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Toxicological Review and Risk Characterization United States Office of Research NCEA-1-0503 Environmental Protection and Development January 16, 2002 Agency Washington, DC 20460 External Review Draft External EPA Perchlorate Environmental Review Draft Contamination: (Do Not Cite Toxicological Review and or Quote) Risk Characterization Notice This document is an external review draft. It has not been formally released by EPA and should not at this stage be construed to represent Agency policy. It is being circulated for comment on its technical accuracy and policy implications. NCEA-1-0503 January 16, 2002 Internal Review Draft Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization Notice This document is an external review draft. It has not been formally released by EPA and should not at this stage be construed to represent Agency policy. It is being circulated for comment on its technical accuracy and policy implications. National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, DC Disclaimer This document is an external 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. ii Table of Contents Page List of Tables................................................................ xi List of Figures .............................................................. xvi Contributors and Reviewers................................................... xxvi Preface................................................................... xxxi Acknowledgments ......................................................... xxxiii EXECUTIVE SUMMARY....................................................E-1 1. INTRODUCTION ....................................................... 1-1 1.1 PRODUCTION USES AND SOURCES OF PERCHLORATE CONTAMINATION................................................ 1-1 1.2 EVOLUTION OF ANALYTICAL DETECTION METHODS AND EMERGING OCCURRENCE DATA...................................1-4 1.3 HEALTH AND ECOTOXICOLOGY RISK ASSESSMENTS— HISTORICAL OVERVIEW ......................................... 1-16 1.3.1 Overview of Perchlorate Health Risk Assessment .................. 1-16 1.3.2 Overview of Ecotoxicology Screening Level Assessment ............ 1-19 1.4 RISK CHARACTERIZATION AND REGULATORY AGENDA ........... 1-20 1.4.1 U.S. Environmental Protection Agency Regulatory Plans ............. 1-20 1.4.2 State Regulatory Plans ........................................ 1-21 1.5 SUMMARY...................................................... 1-23 2. PHYSICOCHEMICAL CHARACTERISTICS................................. 2-1 3. TOXICOKINETICS/TOXICODYNAMICS AND MODE-OF-ACTION TESTING STRATEGY............................................................ 3-1 3.1 ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION OF PERCHLORATE................................................ 3-1 3.1.1 Human Studies ............................................... 3-2 3.1.2 Laboratory Animal Studies ..................................... 3-3 3.2 IODINE METABOLISM AND THYROID PHYSIOLOGY ................. 3-8 3.3 TOXICOKINETICS OF PERCHLORATE.............................. 3-13 3.4 TOXICODYNAMICS OF THYROID HORMONE PERTURBATIONS ...... 3-15 3.4.1 Carcinogenic Effects ......................................... 3-15 3.4.2 Neurodevelopmental Deficits and Other Potential Adverse Effects Resulting from Thyroid Hormone Disruption ...................... 3-21 3.5 DEVELOPMENT OF A TOXICITY TESTING STRATEGY BASED ON MODE OF ACTION............................................... 3-29 4. HUMAN HEALTH EFFECTS DATA ....................................... 4-1 4.1 EPIDEMIOLOGICAL DATA......................................... 4-2 4.1.1 Ecological Studies ............................................ 4-3 iii Table of Contents (cont’d) Page 4.1.2 Occupational Studies ......................................... 4-13 4.2 CLINICAL STUDIES .............................................. 4-19 4.2.1 Studies in Healthy Human Subjects .............................. 4-19 4.2.2 Studies in Patients with Graves’ Disease .......................... 4-25 4.2.2.1 Hematological Effects ................................. 4-27 4.3 SUMMARY OF CONCLUSIONS REGARDING HUMAN HEALTH EFFECTS STUDIES............................................... 4-28 5. TOXICOLOGICAL EFFECTS IN LABORATORY ANIMAL STUDIES ........... 5-1 5.1 CHRONIC STUDIES AND GENOTOXICITY ASSAYS ................... 5-7 5.1.1 Cancer Studies .............................................. 5-11 5.1.2 Genotoxicity Assays .......................................... 5-12 5.1.2.1 In Vitro Assays ...................................... 5-13 5.1.2.2 In Vivo Assays....................................... 5-15 5.1.2.3 Summary of Genotoxicity Battery Results ................. 