DRAFT-DO NOT CITE OR QUOTE EPA/635/R-10/002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 review under applicable information quality 

guidelines. It has not been formally disseminated by EPA. It does not represent and should not 

be construed to represent any Agency determination or policy. It is being circulated for review of 

its technical accuracy and science policy implications.

 U.S. Environmental Protection Agency 

Washington, DC 
This document is a draft for review purposes only and does not constitute Agency policy.

III-ii DRAFT—DO NOT CITE OR QUOTE 

DISCLAIMER

 This document is a preliminary draft for review purposes only. This information is 

distributed solely for the purpose of pre-dissemination peer review under applicable information 

quality guidelines. It has not been formally disseminated by EPA. It does not represent and 

should not be construed to represent any Agency determination or policy. Mention of trade 

names or commercial products does not constitute endorsement or recommendation for use. 
This document is a draft for review purposes only and does not constitute Agency policy.

III-iii DRAFT—DO NOT CITE OR QUOTE 

CONTENTS—TOXICOLOGICAL REVIEW OF FORMALDEHYDE 

(CAS No. 50-00-0) 

LIST OF TABLES ......................................................................................................................... xi 

LIST OF FIGURES....................................................................................................................... xx 

LIST OF ABBREVIATIONS AND ACRONYMS.................................................................... xxv 

FOREWORD ............................................................................................................................ xxxii 

AUTHORS, CONTRIBUTORS, AND REVIEWERS............................................................ xxxiii

VOLUME I 

1. INTRODUCTION................................................................................................................... 1-1 

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

2.1. PHYSICOCHEMICAL PROPERTIES OF FORMALDEHYDE................................ 2-1 

2.2. PRODUCTION, USES, AND SOURCES OF FORMALDEHYDE........................... 2-1 

2.3. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE..................................... 2-4 

2.3.1. Inhalation.......................................................................................................... 2-5 

2.3.2. Ingestion ......................................................................................................... 2-10 

2.3.3. Dermal Contact............................................................................................... 2-11 

3. TOXICOKINETICS ............................................................................................................... 3-1 

3.1. CHEMICAL PROPERTIES AND REACTIVITY....................................................... 3-1 

3.1.1. Binding of Formaldehyde to Proteins............................................................... 3-1 

3.1.2. Endogenous Sources of Formaldehyde ............................................................ 3-3 

3.1.2.1. Normal Cellular Metabolism (Enzymatic) ........................................ 3-3 

3.1.2.2. Normal Metabolism (Non-Enzymatic).............................................. 3-5 

3.1.2.3. Exogenous Sources of Formaldehyde Production............................. 3-5 

3.1.2.4. FA-GSH Conjugate as a Method of Systemic Distribution............... 3-6 

3.1.2.5. Metabolic Products of FA Metabolism (e.g., Formic Acid).............. 3-6 

3.1.2.6. Levels of Endogenous Formaldehyde in Animal and Human 

Tissues.............................................................................................. 3-6 

3.2. ABSORPTION ............................................................................................................. 3-9 

3.2.1. Oral................................................................................................................... 3-9 

3.2.2. Dermal .............................................................................................................. 3-9 

3.2.3. Inhalation.......................................................................................................... 3-9 

3.2.3.1. Formaldehyde Uptake Can be Affected by Effects at the 

Portal of Entry ................................................................................ 3-10 

3.2.3.2. Variability in the Nasal Dosimetry of Formaldehyde in 

Adults and Children........................................................................ 3-12 

3.3. DISTRIBUTION......................................................................................................... 3-13 

3.3.1. Levels in Blood............................................................................................... 3-13 

3.3.2. Levels in Various Tissues............................................................................... 3-15 

3.3.2.1. Disposition of Formaldehyde: Differentiating covalent 

Binding and Metabolic Incorporation............................................. 3-16 
This document is a draft for review purposes only and does not constitute Agency policy.

III-iv DRAFT—DO NOT CITE OR QUOTE 

CONTENTS (continued) 

3.4. METABOLISM .......................................................................................................... 3-20 

3.4.1. In Vitro and In Vivo Characterization of Formaldehyde Metabolism............ 3-20 

3.4.2. Formaldehyde Exposure and Perturbation of Metabolic Pathways................ 3-23 

3.4.3. Evidence for Susceptibility in Formaldehyde Metabolism ............................ 3-24 

3.5. EXCRETION.............................................................................................................. 3-25 

3.5.1. Formaldehyde Excretion in Rodents .............................................................. 3-26 

3.5.2. Formaldehyde Excretion in Exhaled Human Breath...................................... 3-27 

3.5.3. Formaldehyde Excretion in Human Urine...................................................... 3-31 

3.6. MODELING THE TOXICOKINETICS OF FORMALDEHYDE AND DPX.......... 3-32 

3.6.1. Motivation ...................................................................................................... 3-32 

3.6.2. Species Differences in Anatomy: Consequences for Gas Transport and 

Risk................................................................................................................ 3-34 

3.6.3. Modeling Formaldehyde Uptake in Nasal Passages....................................... 3-40 

3.6.3.1. Flux Bins ......................................................................................... 3-41 

3.6.3.2. Flux Estimates ................................................................................. 3-41 

3.6.3.3. Mass Balance Errors........................................................................ 3-42 

3.6.4. Modeling Formaldehyde Uptake in the Lower Respiratory Tract.................. 3-42 

3.6.5. Uncertainties in Formaldehyde Dosimetry Modeling .................................... 3-44 

3.6.5.1. Verification of Predicted Flow Profiles........................................... 3-44 

3.6.5.2. Level of Confidence in Formaldehyde Uptake Simulations............ 3-45 

3.6.6. PBPK Modeling of DNA Protein Cross-Links (DPXs) Formed by 

Formaldehyde ................................................................................................ 3-48 

3.6.6.1. PBPK Models for DPXs.................................................................. 3-48 

3.6.6.2. A PBPK Model for DPXs in the F344 Rat and Rhesus 

Monkey that uses Local Tissue Dose of Formaldehyde ................. 3-50 

3.6.6.3. Uncertainties in Modeling the Rat and Rhesus DPX Data.............. 3-51 

3.6.7. Uncertainty in Prediction of Human DPX Concentrations ............................ 3-53 

VOLUME II 

4. HAZARD CHARACTERIZATION....................................................................................... 4-1 

4.1. HUMAN STUDIES...................................................................................................... 4-1 

4.1.1. Noncancer Health Effects................................................................................. 4-1 

4.1.1.1. Sensory Irritation (Eye, Nose, Throat Irritation)................................ 4-1 

4.1.1.2. Pulmonary Function ........................................................................ 4-11 

4.1.1.3. Asthma............................................................................................. 4-19 

4.1.1.4. Respiratory Tract Pathology............................................................ 4-26 

4.1.1.5. Immunologic Effects ....................................................................... 4-30 

4.1.1.6. Neurological/Behavioral.................................................................. 4-42 

4.1.1.7. Developmental and Reproductive Toxicity..................................... 4-45 

4.1.1.8. Oral Exposure Effects on the Gastrointestinal Tract ....................... 4-56 

4.1.1.9. Summary: Noncarcinogenic Hazard in Humans ............................. 4-56 
This document is a draft for review purposes only and does not constitute Agency policy.

III-v DRAFT—DO NOT CITE OR QUOTE 

CONTENTS (continued) 

4.1.2. Cancer Health Effects..................................................................................... 4-57 

4.1.2.1. Respiratory Tract Cancer................................................................. 4-57 

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 Toxicity................................ 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................................................... 4-324 

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 ..................................................................... 4-344 

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 Systems............................ 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 NONCARCINOGENIC

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 Inform MOAs ..................... 4-385 

4.4.6. Noncancer Modes of Actions ....................................................................... 4-387 

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

III-vi DRAFT—DO NOT CITE OR QUOTE 

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 Mechanistic 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 (Developmental 

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

4.5.2.6. Solid Tumors of Lymphoid Origin................................................ 4-421 

4.5.2.7. Supporting Evidence from Animal Bio-Assays for 

Formaldehyde-Induced Lymphohematopoietic Malignancies...... 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 Respiratory 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 Carcinogenicity...................... 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 ...................................................................................... 4-462 
This document is a draft for review purposes only and does not constitute Agency policy.

III-vii DRAFT—DO NOT CITE OR QUOTE 

CONTENTS (continued) 

4.6.6. Co-Exposures ............................................................................................... 4-464 

4.6.6.1. Cumulative Risk ............................................................................ 4-464 

4.6.6.2. Aggregate Exposure....................................................................... 4-465 

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 RfCs.......................................... 5-33 

5.1.2.1. Selection of Studies for Candidate RfC Derivation......................... 5-33 

5.1.2.2. Derivation of Candidate RfCs from Key Studies ............................ 5-40 

5.1.2.3. Evaluation of the Study-Specific Candidate RfC ............................ 5-66 

5.1.3. Database Uncertainties in the RfC Derivation ............................................... 5-69 

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 NATIONAL 

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 National Cancer 

Institute Cohort............................................................................... 5-76 

5.2.2.2. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer 

Mortality......................................................................................... 5-79

5.2.2.3. Prediction of Lifetime Extra Risk of Nasopharyngeal 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 National Cancer 

Institute Cohort............................................................................... 5-88 
This document is a draft for review purposes only and does not constitute Agency policy.

III-viii DRAFT—DO NOT CITE OR QUOTE 

CONTENTS (continued) 

5.2.3.2. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma 

and Leukemia Mortality ................................................................. 5-91 

5.2.3.3. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma 

and Leukemia Incidence................................................................. 5-93 

5.2.3.4. Sources of Uncertainty .................................................................... 5-95 

5.2.4. Conclusions on Cancer Unit Risk Estimates Based on Human Data............. 5-99 

5.3. DOSE-RESPONSE MODELING OF RISK OF SQUAMOUS CELL 

CARCINOMA IN THE RESPIRATORY TRACT USING ANIMAL DATA ...... 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 Modeling.............................. 5-106 

5.3.2.1. Major Results of the CIIT Modeling Effort................................... 5-111 

5.3.3. This Assessment’s Conclusions from Evaluation of Dose-Response 

Models of DPX Cell-Replication and Genomics Data, and of BBDR 

Models for Risk Estimation......................................................................... 5-111 

5.3.4. Benchmark Dose Approaches to Rat Nasal Tumor Data ............................. 5-118 

5.3.4.1. Benchmark Dose Derived from BBDR Rat Model and Flux 

as Dosimeter ................................................................................. 5-118 

5.3.4.2. Comparison with Other Benchmark Dose Modeling 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 INHALATION... 5-133 

5.4.1. Inhalation Unit Risk Estimates Based on Human Data................................ 5-133 

5.4.2. Inhalation Unit Risk Estimates Based on Rodent Data ................................ 5-133 

5.4.3. Summary of Inhalation Unit Risk Estimates ................................................ 5-135

5.4.4. Application of Age-Dependent Adjustment Factors (ADAFs) .................... 5-136 

5.4.5. Conclusions: Cancer Inhalation Unit Risk Estimates................................... 5-137 

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD 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 Excretion ..................................... 6-1 

6.1.3. Noncancer Health Effects in Humans and Laboratory 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 ....................................... 6-12 
This document is a draft for review purposes only and does not constitute Agency policy.

III-ix DRAFT—DO NOT CITE OR QUOTE 

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 Animals...................................... 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 Concentrations ........................ 6-25 

6.2.1.3. Adequacy of Overall Data Base for RfC Derivation ....................... 6-26 

6.2.1.4. Uncertainties in the Reference Concentration (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 Estimates ............................ 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 PUBLIC 

COMMENTS AND DISPOSITIONS.............................................................. A-1 

APPENDIX B: SIMULATIONS OF INTERINDIVIDUAL AND ADULT-TO-CHILD 

VARIABILITY IN REACTIVE GAS UPTAKE IN A SMALL SAMPLE 

OF PEOPLE (Garcia et al., 2009).....................................................................B-1 

APPENDIX C: LIFETABLE ANALYSIS .................................................................................C-1 

APPENDIX D: MODEL STRUCTURE & CALIBRATION IN CONOLLY ET AL. 

(2003, 2004)..................................................................................................... D-1 

APPENDIX E: EVALUATION OF BBDR MODELING OF NASAL CANCER 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-1 
This document is a draft for review purposes only and does not constitute Agency policy.

III-x DRAFT—DO NOT CITE OR QUOTE 

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 QUANTITATIVE 

EVALUATION OF ANIMAL TOXICOLOGY DATA FOR 

ANALYZING CANCER RISK DUE TO INHALED FORMALDEHYDE... H-1 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xi DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES 

Table 2-1. Physicochemical properties of formaldehyde............................................................ 2-2 

Table 2-2. Ambient air levels by land use category.................................................................... 2-6 

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

Table 3-1. Endogenous formaldehyde levels in animal 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 populations ............................................... 3-25 

Table 3-4. Percent distribution of airborne [14C]-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 levels 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 concentrations in the mouth and nose, 

and in the oral cavity after breath holding in three healthy male laboratory 

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

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

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

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

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

nasopharyngeal cancer) ..........................................................................................4-78 

Table 4-4. Epidemiologic studies of formaldehyde and lymphohematopoietic cancers...........4-98 

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

strains of mice ......................................................................................................4-112 

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

strains of rats ........................................................................................................4-113 

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

mice exposed to 15 ppm.......................................................................................4-116 

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

III-xii DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

respiratory tract.....................................................................................................4-127 

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

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

Table 4-11. Enzymatic activities in nasal respiratory 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 parameters 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 severity) on histopathologic changes in 

the noses and larynxes of male and female albino SPF Wistar rats exposed to 

formaldehyde 6 hours/day for 13 weeks...............................................................4-148 

Table 4-18. Formaldehyde-induced nonneoplastic histopathologic 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 exposure..............................4-149 

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

exposed to formaldehyde (6 hours/day, 5 days/week for 13 weeks) and 

examined at the end of 130 weeks inclusive of exposure ....................................4-150 

Table 4-20. Formaldehyde effects on nasal epithelium for various concentration-bytime products in male albino Wistar rats..............................................................4-153 

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

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

III-xiii DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

formaldehyde-treated and control animals; data pooled for males and 

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

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

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

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

cerebral cortex of male Wistar rats exposed to formaldehyde 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 measurements 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 exposed to inhaled 

formaldehyde and wood dust for 104 weeks .......................................................4-166 

Table 4-30. Histopathologic changes (including tumors) 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 nasal 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 Kerns et al. (1983) 

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

Table 4-33. Incidence and location of nasal squamous 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, trachea, and free lung cells isolated 

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

III-xiv DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

cell count, basal membrane length, proliferation cells, and two measures of 

cell proliferation, LI and ULLI, in male F344 rats ..............................................4-196 

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

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

Table 4-38. Cell population and surface area estimates 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 cell proliferation in the upper 

respiratory tract....................................................................................................4-202 

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

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

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

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

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

MNNG and NaCl in male Wistar rats exposed to formaldehyde (0.5% 

formalin) in drinking water for 8 weeks..............................................................4-212 

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

reported in male and female Sprague-Dawley rats exposed to 

formaldehyde in drinking water at different ages................................................4-214 

Table 4-44. Incidence of hemolymphoreticular neoplasia 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 7001) .................................4-215 

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

B6C3F1 mice after a 3 week, 15-ppm formaldehyde exposure ..........................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 determining 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 .......................................................................4-226 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xv DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

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

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

inhalation, topical application, or footpad injection............................................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 swelling responses and skin mRNA 

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

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

sensitization due to formaldehyde in experimental animals................................4-251 

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

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

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

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

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

male and female LEW.1K rats ............................................................................4-263 

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

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

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

dams exposed via inhalation from mating through gestation..............................4-289 

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

male Wistar rats...................................................................................................4-298 

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

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

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

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

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

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

formaldehyde-treated mice ..................................................................................4-302 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xvi DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

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

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

abnormal sperm after oral administration of formaldehyde to male 

Wistar rats............................................................................................................4-305 

Table 4-66. Effect of formaldehyde on spermatogenic 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 exposure of male rats to formaldehyde...........4-308 

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

exposure studies ..................................................................................................4-311 

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

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

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

exposure studies ..................................................................................................4-318 

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

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

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

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

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

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

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

Table 4-76a. Formaldehyde-DNA reactions (DPX formation)..............................................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 formaldehyde..............................................................4-348 

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

III-xvii DRAFT—DO NOT CITE OR QUOTE 

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 science 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 studies which evaluated the 

incidence of all LHP cancers in formaldehyde-exposed populations 

(ICD-8 Codes: 200-209) and all leukemias (ICD-8 Codes: 204-207).................4-412 

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

disease groupings within the broad category of all lymphohematopoetic 

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

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

leukemia sub-types ..............................................................................................4-420 

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

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

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

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

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

Sprague-Dawley rats............................................................................................4-425 

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

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

III-xviii DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

animal studies .......................................................................................................5-19 

Table 5-2. Effects of formaldehyde exposure on completion 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 formaldehyde RfC development by 

health endpoint category........................................................................................5-36 

Table 5-5. Adjustment for non-occupational exposures 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 from 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-linear 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. EC0005, LEC0005, and inhalation unit risk estimates for NPC mortality from 

formaldehyde exposure based on the Hauptmann et al. (2004) log-linear 

trend analyses for cumulative exposure.................................................................5-81 

Table 5-11. EC0005, LEC0005, and inhalation unit risk estimates for NPC incidence 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 metrics.........................................5-90 

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

from NCI trend test models ...................................................................................5-90 

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

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

III-xix DRAFT—DO NOT CITE OR QUOTE 

LIST OF TABLES (continued) 

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

continuous exposure to formaldehyde...................................................................5-91 

Table 5-16. EC0005, LEC0005, and inhalation unit risk estimates for Hodgkin lymphoma 

mortality from formaldehyde exposure based on Beane Freeman et al. 

(2009) log-linear trend analyses for cumulative exposure.....................................5-93 

Table 5-17. EC005, LEC005, and inhalation unit risk estimates for leukemia mortality 

from formaldehyde exposure based on Beane Freeman et al. (2009) 

log-linear trend analyses for cumulative exposure ................................................5-93 

Table 5-18. EC0005, LEC0005, and inhalation unit risk estimates for Hodgkin 

lymphoma incidence from formaldehyde exposure, based on Beane 

Freeman et al. (2009) log-linear trend analyses for cumulative exposure.............5-94 

Table 5-19. EC005, LEC005, and inhalation unit risk estimates for leukemia incidence 

from formaldehyde exposure based on Beane Freeman et al. (2009) 

log-linear trend analyses for cumulative exposure ................................................5-94 

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

Table 5-21. Calculation of combined cancer incidence unit risk estimate at 0.1 ppm ..........5-100 

Table 5-22. Summary of tumor incidence in long-term bioassays on F344 rats....................5-105 

Table 5-23. BMD modeling of unit risk of SCC in the human respiratory tract ...................5-125 

Table 5-24. Formaldehyde-induced rat tumor incidences......................................................5-128 

Table 5-25. Human benchmark extrapolations of nasal tumors in rats using 

formaldehyde flux and DPX................................................................................5-134 

Table 5-26. Summary of inhalation unit risk estimates .........................................................5-135 

Table 5-27. Total cancer risk from exposure to a constant formaldehyde exposure 

level of 1 μg/m3

 from ages 0–70 years ................................................................5-137 

Table 6-1. Summary of candidate Reference Concentrations (RfC) for co-critical studies.....6-27 

Table 6-2. Effective concentrations (lifetime continuous 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.............................................................................................................6-42 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xx DRAFT—DO NOT CITE OR QUOTE 

LIST OF FIGURES 

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

Figure 2-2. Locations of hazardous air pollutant monitors........................................................2-5 

Figure 2-3. Modeled ambient air concentrations based on 1999 emissions ..............................2-7 

Figure 2-4. Range of formaldehyde air concentrations (ppb) in different environments...........2-9 

Figure 3-1. Formaldehyde-mediated protein modifications.......................................................3-2 

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

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

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

(GSH-dependent)................................................................................................3-20 

Figure 3-4. Metabolism of formate..........................................................................................3-22 

Figure 3-5. Scatter plot of formaldehyde concentrations 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 rat, rhesus monkey, and human................3-36 

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

simulations with water-dye studies ....................................................................3-37 

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

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

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

inspiratory flow rates..........................................................................................3-39 

Figure 3-10. Single-path model simulations of surface 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 et al., 1990) or in rats 

in vivo.................................................................................................................3-45 

Figure 3-12. Formaldehyde-DPX dosimetry in the F344 rat ...................................................3-47 

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

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

III-xxi DRAFT—DO NOT CITE OR QUOTE 

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 oriented to the left)......................................4-121 

Figure 4-4. Main components of the nasal respiratory 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 section levels chosen for morphometry 

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

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

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

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

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

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

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

Figure 4-10. Effect of formaldehyde exposure on cell 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/m3 carbon black, or both ...............................................4-223 

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

following formaldehyde exposure in guinea pigs after OVA sensitization and 

OVA challenge .................................................................................................4-235 

Figure 4-13. OVA-specific IgG1 (1B) in formaldehyde-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 week 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 Wistar rats............................4-239 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xxii DRAFT—DO NOT CITE OR QUOTE 

LIST OF FIGURES (continued) 

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

infiltration (Panel A) and goblet cell proliferation (Panel B) after Der f 

challenge in the nasal mucosa of male ICR mice after sensitization and 

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

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

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

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

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

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

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

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

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

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

after termination of 10-minute formaldehyde exposure ...................................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 the 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 formaldehyde-exposed mice .........................4-274 

Figure 4-27. Mortality corrected cumulative incidences 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 rats exposed to formaldehyde for 

24 months .........................................................................................................4-332 

Figure 4-30. Cumulative leukemia incidence in female 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......................................4-334 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xxiii DRAFT—DO NOT CITE OR QUOTE 

LIST OF FIGURES (continued) 

Figure 4-32. DNA-protein cross-links (DPX) and thymidine 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 formaldehyde exposure and the risk of 

lymphohematopoietic malignancy....................................................................4-415 

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

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

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

human colon carcinoma cells and in (B) human umbilical 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 lymphocytes 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 exposed to formaldehyde in the high 

exposure index category with 8-hour time weighted average 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 concentrations. ..............................5-41 

Figure 5.5. Odds ratios for physician-diagnosed asthma in children associated with inhome formaldehyde levels in air .......................................................................5-45 

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

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

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

in-home formaldehyde levels .............................................................................5-49 

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

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

III-xxiv DRAFT—DO NOT CITE OR QUOTE 

LIST OF FIGURES (continued) 

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

formaldehyde exposures and sensory irritation (burning 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 pharmacokinetic and pharmacodynamic 

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

Figure 5-12. Fit to the rat tumor incidence data using 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, resulting in 20 flux bins ..........5-120 

Figure 5-14. Distribution of cells at risk across flux bins in the F344 rat nasal lining..........5-120 

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

two BBDR models............................................................................................5-124 

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

Monticello et al. (1996) data on tumor incidence showing BMC10 and 

BMCL10 ............................................................................................................5-127 

Figure 5-17. EPA multistate Weibull modeling: nasal 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................................................5-132 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xxv DRAFT—DO NOT CITE OR QUOTE 

LIST OF ABBREVIATIONS AND ACRONYMS 

ACGIH American Conference of Governmental Industrial 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 Registry 

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 concentration 

BMCR binuclated micronucleated cell ratefluoresce 

BMD benchmark dose 

BMDL 95% lower bound on the benchmark dose 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xxvi DRAFT—DO NOT CITE OR QUOTE 

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 Prevention 

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 

CO2 carbon dioxide 

COEHHA California Office of Environmental Health Hazard Assessment 

CREB cyclic AMP responsive element binding proteins 

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 assay 
This document is a draft for review purposes only and does not constitute Agency policy.

III-xxvii DRAFT—DO NOT CITE OR QUOTE 

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 factor 

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 transferase 

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 Cancer 
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III-xxviii DRAFT—DO NOT CITE OR QUOTE 

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 

Km Michaels-Menton constant 

KM Kaplan-Meier 

LD50 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 level 
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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 Research Council/Agriculture and Resource 

Management Council of Australia and New Zealand 

NNK nitrosamine nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-butanone 

N

6

-hmdA N6-hydroxymethyldeoxyadenosine 

N

4

-hmdC N4-hydroxymethylcytidine 

N

2

-hmdG N2-hydroxymethyldeoxyguanosine 

NICNAS National Industrial Chemicals Notification and Assessment Scheme 

NIOSH National Institute for Occupational Safety and 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 volume 
This document is a draft for review purposes only and does not constitute Agency policy.

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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 index 

RA reflex apnea 

RANTES regulated upon activation, normal T–cell expressed and secreted 

RB reflex bradypnea 

RBC red blood cells 

RD50 exposure concentration that results in a 50% reduction 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 dehydrogenase 

SEER Surveillance, Epidemiology, and End Results 

SEM standard error of the mean 

SEN sensitizer 

SH sulfhydryl 

SHE Syrian hamster embryo 

SLMA spontaneous locomotor activity 
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LIST OF ABBREVIATIONS AND ACRONYMS (continued) 

SMR standardized mortality ratio 

SNP single nucleotide polymorphism 

SOD superoxide dismutase 

SOMedA N6

-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 for Europe
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1 5. QUANTITATIVE ASSESSMENT: INHALATION EXPOSURE 

2 

3 

4 This chapter presents the quantitative assessments conducted by EPA for both cancer and 

5 noncancer health effects associated with formaldehyde exposure. The quantitative assessment is 

6 focused on the inhalation route of exposure. The current IRIS reference dose (RfD) is not 

7 reevaluated in this assessment. Although there is some evidence of formaldehyde 

8 carcinogenicity via the oral route of exposure, these data are not evaluated herein nor is an oral 

9 slope factor considered at this time. Therefore, the following sections address derivation of a 

10 reference concentration (RfC) and cancer unit risk estimate for inhalation exposures. 

11 For noncancer effects, the RfC is an estimate (with uncertainty spanning perhaps an order 

12 of magnitude) of a continuous inhalation exposure to the human population (including sensitive 

13 subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. 

14 It can be derived from a NOAEL, LOAEL, or benchmark concentration, with uncertainty factors 

15 generally applied to reflect limitations of the data used. Data from the previous chapters are 

16 evaluated to determine the health effects associated with formaldehyde exposure and which 

17 studies may best inform the exposure response relationship for RfC derivation. Section 5.1 

18 summarizes the observed noncancer health effects, selecting key studies and critical effects for 

19 consideration. Candidate RfCs are derived for each identified key study. Several alternatives are 

20 considered for uncertainty factors addressing human variability for key studies and alternatives 

21 presented (Section 5.1.2.3). Options for addressing the overall database uncertainty factor are 

22 provided which may modify the final RfC (Section 5.1.3). 

23 The derivation of the cancer inhalation unit risk estimate considered data regarding both 

24 respiratory tract cancers and lymphohematopoietic malignancies. Exposure-response modeling 

25 from epidemiologic studies was used to derive a combined unit risk estimate for nasopharyngeal 

26 cancer and lymphohematopoietic cancers (Section 5.2). This unit risk estimate is supported by 

27 an analysis of exposure-response modeling of respiratory tract cancer risk using data from 

28 experimental animal studies (Section 5.3). Analysis of the animal bioassays includes an 

29 evaluation of a published biologically based dose-response model as well as an appraisal of 

30 published dose-response modeling of genomics data and a presentation of benchmark dose 

31 modeling approaches. Finally, Section 5.4 provides a summary and conclusions from the cancer 

32 exposure-response modeling, presenting the final unit risk estimate based on the combined risk 

33 of nasopharyngeal cancer and lymphohematopoietic cancers observed in the human studies. 

34 

35 
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1 

2 5.1. INHALATION REFERENCE CONCENTRATION (RfC) 

3 Prior to the current assessment, the EPA IRIS file for formaldehyde did not provide an 

4 inhalation RfC. As presented in the hazard identification in Chapter 4, a number of noncancer 

5 health effects are associated with formaldehyde exposure. Section 5.1.1 describes each of the 

6 health effect categories considered for RfC derivation and the specific endpoints considered for 

7 each category. The identified effect categories are: sensory irritation (eye, nose, and throat); 

8 upper respiratory tract (URT) pathology; pulmonary function; increased asthma and atopic 

9 sensitization; altered immune function; neurotoxicity and reproductive and developmental 

10 toxicity. For each health effect category,, studies that may adequately inform the exposure11 response relationship for specific critical effects are identified for consideration in RfC 

12 derivation. 

13 EPA employed a screening process across the different health effect categories to select 

14 key studies that would best support the derivation of an inhalation RfC (as described in 

15 Section 5.1.2.1). The following factors were considered in this evaluation: characteristics of the 

16 study population, exposure regimen, quality of exposure assessment, quality of exposure17 response assessment, exposure levels at which effects were seen and statistical power of the 

18 study. Based on this analysis, seven studies were considered for RfC derivation. Candidate RfC 

19 derivation from a key study includes the following steps: 1) define the critical effect(s); 2) 

20 determine appropriate point(s) of departure (PODs) on the basis of inhaled concentration; 3) 

21 adjust each POD by endpoint/study-specific uncertainty factors (UFs), to account for 

22 uncertainties in the extrapolation of study results to conditions of human environmental 

23 exposure. All of the identified key studies were human studies and several studies included 

24 potentially susceptible individuals (e.g. children, asthmatics). The uncertainty factor for human 

25 variability has sometimes been reduced for studies of susceptible populations or lifestages. 

26 However, for five of the seven key studies it was unclear if an uncertainty factor of 3 or 1 for 

27 human variability was most appropriate. Therefore, alternatives are presented for consideration. 

28 Candidate RfCs (cRfCs) are derived for sensory irritation, decreased pulmonary function in 

29 children, increased asthma incidence in children, increased allergic sensitization to common 

30 allergens in children, and decreased fecundability density ratio (FDR) in women (increased time 

31 to pregnancy) (Table 5-7). All of these cRfCs are derived from endpoints identified in residential 

32 studies, with the exception of decreased FDR (observed in an occupational study of women in 

33 the woodworking industry). 

34 The overall literature database of both human and laboratory animal studies examining 

35 the health effects from formaldehyde exposure is large; however, the available studies for some 
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1 types of effects are limited. Limitations in the existing database are discussed in Section 5.1.3, 

2 specifically regarding understanding the reproductive and developmental effects and the 

3 exposure-response relationship for the observed neurological and behavioral effects from 

4 formaldehyde exposure. EPA considers 3 options for addressing these database uncertainties in 

5 the final RfC: (1) providing an RfC derived from studies of respiratory and allergenic responses 

6 and protective of sensory irritation effects, without further adjustment for uncertainties in the 

7 database (noting the need for further research to elucidate reproductive, developmental and 

8 neurotoxic effects); (2) providing an RfC with a database uncertainty factor incorporated to 

9 reflect the potential that reproductive, developmental, or neurotoxic effects might occur at lower 

10 doses; or (3) provide a range for the RfC which encompasses the above two options for the 

11 database uncertainty factor. 

12 

13 5.1.1. Candidate Critical Effects by Health Effect Category 

14 The following subsections describe the best available studies and endpoints for 

15 quantitative RfC derivation within each health effect category. These studies are considered 

16 representative of the health effects attributed to formaldehyde exposure. For more details on 

17 specific studies discussed here, see Sections 4.1.1 and 4.2.1. The identified health effect 

18 categories are: sensory irritation (eye, nose, and throat); upper respiratory tract (URT) pathology; 

19 pulmonary function; increased asthma and allergic sensitization; altered immune function; 

20 neurotoxicity and reproductive and developmental toxicity. Discussions in each subsection 

21 below describe the various health effects observed in human and animal studies for each 

22 category. 

23 For each health effect category, specific studies that may adequately inform the exposure24 response relationship for critical effects are identified for consideration in RfC derivation. In 

25 general, studies are included where study quality and ability to define exposures are considered 

26 adequate for RfC derivation. Whenever possible, greater consideration is typically given to 

27 human data for derivation of an RfC. When laboratory studies conducted in rodents are 

28 considered for RfC derivation, the potential confounding effects of formaldehyde-induced reflex 

29 bradypnea (RB) are evaluated (Section 4.1.1 for a discussion of RB). If the exposure levels are 

30 expected to cause RB, results are evaluated to ensure the effects are not in part attributable to 

31 primary or secondary effects of RB in the rodents. 

32 

33 5.1.1.1. Sensory Irritation of the Eyes, Nose, and Throat 

34 Eye, nose, and throat irritation are common effects of chemically induced sensory 

35 irritation; specific effects include lacrimation, burning of the eyes and nose, rhinitis, burning of 
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1 the throat, and cough (Feron et al., 2001). Chemical irritants such as formaldehyde bind to 

2 protein receptors of the trigeminal nerve, triggering a burning and painful sensation. This 

3 process is distinct from taste and smell (Cometto-Muniz and Cain, 1992; Nielsen, 1991). The 

4 trigeminal nerve has three branches (ophthalmic, maxillary, and mandibular) and not only acts as 

5 an afferent nerve relaying these sensations to the central nervous system but has efferent nerve 

6 activity as well (Meggs, 1993). Stimulation of the trigeminal nerve may result in reflex 

7 responses, including lacrimation, coughing, and sneezing. In this assessment, both the reflex 

8 responses and the sensations (such as burning, pain, and itching of the eyes, nose, and throat) are 

9 considered adverse effects (see Section 4.1 for a full discussion of available human data). 

10 There are studies noting irritant effects in rodents (Sarsilmaz et al., 1999; Holmström et 

11 al., 1989; Dubreuil et al., 1976) and monkeys (Monticello et al., 1989; Rusch et al., 1983). These 

12 animal studies are supportive of the health effects reported in humans. However, given the 

13 uncertainties in extrapolation from responses in laboratory animals to expected responses in 

14 humans, the available human studies are preferred. 

15 In human studies, the endpoints for assessing irritation include subjective self reporting of 

16 symptoms (e.g., pain, burning, itching, increased cough) via questionnaires or objective measures 

17 of irritation that can be assessed during controlled acute exposures (e.g., eye-blink counts, 

18 lacrimation). Several acute chamber studies support development of a concentration-response 

19 relationship for sensory irritation, identifying an effect level for various exposure durations 

20 (Kulle, 1993; Andersen and Mølhave, 1983; Bender et al., 1983; Weber-Tschopp et al., 1977). 

21 Arts et al. (2006b) reviewed several studies and performed BMD analyses, reporting 10% extra 

22 risk BMCL values for reported eye discomfort of 560 and 240 ppb for 3 and 5 hour exposures, 

23 respectively. LOAELs of 1,000 ppb and 1,700 ppb were reported for 1-2 minute exposures 

24 (Bender et al., 1983; Weber-Tschopp et al., 1977). These acute studies support a role for both 

25 concentration and duration in the effect level for eye irritation. Although exposure 

26 concentrations are well-defined in these chamber studies, the chamber studies are not appropriate 

27 for RfC derivation because they are of acute duration and the exposure levels used are much 

28 higher than those reported for chronic exposure scenarios, both occupational and residential. 

29 A study of industrial workers assessed sensory irritation and provided an average 

30 exposure derived from in-plant exposure measurements and the work history of each study 

31 participant (Holmström and Wilhelmsson, 1988). Although average daily exposures were 

32 estimated for each employee, these data were not used to explore an exposure-response 

33 relationship within the worker cohort. The symptom prevalence for sensory irritation (e.g., nasal 

34 discomfort, eye discomfort, and airway discomfort) relative to the referent group was reported for 

the cohort as a whole, where worker exposure ranged from 0.05 to 0.5 mg/m3

35 formaldehyde 8-hr 
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5-5 DRAFT—DO NOT CITE OR QUOTE 

time-weighted average (TWA), with a mean of 0.26 mg/m3 1 (210 ppb). The daily TWA does not 

2 reflect the peak exposures experienced during specific work tasks. Although this study 

3 demonstrated marked increases in symptoms of sensory irritation in the workplace due to 

4 formaldehyde exposure, it provided little data to inform the exposure-response relationship, 

5 especially in the range of environmental exposures.

6 There are three studies that report sensory irritation in humans from chronic exposures in 

7 a residential environment and provide sufficient exposure data to support quantitative assessment 

8 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). Each study reports site9 specific exposure measurements and presents some metric of individual exposure. These 

10 residential studies employ in-home measurements for each study participant, either as average 

11 exposure level (Ritchie and Lehnen, 1987; Hanrahan et al., 1984) or as calculated cumulative 

12 exposure based on the time in the home (Liu et al., 1991). Eye irritation is reported at similar 

13 levels of residential formaldehyde exposure in the three studies (Figures 5-8 and 5-9). Each 

14 study provides an exposure-response relationship for prevalence of sensory irritation in relation 

15 to in-home formaldehyde exposure based on individual level data. The detailed exposure 

16 information and chronic nature of the exposures support the selection of these studies as potential 

17 priniciple studies for RfC derivation. Each of these studies is further evaluated and a cRfC 

18 developed for consideration (Section 5.1.2). 

19 

20 5.1.1.2. Upper Respiratory Tract Pathology

21 Formaldehyde-induced respiratory tract pathology includes inflammation, rhinitis, goblet 

22 cell hyperplasia, metaplastic changes, squamous cell hyperplasia, and impaired mucociliary 

23 transport. A series of laboratory animal studies assessing formaldehyde-induced changes in the 

24 nasal mucosa suggests that these changes may be a protective or adaptive response and that 

25 increased mucus flow and metaplastic changes will progress in relation to the concentration and 

26 duration of exposure to protect the underlying tissue (Swenberg et al., 1983). The degree of 

27 inflammation, hyperplasia, and metaplastic change that is due to sensory irritation-induced 

28 inflammatory responses versus inflammation and tissue remodeling from formaldehyde-induced 

29 direct cell damage cannot be distinguished. These changes have been noted as sensitive 

30 indicators of formaldehyde-induced effects, occurring before gross cellular damage and focal 

31 lesions (Monticello et al., 1989). These responses are considered for RfC derivation, especially 

32 for exposure concentrations where gross damage of the underlying tissue is not expected. 

33 Although well-documented studies demonstrating formaldehyde-induced upper respiratory tract 

34 (URT) pathology have been performed in laboratory animals, including the rat (Zwart et al., 

35 1988; Woutersen et al., 1987; Morgan et al., 1986a, b, 1983; Swenberg et al., 1986, 1983) and 
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5-6 DRAFT—DO NOT CITE OR QUOTE 

1 monkey (Rusch et al., 1983), robust human data are available, and these human data are preferred 

2 for RfC derivation. 

3 Six human studies examined the effects of formaldehyde exposure on URT pathology 

4 (Pazdrak et al., 1993; Boysen et al., 1990; Holmström et al., 1989; Edling et al., 1988; 

5 Holmström and Wilhelmsson, 1988; Andersen and Mølhave, 1983). Of these studies, 

6 Holmström and Wilhelmsson (1988) and Holmström et al. (1989) were identified as the most 

7 robust and sensitive and are included as candidate studies for RfC derivation (see Table 5-1). 

8 Both studies address the same cohort and, thus, were considered together. The Holmström and 

9 Wilhelmsson (1988) study is discussed above under sensory irritation effects. In this study of 70 

10 factory workers exposed to a TWA formaldehyde concentration of 210 ppb, impaired 

11 mucociliary clearance was reported in 20% of the exposed workers and 3% of the 36 nonexposed 

12 workers. Using rhinomanometry, Holmström and Wilhelmsson (1988) also found an increase in 

13 nasal resistance due to mucosal swelling, though this increase was not statistically significant. In 

14 Holmström et al. (1989), nasal biopsy samples were collected from 62 of the 70 formaldehyde15 exposed factory workers (these 62 had been exposed to a TWA formaldehyde concentration of 

16 240 ppb) and also from 32 of the nonexposed workers. A pathologist scored each sample by 

17 using a scale of 0 (normal respiratory epithelium) to 8 (carcinoma). Biopsy scores for both the 

18 exposed and control groups ranged from 0 (normal respiratory epithelium) to 4 (stratified 

19 squamous epithelium with marked horny layer). The mean scores for the two groups—2.16 for 

20 the formaldehyde-exposed workers and 1.56 for the unexposed workers—however, the 

21 difference was statistically significant and the authors reported that the loss of cilia, goblet cell 

22 hyperplasia, and the incidence of cuboidal and squamous cell metaplasia replacing the columnar 

23 epithelium were more frequent in the group exposed to formaldehyde. There was no correlation 

24 between the duration of exposure and histologic changes or between smoking habits and biopsy 

25 scores. The URT effects, taken together (decreased mucous flow, increased inflammation, 

26 decreased nasal flow, and degradation of the respiratory epithelium), demonstrate a range of 

27 formaldehyde-induced URT pathology consistent with effects observed in controlled animal 

28 studies. 

29 

30 5.1.1.3. Pulmonary Function Effects

31 The potential effects of formaldehyde exposure on pulmonary function in humans can be 

32 examined on several time-scales of interest. There are reports examining effects from acute 

33 exposures among naively exposed anatomy graduate students (Kriebel et al., 1993; 2001), 

34 anatomy graduate students with several weeks of episodic exposure (Kriebel et al., 1993), as well 

35 as post-shift versus pre-shift differences in pulmonary function in workers with regular 
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5-7 DRAFT—DO NOT CITE OR QUOTE 

1 occupational exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 

2 1982; Alexandersson and Hedenstierna, 1989). Depending on whether the exposures are naïve, 

3 the epidemiologic studies that assessed the pulmonary effects of acute exposures to formaldehyde 

4 may be assessing different biological responses, namely, the acute effect alone or the acute 

5 effect(s) in people who may have already been sensitized to formaldehyde effects. 

6 Pulmonary effects of acute formaldehyde exposure have been studied in both healthy 

7 volunteers and sensitive populations under controlled conditions (e.g. acute chamber studies). 

8 Although acute chamber studies have the advantage of measured controlled exposures, other 

9 factors can limit the usefulness of the studies for RfC derivation including: acute duration, small 

10 study populations and lack of statistical power to assess the measured parameters. The acute 

11 chamber studies are more fully evaluated in Section 4.1.1 and will not be further considered here 

12 for RfC derivation. 

13 The observed effects in the previously unexposed anatomy students provide additional 

14 information on acute exposures in two naïve populations (Kriebel et al., 1993; 2001), as well as 

15 insight into the intermediate stages of possible sensitization (Kriebel et al., 1993). Kriebel and 

16 colleagues (1993) examined the pre-laboratory and post-laboratory peak expiratory flow (PEF) in 

17 students attending anatomy classes once per week. They found the strongest pulmonary response 

18 when examining the average cross-laboratory decrement in peak expiratory flow in the first 2 

19 weeks of the study when formaldehyde concentrations collected in the breathing zones had a 

20 geometric average concentration of 0.73 ppm. Overall, the students exhibited a 2% decrement in 

21 PEF, while the students with any history of asthma showed a 7.3% decrement in PEF. These 

22 findings of acute decreases in PEF following students’ initial anatomy sessions were 

23 corroborated by the Kriebel et al. (2001) study, which used a similar study design applied to 

24 another class of anatomy students. 

25 The first Kriebel et al. (1993) study also shows how the acute effects of formaldehyde 

exposure were altered following several weeks of weekly episodic exposure. By the 5th 26 week of 

27 class, the pre- and post-laboratory measurements of PEF were no longer reflecting a clearly 

28 demonstrated acute effect but following the 7th week of episodic exposure, both pre-and post29 laboratory PEF continued to drop steadily until the class adjourned after 10 weeks time. While 

30 the acute effects of formaldehyde exposure appeared to diminish after several weeks of exposure, 

31 the intermediate effect across 9 weeks was a 24 liter/minute drop in PEF that was statistically 

32 significant (P<0.01) after statistical control for random person effects, asthma, an interaction 

33 between time and asthma and eye and nose symptoms of irritation. The Kriebel et al. (1993) 

34 study is considered of sufficient quality to support an acute RfC but the quantitative details on 

35 the initial acute effects among the naively exposed students are not adequately provided. The 
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5-8 DRAFT—DO NOT CITE OR QUOTE 

1 findings of the Kriebel et al. (2001) study were confounded by decreased class attendance, which 

2 dropped from 37 in the first week to 20 in week 6 and to just 10 students by week 10. While the 

3 Kriebel et al. (2001) study could be useful as a supportive study for naively exposed students, the 

4 longitudinal component is not strong enough to support RfC development. 

5 Several studies of workers assess both cross-shift and chrinic effects of formaldehyde 

6 exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1982; 

7 Alexandersson and Hedenstierna, 1989). Since formaldehyde exposure may have cumulative 

8 effects over chronic exposures, occupational studies generally showed clinically small but 

9 statistically significant decrements in pulmonary function across shifts. In general these studies 

10 did not identify, have information on or have appropriate statistical control of, potential 

11 confounding co-exposures. While these occupational studies provide evidence that is clearly and 

12 consistently supportive of an acute effect on pulmonary function, they do not directly support 

13 RfC development of an acute effect divorced of the concomitant chronic effects. 

14 Several studies allowed for the examination of potential chronic effects of formaldehyde 

15 exposure. These included an occupational study (Malaka and Kodama, 1990) that reported pre16 shift pulmonary function as a percentage of expected among the formaldehyde exposed 

17 compared to comparable people not exposed to formaldehyde. Studies that did not report pre18 shift pulmonary function as a percentage of expected function (Herbert et al., 1994; 

19 Alexandersson et al., 1982; Alexandersson and Hedenstierna, 1989) contribute less to an 

20 assessment of potential chronic effects because, post-hoc, it is difficult to calibrate for cross21 study comparison the multiple pulmonary function data without knowledge of the age, gender, 

22 smoking status, height, year of birth, etc. that are important determinants of the pulmonary 

23 function metrics of concern. The single study (Malaka and Kodama, 1990) that did report 

24 functional measures in relation to expected value, found that an average 8-hour time weighted 

25 average formaldehyde exposure of 1.13 ppm from area samples was associated with statistically 

26 significant decrements in FEV1, FEV1/FVC and FEF25-75 compared to a referent population. The 

27 strongest response was for FEF25-75, which showed a 12% drop in observed function compared to 

28 expected function in the unexposed, but it is unclear how to interpret the potential chronic health 

29 effect(s) with just the magnitude of the decrement and the length of the average occupational 

30 tenure at this plywood facility (6.5 years), which was not reported by exposure status. 

31 One study reported on the longitudinal follow-up of workers exposed to formaldehyde 

32 (Alexandersson and Hedenstierna, 1989). This investigation not only examined the acute effects 

33 of exposure across shift, but was able to do so among some of the same workers that had been 

34 studied five years earlier (Alexandersson et al., 1982). Statistically significant decreases in 

35 FEV1/FVC and FEF25-75 were noted over the intervening five years in non-smokers after 
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5-9 DRAFT—DO NOT CITE OR QUOTE 

1 correction for normal aging. The decrease in FEF25-75 was 0.212 liters/s (SD=0.066 liters/s) for 

2 each year of exposure and was highly significant (p<0.01). For comparison with the 12% drop in 

3 the same pulmonary metric reported by Malaka and Kodama (1990) over an estimated 6.5 years, 

4 EPA computed the extrapolated percentage decrease in FEF25-75 for the Alexandersson and 

5 Hedenstierna (1989) using the reported yearly decrement applied to the pre-shift values at the 

6 time of the initial study period. EPA calculated that from the predicted value of 4.57 liters/s, a 

7 decrease of 0.168 liters/s could be estimated for each year of exposure regardless of smoking 

8 status. For 6.5 years of exposure, this would result in a 24% drop in FEF25-75. Formaldehyde 

9 concentrations were estimated at 0.42 ppm in the first Alexandersson et al. (1982) study and at 

10 0.50 ppm in the second study, but without better exposure measures, the results of the 

11 longitudinal follow-up cannot support quantitative RfC development. 

12 Information is lacking in these studies such as length or tenure of employment associated 

13 with the pre-shift pulmonary function or how long the residents had lived in their homes. 

14 Likewise, knowledge of how occupational or residential exposure may have changed over time 

15 would have allowed for an examination of the progression of any decrement in function 

16 associated with long-term episodic exposure. Among these studies, the best designed and 

17 executed of the cross-sectional studies was that of Kryzanowski and colleagues (1990). 

18 Municipal employees and their children (613 adults and 298 children) were randomly sampled 

19 and were considered to be representative of a diverse local population. Residential exposures to 

20 formaldehyde were based on repeated samples from each individual’s kitchen, living area and 

21 bedroom. The average formaldehyde concentration was 26 ppb, with a maximum sample value 

22 of 140 ppb. The majority of subjects (83%) lived in homes with 2-week average concentrations 

23 below 40 ppb. Subjects’ peak expiratory flow rates (PEFR) were determined 4 times daily in the 

24 morning, at noon, in the early evening and before bed for 2 weeks. A statistically significant 

25 linear relationship between increased formaldehyde exposure and decreased peak expiratory flow 

26 rate was reported in children but not adults. All statistical models controlled for socioeconomic 

27 status, tobacco smoking (current active or environmental tobacco smoking) and nitrogen dioxide 

28 concentrations. In children, formaldehyde concentrations of 60-140 ppb increased the prevalence 

29 of physician-diagnosed asthma and bronchitis. Among adults, there was a statistically significant 

30 non-linear relationship with decreased morning PEFR for formaldehyde concentration <40 ppb. 

31 Nonetheless, this strong study had only minor weaknesses such as measurement error and the fact 

32 that it was a cross-sectional study. However, random measurement error tends to attenuate any 

33 true effect and is unlikely to have produced a spurious effect. It is unlikely that these findings 

34 were the product of unmeasured or residual confounding as the analyses controlled for smoking 

35 as well as nitrogen dioxide levels and there is no evidence of alternative factors that were 
This document is a draft for review purposes only and does not constitute Agency policy.

5-10 DRAFT—DO NOT CITE OR QUOTE 

1 correlated with formaldehyde concentrations and more strongly associated with pulmonary 

2 function. This study of a large and representative sample from a diverse study population with a 

3 well-quantified concentration-response function and is further considered for RfC derivation. 

4 

5 5.1.1.4. Asthma and Allergic Sensitization (Atopy) 

6 Sensitization to inhalational chemical exposure may manifest as an allergic or asthmatic 

7 response that is characterized by bronchial constriction (BC) or bronchial hyperresponsiveness 

8 (BHR). This sensitization may be a result of immune involvement, as in the case of 

9 hypersensitivity, or a neurogenic sensitization, where a chemical may directly stimulate 

10 inflammation. Asthma is a specific manifestation of IgE-mediated hypersensitivity, 

11 characterized by BHR and airway inflammation, resulting in lower airway obstruction (Fireman, 

12 2003; Kuby, 1991). 

13 A variety of hypersensitivity reactions have been reported following exposure to 

14 formaldehyde. Rashes and skin reactions have been reported in some individuals after dermal 

15 exposures to formaldehyde. Increased expression of Th-2 cytokines in the lymph nodes of mice 

16 given dermal applications of formaldehyde indicates the involvement of an immune component 

17 to the observed sensitization (Dearman et al., 2005; Hilton et al., 1998; Arts et al., 1997). 

18 However, the response does not appear to be IgE mediated (Arts et al., 1997; Lee et al., 1984). 

19 Gorski et al. (1992) observed an increase in formaldehyde-mediated neutrophil burst in 

20 dermatitis patients exposed in a controlled chamber study and suggests a putative role of 

21 oxidative stress and reactive oxygen species (ROS).

22 

23 Epidemiologic Studies: 

24 Inhalation exposure has been associated with increased asthmatic responses in asthmatics 

25 in occupational settings. While few available case reports of bronchial asthma suggest direct 

26 respiratory tract sensitization to formaldehyde gas (Lemiere et al., 1995; Burge et al., 1985; 

27 Hendrick et al., 1982; Hendrick and Lane, 1977, 1975), a greater body of human data provides 

28 evidence of an association between formaldehyde exposure and exacerbation of asthmatic 

29 responses in compromised individuals (Kriebel et al., 1993) and particularly in children 

30 (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski et al., 1990). Increased asthma 

31 incidence reported after inhalation exposure to formaldehyde led to a NOAEL of 30 ppb 

32 (Rumchev et al., 2002). An increased frequency of respiratory symptoms associated with 

33 asthmatic responses and formaldehyde exposure led to a LOAEL of 30 ppb (Garrett et al., 1999). 

34 

35 The association between formaldehyde and asthma has been studied by examining 
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1 occupational exposures (Fransman et al., 2003; Malaka and Kodama, 1990), school-related 

2 exposures (Zhao et al., 2008; Smedje and Norback, 2001; Norback et al., 2000) and residential 

3 exposures (Matsunaga et al., 2008; Tavernier et al., 2006; Gee et al., 2005; Delfino et al., 2003; 

4 Rumchev et al., 2002; Garrett et al., 1999; Palczynski et al., 1999; Norback et al., 1995; 

5 Krzyzanowski et al., 1990). The two occupational studies examined the respiratory health of 

6 plywood workers (Fransman et al., 2003; Malaka and Kodama, 1990). The most recent of these 

7 was conducted in New Zealand by Fransman et al. (2003). Personal samples of formaldehyde 

exposure were taken. The mean level of exposure was 0.08 mg/m3

8 (65 ppb) and the majority of 

samples were below the limit of detection which was reported to be 0.03 mg/m3

9 (24 ppb). 

10 Compared with those with low levels of formaldehyde exposure, workers with high levels of 

11 exposure were more likely to report having asthma (OR=4.3 [95% CI]: 0.7–27.7]). The 

12 association was not seen when examining formaldehyde exposure and use of asthma medication. 

13 The second study of plywood workers was completed in Indonesia. Background levels of 

14 formaldehyde ranged from 0.003 to 0.07 ppm. The highest concentration of formaldehyde 

15 detected in an air sample was in the particleboard unit (range 1.16 to 3.48 ppm). The occurrence 

16 of asthma was found to be positively associated with formaldehyde exposure, where asthma was 

17 defined as, “Have you ever had an attack of wheezing that made you feel short of breath?”, 

18 (Malaka and Kodama, 1990). 

