DRAFT-DO NOT CITE OR QUOTE EPA/635/R-10/002C

www.epa.gov/iris

TOXICOLOGICAL REVIEW OF

FORMALDEHYDE

INHALATION TOXICITY

(CAS No. 50-00-0) 

 

In Support of Summary Information on the 

Integrated Risk Information System (IRIS)

VOLUME 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III-ii DRAFT—DO NOT CITE OR QUOTE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III-iii DRAFT—DO NOT CITE OR QUOTE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. 3

H/14C ratios in macromolecular extracts from rat tissues following exposure 

to 14C and 3

H-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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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

N6

-hmdA N6-hydroxymethyldeoxyadenosine

N4-hmdC N4-hydroxymethylcytidine

N2

-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
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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

36
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1 5.1. INHALATION REFERENCE CONCENTRATION (RfC)

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

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

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

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

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

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

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

9 toxicity. For each health effect category,, studies that may adequately inform the exposure10 response relationship for specific critical effects are identified for consideration in RfC 

11 derivation.

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

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

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

15 study population, exposure regimen, quality of exposure assessment, quality of exposure16 response assessment, exposure levels at which effects were seen and statistical power of the 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

31 residential studies, with the exception of decreased FDR (observed in an occupational study of 

32 women in the woodworking industry). 

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

34 the health effects from formaldehyde exposure is large; however, the available studies for some 

35 types of effects are limited. Limitations in the existing database are discussed in Section 5.1.3, 
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1 specifically regarding understanding the reproductive and developmental effects and the 

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

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

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

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

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

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

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

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

10 database uncertainty factor. 

11

12 5.1.1. Candidate Critical Effects by Health Effect Category

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

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

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

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

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

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

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

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

21 category.

22 For each health effect category, specific studies that may adequately inform the exposure23 response relationship for critical effects are identified for consideration in RfC derivation. In 

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

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

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

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

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

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

30 primary or secondary effects of RB in the rodents. 

31

32 5.1.1.1. Sensory Irritation of the Eyes, Nose, and Throat 

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

34 irritation; specific effects include lacrimation, burning of the eyes and nose, rhinitis, burning of 

35 the throat, and cough (Feron et al., 2001). Chemical irritants such as formaldehyde bind to 
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1 protein receptors of the trigeminal nerve, triggering a burning and painful sensation. This 

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

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

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

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

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

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

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

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

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

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

12 the uncertainties in extrapolation from responses in laboratory animals to expected responses in 

13 humans, the available human studies are preferred. 

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

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

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

17 counts, lacrimation). Several acute chamber studies support development of a concentration18 response relationship for sensory irritation, identifying an effect level for various exposure 

19 durations (Kulle, 1993; Andersen and Mølhave, 1983; Bender et al., 1983; Weber-Tschopp et al., 

20 1977). Arts et al. (2006b) reviewed several studies and performed BMD analyses, reporting 

21 10% extra risk BMCL values for reported eye discomfort of 560 and 240 ppb for 3 and 5 hour 

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

23 exposures (Bender et al., 1983; Weber-Tschopp et al., 1977). These acute studies support a role 

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

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

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

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

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

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

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

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

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

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

for the cohort as a whole, where worker exposure ranged from 0.05 to 0.5 mg/m3 34 formaldehyde 

8-hr time-weighted average (TWA), with a mean of 0.26 mg/m3 35 (210 ppb). The daily TWA does 
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1 not reflect the peak exposures experienced during specific work tasks. Although this study 

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

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

4 especially in the range of environmental exposures.

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

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

7 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). Each study reports site8 specific exposure measurements and presents some metric of individual exposure. These 

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

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

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

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

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

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

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

16 potential priniciple studies for RfC derivation. Each of these studies is further evaluated and a 

17 cRfC developed for consideration (Section 5.1.2).

18

19 5.1.1.2. Upper Respiratory Tract Pathology

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

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

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

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

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

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

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

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

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

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

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

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

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

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

34 1988; Woutersen et al., 1987; Morgan et al., 1986a, b, 1983; Swenberg et al., 1986, 1983) and 
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1 monkey (Rusch et al., 1983), robust human data are available, and these human data are 

2 preferred 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 

35 well as post-shift versus pre-shift differences in pulmonary function in workers with regular 
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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 

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

5 the acute 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) 

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

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

19 first 2 weeks of the study when formaldehyde concentrations collected in the breathing zones 

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

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

22 PEF. These 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 

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

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

33 interaction between time and asthma and eye and nose symptoms of irritation. The Kriebel et al. 

34 (1993) study is considered of sufficient quality to support an acute RfC but the quantitative 

35 details on the initial acute effects among the naively exposed students are not adequately 
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1 provided. The findings of the Kriebel et al. (2001) study were confounded by decreased class 

2 attendance, which dropped from 37 in the first week to 20 in week 6 and to just 10 students by 

3 week 10. While the Kriebel et al. (2001) study could be useful as a supportive study for naively 

4 exposed students, the 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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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 

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

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

28 nitrogen dioxide concentrations. In children, formaldehyde concentrations of 60-140 ppb 

29 increased the prevalence of physician-diagnosed asthma and bronchitis. Among adults, there was 

30 a statistically significant non-linear relationship with decreased morning PEFR for formaldehyde 

31 concentration <40 ppb. Nonetheless, this strong study had only minor weaknesses such as 

32 measurement error and the fact that it was a cross-sectional study. However, random 

33 measurement error tends to attenuate any true effect and is unlikely to have produced a spurious 

34 effect. It is unlikely that these findings were the product of unmeasured or residual confounding 

35 as the analyses controlled for smoking as well as nitrogen dioxide levels and there is no evidence 
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1 of alternative factors that were correlated with formaldehyde concentrations and more strongly 

2 associated with pulmonary function. This study of a large and representative sample from a 

3 diverse study population with a well-quantified concentration-response function and is further 

4 considered for RfC derivation. 

5

6 5.1.1.4. Asthma and Allergic Sensitization (Atopy)

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

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

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

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

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

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

13 2003; Kuby, 1991).

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

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

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

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

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

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

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

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

22 oxidative stress and reactive oxygen species (ROS).

23

24 Epidemiologic Studies:

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

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

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

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

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

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

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

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

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

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

35
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1 The association between formaldehyde and asthma has been studied by examining 

2 occupational exposures (Fransman et al., 2003; Malaka and Kodama, 1990), school-related 

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

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

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

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

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

8 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 9 (65 ppb) and the majority of 

samples were below the limit of detection which was reported to be 0.03 mg/m3 10 (24 ppb). 

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

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

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

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

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

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

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

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

19 (Malaka and Kodama, 1990).

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

21 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/m3 22 ) 

indoors and 5.8 μg/m3 (range 5.0–7.0 μg/m3 23 ) outdoors. Cumulative asthma (i.e., physician24 diagnosed asthma since birth) and daytime attacks of breathlessness were found to be associated 

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

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

27 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 28 ). One difference 

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

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

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

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

33 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 34 [95% 

35 CI: 1.1–2.6]) and at higher total concentrations of mold (OR=4.7 per 10-fold increased in total 
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1 molds [95% CI: 1.2-18.4] in the classroom air. The finding in increase health effects due to 

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

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

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

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

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

7 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 8 ) is OR1=1.13 per GSD and 

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

OR3

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

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

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

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

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

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

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

25.9 μg/m3

, range 2.0–66.8 μg/m3 21 ) (Palczynski et al., 1999), although they noted the incidence 

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

23 were too small for statistical evaluation.

=1.06 for a comparison of risks at the minimum value of total molds (5*103/m3 10 ) to 

11 10*minimum. As it appears that the magnitude of the formaldehyde effect is stronger than that 

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

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

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

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

26 association, but some individual variables showed an increased risk. For example, the reported 

27 risk ratio for having new construction or remodeling performed in the house in the past 4 months 

28 was 2.5 (95% CI: 1.7–3.9). The risk ratio for having new or upholstered furniture in the house 

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

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

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

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

 

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

2 (range 4.27–14.02 ppb). There was a positive association between asthma symptom scores 

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

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

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

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

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

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

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

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

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

12 (2005) was followed up with a more sophisticated analysis of the same children in the same 

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

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

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

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

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

18 two-fold increase in risk.

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

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

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

22 4 seasonal in-home sampling events across the year for bedrooms and 4–day passive samples 

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

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

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

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

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

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

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

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

31 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/m3 32 ) 

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

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

35 sensitization are clearly shown and further substantiated with multivariate regression controlling 
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1 for potential confounders. In logistic regressions, both the prevalence and severity of allergic 

2 sensitization to 12 common allergens increased with increasing formaldehyde concentration in 

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

10 μg/m3 4 was OR=1.34 which increased when adjusted for parental asthma and gender to and 

odds ratio of 1.42 per 10 μg/m3 5 (95% CI: 0.99-2.04). Passive smoking, the presence of pets, 

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

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

8 calculated respiratory symptom score was increased and demonstrated a significant relationship 

9 to increased formaldehyde concentration in a multiple linear regression after adjusting for 

10 multiple risk factors and interactions. For each of these endpoints, severity/incidence was 

increased in the medium (20–50 μg/m3

) and high (>50 μg/m3 11 ) exposure groups relative to the 

low (<20 μg/m3 12 ) exposure group, based on the highest of four seasonal 4-day formaldehyde 

13 measurements in the home. 

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

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

16 2002). The study, which comprises 88 cases of children discharged from the emergency 

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

18 104 controls, provides a positive exposure-response relationship. Seasonal in-home 

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

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

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

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

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

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

25 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 26 (48 ppb) 

27 (OR of 1.39). Analysis of the data with formaldehyde as a continuous variable indicated there 

28 was a statistically significant increase in the risk of asthma (3 % increase in risk per every 

29 10 ug/m3 increase in formaldehyde level. All analyses controlled for other indoor air pollutants, 

30 allergen levels, relative humidity, and indoor temperature as well as other risk factors.

31 A study of 202 households (mean formaldehyde level of 26 ppb) found that among children aged 

32 6–15 years old and exposed to environmental tobacco smoke, the prevalence of asthma was 

33 45.5% for those with measured levels of formaldehyde in the kitchen >60 ppb. The prevalence 

34 of asthma dropped to 15.1% for levels ≤40 ppb and 0% for 41–60 ppb. No trend in asthma 

35
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1 prevalence was seen for children who were not exposed to environmental tobacco smoke 

2 (Krzyzanowski et al., 1990).

3 Finally, a study by Norback et al. (1995) reported mean levels of formaldehyde were 

29 μg/m3 (range <5–110 μg/m3 4 ) in the bedrooms of individuals experiencing nocturnal 

breathlessness compared with formaldehyde levels of 17 μg/m3 (<5–60 μg/m3 5 ) among those 

6 without nocturnal breathlessness. The OR for this association was 12.5 (95% CI: 2.0–77.9) and 

7 the effect was substantially stronger in magnitude than the associations observed for toluene, 

8 terpenes and volatile organic compounds which makes confounding by those co-exposures 

9 unlikely.

10

11 Supporting animal studies:

12 Several animal studies report increased airway resistance and BC due to inhalation 

13 exposures to formaldehyde (Nielsen et al., 1999; Swiecichowski et al., 1993; Biagini et al., 1989; 

14 Amdur, 1960). Changes in pulmonary resistance were observed as early as 10 minutes after 

15 exposure (Biagini et al., 1989), and reported effect levels ranged from 0.3–13 ppm. Other 

16 pulmonary effects were reported in conjunction with BHR, such as increased tracheal reactivity 

17 and decreased pulmonary elasticity (Swiecichowski et al., 1993; Amdur, 1960). Although BHR 

18 is a common result of Type I hypersensitivity reaction to an allergen, the observation of BHR 

19 alone is not sufficient to demonstrate that an agent induces Type 1 hypersensitivity. 

20 BHR may be directly induced both pharmacologically and neurogenically (Joos, 2003; 

21 Cain, 2001; Meggs, 1995). There is little evidence that formaldehyde itself is an allergen 

22 recognized by the immune system, especially via inhalation (Lee et al., 1984). Although 

23 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 

24 experimental systems, these immunomodulatory effects do not support a type 1 hypersensitivity. 

25 IgE was unchanged (Fujimaki et al., 2004a; Lee et al., 1984), and cytokine profiles were not 

26 consistent with the Th-2 cytokines expected in IgE mediated hypersensitivity (Fujimaki et al., 

27 2004a; Ohtsuka et al., 2003). 

28 Formaldehyde-induced dermal sensitization show parallel results. The physical signs of 

29 irritation and sensitization are consistently shown (e.g., rashes, edema). Some involvement of 

30 the immune response has been demonstrated with positive LLNA assays, indicating proliferation 

31 of lymphocytes in lymph nodes draining the affected area (Hilton et al., 1998; Arts et al., 1997). 

32 Increased expression of Th-2 cytokines in the lymph nodes of mice given dermal applications of 

33 formaldehyde does indicate an immune component to the observed sensitization. However, the 

34 response does not seem to be mediated by IgE (Arts et al., 1997; Lee et al., 1984). 

35
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1 Ito et al. (1996) reported that a tachykinin NK1 receptor, but not the histamine H1 or 

2 bradykinin B2 receptors, is involved in formaldehyde-induced vascular permeability. 

3 Neuropeptides NGF and substance P were affected in BAL and stimulated splenocytes from 

4 formaldehyde-exposed mice, with greater effects seen in OVA-immunized mice. Tachykinins 

5 (e.g., substance P and neurokinin A) are produced by nerve cells and can directly stimulate 

6 bronchoconstriction (Van Schoor et al., 2000). Substance P is also a mediator of neurogenic 

7 inflammation. Therefore, although formaldehyde may induce some of the symptoms of type 1 

8 hypersensitivity, these symptoms are more likely neurogenic than immunogenic in origin.

9 In contrast, formaldehyde enhances immunogenic hypersensitivity of known allergens 

10 (Sadakane et al., 2002; Riedel et al., 1996; Tarkowski and Gorski, 1995). This potentiation 

11 varied based on sensitization protocols (respiratory tract versus systemic, frequency and timing 

12 of immunization, allergen, etc.) and formaldehyde exposure regimens (concentration, continuous 

13 versus intermittent exposures). Taken as a whole, the results support the finding that 

14 formaldehyde exposure can aggravate a type 1 hypersensitivity response (Table 4-53).

15 The mechanism underlying this response has not been elucidated. Formaldehyde16 induced IgE production has been reported in some studies (Vandenplas et al., 2004; Wantke et 

17 al., 1996a). Other studies suggest that this effect does not appear to be immunogenic in nature 

18 (Fujimaki et al., 2004; Lee et al., 1984). Although formaldehyde exposure has been reported to 

19 alter cytokine levels and immunoglobulins in some experimental systems (Fujimaki et al., 2004a; 

20 Ohtsuka et al., 2003), these immunomodulatory effects do not support immunogenically 

21 mediated type 1 hypersensitivity.

22 These decrements may be mediated via neurogenic potentiation (Sadakane et al., 2002; 

23 Riedel et al., 1996; Tarkowski and Gorski, 1995). Tarkowski and Gorski (1995) suggest that 

24 formaldehyde may increase permeability of respiratory epithelium and destruction of 

25 immunologic barriers. Tachykinin NK1 receptor and various neuropeptides (NGF and substance 

26 P) have been implicated in formaldehyde-induced sensitization and lend weight of evidence to a 

27 neurogenic MOA (Van Schoor et al., 2000; Ito et al. 1996).

28

29 5.1.1.5 Immune Function

30 Although there are some indications of formaldehyde-induced immunomodulation in 

31 laboratory animal studies (Jakab, 1992; Morgan et al., 1986a, b, c; Leach et al., 1983) and 

32 reports of increased upper respiratory tract infections in formaldehyde-exposed workers 

33 (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness and Nethercott, 1989), the overall 

34 database for toxic effects on immune function and competence is very limited. A study of 

35 workers using carbamide-formaldehyde glue indicates decreased neutrophil respiratory burst 
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1 activity (NRBA) (Lyapina et al., 2004). NRBA was reduced in workers with URT inflammation 

2 and long-lasting respiratory tract infections, compared with healthy controls, and in 

3 formaldehyde-exposed workers with slight or no respiratory infections. The authors 

4 hypothesized that the decreased NRBA in symptomatic workers may be an indication of 

5 formaldehyde effects in a susceptible population. Since the workers have increased respiratory 

6 tract infections as compared with controls, a formaldehyde-specific effect cannot be excluded. 

7 These indications of a functional deficit of the immune system are considered adverse and 

8 appropriate for consideration as a critical effect. Although this was a small study (n = 29), the 

9 exposed workers had increased chronic URT infections and decreased resistance to infections 

10 compared with a control population. Additionally, duration of employment was negatively 

11 correlated with both erythrocyte count and hematocrit. Measured formaldehyde concentrations 

for a work shift were 870 ± 390 μg/m3 12 (722 ± 324 ppb). This average work-shift concentration 

13 is considered to be the LOAEL for increased respiratory tract inflammation and decreased 

14 resistance to infections in a worker population. 

15

16 5.1.1.6. Neurological and Behavioral Toxicity 

17 Studies evaluating the effects of formaldehyde on nervous system structure or function 

18 are described in detail in Section 4.2.1.4 and summarized in Table 4-60. Taken together the 

19 animal and human data support the conclusion that formaldehyde exposure results in 

20 neurological and behavioral toxicity. Observed health effects include impaired memory and 

21 learning, developmental effects seen as both structural changes in the brain and behavioral 

22 changes, and a potential for increased mortality from amyotrophic lateral sclerosis (ALS). 

23 Although studies appropriate for RfC derivation do not exist for each potential neurological and 

24 behavioral health effect, several studies are available that may inform the formaldehyde RfC. 

25 Seven of the available neurotoxicity studies were considered as candidates for RfC 

26 development (listed in Table 5-1). All seven studies provided reliable documentation of 

27 exposure, study design, and evaluation procedures, and all demonstrated robust findings of 

28 changes in nervous system structure or function following formaldehyde exposure. All but one 

29 of the candidate studies present information at multiple exposure levels to provide an 

30 understanding of the exposure response relationship. One selected study (Senichenkova, 1991) 

31 provided less robust information, with evaluation at only a single exposure level, but was 

32 considered useful as supporting the findings of two other studies (Sarsilmaz et al., 2007; Aslan et 

33 al., 2006) regarding neurological sequelae of developmental exposure. All of the selected 

34 studies using experimental animals were conducted in rats, although several studies in mice 

35 demonstrated dose-related neurotoxic effects following formaldehyde exposure. These studies in
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1 mice were not considered for RfC development because of the possibility that results might be 

2 confounded by reflex bradypnea at the doses tested in each study (see Section 4.2.1.4 for 

3 details). 

4 In order to improve transparency and facilitate comparison of health effect levels across 

5 study types and health effects, Table 5-1 summarizes the PODs and exposure scenarios for each 

6 selected study and describes the effects on which the selected POD is based. Dose conversions 

7 used to adjust from actual experimental exposure concentrations to continuous exposure 

8 concentrations are detailed. It should be noted that available studies providing dose-response 

9 information regarding the effects of formaldehyde exposure on the nervous system were all of 

10 short duration, and thus information regarding the relationship between formaldehyde toxicity 

11 and exposure duration (i.e., whether toxicity increases with longer exposures at a given exposure 

12 level, or is more related to the maximum exposure concentration) is limited. However, the 

13 rodent study by Pitten et al. (2000) and the epidemiology study by Weisskopf et al. (2009) 

14 provide strong support for an association between increasing neurotoxicity and increasing 

15 duration of exposure.

16 Although chronic human studies are preferred for RfC derivation, no adequate human 

17 study of chronic duration is available. The available human studies were sufficiently strong to 

18 raise concern regarding formaldehyde effects on the nervous system; however, most did not 

19 provide sufficient exposure information to permit derivation of a POD for use in quantitative 

20 dose-response assessment. Available epidemiologic studies (most notably Weisskopf et al. 

21 [2009] and Kilburn et al. [1987, 1985]) provided limited exposure information. Weisskopf et al. 

22 (2009) demonstrated increased mortality from ALS associated with increased duration of 

23 formaldehyde exposure among 987,229 people followed by an American Cancer Society study, 

24 but no information regarding exposure concentrations was available. Interpretation of the 

25 findings of Kilburn et al. (1987, 1985) is complicated by concomitant exposure of many subjects 

26 to other solvents. Although the chamber study by Lang et al. (2008) included a concentration27 response assessment of changes in reaction time, as previously discussed, the effects detected 

28 were difficult to interpret and the study was not considered useful for RfC derivation

29 .
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Table 5-1. Points of departure (POD) for nervous system toxicity in key human and animal studies.

Reference

PODa Exposure scenario POD duration adjustmentsb

Species Type ppb Hours/day Days/week Duration POD × Hours/day × Days/week = ppb Ratio Effect 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

Volume and cell number 

change in brain regions 

following neonatal 

exposure

Aslan et al. 

(2006) Rat LOAEL 6,000 6 5 30 days 6,000 × 6/24 × 5/7 = 1,070 5.6

Volume and cell number 

change in brain regions 

following neonatal 

exposure

Human neurobehavioral outcomes

Bach et al. 

(1990)d Human NOAEL 170 5.5 1 1 day 170d × × = 170 1

Changes in short-term 

memory and ability to 

concentrate. Single 

5.5-hour exposure 

Psychomotor effects

Senichenko

va (1991) Rat LOAEL 400 4 7 GD 1–19 400 × 4/24 × 7/7 = 67 6

Changes in open field 

motor activity (exploratory 

activity and habituation in 

offspring following in 

utero exposure

Malek et 

al. (2003c) Rat LOAEL 130e 2 1 1 day 130 × 2/4e × = 65 2

Concentration-dependent 

decreases in activity by a 

variety of measures 

following a single 

exposure

Cognitive effects

Pitten et al. 

(2000)f Rat LOAEL 2,600 0.17 7 90 days 2,600f -- -- -- --

Impaired memory in a 

spatial maze. Magnitude 

of effect increased with 

continued exposure 

through 12 weeks
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Malek et 

al. (2003a) Rat LOAEL 100e 2 7 10 days 100 × 2/4e × 7/7 = 50 2

Impaired learning in a 

water maze. Short-term 

(10 day) exposure with 

testing conducted 2 hours 

following daily exposure.

a

1 mg/m3 = 0.813 ppm. b

Both actual levels of experimental exposures, and duration adjusted PODs are shown.

c

POD unadjusted dose / duration-adjusted dose. d

Testing was conducted during or following exposure, duration was not adjusted.

e

Testing was conducted 2 hours postexposure; duration was adjusted to 4 hours to include the entire period between start of exposure and testing. f

Due to the uncertainty in continuous exposure adjustments and the unusually short (10 minutes) exposure in this study, no adjustment to continuous exposure is 

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 

13 presented, but graphical presentations in the article indicated that the effect was seen at all doses 

14 tested, with an apparent NOAEL of 170 ppb (see Figure 5-1).

1516

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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1 No BMD modeling could be performed on these data because the graphical 

2 representation could not be accurately digitized. The statistical analysis indicated no interaction 

3 between formaldehyde effect and previous occupational exposure (i.e., the magnitude and 

4 direction of the effect were similar in previously exposed and previously unexposed subjects) 

5 and separate data were not presented for the two groups; thus, the LOAEL represents effects in 

6 the combined study groups. Overall, the published paper lacks detail and it is difficult to 

7 evaluate some aspects of the reported findings, in particular where magnitude and direction of 

8 effect are not provided. Finally, the authors noted that controls and the high-exposure group 

9 were not well matched on two key parameters (age and education level), adding uncertainty to 

10 the reported exposure-response relationship (at the high dose). Although this study was 

11 considered valuable in documenting neurological effects in humans following exposure to 

12 relatively low concentrations of formaldehyde, the above concerns limit its utility for 

13 quantitative human health risk assessment. Therefore, this study is not considered of sufficient 

14 quality for RfC derivation.

15 In the absence of adequate human data, controlled studies in laboratory animals are 

16 considered. There are no chronic studies and only one subchronic animal study evaluating 

17 neurological and behavioral effects of formaldehyde exposure. Pitten et al. (2000) demonstrated 

18 impaired retention of a previously learned task in rats exposed at concentrations of 2,600 or 

19 4,600 ppb, 10 minutes per day, 7 days/week, for 90 days. In this study, the magnitude of the 

20 impairment increased over time, even though testing was performed 22 hours after exposure, 

21 indicating that repeated formaldehyde exposure led to a worsening of effect. The study design, 

22 test methods, and reporting of the results are all of adequate quality for both hazard assessment 

23 and quantitative risk assessment. However, the short duration (10 minutes) of the repeated daily 

24 exposures is a severe limitation to establishing a chronic RfC based on this study, due to 

25 uncertainties in extrapolating from 10 minutes to a 24-hour exposure (see Table 5-1). Because 

26 this study as designed indicates an accumulation of effect with repeated exposure, it is useful in 

27 documenting the existence of a duration component to the exposure-response relationship. It 

28 follows that concentration alone, without an adjustment for duration of exposure, would be 

29 inadequate as an exposure metric; however inadequate information is available to inform the 

30 appropriate magnitude of the duration effect. Therefore, although Pitten et al. (2000) is a well31 conducted study, the data are of limited utility for RfC derivation.

32 Finally, there are several well-documented acute and subacute animal studies that provide 

33 exposure-response information for neurological and behavioral endpoints relevant for RfC 

34 derivation. Several laboratory animal studies that evaluate neurological effects following in 

35 utero or neonatal exposure address potentially susceptible life stages. Sarsilmaz et al. (2007) and 
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1 Aslan et al. (2006) observed changes in brain structure (cell number and/or volume changes in 

2 specific brain regions) following 30 days of exposure to neonatal rats. A related finding by 

3 Senichenkova (1991) demonstrated changes in behavior (open field motor activity, including 

4 habituation) in young rats following in utero exposure. Effects of concern were seen at all doses 

5 in these studies, resulting in PODs of 67 ppb following in utero exposure and 1,070 ppb 

6 following early postnatal exposure, based on LOAEL values adjusted for continuous exposure 

7 (see Table 5-1). These studies support the possibility of neurodevelopmental effects attributable 

8 to in utero or early postnatal formaldehyde exposure, at levels similar to or below those causing 

9 other types of effects.

10 The other three studies in Table 5-1 evaluate behavioral changes in rats following 

11 exposure to formaldehyde. Malek et al. (2003c) found concentration-related changes in motor 

12 activity following a single 2-hour exposure at concentrations from 130–5,180 ppb (with testing 

13 2 hours following cessation of exposure). In a second study, Malek et al. (2003a) found 

14 concentrated-related changes in performance on a learning task at similar exposure levels (100–

15 5,400 ppb) when 2-hour exposures were repeated for 10 consecutive days; performance was 

16 evaluated 2 hours after cessation of exposure, and concentration-related learning deficits were 

17 seen at all exposure levels (see Table 5-2 and Figure 5-2).

18

19 Table 5-2. Effects of formaldehyde exposure on completion of the labyrinth 

20 test by male and female LEW.1K rats

21

Male rats Swimming time (sec) Error rate (mean)

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 ppma 100 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 

rats

Swimming time (sec) Error rate (mean)

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

22 a 23 Rats were exposed to formaldehyde for 2 hours/day, for 10 consecutive days.

b 24 Different from control, p < 0.05. c 25 Different from control, p < 0.005.

26

27 Source: Malek et al. (2003a).

28
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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) 

18 study that detected cognitive impairments in humans following a single exposure (with a 

19 NOAEL of 170 ppb).

20

21

22

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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1 Summary of neurological and behavioral effects:

2 In summary, the available studies for formaldehyde and nervous system outcomes have 

3 demonstrated that the nervous system is a sensitive target following inhalation of formaldehyde. 

4 In experimental animals, changes in nervous system function were seen following acute and 

5 subchronic exposures; studies evaluating neurological changes following chronic exposure were 

6 unavailable. Available human studies that evaluated nervous system effects following inhalation 

7 exposure were found to have many study-specific uncertainties and, thus, were not suitable to 

8 serve as the primary basis for a chronic RfC. The Weisskopf et al. (2009) study of ALS, in 

9 particular, suggests that humans may be at risk for severe neurological effects from 

10 formaldehyde exposure; however, this study lacked the exposure concentration information 

11 necessary to derive an RfC. Neurological findings from the rodent inhalation (acute and 

12 subchronic) studies that were judged to be adequate for dose-response assessment identified 

13 unadjusted LOAELs ranging from 100 to 6000 ppb, with LOAELs adjusted for continuous 

14 exposure in the range of 50 to 1070 ppb. Use of these PODs in risk assessment would require 

15 addressing uncertainties regarding animal-to-human extrapolation, short study durations, and 

16 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), 

20 which is relevant to humans, and the use of a repeated-exposure paradigm (2 hours/day over a 

21 period of 10 days), which addresses different exposure durations. This choice is supported by 

22 similar effects seen in other studies (Lu et al., 2008; Pitten et al., 2000; Bach et al., 1990) and by 

23 other neurologic effects seen at similar exposure levels (Malek et al., 2003c; Senichenkova, 

24 1991; 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), 

33 growth retardation, and functional development. Additionally, in spite of the lack of a 

34 comprehensive database of studies for the evaluation of the overall effects of formaldehyde on 

35 the reproductive system and its function, the available evidence demonstrates toxicity to the male 
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1 reproductive system in multiple animal studies, as well as effects on the female reproductive 

2 system in both rodents and epidemiologic studies, where an association with impaired fertility 

3 and increased 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 

14 these 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 

31 and 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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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 

7 groups, respectively. The effect on FDR remained in workers both with and without the use of 

8 protective gloves (n=39) but lost statistical significance in the exposed group of workers who 

9 wore gloves (n=22). Figure 5-3 shows the study results stratified by glove use in women in the 

10 high-exposure group. Although this suggests that a component of dermal exposure might 

11 contribute to the effect, it is unclear what, if any, dermal exposure is expected based on the 

12 nature of the work. Regardless, there remains uncertainty as to whether effects are solely due to 

13 inhalation exposure.

14

15

16 Figure 5-3. Fecundity density ratio among women exposed to formaldehyde 

17 in the high exposure index category with 8-hour time-weighted average 

18 formaldehyde exposure concentration of 219 ppb (Taskinen et al., 1999) 

19

20

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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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 

28 days (GDs) 6–20. Decreased male fetal body weight (BW) was modeled with a BMR of 5% 

29 mean change, a BMCL was established, and, as shown in Table 5-3, the resulting duration30 adjusted 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

35
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1 Male reproductive toxicity. 

2 Evidence of adverse effects on male reproductive system endpoints following inhalation 

3 exposure to formaldehyde was observed in a number of animal studies, where adversity is 

4 characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 2006). The 

5 effects include decreased testes weight, changes in Leydig cell quantity and quality, degeneration

6 of seminiferous tubules, decreased testosterone levels, alterations in biomarkers of toxicity in the 

7 testes, and alterations in sperm count, morphology, and/or motility (Golalipour et al., 2007; Xing 

8 et al., 2007; Zhou et al., 2006; Özen et al., 2005, 2002; Sarsilmaz et al., 1999; Guseva, 1972). 

9 Several of these studies included inhalation exposure of rats to formaldehyde 8 hours/day, 

10 5 days/week for 4 and/or 13 weeks (Özen et al., 2005, 2002; Sarsilmaz et al., 1999) and included 

11 exposure-response information that was considered adequate for RfC derivation. In a study by 

12 Özen et al. (2002), increased severity of statistically significant testes weight decreases was 

13 related to both dose and duration of treatment. Similarly, in the study by Golalipour et al. 

14 (2007), seminiferous tubular diameter and epithelial height were reduced in rats following 18 

15 weeks of formaldehyde inhalation exposure, with the severity of outcome positively correlated to 

16 the number of hours/week that the animals were exposed. Sarsilmaz et al. (1999) noted dose 

17 dependent decreases in Leydig cell quantity after 4 weeks of treatment, while decreased testis 

18 weight and atrophy of seminiferous tubules were observed by Zhou et al. (2006) after only 2 

19 weeks of treatment. The reported outcomes in these independent studies illustrate a biologically 

20 consistent toxicological profile of treatment-related male reproductive toxicity. PODs, adjusted 

21 for continuous exposure, ranged from 1,190 to 4,025 ppb, where the lowest POD was associated 

22 with the longest exposure period and vice verse (Table 5-3).

23

24 Female reproductive toxicity. 

25 Evidence of decreased fecundability was observed in the study by Taskinen et al. (1999), 

26 which was described above for spontaneous abortions. Delays in the time to conception that 

27 characterized this outcome, as well as increases in the incidence of endometriosis, were 

28 statistically significantly associated with occupational exposures to formaldehyde. As these 

29 effects were observed in the high exposure group, the unadjusted NOAEL for each of these 

30 effects is 76 ppb (8 hr-TWA) based on the next lowest exposure group. Uncertainties included 

31 lack of information human variability, as well as on the extrapolation of data from studies of 

32 short duration to risk estimates for chronic exposures. As discussed above for spontaneous 

33 abortions, the use of these data for cRfC derivation could result in values that would likely be an 

34 underestimation of risk because they assume that all the risk was from inhalation exposure and 

35 ignore the apparent contribution of dermal exposure (i.e., the dermal-exposure-adjusted 
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1 candidate inhalation RfCs might be higher). For decreased fecundability, a POD can also be 

2 identified based on the data from only the women who wore gloves. The fecundability density 

3 ratio (FDR) for the women in the highest exposure group who wore gloves was 0.79 (95% 

4 confidence interval [CI] 0.47–1.23). Although this FDR is not statistically significant, it can 

5 reasonably be assumed to be part of a trend of decreased FDR with increasing inhalation 

6 exposure, based on the overall data for the association of decreased FDR with formaldehyde 

7 exposure. Whether the highest exposure level is considered to be a NOAEL or a LOAEL for 

8 decreased fecundability in women who wore gloves, the unadjusted POD is 219 ppb (8 hr9 TWA). Evidence of spontaneous abortions in the same study, as described above, may also be 

10 indicative of female reproductive toxicity.

11 In animal studies, assessment of the female reproductive system was quite limited. An 

12 increase in the mean follicle-stimulating hormone (FSH) levels in rats, observed at the highest 

13 exposure level tested in Kitaev et al. (1984) was found to be sufficient to derive a duration14 adjusted POD of 50 ppb (Table 5-3).

15

16 Summary of developmental and reproductive toxicity studies suitable for RfC development. 

17 A review of the developmental and reproductive toxicity studies in humans and animals 

18 that would be suitable for cRfC development demonstrated that the developing organism and the 

19 reproductive system are targets for toxicity following formaldehyde exposure by inhalation. In 

20 the animal studies, effects during early development were observed following maternal 

21 premating or gestational exposures at duration-adjusted PODs ranging from 50-325 ppb. The 

22 minimal data available on female reproductive toxicity demonstrated an adjusted POD of 50 ppb 

23 with subchronic (4-month) premating exposure, while more extensive evaluation of male 

24 reproductive outcomes identified adjusted PODs of 1,190-4,025 for testicular and sperm 

25 abnormalities after exposures of from 2 weeks to 3 months in duration. The animal studies 

26 demonstrate the broad range of adverse outcomes to the reproductive system and the developing 

27 organism following inhalation exposure to formaldehyde and highlight concerns regarding the 

28 inadequacy of the database for the assessment of these outcomes (as described in Chapter 4). 

29 These data also support the human relevance of female reproductive and/or embryonic and fetal 

30 developmental effects, since some outcomes were similarly observed in both human and animal 

31 studies.

32
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Table 5-3. Developmental and reproductive toxicity PODs including duration adjustments – key animal studies

Reference Species

POD Exposure Scenario POD Duration Adjustments

Type ppb a

Hours/

day

Days/

week Duration

POD

(ppb)

Hours/

day

Days/

week

Adjusted 

POD 

(ppb) Ratio b Effect; comments

Spontaneous abortion and fetal death

Kitaev et al. 

(1984)

Rat LOAEL 400 4 5 6 months 

premating

400 × 4/24 × 5/7 = 50 8 Increased (>threefold) embryo 

degeneration on gestational 

days 2–3 after 4 months 

maternal premating treatment

Sheveleva (1971) Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Increased (50%) 

preimplantation lossg

Structural alterations c

Senichenkova 

(1991)

Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Increased (13%) litter 

incidence of internal organ 

anomalies, including 20% 

increase in undescended 

testes; 9% decreased fetal 

incidence of hyoid 

ossification g

Senichenkova 

and Chetobar 

(1996)

Rat LOAEL 400 4 7 GDs 1-19 400 × 4/24 × 7/7 = 70 5.7 Increased (21%) fetal and 

litter incidences of 

cryptorchidism and increased 

(6%) fetal incidences of total 

anomaliesg

Growth retardation

Saillenfait et al. 

(1989)

Rat BMCL 1,300 6 7 GDs 6-20 1,300 × 6/24 × 5/7 = 325 4 Decreased male fetal body 

weightsg (BMR = 5%)

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 Decreased testis weight at 

4 weeks (2%) and 13 weeks 

(8%)

Özen et al. 

(2005)

Rat LOAEL 5,000 8 5 91 days 5,000 × 8/24 × 5/7 = 1,190 4.2 Decreased (40%) serum 

testosterone levels at 91 days

Sarsilmaz et al. 

(1999)

Rat LOAEL 10,000 8 7 4 weeks 10,000 × 8/24 × 7/7 = 2,380 4.2 Decreased (5%) Leydig cell 

numbers at 4 weeks
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Table 5-3. Developmental and reproductive toxicity PODs including duration adjustments – key animal studies

Zhou et al. 

(2006)

Rat LOAEL 8,050 12 7 2 weeks 8,050 × 12/24 × 7/7 = 4,025 2 Decreased (~25%) testis 

weight; alteration of 

epididymal sperm [decreased 

(38%) count, decreased (19%) 

motility, and increased (>3-

fold) abnormal morphology] 

at 2 weeks

Female reproductive toxicity

Kitaev et al. 

(1984)

Rat NOAEL 400 4 5 4 months 

premating

400 × 4/24 × 5/7 = 50 8 Increased (~66%) folliclestimulating hormone at 

4 months

GDs = Gestation days

a 1 mg/m3 = 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 Sarsilmaz et al. [2007]) are 

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 4.2.1.6 and Table 5-2. 
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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 

21 response, immune function, reproductive and developmental toxicity, and neurobehavioral 

22 toxicity. In this chapter, results for each health effect category are reviewed and studies are 

23 identified which are adequate to inform the exposure-response relationship for health effects 

24 from inhalation exposure (Section 5.1.1). Although the database of published studies that are 

25 currently available does not provide adequate quantitative data to derive cRfCs for all 

26 qualitatively identified endpoints, at least one adequate study was identified for each of the 

27 health effect categories discussed above. For all but one of the categories, at least one study was 

28 available that provided epidemiologic (human) data, based on occupational or residential 

29 exposures, which was judged adequate to 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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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 

11 give more precise estimates of response levels associated with specific exposure 

12 levels.

13 • Among the epidemiologic (human) studies, were exposures from an occupational setting or 

14 from a residential setting?

15 o Studies of health effects from residential exposures were generally preferred over 

16 studies of health effects from occupational exposures because residential 

17 exposures tend to have a smaller range of variability and are less prone to large 

18 intermittent exposure peaks. 

19 o Residential exposures are more representative of the exposures of the general 

20 population.

21 • Among the epidemiologic (human) studies, were children among the study population in 

22 which health effects were observed?

23 o Studies of health effects that assessed the effect of formaldehyde on children’s 

24 health, representing a potentially more susceptible life-stage for some effects, 

25 were given some preference because they provide formaldehyde-specific data 

26 relevant to the components of the RfC derivation that address potentially sensitive 

27 life-stages and populations.

28 • Relative to the other studies under consideration for RfC development, how accurately were 

29 formaldehyde concentrations measured?

30 o Studies based on relatively more accurately measured formaldehyde 

31 concentrations were generally preferred over studies that estimated exposures.

32 • Studies that reported effects at relatively lower formaldehyde concentrations, potentially 

33 indicative of more sensitive endpoints, were generally preferred.

34
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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; 

10 however, only the mean and range of exposures for all workers is given. Furthermore, 

11 occupational exposures can include high peak exposures. The residential studies are preferred 

12 for development of candidate RfC. Although there are differences in study size and the quality 

13 of 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 

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

Observed 

effectsa 

(ppb) POD (ppb)

Sensory 

Irritation

Liu et al. (1991) Human Residential Yes 1,394

Two locations at one 

time period (winter or 

summer); 7-day 

passive monitors

Eye irritation

95 LOAEL=95

Ritchie and 

Lehnen (1987) Human Residential Yes 2,007

Two locations at one 

time period; 30-

minute sample

Eye, nose, and 

throat sensory 

irritation

200 NOAEL=50

Hanrahan et al. 

(1984) Human Residential Yes 

(teenagers) 61

Two locations at one 

time period; 60-

minute sample

10% increased 

prevalence of 

burning eyes

130 BMCL10=70

Holmström and 

Wilhelmsson 

(1988)

Human Occupational No 106

Several measurements 

at factory 

workstations taken 

over 7 years

Eye irritation

210 NOAEL=70

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

240 LOAEL=240

Sensitization: 

Asthma and 

atopy

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

28 LOAEL=28

Rumchev et al. 

(2002) Human Residential Yes 192

Two locations at two 

time periods (Winter 

& Summer); 8-hour 

passive monitors

Initial diagnosis 

of asthma

45 NOAEL=33
This document is a draft for 

review purposes only and does 

not constitute Agency policy

5-37 DRAFT

—DO 

Health 

Endpoint 

Category Study Species Setting Children

Study

size

Formaldehyde 

measurements

Specific 

Endpoints

Observed 

effectsa 

(ppb) POD (ppb)

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

27 BMCL10=17

Neurological Malek et al. 

(2003a) Rat Laboratory -- 120

Intentional exposures 

at specific levels

Impaired 

learning 100 LOAEL=100

Reproductive 

and 

Developmental

effects

Taskinen et al. 

(1999) (FDR) Human Occupational No 602

Actual and surrogate 

measurements 

estimated by 

occupational hygienist

Decreased 

fecundity 

density ratio 

(FDR)

226b NOAEL=86

Taskinen et al. 

(1999) (SAB) Human Occupational No 602

Actual and surrogate 

measurements 

estimated by 

occupational hygienist

Increased risk of 

spontaneous 

abortion (SAB) 26b LOAEL=26

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

722 LOAEL=722

a This is the lowest level of exposure at which adverse effects were observed, the LOAEL, in effect, or the cut-off point for adversity for BMCLs.

b See Section 5.1.2.6.2 for methods to adjust exposure levels from Taskinen et al. (1999).
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5-38 DRAFT—DO NOT CITE OR QUOTE

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 

5 presented for children (n = 208) provide an exposure-response relationship for reduced PEFR. 

6 Data quality is considered high for this study, both in terms of the in-home exposure 

7 measurements (7-day passive monitors, two time periods) and the contemporaneous in-home 

8 measurement of pulmonary function. Sources of potential confounding or bias were considered 

9 by the study authors and adequately taken into account in the study. Therefore, this study is 

10 retained for derivation of a candidate RfC.

11 Several studies report increased asthma and/or allergic sensitization in children 

12 associated with increased formaldehyde exposure in school or homes (Section 5.1.4). Of these, 

13 two studies are further evaluated here (Garrett et al., 1999; Rumchev et al., 2002). The study by 

14 Rumchev et al. (2002) is a case-control study of asthma incidence in children, and the study by 

15 Garrett et al. (1999) is designed to study several related health effects (asthma, sensitization and 

16 respiratory 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 

28 following 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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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 

28 (Krzyzanowski et al., 1990); 3) sensitization (atopy and asthma) (Garrett et al., 1999 and 

29 Rumchev et al., 2002); and 4) reduced fecundity and increased spontaneous abortion (Taskinen 

30 et al., 1999). It is recognized that not all identified health effects are represented in these 

31 studies.

32

33

34

35
This document is a draft for review purposes only and does not constitute Agency policy.

5-40 DRAFT—DO NOT CITE OR QUOTE

1 5.1.2.2. Derivation of Candidate RfCs from Key Studies

2 Candidate RfC derivation for Krzyzanowski et al. (1990) (Pulmonary function)

3 The study by Krzyzanowski et al. (1990) is a high quality epidemiology (human) study of 

4 health effects in a random sample of residents and their families. The study was specifically 

5 designed to include only households that had children 5–15 years of age, a sensitive life-stage for 

6 respiratory effects. The study was of moderate size, when the effects in children were analyzed 

7 separately from adults, with the final analysis based on 208 children—a cohort large enough to 

8 show statistically significant results. The formaldehyde monitors were prepared by the 

9 Lawrence Berkeley Laboratories and were considered to be precise and highly reliable. The 7-

10 day passive formaldehyde monitors generally provide the lowest limit of formaldehyde 

11 detection. The investigators specifically tested an a priori hypothesis and conclusively 

12 demonstrated to a high level of statistical significance that increased residential formaldehyde 

13 exposures were associated with decreased pulmonary function as measured by peak expiratory 

14 flow rate (PEFR) in children. This effect was clearly shown at relatively low concentrations of 

15 formaldehyde as the mean concentration in the homes was 26 ppb with more than 83% of homes 

16 having measured concentration less than 40 ppb. This study also reported specific regression 

17 modeling results that allowed EPA to calculate the point of departure for RfC development using 

18 a BMCL as the point of departure. 

19 The effects of formaldehyde exposure on pulmonary function represent a sensitive 

20 endpoint with a reported 10% reduction in PEFR at 27 ppb. Among children with physician21 diagnosed asthma, the observed effects of increased formaldehyde exposure on decreased PEFR 

22 were more pronounced – a clear indication of variability in response. The American Thoracic 

23 Society (ATS, 2000) considers decreased pulmonary function an adverse health effect, even 

24 when it is transient and subclinical. “Assuming that the relationship between the risk factor and 

25 the disease is causal, the committee considered that such a shift in the risk factor distribution, 

26 and hence the risk profile of the exposed population, should be considered adverse, even in the 

27 absence of the immediate occurrence of frank illness” (ATS, 2000). The ATS (2000) stated that 

28 individuals in an exposed population experiencing a shift in the distribution of pulmonary 

29 function were at potential risk from another agent due to the reduction in their reserve capacity to

30 address additional insults. In the study by Krzyzanowski et al. (1990), the investigators 

31 demonstrated statistically significant interaction between formaldehyde exposures, smoking, and 

32 chronic cough. That is, a formaldehyde concentration that caused decreased pulmonary function 

33 at residential levels also caused chronic cough in the presence of environmental tobacco 

34 exposures. Higher prevalence rates of physician-diagnosed asthma and chronic bronchitis were 
This document is a draft for review purposes only and does not constitute Agency policy.

5-41 DRAFT—DO NOT CITE OR QUOTE

1 also shown at higher concentrations of formaldehyde (60–140 ppb), an effect that was 

2 exacerbated by environmental tobacco exposures.

3 Figure 5-4 illustrates the reductions in peak expiratory flow rate (PEFR) in children (<15 

4 years of age) in relation to indoor residential formaldehyde concentrations estimated by a 

5 random effects model based on 3,021 observations in 208 subjects. Formaldehyde levels in the 

6 home were significantly related to reductions in PEFR in children both at bedtime and in the 

7 morning (p < 0.05). PEFR measurements in the morning versus at bedtime were significantly 

8 different (p < 0.05). Formaldehyde-related reductions in PEFR were greater in the morning in 

9 asthmatic children than in non-asthmatic children (p < 0.05).

10

11

12

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

14 children in relation to indoor residential formaldehyde concentrations.

15

16 Source: Krzyzanowski et al. (1990).

17

18

19 Candidate RfC derivation based on Krzyzanowski et al. (1990):

20 Critical effect: Based on this study, which specifically included a susceptible 

21 population, the critical effect is reduction in PEFR in children. PEFR was the most 

22 sensitive measure of disease or impaired lung function reported in this population, with 

23 decreases in lung function reported in children who lived in homes with average 

24 measured formaldehyde concentrations as low as 30 ppb (Krzyzanowski et al. (1990). 

25 Children were more sensitive to formaldehyde-associated decreases in PEFR than adults, 

26 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.5

8

4 Although the authors noted that 

5 asthmatic children were more sensitive, the necessary data were not provided in the 

6 report to calculate a BMCL for asthmatic children alone. Thus, 17 ppb, the BMCL based 

7 on all children in the study, was used as the POD. 

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 

BMCL.
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5-43 DRAFT—DO NOT CITE OR QUOTE

1 Human variability UF = 3: The study was designed to include homes with children, 

2 and a POD can be established based on reduced PEFR in children, who were 

3 more sensitive to the health effects than the adults in the study. Therefore, the 

4 POD represents data for a sensitive life stage, an aspect of human

5 (intraindividual) variability. With respect to the human (interindividual) 

6 variability UF, although environmental tobacco smoke and socioeconomic status 

7 did not affect the formaldehyde results in children, asthmatic children were more 

8 sensitive to the effects of formaldehyde exposure on PEFR; thus, asthmatic 

9 children represent a population with increased susceptibility for this effect. The 

10 prevalence rate for physician-diagnosed asthma in the children was 15.8% in this 

11 study, which is higher than the national prevalence of about 5.9% for ages 5 to 

17 years.6

24

12 Thus the BMCL based on all children may be influenced by a higher 

13 prevalence of susceptible children for the critical effect. The authors do report 

14 that the PEFR was reduced to a greater degree in asthmatic children (as shown in 

15 Figure 5-4), and a lower BMC of 17 ppb can be calculated in this subgroup versus 

16 a BMC of 27 ppb for all children. However, the published regression statistics do 

17 not provide sufficient detail to calculate a BMCL specific for asthmatic children. 

18 In addition, other potentially sensitive populations (for example, elderly 

19 individuals or individuals with respiratory diseases) may not be adequately 

20 represented in the study. Therefore, an UF for human variability of 3 is applied to 

21 address the observed increased sensitivity of asthmatic children in lieu of a 

22 calculated BMCL specific to asthmatic children and to ensure adequate protection 

23 for other potentially sensitive populations.

( ) ( ) ppb ppb

UF UF UF UF

BMCL RfC

A L S H

5.6

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)

30 UFH = 3 (human variability UF)

 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 5.1.2.2.1. Candidate RfC derivation for Rumchev et al. (2002) (Asthma)

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

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

4 2002). While it is acknowledged that accurately diagnosing asthma in young children is 

5 difficult, as the diagnosing physician was unaware of the formaldehyde level in the children’s 

6 home, any diagnostic error would be unrelated to formaldehyde concentrations and would not 

7 induce a spurious association. It is noted that the endpoint is physician-diagnosed asthma. The 

8 study, which comprises 88 cases of children discharged from the emergency department of a 

9 children’s hospital in Perth, Australia, with a primary diagnosis of asthma and 104 controls, 

10 provides a positive exposure-response relationship adequate for RfC derivation. Seasonal in11 home formaldehyde measurements taken in the living room and subject’s bedroom were used to 

12 assess exposure (8-hour passive sampler). The ORs for risk of asthma by formaldehyde 

13 exposure level category were adjusted for numerous risk factors, both familial and 

14 environmental, including familial history of asthma, age, sex, socioeconomic status, smoking, 

15 presence of pets, air conditioning, humidifier, and gas appliances. Of these, age, allergic 

16 sensitization to common allergens, and family history of allergy were independent risk factors 

17 for asthma (OR = 1.09, 2.57, and 2.66, respectively). Odds ratios were further adjusted for the 

18 effects of the measured indoor air pollutants (see Rumchev et al., 2004), indoor allergen levels of 

19 dust mites, relative humidity, and indoor temperature. Categorical analysis of the data indicates 

20 that the ORs for asthma were increased in the two highest formaldehyde exposure groups, 

reaching statistical significance for household exposures > 60 μg/m3 21 (48 ppb) (OR = 1.39) 

22 (Figure 5-5). Analysis of 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/m3 23

24 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/m3 30

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
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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 

17 definition for a chronic study of one-tenth the lifespan. However, asthma often 

18 develops during childhood, indicating a less-than chronic duration of exposure. 

19 Since 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 

25 likely included children predisposed to asthma. Individuals with a family history 

26 of 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 ppb

UF 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 

8 years old with (n = 53) or without (n = 95) doctor-diagnosed asthma. Formaldehyde exposure 

9 was characterized by four seasonal in-home sampling events using 4-day passive samples 

10 collected in bedrooms, living rooms, kitchens, and outdoors. In logistic regressions, both the 

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 ppb

UF 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 prevalence and severity of allergic sensitization to 12 common allergens increased with 

2 increasing formaldehyde concentration in the home. Additionally, a calculated respiratory 

3 symptom score was increased and demonstrated a significant relationship with increased 

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

5 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/m3 6 ) 

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

8 home (Figures 5-6 and 5-7). 

9 

 10 

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

12 with in-home formaldehyde levels. Trend analysis indicates statistical significance in these 

13 increases {percent asthmatic children, unadjusted (p=0.03) and respiratory symptom score 

14 (p=0.03)}. 

15 

16 Source: Garrett et al. (1999).

 17 

 18 

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/m3 16 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

28 Point of departure: For all critical effects, categorical analyses are presented that show

29 an increase in the mid-exposure group (16–40 ppb) and high exposure group (>40 ppb)
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1 relative to the low-exposure group (<16 ppb) (Figures 5-6 and 5-7). However, it is 

2 unknown if the findings in the low-exposure group are comparable to the responses that 

3 would be observed in an unexposed population. Therefore, the low-exposure group 

4 cannot be considered a NOAEL but rather serves as a referent group for the two other 

5 exposure groups. Thus, the LOAEL is based on health effects observed in the mid6 exposure group (16-40 ppb) for all three critical effects. As neither the mean or median 

7 exposure levels are provided for the exposure categories used to analyze the health 

8 effects data, the mid-point of the exposure category is selected for the LOAEL: 28 ppb.

9

10 Application of study-specific Uncertainty Factors (UFs):

11 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study.

12 LOAEL-to-NOAEL UF = 3: As discussed, the mid-exposure group is selected as the 

13 LOAEL since the low-exposure group is the referent group; there is no true 

14 unexposed control. It is unclear whether or not a full LOAEL to NOAEL 

15 uncertainty factor is warranted for these data. The authors did provide evidence 

16 for increased atopy for every increase of 16 ppb of exposure with borderline

17 statistical significance when adjusted for several potential confounders (OR = 1.4; 

18 95% CI: 0.98–2.00). An UF of 3 adjusts the LOAEL to a similar range and is 

19 consistent with this alternative presentation of the data.

20 Subchronic to chronic UF = 1: The study addresses ongoing residential exposure to 

21 formaldehyde. Although information on the duration of exposure for each 

22 participant is not provided, the residential nature of the study suggests a longer 

23 term exposure than the duration of the study. It is judged that a population-based 

24 study of residential exposures is sufficient for derivation of a chronic RfC without 

25 adjusting for a subchronic observation period. 

26 Human variability UF = 1 or 3: This study was designed to assess allergic 

27 sensitization, asthma prevalence and respiratory symptoms in children with 

28 relation to in-home formaldehyde levels. The recruitment of participants was 

29 designed to include households (50%) with asthmatic children, resulting in 

30 43 households with at least one asthmatic child and 37 without asthmatic children 

31 for a total of 148 children (35% asthmatic). Parental allergy and asthma were 

32 also assessed and included as adjustment variables in the data evaluation. 

33 Therefore the study population includes individuals reflecting several key aspects 

34 of human variability for asthma and allergic sensitization (age, familial history of 

35 disease), and addresses the links between allergic sensitization and asthma. Both 
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5-51 DRAFT—DO NOT CITE OR QUOTE

1 asthma and allergic sensitization are risk factors for increased respiratory 

2 symptoms. 

3

4 The two alternatives are described below and cRfCs derived for each alternative

5

6

7

8

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

2.8

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)
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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

9.3

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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5.1.2.2.4. Candidate RfC derivation for Ritchie and Lehnen, 1987; Hanrahan et al., 1984 

and Liu et al., 1991 (Sensory irritation). 

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

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

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

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

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

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

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

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

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

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

12 

 13 

 14 

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

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). 
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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 

24 study included children and the elderly and results were consistent across age groups. Children 
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5-55 DRAFT—DO NOT CITE OR QUOTE

1 <7 years of age were only included in the eye irritation analyses because of concerns about the 

2 quality of parental reporting for nose and throat effects in young children. The selection criteria 

3 for participants indicate that more sensitive individuals may have been over-represented in the 

study population.7

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 

11 and 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. 

15 From 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). 

17 Because the limit of detection for formaldehyde in indoor air was 100 ppb, data or model results 

18 are not provided below 100 ppb.

4 All study participants were self-selected, with a physician’s approval, 

5 perhaps resulting in a higher proportion of individuals experiencing various irritant and upper 

6 respiratory tract symptoms, which may represent a sensitive population for eye, nose, or throat 

7 irritation.

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 % 

30 in the mid- and high-exposure group, respectively, for the summer survey time; winter rates were 

31 slightly lower but showed a similar increase with increasing cumulative exposure. 

