TOXICOLOGICAL PROFILE FOR

FORMALDEHYDE

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

July 1999
FORMALDEHYDE ii

DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the

Agency for Toxic Substances and Disease Registry.
FORMALDEHYDE iii

UPDATE STATEMENT

Toxicological profiles are revised and republished as necessary, but no less than once every three years. 

For information regarding the update status of previously released profiles, contact ATSDR at:

Agency for Toxic Substances and Disease Registry

Division of Toxicology/Toxicology Information Branch

1600 Clifton Road NE, E-29

Atlanta, Georgia 30333



FORMALDEHYDE vii

QUICK REFERENCE FOR HEALTH CARE PROVIDERS

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of

available toxicologic and epidemiologic information on a substance. Health care providers treating

patients potentially exposed to hazardous substances will find the following information helpful for fast

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating

patients about possible exposure to a hazardous substance. It explains a substance’s relevant

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of

the general health effects observed following exposure.

Chapter 2: Health Effects: Specific health effects of a given hazardous compound are reported by route

of exposure, by type of health effect (death, systemic, immunologic, reproductive), and by length

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in

the clinical setting. Please refer to the Public Health Statement to identify

general health effects observed following exposure.

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health

issues:

Section 1.6 How Can (Chemical X) Affect Children?

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?

Section 2.6 Children’s Susceptibility

Section 5.6 Exposures of Children

Other Sections of Interest:

Section 2.7 Biomarkers of Exposure and Effect

Section 2.10 Methods for Reducing Toxic Effects

ATSDR Information Center 

Phone: 1-800-447-1544 (to be replaced by 1-888-42-ATSDR in 1999)

 or 404-639-6357 Fax: 404-639-6359

E-mail: atsdric@cdc.gov Internet: http://atsdr1.atsdr.cdc.gov:8080

The following additional material can be ordered through the ATSDR Information Center:

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an

exposure history and how to conduct one are described, and an example of a thorough exposure

history is provided. Other case studies of interest include Reproductive and Developmental

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide

Toxicity; and numerous chemical-specific case studies.
FORMALDEHYDE viii

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene

(prehospital) and hospital medical management of patients exposed during a hazardous materials incident. 

Volumes I and II are planning guides to assist first responders and hospital emergency department

personnel in planning for incidents that involve hazardous materials. Volume III—Medical Management

Guidelines for Acute Chemical Exposures—is a guide for health care professionals treating patients

exposed to hazardous materials.

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances.

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease,

injury, and disability related to the interactions between people and their environment outside the

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA 30341-

3724 • Phone: 770-488-7000 • FAX: 770-488-7015.

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational

diseases and injuries, responds to requests for assistance by investigating problems of health and

safety in the workplace, recommends standards to the Occupational Safety and Health

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue,

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch,

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998

• Phone: 800-35-NIOSH.

 The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for

biomedical research on the effects of chemical, physical, and biologic environmental agents on

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,

Research Triangle Park, NC 27709 • Phone: 919-541-3212.

Referrals

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics

in the United States to provide expertise in occupational and environmental issues. Contact:

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 •

FAX: 202-347-4950 • e-mail: aoec@dgs.dgsys.com • AOEC Clinic Director: http://occ-envmed.mc.duke.edu/oem/aoec.htm.

The American College of Occupational and Environmental Medicine (ACOEM) is an association of

physicians and other health care providers specializing in the field of occupational and

environmental medicine. Contact: ACOEM, 55 West Seegers Road, Arlington Heights, IL

60005 • Phone: 847-228-6850 • FAX: 847-228-1856.
FORMALDEHYDE ix

CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHORS(S):

Sharon Wilbur, M.A.

ATSDR, Division of Toxicology, Atlanta, GA

M. Olivia Harris, M.A.

ATSDR, Division of Toxicology, Atlanta, GA

Peter R. McClure, Ph.D., DABT

Syracuse Research Corporation, North Syracuse, NY

Wayne Spoo, DVM, DABT, DABVT

Research Triangle Institute, Research Triangle Park, NC

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Health Effects Review. The Health Effects Review Committee examines the health effects

chapter of each profile for consistency and accuracy in interpreting health effects and classifying

end points.

2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to

substance-specific minimal risk levels (MRLs), reviews the health effects database of each

profile, and makes recommendations for derivation of MRLs.

3. Data Needs Review. The Research Implementation Branch reviews data needs sections to assure

consistency across profiles and adherence to instructions in the Guidance.

FORMALDEHYDE xi

PEER REVIEW

A peer review panel was assembled for formaldehyde. The panel consisted of the following members: 

1. Carson Conaway, Research Scientist, American Health Foundation, Valhalla, New York 10595;

2. John Egle, Jr., Professor, Department of Pharmacology and Toxicology, Medical College of

Virginia, Smith Bldg., Room 656, Richmond, VA 23219; and

3. Vincent Garry, Director, Environmental Medicine, University of Minnesota, 421 29th Ave.,

SE Minneapolis, MN 55414.

These experts collectively have knowledge of formaldehyde's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of

risk to humans. All reviewers were selected in conformity with the conditions for peer review specified

in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act,

as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer

reviewers' comments and determined which comments will be included in the profile. A listing of the

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their

exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and

a list of unpublished documents cited are also included in the administrative record.

The citation of the peer review panel should not be understood to imply its approval of the profile's final

content. The responsibility for the content of this profile lies with the ATSDR.

FORMALDEHYDE xiii

CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

QUICK REFERENCE FOR HEALTH CARE PROVIDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xx

1. PUBLIC HEALTH STATEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1 WHAT IS FORMALDEHYDE? ................................................ 1

1.2 WHAT HAPPENS TO FORMALDEHYDE WHEN IT ENTERS THE ENVIRONMENT? . . 2

1.3 HOW MIGHT I BE EXPOSED TO FORMALDEHYDE? ............................ 3

1.4 HOW CAN FORMALDEHYDE ENTER AND LEAVE MY BODY? .................. 4

1.5 HOW CAN FORMALDEHYDE AFFECT MY HEALTH? ........................... 4

1.6 HOW CAN FORMALDEHYDE AFFECT CHILDREN? ............................. 5

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO FORMALDEHYDE? . . 6

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO

FORMALDEHYDE? ......................................................... 7

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.10 WHERE CAN I GET MORE INFORMATION? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

2. HEALTH EFFECTS ............................................................... 9

2.1 INTRODUCTION ........................................................... 9

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .................. 9

2.2.1 Inhalation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2.2.1.1 Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2.2.1.2 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.2.1.3 Immunological and Lymphoreticular Effects . . . . . . . . . . . . . . . . . . . . . . 71

2.2.1.4 Neurological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

2.2.1.5 Reproductive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

2.2.1.6 Developmental Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

2.2.1.7 Genotoxic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

2.2.1.8 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

2.2.2 Oral Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

2.2.2.1 Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

2.2.2.2 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

2.2.2.3 Immunological and Lymphoreticular Effects . . . . . . . . . . . . . . . . . . . . . 144

2.2.2.4 Neurological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

2.2.2.5 Reproductive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

2.2.2.6 Developmental Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

2.2.2.7 Genotoxic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

2.2.2.8 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

2.2.3 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
FORMALDEHYDE xiv

2.2.3.1 Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

2.2.3.2 Systemic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

2.2.3.3 Immunological and Lymphoreticular Effects . . . . . . . . . . . . . . . . . . . . . 162

2.2.3.4 Neurological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

2.2.3.5 Reproductive Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

2.2.3.6 Developmental Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

2.2.3.7 Genotoxic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

2.2.3.8 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

2.3 TOXICOKINETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

2.3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

2.3.1.1 Inhalation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

2.3.1.2 Oral Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

2.3.1.3 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

2.3.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

2.3.2.1 Inhalation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

2.3.2.2 Oral Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

2.3.2.3 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

2.3.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

2.3.3.1 Inhalation Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

2.3.3.2 Oral Exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.3.3.3 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.3.4 Elimination and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.3.4.1 Inhalation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.3.4.2 Oral Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.3.4.3 Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

2.4 MECHANISMS OF ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

2.4.1 Pharmacokinetic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

2.4.2 Mechanisms of Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

2.4.3 Animal-to-Human Extrapolations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

2.5 RELEVANCE TO PUBLIC HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

2.6 CHILDREN’S SUSCEPTIBILITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

2.7 BIOMARKERS OF EXPOSURE AND EFFECT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

2.7.1 Biomarkers Used to Identify or Quantify Exposure to Formaldehyde . . . . . . . . . . 230

2.7.2 Biomarkers Used to Characterize Effects Caused by Formaldehyde . . . . . . . . . . . . 233

2.8 INTERACTIONS WITH OTHER CHEMICALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . . . . . . . . . . . . . . . . . . . . . . 236

2.10 METHODS FOR REDUCING TOXIC EFFECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

2.10.1 Reducing Peak Absorption Following Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

2.10.2 Reducing Body Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

2.10.3 Interfering with the Mechanism of Action for Toxic Effects . . . . . . . . . . . . . . . . . . 239

2.11 ADEQUACY OF THE DATABASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

2.11.1 Existing Information on Health Effects of Formaldehyde . . . . . . . . . . . . . . . . . . . . 240

2.11.2 Identification of Data Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

2.11.3 Ongoing Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

3. CHEMICAL AND PHYSICAL INFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

3.1 CHEMICAL IDENTITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

3.2 PHYSICAL AND CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
FORMALDEHYDE xv

4.1 PRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

4.2 IMPORT/EXPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

4.3 USE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

4.4 DISPOSAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

5. POTENTIAL FOR HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

5.1 OVERVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

5.2 RELEASES TO THE ENVIRONMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

5.2.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

5.2.2 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

5.2.3 Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

5.3 ENVIRONMENTAL FATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

5.3.1 Transport and Partitioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

5.3.2 Transformation and Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

5.3.2.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

5.3.2.2 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

5.3.2.3 Sediment and Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . . . . . . . . . . . . . . . 299

5.4.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

5.4.2 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

5.4.3 Sediment and Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

5.4.4 Other Environmental Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE . . . . . . . . . . . . . . . . . . 305

5.6 EXPOSURES OF CHILDREN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES . . . . . . . . . . . . . . . . . . . . . . 311

5.8 ADEQUACY OF THE DATABASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311

5.8.1 Identification of Data Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

5.8.2 Ongoing Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

6. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

6.1 BIOLOGICAL SAMPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

6.2 ENVIRONMENTAL SAMPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

6.3 ADEQUACY OF THE DATABASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

6.3.1 Identification of Data Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

6.3.2 Ongoing Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

7. REGULATIONS AND ADVISORIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

8. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

9. GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

APPENDICES

A. ATSDR MINIMAL RISK LEVEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1

B. USER’S GUIDE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B-1

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-1
FORMALDEHYDE xvi

LIST OF FIGURES

2-1 Levels of Significant Exposure to Formaldehyde—Inhalation . . . . . . . . . . . . . . . . . . . . . . . . 35

2-2 Levels of Significant Exposure to Formaldehyde—Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

2-3 Metabolic Pathways of Formaldehyde Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

2-4 Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) 

Model for A Hypothetical Chemical Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

2-5 Existing Information on Health Effects of Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

5-1 Frequency of NPL Sites with Formaldehyde Contamination . . . . . . . . . . . . . . . . . . . . . . . . . 284

FORMALDEHYDE xviii

LIST OF TABLES

2-1 Levels of Significant Exposure to Formaldehyde—Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2-2 Definitions of Selected Epidemiology Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

2-3 Meta-analysis of Epidemiology Studies of Cancer of the Nose and Nasal Sinuses and 

Nasopharyngeal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

2-4 Levels of Significant Exposure to Formaldehyde—Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

2-5 Levels of Significant Exposure to Formaldehyde—Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

2-6 Genotoxicity of Formaldehyde In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

2-7 Genotoxicity of Formaldehyde In Vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

2-8 Ongoing Studies on Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

3-1 Chemical Identity of Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

3-2 Physical and Chemical Properties of Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

4-1 Facilities That Manufacture or Process Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

4-2 U.S. Formaldehyde Capacity and Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

4-3 Distribution of Formaldehyde Production According to Uses in the United States . . . . . . . . . . . 277

5-1 Releases to the Environment from Facilities That Manufacture or Process Formaldehyde . . . . . 288

5-2 Environmental Transformation Products of Formaldehyde by Medium . . . . . . . . . . . . . . . . . . . 297

5-3 Indoor Concentrations of Formaldehyde in U.S. Homes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

5-4 Ongoing Studies on the Potential for Human Exposure to Formaldehyde . . . . . . . . . . . . . . . . . . 316

6-1 Analytical Methods for Determining Formaldehyde and Metabolites in Biological Samples . . . 318

6-2 Analytical Methods for Determining Formaldehyde in Environmental Samples . . . . . . . . . . . . . 321

6-3 Ongoing Studies on Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

7-1 Regulations and Guidelines Applicable to Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

FORMALDEHYDE 1

1. PUBLIC HEALTH STATEMENT

This public health statement tells you about formaldehyde and the effects of exposure. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the

nation. These sites make up the National Priorities List (NPL) and are the sites targeted for long-term

federal cleanup activities. Formaldehyde has been found in at least 26 of the 1,428 current or former NPL

sites. However, it’s unknown how many NPL sites have been evaluated for this substance. As more sites

are evaluated, the sites with formaldehyde may increase. This is important because exposure to this

substance may harm you and because these sites may be sources of exposure.

When a substance is released from a large area, such as an industrial plant, or from a container, such as a

drum or bottle, it enters the environment. This release does not always lead to exposure. You are

exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating,

or drinking the substance or by skin contact.

If you are exposed to formaldehyde, many factors determine whether you’ll be harmed. These factors

include the dose (how much), the duration (how long), and how you come in contact with it. You must

also consider the other chemicals you’re exposed to and your age, sex, diet, family traits, lifestyle, and

state of health.

1.1 WHAT IS FORMALDEHYDE?

Formaldehyde is a colorless, flammable gas at room temperature. It has a pungent, distinct odor and may

cause a burning sensation to the eyes, nose, and lungs at high concentrations. Formaldehyde is also

known as methanal, methylene oxide, oxymethylene, methylaldehyde, and oxomethane. Formaldehyde

can react with many other chemicals, and it will break down into methanol (wood alcohol) and carbon

monoxide at very high temperatures.

Formaldehyde is naturally produced in very small amounts in our bodies as a part of our normal,

everyday metabolism and causes us no harm. It can also be found in the air that we breathe at home and

at work, in the food we eat, and in some products that we put on our skin. A major source of

formaldehyde that we breathe every day is found in smog in the lower atmosphere. Automobile exhaust
FORMALDEHYDE 2

1. PUBLIC HEALTH STATEMENT

from cars without catalytic converters or those using oxygenated gasoline also contain formaldehyde. At

home, formaldehyde is produced by cigarettes and other tobacco products, gas cookers, and open

fireplaces. It is also used as a preservative in some foods, such as some types of Italian cheeses, dried

foods, and fish. Formaldehyde is found in many products used every day around the house, such as

antiseptics, medicines, cosmetics, dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners,

glues and adhesives, lacquers, paper, plastics, and some types of wood products. Some people are

exposed to higher levels of formaldehyde if they live in a new mobile home, as formaldehyde is given off

as a gas from the manufactured wood products used in these homes.

Formaldehyde is used in many industries. It is used in the production of fertilizer, paper, plywood, and

urea-formaldehyde resins. It is present in the air in iron foundries. It is also used in the production of

cosmetics and sugar, in well-drilling fluids, in agriculture as a preservative for grains and seed dressings,

in the rubber industry in the production of latex, in leather tanning, in wood preservation, and in

photographic film production. Formaldehyde is combined with methanol and buffers to make embalming

fluid. Formaldehyde is also used in many hospitals and laboratories to preserve tissue specimens.

1.2 WHAT HAPPENS TO FORMALDEHYDE WHEN IT ENTERS THE

ENVIRONMENT?

Most of the formaldehyde you are exposed to in the environment is in the air. Formaldehyde dissolves

easily in water, but it does not last a long time in water and is not commonly found in drinking water

supplies. Most formaldehyde in the air also breaks down during the day. The breakdown products of

formaldehyde in air include formic acid and carbon monoxide. Formaldehyde does not seem to build up

in plants and animals, and although formaldehyde is found in some food, it is not found in large amounts. 

You will find more information about where formaldehyde comes from, how it behaves, and how long it

remains in the environment in Chapter 5.
FORMALDEHYDE 3

1. PUBLIC HEALTH STATEMENT

1.3 HOW MIGHT I BE EXPOSED TO FORMALDEHYDE?

You are exposed to small amounts of formaldehyde in the air. It occurs from both natural and man made

sources although combustion is the largest source. If you live in an unpopulated area, you may be

exposed to about 0.2 parts per billion (ppb) of formaldehyde in the air outdoors. In suburban areas, you

may be exposed to about 2–6 ppb of formaldehyde. If you live in a heavily populated area or near some

industries, you may be exposed to 10–20 ppb. You may also be exposed to higher levels of formaldehyde

during rush hour commutes in highly populated areas because it is formed in automobile and truck

exhaust.

There is usually more formaldehyde present indoors than outdoors. Formaldehyde is released to the air

from many home products and you may breath in formaldehyde while using these products. Latex paint,

fingernail hardener, and fingernail polish release a large amount of formaldehyde to the air. Plywood and

particle board, as well as furniture and cabinets made from them, fiberglass products, new carpets,

decorative laminates, and some permanent press fabrics give off a moderate amount of formaldehyde. 

Some paper products, such as grocery bags and paper towels, give off small amounts of formaldehyde. 

Because these products contain formaldehyde, you may also be exposed on the skin by touching or

coming in direct contact with them. You may also be exposed to small amounts of formaldehyde in the

food you eat. You are not likely to be exposed to formaldehyde in the water you drink because it does not

last a long time in water.

Many other home products contain and give off formaldehyde although the amount has not been

carefully measured. These products include household cleaners, carpet cleaners, disinfectants, cosmetics,

medicines, fabric softeners, glues, lacquers, and antiseptics. You may also breath formaldehyde if you use

unvented gas or kerosene heaters indoors or if you or someone else smokes a cigar, cigarette, or pipe

indoors. The amount of formaldehyde in mobile homes is usually higher than it is in conventional homes

because of their lower air turnover.

People who work at or near chemical plants that make or use formaldehyde can be exposed to higher than

normal amounts of formaldehyde. Doctors, nurses, dentists, veterinarians, pathologists, embalmers,

workers in the clothing industry or in furniture factories, and teachers and students who handle preserved

specimens in laboratories also might be exposed to higher amounts of formaldehyde. The National 
FORMALDEHYDE 4

1. PUBLIC HEALTH STATEMENT

Institute for Occupational Safety and Health (NIOSH) estimates that 1,329,332 individuals in the United

States have had the potential for occupational exposure to formaldehyde.

1.4 HOW CAN FORMALDEHYDE ENTER AND LEAVE MY BODY?

Formaldehyde can enter your body after you breath it in, drink or eat it, or when it comes in contact with

your skin. Formaldehyde is quickly absorbed from the nose and the upper part of your lungs. When

formaldehyde is eaten and drunk, it is also very quickly absorbed. Very small amounts are probably

absorbed from formaldehyde that comes in contact with your skin. Once absorbed, formaldehyde is very

quickly broken down. Almost every tissue in the body has the ability to break down formaldehyde. It is

usually converted to a non-toxic chemical called formate, which is excreted in the urine. Formaldehyde

can also be converted to carbon dioxide and breathed out of the body. It can also be broken down so the

body can use it to make larger molecules needed in your tissues, or it can attach to deoxyribonucleic acid

(DNA) or to protein in your body. Formaldehyde is not stored in fat.

1.5 HOW CAN FORMALDEHYDE AFFECT MY HEALTH?

Formaldehyde is irritating to tissues when it comes into direct contact with them. Some people are more

sensitive to the effects of formaldehyde than others. The most common symptoms include irritation of

the eyes, nose, and throat, along with increased tearing, which occurs at air concentrations of about

0.4–3 parts per million (ppm). NIOSH states that formaldehyde is immediately dangerous to life and

health at 20 ppm. One large study of people with asthma found that they may be more sensitive to the

effects of inhaled formaldehyde than other people; however, many studies show that they are not more

sensitive. Severe pain, vomiting, coma, and possible death can occur after drinking large amounts of

formaldehyde. Skin can become irritated if it comes into contact with a strong solution of formaldehyde.

To protect the public from the harmful effects of toxic chemicals and to find ways to treat people who

have been harmed, scientists use many tests. 

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released

by the body; for some chemicals, animal testing may be necessary. Animal testing may also be used to

identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a

basic method to get information needed to make wise decisions to protect public health. Scientists have
FORMALDEHYDE 5

1. PUBLIC HEALTH STATEMENT

the responsibility to treat research animals with care and compassion. Laws today protect the welfare of

research animals, and scientists must comply with strict animal care guidelines.

Several studies of laboratory rats exposed for life to high amounts of formaldehyde in air found that the

rats developed nose cancer. Some studies of humans exposed to lower amounts of formaldehyde in

workplace air found more cases of cancer of the nose and throat (nasopharyngeal cancer) than expected,

but other studies have not found nasopharyngeal cancer in other groups of workers exposed to

formaldehyde in air. The Department of Health and Human Services (DHHS) has determined that

formaldehyde may reasonably be anticipated to be a human carcinogen (NTP). The International Agency

for Research on Cancer (IARC) has determined that formaldehyde is probably carcinogenic to humans. 

This determination was based on specific judgements that there is limited evidence in humans and

sufficient evidence in laboratory animals that formaldehyde can cause cancer. The Environmental

Protection Agency (EPA) has determined that formaldehyde is a probable human carcinogen based on

limited evidence in humans and sufficient evidence in laboratory animals. More information on the

health effects of formaldehyde can be found in Chapter 2. 

1.6 HOW CAN FORMALDEHYDE AFFECT CHILDREN?

This section discusses potential health effects from exposures during the period from conception to

maturity at 18 years of age in humans. Potential effects on children resulting from exposures of the

parents are also considered.

Children and adults are likely to be exposed to formaldehyde in the same way. The most common way

for children to be exposed to formaldehyde is by breathing it. Children may also be exposed by wearing

some types of new clothes or cosmetics. A small number of studies have looked at the health effects of

formaldehyde in children. It is very likely that breathing formaldehyde will result in nose and eye

irritation (burning feeling, itchy, tearing, and sore throat). We do not know if the irritation would occur at

lower concentrations in children than in adults. Studies in animals suggest that formaldehyde will not

cause birth defects in humans. Inhaled formaldehyde or formaldehyde applied to the skin is not likely to

be transferred from mother to child in breast milk or to reach the developing fetus. 
FORMALDEHYDE 6

1. PUBLIC HEALTH STATEMENT

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO

FORMALDEHYDE?

If your doctor finds that you have been exposed to significant amounts of formaldehyde, ask if children

may also be exposed. When necessary your doctor may need to ask your state department of public

health to investigate.

Formaldehyde is usually found in the air. Formaldehyde levels are also higher indoors than outdoors. 

Opening windows or using a fan to bring in fresh air is the easiest way to lower formaldehyde levels in

the home and reduce the risk of exposure to your family.

Removing formaldehyde sources from the house will also reduce the risk of exposure. Since

formaldehyde is found in tobacco smoke, not smoking or smoking outside will reduce exposure to

formaldehyde. Unvented heaters, such as portable kerosene heaters, also produce formaldehyde. If you

do not use these heaters in your home or shop, you help to prevent the build up of formaldehyde indoors.

Formaldehyde is found in small amounts in many consumer products including antiseptics, medicines,

dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners, glues, adhesives, and lacquers. If

you or a member of your family uses these products, providing fresh outdoor air when you use them, this

will reduce your exposure to formaldehyde. Some cosmetics, such as nail hardeners, have very high

levels of formaldehyde. If you do not use these products in a small room, or if you have plenty of

ventilation when you use them, you will reduce your exposure to formaldehyde. If your children are not

in the room when you use these products, you will also reduce their exposure to formaldehyde.

Formaldehyde is emitted from some wood products such as plywood and particle board, especially when

they are new. The amount of formaldehyde released from them decreases slowly over a few months. If

you put these materials in your house, or buy furniture or cabinets made from them, opening a window

will lower formaldehyde in the house. The amount of formaldehyde emitted to the house will be less if

the wood product is covered with plastic laminate or coated on all sides. If it is not, sealing the

unfinished sides will help to lower the amount of formaldehyde that is given off.

Some permanent press fabrics emit formaldehyde. Washing these new clothes before use will usually

lower the amount of formaldehyde and reduce your family’s risk of exposure.
FORMALDEHYDE 7

1. PUBLIC HEALTH STATEMENT

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN

EXPOSED TO FORMALDEHYDE?

We have no reliable test to determine how much formaldehyde you have been exposed to or whether you

will experience any harmful health effects. 

More information about medical tests for formaldehyde can be found in Chapter 2.

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH?

The federal government develops regulations and recommendations to protect public health. Regulations

can be enforced by law. Federal agencies that develop regulations for toxic substances include the EPA,

the Occupational Safety and Health Administration (OSHA), and the Food and Drug Administration

(FDA). Recommendations provide valuable guidelines to protect public health but cannot be enforced by

law. Federal organizations that develop recommendations for toxic substances include the Agency for

Toxic Substances and Disease Registry (ATSDR) and the NIOSH.

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or food that

are usually based on levels that affect animals, then they are adjusted to help protect people. Sometimes

these not-to-exceed levels differ among federal organizations because of different exposure times (an 8-

hour workday or a 24-hour day), the use of different animal studies, or other factors.

Recommendations and regulations are also periodically updated as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. Some

regulations and recommendations for formaldehyde include the following:

Several international, national, and state authorities have established regulations or guidelines for the use

and production of formaldehyde. OSHA has established the permissible exposure limit (PEL) 8-hour

time-weighted average (TWA) at 0.75 ppm and the 15-minute Short-Term Exposure Limit (STEL) at

2 ppm. The EPA sets regulations for reporting quantities used and how much formaldehyde can legally

be produced from automobile exhaust; the FDA also has regulations about the use of formaldehyde in the

food you eat. 
FORMALDEHYDE 8

1. PUBLIC HEALTH STATEMENT

Non-enforceable guidelines have also been established for formaldehyde. The American Conference of

Governmental and Industrial Hygienists (ACGIH) has established a ceiling limit for occupational

exposure (Threshold Limit Value [TLV]) of 0.4 ppm. NIOSH has a recommended exposure limit for

occupational exposure (8-hour TWA) of 0.016 ppm, and a 15-minute ceiling limit of 0.1 ppm.

More information about the federal and state regulations and guidelines for formaldehyde can be found in

Chapter 7.

1.10 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or

environmental quality department or

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Clifton Road NE, Mailstop E-29

Atlanta, GA 30333

* Information line and technical assistance

Phone: (800) 447-1544

Fax: (404) 639-6359

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics

specialize in recognizing, evaluating, and treating illnesses resulting from exposure to hazardous

substances.

* To order toxicological profiles, contact

National Technical Information Service

5285 Port Royal Road

Springfield, VA 22161

Phone: (800) 553-6847 or (703) 487-4650
FORMALDEHYDE 9

2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and

other interested individuals and groups with an overall perspective on the toxicology of formaldehyde. It

contains descriptions and evaluations of toxicological studies and epidemiological investigations and

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near

hazardous waste sites, the information in this section is organized first by route of exposure— inhalation,

oral, and dermal; and then by health effect—death, systemic, immunological, neurological, reproductive,

developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure

periods—acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or

lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the

studies. LOAELS have been classified into "less serious" or "serious" effects. "Serious" effects are those

that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory

distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction

or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a

considerable amount of judgment may be required in establishing whether an end point should be

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will 

be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the

Agency has established guidelines and policies that are used to classify these end points. ATSDR

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" 

effects is considered to be important because it helps the users of the profiles to identify levels of 
FORMALDEHYDE 10

2. HEALTH EFFECTS

exposure at which major health effects start to appear. LOAELs or NOAELs should also help in

determining whether or not the effects vary with dose and/or duration, and place into perspective the

possible significance of these effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and

figures may differ depending on the user's perspective. Public health officials and others concerned with

appropriate actions to take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of formaldehyde

are indicated in Tables 2-1, 2-4, and 2-5 and Figures 2-1 and 2-2. Because cancer effects could occur at

lower exposure levels, Figure 2-1 also shows a range for the upper bound of estimated excess risks,

ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been

made for formaldehyde. An MRL is defined as an estimate of daily human exposure to a substance that is

likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of

effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. 

MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can

be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. 

Appropriate methodology does not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990c),

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an

example, acute inhalation MRLs may not be protective for health effects that are delayed in development

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic

bronchitis. As these kinds of health effects data become available and methods to assess levels of

significant human exposure improve, these MRLs will be revised.
FORMALDEHYDE 11

2. HEALTH EFFECTS

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

2.2.1 Inhalation Exposure

Formaldehyde vapors used in controlled-exposure inhalation studies can be generated by heating

commercial formalin, aqueous solutions containing 30–50% formaldehyde by weight plus methanol or

other substances to inhibit intrinsic polymerization, or by heating solid paraformaldehyde, a

formaldehyde polymer. Unless noted otherwise, inhalation studies used in the preparation of this profile

provided clear evidence that formaldehyde was the only added gas in the experimental atmosphere.

2.2.1.1 Death

Reports of deaths in humans from short-term inhalation exposure to formaldehyde were not located. 

Increased rates of cancer-related mortality associated with occupational exposure to formaldehyde have

been found in some epidemiological studies, but not in others. A more thorough discussion of available

epidemiological studies is available in Section 2.2.1.8.

Repeated exposure to formaldehyde vapors at 40 ppm, 6 hours/day, 5 days/week for up to 13 weeks

produced 80% mortality in B6C3F1 mice, whereas mice exposed with the same protocol to 20 ppm

showed no mortalities within the exposure period (Maronpot et al. 1986). Deaths occurred predominately

in the fifth and sixth week of exposure and were associated with ataxia, severe body weight depression,

and inflammation and metaplasia in the nasal cavity, larynx, trachea, and lungs. Deaths were attributed to

occlusive tracheal lesions and/or prominent seropurulent rhinitis (Maronpot et al. 1986). 

In other intermediate duration inhalation bioassays, no exposure-related deaths or early mortalities were

found in Wistar rats exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al.

1987), in F344 rats, Cynomolgus monkeys, or Golden Syrian hamsters exposed to up to 2.95 ppm,

22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983), or in Wistar rats exposed to up to 20 ppm,

6 hours/day, 5 days/week for 4, 8, or 13 weeks and subsequently observed for 117 weeks without

exposure (Feron et al. 1988). No exposure-related maternal or fetal deaths occurred in studies that

exposed pregnant Sprague-Dawley rats to up to 10 ppm formaldehyde, 6 hours/day on gestation days 
FORMALDEHYDE 12

2. HEALTH EFFECTS

6 through 15 (Martin 1990) or up to 40 ppm, 6 hours/day on gestation days 6 through 20 (Saillenfait et al.

1989). 

In chronic inhalation bioassays, increased mortality (compared with controls) was found in

Sprague-Dawley rats exposed to 14.2 ppm formaldehyde, 6 hours/day, 5 days/week for up to 588 days

(Albert et al. 1982), in F344 rats exposed to 5.6 or 14.3 ppm (but not 2 ppm), 6 hours/day, 5 days/week

for up to 24 months (Kerns et al. 1983b; Swenberg et al. 1980), in F344 rats exposed to 15 ppm (but not

to 0.7, 2, 6, or 10 ppm) 6 hours/day, 5 days/week for 24 months (Monticello et al. 1996), and in F344 rats

exposed to 15 ppm (but not to 0.3 or 2 ppm), 6 hours/day, 5 days/week for up to 28 months (Kamata et al.

1997). In general, observations of increased mortality in the rat bioassays occurred after about one year

of exposure and were associated with the development of nasal squamous cell carcinomas. Golden Syrian

hamsters exposed to 10 ppm formaldehyde, 5 hours/day, 5 days/week for life showed a small, but

statistically significant, increase in mortality compared with controls, but no increased incidence of nasal

tumors and only a minimal (5% versus zero in controls) increased incidence of hyperplasia or metaplasia

in the nasal epithelium (Dalbey 1982). No exposure-related increased mortality was found in

B6C3F1 mice exposed to up to 14.3 ppm for 6 hours/day, 5 days/week for 24 months (Kerns et al.

1983b). 

The LOAEL values from each reliable study for death in each species and duration category are recorded

in Table 2-1 and plotted in Figure 2-1.

2.2.1.2 Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for each systemic effect in

each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1.




























FORMALDEHYDE 41

2. HEALTH EFFECTS

Results from human and animal studies indicate that the critical target organs to airborne formaldehyde

are the nose and the eyes, with the lungs being a secondary target at high exposure levels. Due to rapid,

detoxifying metabolism of formaldehyde by most, if not all, cells, tissues, and organs distant from portals

of entry are spared toxic effects from formaldehyde at concentrations normally expected to be

encountered in the ambient or workplace atmosphere.

Respiratory Effects. 

The respiratory tract, especially the upper respiratory tract, is a critical target of the toxicity of airborne

formaldehyde as shown by acute controlled exposure human studies, by studies of humans exposed

acutely or repeatedly under occupational or residential conditions, and by studies of animals (including

primates) exposed by inhalation for acute, intermediate, and chronic durations. 

Acute Controlled Exposure Human Studies. More than 15 published studies of respiratory function

and/or irritation of the nose, eyes, and throat are available involving acute controlled exposure of

volunteers, generally at formaldehyde concentrations #3 ppm. Recent reviews of these studies include

those by ACGIH (1992), Krivanek and Imbus (1992), and Paustenbach et al. (1997).

Controlled exposure human studies have found that short-term inhalation exposures to concentrations

ranging from 0.4 to 3 ppm can produce symptoms of mild to moderate irritation of the eyes, nose, and

throat. The odor threshold for formaldehyde in humans has been reported to be 1 ppm (Leonardos et al.

1969), but others have noted that it may range as low as 0.05 ppm (ACGIH 1992). Descriptions follow of

findings for irritation of the eyes, nose, and throat from a sampling of available controlled exposure

studies of acute irritation, emphasizing studies that examined symptoms of irritation at the lower end of

this concentration range (Andersen and Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al.

1992; Krakowiak et al. 1998; Kulle et al. 1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977). Several

of these studies reported that the initial severity of irritation lessened to some degree with continued

exposure (Bender et al. 1983; Day et al. 1984; Green et al. 1987; Weber-Tschopp et al. 1977).

Weber-Tschopp et al. (1977) exposed a group of 33 healthy subjects for 35 minutes to concentrations of

formaldehyde that increased during the period from 0.03 to 3.2 ppm; another group of 48 healthy subjects

was exposed to 0.03, 1.2, 2.1, 2.8, and 4.0 ppm for 1.5 minute intervals. Eye and nose irritation were

reported on a 1–4 scale (1=none to 4=strong) in both experiments, and eye blinking rate was measured in 
FORMALDEHYDE 42

2. HEALTH EFFECTS

the second experiment. Average indices of eye and nose irritation were increased in both experiments to

a small, but statistically significant, extent at 1.2 ppm compared with indices for nonexposed controlled

conditions. The published report of this study graphically showed average severity scores of about

1.3–1.4 for both indices at 1.2 ppm compared with 1.0–1.1 for nonexposed conditions. The average

severity score was increased to a greater degree at higher concentrations, but was less than about 2.5 at

the highest exposure concentration, 4 ppm. Average rates of eye blinking were not significantly affected

at 1.2 ppm, but were statistically significantly increased at 2.1 ppm (about 35 blinks/minute at 2.1 ppm

versus about 22 blinks/minutes under nonexposed conditions). 

Andersen and Molhave (1983) exposed a group of 16 healthy subjects to 0.3, 0.5, 1.0, and 2.0 mg/m3

 (0.2,

0.4, 0.8, and 1.6 ppm) for 4-hour periods preceded by a nonexposed period of two hours. Subjects were

asked to assess “discomfort” on a 0–100 scale ranging from 0=no discomfort to 100=intolerable

discomfort (scores between 1 and 33 were rated as “slight discomfort”). Average peak discomfort scores

for the group generally increased with exposure concentration, but the average discomfort score for the

highest exposure concentration (1.6 ppm) never exceeded 18. Numbers of subjects who reported “No

discomfort” ratings at the end of exposure periods were 7, 13, 10, and 6, respectively for 0.2, 0.4, 0.8, and

1.6 ppm; respective numbers of subjects reporting “conjunctival irritation and dryness in the nose and

throat” were 3, 5, 15, and 15 of the 16 subjects exposed to each respective concentration. A statistical

analysis of these data was not reported.

Bender et al. (1983) exposed groups of 5–28 healthy subjects to 0, 0.35, 0.56, 0.7, 0.9, or 1.0 ppm for

6-minute periods and asked them to note when they experienced eye irritation and to rate eye irritation on

a 0–3 scale (0=none to 3=severe, with 1=slight). The subjects were selected from a larger group of

subjects in a preliminary screening test as those who “responded to 1.3 and 2.2 ppm”. Upper respiratory

tract irritation was not rated in this study. Average initial severity scores for the five exposure

concentrations in increasing order were 0.71, 0.79, 0.86, 0.80, and 1.56; no irritation was noted with

“clean air” exposure. The median times to noting eye irritation (response time measured in seconds)

generally decreased with increasing concentration as follows: 360 (clean air), 268, 217, 72, 119, and

78 seconds. Numbers of subjects who reported response times that were less than their clean air response

time were: 5/12 at 0.35 ppm, 14/26 at 0.56 ppm, 4/7 at 0.7 ppm, 3/5 at 0.9 ppm, and 20/27 at 1.0 ppm. 

The elevation in percentage of subjects with shortened response time was only statistically significant at

the 1 ppm level.
FORMALDEHYDE 43

2. HEALTH EFFECTS

Kulle et al. (1987; Kulle 1993) exposed 19 healthy subjects to 0, 1.0, and 2.0 ppm for 3-hour periods and

asked them to note symptoms of eye and nose/throat irritation and to rate severity on a 0–3 scale: 0=none;

1=mild (present but not annoying); 2=moderate (annoying); and 3=severe (debilitating). Ten of the

subjects were also exposed to 0.5 ppm and nine were exposed to 3 ppm for 3-hour periods. The

frequencies of subjects reporting eye irritation or nose/throat irritation increased with increasing exposure

concentration, especially at concentrations $1 ppm. Under nonexposed conditions, 3/19 subjects noted

mild nose/throat irritation and 1/19 noted mild eye irritation. At 0.5 ppm, 1/10 subjects noted mild

nose/throat irritation, but none reported eye irritation. Frequencies for subjects with mild or moderate eye

irritation were 4/19 at 1 ppm (1 was moderate), 10/19 at 2 ppm (4 were moderate), and 9/9 at 3 ppm

(4 were moderate). The increased frequency for eye irritation (compared with controls) was statistically

significant at $2 ppm. Frequencies for mild nose/throat irritation were 1/19 at 1 ppm, 7/19 at 2 ppm, and

2/9 at 3 ppm. Compared with control frequency for nose/throat irritation, only the response at 2 ppm was

significantly elevated.

In a study of volunteers exposed to 1 ppm for 90 minutes, seven subjects reported eye irritation and three

reported nasal congestion among nine subjects who had previously complained of health effects from

exposure to urea-formaldehyde insulation in their homes (Day et al. 1984). A similar response to 1 ppm

formaldehyde was noted among the other nine subjects in this study who had no previous complaints:

eight reported eye irritation and four reported nasal congestion from the 90-minute exposure. 

In groups of 15 healthy subjects and 15 asthmatics exposed to 2 ppm for 40 minutes while exercising,

“mild” eye irritation (average severity scores of 1.1 and 1.6 on a 5-point scale ranging from 0=none to

4=incapacitating, with 1=mild) was reported by eight healthy and five asthmatic subjects (Schachter et al.

1986; Witek et al. 1986, 1987). Nasal irritation was reported by 5/15 healthy and 5/15 asthmatics

subjects with average severity scores of 1.2 and 1.8, respectively.

Gorski and colleagues have reported that symptoms of upper respiratory tract irritation occurred in three

studies comparing respiratory responses to 2-hour exposures to placebo or 0.5 mg formaldehyde/m3

(0.4 ppm) in healthy, nonexposed subjects, in subjects with formaldehyde-sensitive contact dermatitis

(Gorski et al. 1992; Pazdrak et al. 1993), and in formaldehyde-exposed workers with bronchial asthma

(Krakowiak et al. 1998). Krakowiak et al. (1998) noted that, for these studies, formaldehyde vapors were

generated by evaporating 10 μL of a 10% aqueous solution of formaldehyde in a 12-m, temperature- and

humidity-controlled, exposure chamber. Measured airborne concentrations of formaldehyde ranged from 
FORMALDEHYDE 44

2. HEALTH EFFECTS

0.2 to 0.7 mg/m3 with a mean of 0.5 mg/m3 (0.4 ppm). Gorski et al. (1992) reported that, after exposure

to 0.4 ppm, 1/5 healthy subjects and 3/13 subjects with formaldehyde-sensitive contact dermatitis

experienced nose irritation, sneezing, or eye irritation. Similar exposure produced statistically significant

increases in the average number and proportion of eosinophils and the concentration of albumin and total

protein in nasal lavage fluid, both in groups of 9 sensitized subjects and in groups of 11 nonexposed

subjects; the responses in the two groups were not significantly different (Pazdrak et al. 1993). Pazdrak et

al. (1993) reported that exposure “caused itching, sneezing, and congestion”, but did not indicate the

number of subjects reporting these symptoms. In another experiment, exposure to 0.4 ppm also produced

similar statistically significant increases in eosinophils and protein in nasal lavage fluid in other groups of

10 nonexposed subjects and 10 formaldehyde-exposed workers with bronchial asthma, and “caused

sneezing, itching and congestion in all subjects” (Krakowiak et al. 1998). Pulmonary functions were also

measured in each of these studies, but no exposure-related effects were found in any of the groups (see

below). An acute inhalation MRL of 0.04 ppm was calculated as described in the footnote in Table 2-1

and in Appendix A based on the LOAEL (0.4 ppm) from the study by Pazdrak et al. (1993). 

Formaldehyde-induced effects on human pulmonary function variables including forced vital capacity

(FVC), forced expiratory volume in 1.0 seconds (FEV1.0), peak expiratory flow rate (PEFR), and forced

expiratory flowrate between 25 and 75% FVC (FEFR25–75), have not been found as consistently as

symptoms of eye and nose irritation at acute exposure levels in the range of 0.4–3 ppm. In controlled

exposure studies, no statistically significant exposure-related effects on lung function measurements were

found in 10 healthy subjects exposed to up to 2 ppm for 3 hours (Kulle et al. 1987; Kulle 1993), 

15 healthy subjects exposed to 0 or 2 ppm for 40 minutes with or without exercise (Schachter et al. 1986;

Witek et al. 1986), 15 formaldehyde-exposed laboratory workers exposed to 0 or 2 ppm for 40 minutes

with or without exercise (Schachter et al. 1987), 15 asthmatic volunteers exposed to 0 or 2 ppm for

40 minutes with or without exercise (Witek et al. 1986, 1987), 18 subjects, 9 of whom had complaints of

health effects from exposure to urea-formaldehyde foam insulation in their homes, exposed to 1 ppm for

90 minutes (Day et al. 1984), 16 healthy student volunteers exposed to up to 1.7 ppm for 4 hours

(Andersen and Molhave 1983), 13 subjects with allergic dermal sensitivity to formaldehyde and 5 

healthy subjects exposed to 0.4 ppm for 2 hours (Gorski et al. 1992), 10 formaldehyde-exposed textile 

or shoe manufacturing workers with purported bronchial asthma and 10 nonexposed healthy subjects

exposed to 0.4 ppm for 2 hours (Krakowiak et al. 1998), 13 formaldehyde-exposed subjects, who

previously reported symptoms of chest tightness, coughing, or wheezing, exposed to placebo or up 

to 3 ppm for 20 minutes (Reed and Frigas 1984), or 15 patients with documented severe bronchial 
FORMALDEHYDE 45

2. HEALTH EFFECTS

hyperresponsiveness (to histamine) exposed to room air and up to 0.7 ppm for 90 minutes (Harving et al.

1986, 1990). 

A few controlled exposure studies have found only subtle or infrequent effects of acute exposure to low

concentrations of formaldehyde on pulmonary function variables (Green et al. 1987; Nordman et al. 1985;

Sauder et al. 1986). Nordman et al. (1985) measured PEFR, FVC, and FEV1 during and after a 30-minute

“challenge” exposure to placebo, 1 or 2 ppm in a group of 230 patients who had been occupationally

exposed to formaldehyde and had reported respiratory symptoms consistent with asthma during a 6-year

period. Patients were first challenged with 1 ppm; if no response was found, a second challenge of 2 ppm

was given. Exposure-related drops in PEFR of 15% or greater in response to 2 ppm formaldehyde were

found in 12/230 of the patients; one of these 12 subjects showed a response to 1 ppm. Formaldehyde

concentrations were not measured during each test, but periodic checks of exposure concentrations

indicated that challenge concentrations ranged from 0.8 to 0.9 ppm for the 1 ppm target and 1.7–2.0 ppm

for the 2 ppm target. Nordman et al. (1985) concluded that pulmonary function sensitivity to

formaldehyde, at concentrations of 1 to 2 ppm, is rare. Sauder et al. (1986) measured small, but

statistically significant, decreases in FEV1 (2% decrease) and FEFR25–75 (7% decrease) after 30 minutes of

exposure to 3 ppm, but not after 1 or 3 hours of exposure, in a group of nine healthy subjects who

performed intermittent exercise during exposure and who served as their own controls. Green et al.

(1987) measured statistically significant, but small, average deficits (2–3%) in FEV1, FVC, and FEV3 (but

no change in FEFR25–75) in a group of 22 exercising healthy subjects during and after 1 hour of exposure

to 3 ppm, but found no significant deficits in a group of 16 asthmatic subjects similarly exposed. Among

the 38 subjects in this study, five (13%; 2 normal and 3 asthmatic ) displayed exposure-related percentage

deficits in FEV1 greater than 10%, but generally less than 15%.

