DRAFT-DO NOT CITE OR QUOTE EPA/635/R-10/002C
www.ep a.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, DCThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- ii DISCLAIMER This document is a preliminary draft for review purposes only. This information is
dis tributed 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 pol icy. 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

. DRAFT

— DO NOT CITE OR QUOTE III

- iii CONTENTS

— TOXICOLOGICAL REVIEW OF FORMALDEHYDE (CAS No. 50

- 00

- 0)

LIST OF TABLES

................................ ................................ ................................ ......................... xi LIST OF FIGURES

................................ ................................ ................................ ....................... xx LIST OF ABBREVIATIONS AND ACRONYMS

................................ ................................ ..... xxv F OREWORD

................................ ................................ ................................ ............................ xxxii AUTHORS, CONTRIBUTORS, AND REVIEWERS

................................ ............................ xxxiii

VOLUME I

1. INTRODUCTION

................................ ................................ ................................ .................. 1

- 1

2. BACKGROUND

................................ ................................ ................................ .................... 2

- 1 2.1. PHYSICOCHEMICA L PROPERTIES OF FORM ALDEHYDE

................................ 2

- 1 2.2. PRODUCTION, US ES, AND SOURCES OF F ORMALDEHYDE

........................... 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 PROPE RTIES 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 F A 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: Differentiatin g covalent Binding and Metabolic Incorporation

................................ ............ 3

- 16This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- iv CONTENTS (continued)

3.4. METABOLISM

................................ ................................ ................................ .......... 3

- 20 3.4.1. In Vitro and In Vivo Characterization of 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 TH E 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 E stimates

................................ ................................ ................. 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 o f 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 T issue 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 H ealth 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

- 56This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- v CONTENTS (continued)

4.1.2. Cancer Health Effects

................................ ................................ ..................... 4

- 57 4.1.2.1. Respiratory Tract Cancer

................................ ................................ . 4

- 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 Toxic ity

................................ ... 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 R eactions

................................ ................................ .... 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 Vi tro 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 Genot oxicity

................................ ............................... 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. Pul monary 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. Immunotoxici ty

................................ ................................ ............................ 4

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

. DRAFT

— DO NOT CITE OR QUOTE III

- vi CONTENTS (continued)

4.4.8. Effects on the Nervous System

................................ ................................ .... 4

- 390 4.4.8.1. Irritant Threshold Detection

................................ .......................... 4

- 390 4.4.8.2. Behavioral Effects

................................ ................................ ......... 4

- 391 4.4.8.3. Neurochemistry, Neuropathology, and 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 Developmen t 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 CARCIN OGENICITY

............................ 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 POPULATI ONS

................................ ................................ ............ 4

- 454 4.6.1. Life Stages

................................ ................................ ................................ .... 4

- 454 4.6.1.1. Early Life Stages

................................ ................................ ........... 4

- 455 4.6.1.2. Later Life Stages

................................ ................................ ............ 4

- 459 4.6.1.3. Conclusions on Life

- Stage Susceptibility

................................ ..... 4

- 459 4.6.2. Health/Disease Status

................................ ................................ ................... 4

- 460 4.6.3. Nutritional Status

................................ ................................ .......................... 4

- 461 4.6.4. Gender Differences

................................ ................................ ....................... 4

- 462 4.6.5. Genetic Differences

................................ ................................ ...................... 4

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

. DRAFT

— DO NOT CITE OR QUOTE III

- vii CONTENTS (continued)

4.6.6. Co

- Exposures

................................ ................................ ............................... 4

- 464 4.6.6.1. Cumulative Risk

................................ ................................ ............ 4

- 464 4.6.6.2. Aggregate Exposure

................................ ................................ ...... 4

- 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 REF ERENCE CONCENTRATION (R f C)

................................ ........ 5

- 2 5.1.1. Candidate Critical Effects by Healt h 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. Derivati on 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 C ANCER ASSESSMENT BAS ED ON THE NATIONAL CANCER INSTITUTE COH ORT 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. Exp osure

- Response Modeling of the National Cancer Institute Cohort

................................ ................................ ............... 5

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

. DRAFT

— DO NOT CITE OR QUOTE III

- vi ii 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 CEL L CARCINOMA IN THE RES PIRATORY 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 FR OM THE QUANTITATIVE ASS ESSMENT OF CANCER RISK FROM FOR MALDEHYDE EXPOSURE B Y 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 HUM AN 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 P ulmonary Function

................................ ......................... 6

- 8 6.1.3.4. Asthmatic Responses and Increased Atopic Symptoms

.................... 6

- 9 6.1.3.5. Effects on the Immune System

................................ ........................ 6

- 10 6.1.3.6. Neurological Effects

................................ ................................ ........ 6

- 11 6.1.3.7. Reproductive and Developmental Effects

................................ ....... 6

- 12This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- ix CONTENTS (continued)

6.1.3.8. Effe cts 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 CHARACTERIZ ATION

................................ ........................... 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 Concentration s

........................ 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 Epide miologic 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 CO NCLUSIONS

................................ ................................ ......... 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 C ANCER IN THE F344 RAT: CONOLLY ET AL. (2003) AND ALTERNATIVE IMPLEMENTATIONS

................................ ................................ ..................... E

- 1 APPENDIX F: SENSITIVITY ANALYSIS OF BBDR MODEL FOR FORMALDEHYDE INDUCED RESPIRATORY CANCER IN HUMANS

................................ .... F

- 1This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- x CONTENTS (continued)

APPENDIX G: EVALUATION OF THE CANCER DOSE

- RES PONSE 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

- 1This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xi LIST OF TABLES

Table 2

- 1. Physi cochemical 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 tis sues 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 [ 14 C]

- formaldehyde in F344 rats

.......................... 3

- 26

Table 3

- 5. Apparent formaldehyde levels in exhaled breath of individuals attending a health fair, adjusted for methanol and ethanol 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 formaldehy de 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

- 117This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xii LIST OF TABLES (continued)

Table 4

- 9. Summary of formaldehyde effects on 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 formald ehyde 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 neu trophil 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 respirator y 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

- ind uced 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 concentrat ion

- by

time 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

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

. DRAFT

— DO NOT CITE OR QUOTE III

- xiii LIST OF TABLES (continued)

Table 4

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

- treated and control animals; data 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 concent rations 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 formaldehyde

treated 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 expo sures 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. His topathologic 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, trac hea, and free lung cells isolated from male Wistar rats after inhalation exposures to formaldehyde

.................... 4

- 194This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xiv LIST OF TABLES (continued)

Table 4

- 36. The effect of repeated formaldehyde inhalation exposures for 3 months on cell count, basal membrane length, p roliferation 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 ga strointestinal 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% formal in) 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 asses sed 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

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

. DRAFT

— DO NOT CITE OR QUOTE III

- xv LIST OF TABLES (continued)

Table 4

- 49. Study design for guinea pigs exposed to formaldehyde through different routes of exposure: inhalation, dermal, and injection

................................ ......... 4

- 232

Table 4

- 50. Sensitization response of guinea pigs expose d 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 form aldehyde 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 i nhaled 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 an d 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 expos ure

................................ ..... 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

- tr eated mice

................................ ................................ .................. 4

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

. DRAFT

— DO NOT CITE OR QUOTE III

- xvi LIST OF TABLES (continued)

Table 4

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

................................ ................................ ................................ ............... 4

- 303

Table 4

- 65. Testicular weights, sperm head counts, and percentage incidence of abnormal sperm after oral admini stration 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

T able 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 form aldehyde 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 formal dehyde 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

- 350This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xvii LIST OF TABLES (continued)

Table 4

- 82. Mutagenicity in mammalian cell systems

................................ .......................... 4

- 355

Table 4

- 83. Genotoxicity in laboratory animals

................................ ................................ .... 4

- 361

Table 4

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

................................ ................................ ................................ ....... 4

- 364

Table 4

- 85. MN and SCE formation in mortuary 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 fo rmaldehyde

- 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 lymphohematop oetic 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 f ormaldehyde 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. Availab le evidence for susceptibility factors of concern for formaldehyde
exposure

................................ ................................ ................................ ............... 4

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

. DRAFT

— DO NOT CITE OR QUOTE III

- xviii LIST OF TABLES (continued)

Table 5

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

................................ ................................ ................................ ....... 5

- 19

Table 5

- 2. Effects of formaldehyde expo sure 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

Tabl e 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
morta lity from cumulative exposure to formaldehyde

................................ .......... 5

- 79

Table 5

- 9. Extra risk estimates for NPC mortality from various levels of continuous exposure to formaldehyde

................................ ................................ .................... 5

- 80

Table 5

- 10. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC mortality from f

ormaldehyde exposure based on the Hauptmann et al. (2004) log

- linear trend analyses for cumulative exposure

................................ ................................ 5

- 81

Table 5

- 11. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC incidence from formaldehyde exposure based on the Hauptmann et al. (20 04) 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

- 91This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xix LIST OF TABLES (contin ued)

Table 5

- 15. Extra risk estimates for leukemia mortality from various levels of continuous exposure to formaldehyde

................................ ................................ ... 5

- 91

Table 5

- 16. EC 0005 , LEC 0005 , 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. EC 005 , LEC 005 , 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. EC 0005 , LEC 0005 , 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. EC 005 , LEC 005 , 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 mort ality 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 es timates

................................ ......................... 5

- 135

Table 5

- 27. Total cancer risk from exposure to a constant formaldehyde exposure level of 1 μg/m 3 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 c oncentrations (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

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

. DRAFT

— DO NOT CITE OR QUOTE III

- xx LI ST 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 concentrat ions (ppb) in different environments

.......... 2

- 9

Figure 3

- 1. Formaldehyde

- mediated protein modifications

................................ ...................... 3

- 2

Figure 3

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

- labeled formaldehyde (0.3, 2, 6, 10, 15 ppm)

.............................. 3

- 18

Figure 3

- 3. Formaldehyde clearance by ALDH2 (GSH

- 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 exhale d 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 measuremen ts 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 a fter “painting” 100% formalin for 20 minutes

................................ .......................... 4

- 20This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxi LIST OF FIGURES (continued)

Figure 4

- 2. Formaldehyde effects on minute volume in naïve and formaldehyde

pretreated male B6C3F1 mice and F344 rats

................................ ................... 4

- 115

Figure 4

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

................................ ..... 4

- 121

Figure 4

- 4. Main components of the nasal 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 o f 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/m 3 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 OV A 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

- 239This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxii LIST OF FIGURES (continued)

Figure 4

- 17. The effects of formal dehyde 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 af ter 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

Figur e 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

- 2 60

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 i nhalation 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 f

ormaldehyde for 24 months

................................ ................................ ............ 4

- 333

Figure 4

- 31. Cumulative incidence or tumor bearing animals for lymphoma in female mice exposed to formaldehyde for 24 months

................................ ...... 4

- 334This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxiii LIST OF FIGURES (continued)

Figure 4

- 32. DNA

- protein cross

- links (DPX) and thymidine kinas e ( 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 lympho hematopoietic 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 colo n 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 adeno id

................................ ................................ ............................ 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 lear ning 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 exp iratory 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 in

home 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 exposu re

- response relationships reported for in

- home formaldehyde exposures and sensory irritation (eye irritation)

......................... 5

- 53This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxiv LIST OF FIGURES (continued)

Figure 5

- 9. Positive exposure

- response relationships reported for in

- home formaldehyde exposures and sensory i rritation (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
tw o 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 BMC 10 and BMCL 10
................................ ................................ ................................ ............ 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

- 132This document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxv LIST OF ABBREVIATIONS AND ACRONYMS

ACGIH American Conference of Gove rnmental 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 ALD H 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 a denosine 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 ad enosine 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 ba sed 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 benchma rk concentration BMCL 95% lower bound on the benchmark concentration BMCR binuclated micronucleated cell ratefluoresce BMD benchmark dose BMDL 95% lower bound on the benchmark doseThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxvi LIST OF ABBREVIATIONS AND ACRONYMS (continued)

BMR benchmark response BN Brown

- Norway BrdU bromodeoxyuridine BUN blood urea nitrogen BW body weight CA chromosomal aberrations CalEPA California Environmental Protection Agency CAP College of American Pathologists CASRN Chemical Abstracts Service Registry Number CAT cata lase 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 Chi nese hamster ovary CI confidence interval CIIT Chemical Industry Institute of Toxicology CLL chronic lymphocytic leukemia CML chronic myelogenous leukemia CNS central nervous system CO 2 carbon dioxide COEHHA California Office of Environmental Health 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 assayThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxvii LIST OF ABBREVIATIONS AND ACRONYMS (continued)

EPA U.S. Environmental Protection Agency ERPG emergency response planning guideline ET ethmoid turbinates FALDH formaldehyde dehydro genase 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

- stimulatin g 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 glutathion e 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 CancerThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxviii LIST OF ABBREVIATIONS AND ACRONYMS (c ontinued)

ICD International Classification of Diseases IF interfacial IFN interferon Ig immunoglobulin IL interleukin I.P. intraperitoneal IPCS International Programme on Chemical Safety IRIS Integrated Risk Information System K m Michaels

- Menton c onstant KM Kaplan

- Meier LD 50 median lethal dose LDH lactate dehydrogenase LEC 95% lower bound on the effective concentration LED 95% lower bound on the effective dose LHP lymphohematopoietic LI labeling index LM Listeria monocytogenes LMS lineariz ed 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 c orpuscular 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 maxillotur binate MN micronucleus, micronuclei MNNG N

- methyl

- N

- nitro

- N

- nitrosoguanidine MOA mode of action MoDC monocyte

- derived dendritic cell MP macrophage MPD multistage polynomial degree MPS mononuclear phagocyte system MRL minimum risk levelThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxix LIST OF ABBRE VIATIONS 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 adeni ne 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

- (methylnitr osamino)

- 1

- (3

- pyridyl)

- butanone N 6

- hmdA N 6

- hydroxymethyldeoxyadenosine N 4

- hmdC N 4

- hydroxymethylcytidine N 2

- hmdG N 2

- hydroxymethyldeoxyguanosine NICNAS National Industrial Chemicals Notification and Assessment Scheme NIOSH National Institute for Occupation al 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 Tox icology Program OR odds ratio OSHA Occupational Safety and Health Administration OTS Office of Toxic Substances OVA ovalbumin PBPK physiologically based pharmacokinetic PC Philadelphia chromosome PCA passive cutaneous anaphylaxis PCMR proportionate cancer mortality ratio PCNA proliferating cell nuclear antigen PCR polymerase chain reaction PCV packed cell volumeThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxx LIST OF ABBREVIATIONS AND ACRONYMS (continued)

PECAM platelet endothelial cell adhesion molecule PEF peak expiratory flow PEFR peak ex piratory 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 mortal ity 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 ac tivation, normal T

– cell expressed and secreted RB reflex bradypnea RBC red blood cells RD 50 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 activityThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxxi LIST OF ABBREVIATIONS AND ACRONYMS (continued)

SMR s tandardized mortality ratio SNP single nucleotide polymorphism SOD superoxide dismutase SOMedA N 6

- sulfomethyldeoxyadenosine Sp1 specificity protein SPIR standardized proportionate incidence ratio SSAO semicarbozole

- sensitive amine oxidase SSB single strand breaks STEL short

- term exposure limit TBA tumor bearing animal TH T

- lymphocyte helper THF tetrahydrofolate TK toxicokinetics TL tail length TLV threshold limit value TNF tumor necrosis factor TP total protein TRI Toxic Release Inventory TR PV 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 inde x 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 EuropeThis document is a draft for review purposes only and does not constitute Agency policy

. DRAFT

— DO NOT CITE OR QUOTE III

- xxxii 

### This page intentionally left blank.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 1 5. QUANTITATIVE ASSESSMENT : INHALATION EXPOSU RE 1 2 3 This chapter presents the quantitative assessments conducted by EPA for both cancer and 4 noncancer health effects associated with formaldehyde exposure. The qu antitative assessment is 5 focused on the inhalation route of exposure. The current IRIS reference dose (RfD) is not 6 reevaluated in this assessment. Although there is some evidence of formaldehyde 7 carcinogenicity via the oral route of exposure, these data are not evaluated herein nor is an oral 8 slope factor considered at this time. Therefore, the following sections address derivation of a 9 reference concentration (RfC) and cancer unit risk estimate for inhalation exposures. 10 For noncancer effects, the RfC i s an estimate (with uncertainty spanning perhaps an order 11 of magnitude) of a continuous inhalation exposure to the human population (including sensitive 12 subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. 13 It can be derived from a NOAEL, LOAEL, or benchmark concentration, with uncertainty factors 14 generally applied to reflect limitations of the data used. Data from the previous chapters are 15 evaluated to determine the health effects associated with formaldehyd e exposure and which 16 studies may best inform the exposure response relationship for RfC derivation. Section 5.1 17 summarizes the observed noncancer health effects, selecting key studies and critical effects for 18
consideration. Candidate RfCs are derived for each identified key study. Several alternatives are 19 considered for uncertainty factors addressing human variability for key studies and alternatives 20 presented (Section 5.1.2.3). Options for addressing the overall database uncertainty factor are 21 provided w hich may modify the final RfC (Section 5.1.3). 22 The derivation of the cancer inhalation unit risk estimate considered data regarding both 23 respiratory tract cancers and lymphohematopoietic malignancies. Exposure

- response modeling 24 from epidemiologic studies was used to derive a combined unit risk estimate for nasopharyngeal 25 cancer and lymphohematopoietic cancers (Section 5.2). This unit risk estimate is supported by 26 an analysis of exposure

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

e xperimental animal studies (Section 5.3). Analysis of the animal bioassays includes an 28 evaluation of a published biologically based dose

- response model as well as an appraisal of 29 published dose

- response modeling of genomics data and a presentation of benc hmark dose 30 modeling approaches. Finally, Section 5.4 provides a summary and conclusions from the cancer 31

exposure

- response modeling, presenting the final unit risk estimate based on the combined risk 32 of nasopharyngeal cancer and lymphohematopoietic cancers observed in the human studies. 33
34
35
36This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 2 5.1. INHALATION REFERENCE CONCENTRATION (RfC) 1 Prior to the current assessment, the EPA IRIS file for formaldehyde did not provide an 2
inhalation RfC. As presented in the hazard identification in Chapter 4, a number of n oncancer 3 health effects are associated with formaldehyde exposure. Section 5.1.1 describes each of the 4 health effect categories considered for RfC derivation and the specific endpoints considered for 5 each category. The identified effect categories are: s ensory irritation (eye, nose, and throat); 6 upper respiratory tract (URT) pathology; pulmonary function; increased asthma and atopic 7 sensitization; altered immune function; neurotoxicity and reproductive and developmental 8 toxicity. For each health effect c ategory,, studies that may adequately inform the exposure

9 response relationship for specific critical effects are identified for consideration in RfC 10
derivation. 11 EPA employed a screening process across the different health effect categories to select 12 key studies that would best support the derivation of an inhalation RfC (as described in 13
Section 5.1.2.1). The following factors were considered in this evaluation: characteristics of the 14 study population, exposure regimen, quality of exposure assessment, qu ality of exposure

15 response assessment, exposure levels at which effects were seen and statistical power of the 16 study. Based on this analysis, seven studies were considered for RfC derivation. Candidate RfC 17 derivation from a key study includes the followi ng steps: 1) define the critical effect(s); 2) 18 determine appropriate point(s) of departure (PODs) on the basis of inhaled concentration; 3) 19 adjust each POD by endpoint/study

- specific uncertainty factors (UFs), to account for 20 uncertainties in the extrapola tion of study results to conditions of human environmental 21 exposure. All of the identified key studies were human studies and several studies included 22 potentially susceptible individuals (e.g. children, asthmatics). The uncertainty factor for human 23
varia bility has sometimes been reduced for studies of susceptible populations or lifestages. 24 However, for five of the seven key studies it was unclear if an uncertainty factor of 3 or 1 for 25 human variability was most appropriate. Therefore, alternatives are p resented for consideration. 26 Candidate RfCs (cRfCs) are derived for sensory irritation, decreased pulmonary function in 27 children, increased asthma incidence in children, increased allergic sensitization to common 28 allergens in children, and decreased fecund ability density ratio (FDR) in women (increased time 29 to pregnancy) (Table 5

- 7). All of these cRfCs are derived from endpoints identified in 30 residential studies, with the exception of decreased FDR (observed in an occupational study of 31
women in the woodwor king industry). 32 The overall literature database of both human and laboratory animal studies examining 33 the health effects from formaldehyde exposure is large; however, the available studies for some 34 types of effects are limited. Limitations in the existi ng database are discussed in Section 5.1.3, 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 3 specifically regarding understanding the reproductive and developmental effects and the 1

exposure

- response relationship for the observed neurological and behavioral effects from 2 formaldehyde exposure. EPA conside rs 3 options for addressing these database uncertainties in 3 the final RfC: (1) providing an RfC derived from studies of respiratory and allergenic responses 4 and protective of sensory irritation effects, without further adjustment for uncertainties in the 5
d atabase (noting the need for further research to elucidate reproductive, developmental and 6 neurotoxic effects); (2) providing an RfC with a database uncertainty factor incorporated to 7 reflect the potential that reproductive, developmental, or neurotoxic ef fects might occur at lower 8 doses; or (3) provide a range for the RfC which encompasses the above two options for the 9 database uncertainty factor. 10
11 5.1.1. Candidate Critical Effects by Health Effect Category 12 The following subsections describe the best av ailable studies and endpoints for 13 quantitative RfC derivation within each health effect category. These studies are considered 14 representative of the health effects attributed to formaldehyde exposure. For more details on 15 specific studies discussed here, see Sections 4.1.1 and 4.2.1. The identified health effect 16 categories are: sensory irritation (eye, nose, and throat); upper respiratory tract (URT) pathology; 17 pulmonary function; increased asthma and allergic sensitization; altered immune function; 18

neuro toxicity and reproductive and developmental toxicity. Discussions in each subsection 19
below describe the various health effects observed in human and animal studies for each 20
category. 21 For each health effect category, specific studies that may adequately in form the exposure

22 response relationship for critical effects are identified for consideration in RfC derivation. In 23 general, studies are included where study quality and ability to define exposures are considered 24 adequate for RfC derivation. Whenever pos sible, greater consideration is typically given to 25 human data for derivation of an RfC. When laboratory studies conducted in rodents are 26 considered for RfC derivation, the potential confounding effects of formaldehyde

- induced reflex 27 bradypnea (RB) are eva luated (Section 4.1.1 for a discussion of RB). If the exposure levels are 28 expected to cause RB, results are evaluated to ensure the effects are not in part attributable to 29 primary or secondary effects of RB in the rodents. 30
31
5.1.1.1. Sensory Irritation of the Eyes, Nose, and Throat 32 Eye, nose, and throat irritation are common effects of chemically induced sensory 33 irritation; specific effects include lacrimation, burning of the eyes and nose, rhinitis, burning of 34 the throat, and cough (Feron et al., 2001 ). Chemical irritants such as formaldehyde bind to 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 4 protein receptors of the trigeminal nerve, triggering a burning and painful sensation. This 1 process is distinct from taste and smell (Cometto

- Muniz and Cain, 1992; Nielsen, 1991). The 2 trigeminal nerve h as three branches (ophthalmic, maxillary, and mandibular) and not only acts as 3 an afferent nerve relaying these sensations to the central nervous system but has efferent nerve 4 activity as well (Meggs, 1993). Stimulation of the trigeminal nerve may result in reflex 5 responses, including lacrimation, coughing, and sneezing. In this assessment, both the reflex 6 responses and the sensations (such as burning, pain, and itching of the eyes, nose, and throat) are 7 considered adverse effects (see Section 4.1 for a f ull discussion of available human data). 8 There are studies noting irritant effects in rodents (Sarsilmaz et al., 1999; Holmström et 9 al., 1989; Dubreuil et al., 1976) and monkeys (Monticello et al., 1989; Rusch et al., 1983). 10 These animal studies are suppo rtive of the health effects reported in humans. However, given 11 the uncertainties in extrapolation from responses in laboratory animals to expected responses in 12 humans, the available human studies are preferred. 13 In human studies, the endpoints for assessi ng irritation include subjective self reporting 14 of symptoms (e.g., pain, burning, itching, increased cough) via questionnaires or objective 15 measures of irritation that can be assessed during controlled acute exposures (e.g., eye

- blink 16 counts, lacrimation). Several acute chamber studies support development of a concentration

17 response relationship for sensory irritation, identifying an effect level for various exposure 18 durations (Kulle, 1993; Andersen and Mølhave, 1983; Bender et al., 1983; Weber

- Tschopp et al., 19 1977). Arts et al. (2006b) reviewed several studies and performed BMD analyses, reporting 20 10% extra risk BMCL values for reported eye discomfort of 560 and 240 ppb for 3 and 5 hour 21 exposures, respectively. LOAELs of 1,000 ppb and 1,700 ppb were repo rted for 1

- 2 minute 22 exposures (Bender et al., 1983; Weber

- Tschopp et al., 1977). These acute studies support a role 23 for both concentration and duration in the effect level for eye irritation. Although exposure 24
concentrations are well

- defined in these cha mber studies, the chamber studies are not appropriate 25 for RfC derivation because they are of acute duration and the exposure levels used are much 26 higher than those reported for chronic exposure scenarios, both occupational and residential. 27 A study of indu strial workers assessed sensory irritation and provided an average 28 exposure derived from in

- plant exposure measurements and the work history of each study 29 participant (Holmström and Wilhelmsson, 1988). Although average daily exposures were 30
estimated for e ach employee, these data were not used to explore an exposure

- response 31 relationship within the worker cohort. The symptom prevalence for sensory irritation (e.g., nasal 32 discomfort, eye discomfort, and airway discomfort) relative to the referent group was reported 33 for the cohort as a whole, where worker exposure ranged from 0.05 to 0.5 mg/m 3 formaldehyde 34
8

- hr time

- weighted average (TWA), with a mean of 0.26 mg/m 3 (210 ppb). The daily TWA does 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 5 not reflect the peak exposures experienced during specific work tasks. Although this study 1 demonstrated marked increases in symptoms of sensory irritation in the workplace due to 2 formaldehyde exposure, it provided little data to inform the exposure

- response relationship, 3 especially in the range of environmental exposu res. 4 There are three studies that report sensory irritation in humans from chronic exposures in 5 a residential environment and provide sufficient exposure data to support quantitative assessment 6 (Liu et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). Each study reports site

7 specific exposure measurements and presents some metric of individual exposure. These 8 residential studies employ in

- home measurements for each study participant, either as average 9 exposure level (Ritchie and Lehnen, 1987; H anrahan et al., 1984) or as calculated cumulative 10 exposure based on the time in the home (Liu et al., 1991). Eye irritation is reported at similar 11 levels of residential formaldehyde exposure in the three studies (Figures 5

- 8 and 5

- 9). Each 12 study provides an exposure

- response relationship for prevalence of sensory irritation in relation 13
to in

- home formaldehyde exposure based on individual level data. The detailed exposure 14 information and chronic nature of the exposures support the selection of these studi es as 15 potential priniciple studies for RfC derivation. Each of these studies is further evaluated and a 16 cRfC developed for consideration (Section 5.1.2). 17
18
5.1.1.2. Upper Respiratory Tract Pathology 19 Formaldehyde

- induced respiratory tract pathology include s inflammation, rhinitis, goblet 20 cell hyperplasia, metaplastic changes, squamous cell hyperplasia, and impaired mucociliary 21 transport. A series of laboratory animal studies assessing formaldehyde

- induced changes in the 22 nasal mucosa suggests that these chan ges may be a protective or adaptive response and that 23 increased mucus flow and metaplastic changes will progress in relation to the concentration and 24 duration of exposure to protect the underlying tissue (Swenberg et al., 1983). The degree of 25
inflammation , hyperplasia, and metaplastic change that is due to sensory irritation

- induced 26 inflammatory responses versus inflammation and tissue remodeling from formaldehyde

- induced 27 direct cell damage cannot be distinguished. These changes have been noted as sensiti ve 28 indicators of formaldehyde

- induced effects, occurring before gross cellular damage and focal 29 lesions (Monticello et al., 1989). These responses are considered for RfC derivation, especially 30 for exposure concentrations where gross damage of the underlyi ng tissue is not expected. 31 Although well

- documented studies demonstrating formaldehyde

- induced upper respiratory tract 32 (URT) pathology have been performed in laboratory animals, including the rat (Zwart et al., 33 1988; Woutersen et al., 1987; Morgan et al., 1986a, b, 1983; Swenberg et al., 1986, 1983) and 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 6 monkey (Rusch et al., 1983), robust human data are available, and these human data are 1 preferred for RfC derivation. 2 Six human studies examined the effects of formaldehyde exposure on URT pathology 3 (Pazdra k et al., 1993; Boysen et al., 1990; Holmström et al., 1989; Edling et al., 1988; 4 Holmström and Wilhelmsson, 1988; Andersen and Mølhave, 1983). Of these studies, 5 Holmström and Wilhelmsson (1988) and Holmström et al. (1989) were identified as the most 6
robu st and sensitive and are included as candidate studies for RfC derivation (see Table 5

- 1). 7 Both studies address the same cohort and, thus, were considered together. The Holmström and 8 Wilhelmsson (1988) study is discussed above under sensory irritation ef fects. In this study of 70 9 factory workers exposed to a TWA formaldehyde concentration of 210 ppb, impaired 10 mucociliary clearance was reported in 20% of the exposed workers and 3% of the 36 nonexposed 11 workers. Using rhinomanometry, Holmström and Wilhelms son (1988) also found an increase in 12 nasal resistance due to mucosal swelling, though this increase was not statistically significant. In 13 Holmström et al. (1989), nasal biopsy samples were collected from 62 of the 70 formaldehyde

14 exposed factory workers ( these 62 had been exposed to a TWA formaldehyde concentration of 15 240 ppb) and also from 32 of the nonexposed workers. A pathologist scored each sample by 16 using a scale of 0 (normal respiratory epithelium) to 8 (carcinoma). Biopsy scores for both the 17

expo sed and control groups ranged from 0 (normal respiratory epithelium) to 4 (stratified 18 squamous epithelium with marked horny layer). The mean scores for the two groups

— 2.16 for 19 the formaldehyde

- exposed workers and 1.56 for the unexposed workers

— however, th e 20 difference was statistically significant and the authors reported that the loss of cilia, goblet cell 21 hyperplasia, and the incidence of cuboidal and squamous cell metaplasia replacing the columnar 22 epithelium were more frequent in the group exposed to for maldehyde. There was no correlation 23 between the duration of exposure and histologic changes or between smoking habits and biopsy 24 scores. The URT effects, taken together (decreased mucous flow, increased inflammation, 25 decreased nasal flow, and degradation of the respiratory epithelium), demonstrate a range of 26 formaldehyde

- induced URT pathology consistent with effects observed in controlled animal 27
studies. 28
29
5.1.1.3. Pulmonary Function Effects 30 The potential effects of formaldehyde exposure on pulmonary function in humans can be 31
examined on several time

- scales of interest. There are reports examining effects from acute 32 exposures among naively exposed anatomy graduate students (Kriebel et al., 1993; 2001), 33 anatomy graduate students with several weeks of ep isodic exposure (Kriebel et al., 1993), as 34 well as post

- shift versus pre

- shift differences in pulmonary function in workers with regular 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 7 occupational exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1 1982; Alexandersson and Hed enstierna, 1989). Depending on whether the exposures are naïve, 2 the epidemiologic studies that assessed the pulmonary effects of acute exposures to 3 formaldehyde may be assessing different biological responses, namely, the acute effect alone or 4
the acute ef fect(s) in people who may have already been sensitized to formaldehyde effects. 5 Pulmonary effects of acute formaldehyde exposure have been studied in both healthy 6 volunteers and sensitive populations under controlled conditions (e.g. acute chamber studies ). 7 Although acute chamber studies have the advantage of measured controlled exposures, other 8 factors can limit the usefulness of the studies for RfC derivation including: acute duration, small 9 study populations and lack of statistical power to assess the m easured parameters. The acute 10 chamber studies are more fully evaluated in Section 4.1.1 and will not be further considered here 11
for RfC derivation. 12 The observed effects in the previously unexposed anatomy students provide additional 13
information on acute e xposures in two naïve populations (Kriebel et al., 1993; 2001), as well as 14 insight into the intermediate stages of possible sensitization (Kriebel et al., 1993). Kriebel and 15 colleagues (1993) examined the pre

- laboratory and post

- laboratory peak expiratory flow (PEF) 16 in students attending anatomy classes once per week. They found the strongest pulmonary 17 response when examining the average cross

- laboratory decrement in peak expiratory flow in the 18 first 2 weeks of the study when formaldehyde concentrations col lected in the breathing zones 19 had a geometric average concentration of 0.73 ppm. Overall, the students exhibited a 2% 20 decrement in PEF, while the students with any history of asthma showed a 7.3% decrement in 21 PEF. These findings of acute decreases in PEF f ollowing students’ initial anatomy sessions were 22 corroborated by the Kriebel et al. (2001) study, which used a similar study design applied to 23 another class of anatomy students. 24
The first Kriebel et al. (1993) study also shows how the acute effects of form aldehyde 25 exposure were altered following several weeks of weekly episodic exposure. By the 5 th week of 26 class, the pre

- and post

- laboratory measurements of PEF were no longer reflecting a clearly 27 demonstrated acute effect but following the 7th week of episo dic exposure, both pre

- and post

28 laboratory PEF continued to drop steadily until the class adjourned after 10 weeks time. While 29 the acute effects of formaldehyde exposure appeared to diminish after several weeks of 30 exposure, the intermediate effect across 9 weeks was a 24 liter/minute drop in PEF that was 31 statistically significant (P<0.01) after statistical control for random person effects, asthma, an 32 interaction between time and asthma and eye and nose symptoms of irritation. The Kriebel et al. 33 (1993) stud y is considered of sufficient quality to support an acute RfC but the quantitative 34 details on the initial acute effects among the naively exposed students are not adequately 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 8 provided. The findings of the Kriebel et al. (2001) study were confounded by decre ased class 1 attendance, which dropped from 37 in the first week to 20 in week 6 and to just 10 students by 2 week 10. While the Kriebel et al. (2001) study could be useful as a supportive study for naively 3 exposed students, the longitudinal component is not s trong enough to support RfC development. 4
Several studies of workers assess both cross

- shift and chrinic effects of formaldehyde 5 exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 1982; 6 Alexandersson and Hedenstierna, 1989). Sin ce formaldehyde exposure may have cumulative 7 effects over chronic exposures, occupational studies generally showed clinically small but 8 statistically significant decrements in pulmonary function across shifts. In general these studies 9 did not identify, hav e information on or have appropriate statistical control of, potential 10 confounding co

- exposures. While these occupational studies provide evidence that is clearly and 11 consistently supportive of an acute effect on pulmonary function, they do not directly su pport 12 RfC development of an acute effect divorced of the concomitant chronic effects. 13 Several studies allowed for the examination of potential chronic effects of formaldehyde 14 exposure. These included an occupational study (Malaka and Kodama, 1990) that rep orted pre

15 shift pulmonary function as a percentage of expected among the formaldehyde exposed 16 compared to comparable people not exposed to formaldehyde. Studies that did not report pre

17 shift pulmonary function as a percentage of expected function (Herbert et al., 1994; 18 Alexandersson et al., 1982; Alexandersson and Hedenstierna, 1989) contribute less to an 19 assessment of potential chronic effects because, post

- hoc, it is difficult to calibrate for cross

20 study comparison the multiple pulmonary function data wi thout knowledge of the age, gender, 21 smoking status, height, year of birth, etc. that are important determinants of the pulmonary 22 function metrics of concern. The single study (Malaka and Kodama, 1990) that did report 23 functional measures in relation to expe cted value, found that an average 8

- hour time weighted 24 average formaldehyde exposure of 1.13 ppm from area samples was associated with statistically 25 significant decrements in FEV 1 , FEV 1 /FVC and FEF 25

- 75 compared to a referent population. The 26
strongest resp onse was for FEF 25

- 75, which showed a 12% drop in observed function compared to 27 expected function in the unexposed, but it is unclear how to interpret the potential chronic health 28 effect(s) with just the magnitude of the decrement and the length of the ave rage occupational 29 tenure at this plywood facility (6.5 years), which was not reported by exposure status. 30 One study reported on the longitudinal follow

- up of workers exposed to formaldehyde 31 (Alexandersson and Hedenstierna, 1989). This investigation not onl y examined the acute effects 32 of exposure across shift, but was able to do so among some of the same workers that had been 33 studied five years earlier (Alexandersson et al., 1982). Statistically significant decreases in 34
FEV 1 /FVC and FEF 25

- 75 were noted over the intervening five years in non

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

— DO NOT CITE OR QUOTE 5

- 9 correction for normal aging. The decrease in FEF 25

- 75 was 0.212 liters/s (SD=0.066 liters/s) for 1 each year of exposure and was highly significant (p<0.01). For comparison with the 12% drop in 2 the same pulmona ry metric reported by Malaka and Kodama (1990) over an estimated 6.5 years, 3 EPA computed the extrapolated percentage decrease in FEF 25

- 75 for the Alexandersson and 4 Hedenstierna (1989) using the reported yearly decrement applied to the pre

- shift values at t he 5 time of the initial study period. EPA calculated that from the predicted value of 4.57 liters/s, a 6 decrease of 0.168 liters/s could be estimated for each year of exposure regardless of smoking 7 status. For 6.5 years of exposure, this would result in a 24 % drop in FEF 25

- 75 . Formaldehyde 8 concentrations were estimated at 0.42 ppm in the first Alexandersson et al. (1982) study and at 9 0.50 ppm in the second study, but without better exposure measures, the results of the 10 longitudinal follow

- up cannot support qu antitative RfC development. 11 Information is lacking in these studies such as length or tenure of employment associated 12 with the pre

- shift pulmonary function or how long the residents had lived in their homes. 13 Likewise, knowledge of how occupational or resid ential exposure may have changed over time 14 would have allowed for an examination of the progression of any decrement in function 15 associated with long

- term episodic exposure. Among these studies, the best designed and 16
executed of the cross

- sectional studies was that of Kryzanowski and colleagues (1990). 17 Municipal employees and their children (613 adults and 298 children) were randomly sampled 18 and were considered to be representative of a diverse local population. Residential exposures to 19 formaldehyde were ba sed on repeated samples from each individual’s kitchen, living area and 20 bedroom. The average formaldehyde concentration was 26 ppb, with a maximum sample value 21 of 140 ppb. The majority of subjects (83%) lived in homes with 2

- week average concentrations 22
bel ow 40 ppb. Subjects’ peak expiratory flow rates (PEFR) were determined 4 times daily in the 23 morning, at noon, in the early evening and before bed for 2 weeks. A statistically significant 24 linear relationship between increased formaldehyde exposure and decre ased peak expiratory 25 flow rate was reported in children but not adults. All statistical models controlled for 26 socioeconomic status, tobacco smoking (current active or environmental tobacco smoking) and 27 nitrogen dioxide concentrations. In children, formalde hyde concentrations of 60

- 140 ppb 28 increased the prevalence of physician

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

- linear relationship with decreased morning PEFR for formaldehyde 30 concentration <40 ppb. Nonethe less, this strong study had only minor weaknesses such as 31
measurement error and the fact that it was a cross

- sectional study. However, random 32 measurement error tends to attenuate any true effect and is unlikely to have produced a spurious 33
effect. It is unl ikely that these findings were the product of unmeasured or residual confounding 34 as the analyses controlled for smoking as well as nitrogen dioxide levels and there is no evidence 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 10 of alternative factors that were correlated with formaldehyde concentrations and more strongly 1 associated with pulmonary function. This study of a large and representative sample from a 2 diverse study population with a well

- quantified concentration

- response function and is further 3
considered for RfC derivation. 4
5
5.1.1.4. Asthma an d Allergic Sensitization (Atopy) 6 Sensitization to inhalational chemical exposure may manifest as an allergic or asthmatic 7 response that is characterized by bronchial constriction (BC) or bronchial hyperresponsiveness 8 (BHR). This sensitization may be a res ult of immune involvement, as in the case of 9 hypersensitivity, or a neurogenic sensitization, where a chemical may directly stimulate 10 inflammation. Asthma is a specific manifestation of IgE

- mediated hypersensitivity, 11 characterized by BHR and airway inflam mation, resulting in lower airway obstruction (Fireman, 12 2003; Kuby, 1991). 13 A variety of hypersensitivity reactions have been reported following exposure to 14 formaldehyde. Rashes and skin reactions have been reported in some individuals after dermal 15

exposur es to formaldehyde. Increased expression of Th

- 2 cytokines in the lymph nodes of mice 16 given dermal applications of formaldehyde indicates the involvement of an immune component 17 to the observed sensitization (Dearman et al., 2005; Hilton et al., 1998; Arts et al., 1997). 18 However, the response does not appear to be IgE mediated (Arts et al., 1997; Lee et al., 1984). 19 Gorski et al. (1992) observed an increase in formaldehyde

- mediated neutrophil burst in 20 dermatitis patients exposed in a controlled chamber stu dy and suggests a putative role of 21 oxidative stress and reactive oxygen species (ROS). 22
23 Epidemiologic Studies: 24 Inhalation exposure has been associated with increased asthmatic responses in asthmatics 25 in occupational settings. While few available case repo rts of bronchial asthma suggest direct 26 respiratory tract sensitization to formaldehyde gas (Lemiere et al., 1995; Burge et al., 1985; 27 Hendrick et al., 1982; Hendrick and Lane, 1977, 1975), a greater body of human data provides 28
evidence of an association be tween formaldehyde exposure and exacerbation of asthmatic 29 responses in compromised individuals (Kriebel et al., 1993) and particularly in children 30 (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski et al., 1990). Increased asthma 31 incidence reported after inhalation exposure to formaldehyde led to a NOAEL of 30 ppb 32 (Rumchev et al., 2002). An increased frequency of respiratory symptoms associated with 33 asthmatic responses and formaldehyde exposure led to a LOAEL of 30 ppb (Garrett et al., 1999). 34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

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

- related 2 exposures (Zhao et al., 2008; Smedje and Norback, 2001; Norback et al., 2000) and residential 3 exposures (Matsunaga et al., 2008; Tavernier et al., 2006; Gee et al., 2005; Delfino et al., 2003; 4 Rumchev et al., 2002; Garrett et al., 1999; Palczynski et al., 1999; Norback et al., 1995; 5 Krzyzanowski et al., 1990). The two occupational studies examined the respiratory health of 6 plywood workers (Fransman et al., 2003; Malaka and Kodama, 1990). The most recent of these 7 was conducted in New Zealand by Fransman et al. (2003). Personal samples of formaldehyde 8 exposure were taken. The mean level of exposur e was 0.08 mg/m 3 (65 ppb) and the majority of 9 samples were below the limit of detection which was reported to be 0.03 mg/m 3 (24 ppb). 10 Compared with those with low levels of formaldehyde exposure, workers with high levels of 11 exposure were more likely to re port having asthma (OR=4.3 [95% CI]: 0.7

– 27.7]). The 12 association was not seen when examining formaldehyde exposure and use of asthma medication. 13 The second study of plywood workers was completed in Indonesia. Background levels of 14 formaldehyde ranged fro m 0.003 to 0.07 ppm. The highest concentration of formaldehyde 15 detected in an air sample was in the particleboard unit (range 1.16 to 3.48 ppm). The occurrence 16 of asthma was found to be positively associated with formaldehyde exposure, where asthma was 17
d efined as, “Have you ever had an attack of wheezing that made you feel short of breath?”, 18 (Malaka and Kodama, 1990). 19 Studies of exposure to formaldehyde at schools have been performed in China (Zhao et 20 al., 2008) and in Sweden (Smedje and Norback, 2001). In the study from China (Zhao et al., 21 2008), mean levels of formaldehyde were reported to be 2.3 μg/m 3 (range 1.0

– 5.0 μg/m 3 ) 22 indoors and 5.8 μg/m 3 (range 5.0

– 7.0 μg/m 3 ) outdoors. Cumulative asthma (i.e., physician

23 diagnosed asthma since birth) and daytime attacks of breathlessness were found to be associated 24 with outdoor formaldehyde levels. Neither of these outcomes was associated with indoor 25 concentrations of formaldehyde; however, indoor levels were found to be associated with 26
nocturnal attacks of brea thlessness. In Sweden (Smedje and Norback, 2001), the levels of 27 formaldehyde measured indoors were higher (mean 4, range <5.0

– 72 μg/m 3 ). One difference 28 between the Swedish study and the study conducted in China is that the Swedish study examined 29
the inci dence of asthma over a 4

- year period and did not report an association between 30 formaldehyde exposure and the incidence of asthma (OR 1.2 [95% CI: 0.8

– 1.7]) among the 31 whole study population. However, when the investigators stratified based on history of at opy, 32 they reported that among children without a history of atopy, a new diagnosis of asthma was 33 significantly more likely at higher concentrations of formaldehyde (OR 1.7 per 10 μg /m 3 [95% 34
CI: 1.1

– 2.6]) and at higher total concentrations of mold (OR=4.7 per 10

- fold increased in total 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 12 molds [95% CI: 1.2

- 18.4] in the classroom air. The finding in increase health effects due to 1 formaldehyde and mold exposures did not appear to control for the other exposure and no 2 information on the potential correlation be tween the two exposures was provided. In order to 3 evaluate the potential for confounding of the reported formaldehyde association by the reported 4 mold association, the magnitude of effects must be compared on a appropriate scale since the 5 magnitude of an odds ratio depends on the magnitude of the change in exposure level that is 6 expected to produce increased risk. After standardizing the units to the reported geometric mean 7 standard deviation, the results for formaldehyde (GSM=2.3 μg /m 3 ) is OR 1 =1.13 per GSD and 8
the results for mold is OR 2 =1.02 for a comparison of risks at the GSM to 10*GSM and 9
OR 3

The results of studies measuring residential exposu re to formaldehyde and asthma are 14 varied, with some demonstrating an association and others finding no relationship. A recent 15 study (Matsunaga et al., 2008) found no association between 24

- hour formaldehyde and 16 prevalence of asthma when pregnant women wit h an exposure to ≥47 ppb were compared to 17 those with exposure to <18 ppb. However, they reported an increased risk of atopic eczema. 18 This study did not assess the risk of incident asthma. A study utilizing self

- reported asthma 19 prevalence as an outcome al so found no association with levels of formaldehyde (mean 20
25.9 μg/m 3 , range 2.0

– 66.8 μg/m 3 ) (Palczynski et al., 1999), although they noted the incidence 21 of allergic diseases was greatest in the highest formaldehyde exposure group but that the groups 22

were t oo small for statistical evaluation. 23 =1.06 for a comparison of risks at the minimum value of total molds (5*10 3 /m 3 ) to 10 10*minimum. As it appears that the magnitude of the formaldehyde effect is str onger than that 11 of the mold effect (following standardization of exposure increment), it can be concluded that the 12 reported formaldehyde effect could not have been due to uncontrolled confounding by mold. 13

A study performed by Tuthill (1984) measured formaldehyde exposure for children 24 grades K through 6 by using a combination of proxy variables. Overall, there was no 25 association, but some individual variables showed an i ncreased risk. For example, the reported 26 risk ratio for having new construction or remodeling performed in the house in the past 4 months 27 was 2.5 (95% CI: 1.7

– 3.9). The risk ratio for having new or upholstered furniture in the house 28 (within the past 4 mo nths) was 2.2 (95% CI: 1.2

– 3.9). 29 The study by Delfino et al. (2003) assessed whether the ambient formaldehyde 30 concentration measured at a central monitoring site was associated with asthma symptoms. The 31 study examined 22 10

– 15 year olds with at least 1 yea r of physician

- diagnosed asthma and living 32

1 OR per GSD=exp[ln(OR per μg /m 3 )/ 10 μg /m 3 * 2.3 μg /m 3 ]=exp[ln(1.7)/10*2.3]=1.13 2 OR per GSD=exp[ln(OR per 10

- fold increase)/ (9*GSM)*1.6 μg /m 3 ]=exp[ln(4.7)/162*1.6]=1.02 3 OR per GSD=exp[ln(OR per 10

- fold increase)/ (9*Minimum)*1.6 μg /m 3 ]=exp[ln( 4.7)/45*1.6]=1.06This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 13 in a nonsmoking household. The mean levels of formaldehyde were measured to be 7.21 ppb 1 (range 4.27

– 14.02 ppb). There was a positive association between asthma symptom scores 2 (comparing children who report sympt oms interfering with their daily activities versus those 3 with no symptoms or symptoms not great enough to affect their daily activities) and high current 4 levels of formaldehyde (OR 1.90 [95% CI: 1.13

– 3.19]). 5 Three studies (Tavernier et al., 2006; Gee et al ., 2005; Garrett et al., 1999) were 6 performed by matching children with and without asthma and comparing the levels of 7 formaldehyde in their homes. Gee et al. (2005) reported median formaldehyde levels of 0.03 8 ppm in living rooms and 0.04 ppm in bedrooms. Analyses were limited to univariate 9 comparisons of formaldehyde levels for cases of existing asthma and controls without asthma. 10 The concentrations did not differ in a statistically significant manner. The study by Gee et al 11 (2005) was followed up with a more sophisticated analysis of the same children in the same 12 home. Tavernier et al. (2006) reiterated the earlier finding by Gee et al (2005) that formaldehyde 13 was not found to be associated with existing asthma. Tavernier et al. (2006) did not report the 14 measured levels of formaldehyde but gave the OR for the highest tertile of exposure compared 15 with the lowest tertile of exposure as 0.99 (95% CI: 0.39

– 2.50). The width of this confidence 16 interval suggests that, while no effect was observed, these find ings would still be consistent with 17

two

- fold increase in risk. 18 Garrett et al. (1999) reported on the risk of allergy and asthma

- like respiratory symptoms 19 due to formaldehyde exposure in a cross

- sectional survey of households with children with (n = 20 53) or without (n = 88) doctor

- diagnosed asthma. Formaldehyde exposure was characterized by 21
4 seasonal in

- home sampling events across the year for bedrooms and 4

– day passive samples 22 collected in living rooms, kitchens and outdoors. Statistically significant lin ear trends for 23 increased risk of having asthma were seen with increasing formaldehyde levels (p < 0.02); 24 however, the ORs for the association did not remain statistically significant after controlling for 25 parental allergy and asthma (exact ORs and 95% CIs not given). Garrett et al (1999) also 26 evaluated the prevalence and severity of allergic sensitization to 12 common allergens and 27 reported increased prevalence with increasing formaldehyde concentration in the home. The 28 respiratory symptom score was also increased and demonstrated a significant effect for 29 formaldehyde in a multiple regression after adjusting for multiple risk factors and interactions. 30 For the atopy and respiratory symptom endpoints, severity/incidence was increased in the 31 medium (20

– 50 μg /m 3 ) and high (>50 μg/m 3 ) exposure groups relative to the low (<20 μg/m 3 ) 32 exposure group, based on the highest of four seasonal 4

- day formaldehyde measurements in the 33 home. The associations between formaldehyde concentrations and severity of allergic 34

sens itization are clearly shown and further substantiated with multivariate regression controlling 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 14 for potential confounders. In logistic regressions, both the prevalence and severity of allergic 1 sensitization to 12 common allergens increased with increasing formaldehyde concentration in 2 the home. The crude association for atopy with an increase in formaldehyde concentration per 3
10 μg/m 3 was OR=1.34 which increased when adjusted for parental asthma and gender to and 4 odds ratio of 1.42 per 10 μg/m 3 (95% CI: 0. 99

- 2.04). Passive smoking, the presence of pets, 5 indoor nitrogen dioxide concentrations, airborne fungal spores and house

- dust

- mite allergens did 6 not influence the effect estimates and were unlikely to be confounders. Additionally, a 7 calculated respirato ry symptom score was increased and demonstrated a significant relationship 8 to increased formaldehyde concentration in a multiple linear regression after adjusting for 9 multiple risk factors and interactions. For each of these endpoints, severity/incidence was 10 increased in the medium (20

– 50 μg/m 3 ) and high (>50 μg/m 3 ) exposure groups relative to the 11 low (<20 μg/m 3 ) exposure group, based on the highest of four seasonal 4

- day formaldehyde 12
measurements in the home. 13 Residential formaldehyde exposure was assoc iated with an increased risk of asthma in a 14 population

- based case

- control study of 192 children aged 6 months to 3 years (Rumchev et al., 15 2002). The study, which comprises 88 cases of children discharged from the emergency 16 department of a children’s hosp ital in Perth, Australia, with a primary diagnosis of asthma and 17 104 controls, provides a positive exposure

- response relationship. Seasonal in

- home 18 formaldehyde measurements taken in the living room and subject’s bedroom were used to assess 19 exposure (8

- ho ur passive sampler). The odds ratios (ORs) for risk of asthma by formaldehyde 20 exposure level category were adjusted for numerous risk factors both familial and environmental 21 including, familial history of asthma, age, sex, smoking, presence of pets, and a ttributes of the 22 home. Of these, age, allergic sensitization to common allergens, and family history of allergy 23 were independent risk factors for asthma (ORs of 1.09, 2.57, and 2.66, respectively). Categorical 24 analysis of the data indicates the ORs for a sthma were increased in the two highest formaldehyde 25 exposure groups, reaching statistical significance for household exposures > 60 μg/m 3 (48 ppb) 26 (OR of 1.39). Analysis of the data with formaldehyde as a continuous variable indicated there 27
was a statis tically significant increase in the risk of asthma (3 % increase in risk per every 28
10 ug/m3 increase in formaldehyde level. All analyses controlled for other indoor air pollutants, 29 allergen levels, relative humidity, and indoor temperature as well as othe r risk factors. 30 A study of 202 households (mean formaldehyde level of 26 ppb) found that among children aged 31
6