 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.
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1 Taken together, these three studies report increased eye irritation from residential 

2 exposures that are below the BMCLs calculated from acute exposures in the laboratory. Each 

3 study has the strength of having individual in-home exposure measurements and demonstrates a 

4 positive exposure-response relationship for sensory irritation within a range of residential 

5 formaldehyde exposures (both conventional and mobile homes). Potentially confounding factors 

6 (such as allergens and some other in-home exposures) have been taken into account and 

7 statistical analyses of the data include relevant covariates (e.g., age, sex, smoking status). As 

8 such, these studies provide a basis for development of a cRfC for sensory irritation. 

9 Additionally, the study populations have been drawn from the general population, including 

10 children and the elderly, and have not been limited to those healthy enough for full-time 

11 employment (as is often the case in occupational cohorts). 

12 All three studies support a finding of increased eye irritation for exposures above 100 ppb 

13 (Figures 5-8 and 5-9). However, the shape of the exposure-response curve below 100 ppb, or an 

14 indication of a no-effect level, is less clear. Two of the studies indicate 1–4% eye irritation in 

15 residents where formaldehyde exposures were measured at 100 ppb or less (Ritchie and Lehnen, 

16 1987; Hanrahan et al., 1984). Thus, there is uncertainty in considering 100 ppb as a no-effect 

17 level for increased eye irritation for these studies. When modeled, the 95% CIs around the point 

18 estimate of 4% eye irritation were 1–18% eye irritation, illustrating the range of response rates at 

19 100 ppb that are consistent with the observed data (Hanrahan et al., 1984). Additionally, the 

20 presentation of results by exposure category in Ritchie and Lehnen (1987) is inexact and has 

21 individuals with exposures at the low end of the categorical range being grouped with those at 

22 higher exposures in the range, obscuring any exposure-response relationship within the 

23 categorical range. For these reasons, a POD for RfC derivation from either of these studies 

24 should reflect these uncertainties. Therefore, for the NOAEL representing the category of 

25 individuals with ≤100 ppb, in which 1–2 % eye irritation was observed, the upper end of this 

26 exposure category is not used, but rather the midpoint, 50 ppb (Ritchie and Lehnen, 1987). 

27 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 ppb8

 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 

prevalence. The actual value is unknown but is clearly below 100 ppb, which is the minimum exposure 

concentration depicted in the figure.

28 . No 

29 additional duration adjustments were made from the in-home exposure measurements to 
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1 continuous exposure because neither time away from the home, nor potential exposures outside 

2 of the home, were characterized in either study.

3 Of the three studies, only Liu et al. (1991) provides exposure measurements below 

4 100 ppb, with a reported detection limit of 10 ppb formaldehyde for the in-home air monitoring. 

5 Additionally, air samples were collected using a 7-day passive sampler which is more 

6 representative of average residential exposures than a one-time, 30–60 minute, air sample. 

7 Therefore, the data collected by Liu et al. (1991) are more suited to understanding the exposure8 response relationship for eye irritation of exposures below 100 ppb. In addition to controlling 

9 for age, gender, and smoking status, Liu et al. (1991) controlled for the presence of chronic 

10 respiratory disease when assessing the effects of formaldehyde on symptoms of sensory 

11 irritation. Finally, this study provides results for both summer and winter survey periods, 

12 addressing seasonal variation in both formaldehyde levels and sensory irritation. The use of the 

13 cumulative exposure metric considers not only the concentration of formaldehyde but also the 

14 number of hours during the week each participant spent in their residence. Linear logistic 

15 regression indicates that cumulative formaldehyde exposure was a statistically significant 

16 predictor of burning eyes for both winter and summer survey periods. However, no BMCL can 

17 be calculated because no regression coefficients were provided in the report. Data were 

18 provided for the categorical analysis illustrating a positive exposure-response relationship 

19 (redrawn in Figure 5-9). Based on the categorical results, the mid-exposure group (7–12 ppm20 hours/week) demonstrated an increased response compared with the low-exposed group. Since 

21 the prevalence rate in the low-exposed group was above 10% for burning eyes, this exposure 

22 group does not represent a NOAEL, but rather serves as a referent for the mid-exposure group. 

23 Therefore, the POD is derived from the midpoint of 7–12 ppm-hours/week, 9.5 ppm-hours/week. 

24 Using a conversion factor applied by the authors, the cumulative exposure of this mid-exposure 

25 group corresponds to a continuous home exposure of 70–120 ppb for an individual who spends 

26 60% of the week in the home, with a mid-point of 95 ppb. 

27

28 Candidate RfC derivation for sensory irritation:

29 Critical effect: Prevalence of sensory irritation (eye irritation, burning eyes).

30

31 Point of departure: Each of the studies discussed above has different strengths and 

32 weaknesses for the determination of a POD for sensory irritation. Nevertheless, the 

33 effect levels and PODs derived from each study are in relatively close agreement with 

34 less than a twofold span from lowest to highest. Therefore each POD is carried through 

35 to calculate a cRfC:
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1

2 NOAEL = 50 ppb (Ritchie and Lehnen, 1987)

3 BMCL10 = 70 ppb (Hanrahan et al., 1984) 

4 LOAEL = 95 ppb (Liu et al., 1991) 

5

6 Application of Uncertainty Factors (UFs)

7 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study.

8 LOAEL-to-NOAEL UF: An uncertainty factor of 1 is applied to the NOAEL and 

9 BMCL10 established as PODs from Ritchie and Lehnen, (1987) Hanrahan et al. 

10 (1984) studies. An uncertainty factor of 3 is applied to the LOAEL of 95 ppb 

11 based on the Liu et al. (1991) study, as the prevalence rates for this exposure level 

12 are below 20% for an effect that is of relatively low severity. In addition, the 

13 LOAEL is not significantly above the NOAEL and BMCL10 from the other 

14 studies that evaluated the same endpoint.

15

16 Subchronic to chronic UF = 1: These studies address 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 is judged that a population-based 

20 study of residential exposures is sufficient for derivation of a chronic RfC without 

21 adjusting for a subchronic observation period. 

22

23 Human variability UF = 1 or 3: All three studies were population-based and included 

24 children, the elderly and both sexes. Sample sizes for two of the studies were 

25 very large (1,394 for Liu et al. [1991]; 2,007 for Ritchie and Lehnen [1987]), 

26 increasing the likelihood that sensitive populations were included. Analysis of 

27 the data controlled for sex, smoking status, and age group. 

28

29

30

31

32

33

34

35
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5-59 DRAFT—DO NOT CITE OR QUOTE

1 The two alternatives are described below and cRfCs derived for each alternative

2

3

4

5

6

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

9.5

1 3 1 3

95 = × × × = × × × =
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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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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 

22 increased spontaneous abortions and decreased FDR are supported by independent findings in 

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 ppb

UF UF UF UF

BMCL RfC

A L S H

70

1 1 1 1

10 70 = × × × = × × × =

 

Liu et al (1991): 

( ) ( ) ppb ppb

UF 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 other formaldehyde-exposed cohorts (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 

2 1990; Axelsson et al., 1984). As this study was designed to examine the effect of workplace 

3 formaldehyde exposures on FDR, the study design and data collection best support this finding. 

4 The exposure measurements were conducted to represent what the researchers considered the 

5 relevant time-to-pregnancy exposures. Although data on miscarriages were collected to control 

6 the time-to-pregnancy findings for confounding from formaldehyde-related spontaneous 

7 abortions, it is less certain that the exposure measurements coincide with the defined 

8 spontaneous abortion cases. Spontaneous abortions were only included in calculations of 

9 exposure-specific ORs if a participant indicated that she was employed at the same location 

10 when she had the spontaneous abortion and when the time-to-pregnancy exposure assessment 

11 was done. The analysis showed that there were statistically significantly increased risks of 

12 spontaneous abortion in the lowest exposure group. While this finding was consistent with other 

13 studies showing adverse reproductive effects of formaldehyde and appears to be causal, the 

14 Taskinen et al. (1999) spontaneous abortion results did not clearly control for all the potential 

15 confounders that were controlled for in the FDR analyses (i.e. organic solvents and phenols). 

16 While the other coexposures were not associated with FDR and therefore not confounders, 

17 endometriosis was strongly associated with organic solvents. Therefore, for these endpoints, the 

18 study design and strength of results best support the use of decreased FDR in formaldehyde19 exposed women as the critical effect for this study.

20 It is preferable that the critical effect be the most sensitive of the effects which is well 

21 supported by the given study. As spontaneous abortions are significantly increased in the low22 exposure group and the response in the mid-exposure group is considered a no-effect level for 

23 decreased FDR, there is uncertainty that an RfC based on the FDR NOAEL would be protective 

24 for the more sensitive effect. Although qualitatively the finding of increased spontaneous 

25 abortion is convincing, there is more uncertainty in the applicability of the exposure assessment 

26 for quantitative risk assessment. Additionally, there is greater uncertainty in the use of the 

27 exposure adjustments for the low-exposure group on which the LOAEL is based because they 

28 account for more of the work time in the low-exposure group than the medium and high 

29 exposure groups (Table 5-5). 

30 There are several sources of uncertainty in the exposure estimates for use in RfC 

31 derivation. As discussed above, the average exposure estimate for the low exposure group 

32 includes a greater proportion of non-assessed background exposures. This is evidenced in part 

33 by the reported average exposure being below background levels for these workers, even with 

34 exposure measurements as high as 300 ppb. The unaccounted for non-task exposures may 

35 represent time during the day spent in the work facility, or time in a different job or work 
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1 environment. Additionally, task-level exposure measurements were available for only 27% of 

2 women in the low exposure group, versus 38% and 69% of women in the medium and high 

3 exposure groups, indicating less certainty in exposure classification for the low exposure group. 

4

5 Duration adjustment for candidate study points of departure:

6 Normally, exposures from occupational studies are adjusted to account for the daily 

7 breathing volume appropriate to an environmental (versus occupational) setting and for exposure 

8 every day of the year (EPA, 1993). However, with formaldehyde, there is potential for exposure 

9 outside of work from in-home and environmental sources of formaldehyde (Chapter 2). A 

10 contemporaneous study of formaldehyde exposures in Finland reports average exposure of 21.4 

11 ppb (measured over 48 hours with a personal monitor) (Jurvelin et al., 2001). Furthermore, both 

12 the mean exposure (18 ppb 8hr TWA) and lowest reported exposure (10 ppb 8hr TWA) of the 

13 ‘low exposed’ category are below the reported average ambient exposures for Finland (21.4 

14 ppb). Thus, it is likely that exposure estimates for study participants include time during the 

15 workday when women reported no formaldehyde exposure and a zero exposure was assessed for 

16 a non-formaldehyde related task. Additionally, participants may have qualified for the study 

17 based on employment date but may not have been working with formaldehyde during the entire 

18 time-to-pregnancy period. In both cases, the investigators in Taskinen et al. (1999) appear to 

19 have assumed that, while the women were away from their “exposed” workplace, their exposure 

20 to formaldehyde was zero, not accounting for background occupational exposures and ambient 

21 levels of formaldehyde. This explains why both the mean exposure as well as lower end of 

22 workshift exposures for women in the low exposure group were reported at and below expected 

23 ambient levels. The women in the low exposure category had task-level workplace exposures of 

24 up to 300 ppb in addition to experiencing some work time at background exposure levels. 

25 Compared to women who only experienced background exposure levels, those in the low 

26 exposure category were at significantly higher risk of spontaneous abortion. 

27 The reported data do not provide information to correct for background formaldehyde 

28 exposure during the workday for each participant. However, the published mean exposure 

29 values may be used to provide some idea of the impact of including background exposures on 

30 the study PODs. Comparison of the values listed in Table 4 of Taskinen et al. (1999) allows for 

31 the estimation of the percentage of work time spent performing tasks involving formaldehyde 

32 exposure (Table 5-5, Panel A). For the women in the low exposure category, this percentage is 

33 26% (mean of measured workplace exposures of 70 ppb times 26% equals the mean of the TWA

34 exposure of 18 ppb). Using the same method, the women in the “medium” and "high" exposure 

35 category were performing tasks involving formaldehyde exposure approximately 54% and 66% 
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1 of their work time, respectively. Assuming that the women spent the remainder of their work 

2 time at the background concentration of 21.4 ppb (Jurvelin et al., 2001), a more appropriate 

3 estimate of the women’s 8-hour TWA formaldehyde exposures would be 34 ppb for the low 

4 category, 86 ppb for the medium category, and 226 ppb for the high category (Table 5-5, Panel 

5 B). 

6

7 Table 5-5: Adjustment for nonoccupational exposures to formaldehyde. 

8

9 Panel A: Proportion of workshift corresponding to the exposure group mean 

10 task-level formaldehyde exposure (ppb) and the exposure group daily exposure 

11 index (8 Hr-TWA). 

Exposure group (n)

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.

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

12 a: Calculated as mean exposure (ppb 8Hr-TWA) divided by mean task-level exposures for the exposure group.

13

14 Panel B: Recalculation of daily exposure index (8 Hr –TWA) where background 

15 formaldehyde exposure is estimated for worktime spent on tasks considered 

16 unrelated to occupational use of formaldehyde. 

Exposure 

group (n)

Estimate of Formaldehyde 

exposure during formaldehyderelated work tasks

Estimate of formaldehyde 

exposure from background 

levels during the workshift

Alternativ

e daily 

exposure 

index

(ppb, 8 

Hr-TWA)

Mean task 

level 

exposure

(ppb)

% of worktime in 

formaldehyde 

task

Background 

formaldehyde

(ppb)

% of time in 

nonformaldehyd

e-related task

Low (119) 70 26% 21.4 74% 34

Medium 

(77) 140 54% 21.4 46% 86

High (39) 330 66% 21.4 34% 226

17

18

19

20
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1 Candidate RfC derivation for Taskinen et al, 1999:

2 Critical effect: Decreased FDR.

3

4 Point of departure: For decreased FDR, the mid-exposure level is considered a 

5 NOAEL. The mean exposure as an 8-hour TWA for the workday is reported as 76 ppb. 

6 EPA has adjusted this POD to account for potential background formaldehyde exposures 

7 during the workshift (Table 5-5) resulting in an adjusted POD of 86 ppb. No further 

8 duration adjustment is made to this POD to account for background levels of 

9 formaldehyde exposure outside of the workplace.

10

11 Application of study-specific Uncertainty Factors (UFs):

12 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study.

13 LOAEL-to-NOAEL UF = 1: Selection of an NOAEL as the POD.

14 Subchronic to chronic UF = 1: The study design represents a study population with a 

15 range of exposure durations, including chronic exposures. By drawing the study 

16 population from full-time employees and members of the wood-working union, 

17 there is an expectation that the study population reflects the demographic of that 

18 group as a whole. Although specific summary information is not published for 

19 this study group (e.g., average length of employment), the lack of this reporting in 

20 itself does not seem to justify an UF for subchronic-to-chronic exposure given the 

21 overall study design. As a study adequate for assessing reproductive effects in a 

22 chronically exposed cohort, no further adjustment was considered needed.

23 Human variability UF = 10: The study population included women employed in the 

24 wood-working industry who were healthy enough to be gainfully employed. 

25 Additionally, study inclusion criteria ensured that all study participants had at 

26 least one pregnancy resulting in a live birth during the study period (1985–1995). 

27 Therefore, these women were reproductively successful. The authors judged that 

28 selective participation did not influence potential confounders such as irregular 

29 menstruation or earlier miscarriages, which could impact the time to pregnancy 

30 results. Susceptible populations were not addressed and, in fact, the women in the 

31 study may be considered healthier than the general population in terms of 

32 reproductive health. Therefore, an uncertainty factor of 10 for human variability 

33 was applied.

34
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( ) ( ) ppb ppb

UF UF UF UF

NOAEL RfC

A L S H

8.6

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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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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review purposes only and does 

not constitute Agency policy

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

Endpoint Study Study 

size Homes Children POD (ppb)

Application of 

study-specific UF cRfC 

(ppb) UFL UFS UFH

Respiratory effects / asthma and sensitization

Reduction of PEFR 

in children (10%)

Krzyzanowski 

et al. (1990) 208 Yes Yes BMCL10 = 17 1 1 3 5.6

Asthma incidence

Rumchev et al. 

(2002) 192 Yes Yes NOAEL = 33 1 3

Alternative A

3 3.3

Alternative B

1 11

Increased asthma; 

allergic sensitization Garrett et al. 

(1999) 148 Yes Yes LOAEL = 28 3 1

Alternative A

3 2.8

Alternative B

1 9.3

Sensory Irritation

Eye irritation, 

burning eyes Ritchie and 

Lehnen (1987) 2,007 Yes Yes NOAEL = 50 1 1

Alternative A

3 17

Alternative B

1 50

Hanrahan et al. 

(1984) 61 Yes Some 

teenagers BMCL10 = 70 1 1

Alternative A

3 23

Alternative B

1 70

Liu et al. 

(1991) 1,394 Yes Yes LOAEL = 95 3 1

Alternative A

3 9.5

Alternative B

1 32

Reproductive / Developmental

Decreased 

fecundability 

density ratio (FDR) 

Taskinen et al., 

1999 602 No No NOAEL= 86 1 1 10 8.6

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 digits are retained as common 

practice in mathematics {i.e. one significant diget more that the final result, to avoid rounding errors compounding across multiple mathematical manipulations}. 
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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 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

5.6 11 9.3 = = + + =

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

5.6 3.3 2.8 = = + + =
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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 

13 below 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.
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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

33 PODs identified from BMD models overcome some of the deficiencies associated with 

34 LOAELs and NOAELs. Benchmark models were used for two inhalation data sets, Hanrahan et 

35 al. (1984) and Krzyzanowski et al. (1990).
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1 It should also be noted, however, that even for BMCs/BMDs there is often uncertainty, in 

2 particular for continuous responses, about what response level to select as the BMR, i.e., where 

3 to define the cut-off point between a level of change that is not adverse and one that is adverse. 

4 In addition, BMD models currently in use are purely mathematical models and are not intended 

5 to accurately reflect the biology of the effect being modeled.

6 Another source of uncertainty in the POD is the adjustment for continuous exposure. 

7 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human 

8 and laboratory animal inhalation studies are typically not continuous and assumptions must be 

9 made in converting reported exposure levels to equivalent continuous exposures. Similarly, 

10 there are uncertainties about potential dose rate effects, in particular the effect of peak exposures 

11 in occupational studies.

12

13 Extrapolation from laboratory animal data to humans

14 Because the inhalation database for formaldehyde contains many human studies for a 

15 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 

16 to derive the RfC. Thus, unlike for most RfCs, this is not a source of uncertainty in the RfC for 

17 formaldehyde. 

18

19 Human variation

20 Heterogeneity among humans is another uncertainty associated with extending results 

21 observed in a limited human study population or laboratory animal experiment to a larger, more 

22 diverse human population. 

23 For three of the studies used to derive the RfC, a value of 3 was used for the human 

24 variability UF (rather than the default value of 10) because the studies had an apparent over25 representation of populations expected to have increased susceptibility (Section 5.5.3.1):

26

27  The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 

28 irritation in a large number of subjects, including children and the elderly. As a result of 

29 the study's participation criteria, individuals with greater sensitivity were potentially 

30 over-represented. 

31  Thirty percent of the subjects in the residential study by Krzyzanowski et al. (1990) were 

32 children who are more sensitive to formaldehyde-associated decreases in PEFR than 

33 adults. The cRfC determination for this study focused on the results in the children, 

34 among whom asthmatics were over-represented (roughly three times) compared with the 

35 national average of 9.4% in 2008 (Bloom et al., 2009). 
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1  Garrett et al. (1999) conducted a cross-sectional survey of allergy and asthma-like 

2 symptoms in children with or without a doctor's diagnosis of asthma. The study was 

3 designed to include a high proportion of asthmatic children, a sensitive population for the 

4 effects being studied.

5

6 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 

7 account for certain special attributes of these studies/effects, there is still uncertainty about how 

8 much of the overall population heterogeneity is actually reflected even in these relatively diverse 

9 residential studies. 

10

11 Subchronic-to-chronic extrapolation

12 RfCs are intended to apply to chronic lifetime exposures. If a study is subchronic 

13 (typically less than 10% of a lifetime), a UF for subchronic-to-chronic extrapolation is generally 

14 applied to the cRfC for that study. For the key human residential and occupational studies used 

15 to derive the RfC in this assessment, the average durations of exposure in the households or 

16 workplaces under study are unknown. In this assessment, these studies were considered chronic 

17 in nature and no subchronic-to-chronic UF was applied. However, there is uncertainty about 

18 whether or not the responses observed fully reflected the potential effects of chronic exposure, 

19 especially in children, where, for example, impacts on the developing respiratory and immune 

20 systems could be predisposing the children to further adverse effects later in life.

21

22 5.1.5. Previous Inhalation Assessment

23 There is no previous EPA RfC assessment for formaldehyde with which to compare and 

24 contrast the RfC developed in this assessment.

25

26 5.2. QUANTITATIVE CANCER ASSESSMENT BASED ON THE NATIONAL 

27 CANCER INSTITUTE COHORT STUDY

28 For quantitative assessment of cancer risk, it is generally preferable to use good-quality 

29 epidemiologic data, when available, over laboratory animal data. The follow-up studies by 

30 Hauptmann et al. (2004) and Beane Freeman et al. (2009) of the large National Cancer Institute 

31 (NCI) retrospective cohort mortality study of U.S. workers involved in the production or use of 

32 formaldehyde, with quantitative exposure estimates for the individual workers, present an 

33 opportunity to perform quantitative cancer risk assessments of nasopharyngeal cancer (NPC) and 

34 lymphohematopoietic cancers (Hodgkin lymphoma and leukemia) based on human data. 

35 Although other upper respiratory tract cancers were also identified as being causally associated 

36 with formaldehyde exposure in the weight-of-evidence analysis in section 4.5, NPC was the only 
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1 upper respiratory tract cancer with exposure-response data adequate for the derivation of unit 

2 risk estimates in the Hauptmann et al. (2004) follow-up study of solid tumors. Similarly, the 

3 weight-of evidence analysis in section 4.5 concluded that there were causal relationships 

4 between formaldehyde exposure and all lymphohematopoietic cancers as a group as well as 

5 leukemias as a group (with the strongest evidence for myeloid leukemia); however, from the 

6 Beane Freeman et al. (2009) follow-up study of lymphohematopoietic malignancies, only all 

7 leukemias combined and Hodgkin lymphoma were judged to have exposure-response data 

8 adequate for the derivation of unit risk estimates (see section 5.2.3.1 below).

9

10 5.2.1. Choice of Epidemiology Study

11 Several follow-up studies of formaldehyde exposure in industrial workers have recently 

12 become available. These studies are discussed in more detail in chapter 4 and the appendix 

13 (Human Health) and are reviewed only briefly here. Hauptmann et al. (2004) and 

14 Beane Freeman et al. (2009) presented follow-ups of the NCI study (originally described by 

15 Blair et al. [1986]) of workers at 10 U.S. plants producing or using formaldehyde. Marsh et al. 

16 (2007, 2002) focused on pharyngeal cancer and, in particular, NPC mortality in sequential 

17 follow-up analyses of the Marsh et al. (1996) cohort study, which examined 1 of the 10 plants 

18 studied by NCI. Pinkerton et al. (2004) presented a follow-up of the National Institute for 

19 Occupational Safety and Health (NIOSH) study of workers exposed to formaldehyde in three 

20 U.S. garment plants (originally described by Stayner et al. [1988]). Coggon et al. (2003) 

21 presented an extended follow-up of a study of workers in six British factories where 

22 formaldehyde was produced or used (originally described by Acheson et al. [1984] and 

23 previously followed up by Gardner et al. [1993]).

24 The analyses presented here are based on the NPC (Hauptmann et al., 2004) and 

25 lymphohematopoietic cancer (Beane Freeman et al., 2009) results from the NCI follow-up 

26 studies. The NCI cohort study is the largest of the three independent studies and is the only one 

27 with sufficient individual exposure data for exposure-response modeling. In addition, the NCI 

28 study is the only one of the three studies that used internal comparisons rather than standardized 

29 mortality ratios (SMRs), thus minimizing the impact of the healthy worker effect, which can 

30 attenuate observed effect estimates. The NCI cohort consists of 25,619 workers (88% male) 

31 employed in any of the 10 plants prior to 1966. A follow-up through 1994 presented exposure32 response analyses for nine NPC deaths as well as analyses of deaths from other solid cancers 

33 (Hauptmann et al., 2004). The most recent follow-up (through 2004) analyzed 319 deaths 

34 attributed to lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et 

35 al., 2009). The results for solid cancers from this recent follow-up had not yet been published at 
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1 the time of this draft assessment. A detailed exposure assessment was conducted for each 

2 worker in the NCI cohort, based on exposure estimates for different jobs held and tasks 

3 performed (Stewart et al., 1986). Exposure estimates were made using several different 

4 metrics—peak exposure, average intensity, cumulative exposure, and duration of exposure. 

5 Respirator use and exposures to formaldehyde-containing particulates and other chemicals were 

6 also considered. For the NPCs, significant trends were observed for the cumulative and peak 

7 exposure metrics (Hauptmann et al., 2004). For the lymphohematopoietic cancers, significant 

8 trends were observed primarily for all lymphohematopoietic cancers and for Hodgkin lymphoma 

9 with the peak exposure metric (Beane Freeman et al., 2009). 

10 The NIOSH follow-up study (Pinkerton et al., 2004) analyzed mortality data (2,206 

11 deaths; 59 from lymphatic and hematopoietic cancers) from their cohort of 11,098 workers (82% 

12 female). Leukemia and aleukemia were elevated for workers with >10 years of exposure and for 

13 workers with ≥20 years since first exposure. However, since no historical exposure level data 

14 were available for this cohort, individual worker exposures could not be estimated and exposure15 response modeling was not conducted. The British cohort updated by Coggon et al. (2003)

16 consisted of 14,014 male workers, and the follow-up included 5,185 deaths (83 from 

17 lymphohematopoietic cancers). In this cohort, lung cancer mortality was statistically 

18 significantly increased, especially in workers in the high-exposure category; however, actual 

19 exposure estimates were not available for exposure-response modeling (worker exposures were 

20 categorized as nil/background, low, moderate, or high, depending on the job considered to have 

21 had the highest exposure). Lymphohematopoietic cancers were not elevated in the British 

22 cohort, although, as discussed above, the results were based on external comparisons against 

23 national mortality statistics. Neither the NIOSH nor the British study reported increased risks of 

24 NPC, although only 1 case (0.96) was expected in the NIOSH cohort (Pinkerton et al., 2003) and 

25 only 2.0 cases were expected in the British cohort (Coggon et al., 2003).

26

27 5.2.2. Nasopharyngeal Cancer

28 5.2.2.1. Exposure-Response Modeling of the National Cancer Institute Cohort

29 A detailed exposure assessment was conducted for the NCI cohort, and quantitative 

30 exposure estimates were generated for each worker (Stewart et al., 1986). Formaldehyde 

31 exposure estimates, including 8-hour time-weighted average (TWA) exposures and level and 

32 frequency of peak exposures, were derived for each job, work area, and calendar year 

33 combination. A peak was defined as a short-duration exposure (typically <15 minutes) above 

34 the TWA. Cumulative exposures (in ppm × years) were estimated by multiplying the time a 

35 worker spent in a specific job by the TWA exposure for that job and summing over all the jobs 
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1 held by the worker. Duration was the total time spent in jobs with formaldehyde exposure, and 

2 average intensity was the ratio of cumulative exposure to duration. Formaldehyde exposures 

3 after 1980 were not taken into account in the follow-up study, but this was considered to have a 

4 minimal impact on the results (see section 5.2.2.4).

5 The results of NCI’s internal analyses for NPC, using the peak exposure, average 

6 intensity, cumulative exposure, and duration of exposure metrics, are presented in Table 5-7. 

7 The relative risks (RRs) were estimated using log-linear Poisson regression models stratified by 

8 calendar year, age, sex, and race and adjusted for pay category (salary/wage/unknown). The 

9 NCI investigators used the low-exposure category as the reference category to “minimize the 

10 impact of any unmeasured confounding variables since nonexposed workers may differ from 

11 exposed workers with respect to socioeconomic characteristics” (Hauptmann et al., 2004). A 15-

12 year lag interval was used in estimating exposures in order to account from a minimal latency 

13 period for the development of solid cancers, including NPCs.

14 As can be seen in Table 5-7, peak exposure is the exposure metric that provides the 

15 strongest exposure-response relationship with NPC. However, it is not clear how to extrapolate 

16 RR estimates based on these peak exposure estimates to meaningful estimates of lifetime extra 

17 risk of cancer from environmental exposures, where the risk is usually considered to be from 

18 continuous lifetime exposures to low environmental levels. In addition, peak exposure is a more 

19 subjective measure than the other metrics, it is not based on actual measurements, and it is a 

20 categorical rather than continuous measure. Furthermore, the “true” exposure metric best 

21 describing the biologically relevant delivered dose of formaldehyde is unknown. The 

22 cumulative exposure metric provides a good fit to the data (p trend = 0.029 for all person-years), 

23 and, since this is generally the preferred metric for quantitative risk assessment for 

24 environmental exposure to carcinogens, cumulative exposure was chosen as the exposure metric 

25 for the risk estimate calculations for NPC in this assessment. 

26 The nonexposed person-years were included in the primary cancer risk analyses 

27 presented here in order to be more inclusive of all the exposure-response data. Such data are 

28 typically included in exposure-response modeling. Furthermore, the data were stratified by pay 

29 category, which should alleviate some concerns about the nonexposed workers having different 

30 socioeconomic characteristics. Final results for the exposed person-years only are presented for 

31 comparison.

32

33
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1 Table 5-7. Relative risk estimates for mortality from nasopharyngeal 

2 malignancies (ICD-8 code 147) by level of formaldehyde exposure for 

3 different exposure metrics

4

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

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. d 11 Reference category due to no cases in the low-exposure category.

12

13 Source: Hauptmann et al. (2004).

14

15

16 As described above, Hauptmann et al. (2004) investigated the relationship between 

17 formaldehyde exposure and NPC mortality using log-linear Poisson regression models. They 

also conducted log-linear trend tests using the general model RR = eβX 18 , where β represents the 

19 regression coefficient for exposure and X is exposure as a continuous variable. The trend 

20 models were stratified by calendar year, age, sex, and race and adjusted for pay category. 

21 Dr. Hauptmann provided EPA with the β estimates (and their standard errors) from the trend 

22 tests for NPC and the cumulative exposure metric for all person-years and for exposed person23 years only (personal communication from Michael Hauptmann, NCI, to Jennifer Jinot, EPA, 

24 March 29, 2004). These estimates are presented in Table 5-8.

25

26

27

28
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1 Table 5-8. Regression coefficients from NCI log-linear trend test models for 

NPC mortality from cumulative exposure to formaldehydea 2

3

Person-years

β

(per ppm × year)

Standard error

(per ppm × year)

All 0.05183 0.01915

Exposed only 0.05318 0.01914

4 a 5 Models stratified by calendar year, age, sex, and race and adjusted for pay category; cumulative exposures 

6 calculated using a 15-year lag interval.

7

8 Source: Personal communication from Michael Hauptmann to Jenifer Jinot (March 29, 2004).

9

10

11 5.2.2.2. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Mortality

12 The regression coefficients presented in Table 5-8 were used to predict the extra risk of 

13 NPC mortality from environmental exposure to formaldehyde.

14

15 Extra risk = (Rx–Ro)/(1–Ro),

16

17 where Rx is the lifetime risk in the exposed population and Ro is the lifetime risk in an 

18 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

 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.

19 

20 U.S. age-specific 1999 all-cause mortality rates for all race and gender groups combined 

21 (National Center for Health Statistics [NCHS], 2002) were used to specify the all-cause 

22 background mortality rates in the life-table program. NCHS 1996–2000 age-specific 

23 background mortality rates for NPC were provided by Dr. Eisner of NCI’s Surveillance, 

24 Epidemiology and End Results (SEER) program (personal communication from Milton Eisner, 

25 SEER, to Jennifer Jinot, EPA, December 19, 2003). Risks were computed up to age 85 because 

26 cause-specific mortality (and incidence) rates for ages above 85 years are less reliable. 

27 Conversions between occupational formaldehyde exposures and continuous environmental 

28 exposures were made to 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 29 ). An adjustment was also 

30 made for the 15-year lag period. The reported standard errors for the regression coefficients 
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1 were used to compute the one-sided 95% upper confidence limits (UCLs) for the extra risks 

2 based on a normal approximation. 

3 Point estimates and one-sided 95% UCLs for the extra risk of NPC mortality associated 

4 with varying levels of continuous exposure to formaldehyde are presented in Table 5-9. The 

5 model predicts extra risk estimates that are fairly linear for exposures below about 0.001 to 

6 0.01 ppm but not for exposures above 0.01 ppm.

7

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

9 continuous exposure to formaldehyde

10

Exposure concentration 

(ppm)

Extra risk 95% UCL on extra 

risk

0.0001 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

0.001

0.01

0.1

1

10

11

12

13 Consistent with EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 

14 the same data and methodology were also used to estimate the exposure level (effective 

15 concentration [ECx]) and the associated (one-sided) 95% lower confidence limit (LECx) 

16 corresponding to an extra risk of 0.05% (x = 0.0005). Although EPA guidelines emphasize the 

17 use of exposure levels associated with a 10% extra risk level for the POD for low-dose 

18 extrapolation, that would not be appropriate in this instance. A 10% extra risk level is very high 

19 for responses generally observed in epidemiology studies; thus, a 1% extra risk level is typically 

20 used for epidemiologic data to avoid upward extrapolation. For NPC, however, even the 1% 

21 level of risk is associated with RR estimates that are substantially higher than those observed in 

22 the epidemiology study. Hence, even a 1% extra risk level would be an upward extrapolation. 

23 Based on the life-table program, the RR estimate for an extra risk of 1% for NPC mortality is 46. 

24 Even 0.1% yields an RR estimate on the high end of the observable range of the epidemiology 

25 study (RR = 5.5). A 0.05% extra risk level yields an RR estimate of 3.27, which better 

26 corresponds to the RRs in the range of the data. Thus, 0.05% extra risk was selected for 

27 determination of the POD, and, consistent with EPA’s Guidelines for Carcinogen Risk 

28 Assessment (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the 

29 POD. While this may appear to be an inordinately low response level, it must be recognized that 

30 NPC has a very low background mortality rate (e.g., lifetime background risk is about 0.00022); 
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1 therefore, a 1% extra risk (i.e., 0.01) would be a huge increase relative to the background risk. 

2 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

4 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 

5 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA

6 (section 4.5), a linear low-dose extrapolation was performed in accordance with EPA’s 

7 carcinogen risk assessment guidelines (U.S. EPA, 2005a). The EC0005, LEC0005, and inhalation 

8 unit risk estimates for NPC mortality are presented in Table 5-10.

3 

9

10 Table 5-10. EC0005, LEC0005, and inhalation unit risk estimates for NPC 

11 mortality from formaldehyde exposure based on the Hauptmann et al. (2004) 

12 log-linear trend analyses for cumulative exposure

13

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

14 a 15 Unit risk = 0.0005/LEC0005.

16

17

18 5.2.2.3. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Incidence

19 EPA cancer risk estimates are typically derived to represent a plausible upper bound on 

20 increased risk of cancer incidence, as from experimental animal incidence data. Cancer data 

21 from epidemiology studies are more often mortality data, as is the case in the NCI study. For 

22 cancers with low survival rates, mortality-based estimates are reasonable approximations of 

23 cancer incidence risk. However, for NPC, the survival rate is substantial (51% at 5 years in the 

24 1990s in the U.S., according to Lee and Ko [2005]), and incidence-based risks are preferred 

25 because EPA is concerned with cancer occurrence, not just cancer mortality.

26 Therefore, an additional calculation was done using the same regression coefficients 

27 provided by Dr. Hauptmann (Table 5-8) but with age-specific NPC incidence rates for 1996–

28 2000 from SEER in place of the NPC mortality rates in the life-table program. SEER collects 

29 cancer incidence data from a variety of geographical areas in the U.S. The incidence data used 

30 here are from SEER 12, a registry covering about 14% of the U.S. population, which was the 

31 most current SEER registry at the time this analysis was done. SEER 1996–2000 age-specific 

 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 

comparison analysis, as discussed by Hauptmann et al. (2004).
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1 background incidence rates for NPC were provided by Dr. Eisner of NCI’s SEER program 

2 (personal communication from Milton Eisner, SEER, to Jennifer Jinot, EPA, December 18, 

3 2003). The incidence-based calculation relies on the reasonable assumptions that NPC incidence 

4 and mortality have the same exposure-response relationship for formaldehyde exposure and that 

5 the incidence data are for first occurrences of NPC or that relapses provide a negligible 

6 contribution. The calculation also relies on the fact that NPC incidence rates are small compared 

7 with the all-cause mortality rates. 

8 The resulting EC0005, LEC0005, and inhalation unit risk estimates for NPC incidence are 

9 presented in Table 5-11. The unit risk estimate for cancer incidence is twofold higher than the 

10 corresponding mortality-based estimate, for all person-years. This sizeable discrepancy can be 

11 attributed to the high survival rates for NPC.

12

13 Table 5-11. EC0005, LEC0005, and inhalation unit risk estimates for NPC 

14 incidence from formaldehyde exposure based on the Hauptmann et al. (2004) 

15 trend analyses for cumulative exposure

16

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

17 a 18 Unit risk = 0.0005/LEC0005.

19

20

21 The preferred estimate for the inhalation cancer unit risk for NPC is the estimate of 

1.1 × 10–2 22 per ppm derived using incidence rates for the cause-specific background rates, for all 

23 person-years. The results from the exposed person-years are essentially identical.

24 Because NPC is a rare cancer, with a relatively low number of cases occurring per year in 

25 the U.S., a rough calculation was done to assure that the unit risk estimate derived for NPC 

26 incidence is not implausible in comparison to actual case numbers. For example, assuming an 

27 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 28 . 

29 Assuming an average lifetime of 75 years (this is not EPA's default average lifetime of 70 years 

30 but rather a value more representative of actual demographic data) and a U.S. population of 

31 300,000,000, this lifetime extra risk estimate suggests a crude upper-bound estimate of 220 

32 incident cases of NPC attributable to formaldehyde exposure per year. Alternatively, assuming 

33 an average constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a 

34 crude upper-bound estimate of 880 incident cases of NPC per year. Both upper bound estimates, 
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1 using different assumed lifetime exposure levels, are well below the estimated 2100 total 

2 incident 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

4

3 

5 5.2.2.4. Sources of Uncertainty

6 The two major sources of uncertainty in quantitative cancer risk estimates are generally 

7 interspecies extrapolation and high-to-low dose extrapolation. The risk estimates derived from 

8 the Hauptmann et al. (2004) analyses of the NCI cohort are not subject to interspecies 

9 uncertainty since they are based on human data. However, substantial uncertainty remains in the 

10 extrapolation from occupational exposures to lower environmental exposures. Although the 

11 actual exposure-response relationship at low exposure levels is unknown, the linear low-dose 

12 extrapolation that was used is warranted by the strong support for formaldehyde carcinogenicity 

13 having a mutagenic MOA (section 4.5). The linear low-dose extrapolation from the 95% lower 

14 bound on the exposure level associated with the extra risk level serving as the benchmark 

15 response is generally considered to provide a plausible upper bound on the risk at lower 

16 exposure levels. Actual low-dose risks may be lower to an unknown extent.

17 Other sources of uncertainty emanate from the epidemiologic study and its analysis 

18 (Hauptmann et al., 2004), including the retrospective estimation of formaldehyde exposures in 

19 the cohort, the modeling of the epidemiologic exposure-response data, the appropriate exposure 

20 metric for exposure-response analysis, and potential confounding or modifying factors.

21 The same team of investigators (Stewart et al., 1986) conducted a detailed retrospective 

22 exposure assessment to estimate the individual worker exposures. Formaldehyde exposures 

23 were estimated for specific jobs/tasks based on monitoring data, discussions with workers and 

24 plant managers, and assessment by industrial hygienists. Individual worker estimates were 

25 derived for a variety of exposure metrics based on work histories. This exposure assessment was 

26 a major undertaking, involving over 100 person-months. Hauptmann et al. (2004) suggested that 

27 employment of such a detailed exposure assessment would tend to minimize exposure 

28 misclassification for average and cumulative exposure and duration of exposure but that peak 

29 exposure estimates could be more susceptible to misclassification because they were not based 

30 on actual measurements. In addition, the follow-up study did not take into account exposures 

31 after 1980. Hauptmann et al. (2003) stated that any underestimation of (total) exposure resulting 

 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 

of incident cases per year in the U.S.
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1 from the 1980 cutoff “would be small because only 3.7% of all person-years were contributed by 

2 workers who were 65 years or younger and in exposed jobs in 1980” and because exposure 

3 levels were believed to have been much lower after 1980 than in earlier years. 

4 As discussed in Chapter 4 and the appendix (Human Health), Marsh et al. (1996) also 

5 estimated individual worker exposures at 1 of the 10 plants (Wallingford, Connecticut) studied 

6 by the NCI team, and 5 of the 9 NPC deaths were from that plant. The Marsh et al. (1996) 

7 exposure estimates were about 10-fold lower than those derived by the NCI team for the workers 

8 at the Wallingford plant. Marsh et al. (2002) hypothesized that “the NCI used data from several 

9 facilities to estimate exposures in a single facility.” However, the NCI investigators maintained 

10 that they estimated exposures for each plant separately. While the exact reasons for such a large 

11 discrepancy are unclear, some differences in the assessment procedures which could have 

12 resulted in substantial differences in the estimates are apparent. First, according to Marsh et al. 

13 (1996), 91.7% of the white male Wallingford plant workers were specified as being exposed to 

14 formaldehyde in the NCI study, while only 83.3% were considered to have been exposed in the 

15 Marsh et al. (1996) analysis (it should be noted that these two cohorts of the Wallingford plant 

16 are not identical). Second, the NCI investigators (Stewart et al., 1987, 1986) did their own 

17 exposure monitoring at all the plants, including the Wallingford facility, in order to standardize 

18 the data provided by the plants as well as to fill data gaps for certain jobs. There is no indication 

19 that Marsh et al. (1996) made any additional measurements themselves. Third, although the 

20 Marsh et al. (2002, 1996) papers are not entirely consistent on this point, those investigators 

21 apparently assumed that the job-specific exposures at the plant were essentially constant over the 

22 history of the plant, whereas the NCI team, based on interviews with plant personnel 

23 knowledgeable about equipment and process changes, assumed that past exposures were higher.

24 In any event, despite the discrepancies in the absolute exposure values, the relative 

25 exposures for both the Marsh et al. (2002, 1996) and NCI studies, as reflected in the exposure26 response relationships, are less subject to misclassification and are considered to be reliable. 

27 The Wallingford plant is just 1 of the 10 plants in the NCI study (representing 4,389 of the 

28 25,619 workers in the NCI cohort), but if the Marsh et al. (1996) exposure estimates, which are 

29 roughly 10-fold lower than the NCI estimates, are closer to the actual exposures for those 

30 workers, then the true potency of formaldehyde could be greater than that suggested by the unit 

31 risk estimates calculated above based on the NCI data. Furthermore, if the NCI exposure values 

32 were significantly overestimated across all 10 plants, then the actual potency could be higher 

33 still.

34 With respect to the exposure-response model, the log-linear model used by Hauptmann et 

al. (2003) for their trend tests (i.e., RR = eβX 35 ) is a commonly used model for epidemiologic data 
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1 with exposure as a continuous variable. However, the actual exposure-response relationship is 

2 unknown. Moreover, even if the correct exposure-response model were known, there would be 

3 substantial uncertainty in estimating the model parameters because there are only nine NPC 

4 deaths to model. Furthermore, Beane Freeman et al. (2009) reported that in the follow-up 

5 through 2004 it was discovered that 1,006 deaths that occurred during the 1980 to 1994 

6 follow-up period had not been included in the analyses of the 1994 follow-up study (Hauptmann 

7 et al., 2004, 2003), for reasons that have not been identified. Because NPC is such a rare cancer, 

8 it is not expected that many, if any, NPC deaths were among the 1,006 excluded deaths; 

9 however, it is unknown how inclusion of the 1,006 deaths would have altered the overall 

10 exposure-response relationship and, hence, the regression coefficient. Additionally, a 15-year 

11 lag was used for all the NCI solid cancer models. The actual minimum latency is unknown; 

12 however, the investigators reported that lag intervals between 2 and 20 years yielded similar 

13 results.

14 Another potentially significant source of uncertainty is associated with the exposure 

15 metrics. With the log-linear model used for modeling the occupational data, the peak exposure 

16 metric gave the strongest exposure-response relationship between formaldehyde exposure and 

17 increased risk of NPCs. However, it is unclear how to extrapolate RR estimates based on peak 

18 exposure estimates to meaningful estimates of lifetime extra risk of cancer from environmental 

19 exposure (i.e., extra risk from lifetime continuous low-level environmental exposures). The 

20 cumulative exposure metric also yielded a statistically significant exposure-response relationship 

21 and was used for the primary cancer risk calculations in this assessment. The “true” exposure 

22 metric best describing the toxicologically relevant dose of formaldehyde for nasopharyngeal 

23 carcinogenesis is unknown. If a peak-exposure type of metric is the best representative of the 

24 toxicologically relevant dose, this suggests that there are dose-rate effects in the exposure25 response relationship for formaldehyde and NPC. If this is the case, the unit risk estimates 

26 presented here, which are based on a linear low-dose extrapolation, may overestimate the true 

27 risks to an unknown extent.

28 Hauptmann et al. (2004) gave a lot of consideration to potential confounding and 

29 modifying factors in their analyses. The important factors of age, race, sex, calendar year, and 

30 pay category were taken into account in their Poisson regression and trend analyses. 

31 Furthermore, they used the low-exposure person-years, rather than the unexposed person-years, 

32 as their referent group in an effort to minimize any potential confounding effects resulting from 

33 differences in socioeconomic or other characteristics between exposed and unexposed workers. 

34 When the slope estimate (i.e., regression coefficient) for the exposed person-years only was used 
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1 in the analyses presented here, the unit risk estimate was essentially identical to that calculated 

2 from the slope estimate for all person-years (see Tables 5-12 and 5-13).

3 In addition, these investigators evaluated routine respirator use, exposure to 

4 formaldehyde-containing particulates, durations of exposure to 11 other chemicals/substances in 

5 the plants (antioxidants, asbestos, carbon black, dyes and pigments, hexamethylenetetramine, 

6 melamine, phenol, plasticizers, urea, wood dust, and benzene), and duration of employment as a 

7 chemist or laboratory technician. Only 133 workers ever routinely used a respirator (Hauptmann 

8 et al., 2003). Hauptmann et al. (2004) reported that RR estimates for NPC changed when 

9 adjusted for duration of melamine exposure, although trend tests remained significant for 

10 cumulative formaldehyde exposure (p = 0.006). The investigators suggested that the association 

11 with melamine may be spurious, and the regression coefficients (i.e., β estimates) used in this 

12 assessment were not adjusted for melamine. RR estimates reportedly did not change 

13 substantially when adjusted for exposure to any of the other 10 chemicals/substances. None of 

14 the workers who died of NPC was identified as being exposed to wood dust. On the other hand, 

15 each of the seven formaldehyde-exposed workers who died of NPC was also exposed to 

16 particulates, and neither of the two workers who died of NPC but were not exposed to 

17 formaldehyde was exposed to particulates. However, for those workers exposed to particulates, 

18 NPC risk increased with increasing formaldehyde exposure, suggesting a formaldehyde19 associated effect. Nonetheless, because of the correspondence between formaldehyde and 

20 particulate exposures within the workers who died of NPC, there is uncertainty as to whether or 

21 not particulates were acting as a modifying factor. Adjusting for duration of time spent working 

22 as a chemist or laboratory technician did not substantially alter the results (Hauptmann et al., 

23 2004). 

24 Adjusting for plant may result in overadjustment because plant is highly correlated with 

25 exposure. Moreover, Hauptmann et al. (2004) adjusted for important plant-related factors by 

26 adjusting for the 11 chemicals/substances. Nonetheless, these investigators conducted analyses 

27 adjusted for plant to address potential unmeasured confounders associated with plant, and they 

28 reported that the association with NPC remained. As noted above, five of the nine NPC deaths 

29 were from the Wallingford plant also studied by Marsh et al. (2006, 2002). Marsh et al. (2007) 

30 hypothesized that the excess NPCs in the Wallingford plant could be due to external employment 

31 in metal-working industries, but we found no evidence to support this supposition (see section 

32 4.1.1.1). 

33 Although smoking data were not available for the cohort, smoking is unlikely to explain 

34 the excesses in NPCs because there was no consistent increase for tobacco-related diseases, 
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1 including lung cancer, across the same exposure metrics. No information was available on 

2 Epstein-Barr virus, a major risk factor for NPC, in the cohort.

3 Despite inevitable uncertainties, it is important not to lose sight of the strengths of the 

4 NCI study. In addition to the use of internal analyses and the extensive exposure assessment and 

5 consideration of potential confounding or modifying variables, the NCI study has a large cohort 

6 that has been followed for a long time. The cohort included 25,619 subjects, 75% of whom 

7 entered before 1960, contributing a total of 865,708 person-years (730,312 for the exposed 

8 workers) to the 1994 follow-up. Duration of follow-up in 1994 ranged up to 58 years, with a 

9 median of 35 years. Duration of exposure ranged up to 46 years, with a median of 2 years. 

10 Additional uncertainties are not so much inherent in the exposure-response modeling or 

11 in the epidemiologic data themselves but rather stem from the process of obtaining more general 

12 EPA risk estimates from these specific results. EPA cancer risk estimates typically represent a 

13 plausible upper bound on increased risk of cancer incidence in the general population for all 

14 tissue sites potentially affected by an agent. For experimental animal studies, this is 

15 accomplished by using tumor incidence data and summing across all the tumor sites that 

16 demonstrate significantly increased incidences, generally using data from the most sensitive sex 

17 and species. However, in estimating comparable risks from the NCI epidemiologic data, certain 

18 limitations are encountered. First, the NCI study is a retrospective mortality study, and cancer 

19 incidence data are unavailable for the cohort. Second, these occupational epidemiology data 

20 represent a worker cohort that is generally healthier than the general population 

21 (e.g., SMRs < 1) (see Table 2 of Hauptmann et al. [2004]).

22 The first limitation was addressed quantitatively in the calculation of cancer incidence 

23 risk estimates from the mortality results, and, even though there are assumptions made in using 

24 incidence data this way, the incidence-based estimates are believed to be better estimates of 

25 cancer incidence risk than the mortality-based estimates. With respect to the second limitation, 

26 the healthy worker effect is often an issue in occupational epidemiology studies, and it is 

27 difficult to know to what extent there is a healthy worker effect with respect to the development 

28 of NPC in this study. As discussed above, Hauptmann et al. (2004) sought to minimize potential 

29 confounding effects resulting from differences in socioeconomic or other characteristics between 

30 exposed and unexposed workers by using the low-exposure person-years, rather than the 

31 unexposed person-years, as their referent group. Nonetheless, when the slope estimates for the 

32 exposed person-years only were used in the analyses in this assessment, unit risk estimates 

33 essentially identical to those calculated from the slope estimates for all person-years were 

34 obtained (Tables 5-12 and 5-13). In terms of representing the general population, the NCI cohort 
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1 was somewhat diverse, but the workers were predominantly white males (81%) then white 

2 females (12%), black males (7%), and black females (<1%), and they were all adults.

3 Finally, NPC is just one of the upper respiratory tract cancers concluded to be causally 

4 associated with formaldehyde exposure (section 4.5). These upper respiratory tract cancers are 

5 rare cancers and are difficult to detect in cohort studies. Thus, although NPC was the only such 

6 cancer with an exposure-response relationship amenable to the derivation of a unit risk estimate, 

7 additional, unquantified risk may exist for the other upper respiratory tract cancers. If there was 

8 a strong exposure-response relationship between these cancers and formaldehyde exposure, a 

9 more apparent association in the Hauptmann et al. (2004) study might have been expected, as 

10 was seen for NPC, despite the rare nature of these cancers. Thus, the exposure-response 

11 relationship for these other upper respiratory tract cancers is likely modest, at best, and, because 

12 these are rare cancers, the contribution of the risk for these cancers to the total cancer risk from 

13 formaldehyde exposure is not expected to be large. Nonetheless, with such rare cancers, there is 

14 uncertainty regarding the extent to which the estimate based on NPC may underestimate the risk 

15 for all upper respiratory tract cancers. 

In summary, the inhalation cancer unit risk estimate of 1.1 × 10–2 16 per ppm for NPC is 

17 based on human data from a high-quality epidemiologic study with individual exposure 

18 estimates for each worker. A major uncertainty is the appropriate model/exposure metric for 

19 extrapolation to environmental exposures.

20

21 5.2.3. Lymphohematopoietic Cancer 

22 5.2.3.1. Exposure-Response Modeling of the National Cancer Institute Cohort

23 The results of NCI’s internal analyses for lymphohematopoietic cancers using the peak 

24 exposure, average intensity, and cumulative exposure metrics from the follow-up through 2004 

25 are reported by Beane Freeman et al. (2009). There was reportedly no evidence of associations 

26 with duration of exposure, and those results were not presented. For the peak exposure metric, 

27 statistically significant log-linear trends were observed for all lymphohematopoietic cancers, 

28 Hodgkin lymphoma, and leukemia (the latter only when the unexposed person-years were 

29 included). There was also evidence for potential associations with myeloid leukemia 

30 specifically, especially when risks were viewed over time, and with multiple myeloma. Using 

31 the average exposure metric, there was a significant trend for Hodgkin lymphoma. With the 

32 cumulative exposure metric, there were no statistically significant trends; however, the Hodgkin 

33 lymphoma trend results were of borderline significance (p trends = 0.06 and 0.08 with and 

34 without the unexposed person-years, respectively), as were the leukemia trend results (p trends = 

35 0.08 and 0.12 with and without the unexposed person-years, respectively). As discussed above 
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1 with NPC, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 

2 to meaningful estimates of lifetime extra risk of cancer from environmental exposures. The 

3 average exposure metric is also problematic because it suggests that duration of exposure is not 

4 important (e.g., exposure to a given exposure level for 1 year conveys the same amount of risk 

5 as exposure to the same level for 70 years). Cumulative exposure is generally the preferred 

6 metric for quantitative risk assessment for environmental exposure to carcinogens, and, because 

7 the Hodgkin lymphoma and leukemia trend results were of borderline statistical significance 

8 using the cumulative exposure metric and the elevations in risk with that metric were consistent 

9 with significant elevations observed with the peak exposure (for Hodgkin lymphoma and 

10 leukemia) and average exposure (for Hodgkin lymphoma) metrics (Table 5-12), a determination 

11 was made to calculate unit risk estimates for Hodgkin lymphoma and leukemia based on 

12 cumulative exposure. There is also support for associations between formaldehyde exposure and 

13 both Hodgkin lymphoma and leukemia from other studies (section 4.5.2). No other 

14 lymphohematopoietic cancer responses provided adequate exposure-response data with the 

15 cumulative formaldehyde exposure metric in the NCI cohort from which to derive unit risk 

16 estimates. 

17 As for the NPC results discussed in section 5.2.2, the RR estimates in Table 5-12 were 

18 derived using log-linear Poisson regression models stratified by calendar year, age, sex, and race 

19 and adjusted for pay category (salary/wage/unknown). The NCI investigators used the low20 exposure category as the reference category to “minimize the impact of any unmeasured 

21 confounding variables since nonexposed workers may differ from exposed workers with respect 

22 to socioeconomic characteristics” (Hauptmann et al., 2004). A 2-year lag interval was used to 

23 determine exposures in order to account for a minimal latency period for lymphohematopoietic 

24 cancers.

25 Dr. Beane Freeman provided EPA with the regression coefficient estimates for Hodgkin 

26 lymphoma and leukemia mortality from the log-linear trend test models for cumulative exposure 

(i.e., RR = eβX 27 , with exposure [X] as a continuous variable) used in the NCI analyses (personal 

28 communication from Laura Beane Freeman, NCI, to John Whalan, EPA, August 26, 2009). 

29 These estimates are presented in Table 5-13. As with the NPC calculations in section 5.2.2, the 

30 nonexposed person-years were included in the primary unit risk estimate derivations in order to 

31 be more inclusive of all the exposure-response data. Final results for the exposed person-years 

32 only are presented for comparison.

33
This document is a draft for review purposes only and does not constitute Agency policy.

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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 modelsa 16

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).

23
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1 5.2.3.2. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma and Leukemia Mortality

2 Extra risk estimates for Hodgkin lymphoma and leukemia mortality were calculated 

3 using the same general methodology described above for the NPC mortality estimates (section 

4 5.2.2.2), with the following exceptions. U.S. age-specific 2006 all-cause mortality rates (NCHS, 

5 2009) and NCHS age-specific 2002–2006 background mortality rates for Hodgkin lymphoma 

6 and leukemia (http://seer.cancer.gov/csr/1975_2006/) for all race and gender groups combined 

7 were used in the life-table programs. In addition, a 2-year lag period was used instead of a 

8 15-year lag period.

