EPA/635/R-14/312a External Review Draft www.epa.gov/iris Toxicological Review of Benzo[a]pyrene (CASRN 50-32-8) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2014 NOTICE This document is an External Review 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. National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, DC Toxicological Review of Benzo[a]pyrene 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 of recommendation for use. This document is a draft for review purposes only and does not constitute Agency policy. ii DRAFT—DO NOT CITE OR QUOTE Toxicological Review of Benzo[a]pyrene CONTENTS AUTHORS | CONTRIBUTORS | REVIEWERS ................................................................................................... ix PREFACE ....................................................................................................................................................... xii PREAMBLE TO IRIS TOXICOLOGICAL REVIEWS............................................................................................ xvi EXECUTIVE SUMMARY ............................................................................................................................ xxxiv LITERATURE SEARCH STRATEGY|STUDY SELECTION ................................................................................... xli 1. HAZARD IDENTIFICATION .................................................................................................................... 1-1 1.1. PRESENTATION AND SYNTHESIS OF EVIDENCE BY ORGAN/SYSTEM ............................................ 1-1 1.1.1. Developmental Toxicity ..................................................................................................... 1-1 1.1.2. Reproductive Toxicity ...................................................................................................... 1-22 1.1.3. Immunotoxicity ............................................................................................................... 1-37 1.1.4. Other Toxicity .................................................................................................................. 1-44 1.1.5. Carcinogenicity ................................................................................................................ 1-52 1.2. SUMMARY AND EVALUATION .................................................................................................... 1-81 1.2.1. Weight of Evidence for Effects Other than Cancer ......................................................... 1-81 1.2.2. Weight of Evidence for Carcinogenicity .......................................................................... 1-82 2. DOSE-RESPONSE ANALYSIS ................................................................................................................. 2-1 2.1. ORAL REFERENCE DOSE FOR EFFECTS OTHER THAN CANCER ...................................................... 2-1 2.1.1. Identification of Studies and Effects for Dose-Response Analysis .................................... 2-1 2.1.2. Methods of Analysis .......................................................................................................... 2-5 2.1.3. Derivation of Candidate Values ......................................................................................... 2-8 2.1.4. Derivation of Organ/System-Specific Reference Doses .................................................. 2-12 2.1.5. Selection of the Proposed Overall Reference Dose ........................................................ 2-14 2.1.6. Confidence Statement ..................................................................................................... 2-14 2.1.7. Previous IRIS Assessment: Reference Dose ..................................................................... 2-15 2.2. INHALATION REFERENCE CONCENTRATION FOR EFFECTS OTHER THAN CANCER ..................... 2-15 2.2.1. Identification of Studies and Effects for Dose-Response Analysis .................................. 2-15 2.2.2. Methods of Analysis ........................................................................................................ 2-17 2.2.3. Derivation of Candidate Values ....................................................................................... 2-19 2.2.4. Derivation of Organ/System-Specific Reference Concentrations ................................... 2-22 This document is a draft for review purposes only and does not constitute Agency policy. iii DRAFT—DO NOT CITE OR QUOTE Toxicological Review of Benzo[a]pyrene 2.2.5. Selection of the Proposed Reference Concentration ...................................................... 2-23 2.2.6. Confidence Statement ..................................................................................................... 2-23 2.2.7. Previous IRIS Assessment: Reference Concentration ...................................................... 2-24 2.2.8. Uncertainties in the Derivation of the RfD and RfC ........................................................ 2-24 2.3. ORAL SLOPE FACTOR FOR CANCER ............................................................................................. 2-25 2.3.1. Analysis of Carcinogenicity Data ..................................................................................... 2-25 2.3.2. Dose-Response Analysis—Adjustments and Extrapolation Methods ............................. 2-28 2.3.3. Derivation of the Oral Slope Factor ................................................................................. 2-28 2.3.4. Uncertainties in the Derivation of the Oral Slope Factor ................................................ 2-30 2.3.5. Previous IRIS Assessment: Oral Slope Factor .................................................................. 2-32 2.4. INHALATION UNIT RISK FOR CANCER ......................................................................................... 2-32 2.4.1. Analysis of Carcinogenicity Data ..................................................................................... 2-33 2.4.2. Dose-Response Analysis—Adjustments and Extrapolation Methods ............................. 2-34 2.4.3. Inhalation Unit Risk Derivation ........................................................................................ 2-35 2.4.4. Uncertainties in the Derivation of the Inhalation Unit Risk ............................................ 2-36 2.4.5. Previous IRIS Assessment: Inhalation Unit Risk ............................................................... 2-38 2.5. DERMAL SLOPE FACTOR FOR CANCER ........................................................................................ 2-39 2.5.1. Analysis of Carcinogenicity Data ..................................................................................... 2-39 2.5.2. Dose-Response Analysis—Adjustments and Extrapolation Methods ............................. 2-40 2.5.3. Derivation of the Dermal Slope Factor ............................................................................ 2-42 2.5.4. Dermal Slope Factor Cross-Species Scaling ..................................................................... 2-44 2.5.5. Uncertainties in the Derivation of the Dermal Slope Factor ........................................... 2-45 2.5.6. Previous IRIS Assessment: Dermal Slope Factor ............................................................. 2-47 2.6. APPLICATION OF AGE-DEPENDENT ADJUSTMENT FACTORS (ADAFS) ........................................ 2-47 REFERENCES ............................................................................................................................................... R-1 This document is a draft for review purposes only and does not constitute Agency policy. iv DRAFT—DO NOT CITE OR QUOTE Toxicological Review of Benzo[a]pyrene TABLES Table ES-1. Organ/system-specific RfDs and proposed overall RfD for benzo[a]pyrene ....................... xxxv Table ES-2. Organ/system-specific RfCs and proposed overall RfC for benzo[a]pyrene ...................... xxxvii Table LS-1. Summary of the search strategy employed for benzo[a]pyrene ............................................ xli Table 1-1. Evidence pertaining to developmental effects of benzo[a]pyrene in humans ........................ 1-4 Table 1-2. Evidence pertaining to developmental effects of benzo[a]pyrene in animals ........................ 1-5 Table 1-3. Evidence pertaining to the neurodevelopmental effects of benzo[a]pyrene from PAH mixtures ......................................................................................................................... 1-13 Table 1-4. Evidence pertaining to the neurodevelopmental effects of benzo[a]pyrene in animals ...... 1-15 Table 1-5. Evidence pertaining to the male reproductive toxicity of benzo[a]pyrene in adult