Acute Occupational Exposure Human Studies. Numerous assessments of pulmonary function variables

in formaldehyde-exposed workers during workday shifts have found, similar to findings from controlled

exposure studies, either no effects or only small and subtle effects from formaldehyde exposure during a

work period. Bracken et al. (1985) measured no significant changes in pulmonary function variables

(FVC, FEV1, and FEFR25–75) during a workshift in which 10 laboratory technicians were exposed to

estimated average formaldehyde concentrations ranging from 0.106±0.02 to 0.269±0.05 ppm. No

significant differences in changes in pulmonary function variables across a workshift were found in

groups of 22 embalmers exposed to an estimated mean concentration of 0.36±0.61 ppm (range

0.08–0.81 ppm) during a 2- to 3-hour embalming procedure compared with a nonexposed group of 
FORMALDEHYDE 46

2. HEALTH EFFECTS

13 subjects (Holness and Nethercott 1989) or in groups of 55 plywood workers exposed to estimated

concentrations ranging from 0.22 to 3.48 ppm compared with a nonexposed group of 50 subjects (Malaka

and Kodama 1990). Kilburn et al. (1985a) reported that decreases in FVC, FEV1, and FEFR25–75 occurred

during a workshift in a group of fiberglass batt workers and not in a group of nonexposed hospital

workers, but workplace air concentrations of formaldehyde were not assessed for the batt workers. 

Alexandersson and Hedenstierna (1989) reported that small, but statistically significant, declines in

FEV1/FVC and FEFR25–75 occurred during a workshift in a group of 11 nonsmoking woodworkers, but not

in 10 smokers, who were exposed to an estimated mean TWA formaldehyde concentration of

0.4±0.1 ppm. Alexandersson and Hedenstierna (1989) did not compare workshift changes in the exposed

group to changes in a control group. Horvath et al. (1988) measured small, but statistically significant,

average declines in FEFR50, FEFR75, and FEFR25–75 during a workshift in a group of 109 particle board

workers exposed to estimated TWA formaldehyde concentrations ranging from 0.17 to 2.93 ppm

(mean 0.69 ppm), but no significant workshift change in these variables in a group of 254 nonexposed,

food-processing workers. Median concentrations of airborne nuisance particulates (i.e., wood dust) in the

particle board plant were 0.38 and 0.11 mg/m3

 for total and respirable particulates, respectively. 

Akbar-Khanzadeh et al. (1994) found no statistically significant differences in workshift changes in

pulmonary function variables (FVC, FEV1, FEV3, and FEFR25–75) in a group of 34 students exposed for 2-

to 3-hour periods to an estimated TWA concentration of 1.24±0.61 ppm (range 0.07–2.94 ppm) in a gross

anatomy laboratory compared with a nonexposed group of 12 subjects, except that the exposed group

showed an average 1.2% decline in FEV3 during exposure compared with a 1.3% increase in FEV3 for the

controls during a comparable period. In another group of 50 students exposed to formaldehydecontaining embalming fluid in a 3-hour gross anatomy laboratory and a control group of 36 nonexposed

students in a 3-hour physiotherapy laboratory, pulmonary function variables increased during the 3-hour

periods, but the average increases in FEV1 and FEFR25–75 for the exposed group (2.7% and 2.2%,

respectively) were statistically significantly less than the average increases (5.2% and 9.3%, respectively)

for the control group (Akbar-Khanzadeh and Mlynek 1997). Estimates of breathing zone formaldehyde

concentrations in the anatomy laboratory ranged from 0.3 to 4.45 ppm with a mean of 1.88±0.96 ppm. In

both studies by Akbar-Khanzadeh and colleagues, eye and nose irritation were reported by more than

70% of exposed subjects. 

Repeated-Exposure Human Studies. Studies of formaldehyde-exposed humans with repeated exposure

under occupational or residential conditions provide confirmatory evidence that formaldehyde can be

irritating to the upper respiratory tract (Boysen et al. 1990; Edling et al. 1988; Garry et al. 1980; 
FORMALDEHYDE 47

2. HEALTH EFFECTS

Holmstrom et al. 1989c; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987),

but only limited evidence that pulmonary functions may be adversely affected by repeated exposure to

formaldehyde (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and Nethercott

1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Krzyzanowski et al. 1990;

Malaka and Kodama 1990). 

Garry et al. (1980) surveyed 275 possible cases of formaldehyde exposure for which health complaints

were registered during a 5-month period (February through June) in 1979 with the Minnesota Department

of Health and measured formaldehyde air levels in living rooms and bedrooms of the subjects’ residences. 

Formaldehyde concentrations ranged from approximately 0.1 to 3 ppm; approximate mean values for the

5 months were 0.65, 0.4, 0.2, 0.6, and 1.0 ppm. Eye, nose, and throat irritation was reported in about 75%

of adults (age $18 years, n=102), 60% of children (age 3–12 years, n=30), and 60% of infants (n=36). 

Cough and wheeze reporting percentages were about 35% in adults, 70% in children, and 60% in infants.

This study provided no information on the duration of exposure.

Ritchie and Lehnen (1987) surveyed approximately 2,000 people living in conventional and mobile

homes and measured formaldehyde concentrations in air samples taken from two rooms in each residence. 

Subjects were selected from requests made to the Minnesota Department of Health for formaldehyde

testing. Reporting percentages of subjects with eye irritation, nose/throat irritation, headaches, and skin

rash were recorded for homes with formaldehyde concentrations classified as "low" (<0.1 ppm),

"medium" (0.1 ppm– <0.3 ppm), or "high" (>0.3 ppm). In both conventional and mobile homes with air

concentrations >0.3 ppm, more than 60% of subjects reported eye irritation, nose/throat irritation, or

headache; with air concentrations between 0.1 and 0.3 ppm, respective reporting percentages ranged

approximately from 10 to 20%, 15 to 20%, and 20 to 25%, depending on home type. Reporting

percentages for homes with concentrations <0.1 ppm were less than 10% for each of these three

symptoms. A major limitation associated with this study is that the participants, in order to be eligible for

the study, complained about symptoms and were therefore a self-selected group with a potential bias. 

Holness and Nethercott (1989) surveyed 84 funeral directors and apprentices exposed to an estimated

mean concentration of 0.36±0.19 ppm (range 0.08–0.81 ppm) for an average of 8.2 years and

38 nonexposed control subjects. Embalmers reported that symptoms of irritation of the eyes, upper

respiratory tract, and skin occurred during work more frequently than controls: chronic bronchitis 
FORMALDEHYDE 48

2. HEALTH EFFECTS

(20 versus 3%), shortness of breath (20 versus 3%), and nasal irritation (44 versus 16%) were among the

most common respiratory complaints. 

Horvath et al. (1988) surveyed 109 workers in a particle board and molded plastics plant for symptoms of

respiratory tract irritation. The duration of exposure among exposed workers ranged from <1 year to

20 years, with a mean and median of 10.3 and 10 years, respectively. Estimates of formaldehyde air

concentrations ranged from 0.17 to 2.93 ppm with a mean of 0.69 ppm. Nuisance particles

(predominantly softwood dust) were also detected in the particle board area. The percentages of particle

board workers reporting a number of symptoms of respiratory irritation over a workshift were statistically

significantly greater than workshift reporting percentages for a nonexposed group of 264 food-processing

workers: cough (34.9 versus 18.9%), chest pains (9.2 versus 2%), phlegm production (26.6 versus 9.8%),

burning nose (28.4 versus 2%), stuffy nose (33.9 versus 14.2%), burning or watering eyes (39.5 versus

9.1%), itchy nose (21.1 versus 7.9%), and sore/burning throat (22 versus 3.9%). 

Several studies have histologically examined nasal biopsy specimens in formaldehyde-exposed workers

and observed epithelial lesions that are consistent with the irritant and reactive properties of formaldehyde

(Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). 

Edling et al. (1988) found histological evidence of epithelial damage in biopsied specimens from the nasal

mucosa of 75 workers from two particle board processing plants and a laminate plant. From air

measurements occasionally made during an 8-year period before the study, estimates of TWA

concentrations were calculated ranging from 0.08 to 0.9 ppm. (A mean TWA concentration was not

reported, but the midpoint of this range is 0.49 ppm). Peaks of up to 4.07 ppm were measured during the

8-year period. Air concentrations were qualitatively assessed as being “somewhat higher” during earlier

periods. Wood dust air concentrations in the particle board plants ranged from 0.6 to 1.1 mg/m3

; air in the

laminate plant was reported to be without wood dust. Employment durations ranged from 1 to 39 years

with a mean of 10.5 years. Runny nose, nasal crusting, and runny eyes when at work were reported by

 60 and 75% of the exposed subjects, respectively, but frequencies were not compared in the report with

frequencies of symptoms for a control group of 25 nonexposed subjects. Little information was given

about the selection of the control group, except that they were “selected with regard to age and smoking

habits”, however, 35% of exposed versus 48% of controls were smokers. Gross clinical examination

showed that 25% of exposed workers had either swollen nasal mucosa or dry nasal mucosa; prevalence 

of this condition in the control group was not reported. Nasal mucosal biopsy sections were 
FORMALDEHYDE 49

2. HEALTH EFFECTS

assigned a score as follows: 0 - normal respiratory epithelium; 1 - loss of ciliated epithelium cells;

2 - mixed cuboid/squamous epithelium, metaplasia; 3 - stratified squamous epithelium; 4 - keratosis;

5 - keratosis with budding of epithelium; 6 - mild or moderate dysplasia; 7 - severe dysplasia; and

8 - carcinoma. Normal ciliated epithelium was found only in 3/75 exposed subjects; whereas a loss of

ciliated cells and goblet cell hyperplasia was noted in 59/75 subjects, and 6/75 exposed subjects showed

mild dysplasia. No subjects displayed severe dysplasia or carcinoma. Edling et al. (1988) did not report

incidences of nasal lesions found in the control group, but did report that the average histological score

for the exposed group (2.8) was statistically significantly greater than the control score (1.8). Histological

scores did not increase with increasing employment duration in the exposed group. The authors reported

that there was no difference in average histological scores between the exposed workers from the particle

board plants, where confounding exposure to wood dust occurred, and those from the laminate plant

without wood dust exposure. This observation supports the hypothesis that the observed nasal epithelial

lesions were caused by formaldehyde and not by an interaction between formaldehyde and wood dust.

Holmstrom et al. (1989c) examined histological changes in nasal tissue specimens from a group of

70 workers in a chemical plant that produced formaldehyde and formaldehyde resins for impregnation of

paper, a group of 100 furniture factory workers working with particle board and glue components, and a

nonexposed, control group of 36 office workers in the same village as the furniture factories. Mean

durations of employment in the groups were 10.4 years (sd 7.3, range 1–36 years) for the chemical

workers and 9.0 years (sd 6.3, range 1–30 years) for the furniture workers. Estimates of personal

breathing zone air concentrations ranged from 0.04 to 0.4 ppm (median 0.24±0.13 ppm) for the chemical

workers, from 0.16 to 0.4 ppm (median 0.20±0.04 ppm) for the furniture workers, and from 0.07 to

0.13 ppm in the late summer for the office workers with a year-round office worker median reported as

0.07 ppm with no standard deviation. The mean wood dust concentration in the furniture factory was

reported to have been between 1 and 2 mg/m3

. Nasal mucosa specimens were taken from the medial or

inferior aspect of the middle turbinate. Histology scores were assigned to each specimen based on a

0–8 scale, identical to the scale used by Edling et al. (1988; described previously). Nasal histology scores

ranged from 0 to 4 (mean 2.16, n=62) for the chemical workers, from 0 to 6 (mean 2.07, n=89) for the

furniture workers, and from 0 to 4 (mean 1.46, n=32) for the office workers. The mean histological score

for the chemical workers, but not the furniture workers, was significantly different from the control 

score, thus supporting the hypothesis that the development of the nasal lesions is formaldehyde-related

and not obligatorily related to a possible interaction between formaldehyde and wood dust. The most 
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2. HEALTH EFFECTS

severe epithelial change found (light or moderate epithelial dysplasia) was found in two furniture

workers. Among the chemical workers (not exposed to wood dust), loss of cilia, goblet cell hyperplasia,

and cuboidal and squamous cell metaplasia replacing the columnar epithelium occurred more frequently

than in the control group of office workers. Within both groups of formaldehyde-exposed workers, no

evidence was found for associations between histological score and duration of exposure, index of

accumulated dose, or smoking habit. A chronic inhalation MRL of 0.008 ppm was calculated as

described in Table 2-1 and in Appendix A based on the minimal LOAEL of 0.24 ppm for mild nasal

lesions in chemical factory workers in this study using an uncertainty factor of 30 (3 for the use of a

minimal LOAEL and 10 for human variability). 

Boysen et al. (1990) histologically examined biopsy specimens from the nasal mucosa of 37 workers in a

chemical plant that produced formaldehyde and formaldehyde resin and 37 age-matched, nonexposed

controls. Exposed workers had been employed in the plant for more than 5 years (range 3–36 years,

mean 20 years), had volunteered for the study, and represented about half of the workers in the plant. 

Controls were selected from office staff of two chemical plants, laboratory personnel from a hospital, and

outpatients at an eye, ear, and nose clinic. Workers were classified into five exposure level groups based

on “knowledge of the production process, recent measurements, and previous and present subjective

sensations experienced by the workers”. Exposure measurement data were not reported, but the exposure

levels during the 1950s and 1960s were reported to have been “high”. Workers in exposure level 1

(containing zero exposed workers) were defined as having occasional exposure (not daily) up to the level

of olfactory detection. Twelve exposed workers reported frequent, but not daily, exposure that was

irritating to the eyes or upper respiratory tract (exposure level 2), 17 workers reported daily exposure up

to a level of olfactory detection (level 3), 5 reported daily exposure above the level of irritation (level 4),

and 3 reported daily exposure inducing discomfort (level 5). The investigators surmised that

concentrations between 0.5 and 2 ppm were associated with exposure levels 1–3, and that levels 4 and

5 were associated with concentrations >2 ppm. Biopsy samples were taken from the anterior curvature of

the middle turbinate of the nasal cavity judged to have the best air flow. Specimen sections were assigned

histology scores for the following findings: 1 for stratified cuboidal epithelium, 2 for mixed stratified

cuboidal/stratified squamous epithelium, 3 for nonkeratinizing stratified squamous epithelium, 4 for

keratinizing stratified squamous epithelium, and 5 for dysplasia. Numbers of subjects in the exposed

group assigned histological scores ranging from 0 to 5 were: 3, 16, 5, 9, 1, and 3; respective numbers 

of subjects for the control group were: 5, 17, 10, 5, 0, and 0. The mean histological score for the 

exposed group (1.9) was statistically significantly greater than the mean for the controls (1.4). Much 
FORMALDEHYDE 51

2. HEALTH EFFECTS

of the difference in histological score between the exposed and control groups can be accounted for by

three cases of dysplasia and one case of keratinizing stratified squamous epithelium in the exposed group;

these lesions were not found in the nonexposed group. The workers with dysplasia were purported to

have been exposed to concentrations in the range of 0.5–2.0 ppm and not to concentrations higher than

2 ppm.

Ballarin et al. (1992) examined smears of nasal respiratory mucosa cells sampled from the inner turbinate

of 15 nonsmokers who were exposed to formaldehyde released from a urea-formaldehyde glue used in a

plywood factory and 15 age- and sex-matched nonexposed clerks from outside of the factory. Estimates

of formaldehyde air concentrations ranged from: 0.21 to 0.60 ppm (mean 0.39±0.20 ppm) in the

warehouse where seven subjects worked, 0.08 to 0.14 ppm (mean 0.1±0.02 ppm) in the shearing press

where six subjects worked, and 0.09 ppm (only one sample taken) in the sawmill area where two subjects

worked. Mean wood dust concentrations for the three areas were 0.23±0.1 mg/m3

, 0.41±0.21 mg/m3, and

0.73 mg/m3

, respectively. Exposed subjects worked at the factory for 2–19 years (mean 6.8±5.0 years). 

Nasal mucosal slides were scored as follows: normal cellularity, 1; number of mucus-secreting cells

greater than ciliated cells, 1.5; hyperplasia, 2; squamous metaplasia, 2.5; mild dysplasia, 3; moderate

dysplasia, 4; severe dysplasia, 5; and malignant cells, 6. In the exposed group, all subjects had a greater

number of nonciliated than ciliated cells, 40% had hyperplasia, 67% had squamous metaplasia, and 6%

slight dysplasia. In controls, 26% had normal cytology, 67% had more ciliated than nonciliated cells,

33% had hyperplasia, and 6% had squamous metaplasia. The mean cytology score for the exposed group

(2.3±0.5) was reported to be statistically significantly greater than the control score (1.6±0.5). Also found

in this study was a statistically significantly higher percentage of micronucleated mucosal cells in the

exposed group compared with the control group (0.91%±0.47 versus 0.25%±0.22).

Studies of baseline pulmonary function variables (e.g., FVC, FEV1, FEFR25–75) that have found no

abnormal average values for groups of workers repeatedly exposed to formaldehyde or no statistically

significant exposure-related differences compared with referent, nonexposed workers include those of:

10 laboratory technicians employed for an average 7.7 years in workplaces with estimated mean

concentrations ranging from 0.106±0.2 to 0.269±0.05 ppm (Bracken et al. 1985), 109 particleboard

workers employed for an average 10.3 years (range <1–20 years) in a plant with estimated TWA

concentrations ranging from 0.17 to 2.93 ppm (mean 0.69 ppm) (Horvath et al. 1988), and 64 embalmers

(embalming for an average of 10 years) and 12 embalming apprentices (employed less than a year) 
FORMALDEHYDE 52

2. HEALTH EFFECTS

estimated to have been exposed to formaldehyde concentrations ranging from 0.08 to 0.81 ppm

(mean 0.36±0.19 ppm) (Holness and Nethercott 1989). 

Other studies have presented evidence for generally small or subtle formaldehyde-induced changes in

pulmonary function variables with repeated occupational exposure (Alexandersson and Hedenstierna

1988, 1989; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990). 

Using American Thoracic Society Criteria, Malaka and Kodama (1990) reported that the percentages of

subjects with abnormal values for a number of pulmonary function variables (e.g., FEV1 and FEFR25–75 )

were significantly higher in a group of 93 plywood workers compared with a group of 93 nonexposed

subjects. The plywood workers were employed for a mean of 6.2±2.4 years in workplaces with estimated

formaldehyde air concentrations ranging from 0.22 to 3.48 ppm. The mean product of employment

duration times workplace air formaldehyde concentration was 6.2 ppm/year (sd 2.72 ppm/year) for the

exposed group of workers; division of this value by the average duration of employment (6.2 years)

arrives at an estimated average exposure concentration of 1 ppm formaldehyde. Reported average

respirable and total wood-dust concentrations in workplace air were 0.60 and 1.35 mg/m3

, respectively. 

Mean values of baseline FEV1 and FEFR25–75 , after adjustment for dust exposure, were reportedly

statistically significantly lower in the exposed group of workers compared with the nonexposed group

(FEV1 2.78 L [sd 0.41] versus 2.82 L [sd 0.3]; and FEF25–75 3.14 L/second [sd 0.76] versus

3.44 L/second [sd 0.78]). Malaka and Kodama (1990) noted that although the small differences were

statistically significant, their clinical significance was unclear.

Mean baseline measures of FVC and FEV1 were significantly lower (by <10%) than reference values in a

group of 21 woodworkers employed for an average of 11 years, but mean values of these variables did not

decline significantly when measured 5 years later (Alexandersson and Hedenstierna 1989). Estimates of

workplace air concentrations were 0.3±0.2 ppm at the beginning and 0.4±0.1 ppm at the end of the 5-year

period. 

Mean values for FVC and FEV1 were significantly lower than reference values in a group of 38 workers

exposed to formaldehyde and other solvents used in lacquer applications, but the difference was small

(<5–10% change from reference values) (Alexandersson and Hedenstierna 1988). The workers in the

lacquer-applying workplace were employed for an average of 7.8 years; estimates of formaldehyde

concentrations in workplace air ranged from 0.2 to 2.1 ppm with a TWA mean of 0.3 ppm. 
FORMALDEHYDE 53

2. HEALTH EFFECTS

Mean values of FVC, FEV1/FVC, and maximum mid-expiratory flow rate were significantly lower in a

group of 37 anatomy and histopathology workers compared with values for a control group of

37 nonexposed workers from the same college (FVC 2.18 L versus 2.63 L; FEV1/FVC 0.607

versus 0.787; flow rate 1.55 L/second versus 2.71 L/second) (Khamgaonkar and Fulare 1991). 

Employment durations were not reported in this study, but estimated formaldehyde air concentrations

ranged from 0.036 to 2.27 ppm (mean 1.0±0.55 ppm) in the anatomy and histopathology workplaces

compared with 0 to 0.52 ppm (mean 0.1±0.11 ppm) in the control workplaces. The study authors

suggested that the apparent bronchoconstrictor effect of formaldehyde was due either to a direct effect of

formaldehyde or a reflex response caused by irritation of the nose and throat.

Mean baseline PEFR declined by about 2% over a 10-week period in a group of 24 physical therapy

students who dissected cadavers for 3-hour periods per week (Kriebel et al. 1993). Estimates of breathing

zone formaldehyde concentrations ranged from 0.49 to 0.93 ppm (geometric mean 0.73±1.22 ppm). 

PEFR, the only pulmonary function variable measured in this study, was measured before and after each

exposure period. Postexposure PEFR means were 1–3% lower than preexposure PEFR means during the

first 4 weeks, but this difference was not apparent during the last 6 weeks. Fourteen weeks after the end

of the 10-week period, the mean PEFR for the group returned to the preexposure baseline value. 

Effect levels associated with formaldehyde-induced changes in pulmonary function variables in workers

exposed to airborne formaldehyde concentrations generally less than 1 ppm are not included in Table 2-1

because the observed differences: are not of sufficient magnitude to be of obvious clinical significance,

have not been observed consistently across studies, and may be confounded, in some cases, by the

presence of wood dust particulates which may facilitate transport of adsorbed formaldehyde to deeper

regions of the respiratory tract compared with low-level exposure to formaldehyde alone. In contrast,

mild nasal epithelial lesions observed in formaldehyde-exposed workers: have been observed consistently

across four studies (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c),

do not appear to be confounded by exposure to wood dust (see Edling et al. 1988; Holmstrom et al.

1989c), and are consistent with results from animal toxicity, pharmacokinetic, and anatomical airflow

studies indicating that, at concentrations #1 ppm, inhaled formaldehyde gas does not reach lower regions

of the respiratory tract (see following review of animal inhalation toxicity studies and Sections 2.3 and

2.4).
FORMALDEHYDE 54

2. HEALTH EFFECTS

A single study was located providing suggestive, but to date uncorroborated, evidence that elevated levels

of formaldehyde in residential air may change pulmonary function variables in children, but not adults. 

Krzyzanowski et al. (1990) reported that children who lived in households with formaldehyde air

concentrations greater than 0.06 ppm had greater prevalence rates of physician-diagnosed bronchitis or

asthma compared with children who lived in households with concentrations less than 0.06 ppm. A

statistically significant trend for increasing prevalence rate with increasing formaldehyde air

concentration was found for households with environmental tobacco smoke, but the trend was not

significant in households without tobacco smoke. A statistically significant trend was also found for

decreasing PEFR values in children with increasing household formaldehyde air concentration. The

clinical significance of these findings is uncertain (see Section 2.6 for more discussion).

Acute Inhalation Animal Studies. Studies in animals confirm that the upper respiratory tract is a critical

target for inhaled formaldehyde and describe exposure-response relationships for upper respiratory tract

irritation and epithelial damage in several species. Acute inhalation animal studies show that inhaled

formaldehyde, at appropriate exposure concentrations, damages epithelial tissue in specific regions of the

upper respiratory tract in rats, mice, and monkeys (Chang et al. 1983; Monticello et al. 1989, 1991;

Morgan et al. 1986a, 1986c), that formaldehyde is a more potent sensory irritant in mice (Chang et al.

1981, 1983; Kane and Alarie 1977) than in rats (Chang et al. 1981, 1983), that lung damage from inhaled

formaldehyde occurs at higher concentrations than those only affecting the upper respiratory tract

(Kamata et al. 1996a, 1996b; Swiecichowski et al. 1993), that mice are less susceptible to formaldehydeinduced upper respiratory tract epithelial damage than rats (Chang et al. 1983), that rats and monkeys may

be equally susceptible to epithelial damage from formaldehyde but display similar epithelial lesions in

different regions of the upper respiratory tract (Monticello et al. 1989, 1991), and that formaldehyde

induces bronchoconstriction and airway hyperreactivity in guinea pigs (Amdur 1960; Swiecichowski et

al. 1993). 

Formaldehyde-induced epithelial damage in the nasal cavity of rats (e.g., squamous metaplasia and

hyperplasia) displays regional specificity (anterior regions of the nasal epithelium, posterior to the

vestibule at the lowest effective concentrations) and occurs with acute exposures to concentrations

generally greater than 2–6 ppm. Monticello et al. (1991) found no evidence for histological nasal

epithelial damage in F344 rats exposed to 0.7 or 2 ppm, 6 hours/day for 1, 4, or 9 days, but damage 

was observed at 6, 10, and 15 ppm. Regions of epithelium showing histological lesions also showed

increased rates of cellular proliferation at concentrations greater than 6 ppm (Monticello et al. 1991). 
FORMALDEHYDE 55

2. HEALTH EFFECTS

Site-specific damage to nasal epithelial cells after acute exposure (6 hours/day for 1 to 3 weeks) of

F344 rats to formaldehyde was correlated with inhibition of mucociliary function (i.e., mucostasis) at

concentrations of 2, 6, and 15 ppm, but no effects on these end points were found at 0.5 ppm (Morgan et

al. 1986a, 1986c). Morgan et al. (1986c) reported that mucus flow was stopped after only 1 hour of

exposure to 15 ppm in regions of the nasal epithelium that later developed lesions, and that this effect was

still apparent 18 hours after exposure ceased. Other acute inhalation studies with rats (Bhalla et al. 1991;

Cassee and Feron 1994; Monteiro-Riviere and Popp 1986; Wilmer et al. 1987) provide supporting

evidence that short-term exposure to concentrations in excess of 2 ppm can damage nasal epithelial

tissues in this species (see Table 2-1). 

Upper respiratory tract epithelial lesions similar to those observed in rats have been observed in Rhesus

monkeys exposed to 6 ppm, 6 hours/day, 5 days/week for 1 week; the regional distribution of these

lesions was not restricted to the nasal cavity, as they were in rats exposed to 6 ppm (Monticello et al.

1991), but extended to the trachea and major bronchi (Monticello et al. 1989). Lesions were most severe

in the nasal passages and were minimal in the lower airways (larynx, trachea, and carina). Regions of

epithelium with lesions corresponded with regions in which high rates of cellular proliferation were

measured. No evidence for lesions or changes in cell proliferation rates were found in the maxillary

sinuses. Studies describing exposure-response relationships for upper respiratory tract epithelial damage

in monkeys acutely exposed to inhaled formaldehyde were not located.

Inhaled formaldehyde is a more effective sensory irritant (i.e., stimulates trigeminal nerve endings and

inhibits respiration rate and tidal volume) in mice than in rats (Chang et al. 1981; Kane and Alarie 1977),

whereas nasal effects such as rhinitis and degeneration of respiratory epithelial cells are more severe in

rats than in mice, and increased indices of cell proliferation in nasal epithelium are more frequent in rats

than mice, after exposure to 15 ppm, 6 hours/day for 1 or 5 days (Chang et al. 1983). Measured

RD50 values for mice (2.2–5.9 ppm; concentrations associated with a 50% decrease in respiratory rate)

were much lower than RD50 values for rats (22.7–31.7 ppm) (Chang et al. 1981). Kane and Alarie (1977)

reported a similar RD50 value, 3.1 ppm, for formaldehyde in mice. These results suggest that the lesser

sensitivity of mice to formaldehyde-induced nasal tissue damage may be due, at least in part, to the

mouse’s ability to maintain decreased respiration rates and decreased tidal volumes in the presence of

airborne formaldehyde, whereas the rat does not have this ability and thus sustains a greater degree of

tissue damage. 
FORMALDEHYDE 56

2. HEALTH EFFECTS

Acute inhalation exposure to formaldehyde has been associated with tissue damage in the lungs only at

much higher exposure concentrations than those affecting the nasal region alone. Histological and

ultrastructural examination of lung tissue from rats exposed to 10 ppm, 6 hours/day for 4 days found no

evidence for tissue injury, although these rats showed clinical signs of eye and nose irritations (Dinsdale

et al. 1993). In addition, activities of alkaline phosphatase and γ-glutamyl transpeptidase in

bronchoalveolar lavage fluid and lung tissue concentrations of cytochrome P-450 were not significantly

elevated in exposed rats compared with control rats. These results indicate that very limited amounts of

formaldehyde reach the lungs with exposure to 10 ppm. In contrast, Kamata et al. (1996a) reported that

single 6-hour exposures of male F344 rats to 150 ppm formaldehyde induced histological changes

throughout the nasal turbinates (including hyperkeratosis of the squamous epithelium in the vestibule,

desquamation of the respiratory epithelium), the trachea (increased secretion and desquamation of

mucosal cells), and the lung (hyperplasia of the alveolar wall and plasma-like secretions in the lung),

whereas similar exposure to 15 ppm produced only slight hypersecretion of the nasal and tracheal

mucosal epithelium. Kamata et al. (1996b) also noted that F344 rats exposed to 128 or 295 ppm

formaldehyde for 6 hours showed bloody nasal discharge and pulmonary edema, indicating that, at these

very high concentrations, formaldehyde can reach and damage lung tissue as well as nasal tissue.

Experiments with guinea pigs provide evidence that acute exposure to inhaled formaldehyde can

influence lower airway resistance and hyperreactivity of the lungs (Amdur 1960; Swiecichowski et al.

1993). Amdur (1960) measured significantly increased airway resistance in guinea pigs exposed for

1 hour to formaldehyde concentrations as low as 0.3 ppm; the average increase in resistance was about

14, 29, and 43% over control values at 0.3, 1.2, and 3.6 ppm, respectively. Amdur suggested that the

changes in resistance were due to bronchoconstriction. More recently, Swiecichowski et al. (1993)

reported that pulmonary resistance was significantly increased in guinea pigs exposed to 9.4 ppm for

2 hours, but not in guinea pigs exposed to 3.4 ppm or lower for 2 hours. Longer duration exposure

(8 hours) changed the exposure-response relationship; concentrations as low as 0.3 ppm produced

significantly increased pulmonary resistance. Pulmonary sensitivity to acetylcholine was significantly

increased by 2-hour exposures to concentrations $9.4 ppm and by 8-hour exposures to $0.3 ppm. No

exposure-related epithelial damage or inflammatory response was detected by histological examinations

of portions of the midtrachea.
FORMALDEHYDE 57

2. HEALTH EFFECTS

Intermediate Inhalation Animal Studies. Results from intermediate-duration inhalation studies with rats

(Appelman et al. 1988; Feron et al. 1988; Monticello et al. 1991; Rusch et al. 1983; Woutersen et al.

1987; Zwart et al. 1988), Rhesus monkeys (Monticello et al. 1989), Cynomolgus monkeys (Rusch et al.

1983), mice (Maronpot et al. 1986), and hamsters (Rusch et al. 1983) indicate that the nasal epithelium is

the most sensitive target of inhaled formaldehyde. The studies support the hypothesis that mice and

hamsters are less sensitive than rats and monkeys to formaldehyde-induced nasal damage (Maronpot et al.

1986; Rusch et al. 1983), show that formaldehyde-induced damage to the upper respiratory tract

epithelium (hyperplasia and squamous cell metaplasia) has a wider regional distribution in Rhesus

monkeys than in rats (Monticello et al. 1989, 1991), show that site-specific nasal lesions in both monkeys

and rats corresponded to regions with high rates of cellular proliferation (Casanova et al. 1994;

Monticello et al. 1989, 1991), indicate that damage to the respiratory epithelium is more concentrationdependent than duration-dependent (Wilmer et al. 1987, 1989), and show that concentrations of

DNA-protein cross links are correlated with regional sites of formaldehyde-induced epithelial damage in

the nose of rats (Casanova et al. 1994).

In a study designed to detect potential effects on tissues and organs distant from the nose and to describe

exposure-response relationships for nasal lesions in rats exposed to between 1 and 20 ppm formaldehyde

for intermediate durations, Woutersen et al. (1987) exposed groups of 10 male and 10 female Wistar rats

to 0, 1, 10, or 20 ppm 6 hours/day, 5 days/week for 13 weeks. Sections of the lungs, trachea, larynx, and

nose were microscopically examined in all rats; all other major organs and tissues were also examined

microscopically in control and high-exposure groups. Exposure to 20 ppm produced severe and extensive

keratinized squamous metaplasia of the nasal respiratory epithelium, focal degeneration and squamous

metaplasia of the olfactory epithelium, and squamous metaplasia of the laryngeal epithelium (males only). 

No exposure-related lesions were found in other tissues or organs. Respiratory effects at 10 ppm were

restricted to moderate squamous metaplasia of the nasal respiratory epithelium. Effects noted in the

1-ppm group were restricted to minimal focal hyperplasia and squamous metaplasia of the nasal

respiratory epithelium found in three rats.

Zwart et al. (1988) exposed groups of male and female Wistar rats to formaldehyde at concentrations of 0,

0.3, 1, or 3 ppm, 6 hours/day, 5 days a week for 13 weeks to study details of formaldehyde-induced nasal

tissue damage. Exposure-related nasal tissue histological changes were restricted to a small area of the

anterior region of the nose normally covered with respiratory epithelium and were found only in the highexposure group. Lesions were described as ranging from epithelial disarrangement to epithelial 
FORMALDEHYDE 58

2. HEALTH EFFECTS

hyperplasia and squamous metaplasia. After 3 days of exposure, increased rates of cellular proliferation,

compared with controls, were found in the 1- and 3-ppm groups in epithelial regions where lesions were

found after 13 weeks in the 3-ppm group. After 13 weeks of exposure, cellular proliferation rates were

not increased in the lesion-laden regions of exposed rats, but were increased in more posterior regions of

the nasal epithelium, most notably in rats exposed to 3 ppm. These results are consistent with the

hypothesis that the change of mucus-covered respiratory epithelial cells to squamous epithelial cells is

adaptive. 

Appelman et al. (1988) exposed groups of male SPF Wistar rats to 0, 0.1, 1, or 10 ppm formaldehyde

6 hours/day, 5 days/week for 13 or 52 weeks. Within each exposure group, half of the animals had their

nasal mucosa damaged by acute electrocoagulation prior to formaldehyde exposure. In groups without

predamaged nasal mucosa, exposure-related effects were restricted to rhinitis and hyperplasia and

metaplasia of the nasal respiratory epithelium in the 10-ppm group. Comprehensive histological

examination of major tissues and organs in the control and 10-ppm groups revealed no other exposurerelated lesions. Microscopic examination of nose sections from the 1- and 0.1-ppm groups without

electrocoagulation revealed no exposure-related effects. Rats with predamaged nasal mucosa were more

susceptible to the cytotoxic action of formaldehyde; at 52 weeks, focal squamous metaplasia of the nasal

respiratory epithelium was found in rats exposed to 0.1 or 1 ppm formaldehyde.

Monticello et al. (1991) exposed groups of 36 male F344 rats to 0, 0.7, 2, 6, 10, or 15 ppm, 6 hours/day,

5 days/week for up to 6 weeks and labeled with tritiated thymidine prior to scheduled termination to

determine rates of cellular proliferation in specific regions of the nasal epithelium. After 6 weeks of

exposure to 10 or 15 ppm, epithelial hyperplasia and squamous metaplasia of the respiratory epithelium

were located primarily in the nasoturbinates, just posterior to the nasal vestibule, with milder lesions

extending into more posterior regions including the nasopharynx. Exposure to 6 ppm produced mild

epithelial hyperplasia and squamous metaplasia that was restricted to the most anterior regions of the

respiratory epithelium in the nasoturbinates. Statistically significant increases in cellular proliferation

rates were measured in the groups exposed to 6 ppm or higher. Exposure-related effects on nasal

epithelium were not found in the 2- or 0.7-ppm groups. Sites of cellular injury were well-correlated with

sites of increased rates of cellular proliferation.

Casanova et al. (1994) exposed groups of male F344 rats to 0, 0.7, 2, 6, or 15 ppm 6 hours/day,

5 days/week for 81 days to examine the effect of preexposure to formaldehyde on the concentrations of 
FORMALDEHYDE 59

2. HEALTH EFFECTS

DNA-protein cross links formed in specific regions of nasal cavity epithelium in response to acute

exposure to radiolabeled formaldehyde. DNA-protein cross link concentrations were approximately

6-fold higher in the mucosal lining of the lateral meatus (where formaldehyde-induced lesions develop)

than in the mucosal lining of the medial and posterior meatus (where lesion development is less strong). 

Preexposure to formaldehyde at concentrations #2 ppm did not affect the formation of DNA-protein cross

links, but at higher concentrations, pre-exposed rats showed decreased acute formation of DNA-protein

cross links compared with rats without prior exposure to formaldehyde.

Monticello et al. (1989) exposed groups of three male Rhesus monkeys to 0 or 6 ppm formaldehyde,

6 hours/day, 5 days/week to compare respiratory responses to formaldehyde in primates with those in

rodents. Comprehensive histological examination of respiratory tract tissues (and also extra-respiratory

tissues) was conducted. Exposure-related lesions were confined to the epithelium of the upper respiratory

tract and were described as mild hyperplasia and squamous metaplasia confined to particular regions of

the transitional and respiratory epithelium of the nasal passages and the respiratory epithelium of the

trachea and carina. Cellular proliferation rates were significantly elevated in damaged regions of the

nasal epithelium. Nasal lesions seen in monkeys were similar to those reported in rats exposed to 6 ppm

by a similar exposure protocol and duration in a companion study (Monticello et al. 1991) except that the

lesions extended into the trachea in the monkeys. The lesions in the larynx, trachea, and carina of the

formaldehyde-exposed primates included multifocal loss of cilia and goblet cells, mild epithelial

hyperplasia, and early squamous metaplasia. Cell proliferation rates in the trachea and carina were

increased as well. In both species, regions where lesions were found were well-correlated with regions in

which high rates of cellular proliferation were measured (Monticello et al. 1989, 1991). The investigators

suggested that the difference in the location of the lesions was due to different breathing patterns in the rat

and monkey and differences in the anatomic structure of their respective nasal passages.

Rusch et al. (1983) histologically examined the lungs, trachea, and nasal turbinates of groups of 6 or

12 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female

Golden Syrian hamsters exposed to 0, 0.2, 0.98, or 2.95 ppm for 22 hours/day, 7 days/week for 26 weeks. 

Examination of other organs and tissues at necropsy for gross lesions revealed no exposure-related

effects, but these tissues were not microscopically examined. Monkeys exposed to 2.95 ppm showed an

increased incidence of hoarseness, congestion, and nasal discharge. Monkeys in the lower exposure

groups showed a greater incidence of nasal discharge than control monkeys, but the discharge was “only a 
FORMALDEHYDE 60

2. HEALTH EFFECTS

minimal grade” and was noted sporadically throughout the study. The study authors judged that the nasal

discharge at the two lowest exposure levels was not of biological significance. Body weights of exposed

monkeys were not significantly different from body weights of controls. Monkeys and rats exposed to

2.95 ppm, but not the lower concentrations, showed a significantly increased incidence of squamous

metaplasia and/or basal cell hyperplasia of the nasal cavity epithelium; the response was reported to be

most clearly seen in both species in the mid-region of the nasoturbinates. No lesions were found in the

most anterior sections of the nose or in the ethmoturbinates. Incidences of monkeys with squamous

metaplasia/hyperplasia in nasal turbinate epithelium were 0/12, 0/6, 1/6, or 6/6 at 0, 0.2, 0.98, and

2.95 ppm, respectively. Respective incidences of rats with squamous metaplasia/hyperplasia were 5/77,

1/38, 3/36, and 23/37. The investigators made no mention of any difference in the regional distribution of

the nasal lesions in rats and monkeys or of any histological changes in the trachea or lungs of the exposed

monkeys or rats. Ultrastructural examinations were made of the nasal turbinates, trachea, and lungs from

rats in the control and 0.98-ppm group; no exposure-related changes were found. No histological changes

were found in the nasoturbinates, trachea, or lungs of the exposed hamsters compared with controls. An

intermediate inhalation MRL of 0.03 ppm was calculated as described in Table 2-1 and in Appendix A

based on the NOAEL of 0.98 ppm for nasopharyngeal irritation in Cynomolgus monkeys using an

uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability).

Wilmer et al. (1987) investigated whether varying the exposure to formaldehyde (i.e., continuous versus

intermittent) affected formaldehyde cytotoxicity to upper respiratory tract epithelium. Groups of male

albino Wistar rats were exposed to 0, 5, or 10 ppm formaldehyde, 8 hours/day continuously, or to 10 or

20 ppm formaldehyde, 8 hours/day intermittently (30-minute exposure periods separated by 30-minute

periods of nonexposure). Eighteen hours after the third day or fourth week of exposure, three rats from

each group were injected with 3

H-thymidine, sacrificed, and their nasal cavities were processed and

examined for cell turnover. After 4 weeks of exposure, cell turnover rates in nasal epithelium were

significantly elevated in the rats exposed to 10 and 20 ppm intermittently, but not in rats exposed to 5 and

10 ppm continuously. The majority of cell labeling occurred in the naso- and maxillary turbinates. Focal

thinning and disarrangement of the respiratory epithelium lining were noted in some of the 10-ppm and

all of the 20-ppm rats. Squamous metaplasia with cellular hyperplasia was noted in some of the rats

exposed to 5 ppm and in most of the rats exposed to 10 or 20 ppm. Minimum to moderate rhinitis was

seen in each of the treatment groups. In a similar study, Wilmer et al. (1989) studied the same

toxicological end points in male albino Wistar rats using lower concentrations of 0, 1, or 2 ppm 
FORMALDEHYDE 61

2. HEALTH EFFECTS

formaldehyde, 8 hours/day continuously, or 2 or 4 ppm formaldehyde, 8 hours/day intermittently

(30-minute exposure periods separated by 30-minute periods of nonexposure), all groups were treated for

5 days/week for 13 weeks. After 13 weeks of exposure, there were no statistically significant differences

between the 1 and 2 ppm (continuously dosed), the 2 ppm (intermittently dosed) groups, and the controls

in cell turnover rates, however, the mean cell turnover rate after 13 weeks of exposure in the 4-ppm rats

was 2.9-fold greater than that of control rats. Treatment-related histological changes were noted only in

the 4-ppm intermittent exposure group. The changes consisted of increased disarrangement, hyperplasia,

and squamous metaplasia with or without keratinization of the respiratory epithelium lining of the septum

and nasoturbinates. The group continuously exposed to 2 ppm formaldehyde (i.e., the same total daily

exposure as the 4-ppm intermittent group) did not exhibit an increased incidence of these lesions. These

data suggest that the concentration of formaldehyde is more important in determining epithelial damage

than the duration of exposure. 

 

Maronpot et al. (1986) exposed groups of 10 male and 10 female B6C3F1 mice to formaldehyde

6 hours/day, 5 days/week for 13 weeks at concentrations of 0, 2, 4, 10, 20, or 40 ppm. Comprehensive

histological examinations of major tissues and organs were conducted. Significant mortality and severe

weight loss occurred in the 40-ppm group. Exposure-related lesions were restricted to the respiratory

tract, except for hypoplasia of the uterus and ovaries in the 40-ppm group which were interpreted to be

due to severe body weight loss. In the 40-ppm groups, squamous metaplasia, keratinization, suppurative

inflammatory exudate, serous exudate, and mild degeneration of the epithelium were noted in nasal

sections. Similar lesions were noted in the 20- and 10-ppm groups, although the severity declined with

decreasing concentrations. Similar lesions were seen in only one male mouse at 4 ppm, and in none of

the 4-ppm females; no such lesions were noted in either sex at exposures of 2 ppm. Squamous

metaplasia, suppurative inflammation, and fibrosis was also noted in the trachea and larynx of most mice

in the 40-ppm group; similar, though less severe, lesions were noted in the 20-ppm group. Lung lesions

consisting of epithelial hyperplasia, suppurative inflammation, squamous metaplasia, and fibrosis were

seen in some of the mice exposed to 40 ppm, but were not found in mice exposed to lesser concentrations.

Studies of pulmonary function variables in rats after intermediate-duration exposure to inhaled

formaldehyde have not found marked, exposure-related effects (Dallas et al. 1985, 1986; Saldiva et al.

1985). Dallas and colleagues measured the change in minute volume produced by acute challenges with

formaldehyde administered either intratracheally (Dallas et al. 1986) or by nosepiece (Dallas et al. 1985) 
FORMALDEHYDE 62

2. HEALTH EFFECTS

in rats exposed to 0, 0.5, 3 (nose-piece experiment only), or 15 ppm formaldehyde, 6 hours/day

5 days/week for 8 or 16 weeks. Responses to the acute challenge were compared with responses in agematched, nonexposed rats. A slightly diminished minute volume response to the formaldehyde challenge

was observed in the exposed rats (from the 15-ppm groups only) compared with the response in

nonexposed rats with both types of challenge administration, but this was statistically significant only

with nosepiece administration. Saldiva et al. (1985) found no statistically significant differences between

a group of rats exposed to 5.7 ppm formaldehyde, 8 hours/day, 5 days/week for 5 weeks and a group of

nonexposed rats in mean values for numerous pulmonary function variables including FEV in 1/4 second

and several measures of forced expiratory flow rates. 