19 Studies of exposure to formaldehyde at schools have been performed in China (Zhao et 

20 al., 2008) and in Sweden (Smedje and Norback, 2001). In the study from China (Zhao et al., 

2008), mean levels of formaldehyde were reported to be 2.3 μg/m3

 (range 1.0–5.0 μg/m321 ) indoors 

and 5.8 μg/m3 (range 5.0–7.0 μg/m322 ) outdoors. Cumulative asthma (i.e., physician-diagnosed 

23 asthma since birth) and daytime attacks of breathlessness were found to be associated with 

24 outdoor formaldehyde levels. Neither of these outcomes was associated with indoor 

25 concentrations of formaldehyde; however, indoor levels were found to be associated with 

26 nocturnal attacks of breathlessness. In Sweden (Smedje and Norback, 2001), the levels of 

formaldehyde measured indoors were higher (mean 4, range <5.0–72 μg/m3

27 ). One difference 

28 between the Swedish study and the study conducted in China is that the Swedish study examined 

29 the incidence of asthma over a 4-year period and did not report an association between 

30 formaldehyde exposure and the incidence of asthma (OR 1.2 [95% CI: 0.8–1.7]) among the 

31 whole study population. However, when the investigators stratified based on history of atopy, 

32 they reported that among children without a history of atopy, a new diagnosis of asthma was 

significantly more likely at higher concentrations of formaldehyde (OR 1.7 per 10 μg /m3

33 [95% 

34 CI: 1.1–2.6]) and at higher total concentrations of mold (OR=4.7 per 10-fold increased in total 

35 molds [95% CI: 1.2-18.4] in the classroom air. The finding in increase health effects due to 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 formaldehyde and mold exposures did not appear to control for the other exposure and no 

2 information on the potential correlation between the two exposures was provided. In order to 

3 evaluate the potential for confounding of the reported formaldehyde association by the reported 

4 mold association, the magnitude of effects must be compared on a appropriate scale since the 

5 magnitude of an odds ratio depends on the magnitude of the change in exposure level that is 

6 expected to produce increased risk. After standardizing the units to the reported geometric mean 

standard deviation, the results for formaldehyde (GSM=2.3 μg /m3

7 ) is OR1=1.13 per GSD and 

8 the results for mold is OR2=1.02 for a comparison of risks at the GSM to 10*GSM and 

OR3=1.06 for a comparison of risks at the minimum value of total molds (5*103

/m39 ) to 

10 10*minimum. As it appears that the magnitude of the formaldehyde effect is stronger than that 

11 of the mold effect (following standardization of exposure increment), it can be concluded that the 

12 reported formaldehyde effect could not have been due to uncontrolled confounding by mold. 

13 The results of studies measuring residential exposure to formaldehyde and asthma are 

14 varied, with some demonstrating an association and others finding no relationship. A recent 

15 study (Matsunaga et al., 2008) found no association between 24-hour formaldehyde and 

16 prevalence of asthma when pregnant women with an exposure to ≥47 ppb were compared to 

17 those with exposure to <18 ppb. However, they reported an increased risk of atopic eczema. 

18 This study did not assess the risk of incident asthma. A study utilizing self-reported asthma 

19 prevalence as an outcome also found no association with levels of formaldehyde (mean 

25.9 μg/m3, range 2.0–66.8 μg/m320 ) (Palczynski et al., 1999), although they noted the incidence of 

21 allergic diseases was greatest in the highest formaldehyde exposure group but that the groups 

22 were too small for statistical evaluation. 

23 A study performed by Tuthill (1984) measured formaldehyde exposure for children 

24 grades K through 6 by using a combination of proxy variables. Overall, there was no association, 

25 but some individual variables showed an increased risk. For example, the reported risk ratio for 

26 having new construction or remodeling performed in the house in the past 4 months was 2.5 

27 (95% CI: 1.7–3.9). The risk ratio for having new or upholstered furniture in the house (within 

28 the past 4 months) was 2.2 (95% CI: 1.2–3.9). 

29 The study by Delfino et al. (2003) assessed whether the ambient formaldehyde 

30 concentration measured at a central monitoring site was associated with asthma symptoms. The 

31 study examined 22 10–15 year olds with at least 1 year of physician-diagnosed asthma and living 

32 in a nonsmoking household. The mean levels of formaldehyde were measured to be 7.21 ppb 

 

1 OR per GSD=exp[ln(OR per μg /m3)/ 10 μg /m3 * 2.3 μg /m3]=exp[ln(1.7)/10*2.3]=1.13 

2 OR per GSD=exp[ln(OR per 10-fold increase)/ (9*GSM)*1.6 μg /m3]=exp[ln(4.7)/162*1.6]=1.02 

3 OR per GSD=exp[ln(OR per 10-fold increase)/ (9*Minimum)*1.6 μg /m3]=exp[ln(4.7)/45*1.6]=1.06 
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1 (range 4.27–14.02 ppb). There was a positive association between asthma symptom scores 

2 (comparing children who report symptoms interfering with their daily activities versus those with 

3 no symptoms or symptoms not great enough to affect their daily activities) and high current 

4 levels of formaldehyde (OR 1.90 [95% CI: 1.13–3.19]). 

5 Three studies (Tavernier et al., 2006; Gee et al., 2005; Garrett et al., 1999) were 

6 performed by matching children with and without asthma and comparing the levels of 

7 formaldehyde in their homes. Gee et al. (2005) reported median formaldehyde levels of 0.03 

8 ppm in living rooms and 0.04 ppm in bedrooms. Analyses were limited to univariate 

9 comparisons of formaldehyde levels for cases of existing asthma and controls without asthma. 

10 The concentrations did not differ in a statistically significant manner. The study by Gee et al 

11 (2005) was followed up with a more sophisticated analysis of the same children in the same 

12 home. Tavernier et al. (2006) reiterated the earlier finding by Gee et al (2005) that formaldehyde 

13 was not found to be associated with existing asthma. Tavernier et al. (2006) did not report the 

14 measured levels of formaldehyde but gave the OR for the highest tertile of exposure compared 

15 with the lowest tertile of exposure as 0.99 (95% CI: 0.39–2.50). The width of this confidence 

16 interval suggests that, while no effect was observed, these findings would still be consistent with 

17 two-fold increase in risk. 

18 Garrett et al. (1999) reported on the risk of allergy and asthma-like respiratory symptoms 

19 due to formaldehyde exposure in a cross-sectional survey of households with children with (n = 

20 53) or without (n = 88) doctor-diagnosed asthma. Formaldehyde exposure was characterized by 

21 4 seasonal in-home sampling events across the year for bedrooms and 4–day passive samples 

22 collected in living rooms, kitchens and outdoors. Statistically significant linear trends for 

23 increased risk of having asthma were seen with increasing formaldehyde levels (p < 0.02); 

24 however, the ORs for the association did not remain statistically significant after controlling for 

25 parental allergy and asthma (exact ORs and 95% CIs not given). Garrett et al (1999) also 

26 evaluated the prevalence and severity of allergic sensitization to 12 common allergens and 

27 reported increased prevalence with increasing formaldehyde concentration in the home. The 

28 respiratory symptom score was also increased and demonstrated a significant effect for 

29 formaldehyde in a multiple regression after adjusting for multiple risk factors and interactions. 

30 For the atopy and respiratory symptom endpoints, severity/incidence was increased in the 

medium (20–50 μg/m3

) and high (>50 μg/m3) exposure groups relative to the low (<20 μg/m331 ) 

32 exposure group, based on the highest of four seasonal 4-day formaldehyde measurements in the 

33 home. The associations between formaldehyde concentrations and severity of allergic 

34 sensitization are clearly shown and further substantiated with multivariate regression controlling 

35 for potential confounders. In logistic regressions, both the prevalence and severity of allergic 
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1 sensitization to 12 common allergens increased with increasing formaldehyde concentration in 

2 the home. The crude association for atopy with an increase in formaldehyde concentration per 

10 μg/m3 3 was OR=1.34 which increased when adjusted for parental asthma and gender to and 

odds ratio of 1.42 per 10 μg/m3

4 (95% CI: 0.99-2.04). Passive smoking, the presence of pets, 

5 indoor nitrogen dioxide concentrations, airborne fungal spores and house-dust-mite allergens did 

6 not influence the effect estimates and were unlikely to be confounders. Additionally, a calculated 

7 respiratory symptom score was increased and demonstrated a significant relationship to increased 

8 formaldehyde concentration in a multiple linear regression after adjusting for multiple risk 

9 factors and interactions. For each of these endpoints, severity/incidence was increased in the 

medium (20–50 μg/m3

) and high (>50 μg/m3) exposure groups relative to the low (<20 μg/m310 ) 

11 exposure group, based on the highest of four seasonal 4-day formaldehyde measurements in the 

12 home. 

13 Residential formaldehyde exposure was associated with an increased risk of asthma in a 

14 population-based case-control study of 192 children aged 6 months to 3 years (Rumchev et al., 

15 2002). The study, which comprises 88 cases of children discharged from the emergency 

16 department of a children’s hospital in Perth, Australia, with a primary diagnosis of asthma and 

17 104 controls, provides a positive exposure-response relationship. Seasonal in-home 

18 formaldehyde measurements taken in the living room and subject’s bedroom were used to assess 

19 exposure (8-hour passive sampler). The odds ratios (ORs) for risk of asthma by formaldehyde 

20 exposure level category were adjusted for numerous risk factors both familial and environmental 

21 including, familial history of asthma, age, sex, smoking, presence of pets, and attributes of the 

22 home. Of these, age, allergic sensitization to common allergens, and family history of allergy 

23 were independent risk factors for asthma (ORs of 1.09, 2.57, and 2.66, respectively). Categorical 

24 analysis of the data indicates the ORs for asthma were increased in the two highest formaldehyde 

exposure groups, reaching statistical significance for household exposures > 60 μg/m3

25 (48 ppb) 

26 (OR of 1.39). Analysis of the data with formaldehyde as a continuous variable indicated there 

27 was a statistically significant increase in the risk of asthma (3 % increase in risk per every 

28 10 ug/m3 increase in formaldehyde level. All analyses controlled for other indoor air pollutants, 

29 allergen levels, relative humidity, and indoor temperature as well as other risk factors. 

30 A study of 202 households (mean formaldehyde level of 26 ppb) found that among children aged 

31 6–15 years old and exposed to environmental tobacco smoke, the prevalence of asthma was 

32 45.5% for those with measured levels of formaldehyde in the kitchen >60 ppb. The prevalence 

33 of asthma dropped to 15.1% for levels ≤40 ppb and 0% for 41–60 ppb. No trend in asthma 

34 

35 prevalence was seen for children who were not exposed to environmental tobacco smoke 
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1 (Krzyzanowski et al., 1990). 

2 Finally, a study by Norback et al. (1995) reported mean levels of formaldehyde were 

29 μg/m3

 (range <5–110 μg/m33 ) in the bedrooms of individuals experiencing nocturnal 

breathlessness compared with formaldehyde levels of 17 μg/m3

 (<5–60 μg/m34 ) among those 

5 without nocturnal breathlessness. The OR for this association was 12.5 (95% CI: 2.0–77.9) and 

6 the effect was substantially stronger in magnitude than the associations observed for toluene, 

7 terpenes and volatile organic compounds which makes confounding by those co-exposures 

8 unlikely. 

9 

10 Supporting animal studies: 

11 Several animal studies report increased airway resistance and BC due to inhalation 

12 exposures to formaldehyde (Nielsen et al., 1999; Swiecichowski et al., 1993; Biagini et al., 1989; 

13 Amdur, 1960). Changes in pulmonary resistance were observed as early as 10 minutes after 

14 exposure (Biagini et al., 1989), and reported effect levels ranged from 0.3–13 ppm. Other 

15 pulmonary effects were reported in conjunction with BHR, such as increased tracheal reactivity 

16 and decreased pulmonary elasticity (Swiecichowski et al., 1993; Amdur, 1960). Although BHR 

17 is a common result of Type I hypersensitivity reaction to an allergen, the observation of BHR 

18 alone is not sufficient to demonstrate that an agent induces Type 1 hypersensitivity. 

19 BHR may be directly induced both pharmacologically and neurogenically (Joos, 2003; 

20 Cain, 2001; Meggs, 1995). There is little evidence that formaldehyde itself is an allergen 

21 recognized by the immune system, especially via inhalation (Lee et al., 1984). Although 

22 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 

23 experimental systems, these immunomodulatory effects do not support a type 1 hypersensitivity. 

24 IgE was unchanged (Fujimaki et al., 2004a; Lee et al., 1984), and cytokine profiles were not 

25 consistent with the Th-2 cytokines expected in IgE mediated hypersensitivity (Fujimaki et al., 

26 2004a; Ohtsuka et al., 2003). 

27 Formaldehyde-induced dermal sensitization show parallel results. The physical signs of 

28 irritation and sensitization are consistently shown (e.g., rashes, edema). Some involvement of 

29 the immune response has been demonstrated with positive LLNA assays, indicating proliferation 

30 of lymphocytes in lymph nodes draining the affected area (Hilton et al., 1998; Arts et al., 1997). 

31 Increased expression of Th-2 cytokines in the lymph nodes of mice given dermal applications of 

32 formaldehyde does indicate an immune component to the observed sensitization. However, the 

33 response does not seem to be mediated by IgE (Arts et al., 1997; Lee et al., 1984). 

34 

35 Ito et al. (1996) reported that a tachykinin NK1 receptor, but not the histamine H1 or 
This document is a draft for review purposes only and does not constitute Agency policy.

5-16 DRAFT—DO NOT CITE OR QUOTE 

1 bradykinin B2 receptors, is involved in formaldehyde-induced vascular permeability. 

2 Neuropeptides NGF and substance P were affected in BAL and stimulated splenocytes from 

3 formaldehyde-exposed mice, with greater effects seen in OVA-immunized mice. Tachykinins 

4 (e.g., substance P and neurokinin A) are produced by nerve cells and can directly stimulate 

5 bronchoconstriction (Van Schoor et al., 2000). Substance P is also a mediator of neurogenic 

6 inflammation. Therefore, although formaldehyde may induce some of the symptoms of type 1 

7 hypersensitivity, these symptoms are more likely neurogenic than immunogenic in origin. 

8 In contrast, formaldehyde enhances immunogenic hypersensitivity of known allergens 

9 (Sadakane et al., 2002; Riedel et al., 1996; Tarkowski and Gorski, 1995). This potentiation 

10 varied based on sensitization protocols (respiratory tract versus systemic, frequency and timing of 

11 immunization, allergen, etc.) and formaldehyde exposure regimens (concentration, continuous 

12 versus intermittent exposures). Taken as a whole, the results support the finding that 

13 formaldehyde exposure can aggravate a type 1 hypersensitivity response (Table 4-53). 

14 The mechanism underlying this response has not been elucidated. Formaldehyde-induced 

15 IgE production has been reported in some studies (Vandenplas et al., 2004; Wantke et al., 

16 1996a). Other studies suggest that this effect does not appear to be immunogenic in nature 

17 (Fujimaki et al., 2004; Lee et al., 1984). Although formaldehyde exposure has been reported to 

18 alter cytokine levels and immunoglobulins in some experimental systems (Fujimaki et al., 2004a; 

19 Ohtsuka et al., 2003), these immunomodulatory effects do not support immunogenically 

20 mediated type 1 hypersensitivity. 

21 These decrements may be mediated via neurogenic potentiation (Sadakane et al., 2002; 

22 Riedel et al., 1996; Tarkowski and Gorski, 1995). Tarkowski and Gorski (1995) suggest that 

23 formaldehyde may increase permeability of respiratory epithelium and destruction of 

24 immunologic barriers. Tachykinin NK1 receptor and various neuropeptides (NGF and substance 

25 P) have been implicated in formaldehyde-induced sensitization and lend weight of evidence to a 

26 neurogenic MOA (Van Schoor et al., 2000; Ito et al. 1996). 

27 

28 5.1.1.5 Immune Function 

29 Although there are some indications of formaldehyde-induced immunomodulation in 

30 laboratory animal studies (Jakab, 1992; Morgan et al., 1986a, b, c; Leach et al., 1983) and reports 

31 of increased upper respiratory tract infections in formaldehyde-exposed workers (Lyapina et al., 

32 2004; Krzyzanowski et al., 1990; Holness and Nethercott, 1989), the overall database for toxic 

33 effects on immune function and competence is very limited. A study of workers using 

34 carbamide-formaldehyde glue indicates decreased neutrophil respiratory burst activity (NRBA) 

35 (Lyapina et al., 2004). NRBA was reduced in workers with URT inflammation and long-lasting 
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1 respiratory tract infections, compared with healthy controls, and in formaldehyde-exposed 

2 workers with slight or no respiratory infections. The authors hypothesized that the decreased 

3 NRBA in symptomatic workers may be an indication of formaldehyde effects in a susceptible 

4 population. Since the workers have increased respiratory tract infections as compared with 

5 controls, a formaldehyde-specific effect cannot be excluded. These indications of a functional 

6 deficit of the immune system are considered adverse and appropriate for consideration as a 

7 critical effect. Although this was a small study (n = 29), the exposed workers had increased 

8 chronic URT infections and decreased resistance to infections compared with a control 

9 population. Additionally, duration of employment was negatively correlated with both 

10 erythrocyte count and hematocrit. Measured formaldehyde concentrations for a work shift were 

870 ± 390 μg/m3

11 (722 ± 324 ppb). This average work-shift concentration is considered to be the 

12 LOAEL for increased respiratory tract inflammation and decreased resistance to infections in a 

13 worker population. 

14 

15 5.1.1.6. Neurological and Behavioral Toxicity 

16 Studies evaluating the effects of formaldehyde on nervous system structure or function 

17 are described in detail in Section 4.2.1.4 and summarized in Table 4-60. Taken together the 

18 animal and human data support the conclusion that formaldehyde exposure results in 

19 neurological and behavioral toxicity. Observed health effects include impaired memory and 

20 learning, developmental effects seen as both structural changes in the brain and behavioral 

21 changes, and a potential for increased mortality from amyotrophic lateral sclerosis (ALS). 

22 Although studies appropriate for RfC derivation do not exist for each potential neurological and 

23 behavioral health effect, several studies are available that may inform the formaldehyde RfC. 

24 Seven of the available neurotoxicity studies were considered as candidates for RfC 

25 development (listed in Table 5-1). All seven studies provided reliable documentation of 

26 exposure, study design, and evaluation procedures, and all demonstrated robust findings of 

27 changes in nervous system structure or function following formaldehyde exposure. All but one 

28 of the candidate studies present information at multiple exposure levels to provide an 

29 understanding of the exposure response relationship. One selected study (Senichenkova, 1991) 

30 provided less robust information, with evaluation at only a single exposure level, but was 

31 considered useful as supporting the findings of two other studies (Sarsilmaz et al., 2007; Aslan et 

32 al., 2006) regarding neurological sequelae of developmental exposure. All of the selected studies 

33 using experimental animals were conducted in rats, although several studies in mice 

34 demonstrated dose-related neurotoxic effects following formaldehyde exposure. These studies in 

35 mice were not considered for RfC development because of the possibility that results might be 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 confounded by reflex bradypnea at the doses tested in each study (see Section 4.2.1.4 for details). 

2 

3 In order to improve transparency and facilitate comparison of health effect levels across 

4 study types and health effects, Table 5-1 summarizes the PODs and exposure scenarios for each 

5 selected study and describes the effects on which the selected POD is based. Dose conversions 

6 used to adjust from actual experimental exposure concentrations to continuous exposure 

7 concentrations are detailed. It should be noted that available studies providing dose-response 

8 information regarding the effects of formaldehyde exposure on the nervous system were all of 

9 short duration, and thus information regarding the relationship between formaldehyde toxicity 

10 and exposure duration (i.e., whether toxicity increases with longer exposures at a given exposure 

11 level, or is more related to the maximum exposure concentration) is limited. However, the 

12 rodent study by Pitten et al. (2000) and the epidemiology study by Weisskopf et al. (2009) 

13 provide strong support for an association between increasing neurotoxicity and increasing 

14 duration of exposure. 

15 Although chronic human studies are preferred for RfC derivation, no adequate human 

16 study of chronic duration is available. The available human studies were sufficiently strong to 

17 raise concern regarding formaldehyde effects on the nervous system; however, most did not 

18 provide sufficient exposure information to permit derivation of a POD for use in quantitative 

19 dose-response assessment. Available epidemiologic studies (most notably Weisskopf et al. 

20 [2009] and Kilburn et al. [1987, 1985]) provided limited exposure information. Weisskopf et al. 

21 (2009) demonstrated increased mortality from ALS associated with increased duration of 

22 formaldehyde exposure among 987,229 people followed by an American Cancer Society study, 

23 but no information regarding exposure concentrations was available. Interpretation of the 

24 findings of Kilburn et al. (1987, 1985) is complicated by concomitant exposure of many subjects 

25 to other solvents. Although the chamber study by Lang et al. (2008) included a concentration26 response assessment of changes in reaction time, as previously discussed, the effects detected 

27 were difficult to interpret and the study was not considered useful for RfC derivation 

28 .
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Table 5-1. Points of departure (POD) for nervous system toxicity in key human and animal studies

 POD

a Exposure scenario POD duration adjustments

b

Reference Species Type ppb Hours/day Days/week Duration POD

× Hours/day

× Days/week

= ppb Ratio

c 

Developmental neuropathology effects

Sarsilmaz 

et al. 

(2007) 

Rat LOAEL 6,000 6 5 30 days 6,000 × 6/24 × 5/7 

= 1,070 5.6 

Vcfe

Aslan et al. 

(2006) Rat LOAEL 6,000 6 5 30 days 6,000 × 6/24 × 5/7 

= 1,070 5.6 

Vcfe

Human neurobehavioral outcomes

Bach et al. 

(1990)

d Human NOAEL 170 5.5 1 1 day 170

d × × = 170 1 

Cmc5

Psychomotor effects

Senichenko

va (1991) Rat LOAEL 400 4 7 GD 1–19 400 × 4/24 × 7/7 = 67 6 

Cmaou

Malek et 

al. (2003c) Rat LOAEL 130

e 2 1 1 day 130 × 2/4

e × = 65 2 

Cdvfe

Cognitive effects

Pitten et al. 

(2000)

f Rat LOAEL 2,600 0.17 7 90 days 2,600

f

 -- -- -- -- 

Isoct
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Malek et 

al. (2003a) Rat LOAEL 100

e 2 7 10 days 100 × 2/4

e × 7/7 = 50 2 

Iw(tf

a1 mg/m

3 = 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 anfDue to the uncertainty in continuous exposure adjustments and the unusually short (10 minutes) exposure in this study, no adjustment to 

presented.
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1 One acute human study, Bach et al. (1990), which evaluated changes in cognitive 

2 function following a single formaldehyde exposure, was considered for evaluation of a cRfC as 

3 the chamber exposures were well defined and effects at multiple levels of exposure were 

4 reported. In that study, concentration-related changes in short-term memory and ability to 

5 concentrate were seen during a single 5.5-hour exposure at a range of levels (32, 170, 390, and 

6 890 ppb). The study was designed as a comparison of effects of short-term formaldehyde 

7 exposure in previously occupationally exposed individuals with effects in controls without 

8 previous occupational exposure. Because occupational exposure levels were not assessed, 

9 exposure measurements from the previously exposed workers are not appropriate for use in RfC 

10 derivation. The authors reported a significant exposure-response relationship for three related 

11 cognitive measures (number of additions completed, number of errors, and reaction time) in the 

12 ‘addition test’ assessment indicating a deficit in performance. Complete data were not presented, 

13 but graphical presentations in the article indicated that the effect was seen at all doses tested, with 

14 an apparent NOAEL of 170 ppb (see Figure 5-1). 

15 16 

17 Formaldehyde concentration 

18 

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

20 formaldehyde exposure at 32, 170, 390, or 890 ppb. 

21 Note: Vertical bars are the standard errors of the means, dashed line shows the 

22 95% CI. 

23 Source: Bach et al. (1990). Number of additions made in 10 minutes
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DRAFT—DO NOT CITE OR QUOTE 5-22

1 No BMD modeling could be performed on these data because the graphical representation 

2 could not be accurately digitized. The statistical analysis indicated no interaction between 

3 formaldehyde effect and previous occupational exposure (i.e., the magnitude and direction of the 

4 effect were similar in previously exposed and previously unexposed subjects) and separate data 

5 were not presented for the two groups; thus, the LOAEL represents effects in the combined study 

6 groups. Overall, the published paper lacks detail and it is difficult to evaluate some aspects of 

7 the reported findings, in particular where magnitude and direction of effect are not provided. 

8 Finally, the authors noted that controls and the high-exposure group were not well matched on 

9 two key parameters (age and education level), adding uncertainty to the reported exposure10 response relationship (at the high dose). Although this study was considered valuable in 

11 documenting neurological effects in humans following exposure to relatively low concentrations 

12 of formaldehyde, the above concerns limit its utility for quantitative human health risk 

13 assessment. Therefore, this study is not considered of sufficient quality for RfC derivation. 

14 In the absence of adequate human data, controlled studies in laboratory animals are 

15 considered. There are no chronic studies and only one subchronic animal study evaluating 

16 neurological and behavioral effects of formaldehyde exposure. Pitten et al. (2000) demonstrated 

17 impaired retention of a previously learned task in rats exposed at concentrations of 2,600 or 

18 4,600 ppb, 10 minutes per day, 7 days/week, for 90 days. In this study, the magnitude of the 

19 impairment increased over time, even though testing was performed 22 hours after exposure, 

20 indicating that repeated formaldehyde exposure led to a worsening of effect. The study design, 

21 test methods, and reporting of the results are all of adequate quality for both hazard assessment 

22 and quantitative risk assessment. However, the short duration (10 minutes) of the repeated daily 

23 exposures is a severe limitation to establishing a chronic RfC based on this study, due to 

24 uncertainties in extrapolating from 10 minutes to a 24-hour exposure (see Table 5-1). Because 

25 this study as designed indicates an accumulation of effect with repeated exposure, it is useful in 

26 documenting the existence of a duration component to the exposure-response relationship. It 

27 follows that concentration alone, without an adjustment for duration of exposure, would be 

28 inadequate as an exposure metric; however inadequate information is available to inform the 

29 appropriate magnitude of the duration effect. Therefore, although Pitten et al. (2000) is a well30 conducted study, the data are of limited utility for RfC derivation. 

31 Finally, there are several well-documented acute and subacute animal studies that provide 

32 exposure-response information for neurological and behavioral endpoints relevant for RfC 

33 derivation. Several laboratory animal studies that evaluate neurological effects following in 

34 utero or neonatal exposure address potentially susceptible life stages. Sarsilmaz et al. (2007) and 

35 Aslan et al. (2006) observed changes in brain structure (cell number and/or volume changes in 
This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT—DO NOT CITE OR QUOTE 5-23

1 specific brain regions) following 30 days of exposure to neonatal rats. A related finding by 

2 Senichenkova (1991) demonstrated changes in behavior (open field motor activity, including 

3 habituation) in young rats following in utero exposure. Effects of concern were seen at all doses 

4 in these studies, resulting in PODs of 67 ppb following in utero exposure and 1,070 ppb 

5 following early postnatal exposure, based on LOAEL values adjusted for continuous exposure 

6 (see Table 5-1). These studies support the possibility of neurodevelopmental effects attributable 

7 to in utero or early postnatal formaldehyde exposure, at levels similar to or below those causing 

8 other types of effects. 

9 The other three studies in Table 5-1 evaluate behavioral changes in rats following 

10 exposure to formaldehyde. Malek et al. (2003c) found concentration-related changes in motor 

11 activity following a single 2-hour exposure at concentrations from 130–5,180 ppb (with testing 

12 2 hours following cessation of exposure). In a second study, Malek et al. (2003a) found 

13 concentrated-related changes in performance on a learning task at similar exposure levels (100–

14 5,400 ppb) when 2-hour exposures were repeated for 10 consecutive days; performance was 

15 evaluated 2 hours after cessation of exposure, and concentration-related learning deficits were 

16 seen at all exposure levels (see Table 5-2 and Figure 5-2). 

17 

18 Table 5-2. Effects of formaldehyde exposure on completion of the labyrinth 

19 test by male and female LEW.1K rats 

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 ppma100 12.9 6.07 7.7 5.0 c 3.2c

0.5 ppm 97 16.7 c 7.60b 7.6 4.4 c 1.8c

5.4 ppm 105 25.7 c 10.9c 7.7 5.0 c 2.8c

Female Swimming time (sec) Error rate (mean)

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 3.0c

0.5 ppm 97 14.6 c 7.60b 8.0 4.6 c 2.2c

5.4 ppm 98 23.5 c 9.73c 7.9 5.2 c 2.6c

21 

a

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

b

23 Different from control, p < 0.05. 

c

24 Different from control, p < 0.005. 

25 

26 Source: Malek et al. (2003a). 

27 
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DRAFT—DO NOT CITE OR QUOTE 5-24

1 

2 Figure 5-2. Effects of formaldehyde exposure on the error rate of female 

3 LEW.1K rats performing the water labyrinth learning test. 

4 

5 Source: Drawn from data reported in Malek et al. (2003a). 

6 

7 

8 Although other studies evaluating neurobehavioral effects were available in the 

9 formaldehyde database (see Chapter 4), these studies by Malek et al. (2003a, c) were considered 

10 to be the most robust, documenting effects at relatively low exposure levels. Both studies also 

11 included evaluation at multiple concentrations and showed concentration-related increases in 

12 effect. In the Malek et al. (2003a) study with repeated exposures, it is unclear whether or not the 

13 measured effect primarily reflects the most recent exposure or cumulative exposure; therefore, 

14 the adjustment for continuous exposure was made over the final exposure period and the 2 hours 

15 following exposure (4 hours total), as was done for the single-exposure study (Malek et al., 

16 2003c). After appropriate duration adjustments, PODs for these studies range from 50 to 67 ppb 

17 (based on LOAELs), and the types of effects seen provide support for the Bach et al. (1990) study 

18 that detected cognitive impairments in humans following a single exposure (with a NOAEL of 

19 170 ppb). 

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 test

Errors (mean)

control

0.1 ppm

0.5 ppm

5.4 ppm
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DRAFT—DO NOT CITE OR QUOTE 5-25

1 

2 Summary of neurological and behavioral effects: 

3 In summary, the available studies for formaldehyde and nervous system outcomes have 

4 demonstrated that the nervous system is a sensitive target following inhalation of formaldehyde. 

5 In experimental animals, changes in nervous system function were seen following acute and 

6 subchronic exposures; studies evaluating neurological changes following chronic exposure were 

7 unavailable. Available human studies that evaluated nervous system effects following inhalation 

8 exposure were found to have many study-specific uncertainties and, thus, were not suitable to 

9 serve as the primary basis for a chronic RfC. The Weisskopf et al. (2009) study of ALS, in 

10 particular, suggests that humans may be at risk for severe neurological effects from formaldehyde 

11 exposure; however, this study lacked the exposure concentration information necessary to derive 

12 an RfC. Neurological findings from the rodent inhalation (acute and subchronic) studies that 

13 were judged to be adequate for dose-response assessment identified unadjusted LOAELs ranging 

14 from 100 to 6000 ppb, with LOAELs adjusted for continuous exposure in the range of 50 to 1070 

15 ppb. Use of these PODs in risk assessment would require addressing uncertainties regarding 

16 animal-to-human extrapolation, short study durations, and extrapolation from LOAELs. 

17 Among the adequate studies, EPA considered Malek et al. (2003a) to be the most 

18 appropriate for calculation of a cRfC for neurological and behavioral toxicity, based on the 

19 exposure level at which effects were seen (100 ppb), the type of effect (impaired learning), which 

20 is relevant to humans, and the use of a repeated-exposure paradigm (2 hours/day over a period of 

21 10 days), which addresses different exposure durations. This choice is supported by similar 

22 effects seen in other studies (Lu et al., 2008; Pitten et al., 2000; Bach et al., 1990) and by other 

23 neurologic effects seen at similar exposure levels (Malek et al., 2003c; Senichenkova, 1991; 

24 Sheveleva, 1971). 

25 

26 5.1.1.7. Developmental and Reproductive Toxicity 

27 As described in Sections 4.1 and 4.2 and summarized in Tables 4-68 and 4-71, both 

28 human epidemiologic data and experimental animal studies demonstrate an association between 

29 formaldehyde inhalation exposure and adverse developmental and reproductive effects, where 

30 adversity is characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 

31 2006). Adverse outcomes were observed across the various manifestations of developmental 

32 toxicity, including fetal death, structural alterations (including congenital malformations), growth 

33 retardation, and functional development. Additionally, in spite of the lack of a comprehensive 

34 database of studies for the evaluation of the overall effects of formaldehyde on the reproductive 

35 system and its function, the available evidence demonstrates toxicity to the male reproductive 
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DRAFT—DO NOT CITE OR QUOTE 5-26

1 system in multiple animal studies, as well as effects on the female reproductive system in both 

2 rodents and epidemiologic studies, where an association with impaired fertility and increased 

3 spontaneous abortions were noted. 

4 Potential principal studies for specific adverse outcomes are presented and evaluated 

5 below including reproductive effects (male and female), fetal death, growth retardation, and 

6 structural alterations. The only available evidence for functional alterations is based on 

7 developmental neurotoxicity studies which are presented and evaluated in Section 5.1.1.6. 

8 Table 5-3 summarizes animal studies deemed suitable for deriving quantitative dose-response 

9 information for reproductive and developmental outcomes and their corresponding PODs, 

10 adjusted for continuous exposure. Calculations that were used in dose conversions and exposure 

11 duration adjustments for the POD values are included. In general, repeated daily exposures of 

12 laboratory animals are adjusted from a partial day to a 24-hour exposure and then weighted for 

13 the number of days per week the exposures occurred. No chronic animal studies evaluating these 

14 endpoints were available, so only subchronic and acute studies are considered. Exposure 

15 duration adjustments to the only suitable human study (Taskinen et al., 1999) are more complex 

16 due to uncertainties in the exposure data and the potential for non-occupational exposures. For 

17 this discussion the reported 8-hr TWA exposures will be used for the Taskinen et al. (1999) 

18 study. Further duration adjustments to this study are discussed in Section 5.1.2.2.5 for cRfC 

19 derivation. 

20 

21 Spontaneous abortion and fetal death. 

22 Increased risk of spontaneous abortion following maternal occupational formaldehyde 

23 exposure was reported in a number of epidemiologic studies (Taskinen et al., 1999, 1994; John et 

24 al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). The studies did not appear to be overtly 

25 influenced by common principle biases found in epidemiologic studies. Considered together, the 

26 studies are consistent with an adverse effect of formaldehyde exposure on pregnancy loss, where 

27 adversity is characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 

28 2006). . Of these studies, Taskinen et al. (1999) had the superior quantitative data reporting 

29 reduced fecundity and spontaneous abortion in the exposed workers. Taskinen et al. (1999) is an 

30 occupational study with a well-considered study design, including measurements of exposure and 

31 outcomes, and relatively high study power. The study population consisted of 602 female 

32 workers in Finland who had at least one successful childbirth and first employment in the wood33 working industry beginning at least 6 months prior to the studied pregnancy. Mean daily 

34 formaldehyde inhalation exposures during the time-to-pregnancy period were estimated for each 

35 worker, based on task-level exposure measurements and work history. 
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DRAFT—DO NOT CITE OR QUOTE 5-27

1 Exposure was reported as a daily exposure index representing the average daily exposure 

2 for the time-to-pregnancy period, and three exposure classes were defined as low, medium and 

3 high with equivalent mean work-shift TWA exposure of 18, 76 and 219 ppb, respectively. 

4 Fecundity density ratio (FDR) was significantly reduced in the high exposure group compared to 

5 the referent group (P=0.02), and the risk of spontaneous abortions was increased with reported 

6 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, 

7 respectively. The effect on FDR remained in workers both with and without the use of protective 

8 gloves (n=39) but lost statistical significance in the exposed group of workers who wore gloves 

9 (n=22). Figure 5-3 shows the study results stratified by glove use in women in the high-exposure 

10 group. Although this suggests that a component of dermal exposure might contribute to the 

11 effect, it is unclear what, if any, dermal exposure is expected based on the nature of the work. 

12 Regardless, there remains uncertainty as to whether effects are solely due to inhalation exposure. 

13 

14 

15 Figure 5-3. Fecundity density ratio among women exposed to formaldehyde 

16 in the high exposure index category with 8-hour time-weighted average 

17 formaldehyde exposure concentration of 219 ppb (Taskinen et al., 1999) 

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% CI
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DRAFT—DO NOT CITE OR QUOTE 5-28

1 In some available rodent studies (Kitaev et al., 1984; Sheveleva, 1971), evidence of 

2 increased embryo degeneration in early gestation or of preimplantation loss (findings that are 

3 generally comparable to spontaneous abortion in humans) was observed. In the Kitaev et al. 

4 (1984) study, early implantation losses resulted following treatment of dams prior to mating. 

5 This may support a possible contribution of pre-pregnancy exposures to the spontaneous 

6 abortions observed in Taskinen et al. (1999). Quantification of the findings by Kitaev et al. 

7 (1984) and Sheveleva (1971) resulted in adjusted PODs of 50 and 70 ppb, respectively, based 

8 upon study LOAELs (Table 5-3). 

9 

10 Structural alterations. 

11 Studies of occupational exposures to formaldehyde examined the incidence of congenital 

12 malformations, but exposure and outcome data were not fully characterized and therefore could 

13 not be carried forward to RfC development. Animal studies (Senichenkova and Chetobar, 1996; 

14 Senichenkova, 1991) reported increases in internal organ anomalies; the most frequently 

15 observed structural anomaly was a delay in fetal testis descent (at times characterized as 

16 cryptorchidism in the study reports). For both studies, which exposed rats to formaldehyde for 4 

17 hours/day during gestation, adjusted PODs based upon LOAELs were 70 ppb (Table 5-3). These 

18 studies included only one treatment level, precluding the ability to establish a dose-response 

19 relationship, and the observed outcomes were not noted in other developmental toxicity studies 

20 with similar exposure scenarios, thus limiting the strength of the studies for use in RfC 

21 derivation. 

22 

23 Growth retardation. 

24 Decreased fetal weight was observed in a number of animal studies that exposed pregnant 

25 rats to formaldehyde during gestation. Of these, based on adequacy of dose-response 

26 information, Saillenfait et al. (1989) was considered appropriate for consideration for RfC 

27 development. In this study, rats were administered formaldehyde 6 hours/day on gestational days 

28 (GDs) 6–20. Decreased male fetal body weight (BW) was modeled with a BMR of 5% mean 

29 change, a BMCL was established, and, as shown in Table 5-3, the resulting duration-adjusted 

30 POD of 325 ppb was derived. The relevance of this finding to human exposures was 

31 qualitatively supported by a population-based study by Grazuleviciene et al. (1998) that reported 

32 an association between atmospheric formaldehyde exposure and low birth weight; although a 

33 dose-response relationship could not be adequately quantified from the information provided. 

34 
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DRAFT—DO NOT CITE OR QUOTE 5-29

1 

2 Male reproductive toxicity. 

3 Evidence of adverse effects on male reproductive system endpoints following inhalation 

4 exposure to formaldehyde was observed in a number of animal studies, where adversity is 

5 characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 2006). The 

6 effects include decreased testes weight, changes in Leydig cell quantity and quality, degeneration 

7 of seminiferous tubules, decreased testosterone levels, alterations in biomarkers of toxicity in the 

8 testes, and alterations in sperm count, morphology, and/or motility (Golalipour et al., 2007; Xing 

9 et al., 2007; Zhou et al., 2006; Özen et al., 2005, 2002; Sarsilmaz et al., 1999; Guseva, 1972). 

10 Several of these studies included inhalation exposure of rats to formaldehyde 8 hours/day, 

11 5 days/week for 4 and/or 13 weeks (Özen et al., 2005, 2002; Sarsilmaz et al., 1999) and included 

12 exposure-response information that was considered adequate for RfC derivation. In a study by 

13 Özen et al. (2002), increased severity of statistically significant testes weight decreases was 

14 related to both dose and duration of treatment. Similarly, in the study by Golalipour et al. (2007), 

15 seminiferous tubular diameter and epithelial height were reduced in rats following 18 weeks of 

16 formaldehyde inhalation exposure, with the severity of outcome positively correlated to the 

17 number of hours/week that the animals were exposed. Sarsilmaz et al. (1999) noted dose 

18 dependent decreases in Leydig cell quantity after 4 weeks of treatment, while decreased testis 

19 weight and atrophy of seminiferous tubules were observed by Zhou et al. (2006) after only 2 

20 weeks of treatment. The reported outcomes in these independent studies illustrate a biologically 

21 consistent toxicological profile of treatment-related male reproductive toxicity. PODs, adjusted 

22 for continuous exposure, ranged from 1,190 to 4,025 ppb, where the lowest POD was associated 

23 with the longest exposure period and vice verse (Table 5-3). 

24 

25 Female reproductive toxicity. 

26 Evidence of decreased fecundability was observed in the study by Taskinen et al. (1999), 

27 which was described above for spontaneous abortions. Delays in the time to conception that 

28 characterized this outcome, as well as increases in the incidence of endometriosis, were 

29 statistically significantly associated with occupational exposures to formaldehyde. As these 

30 effects were observed in the high exposure group, the unadjusted NOAEL for each of these 

31 effects is 76 ppb (8 hr-TWA) based on the next lowest exposure group. Uncertainties included 

32 lack of information human variability, as well as on the extrapolation of data from studies of 

33 short duration to risk estimates for chronic exposures. As discussed above for spontaneous 

34 abortions, the use of these data for cRfC derivation could result in values that would likely be an 

35 underestimation of risk because they assume that all the risk was from inhalation exposure and 
This document is a draft for review purposes only and does not constitute Agency policy.

DRAFT—DO NOT CITE OR QUOTE 5-30

1 ignore the apparent contribution of dermal exposure (i.e., the dermal-exposure-adjusted candidate 

2 inhalation RfCs might be higher). For decreased fecundability, a POD can also be identified 

3 based on the data from only the women who wore gloves. The fecundability density ratio (FDR) 

4 for the women in the highest exposure group who wore gloves was 0.79 (95% confidence 

5 interval [CI] 0.47–1.23). Although this FDR is not statistically significant, it can reasonably be 

6 assumed to be part of a trend of decreased FDR with increasing inhalation exposure, based on the 

7 overall data for the association of decreased FDR with formaldehyde exposure. Whether the 

8 highest exposure level is considered to be a NOAEL or a LOAEL for decreased fecundability in 

9 women who wore gloves, the unadjusted POD is 219 ppb (8 hr-TWA). Evidence of spontaneous 

10 abortions in the same study, as described above, may also be indicative of female reproductive 

11 toxicity. 

12 In animal studies, assessment of the female reproductive system was quite limited. An 

13 increase in the mean follicle-stimulating hormone (FSH) levels in rats, observed at the highest 

14 exposure level tested in Kitaev et al. (1984) was found to be sufficient to derive a duration15 adjusted POD of 50 ppb (Table 5-3). 

16 

17 Summary of developmental and reproductive toxicity studies suitable for RfC development. 

18 A review of the developmental and reproductive toxicity studies in humans and animals 

19 that would be suitable for cRfC development demonstrated that the developing organism and the 

20 reproductive system are targets for toxicity following formaldehyde exposure by inhalation. In 

21 the animal studies, effects during early development were observed following maternal 

22 premating or gestational exposures at duration-adjusted PODs ranging from 50-325 ppb. The 

23 minimal data available on female reproductive toxicity demonstrated an adjusted POD of 50 ppb 

24 with subchronic (4-month) premating exposure, while more extensive evaluation of male 

25 reproductive outcomes identified adjusted PODs of 1,190-4,025 for testicular and sperm 

26 abnormalities after exposures of from 2 weeks to 3 months in duration. The animal studies 

27 demonstrate the broad range of adverse outcomes to the reproductive system and the developing 

28 organism following inhalation exposure to formaldehyde and highlight concerns regarding the 

29 inadequacy of the database for the assessment of these outcomes (as described in Chapter 4). 

30 These data also support the human relevance of female reproductive and/or embryonic and fetal 

31 developmental effects, since some outcomes were similarly observed in both human and animal 

32 studies. 

33 
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5-31 DRAFT—DO NOT CITE OR QUOTE

Table 5-3. Developmental and reproductive toxicity PODs including duration adjustments – key animal st

POD Exposure Scenario POD Duration Adjustments 

Reference Species Type ppb a

Hours/

day 

Days/

week Duration 

POD 

(ppb) 

Hours/

day 

Days/

week

Adjusted 

POD 

(ppb) Ratio b Effe

Spontaneous abortion and fetal death

Kitaev et al. (1984) 

Rat LOAEL 400 4 5 6 months 

premating 

400 × 4/24 × 5/7 = 50 8 Incr

degedays mate

Sheveleva (1971) Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Incr

preim

Structural alterations c

Senichenkova (1991) 

Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Incr

incidanomincretesteincid

g

Senichenkova and Chetobar (1996) 

Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Incr

litter cryp(6%anom

Growth retardation

Saillenfait et al. (1989) 

Rat BMCL 1,300 6 7 GDs 6-20 1,300 × 6/24 × 5/7 = 325 4 Dec

weig

Functional development d

Male reproductive toxicity

Özen et al. (2002) 

Rat LOAEL 10,000 8 5 4 or 13 

weeks 

10,000

× 8/24 × 5/7 = 2,380 4.2 Dec

4 we(8%

Özen et al. (2005) 

Rat LOAEL 5,000 8 5 91 days 5,000 × 8/24 × 5/7 = 1,190 4.2 Dec

testo

Sarsilmaz et al. (1999) 

Rat LOAEL 10,000 8 7 4 weeks 10,000

× 8/24 × 7/7 = 2,380 4.2 Dec

num
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5-32 DRAFT—DO NOT CITE OR QUOTE

Table 5-3. Developmental and reproductive toxicity PODs including duration adjustments – key animal stZhou et al. (2006) 

Rat LOAEL 8,050 12 7 2 weeks 8,050 × 12/24 × 7/7 = 4,025 2 Dec

weigepid(38%motifoldat 2 

Female reproductive toxicity

Kitaev et al. (1984) 

Rat NOAEL 400 4 5 4 months 

premating 

400 × 4/24 × 5/7 = 50 8 Incr

stim4 mo

GDs = Gestation days a 1 mg/m

3 = 0.813 ppm. 

b POD unadjusted dose / duration-adjusted dose c Neuropathological alterations following exposures during postnatal development (from the studies by Aslan et al. [2006] and Sarsilma

addressed in the neurobehavioral toxicity Section 4.2.1.6 and Table 5-2. 

d Functional developmental endpoints (from the study by Senichenkova [1991]) are addressed in the neurobehavioral toxicity Section 4.
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5-33 DRAFT—DO NOT CITE OR QUOTE 

1 The animal study data were not selected for RfC derivation, since a high-quality human 

2 study (Taskinen et al., 1999) was available for the purpose of deriving a chronic RfC. This 

3 study, a well-designed population-based case-control study of women who were occupationally 

4 exposed to formaldehyde, included a well-defined study population which was adequately 

5 selected to allow for meaningful comparisons of health effects among individuals with different 

6 levels of exposure to formaldehyde. Potential confounding factors such a selection bias and 

7 inaccurate self-reporting were not considered to have had a significant influence on the study 

8 findings. The increased risk of spontaneous abortion observed in Taskinen et al. (1999), and 

9 perhaps the observed decrease in fecundity, is internally consistent and coherent with other 

10 reports of increased risk of pregnancy loss associated with exposure to formaldehyde (John et al., 

11 1994; Taskinen et al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). It is also supported 

12 by similar adverse outcomes observed in the animal data (Kitaev et al., 1984; Sheveleva, 1971). 

13 

14 5.1.2. Summary of Critical Effects and Candidate RfCs

15 5.1.2.1. Selection of Studies for Candidate RfC Derivation 

16 The above reviews of data from both human and animal studies identified health effects 

17 associated with formaldehyde exposure. Detailed information on these findings is given in 

18 Chapter 4 (sections 4.1 and 4.2), and a qualitative summary of the noncancer hazard 

19 identification is provided in Section 4.4 for each of the identified health effect categories: 

20 sensory irritation, upper respiratory tract pathology, respiratory effects, increased atopic response,

21 immune function, reproductive and developmental toxicity, and neurobehavioral toxicity. In this 

22 chapter, results for each health effect category are reviewed and studies are identified which are 

23 adequate to inform the exposure-response relationship for health effects from inhalation exposure 

24 (Section 5.1.1). Although the database of published studies that are currently available does not 

25 provide adequate quantitative data to derive cRfCs for all qualitatively identified endpoints, at 

26 least one adequate study was identified for each of the health effect categories discussed above. 

27 For all but one of the categories, at least one study was available that provided epidemiologic 

28 (human) data, based on occupational or residential exposures, which was judged adequate to 

29 provide a quantitative basis for a cRfC. 

30 In order to select the principal study or studies most appropriate for use as the basis of the 

31 RfC for formaldehyde, the relative merits of these studies were evaluated with respect to study 

32 quality, characteristics of the study population, the quality and frequency of exposure 

33 measurements, and the exposure levels at which effects are observed. The ideal RfC would be 

34 derived from a reported exposure level without an appreciable risk of deleterious effects in 

35 humans, including sensitive populations, with little uncertainty. Additionally, where possible, 
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5-34 DRAFT—DO NOT CITE OR QUOTE 

1 the RfC should be derived with consideration of all of the identified health effects. The several 

2 factors that were collectively taken into consideration for these studies (in no particular order) 

3 included the following: 

4 

5 • Were studies of laboratory animals or humans? 

6 o Human studies were generally preferred over laboratory animal studies for similar 

7 health effects, when both were of good quality, given the uncertainties in 

8 interspecies extrapolation. 

9 • What was the study size? 

10 o Larger studies were generally preferred over smaller studies because they can give 

11 more precise estimates of response levels associated with specific exposure levels. 

12 • Among the epidemiologic (human) studies, were exposures from an occupational setting or 

13 from a residential setting? 

14 o Studies of health effects from residential exposures were generally preferred over 

15 studies of health effects from occupational exposures because residential 

16 exposures tend to have a smaller range of variability and are less prone to large 

17 intermittent exposure peaks. 

18 o Residential exposures are more representative of the exposures of the general 

19 population. 

20 • Among the epidemiologic (human) studies, were children among the study population in 

21 which health effects were observed? 

22 o Studies of health effects that assessed the effect of formaldehyde on children’s 

23 health, representing a potentially more susceptible life-stage for some effects, 

24 were given some preference because they provide formaldehyde-specific data 

25 relevant to the components of the RfC derivation that address potentially sensitive 

26 life-stages and populations. 

27 • Relative to the other studies under consideration for RfC development, how accurately were 

28 formaldehyde concentrations measured? 

29 o Studies based on relatively more accurately measured formaldehyde 

30 concentrations were generally preferred over studies that estimated exposures. 

31 • Studies that reported effects at relatively lower formaldehyde concentrations, potentially 

32 indicative of more sensitive endpoints, were generally preferred. 

33 
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5-35 DRAFT—DO NOT CITE OR QUOTE 

1 Taking all the factors into consideration collectively, the individual studies are presented 

2 in Table 5-4. 

3 For sensory irritation, four studies are identified with adequate exposure information for 

4 RfC derivation, and all are human studies (Table 5-4). Of these, 3 studies were conducted in 

5 residential populations, including children and the elderly (Liu et al.,1991; Ritchie and Lehnen, 

6 1987; Hanrahan et al., 1984). Each of these studies includes in-home formaldehyde 

7 measurements for each participant. Liu et al. (1991) provide the best exposure measurements, 

8 with 7-day in-home passive air samples collected in two seasons. The occupational study by 

9 Holmström and Wilhelmsson (1988) provides evidence of sensory irritation in workers; however, 

10 only the mean and range of exposures for all workers is given. Furthermore, occupational 

11 exposures can include high peak exposures. The residential studies are preferred for 

12 development of candidate RfC. Although there are differences in study size and the quality of 

13 exposure measurements between the three residential studies, their results are mutually 

14 supportive, defining similar effect levels in similar populations, and the use of the three 

15 residential studies was considered to provide adequate consideration of the sensory irritation 

16 endpoint. Therefore, all 3 studies are selected (Liu et al.,1991; Ritchie and Lehnen, 1987; 

17 Hanrahan et al., 1984) and will be evaluated together in the following section. 

18 Histological changes in the upper respiratory tract are well documented in animal studies 

19 and have been observed in several worker studies (Section 4.4). Although the study of resin 

20 production workers (Holmström and Wilhelmsson, 1988; Holmström et al., 1989) provides the 

21 best documentation of effect level for this health category in humans, it is not carried through for 

22 development of a candidate RfC. As with the sensory irritation endpoint reported in these 

23 studies, exposure is described for the worker cohort by a simple mean, with a range of exposures 

24 given for all workers. Therefore, these data do not provide an exposure-response relationship 

25 and the POD would be the mean exposure level of all workers, regardless of effect. This is less 

26 exact than other available studies which provide exposure-response relationships. Additionally, 

27 animal studies provide a broad database which supports sensory irritation as a more sensitive 

28 endpoint than histological changes in the nasal mucosa. 

29 
This document is a draft for review purposes only and does not constitute Agency policy

5-36 DRAFT—DO NOT CITE OR QUOTE

1 Table 5-4. Summary of candidate studies for formaldehyde RfC development by health endpoint category 

Health 

Endpoint 

Category Study Species Setting Children 

Study 

size 

Formaldehyde 

measurements 

Specific 

Endpoints 

O

Liu et al. (1991) Human Residential Yes 1,394 

Two locations at one time period (winter or summer); 7-day passive monitors 

Eye irritation 

Ritchie and Lehnen (1987) Human Residential Yes 2,007 

Two locations at one time period; 30-minute sample 

Eye, nose, and throat sensory irritation 

Hanrahan et al. (1984) Human Residential Yes (teenagers) 61 Two locations at one time period; 60- minute sample 10% increased prevalence of burning eyes 

Sensory Irritation 

Holmström and Wilhelmsson (1988) 

Human Occupational No 106 

Several measurements at factory workstations taken over 7 years 

Eye irritation 

Upper Respiratory Tract Pathology 

Holmström and Wilhelmsson (1988); Holmström et al. (1989) 

Human Occupational No 

132 

68 with 

pathology 

Several measurements at factory workstations taken over 7 years 

Loss of ciliated epithelium; goblet cell hyperplasia; squamous cell metaplasia 

Garrett et al. (1999) Human Residential Yes 148 

Four locations over up to four time periods; 4-day passive monitors 

Increased allergy; increased asthma-like symptoms 

Sensitization: Asthma and atopy 

Rumchev et al. (2002) Human Residential Yes 192 

Two locations at two time periods (Winter & Summer); 8-hour passive monitors 

Initial diagnosis of asthma 
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Health 

Endpoint 

Category Study Species Setting Children 

Study 

size 

Formaldehyde 

measurements 

Specific 

Endpoints 

O

Pulmonary Function Krzyzanowski et al. (1990) Human Residential Yes 208 

Four locations over two time periods (opposite seasons); 7-day passive monitors 

10% Reduction in PEFR 

Neurological Malek et al. (2003a) Rat Laboratory -- 120 Intentional exposures at specific levels Impaired learning 

Taskinen et al. (1999) (FDR) Human Occupational No 602 

Actual and surrogate measurements estimated by occupational hygienist

Decreased fecundity density ratio (FDR) 

Reproductive and Developmental effects Taskinen et al. 

(1999) (SAB) Human Occupational No 602 

Actual and surrogate measurements estimated by occupational hygienist

Increased risk of spontaneous abortion (SAB) 

Immune Function 

Lyapina et al. (2004) Human Occupational No 29 

Average shift concentrations based on measures 8-hour exposures 

Increased respiratory tract infections, decreased neutrophil respiratory burst activity 

a This is the lowest level of exposure at which adverse effects were observed, the LOAEL, in effect, or the cut-off point for adverb See 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 and does not constitute Agency policy.