9 The resulting point estimates and one-sided 95% UCLs for the extra risk of Hodgkin 

10 lymphoma mortality associated with varying levels of continuous exposure to formaldehyde are 

11 presented in Table 5-14. The results for leukemia are shown in Table 5-15. In both cases, the 

12 models predict extra risk estimates that are fairly linear for exposures below about 0.01–0.1 ppm 

13 but not for exposures above 0.1 ppm. 

14

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

16 various levels of continuous exposure to formaldehyde

17

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

18

19

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

21 of continuous exposure to formaldehyde

22

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

23
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1 As discussed in section 5.2.2.2 above, 1% extra risk levels are typically used as the basis 

2 for the POD for low-dose extrapolation from epidemiologic data. As for NPC, however, 

3 Hodgkin lymphoma has a very low background mortality rate (e.g., lifetime background risk is 

4 about 0.00038), and the 1% level of risk is associated with RR estimates that are substantially 

5 higher than those observed in the epidemiology study. Hence, a 1% extra risk level would be an 

6 upward extrapolation. Based on the life-table program, the RR estimate associated with an extra 

7 risk of 1% for Hodgkin lymphoma mortality is 27. Even 0.1% yields an RR estimate at the 

8 higher end of what was observed in the epidemiology study (RR = 3.6) (note that our primary 

9 analyses include the nonexposed workers, and thus the 0-exposure group becomes the referent 

10 group and the RR estimates presented for Hodgkin lymphoma and cumulative exposure in Table 

11 5-12 would be adjusted upward [about 2.4-fold] relative to the 0-exposure group). A 0.05% 

12 extra risk level yields an RR estimate of 2.3, which better corresponds to the RRs at the lower 

13 end of the observable range. Thus, 0.05% extra risk was selected for determination of the POD 

14 for Hodgkin lymphoma, and, consistent with EPA’s Guidelines for Carcinogen Risk Assessment

15 (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the POD.

16 For leukemia, although the background mortality rates are higher (0.0065), the 1% extra 

17 risk level typically used as the basis for the POD for epidemiologic data still corresponds to an 

18 RR estimate (2.5) that would be above the highest categorical result reported, even after 

19 adjusting the RR estimates upward relative to the 0-exposure group (see above paragraph). A

20 0.5% extra risk level yields an RR estimate of 1.8, which better corresponds to the RRs in the 

21 range of the data. Thus, the LEC value corresponding to 0.5% extra risk was selected for the 

22 POD for leukemia.

23 Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 

24 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA

25 (section 4.5), a linear low-dose extrapolation was performed, also in accordance with EPA’s 

26 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). The EC0005, LEC0005, and 

27 inhalation unit risk estimates for Hodgkin lymphoma mortality are presented in Table 5-16, and 

28 the EC005, LEC005, and inhalation unit risk estimates for leukemia mortality are presented in 

29 Table 5-17.

30

31

32

33
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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 
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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

17

16

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 

10 duration of exposure to the 11 other substances that they considered (see section 5.2.2.4) or for 

11 working as a chemist or laboratory technician “did not meaningfully change results”; results 

12 were not shown. The investigators also reported that excluding the 586 individuals with exposure

13 to benzene, a known leukemogen, did not change the RR estimates for myeloid or lymphoid 

14 leukemia in the highest peak exposure category. Furthermore, Beane Freeman et al. (2009) 

15 found no evidence of heterogeneity of RR estimates for lymphohematopoietic cancers by race, 

16 sex, or pay category, 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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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 

6 by 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, 

11 it 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
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review purposes only and does 

not constitute Agency policy

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

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

age (years)

rate per 100,000

all leuk mort

all leuk inc

myeloid mort

myeloid inc

lymphoid mort

lymphoid inc
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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/m3 13 ). 

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/m3 17 ) 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 

22 cancers thought to be causally associated with formaldehyde exposure. For an approximate 

23 estimate of the combined (upper bound) risk, risk estimates were combined assuming a normal 

24 distribution. For comparability, risk estimates for formaldehyde were combined at a common 

25 level of 0.1 ppm. This level was selected because it is close to the PODs (LEC005s) used above 

26 for leukemia mortality (0.121 ppm) and leukemia incidence (0.0875 ppm), and leukemia is the 

27 predominant cancer type in terms of extra risk. Note that unit risk estimates for the different 

28 cancer types calculated at 0.1 ppm will differ slightly from those reported above (sections 5.2.2 

29 and 5.2.3) because they are calculated at a level other than the PODs used in the above 

30 calculations. To derive the combined risk, maximum likelihood estimates (MLEs) of risk and 

31 their 95% upper bounds (UCLs) were calculated for each cancer type using the same methods

32 and life-table programs employed in sections 5.2.2 and 5.2.3. The standard errors (SEs) were 

33 then estimated 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 = SE2 34 . The 

35 sum of the variances then provides an estimate of the variance for the sum of the MLEs, and the 
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1 95% upper bound on the sum of the MLEs can be estimated by applying the above equations in 

2 reverse. Tables 5-20 and 5-21 provide a summary of the results of these calculations for the 

3 combined cancer mortality and incidence risks, respectively.

4

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

6 0.1 ppm

7

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

8 a 9 Unit risk = 95% upper bound on combined risk/0.1 ppm.

10

11

12 Table 5-21. Calculation of combined cancer incidence unit risk estimate at 

13 0.1 ppm

14

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

15 a 16 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/m3 10 ) 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. 

22 Thus, the value of 

8.1 × 10−2 per ppm (6.6 × 10–5 per μg/m3 23 ) 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

35
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1 5.3. DOSE-RESPONSE MODELING OF RISK OF SQUAMOUS CELL CARCINOMA 

2 IN THE RESPIRATORY TRACT USING ANIMAL DATA

3 In the previous section, dose-response analyses based on human data for 

4 lymphohematopoietic cancer and NPC were presented. The dose-response analyses of cancer 

5 risk presented in this section are based on nasal tumor data from laboratory bioassays using F344 

6 rats. Because the analyses involved are extensive, most of the details are provided in the 

7 appendices. 

8 An increased incidence of nasal squamous cell carcinoma (SCC) was seen in two long9 term bioassays using F344 rats (Monticello et al., 1996; Kerns et al., 1983). Although other 

10 studies in laboratory animals exist, these two studies, when combined, provide the most robust 

11 data for analyses. These inhalation data on nasal SCC tumor incidence were used to estimate 

12 human respiratory cancer risk in the nose and were also extrapolated to the entire respiratory 

13 tract; in other words, a site concordance between rat and human is not assumed. This is 

14 reasonable because the respiratory and transitional epithelial cell types considered to be at risk 

15 of SCC in the upper respiratory tract are also prevalent in the lower human respiratory tract, and 

16 there is greater penetration of formaldehyde flux posteriorly in the nose and in the rest of the 

17 human respiratory tract relative to that of the rat. These considerations are strengthened by the 

18 findings of DNA-protein cross-links (DPXs) in the proximal portions of the rhesus monkey 

19 lower respiratory tract (Casanova et al., 1991). In addition, some epidemiologic studies 

20 (Gardner et al., 1993; Blair et al., 1990, 1986) reported an increase in lung cancer associated 

21 with formaldehyde exposure, while others (Collins et al., 1997; Stayner et al., 1988) reported no 

22 such increases. 

23 EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a BBDR model for 

24 extrapolation when data permit. A BBDR model for formaldehyde was developed by scientists 

25 at the CIIT Centers for Health Research (see Appendix D) (Conolly et al., 2004, 2003, 2000; 

26 Kimbell et al., 2001a, b; Overton et al., 2001; CIIT, 1999), which interfaced several models to 

27 combine the extensive mechanistic information available in studies involving the F344 rat and 

28 rhesus monkey and time-to-tumor incidence data in long-term bioassays, as shown by the 

29 schematic in Figure 5-11. This mechanistic information included formaldehyde and DPX 

30 dosimetry in the rat, monkey, and human airways and cell proliferation data in the rat nasal 

31 lining. This document presents extensive evaluation of the underlying models and data and of 

32 the alternative parametrizations of the models that were also explored for the purpose of the 

33 current assessment (see Appendix E, Appendix F). A summary of conclusions is presented in 

34 section 5.3.3. In particular, the following conclusions by EPA were critical in determining how 

35 the models could be used to inform the quantitative dose-response assessment:
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1 • When used to model the dose-response in the range of the available data, the BBDR 

2 models were judged to have the advantage of being more accurate and biologically based 

3 (than purely statistical descriptions such as the multistage-weibull model) and allowing 

4 utilization of various data in an integrated manner.

5 • Variations to the modeling in Conolly et al. (2003) were examined. Each of these models, 

6 including the modeling in Conolly et al., was judged to be just as biologically plausible 

7 as the other, described the rat tumor incidence equally well, was based on different 

8 characterizations of the same empirical cell kinetic data, and was based on the same 

9 empirical data on DPX measurements. However, the added human risk over baseline 

10 levels estimated by these models (including the original model) ranged from negative to 

11 large positive values at environmental exposure concentrations.

12 • When used for the purpose of extrapolating risk, the BBDR models did not appear to 

13 reasonably constrain either risk estimates extrapolated to human exposures or risk 

14 estimates for the F344 rat when they were extrapolated below the range of observable 

15 data. 

16 • Because human respiratory cancer risk calculated in Conolly et al. (2004) was 

17 numerically unstable, clonal growth modeling was not found to be a useful approach for 

18 human extrapolation of rodent risk estimates.

19 • Thus, the biologically based derivation of human risk estimates in Conolly et al. (2004) 

20 cannot be characterized as a plausible upper bound in the face of model uncertainties (a 

21 key conclusion of those authors).

22

23 For all these reasons, the BBDR modeling of the rat data 

24 • was employed in this assessment to derive multiple PODs (for SCC in the respiratory 

25 tract) in the range of the observed data and using model-derived internal dose estimates,

26 • but was not used to extrapolate far below the observed data., 

27

28 The inhalation unit risk estimates of SCC in the human respiratory tract were derived by 

29 using multiple methods to model the F344 tumor incidence data as follows: conventional 

30 mutistage Weibull time-to-tumor modeling and variations of the model implemented in Conolly 

31 et al. (2003) that were considered in the process of the evaluation.

32 PODs were calculated as exposure concentrations corresponding to the 95% statistical 

33 upper bound extra risks of 0.005, 0.01, and 0.05 (0.005 used only with BBDR modeling). The 

34 inhalation unit risk for SCC in the human respiratory tract (upper and lower) derived from the 

35 above animal bioassay data was then calculated by linear extrapolation to the origin from the 
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1 POD. Linear extrapolation is supported in part by the proven genotoxicity of the chemical and 

2 the observation of cytogenetic effects in human occupational exposures (see chapter 4). In 

3 particular, the formation of DPXs on formaldehyde interaction with DNA has been observed at 

4 doses well below those considered cytotoxic. In results obtained in some implementations of the 

5 biologically based models, formaldehyde-induced mutagenicity (modeled as proportional to 

6 DPX concentration) was found to be a critical determinant of its tumorigenicity, both at the low 

7 dose pertaining to human exposure concentrations as well as in the dose range in which 

8 formaldehyde is considered to be cytotoxic.

9 The human equivalent concentration was calculated by assuming that continuous lifetime 

exposure to a given steady-state flux of formaldehyde (expressed in pmol/mm2 10 -hour) leads to 

11 equivalent risk of nasal cancer across species. Risk per respiratory or transitional epithelial cell 

12 with replicative potential in a given region was computed as a function of formaldehyde flux in 

13 the nasal region and extrapolated to the rest of the respiratory tract. 

14

15 5.3.1. Long-Term Bioassays in Laboratory Animals

16 This section briefly describes the various animal data and dosimetry information utilized 

17 in the above (but not in all) models, based on which estimates for the inhalation unit risk are 

18 derived later in this chapter.

19

20 5.3.1.1. Nasal Tumor Incidence Data

21 Various bioassays have reported the effects of formaldehyde on rats, mice, and rhesus 

22 monkeys and have been discussed at length earlier in this document. Two of these bioassays 

23 (Monticello et al., 1996; Kerns et al., 1983), when combined, allow for the most robust 

24 characterization of the long-term dose response in a laboratory species. These long-term 

25 bioassays found an increased incidence of nasal SCCs in rats exposed to formaldehyde by the 

26 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 27 ) exposure concentrations of formaldehyde. 

28 SCCs were observed only at 6.01 ppm and higher exposure concentrations. Table 5-22 provides 

29 a summary of the tumors from these bioassays, and the time-to-tumor characteristics are as 

30 shown by the data in Figure 5-12 (in section 5.3.3). The focus here is on these two bioassays, 

31 combined, because they provide the most extensive chronic dose-response information. Other 

32 tumor bioassays were also conducted by various researchers and have been detailed in chapter 4.

33

34

35
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1 Table 5-22. Summary of tumor incidence in long-term bioassays on 

2 F344 rats 

3

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

4

5 Sources: Combined data from Monticello et al. (1996) and Kerns et al. (1983).

6

7

8 5.3.1.2. Mechanistic Data

9 The Kerns et al. (1983) and Monticello et al. (1996) tumor studies were accompanied or 

10 followed by additional studies that provided extensive mechanistic information on both 

11 pharmacokinetics and pharmacodynamics. These studies have been summarized elsewhere in 

12 this document and in other reviews (CIIT, 1999; Monticello and Morgan, 1997; Morgan, 1997; 

13 Heck et al., 1990). In addition to the tumor incidence data, the following data and mechanistic 

14 information (some of which were model derived) are used in the quantitative models utilized in 

15 this chapter. In all these cases, additional data for the rhesus monkey are also available that 

16 inform the hazard assessment but which have not been explicitly used in deriving the inhalation 

17 unit risk. Rhesus monkey data have been discussed in chapter 4 and chapter 3 (DPX and 

18 formaldehyde dosimetry).

19 • Formaldehyde interacts with DNA to form DPXs. These cross-links are considered to 

20 induce mutagenic as well as clastogenic effects. Casanova et al. (1994, 1989) carried out 

21 two studies of DPX measurements in F344 rats. In the first study, rats were exposed to 

22 concentrations of 0.3, 0.7, 2, 6, and 10 ppm for 6 hours and DPX measurements were 

23 made over the whole respiratory mucosa of the rat, while, in the second study, the 

24 exposure was to 0.7, 2, 6, or 15 ppm formaldehyde for 3 hours and measurements were 

25 made at “high” and “low” tumor sites. DPX formation was observed at all exposure 

26 concentrations in both studies (0.3 ppm – 15 ppm); the DPX levels were statistically 

27 significantly elevated at concentrations ≥2 ppm, with the trend also indicating elevated 

28 DPXs at 0.7 ppm. These data were used in the development of a PBPK model for 

29 predicting DPX levels in the nasal lining (see chapters 3 and 4). 
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1 • Male F344 rats were exposed to formaldehyde gas over a range of concentrations (0, 0.7, 

2 2, 6, 10, or 15 ppm) in two phases of a labeling study. The first phase (Monticello et al., 

3 1991) employed injection labeling with a 2-hour pulse labeling time, and animals were 

4 exposed to formaldehyde for periods of 1, 4, and 9 days and 6 weeks. The second phase 

5 (Monticello et al., 1996) used osmotic minipumps for labeling with a 120-hour release 

6 time to quantify labeling in animals exposed for 13, 26, 52, and 78 weeks. These data 

7 have been analyzed at length in Appendix E.

8 • Physical and computer models of airflow in anatomically realistic representations of the 

9 F344 rat and human upper respiratory tract have been constructed (Kimbell et al., 1993, 

10 1997; Kepler et al., 1993; Subramaniam et al., 1998; see chapter 3).

11 • Regional uptake of formaldehyde has been calculated for the upper respiratory tract of 

12 the rat and human by using the above computer representations and for the lower 

13 respiratory tract of the human by using an idealized representation of the human lower 

14 respiratory tract (Kimbell et al., 2001a; Overton et al., 2001; also see chapter 3 and 

15 further discussion of uncertainties in Appendix F).

16

17 5.3.2. The CIIT Biologically Based Dose-Response Modeling 

18 The studies mentioned above in 5.3.1.1 and 5.3.1.2 were generated at the CIIT Centers 

19 for Health Research and led to the development of a biologically motivated dose-response model 

20 for formaldehyde-induced cancer as represented in a series of papers and in a health assessment 

21 report (CIIT model) (Conolly et al., 2004, 2003, 2000; Conolly, 2002; Kimbell et al., 2001a, b; 

22 Overton et al., 2001; CIIT, 1999). EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a

23 BBDR model for extrapolation when data permit since it facilitates the incorporation of MOA in 

24 risk assessment. The CIIT modeling and available data were evaluated in a series of peer25 reviewed papers (Klein et al., 2009; Crump et al., 2008; Subramaniam et al., 2008, 2007) and 

26 debated further in the literature (Conolly et al., 2009; Crump et al., 2009). Alternatives to the 

27 parametrization and model structure in the CIIT biological modeling (but based on that original 

28 model) are further explored and evaluated in this assessment (Appendix E). Appendix F carries 

29 out a sensitivity analysis of the human risk estimates in Conolly et al. (2004) based on key 

30 uncertainties evaluated in Appendix E. These BBDR models are used in this assessment to 

31 calculate PODs from the dose-response curve for the F344 rat nasal tumor risk. Extrapolation to 

32 human is then carried out by using EPA’s baseline (“default”) approach (U.S. EPA, 1994) but 

33 using model-derived internal dose metrics. See section 5.3.3 for rationale supporting these 

34 decisions.
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1 First, the key features of the BBDR modeling in Conolly et al. (2003, 2004) are briefly 

2 described, and the following notation is used throughout this section: N cell = normal cell; I cell 

3 = initiated cell; LI = labeling index and is equal to the number of labeled cells/(number labeled + 

4 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 5 ); μN = rate at which an initiated cell is 

6 formed by mutation of a normal cell (per cell division of normal cells).

7 In Conolly et al. (2003), tumor incidence data in the Kerns et al. (1983) and Monticello et 

8 al. (1996) long-term bioassays were modeled by using an approximation of the two-stage clonal 

9 growth model (Moolgavkar et al., 1988) and allowing formaldehyde to have a direct mutagenic 

10 action. Conolly et al. (2003) combined these data with historical control data on 7,684 animals 

11 obtained from National Toxicology Program (NTP) bioassays. These models are based on the 

12 Moolgavkar, Venzon, and Knudson (MVK) stochastic two-stage model of cancer (Moolgavkar 

13 et al., 1988; Moolgavkar and Knudson, 1981; Moolgavkar and Venzon, 1979), which accounts 

14 for growth of a pool of normal cells, mutation of normal cells to initiated cells, clonal expansion 

15 and death of initiated cells, and mutation of initiated cells to fully malignant cells. 

16 The MVK model for formaldehyde accounted for two MOAs as follows that may be 

17 relevant to formaldehyde carcinogenicity:

18 1. An indirect MOA in which the regenerative cell proliferation in response to formaldehyde 

19 cytotoxicity increases the probability of errors in DNA replication. This MOA was modeled 

20 by using labeling data on normal cells in nasal mucosa of rats exposed to formaldehyde. 

21 2. A possible direct mutagenic MOA, based on information indicating that formaldehyde is 

22 mutagenic (Speit and Merk, 2002; Heck et al., 1990; Grafström et al., 1985), was modeled by 

23 using rat data on formaldehyde production of DPXs (Monticello et al., 1996, 1991). In 

24 Conolly et al. (2003), the intracellular dose that induces mutations is considered proportional 

25 to the local DPX dose. 

26

27 The human model for formaldehyde carcinogenicity (Conolly et al., 2004) is 

28 conceptually very similar to the rat model. The model uses, as input, results from a dosimetry 

29 model for an anatomically realistic representation of the human upper airways and an idealized 

30 representation of the lower airways. However, the model does not incorporate any data on 

31 human responses to formaldehyde exposure. 

32 A novel contribution of the CIIT model, described by the schematic in Figure 5-11, is 

33 that 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 34 -hour. This dosimetry is 

35 predicted by computational fluid dynamics (CFD) modeling using anatomically accurate 
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1 representations of the nasal passages of a single F344 rat or Caucasian male human (see 

2 chapter 3). Such a feature is important in incorporating site-specific toxicity in the case of a 

3 highly reactive gas like formaldehyde for which uptake patterns are spatially localized and 

4 significantly different across species (see chapter 3). In the CIIT model, each of these 

5 parameters is characterized by local flux (see Figure 5-11). The inputs to the two-stage cancer 

6 modeling consisted of results from other model predictions as well as empirical data as follows:

7 • Regional uptake of formaldehyde in the respiratory tract was predicted by using CFD 

8 modeling in the F344 rat and human (Kimbell et al., 2001a, b; Overton et al., 2001; 

9 Subramaniam et al., 1998).

10 • Normal cell replication rates were inferred from LI data on rats exposed to formaldehyde 

11 (Monticello et al., 1996, 1991, 1990).

12 • Concentrations of DPXs linked to the regional flux of formaldehyde were predicted by a 

13 PBPK model (Conolly et al., 2000) calibrated to fit the DPX data in F344 rat and rhesus 

14 monkey (Casanova et al., 1994, 1991) and subsequently scaled up to humans. The DPX 

15 concentration levels were incorporated into the two-stage clonal expansion model by 

16 defining mutation rate of normal and initiated cells as the same linear function of DPX. 

17 That is,

18

19 μN = μI = μNbasal + KMU × DPX (5-1)

20

21 where μN is the rate at which an initiated cell is formed by mutation of a normal cell (per 

22 cell division of normal cells), and likewise μI is the rate at which a malignant cell is 

23 formed by mutation of an initiated cell (per cell division of initiated cells). The unknown 

24 constants μNbasal (the baseline rate) and KMU were estimated by fitting model predictions 

25 to the tumor bioassay data. 

26

27 The rat model in Conolly et al. (2003) involved six unknown statistical parameters that 

28 were estimated by fitting the model to the rat formaldehyde bioassay data shown in Table 5-22 

29 (Monticello et al., 1996; Kerns et al., 1983) plus data from several thousand control animals 

30 from all the rat bioassays conducted by the NTP. These NTP bioassays were conducted from 

31 1976 through 1999 and included 7,684 animals with an incidence of 13 SCCs (i.e., 0.17% 

32 incidence). The resulting model predicts the probability of a nasal SCC in the F344 rat as a 

33 function of age and exposure to formaldehyde. The fit to the tumor incidence data is shown in 

34 Figure 5-12 (in section 5.3.3.). (For later reference in Appendix E, this figure compares the fit to 
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1 the data obtained by the modeling in Conolly et al. [2003] with that obtained by the 

2 reimplementation of this model in Subramaniam et al. [2007].)

3 Subsequent to the BBDR model for modeling rat cancer, Conolly et al. (2004) developed 

4 a corresponding model for humans for the purpose of extrapolating the risk to humans estimated 

5 by the rat model. Also, rather than considering only nasal tumors, the model is used to predict 

6 the risk of all human respiratory tumors. The human model for formaldehyde carcinogenicity 

7 (Conolly et al., 2004) is conceptually very similar to the rat model and follows the schematic in 

8 Figure 5-11. The following points need to be noted:

9

10 • The model does not incorporate any data on human responses to formaldehyde exposure. 

11 • The model is based on an anatomically realistic representation of the human nasal 

12 passages (in a single individual) and an idealized representation of the lower respiratory 

13 tract. Local formaldehyde flux to respiratory tissue is estimated by a CFD model for 

14 humans (Kimbell et al., 2001a; Overton et al., 2001; Subramaniam et al., 1998).

15 • Rates of cell division and cell death are, with a minor modification, assumed to be the 

16 same in humans as in rats. 

17 • The concentration of formaldehyde-induced DPXs in humans is estimated by scaling up 

18 from values obtained from experiments in the F344 rat and rhesus monkey (Conolly et 

19 al., 2000, and also discussed further in section 3.6.6 of this document). The statistical 

20 parameters for the human model are either estimated by fitting the model to the human 

21 background data, assumed to have the same value as that obtained in the rat model, or, in 

22 one case, fixed at a value suggested by the epidemiologic literature. The human value for 

23 KMU in eq 1 is obtained by assuming that the ratio KMU/μbasal is invariant across 

24 species.

25

26 Some further clarification pertaining to the structure and calibration of the models in 

27 Conolly et al. (2004, 2003) that are key to understanding model assumptions is provided in 

28 Appendix D.

29
This document is a draft for 

review purposes only and does 

not constitute Agency policy

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—DO 

Figure 5-11. Schematic of integration of pharmacokinetic and pharmacodynamic components in the CIIT 

model.

Note: β = death rate; μ = mutation rate per cell division; αN, N(t), μN are informed (partially or fully) by empirical data; 

other parameters are estimated by fitting to tumor incidence data.

Regional respiratory tract dosimetry model

Input

Cancer

cell

Tumor Tumor

(delay)

Normal

Cells, N(t)

Initiated

cells

αN αI

βI= αN

μN μI

=μN

D

DPX in Rat

DPX in Monkey

DPX in Human 

Respiratory tract

PBPK models for DPX

faldh in air + Human Lung

input

input

Regional respiratory tract dosimetry model

Input

Cancer

cell

Tumor Tumor

(delay)

Normal

Cells, N(t)

Initiated

cells

αN αI

βI= αN

μN μI

=μN

D

DPX in Rat

DPX in Monkey

DPX in Human 

Respiratory tract

PBPK models for DPX

faldh in air + 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 hockey17 stick model for normal cell replication rates when the cell replication dose-response 

18 curve as averaged by the authors had a J shape, used overall respiratory tract cancer 

19 incidence data in humans, and evaluated the model at the statistical upper bound of the 

20 proportionality 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 

36 data from Monticello et al. (1996, 1991) are presented in Appendix E. The most significant 
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1 conclusions resulting from these various analyses, focusing on the ones that have maximal 

2 impact on the dose-response assessment, are presented below.

3

4 Description of time-to-tumor data

5 The overall approach and use of data in Conolly et al. (2004, 2003) have substantial 

6 advantages to offer in describing the dose response observed in animal bioassays. The authors’ 

7 model provides a good statistical description of the time-to-tumor data. The fit to the data was 

8 found to be superior to that obtained by using multistage Weibull time-to-tumor modeling of the 

9 tumor incidence data (comparison based on visual inspection [see Figure 5-12 in this section and 

10 Figures 5-17, 5-18, 5-19 in section 5.3.4]).

11

12 Figure 5-12. Fit to the rat tumor incidence data using the model and 

13 assumptions in Conolly et al. (2003).

14 Note: Fitting was performed on data of Kerns et al. (1983) and Monticello et al. (1996) combined 

15 with ALL NTP historical controls under the assumption that all SCCs are fatal. Figure compares 

16 the fit obtained by Conolly et al. (2003) with the reproduction of these results under identical 

17 conditions, inputs, and assumptions by Subramaniam et al. (2007). There were minor residual 

18 differences among the implementations; see the appendix in Subramaniam et al. (2007) for 

19 explanation.

20 Source: Subramaniam et al. (2007). Reprint permission required.

21

Subramaniam et al. fit

0 200 400 600 800 1000

0.0000

0.0005

0.0010

0.0015

0.0020

0 200 400 600 800 1000

0.00

0.05

0.10

0.15

0.20

0 200 400 600 800 1000

0.0

0.2

0.4

0.6

0.8

1.0

0 200 400 600 800 1000

0.0

0.2

0.4

0.6

0.8

1.0

Probability

Kaplan-Meier 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-Meier Conolly fit Our fit

Age (days)

Probability

Age (days)

0 ppm 6 ppm

10 ppm 15 ppm
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1 Integration of various relevant data

2 The model framework integrates various pharmacokinetic and pharmacodynamic 

3 components (regional formaldehyde flux, DPX, cell-replication, and tumor incidence data) 

4 within a single conceptual framework and thus facilitates description of the dose response that 

5 utilizes the extensive mechanistic information available for formaldehyde.

6

7 Regional dosimetry

8 Regional (site-specific) dosimetry in the upper respiratory tract is considered important 

9 for understanding the tumorigenicity of a reactive chemical like formaldehyde. The regional 

10 dosimetry models discussed in chapter 3 compute local formaldehyde flux to the tissue and are 

11 based on anatomically realistic constructions of the nasal airways in each species. The other 

12 relevant mechanistic data, DPX and cell replication, are expressed as a function of this local 

13 formaldehyde flux.

14

15 Confidence in dosimetry

16 Model predictions of formaldehyde flux to the respiratory lining have not been verified 

17 experimentally, and such verification would present formidable experimental challenges. 

18 Overall, the formaldehyde dosimetry modeling utilized in the CIIT modeling presents a 

19 reasonable level of confidence, as detailed in chapter 3, section 3.6, by virtue of agreement 

20 among multiple model predictions (models that predict airflow profiles as well as a PBPK model 

21 for DPX, which uses the calculated formaldehyde flux as input) and various kinds of available 

22 data. These data comprise airflow profiles in physical casts of the nasal cavity of an F344 rat 

23 (Kimbell et al., 2001a), a human (Subramaniam et al., 1998), and a rhesus monkey (Kepler et al., 

24 1998); DPX data (see discussion of Cohen-Hubal et al. [1997] in chapter 3); and qualitative 

25 concordance between uptake patterns and cell proliferation (Morgan et al., 1997; Monticello et 

26 al., 1996). The CFD models of formaldehyde flux represent only an individual of each species. 

27 However, considerable interindividual differences are to be expected in the regional dosimetry, 

28 particularly in the human (Garcia et al., 2009: Subramaniam et al., 2008). This is discussed 

29 briefly in Chapter 3 (section 3.6) and further in Appendices B and F. 

30

31 Control tumor data

32 In developing their model, Conolly et al. (2004, 2003) included control rats from all NTP 

33 cancer bioassays—a total of 7,684 rats. The inclusion of all NTP historical control animals does 

34 not appear to be supportable and substantially alters dose-response predictions (Crump et al., 

35 2009, 2008; Subramaniam et al., 2008, 2007). There are legitimate questions regarding 
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1 comparability of results in rats from different stocks, studied at different times, in different 

2 laboratories, and by different routes of exposure and evaluated by using somewhat different

3 pathological procedures. If historical controls are used from only those inhalation studies that 

4 present a low potential for genetic and time-related variations in tumor incidence and survival of 

5 animals or if only concurrent controls are used, the model for extrapolation of risk to humans 

6 (the human BBDR model) becomes numerically unstable. In such a model, it is not possible to 

7 bound human risk by using the extrapolation approach applied in the CIIT model. When the 

8 included NTP control data were restricted to all NTP inhalation controls, the upper bound human 

9 risk estimate obtained by Conolly et al. (2004) was increased by 50-fold (Crump et al., 2008).

10

11 Cell replication dose response

12 As discussed in chapter 4, characterization of the uncertainties and variability in the cell 

13 replication dose response is crucial to understanding formaldehyde carcinogenicity. Analyses of 

14 the dose response for cell replication presented in Appendix E demonstrate the following:

15 • Sustained exposure to formaldehyde affects cell division rates (compared to baseline 

16 levels). This effect is seen over a continuum of formaldehyde flux to the nasal lining that 

17 includes flux levels below those thought to be cytotoxic. 

18 • Given the qualitative and quantitative uncertainties in the data and in their interpretation, 

19 a variety of cell replication dose-response models are plausible as reasonable 

20 characterization of the data. Cell replication response differs substantially among nasal 

21 sites and over time during the course of the bioassay. In consideration of these 

22 differences, the shape of the cell replication low-dose response could be alternatively 

23 described as monotonic or non-monotonic. For example, rather different statistical 

24 descriptions of the data result depending on whether 

25 i. different sites and exposure times were modeled separately; 

26 ii. all exposure times were pooled to model the response at each site; 

27 iii. the labeling index was time-weighted and averaged over all sites; 

28 iv. flux and labeling index were weighted by the number of cells at a given site; 

29 v. the short exposure durations in Monticello et al. (1991) were examined separately. In 

30 addition, transient increases in cell turnover at sub-cytotoxic doses are seen in other 

31 experiments in rats exposed to formaldehyde (see chapter 4).

32 • At higher, cytolethal formaldehyde flux levels, regenerative hyperplasia-induced cell 

33 proliferation clearly takes over. 

34

35
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1 Genotoxicity

2 Chapter 4 provides multiple lines of evidence to characterize formaldehyde as a 

3 genotoxicant. Of particular note is the observation of cytogenetic effects at human occupational 

4 exposures and the formation of DPXs upon formaldehyde interaction with DNA at doses well 

5 below those considered cytotoxic. As noted earlier, DPX formation was detected in rats at 

6 exposures ranging from 0.3 ppm to 15 ppm. These DPX levels are seen to be statistically 

7 significantly increased over baseline levels at 2 ppm and above. The DPX measured at 0.7 ppm 

8 shows a trend that is consistent with an increase at this dose (see chapter 3); while not 

9 statistically significant, it is critical to consider “trend” when analyzing low-dose data.

10

11 Inferences on MOA from modeling the data

12 The highly curvilinear nature of dose responses associated with DPX formation, LI data, 

13 and tumor response as well as mechanistic interpretation of these observed data has provided 

14 grounds for arguments in the literature that formaldehyde tumorigenicity (at exposures ≥6 ppm) 

15 should be uncoupled from its potential carcinogenicity in the low-dose region. Furthermore, 

16 researchers have argued that any potential low-dose risk is due to its mutagenicity, that this 

17 mutagenic potential is too weak to be of significance, and that the high-dose risk is entirely due 

18 to cell proliferation induced by regenerative hyperplasia in response to cell injury at cytotoxic 

19 doses (i.e., without a relevant role for the direct mutagenic action of formaldehyde). Conolly et 

20 al. (2004, 2003) represented a quantitative expression of this point of view. However, alternative 

21 parametrizations of the model in Conolly et al. (2004, 2003) have shown that the mutagenic 

22 component can be important in explaining the high-dose effect and that the risk at low dose due 

23 this mutagenicity can be significant (Subramaniam et al., 2007; Appendix E). Accordingly, the 

24 dose-response assessment in this document does not treat formaldehyde as a threshold 

25 carcinogen. 

26 Of further relevance to mode-of-action considerations, analyses detailed in Appendix E 

27 indicate that the chronic rat nasal time-to-tumor incidence data can be quantitatively explained, 

28 and with equal force, by invoking any of the following multiple sets of plausible events induced 

29 by formaldehyde. The role of spontaneously occurring mutations and increased cell turnover 

30 rates in response to various baseline insults to the nasal lining are common to all these scenarios 

31 (and are not separately mentioned).

32 a. Mutations occur over a dose continuum that includes sub-cytotoxic and cytotoxic levels of 

33 exposure. The only cell proliferation induced by formaldehyde is a regenerative response at 

34 cytotoxic concentrations.
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1 b. Cytotoxicity-induced regenerative cell proliferation occurs, but there is no significant 

2 formaldehyde-induced mutational effect. This latter scenario expresses arguments that 

3 formaldehyde-induced mutagenicity may be too weak to be of significance to its 

4 tumorigenicity.

5 c. Both mutations and cell proliferation are induced by formaldehyde only at cytotoxic levels.

6 d. Mutational events occur and cell replication is altered over a continuum that includes low 

7 and high levels of exposure.

8 i. At high dose, the effect on cell replication is regenerative. 

9 ii. At lower doses, the data indicate that both monotonic and non-monotonic dose10 response curves for cell replication are plausible.

11 iii. With respect to the previous argument, the following result was very instructive. The 

12 models were exercized with normal cell replication rates considered to be less than 

13 (non-monotonic) or equal to (threshold) baseline rates over a segment of the low-dose 

14 range in conjunction with the chronic time-to-tumor data for the F344 rat. Such a 

15 scenario did not necessarily lead to lower than baseline or threshold in formaldehyde 

16 respiratory cancer risk in the rat in that low-dose range. This is partly because there 

17 are no data to inform how formaldehyde-induced mutation might alter cell replication 

18 and apoptotic rates (in particular if the mutation is to be construed as an initiating 

19 event in the carcinogenesis).

20 e. Formaldehyde-induced mutagenic action acts only in concert with baseline cell turnover at 

21 low dose. 

22

23 Kinetics of initiated cells

24 Modeling results are hypersensitive to the division and death rate of initiated cells that 

25 cannot be further inferred by the available empirical cell labeling data (Conolly et al., 2009; 

26 Crump et al., 2009, 2008). Several plausible alternate model structures for describing initiated 

27 cell kinetics, none of which degrade the agreement of the model with the underlying data used to 

28 construct the model originally, led to low-dose risk estimates in the rodent that varied by many 

29 orders of magnitude, including negative values (see Figures E-5A,B and E-6A,B in Appendix E). 

30 Extremely small perturbations in the division rate (and, likewise, of death rates) of initiated cells 

31 in the model lead to human risk estimates ranging anywhere from negative values to +0.01 at 

32 0.01 ppm (see Crump et al. 2008 and Appendix F, Figure F-5). These perturbations were small 

33 compared with the normal variation in the division rates of normal cells. 

34 The sensitivity analyses on the basis of which these conclusions were reached have been 

35 criticized as resulting in implausible risk estimates (given the epidemiologic data) as a 
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1 consequence of implementing model variations that are not biologically reasonable (Conolly et 

2 al. 2009). This criticism was rebutted by Crump et al. (2009) on biological and epidemiological 

3 grounds. These debates are discussed fully in Appendix F.

4 In addition, there are major qualitative uncertainties in extrapolating normal cell 

5 replication rates from the rat to human (Table F-1 in Appendix F, and Subramaniam et al. 

6 [2008]). Subramaniam et al. (2008) concluded that several inferences that arise from the 

7 assumptions in the CIIT model on initiated cell replication and death rates cannot be supported 

8 by available biological information. 

9

10 Risk extrapolation 

11 Use of the modeling approach in Conolly et al. (2004) or the variations examined were 

12 determined not to be informative for extrapolation from animal to human at any exposure 

13 concentration because of extreme sensitivity, including numerical instability, to uncertain model 

14 assumptions. In the face of model uncertainties, the biologically based derivation of human risk 

estimates of 10–6 15 or less at exposures of 0.1 ppm and below in Conolly et al. (2004) or CIIT 

16 (1999) cannot be characterized as a plausible upper bound. 

17 The use of this model for extrapolation of risk from high to low exposures in the rodent 

18 followed by a conventional (default) approach to extrapolate the low-dose animal risk to the low19 dose human risk was next evaluated. This avenue was also found not to be informative because 

20 the models do not adequately constrain risk in the rodent. For example, various model 

21 representations as shown in Figure E-6A,B in Appendix E were used to evaluate added MLE risk 

at the 10–5 22 level (Figure F-5A,B in Appendix E) in the F344 rat. Human exposures were then 

23 calculated that would result in equivalent lifetime risk by using formaldehyde flux estimated in 

24 each species as the dosimeter and conventional extrapolation methods (U.S. EPA, 1994b). A 25-

25 fold difference was found between the different models in the equivalent exposure concentration 

26 so derived. Therefore, the CIIT model or its variations were also not used in this assessment as a 

27 biologically based or biologically motivated means of extrapolating outside the observed dose28 response in the F344 rat. Model uncertainty was substantially higher than the statistical 

29 uncertainty arising out of a given model specification.

30 Thus, in view of all the above considerations and in accordance with EPA’s cancer 

31 guidelines (U.S. EPA, 2005a), the derivation in this document of unit risk for human respiratory 

32 cancer from animal bioassay data is based on a linear extrapolation to the origin from a POD on 

33 the dose-response curve. Low-dose linearity was exhibited by the risk estimates from most of 

34 the models that were examined in the sensitivity analysis (see discussion surrounding Figure E35 5A,B in Appendix E). 
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1 BBDR modeling for deriving an “integrated” POD

2 The CIIT BBDR modeling approach provides a good fit to the time-to-tumor data and 

3 therefore allows for an appropriate determination of a POD while at the same time incorporating 

4 a large amount of mechanistic information in an integrated manner and allowing the use of 

5 model-derived internal dose estimates. Thus, use of this model provides an alternative to 

6 developing separate PODs based on several of the underlying components of the data, such as 

7 DPX, flux, and labeling data. Accordingly, the model is used in this assessment to derive a POD 

8 from a dose response, based on the nasal cancers in rats. Uncertainties in the derivation of the 

9 POD were represented by using the variations of the CIIT model examined in this chapter. 

10 These POD calculations as well as others are detailed below.

11

12 Genomics data

13 The genomics data of Thomas et al. (2007) and Andersen et al. (2008) provide additional 

14 insight into formaldehyde’s biological effects and the steep dose-response curve for 

15 tumorigenesis. However, there are various limitations in the interpretation of these genomics 

16 data and their relevance for the pathways contributing to the disease process in humans. In 

17 particular, the data from these studies, as analyzed, do not inform the critical MOA questions 

18 pertaining to formaldehyde carcinogenicity. These insights have been elaborated in a separate 

19 section in chapter 4, and the difficulties in the use and interpretation of the quantitative modeling 

20 of these data, as presented in these studies, are detailed at length in Appendix G.

21

22 5.3.4. Benchmark Dose Approaches to Rat Nasal Tumor Data

23 This section describes various BMD analyses to determine PODs for low-dose 

24 extrapolation of SCC risk in the human respiratory tract (upper and lower).

25

26 5.3.4.1. Benchmark Dose Derived from BBDR Rat Model and Flux as Dosimeter

27 5.3.4.1.1. Response for benchmark dose. Typically, the BMD is calculated at the 5 or 10% 

28 response level. However, it appears appropriate to consider the benchmark response (BMR) at 

29 lower levels in exceptional cases that are supported by empirical data. In the case of the 

30 combined Kerns et al. (1983) and Monticello et al. (1996) bioassays, the lowest observed tumor 

31 response of SCC was below the 1% level (at 0.85%) (see Table 5-22). Additionally, the BBDR 

32 modeling incorporates precursor response in the form of LI data. Therefore, it was determined 

33 that it would also be appropriate to evaluate the POD at the 0.5% level while still staying in the 

34 neighborhood of the experimentally observed response. 
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1 The various data presented earlier in this chapter point to highly curvilinear dose 

2 responses for formaldehyde-induced tumor incidence as well as DPX and cell replication. This 

3 is also borne out by dose-response information based on gene array data (Thomas et al. 2007; 

4 Andersen et al. 2008). Cytotoxicity-driven regenerative replication and epithelial degeneration 

5 play a critical role in the steeply rising nature of the tumor dose-response. These observations 

6 raise the concern that cancer potency derived by straight-line extrapolation from the low end of 

7 observed tumor data (roughly at the 1% response) has the potential to be a significant 

8 overestimate for a reasonable upper bound. Thus, a pertinent question is what is a low-dose 

9 linear dose-response modeling of the data that is statistically consistent with the uncertainties in 

10 the observed time-to-tumor data. To address this question, the risk estimate based on the linear 

11 extrapolation (from a POD to the origin) is compared with that predicted at the low-dose end by 

12 the Multistage Weibull model fitted to the observed time-to-tumor data. The unit risk based on 

13 this model is obtained by calculating q1*, the 95% statistical upper bound on the coefficient 

14 associated with the linear term in the multistage model polynomial. This model fits the data 

15 reasonably well and reflects the highly curvilinear shape of the dose-response because of its 

16 mathematical flexibility while also allowing for low-dose linearity. In particular, it has been 

17 noted that even in cases where the first term (q1) in the multistage model is zero, the upper 

18 bound (q1*) is linear with dose (Subramaniam et al., 2006; Guess et al., 1977). Thus, for 

comparison the following estimates of unit risk are also

20

19 presented:

21 1) Unit risk that is based on q1*, which is derived from fitting the multistage Weibull model to 

22 the observed data. 

23 2) Unit risk based on low-dose linear extrapolation from a POD at the 0.5% level.

24

25 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/mm2 26 -hour to the entire surface of the airway lining but 

27 excluding tissue lined by non-mucus-coated squamous tissue, which was considered to not 

28 absorb formaldehyde). The use of flux as a dosimeter is similar to the calculation of a regional 

29 gas dose ratio (RGDR) as proportional to minute volume divided by the surface area in the given 

30 species and is thus in line with EPA’s prescription for calculating a dosimetric adjustment factor 

31 (DAF) for category 1 gases, whose effects are presumed to be at the POE (U.S. EPA, 1994b) 

32 (i.e., ratio of average flux over the same respiratory region in each species = ratio of the quantity 

33 [minute volume/surface area of the region] between the two species). This lends support to an 

34 interspecies extrapolation based on the equivalence of formaldehyde flux as a determinant of 

35 risk.
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1 The spatial distribution of formaldehyde over the nasal lining was characterized by 

2 partitioning the nasal surface by formaldehyde flux to the tissue, resulting in 20 “flux bins” 

3 (Figure 5-13). Each bin is comprised of elements (not necessarily contiguous) of the nasal 

4 surface that receive a particular interval of formaldehyde flux per ppm of exposure 

5 concentration (Kimbell et al., 2001a). The spatial coordinates of elements comprising a 

6 particular flux bin are fixed for all exposure concentrations, with formaldehyde flux in a bin 

7 scaling linearly with exposure concentration (ppm). The number of cells at risk varies 

8 across the bins, as shown in Figure 5-14.

9

0

500

1000

1500

2000

2500

3000

0 5 10 15 20

Flux Bin No.

Flux Per Unit Exposure Conc

[pmol/(mm2-h-ppm)]

 

10

11

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).

12

13

14 5.3.4.1.3. Extrapolation to humans. For linear extrapolation from the 0.5 and 1% levels, two 

15 alternative versions of the biologically based model in Conolly et al. (2003) for the F344 rat 

16 were used. In both cases, only the historical control data from NTP inhalation studies data were 

17 added to the concurrent controls and weekly averaged DPX concentrations as calculated by a 

18 variant of the PBPK model in Conolly et al. (2000) [described in Subramaniam et al. (2007)] 

19 were used. Both models provided good fits to the tumor incidence data, similar to the fit shown 

20 in Figure 5-12. Neither model could be considered better than the other on the basis of model 

21 description of tumor incidence data.
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1 In Model 1 the normal cell replication dose response was described by the same 

2 hockey-stick-shaped curve used in Conolly et al. (2003). The form of the dose-response 

3 curves for initiated cell kinetics (division and death) was also the same as that considered by 

4 Conolly et al. (2003). 

5 Model 2 was an alternative to the Conolly et al. (2003) model, and is considered in 

6 the sensitivity analysis described in Appendix E. The dose response for normal cell 

7 replication was monotone increasing and did not exhibit a threshold in dose. This was 

8 obtained by fitting the 13-week cell replication data. The cell replication dose response for 

9 initiated cells was a sigmoidal-shaped curve, increasing monotonically with flux from a 

10 background value up to an asymptotic value. The baseline cell-replication for initiated cells 

11 was constrained to not be less than that for normal cells. Initiated cell death rate was 

12 considered proportional to initiated cell birth rate. 

13 Models 1 & 2 predicted monotonic dose-response curves.

14 The sequence of steps in arriving at a unit risk for SCC in human nasal airways from 

15 a given BBDR modeling of the F344 rat nasal tumor incidence data is outlined below. 

16 Extrapolation to the lower respiratory tract is described later.

17 1. Calculate the MLE risk and 95% upper confidence bound on risk at various exposure 

18 concentrations (dRAT in ppm) by exercising the two BBDR models. Here, the POD is 

19 defined as dRAT for which the 95% upper bound added risk is either 0.005 or 0.01. These 

20 values approximate the 95% lower bounds on the BMD corresponding to the added risks 

21 (i.e., the BMDLRAT).

22 2. Using CFD modeling simulations in Kimbell et al. (2001a, b), calculate the average flux 

23 over the entire rat nose at resting breathing rates corresponding to dRAT. Here, the 

24 subscript “i” is over flux bins and N is the number of cells at risk in a given bin.

25

RAT

i i

i

i

i

RAT RAT N

N

ppm

flux

AvgFlux d d























 ⋅

= ×

∑

∑( )

( ) 26 (5-2)

27

28 3. The experiment exposure was for periods of 5 days/week, 6 hours/day. Therefore, 

29 calculate the average daily exposure, obtained by making a 5/7 × 6/24 duration 

30 adjustment; that is, 5/7 × 6/24 × AvgFlux(dRAT).

31 4. Now assume that lifetime exposure to similar levels of average formaldehyde flux to 

32 cells at risk leads to similar lifetime risk (MLE or upper bound, respectively) of tumor 
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1 incidence across animal species. Also, in calculating human equivalent concentrations, 

2 EPA has traditionally assumed chronic animal laboratory exposure scenarios to be 

3 equivalent to human lifetime exposures (U.S. EPA, 1994b).

4 5. Since a CFD model for a human is available (Subramaniam et al., 1998), it is possible to 

5 determine the average wall mass flux in this particular human nose for any specific 

6 breathing scenario. Likewise, a computational model to determine mass flux at any 

7 specific lung depth was available in the form of the single-path model of Overton et al. 

8 (2001); however, risk in the lower respiratory tract will be addressed later. From the 

9 human CFD simulations in Kimbell et al. (2001a, b), the human airborne exposure 

10 concentration level that would yield the same average wall mass flux in the human nose 

11 as [(5/7) × (6/24) × AvgFlux(dRAT)] is then calculated. In other words, given a risk12 specific dose in the rat, the equivalent human exposure concentration is given by

13

HUMAN

i

i

i

i

i

HUMAN RAT

N

ppm

flux

N

d AvgFlux d

























×

= × × ×

∑

∑

( )

14 (5/ 7) (6 / 24) ( ) (5-3)

15

16 6. To use this equivalent human exposure concentration, make the following assumption: 

17 when humans are exposed to the above concentration of formaldehyde (dHUMAN) 

18 throughout the course of a lifetime, the added risks are anticipated to be similar to those 

19 experienced by the animal in the chronic bioassay.

20 7. Let f denote the ratio of the average flux per ppm of exposure concentration in the two 

21 species:

22

HUMAN

i i

i

i

i

RAT

i i

i

i

i

N

N

ppm

flux

N

N

ppm

flux

f























 ×























 ×

=

∑

∑

∑

∑

( )

( )

23 (5-4)

24

25 Now, the olfactory epithelium comprises a substantial fraction of nasal tissue in the rat. 

26 Because the olfactory region in the rat projects directly in the path of main airstreams 
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1 (Kimbell et al., 1997), a sizable flux of formaldehyde is delivered to this region in the 

2 rat. Tumors were not observed in the olfactory tissue of the rat. Therefore, since effects 

3 observed in the rat are being extrapolated to the human, cells from olfactory tissue are 

4 excluded in calculating average flux in the rat in the eq 4. For the human, on the other 

5 hand, both volumetric flow (2.5%, Subramaniam et al. [1998]) and surface area (~5%, 

6 Kelly et al. [2000]) for the olfactory region are relatively small, so inclusion of this 

7 region is not likely to make a difference of much significance in the calculation of 

8 average flux in the human. Since data on formaldehyde flux delivered to the human 

9 olfactory region were not readily available, the olfactory region was not excluded for the 

10 human. The average human flux calculated here uses a working level classification for 

11 the activity profile where an individual spent equal amounts of time in a day at resting 

12 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

14

13 :

15 f = 444[rat]/956.4[human] = 0.46 (5-5)

16

17 8. The airborne exposure concentrations dHUMAN corresponding to a given MLE and upper 

18 bound lifetime added risk levels are the human BMDHUMAN and BMDLHUMAN, 

19 respectively. These are shown in Figure 5-15. (The rather sudden increase by ~0.0015 

20 in the upper confidence bound on risk for model 1 for exposure exceeding ~0.41 ppm 

21 could not be explained. This jump was verified by repeated calculations that used 

22 different initial simulation conditions and convergence criteria.)

23 Next, the human lower respiratory tract is also considered to be potentially at risk. 

24 Therefore, the above calculations of BMD and BMDL need to be augmented to include the 

25 lower respiratory tract for humans. This calculation was facilitated by dosimetry 

26 calculations of formaldehyde wall mass flux to various depths in the lung by using a single 

27 path model. Refer to Overton et al. (2001) for details on their modeling. The calculations 

28 for including the lower respiratory tract in determining an overall BMD and BMDL 

29 involved the following steps:

30 a. As given by eq 5-3, calculate dHUMAN for various MLE risk levels. This gives a dose31 response relationship for lifetime risk of SCC in the human nose due to continuous 

32 exposure to airborne formaldehyde.

33

 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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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

1

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

3 nose for two BBDR models.

4

5 Note: Airborne exposure concentrations dHUMAN corresponding to a given MLE 

6 and upper bound lifetime added risk levels are the human BMDHUMAN and 

7 BMDLHUMAN, respectively.

8

9

10 b. Express this dose-response relationship in terms of average flux over the entire human 

11 nasal lining.

12 c. Next, express this dose-response relationship, calculated here for the entire nose, as risk 

13 per nasal cell versus average flux.

14 d. Now, if the respiratory and transitional cell types in the human lung and nose are equally 

15 susceptible to formaldehyde-induced cancer risk (as is also assumed in Conolly et al. 

16 [2004]), then it appears reasonable to assume that MLE risk per cell at a given value of 

17 formaldehyde flux is the same in the lung as in the nose.

18 e. The number of cells and the average flux in a given flux bin in the lung are known 

19 (Overton et al., 2001). Thus, at a given air concentration, the MLE risk due to cells in 

20 the various flux bins of the lung is obtained.

21 f. One important feature of Overton et al. (2001) was that their flux bins mapped 

22 physically with lung depth. Therefore, in addition to extrapolating risk to the entire 

23 human lung, it was also relatively easy to calculate risk as a function of airway 

24 generation in the lung (corresponding to different lung depths).
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1 g. Because of high formaldehyde reactivity and solubility at the POE, the MLE value risk 

2 to the lower respiratory tract (as determined above in steps 1–5) was a small fraction of 

3 risk to the upper respiratory tract. Therefore, it sufficed to assume that the relative 

4 increase in upper bound risk for the combined upper respiratory tract + lower respiratory 

5 tract compared to that for only the upper respiratory tract would be the same as the 

6 corresponding relative increase in the value of the MLE risk. The upper bound risk to 

7 the entire respiratory tract and consequently the BMDL value corresponding to a given 

8 response were thus determined.

9

10 These calculations indicated that including the risk of SCC in the lower respiratory 

11 tract resulted in at most a 3% increase in the added risk at the lower end of the human 

12 exposure range in Figure 5-16 (i.e., at 0.42 ppm) and about a 1.5% increase at the higher end 

13 of the range in that plot. Therefore, because of the steepness in the dose-response curve in 

14 this exposure range and much lower risk in the lung at any exposure concentration, 

15 including the lower respiratory tract did not appreciably alter the human BMDs and BMDLs 

16 at the 0.5 and 1% response levels.

17 Unit risks of SCC in the human respiratory tract extrapolated in this manner are reported 

18 in Table 5-23.

19

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

21 tract

22

Extra risk level

Benchmark levels (ppm) Unit riska

BMD BMDL (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

23 a 24 Obtained from the mean of the two BMDLs.

25

26 Note: Findings are based on nasal tumors in rats and formaldehyde flux to tissue as dosimeter, using dose27 response curves for the F344 rat predicted by clonal growth modeling. Two chronic bioassays (Monticello 

28 et al., 1996; Kerns et al., 1983) were combined, and control animals from the historical NTP inhalation 

29 bioassays were added to the control animals in these bioassays.

30

31

32 5.3.4.2. Comparison with Other Benchmark Dose Modeling Efforts

33 The CIIT assessment (Schlosser et al., 2003; CIIT, 1999) also presented, as their less 

34 preferred option, a benchmark approach on the data set obtained by combining two chronic 

35 bioassays with similar protocols (Monticello et al., 1996; Kerns et al., 1983) along with data 
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1 from 94 animals that had not been previously examined. These authors used two measures of 

2 response—tumor incidence and cell proliferation—and, in each case, they used two 

3 dosimeters—DPX and formaldehyde flux to the nasal lining.

4 The extrapolation to human was carried out by using a hybrid CFD and pharmacokinetic 

5 model. The CFD model (Kimbell et al., 2001a, b; Kepler et al., 1998; Subramaniam et al., 1998) 

6 enabled calculation of site-specific flux in the nose of the rat, monkey, and human species for 

7 inhaled formaldehyde concentrations, and the PBPK model (Conolly et al., 2000) linked this flux 

8 to predicted DPX levels. The models were constructed for anatomically realistic representations 

9 of a single individual in each species. The CFD and PBPK modeling and uncertainties in these 

10 estimates have been reviewed in the Modeling the Toxicokinetics of Formaldehyde and DPX 

11 section of chapter 3.

12

13 5.3.4.2.1. Benchmark dose using administered concentration. Schlosser et al. (2003) fit 

14 multistage, Weibull, polynomial, and log-probit quantal models to the tumor data and exercised 

15 the models (except the log-probit) with and without requiring that the fits pass through the 

16 origin. The log-probit fit passed through the origin (see Figure 5-16). A fifth degree polynomial 

17 was used in the multistage model. The best fit was obtained with the polynomial and Weibull 

18 models for the tumor incidence data with a non-zero intercept (threshold) on the dose axis. Fits 

19 passing through the origin did not pass the statistical goodness-of-fit criteria (p > 0.01) for 

20 models other than the log-probit. The dose response near the lowest dose was fairly steep, with 

21 the LED10s and LED01s nearly the same for each model, at least to one significant figure. In 

22 terms of administered concentration, the LEDs ranged from 3.8 to 6.4 ppm.