Chronic Inhalation Animal Studies. Chronic-duration exposures to inhaled formaldehyde have also

been studied in rats, mice, and hamsters. In rats exposed to concentrations #15 ppm, formaldehydeinduced effects were restricted to nonneoplastic and neoplastic lesions found primarily in anterior regions

of the nasal epithelium, posterior to the vestibule (Kamata et al. 1997; Kerns et al. 1983b; Monticello et

al. 1996; Swenberg et al. 1980; Woutersen et al. 1989). Nonneoplastic damage to rat nasal epithelium

occurred at concentrations as low as 2 ppm, 6 hours/day, 5 days/week (Kamata et al. 1997), whereas

significantly increased incidences of neoplastic lesions (squamous cell carcinomas, squamous cell

papillomas or polyploid adenomas) were found in rats generally at concentrations greater than 6 ppm

(Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Nonneoplastic

damage to upper respiratory tract epithelium has also been observed in mice exposed to $5.6 ppm,

6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b) and in hamsters exposed to 10 ppm,

5 hours/day, 5 days/week for life (Dalbey 1982). Nasal tumors similar to those found in formaldehydeexposed rats were found in mice exposed to 14.3 ppm for 2 years (Kerns et al. 1983b), but were not found

in formaldehyde-exposed hamsters (Dalbey 1982). See Section 2.2.1.8 for more details of neoplastic

findings from these studies.

Male and female Fischer 344 rats were exposed to 0, 2, 5.6, or 14.3 ppm formaldehyde for 6 hours/day,

5 days/week for 24 months (Kerns et al. 1983b; Swenberg et al. 1980). The exposure period was

followed by a 6-month observation period. Interim sacrifices were performed at 6, 12, 18, 24,

27 (3 months postexposure), and 30 months (6 months postexposure). In the 14.3-ppm treatment group,

early mortalities occurred, rats tended to be dyspneic and emaciated, and many had facial swellings which

were subsequently determined to be nasal cavity carcinomas. Microscopic lesions were limited to the

nasal cavity and trachea, however, lesions were initially seen only in the ventral portion of the nasal 
FORMALDEHYDE 63

2. HEALTH EFFECTS

septum. As the study progressed, the lesions spread and became progressively more severe. In the lowand mid-dose groups, rhinitis, epithelial dysplasia, and squamous metaplasia developed over the course of

the study. Occasionally, animals in the high-dose group exhibited minimal-to-mild epithelial hyperplasia

or dysplasia or squamous metaplasia of the tracheal mucosa; these effects were not seen in the lower-dose

groups and disappeared in the high-dose group during the postexposure periods. Malignant nasal tumors

were found in 5.6- and 14.3-ppm rats (see Section 2.2.1.8). Neoplastic lesions were not found in other

regions of the respiratory tract or in other organ systems. 

Woutersen et al. (1989) investigated the effects of damage to the nasal mucosa on the induction of nonneoplastic tissue changes and tumors from long-term exposure to formaldehyde. Male and female Wistar

rats were used, with 67% of all rats undergoing electrocoagulation of the nasal mucosa. Half of the

animals were exposed to formaldehyde for 28 months and the other half for 3 months, all at doses of 0,

0.1, 1, or 10 ppm for 6 hours/day, 5 days/week. In undamaged noses in the 28-month study,

histopathological changes were not seen in the 0.1 or 1 ppm groups; exposure to 10 ppm resulted in an

increased incidence of squamous metaplasia and basal cell/pseudoepithelial hyperplasia of the respiratory

epithelium, thinning and disarrangement of the olfactory epithelium, and rhinitis. In damaged nasal

mucosa in the long-term study, exposure to all levels of formaldehyde resulted in squamous metaplasia. 

Rats exposed to formaldehyde vapors for 3 months (without electrocoagulation pretreatment) were

sacrificed following a 25-month recovery period. Non-neoplastic nasal lesions with statistically

significant increased incidences, compared with controls, were found only in the most anterior regions of

the nasal cavity in 10-ppm rats: squamous metaplasia of the respiratory epithelium (17/26 compared with

3/26 in controls; p<0.01, Fisher exact test performed by Syracuse Research Corporation), and rhinitis

(13/26 compared with 5/26; p<0.05, Fisher exact test performed by Syracuse Research Corporation). 

Nasal tumors were found only in the 10-ppm, 3-month-exposure group; one rat had a squamous cell

carcinoma and one had a polypoid adenoma (see Section 2.2.1.8 for more details on neoplastic responses

in this study).

Monticello et al. (1996) assessed the role of regional increases in nasal epithelial cell proliferation in the

formation of formaldehyde-induced nasal neoplastic and non-neoplastic tissue damage in male

Fischer 344 rats. Rats were exposed to 0, 0.7, 2, 6, 10, or 15 ppm formaldehyde, 6 hours/day,

5 days/week for 24 months. During the last 5 days of exposure prior to each interim sacrifice period 

(3, 6, 12, and 18 months), 6 rats per dose group were labeled with 3

H-thymidine via osmotic pumps to

measure regional rates of cell proliferation in nasal cavity epithelium. No formaldehyde-induced non-
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neoplastic lesions were found in the nasal cavities of rats from the 0.7- or 2-ppm groups. Nonneoplastic lesions in the 6-ppm group were limited to focal squamous metaplasia in the anterior region of

the nasal cavity. In the 10- and 15-ppm groups, lesions seen included epithelial hypertrophy and

hyperplasia, squamous metaplasia, inflammatory cell infiltration, nasal turbinate adhesions, and olfactory

degeneration. These lesions occurred more frequently and with greatest severity in the 15-ppm group. 

Cell proliferation in nasal epithelium was not affected by formaldehyde exposures of 6 ppm or less;

increases in the cell labeling index were significant at the 10- and 15-ppm exposure levels. Nasal tumors

were found in the 6-, 10-, and 15-ppm groups (see Section 2.1.1.8).

Kamata et al. (1997) exposed groups of 32 male F344 rats by inhalation to formaldehyde concentrations

of 0.3, 2, or 15 ppm, 6 hours/day, 5 days/week for up to 28 months. Two control groups of 32 rats were

included: an inhalation chamber group (“0 ppm”) inhaling 4.2 ppm methanol and a “room control, noexposure group”. Significantly increased mortality (after 9 months) and decreased body weights (after

4 months) were restricted to the 15-ppm group compared with the control groups. No exposure-related

effects on hematological parameters were found. Comprehensive autopsies and histological examination

of the pituitary, thyroid, nasal region, trachea, esophagus, stomach, intestine, prostate gland, spinal cord,

and mesenteric lymph nodes found exposure-related effects only in the nasal cavities. Epithelial cell

hyperplasia, hyperkeratosis, and squamous metaplasia were apparent in all exposure groups and were

predominately restricted to the respiratory epithelium of nasal turbinates and maxilloturbinates, just

posterior to the nasal vestibule. Incidences for epithelial cell hyperplasia with squamous cell metaplasia

were 0/32, 0/32, 4/32, 7/32, and 29/32 in the 0-, room control-, 0.3-, 2-, and 15-ppm groups respectively;

incidences for squamous cell metaplasia without epithelial cell hyperplasia were 0/32, 0/32, 1/32, and

5/32, respectively (this combination of lesions did not occur in the 15-ppm group). Nasal tumors

squamous cell carcinomas and papillomas were found only in the 15-ppm group (see Section 2.2.1.8). 

Kamata et al. (1997) concluded that the study did not identify a NOAEL for nonneoplastic nasal lesions

due to the finding of epithelial cell hyperplasia with squamous cell metaplasia in the 0.3-ppm group, but

the incidences for nonneoplastic nasal lesions in the 0.3-ppm group were not statistically significantly

different compared with the controls. In Table 2-1, 0.3 ppm is noted as a NOAEL for non-neoplastic

lesions in the nasal epithelium. 

Kerns et al. (1983b) exposed male and female B6C3F1 mice to 0, 2, 5.6, or 14.3 ppm formaldehyde for

6 hours/day, 5 days/week for 24 months, followed by a 6-month observation period. Interim sacrifices

were performed at 6, 12, 18, 24, 27, and 30 months. Major tissues from each organ system in control and 
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2. HEALTH EFFECTS

high-exposure mice were examined histologically. Non-neoplastic nasal lesions were found in the 5.6-

and 14.3-ppm groups of mice, most notably inflammatory, dysplastic, and squamous metaplastic changes

in the respiratory epithelium. Minimal to moderate hyperplasia of the squamous epithelium lining the

nasolacrimal duct and atrophy of the olfactory epithelium of the ethmoturbinates also were observed in

the 5.6- and 14.3-ppm groups. At the end of exposure (24 months), nasal lesions were found in >90% of

14.3-ppm mice and “in a few” 5.6-ppm mice (incidence was not specified). Mice sacrificed 3 months

postexposure showed regression of the formaldehyde-induced nasal epithelial lesions. At 24 months,

mice in the 2-ppm group were “free of significant nasal lesions”, but a few mice had serous rhinitis and

minimal hyperplasia of the squamous epithelium lining the nasolacrimal duct. Two male mice in the

14.3-ppm group sacrificed at 24 months displayed squamous cell carcinomas in the nasal cavity similar to

those found in rats. The number of mice sacrificed at 24 months was not specified in the published

report, but the incidence was indicated to be significantly increased compared with controls. No other

tumors were reported in exposed or control mice.

Dalbey (1982) exposed groups of male Golden Syrian hamsters to 0 (n=132) or 10 (n=88) ppm

formaldehyde, 5 hours/day, 5 days/week for life (up to about 110 weeks). Exposed hamsters showed

reduced survival time compared with controls. End points in this study were restricted to

histopathological examinations of respiratory tract tissues. There was no evidence of rhinitis in treated

animals, and no tumors were found in the respiratory tract of treated or control animals. Hyperplastic and

metaplastic areas were seen in the nasal epithelium of 5% of the treated hamsters but were not seen in

controls. Dalbey (1982) also exposed groups of 50 male hamsters to 0 or 30 ppm formaldehyde,

5 hours/day, 1 day/week for life. No respiratory tract tumors were reported to have been found in control

or exposed animals, but Dalbey (1982) did not mention if the nasal epithelium was examined for nonneoplastic changes in these two groups of hamsters.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after

inhalation exposure to formaldehyde.

No histological evidence for formaldehyde effects on cardiovascular tissues was found in intermediateduration inhalation studies, using a 6 hour/day, 5 day/week exposure protocol, with mice exposed to 

up to 40 ppm for 13 weeks (Maronpot et al. 1986), Rhesus monkeys exposed to 6 ppm for 6 weeks

(Monticello et al. 1989), rats exposed to up to 20 ppm for 13 weeks (Woutersen et al. 1987), or rats

exposed to up to 10 ppm for 13 or 52 weeks (Appelman et al. 1988). Similarly, no evidence for 
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2. HEALTH EFFECTS

formaldehyde effects on cardiovascular tissues were found in chronic inhalation studies with rats or mice

exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b). The only study

located that examined cardiovascular function in animals exposed to airborne formaldehyde was a report

that concluded that blood pressure and heart rate were not affected in anesthetized rats exposed for

1 minute to 1,628 ppm formaldehyde (Egle and Hudgins 1974).

Gastrointestinal Effects. Few studies regarding gastrointestinal effects after inhalation exposure

were located. In humans, Kilburn (1994) describes vague gastrointestinal effects in four patients who had

been occupationally exposed to formaldehyde for 14–30 years. Three of the patients were anatomists and

were exposed to formalin; the fourth was a railroad worker who worked next to a wood-products factory

that used large quantities of phenol-formaldehyde resins. Intestinal cramps with flatus and bloody stools

was one of many nonspecific effects noted in this small population.

No histological evidence for formaldehyde effects on the gastrointestinal tract was found in intermediateduration inhalation studies using a 6 hour/day, 5 days/week exposure protocol with mice exposed to up to

40 ppm for 13 weeks (Maronpot et al. 1986), Rhesus monkeys exposed to 6 ppm for 6 weeks (Monticello

et al. 1989), rats exposed to up to 20 ppm for 13 weeks (Woutersen et al. 1987), or rats exposed to up to

10 ppm for 13 or 52 weeks (Appelman et al. 1988). Similarly, no evidence for formaldehyde effects on

gastrointestinal tissues were found in chronic inhalation studies with rats exposed to up to 15 ppm,

6 hours/day, 5 days/week for 2 years or more (Kamata et al. 1997; Kerns et al. 1983b), or in mice exposed

similarly (Kerns et al. 1983b).

Hematological Effects. Pross et al. (1987) evaluated the immunologic response of asthmatic

subjects exposed to urea-formaldehyde foam insulation (UFFI) off-gas products. Subjects consisted of

23 individuals with a history of asthmatic symptoms attributed to UFFI and 4 individuals (controls) with

asthma unrelated to UFFI by-products. Subjects were exposed to one of the following: room air (placebo)

for 30 minutes; 1 ppm formaldehyde gas for 3 hours; UFFI particles (4 μm, 0.5 particles/mL) for 3 hours,

commencing 48 hours after formaldehyde gas exposure; and UFFI off-gas products for 3 hours,

commencing 48 hours after UFFI particle exposure. There were no significant alterations in any of the

white blood cell populations when the four unexposed controls were compared to the subjects (who also

lived in a home where UFFI is present) before or after being exposed to UFFI in the chamber. 

However, there was a significant increase in the percentage and absolute number of eosinophils and 
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2. HEALTH EFFECTS

basophils in the subjects (who also lived in UFFI-homes) after exposure to UFFI in the exposure chamber

when compared to the white blood cell values obtained before chamber exposure to UFFI. 

No exposure-related effects on hematological variables were found in rats exposed to up to 20 ppm

formaldehyde 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987), in rats exposed to up to

10 ppm, 6 hours/day, 5 days/week for up to 52 weeks (Appelman et al. 1988), in rats or mice exposed to

up to 14.3 ppm, 6 hours/day, 5 days/week for up to 24 months (Kerns et al. 1983b), or rats exposed to up

to 15 ppm for 28 months (Kamata et al. 1997). Dean et al. (1984) reported that female mice exposed to

up to 15 ppm for 6 hours/day, 5 days/week for 3 weeks showed a statistically significant decrease in

absolute number of monocytes compared with control values, but no other hematological variable was

affected by exposure in this study.

Musculoskeletal Effects. Few studies were located that described musculoskeletal effects of

formaldehyde after inhalation exposure. Holness and Nethercott (1989) reported that muscle or joint

stiffness was reported more frequently by a surveyed group of funeral directors and embalmers than in a

referent nonexposed group (23 versus 5%), but reporting of similar symptoms has not been frequently

encountered in other health surveys of formaldehyde-exposed groups of workers. 

With 6-hours/day, 5-days/week exposure protocols, no formaldehyde-induced histological changes in

muscle or skeletal tissue were found in mice exposed to up to 40 ppm for 13 weeks (Maronpot et al.

1986), in monkeys (bone marrow of sternum) exposed to 6 ppm for 6 weeks (Monticello et al. 1989), in

rats (femur and muscle tissue) exposed to up to 15 ppm for 28 months (Kamata et al. 1997), or in rats or

mice exposed to up to 14.3 ppm for 24 months (Kerns et al. 1983b).

Hepatic Effects. No studies were located that reported hepatic effects in humans following exposure

to airborne formaldehyde.

Murphy et al. (1964) found increased activities of alkaline phosphatase in livers of rats exposed to

35 ppm formaldehyde for 18 hours and suggested that formaldehyde may be hepatotoxic. More recent

animal studies, however, have found no consistent evidence for formaldehyde-induced hepatotoxicity. 

Woutersen et al. (1987) found statistically significant increased levels of aspartate amino transferase,

alanine amino transferase, and alkaline phosphatase in plasma of rats exposed to 20 ppm, (but not to 

10 or 1 ppm) 6 hours/day, 5 days/week for 13 weeks, but found no exposure-related microscopic lesions 
FORMALDEHYDE 68

2. HEALTH EFFECTS

in the livers of these rats. In another experiment from the same laboratory, Appelman et al. (1988) found

no exposure-related changes in serum aspartate amino transferase, alanine amino transferase, or alkaline

phosphatase in plasma, no changes in liver concentrations of total protein or reduced glutathione, and no

hepatic histological changes in rats exposed to up to 10 ppm by the same protocol for 13 or 52 weeks. 

Kamata et al. (1997) also reported that no exposure-related changes were found, at several sampling

dates, in activities of serum alkaline phosphatase, aspartate amino transferase, or alanine amino

transferase in rats exposed to up to 15 ppm, 6 hours/day, 5 days/week for up to 28 months. In 15-ppm

rats, absolute, but not relative, liver weights were statistically significantly decreased compared with

controls. This effect appears to have been a secondary effect from decreased food consumption at this

exposure level rather than a direct effect of formaldehyde on the liver. No histological liver changes were

found in Rhesus monkeys exposed to 6 ppm formaldehyde, 6 hours/day, 5 days/week for 6 weeks

(Monticello et al. 1989), in mice exposed to up to 40 ppm by a similar protocol for 13 weeks (Maronpot

et al. 1986), or in rats or mice exposed to up to 14.3 ppm for 24 months (Kerns et al. 1983b). The weight

of available evidence suggests that airborne formaldehyde may produce toxic effects on the liver only at

high concentrations that may exceed metabolic and binding capacities in the respiratory tract.

Renal Effects. In the only report located regarding renal effects in humans after inhalation exposure

to formaldehyde, Freestone and Bentley (1989) noted that renal failure occurred in a 68-year-old man

who inhaled and/or ingested an undetermined amount of formaldehyde. He stated that he had inhaled

formaldehyde for a sore throat, however, the medical staff believed that he may have gargled with the

formaldehyde as well. Dopamine was administered until renal function improved and the man was

released. 

No evidence from histological examinations or blood chemistry monitoring for formaldehyde-induced

kidney effects has been found in intermediate-duration inhalation studies with rats, Rhesus monkeys, or

mice (Appelman et al. 1988; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987), or in

chronic inhalation studies with rats and mice (Kamata et al. 1997; Kerns et al. 1983b). Appelman et al.

(1988) noted that rats exposed to 10 ppm, 6 hours/day, 5 days/week for 52 weeks had “frequent oliguria”. 

Kerns et al. (1983b) also measured urinalytic variables in rats and mice exposed to up to 14.3 ppm by a

similar protocol for 24 months, but did not report a similar finding.
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2. HEALTH EFFECTS

Endocrine Effects. No studies were located regarding endocrine effects in humans exposed to

inhaled formaldehyde. No evidence from histological examinations or organ weight measurements for

formaldehyde-induced effects on endocrine organs (e.g., pancreas, pituitary, adrenals, thyroid) has been

found in intermediate-duration inhalation studies with rats, mice or Rhesus monkeys (Appelman et al.

1988; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987), or in chronic inhalation

studies with rats or mice (Kamata et al. 1997; Kerns et al. 1983b).

Dermal Effects. Occupational exposures to formaldehyde have been associated with dermal irritation

and the diagnosis of allergic contact dermatitis by patch testing. Reported historical percentages of

subjects with skin problems showing positive responses to formaldehyde in patch tests performed by

dermatologists using aqueous solutions with 1 or 2% formaldehyde include 7.8% in North America

between 1992 and 1994 (Marks et al. 1995), 1.6% in a 1983–1984 Swedish study (Meding and Swanbeck

1990), 2.6% in a 1988–1989 European study (Menné et al. 1991), and 3.7% in a 1990–1994 Polish study

(Kiec-Swierczynska 1996). Lack of case-specific exposure information for these patients precludes the

determination of the degree to which sensitization may have been caused by direct dermal contact to

formaldehyde in liquids or by contact with formaldehyde gas in air, but the widespread use of

formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents (Flyvholm 1991;

Rastogi 1992) suggest that the dermal route of exposure may be the more important sensitizing route. 

Dermal effects in humans from exposure to formaldehyde are further discussed in Sections 2.2.3.2 and

2.2.3.3.

Acute controlled exposure studies of volunteers exposed to airborne formaldehyde at concentrations

ranging from 0.4 to 3 ppm have not found increased reporting of skin irritation symptoms (Andersen and

Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al.

1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977). Eberlein-Konig et al. (1998), however, found

subtle skin effects in seven subjects described as having formaldehyde atopic eczema compared with

seven nonsensitized subjects. Exposure to 0.08 ppm formaldehyde for 4 hours in an exposure chamber

induced increased transepidermal water loss, but not skin roughness, on the uncovered lower arms of

subjects with atopic eczema; neither transepidermal water loss nor skin roughness were increased by

similar exposure in a group of seven subjects without atopic eczema. Serum levels of eosinophil cationic

protein and soluble interleukin-2 receptor were not increased by exposure in either group.
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2. HEALTH EFFECTS

No evidence for formaldehyde-induced effects on the skin has been reported in intermediate-duration

inhalation studies with rats, hamsters, Rhesus monkeys, or mice (Appelman et al. 1988; Maronpot et al.

1986; Monticello et al. 1989; Woutersen et al. 1987), or in chronic inhalation studies with rats or mice

(Kamata et al. 1997; Kerns et al. 1983b), except that the highest concentration used in these studies

(40 ppm used in the 13-week mouse study by Maronpot et al. 1986) produced severe clinical signs of

toxicity in mice including mouth breathing, ataxia, and “loss of skin elasticity”.

Ocular Effects. From occupational exposure experience and results in controlled acute inhalation

exposure studies in humans, airborne formaldehyde is well-known as an eye irritant. Because

formaldehyde-induced eye irritation and upper respiratory tract irritation have often been noted at similar

exposure concentrations, results from survey studies of occupationally-exposed workers and controlled

acute exposure studies in which subjects reported symptoms of eye irritation were discussed earlier in the

Respiratory Effects part of this section.

Studies of animals exposed to airborne formaldehyde for intermediate and chronic durations have not

found increased incidences of histological changes in the eyes of mice exposed to up to 40 ppm (Kerns et

al. 1983b; Maronpot et al. 1986), rats exposed to up to 20 ppm (Appelman et al. 1988; Kerns et al. 1983b;

Swenberg et al. 1980; Woutersen et al. 1987), or monkeys exposed to 6 ppm (Monticello et al. 1989). 

Kerns et al. (1983b) reported that ophthalmoscopic examinations revealed no exposure-related changes in

rats or mice examined at several intervals during a 2-year period of exposure to concentrations as high as

14.3 ppm. Clinical signs of eye irritation during exposure, however, have been reported in monkeys

(“mild lacrimation and conjunctival hyperemia”) exposed to 6 ppm for up to 6 weeks (Monticello et al.

1989), in rats exposed to 10 ppm for up to 4 days (Dinsdale et al. 1993), and in rats (“ocular discharge”)

exposed to 2 to 15 ppm, but not to 0.5 ppm, for up to 3 weeks (Morgan et al. 1986c). Swenberg et al.

(1980) described the development of a “unilateral ocular discharge” that was associated with the

subsequent development of nasal tumors in rats exposed to 14.3 ppm; this discharge is likely distinct from

the clinical signs of eye irritation noted in the other animal studies and in the human studies. 

Body Weight Effects. Body weight effects have not been associated with formaldehdye exposure in

humans, but exposure-response relationships have been described in animal studies.
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2. HEALTH EFFECTS

Body weight decreases $10% of control values were observed in male rats exposed to 10 ppm, but not to

1 ppm, 6 hours/day, 5 days/week for 13 or 52 weeks (Appelman et al. 1988); in male rats exposed to

2.95 ppm, but not to 0.98 ppm, 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983); in male rats

exposed to 20 ppm, but not to 10 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987); in

male mice exposed to $20 ppm, and female mice exposed to 40 ppm, 6 hours/day, 5 days/week for

13 weeks (Maronpot et al. 1986); in male and female rats exposed to 14.3 ppm, but not to 5.6 ppm,

6 hours/day, 5 days/week for 2 years (Kerns et al. 1983b); in male rats exposed to 15 ppm, but not to

2 ppm, 6 hours, 5 days/week for 4 to 28 months (Kamata et al. 1997); and in male rats exposed to

10 ppm, but not to 1 ppm, 6 hours/day, 5 days/week for 28 months (Woutersen et al. 1989).

No body weight effects were observed in Rhesus monkeys exposed to 6 ppm, 6 hours/day, for 5 days or

5 days/week for 6 weeks (Monticello et al. 1989), in female rats, Cynomolgus monkeys, or hamsters

exposed to up to 2.95 ppm, 22 hours/day, 7 days/week for 26 weeks (Rusch et al. 1983), in female rats

exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987), or in mice

exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 24 months (Kerns et al. 1983b).

2.2.1.3 Immunological and Lymphoreticular Effects

As discussed previously in Section 2.2.1.2 (dermal effects from inhalation exposure), formaldehyde is

commonly diagnosed as a dermal allergen worldwide. Lack of case-specific exposure information

precludes determining the degree to which sensitization may have been caused by direct dermal contact to

formaldehyde in liquids or by contact with formaldehyde gas in air, but the widespread use of

formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents (Flyvholm 1991;

Rastogi 1992) suggest that the dermal route of exposure may be the more important sensitizing route. 

Dermal effects in humans from exposure to formaldehyde, including formaldehyde allergic contact

dermatitis, are further discussed in Section 2.2.3.2 and 2.2.3.3.

Investigations into the possibility of immunologically-mediated respiratory responses in formaldehydeexposed individuals reporting respiratory problems such as bronchial asthma have provided very limited

positive evidence. 

There are only a few available case reports of bronchial asthma suggestive of respiratory tract

sensitization to formaldehyde gas including two renal dialysis nurses (Hendrick and Lane 1975, 1977; 
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2. HEALTH EFFECTS

Hendrick et al. 1982), a plastic moulder (Burge et al. 1985), a printer (Burge et al. 1985), a worker in a

phenol formaldehyde manufacturing plant (Burge et al. 1985), and a carpenter (Lemiere et al. 1995). 

These cases of formaldehyde-exposed workers all displayed marked changes in FEV1 or airflow rates in

response to acute challenges with formaldehyde gas at exposure levels <3 ppm. Nordman et al. (1985)

provided acute formaldehyde (2 ppm) challenges to 230 patients who had been occupationally exposed to

formaldehyde and who had reported respiratory symptoms consistent with asthma, but found challengeinduced decreases in PEFR >15% in only 12 subjects. Although an immunologic-mediated response may

be consistent with the observed airway responses, the mechanism of sensitization in these subjects is

uncertain. Challenge-induced deficits in FEV1 or airflow rates indicative of lower airway sensitization

were not found in studies of: 9 subjects complaining of respiratory problems from urea-formaldehyde

foam insulation in their homes who were challenged with 1–1.2 ppm formaldehyde for 90 minutes (Day

et al. 1984); 10 formaldehyde-exposed textile or shoe manufacturing workers with purported bronchial

asthma who were challenged with 0.41 ppm for 2 hours (Krakowiak et al. 1998); and 13 formaldehydeexposed subjects who had previously reported asthma-like symptoms who were challenged with 0.1, 1, or

3 ppm for 20 minutes (Reed and Frigas 1984). 

Several studies have examined serum for formaldehyde-specific IgE antibodies in groups of

formaldehyde-exposed humans (Dykewicz et al. 1991; Grammar et al. 1990; Kramps et al. 1989; Wantke

et al. 1996a, 1996b). In general, the studies do not provide consistent evidence for a formaldehydeinduced allergic respiratory syndrome, but provide suggestive evidence that children may have an

increased tendency to develop specific antibodies after exposure to low levels of formaldehyde in indoor

air (Wantke et al. 1996a). 

Formaldehyde-specific IgE antibodies could be detected in only 1/86 serum samples from four groups of

formaldehyde-exposed subjects (Kramps et al. 1989). The groups included 28 subjects living or working

in places with formaldehyde-containing construction materials (e.g., chipboard) and estimated

formaldehyde concentrations ranging from 0.08 to 0.37 ppm, 18 occupationally exposed subjects from an

anatomy laboratory and in other unspecified industries where air concentrations were not measured,

12 hospital attendants who worked with formaldehyde-sterilized hemodialysis equipment, and

28 hemodialysis patients treated with formaldehyde-sterilized equipment. Variable symptoms such as

headache, eye irritation, and respiratory complaints were reported by 24/28 subjects in the constructionmaterial group. The group of 18 occupationally exposed subjects reported nonspecific irritation of eyes

and airways associated with their work; the subject with detected formaldehyde-specific IgE displayed no
FORMALDEHYDE 73

2. HEALTH EFFECTS

allergic symptoms. The hospital attendants and hemodialysis patients reported no exposure-related

symptoms. Durations of exposure or employment were not reported for the subjects in this study.

Grammer et al. (1990) studied the immunologic nature of formaldehyde sensitivity in 37 workers who

complained of formaldehyde-related illness and were examined by a group of physicians. Blood samples

were collected and assayed for IgE and IgG activity against formaldehyde and formaldehyde-human

serum albumin (f-HSA). Fourteen workers had symptoms consistent with an irritant syndrome, another

14 had symptoms consistent with a possible irritant, and 9 had no work-related symptoms. Four workers

also had symptoms consistent with formaldehyde allergy. None of the workers had IgG activity against

formaldehyde. Five workers had antiformaldehyde IgE activity, but further testing revealed that the IgE

lacked formaldehyde specificity. The authors concluded that in this group of workers, there was no

evidence of an immunologically mediated response to formaldehyde.

Dykewicz et al. (1991) sought to determine whether IgE or IgG antibodies to formaldehyde were related

to formaldehyde exposure or respiratory symptoms arising from such an exposure. The authors studied

55 hospital histology technicians, internal medicine residents, pathology residents, current smokers,

subjects with known workplace exposure to formaldehyde, and controls with no history of formaldehyde

exposure. Reported workplace formaldehyde concentrations were 0.2–0.64 ppm for pathology residents,

0.64 ppm for histology technicians, and 0.6–11 ppm for miscellaneous formaldehyde exposure scenarios. 

No workplace air concentrations were measured for the other occupations. Average years of occupational

exposure to formaldehyde were 12.45 years for histology technicians, 0.38 years for medical residents,

3.21 years for pathology residents, and 18.34 years for 5 subjects exposed to miscellaneous workplaces

with formaldehyde. Each subject was evaluated by questionnaire for the presence of upper- and lowerrespiratory tract and ocular symptoms and formaldehyde-related illnesses. Blood samples were drawn

from each subject and were analyzed for IgE and IgG reactivity with f-HSA. Three subjects had IgE

against f-HSA; these three and two others had low levels of anti-f-HSA IgG. The presence of IgG and

IgE antibodies to formaldehyde was not clearly related to formaldehyde exposure or pack-years of

smoking. One subject had both IgE and IgG antibodies and also suffered from eye and respiratory

symptoms when exposed to formaldehyde at his workplace. The authors concluded that they could 

not establish a relationship of IgE and IgG to formaldehyde exposure. They further concluded that 

if immunologically mediated rhinitis or conjunctivitis existed, it must occur at extremely low 

frequencies. Several limitations of this study should be noted. First, the investigators recruited

volunteers who may have systematically differed from the general populations from which they were 
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sampled. One of the exposure groups comprised cigarette smokers, who have exposures to many

chemicals in addition to their formaldehyde exposures. Although the study focuses on formaldehyde

antibodies, which would be unaffected by the other chemicals, respiratory symptoms among smokers

would reflect exposures to the other smoke constituents. 

Wantke et al. (1996a) measured elevated levels of formaldehyde-specific IgE in 24/62 8-year-old children

who were students in three particle board-paneled classrooms with estimated formaldehyde air

concentrations of 0.075, 0.069, and 0.043 ppm. In a health survey, the children reported headaches

(29/62), fatigue (21/62), dry nasal mucosa (9/62), rhinitis (23/62), cough (15/62), and nosebleeds (14/62). 

Sums of numbers of children with each of nine symptoms for each classroom decreased with decreasing

formaldehyde concentration (49, 47, and 24, respectively, for the 0.075-, 0.069-, and 0.043-ppm

classrooms), but the investigators reported that elevated levels of specific IgE did not correlate with the

number and severity of symptoms. The children were moved to a new school without particle board

paneling and were evaluated again, 3 months after moving. Estimated formaldehyde concentrations in the

new classrooms were 0.029, 0.023, and 0.026 ppm. The numbers of children reporting symptoms

decreased significantly compared with premoving reporting figures, and mean serum levels of

formaldehyde-specific IgE, measured in 20 of the children, declined significantly compared with

premoving mean levels. 

Formaldehyde-specific IgE was not detected in a group of 45 medical students, before or after the

students attended a 4-week anatomy dissecting course (Wantke et al. 1996b). Estimates of laboratory air

concentrations of formaldehyde ranged from 0.059 to 0.219 ppm (mean 0.124±0.05 ppm). Surveys

revealed frequencies of irritation symptoms consistent with other studies (e.g., itching of the skin in

33/45 students, headache in 15/45, and burning eyes in 13/45). 

Thrasher et al. (1987) assessed the effects of formaldehyde exposure on cellular immunity and antibody

formation in eight symptomatic and eight unexposed individuals. The exposed group was comprised of

three males and five females. Seven of the exposed individuals resided in mobile homes for periods

ranging from 2 to 7 years; the eighth exposed subject was a laboratory worker who resided in a newly

decorated, energy-efficient apartment. Air monitoring in four of the homes revealed formaldehyde vapor

concentrations ranging from 0.07 to 0.55 ppm. Venous blood samples were collected from all subjects

and lymphocytes were used for T- and B-cell enumeration and blastogenesis; serum samples were used to

determine IgG and IgE antibodies to formaldehyde. IgE antibodies to formaldehyde were not detected in 
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2. HEALTH EFFECTS

exposed or control subjects; IgG antibodies in exposed subjects ranged from 1:8 to 1:256, but were

undetected (1:4) in 7 of the controls. T- and B-cell numbers were significantly lower (p<0.05) in mobile

home residents (48 and 12.6%, respectively) compared to control subjects (65.9 and 14.75%,

respectively). Phytohemagglutinin-stimulated T- and B-cell blastogenesis was significantly depressed

(p<0.01) in mobile home residents compared to control subjects (17,882 versus 28,576 counts per minute,

respectively). 

In a later study, Thrasher et al. (1990) evaluated four groups of patients with varying levels and durations

of formaldehyde exposure. The groups consisted of asymptomatic chiropractic students exposed during

anatomy classes (controls), mobile home residents, office workers, patients with multiple symptoms who

had been removed from the source of formaldehyde for at least a year, and occupationally exposed

patients. All groups were assessed for immunologic function via white cell, lymphocyte and T-cell

counts, T-helper/suppressor ratios, B cell counts, and production of antibodies against f-HSA. When

compared to controls (students), the patient groups had significant elevations in formaldehyde antibody

titers and B-cell titers. The level of autoantibodies was also significantly elevated in patients exposed

long-term to formaldehyde.

Gorski et al. (1992) investigated the correlation between formaldehyde-induced contact dermatitis and

granulocyte chemiluminescence resulting from free-radical release in healthy and formaldehyde-sensitive

patients. Thirteen patients with contact dermatitis who were occupationally exposed to formaldehyde and

five healthy volunteers participated in the study. All subjects underwent skin-prick tests for common

allergens as well as a histamine inhalation provocation test. Subjects were exposed to 0.5 mg/m3

(0.41 ppm) formaldehyde for 2 hours, and peak expiratory flow was measured immediately before

exposure, at 60 and 120 minutes of exposure, and at 6 and 21 hours after completion of exposure. In

formaldehyde-sensitive patients, skin-prick tests and total serum IgE were normal; no antiformaldehyde

IgE was detected. In formaldehyde-sensitive patients, peripheral blood granulocyte chemiluminescence

significantly increased within 30 minutes of exposure commencement, and remained elevated 24 hours

later, compared to initial values. Granulocyte chemiluminescence did not increase in healthy patients.

Pross et al. (1987) evaluated the immunologic response of asthmatic subjects exposed to UFFI off-gas

products. Subjects consisted of 23 individuals with a history of asthmatic symptoms attributed to UFFI

and 4 individuals with asthma unrelated to UFFI byproducts. All subjects were exposed to the following

in an environmental chamber: room air (placebo) for 30 minutes; 1 ppm formaldehyde gas for 3 hours; 
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2. HEALTH EFFECTS

UFFI particles (4 μm, 0.5 particles/mL) for 3 hours, commencing 48 hours after formaldehyde gas

exposure; and UFFI off-gas products for 3 hours, commencing 48 hours after UFFI particle exposure. 

There was a significant increase in the percentage and absolute number of eosinophils and basophils in

the subjects that lived in UFFI-homes. There were no differences between exposure groups with respect

to lymphocyte subpopulations either before or after UFFI exposure. However, when T8 suppressor cell

count control values for the UFFI-exposed group were compared to T8 (suppressor) cell count values

collected after UFFI chamber exposure, a small but statistically significant (p<0.01) increase in T8 cell

count was observed. The significance of this change in T8 cell count is not known. Phytohemagglutinand formalin-treated-red-blood-cell-stimulation studies revealed no differences between treatment groups

in nonspecific or specific lymphocyte reactivity in response to UFFI exposure. Likewise, UFFI exposure

had no effect on humoral immunity. Natural killer function was also unaffected by in-home or chamber

exposure to UFFI, as was the interferon-boosted (IFN) natural killer cell response. Approximately half of

the subjects from each group were classified as atopic based on skin-prick tests, but there was little

correlation with NK function. The authors concluded that short-term exposure to formaldehyde was not

immunosuppressive and did not result in systemic immune reactivity.

No histopathological effects on lymphoreticular tissues (e.g., spleen, thymus, lymph nodes) were

observed in Rhesus monkeys exposed to 6 ppm, 6 hours/day, 5 days/week for 6 weeks (Monticello et al.

1989); in rats exposed to up to 10 ppm, 6 hours/day, 5 days/week for 13 or 52 weeks (Appelman et al.

1988); in rats exposed to up to 20 ppm, 6 hours/day, 5 days/week for 13 weeks (Woutersen et al. 1987);

in mice exposed to 40 ppm, 6 hours/day, 5 days/week for 13 weeks (Maronpot et al. 1986); in rats and

mice exposed to up to 14.3 ppm, 6 hours/day, 5 days/week for 24 months (Kerns et al. 1983b); or in rats

exposed to up to 15 ppm, 6 hours/day, 5 days/week for 28 months (Kamata et al. 1997).

In a study by Adams et al. (1987), the effects of exposure to formaldehyde on the maturation of the

mononuclear phagocyte system in female B6C3F1 mice were investigated. Mice were exposed to a target

concentration of 15 ppm formaldehyde 6 hours/day, 5 days/week for 3 weeks. Exposure to formaldehyde for 3 weeks did not affect lymphoid organ weights or the number of resident or activated

macrophages. Formaldehyde exposure resulted in lower peritoneal macrophage leucine aminopeptidase

concentrations, but did not appear to induce maturation of resident macrophages. Formaldehyde

treatment did not alter the ability of induced macrophages to bind and lyse tumor cells. In macrophages

elicited by pyran copolymer MVE-2, the ability to release reactive oxygen intermediates (H2O2) was

increased almost 2-fold as a result of formaldehyde exposure. The authors concluded that formaldehyde 
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2. HEALTH EFFECTS

exposure did not disturb the systemic development of tumoricidal macrophages, but did enhance the

release of reactive oxygen intermediates.

Dean et al. (1984) studied immune function in female B6C3F1 mice 6–8 weeks of age. Mice were

exposed by inhalation to 15 ppm formaldehyde for 6 hours/day, 5 days/week for 3 weeks. Several tests

that evaluated immune function were used: (1) tumor challenge procedure consisting of a subcutaneous

injection of PYB6 sarcoma cells, (2) tumor resistance assessment consisting of an intravenous injection of

B16F10 melanoma cells, and (3) an intravenous challenge using Listeria monocytogenes bacteria. Other

tests that evaluated immune function were cell-mediated immunity (consisting of monitoring the delayed

hypersensitivity response to keyhole limpet hemocyanin); lymphoproliferative responses to T-cell

mitogens (phytohemagglutinin) and B-cell mitogens (Escherichia coli lipopolysaccharide); spontaneous

cytotoxicity (natural killer cell); macrophage function (elicitation, activation, phagocytic); plaque-forming

cell activity; and spleen and bone marrow cellularity. Thymus and spleen weights were unaffected by

formaldehyde exposure. A significant decrease in the absolute number of monocytes was observed in the

formaldehyde-treated mice (4/mm3

 versus 43/mm3 in controls; p<0.05); all other hematological

parameters in treated mice were similar to those of controls. Spleen and bone marrow cellularity were

similar in treated and control groups. Formaldehyde-treated animals experienced lower mortality (30%)

than controls (70%) in response to challenge with Listeria monocytogenes. Formaldehyde-treated mice

were also less susceptible to tumor transfer or formation compared to controls. No differences were noted

in treated and control mice for the following parameters: delayed hypersensitivity reaction; natural killer

cell-mediated tumor cytotoxicity; lymphocyte proliferation; lymphocyte surface markers; macrophage

function; and plaque-forming cell response. The authors concluded that exposure to 15 ppm

formaldehyde for 3 weeks was not immunotoxic; they hypothesized that this was due to the highly

reactive nature of the compound which prevents penetration into the deep lung and tissue penetration in

general.

Holmstrom et al. (1989b) evaluated the long-term inhalation effects of formaldehyde exposure to immune

function in female Sprague-Dawley rats exposed to 12.6 ppm formaldehyde for 6 hours/day, 5 days/week

for 22 months. After 22 months of formaldehyde exposure, the rats were inoculated subcutaneously with

Pneumovax (Merck Sharpe and Dohme) and antitetanus vaccine (National Bacteriological Laboratory). 

Animals were sacrificed at 21–25 days after vaccination. Blood samples were collected from each animal

before vaccination and just prior to sacrifice. The blood was analyzed for response to Pneumovax and

tetanus vaccination using an enzyme-linked immunosorbant assay technique. The results indicated that 
FORMALDEHYDE 78

2. HEALTH EFFECTS

there were no differences between exposed and control animals in IgM production in response to

Pneumovax. Mean overall IgG production in response to Pneumovax was similar between exposed and

control rats; however, a 2-fold increase in IgG production in response to the 19F pneumococcal antigen

was seen in 4 of 8 exposed rats compared to 1 of 6 control rats. The IgM response to tetanus

immunization was similar in the exposed and control groups; levels increased at least 2-fold in a majority

of animals in both groups. Likewise, IgG levels increased significantly in response to tetanus toxoid, but

the response did not differ between treatment groups. The authors concluded that there was no evidence

of immunosuppression in response to long-term exposure to near-maximal levels of formaldehyde in rats.

Whereas other animal experiments have not found convincing evidence that repeated inhalation exposure

to formaldehyde has direct effects on the immune system, there is suggestive evidence that it may have an

indirect effect by facilitating sensitization of nasal tissue to high-molecular weight allergens in mice

(Tarkowski and Gorski 1995). The ability of intranasal administration of 25 μg of ovalbumin (once a

week for 7 weeks) to increase the titer of serum IgE antibodies to ovalbumin (IgE anti-OVA) was

examined in groups of 10 Balb/c mice preexposed to 0 or 1.6 ppm formaldehyde 6 hours/day for 10 days,

or to 0 or 1.6 ppm, 6 hours/day once a week for 7 weeks. In a second experiment, groups of mice were

preexposed to 0 or 1.6 ppm, 6 hours/day for 10 days, injected with up to 4 doses of 1 μg ovalbumin in the

peritoneum, and examined for serum IgE antiOVA titers. Serum titers of IgE antiOVA were significantly

higher (after four intranasal doses of OVA) in mice preexposed to formaldehyde 6 hours/day for 10 days

compared with control titers; mean IgE antiOVA titer at 7 weeks in 10-day preexposed mice

was >60 units compared with about 15 units for controls. No significant difference in IgE-OVA was

found between controls and the group preexposed to formaldehyde once a week for 7 weeks. With

intraperitoneal administration of ovalbumin, preexposure to formaldehyde for 10 consecutive days had no

effect on serum IgE-OVA titers compared with controls. 

In a similar experiment with guinea pigs, Riedel et al. (1996) observed a greater percentage of allergic

responses to inhaled ovalbumin in a group of guinea pigs pre-exposed to 0.25 ppm formaldehyde,

8 hours/day for 5 days than in a control group without preexposure to formaldehyde (10/12 versus 3/12)

(Riedel et al. 1996). 

The highest NOAEL values and all LOAEL values from each reliable study for immunological/

lymphoreticular effects in each species and duration category are recorded in Table 2-1 and plotted in

Figure 2-1. 
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2. HEALTH EFFECTS

2.2.1.4 Neurological Effects

Bach et al. (1990) sought to determine whether humans reacted acutely to formaldehyde exposure, and if

previous chronic-duration exposure to formaldehyde altered the responses noted in acute exposure. 

Thirty-two men with at least 5 years of occupational exposure to formaldehyde and 29 matched controls

were exposed to formaldehyde at concentrations of 0, 0.12, 0.32, or 0.98 ppm for 5.5 hours. During the

exposure period, subjects underwent a battery of performance tests designed to estimate the subject’s

distractibility, short-term memory, and capability to understand and perform certain tasks. Controls

tended to suffer from headaches, "heavy head", and physical tiredness more than the exposed workers. In

both occupationally exposed subjects and nonexposed subjects, decreased performances in several tests

were statistically significantly correlated with increasing acute concentration of formaldehyde. 

Occupationally exposed subjects showed significantly decreased performance, compared with

nonexposed subjects, only in a digit span test, but not in variables for a graphic continuous line test, an

addition test, or a digit symbol test. The authors noted that the typical dose-related symptoms of

respiratory irritation were not seen in this study. 

