DRAFT-DO NOT CITE OR QUOTE EPA/635/R-10/002C www.epa.gov/iris TOXICOLOGICAL REVIEW OF FORMALDEHYDE INHALATION TOXICITY (CAS No. 50-00-0) In Support of Summary Information on the Integrated Risk Information System (IRIS) VOLUME I of IV Introduction, Background, and Toxicokinetics March 17, 2010 NOTICE This document is an Inter-Agency Science Consultation 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. U.S. Environmental Protection Agency Washington, DC 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 or recommendation for use. This document is a draft for review purposes only and does not constitute Agency policy. I-ii DRAFT—DO NOT CITE OR QUOTE CONTENTS—TOXICOLOGICAL REVIEW OF FORMALDEHYDE (CAS No. 50-00-0) LIST OF TABLES ......................................................................................................................... xi LIST OF FIGURES .......................................................................................................................xx LIST OF ABBREVIATIONS AND ACRONYMS .....................................................................xxv FOREWORD ............................................................................................................................ xxxii AUTHORS, CONTRIBUTORS, AND REVIEWERS ............................................................ xxxiii VOLUME I 1. INTRODUCTION .................................................................................................................. 1-1 2. BACKGROUND .................................................................................................................... 2-1 2.1. PHYSICOCHEMICAL PROPERTIES OF FORMALDEHYDE ................................ 2-1 2.2. PRODUCTION, USES, AND SOURCES OF FORMALDEHYDE ........................... 2-1 2.3. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE..................................... 2-4 2.3.1. Inhalation .......................................................................................................... 2-5 2.3.2. Ingestion ......................................................................................................... 2-10 2.3.3. Dermal Contact ............................................................................................... 2-11 3. TOXICOKINETICS ............................................................................................................... 3-1 3.1. CHEMICAL PROPERTIES AND REACTIVITY ...................................................... 3-1 3.1.1. Binding of Formaldehyde to Proteins .............................................................. 3-1 3.1.2. Endogenous Sources of Formaldehyde ............................................................ 3-3 3.1.2.1. Normal Cellular Metabolism (Enzymatic) ........................................ 3-3 3.1.2.2. Normal Metabolism (Non-Enzymatic) .............................................. 3-5 3.1.2.3. Exogenous Sources of Formaldehyde Production ............................. 3-5 3.1.2.4. FA-GSH Conjugate as a Method of Systemic Distribution .............. 3-6 3.1.2.5. Metabolic Products of FA Metabolism (e.g., Formic Acid) .............. 3-6 3.1.2.6. Levels of Endogenous Formaldehyde in Animal and Human Tissues .............................................................................................. 3-6 3.2. ABSORPTION ............................................................................................................. 3-9 3.2.1. Oral ................................................................................................................... 3-9 3.2.2. Dermal .............................................................................................................. 3-9 3.2.3. Inhalation .......................................................................................................... 3-9 3.2.3.1. Formaldehyde Uptake Can be Affected by Effects at the Portal of Entry ................................................................................ 3-10 3.2.3.2. Variability in the Nasal Dosimetry of Formaldehyde in Adults and Children ........................................................................ 3-12 3.3. DISTRIBUTION ........................................................................................................ 3-13 3.3.1. Levels in Blood .............................................................................................. 3-13 3.3.2. Levels in Various Tissues............................................................................... 3-15 3.3.2.1. Disposition of Formaldehyde: Differentiating covalent Binding and Metabolic Incorporation ............................................ 3-16 This document is a draft for review purposes only and does not constitute Agency policy. I-iii DRAFT—DO NOT CITE OR QUOTE CONTENTS (continued) 3.4. METABOLISM .......................................................................................................... 3-20 3.4.1. In Vitro and In Vivo Characterization of Formaldehyde Metabolism ........... 3-20 3.4.2. Formaldehyde Exposure and Perturbation of Metabolic Pathways ............... 3-23 3.4.3. Evidence for Susceptibility in Formaldehyde Metabolism ............................ 3-24 3.5. EXCRETION .............................................................................................................. 3-25 3.5.1. Formaldehyde Excretion in Rodents .............................................................. 3-26 3.5.2. Formaldehyde Excretion in Exhaled Human Breath ...................................... 3-27 3.5.3. Formaldehyde Excretion in Human Urine ..................................................... 3-31 3.6. MODELING THE TOXICOKINETICS OF FORMALDEHYDE AND DPX ......... 3-32 3.6.1. Motivation ...................................................................................................... 3-32 3.6.2. Species Differences in Anatomy: Consequences for Gas Transport and Risk ................................................................................................................ 3-34 3.6.3. Modeling Formaldehyde Uptake in Nasal Passages ...................................... 3-40 3.6.3.1. Flux Bins ......................................................................................... 3-41 3.6.3.2. Flux Estimates ................................................................................. 3-41 3.6.3.3. Mass Balance Errors ........................................................................ 3-42 3.6.4. Modeling Formaldehyde Uptake in the Lower Respiratory Tract ................. 3-42 3.6.5. Uncertainties in Formaldehyde Dosimetry Modeling .................................... 3-44 3.6.5.1. Verification of Predicted Flow Profiles ........................................... 3-44 3.6.5.2. Level of Confidence in Formaldehyde Uptake Simulations ........... 3-45 3.6.6. PBPK Modeling of DNA Protein Cross-Links (DPXs) Formed by Formaldehyde ................................................................................................ 3-48 3.6.6.1. PBPK Models for DPXs .................................................................. 3-48 3.6.6.2. A PBPK Model for DPXs in the F344 Rat and Rhesus Monkey that uses Local Tissue Dose of Formaldehyde ................. 3-50 3.6.6.3. Uncertainties in Modeling the Rat and Rhesus DPX Data .............. 3-51 3.6.7. Uncertainty in Prediction of Human DPX Concentrations ............................ 3-53 VOLUME II 4. HAZARD CHARACTERIZATION ....................................................................................... 4-1 4.1. HUMAN STUDIES ...................................................................................................... 4-1 4.1.1. Noncancer Health Effects ................................................................................. 4-1 4.1.1.1. Sensory Irritation (Eye, Nose, Throat Irritation) ............................... 4-1 4.1.1.2. Pulmonary Function ........................................................................ 4-11 4.1.1.3. Asthma ............................................................................................. 4-19 4.1.1.4. Respiratory Tract Pathology ............................................................ 4-26 4.1.1.5. Immunologic Effects ....................................................................... 4-30 4.1.1.6. Neurological/Behavioral.................................................................. 4-42 4.1.1.7. Developmental and Reproductive Toxicity ..................................... 4-45 4.1.1.8. Oral Exposure Effects on the Gastrointestinal Tract ....................... 4-56 4.1.1.9. Summary: Noncarcinogenic Hazard in Humans ............................. 4-56 This document is a draft for review purposes only and does not constitute Agency policy. I-iv DRAFT—DO NOT CITE OR QUOTE CONTENTS (continued) 4.1.2.