23

24 5.3.4.2.2. Benchmark dose derived with internal dose (flux and DPX) as dose metrics in 

25 Schlosser et al. (2003). 

26 Schlosser et al. (2003) used CFD simulations (Kimbell et al., 2001a, b) of mass flux of 

27 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 28 -minute, to 

29 the entire surface of the airway lining (excluding tissue lined by non-mucus-coated squamous 

30 tissue, which was considered not to absorb formaldehyde).

31
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1

2

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

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

5 BMCL10.

6

7 Source: Adapted from Schlosser et al. (2003).

8

9

10 In the CFD model, flux in any region is linearly related to the airborne exposure 

11 concentration (i.e., flux = f × Cair [ppm], where f is a constant of proportionality and Cair is the 

12 exposure concentration). The ratio of f (rat)/f (human) was determined as given by eq 5-4. This 

13 ratio was equal to 0.71 and differed from the value of 0.46 used in this document (as presented in 

14 eq 4-5) because Schlosser et al. (2003) used resting inspiratory rates. In the next level of 

15 dosimetric complexity, Schlosser et al. (2003) used DPX as the relevant dosimeter based on 

16 values predicted by PBPK models developed by Conolly et al. (2000). This expressed the local 

17 dose as pmol of formaldehyde equivalents covalently bound to DNA per unit volume of nasal 

18 tissue. Human CFD and PBPK models were exercised to determine the airborne concentration 

19 of formaldehyde that yields average DPX levels equal to those in the rat at the BMC. This 

20 airborne concentration was then the HEC. The human benchmark extrapolations in Schlosser et 

21 al. (2003) using flux and DPX are shown in Table 5-25, located at the end of section 5.4.

22 The assumption in using DPX data was that lifetime exposure to the same DPX 

23 concentration for a given duration each day leads to equivalent risk across species. Table 5-25 

24 shows their human benchmark calculations for a continuous environmental exposure. These 
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1 were exposures that resulted in the same steady-state DPX concentrations as the weekly TWA 

2 DPX values in rats at the rat benchmark exposure concentrations.

3

4 5.3.4.2.3. Cell proliferation in CIIT benchmark modeling. 

5 Schlosser et al. (2003) also used cell proliferation as representing the adverse response, 

6 and the BMDs calculated with these data did not differ appreciably from their other benchmark 

7 estimates. The use of cell proliferation as an end point is considered to have the advantage that it 

8 represents an early step contributing to carcinogenesis. In this document, a BMD is not 

9 calculated based solely on cell replication as a response. Instead, cell replication rates are used 

10 as input to the clonal growth model and a BMD based on a fit to the tumor response using that 

11 model is considered a better choice since it integrates cell replication along with other relevant 

12 data, such as the number of cells at risk and DPXs. 

13

14 5.3.4.3. Kaplan-Meier Adjustment

15 In the simplest consideration of the impact of competing risks on the nasal tumor 

16 incidence, tumor incidences were adjusted for early deaths according to Kaplan-Meier (KM) 

17 survival estimates (KS Crump Group, 2001). This procedure allows for the possibility that some 

18 tumors may otherwise have developed in the animals that died early due to other causes. All the 

19 animals in the study were considered except those that were kept past termination of exposure. 

20 A comparison of the adjusted incidence data is presented below in Table 5-24. While the 

21 adjustments have been provided in Table 5-24, it needs to be noted that the data allow for a full 

22 time-to-tumor analysis as presented below.

23

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

25

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

26 a 27 KM adjusted. Numbers not indicated by footnote were not amenable to KM 

28 adjustment because there were no tumors; these numbers at risk reflect all animals 

29 surviving 1 year on study.

30 Source: Monticello et al. (1996); Kerns et al. (1983).
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1 5.3.4.4. EPA Time-to-Tumor Statistical Modeling

2 Instead of using the KM adjustment, EPA has used the multistage Weibull time-to-tumor 

3 model (Portier et al., 1986; Krewski et al., 1983) in other assessments (e.g., ethylene oxide, 

4 1,3-butadiene, chloroprene). This is a dose-response model that includes the exact time of 

5 observation of the tumors and therefore gives appropriate weight to the amount of time each 

6 animal was on study without a tumor and acknowledges earlier tumor incidence with increasing 

7 dose level. The data used in this analysis were obtained from the appendix in Conolly et al. 

8 (2003) with one crucial modification. These data combined the nasal squamous carcinoma data 

9 of Kerns et al. (1983) and Monticello et al. (1996) along with results from an additional 

10 94 animals not previously examined in the Monticello et al. (1996) study. Animals in some 

11 exposure groups were held up to 6 months following the 24-month exposure period; these 

12 animals were deleted from the analysis for the following reason: there were no tumors among 

13 these animals, and inclusion of them would have required estimating an equivalent TWA 

14 exposure over the entire study period for these animals (40 in 2 ppm group, 39 in 6 ppm group, 3 

15 in 15 ppm group), whereas the other animals would be represented by their actual exposure 

16 concentrations. 

17 Due to earlier tumor occurrence with increasing exposure level and increased mortality 

18 with increasing exposure level, methods that can reflect the influence of competing risks and 

19 intercurrent mortality on site-specific tumor incidence rates are preferred. EPA has generally 

20 used the multistage Weibull model because it incorporates the time at which death with tumor 

21 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 + q2d2 + ... + qkdk 22 ) × (t –

t0)

z 23 ], where P(d) represents the lifetime risk (probability) of cancer at dose d (i.e., human 

24 equivalent exposure in this case); parameters qi ≥ 0, for i = 0, 1, ..., k; t is the time at which the 

25 tumor was observed; and z is a parameter estimated in fitting the model, which characterizes the 

26 change in response with age. The parameter t0 represents the time between when a potentially 

27 fatal tumor becomes observable and when it causes death. 

28 A further consideration is the distinction between tumor types as being either fatal or 

29 incidental in order to adjust for competing risks. Incidental tumors are those tumors thought not 

30 to have caused the death of an animal (such as those observed during interim or terminal 

31 sacrifices), while fatal tumors are thought to have resulted in animal death. For these data, nasal 

32 tumors observed with early deaths were considered to be fatal.

33 The dose-response analyses (Figures 5-17, 5-18, 5-19) were conducted by using the 

34 computer software program TOX_RISK, version 5.3 (ICF, Fairfax, VA), which is based on 

35 Weibull models drawn from Krewski et al. (1983). Parameters were estimated by using the 
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1 method of MLE. Specific multistage Weibull models were selected for the individual tumor 

2 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 χ2 3 with 

4 degrees of freedom equal to the difference in the number of stages included in the models being 

5 compared, the models were considered comparable, and the most parsimonious model (i.e., the 

6 lowest-stage model) was selected contingent on visual fits of the data as follows. For incidental 

7 tumors, plots of model fits compared with Hoel-Walburg estimates of cumulative incidence were 

8 also examined for goodness of fit in the lower exposure region of the observed data (Gart et al., 

9 1986) (Figure 5-18). For fatal tumors, plots of model fits were compared with KM estimates of 

10 cumulative incidence. If a model with one more stage fitted the low-dose data better than the 

11 most parsimonious model, then the model with one higher stage was selected. 

12 Due to the sharp increase in responses between 6 and 10 ppm, no adequate fit was 

13 achieved. Data for the highest dose were dropped in an effort to focus the fitting process for this 

14 empirical model on the low-dose region. The model that then provided the best overall fit 

15 included five stages but with coefficients for the lower stages estimated to be zero (see 

16 Figures 5-17, 5-18, 5-19). The parameter t0 was estimated to be zero, consistent with rapidly 

17 fatal tumors. On the other hand, an alternate run treating all tumors as incidental to the death of 

18 the affected animals yielded BMCLs and BMCs within 10% of these estimates (Figure 5-18); 

19 thus, tumor context is not a sensitive consideration for these data.

20 For the same reasons as discussed in section 5.3.3 (the concluding discussion of the 

21 BBDR modeling), a linear low-dose extrapolation approach was used to estimate human 

22 carcinogenic risk associated with formaldehyde exposure. PODs for estimating low-dose risk 

23 were identified at doses at the lower end of the observed data, corresponding to 1% extra risk, 

24 defined as the extra risk over the background tumor rate [P(d) − P(0)]/[1 − P(0)]. PODs 

25 corresponding to 10% extra risk are also provided to facilitate comparison with other chemicals. 

26 Rat benchmark levels obtained by analysis of the tumor data are shown in Table 5-25. PODs 

27 were converted to continuous human-equivalent exposure levels by multiplying by 

28 (5 days/7 days) × (6 hours/24 hours), or 0.178, and by multiplying by the ratio of fluxes 

29 developed in section 5.3.6.1.3. The lifetime continuous inhalation unit risk for humans is 

30 defined as the slope of the line from the lower 95% bound on the exposure at the POD, 

31 calculated by dividing the BMR level (1%) by the corresponding BMCL01. This 95% UCL 

32 represents a plausible upper bound on the true risk.

33

34
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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

1

2 Figure 5-17. EPA Multistage Weibull modeling: nasal tumor dose response.

3

4 Note: Time-to-tumor modeling of Kerns et al. (1983) and Monticello et al. (1996) 

5 data compared with incidences adjusted by using KM estimates evaluated at 

6 104 weeks.

7

8 Source: Adapted from Schlosser et al. (2003).

9
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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 

7 obtained by various methods, including the results in Schlosser et al. (2003), fall within a rather 

8 tight range. In particular, q1* was obtained to within a factor of two of other values even though 

9 q1 itself was zero. The large difference between q1 and q1* aptly reflects the large uncertainty 

10 in 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/m3 17 ) 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) 

33 and biologically based modeling (entire respiratory tract), resulted in a narrow range of 

1.2 × 10−2 to 2.2 × 10–2 34 per ppm. Risk to the lower respiratory tract was numerically 

35 insignificant compared to the nasal cancer risk.
This document is a draft for 

review purposes only and does 

not constitute Agency policy

5-134 DRAFT

—DO 

Table 5-25. Human benchmark extrapolations of nasal tumors in rats by using formaldehyde flux and DPX

Model Source

Rat benchmark levels

(ppm) Extrapolated human benchmark levels (ppm) Unit riska (ppm)–1

1% 5% 10% Dose metricb 1% 5% 10% 1% 5% 10%

Weibullc,d

(with 

threshold)

Schlosser et 

al. (2003) ED

LED

5.91

5.58

6.12

5.94

6.40

6.22

Fluxe ED 0.75 0.78 0.82

LED 0.71 0.76 0.79 1.4 ×10–2 6.6 × 10–2 1.3 × 10–1

DPXf ED 0.76 0.79 0.84

LED 0.71 0.76 0.81 1.4 ×10–2 6.6 × 10–2 1.2 × 10–1

Multistage 

Weibull (timeto-tumor)c,d,g

EPA (this 

assessment)

ED

LED

4.28

3.57

5.93

5.52

6.84

6.41 Fluxh

ED 0.35 0.49 0.57

LED 0.30 0.46 0.53 3.4 ×10–2 1.1 × 10–1 1.9 × 10–1

q1* = 2.2 × 10–2

BBDR models 

(Table 5-23)

EPA (this 

assessment)

See Table 5-23 and associated text at 1%: 2.2 ×10–2

at 0.5%: 1.2 ×10–2

Note 1: Combined tumor incidence data from Kerns et al. (1983) and Monticello et al. (1996) were used for response.

a

Slope of straight line extrapolation from the POD of the dose-response curve at the 1, 5, and 10% extra risk level. b

Flux: 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 package; therefore, fit was 

judged by comparing fitted curve to KM survival estimates (see Figure 5-19). d

For Weibull model, Schlosser et al. (2003) obtained best fit with a positive intercept on dose axis. For multistage Weibull model, curves pass through origin. e

Human benchmark levels extrapolated using flux were multiplied by fHCHO-Rat/fHCHO-Human (= 0.71) for interspecies extrapolation and multiplied by (6/24) × 

(5/7) to adjust for continuous exposure. f

Human benchmark levels using DPX were continuous environmental exposures that would result in steady-state DPX levels in humans equal to the weekly 

TWA DPX levels in rats at the rat BMCs for 6 hours/day and 5 days/week. g

P(d,t) = 1 - exp[-(q0 + q1d + q2d2 + ... + qkdk)* tz]. q0, q1, q2, q3, q4 were all taken to be zero. q5 = 2.9 × 10–22, z = 8.1. h

Human benchmark levels extrapolated using flux were multiplied by fHCHO-Rat/fHCHO-Human = 0.46 for interspecies extrapolation and multiplied by (6/24) × (5/7) 

to adjust for continuous exposure (see section 5.3.6.2).
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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 

7 range, while the unit risk estimate for leukemia and the total cancer unit risk estimate are up to 

8 fourfold 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/m3 22 ) based on human data 

23 for 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

6

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. 

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 

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

exposure level of 1 μg/m3 from ages 0–70 years 

1 

2 

3 

Exposure 

Unit risk concentratio Duration 

Age group ADAF 3 (per μg/m ) 3 n (μg/m ) adjustment Partial risk

0 to < 2 

years

10 6.6 × 10–5 1 2 years/70 years 1.9 × 10–5

2 to < 16 

years

 3 6.6 × 10–5 1 14 years/70 

years

4.0 × 10–5

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

years

5.1 × 10–5

Total risk = 1.1 × 10–4

4 

(Note that the partial risk for each age group is the product of the values in columns 2–5 [e.g., 

10 × (6.6 × 10–5) × 1 × 2/70 = 1.9 × 10–5], and the total risk is the sum of the partial risks. This 70-year risk 

estimate for a constant exposure of 1 μg/m3 is equivalent to a lifetime unit risk of 

1.1 × 10–4 per μg/m3

, adjusted for early-life susceptibility, assuming a 70-year lifetime and constant exposure 

across age groups.) 

In addition to the uncertainties discussed above for the inhalation unit risk estimate, there 

are uncertainties in the application of ADAFs to adjust for potential increased early-life 

susceptibility. The ADAFs are general default factors, and it is uncertain to what extent they 

reflect increased early-life susceptibility for exposure to formaldehyde, if, in fact, early-life 

susceptibility is increased as assumed. To some extent, the unit risk estimates for Hodgkin 

lymphoma and leukemia already reflect some partial risk from early-life exposure because the 

life-table programs include background rates for childhood cancers. However, the impact of this 

partial risk is negligible compared to the effect of the ADAFs on the final risk estimate. For 

example, eliminating the background rates up to age 16 from the life-table programs decreases 

the lifetime extra risks at the PODs by about 0.5% for leukemia and about 1.2% for Hodgkin 

lymphoma. The ADAFs, on the other hand, increased the lifetime unit risk estimate by about 

66%. 

5.4.5 Conclusions: Cancer Inhalation Unit Risk Estimates

 As presented in section 5.4.3, the preferred (plausible upper bound) cancer unit risk 

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/m3) based on (adult) human data for NPC, Hodgkin 

lymphoma, and leukemia. 

5 

6 

7 

8 

9 

10 

11 

12 

13 

14 

15 

16 

17 

18 

19 

20 

21 

22 

23 

24 

25 

26 

27 

28 

29 
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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, 

5 in 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/m3 10 )

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/m3 14 . 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/m3 16 . (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/m3 15 (~ 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 

23 Health Canada and Environment Canada, 2001). Daily intake of formaldehyde has been 

24 estimated to be 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, 

5 formaldehyde decreased to about 70% during light exercise and to 58% during heavy exercise 

6 conditions in the human. During heavy exercise, the absorption of formaldehyde in the first six 

7 to eight generations of the tracheobronchial airways is estimated to be comparable to that in the 

8 nasal 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 

14 breathing 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 

chromatography-mass spectroscopy (GC-MS), dual isotope labeling (3H, 14 17 C) and high18 performance liquid chromatography (HPLC) studies. In a study of rats following exposure to 

19 radiolabeled formaldehyde, the radioactivity was very high in the nasal mucosa but was also 

20 extensively distributed to various tissues including the bone marrow (Heck et al., 1983). The 

elevated 14 21 C in various tissues was thought unlikely to be due to free formaldehyde but instead to 

22 arise from 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; 

24 Casanova-Schmitz et al., 1984). Studies using the GC-MS method indicate that exposure to 

25 formaldehyde over a wide range of exposure concentrations and durations does not result in 

26 elevated levels in blood, above those of endogenous formaldehyde levels in rats, rhesus monkeys 

27 and humans (Heck et al., 1985; Casanova et al., 1998). These GC-MS measurements are 

28 consistent with the conclusions that formaldehyde does not appreciably reach the blood, is 

29 rapidly metabolized, interacts with macromolecules when it escapes metabolism, or is otherwise 

30 undetected.

31 In further studies on the disposition of inhaled formaldehyde, Casanova-Schmitz et al. 

32 (1984) and Casanova-Schmitz and Heck (1983) used dual-isotope labeling of inhaled 

33 formaldehyde as an approach to distinguish between formaldehyde adduct formation and 

34 metabolic incorporation. These were followed by more sensitive experiments using HPLC 

35 measurements in rats and rhesus monkeys exposed to radiolabeled formaldehyde (Casanova et 
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1 al. 1989, 1991). Results from this sets of experiments found that labeling in the nasal mucosa 

2 was due to both covalent binding and metabolic incorporation and labeling of bone marrow 

3 macromolecules was found to be entirely due to metabolic incorporation. Overall, Heck, 

4 Casanova-Schmitz, and their coworkers interpreted the results of these experiments to indicate 

5 that inhaled formaldehyde does not reach distant sites (beyond the portal of entry) at detectable 

6 levels.

7 Formaldehyde is primarily metabolized by glutathione-dependent formaldehyde 

8 dehydrogenase. In humans this enzyme is referred to using the protein code of ADH3. The 

9 major factor in the disposition of formaldehyde is metabolic clearance by oxidation to formate, 

10 which is either further metabolized to CO2 and water, incorporated into the one-carbon pool, 

11 and/or eliminated in the urine as a sodium salt. 

12 In radiolabeling studies, Heck et al. (1983) determined that the relative contributions of 

13 various excretion pathways in F344 rats following inhalation exposure to formaldehyde were 

independent of exposure concentration. Nearly 40% of inhaled [14 14 C]-formaldehyde appeared to 

15 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 16 C]-formaldehyde remained in the 

17 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 18 CO2), 10% excreted in 

19 urine, 1% excreted in feces, and much of the remaining 49% retained within the carcass, 

20 presumably due to metabolic incorporation (IARC, 1995; Buss et al., 1964).

21 Several human and animal studies have attempted to measure the concentration of 

22 formaldehyde in exhaled breath (see section 3.5.2). None of the human studies investigated 

23 whether there is any correlation between exhaled formaldehyde levels and food intake, life stage, 

24 smoking, or health status. Additionally, they were not designed to distinguish between 

25 exogenous (room air) and endogenous (systemic) formaldehyde in exhaled breath. In order to 

26 discern whether endogenous formaldehyde is excreted into the lungs, human subjects must 

27 breathe formaldehyde-free air. Because subjects were breathing room air, which contained 9-10 

28 ppb formaldehyde in two studies and unspecified concentrations in two other studies, there is no 

29 way of knowing whether there was any endogenous formaldehyde in their exhaled breath. This 

30 assessment identifies a critical research need for further studies on the measurement of exhaled 

31 formaldehyde.

32 The most informative study, performed by Cáp et al. (2008), demonstrated that subjects 

33 breathing room air containing 9.6 ±1.5 ppb formaldehyde exhaled a mean formaldehyde 

34 concentration of 2 ppb. This suggests that a substantial portion of inhaled formaldehyde, which 

35 is highly reactive, was retained in the respiratory tract and not exhaled. It is impossible to tell 
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1 whether any portion of the 2 ppb in exhaled breath was of endogenous origin. In this and other 

2 human studies, there was no adjustment for an artifact in the analytical method that makes it 

3 impossible to distinguish between formaldehyde and reaction products for 1% of exhaled 

4 methanol and ethanol because they have the same mass to charge ratio (m/z = 31). In fact, the 

5 concentration of methanol and ethanol that is misidentified as formaldehyde exceeds the reported 

6 concentrations of exhaled formaldehyde. Thus, it is highly likely that the actual exhaled 

7 formaldehyde concentration in Cáp et al. (2008) was significantly lower than 2 ppb, and that 

8 there was little or no endogenous formaldehyde in the exhaled breath. This would be consistent 

9 with an animal study in which Mashford and Jones (1982) detected no exhaled formaldehyde in 

rats injected I.P. with 40 mg/kg [14 10 C]-formaldehyde. In summary, there are insufficient data at 

11 this time to confidently establish a concentration of formaldehyde in exhaled breath that can be 

12 attributed to endogenous sources.

13

14 6.1.3 Noncancer Health Effects in Humans and Laboratory Animals

15 A wide variety of human and animal studies provide evidence for health effects in 

16 response to formaldehyde exposure. Some of these health effects are commonly noted at the 

17 portal of entry, as expected for exposure to a reactive gas. In addition, effects on the nervous 

18 and reproductive systems, developmental effects, and immunomodulation have been reported. 

19 The overall weight of evidence (WOE) of human and animal studies for the hazard potential of 

20 formaldehyde is discussed below, along with information on plausible modes of action (MOAs).

21

22 6.1.3.1. Sensory Irritation

23 Formaldehyde, a chemical irritant, binds to protein receptors of the trigeminal nerve, 

24 triggering a burning and painful sensation in humans. This process is distinct from taste and 

25 smell (Nielsen 1991; Cometto-Muniz and Cain, 1992). The trigeminal nerve, which has three 

26 branches (ophthalmic, maxillary and mandibular), not only acts as an afferent nerve relaying 

27 these sensations to the central nervous system, but also has efferent nerve activity (Stedman’s 

28 Medical Dictionary: Meggs, 1993). Stimulation of the trigeminal nerve may result in reflex 

29 responses including lacrimation, coughing, and sneezing. Both the reflex responses as well as 

30 sensations such as burning, pain, and itching of the eyes, nose, and throat are considered adverse.

31 Formaldehyde-induced eye, nose, and throat irritation has been well documented in a 

32 wide range of epidemiologic studies. Common effects of chemically-induced sensory irritation 

33 include lacrimation, burning of the eyes and nose, rhinitis, burning of the throat, and cough 

34 (Feron et al., 2001). Studies examining these endpoints were either controlled chamber studies 

35 with a defined population (e.g., healthy volunteers or sensitive individuals), worker/student 
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1 studies, or general population studies (e.g., residential). Chamber studies, by design, are acute 

2 studies, although some researchers have investigated the outcomes after repeated exposures. 

3 Occupational, student, and residential exposures are generally of longer duration, although there 

4 is variability in exposure level and duration among subjects. The endpoints for assessing 

5 irritation include self-reporting of symptoms (e.g., pain, burning, itching) and objective measures 

6 of irritation (e.g., eye-blink counts, lacrimation). 

7 Eye irritation is the most sensitive of reported effects in human studies. Two different 

8 short-term chamber studies provide similar 10% BMDLs for eye irritation of 560 ppb and 240 

9 ppb for 3 and 5 hour exposures, respectively (Kulle, 1993; Andersen and Molhave, 1983, 

10 modeled by Arts et al., 2006b). Various occupational studies have noted increased eye irritation 

11 for average exposures ranging from 180 ppb to 690 ppb (Horvath et al., 1988, Alexandersson 

12 and Hedenstiera, 1998; Holmstrom and Wilhelmsson, 1988). The results of residential studies, 

13 where in-home formaldehyde levels are used to document exposure, indicate eye irritation may 

14 increase with increasing exposure from 70 to 200 ppb for these chronic exposure scenarios 

15 (Ritchie and Lehnen, 1987, Hanrahan et al., 1984; Liu et al., 1991.)

16 When a rodent is exposed to an irritant, the inhaled dose and pattern of deposition can be 

17 profoundly affected by reflex bradypnea, a protective reflex observed in rodents but not in 

18 humans. Reflex bradypnea is manifest as markedly decreased activity or prostration, reduced 

19 metabolism, hypothermia (as much as 5oC), significantly reduced respiratory rate and minute 

20 volume, and altered blood and brain chemistry. Reflex bradypnea can occur when the trigeminal 

21 nerve is exposed to a sufficient concentration of an irritant, such as formaldehyde. Because of 

22 their small size, rodents are able to rapidly lower their metabolism and body temperature and 

23 therefore their oxygen demand. The consequence is that their inhaled dose of an irritating 

24 chemical is dramatically lowered. Reflex bradypnea is quantified as the RD50, which is the 

25 concentration of a chemical that results in a 50% decrease in respiratory rate (Tables 4-7 and 

26 4-8). After the irritant exposure is removed, it can take up to two hours for rodents to fully 

27 recover from the effects of reflex bradypnea. Even though humans do not exhibit reflex 

28 bradypnea, involvement of trigeminal nerve stimulation, which is the mechanism for reflex 

29 bradypnea in rodents, may be relevant to MOAs for formaldehyde in other species, such as 

30 primates and humans. For example, trigeminal nerve stimulation has been associated with 

31 sensory irritation in humans, highlighting the relevance of this effect.

32

33 6.1.3.2. Respiratory Tract Pathology

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

35 cell hyperplasia, metaplastic changes, squamous cell hyperplasia, and impaired mucociliary 
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1 transport. Formaldehyde binding to the trigeminal nerve triggers the release of neurogenic 

2 mediators of inflammation resulting in tissue edema, lacrimation, mucus production, and 

3 leukocyte infiltration. Therefore, observed pathological changes may be directly related to 

4 neurogenic inflammation from activation of the trigeminal nerve or result, at least in part, from 

5 formaldehyde-induced cell damage to the mucosal tissue. A series of exposures has also been 

6 positively associated with reduced mucociliary clearance, and the induction of histopathologic 

7 lesions in the nose in both human and animal studies assessing formaldehyde-induced changes in 

8 the nasal mucosa suggest that these changes may be, at least in part, a protective or adaptive 

9 response and that increased mucus flow and metaplastic changes would progress in relation to 

10 the concentration and duration of exposure protecting the underlying tissue (Swenberg et al., 

11 1983).

12 In rodent studies, formaldehyde-induced histopathological lesions ranging from 

13 inflammation to ulceration, necrosis, and metaplasia have been frequently reported in nasal 

14 turbinates, maxilloturbinates, and in goblet and microvilli cells (e.g., Bhalla et al., 1991; 

15 Monteiro-Riviere and Popp, 1986; Cassee and Feron, 1994; Ionescu et al., 1978; Schreibner et 

16 al.,1979; Monticello et al., 1989). These effects were observed after a variety of exposure 

17 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 

18 and 6 or 15 ppm for 6 hrs/day for 1 or 2 days (Monteiro-Riviere and Popp, 1986), 3.6 ppm 

19 intermittently for 3 days (Cassee and Feron, 1994), 3% aerosols of formaldehyde for 3 hrs/day

20 for 50 days (Ionescu et al., 1978)). The progressive pathology of the nasal passages from 

21 formaldehyde inhalation exposure is dependent on increasing concentration and duration of 

22 exposure, as well as from proximal to distal regions of the nasal cavity. For example, some 

23 lesions may be transient (e.g., low-exposure cell proliferation), while others may have a 

24 maximum response and be irreversible (e.g., rhinitis). The nasal epithelium responds with both 

25 adaptive and adverse epithelial changes. As respiratory epithelium transitions to squamous 

26 metaplasia, the effective tissue dose of formaldehyde increases posterior to these lesions. As 

27 epithelial barriers degrade (e.g., squamous metaplasia, keratinization), formaldehyde penetrates 

28 more deeply into the nasal passages. Therefore, the relationship between concentration and 

29 duration of exposure and health outcomes has been difficult to define and, in fact, may be 

30 different for various health effects. Formaldehyde-related histopathological lesions of the nasal 

31 mucosa have been observed at concentrations as low as 2 ppm for chronic exposure and after a 

32 duration as short as 6 hrs at higher concentrations (e.g., 6 ppm) (Table 4-32, table 4-38).

33 Similar pathology has been reported for workers exposed to formaldehyde, including loss 

34 of cilia, goblet cell hyperplasia, and cuboidal and squamous cell metaplasia and dysplasia, and 

35 these pathology scores were significantly elevated in workers over controls (Holmström and 
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1 Wilhelmsson, 1988; Edling et al., 1988; and Boysen et al., 1990). Holmström and Wilhelmsson 

2 (1988) reported associations between the mean daily exposure of 240 ppb (8hr TWA) and these 

3 changes. Edling et al. (1988) reported that workers experienced a range of exposures (80-900 

4 ppb), with peak exposures of 4000 ppb. Boysen et al. (1990) provided a range of estimated 

5 exposures from 500 ppb to more than 2000 ppb for workers with elevated mean pathology 

6 scores. One controlled chamber study indicated formaldehyde-induced inflammatory changes 

7 which persisted for 18 hours in adults exposed at 400 ppb for only 2 hours (Pazdrak et al., 

8 1993)).

9 Short-term formaldehyde exposure also impairs the function of the mucociliary apparatus 

10 which is a critical defensive barrier for the upper respiratory tract. Numerous laboratory animal 

11 studies have reported impaired mucociliary clearance activity associated with formaldehyde 

12 exposures as low as 500 ppb (Table 4-10). Low-concentration or short-term exposures first lead 

13 to an increased rate of ciliary beat, followed by impaired mucus flow, with slowed rate of ciliary 

14 beat and eventual mucostasis (lack of mucus flow) and ciliastasis (lack of ciliary beat) occurring 

15 at higher doses or longer exposure times. These effects have been shown to be both 

16 concentration- and duration-dependent and to occur within 15 minutes after the initial exposure. 

17 Morgan et al. (1983c) suggested that the initial stimulation of ciliary activity may be a defensive 

18 response to the irritant gas, at which time some penetration of formaldehyde to the underlying 

19 epithelial cells may occur. Later effects of mucostasis and ciliastasis may occur as a result of 

20 formaldehyde-induced glycoprotein cross-links, creating a rigid mucus that effectively stops 

21 mucus flow.

22 Formaldehyde-induced cell proliferation has been demonstrated in nasal epithelium in 

23 animal studies after a range of exposure conditions (e.g. Swenberg et al., 1986; Cassee and 

24 Feron, 1994; Reuzel et al., 1990; Woutersen et al., 1987) (Table 4-43). Formaldehyde-induced 

25 histopathology and mitogenesis may occur as a direct effect of exposure (Tyihak et al., 2001) or 

26 as a secondary effect resulting from adaptive responses and/or compensatory tissue repair that 

27 can occur after formaldehyde exposure (Swenberg, 1983). In a study of Rhesus monkeys 

28 Monticello et al. (1996) noted that increased cell proliferation was seen in locations with 

29 minimal histological changes in the respiratory tract indicating that cell proliferation may be a 

30 more sensitive predictor of more severe health effects due to formaldehyde exposure. Cellular 

31 proliferative responses may initiate lesion formation. A number of studies illustrate that the 

32 duration of repeated exposures may be an important determinant of cell proliferation rates 

33 (Wilmer et al., 1987; Swenberg et al., 1986). Reduced mucociliary clearance and the induction 

34 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

5 6.1.3.3. Effects on Pulmonary Function

6 The potential of formaldehyde exposure to cause pulmonary functional deficits in 

7 humans has been examined on several time scales. The epidemiologic literature includes studies 

8 of acute exposures among naïvely exposed anatomy graduate students (Kriebel et al., 1993; 

9 2001), anatomy graduate students with several weeks of episodic exposure (Kriebel et al., 1993), 

10 and post-shift versus pre-shift worker pulmonary function among those with regular 

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

12 1982; Alexandersson and Hedenstierna, 1989). Depending on whether the exposures are naïve 

13 or not, the epidemiologic studies that assessed the pulmonary effects after acute exposures to 

14 formaldehyde are assessing different biological responses, namely, the acute effect alone or the 

15 acute effect(s) in people who may have already been sensitized to different and unknown 

16 degrees.

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

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

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

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

21 in students attending anatomy classes once a week. They found the strongest pulmonary 

22 response when examining the average cross-laboratory decrement in peak expiratory flow in the 

23 first 2 weeks of the study when formaldehyde concentrations collected in the breathing zones 

24 had a geometric average concentration of 0.73 ppm. Overall, the students exhibited a 2% 

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

26 PEF. These findings of acute decreases in PEF following students’ initial formaldehyde 

27 exposure were corroborated by the Kriebel et al. (2001) study, using a similar study design 

28 applied to a separate class of anatomy students. Similar findings have been reported for low29 level residential formaldehyde exposure including decreased peak expiratory flow rates (PEFRs) 

30 (Krzyzanowski et al., 1990). Workers chronically exposed to formaldehyde have exhibited signs 

31 of reduced lung function consistent with bronchial constriction, inflammation, or chronic 

32 obstructive lung disease. Lung function deficits have been reported both in pre-shift versus post33 shift measurements and as a result of chronic exposures (Malaka and Kodama, 1990; Herbert et 

34 al., 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and 

35 Hedenatiena 1989). Decreases in spirometric values, including vital capacity (VC), forced 
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1 expiratory volume (FEV), forced vital capacity (FVC) and FEV/FVC have been reported in 

2 humans. Chronic studies also reported increased respiratory symptoms such as cough, increased 

3 phlegm, asthma, chest tightness and chest colds in exposed workers (Malaka et al., 1990; Herbet 

4 et al., 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and 

5 Hedenatiena 1989). Similar findings have been reported following low-level residential 

6 formaldehyde exposure including decreased PEFRs (Krzyzanowski et al., 1990). 

7 Worker exposures associated with cross-shift differences in spirometric values are 

8 consistent with formaldehyde-induced sensory irritation. Concordance has also been reported 

9 between subjective irritant response and measured changes in pulmonary function further 

10 supporting the possibility that cross-shift and short-term evidence of bronchial constriction may 

11 be a reflexive response to sensory irritation. 

12 A well-conducted residential epidemiology study by Krzyzanowski et al. (1990) was 

13 considered to be the strongest among the candidate studies on the adverse pulmonary function 

14 effects of formaldehyde for the purposes of deriving an RfC. 

15

16 6.1.3.4. Asthmatic Responses and Increased Atopic Symptoms 

17 The health effects of respiratory function, asthma and increased atopic response, have 

18 been shown to be clinically related. For example, asthma affects pulmonary function and may be 

19 triggered by an allergic response. These and other data suggest that there may be mechanistic 

20 links between these two health effects. Formaldehyde-induced sensitization (Section 4.2.1.5) 

21 may enhance the asthmatic response or may enhance an individual’s response to an allergen 

22 (Section 4.4). In both cases, sensitization results in phenotypic switching – or an individual 

23 exhibiting clinical symptoms of a predisposition to asthma or atopy. Because of the connection 

24 between the two endpoints, they are considered together herein.

25 Several cross-sectional studies have described a positive association between 

26 formaldehyde concentration and asthma prevalence. A study on risk factors for the initial 

27 physician diagnosis of asthma have shown concentration-dependent associations between 

28 formaldehyde exposure and asthma (Rumchev et al., 2002). In a categorical analysis, Rumchev 

29 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 30 that were 

31 consistent with a concentration-response relationship. No effect was apparent at concentrations 

in the next lower interval between 30-49 μg/m3 32 . Garrett et al. (1999) reported a borderline 

33 statistically significant association between bedroom formaldehyde concentrations and an 

34 increased risk of atopy. The authors computed a respiratory symptom score for each child based 

35 on the frequency of each of eight respiratory symptoms and this score was substantially and 
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1 statistically significantly higher among the asthmatic children compared to non-asthmatic 

children. Health effects were reported at formaldehyde concentrations greater than 50 μg/m3 2 but 

3 the lowest formaldehyde concentration interval at which health effects were observed was 20-50 

μg/m3 4 . The findings of Garrett et al. (1999) are supported by the results of a chamber study 

5 reported by Casset et al. (2006) of 19 sensitized adult asthmatics exposed to formaldehyde at a 

concentration of 100 μg/m3 6 for 30 minutes. Casset and colleagues observed an increased 

7 bronchial responsiveness to mite allergen exposure (p = 0.05) and noted the provocative dose 

8 (PD20 for FEV1) for mite allergen was 34.3 ng after formaldehyde exposure and 45.4 ng after 

air exposure. However, in study by Ezratty et al. (2007) exposure to 500 μg/m3 9 formaldehyde 

10 did not affect an allergen-induced increase in responsiveness to methacholine (p = 0.42) and 

11 there was no formaldehyde-associated effect on the airway inflammatory response. 

12 These observed health effects in humans are similar to the outcome of studies in 

13 laboratory animals that show that formaldehyde can exacerbate existing immunogenic 

14 hypersensitivity to known allergens (Sadakane et al., 2002; Tarkowski and Gorski, 1995; Riedel 

15 et al., 1996). While potentiation varied based on sensitization protocols and formaldehyde 

16 exposure regimens, the results support the finding that formaldehyde exposure can aggravate a 

17 Type-I hypersensitivity response and may do so via a neurogenically initiated response. 

18 Formaldehyde itself does not function as an allergen recognized by the immune system (Lee et 

19 al., 1984) and does not appear to trigger formation of formaldehyde-specific IgE. Although 

20 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 

21 experimental systems (Fujimaki et al., 2004a; Ohtsuka et al., 2003), these effects do not support 

22 an immunogenically mediated type-I hypersensitivity. In studies in which either egg protein 

23 (ovalbumin, OVA)-sensitized or dust mite (DerF)-sensitized animals were exposed to 

24 formaldehyde, OVA-specific and DerF-specific antibody production was increased over 

25 sensitization alone, suggesting that formaldehyde may potentiate sensitization responses (Riedel 

26 et al., 1996; Sadakane et al., 2002). Formaldehyde-induced sensitivity responses may be 

27 neurogenic in origin based on findings that neurogenic factors such as nerve growth factor 

28 (NGF) and substance P were associated with formaldehyde exposure in sensitization protocols 

29 (Fujimaki et al., 2004).

30

31 6.1.3.5. Effects on the Immune System

32 Formaldehyde-induced systemic immunomodulation in laboratory animals has been 

33 documented in the literature (Leach et al., 1983; Dean et al. 1984; Adams et al., 1987). A 

34 number of studies have evaluated the ability of formaldehyde to induce systemic immunotoxic 

35 effects in humans (Ohtani et al., 2004a, b; Erdei et al., 2003; Thrasher et al., 1990, 1987; Pross et 
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1 al., 1987). Some studies have reported altered innate immune responses associated with 

2 formaldehyde exposure (Erdei et al., 2003), while others have noted adaptive immune response 

3 suppression associated with formaldehyde exposure (Thrasher et al., 1990, 1987) and changes 

4 associated with alterations to a predominant T—lymphocyte helper 2 (Th2) pattern (Ohtani et 

5 al., 2004a, b). In contrast, Pross et al. (1987) did not observe formaldehyde-associated changes 

6 in systemic immune function.

7 Diverse studies have investigated the possibility that formaldehyde exposure leads to 

8 increased respiratory tract infections (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness 

9 and Nethercott, 1989). Lyapina et al. (2004) reported increased respiratory tract infections and 

10 decreased neutrophil respiratory burst activity in formaldehyde-exposed workers (at 722 ppb 

11 TWA). Incidences of doctor-diagnosed chronic bronchitis were more prevalent in children 

12 under age 15 living in homes with higher formaldehyde (>60 ppb) readings in the kitchen (p < 

13 0.001) (Krzyzanowski et al., 1990). Holness and Nethercott (1989) also report increased chronic 

14 bronchitis in formaldehyde-exposed funeral workers (380 ppb average exposure). 

15

16 6.1.3.6. Neurological Effects 

17 Formaldehyde exposure via inhalation has been shown to adversely impact nervous 

18 system function in laboratory animals and humans, although human data for formaldehyde19 induced neurological effects are limited. Studies in formaldehyde-exposed histology technicians 

20 provide evidence of neurological impairment, including lack of concentration, impaired memory, 

21 disturbed sleep, impaired balance, variations in mood and irritability. These effects were 

22 significantly correlated with increasing duration of exposure to formaldehyde, but the findings 

23 are not conclusive due to confounding by concomitant exposures to other neurotoxic solvents 

24 (Kilburn et al., 1985, 1987). In a prospective study, Weisskopf et al. (2009) found a strong 

25 association between duration of formaldehyde exposure and death from amyotrophic lateral 

26 sclerosis (ALS), but information regarding exposure levels was not available. Short-term studies 

27 with controlled exposure to humans (chamber studies) also provide limited support for changes 

28 in cognitive function immediately following a single, controlled formaldehyde exposure (Bach et 

29 al., 1990; Lang et al. 2008).

30 Available animal data provide substantial evidence of behavioral changes in animals 

31 following single or short-term repeated inhalation exposures to relatively low levels of

32 formaldehyde. Among the animal studies, none of the available studies examined effects on 

33 nervous system function following chronic formaldehyde inhalation, however. 

34 Reported perturbations in nervous system function following formaldehyde exposure in 

35 animal studies include reductions in motor activity, lack of habituation, impairment in 
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1 acquisition of a new learning task, deficits in retention of a previously learned task, increases in 

2 corticosterone levels, sensitization to cocaine-induced locomotor activity, and enhanced fear 

3 conditioning using an olfactory conditioned stimulus (CS) (see Table 4-57). Behavioral effects 

4 have been seen in multiple laboratories and in studies conducted by different investigators using 

5 a variety of testing paradigms. Many of these effects were observed at acute exposure levels at 

6 or below 1.0 ppm, and some persisted days to weeks after termination of exposure.

7 More limited data indicate possible effects on the development of the nervous system, 

8 including changes in brain structure and in the behavior of offspring (Table 4-57). Similarly, 

9 there is very little information regarding the mechanism by which effects on the nervous system 

10 might be produced. The data regarding behavioral sensitization provide some support for a 

11 stress-related mechanism for those specific findings, but the applicability of this mechanism to 

12 the behavioral changes seen in the other studies, including the learning deficits and 

13 developmental findings, has not been evaluated. Although there are data supporting stimulation 

14 of the trigeminal nerve by formaldehyde (and documenting the relevance of this interaction to 

15 the sensory irritation caused by formaldehyde), there are no data supporting a causal relationship 

16 between irritant properties of formaldehyde and the behavioral and neurodevelopmental effects 

17 in humans that occur following formaldehyde exposure. In summary, none of the available data 

18 provide sufficient information to allow a determination of the mode of action for effects of 

19 formaldehyde on the adult or developing nervous system. 

20

21 6.1.3.7. Reproductive and Developmental Effects 

22 Formaldehyde inhalation exposure has been associated with adverse developmental and 

23 reproductive outcomes in both epidemiologic studies and experimental animal studies. Observed 

24 developmental outcomes include fetal loss, structural alterations, growth retardation, and delays 

25 in functional development.

26 Several occupational studies found an increased risk of spontaneous abortions among 

27 formaldehyde-exposed women (Taskinen et al., 1999, 1994; John et al., 1994; Seitz and Baron, 

28 1990; Axelsson et al., 1984). The Taskinen et al. (1999) study examined several reproductive 

29 outcomes in women employed in the wood-processing industry, with a range of average daily 

30 formaldehyde exposures. The authors found that formaldehyde was associated with a more than 

31 three-fold increased risk of spontaneous abortion, and with a nearly 50% decrease in a measure 

32 of delayed conception indicating reduced fertility, an increased time to pregnancy, and an 

33 increased risk for endometriosis in this study. In experimental animal studies, early fetal death 

34 was noted following maternal formaldehyde exposures (Kitaev et al., 1984; Sheveleva, 1972), 

35 supporting the epidemiologic findings that the spontaneous abortion is likely related to 
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1 formaldehyde exposure. Kitaev et al. (l984) hypothesized that formaldehyde may affect 

2 reproductive function by stimulating the hypothalamus-pituitary-gonadal (HPG) axis, based on 

3 their observations of increased ovary weight, increased number of ovulating cells, and changes 

4 in blood levels of gonadotropins (LH and FSH) in female rats. Additionally, Maronpot et al. 

5 (l986) reported endometrial hypoplasia with a lack of ovarian luteal tissue in formaldehyde6 exposed female rats. This finding may be relevant to the increased risk for endometriosis noted 

7 in the Taskinen et al. (1999) study. However, additional human and animal studies are needed to 

8 better understand the effects of inhalation exposure to formaldehyde on developmental outcomes 

9 after early gestational windows of exposure or on the female reproductive system.

10 The findings of some occupational studies have suggested formaldehyde-related 

11 associations with congenital malformations and low birth weight. In numerous experimental 

12 animal studies, developmental effects have been noted following inhalation exposures to 

13 formaldehyde (Table 4-68). Exposure of rat dams to formaldehyde during pregnancy has been 

14 shown to result in significantly decreased fetal weight gain (Martin, 1990; Saillenfait et al., 

15 1989; Kilburn and Moro, 1985). Other studies have noted changes in relative organ weight, 

16 undescended testes, biochemical changes (e.g., ascorbic acid), and blood acidosis (Senichenkova 

17 and Chebotar, 1996; Senichenkova, 1991; Kilburn and Moro, 1985; Gofmekler and 

18 Bonashevskaya, 1969; Gofmekler, 1968; Pushkina et al., 1968).

19 Studies designed to assess adult male reproductive system toxicity in rats following 

20 repeated inhalation exposures to formaldehyde have found concentration-dependent decreases in 

21 Leydig cell number and quality, degeneration of seminiferous tubules, decreases in testes weight, 

22 alterations in sperm measures, decreased testosterone levels, alterations in trace metals in the 

23 testes, and/or dominant lethal effects (Guseva, 1972; Özen et al., 2002, 2005; Sarsilmaz et al., 

24 1999; Xing et al., 2007; Zhou et al., 2006) (Table 4-71). 

25

26 6.1.3.8. Effects on General Systemic Toxicity

27 Extrapulmonary effects such as changes in liver function enzymes and focal, chronic 

28 inflammation in the heart and kidney have been observed due to formaldehyde exposure in 

29 experimental animal studies. Most of these changes occurred at exposures of 20 ppm, and those 

30 that occurred at lower formaldehyde exposures (3.7 ppm) were confounded by coexposures. The 

31 underlying modes of action of liver, kidney, and cardiac effects have not been elucidated, and the 

32 human relevance is unknown.

33

34

35
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1 6.1.3.9. Summary

2 Formaldehyde-induced eye, nose and throat irritation, decreased pulmonary function, 

3 decreased mucociliary clearance and histopathological lesions have been extensively 

4 documented in human and laboratory animal studies. These health effects are commonly noted 

5 at the portal of entry as expected for exposure to a reactive gas. In addition, effects on immune 

6 system responses and on the nervous and reproductive systems, including developmental effects, 

7 have also been reported. An association between formaldehyde exposure and increased 

8 incidence and severity of response to allergens (i.e., asthma and atopy) has been noted in 

9 humans. This effect, which has also been studied in laboratory animals, might occur via a 

10 neurogenic mode of action. A limited database of information that evaluates neurological effects 

11 in humans following formaldehyde exposure demonstrates a potential for adverse outcomes, and 

12 studies in laboratory animals have reported a variety of formaldehyde-induced neurobehavioral 

13 and neurodevelopmental effects. Formaldehyde has also been associated with adverse 

14 reproductive outcomes. Human studies have reported an association between formaldehyde 

15 exposure and decreased fertility as well as an increased risk of spontaneous abortions. Other 

16 human studies have suggested formaldehyde-related associations with congenital malformations, 

17 low birth weight, and endometriosis. Animal studies have noted a variety of developmental 

18 effects, including fetal death, structural alterations, and growth retardation (e.g., delayed fetal 

19 skeletal ossification and decreased fetal body weight) following inhalation exposure to 

20 formaldehyde, and adverse reproductive effects have been observed in both males and females. 

21

22 6.1.4 Carcinogenicity in Humans and Laboratory Animals

23 6.1.4.1 Carcinogenicity in Humans

24 Based on the total weight of evidence, including the results from a large and well25 followed longitudinal cohort study of 25,619 industrial workers and several case-control studies, 

26 the epidemiologic evidence is sufficient to characterize the association between formaldehyde 

27 nasopharyngeal cancer as causal in humans (Hauptmann et al., 2004; Hildesheim et al., 2001; 

28 Vaughan et al., 2000). As further evaluated below, the evidence supporting a positive association 

29 between formaldehyde exposure and NPC is unlikely due to chance, bias or confounding. 

30 However, it should be noted that other smaller studies of formaldehyde-exposed workers did not 

31 document increased NPC mortality (e.g., Coggon et al., 2003; Pinkerton et al., 2004). These 

32 smaller study sizes yielded effect estimates with wide confidence intervals that were not 

33 statistically inconsistent with the increased risk of mortality from nasopharyngeal cancer 

34 reported in Hauptmann et al. (2004). 
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1 Luce et al. (2002) evaluated pooled data from 12 case-control studies conducted in seven 

2 countries using a common job-exposure matrix and demonstrated a statistically significant 

3 increased risk between formaldehyde exposure and sinonasal cancer exhibiting a concentration4 response relationship providing further causal evidence of carcinogenicity. This analysis was 

5 based on a very large dataset of 930 cases and 3136 controls, enabling the investigators to 

6 control for multiple potential sources of bias and confounding and to conduct separate analyses 

7 by histological type. These results are particularly convincing, as the association was 

8 consistently seen for a rare sub-type of sinonasal cancer which normally accounts for only 10% 

9 of the reported cases.

10 In addition to the evidence of formaldehyde carcinogenicity in the nasopharynx, nose and 

11 sinuses, other upper respiratory tract sites of direct contact with formaldehyde upon inhalation 

12 (i.e., larynx, mouth and salivary gland) also showed evidence of increasing relative risk with 

13 increasing average intensity and peak exposure in a large cohort study with exposure estimates 

14 for the individual workers, although these trends did not reach the level of statistical significance 

15 (Hauptmann et al., 2004). However, Hauptmann and colleagues (2004) concluded that in spite 

16 of the small numbers of deaths from these rare cancers of the upper respiratory tract, the positive 

17 associations of increased cancer risk with increased formaldehyde exposure were consistent with 

18 the carcinogenicity of formaldehyde at these sites of first contact. Case-control studies also 

19 provide evidence of an association between formaldehyde exposure and oral squamous cell 

20 carcinoma (SCC), esophageal, and laryngeal cancers, and hypopharyngeal cancer (Gustavsson et 

21 al., 1998; Laforest et al., 2000.)

22 The finding that formaldehyde inhalation causes nasal squamous cell carcinoma in 

23 rodents (Section 4.2.1.2) further supports the determination of a causal association of 

24 formaldehyde exposure and increased risk of upper respiratory tract cancer in humans. Both 

25 humans and animals developed tumors within the upper respiratory tract, the site expected to 

26 receive direct exposure to formaldehyde.

27 Several researchers have argued that the relationship between formaldehyde exposure 

28 and nasopharyngeal cancer based on existing studies has not been determined. Several 

29 limitations, such as the rarity of the cancer and the imprecise estimates of exposure, are often 

30 inherent in epidemiologic methods and exposure assessment. These constraints limit the ability 

31 of epidemiologic studies to statistically detect associations and can lead to false negatives. The 

32 results of the largest cohort study of nasopharyngeal cancer (Hauptmann et al., 2004) showed 

33 statistically significant concentration-response relationships with increased risk of cancer 

34 associated with increased formaldehyde exposure. However, even though this study was based 

35 on 25,619 workers, only 9 cases of nasopharyngeal cancer were observed, compared to an 
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1 expected number of 5 cases, for a relative rate of 2.1 (with a confidence interval of 1.05 - 4.21) 

2 (Hauptmann et al., 2004).

3 The next largest cohort study of nasopharyngeal cancer was based on 14,014 workers 

4 (Coggon et al., 2003) and reported only 1 case compared to an expected number of 2 cases, for a 

5 relative risk of 0.5 (with an estimated 95% confidence interval of 0.07 − 3.55; see Bosetti et al., 

6 2007). To put this finding into perspective, it is helpful to note not only the relative risk but also 

7 that this effect estimate is highly unstable due to a lack of statistical power. The large width of 

8 this interval (0.07 − 3.55) indicates that the range of possible true values includes both increased 

9 and decreased NPC mortality and therefore does not contradict the evidence of elevated risk of 

10 nasopharyngeal cancer mortality associated with formaldehyde exposure reported by Hauptmann 

11 et al. (2004). The even smaller study of 11,039 textile workers by Pinkerton et al. (2004) 

12 reported no cases of nasopharyngeal cancer compared to an expected number of one case − 

13 yielding an effective relative risk of zero with a highly unstable 95% confidence interval 

14 estimated at 0 − 3.00 (see Bosetti et al., 2007). While true that Pinkerton et al. (2004) did not 

15 report an increased risk of nasopharyngeal cancer, this study did not have sufficient statistical 

16 power to rule out a true association with less than a 3-fold increase in risk and therefore is 

17 likewise not inconsistent with the finding by Hauptmann et al. (2004). Thus, results from these 

18 cohort studies, with limited power to detect the relatively rare upper respiratory tract cancers 

19 (e.g., NPC), are given less weight in the overall evaluation.

20 The largest occupational cohort study, conducted by the NCI (Hauptman et al., 2004), did 

21 report statistically significant associations of formaldehyde exposure with carcinogenicity at the 

22 sites of first contact with sufficient statistical power to rule out the null hypothesis of no 

23 association. The NCI investigations controlled for potential selection bias due to the healthy 

24 worker effect and for several potential confounders, including calendar year, age, sex, race, and 

25 pay category. However, other potential sources of bias or confounding have been suggested with 

26 respect to the strength of these data to support a causal conclusion.

27 Following reports of increased risk of NPC associated with formaldehyde exposure, a 

28 series of analyses of similar data were undertaken by Marsh and coworkers (Marsh et al., 2007a, 

29 b, 2002, 1996; Marsh and Youk, 2005). Briefly, these studies focused on the specific findings 

30 from a single plant in the NCI cohort (Wallingford, Connecticut) that generated the majority of 

31 the NPC cases. Marsh et al. (1996) confirm a significant adverse association of formaldehyde 

32 with nasopharyngeal cancer but note the effects are predominantly among workers at the 

33 Wallingford plant with less than one year employment. Marsh et al. (2002) report a five-fold 

34 excess in risk of nasopharyngeal cancer associated with formaldehyde in both short-term and 

35 long-term workers but note that the increase was concentrated among workers hired during 
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1 1947-1956. Marsh and Youk (2005) re-evaluated the same Wallingford workers and reported a 

2 regional rate-based standardized mortality ratio (SMR) of 10.32 (95% CI = 3.79 − 22.47) 

3 compared to 0.65 (95% CI = 0.08 − 2.33) for workers at the nine other plants combined. 

4 However, Marsh and Youk (2005) also show that rate-based mortality ratios standardized to both 

5 U.S. and local populations were elevated (non-significantly) not only at the Wallingford plant 

6 but individually at each of the four other plants at which a single case of nasopharyngeal cancer 

7 was reported: Plant 2 (SMRUS = 5.35), Plant 3 (SMRUS = 1.99), Plant 7 (SMRUS = 1.06), and 

8 Plant 10 (SMRUS = 1.44). It should be noted that Plant 1 (Wallingford) and Plant 2 had both the 

9 two highest median formaldehyde exposures and the two highest reported excess risks (Marsh 

10 and Youk, 2005).

11 In another re-analysis of the NCI cohort data on the workers at the Wallingford plant, 

12 Marsh and coworkers (2007a) suggested that an imprecise assessment of formaldehyde exposure 

13 and an inability of the study to separate formaldehyde exposure from other potential chemical or 

14 particulate exposures may have confounded the observed association between formaldehyde and 

15 cancer. However, there was no evidence of any differential measurement error that could have 

16 produced the observation of a spurious association. Any non-differential exposure measurement 

17 error (i.e., random error in the exposure assessment) would likely have led to an attenuated 

18 observed effect of formaldehyde that was less than that which would otherwise have been 

19 observed in the absence of measurement error.

20 The potential for confounding by particulates was explicitly examined by Hauptmann et 

21 al. (2004) and it was shown that there was an exposure-response relationship with formaldehyde 

22 among individuals with high particulate exposures – alleviating the potential for confounding 

23 and thereby strengthening the causal interpretation of the formaldehyde relationship with an 

24 increased risk of NPC. Marsh and coworkers (Marsh et al., 2007b) later suggested the reported 

25 formaldehyde association was confounded by an association between silversmithing and NPC. 

26 However, careful examination of that analysis (Marsh et al., 2007a) suggests that multiple 

27 comparisons may have led to the reported observation with silversmithing. Additionally, the 

28 reported effect was inconsistently reported between the results and the abstract sections using 

29 different confidence intervals, and both sets of confidence intervals around the reported 

30 association were extremely unstable spanning up to several hundred-fold. No prior studies 

31 identified an associated between silversmithing and NPC. Thus it may be that silversmithing is 

32 an artifactual potential confounder. 