Kilburn and colleagues have presented evidence for neurological impairments in several studies of

formaldehyde-exposed histology technicians, but confounding exposure to other neurotoxic solvents

prevents drawing definitive conclusions concerning the neurotoxicity of formaldehyde from these studies

(Kilburn 1994; Kilburn and Warshaw 1992; Kilburn et al. 1985b, 1987). Kilburn et al. (1985b) reported

that a group of 76 female histology technicians reported statistically significantly greater frequencies of

neurobehavioral symptoms such as lack of concentration and loss of memory, disturbed sleep, impaired

balance, variations in mood, and irritability than did a referent group of 56 non-exposed female clerical

workers. The technicians had been employed from 2 to 37 years (mean 12.8 years). Analysis of

workplace air samples indicated concentrations for several solvents ranging from 0.2 to 1.9 ppm for

formaldehyde, 3.2 to 102 ppm for xylene, 2 to 19.1 ppm for chloroform, and 8.9 to 12.6 ppm for toluene. 

Subsequently, Kilburn et al. (1987) administered a battery of 10 tests that assessed memory, balance,

coordination, dexterity, motor speed, and aspects of cognitive function to 305 female histology

technicians and analyzed the results by regression analysis with age, years of smoking, hours per day of

exposure to formaldehyde and other solvents as explanatory variables. Increased daily hours of exposure

to formaldehyde were significantly correlated with decreased performance in several tests, whereas hours

of daily exposure to other solvents were only correlated with decreased perfomance in a single test. 

However, in a later prospective study of performance by 318-494 histology technicians in a battery of 
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2. HEALTH EFFECTS

neurobehavioral tests, no statistically significant cumulative effects due to occupational exposure to

formaldehyde (or other solvents) or of aging were found over a 4-year period (Kilburn and Warshaw

1992). Kilburn (1994) further reported that three anatomists and one railroad worker, who were

occupationally exposed to airborne formaldehyde for 14-30 years and who were disabled, each showed

impaired performance on several neurobehavioral tests (e.g., choice reaction time, abnormal balance, digit

symbol, and tests of perceptual motor speed). 

In laboratory animals, Morgan et al. (1986a) studied male Fischer 344 rats exposed to 15 ppm

formaldehyde for 10, 20, 45, or 90 minutes, or 6 hours. Some additional rats were also exposed to 2 ppm

formaldehyde for 90 minutes or 6 hours to establish whether this level was a no-effect concentration. The

rats exposed to 15 ppm formaldehyde exhibited restless behavior for the first 10–15 minutes of exposure. 

Boja et al. (1985) investigated the effects of low-level formaldehyde exposure on behavior and

neurochemistry in male Sprague-Dawley rats. Animals were exposed to either air or formaldehyde at

concentrations of 5, 10, or 20 ppm for 3 hours. The following day the rats were exposed to either the

same treatment or the opposite treatment (i.e., treatment groups of air-air, air-formaldehyde,

formaldehyde-air, or formaldehyde-formaldehyde). Behavioral activity was periodically monitored. 

After the second day of exposure, rats were sacrificed, their brains were removed, and samples of

striatum, nucleus accumbens, frontal cortex, lateral septum, amygdala, hypothalamus, and hippocampus

were collected and analyzed for norepinephrine, dopamine, and 5-hydroxytryptamine and their major

metabolites. Exposure to 5 ppm formaldehyde resulted in statistically significant decreased motor activity

within 15 minutes. At the beginning of day 2, all of the rats exposed to formaldehyde on day 1 displayed

lower activity levels. Similar effects on motor activity were seen at the 10 ppm formaldehyde exposure

level, whereas effects seen after 20 ppm exposure were reported to be “not readily interpretable” and were

not shown. Exposure to 5 ppm formaldehyde statistically significantly increased concentrations of

5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and dopamine in the hypothalamus, but did

not affect the concentrations of norepinephrine or 5-hydroxytryptamine. Data for other brain regions or

exposure concentrations were not reported (Boja et al. 1985).

Wood and Coleman (1995) assessed the behavioral response to formaldehyde exposure in male Swiss

mice. Eight mice were trained to terminate exposure to noxious gases, using 1,000 ppm ammonia. All

animals learned to terminate 100% of the ammonia exposures. After mice consistently terminated 
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2. HEALTH EFFECTS

ammonia exposures, they were exposed to a series of formaldehyde exposures at concentrations of 0, 1,

1.8, 3, 5.6, and 10 ppm. Beginning at the lowest formaldehyde concentration (1 ppm), mice terminated

significantly more exposures compared to air (p<0.0005). The number of terminations increased and the

time to termination decreased as the concentration of formaldehyde increased. Exposure durations in the

second series were significantly shorter (p=0.0012) than those experienced in the first series, indicating an

increased sensitivity to formaldehyde. Wood and Coleman (1995) suggested that a conditioned response

may have developed in the mice rather than a change in the sensitivity of the sensory epithelium.

In studies of intermediate-duration exposure, Maronpot et al. (1986) studied the effects of formaldehyde

exposure in male and female B6C3F1 mice. Animals were exposed to formaldehyde 6 hours/day,

5 days/week for 13 weeks at target concentrations of 0, 2, 4, 10, 20, or 40 ppm. No obvious gross signs

of neurotoxicity were seen in mice treated with 2, 4, or 10 ppm formaldehyde, but mice in the 20-ppm

group exhibited dyspnea, listlessness, and hunched posture. These symptoms were also noted in the

40-ppm groups with greater severity; in addition, mice in this group exhibited ataxia.

Appelman et al. (1988) examined the effects of preexisting nasal damage and formaldehyde exposure in

male SPF Wistar rats. Groups of 40 rats each were exposed to 0, 0.1, 1, and 10 ppm formaldehyde. 

Within each dose group, half of the animals had their nasal mucosa damaged by electrocoagulation. 

Animals were exposed to formaldehyde 6 hours/day, 5 days/week for either 13 or 52 weeks (n=10 per

dose/nasal damage subgroup). Behavior and appearance were not affected by formaldehyde exposure;

brain weights and histopathology in all of the formaldehyde-treatment groups were not significantly

different from the control animals.

Woutersen et al. (1987) examined the effects of inhalation exposure to formaldehyde in male and female

Wistar rats. Groups of 10 animals per sex were exposed to target concentrations of 1, 10, or 20 ppm

formaldehyde 6 hours/day, 5 days/week for 13 weeks. Uncoordinated movement and wall-climbing were

noted during the first 30 minutes of each exposure period in the 20-ppm group; the rats in the lower-dose

groups did not exhibit abnormal behavior. In the 20-ppm males, relative organ weights were higher in

6 of the 11 animals examined (no further data supplied), and in the females of this dose group, only

relative brain weights were significantly greater than those of controls. No treatment-related gross or

histopathological lesions of the brain were noted in any sex or dose-group at necropsy.
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2. HEALTH EFFECTS

Kerns et al. (1983b) studied the effects of long-term formaldehyde exposure on 120 male and female

Fischer 344 rats and B6C3F1 mice exposed to 0, 2, 5.6, or 14.3 ppm formaldehyde for 6 hours/day,

5 days/week for 24 months. The dosing period was followed by a 6-month observation period. Interim

sacrifices were performed at 6, 12, 18, 24, 27, and 30 months. No dose-related neurofunctional effects

were noted at any dose or interim sacrifice time-point in either sex or species.

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in

each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1.

2.2.1.5 Reproductive Effects

Ward et al. (1984) investigated whether formaldehyde exposure resulted in altered sperm numbers or

morphology in male pathologists. Exposed subjects consisted of 11 men; 10 were employed for

1–11 months (average 4.3 months) and the other was employed for several years. All subjects provided

three semen samples collected at 2–3 month intervals. Sperm samples were analyzed for sperm count,

morphology, and F-body frequency. Time-weighted average air concentrations in workplaces ranged

from 0.61 to 1.32 ppm (midpoint of range 0.97 ppm). The mean sperm count for exposed workers was

lower than that of controls (62.9x106

/mL versus 87.4x106/mL); however, the difference was not

statistically significant. The frequency of abnormal sperm was not greater in exposed subjects. The

frequency of sperm containing 1F- or 2F-bodies was similar between exposed and control subjects. The

small number of subjects in this study limited its detection power. 

Garry et al. (1980) investigated the health effects associated with formaldehyde exposure in Minnesota

residents. A total of 275 cases of possible formaldehyde exposure were investigated between February

and June 1979. Medical histories of the patient and all family members were recorded, and 30-minute air

samples were collected from the living room and bedroom of each residence. Environmental information

(age, type of home, type of insulation, type of heat) was also collected. Formaldehyde levels ranged from

0.1 to 3 ppm. The rate of miscarriages in exposed women in this study (11.6%) did not differ from the

rate of miscarriages seen in other studies of non-exposed women. There is no information on the duration

of exposure; therefore, chronic-duration exposure is assumed.

The possible teratogenic effects of inhaled formaldehyde were investigated in groups of 25 female rats

exposed to airborne formaldehyde at levels of 0, 2, 5, and 10 ppm, 6 hours/day on gestation days 6–15. 
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2. HEALTH EFFECTS

No maternal or fetal deaths occurred, and pregnancy parameters (numbers of corpora lutea, implantation

sites, pre-implantation losses) were not affected by formaldehyde exposure (Martin 1990).

Although maternal toxicity, expressed as a statistically significant decrease in bodyweight gain, was

observed in pregnant Sprague Dawley rats exposed to 40 ppm, but not 20 ppm, 6 hours/day on gestation

days 6–20 (Saillenfait et al. 1989), other statistically significant changes in reproductive variables (e.g.,

number of implantation sites and number of resorptions), however, were not found.

Woutersen et al. (1987) examined the effects of inhalation exposure to formaldehyde in male and female

Wistar rats. Groups of 10 animals per sex were exposed to target concentrations of 1, 10, and 20 ppm

formaldehyde 6 hours/day, 5 days/week for 13 weeks. No treatment-related gross lesions were noted for

the ovaries and testes at necropsy.

Appelman et al. (1988) provided data on the reproductive organs of rats exposed to formaldehyde. Male

SPF Wistar rats were exposed to 0, 0.1, 1, and 10 ppm formaldehyde. Within each dose group, half of the

animals (n=20) had their nasal mucosa damaged by electrocoagulation. Animals were exposed to

formaldehyde 6 hours/day, 5 days/week for either 13 or 52 weeks. No significant changes in testicle

weights of treated rats were noted when compared to controls.

Maronpot et al. (1986) examined the effects of formaldehyde exposure on reproductive organs in male

and female B6C3F1 mice. Animals were exposed to formaldehyde 6 hours/day, 5 days/week for

13 weeks at concentrations of 2, 4, 10, 20, and 40 ppm. Gross and histopathological examination showed

ovarian and uterine hypoplasia characterized by decreased prominence of endometrial glands and stroma

and an associated lack of ovarian luteal tissue in 40-ppm females. Ovarian and uterine hypoplasia were

not observed in the lower exposure groups. No histopathological effects were noted in male reproductive

organs. Maronpot et al. (1986) ascribed to the belief that the ovarian and uterine effects reflected “the

general debility and weight loss rather than a direct target organ effect of formaldehyde”. 

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects for

the intermediate duration category are recorded in Table 2-1 and plotted in Figure 2-1.
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2. HEALTH EFFECTS

2.2.1.6 Developmental Effects

Studies regarding the developmental toxicity of airborne formaldehyde in humans are limited to a

population-based case-control study of 244 mothers with “low-birth weight” newborns in Lithuania

compared with 4,089 control mothers with “normal weight” newborns (Grañulevi...iene et al. 1998). 

Questionnaire information was collected from cases and controls for risk factors including place of

residence. Based on air monitoring data, residential districts were grouped into low (mean concentration

1.6 ppb), moderate (2.8 ppb), or high (3.8 ppb) formaldehyde-exposure districts. After adjustment for

other risk factors such as age, occupation, last pregnancy outcome, and smoking habit, the odds ratio

(OR) for low-birth weight incidence was elevated in those with formaldehyde exposure >2.8 ppb

compared with those with exposure <2.8 ppb, but not to a statistically significant degree (OR=1.37,

95% confidence interval [CI] 0.90–2.09). 

Martin (1990) exposed groups of 25 pregnant Sprague-Dawley rats to 0, 2, 5, or 10 ppm in an inhalation

chamber, 6 hours/day from gestation days 6 to 15. Another nonexposed group of 25 pregnant rats was

housed outside of the inhalation chamber (“room control”). Dams were sacrificed on day 20 and uterine

contents were evaluated. Statistically significant decreased food consumption and weight gain occurred

in the 10-ppm dams. No statistically significant effects from exposure were found on the following

variables: numbers of corpora lutea, implantation sites, live fetuses, dead fetuses and resorptions, fetal

weights, fetal sex ratios, and pre- and postimplantation losses. Likewise, no exposure-related effects were

reported on the incidences of litters and fetuses with major malformations, minor external and visceral

anomalies, and minor skeletal anomalies. The only statistically significant finding reported was for

increased incidences of reduced ossification of the pubic and ischial bones in the 5- and 10-ppm groups,

compared with the 0-ppm groups but not the “room control” group. Martin (1990) did not consider these

findings to be biologically significant, noting that they were considered to be related to the “slightly

lower” fetal weights and “slightly larger” litter sizes in the 5- and 10-ppm groups. The published report,

however, did not provide more details on the quantitative data collected, making assignment of fetal

effect levels in this study uncertain.

Saillenfait et al. (1989) assessed the effects of maternal formaldehyde inhalation on embryonic and fetal

development in Sprague-Dawley rats. Groups of 25 mated females were exposed to 0, 5, 10, 20, and

40 ppm formaldehyde on gestation days 6–20. The dams were weighed on gestation days 0, 6, and 21. 

All dams survived the experiment. On gestation day 21, the dams were sacrificed and their uteri were 
FORMALDEHYDE 85

2. HEALTH EFFECTS

exposed and examined. The following parameters were assessed: maternal weight gain, percentage

pregnant, litter sex ratio, fetal mortality, fetal weight, cleft palate malformations, and alterations of soft

and skeletal tissues. Exposure to 40 ppm formaldehyde resulted in a 51% reduction in weight gain in

dams compared to controls (p<0.01). There were no significant differences between treatment groups in

the incidences of pregnancies; number of implantations or resorptions; numbers of dead or live fetuses;

fetal sex ratios; or the incidences of external, visceral, or skeletal abnormalities. Fetal weights were

significantly lower in male offspring from dams exposed to 20 ppm formaldehyde (p<0.05) and in male

and female offspring from dams exposed to 40 ppm formaldehyde (p<0.01); the decreases seen in the

20 ppm group were <5% of control values. At 40 ppm, the differences in weights averaged 21%. The

authors concluded that maternal exposure to formaldehyde during gestation days 6–20 was not

teratogenic at levels #40 ppm, but was slightly fetotoxic at 20 ppm.

The highest NOAEL value and less serious and serious LOAEL values from the Saillenfait (1989) study

for developmental effects in rats are recorded in Table 2-1 and plotted in Figure 2-1.

2.2.1.7 Genotoxic Effects

Several studies were identified that described the genotoxic effects of formaldehyde after inhalation

exposure. In one study, peripheral lymphocytes from eight anatomy students exposed to formaldehydeembalming solution over a 10-week course were examined for sister chromatid exchange (SCE). Results

were compared with preexposure values for each student. Breathing-zone monitoring revealed mean

exposure of 1.2 ppm (range 0.73–1.95 ppm). A small average increase in the incidence of SCE was

observed in the lymphocytes of the students after exposure (7.2/cell) when compared to values obtained

before exposure (6.39/cell) (Yager et al. 1986). Conversely, Vasudeva and Anand (1996) examined the

effects of formaldehyde exposure on the incidence of chromosomal aberrations in peripheral blood

lymphocytes of 30 medical students exposed to formaldehyde vapors at concentrations of <1 ppm for

15 months. Questionnaires established that the participants were healthy and had insignificant medical

histories. There was no difference in the incidences of chromosomal aberrations among the exposed and

control groups. The mean frequencies of aberrant metaphases in the exposed and control groups were

1.2 and 0.9%, respectively. There was no correlation between reported irritant effects of formaldehyde

and the number of aberrant metaphases, and the authors concluded that exposure to formaldehyde at

concentrations seen in this study does not lead to chromosomal aberrations. 
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Fleig et al. (1982) performed chromosome analyses on 15 exposed and 15 non-exposed employees from

formaldehyde manufacturing facilities. Exposed workers had an average duration of exposure of 28 years

(range 23–35 years). Average exposure concentrations did not exceed 5 ppm prior to 1971 and 1 ppm

after 1971. The formaldehyde exposures of individual workers were classified into one of the three

following categories: Category 1: exposure #25% of the maximum workplace concentration (MAK);

Category 2: exposure up to a maximum of 60% MAK; and Category 3: exposure up to 100% of the

MAK. Peripheral blood samples were collected from each worker and lymphocytes were separated and

cultured for 70–72 hours at 37 EC. Cells were subsequently fixed and examined for chromatid- and

chromosome-type aberrations. There were no differences between exposed and control groups in the

incidence of chromosomal aberrations. The mean frequency of aberrant metaphases among

formaldehyde-exposed persons was 3.07 versus 3.33% in controls. No correlation was found between

formaldehyde exposure levels and the number of aberrant metaphases.

Shaham et al. (1996a) measured the formation of DNA-protein cross links in peripheral white blood cells

of occupationally exposed workers (n=12) and unexposed controls (n=8). The average length of

occupational exposure was 13 years. All subjects completed a questionnaire regarding demographics,

occupational and medical background, and smoking and hygiene habits. Venous blood samples were

collected from each worker and were processed to isolate DNA-protein cross links. Personal and room

concentrations of formaldehyde were collected at various periods during the working day among the

exposed subjects, with formaldehyde room concentrations ranging from 1.38 to 1.6 ppm. Personal

monitoring devices indicated formaldehyde concentrations of 2.8–3.1 ppm during peak work and an

average concentration of 1.46 ppm at times when work was usually completed. Exposure to

formaldehyde resulted in a significant increase in the incidence of DNA-protein cross links. Mean (±sd)

incidences in exposed and nonexposed workers were 28±6 and 22±6%, respectively. Within the exposed

workers group, technicians had significantly greater levels of DNA-protein cross links than physicians

(32.3±4.3 and 26.3±4.4%, respectively). A linear relationship between years of exposure and

DNA-protein cross links formation was also detected. When the data were analyzed considering worker

smoking habits, DNA-protein cross links was consistently elevated among formaldehyde-exposed versus

corresponding controls (p=0.03). The authors concluded that DNA-protein cross links can be used as a

biomarker of exposure; however, the assay measures DNA-protein cross links in general, not those

specific to formaldehyde cross link formation.
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Chebotarev et al. (1986) examined the lymphocytes sister chromatic exchanges (SCEs) of 40 woodworking employees and 22 control workers for chromosomal aberrations, SCEs, and unscheduled DNA

repair or synthesis. The level of chromosomal aberrations in formaldehyde-exposed workers was 2.76%,

which was significantly elevated compared to spontaneous chromosomal aberrations in controls (1.64%,

p<0.05). The incidence of chromosomal breakage in exposed workers (2.95%) was significantly greater

than the frequency of spontaneous breakage (1.64%, p<0.05). No differences between exposed and

control subjects were seen for SCEs either at baseline (8.01 versus 8.24 exchanges per cell) or after

induction with the genotoxin thiotepa (23.32 versus 25.78 exchanges per cell). There were no differences

between formaldehyde-exposed and control samples in unscheduled DNA repair rates at baseline

(335.2 versus 341.9) or after treatment with hydroxyurea (179.8 versus 194.2). However, when treated

with thiotepa, unscheduled DNA repair rates in lymphocytes from formaldehyde-exposed workers were

lower than those from control workers (217.2 versus 270.4, p<0.05). Using another measure of

mutagenicity, Ballarin et al. (1992) evaluated 15 nonsmoking workers (8 males, 7 females) who worked

in a plywood factory for cytopathologic changes in nasal mucosal cells, and compared the results to

matched controls. Mean levels of exposure to formaldehyde ranged from 0.07 to 0.08 ppm in the sawmill

and shearing press departments to 0.32 ppm in the warehouse. The total range of exposure in all areas

containing formaldehyde vapors was 0.06–0.49 ppm. Workers were also exposed to wood dust. Nasal

mucosal cells from exposed workers exhibited significantly increased incidence of micronuclei

(0.9 versus 0.25 for controls), chronic inflammation, and a significantly higher frequency of squamous

metaplasia cells (histological score: 2.3 versus 1.6) than cells from control workers. Micronuclei were

found mainly in the ciliated cells.

In another study, Connor et al. (1985b) tested urine obtained from hospital autopsy service workers

exposed to formaldehyde and from matched control workers for cellular mutagenicity. Exposed workers

had worked in the hospital for at least 6 months. Actual exposure to formaldehyde was determined to be

from 0.1 to 5.8 ppm, using personal breathing zone monitoring; the TWA exposures to formaldehyde in

work areas were estimated to be 0.61–1.32 ppm. Mutagenicity tests using Salmonella typhimurium

(S. typhimurium) TA 100 and TA 98 were conducted, with or without rat S9 (microsomes containing

cytochrome P-450) suspension. No increase was seen in mutagenicity using urine of exposed workers,

compared to control urine. Addition of S9 had no significant effect on the genotoxicity of the urine.

Studies in laboratory animals have also demonstrated that formaldehyde can be genotoxic in some cells

after inhalation exposure. Dallas et al. (1992) exposed male Sprague-Dawley rats to formaldehyde 
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concentrations of 0, 0.5, 3, and 15 ppm, by inhalation for 6 hours/day for 5 days. The rats were

sacrificed, and their pulmonary macrophages and bone marrow cells were harvested and analyzed by flow

cytrometry and cytogenetic analysis. Cell division was arrested using colchicine treatment (1 mg/kg)

2 hours prior to sacrifice. Five days after the beginning of exposure, formaldehyde-exposed groups

exhibited no more than 4% chromosomal aberrations in the bone marrow cells, which was not

significantly different from control values. There were no differences with respect to dose group. 

Chromatid breaks, chromosome breaks, and centric fusions were observed in bone marrow cells, but were

not considered to be associated with formaldehyde exposure. An increase in chromosomal abnormalities

in pulmonary macrophages, predominantly chromatid breaks, was observed in the 15 ppm group

(7.5 versus 3.4% for controls) after 5 days of exposure. Small increases were also seen in the 0.5 and

3 ppm groups, but these were not statistically significant. No chromosome breaks or centric fusions were

observed in control cells obtained by pulmonary lavage. 

Dallas et al. (1992) also extended the exposure treatment time to 1 or 8 weeks. The rats were sacrificed

after 1 or 8 weeks of exposure, and pulmonary macrophages and bone marrow cells were harvested and

analyzed by flow cytrometry and cytogenetic analysis. Formaldehyde-exposed groups exhibited no more

than 4% chromosomal aberrations in the bone marrow cells, which was not significantly different from

control values. Chromatid breaks, chromosome breaks, and centric fusions were observed in bone

marrow cells, and again, were not associated with formaldehyde exposure. With respect to pulmonary

macrophages, an increase in chromosomal abnormalities was observed in the 15 ppm group (9.2 versus

4.8% for controls) after 5 days of exposure. Small increases were also seen in the 0.5 and 3 ppm group,

but these were not statistically significant. The predominant cytogenetic damage was chromatid breaks,

observed in both control and treated cells. No chromosome breaks or centric fusions were observed in

control cells obtained by pulmonary lavage. In formaldehyde-treated animals, chromosome breaks and

centric fusions were noted, but were not dose-related.

Lam et al. (1985) studied the effects of inhalational co-exposure to acrolein and formaldehyde in male

Fischer 344 rats. Rats were exposed for 6 hours to room air (controls), 2 ppm acrolein, 6 ppm

formaldehyde, or a combination of 2 ppm acrolein and 6 ppm formaldehyde. The animals were sacrificed

immediately after completion of exposure, and their nasal tissues were harvested. The DNA was 

isolated and the aqueous and interfacial portions were collected separately. Exposure to formaldehyde significantly increased the percentage of interfacial DNA (12.5%), the specific portion of the 

DNA which contains the DNA cross linked to proteins, compared to rats exposed to room air only 
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(8.1%, p<0.05). Co-exposure to acrolein resulted in a further increase in the percentage of interfacial

DNA (18.6%) which was significantly greater than the effect of formaldehyde alone (p<0.05). The

authors concluded that simultaneous exposure to acrolein enhanced formaldehyde-induced DNA-protein

cross linking.

Other genotoxicity studies are discussed in Section 2.5. More extensive evaluation of the genotoxic

potential of formaldehyde is available (IARC 1995; WHO 1989).

2.2.1.8 Cancer

Human Studies Overview. The finding of nasal tumors in rodents exposed to high levels of airborne

formaldehyde in the early 1980s (Albert et al. 1982; Kerns et al. 1983b; Swenberg et al. 1980) led to a

concern for cancer effects in occupationally exposed workers. There are now more than 40 epidemiology

studies examining the potential for occupational formaldehyde exposure to cause cancer in humans. The

studies include cohort mortality studies of formaldehyde-exposed industrial workers, cohort mortality

studies of formaldehyde-exposed professionals or medical specialists, and case-control studies that looked

for associations between occupational exposure to formaldehyde and cancers of the nose, pharynx, or

lung. Published reviews and evaluations of the epidemiology studies include early reviews by IARC

(1987), Purchase and Paddle (1989), and an ad hoc panel convened by Universities Associated for

Research and Education in Pathology (1988). More recent reviews have been published by Conaway et

al. (1996), ECETOC (1995), IARC (1995), and McLaughlin (1994). In addition, three meta-analyses of

the data have been published (Blair et al. 1990a; Collins et al. 1997; Partanen 1993). Although some of

the epidemiological studies have found some scattered evidence for extra-respiratory site cancers in

groups of formaldehyde-exposed workers, the data are not consistent across studies and adjustment for

potential confounding cancer risk factors has not often been possible. Most, if not all reviewers, have

agreed that cancer of the respiratory tract, particularly the upper respiratory tract, is more biologically

plausible than formaldehyde-induced cancer at distant sites given the reactivity of formaldehyde, the

capacity of tissues to metabolize formaldehyde, and the results from chronic rodent inhalation studies

showing that formaldehyde-induced nonneoplastic and neoplastic effects are restricted to the upper

respiratory tract with exposures to concentrations below 5–10 ppm. Accordingly, the meta-analyses of

the human data have focused on the findings for respiratory cancer deaths in occupationally exposed

humans. 
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Six mortality studies of the following cohorts of formaldehyde-exposed industrial workers are included in

recent reviews and the meta-analyses: 26,561 U.S. workers involved in formaldehyde production, resin

making, and several other activities using formaldehyde (Blair et al. 1986, 1990a); 7,660 workers in six

British plants using formaldehyde (Acheson et al. 1984a; Gardner et al. 1993); 11,030 workers in three

U.S. garment facilities (Stayner et al. 1988); 1332 Italian workers involved in resin making (Bertazzi et al.

1986, 1989); 3929 foundry workers exposed to formaldehyde (Andjelkovich et al. 1994b, 1995a); and

6,039 workers in a Conneticut chemical plant that included some of the workers from the Blair et al. study

(Marsh et al. 1994, 1996). Data from the Blair et al. (1986) study have been independently analyzed by

Sterling and Weinkam (1989, 1995).

In the industrial worker cohort studies, the range of standardized mortality ratios (SMR; see Table 2-2 for

definitions of selected epidemiological terms) relevant to exposure to airborne formaldehyde were (a zero

reflects a finding of no deaths from the subject cancer): 

C for lung cancer - 0.9 to 1.4 (lung cancer deaths were reported in each cohort); 

C for nasopharyngeal cancer - 0 to 3.0 (only the Blair et al. [1986, 1990a] study had

nasopharyngeal cancer deaths: 6 observed versus 2 expected);

C for nasal cancer - 0 to 0.6 (Andjelkovich et al. 1994b, 1995a; Bertazzi et al. 1986, 1989; Marsh et

al. 1994, 1996; and Stayner et al. 1988, however, did not report nasal cancer deaths); and 

C for buccal cavity and/or pharynx cancer - 1.1 to 1.69 (only Bertazzi et al. 1986, 1989 did not

report buccal cavity and/or pharynx cancer). 

Small excess relative risks for buccal cavity and/or pharynx cancer and lung cancer were most

consistently observed across these studies. The increases in risk were generally not of statistical

significance with the exception of the Blair et al. (1986) report of an SMR of 3.0 (95% CI, 1.3–6.6) for

nasopharyngeal cancer.

Nine mortality studies of the following cohorts of formaldehyde-exposed professionals or medical

specialists are included in recent reviews and the meta-analyses: 2,079 British pathologists and

12,944 medical specialists (Harrington and Shannon 1975); 1,263 deceased New York embalmers

(Walrath and Fraumeni 1983); 1,109 deceased California embalmers (Walrath and Fraumeni 1984);

1,477 Ontario funeral workers (Levine et al. 1984a); 2,317 U.S. anatomists (Stroup et al. 1986);

5,810 U.S. pathologists (Matanoski 1991); 5,585 U.S. pathologists (Logue et al. 1986); 4,046 deceased
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Table 2-2. Definitions of Selected Epidemiology Terms

Standardized mortality 

ratio (SMR)

is the ratio of a cause-specific mortality rate in an exposed cohort during

a given period to the mortality rate of an unexposed cohort; mortality

rates are often adjusted for age or other confounding variables. 

Proportionate mortality 

ratio (PMR)

is the ratio of a cause-specific mortality proportion in an exposed group

to the mortality proportion in an unexposed group; mortality proportions

may be adjusted for confounding variables such as age. Cause-specific

mortality proportions can be calculated when the cohort (the population

at risk) cannot be defined due to inadequate records, but the number of

deaths and the causes of deaths are known.

Standardized proportionate

incidence ratio (SPIR)

is similar to a PMR in that it is a ratio of a proportion of a specific

disease in an exposed group compared with the proportion in an

unexposed group.

Odds Ratio(OR) and 

Relative Risk (RR)

are risks expressed as ratios of the incidence of diseased subjects

exposed to a particular risk factor to the incidence of diseased subjects

in a nonexposed referent group.
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 members of U.S. funeral directors’ organizations (Hayes et al. 1990); and 4,512 British pathologists (Hall

et al. 1991).

In the professional worker cohort studies, the range of SMRs or proportionate mortality ratios (PMRs) for

respiratory or buccal cavity sites were: 

C for lung cancer - 0.1 to 1.1 (the group of New York State embalmers [Walreth and Fraumeni

1983] was the only cohort that showed an excess: 72 observed versus 66.8 expected); 

C for nasopharyngeal cancer - 2.1 (the group of deceased U.S. funeral directors was the only

professional cohort reporting this type: 4 observed versus 1.85 expected [Hayes et al. 1990]);

C nasal cancer deaths were either reported as zero or not reported among the nine professional

cohorts; 

C for buccal cavity and/or pharynx cancer - 0.2 to 1.3 (at least one buccal cavity and/or pharyngeal

cancer death was noted in each of the professional cohorts).

Case-control studies examining potential associations between occupational exposure to formaldehyde

and specific types of cancer include those of: 

C lung cancer (Bond et al. 1986; Chiazze et al. 1993; Coggon et al. 1984; Gerin et al. 1989; Jensen

and Andersen 1982; Partanen et al. 1985, 1990) with relative risks ranging from 0.6 to 1.1; 

C nasal cancer (Brinton et al. 1984, 1985; Hayes et al. 1986; Hernberg et al. 1983a, 1983b; Luce et

al. 1993b; Olsen et al. 1984; Rousch et al. 1987; Vaughan et al. 1986a, 1986b) with relative risks

ranging from 0 to 12.6; and 

C nasopharyngeal cancer (Olsen et al. 1984; Rousch et al. 1987; Vaughan et al. 1986a, 1986b;

West et al. 1993) with relative risks ranging from 0.6 to 5.5.

The first two meta-analyses of the epidemiology studies (Blair et al. 1990a; Partanen 1993) took similar

approaches to analyzing the same data, except that Partanen included three case-control studies not

included in the earlier analysis. Both analyses calculated summary or aggregate relative risks for lung

cancer, cancer of the nose and nasal sinuses, and nasopharyngeal cancer, and analyzed data from a subset

of the available studies that were classified into “low/medium” or “substantial” exposure categories based

on exposure level and/or duration of exposure information. Although different methods to calculate

aggregate relative risks across studies were used in the two studies, similar results were obtained and

conclusions reached. 
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In both analyses, aggregate relative risks for lung cancer deaths calculated for formaldehyde-exposed

medical and nonmedical professionals were at or below those expected. Aggregate relative risks for lung

cancer in industrial worker studies showed a small excess relative risk (1.1) in both analyses, but no

evidence for an exposure-related increase in relative risk comparing the “low/medium” relative risks (1.2)

with those of the “substantial” exposure class (1.0 or 1.1). Small excess aggregate relative risks for

occupationally-exposed workers in all of the studies existed for cancer of the nose and nasal sinuses

(1.1 [95% CI, 0.8–1.4] - Blair et al. 1990a; 1.1 [95% CI, 0.8–1.5] - Partanen 1993), and cancer of the

nasopharynx (1.2 [95% CI, 0.8–1.7] - Blair et al. 1990a) and 2.0 [95% CI, 1.4–2.90] - Partanen 1993). 

Relative risks for both types of cancer increased with increasing exposure intensity in Table 2-3.

Both Blair et al. (1990a) and Partanen (1993) concluded that a causal role for formaldehyde in the

induction of the observed cancers of the nasopharynx and nasal cavities was supported by their evidence

for exposure-response relationships, the portal-of-entry site of these cancers, and the consistency of these

findings with results from animal studies.

A third meta-analysis by Collins et al. (1997) arrived at the conflicting conclusion that the available

studies do not support a causal relationship between formaldehyde exposure and nasopharyngeal cancer. 

This study analyzed data from essentially the same case-control studies, but included a few cohort

mortality studies that were not available or included in the earlier meta-analyses (e.g., Andjelkovich et al.

1994b, 1995a; Gardner et al. 1993). Collins et al. (1997) noted that nasopharyngeal cancer rates were

elevated in a minority of the available studies, that most studies did not find any nasopharyngeal cancers,

and that many studies did not report on nasopharyngeal cancer. Unlike the calculational techniques used

in the previous meta-analyses, a calculational technique was used to adjust for underreporting of expected

mortality rates in the calculation of “weighted meta relative risks”. Meta relative risks (with 95% CIs) for

nasopharyngeal cancer were 1.0 (0.5–1.8) for the 14 cohort studies included in the analysis, 1.2 (0.4–2.5)

for the six industrial worker cohort studies, and 1.3 (0.9–2.1) for the seven case-control studies. Collins

et al. (1997) concluded from their review of the available studies that exposure estimates for the casecontrol studies were both lower and less certain than exposures in the industrial worker cohort studies,

and that their analysis does not support an exposure-response relationship between formaldehyde and

nasopharyngeal cancer. 

Recent reviews of the available epidemiology studies arrive at differing conclusions. NTP (1998) notes

that formaldehyde is reasonably anticipated to be a human carcinogen. IARC (1995) concluded, “Taken
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Table 2-3. Meta-analysis of Epidemiology Studies of Cancer of 

the Nose and Nasal Sinuses and Nasopharyngeal Cancer

Cancer site Level or duration of exposure to formaldehyde

Low/medium Substantial

O/Ea RRb O/E RR O/E RR O/E RR

Blair et al. 1990a Partanen 1993 Blair et al. 1990a Partanen 1993

Nose and

nasal sinuses

38/46 0.8 (0.6–1.1) 33/30 1.1 (0.7–1.8) 30/28 1.1 (0.7–1.5) 36/21 1.7 (1.0–2.8)

Nasopharynx 30/27 1.1 (0.7–1.6) 23/16 1.6 (1.0–2.7) 13/6 2.1 (1.1–3.5) 11/4 2.7 (1.4–5.6)

a

 Observed/Expected cancer deaths

b

 Relative risk (with 95% CI); CIs for the Blair et al. 1990a entries were calculated by Partanen (1993).
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 together, the epidemiological studies suggest a causal relationship between exposure to formaldehyde

and nasopharyngeal cancer, although the conclusion is tempered by the small numbers of observed and

expected cases in the cohort studies”. IARC’s overall evaluation that formaldehyde is probably

carcinogenic to humans (Group 2A) was based on specific evaluations that there is limited evidence in

humans for the carcinogenicity of formaldehyde and sufficient evidence in experimental animals. EPA

(1991a) classified formaldehyde in Group B1 - probable human carcinogen, based on an evaluation of

limited human evidence and sufficient laboratory animal evidence. More recently, in a collaborative

review and evaluation of the formaldehyde epidemiology studies, EPA and CIIT (CIIT 1998) concluded,

“It appears that a weak association between nasopharyngeal cancer and formaldehyde exposure cannot be

completely ruled out.” Adopting another view, McLaughlin (1994) concluded, “Clearly, the causal

criteria used by epidemiologists to evaluate an association, such as strength of the association,

consistency, specificity, dose-response, plausibility, and coherence, are not satisfied by the epidemiologic

studies in the formaldehyde-cancer research domain”. ECETOC (1995) similarly concluded, “After a

careful review of the cytologic, cytogenic and epidemiological studies there is an absence of evidence to

support the judgement of an etiologic relationship between formaldehyde and human cancer risk.”

Selected Cohort Mortality Studies. Blair et al. (1986) performed a historical cohort study to evaluate the

mortality experience of 26,561 workers in 10 formaldehyde-producing or -using workplaces. TWA

exposures to formaldehyde were estimated to range from trace amounts to >2 ppm. The mortality

experience of workers exposed to workplace air concentrations $0.1 ppm was compared with that of

“nonexposed” workers in the cohort exposed to concentrations <0.1 ppm. Using national rates of

mortality as reference, greater than expected mortalities for a number of cancer types were noted in the

exposed group, but the elevated rates of mortality were not statistically significantly different than

national rates. Types of cancers with elevated SMRs included: Hodgkin’s disease (SMR=1.42); and

cancers of the liver (SMR=1.02); larynx (SMR=1.42); lung (SMR=1.11); bone (SMR=1.23); prostate

(SMR=1.15); and kidney (SMR=1.23). The nonexposed group generally showed less than expected

deaths from these cancers, (i.e., SMRs<1.00) Mortality from selected cancers were also compared among

several subgroups of the cohort with varying exposure-concentration experiences. Among the

aforementioned cancers, only deaths due to Hodgkin’s disease exhibited a dose response. No individual

exposure category SMR, however, was significantly elevated, and comparisons of the SMRs across

different exposure categories is inappropriate for this indirectly adjusted measure. No unusual cancer

patterns were noted among white women or black men. Among subsites of the buccal cavity, the

nasopharynx had a significantly greater than expected incidence (7 cases observed versus 2.2 cases 
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expected) of cancer. This study demonstrated that there was insufficient evidence to firmly associate

occupational formaldehyde exposure with the observed cancers, even when considering that the SMRs for

the unexposed workers were small. No consistent correlation was noted between cumulative exposure

and the risk of any cancer. This study used a cohort study design with a large study population. 

Additional strengths of this study included the fact that experienced nosologists assigned the cause of

death and in addition to the SMR analysis based on vital statistics data, the study also included analyses

using internal comparison groups. Industrial hygienists made estimates of the intensity of formaldehyde

exposures using all available sources of information (most similar studies estimated only the duration). 

Overall, the analysis was very thorough and allowed for different exposure intensity levels and different

possible “latency” periods between exposure and death. The investigators attempt to rule out

confounding factors from socioeconomic status, and the follow up was good overall (95%), although it

was only 83% for women. Weaknesses included the fact that death certificate data can often be

inaccurate, so some cancers of interest could have been missed. Also, no information about tobacco use

or other nonoccupational exposures was available. 

In a later study by Blair et al. (1990b), the risk of lung cancer was assessed among 20,714 white male

workers exposed to formaldehyde in 10 production plants. The estimated average levels of exposure were

0.1–1.9 ppm formaldehyde. The overall risk of lung cancer did not appear to be correlated with average

formaldehyde levels in each plant. Among the exposed sample, the SMRs did not increase consistently

with any measure of exposure. The SMR for those with cumulative exposures of <0.5 ppm-year was 1.3,

while the SMR for those with >5.5 ppm-year was 1.7. The risk of lung cancer did not increase with the

time from last exposure; however, the risk did increase based upon the year of entry into the industry. 

Among the >20-year latency group, those beginning employment prior to 1958 had a greater risk of

cancer than did those beginning work in 1958 or later (SMR=1.4). Those exposed to formaldehyde at or

after the age of 35 were more likely to have lung cancer than those exposed prior to age 35 (SMR=1.3). 

The interaction of formaldehyde with other noxious substances was investigated and the results suggested

that those exposed to formaldehyde were not at risk of cancer unless exposed to another substance. The

authors concluded that no clear exposure-response trends could be identified from the data. Strengths and

weaknesses of this study were basically the same as those described in the Blair et al. (1986) study.

Data from the Blair et al. (1986) study were reanalyzed by Sterling and Weinkam (1989, 1995) to 

account for the healthy worker effect. The cohort was composed of all workers employed in 10 selected 
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plants. For lung cancer mortalities, mortality risk increased with cumulative exposure, approaching

statistical significance in all workers with cumulative exposures of >2 ppm-years. The authors concluded

that, when comparing workers with high formaldehyde exposures to those with little or no exposure, there

is an increased risk of lung cancer associated with exposure to formaldehyde.

Harrington and Shannon (1975) examined a population of 2,079 British pathologists and 12,944 medical

laboratory technicians or pathologists between January 1, 1955 and December 31, 1973. During that

period, 154 technologists and 156 pathologists died, and copies of all death entries were obtained. The

SMR was 60 for pathologists and 67 for medical technologists. Excess deaths from lymphatic and

hematopoietic neoplasms were noted in male pathologists (observed 8, expected 3.3, p<0.01). No other

neoplastic diseases were noted as causing excess mortality in either occupational group. It should be

noted that the study group was too small for any firm conclusions to be drawn about the carcinogenicity

of formaldehyde exposure in humans. No records were available and no adjustment was made for

smoking or other possible confounding factors.

Levine et al. (1984a) studied the mortality patterns of 1,477 male undertakers licensed from 1928 to 1957

(dose not specified). The numbers of deaths due to malignant neoplasms (SMR=0.87) and specific

cancers (SMR=0.52–1.24) were not significantly elevated. Mortality due to nonmalignant diseases was

slightly elevated, but could not be clearly related to the inhalation of formaldehyde. Strengths of this

study include the following: a cohort design with a high rate of success for ascertaining vital status (96%),

death certificates obtained for most decedents, and underlying cause of death coded by a trained

nosologist. Several apparent weaknesses should be noted, including the sample size, which was small for

detecting rare outcomes of disease. Exposure levels to formaldehyde were low, and the undertakers did

not necessarily engage in embalming work, so the exposures may have been too low to cause mortality

excesses. Death certificate data are often inaccurate, so some cancers of interest could have been missed. 

Exposure began in the late 1920s, but the 40 deaths that occurred before 1950 (13% of all deaths) were

excluded from the analysis. These earlier decedents could have had higher exposure levels than those

who were still alive in 1950, so a potentially important source of information was unavailable due to data

constraints for the reference population.

Harrington and Oakes (1984) established a population of 2,307 men and 413 women to study the

incidence of cancer induction due to formaldehyde exposure in humans. During the study period, 126 of

these pathologists died; death certificates were obtained for 121 of them. Observed and expected deaths 
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from all causes and from certain specific causes were reported as well as the corresponding SMR for

observed deaths as a percentage of expected deaths. Excess deaths from brain tumors were found

(observed 6, expected <2, p<0.02), but no nasal cancers were found. Strengths of this study included the

use of a cohort design and a very low rate of follow up loss (0.6% for pathologists and 1.5% for medical

laboratory technicians). The study also achieved some adjustment for possible confounding effects of

socioeconomic status for one of the analyses by comparing the study cohort mortality experience with

that of other medical groups, although that analysis could only examine broad categories of death. 

Weaknesses of this study included the fact that specific exposures or their possible levels were not

identified for the two cohorts (there is no mention of formaldehyde exposure). The follow up period

(19 years maximum for pathologists and only 11 years for the technicians) was somewhat short, but it is

unclear whether exposures may have occurred before the beginning of the follow up period. Moreover,

the modest number of pathologists (n=2,079) results in low statistical power for detecting any excesses of

rare outcomes. It was also noted that for the primary analysis, there presumably were substantial

socioeconomic differences between the cohort members and the reference population, so confounding

could have occurred. Because the SMR is an indirectly standardized measure (i.e., it uses internal

weights), the comparison of SMRs across occupational groups was considered to be inappropriate.

Walrath and Fraumeni (1984) performed a proportionate mortality study of 1,007 white male embalmers

in California from 1916 to 1978 who were known to have died between 1925 and 1980. Total cancer

mortality was significantly elevated, with PMR of 1.21. Deaths from cancers of the brain and the nervous

system (PMR=1.94), colon (PMR=1.87), prostate (PMR=1.75), and leukemia (PMR=1.75) were

significantly higher than expected. The reported types of brain cancer were for glioblastoma (2),

astrocytoma (3), adenocarcinoma (1), and unspecified cancers (3). No increase in mortality for cancers of

the respiratory tract, including the nasal passages was noted in this study. A parallel mortality study of

embalmers from New York State (Walrath and Fraumeni 1983) showed similar findings with significant

excess of deaths from cancers of the brain and nervous system (PMR=1.56), colon (PMR=1.43), ischemic

heart disease (PMR=1.12), and nonsignificant excess of cirrhosis of the liver (PMR=1.33), and leukemia

(PMR=1.40). PMRs were significantly elevated for cancers of the skin, kidney, and brain among those

who were licensed only as embalmers. Even with these findings, the authors suggested that a more

thorough investigation was needed to quantify the risks of cancer and other chronic diseases in relation 

to formaldehyde exposure. Strengths and weaknesses for both of these studies are similar. Strengths

included the fact that formaldehyde was probably the primary chemical exposure for this PMR 

analysis of embalmers, although embalming fluid does include smaller amounts of other chemicals 
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(methanol, diethylene glycol, propylene glycol, phenol, benzoic acid, fragrances, etc.). Exposure

durations and follow up periods were probably long enough for the study to detect any cancer excesses

associated with formaldehyde exposure, although details about individual decedents were unavailable. 

