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Toxicological Review of Benzene, Non-Cancer Effects (CAS No. 71-43-2)

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Toxicological Review of Benzene, Non-Cancer Effects (CAS No. 71-43-2) EPA/635/R-02/001F TOXICOLOGICAL REVIEW OF BENZENE (NONCANCER EFFECTS) (CAS No. 71-43-2) In Support of Summary Information on the Integrated Risk Information System (IRIS) October 2002 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. Note: This document may undergo revisions in the future. The most up-to-date version will be made available electronically via the IRIS Home Page at http://www.epa.gov/iris. ii CONTENTS—TOXICOLOGICAL REVIEW FOR BENZENE (CAS No. 71-43-2) FOREWORD ............................................................... vii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................... viii LIST OF ACRONYMS AND ABBREVIATIONS ................................... ix EXECUTIVE SUMMARY .................................................... xii 1. INTRODUCTION ..........................................................1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .....2 3. TOXICOKINETICS RELEVANT TO ASSESSMENTS ............................3 3.1. ABSORPTION .....................................................3 3.1.1. Gastrointestinal Absorption ...................................3 3.1.2. Respiratory Absorption ........................................4 3.1.3. Dermal Absorption ...........................................5 3.2. DISTRIBUTION ....................................................8 3.2.1. Oral Exposure ...............................................8 3.2.2. Inhalation Exposure ..........................................8 3.2.3. Dermal Exposure ............................................9 3.3. METABOLISM .....................................................9 3.3.1. Metabolic Pathways .........................................10 3.3.2. Requirement for CYP2E1 .....................................10 3.3.3. Toxicity of Benzene Metabolites ...............................12 3.3.3.1 Phenolic Products ...................................12 3.3.3.2. Trans,trans-Muconaldehyde ...........................13 3.3.3.3. Benzene Oxide ......................................14 3.3.4. Species, Route, and Rate Differences ............................14 3.3.5. Induction of CYP2E1 ........................................15 3.3.6. Mechanism of Toxicity .......................................16 3.3.6.1. Formation of Covalent Adducts .........................16 3.3.6.2 Genotoxicity ........................................18 3.3.6.3 Oxidative Stress .....................................18 3.3.6.4. Inhibition of Cytokine Formation .......................19 3.4. ELIMINATION AND EXCRETION ...................................19 3.4.1. Oral Exposure ..............................................19 3.4.2. Inhalation Exposure .........................................20 3.4.3. Dermal Exposure ...........................................21 3.4.4. Other Routes of Exposure .....................................21 3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS ...........22 3.6. TOXICOKINETICS SUMMARY ......................................26 4. HAZARD IDENTIFICATION ................................................28 iii CONTENTS–TOXICOLOGICAL REVIEW FOR BENZENE (CAS No. 71-43-2) (continued) 4.1. STUDIES IN HUMANS .............................................28 4.1.1. Oral Exposure ..............................................28 4.1.2. Inhalation Exposure .........................................28 4.1.2.1. Hematotoxicity ......................................28 4.1.2.2. Neurotoxicity .......................................43 4.1.2.3. Reproductive Toxicity ................................44 4.1.2.4. Developmental Toxicity ..............................47 4.2. ACUTE AND CHRONIC STUDIES IN EXPERIMENTAL ANIMALS .......50 4.2.1. Hematotoxicity .............................................51 4.2.1.1. Oral Exposure—Subchronic Studies .....................51 4.2.1.2. Oral Exposure—Chronic Studies ........................52 4.2.1.3. Inhalation Exposure—Subchronic Studies ................53 4.2.1.4. Inhalation Exposure—Chronic Studies ...................60 4.2.1.5. Effects on Stem Cell Populations .......................63 4.2.1.6. Summary of Principal Hematotoxic Effects ...............77 4.2.2. Reproductive/Developmental Effects ............................79 4.2.2.1. Reproductive Toxicity ................................79 4.2.2.2. Developmental Toxicity ..............................83 4.2.2.3. Summary of Principal Reproductive/Developmental Toxicity Effects .....................................95 4.2.2.4. Mechanisms of Developmental and Reproductive Toxicity ...96 4.2.3. Neurotoxicity ..............................................97 4.2.3.1. Oral Exposure ......................................97 4.2.3.2. Inhalation Exposure ..................................98 4.2.3.3. Summary of Neurotoxic Effects .......................101 4.2.4. Immunotoxicity ............................................101 4.2.4.1. Oral Exposure .....................................101 4.2.4.2. Inhalation Exposure .................................103 4.2.4.3. Summary of Immunotoxic Effects ......................104 4.3. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND MODE OF ACTION ..........................................104 4.4. SUSCEPTIBLE POPULATIONS .....................................109 4.4.1. Childhood Susceptibility .....................................109 4.4.2. Gender Differences .........................................110 4.4.3. Genetically Susceptible Populations ............................111 4.5. HAZARD IDENTIFICATION SUMMARY ............................113 5. DOSE-RESPONSE ASSESSMENTS .........................................116 5.1. INHALATION REFERENCE CONCENTRATION (RfC) .................117 5.1.1. Choice of Principal Study and Critical Effect ....................117 5.1.2. Benchmark Dose Modeling ..................................119 5.1.3. RfC Derivation ............................................121 5.1.4. Comparison Analysis Based on the LOAEL .....................123 5.1.5. Comparison Analysis Based on the Ward et al. (1985) Experimental iv CONTENTS–TOXICOLOGICAL REVIEW FOR BENZENE (CAS No. 71-43-2) (continued) Animal Study .............................................123 5.2. ORAL REFERENCE DOSE (RfD) ....................................127 5.2.1. Choice of Principal Study and Critical Effect ....................127 5.2.2. Conversion of Inhalation Exposure to Equivalent Oral Dose Rate ....127 5.2.3. RfD Derivation ............................................129 5.2.4. Comparison Analysis Based on the LOAEL .....................130 5.2.5. Comparison Analysis Based on the NTP (1986) Experimental Animal Study .............................................130 5.3 DOSE-RESPONSE SUMMARY .....................................135 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE-RESPONSE ........................................................141 6.1. HUMAN HAZARD POTENTIAL ....................................141 6.2. DOSE-RESPONSE ................................................144 6.2.1. Inhalation RfC .............................................144 6.2.2. Oral RfD .................................................144 7. REFERENCES ...........................................................146 v LIST OF FIGURES Figure 1. Metabolic pathways for benzene .........................................11 Figure 2. Linear model of ALC data .............................................121 Figure 3. Linear model of HCT data .............................................125 LIST OF TABLES Table 1. Hematotoxicity of benzene—occupational exposure ..........................30 Table 2. Median benzene urine metabolites, by exposure category, in a study of workers exposed to benzene in Shanghai, China, 1992 ..............................40 Table 3. Comparison of mean peripheral blood counts with standard deviations, by exposure status, in a study of workers exposed to benzene in Shanghai, China, 1992 ......41 Table 4. Reproductive toxicity of inhaled benzene in humans ..........................45 Table 5. Developmental toxicity of benzene—humans ...............................48 Table 6. Peripheral blood and hematopoietic effects of benzene in animals— inhalation exposure .........................................................54 Table 7. Reproductive toxicity of inhaled benzene in test animals ......................80 Table 8. Developmental toxicity of inhaled benzene in test animals .....................84 Table 9. Joint effects of CYP2E1 activity and NQO1 genotype on benzene-induced hematotoxicity in Chinese Workers ..............................................112 Table 10. Results of BMC modeling of Rothman et al. (1996a) data on benzene and ALC . 122 Table 11. BMD modeling results of the NTP (1986) male mouse and male rat lymphocyte counts, with untransformed data ..............................................133 Table 12. BMD modeling results of the NTP (1986) male mouse and male rat lymphocyte counts, with transformed dose data ............................................134 Table 13. Summary of uncertainty factors used for deriving the RfC and RfD ............137 Table 14. Summary of RfC and RfD estimates using human and experimental animal data, as well as benchmark dose modeling and LOAEL/NOAEL approaches ...............142 vi FOREWORD The National Center for Environmental Assessment-Washington
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