33 The increased NPC mortality observed in the NCI cohort (Hauptmann et al., 2004) has 

34 been thoroughly examined for sources of bias and confounding by both the primary researchers 

35 and Marsh and coworkers (Marsh et al., 2007a, b, 2002, 1996; Marsh and Youk, 2005). Despite 
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1 the extensive scrutiny of these results, no convincing and consistent alternative hypothesis of 

2 causation has been identified. Taken together with the statistically significant association 

3 demonstrating an exposure-response relationship within exposed workers, these data support the 

4 conclusion that the association between formaldehyde exposure and increased risk of NPC is 

5 causal.

6 Therefore, after a thorough examination of potential confounders, the association 

7 between formaldehyde exposure and NPC mortality in the NCI cohort remains significant and 

8 provides a positive exposure-response relationship. Additionally, case-control studies, which 

9 have greater statistical power than cohort studies for rare diseases, provide strong additional 

10 evidence in support of a causal association between formaldehyde exposure and the incidence of 

11 NPC (Hildesheim et al., 2001; Vaughan et al., 2000). As these studies draw from different 

12 demographic groups, regions of the world, and evaluate various confounding factors, there is 

13 little potential for these consistently reported associations to be artifactual, confounded by 

14 common exposures, or a result of bias or chance.

15 Numerous epidemiologic studies have also reported an association between 

16 formaldehyde-exposed workers, especially "professional" workers (e.g., pathologists, 

17 embalmers, and funeral directors), and increased risk of lymphohematopoietic cancers (See 

18 Table 4-82). Positive associations between formaldehyde exposure and lymphohematopoietic 

19 cancers have been reported for chemical workers (Wong et al., 1983; Bertazzi et al., 1986), 

20 embalmers (Walrath and Fraumeni, 1983, 1984; Hayes et al., 1990), anatomists and pathologists 

21 (Harrington and Shannon 1975; Hall et al., 1991; Levine at al., 1984; Stroup et al., 1986; 

22 Matanoski et al., 1989). However, clear associations (in terms of overall standardized mortality 

23 ratios (SMRs) or proportional mortality ratios (PMRs) were not reported in analyses for garment 

24 workers, iron-foundry workers, and a large US industrial cohort (Pinkerton et al., 2004; 

25 Andjelkovich et al., 1995; Beane Freeman et al., 2009; Marsh et al., 1996), although associations 

26 were observed in some of these studies when exposure-response relationships were considered. 

27 Several published meta-analyses are available which more formally assess the strength of 

28 association between formaldehyde exposure and mortality from all lymphohematopoietic 

29 cancers. Pooled SMRs indicate stronger associations for professional workers (embalmers, 

30 anatomists and pathologists) than industry workers (Table 4-83). Bosetti et al. (2008) found 

31 similar relationships, with a pooled SMR of 1.31 (95% CI 1.16-1.47) for ‘professionals’ (i.e. 

32 embalmers, anatomists and pathologists) versus a pooled estimate of 0.85 (95% CI 0.74-0.96) for 

33 industrial workers. A recent meta-analysis by Zhang et al. (2009) reports a summary relative 

34 risk of 1.25 (95% CI 1.09-1.43) for both professional and industry workers for all 

35 lymphohematopoietic cancers (ICD 9 codes 200-209). 
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1 Two well-designed cohort studies found significant positive associations between 

2 formaldehyde-exposed professional workers and lymphohematopoietic cancer, particularly 

3 leukemia, using cumulative exposure measures not previously used and using internal 

4 comparison groups. The largest cohort study of industrial workers exposed to formaldehyde 

5 (N=25,619), with the most extensive exposure assessment (Blair et al., 1986; Stewart et al., 

6 1986) and with the cohort followed for a median duration of 35 years (Hauptmann et al., 2003) 

7 demonstrated that formaldehyde was a risk factor for lymphohematopoietic cancers, independent 

8 of other risk factors, such as benzene exposure and smoking. This finding was re-confirmed 

9 with an additional 10 years of follow-up (Beane Freeman et al., 2009). Another industrial cohort 

10 study reported a significant increase in the risk of leukemia in garment workers 20 years after 

11 their initial exposure and in workers with 10 or more years of exposure to formaldehyde 

12 (Pinkerton et al. 2004). A third large occupational cohort study (Coggon et al., 2003) that did 

13 not evaluate their findings with regard to latency reported somewhat lower mortality from 

14 leukemia and other lymphatic and hematopoietic cancers than expected compared to national 

15 rates. 

16 The associations between myeloid leukemia and formaldehyde exposure are strong and 

17 consistent (Table 4-84). Of the four studies which formally assess myeloid leukemia mortality, 

18 all are positive, including cohorts of both professional and industrial workers (Beane Freeman et 

19 al., 2009; Hayes et al., 1990; Pinkerton at al., 2003; Stroup et al., 1986). Although few cases 

20 exist for further subtype analysis, the available data indicate either no differences in SMRs for 

21 acute myeloid leukemia (AML) versus chronic myeloid leukemia (CML) (Hayes et al., 1990; 

22 Pinkerton et al., 2003) or suggest CML is more prominent (Blair et al., 2000; Stroup et al., 

23 1986). The association between formaldehyde exposure and myeloid leukemia in embalmers has 

24 recently been confirmed in a large nested case control study by Hauptman et al (2009) which 

25 includes cases identified from the previous studies of Hayes et al. (1990) and Walrath and 

26 Fraumeni (1983 and 1984). Exposure estimates were based on interviews with next-of kin for 

27 duration of job actively embalming and total number of embalmings performed. Strong and 

28 statistically significant exposure-response relationships are demonstrated for duration of 

29 exposure, total number of embalmings performed and estimated cumulative exposure to 

30 formaldehyde with odds ratios of 13.6 (1.6-119.7), 12.7(1.4-112.8) and 13.2(1.5-115.4) 

31 respectively (Hauptmann et al., 2009). 

32 The reported associations between formaldehyde exposure and lymphohematopoietic 

33 cancers in general, and leukemia (especially myeloid leukemia) in particular, were in workers 

34 exposed in very different environments (i.e., mortuary, chemical industry and garment industry). 

35 Since coexposures to other agents are considerably different between these work environments, 
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1 it is unlikely that influence of confounding exposures plays a role in the observed associations. 

2 There is no evidence of bias in the published reports, and the consistency across numerous 

3 studies over time is sufficient to conclude that the results are not due to chance.

4 It has been argued that it is biologically implausible for a highly reactive agent such as 

5 formaldehyde, whose primary action is expected to be at the portal of entry, to cause acute 

6 lymphoid or myeloid leukemias (ALL and AML, respectively), which are both commonly 

7 believed to arise from transformation of stem cells in the bone marrow. The modes of action 

8 (MOAs) by which formaldehyde may induce these observed cancers are unknown, although it 

9 has been postulated that circulating stem cells (Hauptmann et al., 2003) (e.g., early progenitor 

10 cells in circulating blood or pluripotent cells in nasal/oral passages) may travel to bone marrow 

11 where they become leukemic stem cells (Zhang et al., 2009). In contrast, the mechanism for the 

12 chronic lymphatic leukemia, lymphomas, multiple myelomas (from plasma B-cells) and 

13 unspecified lymphohematopoietic cancers may involve an etiology in peripheral tissues, such as 

14 cells, cell aggregates, germinal centers and lymph nodes. An association of these cancers to a 

15 reactive exogenous agent primarily acting at the point of entry is biologically plausible.

16

17 6.1.4.2 Carcinogenicity in Laboratory Animals

18 The carcinogenic potential of formaldehyde is well documented in numerous animal 

19 bioassays, especially for sites of first contact. Inhalation exposure of formaldehyde induced 

20 primarily squamous cell carcinomas (SCC) in nasal passages of rats (Feron et al., 1988; 

21 Holmström et al., 1989a; Woutersen et al., 1989; Tobe et al., 1985; Kamata et al., 1997; Albert et 

22 al., 1982; Sellakumar, 1985; Kerns et al., 1983; Monticello et al., 1996) and mice (Battelle 

23 Columbus Laboratories, 1981; Swenberg et al., 1980; Kerns et al., 1983; CIIT, 1982). 

24 Formaldehyde given as 0.5% formalin orally in drinking water to adult rats induced higher 

25 incidences of papillomas in the forestomach, adenomatous hyperplasia in the fundus, and 

26 adenocarcinomas in the pylorus in a 40-week study using an initiation-promotion protocol in rats 

27 (Takahashi et al., 1986). Soffritti et al. (1989) observed a significant increase in rare tumors in 

28 the gastro-intestinal (GI) tract, including both benign (papillomas and acanthomas of the 

29 forestomach and adenomas) and malignant tumors (adenocarcinomas and leiomyosarcomas) in 

30 rats given formaldehyde in drinking water. Formaldehyde is toxic at the portal of entry in 

31 rodents, causing increased cell proliferation, DPX formation, and focal lesions in the GI tract or 

32 upper respiratory tract (depending on the route of exposure). The portal of entry toxicity of 

33 formaldehyde further supports a finding of formaldehyde induced POE cancer in animal 

34 bioassays. 
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1 Direct support for lymphohematopoietic cancers in animal bioassays is less convincing. 

2 Although many of the available chronic studies did not examine lymphoma/leukemia incidence, 

3 two studies provide positive evidence. Inhalation exposure of formaldehyde increased 

4 lymphoma in female mice and leukemia in female F344 rats, but not male rats (Battelle 

5 Laboratories, 1981). Drinking water exposure to formaldehyde caused a dose-dependent 

6 increase in all hemolymphoreticular neoplasias, especially lymphoblastic leukemias and 

7 lymphomas in both male and female Sprauge-Dawley rats (Soffritti et al., 1989, 2002). 

8 Conversely, no increases were seen in male Wistar rats when exposed to formaldehyde in 

9 drinking water at similar levels (Til et al., 1989) or male rats after chronic inhalation exposures 

10 (Sellakumar et al., 1985).

11

12 6.1.4.3 Carcinogenic Mode(s) of Action 

13 Multiple plausible modes of action (MOAs) are presented in the document so as to 

14 explore ways in which a combination of factors may contribute to cancer incidence in a 

15 population exposed to formaldehyde. Multiple MOAs for formaldehyde-induced cancer can be 

16 reasonably supported based on various known biological actions of formaldehyde (e.g., 

17 mutation, cell proliferation, cytotoxicity and regenerative cell proliferation). Additionally, 

18 alternative actions, such as immunosuppression or viral reactivation, are possible, although few 

19 data exist to evaluate their potential relevance. Rather than a single MOA, it is plausible that a 

20 combination of these factors contribute to cancer incidence in an exposed population. 

21 Considering multiple factors may help to better understand the biological and mechanistic basis 

22 for the increases in cancer incidence observed in exposed human populations. Unlike animal 

23 bioassays, results in human epidemiological studies reflect not only the effects of the agent of 

24 concern but also numerous other risk factors (e.g., viral status, diet, smoking, etc.). Additionally, 

25 human studies may be impacted by biological human variability across individuals, cancer 

26 biology (sub-types) and wide variability in exposure regimens in human populations. 

27 A preponderance of the evidence supports a role of mutagenic activity in formaldehyde’s 

28 carcinogenic MOA both for respiratory tract cancer and lymphohematopoietic cancers. As 

29 reviewed in Section 4.3, numerous studies provide evidence of formaldehyde’s direct mutagenic 

30 activity and supports the relevance these data to formaldehyde’s carcinogenicity. It can be 

31 shown that:

32 1) Formaldehyde directly interacts with DNA, generating DNA-protein cross-links and 

33 DNA adducts (in vitro, in vivo) in multiple species,
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1 2) DNA-protein cross-links exhibit a dose-response relationship to formaldehyde 

2 exposure in respiratory tract of laboratory animals and are observed at exposure 

3 concentrations of relevance to some people (0.3 ppm, 0.7 ppm),

4 3) Formaldehyde-induced DNA-protein cross-links have been associated with 

5 formaldehyde-induced micronuclei and chromosomal aberrations (in vitro),

6 4) Mutations induced by formaldehyde due to small deletions and rearrangements in 

7 DNA in various experimental systems are consistent with formaldehyde’s 

8 observed clastogenic effects (micronuclei and chromosomal aberrations) (in vitro, 

9 in vivo),

10 5) Formaldehyde-induced mutations and clastogenic effects occur at levels below where 

11 significant cytotoxicity is detected (in vitro),

12 6) Formaldehyde exposure has been correlated to similar increased micronuclei and 

13 chromosomal aberrations in human buccal and oral cells corresponding to sites 

14 where formaldehyde-induced tumors arise, and

15 7) Chromosomal damage in blood-borne immune cells, relevant to agent-induced 

16 lymphohematopoietic cancers has been documented in formaldehyde exposed 

17 workers including increased micronuclei and chromosomal aberrations, increased 

18 incidence and aneuploidy in hematopoietic stem cells.

19

20 In addition, mutations may arise indirectly from formaldehyde-induced DNA damage 

21 during cell proliferation or due to errors in DNA repair mechanisms. Therefore, formaldehyde’s 

22 DNA reactivity on a population of proliferating cells strengthens the role of formaldehyde23 induced mutagenicity in its carcinogenic MOA. The nasal and gut mucosa are tissues which are 

24 continually sloughing and regenerating cells (Junqueira et al., 1992). Mucosal cells proliferate 

25 in response to environmental challenges in order to repair cell damage, increase adaptive 

26 response and remodel tissue. Additionally, since the pseudostratified epithelium of the 

27 respiratory tract is only 1-2 cells in depth, cells with proliferative capacity would be directly 

28 impacted by formaldehyde during exposure. Formaldehyde-induced clastogenic effects have 

29 been demonstrated in these tissues (e.g. nasal) in humans, as well as in tissues which possess 

30 stratified epithelium (e.g. buccal). Therefore, formaldehyde would not need to transport beyond 

31 the portal of entry to directly impact and induce DNA mutations in routinely proliferating cells.

32 In regards to generating the observed clastogenic effects (micronuclei and chromosomal 

33 aberrations in peripheral blood lymphocytes, aneuploidy in circulating hematopoietic stem cells), 

34 it is less clear as to where formaldehyde is making contact with components of the immune 

35 system. Mature lymphocytes present in nasal and gut tissues, and would be vulnerable to the 
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1 direct toxic actions of formaldehyde including genotoxicity. Since mature lymphocytes 

2 routinely traffic through the body and clonally respond in response to an immune challenge, the 

3 observed effects in peripheral blood lymphocytes (micronuclei and chromosomal aberrations) 

4 are consistent with direct action on these cells. Lymphohematopoietic cancers are known to 

5 arise from mature lymphocytes including: Hodgkin lymphoma, multiple myeloma some 

6 leukemia and non-Hodgkin lymphoma (Greaves 2004, Harris et al., 2000). 

7 Formaldehyde may also be directly acting upon circulating stem cells or more mature 

8 progenitor cell in the peripheral blood (Zhang et al., 2010). Any genetic damage sustain by 

9 circulating cells could contribute to a broad spectrum of lymphohematopoietic cancers if those 

10 cells returned to the bone marrow and contributed to hematopoiesis. Evidence of bone marrow 

11 toxicity and stem cell aneuploidy has been reported in formaldehyde exposed workers (Zhang et 

12 al., 2010). Finally, formaldehyde is readily hydrated in aqueous systems, existing in equilibrium 

13 with its hydrated form methylene glycol, which is able to transport through the blood. It has 

14 been hypothesized that this hydration reaction may allow formaldehyde to act systemically and 

15 therefore on the bone marrow directly (Zhang et al., 2010.) Formaldehyde-induced DNA 

16 damage, and resulting mutation in the bone marrow and circulating stem cells could contribute to 

17 any of the lymphohematopoietic cancers including leukemia (both lymphoid and myeloid) as 

18 well as myeloproliferative disorders.

19 Cell replication allows unrepaired DNA damage to be “fixed” into heritable changes to 

20 the genome. Therefore, increased cell proliferation could serve not only to increase the 

21 mutagenic effects of formaldehyde on a given tissue but also to enhance the mutagenic effects of 

22 other agents in the diet or in the environment. Since epidemiological studies include humans 

23 exposed to a range of agents in the environment, increased cell proliferation could contribute to 

24 increased cancer incidence. The promotion studies in animal bioassays, though limited in 

25 number, support the relevance of formaldehyde’s ability to enhance the actions of other agents 

26 (initiators) on tumor formation. 

27 Although the other biologic effects discussed above have not been explicitly tested in 

28 animal systems, the available data are consistent with these actions contributing to the 

29 carcinogenic potential of formaldehyde. For example, localized immunosuppression by 

30 formaldehyde may serve to increase viral reactivation (e.g., EBV, HPV etc.) or decrease tissue 

31 surveillance and immune activity against preneoplastic cells. Both these actions could contribute 

32 to increased cancer risk in a human population, which may not be evident in animal bioassays, 

33 where the animals are not subject to the many risk factors for human cancer. Even the simple 

34 action of the breakdown of the mucociliary apparatus could increase cancer incidence by 
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1 increasing toxic insult to the URT and increasing URT infections. Again, these actions may be 

2 relevant to human populations, but they have not been adequately tested in animal bioassays.

3 Animal bioassays suggest a role for regenerative proliferation in contributing to 

4 formaldehyde’s carcinogenicity. However, these data are not evidence against a role of direct 

5 mutagenic action either in the observed tumorigenicity or in the potential low-dose 

6 carcinogenicity of formaldehyde. As reviewed, a role for mutagenic action is also consistent 

7 with the results of the animal bioassays (Crump et al, 2008; Subramaniam et al., 2007, USEPA 

8 2008). The mutagenic effects of formaldehyde are well-documented to occur below levels of 

9 significant cytotoxicity. This observation is important for the relevance of formaldehyde10 induced mutagenicity to human health risk. Given the above sequence of evidence - from the 

11 nature of formaldehyde’s DNA reactivity through clastogenic effects observed in human cells 

12 from the various tumor sites - there is an adequate weight of evidence (WOE) to consider 

13 formaldehyde-induced mutations relevant to human carcinogenic risk. Although occupational 

14 exposures may have resulted in high episodic exposures (especially historically), it is unlikely 

15 that any worker would have endured repeated exposures which resulted in gross focal lesions to 

16 the upper respiratory tract (URT) or oro-digestive tract as seen in the animal bioassays. It is 

17 noteworthy that even without these gross formaldehyde-induced lesions, cancer incidence is 

18 increased from occupational (and perhaps non-occupational) exposures to formaldehyde. 

19 Therefore, we believe formaldehyde carcinogenicity can be attributed, at least in part, to a 

20 mutagenic MOA.

21

22 6.1.5 Cancer Hazard Characterization

23 Formaldehyde is carcinogenic to humans by the inhalation route of exposure. There is 

24 sufficient evidence of causal associations between formaldehyde exposure and nasopharyngeal 

25 cancers as well as sinonasal cancers. There is supporting evidence for cancers of the mouth and 

26 throat in humans as well as strong evidence for nasal tumors in animal bioassays. Taking these 

27 findings together along with mode of action considerations, it is concluded that there is sufficient 

28 evidence of a causal relationship between formaldehyde inhalation exposure and upper 

29 respiratory tract cancers as a group.

30 Epidemiologic studies also provide evidence of a causal association of inhalation 

31 exposure to formaldehyde and lymphohematopoietic cancers as a group and leukemias as a 

32 group, with the strongest evidence for myeloid leukemia. There is supporting evidence both in 

33 cohort and case-control studies for specific sub-types of lymphohematopoietic cancers, including 

34 myeloid leukemia, multiple myeloma and Hodgkin lymphoma. There is limited supporting 

35 evidence in animal bioassays for both leukemia and lymphoma. It should be noted that although 
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1 several carcinogenic modes of action have been discussed for leukemia, that this remains an area 

2 of significant scientific debate.

3

4 6.2 DOSE-RESPONSE CHARACTERIZATION

5 6.2.1 Noncancer Toxicity: Reference Concentration (RfC)

6 The portals of entry are major targets for formaldehyde, as can be seen in many studies, 

7 because formaldehyde is highly reactive and water soluble. Human and laboratory animal 

8 studies demonstrate that formaldehyde also causes systemic effects, including neurotoxicity, 

9 reproductive toxicity, developmental toxicity, and immunotoxicity, although the data are less 

10 extensive than those supporting the sensory irritation and respiratory tract effects. Critical data 

11 gaps have been identified and uncertainties associated with data deficiencies are more fully 

12 discussed in Chapter 5 and summarized below.

13

14 6.2.1.1 Assessment Approach Employed

15 RfC values for noncancer effects are derived using EPA’s RfC methodologies (U.S. 

16 EPA, 1994, 1993, EPA 2002b). EPA reviewed the existing literature and identified health 

17 effects associated with formaldehyde exposure, defining health effect categories where evidence 

18 was sufficient: sensory irritation, respiratory tract pathology, pulmonary effects, asthma, 

19 increased allergic sensitization, immune function, neurological and behavioral effects and 

20 reproductive and developmental effects. Specific key studies were identified within each health 

21 effects category which provided adequate exposure-response information to support RfC 

22 derivation (Table 5-4). Although not all identified endpoints are represented by these studies, at 

23 least one study was identified for each category. A screening process (described in section 

24 5.1.3.1) was used to identify key studies for a variety of health effects that would best inform the 

25 derivation of the RfC. For each selected key study, a candidate RfC (cRfC) was derived. In 

26 several cases more than one alternative was considered for application of the uncertainty factor 

27 (UF) addressing human variability (Table 5-6).

28

29 6.2.1.2 Derivation of Candidate Reference Concentrations

30 Seven studies were selected as key studies for further consideration in RfC derivation 

31 (Section 5.3.1, Table 5-4). Candidate RfCs from these studies address various health effects 

32 including: sensory irritation, respiratory effects, asthma, increased allergic sensitization, and 

33 decreased fecundity (Table 5-6). From these studies three co-critical studies were selected which

34 provide similar cRfCs for related health effects (Rumchev et al., 2002; Garrett et al., 1999; 

35 Krzyzanowski et al., 1999). These three studies identify serious health effects in residential 
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1 populations including children: increased asthma incidence, decreased pulmonary function, 

2 increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 2002; 

3 Garrett et al., 1999; Krzyzanowski et al., 1999). Asthma, allergic sensitization, altered 

4 pulmonary function, and symptoms of respiratory disease are not only clinically related, but 

5 etiologically related, and it is reasonable that they should be considered together. These health 

6 effects are observed below the exposure levels that result in sensory irritation, and the resulting 

7 cRfCs are correspondingly lower—ranging from 2.8 to11 ppb—depending on the study, 

8 endpoint considered, and the application of alternative uncertainty factors for human variability 

9 (Table 6-1). Additionally, these cRfCs are considered protective of the decreased fecundability 

10 density ratio (FDR) reported by Taskinen et al. (1999) which yielded a cRfC of 8.6 ppb. One of 

11 the uncertainties in the cRfC for decreased FDR is the use of a time-weighted exposure metric 

12 which does not address possible contributions of peak exposure levels to the observed health 

13 effect thus; it is possible that a cRfC of 8.6 ppb is lower than is needed for protection against 

14 decreased FDR. 

15 As discussed in section 6.2.1.4, there are uncertainties in establishing an RfC which are 

16 not fully captured in the quantitative process or the standard uncertainty factors, as such it is 

17 acknowledged by EPA that the RfC is not exact, perhaps spanning an order of magnitude. The 

18 range of RfCs from the critical studies (even with various alternative considered for the human 

19 variability uncertainty factor are in close agreement spanning only 1⁄2 order of magnitude.) 

20 Therefore EPA is considering a simple mean of these cRfCs as adequately representative of the 

21 three co-critical studies. Alternatives are to take the median as a different way to represent the 

22 three studies together, or the lowest cRfC as most protective. There is little numerical difference 

23 in the result of these decisions.

24

25 6.2.1.3 Adequacy of Overall Data Base for RfC Derivation

26 The database of available laboratory animal studies, clinical and epidemiological studies, 

27 and supporting mechanistic information for formaldehyde is substantial. Many of the health 

28 effects are well studied in animals and humans, especially those endpoints related to sensory 

29 irritation and respiratory effects at the portal of entry, such as impacts on respiratory tract 

30 pathology, asthma and reduced pulmonary function. This is reflected in the number and high 

31 quality of human studies presented in Table 5-4 and supporting data summarized in Chapter 4. 

32

33
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not constitute Agency policy

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Table 6-1: Summary of candidate reference concentrations (RfC) for co-critical studies

Endpoint Study Study 

size Homes Children POD (ppb)

Application of 

study-specific UF cRfC 1

(ppb) UFL UFS UFH

Respiratory effects / asthma and sensitization

Reduction of 

PEFR in children 

(10%)

Krzyzanowski 

et al. (1990) 208 Yes Yes BMCL10 = 17 1 1 3 5.6

Asthma 

prevalence

Rumchev et al. 

(2002) 192 Yes Yes NOAEL = 33 1 3

Alternative A

3 3.3

Alternative B

1 11

Asthma, atopy 

and severity of 

allergic 

sensitization

Garrett et al. 

(1999) 148 Yes Yes LOAEL = 28 3 1

Alternative A

3 2.8

Alternative B

1 9.3

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 digits are 

retained as is common practice in mathematics {i.e. one significant diget more that the final result, to avoid rounding errors compounding across multiple 

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, 

11 for 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 dose2 response 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 

24 and laboratory animal inhalation studies are typically not for continuous exposures, and 

25 assumptions must be made in converting reported exposure levels to equivalent continuous 

26 exposures. Similarly, there are uncertainties about potential dose rate effects, in particular the 

27 effect of peak 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 

12 over-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 

35 cancers 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

8

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:

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

23

22

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, 

21 from the Beane Freeman et al. (2009) follow-up study of lymphohematopoietic malignancies, 

22 only all leukemias combined and Hodgkin lymphoma were judged to have exposure-response 

23 data 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, 

35 although the trends were only of borderline significance (Hodgkin lymphoma p trends = 0.06 
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1 and 0.08 with and without the unexposed person-years, respectively; leukemia p trends = 0.08 

2 and 0.12 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 

28 leukemia (Sections 5.2.2 and 5.2.3). These values approximate the lower confidence bounds on 

29 dose at these extra risk levels. The values for these extra risk levels, 0.0005 and 0.005, were 

30 chosen 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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Linear low-dose extrapolation from the PODs was used to derive unit risk estimates for 

NPC, Hodgkin lymphoma, and leukemia, as discussed in Section 6.2.2.4. To obtain an 

approximate (upper bound) unit risk estimate of the total cancer risk from formaldehyde 

exposure, risk estimates for these three cancer types (NPC, Hodgkin lymphoma, and leukemia) 

were combined assuming a normal distribution (Section 5.2.4). This was considered the most 

reasonable approach for estimating total cancer risk from the available data; however, it should 

be noted that this estimate may not reflect all of the cancer types associated with formaldehyde 

exposure. 

Table 6-2: Effective concentrations (lifetime continuous exposure levels) 

predicted for specified extra cancer risk levels for selected formaldehyderelated cancers1

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

11 

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 

 1. calculated including all person-years (see section 5.2)

2. effective concentration.

3. 95% lower confidence bound on the EC; this value is the POD.

6.2.2.3. Analysis of Laboratory Animal Data 

Various bioassays have been conducted studying the effects of formaldehyde on rats, 

mice, and rhesus monkeys and have been discussed at length earlier in this document. Of these, 

two inhalation bioassays of rats, when combined, allow for the most robust characterization of 

the long-term dose-response relationship in a laboratory species. These long-term bioassays 

found an increased incidence of nasal SCCs in rats exposed to formaldehyde by the inhalation 

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

) exposure 

concentrations of formaldehyde (Monticello et al. 1996; Kerns et al. 1983). SCCs were observed 

only at 6 ppm and higher exposure concentrations. 

A large amount of mechanistic information relevant to the dose-response relationship of 

formaldehyde in the respiratory tract has been generated either following or in conjunction with 

these two bioassays, as reviewed in Chapter 3, 4 and 5. This information includes the following: 

15 

16 

17 

18 

19 

20 

21 

22 

23 

24 

25 

26 

27 

28 

29 

30 

31 

32 
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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 time18 to-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 

10 inform 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 

16 applied when estimating human cancer risk from both leukemia and Hodgkins lymphoma from 

17 the NCI 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 

33 et al. (2003, 2004) developed BBDR models to predict squamous cell carcinoma risk in the rat 
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and human respiratory tract at exposures well below the range of the observed animal data.17

conservative in the face of model uncertainties.

1 

2 The primary conclusion from their modeling effort was that human exposure standards 

3 protective of effects of formaldehyde-induced cytotoxicity should be sufficient to protect from 

4 the potential carcinogenic effects of formaldehyde. The authors assessed that such a conclusion 

5 was 

18

9 The current assessment evaluated the uncertainties in the above BBDR model extensively 

10 and examined alternative parameterizations of the modeling in Conolly et al. (2003, 2004). 

11 These alternatives and the original model were equally consistent with the experimental data but

12 resulted in maximum likelihood estimates of added human risk that ranged from negative to 

13 large positive values at environmental exposure concentrations. Model uncertainty far exceeded 

14 statistical uncertainty (Table E-4 in Appendix E). Each of these models, including the modeling 

15 in Conolly et al., 

6 This assessment’s evaluation of the BBDR 

7 models and alternative implementations (detailed in Section 5.3) finds that these models may not 

8 provide conservative estimates of human cancer risk below the range of observed data.

16

17 1. was judged to be just as biologically plausible, 

18 2. described the rat tumor incidence data equally well,

19 3. was based on different characterizations of the same empirical cell kinetic data, and

20 4. was based on the same empirical data on DPX measurements.

21

This assessment’s evaluation19

 17 In that sense, the authors used the modeling as if it were a BBDR model even though they termed it as 

“biologically-motivated”.

22 of the above models (detailed in Section 5.3) concluded 

23 that these models, including alternative implementations of those in Conolly et al. (2003, 2004), 

24 were too uncertain to be useful for low-dose extrapolation of risk. It may be noted that the 

25 sensitivity analyses on the basis of which these conclusions were reached have been criticized as 

26 resulting in implausible risk estimates (given the epidemiologic data) as a consequence of 

27 implementing model variations that are not biologically reasonable (Conolly et al. 2009). This 

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 

9 data.

10 • Furthermore, human risk calculated from these BBDR models was numerically unstable 

11 when certain parameter conditions were realized (Section 5.3.3 and Appendix F).

12 • Therefore, clonal growth modeling was not found to be a useful approach for human 

13 extrapolation of rodent risk estimates. The current assessment concludes that the result in 

14 Conolly et al. cannot be considered to be “conservative in the face of model 

15 uncertainties.” 

16

17 However, using the BBDR model to characterize the dose-response in the range of the 

18 available data was judged to have the advantage of utilizing the available biological and 

19 dosimetry data on formaldehyde in an integrated manner as well as providing statistically sound 

20 descriptions of the empirical tumor incidence data. Therefore, this assessment uses the BBDR 

21 modeling of the rat data to derive multiple PODs (for SCC in the respiratory tract) in the range of 

22 the observed data and uses model-derived internal dose estimates. For the reasons detailed 

23 above, the BBDR modeling is not used to extrapolate far below the observed data.

24 The lowest observed incidence of SCC in the bioassays used in the dose-response 

25 assessment was equal to 0.0087 (at 6 ppm exposure). In addition, the BBDR modeling used data 

26 on cell proliferation and formation of DPXs that informed the modeling of the tumor data at the 

27 lower exposure concentrations of 0.7 and 2.0 ppm. Thus, the available data supported estimation 

28 of response levels below the 10% response level commonly used in BMD analyses of tumor 

29 data. Therefore, points of departure corresponding to 95% statistical upper bound levels of extra 

30 risk of 0.005, 0.01 and 0.1 were estimated when the BBDR modeling was used.

31

32 Summary:

33 As discussed earlier in the hazard characterization, formaldehyde is a direct-acting 

34 mutagen, and its genotoxic effects have been observed following human occupational 
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exposures.20

9

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). 

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/m3 21 ) 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/m3 20 ) 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

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 

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.

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 

11 uncertainties 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 

24 shown that the directly mutagenic component could be important in explaining the high-dose 

25 effect (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 

33 risk 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/m3 17 ). 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
This document is a draft for review purposes only and does not constitute Agency policy.

6-46 DRAFT—DO NOT CITE OR QUOTE

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/m3 23 ). Applying 

24 the 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/m3 25 ).
This document is a draft for review purposes only and does not constitute Agency policy.

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REFERENCES

Abbas, AK; Fausto, N; Kumar, V. (2004) Robbins and Cotran pathologic basis of disease. W.B. 

Saunders Co. Silver Spring, MD.

ACGIH (American Conference of Governmental Industrial Hygienists). (2002) Documentation 

of the TLVs® and BEIs® with other worldwide occupational exposure values CD-ROM―2002. 

American Conference of Governmental Industrial Hygienists, Cincinnati, OH.

Acheson, ED; Barnes, HR; Gardener, MJ; et al. (1984) Formaldehyde in the British chemical 

industry: an occupational cohort study. Lancet 1:611–616.

Achkor, H; Diaz, M; Fernandez, MR; et al. (2003) Enhanced formaldehyde detoxification by 

overexpression of glutathione-dependent formaldehyde dehydrogenase from Arabidopsis. Plant 

Physiol 132:2248–2255.

Adams, DO; Hamilton, TA; Lauer, LD; et al. (1987) The effect of formaldehyde exposure upon 

the mononuclear phagocyte system of mice. Toxicol Appl Pharmacol 88:165–174.

Ahmad, I; Whitson, TC. (1973) Formaldehyde: how much of a hazard? Ind Med Surg 42:26–27.

Ahmed, S; Tsukahara, S; Tin-Tin-Tin-Shwe; et al. (2007) Effects of low-level formaldehyde 

exposure on synaptic plasticity-related gene expression in the hippocampus of immunized mice. 

J. Neuroimmunol 186:104–111.

Akbar-Khanzadeh, F; Mlynek, JS. (1997) Changes in respiratory function after one and three 

hours of exposure to formaldehyde in non-smoking subjects. Occup Environ Med 54:296–300.

Akbar-Khanzadeh, F; Vaquerano, MU; Akbar-Khanzadeh, M; et al. (1994) Formaldehyde 

exposure, acute pulmonary response, and exposure control options in a gross anatomy 

laboratory. Am J Ind Med 26:61–75.

Alarie, Y. (1981) Toxicological evaluation of airborne chemical irritants and allergens using 

respiratory reflex reactions. In: Leong, B, ed. Proceedings of the inhalation toxicology and 

technology symposium. Ann Arbor, MI: Ann Arbor Science Publishers, Inc.; pp. 207–231.

Albert, RE; Pasternack, BS; Shore, RE; et al. (1975) Mortality patterns among workers exposed 

to chloromethyl ethers-a preliminary report. Environ Health Perspect 11:209–214.

Albert, RE; Sellakumar, AR; Laskin, S; et al. (1982) Gaseous formaldehyde and hydrogen 

chloride induction of nasal cancer in the rat. J Natl Cancer Inst 68:597–603.

Alderson, T. (1985) Formaldehyde-induced mutagenesis: a novel mechanism for its action. 

Mutat Res 154:101-10.

Alexandersson, R; Hedenstierna, G. (1988) Respiratory hazards associated with exposure to 

formaldehyde and solvents in acid-curing paints. Arch Environ Health 43:222–227.

Alexandersson, R; Hedenstierna, G. (1989) Pulmonary function in wood workers exposed to 

formaldehyde: A prospective study. Arch Environ Health 44:5–11.

Alexandersson, R; Hedenstierna, G; Kolmodin-Hedman, B. (1982) Exposure to formaldehyde 

effects on pulmonary function. Arch Environ Health 37:279–284.
This document is a draft for review purposes only and does not constitute Agency policy.

R-2 DRAFT—DO NOT CITE OR QUOTE

Almaguer, D; Blade, LM. (1990) Health hazard evaluation report: Buckeye Hills Career Center, 

Rio Grande, Ohio. National Institute for Occupational Safety and Health, U.S. Department of 

Health and Human Services, Cincinnati, OH; HETA 88-153-2072

Almaguer, D; Klein, M. (1991) Health hazard evaluation report: Northwest Vocational School, 

Cincinnati, Ohio. National Institute for Occupational Safety and Health, U.S. Department of 

Health and Human Services, Cincinnati, OH; HETA 89-170-2100

Amdur, MO. (1960) The response of guinea pigs to inhalation of formaldehyde and formic acid 

alone and with a sodium chloride aerosol. Int J Air Pollut 3:201–220.

Ames, BN; Shigenaga, MK; Gold, LS. (1993) DNA lesions, inducible DNA repair, and cell 

division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 

101(Suppl 5):35–44.

Andersen, I; Lundqvist, GR. (1974) Design and performance of an environmental chamber. Int J 

Biometeor 14:402–405.

Andersen, I; Mølhave, L. (1983) Controlled human studies with formaldehyde. In: Gibson, JE; 

ed. Formaldehyde toxicity. Washington, DC: Hemisphere Publishing Corporation; pp. 154–165.

Andersen, ME; Jarabek, AM. (2001) Nasal tissue dosimetry. Issues and approaches for 

“Category 1” gases: a report on a meeting held in Research Triangle Park, NC, February 11-12, 

1998. Inhal Toxicol 13:415–435.

Andersen, ME; Clewell III, HJ, Bermudez, E; et al. (2008) Genomic signatures and dose 

dependent transitions in nasal epithelial responses to inhaled formaldehyde in the rat. Toxicol 

Sci 105:368–383.

Andersen, I (1979) Indoor climate: Effects on human comfort, performance, and health in 

residential, commercial, and light-industry buildings. In: Fanger, P.O. and Valbjørn; ed. 

Proceedings of the first international indoor climate symposium in Copenhagen Aguust 30-

September 1, 1978. Danish Building Research Institute; Copenhagen; pp. 65-87.

Anderson, H; Dally, KA; Hanrahan, L; et al. (1983) The epidemiology of mobile home 

formaldehyde vapor concentration and residents' health status. Chicago, IL: Region V. 

Available from NTIS, PB84-123504. EPA/905/1-83-001.

Andersson, M; Agurell, E; Vaghef, H, et al. (2003) Extended-term cultures of human Tlymphocytes and the comet assay: a useful combination when testing for genotoxicity in vitro? 

Mutat Res 540:43-55.

Anderson, S; Jensen, O; Oliva, D. (1982) Formaldehyde exposure and lung cancer in Danish 

doctors. Ugeskr Laeg 144:1571–1573.

Andjelkovich, DA; Janszen, DB; Brown, MH; et al. (1995) Mortality of iron foundry workers: 

IV. Analysis of a subcohort exposed to formaldehyde. J Occup Environ Med 37:826–837.

Ang, HL; Deltour, L; Zgombic-Knight, M; et al. (1996a) Expression patterns of class I and class 

IV alcohol dehydrogenase genes in developing epithelia suggest a role for alcohol 

dehydrogenase in local retinoic acid synthesis. Alcohol Clin Exp Res 20:1050–1064.
This document is a draft for review purposes only and does not constitute Agency policy.

R-3 DRAFT—DO NOT CITE OR QUOTE

Ang, HL; Deltour, L; Hayamizu, TF; et al. (1996b) Retinoic acid synthesis in mouse embryos 

during gastrulation and craniofacial development inked to class IV alcohol dehydrogenase gene 

expression. J Biol Chem 271:9526-9534.

Apfelbach, R; Reibenspies, M. (1991) Olfactory learning is inhibited after low-level 

formaldehyde gas exposure in the ferret. Chem Senses 16:498

Apfelbach, R; Weiler, E. (1991) Sensitivity to odors in Wistar rats is reduced after low-level 

formaldehyde-gas exposure. Naturwissenschaften 78:221–223.

Apfelbach, R; Reibenspies, M; Schmidt, R. (1992) The effect of long-lasting formaldehyde gas 

exposure on the olfactory epithelium and on the olfactory discrimination ability in the ferret. 

Chem Senses 17:590–591.

Appelman, LM; Woutersen, RA; Zwart, A; et al. (1988) One-year inhalation toxicity study of 

formaldehyde in male rats with a damaged or undamaged nasal mucosa. J Appl Toxicol 8:85–

90.

Armstrong, RW; Imrey, PB; Lye, MS; et al. (2000) Nasopharyngeal carcinoma in Malaysian 

Chinese: occupational exposures to particles, formaldehyde and heat. Int J Epidemiol 29:991–8.

Arts, JH; Dröge, SC; Spanhaak, S; et al. (1997) Local lymph node activation and IgE responses 

in brown Norway and Wistar rats after dermal application of sensitizing and non-sensitizing 

chemicals. Toxicology 117:229–234.

Ashby, J; Callander, RD; and Rose, FL. (1985) Weak mutagenicity to Salmonella of the 

formaldehyde-releasing anti-tumour agent hexamethylmelamine. Mutat Res 142:121-5.

Aslan, H; Songur, A; Tunc, AT; et al. (2006) Effects of formaldehyde exposure on granule cell 

number and volume of dentate gyrus: A histopathological and stereological study. Brain Res 

1122:191–200.

ASTM (American Society for Testing and Materials). (2000) Standard test method for estimating 

sensory irritancy of airborne chemicals. Annual book of ASTM standards. Designation E981 

(reapproved 2000). Philadelphia, PA: American Society for Testing of Materials. 

ATC (American Thoracic Society). (2000) What constitutes an adverse health effect of air 

pollution? Am J Respir Crit Care Med 161:665–673.

ATSDR (Agency for Toxic Substances and Disease Registry). (1999) Toxicological profile for 

formaldehyde. Public Health Service, U.S. Department of Health and Human Services, Atlanta, 

GA. Available online at http://www.atsdr.cdc.gov/toxprofiles/tp111.html.

ATSDR, 2007. An update and revision of ATSDR's February 2007 health consultation: 

Formaldehyde sampling of FEMA temporary-housing trailers; Baton Rouge, Louisiana 

September-October, 2006. Public Health Service, U.S. Department of Health and Human 

Services, Atlanta, GA. Available online at 

www.atsdr.cdc.gov/substances/formaldehyde/public_assessment.html.

Auerbach, C; Moutschen-Dahmen, M; Moutschen, J. (1977) Genetic and cytogenetical effects of 

formaldehyde and related compounds. Mutat Res 39:317–361.
This document is a draft for review purposes only and does not constitute Agency policy.

R-4 DRAFT—DO NOT CITE OR QUOTE

Axelsson, G; Lűtz, C; Rylander, R. (1984) Exposure to solvents and outcome of pregnancy in 

university laboratory employees. Br J Ind Med 41:305–312.

Baba, K; Yagi, T; Niwa, S; et al. (2000) Measurement of formaldehyde-specific IgE antibodies 

in adult asthmatics. Arerugi 49(5):404–411.

Babiuk, C; Steinhagen, WH; Barrow, CS. (1985) Sensory irritation response to inhaled 

aldehydes after formaldehyde pretreatment. Toxicol Appl Pharmacol 79:143–149.

Bach, B; Pedersen, OF; Mølhave, L. (1990) Human performance during experimental 

formaldehyde exposure. Environ Int 16:105–114.

Baird, DD; Wilcox, AJ. (1985) Cigarette smoking associated with delayed conception. J Am 

Med Assoc 253:2979-2983.

Baker, H; Kawano, T; Margolis, FL; et al. (1983) Transneuronal regulation of tyrosine 

hydroxylase expression in olfactory bulb of mouse and rat. J Neurosci 3:69–78.

Ballarin, C; Sarto, F; Giacomelli, L; et al. (1992) Micronucleated cells in nasal mucosa of 

formaldehyde-exposed workers. Mutat Res 280:1–7.

Barker, S; Weinfeld, M; Murray, D. (2005) DNA-protein crosslinks: Their induction, repair, and 

biological consequences. Mutat Res 589:111–135.

Barrow, CS; Steinhagen, WH; Chang, JCF. (1983) Formaldehyde sensory irritation. In: Gibson, 

JE; ed. Formaldehyde toxicity. Washington, DC: Hemisphere Publishing Corporation; pp. 16–

25.

Bartnik, FG; Gloxhuber, C; Zimmermann, V. (1985) Percutaneous absorption of formaldehyde 

in rats. Toxicol Lett 25:167–172.

Basecke, J; Griesinger, F; Trumper, L; et al. (2002) Leukemia- and lymphoma-associated genetic 

aberrations in healthy individuals. Ann Hematol 81:64–75.

Basler, A; v d Hude, W; and Scheutwinkel-Reich, M. (1985) Formaldehyde-induced sister 

chromatid exchanges in vitro and the influence of the exogenous metabolizing systems S9 mix 

and primary rat hepatocytes. Arch Toxicol 58:10-3.

Battelle Columbus Laboratories. (1981) Final report on a chronic inhalation toxicology study in 

rats and mice exposed to formaldehyde. Prepared by Battelle Columbus Laboratories, 

Columbus, OH for the Chemical Industry Institute of Toxicology (CIIT), Research Triangle 

Park, NC; CIIT Docket # 10922.

Bauchinger, M; Schmid, E. (1985) Cytogenetic effects in lymphocytes of formaldehyde workers 

of a paper factory. Mutat Res 158:195–199.

Beane-Freeman, LE; Blair, A; Lubin, JH; et al. (2009) Mortality from lymphohematopoietic 

malignancies among workers in formaldehyde industries: the National Cancer Institute cohort. J 

Natl Cancer Inst 101:751–761.

Beland, FA; Fullerton, NF; Heflich, RH. (1984) Rapid isolation, hydrolysis and chromatography 

of formaldehyde-modified DNA. J Chromatogr 308:121–131.
This document is a draft for review purposes only and does not constitute Agency policy.

R-5 DRAFT—DO NOT CITE OR QUOTE

Bender, JR; Mullin, LS; Graepel, GJ; et al. (1983) Eye irritation response of humans to 

formaldehyde. Am Ind Hyg Assoc J 44:463–465.

Benedetti, MS; Whomsley, R; Canning, M. (2007) Drug metabolism in the paediatric population 

and in the elderly. Drug Discov Today 12:599–610.

Berke, JH. (1987) Cytologic examination of the nasal mucosa in formaldehyde-exposed workers. 

J Occup Med 29:681–684.

Bermudez, E; Allen, PF. (1984) The assessment of DNA damage and repair in rat nasal 

epithelial cells. Carcinogenesis 5:1453–1458.

Bermudez, E; Chen, Z; Gross, EA, et al. (1994) Characterization of cell lines derived from 

formaldehyde-induced nasal tumors in rats. Mol Carcinog 9:193-199.

Bermudez, E; Delehanty, LL. (1986) The effects of in vitro formaldehyde treatment on the cells 

of the rat nasal epithelium. Environ Mutagen 8 (Suppl.6):11.

Bertazzi, PA; Pesatori, AC; Radice, L; et al. (1986) Exposure to formaldehyde and cancer 

mortality in a cohort of workers producing resins. Scand J Work Environ Health 12:461–468.

Bertazzi, PA; Pesatori, A; Guercilena, S; et al. (1989) Carcinogenic risk for resin producers 

exposed to formaldehyde: extension of follow-up. Med Lav 80:111–122.

Bhalla, DK; Mahavni, V; Nguyen, T; et al. (1991) Effects of acute exposure to formaldehyde on 

surface morphology of nasal epithelia in rats. J Toxicol Environ Health 33:171–188.

Biagini, RE; Moorman, WJ; Knecht, EA; et al. (1989) Acute airway narrowing in monkeys from 

challenge with 2.5 ppm formaldehyde generated from formalin. Arch Environ Health 44:12–17.

Bickis, M; Krewski, D. (1989) Statistical issues in the analysis of the long-term carcinogenicity 

bioassay in small rodents: An empirical evaluation of statistical decision rules. Fundam Appl 

Toxicol 12:202–221.

Binzak, BA; Vockley, JG; Jenkins, RB; et al. (2000) Structure and analysis of the human 

dimethylglycine dehydrogenase gene. Mol Genet Metab 69:181-187.

Black, KA; Eells, JT; Noker, PE; et al. (1985) Role of hepatic tetrahydrofolate in the species 

difference in methanol toxicity. Proc Natl Acad Sci USA 82:3854–3858.

Blackburn, GR; Dooley, JFI; Schreiner, CA; et al. (1991) Specific identification of 

formaldehyde-mediated mutagenicity using the mouse lymphoma L5178Y TK +/- assay 

supplemented with formaldehyde dehydrogenase. In Vitro Toxicol 4:121–132.

Blair, A; Stewart, P; O’Berg, M; et al. (1986) Mortality among industrial workers exposed to 

formaldehyde. J Natl Cancer Inst 76:1071–1084.

Blair, A; Stewart, PA; Hoover, RN; et al. (1987) Cancers of the nasopharynx and oropharynx 

and formaldehyde exposure. J Natl Cancer Inst 78:191–193.

Blair, A; Stewart, PA. (1990) Correlation between different measures of occupational exposure 

to formaldehyde, Am J Epidemiol 131:510–516.

Blair, A; Stewart, PA; Hoover, RN. (1990) Mortality from lung cancer among workers employed 

in formaldehyde industries. Am J Ind Med 17:683–699.
This document is a draft for review purposes only and does not constitute Agency policy.

R-6 DRAFT—DO NOT CITE OR QUOTE

Blair, A; Linos, A; Stewart, A; et al. (1993) Evaluation of risks for Non-Hodgkin's Lymphoma 

by occupation and industry exposures from a case-control study. Am J Ind Med 23:301–312.

Blasiak, J; Trzeciak, A; Malecka-Panas, E, et al. (2000) In vitro genotoxicity of ethanol and 

acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells. Toxicol In Vitro

14:287-295.

Blejer, HP; Miller, BH. (1966) Occupational health report of formaldehyde concentrations and 

effects on workers at the Bayly Manufacturing Company, Visalia, California. Bureau of 

Occupational Health, California Department of Public Health, Los Angeles, CA; Study No. S1806.

Bloom, B; Cohen, RA; Freeman, G. (2009) Summary health statistics for U.S. children: National 

Health Interview Survey, 2008. National Center for Health Statistics. Vital Health Stat 10(244).

Boeniger, MF. (1987) Formate in urine as a biological indicator of formaldehyde exposure: A 

review. Am Ind Hyg Assoc J 48:900–908.

Boffetta, P; Stellman, SD; Garfinkel, L. (1989) A case-control study of multiple myeloma nested 

in the American Cancer Society prospective study. Int J Cancer 43:554–559.

Bogdanffy, MS; Morgan, PH; Starr, TB; et al. (1987) Binding of formaldehyde to human and rat 

nasal mucus and bovine serum albumin. Toxicol Lett 38:145–154.

Bogdanffy, MS; Sarangapani, R; Plowchalk, DR; et al. (1999) A biologically based risk 

assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity. Toxicol Sci 

51:19–35.

Bogdanffy, MS; Plowchalk, DR; Sarangapani, R, et al. (2001) Mode of action-based dosimeters 

for interspecies extrapolation of vinyl acetate inhalation risk. Inhal Toxicol 13:377–396.

Boja, JW; Nielsen, JA; Foldvary, E; et al. (1985) Acute low-level formaldehyde behavioural and 

neurochemical toxicity in the rat. Prog Neuro-Psychopharm 9:671–674.

Bolumar, F; Olsen, J; Boldsen, J. (1996) Smoking reduces fecundity: A European multicenter 

study on fertility and subfecundity. The European study group on infertility and subfecundity. 

Am J Epidemiol 143:578–587.

Bolumar, F; Olsen, J; Boldsen, J. (1997) Smoking reduces fecundity: A European multicenter 

study on infertility and subfecundity. The European study group on infertility and subfecundity. 

Am J Epidemiol 145:81–82.

Bond, G; Flores, G; Shellenberger, R. (1986) Nested case-control study of lung cancer among 

chemical workers. Am J Epidemiol 124:53–66.

Boreiko, CJ; and Ragan, DL (1983). Formaldehyde effects in the C3H/10T1⁄2 cell transformation 

assay. In: Gibson, JE,ed, Formaldehyde toxicity, Washington, DC: Hemisphere Publishing 

Corporation, 63-71.

Bos, PMJ; Zwart, A; Reuzel, PGJ; et al. (1992) Evaluation of the sensory irritation test for the 

assessment of occupational health risk. Crit Rev Toxicol 21:423–450.

Bosetti, C; McLaughlin, JK; Tarone, RE; et al. (2008) Formaldehyde and cancer risk: a 

quantitative review of cohort studies through 2006. Annal Oncol 19:29–43.
This document is a draft for review purposes only and does not constitute Agency policy.

R-7 DRAFT—DO NOT CITE OR QUOTE

Bosworth, D; Crofton-Sleigh, C; Venitt, S. (1987) A forward mutation assay using ampicillinresistance in Escherichia coli designed for investigating the mutagenicity of biological samples. 

Mutagenesis 2:455–467.

Boysen, M; Zadig, E; Digernes, V; et al. (1990) Nasal mucosa in workers exposed to 

formaldehyde: a pilot study. Br J Ind Med 47:116–121.

Brenneman, KA; James, RA; Gross, EA; et al. (2000) Olfactory neuron loss in adult male CD 

rats following subchronic inhalation exposure to hydrogen sulfide. Toxicol Pathol 28:326–333.

Brinton, LA; Blot, W; Becker, J; et al. (1984) A case-control study of cancers of the nasal cavity 

and paranasal sinuses. Am J Epidemiol 119:896–906.

Brooks, SM. (1985) Occupational asthma. In Bronchial Asthma; Mechanism and Therapeutics. 

Second edition. Eds Weiss, EB; Segal, MS; Stein, M. Little, Brown and Co, Boston/Toronto.

Brutlag, D; Schlehuber, C; Bonner, J. (1969) Properties of formaldehyde-treated nucleohistone. 

Biochemistry 8:3214–3218.

Buckley, LA; Jiang, XZ; James, RA; et al. (1984) Respiratory tract lesions induced by sensory 

irritants at the RD50 concentration. Toxicol Appl Pharmacol 74:417–429.

Bull, RJ. (2000) Mode of action of liver tumor induction by trichloroethylene and its 

metabolites, trichloroacetate and dichloroacetate. Environ Health Perspect 108(Suppl 2):241–

259.

Burgaz, S; Çakmak, G; Erdem, O; et al. (2001) Micronuclei frequencies in exfoliated nasal 

mucosa cells from pathology and anatomy laboratory workers exposed to formaldehyde. 

Neoplasma 48:144–147.

Burgaz, S; Erdem, O; Çakmak, G; et al. (2002) Cytogenetic analysis of buccal cells from shoeworkers and pathology and anatomy laboratory workers exposed to n-hexane, toluene, methyl 

ethyl ketone and formaldehyde. Biomarkers 7:151–161.

Burge, PS; Harries, MG; Lam, WK; et al. (1985) Occupational asthma due to formaldehyde. 

Thorax 40:255–260.

Burt, RD; Vaughan, TL; McKnight, B. (1992) Descriptive epidemiology and survival analysis of 

nasopharyngeal carcinoma in the United States. Int J Cancer 52:549–556.

Buss, J; Kuschinsky, K; Kewitz, H; et al. (1964) Enteric resorption of formaldehyde. Naunyn 

Schmiedebergs Arch Pharmacol 247:380–381.

Cain, H. (2001) Bronchoprovocation testing. Clin Chest Med 22:651–659.

Cain, W; See, L; Tosun, T. (1986) Irritation and odor from formaldehyde: chamber studies. In: 

IAQ '86: Managing indoor air for health and energy conservation: proceedings of the American 

Society of Heating, Air Conditioning Engineers Conference, Atlanta, GA; pp. 126–137.

CalEPA (2008) California OEHHA. Hot Spots Guidelines. Air Toxicology and Epidemiology. 

Acute, 8-hour and Chronic Reference Exposure Levels. Appendix D. 

http://oehha.ca.gov/air/hot_spots/2008/AppendixD1_final.pdf
This document is a draft for review purposes only and does not constitute Agency policy.

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Callas, PW; Pastides, H; Hosmer, DW, Jr. (1996) Lung cancer mortality among workers in 

formaldehyde industries. J Occup Environ Med 38:747–748.

Cáp, P; Dryahina, K; Pehal, F; et al. (2008) Selected ion flow tube mass spectrometry of exhaled 

breath condensate headspace. Rapid Commun Mass Spectrom. 22(18):2844–2850.

Carraro, E; Gasparini, S; Petrini, T; et al. (1997) Immune response prevalence to formaldehydehuman serum albumin molecular adduct in a healthy population. J Environ Pathol Toxicol 

Oncol 16(2-3):215–218.

Carson, S; Goldhamer, R; Weinberg, MS. (1966) Characterization of physical, chemical and 

biological properties of mucus in the intact animal. Ann NY Acad Sci 130:935–943.

Casanova, M; Heck, HD. (1987) Further studies of the metabolic incorporation and covalent 

binding of inhaled [3H]- and [14C]formaldehyde in Fischer-344 rats: effects of glutathione 

depletion. Toxicol Appl Pharmacol 89:105-121.

Casanova, M; Heck, HD; Everitt, JI; et al. (1988) Formaldehyde concentrations in the blood of 

rhesus monkeys after inhalation exposure. Food Chem Toxicol 26:715–716.

Casanova, M; Devo, DF; Heck, HD. (1989) Covalent binding of inhaled formaldehyde to DNA 

in the nasal mucus of Fischer 344 rats: analysis of formaldehyde and DNA by high performance 

liquid chromatography and provisional pharmacokinetic interpretation. Fundam Appl Toxicol 

12:397–417.

