EPA/635/R-08/001F www.epa.gov/iris TOXICOLOGICAL REVIEW OF THALLIUM AND COMPOUNDS (CAS No. 7440-28-0) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2009 U.S. Environmental Protection Agency Washington, DC DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii CONTENTS—TOXICOLOGICAL REVIEW OF THALLIUM AND COMPOUNDS (CAS No. 7440-28-0) LIST OF TABLES .......................................................................................................................... v LIST OF FIGURES ...................................................................................................................... vii LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... viii FOREWORD ................................................................................................................................. ix AUTHORS, CONTRIBUTORS, AND REVIEWERS .................................................................. x 1. INTRODUCTION ..................................................................................................................... 1 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................... 3 3. TOXICOKINETICS .................................................................................................................. 5 3.1. ABSORPTION .................................................................................................................. 5 3.2. DISTRIBUTION ............................................................................................................... 5 3.3. METABOLISM ................................................................................................................. 6 3.4. ELIMINATION ................................................................................................................. 6 3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS ...................................... 8 4. HAZARD IDENTIFICATION .................................................................................................. 9 4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS ...................................................................................................................... 9 4.1.1. Incident/Case Reports ............................................................................................. 9 4.1.2. Population Surveys ............................................................................................... 16 4.1.3. Occupational Exposure ......................................................................................... 17 4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS—ORAL AND INHALATION ........................................ 18 4.2.1. Oral Exposure ....................................................................................................... 18 4.2.2. Inhalation Exposure .............................................................................................. 26 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES ..................................................... 26 4.3.1. Reproductive Toxicity .......................................................................................... 26 4.3.2. Developmental Toxicity ....................................................................................... 31 4.4. OTHER ENDPOINT-SPECIFIC STUDIES ................................................................... 32 4.4.1. Liver and Kidney Toxicity ................................................................................... 33 4.4.2. Cardiotoxicity ....................................................................................................... 40 4.4.3. Neurotoxicity ........................................................................................................ 40 4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION ....................................................................................................... 45 4.5.1. Interference with Potassium Transport ................................................................. 45 4.5.2. Disturbance of Mitochondrial Function and Energy Generation ......................... 46 4.5.3. Induction of Oxidative Stress ............................................................................... 46 4.5.4. Reaction with Thiol Groups ................................................................................. 47 4.5.5. Other Endpoint-specific Mechanistic Data .......................................................... 47 4.5.6. Genotoxicity ......................................................................................................... 50 4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ................................................... 51 4.6.1. Oral ....................................................................................................................... 51 4.6.2. Inhalation .............................................................................................................. 54 4.6.3. Mode-of-Action Information ................................................................................ 54 iii 4.7. EVALUATION OF CARCINOGENICITY ................................................................... 55 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................ 56 4.8.1. Possible Childhood Susceptibility ........................................................................ 56 4.8.2. Possible Gender Differences ................................................................................ 56 5. DOSE-RESPONSE ASSESSMENTS ..................................................................................... 57 5.1. ORAL REFERENCE DOSE (RfD) ................................................................................ 57 5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification .......................................................................................................... 57 5.1.2. Methods of Analysis ............................................................................................. 60 5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs)............... 63 5.1.4. Candidate RfD Comparison Information ............................................................. 67 5.1.5. Previous RfD Assessment .................................................................................... 75 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ........................................... 75 5.3. CANCER ASSESSMENT .............................................................................................. 75 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ............................................................................................................................. 76 6.1. HUMAN HAZARD POTENTIAL ................................................................................. 76 6.2. DOSE RESPONSE .......................................................................................................... 78 7. REFERENCES ........................................................................................................................ 79 APPENDIX A. Summary of External Peer Review and Public Comments and Disposition ..... A-1 APPENDIX B. Documentation of Benchmark Dose Modeling ................................................. B-1 iv LIST OF TABLES Table 2-1. Chemical and physical properties of thallium and selected thallium compounds ................................................................................................................... 4 Table 3-1. Urine concentrations of thallium for the U.S. population from NHANES, 1999–2002 ................................................................................................................... 7 Table 4-1. Thallium toxicity in humans following oral exposure ............................................... 10 Table 4-2. Selected clinical observations in Sprague-Dawley rats treated with thallium sulfate for 90 days ...................................................................................................... 20 Table 4-3. Incidence of alopecia in rats ....................................................................................... 21 Table 4-4. Selected blood chemistry values ................................................................................ 22 Table 4-5. Thallium toxicity in animals following oral exposure ............................................... 29 Table 4-6. Thallium toxicity in animals via injection ................................................................ 366 Table 5-1. Incidence data and BMD modeling results for selected clinical observations in Sprague-Dawley rats treated with thallium sulfate for 90 days ................................. 61 Table B-1. A summary of BMDS (version 1.4.1) modeling results based on incidence of rough coat in male Sprague-Dawley rats exposed to thallium sulfate via gavage for 90 days ................................................................................................... B-1 Table B-2. A summary of BMDS (version 1.4.1) modeling results based on incidence of piloerection in male Sprague-Dawley