DRAFT-DO NOT CITE OR QUOTE EPA/635/R-10/002 www.epa.gov/iris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 III of IV

Quantitative Assessment, Major Conclusions in the Characterization of Hazard and Dose Response, and References

March 17, 2010

NOTICE

This document is an Inter-Agency Science Consultation draft . This information is distributed solely for the purpose of pre-dissemination peer re view 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 implicati ons.
U.S. Environmental Protection Agency Washington, DCThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-ii DISCLAIMER This document is a preliminary draft for review pu rposes only. This information is distributed solely for the purpose of pre-dissemina tion peer review under applicable information quality guidelines. It has not been formally disse minated by EPA. It does not represent and should not be construed to represent any Agency det ermination or policy. Mention of trade names or commercial products does not constitute en dorsement or recommendation for use.This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-iii CONTENTS—TOXICOLOGICAL REVIEW OF FORMALDEHYDE (CAS No. 50-00-0)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 Product ion............................. 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 Anim al 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 Ef fects at the Portal of Entry .................................... ............................................ 3-10 3.2.3.2. Variability in the Nasal Dosimetry of For maldehyde 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: Differentiat ing covalent Binding and Metabolic Incorporation................ ............................. 3-16This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-iv CONTENTS (continued)

3.4. METABOLISM ...................................

................................................... .................... 3-20 3.4.1. In Vitro and In Vivo Characterization of Fo rmaldehyde Metabolism............ 3-20 3.4.2. Formaldehyde Exposure and Perturbation of M etabolic 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 Bre ath...................................... 3-27 3.5.3. Formaldehyde Excretion in Human Urine...... ................................................ 3-3 1 3.6. MODELING THE TOXICOKINETICS OF FORMALDEHYDE A ND DPX.......... 3-32 3.6.1. Motivation .................................

................................................... .................. 3-32 3.6.2. Species Differences in Anatomy: Consequence s for Gas Transport and Risk...............................................

................................................... .............. 3-34 3.6.3. Modeling Formaldehyde Uptake in Nasal Passa ges....................................... 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 R espiratory Tract.................. 3-42 3.6.5. Uncertainties in Formaldehyde Dosimetry Mod eling .................................... 3-44 3.6.5.1. Verification of Predicted Flow Profiles.. ......................................... 3-44 3.6.5.2. Level of Confidence in Formaldehyde Uptak e Simulations............ 3-45 3.6.6. PBPK Modeling of DNA Protein Cross-Links (D PXs) 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 Rhe sus DPX Data.............. 3-51 3.6.7. Uncertainty in Prediction of Human DPX Conc entrations ............................ 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 Irr itation)................................ 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.................. ................................................ 4-4 2 4.1.1.7. Developmental and Reproductive Toxicity.. ................................... 4-45 4.1.1.8. Oral Exposure Effects on the Gastrointest inal Tract ....................... 4-56 4.1.1.9. Summary: Noncarcinogenic Hazard in Humans ............................. 4-56This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-v CONTENTS (continued)

4.1.2. Cancer Health Effects......................

................................................... ............ 4-57 4.1.2.1. Respiratory Tract Cancer................. ................................................ 4-5 7 4.1.2.2. Non-Respiratory Tract Cancer............. ............................................ 4-84 4.1.2.3. Summary: Carcinogenic Hazard in Humans ... .............................. 4-107 4.2. ANIMAL STUDIES ...............................

................................................... ............... 4-109 4.2.1. Noncancer Health Effects...................

................................................... ....... 4-110 4.2.1.1. Reflex Bradypnea ......................... ................................................. 4- 110 4.2.1.2. Respiratory Tract Pathology.............. ............................................ 4-120 4.2.1.3. Gastrointestinal Tract and Systemic Toxic ity................................ 4-201 4.2.1.4. Immune Function.......................... ................................................. 4- 216 4.2.1.5. Hypersensitivity and Atopic Reactions.... ...................................... 4-225 4.2.1.6. Neurological and Neurobehavioral Function ................................. 4-250 4.2.1.7. Reproductive and Developmental Toxicity.. ................................. 4-285 4.2.2. Carcinogenic Potential: Animal Bioassays... ................................................ 4-3 24 4.2.2.1. Respiratory Tract ........................

................................................... 4-324 4.2.2.2. Gastrointestinal Tract ................... ................................................. 4- 326 4.2.2.3. Lymphohematopoietic Cancer............... ........................................ 4-328 4.2.2.4. Summary..................................

................................................... ... 4-335 4.3. GENOTOXICITY.................................

................................................... ................. 4-335 4.3.1. Formaldehyde-DNA Reactions .................

................................................... 4-335 4.3.1.1. DNA-Protein Cross-Links (DPXs)........... ..................................... 4-336 4.3.1.2. DNA Adducts .............................. .................................................. 4 -341 4.3.1.3. DNA-DNA Cross-Links (DDXs) ............... ................................... 4-343 4.3.1.4. Single Strand Breaks ..................... ................................................ 4-3 44 4.3.1.5. Other Genetic Effects of Formaldehyde in Mammalian Cells ...... 4-345 4.3.2. In Vitro Clastogenicity ....................

................................................... .......... 4-345 4.3.3. In Vitro Mutagenicity ......................

................................................... .......... 4-347 4.3.3.1. Mutagenicity in Bacterial Systems ........ ........................................ 4-347 4.3.3.2. Mutagenicity in Non-mammalian Cell System s............................ 4-353 4.3.3.3. Mutagenicity in Mammalian Cell Systems... ................................. 4-353 4.3.4. In Vivo Mammalian Genotoxicity.............

................................................... 4-360 4.3.4.1. Genotoxicity in Laboratory Animals ....... ...................................... 4-360 4.3.4.2. Genotoxicity in Humans................... ............................................. 4-362 4.3.5. Summary of Genotoxicity ....................

................................................... ..... 4-370 4.4. SYNTHESIS AND MAJOR EVALUATION OF NONCARCINOG ENIC EFFECTS ............................................

................................................... ................. 4-371 4.4.1. Sensory Irritation .........................

................................................... .............. 4-376 4.4.2. Pulmonary Function .........................

................................................... ......... 4-379 4.4.3. Hypersensitivity and Atopic Reactions ...... .................................................. 4 -382 4.4.4. Upper Respiratory Tract Histopathology..... ................................................. 4- 383 4.4.5. Toxicogenomic and Molecular Data that May I nform MOAs ..................... 4-385 4.4.6. Noncancer Modes of Actions .................

................................................... ... 4-387 4.4.7. Immunotoxicity .............................

................................................... ............ 4-389This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-vi CONTENTS (continued)

4.4.8. Effects on the Nervous System..............

................................................... .... 4-390 4.4.8.1. Irritant Threshold Detection ............. ............................................. 4-390 4.4.8.2. Behavioral Effects ....................... .................................................. 4 -391 4.4.8.3. Neurochemistry, Neuropathology, and Mecha nistic Studies......... 4-392 4.4.8.4. Summary..................................

................................................... ... 4-392 4.4.8.5. Data Gaps ................................

................................................... ... 4-393 4.4.9. Reproductive and Developmental Toxicity.... .............................................. 4-393 4.4.9.1. Spontaneous Abortion and Fetal Death..... .................................... 4-393 4.4.9.2. Congenital Malformations................. ............................................ 4-396 4.4.9.3. Low Birth Weight and Growth Retardation .. ................................ 4-396 4.4.9.4. Functional Development Outcomes (Developm ental Neurotoxicity)..................................... .......................................... 4-397 4.4.9.5. Male Reproductive Toxicity............... ........................................... 4-398 4.4.9.6. Female Reproductive Toxicity ............. ......................................... 4-399 4.4.9.7. Mode of Action...........................

................................................... 4-400 4.4.9.8. Data Gaps ................................

................................................... ... 4-402 4.5. SYNTHESIS AND EVALUATION OF CARCINOGENICITY.. ........................... 4-402 4.5.1. Cancers of the Respiratory Tract ...........

................................................... .... 4-402 4.5.2. Lymphohematopoietic Malignancies........... ................................................. 4- 408 4.5.2.1. Background...............................

................................................... .. 4-408 4.5.2.2. All LHP Malignancies ..................... .............................................. 4-410 4.5.2.3. All Leukemia .............................

................................................... . 4-414 4.5.2.4. Subtype Analysis ......................... .................................................. 4 -418 4.5.2.5. Myeloid Leukemia......................... ................................................ 4-4 19 4.5.2.6. Solid Tumors of Lymphoid Origin.......... ...................................... 4-421 4.5.2.7. Supporting Evidence from Animal Bio-Assay s for Formaldehyde-Induced Lymphohematopoietic Malignanci es...... 4-423 4.5.3. Carcinogenic Mode(s) of Action .............

................................................... .. 4-427 4.5.3.1. Mechanistic Data for Formaldehyde........ ...................................... 4-428 4.5.3.2. Mode of Action Evaluation for Upper Respi ratory Tract Cancer (Nasopharyngeal Cancer, Sino-Nasal) ......... .................... 4-439 4.5.3.3. Mode(s) of Action for Lymphohematpoietic Malignancies .......... 4-446 4.5.4. Hazard Characterization for Formaldlehyde C arcinogenicity...................... 4-453 4.6. SUSCEPTIBLE POPULATIONS ......................

................................................... ... 4-454 4.6.1. Life Stages ................................

................................................... ................. 4-454 4.6.1.1. Early Life Stages........................

................................................... . 4-455 4.6.1.2. Later Life Stages........................

................................................... . 4-459 4.6.1.3. Conclusions on Life-Stage Susceptibility. ..................................... 4-459 4.6.2. Health/Disease Status ......................

................................................... .......... 4-460 4.6.3. Nutritional Status.........................

................................................... .............. 4-461 4.6.4. Gender Differences.........................

................................................... ........... 4-462 4.6.5. Genetic Differences ........................

................................................... ........... 4-462This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-vii CONTENTS (continued)

4.6.6. Co-Exposures ...............................

................................................... ............. 4-464 4.6.6.1. Cumulative Risk .......................... .................................................. 4 -464 4.6.6.2. Aggregate Exposure....................... ................................................ 4-4 65 4.6.7. Uncertainties of Database..................

................................................... ........ 4-465 4.6.7.1. Uncertainties of Exposure ................ ............................................. 4-465 4.6.7.2. Uncertainties of Effect.................. ................................................. 4- 466 4.6.8. Summary of Potential Susceptibility........

................................................... . 4-467

VOLUME III

5. QUANTITATIVE ASSESSMENT: INHALATION EXPOSURE .. ..................................... 5-1 5.1. INHALATION REFERENCE CONCENTRATION (RfC)..... .................................... 5-2 5.1.1. Candidate Critical Effects by Health Effect Category...................................... 5-3 5.1.1.1. Sensory Irritation of the Eyes, Nose, and Throat............................... 5-3 5.1.1.2. Upper Respiratory Tract Pathology ........ ........................................... 5-5 5.1.1.3. Pulmonary Function Effects ............... ............................................... 5-6 5.1.1.4. Asthma and Allergic Sensitization (Atopy) ..................................... 5-10 5.1.1.5. Immune Function..........................

................................................... 5-16 5.1.1.6. Neurological and Behavioral Toxicity..... ........................................ 5-17 5.1.1.7. Developmental and Reproductive Toxicity.. ................................... 5-25 5.1.2. Summary of Critical Effects and Candidate R fCs.......................................... 5-33 5.1.2.1. Selection of Studies for Candidate RfC De rivation......................... 5-33 5.1.2.2. Derivation of Candidate RfCs from Key Stu dies ............................ 5-40 5.1.2.3. Evaluation of the Study-Specific Candidat e RfC ............................ 5-66 5.1.3. Database Uncertainties in the RfC Derivatio n ............................................... 5-6 9 5.1.4. Uncertainties in the RfC Derivation........

................................................... .... 5-72 5.1.5. Previous Inhalation Assessment.............

................................................... ..... 5-74 5.2. QUANTITATIVE CANCER ASSESSMENT BASED ON THE N ATIONAL CANCER INSTITUTE COHORT STUDY...................... ........................................ 5-74 5.2.1. Choice of Epidemiology Study...............

................................................... ..... 5-75 5.2.2. Nasopharyngeal Cancer......................

................................................... ......... 5-76 5.2.2.1. Exposure-Response Modeling of the Nationa l Cancer Institute Cohort................................... ............................................ 5-76 5.2.2.2. Prediction of Lifetime Extra Risk of Naso pharyngeal Cancer Mortality.......................................... ............................................... 5-79 5.2.2.3. Prediction of Lifetime Extra Risk of Naso pharyngeal Cancer Incidence.......................................... ............................................... 5-81 5.2.2.4. Sources of Uncertainty ................... ................................................. 5- 83 5.2.3. Lymphohematopoietic Cancer.................

................................................... .... 5-88 5.2.3.1. Exposure-Response Modeling of the Nationa l Cancer Institute Cohort................................... ............................................ 5-88This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-viii CONTENTS (continued)

5.2.3.2. Prediction of Lifetime Extra Risks for Ho dgkin Lymphoma and Leukemia Mortality ............................. .................................... 5-91 5.2.3.3. Prediction of Lifetime Extra Risks for Ho dgkin Lymphoma and Leukemia Incidence............................. .................................... 5-93 5.2.3.4. Sources of Uncertainty ................... ................................................. 5- 95 5.2.4. Conclusions on Cancer Unit Risk Estimates B ased on Human Data............. 5-99 5.3. DOSE-RESPONSE MODELING OF RISK OF SQUAMOUS CE LL CARCINOMA IN THE RESPIRATORY TRACT USING ANIMAL DAT A ...... 5-102 5.3.1. Long-Term Bioassays in Laboratory Animals.. ............................................ 5-104 5.3.1.1. Nasal Tumor Incidence Data ............... .......................................... 5-104 5.3.1.2. Mechanistic Data ......................... .................................................. 5 -105 5.3.2. The CIIT Biologically Based Dose-Response M odeling.............................. 5-106 5.3.2.1. Major Results of the CIIT Modeling Effort ................................... 5-111 5.3.3. This Assessment’s Conclusions from Evaluati on of Dose-Response Models of DPX Cell-Replication and Genomics Data, a nd of BBDR Models for Risk Estimation......................... ................................................ 5-1 11 5.3.4. Benchmark Dose Approaches to Rat Nasal Tumo r Data ............................. 5-118 5.3.4.1. Benchmark Dose Derived from BBDR Rat Mode l and Flux as Dosimeter ....................................... .......................................... 5-118 5.3.4.2. Comparison with Other Benchmark Dose Mode ling Efforts ........ 5-125 5.3.4.3. Kaplan-Meier Adjustment .................. ........................................... 5-128 5.3.4.4. EPA Time-to-Tumor Statistical Modeling ... ................................. 5-129 5.4. CONCLUSIONS FROM THE QUANTITATIVE ASSESSMENT OF CANCER RISK FROM FORMALDEHYDE EXPOSURE BY INHALATIO N... 5-133 5.4.1. Inhalation Unit Risk Estimates Based on Hum an Data................................ 5-133 5.4.2. Inhalation Unit Risk Estimates Based on Rod ent Data ................................ 5-133 5.4.3. Summary of Inhalation Unit Risk Estimates .. .............................................. 5-135 5.4.4. Application of Age-Dependent Adjustment Fac tors (ADAFs) .................... 5-136 5.4.5. Conclusions: Cancer Inhalation Unit Risk Es timates................................... 5-137

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HA ZARD AND DOSE-RESPONSE......................................

................................................... ...................... 6-1 6.1. SUMMARY OF HUMAN HAZARD POTENTIAL............ ....................................... 6-1 6.1.1. Exposure...................................

................................................... ..................... 6-1 6.1.2. Absorption, Distribution, Metabolism, and E xcretion ..................................... 6-1 6.1.3. Noncancer Health Effects in Humans and Labo ratory Animals....................... 6-4 6.1.3.1. Sensory Irritation .......................

................................................... ..... 6-4 6.1.3.2. Respiratory Tract Pathology.............. ................................................ 6-5 6.1.3.3. Effects on Pulmonary Function ............ ............................................. 6-8 6.1.3.4. Asthmatic Responses and Increased Atopic Symptoms.................... 6-9 6.1.3.5. Effects on the Immune System ............. ........................................... 6-10 6.1.3.6. Neurological Effects .....................

................................................... 6-11 6.1.3.7. Reproductive and Developmental Effects ... .................................... 6-12This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-ix CONTENTS (continued)

6.1.3.8. Effects on General Systemic Toxicity ..... ........................................ 6-13 6.1.3.9. Summary..................................

................................................... ..... 6-14 6.1.4. Carcinogenicity in Human and Laboratory Ani mals...................................... 6-14 6.1.4.1. Carcinogenicity in Humans ................ ............................................. 6-14 6.1.4.2. Carcinogenicity in Laboratory Animals.... ....................................... 6-20 6.1.4.3. Carcinogenic Mode(s) of Action ........... .......................................... 6-21 6.1.5. Cancer Hazard Characterization.............

................................................... ..... 6-24 6.2. DOSE-RESPONSE CHARACTERIZATION ............... ............................................ 6-25 6.2.1. Noncancer Toxicity: Reference Concentration (RfC) .................................... 6-25 6.2.1.1. Assessment Approach Employed ............. ....................................... 6-25 6.2.1.2. Derivation of Candidate Reference Concent rations ........................ 6-25 6.2.1.3. Adequacy of Overall Data Base for RfC Der ivation ....................... 6-26 6.2.1.4. Uncertainties in the Reference Concentrat ion (RfC)....................... 6-29 6.2.1.5. Conclusions ..............................

................................................... .... 6-32 6.2.2. Cancer Risk Estimates......................

................................................... ........... 6-32 6.2.2.1. Choice of Data...........................

................................................... ... 6-32 6.2.2.2. Analysis of Epidemiologic Data........... ........................................... 6-33 6.2.2.3. Analysis of Laboratory Animal Data....... ........................................ 6-36 6.2.2.4. Extrapolation Aporoaches ................. .............................................. 6-37 6.2.2.5. Inhalation Unit Risk Estimates for Cancer ...................................... 6-41 6.2.2.6. Early-Life Susceptibility................ .................................................. 6 -41 6.2.2.7. Uncertainties in the Quantitative Risk Es timates ............................ 6-42 6.2.2.8. Conclusions ..............................

................................................... .... 6-45 6.3. SUMMARY AND CONCLUSIONS ......................

................................................... 6-45

REFERENCES .........................................

................................................... ................................R-1

VOLUME IV

APPENDIX A: SUMMARY OF EXTERNAL PEER REVIEW AND PU BLIC

COMMENTS AND DISPOSITIONS.......................... .................................... A-1 APPENDIX B: SIMULATIONS OF INTERINDIVIDUAL AND ADU LT-TO-CHILD

VARIABILITY IN REACTIVE GAS UPTAKE IN A SMALL SAMPL E OF PEOPLE (Garcia et al., 2009).................... .................................................B- 1 APPENDIX C: LIFETABLE ANALYSIS ....................

................................................... ..........C-1 APPENDIX D: MODEL STRUCTURE & CALIBRATION IN CONOL LY ET AL.

(2003, 2004).......................................

................................................... ........... D-1 APPENDIX E: EVALUATION OF BBDR MODELING OF NASAL C ANCER IN THE

F344 RAT: CONOLLY ET AL. (2003) AND ALTERNATIVE IMPLEMENTATIONS.................................... .................................................E- 1 APPENDIX F: SENSITIVITY ANALYSIS OF BBDR MODEL FOR FORMALDEHYDE

INDUCED RESPIRATORY CANCER IN HUMANS............... .....................F-1This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-x CONTENTS (continued)

APPENDIX G: EVALUATION OF THE CANCER DOSE-RESPONSE MODELING

OF GENOMIC DATA FOR FORMALDEHYDE RISK ASSESSMENT ... .. G-1 APPENDIX H: EXPERT PANEL CONSULTATION ON QUANTITAT IVE

EVALUATION OF ANIMAL TOXICOLOGY DATA FOR ANALYZING CANCER RISK DUE TO INHALED FORMALDEHYDE.. . H-1This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xi LIST OF TABLES

Table 2-1. Physicochemical properties of formaldeh yde................................................ ............ 2-2

Table 2-2. Ambient air levels by land use category

................................................... ................. 2-6

Table 2-3. Studies on residential indoor air level s of formaldehyde (non-occupational)........... 2-8

Table 3-1. Endogenous formaldehyde levels in anima l and human tissues and body fluids...... 3-8

Table 3-2. Formaldehyde kinetics in human and rat tissue samples..................................... .... 3-21

Table 3-3. Allelic frequencies of ADH3 in human po pulations .......................................... ..... 3-25

Table 3-4. Percent distribution of airborne [ 14 C]-formaldehyde in F344 rats....................... .... 3-26

Table 3-5. Apparent formaldehyde levels in exhaled breath of individuals attending a

health fair, adjusted for methanol and ethanol leve ls which contribute to the detection of the protonated species with a mass to charge ratio of 31 reported as formaldehyde ( m/

z = 31)............................................ ........................................3-29

Table 3-6. Measurements of exhaled formaldehyde co ncentrations in the mouth and nose,

and in the oral cavity after breath holding in thre e healthy male laboratory workers ............................................

................................................... ....................3-30

Table 3-7. Extrapolation of parameters for enzymat ic metabolism to the human.................... 3-53

Table 4-1. Cohort and case-control studies of form aldehyde cancer and NPC ........................4-59

Table 4-2. Case-control studies of formaldehyde an d nasal and paranasal cancer ...................4-71

Table 4-3. Epidemiologic studies of formaldehyde a nd pharyngeal cancer (includes

nasopharyngeal cancer) .............................

................................................... ..........4-78

Table 4-4. Epidemiologic studies of formaldehyde a nd lymphohematopoietic cancers...........4-98

Table 4-5. Respiratory effects of formaldehyde-ind uced reflex bradypnea in various

strains of mice ....................................

................................................... ...............4-112

Table 4-6. Respiratory effects of formaldehyde-ind uced reflex bradypnea in various

strains of rats ....................................

................................................... .................4-113

Table 4-7. Inhaled dose of formaldehyde to nasal m ucosa of F344 rats and B6C3F1

mice exposed to 15 ppm.............................

................................................... .......4-116

Table 4-8. Exposure regimen for cross-tolerance st udy................................................ ..........4-117This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xii LIST OF TABLES (continued)

Table 4-9. Summary of formaldehyde effects on muco ciliary function in the upper

respiratory tract..................................

................................................... ................4-127

Table 4-10. Concentration regimens for ultrastruct ural evaluation of male CDF rat

nasoturbinates.....................................

................................................... ...............4-129

Table 4-11. Enzymatic activities in nasal respirat ory epithelium of male Wistar rats

exposed to formaldehyde, ozone, or both............ .................................................4- 130

Table 4-12. Lipid analysis of lung tissue and lung gavage from male F344 rats exposed

to 0, 15, or 145.6 ppm formaldehyde for 6 hours.... .............................................4-138

Table 4-13. Formaldehyde effects on biochemical pa rameters in nasal mucosa and lung

tissue homogenates from male F344 rats exposed to 0 , 15, or 145.6 ppm formaldehyde for 6 hours ...........................

................................................... .......4-139

Table 4-14. Mast cell degranulation and neutrophil infiltration in the lung of rats

exposed to formaldehyde via inhalation............. ..................................................4 -140

Table 4-15. Summary of respiratory tract pathology from inhalation exposures to formaldehyde—short term studies....................

................................................... .4-143

Table 4-16. Location and incidence of respiratory tract lesions in B6C3F1 mice

exposed to formaldehyde............................

................................................... .......4-146

Table 4-17. Formaldehyde effects (incidence and se verity) on histopathologic changes in

the noses and larynxes of male and female albino SP F Wistar rats exposed to formaldehyde 6 hours/day for 13 weeks.............. .................................................4- 148

Table 4-18. Formaldehyde-induced nonneoplastic his topathologic changes in male

albino SPF Wistar rats exposed to 0, 10, or 20 ppm formaldehyde and examined at the end of 130 weeks inclusive of e xposure..............................4-149

Table 4-19. Formaldehyde-induced nasal tumors in m ale albino SPF Wistar rats

exposed to formaldehyde (6 hours/day, 5 days/week f or 13 weeks) and examined at the end of 130 weeks inclusive of expos ure ....................................4-150

Table 4-20. Formaldehyde effects on nasal epitheli um for various concentration-bytime products in male albino Wistar rats...........

................................................... 4-153

Table 4-21. Rhinitis observed in formaldehyde-trea ted animals; data pooled for male

and female animals.................................

................................................... ..........4-154This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xiii LIST OF TABLES (continued)

Table 4-22. Epithelial lesions found in the middle region of nasoturbinates of

formaldehyde-treated and control animals; data pool ed for males and females............................................

................................................... ..................4-155

Table 4-23. Cellular and molecular changes in nasa l tissues of F344 rats exposed to

formaldehyde.......................................

................................................... .............4-156

Table 4-24. Percent body weight gain and concentra tions of iron, zinc, and copper in

cerebral cortex of male Wistar rats exposed to form aldehyde via inhalation for 4 and 13 weeks.................................

................................................... ...........4-158

Table 4-25. Zinc, copper, and iron content of lung tissue from formaldehyde-treated

male Wistar rats...................................

................................................... .............4-158

Table 4-26. Total lung cytochrome P450 measurement s of control and formaldehydetreated male Sprague-Dawley rats...................

................................................... .4-159

Table 4-27. Cytochrome P450 levels in formaldehyde -treated rats...................................... .4-160

Table 4-28. Summary of respiratory tract pathology from inhalation exposures to formaldehyde, subchronic studies ...................

................................................... .4-162

Table 4-29. Histopathologic findings and severity scores in the naso- and

maxilloturbinates of female Sprague-Dawley rats exp osed to inhaled formaldehyde and wood dust for 104 weeks ........... ............................................4-166

Table 4-30. Histopathologic changes (including tum ors) in nasal cavities of male

Sprague-Dawley rats exposed to inhaled formaldehyde or HCl alone and in combination for a lifetime ......................

................................................... ......4-170

Table 4-31. Summary of neoplastic lesions in the n asal cavity of f344 rats exposed to

inhaled formaldehyde for 2 years ...................

................................................... ..4-173

Table 4-32. Apparent sites of origin for the SCCs in the nasal cavity of F344 rats

exposed to 14.3 ppm of formaldehyde gas in the Kern s et al. (1983) bioassay ...........................................

................................................... .................4-174

Table 4-33. Incidence and location of nasal squamo us cell carcinoma in male F344

rats exposed to inhaled formaldehyde for 2 years ... ............................................4-175

Table 4-34. Summary of respiratory tract pathology from chronic inhalation exposures to formaldehyde....................................

................................................... ............4-183

Table 4-35. Cell proliferation in nasal mucosa, tr achea, and free lung cells isolated

from male Wistar rats after inhalation exposures to formaldehyde.....................4-194This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xiv LIST OF TABLES (continued)

Table 4-36. The effect of repeated formaldehyde in halation exposures for 3 months on

cell count, basal membrane length, proliferation ce lls, and two measures of cell proliferation, LI and ULLI, in male F344 rats . .............................................4-196

Table 4-37. Formaldehyde-induced changes in cell p roliferation and (ULLI) in the nasal

passages of male F344 rats exposed 6 hours/day ..... ...........................................4-198

Table 4-38. Cell population and surface area estim ates in untreated male F344 rats and

regional site location of squamous cell carcinomas in formaldehyde exposed rats for correlation to cell proliferation rates.........................................4-199

Table 4-39. Summary of formaldehyde effects on cel l proliferation in the upper

respiratory tract..................................

................................................... ...............4-202

Table 4-40. Summary of lesions observed in the gas trointestinal tracts of Wistar rats

after drinking-water exposure to formaldehyde for 4 weeks...............................4-206

Table 4-41. Incidence of lesions observed in the g astrointestinal tracts of Wistar rats

after drinking-water exposure to formaldehyde for 2 years.................................4-209

Table 4-42. Effect of formaldehyde on gastroduoden al carcinogenesis initiated by

MNNG and NaCl in male Wistar rats exposed to formal dehyde (0.5% formalin) in drinking water for 8 weeks............ ..................................................4 -212

Table 4-43. Summary of benign and malignant gastro intestinal tract neoplasia

reported in male and female Sprague-Dawley rats exp osed to formaldehyde in drinking water at different ages... .............................................4-214

Table 4-44. Incidence of hemolymphoreticular neopl asia reported in male and

female Sprague-Dawley rats exposed to formaldehyde in drinking water from 7 weeks old for up to 2 years (experiment BT 7 001) .................................4-215

Table 4-45. Battery of immune parameters and funct ional tests assessed in female

B6C3F1 mice after a 3 week, 15-ppm formaldehyde exp osure ..........................4-218

Table 4-46. Summary of the effects of formaldehyde inhalation on the mononuclear

phagocyte system (MPS) in female B6C3F1 mice after a 3-week, 15 ppm formaldehyde exposure ( 6 hours/day, 5 days/week).. .........................................4-219

Table 4-47. Formaldehyde exposure regimens for det ermining the effects of

formaldehyde exposure on pulmonary S. aureus infection .................................4-221

Table 4-48. Summary of immune function changes due to inhaled formaldehyde

exposure in experimental animals ...................

................................................... .4-226This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xv LIST OF TABLES (continued)

Table 4-49. Study design for guinea pigs exposed t o formaldehyde through different

routes of exposure: inhalation, dermal, and injecti on..........................................4-232

Table 4-50. Sensitization response of guinea pigs exposed to formaldehyde through

inhalation, topical application, or footpad injecti on............................................4-233

Table 4-51. Cytokine and chemokine levels in lung tissue homogenate supernatants in

formaldehyde-exposed male ICR mice with and without Der f sensitization.....4-240

Table 4-52. Correlation coefficients among ear swe lling responses and skin mRNA

levels in contact hypersensitivity to formaldehyde in mice.................................4-249

Table 4-53. Summary of sensitization and atopy stu dies by inhalation or dermal

sensitization due to formaldehyde in experimental a nimals................................4-251

Table 4-54. Fluctuation of behavioral responses wh en male AB mice inhaled

formaldehyde in a single 2-hour exposure: effects a fter 2 hours.........................4-259

Table 4-55. Fluctuation of behavioral responses wh en male AB mice inhaled

formaldehyde in a single 2-hour exposure: effects a fter 24 hours.......................4-259

Table 4-56. Effects of formaldehyde exposure on co mpletion of the labyrinth test by

male and female LEW.1K rats ........................

................................................... .4-263

Table 4-57. Summary of neurological and neurobehav ioral studies in inhaled

formaldehyde in experimental animals............... .................................................4- 279

Table 4-58. Effects of formaldehyde on body and or gan weights in rat pups from

dams exposed via inhalation from mating through ges tation..............................4-289

Table 4-59. Formaldehyde effects on Leydig cell qu antity and nuclear damage in adult

male Wistar rats...................................

................................................... .............4-298

Table 4-60. Formaldehyde effects on adult male alb ino Wistar rats .................................... .4-299

Table 4-61. Formaldehyde effects on testosterone l evels and seminiferous tubule

diameters in Wistar rats following 91 days of expos ure .....................................4-300

Table 4-62. Effects of formaldehyde exposure on se miniferous tubule diameter and

epithelial height in Wistar rats following 18 weeks of exposure ........................4-302

Table 4-63. Incidence of sperm abnormalities and d ominant lethal effects in

formaldehyde-treated mice ..........................

................................................... .....4-302This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xvi LIST OF TABLES (continued)

Table 4-64. Body weights of pups born to beagles e xposed to formaldehyde during

gestation..........................................

................................................... ..................4-303

Table 4-65. Testicular weights, sperm head counts, and percentage incidence of

abnormal sperm after oral administration of formald ehyde to male Wistar rats........................................

................................................... .................4-305

Table 4-66. Effect of formaldehyde on spermatogeni c parameters in male Wistar rats

exposed intraperitoneally..........................

................................................... ........4-306

Table 4-67. Incidence of sperm head abnormalities in formaldehyde-treated rats ................4-307

Table 4-68. Dominant lethal mutations after exposu re of male rats to formaldehyde...........4-308

Table 4-69. Summary of reported developmental effe cts in formaldehyde inhalation

exposure studies ...................................

................................................... ............4-311

Table 4-70. Summary of reported developmental effe cts in formaldehyde oral exposure

studies............................................

................................................... ...................4-317

Table 4-71. Summary of reported developmental effe cts in formaldehyde dermal

exposure studies ...................................

................................................... ............4-318

Table 4-72. Summary of reported reproductive effec ts in formaldehyde inhalation

studies............................................

................................................... ...................4-319

Table 4-73. Summary of reported reproductive effec ts in formaldehyde oral studies...........4-322

Table 4-74. Summary of reported reproductive effec ts in formaldehyde intraperitoneal

studies............................................

................................................... ...................4-323

Table 4-75. Summary of chronic bioassays which add ress rodent leukemia and

lymphoma...........................................

................................................... ..............4-329

Table 4-76a. Formaldehyde-DNA reactions (DPX forma tion).............................................. 4-340

Table 4-77. Formaldehyde-DNA reactions (DNA adduct formation) ...................................4-343

Table 4-78. Formaldehyde-DNA interactions (single stranded breaks).................................4- 344

Table 4-79. Other genetic effects of formaldehyde in mammalian cells ...............................4- 346

Table 4-80. In vitro clastogenicity of formaldehyd e.................................................. ............4-348

Table 4-81. Summary of mutagenicity of formaldehyd e in bacterial systems.......................4-350This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xvii LIST OF TABLES (continued)

Table 4-82. Mutagenicity in mammalian cell systems

................................................... ........4-355

Table 4-83. Genotoxicity in laboratory animals ....

................................................... .............4-361

Table 4-84. MN frequencies in buccal mucosa cells of volunteers exposed to

formaldehyde.......................................

................................................... .............4-364

Table 4-85. MN and SCE formation in mortuary scien ce students exposed to

formaldehyde for 85 days ...........................

................................................... ......4-364

Table 4-86. Incidence of MN formation in mortuary students exposed to formaldehyde

for 90 days ........................................

................................................... ................4-365

Table 4-87. Multivariate regression models linking genomic instability/occupational

exposures to selected endpoints from the MN assay.. .........................................4-369

Table 4-88. Genotoxicity measures in pathological anatomy laboratory workers and

controls ...........................................

................................................... ..................4-370

Table 4-89. Summary of human cytogenetic studies ..

................................................... ........4-372

Table 4-90. Summary of cohort and case-control stu dies which evaluated the

incidence of all LHP cancers in formaldehyde-expose d populations (ICD-8 Codes: 200-209) and all leukemias (ICD-8 Cod es: 204-207).................4-412

Table 4-91. Secondary analysis of published mortal ity statistics to explore alternative

disease groupings within the broad category of all lymphohematopoetic malignancies.......................................

................................................... ..............4-419

Table 4-92. Summary of studies which provide morta lity statistics for myeloid

leukemia sub-types .................................

................................................... ..........4-420

Table 4-93. Summary of mortality statistics for Ho dgkin’s lymphoma, lymphoma and

multiple myeloma from cohort analyses of formaldehy de exposed workers ......4-422

Table 4-94. Summary of chronic bioassays which add ress rodent leukemia and

lymphoma...........................................

................................................... ..............4-424

Table 4-95. Incidence of lymphoblastic leukemia an d lymphosarcoma orally dosed in

Sprague-Dawley rats................................

................................................... .........4-425

Table 4-96. Available evidence for susceptibility factors of concern for formaldehyde

exposure...........................................

................................................... .................4-469This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xviii LIST OF TABLES (continued)

Table 5-1. Points of departure (POD) for nervous s ystem toxicity in key human and

animal studies ....................................

................................................... ................5-19

Table 5-2. Effects of formaldehyde exposure on com pletion of the labyrinth test by

male and female LEW.1K rats .......................

................................................... ...5-23

Table 5-3. Developmental and reproductive toxicity PODs including dose conversions and duration adjustments – key human study......... ...............................................5-31

Table 5-4. Summary of candidate studies for formal dehyde RfC development by

health endpoint category...........................

................................................... ..........5-36

Table 5-5. Adjustment for non-occupational exposur es to formaldehyde ..............................5- 64

Table 5-6. Summary of reference concentration (RfC ) derivation from critical study and

supporting studies.................................

................................................... ..............5-68

Table 5-7. Relative risk estimates for mortality f rom nasopharyngeal malignancies (ICD-8 code 147) by level of formaldehyde exposure for different exposure metrics...................................

................................................... ..............5-78

Table 5-8. Regression coefficients from NCI log-li near trend test models for NPC

mortality from cumulative exposure to formaldehyde . .........................................5-79

Table 5-9. Extra risk estimates for NPC mortality from various levels of continuous

exposure to formaldehyde ..........................

................................................... .......5-80

Table 5-10. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC mortal ity from

formaldehyde exposure based on the Hauptmann et al. (2004) log-linear trend analyses for cumulative exposure.............

................................................... .5-81

Table 5-11. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC incide nce from

formaldehyde exposure based on the Hauptmann et al. (2004) trend analyses for cumulative exposure...................

................................................... ....5-82

Table 5-12. Relative risk estimates for mortality from Hodgkin lymphoma

(ICD-8 code 201) and leukemia (ICD-8 codes 204–207) by level of formaldehyde exposure for different exposure metric s.........................................5-90

Table 5-13. Regression coefficients for Hodgkin ly mphoma and leukemia mortality

from NCI trend test models .........................

................................................... .......5-90

Table 5-14. Extra risk estimates for Hodgkin lymph oma mortality from various levels

of continuous exposure to formaldehyde............. ..................................................5 -91This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xix LIST OF TABLES (continued)

Table 5-15. Extra risk estimates for leukemia mort ality from various levels of

continuous exposure to formaldehyde................

................................................... 5-91

Table 5-16. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin ly mphoma

mortality from formaldehyde exposure based on Beane Freeman et al. (2009) log-linear trend analyses for cumulative exp osure.....................................5-93

Table 5-17. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia m ortality

from formaldehyde exposure based on Beane Freeman e t al. (2009) log-linear trend analyses for cumulative exposure .. ..............................................5-93

Table 5-18. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin

lymphoma incidence from formaldehyde exposure, base d on Beane Freeman et al. (2009) log-linear trend analyses for cumulative exposure.............5-94

Table 5-19. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia i ncidence

from formaldehyde exposure based on Beane Freeman e t al. (2009) log-linear trend analyses for cumulative exposure .. ..............................................5-94

Table 5-20. Calculation of combined cancer mortali ty unit risk estimate at 0.1 ppm ...........5-100

Table 5-21. Calculation of combined cancer inciden ce unit risk estimate at 0.1 ppm ..........5-100
Table 5-22. Summary of tumor incidence in long-ter m bioassays on F344 rats....................5-105
Table 5-23. BMD modeling of unit risk of SCC in th e human respiratory tract ...................5-125
Table 5-24. Formaldehyde-induced rat tumor inciden ces................................................ ......5-128
Table 5-25. Human benchmark extrapolations of nasa l tumors in rats using

formaldehyde flux and DPX..........................

................................................... ...5-134
Table 5-26. Summary of inhalation unit risk estima tes ................................................ .........5-135
Table 5-27. Total cancer risk from exposure to a c onstant formaldehyde exposure

level of 1 μg/m 3 from ages 0–70 years .............................. ..................................5-137
Table 6-1. Summary of candidate Reference Concentr ations (RfC) for co-critical studies.....6-27
Table 6-2. Effective concentrations (lifetime cont inuous exposure levels) predicted

for specified extra cancer risk levels for selected formaldehyde-related

cancers ............................................

................................................... ....................6-36

Table 6-3. Inhalation unit risk estimates based on epidemiological and experimental

animal data........................................

................................................... ..................6-42This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xx LIST OF FIGURES

Figure 2-1. Chemical structure of formaldehyde ....

................................................... ................2-1

Figure 2-2. Locations of hazardous air pollutant m onitors............................................ ............2-5

Figure 2-3. Modeled ambient air concentrations bas ed on 1999 emissions ..............................2 -7
Figure 2-4. Range of formaldehyde air concentratio ns (ppb) in different environments...........2-9

Figure 3-1. Formaldehyde-mediated protein modifica tions.............................................. .........3-2

Figure 3-2. 3 H/ 14 C ratios in macromolecular extracts from rat tissue s following exposure

to 14 C and 3 H-labeled formaldehyde (0.3, 2, 6, 10, 15 ppm)..... .........................3-18

Figure 3-3. Formaldehyde clearance by ALDH2 (GSH-i ndependent) and ADH3

(GSH-dependent)....................................

................................................... .........3-20

Figure 3-4. Metabolism of formate.................

................................................... ......................3-22

Figure 3-5. Scatter plot of formaldehyde concentra tions measured in ppb in direct breath

exhalations (x axis) and exhaled breath condensate headspace (y axis) ............3-31

Figure 3-6. Reconstructed nasal passages of F344 r at, rhesus monkey, and human................3-36

Figure 3-7. Illustration of interspecies differenc es in airflow and verification of CFD

simulations with water-dye studies .................

................................................... 3-37

Figure 3-8. Lateral view of nasal wall mass flux o f inhaled formaldehyde simulated in

the F344 rat, rhesus monkey, and human ............. ..............................................3-38

Figure 3-9. CFD simulations of formaldehyde flux t o human nasal lining at different

inspiratory flow rates.............................

................................................... ..........3-39

Figure 3-10. Single-path model simulations of surf ace flux per ppm of formaldehyde exposure concentration in an adult male human ...... ..........................................3-43

Figure 3-11. Pressure drop vs. volumetric airflow rate predicted by the CIIT CFD

model compared with pressure drop measurements made in two hollow molds (C1 and C2) of the rat nasal passage (Cheng e t al., 1990) or in rats in vivo............................................

................................................... ..................3-45

Figure 3-12. Formaldehyde-DPX dosimetry in the F34 4 rat .............................................. .....3-47

Figure 4-1. Delayed asthmatic reaction following t he inhalation of formaldehyde after

“painting” 100% formalin for 20 minutes............ ..............................................4-20This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxi LIST OF FIGURES (continued)

Figure 4-2. Formaldehyde effects on minute volume in naïve and formaldehydepretreated male B6C3F1 mice and F344 rats .......... .........................................4-115

Figure 4-3. Sagittal view of the rat nose (nares o riented to the left)............................... .......4-121

Figure 4-4. Main components of the nasal respirato ry epithelium ...................................... ..4-122

Figure 4-5. Decreased mucus clearance and ciliary beat in isolated frog palates

exposed to formaldehyde after 3 days in culture .... ..........................................4-126

Figure 4-6. Diagram of nasal passages showing sect ion levels chosen for morphometry

and autoradiography in male rhesus monkeys exposed to formaldehyde.........4-135

Figure 4-7. Formaldehyde-induced cell proliferatio n in male rhesus monkeys exposed to

formaldehyde.......................................

................................................... ..........4-136

Figure 4-8. Formaldehyde-induced lesions in male r hesus monkeys exposed to formaldehyde

................................................... ................................................... ....................4-137

Figure 4-9. Frequency and location by cross-sectio n level of squamous metaplasia in

the nasal cavity of F344 rats exposed to formaldehy de via inhalation.............4-172

Figure 4-10. Effect of formaldehyde exposure on ce ll proliferation of the respiratory

mucosa of rats and mice ............................

................................................... ....4-190

Figure 4-11. Alveolar MP Fc-mediated phagocytosis from mice exposed to 5 ppm

formaldehyde, 10 mg/m 3 carbon black, or both ............................. ..................4-223

Figure 4-12. Compressed air in milliliters as para meter for airway obstruction

following formaldehyde exposure in guinea pigs afte r OVA sensitization and OVA challenge ......................................

................................................... ........4-235

Figure 4-13. OVA-specific IgG1 (1B) in formaldehyd e-treated sensitized guinea pigs

prior to OVA challenge .............................

................................................... ....4-235

Figure 4-14. Anti-OVA titers in female Balb/C mice exposed to 6.63 ppm

formaldehyde for 10 consecutive days, or once a wee k for 7 weeks................4-236

Figure 4-15. Vascular permeability in the tracheae and bronchi of male Wistar rats

after 10 minutes of formaldehyde inhalation........ ............................................4-238

Figure 4-16. Effect of select receptor antagonists on formaldehyde-induced vascular

permeability in the trachea and bronchi of male Wis tar rats............................4-239This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxii LIST OF FIGURES (continued)

Figure 4-17. The effects of formaldehyde inhalatio n exposures on eosinophil

infiltration (Panel A) and goblet cell proliferatio n (Panel B) after Der f challenge in the nasal mucosa of male ICR mice afte r sensitization and challenge..........................................

................................................... ..............4-241

Figure 4-18. NGF in BAL fluid from formaldehyde-ex posed female C3H/He mice

with and without OA sensitization .................. .................................................4- 243

Figure 4-19. Plasma Substance P levels in formalde hyde-exposed female C3H/He

mice with and without OVA sensitization ............ ...........................................4-244

Figure 4-20. Motor activity in male and female rat s 2 hours after exposure to

formaldehyde expressed as mean number of crossed qu adrants ± SEM..........4-256

Figure 4-21. Habituation of motor activity was obs erved in control rats during the

second observation period (day 2, 24 hours after fo rmaldehyde exposure) .....4-257

Figure 4-22. Motor activity was reduced in male an d female LEW.1K rats 2 hours

after termination of 10-minute formaldehyde exposur e ...................................4-258

Figure 4-23. The effects of the acute formaldehyde (FA) exposures on the

ambulatory and vertical components of SLMA......... .......................................4-260

Figure 4-24. Effects of formaldehyde exposure on t he error rate of female LEW.1K

rats performing the water labyrinth learning test.. ............................................4-264

Figure 4-25. Basal and stress-induced trunk blood corticosterone levels in male

LEW.1K rats after formaldehyde inhalation exposures ...................................4-269

Figure 4-26. NGF production in the brains of forma ldehyde-exposed mice .........................4-274

Figure 4-27. Mortality corrected cumulative incide nces of nasal carcinomas in the

indicated exposure groups ..........................

................................................... ...4-325

Figure 4-28. Leukemia incidence in Sprague-Dawley rats exposed to formaldehyde

in drinking water for 2 years......................

................................................... ....4-330

Figure 4-29. Unscheduled deaths in female F344 rat s exposed to formaldehyde for

24 months ..........................................

................................................... ............4-332

Figure 4-30. Cumulative leukemia incidence in fema le F344 rats exposed to

formaldehyde for 24 months.........................

................................................... .4-333

Figure 4-31. Cumulative incidence or tumor bearing animals for lymphoma in

female mice exposed to formaldehyde for 24 months.. ....................................4-334This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxiii LIST OF FIGURES (continued)

Figure 4-32. DNA-protein cross-links (DPX) and thy midine kinase ( tk ) mutants in

TK6 human lymphoblasts exposed to formaldehyde for 2 hours.....................4-357

Figure 4-33. Developmental origins for cancers of the lymphohematopoietic system..........4-409

Figure 4-34A. Association between peak formaldehyd e exposure and the risk of

lymphohematopoietic malignancy..................... ...............................................4-41 5

Figure 4-34B. Association between average intensit y of formaldehyde exposure and

the risk of lymphohematopoietic malignancy......... ..........................................4-416

Figure 4-35. Effect of various doses of formaldehy de on cell number in (A) HT-29

human colon carcinoma cells and in (B) human umbili cal vein epithelial cells (HUVEC)

................................................... ................................................... ...4-433

Figure 4-36. Integrated MOA scheme for respiratory tract tumors...................................... ..4-446

Figure 4-37. Location of intra-epithelial lymphocy tes along side epithelial cells in

the human adenoid..................................

................................................... .......4-450

Figure 5-1. Change in number of additions made in 10 minutes following formaldehyde

exposure at 32, 170, 390, or 890 ppb ............... ..................................................5 -21

Figure 5-2. Effects of formaldehyde exposure on the error rate of female LEW.1K rats

performing the water labyrinth learning test ....... ...............................................5-24

Figure 5-3. Fecundity density ratio among women ex posed to formaldehyde in the high

exposure index category with 8-hour time weighted a verage formaldehyde exposure concentration of 219 ppb..................

................................................... 5-27

Figure 5-4. Estimated reduction in peak expiratory flow rate (PEFR) in children in

relation to indoor residential formaldehyde concent rations. ..............................5-41

Figure 5.5. Odds ratios for physician-diagnosed as thma in children associated with inhome formaldehyde levels in air ...................

................................................... .5-45

Figure 5-6. Prevalence of asthma and respiratory s ymptom scores in children associated

with in-home formaldehyde levels ................... ..................................................5 -48

Figure 5-7. Prevalence and severity of allergic se nsitization in children associated with

in-home formaldehyde levels ........................

................................................... ..5-49

Figure 5-8. Positive exposure-response relationshi ps reported for in-home

formaldehyde exposures and sensory irritation (eye irritation) ..........................5-53This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxiv LIST OF FIGURES (continued)

Figure 5-9. Positive exposure-response relationshi ps reported for in-home

formaldehyde exposures and sensory irritation (burn ing eyes) ..........................5-54

Figure 5-10. Age-specific mortality and incidence rates for myeloid, lymphoid, and

all leukemia .......................................

................................................... ..............5-98

Figure 5-11. Schematic of integration of pharmacok inetic and pharmacodynamic

components in the CIIT model ....................... ..................................................5 -110

Figure 5-12. Fit to the rat tumor incidence data u sing the model and assumptions in

Conolly et al. (2003)..............................

................................................... ........5-112

Figure 5-13. Spatial distribution of formaldehyde over the nasal lining, as

characterized by partitioning the nasal surface by formaldehyde flux to the tissue per ppm of exposure concentration, resul ting in 20 flux bins ..........5-120

Figure 5-14. Distribution of cells at risk across flux bins in the F344 rat nasal lining..........5-1 20

Figure 5-15. MLE and upper bound (UB) added risk o f SCC in the human nose for

two BBDR models....................................

................................................... .....5-124

Figure 5-16. Replot of log-probit fit of the combi ned Kerns et al. (1983) and

Monticello et al. (1996) data on tumor incidence sh owing BMC 10 and BMCL 10 ................................................... ................................................... ......5-127

Figure 5-17. EPA multistate Weibull modeling: nas al tumor dose response .......................5-131

Figure 5-18. Multistage Weibull model fit .........

................................................... ................5-132

Figure 5-19. Multistage Weibull model fit of tumor incidence data compared with KM estimates of spontaneous tumor incidence........ ........................................5-132This document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxv LIST OF ABBREVIATIONS AND ACRONYMS

ACGIH American Conference of Governmental Industria l Hygienists ADAF age-dependent adjustment factors ADH alcohol dehydrogenase ADS anterior dorsal septum AIC Akaike Information Criterion AIE average intensity of exposure AIHA American Industrial Hygiene Association ALB albumin ALDH aldehyde dehydrogenase ALL acute lymphocytic leukemia ALM anterior lateral meatus ALP alkaline phosphatase ALS amyotrophic lateral sclerosis ALT alanine aminotransferase AML acute myelogenous leukemia AMM anterior medial maxilloturbinate AMPase adenosine monophosphatase AMS anterior medial septum ANAE alpha-naphthylacetate esterase ANOVA analysis of variance APA American Psychiatric Association ARB Air Resources Board AST aspartate aminotransferase ATCM airborne toxic control measure ATP adenosine triphosphate ATPase adenosine triphosphatase ATS American Thoracic Society ATSDR Agency for Toxic Substances and Disease Regis try AUC area under the curve BAL bronchoalveolar lavage BALT bronchus associated lymphoid tissue BBDR biologically based dose response BC bronchial construction BCME bis(chloromethyl)ether BDNF brain-derived neurotrophic factor BEIR biologic effects of ionizing radiation BfR German Federal Institute for Risk Assessment BHR bronchial hyperresponsiveness BMC benchmark concentration BMCL 95% lower bound on the benchmark concentratio n BMCR binuclated micronucleated cell ratefluoresce BMD benchmark dose BMDL 95% lower bound on the benchmark doseThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxvi LIST OF ABBREVIATIONS AND ACRONYMS (continued)

BMR benchmark response BN Brown-Norway BrdU bromodeoxyuridine BUN blood urea nitrogen BW body weight CA chromosomal aberrations CalEPA California Environmental Protection Agency CAP College of American Pathologists CASRN Chemical Abstracts Service Registry Number CAT catalase CBMA cytokinesis-blocked micronucleus assay CBMN cytokinesis-blocked micronucleus CDC U.S. Centers for Disease Control and Preventio n CDHS California Department of Health Services CFD computational fluid dynamics CGM clonal growth model CHO Chinese hamster ovary CI confidence interval CIIT Chemical Industry Institute of Toxicology CLL chronic lymphocytic leukemia CML chronic myelogenous leukemia CNS central nervous system CO 2 carbon dioxide COEHHA California Office of Environmental Health Ha zard Assessment CREB cyclic AMP responsive element binding protein s CS conditioned stimulus C × t concentration times time DA Daltons DAF dosimetric adjustment factor DDX DNA-DNA cross-links DEI daily exposure index DEN diethylnitrosamine Der f common dust mite allergen DMG dimethylglycine DMGDH dimethylglycine dehydrogenase DNA deoxyribonucleic acid DOPAC 3,4-dihydroxyphenylacetic acid DPC / DPX DNA-protein cross-links EBV Epstein-Barr virus EC effective concentration ED effective dose EHC Environmental Health Committee ELISA enzyme-linked immunosorbent assayThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxvii LIST OF ABBREVIATIONS AND ACRONYMS (continued)

EPA U.S. Environmental Protection Agency ERPG emergency response planning guideline ET ethmoid turbinates FALDH formaldehyde dehydrogenase FDA U.S. Food and Drug Administration FDR fecundability density ratio FEF forced expiratory flow FEMA Federal Emergency Management Agency FEV1 forced expiratory volume in 1 second FISH fluorescent in situ hybridization FSH follicle-stimulating hormone FVC forced vital capacity GALT gut-associated lymphoid tissue GC-MS gas chromatography-mass spectrometry GD gestation day GI gastrointestinal GO gene ontology G6PDH glucose-6-phosphate dehydrogenase GPX glutathione peroxidase GR glutathione reductase GM-CSF granulocyte macrophage-colony-stimulating fa ctor GSH reduced glutathione GSNO S-nitrosoglutathione GST glutathione S-transferase HAP hazardous air pollutant Hb hemoglobin HCl hydrochloric acid HCT hematocrit HEC human equivalent concentration 5-HIAA 5-hydroxyindoleacetic acid hm hydroxymethyl HMGSH S-hydroxymethylglutathione HPA hypothalamic-pituitary adrenal HPG hypothalamo-pituitary-gonadal HPLC high-performance liquid chromatography HPRT hypoxanthine-guanine phosphoribosyl transfera se HR high responders HSA human serum albumin HSDB Hazardous Substances Data Bank Hsp heat shock protein HWE healthy worker effect I cell initiated cell IARC International Agency for Research on CancerThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxviii LIST OF ABBREVIATIONS AND ACRONYMS (continued)

ICD International Classification of Diseases IF interfacial IFN interferon Ig immunoglobulin IL interleukin I.P. intraperitoneal IPCS International Programme on Chemical Safety IRIS Integrated Risk Information System K m Michaels-Menton constant KM Kaplan-Meier LD 50 median lethal dose LDH lactate dehydrogenase LEC 95% lower bound on the effective concentration LED 95% lower bound on the effective dose LHP lymphohematopoietic LI labeling index LM Listeria monocytogenes LMS linearized multistage LLNA local lymph node assay LOAEL lowest-observed-adverse-effect level LPS lipopolysaccharide LR low responders LRT lower respiratory tract MA methylamine MALT mucus-associated lymph tissues MCH mean corpuscular hemoglobin MCHC mean corpuscular hemoglobin concentration MCS multiple chemical sensitivity MCV mean corpuscular volume MDA malondialdehyde MEF maximal expiratory flow ML myeloid leukemia MLE maximum likelihood estimate MMS methyl methane sulfonate MMT medial maxilloturbinate MN micronucleus, micronuclei MNNG N-methyl-N-nitro-N-nitrosoguanidine MOA mode of action MoDC monocyte-derived dendritic cell MP macrophage MPD multistage polynomial degree MPS mononuclear phagocyte system MRL minimum risk levelThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxix LIST OF ABBREVIATIONS AND ACRONYMS (continued)

mRNA messenger ribonucleic acid MVE-2 Murray Valley encephalitis virus MVK Moolgavkar, Venzon, and Knudson N cell normal cell NaCl sodium choride NAD+ nicotinamide adenine dinucleotide NADH reduced nicotinamide adenine dinucleotide NALT nasally associated lymphoid tissue NATA National-Scale Air Toxics Assessment NCEA National Center for Environmental Assessment NCHS National Center for Health Statistics NCI National Cancer Institute NEG Nordic Expert Group NER nucleotide excision repair NGF nerve growth factor NHL non-Hodgkin’s lymphoma NHMRC/ARMCANZ National Health and Medical Researc h Council/Agriculture and Resource

Management Council of Australia and New Zealand NNK nitrosamine nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-butanone N 6 -hmdA N 6 -hydroxymethyldeoxyadenosine N 4 -hmdC N 4 -hydroxymethylcytidine N 2 -hmdG N 2 -hydroxymethyldeoxyguanosine NICNAS National Industrial Chemicals Notification a nd Assessment Scheme NIOSH National Institute for Occupational Safety an d Health NLM National Library of Medicine NMDA N-methyl-D-aspartate NO nitric oxide NOAEL no-observed-adverse-effect level NPC nasopharyngeal cancer NRBA neutrophil respiratory burst activity NRC National Research Council NTP National Toxicology Program OR odds ratio OSHA Occupational Safety and Health Administration OTS Office of Toxic Substances OVA ovalbumin PBPK physiologically based pharmacokinetic PC Philadelphia chromosome PCA passive cutaneous anaphylaxis PCMR proportionate cancer mortality ratio PCNA proliferating cell nuclear antigen PCR polymerase chain reaction PCV packed cell volumeThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxx LIST OF ABBREVIATIONS AND ACRONYMS (continued)

PECAM platelet endothelial cell adhesion molecule PEF peak expiratory flow PEFR peak expiratory flow rates PEL permissible exposure limit PFC plaque-forming cell PG periglomerular PHA phytohemagglutinin PLA2 phospholipase A2 PI phagocytic index PLM posterior lateral meatus PMA phorbol 12-myristate 13-acetate PMR proportionate mortality ratio PMS posterior medial septum PND postnatal day POD point of departure POE portal of entry PTZ pentilenetetrazole PUFA polyunsaturated fatty acids PWULLI population weighted unit length labeling ind ex RA reflex apnea RANTES regulated upon activation, normal T–cell exp ressed and secreted RB reflex bradypnea RBC red blood cells RD 50 exposure concentration that results in a 50% redu ction in respiratory rate REL recommended exposure limit RfC reference concentration RfD reference dose RGD regional gas dose RGDR regional gas dose ratio RR relative risk RT reverse transcriptase SAB Science Advisory Board SCC squamous cell carcinoma SCE sister chromatid exchange SCG sodium cromoglycate SD standard deviation SDH succinate dehydrogenase; sarcosine dehydrogena se SEER Surveillance, Epidemiology, and End Results SEM standard error of the mean SEN sensitizer SH sulfhydryl SHE Syrian hamster embryo SLMA spontaneous locomotor activityThis document is a draft for review purposes only a nd does not constitute Agency policy

. DRAFT—DO NOT CITE OR QUOTE III-xxxi LIST OF ABBREVIATIONS AND ACRONYMS (continued)

SMR standardized mortality ratio SNP single nucleotide polymorphism SOD superoxide dismutase SOMedA N 6 -sulfomethyldeoxyadenosine Sp1 specificity protein SPIR standardized proportionate incidence ratio SSAO semicarbozole-sensitive amine oxidase SSB single strand breaks STEL short-term exposure limit TBA tumor bearing animal TH T-lymphocyte helper THF tetrahydrofolate TK toxicokinetics TL tail length TLV threshold limit value TNF tumor necrosis factor TP total protein TRI Toxic Release Inventory TRPV transient receptor potential vanilloid TWA time-weighted average TZCA thiazolidine-4-carboxylate UCL upper confidence limit UDS unscheduled DNA synthesis UF uncertainty factor UFFI urea formaldehyde foam insulation ULLI unit length labeling index URT upper respiratory tract USDA U.S. Department of Agriculture VC vital capacity VOC volatile organic compound WBC white blood cell WDS wet dog shake WHO World Health Organization WHOROE World Health Organization Regional Office fo r EuropeThis document is a draft for review purposes only a nd does not constitute Agency policy