– 15 years old and exposed to environmental tobacco smoke, the prevalence of asthma was 32 45.5% for those with measured levels of formaldehyde in the kitchen >60 ppb. The prevalence 33 of asthma dropped to 15.1% for levels ≤40 ppb and 0% for 41

– 60 ppb. No trend in asthma 34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 15 prevalence was seen for children who were not exposed to environmental tobacco smoke 1 (Krzyzanowski et al., 1990). 2 Finally, a study by Norback et al. (1995) reported mean levels of formaldehyde were 3
29 μg/m 3 (range <5

– 110 μg/m 3 ) in the bedrooms of individuals experiencing nocturnal 4 breathlessness compared with formaldehyde levels of 17 μg/m 3 (<5

– 60 μg/m 3 ) among those 5
without nocturnal breathlessness. The OR for this association was 12.5 (95% CI: 2.0

– 77.9) and 6 the effect was substantially stronger in magnitude than the associations observed for toluene, 7 terpenes and volatile organic compounds which makes confounding by those co

- exposure s 8 unlikely. 9
10 Supporting animal studies: 11 Several animal studies report increased airway resistance and BC due to inhalation 12 exposures to formaldehyde (Nielsen et al., 1999; Swiecichowski et al., 1993; Biagini et al., 1989; 13 Amdur, 1960). Changes in pulmona ry resistance were observed as early as 10 minutes after 14 exposure (Biagini et al., 1989), and reported effect levels ranged from 0.3

– 13 ppm. Other 15 pulmonary effects were reported in conjunction with BHR, such as increased tracheal reactivity 16
and decreased pulmonary elasticity (Swiecichowski et al., 1993; Amdur, 1960). Although BHR 17 is a common result of Type I hypersensitivity reaction to an allergen, the observation of BHR 18 alone is not sufficient to demonstrate that an agent induces Type 1 hypersensitivit y. 19 BHR may be directly induced both pharmacologically and neurogenically (Joos, 2003; 20 Cain, 2001; Meggs, 1995). There is little evidence that formaldehyde itself is an allergen 21 recognized by the immune system, especially via inhalation (Lee et al., 1984) . Although 22 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 23 experimental systems, these immunomodulatory effects do not support a type 1 hypersensitivity. 24 IgE was unchanged (Fujimaki et al., 2004a; Lee et al., 1984), and cytokine profiles were not 25
consistent with the Th

- 2 cytokines expected in IgE mediated hypersensitivity (Fujimaki et al., 26 2004a; Ohtsuka et al., 2003). 27 Formaldehyde

- induced dermal sensitization show parallel results. The physical signs of 28
irri tation and sensitization are consistently shown (e.g., rashes, edema). Some involvement of 29 the immune response has been demonstrated with positive LLNA assays, indicating proliferation 30 of lymphocytes in lymph nodes draining the affected area (Hilton et al ., 1998; Arts et al., 1997). 31 Increased expression of Th

- 2 cytokines in the lymph nodes of mice given dermal applications of 32 formaldehyde does indicate an immune component to the observed sensitization. However, the 33 response does not seem to be mediated b y IgE (Arts et al., 1997; Lee et al., 1984). 34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 16 Ito et al. (1996) reported that a tachykinin NK 1 receptor, but not the histamine H 1 or 1 bradykinin B 2 receptors, is involved in formaldehyde

- induced vascular permeability. 2 Neuropeptides NGF and substance P we re affected in BAL and stimulated splenocytes from 3 formaldehyde

- exposed mice, with greater effects seen in OVA

- immunized mice. Tachykinins 4 (e.g., substance P and neurokinin A) are produced by nerve cells and can directly stimulate 5 bronchoconstriction (Van Schoor et al., 2000). Substance P is also a mediator of neurogenic 6 inflammation. Therefore, although formaldehyde may induce some of the symptoms of type 1 7 hypersensitivity, these symptoms are more likely neurogenic than immunogenic in origin. 8
In contra st, formaldehyde enhances immunogenic hypersensitivity of known allergens 9 (Sadakane et al., 2002; Riedel et al., 1996; Tarkowski and Gorski, 1995). This potentiation 10 varied based on sensitization protocols (respiratory tract versus systemic, frequency and timing 11 of immunization, allergen, etc.) and formaldehyde exposure regimens (concentration, continuous 12 versus intermittent exposures). Taken as a whole, the results support the finding that 13 formaldehyde exposure can aggravate a type 1 hypersensitivity res ponse (Table 4

- 53). 14 The mechanism underlying this response has not been elucidated. Formaldehyde

15 induced IgE production has been reported in some studies (Vandenplas et al., 2004; Wantke et 16 al., 1996a). Other studies suggest that this effect does not app ear to be immunogenic in nature 17 (Fujimaki et al., 2004; Lee et al., 1984). Although formaldehyde exposure has been reported to 18 alter cytokine levels and immunoglobulins in some experimental systems (Fujimaki et al., 2004a; 19 Ohtsuka et al., 2003), these imm unomodulatory effects do not support immunogenically 20 mediated type 1 hypersensitivity. 21 These decrements may be mediated via neurogenic potentiation (Sadakane et al., 2002; 22 Riedel et al., 1996; Tarkowski and Gorski, 1995). Tarkowski and Gorski (1995) sugge st that 23 formaldehyde may increase permeability of respiratory epithelium and destruction of 24 immunologic barriers. Tachykinin NK1 receptor and various neuropeptides (NGF and substance 25 P) have been implicated in formaldehyde

- induced sensitization and lend w eight of evidence to a 26 neurogenic MOA (Van Schoor et al., 2000; Ito et al. 1996). 27
28
5.1.1.5 Immune Function 29 Although there are some indications of formaldehyde

- induced immunomodulation in 30 laboratory animal studies (Jakab, 1992; Morgan et al., 1986a, b, c; Leach et al., 1983) and 31 reports of increased upper respiratory tract infections in formaldehyde

- exposed workers 32 (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness and Nethercott, 1989), the overall 33 database for toxic effects on immune function and competenc e is very limited. A study of 34 workers using carbamide

- formaldehyde glue indicates decreased neutrophil respiratory burst 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 17 activity (NRBA) (Lyapina et al., 2004). NRBA was reduced in workers with URT inflammation 1 and long

- lasting respiratory tract infectio ns, compared with healthy controls, and in 2 formaldehyde

- exposed workers with slight or no respiratory infections. The authors 3 hypothesized that the decreased NRBA in symptomatic workers may be an indication of 4 formaldehyde effects in a susceptible populat ion. Since the workers have increased respiratory 5 tract infections as compared with controls, a formaldehyde

- specific effect cannot be excluded. 6 These indications of a functional deficit of the immune system are considered adverse and 7 appropriate for con sideration as a critical effect. Although this was a small study (n = 29), the 8 exposed workers had increased chronic URT infections and decreased resistance to infections 9 compared with a control population. Additionally, duration of employment was negati vely 10 correlated with both erythrocyte count and hematocrit. Measured formaldehyde concentrations 11 for a work shift were 870 ± 390 μg/m 3 (722 ± 324 ppb). This average work

- shift concentration 12 is considered to be the LOAEL for increased respiratory tract in flammation and decreased 13 resistance to infections in a worker population. 14
15
5.1.1.6. Neurological and Behavioral Toxicity 16 Studies evaluating the effects of formaldehyde on nervous system structure or function 17
are described in detail in Section 4.2.1 .4 and summarized in Table 4

- 60. Taken together the 18 animal and human data support the conclusion that formaldehyde exposure results in 19 neurological and behavioral toxicity. Observed health effects include impaired memory and 20 learning, developmental effec ts seen as both structural changes in the brain and behavioral 21 changes, and a potential for increased mortality from amyotrophic lateral sclerosis (ALS). 22 Although studies appropriate for RfC derivation do not exist for each potential neurological and 23
beha vioral health effect, several studies are available that may inform the formaldehyde RfC. 24 Seven of the available neurotoxicity studies were considered as candidates for RfC 25 development (listed in Table 5

- 1). All seven studies provided reliable document ation of 26 exposure, study design, and evaluation procedures, and all demonstrated robust findings of 27 changes in nervous system structure or function following formaldehyde exposure. All but one 28 of the candidate studies present information at multiple expos ure levels to provide an 29 understanding of the exposure response relationship. One selected study (Senichenkova, 1991) 30 provided less robust information, with evaluation at only a single exposure level, but was 31 considered useful as supporting the findings o f two other studies (Sarsilmaz et al., 2007; Aslan et 32 al., 2006) regarding neurological sequelae of developmental exposure. All of the selected 33 studies using experimental animals were conducted in rats, although several studies in mice 34
demonstrated dose

- r elated neurotoxic effects following formaldehyde exposure. These studies in 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 18 mice were not considered for RfC development because of the possibility that results might be 1 confounded by reflex bradypnea at the doses tested in each study (see Section 4.2.1.4 for 2 details). 3 In order to improve transparency and facilitate comparison of health effect levels across 4 study types and health effects, Table 5

- 1 summarizes the PODs and exposure scenarios for each 5 selected study and describes the effects on which the selected POD is based. Dose conversions 6 used to adjust from actual experimental exposure concentrations to continuous exposure 7 concentrations are detailed. It should be noted that available studies providing dose

- response 8 information regarding the effect s of formaldehyde exposure on the nervous system were all of 9 short duration, and thus information regarding the relationship between formaldehyde toxicity 10 and exposure duration (i.e., whether toxicity increases with longer exposures at a given exposure 11
lev el, or is more related to the maximum exposure concentration) is limited. However, the 12 rodent study by Pitten et al. (2000) and the epidemiology study by Weisskopf et al. (2009) 13 provide strong support for an association between increasing neurotoxicity an d increasing 14 duration of exposure. 15 Although chronic human studies are preferred for RfC derivation, no adequate human 16 study of chronic duration is available. The available human studies were sufficiently strong to 17 raise concern regarding formaldehyde eff ects on the nervous system; however, most did not 18 provide sufficient exposure information to permit derivation of a POD for use in quantitative 19
dose

- response assessment. Available epidemiologic studies (most notably Weisskopf et al. 20 [2009] and Kilburn et al. [1987, 1985]) provided limited exposure information. Weisskopf et al. 21 (2009) demonstrated increased mortality from ALS associated with increased duration of 22 formaldehyde exposure among 987,229 people followed by an American Cancer Society study, 23
but n o information regarding exposure concentrations was available. Interpretation of the 24 findings of Kilburn et al. (1987, 1985) is complicated by concomitant exposure of many subjects 25 to other solvents. Although the chamber study by Lang et al. (2008) inclu ded a concentration

26 response assessment of changes in reaction time, as previously discussed, the effects detected 27 were difficult to interpret and the study was not considered useful for RfC derivation 28

. 29This document is a draft forreview purposes only and doesnot constitute Agency policy5-19DRAFT—DO Table 5

- 1. Points of departure (POD) for nervous sy stem toxicity in key human and animal studies.

Reference POD a Exposure scenario POD duration adjustments b
Effect Species Type ppb Hours/day Days/week Duration POD × Hours/day × Days/week = ppb Ratio c Developmental neuropathology effects

Sarsilmaz

e t 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 170 d × × = 170 1 Changes in short

- term memory and ability to concentrate. Single 5.5

- hour exposure Psychomotor effects

S enichenko 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 130 e 2 1 1 day 130 × 2/4 e × = 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 2,600 f

-- -- -- -- Impaired memory in a spatial maze. Magnitude of effect inc reased with continued exposure through 12 weeksThis document is a draft forreview purposes only and doesnot constitute Agency policy5-20DRAFT—DO Malek et al. (2003a) Rat LOAEL 100 e 2 7 10 days 100 × 2/4 e × 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/m 3 = 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 adj ustment to con tinuous exposure is presented.This document is a draf t for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 21 One acute human study, Bach et al. (1990), which evaluated changes in cognitive 1 function following a single formaldehyde exposure, was considered for evaluation of a cRfC as 2 the chamber exposures were well defined and effect s at multiple levels of exposure were 3 reported. In that study, concentration

- related changes in short

- term memory and ability to 4 concentrate were seen during a single 5.5

- hour exposure at a range of levels (32, 170, 390, and 5 890 ppb). The study was desig ned as a comparison of effects of short

- term formaldehyde 6 exposure in previously occupationally exposed individuals with effects in controls without 7 previous occupational exposure. Because occupational exposure levels were not assessed, 8

exposure measureme nts from the previously exposed workers are not appropriate for use in RfC 9 derivation. The authors reported a significant exposure

- response relationship for three related 10 cognitive measures (number of additions completed, number of errors, and reaction ti me) in the 11 ‘addition test’ assessment indicating a deficit in performance. Complete data were not 12 presented, but graphical presentations in the article indicated that the effect was seen at all doses 13 tested, with an apparent NOAEL of 170 ppb (see Figure 5

- 1). 14

15 16 Formaldehyde concentration 17
18 Figure 5

- 1. Change in number of additions made in 10 minutes following 19 formaldehyde exposure at 32, 170, 390, or 890 ppb. 20 Note: Vertical bars are the standard errors of the means, dashed line shows the 21 95% CI. 22 Sou rce: Bach et al. (1990). 23Number of additions made in 10minutesThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 22 No BMD modeling could be performed on these data because the graphical 1 representation could not be accurately digitized. The statistical analysis indicated no interaction 2 between formaldehyde effect and previous occupational exp osure (i.e., the magnitude and 3 direction of the effect were similar in previously exposed and previously unexposed subjects) 4 and separate data were not presented for the two groups; thus, the LOAEL represents effects in 5 the combined study groups. Overall, the published paper lacks detail and it is difficult to 6 evaluate some aspects of the reported findings, in particular where magnitude and direction of 7 effect are not provided. Finally, the authors noted that controls and the high

- exposure group 8

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

- response relationship (at the high dose). Although this study was 10 considered valuable in documenting neurological effects in humans following exposur e to 11 relatively low concentrations of formaldehyde, the above concerns limit its utility for 12 quantitative human health risk assessment. Therefore, this study is not considered of sufficient 13 quality for RfC derivation. 14 In the absence of adequate human dat a, controlled studies in laboratory animals are 15 considered. There are no chronic studies and only one subchronic animal study evaluating 16 neurological and behavioral effects of formaldehyde exposure. Pitten et al. (2000) demonstrated 17 impaired retention of a previously learned task in rats exposed at concentrations of 2,600 or 18 4,600 ppb, 10 minutes per day, 7 days/week, for 90 days. In this study, the magnitude of the 19 impairment increased over time, even though testing was performed 22 hours after exposure

, 20 indicating that repeated formaldehyde exposure led to a worsening of effect. The study design, 21 test methods, and reporting of the results are all of adequate quality for both hazard assessment 22 and quantitative risk assessment. However, the short durati on (10 minutes) of the repeated daily 23 exposures is a severe limitation to establishing a chronic RfC based on this study, due to 24 uncertainties in extrapolating from 10 minutes to a 24

- hour exposure (see Table 5

- 1). Because 25 this study as designed indicates an accumulation of effect with repeated exposure, it is useful in 26 documenting the existence of a duration component to the exposure

- response relationship. It 27 follows that concentration alone, without an adjustment for duration of exposure, would be 28
inade quate as an exposure metric; however inadequate information is available to inform the 29 appropriate magnitude of the duration effect. Therefore, although Pitten et al. (2000) is a well

30 conducted study, the data are of limited utility for RfC derivation. 31
F inally, there are several well

- documented acute and subacute animal studies that provide 32

exposure

- response information for neurological and behavioral endpoints relevant for RfC 33 derivation. Several laboratory animal studies that evaluate neurological effe cts following in 34 utero or neonatal exposure address potentially susceptible life stages. Sarsilmaz et al. (2007) and 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 23 Aslan et al. (2006) observed changes in brain structure (cell number and/or volume changes in 1 specific brain regions) following 30 days of exposure to neonatal rats. A related finding by 2 Senichenkova (1991) demonstrated changes in behavior (open field motor activity, including 3 habituation) in young rats following in utero exposure. Effects of concern were seen at all doses 4
in these studies , resulting in PODs of 67 ppb following in utero exposure and 1,070 ppb 5 following early postnatal exposure, based on LOAEL values adjusted for continuous exposure 6 (see Table 5

- 1). These studies support the possibility of neurodevelopmental effects attribu table 7 to in utero or early postnatal formaldehyde exposure, at levels similar to or below those causing 8 other types of effects. 9
The other three studies in Table 5

- 1 evaluate behavioral changes in rats following 10 exposure to formaldehyde. Malek et al. (200 3c) found concentration

- related changes in motor 11 activity following a single 2

- hour exposure at concentrations from 130

– 5,180 ppb (with testing 12
2 hours following cessation of exposure). In a second study, Malek et al. (2003a) found 13
concentrated

- related ch anges in performance on a learning task at similar exposure levels (100

– 14 5,400 ppb) when 2

- hour exposures were repeated for 10 consecutive days; performance was 15 evaluated 2 hours after cessation of exposure, and concentration

- related learning deficits were 16 seen at all exposure levels (see Table 5

- 2 and Figure 5

- 2). 17
18
Table 5

- 2. Effects of formaldehyde exposure on completion of the labyrinth 19 test by male and female LEW.1K rats 20 21

Male rats Swimming time (sec) Error rate (mean) Day 1 Day 6 Day 10 Day 1 Day 6 D ay 10 Control 105 12.2 6.33 7.4 0.5 0.0

0.1 ppm a 100 12.9 6.07 7.7 5.0 c 3.2 c 0.5 ppm 97 16.7 c 7.60 b 7.6 4.4 c 1.8 c 5.4 ppm 105 25.7 c 10.9 c 7.7 5.0 c 2.8 c Female

rats Swimming time (sec) Error rate (mean) Day 1 Day 6 Day 10 Day 1 Day 6 Day 10 Con trol 103 12.5 6.47 7.9 0 0.0

0.1 ppm 96 12.3 7.53 7.1 5.2 c 3.0 c 0.5 ppm 97 14.6 c 7.60 b 8.0 4.6 c 2.2 c 5.4 ppm 98 23.5 c 9.73 c 7.9 5.2 c 2.6 c 22

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

b Different from control, p < 0. 05. 24

c Different from control, p < 0.005. 25 26 Source: Malek et al. (2003a). 27 28This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 24 1 Figure 5

- 2. Effects of formaldehyde exposure on the error rate of female 2 LEW.1K rats performing the water labyrinth learning test

. 3 4 Source: Drawn from data reported in Malek et al . (2003a). 5 6 7 Although other studies evaluating neurobehavioral effects were available in the 8 formaldehyde database (see Chapter 4), these studies by Malek et al. (2003a, c) were considered 9 to be the most robust, documenting effects at relatively low expos ure levels. Both studies also 10 included evaluation at multiple concentrations and showed concentration

- related increases in 11 effect. In the Malek et al. (2003a) study with repeated exposures, it is unclear whether or not the 12 measured effect primarily refle cts the most recent exposure or cumulative exposure; therefore, 13 the adjustment for continuous exposure was made over the final exposure period and the 2 hours 14 following exposure (4 hours total), as was done for the single

- exposure study (Malek et al., 15
2003 c). After appropriate duration adjustments, PODs for these studies range from 50 to 67 ppb 16 (based on LOAELs), and the types of effects seen provide support for the Bach et al. (1990) 17 study that detected cognitive impairments in humans following a single e xposure (with a 18 NOAEL of 170 ppb). 19
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 testErrors (mean) control 0.1 ppm 0.5 ppm 5.4 ppmThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 25 Summary of neurological and behavioral effects: 1 In summary, the available studies for formaldehyde and nervous system outcomes have 2 demonstrated that the nervous system is a sensitive target following inhalation of fo rmaldehyde. 3 In experimental animals, changes in nervous system function were seen following acute and 4 subchronic exposures; studies evaluating neurological changes following chronic exposure were 5
unavailable. Available human studies that evaluated nervou s system effects following inhalation 6 exposure were found to have many study

- specific uncertainties and, thus, were not suitable to 7 serve as the primary basis for a chronic RfC. The Weisskopf et al. (2009) study of ALS, in 8 particular, suggests that humans may be at risk for severe neurological effects from 9 formaldehyde exposure; however, this study lacked the exposure concentration information 10 necessary to derive an RfC. Neurological findings from the rodent inhalation (acute and 11 subchronic) studies that were judged to be adequate for dose

- response assessment identified 12 unadjusted LOAELs ranging from 100 to 6000 ppb, with LOAELs adjusted for continuous 13 exposure in the range of 50 to 1070 ppb. Use of these PODs in risk assessment would require 14 addressing u ncertainties regarding animal

- to

- human extrapolation, short study durations, and 15 extrapolation from LOAELs. 16 Among the adequate studies, EPA considered Malek et al. (2003a) to be the most 17 appropriate for calculation of a cRfC for neurological and behavioral toxicity, based on the 18 exposure level at which effects were seen (100 ppb), the type of effect (impaired learning), 19 which is relevant to humans, and the use of a repeated

- exposure paradigm (2 hours/day over a 20 period of 10 days), which addresses different exposure durations. This choice is supported by 21 similar effects seen in other studies (Lu et al., 2008; Pitten et al., 2000; Bach et al., 1990) and by 22 other neurologic effects seen at similar exposure levels (Malek et al., 2003c; Senichenkova, 23 1991; Sheve leva, 1971). 24
25 5.1.1.7. Developmental and Reproductive Toxicity 26
As described in Sections 4.1 and 4.2 and summarized in Tables 4

- 68 and 4

- 71, both 27 human epidemiologic data and experimental animal studies demonstrate an association between 28 formaldehyde inh alation exposure and adverse developmental and reproductive effects, where 29 adversity is characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 30 2006). Adverse outcomes were observed across the various manifestations of developmental 31 toxicity, including fetal death, structural alterations (including congenital malformations), 32 growth retardation, and functional development. Additionally, in spite of the lack of a 33 comprehensive database of studies for the evaluation of the overall effe cts of formaldehyde on 34 the reproductive system and its function, the available evidence demonstrates toxicity to the male 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 26 reproductive system in multiple animal studies, as well as effects on the female reproductive 1 system in both rodents and epidemiologic studies, where an association with impaired fertility 2 and increased spontaneous abortions were noted. 3 Potential principal studies for specific adverse outcomes are presented and evaluated 4 below including reproductive effects (male and female), fetal dea th, growth retardation, and 5 structural alterations. The only available evidence for functional alterations is based on 6 developmental neurotoxicity studies which are presented and evaluated in Section 5.1.1.6. 7
Table 5

- 3 summarizes animal studies deemed su itable for deriving quantitative dose

- response 8 information for reproductive and developmental outcomes and their corresponding PODs, 9 adjusted for continuous exposure. Calculations that were used in dose conversions and exposure 10 duration adjustments for th e POD values are included. In general, repeated daily exposures of 11 laboratory animals are adjusted from a partial day to a 24

- hour exposure and then weighted for 12 the number of days per week the exposures occurred. No chronic animal studies evaluating 13
the se endpoints were available, so only subchronic and acute studies are considered. Exposure 14 duration adjustments to the only suitable human study (Taskinen et al., 1999) are more complex 15 due to uncertainties in the exposure data and the potential for non

- o ccupational exposures. For 16 this discussion the reported 8

- hr TWA exposures will be used for the Taskinen et al. (1999) 17 study. Further duration adjustments to this study are discussed in Section 5.1.2.2.5 for cRfC 18
derivation. 19
20 Spontaneous abortion and f etal death. 21 Increased risk of spontaneous abortion following maternal occupational formaldehyde 22 exposure was reported in a number of epidemiologic studies (Taskinen et al., 1999, 1994; John et 23 al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). T he studies did not appear to be overtly 24 influenced by common principle biases found in epidemiologic studies. Considered together, the 25 studies are consistent with an adverse effect of formaldehyde exposure on pregnancy loss, where 26 adversity is characteriz ed as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 27 2006). . Of these studies, Taskinen et al. (1999) had the superior quantitative data reporting 28 reduced fecundity and spontaneous abortion in the exposed workers. Taskinen et al. (1999) is an 29 occupational study with a well

- considered study design, including measurements of exposure 30 and outcomes, and relatively high study power. The study population consisted of 602 female 31
workers in Finland who had at least one successful childbirth and first employment in the wood

32 working industry beginning at least 6 months prior to the studied pregnancy. Mean daily 33 formaldehyde inhalation exposures during the time

- to

- pregnancy period were estimated for each 34 worker, based on task

- level exposure measure ments and work history. 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 27 Exposure was reported as a daily exposure index representing the average daily exposure 1
for the time

- to

- pregnancy period, and three exposure classes were defined as low, medium and 2 high with equivalent mean work

- shift TWA exposure of 18, 76 and 219 ppb, respectively. 3 Fecundity density ratio (FDR) was significantly reduced in the high exposure group compared to 4 the referent group (P=0.02), and the risk of spontaneous abortions was increased with reported 5 ORs of 3.2 (1.2

- 8.3), 1.8 ( 0.8

- 4) and 2.4 (1.2

- 4.8) for the high, medium and low exposure 6 groups, respectively. The effect on FDR remained in workers both with and without the use of 7 protective gloves (n=39) but lost statistical significance in the exposed group of workers who 8

wore gloves (n=22). Figure 5

- 3 shows the study results stratified by glove use in women in the 9 high

- exposure group. Although this suggests that a component of dermal exposure might 10 contribute to the effect, it is unclear what, if any, dermal exposure is expe cted based on the 11 nature of the work. Regardless, there remains uncertainty as to whether effects are solely due to 12 inhalation exposure. 13
14

15 Figure 5

- 3. Fecundity density ratio among women exposed to formaldehyde 16 in the high exposure index category with 8

- hour time

- weighted average 17 formaldehyde exposure concentration of 219 ppb (Taskinen et al., 1999) 18 19 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% CIThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 28 In some available rodent studies (Kitaev et al., 1984; Sheveleva, 1971), evidence of 1 increased embryo degeneration in early gestation or of preimplantatio n loss (findings that are 2 generally comparable to spontaneous abortion in humans) was observed. In the Kitaev et al. 3 (1984) study, early implantation losses resulted following treatment of dams prior to mating. 4 This may support a possible contribution of pre

- pregnancy exposures to the spontaneous 5 abortions observed in Taskinen et al. (1999). Quantification of the findings by Kitaev et al. 6 (1984) and Sheveleva (1971) resulted in adjusted PODs of 50 and 70 ppb, respectively, based 7 upon study LOAELs (Table 5

- 3). 8
9

Structural alterations. 10 Studies of occupational exposures to formaldehyde examined the incidence of congenital 11 malformations, but exposure and outcome data were not fully characterized and therefore could 12 not be carried forward to RfC development . Animal studies (Senichenkova and Chetobar, 1996; 13 Senichenkova, 1991) reported increases in internal organ anomalies; the most frequently 14 observed structural anomaly was a delay in fetal testis descent (at times characterized as 15 cryptorchidism in the stu dy reports). For both studies, which exposed rats to formaldehyde for 4 16 hours/day during gestation, adjusted PODs based upon LOAELs were 70 ppb (Table 5

- 3). These 17 studies included only one treatment level, precluding the ability to establish a dose

- respo nse 18 relationship, and the observed outcomes were not noted in other developmental toxicity studies 19 with similar exposure scenarios, thus limiting the strength of the studies for use in RfC 20
derivation. 21
22
Growth retardation. 23 Decreased fetal weight was obse rved in a number of animal studies that exposed pregnant 24 rats to formaldehyde during gestation. Of these, based on adequacy of dose

- response 25 information, Saillenfait et al. (1989) was considered appropriate for consideration for RfC 26 development. In this study, rats were administered formaldehyde 6 hours/day on gestational 27 days (GDs) 6

– 20. Decreased male fetal body weight (BW) was modeled with a BMR of 5% 28 mean change, a BMCL was established, and, as shown in Table 5

- 3, the resulting duration

29 adjusted POD of 325 ppb was derived. The relevance of this finding to human exposures was 30 qualitatively supported by a population

- based study by Grazuleviciene et al. (1998) that reported 31 an association between atmospheric formaldehyde exposure and low birth weight; a lthough a 32
dose

- response relationship could not be adequately quantified from the information provided. 33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 29 Male reproductive toxicity. 1 Evidence of adverse effects on male reproductive system endpoints following inhalation 2 exposure to formaldehyde was obse rved in a number of animal studies, where adversity is 3 characterized as per EPA risk assessment guidelines (U.S. EPA, 1991; U.S. EPA, 2006). The 4 effects include decreased testes weight, changes in Leydig cell quantity and quality, degeneration 5
of seminife rous tubules, decreased testosterone levels, alterations in biomarkers of toxicity in the 6 testes, and alterations in sperm count, morphology, and/or motility (Golalipour et al., 2007; Xing 7 et al., 2007; Zhou et al., 2006; Özen et al., 2005, 2002; Sarsilmaz et al., 1999; Guseva, 1972). 8 Several of these studies included inhalation exposure of rats to formaldehyde 8 hours/day, 9
5 days/week for 4 and/or 13 weeks (Özen et al., 2005, 2002; Sarsilmaz et al., 1999) and included 10

exposure

- response information that wa s considered adequate for RfC derivation. In a study by 11 Özen et al. (2002), increased severity of statistically significant testes weight decreases was 12 related to both dose and duration of treatment. Similarly, in the study by Golalipour et al. 13 (2007), s eminiferous tubular diameter and epithelial height were reduced in rats following 18 14 weeks of formaldehyde inhalation exposure, with the severity of outcome positively correlated to 15 the number of hours/week that the animals were exposed. Sarsilmaz et al. (1999) noted dose 16 dependent decreases in Leydig cell quantity after 4 weeks of treatment, while decreased testis 17 weight and atrophy of seminiferous tubules were observed by Zhou et al. (2006) after only 2 18 weeks of treatment. The reported outcomes in these independent studies illustrate a biologically 19 consistent toxicological profile of treatment

- related male reproductive toxicity. PODs, adjusted 20 for continuous exposure, ranged from 1,190 to 4,025 ppb, where the lowest POD was associated 21 with the longest e xposure period and vice verse (Table 5

- 3). 22
23 Female reproductive toxicity. 24 Evidence of decreased fecundability was observed in the study by Taskinen et al. (1999), 25 which was described above for spontaneous abortions. Delays in the time to conception tha t 26 characterized this outcome, as well as increases in the incidence of endometriosis, were 27 statistically significantly associated with occupational exposures to formaldehyde. As these 28 effects were observed in the high exposure group, the unadjusted NOAEL for each of these 29 effects is 76 ppb (8 hr

- TWA) based on the next lowest exposure group. Uncertainties included 30 lack of information human variability, as well as on the extrapolation of data from studies of 31 short duration to risk estimates for chronic expos ures. As discussed above for spontaneous 32 abortions, the use of these data for cRfC derivation could result in values that would likely be an 33 underestimation of risk because they assume that all the risk was from inhalation exposure and 34 ignore the apparent contribution of dermal exposure (i.e., the dermal

- exposure

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

— DO NOT CITE OR QUOTE 5

- 30 candidate inhalation RfCs might be higher). For decreased fecundability, a POD can also be 1 identified based on the data from only the women who wore gloves. The fecundability density 2

ra tio (FDR) for the women in the highest exposure group who wore gloves was 0.79 (95% 3 confidence interval [CI] 0.47

– 1.23). Although this FDR is not statistically significant, it can 4 reasonably be assumed to be part of a trend of decreased FDR with increasin g inhalation 5 exposure, based on the overall data for the association of decreased FDR with formaldehyde 6 exposure. Whether the highest exposure level is considered to be a NOAEL or a LOAEL for 7 decreased fecundability in women who wore gloves, the unadjuste d POD is 219 ppb (8 hr

8 TWA). Evidence of spontaneous abortions in the same study, as described above, may also be 9 indicative of female reproductive toxicity. 10 In animal studies, assessment of the female reproductive system was quite limited. An 11
increase in the mean follicle

- stimulating hormone (FSH) levels in rats, observed at the highest 12 exposure level tested in Kitaev et al. (1984) was found to be sufficient to derive a duration

13 adjusted POD of 50 ppb (Table 5

- 3). 14
15 Summary of developmental and reproduct ive toxicity studies suitable for RfC development. 16 A review of the developmental and reproductive toxicity studies in humans and animals 17 that would be suitable for cRfC development demonstrated that the developing organism and the 18 reproductive system a re targets for toxicity following formaldehyde exposure by inhalation. In 19 the animal studies, effects during early development were observed following maternal 20 premating or gestational exposures at duration

- adjusted PODs ranging from 50

- 325 ppb. The 21
mini mal data available on female reproductive toxicity demonstrated an adjusted POD of 50 ppb 22 with subchronic (4

- month) premating exposure, while more extensive evaluation of male 23 reproductive outcomes identified adjusted PODs of 1,190

- 4,025 for testicular and sperm 24 abnormalities after exposures of from 2 weeks to 3 months in duration. The animal studies 25 demonstrate the broad range of adverse outcomes to the reproductive system and the developing 26 organism following inhalation exposure to formaldehyde and highl ight concerns regarding the 27 inadequacy of the database for the assessment of these outcomes (as described in Chapter 4). 28 These data also support the human relevance of female reproductive and/or embryonic and fetal 29 developmental effects, since some outcom es were similarly observed in both human and animal 30
studies. 31
32This document is a draft forreview purposes only and doesnot constitute Agency policy5-31DRAFT—DO 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 Hou rs/ 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 d egeneration 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 loss g Structural alterations c Senichenkova (1991) Rat LOAEL 400 4 7 GD s 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 4 00 × 4/24 × 7/7 = 70 5.7 Increased (21%) fetal and litter incidences of cryptorchidism and increased (6%) fetal incidences of total anomalies g 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 weights g (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) R at 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 weeksThis document is a draft forreview purposes only and doesnot constitute Agency policy5-32DRAFT—DO 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%) follicle

stimulating hormone at 4 months

GDs = Gestation days

a 1 mg/m 3 = 0.813 ppm.
b POD unadjusted dose / duration

- adjusted dose

c Neuropathol ogical 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 (fro m the study by Senichenkova [1991]) are addressed in the neurobehavioral toxicity Section 4.2.1.6 and Table 5

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

— DO NOT CITE OR QUOTE 5

- 33 The animal study data were not selected for RfC derivation, since a high

- quality human 1 study (Taskinen et al., 1999) was available for the pur pose of deriving a chronic RfC. This 2 study, a well

- designed population

- based case

- control study of women who were occupationally 3 exposed to formaldehyde, included a well

- defined study population which was adequately 4 selected to allow for meaningful compar isons of health effects among individuals with different 5 levels of exposure to formaldehyde. Potential confounding factors such a selection bias and 6
inaccurate self

- reporting were not considered to have had a significant influence on the study 7 findings. The increased risk of spontaneous abortion observed in Taskinen et al. (1999), and 8 perhaps the observed decrease in fecundity, is internally consistent and coherent with other 9 reports of increased risk of pregnancy loss associated with exposure to formalde hyde (John et al., 10 1994; Taskinen et al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). It is also supported 11 by similar adverse outcomes observed in the animal data (Kitaev et al., 1984; Sheveleva, 1971). 12
13 5.1.2. Summary of Critical Effects and Ca ndidate RfCs 14
5.1.2.1. Selection of Studies for Candidate RfC Derivation 15
The above reviews of data from both human and animal studies identified health effects 16 associated with formaldehyde exposure. Detailed information on these findings is given in 17 Chapt er 4 (sections 4.1 and 4.2), and a qualitative summary of the noncancer hazard 18 identification is provided in Section 4.4 for each of the identified health effect categories: 19 sensory irritation, upper respiratory tract pathology, respiratory effects, incre ased atopic 20 response, immune function, reproductive and developmental toxicity, and neurobehavioral 21 toxicity. In this chapter, results for each health effect category are reviewed and studies are 22 identified which are adequate to inform the exposure

- respon se relationship for health effects 23 from inhalation exposure (Section 5.1.1). Although the database of published studies that are 24 currently available does not provide adequate quantitative data to derive cRfCs for all 25 qualitatively identified endpoints, at least one adequate study was identified for each of the 26 health effect categories discussed above. For all but one of the categories, at least one study was 27 available that provided epidemiologic (human) data, based on occupational or residential 28

exposures , which was judged adequate to provide a quantitative basis for a cRfC. 29 In order to select the principal study or studies most appropriate for use as the basis of the 30 RfC for formaldehyde, the relative merits of these studies were evaluated with respect to study 31 quality, characteristics of the study population, the quality and frequency of exposure 32 measurements, and the exposure levels at which effects are observed. The ideal RfC would be 33 derived from a reported exposure level without an appreciable risk of deleterious effects in 34 humans, including sensitive populations, with little uncertainty. Additionally, where possible, 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 34 the RfC should be derived with consideration of all of the identified health effects. The several 1 factors that were collectively ta ken into consideration for these studies (in no particular order) 2 included the following: 3
4

**•** Were studies of laboratory animals or humans? 5

o Human studies were generally preferred over laboratory animal studies for similar 6 health effects, when both were of goo d quality, given the uncertainties in 7 interspecies extrapolation. 8

**•** What was the study size? 9

o Larger studies were generally preferred over smaller studies because they can 10 give more precise estimates of response levels associated with specific exposure 11
levels

. 12

**•** Among the epidemiologic (human) studies, were exposures from an occupational setting or 13 from a residential setting? 14

o Studies of health effects from residential exposures were generally preferred over 15 studies of health effects from occupational exposures b ecause residential 16 exposures tend to have a smaller range of variability and are less prone to large 17 intermittent exposure peaks. 18

o Residential exposures are more representative of the exposures of the general 19 population. 20

**•** Among the epidemiologic (human) st udies, were children among the study population in 21
which health effects were observed? 22

o Studies of health effects that assessed the effect of formaldehyde on children’s 23 health, representing a potentially more susceptible life

- stage for some effects, 24 were gi ven some preference because they provide formaldehyde

- specific data 25 relevant to the components of the RfC derivation that address potentially sensitive 26
life

- stages and populations. 27

**•** Relative to the other studies under consideration for RfC development, how accurately were 28 formaldehyde concentrations measured? 29

o Studies based on relatively more accurately measured formaldehyde 30 concentrations were generally preferred over studies that estimated exposures. 31

**•** Studies that reported effects at relatively lower formald ehyde concentrations, potentially 32 indicative of more sensitive endpoints, were generally preferred. 33
34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 35 Taking all the factors into consideration collectively, the individual studies are presented 1
in Table 5

- 4. 2 For sensory irritation, four studies are identif ied with adequate exposure information for 3 RfC derivation, and all are human studies (Table 5

- 4). Of these, 3 studies were conducted in 4 residential populations, including children and the elderly (Liu et al.,1991; Ritchie and Lehnen, 5 1987; Hanrahan et al. , 1984). Each of these studies includes in

- home formaldehyde 6 measurements for each participant. Liu et al. (1991) provide the best exposure measurements, 7
with 7

- day in

- home passive air samples collected in two seasons. The occupational study by 8
Holmströ m and Wilhelmsson (1988) provides evidence of sensory irritation in workers; 9 however, only the mean and range of exposures for all workers is given. Furthermore, 10 occupational exposures can include high peak exposures. The residential studies are preferre d 11 for development of candidate RfC. Although there are differences in study size and the quality 12 of exposure measurements between the three residential studies, their results are mutually 13 supportive, defining similar effect levels in similar populations, and the use of the three 14 residential studies was considered to provide adequate consideration of the sensory irritation 15 endpoint. Therefore, all 3 studies are selected (Liu et al.,1991; Ritchie and Lehnen, 1987; 16 Hanrahan et al., 1984) and will be evaluate d together in the following section. 17 Histological changes in the upper respiratory tract are well documented in animal studies 18 and have been observed in several worker studies (Section 4.4). Although the study of resin 19 production workers (Holmström and Wi lhelmsson, 1988; Holmström et al., 1989) provides the 20 best documentation of effect level for this health category in humans, it is not carried through for 21 development of a candidate RfC. As with the sensory irritation endpoint reported in these 22 studies, e xposure is described for the worker cohort by a simple mean, with a range of exposures 23 given for all workers. Therefore, these data do not provide an exposure

- response relationship 24 and the POD would be the mean exposure level of all workers, regardless of effect. This is less 25 exact than other available studies which provide exposure

- response relationships. Additionally, 26 animal studies provide a broad database which supports sensory irritation as a more sensitive 27 endpoint than histological changes in the nasal mucosa. 28
29This document is a draft forreview purposes only and doesnot constitute Agency policy5-36DRAFT—DO Table 5

- 4. Summary of candidate studies for formaldehyde RfC development by health endpoint category 1

Health Endpoint Category Study Species Setting Children Study size Formaldehyde measurements Specific Endpoints Observed effects a (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 BMCL 10 =70

Ho lmström 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) Hu man 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 a l. (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 (Winte r & Summer); 8

- hour passive monitors Initial diagnosis of asthma 45 NOAEL=33This document is a draft forreview purposes only and doesnot constitute Agency policy5-37DRAFT—DO Health Endpoint Category Study Species Setting Children Study size Formaldehyde measurements Specific Endpoints Observed effects a (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 BMCL 10 =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 Occupa tional No 602 Actual and surrogate
measurements estimated by occupational hygienist Decreased fecundity density ratio (FDR) 226 b NOAEL=86

Taskinen et al. (1999) (SAB) Human Occupational No 602 Actual and surrogate
measurements estimated by occupational h ygienist Increased risk of spontaneous abortion (SAB) 26 b 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).Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 38 Reduced pulmonary function is associated with formaldehyde exposure in several human 1 studies (students and workers). The best single study demonstrating decreased pulmonary 2 function is the moderate residential study by Krzyzanowski et al. (1990). The study was 3 specifically designed to include homes with children between the ages of 5

- 15. Results 4 presented for children (n = 208) provide an exposure

- response relationship for reduced PEFR. 5 Data quality is considered hi gh for this study, both in terms of the in

- home exposure 6 measurements (7

- day passive monitors, two time periods) and the contemporaneous in

- home 7 measurement of pulmonary function. Sources of potential confounding or bias were considered 8 by the study autho rs and adequately taken into account in the study. Therefore, this study is 9
retained for derivation of a candidate RfC. 10 Several studies report increased asthma and/or allergic sensitization in children 11 associated with increased formaldehyde exposure in sc hool or homes (Section 5.1.4). Of these, 12 two studies are further evaluated here (Garrett et al., 1999; Rumchev et al., 2002). The study by 13 Rumchev et al. (2002) is a case

- control study of asthma incidence in children, and the study by 14 Garrett et al. (199 9) is designed to study several related health effects (asthma, sensitization and 15 respiratory symptoms) in asthmatic and non

- asthmatic children. Both studies measure in

- home 16 formaldehyde levels with multi

- day passive samples. Survey data and health outco me data are 17 considered of high quality in each study. Additionally, sources of potential confounding or bias 18 were considered by the study authors and adequately taken into account in the study. Therefore, 19
both studies are retained for derivation of a cand idate RfCs. Although several studies of school 20 children support these findings, the residential studies were considered more appropriate for RfC 21
derivation because individual in

- home formaldehyde levels were associated with the health 22
outcome data. 23
Mult iple lines of evidence support the occurrence of neurotoxicity following exposure to 24 formaldehyde, however, none of the available human studies were considered to be of adequate 25 quality for derivation of a point of departure for use in quantitative assessm ent. Of the available 26 neurotoxicity studies, Malek et al. (2003a), in which impaired learning was seen in rats 27 following exposure at 100 ppb, was selected as a potential candidate for RfC development (see 28
Section 5.1.6). A NOAEL was not identified for th is effect. In view of the other studies 29 available in the formaldehyde database (including multiple human studies of potentially sensitive 30 populations), and considering the uncertainty in extrapolating from the exposure conditions in 31 the Malek et al. (2003 a) study (two hour exposures, repeated on ten consecutive days) to a 32 chronic exposure scenario, this study was not carried forward for derivation of a candidate RfC. 33 It is important to note that the resulting RfC may therefore not fully consider the docum ented 34 neurotoxic effects of formaldehyde. 35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 39 Of the various reproductive and developmental effects associated with formaldehyde 1 exposure, reduced fecundity and increased risk of spontaneous abortions are primarily studied in 2 humans (Section 5.1.7). Of the av ailable human studies, only one study provides individual 3 exposure estimates of adequate quality to support RfC development (Taskinen et al., 1999). 4 Exposure

- response relationships for decreased fecundability density ratio and increased risk of 5
spontaneou s abortions are seen with increased categories of worker exposures. Several potential 6 confounding exposures are evaluated in the study, and the association of decreased fecundability 7 density ratio observed in the study is most convincingly associated with increased formaldehyde 8 exposure (Taskinen et al., 1999). Potential sources of bias were also adequately addressed in the 9 study. This is considered a high quality study and is retained for cRfC derivation. 10 Although Lyapina et al. (2004) have documented d ecreased neutrophil respiratory burst 11 activity in exposed workers, the overall weight of evidence for deficit in immune function due to 12 formaldehyde exposure is weak. There is a trend for increased respiratory tract infections in 13 formaldehyde

- exposed indi viduals, but it is a direct result of impaired immune function or, 14 perhaps, increased infection due to direct effects on the protective barriers of the nasal mucosa. 15 Animal studies do not support a finding of a deficit in immune function with formaldehyde 16 exposure. The study by Lyapina et al. (2004) is a small study, and the findings of decreased 17 neutrophil respiratory burst activity were in those individuals with more upper respiratory tract 18 infections, so there is some question of causality. The data e valuation does not provide an 19

exposure

- response relationship, but, rather, exposure for the cohort is expressed as a mean 20 exposure of 722 ppb. Although the potential for impairment of immune function is an important 21 health effect, the overall evidence for this effect and this specific study are relatively weak 22 compared to other data available to support RfC derivation for formaldehyde. Therefore, this 23 study is not carried further in the quantitative analysis. 24 In summary, the best studies evaluated herein for the derivation of an RfC for 25 formaldehyde exposure and the related health effects are: 1) Sensory irritation (Liu et al.,1991; 26 Ritchie and Lehnen, 1987; Hanrahan et al., 1984); 2) reduced pulmonary function 27 (Krzyzanowski et al., 1990); 3) sensitizatio n (atopy and asthma) (Garrett et al., 1999 and 28 Rumchev et al., 2002); and 4) reduced fecundity and increased spontaneous abortion (Taskinen 29 et al., 1999). It is recognized that not all identified health effects are represented in these 30
studies. 31
32
33
34
35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 40 5.1. 2.2. Derivation of Candidate RfCs from Key Studies 1 Candidate RfC derivation for Krzyzanowski et al. (1990) (Pulmonary function) 2 The study by Krzyzanowski et al. (1990) is a high quality epidemiology (human) study of 3 health effects in a random sample of r esidents and their families. The study was specifically 4 designed to include only households that had children 5

– 15 years of age, a sensitive life

- stage for 5 respiratory effects. The study was of moderate size, when the effects in children were analyzed 6

se parately from adults, with the final analysis based on 208 children

— a cohort large enough to 7 show statistically significant results. The formaldehyde monitors were prepared by the 8 Lawrence Berkeley Laboratories and were considered to be precise and highly reliable. The 7

- 9 day passive formaldehyde monitors generally provide the lowest limit of formaldehyde 10 detection. The investigators specifically tested an a priori hypothesis and conclusively 11 demonstrated to a high level of statistical significance that i ncreased residential formaldehyde 12 exposures were associated with decreased pulmonary function as measured by peak expiratory 13 flow rate (PEFR) in children. This effect was clearly shown at relatively low concentrations of 14 formaldehyde as the mean concentra tion in the homes was 26 ppb with more than 83% of homes 15 having measured concentration less than 40 ppb. This study also reported specific regression 16 modeling results that allowed EPA to calculate the point of departure for RfC development using 17
a BMCL as the point of departure. 18 The effects of formaldehyde exposure on pulmonary function represent a sensitive 19 endpoint with a reported 10% reduction in PEFR at 27 ppb. Among children with physician

20 diagnosed asthma, the observed effects of increased formalde hyde exposure on decreased PEFR 21 were more pronounced

– a clear indication of variability in response. The American Thoracic 22 Society (ATS, 2000) considers decreased pulmonary function an adverse health effect, even 23
when it is transient and subclinical. “A ssuming that the relationship between the risk factor and 24 the disease is causal, the committee considered that such a shift in the risk factor distribution, 25 and hence the risk profile of the exposed population, should be considered adverse, even in the 26
abs ence of the immediate occurrence of frank illness” (ATS, 2000). The ATS (2000) stated that 27 individuals in an exposed population experiencing a shift in the distribution of pulmonary 28 function were at potential risk from another agent due to the reduction i n their reserve capacity to 29 address additional insults. In the study by Krzyzanowski et al. (1990), the investigators 30 demonstrated statistically significant interaction between formaldehyde exposures, smoking, and 31 chronic cough. That is, a formaldehyde c oncentration that caused decreased pulmonary function 32 at residential levels also caused chronic cough in the presence of environmental tobacco 33 exposures. Higher prevalence rates of physician

- diagnosed asthma and chronic bronchitis were 34Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 41 also shown at highe r concentrations of formaldehyde (60

– 140 ppb), an effect that was 1 exacerbated by environmental tobacco exposures. 2 Figure 5

- 4 illustrates the reductions in peak expiratory flow rate (PEFR) in children (<15 3 years of age) in relation to indoor residential for maldehyde concentrations estimated by a 4 random effects model based on 3,021 observations in 208 subjects. Formaldehyde levels in the 5 home were significantly related to reductions in PEFR in children both at bedtime and in the 6 morning ( p < 0.05). PEFR mea surements in the morning versus at bedtime were significantly 7 different ( p < 0.05). Formaldehyde

- related reductions in PEFR were greater in the morning in 8
asthmatic children than in non

- asthmatic children ( p < 0.05). 9
10

11 12 Figure 5

- 4. Estimated reduction i n peak expiratory flow rate (PEFR) in 13 children in relation to indoor residential formaldehyde concentrations. 14 15 Source: Krzyzanowski et al. (1990). 16 17 18 Candidate RfC derivation based on Krzyzanowski et al. (1990): 19
Critical effect: Based on this study, which specifically included a susceptible 20 population, the critical effect is reduction in PEFR in children. PEFR was the most 21 sensitive measure of disease or impaired lung function reported in this population, with 22 decreases in lung function reported in childr en who lived in homes with average 23 measured formaldehyde concentrations as low as 30 ppb (Krzyzanowski et al. (1990). 24 Children were more sensitive to formaldehyde

- associated decreases in PEFR than adults, 25
so the cRfC derived focused on the results in the 208 children. 26Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 42 Point of departure: A BMR of 10% reduction in PEFR was selected as a cut

- off point 1 for adversity, based on rationales articulated by the ATS (2000) 4

. Using this BMR and 2 the model coefficient in Table 5 of Krzyzanowski et al. (1990), a BMC L 10 of 17 ppb 3 (BMC 10 = 27 ppb) was derived for all children. 5

8 Although the authors noted that 4 asthmatic children were more sensitive, the necessary data were not provided in the 5 report to calculate a BMCL for asthmatic children alone. Thus, 17 ppb, the B MCL based 6 on all children in the study, was used as the POD. 7

Application of study

- specific Uncertainty Factors (UFs) : 9 Interspecies UF = 1: No interspecies adjustment is needed, as this is a human study. 10
LOAEL

- to

- NOAEL UF = 1: Because a BMCL was used f or the POD and the BMR of 11 10% reduction in PEFR was considered to be a cut point for adversity, no 12
LOAEL

- to

- NOAEL UF was needed (UF L = 1). 13
14
15
Subchronic

- to

- chronic UF = 1: The study addresses ongoing residential exposure to 16 formaldehyde. Although inform ation on the duration of exposure for each 17 participant is not provided, the residential nature of the study suggests a longer 18 term exposure than the duration of the study. It was judged that a population

19 based study of residential exposures is sufficient to derive a chronic RfC without 20 adjusting for a subchronic observation period

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

4 The ATS (2000) recommended that “a small, transient loss of lung function, by itself, should not automatically be designated as adverse” and cited EPA’s 1989 review of ozone, which offered a graded classification of lung function change s 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 popul ation 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 populatio n, 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 r elevant 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 Relate d 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/m inute. 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 pp b as the BMCL.Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 43 Human variability UF = 3: The study was designe d to include homes with children, 1 and a POD can be established based on reduced PEFR in children, who were 2 more sensitive to the health effects than the adults in the study. Therefore, the 3 POD represents data for a sensitive life stage, an aspect of human 4 (intraindividual) variability. With respect to the human (interindividual) 5 variability UF, although e nvironmental tobacco smoke and socioeconomic status 6 did not affect the formaldehyde results in children, asthmatic children were more 7
sensitive to the ef fects of formaldehyde exposure on PEFR; thus, asthmatic 8 children represent a population with increased susceptibility for this effect. The 9 prevalence rate for physician

- diagnosed asthma in the children was 15.8% in this 10 study, which is higher than the nat ional prevalence of about 5.9% for ages 5 to 11
17 years. 6

24 Thus the BMCL based on all children may be influenced by a higher 12 prevalence of susceptible children for the critical effect. The authors do report 13 that the PEFR was reduced to a greater degree in a sthmatic children (as shown in 14 Figure 5

- 4), and a lower BMC of 17 ppb can be calculated in this subgroup versus 15 a BMC of 27 ppb for all children. However, the published regression statistics do 16 not provide sufficient detail to calculate a BMCL specific fo r asthmatic children. 17 In addition, other potentially sensitive populations (for example, elderly 18 individuals or individuals with respiratory diseases) may not be adequately 19 represented in the study. Therefore, an UF for human variability of 3 is applied to 20 address the observed increased sensitivity of asthmatic children in lieu of a 21 calculated BMCL specific to asthmatic children and to ensure adequate protection 22 for other potentially sensitive populations. 23



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

H S L A 

### 6

. 5 3 1 1 1 17 10 

### = **× ×**  **× =**  **× ×**  **× =**  25

26
UF A = 1 (interspecies U F) 27 UF L = 1 (LOAEL

- to

- NOAEL UF) 28 UF S = 1 (subchronic

- to

- chronic UF) 29 UF H = 3 (human variability UF) 30

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 ph ysician

- 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.Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 44 5.1.2.2.1. Candidate RfC derivation for Rumchev et al. (2002) (Asthma) 1 Residential formaldehyde exposure was associated with an increased risk of asthma in a 2

p opulation

- based case

- control study of 192 children aged 6 months to 3 years (Rumchev et al., 3 2002). While it is acknowledged that accurately diagnosing asthma in young children is 4 difficult, as the diagnosing physician was unaware of the formaldehyde leve l in the children’s 5 home, any diagnostic error would be unrelated to formaldehyde concentrations and would not 6 induce a spurious association. It is noted that the endpoint is physician

- diagnosed asthma. The 7 study, which comprises 88 cases of children dis charged from the emergency department of a 8 children’s hospital in Perth, Australia, with a primary diagnosis of asthma and 104 controls, 9 provides a positive exposure

- response relationship adequate for RfC derivation. Seasonal in

10 home formaldehyde measurem ents taken in the living room and subject’s bedroom were used to 11 assess exposure (8

- hour passive sampler). The ORs for risk of asthma by formaldehyde 12 exposure level category were adjusted for numerous risk factors, both familial and 13 environmental, includi ng familial history of asthma, age, sex, socioeconomic status, smoking, 14 presence of pets, air conditioning, humidifier, and gas appliances. Of these, age, allergic 15 sensitization to common allergens, and family history of allergy were independent risk fact ors 16 for asthma (OR = 1.09, 2.57, and 2.66, respectively). Odds ratios were further adjusted for the 17 effects of the measured indoor air pollutants (see Rumchev et al., 2004), indoor allergen levels of 18 dust mites, relative humidity, and indoor temperature. Categorical analysis of the data indicates 19 that the ORs for asthma were increased in the two highest formaldehyde exposure groups, 20 reaching statistical significance for household exposures > 60 μg/m 3 (48 ppb) (OR = 1.39) 21 (Figure 5

- 5) . Analysis of the dat a with formaldehyde as a continuous variable provides a 22 statistically significant increase in the risk of asthma (3% increase in risk per every 10 μg/m 3 23 increase in formaldehyde level.) 24
25 5.1.2.2.2. Candidate RfC derivation based on Rumchev et al. (2002): 26
27
Critical effect: Diagnosis of childhood asthma (case

- control study). 28
29 Point of departure: A NOAEL of 33 ppb (40 μg/m 3 ; midpoint of the 30

– 49 μg/m 3 30 category) was selected because the OR for asthma in the next highest exposure category 31
was considered to be part of an exposure

- related trend of increasing asthma risk and, 32 therefore, biologically significant. 33

34Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 45 1 Figure 5

- 5. Odds ratios for physician

- diagnosed asthma in children 2 associated with in

- home formaldehyde levels in air. 3 4 Source: Rumchev et al. ( 2002). 5 6 7 Application of Study

- Specific Uncertainty Factors (UFs) : 8 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 9
LOAEL

- to

- NOAEL UF = 1: No LOAEL

- to

- NOAEL UF was needed because the POD 10 was a NOAEL (UF L = 1). 11
Subchron ic to chronic UF = 3: The study addresses ongoing residential exposure to 12 formaldehyde. Although information on the duration of exposure for each 13 participant is not provided, the residential nature of the study suggests a longer 14 term exposure than the du ration of the study. Study participants were 3 years or 15 younger, therefore the duration of exposure could not meet the expected 16 definition for a chronic study of one

- tenth the lifespan. However, asthma often 17 develops during childhood, indicating a less

- t han chronic duration of exposure. 18 Since asthma may develop throughout childhood it is unclear whether a study of 19 children under 3 years of age would be of adequate duration for this 20 developmental window. Therefore, an uncertainty factor of 3 was applied as a 21 subchronic to chronic adjustment. 22 Human variability UF = 1 or 3: As a case

- control study, all new cases of childhood 23 asthma which met the study criteria were eligible for inclusion and the cases 24 likely included children predisposed to asthma. Individ uals with a family history 25 of asthma and/or genetic markers for genes believed to predispose individuals to 26 asthma would represent a susceptible population. Therefore, the cases in this 27Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 46 study address children as a susceptible population for first diagnosi s of asthma. 1 Additionally, there was an association of a familial history of asthma with the 2 diagnosis of children’s asthma in this cohort (OR = 2.66). Not all sources of 3 human variability which may contribute to a diagnosis of asthma are known, and 4
ther e are likely additional sources of inter

- individual variability among children 5 and among individuals with a family history of asthma, thus it is unlikely that all 6 sources of human variability were adequately represented in the study population. 7
8
The two a lternatives are described below and cRfCs are derived for each alternative. 9
10

11 12
13 Alternative A: Rumchev et al. (2002) Human variability UF = 3:

To account for potentially susceptible individua ls 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

H S L A 

### 3

. 3 3 3 1 1 33

**= ×**  **× ×**  **= ×**  **× ×**  **=**

UF A = 1 (interspecies UF)
UF L = 1 (LOAEL

- to

- NOAEL UF)
UF S = 3 (subchronic

- to

- chronic UF)
UF H = 3 (human variabilit y UF)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 47 1 2 3 5.1.2.2.3. Candidate RfC derivation for Garrett et al. (1999) (Asthma, respiratory 4 symptoms, atopy and severity of al lergic sensitization) 5 Garrett et al. (1999) reported on the risk of allergy and asthma

- like respiratory symptoms 6 due to formaldehyde exposure in a cross

- sectional survey of households with children 7

– 14 7 years old with (n = 53) or without (n = 95) doctor

- di agnosed asthma. Formaldehyde exposure 8 was characterized by four seasonal in

- home sampling events using 4

- day passive samples 9 collected in bedrooms, living rooms, kitchens, and outdoors. In logistic regressions, both the 10 Alternative B: Rumchev et al. (2002) Human variability UF = 1 :

EPA’s Technical Report of the RfD and RfC Processes Technical Report (US EPA, 2002a)
indic ates that UF H 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 childh ood 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 believe d that childhood is a key developmental window for initial diagnosis of asthma. The technical report acknowledges that applying a UF H of 1 may be appropriate where “even within these populations it is possible that some variability still exists.