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1 Reduced pulmonary function is associated with formaldehyde exposure in several human 

2 studies (students and workers). The best single study demonstrating decreased pulmonary 

3 function is the moderate residential study by Krzyzanowski et al. (1990). The study was 

4 specifically designed to include homes with children between the ages of 5-15. Results presented 

5 for children (n = 208) provide an exposure-response relationship for reduced PEFR. Data 

6 quality is considered high for this study, both in terms of the in-home exposure measurements 

7 (7-day passive monitors, two time periods) and the contemporaneous in-home measurement of 

8 pulmonary function. Sources of potential confounding or bias were considered by the study 

9 authors and adequately taken into account in the study. Therefore, this study is retained for 

10 derivation of a candidate RfC. 

11 Several studies report increased asthma and/or allergic sensitization in children associated 

12 with increased formaldehyde exposure in school or homes (Section 5.1.4). Of these, two studies 

13 are further evaluated here (Garrett et al., 1999; Rumchev et al., 2002). The study by Rumchev et 

14 al. (2002) is a case-control study of asthma incidence in children, and the study by Garrett et al. 

15 (1999) is designed to study several related health effects (asthma, sensitization and respiratory 

16 symptoms) in asthmatic and non-asthmatic children. Both studies measure in-home 

17 formaldehyde levels with multi-day passive samples. Survey data and health outcome data are 

18 considered of high quality in each study. Additionally, sources of potential confounding or bias 

19 were considered by the study authors and adequately taken into account in the study. Therefore, 

20 both studies are retained for derivation of a candidate RfCs. Although several studies of school 

21 children support these findings, the residential studies were considered more appropriate for RfC 

22 derivation because individual in-home formaldehyde levels were associated with the health 

23 outcome data. 

24 Multiple lines of evidence support the occurrence of neurotoxicity following exposure to 

25 formaldehyde, however, none of the available human studies were considered to be of adequate 

26 quality for derivation of a point of departure for use in quantitative assessment. Of the available 

27 neurotoxicity studies, Malek et al. (2003a), in which impaired learning was seen in rats following 

28 exposure at 100 ppb, was selected as a potential candidate for RfC development (see 

29 Section 5.1.6). A NOAEL was not identified for this effect. In view of the other studies 

30 available in the formaldehyde database (including multiple human studies of potentially sensitive 

31 populations), and considering the uncertainty in extrapolating from the exposure conditions in 

32 the Malek et al. (2003a) study (two hour exposures, repeated on ten consecutive days) to a 

33 chronic exposure scenario, this study was not carried forward for derivation of a candidate RfC. 

34 It is important to note that the resulting RfC may therefore not fully consider the documented 

35 neurotoxic effects of formaldehyde. 
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5-39 DRAFT—DO NOT CITE OR QUOTE 

1 Of the various reproductive and developmental effects associated with formaldehyde 

2 exposure, reduced fecundity and increased risk of spontaneous abortions are primarily studied in 

3 humans (Section 5.1.7). Of the available human studies, only one study provides individual 

4 exposure estimates of adequate quality to support RfC development (Taskinen et al., 1999). 

5 Exposure-response relationships for decreased fecundability density ratio and increased risk of 

6 spontaneous abortions are seen with increased categories of worker exposures. Several potential 

7 confounding exposures are evaluated in the study, and the association of decreased fecundability 

8 density ratio observed in the study is most convincingly associated with increased formaldehyde 

9 exposure (Taskinen et al., 1999). Potential sources of bias were also adequately addressed in the 

10 study. This is considered a high quality study and is retained for cRfC derivation. 

11 Although Lyapina et al. (2004) have documented decreased neutrophil respiratory burst 

12 activity in exposed workers, the overall weight of evidence for deficit in immune function due to 

13 formaldehyde exposure is weak. There is a trend for increased respiratory tract infections in 

14 formaldehyde-exposed individuals, but it is a direct result of impaired immune function or, 

15 perhaps, increased infection due to direct effects on the protective barriers of the nasal mucosa. 

16 Animal studies do not support a finding of a deficit in immune function with formaldehyde 

17 exposure. The study by Lyapina et al. (2004) is a small study, and the findings of decreased 

18 neutrophil respiratory burst activity were in those individuals with more upper respiratory tract 

19 infections, so there is some question of causality. The data evaluation does not provide an 

20 exposure-response relationship, but, rather, exposure for the cohort is expressed as a mean 

21 exposure of 722 ppb. Although the potential for impairment of immune function is an important 

22 health effect, the overall evidence for this effect and this specific study are relatively weak 

23 compared to other data available to support RfC derivation for formaldehyde. Therefore, this 

24 study is not carried further in the quantitative analysis. 

25 In summary, the best studies evaluated herein for the derivation of an RfC for 

26 formaldehyde exposure and the related health effects are: 1) Sensory irritation (Liu et al.,1991; 

27 Ritchie and Lehnen, 1987; Hanrahan et al., 1984); 2) reduced pulmonary function (Krzyzanowski 

28 et al., 1990); 3) sensitization (atopy and asthma) (Garrett et al., 1999 and Rumchev et al., 2002); 

29 and 4) reduced fecundity and increased spontaneous abortion (Taskinen et al., 1999). It is 

30 recognized that not all identified health effects are represented in these studies. 

31 

32 

33 

34 

35 5.1.2.2. Derivation of Candidate RfCs from Key Studies 
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5-40 DRAFT—DO NOT CITE OR QUOTE 

1 Candidate RfC derivation for Krzyzanowski et al. (1990) (Pulmonary function)

2 The study by Krzyzanowski et al. (1990) is a high quality epidemiology (human) study of 

3 health effects in a random sample of residents and their families. The study was specifically 

4 designed to include only households that had children 5–15 years of age, a sensitive life-stage for 

5 respiratory effects. The study was of moderate size, when the effects in children were analyzed 

6 separately from adults, with the final analysis based on 208 children—a cohort large enough to 

7 show statistically significant results. The formaldehyde monitors were prepared by the Lawrence 

8 Berkeley Laboratories and were considered to be precise and highly reliable. The 7-day passive 

9 formaldehyde monitors generally provide the lowest limit of formaldehyde detection. The 

10 investigators specifically tested an a priori hypothesis and conclusively demonstrated to a high 

11 level of statistical significance that increased residential formaldehyde exposures were associated 

12 with decreased pulmonary function as measured by peak expiratory flow rate (PEFR) in children. 

13 This effect was clearly shown at relatively low concentrations of formaldehyde as the mean 

14 concentration in the homes was 26 ppb with more than 83% of homes having measured 

15 concentration less than 40 ppb. This study also reported specific regression modeling results that 

16 allowed EPA to calculate the point of departure for RfC development using a BMCL as the point 

17 of departure. 

18 The effects of formaldehyde exposure on pulmonary function represent a sensitive 

19 endpoint with a reported 10% reduction in PEFR at 27 ppb. Among children with physician20 diagnosed asthma, the observed effects of increased formaldehyde exposure on decreased PEFR 

21 were more pronounced – a clear indication of variability in response. The American Thoracic 

22 Society (ATS, 2000) considers decreased pulmonary function an adverse health effect, even 

23 when it is transient and subclinical. “Assuming that the relationship between the risk factor and 

24 the disease is causal, the committee considered that such a shift in the risk factor distribution, and

25 hence the risk profile of the exposed population, should be considered adverse, even in the 

26 absence of the immediate occurrence of frank illness” (ATS, 2000). The ATS (2000) stated that 

27 individuals in an exposed population experiencing a shift in the distribution of pulmonary 

28 function were at potential risk from another agent due to the reduction in their reserve capacity to 

29 address additional insults. In the study by Krzyzanowski et al. (1990), the investigators 

30 demonstrated statistically significant interaction between formaldehyde exposures, smoking, and 

31 chronic cough. That is, a formaldehyde concentration that caused decreased pulmonary function 

32 at residential levels also caused chronic cough in the presence of environmental tobacco 

33 exposures. Higher prevalence rates of physician-diagnosed asthma and chronic bronchitis were 

34 also shown at higher concentrations of formaldehyde (60–140 ppb), an effect that was 

35 exacerbated by environmental tobacco exposures. 
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1 Figure 5-4 illustrates the reductions in peak expiratory flow rate (PEFR) in children (<15 

2 years of age) in relation to indoor residential formaldehyde concentrations estimated by a random 

3 effects model based on 3,021 observations in 208 subjects. Formaldehyde levels in the home 

4 were significantly related to reductions in PEFR in children both at bedtime and in the morning 

5 (p < 0.05). PEFR measurements in the morning versus at bedtime were significantly different (p

6 < 0.05). Formaldehyde-related reductions in PEFR were greater in the morning in asthmatic 

7 children than in non-asthmatic children (p < 0.05). 

8 

9 

10 

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

12 children in relation to indoor residential formaldehyde concentrations. 

13 

14 Source: Krzyzanowski et al. (1990). 

15 

16 

17 Candidate RfC derivation based on Krzyzanowski et al. (1990):

18 Critical effect: Based on this study, which specifically included a susceptible 

19 population, the critical effect is reduction in PEFR in children. PEFR was the most 

20 sensitive measure of disease or impaired lung function reported in this population, with 

21 decreases in lung function reported in children who lived in homes with average 

22 measured formaldehyde concentrations as low as 30 ppb (Krzyzanowski et al. (1990). 

23 Children were more sensitive to formaldehyde-associated decreases in PEFR than adults, 

24 so the cRfC derived focused on the results in the 208 children. 
This document is a draft for review purposes only and does not constitute Agency policy.

5-42 DRAFT—DO NOT CITE OR QUOTE 

1 Point of departure: A BMR of 10% reduction in PEFR was selected as a cut-off point 

for adversity, based on rationales articulated by the ATS (2000)4

2 . Using this BMR and 

3 the model coefficient in Table 5 of Krzyzanowski et al. (1990), a BMCL10 of 17 ppb 

(BMC10 = 27 ppb) was derived for all children.54 Although the authors noted that 

5 asthmatic children were more sensitive, the necessary data were not provided in the report 

6 to calculate a BMCL for asthmatic children alone. Thus, 17 ppb, the BMCL based on all 

7 children in the study, was used as the POD. 

8 

9 Application of study-specific Uncertainty Factors (UFs):

10 Interspecies UF = 1: No interspecies adjustment is needed, as this is a human study. 

11 LOAEL-to-NOAEL UF = 1: Because a BMCL was used for the POD and the BMR of 

12 10% reduction in PEFR was considered to be a cut point for adversity, no 

13 LOAEL-to-NOAEL UF was needed (UFL = 1). 

14 

15 

16 Subchronic-to-chronic UF = 1: The study addresses ongoing residential exposure to 

17 formaldehyde. Although information on the duration of exposure for each 

18 participant is not provided, the residential nature of the study suggests a longer 

19 term exposure than the duration of the study. It was judged that a population20 based study of residential exposures is sufficient to derive a chronic RfC without 

21 adjusting for a subchronic observation period  at least for adults and older 

22 children, and the children in this study were mostly older children (e.g., older than 

23 7 years). 

 

4

The ATS (2000) recommended that “a small, transient loss of lung function, by itself, should not automatically 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, 10–20, 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 (compared to individual risk), “[a]ssuming that the relationship between 

the risk factor and the disease is causal, the committee considered that such a shift in the risk factor distribution, and 

hence the risk profile of the exposed population, should be considered adverse.” This was specifically considered by 

ATS (2000) even when “[e]xposure to air pollution could shift the distribution towards lower levels without 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 population. This 

criterion had been similarly applied in EPA’s Air Quality Criteria for Ozone and Related Photochemical Oxidants

(U.S. EPA, 2006d) for pulmonary function. 

5 According to the regression model in Table 5 in Krzyzanowski et al. (1990), the coefficient ± standard error for 

formaldehyde (in ppb) is –1.28 ± 0.46 and the background PEFR is 349.6 L/minute. Thus, a 10% reduction in PEFR 

is –35 L/minute and the 95% (one-sided) upper bound on the slope for PEFR as a function of formaldehyde 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 the 
This document is a draft for review purposes only and does not constitute Agency policy.

5-43 DRAFT—DO NOT CITE OR QUOTE 

1 Human variability UF = 3: The study was designed to include homes with children, and 

2 a POD can be established based on reduced PEFR in children, who were more 

3 sensitive to the health effects than the adults in the study. Therefore, the POD 

4 represents data for a sensitive life stage, an aspect of human (intraindividual) 

5 variability. With respect to the human (interindividual) variability UF, although 

6 environmental tobacco smoke and socioeconomic status did not affect the 

7 formaldehyde results in children, asthmatic children were more sensitive to the 

8 effects of formaldehyde exposure on PEFR; thus, asthmatic children represent a 

9 population with increased susceptibility for this effect. The prevalence rate for 

10 physician-diagnosed asthma in the children was 15.8% in this study, which is 

higher than the national prevalence of about 5.9% for ages 5 to 17 years.6

11 Thus 

12 the BMCL based on all children may be influenced by a higher prevalence of 

13 susceptible children for the critical effect. The authors do report that the PEFR 

14 was reduced to a greater degree in asthmatic children (as shown in Figure 5-4), 

15 and a lower BMC of 17 ppb can be calculated in this subgroup versus a BMC of 

16 27 ppb for all children. However, the published regression statistics do not 

17 provide sufficient detail to calculate a BMCL specific for asthmatic children. In 

18 addition, other potentially sensitive populations (for example, elderly individuals 

19 or individuals with respiratory diseases) may not be adequately represented in the 

20 study. Therefore, an UF for human variability of 3 is applied to address the 

21 observed increased sensitivity of asthmatic children in lieu of a calculated BMCL 

22 specific to asthmatic children and to ensure adequate protection for other 

23 potentially sensitive populations. 

24 

( ) ( ) ppb ppb

UF UF UF UF

BMCL RfC

A L S H

6.5

1 1 1 3

10 17

=

× × ×

=

× × ×

25 =

26 

27 UFA = 1 (interspecies UF) 

28 UFL = 1 (LOAEL-to-NOAEL UF) 

29 UFS = 1 (subchronic-to-chronic UF)

 

BMCL.

6

 The national prevalence rate of asthma in children ages 5-17 is according to the Centers for Disease Control and 

Prevention (CDC) (MMWR 49(40):908-911, 2000). Although the Krzyzanowski et al. (1990) study was conducted 

in the late 1980s, prevalence data from the National Health Interview Survey for 1997 were used for comparison 

because that is the earliest year for which data are available after a 1997 redesign of the survey. Previously, the 

survey asthma question was not specific for physician-diagnosed asthma, so the redesigned results were considered 

to be more comparable to the physician-diagnosed asthma definition in the Krzyzanowski et al. (1990) study. 
This document is a draft for review purposes only and does not constitute Agency policy.

5-44 DRAFT—DO NOT CITE OR QUOTE 

1 UFH = 3 (human variability UF)

2 5.1.2.2.1. Candidate RfC derivation for Rumchev et al. (2002) (Asthma) 

3 Residential formaldehyde exposure was associated with an increased risk of asthma in a 

4 population-based case-control study of 192 children aged 6 months to 3 years (Rumchev et al., 

5 2002). While it is acknowledged that accurately diagnosing asthma in young children is difficult, 

6 as the diagnosing physician was unaware of the formaldehyde level in the children’s home, any 

7 diagnostic error would be unrelated to formaldehyde concentrations and would not induce a 

8 spurious association. It is noted that the endpoint is physician-diagnosed asthma. The study, 

9 which comprises 88 cases of children discharged from the emergency department of a children’s 

10 hospital in Perth, Australia, with a primary diagnosis of asthma and 104 controls, provides a 

11 positive exposure-response relationship adequate for RfC derivation. Seasonal in-home 

12 formaldehyde measurements taken in the living room and subject’s bedroom were used to assess 

13 exposure (8-hour passive sampler). The ORs for risk of asthma by formaldehyde exposure level 

14 category were adjusted for numerous risk factors, both familial and environmental, including 

15 familial history of asthma, age, sex, socioeconomic status, smoking, presence of pets, air 

16 conditioning, humidifier, and gas appliances. Of these, age, allergic sensitization to common 

17 allergens, and family history of allergy were independent risk factors for asthma (OR = 1.09, 

18 2.57, and 2.66, respectively). Odds ratios were further adjusted for the effects of the measured 

19 indoor air pollutants (see Rumchev et al., 2004), indoor allergen levels of dust mites, relative 

20 humidity, and indoor temperature. Categorical analysis of the data indicates that the ORs for 

21 asthma were increased in the two highest formaldehyde exposure groups, reaching statistical 

significance for household exposures > 60 μg/m3

22 (48 ppb) (OR = 1.39) (Figure 5-5). Analysis of 

23 the data with formaldehyde as a continuous variable provides a statistically significant increase in 

the risk of asthma (3% increase in risk per every 10 μg/m324 increase in formaldehyde level.) 

25 

26 5.1.2.2.2. Candidate RfC derivation based on Rumchev et al. (2002):

27 

28 Critical effect: Diagnosis of childhood asthma (case-control study). 

29 

Point of departure: A NOAEL of 33 ppb (40 μg/m3

; midpoint of the 30–49 μg/m330 

31 category) was selected because the OR for asthma in the next highest exposure category 

32 was considered to be part of an exposure-related trend of increasing asthma risk and, 

33 therefore, biologically significant. 

34 
This document is a draft for review purposes only and does not constitute Agency policy.

5-45 DRAFT—DO NOT CITE OR QUOTE 

1 

2 Figure 5-5. Odds ratios for physician-diagnosed asthma in children 

3 associated with in-home formaldehyde levels in air.

4 

5 Source: Rumchev et al. (2002). 

6 

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: No LOAEL-to-NOAEL UF was needed because the POD 

11 was a NOAEL (UFL = 1). 

12 Subchronic to chronic UF = 3: The study addresses ongoing residential exposure to 

13 formaldehyde. Although information on the duration of exposure for each 

14 participant is not provided, the residential nature of the study suggests a longer 

15 term exposure than the duration of the study. Study participants were 3 years or 

16 younger, therefore the duration of exposure could not meet the expected definition 

17 for a chronic study of one-tenth the lifespan. However, asthma often develops 

18 during childhood, indicating a less-than chronic duration of exposure. Since 

19 asthma may develop throughout childhood it is unclear whether a study of 

20 children under 3 years of age would be of adequate duration for this 

21 developmental window. Therefore, an uncertainty factor of 3 was applied as a 

22 subchronic to chronic adjustment.

23 Human variability UF = 1 or 3: As a case-control study, all new cases of childhood

24 asthma which met the study criteria were eligible for inclusion and the cases likely 

25 included children predisposed to asthma. Individuals with a family history of 

26 asthma and/or genetic markers for genes believed to predispose individuals to 

27 asthma would represent a susceptible population. Therefore, the cases in this 
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5-46 DRAFT—DO NOT CITE OR QUOTE 

1 study address children as a susceptible population for first diagnosis of asthma. 

2 Additionally, there was an association of a familial history of asthma with the 

3 diagnosis of children’s asthma in this cohort (OR = 2.66). Not all sources of 

4 human variability which may contribute to a diagnosis of asthma are known, and 

5 there are likely additional sources of inter-individual variability among children 

6 and among individuals with a family history of asthma, thus it is unlikely that all 

7 sources of human variability were adequately represented in the study population. 

8 

9 The two alternatives are described below and cRfCs are derived for each alternative.

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 variability is applied. 

( ) ( ) ppb ppbUF UF UF UF

NOAEL RfC

A L S H

3.3

1 1 3 3

33

=

× × ×

=

× × ×

=

UFA = 1 (interspecies UF) 

UFL = 1 (LOAEL-to-NOAEL UF) 

UFS = 3 (subchronic-to-chronic UF)

UFH = 3 (human variability UF) 
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5-47 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

3 

4 5.1.2.2.3. Candidate RfC derivation for Garrett et al. (1999) (Asthma, respiratory 

5 symptoms, atopy and severity of allergic sensitization) 

6 Garrett et al. (1999) reported on the risk of allergy and asthma-like respiratory symptoms 

7 due to formaldehyde exposure in a cross-sectional survey of households with children 7–14 years 

8 old with (n = 53) or without (n = 95) doctor-diagnosed asthma. Formaldehyde exposure was 

9 characterized by four seasonal in-home sampling events using 4-day passive samples collected in 

10 bedrooms, living rooms, kitchens, and outdoors. In logistic regressions, both the prevalence and 

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 UFH of 1 has been applied in cases where there are data “very specific about 

the particular vulnerability of infants and children within certain age ranges to an agent.” 

Asthma and allergic sensitization to common allergens develop during childhood and 

young adulthood defining a developmental window during which individuals are most 

susceptible to the development of asthma. Since this study includes only children up to 

3 years of age, the UF for subchronic exposure is applied above acknowledging that this 

study does not cover the susceptible developmental window. No additional adjustment is 

applied for inter-individual variability among children. 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 asthma. The technical report 

acknowledges that applying a UFH of 1 may be appropriate where “even within these 

populations it is possible that some variability still exists. 

( ) ( ) ppb ppbUF UF UF UF

NOAEL RfC

A L S H

11

1 1 3 1

33

=

× × ×

=

× × ×

=

UFA = 1 (interspecies UF) 

UFL = 1 (LOAEL-to-NOAEL UF) 

UFS = 3 (subchronic-to-chronic UF)

UFH = 1 (human variability UF) 
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1 severity of allergic sensitization to 12 common allergens increased with increasing formaldehyde 

2 concentration in the home. Additionally, a calculated respiratory symptom score was increased 

3 and demonstrated a significant relationship with increased formaldehyde concentration in a 

4 multiple linear regression after adjusting for multiple risk factors and interactions. For each of 

these endpoints, severity/incidence was increased in the medium (20–50 μg/m35 ) and high 

(>50 μg/m3) exposure groups relative to the low (<20 μg/m36 ) exposure group, based on the 

7 highest of four seasonal 4-day formaldehyde measurements in the home (Figures 5-6 and 5-7). 

8 

9 

10 Figure 5-6. Prevalence of asthma and respiratory symptom scores in children associated 

11 with in-home formaldehyde levels. Trend analysis indicates statistical significance in these 

12 increases {percent asthmatic children, unadjusted (p=0.03) and respiratory symptom score 

13 (p=0.03)}. 

14 

15 Source: Garrett et al. (1999). 

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 (%)
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5-49 DRAFT—DO NOT CITE OR QUOTE 

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 

3 Figure 5-7. Prevalence and severity of allergic sensitization in children 

4 associated with in-home formaldehyde levels. Trend analysis indicates 

5 statistical significance in these increases {percent atopic children (p=0.002), 

6 positive skin prick tests (p=0.001) and severity as allergen wheal ratio 

7 (p=0.004)}. 

8 

9 Note: Skin prick tests included 12 environmental allergens (cat, dog, grass [two 

10 types], house dust, dust mite [two strains] and fungi [five strains]). 

11 Source: Garrett et al. (1999). 

12 

13 

14 The findings of Garrett et al. (1999) are supported by the observation of an increased 

15 bronchial responsiveness to mite allergen in a chamber study of 19 sensitized adult asthmatics 

exposed to formaldehyde at a concentration of 100 μg/m316 for 30 minutes (Casset et al., 2006). 

17 Additionally, inhalation exposures to formaldehyde have been shown to increase an animal’s 

18 response to other common allergens via inhalation (Fujimaki et al., 2004; Sadakane et al., 2002; 

19 Riedel et al., 1996; Tarkowski and Gorski, 1995). 

20 

21 Candidate RfC derivation for increased allergic sensitization from Garrett et al. (1999):

22 Critical effects: Allergic sensitization - Increase in allergic sensitization (proportion of 

23 atopic children). Severity of allergic sensitization measured both as number of positive 

24 skin tests to common allergens and the recorded allergen wheal ratio for those tests. 

25 Asthma – increase in proportion of asthmatic children. Respiratory symptoms – 

26 Increased respiratory symptom score. 

27 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 Point of departure: For all critical effects, categorical analyses are presented that show 

2 an increase in the mid-exposure group (16–40 ppb) and high exposure group (>40 ppb) 

3 relative to the low-exposure group (<16 ppb) (Figures 5-6 and 5-7). However, it is 

4 unknown if the findings in the low-exposure group are comparable to the responses that 

5 would be observed in an unexposed population. Therefore, the low-exposure group 

6 cannot be considered a NOAEL but rather serves as a referent group for the two other 

7 exposure groups. Thus, the LOAEL is based on health effects observed in the mid8 exposure group (16-40 ppb) for all three critical effects. As neither the mean or median 

9 exposure levels are provided for the exposure categories used to analyze the health effects 

10 data, the mid-point of the exposure category is selected for the LOAEL: 28 ppb. 

11 

12 Application of study-specific Uncertainty Factors (UFs):

13 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 

14 LOAEL-to-NOAEL UF = 3: As discussed, the mid-exposure group is selected as the 

15 LOAEL since the low-exposure group is the referent group; there is no true 

16 unexposed control. It is unclear whether or not a full LOAEL to NOAEL 

17 uncertainty factor is warranted for these data. The authors did provide evidence 

18 for increased atopy for every increase of 16 ppb of exposure with borderline 

19 statistical significance when adjusted for several potential confounders (OR = 1.4; 

20 95% CI: 0.98–2.00). An UF of 3 adjusts the LOAEL to a similar range and is 

21 consistent with this alternative presentation of the data. 

22 Subchronic to chronic UF = 1: The study addresses ongoing residential exposure to 

23 formaldehyde. Although information on the duration of exposure for each 

24 participant is not provided, the residential nature of the study suggests a longer 

25 term exposure than the duration of the study. It is judged that a population-based 

26 study of residential exposures is sufficient for derivation of a chronic RfC without 

27 adjusting for a subchronic observation period. 

28 Human variability UF = 1 or 3: This study was designed to assess allergic 

29 sensitization, asthma prevalence and respiratory symptoms in children with 

30 relation to in-home formaldehyde levels. The recruitment of participants was 

31 designed to include households (50%) with asthmatic children, resulting in 

32 43 households with at least one asthmatic child and 37 without asthmatic children 

33 for a total of 148 children (35% asthmatic). Parental allergy and asthma were 

34 also assessed and included as adjustment variables in the data evaluation. 

35 Therefore the study population includes individuals reflecting several key aspects 
This document is a draft for review purposes only and does not constitute Agency policy.

5-51 DRAFT—DO NOT CITE OR QUOTE 

1 of human variability for asthma and allergic sensitization (age, familial history of 

2 disease), and addresses the links between allergic sensitization and asthma. Both 

3 asthma and allergic sensitization are risk factors for increased respiratory 

4 symptoms. 

5 

6 The two alternatives are described below and cRfCs derived for each alternative

7 

8 

9 

10 

Alternative A: Garrett et al. (1999)

Human variability UF = 3: It is unclear whether the effect levels in the study 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

A L S H

8.2

1 3 1 3

28

=

× × ×

=

× × ×

=

UFA = 1 (interspecies UF) 

UFL = 3 (LOAEL-to-NOAEL UF) 

UFS = 1 (subchronic-to-chronic UF)

UFH = 3 (human variability UF) 
This document is a draft for review purposes only and does not constitute Agency policy.

5-52 DRAFT—DO NOT CITE OR QUOTE 

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 provided for individuals with a familial 

history of disease, analyses provided suggest the results 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 likely genetic susceptibility. As shown in 

Figure 5-8, formaldehyde levels are related to increased 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 response on which the POD is based is driven by 

children with a potential for genetic susceptibility. 

 An EPA Technical Report of the RfD and RfC Processes (US EPA, 2002a) indicates 

that a UFH of 1 can be applied in cases where data are “very specific about the particular 

vulnerability of infants and children within certain 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 human variability. The technical report 

acknowledges that “even within these populations it is possible that some variability still 

exists”, but that a UFH of 1 is still applied. 

 

( ) ( ) ppb ppb

UF UF UF UF

LOAEL RfC

A L S H

3.9

1 3 1 1

28

=

× × ×

=

× × ×

=

UFA = 1 (interspecies UF) 

UFL = 3 (LOAEL-to-NOAEL UF) 

UFS = 1 (subchronic-to-chronic UF)

UFH = 1 (human variability UF) 
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5-53 DRAFT—DO NOT CITE OR QUOTE 

1 5.1.2.2.4. Candidate RfC derivation for Ritchie and Lehnen, 1987; Hanrahan et al., 1984 

2 and Liu et al., 1991 (Sensory irritation). 

3 There are three studies that report sensory irritation in humans from chronic exposures in 

4 a residential environment and provide sufficient exposure data to support quantitative assessment 

5 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). Each study reports site6 specific exposure measurements and presents some metric of individual exposure. These 

7 residential studies employ in-home measurements for each study participant, either as average 

8 exposure level (Ritchie and Lehnen, 1987; Hanrahan et al., 1984) or as calculated cumulative 

9 exposure based on the time in the home (Liu et al., 1991). Eye irritation is reported at similar 

10 levels of residential formaldehyde exposure in the three studies (Figures 5-8 and 5-9). Each 

11 study provides an exposure-response relationship for prevalence of sensory irritation in relation 

12 to in-home formaldehyde exposure based on individual level data. 

13 

14 

15 

16 

17 

18 

19 

20 

21 

22 

23 Figure 5-8. Positive exposure-response relationships reported for in-home 

24 formaldehyde exposures and sensory irritation (eye irritation). 

Panel A: Regression of prevalence of eye irritation 

versus indoor formaldehyde concentration (ppm) in 

mobile homes (30–60 minute air sample in each 

home). 

Note: Dashed lines show upper and lower 95th percentile 

confidence intervals on model results. Model based on 

reported eye irritation from individuals in 42 mobile 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 status: 

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-smoker
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5-54 DRAFT—DO NOT CITE OR QUOTE 

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 

3 Figure 5-9. Positive exposure-response relationships reported for in-home 

4 formaldehyde exposures and sensory irritation (burning eyes). 

5 

6 Note: Cumulative formaldehyde exposure was estimated for each participant 

7 from measured in-home formaldehyde levels (7-day passive air sample) and 

8 reported hours spent in the home. Prevalence rates are given for both summer 

9 (n = 1,388) and winter (n = 1,093) survey periods. 

10 Data source: Liu et al. (1991). 

11 

12 

13 Ritchie and Lehnen (1987) examined formaldehyde-associated effects on eye, nose, and 

14 throat irritation in a large residential study with 2,007 participants from 841 homes. Based on 

15 in-home measurements of formaldehyde concentration, participants were categorized into three 

16 exposure groups: low (<100 ppb), mid (100–300 ppb) and high (>300 ppb) (average of two 30–

17 60 minute air samples per home). Ritchie and Lehnen (1987) observed clear exposure-response 

18 relationships in the percentage of residential occupants reporting eye, nose, and throat irritation. 

19 For example, in nonsmoking mobile home residents, incidence scores for eye irritation were 1%, 

20 18% and 86%, and for nose/throat irritation were 5%, 17% and 78%, respectively, for the three 

21 exposure groups. The exposure-response relationships were similar regardless of type of home, 

22 mobile (n = 851) or conventional (n = 1,156). Although smoking status was also a predictor of 

23 irritation, in-home formaldehyde concentrations were a stronger predictor of health effects. The 
This document is a draft for review purposes only and does not constitute Agency policy.

5-55 DRAFT—DO NOT CITE OR QUOTE 

1 study included children and the elderly and results were consistent across age groups. Children 

2 <7 years of age were only included in the eye irritation analyses because of concerns about the 

3 quality of parental reporting for nose and throat effects in young children. The selection criteria 

4 for participants indicate that more sensitive individuals may have been over-represented in the 

study population.75 All study participants were self-selected, with a physician’s approval, perhaps 

6 resulting in a higher proportion of individuals experiencing various irritant and upper respiratory 

7 tract symptoms, which may represent a sensitive population for eye, nose, or throat irritation. 

8 Hanrahan et al. (1984) reported an exposure-response relationship for burning eyes and 

9 eye irritation in a study of 61 teenage and adult residents of mobile homes. As in the Ritchie and 

10 Lehnen (1987) study, in-home formaldehyde measurements were obtained for all participants and 

11 measured formaldehyde levels were used to characterize average in-home exposures (30–

12 60 minute air sample). Eye irritation was associated with in-home formaldehyde exposures 

13 (p < 0.05) (both as “burning eyes” and “eye irritation”), and the authors provided a graphical 

14 representation of the best-fitting regression model for exposures between 100 and 800 ppb. From 

15 inspection of this graph, the prevalence of eye irritation predicted at 100 ppb is approximately 

4% with an upper bound of 18% (95th 16 percentile CI) (Figure 5-8, Panel A). Because the limit of 

17 detection for formaldehyde in indoor air was 100 ppb, data or model results are not provided 

18 below 100 ppb. 

19 The third residential study is a random-sample study of over 1,000 mobile home residents 

20 (1,394 in the summer; 1,096 in the winter) that included both young children and the elderly (Liu 

21 et al., 1991). Cumulative weekly exposures were based on in-home formaldehyde sampling and 

22 a participant survey of time spent at home. Air sampling was conducted for a 7-day period using 

23 a passive sampler in each home (summer and winter). The resulting estimates of cumulative 

24 exposure assumed no formaldehyde exposure outside of the home. Cumulative formaldehyde 

25 exposure was a significant predictor of numerous irritant symptoms in a multivariate linear 

26 logistic regression, including “burning eyes” (p < 0.05). The prevalence of eye irritation 

27 increased with increasing cumulative exposure in a categorical analysis of participants 20–64 

28 years old for both summer and winter exposure estimates (Figure 5-9). Eye irritation was above 

29 10% in the lowest exposure group (0–7.0 ppm-hours/week) and increased to 17.1% and 21.4 % 

 

7

Participants in this study were self-selected residents who were concerned about possible formaldehyde exposure 

and had obtained a written request from a physician to have the Minnesota Department of Health test their 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 exposure levels in participants’ homes. 
This document is a draft for review purposes only and does not constitute Agency policy.

5-56 DRAFT—DO NOT CITE OR QUOTE 

1 in the mid- and high-exposure group, respectively, for the summer survey time; winter rates were 

2 slightly lower but showed a similar increase with increasing cumulative exposure. 

3 Taken together, these three studies report increased eye irritation from residential 

4 exposures that are below the BMCLs calculated from acute exposures in the laboratory. Each 

5 study has the strength of having individual in-home exposure measurements and demonstrates a 

6 positive exposure-response relationship for sensory irritation within a range of residential 

7 formaldehyde exposures (both conventional and mobile homes). Potentially confounding factors 

8 (such as allergens and some other in-home exposures) have been taken into account and 

9 statistical analyses of the data include relevant covariates (e.g., age, sex, smoking status). As 

10 such, these studies provide a basis for development of a cRfC for sensory irritation. 

11 Additionally, the study populations have been drawn from the general population, including 

12 children and the elderly, and have not been limited to those healthy enough for full-time 

13 employment (as is often the case in occupational cohorts). 

14 All three studies support a finding of increased eye irritation for exposures above 100 ppb 

15 (Figures 5-8 and 5-9). However, the shape of the exposure-response curve below 100 ppb, or an 

16 indication of a no-effect level, is less clear. Two of the studies indicate 1–4% eye irritation in 

17 residents where formaldehyde exposures were measured at 100 ppb or less (Ritchie and Lehnen, 

18 1987; Hanrahan et al., 1984). Thus, there is uncertainty in considering 100 ppb as a no-effect 

19 level for increased eye irritation for these studies. When modeled, the 95% CIs around the point 

20 estimate of 4% eye irritation were 1–18% eye irritation, illustrating the range of response rates at 

21 100 ppb that are consistent with the observed data (Hanrahan et al., 1984). Additionally, the 

22 presentation of results by exposure category in Ritchie and Lehnen (1987) is inexact and has 

23 individuals with exposures at the low end of the categorical range being grouped with those at 

24 higher exposures in the range, obscuring any exposure-response relationship within the 

25 categorical range. For these reasons, a POD for RfC derivation from either of these studies 

26 should reflect these uncertainties. Therefore, for the NOAEL representing the category of 

27 individuals with ≤100 ppb, in which 1–2 % eye irritation was observed, the upper end of this 

28 exposure category is not used, but rather the midpoint, 50 ppb (Ritchie and Lehnen, 1987). 

29 Although Hanrahan et al. (1984) provided no model results below 100 ppb, an extrapolation of 

the graphical results (Figure 5-8, Panel A) provides an estimated BMCL10 of 70 ppb830 . No 

 

8

Figure 1 of Hanrahan et al. (1984) shows predicted values and 95% confidence intervals (CIs) for the percent 

prevalence of a burning-eyes response for formaldehyde concentrations ≥100 ppb (See Panel A in Figure 5-9 above). 

 A short extension of the upper 95% CI to the concentration associated with 13% prevalence (i.e., a 10% increased 

prevalence above an assumed background response rate of 3%; this assumed background rate was chosen to be 

conservatively high to err on the side of not underestimating the actual value, given that the value was approximated 

from a visual extension of the upper 95% CI curve) suggests a BMCL of approximately 70 ppb for 10% increased 
This document is a draft for review purposes only and does not constitute Agency policy.

5-57 DRAFT—DO NOT CITE OR QUOTE 

1 additional duration adjustments were made from the in-home exposure measurements to 

2 continuous exposure because neither time away from the home, nor potential exposures outside 

3 of the home, were characterized in either study. 

4 Of the three studies, only Liu et al. (1991) provides exposure measurements below 

5 100 ppb, with a reported detection limit of 10 ppb formaldehyde for the in-home air monitoring. 

6 Additionally, air samples were collected using a 7-day passive sampler which is more 

7 representative of average residential exposures than a one-time, 30–60 minute, air sample. 

8 Therefore, the data collected by Liu et al. (1991) are more suited to understanding the exposure9 response relationship for eye irritation of exposures below 100 ppb. In addition to controlling for 

10 age, gender, and smoking status, Liu et al. (1991) controlled for the presence of chronic 

11 respiratory disease when assessing the effects of formaldehyde on symptoms of sensory irritation. 

12 Finally, this study provides results for both summer and winter survey periods, addressing 

13 seasonal variation in both formaldehyde levels and sensory irritation. The use of the cumulative 

14 exposure metric considers not only the concentration of formaldehyde but also the number of 

15 hours during the week each participant spent in their residence. Linear logistic regression 

16 indicates that cumulative formaldehyde exposure was a statistically significant predictor of 

17 burning eyes for both winter and summer survey periods. However, no BMCL can be calculated 

18 because no regression coefficients were provided in the report. Data were provided for the 

19 categorical analysis illustrating a positive exposure-response relationship (redrawn in 

20 Figure 5-9). Based on the categorical results, the mid-exposure group (7–12 ppm-hours/week) 

21 demonstrated an increased response compared with the low-exposed group. Since the prevalence 

22 rate in the low-exposed group was above 10% for burning eyes, this exposure group does not 

23 represent a NOAEL, but rather serves as a referent for the mid-exposure group. Therefore, the 

24 POD is derived from the midpoint of 7–12 ppm-hours/week, 9.5 ppm-hours/week. Using a 

25 conversion factor applied by the authors, the cumulative exposure of this mid-exposure group 

26 corresponds to a continuous home exposure of 70–120 ppb for an individual who spends 60% of 

27 the week in the home, with a mid-point of 95 ppb. 

28 

29 Candidate RfC derivation for sensory irritation:

30 Critical effect: Prevalence of sensory irritation (eye irritation, burning eyes). 

31 

32 Point of departure: Each of the studies discussed above has different strengths and 

33 weaknesses for the determination of a POD for sensory irritation. Nevertheless, the effect 

 

prevalence. The actual value is unknown but is clearly below 100 ppb, which is the minimum exposure 
This document is a draft for review purposes only and does not constitute Agency policy.

5-58 DRAFT—DO NOT CITE OR QUOTE 

1 levels and PODs derived from each study are in relatively close agreement with less than 

2 a twofold span from lowest to highest. Therefore each POD is carried through to 

3 calculate a cRfC: 

4 

5 NOAEL = 50 ppb (Ritchie and Lehnen, 1987) 

6 BMCL10 = 70 ppb (Hanrahan et al., 1984) 

7 LOAEL = 95 ppb (Liu et al., 1991) 

8 

9 Application of Uncertainty Factors (UFs)

10 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 

11 LOAEL-to-NOAEL UF: An uncertainty factor of 1 is applied to the NOAEL and 

12 BMCL10 established as PODs from Ritchie and Lehnen, (1987) Hanrahan et al. 

13 (1984) studies. An uncertainty factor of 3 is applied to the LOAEL of 95 ppb 

14 based on the Liu et al. (1991) study, as the prevalence rates for this exposure level 

15 are below 20% for an effect that is of relatively low severity. In addition, the 

16 LOAEL is not significantly above the NOAEL and BMCL10 from the other studies 

17 that evaluated the same endpoint. 

18 

19 Subchronic to chronic UF = 1: These studies address ongoing residential exposure to 

20 formaldehyde. Although information on the duration of exposure for each 

21 participant is not provided, the residential nature of the study suggests a longer 

22 term exposure than the duration of the study. It is judged that a population-based 

23 study of residential exposures is sufficient for derivation of a chronic RfC without 

24 adjusting for a subchronic observation period. 

25 

26 Human variability UF = 1 or 3: All three studies were population-based and included 

27 children, the elderly and both sexes. Sample sizes for two of the studies were very 

28 large (1,394 for Liu et al. [1991]; 2,007 for Ritchie and Lehnen [1987]), 

29 increasing the likelihood that sensitive populations were included. Analysis of the 

30 data controlled for sex, smoking status, and age group. 

31 

32 

33 

 

concentration depicted in the figure.
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5-59 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

3 

4 

5 

6 The two alternatives are described below and cRfCs derived for each alternative 

7 

8 

9 

10 

11 

Alternative A 

Sensory irritation studies: 

Human variability UF = 3: For all studies, the analysis was based on prevalence 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 that 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

A L S H

17

1 1 1 3

50

=

× × ×

=

× × ×

=

Hanrahan et al. (1984): 

( ) ( ) ppb ppb

UF UF UF UF

BMCL RfC

A L S H

23

1 1 1 3

10 70

=

× × ×

=

× × ×

=

Liu et al. (1991): 

( ) ( ) ppb ppb

UF UF UF UF

LOAEL RfC

A L S H

5.9

1 3 1 3

95

=

× × ×

=

× × ×

=
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5-60 DRAFT—DO NOT CITE OR QUOTE 

1 

Alternative B

Sensory irritation studies 

Human variability UF = 1: Two studies included a broad age range allowing some 

assessment of human variability due to life stage. Ritchie and Lehnen (1987) 

evaluated the influence of age on sensory irritation 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 greater eye irritation was reported in 

participants of 20–64 years than in those younger than 20 or older than 65 years. The 

elderly population (≥65 years) was well-represented in this study (39% of participants 

in the summer and 34% in the winter). The modeled results on which the BMCL10 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 group considered the most responsive in 

the Liu et al. (1999) study. Therefore the PODs derived from these studies do account 

somewhat for human variability across the life stage. 

The critical effects of sensory irritation (eye, nose, and throat irritation) are considered 

minimally adverse health effects. The nominal response 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 response levels. Additionally, as the data 

are reported as prevalence rates, there is no masking of effect from sensitive 

individuals (as may occur when benchmark responses are average values of biometric 

parameters). 

Finally, sensory irritation is a POE effect. Therefore, sources of human variability such as 

absorption, distribution, and metabolism of a compound are unlikely to influence 

incidence rates for this endpoint. There may be human variability in the sensitivity of 

the trigeminal nerve to formaldehyde binding and stimulation. 

Taken together, these studies address many potential sources of human variability. 

Therefore, it is judged that further adjustment to address human variability is not 

warranted for the minimally adverse health effect of sensory irritation. Thus a UFH of 

1 is applied to all three studies. It is acknowledged that there is the potential for 

sources of variability not captured in these studies. 

 (Continued on next page.) 
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5-61 DRAFT—DO NOT CITE OR QUOTE 

1 

2 

3 

4 5.1.2.2.5. Candidate RfC derivation for Taskinen et al. (1999) (Fecundity ratio)

5 On review of the candidate developmental and reproductive toxicity studies in humans 

6 and animals (presented in Section 5.1.3.2.7), the Taskinen et al. (1999) human study was 

7 considered to be the strongest for the purpose of deriving a chronic RfC. This study was a well8 designed population-based case-control study of women who were occupationally exposed to 

9 formaldehyde. The study population was well defined and adequately selected to allow for 

10 meaningful comparisons of health effects among individuals with different levels of exposure to 

11 formaldehyde. Potential selection bias and the self-reporting of spontaneous abortion are not 

12 considered to have had a significant influence on the study findings. Additionally, the decreased 

13 FDR and increased risk of spontaneous abortion observed in Taskinen et al. (1999) are internally 

14 consistent and coherent with other reports of increased risk of pregnancy loss associated with 

15 exposure to formaldehyde (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 1990; 

16 Axelsson et al., 1984) and is supported by animal data (Kitaev et al., 1984; Sheveleva, 1971). 

17 The Taskinen et al. (1999) study allows the consideration of three potential critical 

18 effects: endometriosis, increased spontaneous abortion, and decreased FDR. However, there is 

19 little independent support for the finding of increased endometriosis and the ORs for organic 

20 solvent exposure within this study (OR = 14.7; 95% CI: 3.1–70) were much greater than for 

21 formaldehyde (OR = 4.5, 95% CI: 1.0–20), indicating a potential for confounding. Both 

Continued from previous page:

Ritchie and Lehnen (1987): 

( ) ( ) ppb ppb

UF UF UF UF

NOAEL RfC

A L S H

50

1 1 1 1

50

=

× × ×

=

× × ×

=

Hanrahan et al. (1984): 

( ) ( ) ppb ppbUF UF UF UF

BMCL RfC

A L S H

70

1 1 1 1

10 70

=

× × ×

=

× × ×

=

 

Liu et al (1991): 

( ) ( ) ppb ppbUF UF UF UF

LOAEL RfC

A L S H

32

1 3 1 1

95

=

× × ×

=

× × ×

=
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5-62 DRAFT—DO NOT CITE OR QUOTE 

1 increased spontaneous abortions and decreased FDR are supported by independent findings in 

2 other formaldehyde-exposed cohorts (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 

3 1990; Axelsson et al., 1984). As this study was designed to examine the effect of workplace 

4 formaldehyde exposures on FDR, the study design and data collection best support this finding. 

5 The exposure measurements were conducted to represent what the researchers considered the 

6 relevant time-to-pregnancy exposures. Although data on miscarriages were collected to control 

7 the time-to-pregnancy findings for confounding from formaldehyde-related spontaneous 

8 abortions, it is less certain that the exposure measurements coincide with the defined 

9 spontaneous abortion cases. Spontaneous abortions were only included in calculations of 

10 exposure-specific ORs if a participant indicated that she was employed at the same location when 

11 she had the spontaneous abortion and when the time-to-pregnancy exposure assessment was 

12 done. The analysis showed that there were statistically significantly increased risks of 

13 spontaneous abortion in the lowest exposure group. While this finding was consistent with other 

14 studies showing adverse reproductive effects of formaldehyde and appears to be causal, the 

15 Taskinen et al. (1999) spontaneous abortion results did not clearly control for all the potential 

16 confounders that were controlled for in the FDR analyses (i.e. organic solvents and phenols). 

17 While the other coexposures were not associated with FDR and therefore not confounders, 

18 endometriosis was strongly associated with organic solvents. Therefore, for these endpoints, the 

19 study design and strength of results best support the use of decreased FDR in formaldehyde20 exposed women as the critical effect for this study. 

21 It is preferable that the critical effect be the most sensitive of the effects which is well 

22 supported by the given study. As spontaneous abortions are significantly increased in the low23 exposure group and the response in the mid-exposure group is considered a no-effect level for 

24 decreased FDR, there is uncertainty that an RfC based on the FDR NOAEL would be protective 

25 for the more sensitive effect. Although qualitatively the finding of increased spontaneous 

26 abortion is convincing, there is more uncertainty in the applicability of the exposure assessment 

27 for quantitative risk assessment. Additionally, there is greater uncertainty in the use of the 

28 exposure adjustments for the low-exposure group on which the LOAEL is based because they 

29 account for more of the work time in the low-exposure group than the medium and high exposure 

30 groups (Table 5-5). 

31 There are several sources of uncertainty in the exposure estimates for use in RfC 

32 derivation. As discussed above, the average exposure estimate for the low exposure group 

33 includes a greater proportion of non-assessed background exposures. This is evidenced in part 

34 by the reported average exposure being below background levels for these workers, even with 

35 exposure measurements as high as 300 ppb. The unaccounted for non-task exposures may 
This document is a draft for review purposes only and does not constitute Agency policy.

5-63 DRAFT—DO NOT CITE OR QUOTE 

1 represent time during the day spent in the work facility, or time in a different job or work 

2 environment. Additionally, task-level exposure measurements were available for only 27% of 

3 women in the low exposure group, versus 38% and 69% of women in the medium and high 

4 exposure groups, indicating less certainty in exposure classification for the low exposure group. 

5 

6 Duration adjustment for candidate study points of departure: 

7 Normally, exposures from occupational studies are adjusted to account for the daily 

8 breathing volume appropriate to an environmental (versus occupational) setting and for exposure 

9 every day of the year (EPA, 1993). However, with formaldehyde, there is potential for exposure 

10 outside of work from in-home and environmental sources of formaldehyde (Chapter 2). A 

11 contemporaneous study of formaldehyde exposures in Finland reports average exposure of 21.4 

12 ppb (measured over 48 hours with a personal monitor) (Jurvelin et al., 2001). Furthermore, both 

13 the mean exposure (18 ppb 8hr TWA) and lowest reported exposure (10 ppb 8hr TWA) of the 

14 ‘low exposed’ category are below the reported average ambient exposures for Finland (21.4 ppb). 

15 Thus, it is likely that exposure estimates for study participants include time during the workday 

16 when women reported no formaldehyde exposure and a zero exposure was assessed for a non17 formaldehyde related task. Additionally, participants may have qualified for the study based on 

18 employment date but may not have been working with formaldehyde during the entire time-to19 pregnancy period. In both cases, the investigators in Taskinen et al. (1999) appear to have 

20 assumed that, while the women were away from their “exposed” workplace, their exposure to 

21 formaldehyde was zero, not accounting for background occupational exposures and ambient 

22 levels of formaldehyde. This explains why both the mean exposure as well as lower end of 

23 workshift exposures for women in the low exposure group were reported at and below expected 

24 ambient levels. The women in the low exposure category had task-level workplace exposures of 

25 up to 300 ppb in addition to experiencing some work time at background exposure levels. 

26 Compared to women who only experienced background exposure levels, those in the low 

27 exposure category were at significantly higher risk of spontaneous abortion. 

28 The reported data do not provide information to correct for background formaldehyde 

29 exposure during the workday for each participant. However, the published mean exposure values 

30 may be used to provide some idea of the impact of including background exposures on the study 

31 PODs. Comparison of the values listed in Table 4 of Taskinen et al. (1999) allows for the 

32 estimation of the percentage of work time spent performing tasks involving formaldehyde 

33 exposure (Table 5-5, Panel A). For the women in the low exposure category, this percentage is 

34 26% (mean of measured workplace exposures of 70 ppb times 26% equals the mean of the TWA 

35 exposure of 18 ppb). Using the same method, the women in the “medium” and "high" exposure 
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1 category were performing tasks involving formaldehyde exposure approximately 54% and 66% 

2 of their work time, respectively. Assuming that the women spent the remainder of their work 

3 time at the background concentration of 21.4 ppb (Jurvelin et al., 2001), a more appropriate 

4 estimate of the women’s 8-hour TWA formaldehyde exposures would be 34 ppb for the low 

5 category, 86 ppb for the medium category, and 226 ppb for the high category (Table 5-5, Panel 

6 B). 

7 

8 Table 5-5: Adjustment for nonoccupational exposures to formaldehyde. 

9 

10 Panel A: Proportion of workshift corresponding to the exposure group mean 

11 task-level formaldehyde exposure (ppb) and the exposure group daily exposure 

12 index (8 Hr-TWA). 

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 

worktimea

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 

13 a: Calculated as mean exposure (ppb 8Hr-TWA) divided by mean task-level exposures for the exposure group. 

14 

15 Panel B: Recalculation of daily exposure index (8 Hr –TWA) where background 

16 formaldehyde exposure is estimated for worktime spent on tasks considered 

17 unrelated to occupational use of formaldehyde. 

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 

20 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 

2 Candidate RfC derivation for Taskinen et al, 1999:

3 Critical effect: Decreased FDR. 

4 

5 Point of departure: For decreased FDR, the mid-exposure level is considered a 

6 NOAEL. The mean exposure as an 8-hour TWA for the workday is reported as 76 ppb. 

7 EPA has adjusted this POD to account for potential background formaldehyde exposures 

8 during the workshift (Table 5-5) resulting in an adjusted POD of 86 ppb. No further 

9 duration adjustment is made to this POD to account for background levels of 

10 formaldehyde exposure outside of the workplace. 

11 

12 Application of study-specific Uncertainty Factors (UFs):

13 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 

14 LOAEL-to-NOAEL UF = 1: Selection of an NOAEL as the POD. 

15 Subchronic to chronic UF = 1: The study design represents a study population with a 

16 range of exposure durations, including chronic exposures. By drawing the study 

17 population from full-time employees and members of the wood-working union, 

18 there is an expectation that the study population reflects the demographic of that 

19 group as a whole. Although specific summary information is not published for 

20 this study group (e.g., average length of employment), the lack of this reporting in 

21 itself does not seem to justify an UF for subchronic-to-chronic exposure given the 

22 overall study design. As a study adequate for assessing reproductive effects in a 

23 chronically exposed cohort, no further adjustment was considered needed. 

24 Human variability UF = 10: The study population included women employed in the

25 wood-working industry who were healthy enough to be gainfully employed. 

26 Additionally, study inclusion criteria ensured that all study participants had at 

27 least one pregnancy resulting in a live birth during the study period (1985–1995). 

28 Therefore, these women were reproductively successful. The authors judged that 

29 selective participation did not influence potential confounders such as irregular 

30 menstruation or earlier miscarriages, which could impact the time to pregnancy 

31 results. Susceptible populations were not addressed and, in fact, the women in the 

32 study may be considered healthier than the general population in terms of 

33 reproductive health. Therefore, an uncertainty factor of 10 for human variability 

34 was applied. 

35 
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( ) ( ) ppb ppb

UF UF UF UF

NOAEL RfC

A L S H

6.8

1 1 1 10

86

=

× × ×

=

× × ×

1 =

2 

3 UFA = 1 (interspecies UF) 

4 UFL = 1 (LOAEL-to-NOAEL UF) 

5 UFS = 1 (subchronic to chronic UF)

6 UFH = 10 (human variability UF) 

7 

8 5.1.2.3. Evaluation of the Study-Specific Candidate RfCs 

9 Seven studies were selected as key studies for consideration in RfC derivation (Section 

10 5.1.2, Table 5-4). Candidate RfCs from these studies address various health effects including: 

11 sensory irritation, respiratory effects, asthma, increased allergic sensitization, and decreased 

12 fecundity (Table 5-6). 

