&EPA TOXICOLOGICAL REVIEW OF INGESTED INORGANIC ARSENIC (CAS No. 7440-38-2) In Support of Summary Information on the Integrated Risk Information System (IRIS) July 2005 NOTICE This document is an IRIS review draft for the Science Advisory Board (SAB). It has not been formally released by the U.S. Environmental Protection Agency and should not at this stage be construed to represent Agency position on this chemical. It is being circulated for review of its technical accuracy and science policy implications. U.S. Environmental Protection Agency Washington DC DRAFT - DO NOT CITE OR QUOTE DISCLAIMER This document is a preliminary draft for review purposes only and does not constitute U.S. Environmental Protection Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. DRAFT - DO NOT CITE OR QUOTE 11 T ABLE OF CONTENTS - TOXICOLOGICAL REVIEW for INORGANIC ARSENIC (CAS No. 7440-38-2) FOREWORD ............................................................ viii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................ viii 1. INTRODUCTION .................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS ........................................................... 3 3. TOXICOKINETICS .....................................................5 3.1. ABSORPTION ................................................. 5 3.2. DISTRIBUTION ............................................... 6 3.3. METABOLISM ............................................... 10 3.4. ELIMINATION ............................................... 14 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS .......... 15 4. HAZARD IDENTIFICATION ................................... 17 4.1. STUDIES IN HUMANS ........................................ 17 4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSA YS IN ANIMALS - ORAL AND INHALATION ......................... 37 4.2.1. Prechronic and Chronic Studies ............................. 37 4.2.2. Cancer Bioassays ......................................... 38 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES - ORAL AND INHALATION ................................................ 41 4.3.1. Oral .................................................. 41 4.4. OTHER STUDIES ............................................. 42 4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS51 4.5.1. Oral ................................................ 51 4.5.2. Inhalation .............................................. 51 4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION .......................................... 51 4.6.1. Summary ofOverall Weight-of-Evidence .................. 51 4.6.2. Synthesis ofHurnan, Animal, and Other Supporting Evidence ..... 51 4.6.3. Mode ofAction Information ............................... 53 4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................ 56 4.7.1. Possible Childhood Susceptibility ........................ 56 4.7.2. Possible Gender Differences ............................... 58 4.7.3. Other ................................................. 59 5. DOSE-RESPONSE ASSESSMENTS ...................................... 59 DRAFT - DO NOT CITE OR QUOTE 11l 5.1. ORAL REFERENCE DOSE (RID) ............................... 59 5.1.1. Choice ofPrincipal Study and Critical Effect .................. 59 5.1.2. Methods ofAnalysis ..................................... 59 5.1.3. RID Derivation ............................ : ............. 59 5.1.4. Previous Oral Assessment ................................. 60 5.2. INHALATION REFERENCE DOSE (RfC) ........................ 60 5.3. CANCER ASSESSMENT (Oral Exposure) ......................... 60 5.3.1. Choice of Study / Data - with Rationale and Justification ......... 60 5.3.2. Dose-response Data ...................................... 61 5.3.3. Dose Conversion ........................................ 62 5.3.4. Extrapolation Method(s) .................................. 62 5.3.5. Oral Slope Factor ........................................ 64 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ........................................................ 67 6.1. HUMAN HAZARD POTENTIAL ................................ 67 6.2. DOSE RESPONSE ............................................ 68 7. REFERENCES ..................................................... 69 APPENDIX A. Summary ofExternal Peer Review and Public Comments and Disposition ......................................................................... 99 APPENDIX B ......................................................... ,. 