For the final analysis, death certificates were available for a large percentage (92%) of the identified

decedents. A trained nosologist coded the underlying cause of death for all death certificate using the

coding rules in effect at the time of each death. Therefore, the assignment of the cause of death should

have been comparable to that used for standard (comparison) population. The analysis controlled for

potential confounding effects from age, race, sex, and calendar year. Several weaknesses of this study

were also noted. In general, PMR studies have a relatively weak design compared to other types of

studies. The analysis included only those deaths reported to the Bureau of Funeral Directing and

Embalming, and the completeness of this reporting is not known. The authors indicate that deaths at ages

>65 years were substantially under reported. Consequently, the causes of death in the analysis could have

differed systematically from the causes found in the total population of deceased embalmers (e.g., for

chronic conditions that led to death at older ages). The total U.S. population was used as the external

comparison population, even though rates from New York state would probably be stable enough to

provide expected values. Possible regional differences in cancer incidence (rather than occupational

exposures) could have affected the observed pattern of mortality excesses and deficits. Study weaknesses

included that cancer deaths are often reported inaccurately on death certificates. Exposure levels for

formaldehyde were unknown, no analyses that combine the white and black decedents (with appropriate

adjustment) were presented, even though there were similarities in the pattern of excess deaths. A

combined analysis presumably would have greater statistical power. Lastly, the expected number of

deaths for nasal cancer, an end point of particular interest, was only 0.7, so the study had low statistical

power to detect an excess of this cancer.

Stroup et al. (1986) evaluated the risk of death due to cancers and other causes in 2,317 anatomists in a

retrospective cohort study. Of the 2,317 in the study population, 33% (n=738) were known to have died. 

SMRs for deaths due to various cancers in anatomists was variable; the only condition with a significantly

elevated SMR (SMR=2.7, p<2.25) was brain cancer. All of the anatomists that died of brain cancer were

in either gross anatomy, microanatomy, or a combination of the two, indicating relatively high exposures

to formaldehyde. The authors concluded that there was a substantial risk of brain cancer among

anatomists, but since these anatomists were also exposed to a large number of biological stains and

solvents, in addition to formalin and formaldehyde, the etiologic agent responsible for these results 

was not certain. This study has several strengths and weaknesses. The study of the anatomists used a 
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classic retrospective cohort design with a well defined denominator; follow up was at least 10 years for all

cohort members. Follow up and death certificate acquisition was good and a trained nosologist coded the

underlying cause of death for all cohort members. In addition to using national disease rates for the SMR

analysis, the authors also used mortality rates from a cohort of psychiatrists, who presumably have similar

demographic and socioeconomic characteristics compared with the anatomists. Subgroups of anatomists

were studied in an attempt to separate possible effects of formaldehyde from those of other occupational

chemical exposures. Among the study weaknesses was the fact that exposure levels for formaldehyde

were unknown and occupational exposures to chemicals other than formaldehyde (or to viruses) could

have been responsible for the observed cancer excesses. Diagnoses from death certificates are unreliable,

but the use of the psychiatrist comparison group helps eliminate the possibility of differential disease

misclassification (i.e., detection bias). The low expected number of deaths (0.5) for cancer of the nasal

cavity and sinus indicates that the study had low statistical power for detecting an excess of nasal cancer. 

Stayner et al. (1985a, 1985b, 1988) evaluated the carcinogenicity of formaldehyde in garment workers by

performing a proportionate mortality study of 256 deaths reported from three shirt-manufacturing plants. 

All three plants had processed formaldehyde-treated fabrics since 1958 and the duration of employment

for the study group averaged 9.4 years. Air monitoring in two of the plants revealed that virtually all

employees were exposed to 0.1–1 ppm formaldehyde. Statistically significant excesses in mortality were

detected for cancers of the buccal cavity (PMR=7.50), biliary passages and liver (PMR=3.13), and other

lymphatic and hematopoietic sites (PMR=4.00). The number of deaths in each organ category was low;

hence, the degree of confidence in PMRs and in the conclusion that cancers are associated with

formaldehyde exposure must also be low. Stayner concluded that, based upon factors such as the long

latency period and lack of exposure to other known carcinogens, the excesses in mortality in garment

workers due to cancers of the buccal cavity, biliary passages and liver, and other lymphatic and

hematopoietic sites were likely associated with formaldehyde exposure. There was no attempt to adjust

the cancer rate for smoking or other confounding factors, and no air sampling records were evaluated. 

Later, Stayner et al. (1988) examined the relationship between formaldehyde exposure and the

development of upper respiratory cancers in garment factory workers. A total of 2,008 men and

9,022 women from three garment factories had a formaldehyde concentration exposure geometric mean

value of 0.15 ppm (range 0.14–0.17 ppm). Across all workers, mortality from all causes was less than

expected, as was mortality from all malignant neoplasms. However, significantly (p<0.05) greater than

expected mortalities were detected for the buccal cavity (SMR=3.43) and connective tissue (SMR=3.64). 
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Nonsignificant elevations were also noted for the trachea/bronchus/lung (SMR=1.14), pharynx

(SMR=1.13), bladder (SMR=1.12), leukemia and aleukemia (SMR=1.14), and other lymphopoietic

neoplasms (SMR=1.70). When stratified by sex and race, white females had significant excesses of

buccal cavity cancer (SMR=4.85). When stratified by latency period, cancers of the buccal cavity

(SMR=7.05) and leukemia (SMR=3.10) were significantly elevated for workers with latencies of 20 years

or more, while cancers of the trachea/bronchus/lung (SMR=1.71) were significantly elevated among

workers with latencies of >10 years. When stratified by duration of exposure, mortalities due to cancers

of the buccal cavity (SMR=7.57) and other lymphopoietic neoplasms (SMR=3.81) were significantly

elevated for workers with exposure durations of 10 years or more, while mortalities due to connective

tissue cancers were significantly elevated in workers exposed for 4–9 years (SMR=6.19). Mortalities due

to cancer of the trachea/bronchus/lung appeared to be inversely related to duration of exposure. In their

discussion, the authors stressed that, while no excesses in nasal cancer were seen, the power of the study

was too low to detect an effect for this rare cancer. Also, the authors noted that the patterns seen in

trachea/bronchus/lung cancers (most prevalent in short duration/latency groups) were inconsistent with

normal dose-response patterns; this was also attributed to a lack of statistical power. A strength of this

study is that the cohort study design is more powerful than the PMR design used in the earlier study

(Stayner et al. 1985a, 1985b) that included some of the same workers. As in the earlier study,

confounding factors from other occupational exposures were unlikely. Vital status was ascertained for a

very high proportion of the cohort members (96%). The authors also used various sources to verify the

employment histories and vital status of the workers and the analyses of mortality by duration of exposure

add credibility to the observed cancer excesses (i.e., the risk was positively associated with duration of

exposure). Some of the weaknesses were the same as in the authors’ earlier PMR study: exposures that

may have been too low to cause a detectable increased risk of mortality and historical exposures that may

have been higher, but with unknown levels. Because of the small study population, the study had only

modest statistical power to detect possible excesses of rare outcomes. Death certificate data are often

inaccurate, so some cancers of interest could have been missed. The authors attempted to rule out

possible nonoccupational confounding factors with mixed results. For example, at least two of the four

who died from buccal cancer had a history of tobacco use (one had used snuff, a fairly strong risk factor

for buccal cancer). The authors concluded that the results of the study should be viewed with caution,

due to limited statistical power and latency periods and the possibility of other confounding factors.
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Bertazzi et al. (1986) attempted to correlate occupational exposure to formaldehyde with cancer rates in

male resin workers using SMR analysis. Based on job descriptions, workers were divided into three

groups: "exposed to formaldehyde", "exposed to other chemicals", or "exposure unknown". An analysis

of the death rates revealed a significantly (p<0.05) elevated rate of deaths from all cancers when

compared to the national rates (SMR=1.54); however, significance declined when the cohort was

compared to the local population trends (SMR=1.06). Among individual cancer types, significantly

elevated SMRs were detected for lung cancer against the national and local trends (SMRs=2.36 and 1.86,

respectively). Deaths from hematologic neoplasms were elevated (SMRs=1.54 and 2.01), but not

significantly. When the cohort was divided by chemical exposure, the group exposed to formaldehyde

tended to have elevated SMR values; however, the trends were not significant. The authors concluded

that, in addition to the significantly elevated lung cancer mortality rate among all workers, the mortality

rates among formaldehyde-exposed workers for all cancers, and cancers of the alimentary tract, lung and

blood system were noteworthy, although nonsignificant. Study strengths included a cohort design with

high rate of follow up (98.6%); formaldehyde exposure levels that were apparently high (although not

well characterized); and past exposures that were not measured but were presumably higher. It appears

that most workers with formaldehyde exposure had not been exposed to other chemicals in the plant

(although this point was not made completely clear by the authors). Subanalyses looked at SMRs with

regard to duration of employment and by formaldehyde exposure status. Some apparent weaknesses of

this study were that the cohort was too small (1,332 persons) to detect increases in rare diseases and that

the follow up period after formaldehyde exposure was somewhat short (as noted by the authors), so that

exposure-related cancers with long latency periods might not have had time to appear during the course of

this study. Environmental measurement data were very sparse and detailed work history records were

unavailable for most cohort members, so “reconstructions” were obtained through interviews of past

workers and others (few details were provided). No exposure levels were provided for 18% of workers. 

Data for individuals with regard to potential confounding variables were unavailable, and no information

was provided on the assignment of the cause of death codes used in the SMR analyses. 

Gardner et al. (1993) assessed the risk of disease and cancers among British male chemical workers

exposed to formaldehyde. The cohort for the study consisted of 7,660 men who began employment prior

to 1965 and 6,357 men who began employment after 1964. Formaldehyde exposure ranged from

<0.1 to >2 ppm. There was one death from nasal cancer and no deaths from nasopharyngeal cancer, nor

were any nonfatal cases of nasopharyngeal reported. Among lung cancer cases, there was no association

of cancer with formaldehyde exposure. Among men classified as exposed to the higher end of possible 
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exposure levels of formaldehyde, there was no indication of a relationship between cancer and duration of

employment, and no association between cancer and cumulative dose. In those employed prior to 1965,

there was a significant excess of lung cancer, with the authors stating that the increase was probably due

to smoking and other environmental pollution. This appears to be related to one factory in which more

men were exposed to high levels of formaldehyde. The determination of exposure levels in this study

was crude and the information on co-exposure to other chemicals was not analyzed. The possibility of

dermal exposure cannot be ruled out in many of these workers. Strengths of this study included the

cohort design, with careful checks of member eligibility and systematic assignment of estimated exposure

levels. SMR analyses use disease rates from local populations to help avoid potential biases due to

regional differences in disease rates and the long follow up period allows time for the manifestation of

any exposure-related cancers. Weaknesses of this study included the observation that no actual

measurements of formaldehyde exposure levels occurred, but the investigators did undertake a detailed

estimation procedure for classifying expected exposure levels. There were also potential confounding

factors from other occupational exposures. In addition, the procedure for assigning the underlying cause

of death for cohort members was not explicitly described, and comparisons of the SMRs across different

exposure categories is inappropriate for this indirectly adjusted measure. The authors presumably could

have used a regression modeling approach to explore possible dose-response associations without the

need for an external referent population. A pronounced “healthy worker effect” is typically expected in

this type of cohort study for all-causes mortality, but only one of the six factory populations showed an

SMR <0.95, even for workers who were hired relatively recently. The authors may have overlooked this

indirect evidence of a health hazard in the factories.

Andjelkovich et al. (1990) examined mortality in a cohort of 8,147 foundry workers who worked in an

automobile manufacturing plant for at least 6 months between 1950 and 1979. For the observation period

of 1950 through 1984, a significant excess was found for lung cancer mortality, but most of the excess of

lung cancer deaths was accounted for by smoking habits. In a subsequent nested case control study of

this cohort that examined risk factors for 220 cases of lung cancer mortality that occurred between 1950

and 1989 compared with 2,200 age- and race-matched controls without lung cancer, cigarette smoking

was a strong predictor of lung cancer mortality, but exposure to formaldehyde was not significantly

associated with lung cancer (Andjelkovich et al. 1994b). In a final phase of these studies, 

Andjelkovich et al. (1995a) studied the mortality experience (for the period between 1960 and 1989) 

of a subset of 3,929 members of the cohort who were exposed to formaldehyde in the foundry during 

the period of January 1960 through 1987, and compared it to the experience of a referent, nonexposed 
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population of 2,032 men who worked at the foundry, but not in formaldehyde-exposed jobs. The

year 1960 was chosen as the starting point of the study because it was the year that formaldehyde was

introduced into the operations used in the foundry. Exposure to formaldehyde was assessed via work

histories and was ranked as high, medium, low, or none (but exposure concentration ranges were not

reported). In the exposed group, elevated SMRs (calculated using national rates for comparison) were

found for deaths from several cancer types, but the elevation was not statistically significant for any

cancer type. Cancer types with elevated SMRs were (with SMRs noted in parentheses): buccal cavity and

pharynx (1.31); stomach (1.64); rectum (1.17); trachea, bronchus, and lung (1.20); and urinary organs

(1.13). Similar SMRs were found for the nonexposed control group. Because of the findings from

animal studies of formaldehyde-induced nasal tumors, special attention was given to malignant and nonmalignant diseases of the respiratory system (cancers of the buccal cavity and pharynx, larynx, or trachea,

bronchus, and lung, and emphysema), but comparison of the cause-specific mortality between the

exposed and nonexposed groups showed no statistically significant difference, except for a significantly

elevated SMR for emphysema in the nonexposed group. 

Strengths of the Andjelkovich et al. (1990, 1994b, 1995a) studies included the nested case-control design,

which provided a high degree of efficiency while ensuring that the controls were selected from the same

population that gave rise to the cases. Incidence density sampling of controls leads to an unbiased

estimate of the mortality rate ratio. The use of conditional logistic regression analysis enabled appropriate

adjustments for covariates and attempts to control for effects of cigarette smoking appeared to be fairly

successful, although the response rate for collecting the smoking information was less than ideal (about

70%). In addition, the follow up duration was long enough for exposure-related lung cancer excesses to

appear, and the data analysis allowed for “latency” periods of different duration. Industrial hygienists

estimated the exposure levels for formaldehyde as well as for silica, a potential confounder of the

formaldehyde-cancer association. There was no opportunity for “recall bias” (except for the smoking

information, which was collected from cohort members or their families). Study weaknesses were related

to lung cancer information, which came almost exclusively from death certificates, which can be

inaccurate. Tumor histology information was unavailable. It seemed apparent that no actual

measurements of formaldehyde exposure levels were available, although some silica measurements were

available. The study authors point out that a only a modest proportion of the cohort was exposed to

formaldehyde, so the statistical power of the study was somewhat low. However, the estimated odds

ratios indicate a lack of association that would presumably be unaffected by an increase in the study’s

sample size. 
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Selected Case-Control Studies. Luce et al. (1993b) attempted to determine whether occupational

exposure to formaldehyde was associated with an increased risk of sinonasal cancer in humans. Case

subjects were patients with primary malignancies of the nasal and paranasal sinuses. Odds ratios for

squamous cell carcinomas in formaldehyde-exposed workers, when adjusted for wood dust and glue

exposure, were not significantly elevated. The odds ratio for adenocarcinomas was confounded by the

frequent co-exposure to wood dust, a known carcinogen. However, in those exposed to wood dust, an

increased odds ratio was noted in those also exposed to formaldehyde. The authors concluded that the

data did not support an increased risk of nasal cancers due to formaldehyde alone. 

Partanen et al. (1985), in a case-referent study, attempted to determine whether respiratory cancer was

associated with formaldehyde exposure in woodworkers. Anatomic sites classified as “respiratory

cancers” included the tongue, mouth, pharynx, nose, sinuses, larynx, epiglottis, lung, trachea, and “other”. 

Fifty-seven male production workers diagnosed with respiratory cancers were selected, with the average

level of formaldehyde exposure being 1 ppm and the average duration of exposure being 10 years. The

odds ratios for respiratory cancers due to formaldehyde, adjusted for latency periods, peak exposures, or

co-exposures, were statistically significant. The authors concluded that a positive relationship between

respiratory cancers and formaldehyde exposure could not be substantiated, because 87% of the workers

exposed to formaldehyde were also exposed to wood dust, a known nasal carcinogen. The strengths of

this study were that cases and controls were sampled from a large cohort, so the population at risk is well

defined. Exposure status was determined from a review of work histories (blinded with regard to disease

status), so recall bias was avoided. Some air measurements were available for assessing exposure levels. 

The investigators used a fairly elaborate exposure matrix approach to classify cases and controls with

regard to exposure status, and at least some control for potential confounding effects from other

occupational exposures and cigarette smoking was possible. Study weaknesses included the notation that

the cohort was too small for studying nasal cancer; there were no reported cases, and the expected number

of cases in the total cohort was <1. In addition, smoking information was missing for a large proportion

of cases and controls, and there was high correlation between formaldehyde and wood dust exposures, so

it was difficult to separate their respective effects. The breaking of the matched case-control pairs in the

analysis can lead to inflation of the odds ratio even if the analysis stratifies by levels of the matching

variables.

In a later study, Partanen et al. (1990) performed a retrospective study that attempted to determine the

association of respiratory cancer (136 cases, 408 controls) with formaldehyde exposure; this case control 
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study was nested in a total cohort of 7,307 woodworkers having had a minimum level of 0.1 ppm and a

minimum cumulative exposure of 3 ppm months to formaldehyde. The odds ratio for respiratory cancers

in exposed versus unexposed workers, when corrected for vital status, smoking, and a latency period of

10 years, was not statistically significant. The strengths were that the study population was an expansion

of that used in the authors' earlier study (Partanen et al. 1985). Additional industries were added and the

follow up period was extended, so the number of workers with respiratory cancers was considerably

larger. The strengths and weaknesses were essentially the same as those in the earlier study. However,

there were improvements over the initial study. First, the study’s statistical power was greater due to the

larger sample size. Second, the authors conducted a more proper analysis by using conditional logistic

regression modeling that preserved the matched sets of cases and controls (the earlier analysis broke the

matched sets). Lastly, the authors presented some separate analyses for lung cancer cases and upper

respiratory cancer cases, so that more homogeneous groups of respiratory cancers that might have

different etiologies were analyzed separately.

In a study by Roush et al. (1987), the potential for mortality from nasopharyngeal cancer and sinonasal

cancer associated with occupational exposure to formaldehyde was investigated. Cases of

nasopharyngeal and sinonasal cancer were identified through the Connecticut Tumor Registry; the list

was restricted to males with these cancers who died in Connecticut during the period 1935–1975. 

Controls were obtained from men dying in Connecticut during the same time period. Information on the

death certificate was used to search for information on the subjects' work history. The work history

information was used by an industrial hygienist to classify each subject into formaldehyde exposure

categories based on likelihood and level of exposure. For those with probable exposure at some point at

least 20 years before death, the odds ratio for nasopharyngeal cancer was 2.3. The odds ratio increased to

4 in the same group when narrowed to those dying at the age of $68. When frequencies of cancers were

analyzed by occupation, the odds ratio for developing either cancer in the rubber industry was elevated

(2.2), but not significantly. All four printers developed cancer. The authors concluded that there is an

increased risk of nasopharyngeal cancer associated with probable exposure to formaldehyde; further, they

concluded that the association is latency- and age-dependent. The authors suggest that the cause of

sinonasal cancer in printers may be due to the presence of mineral oil mist, which has previously been

associated with sinonasal cancer in the metals industry. Strengths of this study included a fairly large

number of cases and a clinical review of medical records conducted for 75% of cases to confirm the

diagnosis. Weaknesses included the fact that all cases and controls were deceased, and the possibility 

that risk factors for nasopharyngeal or sinonasal cancer that also increase the risk of death from other 
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causes (e.g., cigarette smoking) could be over represented in the control groups (a conservative bias

would disguise exposure-disease associations for nasal cancer). Occupational information was

ascertained from death certificates and city directories, so substantial exposure misclassification was

likely. Information about possible occupational or nonoccupational confounders was lacking, as persons

with formaldehyde exposures may also have had other carcinogenic exposures. The low prevalence of

substantial formaldehyde exposures among study participants leads to low statistical power for detecting

exposure-disease associations. This study is also limited because it was dependent on indirect

information in creating the exposure index, nonoccupational exposures to formaldehyde were not

addressed, and exposure to other potentially causal agents was not addressed.

Hayes et al. (1986) attempted to determine the environmental factors associated with nasal cancers in

males from the Netherlands. A total of 91 case and 195 control subjects were included in the study. 

Patients or, if already deceased, close relatives completed interviews concerning work, smoking, and

drinking histories. Based on these interviews, subjects were classified based on probability and level of

formaldehyde exposure. The relative risk (measured as the odds ratio) of adenocarcinomas of the nasal

cavity and sinuses was elevated (11.3) for those working in the wood and paper industries; the relative

risk for all other cancers was not elevated. The relative risk for squamous cell carcinomas associated with

formaldehyde exposure was significantly elevated (p<0.05) when the data were adjusted for wood dust

exposure. Adjustments for smoking did not perceptibly change the relative risk. The authors concluded

that formaldehyde may be a human carcinogen, but conceded that the study’s limitations (questionable

exposure conditions) prevented conclusive statements. Although the authors describe this case-control

study as having low statistical power, they included a substantial number of persons with nasal cancer

(n=116) given the rarity of this tumor. The study included incident (rather than prevalent) cases. Tumor

histology information was available and trained industrial hygienists, who were unaware of each

participant’s case/control status, estimated the potential for formaldehyde and wood dust exposure for

each reported job. The study collected fairly extensive information about exposures and potential

confounders. Regarding study weaknesses, no actual exposure measurements were available for cases or

controls. The disagreements between the two industrial hygienists demonstrate the inherent inaccuracy 

of the exposure assessment (the exposure misclassification presumably caused a conservative bias). 

Because the study relied on interview data for assessing exposures, possible “recall bias” could have 

led to over reporting of exposures by cases (or their next-of-kin) compared to controls. Although

industrial hygienists estimated the potential for formaldehyde exposure based on reported jobs, the cases

compared to controls may have been more likely to remember and report jobs that involved chemical 
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exposure. In addition, next-of-kin interviews were necessary for a substantial number of cases. Response

rates were fairly low (64%) for next-of-kin interviews for cases as well as controls, and those who chose

to participate (especially among families of deceased cases) compared to nonparticipants may have been

those who tended to be aware of jobs held by the decedent that involved chemical exposures.

Hansen and Olsen (1995) investigated the risk of cancer due to occupational exposure to formaldehyde in

Danish male workers. A total of 126,347 men born between 1897 and 1964 and diagnosed with cancer

during the period of 1970–1984 were identified from the Danish Cancer Registry. The risk of cancer at a

specific site was estimated from the standardized proportionate incidence ratio (SPIR), which was the

proportion of cases of a specific cancer among workers from formaldehyde-associated industries versus

the number of cases of the same cancer among all Danish workers. Of the 91,182 subjects with a full

employment history, 2,041 had their longest length of employment at least 10 years prior to their cancer

diagnosis. Among these 2,041 subjects, there were significant increases in the relative risk of cancers of

the sinonasal cavity (SPIR=2.3), kidney (SPIR=1.3), and colon (SPIR=1.2). When analyzed by intensity

of formaldehyde exposure and co-exposure to wood dust, there was a significant elevation in sinonasal

cancers among workers exposed to formaldehyde and wood dust (SPIR=5.0) and workers moderately

exposed to formaldehyde and probably not exposed to wood dust (SPIR=3.0). Workers with a low

exposure to formaldehyde had a SPIR close to unity. The authors concluded that the increased incidences

of kidney and colon cancers were biologically irrelevant due to the rapid metabolism of formaldehyde. 

Strengths of this study included the observation that this population-based proportionate morbidity ratio

study used the entire adult white male population of Denmark as the population at risk. The

determination of exposure status required at least a 10-year interval between first potential exposure to

formaldehyde and the diagnosis of cancer (although a longer interval may have been more appropriate)

and, because the study used cancer incidence (rather than mortality) based on cancer registry records,

disease misclassification was probably low. Several weaknesses were also noted in this study. First, the

exposure classification was crude and was based on having worked in a company that used or

manufactured at least one kilogram of formaldehyde per worker (no exposure measurements were

available), and it was based solely on the longest job held. Exposure misclassification is therefore likely. 

In the extreme case, some workers classified as “exposed” could have had shorter exposure durations than

some who were classified as unexposed. The study authors point out that the study excludes exposures

that occurred before April 1964, so nondifferential exposure misclassification probably occurred. They

correctly state that any nondifferential misclassification should cause a conservative bias (i.e., the SPIR

would underestimate the true magnitude of the association). In addition, use of the 
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“longest job held” approach for classifying exposure status could lead to confounding if, for example, the

longest job was associated with formaldehyde exposures and other shorter jobs were associated with

wood dust exposure. However, there is no reason to believe that such confounding actually occurred. 

Exposure intensity was based on white collar/blue collar status, which presumably is also a surrogate for

socioeconomic status. Confounding by socioeconomic status (e.g., from nutrition differences) could have

occurred between the lower and higher exposure categories.

Gerin et al. (1989) investigated the cancer risk involved with occupational exposure to <1 ppm

formaldehyde in a study which included 3,726 subjects. From the data collected, the OR between

formaldehyde exposure and each type of cancer was estimated. The only cancer with a slightly elevated

OR was adenocarcinoma of the lung in the long-duration/high-exposure group (OR=2.3). The 95% CI

was 0.9–6 and the authors concluded that this result was compatible with the null hypothesis of no

carcinogenic effects of formaldehyde. Cancer diagnoses were pathologically confirmed and extensive

information was collected about possible nonoccupational confounders. Because, by definition, this casecontrol study sampled on disease rather then exposure status, the study population included persons from

many different jobs and industries where formaldehyde exposure occurred, and the assessment of such

exposures was necessarily limited. Controls were samples from electoral lists; registered voters might

differ from the overall population (and the cases) in some respects (e.g., socioeconomic status), although

the investigators presumably collected data that would allow control of such differences. The very low

prevalence of substantial formaldehyde exposures among study participants leads to low statistical power

for detecting exposure-disease associations. The authors also mention that the probable formaldehyde

exposure levels in the "high" group was a TWA of >1 ppm. They further state that the small number in

this group likely led to imprecise results. The study also analyzed the data after correcting for

confounding factors; these factors (listed above) may play a role in the cancer risk.

Animal Cancer Studies. As discussed previously in Section 2.2.1.2 subsection entitled Chronic

Inhalation Animal Studies, chronic exposure to airborne formaldehyde concentrations ranging from about

6 ppm to 15 ppm induced increased incidences of nasal tumors (squamous cell carcinomas, squamous cell

papillomas, or polyploid adenomas) in three bioassays with Fisher 344 rats (Kamata et al. 1997; Kerns et

al. 1983b; Monticello et al. 1996; Swenberg et al. 1980). Increased incidences of lower respiratory tract

tumors or distant site tumors were not found in these studies, and exposure to concentrations of 2 ppm

and lower induced no malignant nasal tumors. 
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In the earliest chronic inhalation rat bioassay (Kerns et al. 1983b; Swenberg et al. 1980), polyploid

adenomas in the nasal cavity were found in 1/232, 8/236, 6/235, and 5/232 Fisher 344 rats (males and

females were included) exposed 6 hours/day, 5 days/week for 24 months to 0, 2, 5.6, and 14.3 ppm,

respectively. Malignant nasal tumors (predominately squamous cell carcinomas) were found in

0/232 control, 0/236 2-ppm, 2/235 5.6-ppm, and 106/232 14.3-ppm rats (Kerns et al. 1983b). 

Monticello et al. (1996) exposed male Fisher 344 rats to 0, 0.7, 2, 6, 10, or 14 ppm, 6 hours/day,

5 days/week for 24 months. Nasal polypoid adenomas, located in or adjacent to the lateral meatus, were

found in 10-ppm (5/90) and 15-ppm (14/147) rats. No polypoid adenomas were found in the control

group or in the 0.7-, 2-, or 6-ppm groups. Squamous cell carcinomas were found in the nasal cavities of

1/90 6-ppm rats, 20/90 10-ppm rats, and 69/147 15-ppm rats. These tumors also were located

predominately in the anterior lateral meatus. Squamous cell carcinomas were not found in the control,

0.7-, or 2-ppm groups. Buccal squamous cell carcinomas were observed in three 15-ppm rats and one

2-ppm rat. 

Kamata et al. (1997) exposed groups of 32 male Fisher 344 rats to 0, 0.3, 2, or 15 ppm, 6 hours/day,

5 days/week for up to 28 months, and found nasal squamous cell carcinomas only in the 15-ppm group

(13/32 rats). In contrast to the studies by Kerns et al. (1983b) and Monticello et al. (1996), no polyploid

adenomas were found, but squamous cell papillomas were found in 3/32 rats in the 15-ppm group. 

In experiments with male Sprague-Dawley rats, nasal tumors (predominately squamous cell carcinomas)

were observed in 10/100 rats exposed to 14.2 ppm, 6 hours/day, 5 days/week for 588 days, compared

with 0/100 in controls (Albert et al. 1982) and in 60/100 rats exposed to 14.8 ppm for up to 128 weeks,

compared with 0/99 in controls (Sellakumar et al. 1985). No tumors were found in the trachea or lungs in

these studies, and tumors found at extra-respiratory sites were not considered by the investigators to be

exposure-related.

Wistar rats appear to be less carcinogenically responsive than Fisher 344 or Sprague-Dawley rats. 

Woutersen et al. (1989) observed nasal squamous cell carcinomas in only 1/26, 1/28, and 1/26 Wistar rats

exposed to 0.1, 1, or 10 ppm, respectively 6 hours/day, 5 days/week for 28 months compared with 0/26 in

controls; early physical damage to the nasal mucosa (electrocoagulation) increased the carcinogenic

response only with subsequent exposure to 10 ppm (15/58 with 28-month exposure to 10 ppm versus

1/54 in nonexposed Wistar rats with electrocoagulation treatment). In 28 Wistar rats exposed to 10 ppm
FORMALDEHYDE 111

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for 3 months followed by a 25-month observation period, only one had a nasal squamous cell carcinoma

and one had a nasal polypoid adenoma (Woutersen et al. 1989). 

In an earlier experiment by the same laboratory, groups of 44–45 male Wistar rats were exposed to 0, 10,

or 20 ppm, 6 hours/day, 5 days/week for 4, 8, or 13 weeks followed by observation periods as long as

126 weeks (Feron et al. 1988). Nasal tumors were found in 1/45 (polyploid adenoma), 1/43 (polyploid

adenoma), and 4/44 (3 squamous cell carcinomas and 1 polyploid adenoma) 20-ppm rats exposed for 4, 8,

or 13 weeks, respectively, compared with 0/45 in a control group. Two other nasal tumors found in the

10-ppm groups were not considered by Feron et al. (1988) to be induced by formaldehyde exposure. 

These results suggest that if nasal epithelial damage from intermediate exposure is sufficiently severe,

then the risk for nasal tumors in later life may be increased.

Nasal tumors, similar to those observed in rats, were observed in two male B6C3F1 mice exposed to

14.3 ppm, 6 hours/day, 5 days/week for 24 months; no nasal tumors were found in control mice or mice

exposed similarly to 2 or 5.6 ppm (Kerns et al. 1983b). No other neoplastic responses were found at other

sites. In each group in this bioassay, less than 25 of the approximately 120 male mice in each group lived

beyond 18 months. Reduced survival among males was attributed to fighting and infections of the

genitourinary tract associated with group housing. The exact incidence of occurrence of nasal tumors in

the Kerns et al. (1983b) mouse study could not be determined from the published report, but the available

data suggest that mice are less carcinogenically responsive to inhaled formaldehyde than rats.

No nasal tumors or tumors at other respiratory tract sites were found in groups of 50 Golden Syrian

hamsters exposed to either 10 ppm, 6 hours/day, 5 days/week for life or 30 ppm, 6 hours/day, once a

week for life (Dalbey 1982). Hyperplastic and metaplastic areas were seen in the nasal epithelium of 5%

of the hamsters exposed to 10 ppm, but were not seen in controls.

NTP (1998) noted that formaldehyde is reasonably anticipated to be a human carcinogen, and IARC

(1995) determined that formaldehyde is probably carcinogenic to humans (Group 2A) based on specific

evaluations that there is limited evidence in humans for the carcinogenicity of formaldehyde and

sufficient evidence in experimental animals. 
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EPA (1991a; IRIS 1999) classified formaldehyde in Group B1 - probable human carcinogen, based 

on an evaluation of limited human evidence and sufficient laboratory animal evidence. 

EPA (1991a) used dose-response data for nasal tumors in rats exposed to high concentrations of

formaldehyde (from Kerns et al. 1983b) to extrapolate to human cancer risk at low exposure

concentrations, using rates of DNA-protein cross links in target tissue as a measure of delivered dose. 

Relationships between formaldehyde air concentrations and rates of formation of DNA-protein cross links

in nasal epithelial tissue of rats (Casanova et al. 1989) or of Rhesus monkeys (Casanova et al. 1991; Heck

et al. 1989) and adjustments to continuous exposure were used to calculate lifetime human cancer unit

risk estimates of 3.3x10-4 per ppm formaldehyde based on the monkey data, and 2.8x10-3 per ppm

formaldehyde based on the rat data (see Section 2.4.3). 

Using the monkey-based human cancer unit risk estimate, air concentrations associated with cancer risk

levels of 10-4 to 10-7 from lifetime exposure are 0.3 to 3x10-4 ppm, respectively, and are plotted in

Figure 2-1. The CEL values from each reliable study for cancer in each animal species and duration

category are recorded in Table 2-1 and plotted in Figure 2-1.

2.2.2 Oral Exposure

Most of the available reports of controlled studies of health effects from oral exposure to formaldehyde

have not provided information regarding how frequently dosing solutions were analyzed for

formaldehyde content. Some studies reported how frequently formaldehyde solutions were prepared

(e.g., in drinking water studies, Til et al. [1988b, 1989] and Tobe et al. [1989] prepared solutions weekly

and twice weekly, respectively), or how frequently formaldehyde was added to the diet (e.g., Hurni and

Ohder [1973] daily sprayed formaldehyde solutions [that were prepared weekly] on food just prior to

feeding dogs). Other study reports, however, provide no information regarding solution-preparation

frequency, conditions of storage, or analysis of test material for formaldehyde content (e.g., Johannsen et

al. 1986; Soffritti et al. 1989; Takahashi et al. 1986a). Because of this reporting deficiency, and because

formaldehyde solutions are very unstable (due to formaldehyde’s high reactivity and volatility), the reader

should be aware that there is uncertainty associated with oral dose levels reported in this profile. 

Another issue of uncertainty regards the impurity of commercially available aqueous solutions of

formaldehyde (often called formalin) which normally contain approximately 10–15% methanol to 

prevent polymerization. Reports of human poisonings from formalin and animal studies that used

formalin (e.g., Marks et al. 1980; Takahashi et al. 1986a) are included in this profile. Attempts have 
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2. HEALTH EFFECTS

been made, however, to note when formalin was the source of the ingested formaldehyde, so that the

reader will be aware of possible confounding effects from methanol.

Exposure to formaldehyde by the oral route can occur, but exposure is not as common as by the inhalation

route because of the instability of formaldehyde in aqueous solution. Much of the information available

about the effects of formaldehyde after oral exposure in humans comes from case reports of acute

poisoning. Small amounts of formaldehyde can occur in foodstuffs, usually added as a preservative.

2.2.2.1 Death

In humans, death has been associated with acute oral exposure to formaldehyde. Four cases are described

in detail here. Burkhart et al. (1990) describe the case of a 58-year-old man who swallowed 4 ounces of

formalin (517 mg formaldehyde/kg) in a suicide attempt. The man was found unconscious by a coworker about 1 hour after his shift began. In the emergency room, the subject regained consciousness but

was lethargic. Laboratory results indicated significant acidosis. Approximately 3 hours after ingesting

the formalin, the patient complained of abdominal pain and began retching without emesis; he was

admitted for observation and treated with ethanol. The patient's abdominal pains became more severe and

he had difficulty breathing. At 5.5 hours after ingestion, the patient became obtund, and both his

respiratory rate and blood pressure fell significantly; he was intubated and placed on 100% oxygen. 

Shortly thereafter, the patient began to experience seizures; treatment with diazepam and phenytoin was

unproductive, but pancuronium was effective in treating the seizures. Intravenous bicarbonate and

ethanol therapies were begun after the seizures started. The patient was transported for dialysis, but on

arrival, had clinical signs of intravascular coagulopathy. He subsequently sustained a cardiac arrest from

which he could not be revived. At autopsy, the patient’s stomach was hard, white, and leathery; the

esophagus and intestines appeared to be normal. 

A 55-year-old woman and a 34-year-old man ingested, with suicidal intent, an unknown amount of what

was reported to have been formalin (Koppel et al. 1990). The female patient was found in a coma and

admitted to the hospital with shock (systolic blood pressure 50 mm Hg), respiratory insufficiency, and

metabolic acidosis. The male patient, who had a history of alcohol abuse, was also hospitalized with

shock (systolic blood pressure 60 mm Hg), respiratory insufficiency, and metabolic acidosis. Both

patients underwent hemodialysis and hemofiltration treatment. Analysis of the formaldehyde samples 
FORMALDEHYDE 114

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ingested by both patients showed no evidence that these products contained methanol, although it was

expected to have been detected. A chemical-toxicological screening indicated that no drugs other than

formaldehyde had been ingested; neither methanol or ethanol were detected in blood samples. Three

weeks after ingestion of formaldehyde, the female patient died of cardiac failure refractory to

catecholamine therapy. The male patient developed adult respiratory distress syndrome and died 8 weeks

after formaldehyde ingestion with signs of cardiac failure.

Eells et al. (1981) describe the case of a 41-year-old woman who swallowed 120 mL formalin (37%

formaldehyde solution; 624 mg formaldehyde/kg). The woman was brought to the emergency room

within 30 minutes. The patient complained of abdominal pain and subsequently lost consciousness. 

Upon admission, the patient was cyanotic, apneic, and hypotensive. Laboratory results indicated

significant acidosis. The patient was intubated, ventilation was initiated, and gastric lavage was

performed. Intravenous fluid therapy consisting of Ringers solution followed by 5% dextrose,

epinephrine, and sodium bicarbonate was initiated and the patient was transferred to intensive care. The

patient was maintained via endotracheal respiration and dopamine therapy. The patient became anuric

approximately 7.5 hours after admission, and her health continued to deteriorate over the next day; she

died 28 hours after admission. 

Mortality data for acute duration experimental animal studies do not present a consistent picture. Reports

of death in animal studies after acute oral exposure were found (Tobe et al. 1989), although other studies

showed no mortality. For instance, groups of male and female Wistar rats were given formaldehyde at 0,

10, 50, and 300 mg/kg/day in their drinking water (Tobe et al. 1989). Animals given 300 mg/kg/day were

observed to have died as early as 9 days after the start of the treatment. The number and sex of rats that

died were not reported. In a group of 34 pregant mice given gavage doses of 185 mg/kg/day on gestation

days 6–15, 22 died by gestation day 18 (Marks et al. 1980). Marks et al. (1980) noted that the drinking

water contained 0.6–0.75% methanol (60–75 mg/kg/day) which possibly could have contributed to the

lethality. However, Johannsen et al. (1986) reported no mortality after acute-duration exposure of

Sprague-Dawley rats of both sexes to doses #150 mg/kg/day. Similarly, Takahashi et al. (1986a)

observed no mortality after exposure of male Wistar rats to 258 mg/kg/day of formaldehyde (as formalin)

for acute duration. 

Intermediate-duration exposure of animals to orally administered formaldehyde resulted in a more

consistent picture of mortality. Vargova et al. (1993) observed no treatment-related mortality in male 
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Wistar rats exposed to doses of formaldehyde by gavage of #80 mg/kg/day for 4 weeks. No deaths were

reported in weanling SPF-bred rats (Cpb WU, Wistar random) that received up to 125 mg/kg/day

formaldehyde in their drinking water for 4 weeks (Til et al. 1988b), in male and female Sprague-Dawley

rats given up to 150 mg/kg/day formaldehyde in drinking water for 90 consecutive days (Johannsen et al.

1986), or in male Wistar rats after administration of 258 mg/kg/day formaldehyde (as formalin) in

drinking water for periods up to 32 weeks (Takahashi et al. 1986a). Mortality rates were calculated for

male and female Wistar rats given 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for

#12 months (Tobe et al. 1989). For the high-dose group, mortality at 3, 6, and 9 months was 10, 15, and

20% for male rats, respectively, and 25, 30, and 30% for female rats, respectively. No mortality was

reported in the low- and mid-dose groups after exposure for periods #9 months (Tobe et al. 1989). 

Four male and 4 female pure-bred Beagle dogs were administered 0, 50, 75, or 100 mg/kg/day

formaldehyde in the diet for 90 consecutive days (Johannsen et al. 1986). No deaths or abnormal

reactions were observed in the treated dogs. 

In chronic-duration animal studies, no dose-related excess mortality was seen in male and female

Sprague-Dawley rats after 104 weeks of exposure to doses #300 mg/kg/day (males) or in SPF-bred rats

exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or 109 mg/kg/day (females) in their

drinking water for 2 years (Til et al. 1989). Deaths were significantly higher than control in males at

15 mg/kg/day in the Til study, but not at 82 mg/kg/day.

Mortality rates were calculated for male and female Wistar rats given 0, 10, 50, or 300 mg/kg/day

formaldehyde in drinking water for up to 24 months (Tobe et al. 1989). For the high-dose group,

mortality at 12, 15, and 18 months was 45, 67, and 67% for male rats, respectively, and 55, 55, and 70%

for female rats respectively (Tobe et al. 1989). All animals in the high-dose group died by 21 (females)

or 24 (males) months. 

The LOAEL values from each reliable study for death in each species and duration category are recorded

in Table 2-4 and plotted in Figure 2-2.


















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2. HEALTH EFFECTS

2.2.2.2 Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each

species and duration category are recorded in Table 2-4 and plotted in Figure 2-2.

Respiratory Effects. Respiratory effects have been observed in humans after ingestion of

formaldehyde. A 55-year-old woman and a 34-year-old man ingested an unknown amount of formalin

with suicidal intent and were admitted to the hospital (Koppel et al. 1990). Respiratory insufficiency was

noted upon admission to the hospital. Both patients died; however, the man developed adult respiratory

distress syndrome prior to death.

Burkhart et al. (1990) describe the case of a 58-year-old man who swallowed 4 ounces (517 mg/kg) of a

formaldehyde solution in a suicide attempt. The man was found unconscious by a co-worker about 1hour

after his shift began. In the emergency room, the subject regained consciousness, but was lethargic. At

5.5 hours after ingestion, the patient became obtund, and his respiratory rate fell significantly; he was

intubated and placed on 100% oxygen. He subsequently sustained a cardiac arrest from which he could

not be revived. 

Eells et al. (1981) described the case of a 41-year-old woman who was brought to the emergency room

30 minutes after ingesting 120 mL of formalin (37% formaldehyde solution; 624 mg/kg). Upon

admission, the patient was cyanotic, apneic, and hypotensive. The patient was intubated and ventilation

was initiated. The patient was maintained via endotracheal respiration and dopamine therapy; she died

28 hours after admission. Other adverse respiratory effects have been noted in other reports of human

ingestion including difficulty breathing and speaking (Freestone and Bentley 1989), increased cough, and

tachypnea after 234 mg/kg formaldehyde (Kochhar et al. 1986).

Intermediate-duration oral exposure data on respiratory effects in experimental animals are limited to

organ weight and/or histopathological results, and are negative. After 90-day exposure to doses of

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no

adverse effects on lung weight or histopathology (Johannsen et al. 1986). Til et al. (1988b) saw no effect

on the histopathology of the nose and pharynx of male and female Wistar rats after 4 weeks of exposure

to 125 mg/kg/day formaldehyde in drinking water. Vargova et al. (1993) saw no adverse effect on the

histopathology of lung tissue of male Wistar rats after 4 weeks of gavage exposure to doses of
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2. HEALTH EFFECTS

formaldehyde of #80 mg/kg/day. No adverse effects on lung weight or histopathology were seen in

Beagle dogs exposed to 100 mg/kg/day of formaldehyde in the diet for 90 days (Johannsen et al. 1986).

Chronic-duration exposure data are similarly limited in scope. Til et al. (1989) saw no adverse effect on

nose and lung tissue or lung weight in male and female Wistar rats exposed to doses #82 mg/kg/day

(male) or 109 mg/kg/day (females) in drinking water for up to 2 years. Tobe et al. (1989) also saw no

effect on lung weight or histopathology from doses of formaldehyde of #300 mg/kg/day in drinking water

administered to male and female Wistar rats for up to 24 months.

Cardiovascular Effects. Shock and cardiac failure have been noted in patients after intentional

ingestion of formaldehyde solution (Koppel et al. 1990). Burkhart et al. (1990) describe the case of a

58-year-old man who swallowed 4 ounces of formalin (517 mg/kg formaldehyde) in a suicide attempt. 

The man was found unconscious by a co-worker about 1hour after his shift began. In the emergency

room, the subject regained consciousness, but was lethargic. At 5.5 hours after ingestion, his blood

pressure fell significantly. He subsequently sustained a cardiac arrest from which he could not be

revived. Other reports of cardiovascular effects in humans after ingestion of formaldehyde include

hypotension after 624 mg/kg formaldehyde (as formalin) (Eells et al. 1981), circulatory collapse

(Freestone and Bentley 1989), and sinus tachycardia after 234 mg/kg formaldehyde (Kochhar et al. 1986).