13 Three of the seven studies address sensory irritation of the eye, nose, and throat (Liu 

14 et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). The PODs for sensory irritation 

15 range from 50 to 95 ppb for a health effect that is considered minimally adverse. 

16 Two alternatives are presented for the human variability uncertainty factor in RfC derivation 

17 based on these SI studies. Alternative A (UFH=3) results in cRfCs from 9.5 to 23 ppb. 

18 Alternative B (UFH=1) results in cRfCs from 32 to 70 ppb. 

19 A cRfC of 9 ppb is derived for decreased FDR in an occupational study of women in the 

20 wood-working industry (Taskinen et al., 1999). This endpoint is supported by four other 

21 epidemiologic studies and is considered a potential health concern for occupationally exposed 

22 women (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). 

23 However, there is some uncertainty regarding the influence of peak exposures in the work place 

24 on the apparent exposure-response relationship based on average workday exposures calculated 

25 for study participants. It is unknown if the observed decreased FDR can be attributed to the 

26 average exposures from which the cRfC is derived or if it is a result of the measured exposures 

27 (as high as 1,000 ppb). If this were the case the cRfC of 9 ppb, based on the average time28 weighted exposures, would be protective for decreased fecundity. 

29 Three studies identify adverse health effects in residential populations including children: 

30 increased incidence of asthma, decreased pulmonary function, increase in respiratory symptoms, 

31 and increased allergic sensitization (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski 

32 et al., 1999). Asthma, allergic sensitization, pulmonary function, and symptoms of respiratory 

33 disease are not only clinically related, but etiologically related, and it is reasonable that they are
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5-67 DRAFT—DO NOT CITE OR QUOTE 

1 considered together from a public health perspective. These health effects are observed below 

2 the exposure levels that result in sensory irritation and the resulting cRfCs are correspondingly 

3 lower, in a range between 2.8 and 11 ppb, depending on the study, endpoint considered, and the 

4 application of alternative uncertainty factors for human variability (Table 5-6). 

5 These three studies of related health effects: asthma, allergic sensitization, pulmonary 

6 function, and symptoms of respiratory disease in children from in-home exposure to 

7 formaldehyde (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski et al., 1999) were 

8 chosen as the basis for the derivation of the RfC. These co-critical studies are mutually 

9 supportive and provide similar cRfCs. Therefore, the RfC is taken as the mean of the cRfCs of 

10 the cRfCs of the three co-critical studies. For two of these studies (Rumchev et al., 2002; Garrett 

11 et al., 1999), EPA is providing alternatives for the application of the UF addressing human 

12 variability. These alternatives result in a threefold difference in cRfCs for each study when 

13 considering the critical effects of childhood asthma and allergic sensitization (Table 5-6). 

14 Alternative A, described above for each study, acknowledges that evaluation of these effects in 

15 children does address some aspects of human variability, but there remains the potential for 

16 additional inter-individual variability within the studied population, thus a UF of 3 is warranted. 

17 Alternative B, described above for each study, also acknowledges that these studies address 

18 human variability and susceptible populations. However in alternative B it is judged that since 

19 children are a sensitive lifestage for these effects (asthma and atopy), and are likely the most 

20 sensitive population, an UF of 1 may be applied. It is acknowledged that some degree of inter21 individual variability may remain. 

22 
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Table 5-6: Summary of reference concentration (RfC) derivation from critical study and supporting studi

Application of 

Endpoint Study study-specific UF Study size Homes Children POD (ppb) 

UFL UFS U

Respiratory effects / asthma and sensitization Reduction of PEFR in children (10%) 

Krzyzanowski et al. (1990) 208 Yes Yes BMCL10 = 17 1 1 

Asthma incidence 

Rumchev et al. (2002) 192 Yes Yes NOAEL = 33 1 3 

Increased asthma; allergic sensitization Garrett et al. 

(1999) 148 Yes Yes LOAEL = 28 3 1 

Sensory Irritation Eye irritation, burning eyes Ritchie and 

Lehnen (1987) 2,007 Yes Yes NOAEL = 50 1 1 Hanrahan et al. (1984) 61 Yes Some teenagers BMCL10 = 70 1 1 Liu et al. (1991) 1,394 Yes Yes LOAEL = 95 3 1 

Reproductive / DevelopmentalDecreased fecundability density ratio (FDR) 

Taskinen et al., 1999 602 No No NOAEL= 86 1 1 1

Notes: 1: The final RfC will be rounded to one significant digit per EPA policy. Since the Candidate RfC is an interim calculation, two-significant di

practice in mathematics {i.e. one significant diget more that the final result, to avoid rounding errors compounding across multiple mathematical mani
This document is a draft for review purposes only and does not constitute Agency policy.

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1 

2 

3 

4 

5 5.1.3. Database Uncertainties in the RfC Derivation 

6 The database of available laboratory animal studies, human clinical and epidemiological 

7 studies, and supporting mechanistic information for formaldehyde is substantial. Many of the 

8 health effects are well studied in animals and humans, especially those endpoints related to 

9 sensory irritation and respiratory effects at the POE, such as respiratory tract pathology, asthma 

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 asthma (Rumchev et al., 2002) 

cRfC = 2.8 ppb - increased asthma, atopy and respiratory symptoms (Garrett et al., 1999) 

RfC: ppb ppb ppb ppb ppb RfC 4

3

11 7.

3

6.5 3.3 8.2

= =

+ +

=

Alternative B: Application of a UF of 1 for human variability

 (UFH = 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 asthma (Rumchev et al., 2002) 

cRfC = 9.3 ppb - increased asthma, atopy and respiratory symptoms (Garrett et al., 1999) 

RfC: ppb ppb ppb ppb ppb RfC 9

3

25 9.

3

6.5 11 3.9

= =

+ +

=
This document is a draft for review purposes only and does not constitute Agency policy.

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1 and reduced pulmonary function. This is reflected in the number and high quality of human 

2 studies presented in Table 5-4 and supporting data summarized in Chapter 4. 

3 The data also indicate effects in other health effect categories, specifically neurotoxic 

4 effects, reproductive toxicity, and developmental effects (Section 5.1.2). These are areas where 

5 additional research are needed to reduce uncertainty and better characterize the potential for 

6 health effects and the concentrations at which they might occur in humans. 

7 The existing database strongly supports formaldehyde’s potential for causing both 

8 reproductive and developmental toxicity. There is, however, no assessment of these endpoints 

9 from a satisfactory two-generation toxicity study to fully evaluate the effect of formaldehyde 

10 exposure on reproductive and developmental endpoints. Data are adequate to derive a cRfC of 9 

11 ppb for decreased fecundability density ratio (FDR) from a human occupational study (Taskinen 

12 et al., 1999). This study also reports an increase in spontaneous abortions, although there is 

13 uncertainty on the exposure levels of concern for this endpoint; spontaneous abortions may also 

14 contribute to the decreased FDR on which one of the cRfCs is based. The greatest uncertainty in 

15 the cRfC for decreased FDR is the use of a time-weighted exposure metric which does not 

16 address possible contributions of peak exposure levels to the observed health effect. As such, it 

17 is possible that this cRfC is lower than is needed for protection against decreased FDR. The 

18 cRfC for decreased FDR does suggest that the RfC derived from the better studied respiratory 

19 effects would be protective of that reproductive/developmental endpoint, but there remain 

20 uncertainties as to the full range of potential reproductive and developmental effects. No data 

21 exist to sufficiently inform the exposure-response relationship for other reproductive and 

22 developmental endpoints as they relate to RfC derivation (Section 5.1.2.6). For example, male 

23 reproductive effects and structural and behavioral developmental effects (including postnatal 

24 development) are not addressed by a study of decreased FDR. This is a database deficiency. A 

25 survey of the currently available data indicates observed effect levels of 5,000–10,000 ppb for 

26 male reproductive endpoints and 400 ppb and above for growth retardation and structural 

27 anomalies in animal studies. However, these studies employed only one treatment level, 

28 precluding the ability to establish a dose-response relationship, thus limiting the strength of the 

29 studies for use in RfC derivation. 

30 Similarly, there is evidence that formaldehyde can cause neurotoxic effects. There is a 

31 deficit of studies with appropriate exposure scenarios to support derivation of an RfC reflecting 

32 the potential for observed neurotoxicity due to formaldehyde exposure. None of the available 

33 human studies that evaluated neurological effects were adequate for use in quantitative risk 

34 assessment, although they did identify neurological effects of concern, including changes in 

35 memory and concentration (e.g., Bach et al. [1990]; Kilburn et al. [1987, 1985]) and increased 
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1 risk of mortality from amyotrophic lateral sclerosis (ALS) with increasing duration of exposure 

2 to formaldehyde (Weisskopf et al., 2009). The human and animal data indicate the potential for 

3 serious neurological and behavioral effects from short-term formaldehyde exposure (Section 

4 5.1.2.6). Limited studies in humans, as well as controlled studies in established animal models, 

5 confirm the neurotoxic effects of formaldehyde at exposure levels of 100–170 ppb (Malek et al., 

6 2003a, c; Bach et al., 1990) (Table 5-1). For example, an adverse effect level of 100 ppb for 

7 impaired learning is reported for short-term exposures (2 hours/day for 10 days) in rats (Malek et 

8 al., 2003a). For this effect, appropriate duration adjustment for extrapolation of a 2-hour 

9 repeated exposure over a limited number of days is uncertain. Given the nature of these health 

10 effects, and the potential for children to be exposed in the home to levels as high as 100 ppb (the 

11 level at which effects were seen in animals following a single exposure), this is a significant data 

12 gap. Studies are inadequate to determine whether exposure to levels of formaldehyde at or below 

13 those that impact children’s respiratory health and sensitization will cause neurotoxicity in 

14 humans, including endpoints such as impaired learning and memory. 

15 

16 

17 

Approaches to the application of a database uncertainty factor:

Options EPA is considering include: 

(1) Provide an RfC derived from studies of respiratory and allergenic responses and protective 

of sensory irritation effects with a database uncertainty factor of one given significant data on 

formaldehyde, but noting that further research reproductive, developmental and neurotoxic 

effects would be valuable. 

(2) Provide an RfC with a database uncertainty factor 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 from studies of respiratory and allergenic 

responses to reflect the potential that reproductive, developmental, or neurotoxic effects might 

occur at lower doses: 

 (3) Provide both an RfC identified as protective of the better-studied effects and an RfC with a 

database uncertainty factor of 3 incorporated to account for limits to the data on reproductive, 

developmental and neurotoxic effects. 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 It is unclear what uncertainty factors are appropriate to account for human variability and 

2 deficiencies in the overall database. For this reason, several alternatives have been presented. 

3 

4 5.1.4. Uncertainties in the RfC Derivation 

5 By design, the RfC is an estimate of an exposure level at which it is unlikely there would 

6 be deleterious effects to the human population (including sensitive subgroups) during a lifetime 

7 of exposure. Although the RfC is derived from the best available studies, there are a number of 

8 uncertainties that underlie the RfC. Some of these uncertainties are addressed quantitatively by 

9 applying UFs on a study-specific a basis for RfCs based on animal studies, less-than-chronic 

10 exposures, use of a LOAEL as the POD, and to address human variability for the relevant 

11 endpoint (Section 5.1.3). This section elaborates on some of the sources of uncertainty in the 

12 final RfC. 

13 As the RfC is derived from human studies, the majority in a residential setting, study 

14 aspects that are often a great source of uncertainty are of no concern (e.g., use of animal studies, 

15 study of a worker population). The uncertainties discussed below apply specifically to the 

16 database of formaldehyde studies and the process to derive the RfC. 

17 

18 Point of departure

19 Most of the studies considered for RfC derivation did not provide enough data to support 

20 BMD modeling. Rather, the PODs for most studies were LOAELs or NOAELs that have a 

21 number of shortcomings relative to a POD obtained from BMD modeling (i.e., a BMC or BMD): 

22 

23 • LOAELs and NOAELs are a reflection of the particular exposure/dose levels used in a 

24 study, contributing some inaccuracy to the POD determination. 

25 • LOAELs and NOAELs are often determined based on statistical significance and, thus, 

26 reflect the number of study subjects or test animals. Studies are typically dissimilar in 

27 detection ability and statistical power, with smaller studies tending to identify higher 

28 exposure levels as NOAELs compared with larger but otherwise similarly designed 

29 studies. 

30 • Different LOAELs and NOAELs represent different response rates, so direct qualitative 

31 and quantitative comparisons are not possible. 

32 
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1 PODs identified from BMD models overcome some of the deficiencies associated with 

2 LOAELs and NOAELs. Benchmark models were used for two inhalation data sets, Hanrahan et 

3 al. (1984) and Krzyzanowski et al. (1990). 

4 It should also be noted, however, that even for BMCs/BMDs there is often uncertainty, in 

5 particular for continuous responses, about what response level to select as the BMR, i.e., where 

6 to define the cut-off point between a level of change that is not adverse and one that is adverse. 

7 In addition, BMD models currently in use are purely mathematical models and are not intended 

8 to accurately reflect the biology of the effect being modeled. 

9 Another source of uncertainty in the POD is the adjustment for continuous exposure. 

10 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human and 

11 laboratory animal inhalation studies are typically not continuous and assumptions must be made 

12 in converting reported exposure levels to equivalent continuous exposures. Similarly, there are 

13 uncertainties about potential dose rate effects, in particular the effect of peak exposures in 

14 occupational studies. 

15 

16 Extrapolation from laboratory animal data to humans

17 Because the inhalation database for formaldehyde contains many human studies for a 

18 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 

19 to derive the RfC. Thus, unlike for most RfCs, this is not a source of uncertainty in the RfC for 

20 formaldehyde. 

21 

22 Human variation

23 Heterogeneity among humans is another uncertainty associated with extending results 

24 observed in a limited human study population or laboratory animal experiment to a larger, more 

25 diverse human population. 

26 For three of the studies used to derive the RfC, a value of 3 was used for the human 

27 variability UF (rather than the default value of 10) because the studies had an apparent over28 representation of populations expected to have increased susceptibility (Section 5.5.3.1): 

29 

30  The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 

31 irritation in a large number of subjects, including children and the elderly. As a result of 

32 the study's participation criteria, individuals with greater sensitivity were potentially over33 represented. 

34  Thirty percent of the subjects in the residential study by Krzyzanowski et al. (1990) were 

35 children who are more sensitive to formaldehyde-associated decreases in PEFR than 
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1 adults. The cRfC determination for this study focused on the results in the children, 

2 among whom asthmatics were over-represented (roughly three times) compared with the 

3 national average of 9.4% in 2008 (Bloom et al., 2009). 

4  Garrett et al. (1999) conducted a cross-sectional survey of allergy and asthma-like 

5 symptoms in children with or without a doctor's diagnosis of asthma. The study was 

6 designed to include a high proportion of asthmatic children, a sensitive population for the 

7 effects being studied. 

8 

9 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 

10 account for certain special attributes of these studies/effects, there is still uncertainty about how 

11 much of the overall population heterogeneity is actually reflected even in these relatively diverse 

12 residential studies. 

13 

14 Subchronic-to-chronic extrapolation

15 RfCs are intended to apply to chronic lifetime exposures. If a study is subchronic 

16 (typically less than 10% of a lifetime), a UF for subchronic-to-chronic extrapolation is generally 

17 applied to the cRfC for that study. For the key human residential and occupational studies used 

18 to derive the RfC in this assessment, the average durations of exposure in the households or 

19 workplaces under study are unknown. In this assessment, these studies were considered chronic 

20 in nature and no subchronic-to-chronic UF was applied. However, there is uncertainty about 

21 whether or not the responses observed fully reflected the potential effects of chronic exposure, 

22 especially in children, where, for example, impacts on the developing respiratory and immune 

23 systems could be predisposing the children to further adverse effects later in life. 

24 

25 5.1.5. Previous Inhalation Assessment 

26 There is no previous EPA RfC assessment for formaldehyde with which to compare and 

27 contrast the RfC developed in this assessment. 

28 

29 5.2. QUANTITATIVE CANCER ASSESSMENT BASED ON THE NATIONAL 

30 CANCER INSTITUTE COHORT STUDY 

31 For quantitative assessment of cancer risk, it is generally preferable to use good-quality 

32 epidemiologic data, when available, over laboratory animal data. The follow-up studies by 

33 Hauptmann et al. (2004) and Beane Freeman et al. (2009) of the large National Cancer Institute 

34 (NCI) retrospective cohort mortality study of U.S. workers involved in the production or use of 

35 formaldehyde, with quantitative exposure estimates for the individual workers, present an 

36 opportunity to perform quantitative cancer risk assessments of nasopharyngeal cancer (NPC) and 
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1 lymphohematopoietic cancers (Hodgkin lymphoma and leukemia) based on human data. 

2 Although other upper respiratory tract cancers were also identified as being causally associated 

3 with formaldehyde exposure in the weight-of-evidence analysis in section 4.5, NPC was the only 

4 upper respiratory tract cancer with exposure-response data adequate for the derivation of unit risk 

5 estimates in the Hauptmann et al. (2004) follow-up study of solid tumors. Similarly, the weight6 of evidence analysis in section 4.5 concluded that there were causal relationships between 

7 formaldehyde exposure and all lymphohematopoietic cancers as a group as well as leukemias as 

8 a group (with the strongest evidence for myeloid leukemia); however, from the Beane Freeman et 

9 al. (2009) follow-up study of lymphohematopoietic malignancies, only all leukemias combined 

10 and Hodgkin lymphoma were judged to have exposure-response data adequate for the derivation 

11 of unit risk estimates (see section 5.2.3.1 below).

12 

13 5.2.1. Choice of Epidemiology Study 

14 Several follow-up studies of formaldehyde exposure in industrial workers have recently 

15 become available. These studies are discussed in more detail in chapter 4 and the appendix 

16 (Human Health) and are reviewed only briefly here. Hauptmann et al. (2004) and 

17 Beane Freeman et al. (2009) presented follow-ups of the NCI study (originally described by Blair 

18 et al. [1986]) of workers at 10 U.S. plants producing or using formaldehyde. Marsh et al. (2007, 

19 2002) focused on pharyngeal cancer and, in particular, NPC mortality in sequential follow-up 

20 analyses of the Marsh et al. (1996) cohort study, which examined 1 of the 10 plants studied by 

21 NCI. Pinkerton et al. (2004) presented a follow-up of the National Institute for Occupational 

22 Safety and Health (NIOSH) study of workers exposed to formaldehyde in three U.S. garment 

23 plants (originally described by Stayner et al. [1988]). Coggon et al. (2003) presented an extended 

24 follow-up of a study of workers in six British factories where formaldehyde was produced or 

25 used (originally described by Acheson et al. [1984] and previously followed up by Gardner et al. 

26 [1993]). 

27 The analyses presented here are based on the NPC (Hauptmann et al., 2004) and 

28 lymphohematopoietic cancer (Beane Freeman et al., 2009) results from the NCI follow-up 

29 studies. The NCI cohort study is the largest of the three independent studies and is the only one 

30 with sufficient individual exposure data for exposure-response modeling. In addition, the NCI 

31 study is the only one of the three studies that used internal comparisons rather than standardized 

32 mortality ratios (SMRs), thus minimizing the impact of the healthy worker effect, which can 

33 attenuate observed effect estimates. The NCI cohort consists of 25,619 workers (88% male) 

34 employed in any of the 10 plants prior to 1966. A follow-up through 1994 presented exposure35 response analyses for nine NPC deaths as well as analyses of deaths from other solid cancers 
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1 (Hauptmann et al., 2004). The most recent follow-up (through 2004) analyzed 319 deaths 

2 attributed to lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et 

3 al., 2009). The results for solid cancers from this recent follow-up had not yet been published at 

4 the time of this draft assessment. A detailed exposure assessment was conducted for each worker 

5 in the NCI cohort, based on exposure estimates for different jobs held and tasks performed 

6 (Stewart et al., 1986). Exposure estimates were made using several different metrics—peak 

7 exposure, average intensity, cumulative exposure, and duration of exposure. Respirator use and 

8 exposures to formaldehyde-containing particulates and other chemicals were also considered. 

9 For the NPCs, significant trends were observed for the cumulative and peak exposure metrics 

10 (Hauptmann et al., 2004). For the lymphohematopoietic cancers, significant trends were 

11 observed primarily for all lymphohematopoietic cancers and for Hodgkin lymphoma with the 

12 peak exposure metric (Beane Freeman et al., 2009). 

13 The NIOSH follow-up study (Pinkerton et al., 2004) analyzed mortality data (2,206 

14 deaths; 59 from lymphatic and hematopoietic cancers) from their cohort of 11,098 workers (82% 

15 female). Leukemia and aleukemia were elevated for workers with >10 years of exposure and for 

16 workers with ≥20 years since first exposure. However, since no historical exposure level data 

17 were available for this cohort, individual worker exposures could not be estimated and exposure18 response modeling was not conducted. The British cohort updated by Coggon et al. (2003) 

19 consisted of 14,014 male workers, and the follow-up included 5,185 deaths (83 from 

20 lymphohematopoietic cancers). In this cohort, lung cancer mortality was statistically 

21 significantly increased, especially in workers in the high-exposure category; however, actual 

22 exposure estimates were not available for exposure-response modeling (worker exposures were 

23 categorized as nil/background, low, moderate, or high, depending on the job considered to have 

24 had the highest exposure). Lymphohematopoietic cancers were not elevated in the British 

25 cohort, although, as discussed above, the results were based on external comparisons against 

26 national mortality statistics. Neither the NIOSH nor the British study reported increased risks of 

27 NPC, although only 1 case (0.96) was expected in the NIOSH cohort (Pinkerton et al., 2003) and 

28 only 2.0 cases were expected in the British cohort (Coggon et al., 2003). 

29 

30 5.2.2. Nasopharyngeal Cancer 

31 5.2.2.1. Exposure-Response Modeling of the National Cancer Institute Cohort

32 A detailed exposure assessment was conducted for the NCI cohort, and quantitative 

33 exposure estimates were generated for each worker (Stewart et al., 1986). Formaldehyde 

34 exposure estimates, including 8-hour time-weighted average (TWA) exposures and level and 

35 frequency of peak exposures, were derived for each job, work area, and calendar year 
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1 combination. A peak was defined as a short-duration exposure (typically <15 minutes) above the 

2 TWA. Cumulative exposures (in ppm × years) were estimated by multiplying the time a worker 

3 spent in a specific job by the TWA exposure for that job and summing over all the jobs held by 

4 the worker. Duration was the total time spent in jobs with formaldehyde exposure, and average 

5 intensity was the ratio of cumulative exposure to duration. Formaldehyde exposures after 1980 

6 were not taken into account in the follow-up study, but this was considered to have a minimal 

7 impact on the results (see section 5.2.2.4). 

8 The results of NCI’s internal analyses for NPC, using the peak exposure, average 

9 intensity, cumulative exposure, and duration of exposure metrics, are presented in Table 5-7. 

10 The relative risks (RRs) were estimated using log-linear Poisson regression models stratified by 

11 calendar year, age, sex, and race and adjusted for pay category (salary/wage/unknown). The NCI 

12 investigators used the low-exposure category as the reference category to “minimize the impact 

13 of any unmeasured confounding variables since nonexposed workers may differ from exposed 

14 workers with respect to socioeconomic characteristics” (Hauptmann et al., 2004). A 15-year lag 

15 interval was used in estimating exposures in order to account from a minimal latency period for 

16 the development of solid cancers, including NPCs. 

17 As can be seen in Table 5-7, peak exposure is the exposure metric that provides the 

18 strongest exposure-response relationship with NPC. However, it is not clear how to extrapolate 

19 RR estimates based on these peak exposure estimates to meaningful estimates of lifetime extra 

20 risk of cancer from environmental exposures, where the risk is usually considered to be from 

21 continuous lifetime exposures to low environmental levels. In addition, peak exposure is a more 

22 subjective measure than the other metrics, it is not based on actual measurements, and it is a 

23 categorical rather than continuous measure. Furthermore, the “true” exposure metric best 

24 describing the biologically relevant delivered dose of formaldehyde is unknown. The cumulative 

25 exposure metric provides a good fit to the data (p trend = 0.029 for all person-years), and, since 

26 this is generally the preferred metric for quantitative risk assessment for environmental exposure 

27 to carcinogens, cumulative exposure was chosen as the exposure metric for the risk estimate 

28 calculations for NPC in this assessment. 

29 The nonexposed person-years were included in the primary cancer risk analyses presented 

30 here in order to be more inclusive of all the exposure-response data. Such data are typically 

31 included in exposure-response modeling. Furthermore, the data were stratified by pay category, 

32 which should alleviate some concerns about the nonexposed workers having different 

33 socioeconomic characteristics. Final results for the exposed person-years only are presented for 

34 comparison. 

35 
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1 

2 Table 5-7. Relative risk estimates for mortality from nasopharyngeal 

3 malignancies (ICD-8 code 147) by level of formaldehyde exposure for 

4 different exposure metrics 

5 

Relative risk (number of deaths) p trendb p trendc 

Peak exposure (ppm) 

0 >0 to <2.0a 2.0 to <4.0 ≥4.0 

 

1.00d (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 

 

1.00d (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

7 Reference category for all categories. 

b

8 Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 

9 peak exposure metric) among all (nonexposed and exposed) person-years. 

c

10 Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 

11 peak exposure metric) among exposed person-years only. 

d

12 Reference category due to no cases in the low-exposure category. 

13 

14 Source: Hauptmann et al. (2004). 

15 

16 

17 As described above, Hauptmann et al. (2004) investigated the relationship between 

18 formaldehyde exposure and NPC mortality using log-linear Poisson regression models. They 

also conducted log-linear trend tests using the general model RR = eβX19 , where β represents the 

20 regression coefficient for exposure and X is exposure as a continuous variable. The trend models 

21 were stratified by calendar year, age, sex, and race and adjusted for pay category. Dr. Hauptmann 

22 provided EPA with the β estimates (and their standard errors) from the trend tests for NPC and 

23 the cumulative exposure metric for all person-years and for exposed person-years only (personal 

24 communication from Michael Hauptmann, NCI, to Jennifer Jinot, EPA, March 29, 2004). These 

25 estimates are presented in Table 5-8. 

26 

27 

28 
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1 

2 Table 5-8. Regression coefficients from NCI log-linear trend test models for 

NPC mortality from cumulative exposure to formaldehydea3 

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

6 Models stratified by calendar year, age, sex, and race and adjusted for pay category; cumulative exposures 

7 calculated using a 15-year lag interval. 

8 

9 Source: Personal communication from Michael Hauptmann to Jenifer Jinot (March 29, 2004). 

10 

11 

12 5.2.2.2. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Mortality

13 The regression coefficients presented in Table 5-8 were used to predict the extra risk of 

14 NPC mortality from environmental exposure to formaldehyde. 

15 

16 Extra risk = (Rx–Ro)/(1–Ro), 

17 

18 where Rx is the lifetime risk in the exposed population and Ro is the lifetime risk in an 

19 unexposed population (i.e., the background risk). Extra risk estimates were calculated using the 

β regression coefficients and a life-table program that accounts for competing causes of death.9 20 

21 U.S. age-specific 1999 all-cause mortality rates for all race and gender groups combined 

22 (National Center for Health Statistics [NCHS], 2002) were used to specify the all-cause 

23 background mortality rates in the life-table program. NCHS 1996–2000 age-specific background 

24 mortality rates for NPC were provided by Dr. Eisner of NCI’s Surveillance, Epidemiology and 

25 End Results (SEER) program (personal communication from Milton Eisner, SEER, to Jennifer 

26 Jinot, EPA, December 19, 2003). Risks were computed up to age 85 because cause-specific 

27 mortality (and incidence) rates for ages above 85 years are less reliable. Conversions between 

28 occupational formaldehyde exposures and continuous environmental exposures were made to 

29 account for differences in the number of days exposed per year (240 versus 365) and in the 

amount of air inhaled per day (10 versus 20 m3

30 ). An adjustment was also made for the 15-year 

 

9

This program is an adaptation of the approach that was previously used in BEIR IV, “Health Risks of Radon and 

Other Internally Deposited Alpha Emitters.” National 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 the extra risk calculation for the derivation of the LEC0005 for NPC 

incidence (see section 5.2.2.3) is presented in Appendix C. 
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1 lag period. The reported standard errors for the regression coefficients were used to compute the 

2 one-sided 95% upper confidence limits (UCLs) for the extra risks based on a normal 

3 approximation. 

4 Point estimates and one-sided 95% UCLs for the extra risk of NPC mortality associated 

5 with varying levels of continuous exposure to formaldehyde are presented in Table 5-9. The 

6 model predicts extra risk estimates that are fairly linear for exposures below about 0.001 to 

7 0.01 ppm but not for exposures above 0.01 ppm. 

8 

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

10 continuous exposure to formaldehyde 

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 

14 Consistent with EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 

15 the same data and methodology were also used to estimate the exposure level (effective 

16 concentration [ECx]) and the associated (one-sided) 95% lower confidence limit (LECx) 

17 corresponding to an extra risk of 0.05% (x = 0.0005). Although EPA guidelines emphasize the 

18 use of exposure levels associated with a 10% extra risk level for the POD for low-dose 

19 extrapolation, that would not be appropriate in this instance. A 10% extra risk level is very high 

20 for responses generally observed in epidemiology studies; thus, a 1% extra risk level is typically 

21 used for epidemiologic data to avoid upward extrapolation. For NPC, however, even the 1% 

22 level of risk is associated with RR estimates that are substantially higher than those observed in 

23 the epidemiology study. Hence, even a 1% extra risk level would be an upward extrapolation. 

24 Based on the life-table program, the RR estimate for an extra risk of 1% for NPC mortality is 46. 

25 Even 0.1% yields an RR estimate on the high end of the observable range of the epidemiology 

26 study (RR = 5.5). A 0.05% extra risk level yields an RR estimate of 3.27, which better 

27 corresponds to the RRs in the range of the data. Thus, 0.05% extra risk was selected for 

28 determination of the POD, and, consistent with EPA’s Guidelines for Carcinogen Risk 

29 Assessment (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the 
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1 POD. While this may appear to be an inordinately low response level, it must be recognized that 

2 NPC has a very low background mortality rate (e.g., lifetime background risk is about 0.00022); 

3 therefore, a 1% extra risk (i.e., 0.01) would be a huge increase relative to the background risk. 

4 This is consistent with the fact that, even with a large cohort followed for a long time, only nine 

NPC deaths were observed in the NCI follow-up through 1994.10 5 

6 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 

7 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA 

8 (section 4.5), a linear low-dose extrapolation was performed in accordance with EPA’s 

9 carcinogen risk assessment guidelines (U.S. EPA, 2005a). The EC0005, LEC0005, and inhalation 

10 unit risk estimates for NPC mortality are presented in Table 5-10. 

11 

12 Table 5-10. EC0005, LEC0005, and inhalation unit risk estimates for NPC 

13 mortality from formaldehyde exposure based on the Hauptmann et al. (2004) 

14 log-linear trend analyses for cumulative exposure 

15 

Person-years 

EC0005

(ppm) 

LEC0005

(ppm) 

Unit riska

(ppm–1) 

All 0.15 0.093 5.4 × 10–3 

Exposed only 0.15 0.091 5.5 × 10–3 

16 

a

17 Unit risk = 0.0005/LEC0005. 

18 

19 

20 5.2.2.3. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Incidence

21 EPA cancer risk estimates are typically derived to represent a plausible upper bound on 

22 increased risk of cancer incidence, as from experimental animal incidence data. Cancer data 

23 from epidemiology studies are more often mortality data, as is the case in the NCI study. For 

24 cancers with low survival rates, mortality-based estimates are reasonable approximations of 

25 cancer incidence risk. However, for NPC, the survival rate is substantial (51% at 5 years in the 

26 1990s in the U.S., according to Lee and Ko [2005]), and incidence-based risks are preferred 

27 because EPA is concerned with cancer occurrence, not just cancer mortality. 

28 Therefore, an additional calculation was done using the same regression coefficients 

29 provided by Dr. Hauptmann (Table 5-8) but with age-specific NPC incidence rates for 1996–

30 2000 from SEER in place of the NPC mortality rates in the life-table program. SEER collects 

31 cancer incidence data from a variety of geographical areas in the U.S. The incidence data used 

 

10 Ten NPCs were reported on death certificates and included in NCI’s SMR analysis, but one of these cases was 

apparently misclassified on the death certificate, so only nine cases were used to estimate the RRs in the internal 
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1 here are from SEER 12, a registry covering about 14% of the U.S. population, which was the 

2 most current SEER registry at the time this analysis was done. SEER 1996–2000 age-specific 

3 background incidence rates for NPC were provided by Dr. Eisner of NCI’s SEER program 

4 (personal communication from Milton Eisner, SEER, to Jennifer Jinot, EPA, December 18, 

5 2003). The incidence-based calculation relies on the reasonable assumptions that NPC incidence 

6 and mortality have the same exposure-response relationship for formaldehyde exposure and that 

7 the incidence data are for first occurrences of NPC or that relapses provide a negligible 

8 contribution. The calculation also relies on the fact that NPC incidence rates are small compared 

9 with the all-cause mortality rates. 

10 The resulting EC0005, LEC0005, and inhalation unit risk estimates for NPC incidence are 

11 presented in Table 5-11. The unit risk estimate for cancer incidence is twofold higher than the 

12 corresponding mortality-based estimate, for all person-years. This sizeable discrepancy can be 

13 attributed to the high survival rates for NPC. 

14 

15 Table 5-11. EC0005, LEC0005, and inhalation unit risk estimates for NPC 

16 incidence from formaldehyde exposure based on the Hauptmann et al. (2004) 

17 trend analyses for cumulative exposure 

18 

Person-years 

EC0005

(ppm) 

LEC0005

(ppm) 

Unit riska

(ppm–1) 

All 0.074 0.046 1.1 × 10–2 

Exposed only 0.072 0.045 1.1 × 10–2 

19 

a

20 Unit risk = 0.0005/LEC0005. 

21 

22 

23 The preferred estimate for the inhalation cancer unit risk for NPC is the estimate of 

1.1 × 10–2 24 per ppm derived using incidence rates for the cause-specific background rates, for all 

25 person-years. The results from the exposed person-years are essentially identical. 

26 Because NPC is a rare cancer, with a relatively low number of cases occurring per year in 

27 the U.S., a rough calculation was done to assure that the unit risk estimate derived for NPC 

28 incidence is not implausible in comparison to actual case numbers. For example, assuming an 

29 average constant lifetime formaldehyde exposure level of 5 ppb for the U.S. population, the 

inhalation unit risk estimate for NPC equates to a lifetime extra risk estimate of 5.5 × 10–5 30 . 

31 Assuming an average lifetime of 75 years (this is not EPA's default average lifetime of 70 years 

32 but rather a value more representative of actual demographic data) and a U.S. population of 

 

comparison analysis, as discussed by Hauptmann et al. (2004). 
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1 300,000,000, this lifetime extra risk estimate suggests a crude upper-bound estimate of 220 

2 incident cases of NPC attributable to formaldehyde exposure per year. Alternatively, assuming 

3 an average constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a 

4 crude upper-bound estimate of 880 incident cases of NPC per year. Both upper bound estimates, 

5 using different assumed lifetime exposure levels, are well below the estimated 2100 total incident 

6 NPC cases per year calculated from a published NPC incidence rate for the U.S. of 0.7/100,000 

person-years (Lee and Ko, 2005).11 7 

8 

9 5.2.2.4. Sources of Uncertainty

10 The two major sources of uncertainty in quantitative cancer risk estimates are generally 

11 interspecies extrapolation and high-to-low dose extrapolation. The risk estimates derived from 

12 the Hauptmann et al. (2004) analyses of the NCI cohort are not subject to interspecies uncertainty 

13 since they are based on human data. However, substantial uncertainty remains in the 

14 extrapolation from occupational exposures to lower environmental exposures. Although the 

15 actual exposure-response relationship at low exposure levels is unknown, the linear low-dose 

16 extrapolation that was used is warranted by the strong support for formaldehyde carcinogenicity 

17 having a mutagenic MOA (section 4.5). The linear low-dose extrapolation from the 95% lower 

18 bound on the exposure level associated with the extra risk level serving as the benchmark 

19 response is generally considered to provide a plausible upper bound on the risk at lower exposure 

20 levels. Actual low-dose risks may be lower to an unknown extent. 

21 Other sources of uncertainty emanate from the epidemiologic study and its analysis 

22 (Hauptmann et al., 2004), including the retrospective estimation of formaldehyde exposures in 

23 the cohort, the modeling of the epidemiologic exposure-response data, the appropriate exposure 

24 metric for exposure-response analysis, and potential confounding or modifying factors. 

25 The same team of investigators (Stewart et al., 1986) conducted a detailed retrospective 

26 exposure assessment to estimate the individual worker exposures. Formaldehyde exposures were 

27 estimated for specific jobs/tasks based on monitoring data, discussions with workers and plant 

28 managers, and assessment by industrial hygienists. Individual worker estimates were derived for 

29 a variety of exposure metrics based on work histories. This exposure assessment was a major 

30 undertaking, involving over 100 person-months. Hauptmann et al. (2004) suggested that 

31 employment of such a detailed exposure assessment would tend to minimize exposure 

 

11 With the application of age-dependent adjustment factors (see Section 5.4.4), the lifetime unit risk estimate for 

NPC would increase by a factor of 1.66, and the crude upper-bound estimates of the incident cases per year 

attributable to formaldehyde exposure would similarly increase by a factor of 1.66. The resulting adjusted estimates 

of 365 and 1460 for 5 ppb and 20 ppb exposure levels, respectively, are still well below the estimated total number 
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1 misclassification for average and cumulative exposure and duration of exposure but that peak 

2 exposure estimates could be more susceptible to misclassification because they were not based 

3 on actual measurements. In addition, the follow-up study did not take into account exposures 

4 after 1980. Hauptmann et al. (2003) stated that any underestimation of (total) exposure resulting 

5 from the 1980 cutoff “would be small because only 3.7% of all person-years were contributed by 

6 workers who were 65 years or younger and in exposed jobs in 1980” and because exposure levels 

7 were believed to have been much lower after 1980 than in earlier years. 

8 As discussed in Chapter 4 and the appendix (Human Health), Marsh et al. (1996) also 

9 estimated individual worker exposures at 1 of the 10 plants (Wallingford, Connecticut) studied 

10 by the NCI team, and 5 of the 9 NPC deaths were from that plant. The Marsh et al. (1996) 

11 exposure estimates were about 10-fold lower than those derived by the NCI team for the workers 

12 at the Wallingford plant. Marsh et al. (2002) hypothesized that “the NCI used data from several 

13 facilities to estimate exposures in a single facility.” However, the NCI investigators maintained 

14 that they estimated exposures for each plant separately. While the exact reasons for such a large 

15 discrepancy are unclear, some differences in the assessment procedures which could have 

16 resulted in substantial differences in the estimates are apparent. First, according to Marsh et al. 

17 (1996), 91.7% of the white male Wallingford plant workers were specified as being exposed to 

18 formaldehyde in the NCI study, while only 83.3% were considered to have been exposed in the 

19 Marsh et al. (1996) analysis (it should be noted that these two cohorts of the Wallingford plant 

20 are not identical). Second, the NCI investigators (Stewart et al., 1987, 1986) did their own 

21 exposure monitoring at all the plants, including the Wallingford facility, in order to standardize 

22 the data provided by the plants as well as to fill data gaps for certain jobs. There is no indication

23 that Marsh et al. (1996) made any additional measurements themselves. Third, although the 

24 Marsh et al. (2002, 1996) papers are not entirely consistent on this point, those investigators 

25 apparently assumed that the job-specific exposures at the plant were essentially constant over the 

26 history of the plant, whereas the NCI team, based on interviews with plant personnel 

27 knowledgeable about equipment and process changes, assumed that past exposures were higher. 

28 In any event, despite the discrepancies in the absolute exposure values, the relative 

29 exposures for both the Marsh et al. (2002, 1996) and NCI studies, as reflected in the exposure30 response relationships, are less subject to misclassification and are considered to be reliable. The 

31 Wallingford plant is just 1 of the 10 plants in the NCI study (representing 4,389 of the 25,619 

32 workers in the NCI cohort), but if the Marsh et al. (1996) exposure estimates, which are roughly 

33 10-fold lower than the NCI estimates, are closer to the actual exposures for those workers, then 

 

of incident cases per year in the U.S. 
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1 the true potency of formaldehyde could be greater than that suggested by the unit risk estimates 

2 calculated above based on the NCI data. Furthermore, if the NCI exposure values were 

3 significantly overestimated across all 10 plants, then the actual potency could be higher still. 

4 With respect to the exposure-response model, the log-linear model used by Hauptmann et 

al. (2003) for their trend tests (i.e., RR = eβX5 ) is a commonly used model for epidemiologic data 

6 with exposure as a continuous variable. However, the actual exposure-response relationship is 

7 unknown. Moreover, even if the correct exposure-response model were known, there would be 

8 substantial uncertainty in estimating the model parameters because there are only nine NPC 

9 deaths to model. Furthermore, Beane Freeman et al. (2009) reported that in the follow-up 

10 through 2004 it was discovered that 1,006 deaths that occurred during the 1980 to 1994 

11 follow-up period had not been included in the analyses of the 1994 follow-up study (Hauptmann 

12 et al., 2004, 2003), for reasons that have not been identified. Because NPC is such a rare cancer, 

13 it is not expected that many, if any, NPC deaths were among the 1,006 excluded deaths; however, 

14 it is unknown how inclusion of the 1,006 deaths would have altered the overall exposure15 response relationship and, hence, the regression coefficient. Additionally, a 15-year lag was used 

16 for all the NCI solid cancer models. The actual minimum latency is unknown; however, the 

17 investigators reported that lag intervals between 2 and 20 years yielded similar results. 

18 Another potentially significant source of uncertainty is associated with the exposure 

19 metrics. With the log-linear model used for modeling the occupational data, the peak exposure 

20 metric gave the strongest exposure-response relationship between formaldehyde exposure and 

21 increased risk of NPCs. However, it is unclear how to extrapolate RR estimates based on peak 

22 exposure estimates to meaningful estimates of lifetime extra risk of cancer from environmental 

23 exposure (i.e., extra risk from lifetime continuous low-level environmental exposures). The 

24 cumulative exposure metric also yielded a statistically significant exposure-response relationship 

25 and was used for the primary cancer risk calculations in this assessment. The “true” exposure 

26 metric best describing the toxicologically relevant dose of formaldehyde for nasopharyngeal 

27 carcinogenesis is unknown. If a peak-exposure type of metric is the best representative of the 

28 toxicologically relevant dose, this suggests that there are dose-rate effects in the exposure29 response relationship for formaldehyde and NPC. If this is the case, the unit risk estimates 

30 presented here, which are based on a linear low-dose extrapolation, may overestimate the true 

31 risks to an unknown extent. 

32 Hauptmann et al. (2004) gave a lot of consideration to potential confounding and 

33 modifying factors in their analyses. The important factors of age, race, sex, calendar year, and 

34 pay category were taken into account in their Poisson regression and trend analyses. 

35 Furthermore, they used the low-exposure person-years, rather than the unexposed person-years, 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 as their referent group in an effort to minimize any potential confounding effects resulting from 

2 differences in socioeconomic or other characteristics between exposed and unexposed workers. 

3 When the slope estimate (i.e., regression coefficient) for the exposed person-years only was used 

4 in the analyses presented here, the unit risk estimate was essentially identical to that calculated 

5 from the slope estimate for all person-years (see Tables 5-12 and 5-13). 

6 In addition, these investigators evaluated routine respirator use, exposure to 

7 formaldehyde-containing particulates, durations of exposure to 11 other chemicals/substances in 

8 the plants (antioxidants, asbestos, carbon black, dyes and pigments, hexamethylenetetramine, 

9 melamine, phenol, plasticizers, urea, wood dust, and benzene), and duration of employment as a 

10 chemist or laboratory technician. Only 133 workers ever routinely used a respirator (Hauptmann 

11 et al., 2003). Hauptmann et al. (2004) reported that RR estimates for NPC changed when 

12 adjusted for duration of melamine exposure, although trend tests remained significant for 

13 cumulative formaldehyde exposure (p = 0.006). The investigators suggested that the association 

14 with melamine may be spurious, and the regression coefficients (i.e., β estimates) used in this 

15 assessment were not adjusted for melamine. RR estimates reportedly did not change 

16 substantially when adjusted for exposure to any of the other 10 chemicals/substances. None of 

17 the workers who died of NPC was identified as being exposed to wood dust. On the other hand, 

18 each of the seven formaldehyde-exposed workers who died of NPC was also exposed to 

19 particulates, and neither of the two workers who died of NPC but were not exposed to 

20 formaldehyde was exposed to particulates. However, for those workers exposed to particulates, 

21 NPC risk increased with increasing formaldehyde exposure, suggesting a formaldehyde22 associated effect. Nonetheless, because of the correspondence between formaldehyde and 

23 particulate exposures within the workers who died of NPC, there is uncertainty as to whether or 

24 not particulates were acting as a modifying factor. Adjusting for duration of time spent working 

25 as a chemist or laboratory technician did not substantially alter the results (Hauptmann et al., 

26 2004). 

27 Adjusting for plant may result in overadjustment because plant is highly correlated with 

28 exposure. Moreover, Hauptmann et al. (2004) adjusted for important plant-related factors by 

29 adjusting for the 11 chemicals/substances. Nonetheless, these investigators conducted analyses 

30 adjusted for plant to address potential unmeasured confounders associated with plant, and they 

31 reported that the association with NPC remained. As noted above, five of the nine NPC deaths 

32 were from the Wallingford plant also studied by Marsh et al. (2006, 2002). Marsh et al. (2007) 

33 hypothesized that the excess NPCs in the Wallingford plant could be due to external employment 

34 in metal-working industries, but we found no evidence to support this supposition (see section 

35 4.1.1.1). 
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1 Although smoking data were not available for the cohort, smoking is unlikely to explain 

2 the excesses in NPCs because there was no consistent increase for tobacco-related diseases, 

3 including lung cancer, across the same exposure metrics. No information was available on 

4 Epstein-Barr virus, a major risk factor for NPC, in the cohort. 

5 Despite inevitable uncertainties, it is important not to lose sight of the strengths of the 

6 NCI study. In addition to the use of internal analyses and the extensive exposure assessment and 

7 consideration of potential confounding or modifying variables, the NCI study has a large cohort 

8 that has been followed for a long time. The cohort included 25,619 subjects, 75% of whom 

9 entered before 1960, contributing a total of 865,708 person-years (730,312 for the exposed 

10 workers) to the 1994 follow-up. Duration of follow-up in 1994 ranged up to 58 years, with a 

11 median of 35 years. Duration of exposure ranged up to 46 years, with a median of 2 years. 

12 Additional uncertainties are not so much inherent in the exposure-response modeling or 

13 in the epidemiologic data themselves but rather stem from the process of obtaining more general 

14 EPA risk estimates from these specific results. EPA cancer risk estimates typically represent a 

15 plausible upper bound on increased risk of cancer incidence in the general population for all 

16 tissue sites potentially affected by an agent. For experimental animal studies, this is 

17 accomplished by using tumor incidence data and summing across all the tumor sites that 

18 demonstrate significantly increased incidences, generally using data from the most sensitive sex 

19 and species. However, in estimating comparable risks from the NCI epidemiologic data, certain 

20 limitations are encountered. First, the NCI study is a retrospective mortality study, and cancer 

21 incidence data are unavailable for the cohort. Second, these occupational epidemiology data 

22 represent a worker cohort that is generally healthier than the general population 

23 (e.g., SMRs < 1) (see Table 2 of Hauptmann et al. [2004]). 

24 The first limitation was addressed quantitatively in the calculation of cancer incidence 

25 risk estimates from the mortality results, and, even though there are assumptions made in using 

26 incidence data this way, the incidence-based estimates are believed to be better estimates of 

27 cancer incidence risk than the mortality-based estimates. With respect to the second limitation, 

28 the healthy worker effect is often an issue in occupational epidemiology studies, and it is difficult 

29 to know to what extent there is a healthy worker effect with respect to the development of NPC 

30 in this study. As discussed above, Hauptmann et al. (2004) sought to minimize potential 

31 confounding effects resulting from differences in socioeconomic or other characteristics between 

32 exposed and unexposed workers by using the low-exposure person-years, rather than the 

33 unexposed person-years, as their referent group. Nonetheless, when the slope estimates for the 

34 exposed person-years only were used in the analyses in this assessment, unit risk estimates 

35 essentially identical to those calculated from the slope estimates for all person-years were 
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1 obtained (Tables 5-12 and 5-13). In terms of representing the general population, the NCI cohort 

2 was somewhat diverse, but the workers were predominantly white males (81%) then white 

3 females (12%), black males (7%), and black females (<1%), and they were all adults. 

4 Finally, NPC is just one of the upper respiratory tract cancers concluded to be causally 

5 associated with formaldehyde exposure (section 4.5). These upper respiratory tract cancers are 

6 rare cancers and are difficult to detect in cohort studies. Thus, although NPC was the only such 

7 cancer with an exposure-response relationship amenable to the derivation of a unit risk estimate, 

8 additional, unquantified risk may exist for the other upper respiratory tract cancers. If there was a

9 strong exposure-response relationship between these cancers and formaldehyde exposure, a more 

10 apparent association in the Hauptmann et al. (2004) study might have been expected, as was seen 

11 for NPC, despite the rare nature of these cancers. Thus, the exposure-response relationship for 

12 these other upper respiratory tract cancers is likely modest, at best, and, because these are rare 

13 cancers, the contribution of the risk for these cancers to the total cancer risk from formaldehyde 

14 exposure is not expected to be large. Nonetheless, with such rare cancers, there is uncertainty 

15 regarding the extent to which the estimate based on NPC may underestimate the risk for all upper 

16 respiratory tract cancers. 

In summary, the inhalation cancer unit risk estimate of 1.1 × 10–2 17 per ppm for NPC is 

18 based on human data from a high-quality epidemiologic study with individual exposure estimates 

19 for each worker. A major uncertainty is the appropriate model/exposure metric for extrapolation 

20 to environmental exposures. 

21 

22 5.2.3. Lymphohematopoietic Cancer 

23 5.2.3.1. Exposure-Response Modeling of the National Cancer Institute Cohort

24 The results of NCI’s internal analyses for lymphohematopoietic cancers using the peak 

25 exposure, average intensity, and cumulative exposure metrics from the follow-up through 2004 

26 are reported by Beane Freeman et al. (2009). There was reportedly no evidence of associations 

27 with duration of exposure, and those results were not presented. For the peak exposure metric, 

28 statistically significant log-linear trends were observed for all lymphohematopoietic cancers, 

29 Hodgkin lymphoma, and leukemia (the latter only when the unexposed person-years were 

30 included). There was also evidence for potential associations with myeloid leukemia 

31 specifically, especially when risks were viewed over time, and with multiple myeloma. Using 

32 the average exposure metric, there was a significant trend for Hodgkin lymphoma. With the 

33 cumulative exposure metric, there were no statistically significant trends; however, the Hodgkin 

34 lymphoma trend results were of borderline significance (p trends = 0.06 and 0.08 with and 

35 without the unexposed person-years, respectively), as were the leukemia trend results (p trends = 
This document is a draft for review purposes only and does not constitute Agency policy.

5-89 DRAFT—DO NOT CITE OR QUOTE 

1 0.08 and 0.12 with and without the unexposed person-years, respectively). As discussed above 

2 with NPC, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 

3 to meaningful estimates of lifetime extra risk of cancer from environmental exposures. The 

4 average exposure metric is also problematic because it suggests that duration of exposure is not 

5 important (e.g., exposure to a given exposure level for 1 year conveys the same amount of risk as 

6 exposure to the same level for 70 years). Cumulative exposure is generally the preferred metric 

7 for quantitative risk assessment for environmental exposure to carcinogens, and, because the 

8 Hodgkin lymphoma and leukemia trend results were of borderline statistical significance using 

9 the cumulative exposure metric and the elevations in risk with that metric were consistent with 

10 significant elevations observed with the peak exposure (for Hodgkin lymphoma and leukemia) 

11 and average exposure (for Hodgkin lymphoma) metrics (Table 5-12), a determination was made 

12 to calculate unit risk estimates for Hodgkin lymphoma and leukemia based on cumulative 

13 exposure. There is also support for associations between formaldehyde exposure and both 

14 Hodgkin lymphoma and leukemia from other studies (section 4.5.2). No other 

15 lymphohematopoietic cancer responses provided adequate exposure-response data with the 

16 cumulative formaldehyde exposure metric in the NCI cohort from which to derive unit risk 

17 estimates. 

18 As for the NPC results discussed in section 5.2.2, the RR estimates in Table 5-12 were 

19 derived using log-linear Poisson regression models stratified by calendar year, age, sex, and race 

20 and adjusted for pay category (salary/wage/unknown). The NCI investigators used the low21 exposure category as the reference category to “minimize the impact of any unmeasured 

22 confounding variables since nonexposed workers may differ from exposed workers with respect 

23 to socioeconomic characteristics” (Hauptmann et al., 2004). A 2-year lag interval was used to 

24 determine exposures in order to account for a minimal latency period for lymphohematopoietic 

25 cancers. 

26 Dr. Beane Freeman provided EPA with the regression coefficient estimates for Hodgkin 

27 lymphoma and leukemia mortality from the log-linear trend test models for cumulative exposure 

(i.e., RR = eβX

28 , with exposure [X] as a continuous variable) used in the NCI analyses (personal 

29 communication from Laura Beane Freeman, NCI, to John Whalan, EPA, August 26, 2009). 

30 These estimates are presented in Table 5-13. As with the NPC calculations in section 5.2.2, the 

31 nonexposed person-years were included in the primary unit risk estimate derivations in order to 

32 be more inclusive of all the exposure-response data. Final results for the exposed person-years 

33 only are presented for comparison. 

34 
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1 Table 5-12. Relative risk estimates for mortality from Hodgkin lymphoma 

2 (ICD-8 code 201) and leukemia (ICD-8 codes 204–207) by level of 

3 formaldehyde exposure for different exposure metrics 

4 

Cancer type Relative risk (number of deaths) p trendb p trendc 

Peak exposure (ppm) 

 0 >0 to <2.0a 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

6 Reference category for all categories. 

b

7 Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 

8 peak exposure metric) among all (nonexposed and exposed) person-years. 

c

9 Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 

10 peak exposure metric) among exposed person-years only. 

11 

12 Source: Beane Freeman et al. (2009). 

13 

14 

15 Table 5-13. Regression coefficients for Hodgkin lymphoma and leukemia 

mortality from NCI trend test modelsa16 

17 

Cancer type Person-years 

β

(per ppm × year) 

Standard error 

(per ppm × year) 

Hodgkin lymphoma All 0.02959 0.01307 

Exposed only 0.02879 0.01333 

Leukemia All 0.01246 0.006421 

Exposed only 0.01131 0.00661 

18 

a

19 Models were stratified by calendar year, age, sex, and race and adjusted for pay category; exposures included a 

20 2-year lag interval. 