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

H S L A 

### 11 1 3 1 1 33

**= ×**  **× ×**  **= ×**  **× ×**  **=**

UF A = 1 (interspecies UF)
UF L = 1 (LOAEL

- to

- NOAEL UF)
UF S = 3 (subchronic

- to

- chronic UF)
UF H = 1 (human variability UF)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 48 prevalence and severity of allergic sensitization to 12 common allergens increased with 1 increasing formaldehyde concentration in the home. Additionally, a calculated respiratory 2 symptom score was increased and demonstrated a significant relationship with increased 3 formaldehyde concentrati on in a multiple linear regression after adjusting for multiple risk 4 factors and interactions. For each of these endpoints, severity/incidence was increased in the 5 medium (20–50 μg/m 3 ) and high (>50 μg/m 3 ) exposure groups relative to the low (<20 μg/m 3 ) 6 exposure group, based on the highest of four seasonal 4-day formaldehyde measurements in the 7 home (Figures 5-6 and 5-7). 8
9

10 Figure 5

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

- home formaldehyde levels. Trend analysis indicates statistical significance in these 12 increases {percent asthmatic children, unadjusted (p=0.03) and respiratory symptom score 13 (p=0.03)}. 14
15 Source: Garrett et al. (1999). 16 17
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 (%)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 49 33% 64% 75%

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

<20 20-50 >50 Exposure group, formaldehyde level (ug/m3)Atopic Children (%)

1 2 Fi g ur e 5

- 7

. P rev a l en ce a n d sev eri t y o f a l l erg i c sen si t i z a t i o n i n c hi l dr e n 3

a s s o c ia te d w ith in

- h o m e f o rm a l d eh y d e l ev el s. T ren d a n a l y si s i n d i ca t es 4 st a t i st i ca l si g n i f i ca n ce i n t h ese i n crea ses {p ercen t a t o p i c ch i l d ren ( p = 0

. 0 0 2 ) , 5
p o si t i v e sk i n p ri ck t est s ( p = 0

. 0 0 1 ) a n d sev eri t y a s a l l erg en w h ea l ra t i o 6 ( p =0.004) }

. 7 8 N o te : S ki n pr i c k t e s t s i nc l ude d 12 e nvi r onm e nt a l a l l e r ge ns ( c a t , dog, gr a s s [ t w o 9
t ype s ] , hous e dus t , dus t m i t e [ t w o s t r a i ns ] a nd f ungi [ f i ve s t r a i ns ] )

. 10 S o u rc e : G a rre tt e t a l. (1 9 9 9 ). 11 12 13
T h e f in d in g s o f G a rre tt e t a l. ( 1999) a r e s uppor t e d by t he obs e r va t i on of a n i n cr eased 14
b r o n ch i al r esp o n si v en ess t o m i t e al l er g en i n a ch am b er st u d y o f 1 9 sen si t i zed ad u l t ast h m at i cs 15

e xpos e d t o f or m a l de hyde a t a c onc e nt r a t i on of 100 μ g/ m 3 f or 30 m i nut e s ( C a s s e t e t a l ., 2006)

. 16
A ddi t i ona l l y, i nha l a t i on e xpos ur e s t o f or m a l de hyde ha v e b een sh o w n t o i n cr ease an an i m al ’ s 17

r e s pons e t o ot he r c om m on a l l e r ge ns vi a i nha l a t i on ( F uj i m a ki e t a l ., 2004; S a da ka ne e t a l ., 2002; 18
R i e de l e t a l ., 1996; T a r kow s ki a nd G or s ki , 1995)

. 19
20
C a n d id a te R fC d e r iv a tio n fo r in c r e a s e d a lle r g ic s e n s itiz a tio n fr o m Ga r r e t t e t al . ( 1999) : 21
C r itic a l e ffe c ts : A lle r g ic s e n s itiz a tio n

- In c re a s e in a lle rg ic s e n s itiz a tio n (p ro p o rtio n o f 22

a t opi c c hi l dr e n) . S e ve r i t y of a l l e r gi c s e ns i t i z a t i on m e a s ur e d bot h a s num be r of pos i t i ve 23
sk i n t est s t o co m m o n al l er g en s an d t h e r eco r d ed al l er g en w h eal r at i o f o r

t h o se t est s. 24
A s th ma

– i nc r e a s e i n pr opor t i on of a s t hm a t i c c hi l dr e n. R esp i ra t o ry sym p t o m s

– 25
I n cr eased r esp i r at o r y sy m p t o m sco r e. 26
27
Po i nt o f de pa r t ur e : F o ral l cr i t i cal ef f

ect s, cat eg o r i cal an al y ses ar e p r esen t ed t h at sh o w 28

an i n cr ease in th e m id

- e xpos ur e gr oup ( 16

– 40 ppb) a nd hi gh e xpos ur e gr oup ( > 40 ppb) 29Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 50 relative to the low

- exposure group (<16 ppb) (Figures 5

- 6 and 5

- 7). However, it is 1 unknown if the findings in the low

- exposure group are comparable to the responses that 2
would be obs erved in an unexposed population . Therefore, the low

- exposure group 3 cannot be considered a NOAEL but rather serves as a referent group for the two other 4 exposure groups. Thus, the LOAEL is based on health effects observed in the mid

5 exposure group (16

- 40 ppb) for all three critical effects. As neither the mean or median 6 exposure levels are provided for the exposure categories used to analyze the health 7 effects data, the mid

- point of the exposure category is selected for the LOAEL: 28 ppb. 8
9 Application of study

- specific Uncertainty Factors (UFs) : 10 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 11
LOAEL

- to

- NOAEL UF = 3: As discussed, the mid

- exposure group is selected as the 12
LOAEL since the low

- exposure group is the refere nt group; there is no true 13 unexposed control. It is unclear whether or not a full LOAEL to NOAEL 14 uncertainty factor is warranted for these data. The authors did provide evidence 15 for increased atopy for every increase of 16 ppb of exposure with borderline 16 statistical significance when adjusted for several potential confounders (OR = 1.4; 17
95% CI: 0.98

– 2.00). An UF of 3 adjusts the LOAEL to a similar range and is 18 consistent with this alternative presentation of the data. 19
Subchronic to chronic UF = 1: The s tudy addresses ongoing residential exposure to 20 formaldehyde. Although information on the duration of exposure for each 21 participant is not provided, the residential nature of the study suggests a longer 22 term exposure than the duration of the study. It is judged that a population

- based 23 study of residential exposures is sufficient for derivation of a chronic RfC without 24 adjusting for a subchronic observation period. 25 Human variability UF = 1 or 3: This study was designed to assess allergic 26 sensitization, a sthma prevalence and respiratory symptoms in children with 27
relation to in

- home formaldehyde levels. The recruitment of participants was 28 designed to include households (50%) with asthmatic children, resulting in 29
43 households with at least one asthmatic ch ild and 37 without asthmatic children 30 for a total of 148 children (35% asthmatic). Parental allergy and asthma were 31 also assessed and included as adjustment variables in the data evaluation. 32 Therefore the study population includes individuals reflecting several key aspects 33 of human variability for asthma and allergic sensitization (age, familial history of 34 disease), and addresses the links between allergic sensitization and asthma. Both 35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 51 asthma and allergic sensitization are risk factors for increased re spiratory 1
symptoms. 2
3 The two alternatives are described below and cRfCs derived for each alternative 4
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

H S L A 

### 8

. 2 3 1 3 1 28

**= ×**  **× ×**  **= ×**  **× ×**  **=**

UF A = 1 (interspecies U F)
UF L = 3 (LOAEL

- to

- NOAEL UF)
UF S = 1 (subchronic

- to

- chronic UF)
UF H = 3 (human variability UF)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 52 1 Alternative B: Garrett et al. (1999) Human variability UF = 1 : Individuals with a family history of asthma and/or genetic markers for genes are believed to be predispo sed 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 familia l 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 si gnificance 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, 200 2a) indicates
that a UF H of 1 can be applied in cases where data are “very specific about the particular vulnerability of infants and children within certain age ranges to an agent.” Asthma and allergic sensitization to common allergens develop during chil dhood 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 UF H of 1 is still applied

.



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

H S L A 

### 3

. 9 1 1 3 1 28

**= ×**  **× ×**  **= ×**  **× ×**  **=**

UF A = 1 (interspecies UF)
UF L = 3 (LOAEL

- to

- NOAEL UF)
UF S = 1 (subchronic

- to

- chronic UF)
UF H = 1 (human variability UF)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5-53 5.1.2.2.4. Candidate RfC derivation for Ritchie and Lehnen, 1987; Hanrahan et al., 1984 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 95 th 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).

N ote: 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 Fi g ur e 5

- 8. P os i t i ve e xp os u r e - resp o n se rel a t i o n sh i p s rep o rt ed f o r i n - ho m e 23 fo r ma l d eh y d e ex p o su res a n d sen so ry i rri t a t i o n ( ey e i rri t a t i o n )

. 24Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 54 13.3% 17.1% 21.4%

10.8% 14.7% 20.6%

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

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

1 2 Figure 5

- 9. Positive exposure

- response relationships reported for in

- home 3 formaldehyde exposures and sensory irritation (burning eyes). 4 5 Note: Cumulative formaldehyde exposure was estimated for each participant 6 from measured in

- home formaldehyde levels (7

- day passive air sample) and 7 reported hours spent in the home. Prevalence rates are given for both summer 8 (n = 1,388) and winter (n = 1,093) survey periods. 9 Data source: Liu et al. (1991). 10 11 12 Ritchie and Lehnen (1987) examined formaldehyde

- associated effects on eye, nose, and 13 throat irritation in a large residential study with 2,007 participants from 841 homes. Based on 14
in

- home measurements of formaldehyde concentration, participants were c ategorized into three 15 exposure groups: low (<100 ppb), mid (100

– 300 ppb) and high (>300 ppb) (average of two 30

– 16 60 minute air samples per home). Ritchie and Lehnen (1987) observed clear exposure

- response 17 relationships in the percentage of residential occu pants reporting eye, nose, and throat irritation. 18 For example, in nonsmoking mobile home residents, incidence scores for eye irritation were 1%, 19 18% and 86%, and for nose/throat irritation were 5%, 17% and 78%, respectively, for the three 20

exposure groups. The exposure

- response relationships were similar regardless of type of home, 21 mobile (n = 851) or conventional (n = 1,156). Although smoking status was also a predictor of 22 irritation, in

- home formaldehyde concentrations were a stronger predictor of healt h effects. The 23 study included children and the elderly and results were consistent across age groups. Children 24Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 55 <7 years of age were only included in the eye irritation analyses because of concerns about the 1 quality of parental reporting for nose and thro at effects in young children. The selection criteria 2 for participants indicate that more sensitive individuals may have been over

- represented in the 3 study population. 7

Hanrahan et al. (1984) reported an exposure

- response relationsh ip for burning eyes and 8 eye irritation in a study of 61 teenage and adult residents of mobile homes. As in the Ritchie and 9 Lehnen (1987) study, in

- home formaldehyde measurements were obtained for all participants 10 and measured formaldehyde levels were used to characterize average in

- home exposures (30

– 11
60 minute air sample). Eye irritation was associated with in

- home formaldehyde exposures 12 ( p < 0.05) (both as “burning eyes” and “eye irritation”), and the authors provided a graphical 13 representation of the be st

- fitting regression model for exposures between 100 and 800 ppb. 14 From inspection of this graph, the prevalence of eye irritation predicted at 100 ppb is 15 approximately 4% with an upper bound of 18% (95 th percentile CI) (Figure 5

- 8, Panel A). 16
Because the limit of detection for formaldehyde in indoor air was 100 ppb, data or model results 17 are not provided below 100 ppb. 18 All study participants were self

- selected, with a physician’s approval, 4 perhaps result ing in a higher proportion of individuals experiencing various irritant and upper 5 respiratory tract symptoms, which may represent a sensitive population for eye, nose, or throat 6
irritation. 7

The third residential study is a random

- sample study of over 1,000 mobile home residents 19 (1,394 in the summer; 1,096 in the winter) that included both young children and the elderly (Liu 20 et al., 1991). Cumulative weekly exposures were based on in

- home formaldehyde sampling and 21 a participant survey of time spent at home. Air sampling was conducted for a 7

- day period using 22 a passive sampler in each home (summer and winter). The resulting estimates of cumulative 23 exposure assumed no formaldehyde exposure outside of the home. Cumulative formaldehyde 24 exposure was a significant predictor of numerous irritant symptoms in a multivariate linear 25
lo gistic regression, including “burning eyes” ( p < 0.05). The prevalence of eye irritation 26 increased with increasing cumulative exposure in a categorical analysis of participants 20

– 64 27 years old for both summer and winter exposure estimates (Figure 5

- 9). E ye irritation was above 28 10% in the lowest exposure group (0

– 7.0 ppm

- hours/week) and increased to 17.1% and 21.4 % 29
in the mid

- and high

- exposure group, respectively, for the summer survey time; winter rates were 30 slightly lower but showed a similar increase with increasing cumulative exposure. 31

7 Participants in this study were self

- selected residents who were concerned abo ut 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 g eneral 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.Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 56 Taken together, these three studies report increased eye irritation from residential 1 exposures that are below the BMCLs calculated from acute exposures in the laboratory. Each 2 study has the strength of having indivi dual in

- home exposure measurements and demonstrates a 3 positive exposure

- response relationship for sensory irritation within a range of residential 4 formaldehyde exposures (both conventional and mobile homes). Potentially confounding factors 5 (such as allerg ens and some other in

- home exposures) have been taken into account and 6 statistical analyses of the data include relevant covariates (e.g., age, sex, smoking status). As 7 such, these studies provide a basis for development of a cRfC for sensory irritation. 8 Additionally, the study populations have been drawn from the general population, including 9 children and the elderly, and have not been limited to those healthy enough for full

- time 10 employment (as is often the case in occupational cohorts). 11
All three st udies support a finding of increased eye irritation for exposures above 100 ppb 12 (Figures 5

- 8 and 5

- 9). However, the shape of the exposure

- response curve below 100 ppb, or an 13
indication of a no

- effect level, is less clear. Two of the studies indicate 1

– 4% eye irritation in 14 residents where formaldehyde exposures were measured at 100 ppb or less (Ritchie and Lehnen, 15 1987; Hanrahan et al., 1984). Thus, there is uncertainty in considering 100 ppb as a no

- effect 16 level for increased eye irritation for these stu dies. When modeled, the 95% CIs around the point 17 estimate of 4% eye irritation were 1

– 18% eye irritation, illustrating the range of response rates at 18 100 ppb that are consistent with the observed data (Hanrahan et al., 1984). Additionally, the 19 presentati on of results by exposure category in Ritchie and Lehnen (1987) is inexact and has 20 individuals with exposures at the low end of the categorical range being grouped with those at 21 higher exposures in the range, obscuring any exposure

- response relationship wi thin the 22 categorical range. For these reasons, a POD for RfC derivation from either of these studies 23 should reflect these uncertainties. Therefore, for the NOAEL representing the category of 24
indiv iduals with ≤100 ppb, in which 1

– 2 % eye irritation was observed, the upper end of this 25 exposure category is not used, but rather the midpoint, 50 ppb (Ritchie and Lehnen, 1987). 26 Although Hanrahan et al. (1984) provided no model results below 100 ppb, an extrapolation of 27 the graphical results (Figure 5

- 8, Panel A) provides an estimated BMCL 10 of 70 ppb 8

8 Figure 1 of Hanrahan et al. (1984) show s 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 pp b 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. . No 28 additional duration adjustments were made from the in

- home exposure measurements to 29Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 57 continuous exposure because neither time away from the home, nor p otential exposures outside 1 of the home, were characterized in either study. 2 Of the three studies, only Liu et al. (1991) provides exposure measurements below 3
100 ppb, with a reported detection limit of 10 ppb formaldehyde for the in

- home air monitoring. 4 Additionally, air samples were collected using a 7

- day passive sampler which is more 5 representative of average residential exposures than a one

- time, 30

– 60 minute, air sample. 6 Therefore, the data collected by Liu et al. (1991) are more suited to understan ding the exposure

7 response relationship for eye irritation of exposures below 100 ppb. In addition to controlling 8 for age, gender, and smoking status, Liu et al. (1991) controlled for the presence of chronic 9 respiratory disease when assessing the effects of formaldehyde on symptoms of sensory 10 irritation. Finally, this study provides results for both summer and winter survey periods, 11 addressing seasonal variation in both formaldehyde levels and sensory irritation. The use of the 12 cumulative exposure metric considers not only the concentration of formaldehyde but also the 13 number of hours during the week each participant spent in their residence. Linear logistic 14 regression indicates that cumulative formaldehyde exposure was a statistically significant 15 predic tor of burning eyes for both winter and summer survey periods. However, no BMCL can 16 be calculated because no regression coefficients were provided in the report. Data were 17 provided for the categorical analysis illustrating a positive exposure

- response re lationship 18 (redrawn in Figure 5

- 9). Based on the categorical results, the mid

- exposure group (7

– 12 ppm

19 hours/week) demonstrated an increased response compared with the low

- exposed group. Since 20 the prevalence rate in the low

- exposed group was above 10% fo r burning eyes, this exposure 21 group does not represent a NOAEL, but rather serves as a referent for the mid

- exposure group. 22 Therefore, the POD is derived from the midpoint of 7

– 12 ppm

- hours/week, 9.5 ppm

- hours/week. 23 Using a conversion factor applied by t he authors, the cumulative exposure of this mid

- exposure 24 group corresponds to a continuous home exposure of 70

– 120 ppb for an individual who spends 25 60% of the week in the home, with a mid

- point of 95 ppb. 26
27 Candidate RfC derivation for sensory irritation: 28
Critical effect: Prevalence of sensory irritation (eye irritation, burning eyes). 29
30 Point of departure: Each of the studies discussed above has different strengths and 31 weaknesses for the determination of a POD for sensory irritation. Nevertheless, the 32

e ffect levels and PODs derived from each study are in relatively close agreement with 33 less than a twofold span from lowest to highest. Therefore each POD is carried through 34
to calculate a cRfC: 35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 58 1 NOAEL = 50 ppb (Ritchie and Lehnen, 1987) 2
BMCL 10 = 70 ppb (Hanrahan et al., 1984) 3 LOAEL = 95 ppb (Liu et al., 1991) 4
5 Application of Uncertainty Factors (UFs ) 6 Interspecies UF = 1: No interspecies adjustment is needed as this is a human study. 7
LOAEL

- to

- NOAEL UF: An uncertainty factor of 1 is applied to the NOAEL and 8
BMCL 10 established as PODs from Ritchie and Lehnen, (1987) Hanrahan et al. 9 (1984) studies. An uncertainty factor of 3 is applied to the LOAEL of 95 ppb 10 based on the Liu et al. (1991) study, as the prevalence rates for this exposure level 11
are bel ow 20% for an effect that is of relatively low severity. In addition, the 12 LOAEL is not significantly above the NOAEL and BMCL 10 from the other 13 studies that evaluated the same endpoint. 14
15
Subchronic to chronic UF = 1: These studies address ongoing resident ial exposure to 16 formaldehyde. Although information on the duration of exposure for each 17 participant is not provided, the residential nature of the study suggests a longer 18 term exposure than the duration of the study. It is judged that a population

- based 19 study of residential exposures is sufficient for derivation of a chronic RfC without 20 adjusting for a subchronic observation period. 21
22 Human variability UF = 1 or 3: All three studies were population

- based and included 23 children, the elderly and both sexes. Sample sizes for two of the studies were 24 very large (1,394 for Liu et al. [1991]; 2,007 for Ritchie and Lehnen [1987]), 25 increasing the likelihood that sensitive populations were included. Analysis of 26 the data controlled for sex, smoking status, and age group. 27
28
29
30
31
32
33
34
35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 59 The two alternatives are described below and cRfCs derived for each alternative 1
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 sensit ive 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 correspond ing 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

H S L A 

### 17 3 1 1 1 50

**= ×**  **× ×**  **= ×**  **× ×**  **=**

Hanrahan et al. (1984):


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

H S L A 

### 23 3 1 1 1 70 10 

### = **× ×**  **× =**  **× ×**  **× =** 

Liu et al. (1991):


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

H S L A 

### 5

. 9 3 1 3 1 95

**= ×**  **× ×**  **= ×**  **× ×**  **=**Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 60 1 Alternative B Sensory irritation studies Human variability UF = 1: Two studies included a broad age range allowing 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 <1y ear, 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

rep orted 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 B MCL 10 is based for Hanrahan et al. (1984) are normalized to 48 years of age (the mean age of respondents), which is consistent with the age 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
i ncidence 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 jud ged that further adjustment to address human variability is not warranted for the minimally adverse health effect of sensory irritation. Thus a UF H of 1 is applied to all three studies. It is acknowledged that there is the potential for
sources of variab ility not captured in these studies. (Continued on next page.)Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 61 1 2 3 5.1.2.2.5. Candidate RfC derivation for Taskinen et al. (1999) ( Fecundity ratio) 4 On review of the candidate developmental and reproductive toxicity studies in humans 5 and animals (presented in Section 5.1.3.2.7), the Taskinen et al. (1999) human study was 6 considered to be the strongest for the purpose of deriving a ch ronic RfC. This study was a well

7 designed population

- based case

- control study of women who were occupationally exposed to 8 formaldehyde. The study population was well defined and adequately selected to allow for 9 meaningful comparisons of health effects am ong individuals with different levels of exposure to 10 formaldehyde. Potential selection bias and the self

- reporting of spontaneous abortion are not 11 considered to have had a significant influence on the study findings. Additionally, the decreased 12
FDR and i ncreased risk of spontaneous abortion observed in Taskinen et al. (1999) are internally 13 consistent and coherent with other reports of increased risk of pregnancy loss associated with 14 exposure to formaldehyde (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 1990; 15 Axelsson et al., 1984) and is supported by animal data (Kitaev et al., 1984; Sheveleva, 1971). 16 The Taskinen et al. (1999) study allows the consideration of three potential critical 17 effects: endometriosis, increased spontaneous abortion, a nd decreased FDR. However, there is 18 little independent support for the finding of increased endometriosis and the ORs for organic 19 solvent exposure within this study (OR = 14.7; 95% CI: 3.1

– 70) were much greater than for 20 formaldehyde (OR = 4.5, 95% CI: 1.0

– 20), indicating a potential for confounding. Both 21 increased spontaneous abortions and decreased FDR are supported by independent findings in 22 Continued from previous page:

Ritchie and Lehnen (1987):


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

H S L A 

### 50 1 1 1 1 50

**= ×**  **× ×**  **= ×**  **× ×**  **=**

Hanrahan et al. (1984):


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

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

Liu et al (1991):


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

H S L A 

### 32 1 1 3 1 95

**= ×**  **× ×**  **= ×**  **× ×**  **=**Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 62 other formaldehyde

- exposed cohorts (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 1 1990; Axelsson et al., 1984). As this study was designed to examine the effect of workplace 2 formaldehyde exposures on FDR, the study design and data collection best support this finding. 3 The exposure measurements were conducted to represent what the researchers considered the 4
relevant time

- to

- pregnancy exposures. Although data on miscarriages were collected to control 5
the time

- to

- pregnancy findings for confounding from formaldehyde

- related spontaneous 6 abortions, it is less certain that the exposure measurements coincide w ith the defined 7 spontaneous abortion cases. Spontaneous abortions were only included in calculations of 8

exposure

- specific ORs if a participant indicated that she was employed at the same location 9 when she had the spontaneous abortion and when the time

- to

- pregnancy exposure assessment 10 was done. The analysis showed that there were statistically significantly increased risks of 11 spontaneous abortion in the lowest exposure group. While this finding was consistent with other 12 studies showing adverse reproductiv e effects of formaldehyde and appears to be causal, the 13 Taskinen et al. (1999) spontaneous abortion results did not clearly control for all the potential 14 confounders that were controlled for in the FDR analyses (i.e. organic solvents and phenols). 15
While t he other coexposures were not associated with FDR and therefore not confounders, 16 endometriosis was strongly associated with organic solvents. Therefore, for these endpoints, the 17 study design and strength of results best support the use of decreased FDR in formaldehyde

18 exposed women as the critical effect for this study. 19 It is preferable that the critical effect be the most sensitive of the effects which is well 20 supported by the given study. As spontaneous abortions are significantly increased in the low

21 exposure group and the response in the mid

- exposure group is considered a no

- effect level for 22 decreased FDR, there is uncertainty that an RfC based on the FDR NOAEL would be protective 23 for the more sensitive effect. Although qualitatively the finding of i ncreased spontaneous 24 abortion is convincing, there is more uncertainty in the applicability of the exposure assessment 25 for quantitative risk assessment. Additionally, there is greater uncertainty in the use of the 26 exposure adjustments for the low

- exposure group on which the LOAEL is based because they 27
account for more of the work time in the low

- exposure group than the medium and high 28 exposure groups (Table 5

- 5). 29 There are several sources of uncertainty in the exposure estimates for use in RfC 30
derivation . As discussed above, the average exposure estimate for the low exposure group 31 includes a greater proportion of non

- assessed background exposures. This is evidenced in part 32 by the reported average exposure being below background levels for these workers, even with 33 exposure measurements as high as 300 ppb. The unaccounted for non

- task exposures may 34 represent time during the day spent in the work facility, or time in a different job or work 35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 63 environment. Additionally, task

- level exposure measurements were available for only 27% of 1 women in the low exposure group, versus 38% and 69% of women in the medium and high 2 exposure groups, indicating less certainty in exposure classification for the low exposure group. 3
4 Duration adjustment for candidate study point s of departure: 5 Normally, exposures from occupational studies are adjusted to account for the daily 6 breathing volume appropriate to an environmental (versus occupational) setting and for exposure 7 every day of the year (EPA, 1993). However, with formaldeh yde, there is potential for exposure 8
outside of work from in

- home and environmental sources of formaldehyde (Chapter 2). A 9 contemporaneous study of formaldehyde exposures in Finland reports average exposure of 21.4 10 ppb (measured over 48 hours with a person al monitor) (Jurvelin et al., 2001). Furthermore, both 11 the mean exposure (18 ppb 8hr TWA) and lowest reported exposure (10 ppb 8hr TWA) of the 12 ‘low exposed’ category are below the reported average ambient exposures for Finland (21.4 13 ppb). Thus, it is lik ely that exposure estimates for study participants include time during the 14 workday when women reported no formaldehyde exposure and a zero exposure was assessed for 15

a non

- formaldehyde related task. Additionally, participants may have qualified for the stu dy 16 based on employment date but may not have been working with formaldehyde during the entire 17
time

- to

- pregnancy period. In both cases, the investigators in Taskinen et al. (1999) appear to 18 have assumed that, while the women were away from their “exposed” workplace, their exposure 19 to formaldehyde was zero, not accounting for background occupational exposures and ambient 20 levels of formaldehyde. This explains why both the mean exposure as well as lower end of 21 workshift exposures for women in the low exposure group were reported at and below expected 22 ambient levels. The women in the low exposure category had task

- level workplace exposures of 23 up to 300 ppb in addition to experiencing some work time at background exposure levels. 24 Compared to women who only exp erienced background exposure levels, those in the low 25 exposure category were at significantly higher risk of spontaneous abortion. 26 The reported data do not provide information to correct for background formaldehyde 27 exposure during the workday for each pa rticipant. However, the published mean exposure 28 values may be used to provide some idea of the impact of including background exposures on 29 the study PODs. Comparison of the values listed in Table 4 of Taskinen et al. (1999) allows for 30
the estimation of t he percentage of work time spent performing tasks involving formaldehyde 31 exposure (Table 5

- 5, Panel A). For the women in the low exposure category, this percentage is 32 26% (mean of measured workplace exposures of 70 ppb times 26% equals the mean of the TWA 33 exposure of 18 ppb). Using the same method, the women in the “medium” and "high" exposure 34 category were performing tasks involving formaldehyde exposure approximately 54% and 66% 35Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 64 of their work time, respectively. Assuming that the women spent the remain der of their work 1 time at the background concentration of 21.4 ppb (Jurvelin et al., 2001), a more appropriate 2
estimate of the women’s 8

- hour TWA formaldehyde exposures would be 34 ppb for the low 3 category, 86 ppb for the medium category, and 226 ppb for t he high category (Table 5

- 5, Panel 4 B). 5
6 Table 5

- 5: Adjustment for nonoccupational exposures to formaldehyde. 7 8 Panel A: Proportion of workshift corresponding to the exposure group mean 9 task

- level formaldehyde exposure (ppb) and the exposure group dai ly exposure 10 index (8 Hr

- TWA). 11

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 workti me a Hours per 8 Hr workshift Low (119) 18 1

- 39 70 10

- 300 26% 2 Medium (77) 76 40

- 129 140 50

- 400 54% 4.3 High (39) 219 130

- 630 330 150

- 1000 66% 5.3
a: Calculated as mean exposure (ppb 8Hr

- TWA) divided by mean task

- level exposures for the exposure grou p. 12 13
Panel B: Recalculation of daily exposure index (8 Hr

– TWA) where background 14 formaldehyde exposure is estimated for worktime spent on tasks considered 15 unrelated to occupational use of formaldehyde. 16

Exposure group (n) Estimate of Formaldehyde
exposure during formaldehyde

related 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 formaldeh yde (ppb) % of time in

non formaldehyd

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
20Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 65 Candidate RfC derivation for Taskinen et al, 1999: 1
Critical effect: Decreased FDR. 2
3 Point of departu re: For decreased FDR, the mid

- exposure level is considered a 4 NOAEL. The mean exposure as an 8

- hour TWA for the workday is reported as 76 ppb. 5 EPA has adjusted this POD to account for potential background formaldehyde exposures 6 during the workshift (Tab le 5

- 5) resulting in an adjusted POD of 86 ppb. No further 7 duration adjustment is made to this POD to account for background levels of 8 formaldehyde exposure outside of the workplace. 9
10 Application of study

- specific Uncertainty Factors (UFs) : 11 Interspecies U F = 1: No interspecies adjustment is needed as this is a human study. 12
LOAEL

- to

- NOAEL UF = 1: Selection of an NOAEL as the POD. 13
Subchronic to chronic UF = 1: The study design represents a study population with a 14 range of exposure durations, including chr onic exposures. By drawing the study 15 population from full

- time employees and members of the wood

- working union, 16 there is an expectation that the study population reflects the demographic of that 17 group as a whole. Although specific summary information is not published for 18 this study group (e.g., average length of employment), the lack of this reporting in 19 itself does not seem to justify an UF for subchronic

- to

- chronic exposure given the 20 overall study design. As a study adequate for assessing reproductive effects in a 21 chronically exposed cohort, no further adjustment was considered needed. 22 Human variability UF = 10: The study population included women employed in the 23
wood

- working industry who were healthy enough to be gainfully employed. 24 Additionally, stu dy inclusion criteria ensured that all study participants had at 25 least one pregnancy resulting in a live birth during the study period (1985

– 1995). 26 Therefore, these women were reproductively successful. The authors judged that 27 selective participation did not influence potential confounders such as irregular 28 menstruation or earlier miscarriages, which could impact the time to pregnancy 29 results. Susceptible populations were not addressed and, in fact, the women in the 30 study may be considered healthier than the general population in terms of 31 reproductive health. Therefore, an uncertainty factor of 10 for human variability 32 was applied. 33
34Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 66 

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

H S L A 

### 6

. 8 10 1 1 1 86

**= ×**  **× ×**  **= ×**  **× ×**  **=** 1

2
UF A = 1 (interspecies UF) 3
UF L = 1 (LOAEL

- to

- NOAEL UF) 4
UF S = 1 (subchronic to chronic UF) 5
UF H = 10 (human variability UF) 6
7 5.1.2.3. Evaluation of the Study

- Specific Candidate RfCs 8 Seven studies were selected as key studies for consideration in RfC derivation (Section 9 5.1.2, Table 5

- 4). Candidate RfCs from these studies address various health effects i ncluding: 10 sensory irritation, respiratory effects, asthma, increased allergic sensitization, and decreased 11 fecundity (Table 5

- 6). 12 Three of the seven studies address sensory irritation of the eye, nose, and throat (Liu 13

et al., 1991; Ritchie and Lehnen, 1987; Hanrahan et al., 1984). The PODs for sensory irritation 14 range from 50 to 95 ppb for a health effect that is considered minimally adverse. 15
Two alternatives are presented for the human variability uncertainty factor in RfC derivation 16
based on these S I studies. Alternative A (UF H =3) results in cRfCs from 9.5 to 23 ppb. 17 Alternative B (UF H =1) results in cRfCs from 32 to 70 ppb. 18 A cRfC of 9 ppb is derived for decreased FDR in an occupational study of women in the 19
wood

- working industry (Taskinen et al., 1999). This endpoint is supported by four other 20 epidemiologic studies and is considered a potential health concern for occupationally exposed 21 women (John et al., 1994; Taskinen et al., 1994; Seitz and Baron, 1990; Axelsson et al., 1984). 22 However, there i s some uncertainty regarding the influence of peak exposures in the work place 23 on the apparent exposure

- response relationship based on average workday exposures calculated 24 for study participants. It is unknown if the observed decreased FDR can be attribut ed to the 25 average exposures from which the cRfC is derived or if it is a result of the measured exposures 26 (as high as 1,000 ppb). If this were the case the cRfC of 9 ppb, based on the average time

27 weighted exposures, would be protective for decreased fecu ndity. 28 Three studies identify adverse health effects in residential populations including children: 29 increased incidence of asthma, decreased pulmonary function, increase in respiratory symptoms, 30 and increased allergic sensitization (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski 31

et al., 1999). Asthma, allergic sensitization, pulmonary function, and symptoms of respiratory 32 disease are not only clinically related, but etiologically related, and it is reasonable that they are 33Th is document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 67 considered together f rom a public health perspective. These health effects are observed below 1 the exposure levels that result in sensory irritation and the resulting cRfCs are correspondingly 2 lower, in a range between 2.8 and 11 ppb, depending on the study, endpoint considere d, and the 3 application of alternative uncertainty factors for human variability (Table 5

- 6). 4 These three studies of related health effects: asthma, allergic sensitization, pulmonary 5 function, and symptoms of respiratory disease in children from in

- home e xposure to 6 formaldehyde (Rumchev et al., 2002; Garrett et al., 1999; Krzyzanowski et al., 1999) were 7
chosen as the basis for the derivation of the RfC. These co

- critical studies are mutually 8 supportive and provide similar cRfCs. Therefore, the RfC is tak en as the mean of the cRfCs of 9
the cRfCs of the three co

- critical studies. For two of these studies (Rumchev et al., 2002; Garrett 10 et al., 1999), EPA is providing alternatives for the application of the UF addressing human 11 variability. These alternatives result in a threefold difference in cRfCs for each study when 12 considering the critical effects of childhood asthma and allergic sensitization (Table 5

- 6). 13 Alternative A, described above for each study, acknowledges that evaluation of these effects in 14
chi ldren does address some aspects of human variability, but there remains the potential for 15
additional inter

- individual variability within the studied population, thus a UF of 3 is warranted. 16 Alternative B, described above for each study, also acknowledges that these studies address 17 human variability and susceptible populations. However in alternative B it is judged that since 18 children are a sensitive lifestage for these effects (asthma and atopy), and are likely the most 19 sensitive population, an UF of 1 ma y be applied. It is acknowledged that some degree of inter

20 individual variability may remain. 21
22This document is a draft forreview purposes only and doesnot constitute Agency policy5-68DRAFT—DO 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) UF L UF S UF H Respiratory effects / asthma and sensitization Reduction of PEFR in children (10%) Krzyzanowski et al. (1990) 208 Yes Yes BMCL 10 = 17 1 1 3 5.6

Asthma incidence Rumchev et al. (2002) 192 Y es 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 BMCL 10 = 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 calc ulation, two

- significant digits are retained as common practice in mathematics {i.e. one significant diget m ore that the final result, to avoid rounding errors compounding across multiple mathematical manipulations}.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 69 1 2

3 4
5.1.3. Database Uncertainties in the RfC Derivation 5
The database of available labora tory animal studies, human clinical and epidemiological 6 studies, and supporting mechanistic information for formaldehyde is substantial. Many of the 7 health effects are well studied in animals and humans, especially those endpoints related to 8 sensory irr itation and respiratory effects at the POE, such as respiratory tract pathology, asthma 9 Alternative B: Application of a U F of 1 for human variability (UF H = 3 remains for Krzyzanowski et al., 1999)

Co

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

Critical endpoints: Asthma, allergic sensitization, pulmonary function, and symp toms 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 respir atory symptoms (Garrett et al., 1999)

RfC: 

### ppb ppb ppb ppb ppb RfC 9 3 9

. 25
3 3

. 9 11 6

. 5

**= =**  **+ +** 

**=** 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: Asthm a, 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 7

. 11
3 8

. 2 3

. 3 6

. 5

**= =**  **+ +** 

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

— DO NOT CITE OR QUOTE 5

- 70 and reduced pulmonary function. This is reflected in the number and high quality of human 1 studies presented in Table 5

- 4 and supporting data summarized in Chapter 4. 2 The data also indicate effects in other health effect categories, specifically neurotoxic 3 effects, reproductive toxicity, and developmental effects (Section 5.1.2). These are areas where 4 additional research are needed to reduce uncertainty and better cha racterize the potential for 5 health effects and the concentrations at which they might occur in humans. 6 The existing database strongly supports formaldehyde’s potential for causing both 7 reproductive and developmental toxicity. There is, however, no assessm ent of these endpoints 8 from a satisfactory two

- generation toxicity study to fully evaluate the effect of formaldehyde 9 exposure on reproductive and developmental endpoints. Data are adequate to derive a cRfC of 9 10 ppb for decreased fecundability density rat io (FDR) from a human occupational study (Taskinen 11 et al., 1999). This study also reports an increase in spontaneous abortions, although there is 12 uncertainty on the exposure levels of concern for this endpoint; spontaneous abortions may also 13
contribute to the decreased FDR on which one of the cRfCs is based. The greatest uncertainty in 14
the cRfC for decreased FDR is the use of a time

- weighted exposure metric which does not 15 address possible contributions of peak exposure levels to the observed health effect . As such, it 16 is possible that this cRfC is lower than is needed for protection against decreased FDR. The 17 cRfC for decreased FDR does suggest that the RfC derived from the better studied respiratory 18 effects would be protective of that reproductive/devel opmental endpoint, but there remain 19 uncertainties as to the full range of potential reproductive and developmental effects. No data 20 exist to sufficiently inform the exposure

- response relationship for other reproductive and 21 developmental endpoints as they relate to RfC derivation (Section 5.1.2.6). For example, male 22 reproductive effects and structural and behavioral developmental effects (including postnatal 23 development) are not addressed by a study of decreased FDR. This is a database deficiency. A 24

surv ey of the currently available data indicates observed effect levels of 5,000

– 10,000 ppb for 25 male reproductive endpoints and 400 ppb and above for growth retardation and structural 26 anomalies in animal studies. However, these studies employed only one treat ment level, 27 precluding the ability to establish a dose

- response relationship, thus limiting the strength of the 28
studies for use in RfC derivation. 29 Similarly, there is evidence that formaldehyde can cause neurotoxic effects. There is a 30
deficit of studies w ith appropriate exposure scenarios to support derivation of an RfC reflecting 31 the potential for observed neurotoxicity due to formaldehyde exposure. None of the available 32 human studies that evaluated neurological effects were adequate for use in quantitat ive risk 33 assessment, although they did identify neurological effects of concern, including changes in 34 memory and concentration (e.g., Bach et al. [1990]; Kilburn et al. [1987, 1985]) and increased 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 71 risk of mortality from amyotrophic lateral sclerosis (ALS) with increasing duration of exposure 1 to formaldehyde (Weisskopf et al., 2009). The human and animal data indicate the potential for 2 serious neurological and behavioral effects from short

- term formaldehyde exposure (Section 3 5.1.2.6). Limited studies in hu mans, as well as controlled studies in established animal models, 4 confirm the neurotoxic effects of formaldehyde at exposure levels of 100

– 170 ppb (Malek et al., 5 2003a, c; Bach et al., 1990) (Table 5

- 1). For example, an adverse effect level of 100 ppb for 6 impaired learning is reported for short

- term exposures (2 hours/day for 10 days) in rats (Malek et 7 al., 2003a). For this effect, appropriate duration adjustment for extrapolation of a 2

- hour 8 repeated exposure over a limited number of days is uncertain. Given the nature of these health 9 effects, and the potential for children to be exposed in the home to levels as high as 100 ppb (the 10 level at which effects were seen in animals following a single exposure), this is a significant data 11 gap. Studies are inad equate to determine whether exposure to levels of formaldehyde at or 12 below those that impact children’s respiratory health and sensitization will cause neurotoxicity in 13 humans, including endpoints such as impaired learning and memory. 14
15

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

(1) Provide an RfC derived from studies of 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 protect ive of the better

- studied effects and an RfC with a database uncertainty factor of 3 incorporated to account for limits to the data on reproductive, developmental and neurotoxic effects.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 72 It is unclear what uncertainty factors are appropriate to account for human variability and 1 deficiencies in the overall database. For this reason, several alternatives have been presented. 2
3
5.1.4. Uncertainties in th e RfC Derivation 4 By design, the RfC is an estimate of an exposure level at which it is unlikely there would 5 be deleterious effects to the human population (including sensitive subgroups) during a lifetime 6 of exposure. Although the RfC is derived from the best available studies, there are a number of 7 uncertainties that underlie the RfC. Some of these uncertainties are addressed quantitatively by 8 applying UFs on a study

- specific a basis for RfCs based on animal studies, less

- than

- chronic 9 exposures, use of a LOAEL as the POD, and to address human variability for the relevant 10 endpoint (Section 5.1.3). This section elaborates on some of the sources of uncertainty in the 11
final RfC. 12 As the RfC is derived from human studies, the majority in a residential settin g, study 13 aspects that are often a great source of uncertainty are of no concern (e.g., use of animal studies, 14 study of a worker population). The uncertainties discussed below apply specifically to the 15 database of formaldehyde studies and the process to de rive the RfC. 16
17 Point of departure 18 Most of the studies considered for RfC derivation did not provide enough data to support 19 BMD modeling. Rather, the PODs for most studies were LOAELs or NOAELs that have a 20 number of shortcomings relative to a POD obtained from BMD modeling (i.e., a BMC or BMD): 21
22

**•** LOAELs and NOAELs are a reflection of the particular exposure/dose levels used in a 23 study, contributing some inaccuracy to the POD determination. 24

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

**•** Different LOAELs and NOAELs represent different response rates, so direct qualitative 30 and quantitative comparisons are not possible. 31
32
PODs identified from BMD models overcome some of the deficiencies associated with 33
LOAELs a nd NOAELs. Benchmark models were used for two inhalation data sets, Hanrahan et 34 al. (1984) and Krzyzanowski et al. (1990). 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 73 It should also be noted, however, that even for BMCs/BMDs there is often uncertainty, in 1 particular for continuous responses, about what response level to select as the BMR, i.e., where 2
to define the cut

- off point between a level of change that is not adverse and one that is adverse. 3 In addition, BMD models currently in use are purely mathematical models and are not intended 4

to accura tely reflect the biology of the effect being modeled. 5 Another source of uncertainty in the POD is the adjustment for continuous exposure. 6 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in human 7 and laboratory animal inha lation studies are typically not continuous and assumptions must be 8 made in converting reported exposure levels to equivalent continuous exposures. Similarly, 9 there are uncertainties about potential dose rate effects, in particular the effect of peak expo sures 10 in occupational studies. 11
12 Extrapolation from laboratory animal data to humans 13 Because the inhalation database for formaldehyde contains many human studies for a 14 variety of health effects, it was not necessary to rely on animal data for the endpoints from which 15 to derive the RfC. Thus, unlike for most RfCs, this is not a source of uncertainty in the RfC for 16 formaldehyde. 17
18
Human variation 19 Heterogeneity among humans is another uncertainty associated with extending results 20
observed in a limited human study population or laboratory animal experiment to a larger, more 21 diverse human population. 22 For three of the studies used to derive the RfC, a value of 3 was used for the human 23 variability UF (rather than the default value of 10) because the studies had an apparent over

24 representation of populations expected to have increased susceptibility (Section 5.5.3.1): 25
26

 The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 27 irritation in a large number of subjects, including children an d the elderly. As a result of 28 the study's participation criteria, individuals with greater sensitivity were potentially 29

over

- represented. 30

 Thirty percent of the subjects in the residential study by Krzyzanowski et al. (1990) were 31
children who are more se nsitive to formaldehyde

- associated decreases in PEFR than 32 adults. The cRfC determination for this study focused on the results in the children, 33 among whom asthmatics were over

- represented (roughly three times) compared with the 34 national average of 9.4% in 2008 (Bloom et al., 2009). 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 74  Garrett et al. (1999) conducted a cross

- sectional survey of allergy and asthma

- like 1 symptoms in children with or without a doctor's diagnosis of asthma. The study was 2 designed to include a high proportion of asthmatic childre n, a sensitive population for the 3 effects being studied. 4
5 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 6 account for certain special attributes of these studies/effects, there is still uncertainty about how 7
much of t he overall population heterogeneity is actually reflected even in these relatively diverse 8
residential studies. 9
10
Subchronic

- to

- chronic extrapolation 11 RfCs are intended to apply to chronic lifetime exposures. If a study is subchronic 12 (typically less than 10% of a lifetime), a UF for subchronic

- to

- chronic extrapolation is generally 13 applied to the cRfC for that study. For the key human residential and occupational studies used 14 to derive the RfC in this assessment, the average durations of exposure in the h ouseholds or 15 workplaces under study are unknown. In this assessment, these studies were considered chronic 16
in nature and no subchronic

- to

- chronic UF was applied. However, there is uncertainty about 17 whether or not the responses observed fully reflected th e potential effects of chronic exposure, 18 especially in children, where, for example, impacts on the developing respiratory and immune 19 systems could be predisposing the children to further adverse effects later in life. 20
21 5.1.5. Previous Inhalation Assessme nt 22 There is no previous EPA RfC assessment for formaldehyde with which to compare and 23 contrast the RfC developed in this assessment. 24
25 5.2. QUANTITATIVE CANCER ASSESSMENT BASED ON THE NATIONAL 26 CANCER INSTITUTE COHORT STUDY 27 For quantitative assessment of ca ncer risk, it is generally preferable to use good

- quality 28 epidemiologic data, when available, over laboratory animal data. The follow