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### This page intentionally left blank.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-1 5. QUANTITATIVE ASSESSMENT: INHALATION EXPOSURE 1 2 3 This chapter presents the quantitative assessments conducted by EPA for both cancer and 4 noncancer health effects associated with formaldehy de exposure. The quantitative assessment is 5 focused on the inhalation route of exposure. The c urrent IRIS reference dose (RfD) is not 6 reevaluated in this assessment. Although there is some evidence of formaldehyde 7 carcinogenicity via the oral route of exposure, the se data are not evaluated herein nor is an oral 8 slope factor considered at this time. Therefore, t he following sections address derivation of a 9 reference concentration (RfC) and cancer unit risk estimate for inhalation exposures. 10 For noncancer effects, the RfC is an estimate (wit h uncertainty spanning perhaps an order 11 of magnitude) of a continuous inhalation exposure t o the human population (including sensitive 12 subgroups) that is likely to be without an apprecia ble risk of deleterious effects during a lifetime. 13 It can be derived from a NOAEL, LOAEL, or benchmar k concentration, with uncertainty factors 14 generally applied to reflect limitations of the dat a used. Data from the previous chapters are 15
evaluated to determine the health effects associate d with formaldehyde exposure and which 16 studies may best inform the exposure response relat ionship for RfC derivation. Section 5.1 17 summarizes the observed noncancer health effects, s electing key studies and critical effects for 18
consideration. Candidate RfCs are derived for each identified key study. Several alternatives are 19 considered for uncertainty factors addressing human variability for key studies and alternatives 20 presented (Section 5.1.2.3). Options for addressin g the overall database uncertainty factor are 21 provided which may modify the final RfC (Section 5. 1.3). 22
The derivation of the cancer inhalation unit risk estimate considered data regarding both 23 respiratory tract cancers and lymphohematopoietic m alignancies. Exposure-response modeling 24 from epidemiologic studies was used to derive a com bined unit risk estimate for nasopharyngeal 25 cancer and lymphohematopoietic cancers (Section 5.2 ). This unit risk estimate is supported by 26 an analysis of exposure-response modeling of respir atory tract cancer risk using data from 27 experimental animal studies (Section 5.3). Analysi s of the animal bioassays includes an 28 evaluation of a published biologically based dose-r esponse model as well as an appraisal of 29 published dose-response modeling of genomics data a nd a presentation of benchmark dose 30 modeling approaches. Finally, Section 5.4 provides a summary and conclusions from the cancer 31 exposure-response modeling, presenting the final un it risk estimate based on the combined risk 32 of nasopharyngeal cancer and lymphohematopoietic ca ncers observed in the human studies. 33
34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-2 1 5.1. INHALATION REFERENCE CONCENTRATION (RfC) 2 Prior to the current assessment, the EPA IRIS file for formaldehyde did not provide an 3
inhalation RfC. As presented in the hazard identification in Chapt er 4, a number of noncancer 4 health effects are associated with formaldehyde exp osure. Section 5.1.1 describes each of the 5 health effect categories considered for RfC derivat ion and the specific endpoints considered for 6 each category. The identified effect categories ar e: sensory irritation (eye, nose, and throat); 7 upper respiratory tract (URT) pathology; pulmonary function; increased asthma and atopic 8 sensitization; altered immune function; neurotoxici ty and reproductive and developmental 9 toxicity. For each health effect category,, studie s that may adequately inform the exposure10 response relationship for specific critical effects are identified for consideration in RfC 11
derivation. 12 EPA employed a screening process across the differ ent health effect categories to select 13 key studies that would best support the derivation of an inhalation RfC (as described in 14 Section 5.1.2.1). The following factors were consi dered in this evaluation: characteristics of the 15 study population, exposure regimen, quality of expo sure assessment, quality of exposure16 response assessment, exposure levels at which effec ts were seen and statistical power of the 17 study. Based on this analysis, seven studies were considered for RfC derivation. Candidate RfC 18 derivation from a key study includes the following steps: 1) define the critical effect(s); 2) 19 determine appropriate point(s) of departure (PODs) on the basis of inhaled concentration; 3) 20 adjust each POD by endpoint/study-specific uncertai nty factors (UFs), to account for 21 uncertainties in the extrapolation of study results to conditions of human environmental 22 exposure. All of the identified key studies were h uman studies and several studies included 23 potentially susceptible individuals (e.g. children, asthmatics). The uncertainty factor for human 24 variability has sometimes been reduced for studies of susceptible populations or lifestages. 25 However, for five of the seven key studies it was u nclear if an uncertainty factor of 3 or 1 for 26 human variability was most appropriate. Therefore, alternatives are presented for consideration. 27 Candidate RfCs (cRfCs) are derived for sensory irri tation, decreased pulmonary function in 28 children, increased asthma incidence in children, i ncreased allergic sensitization to common 29 allergens in children, and decreased fecundability density ratio (FDR) in women (increased time 30 to pregnancy) (Table 5-7). All of these cRfCs are derived from endpoints identified in residential 31 studies, with the exception of decreased FDR (obser ved in an occupational study of women in 32 the woodworking industry). 33
The overall literature database of both human and l aboratory animal studies examining 34 the health effects from formaldehyde exposure is la rge; however, the available studies for some 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-3 types of effects are limited. Limitations in the e xisting database are discussed in Section 5.1.3, 1 specifically regarding understanding the reproducti ve and developmental effects and the 2 exposure-response relationship for the observed neu rological and behavioral effects from 3 formaldehyde exposure. EPA considers 3 options for addressing these database uncertainties in 4 the final RfC: (1) providing an RfC derived from st udies of respiratory and allergenic responses 5 and protective of sensory irritation effects, witho ut further adjustment for uncertainties in the 6 database (noting the need for further research to e lucidate reproductive, developmental and 7 neurotoxic effects); (2) providing an RfC with a da tabase uncertainty factor incorporated to 8 reflect the potential that reproductive, developmen tal, or neurotoxic effects might occur at lower 9 doses; or (3) provide a range for the RfC which enc ompasses the above two options for the 10 database uncertainty factor. 11
12 5.1.1. Candidate Critical Effects by Health Effect Category 13 The following subsections describe the best availab le studies and endpoints for 14 quantitative RfC derivation within each health effe ct category. These studies are considered 15 representative of the health effects attributed to formaldehyde exposure. For more details on 16 specific studies discussed here, see Sections 4.1.1 and 4.2.1. The identified health effect 17 categories are: sensory irritation (eye, nose, and throat); upper respiratory tract (URT) pathology; 18 pulmonary function; increased asthma and allergic s ensitization; altered immune function; 19 neurotoxicity and reproductive and developmental to xicity. Discussions in each subsection 20
below describe the various health effects observed in human and animal studies for each 21 category. 22 For each health effect category, specific studies t hat may adequately inform the exposure23 response relationship for critical effects are iden tified for consideration in RfC derivation. In 24 general, studies are included where study quality a nd ability to define exposures are considered 25 adequate for RfC derivation. Whenever possible, gr eater consideration is typically given to 26
human data for derivation of an RfC. When laborato ry studies conducted in rodents are 27 considered for RfC derivation, the potential confou nding effects of formaldehyde-induced reflex 28 bradypnea (RB) are evaluated (Section 4.1.1 for a d iscussion of RB). If the exposure levels are 29 expected to cause RB, results are evaluated to ensu re the effects are not in part attributable to 30 primary or secondary effects of RB in the rodents. 31
32
5.1.1.1. Sensory Irritation of the Eyes, Nose, and Throat 33 Eye, nose, and throat irritation are common effects of chemically induced sensory 34 irritation; specific effects include lacrimation, b urning of the eyes and nose, rhinitis, burning of 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-4 the throat, and cough (Feron et al., 2001). Chemic al irritants such as formaldehyde bind to 1 protein receptors of the trigeminal nerve, triggeri ng a burning and painful sensation. This 2 process is distinct from taste and smell (Cometto-M uniz and Cain, 1992; Nielsen, 1991). The 3 trigeminal nerve has three branches (ophthalmic, ma xillary, and mandibular) and not only acts as 4 an afferent nerve relaying these sensations to the central nervous system but has efferent nerve 5 activity as well (Meggs, 1993). Stimulation of the trigeminal nerve may result in reflex 6 responses, including lacrimation, coughing, and sne ezing. In this assessment, both the reflex 7 responses and the sensations (such as burning, pain , and itching of the eyes, nose, and throat) are 8 considered adverse effects (see Section 4.1 for a f ull discussion of available human data). 9 There are studies noting irritant effects in rodent s (Sarsilmaz et al., 1999; Holmström et 10 al., 1989; Dubreuil et al., 1976) and monkeys (Mont icello et al., 1989; Rusch et al., 1983). These 11 animal studies are supportive of the health effects reported in humans. However, given the 12 uncertainties in extrapolation from responses in la boratory animals to expected responses in 13 humans, the available human studies are preferred. 14 In human studies, the endpoints for assessing irrit ation include subjective self reporting of 15 symptoms (e.g., pain, burning, itching, increased c ough) via questionnaires or objective measures 16 of irritation that can be assessed during controlle d acute exposures (e.g., eye-blink counts, 17 lacrimation). Several acute chamber studies suppor t development of a concentration-response 18 relationship for sensory irritation, identifying an effect level for various exposure durations 19 (Kulle, 1993; Andersen and Mølhave, 1983; Bender et al., 1983; Weber-Tschopp et al., 1977). 20 Arts et al. (2006b) reviewed several studies and pe rformed BMD analyses, reporting 10% extra 21 risk BMCL values for reported eye discomfort of 560 and 240 ppb for 3 and 5 hour exposures, 22 respectively. LOAELs of 1,000 ppb and 1,700 ppb we re reported for 1-2 minute exposures 23 (Bender et al., 1983; Weber-Tschopp et al., 1977). These acute studies support a role for both 24
concentration and duration in the effect level for eye irritation. Although exposure 25
concentrations are well-defined in these chamber st udies, the chamber studies are not appropriate 26 for RfC derivation because they are of acute durati on and the exposure levels used are much 27 higher than those reported for chronic exposure sce narios, both occupational and residential. 28 A study of industrial workers assessed sensory irr itation and provided an average 29 exposure derived from in-plant exposure measurement s and the work history of each study 30 participant (Holmström and Wilhelmsson, 1988). Alt hough average daily exposures were 31 estimated for each employee, these data were not us ed to explore an exposure-response 32 relationship within the worker cohort. The symptom prevalence for sensory irritation (e.g., nasal 33 discomfort, eye discomfort, and airway discomfort) relative to the referent group was reported for 34 the cohort as a whole, where worker exposure ranged from 0.05 to 0.5 mg/m 3 formaldehyde 8-hr 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-5 time-weighted average (TWA), with a mean of 0.26 mg /m 3 (210 ppb). The daily TWA does not 1 reflect the peak exposures experienced during speci fic work tasks. Although this study 2 demonstrated marked increases in symptoms of sensor y irritation in the workplace due to 3 formaldehyde exposure, it provided little data to i nform the exposure-response relationship, 4 especially in the range of environmental exposures. 5 There are three studies that report sensory irritat ion in humans from chronic exposures in 6 a residential environment and provide sufficient ex posure data to support quantitative assessment 7 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrah an et al., 1984). Each study reports site8 specific exposure measurements and presents some me tric of individual exposure. These 9 residential studies employ in-home measurements for each study participant, either as average 10 exposure level (Ritchie and Lehnen, 1987; Hanrahan et al., 1984) or as calculated cumulative 11 exposure based on the time in the home (Liu et al., 1991). Eye irritation is reported at similar 12 levels of residential formaldehyde exposure in the three studies (Figures 5-8 and 5-9). Each 13 study provides an exposure-response relationship fo r prevalence of sensory irritation in relation 14 to in-home formaldehyde exposure based on individua l level data. The detailed exposure 15 information and chronic nature of the exposures sup port the selection of these studies as potential 16 priniciple studies for RfC derivation. Each of the se studies is further evaluated and a cRfC 17 developed for consideration (Section 5.1.2). 18
19
5.1.1.2. Upper Respiratory Tract Pathology 20 Formaldehyde-induced respiratory tract pathology in cludes inflammation, rhinitis, goblet 21 cell hyperplasia, metaplastic changes, squamous cel l hyperplasia, and impaired mucociliary 22 transport. A series of laboratory animal studies as sessing formaldehyde-induced changes in the 23 nasal mucosa suggests that these changes may be a p rotective or adaptive response and that 24 increased mucus flow and metaplastic changes will p rogress in relation to the concentration and 25 duration of exposure to protect the underlying tiss ue (Swenberg et al., 1983). The degree of 26 inflammation, hyperplasia, and metaplastic change t hat is due to sensory irritation-induced 27 inflammatory responses versus inflammation and tiss ue remodeling from formaldehyde-induced 28 direct cell damage cannot be distinguished. These changes have been noted as sensitive 29 indicators of formaldehyde-induced effects, occurri ng before gross cellular damage and focal 30 lesions (Monticello et al., 1989). These responses are considered for RfC derivation, especially 31 for exposure concentrations where gross damage of t he underlying tissue is not expected. 32 Although well-documented studies demonstrating form aldehyde-induced upper respiratory tract 33 (URT) pathology have been performed in laboratory a nimals, including the rat (Zwart et al., 34 1988; Woutersen et al., 1987; Morgan et al., 1986a, b, 1983; Swenberg et al., 1986, 1983) and 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-6 monkey (Rusch et al., 1983), robust human data are available, and these human data are preferred 1
for RfC derivation. 2
Six human studies examined the effects of formalde hyde exposure on URT pathology 3 (Pazdrak et al., 1993; Boysen et al., 1990; Holmstr öm et al., 1989; Edling et al., 1988; 4 Holmström and Wilhelmsson, 1988; Andersen and Mølha ve, 1983). Of these studies, 5 Holmström and Wilhelmsson (1988) and Holmström et a l. (1989) were identified as the most 6
robust and sensitive and are included as candidate studies for RfC derivation (see Table 5-1). 7 Both studies address the same cohort and, thus, wer e considered together. The Holmström and 8 Wilhelmsson (1988) study is discussed above under s ensory irritation effects. In this study of 70 9 factory workers exposed to a TWA formaldehyde conce ntration of 210 ppb, impaired 10 mucociliary clearance was reported in 20% of the ex posed workers and 3% of the 36 nonexposed 11 workers. Using rhinomanometry, Holmström and Wilhe lmsson (1988) also found an increase in 12 nasal resistance due to mucosal swelling, though th is increase was not statistically significant. In 13 Holmström et al. (1989), nasal biopsy samples were collected from 62 of the 70 formaldehyde14 exposed factory workers (these 62 had been exposed to a TWA formaldehyde concentration of 15 240 ppb) and also from 32 of the nonexposed workers . A pathologist scored each sample by 16 using a scale of 0 (normal respiratory epithelium) to 8 (carcinoma). Biopsy scores for both the 17 exposed and control groups ranged from 0 (normal re spiratory epithelium) to 4 (stratified 18 squamous epithelium with marked horny layer). The mean scores for the two groups—2.16 for 19 the formaldehyde-exposed workers and 1.56 for the u nexposed workers—however, the 20 difference was statistically significant and the au thors reported that the loss of cilia, goblet cell 21 hyperplasia, and the incidence of cuboidal and squa mous cell metaplasia replacing the columnar 22 epithelium were more frequent in the group exposed to formaldehyde. There was no correlation 23 between the duration of exposure and histologic cha nges or between smoking habits and biopsy 24 scores. The URT effects, taken together (decreased mucous flow, increased inflammation, 25 decreased nasal flow, and degradation of the respir atory epithelium), demonstrate a range of 26 formaldehyde-induced URT pathology consistent with effects observed in controlled animal 27
studies. 28
29
5.1.1.3. Pulmonary Function Effects 30 The potential effects of formaldehyde exposure on pulmonary function in humans can be 31
examined on several time-scales of interest. There are reports examining effects from acute 32 exposures among naively exposed anatomy graduate st udents (Kriebel et al., 1993; 2001), 33 anatomy graduate students with several weeks of epi sodic exposure (Kriebel et al., 1993), as well 34 as post-shift versus pre-shift differences in pulmo nary function in workers with regular 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-7 occupational exposure (Malaka and Kodama, 1990; Her bert et al., 1994; Alexandersson et al., 1 1982; Alexandersson and Hedenstierna, 1989). Depend ing on whether the exposures are naïve, 2 the epidemiologic studies that assessed the pulmona ry effects of acute exposures to formaldehyde 3 may be assessing different biological responses, na mely, the acute effect alone or the acute 4 effect(s) in people who may have already been sensi tized to formaldehyde effects. 5 Pulmonary effects of acute formaldehyde exposure ha ve been studied in both healthy 6 volunteers and sensitive populations under controll ed conditions (e.g. acute chamber studies). 7 Although acute chamber studies have the advantage o f measured controlled exposures, other 8
factors can limit the usefulness of the studies for RfC derivation including: acute duration, small 9 study populations and lack of statistical power to assess the measured parameters. The acute 10 chamber studies are more fully evaluated in Section 4.1.1 and will not be further considered here 11
for RfC derivation. 12 The observed effects in the previously unexposed an atomy students provide additional 13 information on acute exposures in two naïve populat ions (Kriebel et al., 1993; 2001), as well as 14 insight into the intermediate stages of possible se nsitization (Kriebel et al., 1993). Kriebel and 15 colleagues (1993) examined the pre-laboratory and p ost-laboratory peak expiratory flow (PEF) in 16 students attending anatomy classes once per week. T hey found the strongest pulmonary response 17 when examining the average cross-laboratory decreme nt in peak expiratory flow in the first 2 18 weeks of the study when formaldehyde concentrations collected in the breathing zones had a 19 geometric average concentration of 0.73 ppm. Overal l, the students exhibited a 2% decrement in 20 PEF, while the students with any history of asthma showed a 7.3% decrement in PEF. These 21 findings of acute decreases in PEF following studen ts’ initial anatomy sessions were 22 corroborated by the Kriebel et al. (2001) study, wh ich used a similar study design applied to 23 another class of anatomy students. 24 The first Kriebel et al. (1993) study also shows ho w the acute effects of formaldehyde 25 exposure were altered following several weeks of we ekly episodic exposure. By the 5 th week of 26 class, the pre- and post-laboratory measurements of PEF were no longer reflecting a clearly 27 demonstrated acute effect but following the 7th wee k of episodic exposure, both pre-and post28 laboratory PEF continued to drop steadily until the class adjourned after 10 weeks time. While 29 the acute effects of formaldehyde exposure appeared to diminish after several weeks of exposure, 30
the intermediate effect across 9 weeks was a 24 lit er/minute drop in PEF that was statistically 31 significant (P<0.01) after statistical control for random person effects, asthma, an interaction 32 between time and asthma and eye and nose symptoms o f irritation. The Kriebel et al. (1993) 33 study is considered of sufficient quality to suppor t an acute RfC but the quantitative details on 34 the initial acute effects among the naively exposed students are not adequately provided. The 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-8 findings of the Kriebel et al. (2001) study were co nfounded by decreased class attendance, which 1 dropped from 37 in the first week to 20 in week 6 a nd to just 10 students by week 10. While the 2 Kriebel et al. (2001) study could be useful as a su pportive study for naively exposed students, the 3 longitudinal component is not strong enough to supp ort RfC development. 4
Several studies of workers assess both cross-shift and chrinic effects of formaldehyde 5 exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1982; 6 Alexandersson and Hedenstierna, 1989). Since forma ldehyde exposure may have cumulative 7 effects over chronic exposures, occupational studie s generally showed clinically small but 8 statistically significant decrements in pulmonary f unction across shifts. In general these studies 9 did not identify, have information on or have appro priate statistical control of, potential 10 confounding co-exposures. While these occupational studies provide evidence that is clearly and 11 consistently supportive of an acute effect on pulmo nary function, they do not directly support 12 RfC development of an acute effect divorced of the concomitant chronic effects. 13 Several studies allowed for the examination of pote ntial chronic effects of formaldehyde 14 exposure. These included an occupational study (Mal aka and Kodama, 1990) that reported pre15 shift pulmonary function as a percentage of expecte d among the formaldehyde exposed 16 compared to comparable people not exposed to formal dehyde. Studies that did not report pre17 shift pulmonary function as a percentage of expecte d function (Herbert et al., 1994; 18 Alexandersson et al., 1982; Alexandersson and Heden stierna, 1989) contribute less to an 19 assessment of potential chronic effects because, po st-hoc, it is difficult to calibrate for cross20 study comparison the multiple pulmonary function da ta without knowledge of the age, gender, 21 smoking status, height, year of birth, etc. that ar e important determinants of the pulmonary 22 function metrics of concern. The single study (Mala ka and Kodama, 1990) that did report 23 functional measures in relation to expected value, found that an average 8-hour time weighted 24 average formaldehyde exposure of 1.13 ppm from area samples was associated with statistically 25 significant decrements in FEV 1 , FEV 1 /FVC and FEF 25-75 compared to a referent population. The 26 strongest response was for FEF 25-75, which showed a 12% drop in observed function compar ed to 27 expected function in the unexposed, but it is uncle ar how to interpret the potential chronic health 28 effect(s) with just the magnitude of the decrement and the length of the average occupational 29 tenure at this plywood facility (6.5 years), which was not reported by exposure status. 30 One study reported on the longitudinal follow-up of workers exposed to formaldehyde 31 (Alexandersson and Hedenstierna, 1989). This invest igation not only examined the acute effects 32 of exposure across shift, but was able to do so amo ng some of the same workers that had been 33 studied five years earlier (Alexandersson et al., 1 982). Statistically significant decreases in 34
FEV 1 /FVC and FEF 25-75 were noted over the intervening five years in non- smokers after 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-9 correction for normal aging. The decrease in FEF 25-75 was 0.212 liters/s (SD=0.066 liters/s) for 1 each year of exposure and was highly significant (p <0.01). For comparison with the 12% drop in 2 the same pulmonary metric reported by Malaka and Ko dama (1990) over an estimated 6.5 years, 3 EPA computed the extrapolated percentage decrease i n FEF 25-75 for the Alexandersson and 4 Hedenstierna (1989) using the reported yearly decre ment applied to the pre-shift values at the 5 time of the initial study period. EPA calculated th at from the predicted value of 4.57 liters/s, a 6
decrease of 0.168 liters/s could be estimated for e ach year of exposure regardless of smoking 7 status. For 6.5 years of exposure, this would resul t in a 24% drop in FEF 25-75 . Formaldehyde 8 concentrations were estimated at 0.42 ppm in the fi rst Alexandersson et al. (1982) study and at 9 0.50 ppm in the second study, but without better ex posure measures, the results of the 10 longitudinal follow-up cannot support quantitative RfC development. 11 Information is lacking in these studies such as len gth or tenure of employment associated 12 with the pre-shift pulmonary function or how long t he residents had lived in their homes. 13 Likewise, knowledge of how occupational or resident ial exposure may have changed over time 14 would have allowed for an examination of the progre ssion of any decrement in function 15 associated with long-term episodic exposure. Among these studies, the best designed and 16
executed of the cross-sectional studies was that of Kryzanowski and colleagues (1990). 17 Municipal employees and their children (613 adults and 298 children) were randomly sampled 18 and were considered to be representative of a diver se local population. Residential exposures to 19 formaldehyde were based on repeated samples from ea ch individual’s kitchen, living area and 20 bedroom. The average formaldehyde concentration was 26 ppb, with a maximum sample value 21 of 140 ppb. The majority of subjects (83%) lived in homes with 2-week average concentrations 22 below 40 ppb. Subjects’ peak expiratory flow rates (PEFR) were determined 4 times daily in the 23 morning, at noon, in the early evening and before b ed for 2 weeks. A statistically significant 24 linear relationship between increased formaldehyde exposure and decreased peak expiratory flow 25 rate was reported in children but not adults. All s tatistical models controlled for socioeconomic 26 status, tobacco smoking (current active or environm ental tobacco smoking) and nitrogen dioxide 27 concentrations. In children, formaldehyde concentra tions of 60-140 ppb increased the prevalence 28 of physician-diagnosed asthma and bronchitis. Among adults, there was a statistically significant 29 non-linear relationship with decreased morning PEFR for formaldehyde concentration <40 ppb. 30 Nonetheless, this strong study had only minor weakn esses such as measurement error and the fact 31 that it was a cross-sectional study. However, rando m measurement error tends to attenuate any 32 true effect and is unlikely to have produced a spur ious effect. It is unlikely that these findings 33 were the product of unmeasured or residual confound ing as the analyses controlled for smoking 34 as well as nitrogen dioxide levels and there is no evidence of alternative factors that were 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-10 correlated with formaldehyde concentrations and mor e strongly associated with pulmonary 1 function. This study of a large and representative sample from a diverse study population with a 2 well-quantified concentration-response function and is further considered for RfC derivation. 3
4
5.1.1.4. Asthma and Allergic Sensitization (Atopy) 5 Sensitization to inhalational chemical exposure may manifest as an allergic or asthmatic 6 response that is characterized by bronchial constri ction (BC) or bronchial hyperresponsiveness 7 (BHR). This sensitization may be a result of immun e involvement, as in the case of 8 hypersensitivity, or a neurogenic sensitization, wh ere a chemical may directly stimulate 9 inflammation. Asthma is a specific manifestation o f IgE-mediated hypersensitivity, 10 characterized by BHR and airway inflammation, resul ting in lower airway obstruction (Fireman, 11 2003; Kuby, 1991). 12 A variety of hypersensitivity reactions have been r eported following exposure to 13 formaldehyde. Rashes and skin reactions have been reported in some individuals after dermal 14 exposures to formaldehyde. Increased expression of Th-2 cytokines in the lymph nodes of mice 15 given dermal applications of formaldehyde indicates the involvement of an immune component 16 to the observed sensitization (Dearman et al., 2005 ; Hilton et al., 1998; Arts et al., 1997). 17 However, the response does not appear to be IgE med iated (Arts et al., 1997; Lee et al., 1984). 18 Gorski et al. (1992) observed an increase in formal dehyde-mediated neutrophil burst in 19 dermatitis patients exposed in a controlled chamber study and suggests a putative role of 20 oxidative stress and reactive oxygen species (ROS). 21
22 Epidemiologic Studies: 23 Inhalation exposure has been associated with increa sed asthmatic responses in asthmatics 24 in occupational settings. While few available case reports of bronchial asthma suggest direct 25 respiratory tract sensitization to formaldehyde gas (Lemiere et al., 1995; Burge et al., 1985; 26 Hendrick et al., 1982; Hendrick and Lane, 1977, 197 5), a greater body of human data provides 27 evidence of an association between formaldehyde exp osure and exacerbation of asthmatic 28 responses in compromised individuals (Kriebel et al ., 1993) and particularly in children 29 (Rumchev et al., 2002; Garrett et al., 1999; Krzyza nowski et al., 1990). Increased asthma 30 incidence reported after inhalation exposure to for maldehyde led to a NOAEL of 30 ppb 31 (Rumchev et al., 2002). An increased frequency of respiratory symptoms associated with 32 asthmatic responses and formaldehyde exposure led t o a LOAEL of 30 ppb (Garrett et al., 1999). 33
34 The association between formaldehyde and asthma has been studied by examining 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-11 occupational exposures (Fransman et al., 2003; Mala ka and Kodama, 1990), school-related 1 exposures (Zhao et al., 2008; Smedje and Norback, 2 001; Norback et al., 2000) and residential 2 exposures (Matsunaga et al., 2008; Tavernier et al. , 2006; Gee et al., 2005; Delfino et al., 2003; 3 Rumchev et al., 2002; Garrett et al., 1999; Palczyn ski et al., 1999; Norback et al., 1995; 4 Krzyzanowski et al., 1990). The two occupational s tudies examined the respiratory health of 5 plywood workers (Fransman et al., 2003; Malaka and Kodama, 1990). The most recent of these 6 was conducted in New Zealand by Fransman et al. (20 03). Personal samples of formaldehyde 7 exposure were taken. The mean level of exposure wa s 0.08 mg/m 3 (65 ppb) and the majority of 8 samples were below the limit of detection which was reported to be 0.03 mg/m 3 (24 ppb). 9 Compared with those with low levels of formaldehyde exposure, workers with high levels of 10 exposure were more likely to report having asthma ( OR=4.3 [95% CI]: 0.7–27.7]). The 11 association was not seen when examining formaldehyd e exposure and use of asthma medication. 12 The second study of plywood workers was completed in Indonesia. Background levels of 13 formaldehyde ranged from 0.003 to 0.07 ppm. The hi ghest concentration of formaldehyde 14 detected in an air sample was in the particleboard unit (range 1.16 to 3.48 ppm). The occurrence 15 of asthma was found to be positively associated wit h formaldehyde exposure, where asthma was 16 defined as, “Have you ever had an attack of wheezin g that made you feel short of breath?”, 17 (Malaka and Kodama, 1990). 18 Studies of exposure to formaldehyde at schools have been performed in China (Zhao et 19 al., 2008) and in Sweden (Smedje and Norback, 2001) . In the study from China (Zhao et al., 20 2008), mean levels of formaldehyde were reported to be 2.3 μg/m 3 (range 1.0–5.0 μg/m 3 ) indoors 21 and 5.8 μg/m 3 (range 5.0–7.0 μg/m 3 ) outdoors. Cumulative asthma (i.e., physician-dia gnosed 22 asthma since birth) and daytime attacks of breathle ssness were found to be associated with 23 outdoor formaldehyde levels. Neither of these outc omes was associated with indoor 24 concentrations of formaldehyde; however, indoor lev els were found to be associated with 25 nocturnal attacks of breathlessness. In Sweden (Sm edje and Norback, 2001), the levels of 26 formaldehyde measured indoors were higher (mean 4, range <5.0–72 μg/m 3 ). One difference 27 between the Swedish study and the study conducted i n China is that the Swedish study examined 28 the incidence of asthma over a 4-year period and di d not report an association between 29 formaldehyde exposure and the incidence of asthma ( OR 1.2 [95% CI: 0.8–1.7]) among the 30 whole study population. However, when the investig ators stratified based on history of atopy, 31 they reported that among children without a history of atopy, a new diagnosis of asthma was 32 significantly more likely at higher concentrations of formaldehyde (OR 1.7 per 10 μg /m 3 [95% 33 CI: 1.1–2.6]) and at higher total concentrations of mold (OR=4.7 per 10-fold increased in total 34 molds [95% CI: 1.2-18.4] in the classroom air. The finding in increase health effects due to 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-12 formaldehyde and mold exposures did not appear to c ontrol for the other exposure and no 1 information on the potential correlation between th e two exposures was provided. In order to 2 evaluate the potential for confounding of the repor ted formaldehyde association by the reported 3 mold association, the magnitude of effects must be compared on a appropriate scale since the 4 magnitude of an odds ratio depends on the magnitude of the change in exposure level that is 5 expected to produce increased risk. After standard izing the units to the reported geometric mean 6 standard deviation, the results for formaldehyde (G SM=2.3 μg /m 3 ) is OR1=1.13 per GSD and 7 the results for mold is OR2=1.02 for a comparison o f risks at the GSM to 10*GSM and 8 OR3=1.06 for a comparison of risks at the minimum v alue of total molds (5*10 3 /m 3 ) to 9 10*minimum. As it appears that the magnitude of th e formaldehyde effect is stronger than that 10 of the mold effect (following standardization of ex posure increment), it can be concluded that the 11 reported formaldehyde effect could not have been du e to uncontrolled confounding by mold. 12 The results of studies measuring residential exposu re to formaldehyde and asthma are 13 varied, with some demonstrating an association and others finding no relationship. A recent 14 study (Matsunaga et al., 2008) found no association between 24-hour formaldehyde and 15 prevalence of asthma when pregnant women with an ex posure to ≥ 47 ppb were compared to 16 those with exposure to <18 ppb. However, they repo rted an increased risk of atopic eczema. 17 This study did not assess the risk of incident asth ma. A study utilizing self-reported asthma 18 prevalence as an outcome also found no association with levels of formaldehyde (mean 19 25.9 μg/m 3 , range 2.0–66.8 μg/m 3 ) (Palczynski et al., 1999), although they noted th e incidence of 20 allergic diseases was greatest in the highest forma ldehyde exposure group but that the groups 21
were too small for statistical evaluation. 22 A study performed by Tuthill (1984) measured formal dehyde exposure for children 23 grades K through 6 by using a combination of proxy variables. Overall, there was no association, 24
but some individual variables showed an increased r isk. For example, the reported risk ratio for 25 having new construction or remodeling performed in the house in the past 4 months was 2.5 26 (95% CI: 1.7–3.9). The risk ratio for having new o r upholstered furniture in the house (within 27 the past 4 months) was 2.2 (95% CI: 1.2–3.9). 28 The study by Delfino et al. (2003) assessed whether the ambient formaldehyde 29 concentration measured at a central monitoring site was associated with asthma symptoms. The 30 study examined 22 10–15 year olds with at least 1 y ear of physician-diagnosed asthma and living 31 in a nonsmoking household. The mean levels of form aldehyde were measured to be 7.21 ppb 32

1 OR per GSD=exp[ln(OR per μg /m 3 )/ 10 μg /m 3 * 2.3 μg /m 3 ]=exp[ln(1.7)/10*2.3]=1.13 2 OR per GSD=exp[ln(OR per 10-fold increase)/ (9*GS M)*1.6 μg /m 3 ]=exp[ln(4.7)/162*1.6]=1.02 3 OR per GSD=exp[ln(OR per 10-fold increase)/ (9*Mi nimum)*1.6 μg /m 3 ]=exp[ln(4.7)/45*1.6]=1.06This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-13 (range 4.27–14.02 ppb). There was a positive assoc iation between asthma symptom scores 1 (comparing children who report symptoms interfering with their daily activities versus those with 2 no symptoms or symptoms not great enough to affect their daily activities) and high current 3 levels of formaldehyde (OR 1.90 [95% CI: 1.13–3.19] ). 4 Three studies (Tavernier et al., 2006; Gee et al., 2005; Garrett et al., 1999) were 5 performed by matching children with and without ast hma and comparing the levels of 6 formaldehyde in their homes. Gee et al. (2005) rep orted median formaldehyde levels of 0.03 7 ppm in living rooms and 0.04 ppm in bedrooms. Anal yses were limited to univariate 8 comparisons of formaldehyde levels for cases of exi sting asthma and controls without asthma. 9
The concentrations did not differ in a statisticall y significant manner. The study by Gee et al 10 (2005) was followed up with a more sophisticated an alysis of the same children in the same 11 home. Tavernier et al. (2006) reiterated the earlie r finding by Gee et al (2005) that formaldehyde 12 was not found to be associated with existing asthma . Tavernier et al. (2006) did not report the 13 measured levels of formaldehyde but gave the OR for the highest tertile of exposure compared 14 with the lowest tertile of exposure as 0.99 (95% CI : 0.39–2.50). The width of this confidence 15 interval suggests that, while no effect was observe d, these findings would still be consistent with 16
two-fold increase in risk. 17 Garrett et al. (1999) reported on the risk of aller gy and asthma-like respiratory symptoms 18 due to formaldehyde exposure in a cross-sectional s urvey of households with children with (n = 19 53) or without (n = 88) doctor-diagnosed asthma. F ormaldehyde exposure was characterized by 20 4 seasonal in-home sampling events across the year for bedrooms and 4–day passive samples 21 collected in living rooms, kitchens and outdoors. Statistically significant linear trends for 22 increased risk of having asthma were seen with incr easing formaldehyde levels (p < 0.02); 23 however, the ORs for the association did not remain statistically significant after controlling for 24 parental allergy and asthma (exact ORs and 95% CIs not given). Garrett et al (1999) also 25 evaluated the prevalence and severity of allergic s ensitization to 12 common allergens and 26 reported increased prevalence with increasing forma ldehyde concentration in the home. The 27 respiratory symptom score was also increased and de monstrated a significant effect for 28 formaldehyde in a multiple regression after adjusti ng for multiple risk factors and interactions. 29 For the atopy and respiratory symptom endpoints, se verity/incidence was increased in the 30 medium (20–50 μg/m 3 ) and high (>50 μg/m 3 ) exposure groups relative to the low (<20 μg/m 3 ) 31 exposure group, based on the highest of four season al 4-day formaldehyde measurements in the 32 home. The associations between formaldehyde concen trations and severity of allergic 33 sensitization are clearly shown and further substan tiated with multivariate regression controlling 34 for potential confounders. In logistic regressions , both the prevalence and severity of allergic 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-14 sensitization to 12 common allergens increased with increasing formaldehyde concentration in 1 the home. The crude association for atopy with an increase in formaldehyde concentration per 2 10 μg/m 3 was OR=1.34 which increased when adjusted for paren tal asthma and gender to and 3 odds ratio of 1.42 per 10 μg/m 3 (95% CI: 0.99-2.04). Passive smoking, the presenc e of pets, 4 indoor nitrogen dioxide concentrations, airborne fu ngal spores and house-dust-mite allergens did 5
not influence the effect estimates and were unlikel y to be confounders. Additionally, a calculated 6 respiratory symptom score was increased and demonst rated a significant relationship to increased 7 formaldehyde concentration in a multiple linear reg ression after adjusting for multiple risk 8 factors and interactions. For each of these endpoi nts, severity/incidence was increased in the 9 medium (20–50 μg/m 3 ) and high (>50 μg/m 3 ) exposure groups relative to the low (<20 μg/m 3 ) 10 exposure group, based on the highest of four season al 4-day formaldehyde measurements in the 11
home. 12 Residential formaldehyde exposure was associated w ith an increased risk of asthma in a 13 population-based case-control study of 192 children aged 6 months to 3 years (Rumchev et al., 14 2002). The study, which comprises 88 cases of chi ldren discharged from the emergency 15 department of a children’s hospital in Perth, Austr alia, with a primary diagnosis of asthma and 16 104 controls, provides a positive exposure-response relationship. Seasonal in-home 17 formaldehyde measurements taken in the living room and subject’s bedroom were used to assess 18 exposure (8-hour passive sampler). The odds ratios (ORs) for risk of asthma by formaldehyde 19 exposure level category were adjusted for numerous risk factors both familial and environmental 20 including, familial history of asthma, age, sex, sm oking, presence of pets, and attributes of the 21 home. Of these, age, allergic sensitization to com mon allergens, and family history of allergy 22 were independent risk factors for asthma (ORs of 1. 09, 2.57, and 2.66, respectively). Categorical 23 analysis of the data indicates the ORs for asthma w ere increased in the two highest formaldehyde 24 exposure groups, reaching statistical significance for household exposures > 60 μg/m 3 (48 ppb) 25 (OR of 1.39). Analysis of the data with formaldeh yde as a continuous variable indicated there 26 was a statistically significant increase in the ris k of asthma (3 % increase in risk per every 27 10 ug/m3 increase in formaldehyde level. All analy ses controlled for other indoor air pollutants, 28 allergen levels, relative humidity, and indoor temp erature as well as other risk factors. 29 A study of 202 households (mean formaldehyde level of 26 ppb) found that among children aged 30 6–15 years old and exposed to environmental tobacco smoke, the prevalence of asthma was 31 45.5% for those with measured levels of formaldehyd e in the kitchen >60 ppb. The prevalence 32 of asthma dropped to 15.1% for levels ≤ 40 ppb and 0% for 41–60 ppb. No trend in asthma 33
34 prevalence was seen for children who were not expos ed to environmental tobacco smoke 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-15 (Krzyzanowski et al., 1990). 1 Finally, a study by Norback et al. (1995) reported mean levels of formaldehyde were 2 29 μg/m 3 (range <5–110 μg/m 3 ) in the bedrooms of individuals experiencing noctu rnal 3 breathlessness compared with formaldehyde levels of 17 μg/m 3 (<5–60 μg/m 3 ) among those 4
without nocturnal breathlessness. The OR for this association was 12.5 (95% CI: 2.0–77.9) and 5 the effect was substantially stronger in magnitude than the associations observed for toluene, 6 terpenes and volatile organic compounds which makes confounding by those co-exposures 7 unlikely. 8
9 Supporting animal studies: 10 Several animal studies report increased airway res istance and BC due to inhalation 11 exposures to formaldehyde (Nielsen et al., 1999; Sw iecichowski et al., 1993; Biagini et al., 1989; 12 Amdur, 1960). Changes in pulmonary resistance were observed as early as 10 minutes after 13 exposure (Biagini et al., 1989), and reported effec t levels ranged from 0.3–13 ppm. Other 14 pulmonary effects were reported in conjunction with BHR, such as increased tracheal reactivity 15 and decreased pulmonary elasticity (Swiecichowski e t al., 1993; Amdur, 1960). Although BHR 16 is a common result of Type I hypersensitivity react ion to an allergen, the observation of BHR 17 alone is not sufficient to demonstrate that an agen t induces Type 1 hypersensitivity. 18 BHR may be directly induced both pharmacologically and neurogenically (Joos, 2003; 19 Cain, 2001; Meggs, 1995). There is little evidence that formaldehyde itself is an allergen 20 recognized by the immune system, especially via inh alation (Lee et al., 1984). Although 21 formaldehyde exposure has been reported to alter cy tokine levels and immunoglobulins in some 22 experimental systems, these immunomodulatory effect s do not support a type 1 hypersensitivity. 23 IgE was unchanged (Fujimaki et al., 2004a; Lee et a l., 1984), and cytokine profiles were not 24 consistent with the Th-2 cytokines expected in IgE mediated hypersensitivity (Fujimaki et al., 25 2004a; Ohtsuka et al., 2003). 26 Formaldehyde-induced dermal sensitization show para llel results. The physical signs of 27 irritation and sensitization are consistently shown (e.g., rashes, edema). Some involvement of 28 the immune response has been demonstrated with posi tive LLNA assays, indicating proliferation 29 of lymphocytes in lymph nodes draining the affected area (Hilton et al., 1998; Arts et al., 1997). 30 Increased expression of Th-2 cytokines in the lymph nodes of mice given dermal applications of 31 formaldehyde does indicate an immune component to t he observed sensitization. However, the 32 response does not seem to be mediated by IgE (Arts et al., 1997; Lee et al., 1984). 33
34 Ito et al. (1996) reported that a tachykinin NK 1 receptor, but not the histamine H 1 or 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-16 bradykinin B 2 receptors, is involved in formaldehyde-induced vas cular permeability. 1 Neuropeptides NGF and substance P were affected in BAL and stimulated splenocytes from 2 formaldehyde-exposed mice, with greater effects see n in OVA-immunized mice. Tachykinins 3 (e.g., substance P and neurokinin A) are produced b y nerve cells and can directly stimulate 4 bronchoconstriction (Van Schoor et al., 2000). Sub stance P is also a mediator of neurogenic 5 inflammation. Therefore, although formaldehyde may induce some of the symptoms of type 1 6 hypersensitivity, these symptoms are more likely ne urogenic than immunogenic in origin. 7 In contrast, formaldehyde enhances immunogenic hype rsensitivity of known allergens 8 (Sadakane et al., 2002; Riedel et al., 1996; Tarkow ski and Gorski, 1995). This potentiation 9 varied based on sensitization protocols (respirator y tract versus systemic, frequency and timing of 10 immunization, allergen, etc.) and formaldehyde expo sure regimens (concentration, continuous 11 versus intermittent exposures). Taken as a whole, the results support the finding that 12 formaldehyde exposure can aggravate a type 1 hypers ensitivity response (Table 4-53). 13 The mechanism underlying this response has not been elucidated. Formaldehyde-induced 14 IgE production has been reported in some studies (V andenplas et al., 2004; Wantke et al., 15 1996a). Other studies suggest that this effect doe s not appear to be immunogenic in nature 16 (Fujimaki et al., 2004; Lee et al., 1984). Althoug h formaldehyde exposure has been reported to 17 alter cytokine levels and immunoglobulins in some e xperimental systems (Fujimaki et al., 2004a; 18 Ohtsuka et al., 2003), these immunomodulatory effec ts do not support immunogenically 19 mediated type 1 hypersensitivity. 20 These decrements may be mediated via neurogenic pot entiation (Sadakane et al., 2002; 21 Riedel et al., 1996; Tarkowski and Gorski, 1995). Tarkowski and Gorski (1995) suggest that 22 formaldehyde may increase permeability of respirato ry epithelium and destruction of 23 immunologic barriers. Tachykinin NK1 receptor and various neuropeptides (NGF and substance 24 P) have been implicated in formaldehyde-induced sen sitization and lend weight of evidence to a 25 neurogenic MOA (Van Schoor et al., 2000; Ito et al. 1996). 26
27
5.1.1.5 Immune Function 28 Although there are some indications of formaldehyd e-induced immunomodulation in 29 laboratory animal studies (Jakab, 1992; Morgan et a l., 1986a, b, c; Leach et al., 1983) and reports 30 of increased upper respiratory tract infections in formaldehyde-exposed workers (Lyapina et al., 31 2004; Krzyzanowski et al., 1990; Holness and Nether cott, 1989), the overall database for toxic 32 effects on immune function and competence is very l imited. A study of workers using 33 carbamide-formaldehyde glue indicates decreased neu trophil respiratory burst activity (NRBA) 34 (Lyapina et al., 2004). NRBA was reduced in worker s with URT inflammation and long-lasting 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-17 respiratory tract infections, compared with healthy controls, and in formaldehyde-exposed 1 workers with slight or no respiratory infections. The authors hypothesized that the decreased 2 NRBA in symptomatic workers may be an indication of formaldehyde effects in a susceptible 3 population. Since the workers have increased respi ratory tract infections as compared with 4 controls, a formaldehyde-specific effect cannot be excluded. These indications of a functional 5 deficit of the immune system are considered adverse and appropriate for consideration as a 6 critical effect. Although this was a small study ( n = 29), the exposed workers had increased 7
chronic URT infections and decreased resistance to infections compared with a control 8 population. Additionally, duration of employment w as negatively correlated with both 9 erythrocyte count and hematocrit. Measured formald ehyde concentrations for a work shift were 10 870 ± 390 μg/m 3 (722 ± 324 ppb). This average work-shift concentr ation is considered to be the 11 LOAEL for increased respiratory tract inflammation and decreased resistance to infections in a 12 worker population. 13
14
5.1.1.6. Neurological and Behavioral Toxicity 15 Studies evaluating the effects of formaldehyde on nervous system structure or function 16
are described in detail in Section 4.2.1.4 and summ arized in Table 4-60. Taken together the 17 animal and human data support the conclusion that f ormaldehyde exposure results in 18 neurological and behavioral toxicity. Observed hea lth effects include impaired memory and 19 learning, developmental effects seen as both struct ural changes in the brain and behavioral 20 changes, and a potential for increased mortality fr om amyotrophic lateral sclerosis (ALS). 21 Although studies appropriate for RfC derivation do not exist for each potential neurological and 22 behavioral health effect, several studies are avail able that may inform the formaldehyde RfC. 23 Seven of the available neurotoxicity studies were considered as candidates for RfC 24 development (listed in Table 5-1). All seven studi es provided reliable documentation of 25 exposure, study design, and evaluation procedures, and all demonstrated robust findings of 26 changes in nervous system structure or function fol lowing formaldehyde exposure. All but one 27 of the candidate studies present information at mul tiple exposure levels to provide an 28 understanding of the exposure response relationship . One selected study (Senichenkova, 1991) 29 provided less robust information, with evaluation a t only a single exposure level, but was 30 considered useful as supporting the findings of two other studies (Sarsilmaz et al., 2007; Aslan et 31 al., 2006) regarding neurological sequelae of devel opmental exposure. All of the selected studies 32 using experimental animals were conducted in rats, although several studies in mice 33
demonstrated dose-related neurotoxic effects follow ing formaldehyde exposure. These studies in 34 mice were not considered for RfC development becaus e of the possibility that results might be 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-18 confounded by reflex bradypnea at the doses tested in each study (see Section 4.2.1.4 for details). 1
2 In order to improve transparency and facilitate co mparison of health effect levels across 3 study types and health effects, Table 5-1 summarize s the PODs and exposure scenarios for each 4 selected study and describes the effects on which t he selected POD is based. Dose conversions 5 used to adjust from actual experimental exposure co ncentrations to continuous exposure 6
concentrations are detailed. It should be noted th at available studies providing dose-response 7 information regarding the effects of formaldehyde e xposure on the nervous system were all of 8 short duration, and thus information regarding the relationship between formaldehyde toxicity 9 and exposure duration (i.e., whether toxicity incre ases with longer exposures at a given exposure 10 level, or is more related to the maximum exposure c oncentration) is limited. However, the 11 rodent study by Pitten et al. (2000) and the epidem iology study by Weisskopf et al. (2009) 12 provide strong support for an association between i ncreasing neurotoxicity and increasing 13 duration of exposure. 14 Although chronic human studies are preferred for R fC derivation, no adequate human 15 study of chronic duration is available. The availa ble human studies were sufficiently strong to 16 raise concern regarding formaldehyde effects on the nervous system; however, most did not 17 provide sufficient exposure information to permit d erivation of a POD for use in quantitative 18 dose-response assessment. Available epidemiologic studies (most notably Weisskopf et al. 19 [2009] and Kilburn et al. [1987, 1985]) provided li mited exposure information. Weisskopf et al. 20 (2009) demonstrated increased mortality from ALS as sociated with increased duration of 21 formaldehyde exposure among 987,229 people followed by an American Cancer Society study, 22 but no information regarding exposure concentration s was available. Interpretation of the 23 findings of Kilburn et al. (1987, 1985) is complica ted by concomitant exposure of many subjects 24 to other solvents. Although the chamber study by L ang et al. (2008) included a concentration25 response assessment of changes in reaction time, as previously discussed, the effects detected 26 were difficult to interpret and the study was not c onsidered useful for RfC derivation 27

. 28This document is a draft for review purposes only a nd does not constitute Agency policy 5-19 DRAFT—DO NOT CITE OR QUOTETable 5-1. Points of departure (POD) for nervous system toxicity in key human and animal studies.PODaExposure scenario POD duration adjustmentsbReferenceSpeciesType ppb Hours/dayDays/weekDurationPOD×Hours/day×Days/week=ppb RatiocEffectDevelopmental neuropathology effectsSarsilmazet al.(2007)Rat LOAEL 6,0006 5 30 days 6,000× 6/24 ×5/7=1,070 5.6Volume and cell numberchange in brain regionsfollowing neonatalexposureAslan et al.(2006)Rat LOAEL 6,0006 5 30 days 6,000× 6/24 ×5/7=1,070 5.6Volume and cell numberchange in brain regionsfollowing neonatalexposureHuman neurobehavioral outcomesBach et al.(1990)dHumanNOAEL 170 5.5 1 1 day 170d× ×=170 1Changes in short-termmemory and ability toconcentrate. Single5.5-hour exposurePsychomotor effectsSenichenkova (1991)Rat LOAEL 400 4 7 GD 1–19400 × 4/24 ×7/7 =67 6Changes in open fieldmotor activity (exploratoryactivity and habituation inoffspring following inutero exposureMalek etal. (2003c)Rat LOAEL 130e2 1 1 day 130 × 2/4e×=65 2Concentration-dependentdecreases in activity by avariety of measuresfollowing a singleexposureCognitive effectsPitten et al.(2000)fRat LOAEL 2,6000.17 7 90 days 2,600f-- -- -- --Impaired memory in aspatial maze. Magnitudeof effect increased withcontinued exposurethrough 12 weeksThis document is a draft for review purposes only a nd does not constitute Agency policy 5-20 DRAFT—DO NOT CITE OR QUOTEMalek etal. (2003a)Rat LOAEL 100e2 7 10 days 100 × 2/4e×7/7 =50 2Impaired learning in awater maze. Short-term(10 day) exposure withtesting conducted 2 hoursfollowing daily exposure.a1 mg/m3= 0.813 ppm.bBoth actual levels of experimental exposures, and duration adjusted PODs are shown.cPOD unadjusted dose / duration-adjusted dose.dTesting was conducted during or following exposure,duration was not adjusted.eTesting was conducted 2 hours postexposure; duration was adjusted to 4 hours to include the entire period between start of exposure and testing.fDue to the uncertainty in continuous exposure adjustments and the unusually short (10 minutes) exposure in this study, no adjustment to continuous exposure ispresented.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-21 One acute human study, Bach et al. (1990), which e valuated changes in cognitive 1 function following a single formaldehyde exposure, was considered for evaluation of a cRfC as 2 the chamber exposures were well defined and effects at multiple levels of exposure were 3 reported. In that study, concentration-related cha nges in short-term memory and ability to 4 concentrate were seen during a single 5.5-hour expo sure at a range of levels (32, 170, 390, and 5 890 ppb). The study was designed as a comparison o f effects of short-term formaldehyde 6 exposure in previously occupationally exposed indiv iduals with effects in controls without 7 previous occupational exposure. Because occupation al exposure levels were not assessed, 8 exposure measurements from the previously exposed w orkers are not appropriate for use in RfC 9 derivation. The authors reported a significant exp osure-response relationship for three related 10 cognitive measures (number of additions completed, number of errors, and reaction time) in the 11 ‘addition test’ assessment indicating a deficit in performance. Complete data were not presented, 12 but graphical presentations in the article indicate d that the effect was seen at all doses tested, wit h 13 an apparent NOAEL of 170 ppb (see Figure 5-1). 14

15 16 Formaldehyde concentration 17
18 Figure 5-1. Change in number of additions made in 10 minutes following 19 formaldehyde exposure at 32, 170, 390, or 890 ppb. 20 Note: Vertical bars are the standard errors of the means, dashed line shows the 21 95% CI. 22 Source: Bach et al. (1990). 23Number of additions made in 10minutesThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-22 No BMD modeling could be performed on these data b ecause the graphical representation 1 could not be accurately digitized. The statistical analysis indicated no interaction between 2 formaldehyde effect and previous occupational expos ure (i.e., the magnitude and direction of the 3 effect were similar in previously exposed and previ ously unexposed subjects) and separate data 4 were not presented for the two groups; thus, the LO AEL represents effects in the combined study 5 groups. Overall, the published paper lacks detail and it is difficult to evaluate some aspects of 6 the reported findings, in particular where magnitud e and direction of effect are not provided. 7 Finally, the authors noted that controls and the hi gh-exposure group were not well matched on 8 two key parameters (age and education level), addin g uncertainty to the reported exposure9 response relationship (at the high dose). Although this study was considered valuable in 10 documenting neurological effects in humans followin g exposure to relatively low concentrations 11 of formaldehyde, the above concerns limit its utili ty for quantitative human health risk 12 assessment. Therefore, this study is not considere d of sufficient quality for RfC derivation. 13 In the absence of adequate human data, controlled studies in laboratory animals are 14 considered. There are no chronic studies and only one subchronic animal study evaluating 15 neurological and behavioral effects of formaldehyde exposure. Pitten et al. (2000) demonstrated 16 impaired retention of a previously learned task in rats exposed at concentrations of 2,600 or 17 4,600 ppb, 10 minutes per day, 7 days/week, for 90 days. In this study, the magnitude of the 18 impairment increased over time, even though testing was performed 22 hours after exposure, 19 indicating that repeated formaldehyde exposure led to a worsening of effect. The study design, 20 test methods, and reporting of the results are all of adequate quality for both hazard assessment 21 and quantitative risk assessment. However, the sho rt duration (10 minutes) of the repeated daily 22 exposures is a severe limitation to establishing a chronic RfC based on this study, due to 23 uncertainties in extrapolating from 10 minutes to a 24-hour exposure (see Table 5-1). Because 24 this study as designed indicates an accumulation of effect with repeated exposure, it is useful in 25 documenting the existence of a duration component t o the exposure-response relationship. It 26 follows that concentration alone, without an adjust ment for duration of exposure, would be 27 inadequate as an exposure metric; however inadequat e information is available to inform the 28 appropriate magnitude of the duration effect. Ther efore, although Pitten et al. (2000) is a well29 conducted study, the data are of limited utility fo r RfC derivation. 30 Finally, there are several well-documented acute a nd subacute animal studies that provide 31 exposure-response information for neurological and behavioral endpoints relevant for RfC 32 derivation. Several laboratory animal studies that evaluate neurological effects following in 33 utero or neonatal exposure address potentially susc eptible life stages. Sarsilmaz et al. (2007) and 34 Aslan et al. (2006) observed changes in brain struc ture (cell number and/or volume changes in 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-23 specific brain regions) following 30 days of exposu re to neonatal rats. A related finding by 1 Senichenkova (1991) demonstrated changes in behavio r (open field motor activity, including 2 habituation) in young rats following in utero expos ure. Effects of concern were seen at all doses 3 in these studies, resulting in PODs of 67 ppb follo wing in utero exposure and 1,070 ppb 4 following early postnatal exposure, based on LOAEL values adjusted for continuous exposure 5 (see Table 5-1). These studies support the possibi lity of neurodevelopmental effects attributable 6 to in utero or early postnatal formaldehyde exposur e, at levels similar to or below those causing 7 other types of effects. 8
The other three studies in Table 5-1 evaluate beha vioral changes in rats following 9 exposure to formaldehyde. Malek et al. (2003c) fou nd concentration-related changes in motor 10 activity following a single 2-hour exposure at conc entrations from 130–5,180 ppb (with testing 11 2 hours following cessation of exposure). In a sec ond study, Malek et al. (2003a) found 12 concentrated-related changes in performance on a le arning task at similar exposure levels (100– 13 5,400 ppb) when 2-hour exposures were repeated for 10 consecutive days; performance was 14 evaluated 2 hours after cessation of exposure, and concentration-related learning deficits were 15 seen at all exposure levels (see Table 5-2 and Figu re 5-2). 16
17 Table 5-2. Effects of formaldehyde exposure on com pletion of the labyrinth 18 test by male and female LEW.1K rats 19 20 Swimming time (sec) Error rate (mean) Male rats Day 1 Day 6 Day 10 Day 1 Day 6 Day 10 Control 105 12.2 6.33 7.4 0.5 0.0 0.1 ppm a 100 12.9 6.07 7.7 5.0 c 3.2 c 0.5 ppm 97 16.7 c 7.60 b 7.6 4.4 c 1.8 c 5.4 ppm 105 25.7 c 10.9 c 7.7 5.0 c 2.8 c

Swimming time (sec) Error rate (mean) Female rats Day 1 Day 6 Day 10 Day 1 Day 6 Day 10 Control 103 12.5 6.47 7.9 0 0.0 0.1 ppm 96 12.3 7.53 7.1 5.2 c 3.0 c 0.5 ppm 97 14.6 c 7.60 b 8.0 4.6 c 2.2 c 5.4 ppm 98 23.5 c 9.73 c 7.9 5.2 c 2.6 c 21

a Rats were exposed to formaldehyde for 2 hours/day, for 10 consecutive days. 22

b Different from control, p < 0.05. 23

c Different from control, p < 0.005. 24 25 Source: Malek et al. (2003a). 26 27This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-24 1 Figure 5-2. Effects of formaldehyde exposure on th e error rate of female 2 LEW.1K rats performing the water labyrinth learning test

. 3 4 Source: Drawn from data reported in Malek et al. ( 2003a). 5 6 7 Although other studies evaluating neurobehavioral effects were available in the 8 formaldehyde database (see Chapter 4), these studie s by Malek et al. (2003a, c) were considered 9 to be the most robust, documenting effects at relat ively low exposure levels. Both studies also 10 included evaluation at multiple concentrations and showed concentration-related increases in 11 effect. In the Malek et al. (2003a) study with rep eated exposures, it is unclear whether or not the 12 measured effect primarily reflects the most recent exposure or cumulative exposure; therefore, 13 the adjustment for continuous exposure was made ove r the final exposure period and the 2 hours 14 following exposure (4 hours total), as was done for the single-exposure study (Malek et al., 15 2003c). After appropriate duration adjustments, PO Ds for these studies range from 50 to 67 ppb 16 (based on LOAELs), and the types of effects seen pr ovide support for the Bach et al. (1990) study 17 that detected cognitive impairments in humans follo wing a single exposure (with a NOAEL of 18 170 ppb). 19
20
21 