Intermediate-duration exposure data on cardiovascular effects in experimental animals are limited to

organ weight and/or histopathological results, and are negative. After 90-day exposure to doses of

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no

adverse effects on heart weight or histopathology (Johannsen et al. 1986). No significant effects on the

histopathology of the heart were observed in Wistar rats after 12 months of exposure to up to

300 mg/kg/day in drinking water (Tobe et al. 1989). In addition, 90-day treatment of male and female

Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet found no effect on heart weight or

histopathology (Johannsen et al. 1986). 

Til et al. (1989) saw no adverse effect on heart tissue or organ weight in male and female Wistar rats

exposed to doses #82 mg/kg/day (male) or #109 mg/kg/day (females) in drinking water for up to 2 years. 

Tobe et al. (1989) also saw no effect on heart weight or histopathology of doses of formaldehyde of

#300 mg/kg/day in drinking water administered to male and female Wistar rats for up to 24 months.
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Gastrointestinal Effects. Formaldehyde is corrosive to mucosal tissues. Intentional ingestion of

formaldehyde has been associated with extensive congestion, hemorrhaging, and necrosis of the

gastrointestinal mucosa (Koppel et al. 1990). Burkhart et al. (1990) described the case of a 58-year-old

man who swallowed 4 ounces (517 mg/kg formaldehyde) of formalin in a suicide attempt. 

Approximately 3 hours after ingesting the formalin, the patient complained of abdominal pain and began

retching without emesis; he was admitted for observation and treated with ethanol. The patient’s

abdominal pains became more severe, and he subsequently died from cardiac arrest. At autopsy, the

patient’s stomach was hard, white, and leathery; the esophagus and intestines appeared to be normal. 

Eells et al. (1981) described the case of a 41-year-old woman who was brought to the emergency room

30 minutes after ingesting 120 mL formalin (624 mg/kg formaldehyde). The patient complained of

abdominal pain and subsequently lost consciousness; she died 28 hours after admission. Freestone and

Bentley (1989) describe gastrointestinal effects after presumed gargling with formaldehyde, including

dysphagia due to esophageal mucosal damage. The patient was placed on parenteral feeding to allow

resting of the gut and to improve nutritional status. After several weeks in intensive care, the patient was

taken off of ventilation; after two additional months, the patient was released.

A 26-year-old woman who ingested 234 mg/kg formaldehyde exhibited extensive gastrointestinal damage

(Kochhar et al. 1986). Immediately after ingesting formaldehyde, the patient experienced repeated

vomiting with occasional streaks of blood. Anti-emetics and antacids were prescribed but did not relieve

symptoms. Examination of the oropharynx revealed ulceration and sloughing of the soft palate and

posterior pharyngeal wall. Indirect laryngoscopy revealed ulceration of the epiglottis, pyriform fossae,

and arytenoids. At 96 hours, an upper gastrointestinal endoscopy revealed that the esophageal mucosa

was edematous and ulcerated with patches of black slough along the entire length. Areas of the stomach

were hyperemic, and there was superficial ulceration in the distal body and antrum; the duodenal mucosa

appeared normal. The patient underwent a feeding jejunostomy and made an uneventful recovery. At

4 weeks, a repeat endoscopy revealed a normal esophagus. The stomach appeared normal with the

exception of slight hyperemia and limited distensibility of the antrum. Barium examination revealed

scarring of the antrum and distal portion of the gastric body. At 6 weeks, the patient was asymptomatic.

Intermediate-duration exposure data on gastrointestinal effects in experimental animals are limited to

organ weight and/or histopathological results, but are sufficient to describe a no-effect level for

gastrointestinal effects in rats. After 90-day exposure to doses up to 150 mg/kg/day formaldehyde in 
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2. HEALTH EFFECTS

drinking water, male and female Sprague-Dawley rats showed no adverse effects on the histopathology of

the gastrointestinal mucosa (Johannsen et al. 1986). In contrast, erosions and/or ulcers, associated with

regenerating mucosa, were noted in the limiting ridge of the fundic mucosa in glandular stomach of male

Wistar rats exposed to 0.5% formalin (258 mg/kg/day formaldehyde) in drinking water for 32 weeks

(Takahashi et al. 1986a). Erosions were described as “diffuse deep gastric pits with clearly increased

numbers of mucous neck cells in the fundic mucosa”. Benign papillomas in the forestomach also were

noted in 8 of the 10 exposed rats in this study, compared with none in 40 controls. Increased incidences

of forestomach squamous cell hyperplasia and glandular stomach glandular hyperplasia were observed in

Wistar rats exposed for 12 months to 300 mg/kg/day in drinking water, but not in rats exposed to

50 mg/kg/day (Tobe et al. 1989). Til et al. (1988b) saw thickening of the limiting ridges of the stomach

and hyperkeratosis in the forestomach of male and female Wistar rats after 4 weeks of exposure to

125 mg/kg/day formaldehyde in drinking water. One of the 10 females receiving this dose also exhibited

moderate papillomatous hyperplasia, presumably of the glandular stomach. Focal atrophic inflammation

was also observed in the glandular stomach. No adverse effects of treatment were observed at

25 mg/kg/day formaldehyde in either sex. An intermediate-duration MRL of 0.3 mg/kg/day was derived

from the data of Til et al. (1988b). The MRL of 0.3 mg/kg/day was based on a NOAEL of 25 mg/kg/day

for lack of gastrointestinal effects in rats and calculated as described in the footnote to Table 2-4 and in

Appendix A of this profile.

Vargova et al. (1993) saw no adverse effect on the histopathology of stomach tissue of male Wistar rats

after 4 weeks of gavage exposure to doses of #80 mg/kg/day formaldehyde. In addition, no effect of

90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet

was found on stomach weight or histopathology (Johannsen et al. 1986). 

Til et al. (1989) observed adverse gastrointestinal effects at 82 mg/kg/day formaldehyde in male and

109 mg/kg/day formaldehyde in female Wistar rats exposed in drinking water for up to 2 years. Lesions

were first seen after 53 weeks. These adverse effects included papillomatous hyperplasia with

hyperkeratosis, chronic atrophic gastritis, focal ulceration in the forestomach, and hyperplasia in the

glandular stomach. No adverse gastrointestinal effects were noted in the male rats receiving a dose of

15 mg/kg/day. A chronic-duration oral MRL of 0.2 mg/kg/day was derived from the data of Til et al.

(1989). The MRL of 0.2 mg/kg/day was based on a NOAEL of 15 mg/kg/day for lack of gastrointestinal

effects in male rats and was calculated as described in the footnote to Table 2-4 and in Appendix A of this

profile. 
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2. HEALTH EFFECTS

Tobe et al. (1989) also saw forestomach hyperkeratosis at a drinking-water dose of 50 mg/kg/day and

severe degenerative lesions in the epithelium of the forestomach and glandular stomach at 300 mg/kg/day

in male and female Wistar exposed for up to 24 months. 

Hematological Effects. Some hematological effects have been noted in humans after acute

ingestion, but do not appear to be primary effects in formaldehyde poisoning. Burkhart et al. (1990)

described intravascular coagulopathy in the case of a 58-year-old man who swallowed 4 ounces of

formalin (517 mg/kg formaldehyde) in a suicide attempt. However, Kochhar et al. (1986) indicated that

normal hematology was observed in a 26-year-old female who ingested a formaldehyde dose of

234 mg/kg (Kochhar et al. 1986). Other reports of human ingestion do not indicate adverse effects on the

hematological system (Eells et al. 1981; Freestone and Bentley 1989; Koppel et al. 1990). 

Intermediate-duration exposure data on hematological effects in experimental animals are limited to

routine hematological parameters and are negative. After 90-day exposure to doses of #150 mg/kg/day

formaldehyde in drinking water, male and female Sprague-Dawley rats showed no adverse effects on

hematocrit or hemoglobin (Johannsen et al. 1986). Similarly, Til et al. (1988b) saw no effect on

hemoglobin concentration, packed cell volume, or erythrocyte counts in male and female Wistar rats after

4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. In a companion study, no effect

was seen on hematological variables in male and female rats exposed to doses #82 mg/kg/day (males) or

109 mg/kg/day (females) for #52 weeks (Til et al. 1989). Vargova et al. (1993) saw a statistically

significant increase in the hematocrit of male Wistar rats after 4 weeks of gavage exposure to doses of

40–80 mg/kg/day formaldehyde. At 80 mg/kg/day, erythrocyte count and hemoglobin were statistically

significantly increased, whereas mean corpuscular hemoglobin was significantly depressed compared to

control animals (Vargova et al. 1993). Vargova et al. (1993) reported that the hemotological effects

noted, although statistically significant, were within the background range for Wistar rats, and were

therefore of questionable clinical significance. No effect of 90-day treatment of male and female Beagle

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on hematological parameters

including hematocrit and hemoglobin (Johannsen et al. 1986). 

Til et al. (1989) observed no adverse hematological effects in male and female rats exposed to 82 and

109 mg/kg/day formaldehyde, respectively, in drinking water for up to 2 years. Similarly, Tobe et al.

(1989) observed no exposure-related effects on red blood cell count, hematocrit, or hemoglobin in rats

exposed to drinking water doses up to 300 mg/kg/day for up to 24 months. 
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Musculoskeletal Effects. No reports of musculoskeletal effects in humans after acute-,

intermediate-, or chronic-duration oral exposure to formaldehyde were found in the literature. 

Til et al. (1989) observed no adverse histopathological effects on the skeletal muscle of male and female

rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in drinking water for up to 2 years.

Hepatic Effects. Intentional ingestion of formaldehyde in a suicide attempt has been associated with

hepatomegaly, icterus, and congestion of the hepatic parenchyma (Koppel et al. 1990). Some reports of

human ingestion of formaldehyde include hepatotoxicity and increased liver enzymes (Freestone and

Bentley 1989), although other reports do not indicate hepatic effects (Eells et al. 1981).

Intermediate-duration exposure data on hepatic effects in experimental animals are limited to

measurement of liver weight and histopathology and are mostly negative. After 90-day exposure to doses

of #150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no

adverse effects on liver weight or histopathology (Johannsen et al. 1986). Similarly, Til et al. (1988b)

saw no effect on liver weight or histopathology in male and female Wistar rats after 4 weeks of exposure

to 125 mg/kg/day formaldehyde in drinking water; however, a decrease in plasma protein and albumin

concentration was observed. Vargova et al. (1993) saw an increase in the incidence of hepatocellular

vacuolization in male Wistar rats after 4 weeks of gavage exposure to doses of 80 mg/kg/day

formaldehyde. No effect of 90-day treatment of male and female Beagle dogs with doses of

#100 mg/kg/day formaldehyde in the diet was found on liver weight, histopathology, or activities of

serum enzymes indicative of liver damage (Johannsen et al. 1986). 

Til et al. (1989) observed no adverse effects on organ weight or histopathology of the liver of male and

female rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in drinking water for up to

2 years. Likewise, hepatic weight determinations and histopathology were negative in the study

conducted by Tobe et al. (1989), wherein male and female Wistar rats were exposed to 0, 10, 50, or

300 mg/kg/day formaldehyde in drinking water for up to 24 months. However, serum protein, albumin,

and total cholesterol were all statistically significantly decreased in both sexes at 300 mg/kg/day at

12 months in this study. In exposed rats, serum hepatic enzyme levels (alkaline phosphatase,

glutamate-oxaloacetic transaminase, and glutamic-pyruvic transaminase) were either not different from or

were significantly lower than control values (Tobe et al. 1989). 
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Renal Effects. Renal failure has been associated with acute intentional ingestion of formaldehyde

(Eells et al. 1981; Freestone and Bentley 1989; Koppel et al. 1990). In the case reported by Eells et al.

(1981), the patient, who ingested 624 mg/kg formaldehyde (as formalin), became anuric approximately

7.5 hours after ingestion, and her health continued to deteriorate over the next day; she died 28 hours after

admission. Koppel et al. (1990) also describe renal failure prior to death, occurring soon after ingestion

of an unknown quantity of formaldehyde. However, in the report by Freestone and Bentley (1989),

hypoalbuminemia and renal failure were noted upon admission to the hospital after the patient gargled

with formaldehyde. Dopamine was given until renal function improved. After several weeks in intensive

care, the patient was taken off of ventilation; after two additional months, the patient was released.

Intermediate-duration exposure data on renal effects in experimental animals are limited to kidney weight

measurement and histopathology and are mostly negative. After 90-day exposure to doses of

#150 mg/kg/day formaldehyde in drinking water, male and female Sprague-Dawley rats showed no

adverse effects on kidney weight or histopathology (Johannsen et al. 1986). Similarly, Til et al. (1988b)

saw no effect on kidney histopathology in male Wistar rats after 4 weeks of exposure to 125 mg/kg/day

formaldehyde in drinking water. Vargova et al. (1993) saw no effect on the weight or histopathology of

the kidneys in male Wistar rats after 4 weeks of gavage exposure to doses of 80 mg/kg/day formaldehyde. 

No effect of 90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day

formaldehyde in the diet was found on kidney weight or histopathology (Johannsen et al. 1986). Til et al.

(1989) reported, however, that male and female Wistar rats had increased urine density, decreased urine

volume, and occult blood (males only) after exposure for 27 to 82 weeks to 109 mg/kg/day formaldehyde

in drinking water, respectively.

In a 2-year drinking water study, Til et al. (1989) observed an increase in the incidence of renal papillary

necrosis in male rats exposed to 82 mg/kg/day and an increase in renal papillary necrosis accompanied by

increased relative kidney weight in female rats exposed to 109 mg/kg/day. Kidney weight determinations

and histopathology were negative in the study conducted by Tobe et al. (1989), wherein male and female

Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for up to

24 months, but blood urea nitrogen was increased in the 300-mg/kg/day group at 12 months.
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Endocrine Effects. No reports describing endocrine effects of acute-, intermediate-, or chronicduration oral exposure to formaldehyde in humans or acute-duration oral exposure in animals were found. 

After 90-day exposure to doses of #150 mg/kg/day formaldehyde in drinking water, male and female

Sprague-Dawley rats showed no adverse effects on adrenal or thyroid weight or histopathology

(Johannsen et al. 1986). Similarly, Til et al. (1988b) saw no effect on adrenal and thyroid weight in male

Wistar rats after 4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. Vargova et al.

(1993) saw no effect on the weight of the adrenals or pituitary in male Wistar rats after 4 weeks of gavage

exposure to doses of 80 mg/kg/day formaldehyde. No effect of 90-day treatment of male and female

Beagle dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on adrenal and thyroid

weight or histopathology (Johannsen et al. 1986). 

Til et al. (1989) observed no effect on the weight of the adrenal, pituitary, and thyroid, or histopathology

of the adrenal, pituitary, thyroid, or pancreas in male and female rats exposed to 82 and 109 mg/kg/day

formaldehyde, respectively, in drinking water for up to 2 years. Adrenal, pituitary, and thyroid weight

determinations and histopathology, in addition to histopathology of the pancreas, were not influenced by

exposure in the study conducted by Tobe et al. (1989), wherein male and female Wistar rats were exposed

to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water for up to 24 months.

Dermal Effects. No reports of dermal effects of acute-, intermediate-, or chronic-duration oral

exposure of humans to formaldehyde were found in the literature.

No adverse histopathology was noted in skin samples from male and female Wistar rats receiving

#109 mg/kg/day formaldehyde in drinking water after 2 years of exposure (Til et al. 1989)

Ocular Effects. No reports of ocular effects after acute-, intermediate-, or chronic-duration oral

exposure of humans, or acute- or intermediate-duration oral exposure of animals to formaldehyde were

found in the literature.

Til et al. (1989) observed no effect on the histopathology of the Harderian and exorbital lachrymal glands

and eye of male and female rats exposed to 82 and 109 mg/kg/day formaldehyde, respectively, in

drinking water for up to 2 years. 
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2. HEALTH EFFECTS

Body Weight Effects. No reports of body weight effects in humans after oral exposure to

formaldehyde were located.

Groups of Sprague-Dawley rats (sex not specified) were administered formaldehyde at 0, 37.5, 75, 150,

or 225 mg/kg/day by gavage for 2 weeks (Johannsen et al. 1986). Mean body weight decreased at

concentrations above 75 mg/kg/day. However, another pilot study conducted by Johannsen et al. (1986),

Sprague-Dawley rats given formaldehyde at 0, 75, 150, or 225 mg/kg/day in drinking water for 2 weeks

showed no significant changes in final body weights. Til et al. (1989) noted a decrease in body weight

gain (unspecified) after 1 week of exposure of male Wistar rats to 82 mg/kg/day formaldehyde in

drinking water, with statistically significant decreases in food consumption reported at 82 mg/kg/day for

males and 109 mg/kg/day for females. No effect on body weight was noted until week 24 in female rats

in the same study exposed to a high dose of 109 mg/kg/day. Body weight was not affected in male and

female Wistar rats exposed to formaldehyde in drinking water at doses #125 mg/kg/day for 4 weeks (Til

et al. 1988b). Likewise, Vargova et al. (1993) saw no effect on body weight in male Wistar rats exposed

by gavage 5 days/week for 4 weeks, to doses of #80 mg/kg/day formaldehyde. 

Johannsen et al. (1986) noted that significant decreases in body weights occurred in both sexes of

Sprague-Dawley rats exposed to 150 mg/kg/day in drinking water for 90 days and in males exposed to

100 mg/kg/day, and that these decreases were associated with decreased water, but not food,

consumption. Terminal mean body weights at these dose levels were about 10–15% lower than control

values, whereas at 50 mg/kg/day for both sexes, and at 100 mg/kg/day for female rats, they were within

10% of control body weight values. In contrast, no significant effects on body weights were noted in

male Wistar rats exposed to 0.5% formalin (258 mg/kg/day formaldehyde) in drinking water for 32 weeks

(Takahashi et al. 1986a). Male and female Beagle dogs exposed to 100 mg/kg/day formaldehyde in the

diet for 90 days had significantly reduced body weights, compared with controls, but not at lower

exposure levels of 50 or 75 mg/kg/day (Johannsen et al. 1986). The magnitude of the decreased body

weight was not specified. Significantly reduced food consumption was noted in males, but not in females,

in the 100-mg/kg/day group and in females, but not males, in the 75-mg/kg/day group.

Wistar rats exposed for up to 2 years to estimated daily drinking water doses of 300 mg/kg/day lost

weight during the first 2 weeks of exposure, whereas control rats and rats exposed to up to 50 mg/kg/day

increased their body weights by about 20–30% during the same period (Tobe et al. 1989). Mean body

weights and food and water intakes were markedly decreased in the 300-mg/kg/day rats, compared with 
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2. HEALTH EFFECTS

controls, throughout the study. After 5–10 weeks of exposure, body weights were about 20–30% lower

than controls. Mean terminal body weights were about 40–45% lower than controls. At doses up to

50 mg/kg/day, terminal body weights were within 10% of control body weights throughout the study. 

In another chronic drinking water study, mean body weights were significantly decreased, compared with

controls, in male Wistar rats after 1 week and in female rats after 24 weeks of exposure to doses of 82 and

109 mg/kg/day, respectively (Til et al. 1989). These decreases were associated with decreases in food

and water intake. Terminal body weights were approximately 10–15% lower than controls. Body weights

were within 10% of control values in male and female rats exposed to up to 15 and 21 mg/kg/day,

respectively.

Metabolic Effects. Metabolic effects have been noted in patients after ingestion of formaldehyde. 

Metabolic acidosis, high plasma formic acid, and hyperlactatemia were noted in two patients who

intentionally ingested formaldehyde in suicide attempts (Koppel et al. 1990). Burkhart et al. (1990)

describe the case of a 58-year-old man who swallowed 4 ounces of formalin (517 mg/kg formaldehyde) in

a suicide attempt. The man was found unconscious by a co-worker about 1 hour after his shift began. 

Laboratory results at the emergency room indicated significant acidosis. Intravenous bicarbonate and

ethanol therapies were begun after the seizures started. Eells et al. (1981) described the case of a

41-year-old woman who was brought to the emergency room 30 minutes after ingesting 120 mL of

formalin (624 mg/kg formaldehyde). Laboratory results indicated significant acidosis. Intravenous fluid

therapy consisting of Ringers solution followed by 5% dextrose, epinephrine, and sodium bicarbonate

was initiated and the patient was transferred to intensive care; she died 28 hours after admission. 

No reports were found of metabolic effects in animals orally exposed to formaldehyde.

Other Systemic Effects. Some effects of acute-duration oral exposure to formaldehyde have been

seen on food and water consumption in animal studies, and may be related to taste aversion at higher

doses in some cases. For example, Johannsen et al. (1986) reported that Sprague-Dawley rats given

formaldehyde at 0, 75, 150, or 225 mg/kg/day in drinking water for 2 weeks showed no significant

changes in food consumption, but mean water consumption decreased proportionately to dose in all three

treated groups. In contrast, food and water consumption were reduced at levels above 75 mg/kg/day in

other groups of Sprague-Dawley rats given formaldehyde at 0, 37.5, 75, 150, or 225 mg/kg/day by

intubation for 2 weeks (Johannsen et al. 1986). 
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2. HEALTH EFFECTS

Intermediate-duration exposure data on food and water consumption are also available from animal

studies. In Sprague-Dawley rats exposed to formaldehyde in drinking water for 90 days, decreases in

water intakes (>10% of control values) were found in females exposed to 100 or 150 mg/kg/day and in

males exposed to 50, 100 or 150 mg/kg/day, but in both sexes, food consumption was not significantly

affected (Johannsen et al. 1986). Four-week exposures to 125 mg/kg/day in drinking water were

associated with 25–42% decreased water intake and decreased food intake in male and female Wistar rats

(Til et al. 1988b). Food consumption was significantly decreased in male Beagle dogs during 90 day

dietary exposure to 100 mg/kg/day; food consumption was significantly decreased in females at

75 mg/kg/day(Johannsen et al. 1986).

With chronic drinking water exposure to formaldehyde, statistically significant decreases in food intake

(ranging from about 7–14% of control values) and water intake (ranging from about 20–50% of control

values) occurred at various intervals throughout a 2-year period of exposure to 82 mg/kg/day in male

Wistar rats and to 109 mg/kg/day in female Wistar rats, but not at respective exposure levels #15 and

21 mg/kg/day (Til et al. 1989). In the other 2-year drinking water study by Tobe et al. (1989),

significantly decreased food intake (about 10–25% of control values) and water intake (about 40–50% of

control values) occurred throughout the exposure period in male and female Wistar rats exposed to

300 mg/kg/day, but not at dose levels of 50 mg/kg/day and lower. In general, the repeated oral exposure

animal studies indicate that dosage levels associated with decreased food and/or water consumption were

associated with decreased body weights and with the development of gastrointestinal tract lesions.

2.2.2.3 Immunological and Lymphoreticular Effects

Little information is available about immunological and lymphoreticular effects of formaldehyde

ingestion in humans. Splenomegaly was observed in one woman who ingested formaldehyde in a suicide

attempt (Koppel et al. 1990). However, this effect was most likely secondary to extensive hemorrhaging

and necrosis of the gastrointestinal system.

Til et al. (1988b) saw no effect on spleen or thymus weight in male or female Wistar rats after 4 weeks of

exposure to 125 mg/kg/day formaldehyde in drinking water. 

No effect of 90-day treatment of male and female Beagle dogs with doses of #100 mg/kg/day

formaldehyde in the diet was found on spleen weight or histopathology (Johannsen et al. 1986). 
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2. HEALTH EFFECTS

Vargova et al. (1993) administered 20, 40, or 90 mg/kg/day formaldehyde 5 days/week for 4 weeks to

male Wistar rats by gavage. Increased absolute and relative lymph node weights were observed

beginning at 40 mg/kg/day. Antibody production was assayed by measurement of total blood IgG and

IgM, a hemagglutination assay, a plaque-forming cell assay, and by measurement of IgM production in

spleen cells. Only the hemagglutination assay showed a significant effect; the combined IgG and IgM

titers were significantly lower than controls at 20 mg/kg/day and above, although individual IgM and IgG

titers were only significantly different from controls at 40 and 80 mg/kg/day. 

Weanling, SPF-bred rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or

109 mg/kg/day (females) formaldehyde in their drinking water for up to 2 years (Til et al. 1989). There

was no effect of treatment on spleen weight or histopathology, or the histopathology of the mesenteric

and axillary lymph nodes. Spleen weight determinations and histopathology, in addition to

histopathology of the lymph nodes, were negative in the study conducted by Tobe et al. (1989), wherein

male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in drinking water

for up to 24 months. 

The LOAEL value decreased IgG and IgM titers and increased lymph node weights in rats (Vargova et al.

1993) and the highest NOAEL values from each reliable study for immunological/lymphoreticular effects

in each species and duration category are recorded in Table 2-4 and plotted in Figure 2-2.

2.2.2.4 Neurological Effects

Little information is available about the neurological effects of formaldehyde ingestion in humans. 

However, neurological effects appear to be prevalent in reported cases of formaldehyde ingestion. A

woman who ingested formaldehyde in a suicide attempt was found in a coma (Koppel et al. 1990). Other

neurological effects observed include lethargy, seizure, and loss of consciousness at 517 mg/kg

formaldehyde (Burkhart et al. 1990). Loss of consciousness was also observed in another woman (Eells

et al. 1981) after ingesting 624 mg/kg formaldehyde. 

No effect of 90-day treatment of male and female Sprague-Dawley rats with doses of #150 mg/kg/day

formaldehyde in drinking water was found on brain weight or histopathology (Johannsen et al. 1986). Til

et al. (1988b) saw no effect on brain weight in male or female Wistar rats after 4 weeks of exposure to

125 mg/kg/day formaldehyde in drinking water. Tobe et al. (1989) saw no effect on the weight or 
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2. HEALTH EFFECTS

histopathology of the brain of male and female Wistar rats exposed to doses of #300 mg/kg/day

formaldehyde in drinking water for 12 months. No effect of 90-day treatment of male and female Beagle

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on brain weight or

histopathology (Johannsen et al. 1986). 

Weanling Wistar rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or

109 mg/kg/day (females) in their drinking water for up to 2 years (Til et al. 1989). Relative brain weights

were statistically significantly increased (by 7–17%) in the high-dose groups of both sexes. However, no

effect of treatment on brain histopathology or the histopathology of the spinal cord or sciatic nerve was

observed. Brain weight determinations and histopathology were negative in the study conducted by Tobe

et al. (1989), wherein male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day

formaldehyde in drinking water for up to 24 months.

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in

each species and duration category are recorded in Table 2-4 and plotted in Figure 2-2.

2.2.2.5 Reproductive Effects

No reports were found describing reproductive effects in humans after acute-, intermediate-, or chronicduration oral exposure to formaldehyde.

Male Wistar rats (5 per group) were weighed and fasted for 18 hours overnight (Cassidy et al. 1983). 

Rats were then administered single dosages of 100 and 200 mg/kg formaldehyde orally. Eleven days

after dosing, rats were weighed, sacrificed, and necropsied. There were no significant changes in testes

weights observed in animals treated with 100 or 200 mg/kg formaldehyde. At 200 mg/kg formaldehyde,

testicular sperm head counts were significantly increased (19%) compared to control values. The

percentage of abnormal sperm heads also significantly increased (5%) in the 200 mg/kg dose groups

compared to control groups. The toxicological significance of these changes in sperm head number and

percentage of abnormal sperm heads is not known since no functional tests of reproductive competence

were conducted. 

Pregnant CD-1 mice were given formaldehyde at 0, 74, 148, and 185 mg/kg by gavage on gestation days

6–15 (Marks et al. 1980). The formaldehyde solution given to the animals in this study contained 
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2. HEALTH EFFECTS

12–15% methanol as a preservative. These animals received formaldehyde solution at 185 mg/kg, which

contained 0.6–0.75% methanol, resulting in a concurrent dose of 60–75 mg/kg/day of methanol. On

gestation day 18, the mice were sacrificed, implantation sites were counted, and general condition of each

conceptus were recorded. Formaldehyde at 74 or 148 mg/kg/day had no consistent and statistically

significant effects on indices of reproduction (e.g., the number of resorptions and the number of

implantation sites per dam), but only 12 of the 34 dams who were exposed to 185 mg/kg/day survived to

gestation days 18. Marks et al. (1980) noted that the methanol could have contributed to the lethality. 

Among the 12 surviving 185-mg/kg/day dams, only 8 (67%) remained pregnant at gestation day 18; the

average percent of resorptions per litter was increased in these dams, compared with controls, but not to a

statistically significant extent.

Formaldehyde was evaluated in the Chernoff/Kavlock developmental toxicity screen (Seidenberg and

Becker 1987). Based on range-finding studies, timed-pregnant ICR/SIM mice were administered a single

minimally toxic dose (not reported) by gavage on gestation days 8–12. Three or four compounds and a

vehicle (corn oil or distilled water) were tested concurrently. Dams were allowed to deliver. The litters

were counted and weighed on days 1 and 3. Dead pups were examined for external abnormalities. Dams

that had not given birth by gestation days 21 or 22 were necropsied, and their uteri were examined for

possible implantation sites. Formaldehyde was designated as a nonteratogen or non-embryotoxin based

on results of the developmental toxicity screen.

No adverse effects of 90-day treatment of male and female Sprague-Dawley rats with doses of

#150 mg/kg/day formaldehyde in drinking water were found on gonad weight or histopathology

(Johannsen et al. 1986). Til et al. (1988b) saw no effect on testis weight in male or ovary weight in

female Wistar rats after 4 weeks of exposure to 125 mg/kg/day formaldehyde in drinking water. Tobe et

al. (1989) saw no effect on the weight or histopathology of the testis of male and ovary of female Wistar

rats exposed to doses of #300 mg/kg/day formaldehyde in drinking water for 12 months. Vargova et al.

(1993) saw no effect on testis or prostate weight of exposure to 80 mg/kg/day formaldehyde by gavage

5 days/week for 4 weeks in male Wistar rats. No effect of 90-day treatment of male and female Beagle

dogs with doses of #100 mg/kg/day formaldehyde in the diet was found on gonad weight or

histopathology (Johannsen et al. 1986). 

Weanling Wistar rats were exposed to 0, 1.2, 15, or 82 mg/kg/day (males) and 0, 1.8, 21, or

109 mg/kg/day (females) in their drinking water for up to 2 years (Til et al. 1989). There was no effect of 
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2. HEALTH EFFECTS

treatment on ovary or testis weight or histopathology, or the histopathology of the mammary gland,

epididymides, prostate, or uterus. Testis and ovary weight determinations and histopathology were

negative, as was histopathological evaluation of the uterus in the study conducted by Tobe et al. (1989),

wherein male and female Wistar rats were exposed to 0, 10, 50, or 300 mg/kg/day formaldehyde in

drinking water for up to 24 months.

Hurni and Ohder (1973) investigated the effects of oral administration of formaldehyde on reproductive

function in female beagle dogs during gestation. Formaldehyde was sprayed on the pelleted food at

dietary levels of 125 and 375 ppm (calculated by authors to be equivalent to 3.1 and 9.4 mg/kg,

respectively). Although the feed was not assayed for formaldehyde content, the authors reported that

formaldehyde solutions, prepared weekly from a commercial 40% aqueous solution, were sprayed daily

on the food just prior to feeding. Ten to 11 mated females were fed the treated feed on gestation

days 4–56. Exposure to formaldehyde did not affect pregnancy rates, maternal body weights, or litter

size.

The serious LOAEL value for rats (Cassidy et al. 1983) and the highest NOAEL value from each reliable

study for reproductive effects in each species and duration category are recorded in Table 2-4 and plotted

in Figure 2-2.

2.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans after oral exposure to formaldehyde.

Pregnant CD-1 mice were given formaldehyde at 0, 74, 148, and 185 mg/kg by gavage on gestation days

6–15 (Marks et al. 1980). On gestation day 18, mice were sacrificed, implantation sites were counted,

and general condition of each conceptus was recorded. Live fetuses were weighed individually, sexed

internally, and examined for external malformations. The viscera of at least one-third of the fetuses of

each litter, as well as stunted fetuses and those having external malformations, were examined for

abnormalities. The heads of the fetuses which were subjected to visceral examination were cut off at the

base and prepared for free-hand sectioning. The formaldehyde solution given to the animals in this study

contained 12–15% methanol as a preservative. Formaldehyde solution at 185 mg/kg contained

0.6–0.75% methanol or 60–75 mg/kg/day. No attempt was made to remove the methanol. There were no

statistically significant effects on fetal weight, ratio of males to females, or incidences of visceral or
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2. HEALTH EFFECTS

skeletal fetal malformations in any exposed group, compared with the control group, even though at the

highest dose group, only 12 of 34 dams survived to gestation day 18.

Formaldehyde was evaluated in the Chernoff/Kavlock developmental toxicity screen (Seidenberg and

Becker 1987). Based on range-finding studies, timed-pregnant ICR/SIM mice were administered a single

minimally toxic dose (not reported) by gavage on gestation days 8–12. Dams were allowed to deliver. 

The litters were counted and weighed on days 1 and 3. Dead pups were examined for external

abnormalities. Dams that had not given birth by gestation days 21 or 22 were necropsied, and their uteri

were examined for possible implantation sites. Formaldehyde was designated as a nonteratogen or

nonembryotoxin based on results of the developmental toxicity screen. Neonatal development was not

affected by formaldehyde treatment. Formaldehyde had no effect in the number of live neonates per litter

or on the average neonatal body weight at birth in this investigation. 

No exposure-related effects on pregnancy success, maternal weight gain, gestation length, litter size, pup

body weight, number of stillborn pups, or numbers of live pups that survived to weaning were found in a

study in which groups of 9–10 pregnant Beagle dogs were fed diets delivering reported doses of 0, 3.1, or

9.4 mg/kg/day on gestation days 4–56 (Hurni and Ohder 1973). In the few stillborn pups that were found,

no internal or skeletal malformations were observed. Formaldehyde solutions were prepared weekly from

a commercial 40% aqueous solution and sprayed daily on the food just prior to feeding. The study

identifies 9.4 mg/kg/day as a NOAEL for maternal and fetal developmental effects. 

The highest NOAELs for developmental effects in the Hurni and Ohder (1973) and Marks et al. (1980)

studies are recorded in Table 2-4 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No reports of genotoxic effects in humans or animals were found after oral exposure to formaldehyde.

Genotoxicity studies are discussed in Section 2.5.
FORMALDEHYDE 150

2. HEALTH EFFECTS

2.2.2.8 Cancer

No studies were located regarding cancer in humans orally exposed to formaldehyde.

Takahashi et al. (1986a) administered 0 or 0.5% formalin (about 0.185% formaldehyde=1,850 ppm

formaldehyde) in drinking water to groups of 10 male Wistar rats for 32 weeks, and evaluated surviving

animals for neoplasms at 40 weeks. An estimated dose of 258 mg/kg/day was calculated using an average

reported body weight of 0.280 kg and a water consumption rate of 0.039 L/day calculated with an

allometric equation based on body weight (EPA 1988e). No carcinoma-bearing animals were reported;

however, 8 of 10 (80%) rats showed benign papillomas of the forestomach in the exposed group

compared with none in 40 control rats. No tumors (benign or malignant) were found in the fundus,

pylorus, or duodenum of the glandular stomach in exposed rats, but erosions and/or ulcers associated with

regenerating mucosa were found along the limiting ridge of the fundic mucosa in exposed rats. 

Soffritti et al. (1989) administered formaldehyde in drinking water to Sprague-Dawley rats for life

beginning at various ages. Groups of 50 male and 50 female rats were exposed to 0 (methanol:water

control), 10, 50, 100, 500, 1000, or 1,500 ppm from 7 weeks of age for life. Another control group

consisted of 100 male and 100 female rats exposed to plain drinking water. Two groups of 18–20 male

and 18–20 female breeders were exposed to 0 or 2,500 ppm formaldehyde starting at 25 weeks of age for

life. Offspring of the breeders, 36–59 males and 37–49 females, received, for life, the same levels of

formaldehyde as their parents. Estimated average doses were calculated, using reference values for

Sprague-Dawley rats of 0.431 kg body weight and 0.054 L water consumed/day (EPA 1988e), as follows:

0, 1, 6, 13, 63, 125, 188, and 313 mg/kg/day. In rats treated from 7 weeks of age, leukemia was reported

in controls and exposed groups at the following incidences: 8/100 (methanol control), 7/200 (plain

control), and 3/100, 9/100, 9/100, 12/100, 13/100, and 18/100 for the 10- through 1,500-ppm groups,

respectively. Leukemia was described as lymphoblastic leukemias and lymphosarcomas, immunoblastic

lymphosarcomas, or hemolymphoreticular neoplasias. Lymphoblastic leukemia-lymphosarcomas were

predominant among the leukemias noted. Pair-wise comparisons using the Fisher exact test (performed

by Syracuse Research Corporation) indicate that only the high-dose incidence was significantly (p<0.05)

increased compared with the methanol controls, but comparisons to the combined control incidence

indicated significantly increased incidence at the 500-, 1,000- and 1,500-ppm levels. In the breeders

exposed from 25 weeks of age, incidences for leukemia were 1/40 for controls and 4/36 for the 
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2. HEALTH EFFECTS

2,500-ppm group, and 6/108 for control offspring and 4/73 for 2,500-ppm offspring. Pair-wise

comparisons of these incidences indicate no statistical difference between control and exposed groups. 

Stomach and intestinal tumors were also reported in the Soffritti et al. (1989) study. In rats treated from

7 weeks of age, a few stomach tumors were found (2/100 at 10 ppm, 1/100 at 1,000 ppm, and 2/100 at

1,500 ppm, but none in the other groups), but no statistically significant association with exposure was

found. A few intestinal tumors were also reported (1/100 at 10 ppm, 2/100 at 50 ppm, 1/100 at

1,000 ppm, and 6/100 at 1,500 ppm), but only the incidence at 1,500 ppm was significantly (p<0.05)

increased compared with the methanol control using the Fisher Exact test (performed by Syracuse

Research Corporation). No significant difference was found in incidence of either type of gastrointestinal

tract tumor in the control and 2,500-ppm exposed breeders, but offspring displayed significantly (p<0.05)

increased incidence of stomach tumors (5/73 versus 0/108) and intestinal tumors (8/73 versus 0/108). 

The neoplasms included benign tumors (papillomas and acanthomas of the forestomach and adenomas)

and malignant tumors (including adenocarcinomas and leiomyosarcomas). Leiomyosarcoma was the

most frequent malignant tumor. The majority of the malignant tumors of the intestine was found in the

duodenum, jejunum, and ileum. 

Two other chronic-duration rat drinking water studies showed no evidence for formaldehyde-induced

carcinogenicity. Groups of 70 male and 70 female Wistar rats were exposed for 2 years to formaldehyde

in drinking water at concentrations that delivered average measured doses of 0, 1.2, 15, or 82 mg/kg/day

(males) and 0, 1.8, 21, or 109 mg/kg/day (females) (Til et al. 1989). Average drinking water

concentrations were reported to be 0, 20, 260, and 1,900 ppm (mg/L). In high-dose animals,

histopathological examination revealed gastric changes (including papillary epithelial hyperplasia

accompanied by hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic

gastritis), but no increased incidences of nonneoplastic lesions were found in groups exposed to lower

concentrations compared with controls. No statistically significant increased incidences of tumors,

benign or malignant, were found in exposed groups compared with controls. Til et al. (1989) concluded

that exposure to 82–109 mg/kg/day formaldehyde in drinking water produced severe damage to the

gastric mucosa, but no tumors. In the other experiment, groups of Wistar rats (20 males, 20 females)

were exposed to formaldehyde in their drinking water at concentrations of 0, 200, 1,000 or 5,000 ppm for

24 months (Tobe et al. 1989). Estimated average doses of 0, 10, 50, and 300 mg/kg/day were reported by

the authors. All animals in the 5,000-ppm group died before 24 months and showed degenerative lesions

in the forestomach (erosions and/or ulcers and hyperplasia of the squamous epithelium with or without 
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hyperkeratosis) and glandular stomach (erosions and/or ulcers accompanied by submucosal inflammatory

cell infiltrates). In animals exposed to 50 mg/kg/day formaldehyde, forestomach hyperkeratosis was

observed in 1 of 6 males and in 1 of 8 females. There were no lesions of the forestomach or glandular

stomach in the 10-mg/kg/day groups. There were no significant differences in the incidences of any

tumors in any exposed group compared with controls.

The evidence for the carcinogenicity of formaldehyde in rats exposed to formaldehyde-containing

drinking water is not strong due to inconsistency of findings across studies and inconsistent evidence of a

dose-response relationship for either leukemia or gastrointestinal tumors in the Soffritti et al. (1989)

study. 

Among the four studies that assessed the potential carcinogenicity of formaldehyde in drinking water

(Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe et al. 1989), only Soffritti et al. (1989)

reported increased incidence of leukemia in exposed rats. Feron et al. (1990) have questioned whether the

increased leukemias may have been “chance effects unrelated to formaldehyde ingestion”, due to reported

wide variation in leukemia incidences in groups of untreated Sprague-Dawley rats of the same colony,

citing reports of leukemia incidences in controls as high as 19% (the highest incidence in Soffriti et al.

exposed groups was 18/100). Another limitation to the strength of the evidence for formaldehydeinduced leukemia is the lack of a consistent dose-response relationship in the Soffritti et al. study. 

Although IARC (1995) has noted that a statistically significant trend for increasing leukemia incidence

with increasing exposure concentration can be demonstrated in the Soffritti et al. data for rats exposed

from 7 weeks of age to dose levels ranging from 1 to 188 mg/kg/day; the second part of the Soffriti et al.

(1989) study found no statistically increased incidence of leukemia in groups of breeding pairs of rats or

their offspring exposed for life to the higher dose level of 313 mg/kg/day. A further limitation is the

absence of corroborating evidence for effects at sites distant from portals-of-entry in the other drinkingwater rat studies, and in inhalation-exposure animal studies. 

Findings for formaldehyde-induced gastrointestinal tract tumors are not consistent across the available

drinking-water rat studies. Significantly increased incidences of intestinal tumors were found only in rats

exposed to 188 mg/kg/day from 7 weeks of age and in offspring of breeding pairs of rats exposed to

313 mg/kg/day, but were not found in groups exposed to lower concentrations or to the breeding pairs

exposed to 313 mg/kg/day (Soffritti et al. 1989). Stomach tumors were found at increased incidence only

in the 313-mg/kg/day offspring of the breeding pairs in the Soffriti et al. (1989) study and in 8/10 rats 
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exposed to 258 mg/kg/day in the Takahashi et al. (1986a) study. Takahashi et al. (1986a) reported only

benign forestomach papillomas, whereas Soffritti et al. (1989) reported papillomas, adenocarcinomas, and

leiomyosarcomas. In contrast, Til et al. (1989) found no increased incidence of gastrointestinal tract

tumors in rats exposed to average dose levels up to 82 or 109 mg/kg/day for life, and Tobe et al. (1989)

likewise found no increase in gastrointestinal tumors in rats exposed to up to 300 mg/kg/day for life. Til

et al. (1989) noted that the difference between their finding of forestomach papillary epithelial

hyperplasia and the finding Takehashi et al. (1986a) of forestomach papillomas might be ascribed to the

use of different lesion-classification criteria. Although there are inconsistencies among the available

studies with respect to formaldehyde-induced gastrointestinal tract tumors from oral exposure, the studies

consistently show that exposure to drinking water dose levels >50 mg/kg/day can damage epithelial tissue

of the gastrointestinal tract, especially at dose levels >100-200 mg/kg/day. The possibility of tumor

occurrence as a portal-of-entry effect from high-level exposure appears biologically plausible given the

reactive nature of formaldehyde, its cytotoxicity at high levels that exceed protective mechanisms, and the

findings for upper respiratory tract tumors in rats exposed to high, but not low, levels of airborne

formaldehyde. 

Given the equivocal nature of the evidence for carcinogenicity from existing studies of rats exposed to

formaldehyde in drinking water, no CEL values are recorded in Table 2-4 or plotted in Figure 2-2.

2.2.3 Dermal Exposure

2.2.3.1 Death

Studies regarding death in humans after dermal exposure to formaldehyde were not located. Repeated

dermal exposure of mice to solutions containing up to 10% formaldehyde produced no increased

mortality. Iversen (1988) applied 4% formaldehyde to the shaved skin of Sencar mice twice weekly for

58 weeks. No increase in mortality was observed. Similarly, applications of 1 or 10% formaldehyde to

the backs of hr/hr Oslo mice for 2 days/week for 60 weeks did not affect mortality (Iversen 1986).
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2.2.3.2 Systemic Effects

No studies were located regarding cardiovascular, gastrointestinal, hematological, musculoskeletal,

hepatic, or renal health effects in humans or animals after dermal exposure to formaldehyde.

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each

species and duration category are recorded in Table 2-5.

Respiratory Effects. No reports were located regarding respiratory effects in humans after

predominantly dermal exposure to formaldehyde or in animals after acute or intermediate-duration dermal

exposure to formaldehyde. 

Iversen (1988) tested the carcinogenic potential of formaldehyde via classical skin-painting experiments. 

Formalin (37% formaldehyde volume for volume) was dissolved in distilled water and used at final

concentrations of 1 and 10% formaldehyde. Hairless mice (hr/hr Oslo strain, in which spontaneous

tumors have not been noted) were used. One group consisting of 16 males and 16 females was dosed

with 200 μL of 1% formaldehyde in water on the skin of the back twice per week (Tuesdays and Fridays)

for a total of 60 weeks. A second group of identical composition received a 10% formaldehyde solution

in an identical manner for 60 weeks. Small, nonspecific granulomas were found in the lungs of

two animals from the 10% group. No exposure-related lesions were found in the nasal mucosa.




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Dermal Effects. As discussed earlier in Section 2.2.1, occupational exposures to formaldehyde have

been associated with dermal irritation and the diagnosis of allergic contact dermatitis by patch tests. 