- up studies by 29 Hauptmann et al. (2004) and Beane Freeman et al. (2009) of the large National Cancer Institute 30 (NCI) retros pective cohort mortality study of U.S. workers involved in the production or use of 31 formaldehyde, with quantitative exposure estimates for the individual workers, present an 32 opportunity to perform quantitative cancer risk assessments of nasopharyngeal canc er (NPC) and 33 lymphohematopoietic cancers (Hodgkin lymphoma and leukemia) based on human data. 34 Although other upper respiratory tract cancers were also identified as being causally associated 35 with formaldehyde exposure in the weight

- of

- evidence analysis in section 4.5, NPC was the only 36This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 75 upper respiratory tract cancer with exposure

- response data adequate for the derivation of unit 1 risk estimates in the Hauptmann et al. (2004) follow

- up study of solid tumors. Similarly, the 2 weight

- of evidence analysis in sect ion 4.5 concluded that there were causal relationships 3 between formaldehyde exposure and all lymphohematopoietic cancers as a group as well as 4 leukemias as a group (with the strongest evidence for myeloid leukemia); however, from the 5 Beane Freeman et al. ( 2009) follow

- up study of lymphohematopoietic malignancies, only all 6 leukemias combined and Hodgkin lymphoma were judged to have exposure

- response data 7 adequate for the derivation of unit risk estimates (see section 5.2.3.1 below). 8
9 5.2.1. Choice of Epidem iology Study 10
Several follow

- up studies of formaldehyde exposure in industrial workers have recently 11 become available. These studies are discussed in more detail in chapter 4 and the appendix 12 (Human Health) and are reviewed only briefly here. Hauptmann et al. (2004) and 13
Beane Freeman et al. (2009) presented follow

- ups of the NCI study (originally described by 14 Blair et al. [1986]) of workers at 10 U.S. plants producing or using formaldehyde. Marsh et al. 15 (2007, 2002) focused on pharyngeal cancer and, in pa rticular, NPC mortality in sequential 16
follow

- up analyses of the Marsh et al. (1996) cohort study, which examined 1 of the 10 plants 17 studied by NCI. Pinkerton et al. (2004) presented a follow

- up of the National Institute for 18 Occupational Safety and Health (NIOSH) study of workers exposed to formaldehyde in three 19 U.S. garment plants (originally described by Stayner et al. [1988]). Coggon et al. (2003) 20 presented an extended follow

- up of a study of workers in six British factories where 21 formaldehyde was produ ced or used (originally described by Acheson et al. [1984] and 22 previously followed up by Gardner et al. [1993]). 23 The analyses presented here are based on the NPC (Hauptmann et al., 2004) and 24 lymphohematopoietic cancer (Beane Freeman et al., 2009) results f rom the NCI follow

- up 25 studies. The NCI cohort study is the largest of the three independent studies and is the only one 26 with sufficient individual exposure data for exposure

- response modeling. In addition, the NCI 27 study is the only one of the three studi es that used internal comparisons rather than standardized 28 mortality ratios (SMRs), thus minimizing the impact of the healthy worker effect, which can 29 attenuate observed effect estimates. The NCI cohort consists of 25,619 workers (88% male) 30 employed in an y of the 10 plants prior to 1966. A follow

- up through 1994 presented exposure

31 response analyses for nine NPC deaths as well as analyses of deaths from other solid cancers 32 (Hauptmann et al., 2004). The most recent follow

- up (through 2004) analyzed 319 dea ths 33 attributed to lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et 34 al., 2009). The results for solid cancers from this recent follow

- up had not yet been published at 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 76 the time of this draft assessment. A detailed exposure ass essment was conducted for each 1 worker in the NCI cohort, based on exposure estimates for different jobs held and tasks 2 performed (Stewart et al., 1986). Exposure estimates were made using several different 3
metrics

— peak exposure, average intensity, cumulat ive exposure, and duration of exposure. 4 Respirator use and exposures to formaldehyde

- containing particulates and other chemicals were 5 also considered. For the NPCs, significant trends were observed for the cumulative and peak 6 exposure metrics (Hauptmann et al., 2004). For the lymphohematopoietic cancers, significant 7 trends were observed primarily for all lymphohematopoietic cancers and for Hodgkin lymphoma 8 with the peak exposure metric (Beane Freeman et al., 2009). 9
The NIOSH follow

- up study (Pinkerton et al., 2004) analyzed mortality data (2,206 10 deaths; 59 from lymphatic and hematopoietic cancers) from their cohort of 11,098 workers (82% 11 female). Leukemia and aleukemia were elevated for workers with >10 years of exposure and for 12
workers with **≥** 20 years since first exposure. However, since no historical exposure level data 13 were available for this cohort, individual worker exposures could not be estimated and exposure

14 response modeling was not conducted. The British cohort updated by Coggon et al. (2003) 15 consisted of 14,014 male workers, and the follow

- up included 5,185 deaths (83 from 16 lymphohematopoietic cancers). In this cohort, lung cancer mortality was statistically 17 significantly increased, especially in workers in the high

- exposure category; however , actual 18 exposure estimates were not available for exposure

- response modeling (worker exposures were 19 categorized as nil/background, low, moderate, or high, depending on the job considered to have 20 had the highest exposure). Lymphohematopoietic cancers were not elevated in the British 21 cohort, although, as discussed above, the results were based on external comparisons against 22 national mortality statistics. Neither the NIOSH nor the British study reported increased risks of 23 NPC, although only 1 case (0.96) w as expected in the NIOSH cohort (Pinkerton et al., 2003) and 24 only 2.0 cases were expected in the British cohort (Coggon et al., 2003). 25
26 5.2.2. Nasopharyngeal Cancer 27
5.2.2.1. Exposure

- Response Modeling of the National Cancer Institute Cohort 28
A detailed ex posure assessment was conducted for the NCI cohort, and quantitative 29 exposure estimates were generated for each worker (Stewart et al., 1986). Formaldehyde 30 exposure estimates, including 8

- hour time

- weighted average (TWA) exposures and level and 31 frequency of peak exposures, were derived for each job, work area, and calendar year 32 combination. A peak was defined as a short

- duration exposure (typically <15 minutes) above 33 the TWA. Cumulative exposures (in ppm **×** years) were estimated by multiplying the time a 34 worker spent in a specific job by the TWA exposure for that job and summing over all the jobs 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 77 held by the worker. Duration was the total time spent in jobs with formaldehyde exposure, and 1 average intensity was the ratio of cumulative exposure to duration. Formaldehyde exposures 2
after 1980 were not taken into account in the follow

- up study, but this was considered to have a 3 minimal impact on the results (see section 5.2.2.4). 4 The results of NCI’s internal analyses for NPC, using the peak exposure, average 5 intensity, cumulative exposure, and duration of exposure metrics, are presented in Table 5

- 7. 6 The relative risks (RRs) were estimated using log

- linear Poisson regression models stratified by 7 calendar year, age, sex, and race and adjusted for pay category (salary/wage/unknown). The 8 NCI investigators used the low

- exposure category as the reference category to “minimize the 9 impact of any unmeasured confounding variables since nonexposed workers may differ from 10 exposed workers with respect to socioeconomic ch aracteristics” (Hauptmann et al., 2004). A 15

- 11 year lag interval was used in estimating exposures in order to account from a minimal latency 12 period for the development of solid cancers, including NPCs. 13
As can be seen in Table 5

- 7, peak exposure is the expo sure metric that provides the 14
strongest exposure

- response relationship with NPC. However, it is not clear how to extrapolate 15 RR estimates based on these peak exposure estimates to meaningful estimates of lifetime extra 16
risk of cancer from environmental ex posures, where the risk is usually considered to be from 17 continuous lifetime exposures to low environmental levels. In addition, peak exposure is a more 18 subjective measure than the other metrics, it is not based on actual measurements, and it is a 19
categor ical rather than continuous measure. Furthermore, the “true” exposure metric best 20 describing the biologically relevant delivered dose of formaldehyde is unknown. The 21 cumulative exposure metric provides a good fit to the data ( p trend = 0.029 for all pers on

- years), 22 and, since this is generally the preferred metric for quantitative risk assessment for 23 environmental exposure to carcinogens, cumulative exposure was chosen as the exposure metric 24
for the risk estimate calculations for NPC in this assessment. 25 The nonexposed person

- years were included in the primary cancer risk analyses 26 presented here in order to be more inclusive of all the exposure

- response data. Such data are 27 typically included in exposure

- response modeling. Furthermore, the data were strat ified by pay 28 category, which should alleviate some concerns about the nonexposed workers having different 29 socioeconomic characteristics. Final results for the exposed person

- years only are presented for 30 comparison. 31
32
33This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 78 Table 5

- 7. Relative risk estimates fo r mortality from nasopharyngeal 1 malignancies (ICD

- 8 code 147) by level of formaldehyde exposure for 2 different exposure metrics 3 4 Relative risk (number of deaths) p trend b p trend c Peak exposure (ppm) 0 >0 to <2.0 a 2.0 to <4.0 **≥** 4.0 1.00 d (2)

– (0)

– (0) 1.83 (7) 0.044 <0.001 Average intensity (ppm) 0 >0 to <0.5 0.5 to <1.0 **≥** 1.0 1.00 d (2)

– (0) 0.38 (1) 1.67 (6) 0.126 0.066 Cumulative exposure (ppm **×** years) 0 >0 to <1.5 1.5 to <5.5 **≥** 5.5 2.40 (2) 1.00 (3) 1.19 (1) 4.14 (3) 0.029 0.025 Dur ation 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 Reference category for all categories. 6
b Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, exc ept for 7 peak exposure metric) among all (nonexposed and exposed) person

- years. 8

c Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 9 peak exposure metric) among exposed person

- years only. 10

d Ref erence category due to no cases in the low

- exposure category. 11 12 Source: Hauptmann et al. (2004). 13 14 15 As described above, Hauptmann et al. (2004) investigated the relationship between 16 formaldehyde exposure and NPC mortality using log

- linear Poisson regression models. They 17 also conducted log

- linear trend tests using the general model RR = e **β** X , where **β** represents the 18 regression coefficient for exposure and X is exposure as a continuous variable. The trend 19 models were stratified by calendar year, age, sex, and race and adjusted for pay category. 20

Dr. Hauptmann provided EPA with the **β** estimates (and their standard errors) from the trend 21 tests for NPC and the cumulative exposure metric for all person

- years and for exposed person

22 years only (personal communication from Michael Hauptmann, NCI, to Jennifer Jinot, EPA, 23 March 29, 2004). These estimates are presented in Table 5

- 8. 24
25
26
27
28This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 79 Table 5

- 8. Regression coefficients from NCI log

- linear trend test models for 1 NPC mortality from cumulative exposure to formaldehyde a 2 3

Pe rson - years **β** (per ppm **×** year) Standard error (per ppm **×** year) All 0.05183 0.01915 Exposed only 0.05318 0.01914 4

a Models stratified by calendar year, age, sex, and race and adjusted for pay category; cumulative exposures 5 calculated using a 15

- year lag i nterval. 6 7 Source: Personal communication from Michael Hauptmann to Jenifer Jinot (March 29, 2004). 8 9 10 5.2.2.2. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Mortality 11 The regression coefficients presented in Table 5

- 8 were used to predict the extra risk of 12 NPC mortality from environmental exposure to formaldehyde. 13
14 Extra risk = (Rx

– Ro)/(1

– Ro), 15
16 where Rx is the lifetime risk in the exposed population and Ro is the lifetime risk in an 17 unexposed population (i.e., the background risk). Extra risk estimates were calculated using the 18 **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 illustrat ing the life table used for the extra risk calculation for the derivation of the LEC 0005 for NPC incidence (see section 5.2.2.3) is presented in Appendix C. 19 U.S. age

- specific 1999 all

- cause mortality rates for all race and gender groups combined 20 (National Center for Health Stat istics [NCHS], 2002) were used to specify the all

- cause 21 background mortality rates in the life

- table program. NCHS 1996

– 2000 age

- specific 22 background mortality rates for NPC were provided by Dr. Eisner of NCI’s Surveillance, 23 Epidemiology and End Results (S EER) program (personal communication from Milton Eisner, 24 SEER, to Jennifer Jinot, EPA, December 19, 2003). Risks were computed up to age 85 because 25

cause

- specific mortality (and incidence) rates for ages above 85 years are less reliable. 26
Conversions betw een occupational formaldehyde exposures and continuous environmental 27 exposures were made to account for differences in the number of days exposed per year (240 28 versus 365) and in the amount of air inhaled per day (10 versus 20 m 3 ). An adjustment was also 29
made for the 15

- year lag period. The reported standard errors for the regression coefficients 30This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 80 were used to compute the one

- sided 95% upper confidence limits (UCLs) for the extra risks 1 based on a normal approximation. 2
Point estimates and one

- sided 95% UC Ls for the extra risk of NPC mortality associated 3 with varying levels of continuous exposure to formaldehyde are presented in Table 5

- 9. The 4 model predicts extra risk estimates that are fairly linear for exposures below about 0.001 to 5
0.01 ppm but not for exposures above 0.01 ppm. 6
7 Table 5

- 9. Extra risk estimates for NPC mortality from various levels of 8 continuous exposure to formaldehyde 9 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 Consistent with EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 13 the same data and methodology were als o used to estimate the exposure level (effective 14 concentration [EC x ]) and the associated (one

- sided) 95% lower confidence limit (LEC x ) 15 corresponding to an extra risk of 0.05% (x = 0.0005). Although EPA guidelines emphasize the 16 use of exposure levels assoc iated with a 10% extra risk level for the POD for low

- dose 17 extrapolation, that would not be appropriate in this instance. A 10% extra risk level is very high 18 for responses generally observed in epidemiology studies; thus, a 1% extra risk level is typicall y 19 used for epidemiologic data to avoid upward extrapolation. For NPC, however, even the 1% 20 level of risk is associated with RR estimates that are substantially higher than those observed in 21 the epidemiology study. Hence, even a 1% extra risk level would be an upward extrapolation. 22
Based on the life

- table program, the RR estimate for an extra risk of 1% for NPC mortality is 46. 23 Even 0.1% yields an RR estimate on the high end of the observable range of the epidemiology 24 study (RR = 5.5). A 0.05% extra ris k level yields an RR estimate of 3.27, which better 25 corresponds to the RRs in the range of the data. Thus, 0.05% extra risk was selected for 26 determination of the POD, and, consistent with EPA’s Guidelines for Carcinogen Risk 27
Assessment (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the 28 POD. While this may appear to be an inordinately low response level, it must be recognized that 29 NPC has a very low background mortality rate (e.g., lifetime background risk is about 0.00022); 30This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 81 therefore, a 1% extra risk (i.e., 0.01) would be a huge increase relative to the background risk. 1 This is consistent with the fact that, even with a large cohort followed for a long time, only nine 2
NPC deaths were observed in the NCI follow

- up through 199 4. 10

Because formaldehyde is a mutagenic carcinogen and the weight of evidence suggests 4 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA 5 (section 4.5), a linear low

- dose extrapolation was performed in accordance wi th EPA’s 6 carcinogen risk assessment guidelines (U.S. EPA, 2005a). The EC 0005 , LEC 0005 , and inhalation 7 unit risk estimates for NPC mortality are presented in Table 5

- 10. 8 3

9
Table 5

- 10. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC 10 mortality fr om formaldehyde exposure based on the Hauptmann et al. (2004) 11 log

- linear trend analyses for cumulative exposure 12 13

Person

- years EC 0005 (ppm) LEC 0005 (ppm) Unit risk a (ppm – 1 ) All 0.15 0.093 5.4 **×** 10
– 3 Exposed only 0.15 0.091 5.5 **×** 10
– 3 14

a Unit risk = 0.0005 /LEC 0005 . 15 16 17 5.2.2.3. Prediction of Lifetime Extra Risk of Nasopharyngeal Cancer Incidence 18 EPA cancer risk estimates are typically derived to represent a plausible upper bound on 19
increased risk of cancer incidence , as from experimental animal incidence dat a. Cancer data 20 from epidemiology studies are more often mortality data, as is the case in the NCI study. For 21 cancers with low survival rates, mortality

- based estimates are reasonable approximations of 22 cancer incidence risk. However, for NPC, the surviva l rate is substantial (51% at 5 years in the 23 1990s in the U.S., according to Lee and Ko [2005]), and incidence

- based risks are preferred 24 because EPA is concerned with cancer occurrence, not just cancer mortality. 25 Therefore, an additional calculation was do ne using the same regression coefficients 26 provided by Dr. Hauptmann (Table 5

- 8) but with age

- specific NPC incidence rates for 1996

– 27 2000 from SEER in place of the NPC mortality rates in the life

- table program. SEER collects 28
cancer incidence data from a var iety of geographical areas in the U.S. The incidence data used 29 here are from SEER 12, a registry covering about 14% of the U.S. population, which was the 30 most current SEER registry at the time this analysis was done. SEER 1996

– 2000 age

- specific 31

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

— DO NOT CITE OR QUOTE 5

- 82 backgroun d incidence rates for NPC were provided by Dr. Eisner of NCI’s SEER program 1 (personal communication from Milton Eisner, SEER, to Jennifer Jinot, EPA, December 18, 2 2003). The incidence

- based calculation relies on the reasonable assumptions that NPC inciden ce 3 and mortality have the same exposure

- response relationship for formaldehyde exposure and that 4 the incidence data are for first occurrences of NPC or that relapses provide a negligible 5
contribution. The calculation also relies on the fact that NPC incid ence rates are small compared 6
with the all

- cause mortality rates. 7 The resulting EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC incidence are 8 presented in Table 5

- 11. The unit risk estimate for cancer incidence is twofold higher than the 9

cor responding mortality

- based estimate, for all person

- years. This sizeable discrepancy can be 10 attributed to the high survival rates for NPC. 11
12
Table 5

- 11. EC 0005 , LEC 0005 , and inhalation unit risk estimates for NPC 13 incidence from formaldehyde exposure based on the Hauptmann et al. (2004) 14 trend analyses for cumulative exposure 15 16

Person

- years EC 0005 (ppm) LEC 0005 (ppm) Unit risk a (ppm – 1 ) All 0.074 0.046 1.1 **×** 10
– 2 Exposed only 0.072 0.045 1.1 **×** 10
– 2 17

a Unit risk = 0.0005/LEC 0005 . 18 19 20 The preferred estimate for the inhalation cancer unit risk for NPC is the estimate of 21
1.1 **×** 10
– 2 per ppm derived using incidence rates for the cause

- specific background rates, for all 22

person

- years. The results from the exposed person

- years are essentially identical. 23
Because NPC is a rare cancer, with a relatively low number of cases occurring per year in 24 the U.S., a rough calculation was done to assure that the unit risk estimate derived for NPC 25 incidence is not implausible in comparison to actual case numbers. For example, assumin g an 26 average constant lifetime formaldehyde exposure level of 5 ppb for the U.S. population, the 27 inhalation unit risk estimate for NPC equates to a lifetime extra risk estimate of 5.5 **×** 10
– 5

. 28 Assuming an average lifetime of 75 years (this is not EPA's def ault average lifetime of 70 years 29 but rather a value more representative of actual demographic data) and a U.S. population of 30 300,000,000, this lifetime extra risk estimate suggests a crude upper

- bound estimate of 220 31
incident cases of NPC attributable to formaldehyde exposure per year. Alternatively, assuming 32 an average constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a 33 crude upper

- bound estimate of 880 incident cases of NPC per year. Both upper bound estimates, 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 83 using dif ferent assumed lifetime exposure levels, are well below the estimated 2100 total 1 incident NPC cases per year calculated from a published NPC incidence rate for the U.S. of 2 0.7/100,000 person

- years (Lee and Ko, 2005). 11

4 3

5.2.2.4. Sources of Uncertainty 5
Th e two major sources of uncertainty in quantitative cancer risk estimates are generally 6 interspecies extrapolation and high

- to

- low dose extrapolation. The risk estimates derived from 7 the Hauptmann et al. (2004) analyses of the NCI cohort are not subject to interspecies 8 uncertainty since they are based on human data. However, substantial uncertainty remains in the 9 extrapolation from occupational exposures to lower environmental exposures. Although the 10 actual exposure

- response relationship at low exposure l evels is unknown, the linear low

- dose 11 extrapolation that was used is warranted by the strong support for formaldehyde carcinogenicity 12 having a mutagenic MOA (section 4.5). The linear low

- dose extrapolation from the 95% lower 13 bound on the exposure level as sociated with the extra risk level serving as the benchmark 14 response is generally considered to provide a plausible upper bound on the risk at lower 15 exposure levels. Actual low

- dose risks may be lower to an unknown extent. 16 Other sources of uncertainty ema nate from the epidemiologic study and its analysis 17 (Hauptmann et al., 2004), including the retrospective estimation of formaldehyde exposures in 18 the cohort, the modeling of the epidemiologic exposure

- response data, the appropriate exposure 19 metric for expos ure

- response analysis, and potential confounding or modifying factors. 20 The same team of investigators (Stewart et al., 1986) conducted a detailed retrospective 21 exposure assessment to estimate the individual worker exposures. Formaldehyde exposures 22

were es timated for specific jobs/tasks based on monitoring data, discussions with workers and 23 plant managers, and assessment by industrial hygienists. Individual worker estimates were 24 derived for a variety of exposure metrics based on work histories. This expos ure assessment was 25 a major undertaking, involving over 100 person

- months. Hauptmann et al. (2004) suggested that 26 employment of such a detailed exposure assessment would tend to minimize exposure 27 misclassification for average and cumulative exposure and du ration of exposure but that peak 28 exposure estimates could be more susceptible to misclassification because they were not based 29 on actual measurements. In addition, the follow

- up study did not take into account exposures 30 after 1980. Hauptmann et al. (2003 ) stated that any underestimation of (total) exposure resulting 31

11 With the application of age

- dependent adjustment factors (see Sec tion 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 a djusted 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.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 84 from the 1980 cutoff “would be small because only 3.7% of all person

- years were contributed by 1 workers who were 65 years or younger and in exposed jobs in 1980” and because exposure 2
levels wer e believed to have been much lower after 1980 than in earlier years. 3 As discussed in Chapter 4 and the appendix (Human Health), Marsh et al. (1996) also 4 estimated individual worker exposures at 1 of the 10 plants (Wallingford, Connecticut) studied 5 by the NCI team, and 5 of the 9 NPC deaths were from that plant. The Marsh et al. (1996) 6 exposure estimates were about 10

- fold lower than those derived by the NCI team for the workers 7 at the Wallingford plant. Marsh et al. (2002) hypothesized that “the NCI use d data from several 8 facilities to estimate exposures in a single facility.” However, the NCI investigators maintained 9 that they estimated exposures for each plant separately. While the exact reasons for such a large 10 discrepancy are unclear, some differen ces in the assessment procedures which could have 11 resulted in substantial differences in the estimates are apparent. First, according to Marsh et al. 12 (1996), 91.7% of the white male Wallingford plant workers were specified as being exposed to 13 formaldehyde in the NCI study, while only 83.3% were considered to have been exposed in the 14 Marsh et al. (1996) analysis (it should be noted that these two cohorts of the Wallingford plant 15 are not identical). Second, the NCI investigators (Stewart et al., 1987, 1986) did their own 16 exposure monitoring at all the plants, including the Wallingford facility, in order to standardize 17 the data provided by the plants as well as to fill data gaps for certain jobs. There is no indication 18 that Marsh et al. (1996) made any addit ional measurements themselves. Third, although the 19 Marsh et al. (2002, 1996) papers are not entirely consistent on this point, those investigators 20 apparently assumed that the job

- specific exposures at the plant were essentially constant over the 21 history o f the plant, whereas the NCI team, based on interviews with plant personnel 22 knowledgeable about equipment and process changes, assumed that past exposures were higher. 23 In any event, despite the discrepancies in the absolute exposure values, the relative 24

ex posures for both the Marsh et al. (2002, 1996) and NCI studies, as reflected in the exposure

25 response relationships, are less subject to misclassification and are considered to be reliable. 26 The Wallingford plant is just 1 of the 10 plants in the NCI study (representing 4,389 of the 27 25,619 workers in the NCI cohort), but if the Marsh et al. (1996) exposure estimates, which are 28 roughly 10

- fold lower than the NCI estimates, are closer to the actual exposures for those 29 workers, then the true potency of formald ehyde could be greater than that suggested by the unit 30 risk estimates calculated above based on the NCI data. Furthermore, if the NCI exposure values 31 were significantly overestimated across all 10 plants, then the actual potency could be higher 32
still. 33
Wit h respect to the exposure

- response model, the log

- linear model used by Hauptmann et 34 al. (2003) for their trend tests (i.e., RR = e βX ) is a commonly used model for epidemiologic data 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 85 with exposure as a continuous variable. However, the actual exposure

- response relationship is 1 unknown. Moreover, even if the correct exposure

- response model were known, there would be 2
substantial uncert ainty in estimating the model parameters because there are only nine NPC 3 deaths to model. Furthermore, Beane Freeman et al. (2009) reported that in the follow

- up 4 through 2004 it was discovered that 1,006 deaths that occurred during the 1980 to 1994 5
follow

- up period had not been included in the analyses of the 1994 follow

- up study (Hauptmann 6 et al., 2004, 2003), for reasons that have not been identified. Because NPC is such a rare cancer, 7 it is not expected that many, if any, NPC deaths were among the 1,00 6 excluded deaths; 8 however, it is unknown how inclusion of the 1,006 deaths would have altered the overall 9

exposure

- response relationship and, hence, the regression coefficient. Additionally, a 15

- year 10 lag was used for all the NCI solid cancer models. Th e actual minimum latency is unknown; 11 however, the investigators reported that lag intervals between 2 and 20 years yielded similar 12
results. 13 Another potentially significant source of uncertainty is associated with the exposure 14 metrics. With the log

- linear model used for modeling the occupational data, the peak exposure 15 metric gave the strongest exposure

- response relationship between formaldehyde exposure and 16 increased risk of NPCs. However, it is unclear how to extrapolate RR estimates based on peak 17

exposu re estimates to meaningful estimates of lifetime extra risk of cancer from environmental 18 exposure (i.e., extra risk from lifetime continuous low

- level environmental exposures). The 19 cumulative exposure metric also yielded a statistically significant exposu re

- response relationship 20 and was used for the primary cancer risk calculations in this assessment. The “true” exposure 21 metric best describing the toxicologically relevant dose of formaldehyde for nasopharyngeal 22 carcinogenesis is unknown. If a peak

- exposu re type of metric is the best representative of the 23 toxicologically relevant dose, this suggests that there are dose

- rate effects in the exposure

24 response relationship for formaldehyde and NPC. If this is the case, the unit risk estimates 25 presented here, which are based on a linear low

- dose extrapolation, may overestimate the true 26
risks to an unknown extent. 27 Hauptmann et al. (2004) gave a lot of consideration to potential confounding and 28 modifying factors in their analyses. The important factors of age, r ace, sex, calendar year, and 29 pay category were taken into account in their Poisson regression and trend analyses. 30 Furthermore, they used the low

- exposure person

- years, rather than the unexposed person

- years, 31 as their referent group in an effort to minimiz e any potential confounding effects resulting from 32 differences in socioeconomic or other characteristics between exposed and unexposed workers. 33 When the slope estimate (i.e., regression coefficient) for the exposed person

- years only was used 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 86 in the analys es presented here, the unit risk estimate was essentially identical to that calculated 1 from the slope estimate for all person

- years (see Tables 5

- 12 and 5

- 13). 2 In addition, these investigators evaluated routine respirator use, exposure to 3 formaldehyde

- cont aining particulates, durations of exposure to 11 other chemicals/substances in 4 the plants (antioxidants, asbestos, carbon black, dyes and pigments, hexamethylenetetramine, 5 melamine, phenol, plasticizers, urea, wood dust, and benzene), and duration of emplo yment as a 6 chemist or laboratory technician. Only 133 workers ever routinely used a respirator (Hauptmann 7 et al., 2003). Hauptmann et al. (2004) reported that RR estimates for NPC changed when 8 adjusted for duration of melamine exposure, although trend te sts remained significant for 9 cumulative formaldehyde exposure ( p = 0.006). The investigators suggested that the association 10 with melamine may be spurious, and the regression coefficients (i.e., β estimates) used in this 11 assessment were not adjusted for me lamine. RR estimates reportedly did not change 12 substantially when adjusted for exposure to any of the other 10 chemicals/substances. None of 13 the workers who died of NPC was identified as being exposed to wood dust. On the other hand, 14
each of the seven f ormaldehyde

- exposed workers who died of NPC was also exposed to 15 particulates, and neither of the two workers who died of NPC but were not exposed to 16 formaldehyde was exposed to particulates. However, for those workers exposed to particulates, 17
NPC risk inc reased with increasing formaldehyde exposure, suggesting a formaldehyde

18 associated effect. Nonetheless, because of the correspondence between formaldehyde and 19 particulate exposures within the workers who died of NPC, there is uncertainty as to whether or 20 not particulates were acting as a modifying factor. Adjusting for duration of time spent working 21 as a chemist or laboratory technician did not substantially alter the results (Hauptmann et al., 22 2004). 23 Adjusting for plant may result in overadjustment bec ause plant is highly correlated with 24 exposure. Moreover, Hauptmann et al. (2004) adjusted for important plant

- related factors by 25 adjusting for the 11 chemicals/substances. Nonetheless, these investigators conducted analyses 26 adjusted for plant to address potential unmeasured confounders associated with plant, and they 27 reported that the association with NPC remained. As noted above, five of the nine NPC deaths 28 were from the Wallingford plant also studied by Marsh et al. (2006, 2002). Marsh et al. (2007) 29
h ypothesized that the excess NPCs in the Wallingford plant could be due to external employment 30
in metal

- working industries, but we found no evidence to support this supposition (see section 31 4.1.1.1). 32 Although smoking data were not available for the cohort , smoking is unlikely to explain 33
the excesses in NPCs because there was no consistent increase for tobacco

- related diseases, 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 87 including lung cancer, across the same exposure metrics. No information was available on 1 Epstein

- Barr virus, a major risk factor f or NPC, in the cohort. 2 Despite inevitable uncertainties, it is important not to lose sight of the strengths of the 3 NCI study. In addition to the use of internal analyses and the extensive exposure assessment and 4 consideration of potential confounding or m odifying variables, the NCI study has a large cohort 5 that has been followed for a long time. The cohort included 25,619 subjects, 75% of whom 6 entered before 1960, contributing a total of 865,708 person

- years (730,312 for the exposed 7 workers) to the 1994 f ollow

- up. Duration of follow

- up in 1994 ranged up to 58 years, with a 8 median of 35 years. Duration of exposure ranged up to 46 years, with a median of 2 years. 9 Additional uncertainties are not so much inherent in the exposure

- response modeling or 10
in th e epidemiologic data themselves but rather stem from the process of obtaining more general 11 EPA risk estimates from these specific results. EPA cancer risk estimates typically represent a 12 plausible upper bound on increased risk of cancer incidence in the g eneral population for all 13 tissue sites potentially affected by an agent. For experimental animal studies, this is 14 accomplished by using tumor incidence data and summing across all the tumor sites that 15 demonstrate significantly increased incidences, genera lly using data from the most sensitive sex 16 and species. However, in estimating comparable risks from the NCI epidemiologic data, certain 17 limitations are encountered. First, the NCI study is a retrospective mortality study, and cancer 18
incidence data are u navailable for the cohort. Second, these occupational epidemiology data 19 represent a worker cohort that is generally healthier than the general population 20 (e.g., SMRs < 1) (see Table 2 of Hauptmann et al. [2004]). 21 The first limitation was addressed quanti tatively in the calculation of cancer incidence 22 risk estimates from the mortality results, and, even though there are assumptions made in using 23 incidence data this way, the incidence

- based estimates are believed to be better estimates of 24
cancer incidence r isk than the mortality

- based estimates. With respect to the second limitation, 25 the healthy worker effect is often an issue in occupational epidemiology studies, and it is 26 difficult to know to what extent there is a healthy worker effect with respect to th e development 27 of NPC in this study. As discussed above, Hauptmann et al. (2004) sought to minimize potential 28 confounding effects resulting from differences in socioeconomic or other characteristics between 29 exposed and unexposed workers by using the low

- ex posure person

- years, rather than the 30 unexposed person

- years, as their referent group. Nonetheless, when the slope estimates for the 31 exposed person

- years only were used in the analyses in this assessment, unit risk estimates 32 essentially identical to those calculated from the slope estimates for all person

- years were 33 obtained (Tables 5

- 12 and 5

- 13). In terms of representing the general population, the NCI cohort 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 88 was somewhat diverse, but the workers were predominantly white males (81%) then white 1 females (1 2%), black males (7%), and black females (<1%), and they were all adults. 2 Finally, NPC is just one of the upper respiratory tract cancers concluded to be causally 3 associated with formaldehyde exposure (section 4.5). These upper respiratory tract cancers a re 4 rare cancers and are difficult to detect in cohort studies. Thus, although NPC was the only such 5 cancer with an exposure

- response relationship amenable to the derivation of a unit risk estimate, 6 additional, unquantified risk may exist for the other upp er respiratory tract cancers. If there was 7 a strong exposure

- response relationship between these cancers and formaldehyde exposure, a 8 more apparent association in the Hauptmann et al. (2004) study might have been expected, as 9 was seen for NPC, despite the rare nature of these cancers. Thus, the exposure

- response 10 relationship for these other upper respiratory tract cancers is likely modest, at best, and, because 11 these are rare cancers, the contribution of the risk for these cancers to the total cancer risk from 12 formaldehyde exposure is not expected to be large. Nonetheless, with such rare cancers, there is 13 uncertainty regarding the extent to which the estimate based on NPC may underestimate the risk 14 for all upper respiratory tract cancers. 15 In summary, the inhalation cancer unit risk estimate of 1.1 **×** 10
– 2 per ppm for NPC is 16 based on human data from a high

- quality epidemiologic study with individual exposure 17 estimates for each worker. A major uncertainty is the appropriate model/exposure metric for 18
extrapo lation to environmental exposures. 19
20 5.2.3. Lymphohematopoietic Cancer 21
5.2.3.1. Exposure

- Response Modeling of the National Cancer Institute Cohort 22 The results of NCI’s internal analyses for lymphohematopoietic cancers using the peak 23 exposure, average int ensity, and cumulative exposure metrics from the follow

- up through 2004 24 are reported by Beane Freeman et al. (2009). There was reportedly no evidence of associations 25 with duration of exposure, and those results were not presented. For the peak exposure m etric, 26 statistically significant log

- linear trends were observed for all lymphohematopoietic cancers, 27 Hodgkin lymphoma, and leukemia (the latter only when the unexposed person

- years were 28 included). There was also evidence for potential associations with m yeloid leukemia 29 specifically, especially when risks were viewed over time, and with multiple myeloma. Using 30 the average exposure metric, there was a significant trend for Hodgkin lymphoma. With the 31 cumulative exposure metric, there were no statistically significant trends; however, the Hodgkin 32 lymphoma trend results were of borderline significance ( p trends = 0.06 and 0.08 with and 33 without the unexposed person

- years, respectively), as were the leukemia trend results ( p trends = 34
0.08 and 0.12 with and with out the unexposed person

- years, respectively). As discussed above 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 89 with NPC, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 1 to meaningful estimates of lifetime extra risk of cancer from environmental exposures. The 2

av erage exposure metric is also problematic because it suggests that duration of exposure is not 3 important (e.g., exposure to a given exposure level for 1 year conveys the same amount of risk 4 as exposure to the same level for 70 years). Cumulative exposure is generally the preferred 5 metric for quantitative risk assessment for environmental exposure to carcinogens, and, because 6 the Hodgkin lymphoma and leukemia trend results were of borderline statistical significance 7 using the cumulative exposure metric and the elevations in risk with that metric were consistent 8 with significant elevations observed with the peak exposure (for Hodgkin lymphoma and 9 leukemia) and average exposure (for Hodgkin lymphoma) metrics (Table 5

- 12), a determination 10
was made to calculate unit risk estimates for Hodgkin lymphoma and leukemia based on 11 cumulative exposure. There is also support for associations between formaldehyde exposure and 12 both Hodgkin lymphoma and leukemia from other studies (section 4.5.2). No other 13 lymphohematopoie tic cancer responses provided adequate exposure

- response data with the 14 cumulative formaldehyde exposure metric in the NCI cohort from which to derive unit risk 15
estimates. 16 As for the NPC results discussed in section 5.2.2, the RR estimates in Table 5

- 12 w ere 17 derived using log

- linear Poisson regression models stratified by calendar year, age, sex, and race 18 and adjusted for pay category (salary/wage/unknown). The NCI investigators used the low

19 exposure category as the reference category to “minimize the imp act of any unmeasured 20 confounding variables since nonexposed workers may differ from exposed workers with respect 21 to socioeconomic characteristics” (Hauptmann et al., 2004). A 2

- year lag interval was used to 22 determine exposures in order to account for a m inimal latency period for lymphohematopoietic 23

cancers. 24 Dr. Beane Freeman provided EPA with the regression coefficient estimates for Hodgkin 25 lymphoma and leukemia mortality from the log

- linear trend test models for cumulative exposure 26 (i.e., RR = e βX , with exposure [X] as a continuous variable) used in the NCI analyses (personal 27 communication from Laura Beane Freeman, NCI, to John Whalan, EPA, August 26, 2009). 28 These estimates are presented in Table 5

- 13. As with the NPC calculations in section 5. 2.2, the 29 nonexposed person

- years were included in the primary unit risk estimate derivations in order to 30 be more inclusive of all the exposure

- response data. Final results for the exposed person

- years 31 only are presented for comparison. 32
33This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 90 Table 5

- 12. Rela tive risk estimates for mortality from Hodgkin lymphoma 1 (ICD

- 8 code 201) and leukemia (ICD

- 8 codes 204

– 207) by level of 2 formaldehyde exposure for different exposure metrics 3 4 Cancer type Relative risk (number of deaths) p trend b p trend c Peak exposure (ppm ) 0 >0 to <2.0 a 2.0 to <4.0 **≥** 4.0 Hodgkin lymphoma 0.67 (2) 1.0 (6) 3.30 (8) 3.96 (11) 0.004 0.01

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

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

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

a Reference category for all categories. 6
b Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 7 peak exposure metric) among all (nonexposed and exposed) person

- years. 8

c Likelihood ratio test (1 degree of freedom) of zero slope for formaldehyde exposure (continuous variable, except for 9 peak exposure metric) among exposed person

- years only. 10 11 Source: Beane Freeman et al. (2009). 12 13 14 Table 5

- 13. Regression coefficients for Hodgkin lymphoma and leukemia 15 mortality from NCI trend test models a 16 17

Cancer type Person

- years **β** (per ppm × year) Standard error (per ppm × year) Hodgkin lymphoma All 0.02959 0.01307 Exposed only 0.02879 0.01333 Leukemia All 0.01246 0.006421 Exp osed only 0.01131 0.00661 18

a Models were stratified by calendar year, age, sex, and race and adjusted for pay category; exposures included a 19 2

- year lag interval. 20 21 Source: Personal communication from Laura Beane Freeman to John Whalan (August 26, 2009). 22 23This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 91 5 .2.3.2. Prediction of Lifetime Extra Risks for Hodgkin Lymphoma and Leukemia Mortality 1 Extra risk estimates for Hodgkin lymphoma and leukemia mortality were calculated 2 using the same general methodology described above for the NPC mortality estimates (sec tion 3 5.2.2.2), with the following exceptions. U.S. age

- specific 2006 all

- cause mortality rates (NCHS, 4 2009) and NCHS age

- specific 2002

– 2006 background mortality rates for Hodgkin lymphoma 5 and leukemia ( http://seer.cancer.gov/csr/1975_2006/ ) for all race and gender groups combined 6
were used in the life

- table programs. In addition, a 2

- year lag period was used instead of a 7
15

- year lag period. 8 The resulting point estimates and one

- sided 95% UCLs for the extra risk of Hodgkin 9 lymphoma mortality associated with varying levels of continuous exposure to formaldehyde are 10 presented in Table 5

- 14. The results for leukemia are shown in Table 5

- 15. In both cases, the 11 models predict extra risk estimates that are fairly linear for exposures below about 0.01

– 0.1 ppm 12 but not for exposures above 0.1 ppm. 13
14
Table 5

- 14. Extra risk estimates for Hodgkin lymphoma mortality from 15 various levels of continuous exposure to formaldehyde 16 17 Exposure concentration (ppm) Extra ris k 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
Table 5

- 15. Extra risk estimates for leukemia mortality from various levels 20 of continuous exposure to formaldehyde 21 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
23This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 92 As discussed in section 5.2.2.2 above, 1% extra risk levels are typically used as the basis 1
for the POD for low

- dose extrapolation from epidemiologic data. As for NPC, however, 2 Hodgkin lymphoma has a very low backgr ound mortality rate (e.g., lifetime background risk is 3 about 0.00038), and the 1% level of risk is associated with RR estimates that are substantially 4 higher than those observed in the epidemiology study. Hence, a 1% extra risk level would be an 5 upward ex trapolation. Based on the life

- table program, the RR estimate associated with an extra 6 risk of 1% for Hodgkin lymphoma mortality is 27. Even 0.1% yields an RR estimate at the 7 higher end of what was observed in the epidemiology study (RR = 3.6) (note that our primary 8 analyses include the nonexposed workers, and thus the 0

- exposure group becomes the referent 9 group and the RR estimates presented for Hodgkin lymphoma and cumulative exposure in Table 10
5

- 12 would be adjusted upward [about 2.4

- fold] relative to t he 0

- exposure group). A 0.05% 11 extra risk level yields an RR estimate of 2.3, which better corresponds to the RRs at the lower 12 end of the observable range. Thus, 0.05% extra risk was selected for determination of the POD 13 for Hodgkin lymphoma, and, consist ent with EPA’s Guidelines for Carcinogen Risk Assessment 14 (U.S. EPA, 2005a), the LEC value corresponding to that risk level was used as the POD. 15 For leukemia, although the background mortality rates are higher (0.0065), the 1% extra 16 risk level typically use d as the basis for the POD for epidemiologic data still corresponds to an 17 RR estimate (2.5) that would be above the highest categorical result reported, even after 18 adjusting the RR estimates upward relative to the 0

- exposure group (see above paragraph). A 19 0.5% extra risk level yields an RR estimate of 1.8, which better corresponds to the RRs in the 20 range of the data. Thus, the LEC value corresponding to 0.5% extra risk was selected for the 21
POD for leukemia. 22
Because formaldehyde is a mutagenic carcinogen a nd the weight of evidence suggests 23 that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA 24 (section 4.5), a linear low

- dose extrapolation was performed, also in accordance with EPA’s 25 Guidelines for Carcinogen Risk Assessme nt (U.S. EPA, 2005a). The EC 0005 , LEC 0005 , and 26 inhalation unit risk estimates for Hodgkin lymphoma mortality are presented in Table 5

- 16, and 27
the EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia mortality are presented in 28
Table 5

- 17. 29
30
31
32
33This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 93 Tab le 5

- 16. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 1 lymphoma mortality from formaldehyde exposure based on Beane Freeman 2 et al. (2009) log

- linear trend analyses for cumulative exposure 3 4

Person

- years EC 0005 (ppm) LEC 0005 (ppm) Unit ris k a (ppm – 1 ) All 0.151 0.0875 5.7 **×** 10
– 3 Exposed only 0.155 0.0881 5.7 **×** 10
– 3 5

a Unit risk = 0.0005/LEC 0005 . 6 7 8 Table 5

- 17. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia 9 mortality from formaldehyde exposure based on Beane Freeman et al. (2 009) 10 log

- linear trend analyses for cumulative exposure 11 12

Person

- years EC 005 (ppm) LEC 005 (ppm) Unit risk a (ppm – 1 ) All 0.224 0.121 4.1 **×** 10
– 2 Exposed only 0.246 0.126 4.0 **×** 10
– 2 13

a Unit risk = 0.005/LEC 005 . 14 15 16 5.2.3.3. Prediction of Lifetime Extra Risks fo r Hodgkin Lymphoma and Leukemia Incidence 17 As for NPC, both Hodgkin lymphoma and leukemia have substantial survival rates 18 (84.7% at 5 years for Hodgkin lymphoma [http://seer.cancer.gov/statfacts/html/hodg.html] and 19 53.1% at 5 years for leukemia [http://seer .cancer.gov/statfacts/html/leuks.html], based on 1999

– 20 2005 SEER data); thus, it is preferable to derive incidence estimates. Unit risk estimates for 21 Hodgkin lymphoma and for leukemia incidence were calculated as described above for the NPC 22
incidence estim ates (section 5.2.2.3). Age

- specific background incidence rates for 2002

– 2006 23 for Hodgkin lymphoma and for leukemia from SEER17, a registry covering about 26% of the 24 U.S. population, were obtained from the SEER Web site (http://seer.cancer.gov/csr/1975_20 06/). 25
The incidence

- based calculation relies on the assumptions that Hodgkin lymphoma (and 26 leukemia) incidence and mortality have the same exposure

- response relationship for 27 formaldehyde exposure and that the incidence data are for first occurrences of Ho dgkin 28 lymphoma (and leukemia) or that relapses provide a negligible contribution. The first 29 assumption is more uncertain for leukemia because it is a grouping of subtypes with different 30 survival rates (see section 5.2.3.4 for further discussion). The cal culation also relies on the fact 31 that Hodgkin lymphoma (and leukemia) incidence rates are small compared with the all

- cause 32This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 94 mortality rates. The resulting EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 1 lymphoma incidence are presented in Table 5

- 18, and the EC 005 , LEC 005 , and inhalation unit risk 2 estimates for leukemia incidence are presented in Table 5

- 19. The unit risk estimate for Hodgkin 3 lymphoma incidence is about threefold higher than the corresponding mortality

- based estimate, 4
for all person

- years. This sizeable discrepancy can be attributed to the high survival rates for 5 Hodgkin lymphoma. For leukemia, the incidence unit risk estimate is about 40% higher than the 6 mortality

- based estimate. This difference is lower than the twofol d difference seen with NPC 7 estimates, despite comparable survival rates, probably because of different age distributions of 8 the mortality and incidence rates. 9
10
Table 5

- 18. EC 0005 , LEC 0005 , and inhalation unit risk estimates for Hodgkin 11 lymphoma incidenc e from formaldehyde exposure, based on Beane Freeman 12 et al. (2009) log

- linear trend analyses for cumulative exposure 13 14

Person

- years EC 0005 (ppm) LEC 0005 (ppm) Unit risk a (ppm – 1 ) All 0.0515 0.0298 1.7 **×** 10
– 2 Exposed only 0.0529 0.0301 1.7 **×** 10
– 2 15

a Unit ri sk = 0.0005/LEC 0005. 16 17 18 Table 5

- 19. EC 005 , LEC 005 , and inhalation unit risk estimates for leukemia 19 incidence from formaldehyde exposure based on Beane Freeman et al. (2009) 20 log

- linear trend analyses for cumulative exposure 21 22

Person

- years EC 005 (ppm) LEC 005 (ppm) Unit risk a (ppm – 1 ) All 0.162 0.0875 5.7 **×** 10
– 2 Exposed only 0.178 0.0909 5.5 **×** 10
– 2 23

a Unit risk = 0.005/LEC 005 . 24 25 26 The preferred estimate for the inhalation cancer unit risk for Hodgkin lymphoma is the 27
estimate of 1.7 **×** 10
– 2 per ppm derived using i ncidence rates for the cause

- specific background 28 rates, for all person

- years. Similarly, the preferred estimate for leukemia is the estimate of 29
5.7 **×** 10
– 2 per ppm derived using incidence rates, for all person

- years. In both cases, the results 30
from the ex posed person

- years only are essentially identical. 31This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 95 Because Hodgkin lymphoma is a rare cancer, with a relatively low number of cases 1 occurring per year in the U.S. (according to SEER statistics, an estimated 8,510 people were 2 diagnosed with Hodgkin lymphoma in the U.S. in 2009 3 [http://seer.cancer.gov/statfacts/html/hodg.html]), a rough calculation was done to assure that the 4 unit risk estimate derived for Hodgkin lymphoma incidence is not implausible in comparison to 5 actual case numbers. For example, assumi ng an average constant lifetime formaldehyde 6 exposure level of 5 ppb for the U.S. population, the inhalation unit risk estimate for Hodgkin 7 lymphoma equates to a lifetime extra risk estimate of 8.5 **×** 10
– 5 . Assuming an average lifetime 8 of 75 years (this is not EPA's default average lifetime of 70 years but rather a value more 9 representative of actual demographic data) and a U.S. population of 300,000,000, this lifetime 10 extra risk estimate suggests a crude upper

- bound estimate of 340 incident cases of Hodgki n 11 lymphoma attributable to formaldehyde exposure per year. Alternatively, assuming an average 12 constant lifetime formaldehyde exposure level of 20 ppb, the calculation suggests a crude upper

13 bound estimate of 1,360 incident cases of Hodgkin lymphoma per ye ar. Both upper bound 14 estimates, using different assumed lifetime exposure levels, are well below the estimated 8,510 15 total incident Hodgkin lymphoma cases diagnosed per year in the U.S. 12

17 16

5.2.3.4. Sources of Uncertainty 18 By and large, the sources of uncer tainty discussed above (section 5.2.2.4) for the NPC 19 risk estimates, such as high

- to

- low dose extrapolation, retrospective exposure estimation, 20 exposure metric/model uncertainties, and application of data from a “healthy” worker cohort to 21
the more diverse general population also apply to the Hodgkin lymphoma and leukemia risk 22 estimates. The Hodgkin lymphoma risk estimates are based on 27 deaths, which is more than 23 were available for the NPC risk estimates, but 27 is still a small number for exposure

- respon se 24 modeling. The leukemia risk estimates are based on 123 deaths, so there is less uncertainty with 25 the parameter estimation from the exposure

- response modeling for that cancer type, although 26 uncertainties still exist about the general model form. A 2

- ye ar lag interval was used for 27

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 adju sted 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 upper

bound 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 leu kemia 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]).This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 96 lymphohematopoietic cancers versus the 15

- year lag for NPC. Beane Freeman et al. (2009) 1 evaluated lag intervals between 2 and 25 years and reported that lag intervals of about 18 years 2 provided the best fit to the lymphohemat opoietic cancer data but did not change the risk 3 estimates; thus, they retained the 2

- year lag interval that was used in the previous follow

- up 4 (Hauptmann et al., 2003). The most appropriate lag intervals for Hodgkin lymphoma and 5 leukemia are unknown, but alternate lags are unlikely to have a large impact on the results. 6 The same potential confounding or modifying factors that were investigated for NPC and 7 the other solid cancers, as discussed in section 5.2.2.4 above, were evaluated for the 8 lymphohemato poietic cancers. Beane Freeman et al. (2009) reported that controlling for 9 duration of exposure to the 11 other substances that they considered (see section 5.2.2.4) or for 10 working as a chemist or laboratory technician “did not meaningfully change results ”; results 11 were not shown. The investigators also reported that excluding the 586 individuals with exposure 12 to benzene, a known leukemogen, did not change the RR estimates for myeloid or lymphoid 13 leukemia in the highest peak exposure category. Furthermore , Beane Freeman et al. (2009) 14 found no evidence of heterogeneity of RR estimates for lymphohematopoietic cancers by race, 15 sex, or pay category, and adjusting for plant reportedly did not substantively change results. 16 A further uncertainty is which lymphohe matopoietic cancer types are linked to 17 formaldehyde exposure. As discussed in section 4.5.2, lymphohematopoietic cancers are a 18 diverse group of cancers with different etiologies, and the epidemiologic database suggests 19 associations with multiple different subtypes of these cancers. Section 4.5 concludes that 20 formaldehyde is causally associated with all lymphohematopoietic cancers as a group and with 21 leukemias as a group (with the strongest evidence for myeloid leukemia). However, at present, 22 exactly whic h subtypes are etiologically linked to formaldehyde exposure is unknown. Cancer 23 risk estimates were derived for Hodgkin lymphoma and leukemia because, in addition to support 24 for an association between these lymphohematopoietic cancer subtypes and formalde hyde 25 exposure with other exposure metrics and from other studies, these had the strongest associations 26 with cumulative exposure in the Beane Freeman et al. (2009) update of the large, high

- quality 27 NCI study. However, it is unknown whether these two subtyp es best represent the total 28 lymphohematopoietic cancer risk. 29 In addition, leukemia itself is a grouping of diverse (e.g., acute lymphocytic, chronic 30 lymphocytic, acute myeloid, chronic myeloid) subtypes, and using this grouping injects 31
additional uncerta inty into the derivation of cancer incidence estimates. One of the assumptions 32
that the incidence

- based calculation relies on is that the cancer incidence and mortality have the 33

same exposure

- response relationship for formaldehyde exposure. This assumpti on may be 34 problematic for the leukemia incidence estimates if not all of the leukemia subtypes represented 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 97 in the grouping are associated with formaldehyde exposure to the same extent. This is because 1 different leukemia subtypes have different survival ra tes, so if a subtype with a relatively high 2 survival rate is included in the background incidence rates while not actually being associated 3 with formaldehyde exposure or being associated to a lesser extent than other subtypes, then the 4
incidence risk will be overestimated. The mortality risk calculations are not similarly affected 5 by including subtypes that may not actually be associated with formaldehyde exposure because 6 background mortality for the subtypes is already taken into account in the regression coefficient. 7 Figure 5