## 0

1 2 3 4 5 6 7 8 9

1 2 3 4 5 6 7 8 9 10

Day of labyrinth testErrors (mean) control 0.1 ppm 0.5 ppm 5.4 ppmThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-25 1 Summary of neurological and behavioral effects: 2 In summary, the available studies for formaldehyde and nervous system outcomes have 3 demonstrated that the nervous system is a sensitive target following inhalation of formaldehyde. 4 In experimental animals, changes in nervous system function were seen following acute and 5 subchronic exposures; studies evaluating neurologic al changes following chronic exposure were 6
unavailable. Available human studies that evaluate d nervous system effects following inhalation 7 exposure were found to have many study-specific unc ertainties and, thus, were not suitable to 8 serve as the primary basis for a chronic RfC. The Weisskopf et al. (2009) study of ALS, in 9 particular, suggests that humans may be at risk for severe neurological effects from formaldehyde 10 exposure; however, this study lacked the exposure c oncentration information necessary to derive 11 an RfC. Neurological findings from the rodent inha lation (acute and subchronic) studies that 12 were judged to be adequate for dose-response assess ment identified unadjusted LOAELs ranging 13 from 100 to 6000 ppb, with LOAELs adjusted for cont inuous exposure in the range of 50 to 1070 14 ppb. Use of these PODs in risk assessment would re quire addressing uncertainties regarding 15 animal-to-human extrapolation, short study duration s, and extrapolation from LOAELs. 16 Among the adequate studies, EPA considered Malek et al. (2003a) to be the most 17 appropriate for calculation of a cRfC for neurologi cal and behavioral toxicity, based on the 18 exposure level at which effects were seen (100 ppb) , the type of effect (impaired learning), which 19 is relevant to humans, and the use of a repeated-ex posure paradigm (2 hours/day over a period of 20 10 days), which addresses different exposure durati ons. This choice is supported by similar 21 effects seen in other studies (Lu et al., 2008; Pit ten et al., 2000; Bach et al., 1990) and by other 22 neurologic effects seen at similar exposure levels (Malek et al., 2003c; Senichenkova, 1991; 23 Sheveleva, 1971). 24
25 5.1.1.7. Developmental and Reproductive Toxicity 26
As described in Sections 4.1 and 4.2 and summarized in Tables 4-68 and 4-71, both 27 human epidemiologic data and experimental animal st udies demonstrate an association between 28 formaldehyde inhalation exposure and adverse develo pmental and reproductive effects, where 29 adversity is characterized as per EPA risk assessme nt guidelines (U.S. EPA, 1991; U.S. EPA, 30 2006). Adverse outcomes were observed across the v arious manifestations of developmental 31 toxicity, including fetal death, structural alterat ions (including congenital malformations), growth 32 retardation, and functional development. Additiona lly, in spite of the lack of a comprehensive 33
database of studies for the evaluation of the overa ll effects of formaldehyde on the reproductive 34 system and its function, the available evidence dem onstrates toxicity to the male reproductive 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-26 system in multiple animal studies, as well as effec ts on the female reproductive system in both 1 rodents and epidemiologic studies, where an associa tion with impaired fertility and increased 2 spontaneous abortions were noted. 3 Potential principal studies for specific adverse ou tcomes are presented and evaluated 4 below including reproductive effects (male and fema le), fetal death, growth retardation, and 5 structural alterations. The only available evidenc e for functional alterations is based on 6 developmental neurotoxicity studies which are prese nted and evaluated in Section 5.1.1.6. 7
Table 5-3 summarizes animal studies deemed suitable for deriving quantitative dose-response 8 information for reproductive and developmental outc omes and their corresponding PODs, 9 adjusted for continuous exposure. Calculations tha t were used in dose conversions and exposure 10 duration adjustments for the POD values are include d. In general, repeated daily exposures of 11 laboratory animals are adjusted from a partial day to a 24-hour exposure and then weighted for 12 the number of days per week the exposures occurred. No chronic animal studies evaluating these 13 endpoints were available, so only subchronic and ac ute studies are considered. Exposure 14 duration adjustments to the only suitable human stu dy (Taskinen et al., 1999) are more complex 15 due to uncertainties in the exposure data and the p otential for non-occupational exposures. For 16 this discussion the reported 8-hr TWA exposures wil l be used for the Taskinen et al. (1999) 17 study. Further duration adjustments to this study are discussed in Section 5.1.2.2.5 for cRfC 18
derivation. 19
20 Spontaneous abortion and fetal death. 21 Increased risk of spontaneous abortion following ma ternal occupational formaldehyde 22 exposure was reported in a number of epidemiologic studies (Taskinen et al., 1999, 1994; John et 23 al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). The studies did not appear to be overtly 24 influenced by common principle biases found in epid emiologic studies. Considered together, the 25
studies are consistent with an adverse effect of fo rmaldehyde exposure on pregnancy loss, where 26 adversity is characterized as per EPA risk assessme nt guidelines (U.S. EPA, 1991; U.S. EPA, 27 2006). . Of these studies, Taskinen et al. (1999) had the superior quantitative data reporting 28 reduced fecundity and spontaneous abortion in the e xposed workers. Taskinen et al. (1999) is an 29 occupational study with a well-considered study des ign, including measurements of exposure and 30 outcomes, and relatively high study power. The stu dy population consisted of 602 female 31
workers in Finland who had at least one successful childbirth and first employment in the wood32 working industry beginning at least 6 months prior to the studied pregnancy. Mean daily 33 formaldehyde inhalation exposures during the time-t o-pregnancy period were estimated for each 34 worker, based on task-level exposure measurements a nd work history. 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-27 Exposure was reported as a daily exposure index rep resenting the average daily exposure 1 for the time-to-pregnancy period, and three exposur e classes were defined as low, medium and 2 high with equivalent mean work-shift TWA exposure o f 18, 76 and 219 ppb, respectively. 3 Fecundity density ratio (FDR) was significantly red uced in the high exposure group compared to 4 the referent group (P=0.02), and the risk of sponta neous abortions was increased with reported 5 ORs of 3.2 (1.2-8.3), 1.8 (0.8-4) and 2.4 (1.2-4.8) for the high, medium and low exposure groups, 6 respectively. The effect on FDR remained in worker s both with and without the use of protective 7 gloves (n=39) but lost statistical significance in the exposed group of workers who wore gloves 8 (n=22). Figure 5-3 shows the study results stratif ied by glove use in women in the high-exposure 9 group. Although this suggests that a component of dermal exposure might contribute to the 10 effect, it is unclear what, if any, dermal exposure is expected based on the nature of the work. 11 Regardless, there remains uncertainty as to whether effects are solely due to inhalation exposure. 12
13

14 Figure 5-3. Fecundity density ratio among women ex posed to formaldehyde 15 in the high exposure index category with 8-hour tim e-weighted average 16 formaldehyde exposure concentration of 219 ppb (Tas kinen et al., 1999) 17 18 19 0

0.2 0.4 0.6 0.8 1 1.2 1.4

All Women (N=39) No Gloves (N=17) Gloves (N=22)FDR with 95% CIThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-28 In some available rodent studies (Kitaev et al., 19 84; Sheveleva, 1971), evidence of 1 increased embryo degeneration in early gestation or of preimplantation loss (findings that are 2 generally comparable to spontaneous abortion in hum ans) was observed. In the Kitaev et al. 3 (1984) study, early implantation losses resulted fo llowing treatment of dams prior to mating. 4 This may support a possible contribution of pre-pre gnancy exposures to the spontaneous 5 abortions observed in Taskinen et al. (1999). Quan tification of the findings by Kitaev et al. 6 (1984) and Sheveleva (1971) resulted in adjusted PO Ds of 50 and 70 ppb, respectively, based 7 upon study LOAELs (Table 5-3). 8
9

Structural alterations. 10 Studies of occupational exposures to formaldehyde e xamined the incidence of congenital 11 malformations, but exposure and outcome data were n ot fully characterized and therefore could 12 not be carried forward to RfC development. Animal studies (Senichenkova and Chetobar, 1996; 13 Senichenkova, 1991) reported increases in internal organ anomalies; the most frequently 14 observed structural anomaly was a delay in fetal te stis descent (at times characterized as 15 cryptorchidism in the study reports). For both stu dies, which exposed rats to formaldehyde for 4 16 hours/day during gestation, adjusted PODs based upo n LOAELs were 70 ppb (Table 5-3). These 17 studies included only one treatment level, precludi ng the ability to establish a dose-response 18 relationship, and the observed outcomes were not no ted in other developmental toxicity studies 19 with similar exposure scenarios, thus limiting the strength of the studies for use in RfC 20
derivation. 21
22
Growth retardation. 23 Decreased fetal weight was observed in a number of animal studies that exposed pregnant 24 rats to formaldehyde during gestation. Of these, b ased on adequacy of dose-response 25 information, Saillenfait et al. (1989) was consider ed appropriate for consideration for RfC 26 development. In this study, rats were administered formaldehyde 6 hours/day on gestational days 27 (GDs) 6–20. Decreased male fetal body weight (BW) was modeled with a BMR of 5% mean 28 change, a BMCL was established, and, as shown in Ta ble 5-3, the resulting duration-adjusted 29 POD of 325 ppb was derived. The relevance of this finding to human exposures was 30 qualitatively supported by a population-based study by Grazuleviciene et al. (1998) that reported 31 an association between atmospheric formaldehyde exp osure and low birth weight; although a 32 dose-response relationship could not be adequately quantified from the information provided. 33
34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-29 1 Male reproductive toxicity. 2 Evidence of adverse effects on male reproductive sy stem endpoints following inhalation 3 exposure to formaldehyde was observed in a number o f animal studies, where adversity is 4 characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 2006). The 5 effects include decreased testes weight, changes in Leydig cell quantity and quality, degeneration 6 of seminiferous tubules, decreased testosterone lev els, alterations in biomarkers of toxicity in the 7 testes, and alterations in sperm count, morphology, and/or motility (Golalipour et al., 2007; Xing 8 et al., 2007; Zhou et al., 2006; Özen et al., 2005, 2002; Sarsilmaz et al., 1999; Guseva, 1972). 9 Several of these studies included inhalation exposu re of rats to formaldehyde 8 hours/day, 10 5 days/week for 4 and/or 13 weeks (Özen et al., 200 5, 2002; Sarsilmaz et al., 1999) and included 11 exposure-response information that was considered a dequate for RfC derivation. In a study by 12 Özen et al. (2002), increased severity of statistic ally significant testes weight decreases was 13
related to both dose and duration of treatment. Si milarly, in the study by Golalipour et al. (2007), 14 seminiferous tubular diameter and epithelial height were reduced in rats following 18 weeks of 15 formaldehyde inhalation exposure, with the severity of outcome positively correlated to the 16 number of hours/week that the animals were exposed. Sarsilmaz et al. (1999) noted dose 17 dependent decreases in Leydig cell quantity after 4 weeks of treatment, while decreased testis 18 weight and atrophy of seminiferous tubules were obs erved by Zhou et al. (2006) after only 2 19 weeks of treatment. The reported outcomes in these independent studies illustrate a biologically 20 consistent toxicological profile of treatment-relat ed male reproductive toxicity. PODs, adjusted 21 for continuous exposure, ranged from 1,190 to 4,025 ppb, where the lowest POD was associated 22 with the longest exposure period and vice verse (Ta ble 5-3). 23
24 Female reproductive toxicity. 25 Evidence of decreased fecundability was observed in the study by Taskinen et al. (1999), 26 which was described above for spontaneous abortions . Delays in the time to conception that 27 characterized this outcome, as well as increases in the incidence of endometriosis, were 28 statistically significantly associated with occupat ional exposures to formaldehyde. As these 29 effects were observed in the high exposure group, t he unadjusted NOAEL for each of these 30 effects is 76 ppb (8 hr-TWA) based on the next lowe st exposure group. Uncertainties included 31 lack of information human variability, as well as o n the extrapolation of data from studies of 32 short duration to risk estimates for chronic exposu res. As discussed above for spontaneous 33 abortions, the use of these data for cRfC derivatio n could result in values that would likely be an 34 underestimation of risk because they assume that al l the risk was from inhalation exposure and 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-30 ignore the apparent contribution of dermal exposure (i.e., the dermal-exposure-adjusted candidate 1 inhalation RfCs might be higher). For decreased fe cundability, a POD can also be identified 2 based on the data from only the women who wore glov es. The fecundability density ratio (FDR) 3 for the women in the highest exposure group who wor e gloves was 0.79 (95% confidence 4 interval [CI] 0.47–1.23). Although this FDR is not statistically significant, it can reasonably be 5 assumed to be part of a trend of decreased FDR with increasing inhalation exposure, based on the 6
overall data for the association of decreased FDR w ith formaldehyde exposure. Whether the 7 highest exposure level is considered to be a NOAEL or a LOAEL for decreased fecundability in 8 women who wore gloves, the unadjusted POD is 219 pp b (8 hr-TWA). Evidence of spontaneous 9 abortions in the same study, as described above, ma y also be indicative of female reproductive 10 toxicity. 11 In animal studies, assessment of the female reprod uctive system was quite limited. An 12 increase in the mean follicle-stimulating hormone ( FSH) levels in rats, observed at the highest 13 exposure level tested in Kitaev et al. (1984) was found to be sufficient to derive a duration14 adjusted POD of 50 ppb (Table 5-3). 15
16 Summary of developmental and reproductive toxicity studies suitable for RfC development. 17 A review of the developmental and reproductive toxi city studies in humans and animals 18 that would be suitable for cRfC development demonst rated that the developing organism and the 19 reproductive system are targets for toxicity follow ing formaldehyde exposure by inhalation. In 20 the animal studies, effects during early developmen t were observed following maternal 21 premating or gestational exposures at duration-adju sted PODs ranging from 50-325 ppb. The 22 minimal data available on female reproductive toxic ity demonstrated an adjusted POD of 50 ppb 23 with subchronic (4-month) premating exposure, while more extensive evaluation of male 24 reproductive outcomes identified adjusted PODs of 1 ,190-4,025 for testicular and sperm 25 abnormalities after exposures of from 2 weeks to 3 months in duration. The animal studies 26 demonstrate the broad range of adverse outcomes to the reproductive system and the developing 27 organism following inhalation exposure to formaldeh yde and highlight concerns regarding the 28 inadequacy of the database for the assessment of th ese outcomes (as described in Chapter 4). 29 These data also support the human relevance of fema le reproductive and/or embryonic and fetal 30 developmental effects, since some outcomes were sim ilarly observed in both human and animal 31
studies. 32
33This document is a draft for review purposes only a nd does not constitute Agency policy 5-31 DRAFT—DO NOT CITE OR QUOTETable 5-3. Developmental and reproductive toxicityPODs including duration adjustments – key animal studiesPOD Exposure Scenario POD Duration AdjustmentsReference SpeciesType ppbaHours/dayDays/weekDurationPOD(ppb)Hours/dayDays/weekAdjustedPOD(ppb) RatiobEffect; commentsSpontaneous abortion and fetal deathKitaev et al.(1984)Rat LOAEL 400 4 5 6 monthspremating400 ×4/24 ×5/7 =50 8 Increased (>threefold) embryodegeneration on gestationaldays 2–3 after 4 monthsmaternal premating treatmentSheveleva (1971)Rat LOAEL 400 4 7 GDs 1-19 400 ×4/24 ×7/7 =70 5.7 Increased (50%)preimplantation lossgStructural alterationscSenichenkova(1991)Rat LOAEL 400 4 7 GDs 1-19 400 ×4/24 ×7/7 =70 5.7 Increased (13%) litterincidence of internal organanomalies, including 20%increase in undescendedtestes; 9% decreased fetalincidence of hyoid ossificationgSenichenkovaand Chetobar(1996)Rat LOAEL 400 4 7 GDs 1-19 400 ×4/24 ×7/7 =70 5.7 Increased (21%) fetal andlitter incidences ofcryptorchidism and increased(6%) fetal incidences of totalanomaliesgGrowth retardationSaillenfait et al.(1989)Rat BMCL 1,300 6 7 GDs 6-20 1,300 ×6/24 ×5/7 =325 4 Decreased male fetal bodyweightsg(BMR = 5%)Functional developmentdMale reproductive toxicityÖzen et al.(2002)Rat LOAEL 10,0008 5 4 or 13weeks10,000×8/24 ×5/7 =2,380 4.2 Decreased testis weight at4 weeks (2%) and 13 weeks(8%)Özen et al.(2005)Rat LOAEL 5,000 8 5 91 days 5,000 ×8/24 ×5/7 =1,190 4.2 Decreased (40%) serumtestosterone levels at 91 daysSarsilmaz et al.(1999)Rat LOAEL 10,0008 7 4 weeks 10,000×8/24 ×7/7 =2,380 4.2 Decreased (5%) Leydig cellnumbers at 4 weeksThis document is a draft for review purposes only a nd does not constitute Agency policy 5-32 DRAFT—DO NOT CITE OR QUOTETable 5-3. Developmental and reproductive toxicityPODs including duration adjustments – key animal studiesZhou et al.(2006)Rat LOAEL 8,050 12 7 2 weeks 8,050 ×12/24 ×7/7 =4,025 2 Decreased (~25%) testisweight; alteration ofepididymal sperm [decreased(38%) count, decreased (19%)motility, and increased (>3-fold) abnormal morphology]at 2 weeksFemale reproductive toxicityKitaev et al.(1984)Rat NOAEL 400 4 5 4 monthspremating400 ×4/24 ×5/7 =50 8 Increased (~66%) folliclestimulating hormone at4 monthsGDs = Gestation daysa1 mg/m3= 0.813 ppm.bPOD unadjusted dose / duration-adjusted dosecNeuropathological alterations following exposuresduring postnatal development (from the studies by Aslan et al. [2006] and Sarsilmaz et al. [2007]) areaddressed in the neurobehavioral toxicity Section 4.2.1.6 and Table 5-2.dFunctional developmental endpoints (from the studyby Senichenkova [1991]) are addressed in the neurobehavioral toxicity Section 4.2.1.6 and Table 5-2.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-33 The animal study data were not selected for RfC der ivation, since a high-quality human 1 study (Taskinen et al., 1999) was available for the purpose of deriving a chronic RfC. This 2 study, a well-designed population-based case-contro l study of women who were occupationally 3 exposed to formaldehyde, included a well-defined st udy population which was adequately 4 selected to allow for meaningful comparisons of hea lth effects among individuals with different 5 levels of exposure to formaldehyde. Potential conf ounding factors such a selection bias and 6 inaccurate self-reporting were not considered to ha ve had a significant influence on the study 7 findings. The increased risk of spontaneous aborti on observed in Taskinen et al. (1999), and 8 perhaps the observed decrease in fecundity, is inte rnally consistent and coherent with other 9 reports of increased risk of pregnancy loss associa ted with exposure to formaldehyde (John et al., 10 1994; Taskinen et al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). It is also supported 11 by similar adverse outcomes observed in the animal data (Kitaev et al., 1984; Sheveleva, 1971). 12
13 5.1.2. Summary of Critical Effects and Candidate R fCs 14
5.1.2.1. Selection of Studies for Candidate RfC Derivation 15
The above reviews of data from both human and anima l studies identified health effects 16 associated with formaldehyde exposure. Detailed in formation on these findings is given in 17 Chapter 4 (sections 4.1 and 4.2), and a qualitative summary of the noncancer hazard 18 identification is provided in Section 4.4 for each of the identified health effect categories: 19 sensory irritation, upper respiratory tract patholo gy, respiratory effects, increased atopic response, 20 immune function, reproductive and developmental tox icity, and neurobehavioral toxicity. In this 21 chapter, results for each health effect category ar e reviewed and studies are identified which are 22 adequate to inform the exposure-response relationsh ip for health effects from inhalation exposure 23 (Section 5.1.1). Although the database of publishe d studies that are currently available does not 24 provide adequate quantitative data to derive cRfCs for all qualitatively identified endpoints, at 25 least one adequate study was identified for each of the health effect categories discussed above. 26 For all but one of the categories, at least one stu dy was available that provided epidemiologic 27 (human) data, based on occupational or residential exposures, which was judged adequate to 28 provide a quantitative basis for a cRfC. 29 In order to select the principal study or studies m ost appropriate for use as the basis of the 30 RfC for formaldehyde, the relative merits of these studies were evaluated with respect to study 31 quality, characteristics of the study population, t he quality and frequency of exposure 32 measurements, and the exposure levels at which effe cts are observed. The ideal RfC would be 33 derived from a reported exposure level without an a ppreciable risk of deleterious effects in 34 humans, including sensitive populations, with littl e uncertainty. Additionally, where possible, 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-34 the RfC should be derived with consideration of all of the identified health effects. The several 1 factors that were collectively taken into considera tion for these studies (in no particular order) 2 included the following: 3
4

• Were studies of laboratory animals or humans? 5

o Human studies were generally preferred over laborat ory animal studies for similar 6 health effects, when both were of good quality, giv en the uncertainties in 7 interspecies extrapolation. 8

• What was the study size? 9

o Larger studies were generally preferred over smalle r studies because they can give 10 more precise estimates of response levels associate d with specific exposure levels. 11

• Among the epidemiologic (human) studies, were expos ures from an occupational setting or 12 from a residential setting? 13

o Studies of health effects from residential exposure s were generally preferred over 14 studies of health effects from occupational exposur es because residential 15 exposures tend to have a smaller range of variabili ty and are less prone to large 16 intermittent exposure peaks. 17

o Residential exposures are more representative of th e exposures of the general 18 population. 19

• Among the epidemiologic (human) studies, were child ren among the study population in 20
which health effects were observed? 21

o Studies of health effects that assessed the effect of formaldehyde on children’s 22 health, representing a potentially more susceptible life-stage for some effects, 23 were given some preference because they provide for maldehyde-specific data 24 relevant to the components of the RfC derivation th at address potentially sensitive 25 life-stages and populations. 26

• Relative to the other studies under consideration f or RfC development, how accurately were 27 formaldehyde concentrations measured? 28

o Studies based on relatively more accurately measure d formaldehyde 29 concentrations were generally preferred over studie s that estimated exposures. 30

• Studies that reported effects at relatively lower f ormaldehyde concentrations, potentially 31 indicative of more sensitive endpoints, were genera lly preferred. 32
33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-35 Taking all the factors into consideration collectiv ely, the individual studies are presented 1
in Table 5-4. 2 For sensory irritation, four studies are identified with adequate exposure information for 3 RfC derivation, and all are human studies (Table 5- 4). Of these, 3 studies were conducted in 4 residential populations, including children and the elderly (Liu et al.,1991; Ritchie and Lehnen, 5 1987; Hanrahan et al., 1984). Each of these studie s includes in-home formaldehyde 6 measurements for each participant. Liu et al. (199 1) provide the best exposure measurements, 7 with 7-day in-home passive air samples collected in two seasons. The occupational study by 8 Holmström and Wilhelmsson (1988) provides evidence of sensory irritation in workers; however, 9 only the mean and range of exposures for all worker s is given. Furthermore, occupational 10 exposures can include high peak exposures. The res idential studies are preferred for 11 development of candidate RfC. Although there are d ifferences in study size and the quality of 12 exposure measurements between the three residential studies, their results are mutually 13 supportive, defining similar effect levels in simil ar populations, and the use of the three 14 residential studies was considered to provide adequ ate consideration of the sensory irritation 15 endpoint. Therefore, all 3 studies are selected (L iu et al.,1991; Ritchie and Lehnen, 1987; 16 Hanrahan et al., 1984) and will be evaluated togeth er in the following section. 17 Histological changes in the upper respiratory tract are well documented in animal studies 18 and have been observed in several worker studies (S ection 4.4). Although the study of resin 19 production workers (Holmström and Wilhelmsson, 1988 ; Holmström et al., 1989) provides the 20
best documentation of effect level for this health category in humans, it is not carried through for 21 development of a candidate RfC. As with the sensor y irritation endpoint reported in these 22 studies, exposure is described for the worker cohor t by a simple mean, with a range of exposures 23 given for all workers. Therefore, these data do no t provide an exposure-response relationship 24 and the POD would be the mean exposure level of all workers, regardless of effect. This is less 25 exact than other available studies which provide ex posure-response relationships. Additionally, 26 animal studies provide a broad database which suppo rts sensory irritation as a more sensitive 27 endpoint than histological changes in the nasal muc osa. 28
29This document is a draft for review purposes only a nd does not constitute Agency policy 5-36 DRAFT—DO NOT CITE OR QUOTETable 5-4. Summary of candidate studies for formaldehyde RfC development by health endpoint category1HealthEndpointCategoryStudySpeciesSettingChildrenStudysizeFormaldehydemeasurementsSpecificEndpointsObservedeffectsa(ppb)POD (ppb)Liu et al. (1991) Human Residential Yes 1,394Two locations at onetime period (winter orsummer); 7-daypassive monitorsEye irritation95 LOAEL=95Ritchie andLehnen (1987)Human Residential Yes 2,007Two locations at onetime period; 30-minute sampleEye, nose, andthroat sensoryirritation200 NOAEL=50Hanrahan et al.(1984)Human ResidentialYes(teenagers)61Two locations at onetime period; 60-minute sample10% increasedprevalence ofburning eyes130 BMCL10=70SensoryIrritationHolmström andWilhelmsson(1988)Human Occupational No 106Several measurementsat factoryworkstations takenover 7 yearsEye irritation210 NOAEL=70UpperRespiratoryTract PathologyHolmström andWilhelmsson(1988);Holmström et al.(1989)Human Occupational No13268 withpathologySeveral measurementsat factoryworkstations takenover 7 yearsLoss of ciliatedepithelium;goblet cellhyperplasia;squamous cellmetaplasia240 LOAEL=240Garrett et al.(1999)Human Residential Yes 148Four locations over upto four time periods;4-day passivemonitorsIncreasedallergy;increasedasthma-likesymptoms28 LOAEL=28Sensitization:Asthma andatopyRumchev et al.(2002)Human Residential Yes 192Two locations at twotime periods (Winter& Summer); 8-hourpassive monitorsInitial diagnosisof asthma45 NOAEL=33This document is a draft for review purposes only a nd does not constitute Agency policy 5-37 DRAFT—DO NOT CITE OR QUOTEHealthEndpointCategoryStudySpeciesSettingChildrenStudysizeFormaldehydemeasurementsSpecificEndpointsObservedeffectsa(ppb)POD (ppb)PulmonaryFunctionKrzyzanowski etal. (1990)Human Residential Yes 208Four locations overtwo time periods(opposite seasons);7-day passivemonitors10% Reductionin PEFR27 BMCL10=17NeurologicalMalek et al.(2003a)Rat Laboratory -- 120Intentional exposuresat specific levelsImpairedlearning100 LOAEL=100Taskinen et al.(1999) (FDR)Human Occupational No 602Actual and surrogatemeasurementsestimated byoccupational hygienistDecreasedfecunditydensity ratio(FDR)226bNOAEL=86ReproductiveandDevelopmentaleffectsTaskinen et al.(1999) (SAB)Human Occupational No 602Actual and surrogatemeasurementsestimated byoccupational hygienistIncreased risk ofspontaneousabortion (SAB)26bLOAEL=26ImmuneFunctionLyapina et al.(2004)Human Occupational No 29Average shiftconcentrations basedon measures 8-hourexposuresIncreasedrespiratory tractinfections,decreasedneutrophilrespiratory burstactivity722 LOAEL=722aThis is the lowest level of exposure at which adverse effects were observed, the LOAEL, in effect, orthe cut-off point for adversity for BMCLs.bSee Section 5.1.2.6.2 for methods to adjust exposure levels from Taskinen et al. (1999).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-38 Reduced pulmonary function is associated with forma ldehyde exposure in several human 1 studies (students and workers). The best single st udy demonstrating decreased pulmonary 2 function is the moderate residential study by Krzyz anowski et al. (1990). The study was 3 specifically designed to include homes with childre n between the ages of 5-15. Results presented 4 for children (n = 208) provide an exposure-response relationship for reduced PEFR. Data 5 quality is considered high for this study, both in terms of the in-home exposure measurements 6 (7-day passive monitors, two time periods) and the contemporaneous in-home measurement of 7 pulmonary function. Sources of potential confoundi ng or bias were considered by the study 8 authors and adequately taken into account in the st udy. Therefore, this study is retained for 9
derivation of a candidate RfC. 10 Several studies report increased asthma and/or alle rgic sensitization in children associated 11 with increased formaldehyde exposure in school or h omes (Section 5.1.4). Of these, two studies 12 are further evaluated here (Garrett et al., 1999; R umchev et al., 2002). The study by Rumchev et 13 al. (2002) is a case-control study of asthma incide nce in children, and the study by Garrett et al. 14 (1999) is designed to study several related health effects (asthma, sensitization and respiratory 15 symptoms) in asthmatic and non-asthmatic children. Both studies measure in-home 16 formaldehyde levels with multi-day passive samples. Survey data and health outcome data are 17 considered of high quality in each study. Additiona lly, sources of potential confounding or bias 18 were considered by the study authors and adequately taken into account in the study. Therefore, 19
both studies are retained for derivation of a candi date RfCs. Although several studies of school 20 children support these findings, the residential st udies were considered more appropriate for RfC 21 derivation because individual in-home formaldehyde levels were associated with the health 22
outcome data. 23 Multiple lines of evidence support the occurrence o f neurotoxicity following exposure to 24 formaldehyde, however, none of the available human studies were considered to be of adequate 25 quality for derivation of a point of departure for use in quantitative assessment. Of the available 26 neurotoxicity studies, Malek et al. (2003a), in whi ch impaired learning was seen in rats following 27 exposure at 100 ppb, was selected as a potential ca ndidate for RfC development (see 28 Section 5.1.6). A NOAEL was not identified for thi s effect. In view of the other studies 29 available in the formaldehyde database (including m ultiple human studies of potentially sensitive 30 populations), and considering the uncertainty in ex trapolating from the exposure conditions in 31 the Malek et al. (2003a) study (two hour exposures, repeated on ten consecutive days) to a 32 chronic exposure scenario, this study was not carri ed forward for derivation of a candidate RfC. 33 It is important to note that the resulting RfC may therefore not fully consider the documented 34 neurotoxic effects of formaldehyde. 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-39 Of the various reproductive and developmental effec ts associated with formaldehyde 1 exposure, reduced fecundity and increased risk of s pontaneous abortions are primarily studied in 2 humans (Section 5.1.7). Of the available human stu dies, only one study provides individual 3 exposure estimates of adequate quality to support R fC development (Taskinen et al., 1999). 4 Exposure-response relationships for decreased fecun dability density ratio and increased risk of 5 spontaneous abortions are seen with increased categ ories of worker exposures. Several potential 6 confounding exposures are evaluated in the study, a nd the association of decreased fecundability 7 density ratio observed in the study is most convinc ingly associated with increased formaldehyde 8 exposure (Taskinen et al., 1999). Potential source s of bias were also adequately addressed in the 9 study. This is considered a high quality study and is retained for cRfC derivation. 10 Although Lyapina et al. (2004) have documented decr eased neutrophil respiratory burst 11 activity in exposed workers, the overall weight of evidence for deficit in immune function due to 12 formaldehyde exposure is weak. There is a trend fo r increased respiratory tract infections in 13 formaldehyde-exposed individuals, but it is a direc t result of impaired immune function or, 14 perhaps, increased infection due to direct effects on the protective barriers of the nasal mucosa. 15 Animal studies do not support a finding of a defici t in immune function with formaldehyde 16 exposure. The study by Lyapina et al. (2004) is a small study, and the findings of decreased 17 neutrophil respiratory burst activity were in those individuals with more upper respiratory tract 18 infections, so there is some question of causality. The data evaluation does not provide an 19 exposure-response relationship, but, rather, exposu re for the cohort is expressed as a mean 20 exposure of 722 ppb. Although the potential for im pairment of immune function is an important 21 health effect, the overall evidence for this effect and this specific study are relatively weak 22 compared to other data available to support RfC der ivation for formaldehyde. Therefore, this 23 study is not carried further in the quantitative an alysis. 24 In summary, the best studies evaluated herein for the derivation of an RfC for 25 formaldehyde exposure and the related health effect s are: 1) Sensory irritation (Liu et al.,1991; 26 Ritchie and Lehnen, 1987; Hanrahan et al., 1984); 2 ) reduced pulmonary function (Krzyzanowski 27 et al., 1990); 3) sensitization (atopy and asthma) (Garrett et al., 1999 and Rumchev et al., 2002); 28 and 4) reduced fecundity and increased spontaneous abortion (Taskinen et al., 1999). It is 29 recognized that not all identified health effects a re represented in these studies. 30
31
32
33
34
5.1.2.2. Derivation of Candidate RfCs from Key Studies 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-40 Candidate RfC derivation for Krzyzanowski et al. (1 990) (Pulmonary function) 1 The study by Krzyzanowski et al. (1990) is a high q uality epidemiology (human) study of 2 health effects in a random sample of residents and their families. The study was specifically 3 designed to include only households that had childr en 5–15 years of age, a sensitive life-stage for 4 respiratory effects. The study was of moderate siz e, when the effects in children were analyzed 5 separately from adults, with the final analysis bas ed on 208 children—a cohort large enough to 6 show statistically significant results. The formal dehyde monitors were prepared by the Lawrence 7 Berkeley Laboratories and were considered to be pre cise and highly reliable. The 7-day passive 8 formaldehyde monitors generally provide the lowest limit of formaldehyde detection. The 9 investigators specifically tested an a priori hypot hesis and conclusively demonstrated to a high 10 level of statistical significance that increased re sidential formaldehyde exposures were associated 11 with decreased pulmonary function as measured by pe ak expiratory flow rate (PEFR) in children. 12 This effect was clearly shown at relatively low co ncentrations of formaldehyde as the mean 13 concentration in the homes was 26 ppb with more tha n 83% of homes having measured 14 concentration less than 40 ppb. This study also re ported specific regression modeling results that 15 allowed EPA to calculate the point of departure for RfC development using a BMCL as the point 16 of departure. 17 The effects of formaldehyde exposure on pulmonary f unction represent a sensitive 18 endpoint with a reported 10% reduction in PEFR at 2 7 ppb. Among children with physician19 diagnosed asthma, the observed effects of increased formaldehyde exposure on decreased PEFR 20 were more pronounced – a clear indication of variab ility in response. The American Thoracic 21 Society (ATS, 2000) considers decreased pulmonary f unction an adverse health effect, even 22 when it is transient and subclinical. “Assuming th at the relationship between the risk factor and 23 the disease is causal, the committee considered tha t such a shift in the risk factor distribution, and 24 hence the risk profile of the exposed population, s hould be considered adverse, even in the 25
absence of the immediate occurrence of frank illnes s” (ATS, 2000). The ATS (2000) stated that 26 individuals in an exposed population experiencing a shift in the distribution of pulmonary 27 function were at potential risk from another agent due to the reduction in their reserve capacity to 28 address additional insults. In the study by Krzyza nowski et al. (1990), the investigators 29 demonstrated statistically significant interaction between formaldehyde exposures, smoking, and 30 chronic cough. That is, a formaldehyde concentrati on that caused decreased pulmonary function 31 at residential levels also caused chronic cough in the presence of environmental tobacco 32 exposures. Higher prevalence rates of physician-di agnosed asthma and chronic bronchitis were 33 also shown at higher concentrations of formaldehyde (60–140 ppb), an effect that was 34 exacerbated by environmental tobacco exposures. 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-41 Figure 5-4 illustrates the reductions in peak expir atory flow rate (PEFR) in children (<15 1 years of age) in relation to indoor residential for maldehyde concentrations estimated by a random 2 effects model based on 3,021 observations in 208 su bjects. Formaldehyde levels in the home 3 were significantly related to reductions in PEFR in children both at bedtime and in the morning 4 ( p < 0.05). PEFR measurements in the morning versus at bedtime were significantly different ( p 5 < 0.05). Formaldehyde-related reductions in PEFR w ere greater in the morning in asthmatic 6 children than in non-asthmatic children ( p < 0.05). 7
8

9 10 Figure 5-4. Estimated reduction in peak expiratory flow rate (PEFR) in 11 children in relation to indoor residential formalde hyde concentrations. 12 13 Source: Krzyzanowski et al. (1990). 14 15 16 Candidate RfC derivation based on Krzyzanowski et a l. (1990): 17
Critical effect: Based on this study, which specifically included a susceptible 18 population, the critical effect is reduction in PEF R in children. PEFR was the most 19 sensitive measure of disease or impaired lung funct ion reported in this population, with 20 decreases in lung function reported in children who lived in homes with average 21 measured formaldehyde concentrations as low as 30 p pb (Krzyzanowski et al. (1990). 22 Children were more sensitive to formaldehyde-associ ated decreases in PEFR than adults, 23
so the cRfC derived focused on the results in the 2 08 children. 24This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-42 Point of departure: A BMR of 10% reduction in PEFR was selected as a cut-off point 1 for adversity, based on rationales articulated by t he ATS (2000) 4 . Using this BMR and 2 the model coefficient in Table 5 of Krzyzanowski et al. (1990), a BMCL 10 of 17 ppb 3 (BMC 10 = 27 ppb) was derived for all children. 5 Although the authors noted that 4 asthmatic children were more sensitive, the necessa ry data were not provided in the report 5
to calculate a BMCL for asthmatic children alone. Thus, 17 ppb, the BMCL based on all 6 children in the study, was used as the POD. 7
8 Application of study-specific Uncertainty Factors ( UFs) : 9 Interspecies UF = 1: No interspecies adjustment is needed, as this is a human study. 10
LOAEL-to-NOAEL UF = 1: Because a BMCL was used for the POD and the BMR o f 11 10% reduction in PEFR was considered to be a cut po int for adversity, no 12 LOAEL-to-NOAEL UF was needed (UF L = 1). 13
14
15
Subchronic-to-chronic UF = 1: The study addresses ongoing residential exposure to 16 formaldehyde. Although information on the duration of exposure for each 17 participant is not provided, the residential nature of the study suggests a longer 18 term exposure than the duration of the study. It w as judged that a population19 based study of residential exposures is sufficient to derive a chronic RfC without 20 adjusting for a subchronic observation period

 at least for adults and older 21 children, and the children in this study were mostl y older children (e.g., older than 22 7 years). 23

4 The ATS (2000) recommended that “a small, transient loss of lung function, by itself, should not autom atically be designated as adverse” and cited EPA’s 1989 review of ozone, which offered a graded classification of lung function changes in persons with asthma as “mild,” “moderate ,” or “severe” for reductions of less than 10, 10–2 0, and more than 20%, respectively (U.S. EPA, 1989). ATS (2000 ) concluded that, in evaluating the adverse health effects of air pollution at the level of population health (compar ed to individual risk), “[a]ssuming that the relati onship between the risk factor and the disease is causal, the comm ittee considered that such a shift in the risk fact or distribution, and hence the risk profile of the exposed population, s hould be considered adverse.” This was specificall y considered by ATS (2000) even when “[e]xposure to air pollution c ould shift the distribution towards lower levels wi thout bringing any individual child to a level that is associated with clinically relevant consequences.” A moderate adverse effect at functional decrements of 10–20% was considered the best indicator of adverse effects in the study popu lation. This criterion had been similarly applied in EPA’s Air Quality Criteria for Ozone and Related Photoche mical Oxidants (U.S. EPA, 2006d) for pulmonary function.
5 According to the regression model in Table 5 in Krz yzanowski et al. (1990), the coefficient ± standard error for formaldehyde (in ppb) is –1.28 ± 0.46 and the backg round PEFR is 349.6 L/minute. Thus, a 10% reductio n in PEFR is –35 L/minute and the 95% (one-sided) upper bound on the slope for PEFR as a function of formaldehyd e exposure is –1.28 – (1.645 × 0.46), or –2.04 L/minute-ppb. Dividing 35 L/minute by 2.04 L/minute-ppb yields 17 ppb as theThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-43 Human variability UF = 3: The study was designed to include homes with childr en, and 1
a POD can be established based on reduced PEFR in c hildren, who were more 2
sensitive to the health effects than the adults in the study. Therefore, the POD 3 represents data for a sensitive life stage, an aspe ct of human (intraindividual) 4 variability. With respect to the human (interindiv idual) variability UF, although 5
environmental tobacco smoke and socioeconomic statu s did not affect the 6 formaldehyde results in children, asthmatic childre n were more sensitive to the 7 effects of formaldehyde exposure on PEFR; thus, ast hmatic children represent a 8 population with increased susceptibility for this e ffect. The prevalence rate for 9 physician-diagnosed asthma in the children was 15.8 % in this study, which is 10 higher than the national prevalence of about 5.9% f or ages 5 to 17 years. 6 Thus 11 the BMCL based on all children may be influenced by a higher prevalence of 12 susceptible children for the critical effect. The authors do report that the PEFR 13 was reduced to a greater degree in asthmatic childr en (as shown in Figure 5-4), 14 and a lower BMC of 17 ppb can be calculated in this subgroup versus a BMC of 15 27 ppb for all children. However, the published re gression statistics do not 16 provide sufficient detail to calculate a BMCL speci fic for asthmatic children. In 17 addition, other potentially sensitive populations ( for example, elderly individuals 18 or individuals with respiratory diseases) may not b e adequately represented in the 19 study. Therefore, an UF for human variability of 3 is applied to address the 20 observed increased sensitivity of asthmatic childre n in lieu of a calculated BMCL 21 specific to asthmatic children and to ensure adequa te protection for other 22 potentially sensitive populations. 23 24


## ( ) ( ) ppb ppb
UF UF UF UF BMCL RfC

H S L A 

### 6.5 3 1 1 1 17 10 

### =

× × × = × × × = 25

26
UF A = 1 (interspecies UF) 27 UF L = 1 (LOAEL-to-NOAEL UF) 28 UF S = 1 (subchronic-to-chronic UF) 29

BMCL. 6 The national prevalence rate of asthma in children ages 5-17 is according to the Centers for Disease C ontrol and Prevention (CDC) (MMWR 49(40):908-911, 2000). Alth ough the Krzyzanowski et al. (1990) study was condu cted in the late 1980s, prevalence data from the Nationa l Health Interview Survey for 1997 were used for co mparison because that is the earliest year for which data ar e available after a 1997 redesign of the survey. P reviously, the survey asthma question was not specific for physici an-diagnosed asthma, so the redesigned results were considered to be more comparable to the physician-diagnosed as thma definition in the Krzyzanowski et al. (1990) s tudy.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-44 UF H = 3 (human variability UF) 1
5.1.2.2.1. Candidate RfC derivation for Rumchev et al. (2002) (Asthma) 2 Residential formaldehyde exposure was associated wi th an increased risk of asthma in a 3 population-based case-control study of 192 children aged 6 months to 3 years (Rumchev et al., 4 2002). While it is acknowledged that accurately di agnosing asthma in young children is difficult, 5 as the diagnosing physician was unaware of the form aldehyde level in the children’s home, any 6 diagnostic error would be unrelated to formaldehyde concentrations and would not induce a 7 spurious association. It is noted that the endpoin t is physician-diagnosed asthma. The study, 8 which comprises 88 cases of children discharged fro m the emergency department of a children’s 9 hospital in Perth, Australia, with a primary diagno sis of asthma and 104 controls, provides a 10 positive exposure-response relationship adequate fo r RfC derivation. Seasonal in-home 11 formaldehyde measurements taken in the living room and subject’s bedroom were used to assess 12 exposure (8-hour passive sampler). The ORs for ris k of asthma by formaldehyde exposure level 13 category were adjusted for numerous risk factors, b oth familial and environmental, including 14 familial history of asthma, age, sex, socioeconomic status, smoking, presence of pets, air 15 conditioning, humidifier, and gas appliances. Of t hese, age, allergic sensitization to common 16 allergens, and family history of allergy were indep endent risk factors for asthma (OR = 1.09, 17 2.57, and 2.66, respectively). Odds ratios were fu rther adjusted for the effects of the measured 18 indoor air pollutants (see Rumchev et al., 2004), i ndoor allergen levels of dust mites, relative 19 humidity, and indoor temperature. Categorical anal ysis of the data indicates that the ORs for 20 asthma were increased in the two highest formaldehy de exposure groups, reaching statistical 21 significance for household exposures > 60 μg/m 3 (48 ppb) (OR = 1.39) (Figure 5-5). Analysis of 22 the data with formaldehyde as a continuous variable provides a statistically significant increase in 23 the risk of asthma (3% increase in risk per every 1 0 μg/m 3 increase in formaldehyde level.) 24
25
5.1.2.2.2. Candidate RfC derivation based on Rumche v et al. (2002): 26
27
Critical effect: Diagnosis of childhood asthma (case-control study ). 28
29 Point of departure: A NOAEL of 33 ppb (40 μg/m 3 ; midpoint of the 30–49 μg/m 3 30 category) was selected because the OR for asthma in the next highest exposure category 31 was considered to be part of an exposure-related tr end of increasing asthma risk and, 32 therefore, biologically significant. 33

34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-45 1 Figure 5-5. Odds ratios for physician-diagnosed as thma in children 2 associated with in-home formaldehyde levels in air. 3 4 Source: Rumchev et al. (2002). 5 6 7 Application of Study-Specific Uncertainty Factors ( UFs) : 8 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 9
LOAEL-to-NOAEL UF = 1: No LOAEL-to-NOAEL UF was needed because the POD 10 was a NOAEL (UF L = 1). 11
Subchronic to chronic UF = 3: The study addresses ongoing residential exposure to 12 formaldehyde. Although information on the duration of exposure for each 13 participant is not provided, the residential nature of the study suggests a longer 14 term exposure than the duration of the study. Stud y participants were 3 years or 15 younger, therefore the duration of exposure could n ot meet the expected definition 16 for a chronic study of one-tenth the lifespan. How ever, asthma often develops 17 during childhood, indicating a less-than chronic du ration of exposure. Since 18 asthma may develop throughout childhood it is uncle ar whether a study of 19 children under 3 years of age would be of adequate duration for this 20 developmental window. Therefore, an uncertainty fa ctor of 3 was applied as a 21 subchronic to chronic adjustment. 22 Human variability UF = 1 or 3: As a case-control study, all new cases of childhood 23 asthma which met the study criteria were eligible f or inclusion and the cases likely 24 included children predisposed to asthma. Individua ls with a family history of 25 asthma and/or genetic markers for genes believed to predispose individuals to 26 asthma would represent a susceptible population. T herefore, the cases in this 27This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-46 study address children as a susceptible population for first diagnosis of asthma. 1 Additionally, there was an association of a familia l history of asthma with the 2 diagnosis of children’s asthma in this cohort (OR = 2.66). Not all sources of 3 human variability which may contribute to a diagnos is of asthma are known, and 4 there are likely additional sources of inter-indivi dual variability among children 5 and among individuals with a family history of asth ma, thus it is unlikely that all 6 sources of human variability were adequately repres ented in the study population. 7
8 The two alternatives are described below and cRfCs are derived for each alternative. 9
10

11 12
13 Alternative A: Rumchev et al. (2002)

Human variability UF = 3:

To account for potentially susceptible individuals beyond those represented in the study population, an uncertainty factor of 3 for human va riability is applied.



## ( ) ( ) ppb ppb
UF UF UF UF NOAEL RfC

H S L A 3.3 3 3 1 1 33

= × × × = × × × =

UF A = 1 (interspecies UF)
UF L = 1 (LOAEL-to-NOAEL UF)
UF S = 3 (subchronic-to-chronic UF)
UF H = 3 (human variability UF)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-47 1 2 3 5.1.2.2.3. Candidate RfC derivation for Garrett et al. (1999) (Asthma, respiratory 4 symptoms, atopy and severity of allergic sensitizat ion) 5 Garrett et al. (1999) reported on the risk of aller gy and asthma-like respiratory symptoms 6 due to formaldehyde exposure in a cross-sectional s urvey of households with children 7–14 years 7 old with (n = 53) or without (n = 95) doctor-diagno sed asthma. Formaldehyde exposure was 8 characterized by four seasonal in-home sampling eve nts using 4-day passive samples collected in 9 bedrooms, living rooms, kitchens, and outdoors. In logistic regressions, both the prevalence and 10 Alternative B: Rumchev et al. (2002) Human variability UF = 1 :

EPA’s Technical Report of the RfD and RfC Processes Technical Report (US EPA, 2002a)
indicates that UF H of 1 has been applied in cases where there are dat a “very specific about the particular vulnerability of infants and childre n within certain age ranges to an agent.” Asthma and allergic sensitization to common allerge ns develop during childhood and young adulthood defining a developmental window dur ing which individuals are most susceptible to the development of asthma. Since th is study includes only children up to 3 years of age, the UF for subchronic exposure is a pplied above acknowledging that this study does not cover the susceptible developmental window. No additional adjustment is applied for inter-individual variability among chil dren. It is acknowledged that additional sources of human variability are possible – but it is believed that childhood is a key developmental window for initial diagnosis of asthm a. The technical report acknowledges that applying a UF H of 1 may be appropriate where “even within these populations it is possible that some variability st ill exists.



## ( ) ( ) ppb ppb
UF UF UF UF NOAEL RfC

H S L A 11 1 3 1 1 33

= × × × = × × × =

UF A = 1 (interspecies UF)
UF L = 1 (LOAEL-to-NOAEL UF)
UF S = 3 (subchronic-to-chronic UF)
UF H = 1 (human variability UF)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-48 severity of allergic sensitization to 12 common all ergens increased with increasing formaldehyde 1 concentration in the home. Additionally, a calcula ted respiratory symptom score was increased 2 and demonstrated a significant relationship with in creased formaldehyde concentration in a 3 multiple linear regression after adjusting for mult iple risk factors and interactions. For each of 4 these endpoints, severity/incidence was increased i n the medium (20–50 μg/m 3 ) and high 5 (>50 μg/m 3 ) exposure groups relative to the low (<20 μg/m 3 ) exposure group, based on the 6 highest of four seasonal 4-day formaldehyde measure ments in the home (Figures 5-6 and 5-7). 7
8

9 Figure 5-6. Prevalence of asthma and respiratory s ymptom scores in children associated 10 with in-home formaldehyde levels. Trend analysis i ndicates statistical significance in these 11 increases {percent asthmatic children, unadjusted ( p=0.03) and respiratory symptom score 12 (p=0.03)}. 13
14 Source: Garrett et al. (1999). 15 16
17 16% 39% 44%

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%

<20 20-50 >50 Exposure group, formaldehyde level

(ug/m3)Asthmatic Children (%)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-49 33% 64% 75%

0% 10% 20% 30% 40% 50% 60% 70% 80%

<20 20-50 >50 Exposure group, formaldehyde level

(ug/m3)Atopic Children (%)

1 2 Figure 5-7. Prevalence and severity of allergic se nsitization in children 3 associated with in-home formaldehyde levels. Trend analysis indicates 4 statistical significance in these increases {percen t atopic children (p=0.002), 5 positive skin prick tests (p=0.001) and severity as allergen wheal ratio 6 (p=0.004)}. 7 8 Note: Skin prick tests included 12 environmental a llergens (cat, dog, grass [two 9 types], house dust, dust mite [two strains] and fun gi [five strains]). 10 Source: Garrett et al. (1999). 11 12 13 The findings of Garrett et al. (1999) are supporte d by the observation of an increased 14 bronchial responsiveness to mite allergen in a cham ber study of 19 sensitized adult asthmatics 15 exposed to formaldehyde at a concentration of 100 μ g/m 3 for 30 minutes (Casset et al., 2006). 16 Additionally, inhalation exposures to formaldehyde have been shown to increase an animal’s 17 response to other common allergens via inhalation ( Fujimaki et al., 2004; Sadakane et al., 2002; 18 Riedel et al., 1996; Tarkowski and Gorski, 1995). 19
20 Candidate RfC derivation for increased allergic sen sitization from Garrett et al. (1999): 21
Critical effects: Allergic sensitization - Increase in allergic sensitization (proportion o f 22 atopic children). Severity of allergic sensitizati on measured both as number of positive 23 skin tests to common allergens and the recorded all ergen wheal ratio for those tests. 24
Asthma – increase in proportion of asthmatic children. Respiratory symptoms – 25 Increased respiratory symptom score. 26
27This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-50 Point of departure: For all critical effects, categorical analyses ar e presented that show 1 an increase in the mid-exposure group (16–40 ppb) a nd high exposure group (>40 ppb) 2 relative to the low-exposure group (<16 ppb) (Figur es 5-6 and 5-7). However, it is 3 unknown if the findings in the low-exposure group a re comparable to the responses that 4 would be observed in an unexposed population. Ther efore, the low-exposure group 5
cannot be considered a NOAEL but rather serves as a referent group for the two other 6 exposure groups. Thus, the LOAEL is based on healt h effects observed in the mid7 exposure group (16-40 ppb) for all three critical e ffects. As neither the mean or median 8 exposure levels are provided for the exposure categ ories used to analyze the health effects 9 data, the mid-point of the exposure category is sel ected for the LOAEL: 28 ppb. 10
11 Application of study-specific Uncertainty Factors ( UFs) : 12 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 13
LOAEL-to-NOAEL UF = 3: As discussed, the mid-exposure group is selected as the 14 LOAEL since the low-exposure group is the referent group; there is no true 15 unexposed control. It is unclear whether or not a full LOAEL to NOAEL 16 uncertainty factor is warranted for these data. Th e authors did provide evidence 17 for increased atopy for every increase of 16 ppb of exposure with borderline 18 statistical significance when adjusted for several potential confounders (OR = 1.4; 19 95% CI: 0.98–2.00). An UF of 3 adjusts the LOAEL t o a similar range and is 20 consistent with this alternative presentation of th e data. 21
Subchronic to chronic UF = 1: The study addresses ongoing residential exposure to 22 formaldehyde. Although information on the duration of exposure for each 23 participant is not provided, the residential nature of the study suggests a longer 24 term exposure than the duration of the study. It i s judged that a population-based 25 study of residential exposures is sufficient for de rivation of a chronic RfC without 26 adjusting for a subchronic observation period. 27 Human variability UF = 1 or 3: This study was designed to assess allergic 28 sensitization, asthma prevalence and respiratory sy mptoms in children with 29 relation to in-home formaldehyde levels. The recru itment of participants was 30 designed to include households (50%) with asthmatic children, resulting in 31
43 households with at least one asthmatic child and 37 without asthmatic children 32 for a total of 148 children (35% asthmatic). Pare ntal allergy and asthma were 33 also assessed and included as adjustment variables in the data evaluation. 34 Therefore the study population includes individuals reflecting several key aspects 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-51 of human variability for asthma and allergic sensit ization (age, familial history of 1 disease), and addresses the links between allergic sensitization and asthma. Both 2 asthma and allergic sensitization are risk factors for increased respiratory 3 symptoms. 4
5 The two alternatives are described below and cRfCs derived for each alternative 6
7

8 9
10 Alternative A: Garrett et al. (1999)

Human variability UF = 3: It is unclear whether the effect levels in the stud y truly reflect the effect levels in sensitive populations, since study findings controlled for both asthma and family history. Therefore, a value of 3 was used for the human variability UF.



# ( ) ( ) ppb ppb
UF UF UF UF LOAEL RfC

H S L A 

### 8.2 3 1 3 1 28

= × × × = × × × =

UF A = 1 (interspecies UF)

UF L = 3 (LOAEL-to-NOAEL UF)
UF S = 1 (subchronic-to-chronic UF)
UF H = 3 (human variability UF)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-52 1 Alternative B: Garrett et al. (1999) Human variability UF = 1 :

Individuals with a family history of asthma and/or genetic markers for genes are believed to be predisposed to asthma and this would define a susceptible population within children. In this study parental disease status is a marker for potential genetic susceptibility. Although exposure-response relationships are not pr ovided for individuals with a familial history of disease, analyses provided suggest the r esults reflect responses from these individuals. Among children with parental allergy, allergic children were exposed to higher formaldehyde levels than non-allergic children ( p = 0.02), relating higher formaldehyde exposure to sensitization even among those with a l ikely genetic susceptibility. As shown in Figure 5-8, formaldehyde levels are related to incr eased asthma incidence with a significant linear trend (

p = 0.02), yet this relationship loses significance when controlling for parental allergy and asthma, suggesting the measured respons e on which the POD is based is driven by children with a potential for genetic susceptibilit y. An EPA Technical Report of the RfD and RfC Proces ses (US EPA, 2002a) indicates
that a UF H of 1 can be applied in cases where data are “very specific about the particular vulnerability of infants and children within certai n age ranges to an agent.” Asthma and allergic sensitization to common allergens develop during childhood and young adulthood. Therefore no additional adjustment is applied for h uman variability. The technical report acknowledges that “even within these populations it is possible that some variability still exists”, but that a UF H of 1 is still applied.



# ( ) ( ) ppb ppb
UF UF UF UF LOAEL RfC

H S L A 

### 3.9 1 1 3 1 28

= × × × = × × × =

UF A = 1 (interspecies UF)
UF L = 3 (LOAEL-to-NOAEL UF)
UF S = 1 (subchronic-to-chronic UF)
UF H = 1 (human variability UF)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-53 5.1.2.2.4. Candidate RfC derivation for Ritchie and Lehnen, 1987; Hanrahan et al., 1984 1 and Liu et al., 1991 (Sensory irritation). 2 There are three studies that report sensory irritat ion in humans from chronic exposures in 3 a residential environment and provide sufficient ex posure data to support quantitative assessment 4 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrah an et al., 1984). Each study reports site5 specific exposure measurements and presents some me tric of individual exposure. These 6 residential studies employ in-home measurements for each study participant, either as average 7 exposure level (Ritchie and Lehnen, 1987; Hanrahan et al., 1984) or as calculated cumulative 8 exposure based on the time in the home (Liu et al., 1991). Eye irritation is reported at similar 9 levels of residential formaldehyde exposure in the three studies (Figures 5-8 and 5-9). Each 10 study provides an exposure-response relationship fo r prevalence of sensory irritation in relation 11 to in-home formaldehyde exposure based on individua l level data. 12
13
14

15
16
17
18 19 20 21 22 Figure 5-8. Positive exposure-response relationshi ps reported for in-home 23 formaldehyde exposures and sensory irritation (eye irritation). 24 Panel A: Regression of prevalence of eye irritatio n

versus indoor formaldehyde concentration (ppm) in mobile homes (30–60 minute air sample in each home).

Note: Dashed lines show upper and lower 95 th percentile confidence intervals on model results. Model based on reported eye irritation from individuals in 42 mobi le homes.

In

- home formaldehyde concentration (ppm)

Panel B: Prevalence of eye irritation in groups defined by in-home formaldehyde exposure (30– 60 minute air sample in each mobile home).

Note: Eye irritation rate is given by smoking stat us: active smokers (n = 143), passive exposure to smoke (n = 133) and nonsmokers (n = 180).

Data source: Ritchie and Lehnen (1987).