Reported historical percentages of subjects with skin problems showing positive allergic responses to

formaldehyde in patch tests performed by dermatologists using aqueous solutions with 1 or 2%

formaldehyde include 7.8% in North America between 1992 and 1994 (Marks et al. 1995), 1.6% in a

1983–1984 Swedish study (Meding and Swanbeck 1990), 2.6% in a 1988–1989 European study (Menné

et al. 1991), and 3.7% in a 1990–1994 Polish study (Kiec-Swierczynska 1996). Fischer et al. (1995)

generally concluded that, in more than 30 years of experience with patch test reporting, about 1–4% of

tested subjects are sensitive to formaldehyde. With standard patch testing protocols, formaldehyde

concentrations of 2% and higher may produce skin irritation in nonsensitized individuals demonstrating

that concentrations that evoke a skin irritation response can be similar to those evoking allergic skin

responses (Fischer et al. 1995; Maibach 1983). Because of the reactive and irritating properties of

formaldehyde, early use of formaldehyde concentrations as high as 5% in patch tests, and inexperience on

the part of test administrators, Maibach (1983) speculated that many cases of irritant responses have been

incorrectly interpreted as allergic responses. Lack of specific exposure information for many cases

precludes determining the degree to which reported cases of dermal sensitization may have been caused

by direct dermal contact to formaldehyde in liquids or by contact with formaldehyde gas in air, but the

widespread use of formaldehyde or formaldehyde-releasing chemicals in cosmetics and cleaning agents

(Flyvholm 1991; Rastogi 1992) suggest that the dermal route of exposure may be the more important

sensitizing route. Studies showing that allergic skin responses in sensitized subjects exposed to

formaldehyde in aqueous solutions are rare at concentrations below 0.025–0.05% are discussed in

Section 2.2.3.3.

A study by Nethercott and Holness (1988) examined the prevalence of cutaneous disease in selected

funeral service workers in Toronto, Canada. Eighty-four workers from funeral homes in the Toronto area

were evaluated via a questionnaire which focused on past and family medical histories, present

symptoms, and work practices. Physical examination of the participants’ skin was performed, and all

participants underwent skin-patch testing for formaldehyde and glutaraldehyde sensitivity. Embalmers

were divided into high- and low-exposure groups for comparative analysis. Cutaneous examinations

revealed a greater incidence of contact dermatitis among exposed workers (11%) compared to controls

(0%), and the prevalence of positive skin-patch tests for formaldehyde was greater among exposed

workers (3%) than among controls (0%). Among exposed workers, there were no differences between
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the high- and low-exposure groups with regard to prevalence of contact dermatitis or positive skin-patch

results.

Cases of contact dermatitis caused by formaldehyde released from “no-iron” textiles were described

frequently in the literature from the late 1950s until the mid-1970s; after this period, the finishing

processes for these types of textiles were changed so that only small amounts of formaldehyde are

released after finishing (see Peters and Heese 1997 for review). In most cases of clothing-induced contact

dermatitis, the dermatitis developed specifically in areas of very close contact between the skin and the

clothing (e.g., the underarms, the elbows, the insides of the thighs). 

Formaldehyde has also been shown to cause dermal allergic reactions in nurses and doctors (Rudzki et al.

1989). One hundred-sixty-seven doctors, 92 dentists, and 333 nurses were patch-tested with a standard

panel of allergens plus allergens common to their work environment. Among nurses, formaldehyde was

the disinfectant that most frequently caused allergic reactions (9.6%). Three doctors also had positive

skin tests for formaldehyde.

Albino guinea pigs (Hartley strain) were treated with 0.1 mL of various dilutions of formalin (1, 3, and

10% formalin; –0.4, 1.2, and 4% formaldehyde) to demarcated test sites, and the formalin solution was

gently rubbed into the skin with a cotton-tipped applicator (Wahlberg 1993). An unexposed control site

and a vehicle control were used in each series. The sites were left unoccluded and the treatments were

repeated once daily immediately after skin-fold measurements. Each site was examined prior to skin-fold

measurements for the presence of erythema, edema, fissuring, and scaling. From a mean of 10 sites,

erythema appeared on day 2 (4%), day 5 (1.2%), and day 6 (0.4%). Increased skin-fold thickness was

statistically significant on day 3 (4%), day 7 (1.2%), and day 9 (.04%) after daily treatment with various

concentrations of formaldehyde. 

Iversen (1988) tested the carcinogenic potential of formaldehyde via classical skin-painting experiments. 

Formalin (37% formaldehyde volume for volume) was dissolved in distilled water and used at final

concentrations of 1 and 10% formaldehyde. Hairless mice (hr/hr Oslo strain, in which spontaneous

tumors have not been noted) were used. Two groups consisting of 16 males and 16 females were dosed

with 0.2 mL of 1 or 10% formaldehyde in water on the skin of the back twice per week (Tuesdays and

Fridays) for a total of 60 weeks. Animals dosed with 10% formaldehyde, but not with 1% solutions,
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generally had slight epidermal hyperplasia, and a few mice had cutaneous ulcers. These studies indicate

that formaldehyde applied dermally is irritating to the skin (hyperplasia and ulcers) and can also induce

an inflammatory response.

Ocular Effects. As discussed in Section 2.2.1.2 (in the Respiratory Effects and Ocular Effects

sections), health surveys of occupationally-exposed workers and acute controlled exposure studies with

volunteers have demonstrated that exposure to formaldehyde air concentrations in the range of

0.4–3.0 ppm and above can cause eye irritation. 

To examine the dependence of ocular response to formaldehyde irritation on the trigeminal sensory nerve,

Krootila et al. (1986) topically applied a 1% solution of formaldehyde in an aqueous phosphate buffer

(pH 7.4) to the right eye of a group of unoperated male Sprague-Dawley rats and two groups of

denervated rats. Rats were anesthetized with pentobarbital for the experiments and operations. Sensory

denervation of the right eye was accomplished in one group by coagulation of the intracranial, opthalmic

branch of the right trigeminal nerve, and, in the other group, unilateral sympathetic denervation was

accomplished by removing the right superior cervical ganglion. Application of 1% formaldehyde to the

eye of unoperated rats caused a breakdown of the blood-aqueous barrier of the eye indicated by increased

protein concentration in the aqueous humor or increased leakage of Evans blue dye from the iris vessels. 

This response was also observed in rats without the right superior cervical ganglion, but was absent in rats

with a coagulated right trigeminal nerve. The authors concluded that the irritative response of the eye to

formaldehyde is dependent on the trigeminal sensory nerve, but not the superior cervical ganglion.

Body Weight Effects. No studies were located regarding body weight effects in humans following

dermal exposure to formaldehyde.

Exposure-related effects on body weight were not found in pregnant hamsters dermally exposed during

gestation to 0.5 mL solutions of 37% formaldehyde (Overman 1985) or in guinea pigs dermally exposed

for 9 days to 4% formaldehyde solutions (Wahlberg 1993). In the Overman (1985) experiment, the

control and exposed pregnant hamsters were anesthetized during treatment to prevent grooming; exposure

was for 2 hours on gestation day 8, 9, 10, or 11.
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2.2.3.3 Immunological and Lymphoreticular Effects

As discussed earlier in Section 2.2.1.2, 2.2.1.3, and 2.2.3.2, formaldehyde is a commonly diagnosed

contact allergen, accounting for about 1–4% of cases presented at dermatology clinics (Fischer et al.

1995; Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and Swanbeck 1990; Menné

et al. 1991). Studies of concentration-response relationships for skin allergic reactions induced by

occluded dermal exposures to formaldehyde in formaldehyde-sensitive subjects suggest that a dermal

allergic response to formaldehyde concentrations below about 0.025–0.05% is rare. In a serial dilution

test, the lowest concentration tested, 0.1%, produced allergic reactions in 8/35 formaldehyde-sensitive

subjects (DeGroot et al. 1988). Another serial dilution test, examining concentrations of 1, 0.5, 0.25,

0.13, 0.063, 0.032, and 0.015% in 25 formaldehyde-sensitive subjects, found decreasing frequency of

response with decreasing exposure concentration; positive reactions were found in 3/25 at 0.063%,

1/25 at 0.032%, and 1/25 at 0.015% (Fischer et al. 1995). Flyvholm et al. (1997) reported that, in an

occluded patch test study of 20 sensitized subjects and 20 healthy volunteers, no skin irritation occurred

in the controls exposed to 1% formaldehyde. In sensitized subjects, the frequency of response decreased

with decreasing formaldehyde concentrations as follows: 9/20 at 0.5%, 3/20 at 0.1%, 2/20 at 0.05%, and

1/20 at 0.025%.

A report by Maurice et al. (1986) describes the case study of 20-year-old woman who experienced

anaphylactic shock after exposure to a dialyzer sterilized with formaldehyde. The woman, who required

long-term hemodialysis due to renal failure, had previously experienced mild episodes of localized,

delayed-type hypersensitivity contact dermatitis from adhesives sterilized with formaldehyde. After

experiencing the episode of anaphylaxis, the patient was tested for formaldehyde sensitivity by a skinprick test using 0.1 and 1% formaldehyde solutions, and a skin-patch test using a 1% solution. The

patient developed a strong positive response to skin pricks using both 0.1 and 1% formaldehyde solutions. 

Twenty-six hours after skin application of formaldehyde, the patient developed anaphylactic symptoms

characterized by laryngeal edema and bronchospasm. The patient was treated with subcutaneous

epinephrine and all symptoms other than angioedema resolved rapidly.

Potter and Wederbrand (1995) examined the IgE response to dermal exposure to formaldehyde in female

BALB/c mice. Ten mice per dose received 0.42–6.8 mg formaldehyde in 50 μL water:acetone (50:50),

administered topically to the shaved flank. Seven days later, the animals received 25 μL of a halfstrength solution, applied to the dorsal surface of each ear. Serum samples were collected 14 days after
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the initial treatment. Dermal exposure to 0.42–6.8 mg formaldehyde in acetone:water did not induce IgE

production.

Hilton et al. (1996) assessed the sensitizing properties of topical applications of formaldehyde in guinea

pigs using standard tests (guinea pig maximization test and Buehler test) and in mice using a test for IgE

production after dermal exposure, a local lymph node assay, and an assay for cytokine secretion by

draining lymph node cells. In the guinea pig maximization test, pretreatment with a series of intradermal

injections of 0.25% formaldehyde solutions and occluded patch exposure to 10% formaldehyde produced

sensitization to 48-hour occluded patch dermal exposures to 2% formaldehyde solutions in 100% of

treated animals. In the Buehler test, a series of 6-hour occluded patch dermal exposures to

5% formaldehyde solutions produced sensitization to subsequent exposures to 1% formaldehyde in 70%

of treated animals. In mice treated with topical applications of solutions containing up to 50% formalin

(approximately 18.5% formaldehyde), no increase in serum IgE concentrations occurred, whereas in mice

similarly treated with solutions containing 25% trimellitic anhydride, a well-documented respiratory

sensitizing agent, serum concentrations of IgE were markedly increased. Application of 10, 25, or 50%

formalin solutions (3.7, 9.25, and 18.5% formaldehyde) to the dorsum of ears of mice stimulated cellular

proliferation in lymph node cells cultured from draining auricular lymph nodes excised from the mice. 

Profiles of cytokines produced by draining lymph node cells from mice topically treated with 10, 25, or

50% formalin solutions were different from those produced by a solution of 10% trimellitic anhydride;

formalin solutions stimulated production of IFN-γ, whereas trimellitic anhydride stimulated production of

IL-10. The investigators concluded that these data are consistent with studies of occupationally-exposed

workers suggesting that formaldehyde is a contact dermal allergen, but an equivocal agent for respiratory

sensitization.

The highest NOAEL values and all LOAEL values from each reliable study for immunological/

lymphoreticular effects in each species and duration category are recorded in Table 2-5.

2.2.3.4 Neurological Effects

No studies were located regarding neurological effects in humans or animals following dermal exposure

to formaldehyde.
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2.2.3.5 Reproductive Effects

No reports of reproductive effects in humans after dermal exposure were found. 

Overman (1985) conducted a study designed to evaluate the embryotoxic effects of topical exposure to

formaldehyde in pregnant hamsters. Virgin female hamsters (Lak LVG[SYR] Golden Syrian) were bred

and then treated directly on the skin with 0.5 mL formaldehyde solution (37%) on gestation days 8, 9, 10,

or 11 for 2 hours. The animals (including controls) were anesthetized during treatment to prevent

grooming. After the 2-hour treatment period, the skin of the animals was washed thoroughly with water

to remove any remaining formaldehyde. Fetuses were recovered by laparotomy at gestation day 15, fixed

in Bouin's fixative or in 95% ethyl alcohol. Fixed fetuses were blotted dry, weighed, measured (crownrump length), and examined for malformations by free-hand sectioning technique. Fetuses fixed in ethyl

alcohol were cleared and stained for skeletal tissue observation. Exposure did not significantly affect

maternal weight gain, but a statistically significant increased incidence of resorptions in treated litters was

observed (3–8% of sites resorbed versus none in controls). Overman (1985) suggested that this effect

may have been caused by the stress of treatment during pregnancy rather than to a direct effect of

formaldehyde, noting that exposed animals scratched at treated areas and were “irritable and hard to

handle” for 1 to 2 days after treatment. 

The LOAEL value of 0.5 mL of a 37% solution for increased resorptions is recorded in Table 2-5.

2.2.3.6 Developmental Effects

No reports of developmental effects in humans after dermal exposure to formaldehyde were found. 

In the hamster study by Overman (1985) described in the previous section, formaldehyde treatment did

not significantly change fetal crown rump length or fetal body weights. After treatment on day 8,

two fetuses from the same litter were significantly smaller than their littermates (>3 sd below mean). 

After treatment on day 10, one fetus of normal size had a subcutaneous hemorrhage in the dorsal cervical

region. There were no skeletal malformations found, and no other malformations were observed during

the course of the study.

The NOAEL value of 0.5 mL of 37% solution for no developmental effects is recorded in Table 2-5.
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2.2.3.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans or animals after dermal exposure to

formaldehyde. Other genotoxicity studies are discussed in Section 2.5.

2.2.3.8 Cancer

Studies on cancer incidence in humans exposed occupationally to formaldehyde are discussed in

Section 2.2.1.8. 

In one laboratory animal study reported by Iversen (1986), the carcinogenic potential of formaldehyde

using classical skin painting experiments was determined. Formalin (37% formaldehyde volume/volume)

was dissolved in distilled water at final concentrations of 1 and 10% formaldehyde. Groups of hairless

mice (hr/hr Oslo strain) consisting of 16 males and 16 females were dosed with 0.2 mL of 1%

formaldehyde in water on the skin of the back twice per week for a total of 60 weeks. A second group of

identical composition was dosed with a 10% formaldehyde solution in like manner for 60 weeks. A third

group of mice was initially painted with 51.2 μg dimethylbenz(a)anthracene (DMBA) in 0.1 mL acetone

and 9 days later, received a twice weekly treatment regimen of paintings with 10% formaldehyde in

water. Animals dosed with 10% formaldehyde generally had slight epidermal hyperplasia, and a few

animals had cutaneous ulcers and scratches. In animals dosed with DMBA followed by formaldehyde,

3 animals developed lung adenomas, while 11 animals developed a total of 25 skin tumors (3 squamous

cell carcinomas and 22 papillomas). There was no evidence of any other tumor type. Skin painting with

either 1 or 10% formaldehyde alone had no significant carcinogenic potential; however, dermal exposure

to 10% formaldehyde after DMBA dosing significantly reduced the latency period of DMBA-induced

tumors.

No statistically significant increased incidence of formaldehyde-induced skin tumors was found in a

second study with SENCAR mice, a strain of mouse bred for maximal sensitivity to chemically induced

tumors (Iverson 1988). Groups of 16 male and 16 female mice were dosed with 0.1 mL acetone or

0.2 mL 4% formaldehyde (in water) twice weekly for 58 weeks. Two animals with small benign skin

papillomas were found in the exposed group and also in the acetone-control group. In this study, twice

weekly dermal application of 0.2 mL 4% formaldehyde following application of a single 51.2 μg dose of

DMBA did not significantly affect the skin tumor yield compared with DMBA alone, but, like in the 
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study with hr/hr Oslo mice, decreased the latency period for the appearance of DMBA-induced skin

tumors. The report of this study did not mention if non-neoplastic skin lesions were produced by

exposure with 4% formaldehyde solutions.

2.3 TOXICOKINETICS

The toxicokinetics of formaldehyde after inhalation, oral, or dermal exposure has been reported in several

species by many investigators. The toxicokinetics in all of the animals studied is similar across species

lines. Formaldehyde is an essential metabolic intermediate in all cells. It is produced during the normal

metabolism of serine, glycine, methionine, and choline and also by the demethylation of N-, S-, and

O-methyl compounds. After oxidation of formaldehyde to formate, the carbon atom is further oxidized to

carbon dioxide (CO2) or incorporated into purines, thymidine, and amino acids via tetrahydrofolatedependent one-carbon biosynthetic pathways. Exogenous formaldehyde appears to be readily absorbed

from the respiratory and gastrointestinal tracts, but poorly absorbed following dermal application. 

Formaldehyde is metabolized to formate by the enzyme formaldehyde dehydrogenase; this appears to

take place at the initial site of contact. Being normal components of intermediary metabolism, neither

formaldehyde nor formate are stored to any significant extent in any tissue of the body. Formate is either

excreted in the urine (primarily as formic acid), incorporated into other cellular molecules, or oxidized to

carbon dioxide and exhaled.

In the metabolic labeling studies using 14C-formaldehyde discussed below, it should be noted that the

detection of the 14C radiolabel does not imply that it is still in the form of unmetabolized formaldehyde. 

2.3.1 Absorption

Formaldehyde vapors are readily absorbed from the respiratory tract. Due to rapid metabolism to

formate, little, if any, intact formaldehyde can be found in the blood of humans or animals exposed to

formaldehyde. Formaldehyde is also readily absorbed from the gastrointestinal tract and meets with the

same metabolic fate as formaldehyde after inhalation exposure. The studies available in the open

literature suggest that very little formaldehyde is absorbed via the dermal route. In all cases, absorption

appears to be limited to cell layers immediately adjacent to the point of contact. Entry of formaldehyde

into the blood (i.e., systemic absorption) occurs to a very limited extent, if at all. 
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2.3.1.1 Inhalation Exposure

Formaldehyde is absorbed by the tissues of the respiratory tract during inhalation exposure in several

species. Heck et al. (1985) determined the fate of inhaled formaldehyde in humans. Four men and

two women were exposed to a 1.9 ppm air concentration of formaldehyde in a large walkin chamber for

40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken from each

person (each person served as his/her own control) and the blood was analyzed for formaldehyde content. 

Mean venous blood formaldehyde concentrations in humans prior to exposure showed a blood

concentration of 2.61±0.41 μg/g of blood. Individual variability was markedly present. Immediately

after a 40-minute exposure, mean blood concentration of formaldehyde was 2.77±0.28 μg/g of blood. 

There was no significant difference between pre- and postexposure blood concentrations of formaldehyde

at the formaldehyde air concentrations tested in this study. This result suggests that formaldehyde was

absorbed only into the tissues of the respiratory tract. The absence of increased formaldehyde

concentrations in the blood is likely due to its rapid metabolism in these tissues and/or fast reaction with

cellular macromolecules.

Heck et al. (1985) also determined the fate of inhaled formaldehyde in the rat. Male Fischer 344 rats

were placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air concentration of

formaldehyde for 2 hours, were sacrificed, and a venous blood sample was collected and analyzed for

formaldehyde content. Unexposed control rats had a mean formaldehyde blood level of 2.24±0.07 μg/g

of blood. Rats exposed to the 14.4 ppm air concentration of formaldehyde had blood concentrations of

2.25±0.07 μg/g. These results indicate that during a nose-only inhalation exposure of rats to this

concentration of formaldehyde, no significant quantities of formaldehyde could be detected in the blood. 

Lack of increase in blood formaldehyde levels indicates that only local absorption took place and

absorbed formaldehyde was metabolized before reaching the bloodstream. In a similar study by Heck et

al. (1983), Fischer 344 rats were exposed by inhalation to 14C-formaldehyde at 8 ppm for 6 hours. 

Concentrations of total 14C radioactivity (most likely as 14C-formate) in the whole blood and plasma were

monitored for an additional 8 days. Plasma concentrations of 14C increased over the exposure period,

reaching a maximum at the termination of exposure. Plasma 14C concentrations then declined slowly over

the next few days.

Using dogs as a model, Egle(1972) determined the respiratory fate of formaldehyde and other aldehydes. 

This study measured the retention of formaldehyde along the entire respiratory tract, both upper and 
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lower portions, and measured the effects of ventilation rate, tidal volume, and concentration of inhaled

formaldehyde. Mongrel dogs of both sexes (at least 4 dogs per experiment) were anesthetized and

exposed to 0.15–0.35 μg (122–235 ppm) of formaldehyde vapor produced from formalin. The retention

of formaldehyde was measured over the entire respiratory tract, including the upper region only (nose and

trachea, down to the bifurcation of the trachea), lower region only (from the bifurcation of the trachea,

bronchioles, and below), and over the entire respiratory tract. Retention of formaldehyde (amount of

formaldehyde not returning after an exhalation) when the entire upper and lower respiratory tract was

exposed to formaldehyde vapors was near 100% and seemed to be independent of the airborne

concentration of formaldehyde or variations in the tidal volume. When the upper respiratory tract was

isolated from the lungs, the 2-way exposures showed a 100% uptake of formaldehyde. The 1-way

exposures of formaldehyde showed that the retention of formaldehyde was slightly lower than in the

2-way exposure, but the uptake of formaldehyde still exceeded 95% at all respiratory rates. When the

lower respiratory tract was isolated and examined, the uptake of formaldehyde still exceeded 95%;

however, it appeared to decrease slightly as the ventilation rates increased. This study concluded that

when formaldehyde is inhaled at the concentrations studied, very little formaldehyde vapor would

actually reach the lower respiratory tract.

In another study by Casanova et al. (1988), blood levels of formaldehyde were determined in Rhesus

monkeys after exposure to 6 ppm formaldehyde for 6 hours/day, 5 days/week for 4 weeks. Immediately

after the last exposure, the monkeys were sedated and blood samples were collected within 7 minutes and

at 45 hours after exposure. Blood samples were analyzed for formaldehyde content by gas

chromatography/mass spectrometry (GC/MS). Mean blood concentrations at 7 minutes and 45 hours

postexposure were 1.84 and 2.04 μg/g, respectively. Blood concentrations of formaldehyde in the

three nonexposed monkeys (2.42 μg/g) were not significantly different from those of the exposed group. 

The authors concluded that exposure to moderately high levels of formaldehyde had no effect on blood

concentrations due to rapid local metabolism.

2.3.1.2 Oral Exposure

Formaldehyde is absorbed from the gastrointestinal system after ingestion. Eells et al. (1981) described

the case of a 41-year-old woman who swallowed 120 mL (624 mg/kg) of a formaldehyde solution (as

formalin). Formic acid accumulated in the blood rapidly after formaldehyde ingestion. Burkhart et al.

(1990) describe the case of a 58-year-old man who swallowed 4 ounces of a formaldehyde solution
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containing methanol in a suicide attempt. Blood methanol levels continued to climb throughout 12 hours

of observation. The apparent half-life for formaldehyde was 3.3 hours. 

In a study by Galli et al. (1983), the absorption, fate, and excretion of the complexes between

14C-formaldehyde and milk proteins in mice and rats, and their toxicological significance were examined. 

Male Sprague-Dawley rats were given a single oral dose of 2.2 g (18 μCi) 14C-labeled grana cheese. 

Groups of rats were sacrificed 4, 8, 16, 32, and 64 hours after the end of food consumption. Blood, liver,

gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were removed, and urine

and feces were collected from metabolic chambers. In all cases, the biological samples were immediately

frozen after removal until used for radioactivity measurement. Within 32 hours of administration, 67% of

the radioactivity had been excreted in the feces and urine and 28% of the radioactivity had been exhaled

as 14CO2 in rats, indicating absorption from the ingested cheese. In the companion study, male Swiss

albino mice (CD-1) were given a single oral dose of 0.5 g (4 μCi) 14C-labeled grana cheese. The cheese

was made by following the usual process but using milk with added 14C-formaldehyde. Rats fed with

unlabeled cheese were used as controls. Groups of mice were sacrificed after 2, 4, 8, 16, 32, 64, and

96 hours and 8 and 12 days. Within 32 hours of administration, 64% of the radioactivity had been

excreted in the feces and urine and 24% of the radioactivity had been exhaled as 14CO2, indicating

absorption from the ingested cheese.

A study by Barry and Tome (1991) sought to quantitate the concentration of formaldehyde in the milk of

goats given feed containing varying amounts of formaldehyde-treated soybean oil-meal. The goat ration

consisted of 750 g medium quality grass hay, 600 g maize-based concentrate, and 600 g soybean oilmeal; the soybean oil-meal was either treated with formaldehyde, untreated, or a 50:50 mixture. Five

lactating adult Alpine goats each received 1 of 3 diets (no formaldehyde; 28 mg/kg formaldehyde; a

50:50 mixture of the 2 rations, equal to 14 mg/kg formaldehyde) for 1 week. Milk samples from the last

5 days of each dosing period were collected and analyzed for formaldehyde content by high performance

liquid chromatography. Mean milk formaldehyde concentrations were 0.033, 0.083, and 0.153 mg/kg in

the 0, 14, and 28 mg/kg/day groups, respectively. These values were significantly different from each

other (p<0.05), and were highly correlated with formaldehyde intake (r=0.938, p<0.01), and indicate

absorption from the gastrointestinal tract.

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. Twelve Holstein cows in their first trimester of lactation were used in a series of three 
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feeding trials lasting 35 days and separated from each other by 14 days. Six of the cows received a diet

consisting of low-energy pelleted concentrate, liquid acid whey, and grass hay. The whey was fed once a

day beginning at 10:00 am, and all whey was consumed by 4:30 pm. In the three trials, the calculated

amounts of ingested formalin were 19.9, 39.7, and 59.4 mg/kg/day, respectively. The remaining six cows

received untreated whey throughout the three trials. Morning milk was sampled on days 3, 2, 3, 4, 5, 6,

13, 20, 27, and 34 of each 35-day trial. Blood samples were collected on the day before initiation of the

third trial, and on days 9 and 33. Formaldehyde levels were below detectable limits prior to and at

46 hours after the completion of each trial. The levels of formaldehyde in milk were positively correlated

to dose (p<0.01, no other details given). In a companion study (Buckley et al. 1988), formaldehyde levels

were measured in the muscle tissues of dairy calves fed formalin-treated whey. Eighteen Holstein bull

calves were fed diets containing whey treated with formalin at doses of 0, 0.05, or 0.1% (n=6 per

treatment group). Calves were individually fed the formalin-treated whey in two equal feedings daily. 

Two calves from each treatment group were sacrificed at days 81, 88, and 95. Blood samples were

collected on the day before sacrifice. At sacrifice, sections of muscle, kidney, liver, and heart were

obtained for formaldehyde determinations. Concentrations of formaldehyde in fresh muscle samples of

the high-dose group (0.256 μg/g) were significantly greater than those of controls (0.178 μg/g) (p<0.05). 

Concentrations of formaldehyde in fresh blood and frozen heart, kidney, liver, and muscle samples of

treated animals were similar across treatment groups.

2.3.1.3 Dermal Exposure

Jeffcoat et al. (1983) studied the absorption and disposition of 14C-formaldehyde administered topically to

Fischer 344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. One day prior to formaldehyde

exposure, each monkey had a portion of its posterior shaved and had a carotid artery catheter implanted. 

Monkeys were placed in restraining chairs for drug delivery, and plexiglass hoods were placed around the

animals’ heads for the collection of expired air. Animals were dosed with 2 mg 14C-formaldehyde in

200 μL of aqueous carrier solution, applied to an 18 cm2

 area. The 14C content in each dose was

approximately 590–730 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. 

Urine and feces were collected at daily intervals for 3 days. Expired air was passed through two sodium

hydroxide (NaOH) traps which were changed each time a blood sample was collected. Rats and guinea

pigs were housed individually in glass metabolism cages, which allowed the collection of urine, feces,

and the combination of expired air and evaporation products from excreta. One day prior to

formaldehyde exposure, each animal had a portion of its back shaved and had a carotid artery catheter 
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implanted. Animals were dosed with an aqueous solution which was applied to a 2 cm2 area. The dose

applied was either 0.1 mg in 10 μL of solution or 11.2 mg in 40 μL of solution; the 14C content in each

dose was approximately 30 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. 

Animals were sacrificed 72 hours after exposure began. Data from the monkeys were more variable than

the rats and guinea pigs. The sum of 14C recovered in the excreta of monkeys (urine, feces, and expired

air) was <1%. The concentration of 14C in the blood was extremely low, averaging approximately

0.015% of the dose over the estimated blood volume. After 72 hours, no large accumulation of

formaldehyde occurred in any tissue measured. The application site contained approximately 9.5% of the

14C dose. In rats dosed with 0.05 or 5.6 mg/cm2 14C-formaldehyde, the total recoveries of 14C for the low

and high doses were 73.4 and 60.4%, respectively. Approximately 28% of the low dose and 22% of the

high dose was collected in the air traps, most within the first 2 hours. Less than 3% of 14C in the air was

in the form of CO2. The concentration of 14C in the blood remained fairly constant throughout the

experiment, averaging approximately 0.12% of the low dose and 0.13% of the high dose over the total

estimated blood volume. At 72 hours, no large accumulation of formaldehyde occurred in any tissue

measured. The application site contained approximately 16% of the low-14C dose and 3% of the high

dose. In guinea pigs receiving 0.05 or 5.6 mg/cm2 14C-formaldehyde, total recoveries of 14C for the low

and high doses were 70 and 63.6%, respectively. Approximately 21% of the low dose and 24% of the

high dose was collected in the air traps, most within the first 2 hours. Less than 3% of 14C in the air was

in the form of CO2. About 6% of the low dose and 8% of the high dose was excreted in the urine and

feces combined. The concentration of 14C in the blood remained fairly constant throughout the

experiment, averaging approximately 0.1% of the low dose and 0.09% of the high dose of the estimated

blood volume. After 72 hours, no large accumulation of formaldehyde occurred in any tissue measured. 

The application site contained approximately 16% of the low-14C dose and 4% of the high dose. It

appears that the skin of the monkey is much less permeable to formaldehyde than the skin of the rodent. 

Significant evaporation of formaldehyde from the skin application site also probably occurred in this

study.

Bartnik et al. (1985) sought to characterize the absorption and excretion of percutaneously applied

formaldehyde in male and female WISW rats. Twenty-four hours prior to dosing, the dorsal skin hair of

all rats was carefully clipped to avoid abrasions. Ten male and 4 female rats were dosed with 200 mg of

cream containing 0.1% 14C-formaldehyde. The dosing area of each rat was covered with a glass capsule;

in all cases except two males, the glass capsules were perforated, resulting in a nonocclusive application. 

The dose areas of the remaining two males were covered with solid glass capsules, resulting in an 
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occluded application. The cream remained on the skin for 48 hours, during which time urine, feces, and

air samples were collected. Air samples were passed through a series of filters to separate

14C-formaldehyde and 14CO2. At the end of the study, rats were sacrificed, the treated area of skin was

removed and dissolved, fecal samples and the remaining carcass were homogenized, and air-trap samples

were processed for 14C determinations. The amount of 14C remaining in the treated skin was similar in

occluded and nonoccluded animals (69.9 versus 70.2%). Total percutaneous absorption in 48 hours was

6.1% of the applied radioactivity. Of this amount, 38% was recovered in urine, 11% in the feces, 21% as

respired CO2, and 30% in the carcass. Absorption was lower in occluded (3.4%) than in nonoccluded

animals (6.1%). The authors speculate that the greater formaldehyde absorption seen in the animals with

nonoccluded dose sites was due to some of the volatilized formaldehyde being inhaled by the animals

prior to being trapped. The authors did not specify the fate of dose in the treated skin (i.e., loose or bound

on surface, or actually integrated into skin).

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

No studies were located that described the distribution of formaldehyde or its metabolites in humans after

inhalation exposure. Several studies are available that describe the distribution of formaldehyde in

laboratory animals. Heck et al. (1983) examined the fate of 14C-formaldehyde in Fischer 344 rats. Rats

were exposed by inhalation to 14C-formaldehyde at 8 ppm for 6 hours. Concentrations of total

radioactivity in the whole blood and plasma were monitored for 8 days. The terminal half-life of the 14C

was approximately 55 hours, which was considerably longer than the known half-life of formaldehyde

(about 1.5 minutes in monkeys), indicating both the metabolism of 14C-CH2O to other molecules (i.e.,

formate) and incorporation into other molecules. Radioactivity in the packed blood cell fraction was

multiphasic; it initially increased during exposure, declined during the first hour postexposure, then began

to increase again, reaching a maximum at approximately 35 hours postexposure. The terminal phase of

the packed red blood cell fraction had a very slow decline in radioactivity, which would likely continue

for several weeks after exposure ended (half-life >55 hours).

Heck et al. (1983) also examined distribution of 14C-formaldehyde in formaldehyde-naive and

formaldehyde-pretreated male Fischer 344 rats. Pretreated rats were exposed whole-body to 15 ppm

formaldehyde 6 hours/day for 9 days. On the tenth day, these rats and the formaldehyde-naive rats (never 
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exposed to formaldehyde vapors) were then exposed head-only to 14C-formaldehyde at concentrations of

14.9 ppm for 6 hours. All rats were sacrificed immediately after completion of the 14C-formaldehyde

exposure. Immediately after completion of the inhalation exposure, 14C concentrations were greatest in

the mucosal tissues. At 15 ppm, 14C concentrations were as follows: nasal mucosa, 2 μmole equivalents/g

tissue; trachea, 0.3 μmole equivalents/g tissue; and plasma, 0.1 μmole equivalents/g tissue. Radioactive

concentrations were relatively equivalent in all of the mucosal linings monitored. Tissue concentrations

of 14C in naive and pretreated rats did not differ from each other. Tissue concentrations of 14C were low,

resembling plasma concentrations; the ratio of 14C in internal organs to that in plasma were: esophagus,

4.94±1.23; kidney, 3.12±0.47; liver, 2.77±0.25; intestine, 2.64±0.48; lung, 2.05±0.36; spleen, 1.59±0.50;

heart, 1.09±0.09; brain, 0.37±0.06; testes, 0.31±0.05; and erythrocytes, 0.30±0.08. 

Distribution studies by Chang et al. (1983) investigated the effects of previous formaldehyde exposure on

its distribution after inhalation exposure in male Fischer 344 rats and male B6C3F1 mice. Some rats and

mice were exposed to only one dose of 14C-formaldehyde (15 ppm for 6 hours) (naive mice), while

another group was exposed to formaldehyde (nose-only) at a concentration of 15 ppm for 6 hours/day for

4 days and then additionally exposed to 14C-formaldehyde (nose-only) at a concentration of 15 ppm for

6 hours (pretreated group). After exposure, the mice were immediately sacrificed and prepared for wholebody radiography. The amounts of radioactivity deposited in the nasal cavities of naive and pretreated

rats were similar. Pretreated rats had less visceral radioactivity compared to naive animals. However,

more radioactivity was found in the nasal cavity of naive mice than in pretreated mice. The decreased

visceral radioactivity seen in the pretreated mice was thought to be due to decreased grooming and

mucociliary clearance.

Early studies by Casanova-Schmitz et al. (1984a) examined the mechanisms of labeling of

macromolecules (DNA, RNA, and proteins) in the respiratory and olfactory mucosa and bone marrow of

male Fischer 344 rats. Rats were exposed nose-only for 6 hours to 0.3, 2, 6, 10, or 15 ppm mixtures of

14C and 3

H-formaldehyde 1 day after a 6-hour exposure to the same concentration of unlabeled

formaldehyde. The predominant route of macromolecule labeling was metabolic incorporation. There

was some evidence of DNA-protein cross linking present in the nasal tissues. It was found that

concentrations of 14C DNA in respiratory and olfactory mucosa tissues increased linearly with dose; at

any given dose, the concentrations of 14C DNA in respiratory mucosa tissues were approximately two to

three times that in olfactory mucosa tissues. Incorporation of 14C into DNA increased with exposure

concentrations #6 ppm, but decreased at 10 and 15 ppm, suggesting an inhibition of DNA synthesis.
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Studies by Casanova et al. (1991a, 1991b) described the formation of DNA-protein cross links in the

respiratory tract measured in male Fischer 344 rats and Rhesus monkeys. Rats were exposed nose-only to

a mixture of 14C-labeled and nonradiolabeled formaldehyde at concentrations of 0.3, 0.7, 2, 6, or 10 ppm

for 6 hours. Formaldehyde-DNA-protein cross links were detected at all concentrations tested. Male

Rhesus monkeys were exposed to 0.7, 2, or 6 ppm formaldehyde 14C-labeled and nonradiolabeled mixture

for 6 hours, and it was determined that approximately 90% of all 14C was associated with the thymine,

while 10% was associated with the guanine and adenine. Concentrations of formaldehyde-protein cross

links were greatest in the middle turbinate tissues and lowest in the nasopharyngeal tissues. Some

evidence of cross link formation was seen in the larynx/trachea/carina and major intrapulmonary airway

tissues of two monkeys in the high-dose group. No evidence of cross link formation was seen in the sinus

or lung tissues at any exposure concentration. 

2.3.2.2 Oral Exposure

In a study by Galli et al. (1983), the fate of the complexes between 14C-formaldehyde and milk proteins in

mice and rats, and their toxicological significance were examined. Male Sprague-Dawley rats were given

a single oral dose of 2.2 g (18 μCi) 14C-labeled grana cheese. The cheese was made by following the

usual process but using milk with added 14C-formaldehyde. Animals fed with unlabeled cheese were used

as controls. Groups of rats were sacrificed 4, 8, 16, 32, and 64 hours after the end of food consumption. 

Blood, liver, gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were

removed, and urine and feces were collected from metabolic chambers. In all cases, the biological

samples were immediately frozen after removal until used for radioactivity measurement. Peak

radioactivity concentrations in the tissues occurred 16 hours after food consumption. The maximum

concentrations of 14C-activity equivalent to a value of 0.08% of the dose were present after 8 hours in the

rat blood. In the companion study, male Swiss albino mice (CD-1) were given a single oral dose of 0.5 g

(4 μCi) 14C-labeled grana cheese. The highest concentrations of radioactivity in the liver, kidney, adipose

tissue, spleen, testes, brain, and muscle occurred 4 hours after administration. The maximum

concentrations of 14C-activity equivalent to a value of 0.03% of the dose were present after 2 hours in the

blood of mice. 

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. There was a high degree of variability in milk and blood concentrations, presumably due to

the variable amount of time (several minutes to 7 hours) taken to consume the treated feed. In a 
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companion study, Buckley et al. (1988) measured formaldehyde levels in the muscle tissues of dairy

calves fed formalin-treated whey. Eighteen Holstein bull calves were fed diets containing whey treated

with formalin at doses of 0, 0.05, or 0.1%. Calves were individually fed the formalin-treated whey in two

equal feedings daily. Two calves from each treatment group were sacrificed at days 81, 88, and 95. 

Blood samples were collected on the day before sacrifice. At sacrifice, sections of muscle, kidney, liver,

and heart were obtained for formaldehyde determinations. Concentrations of formaldehyde in fresh

muscle samples of the high-dose group (0.256 μg/g) were significantly greater than those of controls

(0.178 μg/g). Concentrations of formaldehyde in fresh blood and frozen heart, kidney, liver, and muscle

samples were similar across treatment groups.

2.3.2.3 Dermal Exposure

Jeffcoat et al. (1983) studied the disposition of 14C-formaldehyde administered topically to Fischer

344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. One day prior to formaldehyde

exposure, each monkey had a portion of its posterior shaved and had a carotid artery catheter implanted. 

Monkeys were placed in restraining chairs for drug delivery, and a plexiglass hood was placed around

their heads for the collection of expired air. Animals were dosed with an aqueous solution which was

applied to an 18 cm2

 area. A dose of 2 mg in 200 μL of solution was applied to the skin surface; the 14C

content in each dose was approximately 590–730 μCi. Blood samples were collected at 1, 2, 3, 4, 7, and

24 hours after dosing. Urine and feces were collected at daily intervals for 3 days. Expired air was

passed through two NaOH traps which were changed each time a blood sample was collected. At

72 hours after dosing, the animals were sacrificed and the following tissues were collected and analyzed

for 14C content: heart, liver, lung, spleen, kidney, leg, brain, gonads, application site skin, and distant skin;

the remaining carcass was also analyzed for 14C content. Rats and guinea pigs were housed individually

in glass metabolism cages, which allowed the collection of urine, feces, and the combination of expired

air and evaporation products from excreta. One day prior to formaldehyde exposure, each animal had a

portion of its back shaved and had a carotid artery catheter implanted. Animals were dosed with an

aqueous solution which was applied to a 2 cm2

 area. The dose applied was either 0.1 mg in 10 μL of

solution or 11.2 mg in 40 μL of solution; the 14C content in each dose was approximately 30 μCi. Blood

samples were collected at 1, 2, 3, 4, 7, and 24 hours after dosing. Urine and feces were collected at daily

intervals for 3 days. Air exiting the metabolism cages was passed through two NaOH traps which were

changed each time a blood sample was collected and at 48 and 72 hours after dosing. At 72 hours after

dosing, the animals were sacrificed and the following tissues were collected and analyzed for 14C content:

heart, liver, lung, spleen, kidney, leg, brain, gonads, application site skin, and distant skin; the remaining
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carcass was also analyzed for 14C content. Data from the monkeys were more variable than the rats and

guinea pigs. The sum of 14C recovered in the excreta (urine, feces, and expired air) was <1%. The

concentration of 14C in the blood was also low, averaging approximately 0.015% of the dose over the

estimated blood volume. At 72 hours, no large accumulation of formaldehyde occurred in any tissue

measured. The total amount of radioactivity recovered in all internal organs combined was <0.05% of the

applied dose; the 14C was distributed fairly evenly across all tissues. 

In rats, the application site contained approximately 9.5% of the 14C activity, with a total recoveries of 14C

for the low and high doses of 73.4 and 60.4%, respectively. Less than 3% of 14C in the air was in the

form of CO2. About 7% of the low dose and 9% of the high dose was excreted in the urine and feces

combined. The concentration of 14C in the blood remained fairly constant throughout the experiment,

averaging approximately 0.12% of the low dose and 0.13% of the high dose over the total estimated blood

volume. After 72 hours, no large accumulation of 14C radioactivity occurred in any tissue measured in

rats. The application site contained approximately 16% of the low-14C dose and 3% of the high dose. 

In guinea pigs, total recoveries of 14C for the low and high doses were 70 and 63.6%, respectively. 

Approximately 21% of the low dose and 24% of the high dose were collected in the air traps, most within

the first 2 hours. Less than 3% of 14C in the air was in the form of CO2. About 6% of the low dose and

8% of the high dose was excreted in the urine and feces combined. The concentration of 14C in the blood

remained fairly constant throughout the experiment, averaging approximately 0.1% of the low dose and

0.09% of the high dose over the total estimated blood volume. After 72 hours, no large accumulation of

14C occurred in any tissue measured. The application site contained approximately 16% of the

low-14C dose and 4% of the high dose. The authors concluded that topically applied formaldehyde, once

absorbed, was primarily excreted by the urinary and fecal routes.

2.3.3 Metabolism

Formaldehyde is rapidly metabolized and storage is not a factor in its toxicity. The metabolism of

formaldehyde to formate (via formaldehyde dehydrogenase/class III alcohol dehydrogenase) takes place

in all of the tissues of the body as a consequence of endogenous formation of formaldehyde, and the

formate is quickly removed by the supporting blood supply (Heck et al. 1982). Formaldehyde 
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dehydrogenase (FDH) is the major metabolic enzyme involved in the metabolism of formaldehyde in all

of the tissues studied; it is widely distributed in animal tissues, particularly in the rat nasal mucosa, and is

specific for the glutathione adduct of formaldehyde. If formaldehyde is not metabolized by FDH, then it

can form cross linkages between proteins, between protein and single-stranded DNA (see Figure 2-3) or

enter the 1 carbon intermediary metabolic pool by initially binding to tetrahydrofolate (Bolt 1987). 

Several enzymes can catalyze the reaction that oxidizes formaldehyde to formic acid (i.e., nonspecific

aldehyde dehydrogenase and catalase); however, FDH is the primary enzyme that performs this function

and is specific for formaldehyde; other aldehydes are left intact in the presence of FDH. Endogenous or

exogenous formaldehyde enters the FDH metabolic pathway and is eliminated from the body as

metabolites, primarily as formate or CO2. Formaldehyde dehydrogenase activity does not increase (i.e.,

not inducible) in response to formaldehyde exposure (Casanova-Schmitz et al. 1984b); thus no increase in

metabolism occurs.

A summary of the metabolic pathways for formaldehyde metabolism is represented in Figure 2-3.

2.3.3.1 Inhalation Exposure.

Heck et al. (1985) determined the fate of inhaled formaldehyde in the human. Four men and two women

were exposed to a 1.9±0.06 ppm air concentration of formaldehyde in a large walk-in chamber for

40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken from each

person (each person served as his/her own control) and the blood was analyzed for formaldehyde content. 

Mean venous blood formaldehyde concentrations in humans prior to exposure showed a blood

concentration of 2.61±0.41 μg/g of blood. Individual variability was markedly present. Immediately

after a 40-minute exposure, mean blood concentration of formaldehyde was 2.77±0.28 μg/g of blood. 

There was no significant difference between pre- and postexposure blood concentrations of formaldehyde

at the formaldehyde air concentrations tested in this study, most likely indicating rapid metabolism and/or

local absorption in the respiratory tract mucosa rather than systemic absorption into the blood. In the

same report by Heck et al. (1985), the fate of inhaled formaldehyde was determined in the rat. Male

Fischer 344 rats were placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air

concentration of formaldehyde for 2 hours, were sacrificed, and a venous blood sample was collected and

analyzed for formaldehyde content. Unexposed control rats had a mean formaldehyde blood level of

2.24±0.07 μg/g of blood while rats exposed to the 14.4 ppm air concentration of formaldehyde had blood

concentrations of 2.25±0.07 μg/g. These results indicate that during a nose-only

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inhalation exposure of rats to this concentration of formaldehyde, no significant quantities of

formaldehyde can be detected in the blood, most likely indicating fast metabolism and/or local absorption

in the respiratory tract mucosa. 