- 10 shows the mortality versus incidence rates for all leukemia and the two main 8 subtypes, myeloid leukemia and lymphoid leukemia. This figure does not show the acute versus 9 chronic myeloid and leukemia subtypes or the monocytic or o ther leukemia subtypes; however, 10 it serves to illustrate the impact of using rates for groupings that contain subtypes with different 11 survival rates. For example, if lymphoid leukemia is the predominant subtype associated with 12 formaldehyde exposure, then using the leukemia grouping for the incidence rates may 13 underestimate the cancer incidence risk because the incidence rates for leukemia (relative to the 14 mortality rates) are diluted with inclusion of the incidence rates for myeloid leukemia, which has 15

a s maller incidence

- to

- mortality ratio (i.e., poorer survival). On the other hand, if myeloid 16 leukemia is the predominant subtype associated with formaldehyde exposure, then using the 17 leukemia grouping for the incidence rates may overestimate cancer incidenc e risk. If incidence 18 risks are being overestimated, the effect should be minimal because the incidence risk estimates 19 for leukemia calculated in section 5.2.3.3 are not that much greater (about 40%) than the 20 mortality

- only estimates. 21 Finally, as for the N PC risk estimates, when the slope estimates for the exposed person

22 years only were used for the Hodgkin lymphoma and leukemia risk calculations, unit risk 23 estimates similar to those calculated from the slope estimates for all person

- years were obtained 24 (Ta bles 5

- 18 and 5

- 19); thus, the impacts of including the unexposed person

- years are minimal. 25 As discussed in section 5.2.2.4, despite inevitable uncertainties, it is important not to lose 26 sight of the strengths of the NCI study. In addition to the use of i nternal analyses and extensive 27 exposure assessment and consideration of potential confounding or modifying variables, the NCI 28 study has a large cohort that has been followed for a long time. With the additional follow

- up 29 through 2004, reflected in the lymphohematopoietic cancer results of Beane Freeman et al. 30 (2009), the median duration of follow

- up was 42 years, and the 25,619 cohort members had 31 accrued 998,106 person

- years of follow

- up. Over half of the cohort was deceased, and there was 32
a substantial n umber of lymphohematopoietic deaths (319 total; 286 in the exposed workers). 33
34This document is a draft forreview purposes only and doesnot constitute Agency policy5-98DRAFT—DO 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 incThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 99 In summary, the inhalation cancer incidence unit risk estimates of 1.7 **×** 10
– 2 per ppm for 1 Hodgkin lymphoma and 5.7 **×** 10
– 2 per ppm for leukemia are based on human data from a high

2 quality epidemiologic study with individual exposure estimates for each worker. The major 3 source of uncertainty in both risk estimates is the extrapolati on to environmental exposures. 4
5
5.2.4. Conclusions on Cancer Unit Risk Estimates Based on Human Data 6 In this assessment, a (plausible upper bound) lifetime extra cancer unit risk of 5.4 **×** 10
– 3 7 per ppm of continuous formaldehyde exposure was estimated usin g a life

- table program and 8
linear low

- dose extrapolation of the excess NPC mortality and log

- linear modeling results (for 9 cumulative exposure) reported in a high

- quality occupational epidemiologic study (based on nine 10 NPC deaths). Applying the same regres sion coefficient and life

- table program to background 11 NPC incidence rates yielded a lifetime extra cancer unit risk estimate of 1.1 **×** 10
– 2 per ppm 12 (8.8 **×** 10
– 6 per μg/m 3 ). 13 Using similar methods and data for Hodgkin lymphoma (27 deaths) and leukemia 14 (123 d eaths) mortality based on the cumulative exposure metric, from a further follow

- up of the 15 same cohort study, (plausible upper bound) lifetime extra cancer risk estimates of 1.7 **×** 10
– 2 per 16 ppm (1.4 **×** 10
– 5 per μg/m 3 ) and 5.7 **×** 10
– 2 per ppm (4.6 **×** 10
– 5 per μg /m 3 ) for Hodgkin 17 lymphoma incidence and leukemia incidence, respectively, were derived. 18 To estimate the total cancer risk from formaldehyde exposure, risk estimates for these 19 three cancer types (NPC, Hodgkin lymphoma, and leukemia) were combined, although, as 20 discussed above, these three cancer types may not fully reflect the total cancer risk for all 21 cancers thought to be causally associated with formaldehyde exposure. For an approximate 22 estimate of the combined (upper bound) risk, risk estimates were com bined assuming a normal 23 distribution. For comparability, risk estimates for formaldehyde were combined at a common 24 level of 0.1 ppm. This level was selected because it is close to the PODs (LEC 005 s) used above 25 for leukemia mortality (0.121 ppm) and leuke mia incidence (0.0875 ppm), and leukemia is the 26 predominant cancer type in terms of extra risk. Note that unit risk estimates for the different 27 cancer types calculated at 0.1 ppm will differ slightly from those reported above (sections 5.2.2 28 and 5.2.3) be cause they are calculated at a level other than the PODs used in the above 29 calculations. To derive the combined risk, maximum likelihood estimates (MLEs) of risk and 30 their 95% upper bounds (UCLs) were calculated for each cancer type using the same methods 31
and life

- table programs employed in sections 5.2.2 and 5.2.3. The standard errors (SEs) were 32 then estimated from the risk estimates using the equation: UCL = MLE + 1.645 × SE. The 33 variances can then be calculated from the SEs according to the equation: Variance = SE 2 . The 34 sum of the variances then provides an estimate of the variance for the sum of the MLEs, and the 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 100 95% upper bound on the sum of the MLEs can be estimated by applying the above equations in 1
reverse. Tables 5

- 20 and 5

- 21 provide a summary of the results of these calculations for the 2 combined cancer mortality and incidence risks, respectively. 3
4
Table 5

- 20. Calculation of combined cancer mortality unit risk estimate at 5 0.1 ppm 6 7

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

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

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

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

8

a Unit risk = 95% upper bound on combined risk/0.1 ppm. 9 10 11 Table 5

- 21. Calculation of combined cancer incidence unit risk estimate at 12 0.1 ppm 13 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 risk a (per ppm) 8.10 × 10
– 2

15

a Unit risk = 95% upper bound on combined risk/0.1 ppm. 16This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 101 As can be seen from the results in Table 5

- 20, the upper bound risk estimates for cancer 1 mortality for the individual cancer types at 0.1 ppm a re within 10% of the values that would be 2 obtained from the unit risk estimates derived in sections 5.2.2 and 5.2.3 (Tables 5

- 10, 5

- 16, and 3
5

- 17). Furthermore, the combined unit risk estimate for mortality for the three cancer types 4 (4.5 × 10
– 2 per ppm) is appropriately bounded by the mortality unit risk estimate for leukemia 5 (4.1 × 10
– 2 per ppm), which has the highest individual mortality unit risk estimate, and by the 6 sum (5.2 × 10
– 2 per ppm) of the individual unit risk estimates presented in sections 5 .2.2 and 7 5.2.3. Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of 8 the MLEs and the sum of the 95% upper bounds for the individual risks calculated at 0.1 ppm. 9 Thus, the value of 4.5 × 10
– 2 per ppm (3.7 **×** 10
– 5 per μg/ m 3 ) calculated at 0.1 ppm for the 10 combined unit risk is a reasonable estimate for the total cancer mortality unit risk (based on the 11 three cancer types considered). 12
As can be seen from the results in Table 5

- 21, the upper bound risk estimates for cancer 13
in cidence for the individual cancer types at 0.1 ppm are within 33% of the values that would be 14 obtained from the unit risk estimates derived in sections 5.2.2 and 5.2.3 (Tables 5

- 13, 5

- 20, and 15
5

- 21). Furthermore, the combined (incidence) unit risk estimate for the three cancer types 16 (8.1 × 10 −2 per ppm) is appropriately bounded by the unit risk estimate for leukemia 17 (5.7× 10 - 2 per ppm), which has the highest individual unit risk estimate, and by the sum (8.6 × 18
10
– 2 per ppm) of the individual unit risk estimates presented in sections 5.2.2 and 5.2.3. 19 Similarly, the combined risk calculated at 0.1 ppm is necessarily bounded by the sum of the 20 MLEs and the sum of the 95% upper bounds for the individual risks calculated at 0.1 ppm. 21 Thus, the value of 22
8.1 × 10 −2 per ppm (6.6 **×** 10
– 5 per μg/m 3 ) calc ulated at 0.1 ppm for the combined unit risk is a 23 reasonable estimate for the total cancer unit risk (based on the three cancer types considered). 24 As documented in section 4.5, formaldehyde is a 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 chemical

- specific data to evaluate susceptibility 27 of different life stages, increased early

- life susceptibility should be assumed, and, if there is 28 early

- life exposure, the age

- dependent adjustment factors (ADAFs) should be applied in 29
accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early

- Life 30 Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 below fo r more details on the 31 application of the ADAFs. 32
33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 102 5.3. DOSE

- RESPONSE MODELING OF RISK OF SQUAMOUS CELL CARCINOMA 1 IN THE RESPIRATORY TRACT USING ANIMAL DATA 2 In the previous section, dose

- response analyses based on human data for 3 lymphohematopoietic cancer and NPC were presented. The dose

- response analyses of cancer 4 risk presented in this section are based on nasal tumor data from laboratory bioassays using F344 5 rats. Because the analyses involved are extensive, most of the details are provided in the 6 appendi ces. 7 An increased incidence of nasal squamous cell carcinoma (SCC) was seen in two long

8 term bioassays using F344 rats (Monticello et al., 1996; Kerns et al., 1983). Although other 9 studies in laboratory animals exist, these two studies, when combined, pr ovide the most robust 10 data for analyses. These inhalation data on nasal SCC tumor incidence were used to estimate 11 human respiratory cancer risk in the nose and were also extrapolated to the entire respiratory 12 tract; in other words, a site concordance betw een rat and human is not assumed. This is 13 reasonable because the respiratory and transitional epithelial cell types considered to be at risk 14 of SCC in the upper respiratory tract are also prevalent in the lower human respiratory tract, and 15 there is greate r penetration of formaldehyde flux posteriorly in the nose and in the rest of the 16 human respiratory tract relative to that of the rat. These considerations are strengthened by the 17 findings of DNA

- protein cross

- links (DPXs) in the proximal portions of the rhesus monkey 18 lower respiratory tract (Casanova et al., 1991). In addition, some epidemiologic studies 19 (Gardner et al., 1993; Blair et al., 1990, 1986) reported an increase in lung cancer associated 20 with formaldehyde exposure, while others (Collins et al. , 1997; Stayner et al., 1988) reported no 21
such increases. 22 EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a BBDR model for 23 extrapolation when data permit. A BBDR model for formaldehyde was developed by scientists 24
at the CIIT Centers for Health R esearch (see Appendix D) (Conolly et al., 2004, 2003, 2000; 25 Kimbell et al., 2001a, b; Overton et al., 2001; CIIT, 1999), which interfaced several models to 26 combine the extensive mechanistic information available in studies involving the F344 rat and 27
rhesus monkey and time

- to

- tumor incidence data in long

- term bioassays, as shown by the 28 schematic in Figure 5

- 11. This mechanistic information included formaldehyde and DPX 29 dosimetry in the rat, monkey, and human airways and cell proliferation data in the rat na sal 30 lining. This document presents extensive evaluation of the underlying models and data and of 31 the alternative parametrizations of the models that were also explored for the purpose of the 32 current assessment (see Appendix E, Appendix F). A summary of c onclusions is presented in 33 section 5.3.3. In particular, the following conclusions by EPA were critical in determining how 34 the models could be used to inform the quantitative dose

- response assessment: 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 103 **•** When used to model the dose

- response in the range of t he available data, the BBDR 1 models were judged to have the advantage of being more accurate and biologically based 2 (than purely statistical descriptions such as the multistage

- weibull model) and allowing 3 utilization of various data in an integrated manner. 4

**•** Variations to the modeling in Conolly et al. (2003) were examined. Each of these models, 5 including the modeling in Conolly et al., was judged to be just as biologically plausible 6 as the other, described the rat tumor incidence equally well, was based on different 7 characterizations of the same empirical cell kinetic data, and was based on the same 8 empirical data on DPX measurements. However, the added human risk over baseline 9 levels estimated by these models (including the original model) ranged from negat ive to 10 large positive values at environmental exposure concentrations. 11

**•** When used for the purpose of extrapolating risk, the BBDR models did not appear to 12 reasonably constrain either risk estimates extrapolated to human exposures or risk 13
estimates for the F 344 rat when they were extrapolated below the range of observable 14
data. 15

**•** Because human respiratory cancer risk calculated in Conolly et al. (2004) was 16 numerically unstable, clonal growth modeling was not found to be a useful approach for 17 human extrapolatio n of rodent risk estimates. 18

**•** Thus, the biologically based derivation of human risk estimates in Conolly et al. (2004) 19 cannot be characterized as a plausible upper bound in the face of model uncertainties (a 20 key conclusion of those authors). 21
22
For all these r easons, the BBDR modeling of the rat data 23

**•** was employed in this assessment to derive multiple PODs (for SCC in the respiratory 24 tract) in the range of the observed data and using model

- derived internal dose estimates, 25

**•** but was not used to extrapolate far bel ow the observed data., 26
27 The inhalation unit risk estimates of SCC in the human respiratory tract were derived by 28 using multiple methods to model the F344 tumor incidence data as follows: conventional 29 mutistage Weibull time

- to

- tumor modeling and variation s of the model implemented in Conolly 30 et al. (2003) that were considered in the process of the evaluation. 31 PODs were calculated as exposure concentrations corresponding to the 95% statistical 32 upper bound extra risks of 0.005, 0.01, and 0.05 (0.005 used onl y with BBDR modeling). The 33 inhalation unit risk for SCC in the human respiratory tract (upper and lower) derived from the 34 above animal bioassay data was then calculated by linear extrapolation to the origin from the 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 104 POD. Linear extrapolation is supported in part by the proven genotoxicity of the chemical and 1 the observation of cytogenetic effects in human occupational exposures (see chapter 4). In 2 particular, the formation of DPXs on formaldehyde interaction with DNA has been observed at 3
doses well below those considered cytotoxic. In results obtained in some implementations of the 4 biologically based models, formaldehyde

- induced mutagenicity (modeled as proportional to 5 DPX concentration) was found to be a critical determinant of its tumorigenicity, both at the low 6 dose pertaining to human exposure concentrations as well as in the dose range in which 7 formaldehyde is considered to be cytotoxic. 8 The human equivalent concentration was calculated by assuming that continuous lifetime 9 exposure to a given steady

- state flux of formaldehyde (expressed in pmol/mm 2

- hour) leads to 10 equivalent risk of nasal cancer across species. Risk per respiratory or transitional epithelial cell 11 with replicative potential in a given region was computed as a function of formaldehyde f lux in 12 the nasal region and extrapolated to the rest of the respiratory tract. 13
14
5.3.1. L ong - Term B ioassays in L aboratory A nimals 15 This section briefly describes the various animal data and dosimetry information utilized 16 in the above (but not in all) mode ls, based on which estimates for the inhalation unit risk are 17 derived later in this chapter. 18
19
5.3.1.1. Nasal Tumor Incidence Data 20 Various bioassays have reported the effects of formaldehyde on rats, mice, and rhesus 21 monkeys and have been discussed at len gth earlier in this document. Two of these bioassays 22 ( Monticello et al., 1996; Kerns et al., 1983) , when combined, allow for the most robust 23 characterization of the long

- term dose response in a laboratory species. These long

- term 24 bioassays found an incre ased incidence of nasal SCCs in rats exposed to formaldehyde by the 25 inhalation route. In these combined data, rats were exposed to 0, 0.7, 2.0, 6.01, 9.93, and 26
14.96 ppm (0, 0.86, 2.5, 7.4, 12.2, and 18.4 mg/m 3 ) exposure concentrations of formaldehyde. 27
S CCs were observed only at 6.01 ppm and higher exposure concentrations. Table 5

- 22 provides 28 a summary of the tumors from these bioassays, and the time

- to

- tumor characteristics are as 29 shown by the data in Figure 5

- 12 (in section 5.3.3). The focus here is o n these two bioassays, 30 combined, because they provide the most extensive chronic dose

- response information. Other 31 tumor bioassays were also conducted by various researchers and have been detailed in chapter 4. 32
33 34 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 105 Table 5

- 22. Summary of tumor incidence in long

- term bioassays on 1 F344 rats 2 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 Sources: Combined data from Monticello et al. (1996) and Kerns et al. (1983). 5 6 7 5.3.1.2. Mechanistic Data 8
The Kerns et al. (1983) and Monticello et al. (1996) tumor studies were accompanied or 9 followed by additional studies that provided extensive mechanistic information on bo th 10 pharmacokinetics and pharmacodynamics. These studies have been summarized elsewhere in 11 this document and in other reviews (CIIT, 1999; Monticello and Morgan, 1997; Morgan, 1997; 12 Heck et al., 1990). In addition to the tumor incidence data, the followin g data and mechanistic 13 information (some of which were model derived) are used in the quantitative models utilized in 14 this chapter. In all these cases, additional data for the rhesus monkey are also available that 15
inform the hazard assessment but which ha ve not been explicitly used in deriving the inhalation 16 unit risk. Rhesus monkey data have been discussed in chapter 4 and chapter 3 (DPX and 17 formaldehyde dosimetry). 18

**•** Formaldehyde interacts with DNA to form DPXs. These cross

- links are considered to 19
induce mutagenic as well as clastogenic effects. Casanova et al. (1994, 1989) carried out 20 two studies of DPX measurements in F344 rats. In the first study, rats were exposed to 21 concentrations of 0.3, 0.7, 2, 6, and 10 ppm for 6 hours and DPX measurements were 22 made over the whole respiratory mucosa of the rat, while, in the second study, the 23 exposure was to 0.7, 2, 6, or 15 ppm formaldehyde for 3 hours and measurements were 24 made at “high” and “low” tumor sites. DPX formation was observed at all exposure 25

concent rations in both studies (0.3 ppm

– 15 ppm); the DPX levels were statistically 26 significantly elevated at concentrations ≥2 ppm, with the trend also indicating elevated 27 DPXs at 0.7 ppm. These data were used in the development of a PBPK model for 28 predicting DPX levels in the nasal lining (see chapters 3 and 4). 29This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 106 **•** Male F344 rats were exposed to formaldehyde gas over a range of concentrations (0, 0.7, 1 2, 6, 10, or 15 ppm) in two phases of a labeling study. The first phase (Monticello et al., 2 1991) employed inje ction labeling with a 2

- hour pulse labeling time, and animals were 3 exposed to formaldehyde for periods of 1, 4, and 9 days and 6 weeks. The second phase 4 (Monticello et al., 1996) used osmotic minipumps for labeling with a 120

- hour release 5 time to quantify labeling in animals exposed for 13, 26, 52, and 78 weeks. These data 6 have been analyzed at length in Appendix E. 7

**•** Physical and computer models of airflow in anatomically realistic representations of the 8 F344 rat and human upper respiratory tract have been constructed (Kimbell et al., 1993, 9 1997; Kepler et al., 1993; Subramaniam et al., 1998; see chapter 3). 10

**•** Regional uptake of formaldehyde has been calculated for the upper respiratory tract of 11 the rat and human by using the above computer representations an d for the lower 12 respiratory tract of the human by using an idealized representation of the human lower 13 respiratory tract (Kimbell et al., 2001a; Overton et al., 2001; also see chapter 3 and 14 further discussion of uncertainties in Appendix F). 15
16
5.3.2. The C IIT Biologically Based Dose

- Response Modeling 17 The studies mentioned above in 5.3.1.1 and 5.3.1.2 were generated at the CIIT Centers 18 for Health Research and led to the development of a biologically motivated dose

- response model 19 for formaldehyde

- induced can cer as represented in a series of papers and in a health assessment 20 report (CIIT model) (Conolly et al., 2004, 2003, 2000; Conolly, 2002; Kimbell et al., 2001a, b; 21 Overton et al., 2001; CIIT, 1999). EPA’s cancer guidelines (U.S. EPA, 2005a) suggest using a 22 BBDR model for extrapolation when data permit since it facilitates the incorporation of MOA in 23
risk assessment . The CIIT modeling and available data were evaluated in a series of peer

24 reviewed papers (Klein et al., 2009; Crump et al., 2008; Subramaniam e t al., 2008, 2007) and 25 debated further in the literature (Conolly et al., 2009; Crump et al., 2009). Alternatives to the 26 parametrization and model structure in the CIIT biological modeling (but based on that original 27 model) are further explored and evalua ted in this assessment (Appendix E). Appendix F carries 28 out a sensitivity analysis of the human risk estimates in Conolly et al. (2004) based on key 29 uncertainties evaluated in Appendix E. These BBDR models are used in this assessment to 30
calculate PODs fr om the dose

- response curve for the F344 rat nasal tumor risk. Extrapolation to 31 human is then carried out by using EPA’s baseline (“default”) approach (U.S. EPA, 1994) but 32 using model

- derived internal dose metrics. See section 5.3.3 for rationale supporti ng these 33
decisions. 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 107 First, the key features of the BBDR modeling in Conolly et al. (2003, 2004) are briefly 1 described, and the following notation is used throughout this section: N cell = normal cell; I cell 2 = initiated cell; LI = labeling index and is equ al to the number of labeled cells/(number labeled + 3 unlabeled cells); ULLI = unit length LI equal to the number of labeled cells/length of basement 4 membrane; **α** N = division rate of normal cells (hour
– 1 ); μ N = rate at which an initiated cell is 5 formed by mut ation of a normal cell (per cell division of normal cells). 6 In Conolly et al. (2003), tumor incidence data in the Kerns et al. (1983) and Monticello et 7 al. (1996) long

- term bioassays were modeled by using an approximation of the two

- stage clonal 8 growth mod el (Moolgavkar et al., 1988) and allowing formaldehyde to have a direct mutagenic 9
action. Conolly et al. (2003) combined these data with historical control data on 7,684 animals 10 obtained from National Toxicology Program (NTP) bioassays. These models are based on the 11 Moolgavkar, Venzon, and Knudson (MVK) stochastic two

- stage model of cancer (Moolgavkar 12 et al., 1988; Moolgavkar and Knudson, 1981; Moolgavkar and Venzon, 1979), which accounts 13 for growth of a pool of normal cells, mutation of normal cells to i nitiated cells, clonal expansion 14 and death of initiated cells, and mutation of initiated cells to fully malignant cells. 15 The MVK model for formaldehyde accounted for two MOAs as follows that may be 16 relevant to formaldehyde carcinogenicity: 17
1. An indirect MO A in which the regenerative cell proliferation in response to formaldehyde 18 cytotoxicity increases the probability of errors in DNA replication. This MOA was modeled 19 by using labeling data on normal cells in nasal mucosa of rats exposed to formaldehyde. 20
2. A possible direct mutagenic MOA, based on information indicating that formaldehyde is 21 mutagenic (Speit and Merk, 2002; Heck et al., 1990; Grafström et al., 1985), was modeled by 22 using rat data on formaldehyde production of DPXs (Monticello et al., 1996, 19 91). In 23 Conolly et al. (2003), the intracellular dose that induces mutations is considered proportional 24
to the local DPX dose. 25
26 The human model for formaldehyde carcinogenicity (Conolly et al., 2004) is 27 conceptually very similar to the rat model. The mo del uses, as input, results from a dosimetry 28 model for an anatomically realistic representation of the human upper airways and an idealized 29 representation of the lower airways. However, the model does not incorporate any data on 30 human responses to formald ehyde exposure. 31 A novel contribution of the CIIT model, described by the schematic in Figure 5

- 11, is 32 that cell replication rates and DPX concentrations are driven by local dose, which is 33 formaldehyde flux to each region of nasal tissue expressed as pmol /mm 2

- hour . This dosimetry is 34 predicted by computational fluid dynamics (CFD) modeling using anatomically accurate 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 108 representations of the nasal passages of a single F344 rat or Caucasian male human (see 1 chapter 3). Such a feature is important in incorpora ting site

- specific toxicity in the case of a 2 highly reactive gas like formaldehyde for which uptake patterns are spatially localized and 3 significantly different across species (see chapter 3) . In the CIIT model, each of these 4 parameters is characterized b y local flux (see Figure 5

- 11). The inputs to the two

- stage cancer 5 modeling consisted of results from other model predictions as well as empirical data as follows: 6

**•** Regional uptake of formaldehyde in the respiratory tract was predicted by using CFD 7
modelin g in the F344 rat and human (Kimbell et al., 2001a, b; Overton et al., 2001; 8 Subramaniam et al., 1998). 9

**•** Normal cell replication rates were inferred from LI data on rats exposed to formaldehyde 10 (Monticello et al., 1996, 1991, 1990). 11

**•** Concentrations of DPXs l inked to the regional flux of formaldehyde were predicted by a 12 PBPK model (Conolly et al., 2000) calibrated to fit the DPX data in F344 rat and rhesus 13 monkey (Casanova et al., 1994, 1991) and subsequently scaled up to humans. The DPX 14
concentration levels were incorporated into the two

- stage clonal expansion model by 15 defining mutation rate of normal and initiated cells as the same linear function of DPX. 16 That is, 17
18

μ N = μ I = μ Nbasal + KMU × DPX (5

- 1) 19
20 where μ N is the rate at which an initiated cell is formed by mutation of a normal cell (per 21 cell division of normal cells), and likewise μ I is the rate at which a malignant cell is 22 formed by mutation of an initiated cell (per cell division of initiated cells). The unknown 23 constants μ Nbasal (the baseline rate) and KMU were estimated by fitting model predictions 24 to the tumor bioassay data. 25
26 The rat model in Conolly et al. (2003) involved six unknown statistical parameters that 27 were estimated by fitting the model to the rat formaldehyde bioassay data shown in Table 5

- 22 28 ( Monticello et al., 1996; Kerns et al., 1983 ) plus data from several thousand control animals 29 from all the rat bioassays conducted by the NTP. These NTP bioassays were conducted from 30 1976 through 1999 and included 7,684 animals with an incid ence of 13 SCCs (i.e., 0.17% 31 incidence). The resulting model predicts the probability of a nasal SCC in the F344 rat as a 32 function of age and exposure to formaldehyde. The fit to the tumor incidence data is shown in 33 Figure 5

- 12 (in section 5.3.3.). (For later reference in Appendix E, this figure compares the fit to 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 109 the data obtained by the modeling in Conolly et al. [2003] with that obtained by the 1 reimplementation of this model in Subramaniam et al. [2007].) 2 Subsequent to the BBDR model for modeling rat cancer, Conolly et al. (2004) developed 3 a corresponding model for humans for the purpose of extrapolating the risk to humans estimated 4 by the rat model. Also, rather than considering only nasal tumors, the model is used to predict 5
the risk of all human r espiratory tumors. The human model for formaldehyde carcinogenicity 6 (Conolly et al., 2004) is conceptually very similar to the rat model and follows the schematic in 7 Figure 5

- 11 . The following points need to be noted: 8
9

**•** The model does not incorporate any data on human responses to formaldehyde exposure. 10

**•** The model is based on an anatomically realistic representation of the human nasal 11 passages (in a single individual) and an idealized representation of the lower respiratory 12 tract. Local formaldehyde flux to respiratory tissue is estimated by a CFD model for 13 humans (Kimbell et al., 2001a; Overton et al., 2001; Subramaniam et al., 1998). 14

**•** Rates of cell division and cell death are, with a minor modification, assumed to be the 15
same in humans as in rats. 16

**•** The co ncentration of formaldehyde

- induced DPXs in humans is estimated by scaling up 17 from values obtained from experiments in the F344 rat and rhesus monkey (Conolly et 18 al., 2000, and also discussed further in section 3.6.6 of this document). The statistical 19

para meters for the human model are either estimated by fitting the model to the human 20 background data, assumed to have the same value as that obtained in the rat model, or, in 21 one case, fixed at a value suggested by the epidemiologic literature. The human val ue for 22 KMU in eq 1 is obtained by assuming that the ratio KMU/μ basal is invariant across 23 species. 24
25 Some further clarification pertaining to the structure and calibration of the models in 26 Conolly et al. (2004, 2003) that are key to understanding model assu mptions is provided in 27 Appendix D. 28
29This document is a draft forreview purposes only and doesnot constitute Agency policy5-110DRAFT—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; α N , N(t), μ N 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 

## α N 

## α I



## β I 

## = α N 

## μ N 

## μ I 

## = **μ** N 

## 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 

## α N 

## α I



## β I 

## = α N 

## μ N 

## μ I 

## = **μ** N 

## D DPX in Rat
DPX in Monkey DPX in Human Respiratory tract PBPK models for DPX

faldh in air + Human Lung 

### input

inputThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 111 5.3.2.1. Major Results of the CIIT Modeling Effort 1
Based on the biol ogically based modeling of the rat SCC data, CIIT (1999) and Conolly 2 et al. (2004, 2003) presented the following major conclusions. The evaluation of the strength of 3 these conclusions is summarized in section 5.3.3., and as addressed in that section, this current 4 assessment is not in agreement with these conclusions. 5

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

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

**•** Therefore, exposure standards protective of effects of formaldehyde

- induced cytotoxicity 13 should be sufficient to protect from its potential carcinogenic effects. 14

**•** The human risk e stimates in Conolly et al. (2004) were judged by the authors to be 15
conservative in the face of model uncertainties because the model included a hockey

16 stick model for normal cell replication rates when the cell replication dose

- response 17 curve as averaged b y the authors had a J shape, used overall respiratory tract cancer 18 incidence data in humans, and evaluated the model at the statistical upper bound of the 19 proportionality parameter relating DPXs to the probability of mutation. 20

**•** The dose

- response assessment in Conolly et al. (2004) did not explicitly evaluate the risk 21 of lymphohematopoietic cancers. However, Conolly et al. (2004) argued that 22 formaldehyde was unlikely to cause the cancers reported in Hauptmann et al. (2003). 23 Their reasoning was based on the s teepness of the dose

- response curve predicted in 24 Conolly et al. (2004) for respiratory cancer at exposures of 1 ppm and above and the 25 conclusions in Heck and Casanova (2004). 26 27 5.3.3. This Assessment’s Conclusions from Evaluation of Dose

- Response Models o f DPX, 28 Cell

- Replication and Genomics Data, and of BBDR Models for Risk Estimation 29 The CIIT modeling and alternative approaches that were developed based on the 30 conceptual framework in that modeling were extensively evaluated for this assessment and are 31

pr esented in Appendices D, E (BBDR modeling of the rat data), and F (sensitivity analysis of 32 BBDR model results for human risk). In particular, Table E

- 1 in Appendix E and Table F

- 1 in 33 Appendix F list all the uncertainties and assumptions that were examined and summarize the 34 results of the evaluation. The quantitative and qualitative characterization of the cell replication 35 data from Monticello et al. (1996, 1991) are presented in Appendix E. The most significant 36This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 112 conclusions resulting from these various an alyses, focusing on the ones that have maximal 1 impact on the dose

- response assessment, are presented below

. 2 3 Description of time

- to

- tumor data 4 The overall approach and use of data in Conolly et al. (2004, 2003) have substantial 5 advantages to offer in desc ribing the dose response observed in animal bioassays. The authors’ 6 model provides a good statistical description of the time

- to

- tumor data. The fit to the data was 7 found to be superior to that obtained by using multistage Weibull time

- to

- tumor modeling of the 8 tumor incidence data (comparison based on visual inspection [see Figure 5

- 12 in this section and 9 Figures 5

- 17, 5

- 18, 5

- 19 in section 5.3.4]). 10 11

Figure 5

- 12. Fit to the rat tumor incidence data using the model and 12 assumptions in Conolly et al. (20 03). 13 Note: Fitting was performed on data of Kerns et al. (1983) and Monticello et al. (1996) combined 14 with ALL NTP historical controls under the assumption that all SCCs are fatal. Figure compares 15 the fit obtained by Conolly et al. (2003) with the reprodu ction of these results under identical 16 conditions, inputs, and assumptions by Subramaniam et al. (2007). There were minor residual 17 differences among the implementations; see the appendix in Subramaniam et al. (2007) for 18 explanation. 19 Source: Subramaniam e t al. (2007). Reprint permission required. 20 21 Subramaniam et al. fit 0 200 400 600 800 1000 0.0000 0.0005 0.0010 0.0015 0.0020

0 200 400 600 800 1000 0.00 0.05 0.10 0.15 0.20

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

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

Kaplan-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 1.0Probability

Kaplan-Meier Conolly fit Our fit Age (days)Probability

Age (days)

0 ppm 6 ppm

10 ppm 15 ppmThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 113 Integration of various relevant data 1 The model framework integrates various pharmacokinetic and pharmacodynamic 2 components (regional formaldehyde flux, DPX, cell

- replication, and tumor incidence data) 3
within a single conceptual framework and thus facilitates description of the dose response that 4 utilizes the extensive mechanistic information available for formaldehyde. 5
6 Regional dosimetry 7 Regional (site

- specific) dosimetry in the upper respiratory tract is cons idered important 8 for understanding the tumorigenicity of a reactive chemical like formaldehyde. The regional 9 dosimetry models discussed in chapter 3 compute local formaldehyde flux to the tissue and are 10 based on anatomically realistic constructions of the nasal airways in each species. The other 11 relevant mechanistic data, DPX and cell replication, are expressed as a function of this local 12 formaldehyde flux. 13
14 Confidence in dosimetry 15 Model predictions of formaldehyde flux to the respiratory lining have not been verified 16 experimentally, and such verification would present formidable experimental challenges. 17 Overall, the formaldehyde dosimetry modeling utilized in the CIIT modeling presents a 18 reasonable level of confidence, as detailed in chapter 3, section 3.6, by virtue of agreement 19 among multiple model predictions (models that predict airflow profiles as well as a PBPK model 20 for DPX, which uses the calculated formaldehyde flux as input) and various kinds of available 21 data. These data comprise airflow prof iles in physical casts of the nasal cavity of an F344 rat 22 (Kimbell et al., 2001a), a human (Subramaniam et al., 1998), and a rhesus monkey (Kepler et al., 23 1998); DPX data (see discussion of Cohen

- Hubal et al. [1997] in chapter 3); and qualitative 24
concordan ce between uptake patterns and cell proliferation (Morgan et al., 1997; Monticello et 25 al., 1996). The CFD models of formaldehyde flux represent only an individual of each species. 26 However, considerable interindividual differences are to be expected in th e regional dosimetry, 27 particularly in the human (Garcia et al., 2009: Subramaniam et al., 2008). This is discussed 28 briefly in Chapter 3 (section 3.6) and further in Appendices B and F. 29
30
Control tumor data 31 In developing their model, Conolly et al. (200 4, 2003) included control rats from all NTP 32 cancer bioassays

— a total of 7,684 rats. The inclusion of all NTP historical control animals does 33 not appear to be supportable and substantially alters dose

- response predictions (Crump et al., 34 2009, 2008; Subrama niam et al., 2008, 2007). There are legitimate questions regarding 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 114 comparability of results in rats from different stocks, studied at different times, in different 1 laboratories, and by different routes of exposure and evaluated by using somewhat different 2 pathological procedures. If historical controls are used from only those inhalation studies that 3 present a low potential for genetic and time

- related variations in tumor incidence and survival of 4 animals or if only concurrent controls are used, the model for extrapolation of risk to humans 5 (the human BBDR model) becomes numerically unstable. In such a model, it is not possible to 6 bound human risk by using the extrapolation approach applied in the CIIT model. When the 7
included NTP control data were restr icted to all NTP inhalation controls, the upper bound human 8 risk estimate obtained by Conolly et al. (2004) was increased by 50

- fold (Crump et al., 2008). 9
10 Cell replication dose response 11 As discussed in chapter 4, characterization of the uncertainties and variability in the cell 12 replication dose response is crucial to understanding formaldehyde carcinogenicity. Analyses of 13 the dose response for cell replication presented in Appendix E demonstrate the following: 14

**•** Sustained exposure to formaldehyde affects c ell division rates (compared to baseline 15 levels). This effect is seen over a continuum of formaldehyde flux to the nasal lining that 16 includes flux levels below those thought to be cytotoxic. 17

**•** Given the qualitative and quantitative uncertainties in the dat a and in their interpretation, 18 a variety of cell replication dose

- response models are plausible as reasonable 19 characterization of the data. Cell replication response differs substantially among nasal 20 sites and over time during the course of the bioassay. In consideration of these 21 differences, the shape of the cell replication low

- dose response could be alternatively 22
described as monotonic or non

- monotonic. For example, rather different statistical 23 descriptions of the data result depending on whether 24
i. dif ferent sites and exposure times were modeled separately; 25
ii. all exposure times were pooled to model the response at each site; 26
iii. the labeling index was time

- weighted and averaged over all sites; 27
iv. flux and labeling index were weighted by the number of cells at a given site; 28

v. the short exposure durations in Monticello et al. (1991) were examined separately. In 29 addition, transient increases in cell turnover at sub

- cytotoxic doses are seen in other 30 experiments in rats exposed to formaldehyde (see chapter 4). 31

**•** At h igher, cytolethal formaldehyde flux levels, regenerative hyperplasia

- induced cell 32 proliferation clearly takes over. 33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 115 Genotoxicity 1 Chapter 4 provides multiple lines of evidence to characterize formaldehyde as a 2 genotoxicant. Of particular note is the ob servation of cytogenetic effects at human occupational 3 exposures and the formation of DPXs upon formaldehyde interaction with DNA at doses well 4 below those considered cytotoxic. As noted earlier, DPX formation was detected in rats at 5 exposures ranging fro m 0.3 ppm to 15 ppm. These DPX levels are seen to be statistically 6 significantly increased over baseline levels at 2 ppm and above. The DPX measured at 0.7 ppm 7 shows a trend that is consistent with an increase at this dose (see chapter 3); while not 8
stati stically significant, it is critical to consider “trend” when analyzing low

- dose data. 9
10 Inferences on MOA from modeling the data 11 The highly curvilinear nature of dose responses associated with DPX formation, LI data, 12 and tumor response as well as mechanis tic interpretation of these observed data has provided 13 grounds for arguments in the literature that formaldehyde tumorigenicity (at exposures ≥6 ppm) 14 should be uncoupled from its potential carcinogenicity in the low

- dose region. Furthermore, 15
researchers h ave argued that any potential low

- dose risk is due to its mutagenicity, that this 16 mutagenic potential is too weak to be of significance, and that the high

- dose risk is entirely due 17 to cell proliferation induced by regenerative hyperplasia in response to ce ll injury at cytotoxic 18 doses (i.e., without a relevant role for the direct mutagenic action of formaldehyde). Conolly et 19 al. (2004, 2003) represented a quantitative expression of this point of view. However, alternative 20 parametrizations of the model in C onolly et al. (2004, 2003) have shown that the mutagenic 21 component can be important in explaining the high

- dose effect and that the risk at low dose due 22 this mutagenicity can be significant (Subramaniam et al., 2007; Appendix E). Accordingly, the 23
dose

- res ponse assessment in this document does not treat formaldehyde as a threshold 24 carcinogen. 25
Of further relevance to mode

- of

- action considerations, analyses detailed in Appendix E 26
indicate that the chronic rat nasal time

- to

- tumor incidence data can be quanti tatively explained, 27 and with equal force, by invoking any of the following multiple sets of plausible events induced 28 by formaldehyde. The role of spontaneously occurring mutations and increased cell turnover 29 rates in response to various baseline insults t o the nasal lining are common to all these scenarios 30 (and are not separately mentioned). 31

a. Mutations occur over a dose continuum that includes sub

- cytotoxic and cytotoxic levels of 32 exposure. The only cell proliferation induced by formaldehyde is a regenerat ive response at 33 cytotoxic concentrations. 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 116 b. Cytotoxicity

- induced regenerative cell proliferation occurs, but there is no significant 1 formaldehyde

- induced mutational effect. This latter scenario expresses arguments that 2 formaldehyde

- induced mutagenicity may be too weak to be of significance to its 3 tumorigenicity. 4

c. Both mutations and cell proliferation are induced by formaldehyde only at cytotoxic levels. 5
d. Mutational events occur and cell replication is altered over a continuum that includes low 6 and high levels of exposure. 7
i. At high dose, the effect on cell replication is regenerative. 8
ii. At lower doses, the data indicate that both monotonic and non

- monotonic dose

9 response curves for cell replication are plausible. 10
iii. With respect to the previous argument, the followin g result was very instructive. The 11 models were exercized with normal cell replication rates considered to be less than 12 (non

- monotonic) or equal to (threshold) baseline rates over a segment of the low

- dose 13 range in conjunction with the chronic time

- to

- tumo r data for the F344 rat. Such a 14 scenario did not necessarily lead to lower than baseline or threshold in formaldehyde 15 respiratory cancer risk in the rat in that low

- dose range. This is partly because there 16 are no data to inform how formaldehyde

- induced m utation might alter cell replication 17 and apoptotic rates (in particular if the mutation is to be construed as an initiating 18 event in the carcinogenesis). 19

e. Formaldehyde

- induced mutagenic action acts only in concert with baseline cell turnover at 20
low dose. 21
22 Kinetics of initiated cells 23 Modeling results are hypersensitive to the division and death rate of initiated cells that 24 cannot be further inferred by the available empirical cell labeling data (Conolly et al., 2009; 25 Crump et al., 2009, 2008). Several plau sible alternate model structures for describing initiated 26 cell kinetics, none of which degrade the agreement of the model with the underlying data used to 27 construct the model originally, led to low

- dose risk estimates in the rodent that varied by many 28
orde rs of magnitude, including negative values (see Figures E

- 5A,B and E

- 6A,B in Appendix E). 29 Extremely small perturbations in the division rate (and, likewise, of death rates) of initiated cells 30 in the model lead to human risk estimates ranging anywhere from negative values to +0.01 at 31 0.01 ppm (see Crump et al. 2008 and Appendix F, Figure F

- 5). These perturbations were small 32 compared with the normal variation in the division rates of normal cells. 33 The sensitivity analyses on the basis of which these concl usions were reached have been 34 criticized as resulting in implausible risk estimates (given the epidemiologic data) as a 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 117 consequence of implementing model variations that are not biologically reasonable (Conolly et 1 al. 2009). This criticism was rebutted by Crump et al. (2009) on biological and epidemiological 2 grounds. These debates are discussed fully in Appendix F. 3 In addition, there are major qualitative uncertainties in extrapolating normal cell 4 replication rates from the rat to human (Table F

- 1 in Append ix F, and Subramaniam et al. 5 [2008]). Subramaniam et al. (2008) concluded that several inferences that arise from the 6 assumptions in the CIIT model on initiated cell replication and death rates cannot be supported 7 by available biological information. 8
9
R isk extrapolation 10 Use of the modeling approach in Conolly et al. (2004) or the variations examined were 11 determined not to be informative for extrapolation from animal to human at any exposure 12 concentration because of extreme sensitivity, including numeric al instability, to uncertain model 13 assumptions. In the face of model uncertainties, the biologically based derivation of human risk 14
estimates of 10
– 6 or less at exposures of 0.1 ppm and below in Conolly et al. (2004) or CIIT 15 (1999) cannot be characterized as a plausible upper bound. 16 The use of this model for extrapolation of risk from high to low exposures in the rodent 17 followed by a conventional (default) approach to extrapolate the low

- dose animal risk to the low

18
dose human risk was next evaluated. Th is avenue was also found not to be informative because 19 the models do not adequately constrain risk in the rodent. For example, various model 20 representations as shown in Figure E

- 6A,B in Appendix E were used to evaluate added MLE risk 21
at the 10
– 5 level (Fi gure F

- 5A,B in Appendix E) in the F344 rat. Human exposures were then 22 calculated that would result in equivalent lifetime risk by using formaldehyde flux estimated in 23 each species as the dosimeter and conventional extrapolation methods (U.S. EPA, 1994b). A 25

- 24 fold difference was found between the different models in the equivalent exposure concentration 25 so derived. Therefore, the CIIT model or its variations were also not used in this assessment as a 26 biologically based or biologically motivated means of extrapolating outside the observed dose

27 response in the F344 rat. Model uncertainty was substantially higher than the statistical 28 uncertainty arising out of a given model specification. 29 Thus, in view of all the above considerations and in accordance with EPA’s cancer 30 guidelines (U.S. EPA, 2005a), the derivation in this document of unit risk for human respiratory 31 cancer from animal bioassay data is based on a linear extrapolation to the origin from a POD on 32
the dose

- response curve. Low

- dose linearity was exhibited by the risk estimates from most of 33 the models that were examined in the sensitivity analysis (see discussion surrounding Figure E

34 5A,B in Appendix E). 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 118 BBDR modeling for deriving an “integrated” POD 1 The CIIT BBDR modeling approach provides a goo d fit to the time

- to

- tumor data and 2 therefore allows for an appropriate determination of a POD while at the same time incorporating 3 a large amount of mechanistic information in an integrated manner and allowing the use of 4
model

- derived internal dose estima tes. Thus, use of this model provides an alternative to 5 developing separate PODs based on several of the underlying components of the data, such as 6 DPX, flux, and labeling data. Accordingly, the model is used in this assessment to derive a POD 7
from a dos e response, based on the nasal cancers in rats. Uncertainties in the derivation of the 8 POD were represented by using the variations of the CIIT model examined in this chapter. 9
These POD calculations as well as others are detailed below. 10
11
Genomics data 12
T he genomics data of Thomas et al. (2007) and Andersen et al. (2008) provide additional 13 insight into formaldehyde’s biological effects and the steep dose

- response curve for 14 tumorigenesis. However, there are various limitations in the interpretation of thes e genomics 15 data and their relevance for the pathways contributing to the disease process in humans. In 16 particular, the data from these studies, as analyzed, do not inform the critical MOA questions 17 pertaining to formaldehyde carcinogenicity. These insigh ts have been elaborated in a separate 18 section in chapter 4, and the difficulties in the use and interpretation of the quantitative modeling 19 of these data, as presented in these studies, are detailed at length in Appendix G. 20
21
5.3.4. B enchmark Dose Approaches to Rat Nasal Tumor Data 22 This section describes various BMD analyses to determine PODs for low

- dose 23 extrapolation of SCC risk in the human respiratory tract (upper and lower). 24
25
5.3.4.1. Benchmark Dose Derived from BBDR Rat Model an d Flux as Dosimeter 26
5.3.4.1.1. Response for benchmark dose . Typically, the BMD is calculated at the 5 or 10% 27 response level. However, it appears appropriate to consider the benchmark response (BMR) at 28 lower levels in exceptional cases that are supported by empirical data. In the case of the 29 combined Kerns et al. (1983) and Monticello et al. (1996) bioassays, the lowest observed tumor 30 response of SCC was below the 1% level (at 0.85%) (see Table 5

- 22). Additionally, the BBDR 31 modeling incorporates precurs or response in the form of LI data. Therefore, it was determined 32 that it would also be appropriate to evaluate the POD at the 0.5% level while still staying in the 33 neighborhood of the experimentally observed response. 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 119 The various data presented earlier in this chapter point to highly curvilinear dose 1 responses for formaldehyde

- induced tumor incidence as well as DPX and cell replication. This 2 is also borne out by dose

- response information based on gene array data (Thomas et al. 2007; 3
Andersen et al. 200 8). Cytotoxicity

- driven regenerative replication and epithelial degeneration 4 play a critical role in the steeply rising nature of the tumor dose

- response. These observations 5 raise the concern that cancer potency derived by straight

- line extrapolation from the low end of 6 observed tumor data (roughly at the 1% response) has the potential to be a significant 7 overestimate for a reasonable upper bound. Thus, a pertinent question is what is a low

- dose 8
linear dose

- response modeling of the data that is statistica lly consistent with the uncertainties in 9
the observed time

- to

- tumor data. To address this question, the risk estimate based on the linear 10 extrapolation (from a POD to the origin) is compared with that predicted at the low

- dose end by 11 the Multistage Weibul l model fitted to the observed time

- to

- tumor data. The unit risk based on 12 this model is obtained by calculating q1*, the 95% statistical upper bound on the coefficient 13 associated with the linear term in the multistage model polynomial. This model fits th e data 14 reasonably well and reflects the highly curvilinear shape of the dose

- response because of its 15 mathematical flexibility while also allowing for low

- dose linearity. In particular, it has been 16 noted that even in cases where the first term (q1) in the multistage model is zero, the upper 17 bound (q1*) is linear with dose (Subramaniam et al., 2006; Guess et al., 1977). Thus, for 18 comparison the following estimates of unit risk are also
20 presented: 19

1) Unit risk that is based on q1*, which is derived from fittin g the multistage Weibull model to 21
the observed data. 22 2) Unit risk based on low

- dose linear extrapolation from a POD at the 0.5% level. 23
24
5.3.4.1.2. Dose metric. The dose metric used for the extrapolation was the average wall mass 25 flux of formaldehyde (expr essed in pmol/mm 2

- hour to the entire surface of the airway lining but 26 excluding tissue lined by non

- mucus

- coated squamous tissue, which was considered to not 27 absorb formaldehyde). The use of flux as a dosimeter is similar to the calculation of a regional 28 gas dose ratio (RGDR) as proportional to minute volume divided by the surface area in the given 29 species and is thus in line with EPA’s prescription for calculating a dosimetric adjustment factor 30 (DAF) for category 1 gases, whose effects are presumed to be at the POE (U.S. EPA, 1994b) 31 (i.e., ratio of average flux over the same respiratory region in each species = ratio of the quantity 32 [minute volume/surface area of the region] between the two species). This lends support to an 33 interspecies extrapolation bas ed on the equivalence of formaldehyde flux as a determinant of 34
risk. 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 120 The spatial distribution of formaldehyde over the nasal lining was characterized by 1 partitioning the nasal surface by formaldehyde flux to the tissue, resulting in 20 “flux bins” 2 (Figure 5

- 13). Each bin is comprised of elements (not necessarily contiguous) of the nasal 3 surface that receive a particular interval of formaldehyde flux per ppm of exposure 4 concentration (Kimbell et al., 2001a). The spatial coordinates of elements comprising a 5 particular flux bin are fixed for all exposure concentrations, with formaldehyde flux in a bin 6 scaling linearly with exposure concentration (ppm). The number of cells at risk varies 7 across the bins, as shown in Figure 5

- 14. 8
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 di stribution 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 5.3.4.1.3. Extrapolation to humans. For linear extrapolation from the 0.5 and 1% levels, two 14 alternative versions of the biologically based m odel in Conolly et al. (2003) for the F344 rat 15 were used. In both cases, only the historical control data from NTP inhalation studies data were 16 added to the concurrent controls and weekly averaged DPX concentrations as calculated by a 17
variant of the PBPK model in Conolly et al. (2000) [described in Subramaniam et al. (2007)] 18 were used. Both models provided good fits to the tumor incidence data, similar to the fit shown 19 in Figure 5

- 12. Neither model could be considered better than the other on the basis o f model 20 description of tumor incidence data. 21This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 121 In Model 1 the normal cell replication dose response was described by the same 1 hockey

- stick

- shaped curve used in Conolly et al. (2003). The form of the dose

- response 2 curves for initiated cell kinetics (divisio n and death) was also the same as that considered by 3 Conolly et al. (2003). 4 Model 2 was an alternative to the Conolly et al. (2003) model, and is considered in 5 the sensitivity analysis described in Appendix E. The dose response for normal cell 6 replicati on was monotone increasing and did not exhibit a threshold in dose. This was 7 obtained by fitting the 13

- week cell replication data. The cell replication dose response for 8 initiated cells was a sigmoidal

- shaped curve, increasing monotonically with flux fr om a 9 background value up to an asymptotic value. The baseline cell

- replication for initiated cells 10
was constrained to not be less than that for normal cells. Initiated cell death rate was 11 considered proportional to initiated cell birth rate. 12
Models 1 & 2 predicted monotonic dose

- response curves. 13 The sequence of steps in arriving at a unit risk for SCC in human nasal airways from 14 a given BBDR modeling of the F344 rat nasal tumor incidence data is outlined below. 15 Extrapolation to the lower respiratory tra ct is described later. 16
1. Calculate the MLE risk and 95% upper confidence bound on risk at various exposure 17 concentrations ( d RAT in ppm) by exercising the two BBDR models. Here, the POD is 18
defined as d RAT for which the 95% upper bound added risk is either 0. 005 or 0.01. These 19 values approximate the 95% lower bounds on the BMD corresponding to the added risks 20 (i.e., the BMDL RAT ). 21
2. Using CFD modeling simulations in Kimbell et al. (2001a, b), calculate the average flux 22 over the entire rat nose at resting breathi ng rates corresponding to d RAT . Here, the 23 subscript “i” is over flux bins and N is the number of cells at risk in a given bin. 24
25

RAT i i i i i

RAT RAT 

### N N ppm flux

d d AvgFlux ** **  ** ** 

** ** 

** **  ** ** 

** ** 

**⋅**

**× =**  

# ∑ **∑** ) ( ) ( (5

- 2) 26

27
3. The experiment exposure was for periods of 5 days/week, 6 hours/day. Therefore, 28
calculate t he average daily exposure, obtained by making a 5/7 × 6/24 duration 29 adjustment; that is, 5/7 × 6/24 × AvgFlux(d RAT ). 30
4. Now assume that lifetime exposure to similar levels of average formaldehyde flux to 31 cells at risk leads to similar lifetime risk (MLE or up per bound, respectively) of tumor 32This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 122 incidence across animal species. Also, in calculating human equivalent concentrations, 1 EPA has traditionally assumed chronic animal laboratory exposure scenarios to be 2 equivalent to human lifetime exposures (U.S. EPA, 199 4b). 3
5. Since a CFD model for a human is available (Subramaniam et al., 1998), it is possible to 4 determine the average wall mass flux in this particular human nose for any specific 5 breathing scenario. Likewise, a computational model to determine mass flux at any 6 specific lung depth was available in the form of the single