2% 32% 93%

1% 20% 88%

1% 18% 86%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

< 100 100-300 >300

Formaldehyde Concentration (ppb)Eye irritation (% of residents)

Active Passive Non-smokerThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-54 13.3% 17.1% 21.4%

10.8% 14.7% 20.6%

0% 5% 10% 15% 20% 25%

< 7 7 - 12 > 12 Formaldehyde Exposure (ppm-hr per week)Prevalence of burning/tearing eyes (%) Summer
Winter

1 2 Figure 5-9. Positive exposure-response relationshi ps reported for in-home 3 formaldehyde exposures and sensory irritation (burn ing eyes). 4 5 Note: Cumulative formaldehyde exposure was estimat ed for each participant 6 from measured in-home formaldehyde levels (7-day pa ssive air sample) and 7 reported hours spent in the home. Prevalence rates are given for both summer 8 (n = 1,388) and winter (n = 1,093) survey periods. 9 Data source: Liu et al. (1991). 10 11 12 Ritchie and Lehnen (1987) examined formaldehyde-as sociated effects on eye, nose, and 13 throat irritation in a large residential study with 2,007 participants from 841 homes. Based on 14 in-home measurements of formaldehyde concentration, participants were categorized into three 15 exposure groups: low (<100 ppb), mid (100–300 ppb) and high (>300 ppb) (average of two 30– 16 60 minute air samples per home). Ritchie and Lehne n (1987) observed clear exposure-response 17 relationships in the percentage of residential occu pants reporting eye, nose, and throat irritation. 18 For example, in nonsmoking mobile home residents, i ncidence scores for eye irritation were 1%, 19 18% and 86%, and for nose/throat irritation were 5% , 17% and 78%, respectively, for the three 20 exposure groups. The exposure-response relationshi ps were similar regardless of type of home, 21 mobile (n = 851) or conventional (n = 1,156). Alth ough smoking status was also a predictor of 22 irritation, in-home formaldehyde concentrations wer e a stronger predictor of health effects. The 23This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-55 study included children and the elderly and results were consistent across age groups. Children 1 <7 years of age were only included in the eye irrit ation analyses because of concerns about the 2 quality of parental reporting for nose and throat e ffects in young children. The selection criteria 3 for participants indicate that more sensitive indiv iduals may have been over-represented in the 4 study population. 7 All study participants were self-selected, with a physician’s approval, perhaps 5 resulting in a higher proportion of individuals exp eriencing various irritant and upper respiratory 6 tract symptoms, which may represent a sensitive pop ulation for eye, nose, or throat irritation. 7 Hanrahan et al. (1984) reported an exposure-resp onse relationship for burning eyes and 8 eye irritation in a study of 61 teenage and adult r esidents of mobile homes. As in the Ritchie and 9 Lehnen (1987) study, in-home formaldehyde measureme nts were obtained for all participants and 10 measured formaldehyde levels were used to character ize average in-home exposures (30– 11 60 minute air sample). Eye irritation was associat ed with in-home formaldehyde exposures 12 ( p < 0.05) (both as “burning eyes” and “eye irritatio n”), and the authors provided a graphical 13 representation of the best-fitting regression model for exposures between 100 and 800 ppb. From 14 inspection of this graph, the prevalence of eye irr itation predicted at 100 ppb is approximately 15 4% with an upper bound of 18% (95 th percentile CI) (Figure 5-8, Panel A). Because the limit of 16 detection for formaldehyde in indoor air was 100 pp b, data or model results are not provided 17 below 100 ppb. 18 The third residential study is a random-sample stu dy of over 1,000 mobile home residents 19 (1,394 in the summer; 1,096 in the winter) that inc luded both young children and the elderly (Liu 20 et al., 1991). Cumulative weekly exposures were ba sed on in-home formaldehyde sampling and 21 a participant survey of time spent at home. Air sa mpling was conducted for a 7-day period using 22 a passive sampler in each home (summer and winter). The resulting estimates of cumulative 23 exposure assumed no formaldehyde exposure outside o f the home. Cumulative formaldehyde 24 exposure was a significant predictor of numerous ir ritant symptoms in a multivariate linear 25 logistic regression, including “burning eyes” ( p < 0.05). The prevalence of eye irritation 26 increased with increasing cumulative exposure in a categorical analysis of participants 20–64 27 years old for both summer and winter exposure estim ates (Figure 5-9). Eye irritation was above 28 10% in the lowest exposure group (0–7.0 ppm-hours/w eek) and increased to 17.1% and 21.4 % 29

7 Participants in this study were self-selected resid ents who were concerned about possible formaldehyde exposure and had obtained a written request from a physician to have the Minnesota Department of Health test th eir homes as part of a free program; thus, people with symptoms may be overrepresented in this study compared with the general population. This potential overrepresentation does not necessarily imply a selection bias because it is unlikely that it was associated with the measured formaldehyde expos ure levels in participants’ homes.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-56 in the mid- and high-exposure group, respectively, for the summer survey time; winter rates were 1 slightly lower but showed a similar increase with i ncreasing cumulative exposure. 2 Taken together, these three studies report increas ed eye irritation from residential 3 exposures that are below the BMCLs calculated from acute exposures in the laboratory. Each 4 study has the strength of having individual in-home exposure measurements and demonstrates a 5 positive exposure-response relationship for sensory irritation within a range of residential 6 formaldehyde exposures (both conventional and mobil e homes). Potentially confounding factors 7 (such as allergens and some other in-home exposures ) have been taken into account and 8 statistical analyses of the data include relevant c ovariates (e.g., age, sex, smoking status). As 9 such, these studies provide a basis for development of a cRfC for sensory irritation. 10 Additionally, the study populations have been drawn from the general population, including 11 children and the elderly, and have not been limited to those healthy enough for full-time 12 employment (as is often the case in occupational co horts). 13 All three studies support a finding of increased e ye irritation for exposures above 100 ppb 14 (Figures 5-8 and 5-9). However, the shape of the e xposure-response curve below 100 ppb, or an 15 indication of a no-effect level, is less clear. Tw o of the studies indicate 1–4% eye irritation in 16 residents where formaldehyde exposures were measure d at 100 ppb or less (Ritchie and Lehnen, 17 1987; Hanrahan et al., 1984). Thus, there is uncer tainty in considering 100 ppb as a no-effect 18 level for increased eye irritation for these studie s. When modeled, the 95% CIs around the point 19 estimate of 4% eye irritation were 1–18% eye irrita tion, illustrating the range of response rates at 20 100 ppb that are consistent with the observed data (Hanrahan et al., 1984). Additionally, the 21 presentation of results by exposure category in Rit chie and Lehnen (1987) is inexact and has 22 individuals with exposures at the low end of the ca tegorical range being grouped with those at 23 higher exposures in the range, obscuring any exposu re-response relationship within the 24 categorical range. For these reasons, a POD for Rf C derivation from either of these studies 25 should reflect these uncertainties. Therefore, for the NOAEL representing the category of 26
individuals with ≤ 100 ppb, in which 1–2 % eye irritation was observed , the upper end of this 27 exposure category is not used, but rather the midpo int, 50 ppb (Ritchie and Lehnen, 1987). 28 Although Hanrahan et al. (1984) provided no model r esults below 100 ppb, an extrapolation of 29 the graphical results (Figure 5-8, Panel A) provide s an estimated BMCL 10 of 70 ppb 8 . No 30

8 Figure 1 of Hanrahan et al. (1984) shows predicted values and 95% confidence intervals (CIs) for the p ercent prevalence of a burning-eyes response for formaldeh yde concentrations ≥ 100 ppb (See Panel A in Figure 5-9 above). A short extension of the upper 95% CI to the conce ntration associated with 13% prevalence (i.e., a 10 % increased prevalence above an assumed background response rat e of 3%; this assumed background rate was chosen to be conservatively high to err on the side of not under estimating the actual value, given that the value w as approximated from a visual extension of the upper 95% CI curve) suggests a BMCL of approximately 70 ppb for 10% inc reasedThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-57 additional duration adjustments were made from the in-home exposure measurements to 1 continuous exposure because neither time away from the home, nor potential exposures outside 2 of the home, were characterized in either study. 3 Of the three studies, only Liu et al. (1991) provi des exposure measurements below 4 100 ppb, with a reported detection limit of 10 ppb formaldehyde for the in-home air monitoring. 5 Additionally, air samples were collected using a 7- day passive sampler which is more 6 representative of average residential exposures tha n a one-time, 30–60 minute, air sample. 7 Therefore, the data collected by Liu et al. (1991) are more suited to understanding the exposure8 response relationship for eye irritation of exposur es below 100 ppb. In addition to controlling for 9 age, gender, and smoking status, Liu et al. (1991) controlled for the presence of chronic 10 respiratory disease when assessing the effects of f ormaldehyde on symptoms of sensory irritation. 11 Finally, this study provides results for both summ er and winter survey periods, addressing 12 seasonal variation in both formaldehyde levels and sensory irritation. The use of the cumulative 13 exposure metric considers not only the concentratio n of formaldehyde but also the number of 14 hours during the week each participant spent in the ir residence. Linear logistic regression 15 indicates that cumulative formaldehyde exposure was a statistically significant predictor of 16 burning eyes for both winter and summer survey peri ods. However, no BMCL can be calculated 17 because no regression coefficients were provided in the report. Data were provided for the 18 categorical analysis illustrating a positive exposu re-response relationship (redrawn in 19 Figure 5-9). Based on the categorical results, the mid-exposure group (7–12 ppm-hours/week) 20 demonstrated an increased response compared with th e low-exposed group. Since the prevalence 21 rate in the low-exposed group was above 10% for bur ning eyes, this exposure group does not 22 represent a NOAEL, but rather serves as a referent for the mid-exposure group. Therefore, the 23 POD is derived from the midpoint of 7–12 ppm-hours/ week, 9.5 ppm-hours/week. Using a 24 conversion factor applied by the authors, the cumul ative exposure of this mid-exposure group 25 corresponds to a continuous home exposure of 70–120 ppb for an individual who spends 60% of 26 the week in the home, with a mid-point of 95 ppb. 27
28 Candidate RfC derivation for sensory irritation: 29
Critical effect: Prevalence of sensory irritation (eye irritation, burning eyes). 30
31 Point of departure: Each of the studies discussed above has different strengths and 32
weaknesses for the determination of a POD for senso ry irritation. Nevertheless, the effect 33

prevalence. The actual value is unknown but is cle arly below 100 ppb, which is the minimum exposureThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-58 levels and PODs derived from each study are in rela tively close agreement with less than 1 a twofold span from lowest to highest. Therefore e ach POD is carried through to 2
calculate a cRfC: 3
4 NOAEL = 50 ppb (Ritchie and Lehnen, 1987) 5
BMCL 10 = 70 ppb (Hanrahan et al., 1984) 6 LOAEL = 95 ppb (Liu et al., 1991) 7
8 Application of Uncertainty Factors (UFs ) 9 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 10
LOAEL-to-NOAEL UF: An uncertainty factor of 1 is applied to the NOAE L and 11
BMCL 10 established as PODs from Ritchie and Lehnen, (1987 ) Hanrahan et al. 12 (1984) studies. An uncertainty factor of 3 is appl ied to the LOAEL of 95 ppb 13 based on the Liu et al. (1991) study, as the preval ence rates for this exposure level 14 are below 20% for an effect that is of relatively l ow severity. In addition, the 15 LOAEL is not significantly above the NOAEL and BMCL 10 from the other studies 16 that evaluated the same endpoint. 17
18
Subchronic to chronic UF = 1: These studies address ongoing residential exposur e to 19 formaldehyde. Although information on the duration of exposure for each 20 participant is not provided, the residential nature of the study suggests a longer 21 term exposure than the duration of the study. It i s judged that a population-based 22 study of residential exposures is sufficient for de rivation of a chronic RfC without 23 adjusting for a subchronic observation period. 24
25 Human variability UF = 1 or 3: All three studies were population-based and include d 26 children, the elderly and both sexes. Sample sizes for two of the studies were very 27 large (1,394 for Liu et al. [1991]; 2,007 for Ritch ie and Lehnen [1987]), 28 increasing the likelihood that sensitive population s were included. Analysis of the 29 data controlled for sex, smoking status, and age gr oup. 30
31
32
33

concentration depicted in the figure.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-59 1
2
3
4
5 The two alternatives are described below and cRfCs derived for each alternative 6
7

8 9 10 11 Alternative A Sensory irritation studies: Human variability UF = 3: For all studies, the analysis was based on prevalen ce rates, decreasing the likelihood that effects on sensitive individuals would be lost due to response averaging. For Ritchie and Lehnen (1987), the prevalence rate in the <100 ppb exposure group (represented by a NOAEL of 50 ppb, the midpoint) was 1– 4%. For Hanrahan et al. (1984), the POD is a BMCL corresponding to a 10% response rate. Given these prevalence rates and the fact th at the sensory irritation effects assessed are considered minimally adverse, a human variability UF of 3 was considered adequate for this endpoint.

Ritchie and Lehnen (1987):


# ( ) ( ) ppb ppb
UF UF UF UF NOAEL RfC

H S L A 

### 17 3 1 1 1 50

= × × × = × × × =

Hanrahan et al. (1984):


# ( ) ( ) ppb ppb
UF UF UF UF BMCL RfC

H S L A 

### 23 3 1 1 1 70 10 

### =

× × × = × × × =

Liu et al. (1991):


# ( ) ( ) ppb ppb
UF UF UF UF LOAEL RfC

H S L A 

### 5.9 3 1 3 1 95

= × × × = × × × =This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-60 1 Alternative B Sensory irritation studies Human variability UF = 1: Two studies included a broad age range allowing s ome assessment of human variability due to life stage. Ritchie and Lehnen (1987) evaluated the influence of age on sensory irritatio n in the following age groups <1year, 2–6 years, 7–14 years, 15–20 years, 21–54 years, 55 –64 years, and ≥ 65 years. An age effect for eye irritation was not evident in these data and pooled data are presented for this endpoint. Liu et al. (1991) report that great er eye irritation was reported in participants of 20–64 years than in those younger t han 20 or older than 65 years. The elderly population ( ≥ 65 years) was well-represented in this study (39% o f participants in the summer and 34% in the winter). The modeled results on which the BMCL 10 is based for Hanrahan et al. (1984) are normalized to 48 years of age (the mean age of respondents), which is consistent with the age grou p considered the most responsive in the Liu et al. (1999) study. Therefore the PODs de rived from these studies do account somewhat for human variability across the life stag e. The critical effects of sensory irritation (eye, no se, and throat irritation) are considered minimally adverse health effects. The nominal resp onse rates for eye irritation of 1−4% for in-home exposures below 100 ppb from which the PODs were derived suggest that the PODs are below significant respons e levels. Additionally, as the data are reported as prevalence rates, there is no maski ng of effect from sensitive individuals (as may occur when benchmark responses are average values of biometric parameters). Finally, sensory irritation is a POE effect. There fore, sources of human variability such as absorption, distribution, and metabolism of a compo und are unlikely to influence incidence rates for this endpoint. There may be hu man variability in the sensitivity of the trigeminal nerve to formaldehyde binding and st imulation. Taken together, these studies address many potentia l sources of human variability. Therefore, it is judged that further adjustment to address human variability is not warranted for the minimally adverse health effect o f sensory irritation. Thus a UF H of 1 is applied to all three studies. It is acknowled ged that there is the potential for sources of variability not captured in these studie s. (Continued on next page.)This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-61 1 2 3 5.1.2.2.5. Candidate RfC derivation for Taskinen et al. (1999) (Fecundity ratio) 4 On review of the candidate developmental and reprod uctive toxicity studies in humans 5 and animals (presented in Section 5.1.3.2.7), the T askinen et al. (1999) human study was 6 considered to be the strongest for the purpose of d eriving a chronic RfC. This study was a well7 designed population-based case-control study of wom en who were occupationally exposed to 8 formaldehyde. The study population was well define d and adequately selected to allow for 9 meaningful comparisons of health effects among indi viduals with different levels of exposure to 10 formaldehyde. Potential selection bias and the sel f-reporting of spontaneous abortion are not 11 considered to have had a significant influence on t he study findings. Additionally, the decreased 12 FDR and increased risk of spontaneous abortion obse rved in Taskinen et al. (1999) are internally 13 consistent and coherent with other reports of incre ased risk of pregnancy loss associated with 14 exposure to formaldehyde (John et al., 1994; Taskin en et al., 1994; Seitz and Baron, 1990; 15 Axelsson et al., 1984) and is supported by animal d ata (Kitaev et al., 1984; Sheveleva, 1971). 16 The Taskinen et al. (1999) study allows the conside ration of three potential critical 17 effects: endometriosis, increased spontaneous abort ion, and decreased FDR. However, there is 18 little independent support for the finding of incre ased endometriosis and the ORs for organic 19 solvent exposure within this study (OR = 14.7; 95% CI: 3.1–70) were much greater than for 20 formaldehyde (OR = 4.5, 95% CI: 1.0–20), indicating a potential for confounding. Both 21 Continued from previous page:

Ritchie and Lehnen (1987):



## ( ) ( ) ppb ppb
UF UF UF UF NOAEL RfC

H S L A 50 1 1 1 1 50

= × × × = × × × =

Hanrahan et al. (1984):



## ( ) ( ) ppb ppb
UF UF UF UF BMCL RfC

H S L A 70 1 1 1 1 70 10 =

× × × = × × × =

Liu et al (1991):



## ( ) ( ) ppb ppb
UF UF UF UF LOAEL RfC

H S L A 32 1 1 3 1 95

= × × × = × × × =This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-62 increased spontaneous abortions and decreased FDR a re supported by independent findings in 1 other formaldehyde-exposed cohorts (John et al., 19 94; Taskinen et al., 1994; Seitz and Baron, 2 1990; Axelsson et al., 1984). As this study was de signed to examine the effect of workplace 3 formaldehyde exposures on FDR, the study design and data collection best support this finding. 4 The exposure measurements were conducted to represe nt what the researchers considered the 5 relevant time-to-pregnancy exposures. Although dat a on miscarriages were collected to control 6 the time-to-pregnancy findings for confounding from formaldehyde-related spontaneous 7 abortions, it is less certain that the exposure mea surements coincide with the defined 8 spontaneous abortion cases. Spontaneous abortions were only included in calculations of 9 exposure-specific ORs if a participant indicated th at she was employed at the same location when 10 she had the spontaneous abortion and when the time- to-pregnancy exposure assessment was 11 done. The analysis showed that there were statisti cally significantly increased risks of 12 spontaneous abortion in the lowest exposure group. While this finding was consistent with other 13 studies showing adverse reproductive effects of for maldehyde and appears to be causal, the 14 Taskinen et al. (1999) spontaneous abortion results did not clearly control for all the potential 15
confounders that were controlled for in the FDR ana lyses (i.e. organic solvents and phenols). 16 While the other coexposures were not associated wit h FDR and therefore not confounders, 17 endometriosis was strongly associated with organic solvents. Therefore, for these endpoints, the 18 study design and strength of results best support t he use of decreased FDR in formaldehyde19 exposed women as the critical effect for this study

. 20 It is preferable that the critical effect be the m ost sensitive of the effects which is well 21 supported by the given study. As spontaneous abort ions are significantly increased in the low22 exposure group and the response in the mid-exposure group is considered a no-effect level for 23 decreased FDR, there is uncertainty that an RfC bas ed on the FDR NOAEL would be protective 24 for the more sensitive effect. Although qualitativ ely the finding of increased spontaneous 25 abortion is convincing, there is more uncertainty i n the applicability of the exposure assessment 26 for quantitative risk assessment. Additionally, th ere is greater uncertainty in the use of the 27 exposure adjustments for the low-exposure group on which the LOAEL is based because they 28 account for more of the work time in the low-exposu re group than the medium and high exposure 29 groups (Table 5-5). 30 There are several sources of uncertainty in the exp osure estimates for use in RfC 31 derivation. As discussed above, the average exposu re estimate for the low exposure group 32 includes a greater proportion of non-assessed backg round exposures. This is evidenced in part 33 by the reported average exposure being below backgr ound levels for these workers, even with 34 exposure measurements as high as 300 ppb. The unac counted for non-task exposures may 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-63 represent time during the day spent in the work fac ility, or time in a different job or work 1 environment. Additionally, task-level exposure mea surements were available for only 27% of 2 women in the low exposure group, versus 38% and 69% of women in the medium and high 3 exposure groups, indicating less certainty in expos ure classification for the low exposure group. 4
5 Duration adjustment for candidate study points of d eparture: 6 Normally, exposures from occupational studies are adjusted to account for the daily 7 breathing volume appropriate to an environmental (v ersus occupational) setting and for exposure 8 every day of the year (EPA, 1993). However, with f ormaldehyde, there is potential for exposure 9
outside of work from in-home and environmental sour ces of formaldehyde (Chapter 2). A 10 contemporaneous study of formaldehyde exposures in Finland reports average exposure of 21.4 11 ppb (measured over 48 hours with a personal monitor ) (Jurvelin et al., 2001). Furthermore, both 12 the mean exposure (18 ppb 8hr TWA) and lowest repor ted exposure (10 ppb 8hr TWA) of the 13 ‘low exposed’ category are below the reported avera ge ambient exposures for Finland (21.4 ppb). 14 Thus, it is likely that exposure estimates for stu dy participants include time during the workday 15 when women reported no formaldehyde exposure and a zero exposure was assessed for a non16 formaldehyde related task. Additionally, participa nts may have qualified for the study based on 17 employment date but may not have been working with formaldehyde during the entire time-to18 pregnancy period. In both cases, the investigators in Taskinen et al. (1999) appear to have 19 assumed that, while the women were away from their “exposed” workplace, their exposure to 20 formaldehyde was zero, not accounting for backgroun d occupational exposures and ambient 21 levels of formaldehyde. This explains why both the mean exposure as well as lower end of 22 workshift exposures for women in the low exposure g roup were reported at and below expected 23 ambient levels. The women in the low exposure cate gory had task-level workplace exposures of 24 up to 300 ppb in addition to experiencing some work time at background exposure levels. 25 Compared to women who only experienced background e xposure levels, those in the low 26 exposure category were at significantly higher risk of spontaneous abortion. 27 The reported data do not provide information to cor rect for background formaldehyde 28 exposure during the workday for each participant. However, the published mean exposure values 29 may be used to provide some idea of the impact of i ncluding background exposures on the study 30 PODs. Comparison of the values listed in Table 4 o f Taskinen et al. (1999) allows for the 31 estimation of the percentage of work time spent per forming tasks involving formaldehyde 32 exposure (Table 5-5, Panel A). For the women in th e low exposure category, this percentage is 33 26% (mean of measured workplace exposures of 70 ppb times 26% equals the mean of the TWA 34 exposure of 18 ppb). Using the same method, the wo men in the “medium” and "high" exposure 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-64 category were performing tasks involving formaldehy de exposure approximately 54% and 66% 1 of their work time, respectively. Assuming that th e women spent the remainder of their work 2 time at the background concentration of 21.4 ppb (J urvelin et al., 2001), a more appropriate 3 estimate of the women’s 8-hour TWA formaldehyde exp osures would be 34 ppb for the low 4 category, 86 ppb for the medium category, and 226 p pb for the high category (Table 5-5, Panel 5 B). 6 7 Table 5-5: Adjustment for nonoccupational exposure s to formaldehyde. 8 9 Panel A: Proportion of workshift corresponding to the expo sure group mean 10 task-level formaldehyde exposure (ppb) and the expo sure group daily exposure 11 index (8 Hr-TWA). 12
Reported mean exposure (ppb, 8 hr-TWA) Measured task-level exposures (ppb) Estimate of time

during workday for formaldehyde related tasks assuming mean exposure levels.
Exposure group (n) Mean Range Mean Range % of worktime a Hours per

8 Hr workshift Low (119) 18 1-39 70 10-300 26% 2 Medium (77) 76 40-129 140 50-400 54% 4.3 High (39) 219 130-630 330 150-1000 66% 5.3 a: Calculated as mean exposure (ppb 8Hr-TWA) divide d by mean task-level exposures for the exposure gro up. 13 14
Panel B: Recalculation of daily exposure index (8 Hr –TWA) where background 15 formaldehyde exposure is estimated for worktime spe nt on tasks considered 16 unrelated to occupational use of formaldehyde. 17 Estimate of Formaldehyde

exposure during formaldehyderelated work tasks Estimate of formaldehyde exposure from background levels during the workshift

Exposure group (n) Mean task

level exposure (ppb) % of worktime in

formaldehyde task Background

formaldehyde (ppb) % of time in

nonformaldehyd e-related task Alternativ

e daily
exposure index

(ppb, 8 Hr-TWA) Low (119) 70 26% 21.4 74% 34 Medium (77) 140 54% 21.4 46% 86 High (39) 330 66% 21.4 34% 226 18
19
20This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-65 1 Candidate RfC derivation for Taskinen et al, 1999: 2
Critical effect: Decreased FDR. 3
4 Point of departure: For decreased FDR, the mid-exposure level is cons idered a 5 NOAEL. The mean exposure as an 8-hour TWA for the workday is reported as 76 ppb. 6 EPA has adjusted this POD to account for potential background formaldehyde exposures 7 during the workshift (Table 5-5) resulting in an ad justed POD of 86 ppb. No further 8 duration adjustment is made to this POD to account for background levels of 9 formaldehyde exposure outside of the workplace. 10
11 Application of study-specific Uncertainty Factors ( UFs) : 12 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 13
LOAEL-to-NOAEL UF = 1: Selection of an NOAEL as the POD. 14
Subchronic to chronic UF = 1: The study design represents a study population wi th a 15 range of exposure durations, including chronic expo sures. By drawing the study 16 population from full-time employees and members of the wood-working union, 17 there is an expectation that the study population r eflects the demographic of that 18 group as a whole. Although specific summary inform ation is not published for 19 this study group (e.g., average length of employmen t), the lack of this reporting in 20 itself does not seem to justify an UF for subchroni c-to-chronic exposure given the 21 overall study design. As a study adequate for asse ssing reproductive effects in a 22 chronically exposed cohort, no further adjustment w as considered needed. 23 Human variability UF = 10: The study population included women employed in the 24 wood-working industry who were healthy enough to be gainfully employed. 25 Additionally, study inclusion criteria ensured that all study participants had at 26 least one pregnancy resulting in a live birth durin g the study period (1985–1995). 27 Therefore, these women were reproductively successf ul. The authors judged that 28 selective participation did not influence potential confounders such as irregular 29 menstruation or earlier miscarriages, which could i mpact the time to pregnancy 30 results. Susceptible populations were not addresse d and, in fact, the women in the 31 study may be considered healthier than the general population in terms of 32 reproductive health. Therefore, an uncertainty fac tor of 10 for human variability 33 was applied. 34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-66 

# ( ) ( ) ppb ppb
UF UF UF UF NOAEL RfC

H S L A 

### 6.8 10 1 1 1 86

= × × × = × × × = 1

2
UF A = 1 (interspecies UF) 3
UF L = 1 (LOAEL-to-NOAEL UF) 4
UF S = 1 (subchronic to chronic UF) 5
UF H = 10 (human variability UF) 6
7 5.1.2.3. Evaluation of the Study-Specific Candidat e RfCs 8 Seven studies were selected as key studies for cons ideration in RfC derivation (Section 9 5.1.2, Table 5-4). Candidate RfCs from these studi es address various health effects including: 10 sensory irritation, respiratory effects, asthma, in creased allergic sensitization, and decreased 11 fecundity (Table 5-6). 12 Three of the seven studies address sensory irrita tion of the eye, nose, and throat (Liu 13 et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). The PODs for sensory irritation 14 range from 50 to 95 ppb for a health effect that is considered minimally adverse. 15 Two alternatives are presented for the human variab ility uncertainty factor in RfC derivation 16 based on these SI studies. Alternative A (UF H =3) results in cRfCs from 9.5 to 23 ppb. 17 Alternative B (UF H =1) results in cRfCs from 32 to 70 ppb. 18 A cRfC of 9 ppb is derived for decreased FDR in an occupational study of women in the 19 wood-working industry (Taskinen et al., 1999). Thi s endpoint is supported by four other 20 epidemiologic studies and is considered a potential health concern for occupationally exposed 21 women (John et al., 1994; Taskinen et al., 1994; Se itz and Baron, 1990; Axelsson et al., 1984). 22 However, there is some uncertainty regarding the in fluence of peak exposures in the work place 23 on the apparent exposure-response relationship base d on average workday exposures calculated 24 for study participants. It is unknown if the obser ved decreased FDR can be attributed to the 25 average exposures from which the cRfC is derived or if it is a result of the measured exposures 26 (as high as 1,000 ppb). If this were the case the cRfC of 9 ppb, based on the average time27 weighted exposures, would be protective for decreas ed fecundity. 28 Three studies identify adverse health effects in re sidential populations including children: 29 increased incidence of asthma, decreased pulmonary function, increase in respiratory symptoms, 30 and increased allergic sensitization (Rumchev et al ., 2002; Garrett et al., 1999; Krzyzanowski 31 et al., 1999). Asthma, allergic sensitization, pul monary function, and symptoms of respiratory 32 disease are not only clinically related, but etiolo gically related, and it is reasonable that they are 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-67 considered together from a public health perspectiv e. These health effects are observed below 1 the exposure levels that result in sensory irritati on and the resulting cRfCs are correspondingly 2 lower, in a range between 2.8 and 11 ppb, depending on the study, endpoint considered, and the 3 application of alternative uncertainty factors for human variability (Table 5-6). 4
These three studies of related health effects: asth ma, allergic sensitization, pulmonary 5 function, and symptoms of respiratory disease in ch ildren from in-home exposure to 6 formaldehyde (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski et al., 1999) were 7
chosen as the basis for the derivation of the RfC. These co-critical studies are mutually 8 supportive and provide similar cRfCs. Therefore, t he RfC is taken as the mean of the cRfCs of 9
the cRfCs of the three co-critical studies. For tw o of these studies (Rumchev et al., 2002; Garrett 10 et al., 1999), EPA is providing alternatives for th e application of the UF addressing human 11 variability. These alternatives result in a threef old difference in cRfCs for each study when 12 considering the critical effects of childhood asthm a and allergic sensitization (Table 5-6). 13 Alternative A, described above for each study, ackn owledges that evaluation of these effects in 14 children does address some aspects of human variabi lity, but there remains the potential for 15 additional inter-individual variability within the studied population, thus a UF of 3 is warranted. 16 Alternative B, described above for each study, also acknowledges that these studies address 17 human variability and susceptible populations. How ever in alternative B it is judged that since 18 children are a sensitive lifestage for these effect s (asthma and atopy), and are likely the most 19 sensitive population, an UF of 1 may be applied. I t is acknowledged that some degree of inter20 individual variability may remain. 21
22This document is a draft for review purposes only a nd does not constitute Agency policy 5-68 DRAFT—DO NOT CITE OR QUOTETable 5-6: Summary of reference concentration (RfC) derivation from critical study and supporting studies.Application ofstudy-specific UFEndpointStudyStudysizeHomesChildrenPOD (ppb)UFLUFSUFHcRfC(ppb)Respiratory effects / asthma and sensitizationReduction of PEFRin children (10%)Krzyzanowskiet al. (1990)208 Yes Yes BMCL10= 17 1 1 35.6Alternative A33.3Alternative BAsthma incidenceRumchev et al.(2002)192 Yes Yes NOAEL = 33 1 3111Alternative A32.8Alternative BIncreased asthma;allergic sensitizationGarrett et al.(1999)148 Yes Yes LOAEL = 28 3 119.3Sensory IrritationAlternative A317Alternative BEye irritation,burning eyesRitchie andLehnen (1987)2,007 Yes Yes NOAEL = 50 1 1150Alternative A323Alternative BHanrahan et al.(1984)61 YesSometeenagersBMCL10= 70 1 1170Alternative A39.5Alternative BLiu et al.(1991)1,394 Yes Yes LOAEL = 95 3 1132Reproductive / DevelopmentalDecreasedfecundability densityratio (FDR)Taskinen et al.,1999 602 No No NOAEL= 86 1 1 108.6Notes: 1: The final RfC will be rounded to one significant digit per EPA policy. Since the CandidateRfC is an interim calculation, two-significant digits are retained as commonpractice in mathematics {i.e. one significant digetmore that the final result, to avoid rounding errors compounding across multiple mathematical manipulations}.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-69 1 2

3 4
5.1.3. Database Uncertainties in the RfC Derivatio n 5 The database of available laboratory animal studies , human clinical and epidemiological 6 studies, and supporting mechanistic information for formaldehyde is substantial. Many of the 7
health effects are well studied in animals and huma ns, especially those endpoints related to 8 sensory irritation and respiratory effects at the P OE, such as respiratory tract pathology, asthma 9 Alternative A: Application of a UF of 3 for human variability

Co-critical studies: Rumchev et al. (2002); Krzyzanowski et al. (1999); Garrett et al. (1999)

Critical endpoints: Asthma, allergic sensitization, pulmonary function, and symptoms of respiratory disease in children.

Candidate RfCs: cRfC = 5.6 ppb - decreased PEFR (Krzyzanowski et al., 1999) cRfC = 3.3 ppb - increased physician-diagnosed a sthma (Rumchev et al., 2002) cRfC = 2.8 ppb - increased asthma, atopy and res piratory symptoms (Garrett et al., 1999)

RfC: 

### ppb ppb ppb ppb ppb RfC 4 3 7. 11 3 8.2 3.3 6.5

= = + +

=

Alternative B: Application of a UF of 1 for human variability (UF H = 3 remains for Krzyzanowski et al., 1999)

Co-critical studies: Rumchev et al. (2002); Krzyzanowski et al. (1999); Garrett et al. (1999)

Critical endpoints: Asthma, allergic sensitization, pulmonary function, and symptoms of respiratory disease in children.

Candidate RfCs: cRfC = 5.6 ppb - decreased PEFR (Krzyzanowski et al., 1999) cRfC = 11 ppb - increased physician diagnosed as thma (Rumchev et al., 2002) cRfC = 9.3 ppb - increased asthma, atopy and res piratory symptoms (Garrett et al., 1999)

RfC: 

### ppb ppb ppb ppb ppb RfC 9 3 9. 25 3 3.9 11 6.5

= = + +

=This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-70 and reduced pulmonary function. This is reflected in the number and high quality of human 1 studies presented in Table 5-4 and supporting data summarized in Chapter 4. 2
The data also indicate effects in other health effe ct categories, specifically neurotoxic 3 effects, reproductive toxicity, and developmental e ffects (Section 5.1.2). These are areas where 4
additional research are needed to reduce uncertaint y and better characterize the potential for 5 health effects and the concentrations at which they might occur in humans. 6 The existing database strongly supports formaldehyd e’s potential for causing both 7 reproductive and developmental toxicity. There is, however, no assessment of these endpoints 8 from a satisfactory two-generation toxicity study t o fully evaluate the effect of formaldehyde 9 exposure on reproductive and developmental endpoint s. Data are adequate to derive a cRfC of 9 10 ppb for decreased fecundability density ratio (FDR) from a human occupational study (Taskinen 11 et al., 1999). This study also reports an increase in spontaneous abortions, although there is 12 uncertainty on the exposure levels of concern for t his endpoint; spontaneous abortions may also 13
contribute to the decreased FDR on which one of the cRfCs is based. The greatest uncertainty in 14
the cRfC for decreased FDR is the use of a time-wei ghted exposure metric which does not 15 address possible contributions of peak exposure lev els to the observed health effect. As such, it 16 is possible that this cRfC is lower than is needed for protection against decreased FDR. The 17 cRfC for decreased FDR does suggest that the RfC de rived from the better studied respiratory 18 effects would be protective of that reproductive/de velopmental endpoint, but there remain 19 uncertainties as to the full range of potential rep roductive and developmental effects. No data 20 exist to sufficiently inform the exposure-response relationship for other reproductive and 21 developmental endpoints as they relate to RfC deriv ation (Section 5.1.2.6). For example, male 22 reproductive effects and structural and behavioral developmental effects (including postnatal 23 development) are not addressed by a study of decrea sed FDR. This is a database deficiency. A 24 survey of the currently available data indicates ob served effect levels of 5,000–10,000 ppb for 25 male reproductive endpoints and 400 ppb and above f or growth retardation and structural 26 anomalies in animal studies. However, these studie s employed only one treatment level, 27 precluding the ability to establish a dose-response relationship, thus limiting the strength of the 28
studies for use in RfC derivation. 29 Similarly, there is evidence that formaldehyde can cause neurotoxic effects. There is a 30 deficit of studies with appropriate exposure scenar ios to support derivation of an RfC reflecting 31 the potential for observed neurotoxicity due to for maldehyde exposure. None of the available 32 human studies that evaluated neurological effects w ere adequate for use in quantitative risk 33 assessment, although they did identify neurological effects of concern, including changes in 34 memory and concentration (e.g., Bach et al. [1990]; Kilburn et al. [1987, 1985]) and increased 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-71 risk of mortality from amyotrophic lateral sclerosi s (ALS) with increasing duration of exposure 1 to formaldehyde (Weisskopf et al., 2009). The huma n and animal data indicate the potential for 2 serious neurological and behavioral effects from sh ort-term formaldehyde exposure (Section 3 5.1.2.6). Limited studies in humans, as well as co ntrolled studies in established animal models, 4 confirm the neurotoxic effects of formaldehyde at e xposure levels of 100–170 ppb (Malek et al., 5 2003a, c; Bach et al., 1990) (Table 5-1). For exam ple, an adverse effect level of 100 ppb for 6 impaired learning is reported for short-term exposu res (2 hours/day for 10 days) in rats (Malek et 7 al., 2003a). For this effect, appropriate duration adjustment for extrapolation of a 2-hour 8 repeated exposure over a limited number of days is uncertain. Given the nature of these health 9 effects, and the potential for children to be expos ed in the home to levels as high as 100 ppb (the 10
level at which effects were seen in animals followi ng a single exposure), this is a significant data 11 gap. Studies are inadequate to determine whether e xposure to levels of formaldehyde at or below 12 those that impact children’s respiratory health and sensitization will cause neurotoxicity in 13 humans, including endpoints such as impaired learni ng and memory. 14
15

16 17 Approaches to the application of a database uncerta inty factor: Options EPA is considering include:

(1) Provide an RfC derived from studies of respirat ory and allergenic responses and protective of sensory irritation effects with a database uncer tainty factor of one given significant data on formaldehyde, but noting that further research repr oductive, developmental and neurotoxic
effects would be valuable.

(2) Provide an RfC with a database uncertainty fact or of one, with this RfC explicitly identified as being protective of the well-studied effects.

(3) Apply a database UF of 3 to the RfC derived fro m studies of respiratory and allergenic responses to reflect the potential that reproductiv e, developmental, or neurotoxic effects might
occur at lower doses:

(3) Provide both an RfC identified as protective o f the better-studied effects and an RfC with a database uncertainty factor of 3 incorporated to ac count for limits to the data on reproductive, developmental and neurotoxic effects.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-72 It is unclear what uncertainty factors are appropr iate to account for human variability and 1
deficiencies in the overall database. For this rea son, several alternatives have been presented. 2
3
5.1.4. Uncertainties in the RfC Derivation 4 By design, the RfC is an estimate of an exposure le vel at which it is unlikely there would 5 be deleterious effects to the human population (inc luding sensitive subgroups) during a lifetime 6 of exposure. Although the RfC is derived from the best available studies, there are a number of 7
uncertainties that underlie the RfC. Some of these uncertainties are addressed quantitatively by 8 applying UFs on a study-specific a basis for RfCs b ased on animal studies, less-than-chronic 9 exposures, use of a LOAEL as the POD, and to addres s human variability for the relevant 10 endpoint (Section 5.1.3). This section elaborates on some of the sources of uncertainty in the 11
final RfC. 12 As the RfC is derived from human studies, the major ity in a residential setting, study 13 aspects that are often a great source of uncertaint y are of no concern (e.g., use of animal studies, 14 study of a worker population). The uncertainties d iscussed below apply specifically to the 15 database of formaldehyde studies and the process to derive the RfC. 16
17 Point of departure 18
Most of the studies considered for RfC derivation d id not provide enough data to support 19 BMD modeling. Rather, the PODs for most studies we re LOAELs or NOAELs that have a 20 number of shortcomings relative to a POD obtained f rom BMD modeling (i.e., a BMC or BMD): 21
22

• LOAELs and NOAELs are a reflection of the particula r exposure/dose levels used in a 23 study, contributing some inaccuracy to the POD dete rmination. 24

• LOAELs and NOAELs are often determined based on sta tistical significance and, thus, 25 reflect the number of study subjects or test animal s. Studies are typically dissimilar in 26 detection ability and statistical power, with small er studies tending to identify higher 27 exposure levels as NOAELs compared with larger but otherwise similarly designed 28
studies. 29

• Different LOAELs and NOAELs represent different res ponse rates, so direct qualitative 30 and quantitative comparisons are not possible. 31
32This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-73 PODs identified from BMD models overcome some of th e deficiencies associated with 1
LOAELs and NOAELs. Benchmark models were used for two inhalation data sets, Hanrahan et 2 al. (1984) and Krzyzanowski et al. (1990). 3 It should also be noted, however, that even for BMC s/BMDs there is often uncertainty, in 4 particular for continuous responses, about what res ponse level to select as the BMR, i.e., where 5 to define the cut-off point between a level of chan ge that is not adverse and one that is adverse. 6 In addition, BMD models currently in use are purely mathematical models and are not intended 7 to accurately reflect the biology of the effect bei ng modeled. 8 Another source of uncertainty in the POD is the adj ustment for continuous exposure. 9 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human and 10 laboratory animal inhalation studies are typically not continuous and assumptions must be made 11 in converting reported exposure levels to equivalen t continuous exposures. Similarly, there are 12 uncertainties about potential dose rate effects, in particular the effect of peak exposures in 13 occupational studies. 14
15 Extrapolation from laboratory animal data to humans 16 Because the inhalation database for formaldehyde co ntains many human studies for a 17 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 18 to derive the RfC. Thus, unlike for most RfCs, thi s is not a source of uncertainty in the RfC for 19 formaldehyde. 20
21
Human variation 22 Heterogeneity among humans is another uncertainty associated with extending results 23 observed in a limited human study population or lab oratory animal experiment to a larger, more 24 diverse human population. 25 For three of the studies used to derive the RfC, a value of 3 was used for the human 26 variability UF (rather than the default value of 10 ) because the studies had an apparent over27 representation of populations expected to have incr eased susceptibility (Section 5.5.3.1): 28
29

 The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 30 irritation in a large number of subjects, including children and the elderly. As a result of 31 the study's participation criteria, individuals wit h greater sensitivity were potentially over32 represented. 33

 Thirty percent of the subjects in the residential s tudy by Krzyzanowski et al. (1990) were 34 children who are more sensitive to formaldehyde-ass ociated decreases in PEFR than 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-74 adults. The cRfC determination for this study focu sed on the results in the children, 1 among whom asthmatics were over-represented (roughl y three times) compared with the 2 national average of 9.4% in 2008 (Bloom et al., 200 9). 3

 Garrett et al. (1999) conducted a cross-sectional s urvey of allergy and asthma-like 4 symptoms in children with or without a doctor's dia gnosis of asthma. The study was 5 designed to include a high proportion of asthmatic children, a sensitive population for the 6 effects being studied. 7
8 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 9 account for certain special attributes of these stu dies/effects, there is still uncertainty about how 10 much of the overall population heterogeneity is act ually reflected even in these relatively diverse 11
residential studies. 12
13 Subchronic-to-chronic extrapolation 14 RfCs are intended to apply to chronic lifetime exp osures. If a study is subchronic 15 (typically less than 10% of a lifetime), a UF for s ubchronic-to-chronic extrapolation is generally 16 applied to the cRfC for that study. For the key hu man residential and occupational studies used 17 to derive the RfC in this assessment, the average d urations of exposure in the households or 18 workplaces under study are unknown. In this assess ment, these studies were considered chronic 19 in nature and no subchronic-to-chronic UF was appli ed. However, there is uncertainty about 20 whether or not the responses observed fully reflect ed the potential effects of chronic exposure, 21 especially in children, where, for example, impacts on the developing respiratory and immune 22 systems could be predisposing the children to furth er adverse effects later in life. 23
24 5.1.5. Previous Inhalation Assessment 25 There is no previous EPA RfC assessment for formald ehyde with which to compare and 26 contrast the RfC developed in this assessment. 27
28 5.2. QUANTITATIVE CANCER ASSESSMENT BASED ON THE N ATIONAL 29 CANCER INSTITUTE COHORT STUDY 30 For quantitative assessment of cancer risk, it is g enerally preferable to use good-quality 31 epidemiologic data, when available, over laboratory animal data. The follow-up studies by 32 Hauptmann et al. (2004) and Beane Freeman et al. (2 009) of the large National Cancer Institute 33 (NCI) retrospective cohort mortality study of U.S. workers involved in the production or use of 34 formaldehyde, with quantitative exposure estimates for the individual workers, present an 35 opportunity to perform quantitative cancer risk ass essments of nasopharyngeal cancer (NPC) and 36This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-75 lymphohematopoietic cancers (Hodgkin lymphoma and l eukemia) based on human data. 1 Although other upper respiratory tract cancers were also identified as being causally associated 2 with formaldehyde exposure in the weight-of-evidenc e analysis in section 4.5, NPC was the only 3 upper respiratory tract cancer with exposure-respon se data adequate for the derivation of unit risk 4 estimates in the Hauptmann et al. (2004) follow-up study of solid tumors. Similarly, the weight5 of evidence analysis in section 4.5 concluded that there were causal relationships between 6 formaldehyde exposure and all lymphohematopoietic c ancers as a group as well as leukemias as 7 a group (with the strongest evidence for myeloid le ukemia); however, from the Beane Freeman et 8 al. (2009) follow-up study of lymphohematopoietic m alignancies, only all leukemias combined 9 and Hodgkin lymphoma were judged to have exposure-r esponse data adequate for the derivation 10 of unit risk estimates (see section 5.2.3.1 below). 11
12 5.2.1. Choice of Epidemiology Study 13 Several follow-up studies of formaldehyde exposure in industrial workers have recently 14
become available. These studies are discussed in m ore detail in chapter 4 and the appendix 15 (Human Health) and are reviewed only briefly here. Hauptmann et al. (2004) and 16 Beane Freeman et al. (2009) presented follow-ups of the NCI study (originally described by Blair 17 et al. [1986]) of workers at 10 U.S. plants produci ng or using formaldehyde. Marsh et al. (2007, 18 2002) focused on pharyngeal cancer and, in particul ar, NPC mortality in sequential follow-up 19 analyses of the Marsh et al. (1996) cohort study, w hich examined 1 of the 10 plants studied by 20 NCI. Pinkerton et al. (2004) presented a follow-up of the National Institute for Occupational 21 Safety and Health (NIOSH) study of workers exposed to formaldehyde in three U.S. garment 22 plants (originally described by Stayner et al. [198 8]). Coggon et al. (2003) presented an extended 23 follow-up of a study of workers in six British fact ories where formaldehyde was produced or 24 used (originally described by Acheson et al. [1984] and previously followed up by Gardner et al. 25 [1993]). 26 The analyses presented here are based on the NPC (H auptmann et al., 2004) and 27 lymphohematopoietic cancer (Beane Freeman et al., 2 009) results from the NCI follow-up 28 studies. The NCI cohort study is the largest of th e three independent studies and is the only one 29 with sufficient individual exposure data for exposu re-response modeling. In addition, the NCI 30 study is the only one of the three studies that use d internal comparisons rather than standardized 31 mortality ratios (SMRs), thus minimizing the impact of the healthy worker effect, which can 32
attenuate observed effect estimates. The NCI cohor t consists of 25,619 workers (88% male) 33 employed in any of the 10 plants prior to 1966. A follow-up through 1994 presented exposure34 response analyses for nine NPC deaths as well as an alyses of deaths from other solid cancers 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-76 (Hauptmann et al., 2004). The most recent follow-u p (through 2004) analyzed 319 deaths 1 attributed to lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et 2 al., 2009). The results for solid cancers from thi s recent follow-up had not yet been published at 3 the time of this draft assessment. A detailed expo sure assessment was conducted for each worker 4 in the NCI cohort, based on exposure estimates for different jobs held and tasks performed 5 (Stewart et al., 1986). Exposure estimates were ma de using several different metrics—peak 6 exposure, average intensity, cumulative exposure, a nd duration of exposure. Respirator use and 7 exposures to formaldehyde-containing particulates a nd other chemicals were also considered. 8 For the NPCs, significant trends were observed for the cumulative and peak exposure metrics 9 (Hauptmann et al., 2004). For the lymphohematopoie tic cancers, significant trends were 10 observed primarily for all lymphohematopoietic canc ers and for Hodgkin lymphoma with the 11 peak exposure metric (Beane Freeman et al., 2009). 12 The NIOSH follow-up study (Pinkerton et al., 2004) analyzed mortality data (2,206 13 deaths; 59 from lymphatic and hematopoietic cancers ) from their cohort of 11,098 workers (82% 14 female). Leukemia and aleukemia were elevated for workers with >10 years of exposure and for 15
workers with ≥ 20 years since first exposure. However, since no h istorical exposure level data 16 were available for this cohort, individual worker e xposures could not be estimated and exposure17 response modeling was not conducted. The British c ohort updated by Coggon et al. (2003) 18 consisted of 14,014 male workers, and the follow-up included 5,185 deaths (83 from 19 lymphohematopoietic cancers). In this cohort, lung cancer mortality was statistically 20 significantly increased, especially in workers in t he high-exposure category; however, actual 21 exposure estimates were not available for exposure- response modeling (worker exposures were 22 categorized as nil/background, low, moderate, or hi gh, depending on the job considered to have 23 had the highest exposure). Lymphohematopoietic can cers were not elevated in the British 24 cohort, although, as discussed above, the results w ere based on external comparisons against 25 national mortality statistics. Neither the NIOSH n or the British study reported increased risks of 26 NPC, although only 1 case (0.96) was expected in th e NIOSH cohort (Pinkerton et al., 2003) and 27 only 2.0 cases were expected in the British cohort (Coggon et al., 2003). 28
29 5.2.2. Nasopharyngeal Cancer 30
5.2.2.1. Exposure-Response Modeling of the National Cancer Institute Cohort 31 A detailed exposure assessment was conducted for th e NCI cohort, and quantitative 32 exposure estimates were generated for each worker ( Stewart et al., 1986). Formaldehyde 33 exposure estimates, including 8-hour time-weighted average (TWA) exposures and level and 34 frequency of peak exposures, were derived for each job, work area, and calendar year 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-77 combination. A peak was defined as a short-duratio n exposure (typically <15 minutes) above the 1 TWA. Cumulative exposures (in ppm × years) were estimated by multiplying the time a wo rker 2 spent in a specific job by the TWA exposure for tha t job and summing over all the jobs held by 3 the worker. Duration was the total time spent in j obs with formaldehyde exposure, and average 4 intensity was the ratio of cumulative exposure to d uration. Formaldehyde exposures after 1980 5 were not taken into account in the follow-up study, but this was considered to have a minimal 6 impact on the results (see section 5.2.2.4). 7 The results of NCI’s internal analyses for NPC, usi ng the peak exposure, average 8 intensity, cumulative exposure, and duration of exp osure metrics, are presented in Table 5-7. 9 The relative risks (RRs) were estimated using log-l inear Poisson regression models stratified by 10 calendar year, age, sex, and race and adjusted for pay category (salary/wage/unknown). The NCI 11 investigators used the low-exposure category as the reference category to “minimize the impact 12 of any unmeasured confounding variables since nonex posed workers may differ from exposed 13 workers with respect to socioeconomic characteristi cs” (Hauptmann et al., 2004). A 15-year lag 14 interval was used in estimating exposures in order to account from a minimal latency period for 15 the development of solid cancers, including NPCs. 16 As can be seen in Table 5-7, peak exposure is the e xposure metric that provides the 17 strongest exposure-response relationship with NPC. However, it is not clear how to extrapolate 18 RR estimates based on these peak exposure estimates to meaningful estimates of lifetime extra 19 risk of cancer from environmental exposures, where the risk is usually considered to be from 20 continuous lifetime exposures to low environmental levels. In addition, peak exposure is a more 21 subjective measure than the other metrics, it is no t based on actual measurements, and it is a 22 categorical rather than continuous measure. Furthe rmore, the “true” exposure metric best 23 describing the biologically relevant delivered dose of formaldehyde is unknown. The cumulative 24 exposure metric provides a good fit to the data ( p trend = 0.029 for all person-years), and, since 25 this is generally the preferred metric for quantita tive risk assessment for environmental exposure 26 to carcinogens, cumulative exposure was chosen as t he exposure metric for the risk estimate 27
calculations for NPC in this assessment. 28 The nonexposed person-years were included in the pr imary cancer risk analyses presented 29 here in order to be more inclusive of all the expos ure-response data. Such data are typically 30 included in exposure-response modeling. Furthermor e, the data were stratified by pay category, 31
which should alleviate some concerns about the none xposed workers having different 32
socioeconomic characteristics. Final results for t he exposed person-years only are presented for 33 comparison. 34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-78 1 Table 5-7. Relative risk estimates for mortality f rom nasopharyngeal 2 malignancies (ICD-8 code 147) by level of formaldeh yde exposure for 3 different exposure metrics 4 5 Relative risk (number of deaths) p trend b p trend c Peak exposure (ppm) 0 >0 to <2.0 a 2.0 to <4.0 ≥ 4.0 1.00 d (2) – (0) – (0) 1.83 (7) 0.044 <0.001

Average intensity (ppm) 0 >0 to <0.5 0.5 to <1.0 ≥ 1.0 1.00 d (2) – (0) 0.38 (1) 1.67 (6) 0.126 0.066

Cumulative exposure (ppm × years) 0 >0 to <1.5 1.5 to <5.5 ≥ 5.5 2.40 (2) 1.00 (3) 1.19 (1) 4.14 (3) 0.029 0.025

Duration of exposure (years) 0 >0 to <5 5 to <15 ≥ 15 1.77 (2) 1.00 (4) 0.83 (1) 4.18 (2) 0.206 0.147 6

a Reference category for all categories. 7
b Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variab le, except for 8 peak exposure metric) among all (nonexposed and exp osed) person-years. 9

c Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variab le, except for 10 peak exposure metric) among exposed person-years on ly. 11

d Reference category due to no cases in the low-expos ure category. 12 13 Source: Hauptmann et al. (2004). 14 15 16 As described above, Hauptmann et al. (2004) investi gated the relationship between 17 formaldehyde exposure and NPC mortality using log-l inear Poisson regression models. They 18 also conducted log-linear trend tests using the gen eral model RR = e β X , where β represents the 19 regression coefficient for exposure and X is exposu re as a continuous variable. The trend models 20 were stratified by calendar year, age, sex, and rac e and adjusted for pay category. Dr. Hauptmann 21 provided EPA with the β estimates (and their standard errors) from the tre nd tests for NPC and 22 the cumulative exposure metric for all person-years and for exposed person-years only (personal 23 communication from Michael Hauptmann, NCI, to Jenni fer Jinot, EPA, March 29, 2004). These 24 estimates are presented in Table 5-8. 25
26
27
28This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-79 1 Table 5-8. Regression coefficients from NCI log-li near trend test models for 2 NPC mortality from cumulative exposure to formaldeh yde a 3 4

Person-years β (per ppm × year) Standard error (per ppm × year) All 0.05183 0.01915 Exposed only 0.05318 0.01914 5

a Models stratified by calendar year, age, sex, and r ace and adjusted for pay category; cumulative expos ures 6 calculated using a 15-year lag interval. 7 8 Source: Personal communication from Michael Hauptm ann to Jenifer Jinot (March 29, 2004). 9 10 11 5.2.2.2. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Mortality 12 The regression coefficients presented in Table 5-8 were used to predict the extra risk of 13 NPC mortality from environmental exposure to formal dehyde. 14
15 Extra risk = (Rx–Ro)/(1–Ro), 16
17 where Rx is the lifetime risk in the exposed popula tion and Ro is the lifetime risk in an 18 unexposed population (i.e., the background risk). Extra risk estimates were calculated using the 19 β regression coefficients and a life-table program t hat accounts for competing causes of death. 9 20 U.S. age-specific 1999 all-cause mortality rates fo r all race and gender groups combined 21 (National Center for Health Statistics [NCHS], 2002 ) were used to specify the all-cause 22 background mortality rates in the life-table progra m. NCHS 1996–2000 age-specific background 23 mortality rates for NPC were provided by Dr. Eisner of NCI’s Surveillance, Epidemiology and 24 End Results (SEER) program (personal communication from Milton Eisner, SEER, to Jennifer 25 Jinot, EPA, December 19, 2003). Risks were compute d up to age 85 because cause-specific 26 mortality (and incidence) rates for ages above 85 y ears are less reliable. Conversions between 27 occupational formaldehyde exposures and continuous environmental exposures were made to 28 account for differences in the number of days expos ed per year (240 versus 365) and in the 29 amount of air inhaled per day (10 versus 20 m 3 ). An adjustment was also made for the 15-year 30

9 This program is an adaptation of the approach that was previously used in BEIR IV, “Health Risks of Ra don and Other Internally Deposited Alpha Emitters.” Nation al Academy Press, Washington, DC, 1988, pp. 131–134 . The same methodology was also used more recently in EPA ’s 1,3-butadiene health risk assessment (U.S. EPA, 2002). A spreadsheet illustrating the life table used for th e extra risk calculation for the derivation of the LEC 0005 for NPC incidence (see section 5.2.2.3) is presented in App endix C.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-80 lag period. The reported standard errors for the r egression coefficients were used to compute the 1 one-sided 95% upper confidence limits (UCLs) for th e extra risks based on a normal 2 approximation. 3
Point estimates and one-sided 95% UCLs for the extr a risk of NPC mortality associated 4 with varying levels of continuous exposure to forma ldehyde are presented in Table 5-9. The 5 model predicts extra risk estimates that are fairly linear for exposures below about 0.001 to 6 0.01 ppm but not for exposures above 0.01 ppm. 7
8 Table 5-9. Extra risk estimates for NPC mortality from various levels of 9 continuous exposure to formaldehyde 10 11 Exposure concentration

(ppm) Extra risk 95% UCL on extra risk 0.0001 0.001 0.01 0.1 1 10 1.69 × 10 –7
1.69 × 10 –6
1.76 × 10 –5
2.63 × 10 –4
6.22 × 10 –1
9.82 × 10 –1 2.71 × 10 –7
2.73 × 10 –6
2.90 × 10 –5
5.75 × 10 –4
9.00 × 10 –1
9.85 × 10 –1
12 13 Consistent with EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 14 the same data and methodology were also used to est imate the exposure level (effective 15 concentration [EC x ]) and the associated (one-sided) 95% lower confide nce limit (LEC x ) 16 corresponding to an extra risk of 0.05% (x = 0.0005 ). Although EPA guidelines emphasize the 17 use of exposure levels associated with a 10% extra risk level for the POD for low-dose 18 extrapolation, that would not be appropriate in thi s instance. A 10% extra risk level is very high 19 for responses generally observed in epidemiology st udies; thus, a 1% extra risk level is typically 20 used for epidemiologic data to avoid upward extrapo lation. For NPC, however, even the 1% 21
level of risk is associated with RR estimates that are substantially higher than those observed in 22 the epidemiology study. Hence, even a 1% extra ris k level would be an upward extrapolation. 23 Based on the life-table program, the RR estimate fo r an extra risk of 1% for NPC mortality is 46. 24 Even 0.1% yields an RR estimate on the high end of the observable range of the epidemiology 25 study (RR = 5.5). A 0.05% extra risk level yields an RR estimate of 3.27, which better 26 corresponds to the RRs in the range of the data. T hus, 0.05% extra risk was selected for 27 determination of the POD, and, consistent with EPA’ s Guidelines for Carcinogen Risk 28
Assessment

(U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the 29This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-81 POD. While this may appear to be an inordinately l ow response level, it must be recognized that 1 NPC has a very low background mortality rate (e.g., lifetime background risk is about 0.00022); 2 therefore, a 1% extra risk (i.e., 0.01) would be a huge increase relative to the background risk. 3 This is consistent with the fact that, even with a large cohort followed for a long time, only nine 4 NPC deaths were observed in the NCI follow-up throu gh 1994. 10 5 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 6 that formaldehyde carcinogenicity can be attributed , at least in part, to a mutagenic MOA 7 (section 4.5), a linear low-dose extrapolation was performed in accordance with EPA’s 8 carcinogen risk assessment guidelines (U.S. EPA, 20 05a). The EC 0005 , LEC 0005 , and inhalation 9 unit risk estimates for NPC mortality are presented in Table 5-10. 10
11
Table 5-10. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC 12 mortality from formaldehyde exposure based on the H auptmann et al. (2004) 13 log-linear trend analyses for cumulative exposure 14 15

Person-years EC 0005 (ppm) LEC 0005

(ppm) Unit risk a (ppm –1 ) All 0.15 0.093 5.4 × 10 –3 Exposed only 0.15 0.091 5.5 × 10 –3 16

a Unit risk = 0.0005/LEC 0005 . 17 18 19 5.2.2.3. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Incidence 20 EPA cancer risk estimates are typically derived to represent a plausible upper bound on 21
increased risk of cancer incidence , as from experimental animal incidence data. Canc er data 22 from epidemiology studies are more often mortality data, as is the case in the NCI study. For 23 cancers with low survival rates, mortality-based es timates are reasonable approximations of 24 cancer incidence risk. However, for NPC, the survi val rate is substantial (51% at 5 years in the 25 1990s in the U.S., according to Lee and Ko [2005]), and incidence-based risks are preferred 26 because EPA is concerned with cancer occurrence, no t just cancer mortality. 27 Therefore, an additional calculation was done using the same regression coefficients 28 provided by Dr. Hauptmann (Table 5-8) but with age- specific NPC incidence rates for 1996– 29 2000 from SEER in place of the NPC mortality rates in the life-table program. SEER collects 30 cancer incidence data from a variety of geographica l areas in the U.S. The incidence data used 31

10 Ten NPCs were reported on death certificates and i ncluded in NCI’s SMR analysis, but one of these cas es was apparently misclassified on the death certificate, so only nine cases were used to estimate the RRs in the internalThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-82 here are from SEER 12, a registry covering about 14 % of the U.S. population, which was the 1 most current SEER registry at the time this analysi s was done. SEER 1996–2000 age-specific 2 background incidence rates for NPC were provided by Dr. Eisner of NCI’s SEER program 3 (personal communication from Milton Eisner, SEER, t o Jennifer Jinot, EPA, December 18, 4 2003). The incidence-based calculation relies on t he reasonable assumptions that NPC incidence 5 and mortality have the same exposure-response relat ionship for formaldehyde exposure and that 6
the incidence data are for first occurrences of NPC or that relapses provide a negligible 7
contribution. The calculation also relies on the f act that NPC incidence rates are small compared 8 with the all-cause mortality rates. 9 The resulting EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC incide nce are 10 presented in Table 5-11. The unit risk estimate fo r cancer incidence is twofold higher than the 11 corresponding mortality-based estimate, for all per son-years. This sizeable discrepancy can be 12 attributed to the high survival rates for NPC. 13
14
Table 5-11. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC 15 incidence from formaldehyde exposure based on the H auptmann et al. (2004) 16 trend analyses for cumulative exposure 17 18

Person-years EC 0005 (ppm) LEC 0005

(ppm) Unit risk a

(ppm –1 ) All 0.074 0.046 1.1 × 10 –2 Exposed only 0.072 0.045 1.1 × 10 –2 19

a Unit risk = 0.0005/LEC 0005 . 20 21 22 The preferred estimate for the inhalation cancer un it risk for NPC is the estimate of 23
1.1 × 10 –2 per ppm derived using incidence rates for the caus e-specific background rates, for all 24 person-years. The results from the exposed person- years are essentially identical. 25 Because NPC is a rare cancer, with a relatively low number of cases occurring per year in 26 the U.S., a rough calculation was done to assure th at the unit risk estimate derived for NPC 27 incidence is not implausible in comparison to actua l case numbers. For example, assuming an 28 average constant lifetime formaldehyde exposure lev el of 5 ppb for the U.S. population, the 29 inhalation unit risk estimate for NPC equates to a lifetime extra risk estimate of 5.5 × 10 –5

. 30 Assuming an average lifetime of 75 years (this is n ot EPA's default average lifetime of 70 years 31 but rather a value more representative of actual de mographic data) and a U.S. population of 32

comparison analysis, as discussed by Hauptmann et a l. (2004).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-83 300,000,000, this lifetime extra risk estimate sugg ests a crude upper-bound estimate of 220 1 incident cases of NPC attributable to formaldehyde exposure per year. Alternatively, assuming 2 an average constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a 3 crude upper-bound estimate of 880 incident cases of NPC per year. Both upper bound estimates, 4 using different assumed lifetime exposure levels, a re well below the estimated 2100 total incident 5 NPC cases per year calculated from a published NPC incidence rate for the U.S. of 0.7/100,000 6 person-years (Lee and Ko, 2005). 11 7
8
5.2.2.4. Sources of Uncertainty 9 The two major sources of uncertainty in quantitativ e cancer risk estimates are generally 10 interspecies extrapolation and high-to-low dose ext rapolation. The risk estimates derived from 11 the Hauptmann et al. (2004) analyses of the NCI coh ort are not subject to interspecies uncertainty 12 since they are based on human data. However, subst antial uncertainty remains in the 13 extrapolation from occupational exposures to lower environmental exposures. Although the 14 actual exposure-response relationship at low exposu re levels is unknown, the linear low-dose 15 extrapolation that was used is warranted by the str ong support for formaldehyde carcinogenicity 16 having a mutagenic MOA (section 4.5). The linear l ow-dose extrapolation from the 95% lower 17 bound on the exposure level associated with the ext ra risk level serving as the benchmark 18 response is generally considered to provide a plaus ible upper bound on the risk at lower exposure 19 levels. Actual low-dose risks may be lower to an u nknown extent. 20 Other sources of uncertainty emanate from the epide miologic study and its analysis 21 (Hauptmann et al., 2004), including the retrospecti ve estimation of formaldehyde exposures in 22 the cohort, the modeling of the epidemiologic expos ure-response data, the appropriate exposure 23 metric for exposure-response analysis, and potentia l confounding or modifying factors. 24 The same team of investigators (Stewart et al., 198 6) conducted a detailed retrospective 25 exposure assessment to estimate the individual work er exposures. Formaldehyde exposures were 26 estimated for specific jobs/tasks based on monitori ng data, discussions with workers and plant 27 managers, and assessment by industrial hygienists. Individual worker estimates were derived for 28 a variety of exposure metrics based on work histori es. This exposure assessment was a major 29 undertaking, involving over 100 person-months. Hau ptmann et al. (2004) suggested that 30 employment of such a detailed exposure assessment w ould tend to minimize exposure 31