21 

22 Source: Personal communication from Laura Beane Freeman to John Whalan (August 26, 2009). 
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1 

2 5.2.3.2. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma and Leukemia Mortality

3 Extra risk estimates for Hodgkin lymphoma and leukemia mortality were calculated using 

4 the same general methodology described above for the NPC mortality estimates (section 5.2.2.2), 

5 with the following exceptions. U.S. age-specific 2006 all-cause mortality rates (NCHS, 2009) 

6 and NCHS age-specific 2002–2006 background mortality rates for Hodgkin lymphoma and 

7 leukemia (http://seer.cancer.gov/csr/1975_2006/) for all race and gender groups combined were 

8 used in the life-table programs. In addition, a 2-year lag period was used instead of a 15-year lag 

9 period. 

10 The resulting point estimates and one-sided 95% UCLs for the extra risk of Hodgkin 

11 lymphoma mortality associated with varying levels of continuous exposure to formaldehyde are 

12 presented in Table 5-14. The results for leukemia are shown in Table 5-15. In both cases, the 

13 models predict extra risk estimates that are fairly linear for exposures below about 0.01–0.1 ppm 

14 but not for exposures above 0.1 ppm. 

15 

16 Table 5-14. Extra risk estimates for Hodgkin lymphoma mortality from 

17 various levels of continuous exposure to formaldehyde 

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 

21 Table 5-15. Extra risk estimates for leukemia mortality from various levels 

22 of continuous exposure to formaldehyde 

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 × 10–1 
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1 

2 As discussed in section 5.2.2.2 above, 1% extra risk levels are typically used as the basis 

3 for the POD for low-dose extrapolation from epidemiologic data. As for NPC, however, 

4 Hodgkin lymphoma has a very low background mortality rate (e.g., lifetime background risk is 

5 about 0.00038), and the 1% level of risk is associated with RR estimates that are substantially 

6 higher than those observed in the epidemiology study. Hence, a 1% extra risk level would be an 

7 upward extrapolation. Based on the life-table program, the RR estimate associated with an extra 

8 risk of 1% for Hodgkin lymphoma mortality is 27. Even 0.1% yields an RR estimate at the 

9 higher end of what was observed in the epidemiology study (RR = 3.6) (note that our primary 

10 analyses include the nonexposed workers, and thus the 0-exposure group becomes the referent 

11 group and the RR estimates presented for Hodgkin lymphoma and cumulative exposure in Table 

12 5-12 would be adjusted upward [about 2.4-fold] relative to the 0-exposure group). A 0.05% 

13 extra risk level yields an RR estimate of 2.3, which better corresponds to the RRs at the lower 

14 end of the observable range. Thus, 0.05% extra risk was selected for determination of the POD 

15 for Hodgkin lymphoma, and, consistent with EPA’s Guidelines for Carcinogen Risk Assessment

16 (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the POD. 

17 For leukemia, although the background mortality rates are higher (0.0065), the 1% extra 

18 risk level typically used as the basis for the POD for epidemiologic data still corresponds to an 

19 RR estimate (2.5) that would be above the highest categorical result reported, even after 

20 adjusting the RR estimates upward relative to the 0-exposure group (see above paragraph). A 

21 0.5% extra risk level yields an RR estimate of 1.8, which better corresponds to the RRs in the 

22 range of the data. Thus, the LEC value corresponding to 0.5% extra risk was selected for the 

23 POD for leukemia. 

24 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 

25 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA 

26 (section 4.5), a linear low-dose extrapolation was performed, also in accordance with EPA’s 

27 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). The EC0005, LEC0005, and 

28 inhalation unit risk estimates for Hodgkin lymphoma mortality are presented in Table 5-16, and 

29 the EC005, LEC005, and inhalation unit risk estimates for leukemia mortality are presented in 

30 Table 5-17. 

31 

32 

33 

34 
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1 Table 5-16. EC0005, LEC0005, and inhalation unit risk estimates for Hodgkin 

2 lymphoma mortality from formaldehyde exposure based on Beane Freeman 

3 et al. (2009) log-linear trend analyses for cumulative exposure 

4 

Person-years 

EC0005

(ppm) 

LEC0005

(ppm) 

Unit riska

(ppm–1) 

All 0.151 0.0875 5.7 × 10–3 

Exposed only 0.155 0.0881 5.7 × 10–3 

5 

a

6 Unit risk = 0.0005/LEC0005. 

7 

8 

9 Table 5-17. EC005, LEC005, and inhalation unit risk estimates for leukemia 

10 mortality from formaldehyde exposure based on Beane Freeman et al. (2009) 

11 log-linear trend analyses for cumulative exposure 

12 

Person-years 

EC005

(ppm) 

LEC005

(ppm) 

Unit riska

(ppm–1) 

All 0.224 0.121 4.1 × 10–2 

Exposed only 0.246 0.126 4.0 × 10–2 

13 

a

14 Unit risk = 0.005/LEC005. 

15 

16 

17 5.2.3.3. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma and Leukemia Incidence

18 As for NPC, both Hodgkin lymphoma and leukemia have substantial survival rates 

19 (84.7% at 5 years for Hodgkin lymphoma [http://seer.cancer.gov/statfacts/html/hodg.html] and 

20 53.1% at 5 years for leukemia [http://seer.cancer.gov/statfacts/html/leuks.html], based on 1999–

21 2005 SEER data); thus, it is preferable to derive incidence estimates. Unit risk estimates for 

22 Hodgkin lymphoma and for leukemia incidence were calculated as described above for the NPC 

23 incidence estimates (section 5.2.2.3). Age-specific background incidence rates for 2002–2006 

24 for Hodgkin lymphoma and for leukemia from SEER17, a registry covering about 26% of the 

25 U.S. population, were obtained from the SEER Web site (http://seer.cancer.gov/csr/1975_2006/). 

26 The incidence-based calculation relies on the assumptions that Hodgkin lymphoma (and 

27 leukemia) incidence and mortality have the same exposure-response relationship for 

28 formaldehyde exposure and that the incidence data are for first occurrences of Hodgkin 

29 lymphoma (and leukemia) or that relapses provide a negligible contribution. The first 

30 assumption is more uncertain for leukemia because it is a grouping of subtypes with different 

31 survival rates (see section 5.2.3.4 for further discussion). The calculation also relies on the fact 

32 that Hodgkin lymphoma (and leukemia) incidence rates are small compared with the all-cause 
This document is a draft for review purposes only and does not constitute Agency policy.

5-94 DRAFT—DO NOT CITE OR QUOTE 

1 mortality rates. The resulting EC0005, LEC0005, and inhalation unit risk estimates for Hodgkin 

2 lymphoma incidence are presented in Table 5-18, and the EC005, LEC005, and inhalation unit risk 

3 estimates for leukemia incidence are presented in Table 5-19. The unit risk estimate for Hodgkin 

4 lymphoma incidence is about threefold higher than the corresponding mortality-based estimate, 

5 for all person-years. This sizeable discrepancy can be attributed to the high survival rates for 

6 Hodgkin lymphoma. For leukemia, the incidence unit risk estimate is about 40% higher than the 

7 mortality-based estimate. This difference is lower than the twofold difference seen with NPC 

8 estimates, despite comparable survival rates, probably because of different age distributions of 

9 the mortality and incidence rates. 

10 

11 Table 5-18. EC0005, LEC0005, and inhalation unit risk estimates for Hodgkin 

12 lymphoma incidence from formaldehyde exposure, based on Beane Freeman 

13 et al. (2009) log-linear trend analyses for cumulative exposure 

14 

Person-years 

EC0005

(ppm) 

LEC0005

(ppm) 

Unit riska

(ppm–1) 

All 0.0515 0.0298 1.7 × 10–2 

Exposed only 0.0529 0.0301 1.7 × 10–2 

15 

a

16 Unit risk = 0.0005/LEC0005. 

17 

18 

19 Table 5-19. EC005, LEC005, and inhalation unit risk estimates for leukemia 

20 incidence from formaldehyde exposure based on Beane Freeman et al. (2009) 

21 log-linear trend analyses for cumulative exposure 

22 

Person-years 

EC005

(ppm) 

LEC005

(ppm) 

Unit riska

(ppm–1) 

All 0.162 0.0875 5.7 × 10–2 

Exposed only 0.178 0.0909 5.5 × 10–2 

23 

a

24 Unit risk = 0.005/LEC005. 

25 

26 

27 The preferred estimate for the inhalation cancer unit risk for Hodgkin lymphoma is the 

estimate of 1.7 × 10–2 28 per ppm derived using incidence rates for the cause-specific background 

29 rates, for all person-years. Similarly, the preferred estimate for leukemia is the estimate of 

5.7 × 10–2 30 per ppm derived using incidence rates, for all person-years. In both cases, the results 

31 from the exposed person-years only are essentially identical. 
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1 Because Hodgkin lymphoma is a rare cancer, with a relatively low number of cases 

2 occurring per year in the U.S. (according to SEER statistics, an estimated 8,510 people were 

3 diagnosed with Hodgkin lymphoma in the U.S. in 2009

4 [http://seer.cancer.gov/statfacts/html/hodg.html]), a rough calculation was done to assure that the 

5 unit risk estimate derived for Hodgkin lymphoma incidence is not implausible in comparison to 

6 actual case numbers. For example, assuming an average constant lifetime formaldehyde 

7 exposure level of 5 ppb for the U.S. population, the inhalation unit risk estimate for Hodgkin 

lymphoma equates to a lifetime extra risk estimate of 8.5 × 10–5 8 . Assuming an average lifetime 

9 of 75 years (this is not EPA's default average lifetime of 70 years but rather a value more 

10 representative of actual demographic data) and a U.S. population of 300,000,000, this lifetime 

11 extra risk estimate suggests a crude upper-bound estimate of 340 incident cases of Hodgkin 

12 lymphoma attributable to formaldehyde exposure per year. Alternatively, assuming an average 

13 constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a crude upper14 bound estimate of 1,360 incident cases of Hodgkin lymphoma per year. Both upper bound 

15 estimates, using different assumed lifetime exposure levels, are well below the estimated 8,510 

total incident Hodgkin lymphoma cases diagnosed per year in the U.S.12 16 

17 

18 5.2.3.4. Sources of Uncertainty

19 By and large, the sources of uncertainty discussed above (section 5.2.2.4) for the NPC 

20 risk estimates, such as high-to-low dose extrapolation, retrospective exposure estimation, 

21 exposure metric/model uncertainties, and application of data from a “healthy” worker cohort to 

22 the more diverse general population also apply to the Hodgkin lymphoma and leukemia risk 

23 estimates. The Hodgkin lymphoma risk estimates are based on 27 deaths, which is more than 

24 were available for the NPC risk estimates, but 27 is still a small number for exposure-response 

25 modeling. The leukemia risk estimates are based on 123 deaths, so there is less uncertainty with 

26 the parameter estimation from the exposure-response modeling for that cancer type, although 

27 uncertainties still exist about the general model form. A 2-year lag interval was used for 

 

12 With the application of age-dependent adjustment factors (see Section 5.4.4), the lifetime unit risk estimate for 

Hodgkin lymphoma would increase by a factor of 1.66, and the crude upper-bound estimates of the incident cases 

per year attributable to formaldehyde exposure would similarly increase by a factor of 1.66. The resulting adjusted 

estimates of 564 and 2260 for 5 ppb and 20 ppb exposure levels, respectively, are still well below the estimated total 

number of incident cases per year in the U.S.. Similar calculations for leukemia yield even lower relative upperbound estimates of cases attributable to formaldehyde exposure, in comparison to estimated total incidenct cases, 

because, although the unit risk estimate for leukemia is about 3.3 times the unit risk estimate for Hodgkin lymphoma, 

the total estimated number of incident leukemia cases in the U.S. is 5.3 times the estimate for Hodgkin lymphoma 

(an estimated 44,790 cases diagnosed in the U.S. for 2009, according to SEER 

[http://seer.cancer.gov/statfacts/html/leuks.html]). 
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1 lymphohematopoietic cancers versus the 15-year lag for NPC. Beane Freeman et al. (2009) 

2 evaluated lag intervals between 2 and 25 years and reported that lag intervals of about 18 years 

3 provided the best fit to the lymphohematopoietic cancer data but did not change the risk 

4 estimates; thus, they retained the 2-year lag interval that was used in the previous follow-up 

5 (Hauptmann et al., 2003). The most appropriate lag intervals for Hodgkin lymphoma and 

6 leukemia are unknown, but alternate lags are unlikely to have a large impact on the results. 

7 The same potential confounding or modifying factors that were investigated for NPC and 

8 the other solid cancers, as discussed in section 5.2.2.4 above, were evaluated for the 

9 lymphohematopoietic cancers. Beane Freeman et al. (2009) reported that controlling for duration 

10 of exposure to the 11 other substances that they considered (see section 5.2.2.4) or for working as 

11 a chemist or laboratory technician “did not meaningfully change results”; results were not shown. 

12 The investigators also reported that excluding the 586 individuals with exposure to benzene, a 

13 known leukemogen, did not change the RR estimates for myeloid or lymphoid leukemia in the 

14 highest peak exposure category. Furthermore, Beane Freeman et al. (2009) found no evidence of 

15 heterogeneity of RR estimates for lymphohematopoietic cancers by race, sex, or pay category, 

16 and adjusting for plant reportedly did not substantively change results. 

17 A further uncertainty is which lymphohematopoietic cancer types are linked to 

18 formaldehyde exposure. As discussed in section 4.5.2, lymphohematopoietic cancers are a 

19 diverse group of cancers with different etiologies, and the epidemiologic database suggests 

20 associations with multiple different subtypes of these cancers. Section 4.5 concludes that 

21 formaldehyde is causally associated with all lymphohematopoietic cancers as a group and with 

22 leukemias as a group (with the strongest evidence for myeloid leukemia). However, at present, 

23 exactly which subtypes are etiologically linked to formaldehyde exposure is unknown. Cancer 

24 risk estimates were derived for Hodgkin lymphoma and leukemia because, in addition to support 

25 for an association between these lymphohematopoietic cancer subtypes and formaldehyde 

26 exposure with other exposure metrics and from other studies, these had the strongest associations 

27 with cumulative exposure in the Beane Freeman et al. (2009) update of the large, high-quality 

28 NCI study. However, it is unknown whether these two subtypes best represent the total 

29 lymphohematopoietic cancer risk. 

30 In addition, leukemia itself is a grouping of diverse (e.g., acute lymphocytic, chronic 

31 lymphocytic, acute myeloid, chronic myeloid) subtypes, and using this grouping injects 

32 additional uncertainty into the derivation of cancer incidence estimates. One of the assumptions 

33 that the incidence-based calculation relies on is that the cancer incidence and mortality have the 

34 same exposure-response relationship for formaldehyde exposure. This assumption may be 

35 problematic for the leukemia incidence estimates if not all of the leukemia subtypes represented 
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5-97 DRAFT—DO NOT CITE OR QUOTE 

1 in the grouping are associated with formaldehyde exposure to the same extent. This is because 

2 different leukemia subtypes have different survival rates, so if a subtype with a relatively high 

3 survival rate is included in the background incidence rates while not actually being associated 

4 with formaldehyde exposure or being associated to a lesser extent than other subtypes, then the 

5 incidence risk will be overestimated. The mortality risk calculations are not similarly affected by 

6 including subtypes that may not actually be associated with formaldehyde exposure because 

7 background mortality for the subtypes is already taken into account in the regression coefficient. 

8 Figure 5-10 shows the mortality versus incidence rates for all leukemia and the two main 

9 subtypes, myeloid leukemia and lymphoid leukemia. This figure does not show the acute versus 

10 chronic myeloid and leukemia subtypes or the monocytic or other leukemia subtypes; however, it 

11 serves to illustrate the impact of using rates for groupings that contain subtypes with different 

12 survival rates. For example, if lymphoid leukemia is the predominant subtype associated with 

13 formaldehyde exposure, then using the leukemia grouping for the incidence rates may 

14 underestimate the cancer incidence risk because the incidence rates for leukemia (relative to the 

15 mortality rates) are diluted with inclusion of the incidence rates for myeloid leukemia, which has 

16 a smaller incidence-to-mortality ratio (i.e., poorer survival). On the other hand, if myeloid 

17 leukemia is the predominant subtype associated with formaldehyde exposure, then using the 

18 leukemia grouping for the incidence rates may overestimate cancer incidence risk. If incidence 

19 risks are being overestimated, the effect should be minimal because the incidence risk estimates 

20 for leukemia calculated in section 5.2.3.3 are not that much greater (about 40%) than the 

21 mortality-only estimates. 

22 Finally, as for the NPC risk estimates, when the slope estimates for the exposed person23 years only were used for the Hodgkin lymphoma and leukemia risk calculations, unit risk 

24 estimates similar to those calculated from the slope estimates for all person-years were obtained 

25 (Tables 5-18 and 5-19); thus, the impacts of including the unexposed person-years are minimal. 

26 As discussed in section 5.2.2.4, despite inevitable uncertainties, it is important not to lose 

27 sight of the strengths of the NCI study. In addition to the use of internal analyses and extensive 

28 exposure assessment and consideration of potential confounding or modifying variables, the NCI 

29 study has a large cohort that has been followed for a long time. With the additional follow-up 

30 through 2004, reflected in the lymphohematopoietic cancer results of Beane Freeman et al. 

31 (2009), the median duration of follow-up was 42 years, and the 25,619 cohort members had 

32 accrued 998,106 person-years of follow-up. Over half of the cohort was deceased, and there was 

33 a substantial number of lymphohematopoietic deaths (319 total; 286 in the exposed workers). 

34 
This document is a draft for review purposes only and does not constitute Agency policy

5-98 DRAFT—DO NOT CITE OR QUOTE Figure 5-10. Age-specific mortality and incidence rates for myeloid, lymphoid, and all leukemia. 0.0 10.0 20.0 30.0

40.050.060.070.080.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

age (years)

rate per 100,000
This document is a draft for review purposes only and does not constitute Agency policy.

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In summary, the inhalation cancer incidence unit risk estimates of 1.7 × 10–2 1 per ppm for 

Hodgkin lymphoma and 5.7 × 10–2 2 per ppm for leukemia are based on human data from a high3 quality epidemiologic study with individual exposure estimates for each worker. The major 

4 source of uncertainty in both risk estimates is the extrapolation to environmental exposures. 

5 

6 5.2.4. Conclusions on Cancer Unit Risk Estimates Based on Human Data 

In this assessment, a (plausible upper bound) lifetime extra cancer unit risk of 5.4 × 10–3 7 

8 per ppm of continuous formaldehyde exposure was estimated using a life-table program and 

9 linear low-dose extrapolation of the excess NPC mortality and log-linear modeling results (for 

10 cumulative exposure) reported in a high-quality occupational epidemiologic study (based on nine 

11 NPC deaths). Applying the same regression coefficient and life-table program to background 

NPC incidence rates yielded a lifetime extra cancer unit risk estimate of 1.1 × 10–2 12 per ppm 

(8.8 × 10–6 per μg/m313 ). 

14 Using similar methods and data for Hodgkin lymphoma (27 deaths) and leukemia 

15 (123 deaths) mortality based on the cumulative exposure metric, from a further follow-up of the 

same cohort study, (plausible upper bound) lifetime extra cancer risk estimates of 1.7 × 10–2 16 per 

ppm (1.4 × 10–5 per μg/m3) and 5.7 × 10–2 per ppm (4.6 × 10–5 per μg/m317 ) for Hodgkin 

18 lymphoma incidence and leukemia incidence, respectively, were derived. 

19 To estimate the total cancer risk from formaldehyde exposure, risk estimates for these 

20 three cancer types (NPC, Hodgkin lymphoma, and leukemia) were combined, although, as 

21 discussed above, these three cancer types may not fully reflect the total cancer risk for all cancers 

22 thought to be causally associated with formaldehyde exposure. For an approximate estimate of 

23 the combined (upper bound) risk, risk estimates were combined assuming a normal distribution. 

24 For comparability, risk estimates for formaldehyde were combined at a common level of 0.1 

25 ppm. This level was selected because it is close to the PODs (LEC005s) used above for leukemia 

26 mortality (0.121 ppm) and leukemia incidence (0.0875 ppm), and leukemia is the predominant 

27 cancer type in terms of extra risk. Note that unit risk estimates for the different cancer types 

28 calculated at 0.1 ppm will differ slightly from those reported above (sections 5.2.2 and 5.2.3) 

29 because they are calculated at a level other than the PODs used in the above calculations. To 

30 derive the combined risk, maximum likelihood estimates (MLEs) of risk and their 95% upper 

31 bounds (UCLs) were calculated for each cancer type using the same methods and life-table 

32 programs employed in sections 5.2.2 and 5.2.3. The standard errors (SEs) were then estimated 

33 from the risk estimates using the equation: UCL = MLE + 1.645 × SE. The variances can then be 

calculated from the SEs according to the equation: Variance = SE234 . The sum of the variances 
This document is a draft for review purposes only and does not constitute Agency policy.

5-100 DRAFT—DO NOT CITE OR QUOTE 

1 then provides an estimate of the variance for the sum of the MLEs, and the 95% upper bound on 

2 the sum of the MLEs can be estimated by applying the above equations in reverse. Tables 5-20 

3 and 5-21 provide a summary of the results of these calculations for the combined cancer 

4 mortality and incidence risks, respectively. 

5 

6 Table 5-20. Calculation of combined cancer mortality unit risk estimate at 

7 0.1 ppm 

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 

riska

(per ppm) 

 4.49 × 10–2

 

9 

a

10 Unit risk = 95% upper bound on combined risk/0.1 ppm. 

11 

12 

13 Table 5-21. Calculation of combined cancer incidence unit risk estimate at 

14 0.1 ppm 

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 

riska

(per ppm) 

 8.10 × 10–2 

16 

a

17 Unit risk = 95% upper bound on combined risk/0.1 ppm.
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1 As can be seen from the results in Table 5-20, the upper bound risk estimates for cancer 

2 mortality for the individual cancer types at 0.1 ppm are within 10% of the values that would be 

3 obtained from the unit risk estimates derived in sections 5.2.2 and 5.2.3 (Tables 5-10, 5-16, and 

4 5-17). Furthermore, the combined unit risk estimate for mortality for the three cancer types 

(4.5 × 10–2 5 per ppm) is appropriately bounded by the mortality unit risk estimate for leukemia 

(4.1 × 10–2 6 per ppm), which has the highest individual mortality unit risk estimate, and by the 

sum (5.2 × 10–2 7 per ppm) of the individual unit risk estimates presented in sections 5.2.2 and 

8 5.2.3. Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of 

9 the MLEs and the sum of the 95% upper bounds for the individual risks calculated at 0.1 ppm. 

Thus, the value of 4.5 × 10–2 per ppm (3.7 × 10–5 per μg/m310 ) calculated at 0.1 ppm for the 

11 combined unit risk is a reasonable estimate for the total cancer mortality unit risk (based on the 

12 three cancer types considered). 

13 As can be seen from the results in Table 5-21, the upper bound risk estimates for cancer 

14 incidence for the individual cancer types at 0.1 ppm are within 33% of the values that would be 

15 obtained from the unit risk estimates derived in sections 5.2.2 and 5.2.3 (Tables 5-13, 5-20, and 

16 5-21). Furthermore, the combined (incidence) unit risk estimate for the three cancer types 

(8.1 × 10−2 17 per ppm) is appropriately bounded by the unit risk estimate for leukemia 

(5.7× 10-2 18 per ppm), which has the highest individual unit risk estimate, and by the sum (8.6 × 

10–2 19 per ppm) of the individual unit risk estimates presented in sections 5.2.2 and 5.2.3. 

20 Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of the 

21 MLEs and the sum of the 95% upper bounds for the individual risks calculated at 0.1 ppm. Thus, 

22 the value of 

8.1 × 10−2 per ppm (6.6 × 10–5 per μg/m323 ) calculated at 0.1 ppm for the combined unit risk is a 

24 reasonable estimate for the total cancer unit risk (based on the three cancer types considered). 

25 As documented in section 4.5, formaldehyde is a mutagenic carcinogen and the weight of 

26 evidence suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a 

27 mutagenic MOA. Therefore, since there are no chemical-specific data to evaluate susceptibility 

28 of different life stages, increased early-life susceptibility should be assumed, and, if there is 

29 early-life exposure, the age-dependent adjustment factors (ADAFs) should be applied in 

30 accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 

31 Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 below for more details on the 

32 application of the ADAFs. 

33 

34 
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1 

2 5.3. DOSE-RESPONSE MODELING OF RISK OF SQUAMOUS CELL CARCINOMA 

3 IN THE RESPIRATORY TRACT USING ANIMAL DATA 

4 In the previous section, dose-response analyses based on human data for 

5 lymphohematopoietic cancer and NPC were presented. The dose-response analyses of cancer 

6 risk presented in this section are based on nasal tumor data from laboratory bioassays using F344 

7 rats. Because the analyses involved are extensive, most of the details are provided in the 

8 appendices. 

9 An increased incidence of nasal squamous cell carcinoma (SCC) was seen in two long10 term bioassays using F344 rats (Monticello et al., 1996; Kerns et al., 1983). Although other 

11 studies in laboratory animals exist, these two studies, when combined, provide the most robust 

12 data for analyses. These inhalation data on nasal SCC tumor incidence were used to estimate 

13 human respiratory cancer risk in the nose and were also extrapolated to the entire respiratory 

14 tract; in other words, a site concordance between rat and human is not assumed. This is 

15 reasonable because the respiratory and transitional epithelial cell types considered to be at risk 

16 of SCC in the upper respiratory tract are also prevalent in the lower human respiratory tract, and 

17 there is greater penetration of formaldehyde flux posteriorly in the nose and in the rest of the 

18 human respiratory tract relative to that of the rat. These considerations are strengthened by the 

19 findings of DNA-protein cross-links (DPXs) in the proximal portions of the rhesus monkey 

20 lower respiratory tract (Casanova et al., 1991). In addition, some epidemiologic studies 

21 (Gardner et al., 1993; Blair et al., 1990, 1986) reported an increase in lung cancer associated 

22 with formaldehyde exposure, while others (Collins et al., 1997; Stayner et al., 1988) reported no 

23 such increases. 

24 EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a BBDR model for 

25 extrapolation when data permit. A BBDR model for formaldehyde was developed by scientists 

26 at the CIIT Centers for Health Research (see Appendix D) (Conolly et al., 2004, 2003, 2000; 

27 Kimbell et al., 2001a, b; Overton et al., 2001; CIIT, 1999), which interfaced several models to 

28 combine the extensive mechanistic information available in studies involving the F344 rat and 

29 rhesus monkey and time-to-tumor incidence data in long-term bioassays, as shown by the 

30 schematic in Figure 5-11. This mechanistic information included formaldehyde and DPX 

31 dosimetry in the rat, monkey, and human airways and cell proliferation data in the rat nasal 

32 lining. This document presents extensive evaluation of the underlying models and data and of 

33 the alternative parametrizations of the models that were also explored for the purpose of the 

34 current assessment (see Appendix E, Appendix F). A summary of conclusions is presented in 
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1 section 5.3.3. In particular, the following conclusions by EPA were critical in determining how 

2 the models could be used to inform the quantitative dose-response assessment: 

3 • When used to model the dose-response in the range of the available data, the BBDR 

4 models were judged to have the advantage of being more accurate and biologically based 

5 (than purely statistical descriptions such as the multistage-weibull model) and allowing 

6 utilization of various data in an integrated manner. 

7 • Variations to the modeling in Conolly et al. (2003) were examined. Each of these models, 

8 including the modeling in Conolly et al., was judged to be just as biologically plausible as 

9 the other, described the rat tumor incidence equally well, was based on different 

10 characterizations of the same empirical cell kinetic data, and was based on the same 

11 empirical data on DPX measurements. However, the added human risk over baseline 

12 levels estimated by these models (including the original model) ranged from negative to 

13 large positive values at environmental exposure concentrations. 

14 • When used for the purpose of extrapolating risk, the BBDR models did not appear to 

15 reasonably constrain either risk estimates extrapolated to human exposures or risk 

16 estimates for the F344 rat when they were extrapolated below the range of observable 

17 data. 

18 • Because human respiratory cancer risk calculated in Conolly et al. (2004) was 

19 numerically unstable, clonal growth modeling was not found to be a useful approach for 

20 human extrapolation of rodent risk estimates. 

21 • Thus, the biologically based derivation of human risk estimates in Conolly et al. (2004) 

22 cannot be characterized as a plausible upper bound in the face of model uncertainties (a 

23 key conclusion of those authors). 

24 

25 For all these reasons, the BBDR modeling of the rat data 

26 • was employed in this assessment to derive multiple PODs (for SCC in the respiratory 

27 tract) in the range of the observed data and using model-derived internal dose estimates, 

28 • but was not used to extrapolate far below the observed data., 

29 

30 The inhalation unit risk estimates of SCC in the human respiratory tract were derived by 

31 using multiple methods to model the F344 tumor incidence data as follows: conventional 

32 mutistage Weibull time-to-tumor modeling and variations of the model implemented in Conolly 

33 et al. (2003) that were considered in the process of the evaluation. 
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1 PODs were calculated as exposure concentrations corresponding to the 95% statistical 

2 upper bound extra risks of 0.005, 0.01, and 0.05 (0.005 used only with BBDR modeling). The 

3 inhalation unit risk for SCC in the human respiratory tract (upper and lower) derived from the 

4 above animal bioassay data was then calculated by linear extrapolation to the origin from the 

5 POD. Linear extrapolation is supported in part by the proven genotoxicity of the chemical and 

6 the observation of cytogenetic effects in human occupational exposures (see chapter 4). In 

7 particular, the formation of DPXs on formaldehyde interaction with DNA has been observed at 

8 doses well below those considered cytotoxic. In results obtained in some implementations of the 

9 biologically based models, formaldehyde-induced mutagenicity (modeled as proportional to DPX 

10 concentration) was found to be a critical determinant of its tumorigenicity, both at the low dose 

11 pertaining to human exposure concentrations as well as in the dose range in which formaldehyde 

12 is considered to be cytotoxic. 

13 The human equivalent concentration was calculated by assuming that continuous lifetime 

exposure to a given steady-state flux of formaldehyde (expressed in pmol/mm2

14 -hour) leads to 

15 equivalent risk of nasal cancer across species. Risk per respiratory or transitional epithelial cell 

16 with replicative potential in a given region was computed as a function of formaldehyde flux in 

17 the nasal region and extrapolated to the rest of the respiratory tract. 

18 

19 5.3.1. Long-Term Bioassays in Laboratory Animals 

20 This section briefly describes the various animal data and dosimetry information utilized 

21 in the above (but not in all) models, based on which estimates for the inhalation unit risk are 

22 derived later in this chapter. 

23 

24 5.3.1.1. Nasal Tumor Incidence Data

25 Various bioassays have reported the effects of formaldehyde on rats, mice, and rhesus 

26 monkeys and have been discussed at length earlier in this document. Two of these bioassays 

27 (Monticello et al., 1996; Kerns et al., 1983), when combined, allow for the most robust 

28 characterization of the long-term dose response in a laboratory species. These long-term 

29 bioassays found an increased incidence of nasal SCCs in rats exposed to formaldehyde by the 

30 inhalation route. In these combined data, rats were exposed to 0, 0.7, 2.0, 6.01, 9.93, and 

14.96 ppm (0, 0.86, 2.5, 7.4, 12.2, and 18.4 mg/m3

31 ) exposure concentrations of formaldehyde. 

32 SCCs were observed only at 6.01 ppm and higher exposure concentrations. Table 5-22 provides 

33 a summary of the tumors from these bioassays, and the time-to-tumor characteristics are as 

34 shown by the data in Figure 5-12 (in section 5.3.3). The focus here is on these two bioassays, 
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1 combined, because they provide the most extensive chronic dose-response information. Other 

2 tumor bioassays were also conducted by various researchers and have been detailed in chapter 4. 

3 

4 

5 

6 Table 5-22. Summary of tumor incidence in long-term bioassays on 

7 F344 rats 

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 

10 Sources: Combined data from Monticello et al. (1996) and Kerns et al. (1983). 

11 

12 

13 5.3.1.2. Mechanistic Data

14 The Kerns et al. (1983) and Monticello et al. (1996) tumor studies were accompanied or 

15 followed by additional studies that provided extensive mechanistic information on both 

16 pharmacokinetics and pharmacodynamics. These studies have been summarized elsewhere in 

17 this document and in other reviews (CIIT, 1999; Monticello and Morgan, 1997; Morgan, 1997; 

18 Heck et al., 1990). In addition to the tumor incidence data, the following data and mechanistic 

19 information (some of which were model derived) are used in the quantitative models utilized in 

20 this chapter. In all these cases, additional data for the rhesus monkey are also available that 

21 inform the hazard assessment but which have not been explicitly used in deriving the inhalation 

22 unit risk. Rhesus monkey data have been discussed in chapter 4 and chapter 3 (DPX and 

23 formaldehyde dosimetry). 

24 • Formaldehyde interacts with DNA to form DPXs. These cross-links are considered to 

25 induce mutagenic as well as clastogenic effects. Casanova et al. (1994, 1989) carried out 

26 two studies of DPX measurements in F344 rats. In the first study, rats were exposed to 

27 concentrations of 0.3, 0.7, 2, 6, and 10 ppm for 6 hours and DPX measurements were 

28 made over the whole respiratory mucosa of the rat, while, in the second study, the 

29 exposure was to 0.7, 2, 6, or 15 ppm formaldehyde for 3 hours and measurements were 

30 made at “high” and “low” tumor sites. DPX formation was observed at all exposure 

31 concentrations in both studies (0.3 ppm – 15 ppm); the DPX levels were statistically 
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5-106 DRAFT—DO NOT CITE OR QUOTE 

1 significantly elevated at concentrations ≥2 ppm, with the trend also indicating elevated 

2 DPXs at 0.7 ppm. These data were used in the development of a PBPK model for 

3 predicting DPX levels in the nasal lining (see chapters 3 and 4). 

4 • Male F344 rats were exposed to formaldehyde gas over a range of concentrations (0, 0.7, 

5 2, 6, 10, or 15 ppm) in two phases of a labeling study. The first phase (Monticello et al., 

6 1991) employed injection labeling with a 2-hour pulse labeling time, and animals were 

7 exposed to formaldehyde for periods of 1, 4, and 9 days and 6 weeks. The second phase 

8 (Monticello et al., 1996) used osmotic minipumps for labeling with a 120-hour release 

9 time to quantify labeling in animals exposed for 13, 26, 52, and 78 weeks. These data 

10 have been analyzed at length in Appendix E. 

11 • Physical and computer models of airflow in anatomically realistic representations of the 

12 F344 rat and human upper respiratory tract have been constructed (Kimbell et al., 1993, 

13 1997; Kepler et al., 1993; Subramaniam et al., 1998; see chapter 3). 

14 • Regional uptake of formaldehyde has been calculated for the upper respiratory tract of the 

15 rat and human by using the above computer representations and for the lower respiratory 

16 tract of the human by using an idealized representation of the human lower respiratory 

17 tract (Kimbell et al., 2001a; Overton et al., 2001; also see chapter 3 and further discussion 

18 of uncertainties in Appendix F). 

19 

20 5.3.2. The CIIT Biologically Based Dose-Response Modeling 

21 The studies mentioned above in 5.3.1.1 and 5.3.1.2 were generated at the CIIT Centers for 

22 Health Research and led to the development of a biologically motivated dose-response model for 

23 formaldehyde-induced cancer as represented in a series of papers and in a health assessment 

24 report (CIIT model) (Conolly et al., 2004, 2003, 2000; Conolly, 2002; Kimbell et al., 2001a, b; 

25 Overton et al., 2001; CIIT, 1999). EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a 

26 BBDR model for extrapolation when data permit since it facilitates the incorporation of MOA in 

27 risk assessment. The CIIT modeling and available data were evaluated in a series of peer28 reviewed papers (Klein et al., 2009; Crump et al., 2008; Subramaniam et al., 2008, 2007) and 

29 debated further in the literature (Conolly et al., 2009; Crump et al., 2009). Alternatives to the 

30 parametrization and model structure in the CIIT biological modeling (but based on that original 

31 model) are further explored and evaluated in this assessment (Appendix E). Appendix F carries 

32 out a sensitivity analysis of the human risk estimates in Conolly et al. (2004) based on key 

33 uncertainties evaluated in Appendix E. These BBDR models are used in this assessment to 

34 calculate PODs from the dose-response curve for the F344 rat nasal tumor risk. Extrapolation to 
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5-107 DRAFT—DO NOT CITE OR QUOTE 

1 human is then carried out by using EPA’s baseline (“default”) approach (U.S. EPA, 1994) but 

2 using model-derived internal dose metrics. See section 5.3.3 for rationale supporting these 

3 decisions. 

4 First, the key features of the BBDR modeling in Conolly et al. (2003, 2004) are briefly 

5 described, and the following notation is used throughout this section: N cell = normal cell; I cell 

6 = initiated cell; LI = labeling index and is equal to the number of labeled cells/(number labeled + 

7 unlabeled cells); ULLI = unit length LI equal to the number of labeled cells/length of basement 

membrane; αN = division rate of normal cells (hour–1 8 ); μN = rate at which an initiated cell is 

9 formed by mutation of a normal cell (per cell division of normal cells). 

10 In Conolly et al. (2003), tumor incidence data in the Kerns et al. (1983) and Monticello et 

11 al. (1996) long-term bioassays were modeled by using an approximation of the two-stage clonal 

12 growth model (Moolgavkar et al., 1988) and allowing formaldehyde to have a direct mutagenic 

13 action. Conolly et al. (2003) combined these data with historical control data on 7,684 animals 

14 obtained from National Toxicology Program (NTP) bioassays. These models are based on the 

15 Moolgavkar, Venzon, and Knudson (MVK) stochastic two-stage model of cancer (Moolgavkar et 

16 al., 1988; Moolgavkar and Knudson, 1981; Moolgavkar and Venzon, 1979), which accounts for 

17 growth of a pool of normal cells, mutation of normal cells to initiated cells, clonal expansion and 

18 death of initiated cells, and mutation of initiated cells to fully malignant cells. 

19 The MVK model for formaldehyde accounted for two MOAs as follows that may be 

20 relevant to formaldehyde carcinogenicity: 

21 1. An indirect MOA in which the regenerative cell proliferation in response to formaldehyde 

22 cytotoxicity increases the probability of errors in DNA replication. This MOA was modeled 

23 by using labeling data on normal cells in nasal mucosa of rats exposed to formaldehyde. 

24 2. A possible direct mutagenic MOA, based on information indicating that formaldehyde is 

25 mutagenic (Speit and Merk, 2002; Heck et al., 1990; Grafström et al., 1985), was modeled by 

26 using rat data on formaldehyde production of DPXs (Monticello et al., 1996, 1991). In 

27 Conolly et al. (2003), the intracellular dose that induces mutations is considered proportional 

28 to the local DPX dose. 

29 

30 The human model for formaldehyde carcinogenicity (Conolly et al., 2004) is conceptually 

31 very similar to the rat model. The model uses, as input, results from a dosimetry model for an 

32 anatomically realistic representation of the human upper airways and an idealized representation 

33 of the lower airways. However, the model does not incorporate any data on human responses to 

34 formaldehyde exposure. 
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1 A novel contribution of the CIIT model, described by the schematic in Figure 5-11, is that 

2 cell replication rates and DPX concentrations are driven by local dose, which is formaldehyde 

flux to each region of nasal tissue expressed as pmol/mm2

3 -hour. This dosimetry is predicted by 

4 computational fluid dynamics (CFD) modeling using anatomically accurate representations of the 

5 nasal passages of a single F344 rat or Caucasian male human (see chapter 3). Such a feature is 

6 important in incorporating site-specific toxicity in the case of a highly reactive gas like 

7 formaldehyde for which uptake patterns are spatially localized and significantly different across 

8 species (see chapter 3). In the CIIT model, each of these parameters is characterized by local flux 

9 (see Figure 5-11). The inputs to the two-stage cancer modeling consisted of results from other 

10 model predictions as well as empirical data as follows: 

11 • Regional uptake of formaldehyde in the respiratory tract was predicted by using CFD 

12 modeling in the F344 rat and human (Kimbell et al., 2001a, b; Overton et al., 2001; 

13 Subramaniam et al., 1998). 

14 • Normal cell replication rates were inferred from LI data on rats exposed to formaldehyde 

15 (Monticello et al., 1996, 1991, 1990). 

16 • Concentrations of DPXs linked to the regional flux of formaldehyde were predicted by a 

17 PBPK model (Conolly et al., 2000) calibrated to fit the DPX data in F344 rat and rhesus 

18 monkey (Casanova et al., 1994, 1991) and subsequently scaled up to humans. The DPX 

19 concentration levels were incorporated into the two-stage clonal expansion model by 

20 defining mutation rate of normal and initiated cells as the same linear function of DPX. 

21 That is, 

22 

μN = μI = μNbasal 23 + KMU × DPX (5-1) 

24 

25 where μN is the rate at which an initiated cell is formed by mutation of a normal cell (per 

cell division of normal cells), and likewise μI 26 is the rate at which a malignant cell is 

27 formed by mutation of an initiated cell (per cell division of initiated cells). The unknown 

constants μNbasal 28 (the baseline rate) and KMU were estimated by fitting model predictions 

29 to the tumor bioassay data. 

30 

31 The rat model in Conolly et al. (2003) involved six unknown statistical parameters that 

32 were estimated by fitting the model to the rat formaldehyde bioassay data shown in Table 5-22 

33 (Monticello et al., 1996; Kerns et al., 1983) plus data from several thousand control animals from 

34 all the rat bioassays conducted by the NTP. These NTP bioassays were conducted from 1976 
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5-109 DRAFT—DO NOT CITE OR QUOTE 

1 through 1999 and included 7,684 animals with an incidence of 13 SCCs (i.e., 0.17% incidence). 

2 The resulting model predicts the probability of a nasal SCC in the F344 rat as a function of age 

3 and exposure to formaldehyde. The fit to the tumor incidence data is shown in Figure 5-12 (in 

4 section 5.3.3.). (For later reference in Appendix E, this figure compares the fit to the data 

5 obtained by the modeling in Conolly et al. [2003] with that obtained by the reimplementation of 

6 this model in Subramaniam et al. [2007].) 

7 Subsequent to the BBDR model for modeling rat cancer, Conolly et al. (2004) developed 

8 a corresponding model for humans for the purpose of extrapolating the risk to humans estimated 

9 by the rat model. Also, rather than considering only nasal tumors, the model is used to predict 

10 the risk of all human respiratory tumors. The human model for formaldehyde carcinogenicity 

11 (Conolly et al., 2004) is conceptually very similar to the rat model and follows the schematic in 

12 Figure 5-11. The following points need to be noted: 

13 

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

15 • The model is based on an anatomically realistic representation of the human nasal 

16 passages (in a single individual) and an idealized representation of the lower respiratory 

17 tract. Local formaldehyde flux to respiratory tissue is estimated by a CFD model for 

18 humans (Kimbell et al., 2001a; Overton et al., 2001; Subramaniam et al., 1998). 

19 • Rates of cell division and cell death are, with a minor modification, assumed to be the 

20 same in humans as in rats. 

21 • The concentration of formaldehyde-induced DPXs in humans is estimated by scaling up 

22 from values obtained from experiments in the F344 rat and rhesus monkey (Conolly et 

23 al., 2000, and also discussed further in section 3.6.6 of this document). The statistical 

24 parameters for the human model are either estimated by fitting the model to the human 

25 background data, assumed to have the same value as that obtained in the rat model, or, in 

26 one case, fixed at a value suggested by the epidemiologic literature. The human value for 

27 KMU in eq 1 is obtained by assuming that the ratio KMU/μbasal is invariant across species. 

28 

29 Some further clarification pertaining to the structure and calibration of the models in 

30 Conolly et al. (2004, 2003) that are key to understanding model assumptions is provided in 

31 Appendix D. 

32 
This document is a draft for review purposes only and does not constitute Agency policy

5-110 DRAFT—DO NOT CITE OR QUOTE Figure 5-11. Schematic of integration of pharmacokinetic and pharmacodynamic components in th

model. Note: β = death rate; μ = mutation rate per cell division; 

α

N, N(t), μ

N are informed (partially or fully) by e

other parameters are estimated by fitting to tumor incidence data. 

Regional respiratory tract dosimetry 

Input

Cancer

cell

Tumor

(delay)

Normal

Cells, N(t)

Initiated

cells

α

N

αI

βI= 

α

N

μ

N

μI=

μ

N

D

DPX in Rat

DPX in Monkey

DPX in Human Respiratory tract

PBPK models for DPX

+ Human Lung

input

input

Regional respiratory tract dosimetry 

Input

Cancer

cell

Tumor

(delay)

Normal

Cells, N(t)

Initiated

cells

α

N

αI

βI= 

α

N

μ

N

μI=

μ

N

D

DPX in Rat

DPX in Monkey

DPX in Human Respiratory tract

PBPK models for DPX

+ Human Lung

input

input
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1 5.3.2.1. Major Results of the CIIT Modeling Effort 

2 Based on the biologically based modeling of the rat SCC data, CIIT (1999) and Conolly 

3 et al. (2004, 2003) presented the following major conclusions. The evaluation of the strength of 

4 these conclusions is summarized in section 5.3.3., and as addressed in that section, this current 

5 assessment is not in agreement with these conclusions. 

6 • The putative, directly mutagenic action of formaldehyde “does not play a significant role 

7 in the tumor response in the rat (and also in the human), [and such a conclusion] should 

8 be robust for any potentially mutagenic effect of formaldehyde with a time course similar 

9 to that of DPX.” 

• Respiratory cancer risks associated with inhaled formaldehyde are de minimis (10–6 10 or 

11 less) at relevant human exposure levels. This was based on using an upper bound on the 

12 model estimate for the directly mutagenic action of formaldehyde. 

13 • Therefore, exposure standards protective of effects of formaldehyde-induced cytotoxicity 

14 should be sufficient to protect from its potential carcinogenic effects. 

15 • The human risk estimates in Conolly et al. (2004) were judged by the authors to be 

16 conservative in the face of model uncertainties because the model included a hockey-stick 

17 model for normal cell replication rates when the cell replication dose-response curve as 

18 averaged by the authors had a J shape, used overall respiratory tract cancer incidence data 

19 in humans, and evaluated the model at the statistical upper bound of the proportionality 

20 parameter relating DPXs to the probability of mutation. 

21 • The dose-response assessment in Conolly et al. (2004) did not explicitly evaluate the risk 

22 of lymphohematopoietic cancers. However, Conolly et al. (2004) argued that 

23 formaldehyde was unlikely to cause the cancers reported in Hauptmann et al. (2003). 

24 Their reasoning was based on the steepness of the dose-response curve predicted in 

25 Conolly et al. (2004) for respiratory cancer at exposures of 1 ppm and above and the 

26 conclusions in Heck and Casanova (2004). 

27 

28 5.3.3. This Assessment’s Conclusions from Evaluation of Dose-Response Models of DPX, 

29 Cell-Replication and Genomics Data, and of BBDR Models for Risk Estimation 

30 The CIIT modeling and alternative approaches that were developed based on the 

31 conceptual framework in that modeling were extensively evaluated for this assessment and are 

32 presented in Appendices D, E (BBDR modeling of the rat data), and F (sensitivity analysis of 

33 BBDR model results for human risk). In particular, Table E-1 in Appendix E and Table F-1 in 

34 Appendix F list all the uncertainties and assumptions that were examined and summarize the 

35 results of the evaluation. The quantitative and qualitative characterization of the cell replication 
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1 data from Monticello et al. (1996, 1991) are presented in Appendix E. The most significant 

2 conclusions resulting from these various analyses, focusing on the ones that have maximal 

3 impact on the dose-response assessment, are presented below.

4 

5 Description of time-to-tumor data 

6 The overall approach and use of data in Conolly et al. (2004, 2003) have substantial 

7 advantages to offer in describing the dose response observed in animal bioassays. The authors’ 

8 model provides a good statistical description of the time-to-tumor data. The fit to the data was 

9 found to be superior to that obtained by using multistage Weibull time-to-tumor modeling of the 

10 tumor incidence data (comparison based on visual inspection [see Figure 5-12 in this section and 

11 Figures 5-17, 5-18, 5-19 in section 5.3.4]). 

12 

13 Figure 5-12. Fit to the rat tumor incidence data using the model and 

14 assumptions in Conolly et al. (2003). 

15 Note: Fitting was performed on data of Kerns et al. (1983) and Monticello et al. (1996) combined 

16 with ALL NTP historical controls under the assumption that all SCCs are fatal. Figure compares 

17 the fit obtained by Conolly et al. (2003) with the reproduction of these results under identical 

18 conditions, inputs, and assumptions by Subramaniam et al. (2007). There were minor residual 

19 differences among the implementations; see the appendix in Subramaniam et al. (2007) for 

20 explanation. 

21 Source: Subramaniam et al. (2007). Reprint permission required. 

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

1.0

Probability

 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

1.0

Probability

 Kaplan-M eier Conolly fit Our fit

Age (days)

Probability

Age (days)

0 ppm 6 ppm

10 ppm 15 ppm
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1 

2 Integration of various relevant data 

3 The model framework integrates various pharmacokinetic and pharmacodynamic 

4 components (regional formaldehyde flux, DPX, cell-replication, and tumor incidence data) 

5 within a single conceptual framework and thus facilitates description of the dose response that 

6 utilizes the extensive mechanistic information available for formaldehyde. 

7 

8 Regional dosimetry 

9 Regional (site-specific) dosimetry in the upper respiratory tract is considered important 

10 for understanding the tumorigenicity of a reactive chemical like formaldehyde. The regional 

11 dosimetry models discussed in chapter 3 compute local formaldehyde flux to the tissue and are 

12 based on anatomically realistic constructions of the nasal airways in each species. The other 

13 relevant mechanistic data, DPX and cell replication, are expressed as a function of this local 

14 formaldehyde flux. 

15 

16 Confidence in dosimetry 

17 Model predictions of formaldehyde flux to the respiratory lining have not been verified 

18 experimentally, and such verification would present formidable experimental challenges. 

19 Overall, the formaldehyde dosimetry modeling utilized in the CIIT modeling presents a 

20 reasonable level of confidence, as detailed in chapter 3, section 3.6, by virtue of agreement 

21 among multiple model predictions (models that predict airflow profiles as well as a PBPK model 

22 for DPX, which uses the calculated formaldehyde flux as input) and various kinds of available 

23 data. These data comprise airflow profiles in physical casts of the nasal cavity of an F344 rat 

24 (Kimbell et al., 2001a), a human (Subramaniam et al., 1998), and a rhesus monkey (Kepler et al., 

25 1998); DPX data (see discussion of Cohen-Hubal et al. [1997] in chapter 3); and qualitative 

26 concordance between uptake patterns and cell proliferation (Morgan et al., 1997; Monticello et 

27 al., 1996). The CFD models of formaldehyde flux represent only an individual of each species. 

28 However, considerable interindividual differences are to be expected in the regional dosimetry, 

29 particularly in the human (Garcia et al., 2009: Subramaniam et al., 2008). This is discussed 

30 briefly in Chapter 3 (section 3.6) and further in Appendices B and F. 

31 

32 Control tumor data 

33 In developing their model, Conolly et al. (2004, 2003) included control rats from all NTP 

34 cancer bioassays—a total of 7,684 rats. The inclusion of all NTP historical control animals does 

35 not appear to be supportable and substantially alters dose-response predictions (Crump et al., 
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1 2009, 2008; Subramaniam et al., 2008, 2007). There are legitimate questions regarding 

2 comparability of results in rats from different stocks, studied at different times, in different 

3 laboratories, and by different routes of exposure and evaluated by using somewhat different 

4 pathological procedures. If historical controls are used from only those inhalation studies that 

5 present a low potential for genetic and time-related variations in tumor incidence and survival of 

6 animals or if only concurrent controls are used, the model for extrapolation of risk to humans (the 

7 human BBDR model) becomes numerically unstable. In such a model, it is not possible to bound 

8 human risk by using the extrapolation approach applied in the CIIT model. When the included 

9 NTP control data were restricted to all NTP inhalation controls, the upper bound human risk 

10 estimate obtained by Conolly et al. (2004) was increased by 50-fold (Crump et al., 2008). 

11 

12 Cell replication dose response 

13 As discussed in chapter 4, characterization of the uncertainties and variability in the cell 

14 replication dose response is crucial to understanding formaldehyde carcinogenicity. Analyses of 

15 the dose response for cell replication presented in Appendix E demonstrate the following: 

16 • Sustained exposure to formaldehyde affects cell division rates (compared to baseline 

17 levels). This effect is seen over a continuum of formaldehyde flux to the nasal lining that 

18 includes flux levels below those thought to be cytotoxic. 

19 • Given the qualitative and quantitative uncertainties in the data and in their interpretation, 

20 a variety of cell replication dose-response models are plausible as reasonable 

21 characterization of the data. Cell replication response differs substantially among nasal 

22 sites and over time during the course of the bioassay. In consideration of these 

23 differences, the shape of the cell replication low-dose response could be alternatively 

24 described as monotonic or non-monotonic. For example, rather different statistical 

25 descriptions of the data result depending on whether 

26 i. different sites and exposure times were modeled separately; 

27 ii. all exposure times were pooled to model the response at each site; 

28 iii. the labeling index was time-weighted and averaged over all sites; 

29 iv. flux and labeling index were weighted by the number of cells at a given site; 

30 v. the short exposure durations in Monticello et al. (1991) were examined separately. In 

31 addition, transient increases in cell turnover at sub-cytotoxic doses are seen in other 

32 experiments in rats exposed to formaldehyde (see chapter 4). 

33 • At higher, cytolethal formaldehyde flux levels, regenerative hyperplasia-induced cell 

34 proliferation clearly takes over. 
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1 

2 

3 Genotoxicity 

4 Chapter 4 provides multiple lines of evidence to characterize formaldehyde as a 

5 genotoxicant. Of particular note is the observation of cytogenetic effects at human occupational 

6 exposures and the formation of DPXs upon formaldehyde interaction with DNA at doses well 

7 below those considered cytotoxic. As noted earlier, DPX formation was detected in rats at 

8 exposures ranging from 0.3 ppm to 15 ppm. These DPX levels are seen to be statistically 

9 significantly increased over baseline levels at 2 ppm and above. The DPX measured at 0.7 ppm 

10 shows a trend that is consistent with an increase at this dose (see chapter 3); while not 

11 statistically significant, it is critical to consider “trend” when analyzing low-dose data. 

