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EPA/635/R-05/004 TOXICOLOGICAL REVIEW OF TOLUENE (CAS No. 108-88-3) In Support of Summary Information on the Integrated Risk Information System (IRIS) September 2005 U.S. Environmental Protection Agency Washington D.C. 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. i CONTENTS —TOXICOLOGICAL REVIEW OF TOLUENE (CAS No. 108-88-3) LIST OF TABLES.............................................................v LIST OF FIGURES ........................................................... vi FREQUENTLY USED ABBREVIATIONS AND ACRONYMS ...................... vii FOREWORD ................................................................x AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................ xi 1. INTRODUCTION ..........................................................1 2. CHEMICAL AND PHYSICAL INFORMATION RELEVANT TO ASSESSMENTS .....3 3. TOXICOKINETICS RELEVANT TO ASSESSMENTS ............................4 3.1. ABSORPTION .....................................................4 3.1.1. Oral Exposure ...............................................4 3.1.2. Inhalation Exposure ..........................................4 3.1.3. Dermal Exposure ............................................5 3.2. DISTRIBUTION ....................................................6 3.3. METABOLISM .....................................................6 3.4. ELIMINATION .....................................................9 3.5. PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELS ....10 4. HAZARD IDENTIFICATION................................................11 4.1. STUDIES IN HUMANS .............................................11 4.1.1. Oral Exposure ..............................................11 4.1.2. Inhalation Exposure .........................................12 4.1.2.1. Acute and Case Studies ...............................12 4.1.2.2. Pre-chronic and Chronic Studies .......................15 4.1.2.3. Cancer Studies ......................................31 4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN ANIMALS - ORAL AND INHALATION .............................32 4.2.1. Oral Exposure ..............................................32 4.2.1.1. Prechronic Studies ...................................32 4.2.1.2. Chronic Studies .....................................38 4.2.2. Inhalation Exposure .........................................39 4.2.2.1. Prechronic Studies ...................................39 4.2.2.2. Chronic Studies .....................................42 4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES - ORAL AND INHALATION ...............................................................44 4.3.1. Studies in Humans ..........................................44 4.3.2. Studies in Animals ..........................................45 4.3.2.1. Oral Exposure ......................................45 4.3.2.2. Inhalation Exposure ..................................47 4.4. OTHER STUDIES ..................................................51 4.4.1. Acute Toxicity Data .........................................51 ii 4.4.1.1. Oral Exposure ......................................51 4.4.1.2. Inhalation Exposure ..................................52 4.4.2. Genotoxicity ...............................................53 4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS – ORAL AND INHALATION ........................................54 4.5.1. Oral Exposure ..............................................54 4.5.2. Inhalation Exposure .........................................55 4.5.3. Mode of Action .............................................57 4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION ...........................................60 4.6.1. Summary of Overall Weight-of-Evidence ........................60 4.6.2. Synthesis of Human, Animal, and Other Supporting Evidence ........61 4.7. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ....................62 4.7.1. Possible Childhood Susceptibility ..............................62 4.7.2. Possible Gender Differences ...................................63 4.7.3. Other .....................................................64 5. DOSE RESPONSE ASSESSMENTS ..........................................64 5.1. ORAL REFERENCE DOSE (RfD) .....................................64 5.1.1. Choice of Principal Study and Critical Effect .....................64 5.1.2. Methods of Analysis .........................................67 5.1.3. RfD Derivation - Including Application of Uncertainty Factors .......68 5.1.4. Previous RfD Assessment .....................................70 5.2. INHALATION REFERENCE CONCENTRATION (RfC) ..................70 5.2.1. Choice of Principal Study and Critical Effect .....................70 5.2.2. Methods of Analysis .........................................83 5.2.3. RfC Derivation - Including Application of Uncertainty Factors .......84 5.2.4. Previous RfC Assessment .....................................86 5.3. CANCER ASSESSMENT ............................................86 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE RESPONSE ........................................87 6.1. HUMAN HAZARD POTENTIAL .....................................87 6.2. DOSE RESPONSE .................................................89 6.2.1. Noncancer/Oral .............................................89 6.2.2. Noncancer/Inhalation ........................................90 6.2.3. Cancer/Oral and Inhalation ....................................90 7. REFERENCES ............................................................91 Appendix A1. Summary of External Peer Review and Public Comments and Disposition .................................................................. A1-1 iii Appendix A2. Summary of External Peer Review and Public Comments and Disposition .................................................................. A2-1 Appendix B1. Benchmark Dose Modeling Results for the Derivation of the RfD (NTP, 1990) ...................................................................B1-1 Appendix B2. Benchmark Dose Modeling Results for the Derivation of the RfD (Selected Immunotoxicity Studies) ...................................................................B2-1 iv LIST OF TABLES Table 1. Selected subset of occupational studies of neurological effects from toluene inhalation .......................................................74 Table 2. Summary of subchronic and chronic toluene inhalation studies in animals ....80 Table B1-1. Benchmark modeling summary for relative kidney weight, NTP 1990 .....................................................B1-2 Table B2-1. Results of BMDS analyses from Hsieh et al. (1989) study with maximum p for hypothesis 4, goodness of fit of means ..............................B2-5 Table B2-2. Results of BMDS analyses from Hsieh et al. (1989) study with minimum AIC for hypothesis 4, goodness of fit of means ..............................B2-6 Table B2-3. Results of BMDS analyses from Hsieh et al. (1989, 1990b) study with maximum p for hypothesis 4, goodness of fit of means ..........................B2-7 Table B2-4. Benchmark responses for the endpoints reported in Hsieh et al. (1989) .....B2-8 Table B2-5. Basic sensitivity analyses for BMDS results ..........................B2-9 v LIST OF FIGURES Figure 1. Proposed pathways for toluene metabolism .............................8 Figure 2. Summary of NOAELs/LOAELs for neurological endpoints for a subset of occupational studies of chronic inhalation exposure to toluene .............73 vi FREQUENTLY USED ABBREVIATIONS AND ACRONYMS [3H]TdR [3H]thymidine 5-HIAA 5-Hydroxyindoleacetic acid 5-HT 5-Hydroxytryptamine (serotonin) AACCI Alcohol intake-adjusted color confusion index ACGIH American Conference of Governmental Industrial Hygienists ACTH Adrenocorticotropic hormone AIC Akaike Information Criterion ALT L-alanine-aminotransferase anti-GBM Antiglomerular basement membrane antibody anti-LAM Antilaminin antibody ASPH Association of Schools of Public Health ATSDR Agency for Toxic Substances and Disease Registry BAEP Brainstem auditory evoked potentials BMD Benchmark dose BMDL BMD lower 95% confidence limit BMDS Benchmark dose modeling software BMR Benchmark response BTEX Benzene, toluene, ethylbenzene, and xylenes CAS Chemical Abstracts Service CASRN Chemical Abstracts Service Registry Number CATSYS Computerized test system for neurotoxicity CCI Color confusion index CDP Cubic distortion-product CH50 Number of cells necessary to lyse 50% of target cells CHO Chinese hamster ovary CI Confidence interval CIIT Chemical Industry Institute of Toxicology CNS Central Nervous System CoA Coenzyme A Con A Concanavalin A CYP Cytochrome P-450 DA Dopamine DCV Distribution of nerve conduction velocities DH Dehydrogenase DNA Deoxyribonucleic acid DOPAC 3,4-Dihydroxyphenylacetic acid ECG Electrocardiograph ELISA Enzyme-linked immunosorbent assay F0 Parent generation vii F1 First filial generation F2 Second filial generation FEP Flash-evoked potential FOB Functional observation battery GABA (-Aminobutyric acid GSH Glutathione (reduced) HEC Human equivalent concentration HVA Homovanillic acid IARC International Agency for Research on Cancer IgE Immunoglobulin E IgG Immunoglobulin G IgM Immunoglobulin M IL-2 Interleukin-2 IRIS Integrated Risk Information System LOAEL Lowest observed adverse effect level LPS Lipopolysaccharide LWAE Lifetime weighted average exposure MCV Maximal
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