11 With the application of age-dependent adjustment f actors (see Section 5.4.4), the lifetime unit risk estimate for NPC would increase by a factor of 1.66, and the cru de upper-bound estimates of the incident cases per year attributable to formaldehyde exposure would similar ly increase by a factor of 1.66. The resulting adj usted estimates of 365 and 1460 for 5 ppb and 20 ppb exposure level s, respectively, are still well below the estimated total numberThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-84 misclassification for average and cumulative exposu re and duration of exposure but that peak 1 exposure estimates could be more susceptible to mis classification because they were not based 2 on actual measurements. In addition, the follow-up study did not take into account exposures 3 after 1980. Hauptmann et al. (2003) stated that an y underestimation of (total) exposure resulting 4 from the 1980 cutoff “would be small because only 3 .7% of all person-years were contributed by 5 workers who were 65 years or younger and in exposed jobs in 1980” and because exposure levels 6
were believed to have been much lower after 1980 th an in earlier years. 7 As discussed in Chapter 4 and the appendix (Human H ealth), Marsh et al. (1996) also 8 estimated individual worker exposures at 1 of the 1 0 plants (Wallingford, Connecticut) studied 9 by the NCI team, and 5 of the 9 NPC deaths were fro m that plant. The Marsh et al. (1996) 10 exposure estimates were about 10-fold lower than th ose derived by the NCI team for the workers 11 at the Wallingford plant. Marsh et al. (2002) hypo thesized that “the NCI used data from several 12 facilities to estimate exposures in a single facili ty.” However, the NCI investigators maintained 13 that they estimated exposures for each plant separa tely. While the exact reasons for such a large 14 discrepancy are unclear, some differences in the as sessment procedures which could have 15
resulted in substantial differences in the estimate s are apparent. First, according to Marsh et al. 16 (1996), 91.7% of the white male Wallingford plant w orkers were specified as being exposed to 17 formaldehyde in the NCI study, while only 83.3% wer e considered to have been exposed in the 18 Marsh et al. (1996) analysis (it should be noted th at these two cohorts of the Wallingford plant 19 are not identical). Second, the NCI investigators (Stewart et al., 1987, 1986) did their own 20 exposure monitoring at all the plants, including th e Wallingford facility, in order to standardize 21 the data provided by the plants as well as to fill data gaps for certain jobs. There is no indication 22 that Marsh et al. (1996) made any additional measur ements themselves. Third, although the 23 Marsh et al. (2002, 1996) papers are not entirely c onsistent on this point, those investigators 24 apparently assumed that the job-specific exposures at the plant were essentially constant over the 25 history of the plant, whereas the NCI team, based o n interviews with plant personnel 26 knowledgeable about equipment and process changes, assumed that past exposures were higher. 27 In any event, despite the discrepancies in the abso lute exposure values, the relative 28 exposures for both the Marsh et al. (2002, 1996) an d NCI studies, as reflected in the exposure29 response relationships, are less subject to misclas sification and are considered to be reliable. The 30 Wallingford plant is just 1 of the 10 plants in the NCI study (representing 4,389 of the 25,619 31 workers in the NCI cohort), but if the Marsh et al. (1996) exposure estimates, which are roughly 32 10-fold lower than the NCI estimates, are closer to the actual exposures for those workers, then 33

of incident cases per year in the U.S.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-85 the true potency of formaldehyde could be greater t han that suggested by the unit risk estimates 1
calculated above based on the NCI data. Furthermor e, if the NCI exposure values were 2 significantly overestimated across all 10 plants, t hen the actual potency could be higher still. 3 With respect to the exposure-response model, the lo g-linear model used by Hauptmann et 4 al. (2003) for their trend tests (i.e., RR = e β X ) is a commonly used model for epidemiologic data 5 with exposure as a continuous variable. However, t he actual exposure-response relationship is 6 unknown. Moreover, even if the correct exposure-re sponse model were known, there would be 7 substantial uncertainty in estimating the model par ameters because there are only nine NPC 8 deaths to model. Furthermore, Beane Freeman et al. (2009) reported that in the follow-up 9 through 2004 it was discovered that 1,006 deaths th at occurred during the 1980 to 1994 10 follow-up period had not been included in the analy ses of the 1994 follow-up study (Hauptmann 11 et al., 2004, 2003), for reasons that have not been identified. Because NPC is such a rare cancer, 12 it is not expected that many, if any, NPC deaths we re among the 1,006 excluded deaths; however, 13 it is unknown how inclusion of the 1,006 deaths wou ld have altered the overall exposure14 response relationship and, hence, the regression co efficient. Additionally, a 15-year lag was used 15
for all the NCI solid cancer models. The actual mi nimum latency is unknown; however, the 16 investigators reported that lag intervals between 2 and 20 years yielded similar results. 17 Another potentially significant source of uncertain ty is associated with the exposure 18 metrics. With the log-linear model used for modeli ng the occupational data, the peak exposure 19 metric gave the strongest exposure-response relatio nship between formaldehyde exposure and 20 increased risk of NPCs. However, it is unclear how to extrapolate RR estimates based on peak 21 exposure estimates to meaningful estimates of lifet ime extra risk of cancer from environmental 22 exposure (i.e., extra risk from lifetime continuous low-level environmental exposures). The 23 cumulative exposure metric also yielded a statistic ally significant exposure-response relationship 24 and was used for the primary cancer risk calculatio ns in this assessment. The “true” exposure 25 metric best describing the toxicologically relevant dose of formaldehyde for nasopharyngeal 26 carcinogenesis is unknown. If a peak-exposure type of metric is the best representative of the 27 toxicologically relevant dose, this suggests that t here are dose-rate effects in the exposure28 response relationship for formaldehyde and NPC. If this is the case, the unit risk estimates 29 presented here, which are based on a linear low-dos e extrapolation, may overestimate the true 30
risks to an unknown extent. 31 Hauptmann et al. (2004) gave a lot of consideration to potential confounding and 32 modifying factors in their analyses. The important factors of age, race, sex, calendar year, and 33 pay category were taken into account in their Poiss on regression and trend analyses. 34 Furthermore, they used the low-exposure person-year s, rather than the unexposed person-years, 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-86 as their referent group in an effort to minimize an y potential confounding effects resulting from 1
differences in socioeconomic or other characteristi cs between exposed and unexposed workers. 2 When the slope estimate (i.e., regression coefficie nt) for the exposed person-years only was used 3 in the analyses presented here, the unit risk estim ate was essentially identical to that calculated 4 from the slope estimate for all person-years (see T ables 5-12 and 5-13). 5 In addition, these investigators evaluated routine respirator use, exposure to 6 formaldehyde-containing particulates, durations of exposure to 11 other chemicals/substances in 7 the plants (antioxidants, asbestos, carbon black, d yes and pigments, hexamethylenetetramine, 8 melamine, phenol, plasticizers, urea, wood dust, an d benzene), and duration of employment as a 9 chemist or laboratory technician. Only 133 workers ever routinely used a respirator (Hauptmann 10 et al., 2003). Hauptmann et al. (2004) reported th at RR estimates for NPC changed when 11 adjusted for duration of melamine exposure, althoug h trend tests remained significant for 12 cumulative formaldehyde exposure ( p = 0.006). The investigators suggested that the as sociation 13 with melamine may be spurious, and the regression c oefficients (i.e., β estimates) used in this 14 assessment were not adjusted for melamine. RR esti mates reportedly did not change 15 substantially when adjusted for exposure to any of the other 10 chemicals/substances. None of 16 the workers who died of NPC was identified as being exposed to wood dust. On the other hand, 17 each of the seven formaldehyde-exposed workers who died of NPC was also exposed to 18 particulates, and neither of the two workers who di ed of NPC but were not exposed to 19 formaldehyde was exposed to particulates. However, for those workers exposed to particulates, 20 NPC risk increased with increasing formaldehyde exp osure, suggesting a formaldehyde21 associated effect. Nonetheless, because of the cor respondence between formaldehyde and 22 particulate exposures within the workers who died o f NPC, there is uncertainty as to whether or 23 not particulates were acting as a modifying factor. Adjusting for duration of time spent working 24 as a chemist or laboratory technician did not subst antially alter the results (Hauptmann et al., 25 2004). 26 Adjusting for plant may result in overadjustment be cause plant is highly correlated with 27 exposure. Moreover, Hauptmann et al. (2004) adjust ed for important plant-related factors by 28 adjusting for the 11 chemicals/substances. Nonethe less, these investigators conducted analyses 29 adjusted for plant to address potential unmeasured confounders associated with plant, and they 30 reported that the association with NPC remained. A s noted above, five of the nine NPC deaths 31 were from the Wallingford plant also studied by Mar sh et al. (2006, 2002). Marsh et al. (2007) 32 hypothesized that the excess NPCs in the Wallingfor d plant could be due to external employment 33 in metal-working industries, but we found no eviden ce to support this supposition (see section 34 4.1.1.1). 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-87 Although smoking data were not available for the co hort, smoking is unlikely to explain 1
the excesses in NPCs because there was no consisten t increase for tobacco-related diseases, 2 including lung cancer, across the same exposure met rics. No information was available on 3 Epstein-Barr virus, a major risk factor for NPC, in the cohort. 4 Despite inevitable uncertainties, it is important n ot to lose sight of the strengths of the 5 NCI study. In addition to the use of internal anal yses and the extensive exposure assessment and 6 consideration of potential confounding or modifying variables, the NCI study has a large cohort 7 that has been followed for a long time. The cohort included 25,619 subjects, 75% of whom 8 entered before 1960, contributing a total of 865,70 8 person-years (730,312 for the exposed 9 workers) to the 1994 follow-up. Duration of follow -up in 1994 ranged up to 58 years, with a 10 median of 35 years. Duration of exposure ranged up to 46 years, with a median of 2 years. 11
Additional uncertainties are not so much inherent i n the exposure-response modeling or 12 in the epidemiologic data themselves but rather ste m from the process of obtaining more general 13 EPA risk estimates from these specific results. EP A cancer risk estimates typically represent a 14 plausible upper bound on increased risk of cancer i ncidence in the general population for all 15 tissue sites potentially affected by an agent. For experimental animal studies, this is 16 accomplished by using tumor incidence data and summ ing across all the tumor sites that 17 demonstrate significantly increased incidences, gen erally using data from the most sensitive sex 18 and species. However, in estimating comparable ris ks from the NCI epidemiologic data, certain 19 limitations are encountered. First, the NCI study is a retrospective mortality study, and cancer 20
incidence data are unavailable for the cohort. Sec ond, these occupational epidemiology data 21 represent a worker cohort that is generally healthi er than the general population 22 (e.g., SMRs < 1) (see Table 2 of Hauptmann et al. [ 2004]). 23 The first limitation was addressed quantitatively i n the calculation of cancer incidence 24 risk estimates from the mortality results, and, eve n though there are assumptions made in using 25 incidence data this way, the incidence-based estima tes are believed to be better estimates of 26 cancer incidence risk than the mortality-based esti mates. With respect to the second limitation, 27 the healthy worker effect is often an issue in occu pational epidemiology studies, and it is difficult 28 to know to what extent there is a healthy worker ef fect with respect to the development of NPC 29 in this study. As discussed above, Hauptmann et al . (2004) sought to minimize potential 30 confounding effects resulting from differences in s ocioeconomic or other characteristics between 31 exposed and unexposed workers by using the low-expo sure person-years, rather than the 32 unexposed person-years, as their referent group. N onetheless, when the slope estimates for the 33 exposed person-years only were used in the analyses in this assessment, unit risk estimates 34 essentially identical to those calculated from the slope estimates for all person-years were 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-88 obtained (Tables 5-12 and 5-13). In terms of repre senting the general population, the NCI cohort 1 was somewhat diverse, but the workers were predomin antly white males (81%) then white 2 females (12%), black males (7%), and black females (<1%), and they were all adults. 3 Finally, NPC is just one of the upper respiratory t ract cancers concluded to be causally 4 associated with formaldehyde exposure (section 4.5) . These upper respiratory tract cancers are 5
rare cancers and are difficult to detect in cohort studies. Thus, although NPC was the only such 6 cancer with an exposure-response relationship amena ble to the derivation of a unit risk estimate, 7 additional, unquantified risk may exist for the oth er upper respiratory tract cancers. If there was a 8 strong exposure-response relationship between these cancers and formaldehyde exposure, a more 9 apparent association in the Hauptmann et al. (2004) study might have been expected, as was seen 10 for NPC, despite the rare nature of these cancers. Thus, the exposure-response relationship for 11 these other upper respiratory tract cancers is like ly modest, at best, and, because these are rare 12 cancers, the contribution of the risk for these can cers to the total cancer risk from formaldehyde 13 exposure is not expected to be large. Nonetheless, with such rare cancers, there is uncertainty 14 regarding the extent to which the estimate based on NPC may underestimate the risk for all upper 15 respiratory tract cancers. 16 In summary, the inhalation cancer unit risk estimat e of 1.1 × 10 –2 per ppm for NPC is 17 based on human data from a high-quality epidemiolog ic study with individual exposure estimates 18 for each worker. A major uncertainty is the approp riate model/exposure metric for extrapolation 19 to environmental exposures. 20
21 5.2.3. Lymphohematopoietic Cancer 22
5.2.3.1. Exposure-Response Modeling of the National Cancer Institute Cohort 23 The results of NCI’s internal analyses for lymphohe matopoietic cancers using the peak 24 exposure, average intensity, and cumulative exposur e metrics from the follow-up through 2004 25 are reported by Beane Freeman et al. (2009). There was reportedly no evidence of associations 26 with duration of exposure, and those results were n ot presented. For the peak exposure metric, 27 statistically significant log-linear trends were ob served for all lymphohematopoietic cancers, 28 Hodgkin lymphoma, and leukemia (the latter only whe n the unexposed person-years were 29 included). There was also evidence for potential a ssociations with myeloid leukemia 30 specifically, especially when risks were viewed ove r time, and with multiple myeloma. Using 31 the average exposure metric, there was a significan t trend for Hodgkin lymphoma. With the 32 cumulative exposure metric, there were no statistic ally significant trends; however, the Hodgkin 33 lymphoma trend results were of borderline significa nce ( p trends = 0.06 and 0.08 with and 34 without the unexposed person-years, respectively), as were the leukemia trend results ( p trends = 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-89 0.08 and 0.12 with and without the unexposed person -years, respectively). As discussed above 1 with NPC, it is not clear how to extrapolate RR est imates based on the peak exposure estimates 2 to meaningful estimates of lifetime extra risk of c ancer from environmental exposures. The 3 average exposure metric is also problematic because it suggests that duration of exposure is not 4 important (e.g., exposure to a given exposure leve l for 1 year conveys the same amount of risk as 5 exposure to the same level for 70 years). Cumulati ve exposure is generally the preferred metric 6 for quantitative risk assessment for environmental exposure to carcinogens, and, because the 7 Hodgkin lymphoma and leukemia trend results were of borderline statistical significance using 8 the cumulative exposure metric and the elevations i n risk with that metric were consistent with 9 significant elevations observed with the peak expos ure (for Hodgkin lymphoma and leukemia) 10 and average exposure (for Hodgkin lymphoma) metrics (Table 5-12), a determination was made 11 to calculate unit risk estimates for Hodgkin lympho ma and leukemia based on cumulative 12 exposure. There is also support for associations b etween formaldehyde exposure and both 13 Hodgkin lymphoma and leukemia from other studies (s ection 4.5.2). No other 14 lymphohematopoietic cancer responses provided adequ ate exposure-response data with the 15 cumulative formaldehyde exposure metric in the NCI cohort from which to derive unit risk 16
estimates. 17 As for the NPC results discussed in section 5.2.2, the RR estimates in Table 5-12 were 18 derived using log-linear Poisson regression models stratified by calendar year, age, sex, and race 19 and adjusted for pay category (salary/wage/unknown) . The NCI investigators used the low20 exposure category as the reference category to “min imize the impact of any unmeasured 21 confounding variables since nonexposed workers may differ from exposed workers with respect 22 to socioeconomic characteristics” (Hauptmann et al. , 2004). A 2-year lag interval was used to 23 determine exposures in order to account for a minim al latency period for lymphohematopoietic 24

cancers. 25 Dr. Beane Freeman provided EPA with the regression coefficient estimates for Hodgkin 26 lymphoma and leukemia mortality from the log-linear trend test models for cumulative exposure 27 (i.e., RR = e β X , with exposure [X] as a continuous variable) used in the NCI analyses (personal 28 communication from Laura Beane Freeman, NCI, to Joh n Whalan, EPA, August 26, 2009). 29 These estimates are presented in Table 5-13. As wi th the NPC calculations in section 5.2.2, the 30 nonexposed person-years were included in the primar y unit risk estimate derivations in order to 31 be more inclusive of all the exposure-response data . Final results for the exposed person-years 32 only are presented for comparison. 33
34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-90 Table 5-12. Relative risk estimates for mortality from Hodgkin lymphoma 1 (ICD-8 code 201) and leukemia (ICD-8 codes 204–207) by level of 2 formaldehyde exposure for different exposure metric s 3 4 Cancer type Relative risk (number of deaths) p trend b p trend c Peak exposure (ppm) 0 >0 to <2.0 a 2.0 to <4.0 ≥ 4.0 Hodgkin lymphoma 0.67 (2) 1.0 (6) 3.30 (8) 3.96 (11) 0.004 0.01

Leukemia 0.59 (7) 1.0 (41) 0.98 (27) 1.42 (48) 0.02 0.12 Average intensity (ppm) 0 >0 to <0.5 0.5 to <1.0 ≥ 1.0 Hodgkin lymphoma 0.53 (2) 1.0 (10) 3.62 (9) 2.48 (6) 0.03 0.05

Leukemia 0.54 (7) 1.0 (67) 1.13 (25) 1.10 (24) 0.50 >0.5 0 Cumulative exposure (ppm × years) 0 >0 to <1.5 1.5 to <5.5 ≥ 5.5 Hodgkin lymphoma 0.42 (2) 1.0 (14) 1.71 (7) 1.30 (4) 0.06 0.08

Leukemia 0.53 (7) 1.0 (63) 0.96 (24) 1.11 (29) 0.08 0.12 5

a Reference category for all categories. 6
b Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variab le, except for 7 peak exposure metric) among all (nonexposed and exp osed) person-years. 8

c Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variab le, except for 9 peak exposure metric) among exposed person-years on ly. 10 11 Source: Beane Freeman et al. (2009). 12 13 14 Table 5-13. Regression coefficients for Hodgkin ly mphoma and leukemia 15 mortality from NCI trend test models a 16 17

Cancer type Person-years β (per ppm × year) Standard error

(per ppm × year) All 0.02959 0.01307 Hodgkin lymphoma Exposed only 0.02879 0.01333 All 0.01246 0.006421 Leukemia Exposed only 0.01131 0.00661 18

a Models were stratified by calendar year, age, sex, and race and adjusted for pay category; exposures i ncluded a 19 2-year lag interval. 20 21 Source: Personal communication from Laura Beane Fr eeman to John Whalan (August 26, 2009). 22This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-91 1 5.2.3.2. Prediction of Lifetime Extra Risks for Hodgkin Ly mphoma and Leukemia Mortality 2 Extra risk estimates for Hodgkin lymphoma and leuke mia mortality were calculated using 3 the same general methodology described above for th e NPC mortality estimates (section 5.2.2.2), 4 with the following exceptions. U.S. age-specific 2 006 all-cause mortality rates (NCHS, 2009) 5 and NCHS age-specific 2002–2006 background mortalit y rates for Hodgkin lymphoma and 6 leukemia (http://seer.cancer.gov/csr/1975_2006/) fo r all race and gender groups combined were 7 used in the life-table programs. In addition, a 2- year lag period was used instead of a 15-year lag 8 period. 9 The resulting point estimates and one-sided 95% UCL s for the extra risk of Hodgkin 10 lymphoma mortality associated with varying levels o f continuous exposure to formaldehyde are 11 presented in Table 5-14. The results for leukemia are shown in Table 5-15. In both cases, the 12 models predict extra risk estimates that are fairly linear for exposures below about 0.01–0.1 ppm 13 but not for exposures above 0.1 ppm. 14
15 Table 5-14. Extra risk estimates for Hodgkin lymph oma mortality from 16 various levels of continuous exposure to formaldehy de 17 18 Exposure concentration

(ppm) Extra risk 95% UCL on extra risk

0.0001 0.001 0.01 0.1 1 10 2.04 × 10 –7
2.05 × 10 –6
2.10 × 10 –5
2.79 × 10 –4
1.63 × 10 –1
9.89 × 10 –1 3.53 × 10 –7
3.55 × 10 –6
3.71 × 10 –5
6.17 × 10 –4
8.36 × 10 –1
9.90 × 10 –1
19 20
Table 5-15. Extra risk estimates for leukemia mort ality from various levels 21 of continuous exposure to formaldehyde 22 23 Exposure concentration

(ppm) Extra risk 95% UCL on extra risk

0.0001 0.001 0.01 0.1 1 10 1.64 × 10 –6
1.64 × 10 –5
1.66 × 10 –4
1.87 × 10 –3
8.07 × 10 –2
9.80 × 10 –1 3.02 × 10 –6
3.03 × 10 –5
3.10 × 10 –4
3.90 × 10 –3
5.19 × 10 –1
9.89 × 10 –1This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-92 1 As discussed in section 5.2.2.2 above, 1% extra ris k levels are typically used as the basis 2 for the POD for low-dose extrapolation from epidemi ologic data. As for NPC, however, 3 Hodgkin lymphoma has a very low background mortalit y rate (e.g., lifetime background risk is 4 about 0.00038), and the 1% level of risk is associa ted with RR estimates that are substantially 5 higher than those observed in the epidemiology stud y. Hence, a 1% extra risk level would be an 6 upward extrapolation. Based on the life-table prog ram, the RR estimate associated with an extra 7 risk of 1% for Hodgkin lymphoma mortality is 27. E ven 0.1% yields an RR estimate at the 8 higher end of what was observed in the epidemiology study (RR = 3.6) (note that our primary 9 analyses include the nonexposed workers, and thus t he 0-exposure group becomes the referent 10 group and the RR estimates presented for Hodgkin ly mphoma and cumulative exposure in Table 11 5-12 would be adjusted upward [about 2.4-fold] rela tive to the 0-exposure group). A 0.05% 12 extra risk level yields an RR estimate of 2.3, whic h better corresponds to the RRs at the lower 13 end of the observable range. Thus, 0.05% extra ris k was selected for determination of the POD 14 for Hodgkin lymphoma, and, consistent with EPA’s Guidelines for Carcinogen Risk Assessment 15 (U.S. EPA, 2005a), the LEC value corresponding to t hat risk level was used as the POD. 16 For leukemia, although the background mortality rat es are higher (0.0065), the 1% extra 17 risk level typically used as the basis for the POD for epidemiologic data still corresponds to an 18 RR estimate (2.5) that would be above the highest c ategorical result reported, even after 19 adjusting the RR estimates upward relative to the 0 -exposure group (see above paragraph). A 20 0.5% extra risk level yields an RR estimate of 1.8, which better corresponds to the RRs in the 21 range of the data. Thus, the LEC value correspondi ng to 0.5% extra risk was selected for the 22
POD for leukemia. 23 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 24 that formaldehyde carcinogenicity can be attributed , at least in part, to a mutagenic MOA 25 (section 4.5), a linear low-dose extrapolation was performed, also in accordance with EPA’s 26 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). The EC 0005 , LEC 0005 , and 27 inhalation unit risk estimates for Hodgkin lymphoma mortality are presented in Table 5-16, and 28
the EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia m ortality are presented in 29
Table 5-17. 30
31
32
33
34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-93 Table 5-16. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 1 lymphoma mortality from formaldehyde exposure based on Beane Freeman 2 et al. (2009) log-linear trend analyses for cumulat ive exposure 3 4

Person-years EC 0005 (ppm) LEC 0005

(ppm) Unit risk a (ppm –1 ) All 0.151 0.0875 5.7 × 10 –3 Exposed only 0.155 0.0881 5.7 × 10 –3 5

a Unit risk = 0.0005/LEC 0005 . 6 7 8 Table 5-17. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia 9 mortality from formaldehyde exposure based on Beane Freeman et al. (2009) 10 log-linear trend analyses for cumulative exposure 11 12

Person-years EC 005 (ppm) LEC 005

(ppm) Unit risk a (ppm –1 ) All 0.224 0.121 4.1 × 10 –2 Exposed only 0.246 0.126 4.0 × 10 –2 13

a Unit risk = 0.005/LEC 005 . 14 15 16 5.2.3.3. Prediction of Lifetime Extra Risks for Hodgkin Ly mphoma and Leukemia Incidence 17 As for NPC, both Hodgkin lymphoma and leukemia have substantial survival rates 18 (84.7% at 5 years for Hodgkin lymphoma [http://seer .cancer.gov/statfacts/html/hodg.html] and 19 53.1% at 5 years for leukemia [http://seer.cancer.g ov/statfacts/html/leuks.html], based on 1999– 20 2005 SEER data); thus, it is preferable to derive i ncidence estimates. Unit risk estimates for 21 Hodgkin lymphoma and for leukemia incidence were ca lculated as described above for the NPC 22 incidence estimates (section 5.2.2.3). Age-specifi c background incidence rates for 2002–2006 23 for Hodgkin lymphoma and for leukemia from SEER17, a registry covering about 26% of the 24 U.S. population, were obtained from the SEER Web si te (http://seer.cancer.gov/csr/1975_2006/). 25
The incidence-based calculation relies on the assu mptions that Hodgkin lymphoma (and 26 leukemia) incidence and mortality have the same exp osure-response relationship for 27 formaldehyde exposure and that the incidence data a re for first occurrences of Hodgkin 28 lymphoma (and leukemia) or that relapses provide a negligible contribution. The first 29 assumption is more uncertain for leukemia because i t is a grouping of subtypes with different 30 survival rates (see section 5.2.3.4 for further dis cussion). The calculation also relies on the fact 31 that Hodgkin lymphoma (and leukemia) incidence rate s are small compared with the all-cause 32This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-94 mortality rates. The resulting EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 1 lymphoma incidence are presented in Table 5-18, and the EC 005 , LEC 005 , and inhalation unit risk 2 estimates for leukemia incidence are presented in T able 5-19. The unit risk estimate for Hodgkin 3 lymphoma incidence is about threefold higher than t he corresponding mortality-based estimate, 4 for all person-years. This sizeable discrepancy ca n be attributed to the high survival rates for 5 Hodgkin lymphoma. For leukemia, the incidence unit risk estimate is about 40% higher than the 6 mortality-based estimate. This difference is lower than the twofold difference seen with NPC 7 estimates, despite comparable survival rates, proba bly because of different age distributions of 8 the mortality and incidence rates. 9
10
Table 5-18. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 11 lymphoma incidence from formaldehyde exposure, base d on Beane Freeman 12 et al. (2009) log-linear trend analyses for cumulat ive exposure 13 14

Person-years EC 0005 (ppm) LEC 0005

(ppm) Unit risk a (ppm –1 ) All 0.0515 0.0298 1.7 × 10 –2 Exposed only 0.0529 0.0301 1.7 × 10 –2 15

a Unit risk = 0.0005/LEC 0005. 16 17 18 Table 5-19. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia 19 incidence from formaldehyde exposure based on Beane Freeman et al. (2009) 20 log-linear trend analyses for cumulative exposure 21 22

Person-years EC 005 (ppm) LEC 005

(ppm) Unit risk a (ppm –1 ) All 0.162 0.0875 5.7 × 10 –2 Exposed only 0.178 0.0909 5.5 × 10 –2 23

a Unit risk = 0.005/LEC 005 . 24 25 26 The preferred estimate for the inhalation cancer un it risk for Hodgkin lymphoma is the 27
estimate of 1.7 × 10 –2 per ppm derived using incidence rates for the caus e-specific background 28 rates, for all person-years. Similarly, the prefer red estimate for leukemia is the estimate of 29
5.7 × 10 –2 per ppm derived using incidence rates, for all per son-years. In both cases, the results 30 from the exposed person-years only are essentially identical. 31This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-95 Because Hodgkin lymphoma is a rare cancer, with a r elatively low number of cases 1 occurring per year in the U.S. (according to SEER s tatistics, an estimated 8,510 people were 2 diagnosed with Hodgkin lymphoma in the U.S. in 2009 3 [http://seer.cancer.gov/statfacts/html/hodg.html]), a rough calculation was done to assure that the 4 unit risk estimate derived for Hodgkin lymphoma inc idence is not implausible in comparison to 5 actual case numbers. For example, assuming an aver age constant lifetime formaldehyde 6 exposure level of 5 ppb for the U.S. population, th e inhalation unit risk estimate for Hodgkin 7 lymphoma equates to a lifetime extra risk estimate of 8.5 × 10 –5 . Assuming an average lifetime 8 of 75 years (this is not EPA's default average life time of 70 years but rather a value more 9 representative of actual demographic data) and a U. S. population of 300,000,000, this lifetime 10 extra risk estimate suggests a crude upper-bound es timate of 340 incident cases of Hodgkin 11 lymphoma attributable to formaldehyde exposure per year. Alternatively, assuming an average 12 constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a crude upper13 bound estimate of 1,360 incident cases of Hodgkin l ymphoma per year. Both upper bound 14 estimates, using different assumed lifetime exposur e levels, are well below the estimated 8,510 15 total incident Hodgkin lymphoma cases diagnosed per year in the U.S. 12 16
17
5.2.3.4. Sources of Uncertainty 18 By and large, the sources of uncertainty discussed above (section 5.2.2.4) for the NPC 19 risk estimates, such as high-to-low dose extrapolat ion, retrospective exposure estimation, 20 exposure metric/model uncertainties, and applicatio n of data from a “healthy” worker cohort to 21 the more diverse general population also apply to t he Hodgkin lymphoma and leukemia risk 22 estimates. The Hodgkin lymphoma risk estimates are based on 27 deaths, which is more than 23 were available for the NPC risk estimates, but 27 i s still a small number for exposure-response 24 modeling. The leukemia risk estimates are based on 123 deaths, so there is less uncertainty with 25 the parameter estimation from the exposure-response modeling for that cancer type, although 26 uncertainties still exist about the general model f orm. A 2-year lag interval was used for 27

12 With the application of age-dependent adjustment fa ctors (see Section 5.4.4), the lifetime unit risk e stimate for Hodgkin lymphoma would increase by a factor of 1.66 , and the crude upper-bound estimates of the incide nt cases per year attributable to formaldehyde exposure woul d similarly increase by a factor of 1.66. The resu lting adjusted estimates of 564 and 2260 for 5 ppb and 20 ppb expo sure levels, respectively, are still well below the estimated total number of incident cases per year in the U.S.. Sim ilar calculations for leukemia yield even lower rel ative upperbound estimates of cases attributable to formaldehy de exposure, in comparison to estimated total incid enct cases, because, although the unit risk estimate for leukem ia is about 3.3 times the unit risk estimate for Ho dgkin lymphoma, the total estimated number of incident leukemia cas es in the U.S. is 5.3 times the estimate for Hodgki n lymphoma (an estimated 44,790 cases diagnosed in the U.S. fo r 2009, according to SEER [http://seer.cancer.gov/statfacts/html/leuks.html])

.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-96 lymphohematopoietic cancers versus the 15-year lag for NPC. Beane Freeman et al. (2009) 1 evaluated lag intervals between 2 and 25 years and reported that lag intervals of about 18 years 2 provided the best fit to the lymphohematopoietic ca ncer data but did not change the risk 3 estimates; thus, they retained the 2-year lag inter val that was used in the previous follow-up 4 (Hauptmann et al., 2003). The most appropriate lag intervals for Hodgkin lymphoma and 5 leukemia are unknown, but alternate lags are unlike ly to have a large impact on the results. 6 The same potential confounding or modifying factors that were investigated for NPC and 7 the other solid cancers, as discussed in section 5. 2.2.4 above, were evaluated for the 8 lymphohematopoietic cancers. Beane Freeman et al. (2009) reported that controlling for duration 9 of exposure to the 11 other substances that they co nsidered (see section 5.2.2.4) or for working as 10 a chemist or laboratory technician “did not meaning fully change results”; results were not shown. 11 The investigators also reported that excluding the 586 individuals with exposure to benzene, a 12 known leukemogen, did not change the RR estimates f or myeloid or lymphoid leukemia in the 13 highest peak exposure category. Furthermore, Beane Freeman et al. (2009) found no evidence of 14 heterogeneity of RR estimates for lymphohematopoiet ic cancers by race, sex, or pay category, 15 and adjusting for plant reportedly did not substant ively change results. 16 A further uncertainty is which lymphohematopoietic cancer types are linked to 17 formaldehyde exposure. As discussed in section 4.5 .2, lymphohematopoietic cancers are a 18 diverse group of cancers with different etiologies, and the epidemiologic database suggests 19 associations with multiple different subtypes of th ese cancers. Section 4.5 concludes that 20 formaldehyde is causally associated with all lympho hematopoietic cancers as a group and with 21 leukemias as a group (with the strongest evidence f or myeloid leukemia). However, at present, 22 exactly which subtypes are etiologically linked to formaldehyde exposure is unknown. Cancer 23 risk estimates were derived for Hodgkin lymphoma an d leukemia because, in addition to support 24 for an association between these lymphohematopoieti c cancer subtypes and formaldehyde 25 exposure with other exposure metrics and from other studies, these had the strongest associations 26 with cumulative exposure in the Beane Freeman et al . (2009) update of the large, high-quality 27 NCI study. However, it is unknown whether these tw o subtypes best represent the total 28 lymphohematopoietic cancer risk. 29 In addition, leukemia itself is a grouping of diver se (e.g., acute lymphocytic, chronic 30 lymphocytic, acute myeloid, chronic myeloid) subtyp es, and using this grouping injects 31 additional uncertainty into the derivation of cance r incidence estimates. One of the assumptions 32
that the incidence-based calculation relies on is t hat the cancer incidence and mortality have the 33 same exposure-response relationship for formaldehyd e exposure. This assumption may be 34 problematic for the leukemia incidence estimates if not all of the leukemia subtypes represented 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-97 in the grouping are associated with formaldehyde ex posure to the same extent. This is because 1 different leukemia subtypes have different survival rates, so if a subtype with a relatively high 2 survival rate is included in the background inciden ce rates while not actually being associated 3 with formaldehyde exposure or being associated to a lesser extent than other subtypes, then the 4
incidence risk will be overestimated. The mortalit y risk calculations are not similarly affected by 5 including subtypes that may not actually be associa ted with formaldehyde exposure because 6 background mortality for the subtypes is already ta ken into account in the regression coefficient. 7 Figure 5-10 shows the mortality versus incidence ra tes for all leukemia and the two main 8 subtypes, myeloid leukemia and lymphoid leukemia. This figure does not show the acute versus 9 chronic myeloid and leukemia subtypes or the monocy tic or other leukemia subtypes; however, it 10 serves to illustrate the impact of using rates for groupings that contain subtypes with different 11 survival rates. For example, if lymphoid leukemia is the predominant subtype associated with 12 formaldehyde exposure, then using the leukemia grou ping for the incidence rates may 13
underestimate the cancer incidence risk because the incidence rates for leukemia (relative to the 14 mortality rates) are diluted with inclusion of the incidence rates for myeloid leukemia, which has 15 a smaller incidence-to-mortality ratio (i.e., poore r survival). On the other hand, if myeloid 16 leukemia is the predominant subtype associated with formaldehyde exposure, then using the 17 leukemia grouping for the incidence rates may overe stimate cancer incidence risk. If incidence 18 risks are being overestimated, the effect should be minimal because the incidence risk estimates 19
for leukemia calculated in section 5.2.3.3 are not that much greater (about 40%) than the 20 mortality-only estimates. 21 Finally, as for the NPC risk estimates, when the sl ope estimates for the exposed person22 years only were used for the Hodgkin lymphoma and l eukemia risk calculations, unit risk 23 estimates similar to those calculated from the slop e estimates for all person-years were obtained 24 (Tables 5-18 and 5-19); thus, the impacts of includ ing the unexposed person-years are minimal. 25 As discussed in section 5.2.2.4, despite inevitable uncertainties, it is important not to lose 26 sight of the strengths of the NCI study. In additi on to the use of internal analyses and extensive 27 exposure assessment and consideration of potential confounding or modifying variables, the NCI 28 study has a large cohort that has been followed for a long time. With the additional follow-up 29 through 2004, reflected in the lymphohematopoietic cancer results of Beane Freeman et al. 30 (2009), the median duration of follow-up was 42 yea rs, and the 25,619 cohort members had 31 accrued 998,106 person-years of follow-up. Over ha lf of the cohort was deceased, and there was 32 a substantial number of lymphohematopoietic deaths (319 total; 286 in the exposed workers). 33
34This document is a draft for review purposes only a nd does not constitute Agency policy 5-98 DRAFT—DO NOT CITE OR QUOTEFigure 5-10. Age-specific mortality and incidencerates for myeloid, lymphoid, and all leukemia.0.010.020.030.040.050.060.070.080.00.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0age (years)

rate per 100,000all leuk mortall leuk incmyeloid mortmyeloid inclymphoid mortlymphoid incThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-99 In summary, the inhalation cancer incidence unit ri sk estimates of 1.7 × 10 –2 per ppm for 1 Hodgkin lymphoma and 5.7 × 10 –2 per ppm for leukemia are based on human data from a high2 quality epidemiologic study with individual exposur e estimates for each worker. The major 3 source of uncertainty in both risk estimates is the extrapolation to environmental exposures. 4
5
5.2.4. Conclusions on Cancer Unit Risk Estimates B ased on Human Data 6 In this assessment, a (plausible upper bound) lifet ime extra cancer unit risk of 5.4 × 10 –3 7 per ppm of continuous formaldehyde exposure was est imated using a life-table program and 8 linear low-dose extrapolation of the excess NPC mor tality and log-linear modeling results (for 9 cumulative exposure) reported in a high-quality occ upational epidemiologic study (based on nine 10 NPC deaths). Applying the same regression coeffici ent and life-table program to background 11 NPC incidence rates yielded a lifetime extra cancer unit risk estimate of 1.1 × 10 –2 per ppm 12 (8.8 × 10 –6 per μg/m 3 ). 13 Using similar methods and data for Hodgkin lymphoma (27 deaths) and leukemia 14 (123 deaths) mortality based on the cumulative expo sure metric, from a further follow-up of the 15 same cohort study, (plausible upper bound) lifetime extra cancer risk estimates of 1.7 × 10 –2 per 16 ppm (1.4 × 10 –5 per μg/m 3 ) and 5.7 × 10 –2 per ppm (4.6 × 10 –5 per μg/m 3 ) for Hodgkin 17 lymphoma incidence and leukemia incidence, respecti vely, were derived. 18 To estimate the total cancer risk from formaldehyde exposure, risk estimates for these 19 three cancer types (NPC, Hodgkin lymphoma, and leuk emia) were combined, although, as 20 discussed above, these three cancer types may not f ully reflect the total cancer risk for all cancers 21 thought to be causally associated with formaldehyde exposure. For an approximate estimate of 22 the combined (upper bound) risk, risk estimates wer e combined assuming a normal distribution. 23 For comparability, risk estimates for formaldehyde were combined at a common level of 0.1 24 ppm. This level was selected because it is close t o the PODs (LEC 005 s) used above for leukemia 25 mortality (0.121 ppm) and leukemia incidence (0.087 5 ppm), and leukemia is the predominant 26 cancer type in terms of extra risk. Note that unit risk estimates for the different cancer types 27 calculated at 0.1 ppm will differ slightly from tho se reported above (sections 5.2.2 and 5.2.3) 28 because they are calculated at a level other than t he PODs used in the above calculations. To 29 derive the combined risk, maximum likelihood estima tes (MLEs) of risk and their 95% upper 30 bounds (UCLs) were calculated for each cancer type using the same methods and life-table 31 programs employed in sections 5.2.2 and 5.2.3. The standard errors (SEs) were then estimated 32 from the risk estimates using the equation: UCL = M LE + 1.645 × SE. The variances can then be 33 calculated from the SEs according to the equation: Variance = SE 2 . The sum of the variances 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-100 then provides an estimate of the variance for the s um of the MLEs, and the 95% upper bound on 1 the sum of the MLEs can be estimated by applying th e above equations in reverse. Tables 5-20 2 and 5-21 provide a summary of the results of these calculations for the combined cancer 3 mortality and incidence risks, respectively. 4
5
Table 5-20. Calculation of combined cancer mortali ty unit risk estimate at 6 0.1 ppm 7 8

Cancer type MLE of risk 95% upper bound on risk SE Variance NPC 2.63 × 10 –4 5.75 × 10 –4 1.90 × 10 –4 3.60 × 10 –8 Hodgkin lymphoma 2.79 × 10 –4 6.17 × 10 –4 2.05 × 10 –4 4.22 × 10 –8

Leukemia 1.87 × 10 –3 3.90 × 10 –3 1.23 × 10 –3 1.52 × 10 –6

Sum 2.41 × 10 –3 5.09 × 10 –3 1.60 × 10 –6 Combined risk 4.49 × 10 –3 1.27 × 10 –3

Combined unit risk a (per ppm) 4.49 × 10 –2

9

a Unit risk = 95% upper bound on combined risk/0.1 pp m. 10 11 12 Table 5-21. Calculation of combined cancer inciden ce unit risk estimate at 13 0.1 ppm 14 15

Cancer type MLE of risk 95% upper bound on risk SE Variance NPC 7.56 × 10 –4 1.62 × 10 –3 5.25 × 10 –4 2.76 × 10 –7 Hodgkin lymphoma 1.10 × 10 –3 2.35 × 10 –3 7.60 × 10 –4 5.77 × 10 –7

Leukemia 2.84 × 10 –3 5.89 × 10 –3 1.85 × 10 –3 3.44 × 10 –6

Sum 4.70 × 10 –3 9.86 × 10 –3 4.29 × 10 –6
Combined risk 8.10 × 10 –3 2.07 × 10 –3

Combined unit risk a (per ppm) 8.10 × 10 –2

16

a Unit risk = 95% upper bound on combined risk/0.1 pp m. 17This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-101 As can be seen from the results in Table 5-20, the upper bound risk estimates for cancer 1 mortality for the individual cancer types at 0.1 pp m are within 10% of the values that would be 2
obtained from the unit risk estimates derived in se ctions 5.2.2 and 5.2.3 (Tables 5-10, 5-16, and 3 5-17). Furthermore, the combined unit risk estimat e for mortality for the three cancer types 4 (4.5 × 10 –2 per ppm) is appropriately bounded by the mortality unit risk estimate for leukemia 5 (4.1 × 10 –2 per ppm), which has the highest individual mortali ty unit risk estimate, and by the 6 sum (5.2 × 10 –2 per ppm) of the individual unit risk estimates pre sented in sections 5.2.2 and 7 5.2.3. Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of 8 the MLEs and the sum of the 95% upper bounds for th e individual risks calculated at 0.1 ppm. 9 Thus, the value of 4.5 × 10 –2 per ppm (3.7 × 10 –5 per μg/m 3 ) calculated at 0.1 ppm for the 10
combined unit risk is a reasonable estimate for the total cancer mortality unit risk (based on the 11 three cancer types considered). 12 As can be seen from the results in Table 5-21, the upper bound risk estimates for cancer 13 incidence for the individual cancer types at 0.1 pp m are within 33% of the values that would be 14
obtained from the unit risk estimates derived in se ctions 5.2.2 and 5.2.3 (Tables 5-13, 5-20, and 15 5-21). Furthermore, the combined (incidence) unit risk estimate for the three cancer types 16 (8.1 × 10 −2 per ppm) is appropriately bounded by the unit risk estimate for leukemia 17 (5.7× 10 -2 per ppm), which has the highest individual unit ri sk estimate, and by the sum (8.6 × 18
10 –2 per ppm) of the individual unit risk estimates pre sented in sections 5.2.2 and 5.2.3. 19 Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of the 20 MLEs and the sum of the 95% upper bounds for the in dividual risks calculated at 0.1 ppm. Thus, 21
the value of 22
8.1 × 10 −2 per ppm (6.6 × 10 –5 per μg/m 3 ) calculated at 0.1 ppm for the combined unit risk is a 23
reasonable estimate for the total cancer unit risk (based on the three cancer types considered). 24 As documented in section 4.5, formaldehyde is a mut agenic carcinogen and the weight of 25 evidence suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a 26 mutagenic MOA. Therefore, since there are no chemi cal-specific data to evaluate susceptibility 27 of different life stages, increased early-life susc eptibility should be assumed, and, if there is 28 early-life exposure, the age-dependent adjustment f actors (ADAFs) should be applied in 29
accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 30 Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 below for mo re details on the 31 application of the ADAFs. 32
33
34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-102 1 5.3. DOSE-RESPONSE MODELING OF RISK OF SQUAMOUS CE LL CARCINOMA 2 IN THE RESPIRATORY TRACT USING ANIMAL DATA 3 In the previous section, dose-response analyses bas ed on human data for 4 lymphohematopoietic cancer and NPC were presented. The dose-response analyses of cancer 5 risk presented in this section are based on nasal t umor data from laboratory bioassays using F344 6 rats. Because the analyses involved are extensive, most of the details are provided in the 7 appendices. 8 An increased incidence of nasal squamous cell carci noma (SCC) was seen in two long9 term bioassays using F344 rats (Monticello et al., 1996; Kerns et al., 1983). Although other 10 studies in laboratory animals exist, these two stud ies, when combined, provide the most robust 11 data for analyses. These inhalation data on nasal SCC tumor incidence were used to estimate 12 human respiratory cancer risk in the nose and were also extrapolated to the entire respiratory 13 tract; in other words, a site concordance between r at and human is not assumed. This is 14 reasonable because the respiratory and transitional epithelial cell types considered to be at risk 15 of SCC in the upper respiratory tract are also prev alent in the lower human respiratory tract, and 16 there is greater penetration of formaldehyde flux p osteriorly in the nose and in the rest of the 17 human respiratory tract relative to that of the rat . These considerations are strengthened by the 18 findings of DNA-protein cross-links (DPXs) in the p roximal portions of the rhesus monkey 19 lower respiratory tract (Casanova et al., 1991). I n addition, some epidemiologic studies 20 (Gardner et al., 1993; Blair et al., 1990, 1986) re ported an increase in lung cancer associated 21 with formaldehyde exposure, while others (Collins e t al., 1997; Stayner et al., 1988) reported no 22
such increases. 23 EPA’s cancer guidelines (U.S. EPA, 2005a) suggest u sing a BBDR model for 24 extrapolation when data permit. A BBDR model for f ormaldehyde was developed by scientists 25 at the CIIT Centers for Health Research (see Append ix D) (Conolly et al., 2004, 2003, 2000; 26 Kimbell et al., 2001a, b; Overton et al., 2001; CII T, 1999), which interfaced several models to 27
combine the extensive mechanistic information avail able in studies involving the F344 rat and 28 rhesus monkey and time-to-tumor incidence data in l ong-term bioassays, as shown by the 29 schematic in Figure 5-11. This mechanistic informa tion included formaldehyde and DPX 30 dosimetry in the rat, monkey, and human airways and cell proliferation data in the rat nasal 31 lining. This document presents extensive evaluatio n of the underlying models and data and of 32 the alternative parametrizations of the models that were also explored for the purpose of the 33 current assessment (see Appendix E, Appendix F). A summary of conclusions is presented in 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-103 section 5.3.3. In particular, the following conclu sions by EPA were critical in determining how 1 the models could be used to inform the quantitative dose-response assessment: 2

• When used to model the dose-response in the range o f the available data, the BBDR 3 models were judged to have the advantage of being m ore accurate and biologically based 4 (than purely statistical descriptions such as the m ultistage-weibull model) and allowing 5 utilization of various data in an integrated manner

. 6

• Variations to the modeling in Conolly et al. (2003) were examined. Each of these models, 7 including the modeling in Conolly et al., was judge d to be just as biologically plausible as 8 the other, described the rat tumor incidence equall y well, was based on different 9 characterizations of the same empirical cell kineti c data, and was based on the same 10 empirical data on DPX measurements. However, the ad ded human risk over baseline 11 levels estimated by these models (including the ori ginal model) ranged from negative to 12 large positive values at environmental exposure con centrations. 13

• When used for the purpose of extrapolating risk, th e BBDR models did not appear to 14 reasonably constrain either risk estimates extrapol ated to human exposures or risk 15 estimates for the F344 rat when they were extrapola ted below the range of observable 16
data. 17

• Because human respiratory cancer risk calculated in Conolly et al. (2004) was 18 numerically unstable, clonal growth modeling was no t found to be a useful approach for 19 human extrapolation of rodent risk estimates. 20

• Thus, the biologically based derivation of human ri sk estimates in Conolly et al. (2004) 21 cannot be characterized as a plausible upper bound in the face of model uncertainties (a 22 key conclusion of those authors). 23
24 For all these reasons, the BBDR modeling of the rat data 25

• was employed in this assessment to derive multiple PODs (for SCC in the respiratory 26 tract) in the range of the observed data and using model-derived internal dose estimates, 27

• but was not used to extrapolate far below the obser ved data., 28
29
The inhalation unit risk estimates of SCC in the hu man respiratory tract were derived by 30 using multiple methods to model the F344 tumor inci dence data as follows: conventional 31 mutistage Weibull time-to-tumor modeling and variat ions of the model implemented in Conolly 32 et al. (2003) that were considered in the process o f the evaluation. 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-104 PODs were calculated as exposure concentrations cor responding to the 95% statistical 1 upper bound extra risks of 0.005, 0.01, and 0.05 (0 .005 used only with BBDR modeling). The 2 inhalation unit risk for SCC in the human respirato ry tract (upper and lower) derived from the 3 above animal bioassay data was then calculated by l inear extrapolation to the origin from the 4 POD. Linear extrapolation is supported in part by the proven genotoxicity of the chemical and 5 the observation of cytogenetic effects in human occ upational exposures (see chapter 4). In 6 particular, the formation of DPXs on formaldehyde i nteraction with DNA has been observed at 7 doses well below those considered cytotoxic. In re sults obtained in some implementations of the 8 biologically based models, formaldehyde-induced mut agenicity (modeled as proportional to DPX 9 concentration) was found to be a critical determina nt of its tumorigenicity, both at the low dose 10 pertaining to human exposure concentrations as well as in the dose range in which formaldehyde 11 is considered to be cytotoxic. 12 The human equivalent concentration was calculated b y assuming that continuous lifetime 13 exposure to a given steady-state flux of formaldehy de (expressed in pmol/mm 2 -hour) leads to 14 equivalent risk of nasal cancer across species. Ri sk per respiratory or transitional epithelial cell 15 with replicative potential in a given region was co mputed as a function of formaldehyde flux in 16 the nasal region and extrapolated to the rest of th e respiratory tract. 17
18 5.3.1. Long-Term Bioassays in Laboratory Animals 19 This section briefly describes the various animal data and dosimetry information utilized 20 in the above (but not in all) models, based on whic h estimates for the inhalation unit risk are 21 derived later in this chapter. 22
23
5.3.1.1. Nasal Tumor Incidence Data 24 Various bioassays have reported the effects of for maldehyde on rats, mice, and rhesus 25 monkeys and have been discussed at length earlier i n this document. Two of these bioassays 26 (Monticello et al., 1996; Kerns et al., 1983), when combined, allow for the most robust 27 characterization of the long-term dose response in a laboratory species. These long-term 28 bioassays found an increased incidence of nasal SCC s in rats exposed to formaldehyde by the 29 inhalation route. In these combined data, rats wer e exposed to 0, 0.7, 2.0, 6.01, 9.93, and 30 14.96 ppm (0, 0.86, 2.5, 7.4, 12.2, and 18.4 mg/m 3 ) exposure concentrations of formaldehyde. 31 SCCs were observed only at 6.01 ppm and higher expo sure concentrations. Table 5-22 provides 32 a summary of the tumors from these bioassays, and t he time-to-tumor characteristics are as 33 shown by the data in Figure 5-12 (in section 5.3.3) . The focus here is on these two bioassays, 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-105 combined, because they provide the most extensive c hronic dose-response information. Other 1 tumor bioassays were also conducted by various rese archers and have been detailed in chapter 4. 2
3 4 5 Table 5-22. Summary of tumor incidence in long-ter m bioassays on 6 F344 rats 7 8 Formaldehyde

exposure, ppm Number

of animals Number

with SCC Percent

with SCC 0.0 341 0 0 0.7 107 0 0 2 .0 353 0 0 6.01 343 3 0.87 9.93 103 22 21.4 14.96 386 162 42.0 9 Sources: Combined data from Monticello et al. (19 96) and Kerns et al. (1983). 10 11 12 5.3.1.2. Mechanistic Data 13 The Kerns et al. (1983) and Monticello et al. (1996 ) tumor studies were accompanied or 14 followed by additional studies that provided extens ive mechanistic information on both 15 pharmacokinetics and pharmacodynamics. These studi es have been summarized elsewhere in 16 this document and in other reviews (CIIT, 1999; Mon ticello and Morgan, 1997; Morgan, 1997; 17 Heck et al., 1990). In addition to the tumor incid ence data, the following data and mechanistic 18 information (some of which were model derived) are used in the quantitative models utilized in 19 this chapter. In all these cases, additional data for the rhesus monkey are also available that 20
inform the hazard assessment but which have not bee n explicitly used in deriving the inhalation 21 unit risk. Rhesus monkey data have been discussed in chapter 4 and chapter 3 (DPX and 22 formaldehyde dosimetry). 23

• Formaldehyde interacts with DNA to form DPXs. Thes e cross-links are considered to 24 induce mutagenic as well as clastogenic effects. C asanova et al. (1994, 1989) carried out 25
two studies of DPX measurements in F344 rats. In t he first study, rats were exposed to 26 concentrations of 0.3, 0.7, 2, 6, and 10 ppm for 6 hours and DPX measurements were 27 made over the whole respiratory mucosa of the rat, while, in the second study, the 28 exposure was to 0.7, 2, 6, or 15 ppm formaldehyde f or 3 hours and measurements were 29 made at “high” and “low” tumor sites. DPX formatio n was observed at all exposure 30 concentrations in both studies (0.3 ppm – 15 ppm); the DPX levels were statistically 31This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-106 significantly elevated at concentrations ≥ 2 ppm, with the trend also indicating elevated 1 DPXs at 0.7 ppm. These data were used in the devel opment of a PBPK model for 2 predicting DPX levels in the nasal lining (see chap ters 3 and 4). 3

• Male F344 rats were exposed to formaldehyde gas ove r a range of concentrations (0, 0.7, 4 2, 6, 10, or 15 ppm) in two phases of a labeling st udy. The first phase (Monticello et al., 5 1991) employed injection labeling with a 2-hour pul se labeling time, and animals were 6 exposed to formaldehyde for periods of 1, 4, and 9 days and 6 weeks. The second phase 7 (Monticello et al., 1996) used osmotic minipumps fo r labeling with a 120-hour release 8 time to quantify labeling in animals exposed for 13 , 26, 52, and 78 weeks. These data 9 have been analyzed at length in Appendix E. 10

• Physical and computer models of airflow in anatomic ally realistic representations of the 11 F344 rat and human upper respiratory tract have bee n constructed (Kimbell et al., 1993, 12 1997; Kepler et al., 1993; Subramaniam et al., 1998 ; see chapter 3). 13

• Regional uptake of formaldehyde has been calculated for the upper respiratory tract of the 14 rat and human by using the above computer represent ations and for the lower respiratory 15 tract of the human by using an idealized representa tion of the human lower respiratory 16 tract (Kimbell et al., 2001a; Overton et al., 2001; also see chapter 3 and further discussion 17 of uncertainties in Appendix F). 18
19 5.3.2. The CIIT Biologically Based Dose-Response M odeling 20
The studies mentioned above in 5.3.1.1 and 5.3.1.2 were generated at the CIIT Centers for 21 Health Research and led to the development of a bio logically motivated dose-response model for 22 formaldehyde-induced cancer as represented in a ser ies of papers and in a health assessment 23 report (CIIT model) (Conolly et al., 2004, 2003, 20 00; Conolly, 2002; Kimbell et al., 2001a, b; 24 Overton et al., 2001; CIIT, 1999). EPA’s cancer gui delines (U.S. EPA, 2005a) suggest using a 25 BBDR model for extrapolation when data permit since it facilitates the incorporation of MOA in 26 risk assessment. The CIIT modeling and available d ata were evaluated in a series of peer27 reviewed papers (Klein et al., 2009; Crump et al., 2008; Subramaniam et al., 2008, 2007) and 28 debated further in the literature (Conolly et al., 2009; Crump et al., 2009). Alternatives to the 29 parametrization and model structure in the CIIT bio logical modeling (but based on that original 30 model) are further explored and evaluated in this a ssessment (Appendix E). Appendix F carries 31 out a sensitivity analysis of the human risk estima tes in Conolly et al. (2004) based on key 32 uncertainties evaluated in Appendix E. These BBDR models are used in this assessment to 33 calculate PODs from the dose-response curve for the F344 rat nasal tumor risk. Extrapolation to 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-107 human is then carried out by using EPA’s baseline ( “default”) approach (U.S. EPA, 1994) but 1 using model-derived internal dose metrics. See sec tion 5.3.3 for rationale supporting these 2
decisions. 3 First, the key features of the BBDR modeling in Con olly et al. (2003, 2004) are briefly 4 described, and the following notation is used throu ghout this section: N cell = normal cell; I cell 5 = initiated cell; LI = labeling index and is equal to the number of labeled cells/(number labeled + 6 unlabeled cells); ULLI = unit length LI equal to th e number of labeled cells/length of basement 7 membrane; α N = division rate of normal cells (hour –1 ); μ N = rate at which an initiated cell is 8 formed by mutation of a normal cell (per cell divis ion of normal cells). 9 In Conolly et al. (2003), tumor incidence data in t he Kerns et al. (1983) and Monticello et 10 al. (1996) long-term bioassays were modeled by usin g an approximation of the two-stage clonal 11 growth model (Moolgavkar et al., 1988) and allowing formaldehyde to have a direct mutagenic 12 action. Conolly et al. (2003) combined these data with historical control data on 7,684 animals 13 obtained from National Toxicology Program (NTP) bio assays. These models are based on the 14 Moolgavkar, Venzon, and Knudson (MVK) stochastic tw o-stage model of cancer (Moolgavkar et 15 al., 1988; Moolgavkar and Knudson, 1981; Moolgavkar and Venzon, 1979), which accounts for 16 growth of a pool of normal cells, mutation of norma l cells to initiated cells, clonal expansion and 17 death of initiated cells, and mutation of initiated cells to fully malignant cells. 18 The MVK model for formaldehyde accounted for two MO As as follows that may be 19 relevant to formaldehyde carcinogenicity: 20
1. An indirect MOA in which the regenerative cell prol iferation in response to formaldehyde 21 cytotoxicity increases the probability of errors in DNA replication. This MOA was modeled 22 by using labeling data on normal cells in nasal muc osa of rats exposed to formaldehyde. 23
2. A possible direct mutagenic MOA, based on informati on indicating that formaldehyde is 24 mutagenic (Speit and Merk, 2002; Heck et al., 1990; Grafström et al., 1985), was modeled by 25 using rat data on formaldehyde production of DPXs ( Monticello et al., 1996, 1991). In 26 Conolly et al. (2003), the intracellular dose that induces mutations is considered proportional 27
to the local DPX dose. 28
29 The human model for formaldehyde carcinogenicity (C onolly et al., 2004) is conceptually 30 very similar to the rat model. The model uses, as input, results from a dosimetry model for an 31 anatomically realistic representation of the human upper airways and an idealized representation 32 of the lower airways. However, the model does not incorporate any data on human responses to 33 formaldehyde exposure. 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-108 A novel contribution of the CIIT model, described b y the schematic in Figure 5-11, is that 1 cell replication rates and DPX concentrations are d riven by local dose, which is formaldehyde 2 flux to each region of nasal tissue expressed as pm ol/mm 2 -hour. This dosimetry is predicted by 3 computational fluid dynamics (CFD) modeling using a natomically accurate representations of the 4 nasal passages of a single F344 rat or Caucasian ma le human (see chapter 3). Such a feature is 5 important in incorporating site-specific toxicity i n the case of a highly reactive gas like 6 formaldehyde for which uptake patterns are spatiall y localized and significantly different across 7 species (see chapter 3). In the CIIT model, each o f these parameters is characterized by local flux 8 (see Figure 5-11). The inputs to the two-stage can cer modeling consisted of results from other 9 model predictions as well as empirical data as foll ows: 10

