EPA/635/R-17/003Fb www.epa.gov/iris Toxicological Review of Benzo[a]pyrene [CASRN 50-32-8] Supplemental Information January 2017 Integrated Risk Information System National Center for Environmental Assessment Office of Research and Development 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 APPENDIX A. CHEMICAL PROPERTIES AND EXPOSURE INFORMATION ................................................ A-1 APPENDIX B. ASSESSMENTS BY OTHER NATIONAL AND INTERNATIONAL HEALTH AGENCIES ............ B-1 APPENDIX C. LITERATURE SEARCH STRATEGY ...................................................................................... C-1 APPENDIX D. INFORMATION IN SUPPORT OF HAZARD IDENTIFICATION AND DOSE-RESPONSE ANALYSIS ......................................................................................................................... D-1 D.1. TOXICOKINETICS .................................................................................................... D-1 D.1.1. Overview .................................................................................................. D-1 D.1.2. Absorption................................................................................................ D-1 D.1.3. Distribution .............................................................................................. D-3 D.1.4. Metabolism .............................................................................................. D-4 D.1.5. Elimination ............................................................................................. D-11 D.2. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS ........................ D-12 D.2.1. Recommendations for the Use of PBPK Models in Toxicity Value Derivation ............................................................................................... D-15 D.3. HUMAN STUDIES ................................................................................................. D-15 D.3.1. Noncancer Endpoints ............................................................................. D-15 D.3.2. Cancer-related Endpoints ...................................................................... D-26 D.3.3. Epidemiologic Findings in Humans ........................................................ D-29 D.4. ANIMAL STUDIES ................................................................................................. D-42 D.4.1. Oral Bioassays ........................................................................................ D-42 D.4.2. Inhalation Studies .................................................................................. D-61 D.4.3. Dermal studies ....................................................................................... D-64 D.4.4. Reproductive and Developmental Toxicity Studies ............................... D-74 D.4.5. Inhalation ............................................................................................... D-90 D.5. OTHER PERTINENT TOXICITY INFORMATION ...................................................... D-94 D.5.1. Genotoxicity Information ....................................................................... D-94 D.5.2. Tumor Promotion and Progression ...................................................... D-122 D.5.3. Benzo[a]pyrene Transcriptomic Microarray Analysis .......................... D-126 iii APPENDIX E. DOSE-RESPONSE MODELING FOR THE DERIVATION OF REFERENCE VALUES FOR EFFECTS OTHER THAN CANCER AND THE DERIVATION OF CANCER RISK ESTIMATES ....................................................................................................................... E-1 E.1. NONCANCER ENDPOINTS ....................................................................................... E-1 E.1.1. Data Sets ................................................................................................... E-1 E.1.2. Dose Response Modeling for Noncancer Endpoints................................. E-3 E.1.3. Dosimetry Modeling for Estimation of Human Equivalent Concentrations for Reference Concentration (RfC) ................................ E-40 E.2. Cancer Endpoints ................................................................................................. E-43 E.2.1. Dose-Response Modeling for the Oral Slope Factor ............................... E-43 E.2.2. Dose-Response Modeling for the Inhalation Unit Risk ........................... E-90 APPENDIX F. SUMMARY OF SAB PEER REVIEW COMMENTS AND EPA’S DISPOSITION ....................... F-1 REFERENCES FOR APPENDICES .................................................................................................................. R-1 iv TABLES Table A-1. Chemical and physical properties of benzo[a]pyrene ............................................................. A-2 Table A-2. Benzo[a]pyrene concentrations in air ..................................................................................... A-4 Table A-3. Benzo[a]pyrene levels in food ................................................................................................. A-5 Table A-4. Levels of benzo[a]pyrene in soil .............................................................................................. A-7 Table B-1. Health assessments and regulatory limits by other national and international agencies ........................................................................................................................... B-1 Table C-1. Summary of detailed search strategies for benzo[a]pyrene comprehensive literature searches (Pubmed, Toxline, Toxcenter, TSCATS) ............................................................. C-1 Table C-2. Summary of detailed literature search strategies for benzo(a)pyrene cardiovascular toxicity.............................................................................................................................. C-9 Table D-1. Exposure to benzo[a]pyrene and mortality from cardiovascular diseases in a European cohort of asphalt paving workers ................................................................. D-16 Table D-2. Exposure to benzo[a]pyrene and mortality from cardiovascular diseases in a Canadian cohort of male aluminum smelter workers .................................................. D-18 Table D-3. Exposure-related effects in Chinese coke oven workers or warehouse controls exposed to benzo[a]pyrene in the workplace .............................................................. D-24 Table D-4. Exposure-related effects in Chinese coke oven workers or warehouse controls exposed to benzo[a]pyrene in the workplace, stratified by urinary metabolite levels ............................................................................................................................. D-24 Table D-5. Background information on Chinese coke oven workers or warehouse controls exposed to benzo[a]pyrene in the workplace .............................................................. D-26 Table D-6. Studies examining skin cancer risk in relation to therapeutic coal tar ................................. D-34 Table D-7. Exposure-related effects in male Wistar rats exposed to benzo[a]pyrene by gavage 5 days/week for 5 weeks ................................................................................................. D-43 Table D-8. Exposure-related effects in Wistar rats exposed to benzo[a]pyrene by gavage 5 days/week for 5 weeks ................................................................................................. D-46 Table D-9. Means ± SDa for liver and thymus weights in Wistar rats exposed to benzo[a]pyrene by gavage 5 days/week for 90 days .............................................................................. D-48 Table D-10. Incidences of exposure-related neoplasms in Wistar rats treated by gavage with benzo[a]pyrene, 5 days/week, for 104 weeks .............................................................. D-50 Table D-11. Incidences of alimentary tract tumors in Sprague-Dawley rats chronically exposed to benzo[a]pyrene in the diet or by gavage in caffeine solution ...................................... D-53 Table D-12. Incidence of nonneoplastic and neoplastic lesions in female B6C3F1 mice fed benzo[a]pyrene in the diet for up to 2 years ................................................................ D-56 Table D-13. Other oral exposure cancer bioassays in mice ................................................................... D-57 Table D-14. Tumor incidence in the respiratory tract and upper digestive tract for male Syrian golden hamsters exposed to benzo[a]pyrene via inhalation for lifetime— Thyssen et al. (1981)a .................................................................................................... D-63 Table D-15. Skin tumor incidence and time of appearance in male C57L mice dermally exposed to benzo[a]pyrene for up to 103 weeks ....................................................................... D-66 Table D-16. Skin tumor incidence and time of appearance in male SWR, C3HeB, and A/He mice dermally exposed to benzo[a]pyrene for life or until a skin tumor was detected ....... D-67 Table D-17. Tumor incidence in female Swiss mice dermally exposed to benzo[a]pyrene for up to 93 weeks ..................................................................................................................