- path model of Overton et al. 7 (2001); however, risk in the lower respiratory tract will be addressed later. From the 8 human CFD simulations in Kimbell et al. (2001a, b), the human airborne exp osure 9 concentration level that would yield the same average wall mass flux in the human nose 10 as [(5/7) × (6/24) × AvgFlux(d RAT )] is then calculated. In other words, given a risk

11 specific dose in the rat, the equivalent human exposure concentration is give n by 12
13

HUMAN i i i i i

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

** ** 

** **  ** ** 

** ** 

**× ×**  **× ×**  **=** 

# ∑ **∑**

) ( ) ( ) 24 / 6 ( ) 7 / 5 ( (5

- 3) 14

15
6. To use this equivalent human exposure concentration, make the following assumption: 16 when humans are exposed to the above concentration of formaldehyde (d HUMAN ) 17 throughout the course of a lifetime, the added risks are an ticipated to be similar to those 18 experienced by the animal in the chronic bioassay. 19
7. Let f denote the ratio of the average flux per ppm of exposure concentration in the two 20 species: 21
22

HUMAN i i i i i RAT i i i i i

N N ppm flux N N ppm flux

f

** **  ** ** 

** ** 

** **  ** ** 

** ** 

**× **  ** **  ****

** ** 

** **  ** ** 

** ** 

**×**

**=**


## ∑ **∑ ∑**  **∑**

) ( ) (

(5

- 4) 23

24 Now, the olfactory epithelium comprises a substantial fraction of nasal tissue in the rat. 25 Because the olfactory region in the rat projects directly in the path of main airstreams 26This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 123 (Kimbell et al., 1997), a sizable flux of formaldehyde is delivered to this region in the 1
rat. Tumors were not ob served in the olfactory tissue of the rat. Therefore, since effects 2 observed in the rat are being extrapolated to the human, cells from olfactory tissue are 3 excluded in calculating average flux in the rat in the eq 4. For the human, on the other 4 hand, bo th volumetric flow (2.5%, Subramaniam et al. [1998]) and surface area (~5%, 5 Kelly et al. [2000]) for the olfactory region are relatively small, so inclusion of this 6 region is not likely to make a difference of much significance in the calculation of 7

averag e flux in the human. Since data on formaldehyde flux delivered to the human 8 olfactory region were not readily available, the olfactory region was not excluded for the 9 human. The average human flux calculated here uses a working level classification for 10

t he activity profile where an individual spent equal amounts of time in a day at resting 11 and light and moderate activity levels, corresponding to minute volumes of 7.5, 9, and 12
25 L/minute, respectively. This resulted in the following ratio 13

14 : 13

f = 444 [rat] /956.4 [human] = 0.46 (5

- 5) 15
16
8. The airborne exposure concentrations d HUMAN corresponding to a given MLE and upper 17
bound lifetime added risk levels are the human BMD HUMAN and BMDL HUMAN , 18 respectively. These are shown in Figure 5

- 15. (The rather sudden incr ease by ~0.0015 19 in the upper confidence bound on risk for model 1 for exposure exceeding ~0.41 ppm 20 could not be explained. This jump was verified by repeated calculations that used 21 different initial simulation conditions and convergence criteria.) 22 Next, t he human lower respiratory tract is also considered to be potentially at risk. 23 Therefore, the above calculations of BMD and BMDL need to be augmented to include the 24 lower respiratory tract for humans. This calculation was facilitated by dosimetry 25
calcula tions of formaldehyde wall mass flux to various depths in the lung by using a single 26 path model. Refer to Overton et al. (2001) for details on their modeling. The calculations 27 for including the lower respiratory tract in determining an overall BMD and BM DL 28 involved the following steps: 29

a. As given by eq 5

- 3, calculate d HUMAN for various MLE risk levels. This gives a dose

30 response relationship for lifetime risk of SCC in the human nose due to continuous 31 exposure to airborne formaldehyde. 32
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.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 124 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 Figure 5

- 15. MLE and upper bound (UB) added risk of SCC in the human 2 nose for two BBDR models. 3 4 Note: Airborne exposure concentrations d HUMAN corresponding to a given MLE 5 and upper bound lifetime added risk levels are the human BMD HUMAN and 6 BMDL HUMAN , respectively. 7 8 9 b. Expr ess this dose

- response relationship in terms of average flux over the entire human 10 nasal lining. 11

c. Next, express this dose

- response relationship, calculated here for the entire nose, as risk 12 per nasal cell versus average flux. 13
d. Now, if the respiratory and tra nsitional cell types in the human lung and nose are equally 14 susceptible to formaldehyde

- induced cancer risk (as is also assumed in Conolly et al. 15 [2004]), then it appears reasonable to assume that MLE risk per cell at a given value of 16 formaldehyde flux is the same in the lung as in the nose. 17

e. The number of cells and the average flux in a given flux bin in the lung are known 18 (Overton et al., 2001). Thus, at a given air concentration, the MLE risk due to cells in 19 the various flux bins of the lung is obtained. 20
f. One important feature of Overton et al. (2001) was that their flux bins mapped 21 physically with lung depth. Therefore, in addition to extrapolating risk to the entire 22 human lung, it was also relatively easy to calculate risk as a function of airway 23

gener ation in the lung (corresponding to different lung depths). 24This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 125 g. Because of high formaldehyde reactivity and solubility at the POE, the MLE value risk 1 to the lower respiratory tract (as determined above in steps 1

– 5) was a small fraction of 2 risk to the upper re spiratory tract. Therefore, it sufficed to assume that the relative 3 increase in upper bound risk for the combined upper respiratory tract + lower respiratory 4 tract compared to that for only the upper respiratory tract would be the same as the 5 correspondin g relative increase in the value of the MLE risk. The upper bound risk to 6 the entire respiratory tract and consequently the BMDL value corresponding to a given 7 response were thus determined. 8
9 These calculations indicated that including the risk of SCC in the lower respiratory 10
tract resulted in at most a 3% increase in the added risk at the lower end of the human 11 exposure range in Figure 5

- 16 (i.e., at 0.42 ppm) and about a 1.5% increase at the higher end 12 of the range in that plot. Therefore, because of t he steepness in the dose

- response curve in 13 this exposure range and much lower risk in the lung at any exposure concentration, 14 including the lower respiratory tract did not appreciably alter the human BMDs and BMDLs 15 at the 0.5 and 1% response levels. 16
Unit r isks of SCC in the human respiratory tract extrapolated in this manner are reported 17
in Table 5

- 23. 18
19
Table 5

- 23. BMD modeling of unit risk of SCC in the human respiratory 20 tract 21 22

Extra risk level Benchmark levels (ppm) Unit risk a (per ppm) BMD BMDL 0.00 5 0.415

– 0.450 0.410

– 0.435 1.2 **×** 10
– 2
0.010 0.430

– 0.460 2.2 **×** 10
– 2 23

a Obtained from the mean of the two BMDLs. 24 25 Note: Findings are based on nasal tumors in rats and formaldehyde flux to tissue as dosimeter, using dose

26 response curves for the F344 rat pre dicted by clonal growth modeling. Two chronic bioassays (Monticello 27 et al., 1996; Kerns et al., 1983) were combined, and control animals from the historical NTP inhalation 28 bioassays were added to the control animals in these bioassays. 29 30 31 5.3.4.2. Compari son with Other Benchmark Dose Modeling Efforts 32 The CIIT assessment (Schlosser et al., 2003; CIIT, 1999) also presented, as their less 33 preferred option, a benchmark approach on the data set obtained by combining two chronic 34 bioassays with similar protocols (Monticello et al., 1996; Kerns et al., 1983) along with data 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 126 from 94 animals that had not been previously examined. These authors used two measures of 1

response

— tumor incidence and cell proliferation

— and, in each case, they used two 2
dosimeters

— DPX and for maldehyde flux to the nasal lining. 3 The extrapolation to human was carried out by using a hybrid CFD and pharmacokinetic 4 model. The CFD model (Kimbell et al., 2001a, b; Kepler et al., 1998; Subramaniam et al., 1998) 5
enabled calculation of site

- specific f lux in the nose of the rat, monkey, and human species for 6 inhaled formaldehyde concentrations, and the PBPK model (Conolly et al., 2000) linked this flux 7 to predicted DPX levels. The models were constructed for anatomically realistic representations 8
of a single individual in each species. The CFD and PBPK modeling and uncertainties in these 9 estimates have been reviewed in the Modeling the Toxicokinetics of Formaldehyde and DPX 10 section of chapter 3. 11
12
5.3.4.2.1. Benchmark dose using administered concentrat ion. Schlosser et al. (2003) fit 13 multistage, Weibull, polynomial, and log

- probit quantal models to the tumor data and exercised 14 the models (except the log

- probit) with and without requiring that the fits pass through the 15 origin. The log

- probit fit passed through the origin (see Figure 5

- 16). A fifth degree polynomial 16 was used in the multistage model. The best fit was obtained with the polynomial and Weibull 17
models for the tumor incidence data with a non

- zero intercept (threshold) on the dose axis. Fits 18 passing through the origin did not pass the statistical goodness

- of

- fit criteria ( p > 0.01) for 19 models other than the log

- probit. The dose response near the lowest dose was fairly steep, with 20
the LED 10 s and LED 01 s nearly the same for each model, at least to one significant figure. In 21 terms of administered concentration, the LEDs ranged from 3.8 to 6.4 ppm. 22
23
5.3.4.2.2 . Benchmark dose derived with internal dose (flux and DPX) as dose metrics in 24 Schlosser et al. (2003). 25 Schlosser et al. (2003) used CFD s imulations (Kimbell et al., 2001a, b) of mass flux of 26 formaldehyde delivered across the nasal lining. The dose metric used by Schlosser et al. (2003) 27 for the extrapolation was the average flux of formaldehyde, expressed in pmol/cm 2

- minute, to 28
the entire s urface of the airway lining (excluding tissue lined by non

- mucus

- coated squamous 29 tissue, which was considered not to absorb formaldehyde). 30
31This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 127 1 2 Figure 5

- 16. Replot of log

- probit fit of the combined Kerns et al. (1983) and 3 Monticello et al. (1996) data on t umor incidence showing BMC 10 and 4 BMCL 10 . 5 6 Source: Adapted from Schlosser et al. (2003). 7 8 9 In the CFD model, flux in any region is linearly related to the airborne exposure 10 concentration (i.e., flux = f × C air [ppm], where f is a constant of proportionalit y and C air is the 11 exposure concentration). The ratio of f (rat)/f (human) was determined as given by eq 5

- 4. This 12 ratio was equal to 0.71 and differed from the value of 0.46 used in this document (as presented in 13 eq 4

- 5) because Schlosser et al. (2003) u sed resting inspiratory rates. In the next level of 14 dosimetric complexity, Schlosser et al. (2003) used DPX as the relevant dosimeter based on 15 values predicted by PBPK models developed by Conolly et al. (2000). This expressed the local 16 dose as pmol of fo rmaldehyde equivalents covalently bound to DNA per unit volume of nasal 17
tissue. Human CFD and PBPK models were exercised to determine the airborne concentration 18 of formaldehyde that yields average DPX levels equal to those in the rat at the BMC. This 19
air borne concentration was then the HEC. The human benchmark extrapolations in Schlosser et 20 al. (2003) using flux and DPX are shown in Table 5

- 25, located at the end of section 5.4. 21 The assumption in using DPX data was that lifetime exposure to the same DPX 22 concentration for a given duration each day leads to equivalent risk across species. Table 5

- 25 23 shows their human benchmark calculations for a continuous environmental exposure. These 24This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 128 were exposures that resulted in the same steady

- state DPX concentratio ns as the weekly TWA 1 DPX values in rats at the rat benchmark exposure concentrations. 2
3
5.3.4.2.3. Cell proliferation in CIIT benchmark modeling. 4 Schlosser et al. (2003) also used cell proliferation as representing the adverse response, 5
and the BMDs cal culated with these data did not differ appreciably from their other benchmark 6 estimates. The use of cell proliferation as an end point is considered to have the advantage that it 7 represents an early step contributing to carcinogenesis. In this document, a BMD is not 8 calculated based solely on cell replication as a response. Instead, cell replication rates are used 9 as input to the clonal growth model and a BMD based on a fit to the tumor response using that 10
model is considered a better choice since it int egrates cell replication along with other relevant 11 data, such as the number of cells at risk and DPXs. 12
13
5.3.4.3. Kaplan

- Meier Adjustment 14 In the simplest consideration of the impact of competing risks on the nasal tumor 15 incidence, tumor incidences were a djusted for early deaths according to Kaplan

- Meier (KM) 16 survival estimates (KS Crump Group, 2001). This procedure allows for the possibility that some 17 tumors may otherwise have developed in the animals that died early due to other causes. All the 18
animals in the study were considered except those that were kept past termination of exposure. 19 A comparison of the adjusted incidence data is presented below in Table 5

- 24. While the 20 adjustments have been provided in Table 5

- 24, it needs to be noted that the da ta allow for a full 21
time

- to

- tumor analysis as presented below. 22
23
Table 5

- 24. Formaldehyde

- induced rat tumor incidences 24
25

Exposure level (ppm) KM adjusted incidence Observed tumors/ number at risk a 0.0 0.0 0/242 0.7 0.0 0/70 2.0 0.0 0/254 6.0 0.02 3/120 a 10.0 0.61 22/36 a 15.0 0.83 157/190 a 26

a KM adjusted. Numbers not indicated by footnote were not amenable to KM 27 adjustment because there were no tumors; these numbers at risk reflect all animals 28 surviving 1 yea r on study. 29 Source: Monticello et al. (1996); Kerns et al. (1983). 30This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 129 5.3.4.4. EPA Time

- to

- Tumor Statistical Modeling 1 Instead of using the KM adjustment, EPA has used the multistage Weibull time

- to

- tumor 2 model (Portier et al., 1986; Krewski et al., 1983) in other assessments (e.g., ethylene oxide, 3 1,3

- butadiene, chloroprene). This is a dose

- response model that includes the exact time of 4 observation of the tumors and therefore gives appropriate weight to the amount of time each 5 animal was on study without a tumor and acknowledges earlier tumor incidence with increasing 6 dose level. The data used in this analysis were obtained from the appendix in Conolly et al. 7 (2003) with one crucial modification. These data combined the nasal squamous carcinoma data 8
of Ker ns et al. (1983) and Monticello et al. (1996) along with results from an additional 9
94 animals not previously examined in the Monticello et al. (1996) study. Animals in some 10 exposure groups were held up to 6 months following the 24

- month exposure period; these 11 animals were deleted from the analysis for the following reason: there were no tumors among 12 these animals, and inclusion of them would have required estimating an equivalent TWA 13 exposure over the entire study period for these animals (40 in 2 ppm gro up, 39 in 6 ppm group, 3 14 in 15 ppm group), whereas the other animals would be represented by their actual exposure 15
concentrations. 16 Due to earlier tumor occurrence with increasing exposure level and increased mortality 17 with increasing exposure level, metho ds that can reflect the influence of competing risks and 18 intercurrent mortality on site

- specific tumor incidence rates are preferred. EPA has generally 19 used the multistage Weibull model because it incorporates the time at which death with tumor 20 occurred, giving appropriate weight to the amount of time each animal was on study without a 21 tumor; the model has the following form: P(d) = 1

– exp[

– (q 0 + q 1 d + q 2 d 2 + ... + q k d k ) × (t

– 22

t 0 ) z ], where P(d) represents the lifetime risk (probability) of cancer at dose d (i.e., human 23 equivalent exposure in this case); parameters q i ≥ 0, for i = 0, 1, ..., k; t is the time at which the 24 tumor was observed; and z is a parameter estimated in fitting the model, which characterizes the 25 change in response with age. The parameter t 0 represents the time between when a potentially 26
fatal tumo r becomes observable and when it causes death. 27 A further consideration is the distinction between tumor types as being either fatal or 28 incidental in order to adjust for competing risks. Incidental tumors are those tumors thought not 29
to have caused the d eath of an animal (such as those observed during interim or terminal 30 sacrifices), while fatal tumors are thought to have resulted in animal death. For these data, nasal 31 tumors observed with early deaths were considered to be fatal. 32
The dose

- response analy ses (Figures 5

- 17, 5

- 18, 5

- 19) were conducted by using the 33 computer software program TOX_RISK, version 5.3 (ICF, Fairfax, VA), which is based on 34 Weibull models drawn from Krewski et al. (1983). Parameters were estimated by using the 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 130 method of MLE. Specif ic multistage Weibull models were selected for the individual tumor 1 types for each sex, based on the values of the log likelihoods according to the strategy used by 2 EPA (U.S. EPA, 2002b). If twice the difference in log

- likelihoods was less than a **χ** 2 with 3 degrees of freedom equal to the difference in the number of stages included in the models being 4 compared, the models were considered comparable, and the most parsimonious model (i.e., the 5
lowest

- stage model) was selected contingent on visual fits of the da ta as follows. For incidental 6 tumors, plots of model fits compared with Hoel

- Walburg estimates of cumulative incidence were 7 also examined for goodness of fit in the lower exposure region of the observed data (Gart et al., 8 1986) (Figure 5

- 18). For fatal t umors, plots of model fits were compared with KM estimates of 9 cumulative incidence. If a model with one more stage fitted the low

- dose data better than the 10 most parsimonious model, then the model with one higher stage was selected. 11 Due to the sharp incre ase in responses between 6 and 10 ppm, no adequate fit was 12 achieved. Data for the highest dose were dropped in an effort to focus the fitting process for this 13 empirical model on the low

- dose region. The model that then provided the best overall fit 14
inclu ded five stages but with coefficients for the lower stages estimated to be zero (see 15 Figures 5

- 17, 5

- 18, 5

- 19). The parameter t 0 was estimated to be zero, consistent with rapidly 16 fatal tumors. On the other hand, an alternate run treating all tumors as in cidental to the death of 17 the affected animals yielded BMCLs and BMCs within 10% of these estimates (Figure 5

- 18); 18 thus, tumor context is not a sensitive consideration for these data. 19 For the same reasons as discussed in section 5.3.3 (the concluding discus sion of the 20 BBDR modeling), a linear low

- dose extrapolation approach was used to estimate human 21 carcinogenic risk associated with formaldehyde exposure. PODs for estimating low

- dose risk 22 were identified at doses at the lower end of the observed data, corr esponding to 1% extra risk, 23
defined as the extra risk ove r the background tumor rate [P(d) − P(0)]/[1 − P(0)]. PODs 24 corresponding to 10% extra risk are also provided to facilitate comparison with other chemicals. 25 Rat benchmark levels obtained by analysis of the tumor data are shown in Table 5

- 25. PODs 26

were co nverted to continuous human

- equivalent exposure levels by multiplying by 27 (5 days/7 days) **×** (6 hours/24 hours), or 0.178, and by multiplying by the ratio of fluxes 28 developed in section 5.3.6.1.3. The lifetime continuous inhalation unit risk for humans is 29 defined as the slope of the line from the lower 95% bound on the exposure at the POD, 30 calculated by dividing the BMR level (1%) by the corresponding BMCL 01 . This 95% UCL 31 represents a plausible upper bound on the true risk. 32
33
34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 131 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 Figure 5

- 17. EPA Multistage Weibull modeling: nasal tumor dose response. 2 3 Note: Time

- to

- tumor modeling of Kerns et al. (1983) and Monticello et al. (1996) 4 data compared with incidences adjusted by using KM estimates evaluated at 5 104 weeks. 6 7 Source: Adapted from Schlosser et al. (20 03). 8
9This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 132 1 Figure 5

- 18. Multistage Weibull model fit. 2 Note: Data of Kerns et al. (1983) and Monticello et al. (1996) compared with 3 Hoel

- Walburg estimates of tumor incidences occurring at interim and terminal 4 sacrifices. 5 6 7

8 9 Figure 5

- 19. Multistage Weibull model fit of tumor incidence data compared 10 with KM estimates of spontaneous tumor incidence. 11 Source: Developed from data reported in Kerns et al. (1983) and Monticello et al. 12 (1996). 13This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 133 The extrapolation to humans in terms of using formaldehyde flux to tissu e as the dose 1
metric is shown in Table 5

- 25, where unit risk in terms of q1*, the statistical upper bound on the 2 coefficient of the term linear in dose in the multistage model, is also presented. q1* is presented 3 even though this is no longer done, as per current EPA practice (see section 5.3.6 for discussion). 4 These results are to be compared with the preferred benchmark estimates obtained in 5
Table 5

- 23 by using the results of biologically based models. In summary, the unit risks 6 obtained by various meth ods, including the results in Schlosser et al. (2003), fall within a rather 7 tight range. In particular, q1* was obtained to within a factor of two of other values even though 8 q1 itself was zero. The large difference between q1 and q1* aptly reflects the large uncertainty 9
in the low

- dose response. 10
11 5.4. CONCLUSIONS FROM THE QUANTITATIVE ASSESSMENT OF CANCER RISK 12 FROM FORMALDEHYDE EXPOSURE BY INHALATION 13 14 5.4.1. Inhalation Unit Risk Estimates Based on Human Data 15 As described in section 5.2, a (plausible upp er bound) lifetime extra cancer unit risk of 16
1.1 **×** 10
– 2 per ppm (8.8 **×** 10
– 6 per μg/m 3 ) of continuous formaldehyde exposure was estimated 17 for NPC incidence using the log

- linear modeling results (for NPC mortality from cumulative 18 exposure) from a high

- qualit y occupational epidemiologic study in a life

- table analysis to obtain 19 a POD and then applying linear low

- dose extrapolation from the POD. Using similar methods 20 and data from the same study for Hodgkin lymphoma and leukemia mortality from cumulative 21
formal dehyde exposure, (plausible upper bound) lifetime extra cancer risk estimates of 1.7 **×** 10
– 2 22 per ppm (1.4 **×** 10
– 5 per μg/m 3 ) for Hodgkin lymphoma incidence and 5.7 **×** 10
– 2 per ppm 23 (4.6 **×** 10
– 5 per μg/m 3 ) for leukemia incidence were derived. Sources of uncert ainty in these 24
estimates are discussed in sections 5.2.2.4 and 5.2.3.4. For the incidence risk for these three 25 cancer types combined, a total (upper bound) cancer unit risk estimate of 8.1 × 10 −2 per ppm 26 (6.6 **×** 10
– 5 per μg/m 3 ) was obtained (section 5.2.4)

. 27
28 5.4.2. Inhalation Unit Risk Estimates Based on Rodent Data 29 As described in section 5.3, the unit risk derived for SCC in the upper and lower 30 respiratory tract (combined) based on linear extrapolation from PODs from several plausible 31 models, including p urely statistical modeling (nose only, quantal and time

- to

- tumor modeling) 32 and biologically based modeling (entire respiratory tract), resulted in a narrow range of 33
1.2 × 10 −2 to 2.2 × 10
– 2 per ppm. Risk to the lower respiratory tract was numerically 34 insignificant compared to the nasal cancer risk. 35This document is a draft forreview purposes only and doesnot constitute Agency policy5-134DRAFT—DO Table 5

- 25. Human benchmark extrapolations of nasal tumors in rats by using formaldehyde flux and DPX

Model Source Rat benchm ark levels (ppm) Extrapolated human benchmark levels (ppm) Unit risk a (ppm)
– 1
1% 5% 10% Dose metric b 1% 5% 10% 1% 5% 10%
Weibull c,d

(with threshold) Schlosser et al. (2003) ED
LED 5.91 5.58 6.12 5.94 6.40 6.22 Flux e 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

DPX f 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 (time

to

- tumor) c,d,g EPA (this assessment) ED
LED 4.28 3.57 5.93 5.52 6.84 6.41 Flux h ED 0.35 0.49 0.57
L ED 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 mode l 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) obtaine d 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 f HCHO

- Rat /f

HCHO

- Human (= 0.71) for interspecies extrapolation and multiplied b y (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[

- (q 0 + q 1 d + q 2 d 2 + ... + q k d k )* t z ]. q 0 , q 1 , q 2 , q 3 , q 4 were all taken to be zero. q 5 = 2.9 × 10

– 22 , z = 8.1.
h Human benchmark levels extrapolated using flux were multiplied by f HCHO

- Rat /f

HCHO

- Human = 0.46 for interspe cies extrapolation and multiplied by (6/24) × (5/7) to adjust for continuous exposure (see section 5.3.6.2).This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 135 5.4.3. Summary of Inhalation Unit Risk Estimates 1 The epidemiologic and rodent inhalation data indicate multiple sites of concern. Unit risk 2
estim ates calculated separately from these data are presented in Table 5

- 26. 3 As can be seen in the summary table (Table 5

- 26), the unit risk estimate based on human 4 data for NPC is in the range of the estimates calculated for respiratory tract cancer from the 5 rodent nasal cancer data. The unit risk estimate for Hodgkin lymphoma is also in the same 6 range, while the unit risk estimate for leukemia and the total cancer unit risk estimate are up to 7 fourfold higher. 8
9
Table 5

- 26. Summary of inhalation unit risk esti mates 10 11

Cancer type a Dose metric Unit risk estimate (ppm – 1 ) Based on epidemiologic data Nasopharyngeal Cumulative exposure 0.011 Hodgkin lymphoma Cumulative exposure 0.017
Leukemia Cumulative exposure 0.057
Total cancer risk b Cumulative exposure 0.081

Based on experimental animal data
SCC of the respiratory
tract Local dose (flux) of formaldehyde in pmol/mm 2

- hour 0.011

– 0.022

12

a The unit risk estimates are all for cancer incidence. 13

b The total cancer unit risk estimate is an estimate of the upper boun d on the sum of risk estimates calculated 14 for the 3 individual cancer types (nasopharyngeal cancer, Hodgkin lymphoma, and leukemia); it is not the 15 sum of the individual (upper bound) unit risk estimates (see Section 5.2.4). 16 17 18 As noted in EPA’s Guidelines f or Carcinogen Risk Assessment (U.S. EPA, 2005a), when 19 high

- quality human data are available, they are generally preferred over laboratory animal data 20 for quantitative risk assessment. Thus, the preferred (plausible upper bound) unit risk estimate in 21
this assessment is the value of 8.1 × 10
– 2 per ppm (6.6 **×** 10
– 5 per μg/m 3 ) based on human data 22 for NPC, Hodgkin lymphoma, and leukemia. 23 As documented in section 4.5, formaldehyde is a mutagenic carcinogen and the weight of 24 evidence suggests that formaldehyd e carcinogenicity can be attributed, at least in part, to a 25 mutagenic MOA. Therefore, since there are no adequate chemical

- specific data to evaluate the 26This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 136 susceptibilities of different life stages by the inhalation route of exposure 14

6 , increased early

- life 1

s usceptibility should be assumed, and, if there is early

- life exposure, the ADAFs should be 2 applied, in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from 3 Early

- Life Exposure to Carcinogens (U.S. EPA, 2005b). See section 5.4.4 be low for more 4 details on the application of the ADAFs. 5

5.4.4. Application of Age

- Dependent Adjustment Factors (ADAFs) 7 When there is sufficient weight of evidence to conclude that a mutagenic MOA is 8 operative in a chemical's carcinogenicity and there are inadequate chemical

- specific data to 9

assess age

- specific susceptibility, as is the case for formaldehyde (by inhalation exposure; see 10 section 5.4.3), U.S. EPA’s Supplemental Guidance for Assessing Susceptibility from Early

- Life 11 Exposure to Carcinogens (U. S. EPA, 2005b) recommends the application of default ADAFs to 12 adjust for potential increased susceptibility from early

- life exposure (see U.S. EPA [2005b] for 13 detailed information on the general application of these adjustment factors). In brief, U.S. EPA 14 (2005b) establishes ADAFs for three specific age groups : 10 (for <2 years), 3 (for 2 to 15
<16 years), and 1 (for 16 years and above). For risk assessments based on specific exposure 16 assessments, the 10

- fold and threefold adjustments to the unit risk estima tes are to be combined 17 with age

- specific exposure estimates when estimating cancer risks from early

- life (<16 years 18 age) exposure. The ADAFs and their age groups may be revised over time. The most current 19 information on the application of ADAFs for cance r risk assessment can be found at 20 www.epa.gov/cancerguidelines. 21 For inhalation exposures, assuming ppm equivalence across age groups (i.e., equivalent 22 risk from equivalent exposure levels, independent of body size) and using the preferred unit risk 23
estima te of 6.6 × 10
– 5 per μg/m 3 from section 5.4.3, the calculation is fairly straightforward. The 24
ADAF

- adjusted lifetime total cancer unit risk estimate is calculated as shown in Table 5

- 27: 25
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, ther e 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 hemolymphoret icular cancer results from the Soffritti et al. (1989) paper uncertain (see Section 4.5).This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5-137 Table 5 -27. Total cancer risk from exposure to a constant formaldehyde exposure level of 1 μg/m 3 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/m 3 is equivalent to a lifetime unit risk of 1.1 × 10 –4 per μg/m 3 , adjusted for early

- life susceptibility, assuming a 70 -y ear 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 est imates 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/m 3 ) 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
29This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 5

- 138 In addition, as described in section 5.4.4, because the weight of evidence suggests th at 1 formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic MOA and there 2 are inadequate chemical

- specific data to assess age

- specific susceptibility, increased early

- life 3 susceptibility should be assumed and, if there is early

- life exposure, ADAFs should be applied, 4
in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early

- Life 5 Exposure to Carcinogens (U.S. EPA, 2005b). Consequently, applying the ADAFs to the 6 preferred unit risk estimate to obtain a ful l lifetime unit risk estimate yields 7
8 0.081/ppm × [(10 × 2 years/70 years) + (3 × 14/70) + (1 × 54/70)] 9

= 0.13/ppm = 1.1 × 10 – 4 /(μg/m 3 ) 10
11 Using the above full lifetime unit risk estimate of 0.13 per ppm, the lifetime chronic 12 exposure level of formaldehyd e corresponding to an increased cancer risk of 10
– 6 can be 13 estimated as follows: (10
– 6 )/(0.13/ppm) = 7.7 × 10
– 6 ppm = 0.008 ppb = 0.009 μg/m 3 . Similarly, 14 the lifetime chronic exposure level of formaldehyde corresponding to an increased cancer risk of 15
10
– 4 is 0.8 ppb, or 0.9 μg/m 3 . (Note that for less

- than

- lifetime exposures scenarios [or for 16 exposures that vary with age], the adult

- based combined estimate of 0.081 per ppm should be 17 used, but if there is early

- life exposure, the ADAFs should be applied in accordance with EPA’s 18 Supplemental Guidance [see section 5.4.4]). 19
20This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 1 6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND 1 DOSE

- RESPONSE 2 3 4 6.1 SUMMARY OF HUMAN HAZARD POTENTIAL 5
6.1.1 Exposure 6 Formaldehyde (CH 2 O) occurs as a gas at room temperature. It is hig hly reactive and 7 dissolves readily in water. Formaldehyde is present in a wide variety of products including 8 plywood adhesives, abrasive materials, insulation, insecticides and embalming fluids (IPCS, 9 2002a; Agency for Toxic Substances and Disease Registr y [ATSDR], 1999). The major sources 10 of anthropogenic emissions of formaldehyde are motor vehicle exhaust, power plants, 11 manufacturing plants that produce or use formaldehydes or substances that contain formaldehyde 12 ( i.e. , glues), petroleum refineries, cok ing operations, incineration, wood burning, and tobacco 13 smoke (INEG, 200 3). Reported outdoor air concentrations of formaldehyde in urban and 14 suburban areas are near 3 μg/m 3 (~ 3 ppb) (U.S. EPA, 2008) and indoor residential levels are 15 approximately 10 times higher (Health Canada and Environment Canada, 2001). 16
Limited U.S. d ata indicate that the upper end of the formaldehyde concentration range in 17 drinking water is approximately 10 μg/L IPCS, 2002a). Formaldehyde is a natural component of 18 a variety of foodstuffs (IARC, 1995; IPCS, 1989). In addition, foods may also be conta minated 19 with formaldehyde as a result of fumigation (e.g., grain, seeds), cooking (as a combustion 20 product), and release from formaldehyde resin

- based tableware (IARC, 1995). Limited data 21 measuring formaldehyde in food indicates that the concentration ran ge is <0.03

– 14 mg/kg 22 Health Canada and Environment Canada, 2001). Daily intake of formaldehyde has been 23
estimated to be between 1.5 and 14 mg/day for an average adult (IPCS, 1989; Fishbein, 1992). 24
25
6.1.2 Absorption, Distribution, Metabolism, and Excretion 26
In water, less than 0.1% of formaldehyde exists unhydrated, with the majority reported to 27 be in the hydrated form, methylene glycol (CH 2 (OH) 2 ) (Priha et al., 1996) . Formaldehyde is a 28 reactive molecule that can react with both low molecular weight cellular components (e.g., GSH) 29 as well as high molecular weight components. It is also a well

- known cross

- linking agent. 30 Further, fo rmaldehyde is a product of normal cellular metabolic processes. Endogenous 31 formaldehyde is a constituent of the one

- carbon pool. It is thought that most endogenous 32 formaldehyde exists in a form that is reversibly bound to nucleophiles (Heck et al., 1990; 1982) 33 and that the formaldehyde hemithioacetal adduct formed with glutathione could account for 50

– 34 80% of the total formaldehyde normally present in cells (Heck et al., 1982). 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 2 Inhaled formaldehyde is efficiently absorbed (“scrubbed”) in the upper respir atory tract. 1 The fraction that is absorbed was determined to be approximately 97% in rats (Morgan et al., 2 1986), and 85% and 90% respectively in computer simulations of one rhesus monkey and human 3 at rest (Kepler et al., 1998; Kimbell et al., 2001). As th e inspiratory rate increased, 4 formaldehyde decreased to about 70% during light exercise and to 58% during heavy exercise 5 conditions in the human. During heavy exercise, the absorption of formaldehyde in the first six 6 to eight generations of the tracheobro nchial airways is estimated to be comparable to that in the 7 nasal region (Overton et al., 2001). 8 Airway geometry is an important determinant of inhaled

- formaldehyde dosimetry in the 9 respiratory tract. There are large differences across species in the an atomy of the upper 10 respiratory tract and in airflow patterns. Using computer simulation, the regional uptake patterns 11 of formaldehyde in the upper respiratory tract are observed to be spatially non

- homogenous and 12 to exhibit strong species differences. Ai rflow patterns are also significantly different as 13 breathing patterns and activity profiles change, depending on whether breathing is oral or nasal. 14 The overall information on the disposition of inhaled formaldehyde comes from many 15 studies using differen t experimental methods including: [ 14 C] radiolabeling, gas 16 chromatography

- mass spectroscopy (GC

- MS), dual isotope labeling ( 3 H, 14 C) and high

17 performance liquid chromatography (HPLC) studies. In a study of rats following exposure to 18
radiolabeled formaldeh yde, the radioactivity was very high in the nasal mucosa but was also 19 extensively distributed to various tissues including the bone marrow (Heck et al., 1983). The 20
elevated 14 C in various tissues was thought unlikely to be due to free formaldehyde but ins tead to 21 arise from either rapid metabolic incorporation or formation of covalent adducts or incorporation 22 via carboxylation reactions of the 14 CO 2 formed during metabolism (Heck et al., 1983; 23
Casanova

- Schmitz et al., 1984). Studies using the GC

- MS method indicate that exposure to 24 formaldehyde over a wide range of exposure concentrations and durations does not result in 25 elevated levels in blood, above those of endogenous formaldehyde levels in rats, rhesus monkeys 26 and humans (Heck et al., 1985; Casanova et al., 1998). These GC

- MS measurements are 27 consistent with the conclusions that formaldehyde does not appreciably reach the blood, is 28 rapidly metabolized, interacts with macromolecules when it escapes metabolism, or is otherwise 29
undetected. 30
In further studi es on the disposition of inhaled formaldehyde, Casanova

- Schmitz et al. 31 (1984) and Casanova

- Schmitz and Heck (1983) used dual

- isotope labeling of inhaled 32 formaldehyde as an approach to distinguish between formaldehyde adduct formation and 33 metabolic incorpor ation. These were followed by more sensitive experiments using HPLC 34 measurements in rats and rhesus monkeys exposed to radiolabeled formaldehyde (Casanova et 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 3 al. 1989, 1991). Results from this sets of experiments found that labeling in the nasal mucosa 1

w as due to both covalent binding and metabolic incorporation and labeling of bone marrow 2 macromolecules was found to be entirely due to metabolic incorporation. Overall, Heck, 3
Casanova

- Schmitz, and their coworkers interpreted the results of these experimen ts to indicate 4 that inhaled formaldehyde does not reach distant sites (beyond the portal of entry) at detectable 5
levels. 6 Formaldehyde is primarily metabolized by glutathione

- dependent formaldehyde 7 dehydrogenase. In humans this enzyme is referred to using the protein code of ADH3. The 8 major factor in the disposition of formaldehyde is metabolic clearance by oxidation to formate, 9
which is either further metabolized to CO 2 and water, incorporated into the one

- carbon pool, 10
and/or eliminated in the urine as a sodium salt. 11 In radiolabeling studies, Heck et al. (1983) determined that the relative contributions of 12 various excretion pathways in F344 rats following inhalation exposure to formaldehyde were 13 independent of exposure concentration. Nearly 40% of inhaled [ 14 C]

- formaldehyde appeared to 14 be eliminated via expiration, presumably as CO 2 , while about 17% and 5% was eliminated in the 15 urine and feces, respectively. Nearly 40% of inhaled [ 14 C]

- formaldehyde remained in the 16 carcass, presumably due to metabolic incorpor ation. For exposure via the oral route, absorption 17 of [ 14 C]

- formaldehyde (7 mg/kg) in rats resulted in 40% exhaled (as 14 CO 2 ), 10% excreted in 18 urine, 1% excreted in feces, and much of the remaining 49% retained within the carcass, 19 presumably due to metabo lic incorporation (IARC, 1995; Buss et al., 1964). 20 Several human and animal studies have attempted to measure the concentration of 21 formaldehyde in exhaled breath (see section 3.5.2). None of the human studies investigated 22 whether there is any correlation between exhaled formaldehyde levels and food intake, life stage, 23 smoking, or health status. Additionally, they were not designed to distinguish between 24 exogenous (room air) and endogenous (systemic) formaldehyde in exhaled breath. In order to 25
discern whe ther endogenous formaldehyde is excreted into the lungs, human subjects must 26 breathe formaldehyde

- free air. Because subjects were breathing room air, which contained 9

- 10 27 ppb formaldehyde in two studies and unspecified concentrations in two other studies, there is no 28 way of knowing whether there was any endogenous formaldehyde in their exhaled breath. This 29
assessment identifies a critical research need for further studies on the measurement of exhaled 30 formaldehyde. 31 The most informative study, performed by Cáp et al. (2008), demonstrated that subjects 32 breathing room air containing 9.6 ±1.5 ppb formaldehyde exhaled a mean formaldehyde 33 concentration of 2 ppb. This suggests that a substantial portion of inhaled formaldehyde, which 34 is highly reactive, was reta ined in the respiratory tract and not exhaled. It is impossible to tell 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 4 whether any portion of the 2 ppb in exhaled breath was of endogenous origin. In this and other 1 human studies, there was no adjustment for an artifact in the analytical method that ma kes it 2 impossible to distinguish between formaldehyde and reaction products for 1% of exhaled 3 methanol and ethanol because they have the same mass to charge ratio ( m/z = 31). In fact, the 4
concentration of methanol and ethanol that is misidentified as form aldehyde exceeds the reported 5 concentrations of exhaled formaldehyde. Thus, it is highly likely that the actual exhaled 6 formaldehyde concentration in Cáp et al. (2008) was significantly lower than 2 ppb, and that 7 there was little or no endogenous formalde hyde in the exhaled breath. This would be consistent 8 with an animal study in which Mashford and Jones (1982) detected no exhaled formaldehyde in 9 rats injected I.P. with 40 mg/kg [ 14 C]

- formaldehyde. In summary, there are insufficient data at 10
this time to confidently establish a concentration of formaldehyde in exhaled breath that can be 11 attributed to endogenous sources. 12
13
6.1.3 Noncancer Health Effects in Humans and Laboratory Animals 14 A wide variety of human and animal studies provide evidence for health effects in 15 response to formaldehyde exposure. Some of these health effects are commonly noted at the 16 portal of entry, as expected for exposure to a reactive gas. In addition, effects on the nervous 17 and reproductive systems, developmental effects, and immunomodul ation have been reported. 18 The overall weight of evidence (WOE) of human and animal studies for the hazard potential of 19 formaldehyde is discussed below, along with information on plausible modes of action (MOAs). 20
21
6.1.3.1. Sensory Irritation 22 Formaldehyde, a chemical irritant, binds to protein receptors of the trigeminal nerve, 23 triggering a burning and painful sensation in humans. This process is distinct from taste and 24 smell (Nielsen 1991; Cometto

- Muniz and Cain, 1992). The trigeminal nerve, which has th ree 25 branches (ophthalmic, maxillary and mandibular), not only acts as an afferent nerve relaying 26 these sensations to the central nervous system, but also has efferent nerve activity (Stedman’s 27 Medical Dictionary: Meggs, 1993). Stimulation of the trigemina l nerve may result in reflex 28 responses including lacrimation, coughing, and sneezing. Both the reflex responses as well as 29 sensations such as burning, pain, and itching of the eyes, nose, and throat are considered adverse. 30 Formaldehyde

- induced eye, nose, and throat irritation has been well documented in a 31 wide range of epidemiologic studies. Common effects of chemically

- induced sensory irritation 32 include lacrimation, burning of the eyes and nose, rhinitis, burning of the throat, and cough 33 (Feron et al., 2 001). Studies examining these endpoints were either controlled chamber studies 34 with a defined population (e.g., healthy volunteers or sensitive individuals), worker/student 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 5 studies, or general population studies (e.g., residential). Chamber studies, by d esign, are acute 1 studies, although some researchers have investigated the outcomes after repeated exposures. 2 Occupational, student, and residential exposures are generally of longer duration, although there 3 is variability in exposure level and duration am ong subjects. The endpoints for assessing 4
irritation include self

- reporting of symptoms (e.g., pain, burning, itching) and objective measures 5 of irritation (e.g., eye

- blink counts, lacrimation). 6 Eye irritation is the most sensitive of reported effects i n human studies. Two different 7
short

- term chamber studies provide similar 10% BMDLs for eye irritation of 560 ppb and 240 8 ppb for 3 and 5 hour exposures, respectively (Kulle, 1993; Andersen and Molhave, 1983, 9 modeled by Arts et al., 2006b). Various occupa tional studies have noted increased eye irritation 10 for average exposures ranging from 180 ppb to 690 ppb (Horvath et al., 1988, Alexandersson 11 and Hedenstiera, 1998; Holmstrom and Wilhelmsson, 1988). The results of residential studies, 12
where in

- home formal dehyde levels are used to document exposure, indicate eye irritation may 13 increase with increasing exposure from 70 to 200 ppb for these chronic exposure scenarios 14 (Ritchie and Lehnen, 1987, Hanrahan et al., 1984; Liu et al., 1991.) 15 When a rodent is exposed to an irritant, the inhaled dose and pattern of deposition can be 16 profoundly affected by reflex bradypnea, a protective reflex observed in rodents but not in 17 humans. Reflex bradypnea is manifest as markedly decreased activity or prostration, reduced 18

meta bolism, hypothermia (as much as 5oC), significantly reduced respiratory rate and minute 19 volume, and altered blood and brain chemistry. Reflex bradypnea can occur when the trigeminal 20 nerve is exposed to a sufficient concentration of an irritant, such as fo rmaldehyde. Because of 21 their small size, rodents are able to rapidly lower their metabolism and body temperature and 22 therefore their oxygen demand. The consequence is that their inhaled dose of an irritating 23 chemical is dramatically lowered. Reflex brad ypnea is quantified as the RD 50 , which is the 24 concentration of a chemical that results in a 50% decrease in respiratory rate (Tables 4

- 7 and 25
4

- 8). After the irritant exposure is removed, it can take up to two hours for rodents to fully 26
recover from the ef fects of reflex bradypnea. Even though humans do not exhibit reflex 27 bradypnea, involvement of trigeminal nerve stimulation, which is the mechanism for reflex 28 bradypnea in rodents, may be relevant to MOAs for formaldehyde in other species, such as 29 primates and humans. For example, trigeminal nerve stimulation has been associated with 30 sensory irritation in humans, highlighting the relevance of this effect. 31
32
6.1.3.2. Respiratory Tract Pathology 33 Formaldehyde

- induced respiratory tract pathology includes infla mmation, rhinitis, goblet 34 cell hyperplasia, metaplastic changes, squamous cell hyperplasia, and impaired mucociliary 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 6 transport. Formaldehyde binding to the trigeminal nerve triggers the release of neurogenic 1 mediators of inflammation resulting in tissue e dema, lacrimation, mucus production, and 2 leukocyte infiltration. Therefore, observed pathological changes may be directly related to 3 neurogenic inflammation from activation of the trigeminal nerve or result, at least in part, from 4 formaldehyde

- induced cel l damage to the mucosal tissue. A series of exposures has also been 5 positively associated with reduced mucociliary clearance, and the induction of histopathologic 6 lesions in the nose in both human and animal studies assessing formaldehyde

- induced changes i n 7 the nasal mucosa suggest that these changes may be, at least in part, a protective or adaptive 8 response and that increased mucus flow and metaplastic changes would progress in relation to 9 the concentration and duration of exposure protecting the underlyi ng tissue (Swenberg et al., 10 1983). 11 In rodent studies, formaldehyde

- induced histopathological lesions ranging from 12 inflammation to ulceration, necrosis, and metaplasia have been frequently reported in nasal 13 turbinates, maxilloturbinates, and in goblet and m icrovilli cells (e.g., Bhalla et al., 1991; 14
Monteiro

- Riviere and Popp, 1986; Cassee and Feron, 1994; Ionescu et al., 1978; Schreibner et 15 al.,1979; Monticello et al., 1989). These effects were observed after a variety of exposure 16 scenarios (e.g., 10 ppm fo r 4 hrs (Bhalla et al., 1991), 0.5 or 2 ppm for 6 hrs/day for 1 or 4 days 17 and 6 or 15 ppm for 6 hrs/day for 1 or 2 days (Monteiro

- Riviere and Popp, 1986), 3.6 ppm 18 intermittently for 3 days (Cassee and Feron, 1994), 3% aerosols of formaldehyde for 3 hrs/day 19 for 50 days (Ionescu et al., 1978)). The progressive pathology of the nasal passages from 20 formaldehyde inhalation exposure is dependent on increasing concentration and duration of 21 exposure, as well as from proximal to distal regions of the nasal cavity. For example, some 22 lesions may be transient (e.g., low

- exposure cell proliferation), while others may have a 23 maximum response and be irreversible (e.g., rhinitis). The nasal epithelium responds with both 24 adaptive and adverse epithelial changes. As respir atory epithelium transitions to squamous 25 metaplasia, the effective tissue dose of formaldehyde increases posterior to these lesions. As 26 epithelial barriers degrade (e.g., squamous metaplasia, keratinization), formaldehyde penetrates 27 more deeply into the n asal passages. Therefore, the relationship between concentration and 28 duration of exposure and health outcomes has been difficult to define and, in fact, may be 29 different for various health effects. Formaldehyde

- related histopathological lesions of the na sal 30 mucosa have been observed at concentrations as low as 2 ppm for chronic exposure and after a 31 duration as short as 6 hrs at higher concentrations (e.g., 6 ppm) (Table 4

- 32, table 4

- 38). 32 Similar pathology has been reported for workers exposed to formalde hyde, including loss 33 of cilia, goblet cell hyperplasia, and cuboidal and squamous cell metaplasia and dysplasia, and 34 these pathology scores were significantly elevated in workers over controls (Holmström and 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 7 Wilhelmsson, 1988; Edling et al., 1988; and Boys en et al., 1990). Holmström and Wilhelmsson 1 (1988) reported associations between the mean daily exposure of 240 ppb (8hr TWA) and these 2 changes. Edling et al. (1988) reported that workers experienced a range of exposures (80

- 900 3 ppb), with peak exposures of 4000 ppb. Boysen et al. (1990) provided a range of estimated 4 exposures from 500 ppb to more than 2000 ppb for workers with elevated mean pathology 5 scores. One controlled chamber study indicated formaldehyde

- induced inflammatory changes 6 which persiste d for 18 hours in adults exposed at 400 ppb for only 2 hours (Pazdrak et al., 7 1993)). 8
Short

- term formaldehyde exposure also impairs the function of the mucociliary apparatus 9 which is a critical defensive barrier for the upper respiratory tract. Numerous l aboratory animal 10 studies have reported impaired mucociliary clearance activity associated with formaldehyde 11 exposures as low as 500 ppb (Table 4

- 10). Low

- concentration or short

- term exposures first lead 12 to an increased rate of ciliary beat, followed by im paired mucus flow, with slowed rate of ciliary 13 beat and eventual mucostasis (lack of mucus flow) and ciliastasis (lack of ciliary beat) occurring 14 at higher doses or longer exposure times. These effects have been shown to be both 15
concentration

- and duratio n

- dependent and to occur within 15 minutes after the initial exposure. 16 Morgan et al. (1983c) suggested that the initial stimulation of ciliary activity may be a defensive 17 response to the irritant gas, at which time some penetration of formaldehyde to the underlying 18 epithelial cells may occur. Later effects of mucostasis and ciliastasis may occur as a result of 19 formaldehyde

- induced glycoprotein cross

- links, creating a rigid mucus that effectively stops 20
mucus flow. 21 Formaldehyde

- induced cell proliferation ha s been demonstrated in nasal epithelium in 22 animal studies after a range of exposure conditions (e.g. Swenberg et al., 1986; Cassee and 23 Feron, 1994; Reuzel et al., 1990; Woutersen et al., 1987) (Table 4

- 43). Formaldehyde

- induced 24 histopathology and mitogen esis may occur as a direct effect of exposure (Tyihak et al., 2001) or 25 as a secondary effect resulting from adaptive responses and/or compensatory tissue repair that 26 can occur after formaldehyde exposure (Swenberg, 1983). In a study of Rhesus monkeys 27
Mont icello et al. (1996) noted that increased cell proliferation was seen in locations with 28 minimal histological changes in the respiratory tract indicating that cell proliferation may be a 29 more sensitive predictor of more severe health effects due to formalde hyde exposure. Cellular 30 proliferative responses may initiate lesion formation. A number of studies illustrate that the 31 duration of repeated exposures may be an important determinant of cell proliferation rates 32 (Wilmer et al., 1987; Swenberg et al., 1986) . Reduced mucociliary clearance and the induction 33 of histopathologic lesions in the nose effects have been noted in human formaldehyde studies. 34This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 8 Histopathological lesions and biochemical changes have been reported in the lung 1 following formaldehyde inhal ation exposure in experimental animal studies (Kamata et al., 2 1996a; Ionescu et al., 1978) following high exposure levels (128.4 or 294.5 ppm formaldehyde). 3
4
6.1.3.3. Effects on Pulmonary Function 5 The potential of formaldehyde exposure to cause pulmonary functional deficits in 6 humans has been examined on several time scales. The epidemiologic literature includes studies 7 of acute exposures among naïvely exposed anatomy graduate students (Kriebel et al., 1993; 8 2001), anatomy graduate students with several weeks of episodic exposure (Kriebel et al., 1993), 9 and post

- shift versus pre

- shift worker pulmonary function among those with regular 10 occupational exposure (Malaka and Kodama, 1990; Herbert et al., 1994; Alexandersson et al., 11 1982; Alexandersson and Hedens tierna, 1989). Depending on whether the exposures are naïve 12 or not, the epidemiologic studies that assessed the pulmonary effects after acute exposures to 13 formaldehyde are assessing different biological responses, namely, the acute effect alone or the 14

acu te effect(s) in people who may have already been sensitized to different and unknown 15 degrees. 16 The observed effects in the previously unexposed anatomy students provide additional 17 information on acute exposures in two naïve populations (Kriebel et al., 1993 ; 2001), as well as 18 insight into the possible intermediate stages of sensitization (Kriebel et al., 1993). Kriebel and 19 colleagues (1993) examined the pre

- laboratory and post

- laboratory peak expiratory flow (PEF) 20 in students attending anatomy classes once a week. They found the strongest pulmonary 21 response when examining the average cross

- laboratory decrement in peak expiratory flow in the 22 first 2 weeks of the study when formaldehyde concentrations collected in the breathing zones 23 had a geometric average c oncentration of 0.73 ppm. Overall, the students exhibited a 2% 24 decrement in PEF, while the students with any history of asthma showed a 7.3% decrement in 25 PEF. These findings of acute decreases in PEF following students’ initial formaldehyde 26

exposure were corroborated by the Kriebel et al. (2001) study, using a similar study design 27 applied to a separate class of anatomy students. Similar findings have been reported for low

28 level residential formaldehyde exposure including decreased peak expiratory flow ra tes (PEFRs) 29 (Krzyzanowski et al., 1990). Workers chronically exposed to formaldehyde have exhibited signs 30 of reduced lung function consistent with bronchial constriction, inflammation, or chronic 31 obstructive lung disease. Lung function deficits have been reported both in pre

- shift versus post

32
shift measurements and as a result of chronic exposures (Malaka and Kodama, 1990; Herbert et 33 al., 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and 34 Hedenatiena 1989). Decreases in spir ometric values, including vital capacity (VC), forced 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 9 expiratory volume (FEV), forced vital capacity (FVC) and FEV/FVC have been reported in 1 humans. Chronic studies also reported increased respiratory symptoms such as cough, increased 2 phlegm, asthma, ches t tightness and chest colds in exposed workers (Malaka et al., 1990; Herbet 3 et al., 1994; Pourmahabadian et al., 2006, Alexandersson et al., 1982; Alexandersson and 4 Hedenatiena 1989). Similar findings have been reported following low