12 

13 Inferences on MOA from modeling the data 

14 The highly curvilinear nature of dose responses associated with DPX formation, LI data, 

15 and tumor response as well as mechanistic interpretation of these observed data has provided 

16 grounds for arguments in the literature that formaldehyde tumorigenicity (at exposures ≥6 ppm) 

17 should be uncoupled from its potential carcinogenicity in the low-dose region. Furthermore, 

18 researchers have argued that any potential low-dose risk is due to its mutagenicity, that this 

19 mutagenic potential is too weak to be of significance, and that the high-dose risk is entirely due 

20 to cell proliferation induced by regenerative hyperplasia in response to cell injury at cytotoxic 

21 doses (i.e., without a relevant role for the direct mutagenic action of formaldehyde). Conolly et 

22 al. (2004, 2003) represented a quantitative expression of this point of view. However, alternative 

23 parametrizations of the model in Conolly et al. (2004, 2003) have shown that the mutagenic 

24 component can be important in explaining the high-dose effect and that the risk at low dose due 

25 this mutagenicity can be significant (Subramaniam et al., 2007; Appendix E). Accordingly, the 

26 dose-response assessment in this document does not treat formaldehyde as a threshold 

27 carcinogen. 

28 Of further relevance to mode-of-action considerations, analyses detailed in Appendix E 

29 indicate that the chronic rat nasal time-to-tumor incidence data can be quantitatively explained, 

30 and with equal force, by invoking any of the following multiple sets of plausible events induced 

31 by formaldehyde. The role of spontaneously occurring mutations and increased cell turnover 

32 rates in response to various baseline insults to the nasal lining are common to all these scenarios 

33 (and are not separately mentioned). 
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1 a. Mutations occur over a dose continuum that includes sub-cytotoxic and cytotoxic levels of 

2 exposure. The only cell proliferation induced by formaldehyde is a regenerative response at 

3 cytotoxic concentrations. 

4 b. Cytotoxicity-induced regenerative cell proliferation occurs, but there is no significant 

5 formaldehyde-induced mutational effect. This latter scenario expresses arguments that 

6 formaldehyde-induced mutagenicity may be too weak to be of significance to its 

7 tumorigenicity. 

8 c. Both mutations and cell proliferation are induced by formaldehyde only at cytotoxic levels. 

9 d. Mutational events occur and cell replication is altered over a continuum that includes low and 

10 high levels of exposure. 

11 i. At high dose, the effect on cell replication is regenerative. 

12 ii. At lower doses, the data indicate that both monotonic and non-monotonic dose13 response curves for cell replication are plausible.

14 iii. With respect to the previous argument, the following result was very instructive. The 

15 models were exercized with normal cell replication rates considered to be less than 

16 (non-monotonic) or equal to (threshold) baseline rates over a segment of the low-dose 

17 range in conjunction with the chronic time-to-tumor data for the F344 rat. Such a 

18 scenario did not necessarily lead to lower than baseline or threshold in formaldehyde 

19 respiratory cancer risk in the rat in that low-dose range. This is partly because there 

20 are no data to inform how formaldehyde-induced mutation might alter cell replication 

21 and apoptotic rates (in particular if the mutation is to be construed as an initiating 

22 event in the carcinogenesis). 

23 e. Formaldehyde-induced mutagenic action acts only in concert with baseline cell turnover at 

24 low dose. 

25 

26 Kinetics of initiated cells 

27 Modeling results are hypersensitive to the division and death rate of initiated cells that 

28 cannot be further inferred by the available empirical cell labeling data (Conolly et al., 2009; 

29 Crump et al., 2009, 2008). Several plausible alternate model structures for describing initiated 

30 cell kinetics, none of which degrade the agreement of the model with the underlying data used to 

31 construct the model originally, led to low-dose risk estimates in the rodent that varied by many 

32 orders of magnitude, including negative values (see Figures E-5A,B and E-6A,B in Appendix E). 

33 Extremely small perturbations in the division rate (and, likewise, of death rates) of initiated cells

34 in the model lead to human risk estimates ranging anywhere from negative values to +0.01 at 
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1 0.01 ppm (see Crump et al. 2008 and Appendix F, Figure F-5). These perturbations were small 

2 compared with the normal variation in the division rates of normal cells. 

3 The sensitivity analyses on the basis of which these conclusions were reached have been 

4 criticized as resulting in implausible risk estimates (given the epidemiologic data) as a 

5 consequence of implementing model variations that are not biologically reasonable (Conolly et 

6 al. 2009). This criticism was rebutted by Crump et al. (2009) on biological and epidemiological 

7 grounds. These debates are discussed fully in Appendix F. 

8 In addition, there are major qualitative uncertainties in extrapolating normal cell 

9 replication rates from the rat to human (Table F-1 in Appendix F, and Subramaniam et al. 

10 [2008]). Subramaniam et al. (2008) concluded that several inferences that arise from the 

11 assumptions in the CIIT model on initiated cell replication and death rates cannot be supported 

12 by available biological information. 

13 

14 Risk extrapolation 

15 Use of the modeling approach in Conolly et al. (2004) or the variations examined were 

16 determined not to be informative for extrapolation from animal to human at any exposure 

17 concentration because of extreme sensitivity, including numerical instability, to uncertain model 

18 assumptions. In the face of model uncertainties, the biologically based derivation of human risk 

estimates of 10–6 19 or less at exposures of 0.1 ppm and below in Conolly et al. (2004) or CIIT 

20 (1999) cannot be characterized as a plausible upper bound. 

21 The use of this model for extrapolation of risk from high to low exposures in the rodent 

22 followed by a conventional (default) approach to extrapolate the low-dose animal risk to the low23 dose human risk was next evaluated. This avenue was also found not to be informative because 

24 the models do not adequately constrain risk in the rodent. For example, various model 

25 representations as shown in Figure E-6A,B in Appendix E were used to evaluate added MLE risk 

at the 10–5 26 level (Figure F-5A,B in Appendix E) in the F344 rat. Human exposures were then 

27 calculated that would result in equivalent lifetime risk by using formaldehyde flux estimated in 

28 each species as the dosimeter and conventional extrapolation methods (U.S. EPA, 1994b). A 25-

29 fold difference was found between the different models in the equivalent exposure concentration 

30 so derived. Therefore, the CIIT model or its variations were also not used in this assessment as a 

31 biologically based or biologically motivated means of extrapolating outside the observed dose32 response in the F344 rat. Model uncertainty was substantially higher than the statistical 

33 uncertainty arising out of a given model specification.

34 Thus, in view of all the above considerations and in accordance with EPA’s cancer 

35 guidelines (U.S. EPA, 2005a), the derivation in this document of unit risk for human respiratory 
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1 cancer from animal bioassay data is based on a linear extrapolation to the origin from a POD on 

2 the dose-response curve. Low-dose linearity was exhibited by the risk estimates from most of the 

3 models that were examined in the sensitivity analysis (see discussion surrounding Figure E-5A,B 

4 in Appendix E). 

5 BBDR modeling for deriving an “integrated” POD 

6 The CIIT BBDR modeling approach provides a good fit to the time-to-tumor data and 

7 therefore allows for an appropriate determination of a POD while at the same time incorporating 

8 a large amount of mechanistic information in an integrated manner and allowing the use of 

9 model-derived internal dose estimates. Thus, use of this model provides an alternative to 

10 developing separate PODs based on several of the underlying components of the data, such as 

11 DPX, flux, and labeling data. Accordingly, the model is used in this assessment to derive a POD 

12 from a dose response, based on the nasal cancers in rats. Uncertainties in the derivation of the 

13 POD were represented by using the variations of the CIIT model examined in this chapter. These 

14 POD calculations as well as others are detailed below. 

15 

16 Genomics data

17 The genomics data of Thomas et al. (2007) and Andersen et al. (2008) provide additional 

18 insight into formaldehyde’s biological effects and the steep dose-response curve for 

19 tumorigenesis. However, there are various limitations in the interpretation of these genomics 

20 data and their relevance for the pathways contributing to the disease process in humans. In 

21 particular, the data from these studies, as analyzed, do not inform the critical MOA questions 

22 pertaining to formaldehyde carcinogenicity. These insights have been elaborated in a separate 

23 section in chapter 4, and the difficulties in the use and interpretation of the quantitative modeling 

24 of these data, as presented in these studies, are detailed at length in Appendix G. 

25 

26 5.3.4. Benchmark Dose Approaches to Rat Nasal Tumor Data 

27 This section describes various BMD analyses to determine PODs for low-dose 

28 extrapolation of SCC risk in the human respiratory tract (upper and lower). 

29 

30 5.3.4.1. Benchmark Dose Derived from BBDR Rat Model and Flux as Dosimeter

31 5.3.4.1.1. Response for benchmark dose. Typically, the BMD is calculated at the 5 or 10%

32 response level. However, it appears appropriate to consider the benchmark response (BMR) at 

33 lower levels in exceptional cases that are supported by empirical data. In the case of the 

34 combined Kerns et al. (1983) and Monticello et al. (1996) bioassays, the lowest observed tumor 

35 response of SCC was below the 1% level (at 0.85%) (see Table 5-22). Additionally, the BBDR 
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1 modeling incorporates precursor response in the form of LI data. Therefore, it was determined 

2 that it would also be appropriate to evaluate the POD at the 0.5% level while still staying in the 

3 neighborhood of the experimentally observed response. 

4 The various data presented earlier in this chapter point to highly curvilinear dose 

5 responses for formaldehyde-induced tumor incidence as well as DPX and cell replication. This is 

6 also borne out by dose-response information based on gene array data (Thomas et al. 2007; 

7 Andersen et al. 2008). Cytotoxicity-driven regenerative replication and epithelial degeneration 

8 play a critical role in the steeply rising nature of the tumor dose-response. These observations 

9 raise the concern that cancer potency derived by straight-line extrapolation from the low end of 

10 observed tumor data (roughly at the 1% response) has the potential to be a significant 

11 overestimate for a reasonable upper bound. Thus, a pertinent question is what is a low-dose 

12 linear dose-response modeling of the data that is statistically consistent with the uncertainties in 

13 the observed time-to-tumor data. To address this question, the risk estimate based on the linear 

14 extrapolation (from a POD to the origin) is compared with that predicted at the low-dose end by 

15 the Multistage Weibull model fitted to the observed time-to-tumor data. The unit risk based on 

16 this model is obtained by calculating q1*, the 95% statistical upper bound on the coefficient 

17 associated with the linear term in the multistage model polynomial. This model fits the data 

18 reasonably well and reflects the highly curvilinear shape of the dose-response because of its 

19 mathematical flexibility while also allowing for low-dose linearity. In particular, it has been 

20 noted that even in cases where the first term (q1) in the multistage model is zero, the upper 

21 bound (q1*) is linear with dose (Subramaniam et al., 2006; Guess et al., 1977). Thus, for 

22 comparison the following estimates of unit risk are also presented: 

23 

24 1) Unit risk that is based on q1*, which is derived from fitting the multistage Weibull model to 

25 the observed data. 

26 2) Unit risk based on low-dose linear extrapolation from a POD at the 0.5% level. 

27 

28 5.3.4.1.2. Dose metric. The dose metric used for the extrapolation was the average wall mass 

flux of formaldehyde (expressed in pmol/mm229 -hour to the entire surface of the airway lining but 

30 excluding tissue lined by non-mucus-coated squamous tissue, which was considered to not 

31 absorb formaldehyde). The use of flux as a dosimeter is similar to the calculation of a regional 

32 gas dose ratio (RGDR) as proportional to minute volume divided by the surface area in the given 

33 species and is thus in line with EPA’s prescription for calculating a dosimetric adjustment factor 

34 (DAF) for category 1 gases, whose effects are presumed to be at the POE (U.S. EPA, 1994b) 

35 (i.e., ratio of average flux over the same respiratory region in each species = ratio of the quantity 
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1 [minute volume/surface area of the region] between the two species). This lends support to an 

2 interspecies extrapolation based on the equivalence of formaldehyde flux as a determinant of 

3 risk.

4 The spatial distribution of formaldehyde over the nasal lining was characterized by 

5 partitioning the nasal surface by formaldehyde flux to the tissue, resulting in 20 “flux bins” 

6 (Figure 5-13). Each bin is comprised of elements (not necessarily contiguous) of the nasal 

7 surface that receive a particular interval of formaldehyde flux per ppm of exposure 

8 concentration (Kimbell et al., 2001a). The spatial coordinates of elements comprising a 

9 particular flux bin are fixed for all exposure concentrations, with formaldehyde flux in a bin 

10 scaling linearly with exposure concentration (ppm). The number of cells at risk varies across 

11 the bins, as shown in Figure 5-14. 

12 

0

500

1000

1500

2000

2500

3000

0 5 10 15 20

Flux Bin No.

Flux Per Unit Exposure Conc

[pmol/(mm

2-h-ppm)]

Flux Bin No.

0 5 10 15 20

No. 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: Subramaniam et al. (2008). 

15 

16 

17 5.3.4.1.3. Extrapolation to humans. For linear extrapolation from the 0.5 and 1% levels, two 

18 alternative versions of the biologically based model in Conolly et al. (2003) for the F344 rat were 

19 used. In both cases, only the historical control data from NTP inhalation studies data were added 

20 to the concurrent controls and weekly averaged DPX concentrations as calculated by a variant of 

21 the PBPK model in Conolly et al. (2000) [described in Subramaniam et al. (2007)] were used. 
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1 Both models provided good fits to the tumor incidence data, similar to the fit shown in Figure 5-

2 12. Neither model could be considered better than the other on the basis of model description of 

3 tumor incidence data. 

4 In Model 1 the normal cell replication dose response was described by the same 

5 hockey-stick-shaped curve used in Conolly et al. (2003). The form of the dose-response 

6 curves for initiated cell kinetics (division and death) was also the same as that considered by 

7 Conolly et al. (2003). 

8 Model 2 was an alternative to the Conolly et al. (2003) model, and is considered in 

9 the sensitivity analysis described in Appendix E. The dose response for normal cell 

10 replication was monotone increasing and did not exhibit a threshold in dose. This was 

11 obtained by fitting the 13-week cell replication data. The cell replication dose response for 

12 initiated cells was a sigmoidal-shaped curve, increasing monotonically with flux from a 

13 background value up to an asymptotic value. The baseline cell-replication for initiated cells 

14 was constrained to not be less than that for normal cells. Initiated cell death rate was 

15 considered proportional to initiated cell birth rate. 

16 Models 1 & 2 predicted monotonic dose-response curves. 

17 The sequence of steps in arriving at a unit risk for SCC in human nasal airways from 

18 a given BBDR modeling of the F344 rat nasal tumor incidence data is outlined below. 

19 Extrapolation to the lower respiratory tract is described later. 

20 1. Calculate the MLE risk and 95% upper confidence bound on risk at various exposure 

21 concentrations (dRAT in ppm) by exercising the two BBDR models. Here, the POD is 

22 defined as dRAT for which the 95% upper bound added risk is either 0.005 or 0.01. These 

23 values approximate the 95% lower bounds on the BMD corresponding to the added risks 

24 (i.e., the BMDLRAT). 

25 2. Using CFD modeling simulations in Kimbell et al. (2001a, b), calculate the average flux 

26 over the entire rat nose at resting breathing rates corresponding to dRAT. Here, the 

27 subscript “i” is over flux bins and N is the number of cells at risk in a given bin. 

28 

RAT

i

i

i

i

i

RAT RAT N

N

ppm

flux

AvgFlux d d

























⋅

= ×

∑

∑( )

( ) 29 (5-2) 

30 
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1 3. The experiment exposure was for periods of 5 days/week, 6 hours/day. Therefore, 

2 calculate the average daily exposure, obtained by making a 5/7 × 6/24 duration 

3 adjustment; that is, 5/7 × 6/24 × AvgFlux(dRAT). 

4 4. Now assume that lifetime exposure to similar levels of average formaldehyde flux to 

5 cells at risk leads to similar lifetime risk (MLE or upper bound, respectively) of tumor 

6 incidence across animal species. Also, in calculating human equivalent concentrations, 

7 EPA has traditionally assumed chronic animal laboratory exposure scenarios to be 

8 equivalent to human lifetime exposures (U.S. EPA, 1994b). 

9 5. Since a CFD model for a human is available (Subramaniam et al., 1998), it is possible to 

10 determine the average wall mass flux in this particular human nose for any specific 

11 breathing scenario. Likewise, a computational model to determine mass flux at any 

12 specific lung depth was available in the form of the single-path model of Overton et al. 

13 (2001); however, risk in the lower respiratory tract will be addressed later. From the 

14 human CFD simulations in Kimbell et al. (2001a, b), the human airborne exposure 

15 concentration level that would yield the same average wall mass flux in the human nose 

16 as [(5/7) × (6/24) × AvgFlux(dRAT)] is then calculated. In other words, given a risk17 specific dose in the rat, the equivalent human exposure concentration is given by 

18 

HUMAN

i

i

i

i

i

HUMAN RAT

N

ppm

flux

N

d AvgFlux d

























×

= × × ×

∑

∑

( )

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

20 

21 6. To use this equivalent human exposure concentration, make the following assumption: 

22 when humans are exposed to the above concentration of formaldehyde (dHUMAN) 

23 throughout the course of a lifetime, the added risks are anticipated to be similar to those 

24 experienced by the animal in the chronic bioassay. 

25 7. Let f denote the ratio of the average flux per ppm of exposure concentration in the two 

26 species: 

27 
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HUMAN

i

i

i

i

i

RAT

i

i

i

i

i

N

N

ppm

flux

N

N

ppm

flux

f

























×

























×

=

∑

∑

∑

∑

( )

( )

1 (5-4) 

2 

3 Now, the olfactory epithelium comprises a substantial fraction of nasal tissue in the rat. 

4 Because the olfactory region in the rat projects directly in the path of main airstreams 

5 (Kimbell et al., 1997), a sizable flux of formaldehyde is delivered to this region in the 

6 rat. Tumors were not observed in the olfactory tissue of the rat. Therefore, since effects 

7 observed in the rat are being extrapolated to the human, cells from olfactory tissue are 

8 excluded in calculating average flux in the rat in the eq 4. For the human, on the other 

9 hand, both volumetric flow (2.5%, Subramaniam et al. [1998]) and surface area (~5%, 

10 Kelly et al. [2000]) for the olfactory region are relatively small, so inclusion of this 

11 region is not likely to make a difference of much significance in the calculation of 

12 average flux in the human. Since data on formaldehyde flux delivered to the human 

13 olfactory region were not readily available, the olfactory region was not excluded for the 

14 human. The average human flux calculated here uses a working level classification for 

15 the activity profile where an individual spent equal amounts of time in a day at resting 

16 and light and moderate activity levels, corresponding to minute volumes of 7.5, 9, and 

25 L/minute, respectively. This resulted in the following ratio13 17 : 

18 

f = 444[rat]/956.4[human] 19 = 0.46 (5-5) 

20 

21 8. The airborne exposure concentrations dHUMAN corresponding to a given MLE and upper 

22 bound lifetime added risk levels are the human BMDHUMAN and BMDLHUMAN, 

23 respectively. These are shown in Figure 5-15. (The rather sudden increase by ~0.0015 

24 in the upper confidence bound on risk for model 1 for exposure exceeding ~0.41 ppm 

25 could not be explained. This jump was verified by repeated calculations that used 

26 different initial simulation conditions and convergence criteria.) 

 

13 This is to be contrasted with a corresponding value of 0.71 in Schlosser et al. (2003) who used only resting 

inspiratory rates. 
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1 Next, the human lower respiratory tract is also considered to be potentially at risk. 

2 Therefore, the above calculations of BMD and BMDL need to be augmented to include the 

3 lower respiratory tract for humans. This calculation was facilitated by dosimetry 

4 calculations of formaldehyde wall mass flux to various depths in the lung by using a single 

5 path model. Refer to Overton et al. (2001) for details on their modeling. The calculations 

6 for including the lower respiratory tract in determining an overall BMD and BMDL involved 

7 the following steps: 

8 a. As given by eq 5-3, calculate dHUMAN for various MLE risk levels. This gives a dose9 response relationship for lifetime risk of SCC in the human nose due to continuous 

10 exposure to airborne formaldehyde. 

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 

13 Figure 5-15. MLE and upper bound (UB) added risk of SCC in the human 

14 nose for two BBDR models. 

15 

16 Note: Airborne exposure concentrations dHUMAN corresponding to a given MLE 

17 and upper bound lifetime added risk levels are the human BMDHUMAN and 

18 BMDLHUMAN, respectively.

19 

20 

21 b. Express this dose-response relationship in terms of average flux over the entire human 

22 nasal lining. 

23 c. Next, express this dose-response relationship, calculated here for the entire nose, as risk 

24 per nasal cell versus average flux. 
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1 d. Now, if the respiratory and transitional cell types in the human lung and nose are equally 

2 susceptible to formaldehyde-induced cancer risk (as is also assumed in Conolly et al. 

3 [2004]), then it appears reasonable to assume that MLE risk per cell at a given value of 

4 formaldehyde flux is the same in the lung as in the nose. 

5 e. The number of cells and the average flux in a given flux bin in the lung are known 

6 (Overton et al., 2001). Thus, at a given air concentration, the MLE risk due to cells in 

7 the various flux bins of the lung is obtained. 

8 f. One important feature of Overton et al. (2001) was that their flux bins mapped physically 

9 with lung depth. Therefore, in addition to extrapolating risk to the entire human lung, it 

10 was also relatively easy to calculate risk as a function of airway generation in the lung 

11 (corresponding to different lung depths). 

12 g. Because of high formaldehyde reactivity and solubility at the POE, the MLE value risk to 

13 the lower respiratory tract (as determined above in steps 1–5) was a small fraction of risk 

14 to the upper respiratory tract. Therefore, it sufficed to assume that the relative increase 

15 in upper bound risk for the combined upper respiratory tract + lower respiratory tract 

16 compared to that for only the upper respiratory tract would be the same as the 

17 corresponding relative increase in the value of the MLE risk. The upper bound risk to 

18 the entire respiratory tract and consequently the BMDL value corresponding to a given 

19 response were thus determined. 

20 

21 These calculations indicated that including the risk of SCC in the lower respiratory 

22 tract resulted in at most a 3% increase in the added risk at the lower end of the human 

23 exposure range in Figure 5-16 (i.e., at 0.42 ppm) and about a 1.5% increase at the higher end 

24 of the range in that plot. Therefore, because of the steepness in the dose-response curve in 

25 this exposure range and much lower risk in the lung at any exposure concentration, including 

26 the lower respiratory tract did not appreciably alter the human BMDs and BMDLs at the 0.5 

27 and 1% response levels. 

28 Unit risks of SCC in the human respiratory tract extrapolated in this manner are reported 

29 in Table 5-23. 

30 
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1 Table 5-23. BMD modeling of unit risk of SCC in the human respiratory 

2 tract 

3 

Benchmark levels (ppm) 

Extra risk level BMD BMDL 

Unit riska

(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

5 Obtained from the mean of the two BMDLs. 

6 

7 Note: Findings are based on nasal tumors in rats and formaldehyde flux to tissue as dosimeter, using dose8 response curves for the F344 rat predicted by clonal growth modeling. Two chronic bioassays (Monticello 

9 et al., 1996; Kerns et al., 1983) were combined, and control animals from the historical NTP inhalation 

10 bioassays were added to the control animals in these bioassays. 

11 

12 

13 5.3.4.2. Comparison with Other Benchmark Dose Modeling Efforts

14 The CIIT assessment (Schlosser et al., 2003; CIIT, 1999) also presented, as their less 

15 preferred option, a benchmark approach on the data set obtained by combining two chronic 

16 bioassays with similar protocols (Monticello et al., 1996; Kerns et al., 1983) along with data 

17 from 94 animals that had not been previously examined. These authors used two measures of 

18 response—tumor incidence and cell proliferation—and, in each case, they used two dosimeters—

19 DPX and formaldehyde flux to the nasal lining. 

20 The extrapolation to human was carried out by using a hybrid CFD and pharmacokinetic 

21 model. The CFD model (Kimbell et al., 2001a, b; Kepler et al., 1998; Subramaniam et al., 1998) 

22 enabled calculation of site-specific flux in the nose of the rat, monkey, and human species for 

23 inhaled formaldehyde concentrations, and the PBPK model (Conolly et al., 2000) linked this flux 

24 to predicted DPX levels. The models were constructed for anatomically realistic representations 

25 of a single individual in each species. The CFD and PBPK modeling and uncertainties in these 

26 estimates have been reviewed in the Modeling the Toxicokinetics of Formaldehyde and DPX 

27 section of chapter 3. 

28 

29 5.3.4.2.1. Benchmark dose using administered concentration. Schlosser et al. (2003) fit 

30 multistage, Weibull, polynomial, and log-probit quantal models to the tumor data and exercised 

31 the models (except the log-probit) with and without requiring that the fits pass through the origin. 

32 The log-probit fit passed through the origin (see Figure 5-16). A fifth degree polynomial was 

33 used in the multistage model. The best fit was obtained with the polynomial and Weibull models 

34 for the tumor incidence data with a non-zero intercept (threshold) on the dose axis. Fits passing 

35 through the origin did not pass the statistical goodness-of-fit criteria (p > 0.01) for models other 
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1 than the log-probit. The dose response near the lowest dose was fairly steep, with the LED10s 

2 and LED01s nearly the same for each model, at least to one significant figure. In terms of 

3 administered concentration, the LEDs ranged from 3.8 to 6.4 ppm. 

4 

5 5.3.4.2.2. Benchmark dose derived with internal dose (flux and DPX) as dose metrics in 

6 Schlosser et al. (2003). 

7 Schlosser et al. (2003) used CFD simulations (Kimbell et al., 2001a, b) of mass flux of 

8 formaldehyde delivered across the nasal lining. The dose metric used by Schlosser et al. (2003) 

for the extrapolation was the average flux of formaldehyde, expressed in pmol/cm2

9 -minute, to the 

10 entire surface of the airway lining (excluding tissue lined by non-mucus-coated squamous tissue, 

11 which was considered not to absorb formaldehyde). 

12 

13 

14 

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

16 Monticello et al. (1996) data on tumor incidence showing BMC10 and 

17 BMCL10. 

18 

19 Source: Adapted from Schlosser et al. (2003). 

20 

21 

22 In the CFD model, flux in any region is linearly related to the airborne exposure 

concentration (i.e., flux = f × Cair [ppm], where f is a constant of proportionality and Cair 23 is the 

24 exposure concentration). The ratio of f (rat)/f (human) was determined as given by eq 5-4. This 
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1 ratio was equal to 0.71 and differed from the value of 0.46 used in this document (as presented in 

2 eq 4-5) because Schlosser et al. (2003) used resting inspiratory rates. In the next level of 

3 dosimetric complexity, Schlosser et al. (2003) used DPX as the relevant dosimeter based on 

4 values predicted by PBPK models developed by Conolly et al. (2000). This expressed the local 

5 dose as pmol of formaldehyde equivalents covalently bound to DNA per unit volume of nasal 

6 tissue. Human CFD and PBPK models were exercised to determine the airborne concentration 

7 of formaldehyde that yields average DPX levels equal to those in the rat at the BMC. This 

8 airborne concentration was then the HEC. The human benchmark extrapolations in Schlosser et 

9 al. (2003) using flux and DPX are shown in Table 5-25, located at the end of section 5.4. 

10 The assumption in using DPX data was that lifetime exposure to the same DPX 

11 concentration for a given duration each day leads to equivalent risk across species. Table 5-25 

12 shows their human benchmark calculations for a continuous environmental exposure. These 

13 were exposures that resulted in the same steady-state DPX concentrations as the weekly TWA 

14 DPX values in rats at the rat benchmark exposure concentrations. 

15 

16 5.3.4.2.3. Cell proliferation in CIIT benchmark modeling. 

17 Schlosser et al. (2003) also used cell proliferation as representing the adverse response, 

18 and the BMDs calculated with these data did not differ appreciably from their other benchmark 

19 estimates. The use of cell proliferation as an end point is considered to have the advantage that it 

20 represents an early step contributing to carcinogenesis. In this document, a BMD is not 

21 calculated based solely on cell replication as a response. Instead, cell replication rates are used as 

22 input to the clonal growth model and a BMD based on a fit to the tumor response using that 

23 model is considered a better choice since it integrates cell replication along with other relevant 

24 data, such as the number of cells at risk and DPXs. 

25 

26 5.3.4.3. Kaplan-Meier Adjustment

27 In the simplest consideration of the impact of competing risks on the nasal tumor 

28 incidence, tumor incidences were adjusted for early deaths according to Kaplan-Meier (KM) 

29 survival estimates (KS Crump Group, 2001). This procedure allows for the possibility that some 

30 tumors may otherwise have developed in the animals that died early due to other causes. All the 

31 animals in the study were considered except those that were kept past termination of exposure. A 

32 comparison of the adjusted incidence data is presented below in Table 5-24. While the 

33 adjustments have been provided in Table 5-24, it needs to be noted that the data allow for a full 

34 time-to-tumor analysis as presented below. 

35 
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1 Table 5-24. Formaldehyde-induced rat tumor incidences 

2 

Exposure level (ppm) KM adjusted incidence 

Observed tumors/ 

number at riska

 0.0 0.0 0/242 

 0.7 0.0 0/70 

 2.0 0.0 0/254 

 6.0 0.02 3/120a

10.0 0.61 22/36a

15.0 0.83 157/190a

3 

a

4 KM adjusted. Numbers not indicated by footnote were not amenable to KM 

5 adjustment because there were no tumors; these numbers at risk reflect all animals 

6 surviving 1 year on study. 

7 Source: Monticello et al. (1996); Kerns et al. (1983).

8 5.3.4.4. EPA Time-to-Tumor Statistical Modeling

9 Instead of using the KM adjustment, EPA has used the multistage Weibull time-to-tumor 

10 model (Portier et al., 1986; Krewski et al., 1983) in other assessments (e.g., ethylene oxide, 

11 1,3-butadiene, chloroprene). This is a dose-response model that includes the exact time of 

12 observation of the tumors and therefore gives appropriate weight to the amount of time each 

13 animal was on study without a tumor and acknowledges earlier tumor incidence with increasing 

14 dose level. The data used in this analysis were obtained from the appendix in Conolly et al. 

15 (2003) with one crucial modification. These data combined the nasal squamous carcinoma data 

16 of Kerns et al. (1983) and Monticello et al. (1996) along with results from an additional 

17 94 animals not previously examined in the Monticello et al. (1996) study. Animals in some 

18 exposure groups were held up to 6 months following the 24-month exposure period; these 

19 animals were deleted from the analysis for the following reason: there were no tumors among 

20 these animals, and inclusion of them would have required estimating an equivalent TWA 

21 exposure over the entire study period for these animals (40 in 2 ppm group, 39 in 6 ppm group, 3 

22 in 15 ppm group), whereas the other animals would be represented by their actual exposure 

23 concentrations. 

24 Due to earlier tumor occurrence with increasing exposure level and increased mortality 

25 with increasing exposure level, methods that can reflect the influence of competing risks and 

26 intercurrent mortality on site-specific tumor incidence rates are preferred. EPA has generally 

27 used the multistage Weibull model because it incorporates the time at which death with tumor 

28 occurred, giving appropriate weight to the amount of time each animal was on study without a 

tumor; the model has the following form: P(d) = 1 – exp[–(q0 + q1d + q2d

2

 + ... + qkd

k

) × (t – t0)

z

29 ], 

30 where P(d) represents the lifetime risk (probability) of cancer at dose d (i.e., human equivalent 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 exposure in this case); parameters qi ≥ 0, for i = 0, 1, ..., k; t is the time at which the tumor was 

2 observed; and z is a parameter estimated in fitting the model, which characterizes the change in 

3 response with age. The parameter t0 represents the time between when a potentially fatal tumor 

4 becomes observable and when it causes death. 

5 A further consideration is the distinction between tumor types as being either fatal or 

6 incidental in order to adjust for competing risks. Incidental tumors are those tumors thought not 

7 to have caused the death of an animal (such as those observed during interim or terminal 

8 sacrifices), while fatal tumors are thought to have resulted in animal death. For these data, nasal 

9 tumors observed with early deaths were considered to be fatal. 

10 The dose-response analyses (Figures 5-17, 5-18, 5-19) were conducted by using the 

11 computer software program TOX_RISK, version 5.3 (ICF, Fairfax, VA), which is based on 

12 Weibull models drawn from Krewski et al. (1983). Parameters were estimated by using the 

13 method of MLE. Specific multistage Weibull models were selected for the individual tumor 

14 types for each sex, based on the values of the log likelihoods according to the strategy used by 

EPA (U.S. EPA, 2002b). If twice the difference in log-likelihoods was less than a χ

2 15 with 

16 degrees of freedom equal to the difference in the number of stages included in the models being 

17 compared, the models were considered comparable, and the most parsimonious model (i.e., the 

18 lowest-stage model) was selected contingent on visual fits of the data as follows. For incidental 

19 tumors, plots of model fits compared with Hoel-Walburg estimates of cumulative incidence were 

20 also examined for goodness of fit in the lower exposure region of the observed data (Gart et al., 

21 1986) (Figure 5-18). For fatal tumors, plots of model fits were compared with KM estimates of 

22 cumulative incidence. If a model with one more stage fitted the low-dose data better than the 

23 most parsimonious model, then the model with one higher stage was selected. 

24 Due to the sharp increase in responses between 6 and 10 ppm, no adequate fit was 

25 achieved. Data for the highest dose were dropped in an effort to focus the fitting process for this 

26 empirical model on the low-dose region. The model that then provided the best overall fit 

27 included five stages but with coefficients for the lower stages estimated to be zero (see 

28 Figures 5-17, 5-18, 5-19). The parameter t0 was estimated to be zero, consistent with rapidly 

29 fatal tumors. On the other hand, an alternate run treating all tumors as incidental to the death of 

30 the affected animals yielded BMCLs and BMCs within 10% of these estimates (Figure 5-18); 

31 thus, tumor context is not a sensitive consideration for these data. 

32 For the same reasons as discussed in section 5.3.3 (the concluding discussion of the 

33 BBDR modeling), a linear low-dose extrapolation approach was used to estimate human 

34 carcinogenic risk associated with formaldehyde exposure. PODs for estimating low-dose risk 

35 were identified at doses at the lower end of the observed data, corresponding to 1% extra risk, 
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1 defined as the extra risk over the background tumor rate [P(d) − P(0)]/[1 − P(0)]. PODs 

2 corresponding to 10% extra risk are also provided to facilitate comparison with other chemicals. 

3 Rat benchmark levels obtained by analysis of the tumor data are shown in Table 5-25. PODs 

4 were converted to continuous human-equivalent exposure levels by multiplying by 

5 (5 days/7 days) × (6 hours/24 hours), or 0.178, and by multiplying by the ratio of fluxes 

6 developed in section 5.3.6.1.3. The lifetime continuous inhalation unit risk for humans is defined 

7 as the slope of the line from the lower 95% bound on the exposure at the POD, calculated by 

8 dividing the BMR level (1%) by the corresponding BMCL01. This 95% UCL represents a 

9 plausible upper bound on the true risk. 

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 

13 Figure 5-17. EPA Multistage Weibull modeling: nasal tumor dose response. 

14 

15 Note: Time-to-tumor modeling of Kerns et al. (1983) and Monticello et al. (1996) 

16 data compared with incidences adjusted by using KM estimates evaluated at 

17 104 weeks. 

18 

19 Source: Adapted from Schlosser et al. (2003). 
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1 

2 Figure 5-18. Multistage Weibull model fit. 

3 Note: Data of Kerns et al. (1983) and Monticello et al. (1996) compared with 

4 Hoel-Walburg estimates of tumor incidences occurring at interim and terminal 

5 sacrifices. 

6 

7 

8 

9 

10 Figure 5-19. Multistage Weibull model fit of tumor incidence data compared 

11 with KM estimates of spontaneous tumor incidence. 

12 Source: Developed from data reported in Kerns et al. (1983) and Monticello et al. 

13 (1996). 
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1 The extrapolation to humans in terms of using formaldehyde flux to tissue as the dose 

2 metric is shown in Table 5-25, where unit risk in terms of q1*, the statistical upper bound on the 

3 coefficient of the term linear in dose in the multistage model, is also presented. q1* is presented 

4 even though this is no longer done, as per current EPA practice (see section 5.3.6 for discussion). 

5 These results are to be compared with the preferred benchmark estimates obtained in 

6 Table 5-23 by using the results of biologically based models. In summary, the unit risks obtained 

7 by various methods, including the results in Schlosser et al. (2003), fall within a rather tight 

8 range. In particular, q1* was obtained to within a factor of two of other values even though q1 

9 itself was zero. The large difference between q1 and q1* aptly reflects the large uncertainty in 

10 the low-dose response. 

11 

12 5.4. CONCLUSIONS FROM THE QUANTITATIVE ASSESSMENT OF CANCER RISK 

13 FROM FORMALDEHYDE EXPOSURE BY INHALATION 

14 

15 5.4.1. Inhalation Unit Risk Estimates Based on Human Data

16 As described in section 5.2, a (plausible upper bound) lifetime extra cancer unit risk of 

1.1 × 10–2 per ppm (8.8 × 10–6 per μg/m317 ) of continuous formaldehyde exposure was estimated

18 for NPC incidence using the log-linear modeling results (for NPC mortality from cumulative 

19 exposure) from a high-quality occupational epidemiologic study in a life-table analysis to obtain 

20 a POD and then applying linear low-dose extrapolation from the POD. Using similar methods 

21 and data from the same study for Hodgkin lymphoma and leukemia mortality from cumulative 

formaldehyde exposure, (plausible upper bound) lifetime extra cancer risk estimates of 1.7 × 10–2 22 

per ppm (1.4 × 10–5 per μg/m3) for Hodgkin lymphoma incidence and 5.7 × 10–2 23 per ppm 

(4.6 × 10–5 per μg/m3

24 ) for leukemia incidence were derived. Sources of uncertainty in these 

25 estimates are discussed in sections 5.2.2.4 and 5.2.3.4. For the incidence risk for these three 

cancer types combined, a total (upper bound) cancer unit risk estimate of 8.1 × 10−2 26 per ppm 

(6.6 × 10–5 per μg/m3

27 ) was obtained (section 5.2.4). 

28 

29 5.4.2. Inhalation Unit Risk Estimates Based on Rodent Data

30 As described in section 5.3, the unit risk derived for SCC in the upper and lower 

31 respiratory tract (combined) based on linear extrapolation from PODs from several plausible 

32 models, including purely statistical modeling (nose only, quantal and time-to-tumor modeling) 

and biologically based modeling (entire respiratory tract), resulted in a narrow range of 1.2 × 10−2 33 

to 2.2 × 10–2 34 per ppm. Risk to the lower respiratory tract was numerically insignificant compared 

35 to the nasal cancer risk.
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Table 5-25. Human benchmark extrapolations of nasal tumors in rats by using formaldehyde flux 

Rat benchmark levels 

(ppm) Extrapolated human benchmark levels (ppm) Unit 

Model Source 1% 5% 10% Dose metric

b 1% 5% 10% 1% 

ED 0.75 0.78 0.82 Flux

e

LED 0.71 0.76 0.79 1.4 

×10–2 

ED 0.76 0.79 0.84 

Weibullc,d 

(with 

threshold) 

Schlosser et 

al. (2003) ED 

LED 

5.91 5.58 

6.12 5.94 

6.40 6.22 

DPX

f

LED 0.71 0.76 0.81 1.4 

×10–2 

ED ED 0.35 0.49 0.57 

LED 

4.28 3.57 

5.93 5.52 

6.84 6.41 LED 0.30 0.46 0.53 3.4 

×10–2 

Multistage 

Weibull (timeto-tumor)c,d,g 

EPA (this 

assessment) Flux

h

q1* 

at 1

BBDR models (Table 5-23) EPA (this assessment) See Table 5-23 and associated text 

at 0

Note 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. c

p Value for Weibull model fit = 0.90. For the time-to-tumor modeling, goodness-of-fit 

p value was not provided by software packag

judged by comparing fitted curve to KM survival estimates (see Figure 5-19). 

dFor Weibull model, Schlosser et al. (2003) obtained best fit with a positive intercept on dose axis. For multistage Weibull model, cueHuman benchmark levels extrapolated using flux were multiplied by fHCHO-Rat/fHCHO-Human (= 0.71) for interspecies extrapolation and m

(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 huma

TWA DPX levels in rats at the rat BMCs for 6 hours/day and 5 days/week. 

gP(d,t) = 1 - exp[-(q0 + q1d + q2d

2 + ... + qkd

k)* t

z]. q0, q1, q2, q3, q4 were all taken to be zero. q5 = 2.9 × 10–22, z = 8.1. 

hHuman benchmark levels extrapolated using flux were multiplied by fHCHO-Rat/fHCHO-Human = 0.46 for interspecies extrapolation and mu

to adjust for continuous exposure (see section 5.3.6.2).
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1 5.4.3. Summary of Inhalation Unit Risk Estimates 

2 The epidemiologic and rodent inhalation data indicate multiple sites of concern. Unit risk 

3 estimates calculated separately from these data are presented in Table 5-26. 

4 As can be seen in the summary table (Table 5-26), the unit risk estimate based on human 

5 data for NPC is in the range of the estimates calculated for respiratory tract cancer from the 

6 rodent nasal cancer data. The unit risk estimate for Hodgkin lymphoma is also in the same range, 

7 while the unit risk estimate for leukemia and the total cancer unit risk estimate are up to fourfold 

8 higher. 

9 

10 Table 5-26. Summary of inhalation unit risk estimates 

11 

Cancer typea 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 riskb Cumulative exposure 0.081 

Based on experimental animal data 

SCC of the respiratory 

tract 

Local dose (flux) of 

formaldehyde in pmol/mm2

-

hour 

0.011 – 0.022 

12 

a

13 The unit risk estimates are all for cancer incidence. 

b

14 The total cancer unit risk estimate is an estimate of the upper bound on the sum of risk estimates calculated 

15 for the 3 individual cancer types (nasopharyngeal cancer, Hodgkin lymphoma, and leukemia); it is not the 

16 sum of the individual (upper bound) unit risk estimates (see Section 5.2.4). 

17 

18 

19 As noted in EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), when 

20 high-quality human data are available, they are generally preferred over laboratory animal data 

21 for quantitative risk assessment. Thus, the preferred (plausible upper bound) unit risk estimate in 

this assessment is the value of 8.1 × 10–2 per ppm (6.6 × 10–5 per μg/m322 ) based on human data for 

23 NPC, Hodgkin lymphoma, and leukemia. 

24 As documented in section 4.5, formaldehyde is a mutagenic 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 adequate chemical-specific data to evaluate the 
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susceptibilities of different life stages by the inhalation route of exposure14 1 , increased early-life 

2 susceptibility should be assumed, and, if there is early-life exposure, the ADAFs should be 

3 applied, in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from 

4 Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 below for more 

5 details on the application of the ADAFs. 

6 

7 5.4.4. Application of Age-Dependent Adjustment Factors (ADAFs) 

8 When there is sufficient weight of evidence to conclude that a mutagenic MOA is 

9 operative in a chemical's carcinogenicity and there are inadequate chemical-specific data to 

10 assess age-specific susceptibility, as is the case for formaldehyde (by inhalation exposure; see 

11 section 5.4.3), U.S. EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 

12 Exposure to Carcinogens (U.S. EPA, 2005b) recommends the application of default ADAFs to 

13 adjust for potential increased susceptibility from early-life exposure (see U.S. EPA [2005b] for 

14 detailed information on the general application of these adjustment factors). In brief, U.S. EPA 

15 (2005b) establishes ADAFs for three specific age groups: 10 (for <2 years), 3 (for 2 to 

16 <16 years), and 1 (for 16 years and above). For risk assessments based on specific exposure 

17 assessments, the 10-fold and threefold adjustments to the unit risk estimates are to be combined 

18 with age-specific exposure estimates when estimating cancer risks from early-life (<16 years age) 

19 exposure. The ADAFs and their age groups may be revised over time. The most current 

20 information on the application of ADAFs for cancer risk assessment can be found at 

21 www.epa.gov/cancerguidelines. 

22 For inhalation exposures, assuming ppm equivalence across age groups (i.e., equivalent 

23 risk from equivalent exposure levels, independent of body size) and using the preferred unit risk 

estimate of 6.6 × 10–5 per μg/m3

24 from section 5.4.3, the calculation is fairly straightforward. The 

25 ADAF-adjusted lifetime total cancer unit risk estimate is calculated as shown in Table 5-27: 

26 

27 

28 

29 

30 

 

14 The oral exposure bioassay of Soffritti et al. (1989) provides evidence of increased early-life susceptibility for 

carcinogenicity at the portal of entry (i.e., gastrointestinal tract cancers), but it is unclear how to extrapolate the 

increased susceptibility quantitatively to portal-of-entry cancers from inhalation exposures. There was no apparent 

increased early-life susceptibility for hemolymphoreticular cancers; however, there are unresolved discrepancies 

between the Soffritti et al. (1989) and the Soffritti et al. (2002) reportings of the hemolymphoreticular cancer results 

for the adult-only exposure component of the study which make interpretation of all of the hemolymphoreticular 

cancer results from the Soffritti et al. (1989) paper uncertain (see Section 4.5). 
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1 Table 5-27. Total cancer risk from exposure to a constant formaldehyde 

exposure level of 1 μg/m32 from ages 0–70 years 

3 

Age group ADAF 

Unit risk 

(per μg/m3) 

Exposure 

concentration 

(μg/m3) 

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 

5 (Note that the partial risk for each age group is the product of the values in columns 2–5 [e.g., 

10 × (6.6 × 10–5) × 1 × 2/70 = 1.9 × 10–5 6 ], and the total risk is the sum of the partial risks. This 70-year risk 

estimate for a constant exposure of 1 μg/m37 is equivalent to a lifetime unit risk of 

1.1 × 10–4 per μg/m38 , adjusted for early-life susceptibility, assuming a 70-year lifetime and constant exposure 

9 across age groups.) 

10 

11 

12 In addition to the uncertainties discussed above for the inhalation unit risk estimate, there 

13 are uncertainties in the application of ADAFs to adjust for potential increased early-life 

14 susceptibility. The ADAFs are general default factors, and it is uncertain to what extent they 

15 reflect increased early-life susceptibility for exposure to formaldehyde, if, in fact, early-life 

16 susceptibility is increased as assumed. To some extent, the unit risk estimates for Hodgkin 

17 lymphoma and leukemia already reflect some partial risk from early-life exposure because the 

18 life-table programs include background rates for childhood cancers. However, the impact of this 

19 partial risk is negligible compared to the effect of the ADAFs on the final risk estimate. For 

20 example, eliminating the background rates up to age 16 from the life-table programs decreases 

21 the lifetime extra risks at the PODs by about 0.5% for leukemia and about 1.2% for Hodgkin 

22 lymphoma. The ADAFs, on the other hand, increased the lifetime unit risk estimate by about 

23 66%. 

24 

25 5.4.5 Conclusions: Cancer Inhalation Unit Risk Estimates 

26 As presented in section 5.4.3, the preferred (plausible upper bound) cancer unit risk 

27 estimate for formaldehyde exposure in this assessment is the total cancer risk estimate of 

8.1 × 10–2 per ppm (6.6 × 10–5 per μg/m328 ) based on (adult) human data for NPC, Hodgkin 

29 lymphoma, and leukemia. 
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1 In addition, as described in section 5.4.4, because the weight of evidence suggests that 

2 formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA and there 

3 are inadequate chemical-specific data to assess age-specific susceptibility, increased early-life 

4 susceptibility should be assumed and, if there is early-life exposure, ADAFs should be applied, in 

5 accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 

6 Exposure to Carcinogens (U.S. EPA, 2005b). Consequently, applying the ADAFs to the 

7 preferred unit risk estimate to obtain a full lifetime unit risk estimate yields 

8 

9 0.081/ppm × [(10 × 2 years/70 years) + (3 × 14/70) + (1 × 54/70)] 

= 0.13/ppm = 1.1 × 10–4/(μg/m310 )

11 

12 Using the above full lifetime unit risk estimate of 0.13 per ppm, the lifetime chronic 

exposure level of formaldehyde corresponding to an increased cancer risk of 10–6 13 can be 

estimated as follows: (10–6)/(0.13/ppm) = 7.7 × 10–6 ppm = 0.008 ppb = 0.009 μg/m314 . Similarly, 

15 the lifetime chronic exposure level of formaldehyde corresponding to an increased cancer risk of 

10–4 is 0.8 ppb, or 0.9 μg/m316 . (Note that for less-than-lifetime exposures scenarios [or for 

17 exposures that vary with age], the adult-based combined estimate of 0.081 per ppm should be 

18 used, but if there is early-life exposure, the ADAFs should be applied in accordance with EPA’s 

19 Supplemental Guidance [see section 5.4.4]). 

20 
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1 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND 

2 DOSE-RESPONSE 

3 

4 

5 6.1 SUMMARY OF HUMAN HAZARD POTENTIAL 

6 6.1.1 Exposure 

7 Formaldehyde (CH2O) occurs as a gas at room temperature. It is highly reactive and 

8 dissolves readily in water. Formaldehyde is present in a wide variety of products including 

9 plywood adhesives, abrasive materials, insulation, insecticides and embalming fluids (IPCS, 

10 2002a; Agency for Toxic Substances and Disease Registry [ATSDR], 1999). The major sources 

11 of anthropogenic emissions of formaldehyde are motor vehicle exhaust, power plants, 

12 manufacturing plants that produce or use formaldehydes or substances that contain formaldehyde 

13 (i.e., glues), petroleum refineries, coking operations, incineration, wood burning, and tobacco 

14 smoke (INEG, 2003). Reported outdoor air concentrations of formaldehyde in urban and 

suburban areas are near 3 μg/m315 (~ 3 ppb) (U.S. EPA, 2008) and indoor residential levels are 

16 approximately 10 times higher (Health Canada and Environment Canada, 2001). 

17 Limited U.S. data indicate that the upper end of the formaldehyde concentration range in 

18 drinking water is approximately 10 μg/L IPCS, 2002a). Formaldehyde is a natural component of 

19 a variety of foodstuffs (IARC, 1995; IPCS, 1989). In addition, foods may also be contaminated 

20 with formaldehyde as a result of fumigation (e.g., grain, seeds), cooking (as a combustion 

21 product), and release from formaldehyde resin-based tableware (IARC, 1995). Limited data 

22 measuring formaldehyde in food indicates that the concentration range is <0.03–14 mg/kg Health 

23 Canada and Environment Canada, 2001). Daily intake of formaldehyde has been estimated to be 

24 between 1.5 and 14 mg/day for an average adult (IPCS, 1989; Fishbein, 1992). 

25 

26 6.1.2 Absorption, Distribution, Metabolism, and Excretion

27 In water, less than 0.1% of formaldehyde exists unhydrated, with the majority reported to 

28 be in the hydrated form, methylene glycol (CH2(OH)2) (Priha et al., 1996). Formaldehyde is a 

29 reactive molecule that can react with both low molecular weight cellular components (e.g., GSH) 

30 as well as high molecular weight components. It is also a well-known cross-linking agent. 

31 Further, formaldehyde is a product of normal cellular metabolic processes. Endogenous 

32 formaldehyde is a constituent of the one-carbon pool. It is thought that most endogenous 

33 formaldehyde exists in a form that is reversibly bound to nucleophiles (Heck et al., 1990; 1982) 

34 and that the formaldehyde hemithioacetal adduct formed with glutathione could account for 50–

35 80% of the total formaldehyde normally present in cells (Heck et al., 1982). 
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1 Inhaled formaldehyde is efficiently absorbed (“scrubbed”) in the upper respiratory tract. 

2 The fraction that is absorbed was determined to be approximately 97% in rats (Morgan et al., 

3 1986), and 85% and 90% respectively in computer simulations of one rhesus monkey and human 

4 at rest (Kepler et al., 1998; Kimbell et al., 2001). As the inspiratory rate increased, formaldehyde 

5 decreased to about 70% during light exercise and to 58% during heavy exercise conditions in the 

6 human. During heavy exercise, the absorption of formaldehyde in the first six to eight 

7 generations of the tracheobronchial airways is estimated to be comparable to that in the nasal 

8 region (Overton et al., 2001). 

9 Airway geometry is an important determinant of inhaled-formaldehyde dosimetry in the 

10 respiratory tract. There are large differences across species in the anatomy of the upper 

11 respiratory tract and in airflow patterns. Using computer simulation, the regional uptake patterns 

12 of formaldehyde in the upper respiratory tract are observed to be spatially non-homogenous and 

13 to exhibit strong species differences. Airflow patterns are also significantly different as breathing

14 patterns and activity profiles change, depending on whether breathing is oral or nasal. 

15 The overall information on the disposition of inhaled formaldehyde comes from many 

studies using different experimental methods including: [14 16 C] radiolabeling, gas chromatographymass spectroscopy (GC-MS), dual isotope labeling (3H, 14 17 C) and high-performance liquid 

18 chromatography (HPLC) studies. In a study of rats following exposure to radiolabeled 

19 formaldehyde, the radioactivity was very high in the nasal mucosa but was also extensively 

distributed to various tissues including the bone marrow (Heck et al., 1983). The elevated 14 20 C in 

21 various tissues was thought unlikely to be due to free formaldehyde but instead to arise from 

22 either rapid metabolic incorporation or formation of covalent adducts or incorporation via 

carboxylation reactions of the 14 23 CO2 formed during metabolism (Heck et al., 1983; Casanova24 Schmitz et al., 1984). Studies using the GC-MS method indicate that exposure to formaldehyde 

25 over a wide range of exposure concentrations and durations does not result in elevated levels in 

26 blood, above those of endogenous formaldehyde levels in rats, rhesus monkeys and humans 

27 (Heck et al., 1985; Casanova et al., 1998). These GC-MS measurements are consistent with the 

28 conclusions that formaldehyde does not appreciably reach the blood, is rapidly metabolized, 

29 interacts with macromolecules when it escapes metabolism, or is otherwise undetected. 

30 In further studies on the disposition of inhaled formaldehyde, Casanova-Schmitz et al. 

31 (1984) and Casanova-Schmitz and Heck (1983) used dual-isotope labeling of inhaled 

32 formaldehyde as an approach to distinguish between formaldehyde adduct formation and 

33 metabolic incorporation. These were followed by more sensitive experiments using HPLC 

34 measurements in rats and rhesus monkeys exposed to radiolabeled formaldehyde (Casanova et al. 

35 1989, 1991). Results from this sets of experiments found that labeling in the nasal mucosa was 
This document is a draft for review purposes only and does not constitute Agency policy.

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1 due to both covalent binding and metabolic incorporation and labeling of bone marrow 

2 macromolecules was found to be entirely due to metabolic incorporation. Overall, Heck, 

3 Casanova-Schmitz, and their coworkers interpreted the results of these experiments to indicate 

4 that inhaled formaldehyde does not reach distant sites (beyond the portal of entry) at detectable 

5 levels. 

6 Formaldehyde is primarily metabolized by glutathione-dependent formaldehyde 

7 dehydrogenase. In humans this enzyme is referred to using the protein code of ADH3. The 

8 major factor in the disposition of formaldehyde is metabolic clearance by oxidation to formate, 

9 which is either further metabolized to CO2 and water, incorporated into the one-carbon pool, 

10 and/or eliminated in the urine as a sodium salt. 