Casanova, M; Morgan, KT; Steinhagen, WH; et al. (1991) Covalent binding of inhaled 

formaldehyde to DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, rat-tomonkey interspecies scaling, and extrapolation to man. Fundam Appl Toxicol 17:409–428.

Casanova, M; Morgan, KT; Gross, EA; et al. (1994) DNA-protein cross-links and cell 

replication at specific sites in the nose of F344 rats exposed subchronically to formaldehyde. 

Fundam Appl Toxicol 23:525–536.

Casanova, M; Bell, DA; and Heck, HD. (1997) Dichloromethane metabolism to formaldehyde 

and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with and 

without glutathione S-transferase T1 and M1 genes. Fundam Appl Toxicol 37:168-180.

Casanova, M; and Heck, HA. (1997) Lack of evidence for the involvement of formaldehyde in 

the hepatocarcinogenicity of methyl tertiary-butyl ether in CD-1 mice. Chem Biol Interact 

105:131-143.

Casanova, M; Cole, P; Collins, JJ; et al. (2004) Re: mortality from lymphohematopoietic 

malignancies among workers in formaldehyde industries. J Natl Cancer Inst 96:966–967.

Casanova-Schmitz, M; Heck, HD. (1983) Effects of formaldehyde exposure on the extractability 

of DNA from proteins in the rat nasal mucosa. Toxicol Appl Pharmacol 70:121–132.

Casanova-Schmitz, M; David, RM; Heck, HD. (1984a) Oxidation of formaldehyde and 

acetaldehyde by NAD+-dependent dehydrogenases in rat nasal mucosal homogenates. Biochem 

Pharmacol 33:1137–1142.
This document is a draft for review purposes only and does not constitute Agency policy.

R-9 DRAFT—DO NOT CITE OR QUOTE

Casanova-Schmitz, M; Starr, TB; Heck, HD. (1984b) Differentiation between metabolic 

incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa 

and bone marrow by inhaled [14C]- and [3H]-formaldehyde. Toxicol Appl Pharmacol 76:26–44.

Cascieri, T; Clary, JJ. (1992) Formaldehyde--oral toxicity assessment. Comments Toxicol 

4:295–304.

Cassee, FR; Arts, JH; Groten, JP; et al. (1996) Sensory irritation to mixtures of formaldehyde, 

acrolein, and acetaldehyde in rats. Arch Toxicol 70:329–337.

Cassee, FR; Feron, VJ. (1994) Biochemical and histopathological changes in nasal epithelium of 

rats after 3-day intermittent exposure to formaldehyde and ozone alone or in combination. 

Toxicol Lett 72:257–268.

Cassee, FR; Groten, JP; Feron, VJ. (1996) Changes in the nasal epithelium of rats exposed by 

inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundam Appl Toxicol 

29:208–218.

Casset, A; Purohit, A; Marchand, C; et al. (2006) The bronchial response to inhaled 

formaldehyde. Rev Mal Respir 23(1 Suppl):3S25–3S34.

Cassidy, SL; Dix, KM; Jenkins, T. (1983) Evaluation of a testicular sperm head counting 

technique using rats exposed to dimethoxyethyl phthalate (DMEP), glycerol alphamonochlorohydrin (GMCH), epichlorohydrin (ECH), formaldehyde (FA), or methyl 

methanesulphonate (MMS). Arch Toxicol 53:71–78.

Castonguay, A; Pepin, P; Briere, N. (1991) Modulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1 

butanone demethylation and denitrosation by rat liver microsomes. Cancer Lett 59:67-74.

CDC (U.S. Centers for Disease Control and Prevention). (2000) Measuring childhood asthma 

prevalence before and after the 1997 redesign of the National Health Interview Survey -- United 

States. MMWR 49:908–911.

CDC. (2008) Final report on formaldehyde levels in FEMA-supplied travel trailers, park 

models, and mobile homes. Available from 

http://www.cdc.gov/nceh/ehhe/trailerstudy/residents.htm#final.

Ceder, R; Merne, M; Staab, C; et al. (2007) The application of normal, SV40 T-antigenimmortalized and tumour-derived oral keratinocytes, under serum-free conditions, to the study of 

the probability of cancer progression as a result of environmental exposure to chemicals. 

Alternatives to Laboratory Animals 35:621–639.

Cederbaum, AI; Qureshi, A. (1982) Role of catalase and hydroxyl radicals in the oxidation of 

methanol by rat liver microsomes. Biochem Pharmacol 31:329-335. 

Chang, JC; Barrow, CS. (1984) Sensory irritation tolerance and cross-tolerance in F-344 rats 

exposed to chlorine or formaldehyde gas. Toxicol Appl Pharmacol 76:319–327.

Chang, JC; Steinhagen, WH; Barrow, CS. (1981) Effect of single or repeated formaldehyde 

exposure on minute volume of B6C3F1 mice and F-344 rats. Toxicol Appl Pharmacol 61:451–

459.
This document is a draft for review purposes only and does not constitute Agency policy.

R-10 DRAFT—DO NOT CITE OR QUOTE

Chang, JC; Gross, EA; Swenberg, JA; et al. (1983) Nasal cavity deposition, histopathology, and 

cell proliferation after single or repeated formaldehyde exposures in B6C3F1 mice and F-344 

rats. Toxicol Appl Pharmacol 68:161-176.

Chebotarev, AN; Titenko, NV; Selezneva, TG, et al. (1986) [Comparison of chromosome 

aberrations, sister chromatid exchanges and unscheduled DNA synthesis in the evaluation of the 

mutagenicity of environmental factors]. Tsitol Genet 20:109-115.

Cheng, YS; Hansen, GK; Su, FY; et al. (1990) Deposition of ultrafine aerosols in rat nasal 

molds. Toxicol Appl Pharmacol 106:222–233.

Cheng, G; Shi, Y; Sturla, SJ; et al. (2003) Reactions of formaldehyde plus acetaldehyde with 

deoxyguanosine and DNA: formation of cyclic deoxyguanosine adducts and formaldehyde 

cross-links. Chem Res Toxicol 16:145–152.

Cheng, XM; Zhao, J; Feng, B; et al. (2008) Relationship between susceptibility of formaldehyde 

metabolism and genetic polymorphisms of ALD2 and cytochrome P4502E1. Zhonghua Yu Fang 

Yi Xue Za Zhi 42:582–587.

Cheng, G; Wang, M; Upadhyaya, P, et al. (2008) Formation of formaldehyde adducts in the 

reactions of DNA and deoxyribonucleosides with alpha-acetates of 4-(methylnitrosamino)-1-(3-

pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and Nnitrosodimethylamine (NDMA). Chem Res Toxicol 21:746-751.

Chernoff, N; Kavlock, RJ. (1982) An in vivo teratology screen utilizing pregnant mice. J 

Toxicol Environ Health 10:541–550.

Cho, JY; Min, N; Franzen, L; et al. (1996) Rapid down-regulation of tyrosine hydroxylase 

expression in the olfactory bulb of naris-occluded adult rats. J Comp Neurol 369:264–276.

Chowdhury, AR; Gautam, AK; Patel, KG; et al. (1992) Steroidogenic inhibition in testicular 

tissue of formaldehyde exposed rats. Ind J Physiol Pharmacol 36:162–168.

CIIT (Chemical Industry Institute of Toxicology). (1982) Summary of final report on 

formaldehyde study. CIIT Activities 2:1, 9–10.

CIIT. (1999) Formaldehyde: Hazard characterization and dose-response assessment for 

carcinogenicity by the route of inhalation (Revised Edition). Research Triangle Park, NC: 

Chemical Industry Institute of Toxicology.

Claeys, S; Cuvelier, C; Quatacker, J; et al. (1996a) Ultrastructural investigation of M-cells and 

lymphoepithelial contacts in naso-pharangeal associated lymphoid tissue (NALT). Acta 

Otolaryngeal Supple 523:40–42.

Claeys, S; Cuvelier, C; Van Cauwenberge, P. (1996b) Immunohistochemical analyses of the 

lymphoepithelium in human nasopharyngeal associated lymphoid tissue (NALT) Acta 

Otolaryngol Suppl 523:38–39.

Coggon, D; Pannett, B; Acheson, ED. (1984) Use of job-exposure matrix in an occupational 

analysis of lung and bladder cancers on the basis of death certificates. J Natl Cancer Inst 

72(1):61–65.
This document is a draft for review purposes only and does not constitute Agency policy.

R-11 DRAFT—DO NOT CITE OR QUOTE

Coggon, D; Harris, EC; Poole, J; et al. (2003) Extended follow-up of a cohort of British 

chemical workers exposed to formaldehyde. J Natl Cancer Inst 95:1608–1615.

Cohen-Hubal, EA; Schlosser, PM; Conolly, RB; et al. (1997) Comparison of inhaled 

formaldehyde dosimetry predictions with DNA-protein cross-link measurements in the rat nasal 

passages. Toxicol Appl Pharmacol 143:47-55.

Cole, P; Axten, C. (2004) Formaldehyde and leukemia: an improbable causal relationship. 

Regul Toxicol Pharmacol 40:107–112.

Collins, JJ. (2004) Formaldehyde exposure and leukemia. Occup Environ Med 61:875–876.

Collins, JJ; Lineker, GA. (2004) A review and meta-analysis of formaldehyde exposure and 

leukemia. Regul Toxicol Pharmacol 40:81–91.

Collins, JJ; Acquavella, JF; Esmen, NA. (1997) An updated analysis of formaldehyde exposure 

and upper respiratory tract cancers. J Occup Environ Med 39: 639–651.

Collins, JJ; Esmen, NA; Hall, TA. (2001a) A review and meta-analysis of formaldehyde 

exposure and pancreatic cancer. Am J Ind Med 39:336–345.

Collins, JJ; Ness, R; Tyl, RW; et al. (2001b) A review of adverse pregnancy outcomes and 

formaldehyde exposure in human and animal studies. Regul Toxicol Pharmacol 34:17–34.

Cometto-Muňiz, JE; Cain, WS. (1992) Sensory irritation. Relation to indoor air pollution. Ann 

NY Acad Sci 641:137–151.

Conaway, CC; Whysner, J; Verna, LK, et al. (1996) Formaldehyde mechanistic data and risk 

assessment: endogenous protection from DNA adduct formation. Pharmacol Ther 71:29-55.

Connor, TH; Barrie, MD; Theiss, JC; et al. (1983) Mutagenicity of formalin in the Ames assay. 

Mutat Res 119:145-149.

Connor, TH; Theiss, JC; Hanna, HA; et al. (1985) Genotoxicity of organic chemicals frequently 

found in the air of mobile homes. Toxicol Lett 25:33–40.

Conolly, RB, (1995) Cancer and non-cancer risk assessment: Not so different if you consider 

mechanisms. Toxicology 102:179–188.

Conolly, RB. (2002) The use of biologically based modeling in risk assessment. Toxicology 

181–182:275–279.

Conolly, RB. (2009) Commentary on “Toxicity testing in the 21st century: Implications for 

human health risk assessment” by Krewski et al. Risk Anal 29:480–481.

Conolly, RB; Lutz, WK. (2004) Nonmonotonic dose-response relationships: Mechanistic basis, 

kinetic modeling, and implications for risk assessment. Toxicol Sci 77:151–157.

Conolly, RB; Lilly, PD; Kimbell, JS. (2000) Simulation modeling of the tissue disposition of 

formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and 

humans. Environ Health Perspect 108 Suppl 5:919–924.

Conolly, RB; Kimbell, JS; Janszen, D; et al. (2003) Biologically motivated computational 

modeling of formaldehyde carcinogenicity in the F344 rat. Toxicol Sci 75:432–447.
This document is a draft for review purposes only and does not constitute Agency policy.

R-12 DRAFT—DO NOT CITE OR QUOTE

Conolly, RB; Kimbell, JS; Janszen, D; et al. (2004) Human respiratory tract cancer risks of 

inhaled formaldehyde: dose-response predictions derived from biologically-motivated 

computational modeling of a combined rodent and human dataset. Toxicol Sci 82:279–296.

Conolly, RB; Miller, FJ; Kimbell, JS; et al. (2009) Formaldehyde risk assessment. Ann Hyg 

53:181–184.

Cook, RJ; Champion, KM; Giometti, CS. (2001) Methanol toxicity and formate oxidation in 

NEUT2 mice. Arch Biochem Biophys 393:192–198.

Coon, RA; Jones, RA; Jenkins, LJ, Jr; et al. (1970) Animal inhalation studies on ammonia, 

ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol Appl Pharmacol 16:646–

655.

Correa, A; Gray, RH; Cohen, R; et al. (1996) Ethylene glycol ethers and risks of spontaneous 

abortion and subfertility. Am J Epidemiol 143:707–717.

Cosma, GN; Marchok, AC. (1988) Benzo[a]pyrene- and formaldehyde-induced DNA damage 

and repair in rat tracheal epithelial cells. Toxicology 51:309–320.

Cosma, GN; Jamasbi, R; Marchok, AC. (1988) Growth inhibition and DNA damage induced by 

benzo[a]pyrene and formaldehyde in primary cultures of rat tracheal epithelial cells. Mutat Res 

201:161–168.

Cosma, GN; Wilhite, AS; and Marchok, AC. (1988) The detection of DNA-protein cross-links 

in rat tracheal implants exposed in vivo to benzo[a]pyrene and formaldehyde. Cancer Lett 42:13-

21.

Costa, M; Zhitkovich, A; Harris, M; et al. (1997) DNA-protein cross-links produced by various 

chemicals in cultured human lymphoma cells. J Toxicol Environ Health 50:433–449.

Costa, S; Coelho, P; Costa, C, et al. (2008) Genotoxic damage in pathology anatomy laboratory 

workers exposed to formaldehyde. Toxicology 252:40–48.

Coste, A; Rateau, JG; Roudot-Thoraval, F; et al. (1996) Increased epithelial cell proliferation in 

nasal polyps. Arch Otol Head Neck Surg 122:432–436.

Couch, DB; Allen, PF; and Eales, HC. (1982) The mutagenicity of formaldehyde to Salmonella 

typhimurium [Abstract]. Environ Mutagen 4:336-337.

Cox, DR. (1972) Regression models and life tables (with discussion). J Roy Stat Soc (Series B) 

34:187–220. (as cited in Battelle Columbus Laboratories [1981]).

Cox, D; Hinkley, D. (1974) Theoretical Statistics. Chapman and Hall, London, UK.

Cox, D; Oakes, D. (1984) Analysis of Survival Data. Chapman and Hall, London, UK.

Craft, TR; Bermudez, E; Skopek, TR. (1987) Formaldehyde mutagenesis and formation of DNAprotein crosslinks in human lymphoblasts in vitro. Mutat Res 176:147–155.

Cralley, LV. (1942) The effect of irritant gases upon the rate of ciliary activity. J Ind Hyg 

Toxicol 24:193–198.

Crosby, RM; Richardson, KK; Craft, TR; et al. (1988) Molecular analysis of formaldehydeinduced mutations in human lymphoblasts and E. coli. Environ Mol Mutagen 12:155–166.
This document is a draft for review purposes only and does not constitute Agency policy.

R-13 DRAFT—DO NOT CITE OR QUOTE

Crump, KS. (1994a) Limitations of biological models of carcinogenesis for low-dose 

extrapolation. Risk Anal 14:883–886.

Crump, KS. (1994b) Use of mechanistic models to estimate low-dose cancer risks. Risk Anal 

14:1033–1038.

Crump, K. (2002) Benchmark analysis. In: Encyclopedia of Environmetrics. Eds: El-Shaarawi, 

A; Piegorsch, WW. Wiley, West Sussex, UK.

Crump, KS; Subramaniam, RP; Van Landingham, C. (2005) A numerical solution to the nonhomogenous two-stage MVK model of cancer. Risk Anal 25:921–926.

Crump, K; Subramanian, RP; Van Landingham, C. (2006) Acknowledgment of prior solution to 

MVK cancer model. Risk Anal 26:3–4.

Crump, KS; Chen, C; Fox, JF; et al. (2008) Sensitivity analysis of biologically motivated model 

for formaldehyde-induced respiratory cancer in humans. Ann Occup Hyg 52:481–495.

Crump, KS; Chen, C; Fox, JF; et al. (2009) Reply to Conolly et al. (2009) Ann Hyg 53:184–

189.

Dahl, AR; Hadley, WM. (1983) Formaldehyde production promoted by rat nasal cytochrome P450-dependent monooxygenases with nasal decongestants, essences, solvents, air pollutants, 

nicotine, and cocaine as substrates. Toxicol Appl Pharmacol 67:200-205. 

Dalbey, WE. (1982) Formaldehyde and tumors in hamster respiratory tract. Toxicology 24:9–

14.

Dalhamn, T. (1956) Mucus flow and ciliary activity in the trachea of healthy rats and rats 

exposed to respiratory irritant gases (SO2, H3N, HCHO): a functional and morphologic (light

microscopy and electron microscopy) study, with special reference to technique. Acta Physiol 

Scand 36(Suppl):1–161.

Dallas, CE; Badeaux, P; Theiss, JC; et al. (1989) The influence of inhaled formaldehyde on rat 

lung cytochrome P450. Environ Res 49:50–59.

Dallas, CE; Scott, MJ; Ward, JB, Jr.; et al. (1992) Cytogenetic analysis of pulmonary lavage and 

bone marrow cells of rats after repeated formaldehyde inhalation. J Appl Toxicol 12:199–203.

Dally, K; Hanrahan, L; Woodbury, M; et al. (1981) Formaldehyde exposure in nonoccupational 

environments. Arch Environ Health 36(6):277–284.

Dalton, P. (2003) Upper airway irritation, odor perception and health risk due to airborne 

chemicals. Toxicol Lett 140–141:239–248.

Dasgupta PK, J Li, G Zhang, WT Luke, WA McClenny, J Stutz and A Fried. Summertime 

ambient formaldyde in five U.S. metropolitan areas: Nashville, Atlanta, Houston, Philadelphia 

and Tampa. Environ Sci Technol 39:4767-4783.

Daston, GP. (2008) Gene expression, dose-response, and phenotypic anchoring: Applications for 

toxicogenomics in risk assessment. Toxicol Sci 105:233–234.

Day, JH; Lees, RE; Clark, RH; et al. (1984) Respiratory response to formaldehyde and off-gas of 

urea formaldehyde foam insulation. Can Med Assoc J 131:1061–1065.
This document is a draft for review purposes only and does not constitute Agency policy.

R-14 DRAFT—DO NOT CITE OR QUOTE

De Ceaurriz, JC; Micillino, JC; Bonnet, P; et al. (1981) Sensory irritation caused by various 

industrial airborne chemicals. Toxicol Lett 9:137–143.

De Flora, S. (1981) Study of 106 organic and inorganic compounds in the Salmonella/microsome 

test. Carcinogenesis 2:283-98.

de Flora, S; Camoirano, A; Zanacchi, P, et al. (1984) Mutagenicity testing with TA97 and 

TA102 of 30 DNA-damaging compounds, negative with other Salmonella strains. Mutat Res 

134:159-165.

De Stefani, E; Boffetta, P; Brennan, P; et al. (2005) Occupational exposures and risk of 

adenocarcinoma of the lung in Uruguay. Cancer Causes and Control 16:851–856.

Dean, JH; Lauer, LD; House, RV; et al. (1984) Studies of immune function and host resistance 

in B6C3F1 mice exposed to formaldehyde. Toxicol Appl Pharmacol 72:519–529.

Dearman, RJ; Humphreys, N; Skinner, RA; et al. (2005) Allergen-induced cytokine phenotypes 

in mice: role of CD4 and CD8 T cell populations. Clin Exp Allergy 35:498–505.

Degitz, SJ; Zucker, RM; Kawanishi, CY; et al. (2004a) Pathogenesis of methanol-induced 

cranofacial defects in C57BL/6J mice. Birth Defects A Clin Mol Teratol 70:172–178.

Degitz, SJ; Rogers, JM; Zucker, RM; et al. (2004b) Developmental toxicity of methanol: 

Pathogenesis in CD-1 and C57BL/6J mice exposed in whole embryo culture. Birth Defects Res 

A Clin Mol Teratol. 70(4):179–184.

Delfino, RJ. (2002) Epidemiologic evidence for asthma and exposure to air toxics: linkages 

between occupational, indoor, and community air pollution research. Environ Health Perspect 

110 Suppl 4:573–589.

Delfino, RJ; Gong, H Jr; Linn, WS; et al. (2003) Asthma symptoms in Hispanic children and 

daily ambient exposures to toxic and criteria air pollutants. Environ Health Perspect 111:647–

656.

Dell, L; Teta, MJ. (1995) Mortality among workers at a plastics manufacturing and research and 

development facility: 1946-1988. Am J Ind Med 28:373–384.

Deltour, L; Foglio, MH; Duester, G. (1999) Metabolic deficiencies in alcohol dehydrogenase 

Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol 

clearance and metabolism of retinol to retinoic acid. J Biol Chem 274:16796–16801.

Demkowicz-Dobrzanski, K; and Castonguay, A. (1992) Modulation by glutathione of DNA 

strand breaks induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its aldehyde 

metabolites in rat hepatocytes. Carcinogenesis 13:1447-1454.

Dicker, E; Cederbaum, AI. (1986) Inhibition of the low-Km mitochondrial aldehyde 

dehydrogenase by diethyl maleate and phorone in vivo and in vitro. Implications for 

formaldehyde metabolism. Biochem J 240:821–827.

Dikalova, AE; Kadiiska, MB; Mason, RP. (2001) An in vivo ESR spin-trapping study: free 

radical generation in rats from formate intoxication--role of the Fenton reaction. Proc Natl Acad 

Sci USA 98:13549–13553.
This document is a draft for review purposes only and does not constitute Agency policy.

R-15 DRAFT—DO NOT CITE OR QUOTE

Dillon, D; Combes, R; Zeiger, E. (1998) The effectiveness of Salmonella strains TA100, TA102 

and TA104 for detecting mutagenicity of some aldehydes and peroxides. Mutagenesis 13:19–26.

Dinsdale, D; Riley, RA; Verschoyle, RD. (1993) Pulmonary cytochrome P450 in rats exposed to 

formaldehyde vapor. Environ Res 62:19–27.

Doenecke, D. (1978) Digestion of chromosomal proteins in formaldehyde treated chromatin. 

Hoppe Seylers Z Physiol Chem 359:1343–1352.

Doi, S; Suzuki, S; Morishita, M; et al. (2003) The prevalence of IgE sensitization to 

formaldehyde in asthmatic children. Allergy 58(7):668–671.

Doll, R; Peto, R. (1978) Cigarette smoking and bronchial carcinoma: Dose and time 

relationships among regular smoker and lifetime nonsmokers. J Epidem Commun Health 

32:303–313.

Donovan, SM; Krahn, DF; Stewart, JA; et al. (1983) Mutagenic activities of formaldehyde 

(HCHO) and hexamethylphosphoramide (HMPA) in reverse and forward Salmonella 

typhimurium mutation assays. Environ Mutagen 5:476.

Doolittle, DJ; Furlong, JW; and Butterworth, BE. (1985) Assessment of chemically induced 

DNA repair in primary cultures of human bronchial epithelial cells. Toxicol Appl Pharmacol 

79:28-38.

Doty, RL; Cometto-Muňiz, JE; Jalowayski, AA; et al. (2004) Assessment of upper respiratory 

tract and ocular irritative effects of volatile chemicals in humans. Crit Rev Toxicol 34:85–142.

Dragan, YP; Hully, J; Baker, K; et al. (1995) Comparison of experimental and theoretical 

parameters of the Moolgavkar-Venzon-Knudson incidence function for the stages of initiation 

and promotion in rat hepatocarcinogenesis. Toxicology 102:161–175.

Dresp, J; and Bauchinger, M. (1988) Direct analysis of the clastogenic effect of formaldehyde in 

unstimulated human lymphocytes by means of the premature chromosome condensation 

technique. Mutat Res 204:349-352.

Dubreuil, A; Bouley, G; Godin, J; et al. (1976) Continuous inhalation of small amounts of 

formaldehyde: experimental study in the rat. Eur J Toxicol Environ Hyg 9:245–250.

Dulskienė, V; Gražulevičienė, R. (2005) Environmental risk factors and outdoor formaldehyde 

and risk of congenital heart malformations. Medicina (Kaunas) 41:787–795.

Dykewicz, M; Patterson, R; Cugell, DW; et al. (1991) Serum IgE and IgG to formaldehydehuman serum albumin lack of relation to gaseous formaldehyde exposure and symptoms. J 

Allergy Clin Immunol 87:48–57.

Edling, C; Jarvholm, B; Andersson, L; et al. (1987) Mortality and cancer incidence among 

workers in an abrasive manufacturing industry. Br J Ind Med 44:57–59.

Edling, C; Hellquist, H; Ödkvist, L. (1988) Occupational exposure to formaldehyde and 

histopathological changes in the nasal mucosa. Br J Ind Med 45:761–765.

Egle, JL, Jr. (1972) Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the 

dog. Arch Environ Health 25:119–124.
This document is a draft for review purposes only and does not constitute Agency policy.

R-16 DRAFT—DO NOT CITE OR QUOTE

Ehlers, CL. (2007) Variations in ADH and ALDH in Southwest California Indians. Alcohol Res 

Health 30:14–17.

Emri, G; Schaefer, D; Held, B; et al. (2004) Low concentrations of formaldehyde induce DNA 

damage and delay DNA repair after UV irradiation in human skin cells. Exp Dermatol 13:305–

315.

Environment California. (2008) New Report: Formaldehyde from baby nursery furniture 

contaminates indoor air Californis’s green chemistry initative can protect consumers. Available 

at http://www.environmentcalifornia.org/newsroom/environmental-health/environmentalhealth/new-report-formaldehyde-from-baby-nursery-furniture-contaminates-indoor-air.

Epstein, S.S.; Shafner, H. (1968) Chemical mutagens in human environment. Nature 219: 385.

Epstein, S.S. et al (1972) Detection of chemical mutagens by the dominant lethal assay in the 

mosue. Toxicol. Appl. Pharmacol. 23:288.

Erdei, E; Bobvos, J; Brózik, M; et al. (2003) Indoor air pollutants and immune biomarkers 

among Hungarian asthmatic children. Arch Environ Health 58:337–347.

Estonius, M; Svensson, S; Höög, JO. (1996) Alcohol dehydrogenase in human tissues: 

localization of transcript coding for five classes of the enzyme. FEBS Lett 397:338–342.

Ezratty, V; Bonay, M; Neukirch, C; et al. (2007) Effect of formaldehyde on asthmatic response 

to inhaled allergen challenge. Environ Health Perspect 115(2):210–214.

Fanucchi, MV; Buckpitt, AR; Murphy, ME; et al. (1997) Naphthalene cytotoxicity of 

differentiating Clara cells in neonatal mice. Toxicol Appl Pharmacol 144:96–104.

Fanucchi, MV; Buckpitt, AR; Murphy, ME; et al. (2000) Development of phase II xenobiotic 

metabolizing enzymes in differentiating murine Clara cells. Toxicol Appl Pharmacol 168:253–

267.

Fanucchi, MV; Day, KC; Clay, CC; et al. (2004) Increased vulnerability of neonatal rats and 

mice to 1-nitronaphthalene-induced pulmonary injury. Toxicol Appl Pharmacol 201:53–65.

Farooqui, MY; Upreti, RK; Ahmed, AE; et al. (1986) Influence of intraperitoneally administered 

formaldehyde on bile production and tissue glutathione levels in rats. Res Commun Chem 

Pathol Pharmacol 53:233–236.

Fayerweather, WE; Pell, S; Bender, J. (1983) Case-control study of cancer deaths in DuPont 

workers with potential exposure to formaldehyde. In: Clary, J; Gibson, J; Waritz, RS; eds. 

Formaldehyde: toxicology, epidemiology, and mechanisms. New York: Marcel Dekker; pp. 47–

121.

Fennell, TR. (1994) Development of methods for measuring biological markers of formaldehyde 

exposure. Res Rep Health Eff Inst:1–20; discussion 21–26.

Fernandez, MR; Biosca, JA; Pares, X. (2003) S-nitrosoglutathione reductase activity of human 

and yeast glutathione-dependent formaldehyde dehydrogenase and its nuclear and cytoplasmic 

localization. Cell Mol Life Sci 60:1013–1018.
This document is a draft for review purposes only and does not constitute Agency policy.

R-17 DRAFT—DO NOT CITE OR QUOTE

Feron, VJ; Woutersen, RA; Appelman, LM. (1984) Epithelial damage and tumours of the nose 

after exposure to four different aldehydes by inhalation. In: Grosdanoff, P; Bass, R; 

Hackenberg, U; et al.; eds. Problems of inhalation toxicity studies. Munich: MMV Medizin 

Verlag; pp. 587–610.

Feron, VJ; Bruyntjes, JP; Woutersen, RA; et al. (1988) Nasal tumours in rats after short-term 

exposure to a cytotoxic concentration of formaldehyde. Cancer Lett 39:101–111.

Feron, VJ; Wilmer, JW; Woutersen, RA; et al. (1989) Inhalation toxicity and carcinogenicity of 

formaldehyde in animals: significance for assessment of human health risk. In: Bates, D; 

Dungworth, DL; Lee, P; et al.; eds. Assessment of inhalation hazards: integration and 

extrapolation using diverse data. Berlin: Springer-Verlag; pp. 131–138.

Feron, VJ; Til, HP; de Vrijer, F; et al. (1991) Aldehydes: occurrence, carcinogenic potential, 

mechanism of action and risk assessment. Mutat Res 259:363–385.

Feron, VJ; Arts, JH; Kuper, CF; et al. (2001) Health risks associated with inhaled nasal 

toxicants. Crit Rev Toxicol 31:313–347.

Fiddler, W; Miller, AJ; Pensabene, JW; et al. (1984) Investigation on the mutagenicity of Nnitrosothiazolidine using the Ames Salmonella test. IARC Sci Publ:95–100.

Figuero, WG; Raszkowski, R; Weiss, W. (1973) Lung cancer in chloromethyl ether workers. N 

Engl J Med 288:1096–1097.

Fireman, P. (2003) Understanding asthma pathophysiology. Allergy Asthma Proc 24:79–83.

Fishbein, L. (1992) Exposure from occupational versus other sources. Scand J Work Environ 

Health 18(Suppl 1):5-16.

Fleig, I; Petri, N; Stocker, WG; et al. (1982) Cytogenetic analyses of blood lymphocytes of 

workers exposed to formaldehyde in formaldehyde manufacturing and processing. J Occup Med 

24:1009–1012.

Fleisher, J. (1987) Medical students' exposure to formaldehyde in gross anatomy laboratories. N 

Y State J Med 87(7):385–388.

Fló-Neyret, C; Lorenzl-Filho, G; Macchione, M; et al. (2001) Effects of formaldehyde on the 

frog’s mucociliary epithelium as a surrogate to evaluate air pollution effects on the respiratory 

epithelium. J Med Bil Res 34:639–643.

Fontignie-Houbrechts, N. (1981) Genetic effects of formaldehyde in the mouse. Mutat Res 

88:109–114.

Fontignie-Houbrechts, N; Moutschen-Dahmen, M; Degraeve, N; et al. (1982) Genetic effects in 

the mouse of formaldehyde in combination with adenosine and hydrogen peroxide. Mutat Res 

104:371–376.

Fornace, AJ, Jr. (1982) Detection of DNA single-strand breaks produced during the repair of 

damage by DNA-protein cross-linking agents. Cancer Res 42:145-149.

Franklin, P; Dingle, P; Stick, S. (2000) Raised exhaled nitric oxide in healthy children is 

associated with domestic formaldehyde levels. Am J Respir Crit Care Med 161:1757–1759.
This document is a draft for review purposes only and does not constitute Agency policy.

R-18 DRAFT—DO NOT CITE OR QUOTE

Franks, SJ. (2005) A mathematical model for the absorption and metabolism of formaldehyde 

vapour in humans. Toxicol Appl Pharmacol 206:309–320.

Fransman, W; McLean, D; Douwes, J; et al. (2003) Respiratory symptoms and occupational 

exposures in New Zealand plywood mill workers. Ann Occup Hyg 47(4):287–295.

Frazelle, JH; Abernethy, DJ; and Boreiko, CJ. (1983) Weak promotion of C3H/10T1/2 cell 

transformation by repeated treatments with formaldehyde. Cancer Res 43:3236-3239.

Frei, E; Pool, BL; Plesch, W; et al. (1984) Biochemical and biological properties of prospective 

N-nitrodialkylamine metabolites and their derivatives. IARC Sci Publ:491–497.

Friedman, GD; Ury, HK. (1983) Screening for possible drug carcinogenicity: second report of 

findings. J Natl Cancer Inst 71:1165–1175.

Frigas, E; Filley, WV; Reed, CE. (1984) Bronchial challenge with formaldehyde gas: lack of 

bronchoconstriction in 13 patients suspected of having formaldehyde-induced asthma. Mayo 

Clin Proc 59:295–299.

Fujimaki, H; Kurokawa, Y; Kunugita, N; et al. (2004a) Differential immunogenic and 

neurogenic inflammatory responses in an allergic mouse model exposed to low levels of 

formaldehyde. Toxicology 197:1–13.

Fujimaki, H; Kurokawa, Y; Kakeyama, M; et al. (2004b) Inhalation of low-level formaldehyde 

enhances nerve growth factor production in the hippocampus of mice. Neuroimmunomodulation 

11:373–375.

Fujimura, Y. (2000) Evidence of M cells as portals of entry for antigens in the nasopharyngeal 

lymphoid tissue of humans. Virchows Arch 436:560–566.

Galloway, SM; Bloom, AD; Resnick, M, et al. (1985) Development of a standard protocol for in 

vitro cytogenetic testing with Chinese hamster ovary cells: comparison of results for 22 

compounds in two laboratories. Environ Mutagen 7:1-51.

Galter, D; Carmine, A; Buervenich, S; et al. (2003) Distribution of class I, III and IV alcohol 

dehydrogenase mRNAs in the adult rat, mouse and human brain. Eur J Biochem 270:1316–

1326.

Gandhi, M; Aweeka, F; Greenblatt, RM; et al. (2004) Sex differences in pharmacokinetics and 

pharmaco-dynamics Ann Rev Pharmacol Toxicol 44:499–523.

Garcia, CL; Mechilli, M; De Santis, LP, et al. (2009) Relationship between DNA lesions, DNA 

repair and chromosomal damage induced by acetaldehyde. Mutat Res 662:3-9.

Garcia, GJ; Schroeter, JD; Segal, RA; et al. (2009) Dosimetry of nasal uptake of water-soluble 

and reactive gases: a first study of interhuman variability. Inhal Toxicol. 21(7):607-18.

Gardner, MJ; Pannett, B; Winter, PD; et al. (1993) A cohort study of workers exposed to 

formaldehyde in the British chemical industry: an update. Br J Ind Med 50:827–834.

Gardner, RJ; Burgess, BA; Kennedy, GL, Jr. (1985) Sensory irritation potential of selected nasal 

tumorigens in the rat. Food Chem Toxicol 23:87–92.
This document is a draft for review purposes only and does not constitute Agency policy.

R-19 DRAFT—DO NOT CITE OR QUOTE

Garrett, MH; Hooper, MA; Hooper, BM; et al. (1999) Increased risk of allergy in children due to 

formaldehyde exposure in homes. Allergy 34:330–337.

Garry, VF; Kreiger, RA; and Wiencke, JK. (1981) The mutagenic and cytotoxic effects of 

formaldehyde in cultured human lymphocytes [Abstract]. Environ Mutagen 3:341.

Gart, JJ; Krewski, D; Lee, PN; et al. (1986) Statistical methods in cancer research. Volume III--

The design and analysis of long-term animal experiments. IARC Sci Publ (79):1–219.

Gaylor, DW; Zheng, O. (1996) Risk assessment of nongenotoxic carcinogens based upon cell 

proliferation/death rates in rodents. Risk Anal 16:221–225.

Gaylor, DW; Lutz, WK; Conolly, RB. (2004) Statistical analysis of nonmonotonic dose-response 

relationships: Research design and analysis of nasal cell proliferation in rats exposed to 

formaldehyde. Toxicol Sci 77:158–164.

Gee, IL; Watson, AFR; Tavernier, G; et al. (2005) Indoor air quality, environmental tobacco 

smoke and asthma: A case control study of asthma in a community population. Indoor Built 

Environ 14(3-4):215–219.

Georgieva, AV; Kimbell, JS; Schlosser, PM. (2003) A distributed-parameter model for 

formaldehyde uptake and disposition in the rat nasal lining. Inhal Toxicol 15:1435–1463.

Gerard, C. (2005) Biomedicine. Asthmatics breathe easier when its SNO-ing. Science 

308:1560–1561.

Gerberich, HR; Seaman, GC. (1994) Formaldehyde. In: Kroshwitz, JI; Howe-Grant, M; eds. 

Kirk-Othmer encyclopedia of chemical technology. Vol. 11. 4th edition. New York, NY: John 

Wiley and Sons; pp. 929–951.

Gerde, P; Cheng, YS; Medinsky, MA. (1991) In vitro deposition of ultrafine aerosols in the nasal 

airways of the rat. Fundam Appl Toxicol 16:330–336.

Gerin, M; Siemiatycki, J; Nadon, L; et al. (1989) Cancer risks due to occupational exposure to 

formaldehyde: Results of a multi-site case-control study in Montreal Canada. Int J Cancer 

44:53–58.

Ginsberg, G; Smolenski, S; Hattis, D; et al. (2002) Population distribution of aldehyde 

dehydrogenase-2 genetic polymorphism: implications for risk assessment. Regul Toxicol 

Pharmacol 36:297–309.

Ginsberg, G; Hattis, D; Sonawane, B. (2004) Incorporating pharmacokinetic differences between 

children and adults in assessing children’s risks to environmental toxicants. Toxicol Appl 

Pharmacol 198:164–183.

Ginsberg, G; Foos, B; Firestone, M. (2005) Review and Analysis of Inhalation Dosimetry 

Methods for Application to Children’s Risk Assessment. J. Tox. & Env. Health 68:573-615.

Ginsberg,G; Asgharian, B; Kimbell, J; et al. (2008) Modeling approaches for estimating the 

dosimetry of inhaled toxicants in children. J. Tox. & Env. Health 71:166-195.

Global Insight, 2006. Economic primer on formaldehyde. Prepared for Formaldehyde Council, 

Inc. http://www.formaldehyde.org/pdfs/GIEconomicPrimer-04-20-06.pdf.
This document is a draft for review purposes only and does not constitute Agency policy.

R-20 DRAFT—DO NOT CITE OR QUOTE

Gochfeld, M. (2007) Framework for gender differences in human and animal toxicology. 

Environ Res 104:4–21.

Gofmekler, V. (1968) Embryotropic action of benzene and formaldehyde inhalation. Hyg Sanit 

33:327–332.

Gofmekler, V; Bonashevskaya, T. (1969) Experimental studies of teratogenic properties of 

formaldehyde, based on pathological investigations. Hyg Sanit 34:266–268.

Golaliour MJ; Azarhoush R; Ghafari S; Gharravi AM; Fazeli SA; Davarian A. 2007. 

Formaldehyde exposure induces histopathological and morphometric changes in the rat testis. 

Folia Morphol. 66(3): 167-171.

Golden, R; Pyatt, D; Shields, PG. (2006) Formaldehyde as a potential human leukemogen; An 

assessment of biological plausibility. Crit Rev Toxicol 36:135–153.

Goldmacher, VS; and Thilly, WG. (1983) Formaldehyde is mutagenic for cultured human cells. 

Mutat Res 116:417-422.

Goldstein, BD. (1973) Textiles and the chemical industry: A marriage. J Am Assoc Textile 

Chemists and Colorists 10:209–214.

Gordon, MY; Marley, SB; Apperley, JF; et al. (2003) Clinical heterogeneity in chronic myeloid 

leukemia reflecting biological diversity in normal persons. Brit J Haematol 122:424–429.

Gordon, CJ; Spencer, PJ; Hotchkiss, J; et al. (2008) Thermoregulation and its influence on risk 

assessment. Toxicology 244:87–97.

Gorski, P; Tarkowski, M; Krakowiak, A; et al. (1992) Neutrophil chemiluminescence following 

exposure to formaldehyde in healthy subjects and in patients with contact dermatitis. 

Immunologia Clinica 11:53–58.

Gottschling, LM; Beaulieu, HJ; Melvin, WW. (1984) Monitoring of formic acid in urine of 

humans exposed to low levels of formaldehyde. Am Ind Hyg Assoc J 45:19–23.

Grafström, RC; Fornace, AJ, Jr.; Autrup, H; et al. (1983) Formaldehyde damage to DNA and 

inhibition of DNA repair in human bronchial cells. Science 220:216–218.

Grafström, RC; Fornace, A, Jr.; Harris, CC. (1984) Repair of DNA damage caused by 

formaldehyde in human cells. Cancer Res 44:4323–4327.

Grafström, RC; Curren, RD; Yang, LL; et al. (1985) Genotoxicity of formaldehyde in cultured 

human bronchial fibroblasts. Science 228:89–91.

Grafstrom, RC. (1990) In vitro studies of aldehyde effects related to human respiratory 

carcinogenesis. Mutat Res 238:175-84.

Grafstrom, RC; Hsu, IC; and Harris, CC. (1993) Mutagenicity of formaldehyde in Chinese 

hamster lung fibroblasts: synergy with ionizing radiation and N-nitroso-N-methylurea. Chem 

Biol Interact 86:41-49.

Grammer, LC; Harris, KE; Shaughnessy, M; et al. (1990) Clinical and immunologic evaluation 

of 37 workers exposed to gaseous formaldehyde. J Allergy Clin Immunol 86:177–181.
This document is a draft for review purposes only and does not constitute Agency policy.

R-21 DRAFT—DO NOT CITE OR QUOTE

Grammer, LC; Harris, KE; Cugell, DW; et al. (1993) Evaluation of a worker with possible 

formaldehyde-induced asthma. J Allergy Clin Immunol 92:29–33.

Grasl-Kraupp, B; Luebeck, G; Wagner, A; et al. (2000) Quantitative analysis of tumor initiation 

in rat liver: Role of cell replication and cell death (apoptosis). Carcinogenesis 21:1411–1421.

Graves, RJ; Callander, RD; and Green, T. (1994) The role of formaldehyde and Schloromethylglutathione in the bacterial mutagenicity of methylene chloride. Mutat Res 

320:235-243.

Graves, RJ; Trueman, P; Jones, S; et al. (1996) DNA sequence analysis of methylene chlorideinduced HPRT mutations in Chinese hamster ovary cells: comparison with the mutation 

spectrum obtained for 1,2-dibromoethane and formaldehyde. Mutagenesis 11:229–233.

Gray, RH; Wu, LY. (2000) Subfertility and risk of spontaneous abortion. Am J Public Health 

90:1452–1454.

Gražulevičienė, R; Dulskienė, V; Venclovienė, J. (1998) Formaldehyde exposure and low birth 

weight incidence. J Occup Health 40:61–67.

Greaves, MA. (2004) Biological models for leukemia and lymphoma. IARC Sci Publ 

(157):351–372.

Green, DJ; Sauder, LR; Kulle, TJ; et al. (1987) Acute response to 3.0 ppm formaldehyde in 

exercising healthy nonsmokers and asthmatics. Am Rev Respir Dis 135:1261–1266.

Green, DJ; Bascom, R; Healey, EM; et al. (1989) Acute pulmonary response in healthy, 

nonsmoking adults to inhalation of formaldehyde and carbon. Toxicol Environ Health 28:261–

275.

Griesemer, RA; Boreiko, CJ; de Serres, FJ; et al. (1985) Report on the consensus workshop on 

formaldehyde: Carcinogenicity/Histopathology/Genotoxicity Panel report. Environ Health 

Perspect 58:340–343.

Guess, H; Crump, K; Peto, R. (1977) Uncertainty estimates for low dose-rate extrapolations of 

animal carcinogenicity data. Cancer Res 37:3475–3483.

Guseva, VA. (1972) Study of the gonadotropic effect in male rats under the effect of 

formaldehyde administered simultaneously with air and water [translation]. Gig Sanit 37:101–

102.

Gustavsson, P; Jakobsson, R; Johannson, H; et al. (1998) Occupational exposures and squamous 

cell carcinoma of the oral cavity, pharynx, larynx, and oesophagus: a case-control study in 

Sweden. Occup Environ Med 55:393–400.

Hagiwara, M; Watanabe, E; Barrett, JC, et al. (2006) Assessment of genotoxicity of 14 chemical 

agents used in dental practice: ability to induce chromosome aberrations in Syrian hamster 

embryo cells. Mutat Res 603:111-120.

Hakim, RB; Gray, RH; Zacur, H. (1995) Infertility and early pregnancy loss. Am J Obstet 

Gynecol 172:1510–1517.

Hall, A; Harrington, J; Aw, TC. (1991) Mortality study of British pathologists. Am J Ind Med 

20:83–89.
This document is a draft for review purposes only and does not constitute Agency policy.

R-22 DRAFT—DO NOT CITE OR QUOTE

Hamaguchi, F; and Tsutsui, T. (2000) Assessment of genotoxicity of dental antiseptics: ability 

of phenol, guaiacol, p-phenolsulfonic acid, sodium hypochlorite, p-chlorophenol, m-cresol or 

formaldehyde to induce unscheduled DNA synthesis in cultured Syrian hamster embryo cells. 

Jpn J Pharmacol 83:273-276.

Hanahan, D; Weinberg, RA. (2000) The hallmarks of cancer. Cell 100:57–70.

Hanrahan, LP; Dally, KA; Anderson, HA; et al. (1984) Formaldehyde vapor in mobile homes: a 

cross sectional survey of concentrations and irritant effects. Am J Public Health 74(9):1026–

1027.

Hansen, J; Olsen, JH. (1995) Formaldehyde and cancer morbidity among male employees in 

Denmark. Cancer Causes Control 6:354–360.

Hanzlik, RP; Fowler, SC; Eells, JT. (2005) Absorption and elimination of formate following oral 

administration of calcium formate in female human subjects. Drug Metab Dispos 33:282–286.

Harrington, JM; Shannon, H. (1975) Mortality study of pathologists and medical laboratory 

technicians. Br Med J 4:329–332.

Harrington, JM; Oakes, D. (1984) Mortality study of British pathologists 1974-80. Br J Ind Med 

41:188–191.

Harris, NL; Jaffe, ES; Diebold, J; et al. (2000a) The World Health Organization classification of 

neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee 

meeting―Airlie House, Virginia, November, 1997. Hematol J 1:53–66.

Harris, NL; Jaffe, ES; Diebold, J; et al. (2000b) The World Health Organization classification of 

hematological malignancies report of the Clinical Advisory Committee meeting, Airlie House, 

Virginia, November 1997. Mod Pathol 13:193–207.

Harris, C; Wand, S-W; Lauchu, JJ; et al. (2003) Methanol metabolism and embryotoxicity in rat 

and mouse conceptuses: comparison of alcohol dehydrogenase (ADH1), formaldehyde 

dehydrogenase (ADH3), and catalase. Reprod Toxicol 17:349–357.

Harving, H; Korsgaard, J; Pedersen, OF; et al. (1990) Pulmonary function and bronchial 

reactivity in asthmatics during low-level formaldehyde exposure. Lung 168:15–21.

Haseman, JK. (1995) Data analysis: Statistical analysis and use of historical control data. Regul 

Toxicol Pharmacol 21:52–59.

Hauptmann, M; Lubin, JH; Stewart, PA; et al. (2003) Mortality from lymphohematopoietic 

malignancies among workers in formaldehyde industries. J Natl Cancer Inst 95:1615–1623.

Hauptmann, M; Lubin, JH; Stewart, PA; et al. (2004a) Mortality from solid cancers among 

workers in formaldehyde industries. Am J Epidemiol 159:1117–1130.

Hauptmann, M; Lubin, JH; Stewart, PA; et al. (2004b) Response. J Natl Cancer Inst 96:967–

968.

Haworth, S; Lawlor, T; Mortelmans, K; et al. (1983) Salmonella mutagenicity test results for 250 

chemicals. Environ Mutagen 5 Suppl 1:1–142.
This document is a draft for review purposes only and does not constitute Agency policy.

R-23 DRAFT—DO NOT CITE OR QUOTE

Hayashi, H; Kunugita, N; Arashidani, K; et al. (2004) Long-term exposure to low levels of 

formaldehyde increases the number of tyrosine hydroxylase-immunopositive periglomerular 

cells in mouse main olfactory bulb. Brain Res 1007:192–197.

Hayes, RB; Raatgever, JW; de Bruyn, A; et al. (1986) Cancer of the nasal cavity and paranasal 

sinuses, and formaldehyde exposure. Int J Cancer 37:487–492.

Hayes, RB; Blair, A; Stewart, PA; et al. (1990) Mortality of U.S. embalmers and funeral 

directors. Am J Ind Med 18:641–652.

Hayes, RB; Klein, S; Suruda, A, et al. (1997) O6-alkylguanine DNA alkyltransferase activity in

student embalmers. Am J Ind Med 31:361-365.

He, JL; Jin, LF; Jin, HY. (1998) Detection of cytogenetic effects in peripheral lymphocytes of 

students exposed to formaldehyde with cytokinesis-blocked micronucleus assay. Biomed 

Environ Sci 11:87–92.

Health Canada and Environment Canada. (2001) Priority substances list assessment report: 

formaldehyde. Hull, Quebec, Canada: Environment Canada and Health Canada.

Heck, HD, Casanova-Schmitz, M. (1984) The relevance of disposition studies to the toxicology 

of formaldehyde. CIIT Activities 4:1–5.

Heck HD; Casanova, M. (1987) Isotope effects and their implications for the covalent binding of 

inhaled [3H]- and [14C]formaldehyde in the rat nasal mucosa. Toxicol Appl Pharmacol 89:122–

134.

Heck, HD; Casanova, M. (1999) Pharmacodynamics of formaldehyde: applications of a model 

for the arrest of DNA replication by DNA-protein cross-links. Toxicol Appl Pharmacol 160:86–

100.

Heck, HD, Casanova, M. (2004) The implausibility of leukemia induction by formaldehyde: A 

critical review of the biological evidence on distant-site toxicity. Regul Toxicol Pharmacol 

40:92–106.

Heck, HD; White, EL; Casanova-Schmitz, M. (1982) Determination of formaldehyde in 

biological tissues by gas chromatography/mass spectrometry. Biomed Mass Spectrom 9:347–

353.

Heck, HD; Chin, TY; Schmitz, MC. (1983) Distribution of [14C] formaldehyde in rats after 

inhalation exposure. In: Gibson, J E , eds. Formaldehyde Toxicity. Washington, DC: 

Hemisphere Publishing Corporation; pp. 26–37.

Heck Hd, A; Casanova, M; L., C-W, et al. (1986). The formation of DNA-protein crosslinks by 

aldehydes present in tobacco smoke. In: Hoffman, D and CC Harris,ed, Mechanisms in Tobacco 

Carcinogenesis: Cold Spring Harbor, New York: CSH Press, 215-230.

Heck, HD; Casanova-Schmitz, M; Dodd, PB; et al. (1985) Formaldehyde (CH2O) concentrations 

in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions. Am 

Ind Hyg Assoc J 46:1–3.

Heck, HD; Casanova, M; Starr, TB. (1990) Formaldehyde toxicity--new understanding. Crit Rev 

Toxicol 20:397-426.
This document is a draft for review purposes only and does not constitute Agency policy.

R-24 DRAFT—DO NOT CITE OR QUOTE

Hedberg, JJ; Høøg, JO; Nilsson, JA; et al. (2000) Expression of alcohol dehydrogenase 3 in 

tissue and cultured cells from human oral mucosa. Am J Pathol 157:1745–1755.

Hedberg, JJ; Grafström, RC; Vondracek, M; et al. (2001a) Micro-array chip analysis of 

carbonyl-metabolizing enzymes in normal, immortalized and malignant human oral 

keratinocytes. Cell Mol Life Sci 58:1719–1726.

Hedberg, JJ; Backlund, M; Stromberg, P; et al. (2001b) Functional polymorphism in the alcohol 

dehydrogenase 3 (ADH3) promoter. Pharmacogenetics 11:815–824.

Hedberg, JJ; Griffiths, WJ; Nilsson, SJ; et al. (2003) Reduction of S-nitrosoglutathione by 

human alcohol dehydrogenase 3 is an irreversible reaction as analyzed by electrospray mass 

spectrometry. Eur J Biochem 270:1249–1256.

Heikkilä, P; Priha, E; Savola, A. (1991) Exposure at work. 14. Formaldehyde. Institute of 

Occupational Health. Finnish Work Environmental Fund.

Heineman, EF; Olsen, JH; Pottern, LM; et al. (1992) Occupational risk factors for multiple 

myeloma among Danish men. Cancer Causes Control 3:555–568.

Hemminki, K; Mutanen, P; Salonienmi, I; et al. (1982) Spontaneous abortions in hospital staff 

engaged in sterilizing instruments with chemical agents. Br Med J 285:1461–1463.

Hemminki, K; Kyyrönen, P; Lindbohm, ML. (1985) Spontaneous abortions and malformations 

in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential 

hazards in hospitals, based on registered information of outcome. J Epidemiol Community 

Health 39:141–147.

Hendrick, DJ; Lane, DJ. (1975) Formalin asthma in hospital staff. Br Med J 1(5958):607–608.

Hendrick, DJ; Lane, DJ. (1977) Occupational formalin asthma. Br J Ind Med 34:11–18.

Hendrick, DJ; Rando, RJ; Lane, DJ; et al. (1982) Formaldehyde asthma: challenge exposure 

levels and fate after five years. J Occup Med 24:893–897.

Herbert, FA; Hessel, PA; Melenka, LS; et al. (1994) Respiratory consequences of exposure to 

wood dust and formaldehyde of workers manufacturing oriented strand board. Arch Environ 

Health 49(6):465–470.

Hernandez, O; Rhomberg, L; Hogan, K; et al. (1994) Risk assessment of formaldehyde. J 

Hazard Mater 39:161-172.

Hess, DT; Matsumoto, A; Kim, SO; et al. (2005) Protein S-nitrosylation: purview and 

parameters. Nat Rev Mol Cell Biol 6:150–166.

Hester, SD; Benavides, GB; Yoon, L; et al. (2003) Formaldehyde-induced gene expression in 

F344 rat nasal respiratory epithelium. Toxicology 187:13–24.

Hester, SD; Barry, WT; Zou, F; et al. (2005) Transcriptomic analysis of F344 rat nasal 

epithelium suggests that the lack of carcinogenic response to glutaraldehyde is due to its greater 

toxicity compared to formaldehyde. Toxicol Pathol 33:415–424.
This document is a draft for review purposes only and does not constitute Agency policy.

R-25 DRAFT—DO NOT CITE OR QUOTE

Hikiba, H; Watanabe, E; Barrett, JC; et al. (2005) Ability of fourteen chemical agents used in 

dental practice to induce chromosome aberrations in Syrian hamster embryo cells. J Pharmacol 

Sci 97:146–152.

Hildesheim, A; Dosemeci, M; Chan, CC; et al. (2001) Occupational exposure to wood, 

formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol 

Biomarkers Prev 10:1145–1153.

Hileman, B. (1984) Formaldehyde: assessing the risk. Environ Sci Technol 18:216A–221A.

Hilton, J; Dearman, RJ; Harvey, P; et al. (1998) Estimation of relative skin sensitizing potency 

using the local lymph node assay: a comparison of formaldehyde with glutaraldehyde. Am J 

Contact Dermat 9:29–33.

Hines, RN; McCarver, DG. (2002) The ontogeny of human drug-metabolizing enzymes: phase I 

oxidative enzymes. J Pharmacol Exp Ther 300:361–366.

Holly, EA; Aston, DA; Ahn, DK; et al. (1996) Intraocular melanoma linked to occupations and 

chemical exposures. Epidemiology 7:55–61.

Holmström, M; Wilhelmsson, B. (1988) Respiratory symptoms and pathophysiological effects of 

occupational exposure to formaldehyde and wood dust. Scand J Work Environ Health 14:306–

311.

Holmström, M; Wilhelmsson, B; Hellquist, H. (1989a) Histological changes in the nasal mucosa 

in rats after long-term exposure to formaldehyde and wood dust. Acta Otolaryngol 108:274–

283.

Holmström, M; Rynnel-Dagöö, B; Wilhelmsson, B. (1989b) Antibody production in rats after 

long-term exposure to formaldehyde. Toxicol Appl Pharmacol 100:328–333.

Holmström, M; Wilhelmsson, B; Hellquist, H; et al. (1989c) Histological changes in the nasal 

mucosa in persons occupationally exposed to formaldehyde alone and in combination with wood 

dust. Acta Otolaryngol 107:120–129.

Holness, DL; Nethercott, JR. (1989) Health status of funeral service workers exposed to 

formaldehyde. Arch Environ Health 44:222–228.

Höög, JO; Hedberg, JJ; Strömberg, P; et al. (2001) Mammalian alcohol dehydrogenase -

functional and structural implications. J Biomed Sci 8:71–76.

