Toxicological Review of Benzo[a]pyrene (Final Report)

1 EPA/635/R-17/003Fa Toxicological Review of Benzo[a]pyrene [CASRN 50-32-8]. January 2017. Integrated Risk Information System National Center for Environmental Assessment Office of Research and Development Environmental Protection Agency Washington, DC. Toxicological Review of Benzo[a]pyrene DISCLAIMER. This document has been reviewed in accordance with Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii Toxicological Review of Benzo[a]pyrene CONTENTS.

2 AUTHORS | CONTRIBUTORS | REVIEWERS .. x PREFACE .. xiv PREAMBLE TO IRIS Toxicological xviii EXECUTIVE SUMMARY .. xxvi LITERATURE SEARCH STRATEGY|STUDY SELECTION .. xxxiii 1. HAZARD IDENTIFICATION .. 1-1. PRESENTATION AND SYNTHESIS OF EVIDENCE BY ORGAN/SYSTEM .. 1-1. Developmental Toxicity .. 1-1. Reproductive Toxicity .. 1-30. Immunotoxicity .. 1-50. Other Toxicity .. 1-61. Carcinogenicity .. 1-71. SUMMARY AND EVALUATION .. 1-101. Weight of Evidence for Effects Other than Cancer .. 1-101. Weight of Evidence for Carcinogenicity .. 1-104. 2. DOSE-RESPONSE ANALYSIS .. 2-1.

3 ORAL REFERENCE DOSE FOR EFFECTS OTHER THAN CANCER .. 2-1. Identification of Studies and Effects for Dose-Response Analysis .. 2-1. Methods of Analysis .. 2-5. Derivation of Candidate Values .. 2-10. Derivation of Organ/System-Specific Reference Doses .. 2-15. Selection of the Overall Reference Dose .. 2-16. Confidence Statement .. 2-17. Previous IRIS Assessment: Reference 2-17. INHALATION REFERENCE CONCENTRATION FOR EFFECTS OTHER THAN 2-17. Identification of Studies and Effects for Dose-Response Analysis .. 2-18. Methods of Analysis .. 2-19. Derivation of Candidate Values.

4 2-23. Derivation of Organ/System-Specific Reference Concentrations .. 2-26. iii Toxicological Review of Benzo[a]pyrene Selection of the Reference Concentration .. 2-27. Confidence Statement .. 2-27. Previous IRIS Assessment: Reference 2-28. Uncertainties in the Derivation of the RfD and RfC .. 2-28. ORAL SLOPE FACTOR FOR CANCER .. 2-30. Analysis of Carcinogenicity Data .. 2-30. Dose-Response Analysis Adjustments and Extrapolation Methods .. 2-32. Derivation of the Oral Slope Factor .. 2-34. Uncertainties in the Derivation of the Oral Slope Factor .. 2-37. Previous IRIS Assessment: Oral Slope Factor.

5 2-39. INHALATION UNIT RISK FOR CANCER .. 2-40. Analysis of Carcinogenicity Data .. 2-40. Dose-Response Analysis Adjustments and Extrapolation Methods .. 2-41. Inhalation Unit Risk 2-42. Uncertainties in the Derivation of the Inhalation Unit Risk .. 2-43. Previous IRIS Assessment: Inhalation Unit 2-47. APPLICATION OF AGE-DEPENDENT ADJUSTMENT FACTORS (ADAFs) .. 2-47. REFERENCES .. R-1. iv Toxicological Review of Benzo[a]pyrene TABLES. Table ES-1. Organ/system-specific RfDs and overall RfD for Benzo[a]pyrene .. xxviii Table ES-2. Organ/system-specific RfCs and overall RfC for Benzo[a]pyrene .

6 Xxix Table LS-1. Summary of the search strategy employed for Benzo[a]pyrene .. xxxiii 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 after oral or inhalation exposure .. 1-7. Table 1-3. Evidence pertaining to the neurodevelopmental effects of Benzo[a]pyrene from PAH. mixtures .. 1-18. Table 1-4. Evidence pertaining to the neurodevelopmental effects of Benzo[a]pyrene in animals .. 1-20. Table 1-5. Evidence pertaining to the male reproductive toxicity of Benzo[a]pyrene in adult animals after oral or inhalation 1-34.

7 Table 1-6. Evidence pertaining to the female reproductive effects of Benzo[a]pyrene in humans .. 1-42. Table 1-7. Evidence pertaining to the female reproductive effects of Benzo[a]pyrene in adult animals after oral or inhalation 1-43. Table 1-8. Evidence pertaining to immune effects of Benzo[a]pyrene in 1-55. Table 1-9. Evidence pertaining to the immune effects of Benzo[a]pyrene in animals after oral or inhalation exposure .. 1-55. Table 1-10. Evidence pertaining to liver, kidney, and cardiovascular effects of Benzo[a]pyrene in animals after oral or inhalation 1-68. Table 1-11.

8 Evidence pertaining to neurotoxicity following repeated oral or inhalation exposure to Benzo[a]pyrene in adult humans and animals .. 1-69. Table 1-12. Cancer sites for PAH-related agents reviewed by the International Agency for Research on Cancer (IARC) .. 1-74. Table 1-13. Summary of epidemiologic studies of Benzo[a]pyrene (direct measures) in relation to lung cancer risk: Tier 1 studies .. 1-75. Table 1-14. Summary of epidemiologic studies of Benzo[a]pyrene (direct measures) in relation to lung cancer risk: Tier 2 studies .. 1-76. Table 1-15. Summary of epidemiologic studies of Benzo[a]pyrene (direct measures) in relation to bladder cancer risk.

9 1-79. Table 1-16. Tumors observed in chronic oral animal bioassays .. 1-82. Table 1-17. Tumors observed in chronic inhalation animal bioassays .. 1-85. Table 1-18. Tumors observed in chronic dermal animal bioassays .. 1-87. Table 1-19. Experimental support for the postulated key events for mutagenic mode of action .. 1-95. Table 1-20. Supporting evidence for the carcinogenic to humans cancer descriptor for Benzo[a]pyrene .. 1-108. Table 2-1. Summary of derivation of PODs .. 2-8. Table 2-2. Effects and corresponding derivation of candidate values .. 2-12. Table 2-3. Organ/system-specific RfDs and overall RfD for Benzo[a]pyrene .

10 2-15. Table 2-4. Summary of derivation of PODs .. 2-22. Table 2-5. Effects and corresponding derivation of candidate values .. 2-25. Table 2-6. Organ/system-specific RfCs and overall RfC for Benzo[a]pyrene .. 2-26. Table 2-7. Summary of the oral slope factor derivations .. 2-34. Table 2-8. Summary of uncertainties in the derivation of Benzo[a]pyrene oral slope factor .. 2-38. Table 2-9. Summary of the inhalation unit risk derivation .. 2-43. v Toxicological Review of Benzo[a]pyrene Table 2-10. Summary of uncertainties in the derivation of cancer risk values for Benzo[a]pyrene (inhalation unit risk).