11 In radiolabeling studies, Heck et al. (1983) determined that the relative contributions of 

12 various excretion pathways in F344 rats following inhalation exposure to formaldehyde were 

independent of exposure concentration. Nearly 40% of inhaled [14 13 C]-formaldehyde appeared to 

14 be eliminated via expiration, presumably as CO2, while about 17% and 5% was eliminated in the 

urine and feces, respectively. Nearly 40% of inhaled [14 15 C]-formaldehyde remained in the 

16 carcass, presumably due to metabolic incorporation. For exposure via the oral route, absorption 

of [14C]-formaldehyde (7 mg/kg) in rats resulted in 40% exhaled (as 14 17 CO2), 10% excreted in 

18 urine, 1% excreted in feces, and much of the remaining 49% retained within the carcass, 

19 presumably due to metabolic incorporation (IARC, 1995; Buss et al., 1964). 

20 Several human and animal studies have attempted to measure the concentration of 

21 formaldehyde in exhaled breath (see section 3.5.2). None of the human studies investigated 

22 whether there is any correlation between exhaled formaldehyde levels and food intake, life stage, 

23 smoking, or health status. Additionally, they were not designed to distinguish between 

24 exogenous (room air) and endogenous (systemic) formaldehyde in exhaled breath. In order to 

25 discern whether endogenous formaldehyde is excreted into the lungs, human subjects must 

26 breathe formaldehyde-free air. Because subjects were breathing room air, which contained 9-10 

27 ppb formaldehyde in two studies and unspecified concentrations in two other studies, there is no 

28 way of knowing whether there was any endogenous formaldehyde in their exhaled breath. This 

29 assessment identifies a critical research need for further studies on the measurement of exhaled 

30 formaldehyde. 

31 The most informative study, performed by Cáp et al. (2008), demonstrated that subjects 

32 breathing room air containing 9.6 ±1.5 ppb formaldehyde exhaled a mean formaldehyde 

33 concentration of 2 ppb. This suggests that a substantial portion of inhaled formaldehyde, which 

34 is highly reactive, was retained in the respiratory tract and not exhaled. It is impossible to tell 

35 whether any portion of the 2 ppb in exhaled breath was of endogenous origin. In this and other 
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1 human studies, there was no adjustment for an artifact in the analytical method that makes it 

2 impossible to distinguish between formaldehyde and reaction products for 1% of exhaled 

3 methanol and ethanol because they have the same mass to charge ratio (m/z = 31). In fact, the 

4 concentration of methanol and ethanol that is misidentified as formaldehyde exceeds the reported 

5 concentrations of exhaled formaldehyde. Thus, it is highly likely that the actual exhaled 

6 formaldehyde concentration in Cáp et al. (2008) was significantly lower than 2 ppb, and that 

7 there was little or no endogenous formaldehyde in the exhaled breath. This would be consistent 

8 with an animal study in which Mashford and Jones (1982) detected no exhaled formaldehyde in 

rats injected I.P. with 40 mg/kg [14 9 C]-formaldehyde. In summary, there are insufficient data at 

10 this time to confidently establish a concentration of formaldehyde in exhaled breath that can be 

11 attributed to endogenous sources. 

12 

13 6.1.3 Noncancer Health Effects in Humans and Laboratory Animals 

14 A wide variety of human and animal studies provide evidence for health effects in 

15 response to formaldehyde exposure. Some of these health effects are commonly noted at the 

16 portal of entry, as expected for exposure to a reactive gas. In addition, effects on the nervous and 

17 reproductive systems, developmental effects, and immunomodulation have been reported. The 

18 overall weight of evidence (WOE) of human and animal studies for the hazard potential of 

19 formaldehyde is discussed below, along with information on plausible modes of action (MOAs). 

20 

21 6.1.3.1. Sensory Irritation 

22 Formaldehyde, a chemical irritant, binds to protein receptors of the trigeminal nerve, 

23 triggering a burning and painful sensation in humans. This process is distinct from taste and 

24 smell (Nielsen 1991; Cometto-Muniz and Cain, 1992). The trigeminal nerve, which has three 

25 branches (ophthalmic, maxillary and mandibular), not only acts as an afferent nerve relaying 

26 these sensations to the central nervous system, but also has efferent nerve activity (Stedman’s 

27 Medical Dictionary: Meggs, 1993). Stimulation of the trigeminal nerve may result in reflex 

28 responses including lacrimation, coughing, and sneezing. Both the reflex responses as well as 

29 sensations such as burning, pain, and itching of the eyes, nose, and throat are considered adverse. 

30 Formaldehyde-induced eye, nose, and throat irritation has been well documented in a 

31 wide range of epidemiologic studies. Common effects of chemically-induced sensory irritation 

32 include lacrimation, burning of the eyes and nose, rhinitis, burning of the throat, and cough 

33 (Feron et al., 2001). Studies examining these endpoints were either controlled chamber studies 

34 with a defined population (e.g., healthy volunteers or sensitive individuals), worker/student 

35 studies, or general population studies (e.g., residential). Chamber studies, by design, are acute 
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1 studies, although some researchers have investigated the outcomes after repeated exposures. 

2 Occupational, student, and residential exposures are generally of longer duration, although there 

3 is variability in exposure level and duration among subjects. The endpoints for assessing 

4 irritation include self-reporting of symptoms (e.g., pain, burning, itching) and objective measures 

5 of irritation (e.g., eye-blink counts, lacrimation). 

6 Eye irritation is the most sensitive of reported effects in human studies. Two different 

7 short-term chamber studies provide similar 10% BMDLs for eye irritation of 560 ppb and 240 

8 ppb for 3 and 5 hour exposures, respectively (Kulle, 1993; Andersen and Molhave, 1983, 

9 modeled by Arts et al., 2006b). Various occupational studies have noted increased eye irritation 

10 for average exposures ranging from 180 ppb to 690 ppb (Horvath et al., 1988, Alexandersson and 

11 Hedenstiera, 1998; Holmstrom and Wilhelmsson, 1988). The results of residential studies, 

12 where in-home formaldehyde levels are used to document exposure, indicate eye irritation may 

13 increase with increasing exposure from 70 to 200 ppb for these chronic exposure scenarios 

14 (Ritchie and Lehnen, 1987, Hanrahan et al., 1984; Liu et al., 1991.) 

15 When a rodent is exposed to an irritant, the inhaled dose and pattern of deposition can be 

16 profoundly affected by reflex bradypnea, a protective reflex observed in rodents but not in 

17 humans. Reflex bradypnea is manifest as markedly decreased activity or prostration, reduced 

18 metabolism, hypothermia (as much as 5oC), significantly reduced respiratory rate and minute 

19 volume, and altered blood and brain chemistry. Reflex bradypnea can occur when the trigeminal 

20 nerve is exposed to a sufficient concentration of an irritant, such as formaldehyde. Because of 

21 their small size, rodents are able to rapidly lower their metabolism and body temperature and 

22 therefore their oxygen demand. The consequence is that their inhaled dose of an irritating 

23 chemical is dramatically lowered. Reflex bradypnea is quantified as the RD50, which is the 

24 concentration of a chemical that results in a 50% decrease in respiratory rate (Tables 4-7 and 

25 4-8). After the irritant exposure is removed, it can take up to two hours for rodents to fully 

26 recover from the effects of reflex bradypnea. Even though humans do not exhibit reflex 

27 bradypnea, involvement of trigeminal nerve stimulation, which is the mechanism for reflex 

28 bradypnea in rodents, may be relevant to MOAs for formaldehyde in other species, such as 

29 primates and humans. For example, trigeminal nerve stimulation has been associated with 

30 sensory irritation in humans, highlighting the relevance of this effect. 

31 

32 6.1.3.2. Respiratory Tract Pathology 

33 Formaldehyde-induced respiratory tract pathology includes inflammation, rhinitis, goblet 

34 cell hyperplasia, metaplastic changes, squamous cell hyperplasia, and impaired mucociliary 

35 transport. Formaldehyde binding to the trigeminal nerve triggers the release of neurogenic 
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1 mediators of inflammation resulting in tissue edema, lacrimation, mucus production, and 

2 leukocyte infiltration. Therefore, observed pathological changes may be directly related to 

3 neurogenic inflammation from activation of the trigeminal nerve or result, at least in part, from 

4 formaldehyde-induced cell damage to the mucosal tissue. A series of exposures has also been 

5 positively associated with reduced mucociliary clearance, and the induction of histopathologic 

6 lesions in the nose in both human and animal studies assessing formaldehyde-induced changes in 

7 the nasal mucosa suggest that these changes may be, at least in part, a protective or adaptive 

8 response and that increased mucus flow and metaplastic changes would progress in relation to 

9 the concentration and duration of exposure protecting the underlying tissue (Swenberg et al., 

10 1983). 

11 In rodent studies, formaldehyde-induced histopathological lesions ranging from 

12 inflammation to ulceration, necrosis, and metaplasia have been frequently reported in nasal 

13 turbinates, maxilloturbinates, and in goblet and microvilli cells (e.g., Bhalla et al., 1991; 

14 Monteiro-Riviere and Popp, 1986; Cassee and Feron, 1994; Ionescu et al., 1978; Schreibner et 

15 al.,1979; Monticello et al., 1989). These effects were observed after a variety of exposure 

16 scenarios (e.g., 10 ppm for 4 hrs (Bhalla et al., 1991), 0.5 or 2 ppm for 6 hrs/day for 1 or 4 days 

17 and 6 or 15 ppm for 6 hrs/day for 1 or 2 days (Monteiro-Riviere and Popp, 1986), 3.6 ppm 

18 intermittently for 3 days (Cassee and Feron, 1994), 3% aerosols of formaldehyde for 3 hrs/day for 

19 50 days (Ionescu et al., 1978)). The progressive pathology of the nasal passages from 

20 formaldehyde inhalation exposure is dependent on increasing concentration and duration of 

21 exposure, as well as from proximal to distal regions of the nasal cavity. For example, some 

22 lesions may be transient (e.g., low-exposure cell proliferation), while others may have a 

23 maximum response and be irreversible (e.g., rhinitis). The nasal epithelium responds with both 

24 adaptive and adverse epithelial changes. As respiratory epithelium transitions to squamous 

25 metaplasia, the effective tissue dose of formaldehyde increases posterior to these lesions. As 

26 epithelial barriers degrade (e.g., squamous metaplasia, keratinization), formaldehyde penetrates 

27 more deeply into the nasal passages. Therefore, the relationship between concentration and 

28 duration of exposure and health outcomes has been difficult to define and, in fact, may be 

29 different for various health effects. Formaldehyde-related histopathological lesions of the nasal 

30 mucosa have been observed at concentrations as low as 2 ppm for chronic exposure and after a 

31 duration as short as 6 hrs at higher concentrations (e.g., 6 ppm) (Table 4-32, table 4-38). 

32 Similar pathology has been reported for workers exposed to formaldehyde, including loss 

33 of cilia, goblet cell hyperplasia, and cuboidal and squamous cell metaplasia and dysplasia, and 

34 these pathology scores were significantly elevated in workers over controls (Holmström and 

35 Wilhelmsson, 1988; Edling et al., 1988; and Boysen et al., 1990). Holmström and Wilhelmsson 
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1 (1988) reported associations between the mean daily exposure of 240 ppb (8hr TWA) and these 

2 changes. Edling et al. (1988) reported that workers experienced a range of exposures (80-900 

3 ppb), with peak exposures of 4000 ppb. Boysen et al. (1990) provided a range of estimated 

4 exposures from 500 ppb to more than 2000 ppb for workers with elevated mean pathology 

5 scores. One controlled chamber study indicated formaldehyde-induced inflammatory changes 

6 which persisted for 18 hours in adults exposed at 400 ppb for only 2 hours (Pazdrak et al., 

7 1993)). 

8 Short-term formaldehyde exposure also impairs the function of the mucociliary apparatus 

9 which is a critical defensive barrier for the upper respiratory tract. Numerous laboratory animal 

10 studies have reported impaired mucociliary clearance activity associated with formaldehyde 

11 exposures as low as 500 ppb (Table 4-10). Low-concentration or short-term exposures first lead 

12 to an increased rate of ciliary beat, followed by impaired mucus flow, with slowed rate of ciliary 

13 beat and eventual mucostasis (lack of mucus flow) and ciliastasis (lack of ciliary beat) occurring 

14 at higher doses or longer exposure times. These effects have been shown to be both 

15 concentration- and duration-dependent and to occur within 15 minutes after the initial exposure. 

16 Morgan et al. (1983c) suggested that the initial stimulation of ciliary activity may be a defensive 

17 response to the irritant gas, at which time some penetration of formaldehyde to the underlying 

18 epithelial cells may occur. Later effects of mucostasis and ciliastasis may occur as a result of 

19 formaldehyde-induced glycoprotein cross-links, creating a rigid mucus that effectively stops 

20 mucus flow. 

21 Formaldehyde-induced cell proliferation has been demonstrated in nasal epithelium in 

22 animal studies after a range of exposure conditions (e.g. Swenberg et al., 1986; Cassee and 

23 Feron, 1994; Reuzel et al., 1990; Woutersen et al., 1987) (Table 4-43). Formaldehyde-induced 

24 histopathology and mitogenesis may occur as a direct effect of exposure (Tyihak et al., 2001) or 

25 as a secondary effect resulting from adaptive responses and/or compensatory tissue repair that 

26 can occur after formaldehyde exposure (Swenberg, 1983). In a study of Rhesus monkeys 

27 Monticello et al. (1996) noted that increased cell proliferation was seen in locations with minimal 

28 histological changes in the respiratory tract indicating that cell proliferation may be a more 

29 sensitive predictor of more severe health effects due to formaldehyde exposure. Cellular 

30 proliferative responses may initiate lesion formation. A number of studies illustrate that the 

31 duration of repeated exposures may be an important determinant of cell proliferation rates 

32 (Wilmer et al., 1987; Swenberg et al., 1986). Reduced mucociliary clearance and the induction 

33 of histopathologic lesions in the nose effects have been noted in human formaldehyde studies. 
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1 Histopathological lesions and biochemical changes have been reported in the lung 

2 following formaldehyde inhalation exposure in experimental animal studies (Kamata et al., 

3 1996a; Ionescu et al., 1978) following high exposure levels (128.4 or 294.5 ppm formaldehyde). 

4 6.1.3.3. Effects on Pulmonary Function 

5 The potential of formaldehyde exposure to cause pulmonary functional deficits in humans 

6 has been examined on several time scales. The epidemiologic literature includes studies of acute 

7 exposures among naïvely exposed anatomy graduate students (Kriebel et al., 1993; 2001), 

8 anatomy graduate students with several weeks of episodic exposure (Kriebel et al., 1993), and 

9 post-shift versus pre-shift worker pulmonary function among those with regular occupational 

10 exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1982; 

11 Alexandersson and Hedenstierna, 1989). Depending on whether the exposures are naïve or not, 

12 the epidemiologic studies that assessed the pulmonary effects after acute exposures to 

13 formaldehyde are assessing different biological responses, namely, the acute effect alone or the 

14 acute effect(s) in people who may have already been sensitized to different and unknown 

15 degrees.

16 The observed effects in the previously unexposed anatomy students provide additional 

17 information on acute exposures in two naïve populations (Kriebel et al., 1993; 2001), as well as 

18 insight into the possible intermediate stages of sensitization (Kriebel et al., 1993). Kriebel and 

19 colleagues (1993) examined the pre-laboratory and post-laboratory peak expiratory flow (PEF) in 

20 students attending anatomy classes once a week. They found the strongest pulmonary response 

21 when examining the average cross-laboratory decrement in peak expiratory flow in the first 2 

22 weeks of the study when formaldehyde concentrations collected in the breathing zones had a 

23 geometric average concentration of 0.73 ppm. Overall, the students exhibited a 2% decrement in 

24 PEF, while the students with any history of asthma showed a 7.3% decrement in PEF. These 

25 findings of acute decreases in PEF following students’ initial formaldehyde exposure were 

26 corroborated by the Kriebel et al. (2001) study, using a similar study design applied to a separate 

27 class of anatomy students. Similar findings have been reported for low-level residential 

28 formaldehyde exposure including decreased peak expiratory flow rates (PEFRs) (Krzyzanowski 

29 et al., 1990). Workers chronically exposed to formaldehyde have exhibited signs of reduced lung 

30 function consistent with bronchial constriction, inflammation, or chronic obstructive lung 

31 disease. Lung function deficits have been reported both in pre-shift versus post-shift 

32 measurements and as a result of chronic exposures (Malaka and Kodama, 1990; Herbert et al., 

33 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and Hedenatiena 

34 1989). Decreases in spirometric values, including vital capacity (VC), forced expiratory volume 

35 (FEV), forced vital capacity (FVC) and FEV/FVC have been reported in humans. Chronic 
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1 studies also reported increased respiratory symptoms such as cough, increased phlegm, asthma, 

2 chest tightness and chest colds in exposed workers (Malaka et al., 1990; Herbet et al., 1994; 

3 Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and Hedenatiena 1989). 

4 Similar findings have been reported following low-level residential formaldehyde exposure 

5 including decreased PEFRs (Krzyzanowski et al., 1990). 

6 Worker exposures associated with cross-shift differences in spirometric values are 

7 consistent with formaldehyde-induced sensory irritation. Concordance has also been reported 

8 between subjective irritant response and measured changes in pulmonary function further 

9 supporting the possibility that cross-shift and short-term evidence of bronchial constriction may 

10 be a reflexive response to sensory irritation. 

11 A well-conducted residential epidemiology study by Krzyzanowski et al. (1990) was 

12 considered to be the strongest among the candidate studies on the adverse pulmonary function 

13 effects of formaldehyde for the purposes of deriving an RfC. 

14 

15 6.1.3.4. Asthmatic Responses and Increased Atopic Symptoms 

16 The health effects of respiratory function, asthma and increased atopic response, have 

17 been shown to be clinically related. For example, asthma affects pulmonary function and may be 

18 triggered by an allergic response. These and other data suggest that there may be mechanistic 

19 links between these two health effects. Formaldehyde-induced sensitization (Section 4.2.1.5) 

20 may enhance the asthmatic response or may enhance an individual’s response to an allergen 

21 (Section 4.4). In both cases, sensitization results in phenotypic switching – or an individual 

22 exhibiting clinical symptoms of a predisposition to asthma or atopy. Because of the connection 

23 between the two endpoints, they are considered together herein. 

24 Several cross-sectional studies have described a positive association between 

25 formaldehyde concentration and asthma prevalence. A study on risk factors for the initial 

26 physician diagnosis of asthma have shown concentration-dependent associations between 

27 formaldehyde exposure and asthma (Rumchev et al., 2002). In a categorical analysis, Rumchev 

28 et al. (2002) observed statistically significant effects above in-home formaldehyde concentrations 

of 60 μg/m3

, with increased but non-significant effects at 50-59 μg/m3 29 that were consistent with a 

30 concentration-response relationship. No effect was apparent at concentrations in the next lower 

interval between 30-49 μg/m331 . Garrett et al. (1999) reported a borderline statistically significant 

32 association between bedroom formaldehyde concentrations and an increased risk of atopy. The 

33 authors computed a respiratory symptom score for each child based on the frequency of each of 

34 eight respiratory symptoms and this score was substantially and statistically significantly higher 

35 among the asthmatic children compared to non-asthmatic children. Health effects were reported 
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at formaldehyde concentrations greater than 50 μg/m31 but the lowest formaldehyde concentration 

interval at which health effects were observed was 20-50 μg/m3

2 . The findings of Garrett et al. 

3 (1999) are supported by the results of a chamber study reported by Casset et al. (2006) of 19 

sensitized adult asthmatics exposed to formaldehyde at a concentration of 100 μg/m3

4 for 30 

5 minutes. Casset and colleagues observed an increased bronchial responsiveness to mite allergen 

6 exposure (p = 0.05) and noted the provocative dose (PD20 for FEV1) for mite allergen was 34.3 

7 ng after formaldehyde exposure and 45.4 ng after air exposure. However, in study by Ezratty et 

al. (2007) exposure to 500 μg/m3

8 formaldehyde did not affect an allergen-induced increase in 

9 responsiveness to methacholine (p = 0.42) and there was no formaldehyde-associated effect on 

10 the airway inflammatory response. 

11 These observed health effects in humans are similar to the outcome of studies in 

12 laboratory animals that show that formaldehyde can exacerbate existing immunogenic 

13 hypersensitivity to known allergens (Sadakane et al., 2002; Tarkowski and Gorski, 1995; Riedel 

14 et al., 1996). While potentiation varied based on sensitization protocols and formaldehyde 

15 exposure regimens, the results support the finding that formaldehyde exposure can aggravate a 

16 Type-I hypersensitivity response and may do so via a neurogenically initiated response. 

17 Formaldehyde itself does not function as an allergen recognized by the immune system (Lee et 

18 al., 1984) and does not appear to trigger formation of formaldehyde-specific IgE. Although 

19 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 

20 experimental systems (Fujimaki et al., 2004a; Ohtsuka et al., 2003), these effects do not support 

21 an immunogenically mediated type-I hypersensitivity. In studies in which either egg protein 

22 (ovalbumin, OVA)-sensitized or dust mite (DerF)-sensitized animals were exposed to 

23 formaldehyde, OVA-specific and DerF-specific antibody production was increased over 

24 sensitization alone, suggesting that formaldehyde may potentiate sensitization responses (Riedel 

25 et al., 1996; Sadakane et al., 2002). Formaldehyde-induced sensitivity responses may be 

26 neurogenic in origin based on findings that neurogenic factors such as nerve growth factor (NGF) 

27 and substance P were associated with formaldehyde exposure in sensitization protocols 

28 (Fujimaki et al., 2004). 

29 

30 6.1.3.5. Effects on the Immune System 

31 Formaldehyde-induced systemic immunomodulation in laboratory animals has been 

32 documented in the literature (Leach et al., 1983; Dean et al. 1984; Adams et al., 1987). A 

33 number of studies have evaluated the ability of formaldehyde to induce systemic immunotoxic 

34 effects in humans (Ohtani et al., 2004a, b; Erdei et al., 2003; Thrasher et al., 1990, 1987; Pross et 

35 al., 1987). Some studies have reported altered innate immune responses associated with 
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1 formaldehyde exposure (Erdei et al., 2003), while others have noted adaptive immune response 

2 suppression associated with formaldehyde exposure (Thrasher et al., 1990, 1987) and changes 

3 associated with alterations to a predominant T—lymphocyte helper 2 (Th2) pattern (Ohtani et al., 

4 2004a, b). In contrast, Pross et al. (1987) did not observe formaldehyde-associated changes in 

5 systemic immune function. 

6 Diverse studies have investigated the possibility that formaldehyde exposure leads to 

7 increased respiratory tract infections (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness 

8 and Nethercott, 1989). Lyapina et al. (2004) reported increased respiratory tract infections and 

9 decreased neutrophil respiratory burst activity in formaldehyde-exposed workers (at 722 ppb 

10 TWA). Incidences of doctor-diagnosed chronic bronchitis were more prevalent in children under 

11 age 15 living in homes with higher formaldehyde (>60 ppb) readings in the kitchen (p < 0.001) 

12 (Krzyzanowski et al., 1990). Holness and Nethercott (1989) also report increased chronic 

13 bronchitis in formaldehyde-exposed funeral workers (380 ppb average exposure). 

14 

15 6.1.3.6. Neurological Effects 

16 Formaldehyde exposure via inhalation has been shown to adversely impact nervous 

17 system function in laboratory animals and humans, although human data for formaldehyde18 induced neurological effects are limited. Studies in formaldehyde-exposed histology technicians 

19 provide evidence of neurological impairment, including lack of concentration, impaired memory, 

20 disturbed sleep, impaired balance, variations in mood and irritability. These effects were 

21 significantly correlated with increasing duration of exposure to formaldehyde, but the findings 

22 are not conclusive due to confounding by concomitant exposures to other neurotoxic solvents 

23 (Kilburn et al., 1985, 1987). In a prospective study, Weisskopf et al. (2009) found a strong 

24 association between duration of formaldehyde exposure and death from amyotrophic lateral 

25 sclerosis (ALS), but information regarding exposure levels was not available. Short-term studies 

26 with controlled exposure to humans (chamber studies) also provide limited support for changes 

27 in cognitive function immediately following a single, controlled formaldehyde exposure (Bach et 

28 al., 1990; Lang et al. 2008). 

29 Available animal data provide substantial evidence of behavioral changes in animals 

30 following single or short-term repeated inhalation exposures to relatively low levels of 

31 formaldehyde. Among the animal studies, none of the available studies examined effects on 

32 nervous system function following chronic formaldehyde inhalation, however. 

33 Reported perturbations in nervous system function following formaldehyde exposure in 

34 animal studies include reductions in motor activity, lack of habituation, impairment in 

35 acquisition of a new learning task, deficits in retention of a previously learned task, increases in 
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1 corticosterone levels, sensitization to cocaine-induced locomotor activity, and enhanced fear 

2 conditioning using an olfactory conditioned stimulus (CS) (see Table 4-57). Behavioral effects 

3 have been seen in multiple laboratories and in studies conducted by different investigators using 

4 a variety of testing paradigms. Many of these effects were observed at acute exposure levels at or 

5 below 1.0 ppm, and some persisted days to weeks after termination of exposure. 

6 More limited data indicate possible effects on the development of the nervous system, 

7 including changes in brain structure and in the behavior of offspring (Table 4-57). Similarly, 

8 there is very little information regarding the mechanism by which effects on the nervous system 

9 might be produced. The data regarding behavioral sensitization provide some support for a 

10 stress-related mechanism for those specific findings, but the applicability of this mechanism to 

11 the behavioral changes seen in the other studies, including the learning deficits and 

12 developmental findings, has not been evaluated. Although there are data supporting stimulation 

13 of the trigeminal nerve by formaldehyde (and documenting the relevance of this interaction to the 

14 sensory irritation caused by formaldehyde), there are no data supporting a causal relationship 

15 between irritant properties of formaldehyde and the behavioral and neurodevelopmental effects 

16 in humans that occur following formaldehyde exposure. In summary, none of the available data 

17 provide sufficient information to allow a determination of the mode of action for effects of 

18 formaldehyde on the adult or developing nervous system. 

19 

20 6.1.3.7. Reproductive and Developmental Effects 

21 Formaldehyde inhalation exposure has been associated with adverse developmental and 

22 reproductive outcomes in both epidemiologic studies and experimental animal studies. Observed 

23 developmental outcomes include fetal loss, structural alterations, growth retardation, and delays 

24 in functional development. 

25 Several occupational studies found an increased risk of spontaneous abortions among 

26 formaldehyde-exposed women (Taskinen et al., 1999, 1994; John et al., 1994; Seitz and Baron, 

27 1990; Axelsson et al., 1984). The Taskinen et al. (1999) study examined several reproductive 

28 outcomes in women employed in the wood-processing industry, with a range of average daily 

29 formaldehyde exposures. The authors found that formaldehyde was associated with a more than 

30 three-fold increased risk of spontaneous abortion, and with a nearly 50% decrease in a measure 

31 of delayed conception indicating reduced fertility, an increased time to pregnancy, and an 

32 increased risk for endometriosis in this study. In experimental animal studies, early fetal death 

33 was noted following maternal formaldehyde exposures (Kitaev et al., 1984; Sheveleva, 1972), 

34 supporting the epidemiologic findings that the spontaneous abortion is likely related to 

35 formaldehyde exposure. Kitaev et al. (l984) hypothesized that formaldehyde may affect 
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1 reproductive function by stimulating the hypothalamus-pituitary-gonadal (HPG) axis, based on 

2 their observations of increased ovary weight, increased number of ovulating cells, and changes in 

3 blood levels of gonadotropins (LH and FSH) in female rats. Additionally, Maronpot et al. (l986) 

4 reported endometrial hypoplasia with a lack of ovarian luteal tissue in formaldehyde-exposed 

5 female rats. This finding may be relevant to the increased risk for endometriosis noted in the 

6 Taskinen et al. (1999) study. However, additional human and animal studies are needed to better 

7 understand the effects of inhalation exposure to formaldehyde on developmental outcomes after 

8 early gestational windows of exposure or on the female reproductive system. 

9 The findings of some occupational studies have suggested formaldehyde-related 

10 associations with congenital malformations and low birth weight. In numerous experimental 

11 animal studies, developmental effects have been noted following inhalation exposures to 

12 formaldehyde (Table 4-68). Exposure of rat dams to formaldehyde during pregnancy has been 

13 shown to result in significantly decreased fetal weight gain (Martin, 1990; Saillenfait et al., 1989; 

14 Kilburn and Moro, 1985). Other studies have noted changes in relative organ weight, 

15 undescended testes, biochemical changes (e.g., ascorbic acid), and blood acidosis (Senichenkova 

16 and Chebotar, 1996; Senichenkova, 1991; Kilburn and Moro, 1985; Gofmekler and 

17 Bonashevskaya, 1969; Gofmekler, 1968; Pushkina et al., 1968). 

18 Studies designed to assess adult male reproductive system toxicity in rats following 

19 repeated inhalation exposures to formaldehyde have found concentration-dependent decreases in 

20 Leydig cell number and quality, degeneration of seminiferous tubules, decreases in testes weight, 

21 alterations in sperm measures, decreased testosterone levels, alterations in trace metals in the 

22 testes, and/or dominant lethal effects (Guseva, 1972; Özen et al., 2002, 2005; Sarsilmaz et al., 

23 1999; Xing et al., 2007; Zhou et al., 2006) (Table 4-71). 

24 

25 6.1.3.8. Effects on General Systemic Toxicity 

26 Extrapulmonary effects such as changes in liver function enzymes and focal, chronic 

27 inflammation in the heart and kidney have been observed due to formaldehyde exposure in 

28 experimental animal studies. Most of these changes occurred at exposures of 20 ppm, and those 

29 that occurred at lower formaldehyde exposures (3.7 ppm) were confounded by coexposures. The 

30 underlying modes of action of liver, kidney, and cardiac effects have not been elucidated, and the 

31 human relevance is unknown. 

32 

33 

34 

35 6.1.3.9. Summary 
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1 Formaldehyde-induced eye, nose and throat irritation, decreased pulmonary function, 

2 decreased mucociliary clearance and histopathological lesions have been extensively documented 

3 in human and laboratory animal studies. These health effects are commonly noted at the portal 

4 of entry as expected for exposure to a reactive gas. In addition, effects on immune system 

5 responses and on the nervous and reproductive systems, including developmental effects, have 

6 also been reported. An association between formaldehyde exposure and increased incidence and 

7 severity of response to allergens (i.e., asthma and atopy) has been noted in humans. This effect, 

8 which has also been studied in laboratory animals, might occur via a neurogenic mode of action. 

9 A limited database of information that evaluates neurological effects in humans following 

10 formaldehyde exposure demonstrates a potential for adverse outcomes, and studies in laboratory 

11 animals have reported a variety of formaldehyde-induced neurobehavioral and 

12 neurodevelopmental effects. Formaldehyde has also been associated with adverse reproductive 

13 outcomes. Human studies have reported an association between formaldehyde exposure and 

14 decreased fertility as well as an increased risk of spontaneous abortions. Other human studies 

15 have suggested formaldehyde-related associations with congenital malformations, low birth 

16 weight, and endometriosis. Animal studies have noted a variety of developmental effects, 

17 including fetal death, structural alterations, and growth retardation (e.g., delayed fetal skeletal 

18 ossification and decreased fetal body weight) following inhalation exposure to formaldehyde, and 

19 adverse reproductive effects have been observed in both males and females. 

20 

21 6.1.4 Carcinogenicity in Humans and Laboratory Animals 

22 6.1.4.1 Carcinogenicity in Humans 

23 Based on the total weight of evidence, including the results from a large and well24 followed longitudinal cohort study of 25,619 industrial workers and several case-control studies, 

25 the epidemiologic evidence is sufficient to characterize the association between formaldehyde 

26 nasopharyngeal cancer as causal in humans (Hauptmann et al., 2004; Hildesheim et al., 2001; 

27 Vaughan et al., 2000). As further evaluated below, the evidence supporting a positive association 

28 between formaldehyde exposure and NPC is unlikely due to chance, bias or confounding. 

29 However, it should be noted that other smaller studies of formaldehyde-exposed workers did not 

30 document increased NPC mortality (e.g., Coggon et al., 2003; Pinkerton et al., 2004). These 

31 smaller study sizes yielded effect estimates with wide confidence intervals that were not 

32 statistically inconsistent with the increased risk of mortality from nasopharyngeal cancer reported 

33 in Hauptmann et al. (2004). 

34 Luce et al. (2002) evaluated pooled data from 12 case-control studies conducted in seven 

35 countries using a common job-exposure matrix and demonstrated a statistically significant 
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1 increased risk between formaldehyde exposure and sinonasal cancer exhibiting a concentration2 response relationship providing further causal evidence of carcinogenicity. This analysis was 

3 based on a very large dataset of 930 cases and 3136 controls, enabling the investigators to control 

4 for multiple potential sources of bias and confounding and to conduct separate analyses by 

5 histological type. These results are particularly convincing, as the association was consistently 

6 seen for a rare sub-type of sinonasal cancer which normally accounts for only 10% of the 

7 reported cases. 

8 In addition to the evidence of formaldehyde carcinogenicity in the nasopharynx, nose and 

9 sinuses, other upper respiratory tract sites of direct contact with formaldehyde upon inhalation 

10 (i.e., larynx, mouth and salivary gland) also showed evidence of increasing relative risk with 

11 increasing average intensity and peak exposure in a large cohort study with exposure estimates 

12 for the individual workers, although these trends did not reach the level of statistical significance 

13 (Hauptmann et al., 2004). However, Hauptmann and colleagues (2004) concluded that in spite of 

14 the small numbers of deaths from these rare cancers of the upper respiratory tract, the positive 

15 associations of increased cancer risk with increased formaldehyde exposure were consistent with 

16 the carcinogenicity of formaldehyde at these sites of first contact. Case-control studies also 

17 provide evidence of an association between formaldehyde exposure and oral squamous cell 

18 carcinoma (SCC), esophageal, and laryngeal cancers, and hypopharyngeal cancer (Gustavsson et 

19 al., 1998; Laforest et al., 2000.) 

20 The finding that formaldehyde inhalation causes nasal squamous cell carcinoma in 

21 rodents (Section 4.2.1.2) further supports the determination of a causal association of 

22 formaldehyde exposure and increased risk of upper respiratory tract cancer in humans. Both 

23 humans and animals developed tumors within the upper respiratory tract, the site expected to 

24 receive direct exposure to formaldehyde. 

25 Several researchers have argued that the relationship between formaldehyde exposure and 

26 nasopharyngeal cancer based on existing studies has not been determined. Several limitations, 

27 such as the rarity of the cancer and the imprecise estimates of exposure, are often inherent in 

28 epidemiologic methods and exposure assessment. These constraints limit the ability of 

29 epidemiologic studies to statistically detect associations and can lead to false negatives. The 

30 results of the largest cohort study of nasopharyngeal cancer (Hauptmann et al., 2004) showed 

31 statistically significant concentration-response relationships with increased risk of cancer 

32 associated with increased formaldehyde exposure. However, even though this study was based 

33 on 25,619 workers, only 9 cases of nasopharyngeal cancer were observed, compared to an 

34 expected number of 5 cases, for a relative rate of 2.1 (with a confidence interval of 1.05 - 4.21) 

35 (Hauptmann et al., 2004). 
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1 The next largest cohort study of nasopharyngeal cancer was based on 14,014 workers 

2 (Coggon et al., 2003) and reported only 1 case compared to an expected number of 2 cases, for a 

3 relative risk of 0.5 (with an estimated 95% confidence interval of 0.07 − 3.55; see Bosetti et al., 

4 2007). To put this finding into perspective, it is helpful to note not only the relative risk but also 

5 that this effect estimate is highly unstable due to a lack of statistical power. The large width of 

6 this interval (0.07 − 3.55) indicates that the range of possible true values includes both increased 

7 and decreased NPC mortality and therefore does not contradict the evidence of elevated risk of 

8 nasopharyngeal cancer mortality associated with formaldehyde exposure reported by Hauptmann 

9 et al. (2004). The even smaller study of 11,039 textile workers by Pinkerton et al. (2004) 

10 reported no cases of nasopharyngeal cancer compared to an expected number of one case − 

11 yielding an effective relative risk of zero with a highly unstable 95% confidence interval 

12 estimated at 0 − 3.00 (see Bosetti et al., 2007). While true that Pinkerton et al. (2004) did not 

13 report an increased risk of nasopharyngeal cancer, this study did not have sufficient statistical 

14 power to rule out a true association with less than a 3-fold increase in risk and therefore is 

15 likewise not inconsistent with the finding by Hauptmann et al. (2004). Thus, results from these 

16 cohort studies, with limited power to detect the relatively rare upper respiratory tract cancers 

17 (e.g., NPC), are given less weight in the overall evaluation. 

18 The largest occupational cohort study, conducted by the NCI (Hauptman et al., 2004), did 

19 report statistically significant associations of formaldehyde exposure with carcinogenicity at the 

20 sites of first contact with sufficient statistical power to rule out the null hypothesis of no 

21 association. The NCI investigations controlled for potential selection bias due to the healthy 

22 worker effect and for several potential confounders, including calendar year, age, sex, race, and 

23 pay category. However, other potential sources of bias or confounding have been suggested with 

24 respect to the strength of these data to support a causal conclusion. 

25 Following reports of increased risk of NPC associated with formaldehyde exposure, a 

26 series of analyses of similar data were undertaken by Marsh and coworkers (Marsh et al., 2007a, 

27 b, 2002, 1996; Marsh and Youk, 2005). Briefly, these studies focused on the specific findings 

28 from a single plant in the NCI cohort (Wallingford, Connecticut) that generated the majority of 

29 the NPC cases. Marsh et al. (1996) confirm a significant adverse association of formaldehyde 

30 with nasopharyngeal cancer but note the effects are predominantly among workers at the 

31 Wallingford plant with less than one year employment. Marsh et al. (2002) report a five-fold 

32 excess in risk of nasopharyngeal cancer associated with formaldehyde in both short-term and 

33 long-term workers but note that the increase was concentrated among workers hired during 1947-

34 1956. Marsh and Youk (2005) re-evaluated the same Wallingford workers and reported a 

35 regional rate-based standardized mortality ratio (SMR) of 10.32 (95% CI = 3.79 − 22.47) 
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1 compared to 0.65 (95% CI = 0.08 − 2.33) for workers at the nine other plants combined. 

2 However, Marsh and Youk (2005) also show that rate-based mortality ratios standardized to both 

3 U.S. and local populations were elevated (non-significantly) not only at the Wallingford plant but 

4 individually at each of the four other plants at which a single case of nasopharyngeal cancer was 

5 reported: Plant 2 (SMRUS = 5.35), Plant 3 (SMRUS = 1.99), Plant 7 (SMRUS = 1.06), and Plant 10 

6 (SMRUS = 1.44). It should be noted that Plant 1 (Wallingford) and Plant 2 had both the two 

7 highest median formaldehyde exposures and the two highest reported excess risks (Marsh and 

8 Youk, 2005). 

9 In another re-analysis of the NCI cohort data on the workers at the Wallingford plant, 

10 Marsh and coworkers (2007a) suggested that an imprecise assessment of formaldehyde exposure 

11 and an inability of the study to separate formaldehyde exposure from other potential chemical or 

12 particulate exposures may have confounded the observed association between formaldehyde and 

13 cancer. However, there was no evidence of any differential measurement error that could have 

14 produced the observation of a spurious association. Any non-differential exposure measurement 

15 error (i.e., random error in the exposure assessment) would likely have led to an attenuated 

16 observed effect of formaldehyde that was less than that which would otherwise have been 

17 observed in the absence of measurement error. 

18 The potential for confounding by particulates was explicitly examined by Hauptmann et 

19 al. (2004) and it was shown that there was an exposure-response relationship with formaldehyde 

20 among individuals with high particulate exposures – alleviating the potential for confounding and 

21 thereby strengthening the causal interpretation of the formaldehyde relationship with an increased 

22 risk of NPC. Marsh and coworkers (Marsh et al., 2007b) later suggested the reported 

23 formaldehyde association was confounded by an association between silversmithing and NPC. 

24 However, careful examination of that analysis (Marsh et al., 2007a) suggests that multiple 

25 comparisons may have led to the reported observation with silversmithing. Additionally, the 

26 reported effect was inconsistently reported between the results and the abstract sections using 

27 different confidence intervals, and both sets of confidence intervals around the reported 

28 association were extremely unstable spanning up to several hundred-fold. No prior studies 

29 identified an associated between silversmithing and NPC. Thus it may be that silversmithing is 

30 an artifactual potential confounder. 

31 The increased NPC mortality observed in the NCI cohort (Hauptmann et al., 2004) has 

32 been thoroughly examined for sources of bias and confounding by both the primary researchers 

33 and Marsh and coworkers (Marsh et al., 2007a, b, 2002, 1996; Marsh and Youk, 2005). Despite 

34 the extensive scrutiny of these results, no convincing and consistent alternative hypothesis of 

35 causation has been identified. Taken together with the statistically significant association 
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1 demonstrating an exposure-response relationship within exposed workers, these data support the 

2 conclusion that the association between formaldehyde exposure and increased risk of NPC is 

3 causal. 

4 Therefore, after a thorough examination of potential confounders, the association between 

5 formaldehyde exposure and NPC mortality in the NCI cohort remains significant and provides a 

6 positive exposure-response relationship. Additionally, case-control studies, which have greater 

7 statistical power than cohort studies for rare diseases, provide strong additional evidence in 

8 support of a causal association between formaldehyde exposure and the incidence of NPC 

9 (Hildesheim et al., 2001; Vaughan et al., 2000). As these studies draw from different 

10 demographic groups, regions of the world, and evaluate various confounding factors, there is 

11 little potential for these consistently reported associations to be artifactual, confounded by 

12 common exposures, or a result of bias or chance. 

13 Numerous epidemiologic studies have also reported an association between 

14 formaldehyde-exposed workers, especially "professional" workers (e.g., pathologists, embalmers, 

15 and funeral directors), and increased risk of lymphohematopoietic cancers (See Table 4-82). 

16 Positive associations between formaldehyde exposure and lymphohematopoietic cancers have 

17 been reported for chemical workers (Wong et al., 1983; Bertazzi et al., 1986), embalmers 

18 (Walrath and Fraumeni, 1983, 1984; Hayes et al., 1990), anatomists and pathologists (Harrington 

19 and Shannon 1975; Hall et al., 1991; Levine at al., 1984; Stroup et al., 1986; Matanoski et al., 

20 1989). However, clear associations (in terms of overall standardized mortality ratios (SMRs) or 

21 proportional mortality ratios (PMRs) were not reported in analyses for garment workers, iron22 foundry workers, and a large US industrial cohort (Pinkerton et al., 2004; Andjelkovich et al., 

23 1995; Beane Freeman et al., 2009; Marsh et al., 1996), although associations were observed in 

24 some of these studies when exposure-response relationships were considered. Several published 

25 meta-analyses are available which more formally assess the strength of association between 

26 formaldehyde exposure and mortality from all lymphohematopoietic cancers. Pooled SMRs 

27 indicate stronger associations for professional workers (embalmers, anatomists and pathologists) 

28 than industry workers (Table 4-83). Bosetti et al. (2008) found similar relationships, with a 

29 pooled SMR of 1.31 (95% CI 1.16-1.47) for ‘professionals’ (i.e. embalmers, anatomists and 

30 pathologists) versus a pooled estimate of 0.85 (95% CI 0.74-0.96) for industrial workers. A 

31 recent meta-analysis by Zhang et al. (2009) reports a summary relative risk of 1.25 (95% CI 1.09-

32 1.43) for both professional and industry workers for all lymphohematopoietic cancers (ICD 9 

33 codes 200-209). 

34 Two well-designed cohort studies found significant positive associations between 

35 formaldehyde-exposed professional workers and lymphohematopoietic cancer, particularly 
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1 leukemia, using cumulative exposure measures not previously used and using internal 

2 comparison groups. The largest cohort study of industrial workers exposed to formaldehyde 

3 (N=25,619), with the most extensive exposure assessment (Blair et al., 1986; Stewart et al., 

4 1986) and with the cohort followed for a median duration of 35 years (Hauptmann et al., 2003) 

5 demonstrated that formaldehyde was a risk factor for lymphohematopoietic cancers, independent 

6 of other risk factors, such as benzene exposure and smoking. This finding was re-confirmed with 

7 an additional 10 years of follow-up (Beane Freeman et al., 2009). Another industrial cohort 

8 study reported a significant increase in the risk of leukemia in garment workers 20 years after 

9 their initial exposure and in workers with 10 or more years of exposure to formaldehyde 

10 (Pinkerton et al. 2004). A third large occupational cohort study (Coggon et al., 2003) that did not 

11 evaluate their findings with regard to latency reported somewhat lower mortality from leukemia 

12 and other lymphatic and hematopoietic cancers than expected compared to national rates. 

13 The associations between myeloid leukemia and formaldehyde exposure are strong and 

14 consistent (Table 4-84). Of the four studies which formally assess myeloid leukemia mortality, 

15 all are positive, including cohorts of both professional and industrial workers (Beane Freeman et 

16 al., 2009; Hayes et al., 1990; Pinkerton at al., 2003; Stroup et al., 1986). Although few cases 

17 exist for further subtype analysis, the available data indicate either no differences in SMRs for 

18 acute myeloid leukemia (AML) versus chronic myeloid leukemia (CML) (Hayes et al., 1990; 

19 Pinkerton et al., 2003) or suggest CML is more prominent (Blair et al., 2000; Stroup et al., 1986). 

20 The association between formaldehyde exposure and myeloid leukemia in embalmers has 

21 recently been confirmed in a large nested case control study by Hauptman et al (2009) which 

22 includes cases identified from the previous studies of Hayes et al. (1990) and Walrath and 

23 Fraumeni (1983 and 1984). Exposure estimates were based on interviews with next-of kin for 

24 duration of job actively embalming and total number of embalmings performed. Strong and 

25 statistically significant exposure-response relationships are demonstrated for duration of 

26 exposure, total number of embalmings performed and estimated cumulative exposure to 

27 formaldehyde with odds ratios of 13.6 (1.6-119.7), 12.7(1.4-112.8) and 13.2(1.5-115.4) 

28 respectively (Hauptmann et al., 2009). 

29 The reported associations between formaldehyde exposure and lymphohematopoietic 

30 cancers in general, and leukemia (especially myeloid leukemia) in particular, were in workers 

31 exposed in very different environments (i.e., mortuary, chemical industry and garment industry). 

32 Since coexposures to other agents are considerably different between these work environments, it 

33 is unlikely that influence of confounding exposures plays a role in the observed associations. 

34 There is no evidence of bias in the published reports, and the consistency across numerous 

35 studies over time is sufficient to conclude that the results are not due to chance. 
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1 It has been argued that it is biologically implausible for a highly reactive agent such as 

2 formaldehyde, whose primary action is expected to be at the portal of entry, to cause acute 

3 lymphoid or myeloid leukemias (ALL and AML, respectively), which are both commonly 

4 believed to arise from transformation of stem cells in the bone marrow. The modes of action 

5 (MOAs) by which formaldehyde may induce these observed cancers are unknown, although it 

6 has been postulated that circulating stem cells (Hauptmann et al., 2003) (e.g., early progenitor 

7 cells in circulating blood or pluripotent cells in nasal/oral passages) may travel to bone marrow 

8 where they become leukemic stem cells (Zhang et al., 2009). In contrast, the mechanism for the 

9 chronic lymphatic leukemia, lymphomas, multiple myelomas (from plasma B-cells) and 

10 unspecified lymphohematopoietic cancers may involve an etiology in peripheral tissues, such as 

11 cells, cell aggregates, germinal centers and lymph nodes. An association of these cancers to a 

12 reactive exogenous agent primarily acting at the point of entry is biologically plausible. 

13 

14 6.1.4.2 Carcinogenicity in Laboratory Animals 

15 The carcinogenic potential of formaldehyde is well documented in numerous animal 

16 bioassays, especially for sites of first contact. Inhalation exposure of formaldehyde induced 

17 primarily squamous cell carcinomas (SCC) in nasal passages of rats (Feron et al., 1988; 

18 Holmström et al., 1989a; Woutersen et al., 1989; Tobe et al., 1985; Kamata et al., 1997; Albert et 

19 al., 1982; Sellakumar, 1985; Kerns et al., 1983; Monticello et al., 1996) and mice (Battelle 

20 Columbus Laboratories, 1981; Swenberg et al., 1980; Kerns et al., 1983; CIIT, 1982). 

21 Formaldehyde given as 0.5% formalin orally in drinking water to adult rats induced higher 

22 incidences of papillomas in the forestomach, adenomatous hyperplasia in the fundus, and 

23 adenocarcinomas in the pylorus in a 40-week study using an initiation-promotion protocol in rats 

24 (Takahashi et al., 1986). Soffritti et al. (1989) observed a significant increase in rare tumors in 

25 the gastro-intestinal (GI) tract, including both benign (papillomas and acanthomas of the 

26 forestomach and adenomas) and malignant tumors (adenocarcinomas and leiomyosarcomas) in 

27 rats given formaldehyde in drinking water. Formaldehyde is toxic at the portal of entry in 

28 rodents, causing increased cell proliferation, DPX formation, and focal lesions in the GI tract or 

29 upper respiratory tract (depending on the route of exposure). The portal of entry toxicity of 

30 formaldehyde further supports a finding of formaldehyde induced POE cancer in animal 

31 bioassays. 

32 Direct support for lymphohematopoietic cancers in animal bioassays is less convincing. 

33 Although many of the available chronic studies did not examine lymphoma/leukemia incidence, 

34 two studies provide positive evidence. Inhalation exposure of formaldehyde increased 

35 lymphoma in female mice and leukemia in female F344 rats, but not male rats (Battelle 
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1 Laboratories, 1981). Drinking water exposure to formaldehyde caused a dose-dependent increase 

2 in all hemolymphoreticular neoplasias, especially lymphoblastic leukemias and lymphomas in 

3 both male and female Sprauge-Dawley rats (Soffritti et al., 1989, 2002). Conversely, no 

4 increases were seen in male Wistar rats when exposed to formaldehyde in drinking water at 

5 similar levels (Til et al., 1989) or male rats after chronic inhalation exposures (Sellakumar et al., 

6 1985). 

7 

8 6.1.4.3 Carcinogenic Mode(s) of Action 

9 Multiple plausible modes of action (MOAs) are presented in the document so as to 

10 explore ways in which a combination of factors may contribute to cancer incidence in a 

11 population exposed to formaldehyde. Multiple MOAs for formaldehyde-induced cancer can be 

12 reasonably supported based on various known biological actions of formaldehyde (e.g., mutation, 

13 cell proliferation, cytotoxicity and regenerative cell proliferation). Additionally, alternative 

14 actions, such as immunosuppression or viral reactivation, are possible, although few data exist to 

15 evaluate their potential relevance. Rather than a single MOA, it is plausible that a combination 

16 of these factors contribute to cancer incidence in an exposed population. Considering multiple 

17 factors may help to better understand the biological and mechanistic basis for the increases in 

18 cancer incidence observed in exposed human populations. Unlike animal bioassays, results in 

19 human epidemiological studies reflect not only the effects of the agent of concern but also 

20 numerous other risk factors (e.g., viral status, diet, smoking, etc.). Additionally, human studies 

21 may be impacted by biological human variability across individuals, cancer biology (sub-types) 

22 and wide variability in exposure regimens in human populations. 

23 A preponderance of the evidence supports a role of mutagenic activity in formaldehyde’s 

24 carcinogenic MOA both for respiratory tract cancer and lymphohematopoietic cancers. As 

25 reviewed in Section 4.3, numerous studies provide evidence of formaldehyde’s direct mutagenic 

26 activity and supports the relevance these data to formaldehyde’s carcinogenicity. It can be shown 

27 that: 

28 1) Formaldehyde directly interacts with DNA, generating DNA-protein cross-links and 

29 DNA adducts (in vitro, in vivo) in multiple species, 

30 2) DNA-protein cross-links exhibit a dose-response relationship to formaldehyde 

31 exposure in respiratory tract of laboratory animals and are observed at exposure 

32 concentrations of relevance to some people (0.3 ppm, 0.7 ppm), 

33 3) Formaldehyde-induced DNA-protein cross-links have been associated with 

34 formaldehyde-induced micronuclei and chromosomal aberrations (in vitro), 
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1 4) Mutations induced by formaldehyde due to small deletions and rearrangements in 

2 DNA in various experimental systems are consistent with formaldehyde’s 

3 observed clastogenic effects (micronuclei and chromosomal aberrations) (in vitro, 

4 in vivo), 

5 5) Formaldehyde-induced mutations and clastogenic effects occur at levels below where 

6 significant cytotoxicity is detected (in vitro), 

7 6) Formaldehyde exposure has been correlated to similar increased micronuclei and 

8 chromosomal aberrations in human buccal and oral cells corresponding to sites 

9 where formaldehyde-induced tumors arise, and 

10 7) Chromosomal damage in blood-borne immune cells, relevant to agent-induced 

11 lymphohematopoietic cancers has been documented in formaldehyde exposed 

12 workers including increased micronuclei and chromosomal aberrations, increased 

13 incidence and aneuploidy in hematopoietic stem cells. 

14 

15 In addition, mutations may arise indirectly from formaldehyde-induced DNA damage 

16 during cell proliferation or due to errors in DNA repair mechanisms. Therefore, formaldehyde’s 

17 DNA reactivity on a population of proliferating cells strengthens the role of formaldehyde18 induced mutagenicity in its carcinogenic MOA. The nasal and gut mucosa are tissues which are 

19 continually sloughing and regenerating cells (Junqueira et al., 1992). Mucosal cells proliferate in 

20 response to environmental challenges in order to repair cell damage, increase adaptive response 

21 and remodel tissue. Additionally, since the pseudostratified epithelium of the respiratory tract is 

22 only 1-2 cells in depth, cells with proliferative capacity would be directly impacted by 

23 formaldehyde during exposure. Formaldehyde-induced clastogenic effects have been 

24 demonstrated in these tissues (e.g. nasal) in humans, as well as in tissues which possess stratified 

25 epithelium (e.g. buccal). Therefore, formaldehyde would not need to transport beyond the portal 

26 of entry to directly impact and induce DNA mutations in routinely proliferating cells. 

27 In regards to generating the observed clastogenic effects (micronuclei and chromosomal 

28 aberrations in peripheral blood lymphocytes, aneuploidy in circulating hematopoietic stem cells), 

29 it is less clear as to where formaldehyde is making contact with components of the immune 

30 system. Mature lymphocytes present in nasal and gut tissues, and would be vulnerable to the 

31 direct toxic actions of formaldehyde including genotoxicity. Since mature lymphocytes routinely 

32 traffic through the body and clonally respond in response to an immune challenge, the observed 

33 effects in peripheral blood lymphocytes (micronuclei and chromosomal aberrations) are 

34 consistent with direct action on these cells. Lymphohematopoietic cancers are known to arise 
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1 from mature lymphocytes including: Hodgkin lymphoma, multiple myeloma some leukemia and 

2 non-Hodgkin lymphoma (Greaves 2004, Harris et al., 2000). 