- level residential 5
for maldehyde exposure including decreased PEFRs (Krzyzanowski et al., 1990). 6 Worker exposures associated with cross

- shift differences in spirometric values are 7 consistent with formaldehyde

- induced sensory irritation. Concordance has also been reported 8
betw een subjective irritant response and measured changes in pulmonary function further 9 supporting the possibility that cross

- shift and short

- term evidence of bronchial constriction may 10 be a reflexive response to sensory irritation. 11
A well

- conducted resident ial epidemiology study by Krzyzanowski et al. (1990) was 12 considered to be the strongest among the candidate studies on the adverse pulmonary function 13 effects of formaldehyde for the purposes of deriving an RfC. 14
15
6.1.3.4. Asthmatic Responses and Increase d Atopic Symptoms 16 The health effects of respiratory function, asthma and increased atopic response, have 17 been shown to be clinically related. For example, asthma affects pulmonary function and may be 18 triggered by an allergic response. These and other da ta suggest that there may be mechanistic 19 links between these two health effects. Formaldehyde

- induced sensitization (Section 4.2.1.5) 20 may enhance the asthmatic response or may enhance an individual’s response to an allergen 21 (Section 4.4). In both cases, sensitization results in phenotypic switching

– or an individual 22 exhibiting clinical symptoms of a predisposition to asthma or atopy. Because of the connection 23 between the two endpoints, they are considered together herein. 24
Several cross

- sectional studies have described a positive association between 25 formaldehyde concentration and asthma prevalence. A study on risk factors for the initial 26 physician diagnosis of asthma have shown concentration

- dependent associations between 27 formaldehyde exposure and asthma (Rumchev et al., 2002). In a categorical analysis, Rumchev 28 et al. (2002) observed statistically significant effects above in

- home formaldehyde 29 concentrations of 60 μg/m 3 , with increased but non

- significant effects at 50

- 59 μg/m 3 that were 30
consistent with a concentration

- response relationship. No effect was apparent at concentrations 31
in the next lower interval b etween 30

- 49 μg/m 3 . Garrett et al. (1999) reported a borderline 32 statistically significant association between bedroom formaldehyde concentrations and an 33 increased risk of atopy. The authors computed a respiratory symptom score for each child based 34
on the frequency of each of eight respiratory symptoms and this score was substantially and 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 10 statistically significantly higher among the asthmatic children compared to non

- asthmatic 1 children. Health effects were reported at formaldehyde concentrations greater t han 50 μg/m 3 but 2 the lowest formaldehyde concentration interval at which health effects were observed was 20

- 50 3 μg/m 3 . The findings of Garrett et al. (1999) are supported by the results of a chamber study 4 reported by Casset et al. (2006) of 19 sensitized adult asthmatics exposed to formaldehyde at a 5 concentration of 100 μg/m 3 for 30 minutes. Casset and colleagues observed an increased 6 bronchial responsiveness to mite allergen exposure (p = 0.05) and noted the provocative dose 7 (PD20 for FEV1) for mite allergen w as 34.3 ng after formaldehyde exposure and 45.4 ng after 8 air exposure. However, in study by Ezratty et al. (2007) exposure to 500 μg/m 3 formaldehyde 9 did not affect an allergen

- induced increase in responsiveness to methacholine (p = 0.42) and 10
there was no formaldehyde

- associated effect on the airway inflammatory response. 11
These observed health effects in humans are similar to the outcome of studies in 12 laboratory animals that show that formaldehyde can exacerbate existing immunogenic 13 hypersensitivity to kn own allergens (Sadakane et al., 2002; Tarkowski and Gorski, 1995; Riedel 14 et al., 1996). While potentiation varied based on sensitization protocols and formaldehyde 15 exposure regimens, the results support the finding that formaldehyde exposure can aggravate a 16 Type

- I hypersensitivity response and may do so via a neurogenically initiated response. 17 Formaldehyde itself does not function as an allergen recognized by the immune system (Lee et 18 al., 1984) and does not appear to trigger formation of formaldehyde

- spe cific IgE. Although 19 formaldehyde exposure has been reported to alter cytokine levels and immunoglobulins in some 20 experimental systems (Fujimaki et al., 2004a; Ohtsuka et al., 2003), these effects do not support 21 an immunogenically mediated type

- I hypersens itivity. In studies in which either egg protein 22 (ovalbumin, OVA)

- sensitized or dust mite (DerF)

- sensitized animals were exposed to 23 formaldehyde, OVA

- specific and DerF

- specific antibody production was increased over 24 sensitization alone, suggesting that for maldehyde may potentiate sensitization responses (Riedel 25 et al., 1996; Sadakane et al., 2002). Formaldehyde

- induced sensitivity responses may be 26 neurogenic in origin based on findings that neurogenic factors such as nerve growth factor 27 (NGF) and substance P were associated with formaldehyde exposure in sensitization protocols 28 (Fujimaki et al., 2004). 29
30
6.1.3.5. Effects on the Immune System 31 Formaldehyde

- induced systemic immunomodulation in laboratory animals has been 32 documented in the literature (Leach et a l., 1983; Dean et al. 1984; Adams et al., 1987). A 33 number of studies have evaluated the ability of formaldehyde to induce systemic immunotoxic 34 effects in humans (Ohtani et al., 2004a, b; Erdei et al., 2003; Thrasher et al., 1990, 1987; Pross et 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 11 al., 1987) . Some studies have reported altered innate immune responses associated with 1 formaldehyde exposure (Erdei et al., 2003), while others have noted adaptive immune response 2 suppression associated with formaldehyde exposure (Thrasher et al., 1990, 1987) and c hanges 3 associated with alterations to a predominant T

— lymphocyte helper 2 (Th2) pattern (Ohtani et 4 al., 2004a, b). In contrast, Pross et al. (1987) did not observe formaldehyde

- associated changes 5 in systemic immune function. 6 Diverse studies have investiga ted the possibility that formaldehyde exposure leads to 7 increased respiratory tract infections (Lyapina et al., 2004; Krzyzanowski et al., 1990; Holness 8 and Nethercott, 1989). Lyapina et al. (2004) reported increased respiratory tract infections and 9
decre ased neutrophil respiratory burst activity in formaldehyde

- exposed workers (at 722 ppb 10 TWA). Incidences of doctor

- diagnosed chronic bronchitis were more prevalent in children 11 under age 15 living in homes with higher formaldehyde (>60 ppb) readings in the kitchen ( p < 12 0.001) (Krzyzanowski et al., 1990). Holness and Nethercott (1989) also report increased chronic 13 bronchitis in formaldehyde

- exposed funeral workers (380 ppb average exposure). 14
15
6.1.3.6. Neurological Effects 16 Formaldehyde exposure via inhala tion has been shown to adversely impact nervous 17 system function in laboratory animals and humans, although human data for formaldehyde

18 induced neurological effects are limited. Studies in formaldehyde

- exposed histology technicians 19 provide evidence of neur ological impairment, including lack of concentration, impaired memory, 20 disturbed sleep, impaired balance, variations in mood and irritability. These effects were 21 significantly correlated with increasing duration of exposure to formaldehyde, but the findin gs 22 are not conclusive due to confounding by concomitant exposures to other neurotoxic solvents 23 (Kilburn et al., 1985, 1987). In a prospective study, Weisskopf et al. (2009) found a strong 24 association between duration of formaldehyde exposure and death fro m amyotrophic lateral 25 sclerosis (ALS), but information regarding exposure levels was not available. Short

- term studies 26 with controlled exposure to humans (chamber studies) also provide limited support for changes 27 in cognitive function immediately followin g a single, controlled formaldehyde exposure (Bach et 28 al., 1990; Lang et al. 2008). 29 Available animal data provide substantial evidence of behavioral changes in animals 30 following single or short

- term repeated inhalation exposures to relatively low levels of 31 formaldehyde. Among the animal studies, none of the available studies examined effects on 32 nervous system function following chronic formaldehyde inhalation, however. 33 Reported perturbations in nervous system function following formaldehyde exposure in 34

a nimal studies include reductions in motor activity, lack of habituation, impairment in 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 12 acquisition of a new learning task, deficits in retention of a previously learned task, increases in 1 corticosterone levels, sensitization to cocaine

- induced locomotor ac tivity, and enhanced fear 2 conditioning using an olfactory conditioned stimulus (CS) (see Table 4

- 57). Behavioral effects 3 have been seen in multiple laboratories and in studies conducted by different investigators using 4 a variety of testing paradigms. Man y of these effects were observed at acute exposure levels at 5 or below 1.0 ppm, and some persisted days to weeks after termination of exposure. 6 More limited data indicate possible effects on the development of the nervous system, 7 including changes in brain structure and in the behavior of offspring (Table 4

- 57). Similarly, 8 there is very little information regarding the mechanism by which effects on the nervous system 9 might be produced. The data regarding behavioral sensitization provide some support for a 10

stress

- related mechanism for those specific findings, but the applicability of this mechanism to 11 the behavioral changes seen in the other studies, including the learning deficits and 12 developmental findings, has not been evaluated. Although there are data supporting stimulation 13 of the trigeminal nerve by formaldehyde (and documenting the relevance of this interaction to 14 the sensory irritation caused by formaldehyde), there are no data supporting a causal relationship 15 between irritant properties of formaldeh yde and the behavioral and neurodevelopmental effects 16 in humans that occur following formaldehyde exposure. In summary, none of the available data 17 provide sufficient information to allow a determination of the mode of action for effects of 18 formaldehyde on the adult or developing nervous system. 19
20
6.1.3.7. Reproductive and Developmental Effects 21 Formaldehyde inhalation exposure has been associated with adverse developmental and 22 reproductive outcomes in both epidemiologic studies and experimental animal st udies. Observed 23 developmental outcomes include fetal loss, structural alterations, growth retardation, and delays 24 in functional development. 25 Several occupational studies found an increased risk of spontaneous abortions among 26 formaldehyde

- exposed women (Ta skinen et al., 1999, 1994; John et al., 1994; Seitz and Baron, 27 1990; Axelsson et al., 1984). The Taskinen et al. (1999) study examined several reproductive 28 outcomes in women employed in the wood

- processing industry, with a range of average daily 29
formaldeh yde exposures. The authors found that formaldehyde was associated with a more than 30
three

- fold increased risk of spontaneous abortion, and with a nearly 50% decrease in a measure 31 of delayed conception indicating reduced fertility, an increased time to preg nancy, and an 32 increased risk for endometriosis in this study. In experimental animal studies, early fetal death 33 was noted following maternal formaldehyde exposures (Kitaev et al., 1984; Sheveleva, 1972), 34 supporting the epidemiologic findings that the spon taneous abortion is likely related to 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 13 formaldehyde exposure. Kitaev et al. (l984) hypothesized that formaldehyde may affect 1 reproductive function by stimulating the hypothalamus

- pituitary

- gonadal (HPG) axis, based on 2 their observations of increased ovary weight, increased number of ovulating cells, and changes 3 in blood levels of gonadotropins (LH and FSH) in female rats. Additionally, Maronpot et al. 4 (l986) reported endometrial hypoplasia with a lack of ovarian luteal tissue in formaldehyde

5 exposed female rats. This finding may be relevant to the increased risk for endometriosis noted 6 in the Taskinen et al. (1999) study. However, additional human and animal studies are needed to 7 better understand the effects of inhalation exposure to formaldehyde on deve lopmental outcomes 8 after early gestational windows of exposure or on the female reproductive system. 9 The findings of some occupational studies have suggested formaldehyde

- related 10 associations with congenital malformations and low birth weight. In numerous experimental 11 animal studies, developmental effects have been noted following inhalation exposures to 12 formaldehyde (Table 4

- 68). Exposure of rat dams to formaldehyde during pregnancy has been 13 shown to result in significantly decreased fetal weight gain (M artin, 1990; Saillenfait et al., 14 1989; Kilburn and Moro, 1985). Other studies have noted changes in relative organ weight, 15 undescended testes, biochemical changes (e.g., ascorbic acid), and blood acidosis (Senichenkova 16 and Chebotar, 1996; Senichenkova, 19 91; Kilburn and Moro, 1985; Gofmekler and 17 Bonashevskaya, 1969; Gofmekler, 1968; Pushkina et al., 1968). 18 Studies designed to assess adult male reproductive system toxicity in rats following 19 repeated inhalation exposures to formaldehyde have found concentrat ion

- dependent decreases in 20 Leydig cell number and quality, degeneration of seminiferous tubules, decreases in testes weight, 21 alterations in sperm measures, decreased testosterone levels, alterations in trace metals in the 22 testes, and/or dominant lethal eff ects (Guseva, 1972; Özen et al., 2002, 2005; Sarsilmaz et al., 23 1999; Xing et al., 2007; Zhou et al., 2006) (Table 4

- 71). 24
25
6.1.3.8. Effects on General Systemic Toxicity 26 Extrapulmonary effects such as changes in liver function enzymes and focal, chronic 27
i nflammation in the heart and kidney have been observed due to formaldehyde exposure in 28 experimental animal studies. Most of these changes occurred at exposures of 20 ppm, and those 29 that occurred at lower formaldehyde exposures (3.7 ppm) were confounded by coexposures. The 30 underlying modes of action of liver, kidney, and cardiac effects have not been elucidated, and the 31
human relevance is unknown. 32
33
34
35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 14 6.1.3.9. Summary 1 Formaldehyde

- induced eye, nose and throat irritation, decreased pulmonary function, 2
decre ased mucociliary clearance and histopathological lesions have been extensively 3 documented in human and laboratory animal studies. These health effects are commonly noted 4 at the portal of entry as expected for exposure to a reactive gas. In addition, effe cts on immune 5 system responses and on the nervous and reproductive systems, including developmental effects, 6 have also been reported. An association between formaldehyde exposure and increased 7 incidence and severity of response to allergens (i.e., asthma and atopy) has been noted in 8 humans. This effect, which has also been studied in laboratory animals, might occur via a 9 neurogenic mode of action. A limited database of information that evaluates neurological effects 10 in humans following formaldehyde expos ure demonstrates a potential for adverse outcomes, and 11 studies in laboratory animals have reported a variety of formaldehyde

- induced neurobehavioral 12 and neurodevelopmental effects. Formaldehyde has also been associated with adverse 13 reproductive outcomes. Human studies have reported an association between formaldehyde 14 exposure and decreased fertility as well as an increased risk of spontaneous abortions. Other 15 human studies have suggested formaldehyde

- related associations with congenital malformations, 16
lo w birth weight, and endometriosis. Animal studies have noted a variety of developmental 17 effects, including fetal death, structural alterations, and growth retardation (e.g., delayed fetal 18 skeletal ossification and decreased fetal body weight) following in halation exposure to 19 formaldehyde, and adverse reproductive effects have been observed in both males and females. 20
21
6.1.4 Carcinogenicity in Humans and Laboratory Animals 22
6.1.4.1 Carcinogenicity in Humans 23 Based on the total weight of evidence, including the res ults from a large and well

24 followed longitudinal cohort study of 25,619 industrial workers and several case

- control studies, 25 the epidemiologic evidence is sufficient to characterize the association between formaldehyde 26 nasopharyngeal cancer as causal in hu mans (Hauptmann et al., 2004; Hildesheim et al., 2001; 27 Vaughan et al., 2000). As further evaluated below, the evidence supporting a positive association 28 between formaldehyde exposure and NPC is unlikely due to chance, bias or confounding. 29 However, it shou ld be noted that other smaller studies of formaldehyde

- exposed workers did not 30 document increased NPC mortality (e.g., Coggon et al., 2003; Pinkerton et al., 2004). These 31 smaller study sizes yielded effect estimates with wide confidence intervals that were not 32 statistically inconsistent with the increased risk of mortality from nasopharyngeal cancer 33 reported in Hauptmann et al. (2004). 34This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 15 Luce et al. (2002) evaluated pooled data from 12 case

- control studies conducted in seven 1 countries using a common job

- exp osure matrix and demonstrated a statistically significant 2 increased risk between formaldehyde exposure and sinonasal cancer exhibiting a concentration

3 response relationship providing further causal evidence of carcinogenicity. This analysis was 4
based on a very large dataset of 930 cases and 3136 controls, enabling the investigators to 5 control for multiple potential sources of bias and confounding and to conduct separate analyses 6 by histological type. These results are particularly convincing, as the assoc iation was 7 consistently seen for a rare sub

- type of sinonasal cancer which normally accounts for only 10% 8 of the reported cases. 9 In addition to the evidence of formaldehyde carcinogenicity in the nasopharynx, nose and 10 sinuses, other upper respiratory tract sites of direct contact with formaldehyde upon inhalation 11 (i.e., larynx, mouth and salivary gland) also showed evidence of increasing relative risk with 12 increasing average intensity and peak exposure in a large cohort study with exposure estimates 13
for the individual workers, although these trends did not reach the level of statistical significance 14 (Hauptmann et al., 2004). However, Hauptmann and colleagues (2004) concluded that in spite 15 of the small numbers of deaths from these rare cancers of the upper r espiratory tract, the positive 16 associations of increased cancer risk with increased formaldehyde exposure were consistent with 17 the carcinogenicity of formaldehyde at these sites of first contact. Case

- control studies also 18 provide evidence of an associatio n between formaldehyde exposure and oral squamous cell 19 carcinoma (SCC), esophageal, and laryngeal cancers, and hypopharyngeal cancer (Gustavsson et 20 al., 1998; Laforest et al., 2000.) 21 The finding that formaldehyde inhalation causes nasal squamous cell carci noma in 22 rodents (Section 4.2.1.2) further supports the determination of a causal association of 23 formaldehyde exposure and increased risk of upper respiratory tract cancer in humans. Both 24 humans and animals developed tumors within the upper respiratory tra ct, the site expected to 25 receive direct exposure to formaldehyde. 26 Several researchers have argued that the relationship between formaldehyde exposure 27 and nasopharyngeal cancer based on existing studies has not been determined. Several 28 limitations, such as the rarity of the cancer and the imprecise estimates of exposure, are often 29 inherent in epidemiologic methods and exposure assessment. These constraints limit the ability 30 of epidemiologic studies to statistically detect associations and can lead to false negatives. The 31 results of the largest cohort study of nasopharyngeal cancer (Hauptmann et al., 2004) showed 32 statistically significant concentration

- response relationships with increased risk of cancer 33 associated with increased formaldehyde exposure. How ever, even though this study was based 34 on 25,619 workers, only 9 cases of nasopharyngeal cancer were observed, compared to an 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 16 expected number of 5 cases, for a relative rate of 2.1 (with a confidence interval of 1.05

- 4.21) 1 (Hauptmann et al., 2004). 2
The n ext largest cohort study of nasopharyngeal cancer was based on 14,014 workers 3 (Coggon et al., 2003) and reported only 1 case compared to an expected number of 2 cases, for a 4 relative risk of 0.5 (with an estimated 95% confidence interval of 0.07 − 3.55; se e Bosetti et al., 5 2007). To put this finding into perspective, it is helpful to note not only the relative risk but also 6 that this effect estimate is highly unstable due to a lack of statistical power. The large width of 7 this interval (0.07 − 3.55) indic ates that the range of possible true values includes both increased 8 and decreased NPC mortality and therefore does not contradict the evidence of elevated risk of 9 nasopharyngeal cancer mortality associated with formaldehyde exposure reported by Hauptmann 10

e t al. (2004). The even smaller study of 11,039 textile workers by Pinkerton et al. (2004) 11 reported no cases of nasopharyngeal cancer compared to an expected number of one case − 12 yielding an effective relative risk of zero with a highly unstable 95% confid ence interval 13
estimated at 0 − 3.00 (see Bosetti et al., 2007). While true that Pinkerton et al. (2004) did not 14 report an increased risk of nasopharyngeal cancer, this study did not have sufficient statistical 15 power to rule out a true association with les s than a 3

- fold increase in risk and therefore is 16 likewise not inconsistent with the finding by Hauptmann et al. (2004). Thus, results from these 17 cohort studies, with limited power to detect the relatively rare upper respiratory tract cancers 18 (e.g., NPC), are given less weight in the overall evaluation. 19 The largest occupational cohort study, conducted by the NCI (Hauptman et al., 2004), did 20 report statistically significant associations of formaldehyde exposure with carcinogenicity at the 21
sites of first cont act with sufficient statistical power to rule out the null hypothesis of no 22 association. The NCI investigations controlled for potential selection bias due to the healthy 23 worker effect and for several potential confounders, including calendar year, age, s ex, race, and 24 pay category. However, other potential sources of bias or confounding have been suggested with 25 respect to the strength of these data to support a causal conclusion. 26 Following reports of increased risk of NPC associated with formaldehyde expo sure, a 27 series of analyses of similar data were undertaken by Marsh and coworkers (Marsh et al., 2007a, 28 b, 2002, 1996; Marsh and Youk, 2005). Briefly, these studies focused on the specific findings 29 from a single plant in the NCI cohort (Wallingford, Conne cticut) that generated the majority of 30 the NPC cases. Marsh et al. (1996) confirm a significant adverse association of formaldehyde 31 with nasopharyngeal cancer but note the effects are predominantly among workers at the 32 Wallingford plant with less than one year employment. Marsh et al. (2002) report a five

- fold 33 excess in risk of nasopharyngeal cancer associated with formaldehyde in both short

- term and 34 long

- term workers but note that the increase was concentrated among workers hired during 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 17 1947

- 1956. Marsh a nd Youk (2005) re

- evaluated the same Wallingford workers and reported a 1 regional rate

- based standardized mortality ratio (SMR) of 10.32 (95% CI = 3.79 − 22.47) 2 compared to 0.65 (95% CI = 0.08 − 2.33) for workers at the nine other plants combined. 3 However, Marsh and Youk (2005) also show that rate

- based mortality ratios standardized to both 4 U.S. and local populations were elevated (non

- significantly) not only at the Wallingford plant 5 but individually at each of the four other plants at which a single case of nasopharyngeal cancer 6 was reported: Plant 2 (SMR US = 5.35), Plant 3 (SMR US = 1.99), Plant 7 (SMR US = 1.06), and 7 Plant 10 (SMR US = 1.44). It should b e noted that Plant 1 (Wallingford) and Plant 2 had both the 8 two highest median formaldehyde exposures and the two highest reported excess risks (Marsh 9 and Youk, 2005). 10
In another re

- analysis of the NCI cohort data on the workers at the Wallingford plant, 11
M arsh and coworkers (2007a) suggested that an imprecise assessment of formaldehyde exposure 12 and an inability of the study to separate formaldehyde exposure from other potential chemical or 13 particulate exposures may have confounded the observed association b etween formaldehyde and 14 cancer. However, there was no evidence of any differential measurement error that could have 15 produced the observation of a spurious association. Any non

- differential exposure measurement 16 error (i.e., random error in the exposure a ssessment) would likely have led to an attenuated 17 observed effect of formaldehyde that was less than that which would otherwise have been 18
observed in the absence of measurement error. 19 The potential for confounding by particulates was explicitly examined by Hauptmann et 20 al. (2004) and it was shown that there was an exposure

- response relationship with formaldehyde 21 among individuals with high particulate exposures

– alleviating the potential for confounding 22 and thereby strengthening the causal interpretation o f the formaldehyde relationship with an 23 increased risk of NPC. Marsh and coworkers (Marsh et al., 2007b) later suggested the reported 24 formaldehyde association was confounded by an association between silversmithing and NPC. 25 However, careful examination o f that analysis (Marsh et al., 2007a) suggests that multiple 26 comparisons may have led to the reported observation with silversmithing. Additionally, the 27 reported effect was inconsistently reported between the results and the abstract sections using 28
differ ent confidence intervals, and both sets of confidence intervals around the reported 29 association were extremely unstable spanning up to several hundred

- fold. No prior studies 30 identified an associated between silversmithing and NPC. Thus it may be that sil versmithing is 31 an artifactual potential confounder. 32 The increased NPC mortality observed in the NCI cohort (Hauptmann et al., 2004) has 33 been thoroughly examined for sources of bias and confounding by both the primary researchers 34 and Marsh and coworkers ( Marsh et al., 2007a, b, 2002, 1996; Marsh and Youk, 2005). Despite 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 18 the extensive scrutiny of these results, no convincing and consistent alternative hypothesis of 1 causation has been identified. Taken together with the statistically significant associatio n 2 demonstrating an exposure

- response relationship within exposed workers, these data support the 3 conclusion that the association between formaldehyde exposure and increased risk of NPC is 4
causal. 5 Therefore, after a thorough examination of potential confoun ders, the association 6 between formaldehyde exposure and NPC mortality in the NCI cohort remains significant and 7 provides a positive exposure

- response relationship. Additionally, case

- control studies, which 8 have greater statistical power than cohort studie s for rare diseases, provide strong additional 9 evidence in support of a causal association between formaldehyde exposure and the incidence of 10 NPC (Hildesheim et al., 2001; Vaughan et al., 2000). As these studies draw from different 11 demographic groups, reg ions of the world, and evaluate various confounding factors, there is 12 little potential for these consistently reported associations to be artifactual, confounded by 13 common exposures, or a result of bias or chance. 14 Numerous epidemiologic studies have also r eported an association between 15 formaldehyde

- exposed workers, especially "professional" workers (e.g., pathologists, 16 embalmers, and funeral directors), and increased risk of lymphohematopoietic cancers (See 17
Table 4

- 82). Positive associations between formal dehyde exposure and lymphohematopoietic 18 cancers have been reported for chemical workers (Wong et al., 1983; Bertazzi et al., 1986), 19 embalmers (Walrath and Fraumeni, 1983, 1984; Hayes et al., 1990), anatomists and pathologists 20 (Harrington and Shannon 1975; Hall et al., 1991; Levine at al., 1984; Stroup et al., 1986; 21 Matanoski et al., 1989). However, clear associations (in terms of overall standardized mortality 22 ratios (SMRs) or proportional mortality ratios (PMRs) were not reported in analyses for garment 23

w orkers, iron

- foundry workers, and a large US industrial cohort (Pinkerton et al., 2004; 24 Andjelkovich et al., 1995; Beane Freeman et al., 2009; Marsh et al., 1996), although associations 25 were observed in some of these studies when exposure

- response relation ships were considered. 26 Several published meta

- analyses are available which more formally assess the strength of 27 association between formaldehyde exposure and mortality from all lymphohematopoietic 28 cancers. Pooled SMRs indicate stronger associations for p rofessional workers (embalmers, 29 anatomists and pathologists) than industry workers (Table 4

- 83). Bosetti et al. (2008) found 30 similar relationships, with a pooled SMR of 1.31 (95% CI 1.16

- 1.47) for ‘professionals’ (i.e. 31 embalmers, anatomists and pathologis ts) versus a pooled estimate of 0.85 (95% CI 0.74

- 0.96) for 32
industrial workers. A recent meta

- analysis by Zhang et al. (2009) reports a summary relative 33 risk of 1.25 (95% CI 1.09

- 1.43) for both professional and industry workers for all 34 lymphohematopoietic cancers (ICD 9 codes 200

- 209). 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 19 Two well

- designed cohort studies found significant positive associations between 1 formaldehyde

- exposed professional workers and lymphohematopoietic cancer, particularly 2 leukemia, using cumulative exposure measures not previo usly used and using internal 3 comparison groups. The largest cohort study of industrial workers exposed to formaldehyde 4 (N=25,619), with the most extensive exposure assessment (Blair et al., 1986; Stewart et al., 5 1986) and with the cohort followed for a me dian duration of 35 years (Hauptmann et al., 2003) 6 demonstrated that formaldehyde was a risk factor for lymphohematopoietic cancers, independent 7 of other risk factors, such as benzene exposure and smoking. This finding was re

- confirmed 8
with an additional 10 years of follow

- up (Beane Freeman et al., 2009). Another industrial cohort 9 study reported a significant increase in the risk of leukemia in garment workers 20 years after 10 their initial exposure and in workers with 10 or more years of exposure to formal dehyde 11 (Pinkerton et al. 2004). A third large occupational cohort study (Coggon et al., 2003) that did 12 not evaluate their findings with regard to latency reported somewhat lower mortality from 13 leukemia and other lymphatic and hematopoietic cancers than ex pected compared to national 14

rates. 15 The associations between myeloid leukemia and formaldehyde exposure are strong and 16 consistent (Table 4

- 84). Of the four studies which formally assess myeloid leukemia mortality, 17 all are positive, including cohorts of both professional and industrial workers (Beane Freeman et 18 al., 2009; Hayes et al., 1990; Pinkerton at al., 2003; Stroup et al., 1986). Although few cases 19 exist for further subtype analysis, the available data indicate either no differences in SMRs for 20

ac ute myeloid leukemia (AML) versus chronic myeloid leukemia (CML) ( Hayes et al., 1990; 21 Pinkerton et al., 2003) or suggest CML is more prominent (Blair et al., 2000; Stroup et al., 22 1986). The association between formaldehyde exposure and myeloid leukemia in embalmers has 23 recently been confirmed in a large nested case control study by Hauptman et al (2009) which 24 includes cases identified from the previous studies of Hayes et al. (1990) and Walrath and 25 Fraumeni (1983 and 1984). Exposure estimates were based o n interviews with next

- of kin for 26 duration of job actively embalming and total number of embalmings performed. Strong and 27 statistically significant exposure

- response relationships are demonstrated for duration of 28 exposure, total number of embalmings perf ormed and estimated cumulative exposure to 29 formaldehyde with odds ratios of 13.6 (1.6

- 119.7), 12.7(1.4

- 112.8) and 13.2(1.5

- 115.4) 30 respectively (Hauptmann et al., 2009). 31 The reported associations between formaldehyde exposure and lymphohematopoietic 32

cance rs in general, and leukemia (especially myeloid leukemia) in particular, were in workers 33 exposed in very different environments (i.e., mortuary, chemical industry and garment industry). 34 Since coexposures to other agents are considerably different between t hese work environments, 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 20 it is unlikely that influence of confounding exposures plays a role in the observed associations. 1 There is no evidence of bias in the published reports, and the consistency across numerous 2
studies over time is sufficient to conclude that the results are not due to chance. 3 It has been argued that it is biologically implausible for a highly reactive agent such as 4 formaldehyde, whose primary action is expected to be at the portal of entry, to cause acute 5 lymphoid or myeloid leukemias (A LL and AML, respectively), which are both commonly 6
believed to arise from transformation of stem cells in the bone marrow. The modes of action 7 (MOAs) by which formaldehyde may induce these observed cancers are unknown, although it 8 has been postulated that circulating stem cells (Hauptmann et al., 2003) (e.g., early progenitor 9 cells in circulating blood or pluripotent cells in nasal/oral passages) may travel to bone marrow 10 where they become leukemic stem cells (Zhang et al., 2009). In contrast, the mechani sm for the 11 chronic lymphatic leukemia, lymphomas, multiple myelomas (from plasma B

- cells) and 12 unspecified lymphohematopoietic cancers may involve an etiology in peripheral tissues, such as 13 cells, cell aggregates, germinal centers and lymph nodes. An assoc iation of these cancers to a 14 reactive exogenous agent primarily acting at the point of entry is biologically plausible. 15
16
6.1.4.2 Carcinogenicity in Laboratory Animals 17 The carcinogenic potential of formaldehyde is well documented in numerous animal 18 bioassays, espec ially for sites of first contact. Inhalation exposure of formaldehyde induced 19 primarily squamous cell carcinomas (SCC) in nasal passages of rats (Feron et al., 1988; 20 Holmström et al., 1989a; Woutersen et al., 1989; Tobe et al., 1985; Kamata et al., 1997; Albert et 21 al., 1982; Sellakumar, 1985; Kerns et al., 1983; Monticello et al., 1996) and mice (Battelle 22 Columbus Laboratories, 1981; Swenberg et al., 1980; Kerns et al., 1983; CIIT, 1982). 23 Formaldehyde given as 0.5% formalin orally in drinking water to adu lt rats induced higher 24 incidences of papillomas in the forestomach, adenomatous hyperplasia in the fundus, and 25 adenocarcinomas in the pylorus in a 40

- week study using an initiation

- promotion protocol in rats 26 (Takahashi et al., 1986). Soffritti et al. (198 9) observed a significant increase in rare tumors in 27 the gastro

- intestinal (GI) tract, including both benign (papillomas and acanthomas of the 28 forestomach and adenomas) and malignant tumors (adenocarcinomas and leiomyosarcomas) in 29 rats given formaldehyde i n drinking water. Formaldehyde is toxic at the portal of entry in 30 rodents, causing increased cell proliferation, DPX formation, and focal lesions in the GI tract or 31 upper respiratory tract (depending on the route of exposure). The portal of entry toxicit y of 32 formaldehyde further supports a finding of formaldehyde induced POE cancer in animal 33 bioassays. 34This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 21 Direct support for lymphohematopoietic cancers in animal bioassays is less convincing. 1 Although many of the available chronic studies did not examine ly mphoma/leukemia incidence, 2 two studies provide positive evidence. Inhalation exposure of formaldehyde increased 3 lymphoma in female mice and leukemia in female F344 rats, but not male rats (Battelle 4 Laboratories, 1981). Drinking water exposure to formalde hyde caused a dose

- dependent 5 increase in all hemolymphoreticular neoplasias, especially lymphoblastic leukemias and 6 lymphomas in both male and female Sprauge

- Dawley rats (Soffritti et al., 1989, 2002). 7 Conversely, no increases were seen in male Wistar rat s when exposed to formaldehyde in 8 drinking water at similar levels (Til et al., 1989) or male rats after chronic inhalation exposures 9 (Sellakumar et al., 1985). 10
11
6.1.4.3 Carcinogenic Mode(s) of Action 12 Multiple plausible modes of action (MOAs) are present ed in the document so as to 13 explore ways in which a combination of factors may contribute to cancer incidence in a 14 population exposed to formaldehyde. Multiple MOAs for formaldehyde

- induced cancer can be 15 reasonably supported based on various known biologi cal actions of formaldehyde (e.g., 16 mutation, cell proliferation, cytotoxicity and regenerative cell proliferation). Additionally, 17 alternative actions, such as immunosuppression or viral reactivation, are possible, although few 18
data exist to evaluate their potential relevance. Rather than a single MOA, it is plausible that a 19 combination of these factors contribute to cancer incidence in an exposed population. 20 Considering multiple factors may help to better understand the biological and mechanistic basis 21
f or the increases in cancer incidence observed in exposed human populations. Unlike animal 22 bioassays, results in human epidemiological studies reflect not only the effects of the agent of 23 concern but also numerous other risk factors (e.g., viral status, di et, smoking, etc.). Additionally, 24 human studies may be impacted by biological human variability across individuals, cancer 25 biology (sub

- types) and wide variability in exposure regimens in human populations. 26 A preponderance of the evidence supports a rol e of mutagenic activity in formaldehyde’s 27 carcinogenic MOA both for respiratory tract cancer and lymphohematopoietic cancers. As 28 reviewed in Section 4.3, numerous studies provide evidence of formaldehyde’s direct mutagenic 29 activity and supports the releva nce these data to formaldehyde’s carcinogenicity. It can be 30
shown that: 31 1) Formaldehyde directly interacts with DNA, generating DNA

- protein cross

- links and 32 DNA adducts (in vitro, in vivo) in multiple species, 33This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 22 2) DNA

- protein cross

- links exhibit a dose

- resp onse relationship to formaldehyde 1 exposure in respiratory tract of laboratory animals and are observed at exposure 2 concentrations of relevance to some people (0.3 ppm, 0.7 ppm), 3 3) Formaldehyde

- induced DNA

- protein cross

- links have been associated with 4
form aldehyde

- induced micronuclei and chromosomal aberrations (in vitro), 5 4) Mutations induced by formaldehyde due to small deletions and rearrangements in 6 DNA in various experimental systems are consistent with formaldehyde’s 7 observed clastogenic effects (micr onuclei and chromosomal aberrations) (in vitro, 8 in vivo), 9 5) Formaldehyde

- induced mutations and clastogenic effects occur at levels below where 10 significant cytotoxicity is detected (in vitro), 11 6) Formaldehyde exposure has been correlated to similar increas ed micronuclei and 12 chromosomal aberrations in human buccal and oral cells corresponding to sites 13 where formaldehyde

- induced tumors arise, and 14 7) Chromosomal damage in blood

- borne immune cells, relevant to agent

- induced 15 lymphohematopoietic cancers has been documented in formaldehyde exposed 16 workers including increased micronuclei and chromosomal aberrations, increased 17 incidence and aneuploidy in hematopoietic stem cells. 18
19 In addition, mutations may arise indirectly from formaldehyde

- induced DNA damage 20
durin g cell proliferation or due to errors in DNA repair mechanisms. Therefore, formaldehyde’s 21 DNA reactivity on a population of proliferating cells strengthens the role of formaldehyde

22 induced mutagenicity in its carcinogenic MOA. The nasal and gut mucosa are tissues which are 23 continually sloughing and regenerating cells (Junqueira et al., 1992). Mucosal cells proliferate 24 in response to environmental challenges in order to repair cell damage, increase adaptive 25 response and remodel tissue. Additionally, since the pseudostratified epithelium of the 26 respiratory tract is only 1

- 2 cells in depth, cells with proliferative capacity would be directly 27 impacted by formaldehyde during exposure. Formaldehyde

- induced clastogenic effects have 28
been demonstrated in these ti ssues (e.g. nasal) in humans, as well as in tissues which possess 29 stratified epithelium (e.g. buccal). Therefore, formaldehyde would not need to transport beyond 30 the portal of entry to directly impact and induce DNA mutations in routinely proliferating ce lls. 31 In regards to generating the observed clastogenic effects (micronuclei and chromosomal 32 aberrations in peripheral blood lymphocytes, aneuploidy in circulating hematopoietic stem cells), 33 it is less clear as to where formaldehyde is making contact with c omponents of the immune 34 system. Mature lymphocytes present in nasal and gut tissues, and would be vulnerable to the 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 23 direct toxic actions of formaldehyde including genotoxicity. Since mature lymphocytes 1 routinely traffic through the body and clonally resp ond in response to an immune challenge, the 2 observed effects in peripheral blood lymphocytes (micronuclei and chromosomal aberrations) 3 are consistent with direct action on these cells. Lymphohematopoietic cancers are known to 4 arise from mature lymphocytes including: Hodgkin lymphoma, multiple myeloma some 5
leukemia and non

- Hodgkin lymphoma (Greaves 2004, Harris et al., 2000). 6 Formaldehyde may also be directly acting upon circulating stem cells or more mature 7 progenitor cell in the peripheral blood (Zhang et al., 2010). Any genetic damage sustain by 8 circulating cells could contribute to a broad spectrum of lymphohematopoietic cancers if those 9 cells returned to the bone marrow and contributed to hematopoiesis. Evidence of bone marrow 10 toxicity and stem cell aneuploidy has been reported in formaldehyde exposed workers (Zhang et 11 al., 2010). Finally, formaldehyde is readily hydrated in aqueous systems, existing in equilibrium 12 with its hydrated form methylene glycol, which is able to transport through the blood . It has 13 been hypothesized that this hydration reaction may allow formaldehyde to act systemically and 14 therefore on the bone marrow directly (Zhang et al., 2010.) Formaldehyde

- induced DNA 15 damage, and resulting mutation in the bone marrow and circulating stem cells could contribute to 16 any of the lymphohematopoietic cancers including leukemia (both lymphoid and myeloid) as 17 well as myeloproliferative disorders. 18 Cell replication allows unrepaired DNA damage to be “fixed” into heritable changes to 19 the genome. Therefore, increased cell proliferation could serve not only to increase the 20 mutagenic effects of formaldehyde on a given tissue but also to enhance the mutagenic effects of 21 other agents in the diet or in the environment. Since epidemiological studies i nclude humans 22 exposed to a range of agents in the environment, increased cell proliferation could contribute to 23 increased cancer incidence. The promotion studies in animal bioassays, though limited in 24 number, support the relevance of formaldehyde’s abilit y to enhance the actions of other agents 25 (initiators) on tumor formation. 26 Although the other biologic effects discussed above have not been explicitly tested in 27 animal systems, the available data are consistent with these actions contributing to the 28

carc inogenic potential of formaldehyde. For example, localized immunosuppression by 29 formaldehyde may serve to increase viral reactivation (e.g., EBV, HPV etc.) or decrease tissue 30 surveillance and immune activity against preneoplastic cells. Both these action s could contribute 31 to increased cancer risk in a human population, which may not be evident in animal bioassays, 32 where the animals are not subject to the many risk factors for human cancer. Even the simple 33 action of the breakdown of the mucociliary appara tus could increase cancer incidence by 34This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 24 increasing toxic insult to the URT and increasing URT infections. Again, these actions may be 1 relevant to human populations, but they have not been adequately tested in animal bioassays. 2 Animal bioassays suggest a ro le for regenerative proliferation in contributing to 3 formaldehyde’s carcinogenicity. However, these data are not evidence against a role of direct 4 mutagenic action either in the observed tumorigenicity or in the potential low

- dose 5 carcinogenicity of forma ldehyde. As reviewed, a role for mutagenic action is also consistent 6 with the results of the animal bioassays (Crump et al, 2008; Subramaniam et al., 2007, USEPA 7 2008). The mutagenic effects of formaldehyde are well

- documented to occur below levels of 8
si gnificant cytotoxicity. This observation is important for the relevance of formaldehyde

9 induced mutagenicity to human health risk. Given the above sequence of evidence

- from the 10 nature of formaldehyde’s DNA reactivity through clastogenic effects observe d in human cells 11
from the various tumor sites

- there is an adequate weight of evidence (WOE) to consider 12 formaldehyde

- induced mutations relevant to human carcinogenic risk. Although occupational 13 exposures may have resulted in high episodic exposures (esp ecially historically), it is unlikely 14 that any worker would have endured repeated exposures which resulted in gross focal lesions to 15 the upper respiratory tract (URT) or oro

- digestive tract as seen in the animal bioassays. It is 16 noteworthy that even witho ut these gross formaldehyde

- induced lesions, cancer incidence is 17 increased from occupational (and perhaps non

- occupational) exposures to formaldehyde. 18 Therefore, we believe formaldehyde carcinogenicity can be attributed, at least in part, to a 19 mutagenic M OA. 20
21
6.1.5 Cancer Hazard Characterization 22 Formaldehyde is carcinogenic to humans by the inhalation route of exposure. There is 23 sufficient evidence of causal associations between formaldehyde exposure and nasopharyngeal 24
cancers as well as sinonasal cancer s

. There is supporting evidence for cancers of the mouth and 25 throat in humans as well as strong evidence for nasal tumors in animal bioassays. Taking these 26 findings together along with mode of action considerations, it is concluded that there is sufficie nt 27 evidence of a causal relationship between formaldehyde inhalation exposure and upper 28 respiratory tract cancers as a group. 29 Epidemiologic studies also provide evidence of a causal association of inhalation 30 exposure to formaldehyde and lymphohematopoietic cancers as a group and leukemias as a 31 group, with the strongest evidence for myeloid leukemia. There is supporting evidence both in 32
cohort and case

- control studies for specific sub

- types of lymphohematopoietic cancers, including 33 myeloid leukemia, multipl e myeloma and Hodgkin lymphoma. There is limited supporting 34 evidence in animal bioassays for both leukemia and lymphoma. It should be noted that although 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 25 several carcinogenic modes of action have been discussed for leukemia, that this remains an area 1
of significant scientific debate. 2
3
6.2 DOSE

- RESPONSE CHARACTERIZATION 4
6.2.1 Noncancer Toxicity: Reference Concentration (RfC) 5 The portals of entry are major targets for formaldehyde, as can be seen in many studies, 6 because formaldehyde is highly reactive and water so luble. Human and laboratory animal 7 studies demonstrate that formaldehyde also causes systemic effects, including neurotoxicity, 8 reproductive toxicity, developmental toxicity, and immunotoxicity, although the data are less 9 extensive than those supporting t he sensory irritation and respiratory tract effects. Critical data 10 gaps have been identified and uncertainties associated with data deficiencies are more fully 11 discussed in Chapter 5 and summarized below. 12
13
6.2.1.1 Assessment Approach Employed 14
RfC values for nonca ncer effects are derived using EPA’s RfC methodologies (U.S. 15 EPA, 1994, 1993, EPA 2002b). EPA reviewed the existing literature and identified health 16 effects associated with formaldehyde exposure, defining health effect categories where evidence 17
was suffi cient: sensory irritation, respiratory tract pathology, pulmonary effects, asthma, 18 increased allergic sensitization, immune function, neurological and behavioral effects and 19 reproductive and developmental effects. Specific key studies were identified wi thin each health 20 effects category which provided adequate exposure

- response information to support RfC 21 derivation (Table 5

- 4). Although not all identified endpoints are represented by these studies, at 22 least one study was identified for each category. A screening process (described in section 23 5.1.3.1) was used to identify key studies for a variety of health effects that would best inform the 24 derivation of the RfC. For each selected key study, a candidate RfC (cRfC) was derived. In 25
several cases more th an one alternative was considered for application of the uncertainty factor 26 (UF) addressing human variability (Table 5

- 6). 27
28
6.2.1.2 Derivation of Candidate Reference Concentrations 29 Seven studies were selected as key studies for further consideration in RfC derivat ion 30 (Section 5.3.1, Table 5

- 4). Candidate RfCs from these studies address various health effects 31 including: sensory irritation, respiratory effects, asthma, increased allergic sensitization, and 32 decreased fecundity (Table 5

- 6). From these studies three c o

- critical studies were selected which 33 provide similar cRfCs for related health effects (Rumchev et al., 2002; Garrett et al., 1999; 34 Krzyzanowski et al., 1999). These three studies identify serious health effects in residential 35This document is a draft for review purposes only and d oes not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 26 populations including child ren: increased asthma incidence, decreased pulmonary function, 1 increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 2002; 2 Garrett et al., 1999; Krzyzanowski et al., 1999). Asthma, allergic sensitization, altered 3 pulmonar y function, and symptoms of respiratory disease are not only clinically related, but 4 etiologically related, and it is reasonable that they should be considered together. These health 5 effects are observed below the exposure levels that result in sensory ir ritation, and the resulting 6 cRfCs are correspondingly lower

— ranging from 2.8 to11 ppb

— depending on the study, 7 endpoint considered, and the application of alternative uncertainty factors for human variability 8 (Table 6

- 1). Additionally, these cRfCs are con sidered protective of the decreased fecundability 9 density ratio (FDR) reported by Taskinen et al. (1999) which yielded a cRfC of 8.6 ppb. One of 10
the uncertainties in the cRfC for decreased FDR is the use of a time

- weighted exposure metric 11
which does not a ddress possible contributions of peak exposure levels to the observed health 12 effect thus; it is possible that a cRfC of 8.6 ppb is lower than is needed for protection against 13
decreased FDR. 14 As discussed in section 6.2.1.4, there are uncertainties in esta blishing an RfC which are 15 not fully captured in the quantitative process or the standard uncertainty factors, as such it is 16 acknowledged by EPA that the RfC is not exact, perhaps spanning an order of magnitude. The 17 range of RfCs from the critical studies (even with various alternative considered for the human 18 variability uncertainty factor are in close agreement spanning only 1⁄2 order of magnitude.) 19 Therefore EPA is considering a simple mean of these cRfCs as adequately representative of the 20
three co

- crit ical studies. Alternatives are to take the median as a different way to represent the 21 three studies together, or the lowest cRfC as most protective. There is little numerical difference 22
in the result of these decisions. 23
24
6.2.1.3 Adequacy of Overall Data Base for RfC Derivation 25 The database of available laboratory animal studies, clinical and epidemiological studies, 26 and supporting mechanistic information for formaldehyde is substantial. Many of the health 27 effects are well studied in animals and humans, especiall y those endpoints related to sensory 28 irritation and respiratory effects at the portal of entry, such as impacts on respiratory tract 29 pathology, asthma and reduced pulmonary function. This is reflected in the number and high 30 quality of human studies presen ted in Table 5

- 4 and supporting data summarized in Chapter 4. 31
32
33This document is a draft forreview purposes only and doesnot constitute Agency policy6-27DRAFT—DO 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) UF L UF S UF H Respiratory effects / asthma and sensitization

Reduction of PEFR in children (10%) Krzyzanowski et al. (1990) 208 Yes Yes BMCL 10 = 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 error s compoundi ng across multiple mathematical manipulations.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 28 The data also indicate effects in other health effect categories, specifically neurotoxic 1 effects, reproductive toxicity, and developmental toxicity (Section 5.1.2). These non

- portal of 2 entry effects are areas where additional research may be warranted to reduce uncertainty and 3 better characterize the potential for health effects and the formaldehyde concentrations at which 4 they might occur in humans. 5 EPA guidance indicates that an uncertainty factor for database deficiencies should be 6 applied where there is an indication that the existing studies may not completely characterize the 7 hazard of a specific agent. This may be the result of lacking studies to assess toxicity to key 8 functional areas or organ sy stems, or where “... a review of existing data may also suggest that a 9 lower reference value might result if additional data were available.” (EPA 2002b) 10 Application of an uncertainty factor of 3 was considered by EPA based on the lack of a 11 satisfactory tw o

- generation study to fully evaluate the effects of formaldehyde exposure on 12 reproductive and developmental endpoints and limitations of the available studies evaluating 13 neurotoxic effects. An uncertainty factor of 3 rather than 10 was considered given th e relative 14 completeness of the database across all major health effect categories such that it is believed all 15 major health effects have been identified at least qualitatively. The observed adverse health 16 effect levels (LOAELs) for those endpoints where t he database is not adequate for alternative 17 RfC derivation are above the range of candidate RfCs; however, it is unclear if the candidate 18 RfCs would be protective of these other health effects (neurotoxic, reproductive and 19 developmental) since NOAELs were not identified for several observed health effects. 20 Therefore EPA is considering several options to address database deficiencies in the final 21
RfC. 22
23This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 29 1 2 It is unclear what uncertainty factors are appropriate to account for human variability and 3 deficiencies in the overall database. For this reason, several alternatives have been presented. 4
5
6.2.1.4 Uncertainties in the Reference Concentration (RfC) 6 A number of uncertainties that underlie the RfC for formaldehyde are discussed in this 7 section. A fundamental uncertainty in an RfC is that the critical study(ies) and endpoint(s) 8 selected reflect an actual hazard, i.e., a chemically related effect. As summarized in Section 9 6.1.3, there is strong and consistent evidence, from both human an d laboratory animal studies, 10 for the critical effects that form the basis of the RfC for formaldehyde. This section pertains to 11 uncertainties in the quantitative derivation of the RfC. 12
13 Point of Departure (POD) 14
Most of the studies considered for RfC der ivation did not provide enough data to support 15 benchmark dose modeling. Rather, the PODs for most studies were LOAELs or NOAELs, 16 Approaches to the application of a database 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

- stud ied 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 ident ified as protective of the better

- studied effects and an RfC with a database uncertainty factor of 3 incorporated to account for limits to the data on reproductive, developmental and neurotoxic effects.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 30 which have a number of shortcomings relative to a POD obtained from benchmark dose

1 response modeling (i.e., a benchmark concen tration or dose): 2
3

 LOAELs and NOAELs are a reflection of the particular exposure/dose levels used in a 4 study, contributing some inaccuracy to the POD determination. 5

 LOAELs and NOAELs are often determined based on statistical significance and, thus, 6
reflect the number of study subjects or test animals. Studies are typically dissimilar in 7 detection ability and statistical power, with smaller studies tending to identify higher 8 exposure levels as NOAELs relative to larger, but otherwise similarly designed, stu dies. 9

 Different LOAELs and NOAELs represent different response rates, so direct qualitative 10 and quantitative comparisons are not possible. 11
12
PODs identified from benchmark dose models overcome some of the deficiencies 13
associated with LOAELs and NOAELs. Benchmark models were used for two inhalation data 14

sets

— Hanrahan et al. (1984) and Krzyzanowski et al. (1990). 15 It should also be noted, however, that even for benchmark concentrations/doses there is 16 often uncertainty, in particular for continuous response s, about what response level to select as 17 the benchmark response, i.e., where to define the cut

- point between a level of change that is not 18 adverse and one that is adverse. In addition, benchmark dose models currently in use are purely 19
mathematical models and are not intended to accurately reflect the biology of the effect being 20
modeled. 21 Another source of uncertainty in the POD is the adjustment for continuous exposure. 22 RfCs are meant to apply to continuous (24 hour/day) exposures. Exposure patterns in h uman 23 and laboratory animal inhalation studies are typically not for continuous exposures, and 24 assumptions must be made in converting reported exposure levels to equivalent continuous 25 exposures. Similarly, there are uncertainties about potential dose rate effects, in particular the 26 effect of peak exposures in occupational studies. 27
28 Extrapolation from Laboratory Animal Data to Humans 29 Because the inhalation database for formaldehyde contains many human studies for a 30 variety of health effects, it was not neces sary to rely on animal data for the endpoints from which 31 the RfC was derived. Thus, unlike for most RfCs, this is not a source of uncertainty in the RfC 32 for formaldehyde. 33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 31 Human Variation 1 Heterogeneity among humans is another uncertainty associated wi th extending results 2 observed in a limited human study population or laboratory animal experiment to a larger, more 3 diverse human population. 4 For three of the studies used to derive the RfC, a value of 3 was used for the human 5 variability UF (rather than the default value of 10) because the studies had an apparent over

6 representation of populations expected to have increased susceptibility (section 5.5.3.1): 7
8