Höög, JO; Strömberg, P; Hedberg, JJ; et al. (2003) The mammalian alcohol dehydrogenases 

interact in several metabolic pathways. Chem Biol Interact 143–144:175–181.

Hoogenveen, R; Clewell, H; Andersen, M; et al. (1999) An alternative exact solution of the twostage clonal growth model of cancer. Risk Anal 19:9–14.

Horton, A; Tye, R; Stemmer, K. (1963) Experimental carcinogenesis of the lung. Inhalation of 

gaseous formaldehyde or an aerosol of coal tar by C3H mice. J Natl Cancer Inst 30:31–43.

Horvath, E, Jr; Anderson, J; Pierce, WE; et al. (1988) Effects of formaldehyde on the mucous 

membranes and lungs: A study of an industrial population. JAMA 259:701–707.
This document is a draft for review purposes only and does not constitute Agency policy.

R-26 DRAFT—DO NOT CITE OR QUOTE

Hou, Y; Hu, WG; Hirano, T; et al. (2002) A new intra-NALT route elicits mucosal and systemic 

immunity against Moraxella catarrhalis in a mouse challenge model. Vaccine 20:2375–2381.

HSDB (Hazardous Substances Data Bank). (2001) Formaldehyde. National Library of 

Medicine, Bethesda, MD. Available from <http://toxnet.nlm.nih.gov>.

Hurni, H; Ohder, H. (1973) Reproduction study with formaldehyde and hexamethylenetetramine 

in beagle dogs. Food Cosmet Toxicol 11:459–462.

IARC (International Agency for Research on Cancer). (1995) IARC monographs on the 

evaluation of carcinogenic risks to humans. Vol. 62. Wood dust and formaldehyde. Lyon, 

France: International Agency for Research on Cancer. Available from 

<http://www.inchem.org/documents/iarc/vol62/wood.html> and 

<http://www.inchem.org/documents/iarc/vol62/formal.html>.

IARC (2006) IARC Monographs on the evaluation of carcinogenic risks to humans. 

Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxy-2-propanol, vol. 88. IARC, Lyon, France. 

http://monographs.iarc.fr/ENG/Monographs/vol88/mono88-6A.pdf

Iarmarcovai, G; Botta, A; Orsière, T. (2006a) Number of centromeric signals in micronuclei and 

mechanisms of aneuploidy. Toxicol Lett 166:1–10.

Iarmarcovai, G; Orsière, T; Sari-Minodier, I; et al. (2006b) Different pathways of centromeric 

micronuclei formation in peripheral blood lymphocytes of cancer patients and workers 

occupationally exposed to mutagens/carcinogens? Advances in Molecular and Clinical Aspects 

of Cancer Prevention,4th International Conference on Cancer Prevention 2006, 4:54–55, 

Switzerland.

Iarmarcovai, G; Bonassi, S; Sari-Minodier, I; et al. (2007) Exposure to genotoxic agents, host 

factors, and lifestyle influence the number of centromeric signals in micronuclei: a pooled reanalysis. Mutat Res 615:18–27.

Ibanes, JD; Leininger, JR; Jarabek, AM; et al. (1996) Reexamination of respiratory tract 

responses in rats, mice, and rhesus monkeys chronically exposed to inhaled chlorine. Inhal Tox 

8:859–876.

ICRP (International Commission on Radiological Protection). (1994) Human respiratory tract 

model for radiological protection. Publication 66 Annals of the ICRP Vol 24; Pergamon Press, 

Oxford, UK.

Ihrig, A; Hoffmann, J; Triebig, G. (2006) Examination of the influence of personal traits and 

habituation on the reporting of complaints at experimental exposure to ammonia. Int Arch 

Occup Environ Health 79:332–338.

ILSI (International Life Sciences Institute). (2003) Final report of a workshop to develop a 

framework for assessing risks to children from exposures to environmental agents. ILSI Risk 

Science Institute, Washington, DC.

Im, H; Oh, E; Mun, J; et al. (2006) Evaluation of toxicological monitoring markers using 

proteomic analysis in rats exposed to formaldehyde. J Proteome Res 5:1354–1366.
This document is a draft for review purposes only and does not constitute Agency policy.

R-27 DRAFT—DO NOT CITE OR QUOTE

Ionescu, J; Marinescu, D; Tapu, V; et al. (1978) Experimental chronic obstructive lung disease. 

I. Bronchopulmonary changes induced in rabbits by prolonged exposure to formaldehyde. 

Morphol Embryol 24:233-242.

IPCS (International Programme on Chemical Safety). (1989) Environmental Health Criteria. 

Vol. 89. Formaldehyde. Geneva, Switzerland: World Health Organization. Available from 

<http://www.inchem.org/documents/ehc/ehc/ehc89.htm>.

IPCS (International Programme on Chemical Safety). (1997) Environmental Health Criteria 196 

-- Methanol 180. 

IPCS. (2002) Formaldehyde. Concise international chemical assessment document. Vol. 40. 

World Health Organization, Geneva, Switzerland. Available online at 

http://www.inchem.org/documents/cicads/cicads/cicad40.htm.

Iravani, J. (1974) Clearance function of the respiratory ciliated epithelium in normal and 

bronchitic rats. Inhaled Part 1:143–148.

Iravani, J; Melville, GN. (1974) Long-term effect of cigarette smoke on mucociliary function in 

animals. Respiration 31:358–366.

Ishidate, JM; Sofuni, T; and Yoshikawa, K. (1981) Chromosomal aberration tests in vitro as a 

primary screening tool for environmental mutagens and/or carcinogens. GANN Monogr Cancer 

Res 27:95-108.

Ito, K; Sakamoto, T; Hayashi, Y; et al. (1996) Role of tachykinin and bradykinin receptors and 

mast cells in gaseous formaldehyde-induced airway microvascular leakage in rats. Eur J 

Pharmacol 307:291–298.

Jaeger, RJ; Gearhart, JM. (1982) Respiratory and metabolic response of rats and mice to 

formalin vapor. Toxicology 25:299–309.

Jaiswal, S; Traver, D; Miyamoto, T; et al. (2003) Expression of BCR/ABL and BCL-2 in 

myeloid progenitors leads to myeloid leukemias. Proc Natl Acad Sci USA 100:10002–10007.

Jakab, GJ. (1992) Relationship between carbon black particulate-bound formaldehyde, 

pulmonary antibacterial defenses, and alveolar macrophage phagocytosis. Inhal Toxicol 4:325–

342.

James, JT; Limero, TF; Beck, SW; et al. (2002) Environmental Monitoring Air Quality. Report 

of the Lunar-Mars Support Test Project (LMLSTP4.1). In: Isolation: NASA Experiments in 

Closed Environment Living. Eds: Lane, HW; Sauer, RL; Feeback, DL. Univeit, Inc, San Diego, 

CA. 104:177–191. Data also available at National Aeronautics and Space Administration Life 

Sciences Data Archive, Houston, TX. Available at 

http://lsda.jsc.nasa.gov/docs/research/research_detail.cfm?experiment_type_code=24&researcht

ype=.

Jarabek, AM; Fisher, JW; Rubenstein, R; et al. (1994) Mechanistic insights aid the search for 

CFC substitutes: risk assessment of HCHC-123 as an example. Risk Anal 14:231–250.

Javdan, M; Taher, TE. (2000) The short and long term effects of formaldehyde vapour (2 ppm 

and 5 ppm) on rat nasal epithelium. Pathol Int 50:A77.
This document is a draft for review purposes only and does not constitute Agency policy.

R-28 DRAFT—DO NOT CITE OR QUOTE

Jeffcoat, AR; Chasalow, F; Feldman, DB; et al. (1983) Disposition of [14C] formaldehyde after 

topical exposure to rats, guinea pigs, and monkeys. In: Gibson, J E , eds. Formaldehyde 

Toxicity. Washington, DC: Hemisphere; pp. 38-50.

Jensen, DE; Belka, GK; Du Bois, GC. (1998) S-Nitrosoglutathione is a substrate for rat alcohol 

dehydrogenase class III isoenzyme. Biochem J 331 ( Pt 2):659–668.

Johannsen, FR; Levinskas, GJ; Tegeris, AS. (1986) Effects of formaldehyde in the rat and dog 

following oral exposure. Toxicol Lett 30:1–6.

John, EM; Savitz, DA; Shy, CM. (1994) Spontaneous abortions among cosmetologists. 

Epidemiology 5:147–155.

Joos, GF. (2003) Bronchial hyperresponsiveness: too complex to be useful? Curr Opin 

Pharmacol 3:233–238.

Jörnvall, H; Höög, JO; Persson, B; et al. (2000) Pharmacogenetics of the alcohol dehydrogenase 

system. Pharmacology 61:184–191.

Junqueira, LC; Carneiro, J; Kelley, RO. (1992) Basic Histology. Appleton and Lange, Norwalk, 

CN.

Jung, R; Engelhart, G; Herbolt, B; et al. (1992) Collaborative study of mutagenicity with 

Salmonella typhimurium TA102. Mutat Res 278:265–270.

Jurvelin, J; Vartiainen, M; Jantunen, M; et al. (2001) Personal exposure levels and 

microenvironmental concentrations of formaldehyde and acetaldehyde in the Helsinki 

metropolitan area. J Air Waste Manag Assoc 51:17–24.

K S Crump Group. (2001) TOX_RISK dose-response software, version 5.2 (2000–2001). KS 

Crump Group.

Kakeyama, M; Kurokawa, Y; Kunugita, N; et al. (2004) Low dose exposure to formaldehyde 

alters glutamate NMDA receptor mRNA expressions in the rat neocortex. Neurotoxicology 

25:717.

Kalasz, H. (2003) Biological role of formaldehyde, and cycles related to methylation, 

demethylation, and formaldehyde production. Mini Rev Med Chem 3:175-192. 

Kallen, RG; Jencks, WP. (1966a) The dissociation constants of tetrahydrofolic acid. J Biol Chem 

241:5845-5850.

Kallen, RG; Jencks, WP. (1966b) The mechanism of the condensation of formaldehyde with 

tetrahydrofolic acid. J Biol Chem 241:5851-5863.

Kamata, E; Nakadate, M; Ogawa, Y; et al. (1996a) Acute inhalation toxicity study of 

formaldehyde in rats: effect of vapor on the pulmonary surfactant. Oyo Yakuri 51:33–37.

Kamata, E; Nakadate, M; Uchida, O; et al. (1996b) Effects of formaldehyde vapor on the nasal 

cavity and lungs of F-344 rats. J Environ Pathol Toxicol Oncol 15:1–8.

Kamata, E; Nakadate, M; Uchida, O; et al. (1997) Results of a 28-month chronic inhalation 

toxicity study of formaldehyde in male Fisher-344 rats. J Toxicol Sci 22:239–254.
This document is a draft for review purposes only and does not constitute Agency policy.

R-29 DRAFT—DO NOT CITE OR QUOTE

Kane, LE; Alarie, Y. (1977) Sensory irritation to formaldehyde and acrolein during single and 

repeated exposures in mice. Am Ind Hyg Assoc J 38:509–522.

Kane, LE; Alarie, Y. (1978) Evaluation of sensory irritation from acrolein-formaldehyde 

mixtures. Am Ind Hyg Assoc J 39:270–274.

Kane, LE; Barrow, CS; Alarie, Y. (1979) A short-term test to predict acceptable levels of 

exposure to airborne sensory irritants. Am Ind Hyg Assoc J 40:207–229.

Kedderis, GL; Hollenberg, PF. (1983) Steady state kinetics of chloroperoxidase-catalyzed Ndemethylation reactions. J Biol Chem 258:12413-12419. 

Kelly, JT; Prasad, AK; Wexler, AS. (2000) Detailed flow patterns in the nasal cavity. J Appl 

Physiol 89:323–337.

Kennedy, G; Slaich, PK; Golding, BT; et al. (1996) Structure and mechanism of formation of a 

new adduct from formaldehyde and guanosine. Chem Biol Interact 102:93–100.

Kepler, GM; Richardson, RB; Morgan, KT; et al. (1998) Computer simulation of inspiratory 

nasal airflow and inhaled gas uptake in a rhesus monkey. Toxicol Appl Pharmacol 150:1–11.

Kernan, GJ; Ji, BT; Dosemeci, M; et al. (1999) Occupational risk factors for pancreatic cancer: 

A case-control study based on death certificates from 24 U.S. states. Am J Ind Med 36:260–270.

Kerns, WD; Pavkov, KL; Donofrio, DJ; et al. (1983) Carcinogenicity of formaldehyde in rats 

and mice after long-term inhalation exposure. Cancer Res 43:4382–4392.

Khamgaonkar, MB; Fulare, MB. (1991) Pulmonary effects of formaldehyde exposure—an 

environmental-epidemiological study. Ind J Chest Dis Allied Sci 33:9–13.

Kiernan, JA. (2000) Formaldehyde, formalin, paraformaldehyde and glutaraldehyde: What they 

are and what they do. Microscopy Today 00-1 pp. 8–12.

Kilburn, KH. (1994) Neurobehavioral impairment and seizures from formaldehyde. Arch 

Environ Health 49:37–44.

Kilburn, KH; Moro, A. (1985) Reproductive and maternal effects of formaldehyde (HCH0) in 

rats. Fed Proc 44:535.

Kilburn, KH; Warshaw, R. (1992) Neurobehavioral effects of formaldehyde and solvents on 

histology technicians: repeated testing across time. Environ Res 58:134–146.

Kilburn, KH; Seidman, BC; Warshaw, R. (1985) Neurobehavioral and respiratory symptoms of 

formaldehyde and xylene exposure in histology technicians. Arch Environ Health 40:229–233.

Kilburn, KH; Warshaw, R; Thornton, JC. (1987) Formaldehyde impairs memory equilibrium and 

dexterity in histology technicians effects which persist for days after exposure. Arch Environ 

Health 42:117–120.

Kim, CW; Song, JS; Ahn, YS; et al. (2001) Occupational asthma due to formaldehyde. Yonsei 

Med J 42:440–445.

Kim, KC; Hisatsune, A; Kim, DJ; et al. (2003) Pharmacology of airway goblet cell mucin 

release. J. Pharmacol Sci 92:301–307.
This document is a draft for review purposes only and does not constitute Agency policy.

R-30 DRAFT—DO NOT CITE OR QUOTE

Kimbell, JS; Gross, EA; Joyner, DR; et al. (1993) Application of computational fluid dynamics 

to regional dosimetry of inhaled chemicals in the upper respiratory tract of the rat. Toxicol Appl 

Pharmacol 121:253–263.

Kimbell, JS; Godo, MN; Gross, EA; et al. (1997a) Computer simulation of inspiratory airflow in 

all regions of the F344 rat nasal passages. Toxicol Appl Pharmacol 145:388–398.

Kimbell, JS; Gross, EA; Richardson RB; et al. (1997b) Correlation of regional formaldehyde 

flux predictions with the distribution of formaldehyde-induced squamous metaplasia in F344 rat 

nasal passages. Mutat Res 380:143–154.

Kimbell, JS; Subramaniam, RP; Gross, EA; et al. (2001a) Dosimetry modeling of inhaled 

formaldehyde: comparisons of local flux predictions in the rat, monkey, and human nasal 

passages. Toxicol Sci 64:100–110.

Kimbell, JS; Overton, JH; Subramaniam, RP; et al. (2001b) Dosimetry modeling of inhaled 

formaldehyde: binning nasal flux predictions for quantitative risk assessment. Toxicol Sci 

64:111–121.

Kimbell, JS. (2006) Nasal dosimetry of inhaled gases and particles: Where do inhaled agents go 

in the nose? Toxicol Pathol 34:270–273.

Kinzler, KW; Vogelstein, B. (1997) Cancer-susceptibility genes. Gatekeepers and caretakers. 

Nature 386:761–763.

Kitaev, ÉM; Savchenko, O; Lovchikov, VA; et al. (1984) Embryonic development and various 

indicators of reproductive function in rats after inhalation of formaldehyde in the preimplantation 

phase [translation]. Akush Ginekol 10:49–52.

Kitaeva, LV; Kitaev, E; Pimenova, MN. (1990) Cytopathic and cytogenetic effects of chronic 

inhalation of formaldehyde on the female rat's germ marrow cells [translation]. Tsitologiia 

32:1212–1216.

Kitaeva, LV; Mikheeva, EA; Shelomova, LF; et al. (1996) Genotoxic effect of formaldehyde in 

somatic human cells in vivo [translation]. Genetika 32(9):1287–1290. Translated from Russian 

by Ted Crump, Translator. NIH Library Translation. National Institutes of Health, Public Health 

Service, U.S. Department of Health and Human Services; NIH-03-640.

Klaassen, CD. (2001) Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th 

Edition. McGraw-Hill, New York, NY.

Klein, M; Sinha, B; Subramaniam, RP. (2009) Statistical inferences from formaldehyde DNAprotein cross-link data: Improving methods for characterization of uncertainty. J. 

Biopharmaceutical Statistics. [Submitted]

Kligerman, AD; Phelps, MC; Erexson, GL. (1984) Cytogenetic analysis of lymphocytes from 

rats following formaldehyde inhalation. Toxicol Lett 21:241–246.

Klonisch, T; Steger, K; Kehlen, A; et al. (2004) INSL-3 ligand-receptor system in the equine 

testis. Biol Reprod 68:1975–1981.
This document is a draft for review purposes only and does not constitute Agency policy.

R-31 DRAFT—DO NOT CITE OR QUOTE

Koppel, C; Tenczer, J; Peixoto-Menezes, KM. (1991) Formation of formaldehyde adducts from 

various drugs by use of methanol in a toxicological screening procedure with gas 

chromatography-mass spectrometry. J Chromatogr 563:73–81.

Korczynski, RE. (1994) Formaldehyde exposure in the funeral industry. Appl Occup Environ 

Hyg 9:575–579.

Krakowiak, A; Gorski, P; Pazdrak, K; et al. (1998) Airway response to formaldehyde inhalation 

in asthmatic subjects with suspected respiratory formaldehyde sensitization. Am J Ind Med 

33:274–281.

Kramps, JA; Peltenburg, LT; Kerklaan, PR; et al. (1989) Measurement of specific IgE antibodies 

in individuals exposed to formaldehyde. Clin Exp Allergy 19:509–514.

Krewski, D; Crump, KS; Farmer, J; et al. (1983) A comparison of statistical methods for low 

dose extrapolation utilizing time-to-tumor data. Fundam Appl Toxicol 3:140–160.

Kriebel, D; Sama, SR; Cocanour, B. (1993) Reversible pulmonary responses to formaldehyde. A 

study of clinical anatomy students. Am Rev Respir Dis 148:1509–1515.

Kriebel, D; Myers, D; Cheng, M; et al. (2001) Short-term effects of formaldehyde on peak 

expiratory flow and irritant symptoms. Arch Environ Health 56(1):11–18.

Kreiger, RA; and Garry, VF. (1983) Formaldehyde-induced cytotoxicity and sister-chromatid 

exchanges in human lymphocyte cultures. Mutat Res 120:51-55.

Krimsky, MM. (1986) Letter to the editor regarding Sallakumar et al., 1985. Toxicol Appl 

Pharmacol 85:295.

Krzyzanowski, M; Quackenboss, JJ; Lebowitz, MD. (1990) Chronic respiratory effects of indoor 

formaldehyde exposure. Environ Res 52:117–125.

Kuby, J. (1991) Immunology. 2nd edition. New York, NY: W.H. Freeman and Company.

Kulle, TJ. (1993) Acute odor and irritation response in healthy nonsmokers with formaldehyde 

exposure. Inhal Toxicol 5:323–332.

Kulle, TJ; Cooper, GP. (1975) Effects of formaldehyde and ozone on the trigeminal nasal 

sensory system. Arch Environ Health 30:237–243.

Kulle, TJ; Sauder, LR; Hebel, R; et al. (1987) Formaldehyde dose-response in healthy 

nonsmokers. JAPCA 37:919–924.

Kum, C; Kiral, F; Sekkin, S; et al. (2007) Effects of xylene and formaldehyde inhalations on 

oxidative stress in adult and developing rats livers. Exp Anim 56:35–42.

Kuper, CF; Hameleers, DMH; Bruijntjes, JP; et al. (1990) Lymphoid and non-lymphoid cells in 

nasal-associated lymphoid tissue (NALT) in the rat. Cell Tissue Res 259:371–377.

Kuppers, R; Klein, U; Hansmann, M-L; et al. (1999) Cellular origin of human B-cell 

lymphomas. New Eng J Med 341:1520–1529.

Kuschner, M; Laskin, S; Drew, RT; et al. (1975) Inhalation carcinogenicity of alpha halo ethers. 

III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm. Arch 

Environ Health 30:73–77.
This document is a draft for review purposes only and does not constitute Agency policy.

R-32 DRAFT—DO NOT CITE OR QUOTE

Laforest, L; Luce, D; Goldberg, P; et al. (2000) Laryngeal and hypopharyngeal cancers and 

occupational exposure to formaldehyde and various dusts: a case-control study in France. Occup 

Environ Med 57:767–773.

Lam, CW; Casanova, M; Heck, HD. (1985) Depletion of nasal mucosal glutathione by acrolein 

and enhancement of formaldehyde-induced DNA-protein cross-linking by simultaneous 

exposure to acrolein. Arch Toxicol 58:67–71.

Lang, I; Bruckner, T; Triebig, G. (2008) Formaldehyde and chemosensory irritation in humans: 

A controlled human exposure study. Regul Toxicol Pharmacol 50:23–36.

Lash, LH; Parker, JC. (2001) Hepatic and renal toxicities associated with perchloroethylene. 

Pharmacol Rev 53:177–208.

Laskin, S; Kuschner, M; Drew, RT; et al. (1971) Tumors of the respiratory tract induced by 

inhalation of bis(chloromethyl)ether. Arch Environ Health 23:135–136.

Lazutka, JR; Lekevicius, R; Dedonyte, V, et al. (1999) Chromosomal aberrations and sisterchromatid exchanges in Lithuanian populations: effects of occupational and environmental 

exposures. Mutat Res 445:225-239.

Le Curieux, F; Marzin, D; Erb, F. (1993) Comparison of three short-term assays: results on 

seven chemicals. Potential contribution to the control of water genotoxicity. Mutat Res 

319:223–236.

Leach, C; Sharma, R; Oberg, S. (1983) Immunotoxic and pathologic effects of inhalation of

various levels of formaldehyde vapor in F-344 rats. Toxicologist 3:73.

Lee, H; Alarie, Y; Karol, M. (1984) Induction of formaldehyde sensitivity in guinea pigs. 

Toxicol Appl Pharmacol 75:147–155.

Lee, MH; Kim, YA; Na, TY; et al. (2008) Identification of formaldehyde-responsive genes by 

suppression subtractive hybridization. Toxicology 243:224–235.

Lemière, C; Desjardins, A; Cloutier, Y; et al. (1995) Occupational asthma due to formaldehyde 

resin dust with and without reaction to formaldehyde gas. Eur Respir J 8:861–865.

Levine, RJ; Andjelkovich, DA; Shaw, L. (1984) The mortality of Ontario undertakers and a 

review of formaldehyde-related mortality studies. J Occup Med 26:740–746.

Levy, S; Nocentini, S; and Billardon, C. (1983) Induction of cytogenetic effects in human 

fibroblast cultures after exposure to formaldehyde or X-rays. Mutat Res 119:309-317.

Li, G-Y; Lee, H-Y; Shin, H-S; et al. (2007) Identification of gene markers for formaldehyde 

exposure in humans. Environ Health Perspect 115:1460–1466.

Li, R; Lu, ZS; Qiao, Y; et al. (2004) Study on the formaldehyde-induced DNA damage with 

comet assay. Shi Yan Sheng Wu Xue Bao 37:262–268.

Liber, HL; Benforado, K; Crosby, RM; et al. (1989) Formaldehyde-induced and spontaneous 

alterations in human hprt DNA sequence and mRNA expression. Mutat Res 226:31–37.

Lidén, S; Scheynius, A; Fischer, T; et al. (1993) Absence of specific IgE antibodies in allergic 

contact sensitivity to formaldehyde. Allergy 48(7):525–529.
This document is a draft for review purposes only and does not constitute Agency policy.

R-33 DRAFT—DO NOT CITE OR QUOTE

Liebling, T; Rosenman, KD; Griffith, RG; et al. (1984) Cancer mortality among workers 

exposed to formaldehyde. Am J Ind Med 5:423–428.

Liesivuori, J; Savolainen, H. (1987) Urinary formic acid as an indicator of occupational exposure 

to formic acid and methanol. Am Ind Hyg Assoc J 48:32–34.

Lin, Z; Luo, W; Li, H; et al. (2005) The effect of endogenous formaldehyde on the rat aorta 

endothelial cells. Toxicol Lett 159:134–143.

Lindbohm, ML; Hemminki, K; Bonhomme, MG; et al. (1991) Effects of paternal occupational 

exposure on spontaneous abortions. Am J Public Health 81:1029–1033.

Lino dos Santos Franco, A; Damazo, AS; Beraldo de Souza, HR; et al. (2006) Pulmonary 

neutrophil recruitment and bronchial reactivity in formaldehyde-exposed rats are modulated by 

mast cells and differentially by neuropeptides and nitric oxide. Toxicol Appl Pharmacol 214:35–

42.

Lino dos Santos Franco, A; Domingos, HV; Damazo, AS; et al. (2009) Reduced allergic lung 

inflammation in rats following formaldehyde exposure: long term effects on multiple effector 

systems. Toxicology. 256: 157–163.

Liu, KS; Huang, FY; Hayward, SB; et al. (1991) Irritant effects of formaldehyde exposure in 

mobile homes. Environ Health Perspect 94:91–94.

Liu, L; Hausladen, A; Zeng, M; et al. (2001) A metabolic enzyme for S-nitrosothiol conserved 

from bacteria to humans. Nature 410:490–494.

Liu, L; Yan, Y; Zeng, M; et al. (2004) Essential roles of S-nitrosothiols in vascular homeostasis 

and endotoxic shock. Cell 116:617–628.

Liu, Y; Li, CM; Lu, Z; et al. (2006) Studies on formation and repair of formaldehyde-damaged 

DNA by detection of DNA-protein crosslinks and DNA breaks. Front Biosci 11:991–997.

Logue, J; Barrick, M; Jessup, G. (1986) Mortality of radiologists and pathologists in the 

radiation registry of physicians. J Occup Med 28:91–99.

Lu, Z; Li, CM; Qiao, Y; et al. (2008) Effect of inhaled formaldehyde on learning and memory in 

mice. Indoor Air 18:77–83.

Luce, D; Gerin, M; Leclerc, A; et al. (1993) Sinonasal cancer and occupational exposure to 

formaldehyde and other substances. Int J Cancer 53:224–231.

Luce, D; Leclerc, A; Begin, D; et al. (2002) Sinonasal cancer and occupational exposures: a 

pooled analysis of 12 case-control studies. Cancer Causes Control 13:147–157.

Luebeck, EG; Grasl-Kraupp, B; Timmermann-Trosiener, I; et al. (1995) Growth kinetics of 

enzyme-altered liver foci in rats treated with phenobarbital or alpha-hexachlorocyclohexane. 

Toxicol Appl Pharmacol 130:304–315.

Luebeck, EG; Buchmann, A; Stinchcombe, S; et al. (2000) Effects of 2,3,7,8-tetrachlorodibenzop-dioxin on initiation and promotion of GST-P-positive foci in rat liver: A quantitative analysis 

of experimental data using a stochastic model. Toxicol Appl Pharmacol 167:63–73.
This document is a draft for review purposes only and does not constitute Agency policy.

R-34 DRAFT—DO NOT CITE OR QUOTE

Luo, W; Li, H; Zhang, Y; et al. (2001) Determination of formaldehyde in blood plasma by highperformance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci 

Appl 753:253-257. 

Lyapina, M; Zhelezova, G; Petrova, E; et al. (2004) Flow cytometric determination of neutrophil 

burst activity in workers exposed to formaldehyde. Int Arch Occup Environ Health 77:335–340.

Ma, TH; Harris, MM. (1988) Review of the genotoxicity of formaldehyde. Mutat Res 196:37–

59.

Mackerer, CR; Angelosanto, FA; Blackburn, GR, et al. (1996) Identification of formaldehyde as 

the metabolite responsible for the mutagenicity of methyl tertiary-butyl ether in the activiated 

mouse lymphoma assay. Proc. Soc. exp. Biol. Med 212:338-341.

Magana-Schwencke, N; and Ekert, B. (1978) Biochemical analysis of damage induced in yeast 

by formaldehyde. II. Induction of cross-links between DNA and protein. Mutat Res 51:11-19.

Main, D; Hogan, TJ. (1983) Health effects of low level exposure to formaldehyde. J Occup Med 

25(12):896–900.

Majumder, PK; Kumar, VL. (1995) Inhibitory effects of formaldehyde on the reproductive 

system of male rats. Indian J Physiol Pharmacol 39:80–82.

Malaka, T; Kodama, AM. (1990) Respiratory health of plywood workers occupationally exposed 

to formaldehyde. Arch Environ Health 45:288–294.

Malek, FA; Möritz, KU; Fanghänel, J. (2003a) A study on the effect of inhalative formaldehyde 

exposure on water labyrinth test performance in rats. Ann Anat 185:277–285.

Malek, FA; Möritz, KU; Fanghänel, J. (2003b) Formaldehyde inhalation and open field 

behaviour in rats. Indian J Med Res 118:90–96.

Malek, FA; Möritz, KU; Fanghänel, J. (2003c) A study on specific behavioral effects of 

formaldehyde in the rat. J Exp Anim Sci 42:160–170.

Malek, FA; Möritz, KU; Fanghänel, J. (2004) Effects of a single inhalative exposure to 

formaldehyde on the open field behavior of mice. Int J Hyg Environ Health 207:151–158.

Mannix, RC; Phalen, RF; Walters, RF; et al. (1983) Effects of sulfur dioxide and formaldehyde 

on particle clearance in the rat. J Toxicol Environ Health 12:429–440.

Marinari, UM; Ferro, M; Sciaba, L, et al. (1984) DNA-damaging activity of biotic and 

xenobiotic aldehydes in Chinese hamster ovary cells. Cell Biochem Funct 2:243-248.

Marks, TA; Worthy, WC; Staples, RE. (1980) Influence of formaldehyde and sonacide 

(potentiated acid glutaraldehyde) on embryo and fetal development in mice. Teratology 22:51–

58.

Marnett, LJ; Hurd, HK; Hollstein, MC; et al. (1985) Naturally occurring carbonyl compounds 

are mutagens in Salmonella tester strain TA104. Mutat Res 148:25–34.

Maronpot, RR; Miller, RA; Clarke, WJ; et al. (1986) Toxicity of formaldehyde vapor in B6C3F1 

mice exposed for 13 weeks. Toxicology 41:253–266.
This document is a draft for review purposes only and does not constitute Agency policy.

R-35 DRAFT—DO NOT CITE OR QUOTE

Marsh, GM. (1982) Proportional mortality patterns among chemical plant workers exposed to 

formaldehyde. Br J Ind Med 39:313–322.

Marsh, GM; Youk, AO. (2005) Reevaluation of mortality risks for nasopharyngeal cancer in the 

formaldehyde cohort study of the National Cancer Institute. Regul Pharmacol Toxicol 42:275–

283.

Marsh, GM; Stone, RA; Henderson, VL. (1992a) A reanalysis of the National Cancer Institute 

study on lung cancer mortality among industrial workers exposed to formaldehyde. J Occup 

Med 34:42–44.

Marsh, GM; Stone, RA; Henderson, VL. (1992b) Lung cancer mortality among industrial 

workers exposed to formaldehyde: a Poisson regression analysis of the National Cancer Institute 

Study. Am Ind Hyg Assoc J 53:681-691.

Marsh, GM; Stone, RA; Esmen, NA; et al. (1994) Mortality patterns among chemical plant 

workers exposed to formaldehyde and other substances. J Natl Cancer Inst 86:384–386.

Marsh, GM; Stone, RA; Esmen, NA; et al. (1996) Mortality among chemical workers in a 

factory where formaldehyde was used. Occup Environ Med 53:613–627.

Marsh, GM; Youk, AO; Buchanich, JM; et al. (2002) Pharyngeal cancer mortality among 

chemical plant workers exposed to formaldehyde. Toxicol Ind Health 18:257–268.

Marsh, GM; Youk, AO; Buchanich, JM; et al. (2007a) Work in the metal industry and 

nasopharyngeal cancer mortality among formaldehyde-exposed workers. Regul Toxicol 

Pharmacol 48:308–319.

Marsh, GM; Youk, AO; Morfeld, P. (2007b) Mis-specified and non-robust mortality risk models 

for nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study. 

Regul Toxicol Pharmacol 47:59–67.

Martin, CN; McDermid, AC; and Garner, RC. (1978) Testing of known carcinogens and 

noncarcinogens for their ability to induce unscheduled DNA synthesis in HeLa cells. Cancer Res 

38:2621-2627.

Martin, WJ. (1990) A teratology study of inhaled formaldehyde in the rat. Reprod Toxicol 

4:237–239.

Mashford, PM; Jones, AR. (1982) Formaldehyde metabolism by the rat: a re-appraisal. 

Xenobiotica 12:119–124.

Matanoski, GM. (1989) Risks of pathologists exposed to formaldehyde. National Institute for 

Occupational Safety and Health, Cincinnati, OH. Available from the National Technical 

Information Service, Springfield, VA; PB91-173682.

Matsunaga, I; Miyake, Y; Yoshida, T; et al. (2008) Ambient formaldehyde levels and allergic 

disorders among Japanese women: baseline data from the Osaka maternal and child health study. 

Ann Epidemiol 18:78–84.

Mauderly, JL. (1986) Respiration of F344 rats in nose-only inhalation exposure tubes. J Appl 

Toxicol 6:25–30.
This document is a draft for review purposes only and does not constitute Agency policy.

R-36 DRAFT—DO NOT CITE OR QUOTE

Maurice, F; Rivory, JP; Larsson, PH; et al. (1986) Anaphylactic shock caused by formaldehyde 

in a patient undergoing long-term hemodialysis. J Allergy Clin Immunol 77:594–597.

McGhee, JD; von Hippel, PH. (1975a) Formaldehyde as a probe of DNA structure. I. Reaction 

with exocyclic amino groups of DNA bases. Biochemistry 14:1281–1296.

McGhee, JD; von Hippel, PH. (1975b) Formaldehyde as a probe of DNA structure. II. Reaction 

with endocyclic imino groups of DNA bases. Biochemistry 14:1297–1303.

McGhee, JD; von Hippel, PH. (1977a) Formaldehyde as a probe of DNA structure. 3. 

Equilibrium denaturation of DNA and synthetic polynucleotides. Biochemistry 16:3267–3276.

McGhee, JD; von Hippel, PH. (1977b) Formaldehyde as a probe of DNA structure. r. 

Mechanism of the initial reaction of Formaldehyde with DNA. Biochemistry 16:3276–3293.

McKone, TE; Daniels, JI. (1991) Estimating human exposure through multiple pathways from 

air, water, and soil. Regul Toxicol Pharmacol 13:36–61.

McLean, JH; Shipley, MT. (1988) Postmitotic, postmigrational expression of tyrosine 

hydroxylase in olfactory bulb dopaminergic neurons. J Neurosci 8:3658–3669.

McMartin, KE; Martin-Amat, G; Noker, PE; et al. (1979) Lack of a role for formaldehyde in 

methanol poisoning in the monkey. Biochem Pharmacol 28:645-649. 

Meggs, WJ. (1993) Neurogenic inflammation and sensitivity to environmental chemicals. 

Environ Health Perspect 101:234–238.

Meggs, WJ. (1995) Neurogenic switching: a hypothesis for a mechanism for shifting the site of 

inflammation in allergy and chemical sensitivity. Environ Health Perspect 103:54–56.

Merk, O; Speit, G. (1998) Significance of formaldehyde-induced DNA-protein crosslinks for 

mutagenesis. Environ Mol Mutagen 32:260–268.

Merk, O; and Speit, G. (1999) Detection of crosslinks with the comet assay in relationship to 

genotoxicity and cytotoxicity. Environ Mol Mutagen 33:167-172.

Merletti, F; Boffetta, P; Ferro, G; et al. (1991) Occupation and cancer of the oral cavity or 

oropharynx in Turin, Italy. Scand J Work Environ Health 17:248–254.

Mery, S; Gross, EA; Joyner, DR; et al. (1994) Nasal diagrams: a tool for recording the 

distribution of nasal lesions in rats and mice. Toxicol Pathol 22:353–372.

Metz, B; Kersten, GF; Hoogerhout, P; et al. (2004) Identification of formaldehyde-induced 

modifications in proteins: reactions with model peptides. J Biol Chem 279:6235–6243.

Metz, B; Kersten, GF; Baart, GJ; et al. (2006) Identification of formaldehyde-induced 

modifications in proteins: reactions with insulin. Bioconjug Chem 17:815–822.

Migliore, L; Ventura, L; Barale, R; et al. (1989) Micronuclei and nuclear anomalies induced in 

the gastro-intestinal epithelium of rats treated with formaldehyde. Mutagenesis 4:327–334.

Miretskaia, LV; and Shvartsman, P. (1982) [Chromosome damages in human lymphocytes as 

affected by formaldehyde. I. Formaldehyde treatment of lymphocytes in culture]. Tsitologiia 

24:1056-1060.
This document is a draft for review purposes only and does not constitute Agency policy.

R-37 DRAFT—DO NOT CITE OR QUOTE

Miyachi, T; Tsutsui, T. (2005) Ability of 13 chemical agents used in dental practice to induce 

sister-chromatid exchanges in Syrian hamster embryo cells. Odontology 93:24–29.

Molotkov, A; Fan, X; Deltour, L; et al. (2002) Stimulation of retinoic acid production and 

growth by ubiquitously expressed alcohol dehydrogenase Adh3. Proc Natl Acad Sci USA 

99:5337–5342.

Monteiro-Riviere, NA; Popp, JA. (1986) Ultrastructural evaluation of acute nasal toxicity in the 

rat respiratory epithelium in response to formaldehyde gas. Fundam Appl Toxicol 6:251–262.

Monticello, TM; Morgan, KT. (1994) Cell proliferation and formaldehyde-induced respiratory 

carcinogenesis. Risk Anal 14:313–319.

Monticello, TM; Morgan, KT. (1997) Chemically induced nasal carcinogenesis and epithelial 

cell proliferation: a brief review. Mutat Res 380:33–41.

Monticello, TM; Morgan, KT; Everitt, JI; et al. (1989) Effects of formaldehyde gas on the 

respiratory tract of rhesus monkeys. Pathology and cell proliferation. Am J Pathol 134:515–527.

Monticello, TM; Morgan, KT; Hurtt, ME. (1990) Unit length as the denominator for quantitation 

of cell proliferation in nasal epithelia. Toxicol Pathol 18:24–31.

Monticello, TM; Miller, FJ; Morgan, KT. (1991) Regional increases in rat nasal epithelial cell 

proliferation following acute and subchronic inhalation of formaldehyde. Toxicol Appl 

Pharmacol 111:409–421.

Monticello, TM; Swenberg, JA; Gross, EA; et al. (1996) Correlation of regional and nonlinear 

formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res 56:1012–

1022.

Moolgavkar, SH. (1994) Biological models of carcinogenesis and quantitative cancer risk 

assessment. Risk Anal 14:879–882.

Moolgavkar, SH; Venzon, DJ. (1979) Two-event models for carcinogenesis: Incidence curves 

for childhood and adult tumors. Math Biosci 47:55–77.

Moolgavkar, SH; Knudson, AJ. (1981) Mutation and cancer: A model for human carcinogenesis. 

J Natl Cancer Inst 66:1037–1052.

Moolgavkar, SH; Luebeck, EG. (1992) Interpretation of labeling indices in the presence of cell 

death. Carcinogenesis 13:1007–1010.

Moolgavkar, SH; Dewanji, A; Venzon, D. (1988) A stochastic two-stage model for cancer risk 

assessment. I. The hazard function and the probability of tumor. Risk Anal 8:383–392.

Moolgavkar, SH; Luebeck, EG; Krewski, D; et al. (1993) Radon, cigarette smoke, and lung 

cancer: A reanalysis of the Colorado plateau uranium miner’s data. Epidemiology 4:204–217.

Moore, L; Ogrodnik, EC. (1986) Occupational exposure to formaldehyde in mortuaries. J 

Environ Health 49:32–35.

Moore, S; Montane-Jaime, K; Shafe, S; et al. (2007) Association of ALDH1 promoter 

polymorphisms with alcohol-related phenotypes in Trinidad and Tobago. J Stud Alcohol Drugs 

68:192–196.
This document is a draft for review purposes only and does not constitute Agency policy.

R-38 DRAFT—DO NOT CITE OR QUOTE

Morgan, KT. (1997) A brief review of formaldehyde carcinogenesis in relation to rat nasal 

pathology and human health risk assessment. Toxicol Pathol 25:291–307.

Morgan, KT; Patterson, DL; Gross, EA (1983) Localization of areas of inhibition of nasal 

mucociliary function in rats following in vivo exposure to formaldehyde. Am Rev Respir Dis 

127:166–166.

Morgan, KT; Patterson, DL; Gross, EA. (1984a) Frog palate mucociliary apparatus: structure, 

function, and response to formaldehyde gas. Fundam Appl Toxicol 4:58–68.

Morgan, KT; Jiang, X-Z; Patterson, DL; et al. (1984b) The nasal mucociliary apparatus. Am 

Rev Respir Dis 130:275–281.

Morgan, KT; Gross, EA; Patterson, DL. (1986a) Distribution, progression, and recovery of acute 

formaldehyde-induced inhibition of nasal mucociliary function in F-344 rats. Toxicol Appl 

Pharmacol. 86(3):448–456.

Morgan, KT; Jiang, XZ; Starr, TB; et al. (1986b) More precise localization of nasal tumors 

associated with chronic exposure of F-344 rats to formaldehyde gas. Toxicol Appl Pharmacol 

82:264–271.

Morgan, KT; Patterson, DL; Gross, EA. (1986c) Responses of the nasal mucociliary apparatus of 

F-344 rats to formaldehyde gas. Toxicol Appl Pharmacol 82:1–13.

Morgan, K; Patterson, DL; Gross, E. (1986d) Responses of the nasal mucociliary apparatus to 

airborne irritants. In: Barrow, CS; ed. Toxicology of the nasal passages. Washington, DC: 

Hemisphere Publishing Corporation; pp. 123–133.

Morgan, KT; Kimbell, JS; Monticello, TM; et al. (1991) Studies of inspiratory airflow patterns 

in the nasal passages of the F344 rat and rhesus monkey using nasal molds: relevance to 

formaldehyde toxicity. Toxicol Appl Pharmacol 110:223–240.

Moser, B; Bodrogi, F; Eibl, G; et al. (2005) Mass spectrometric profile of exhaled breath-field 

study by PTR-MS. Respir Physiol Neurobiol 145:295–300.

Muller, W; Engelhart, G; Herbold, B; et al. (1993) Evaluation of mutagenicity testing with 

Salmonella typhimurium TA102 in three different laboratories. Environ Health Perspect 101 

Suppl 3:33–36.

Natarajan, AT; Darroudi, F; Bussman, CJ; et al. (1983) Evaluation of the mutagenicity of 

formaldehyde in mammalian cytogenetic assays in vivo and vitro. Mutat Res 122:355–360.

NCHS (National Center for Health Statistics). (2002) United States Life Tables, 1999. National 

Vital Statistics Reports, vol. 50, no. 6, March 21, pp. 7–8.

NCI (National Cancer Institute). (2003) SEER Cancer Statistics Review, 1975–2000. Bethesda, 

MD. http://seer.cancer.gov/csr/1975_2000/.

NEG (Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals); 

DECOS (Dutch Expert Committee on Occupational Standards). (2003) 132. Formaldehyde. 

Stockholm, Sweden: National Institute for Working Life. Available from 

<http://ebib.arbetslivsinstitutet.se/ah/2003/ah2003_11.pdf>. 2003: 11.
This document is a draft for review purposes only and does not constitute Agency policy.

R-39 DRAFT—DO NOT CITE OR QUOTE

Neri, M; Bonassi, S; Knudsen, LE, et al. (2006) Children's exposure to environmental pollutants 

and biomarkers of genetic damage. I. Overview and critical issues. Mutat Res 612:1-13.

Nielsen, GD. (1991) Mechanisms of activation of the sensory irritant receptor by airborne 

chemicals. Crit Rev Toxicol 21:183–208.

Nielsen, GD; Hougaard, KS; Larsen, ST; et al. (1999) Acute airway effects of formaldehyde and 

ozone in Balb/c mice. Hum Exp Toxicol 18:400–409.

Niinimaa, V; Cole, P; Mintz, S; et al. (1981) Oronasal distribution of respiratory airflow. Respir 

Physiol 43:69–75.

Nilsson, JA; Hedberg, JJ; Vondracek, M; et al. (2004) Alcohol dehydrogenase 3 transcription 

associates with proliferation of human oral keratinocytes. Cell Mol Life Sci 61:610–617.

Norbäck, D; Björnsson, E; Janson, C; et al. (1995) Asthmatic symptoms and volatile organic 

compounds, formaldehyde, and carbon dioxide in dwellings. Occup Environ Med 52(6):388–

395.

NRC (National Research Council). (1983) Risk assessment in the federal government: managing 

the process. Washington, DC: National Academy Press.

NRC (1988) Health risks of radon and other internally deposited alpha-emitters: BEIR IV. 

Committee on the Biological Effects of Ionizing Radiations. Washington, DC: National 

Academy Press.

NRC. (1993) Understanding child abuse and neglect. Panel on Research on Child Abuse and 

Neglect. National Research Council, National academy Press, Washington, DC.

NTP (National Toxicology Program). (2002) Report on Carcinogens. Tenth Edition. Research 

Triangle Park, NC: National Institute of Environmental Health Services, Public Health Service, 

U.S. Department of Health and Human Services. Available from: 

<http://ehp.niehs.nih.gov/roc/tenth/profiles/s089form.pdf>.

NTP. (2005) Control data from NTP Technical Report Series Nos. 210, 267, 272, 306, 311, 314, 

329, 346, 363, 371, 375, 377, 379, 380, 386, 421, 437, 440, 447, 448, 450, 451, 453, 454, 461, 

462, 466, 467, 468, 471, 472, 475, 482, 486, 487, 490, 492, 499, 400, 507, 513, 515, 519 and 

control data from the wollastonite calcium silicates study. U.S. Department of Health and 

Human Services, NTP, Research Triangle Park, NC. Available at http://ntpapps.niehs.nih.gov/ntp.tox/index.cfm.

Neuss, S; and Speit, G. (2008) Further characterization of the genotoxicity of formaldehyde in 

vitro by the sister chromatid exchange test and co-cultivation experiments. Mutagenesis 23:355-

7.

Nunn, A; Craigen, A; Darbyshire, J; et al. (1990) Six year follow up of lung function in men 

occupationally exposed to formaldehyde. Br J Ind Med 47:747–752.

Obe, G; and Beek, B. (1979) Mutagenic activity of aldehydes. Drug Alcohol Depend 4:91-94.

O'Connor, PM; and Fox, BW. (1987) Comparative studies of DNA cross-linking reactions 

following methylene dimethanesulphonate and its hydrolytic product, formaldehyde. Cancer 

Chemother Pharmacol 19:11-5.
This document is a draft for review purposes only and does not constitute Agency policy.

R-40 DRAFT—DO NOT CITE OR QUOTE

Odeigah, PGC. (1997) sperm head abnormalities and dominant lethal effects of formaldehyde in 

albino rats. Mutat Res 389:141–148.

O'Donovan, MR; Mee, CD. (1993) Formaldehyde is a bacterial mutagen in a range of 

Salmonella and Escherichia indicator strains. Mutagenesis 8:577–581.

Oerstavik, D; and Hongslo, JK. (1985) Mutagenicity of endodontic sealers. Biomaterials 6:129-

132.

Ohba, Y; Morimitsu, Y; Watarai, A. (1979) Reaction of formaldehyde with calf-thymus 

nucleohistone. Eur J Biochem 100:285–293.

Ohmichi, K; Komiyama, M; Matsuno, Y; et al. (2006) Relationship between exposure to 

formaldehyde and immunoglobulin E (IgE) production during the gross anatomy laboratory. J 

Health Sci 52/5:642–647.

Ohta, T; Watanabe-Akanuma, M; Tokishita, S; et al. (1999) Mutation spectra of chemical 

mutagens determined by Lac+ reversion assay with Escherichia coli WP3101P-WP3106P tester 

strains. Mutat Res 440:59–74.

Ohta, T; Watanabe-Akanuma, M; Yamagata, H. (2000) A comparison of mutation spectra 

detected by the Escherichia coli lac(+) reversion assay and the Salmonella typhimurium his(+) 

reversion assay. Mutagenesis 15:317–23.

Ohtani, T; Mizuashi, M; Nakagawa, S; et al. (2004a) Diesel exhaust particles and formaldehyde 

deviate human immune system to Th2-dominant pattern by affecting both T cells and dendritic 

cells. J Invest Dermatol 122:A121.

Ohtani, T; Kurosawa, W; Mizuashi, M; et al. (2004b) Effects of diesel exhaust particles (DEP) 

and formaldehyde on human monocyte-derived dendritic cells (MoDCs) and T cells. J Dermatol 

Sci 34:134.

Ohtsuka, R; Shuto, Y; Fujie, H; et al. (1997) Response of respiratory epithelium of BN and F344 

rats to formaldehyde inhalation. Exp Anim 46:279–286.

Ohtsuka, R; Shutoh, Y; Fujie, H; et al. (2003) Rat strain difference in histology and expression 

of Th1- and Th2-related cytokines in nasal mucosa after short-term formaldehyde inhalation. 

Exp Toxicol Pathol 54:287–291.

Olin, KL; Cherr, GN; Rifkin, E, et al. (1996) The effects of some redox-active metals and 

reactive aldehydes on DNA-protein cross-links in vitro. Toxicology 110:1-8.

Olsen, JH; Dossing, M. (1982) Formaldehyde induced symptoms in day care centers. Am Ind 

Hyg Assoc J 43:366-370.

Olsen, JH; Asnaes, S. (1986) Formaldehyde and the risk of squamous cell carcinoma of the 

sinonasal cavities. Br J Ind Med 43:769–774.

Olsen, JH; Jensen, SP; Hink, M; et al. (1984) Occupational formaldehyde exposure and 

increased nasal cancer risk in man. Int J Cancer 34:639–644.

Olsen, GW; Lacy, SE; Bodner, KM; et al. (1997) Mortality from pancreatic and lymphopoietic 

cancer among workers in ethylene and propylene chlorohydrin production. Occup Environ Med 

54:592–598.
This document is a draft for review purposes only and does not constitute Agency policy.

R-41 DRAFT—DO NOT CITE OR QUOTE

Orsière, T; Sari-Minodier, I; Iarmarcovai, G; et al. (2006) Genotoxic risk assessment of 

pathology and anatomy laboratory workers exposed to formaldehyde by use of personal air 

sampling and analysis of DNA damage of peripheral lymphocytes. Mutat Res 605:30–41.

Orstavik, D; Hongslo, JK. (1985) Mutagenicity of endodontic sealers. Biomaterials 6:129–132.

Oshino, N; Chance, B; Sies, H; et al. (1973) The role of H2O2 generation in perfused rat liver 

and the reaction of catalase compound I and hydrogen donors. Arch Biochem Biophys 154:117-

131. 

Ostojić, L; Bradarić, A; Miše, K; et al. (2006) Pulmonary function in persons who are 

professionally exposed to formaldehyde fumes. Coll Antropol 30(3):507–511.

Overman, DO. (1985) Absence of embryotoxic effects of formaldehyde after percutaneous 

exposure in hamsters. Toxicol Lett 24:107–110.

Overton, JH; Kimbell, JS; Miller, FJ. (2001) Dosimetry modeling of inhaled formaldehyde: the 

human respiratory tract. Toxicol Sci 64:122–134.

Øvrebø, S; Haugen, A; Skaug, V. (2002) Biotransformation of formaldehyde in cultured human 

bronchus. Environ Res 89:38–42.

Owen, BA; Dudney, CS; Tan, E; et al. (1990a) Comparative Hazard Evaluation, An Approach 

To Regulation:Formaldehyde in Drinking Water. Health and Safety Research Division, Oak 

Ridge National Laboratory

Owen, BA; Dudney, CS; Tan, EL; et al. (1990b) Formaldehyde in drinking water: comparative 

hazard evaluation and an approach to regulation. Regul Toxicol Pharmacol 11:220–236.

Özen, OA; Yaman, M; Sarsilmaz, M; et al. (2002) Testicular zinc, copper and iron 

concentrations in male rats exposed to subacute and subchronic formaldehyde gas inhalation. J 

Trace Elem Med Biol 16:119–122.

Özen, OA; Songur, A; Sarsilmaz, M; et al. (2003a) Changes of zinc, copper, and iron levels in 

the lung of male rats after subacute (4-week) and subchronic (13-week) exposure to 

formaldehyde. J Trace Elem Exp Med 16:67–74.

Özen, OA; Songur, A; Sarsilmaz, M; et al. (2003b) Zinc, copper and iron concentrations in 

cerebral cortex of male rats exposed to formaldehyde inhalation. J Trace Elem Med Biol 

17:207–209.

Özen, OA; Akpolat, N; Songur, A; et al. (2005) Effect of formaldehyde inhalation on Hsp70 in 

seminiferous tubules of rat testes: An immunohistochemical study. Toxicol Ind Health 21:249–

254.

Palczyński, C; Krakowiak, A; Hanke, W; et al. (1999) Indoor formaldehyde exposure and airway 

allergic diseases. Int Rev Allergol Clin Immunol 5:65–69.

Park, H-S; Francis, KP; Yu, J; et al. (2003) Membranous cells in nasal-associated lymphoid 

tissue: a portal of entry for the respiratory mucosal pathogen group A streptococcus. J Immunol 

171:2532–2537.

Partanen, T; Kauppinen, T; Hernberg, S; et al. (1990) Formaldehyde exposure and respiratory 

cancer among woodworkers: an update. Scand J Work Environ Health 16:394–400.
This document is a draft for review purposes only and does not constitute Agency policy.

R-42 DRAFT—DO NOT CITE OR QUOTE

Passegue, E; Jamieson, CH; Ailles, LE; et al. (2003) Normal and leukemic hematopoiesis: are 

leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci 

U.S.A. 100(Suppl 1):11842–11849.

Pauluhn, J. (1996) Predictive testing for respiratory sensitization Toxicol Lett 86:177–185.

Pauluhn, J. (2003) Issues of dosimetry in inhalation toxicity. Toxicol Lett 140–141:229–238.

Pazdrak, K; Górski, P; Krakowiak, A; et al. (1993) Changes in nasal lavage fluid due to 

formaldehyde inhalation. Int Arch Occup Environ Health 64:515–519.

Peddada, SD; Dinse, GE; Kissling, GE. (2007) Incorporating historical control data when 

comparing tumor incidence rates. J Am Stat Assoc 102:1212–1220.

Pinkerton, LE; Hein, MJ; Stayner, LT. (2004) Mortality among a cohort of garment workers 

exposed to formaldehyde: an update. Occup Environ Med 61:193–200.

Pitten, FA; Kramer, A; Herrmann, K; et al. (2000) Formaldehyde neurotoxicity in animal 

experiments. Pathol Res Pract 196:193–198.

Plesner, BH; and Hansen, K. (1983) Formaldehyde and hexamethylenetetramine in Styles' cell 

transformation assay. Carcinogenesis 4:457-459.

Plopper, CG; Weir, AJ; Nishio, SJ; et al. (1994) Elevated susceptibility to 4-ipomeanol 

cytotoxicity in immature Clara cells of neonatal rabbits. J Pharmacol Exp Ther 269:867–880.

Poortmans, JR; Kumps, A; Duez, P; et al. (2005) Effect of oral creatine supplementation on 

urinary methylamine, formaldehyde, and formate. Med Sci Sports Exerc 37:1717-1720. 

Portier, CJ; Hedges, JC; Hoel, DG. (1986) Age-specific models of mortality and tumor onset for 

historical control animals in the National Toxicology Program’s carcinogenicity experiments. 

Cancer Res 46:4372–4378.

Pottern, LM; Heineman, EF; Olsen, JH; et al. (1992) Multiple myeloma among Danish women: 

employment history and workplace exposures. Cancer Causes Control 3:427–432.

Pourmahabadian, M; Azam, K; Ghasemkhani, M. (2006) Pulmonary function study between 

formaldehyde exposed and non-exposed staffs at some of the Tehran Educational Hospitals. J 

Med Sci 6/4:621–625.

Priha, E; Liesivuori, J; Santa, H; et al. (1996) Reactions of hydrated formaldehyde in nasal 

mucus. Chemosphere 32:1077–1082.

Proctor, BL; Gaulden, ME; Dowd, MA. (1986) Reactivity and fate of benzene and formaldehyde 

in culture medium with and without fetal calf serum; relevance to in vitro mutagenicity testing. 