3 Formaldehyde may also be directly acting upon circulating stem cells or more mature 

4 progenitor cell in the peripheral blood (Zhang et al., 2010). Any genetic damage sustain by 

5 circulating cells could contribute to a broad spectrum of lymphohematopoietic cancers if those 

6 cells returned to the bone marrow and contributed to hematopoiesis. Evidence of bone marrow 

7 toxicity and stem cell aneuploidy has been reported in formaldehyde exposed workers (Zhang et 

8 al., 2010). Finally, formaldehyde is readily hydrated in aqueous systems, existing in equilibrium 

9 with its hydrated form methylene glycol, which is able to transport through the blood. It has been 

10 hypothesized that this hydration reaction may allow formaldehyde to act systemically and 

11 therefore on the bone marrow directly (Zhang et al., 2010.) Formaldehyde-induced DNA 

12 damage, and resulting mutation in the bone marrow and circulating stem cells could contribute to 

13 any of the lymphohematopoietic cancers including leukemia (both lymphoid and myeloid) as 

14 well as myeloproliferative disorders. 

15 Cell replication allows unrepaired DNA damage to be “fixed” into heritable changes to 

16 the genome. Therefore, increased cell proliferation could serve not only to increase the 

17 mutagenic effects of formaldehyde on a given tissue but also to enhance the mutagenic effects of 

18 other agents in the diet or in the environment. Since epidemiological studies include humans 

19 exposed to a range of agents in the environment, increased cell proliferation could contribute to 

20 increased cancer incidence. The promotion studies in animal bioassays, though limited in 

21 number, support the relevance of formaldehyde’s ability to enhance the actions of other agents 

22 (initiators) on tumor formation. 

23 Although the other biologic effects discussed above have not been explicitly tested in 

24 animal systems, the available data are consistent with these actions contributing to the 

25 carcinogenic potential of formaldehyde. For example, localized immunosuppression by 

26 formaldehyde may serve to increase viral reactivation (e.g., EBV, HPV etc.) or decrease tissue 

27 surveillance and immune activity against preneoplastic cells. Both these actions could contribute 

28 to increased cancer risk in a human population, which may not be evident in animal bioassays, 

29 where the animals are not subject to the many risk factors for human cancer. Even the simple 

30 action of the breakdown of the mucociliary apparatus could increase cancer incidence by 

31 increasing toxic insult to the URT and increasing URT infections. Again, these actions may be 

32 relevant to human populations, but they have not been adequately tested in animal bioassays. 

33 Animal bioassays suggest a role for regenerative proliferation in contributing to 

34 formaldehyde’s carcinogenicity. However, these data are not evidence against a role of direct 

35 mutagenic action either in the observed tumorigenicity or in the potential low-dose 
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1 carcinogenicity of formaldehyde. As reviewed, a role for mutagenic action is also consistent 

2 with the results of the animal bioassays (Crump et al, 2008; Subramaniam et al., 2007, USEPA 

3 2008). The mutagenic effects of formaldehyde are well-documented to occur below levels of 

4 significant cytotoxicity. This observation is important for the relevance of formaldehyde-induced 

5 mutagenicity to human health risk. Given the above sequence of evidence - from the nature of 

6 formaldehyde’s DNA reactivity through clastogenic effects observed in human cells from the 

7 various tumor sites - there is an adequate weight of evidence (WOE) to consider formaldehyde8 induced mutations relevant to human carcinogenic risk. Although occupational exposures may 

9 have resulted in high episodic exposures (especially historically), it is unlikely that any worker 

10 would have endured repeated exposures which resulted in gross focal lesions to the upper 

11 respiratory tract (URT) or oro-digestive tract as seen in the animal bioassays. It is noteworthy 

12 that even without these gross formaldehyde-induced lesions, cancer incidence is increased from 

13 occupational (and perhaps non-occupational) exposures to formaldehyde. Therefore, we believe 

14 formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA. 

15 

16 6.1.5 Cancer Hazard Characterization 

17 Formaldehyde is carcinogenic to humans by the inhalation route of exposure. There is 

18 sufficient evidence of causal associations between formaldehyde exposure and nasopharyngeal 

19 cancers as well as sinonasal cancers. There is supporting evidence for cancers of the mouth and 

20 throat in humans as well as strong evidence for nasal tumors in animal bioassays. Taking these 

21 findings together along with mode of action considerations, it is concluded that there is sufficient 

22 evidence of a causal relationship between formaldehyde inhalation exposure and upper 

23 respiratory tract cancers as a group. 

24 Epidemiologic studies also provide evidence of a causal association of inhalation exposure 

25 to formaldehyde and lymphohematopoietic cancers as a group and leukemias as a group, with the 

26 strongest evidence for myeloid leukemia. There is supporting evidence both in cohort and case27 control studies for specific sub-types of lymphohematopoietic cancers, including myeloid 

28 leukemia, multiple myeloma and Hodgkin lymphoma. There is limited supporting evidence in 

29 animal bioassays for both leukemia and lymphoma. It should be noted that although several 

30 carcinogenic modes of action have been discussed for leukemia, that this remains an area of 

31 significant scientific debate. 

32 

33 6.2 DOSE-RESPONSE CHARACTERIZATION 

34 6.2.1 Noncancer Toxicity: Reference Concentration (RfC) 
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1 The portals of entry are major targets for formaldehyde, as can be seen in many studies, 

2 because formaldehyde is highly reactive and water soluble. Human and laboratory animal studies 

3 demonstrate that formaldehyde also causes systemic effects, including neurotoxicity, 

4 reproductive toxicity, developmental toxicity, and immunotoxicity, although the data are less 

5 extensive than those supporting the sensory irritation and respiratory tract effects. Critical data 

6 gaps have been identified and uncertainties associated with data deficiencies are more fully 

7 discussed in Chapter 5 and summarized below. 

8 

9 6.2.1.1 Assessment Approach Employed 

10 RfC values for noncancer effects are derived using EPA’s RfC methodologies (U.S. 

11 EPA, 1994, 1993, EPA 2002b). EPA reviewed the existing literature and identified health effects 

12 associated with formaldehyde exposure, defining health effect categories where evidence was 

13 sufficient: sensory irritation, respiratory tract pathology, pulmonary effects, asthma, increased 

14 allergic sensitization, immune function, neurological and behavioral effects and reproductive and 

15 developmental effects. Specific key studies were identified within each health effects category 

16 which provided adequate exposure-response information to support RfC derivation (Table 5-4). 

17 Although not all identified endpoints are represented by these studies, at least one study was 

18 identified for each category. A screening process (described in section 5.1.3.1) was used to 

19 identify key studies for a variety of health effects that would best inform the derivation of the 

20 RfC. For each selected key study, a candidate RfC (cRfC) was derived. In several cases more 

21 than one alternative was considered for application of the uncertainty factor (UF) addressing 

22 human variability (Table 5-6). 

23 

24 6.2.1.2 Derivation of Candidate Reference Concentrations 

25 Seven studies were selected as key studies for further consideration in RfC derivation 

26 (Section 5.3.1, Table 5-4). Candidate RfCs from these studies address various health effects 

27 including: sensory irritation, respiratory effects, asthma, increased allergic sensitization, and 

28 decreased fecundity (Table 5-6). From these studies three co-critical studies were selected which 

29 provide similar cRfCs for related health effects (Rumchev et al., 2002; Garrett et al., 1999; 

30 Krzyzanowski et al., 1999). These three studies identify serious health effects in residential 

31 populations including children: increased asthma incidence, decreased pulmonary function, 

32 increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 2002; 

33 Garrett et al., 1999; Krzyzanowski et al., 1999). Asthma, allergic sensitization, altered 

34 pulmonary function, and symptoms of respiratory disease are not only clinically related, but 

35 etiologically related, and it is reasonable that they should be considered together. These health 
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1 effects are observed below the exposure levels that result in sensory irritation, and the resulting 

2 cRfCs are correspondingly lower—ranging from 2.8 to11 ppb—depending on the study, endpoint 

3 considered, and the application of alternative uncertainty factors for human variability 

4 (Table 6-1). Additionally, these cRfCs are considered protective of the decreased fecundability 

5 density ratio (FDR) reported by Taskinen et al. (1999) which yielded a cRfC of 8.6 ppb. One of 

6 the uncertainties in the cRfC for decreased FDR is the use of a time-weighted exposure metric 

7 which does not address possible contributions of peak exposure levels to the observed health 

8 effect thus; it is possible that a cRfC of 8.6 ppb is lower than is needed for protection against 

9 decreased FDR. 

10 As discussed in section 6.2.1.4, there are uncertainties in establishing an RfC which are 

11 not fully captured in the quantitative process or the standard uncertainty factors, as such it is 

12 acknowledged by EPA that the RfC is not exact, perhaps spanning an order of magnitude. The 

13 range of RfCs from the critical studies (even with various alternative considered for the human 

14 variability uncertainty factor are in close agreement spanning only 1⁄2 order of magnitude.) 

15 Therefore EPA is considering a simple mean of these cRfCs as adequately representative of the 

16 three co-critical studies. Alternatives are to take the median as a different way to represent the 

17 three studies together, or the lowest cRfC as most protective. There is little numerical difference 

18 in the result of these decisions. 

19 

20 6.2.1.3 Adequacy of Overall Data Base for RfC Derivation 

21 The database of available laboratory animal studies, clinical and epidemiological studies, 

22 and supporting mechanistic information for formaldehyde is substantial. Many of the health 

23 effects are well studied in animals and humans, especially those endpoints related to sensory 

24 irritation and respiratory effects at the portal of entry, such as impacts on respiratory tract 

25 pathology, asthma and reduced pulmonary function. This is reflected in the number and high 

26 quality of human studies presented in Table 5-4 and supporting data summarized in Chapter 4. 

27 

28 
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Table 6-1: Summary of candidate reference concentrations (RfC) for co-critical studies 

Application of 

Endpoint Study study-specific UF Study size Homes Children POD (ppb) 

UF

L UFS U

Respiratory effects / asthma and sensitization Reduction of PEFR in children (10%) 

Krzyzanowski et al. (1990) 208 Yes Yes BMCL10 = 17 1 1 

A

A

Asthma prevalence 

Rumchev et al. (2002) 192 Yes Yes NOAEL = 33 1 3 

A

A

Asthma, atopy and severity of allergic sensitization 

Garrett et al. (1999) 148 Yes Yes LOAEL = 28 3 1 

Notes: 1: The final RfC will be rounded to one significant digit per EPA policy. Since the Candidate RfC is an interim calculation, two

retained as is common practice in mathematics {i.e. one significant diget more that the final result, to avoid rounding errors compoundin

mathematical manipulations. 
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1 The data also indicate effects in other health effect categories, specifically neurotoxic 

2 effects, reproductive toxicity, and developmental toxicity (Section 5.1.2). These non-portal of 

3 entry effects are areas where additional research may be warranted to reduce uncertainty and 

4 better characterize the potential for health effects and the formaldehyde concentrations at which 

5 they might occur in humans. 

6 EPA guidance indicates that an uncertainty factor for database deficiencies should be 

7 applied where there is an indication that the existing studies may not completely characterize the 

8 hazard of a specific agent. This may be the result of lacking studies to assess toxicity to key 

9 functional areas or organ systems, or where “... a review of existing data may also suggest that a 

10 lower reference value might result if additional data were available.” (EPA 2002b) 

11 Application of an uncertainty factor of 3 was considered by EPA based on the lack of a 

12 satisfactory two-generation study to fully evaluate the effects of formaldehyde exposure on 

13 reproductive and developmental endpoints and limitations of the available studies evaluating 

14 neurotoxic effects. An uncertainty factor of 3 rather than 10 was considered given the relative 

15 completeness of the database across all major health effect categories such that it is believed all 

16 major health effects have been identified at least qualitatively. The observed adverse health 

17 effect levels (LOAELs) for those endpoints where the database is not adequate for alternative 

18 RfC derivation are above the range of candidate RfCs; however, it is unclear if the candidate 

19 RfCs would be protective of these other health effects (neurotoxic, reproductive and 

20 developmental) since NOAELs were not identified for several observed health effects. 

21 Therefore EPA is considering several options to address database deficiencies in the final 

22 RfC. 

23 
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1 

2 

3 It is unclear what uncertainty factors are appropriate to account for human variability and 

4 deficiencies in the overall database. For this reason, several alternatives have been presented. 

5 

6 6.2.1.4 Uncertainties in the Reference Concentration (RfC)

7 A number of uncertainties that underlie the RfC for formaldehyde are discussed in this 

8 section. A fundamental uncertainty in an RfC is that the critical study(ies) and endpoint(s) 

9 selected reflect an actual hazard, i.e., a chemically related effect. As summarized in Section 

10 6.1.3, there is strong and consistent evidence, from both human and laboratory animal studies, for 

11 the critical effects that form the basis of the RfC for formaldehyde. This section pertains to 

12 uncertainties in the quantitative derivation of the RfC. 

13 

14 Point of Departure (POD)

15 Most of the studies considered for RfC derivation did not provide enough data to support 

16 benchmark dose modeling. Rather, the PODs for most studies were LOAELs or NOAELs, 

Approaches to the application of a database uncertainty factor:

Options EPA is considering include: 

(1) Provide an RfC derived from studies of respiratory and allergenic responses and protective 

of sensory irritation effects with a database uncertainty factor of one given significant data on 

formaldehyde, but noting that further research reproductive, developmental and neurotoxic 

effects would be valuable. 

(2) Provide an RfC with a database uncertainty factor 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 from studies of respiratory and allergenic 

responses to reflect the potential that reproductive, developmental, or neurotoxic effects might 

occur at lower doses: 

 (3) Provide both an RfC identified as protective of the better-studied effects and an RfC with a 

database uncertainty factor of 3 incorporated to account for limits to the data on reproductive, 

developmental and neurotoxic effects. 
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1 which have a number of shortcomings relative to a POD obtained from benchmark dose-response 

2 modeling (i.e., a benchmark concentration or dose):

3 

4  LOAELs and NOAELs are a reflection of the particular exposure/dose levels used in a 

5 study, contributing some inaccuracy to the POD determination. 

6  LOAELs and NOAELs are often determined based on statistical significance and, thus, 

7 reflect the number of study subjects or test animals. Studies are typically dissimilar in 

8 detection ability and statistical power, with smaller studies tending to identify higher 

9 exposure levels as NOAELs relative to larger, but otherwise similarly designed, studies. 

10  Different LOAELs and NOAELs represent different response rates, so direct qualitative 

11 and quantitative comparisons are not possible. 

12 

13 PODs identified from benchmark dose models overcome some of the deficiencies 

14 associated with LOAELs and NOAELs. Benchmark models were used for two inhalation data 

15 sets—Hanrahan et al. (1984) and Krzyzanowski et al. (1990). 

16 It should also be noted, however, that even for benchmark concentrations/doses there is 

17 often uncertainty, in particular for continuous responses, about what response level to select as 

18 the benchmark response, i.e., where to define the cut-point between a level of change that is not 

19 adverse and one that is adverse. In addition, benchmark dose models currently in use are purely 

20 mathematical models and are not intended to accurately reflect the biology of the effect being 

21 modeled. 

22 Another source of uncertainty in the POD is the adjustment for continuous exposure. 

23 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human and 

24 laboratory animal inhalation studies are typically not for continuous exposures, and assumptions 

25 must be made in converting reported exposure levels to equivalent continuous exposures. 

26 Similarly, there are uncertainties about potential dose rate effects, in particular the effect of peak

27 exposures in occupational studies. 

28 

29 Extrapolation from Laboratory Animal Data to Humans

30 Because the inhalation database for formaldehyde contains many human studies for a 

31 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 

32 the RfC was derived. Thus, unlike for most RfCs, this is not a source of uncertainty in the RfC 

33 for formaldehyde. 

34 

35 
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1 Human Variation

2 Heterogeneity among humans is another uncertainty associated with extending results 

3 observed in a limited human study population or laboratory animal experiment to a larger, more 

4 diverse human population. 

5 For three of the studies used to derive the RfC, a value of 3 was used for the human 

6 variability UF (rather than the default value of 10) because the studies had an apparent over7 representation of populations expected to have increased susceptibility (section 5.5.3.1): 

8 

9  The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 

10 irritation in a large number of subjects, including children and the elderly. As a result of 

11 the study's participation criteria, individuals with greater sensitivity were potentially over12 represented. 

13  Thirty percent of the subjects in the residential study by Krzyzanowski et al. (1990) are 

14 children, who are more sensitive to formaldehyde-associated decreases in peak expiratory 

15 flow rates (PEFR) than adults. The candidate RfC determination for this study focused 

16 on the results in the children, among which asthmatics were over-represented (roughly 3-

17 times) compared to the national average. 

18  Garrett et al. (1999) conducted a cross-sectional survey of allergy and asthma-like 

19 symptoms in children with or without a doctor's diagnosis of asthma. The study was 

20 designed to include a high proportion of asthmatic children, a sensitive population for the 

21 effects being studied. 

22 

23 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 

24 attempt to account for certain special attributes of these studies/effects, there is still uncertainty

25 about how much of the overall population heterogeneity is actually reflected even in these 

26 relatively diverse residential studies. 

27 

28 Subchronic-to-Chronic Extrapolation

29 RfCs are intended to apply to chronic lifetime exposures. If a study is subchronic 

30 (typically less than 10% of lifetime), an UF for subchronic-to-chronic extrapolation is generally 

31 applied to the candidate RfC for that study. For the human residential and occupational studies 

32 comprising the key studies for the RfC in this assessment, the average durations of exposure in 

33 the households or workplaces under study is unknown. In this assessment, these studies were 

34 considered chronic in nature and no subchronic-to-chronic UF was applied. However, there is 

35 uncertainty about whether or not the responses observed fully reflected the potential effects of 
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1 chronic exposure, especially for effects in children, where effects on the developing respiratory 

2 and immune systems, for example, could be predisposing the children to further health effects 

3 later in life. 

4 

5 6.2.1.5 Conclusions 

6 Seven different non-cancer health effects were identified from formaldehyde inhalation 

7 exposure studies, including: 1) sensory irritation of the eyes, nose, and throat, 2) upper 

8 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 

9 behavioral toxicity, 6) reproductive and developmental toxicity, and 7) immunological toxicity. 

10 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 

11 derived candidate RfCs for critical effects based on seven key studies. Three co-critical studies 

12 were selected which provide similar cRfCs for related adverse health effects observed in 

13 residential populations including children i.e., increased asthma incidence, decreased pulmonary 

14 function, increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 

15 2002; Garrett et al., 1999; Krzyzanowski et al., 1999). The resulting cRfCs fall in a range 

16 between 2.8 and 11 ppb, depending on the study, or endpoints considered, and the application of 

17 alternative uncertainty factors for human variability (Table 6-1). The RfC is taken as the 

18 average of the cRfCs from the three co-critical studies (See Section 6.2.1.2). 

19 EPA has assessed the adequacy of the overall database for RfC derivation, and although 

20 the database is quite large, and provides significant information on well studied POE effects. 

21 There are remaining uncertainties in the database. Most notably, there is a need for additional 

22 exposure-response information for observed neurotoxic effects, reproductive and developmental 

23 effects as well as a two-generation study to evaluate the effects of formaldehyde exposure on 

24 reproductive and developmental endpoints. EPA is considering 4 options to address database 

25 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 

26 appropriate to account for human variability and deficiencies in the overall database. For this 

27 reason, several alternatives have been presented. EPA is seeking advice from the NAS and the 

28 public on this matter. 

29 

30 6.2.2. Cancer Risk Estimates 

31 6.2.2.1. Choice of Data 

32 As explained above, the human epidemiologic data and the animal bioassay data indicate 

33 multiple sites of concern, remote as well as at the portal of entry. The quantitative cancer risk 

34 derivations in this document consider the risks of lymphohematopoietic cancers and solid cancers 

35 of the respiratory tract. When adequate human data are available, as is the case with 
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1 formaldehyde, it is generally preferable to base cancer risk estimates on the human data rather 

2 than on data from experimental animals because of the inherent uncertainties associated with 

3 interspecies extrapolation. Sufficient exposure-response data from a large, high-quality 

4 epidemiologic study for the quantitative estimation of risk were available for some 

lymphohematopoietic cancers and for nasopharyngeal cancer.

15 5 Risk estimates based on nasal 

6 tumors in rats were also derived for comparison with the estimates based on human data. The 

7 data used for the quantitative risk assessment are as follows: 

8 

9 1. Nasopharyngeal cancer (NPC): The dose-response modeling of NPCs is based on results 

10 from a large NCI cohort study of over 25,000 workers in 10 U.S. plants producing or 

11 using formaldehyde (Hauptmann et al., 2004). 

12 2. Lymphohematopoietic cancers: The dose-response modeling of select 

13 lymphohematopoietic cancers is based on results from a more recent follow-up study (of 

14 lymphohematopoietic malignancies only) of the same NCI cohort (Beane Freeman et al., 

15 2009). 

16 3. Squamous cell carcinoma (SCC) in the upper and lower respiratory tract: An increased 

17 incidence of nasal SCC was seen in two large long-term bioassays using F344 rats (Kerns 

18 et al., 1983; Monticello et al., 1996). Although other studies in laboratory animals exist, 

19 

20 4. these two studies, when combined, provided the most robust data for analyses. The nasal 

21 tumor incidence data from these rat bioassays is used for extrapolating the risk of SCC to 

the entire human respiratory tract.16 22 

23 

24 6.2.2.2. Analysis of Epidemiologic Data

25 The NCI cohort consisted of 25,619 workers employed in 10 plants prior to 1966. A 

26 follow-up through 1994 presented exposure-response analyses for 9 NPC deaths, as well as 

 

15 Only one other epidemiological study was available with quantitative exposure estimates for the individual 

workers. It was a much smaller study (it focused on one of the ten plants covered in the selected study), and it 

evaluated only pharyngeal cancers. 

16 That is, we do not assume site concordance between rat and human. This is reasonable because the respiratory 

and transitional cell types considered to be at risk of SCC in the upper respiratory tract are also prevalent in the 

lower human respiratory tract. Greater fractional penetration of formaldehyde is thought to occur posteriorly in the 

human respiratory tract compared to the rat (Kimbell et al. 2001, Overton et al. 2001). Furthermore, some 

epidemiological studies reported an increase in lung cancer with formaldehyde exposure (Gardner et al. 1993, Blair 

et al. 1990, 1986), and lesions were seen in the lower respiratory tract of rhesus monkeys exposed to formaldehyde 

(Monticello et al. 1989). 
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1 analyses of deaths from other solid cancers (Hauptmann et al., 2004). The most recent follow-up 

2 (through 2004; lymphohematopoietic cancers only) analyzed 319 deaths attributed to 

3 lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et al., 2009). A 

4 detailed exposure assessment was conducted for each worker, based on exposure estimates for 

5 different jobs held and tasks performed (Stewart et al., 1986). Exposure estimates were made 

6 using several different metrics—peak exposure, average intensity, cumulative exposure, and 

7 duration of exposure. Respirator use and exposures to formaldehyde-containing particulates and 

8 other chemicals were also considered. Relative Risks (RRs) were estimated using log-linear 

9 Poisson regression models stratified by calendar year, age, sex, and race and adjusted for pay 

10 category (salary/wage/unknown). The NCI investigators used the low-exposure category as the 

11 reference category to “minimize the impact of any unmeasured confounding variables since 

12 nonexposed workers may differ from exposed workers with respect to socioeconomic 

13 characteristics.” 

14 Although other upper respiratory tract cancers were also identified as being causally 

15 associated with formaldehyde exposure in the weight-of-evidence analysis in section 4.5, NPC 

16 was the only upper respiratory tract cancer with exposure-response data adequate for the 

17 derivation of unit risk estimates in the Hauptmann et al. (2004) follow-up study of solid tumors. 

18 Similarly, the weight-of evidence analysis in section 4.5 concluded that there were causal 

19 relationships between formaldehyde exposure and all lymphohematopoietic cancers as a group as 

20 well as leukemias as a group (with the strongest evidence for myeloid leukemia). However, from 

21 the Beane Freeman et al. (2009) follow-up study of lymphohematopoietic malignancies, only all 

22 leukemias combined and Hodgkin lymphoma were judged to have exposure-response data 

23 adequate for the derivation of unit risk estimates.

24 For the NPCs, significant trends were observed for the cumulative and peak exposure 

25 metrics. The cumulative exposure metric provides a good fit to the data (p trend = 0.029 for all 

26 person-years). Since this is generally the preferred metric for quantitative risk assessment for 

27 environmental exposure to carcinogens, cumulative exposure is chosen as the exposure metric 

28 for the risk estimate calculations for NPC in this assessment. For the latency of solid cancers, 

29 including nasopharyngeal tumors, a 15-year lag interval was used by Hauptmann et al. (2004). 

30 For the lymphohematopoietic cancers, using the peak exposure metric, statistically 

31 significant log-linear trends were observed for all lymphohematopoietic cancers, Hodgkin 

32 lymphoma, and leukemia (the latter only when the unexposed person-years were included) 

33 (Beane Freeman et al., 2009). Using the average exposure metric, there was a significant trend 

34 for Hodgkin lymphoma. Similar results were seen with the cumulative exposure metric, although 

35 the trends were only of borderline significance (Hodgkin lymphoma p trends = 0.06 and 0.08 
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1 with and without the unexposed person-years, respectively; leukemia p trends = 0.08 and 0.12 

2 with and without the unexposed person-years, respectively). For the latency of 

3 lymphohematopoietic cancers, a 2-year lag interval was used by Beane Freeman et al. (2009). 

4 Although the peak exposure metric provides the most statistically robust dose-response 

5 relationship, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 

6 to meaningful estimates of lifetime extra risk of cancer from environmental exposures. The 

7 average exposure metric is also problematic because it suggests that duration of exposure is not 

8 important, i.e., exposure to a given exposure level for one year conveys the same amount of risk 

9 as exposure to the same level for 70 years. 

10 Cumulative exposure is generally the preferred metric for quantitative risk assessment for 

11 environmental exposure to carcinogens. Given the consistency of increased mortality from 

12 Hodgkin lymphoma and leukemia overall (exposed versus unexposed) and for each exposure 

13 metric (Table 5-12), indicating risk from these cancers is more than chance, a determination was 

14 made that the cumulative exposure results for these two cancer types constituted the best data 

15 sets from which to calculate unit risk estimates for lymphohematopoietic cancers from the NCI 

16 cohort. 

17 Regression coefficients from the NCI log-linear trend test models for the NPCs 

18 (Hauptmann et al., 2004) and the various lymphohematopoietic cancers (Beane Freeman et al., 

19 2009) were provided by Drs. Hauptmann and Beane Freeman, respectively. These trend tests 

were of the form RR = eβ*exposure 20 . The coefficients (i.e., β) were used in lifetable analyses to 

21 calculate lifetime extra cancer risks from formaldehyde exposure (Section 5.2). Extra risk 

22 estimates for cancer incidence for the three cancer types were approximated by assuming that 

23 cancer incidence and cancer mortality have the same dose-response relationships and then using 

24 background cause-specific incidence rates instead of mortality rates in the lifetable analysis. 

25 Points of departure (PODs) based on the dose-response modeling of these cancers were 

26 calculated as the exposure concentration at which the 95% upper confidence bound on extra risk 

27 was 0.0005 (i.e., 0.05%) for NPC and for Hodgkin lymphoma and 0.005 (i.e., 0.5%) for leukemia 

28 (Sections 5.2.2 and 5.2.3). These values approximate the lower confidence bounds on dose at 

29 these extra risk levels. The values for these extra risk levels, 0.0005 and 0.005, were chosen 

30 because they are near the lower end of the observable range of the data. Having such low 

31 response levels associated with the points of departure is warranted because of the low 

32 background lifetime risks for these cancer types (e.g., 0.00022 for NPC mortality). Higher extra 

33 risk levels would entail extrapolation above the range of the bulk of the observable data to obtain 

34 PODs. The resulting effective concentration values for the selected extra risk values for cancer 

35 incidence are presented in Table 6-2. 
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1 Linear low-dose extrapolation from the PODs was used to derive unit risk estimates for 

2 NPC, Hodgkin lymphoma, and leukemia, as discussed in Section 6.2.2.4. To obtain an 

3 approximate (upper bound) unit risk estimate of the total cancer risk from formaldehyde 

4 exposure, risk estimates for these three cancer types (NPC, Hodgkin lymphoma, and leukemia) 

5 were combined assuming a normal distribution (Section 5.2.4). This was considered the most 

6 reasonable approach for estimating total cancer risk from the available data; however, it should 

7 be noted that this estimate may not reflect all of the cancer types associated with formaldehyde 

8 exposure. 

9 

10 Table 6-2: Effective concentrations (lifetime continuous exposure levels) 

11 predicted for specified extra cancer risk levels for selected formaldehyderelated cancers1

12 

13 

Cancer Type Extra Risk Level EC2 (ppm) LEC3 (ppm) 

NPC 0.0005 0.074 0.046 

Hodgkin 

lymphoma 

0.0005 0.052 0.030 

Leukemias 0.005 0.16 0.088 

14 

15 1. calculated including all person-years (see section 5.2) 

16 2. effective concentration. 

17 3. 95% lower confidence bound on the EC; this value is the POD. 

18 

19 

20 6.2.2.3. Analysis of Laboratory Animal Data 

21 Various bioassays have been conducted studying the effects of formaldehyde on rats, 

22 mice, and rhesus monkeys and have been discussed at length earlier in this document. Of these, 

23 two inhalation bioassays of rats, when combined, allow for the most robust characterization of 

24 the long-term dose-response relationship in a laboratory species. These long-term bioassays 

25 found an increased incidence of nasal SCCs in rats exposed to formaldehyde by the inhalation 

26 route (Monticello et al., 1996; Kerns et al., 1983). In the combined data, rats were exposed to 0, 

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/m3

27 ) exposure 

28 concentrations of formaldehyde (Monticello et al. 1996; Kerns et al. 1983). SCCs were observed 

29 only at 6 ppm and higher exposure concentrations. 

30 A large amount of mechanistic information relevant to the dose-response relationship of 

31 formaldehyde in the respiratory tract has been generated either following or in conjunction with 

32 these two bioassays, as reviewed in Chapter 3, 4 and 5. This information includes the following: 
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1 1. Measurements of DNA-protein cross-links (DPXs) formed by formaldehyde in F344 rats 

2 and rhesus monkeys (Casanova et al., 1989, 1994). Several PBPK models have been 

3 developed in the literature based on these data. Some of these efforts integrated the data 

4 in both species (Casanova et al., 1991; Conolly et al., 2000; Klein et al., 2009). 

5 2. Measurements of cell proliferation in F344 rats and rhesus monkeys (Monticello et al., 

6 1989, 1990, 1991, 1996). 

7 3. Simulations of airflow in anatomically realistic representations of the upper respiratory 

8 tract of the F344 rat, rhesus monkey and human, and in an idealized representation of the 

9 human lower respiratory tract, using computer and physical models (Kimbell et al., 1993; 

10 Kepler et al., 1998; Subramaniam et al., 1998). These simulations were used to predict 

11 regional formaldehyde dosimetry in the corresponding sections of the respiratory tract of 

12 these three species (Kimbell et al., 2001a, b; Overton et al., 2001). 

13 

14 The combined nasal tumor incidence data were analyzed using a multistage-weibull time15 to-tumor approach as well as biologically based dose-response (BBDR) models derived from 

16 Conolly et al. (2003) [see Crump et al. (2005), Subramaniam et al. (2007), and Appendix E for 

17 details]. The BBDR approach enabled integration of the mechanistic information and the time-to18 tumor incidence data within a single conceptual framework. 

19 

20 6.2.2.4. Extrapolation Approaches

21 An EPA inhalation unit risk is developed to estimate cancer risk from environmental 

22 exposures or in order to determine exposure levels corresponding with cancer risks as low as 1 

23 excess cancer in 10,000 or 1 excess cancer in 1 million. As neither data from animal studies, nor 

24 human epidemiological studies, provide direct observation of these low level risks, the observed 

25 exposure response relationship is extrapolated to estimate low dose risk. The model used to 

26 extrapolate below the range of exposures clearly associated with increased risk of health effects 

27 has a great influence on the inhalation unit risk, as there may be several orders of magnitude 

28 difference between the observed risk and the target risk range. In the absence of empirical data 

29 or a biologically-informed model, the EPA applies a simple straight line extrapolation from the 

30 point of departure to zero exposure (U.S. EPA, 2005a). The Mode of Action evaluation reviews 

31 available data and determines if an MOA can be sufficiently established and whether it informs 

32 the shape of the exposure-response relationship. 

33 

34 

35 
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1 Low-dose extrapolation for Lymphohematopoietic cancers: 

2 Formaldehyde is a mutagen, and known to act directly on cells at the site of first contact. 

3 Clastogenic effects have been documented in formaldehyde-exposed workers including 

4 peripheral blood lymphocytes and circulating stem cells (Zhang et al., 2010). Thus a mutagenic 

5 MOA has been hypothesized for lymphohematopoeitic cancers, and supports a linear low-dose 

6 extrapolation of human cancer risk. Additionally, formaldehyde may also induce some form of 

7 bone marrow toxicity, as suggested by observed pancytopenia in exposed workers (Tang et al., 

8 2008, Zhang et al., 2010). However, as the mechanism of transport to the bone marrow, and 

9 biological activity leading to the observed toxicity are unknown, this information does not inform 

10 the low-dose extrapolation. Although the mechanisms underlying formaldehyde-induced 

11 leukemia and lymphoma are still largely speculative, there is little doubt of an association 

12 between formaldehyde exposures and lymphohematopoeitic cancer mortality, especially for 

13 myeloid leukemia. Therefore, without a known MOA which would justify an alternative 

14 approach, and with a hypothesized mutagenic MOA under consideration which supports a simple 

15 straight line extrapolation from the point of departure to zero risk at zero exposure, this is applied

16 when estimating human cancer risk from both leukemia and Hodgkins lymphoma from the NCI 

17 cohort. 

18 

19 Low-dose extrapolation for cancer of the upper respiratory tract: 

20 There are multiple plausible MOAs for formaldehyde carcinogenesis regarding upper 

21 respiratory tract cancers (Section 4.5.3), however they are not all applicable to the lower end of 

22 the exposure response curve. For example, although regenerative cell proliferation associated 

23 with focal and gross tissue lesions due to cell death may contribute to the high incidence of rat 

24 nasal tumor in F344 rats, these mechanisms may not be operative in the low exposure region 

25 expected for human environmental exposure (e.g. less than 1ppm) and therefore may not inform 

26 low-dose extrapolation. There are MOAs which are more appropriate to the low-dose region. 

27 Specifically, formaldehyde is a known mutagen, may inhibit DNA repair activity and may have 

28 additional activity as a tumor promoter. Finally, other affects such as formaldehyde-induced cell 

29 proliferation, imunosuppression and disruption of the mucociliary apparatus may influence both 

30 the level of tissue damage and ultimately cancer incidence. 

31 EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) recommend using 

32 biologically based dose-response (BBDR) models for extrapolation when data permit. Conolly et 

33 al. (2003, 2004) developed BBDR models to predict squamous cell carcinoma risk in the rat and 
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human respiratory tract at exposures well below the range of the observed animal data.17 1 The 

2 primary conclusion from their modeling effort was that human exposure standards protective of 

3 effects of formaldehyde-induced cytotoxicity should be sufficient to protect from the potential 

4 carcinogenic effects of formaldehyde. The authors assessed that such a conclusion was 

conservative in the face of model uncertainties.18 5 This assessment’s evaluation of the BBDR 

6 models and alternative implementations (detailed in Section 5.3) finds that these models may not 

7 provide conservative estimates of human cancer risk below the range of observed data. 

8 The current assessment evaluated the uncertainties in the above BBDR model extensively 

9 and examined alternative parameterizations of the modeling in Conolly et al. (2003, 2004). These 

10 alternatives and the original model were equally consistent with the experimental data but 

11 resulted in maximum likelihood estimates of added human risk that ranged from negative to large 

12 positive values at environmental exposure concentrations. Model uncertainty far exceeded 

13 statistical uncertainty (Table E-4 in Appendix E). Each of these models, including the modeling 

14 in Conolly et al., 

15 

16 1. was judged to be just as biologically plausible, 

17 2. described the rat tumor incidence data equally well, 

18 3. was based on different characterizations of the same empirical cell kinetic data, and 

19 4. was based on the same empirical data on DPX measurements. 

20 

This assessment’s evaluation19 21 of the above models (detailed in Section 5.3) concluded 

22 that these models, including alternative implementations of those in Conolly et al. (2003, 2004), 

23 were too uncertain to be useful for low-dose extrapolation of risk. It may be noted that the 

24 sensitivity analyses on the basis of which these conclusions were reached have been criticized as 

25 resulting in implausible risk estimates (given the epidemiologic data) as a consequence of 

26 implementing model variations that are not biologically reasonable (Conolly et al. 2009). This 

 

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, 2004) concluded that the directly mutagenic action of formaldehyde 

does not play a significant role in formaldehyde carcinogenicity. 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 action of formaldehyde was used. 

19 The scope of this evaluation was informed by views provided by several experts convened by EPA in October 

2004. The participants were Drs. Rory Conolly, Kenny Crump, Linda Hanna, Dale Hattis, Julia Kimbell, George 

Lucier, Christopher Portier and Fred Miller (guest participant). The meeting agenda and summary are provided in 

Appendix H. 
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1 criticism was rebutted by Crump et al. (2009) on biological and epidemiological grounds. These 

2 debates have been discussed fully in Appendix F. In particular, the assessment concludes that: 

3 

4 • When used for the purpose of extrapolating risk, the BBDR models did not appear to 

5 reasonably constrain either 

6 risk estimates extrapolated from the F344 rat to the human, regardless of whether the 

7 extrapolation was carried out at low or comparable exposures, or 

8 risk estimates for the F344 rat when extrapolated outside the range of observable data. 

9 • Furthermore, human risk calculated from these BBDR models was numerically unstable 

10 when certain parameter conditions were realized (Section 5.3.3 and Appendix F). 

11 • Therefore, clonal growth modeling was not found to be a useful approach for human 

12 extrapolation of rodent risk estimates. The current assessment concludes that the result in 

13 Conolly et al. cannot be considered to be “conservative in the face of model 

14 uncertainties.” 

15 

16 However, using the BBDR model to characterize the dose-response in the range of the 

17 available data was judged to have the advantage of utilizing the available biological and 

18 dosimetry data on formaldehyde in an integrated manner as well as providing statistically sound 

19 descriptions of the empirical tumor incidence data. Therefore, this assessment uses the BBDR 

20 modeling of the rat data to derive multiple PODs (for SCC in the respiratory tract) in the range of 

21 the observed data and uses model-derived internal dose estimates. For the reasons detailed above, 

22 the BBDR modeling is not used to extrapolate far below the observed data. 

23 The lowest observed incidence of SCC in the bioassays used in the dose-response 

24 assessment was equal to 0.0087 (at 6 ppm exposure). In addition, the BBDR modeling used data 

25 on cell proliferation and formation of DPXs that informed the modeling of the tumor data at the 

26 lower exposure concentrations of 0.7 and 2.0 ppm. Thus, the available data supported estimation 

27 of response levels below the 10% response level commonly used in BMD analyses of tumor data. 

28 Therefore, points of departure corresponding to 95% statistical upper bound levels of extra risk 

29 of 0.005, 0.01 and 0.1 were estimated when the BBDR modeling was used. 

30 

31 Summary: 

32 As discussed earlier in the hazard characterization, formaldehyde is a direct-acting 

33 mutagen, and its genotoxic effects have been observed following human occupational 
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exposures.

20 1 Furthermore, a low-dose nonlinear MOA for formaldehyde-induced 

2 lymphohematopoietic cancers, NPCs, or cancers in other regions of the respiratory tract has not 

3 been established. In particular, the formation of DPXs by formaldehyde, considered a dose 

4 surrogate for the molecular dose associated with formaldehyde’s mutagenic action, has been 

5 observed at doses well below those considered cytotoxic. Therefore, linear low-dose 

6 extrapolation from the suitably chosen PODs was considered most appropriate for all the cancers 

7 (whether the PODs were based on epidemiological data or rodent bioassay data), which is also in 

8 accordance with EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). 

9 

10 6.2.2.5. Inhalation Unit Risk Estimates for Cancer

11 The epidemiological and rodent inhalation data indicate multiple sites of concern. Unit 

12 risk estimates calculated separately from these data are summarized in Table 6-3. 

13 As can be seen in the Table 6-3, the unit risk estimate based on human data for NPC is in 

14 the range of the estimates calculated for respiratory tract cancer from the rodent nasal cancer 

15 data. Experimental animal data were inadequate for estimating risk of lymphohematopoietic 

16 cancers. The unit risk estimate for Hodgkin lymphoma is also in the same range, while the unit 

17 risk estimate for leukemia and the total cancer unit risk estimate are up to 4-fold higher. 

18 As documented in EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 

19 when high-quality human data are available, they are generally preferred over laboratory animal 

20 data for quantitative risk assessment. Thus, the preferred (plausible upper bound) unit risk 

estimate in this assessment is the value of 8.1 × 10–2 per ppm (6.6 × 10–5 per μg/m321 ) based on 

22 (adult) human data for NPC, Hodgkin lymphoma, and leukemia. Note that, as discussed in 

23 Section 6.2.2.6 below, if there is early-life exposure, the age-dependent adjustment factors 

24 (ADAFs) should be applied, in accordance with EPA’s Supplemental Guidance for Assessing 

25 Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). 

26 

27 6.2.2.6. Early-Life Susceptibility 

28 There are no chemical-specific data for quantitatively addressing the susceptibility of 

29 different life stages to carcinogenicity from inhalation exposure to formaldehyde. As 

30 documented in section 4.5, formaldehyde is a mutagenic carcinogen and the weight of evidence 

31 suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic 

32 MOA. Therefore, increased early-life susceptibility should be assumed and, if there is early-life 

 

20 While formaldehyde may also contribute to mutations indirectly, such an effect is likely to be relevant only at the 

higher doses. 
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1 exposure, the ADAFs should be applied, in accordance with EPA’s Supplemental Guidance for 

2 Assessing Susceptibility from Early-Life Exposure to Carcinogens (U.S. EPA, 2005b). See 

3 Section 5.4.4 for details on the application of the ADAFs. 

4 

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

6 experimental animal data 

7 

Cancer typea Dose metric Unit Risk Estimateb

(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: 0.081c

Based on Experimental Animal Data 

Squamous cell carcinoma 

of the respiratory tract 

Local dose (flux) of 

formaldehyde in 

pmol/mm2/hour 

0.011 – 0.022d 

8 

a 9 the unit risk estimates are all for cancer incidence. 

b 10 these unit risk estimates do not include ADAFs (see Section 6.2.2.6 below). 

c

11 this total cancer unit risk estimate is an estimate of the upper bound on the sum of risk estimates calculated 

12 for the 3 individual cancer types (nasopharyngeal cancer, Hodgkin lymphoma, and leukemia); it is not the 

13 sum of the individual (upper bound) unit risk estimates (see Section 5.2.4). 

d

14 values are similar to estimates from Schlosser et al. (2003). These authors determined their PODs based 

15 on tumor and cell proliferation as endpoints, and extrapolated benchmark exposure concentrations to 

16 humans using formaldehyde flux to the tissue and DPX concentrations as internal dose metrics. 

17 

18 

19 Accordingly, for full lifetime exposures, the overall (plausible upper bound) unit risk 

estimate is 0.13 per ppm (1.1 × 10–4 per μg/m320 ) for the three cancer types (NPC, Hodgkin 

21 lymphoma, and leukemia) combined (see Table 5-26 for calculations). 

22 

23 6.2.2.7. Uncertainties in the Quantitative Risk Estimates 

24 Uncertainties in the risk estimates based on the human data are discussed in detail in 

25 Sections 5.2.2.4 and 5.2.3.4. Major uncertainties inherent in the NPC, Hodgkin lymphoma, and 

26 leukemia risk estimates are 

27 
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1  the retrospective exposure estimation, 

2  the appropriateness of the dose-response model and exposure metric, and 

3  the extrapolation from occupational exposures to lower environmental exposures. 

4 

5 In addition, the NPC and Hodgkin lymphoma estimates are limited by the sparse data for these 

6 cancers in the NCI cohort study (estimates are based on the exposure-response modeling of only 

7 9 NPC deaths and 27 Hodgkin lymphoma deaths). 

8 Of note, Marsh et al. (2002, 1996) independently studied one of the 10 plants that was in 

9 the NCI study, and there were large differences in the exposure estimates for that plant from the 

10 two different studies. If the exposure estimates of Marsh et al. (2002) are closer to the true 

11 exposures, then the potency of formaldehyde could be greater than reflected in the risk estimates 

12 derived from the NCI data. 

13 The linear low-dose extrapolation (see Section 6.2.2.4) from the 95% lower bound on the 

14 exposure level associated with the benchmark response is generally considered to provide a 

15 plausible upper bound on the risk at lower exposure levels. The strong association with peak 

16 exposures for all 3 cancer types in the NCI study suggests that dose-rate effects may be operative 

17 (i.e., the risk from peak occupational exposures may be greater than the [linearly] proportional 

18 risks from lower exposures and, similarly, the risk from an occupational cumulative exposure 

may be greater than the proportional risk from a lower environmental cumulative exposure).21 19 

20 Any such dose-rate effects would not be reflected in the linear low-dose extrapolation approach 

21 used in this assessment. Actual low-dose risks may be lower to an unknown extent. 

22 Other significant uncertainties may also remain. For example, risk estimates could not be 

23 derived from the NCI cohort study for rare upper respiratory tract cancers other than NPC. In 

24 addition, although unit risk estimates were derived for Hodgkin lymphoma and leukemia because 

25 they exhibited the strongest trend results of the lymphohematopoietic cancers using the 

26 cumulative exposure metric, it is uncertain which specific lymphohematopoietic cancer subtypes 

27 are associated with formaldehyde exposure. Furthermore, the potential role of particulates in the 

28 NPC risk is unclear. Moreover, as for all occupational epidemiology studies, there is uncertainty 

29 in extrapolating risk from an adult worker population (in this case predominantly white males) to 

30 the more diverse general population. 

31 

 

21 Dose-rate effects are also suggested by the very steep, nonlinear exposure-response relationships observed in the 

rodent cancer bioassays, although, in the rodents, this steep increase in tumor incidence at high exposures is thought 

to be due to the contribution of cytotoxicity and regenerative proliferation, which is not apparent with the human 

exposures (Section 4.5). 
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1 Despite inevitable uncertainties, it is important not to lose sight of the strengths of the 

2 estimates, which are based on human data from a high-quality NCI study. In addition to the use 

3 of internal analyses and the extensive exposure assessment and consideration of potential 

4 confounding or modifying variables, the NCI study has a large cohort that has been followed for 

5 a long time. With the additional follow-up through 2004, reflected in the lymphohematopoietic 

6 cancer results of Beane Freeman et al. (2009), the median duration of follow-up was 42 years, 

7 and the 25,619 cohort members had accrued 998,106 person-years of follow-up. 

8 Significant uncertainties also exist in the risk estimates derived from the rodent bioassay 

9 data. In general, the difficulties in extrapolating from experimental animal bioassays are 

10 considerable, and the use of human data is preferred, while recognizing the different uncertainties 

11 that are present in risk estimates based on epidemiological data. 

12 In the case of formaldehyde, this general uncertainty associated with extrapolation from 

13 rodent data is increased due to the highly curvilinear nature of the dose–response relationships 

14 associated with DPX formation, labeling index data, and tumor responses. The mechanistic 

15 interpretation of these observed data has provided grounds for arguments in the literature that 

16 formaldehyde tumorigenicity (at exposures ≥ 6 ppm) should be uncoupled from its potential 

17 carcinogenicity in the low-dose region. 

18 Quantitative models have been used in the literature to further argue that the observed 

19 risk in animal experiments is entirely due to cell proliferation induced by regenerative 

20 hyperplasia in response to cell injury at cytotoxic doses, i.e., without a relevant role for the direct 

21 mutagenic action of formaldehyde. In the context of using these data for quantitative risk 

22 assessment, this document notes that such an inference of the data has been found to be 

23 extremely uncertain. An analysis of the uncertainties in interpreting the available data has shown 

24 that the directly mutagenic component could be important in explaining the high-dose effect 

25 (Subramaniam et al., 2007). 

26 While acknowledging these substantial difficulties, the quantitative dose-response 

27 modeling of the rat data does allow inference about upper bound risks for respiratory cancer, 

28 consistent with the observed experimental tumorigenicity. These upper bound risk estimates are 

29 consistent with those estimated from the epidemiological data; however, such a consistency may 

30 be entirely artifactual. As noted earlier, the BBDR modeling helped characterize some of the 

31 uncertainty associated with extrapolating from the rodent data to the environmental risk in 

32 people. The actual risk may be substantially lower or higher than the reasonable upper bound risk 

33 estimated from the animal data. 

34 

35 
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1 6.2.2.8 Conclusions 

2 Cancer unit risk estimates for formaldehyde inhalation exposure were derived from both 

3 human and laboratory animal data. As documented in EPA's Guidelines for Carcinogen Risk 

4 Assessment (U.S. EPA, 2005a), when high-quality human data are available, they are generally 

5 preferred over laboratory animal data for quantitative risk assessment. Thus, the preferred unit 

6 risk estimate in this assessment is based on human data for NPC, Hodgkin lymphoma, and 

7 leukemia from a high-quality NCI occupational cohort study (Hauptmann et al., 2004; Beane 

8 Freeman et al., 2009). (The qualitative hazard assessment suggests causal associations between 

9 formaldehyde exposure and other cancer types as well [e.g., other upper respiratory tract cancers 

10 and possibly other lymphohematopoietic cancers; see Section 4.5], but quantitative data from the 

11 NCI cohort study were not amenable for deriving quantitative risk estimates for those cancer 

12 types. Because there were not clear exposure-response data for these cancer types in that cohort 

13 study [based on cumulative exposure], any contributions to the total cancer risk from 

14 environmental formaldehyde exposure for these cancers are not expected to be large; however, 

15 this is a source of uncertainty.) 

16 The unit risk estimate for the total cancer incidence extra risk for these three cancer types 

combined based on the (adult) human data is 8.1 × 10

-2 per ppm (6.6 × 10-5

 per μg/m317 ). As 

18 documented in Section 4.5, formaldehyde is a mutagenic carcinogen and the weight of evidence 

19 suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic 

20 MOA. Therefore, as there are no chemical-specific inhalation data on cancer susceptibility at 

21 different life-stages, increased early-life susceptibility is assumed and ADAFs should be applied 

22 in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early-Life 

23 Exposure to Carcinogens (U.S. EPA, 2005b). Applying the ADAFs, the overall (upper bound) 

unit risk estimate for full lifetime exposure is 0.13 per ppm (1.1 × 10–4 per μg/m3

24 ) for the three 

25 cancer types (NPC, Hodgkin lymphoma, and leukemia) combined. Using this lifetime unit risk 

estimate, the upper bound estimate of the cancer risk at the RfC of 1 ppb is 1 × 10–4 26 . 

27 

28 6.3. SUMMARY AND CONCLUSIONS 

29 Seven different non-cancer health effects were identified from formaldehyde inhalation 

30 exposure studies, including: 1) sensory irritation of the eyes, nose, and throat, 2) upper 

31 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 

32 behavioral toxicity, 6) reproductive and developmental toxicity, and 7) immunological toxicity. 

33 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 

34 derived candidate RfCs for critical effects based on seven key studies. Three co-critical studies 

35 were selected which provide similar cRfCs for related adverse health effects observed in 
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1 residential populations including children i.e., increased asthma incidence, decreased pulmonary 

2 function, increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 

3 2002; Garrett et al., 1999; Krzyzanowski et al., 1999). The resulting cRfCs fall in a range 

4 between 2.8 and 11 ppb, depending on the study, or endpoints considered, and the application of 

5 alternative uncertainty factors for human variability (Table 6-1). The representative RfC for the 

6 co-critical studies is taken as the average of the cRfCs (Section 6.2.1.2). 

7 EPA has assessed the adequacy of the overall database for RfC derivation, and although 

8 the database is quite large, and provides significant information on well studied POE effects. 

9 There are remaining uncertainties in the database. Most notably, there is a need for additional 

10 exposure-response information for observed neurotoxic effects, reproductive and developmental 

11 effects as well as a two-generation study to evaluate the effects of formaldehyde exposure on 

12 reproductive and developmental endpoints. EPA is considering 4 options to address database 

13 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 

14 appropriate to account for human variability and deficiencies in the overall database. For this 

15 reason, several alternatives have been presented. EPA is seeking advice from the NAS and the 

16 public on this matter. 

17 Formaldehyde is carcinogenic to humans by the inhalation route of exposure. There is 

18 sufficient evidence of a causal association between formaldehyde exposure and cancers of the 

19 upper respiratory tracts, with the strongest evidence for nasopharyngeal and sino-nasal cancers. 

20 There is also sufficient evidence of a causal association between formaldehyde exposure and 

21 lymphohematopoietic cancers, with the strongest evidence for Hodgkin lymphoma and leukemia, 

22 particularly myeloid leukemia. The (upper bound) unit risk estimate for the total cancer 

incidence based on (adult) human data is 8.1 × 10-2 per ppm (6.6 × 10-5

 per μg/m323 ). Applying the 

24 age-dependent adjustment factors for increased early-life susceptibility, the overall combined 

cancer unit risk estimate for full lifetime exposure is 0.13 per ppm (1.1 × 10–4 per μg/m325 ). 
This document is a draft for review purposes only and does not constitute Agency policy.

R-1 DRAFT—DO NOT CITE OR QUOTE 

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This document is a draft for review purposes only and does not constitute Agency policy.

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This document is a draft for review purposes only and does not constitute Agency policy.

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from exposure to formaldehyde. Office of Pesticides and Toxic Substances, Washington, DC. 

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assessment. Prepared by the Environmental Criteria and Assessment Office, Office of Health and 

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Substances, Washington, DC. 

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toxicity studies. Federal Register 59(206):53799. Available from: 

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This document is a draft for review purposes only and does not constitute Agency policy.

R-55 DRAFT—DO NOT CITE OR QUOTE 

U.S. EPA. (2000b) Benchmark dose technical guidance document [external review draft]. Risk 

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<http://www.epa.gov/iris/backgr-d.htm>. 

U.S. EPA. (2000c) Supplementary guidance for conducting for health risk assessment of 

chemical mixtures. Risk Assessment Forum, Washington, DC; EPA/630/R-00/002. Available 

from: <http://www.epa.gov/iris/backgr-d.htm>. 

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U.S. EPA. (2002b) Toxicological Review and IRIS Summary of 1,3-Butadiene. Integrated Risk 

Information System, National Center for Environmental Assessment, Washington, DC. 

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Policy Council. 

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applications at EPA. Prepared by the Genomics Task Force Workgroup. EPA 100/B-04/002. 

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Washington, DC; EPA/630/P-03/001B. Available from: <http://www.epa.gov/iris/backgrd.htm>. 

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This document is a draft for review purposes only and does not constitute Agency policy.

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