 The residential study by Ritchie and Lehnen (1987) evaluated eye, nose, and throat 9
irritation in a large number of subjects, including children and the elderly. As a result of 10 the study's participation criteria, individuals with greater sensitivity were potentially 11

over

- represented. 12

 Thirty percent of the subjects in the residential study by Krzyzan owski et al. (1990) are 13 children, who are more sensitive to formaldehyde

- associated decreases in peak expiratory 14 flow rates (PEFR) than adults. The candidate RfC determination for this study focused 15 on the results in the children, among which asthmatics w ere over

- represented (roughly 3

- 16 times) compared to the national average. 17

 Garrett et al. (1999) conducted a cross

- sectional survey of allergy and asthma

- like 18 symptoms in children with or without a doctor's diagnosis of asthma. The study was 19 designed to inc lude a high proportion of asthmatic children, a sensitive population for the 20 effects being studied. 21
22 EPA notes, however, that, while a human variability UF of 3 rather than 10 was used to 23 attempt to account for certain special attributes of these studies/ effects, there is still uncertainty 24 about how much of the overall population heterogeneity is actually reflected even in these 25 relatively diverse residential studies. 26
27
Subchronic

- to

- Chronic Extrapolation 28 RfCs are intended to apply to chronic lifetime ex posures. If a study is subchronic 29 (typically less than 10% of lifetime), an UF for subchronic

- to

- chronic extrapolation is generally 30 applied to the candidate RfC for that study. For the human residential and occupational studies 31 comprising the key studies for the RfC in this assessment, the average durations of exposure in 32 the households or workplaces under study is unknown. In this assessment, these studies were 33
considered chronic in nature and no subchronic

- to

- chronic UF was applied. However, there is 34 uncertainty about whether or not the responses observed fully reflected the potential effects of 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 32 chronic exposure, especially for effects in children, where effects on the developing respiratory 1 and immune systems, for example, could be predisposing the ch ildren to further health effects 2
later in life. 3
4
6.2.1.5 Conclusions 5
Seven different non

- cancer health effects were identified from formaldehyde inhalation 6 exposure studies, including: 1) sensory irritation of the eyes, nose, and throat, 2) upper 7 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 8 behavioral toxicity, 6) reproductive and developmental toxicity, and 7) immunological toxicity. 9 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 10 derived candidate RfCs for critical effects based on seven key studies. Three co

- critical studies 11 were selected which provide similar cRfCs for related adverse health effects observed in 12 residential populations including children i.e., increased a sthma incidence, decreased pulmonary 13 function, increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 14 2002; Garrett et al., 1999; Krzyzanowski et al., 1999). The resulting cRfCs fall in a range 15 between 2.8 and 11 ppb, depe nding on the study, or endpoints considered, and the application of 16 alternative uncertainty factors for human variability (Table 6

- 1). The RfC is taken as the 17 average of the cRfCs from the three co

- critical studies (See Section 6.2.1.2). 18
EPA has assessed the adequacy of the overall database for RfC derivation, and although 19 the database is quite large, and provides significant information on well studied POE effects. 20 There are remaining uncertainties in the database. Most notably, there is a need for ad ditional 21

exposure

- response information for observed neurotoxic effects, reproductive and developmental 22
effects as well as a two

- generation study to evaluate the effects of formaldehyde exposure on 23 reproductive and developmental endpoints. EPA is consideri ng 4 options to address database 24 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 25 appropriate to account for human variability and deficiencies in the overall database. For this 26 reason, several alternatives hav e been presented. EPA is seeking advice from the NAS and the 27 public on this matter. 28
29
6.2.2. Cancer Risk Estimates 30
6.2.2.1. Choice of Data 31 As explained above, the human epidemiologic data and the animal bioassay data indicate 32 multiple sites of concern, r emote as well as at the portal of entry. The quantitative cancer risk 33 derivations in this document consider the risks of lymphohematopoietic cancers and solid 34 cancers of the respiratory tract. When adequate human data are available, as is the case with 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 33 f

ormaldehyde, it is generally preferable to base cancer risk estimates on the human data rather 1 than on data from experimental animals because of the inherent uncertainties associated with 2 interspecies extrapolation. Sufficient exposure

- response data from a large, high

- quality 3 epidemiologic study for the quantitative estimation of risk were available for some 4 lymphohematopoietic cancers and for nasopharyngeal cancer. 15

8 Risk estimates based on nasal 5 tumors in rats were also derived for comparison with the es timates based on human data. The 6 data used for the quantitative risk assessment are as follows: 7

1. Nasopharyngeal cancer (NPC): The dose

- response modeling of NPCs is based on results 9 from a large NCI cohort study of over 25,000 workers in 10 U.S. plants pr oducing or 10 using formaldehyde (Hauptmann et al., 2004). 11
2. Lymphohematopoietic cancers: The dose

- response modeling of select 12 lymphohematopoietic cancers is based on results from a more recent follow

- up study (of 13 lymphohematopoietic malignancies only) of the same NCI cohort (Beane Freeman et al., 14 2009). 15
3. Squamous cell carcinoma (SCC) in the upper and lower respiratory tract: An increased 16 incidence of nasal SCC was seen in two large long

- term bioassays using F344 rats (Kerns 17 et al., 1983; Monticello et al., 1 996). Although other studies in laboratory animals exist, 18
19
4. these two studies, when combined, provided the most robust data for analyses. The nasal 20 tumor incidence data from these rat bioassays is used for extrapolating the risk of SCC to 21
the entire huma n respiratory tract. 16

23 22

6.2.2.2. Analysis of Epidemiologic Data 24 The NCI cohort consisted of 25,619 workers employed in 10 plants prior to 1966. A 25
follow

- up through 1994 presented exposure

- response analyses for 9 NPC deaths, as well as 26

15 Only one other epidemiological study was available with quantitative exposure estimates for the individual workers. It was a much smaller study (it focused on o ne 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, Ove rton 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 fo rmaldehyde (Monticello et al. 1989).This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 34 analyses of deaths from other solid cancers (Hauptmann et al., 2004). The most recent follow

- up 1 (through 2004; lymphohematopoietic cancers only) analyzed 319 deaths attributed to 2 lymphohematopoietic malignancy from a total of 13,951 deaths (Beane Freeman et al., 2009). A 3
d etailed exposure assessment was conducted for each worker, based on exposure estimates for 4 different jobs held and tasks performed (Stewart et al., 1986). Exposure estimates were made 5 using several different metrics

— peak exposure, average intensity, cumul ative exposure, and 6 duration of exposure. Respirator use and exposures to formaldehyde

- containing particulates and 7 other chemicals were also considered. Relative Risks (RRs) were estimated using log

- linear 8 Poisson regression models stratified by calendar year, age, sex, and race and adjusted for pay 9 category (salary/wage/unknown). The NCI investigators used the low

- exposure category as the 10 reference category to “minimize the impact of any unmeasured confounding variables since 11 nonexposed workers may diff er from exposed workers with respect to socioeconomic 12
characteristics.” 13 Although other upper respiratory tract cancers were also identified as being causally 14 associated with formaldehyde exposure in the weight

- of

- evidence analysis in section 4.5, NPC 15

was t he only upper respiratory tract cancer with exposure

- response data adequate for the 16 derivation of unit risk estimates in the Hauptmann et al. (2004) follow

- up study of solid tumors. 17 Similarly, the weight

- of evidence analysis in section 4.5 concluded that there were causal 18 relationships between formaldehyde exposure and all lymphohematopoietic cancers as a group as 19 well as leukemias as a group (with the strongest evidence for myeloid leukemia). However, 20 from the Beane Freeman et al. (2009) follow

- up study of lymphohematopoietic malignancies, 21 only all leukemias combined and Hodgkin lymphoma were judged to have exposure

- response 22 data adequate for the derivation of unit risk estimates. 23 For the NPCs, significant trends were observed for the cumulative and peak exposure 24 metrics. The cumulative exposure metric provides a good fit to the data ( p trend = 0.029 for all 25

person

- years). Since this is generally the preferred metric for quantitative risk assessment for 26 environmental exposure to carcinogens, cumulative e xposure is chosen as the exposure metric 27 for the risk estimate calculations for NPC in this assessment. For the latency of solid cancers, 28 including nasopharyngeal tumors, a 15

- year lag interval was used by Hauptmann et al. (2004). 29 For the lymphohematopoie tic cancers, using the peak exposure metric, statistically 30 significant log

- linear trends were observed for all lymphohematopoietic cancers, Hodgkin 31 lymphoma, and leukemia (the latter only when the unexposed person

- years were included) 32 (Beane Freeman et al. , 2009). Using the average exposure metric, there was a significant trend 33 for Hodgkin lymphoma. Similar results were seen with the cumulative exposure metric, 34 although the trends were only of borderline significance (Hodgkin lymphoma p trends = 0.06 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 35 and 0.08 with and without the unexposed person

- years, respectively; leukemia p trends = 0.08 1 and 0.12 with and without the unexposed person

- years, respectively). For the latency of 2 lymphohematopoietic cancers, a 2

- year lag interval was used by Beane Freeman e t al. (2009). 3 Although the peak exposure metric provides the most statistically robust dose

- response 4 relationship, it is not clear how to extrapolate RR estimates based on the peak exposure estimates 5 to meaningful estimates of lifetime extra risk of cance r from environmental exposures. The 6 average exposure metric is also problematic because it suggests that duration of exposure is not 7 important, i.e., exposure to a given exposure level for one year conveys the same amount of risk 8 as exposure to the same level for 70 years. 9 Cumulative exposure is generally the preferred metric for quantitative risk assessment for 10 environmental exposure to carcinogens. Given the consistency of increased mortality from 11 Hodgkin lymphoma and leukemia overall (exposed versus unexposed) and for each exposure 12 metric (Table 5

- 12), indicating risk from these cancers is more than chance, a determination was 13 made that the cumulative exposure results for these two cancer types constituted the best data 14
sets from which to calculate u nit risk estimates for lymphohematopoietic cancers from the NCI 15
cohort. 16 Regression coefficients from the NCI log

- linear trend test models for the NPCs 17 (Hauptmann et al., 2004) and the various lymphohematopoietic cancers (Beane Freeman et al., 18 2009) were provided by Drs. Hauptmann and Beane Freeman, respectively. These trend tests 19
were of the form RR = e β*exposure . The coefficients (i.e., β) were used in lifetable analyses to 20 calculate lifetime extra cancer risks from formaldehyde exposure (Section 5.2). Extra risk 21 estimates for cancer incidence for the three cancer types were approximated by assuming that 22 cancer incidence and cancer mortality have the same dose

- response relationships and then using 23 background cause

- specific incidence rates instead of mo rtality rates in the lifetable analysis. 24 Points of departure (PODs) based on the dose

- response modeling of these cancers were 25 calculated as the exposure concentration at which the 95% upper confidence bound on extra risk 26 was 0.0005 (i.e., 0.05%) for NPC an d for Hodgkin lymphoma and 0.005 (i.e., 0.5%) for 27 leukemia (Sections 5.2.2 and 5.2.3) . These values approximate the lower confidence bounds on 28 dose at these extra risk levels. The values for these extra risk levels, 0.0005 and 0.005, were 29
chosen because they are near the lower end of the observable range of the data. Having such low 30 response levels associated with the points of departure is warranted because of the low 31 background lifetime risks for these cancer types (e.g., 0.00022 for NPC mortality). H igher extra 32 risk levels would entail extrapolation above the range of the bulk of the observable data to obtain 33 PODs. The resulting effective concentration values for the selected extra risk values for cancer 34 incidence are presented in Table 6

- 2. 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6-36 Linear l ow- 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 formaldehyde

related cancers 1 1
2
3
4
5
6
7
8
9
10 11 12 13 Cancer Type Extra Risk Level EC 2 (ppm) LEC 3 (ppm)
NPC 0.0005 0.074 0.046 Hodgkin lymphoma 0.0005 0.052 0.030

Leukemias 0.005 0.16 0.088
14 1. calculated including all person

- years (see section 5.2) 2. effectiv e 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/m 3 ) e xposure 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
32This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 37 1. Measurements of DNA

- protein cross

- links (DPXs) formed by formaldehyde in F3 44 rats 1 and rhesus monkeys (Casanova et al., 1989, 1994). Several PBPK models have been 2 developed in the literature based on these data. Some of these efforts integrated the data 3 in both species (Casanova et al., 1991; Conolly et al., 2000; Klein et al., 2009). 4
2. Measurements of cell proliferation in F344 rats and rhesus monkeys (Monticello et al., 5 1989, 1990, 1991, 1996). 6
3. Simulations of airflow in anatomically realistic representations of the upper respiratory 7 tract of the F344 rat, rhesus monkey and hum an, and in an idealized representation of the 8 human lower respiratory tract, using computer and physical models (Kimbell et al., 1993; 9 Kepler et al., 1998; Subramaniam et al., 1998). These simulations were used to predict 10 regional formaldehyde dosimetry i n the corresponding sections of the respiratory tract of 11 these three species (Kimbell et al., 2001a, b; Overton et al., 2001). 12
13
The combined nasal tumor incidence data were analyzed using a multistage

- weibull time

14

to

- tumor approach as well as biologically based dose

- response (BBDR) models derived from 15 Conolly et al. (2003) [see Crump et al. (2005), Subramaniam et al. (2007), and Appendix E for 16 details]. The BBDR approach enabled integration of the mechanistic information and the time

17

to

- tumor incidence dat a within a single conceptual framework. 18
19
6.2.2.4. Extrapolation Approaches 20 An EPA inhalation unit risk is developed to estimate cancer risk from environmental 21 exposures or in order to determine exposure levels corresponding with cancer risks as low as 1 22 excess cancer in 10,000 or 1 excess cancer in 1 million. As neither data from animal studies, nor 23 human epidemiological studies, provide direct observation of these low level risks, the observed 24 exposure response relationship is extrapolated to estimate l ow dose risk. The model used to 25 extrapolate below the range of exposures clearly associated with increased risk of health effects 26 has a great influence on the inhalation unit risk, as there may be several orders of magnitude 27
difference between the observe d risk and the target risk range. In the absence of empirical data 28 or a biologically

- informed model, the EPA applies a simple straight line extrapolation from the 29 point of departure to zero exposure (U.S. EPA, 2005a). The Mode of Action evaluation reviews 30 available data and determines if an MOA can be sufficiently established and whether it informs 31 the shape of the exposure

- response relationship. 32
33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 38 Low

- dose extrapolation for Lymphohematopoietic cancers: 1 Formaldehyde is a mutagen, and known to act direct ly on cells at the site of first contact. 2 Clastogenic effects have been documented in formaldehyde

- exposed workers including 3 peripheral blood lymphocytes and circulating stem cells (Zhang et al., 2010). Thus a mutagenic 4 MOA has been hypothesized for lymp hohematopoeitic cancers, and supports a linear low

- dose 5 extrapolation of human cancer risk. Additionally, formaldehyde may also induce some form of 6 bone marrow toxicity, as suggested by observed pancytopenia in exposed workers (Tang et al., 7 2008, Zhang et al., 2010). However, as the mechanism of transport to the bone marrow, and 8 biological activity leading to the observed toxicity are unknown, this information does not 9
inform the low

- dose extrapolation. Although the mechanisms underlying formaldehyde

- ind uced 10 leukemia and lymphoma are still largely speculative, there is little doubt of an association 11 between formaldehyde exposures and lymphohematopoeitic cancer mortality, especially for 12 myeloid leukemia. Therefore, without a known MOA which would justify an alternative 13 approach, and with a hypothesized mutagenic MOA under consideration which supports a simple 14 straight line extrapolation from the point of departure to zero risk at zero exposure, this is 15 applied when estimating human cancer risk from both le ukemia and Hodgkins lymphoma from 16
the NCI cohort. 17
18
Low

- dose extrapolation for cancer of the upper respiratory tract: 19 There are multiple plausible MOAs for formaldehyde carcinogenesis regarding upper 20 respiratory tract cancers (Section 4.5.3), however they a re not all applicable to the lower end of 21 the exposure response curve. For example, although regenerative cell proliferation associated 22 with focal and gross tissue lesions due to cell death may contribute to the high incidence of rat 23
nasal tumor in F344 r ats, these mechanisms may not be operative in the low exposure region 24 expected for human environmental exposure (e.g. less than 1ppm) and therefore may not inform 25
low

- dose extrapolation. There are MOAs which are more appropriate to the low

- dose region. 26
S pecifically, formaldehyde is a known mutagen, may inhibit DNA repair activity and may have 27 additional activity as a tumor promoter. Finally, other affects such as formaldehyde

- induced cell 28 proliferation, imunosuppression and disruption of the mucociliary apparatus may influence both 29 the level of tissue damage and ultimately cancer incidence. 30
EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a) recommend using 31 biologically based dose

- response (BBDR) models for extrapolation when data permit. C onolly 32 et al. (2003, 2004) developed BBDR models to predict squamous cell carcinoma risk in the rat 33This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 39 and human respiratory tract at exposures well below the range of the observed animal data. 17

conservative in the face of model unc ertainties. 1 The primary conclusion from their modeling effort was that hum an exposure standards 2 protective of effects of formaldehyde

- induced cytotoxicity should be sufficient to protect from 3 the potential carcinogenic effects of formaldehyde. The authors assessed that such a conclusion 4

was 5

18

The current assess ment evaluated the uncertainties in the above BBDR model extensively 9 and examined alternative parameterizations of the modeling in Conolly et al. (2003, 2004). 10 These alternatives and the original model were equally consistent with the experimental data but 11 resulted in maximum likelihood estimates of added human risk that ranged from negative to 12 large positive values at environmental exposure concentrations. Model uncertainty far exceeded 13 statistical uncertainty (Table E

- 4 in Appendix E). Each of these mode ls, including the modeling 14 in Conolly et al., 15 This assessment’s evaluation of the BBDR

6 models and alternative implementations (detailed in Section 5.3) finds that these models may not 7 provide conservative estimates of human cancer risk below the range of observed data. 8

16
1. was judged to be just as biologically plausible, 17
2. described the rat tumor incidence data equally well, 18
3. was based on different characterizations of the same empirical cell kinetic data, and 19
4. was based on the sa me empirical data on DPX measurements. 20
21
This assessment’s evaluation 19

17 In that sense, the authors used the modeling as if it were a BBDR model even though they termed it as “biologically

- motivated”. of the above models (detailed in Section 5.3) concluded 22 that these models, including alternative implementations of those in Conolly et al. (2003, 2004), 23
were too uncertain to be useful for low

- dose extrapolation of risk. It may be noted that the 24 sensitivity analyses on the basis of which these conclusions were reached have been criticized as 25 resulting in implausible risk estimates (given the epidemiologic data) as a consequence of 26 imple menting model variations that are not biologically reasonable (Conolly et al. 2009). This 27

18 Based on their modeling, Conolly et al. (2003, 2004) concluded that the directly mutag enic 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 boun d 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, Lind a Hanna, Dale Hattis, Julia Kimbell, George Lucier, Christopher Portier and Fred Miller (guest participant). The meeting agenda and summary are provided in Appendix H.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 40 criticism was rebutted by Crump et al. (2009) on biological and epidemiological grounds. These 1 debates have been discussed fully in Appendix F. In particular, the ass essment concludes that: 2
3

**•** When used for the purpose of extrapolating risk, the BBDR models did not appear to 4 reasonably constrain either 5  risk estimates extrapolated from the F344 rat to the human, regardless of whether the 6 extrapolation was carried out at l ow or comparable exposures, or 7  risk estimates for the F344 rat when extrapolated outside the range of observable 8
data. 9

**•** Furthermore, human risk calculated from these BBDR models was numerically unstable 10 when certain parameter conditions were realized (Sec tion 5.3.3 and Appendix F). 11

**•** Therefore, clonal growth modeling was not found to be a useful approach for human 12 extrapolation of rodent risk estimates. The current assessment concludes that the result in 13 Conolly et al. cannot be considered to be “conservativ e in the face of model 14
uncertainties.” 15
16 However, using the BBDR model to characterize the dose

- response in the range of the 17 available data was judged to have the advantage of utilizing the available biological and 18 dosimetry data on formaldehyde in an inte grated manner as well as providing statistically sound 19 descriptions of the empirical tumor incidence data. Therefore, this assessment uses the BBDR 20 modeling of the rat data to derive multiple PODs (for SCC in the respiratory tract) in the range of 21
the obs erved data and uses model

- derived internal dose estimates. For the reasons detailed 22 above, the BBDR modeling is not used to extrapolate far below the observed data. 23 The lowest observed incidence of SCC in the bioassays used in the dose

- response 24

assessment was equal to 0.0087 (at 6 ppm exposure). In addition, the BBDR modeling used data 25 on cell proliferation and formation of DPXs that informed the modeling of the tumor data at the 26 lower exposure concentrations of 0.7 and 2.0 ppm. Thus, the available data s upported estimation 27 of response levels below the 10% response level commonly used in BMD analyses of tumor 28 data. Therefore, points of departure corresponding to 95% statistical upper bound levels of extra 29 risk of 0.005, 0.01 and 0.1 were estimated when th e BBDR modeling was used. 30
31 Summary: 32 As discussed earlier in the hazard characterization, formaldehyde is a direct

- acting 33 mutagen, and its genotoxic effects have been observed following human occupational 34This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 41 exposures. 20

9 Furthermore, a low

- dose nonlinear MOA f or formaldehyde

- induced 1 lymphohematopoietic cancers, NPCs, or cancers in other regions of the respiratory tract has not 2
been established. In particular, the formation of DPXs by formaldehyde, considered a dose 3 surrogate for the molecular dose associated w ith formaldehyde’s mutagenic action, has been 4 observed at doses well below those considered cytotoxic. Therefore, linear low

- dose 5 extrapolation from the suitably chosen PODs was considered most appropriate for all the cancers 6 (whether the PODs were based on epidemiological data or rodent bioassay data), which is also in 7
accordance with EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). 8

6.2.2.5. Inhalation Unit Risk Estimates for Cancer 10 The epidemiological and rodent inhalation data indic ate multiple sites of concern. Unit 11 risk estimates calculated separately from these data are summarized in Table 6

- 3. 12
As can be seen in the Table 6

- 3, the unit risk estimate based on human data for NPC is in 13 the range of the estimates calculated for respir atory tract cancer from the rodent nasal cancer 14 data. Experimental animal data were inadequate for estimating risk of lymphohematopoietic 15 cancers. The unit risk estimate for Hodgkin lymphoma is also in the same range, while the unit 16
risk estimate for leu kemia and the total cancer unit risk estimate are up to 4

- fold higher. 17
As documented in EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 18 when high

- quality human data are available, they are generally preferred over laboratory animal 19
data for quantitative risk assessment. Thus, the preferred (plausible upper bound) unit risk 20
estimate in this assessment is the value of 8.1 × 10 – 2 per ppm (6.6 **×** 10 – 5 per μg/m 3 ) based on 21 ( adult ) human data for NPC, Hodgkin lymphoma, and leukemia. Note that, as discussed in 22 Section 6.2.2.6 below, if there is early

- life exposure, the age

- dependent adjustment factors 23 (ADAFs) should be applied, in accordance with EPA’s Supplemental Guidance for Assessing 24 Susceptibility from Early

- Life Exposure to Carcinogens (U.S . EPA, 2005b). 25
26
6.2.2.6. Early

- Life Susceptibility 27
There are no chemical

- specific data for quantitatively addressing the susceptibility of 28 different life stages to carcinogenicity from inhalation exposure to formaldehyde. As 29 documented in section 4.5, fo rmaldehyde is a mutagenic carcinogen and the weight of evidence 30 suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic 31 MOA. Therefore, increased early

- life susceptibility should be assumed and, if there is early

- lif e 32

20 While formaldehyde may also contribute to mutations indirectly, such an effect is li kely to be relevant only at the higher doses.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 42 exposure, the ADAFs should be applied, in accordance with EPA’s Supplemental Guidance for 1 Assessing Susceptibility from Early

- Life Exposure to Carcinogens (U.S. EPA, 2005b). See 2 Section 5.4.4 for details on the application of the ADAFs. 3
4
Table 6

- 3 Inh alation unit risk estimates based on epidemiological and 5 experimental animal data 6 7 

### Cancer type a 

### Dose metric Unit Risk Estimate b (ppm – 1 ) Based on Epidemiological Data Nasopharyngeal Cumulative exposure 0.011 Hodgkin lymphoma Cumulative exposure 0.017
Le ukemia Cumulative exposure 0.057

All three cancer sites combined: 0.081 c

Based on Experimental Animal Data

Squamous cell carcinoma

of the respiratory tract Local dose (flux) of formaldehyde in pmol/mm 2 /hour 0.011

– 0.022 d

8

a the unit risk estimates are all for cancer incidence. 9

b these unit risk estimates do not include ADAFs (see Section 6.2.2.6 below). 10

c this total cancer unit risk estimate is an estimate of the upper bound on the sum of risk estimates calculated 11 for the 3 individual cancer types ( nasopharyngeal cancer, Hodgkin lymphoma, and leukemia); it is not the 12 sum of the individual (upper bound) unit risk estimates (see Section 5.2.4). 13

d values are similar to estimates from Schlosser et al. (2003). These authors determined their PODs based 14

on tumor and cell proliferation as endpoints, and extrapolated benchmark exposure concentrations to 15 humans using formaldehyde flux to the tissue and DPX concentrations as internal dose metrics. 16 17
18 Accordingly, for full lifetime exposures, the overall (plausi ble upper bound) unit risk 19 estimate is 0.13 per ppm (1.1 **×** 10 – 4 per μg/m 3 ) for the three cancer types (NPC, Hodgkin 20 lymphoma, and leukemia) combined (see Table 5

- 26 for calculations). 21
22
6.2.2.7. Uncertainties in the Quantitative Risk Estimates 23
Uncertaint ies in the risk estimates based on the human data are discussed in detail in 24 Sections 5.2.2.4 and 5.2.3.4. Major uncertainties inherent in the NPC, Hodgkin lymphoma, and 25
leukemia risk estimates are 26
27This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 43  the retrospective exposure estimation, 1

 the appropriaten ess of the dose

- response model and exposure metric, and 2

 the extrapolation from occupational exposures to lower environmental exposures

. 3
4 In addition, the NPC and Hodgkin lymphoma estimates are limited by the sparse data for these 5
cancers in the NCI cohor t study (estimates are based on the exposure

- response modeling of only 6 9 NPC deaths and 27 Hodgkin lymphoma deaths). 7 Of note, Marsh et al. (2002, 1996) independently studied one of the 10 plants that was in 8 the NCI study, and there were large differences i n the exposure estimates for that plant from the 9 two different studies. If the exposure estimates of Marsh et al. (2002) are closer to the true 10 exposures, then the potency of formaldehyde could be greater than reflected in the risk estimates 11
derived from the NCI data. 12
The linear low

- dose extrapolation (see Section 6.2.2.4) from the 95% lower bound on the 13 exposure level associated with the benchmark response is generally considered to provide a 14 plausible upper bound on the risk at lower exposure levels. T he strong association with peak 15 exposures for all 3 cancer types in the NCI study suggests that dose

- rate effects may be operative 16 (i.e., the risk from peak occupational exposures may be greater than the [linearly] proportional 17 risks from lower exposures a nd, similarly, the risk from an occupational cumulative exposure 18 may be greater than the proportional risk from a lower environmental cumulative exposure). 21

Other significant uncertainties may also remain. For example, risk estimates could not be 22 derived from the NCI cohort study for rare upper respiratory tract cancers other tha n NPC. In 23 addition, although unit risk estimates were derived for Hodgkin lymphoma and leukemia because 24 they exhibited the strongest trend results of the lymphohematopoietic cancers using the 25 cumulative exposure metric, it is uncertain which specific lymp hohematopoietic cancer subtypes 26

are associated with formaldehyde exposure. Furthermore, the potential role of particulates in the 27 NPC risk is unclear. Moreover, as for all occupational epidemiology studies, there is uncertainty 28 19 Any such dose

- rate effects would not be reflected in the linear low

- dose extrapolation approach 20

us ed in this assessment. Actual low

- dose risks may be lower to an unknown extent. 21

in extrapolating risk fro m an adult worker population (in this case predominantly white males) to 29 the more diverse general population. 30
31

21 Dose

- rate effects are also suggested by the very 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).This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 44 Despite inevitable uncertainties, it is important not to lose sight of the strengths of the 1 estimates, which are based on human data from a high

- quality NCI study. In addition to the use 2 of internal analyses and the extensive exposure assessment and consideration of potential 3 confounding or modifying variables, the NCI study has a large cohort that has been followed for 4 a long time. With the add itional follow

- up through 2004, reflected in the lymphohematopoietic 5 cancer results of Beane Freeman et al. (2009), the median duration of follow

- up was 42 years, 6 and the 25,619 cohort members had accrued 998,106 person

- years of follow

- up. 7 Significant un certainties also exist in the risk estimates derived from the rodent bioassay 8 data. In general, the difficulties in extrapolating from experimental animal bioassays are 9 considerable, and the use of human data is preferred, while recognizing the different 10 uncertainties that are present in risk estimates based on epidemiological data. 11 In the case of formaldehyde, this general uncertainty associated with extrapolation from 12
rodent data is increased due to the highly curvilinear nature of the dose

– response re lationships 13 associated with DPX formation, labeling index data, and tumor responses. The mechanistic 14 interpretation of these observed data has provided grounds for arguments in the literature that 15 formaldehyde tumorigenicity (at exposures ≥ 6 ppm) should be uncoupled from its potential 16 carcinogenicity in the low

- dose region. 17 Quantitative models have been used in the literature to further argue that the observed 18 risk in animal experiments is entirely due to cell proliferation induced by regenerative 19 hyper plasia in response to cell injury at cytotoxic doses, i.e., without a relevant role for the direct 20 mutagenic action of formaldehyde. In the context of using these data for quantitative risk 21 assessment, this document notes that such an inference of the dat a has been found to be 22 extremely uncertain. An analysis of the uncertainties in interpreting the available data has 23 shown that the directly mutagenic component could be important in explaining the high

- dose 24 effect (Subramaniam et al., 2007). 25
While ackno wledging these substantial difficulties, the quantitative dose

- response 26 modeling of the rat data does allow inference about upper bound risks for respiratory cancer, 27 consistent with the observed experimental tumorigenicity. These upper bound risk estimate s are 28 consistent with those estimated from the epidemiological data; however, such a consistency may 29 be entirely artifactual. As noted earlier, the BBDR modeling helped characterize some of the 30 uncertainty associated with extrapolating from the rodent data to the environmental risk in 31 people. The actual risk may be substantially lower or higher than the reasonable upper bound 32
risk estimated from the animal data. 33
34
35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 45 6.2.2.8 Conclusions 1 Cancer unit risk estimates for formaldehyde inhalation exposure were derived from both 2 human and laboratory animal data. As documented in EPA's Guidelines for Carcinogen Risk 3
Assessment (U.S. EPA, 2005a), when high

- quality human data are available, they are generally 4 preferred over laboratory animal data for quantitative risk assessme nt. Thus, the preferred unit 5 risk estimate in this assessment is based on human data for NPC, Hodgkin lymphoma, and 6 leukemia from a high

- quality NCI occupational cohort study (Hauptmann et al., 2004; Beane 7 Freeman et al., 2009). (The qualitative hazard a ssessment suggests causal associations between 8 formaldehyde exposure and other cancer types as well [e.g., other upper respiratory tract cancers 9 and possibly other lymphohematopoietic cancers; see Section 4.5], but quantitative data from the 10
NCI cohort stu dy were not amenable for deriving quantitative risk estimates for those cancer 11 types. Because there were not clear exposure

- response data for these cancer types in that cohort 12 study [based on cumulative exposure], any contributions to the total cancer ris k from 13 environmental formaldehyde exposure for these cancers are not expected to be large; however, 14 this is a source of uncertainty.) 15 The unit risk estimate for the total cancer incidence extra risk for these three cancer types 16 combined based on the (adu lt) human data is 8.1 × 10 - 2 per ppm (6.6 × 10 - 5 per μg/m 3 ). As 17 documented in Section 4.5, formaldehyde is a mutagenic carcinogen and the weight of evidence 18 suggests that formaldehyde carcinogenicity can be attributed, at least in part, to a mutagenic 19 MOA. Therefore, as there are no chemical

- specific inhalation data on cancer susceptibility at 20
different life

- stages, increased early

- life susceptibility is assumed and ADAFs should be applied 21
in accordance with EPA’s Supplemental Guidance for Assessing Susceptibility from Early

- Life 22 Exposure to Carcinogen s (U.S. EPA, 2005b). Applying the ADAFs, the overall (upper bound) 23
unit risk estimate for full lifetime exposure is 0.13 per ppm (1.1 **×** 10
– 4 per μg/m 3 ) for the three 24 cancer types (NPC, Hodgkin lymphoma, and leukemia) combined. Using this lifetime unit r isk 25 estimate, the upper bound estimate of the cancer risk at the RfC of 1 ppb is 1 × 10
– 4

. 26
27
6.3. SUMMARY AND CONCLUSIONS 28
Seven different non

- cancer health effects were identified from formaldehyde inhalation 29 exposure studies, including: 1) sensory irritat ion of the eyes, nose, and throat, 2) upper 30 respiratory tract pathology, 3) pulmonary function, 4) asthma and atopy, 5) neurologic and 31 behavioral toxicity, 6) reproductive and developmental toxicity, and 7) immunological toxicity. 32 Of note, epidemiological evidence is available for most of these noncancer effects. EPA has 33 derived candidate RfCs for critical effects based on seven key studies. Three co

- critical studies 34 were selected which provide similar cRfCs for related adverse health effects observed in 35This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE 6

- 46 residential populations including children i.e., increased asthma incidence, decreased pulmonary 1 function, increase in respiratory symptoms, and increased allergic sensitization (Rumchev et al., 2 2002; Garrett et al., 1999; Krzyzanowski et al., 1999). The resulting cRfCs fall in a range 3 between 2.8 and 11 ppb, depending on the study, or endpoints considered, and the application of 4 alternative uncertainty factors for human variability (Table 6

- 1). The representative RfC for the 5

co

- critical studies is taken as the average of the cRfCs (Section 6.2.1.2). 6 EPA has assessed the adequacy of the overall database for RfC derivation, and although 7 the database is quite large, and provides significant information on well studied POE effects. 8 There are remaining unce rtainties in the database. Most notably, there is a need for additional 9

exposure

- response information for observed neurotoxic effects, reproductive and developmental 10
effects as well as a two

- generation study to evaluate the effects of formaldehyde exposur e on 11 reproductive and developmental endpoints. EPA is considering 4 options to address database 12 uncertainties in the final RfC (Section 6.2.1.3). It is unclear what uncertainty factors are 13 appropriate to account for human variability and deficiencies in the overall database. For this 14 reason, several alternatives have been presented. EPA is seeking advice from the NAS and the 15 public on this matter. 16 Formaldehyde is carcinogenic to humans by the inhalation route of exposure. There is 17
sufficient evidence of a causal association between formaldehyde exposure and cancers of the 18 upper respiratory tracts, with the strongest evidence for nasopharyngeal and sino

- nasal cancers. 19 There is also sufficient evidence of a causal association between formaldehyde exposur e and 20 lymphohematopoietic cancers, with the strongest evidence for Hodgkin lymphoma and leukemia, 21 particularly myeloid leukemia. The (upper bound) unit risk estimate for the total cancer 22 incidence based on (adult) human data is 8.1 × 10 - 2 per ppm (6.6 × 1 0 - 5 per μg/m 3 ). Applying 23 the age

- dependent adjustment factors for increased early

- life susceptibility, the overall combined 24 cancer unit risk estimate for full lifetime exposure is 0.13 per ppm (1.1 **×** 10
– 4 per μg/m 3 )

. 25This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE R

- 1 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 valu es CD

- RO M―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; Fer nandez, 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 formaldehyd e 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

- l evel 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 fo rmaldehyde 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 M ed 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; Hedenstie rna, 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 prospec tive 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. DRAFT

— DO NOT CITE OR QUOTE R

- 2 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 V ocational 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 form ic 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. Was hington, 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 Tox icol 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: Ef fects 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 T

lymphocytes and the comet assay: a useful combination when testing for genotoxicity in vitro? Mutat Res 540:43

- 55. Anderson, S; Jensen, O; Oliva, D. (19 82) 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 Re s 20:1050

– 1064.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE R

- 3 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. N aturwissenschaften 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 Malay sian 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 met hod 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 advers e 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_assessm ent.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. DRAFT

— DO NOT CITE OR QUOTE R

- 4 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 asth matics. 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 regulati on 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. Washingt on, 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

- as sociated 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

a nd 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 Chemi cal 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, hyd rolysis 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. DRAFT

— DO NOT CITE OR QUOTE R

- 5 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) Th e 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, D K; 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 statis tical 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) Ro le 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 lymp homa 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; Stewa rt, 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 Epid emiol 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. DRAFT

— DO NOT CITE OR QUOTE R

- 6 Blair, A; Linos, A; Stewart, A; et al. (1993) Evaluation of risks for Non

- Hodgkin's Lymphom a 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 mucos a cells. Toxicol I n 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 Depart ment of Public Health, Los Angeles, CA; Study No. S

1806. 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). Boenige r, 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 pros pective 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 Eur opean 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 studie s through 2006. Annal Oncol 19:29

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

— DO NOT CITE OR QUOTE R

- 7 Bosworth, D; Crofton

- Sleigh, C; Venitt, S. (1987) A forward mutation assay using ampicillin

resistance in Escherichia coli designed for investigating the mutagenicity of biological samples. Mutagenesis 2:455

– 467. Boy sen, 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 inhal ation 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 RD 50 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 expos ed to formaldehyde. Neoplasma 48:144

– 147. Burgaz, S; Erdem, O; Ç akmak, G; et al. (2002) Cytogenetic analysis of buccal cells from shoe

workers 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.pdfThis document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE R

- 8 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 formaldehyde

human 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 inhal ed [ 3 H]

- and [ 14 C]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 phar macokinetic 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

- to

monkey interspecies sca ling, 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. Fun dam 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. DRAFT

— DO NOT CITE OR QUOTE R

- 9 Ca sanova

- 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, V J. (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 formaldehy de. 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 alpha

monochlorohydrin (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 formalde hyde 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

- antigen

immortalized an d 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) Ro le 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. DRAFT

— DO NOT CITE OR QUOTE R

- 10 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) [Compari son 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 Re s 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; Upadhya ya, 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 N

nitrosodimethyl amine (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 hydroxylas e 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

– 16 8. 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 inha lation (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 lymph oid 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.

Co ggon, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 11 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 measuremen ts 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 Env iron 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 rev iew 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 21 st century: Implications for human he alth 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, P D; 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. DRAFT

— DO NOT CITE OR QUOTE R

- 12 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, dimethyl amine, 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 exp osed 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 mutagenici ty 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; Hi nkley, 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 DNA

protein cros slinks 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 for maldehyde

induced 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. DRAFT

— DO NOT CITE OR QUOTE R

- 13 Crump, KS. (1994a) Limitations of biological models of carcinogenesis for low

- dose extrapolation. Risk Anal 14:883

– 886. Crump, KS. (1994b) Use of mechanistic m odels 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 non

homogenous 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 P

450

- dependent monooxygenases with nasal decongestants, essences, solvents, air pollutants, nicotine, and cocaine as substrates. Toxicol Appl Pharmacol 67:200

- 205. Dalbey, WE. (1982) F ormaldehyde 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 (SO 2 , H 3 N, 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) Formaldehyd e 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 McC lenny, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 14 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) Occupatio nal 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 Phar macol 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 cu lture. 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 pl astics 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

- butanon e 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 formaldehyd e 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. DRAFT

— DO NOT CITE OR QUOTE R

- 15 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 r ats 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

– 3 13. 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 Bu tterworth, 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 condensa tion 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) Envi ronmental 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 formaldehyde

human serum albumin lack of relation to gaseou s 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. DRAFT

— DO NOT CITE OR QUOTE R

- 16 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 irradiati on 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/environmental

health/new

- repor t

- 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

mo sue. 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 dehydro genase 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 o f 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.

F ayerweather, 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 D ekker; 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. DRAFT

— DO NOT CITE OR QUOTE R

- 17 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 afte r 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 healt h 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, car cinogenic 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; e t al. (1984) Investigation on the mutagenicity of N

nitrosothiazolidine 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 analy ses 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

– 38 8.

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 R es 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 c hildren 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. DRAFT

— DO NOT CITE OR QUOTE R

- 18 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 b y 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 suspecte d 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. Tox icology 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 p ortals 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 cell s: 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 Bioch em 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, DN A 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. DRAFT

— DO NOT CITE OR QUOTE R

- 19 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 lo ng

- 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) Statistic al 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 na sal 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; Siemi atycki, 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 childre n’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.

Gin sberg,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 Counci l, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 20 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 S anit 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 p ersons. 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 follo wing 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. DRAFT

— DO NOT CITE OR QUOTE R

- 21 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 (apopt osis). Carcinogenesis 21:1411

– 1421. Graves, RJ; Callander, RD; and Green, T. (1994) The role of formaldehyde and S

chloromethylglutathione 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 chloride

induced 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) Subfertilit y 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; Ku lle, 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 inhal ation 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 Pers pect 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 forma ldehyde 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 ce lls. 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. DRAFT

— DO NOT CITE OR QUOTE R

- 22 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 emb ryo 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 irrita nt 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 form ate 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 Clin ical 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 Committ ee 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 dehydro genase (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 analy sis: 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 In st 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 9 6:967

– 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. DRAFT

— DO NOT CITE OR QUOTE R

- 23 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 C anada 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 form aldehyde. 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 Spect rom 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 understand ing. Crit Rev Toxicol 20:397

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

— DO NOT CITE OR QUOTE R

- 24 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. (200 1a) 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 de hydrogenase 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.

Hemmink i, 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 Co mmunity 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) Fo rmaldehyde 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 F3 44 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. DRAFT

— DO NOT CITE OR QUOTE R

- 25 Hikiba, H; Watanabe, E; Barrett, JC; et al. (2005) Ability of fourteen chemical a gents 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 nasopharyn geal 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 formaldeh yde 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.

Holmströ m, 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.

H öög, 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 me tabolic pathways. Chem Biol Interact 143

– 144:175

– 181. Hoogenveen, R; Clewell, H; Andersen, M; et al. (1999) An alternative exact solution of the two

stage clonal growth model of cancer. Risk Anal 19:9

– 14. Horton, A; Tye, R; Stemmer, K. (1963) Experimenta l 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. DRAFT

— DO NOT CITE OR QUOTE R

- 26 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 Substanc es 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://w ww.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

me chanisms 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 mu tagens/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, hos t factors, and lifestyle influence the number of centromeric signals in micronuclei: a pooled re

analysis. Mutat Res 615:18

– 27. Ibanes, JD; Leininger, JR; Jarabek, AM; et al. (1996) Reexamination of respiratory tract responses in rats, mice, and rhesus mo nkeys 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, Ox ford, 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 Scie nces 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. DRAFT

— DO NOT CITE OR QUOTE R

- 27 Ionescu, J; Marinescu, D; Tapu, V; et al. (1978) Experimental chronic obstructive lung disease. I. Bronchopulmonary changes induced in rabbits by pro longed 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 Organizat ion, Geneva, Switzerland. Available online at http://www.inchem.org/documents/cicads/cicads/cicad40.htm

. Iravani, J. (1974) Clearance function of the respiratory ciliated epitheliu m 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 aberr ation 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 formaldeh yde

- 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 Livin g. 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. DRAFT

— DO NOT CITE OR QUOTE R

- 28 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

- N itrosoglutathione 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 are a. 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 m RNA 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) T he 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. DRAFT

— DO NOT CITE OR QUOTE R

- 29 Kane, LE; Alarie, Y. (1977) Sensory irri tation 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 N

demethylation 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 add uct 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 f ormaldehyde 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.

Kilbu rn, 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. Enviro n 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) Formaldehyd e 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. DRAFT

— DO NOT CITE OR QUOTE R

- 30 Kimbell, JS; Gross, EA; Joyner, DR; et al. (1993) Application of computational fluid dynamics to regional dosimetry of inhaled ch emicals 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 145:3 88

– 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; Subramani am, 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 m odeling 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

– 27 3. 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 i nhalation 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 [tran slation]. 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 Lib rary 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 DNA

protein cross

- link data: Improving methods for characterization of uncertainty. J. Biopharmaceutical Statistics. [Submitted] Kligerman, AD; Phelps, MC; Erexson, GL. (1 984) 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. DRAFT

— DO NOT CITE OR QUOTE R

- 31 Koppel, C; Tencz er, 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 exposu re 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

– 2 81. 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 i n 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 forma ldehyde 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.

Ku lle, 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

na sal

- 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) Inha lation 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. DRAFT

— DO NOT CITE OR QUOTE R

- 32 Laforest, L; Luce, D; Goldberg, P; et al. (2000) Laryngeal and hypopharyngeal cancers an d 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 He alth 23:135

– 136. Lazutka, JR; Lekevicius, R; Dedonyte, V, et al. (1999) Chromosomal aberrations and sister

chromatid 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 R espir 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.

L i, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 33 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; L uo, 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 ba cteria 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 formald ehyde

- 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

- tetrachlorodibenzo

p

- dioxin on initiati on 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. DRAFT

— DO NOT CITE OR QUOTE R

- 34 Luo, W; Li, H; Zhang, Y; et al. (2001) Determination of formaldehyde in blood plasma by high

per formance 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 cro ss

- 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 syste m 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 e ffect 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; Mö ritz, 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 o f 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 f etal 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. DRAFT

— DO NOT CITE OR QUOTE R

- 35 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
stu dy 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 N ational 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, R A; 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 form aldehyde. 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; Morfel d, 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 kn own 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 Tech nical 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 Epidemio l 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. DRAFT

— DO NOT CITE OR QUOTE R

- 36 Maurice, F; Rivory, JP; Larsson, PH; et al. (1986) Anaphylactic shock caused by formaldehyde in a patient undergoing long

- term hemodi alysis. 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. B iochemistry 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 thr ough 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

- induce d 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 lesion s 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 epithe lium 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. DRAFT

— DO NOT CITE OR QUOTE R

- 37 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 pro duction 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 forma ldehyde 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 ep ithelial 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.

Mo nticello, 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
p roliferation 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 p opulations 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 curv es 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; Lue beck, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 38 Morgan, KT. (1997) A brief review of formaldehyde carc inogenesis 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; Gro ss, 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 u sing 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; En gelhart, 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 Healt h 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. DRAFT

— DO NOT CITE OR QUOTE R

- 39 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 di stribution 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; B jörnsson, 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: man aging 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 Trian gle 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 t he wollastonite calcium silicates study. U.S. Department of Health and Human Services, NTP, Research Triangle Park, NC. Available at http://ntp

apps.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. DRAFT

— DO NOT CITE OR QUOTE R

- 40 Odeigah, PGC. (1997) sperm head abnormalities and dominant lethal effects of formaldehyde in albino rats. Mutat Res 389:141

– 14 8. 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.

Ohb a, 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) producti on 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. Mu tat 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) E ffects 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 formal dehyde 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 54:28 7

– 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. A m 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 increa sed 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. DRAFT

— DO NOT CITE OR QUOTE R

- 41 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.

O rstavik, 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 Bi ochem 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
exposur e 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

Ow en, 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

c oncentrations 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 subacut e (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 Trac e 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. Palczy ński, 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 16:39 4

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

— DO NOT CITE OR QUOTE R

- 42 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) Predi ctive 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 form aldehyde 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 myelo ma 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 Educa tional 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 formaldeh yde 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

- formaldeh yde 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 66:5 1

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

— DO NOT CITE OR QUOTE R

- 43 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 experiment al 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 fun ction. 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 spontane ous 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 muta tions 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 effe cts 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. A llergy 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; p p. 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/J

92/350 (NTIS PB93106979). Rogers, JM; Brannen, KC; Barbee, B D; 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 da mage and survival in formaldehyde

treated mouse cells. Mutat Res 79:277

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

— DO NOT CITE OR QUOTE R

- 44 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. (19 86) 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 st udy 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 f

ormaldehyde 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.

Sa dakane, K; Takano, H; Ichinose, T; et al. (2002) Formaldehyde enhances mite allergen

induced 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 mate rnally 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. To xicology 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 p revalence 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.

Saltha mmer 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 t issue in rats. Toxicol Ind Health 23:471

– 477. Sanghani, PC; Stone, CL; Ray, BD; et al. (2000) Kinetic mechanism of human glutathione

dependent formaldehyde dehydrogenase. Biochemistry 39:10720

- 10729.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE R

- 45 Sanotskii, IV; Fomenko, VN; Sheveleva, GA; et al. (197 6) 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 histopathol ogic 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 incorpo ration, 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 E nviron 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; Conol ly, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 46 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 resp onse 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; Ma rian, 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 mo use. 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 wind ows 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 iro n microelementosis [translation]. Ontogenez 27:108

– 113. Shaham, J; Bomstein, Y; Meltzer, A; et al. (1996a) DNA

- protein crosslinks, a biomarker of exposure to formald ehyde―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; Szes zenia

- 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. DRAFT

— DO NOT CITE OR QUOTE R

- 47 Sharpe, JA; Hostovsky, M; Bilbao, JM; et al. (1982) Methanol optic neuropathy. A histopathol ogical 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) L ack 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 incre ased 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 transiti ons 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. DRAFT

— DO NOT CITE OR QUOTE R

- 48 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 a nd 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 l ow

- 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 e nhanced fear conditioning to odor in male, but not female, rats. Brain Res 1008:11

– 19. Špan ĕl, 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 DNA

protein 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. Mutage nesis 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. DRAFT

— DO NOT CITE OR QUOTE R

- 49 Speit, G; Zeller, J; Schmid, O, et al. (2009) Inh alation 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; Höö g, 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 mortali ty study of workers exposed to formaldehyde in the garment industry. Am J In Med 13:667

– 681. Stedman’s Medical Dictionary. (2005) 28 th edition. Lippincott Williams, and Wilkins, New York, NY. Steinhagen, WH; Barrow, CS. (1984) Sensory irritation structur e

- 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 p revention 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.

Sterli ng, 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 mort ality 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 w orkers 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. DRAFT

— DO NOT CITE OR QUOTE R

- 50 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 31 1:223

– 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 A nal 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) Gen e 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

c ancer 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; Rand all, 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 radiomet ric 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. DRAFT

— DO NOT CITE OR QUOTE R

- 51 Takahashi, M; Hasegawa, R; Furukawa, F; et al. (1986) Effects of e thanol, 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 stud y 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 analys is. 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; Alle n, 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 formaldehyd e

- 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. DRAFT

— DO NOT CITE OR QUOTE R

- 52 Th omson, EJ; Shackleton, S; Harrington, JM. (1984) Chromosome aberrations and sister

chromatid exchange frequencies in pathology staff occupationally exposed to formaldehyde. Mutat Res 141:89

– 93. Thorndike, J; Beck, WS. (1977) Production of formaldehyde fro m 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 hom es. 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. (1 988) 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 Ch em 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 stud y 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 formaldehyd e 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.

Turn er, 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. DRAFT

— DO NOT CITE OR QUOTE R

- 53 Tuthill, RW. (1984) Woodstove s, 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 a l. (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 b y 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 fo r 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, Washingto n, 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, RT P, NC, EPA

450/2

- 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) Interi m 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 concentration s 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. DRAFT

— DO NOT CITE OR QUOTE R

- 54 U.S. EPA. (1995) Use of the benchmark dose approach in health risk assessment. Risk As sessment 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/bac kgr

- 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 ass essment 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, Wa shington, 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, Washingto n, 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 assessme nt 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/backgr

d.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 frame work for assessing health risk of environmental exposures to children. National Center for Environmental Assessment

- Washington, DC, EPA/600/R

05/093F. Available from: < http://cfpu b.epa.gov/ncea/cfm/recordisplay.cfm?deid=158363 >.This document is a draft for review purposes only and does not constitute Agency policy. DRAFT

— DO NOT CITE OR QUOTE R

- 55 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 qu ality 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 Pestici de 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; B ernstein, 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,
prope rties, 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 a nd 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) A nalysis 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 labor atory. 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) F ormaldehyde 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. DRAFT

— DO NOT CITE OR QUOTE R

- 56 Vaughan, TL; Stewart, PA; Teschke, K; et al. (2000) Occupational exposure to formaldehyde and wood dust and nasopharyngeal carcinoma. Occu p 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 form aldehyde 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 colorectal

tumor development. N Engl J Med 319:525

– 532. Von Hippe l, 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 pat terns 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

assess ed 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, Špan ĕl P, Smith D. (2008) Analysis of breath, exhaled via
t he 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. (1996 a) 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. DRAFT

— DO NOT CITE OR QUOTE R

- 57 Wata nabe, 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; Grandje an, 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 sensitiv ity 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 f or 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) Acc uracy 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. (199 2) 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 formal dehyde 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 v ersus 8

- hour continuous exposures. Toxicol Lett 47:287

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

— DO NOT CITE OR QUOTE R

- 58 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; Lyg ht, 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 clearan ce. 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: He misphere 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 Me d 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 af ter 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; Romi eu, 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 m ale 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. DRAFT

— DO NOT CITE OR QUOTE R

- 59 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 su bsets 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.

Y u, 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

- 1 210. 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 wint er 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 biomar kers 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. DRAFT

— DO NOT CITE OR QUOTE R

- 60 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 N

nitrosomethylaniline 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.



# - End of Volume III

-