE OF CONTENTS—TOXICOLOGICAL REVIEW of INORGANIC ARSENIC (CAS No. 7440-38-2) LIST OF TABLES ......................................................................................................................VI LIST OF FIGURES .................................................................................................................. VII LIST OF ABBREVIATIONS .................................................................................................VIII FOREWORD............................................................................................................................XIII AUTHORS, CONTRIBUTORS, AND REVIEWERS ......................................................... XIV 1. INTRODUCTION..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS 3 2.1. PROPERTIES.............................................................................................................. 3 2.2. USES............................................................................................................................ 3 2.3. OCCURRENCE........................................................................................................... 4 2.4. ENVIRONMENTAL FATE........................................................................................ 5 3. TOXICOKINETICS................................................................................................................. 6 3.1. ABSORPTION ............................................................................................................ 7 3.2. DISTRIBUTION.......................................................................................................... 9 3.2.1. Transport in Blood............................................................................................. 9 3.2.2. Tissue Distribution .......................................................................................... 10 3.2.3. Cellular Uptake, Distribution, and Transport.................................................. 14 3.3. METABOLISM ......................................................................................................... 15 3.3.1. Reduction......................................................................................................... 19 3.3.2. Arsenic Methylation........................................................................................ 20 3.3.3. Species Differences in the Methylation of Arsenic......................................... 23 3.3.4. Thioarsenical Metabolites ............................................................................... 24 3.4. ELIMINATION ......................................................................................................... 26 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS............................... 27 4. HAZARD IDENTIFICATION .............................................................................................. 31 4.1. STUDIES IN HUMANS............................................................................................ 31 4.1.1. Taiwan ............................................................................................................. 32 4.1.2. Japan................................................................................................................ 46 4.1.3. South America................................................................................................. 47 4.1.4. North America (United States and Mexico).................................................... 52 4.1.5. China................................................................................................................ 58 4.1.6. Finland............................................................................................................. 59 4.1.7. Denmark .......................................................................................................... 61 4.1.8. Australia .......................................................................................................... 61 4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL.................................................................................................. 62 4.2.1. Prechronic and Chronic Studies ...................................................................... 62 4.2.2. Cancer Bioassays............................................................................................. 62 4.2.2.1. Mice—Transplacental ...................................................................... 62 iii DRAFT—DO NOT CITE OR QUOTE 4.2.2.2. Rat—Oral.......................................................................................... 65 4.2.2.3. Other ................................................................................................. 66 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL................................. 67 4.4. OTHER STUDIES..................................................................................................... 67 4.4.1. Possible Modes of Action and Key Events of Possible Importance ............... 67 4.4.1.1. In Vivo Human Studies .................................................................... 71 4.4.1.2. In Vivo Experiments Using Laboratory Animals............................. 75 4.4.1.3. In Vitro Experiments ........................................................................ 81 4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS ......... 93 4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION........................................................................................... 94 4.6.1. Summary of Overall Weight-of-Evidence....................................................... 94 4.6.2. Synthesis of Human, Animal, and Other Supporting Evidence ...................... 94 4.6.2.1. Skin Cancer....................................................................................... 96 4.6.2.2. Lung Cancer...................................................................................... 96 4.6.2.3. Kidney, Bladder, and Liver Cancer .................................................. 97 4.6.2.4. In Utero Exposure............................................................................. 98 4.6.3. Mode of Action Information ........................................................................... 98 4.6.3.1. General Comments on MOAs .......................................................... 98 4.6.3.2. Low-Dose Extrapolation................................................................. 102 4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ........................................ 102 4.7.1. Possible Childhood Susceptibility................................................................. 102 4.7.2. Possible Gender Differences ......................................................................... 105 4.7.3. Other.............................................................................................................. 106 4.7.3.1. Genetic Polymorphism ................................................................... 106 4.7.3.2. Nutritional Status............................................................................ 109 4.7.3.3. Cigarette Smokers........................................................................... 111 5. DOSE-RESPONSE ASSESSMENTS.................................................................................. 112 5.1. ORAL REFERENCE DOSE (RfD)......................................................................... 112 5.2. INHALATION REFERENCE CONCENTRATION (RfC).................................... 112 5.3. CANCER ASSESSMENT (ORAL EXPOSURE)................................................... 112 5.3.1. Background: History of Cancer Risk Assessments for Arsenic.................... 112 5.3.2. Choice of Study/Data, Estimation Approach, and Input Assumptions ......... 119 5.3.3. Dose-Response Model Selection for Cancer Mortality in Taiwan................ 120 5.3.4. Selection of Cancer Endpoints and Estimation of Risks for U.S. Populations ................................................................................................................................. 121 5.3.5. Nonwater Arsenic Intake and Drinking Water Consumption ....................... 123 5.3.6. Dose-Response Data.....................................................................................
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