• Regional uptake of formaldehyde in the respiratory tract was predicted by using CFD 11 modeling in the F344 rat and human (Kimbell et al., 2001a, b; Overton et al., 2001; 12 Subramaniam et al., 1998). 13

• Normal cell replication rates were inferred from LI data on rats exposed to formaldehyde 14 (Monticello et al., 1996, 1991, 1990). 15

• Concentrations of DPXs linked to the regional flux of formaldehyde were predicted by a 16 PBPK model (Conolly et al., 2000) calibrated to fit the DPX data in F344 rat and rhesus 17 monkey (Casanova et al., 1994, 1991) and subsequent ly scaled up to humans. The DPX 18 concentration levels were incorporated into the two -stage clonal expansion model by 19 defining mutation rate of normal and initiated cell s as the same linear function of DPX. 20 That is, 21
22

μ N = μ I = μ Nbasal + KMU × DPX (5-1) 23
24 where μ N is the rate at which an initiated cell is formed b y mutation of a normal cell (per 25 cell division of normal cells), and likewise μ I is the rate at which a malignant cell is 26 formed by mutation of an initiated cell (per cell d ivision of initiated cells). The unknown 27

constants μ Nbasal (the baseline rate) and KMU were estimated by fitt ing model predictions 28 to the tumor bioassay data. 29
30 The rat model in Conolly et al. (2003) involved six unknown statistical parameters that 31 were estimated by fitting the model to the rat form aldehyde bioassay data shown in Table 5-22 32 (Monticello et al., 1996; Kerns et al., 1983) plus data from several thousand control anima ls from 33 all the rat bioassays conducted by the NTP. These NTP bioassays were conducted from 1976 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-109 through 1999 and included 7,684 animals with an inc idence of 13 SCCs (i.e., 0.17% incidence). 1 The resulting model predicts the probability of a n asal SCC in the F344 rat as a function of age 2 and exposure to formaldehyde. The fit to the tumor incidence data is shown in Figure 5-12 (in 3 section 5.3.3.). (For later reference in Appendix E, this figure compares the fit to the data 4 obtained by the modeling in Conolly et al. [2003] w ith that obtained by the reimplementation of 5 this model in Subramaniam et al. [2007].) 6 Subsequent to the BBDR model for modeling rat cance r, Conolly et al. (2004) developed 7 a corresponding model for humans for the purpose of extrapolating the risk to humans estimated 8 by the rat model. Also, rather than considering on ly nasal tumors, the model is used to predict 9 the risk of all human respiratory tumors. The huma n model for formaldehyde carcinogenicity 10 (Conolly et al., 2004) is conceptually very similar to the rat model and follows the schematic in 11 Figure 5-11. The following points need to be noted : 12
13

• The model does not incorporate any data on human re sponses to formaldehyde exposure. 14

• The model is based on an anatomically realistic rep resentation of the human nasal 15 passages (in a single individual) and an idealized representation of the lower respiratory 16 tract. Local formaldehyde flux to respiratory tiss ue is estimated by a CFD model for 17 humans (Kimbell et al., 2001a; Overton et al., 2001 ; Subramaniam et al., 1998). 18

• Rates of cell division and cell death are, with a m inor modification, assumed to be the 19
same in humans as in rats. 20

• The concentration of formaldehyde-induced DPXs in h umans is estimated by scaling up 21 from values obtained from experiments in the F344 r at and rhesus monkey (Conolly et 22 al., 2000, and also discussed further in section 3. 6.6 of this document). The statistical 23 parameters for the human model are either estimated by fitting the model to the human 24 background data, assumed to have the same value as that obtained in the rat model, or, in 25 one case, fixed at a value suggested by the epidemi ologic literature. The human value for 26 KMU in eq 1 is obtained by assuming that the ratio KMU/μ basal is invariant across species. 27
28 Some further clarification pertaining to the struc ture and calibration of the models in 29 Conolly et al. (2004, 2003) that are key to underst anding model assumptions is provided in 30 Appendix D. 31
32This document is a draft for review purposes only a nd does not constitute Agency policy 5-110 DRAFT—DO NOT CITE OR QUOTEFigure 5-11. Schematic of integration of pharmacokinetic and pharmacodynamic components in the CIITmodel.Note:β= death rate;μ= mutation rate per cell division;αN, N(t), μNare informed (partially or fully) by empirical data;other parameters are estimated by fitting to tumorincidence data.Regional respiratory tract dosimetry model

I n p u tCancercellTumor(delay)NormalCells,N(t)InitiatedcellsαNαIβI=αNμNμI=μNDDPX in RatDPX in MonkeyDPX in HumanRespiratory tractPBPK models for DPXfaldh in air+ Human LunginputinputRegional respiratory tract dosimetry model

I n p u tCancercellTumor(delay)NormalCells,N(t)InitiatedcellsαNαIβI=αNμNμI=μNDDPX in RatDPX in MonkeyDPX in HumanRespiratory tractPBPK models for DPXfaldh in air+ Human LunginputinputThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-111 5.3.2.1. Major Results of the CIIT Modeling Effort 1 Based on the biologically based modeling of the rat SCC data, CIIT (1999) and Conolly 2 et al. (2004, 2003) presented the following major c onclusions. The evaluation of the strength of 3 these conclusions is summarized in section 5.3.3., and as addressed in that section, this current 4 assessment is not in agreement with these conclusio ns. 5

• The putative, directly mutagenic action of formalde hyde “does not play a significant role 6 in the tumor response in the rat (and also in the h uman), [and such a conclusion] should 7 be robust for any potentially mutagenic effect of f ormaldehyde with a time course similar 8
to that of DPX.” 9

• Respiratory cancer risks associated with inhaled fo rmaldehyde are de minimis (10 –6 or 10 less) at relevant human exposure levels. This was based on using an upper bound on the 11 model estimate for the directly mutagenic action of formaldehyde. 12

• Therefore, exposure standards protective of effects of formaldehyde-induced cytotoxicity 13 should be sufficient to protect from its potential carcinogenic effects. 14

• The human risk estimates in Conolly et al. (2004) w ere judged by the authors to be 15
conservative in the face of model uncertainties bec ause the model included a hockey-stick 16 model for normal cell replication rates when the ce ll replication dose-response curve as 17 averaged by the authors had a J shape, used overall respiratory tract cancer incidence data 18 in humans, and evaluated the model at the statistic al upper bound of the proportionality 19 parameter relating DPXs to the probability of mutat ion. 20

• The dose-response assessment in Conolly et al. (200 4) did not explicitly evaluate the risk 21 of lymphohematopoietic cancers. However, Conolly e t al. (2004) argued that 22 formaldehyde was unlikely to cause the cancers repo rted in Hauptmann et al. (2003). 23 Their reasoning was based on the steepness of the d ose-response curve predicted in 24 Conolly et al. (2004) for respiratory cancer at exp osures of 1 ppm and above and the 25 conclusions in Heck and Casanova (2004). 26 27 5.3.3. This Assessment’s Conclusions from Evaluati on of Dose-Response Models of DPX, 28 Cell-Replication and Genomics Data, and of BBDR Mod els for Risk Estimation 29 The CIIT modeling and alternative approaches that were developed based on the 30 conceptual framework in that modeling were extensiv ely evaluated for this assessment and are 31 presented in Appendices D, E (BBDR modeling of the rat data), and F (sensitivity analysis of 32 BBDR model results for human risk). In particular, Table E-1 in Appendix E and Table F-1 in 33 Appendix F list all the uncertainties and assumptio ns that were examined and summarize the 34 results of the evaluation. The quantitative and qu alitative characterization of the cell replication 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-112 data from Monticello et al. (1996, 1991) are presen ted in Appendix E. The most significant 1 conclusions resulting from these various analyses, focusing on the ones that have maximal 2 impact on the dose-response assessment, are present ed below

. 3 4 Description of time-to-tumor data 5 The overall approach and use of data in Conolly et al. (2004, 2003) have substantial 6 advantages to offer in describing the dose response observed in animal bioassays. The authors’ 7 model provides a good statistical description of th e time-to-tumor data. The fit to the data was 8 found to be superior to that obtained by using mult istage Weibull time-to-tumor modeling of the 9 tumor incidence data (comparison based on visual in spection [see Figure 5-12 in this section and 10 Figures 5-17, 5-18, 5-19 in section 5.3.4]). 11 12

Figure 5-12. Fit to the rat tumor incidence data u sing the model and 13 assumptions in Conolly et al. (2003). 14 Note: Fitting was performed on data of Kerns et al. (1983) and Monticello et al. (1996) combined 15 with ALL NTP historical controls under the assumpti on that all SCCs are fatal. Figure compares 16 the fit obtained by Conolly et al. (2003) with the reproduction of these results under identical 17 conditions, inputs, and assumptions by Subramaniam et al. (2007). There were minor residual 18 differences among the implementations; see the appe ndix in Subramaniam et al. (2007) for 19 explanation. 20 Source: Subramaniam et al. (2007). Reprint permis sion required. 21 Subramaniam et al. fit 0 200 400 600 800 1000 0.0000 0.0005 0.0010 0.0015 0.0020

0 200 400 600 800 1000 0.00 0.05 0.10 0.15 0.20

0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0

0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0Probability

Kaplan-M eier Conolly fit Our fit Age (days)Probability

Age (days) 0 ppm 6 ppm

10 ppm 15 ppm 0 200 400 600 800 1000 0.0000 0.0005 0.0010 0.0015 0.0020

0 200 400 600 800 1000 0.00 0.05 0.10 0.15 0.20

0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0

0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0Probability

Kaplan-M eier Conolly fit Our fit Age (days)Probability

Age (days) 0 ppm 6 ppm

10 ppm 15 ppmThis document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-113 1 Integration of various relevant data 2 The model framework integrates various pharmacokine tic and pharmacodynamic 3 components (regional formaldehyde flux, DPX, cell-r eplication, and tumor incidence data) 4 within a single conceptual framework and thus facil itates description of the dose response that 5
utilizes the extensive mechanistic information avai lable for formaldehyde. 6
7 Regional dosimetry 8 Regional (site-specific) dosimetry in the upper res piratory tract is considered important 9 for understanding the tumorigenicity of a reactive chemical like formaldehyde. The regional 10 dosimetry models discussed in chapter 3 compute loc al formaldehyde flux to the tissue and are 11 based on anatomically realistic constructions of th e nasal airways in each species. The other 12 relevant mechanistic data, DPX and cell replication , are expressed as a function of this local 13 formaldehyde flux. 14
15 Confidence in dosimetry 16 Model predictions of formaldehyde flux to the resp iratory lining have not been verified 17 experimentally, and such verification would present formidable experimental challenges. 18 Overall, the formaldehyde dosimetry modeling utiliz ed in the CIIT modeling presents a 19 reasonable level of confidence, as detailed in chap ter 3, section 3.6, by virtue of agreement 20 among multiple model predictions (models that predi ct airflow profiles as well as a PBPK model 21 for DPX, which uses the calculated formaldehyde flu x as input) and various kinds of available 22 data. These data comprise airflow profiles in phys ical casts of the nasal cavity of an F344 rat 23 (Kimbell et al., 2001a), a human (Subramaniam et al ., 1998), and a rhesus monkey (Kepler et al., 24 1998); DPX data (see discussion of Cohen-Hubal et a l. [1997] in chapter 3); and qualitative 25 concordance between uptake patterns and cell prolif eration (Morgan et al., 1997; Monticello et 26 al., 1996). The CFD models of formaldehyde flux re present only an individual of each species. 27 However, considerable interindividual differences a re to be expected in the regional dosimetry, 28 particularly in the human (Garcia et al., 2009: Sub ramaniam et al., 2008). This is discussed 29 briefly in Chapter 3 (section 3.6) and further in A ppendices B and F. 30
31
Control tumor data 32 In developing their model, Conolly et al. (2004, 2 003) included control rats from all NTP 33 cancer bioassays—a total of 7,684 rats. The inclus ion of all NTP historical control animals does 34 not appear to be supportable and substantially alte rs dose-response predictions (Crump et al., 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-114 2009, 2008; Subramaniam et al., 2008, 2007). There are legitimate questions regarding 1 comparability of results in rats from different sto cks, studied at different times, in different 2 laboratories, and by different routes of exposure a nd evaluated by using somewhat different 3 pathological procedures. If historical controls ar e used from only those inhalation studies that 4 present a low potential for genetic and time-relate d variations in tumor incidence and survival of 5 animals or if only concurrent controls are used, th e model for extrapolation of risk to humans (the 6 human BBDR model) becomes numerically unstable. In such a model, it is not possible to bound 7 human risk by using the extrapolation approach appl ied in the CIIT model. When the included 8
NTP control data were restricted to all NTP inhalat ion controls, the upper bound human risk 9 estimate obtained by Conolly et al. (2004) was incr eased by 50-fold (Crump et al., 2008). 10
11 Cell replication dose response 12 As discussed in chapter 4, characterization of the uncertainties and variability in the cell 13 replication dose response is crucial to understandi ng formaldehyde carcinogenicity. Analyses of 14 the dose response for cell replication presented in Appendix E demonstrate the following: 15

• Sustained exposure to formaldehyde affects cell div ision rates (compared to baseline 16 levels). This effect is seen over a continuum of f ormaldehyde flux to the nasal lining that 17 includes flux levels below those thought to be cyto toxic. 18

• Given the qualitative and quantitative uncertaintie s in the data and in their interpretation, 19 a variety of cell replication dose-response models are plausible as reasonable 20 characterization of the data. Cell replication res ponse differs substantially among nasal 21 sites and over time during the course of the bioass ay. In consideration of these 22 differences, the shape of the cell replication low- dose response could be alternatively 23 described as monotonic or non-monotonic. For examp le, rather different statistical 24 descriptions of the data result depending on whethe r 25
i. different sites and exposure times were modeled sep arately; 26
ii. all exposure times were pooled to model the respons e at each site; 27
iii. the labeling index was time-weighted and averaged o ver all sites; 28
iv. flux and labeling index were weighted by the number of cells at a given site; 29

v. the short exposure durations in Monticello et al. ( 1991) were examined separately. In 30 addition, transient increases in cell turnover at s ub-cytotoxic doses are seen in other 31 experiments in rats exposed to formaldehyde (see ch apter 4). 32

• At higher, cytolethal formaldehyde flux levels, reg enerative hyperplasia-induced cell 33 proliferation clearly takes over. 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-115 1
2 Genotoxicity 3 Chapter 4 provides multiple lines of evidence to ch aracterize formaldehyde as a 4 genotoxicant. Of particular note is the observatio n of cytogenetic effects at human occupational 5 exposures and the formation of DPXs upon formaldehy de interaction with DNA at doses well 6 below those considered cytotoxic. As noted earlier , DPX formation was detected in rats at 7 exposures ranging from 0.3 ppm to 15 ppm. These DPX levels are seen to be statistically 8 significantly increased over baseline levels at 2 p pm and above. The DPX measured at 0.7 ppm 9
shows a trend that is consistent with an increase a t this dose (see chapter 3); while not 10 statistically significant, it is critical to consid er “trend” when analyzing low-dose data. 11
12 Inferences on MOA from modeling the data 13 The highly curvilinear nature of dose responses as sociated with DPX formation, LI data, 14 and tumor response as well as mechanistic interpret ation of these observed data has provided 15 grounds for arguments in the literature that formal dehyde tumorigenicity (at exposures ≥ 6 ppm) 16 should be uncoupled from its potential carcinogenic ity in the low-dose region. Furthermore, 17 researchers have argued that any potential low-dose risk is due to its mutagenicity, that this 18 mutagenic potential is too weak to be of significan ce, and that the high-dose risk is entirely due 19 to cell proliferation induced by regenerative hyper plasia in response to cell injury at cytotoxic 20 doses (i.e., without a relevant role for the direct mutagenic action of formaldehyde). Conolly et 21 al. (2004, 2003) represented a quantitative express ion of this point of view. However, alternative 22 parametrizations of the model in Conolly et al. (20 04, 2003) have shown that the mutagenic 23 component can be important in explaining the high-d ose effect and that the risk at low dose due 24 this mutagenicity can be significant (Subramaniam e t al., 2007; Appendix E). Accordingly, the 25 dose-response assessment in this document does not treat formaldehyde as a threshold 26 carcinogen. 27
Of further relevance to mode-of-action considerati ons, analyses detailed in Appendix E 28
indicate that the chronic rat nasal time-to-tumor i ncidence data can be quantitatively explained, 29 and with equal force, by invoking any of the follow ing multiple sets of plausible events induced 30 by formaldehyde. The role of spontaneously occurri ng mutations and increased cell turnover 31 rates in response to various baseline insults to th e nasal lining are common to all these scenarios 32 (and are not separately mentioned). 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-116 a. Mutations occur over a dose continuum that includes sub-cytotoxic and cytotoxic levels of 1 exposure. The only cell proliferation induced by f ormaldehyde is a regenerative response at 2 cytotoxic concentrations. 3
b. Cytotoxicity-induced regenerative cell proliferatio n occurs, but there is no significant 4 formaldehyde-induced mutational effect. This latte r scenario expresses arguments that 5 formaldehyde-induced mutagenicity may be too weak t o be of significance to its 6 tumorigenicity. 7

c. Both mutations and cell proliferation are induced b y formaldehyde only at cytotoxic levels. 8
d. Mutational events occur and cell replication is alt ered over a continuum that includes low and 9 high levels of exposure. 10
i. At high dose, the effect on cell replication is reg enerative. 11
ii. At lower doses, the data indicate that both monoton ic and non-monotonic dose12 response curves for cell replication are plausible. 13
iii. With respect to the previous argument, the followin g result was very instructive. The 14 models were exercized with normal cell replication rates considered to be less than 15 (non-monotonic) or equal to (threshold) baseline ra tes over a segment of the low-dose 16 range in conjunction with the chronic time-to-tumor data for the F344 rat. Such a 17 scenario did not necessarily lead to lower than bas eline or threshold in formaldehyde 18 respiratory cancer risk in the rat in that low-dose range. This is partly because there 19 are no data to inform how formaldehyde-induced muta tion might alter cell replication 20 and apoptotic rates (in particular if the mutation is to be construed as an initiating 21 event in the carcinogenesis). 22

e. Formaldehyde-induced mutagenic action acts only in concert with baseline cell turnover at 23
low dose. 24
25 Kinetics of initiated cells 26 Modeling results are hypersensitive to the division and death rate of initiated cells that 27 cannot be further inferred by the available empiric al cell labeling data (Conolly et al., 2009; 28 Crump et al., 2009, 2008). Several plausible alter nate model structures for describing initiated 29 cell kinetics, none of which degrade the agreement of the model with the underlying data used to 30 construct the model originally, led to low-dose ris k estimates in the rodent that varied by many 31 orders of magnitude, including negative values (see Figures E-5A,B and E-6A,B in Appendix E). 32 Extremely small perturbations in the division rate (and, likewise, of death rates) of initiated cells 33 in the model lead to human risk estimates ranging a nywhere from negative values to +0.01 at 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-117 0.01 ppm (see Crump et al. 2008 and Appendix F, Fig ure F-5). These perturbations were small 1 compared with the normal variation in the division rates of normal cells. 2 The sensitivity analyses on the basis of which thes e conclusions were reached have been 3 criticized as resulting in implausible risk estimat es (given the epidemiologic data) as a 4 consequence of implementing model variations that a re not biologically reasonable (Conolly et 5 al. 2009). This criticism was rebutted by Crump et al. (2009) on biological and epidemiological 6 grounds. These debates are discussed fully in Appen dix F. 7 In addition, there are major qualitative uncertaint ies in extrapolating normal cell 8 replication rates from the rat to human (Table F-1 in Appendix F, and Subramaniam et al. 9 [2008]). Subramaniam et al. (2008) concluded that several inferences that arise from the 10 assumptions in the CIIT model on initiated cell rep lication and death rates cannot be supported 11 by available biological information. 12
13 Risk extrapolation 14 Use of the modeling approach in Conolly et al. (200 4) or the variations examined were 15 determined not to be informative for extrapolation from animal to human at any exposure 16 concentration because of extreme sensitivity, inclu ding numerical instability, to uncertain model 17 assumptions. In the face of model uncertainties, t he biologically based derivation of human risk 18
estimates of 10 –6 or less at exposures of 0.1 ppm and below in Conol ly et al. (2004) or CIIT 19 (1999) cannot be characterized as a plausible upper bound. 20 The use of this model for extrapolation of risk fro m high to low exposures in the rodent 21 followed by a conventional (default) approach to ex trapolate the low-dose animal risk to the low22
dose human risk was next evaluated. This avenue wa s also found not to be informative because 23 the models do not adequately constrain risk in the rodent. For example, various model 24 representations as shown in Figure E-6A,B in Append ix E were used to evaluate added MLE risk 25
at the 10 –5 level (Figure F-5A,B in Appendix E) in the F344 ra t. Human exposures were then 26 calculated that would result in equivalent lifetime risk by using formaldehyde flux estimated in 27 each species as the dosimeter and conventional extr apolation methods (U.S. EPA, 1994b). A 25- 28
fold difference was found between the different mod els in the equivalent exposure concentration 29 so derived. Therefore, the CIIT model or its varia tions were also not used in this assessment as a 30 biologically based or biologically motivated means of extrapolating outside the observed dose31 response in the F344 rat. Model uncertainty was su bstantially higher than the statistical 32 uncertainty arising out of a given model specificat ion. 33 Thus, in view of all the above considerations and in accordance with EPA’s cancer 34 guidelines (U.S. EPA, 2005a), the derivation in thi s document of unit risk for human respiratory 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-118 cancer from animal bioassay data is based on a line ar extrapolation to the origin from a POD on 1 the dose-response curve. Low-dose linearity was ex hibited by the risk estimates from most of the 2 models that were examined in the sensitivity analys is (see discussion surrounding Figure E-5A,B 3 in Appendix E). 4 BBDR modeling for deriving an “integrated” POD 5 The CIIT BBDR modeling approach provides a good fi t to the time-to-tumor data and 6 therefore allows for an appropriate determination o f a POD while at the same time incorporating 7 a large amount of mechanistic information in an int egrated manner and allowing the use of 8 model-derived internal dose estimates. Thus, use o f this model provides an alternative to 9 developing separate PODs based on several of the un derlying components of the data, such as 10 DPX, flux, and labeling data. Accordingly, the mod el is used in this assessment to derive a POD 11 from a dose response, based on the nasal cancers in rats. Uncertainties in the derivation of the 12 POD were represented by using the variations of the CIIT model examined in this chapter. These 13
POD calculations as well as others are detailed bel ow. 14
15
Genomics data 16 The genomics data of Thomas et al. (2007) and Ander sen et al. (2008) provide additional 17 insight into formaldehyde’s biological effects and the steep dose-response curve for 18 tumorigenesis. However, there are various limitati ons in the interpretation of these genomics 19 data and their relevance for the pathways contribut ing to the disease process in humans. In 20 particular, the data from these studies, as analyze d, do not inform the critical MOA questions 21 pertaining to formaldehyde carcinogenicity. These insights have been elaborated in a separate 22 section in chapter 4, and the difficulties in the u se and interpretation of the quantitative modeling 23 of these data, as presented in these studies, are d etailed at length in Appendix G. 24
25 5.3.4. Benchmark Dose Approaches to Rat Nasal Tumo r Data 26 This section describes various BMD analyses to dete rmine PODs for low-dose 27 extrapolation of SCC risk in the human respiratory tract (upper and lower). 28
29
5.3.4.1. Benchmark Dose Derived from BBDR Rat Model and Flux as Dosimeter 30
5.3.4.1.1. Response for benchmark dose . Typically, the BMD is calculated at the 5 or 10% 31 response level. However, it appears appropriate to consider the benchmark response (BMR) at 32 lower levels in exceptional cases that are supporte d by empirical data. In the case of the 33 combined Kerns et al. (1983) and Monticello et al. (1996) bioassays, the lowest observed tumor 34 response of SCC was below the 1% level (at 0.85%) ( see Table 5-22). Additionally, the BBDR 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-119 modeling incorporates precursor response in the for m of LI data. Therefore, it was determined 1 that it would also be appropriate to evaluate the P OD at the 0.5% level while still staying in the 2 neighborhood of the experimentally observed respons e. 3 The various data presented earlier in this chapter point to highly curvilinear dose 4 responses for formaldehyde-induced tumor incidence as well as DPX and cell replication. This is 5 also borne out by dose-response information based o n gene array data (Thomas et al. 2007; 6 Andersen et al. 2008). Cytotoxicity-driven regenera tive replication and epithelial degeneration 7 play a critical role in the steeply rising nature o f the tumor dose-response. These observations 8 raise the concern that cancer potency derived by st raight-line extrapolation from the low end of 9 observed tumor data (roughly at the 1% response) ha s the potential to be a significant 10 overestimate for a reasonable upper bound. Thus, a pertinent question is what is a low-dose 11 linear dose-response modeling of the data that is s tatistically consistent with the uncertainties in 12 the observed time-to-tumor data. To address this q uestion, the risk estimate based on the linear 13 extrapolation (from a POD to the origin) is compare d with that predicted at the low-dose end by 14 the Multistage Weibull model fitted to the observed time-to-tumor data. The unit risk based on 15 this model is obtained by calculating q1*, the 95% statistical upper bound on the coefficient 16 associated with the linear term in the multistage m odel polynomial. This model fits the data 17 reasonably well and reflects the highly curvilinear shape of the dose-response because of its 18 mathematical flexibility while also allowing for lo w-dose linearity. In particular, it has been 19 noted that even in cases where the first term (q1) in the multistage model is zero, the upper 20 bound (q1*) is linear with dose (Subramaniam et al. , 2006; Guess et al., 1977). Thus, for 21 comparison the following estimates of unit risk are also presented: 22
23 1) Unit risk that is based on q1*, which is derived fr om fitting the multistage Weibull model to 24
the observed data. 25 2) Unit risk based on low-dose linear extrapolation fr om a POD at the 0.5% level. 26
27
5.3.4.1.2. Dose metric. The dose metric used for the extrapolation was the average wall mass 28 flux of formaldehyde (expressed in pmol/mm 2 -hour to the entire surface of the airway lining bu t 29 excluding tissue lined by non-mucus-coated squamous tissue, which was considered to not 30 absorb formaldehyde). The use of flux as a dosimet er is similar to the calculation of a regional 31 gas dose ratio (RGDR) as proportional to minute vol ume divided by the surface area in the given 32 species and is thus in line with EPA’s prescription for calculating a dosimetric adjustment factor 33 (DAF) for category 1 gases, whose effects are presu med to be at the POE (U.S. EPA, 1994b) 34 (i.e., ratio of average flux over the same respirat ory region in each species = ratio of the quantity 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-120 [minute volume/surface area of the region] between the two species). This lends support to an 1 interspecies extrapolation based on the equivalence of formaldehyde flux as a determinant of 2
risk. 3 The spatial distribution of formaldehyde over the nasal lining was characterized by 4 partitioning the nasal surface by formaldehyde flux to the tissue, resulting in 20 “flux bins” 5 (Figure 5-13). Each bin is comprised of elements ( not necessarily contiguous) of the nasal 6 surface that receive a particular interval of forma ldehyde flux per ppm of exposure 7 concentration (Kimbell et al., 2001a). The spatial coordinates of elements comprising a 8 particular flux bin are fixed for all exposure conc entrations, with formaldehyde flux in a bin 9 scaling linearly with exposure concentration (ppm). The number of cells at risk varies across 10 the bins, as shown in Figure 5-14. 11
12

0 500 1000 1500 2000 2500 3000

0 5 10 15 20 Flux Bin No.Flux Per Unit Exposure Conc[pmol/(mm2-h-ppm)]

Flux Bin No. 0 5 10 15 20No. of cells at risk

0 1e+7 2e+7 3e+7

13 14 Figure 5-13. Spatial distribution of formaldehyde over the nasal lining, as characterized by partitioning the nasal surface by formaldehyde flux to the tissue per ppm of exposure concentration, resulting in 20 flux bins. Figure 5-14. Distribution of cells at risk across flux bins in the F344 rat nasal lining.

Source: Subramaniam et al. (2008). Source: Subra maniam et al. (2008). 15 16 5.3.4.1.3. Extrapolation to humans. For linear extrapolation from the 0.5 and 1% levels , two 17 alternative versions of the biologically based mode l in Conolly et al. (2003) for the F344 rat were 18 used. In both cases, only the historical control d ata from NTP inhalation studies data were added 19 to the concurrent controls and weekly averaged DPX concentrations as calculated by a variant of 20 the PBPK model in Conolly et al. (2000) [described in Subramaniam et al. (2007)] were used. 21This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-121 Both models provided good fits to the tumor inciden ce data, similar to the fit shown in Figure 5- 1
12. Neither model could be considered better than the other on the basis of model description of 2
tumor incidence data. 3 In Model 1 the normal cell replication dose respon se was described by the same 4 hockey-stick-shaped curve used in Conolly et al. (2 003). The form of the dose-response 5 curves for initiated cell kinetics (division and de ath) was also the same as that considered by 6 Conolly et al. (2003). 7 Model 2 was an alternative to the Conolly et al. ( 2003) model, and is considered in 8 the sensitivity analysis described in Appendix E. The dose response for normal cell 9 replication was monotone increasing and did not exh ibit a threshold in dose. This was 10 obtained by fitting the 13-week cell replication da ta. The cell replication dose response for 11 initiated cells was a sigmoidal-shaped curve, incre asing monotonically with flux from a 12 background value up to an asymptotic value. The ba seline cell-replication for initiated cells 13
was constrained to not be less than that for normal cells. Initiated cell death rate was 14 considered proportional to initiated cell birth rat e. 15 Models 1 & 2 predicted monotonic dose-response cur ves. 16 The sequence of steps in arriving at a unit risk f or SCC in human nasal airways from 17 a given BBDR modeling of the F344 rat nasal tumor i ncidence data is outlined below. 18 Extrapolation to the lower respiratory tract is des cribed later. 19
1. Calculate the MLE risk and 95% upper confidence bou nd on risk at various exposure 20 concentrations (d RAT in ppm) by exercising the two BBDR models. Here, t he POD is 21
defined as d RAT for which the 95% upper bound added risk is either 0.005 or 0.01. These 22 values approximate the 95% lower bounds on the BMD corresponding to the added risks 23 (i.e., the BMDL RAT ). 24
2. Using CFD modeling simulations in Kimbell et al. (2 001a, b), calculate the average flux 25 over the entire rat nose at resting breathing rates corresponding to d RAT . Here, the 26 subscript “i” is over flux bins and N is the number of cells at risk in a given bin. 27
28

RAT i i i i i

RAT RAT 

### N N

ppm flux

d d AvgFlux    

 

   

 

⋅
× = 

# ∑ ∑ ) ( ) ( (5-2) 29

30This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-122 3. The experiment exposure was for periods of 5 days/w eek, 6 hours/day. Therefore, 1 calculate the average daily exposure, obtained by m aking a 5/7 × 6/24 duration 2 adjustment; that is, 5/7 × 6/24 × AvgFlux(d RAT ). 3
4. Now assume that lifetime exposure to similar levels of average formaldehyde flux to 4 cells at risk leads to similar lifetime risk (MLE o r upper bound, respectively) of tumor 5 incidence across animal species. Also, in calculat ing human equivalent concentrations, 6 EPA has traditionally assumed chronic animal labora tory exposure scenarios to be 7 equivalent to human lifetime exposures (U.S. EPA, 1 994b). 8
5. Since a CFD model for a human is available (Subrama niam et al., 1998), it is possible to 9 determine the average wall mass flux in this partic ular human nose for any specific 10 breathing scenario. Likewise, a computational mode l to determine mass flux at any 11 specific lung depth was available in the form of th e single-path model of Overton et al. 12 (2001); however, risk in the lower respiratory trac t will be addressed later. From the 13 human CFD simulations in Kimbell et al. (2001a, b), the human airborne exposure 14 concentration level that would yield the same avera ge wall mass flux in the human nose 15 as [(5/7) × (6/24) × AvgFlux(d RAT )] is then calculated. In other words, given a ris k16 specific dose in the rat, the equivalent human expo sure concentration is given by 17
18

HUMAN i i i i i

RAT HUMAN N ppm flux N d AvgFlux d    

 

   

 

× × × × = 

## ∑ ∑

) ( ) ( ) 24/6( )7/5( (5-3) 19

20
6. To use this equivalent human exposure concentration , make the following assumption: 21 when humans are exposed to the above concentration of formaldehyde (d HUMAN ) 22 throughout the course of a lifetime, the added risk s are anticipated to be similar to those 23 experienced by the animal in the chronic bioassay. 24
7. Let f

denote the ratio of the average flux per ppm of ex posure concentration in the two 25 species: 26
27This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-123 HUMAN i i i i i RAT i i i i i

N N ppm flux N N ppm flux

f

   

 

   

  ×    

 

   

  ×

=


## ∑

∑ ∑ ∑

) ( ) (

(5-4) 1

2 Now, the olfactory epithelium comprises a substanti al fraction of nasal tissue in the rat. 3 Because the olfactory region in the rat projects di rectly in the path of main airstreams 4 (Kimbell et al., 1997), a sizable flux of formaldeh yde is delivered to this region in the 5 rat. Tumors were not observed in the olfactory tis sue of the rat. Therefore, since effects 6 observed in the rat are being extrapolated to the h uman, cells from olfactory tissue are 7 excluded in calculating average flux in the rat in the eq 4. For the human, on the other 8 hand, both volumetric flow (2.5%, Subramaniam et al . [1998]) and surface area (~5%, 9 Kelly et al. [2000]) for the olfactory region are r elatively small, so inclusion of this 10 region is not likely to make a difference of much s ignificance in the calculation of 11 average flux in the human. Since data on formaldeh yde flux delivered to the human 12 olfactory region were not readily available, the ol factory region was not excluded for the 13 human. The average human flux calculated here uses a working level classification for 14 the activity profile where an individual spent equa l amounts of time in a day at resting 15 and light and moderate activity levels, correspondi ng to minute volumes of 7.5, 9, and 16 25 L/minute, respectively. This resulted in the fo llowing ratio 13 : 17
18 f = 444 [rat] /956.4 [human] = 0.46 (5-5) 19
20
8. The airborne exposure concentrations d HUMAN corresponding to a given MLE and upper 21
bound lifetime added risk levels are the human BMD HUMAN and BMDL HUMAN , 22 respectively. These are shown in Figure 5-15. (Th e rather sudden increase by ~0.0015 23 in the upper confidence bound on risk for model 1 f or exposure exceeding ~0.41 ppm 24 could not be explained. This jump was verified by repeated calculations that used 25 different initial simulation conditions and converg ence criteria.) 26

13 This is to be contrasted with a corresponding valu e of 0.71 in Schlosser et al. (2003) who used only resting inspiratory rates.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-124 Next, the human lower respiratory tract is also con sidered to be potentially at risk. 1 Therefore, the above calculations of BMD and BMDL n eed to be augmented to include the 2 lower respiratory tract for humans. This calculati on was facilitated by dosimetry 3 calculations of formaldehyde wall mass flux to vari ous depths in the lung by using a single 4 path model. Refer to Overton et al. (2001) for det ails on their modeling. The calculations 5 for including the lower respiratory tract in determ ining an overall BMD and BMDL involved 6 the following steps: 7

a. As given by eq 5-3, calculate d HUMAN for various MLE risk levels. This gives a dose8 response relationship for lifetime risk of SCC in t he human nose due to continuous 9 exposure to airborne formaldehyde. 10
11

0 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016

0.4 0.41 0.42 0.43 0.44 0.45 0.46 0.47 0.48 0.49 human exposure conc (ppm)human added risk

model 2 mle model 2 UB model 1 mle model 1 UB

0 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016

0.4 0.41 0.42 0.43 0.44 0.45 0.46 0.47 0.48 0.49 human exposure conc (ppm)human added risk

model 2 mle model 2 UB model 1 mle model 1 UB

12 Figure 5-15. MLE and upper bound (UB) added risk o f SCC in the human 13 nose for two BBDR models. 14 15 Note: Airborne exposure concentrations d HUMAN corresponding to a given MLE 16 and upper bound lifetime added risk levels are the human BMD HUMAN and 17 BMDL HUMAN , respectively. 18 19 20 b. Express this dose-response relationship in terms of average flux over the entire human 21 nasal lining. 22

c. Next, express this dose-response relationship, calc ulated here for the entire nose, as risk 23 per nasal cell versus average flux. 24This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-125 d. Now, if the respiratory and transitional cell types in the human lung and nose are equally 1 susceptible to formaldehyde-induced cancer risk (as is also assumed in Conolly et al. 2 [2004]), then it appears reasonable to assume that MLE risk per cell at a given value of 3 formaldehyde flux is the same in the lung as in the nose. 4

e. The number of cells and the average flux in a given flux bin in the lung are known 5 (Overton et al., 2001). Thus, at a given air concentration, the MLE risk due to cells in 6 the various flux bins of the lung is obtained. 7
f. One important feature of Overton et al. (2001) was that their flux bins mapped physically 8 with lung depth. Therefore, in addition to extrapo lating risk to the entire human lung, it 9 was also relatively easy to calculate risk as a fun ction of airway generation in the lung 10 (corresponding to different lung depths). 11

g. Because of high formaldehyde reactivity and solubil ity at the POE, the MLE value risk to 12 the lower respiratory tract (as determined above in steps 1–5) was a small fraction of risk 13 to the upper respiratory tract. Therefore, it suff iced to assume that the relative increase 14 in upper bound risk for the combined upper respirat ory tract + lower respiratory tract 15 compared to that for only the upper respiratory tra ct would be the same as the 16 corresponding relative increase in the value of the MLE risk. The upper bound risk to 17 the entire respiratory tract and consequently the B MDL value corresponding to a given 18 response were thus determined. 19
20 These calculations indicated that including the ri sk of SCC in the lower respiratory 21
tract resulted in at most a 3% increase in the adde d risk at the lower end of the human 22 exposure range in Figure 5-16 (i.e., at 0.42 ppm) a nd about a 1.5% increase at the higher end 23 of the range in that plot. Therefore, because of t he steepness in the dose-response curve in 24 this exposure range and much lower risk in the lung at any exposure concentration, including 25 the lower respiratory tract did not appreciably alt er the human BMDs and BMDLs at the 0.5 26 and 1% response levels. 27 Unit risks of SCC in the human respiratory tract ex trapolated in this manner are reported 28
in Table 5-23. 29
30This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-126 Table 5-23. BMD modeling of unit risk of SCC in th e human respiratory 1 tract 2 3 Benchmark levels (ppm)

Extra risk level BMD BMDL Unit risk a (per ppm)
0.005 0.415–0.450 0.410–0.435 1.2 × 10 –2
0.010 0.430–0.460 2.2 × 10 –2
4

a Obtained from the mean of the two BMDLs. 5 6 Note: Findings are based on nasal tumors in rats an d formaldehyde flux to tissue as dosimeter, using d ose7 response curves for the F344 rat predicted by clona l growth modeling. Two chronic bioassays (Monticel lo 8 et al., 1996; Kerns et al., 1983) were combined, an d control animals from the historical NTP inhalatio n 9 bioassays were added to the control animals in thes e bioassays. 10 11 12 5.3.4.2. Comparison with Other Benchmark Dose Modeling Effor ts 13 The CIIT assessment (Schlosser et al., 2003; CIIT, 1999) also presented, as their less 14 preferred option, a benchmark approach on the data set obtained by combining two chronic 15 bioassays with similar protocols (Monticello et al. , 1996; Kerns et al., 1983) along with data 16 from 94 animals that had not been previously examin ed. These authors used two measures of 17 response—tumor incidence and cell proliferation—and , in each case, they used two dosimeters— 18 DPX and formaldehyde flux to the nasal lining. 19 The extrapolation to human was carried out by usin g a hybrid CFD and pharmacokinetic 20 model. The CFD model (Kimbell et al., 2001a, b; Ke pler et al., 1998; Subramaniam et al., 1998) 21 enabled calculation of site-specific flux in the no se of the rat, monkey, and human species for 22 inhaled formaldehyde concentrations, and the PBPK m odel (Conolly et al., 2000) linked this flux 23 to predicted DPX levels. The models were construct ed for anatomically realistic representations 24 of a single individual in each species. The CFD an d PBPK modeling and uncertainties in these 25 estimates have been reviewed in the Modeling the To xicokinetics of Formaldehyde and DPX 26 section of chapter 3. 27
28
5.3.4.2.1. Benchmark dose using administered concentration. Schlosser et al. (2003) fit 29 multistage, Weibull, polynomial, and log-probit qua ntal models to the tumor data and exercised 30 the models (except the log-probit) with and without requiring that the fits pass through the origin. 31 The log-probit fit passed through the origin (see F igure 5-16). A fifth degree polynomial was 32 used in the multistage model. The best fit was obt ained with the polynomial and Weibull models 33
for the tumor incidence data with a non-zero interc ept (threshold) on the dose axis. Fits passing 34 through the origin did not pass the statistical goo dness-of-fit criteria ( p > 0.01) for models other 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-127 than the log-probit. The dose response near the lo west dose was fairly steep, with the LED 10 s 1
and LED 01 s nearly the same for each model, at least to one s ignificant figure. In terms of 2 administered concentration, the LEDs ranged from 3. 8 to 6.4 ppm. 3
4
5.3.4.2.2 . Benchmark dose derived with internal dose (flux and DPX) as dose metrics in 5 Schlosser et al. (2003). 6 Schlosser et al. (2003) used CFD simulations (Kimb ell et al., 2001a, b) of mass flux of 7 formaldehyde delivered across the nasal lining. Th e dose metric used by Schlosser et al. (2003) 8 for the extrapolation was the average flux of forma ldehyde, expressed in pmol/cm 2 -minute, to the 9 entire surface of the airway lining (excluding tiss ue lined by non-mucus-coated squamous tissue, 10 which was considered not to absorb formaldehyde). 11
12

13 14 Figure 5-16. Replot of log-probit fit of the combi ned Kerns et al. (1983) and 15 Monticello et al. (1996) data on tumor incidence sh owing BMC 10 and 16 BMCL 10 . 17 18 Source: Adapted from Schlosser et al. (2003). 19 20 21 In the CFD model, flux in any region is linearly re lated to the airborne exposure 22 concentration (i.e., flux = f × C air [ppm], where f is a constant of proportionality an d C air is the 23 exposure concentration). The ratio of f (rat)/f (h uman) was determined as given by eq 5-4. This 24This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-128 ratio was equal to 0.71 and differed from the value of 0.46 used in this document (as presented in 1 eq 4-5) because Schlosser et al. (2003) used restin g inspiratory rates. In the next level of 2 dosimetric complexity, Schlosser et al. (2003) used DPX as the relevant dosimeter based on 3 values predicted by PBPK models developed by Conoll y et al. (2000). This expressed the local 4 dose as pmol of formaldehyde equivalents covalently bound to DNA per unit volume of nasal 5
tissue. Human CFD and PBPK models were exercised t o determine the airborne concentration 6 of formaldehyde that yields average DPX levels equa l to those in the rat at the BMC. This 7
airborne concentration was then the HEC. The human benchmark extrapolations in Schlosser et 8 al. (2003) using flux and DPX are shown in Table 5- 25, located at the end of section 5.4. 9 The assumption in using DPX data was that lifetime exposure to the same DPX 10 concentration for a given duration each day leads t o equivalent risk across species. Table 5-25 11
shows their human benchmark calculations for a cont inuous environmental exposure. These 12 were exposures that resulted in the same steady-sta te DPX concentrations as the weekly TWA 13 DPX values in rats at the rat benchmark exposure co ncentrations. 14
15
5.3.4.2.3. Cell proliferation in CIIT benchmark modeling. 16 Schlosser et al. (2003) also used cell proliferatio n as representing the adverse response, 17
and the BMDs calculated with these data did not dif fer appreciably from their other benchmark 18 estimates. The use of cell proliferation as an end point is considered to have the advantage that it 19 represents an early step contributing to carcinogen esis. In this document, a BMD is not 20 calculated based solely on cell replication as a re sponse. Instead, cell replication rates are used a s 21 input to the clonal growth model and a BMD based on a fit to the tumor response using that 22 model is considered a better choice since it integr ates cell replication along with other relevant 23 data, such as the number of cells at risk and DPXs. 24
25
5.3.4.3. Kaplan-Meier Adjustment 26 In the simplest consideration of the impact of comp eting risks on the nasal tumor 27 incidence, tumor incidences were adjusted for early deaths according to Kaplan-Meier (KM) 28 survival estimates (KS Crump Group, 2001). This pr ocedure allows for the possibility that some 29 tumors may otherwise have developed in the animals that died early due to other causes. All the 30 animals in the study were considered except those t hat were kept past termination of exposure. A 31 comparison of the adjusted incidence data is presen ted below in Table 5-24. While the 32 adjustments have been provided in Table 5-24, it ne eds to be noted that the data allow for a full 33 time-to-tumor analysis as presented below. 34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-129 Table 5-24. Formaldehyde-induced rat tumor inciden ces 1
2

Exposure level (ppm) KM adjusted incidence Observed tumors/ number at risk a 0.0 0.0 0/242 0.7 0.0 0/70 2.0 0.0 0/254 6.0 0.02 3/120 a 10.0 0.61 22/36 a 15.0 0.83 157/190 a 3

a KM adjusted. Numbers not indicated by footnote wer e not amenable to KM 4 adjustment because there were no tumors; these numb ers at risk reflect all animals 5 surviving 1 year on study. 6 Source: Monticello et al. (1996); Kerns et al. (19 83). 7 5.3.4.4. EPA Time-to-Tumor Statistical Modeling 8 Instead of using the KM adjustment, EPA has used th e multistage Weibull time-to-tumor 9 model (Portier et al., 1986; Krewski et al., 1983) in other assessments (e.g., ethylene oxide, 10 1,3-butadiene, chloroprene). This is a dose-respon se model that includes the exact time of 11 observation of the tumors and therefore gives appro priate weight to the amount of time each 12 animal was on study without a tumor and acknowledge s earlier tumor incidence with increasing 13 dose level. The data used in this analysis were ob tained from the appendix in Conolly et al. 14 (2003) with one crucial modification. These data c ombined the nasal squamous carcinoma data 15 of Kerns et al. (1983) and Monticello et al. (1996) along with results from an additional 16 94 animals not previously examined in the Monticell o et al. (1996) study. Animals in some 17 exposure groups were held up to 6 months following the 24-month exposure period; these 18 animals were deleted from the analysis for the foll owing reason: there were no tumors among 19 these animals, and inclusion of them would have req uired estimating an equivalent TWA 20 exposure over the entire study period for these ani mals (40 in 2 ppm group, 39 in 6 ppm group, 3 21 in 15 ppm group), whereas the other animals would b e represented by their actual exposure 22
concentrations. 23 Due to earlier tumor occurrence with increasing exp osure level and increased mortality 24 with increasing exposure level, methods that can re flect the influence of competing risks and 25 intercurrent mortality on site-specific tumor incid ence rates are preferred. EPA has generally 26 used the multistage Weibull model because it incorp orates the time at which death with tumor 27 occurred, giving appropriate weight to the amount o f time each animal was on study without a 28 tumor; the model has the following form: P(d) = 1 – exp[–(q 0 + q 1 d + q 2 d 2 + ... + q k d k ) × (t – t 0 ) z ], 29
where P(d) represents the lifetime risk (probability) of canc er at dose d (i.e., human equivalent 30This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-130 exposure in this case); parameters q i ≥ 0, for i = 0, 1, ..., k; t is the time at which the tumor was 1 observed; and z is a parameter estimated in fitting the model, whi ch characterizes the change in 2 response with age. The parameter t 0 represents the time between when a potentially fat al tumor 3
becomes observable and when it causes death. 4
A further consideration is the distinction between tumor types as being either fatal or 5 incidental in order to adjust for competing risks. Incidental tumors are those tumors thought not 6 to have caused the death of an animal (such as thos e observed during interim or terminal 7 sacrifices), while fatal tumors are thought to have resulted in animal death. For these data, nasal 8 tumors observed with early deaths were considered t o be fatal. 9 The dose-response analyses (Figures 5-17, 5-18, 5-1 9) were conducted by using the 10 computer software program TOX_RISK, version 5.3 (IC F, Fairfax, VA), which is based on 11 Weibull models drawn from Krewski et al. (1983). P arameters were estimated by using the 12 method of MLE. Specific multistage Weibull models were selected for the individual tumor 13 types for each sex, based on the values of the log likelihoods according to the strategy used by 14 EPA (U.S. EPA, 2002b). If twice the difference in log-likelihoods was less than a χ 2 with 15 degrees of freedom equal to the difference in the n umber of stages included in the models being 16 compared, the models were considered comparable, an d the most parsimonious model (i.e., the 17 lowest-stage model) was selected contingent on visu al fits of the data as follows. For incidental 18 tumors, plots of model fits compared with Hoel-Walb urg estimates of cumulative incidence were 19 also examined for goodness of fit in the lower expo sure region of the observed data (Gart et al., 20 1986) (Figure 5-18). For fatal tumors, plots of mo del fits were compared with KM estimates of 21
cumulative incidence. If a model with one more sta ge fitted the low-dose data better than the 22 most parsimonious model, then the model with one hi gher stage was selected. 23 Due to the sharp increase in responses between 6 an d 10 ppm, no adequate fit was 24 achieved. Data for the highest dose were dropped i n an effort to focus the fitting process for this 25 empirical model on the low-dose region. The model that then provided the best overall fit 26 included five stages but with coefficients for the lower stages estimated to be zero (see 27 Figures 5-17, 5-18, 5-19). The parameter t 0 was estimated to be zero, consistent with rapidly 28 fatal tumors. On the other hand, an alternate run treating all tumors as incidental to the death of 29 the affected animals yielded BMCLs and BMCs within 10% of these estimates (Figure 5-18); 30 thus, tumor context is not a sensitive consideratio n for these data. 31
For the same reasons as discussed in section 5.3.3 (the concluding discussion of the 32 BBDR modeling), a linear low-dose extrapolation app roach was used to estimate human 33 carcinogenic risk associated with formaldehyde expo sure. PODs for estimating low-dose risk 34
were identified at doses at the lower end of the ob served data, corresponding to 1% extra risk, 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-131 defined as the extra risk over the background tumor rate [P(d) − P(0)]/[1 − P(0)]. PODs 1 corresponding to 10% extra risk are also provided t o facilitate comparison with other chemicals. 2 Rat benchmark levels obtained by analysis of the tu mor data are shown in Table 5-25. PODs 3 were converted to continuous human-equivalent expos ure levels by multiplying by 4 (5 days/7 days) × (6 hours/24 hours), or 0.178, and by multiplying b y the ratio of fluxes 5 developed in section 5.3.6.1.3. The lifetime conti nuous inhalation unit risk for humans is defined 6 as the slope of the line from the lower 95% bound o n the exposure at the POD, calculated by 7 dividing the BMR level (1%) by the corresponding BM CL 01 . This 95% UCL represents a 8 plausible upper bound on the true risk. 9
10
11

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

0 2 4 6 8 10 12 14 16 Formaldehyde exposure (ppm)Proportion responding Kaplan-Meier adjusted incidence, from Schlosser et al. (2003) Multistage-Weibull estimate at 104 w eeks, omitting high dose from fit

12 Figure 5-17. EPA Multistage Weibull modeling: nasa l tumor dose response. 13 14 Note: Time-to-tumor modeling of Kerns et al. (1983) and Monticello et al. (1996) 15 data compared with incidences adjusted by using KM estimates evaluated at 16 104 weeks. 17 18 Source: Adapted from Schlosser et al. (2003). 19This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-132 1 Figure 5-18. Multistage Weibull model fit. 2 Note: Data of Kerns et al. (1983) and Monticello et al. (1996) compared with 3 Hoel-Walburg estimates of tumor incidences occurrin g at interim and terminal 4 sacrifices. 5 6 7

8 9 Figure 5-19. Multistage Weibull model fit of tumor incidence data compared 10 with KM estimates of spontaneous tumor incidence. 11 Source: Developed from data reported in Kerns et a l. (1983) and Monticello et al. 12 (1996). 13This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-133 The extrapolation to humans in terms of using forma ldehyde flux to tissue as the dose 1 metric is shown in Table 5-25, where unit risk in t erms of q1*, the statistical upper bound on the 2
coefficient of the term linear in dose in the multi stage model, is also presented. q1* is presented 3 even though this is no longer done, as per current EPA practice (see section 5.3.6 for discussion). 4 These results are to be compared with the preferred benchmark estimates obtained in 5 Table 5-23 by using the results of biologically bas ed models. In summary, the unit risks obtained 6 by various methods, including the results in Schlos ser et al. (2003), fall within a rather tight 7 range. In particular, q1* was obtained to within a factor of two of other values even though q1 8 itself was zero. The large difference between q1 a nd q1* aptly reflects the large uncertainty in 9 the low-dose response. 10
11 5.4. CONCLUSIONS FROM THE QUANTITATIVE ASSESSMENT OF CANCER RISK 12 FROM FORMALDEHYDE EXPOSURE BY INHALATION 13 14 5.4.1. Inhalation Unit Risk Estimates Based on Huma n Data 15 As described in section 5.2, a (plausible upper bou nd) lifetime extra cancer unit risk of 16
1.1 × 10 –2 per ppm (8.8 × 10 –6 per μg/m 3 ) of continuous formaldehyde exposure was estimated 17 for NPC incidence using the log-linear modeling res ults (for NPC mortality from cumulative 18 exposure) from a high-quality occupational epidemio logic study in a life-table analysis to obtain 19 a POD and then applying linear low-dose extrapolati on from the POD. Using similar methods 20 and data from the same study for Hodgkin lymphoma a nd leukemia mortality from cumulative 21 formaldehyde exposure, (plausible upper bound) life time extra cancer risk estimates of 1.7 × 10 –2 22 per ppm (1.4 × 10 –5 per μg/m 3 ) for Hodgkin lymphoma incidence and 5.7 × 10 –2 per ppm 23 (4.6 × 10 –5 per μg/m 3 ) for leukemia incidence were derived. Sources of uncertainty in these 24
estimates are discussed in sections 5.2.2.4 and 5.2 .3.4. For the incidence risk for these three 25 cancer types combined, a total (upper bound) cancer unit risk estimate of 8.1 × 10 −2 per ppm 26 (6.6 × 10 –5 per μg/m 3 ) was obtained (section 5.2.4). 27
28 5.4.2. Inhalation Unit Risk Estimates Based on Rod ent Data 29 As described in section 5.3, the unit risk derived for SCC in the upper and lower 30 respiratory tract (combined) based on linear extrap olation from PODs from several plausible 31 models, including purely statistical modeling (nose only, quantal and time-to-tumor modeling) 32 and biologically based modeling (entire respiratory tract), resulted in a narrow range of 1.2 × 10 −2 33
to 2.2 × 10 –2 per ppm. Risk to the lower respiratory tract was numerically insignificant compared 34
to the nasal cancer risk. 35This document is a draft for review purposes only a nd does not constitute Agency policy 5-134 DRAFT—DO NOT CITE OR QUOTETable 5-25. Human benchmark extrapolations of nasal tumors in rats by using formaldehyde flux and DPXRat benchmark levels(ppm) Extrapolated human benchmark levels (ppm) Unit riska(ppm)–1Model Source1%5%10%Dose metricb1%5%10%1%5%10%ED 0.75 0.78 0.82FluxeLED 0.71 0.76 0.791.4×10–26.6×10–21.3×10–1ED 0.76 0.79 0.84Weibullc,d(withthreshold)Schlosser etal. (2003)EDLED5.915.586.125.946.406.22DPXfLED 0.71 0.76 0.811.4×10–26.6×10–21.2×10–1ED 0.35 0.49 0.57EDLED4.283.575.935.526.846.41LED 0.30 0.46 0.533.4×10–21.1×10–11.9×10–1MultistageWeibull (timeto-tumor)c,d,gEPA (thisassessment)Fluxhq1* = 2.2×10–2at 1%: 2.2×10–2BBDR models(Table 5-23)EPA (thisassessment)See Table 5-23 and associated textat 0.5%: 1.2×10–2Note 1:Combined tumor incidence data from Kerns et al. (1983) and Monticello et al. (1996) were used for response.aSlope of straight line extrapolation from the POD of the dose-response curve at the 1, 5, and 10% extra risk level.bFlux: CFD modeling. DPX: CFD + PBPK modeling.cpValue for Weibull model fit = 0.90. For the time-to-tumor modeling, goodness-of-fitpvalue was not provided by software package; therefore, fit wasjudged by comparing fitted curve to KM survival estimates (see Figure 5-19).dFor Weibull model, Schlosser et al. (2003) obtainedbest fit with a positive intercept on dose axis.For multistage Weibull model, curves pass through origin.eHuman benchmark levels extrapolated using flux weremultiplied by fHCHO-Rat/fHCHO-Human(= 0.71) for interspecies extrapolation andmultiplied by (6/24) ×(5/7) to adjust for continuous exposure.fHuman benchmark levels using DPX were continuous environmental exposures that would result in steady-state DPX levels in humans equal to the weeklyTWA DPX levels in rats at the rat BMCs for 6 hours/day and 5 days/week.gP(d,t) = 1 - exp[-(q0+ q1d + q2d2+ ... + qkdk)* tz]. q0, q1, q2, q3, q4were all taken to be zero. q5= 2.9 × 10–22, z = 8.1.hHuman benchmark levels extrapolated using flux weremultiplied by fHCHO-Rat/fHCHO-Human= 0.46 for interspecies extrapolation and multiplied by (6/24) × (5/7)to adjust for continuous exposure (see section 5.3.6.2).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-135 5.4.3. Summary of Inhalation Unit Risk Estimates 1 The epidemiologic and rodent inhalation data indica te multiple sites of concern. Unit risk 2 estimates calculated separately from these data are presented in Table 5-26. 3 As can be seen in the summary table (Table 5-26), the unit risk estimate based on human 4 data for NPC is in the range of the estimates calcu lated for respiratory tract cancer from the 5
rodent nasal cancer data. The unit risk estimate f or Hodgkin lymphoma is also in the same range, 6
while the unit risk estimate for leukemia and the t otal cancer unit risk estimate are up to fourfold 7 higher. 8
9 Table 5-26. Summary of inhalation unit risk estimat es 10 11

Cancer type a Dose metric Unit risk estimate (ppm –1 ) Based on epidemiologic data Nasopharyngeal Cumulative exposure 0.011 Hodgkin lymphoma Cumulative exposure 0.017 Leukemia Cumulative exposure 0.057
Total cancer risk b Cumulative exposure 0.081 Based on experimental animal data
SCC of the respiratory
tract Local dose (flux) of

formaldehyde in pmol/mm 2

-

hour 0.011 – 0.022

12

a The unit risk estimates are all for cancer incidenc e. 13

b The total cancer unit risk estimate is an estimate of the upper bound on the sum of risk estimates cal culated 14 for the 3 individual cancer types (nasopharyngeal c ancer, Hodgkin lymphoma, and leukemia); it is not t he 15 sum of the individual (upper bound) unit risk estim ates (see Section 5.2.4). 16 17 18 As noted in EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), when 19 high-quality human data are available, they are gen erally preferred over laboratory animal data 20 for quantitative risk assessment. Thus, the prefer red (plausible upper bound) unit risk estimate in 21
this assessment is the value of 8.1 × 10 –2 per ppm (6.6 × 10 –5 per μg/m 3 ) based on human data for 22 NPC, Hodgkin lymphoma, and leukemia. 23 As documented in section 4.5, formaldehyde is a mu tagenic carcinogen and the weight of 24 evidence suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a 25 mutagenic MOA. Therefore, since there are no adequ ate chemical-specific data to evaluate the 26This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-136 susceptibilities of different life stages by the in halation route of exposure 14 , increased early-life 1 susceptibility should be assumed, and, if there is early-life exposure, the ADAFs should be 2 applied, in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from 3 Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 below for mo re 4 details on the application of the ADAFs. 5
6 5.4.4. Application of Age-Dependent Adjustment Fac tors (ADAFs) 7 When there is sufficient weight of evidence to conc lude that a mutagenic MOA is 8 operative in a chemical's carcinogenicity and there are inadequate chemical-specific data to 9 assess age-specific susceptibility, as is the case for formaldehyde (by inhalation exposure; see 10 section 5.4.3), U.S. EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 11 Exposure to Carcinogens (U.S. EPA, 2005b) recommends the application of de fault ADAFs to 12 adjust for potential increased susceptibility from early-life exposure (see U.S. EPA [2005b] for 13 detailed information on the general application of these adjustment factors). In brief, U.S. EPA 14 (2005b) establishes ADAFs for three specific age gr oups: 10 (for <2 years), 3 (for 2 to 15 <16 years), and 1 (for 16 years and above). For ri sk assessments based on specific exposure 16 assessments, the 10-fold and threefold adjustments to the unit risk estimates are to be combined 17 with age-specific exposure estimates when estimatin g cancer risks from early-life (<16 years age) 18 exposure. The ADAFs and their age groups may be re vised over time. The most current 19 information on the application of ADAFs for cancer risk assessment can be found at 20 www.epa.gov/cancerguidelines. 21 For inhalation exposures, assuming ppm equivalence across age groups (i.e., equivalent 22 risk from equivalent exposure levels, independent o f body size) and using the preferred unit risk 23
estimate of 6.6 × 10 –5 per μg/m 3 from section 5.4.3, the calculation is fairly strai ghtforward. The 24 ADAF-adjusted lifetime total cancer unit risk estim ate is calculated as shown in Table 5-27: 25
26 27 28 29 30

