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IRIS Toxicological Review of Benzo[A]Pyrene EPA/635/R-10/006 DRAFT - DO NOT CITE OR QUOTE www.epa.gov/iris TOXICOLOGICAL REVIEW OF BENZO[a]PYRENE (CAS No. 50-32-8) In Support of Summary Information on the Integrated Risk Information System (IRIS) June 2011 NOTICE This document is an Interagency Science Consultation 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 preliminary 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 ii DRAFT - DO NOT CITE OR QUOTE 1 CONTENTS TOXICOLOGICAL REVIEW OF BENZO[a]PYRENE (CAS No. 50-32-8) 2 3 4 LIST OF TABLES ....................................................................................................................... VII 5 LIST OF FIGURES ....................................................................................................................... X 6 LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... XII 7 FOREWORD ............................................................................................................................. XVI 8 AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................ XVII 9 10 1. INTRODUCTION ..................................................................................................................... 1 11 12 2. CHEMICAL AND PHYSICAL INFORMATION ................................................................... 3 13 14 3. TOXICOKINETICS .................................................................................................................. 9 15 3.1. ABSORPTION .................................................................................................................... 9 16 3.1.1. Inhalation Exposure ...................................................................................................... 9 17 3.1.1.1. Inhalation Exposure in Humans ........................................................................... 9 18 3.1.1.2. Inhalation Exposure in Animals.......................................................................... 11 19 3.1.2. Oral Exposure ............................................................................................................. 17 20 3.1.2.1. Oral Exposure in Humans .................................................................................. 18 21 3.1.2.2. Oral Exposure in Animals ................................................................................... 18 22 3.1.3. Dermal Exposure ........................................................................................................ 20 23 3.1.3.1. Dermal Exposure in Humans .............................................................................. 20 24 3.1.3.2. Dermal Exposure in Animals .............................................................................. 23 25 3.1.4. Other Types of Exposure ............................................................................................ 25 26 3.2. DISTRIBUTION ............................................................................................................... 26 27 3.2.1. Inhalation Exposure .................................................................................................... 26 28 3.2.2. Oral Exposure ............................................................................................................. 28 29 3.2.3. Dermal and Other Exposures...................................................................................... 29 30 3.3. METABOLISM ................................................................................................................ 32 31 3.3.1. Phase I Metabolism .................................................................................................... 34 32 3.3.1.1. CYP450-dependent Reactions ............................................................................. 34 33 3.3.1.2. Non-CYP-related metabolic pathways ................................................................ 38 34 3.3.2. Phase II Metabolism ................................................................................................... 40 35 3.3.3. Tissue-specific Metabolism ........................................................................................ 43 36 3.3.3.1. Respiratory Tract Tissues ................................................................................... 43 37 3.3.3.2. GI Tract and Liver Tissues ................................................................................. 47 38 3.3.3.3. Skin ...................................................................................................................... 48 39 3.3.3.4. Reproductive Tissues and Fetal Metabolism ...................................................... 50 40 3.3.3.5. Other Tissues ...................................................................................................... 53 41 3.4. ELIMINATION ................................................................................................................ 53 42 3.4.1. Inhalation Exposure .................................................................................................... 53 43 3.4.2. Oral Exposure ............................................................................................................. 56 44 3.4.3. Dermal Exposure and Other Exposure Routes ........................................................... 57 45 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS ................. 59 46 47 4. HAZARD IDENTIFICATION ................................................................................................ 64 48 4.1. HUMANS STUDIES ........................................................................................................ 64 49 4.1.1. Sources of Human Exposure ...................................................................................... 64 50 4.1.2. Biomonitoring of benzo[a]pyrene Exposure and Effects In Humans ........................ 64 iii DRAFT - DO NOT CITE OR QUOTE 1 4.1.2.1. Urinary Excretion of benzo[a]pyrene ................................................................. 65 2 4.1.2.2. Adduct Formation with DNA and Protein .......................................................... 66 3 4.1.2.2.1. DNA Adduct measures in blood ........................................................................ 69 4 4.1.2.2.2. Adduct measures in reproductive tissues .......................................................... 72 5 4.1.2.3. Benzo[a]pyrene-Induced Cytogenetic Damage .................................................. 73 6 4.1.3. Epidemiologic Findings in Humans ........................................................................... 75 7 4.1.3.1. Molecular Epidemiology and Case-Control Cancer Studies .............................. 76 8 4.1.3.2. Cohort Cancer Studies ........................................................................................ 77 9 4.1.3.3. Noncancer Disease Caused by benzo[a]pyrene ................................................. 81 10 4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 11 ANIMALS—ORAL, INHALATION, AND DERMAL .................................................. 85 12 4.2.1. Oral ............................................................................................................................. 85 13 4.2.1.1. Subchronic Studies .............................................................................................. 85 14 4.2.1.2. Chronic Studies and Cancer Bioassays .............................................................. 93 15 4.2.2. Inhalation .................................................................................................................. 106 16 4.2.2.1. Short-term and Subchronic Studies .................................................................. 106 17 4.2.2.2. Chronic Studies and Cancer Bioassays ............................................................ 106 18 4.2.3. Dermal Exposure ...................................................................................................... 108 19 4.2.3.1. Skin-Tumor Initiation-Promotion Assays ......................................................... 108 20 4.2.3.2. Carcinogenicity Dermal Bioassays................................................................... 109 21 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL, INHALATION, AND 22 DERMAL ........................................................................................................................ 118 23 4.3.1. Oral ........................................................................................................................... 118 24 4.3.2. Inhalation .................................................................................................................. 124 25 4.4. OTHER DURATION OR ENDPOINT-SPECIFIC STUDIES .....................................
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