5-16 5.2 GENERAL TOXICITY: SHORT-TERM AND SUBCHRONIC TESTING .... 5-17 5.2.1 Historical Data .............................................. 5-17 5.2.2 Caldwell et al. (1995) 14-Day Study ............................. 5-19 5.2.2.1 Thyroid Histology Data ................................ 5-20 5.2.2.2 Thyroid and Pituitary Hormone Analyses .................. 5-21 5.2.3 The 90-Day Testing Strategy Bioassay in Rats ..................... 5-23 5.2.3.1 General Toxicity, Thyroid Histopathology Results, and Satellite Reproductive Assay ............................ 5-25 5.2.3.2 Thyroid and Pituitary Hormone Analyses .................. 5-27 5.3 DEVELOPMENTAL NEUROTOXICITY STUDIES ..................... 5-33 5.3.1 The 1998 Developmental Neurotoxicity Study ..................... 5-33 5.3.1.1 Results of General Toxicity Measures, Neurohistology, and Morphology ..................................... 5-35 5.3.1.2 Evaluation of Thyroid Histopathology .................... 5-38 5.3.1.3 Thyroid and Pituitary Hormone Analyses .................. 5-41 5.3.1.4 Behavioral Evaluations ................................ 5-43 5.3.2 Motor Activity Study (Bekkedal et al., 2000) ...................... 5-47 5.3.2.1 EPA and NIEHS Statistical Analyses of Motor Activity Effects............................................. 5-48 5.3.3 The 2001 “Effects Study” ..................................... 5-52 5.3.3.1 Results of General Toxicity Measures .................... 5-53 5.3.3.2 Evaluation of Thyroid Histopathology .................... 5-53 5.3.3.3 Thyroid and Pituitary Hormone Analyses .................. 5-57 5.3.3.3.1 Maternal Hormone Analyses ................... 5-59 5.3.3.3.2 Fetal and Neonatal Hormone Analyses ........... 5-59 5.3.3.4 Brain Morphometry Effects ............................. 5-60 iv Table of Contents (cont’d) Page 5.4 DEVELOPMENTAL STUDIES...................................... 5-74 5.4.1 Historical Studies ............................................ 5-74 5.4.2 Segment II Developmental Toxicity Study in Rabbits ................ 5-76 5.4.2.1 Results of Maternal Examinations and Thyroid Histopathology ...................................... 5-78 5.4.2.2 Developmental Endpoints .............................. 5-78 5.4.2.3 Maternal Thyroid and Pituitary Hormone Analyses .......... 5-79 5.4.3 Segment II Developmental Study in Rats ......................... 5-81 5.4.3.1 Results of Maternal Examinations ....................... 5-82 5.4.3.2 Developmental Endpoints .............................. 5-82 5.4.3.3 Conclusions Regarding Developmental Toxicity in Rats ...... 5-83 5.5 TWO-GENERATION REPRODUCTIVE TOXICITY STUDY ............. 5-83 5.5.1 General Toxicity Results and Evaluation of Reproductive Parameters . 5-85 5.5.2 Evaluation of Thyroid Histology ................................ 5-86 5.5.2.1 Colloid Depletion, Hypertrophy, and Hyperplasia ........... 5-87 5.5.2.2 Bayesian Analysis of Tumor Incidence .................... 5-88 5.5.3 Thyroid and Pituitary Hormone Analyses ......................... 5-91 5.6 IMMUNOTOXICITY STUDIES ..................................... 5-92 5.6.1 Results for General Toxicity, Organ Weight, and Cellularity Measures .................................................. 5-97 5.6.2 Evaluation of Thyroid Histology ................................ 5-97 5.6.3 Thyroid and Pituitary Hormone Analyses ......................... 5-98 5.6.4 Results of Immune Function Assays ............................. 5-99 5.6.5 Results for Evaluations of Hematological Parameters ............... 5-102 5.6.6 Results Summary ........................................... 5-103 6. CONSTRUCTION OF PBPK MODELS TO ADDRESS PERCHLORATE’S MODE-OF-ACTION..................................................... 6-1 6.1 MODE-OF-ACTION FRAMEWORK AND UNDERLYING MODELING APPROACH ...................................................... 6-3 6.1.1 Parallelogram Approach to Interspecies Extrapolation ................ 6-4 6.1.2 Extending the Parallelogram Approach to Various Experimental Life Stages.................................................. 6-8 6.2 ADULT RAT AND HUMAN MODEL STRUCTURES .................... 6-9 6.2.1 Data and Methods ........................................... 6-15 6.2.1.1 Studies in Laboratory Rats ............................. 6-15 6.2.1.1.1 Acute iv Experiments in Rats ................... 6-18 6.2.1.1.2 Drinking Water Studies in Rats ................. 6-19 6.2.1.2 Human Studies ...................................... 6-19 6.2.1.2.1 Human Iodide Kinetic Data .................... 6-19 v Table of Contents (cont’d) Page 6.2.1.2.2 Perchlorate Kinetics and Inhibition of Thyroid Iodide Uptake............................... 6-20 6.2.1.2.3 Supporting
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