14 The oral exposure bioassay of Soffritti et al. (198 9) provides evidence of increased early-life suscep tibility for carcinogenicity at the portal of entry (i.e., gastr ointestinal tract cancers), but it is unclear how t o extrapolate the increased susceptibility quantitatively to portal-o f-entry cancers from inhalation exposures. There w as no apparent increased early-life susceptibility for hemolymphor eticular cancers; however, there are unresolved dis crepancies between the Soffritti et al. (1989) and the Soffrit ti et al. (2002) reportings of the hemolymphoreticu lar cancer results for the adult-only exposure component of the study which make interpretation of all of the hemolymphor eticular cancer results from the Soffritti et al. (1989) pap er uncertain (see Section 4.5).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-137 Table 5-27. Total cancer risk from exposure to a c onstant formaldehyde 1 exposure level of 1 μ g/m 3 from ages 0–70 years 2 3

Age group ADAF Unit risk (per μ g/m 3 ) Exposure

concentration ( μ g/m 3 ) Duration

adjustment Partial risk 0 to < 2
years 10 6.6 × 10 –5 1 2 years/70 years 1.9 × 10 –5

2 to < 16
years 3 6.6 × 10 –5 1 14 years/70
years 4.0 × 10 –5

≥ 16 years 1 6.6 × 10 –5 1 54 years/70
years 5.1 × 10 –5

Total risk = 1.1 × 10 –4
4 (Note that the partial risk for each age group is t he product of the values in columns 2–5 [e.g., 5 10 × (6.6 × 10 –5 ) × 1 × 2/70 = 1.9 × 10 –5 ], and the total risk is the sum of the partial ris ks. This 70-year risk 6 estimate for a constant exposure of 1 μ g/m 3 is equivalent to a lifetime unit risk of 7 1.1 × 10 –4 per μ g/m 3 , adjusted for early-life susceptibility, assuming a 70-year lifetime and constant exposure 8 across age groups.) 9 10 11 In addition to the uncertainties discussed above fo r the inhalation unit risk estimate, there 12 are uncertainties in the application of ADAFs to ad just for potential increased early-life 13 susceptibility. The ADAFs are general default fact ors, and it is uncertain to what extent they 14 reflect increased early-life susceptibility for exp osure to formaldehyde, if, in fact, early-life 15 susceptibility is increased as assumed. To some ex tent, the unit risk estimates for Hodgkin 16 lymphoma and leukemia already reflect some partial risk from early-life exposure because the 17 life-table programs include background rates for ch ildhood cancers. However, the impact of this 18 partial risk is negligible compared to the effect o f the ADAFs on the final risk estimate. For 19 example, eliminating the background rates up to age 16 from the life-table programs decreases 20 the lifetime extra risks at the PODs by about 0.5% for leukemia and about 1.2% for Hodgkin 21 lymphoma. The ADAFs, on the other hand, increased the lifetime unit risk estimate by about 22
66%. 23
24
5.4.5 Conclusions: Cancer Inhalation Unit Risk Es timates 25 As presented in section 5.4.3, the preferred (plau sible upper bound) cancer unit risk 26 estimate for formaldehyde exposure in this assessme nt is the total cancer risk estimate of 27
8.1 × 10 –2 per ppm (6.6 × 10 –5 per μg/m 3 ) based on (adult) human data for NPC, Hodgkin 28 lymphoma, and leukemia

. 29This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 5-138 In addition, as described in section 5.4.4, becaus e the weight of evidence suggests that 1 formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA and there 2 are inadequate chemical-specific data to assess age -specific susceptibility, increased early-life 3 susceptibility should be assumed and, if there is e arly-life exposure, ADAFs should be applied, in 4
accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 5 Exposure to Carcinogens (U.S. EPA, 2005b). Consequently, applying the ADA Fs to the 6 preferred unit risk estimate to obtain a full lifetime unit risk estimate yields 7
8 0.081/ppm × [(10 × 2 years/70 years) + (3 × 14/70) + (1 × 54/70)] 9

= 0.13/ppm = 1.1 × 10 –4 /( μ g/m 3 ) 10
11 Using the above full lifetime unit risk estimate o f 0.13 per ppm, the lifetime chronic 12 exposure level of formaldehyde corresponding to an increased cancer risk of 10 –6 can be 13 estimated as follows: (10 –6 )/(0.13/ppm) = 7.7 × 10 –6 ppm = 0.008 ppb = 0.009 μ g/m 3 . Similarly, 14 the lifetime chronic exposure level of formaldehyde corresponding to an increased cancer risk of 15
10 –4 is 0.8 ppb, or 0.9 μ g/m 3 . (Note that for less-than-lifetime exposures scen arios [or for 16 exposures that vary with age], the adult-based comb ined estimate of 0.081 per ppm should be 17 used, but if there is early-life exposure, the ADAF s should be applied in accordance with EPA’s 18 Supplemental Guidance [see section 5.4.4]). 19
20This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-1 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND 1 DOSE-RESPONSE 2 3 4 6.1 SUMMARY OF HUMAN HAZARD POTENTIAL 5
6.1.1 Exposure 6 Formaldehyde (CH 2 O) occurs as a gas at room temperature. It is high ly reactive and 7 dissolves readily in water. Formaldehyde is presen t in a wide variety of products including 8 plywood adhesives, abrasive materials, insulation, insecticides and embalming fluids (IPCS, 9 2002a; Agency for Toxic Substances and Disease Regi stry [ATSDR], 1999). The major sources 10 of anthropogenic emissions of formaldehyde are moto r vehicle exhaust, power plants, 11 manufacturing plants that produce or use formaldehy des or substances that contain formaldehyde 12 (i.e., glues), petroleum refineries, coking operati ons, incineration, wood burning, and tobacco 13 smoke (INEG, 2003). Reported outdoor air concentra tions of formaldehyde in urban and 14
suburban areas are near 3 μ g/m 3 (~ 3 ppb) (U.S. EPA, 2008) and indoor residential levels are 15 approximately 10 times higher (Health Canada and En vironment Canada, 2001). 16 Limited U.S. data indicate that the upper end of th e formaldehyde concentration range in 17 drinking water is approximately 10 μg/L IPCS, 2002a ). Formaldehyde is a natural component of 18 a variety of foodstuffs (IARC, 1995; IPCS, 1989). In addition, foods may also be contaminated 19 with formaldehyde as a result of fumigation (e.g., grain, seeds), cooking (as a combustion 20 product), and release from formaldehyde resin-based tableware (IARC, 1995). Limited data 21 measuring formaldehyde in food indicates that the c oncentration range is <0.03–14 mg/kg Health 22 Canada and Environment Canada, 2001). Daily intake of formaldehyde has been estimated to be 23 between 1.5 and 14 mg/day for an average adult (IPC S, 1989; Fishbein, 1992). 24
25
6.1.2 Absorption, Distribution, Metabolism, and Excretion 26 In water, less than 0.1% of formaldehyde exists un hydrated, with the majority reported to 27 be in the hydrated form, methylene glycol (CH 2 (OH) 2 ) (Priha et al., 1996). Formaldehyde is a 28
reactive molecule that can react with both low mole cular weight cellular components (e.g., GSH) 29 as well as high molecular weight components. It is also a well-known cross-linking agent. 30 Further, formaldehyde is a product of normal cellul ar metabolic processes. Endogenous 31 formaldehyde is a constituent of the one-carbon poo l. It is thought that most endogenous 32 formaldehyde exists in a form that is reversibly bo und to nucleophiles (Heck et al., 1990; 1982) 33 and that the formaldehyde hemithioacetal adduct for med with glutathione could account for 50– 34 80% of the total formaldehyde normally present in c ells (Heck et al., 1982). 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-2 Inhaled formaldehyde is efficiently absorbed (“scru bbed”) in the upper respiratory tract. 1
The fraction that is absorbed was determined to be approximately 97% in rats (Morgan et al., 2 1986), and 85% and 90% respectively in computer sim ulations of one rhesus monkey and human 3 at rest (Kepler et al., 1998; Kimbell et al., 2001) . As the inspiratory rate increased, formaldehyde 4 decreased to about 70% during light exercise and to 58% during heavy exercise conditions in the 5 human. During heavy exercise, the absorption of fo rmaldehyde in the first six to eight 6 generations of the tracheobronchial airways is esti mated to be comparable to that in the nasal 7 region (Overton et al., 2001). 8 Airway geometry is an important determinant of inha led-formaldehyde dosimetry in the 9 respiratory tract. There are large differences acr oss species in the anatomy of the upper 10 respiratory tract and in airflow patterns. Using c omputer simulation, the regional uptake patterns 11 of formaldehyde in the upper respiratory tract are observed to be spatially non-homogenous and 12 to exhibit strong species differences. Airflow pat terns are also significantly different as breathing 13 patterns and activity profiles change, depending on whether breathing is oral or nasal. 14 The overall information on the disposition of inhal ed formaldehyde comes from many 15 studies using different experimental methods includ ing: [ 14 C] radiolabeling, gas chromatography16 mass spectroscopy (GC-MS), dual isotope labeling ( 3 H, 14 C) and high-performance liquid 17 chromatography (HPLC) studies. In a study of rats following exposure to radiolabeled 18 formaldehyde, the radioactivity was very high in th e nasal mucosa but was also extensively 19 distributed to various tissues including the bone m arrow (Heck et al., 1983). The elevated 14 C in 20 various tissues was thought unlikely to be due to f ree formaldehyde but instead to arise from 21 either rapid metabolic incorporation or formation o f covalent adducts or incorporation via 22 carboxylation reactions of the 14 CO 2 formed during metabolism (Heck et al., 1983; Casano va23 Schmitz et al., 1984). Studies using the GC-MS met hod indicate that exposure to formaldehyde 24 over a wide range of exposure concentrations and du rations does not result in elevated levels in 25 blood, above those of endogenous formaldehyde level s in rats, rhesus monkeys and humans 26 (Heck et al., 1985; Casanova et al., 1998). These GC-MS measurements are consistent with the 27 conclusions that formaldehyde does not appreciably reach the blood, is rapidly metabolized, 28 interacts with macromolecules when it escapes metab olism, or is otherwise undetected. 29 In further studies on the disposition of inhaled fo rmaldehyde, Casanova-Schmitz et al. 30 (1984) and Casanova-Schmitz and Heck (1983) used du al-isotope labeling of inhaled 31 formaldehyde as an approach to distinguish between formaldehyde adduct formation and 32 metabolic incorporation. These were followed by mo re sensitive experiments using HPLC 33 measurements in rats and rhesus monkeys exposed to radiolabeled formaldehyde (Casanova et al. 34 1989, 1991). Results from this sets of experiments found that labeling in the nasal mucosa was 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-3 due to both covalent binding and metabolic incorpor ation and labeling of bone marrow 1 macromolecules was found to be entirely due to meta bolic incorporation. Overall, Heck, 2 Casanova-Schmitz, and their coworkers interpreted t he results of these experiments to indicate 3 that inhaled formaldehyde does not reach distant si tes (beyond the portal of entry) at detectable 4
levels. 5 Formaldehyde is primarily metabolized by glutathion e-dependent formaldehyde 6 dehydrogenase. In humans this enzyme is referred t o using the protein code of ADH3. The 7 major factor in the disposition of formaldehyde is metabolic clearance by oxidation to formate, 8
which is either further metabolized to CO 2 and water, incorporated into the one-carbon pool, 9
and/or eliminated in the urine as a sodium salt. 10 In radiolabeling studies, Heck et al. (1983) determ ined that the relative contributions of 11 various excretion pathways in F344 rats following i nhalation exposure to formaldehyde were 12 independent of exposure concentration. Nearly 40% of inhaled [ 14 C]-formaldehyde appeared to 13 be eliminated via expiration, presumably as CO 2 , while about 17% and 5% was eliminated in the 14 urine and feces, respectively. Nearly 40% of inhal ed [ 14 C]-formaldehyde remained in the 15 carcass, presumably due to metabolic incorporation. For exposure via the oral route, absorption 16 of [ 14 C]-formaldehyde (7 mg/kg) in rats resulted in 40% e xhaled (as 14 CO 2 ), 10% excreted in 17 urine, 1% excreted in feces, and much of the remain ing 49% retained within the carcass, 18 presumably due to metabolic incorporation (IARC, 19 95; Buss et al., 1964). 19 Several human and animal studies have attempted to measure the concentration of 20 formaldehyde in exhaled breath (see section 3.5.2). None of the human studies investigated 21 whether there is any correlation between exhaled fo rmaldehyde levels and food intake, life stage, 22 smoking, or health status. Additionally, they were not designed to distinguish between 23 exogenous (room air) and endogenous (systemic) form aldehyde in exhaled breath. In order to 24 discern whether endogenous formaldehyde is excreted into the lungs, human subjects must 25 breathe formaldehyde-free air. Because subjects we re breathing room air, which contained 9-10 26 ppb formaldehyde in two studies and unspecified con centrations in two other studies, there is no 27 way of knowing whether there was any endogenous for maldehyde in their exhaled breath. This 28
assessment identifies a critical research need for further studies on the measurement of exhaled 29 formaldehyde. 30 The most informative study, performed by Cáp et al. (2008), demonstrated that subjects 31 breathing room air containing 9.6 ±1.5 ppb formalde hyde exhaled a mean formaldehyde 32 concentration of 2 ppb. This suggests that a subst antial portion of inhaled formaldehyde, which 33 is highly reactive, was retained in the respiratory tract and not exhaled. It is impossible to tell 34 whether any portion of the 2 ppb in exhaled breath was of endogenous origin. In this and other 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-4 human studies, there was no adjustment for an artif act in the analytical method that makes it 1 impossible to distinguish between formaldehyde and reaction products for 1% of exhaled 2 methanol and ethanol because they have the same mas s to charge ratio ( m/z = 31). In fact, the 3
concentration of methanol and ethanol that is misid entified as formaldehyde exceeds the reported 4 concentrations of exhaled formaldehyde. Thus, it i s highly likely that the actual exhaled 5 formaldehyde concentration in Cáp et al. (2008) was significantly lower than 2 ppb, and that 6 there was little or no endogenous formaldehyde in t he exhaled breath. This would be consistent 7 with an animal study in which Mashford and Jones (1 982) detected no exhaled formaldehyde in 8 rats injected I.P. with 40 mg/kg [ 14 C]-formaldehyde. In summary, there are insufficien t data at 9 this time to confidently establish a concentration of formaldehyde in exhaled breath that can be 10 attributed to endogenous sources. 11
12
6.1.3 Noncancer Health Effects in Humans and Laboratory A nimals 13 A wide variety of human and animal studies provide evidence for health effects in 14 response to formaldehyde exposure. Some of these h ealth effects are commonly noted at the 15 portal of entry, as expected for exposure to a reac tive gas. In addition, effects on the nervous and 16 reproductive systems, developmental effects, and im munomodulation have been reported. The 17 overall weight of evidence (WOE) of human and anima l studies for the hazard potential of 18 formaldehyde is discussed below, along with informa tion on plausible modes of action (MOAs). 19
20
6.1.3.1. Sensory Irritation 21 Formaldehyde, a chemical irritant, binds to protein receptors of the trigeminal nerve, 22 triggering a burning and painful sensation in human s. This process is distinct from taste and 23 smell (Nielsen 1991; Cometto-Muniz and Cain, 1992). The trigeminal nerve, which has three 24 branches (ophthalmic, maxillary and mandibular), no t only acts as an afferent nerve relaying 25 these sensations to the central nervous system, but also has efferent nerve activity (Stedman’s 26 Medical Dictionary: Meggs, 1993). Stimulation of t he trigeminal nerve may result in reflex 27 responses including lacrimation, coughing, and snee zing. Both the reflex responses as well as 28 sensations such as burning, pain, and itching of th e eyes, nose, and throat are considered adverse. 29 Formaldehyde-induced eye, nose, and throat irritati on has been well documented in a 30 wide range of epidemiologic studies. Common effect s of chemically-induced sensory irritation 31 include lacrimation, burning of the eyes and nose, rhinitis, burning of the throat, and cough 32 (Feron et al., 2001). Studies examining these endp oints were either controlled chamber studies 33 with a defined population (e.g., healthy volunteers or sensitive individuals), worker/student 34 studies, or general population studies (e.g., resid ential). Chamber studies, by design, are acute 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-5 studies, although some researchers have investigate d the outcomes after repeated exposures. 1 Occupational, student, and residential exposures ar e generally of longer duration, although there 2 is variability in exposure level and duration among subjects. The endpoints for assessing 3 irritation include self-reporting of symptoms (e.g. , pain, burning, itching) and objective measures 4 of irritation (e.g., eye-blink counts, lacrimation)

. 5 Eye irritation is the most sensitive of reported ef fects in human studies. Two different 6 short-term chamber studies provide similar 10% BMDL s for eye irritation of 560 ppb and 240 7 ppb for 3 and 5 hour exposures, respectively (Kulle , 1993; Andersen and Molhave, 1983, 8 modeled by Arts et al., 2006b). Various occupation al studies have noted increased eye irritation 9 for average exposures ranging from 180 ppb to 690 p pb (Horvath et al., 1988, Alexandersson and 10 Hedenstiera, 1998; Holmstrom and Wilhelmsson, 1988) . The results of residential studies, 11 where in-home formaldehyde levels are used to docum ent exposure, indicate eye irritation may 12 increase with increasing exposure from 70 to 200 pp b for these chronic exposure scenarios 13 (Ritchie and Lehnen, 1987, Hanrahan et al., 1984; L iu et al., 1991.) 14 When a rodent is exposed to an irritant, the inhale d dose and pattern of deposition can be 15 profoundly affected by reflex bradypnea, a protecti ve reflex observed in rodents but not in 16 humans. Reflex bradypnea is manifest as markedly d ecreased activity or prostration, reduced 17 metabolism, hypothermia (as much as 5oC), significa ntly reduced respiratory rate and minute 18 volume, and altered blood and brain chemistry. Ref lex bradypnea can occur when the trigeminal 19 nerve is exposed to a sufficient concentration of a n irritant, such as formaldehyde. Because of 20 their small size, rodents are able to rapidly lower their metabolism and body temperature and 21 therefore their oxygen demand. The consequence is that their inhaled dose of an irritating 22 chemical is dramatically lowered. Reflex bradypnea is quantified as the RD 50 , which is the 23
concentration of a chemical that results in a 50% d ecrease in respiratory rate (Tables 4-7 and 24 4-8). After the irritant exposure is removed, it c an take up to two hours for rodents to fully 25 recover from the effects of reflex bradypnea. Even though humans do not exhibit reflex 26 bradypnea, involvement of trigeminal nerve stimulat ion, which is the mechanism for reflex 27 bradypnea in rodents, may be relevant to MOAs for f ormaldehyde in other species, such as 28 primates and humans. For example, trigeminal nerve stimulation has been associated with 29 sensory irritation in humans, highlighting the rele vance of this effect. 30
31
6.1.3.2. Respiratory Tract Pathology 32 Formaldehyde-induced respiratory tract pathology in cludes inflammation, rhinitis, goblet 33 cell hyperplasia, metaplastic changes, squamous cel l hyperplasia, and impaired mucociliary 34 transport. Formaldehyde binding to the trigeminal nerve triggers the release of neurogenic 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-6 mediators of inflammation resulting in tissue edema , lacrimation, mucus production, and 1 leukocyte infiltration. Therefore, observed pathol ogical changes may be directly related to 2 neurogenic inflammation from activation of the trig eminal nerve or result, at least in part, from 3 formaldehyde-induced cell damage to the mucosal tis sue. A series of exposures has also been 4 positively associated with reduced mucociliary clea rance, and the induction of histopathologic 5
lesions in the nose in both human and animal studie s assessing formaldehyde-induced changes in 6 the nasal mucosa suggest that these changes may be, at least in part, a protective or adaptive 7 response and that increased mucus flow and metaplas tic changes would progress in relation to 8 the concentration and duration of exposure protecti ng the underlying tissue (Swenberg et al., 9 1983). 10 In rodent studies, formaldehyde-induced histopathol ogical lesions ranging from 11 inflammation to ulceration, necrosis, and metaplasi a have been frequently reported in nasal 12 turbinates, maxilloturbinates, and in goblet and mi crovilli cells (e.g., Bhalla et al., 1991; 13 Monteiro-Riviere and Popp, 1986; Cassee and Feron, 1994; Ionescu et al., 1978; Schreibner et 14 al.,1979; Monticello et al., 1989). These effects were observed after a variety of exposure 15 scenarios (e.g., 10 ppm for 4 hrs (Bhalla et al., 1 991), 0.5 or 2 ppm for 6 hrs/day for 1 or 4 days 16 and 6 or 15 ppm for 6 hrs/day for 1 or 2 days (Mont eiro-Riviere and Popp, 1986), 3.6 ppm 17 intermittently for 3 days (Cassee and Feron, 1994), 3% aerosols of formaldehyde for 3 hrs/day for 18 50 days (Ionescu et al., 1978)). The progressive p athology of the nasal passages from 19 formaldehyde inhalation exposure is dependent on in creasing concentration and duration of 20 exposure, as well as from proximal to distal region s of the nasal cavity. For example, some 21 lesions may be transient (e.g., low-exposure cell p roliferation), while others may have a 22 maximum response and be irreversible (e.g., rhiniti s). The nasal epithelium responds with both 23 adaptive and adverse epithelial changes. As respir atory epithelium transitions to squamous 24 metaplasia, the effective tissue dose of formaldehy de increases posterior to these lesions. As 25 epithelial barriers degrade (e.g., squamous metapla sia, keratinization), formaldehyde penetrates 26 more deeply into the nasal passages. Therefore, th e relationship between concentration and 27 duration of exposure and health outcomes has been d ifficult to define and, in fact, may be 28 different for various health effects. Formaldehyde -related histopathological lesions of the nasal 29
mucosa have been observed at concentrations as low as 2 ppm for chronic exposure and after a 30 duration as short as 6 hrs at higher concentrations (e.g., 6 ppm) (Table 4-32, table 4-38). 31 Similar pathology has been reported for workers exp osed to formaldehyde, including loss 32 of cilia, goblet cell hyperplasia, and cuboidal and squamous cell metaplasia and dysplasia, and 33 these pathology scores were significantly elevated in workers over controls (Holmström and 34 Wilhelmsson, 1988; Edling et al., 1988; and Boysen et al., 1990). Holmström and Wilhelmsson 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-7 (1988) reported associations between the mean daily exposure of 240 ppb (8hr TWA) and these 1 changes. Edling et al. (1988) reported that worker s experienced a range of exposures (80-900 2 ppb), with peak exposures of 4000 ppb. Boysen et a l. (1990) provided a range of estimated 3 exposures from 500 ppb to more than 2000 ppb for wo rkers with elevated mean pathology 4 scores. One controlled chamber study indicated for maldehyde-induced inflammatory changes 5 which persisted for 18 hours in adults exposed at 4 00 ppb for only 2 hours (Pazdrak et al., 6 1993)). 7 Short-term formaldehyde exposure also impairs the f unction of the mucociliary apparatus 8 which is a critical defensive barrier for the upper respiratory tract. Numerous laboratory animal 9 studies have reported impaired mucociliary clearanc e activity associated with formaldehyde 10 exposures as low as 500 ppb (Table 4-10). Low-conc entration or short-term exposures first lead 11 to an increased rate of ciliary beat, followed by i mpaired mucus flow, with slowed rate of ciliary 12 beat and eventual mucostasis (lack of mucus flow) a nd ciliastasis (lack of ciliary beat) occurring 13 at higher doses or longer exposure times. These ef fects have been shown to be both 14 concentration- and duration-dependent and to occur within 15 minutes after the initial exposure. 15 Morgan et al. (1983c) suggested that the initial st imulation of ciliary activity may be a defensive 16 response to the irritant gas, at which time some pe netration of formaldehyde to the underlying 17 epithelial cells may occur. Later effects of mucos tasis and ciliastasis may occur as a result of 18 formaldehyde-induced glycoprotein cross-links, crea ting a rigid mucus that effectively stops 19
mucus flow. 20 Formaldehyde-induced cell proliferation has been de monstrated in nasal epithelium in 21 animal studies after a range of exposure conditions (e.g. Swenberg et al., 1986; Cassee and 22 Feron, 1994; Reuzel et al., 1990; Woutersen et al., 1987) (Table 4-43). Formaldehyde-induced 23 histopathology and mitogenesis may occur as a direc t effect of exposure (Tyihak et al., 2001) or 24 as a secondary effect resulting from adaptive respo nses and/or compensatory tissue repair that 25 can occur after formaldehyde exposure (Swenberg, 19 83). In a study of Rhesus monkeys 26 Monticello et al. (1996) noted that increased cell proliferation was seen in locations with minimal 27 histological changes in the respiratory tract indic ating that cell proliferation may be a more 28 sensitive predictor of more severe health effects d ue to formaldehyde exposure. Cellular 29 proliferative responses may initiate lesion formati on. A number of studies illustrate that the 30 duration of repeated exposures may be an important determinant of cell proliferation rates 31 (Wilmer et al., 1987; Swenberg et al., 1986). Redu ced mucociliary clearance and the induction 32 of histopathologic lesions in the nose effects have been noted in human formaldehyde studies. 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-8 Histopathological lesions and biochemical changes h ave been reported in the lung 1 following formaldehyde inhalation exposure in exper imental animal studies (Kamata et al., 2 1996a; Ionescu et al., 1978) following high exposur e levels (128.4 or 294.5 ppm formaldehyde). 3
6.1.3.3. Effects on Pulmonary Function 4 The potential of formaldehyde exposure to cause pul monary functional deficits in humans 5 has been examined on several time scales. The epid emiologic literature includes studies of acute 6 exposures among naïvely exposed anatomy graduate st udents (Kriebel et al., 1993; 2001), 7 anatomy graduate students with several weeks of epi sodic exposure (Kriebel et al., 1993), and 8 post-shift versus pre-shift worker pulmonary functi on among those with regular occupational 9 exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1982; 10 Alexandersson and Hedenstierna, 1989). Depending o n whether the exposures are naïve or not, 11 the epidemiologic studies that assessed the pulmona ry effects after acute exposures to 12 formaldehyde are assessing different biological res ponses, namely, the acute effect alone or the 13 acute effect(s) in people who may have already been sensitized to different and unknown 14 degrees. 15 The observed effects in the previously unexposed an atomy students provide additional 16 information on acute exposures in two naïve populat ions (Kriebel et al., 1993; 2001), as well as 17 insight into the possible intermediate stages of se nsitization (Kriebel et al., 1993). Kriebel and 18 colleagues (1993) examined the pre-laboratory and p ost-laboratory peak expiratory flow (PEF) in 19 students attending anatomy classes once a week. Th ey found the strongest pulmonary response 20 when examining the average cross-laboratory decreme nt in peak expiratory flow in the first 2 21 weeks of the study when formaldehyde concentrations collected in the breathing zones had a 22 geometric average concentration of 0.73 ppm. Overa ll, the students exhibited a 2% decrement in 23 PEF, while the students with any history of asthma showed a 7.3% decrement in PEF. These 24 findings of acute decreases in PEF following studen ts’ initial formaldehyde exposure were 25 corroborated by the Kriebel et al. (2001) study, us ing a similar study design applied to a separate 26 class of anatomy students. Similar findings have b een reported for low-level residential 27 formaldehyde exposure including decreased peak expi ratory flow rates (PEFRs) (Krzyzanowski 28 et al., 1990). Workers chronically exposed to form aldehyde have exhibited signs of reduced lung 29 function consistent with bronchial constriction, in flammation, or chronic obstructive lung 30 disease. Lung function deficits have been reported both in pre-shift versus post-shift 31

measurements and as a result of chronic exposures (Malaka and Kodama , 1990; Herbert et al., 32 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and Hedenatiena 33 1989). Decreases in spirometric values, including vital capacity (VC), forced expiratory volume 34 (FEV), forced vital capacity (FVC) and FEV/FVC have been reported in humans. Chronic 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-9 studies also reported increased respiratory symptom s such as cough, increased phlegm, asthma, 1 chest tightness and chest colds in exposed workers (Malaka et al., 1990; Herbet et al., 1994; 2 Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and Hedenatiena 1989). 3 Similar findings have been reported following low- level residential formaldehyde exposure 4 including decreased PEFRs (Krzyzanowski et al., 199 0). 5 Worker exposures associated with cross-shift differ ences in spirometric values are 6 consistent with formaldehyde-induced sensory irrita tion. Concordance has also been reported 7 between subjective irritant response and measured c hanges in pulmonary function further 8 supporting the possibility that cross-shift and sho rt-term evidence of bronchial constriction may 9 be a reflexive response to sensory irritation. 10 A well-conducted residential epidemiology study by Krzyzanowski et al. (1990) was 11 considered to be the strongest among the candidate studies on the adverse pulmonary function 12 effects of formaldehyde for the purposes of derivin g an RfC. 13
14
6.1.3.4. Asthmatic Responses and Increased Atopic Symptoms 15 The health effects of respiratory function, asthma and increased atopic response, have 16 been shown to be clinically related. For example, asthma affects pulmonary function and may be 17 triggered by an allergic response. These and other data suggest that there may be mechanistic 18 links between these two health effects. Formaldehy de-induced sensitization (Section 4.2.1.5) 19 may enhance the asthmatic response or may enhance a n individual’s response to an allergen 20 (Section 4.4). In both cases, sensitization result s in phenotypic switching – or an individual 21 exhibiting clinical symptoms of a predisposition to asthma or atopy. Because of the connection 22 between the two endpoints, they are considered toge ther herein. 23 Several cross-sectional studies have described a po sitive association between 24 formaldehyde concentration and asthma prevalence. A study on risk factors for the initial 25 physician diagnosis of asthma have shown concentrat ion-dependent associations between 26 formaldehyde exposure and asthma (Rumchev et al., 2 002). In a categorical analysis, Rumchev 27 et al. (2002) observed statistically significant ef fects above in-home formaldehyde concentrations 28
of 60 μ g/m 3 , with increased but non-significant effects at 50- 59 μ g/m 3 that were consistent with a 29 concentration-response relationship. No effect was apparent at concentrations in the next lower 30
interval between 30-49 μ g/m 3 . Garrett et al. (1999) reported a borderline stat istically significant 31 association between bedroom formaldehyde concentrat ions and an increased risk of atopy. The 32 authors computed a respiratory symptom score for ea ch child based on the frequency of each of 33 eight respiratory symptoms and this score was subst antially and statistically significantly higher 34 among the asthmatic children compared to non-asthma tic children. Health effects were reported 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-10 at formaldehyde concentrations greater than 50 μ g/m 3 but the lowest formaldehyde concentration 1
interval at which health effects were observed was 20-50 μ g/m 3 . The findings of Garrett et al. 2 (1999) are supported by the results of a chamber st udy reported by Casset et al. (2006) of 19 3 sensitized adult asthmatics exposed to formaldehyde at a concentration of 100 μ g/m 3 for 30 4 minutes. Casset and colleagues observed an increas ed bronchial responsiveness to mite allergen 5 exposure (p = 0.05) and noted the provocative dose (PD20 for FEV1) for mite allergen was 34.3 6 ng after formaldehyde exposure and 45.4 ng after ai r exposure. However, in study by Ezratty et 7 al. (2007) exposure to 500 μg/m 3 formaldehyde did not affect an allergen-induced in crease in 8 responsiveness to methacholine (p = 0.42) and there was no formaldehyde-associated effect on 9 the airway inflammatory response. 10
These observed health effects in humans are similar to the outcome of studies in 11 laboratory animals that show that formaldehyde can exacerbate existing immunogenic 12 hypersensitivity to known allergens (Sadakane et al ., 2002; Tarkowski and Gorski, 1995; Riedel 13 et al., 1996). While potentiation varied based on sensitization protocols and formaldehyde 14 exposure regimens, the results support the finding that formaldehyde exposure can aggravate a 15 Type-I hypersensitivity response and may do so via a neurogenically initiated response. 16 Formaldehyde itself does not function as an allerge n recognized by the immune system (Lee et 17 al., 1984) and does not appear to trigger formation of formaldehyde-specific IgE. Although 18 formaldehyde exposure has been reported to alter cy tokine levels and immunoglobulins in some 19 experimental systems (Fujimaki et al., 2004a; Ohtsu ka et al., 2003), these effects do not support 20 an immunogenically mediated type-I hypersensitivity . In studies in which either egg protein 21 (ovalbumin, OVA)-sensitized or dust mite (DerF)-sen sitized animals were exposed to 22 formaldehyde, OVA-specific and DerF-specific antibo dy production was increased over 23 sensitization alone, suggesting that formaldehyde m ay potentiate sensitization responses (Riedel 24 et al., 1996; Sadakane et al., 2002). Formaldehyde -induced sensitivity responses may be 25 neurogenic in origin based on findings that neuroge nic factors such as nerve growth factor (NGF) 26 and substance P were associated with formaldehyde e xposure in sensitization protocols 27 (Fujimaki et al., 2004). 28
29
6.1.3.5. Effects on the Immune System 30 Formaldehyde-induced systemic immunomodulation in l aboratory animals has been 31 documented in the literature (Leach et al., 1983; D ean et al. 1984; Adams et al., 1987). A 32 number of studies have evaluated the ability of for maldehyde to induce systemic immunotoxic 33 effects in humans (Ohtani et al., 2004a, b; Erdei e t al., 2003; Thrasher et al., 1990, 1987; Pross et 34 al., 1987). Some studies have reported altered inn ate immune responses associated with 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-11 formaldehyde exposure (Erdei et al., 2003), while o thers have noted adaptive immune response 1 suppression associated with formaldehyde exposure ( Thrasher et al., 1990, 1987) and changes 2 associated with alterations to a predominant T—lymp hocyte helper 2 (Th2) pattern (Ohtani et al., 3 2004a, b). In contrast, Pross et al. (1987) did no t observe formaldehyde-associated changes in 4 systemic immune function. 5 Diverse studies have investigated the possibility t hat formaldehyde exposure leads to 6 increased respiratory tract infections (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness 7 and Nethercott, 1989). Lyapina et al. (2004) repor ted increased respiratory tract infections and 8 decreased neutrophil respiratory burst activity in formaldehyde-exposed workers (at 722 ppb 9 TWA). Incidences of doctor-diagnosed chronic bronc hitis were more prevalent in children under 10 age 15 living in homes with higher formaldehyde (>6 0 ppb) readings in the kitchen ( p < 0.001) 11 (Krzyzanowski et al., 1990). Holness and Nethercot t (1989) also report increased chronic 12 bronchitis in formaldehyde-exposed funeral workers (380 ppb average exposure). 13
14
6.1.3.6. Neurological Effects 15 Formaldehyde exposure via inhalation has been shown to adversely impact nervous 16 system function in laboratory animals and humans, a lthough human data for formaldehyde17 induced neurological effects are limited. Studies in formaldehyde-exposed histology technicians 18 provide evidence of neurological impairment, includ ing lack of concentration, impaired memory, 19 disturbed sleep, impaired balance, variations in mo od and irritability. These effects were 20 significantly correlated with increasing duration o f exposure to formaldehyde, but the findings 21 are not conclusive due to confounding by concomitan t exposures to other neurotoxic solvents 22 (Kilburn et al., 1985, 1987). In a prospective stu dy, Weisskopf et al. (2009) found a strong 23 association between duration of formaldehyde exposu re and death from amyotrophic lateral 24 sclerosis (ALS), but information regarding exposure levels was not available. Short-term studies 25 with controlled exposure to humans (chamber studies ) also provide limited support for changes 26 in cognitive function immediately following a singl e, controlled formaldehyde exposure (Bach et 27 al., 1990; Lang et al. 2008). 28 Available animal data provide substantial evidence of behavioral changes in animals 29 following single or short-term repeated inhalation exposures to relatively low levels of 30 formaldehyde. Among the animal studies, none of th e available studies examined effects on 31 nervous system function following chronic formaldeh yde inhalation, however. 32 Reported perturbations in nervous system function f ollowing formaldehyde exposure in 33 animal studies include reductions in motor activity , lack of habituation, impairment in 34 acquisition of a new learning task, deficits in ret ention of a previously learned task, increases in 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-12 corticosterone levels, sensitization to cocaine-ind uced locomotor activity, and enhanced fear 1 conditioning using an olfactory conditioned stimulu s (CS) (see Table 4-57). Behavioral effects 2 have been seen in multiple laboratories and in stud ies conducted by different investigators using 3 a variety of testing paradigms. Many of these effe cts were observed at acute exposure levels at or 4 below 1.0 ppm, and some persisted days to weeks aft er termination of exposure. 5 More limited data indicate possible effects on the development of the nervous system, 6 including changes in brain structure and in the beh avior of offspring (Table 4-57). Similarly, 7 there is very little information regarding the mech anism by which effects on the nervous system 8 might be produced. The data regarding behavioral s ensitization provide some support for a 9 stress-related mechanism for those specific finding s, but the applicability of this mechanism to 10 the behavioral changes seen in the other studies, i ncluding the learning deficits and 11 developmental findings, has not been evaluated. Al though there are data supporting stimulation 12 of the trigeminal nerve by formaldehyde (and docume nting the relevance of this interaction to the 13 sensory irritation caused by formaldehyde), there a re no data supporting a causal relationship 14 between irritant properties of formaldehyde and the behavioral and neurodevelopmental effects 15 in humans that occur following formaldehyde exposur e. In summary, none of the available data 16 provide sufficient information to allow a determina tion of the mode of action for effects of 17 formaldehyde on the adult or developing nervous sys tem. 18
19
6.1.3.7. Reproductive and Developmental Effects 20 Formaldehyde inhalation exposure has been associate d with adverse developmental and 21 reproductive outcomes in both epidemiologic studies and experimental animal studies. Observed 22 developmental outcomes include fetal loss, structur al alterations, growth retardation, and delays 23 in functional development. 24 Several occupational studies found an increased ris k of spontaneous abortions among 25 formaldehyde-exposed women (Taskinen et al., 1999, 1994; John et al., 1994; Seitz and Baron, 26 1990; Axelsson et al., 1984). The Taskinen et al. (1999) study examined several reproductive 27 outcomes in women employed in the wood-processing i ndustry, with a range of average daily 28 formaldehyde exposures. The authors found that for maldehyde was associated with a more than 29 three-fold increased risk of spontaneous abortion, and with a nearly 50% decrease in a measure 30 of delayed conception indicating reduced fertility, an increased time to pregnancy, and an 31 increased risk for endometriosis in this study. In experimental animal studies, early fetal death 32 was noted following maternal formaldehyde exposures (Kitaev et al., 1984; Sheveleva, 1972), 33 supporting the epidemiologic findings that the spon taneous abortion is likely related to 34 formaldehyde exposure. Kitaev et al. (l984) hypoth esized that formaldehyde may affect 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-13 reproductive function by stimulating the hypothalam us-pituitary-gonadal (HPG) axis, based on 1 their observations of increased ovary weight, incre ased number of ovulating cells, and changes in 2 blood levels of gonadotropins (LH and FSH) in femal e rats. Additionally, Maronpot et al. (l986) 3 reported endometrial hypoplasia with a lack of ovar ian luteal tissue in formaldehyde-exposed 4 female rats. This finding may be relevant to the i ncreased risk for endometriosis noted in the 5 Taskinen et al. (1999) study. However, additional human and animal studies are needed to better 6 understand the effects of inhalation exposure to fo rmaldehyde on developmental outcomes after 7 early gestational windows of exposure or on the fem ale reproductive system. 8 The findings of some occupational studies have sugg ested formaldehyde-related 9 associations with congenital malformations and low birth weight. In numerous experimental 10 animal studies, developmental effects have been not ed following inhalation exposures to 11 formaldehyde (Table 4-68). Exposure of rat dams to formaldehyde during pregnancy has been 12 shown to result in significantly decreased fetal we ight gain (Martin, 1990; Saillenfait et al., 1989; 13 Kilburn and Moro, 1985). Other studies have noted changes in relative organ weight, 14 undescended testes, biochemical changes (e.g., asco rbic acid), and blood acidosis (Senichenkova 15 and Chebotar, 1996; Senichenkova, 1991; Kilburn and Moro, 1985; Gofmekler and 16 Bonashevskaya, 1969; Gofmekler, 1968; Pushkina et a l., 1968). 17 Studies designed to assess adult male reproductive system toxicity in rats following 18 repeated inhalation exposures to formaldehyde have found concentration-dependent decreases in 19 Leydig cell number and quality, degeneration of sem iniferous tubules, decreases in testes weight, 20 alterations in sperm measures, decreased testostero ne levels, alterations in trace metals in the 21 testes, and/or dominant lethal effects (Guseva, 197 2; Özen et al., 2002, 2005; Sarsilmaz et al., 22 1999; Xing et al., 2007; Zhou et al., 2006) (Table 4-71). 23
24
6.1.3.8. Effects on General Systemic Toxicity 25 Extrapulmonary effects such as changes in liver fun ction enzymes and focal, chronic 26 inflammation in the heart and kidney have been obse rved due to formaldehyde exposure in 27 experimental animal studies. Most of these changes occurred at exposures of 20 ppm, and those 28 that occurred at lower formaldehyde exposures (3.7 ppm) were confounded by coexposures. The 29 underlying modes of action of liver, kidney, and ca rdiac effects have not been elucidated, and the 30
human relevance is unknown. 31
32
33
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6.1.3.9. Summary 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-14 Formaldehyde-induced eye, nose and throat irritatio n, decreased pulmonary function, 1 decreased mucociliary clearance and histopathologic al lesions have been extensively documented 2 in human and laboratory animal studies. These heal th effects are commonly noted at the portal 3 of entry as expected for exposure to a reactive gas . In addition, effects on immune system 4 responses and on the nervous and reproductive syste ms, including developmental effects, have 5 also been reported. An association between formald ehyde exposure and increased incidence and 6 severity of response to allergens (i.e., asthma and atopy) has been noted in humans. This effect, 7 which has also been studied in laboratory animals, might occur via a neurogenic mode of action. 8
A limited database of information that evaluates ne urological effects in humans following 9 formaldehyde exposure demonstrates a potential for adverse outcomes, and studies in laboratory 10 animals have reported a variety of formaldehyde-ind uced neurobehavioral and 11 neurodevelopmental effects. Formaldehyde has also been associated with adverse reproductive 12 outcomes. Human studies have reported an associati on between formaldehyde exposure and 13 decreased fertility as well as an increased risk of spontaneous abortions. Other human studies 14 have suggested formaldehyde-related associations wi th congenital malformations, low birth 15 weight, and endometriosis. Animal studies have not ed a variety of developmental effects, 16 including fetal death, structural alterations, and growth retardation (e.g., delayed fetal skeletal 17 ossification and decreased fetal body weight) follo wing inhalation exposure to formaldehyde, and 18 adverse reproductive effects have been observed in both males and females. 19
20
6.1.4 Carcinogenicity in Humans and Laboratory Animals 21
6.1.4.1 Carcinogenicity in Humans 22 Based on the total weight of evidence, including th e results from a large and well23 followed longitudinal cohort study of 25,619 indust rial workers and several case-control studies, 24 the epidemiologic evidence is sufficient to charact erize the association between formaldehyde 25 nasopharyngeal cancer as causal in humans (Hauptman n et al., 2004; Hildesheim et al., 2001; 26 Vaughan et al., 2000). As further evaluated below, the evidence supporting a positive association 27 between formaldehyde exposure and NPC is unlikely d ue to chance, bias or confounding. 28 However, it should be noted that other smaller stud ies of formaldehyde-exposed workers did not 29 document increased NPC mortality (e.g., Coggon et a l., 2003; Pinkerton et al., 2004). These 30 smaller study sizes yielded effect estimates with w ide confidence intervals that were not 31 statistically inconsistent with the increased risk of mortality from nasopharyngeal cancer reported 32 in Hauptmann et al. (2004). 33 Luce et al. (2002) evaluated pooled data from 12 ca se-control studies conducted in seven 34 countries using a common job-exposure matrix and de monstrated a statistically significant 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-15 increased risk between formaldehyde exposure and si nonasal cancer exhibiting a concentration1 response relationship providing further causal evid ence of carcinogenicity. This analysis was 2 based on a very large dataset of 930 cases and 3136 controls, enabling the investigators to control 3 for multiple potential sources of bias and confound ing and to conduct separate analyses by 4 histological type. These results are particularly convincing, as the association was consistently 5 seen for a rare sub-type of sinonasal cancer which normally accounts for only 10% of the 6 reported cases. 7 In addition to the evidence of formaldehyde carcino genicity in the nasopharynx, nose and 8 sinuses, other upper respiratory tract sites of dir ect contact with formaldehyde upon inhalation 9 (i.e., larynx, mouth and salivary gland) also showe d evidence of increasing relative risk with 10 increasing average intensity and peak exposure in a large cohort study with exposure estimates 11 for the individual workers, although these trends d id not reach the level of statistical significance 12 (Hauptmann et al., 2004). However, Hauptmann and c olleagues (2004) concluded that in spite of 13
the small numbers of deaths from these rare cancers of the upper respiratory tract, the positive 14
associations of increased cancer risk with increase d formaldehyde exposure were consistent with 15 the carcinogenicity of formaldehyde at these sites of first contact. Case-control studies also 16 provide evidence of an association between formalde hyde exposure and oral squamous cell 17 carcinoma (SCC), esophageal, and laryngeal cancers, and hypopharyngeal cancer (Gustavsson et 18 al., 1998; Laforest et al., 2000.) 19 The finding that formaldehyde inhalation causes nas al squamous cell carcinoma in 20 rodents (Section 4.2.1.2) further supports the dete rmination of a causal association of 21 formaldehyde exposure and increased risk of upper r espiratory tract cancer in humans. Both 22 humans and animals developed tumors within the uppe r respiratory tract, the site expected to 23 receive direct exposure to formaldehyde. 24 Several researchers have argued that the relationsh ip between formaldehyde exposure and 25 nasopharyngeal cancer based on existing studies has not been determined. Several limitations, 26 such as the rarity of the cancer and the imprecise estimates of exposure, are often inherent in 27 epidemiologic methods and exposure assessment. The se constraints limit the ability of 28 epidemiologic studies to statistically detect assoc iations and can lead to false negatives. The 29 results of the largest cohort study of nasopharynge al cancer (Hauptmann et al., 2004) showed 30 statistically significant concentration-response re lationships with increased risk of cancer 31 associated with increased formaldehyde exposure. H owever, even though this study was based 32 on 25,619 workers, only 9 cases of nasopharyngeal c ancer were observed, compared to an 33 expected number of 5 cases, for a relative rate of 2.1 (with a confidence interval of 1.05 - 4.21) 34 (Hauptmann et al., 2004). 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-16 The next largest cohort study of nasopharyngeal can cer was based on 14,014 workers 1 (Coggon et al., 2003) and reported only 1 case comp ared to an expected number of 2 cases, for a 2 relative risk of 0.5 (with an estimated 95% confide nce interval of 0.07 − 3.55; see Bosetti et al., 3 2007). To put this finding into perspective, it is helpful to note not only the relative risk but als o 4 that this effect estimate is highly unstable due to a lack of statistical power. The large width of 5 this interval (0.07 − 3.55) indicates that the rang e of possible true values includes both increased 6 and decreased NPC mortality and therefore does not contradict the evidence of elevated risk of 7 nasopharyngeal cancer mortality associated with for maldehyde exposure reported by Hauptmann 8 et al. (2004). The even smaller study of 11,039 te xtile workers by Pinkerton et al. (2004) 9 reported no cases of nasopharyngeal cancer compared to an expected number of one case − 10 yielding an effective relative risk of zero with a highly unstable 95% confidence interval 11 estimated at 0 − 3.00 (see Bosetti et al., 2007). While true that Pinkerton et al. (2004) did not 12 report an increased risk of nasopharyngeal cancer, this study did not have sufficient statistical 13 power to rule out a true association with less than a 3-fold increase in risk and therefore is 14 likewise not inconsistent with the finding by Haupt mann et al. (2004). Thus, results from these 15 cohort studies, with limited power to detect the re latively rare upper respiratory tract cancers 16 (e.g., NPC), are given less weight in the overall e valuation. 17 The largest occupational cohort study, conducted by the NCI (Hauptman et al., 2004), did 18 report statistically significant associations of fo rmaldehyde exposure with carcinogenicity at the 19
sites of first contact with sufficient statistical power to rule out the null hypothesis of no 20 association. The NCI investigations controlled for potential selection bias due to the healthy 21 worker effect and for several potential confounders , including calendar year, age, sex, race, and 22 pay category. However, other potential sources of bias or confounding have been suggested with 23 respect to the strength of these data to support a causal conclusion. 24 Following reports of increased risk of NPC associat ed with formaldehyde exposure, a 25 series of analyses of similar data were undertaken by Marsh and coworkers (Marsh et al., 2007a, 26 b, 2002, 1996; Marsh and Youk, 2005). Briefly, the se studies focused on the specific findings 27 from a single plant in the NCI cohort (Wallingford, Connecticut) that generated the majority of 28 the NPC cases. Marsh et al. (1996) confirm a signif icant adverse association of formaldehyde 29 with nasopharyngeal cancer but note the effects are predominantly among workers at the 30 Wallingford plant with less than one year employmen t. Marsh et al. (2002) report a five-fold 31 excess in risk of nasopharyngeal cancer associated with formaldehyde in both short-term and 32 long-term workers but note that the increase was co ncentrated among workers hired during 1947- 33 1956. Marsh and Youk (2005) re-evaluated the same Wallingford workers and reported a 34 regional rate-based standardized mortality ratio (S MR) of 10.32 (95% CI = 3.79 − 22.47) 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-17 compared to 0.65 (95% CI = 0.08 − 2.33) for workers at the nine other plants combined. 1 However, Marsh and Youk (2005) also show that rate- based mortality ratios standardized to both 2 U.S. and local populations were elevated (non-signi ficantly) not only at the Wallingford plant but 3 individually at each of the four other plants at wh ich a single case of nasopharyngeal cancer was 4 reported: Plant 2 (SMR US = 5.35), Plant 3 (SMR US = 1.99), Plant 7 (SMR US = 1.06), and Plant 10 5 (SMR US = 1.44). It should be noted that Plant 1 (Wallingf ord) and Plant 2 had both the two 6 highest median formaldehyde exposures and the two h ighest reported excess risks (Marsh and 7 Youk, 2005). 8 In another re-analysis of the NCI cohort data on th e workers at the Wallingford plant, 9 Marsh and coworkers (2007a) suggested that an impre cise assessment of formaldehyde exposure 10 and an inability of the study to separate formaldeh yde exposure from other potential chemical or 11 particulate exposures may have confounded the obser ved association between formaldehyde and 12 cancer. However, there was no evidence of any diff erential measurement error that could have 13 produced the observation of a spurious association. Any non-differential exposure measurement 14 error (i.e., random error in the exposure assessmen t) would likely have led to an attenuated 15 observed effect of formaldehyde that was less than that which would otherwise have been 16
observed in the absence of measurement error. 17 The potential for confounding by particulates was e xplicitly examined by Hauptmann et 18 al. (2004) and it was shown that there was an expos ure-response relationship with formaldehyde 19 among individuals with high particulate exposures – alleviating the potential for confounding and 20 thereby strengthening the causal interpretation of the formaldehyde relationship with an increased 21 risk of NPC. Marsh and coworkers (Marsh et al., 20 07b) later suggested the reported 22 formaldehyde association was confounded by an assoc iation between silversmithing and NPC. 23 However, careful examination of that analysis (Mars h et al., 2007a) suggests that multiple 24 comparisons may have led to the reported observatio n with silversmithing. Additionally, the 25 reported effect was inconsistently reported between the results and the abstract sections using 26 different confidence intervals, and both sets of co nfidence intervals around the reported 27 association were extremely unstable spanning up to several hundred-fold. No prior studies 28 identified an associated between silversmithing and NPC. Thus it may be that silversmithing is 29 an artifactual potential confounder. 30 The increased NPC mortality observed in the NCI coh ort (Hauptmann et al., 2004) has 31 been thoroughly examined for sources of bias and co nfounding by both the primary researchers 32 and Marsh and coworkers (Marsh et al., 2007a, b, 20 02, 1996; Marsh and Youk, 2005). Despite 33 the extensive scrutiny of these results, no convinc ing and consistent alternative hypothesis of 34 causation has been identified. Taken together with the statistically significant association 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-18 demonstrating an exposure-response relationship wit hin exposed workers, these data support the 1 conclusion that the association between formaldehyd e exposure and increased risk of NPC is 2
causal. 3 Therefore, after a thorough examination of potentia l confounders, the association between 4 formaldehyde exposure and NPC mortality in the NCI cohort remains significant and provides a 5 positive exposure-response relationship. Additiona lly, case-control studies, which have greater 6 statistical power than cohort studies for rare dise ases, provide strong additional evidence in 7 support of a causal association between formaldehyd e exposure and the incidence of NPC 8 (Hildesheim et al., 2001; Vaughan et al., 2000). A s these studies draw from different 9 demographic groups, regions of the world, and evalu ate various confounding factors, there is 10 little potential for these consistently reported as sociations to be artifactual, confounded by 11 common exposures, or a result of bias or chance. 12 Numerous epidemiologic studies have also reported a n association between 13 formaldehyde-exposed workers, especially "professio nal" workers (e.g., pathologists, embalmers, 14 and funeral directors), and increased risk of lymph ohematopoietic cancers (See Table 4-82). 15 Positive associations between formaldehyde exposure and lymphohematopoietic cancers have 16 been reported for chemical workers (Wong et al., 19 83; Bertazzi et al., 1986), embalmers 17 (Walrath and Fraumeni, 1983, 1984; Hayes et al., 19 90), anatomists and pathologists (Harrington 18 and Shannon 1975; Hall et al., 1991; Levine at al., 1984; Stroup et al., 1986; Matanoski et al., 19 1989). However, clear associations (in terms of ov erall standardized mortality ratios (SMRs) or 20 proportional mortality ratios (PMRs) were not repor ted in analyses for garment workers, iron21 foundry workers, and a large US industrial cohort ( Pinkerton et al., 2004; Andjelkovich et al., 22 1995; Beane Freeman et al., 2009; Marsh et al., 199 6), although associations were observed in 23 some of these studies when exposure-response relati onships were considered. Several published 24 meta-analyses are available which more formally ass ess the strength of association between 25 formaldehyde exposure and mortality from all lympho hematopoietic cancers. Pooled SMRs 26 indicate stronger associations for professional wor kers (embalmers, anatomists and pathologists) 27 than industry workers (Table 4-83). Bosetti et al. (2008) found similar relationships, with a 28 pooled SMR of 1.31 (95% CI 1.16-1.47) for ‘professi onals’ (i.e. embalmers, anatomists and 29 pathologists) versus a pooled estimate of 0.85 (95% CI 0.74-0.96) for industrial workers. A 30 recent meta-analysis by Zhang et al. (2009) reports a summary relative risk of 1.25 (95% CI 1.09- 31 1.43) for both professional and industry workers fo r all lymphohematopoietic cancers (ICD 9 32 codes 200-209). 33 Two well-designed cohort studies found significant positive associations between 34 formaldehyde-exposed professional workers and lymph ohematopoietic cancer, particularly 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-19 leukemia, using cumulative exposure measures not pr eviously used and using internal 1 comparison groups. The largest cohort study of ind ustrial workers exposed to formaldehyde 2 (N=25,619), with the most extensive exposure assess ment (Blair et al., 1986; Stewart et al., 3 1986) and with the cohort followed for a median dur ation of 35 years (Hauptmann et al., 2003) 4 demonstrated that formaldehyde was a risk factor fo r lymphohematopoietic cancers, independent 5 of other risk factors, such as benzene exposure and smoking. This finding was re-confirmed with 6 an additional 10 years of follow-up (Beane Freeman et al., 2009). Another industrial cohort 7 study reported a significant increase in the risk o f leukemia in garment workers 20 years after 8 their initial exposure and in workers with 10 or mo re years of exposure to formaldehyde 9 (Pinkerton et al. 2004). A third large occupationa l cohort study (Coggon et al., 2003) that did not 10 evaluate their findings with regard to latency repo rted somewhat lower mortality from leukemia 11 and other lymphatic and hematopoietic cancers than expected compared to national rates. 12 The associations between myeloid leukemia and forma ldehyde exposure are strong and 13 consistent (Table 4-84). Of the four studies which formally assess myeloid leukemia mortality, 14 all are positive, including cohorts of both profess ional and industrial workers (Beane Freeman et 15 al., 2009; Hayes et al., 1990; Pinkerton at al., 20 03; Stroup et al., 1986). Although few cases 16 exist for further subtype analysis, the available d ata indicate either no differences in SMRs for 17 acute myeloid leukemia (AML) versus chronic myeloid leukemia (CML) (Hayes et al., 1990; 18 Pinkerton et al., 2003) or suggest CML is more prom inent (Blair et al., 2000; Stroup et al., 1986). 19 The association between formaldehyde exposure and myeloid leukemia in embalmers has 20 recently been confirmed in a large nested case cont rol study by Hauptman et al (2009) which 21 includes cases identified from the previous studies of Hayes et al. (1990) and Walrath and 22 Fraumeni (1983 and 1984). Exposure estimates were based on interviews with next-of kin for 23 duration of job actively embalming and total number of embalmings performed. Strong and 24 statistically significant exposure-response relatio nships are demonstrated for duration of 25 exposure, total number of embalmings performed and estimated cumulative exposure to 26 formaldehyde with odds ratios of 13.6 (1.6-119.7), 12.7(1.4-112.8) and 13.2(1.5-115.4) 27 respectively (Hauptmann et al., 2009). 28 The reported associations between formaldehyde expo sure and lymphohematopoietic 29 cancers in general, and leukemia (especially myeloi d leukemia) in particular, were in workers 30 exposed in very different environments (i.e., mortu ary, chemical industry and garment industry). 31 Since coexposures to other agents are considerably different between these work environments, it 32 is unlikely that influence of confounding exposures plays a role in the observed associations. 33 There is no evidence of bias in the published repor ts, and the consistency across numerous 34
studies over time is sufficient to conclude that th e results are not due to chance. 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-20 It has been argued that it is biologically implausi ble for a highly reactive agent such as 1 formaldehyde, whose primary action is expected to b e at the portal of entry, to cause acute 2 lymphoid or myeloid leukemias (ALL and AML, respect ively), which are both commonly 3
believed to arise from transformation of stem cells in the bone marrow. The modes of action 4 (MOAs) by which formaldehyde may induce these obser ved cancers are unknown, although it 5 has been postulated that circulating stem cells (Ha uptmann et al., 2003) (e.g., early progenitor 6 cells in circulating blood or pluripotent cells in nasal/oral passages) may travel to bone marrow 7 where they become leukemic stem cells (Zhang et al. , 2009). In contrast, the mechanism for the 8 chronic lymphatic leukemia, lymphomas, multiple mye lomas (from plasma B-cells) and 9 unspecified lymphohematopoietic cancers may involve an etiology in peripheral tissues, such as 10 cells, cell aggregates, germinal centers and lymph nodes. An association of these cancers to a 11 reactive exogenous agent primarily acting at the po int of entry is biologically plausible. 12
13
6.1.4.2 Carcinogenicity in Laboratory Animals 14 The carcinogenic potential of formaldehyde is well documented in numerous animal 15 bioassays, especially for sites of first contact. Inhalation exposure of formaldehyde induced 16 primarily squamous cell carcinomas (SCC) in nasal p assages of rats (Feron et al., 1988; 17 Holmström et al., 1989a; Woutersen et al., 1989; To be et al., 1985; Kamata et al., 1997; Albert et 18 al., 1982; Sellakumar, 1985; Kerns et al., 1983; Mo nticello et al., 1996) and mice (Battelle 19 Columbus Laboratories, 1981; Swenberg et al., 1980; Kerns et al., 1983; CIIT, 1982). 20 Formaldehyde given as 0.5% formalin orally in drink ing water to adult rats induced higher 21 incidences of papillomas in the forestomach, adenom atous hyperplasia in the fundus, and 22 adenocarcinomas in the pylorus in a 40-week study u sing an initiation-promotion protocol in rats 23 (Takahashi et al., 1986). Soffritti et al. (1989) observed a significant increase in rare tumors in 24 the gastro-intestinal (GI) tract, including both be nign (papillomas and acanthomas of the 25 forestomach and adenomas) and malignant tumors (ade nocarcinomas and leiomyosarcomas) in 26 rats given formaldehyde in drinking water. Formald ehyde is toxic at the portal of entry in 27 rodents, causing increased cell proliferation, DPX formation, and focal lesions in the GI tract or 28 upper respiratory tract (depending on the route of exposure). The portal of entry toxicity of 29 formaldehyde further supports a finding of formalde hyde induced POE cancer in animal 30 bioassays. 31 Direct support for lymphohematopoietic cancers in a nimal bioassays is less convincing. 32 Although many of the available chronic studies did not examine lymphoma/leukemia incidence, 33 two studies provide positive evidence. Inhalation exposure of formaldehyde increased 34 lymphoma in female mice and leukemia in female F344 rats, but not male rats (Battelle 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-21 Laboratories, 1981). Drinking water exposure to fo rmaldehyde caused a dose-dependent increase 1 in all hemolymphoreticular neoplasias, especially l ymphoblastic leukemias and lymphomas in 2 both male and female Sprauge-Dawley rats (Soffritti et al., 1989, 2002). Conversely, no 3 increases were seen in male Wistar rats when expose d to formaldehyde in drinking water at 4 similar levels (Til et al., 1989) or male rats afte r chronic inhalation exposures (Sellakumar et al., 5 1985). 6
7
6.1.4.3 Carcinogenic Mode(s) of Action 8 Multiple plausible modes of action (MOAs) are pres ented in the document so as to 9 explore ways in which a combination of factors may contribute to cancer incidence in a 10 population exposed to formaldehyde. Multiple MOAs for formaldehyde-induced cancer can be 11 reasonably supported based on various known biologi cal actions of formaldehyde (e.g., mutation, 12 cell proliferation, cytotoxicity and regenerative c ell proliferation). Additionally, alternative 13 actions, such as immunosuppression or viral reactiv ation, are possible, although few data exist to 14 evaluate their potential relevance. Rather than a single MOA, it is plausible that a combination 15
of these factors contribute to cancer incidence in an exposed population. Considering multiple 16 factors may help to better understand the biologica l and mechanistic basis for the increases in 17 cancer incidence observed in exposed human populati ons. Unlike animal bioassays, results in 18 human epidemiological studies reflect not only the effects of the agent of concern but also 19 numerous other risk factors (e.g., viral status, di et, smoking, etc.). Additionally, human studies 20 may be impacted by biological human variability acr oss individuals, cancer biology (sub-types) 21 and wide variability in exposure regimens in human populations. 22 A preponderance of the evidence supports a role of mutagenic activity in formaldehyde’s 23 carcinogenic MOA both for respiratory tract cancer and lymphohematopoietic cancers. As 24 reviewed in Section 4.3, numerous studies provide e vidence of formaldehyde’s direct mutagenic 25 activity and supports the relevance these data to f ormaldehyde’s carcinogenicity. It can be shown 26
that: 27 1) Formaldehyde directly interacts with DNA, genera ting DNA-protein cross-links and 28 DNA adducts (in vitro, in vivo) in multiple species
, 29 2) DNA-protein cross-links exhibit a dose-response relationship to formaldehyde 30 exposure in respiratory tract of laboratory animals and are observed at exposure 31 concentrations of relevance to some people (0.3 ppm , 0.7 ppm), 32 3) Formaldehyde-induced DNA-protein cross-links hav e been associated with 33 formaldehyde-induced micronuclei and chromosomal ab errations (in vitro), 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-22 4) Mutations induced by formaldehyde due to small d eletions and rearrangements in 1 DNA in various experimental systems are consistent with formaldehyde’s 2 observed clastogenic effects (micronuclei and chrom osomal aberrations) (in vitro, 3 in vivo), 4 5) Formaldehyde-induced mutations and clastogenic e ffects occur at levels below where 5 significant cytotoxicity is detected (in vitro), 6 6) Formaldehyde exposure has been correlated to sim ilar increased micronuclei and 7
chromosomal aberrations in human buccal and oral ce lls corresponding to sites 8 where formaldehyde-induced tumors arise, and 9 7) Chromosomal damage in blood-borne immune cells, relevant to agent-induced 10 lymphohematopoietic cancers has been documented in formaldehyde exposed 11 workers including increased micronuclei and chromos omal aberrations, increased 12 incidence and aneuploidy in hematopoietic stem cell s. 13
14 In addition, mutations may arise indirectly from fo rmaldehyde-induced DNA damage 15 during cell proliferation or due to errors in DNA r epair mechanisms. Therefore, formaldehyde’s 16 DNA reactivity on a population of proliferating cel ls strengthens the role of formaldehyde17 induced mutagenicity in its carcinogenic MOA. The nasal and gut mucosa are tissues which are 18 continually sloughing and regenerating cells (Junqu eira et al., 1992). Mucosal cells proliferate in 19 response to environmental challenges in order to re pair cell damage, increase adaptive response 20 and remodel tissue. Additionally, since the pseudo stratified epithelium of the respiratory tract is 21 only 1-2 cells in depth, cells with proliferative c apacity would be directly impacted by 22 formaldehyde during exposure. Formaldehyde-induced clastogenic effects have been 23 demonstrated in these tissues (e.g. nasal) in human s, as well as in tissues which possess stratified 24 epithelium (e.g. buccal). Therefore, formaldehyde would not need to transport beyond the portal 25 of entry to directly impact and induce DNA mutation s in routinely proliferating cells. 26 In regards to generating the observed clastogenic e ffects (micronuclei and chromosomal 27 aberrations in peripheral blood lymphocytes, aneupl oidy in circulating hematopoietic stem cells), 28 it is less clear as to where formaldehyde is making contact with components of the immune 29 system. Mature lymphocytes present in nasal and gu t tissues, and would be vulnerable to the 30 direct toxic actions of formaldehyde including geno toxicity. Since mature lymphocytes routinely 31 traffic through the body and clonally respond in re sponse to an immune challenge, the observed 32 effects in peripheral blood lymphocytes (micronucle i and chromosomal aberrations) are 33 consistent with direct action on these cells. Lymp hohematopoietic cancers are known to arise 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-23 from mature lymphocytes including: Hodgkin lymphoma , multiple myeloma some leukemia and 1 non-Hodgkin lymphoma (Greaves 2004, Harris et al., 2000). 2 Formaldehyde may also be directly acting upon circu lating stem cells or more mature 3 progenitor cell in the peripheral blood (Zhang et a l., 2010). Any genetic damage sustain by 4 circulating cells could contribute to a broad spect rum of lymphohematopoietic cancers if those 5
cells returned to the bone marrow and contributed t o hematopoiesis. Evidence of bone marrow 6 toxicity and stem cell aneuploidy has been reported in formaldehyde exposed workers (Zhang et 7 al., 2010). Finally, formaldehyde is readily hydra ted in aqueous systems, existing in equilibrium 8 with its hydrated form methylene glycol, which is a ble to transport through the blood. It has been 9 hypothesized that this hydration reaction may allow formaldehyde to act systemically and 10 therefore on the bone marrow directly (Zhang et al. , 2010.) Formaldehyde-induced DNA 11 damage, and resulting mutation in the bone marrow a nd circulating stem cells could contribute to 12 any of the lymphohematopoietic cancers including le ukemia (both lymphoid and myeloid) as 13 well as myeloproliferative disorders. 14 Cell replication allows unrepaired DNA damage to b e “fixed” into heritable changes to 15 the genome. Therefore, increased cell proliferatio n could serve not only to increase the 16 mutagenic effects of formaldehyde on a given tissue but also to enhance the mutagenic effects of 17 other agents in the diet or in the environment. Si nce epidemiological studies include humans 18 exposed to a range of agents in the environment, in creased cell proliferation could contribute to 19 increased cancer incidence. The promotion studies in animal bioassays, though limited in 20 number, support the relevance of formaldehyde’s abi lity to enhance the actions of other agents 21 (initiators) on tumor formation. 22 Although the other biologic effects discussed above have not been explicitly tested in 23 animal systems, the available data are consistent w ith these actions contributing to the 24 carcinogenic potential of formaldehyde. For exampl e, localized immunosuppression by 25 formaldehyde may serve to increase viral reactivati on (e.g., EBV, HPV etc.) or decrease tissue 26 surveillance and immune activity against preneoplas tic cells. Both these actions could contribute 27 to increased cancer risk in a human population, whi ch may not be evident in animal bioassays, 28 where the animals are not subject to the many risk factors for human cancer. Even the simple 29 action of the breakdown of the mucociliary apparatu s could increase cancer incidence by 30 increasing toxic insult to the URT and increasing U RT infections. Again, these actions may be 31 relevant to human populations, but they have not be en adequately tested in animal bioassays. 32 Animal bioassays suggest a role for regenerative pr oliferation in contributing to 33 formaldehyde’s carcinogenicity. However, these dat a are not evidence against a role of direct 34 mutagenic action either in the observed tumorigenic ity or in the potential low-dose 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-24 carcinogenicity of formaldehyde. As reviewed, a ro le for mutagenic action is also consistent 1 with the results of the animal bioassays (Crump et al, 2008; Subramaniam et al., 2007, USEPA 2 2008). The mutagenic effects of formaldehyde are w ell-documented to occur below levels of 3 significant cytotoxicity. This observation is impo rtant for the relevance of formaldehyde-induced 4 mutagenicity to human health risk. Given the above sequence of evidence - from the nature of 5 formaldehyde’s DNA reactivity through clastogenic e ffects observed in human cells from the 6 various tumor sites - there is an adequate weight o f evidence (WOE) to consider formaldehyde7 induced mutations relevant to human carcinogenic ri sk. Although occupational exposures may 8 have resulted in high episodic exposures (especiall y historically), it is unlikely that any worker 9 would have endured repeated exposures which resulte d in gross focal lesions to the upper 10 respiratory tract (URT) or oro-digestive tract as s een in the animal bioassays. It is noteworthy 11 that even without these gross formaldehyde-induced lesions, cancer incidence is increased from 12 occupational (and perhaps non-occupational) exposur es to formaldehyde. Therefore, we believe 13 formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA. 14
15
6.1.5 Cancer Hazard Characterization 16 Formaldehyde is carcinogenic to humans by the inhal ation route of exposure. There is 17
sufficient evidence of causal associations between formaldehyde exposure and nasopharyngeal 18 cancers as well as sinonasal cancers. There is sup porting evidence for cancers of the mouth and 19 throat in humans as well as strong evidence for nas al tumors in animal bioassays. Taking these 20 findings together along with mode of action conside rations, it is concluded that there is sufficient 21 evidence of a causal relationship between formaldeh yde inhalation exposure and upper 22 respiratory tract cancers as a group. 23 Epidemiologic studies also provide evidence of a ca usal association of inhalation exposure 24 to formaldehyde and lymphohematopoietic cancers as a group and leukemias as a group, with the 25 strongest evidence for myeloid leukemia. There is supporting evidence both in cohort and case26 control studies for specific sub-types of lymphohem atopoietic cancers, including myeloid 27 leukemia, multiple myeloma and Hodgkin lymphoma. T here is limited supporting evidence in 28 animal bioassays for both leukemia and lymphoma. I t should be noted that although several 29 carcinogenic modes of action have been discussed fo r leukemia, that this remains an area of 30 significant scientific debate. 31
32
6.2 DOSE-RESPONSE CHARACTERIZATION 33
6.2.1 Noncancer Toxicity: Reference Concentration (RfC) 34This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-25 The portals of entry are major targets for formald ehyde, as can be seen in many studies, 1 because formaldehyde is highly reactive and water s oluble. Human and laboratory animal studies 2 demonstrate that formaldehyde also causes systemic effects, including neurotoxicity, 3 reproductive toxicity, developmental toxicity, and immunotoxicity, although the data are less 4 extensive than those supporting the sensory irritat ion and respiratory tract effects. Critical data 5 gaps have been identified and uncertainties associa ted with data deficiencies are more fully 6 discussed in Chapter 5 and summarized below. 7
8
6.2.1.1 Assessment Approach Employed 9 RfC values for noncancer effects are derived using EPA’s RfC methodologies (U.S. 10 EPA, 1994, 1993, EPA 2002b). EPA reviewed the exis ting literature and identified health effects 11 associated with formaldehyde exposure, defining hea lth effect categories where evidence was 12 sufficient: sensory irritation, respiratory tract pathology, pulmonary effects, asthma, increased 13 allergic sensitization, immune function, neurologic al and behavioral effects and reproductive and 14 developmental effects. Specific key studies were identified within each health effects category 15 which provided adequate exposure-response informati on to support RfC derivation (Table 5-4). 16 Although not all identified endpoints are represent ed by these studies, at least one study was 17 identified for each category. A screening process (described in section 5.1.3.1) was used to 18 identify key studies for a variety of health effect s that would best inform the derivation of the 19 RfC. For each selected key study, a candidate RfC (cRfC) was derived. In several cases more 20 than one alternative was considered for application of the uncertainty factor (UF) addressing 21 human variability (Table 5-6). 22
23
6.2.1.2 Derivation of Candidate Reference Concentrations 24 Seven studies were selected as key studies for furt her consideration in RfC derivation 25 (Section 5.3.1, Table 5-4). Candidate RfCs from th ese studies address various health effects 26 including: sensory irritation, respiratory effects, asthma, increased allergic sensitization, and 27 decreased fecundity (Table 5-6). From these studie s three co-critical studies were selected which 28 provide similar cRfCs for related health effects (R umchev et al., 2002; Garrett et al., 1999; 29 Krzyzanowski et al., 1999). These three studies id entify serious health effects in residential 30 populations including children: increased asthma in cidence, decreased pulmonary function, 31 increase in respiratory symptoms, and increased all ergic sensitization (Rumchev et al., 2002; 32 Garrett et al., 1999; Krzyzanowski et al., 1999). Asthma, allergic sensitization, altered 33 pulmonary function, and symptoms of respiratory dis ease are not only clinically related, but 34 etiologically related, and it is reasonable that th ey should be considered together. These health 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-26 effects are observed below the exposure levels that result in sensory irritation, and the resulting 1 cRfCs are correspondingly lower—ranging from 2.8 to 11 ppb—depending on the study, endpoint 2 considered, and the application of alternative unce rtainty factors for human variability 3 (Table 6-1). Additionally, these cRfCs are consid ered protective of the decreased fecundability 4 density ratio (FDR) reported by Taskinen et al. (19 99) which yielded a cRfC of 8.6 ppb. One of 5
the uncertainties in the cRfC for decreased FDR is the use of a time-weighted exposure metric 6 which does not address possible contributions of pe ak exposure levels to the observed health 7 effect thus; it is possible that a cRfC of 8.6 ppb is lower than is needed for protection against 8
decreased FDR. 9 As discussed in section 6.2.1.4, there are uncertai nties in establishing an RfC which are 10 not fully captured in the quantitative process or t he standard uncertainty factors, as such it is 11 acknowledged by EPA that the RfC is not exact, perh aps spanning an order of magnitude. The 12 range of RfCs from the critical studies (even with various alternative considered for the human 13 variability uncertainty factor are in close agreeme nt spanning only 1⁄2 order of magnitude.) 14 Therefore EPA is considering a simple mean of these cRfCs as adequately representative of the 15
three co-critical studies. Alternatives are to tak e the median as a different way to represent the 16 three studies together, or the lowest cRfC as most protective. There is little numerical difference 17
in the result of these decisions. 18
19
6.2.1.3 Adequacy of Overall Data Base for RfC Derivation 20 The database of available laboratory animal studies , clinical and epidemiological studies, 21 and supporting mechanistic information for formalde hyde is substantial. Many of the health 22 effects are well studied in animals and humans, esp ecially those endpoints related to sensory 23 irritation and respiratory effects at the portal of entry, such as impacts on respiratory tract 24 pathology, asthma and reduced pulmonary function. This is reflected in the number and high 25 quality of human studies presented in Table 5-4 and supporting data summarized in Chapter 4. 26
27
28This document is a draft for review purposes only a nd does not constitute Agency policy 6-27 DRAFT—DO NOT CITE OR QUOTETable 6-1: Summary of candidate reference concentrations (RfC) for co-critical studiesApplication ofstudy-specific UFEndpointStudyStudysizeHomesChildrenPOD (ppb)UFLUFSUFHcRfC1(ppb)Respiratory effects / asthma and sensitizationReduction ofPEFR in children(10%)Krzyzanowskiet al. (1990)208 Yes Yes BMCL10= 17 1 135.6Alternative A33.3Alternative BAsthmaprevalenceRumchev et al.(2002)192 Yes Yes NOAEL = 33 1 3111Alternative A32.8Alternative BAsthma, atopyand severity ofallergicsensitizationGarrett et al.(1999)148 Yes Yes LOAEL = 28 3 119.3Notes: 1: The final RfC will be rounded to one significant digit per EPA policy. Since the CandidateRfC is an interim calculation, two-significant digits areretained as is common practice in mathematics {i.e.one significant diget more that the final result,to avoid rounding errors compounding across multiplemathematical manipulations.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-28 The data also indicate effects in other health effe ct categories, specifically neurotoxic 1 effects, reproductive toxicity, and developmental t oxicity (Section 5.1.2). These non-portal of 2 entry effects are areas where additional research m ay be warranted to reduce uncertainty and 3 better characterize the potential for health effect s and the formaldehyde concentrations at which 4 they might occur in humans. 5 EPA guidance indicates that an uncertainty factor for database deficiencies should be 6 applied where there is an indication that the exist ing studies may not completely characterize the 7 hazard of a specific agent. This may be the result of lacking studies to assess toxicity to key 8 functional areas or organ systems, or where “... a re view of existing data may also suggest that a 9 lower reference value might result if additional da ta were available.” (EPA 2002b) 10 Application of an uncertainty factor of 3 was consi dered by EPA based on the lack of a 11 satisfactory two-generation study to fully evaluate the effects of formaldehyde exposure on 12 reproductive and developmental endpoints and limita tions of the available studies evaluating 13 neurotoxic effects. An uncertainty factor of 3 rat her than 10 was considered given the relative 14 completeness of the database across all major healt h effect categories such that it is believed all 15 major health effects have been identified at least qualitatively. The observed adverse health 16 effect levels (LOAELs) for those endpoints where th e database is not adequate for alternative 17 RfC derivation are above the range of candidate RfC s; however, it is unclear if the candidate 18 RfCs would be protective of these other health effe cts (neurotoxic, reproductive and 19 developmental) since NOAELs were not identified for several observed health effects. 20 Therefore EPA is considering several options to ad dress database deficiencies in the final 21
RfC. 22
23This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-29 1 2 It is unclear what uncertainty factors are appropri ate to account for human variability and 3
deficiencies in the overall database. For this rea son, several alternatives have been presented. 4
5
6.2.1.4 Uncertainties in the Reference Concentration (RfC) 6
A number of uncertainties that underlie the RfC for formaldehyde are discussed in this 7 section. A fundamental uncertainty in an RfC is th at the critical study(ies) and endpoint(s) 8 selected reflect an actual hazard, i.e., a chemical ly related effect. As summarized in Section 9 6.1.3, there is strong and consistent evidence, fro m both human and laboratory animal studies, for 10
the critical effects that form the basis of the RfC for formaldehyde. This section pertains to 11 uncertainties in the quantitative derivation of the RfC. 12
13 Point of Departure (POD) 14
Most of the studies considered for RfC derivation d id not provide enough data to support 15 benchmark dose modeling. Rather, the PODs for most studies were LOAELs or NOAELs, 16 Approaches to the application of a database uncerta inty factor: Options EPA is considering include:

(1) Provide an RfC derived from studies of respirat ory and allergenic responses and protective of sensory irritation effects with a database uncer tainty factor of one given significant data on formaldehyde, but noting that further research repr oductive, developmental and neurotoxic
effects would be valuable.

(2) Provide an RfC with a database uncertainty fact or of one, with this RfC explicitly identified as being protective of the well-studied effects.

(3) Apply a database UF of 3 to the RfC derived fro m studies of respiratory and allergenic responses to reflect the potential that reproductiv e, developmental, or neurotoxic effects might
occur at lower doses:

(3) Provide both an RfC identified as protective o f the better-studied effects and an RfC with a database uncertainty factor of 3 incorporated to ac count for limits to the data on reproductive, developmental and neurotoxic effects.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-30 which have a number of shortcomings relative to a P OD obtained from benchmark dose-response 1 modeling (i.e., a benchmark concentration or dose): 2
3

 LOAELs and NOAELs are a reflection of the particula r exposure/dose levels used in a 4 study, contributing some inaccuracy to the POD dete rmination. 5

 LOAELs and NOAELs are often determined based on sta tistical significance and, thus, 6 reflect the number of study subjects or test animal s. Studies are typically dissimilar in 7 detection ability and statistical power, with small er studies tending to identify higher 8 exposure levels as NOAELs relative to larger, but o therwise similarly designed, studies. 9

 Different LOAELs and NOAELs represent different res ponse rates, so direct qualitative 10 and quantitative comparisons are not possible. 11
12
PODs identified from benchmark dose models overcome some of the deficiencies 13
associated with LOAELs and NOAELs. Benchmark model s were used for two inhalation data 14 sets—Hanrahan et al. (1984) and Krzyzanowski et al. (1990). 15 It should also be noted, however, that even for ben chmark concentrations/doses there is 16 often uncertainty, in particular for continuous res ponses, about what response level to select as 17 the benchmark response, i.e., where to define the c ut-point between a level of change that is not 18 adverse and one that is adverse. In addition, benc hmark dose models currently in use are purely 19
mathematical models and are not intended to accurat ely reflect the biology of the effect being 20
modeled. 21 Another source of uncertainty in the POD is the adj ustment for continuous exposure. 22 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human and 23 laboratory animal inhalation studies are typically not for continuous exposures, and assumptions 24 must be made in converting reported exposure levels to equivalent continuous exposures. 25 Similarly, there are uncertainties about potential dose rate effects, in particular the effect of peak 26 exposures in occupational studies. 27
28 Extrapolation from Laboratory Animal Data to Humans 29 Because the inhalation database for formaldehyde co ntains many human studies for a 30 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 31 the RfC was derived. Thus, unlike for most RfCs, t his is not a source of uncertainty in the RfC 32 for formaldehyde. 33
34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-31 Human Variation 1 Heterogeneity among humans is another uncertainty associated with extending results 2 observed in a limited human study population or lab oratory animal experiment to a larger, more 3 diverse human population. 4 For three of the studies used to derive the RfC, a value of 3 was used for the human 5 variability UF (rather than the default value of 10 ) because the studies had an apparent over6 representation of populations expected to have incr eased susceptibility (section 5.5.3.1): 7
8

 The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 9 irritation in a large number of subjects, including children and the elderly. As a result of 10 the study's participation criteria, individuals wit h greater sensitivity were potentially over11 represented. 12

 Thirty percent of the subjects in the residential s tudy by Krzyzanowski et al. (1990) are 13 children, who are more sensitive to formaldehyde-as sociated decreases in peak expiratory 14 flow rates (PEFR) than adults. The candidate RfC d etermination for this study focused 15 on the results in the children, among which asthmat ics were over-represented (roughly 3- 16 times) compared to the national average. 17

 Garrett et al. (1999) conducted a cross-sectional s urvey of allergy and asthma-like 18 symptoms in children with or without a doctor's dia gnosis of asthma. The study was 19 designed to include a high proportion of asthmatic children, a sensitive population for the 20 effects being studied. 21
22 EPA notes, however, that, while a human variabilit y UF of 3 rather than 10 was used to 23 attempt to account for certain special attributes o f these studies/effects, there is still uncertainty 24 about how much of the overall population heterogene ity is actually reflected even in these 25 relatively diverse residential studies. 26
27 Subchronic-to-Chronic Extrapolation 28 RfCs are intended to apply to chronic lifetime exp osures. If a study is subchronic 29 (typically less than 10% of lifetime), an UF for su bchronic-to-chronic extrapolation is generally 30 applied to the candidate RfC for that study. For t he human residential and occupational studies 31 comprising the key studies for the RfC in this asse ssment, the average durations of exposure in 32 the households or workplaces under study is unknown . In this assessment, these studies were 33
considered chronic in nature and no subchronic-to-c hronic UF was applied. However, there is 34 uncertainty about whether or not the responses obse rved fully reflected the potential effects of 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-32 chronic exposure, especially for effects in childre n, where effects on the developing respiratory 1 and immune systems, for example, could be predispos ing the children to further health effects 2
later in life. 3
4
6.2.1.5 Conclusions 5
Seven different non-cancer health effects were iden tified from formaldehyde inhalation 6 exposure studies, including: 1) sensory irritation of the eyes, nose, and throat, 2) upper 7 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 8 behavioral toxicity, 6) reproductive and developmen tal toxicity, and 7) immunological toxicity. 9 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 10
derived candidate RfCs for critical effects based o n seven key studies. Three co-critical studies 11 were selected which provide similar cRfCs for relat ed adverse health effects observed in 12 residential populations including children i.e., in creased asthma incidence, decreased pulmonary 13 function, increase in respiratory symptoms, and inc reased allergic sensitization (Rumchev et al., 14 2002; Garrett et al., 1999; Krzyzanowski et al., 19 99). The resulting cRfCs fall in a range 15 between 2.8 and 11 ppb, depending on the study, or endpoints considered, and the application of 16 alternative uncertainty factors for human variabili ty (Table 6-1). The RfC is taken as the 17 average of the cRfCs from the three co-critical stu dies (See Section 6.2.1.2). 18 EPA has assessed the adequacy of the overall databa se for RfC derivation, and although 19 the database is quite large, and provides significa nt information on well studied POE effects. 20 There are remaining uncertainties in the database. Most notably, there is a need for additional 21 exposure-response information for observed neurotox ic effects, reproductive and developmental 22 effects as well as a two-generation study to evalua te the effects of formaldehyde exposure on 23 reproductive and developmental endpoints. EPA is c onsidering 4 options to address database 24 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 25 appropriate to account for human variability and de ficiencies in the overall database. For this 26 reason, several alternatives have been presented. EPA is seeking advice from the NAS and the 27 public on this matter. 28
29
6.2.2. Cancer Risk Estimates 30
6.2.2.1. Choice of Data 31 As explained above, the human epidemiologic data an d the animal bioassay data indicate 32 multiple sites of concern, remote as well as at the portal of entry. The quantitative cancer risk 33
derivations in this document consider the risks of lymphohematopoietic cancers and solid cancers 34 of the respiratory tract. When adequate human data are available, as is the case with 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-33 formaldehyde, it is generally preferable to base ca ncer risk estimates on the human data rather 1 than on data from experimental animals because of t he inherent uncertainties associated with 2 interspecies extrapolation. Sufficient exposure-re sponse data from a large, high-quality 3 epidemiologic study for the quantitative estimation of risk were available for some 4 lymphohematopoietic cancers and for nasopharyngeal cancer. 15 Risk estimates based on nasal 5 tumors in rats were also derived for comparison wit h the estimates based on human data. The 6 data used for the quantitative risk assessment are as follows: 7
8
1. Nasopharyngeal cancer (NPC): The dose-response mod eling of NPCs is based on results 9 from a large NCI cohort study of over 25,000 worker s in 10 U.S. plants producing or 10 using formaldehyde (Hauptmann et al., 2004). 11
2. Lymphohematopoietic cancers: The dose-response mod eling of select 12 lymphohematopoietic cancers is based on results fro m a more recent follow-up study (of 13 lymphohematopoietic malignancies only) of the same NCI cohort (Beane Freeman et al., 14 2009). 15
3. Squamous cell carcinoma (SCC) in the upper and lowe r respiratory tract: An increased 16 incidence of nasal SCC was seen in two large long-t erm bioassays using F344 rats (Kerns 17 et al., 1983; Monticello et al., 1996). Although o ther studies in laboratory animals exist, 18
19
4. these two studies, when combined, provided the most robust data for analyses. The nasal 20 tumor incidence data from these rat bioassays is us ed for extrapolating the risk of SCC to 21 the entire human respiratory tract. 16 22
23
6.2.2.2. Analysis of Epidemiologic Data 24 The NCI cohort consisted of 25,619 workers employed in 10 plants prior to 1966. A 25 follow-up through 1994 presented exposure-response analyses for 9 NPC deaths, as well as 26

15 Only one other epidemiological study was available with quantitative exposure estimates for the indiv idual workers. It was a much smaller study (it focused o n one of the ten plants covered in the selected stu dy), and it evaluated only pharyngeal cancers.

16 That is, we do not assume site concordance betwee n rat and human. This is reasonable because the re spiratory and transitional cell types considered to be at ris k of SCC in the upper respiratory tract are also pr evalent in the lower human respiratory tract. Greater fractional p enetration of formaldehyde is thought to occur post eriorly in the human respiratory tract compared to the rat (Kimbel l et al. 2001, Overton et al. 2001). Furthermore, s ome epidemiological studies reported an increase in lun g cancer with formaldehyde exposure (Gardner et al. 1993, Blair et al. 1990, 1986), and lesions were seen in the lo wer respiratory tract of rhesus monkeys exposed to formaldehyde (Monticello et al. 1989).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-34 analyses of deaths from other solid cancers (Hauptm ann et al., 2004). The most recent follow-up 1 (through 2004; lymphohematopoietic cancers only) an alyzed 319 deaths attributed to 2 lymphohematopoietic malignancy from a total of 13,9 51 deaths (Beane Freeman et al., 2009). A 3 detailed exposure assessment was conducted for each worker, based on exposure estimates for 4 different jobs held and tasks performed (Stewart et al., 1986). Exposure estimates were made 5 using several different metrics—peak exposure, aver age intensity, cumulative exposure, and 6 duration of exposure. Respirator use and exposures to formaldehyde-containing particulates and 7
other chemicals were also considered. Relative Ris ks (RRs) were estimated using log-linear 8 Poisson regression models stratified by calendar ye ar, age, sex, and race and adjusted for pay 9 category (salary/wage/unknown). The NCI investigat ors used the low-exposure category as the 10 reference category to “minimize the impact of any u nmeasured confounding variables since 11 nonexposed workers may differ from exposed workers with respect to socioeconomic 12
characteristics.” 13 Although other upper respiratory tract cancers were also identified as being causally 14 associated with formaldehyde exposure in the weight -of-evidence analysis in section 4.5, NPC 15 was the only upper respiratory tract cancer with ex posure-response data adequate for the 16 derivation of unit risk estimates in the Hauptmann et al. (2004) follow-up study of solid tumors. 17 Similarly, the weight-of evidence analysis in secti on 4.5 concluded that there were causal 18 relationships between formaldehyde exposure and all lymphohematopoietic cancers as a group as 19 well as leukemias as a group (with the strongest ev idence for myeloid leukemia). However, from 20 the Beane Freeman et al. (2009) follow-up study of lymphohematopoietic malignancies, only all 21 leukemias combined and Hodgkin lymphoma were judged to have exposure-response data 22 adequate for the derivation of unit risk estimates. 23 For the NPCs, significant trends were observed for the cumulative and peak exposure 24 metrics. The cumulative exposure metric provides a good fit to the data ( p trend = 0.029 for all 25 person-years). Since this is generally the preferr ed metric for quantitative risk assessment for 26 environmental exposure to carcinogens, cumulative e xposure is chosen as the exposure metric 27
for the risk estimate calculations for NPC in this assessment. For the latency of solid cancers, 28 including nasopharyngeal tumors, a 15-year lag inte rval was used by Hauptmann et al. (2004). 29 For the lymphohematopoietic cancers, using the peak exposure metric, statistically 30 significant log-linear trends were observed for all lymphohematopoietic cancers, Hodgkin 31 lymphoma, and leukemia (the latter only when the un exposed person-years were included) 32 (Beane Freeman et al., 2009). Using the average ex posure metric, there was a significant trend 33 for Hodgkin lymphoma. Similar results were seen wi th the cumulative exposure metric, although 34 the trends were only of borderline significance (Ho dgkin lymphoma p trends = 0.06 and 0.08 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-35 with and without the unexposed person-years, respec tively; leukemia p trends = 0.08 and 0.12 1 with and without the unexposed person-years, respec tively). For the latency of 2 lymphohematopoietic cancers, a 2-year lag interval was used by Beane Freeman et al. (2009). 3 Although the peak exposure metric provides the most statistically robust dose-response 4 relationship, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 5 to meaningful estimates of lifetime extra risk of c ancer from environmental exposures. The 6 average exposure metric is also problematic because it suggests that duration of exposure is not 7 important, i.e., exposure to a given exposure leve l for one year conveys the same amount of risk 8 as exposure to the same level for 70 years. 9 Cumulative exposure is generally the preferred metr ic for quantitative risk assessment for 10 environmental exposure to carcinogens. Given the co nsistency of increased mortality from 11 Hodgkin lymphoma and leukemia overall (exposed vers us unexposed) and for each exposure 12 metric (Table 5-12), indicating risk from these can cers is more than chance, a determination was 13 made that the cumulative exposure results for these two cancer types constituted the best data 14
sets from which to calculate unit risk estimates fo r lymphohematopoietic cancers from the NCI 15
cohort. 16 Regression coefficients from the NCI log-linear tre nd test models for the NPCs 17 (Hauptmann et al., 2004) and the various lymphohema topoietic cancers (Beane Freeman et al., 18 2009) were provided by Drs. Hauptmann and Beane Fre eman, respectively. These trend tests 19
were of the form RR = e β *exposure . The coefficients (i.e., β ) were used in lifetable analyses to 20
calculate lifetime extra cancer risks from formalde hyde exposure (Section 5.2). Extra risk 21
estimates for cancer incidence for the three cancer types were approximated by assuming that 22 cancer incidence and cancer mortality have the same dose-response relationships and then using 23 background cause-specific incidence rates instead o f mortality rates in the lifetable analysis. 24 Points of departure (PODs) based on the dose-respon se modeling of these cancers were 25 calculated as the exposure concentration at which t he 95% upper confidence bound on extra risk 26 was 0.0005 (i.e., 0.05%) for NPC and for Hodgkin ly mphoma and 0.005 (i.e., 0.5%) for leukemia 27 (Sections 5.2.2 and 5.2.3). These values approxima te the lower confidence bounds on dose at 28
these extra risk levels. The values for these extr a risk levels, 0.0005 and 0.005, were chosen 29 because they are near the lower end of the observab le range of the data. Having such low 30 response levels associated with the points of depar ture is warranted because of the low 31 background lifetime risks for these cancer types (e .g., 0.00022 for NPC mortality). Higher extra 32 risk levels would entail extrapolation above the ra nge of the bulk of the observable data to obtain 33 PODs. The resulting effective concentration values for the selected extra risk values for cancer 34 incidence are presented in Table 6-2. 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-36 Linear low-dose extrapolation from the PODs was use d to derive unit risk estimates for 1 NPC, Hodgkin lymphoma, and leukemia, as discussed i n Section 6.2.2.4. To obtain an 2 approximate (upper bound) unit risk estimate of the total cancer risk from formaldehyde 3 exposure, risk estimates for these three cancer typ es (NPC, Hodgkin lymphoma, and leukemia) 4 were combined assuming a normal distribution (Secti on 5.2.4). This was considered the most 5 reasonable approach for estimating total cancer ris k from the available data; however, it should 6 be noted that this estimate may not reflect all of the cancer types associated with formaldehyde 7

exposure. 8
9 Table 6-2: Effective concentrations (lifetime cont inuous exposure levels) 10 predicted for specified extra cancer risk levels fo r selected formaldehyde11 related cancers 1 12 13 Cancer Type Extra Risk Level EC 2 (ppm) LEC 3 (ppm)
NPC 0.0005 0.074 0.046 Hodgkin lymphoma 0.0005 0.052 0.030

Leukemias 0.005 0.16 0.088
14 1. calculated including all person-years (see s ection 5.2) 15 2. effective concentration. 16 3. 95% lower confidence bound on the EC; this valu e is the POD. 17 18 19
6.2.2.3. Analysis of Laboratory Animal Data 20 Various bioassays have been conducted studying the effects of formaldehyde on rats, 21 mice, and rhesus monkeys and have been discussed at length earlier in this document. Of these, 22 two inhalation bioassays of rats, when combined, al low for the most robust characterization of 23 the long-term dose-response relationship in a labor atory species. These long-term bioassays 24
found an increased incidence of nasal SCCs in rats exposed to formaldehyde by the inhalation 25 route (Monticello et al., 1996; Kerns et al., 1983) . In the combined data, rats were exposed to 0, 26 0.7, 2.0, 6.0, 9.93, and 14.96 ppm (0, 0.86, 2.5, 7 .4, 12.2, and 18.4 mg/m 3 ) exposure 27 concentrations of formaldehyde (Monticello et al. 1 996; Kerns et al. 1983). SCCs were observed 28 only at 6 ppm and higher exposure concentrations. 29 A large amount of mechanistic information relevant to the dose-response relationship of 30 formaldehyde in the respiratory tract has been gene rated either following or in conjunction with 31 these two bioassays, as reviewed in Chapter 3, 4 an d 5. This information includes the following: 32This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-37 1. Measurements of DNA-protein cross-links (DPXs) form ed by formaldehyde in F344 rats 1 and rhesus monkeys (Casanova et al., 1989, 1994). Several PBPK models have been 2 developed in the literature based on these data. S ome of these efforts integrated the data 3 in both species (Casanova et al., 1991; Conolly et al., 2000; Klein et al., 2009). 4
2. Measurements of cell proliferation in F344 rats and rhesus monkeys (Monticello et al., 5 1989, 1990, 1991, 1996). 6
3. Simulations of airflow in anatomically realistic re presentations of the upper respiratory 7 tract of the F344 rat, rhesus monkey and human, and in an idealized representation of the 8 human lower respiratory tract, using computer and p hysical models (Kimbell et al., 1993; 9 Kepler et al., 1998; Subramaniam et al., 1998). Th ese simulations were used to predict 10 regional formaldehyde dosimetry in the correspondin g sections of the respiratory tract of 11 these three species (Kimbell et al., 2001a, b; Over ton et al., 2001). 12
13 The combined nasal tumor incidence data were analyz ed using a multistage-weibull time14 to-tumor approach as well as biologically based dos e-response (BBDR) models derived from 15 Conolly et al. (2003) [see Crump et al. (2005), Sub ramaniam et al. (2007), and Appendix E for 16 details]. The BBDR approach enabled integration of the mechanistic information and the time-to17 tumor incidence data within a single conceptual fra mework. 18
19
6.2.2.4. Extrapolation Approaches 20 An EPA inhalation unit risk is developed to estimat e cancer risk from environmental 21 exposures or in order to determine exposure levels corresponding with cancer risks as low as 1 22 excess cancer in 10,000 or 1 excess cancer in 1 mil lion. As neither data from animal studies, nor 23 human epidemiological studies, provide direct obser vation of these low level risks, the observed 24 exposure response relationship is extrapolated to e stimate low dose risk. The model used to 25 extrapolate below the range of exposures clearly as sociated with increased risk of health effects 26 has a great influence on the inhalation unit risk, as there may be several orders of magnitude 27 difference between the observed risk and the target risk range. In the absence of empirical data 28 or a biologically-informed model, the EPA applies a simple straight line extrapolation from the 29 point of departure to zero exposure (U.S. EPA, 2005 a). The Mode of Action evaluation reviews 30
available data and determines if an MOA can be suff iciently established and whether it informs 31 the shape of the exposure-response relationship. 32
33
34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-38 Low-dose extrapolation for Lymphohematopoietic canc ers: 1 Formaldehyde is a mutagen, and known to act directl y on cells at the site of first contact. 2 Clastogenic effects have been documented in formald ehyde-exposed workers including 3 peripheral blood lymphocytes and circulating stem c ells (Zhang et al., 2010). Thus a mutagenic 4 MOA has been hypothesized for lymphohematopoeitic c ancers, and supports a linear low-dose 5 extrapolation of human cancer risk. Additionally, formaldehyde may also induce some form of 6 bone marrow toxicity, as suggested by observed panc ytopenia in exposed workers (Tang et al., 7 2008, Zhang et al., 2010). However, as the mechani sm of transport to the bone marrow, and 8 biological activity leading to the observed toxicit y are unknown, this information does not inform 9 the low-dose extrapolation. Although the mechanism s underlying formaldehyde-induced 10 leukemia and lymphoma are still largely speculative , there is little doubt of an association 11 between formaldehyde exposures and lymphohematopoei tic cancer mortality, especially for 12 myeloid leukemia. Therefore, without a known MOA w hich would justify an alternative 13 approach, and with a hypothesized mutagenic MOA und er consideration which supports a simple 14 straight line extrapolation from the point of depar ture to zero risk at zero exposure, this is applied 15 when estimating human cancer risk from both leukemi a and Hodgkins lymphoma from the NCI 16
cohort. 17
18 Low-dose extrapolation for cancer of the upper resp iratory tract: 19 There are multiple plausible MOAs for formaldehyde carcinogenesis regarding upper 20 respiratory tract cancers (Section 4.5.3), however they are not all applicable to the lower end of 21 the exposure response curve. For example, although regenerative cell proliferation associated 22 with focal and gross tissue lesions due to cell dea th may contribute to the high incidence of rat 23 nasal tumor in F344 rats, these mechanisms may not be operative in the low exposure region 24 expected for human environmental exposure (e.g. les s than 1ppm) and therefore may not inform 25 low-dose extrapolation. There are MOAs which are m ore appropriate to the low-dose region. 26 Specifically, formaldehyde is a known mutagen, may inhibit DNA repair activity and may have 27 additional activity as a tumor promoter. Finally, other affects such as formaldehyde-induced cell 28 proliferation, imunosuppression and disruption of t he mucociliary apparatus may influence both 29 the level of tissue damage and ultimately cancer in cidence. 30
EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) recommend using 31 biologically based dose-response (BBDR) models for extrapolation when data permit. Conolly et 32 al. (2003, 2004) developed BBDR models to predict s quamous cell carcinoma risk in the rat and 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-39 human respiratory tract at exposures well below the range of the observed animal data. 17 The 1 primary conclusion from their modeling effort was t hat human exposure standards protective of 2 effects of formaldehyde-induced cytotoxicity should be sufficient to protect from the potential 3 carcinogenic effects of formaldehyde. The authors a ssessed that such a conclusion was 4
conservative in the face of model uncertainties. 18 This assessment’s evaluation of the BBDR 5 models and alternative implementations (detailed in Section 5.3) finds that these models may not 6 provide conservative estimates of human cancer risk below the range of observed data. 7
The current assessment evaluated the uncertainties in the above BBDR model extensively 8 and examined alternative parameterizations of the m odeling in Conolly et al. (2003, 2004). These 9 alternatives and the original model were equally co nsistent with the experimental data but 10
resulted in maximum likelihood estimates of added h uman risk that ranged from negative to large 11 positive values at environmental exposure concentra tions. Model uncertainty far exceeded 12 statistical uncertainty (Table E-4 in Appendix E). Each of these models, including the modeling 13 in Conolly et al., 14
15
1. was judged to be just as biologically plausible, 16
2. described the rat tumor incidence data equally well
, 17
3. was based on different characterizations of the sam e empirical cell kinetic data, and 18
4. was based on the same empirical data on DPX measure ments. 19
20
This assessment’s evaluation 19 of the above models (detailed in Section 5.3) conc luded 21 that these models, including alternative implementa tions of those in Conolly et al. (2003, 2004), 22 were too uncertain to be useful for low-dose extrap olation of risk. It may be noted that the 23 sensitivity analyses on the basis of which these co nclusions were reached have been criticized as 24 resulting in implausible risk estimates (given the epidemiologic data) as a consequence of 25 implementing model variations that are not biologic ally reasonable (Conolly et al. 2009). This 26

17 In that sense, the authors used the modeling as if it were a BBDR model even though they termed it as “biologically-motivated”.
18 Based on their modeling, Conolly et al. (2003, 200 4) concluded that the directly mutagenic action of formaldehyde does not play a significant role in formaldehyde ca rcinogenicity. Respiratory cancer risks associated with inhaled formaldehyde were predicted to be de minimis (10 –6 or less) at relevant human exposure levels when an upper bound on the model estimate for the directly mutagenic ac tion of formaldehyde was used.
19 The scope of this evaluation was informed by views provided by several experts convened by EPA in Oct ober 2004. The participants were Drs. Rory Conolly, Kenn y Crump, Linda Hanna, Dale Hattis, Julia Kimbell, G eorge Lucier, Christopher Portier and Fred Miller (guest participant). The meeting agenda and summary are pr ovided in Appendix H.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-40 criticism was rebutted by Crump et al. (2009) on bi ological and epidemiological grounds. These 1 debates have been discussed fully in Appendix F. In particular, the assessment concludes that: 2
3

• When used for the purpose of extrapolating risk, th e BBDR models did not appear to 4 reasonably constrain either 5 risk estimates extrapolated from the F344 rat to th e human, regardless of whether the 6 extrapolation was carried out at low or comparable exposures, or 7 risk estimates for the F344 rat when extrapolated o utside the range of observable data. 8

• Furthermore, human risk calculated from these BBDR models was numerically unstable 9 when certain parameter conditions were realized (Se ction 5.3.3 and Appendix F). 10

• Therefore, clonal growth modeling was not found to be a useful approach for human 11 extrapolation of rodent risk estimates. The current assessment concludes that the result in 12 Conolly et al. cannot be considered to be “conserva tive in the face of model 13
uncertainties.” 14
15 However, using the BBDR model to characterize the d ose-response in the range of the 16 available data was judged to have the advantage of utilizing the available biological and 17 dosimetry data on formaldehyde in an integrated man ner as well as providing statistically sound 18 descriptions of the empirical tumor incidence data. Therefore, this assessment uses the BBDR 19 modeling of the rat data to derive multiple PODs (f or SCC in the respiratory tract) in the range of 20
the observed data and uses model-derived internal d ose estimates. For the reasons detailed above, 21 the BBDR modeling is not used to extrapolate far be low the observed data. 22
The lowest observed incidence of SCC in the bioassa ys used in the dose-response 23 assessment was equal to 0.0087 (at 6 ppm exposure). In addition, the BBDR modeling used data 24 on cell proliferation and formation of DPXs that in formed the modeling of the tumor data at the 25 lower exposure concentrations of 0.7 and 2.0 ppm. Thus, the available data supported estimation 26 of response levels below the 10% response level com monly used in BMD analyses of tumor data. 27 Therefore, points of departure corresponding to 95 % statistical upper bound levels of extra risk 28 of 0.005, 0.01 and 0.1 were estimated when the BBDR modeling was used. 29
30 Summary: 31
As discussed earlier in the hazard characterization , formaldehyde is a direct-acting 32 mutagen, and its genotoxic effects have been observ ed following human occupational 33This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-41 exposures. 20 Furthermore, a low-dose nonlinear MOA for formald ehyde-induced 1 lymphohematopoietic cancers, NPCs, or cancers in ot her regions of the respiratory tract has not 2 been established. In particular, the formation of DPXs by formaldehyde, considered a dose 3 surrogate for the molecular dose associated with fo rmaldehyde’s mutagenic action, has been 4 observed at doses well below those considered cytot oxic. Therefore, linear low-dose 5 extrapolation from the suitably chosen PODs was con sidered most appropriate for all the cancers 6 (whether the PODs were based on epidemiological dat a or rodent bioassay data), which is also in 7
accordance with EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). 8
9
6.2.2.5. Inhalation Unit Risk Estimates for Cancer 10 The epidemiological and rodent inhalation data indi cate multiple sites of concern. Unit 11 risk estimates calculated separately from these dat a are summarized in Table 6-3. 12 As can be seen in the Table 6-3, the unit risk esti mate based on human data for NPC is in 13 the range of the estimates calculated for respirato ry tract cancer from the rodent nasal cancer 14 data. Experimental animal data were inadequate for estimating risk of lymphohematopoietic 15 cancers. The unit risk estimate for Hodgkin lympho ma is also in the same range, while the unit 16
risk estimate for leukemia and the total cancer uni t risk estimate are up to 4-fold higher. 17
As documented in EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 18 when high-quality human data are available, they ar e generally preferred over laboratory animal 19 data for quantitative risk assessment. Thus, the p referred (plausible upper bound) unit risk 20
estimate in this assessment is the value of 8.1 × 10 –2 per ppm (6.6 × 10 –5 per μg/m 3 ) based on 21 ( adult ) human data for NPC, Hodgkin lymphoma, and leukemi a. Note that, as discussed in 22 Section 6.2.2.6 below, if there is early-life expos ure, the age-dependent adjustment factors 23 (ADAFs) should be applied, in accordance with EPA’s Supplemental Guidance for Assessing 24 Susceptibility from Early-Life Exposure to Carcinog ens (U.S. EPA, 2005b). 25
26
6.2.2.6. Early-Life Susceptibility 27 There are no chemical-specific data for quantitativ ely addressing the susceptibility of 28 different life stages to carcinogenicity from inhal ation exposure to formaldehyde. As 29 documented in section 4.5, formaldehyde is a mutage nic carcinogen and the weight of evidence 30 suggests that formaldehyde carcinogenicity can be a ttributed, at least in part, to a mutagenic 31 MOA. Therefore, increased early-life susceptibilit y should be assumed and, if there is early-life 32

20 While formaldehyde may also contribute to mutation s indirectly, such an effect is likely to be releva nt only at the higher doses.This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-42 exposure, the ADAFs should be applied, in accordanc e with EPA’s Supplemental Guidance for 1 Assessing Susceptibility from Early-Life Exposure t o Carcinogens (U.S. EPA, 2005b). See 2 Section 5.4.4 for details on the application of the ADAFs. 3
4
Table 6-3 Inhalation unit risk estimates based on epidemiological and 5 experimental animal data 6 7 

### Cancer type a 

### Dose metric Unit Risk Estimate b (ppm –1 ) Based on Epidemiological Data Nasopharyngeal Cumulative exposure 0.011 Hodgkin lymphoma Cumulative exposure 0.017 Leukemia Cumulative exposure 0.057

All three cancer sites combined: 0.081 c

Based on Experimental Animal Data

Squamous cell carcinoma of the respiratory tract Local dose (flux) of formaldehyde in pmol/mm 2 /hour 0.011 – 0.022 d

8

a the unit risk estimates are all for cancer incidenc e. 9
b these unit risk estimates do not include ADAFs (see Section 6.2.2.6 below). 10

c this total cancer unit risk estimate is an estimat e of the upper bound on the sum of risk estimates c alculated 11 for the 3 individual cancer types (nasopharyngeal c ancer, Hodgkin lymphoma, and leukemia); it is not t he 12 sum of the individual (upper bound) unit risk estim ates (see Section 5.2.4). 13

d values are similar to estimates from Schlosser et al. (2003). These authors determined their PODs ba sed 14 on tumor and cell proliferation as endpoints, and e xtrapolated benchmark exposure concentrations to 15 humans using formaldehyde flux to the tissue and DP X concentrations as internal dose metrics. 16 17
18 Accordingly, for full lifetime exposures, the overall (plausible upper bound) uni t risk 19 estimate is 0.13 per ppm (1.1 × 10 –4 per μg/m 3 ) for the three cancer types (NPC, Hodgkin 20 lymphoma, and leukemia) combined (see Table 5-26 fo r calculations). 21
22
6.2.2.7. Uncertainties in the Quantitative Risk Estimates 23
Uncertainties in the risk estimates based on the hu man data are discussed in detail in 24 Sections 5.2.2.4 and 5.2.3.4. Major uncertainties inherent in the NPC, Hodgkin lymphoma, and 25
leukemia risk estimates are 26
27This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-43  the retrospective exposure estimation, 1

 the appropriateness of the dose-response model and exposure metric, and 2

 the extrapolation from occupational exposures to lo wer environmental exposures. 3
4 In addition, the NPC and Hodgkin lymphoma estimates are limited by the sparse data for these 5 cancers in the NCI cohort study (estimates are base d on the exposure-response modeling of only 6 9 NPC deaths and 27 Hodgkin lymphoma deaths). 7 Of note, Marsh et al. (2002, 1996) independently st udied one of the 10 plants that was in 8 the NCI study, and there were large differences in the exposure estimates for that plant from the 9 two different studies. If the exposure estimates o f Marsh et al. (2002) are closer to the true 10 exposures, then the potency of formaldehyde could b e greater than reflected in the risk estimates 11
derived from the NCI data. 12 The linear low-dose extrapolation (see Section 6.2. 2.4) from the 95% lower bound on the 13 exposure level associated with the benchmark respon se is generally considered to provide a 14 plausible upper bound on the risk at lower exposure levels. The strong association with peak 15 exposures for all 3 cancer types in the NCI study s uggests that dose-rate effects may be operative 16 (i.e., the risk from peak occupational exposures ma y be greater than the [linearly] proportional 17 risks from lower exposures and, similarly, the risk from an occupational cumulative exposure 18 may be greater than the proportional risk from a lo wer environmental cumulative exposure). 21 19 Any such dose-rate effects would not be reflected i n the linear low-dose extrapolation approach 20 used in this assessment. Actual low-dose risks may be lower to an unknown extent. 21 Other significant uncertainties may also remain. F or example, risk estimates could not be 22 derived from the NCI cohort study for rare upper re spiratory tract cancers other than NPC. In 23 addition, although unit risk estimates were derived for Hodgkin lymphoma and leukemia because 24 they exhibited the strongest trend results of the l ymphohematopoietic cancers using the 25 cumulative exposure metric, it is uncertain which s pecific lymphohematopoietic cancer subtypes 26 are associated with formaldehyde exposure. Further more, the potential role of particulates in the 27 NPC risk is unclear. Moreover, as for all occupati onal epidemiology studies, there is uncertainty 28 in extrapolating risk from an adult worker populati on (in this case predominantly white males) to 29 the more diverse general population. 30
31

21 Dose-rate effects are also suggested by the very s teep, nonlinear exposure-response relationships obs erved in the rodent cancer bioassays, although, in the rodents, this steep increase in tumor incidence at high expo sures is thought to be due to the contribution of cytotoxicity and r egenerative proliferation, which is not apparent wi th the human exposures (Section 4.5).This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-44 Despite inevitable uncertainties, it is important n ot to lose sight of the strengths of the 1 estimates, which are based on human data from a hig h-quality NCI study. In addition to the use 2 of internal analyses and the extensive exposure ass essment and consideration of potential 3 confounding or modifying variables, the NCI study h as a large cohort that has been followed for 4 a long time. With the additional follow-up through 2004, reflected in the lymphohematopoietic 5 cancer results of Beane Freeman et al. (2009), the median duration of follow-up was 42 years, 6 and the 25,619 cohort members had accrued 998,106 p erson-years of follow-up. 7 Significant uncertainties also exist in the risk es timates derived from the rodent bioassay 8 data. In general, the difficulties in extrapolatin g from experimental animal bioassays are 9 considerable, and the use of human data is preferre d, while recognizing the different uncertainties 10 that are present in risk estimates based on epidemi ological data. 11 In the case of formaldehyde, this general uncertain ty associated with extrapolation from 12 rodent data is increased due to the highly curvilin ear nature of the dose–response relationships 13 associated with DPX formation, labeling index data, and tumor responses. The mechanistic 14 interpretation of these observed data has provided grounds for arguments in the literature that 15 formaldehyde tumorigenicity (at exposures ≥ 6 ppm) should be uncoupled from its potential 16 carcinogenicity in the low-dose region. 17 Quantitative models have been used in the literatur e to further argue that the observed 18 risk in animal experiments is entirely due to cell proliferation induced by regenerative 19 hyperplasia in response to cell injury at cytotoxic doses, i.e., without a relevant role for the direc t 20 mutagenic action of formaldehyde. In the context o f using these data for quantitative risk 21 assessment, this document notes that such an infere nce of the data has been found to be 22 extremely uncertain. An analysis of the uncertaint ies in interpreting the available data has shown 23 that the directly mutagenic component could be impo rtant in explaining the high-dose effect 24 (Subramaniam et al., 2007). 25 While acknowledging these substantial difficulties, the quantitative dose-response 26 modeling of the rat data does allow inference about upper bound risks for respiratory cancer, 27 consistent with the observed experimental tumorigen icity. These upper bound risk estimates are 28 consistent with those estimated from the epidemiolo gical data; however, such a consistency may 29 be entirely artifactual. As noted earlier, the BBDR modeling helped characterize some of the 30 uncertainty associated with extrapolating from the rodent data to the environmental risk in 31 people. The actual risk may be substantially lower or higher than the reasonable upper bound risk 32
estimated from the animal data. 33
34
35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-45 6.2.2.8 Conclusions 1 Cancer unit risk estimates for formaldehyde inhalat ion exposure were derived from both 2 human and laboratory animal data. As documented in EPA's Guidelines for Carcinogen Risk 3
Assessment

(U.S. EPA, 2005a), when high-quality human data a re available, they are generally 4 preferred over laboratory animal data for quantitat ive risk assessment. Thus, the preferred unit 5
risk estimate in this assessment is based on human data for NPC, Hodgkin lymphoma, and 6 leukemia from a high-quality NCI occupational cohor t study (Hauptmann et al., 2004; Beane 7 Freeman et al., 2009). (The qualitative hazard ass essment suggests causal associations between 8 formaldehyde exposure and other cancer types as wel l [e.g., other upper respiratory tract cancers 9 and possibly other lymphohematopoietic cancers; see Section 4.5], but quantitative data from the 10 NCI cohort study were not amenable for deriving qua ntitative risk estimates for those cancer 11 types. Because there were not clear exposure-respo nse data for these cancer types in that cohort 12 study [based on cumulative exposure], any contribut ions to the total cancer risk from 13 environmental formaldehyde exposure for these cance rs are not expected to be large; however, 14 this is a source of uncertainty.) 15
The unit risk estimate for the total cancer inciden ce extra risk for these three cancer types 16 combined based on the (adult) human data is 8.1 × 1 0 -2 per ppm (6.6 × 10 -5 per μ g/m 3 ). As 17 documented in Section 4.5, formaldehyde is a mutage nic carcinogen and the weight of evidence 18 suggests that formaldehyde carcinogenicity can be a ttributed, at least in part, to a mutagenic 19 MOA. Therefore, as there are no chemical-specific inhalation data on cancer susceptibility at 20 different life-stages, increased early-life suscept ibility is assumed and ADAFs should be applied 21
in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 22 Exposure to Carcinogens (U.S. EPA, 2005b). Applying the ADAFs, the overa ll (upper bound) 23
unit risk estimate for full lifetime exposure is 0.13 per ppm (1.1 × 10 –4 per μg/m 3 ) for the three 24 cancer types (NPC, Hodgkin lymphoma, and leukemia) combined. Using this lifetime unit risk 25 estimate, the upper bound estimate of the cancer ri sk at the RfC of 1 ppb is 1 × 10 –4

. 26
27
6.3. SUMMARY AND CONCLUSIONS 28
Seven different non-cancer health effects were iden tified from formaldehyde inhalation 29 exposure studies, including: 1) sensory irritation of the eyes, nose, and throat, 2) upper 30 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 31 behavioral toxicity, 6) reproductive and developmen tal toxicity, and 7) immunological toxicity. 32 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 33
derived candidate RfCs for critical effects based o n seven key studies. Three co-critical studies 34 were selected which provide similar cRfCs for relat ed adverse health effects observed in 35This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE 6-46 residential populations including children i.e., in creased asthma incidence, decreased pulmonary 1 function, increase in respiratory symptoms, and inc reased allergic sensitization (Rumchev et al., 2 2002; Garrett et al., 1999; Krzyzanowski et al., 19 99). The resulting cRfCs fall in a range 3 between 2.8 and 11 ppb, depending on the study, or endpoints considered, and the application of 4 alternative uncertainty factors for human variabili ty (Table 6-1). The representative RfC for the 5 co-critical studies is taken as the average of the cRfCs (Section 6.2.1.2). 6 EPA has assessed the adequacy of the overall databa se for RfC derivation, and although 7 the database is quite large, and provides significa nt information on well studied POE effects. 8 There are remaining uncertainties in the database. Most notably, there is a need for additional 9 exposure-response information for observed neurotox ic effects, reproductive and developmental 10 effects as well as a two-generation study to evalua te the effects of formaldehyde exposure on 11 reproductive and developmental endpoints. EPA is c onsidering 4 options to address database 12 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 13 appropriate to account for human variability and de ficiencies in the overall database. For this 14 reason, several alternatives have been presented. EPA is seeking advice from the NAS and the 15 public on this matter. 16 Formaldehyde is carcinogenic to humans by the inha lation route of exposure. There is 17
sufficient evidence of a causal association between formaldehyde exposure and cancers of the 18 upper respiratory tracts, with the strongest eviden ce for nasopharyngeal and sino-nasal cancers. 19
There is also sufficient evidence of a causal assoc iation between formaldehyde exposure and 20 lymphohematopoietic cancers, with the strongest evi dence for Hodgkin lymphoma and leukemia, 21 particularly myeloid leukemia. The (upper bound) u nit risk estimate for the total cancer 22 incidence based on (adult) human data is 8.1 × 10 -2 per ppm (6.6 × 10 -5 per μ g/m 3 ). Applying the 23 age-dependent adjustment factors for increased earl y-life susceptibility, the overall combined 24 cancer unit risk estimate for full lifetime exposur e is 0.13 per ppm (1.1 × 10 –4 per μg/m 3 ). 25This document is a draft for review purposes only a nd does not constitute Agency policy. DRAFT—DO NOT CITE OR QUOTE R-1 REFERENCES

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