ADDENDUM TO THE TOXICOLOGICAL PROFILE FOR ARSENIC Agency for Toxic Substances and Disease Registry Division of Toxicology and Human Health Sciences Atlanta, GA 30329-4027 February 2016 ARSENIC i CONTENTS LIST OF FIGURES ..................................................................................................................................... iii LIST OF TABLES ....................................................................................................................................... iv 3. HEALTH EFFECTS ................................................................................................................................ 1 3.1 INTRODUCTION ........................................................................................................................ 1 3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ...................................... 2 3.2.1 Inhalation Exposure .............................................................................................................. 2 3.2.1.3 Immunological and Lymphoreticular Effects ............................................................... 2 3.2.2 Oral Exposure ....................................................................................................................... 3 3.2.2.1 Death ............................................................................................................................. 3 3.2.2.2 Systemic Effects ............................................................................................................ 3 3.2.2.3 Immunological and Lymphoreticular Effects ............................................................. 45 3.2.2.4 Neurological Effects ................................................................................................... 48 3.2.2.5 Reproductive Effects ................................................................................................... 52 3.2.2.6 Developmental Effects ................................................................................................ 58 3.2.2.7 Cancer ......................................................................................................................... 78 3.3 GENOTOXICITY ....................................................................................................................... 84 3.4 TOXICOKINETICS ................................................................................................................... 85 3.4.1 Absorption ........................................................................................................................... 85 3.4.1.2 Oral Exposure ............................................................................................................. 85 3.4.1.3 Dermal Exposure ......................................................................................................... 94 3.4.2 Distribution ......................................................................................................................... 94 3.4.2.1 Inhalation Exposure .................................................................................................... 94 3.4.3 Metabolism ......................................................................................................................... 94 3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 95 3.4.5.1 Summary of PBPK Models ......................................................................................... 95 3.4.5.2 Arsenic PBPK Model Comparison ............................................................................. 98 3.4.5.3 Discussion of Models .................................................................................................. 99 3.5 MECHANISMS OF ACTION .................................................................................................. 100 3.5.1 Pharmacokinetic Mechanisms ........................................................................................... 100 3.5.2 Mechanisms of Toxicity .................................................................................................... 100 3.7 CHILDREN’S SUSCEPTIBILITY .......................................................................................... 102 3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .............................................. 103 4. CHEMICAL AND PHYSICAL INFORMATION .............................................................................. 103 5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .......................................................... 103 5.1 PRODUCTION ......................................................................................................................... 103 5.2 IMPORT/EXPORT ................................................................................................................... 103 5.3 USE ........................................................................................................................................... 104 5.4 DISPOSAL ............................................................................................................................... 104 6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 105 6.1 OVERVIEW ............................................................................................................................. 105 6.2 RELEASES TO THE ENVIRONMENT ................................................................................. 105 6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ................................ 105 6.4.1 Air ..................................................................................................................................... 105 ARSENIC ii 6.4.2 Water ................................................................................................................................. 105 6.4.3 Sediment and Soil ............................................................................................................. 111 6.4.4 Other Environmental Media .............................................................................................. 112 6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ....................................... 118 6.6 EXPOSURES OF CHILDREN ................................................................................................ 156 6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ............................................. 158 6.8 ADEQUACY OF THE DATA BASE ...................................................................................... 159 6.8.1 Identification of Data Needs ............................................................................................. 159 6.8.2 Ongoing Studies ................................................................................................................ 159 7. ANALYTICAL METHODS................................................................................................................ 159 7.1 BIOLOGICAL SAMPLES ....................................................................................................... 159 7.2 ENVIRONMENTAL SAMPLES ............................................................................................. 160 8. REGULATIONS AND ADVISORIES ............................................................................................... 162 9. REFERENCES .................................................................................................................................... 167 ARSENIC iii LIST OF FIGURES 3-1. Flow- and Diffusion-Limited DMA(V) PBPK Model ....................................................................... 97 ARSENIC iv LIST OF TABLES 3-1. Respiratory Effects of Oral Exposure to Inorganic Arsenicals in Humans .......................................... 4 3-2. Cardiovascular Effects of Oral Exposure to Inorganic Arsenicals in Humans ................................... 13 3-3. Gastrointestinal Effects of Oral Exposure to Inorganic Arsenicals in Humans .................................. 30 3-4. Endocrine Effects of Oral Exposure to Inorganic Arsenicals in Humans .......................................... 33 3-5. Ocular Effects of Oral Exposure to Inorganic Arsenicals in Humans ................................................ 46 3-6. Neurological Effects of Oral Exposure to Inorganic Arsenicals in Humans ...................................... 49 3-7. Reproductive Effects of Oral Exposure to Inorganic Arsenicals in Humans ..................................... 53 3-8. Reproductive Effects of Oral Exposure to Inorganic Arsenicals in Animals ..................................... 54 3-9. Developmental Effects of Oral Exposure to Inorganic Arsenicals in Humans .................................. 59 3-10. Developmental Effects of Oral Exposure to Inorganic Arsenicals in Animals ................................ 76 3-11. Cancer in Humans Following In Utero and/or Early Life Exposure to Arsenic in Drinking Water ................................................................................................................................................ 80 3-12. Genotoxicity in Humans Exposed to Oral Arsenic ........................................................................... 86 3-13. Comparison of Major Features of PBPK Models for Arsenic .......................................................... 98 6-1. Speciation of Arsenic in U.S. Commercial Rice .............................................................................