Mutat Res 160:259–266.

Pross, HF; Day, JH; Clark, RH; et al. (1987) Immunologic studies of subjects with asthma 

exposed to formaldehyde and urea-formaldehyde foam insulation (UFFI) off products. J Allergy 

Clin Immunol 79:797–810.

Pushkina, N; Gofmekler, V; Klevtsova, G. (1968) Changes in ascorbic-acid and nucleic-acid 

content during benzol and formaldehyde action rat [translation]. Bull Exp Biol Med 66:51–53.
This document is a draft for review purposes only and does not constitute Agency policy.

R-43 DRAFT—DO NOT CITE OR QUOTE

Pyatt, D; Natelson, E; Golden, R. (2008) Is inhalation exposure to formaldehyde a biologically 

plausible cause of lymphohematopoietic malignancies? Regul Toxicol Pharmacol 51:119–133.

Que, LG; Liu, L; Yan, Y; et al. (2005) Protection from experimental asthma by an endogenous 

bronchodilator. Science 308:1618–1621.

Quievryn, G; Zhitkovich, A. (2000) Loss of DNA-protein crosslinks from formaldehyde-exposed 

cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome 

function. Carcinogenesis 21:1573–1580.

Ragan, DL; and Boreiko, CJ. (1981) Initiation of C3H/10T1/2 cell transformation by 

formaldehyde. Cancer Lett 13:325-331.

Rao, GN; Piegorsch, WW; Haseman, JK. (1987) Influence of body weight on the incidence of 

spontaneous neoplasms in rats and mice of long-term studies. Am J Clin Nutr. 45:252–260.

Rapoport, IA. (1946) Carbonyl compounds and the chemical mechanisms of mutation. Compt 

Rend Acad Sci (U.S.S.R.) 54:65–67.

Recio, L; Sisk, S; Pluta, L, et al. (1992) p53 mutations in formaldehyde-induced nasal squamous 

cell carcinomas in rats. Cancer Res 52:6113-6116.

Report of the Federal Panel on Formaldehyde. (1982) Environ Health Perspect 43:139–168.

Reuzel, PGJ; Wilmer, JWGM; Woutersen, RA; et al. (1990) Interactive effects of ozone and 

formaldehyde on the nasal respiratory lining epithelium in rats. J Toxicol Environ Health 

29:279–292.

Riedel, F; Hasenauer, E; Barth, PJ; et al. (1996) Formaldehyde exposure enhances inhalative 

allergic sensitization in the guinea pig. Allergy 51:94–99.

Ritchie, IM; Lehnen, RG. (1987) Formaldehyde-related health complaints of residents living in 

mobile and conventional homes. Am J Public Health 77:323–328.

Robins, J; Ambrun, M; Hute, C; et al. (1988) Estimating the effect of formaldehyde exposure on 

long cancer and non-malignant respiratory disease (NMRD) mortality using a new method to 

control for the health worker survivor effect. In: Hogstedt, C; Reuterwall, C; eds. Progress in 

occupational epidemiology. Amsterdam: Elsevier Science; pp. 75–78.

Roemer, E; Anton, HJ; Kindt, R. (1993) Cell proliferation in the respiratory tract of the rat after 

acute inhalation of formaldehyde or acrolein. J Appl Toxicol 13:103–107.

Rogers, J; Mole, M; Chernoff, N; et al. (2002) Developmental toxicity of inhaled methanol in the 

CD-1 mouse, with application of quantitative dose-response modeling for estimation of 

benchmark dosages. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J92/350 (NTIS PB93106979).

Rogers, JM; Brannen, KC; Barbee, BD; et al. (2004) Methanol exposure during gastrulation 

causes holoprosencephaly, facial dysgenesis, and cervical vertebral malformations in C57BL/6J 

mice Birth Defects B Dev Reprod Toxicol 71:80–88.

Ross, WE; Shipley, N. (1980) Relationship between DNA damage and survival in formaldehydetreated mouse cells. Mutat Res 79:277–283.
This document is a draft for review purposes only and does not constitute Agency policy.

R-44 DRAFT—DO NOT CITE OR QUOTE

Ross, WE; McMillan, DR; and Ross, CF. (1981) Comparison of DNA damage by 

methylmelamines and formaldehyde. J Natl Cancer Inst 67:217-221.

Rotstein, J; Sarma, DSR; Farber, E. (1986) Sequential alterations in growth control and cell 

dynamics of rat hepatocytes in early precancerous steps in hepatocarcinogenesis. Cancer Res 

46:2377–2385.

Roush, GC; Walrath, J; Stayner, LT; et al. (1987) Nasopharyngeal cancer, sinonasal cancer, and 

occupations related to formaldehyde: a case-control study. J Natl Cancer Inst 79:1221–1224.

Rumchev, KB; Spickett, JT; Bulsara, MK; et al. (2002) Domestic exposure to formaldehyde 

significantly increases the risk of asthma in young children. Eur Respir J 20:403–408.

Rumchev, K; Spickett, J; Bulsara, M; et al. (2004) Association of domestic exposure to volatile 

organic compounds with asthma in young children. Thorax 59: 746-751.

Rusch, GM; Bolte, HF; Rinehart, WE. (1983a) A 26-week inhalation toxicity study with 

formaldehyde in the monkey, rat, and hamster. In: Gibson, JE; ed. Formaldehyde toxicity. 

Washington, DC: Hemisphere Publishing Corporation; pp. 98–110.

Rusch, GM; Clary, JJ; Rinehart, WE; et al. (1983b) A 26-week inhalation toxicity study with 

formaldehyde in the monkey, rat and hamster. Toxicol Appl Pharmacol 68:329–343.

Rydén, E; Ekström, C; Hellmér, L; et al. (2000) Comparison of the sensitivities of Salmonella 

typhimurium strains TA102 and TA2638A to 16 mutagens. Mutagenesis 15:495–502.

Sadakane, K; Takano, H; Ichinose, T; et al. (2002) Formaldehyde enhances mite allergeninduced eosinophilic inflammation in the murine airway. J Environ Pathol Toxicol Oncol 

21:267–276.

Saillenfait, AM; Bonnet, P; de Ceaurriz, J. (1989) The effects of maternally inhaled 

formaldehyde on embryonal and foetal development in rats. Food Chem Toxicol 27:545–548.

Saito, Y; Nishio, K; Yoshida, Y, et al. (2005) Cytotoxic effect of formaldehyde with free radicals 

via increment of cellular reactive oxygen species. Toxicology 210:235-245.

Saladino, AJ; Willey, JC; Lechner, JF, et al. (1985) Effects of formaldehyde, acetaldehyde, 

benzoyl peroxide, and hydrogen peroxide on cultured normal human bronchial epithelial cells. 

Cancer Res 45:2522-2526.

Salkie, ML. (1991) The prevalence of atopy and hypersensitivity to formaldehyde in 

pathologists. Arch Pathol Lab Med 115(6):614–616

Sallmén, M; Lindbohm, ML; Kyyronen, P; et al. (1995) Reduced fertility among women 

exposed to organic solvents. Am J Ind Med 27(5):699–713.

Salthammer T, S Mentese and R Marutzky (2010). Formaldehyde in the Indoor Environment. 

Chem. Rev., DOI: 10.1021/cr800399g

Sandikci, M; Eren, U; Kum, S. (2007) Effects of formaldehyde and xylene on CD4- and CD8-

positive T cells in bronchus-associated lymphoid tissue in rats. Toxicol Ind Health 23:471–477.

Sanghani, PC; Stone, CL; Ray, BD; et al. (2000) Kinetic mechanism of human glutathionedependent formaldehyde dehydrogenase. Biochemistry 39:10720-10729. 
This document is a draft for review purposes only and does not constitute Agency policy.

R-45 DRAFT—DO NOT CITE OR QUOTE

Sanotskii, IV; Fomenko, VN; Sheveleva, GA; et al. (1976) Study of the effect of pregnancy of 

animals to chemical agents. Gig Tr Prof Zabol 1:25–28.

Santiago, LY; Hann, MC; Ben-Jebria, A; et al. (2001) Ozone absorption in the human nose 

during unidirectional airflow. J Appl Physiol 91:725–732.

Sari-Minodier, I; Orsière, T; Auquier, P; et al. (2001) Use of the micronucleus assay in the 

mutagenic risk assessment: A case of 10 workers occupationally exposed to formaldehyde. Arch 

Mal Prof 62:75–82.

Sarsilmaz, M; Özen, O; Akpolat, N; et al. (1999) The histopathologic effects of inhaled 

formaldehyde on Leydig cells of the rats in subacute period [translation]. Firat Univ Med Sci J 

13:37–40.

Sarsilmaz, M; Kaplan, S; Songur, A; et al. (2007) Effects of postnatal formaldehyde exposure on 

pyramidal cell number, volume of cell layer in hippocampus and hemisphere in therat: A 

stereological study. Brain Res 1145:157–167.

Sarrif, AM; Krahn, DF; Donovan, SM, et al. (1997) Evaluation of hexamethylphosphoramide for 

gene mutations in Salmonella typhimurium using plate incorporation, preincubation, and 

suspension assays. Mutat Res 380:167-177.

Sauder, LR; Chatham, MD; Green, DJ; et al. (1986) Acute pulmonary response to formaldehyde 

exposure in healthy nonsmokers. J Occup Med 28:420–424.

Sauder, LR; Green, DJ; Chatham, MD; et al. (1987) Acute pulmonary response of asthmatics to 

3.0 ppm formaldehyde. Toxicol Ind Health 3:569–578. 

Schachter, EN; Witek, TJ, Jr; Tosun, T; et al. (1986) A study of respiratory effects from 

exposure to 2 ppm formaldehyde in healthy subjects. Arch Environ Health 41:229–239.

Schachter, EN; Witek, TJ, Jr; Brody, DJ; et al. (1987) A study of respiratory effects from 

exposure to 2.0 ppm formaldehyde in occupationally exposed workers. Environ Res 44:188–

205.

Schauenstein, E; Esterbauer, H; Zollner, H. (1977) Aldehydes in biological systems. London: 

Pion Limited. 

Schlosser, PM. (1999) Relative roles of convection and chemical reaction for the disposition of 

formaldehyde and ozone in nasal mucus. Inhal Toxicol 11:967–980.

Schlosser, PM; Lilly, PD; Conolly, RB; et al. (2003) Benchmark dose risk assessment for 

formaldehyde using airflow modeling and a single-compartment, DNA-protein cross-link 

dosimetry model to estimate human equivalent doses. Risk Anal 23:473–487.

Schmid, E; Goggelmann, W; Bauchinger, M. (1986) Formaldehyde-induced cytotoxic, genotoxic 

and mutagenic response in human lymphocytes and Salmonella typhimurium. Mutagenesis 

1:427–431.

Schmid, O; Speit, G. (2007) Genotoxic effects induced by formaldehyde in human blood and 

implications for the interpretation of biomonitoring studies. Mutagenesis 22:69–74.

Schoenberg, JB; Beck, GJ; Bouhuys, A. (1978) Growth and decay of pulmonary function in 

healthy blacks and whites. Respir Physiol 33:367–393.
This document is a draft for review purposes only and does not constitute Agency policy.

R-46 DRAFT—DO NOT CITE OR QUOTE

Schreiber, H; Bibbo, M; Wied, GL; et al. (1979) Bronchial metaplasia as a benign or 

premalignant lesion. I. Cytologic and ultrastructural discrimination between acute carcinogen 

effects and toxin-induced changes. Acta Cytol 23:496–503.

Schuck, EA; Stephens, ER; Middleton, JT. (1966) Eye irritation response at low concentrations 

of irritants. Arch Environ Health 13(5):570–575.

Schulte-Hermann, R; Bursch, W; Grasl-Kraupp, B; et al. (1997) Concepts of cell death and 

application to carcinogenesis. Toxicol Pathol 25:89–93.

Schulte-Hermann, R; Bursch, W; Marian, B; et al. (1999) Active cell death (apoptosis) and 

cellular proliferation as indicators of exposure to carcinogens. IARC Sci.Publ 273–285.

Seidenberg, J; Anderson, DG; Becker, R. (1986) Validation of an in vivo developmental toxicity 

screen in the mouse. Teratog Carcinog Mutagen 6:361–374.

Seidenberg, J; Becker, R. (1987) A summary of the results of 55 chemicals screened for 

developmental toxicity in mice. Teratog Carcinog Mutagen 7:17–28.

Seitz, T; Baron, S. (1990) Health hazard evaluation report: Rockcastle Manufacturing, Mount 

Vernon, Kentucky. National Institute for Occupational Safety and Health, U.S. Department of 

Health and Human Services, Cincinnati, OH; HETA 87-349-2022.

Selevan, SG; Kimmel, CA; Mendola, P. (2000) Identifying critical windows of exposure for 

children’s health. Environ Health Perspect 108 Suppl 3:451–455.

Sellakumar, AR; Snyder, CA; Solomon, JJ; et al. (1985) Carcinogenicity of formaldehyde and 

hydrogen chloride in rats. Toxicol Appl Pharmacol 81:401–406.

Senichenkova, IN. (1991) The embryotoxic effect of industrial environmental pollutants 

formaldehyde and gasoline [translation]. Gig Sanit 9:35–38.

Senichenkova, IN; Chebotar, NA. (1996) Effects of gasoline and formaldehyde on prenatal 

development of rats with induced iron microelementosis [translation]. Ontogenez 27:108–113.

Shaham, J; Bomstein, Y; Meltzer, A; et al. (1996a) DNA-protein crosslinks, a biomarker of 

exposure to formaldehyde―in vitro and in vivo studies. Carcinogenesis 17:121–125.

Shaham, J; Bomstein, Y; Meltzer, A; et al. (1996b) Response to Letter to Editor by Casanova et 

al. (1996) in the same issue. Carcinogenesis 17:2098–210l.

Shaham, J; Bomstein, Y; Melzer, A; et al. (1997) DNA-protein crosslinks and sister chromatid 

exchanges as biomarkers of exposure to formaldehyde. Int J Occup Environ Health 3:95–104.

Shaham, J; Gurvich, R; Kaufman, Z. (2002) Sister chromatid exchange in pathology staff 

occupationally exposed to formaldehyde. Mutat Res 514:115–123.

Shaham, J; Bomstein, Y; Gurvich, R; et al. (2003) DNA-protein crosslinks and p53 protein 

expression in relation to occupational exposure to formaldehyde. Occup Environ Med 60:403–

409.

Shangina, O; Brennan, P; Szeszenia-Dabrowska, N; et al. (2006) Occupational exposure and 

laryngeal and hypopharyngeal cancer risk in central and eastern Europe. Am J Epidemiol 

164(4):367–375.
This document is a draft for review purposes only and does not constitute Agency policy.

R-47 DRAFT—DO NOT CITE OR QUOTE

Sharpe, JA; Hostovsky, M; Bilbao, JM; et al. (1982) Methanol optic neuropathy. A 

histopathological study. Neurology 32:1093–1100.

Shelby, M; Portier, C; Goldman, L; et al. (2004) NTP-CERHR expert panel report on the 

reproductive and developmental toxicity of methanol. Reprod Toxicol 18:303-390. 

Sheppard, D; Eschenbacher, W; Epstein, J. (1984) Lack of bronchomotor response to up to 3 

ppm formaldehyde in subjects with asthma. Environ Res 35:133–139.

Sheveleva (1971) In Toxicology of New Industrial Chemicals. 12:78–86.

Shibamoto, T. (2006) Analytical methods for trace levels of reactive carbonyl compounds 

formed in lipid peroxidation systems. J Pharm Biomed Anal 41:12-25. 

Shin, HS; Ahn, HS; Lee, BH. (2007) Determination of thiazolidine-4 carboxylates in urine by 

chloroformate derivatization and gas chromatography-electron impact mass spectrometry. J 

Mass Spectrom 42:1225–1232.

Shipkovitz, HD. (1966) Formaldehyde vapor in the permanent-press fabrics industry. 

Occupational Health Program, Public Health Service, U.S. Department of Health, Education, and 

Welfare, Cincinnati, OH; Report-TR-52.

Singh, GD; McNamara, JA Jr; Lozanoff, S. (1998) Morphometry of the midfacial complex in 

subjects with class III malocclusions: Procrustes, Euclidean, and cephalometric analyses. Clin 

Anat 11:162–170.

Skrzydlewska, E. (1996) Decreased antioxidant status and increased lipid peroxidation in rats 

after methanol intoxication. Rocz Akad Med Bialymst 41:397–404.

Slater, TF. (1984) Free-radical mechanisms in tissue injury. Biochem J 222:1-15. 

Slikker, WJ; Andersen, M; Bogdanffy, M; et al. (2004) Dose-dependent transitions in 

mechanisms of toxicity: Case studies. Toxicol Appl Pharmacol 201:226–294.

Smedje, G; Norbäck, D. (2001) Incidence of asthma diagnosis and self-reported allergy in 

relation to the school environment―a four-year follow-up study in schoolchildren. Int J Tuberc 

Lung Dis 5:1059–1066.

Smith, AE; Coit, DW. (1995) Penalty Functions. In Environmental Computation 2. Eds: Back,

T; Fogel, DB; Michalewicz., Z. 41–48. Institute of Physics Publishing and Oxford University 

Press, New York, NY.

Kusch, I; Schwarz, K; Schwentner, L; et al. (2008) Compounds enhanced in a mass 

spectrometric profile of smokers’ exhaled breath versus non-smokers as determined in a pilot 

study using PTR-MS. J. Breath Res. 2: 1-26.

Snedecor, GW; Cochran, WG. (1980) Statistical Methods, Seventh Edition. Iowa State 

University Press, Ames, IA.

Snyder, RD; van Houten, B. (1986) Genotoxicity of formaldehyde and an evaluation of its 

effects on the DNA repair process in human diploid fibroblasts. Mutat Res 165:21–30.

Soffritti, M; Maltoni, C; Maffei, F; et al. (1989) Formaldehyde: an experimental multipotential 

carcinogen. Toxicol Ind Health 5:699–730.
This document is a draft for review purposes only and does not constitute Agency policy.

R-48 DRAFT—DO NOT CITE OR QUOTE

Soffritti, M; Belpoggi, F; Lambertin, L; et al. (2002) Results of long-term experimental studies 

on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann NY Acad Sci 982:87–

105.

Songur, A; Kus, I; Sahin, S; Sogut, S; Ozen, OA; Yaman, M; Sarsilmaz, M. (2005) The changes 

of zinc, copper, and iron levels in lung tissue after formaldehyde inhalation during the early 

postnatal period of rats. Eur J Gen Med 2(2):62-68.

Songur, A; Sarsilmaz, M; Özen, OA. (2008) The effects of inhaled formaldehyde on oxidant and 

antioxidant systems of rat cerebellum during the postnatal development process. Toxicol 

Mechan Methods 18:569–574.

Sorg, BA; Hochstatter, T. (1999) Behavioral sensitization after repeated formaldehyde exposure 

in rats. Toxicol Ind Health 15:346–355.

Sorg, BA; Willis, JR; See, RE; et al. (1996) Repeated low-level formaldehyde exposure produces 

long-term cross-sensitization to cocaine: relevance to an animal model for multiple chemical 

sensitivity. Soc Neurosci Abstr 22:2064

Sorg, BA; Willis, JR; See, RE; et al. (1998) Repeated low-level formaldehyde exposure produces 

cross-sensitization to cocaine: Possible relevance to chemical sensitivity in humans. 

Neuropsychopharm 18:385–394.

Sorg, BA; Bailie, TM; Tschirgi, ML; et al. (2001) Exposure to repeated low-level formaldehyde 

in rats increases basal corticosterone levels and enhances the corticosterone response to 

subsequent formaldehyde. Brain Res 898:314–320.

Sorg, BA; Swindell, S; Tschirgi, ML. (2004) Repeated low level formaldehyde exposure 

produces enhanced fear conditioning to odor in male, but not female, rats. Brain Res 1008:11–

19.

Španĕl, P and Smith, D. (2008) Quantification of trace levels of the potential cancer biomarkets 

formaldehyde, acetaldehyde and propanol in breath by SIFT-MS. J. Breath Res. 2: 1-10.

Speit, G; Merk, O. (2002) Evaluation of mutagenic effects of formaldehyde in vitro: detection of 

crosslinks and mutations in mouse lymphoma cells. Mutagenesis 17:183–187.

Speit, G; Schmid, O. (2006) Local genotoxic effects of formaldehyde in humans measured by the 

micronucleus test with exfoliated epithelial cells. Mutat Res 613:1–9.

Speit, G; Schutz, P; Merk, O. (2000) Induction and repair of formaldehyde-induced DNAprotein crosslinks in repair-deficient human cell lines. Mutagenesis 15:85–90.

Speit, G; Schmid, O; Fröhler-Keller, M; et al. (2007a) Assessment of local genotoxic effects of 

formaldehyde in humans measured by the micronucleus test with exfoliated buccal mucosa cells. 

Mutat Res 627:129–135.

Speit, G; Schutz, P; Hogel, J, et al. (2007b) Characterization of the genotoxic potential of 

formaldehyde in V79 cells. Mutagenesis 22:387-394.

Speit, G; Schmid, O; Neuss, S, et al. (2008) Genotoxic effects of formaldehyde in the human 

lung cell line A549 and in primary human nasal epithelial cells. Environ Mol Mutagen 49:300-

307.
This document is a draft for review purposes only and does not constitute Agency policy.

R-49 DRAFT—DO NOT CITE OR QUOTE

Speit, G; Zeller, J; Schmid, O, et al. (2009) Inhalation of formaldehyde does not induce systemic 

genotoxic effects in rats. Mutat Res. (In Press)

Squire, RA; Cameron, LL. (1984) An analysis of potential carcinogenic risk from formaldehyde. 

Regul Toxicol Pharmacol 4:107–129.

Staab, CA; Hellgren, M; Höög, J-O. (2008a) Dual functions of alcohol dehydrogenase 3: 

Implications with focus on formaldehyde dehydrogenase and S-nitrosoglutathione reductase 

activities. Cell Mol Life Sci 65:3950–3960.

Staab, CA; Ålander, J; Brandt, M; et al. (2008b) Reduction of S-nitrosoglutathione by alcohol 

dehydrogenase 3 is facilated by substrate alcohols via direct cofactor recycling and leads to 

GSH-controlled formation of glutathione transferase inhibitors. Biochem J 41:493–504.

Staab, CA; Hellgren, M; Grafström, RC; et al. (2009) Medium-chain fatty acids and glutathione 

derivatives as inhibitors of S-nitroglutathione reduction mediated by alcohol dehydrogenase 3. 

Chem Biol Interact 180:113–118.

Stayner, LT; Elliot, L; Blade, L; et al. (1988) A retrospective cohort mortality study of workers 

exposed to formaldehyde in the garment industry. Am J In Med 13:667–681.

Stedman’s Medical Dictionary. (2005) 28th edition. Lippincott Williams, and Wilkins, New 

York, NY.

Steinhagen, WH; Barrow, CS. (1984) Sensory irritation structure-activity study of inhaled 

aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol Appl Pharmacol 72:495–503.

Stellman, SD; Demers, PA; Colin, D; et al. (1998) Cancer mortality and wood dust exposure 

among participants in the American cancer Society cancer prevention study-II (CPS-II). Am J 

Ind Med 34:229–237.

Sterling, TD; Weinkam, JJ. (1988) Reanalysis of lung cancer mortality in a National Cancer 

Institute study on mortality among industrial workers exposed to formaldehyde. J Occup Med 

30:895–901.

Sterling, TD; Weinkam, JJ. (1989a) Reanalysis of lung cancer mortality in a National Cancer 

Institute study on “Mortality among industrial workers exposed to formaldehyde.” Exp Pathol 

37:128–132.

Sterling, TD; Weinkam, JJ. (1989b) Reanalysis of lung cancer mortality in a National Cancer 

Institute study of “Mortality among industrial workers exposed to formaldehyde:” additional 

discussion. J Occup Med 31:881–884.

Sterling, TD; Weinkam, JJ. (1994) Mortality from respiratory cancers (including lung cancer) 

among workers employed in formaldehyde industries. Am J Ind Med 25:593–602.

Stewart, PA; Blair, A; Cubit, DA; et al. (1986) Estimating historical exposures to formaldehyde 

in a retrospective mortality study. Appl Ind Hyg 1:34–41.

Stewart, PA; Cubit, D; Blair, A. (1987) Formaldehyde levels in seven industries. Appl Ind Hyg 

2:231–236.
This document is a draft for review purposes only and does not constitute Agency policy.

R-50 DRAFT—DO NOT CITE OR QUOTE

Stewart, PA; Herrick, RF; Feigley, CE; et al. (1992) Study design for assessing exposures of 

embalmers for a case-control study. Part I. Monitoring results. Appl Occup Environ Hyg 7:532–

540.

Stone, DM; Grillo, M; Margolis, FL; et al. (1991) Differential effect of functional olfactory bulb 

deafferentation on tyrosine hydroxylase and glutamic acid decarboxylase messenger RNA levels 

in rodent juxtaglomerular neurons. J Comp Neurol 311:223–233.

Stroup, NE; Blair, A; Erikson, GE. (1986) Brain cancer and other causes of death in anatomists. 

J Natl Cancer Inst 77:1217–1224.

Subramaniam, RP; Richardson, RB; Morgan, KT; et al. (1998) Computational fluid dynamics 

simulations of inspiratory airflow in the human nose and nasopharynx. Inhal Toxicol 10:92–120.

Subramaniam, RP; Crump, KS; Van Landingham, C; et al. (2007) Uncertainties in the CIIT 

model for formaldehyde-induced carcinogenicity in the rat: A limited sensitivity analysis-I. Risk 

Anal 27:1237–1254.

Subramaniam, RP, Chen, C; Crump, KS; et al. (2008) Uncertainties in biologically-based 

modeling of formaldehyde-induced respiratory cancer risk: Identification of key issues. Risk 

Anal 28:907–923.

Sul, D; Kim, H; Oh, E; et al. (2007) Gene expression profiling in lung tissues from rats exposed 

to formaldehyde. Arch Toxicol 81:589–597.

Suruda, A; Schulte, P; Boeniger, M; et al. (1993) Cytogenetic effects of formaldehyde exposure 

in students of mortuary science. Cancer Epidemiol Biomarkers Prev 2:453–460.

Suskov, II; and Sazonova, LA. (1982) Cytogenetic effects of epoxy, phenolformaldehyde and 

polyvinylchloride resins in man. Mutat Res 104:137-140.

Sweeney, MH; Beaumont, JJ; Waxweiler, RJ; et al. (1986) An investigation of mortality from 

cancer and other causes of death among workers employed at an East Texas chemical plant. 

Arch Environ Health 41:23–28.

Swenberg, JA; Kerns, WD; Mitchell, RI; et al. (1980) Induction of squamous cell carcinomas of 

the rat nasal cavity by inhalation exposure to formaldehyde vapor. Cancer Res 40:3398–3402.

Swenberg, JA; Gross, EA, Martin, J; et al. (1983) Mechanisms of formaldehyde toxicity. In: 

Formaldehyde toxicity, Ed: Gibson, JE. Hemisphere Publishing Corp. Washington, D.C.

Swenberg, JA; Gross, EA; Randall, HW. (1986) Localization and quantitation of cell 

proliferation following exposure to nasal irritants. In Toxicology of Nasal Passages, ed: Barrow, 

CS. Hemisphere Publishing Corp. Washington, D.C.

Swiecichowski, AL; Long, KJ; Miller, ML; et al. (1993) Formaldehyde-induced airway 

hyperreactivity in vivo and ex vivo in guinea pigs. Environ Res 61:185–199.

Szarvas, T; Szatloczky, E; Volford, J; et al. (1986) Determination of endogenous formaldehyde 

level in human blood and urine by dimedone-14C radiometric method. J Radioanaly Nucl Chem 

Letters 106:357-367. 

Takahashi, K; Morita, T; Kawazoe, Y. (1985) Mutagenic characteristics of formaldehyde on 

bacterial systems. Mutat Res 156:153–161.
This document is a draft for review purposes only and does not constitute Agency policy.

R-51 DRAFT—DO NOT CITE OR QUOTE

Takahashi, M; Hasegawa, R; Furukawa, F; et al. (1986) Effects of ethanol, potassium 

metabisulfite, formaldehyde and hydrogen peroxide on gastric carcinogenesis in rats after 

initiation with N-methyl-N'-nitro-N-nitrosoguanidine. Jpn J Cancer Res 77:118–124.

Takahashi, S; Tsuji, K; Fujii, K; et al. (2007) Prospective study of clinical symptoms and skin 

test reactions in medical students exposed to formaldehyde gas. J Dermatol 34(5):283–289.

Takigawa, T; Usami, M; Yamasaki, Y; et al. (2005) Reduction of indoor formaldehyde 

concentrations and subjective symptoms in a gross anatomy laboratory. Bull Environ Contam 

Toxicol 74:1027–1033.

Tarkowski, M; Gorski, P. (1995) Increased IgE antiovalbumin level in mice exposed to 

formaldehyde. Int Arch Allergy Immunol 106:422–424.

Tarone, RE. (1975) Tests for trend in life table analysis. Biometrika 62:679–682. (as cited in 

Battelle Columbus Laboratories [1981])

Tarone, R; McLaughlin, JK. (2005) Re: “mortality from solid cancers among workers in 

formaldehyde industries.” Am J Epidemiol 161:1089–1091.

Taskinen, H; Kyyronen, P; Hemminki, K. (1994) Laboratory work and pregnancy outcome. J 

Occup Med 36:311-319.

Taskinen, HK; Kyyronen, P; Sallmen, M; et al. (1999) Reduced fertility among female wood 

workers exposed to formaldehyde. Am J Ind Med 36:206–212.

Tavernier, G; Fletcher, G; Gee, I; et al. (2006) IPEADAM study: Indoor endotoxin exposure, 

family status, and some housing characteristics in English children. J Allergy Clin Immunol 

117:656–662.

Temcharoen, P; Thilly, WG. (1983) Toxic and mutagenic effects of formaldehyde in Salmonella

typhimurium. Mutat Res 119:89–93.

Teng, S; Beard, K; Pourahmad, J; et al. (2001) The formaldehyde metabolic detoxification 

enzyme systems and molecular cytotoxic mechanism in isolated rat hepatocytes. Chem Biol 

Interact 130–132:285–296.

Thomas, RS; Allen, BC; Nong, A; et al. (2007) A method to integrate benchmark dose estimates 

with genomic data to assess the functional effects of chemical exposure. Toxicol Sci 98(1):240–

248.

Thompson, CM; Grafström, RC. (2008) Mechanistic considerations for formaldehyde-induced 

bronchoconstriction involving S-nitrosoglutathione reductase. J Toxicol Environ Health A 

71:244–248.

Thompson, CM; Subramaniam, RP; Grafström, RC. (2008) Mechanistic and dose considerations 

for supporting adverse pulmonary physiology in response to formaldehyde. Toxicol Appl 

Pharmacol 233:355–359.

Thompson, CM; Sonawane, B; Grafström, RC. (2009) The ontogeny, distribution and regulation 

of alcohol dehydrogenase 3: implications for pulmonary physiology. Drug Metab Dispos. [Epub 

ahead of print]
This document is a draft for review purposes only and does not constitute Agency policy.

R-52 DRAFT—DO NOT CITE OR QUOTE

Thomson, EJ; Shackleton, S; Harrington, JM. (1984) Chromosome aberrations and sisterchromatid exchange frequencies in pathology staff occupationally exposed to formaldehyde. 

Mutat Res 141:89–93.

Thorndike, J; Beck, WS. (1977) Production of formaldehyde from N5-methyltetrahydrofolate by 

normal and leukemic leukocytes. Cancer Res 37:1125-1132. 

Thrasher, JD; Wojdani, A; Cheung, G; et al. (1987) Evidence for formaldehyde antibodies and 

altered cellular immunity in subjects exposed to formaldehyde in mobile homes. Arch Environ 

Health 42:347–350.

Thrasher, JD; Broughton, A; Gard, Z. (1988) Indoor formaldehyde and the elderly. Clin 

Gerontol 7(3-4):63–66.

Thrasher, JD; Broughton, A; Madison, R. (1990) Immune activation and autoantibodies in 

humans with long-term inhalation exposure to formaldehyde. Arch Environ Health 45:217–223.

Thun, MJ; Lakat, M; Altman, R. (1982) Symptom survey of residents of homes insulated with 

urea formaldehyde foam. Environ Res 29(2):320–334.

Til, HP; Woutersen, RA; Feron, VJ; et al. (1988) Evaluation of the oral toxicity of acetaldehyde 

and formaldehyde in a 4-week drinking-water study in rats. Food Chem Toxicol 26:447–452.

Til, HP; Woutersen, RA; Feron, VJ; et al. (1989) Two-year drinking-water study of 

formaldehyde in rats. Food Chem Toxicol 27:77–87.

Titenko-Holland, N; Levine, AJ; Smith, MT; et al. (1996) Quantification of epithelial cell 

micronuclei by fluorescence in situ hybridization (FISH) in mortuary science students exposed to 

formaldehyde. Mutat Res 371:237–248.

Tobe, M; Kaneko, Y; Uchida, Y; et al. (1985) Studies of the inhalation toxicity of formaldehyde. 

National Sanitary and Medical Laboratory Service, Toxicity, Tokyo, Japan; T-85-0236. (cited in 

IPCS, 2002)

Tobe, M; Naito, K; Kurokawa, Y. (1989) Chronic toxicity study on formaldehyde administered 

orally to rats. Toxicology 56:79–86.

Togias, A. (1999) Mechanisms of nose-lung interaction. Allergy 54:94–105.

Trezl, L; Hullan, L; Jaszay, ZM; et al. (2003) Antagonistic reactions of arginine and lysine 

against formaldehyde and their relation to cell proliferation, apoptosis, folate cycle and 

photosynthesis. Mol Cell Biochem 244:167–176.

Tsubone, H; Kawata, M. (1991) Stimulation to the trigeminal afferent nerve of the nose by 

formaldehyde, acrolein, and acetaldehyde gases. Inhal Toxicol 3:211–222.

Tsukahara, S; Yamamoto, S; Tin-Tin-Tin-Shwe; et al. (2006) Inhalation of low-level 

formaldehyde increases the Bcl-2/Bax expression ratio in the hippocampus of immunologically 

sensitized mice. Neuroimmunomodulation 13:63–68.

Turner, C; Parekh, B; Walton, C; et al. (2008) An exploratory comparative study of volatile 

compounds in exhaled breath and emitted by skin using selected ion flow tube mass 

spectrometry. Rapid Commun Mass Spectrom. 22(4):526–532.
This document is a draft for review purposes only and does not constitute Agency policy.

R-53 DRAFT—DO NOT CITE OR QUOTE

Tuthill, RW. (1984) Woodstoves, formaldehyde, and respiratory disease. Am J Epidemiol 

120:952–955.

Tyihák, E; Albert, L; Nemeth, ZI; et al. (1998) Formaldehyde cycle and the natural 

formaldehyde generators and capturers. Acta Biol Hung 49:225-238. 

Tyihák, E; Bocsi, J; Timár, F; et al. (2001) Formaldehyde promotes and inhibits the proliferation 

of cultured tumour and endothelial cells. Cell Prolif 34:135–141.

U.S. EPA (U.S. Environmental Protection Agency). (1985) Health and environmental effects 

profile for formaldehyde. Prepared by the U.S. Environmental Protection Agency, Office of 

Research and Development, Cincinnati, OH for the Office of Solid Waste and Emergency 

Response, Washington, D.C.; EPA 600/X-85/362.

U.S. EPA (Environmental Protection Agency). (1986a) Guidelines for the health risk assessment 

of chemical mixtures. Federal Register 51(185):34014-34025. Available from: 

<http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1986b) Guidelines for mutagenicity risk assessment. Federal Register 

51(185):34006-34012. Available from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1987) Assessment of health risks to garment workers and certain home residents 

from exposure to formaldehyde. Office of Pesticides and Toxic Substances, Washington, DC.

U.S. EPA. (1988) Recommendations for and documentation of biological values for use in risk 

assessment. Prepared by the Environmental Criteria and Assessment Office, Office of Health and 

Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency 

Response, Washington, DC; EPA 600/6-87/008. Available from: 

<http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1989) Review of the national ambient air quality standard for ozone, assessment for 

scientific and technical information. U.S. Environmental Protection Agency, RTP, NC, EPA450/2-92.

U.S. EPA. (1991a) Guidelines for developmental toxicity risk assessment. Federal Register 

56(234):63798-63826. Available from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1991b) Formaldehyde Risk Assessment Update. Prepared by the Office of Toxic 

Substances, Washington, DC.

U.S. EPA. (1991c) Formaldehyde. Integrated Risk Information System (IRIS). National Center 

for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/iris.

U.S. EPA. (1994a) Interim policy for particle size and limit concentration issues in inhalation 

toxicity studies. Federal Register 59(206):53799. Available from: 

<http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1994b) Methods for derivation of inhalation reference concentrations and application 

of inhalation dosimetry. Office of Research and Development, Washington, DC; EPA/600/8-

90/066F. Available from: <http://www.epa.gov/iris/backgr-d.htm>.
This document is a draft for review purposes only and does not constitute Agency policy.

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U.S. EPA. (1995) Use of the benchmark dose approach in health risk assessment. Risk 

Assessment Forum, Washington, DC; EPA/630/R-94/007. Available from: 

<http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=42601>.

U.S. EPA. (1996) Guidelines for reproductive toxicity risk assessment. Federal Register 

61(212):56274-56322. Available from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (1998) Guidelines for neurotoxicity risk assessment. Federal Register 63(93):26926-

26954. Available from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (2000a) Science policy council handbook: risk characterization. Office of Science 

Policy, Office of Research and Development, Washington, DC; EPA 100-B-00-002. Available 

from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (2000b) Benchmark dose technical guidance document [external review draft]. Risk 

Assessment Forum, Washington, DC; EPA/630/R-00/001. Available from: 

<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>.

U.S. EPA. (2002a) A review of the reference dose and reference concentration processes. Risk 

Assessment Forum, Washington, DC; EPA/630/P-02/0002F. Available from: 

<http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (2002b) Toxicological Review and IRIS Summary of 1,3-Butadiene. Integrated Risk 

Information System, National Center for Environmental Assessment, Washington, DC. 

Accessed at http://www.epa.gov/EPA/iris/subst/0139.htm.

U.S. EPA. (2002c) Memorandum: Interim genomics policy. Office of the Administrator Science 

Policy Council.

U.S. EPA. (2004) Potential implications of genomics for regulatory and risk assessment 

applications at EPA. Prepared by the Genomics Task Force Workgroup. EPA 100/B-04/002.

U.S. EPA. (2005a) Guidelines for carcinogen risk assessment. Risk Assessment Forum, 

Washington, DC; EPA/630/P-03/001B. Available from: <http://www.epa.gov/iris/backgrd.htm>.

U.S. EPA. (2005b) Supplemental guidance for assessing susceptibility from early-life exposure 

to carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R-03/003F. Available from: 

<http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (2006a) Science policy council handbook: peer review. Third edition. Office of 

Science Policy, Office of Research and Development, Washington, DC; EPA/100/B-06/002. 

Available from: <http://www.epa.gov/iris/backgr-d.htm>.

U.S. EPA. (2006b) A framework for assessing health risk of environmental exposures to 

children. National Center for Environmental Assessment - Washington, DC, EPA/600/R05/093F. Available from: <http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158363>.
This document is a draft for review purposes only and does not constitute Agency policy.

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U.S. EPA. (2006c) Technology transfer network 1999 national-scale air toxics assessment. 

Available from http://www.gov/ttn/atw/nata/.

U.S. EPA. (2006d) Air quality criteria for ozone and related photochemical oxidants (Final). 

U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-05/004aF-cF.

U.S. EPA (2008) Reregistration eligibility decision for formaldehyde and paraformaldehyde. 

Office of Pesticide Programs. Available from: 

http://www.epa.gov/pesticides/reregistration/formaldehyde/.

U.S. EPA (2009a) Formaldehyde: Chemical Report. TRI Explorer. Available from 

http://www.epa.gov/triexplorer/chemical.htm.

U.S. EPA (2009b) AirData. Available from http://www.epa.gov/air/data/index.html.

Uba, G; Pachorek, D; Bernstein, J; et al. (1989) Prospective study of respiratory effects of 

formaldehyde among healthy and asthmatic medical students. Am J Ind Med 15(1):91–101.

Uotila, L; Koivusalo, M. (1974a) Formaldehyde dehydrogenase from human liver. Purification, 

properties, and evidence for the formation of glutathione thiol esters by the enzyme. J Biol 

Chem 249:7653–7663.

Uotila, L, Koivusalo, M. (1974b) Purification and properties of S-formylglutathione hydrolase 

from human liver. J Biol Chem 249:7664–7672.

Ura, H; Nowak, P; Litwin, S; et al. (1989) Effects of formaldehyde on normal xenotransplanted 

human tracheobronchial epithelium. Am J Pathol 134:99–106.

Usanmaz, SE; Akarsu, ES; Vural, N. (2002) Neurotoxic effects of acute and subacute 

formaldehyde exposures in mice. Environ Toxicol Pharmacol 11:93–100.

USDA (U.S. Department of Agriculture). (1979) Food intakes: Individuals in 48 States, Year 

1977–78, Nationwide Food Consumption Survey 1977-78, Rep No I-1. Technical report no. 

PB91-103523INZ.

van Birgelen, APJM; Chou, BJ; Renne, RA; et al. (2000) Effects of glutaraldehyde in a 2-year 

inhalation study in rats and mice. Toxicol Sci 55:195–205.

Van Schoor, J; Joos, GF; Pauwels, RA. (2000) Indirect bronchial hyperresponsiveness in asthma: 

mechanisms, pharmacology and implications for clinical research. Eur Respir J 16:514–533.

Vandenplas, O; Fievez, P; Delwiche, JP; et al. (2004) Persistent asthma following accidental 

exposure to formaldehyde. Allergy 59:115–116.

Vargová, M; Janota, S; Karelová, J; et al. (1992) Analysis of the health risk of occupational 

exposure to formaldehyde using biological markers. Analysis 20:451–454.

Vasudeva, N; Anand, C. (1996) Cytogenetic evaluation of medical students exposed to 

formaldehyde vapor in the gross anatomy dissection laboratory. J Am Coll Health 44:177–179.

Vaughan, TL; Strader, C; Davis, S; et al. (1986a) Formaldehyde and cancers of the pharynx, 

sinus and nasal cavity: I. Occupational exposures. Int J Cancer 38:677–683.

Vaughan, TL; Strader, C; Davis, S; et al. (1986b) Formaldehyde and cancers of the pharynx, 

sinus and nasal cavity: II. Residential exposures. Int J Cancer 38:685–688.
This document is a draft for review purposes only and does not constitute Agency policy.

R-56 DRAFT—DO NOT CITE OR QUOTE

Vaughan, TL; Stewart, PA; Teschke, K; et al. (2000) Occupational exposure to formaldehyde 

and wood dust and nasopharyngeal carcinoma. Occup Environ Med 57:376–384.

Venkatakrishna-Bhatt, H; Panchal, GM. (1992) Behavioural change in rats due to chronic oral 

and systemic formaldehyde. Ind J Physiol Pharmacol 36:270–272.

Venkatakrishna-Bhatt, H and Panchal, GM (1997). Chronic exposure to formaldehyde in 

drinking water and behavioral changes in rats. Ind. J. Physioil. & Allied Sci. 51(4):181-184.

Vogelstein, B; Fearon, ER; Hamilton, SR; et al. (1988) Genetic alterations during colorectaltumor development. N Engl J Med 319:525–532.

Von Hippel, PH; and Wong, KY. (1971) Dynamic aspects of native DNA structure: kinetics of 

the formaldehyde reaction with calf thymus DNA. J Mol Biol 61:587-613.

Wahlberg, JE. (1993) Measurement of skin-fold thickness in the guinea pig. Assessment of 

edema-inducing capacity of cutting fluids, acids, alkalis, formalin and dimethyl sulfoxide. 

Contact Dermatitis 28:141–145.

Walker, JF. (1975) Formaldehyde. 3rd edition. Huntington, NY: R.E. Krieger Publishing 

Company.

Walrath, J; Fraumeni, JF, Jr. (1983) Mortality patterns among embalmers. Int J Cancer 31:407–

411.

Walrath, J; Fraumeni, JF, Jr. (1984) Cancer and other causes of death among embalmers. Cancer 

Res 44:4638-4641.

Wang, B; and Liu, DD. (2006) [Detection of formaldehyde induced developmental toxicity 

assessed with single cell gel electrophoresis]. Fen Zi Xi Bao Sheng Wu Xue Bao 39:462-466.

Wang, M; Cheng, G; Villalta, PW; et al. (2007) Development of liquid chromatography 

electrospray ionization tandem mass spectrometry methods for analysis of DNA adducts of

formaldehyde and their application to rats treated with N-nitrosodimethylamine or 4-

(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Res Toxicol 20:1141–1148.

Wang TS, Pysanenko A, Dryahina K, Španĕl P, Smith D. (2008) Analysis of breath, exhaled via 

the mouth and nose, and the air in the oral cavity. J. Breath Res. 2:1-13. 

Wangenheim, J; and Bolcsfoldi, G. (1988) Mouse lymphoma L5178Y thymidine kinase locus 

assay of 50 compounds. Mutagenesis 3:193-205.

Wantke, F; Demmer, CM; Tappler, P; et al. (1996a) Exposure to gaseous formaldehyde induces 

IgE-mediated sensitization to formaldehyde in school-children. Clin Exp Allergy 26:276–280.

Wantke, F; Focke, M; Hemmer, W; et al. (1996b) Formaldehyde and phenol exposure during an 

anatomy dissection course: a possible source of IgE-mediated sensitization. Allergy 51:837–

841.

Ward, Jr., JB; Hokanson, JA; Smith, ER; et al. (1984) Sperm count, morphology and fluorescent 

body frequency in autopsy service workers exposed to formaldehyde. Mutat Res 30:417–424.
This document is a draft for review purposes only and does not constitute Agency policy.

R-57 DRAFT—DO NOT CITE OR QUOTE

Watanabe, K; Sakamoto, K; Sasaki, T. (1996) Comparisons on chemically-induced mutagenicity 

among four bacterial strains, Salmonella typhimurium TA102 and TA2638, and Escherichia coli 

WP2/pKM101 and WP2 uvrA/pKM101: collaborative study I. Mutat Res 361:143–155.

Waydhas, C; Weigl, K; Sies, H. (1978) The disposition of formaldehyde and formate arising 

from drug N-demethylations dependent on cytochrome P-450 in hepatocytes and in perfused rat 

liver. Eur J Biochem 89:143-150. 

Weber-Tschopp, A; Fischer, T; Grandjean, E. (1977) Irritating effects of formaldehyde on man. 

Int Arch Occup Environ Health 39(4):207–218.

Weibel, ER. (1963) Morphometry of the human lung. Springer-Verlag, Berlin.

Weiler, E; Apfelbach, R. (1992) Age-related differences in olfactory sensitivity in Wistar rats 

after low-level formaldehyde gas exposure. Chem Senses 17:717–718.

Weiss, B; Stern, S; Soderholm, SC; et al. (1996) Developmental neurotoxicity of methanol 

exposure by inhalation in rats. Research Report (Health Effects Institute) 73:1–64.

Weisskopf, M; Morozova, N; O’Reilly, EJ; et al. (2009) Prospective study of chemical exposures

and amyotrophic lateral sclerosis mortality. J Neurol Neurosurg Psychiatry 80:558–561.

West, S; Hildesheim, A; Dosemeci, M. (1993) Non-viral risk factors for nasopharyngeal 

carcinoma in the Philippines: results from a case-control study. Int J Cancer 55:722–727.

Westerlund, M; Galter, D; Carmine, A; et al. (2005) Tissue- and species-specific expression 

patterns of class I, III, and IV ADH and ALDH1 mRNAs in rodent embryos. Cell Tissue Res 

322:227–236.

WHO (World Health Organization). (1987) Laboratory manual for the examination of human 

semen and sperm-cervical mucus interaction. Cambridge, UK: Cambridge University Press.

Wilcox, AJ; Horney, LF. (1984) Accuracy of spontaneous abortion recall. Am J Epidemiol 

120:727–733.

Wilcox, P; Naidoo, A; Wedd, DJ; et al. (1990) Comparison of Salmonella typhimurium TA102 

with Escherichia coli WP2 tester strains. Mutagenesis 5:285–291.

Wilhelmsson, B; Holmström, M. (1992) Possible mechanisms of formaldehyde-induced 

discomfort in the upper airways. Scand J Work Environ Health 18:403–407.

Wilkins, RJ; and Macleod, HD. (1976) Formaldehyde induced DNA-protein crosslinks in 

Escherichia Coli. Mutat Res 36:11-6.

Williams, GM; Mori, H; and McQueen, CA. (1989) Structure-activity relationships in the rat 

hepatocyte DNA-repair test for 300 chemicals. Mutat Res 221:263-286.

Wilmer, JW; Woutersen, RA; Appelman, LM; et al. (1987) Subacute (4-week) inhalation 

toxicity study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous 

exposures. J Appl Toxicol 7:15–16.

Wilmer, JW; Woutersen, RA; Appelman, LM; et al. (1989) Subchronic (13-week) inhalation 

toxicity study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous 

exposures. Toxicol Lett 47:287–293.
This document is a draft for review purposes only and does not constitute Agency policy.

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Witek, TJ, Jr; Schachter, EN; Tosun, T. (1986) Controlled human studies on the pulmonary 

effects of indoor air pollution: experiences with sulfur dioxide and formaldehyde. Environ Int 

12:129–135.

Witek, TJ, Jr; Schachter, EN; Tosun, T; et al. (1987) An evaluation of respiratory effects 

following exposure to 2.0 ppm formaldehyde in asthmatics: lung function, symptoms, and 

airway reactivity. Arch Environ Health 42:230-237.

Wolf, DC; Gross, EA; Lyght, O, et al. (1995) Immunohistochemical localization of p53, PCNA, 

and TGF-alpha proteins in formaldehyde-induced rat nasal squamous cell carcinomas. Toxicol 

Appl Pharmacol 132:27-35.

Wolfe, RK. (1986) Effects of airborne pollutants on mucociliary clearance. Environ Health 

Perspect 66: 223–237.

Wong, O. (1983) An epidemiologic mortality study of a cohort of chemical workers potentially 

exposed to formaldehyde, with a discussion on SMR and PMR. In: Gibson, J; ed. Formaldehyde 

toxicity. Washington, DC: Hemisphere Publishing Corporation; pp. 256–272.

Wong, EY; Ray, R; Gao, DL; et al. (2006) Reproductive history, occupational exposures, and 

thyroid cancer risk among women textile workers in Shanghai, China. Int Arch Occup Environ 

Health 79:251–158.

Wood, RW; Coleman, JB. (1995) Behavioral evaluation of the irritant properties of 

formaldehyde. Toxicol Appl Pharmacol 130:67–72.

Wortley, P; Vaughan, TL; Davis, S; et al. (1992) A case-control study of occupational risk 

factors for laryngeal cancer. Br J Ind Med 49:837–844.

Woutersen, RA; Appelman, LM; Wilmer, JW; et al. (1987) Subchronic (13-week) inhalation 

toxicity study of formaldehyde in rats. J Appl Toxicol 7:43–49.

Woutersen, RA; Garderen-Hoetmer, A; Bruijntjes, JP; et al. (1989) Nasal tumours in rats after 

severe injury to the nasal mucosa and prolonged exposure to 10 ppm formaldehyde. J Appl 

Toxicol 9:39–46.

Wu, H-Y; Nguyen, HH; Russell, MW. (1997) Nasal lymphoid tissue (NALT) as a mucosal 

immune inductive site. Scand J Immunol 46:506–513.

Wu, H; Romieu, I; Sienra-Monge, J-J; et al. (2007) Genetic variation in S-nitrosoglutathione 

reductase (GSNOR) and childhood asthma. J Allergy Clin Immunol 120:322–328.

Xing S-Y; Ye. L; Wang, N-N. (2007) Toxic effect of formaldehyde on reproduction and heredity 

in male mice. J Jilin Univ 33:716–718.

Xu, B; Aoyama, K; Takeuchi, M; et al. (2002) Expression of cytokine mRNAs in mice 

cutaneously exposed to formaldehyde. Immunol Lett 84:49–55.

Yager, JW; Cohn, KL; Spear, RC; et al. (1986) Sister-chromatid exchanges in lymphocytes of 

anatomy students exposed to formaldehyde-embalming solution. Mutat Res 174:135–139.

Yang, X; Zhang, YP; Chen, D; et al. (2001) Eye irritation caused by formaldehyde as an indoor 

air pollution―a controlled human exposure experiment. Biomed Environ Sci 14:229–236.
This document is a draft for review purposes only and does not constitute Agency policy.

R-59 DRAFT—DO NOT CITE OR QUOTE

Yang, YH; Xi, ZG; Chao, FH; et al. (2005) Effects of formaldehyde inhalation on lung of rats. 

Biomed Environ Sci 18:164–168.

Ye, X; Yan, W; Xie, H; et al. (2005) Cytogenetic analysis of nasal mucosa cells and 

lymphocytes from high-level long-term formaldehyde exposed workers and low-level short-term 

exposed waiters. Mutat Res 588:22–27.

Yi C, Ke K, Xiaohua L and Xu Y (2007). Up-regulation of GSNO reductase in mice lungs by 

formaldehyde inhalation. Bioinform Biomed Engineering 6-8: 294-297.

Ying, CJ; Yan, WS; Zhao, MY; et al. (1997) Micronuclei in nasal mucosa, oral mucosa and 

lymphocytes in students exposed to formaldehyde vapor in anatomy class. Biomed Environ Sci 

10:451–455.

Ying, CJ; Ye, XL; Xie, H; et al. (1999) Lymphocyte subsets and sister-chromatid exchanges in 

the students exposed to formaldehyde vapor. Biomed Environ Sci 12:88–94.

Yokley, KA; Tran, H; Schlosser, PM. (2008) Sensory irritation response in rats: modeling, 

analysis and validation. Bull Math Biol 70:555–588.

Young, JT. (1981) Histopathologic examination of the rat nasal cavity. Fundam Appl Toxicol 

1:309–312.

Yu, L-Q; Jiang, S-F; Leng, S-G; et al. (2005) Early genetic effects on workers occupationally 

exposed to formaldehyde. Chin J Prevent Med 39:392–395.

Yu, PH; Zuo, DM. (1996) Formaldehyde produced endogenously via deamination of 

methylamine. A potential risk factor for initiation of endothelial injury. Atherosclerosis 120:189-

197. 

Yu, PH; Lai, CT; Zuo, DM. (1997) Formation of formaldehyde from adrenaline in vivo; a 

potential risk factor for stress-related angiopathy. Neurochem Res 22:615-620.

Yu, PH. (1998) Increase of formation of methylamine and formaldehyde in vivo after 

administration of nicotine and the potential cytotoxicity. Neurochem Res 23:1205-1210.

Zhang, L; Steinmaus, C; Eastmond, DA; et al. (2009) Formaldehyde exposure and leukemia: A 

new meta-analysis and potential mechanisms. Mutat Res 681:150–168.

Zhao, Z; Zhang, Z; Wang, Z; et al. (2008) Asthmatic symptoms among pupils in relation to 

winter indoor and outdoor air pollution in schools in Taiyaun, China. Environ Health Perspect 

116:90–97.

Zhitkovich, A; and Costa, M. (1992) A simple, sensitive assay to detect DNA-protein crosslinks 

in intact cells and in vivo. Carcinogenesis 13:1485-1489.

Zhong, W; Que Hee, S. (2004a) Quantitation of normal and formaldehyde-modified 

deoxynucleosides by high-performance liquid chromatography/UV detection. Biomed 

Chromatogr 18:462–469.

Zhong, W; Que Hee, SS. (2004b) Formaldehyde-induced DNA adducts as biomarkers of in vitro 

human nasal epithelial cell exposure to formaldehyde. Mutat Res 563:13–24.
This document is a draft for review purposes only and does not constitute Agency policy.

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Zhou, DX; Qiu, SD; Zhang, J; et al. (2006) Reproductive toxicity of formaldehyde to adult male 

rats and the functional mechanism concerned. Sichuan Da Xue Xue Bao Yi Xue Ban 37:566–

569.

Zielenska, M; Guttenplan, JB. (1988) Mutagenic activity and specificity of Nnitrosomethylaniline and N-nitrosodiphenylamine in Salmonella. Mutat Res 202:269–76.

Zuercher, AW; Cebra, JJ. (2002) Structural and functional differences between putative mucosal 

inductive sites of the rat. Eur J Immunol 32:3191–3196.

Zuercher, AW; Coffin, SE; Thurnheer, MC; et al. (2002) Nasal-associated lymphoid tissue is a 

mucosal inductive site for virus-specific humoral and cellular immune responses. J Immunol 

168:1796–1803.

Zwart, A; Woutersen, RA; Wilmer, JW; et al. (1988) Cytotoxic and adaptive effects in rat nasal 

epithelium after 3-day and 13-week exposure to low concentrations of formaldehyde vapour. 

Toxicology 51:87–99.

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