100 DRAFT - DO NOT CITE OR QUOTE IV List of Tables Table 2-1. Chemical and Physical Properties of Arsenic and Selected Inorganic Arsenic Compounds ......................................................... 3 Table 4-1. SMRs in Taiwan by Sex ............................................ 19 Table 4-2. Age-Adjusted Mortality Rates (per 100,000) in Taiwan ................... 20 Table 4-3. Model Parameters and Potency Index ................................. 21 Table 4-4. Estimated values for Chen et al. (1992) ............................... 22 Table 4-5. Statistically Significant (p<0.05) SMRs for Cancers in a Blackfoot Disease Endemic Area of Taiwan Compared to Local and National Controls ........... 24 Table 4-6. Risk Statistics of Best Fitting Models from Morales et al. 2000 ............. 26 Table 4-7. SMRs in Japanese Cohort .......................................... 29 Table 4-8. NRC 2001 Maximum Likelihood Estimates of Excess Lifetime Risk ........ 37 Table 5-4. Calculation for Male Lung Cancer Risk from Arsenic in Drinking Water ..... 66 Table 5-5. Calculation for Female Lung Cancer Risk from Arsenic in Drinking Water ... 66 Table 5-6. Calculation for Male Bladder Cancer Risk from Arsenic in Drinking Water ... 67 Table 5-7. Calculation for Female Bladder Cancer Risk from Arsenic in Drinking Water .67 Table B-1. Poisson modeling options. (Modified from Morales et al., 2000) ........... 100 DRAFT - DO NOT CITE OR QUOTE v 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. In Section 6, EPA has characterized its overall confidence in the quantitative and qualitative aspects of hazard and dose response. Matters considered in this characterization include knowledge gaps, uncertainties, quality of data, and scientific controversies. This characterization is presented in an effort to make apparent the limitations ofthe 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 301-345-2870. AUTHORS, CONTRIBUTORS, AND REVIEWERS Chemical Manager/Author Elizabeth A. Doyle, Ph.D. Office of Water U.S. Environmental Protection Agency Washington, DC Robyn B. Blain, Ph.D. Gregory M. Blumenthal, Ph.D. Welford C. Roberts, Ph.D. ICF Consulting Fairfax, VA Reviewers This document and summary information on IRIS have received peer review both by EP A scientists and by independent scientists external to EPA. Subsequent to external review and incorporation of comments, this assessment has undergone an Agency-wide review process whereby the IRIS Program Director has achieved a consensus approval among the Office of Research and Development; Office of Air and Radiation; Office of Prevention, Pesticides, and Toxic Substances; Office of Solid Waste and Emergency Response; Office of Water; Office of Policy, Economics, and Innovation; Office of Children's Health Protection; Office of Environmental Information; and the Regional Offices. DRAFT - DO NOT CITE OR QUOTE vi List of Abbreviations 8-0HdG 8-hydroxydeoxyguanosine AIC Akaike Information Criterion ATSDR Agency for Toxic Substances and Disease Registry AsIIl arsenite Asv arsenate BFD blackfoot disease BMD benchmark dose BMDIO benchmark dose at 10% effect BMDL lower 95% confidence limit on the benchmark dose BMDS benchmark dose software BMI body mass index BrdU bromodeoxyuridine CA chromosome aberrations CASRN CAS registry number CCR chromate copper arsenate CHO Chinese hamster ovary CI confidence interval COPD chronic obstructive pulmonary disease DAAC diseases of the arteries, arterioles and capillaries DHLP dihydrolipoic acid DMAIII dimethylarsenous acid DMAv dimethyl arsinic acid DMA dimethyl arsenic-used when the oxidative state is unknown or not specified DMPS 2,3 -dimercaptopropane-l-sulfonic acid DMSO dimethyl sulfoxide DTT dithiothreitol ED effective dose EKG electrocardiogram eNOS endothelial nitric oxide synthase EPA Environmental Protection Agency GAPDH glyceraldehyde-3-phosphate dehydrogenase GI gastrointestinal GM-CSF granulocyte macrophage-colony stimulating factor GSH glutathione GSSG oxidized glutathione HSDB Hazardous Substance Data Base IGF-l insulin-like growth factor 1 IGFBP-l IGF-l binding protein IRIS Integrated Risk Information System ISHD ischemic heart disease DRAFT - DO NOT CITE OR QUOTE VB JNCV Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure LDso lethal dose 50% LOAEL lowest-0bserved -adverse-effect-level MH-PR Mantel Haenzel-weighted prevalence ratios MMAIII monomethylarsonous acid MMAIIIO methylarsine oxide MMAv monomethyl arsonic acid MMA monomethyl arsenic-used