Heck et al. (1982) studied the effects of formaldehyde exposure on nasal mucosal tissue in male

Fischer 344 rats. Rats were exposed to clean air or air containing 6 ppm formaldehyde for 10 days,

6 hours/day. Immediately after the last exposure, animals were sacrificed and nasal mucosal tissues were

isolated. The tissues were homogenized and formaldehyde was extracted and analyzed by GC/MS. The

mean concentration of formaldehyde in the nasal mucosal tissues of rats exposed to 6 ppm formaldehyde

(0.39 μmol/g tissue) was not significantly different from the mean concentrations found in the tissues of

control animals (0.42 μmol/g tissue). The authors attributed this to the rapid metabolism of formaldehyde

to formate or the rapid irreversible binding of formaldehyde to macromolecules.

The ability of respiratory and olfactory tissues to oxidize formaldehyde was examined in male

Fischer 344 rats. To determine the effects of repeated formaldehyde exposure on enzyme activities, rats

were exposed to 15 ppm formaldehyde 6 hours/day for 10 days. At the completion of formaldehyde

exposure, rats were sacrificed and respiratory and olfactory mucosal tissues were harvested. The

enzymatic capacity of the tissues was determined in the presence and absence of glutathione. Tissue

homogenates from both the respiratory and olfactory mucosae demonstrated the ability to oxidize

formaldehyde; the oxidation of formaldehyde occurred at similar rates in the respiratory and olfactory

mucosal homogenates (Casanova-Schmitz et al. 1984b).

The effects of glutathione depletion on the cross linking of formaldehyde with macromolecules (DNA,

RNA, and proteins) in the respiratory and olfactory mucosa and bone marrow of male Fischer 344 rats

were examined by Casanova and Heck (1987). Rats were exposed nose-only for 3 hours to 0.9, 2, 4, 6, or

10 ppm mixtures of 14C- and 3

H-formaldehyde 1 day after a 3-hour exposure to the same concentration of

unlabeled formaldehyde. Two hours prior to the second exposure, five of the rats were injected with

phorone in corn oil, and the other three were injected with corn oil alone. Phorone successfully depleted

nonprotein sulfhydryls levels to minimal values. The metabolic incorporation of label into

macromolecules was significantly decreased by this treatment, whereas the amount of DNA-protein cross

linking significantly increased. Since formaldehyde oxidation depends on glutathione, this experiment

suggests that when this process is inhibited, formaldehyde levels rise high enough to form DNA-protein

cross links. 
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2.3.3.2 Oral Exposure.

Eells et al. (1981) describe the case of a 41-year-old woman who was brought to the emergency room

30 minutes after ingesting approximately 120 mL of formalin (624 mg/kg formaldehyde). Formic acid

accumulated in the blood rapidly after formaldehyde ingestion. 

2.3.3.3 Dermal Exposure

No information on metabolism of formaldehyde after dermal exposure was found in the literature.

2.3.4 Elimination and Excretion

2.3.4.1 Inhalation Exposure

Heck et al. (1983) examined the fate of 14C-formaldehyde in male Fischer 344 rats. Rats were exposed to

0.63 or 13.1 ppm formaldehyde for 6 hours. Upon completion of the exposure, the rats were placed in

metabolic cages which allowed the continuous collection of urine, feces, and expired air; they remained in

the cages for 70 hours and were then sacrificed. The average 14CO2 excretion was biphasic, with a rapid

decline over the first 12 hours followed by a more gradual decline in excretion over the remainder of

time. Changing the concentration of formaldehyde did not affect the proportion of dose recovered in each

type of excreta. Radioactivity in urine accounted for 17.6 and 17.3% of the total radioactivity detected

for low- and high-dose rats, respectively; radioactivity in feces accounted for 4.2 and 5.3% of the total

respective amounts of recovered radioactivity. Exhalation was the major route of excretion, accounting

for 39.4% of the low dose and 41.9% of the high dose. The amount of 14C remaining in the carcass after

70 hours was roughly equivalent (38.9% of low dose; 35.2% of high dose) to that expired over the same

period. At 15 ppm, 14C concentrations exposure were as follows: nasal mucosa, 2 μmole equivalents/g

tissue; trachea, 0.3 μmole equivalents/g tissue; and plasma, 0.1 μmole equivalents/g tissue. 

2.3.4.2 Oral Exposure

In a study by Galli et al. (1983), the excretion of the complexes between 14C-formaldehyde and milk

proteins in mice and rats, and their toxicological significance were examined. Male Sprague-Dawley rats

were given a single oral dose of 14C-labeled grana cheese. Rats fed with unlabeled cheese were used as 
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controls. Groups of rats were sacrificed at 4, 8, 16, 32, and 64 hours after the end of food consumption. 

Blood, liver, gastrointestinal tract, kidneys, spleen, testes, brain, muscle, and adipose tissues were

removed, and urine and feces were collected from metabolic chambers. In all cases, the biological

samples were immediately frozen after removal until used for radioactivity measurement. Within

32 hours of administration in rats, 67% of the radioactivity had been excreted in the feces and urine and

28% of the radioactivity had been exhaled as 14CO2. The half-life calculated from the regression line of

the β phase (where C(t)=C0 [e-αt

 + e-βt]) in blood was found to be 26.4 hours for the rats. The liver was the

only tissue where the radioactivity concentration/g tissue was equivalent to more than 0.1% of the

administered dose 64 hours after the ingestion of 14C-labeled cheese. Excretion of radioactivity by all

routes from rats was completed within 32 hours. In the companion study, male Swiss albino mice (CD-1)

were given a single oral dose of 0.5 g (4 μCi) 14C-labeled grana cheese. Mice were sacrificed 2, 4, 8, 16,

32, 64, and 96 hours and 8 and 12 days. Within 32 hours of administration, 64% of the radioactivity had

been excreted in the feces and urine and 24% of the radioactivity had been exhaled as 14CO2. The halflife calculated from the regression line of the β phase in blood was found to be 27.8 hours for the mice. 

After 96 hours in all of the mouse tissues, the radioactivity concentration/g tissue was lower than 0.5% of

the administered dose, and no radioactivity was detectable after 8 days. Excretion of radioactivity by all

routes from mice was completed within 32 hours. 

A study by Barry and Tome (1991) sought to quantitate the concentration of formaldehyde in the milk of

goats given feed containing varying amounts of formaldehyde-treated soybean oil-meal. Mean milk

formaldehyde concentrations were 0.033, 0.083, and 0.153 mg/kg in the 0, 14, and 28 mg/kg/day groups,

respectively. These values were significantly different from each other (p<0.05) and were highly

correlated with formaldehyde intake (r=0.938, p<0.01). The authors concluded that dietary formaldehyde

is excreted in the milk of goats. 

Buckley et al. (1988) measured formaldehyde levels in the milk and blood of dairy cows given formalintreated whey. Twelve Holstein cows in their first trimester of lactation were used in a series of three

feeding trials lasting 35 days and separated from each other by 14 days. Six of the cows received a diet

consisting of low-energy pelleted concentrate, liquid acid whey, and grass hay. The whey was fed once a

day beginning at 10:00 am, and all whey was consumed by 4:30 pm. In the three trials, the calculated

amounts of ingested formalin were 19.9, 39.7, and 59.4 mg/kg/day, respectively. The remaining six cows

received untreated whey throughout the three trials. The average total excretion of formaldehyde in milk

in each of the three dose groups during each trial was 0.53, 1.41, and 2.80 mg, respectively.
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2.3.4.3 Dermal Exposure

Jeffcoat et al. (1983) studied the elimination of 14C-formaldehyde administered topically to

Fischer 344 rats, Dunkin-Hartley guinea pigs, and Cynomolgus monkeys. Data from the monkeys were

more variable than the rats and guinea pigs. The sum of 14C recovered in the excreta (urine, feces, and

expired air) was >1%. In rats, total recoveries of 14C for the low and high doses were 73.4 and 60.4%,

respectively. Approximately 28% of the low dose and 22% of the high dose was collected in the air traps,

most within the first 2 hours. Less than 3% of 14C in the air was in the form of CO2. About 7% of the low

dose and 9% of the high dose was excreted in the urine and feces combined. In guinea pigs, total

recoveries of 14C for the low and high doses were 70 and 63.6%, respectively. Approximately 21% of the

low dose and 24% of the high dose was collected in the air traps, most within the first 2 hours. Less than

3% of 14C in the air was in the form of CO2. About 6% of the low dose and 8% of the high dose was

excreted in the urine and feces combined. The authors concluded that the fate of topically applied

formaldehyde differed significantly from that of formaldehyde administered internally.

Bartnik et al. (1985) sought to characterize the absorption and excretion of percutaneously applied

formaldehyde in male and female WISW rats using occluded and nonoccluded application. Ten male and

four female rats were dosed with 200 mg of cream containing 0.1% 14C-formaldehyde. Excretion of 14C

(presumably formate) via feces, urine, and expired air was consistently lower in animals with occluded

dose sites (0.2 versus 0.7%; 1.2 versus 2.3%; and 0.9 versus 1.3%, respectively). The authors speculate

that the greater formaldehyde absorption seen in the animals with nonoccluded dose sites was due to some

of the volatilized formaldehyde being inhaled by the animals prior to being trapped. The authors did not

specify the fate of dose in the treated skin (i.e., loose or bound on surface, or actually integrated into

skin).

2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and

disposition of chemical substances to quantitatively describe the relationships among critical biological

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based
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pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to

delineate and characterize the relationships between: (1) the external/exposure concentration and target

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al.

1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from

route to route, between species, and between subpopulations within a species. The biological basis of

PBPK models results in more meaningful extrapolations than those generated with the more conventional

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The

numerical estimates of these model parameters are incorporated within a set of differential and algebraic

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations

provides the predictions of tissue dose. Computers then provide process simulations based on these

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true

complexities of biological systems. If the uptake and disposition of the chemical substance(s) is

adequately described, however, this simplification is desirable because data are often unavailable for

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of

PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 
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humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 2-4 shows a conceptualized representation of a PBPK model.

PBPK models for formaldehyde are discussed in this section in terms of their use in risk assessment,

tissue dosimetry, and dose, route, and species extrapolations.

Pharmacokinetic models to describe, as a function of formaldehyde air concentration, the rate of

formation of formaldehyde-induced DNA-protein cross links in different regions of the nasal cavity have

been developed for rats and monkeys (Casanova et al. 1991; Heck and Casanova 1994). Rates of

formation of DNA-protein cross links have been used as a dose surrogate for formaldehyde tissue

concentrations in extrapolating exposure-response relationships for nasal tumors in rats to estimate cancer

risks for humans (EPA 1991a; see Section 2.4.3). The models assume that rates of cross link formation

are proportional to tissue concentration of formaldehyde and include saturable and nonsaturable

elimination pathways, and that regional and species differences in cross link formation are primarily

dependent on anatomical parameters (e.g., minute volume and quantity of nasal mucosa) rather than

biochemical parameters. The models were developed with data from studies in which concentrations of

DNA-protein cross links were measured in different regions of the nasal cavities of rats (Casanova et al.

1989) and Rhesus monkeys (Casanova et al. 1991; Heck et al. 1989) exposed by inhalation to

radiolabeled formaldehyde. In agreement with the observed data, the models predict that overall rates of

DNA-protein cross link formation in rat respiratory mucosa are higher than rates in Rhesus monkeys, and

that there is a nonlinear, convex relationship between this dose surrogate in nasal tissues and increasing

air concentrations of formaldehyde (Casanova et al. 1991). Similar nonlinear, convex exposure-response

relationships have also been observed in formaldehyde-exposed rats for nasal tumor incidence (Kerns et

al. 1983b; Monticello et al. 1996) and cell proliferation indices in regions of the rat nasal epithelium

where tumors develop (Monticello et al. 1996). 

Computational fluid dynamics (CFD) models of airflow in the nasal passages of rats, monkeys, and

humans have been developed to determine the degree to which interspecies and interregional differences

in uptake patterns along airway passages may account for differing distributions of formaldehyde-induced

upper respiratory tract lesions in rats and primates. These models enable extrapolation of exposures

associated with upper respiratory tract tissue damage in rats or monkeys to human exposures 
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Skin

Kidney

Richly

perfused

tissues

Slowly 

perfused

tissues

Fat

Liver

Lungs

A

R

T

E

R

I

A

L

B

L

O

O

D

V

E

N

O

U

S

B

L

O

O

D

GI

Tract

Vmax Km

Urine

Chemicals in air

contacting skin

Inhaled chemical Exhaled chemical

Ingestion

Figure 2-4. Conceptual Representation of a Physiologically Based

Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance

Source: adapted from Krishnan et al. 1994

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model

for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin,

by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation.
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(Cohen Hubal et al. 1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a,1997b; Morgan 1997; Morgan et

al. 1991; Subramaniam et al. 1998). Airflow pattern is expected to be one of three important determinants

of upper respiratory tract tissue uptake, along with interactions at the airway/tissue interface such as offgassing and tissue properties influencing absorption rates (e.g., mucociliary clearance or rate of

metabolism). 

Driving forces behind the development of these airflow models include: (1) differences in nasal anatomy

and breathing patterns between rats and primates; (2) observations that nonneoplastic respiratory tract

lesions in rats exposed to 6 ppm formaldehyde are confined to epithelial tissue in specific anterior regions

of the nose posterior to the vestibule (Chang et al. 1983; Morgan et al. 1986b), whereas monkeys exposed

to 6 ppm formaldehyde show a wider distribution of similar epithelial lesions in the nose posterior to the

vestibule and some extension of the lesions into the tracheal and bronchial regions (Monticello et al.

1989); (3) histochemical localization observations suggesting that regional differences in formaldehyde

dehydrogenase, a key enzyme in formaldehyde detoxification, were insufficient to account for localized

toxicity in the rat nose (Keller et al. 1990); and (4) observations of correlations between sites of

formaldehyde-induced lesions in the nasal epithelium of rats and Rhesus monkeys and site-specific rates

of DNA-protein cross link formation (a putative internal dosimeter for formaldehyde as discussed earlier;

Casanova et al. 1989, 1991, 1994) or site-specific rates of cellular proliferation (Monticello et al. 1989,

1996).

Using three-dimensional reconstructions of the nasal passages of a F344 rat (Kimbell et al. 1993), a

Rhesus monkey (Kepler et al. 1995), and a human (Subramaniam et al. 1998), CFD models were

developed to predict patterns of airflow and regional uptake of formaldehyde in the nose of these species. 

The rat and monkey models were constructed from tracings of embedded tissue specimens, whereas the

human model was constructed from tracings of magnetic resonance image scans. The CFD models

assume that: (1) rat, monkey, and human nasal epithelial tissues are similar in all characteristics except

thickness and location in nasal airways (values for these parameters were estimated from the literature or

measured); (2) formaldehyde is absorbed only during inspiration, and that major patterns of inhaled

airflow during resting breathing are similar to those at steady-state; (3) air is an incompressible

Newtonian fluid; (4) the air-phase diffusivity of formaldehyde is constant throughout the nasal passages;

(5) the nasal airway walls are inflexible and have no mucus movement or nasal hairs; and (6)

formaldehyde absorption is maximal (i.e., fast and complete) in mucus-covered, nonsquamous epithelium

regions of the nose so that concentrations at the surface of these airway walls are taken to be zero. 
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Simulations of airflow patterns were comparable with descriptions and measurements of flow in nasal

molds of each species (Kepler et al. 1998; Kimbell et al. 1997a; Subramaniam et al. 1998). 

Regions of high flux predicted by the rat and monkey CFD models correlated with the distribution of

formaldehyde-induced squamous metaplasia in nasal passages of rats exposed to 10 or 15 ppm

formaldehyde for 6 months (Kimbell et al. 1993, 1997a) and of Rhesus monkeys exposed to 6 ppm

formaldehyde for 6 weeks (Kepler et al. 1998). Results from these studies support the hypothesis that

airflow patterns are key determinants of the amount of formaldehyde reaching the site of formaldehydeinduced nasal lesions. 

The rat CFD model and a modified version of the Casanova et al. (1991) pharmacokinetics model of

formaldehyde disposition in the rat nasal lining have been linked to make predictions of DNA-protein

cross link formation rates in nasal epithelial regions as a function of formaldehyde concentration in air

(Cohen Hubal et al. 1997). The rat nasal lining model assumed a single compartment with three

competing disposition processes for formaldehyde: saturable metabolism, nonsaturable metabolism, and

DNA-protein cross link formation. The model parameters were kinetic rate constants for formation and

loss of DNA-protein cross links, the nasal-lining thickness, rate constants for formaldehyde metabolism

by saturable pathways (Vmax and Km), and a pseudo-first-order rate constant for nonsaturable

formaldehyde metabolism. Saturable and nonsaturable metabolic rate constants were estimated by

iterative fitting of the model to whole-nose data for DNA-protein cross links in rats exposed for 6 hours to

radiolabeled formaldehyde, collected by Casanova et al. (1989). The combined airflow and

pharmacokinetics models were then used to predict DNA-protein concentrations in the rat nasal epithelial

region with high tumor incidence; predicted values compared well with measured DNA-protein cross link

values in this region of the rat nasal epithelium (Cohen Hubal et al. 1997).

The Chemical Industry Institute of Toxicology and the U.S. EPA (CIIT 1998) are currently exploring

options in using the CFD and pharmacokinetic models to extrapolate exposure-response relationships for

formaldehyde-induced rat nasal tumors and related end points, such as rates of cellular proliferation in

specific regions of the nasal epithelium, to derive estimates of cancer risk in humans exposed to inhaled

formaldehyde. One approach being explored makes predictions for nasal and lung tumor risk in humans

exposed to inhaled formaldehyde using two-stage clonal-growth cancer models incorporating data on cell

division rates, numbers of cell at risk, tumor incidence, and site-specific flux of formaldehyde (see also

CIIT 1998; Conolly et al. 1992; Conolly and Andersen 1993; Morgan 1997). A second approach (a 
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2. HEALTH EFFECTS

benchmark dose approach) makes predictions of nasal cancer risk in humans using curve fitting of

relevant rat exposure-response data (e.g., nasal tumors or precursor lesions such as preneoplastic foci or

squamous papillomas, rates of cellular proliferation, or rates of DNA-protein cross link formation) and

CFD modeling and/or pharmacokinetic modeling for extrapolation purposes (CIIT 1998). 

2.4 MECHANISMS OF ACTION

2.4.1 Pharmacokinetic Mechanisms

Absorption. Formaldehyde is a small, reactive, water soluble molecule (molecular weight 30.03)

which is readily absorbed in the tissues of the respiratory tract (inhalation exposure) and gastrointestinal

tract (oral exposure). Absorption from the nasal portion of the respiratory tract is estimated to be at or

near 100%. Studies in obligate nose-breathing animals (rats, mice) have demonstrated near 100%

absorption in the nasal cavity/mucosa (Casanova-Schmitz et al. 1984a; Casanova et al. 1991; Heck et al.

1982, 1983) primarily in the anterior nasal mucosa in rats (Chang et al. 1983). Absorption from the nasal

mucosa, trachea, and bronchi is expected for the oronasal-breathing animals (primates, humans, dogs

etc.). Tracheal and bronchial absorption ultimately results from deeper penetration because of the

formaldehyde vapors not passing over and coming into contact with the nasal mucosa; however, near

100% absorption of the formaldehyde vapor is still likely, at least in the dog (Egle 1972) and very likely

in humans as well. Studies in humans exposed to 1.9 ppm for 40 minutes failed to detect increases in

blood formaldehyde levels, which is probably related to formaldehyde's very fast metabolism by one or a

combination of metabolic pathways (see Figure 2-3) and not due to lack of local absorption. Similar

results were obtained in rats exposed to 14.4 ppm for 2 hours (Heck et al. 1985). Little information is

available on the oral absorption characteristics of formaldehyde in humans; however, based on two

studies, either the formaldehyde is quickly metabolized to formate in the gastrointestinal tract and the

formate is absorbed fairly quickly, the formaldehyde is absorbed quickly and is metabolized to formate in

the blood, or a combination of the two mechanisms is responsible for the sharp increases in blood formate

levels (Burkhart et al. 1990; Eells et al. 1981). Formaldehyde appears to be rapidly absorbed after oral

exposure in rats (Galli et al. 1983) and food-producing animals (Barry and Tome 1991; Buckley et al.

1988). Dermal absorption in monkeys has been shown to be quite low (0.5% of the applied dose); most

was either lost to evaporation or bound within the skin (Jeffcoat 1983). 
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Distribution. Formaldehyde does not appear to be absorbed into the blood stream as an intact

molecule, except possibly at very high doses that overwhelm the metabolic capabilities of the tissue with

which it comes into contact. Given this rapid metabolic capability of animal tissues, the distribution of

the intact formaldehyde molecule to other more distant organs (kidney, fat, spleen, etc.) in the body is not

likely and is not considered a major factor in formaldehyde toxicity. Toxicity is generally demonstrated

at the point of formaldehyde contact (see Mechanisms of Toxicity, below). Heck et al. (1983) found that

in rats, inhaled 14C-formaldehyde (8 ppm for 6 hours) had elevated concentrations of radioactivity in their

blood for several days after exposure (terminal half-life 55 hours). Since it is known that blood

formaldehyde levels do not increase after inhalation exposure (Heck et al. 1985), the data suggested that

there was an incorporation of 14C into the macromolecules of the body. The long plasma half-life may

also have been due to formaldehyde's rapid metabolism to formate or CO2 awaiting excretion into the

urine and lung, respectively.

In one study (Casanova et al. 1991), much of the 14C was localized in the nasal mucosa; however,

detectable levels of 14C activity were noted in the esophagus, kidney, liver, intestine, lung, spleen, heart,

brain, testes, and erythrocytes in some reports (Heck et al. 1983; Swenberg et al. 1983). The geometry of

the nasal passages of different species, which results in different airflow patterns through the nose, has a

large effect on the local distribution of formaldehyde vapor as well (Schreider 1986). In a study by

Casanova-Schmitz et al. (1984a) using male rats exposed to concentrations of 0.3–15 ppm of 14C and 3

H

labeled formaldehyde for 6 hours, concentrations of 14C-formaldehyde in respiratory and olfactory

mucosa tissues increased linearly with dose and at any given dose, the concentrations of

14C-formaldehyde in respiratory mucosa tissues were approximately 2–3 times that in olfactory mucosa

tissues. The 3

H and 14C radioisotopes were chosen to distinguish between metabolic incorporation of

oxidized formaldehyde metabolites (14C) and covalent binding (3

H) into macromolecules. At all exposure

concentrations, RNA was the most heavily 14C-labeled macromolecule in the respiratory and olfactory

mucosa. DNA from the respiratory and olfactory mucosa was 14C-labeled at equivalent or greater levels

than proteins. In the bone marrow, DNA was the most heavily 14C-labeled macromolecule. DNA-protein

cross links have also been identified in male rats and male Rhesus monkeys exposed to formaldehyde

concentrations of #9.87 ppm for 6 hours. Concentrations of formaldehyde-protein cross links were

greatest in the middle turbinate tissues and lowest in the nasopharyngeal tissues, with some evidence of

cross link formation seen in the larynx, trachea, carina, and major intrapulmonary airway tissues of two of

the monkeys tested (Casanova et al. 1989a).
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Metabolism. Formaldehyde is a normal metabolic product of animal metabolism, with varying

endogenous levels present at all times (Bolt 1987). The major sources of endogenously produced

formaldehyde are glycine and serine.

Formaldehyde is rapidly metabolized and storage is not a factor in its toxicity. The metabolism of

formaldehyde to formate (via FDH/class III alcohol dehydrogenase) takes place in all of the tissues of the

body as a consequence of endogenous formation of formaldehyde and is quickly removed by the

supporting blood supply (Heck et al. 1982). FDH is the major metabolic enzyme involved in the

metabolism of formaldehyde in all of the tissues studied; is widely distributed in animal tissues,

particularly in the rat nasal mucosa; and is specific for the glutathione adduct of formaldehyde. If

formaldehyde is not metabolized by FDH, then it can form cross linkages between protein and singlestranded DNA (see Figure 2-3) or enter the 1 carbon intermediary metabolic pool by initially binding to

tetrahydrofolate (Bolt 1987). Several enzymes can catalyze the reaction that oxidizes formaldehyde to

formic acid (i.e., nonspecific aldehyde dehydrogenase and catalase); however, FDH is the primary

enzyme tasked to perform this function and is specific for formaldehyde; other aldehydes are left intact in

the presence of FDH. Endogenous or exogenous formaldehyde enters FDH metabolic pathway and is

eliminated from the body as metabolites, primarily as formate or CO2. FDH activity does not increase

(i.e., not inducible) in response to formaldehyde exposure (Casanova-Schmitz et al. 1984b). Heck et al.

(1985) provided some indirect evidence in both the human and the rat that inhaled formaldehyde (1.9 ppm

for 40 minutes for the human, 14.4 ppm for 2 hours in the rat) is quickly metabolized (probably by FDH)

and did not raise blood formaldehyde concentrations beyond the measured endogenous levels, although

this finding may have also been due to low systemic absorption. Little information about the metabolism

of formaldehyde after oral or dermal exposures was available.

Increasing the amounts of formaldehyde in the diet of some lactating ruminants (cows, sheep, goats, etc.)

will increase the amount of intact formaldehyde present in their milk (Barry and Tome 1991; Buckley et

al. 1988). Neither of these reports offered an explanation for these findings. However, given the marked

differences in blood and plasma characteristics and the differences in gastrointestinal anatomy, it is

plausible to assume that there are some fundamental differences between formaldehyde metabolism in

ruminant animals and in humans (or other monogastrics), which leads to increased milk levels of

formaldehyde. There is a close relationship between the amount of formaldehyde ingested and the

amount of formaldehyde present in the milk (Barry and Tome 1991). Milk formaldehyde concentrations 
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2. HEALTH EFFECTS

are not influenced by the level of milk production, which suggests that the passage of formaldehyde from

the blood to the milk is a passive event (Barry and Tome 1991).

Excretion. Given the rapid conversion of formaldehyde to formate and subsequent incorporation into

naturally occurring cellular constituents, excretion does not appear to be a factor in the toxicity of

formaldehyde. The metabolism of formaldehyde to formate takes place in all of the tissues of the body as

a consequence of endogenous formation of formaldehyde. Exogenous formaldehyde enters this pathway

and is eliminated from the body as metabolites, primarily CO2. For example, in rats exposed to

14C-formaldehyde via inhalation, 40% of the radioactivity was recovered as 14CO2 (Heck et al. 1983). 

After oral exposure to formaldehyde in male rats administered 2.2 g (18 μCi) of 14C-formaldehyde, 67%

of the radioactivity dose was excreted in the feces and 32% exhaled as CO2 within 32 hours after dosing. 

The 14C plasma elimination half-life was calculated to be 26.4 hours (Galli et al. 1983); however, it is

unclear what percentage of this activity involves intact formaldehyde and what involves metabolites (i.e.,

formate). In a similar study in male mice administered 0.5 g (4 μCi) of 14C-formaldehyde, 64% of the

total dose of radioactivity was eliminated via the feces and 24% eliminated as exhaled CO2. The plasma

half-life was calculated to be 27.8 hours in this study (Galli et al. 1983). Intact formaldehyde is excreted

in the milk in goats (Barry and Tome 1991) and dairy cows (Buckley et al. 1988).

2.4.2 Mechanisms of Toxicity

The exact mechanism by which formaldehyde exerts its irritant, corrosive, and cytotoxic effects is not

known. Aldehydes as a group are reactive chemicals with a highly electronegative oxygen atom and less

electronegative atoms of carbon(s), and hence have a substantial dipole moment. The carbonyl atom is

the electrophilic site of these type of molecules, making it react easily with nucleophilic sites on cell

membranes and in body tissues and fluids such as the amino groups in protein and DNA (Feron et al.

1991). 

It is also known that formaldehyde can form cross links between protein and DNA in vivo. 

Casanova-Schmitz et al. (1984a) reported that the predominant route of formaldehyde metabolism was

metabolic incorporation into macromolecules (DNA, RNA, and proteins) in the respiratory and olfactory

mucosa and bone marrow of male Fischer 344 rats. Rats were exposed nose-only for 6 hours to 0.3, 2, 6,

10, or 15 ppm mixtures of 14C and 3

H-formaldehyde 1 day after a 6-hour exposure to the same

concentration of unlabeled formaldehyde. There was some evidence of DNA-protein cross linking 
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present in the nasal tissues. Concentrations of 14C DNA in respiratory and olfactory mucosa tissues

increased linearly with dose; at all doses, the concentrations of 14C DNA in respiratory mucosa tissues

were approximately two to three times that in olfactory mucosa tissues. Later studies by Casanova et al.

(1991a, 1991b) described the formation of DNA-protein cross links in the respiratory tract measured in

male Fischer 344 rats as well as in Rhesus monkeys. Rats were again exposed nose-only to a mixture of

14C-labeled and nonradiolabeled formaldehyde, using concentrations of 0.3, 0.7, 2, 6, or 10 ppm for

6 hours. Formaldehyde was again observed in the form of formaldehyde-DNA-protein cross links, and

was detected at all concentrations tested. Male Rhesus monkeys were exposed to 0.7, 2, or 6 ppm

formaldehyde 14C-labeled and nonradiolabeled mixture for 6 hours and it was determined that

approximately 90% of all 14C was associated with the thymine, while 10% was associated with the

guanine and adenine. Concentrations of DNA-protein cross links were greatest in the middle turbinate

tissues and lowest in the nasopharyngeal tissues, with some evidence of cross link formation observed in

the larynx/trachea/carina and major intrapulmonary airway tissues of two monkeys in the 6-ppm dose

group. No evidence of cross link formation was seen in the sinus or lung tissues at any exposure

concentration.

The mechanism by which formaldehyde exerts its toxicological effects is not known; however, it is

known that formaldehyde readily combines with free, unprotonated amino groups of amino acids to yield

hydroxymethyl amino acid derivatives and a proton (H+

), which is believed to be related to its germicidal

properties. Higher concentrations will precipitate protein (Loomis 1979). Either one of these mechanistic

properties or perhaps other unknown properties may be responsible for the irritation effects seen with

formaldehyde exposure. It is probable that formaldehyde toxicity occurs when intracellular levels

saturate formaldehyde dehydrogenase activity, overwhelming the natural protection against

formaldehyde, and allowing the unmetabolized intact molecule to exert its effects locally. The primary

metabolite of formaldehyde, formate, is not expected to be as reactive as formaldehyde itself and is

subject to excretion as a salt in the urine, entrance into the one-carbon metabolic pool for incorporation

into other cellular components, or further metabolism to carbon dioxide. 

The toxicity of formaldehyde is route-dependent. Irritation at the point of contact is seen by inhalation,

oral, and dermal routes. High doses are cytotoxic and result in degeneration and necrosis of mucosal and

epithelial cell layers. These observations are consistent with the hypothesis that toxic effects are 

mediated by formaldehyde itself and not by metabolites. No specific target molecule has been identified,

although DNA-protein cross links have been identified (Casanova and Heck 1987). As discussed in 
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Section 2.2, oral and inhalation toxicity studies with animals generally have found that toxic effects from

formaldehyde are restricted to portal-of-entry tissue, but there are scattered reports of toxic effects at sites

distant from portals-of-entry. The mechanism whereby distant site toxicity may be expressed is unclear,

but given the highly reactive nature of formaldehyde and the ubiquitous metabolic capability of cells to

metabolize formaldehyde, it is plausible that distant site effects may occur only when the capacity for

local disposition of formaldehyde is exceeded.

An example of a local effect of formaldehyde vapor was demonstrated in the rat nasal epithelium. In rat

studies where cell turnover was measured (a measure of formaldehyde cytotoxicity), the no-effect level is

approximately 2 ppm (Monticello et al. 1991; Swenberg et al. 1983) for 6 hours/day exposures for

#9 days. At higher concentrations (6, 10, or 15 ppm), higher rates of cell turnover were seen (Monticello

et al. 1991), and a dose-response was observed. The increase in cell proliferation (as measured by

thymidine incorporation) was more sensitive to formaldehyde exposure than histopathological changes. 

Similar results were seen in a 6-week experiment at these same doses in which the rats were exposed

5 days/week. The relationship between concentration and total dose has been studied in experiments

where rats were exposed to a range of concentrations for various lengths of time so that the total inhaled

dose was constant (Wilmer et al. 1987, 1989). Studies have shown that formaldehyde concentration in

the inspired air may be more important than exposure duration in determining the extent of nasal damage

(Wilmer et al. 1987, 1989) (see Section 2.5). Monticello et al. (1996) also determined that the nasal cell

target population size, increased cell proliferation of specific target cells (due to differences in regional

airflow with the rat nasal cavity), and the nonlinear kinetics of formaldehyde binding to DNA explain

why specific regions of the rat nose are more prone to develop formaldehyde-induced nasal squamous cell

carcinomas than other sites in the nasal cavity. 

Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations

of cells has been studied. Monticello et al. (1996) assessed the role of regional increases in nasal

epithelial cell proliferation in the formation of formaldehyde-induced nasal cancer in male Fisher 344 rats

whole-body exposed to formaldehyde up to 15 ppm for 24 months. The majority of formaldehydeinduced neoplasms consisted of squamous cell carcinomas and polyploid adenomas; however, cell

proliferation was not affected by formaldehyde exposures of 6.01 ppm or less. Increases in the cell

labeling index were significant at the 10 and 15 ppm exposure levels, and there was a highly significant

correlation between formation of tumor cells and proliferating cells within the rat nasal cavity.
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Although there is evidence to suggest that exposure concentration is more important than exposure

duration in determining the extent of formaldehyde-induced nasal epithelial damage, the development of

formaldehyde-induced nasal squamous cell carcinomas is likely to require repeated and prolonged

damage to the nasal epithelium. Several key points or events determine the mechanism by which

formaldehyde induces cancer in rats. First, a single high dose (#40 ppm) for acute durations is not likely

sufficient to induce squamous cell carcinoma cancer (Bhalla et al. 1990; Monteiro-Riviere and Popp

1986; Wilmer et al. 1987); repeated exposures for protracted durations are required to induce nasal cancer

in rats. Second, the data indicate that a sequence of cellular events must occur in order to induce nasal

carcinomas. The induction of nasal cancer in rats by formaldehyde requires repeated exposure for

prolonged periods of time to high concentrations that are both irritating and that cause cell damage to a

population of the nasal mucosa cells lining the nose. Exposure to high concentrations for prolonged

periods during inhalation exposure overwhelms or otherwise exhausts the inherent defense mechanisms to

formaldehyde (mucociliary clearance, FDH, DNA repair). This cellular and tissue damage inflicted by

unmetabolized formaldehyde is then followed by a regenerative hyperplasia and metaplasia phase (Chang

et al. 1983; Feron et al. 1988; Rusch et al. 1983; Wilmer et al. 1987; Woutersen et al. 1987, 1989), which

results in increased cell-turnover rates within the mucosa. Formaldehyde has been demonstrated to be

genotoxic in some (but not all) cell lines and test systems (Basler et al. 1985; Donovan et al. 1983;

Grafstrom et al. 1985, 1993; Rithidech et al. 1987; Snyder and Van Houten 1986; Valencia et al. 1989;

Woodruff et al. 1985; Yager et al. 1986). DNA-protein cross links have been demonstrated in

experimental animals after inhalation exposure to formaldehyde and can cause mutation or chromosomal

aberrations if not repaired prior to cell replication. The DNA damage that occurs in these altered cells is

carried into subsequent cell populations and thereby greatly enhances the progression of preneoplastic

cells to cancer. In this manner, formaldehyde likely can act as a complete carcinogen (providing

initiation, promotion, and progression) with repeated and prolonged duration of exposure at cytotoxic

concentrations. Point mutations in the p53 tumor suppressor gene were found in 5 of 11 nasal tumors

examined from rats exposed to 15 ppm formaldehyde for 2 years (Recio et al. 1992). The tissues in the

Recio et al. (1992) study were reanalyzed using antibodies against p53. One was a monoclonal antibody

to mutant p53, and the other a polyclonal antibody directed against epitopes in mutant and wild type p53

(Wolf et al. 1995). Morphologically normal nasal mucosa and metaplastic and hyperplastic tissues were

negative for p53 immunoreactivity. In squamous cell carcinomas (the five with previously identified p53

mutations and three of six tumors with no mutations identified), p53 immunoreactivity was focal to

diffuse, and the authors stated that their results using these antibodies were solely from reactions with

mutant p53.
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2.4.3 Animal-to-Human Extrapolations

The target organs for formaldehyde appear to be similar in humans and laboratory animals exposed to

airborne, ingested, or dermally-applied formaldehyde. As discussed in Section 2.2.1, airborne

formaldehyde is an acute contact irritant in humans and laboratory animals, causing irritation of the eyes

and upper respiratory tract during an inhalation exposure. Repeated exposure to airborne formaldehyde

has been associated with region-specific damage to the upper respiratory tract epithelium in rats,

monkeys, and mice (e.g., Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al.

1989, 1996), and evidence for similar lesions has been found in nasal tissue specimens sampled from

occupationally-exposed workers (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom

et al. 1989c). Lifetime exposure to formaldehyde concentrations between 10 and 15 ppm produced nasal

tumors in rats, but no evidence of malignant neoplastic lesions has been found in numerous rat studies at

concentrations #2 ppm (e.g., Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et

al. 1989). Some studies of formaldehyde-exposed workers, typically exposed to average concentrations

below 2 ppm, have found evidence for an increase in nasopharyngeal cancer death rate, whereas other

studies of other groups of exposed workers have found no cases of nasopharyngeal cancer (see

Section 2.2.1.8). Gastric lesions have been induced in rats (e.g., Til et al. 1988b) and in humans

(Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986; Koppel et al. 1990) after oral exposure. 

Formaldehyde is produced endogenously in all animal species studied. Absorption, distribution,

metabolism, and excretion of formaldehyde are similar across species; however, species differences in

upper respiratory tract anatomy and physiology likely play a role in determining the location of

nonneoplastic (and neoplastic) lesions from inhaled formaldehyde. Formaldehyde-induced epithelial

lesions, such as squamous metaplasia, showed a wider distribution of occurrence in the upper respiratory

tract of Rhesus (Monticello et al. 1989) and Cynomolgus (Rusch et al. 1983) monkeys than similar

lesions which were mostly confined to the anterior portion of the nasal cavity in formaldehyde-exposed

rats (Bhalla et al. 1991; Monteiro-Riviere and Popp 1986; Morgan et al. 1986a; Wilmer et al. 1987;

Woutersen et al. 1987). The differences in location of these lesions are likely due to differences in

airflow pattern through the nasal cavity, resulting in different deposition patterns. The fact that rats are

obligate nose-breathers and monkeys have an oronasal breathing pattern likely also has an impact on the

location of these lesions. Other species differences have been noted between rats and mice. Mice tend to

be more efficient at reducing their minute volumes during formaldehyde exposures than rats, which may 
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partially account for the differences in the decreased incidences of nonneoplastic lesions (Maronpot et al.

1986) and neoplastic lesions in mice compared rats (Chang et al. 1981, 1983).

Available studies of animals exposed by the oral or inhalation routes clearly show that formaldehydeinduced health effects are restricted to portals-of-entry and that inhaled formaldehyde, at

concentrations $6 ppm, produces nasal tumors in rats (as discussed earlier in Section 2.2.1.8). In contrast,

epidemiology studies of occupationally-exposed humans have provided only equivocal evidence for

respiratory tract cancer. Even so, this does not negate the need to determine human cancer risk estimates,

perhaps by employing means other than epidemiological information. The U.S. EPA (1991a) used doseresponse data for nasal tumors in rats exposed to high concentrations of formaldehyde to extrapolate to

human cancer risk at low exposure concentrations, using the rate of DNA-protein cross links in target

tissue as a measure of delivered dose. Estimates of delivered dose and observed rat nasal tumor incidence

were modeled with a linearized multistage procedure (i.e., were fit to an exponential polynomial model)

to obtain a 95% upper confidence limit on the slope in the low-dose region of the dose-response curve (a

rat unit cancer risk estimate of 1.6x10-4 per [pmol DNA-protein cross links/mg DNA/day]). Relationships

between formaldehyde air concentrations and rates of formation of DNA-protein cross links in nasal

epithelial tissue of rats (Casanova et al. 1989) or of Rhesus monkeys (Casanova et al. 1991; Heck et al.

1989) and adjustments to continuous exposure were then used to calculate lifetime human cancer unit risk

estimates of 3.3x10-4 per ppm formaldehyde based on the monkey data, and 2.8x10-3 per ppm

formaldehyde based on the rat data. 

The use of DNA-protein cross link formation as a formaldehyde dosimeter in cancer target tissues is

supported by correlative observations of nonlinear (convex) relationships between DNA-protein cross

link formation in nasal epithelium of rats and monkeys and formaldehyde air concentrations and similar

convex exposure-response relationships for formaldehyde-induced tumors in rats (Casanova et al. 1991;

EPA 1991a). The convex nature of these relationships may be explained by a number of mechanisms,

including saturation of enzymes involved in metabolism of formaldehyde, a decrease in the functioning of

the mucociliary apparatus that may trap and remove formaldehyde before it reaches target tissues,

saturation of protein-binding kinetic mechanisms, and saturation of inherent DNA-protein cross link

repair mechanisms. 

As discussed in Section 2.3.5, The Chemical Industry Institute of Toxicology and the U.S. EPA (CIIT

1998) are currently exploring options in using CFD models of nasal airflow and uptake of formaldehyde, 
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pharmacokinetic models of nasal disposition of formaldehyde, and two-stage clonal growth cancer

models to derive estimates of cancer risk in humans exposed to inhaled formaldehyde based on nasal

epithelial responses observed in rats chronically exposed to formaldehyde.

2.5 RELEVANCE TO PUBLIC HEALTH

Overview. 

Although formaldehyde is a normal intermediary cellular metabolite involved in the biosynthesis of

purines, thymidine, and several amino acids, it is a highly reactive molecule that can be directly irritating

to tissues with which it comes into contact. Human and animal studies indicate that formaldehyde, at

appropriate exposure levels, can be irritating to the upper respiratory tract and eyes with inhalation

exposure, to the skin with dermal exposure, and to the gastrointestinal tract with oral exposure. Reports

of allergic dermal sensitization to formaldehyde are widespread and supported by results from animal

studies, but the evidence that formaldehyde sensitizes the respiratory tract is less convincing.

 

Studies of volunteers exposed to airborne formaldehyde for short periods of time (8 hours or less) indicate

that eye, nose, and throat irritation occurs at concentrations in the range of 0.4–3 ppm (Andersen and

Molhave 1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al.

1987; Pazdrak et al. 1993; Weber-Tschopp et al. 1977; Witek et al. 1986). At the lower end of this range,

the irritation is typically described as mild and noted by a lower percentage of exposed subjects than at

the upper end of the range. Studies of monkeys, rats, and mice exposed to higher concentrations in the

range of 3–9 ppm for acute to intermediate periods of time demonstrate that formaldehyde nonneoplastic

toxic effects are restricted to lesions (squamous metaplasia and hyperplasia) in the epithelium of the upper

respiratory tract (Chang et al. 1983; Monticello et al. 1989; Morgan et al. 1986a, 1986c; Rusch et al.

1983; Woutersen et al. 1987; Zwart et al. 1988). 

Studies of animals exposed for life to formaldehyde in air or drinking water also show that formaldehyde

primarily damages tissue at portals-of-entry (i.e., the upper respiratory tract and the gastrointestinal 

tract); evidence for toxic effects at distant sites is less consistent. Replicated inhalation studies have

shown that formaldehyde induced malignant nasal tumors in rats at high exposure concentrations (10–

15 ppm) that also induced nasal epithelial necrosis and cellular proliferation, but not at lower 

concentrations (0.3–2 ppm) that did not markedly damage nasal epithelial tissue (Albert et al. 1982; 
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Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Exposure-related

cancer or noncancer lesions at other sites were not found in these studies. Statistically significant

increased incidences of nasal tumors, however, were not found in mice exposed by inhalation for 2 years

(Kerns et al. 1983b) or in hamsters exposed for 18 months (Dalbey 1982) at concentrations similar to

those producing nasal tumors in rats. Nonneoplastic nasal epithelial damage was found in mice exposed

to 14 ppm, but not in mice exposed to 2 ppm (Kerns et al. 1983b). Three lifetime drinking-water

exposure studies in rats that found no consistent, exposure-related cancer or noncancer effects at sites

distant from the gastrointestinal tract (Soffriti et al. 1989; Til et al. 1989; Tobe et al. 1989) provide

support for the expectation that formaldehyde-induced health effects are restricted to portals-of-entry. 

More than 40 epidemiology studies (cohort studies of industrial workers, cohort studies of medical

specialists and embalmers, and case-control studies) examining the potential for occupational

formaldehyde exposure to induce cancer have provided only equivocal evidence of a relationship between

formaldehyde and nasopharyngeal cancer in humans, and even less convincing evidence for extrarespiratory cancer.

Occupational and residential exposure to formaldehyde has been associated with reports of symptoms of

eye, nose, and throat irritation from exposure to airborne formaldehyde (Garry et al. 1980; Holness and

Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987), and there are numerous reports of skin

irritation and contact dermatitis most likely resulting from dermal exposure to formaldehyde in liquids

(Fischer et al. 1995; Kiec-Swierczynska 1996; Maibach 1983; Meding and Swanbeck 1990; Menné et al.

1991). Several cross-sectional studies of nasal epithelial tissue specimens from workers exposed to

airborne formaldehyde in the approximate average concentration range of 0.2–1 ppm found evidence in

some of the workers for mild lesions (stratified squamous epithelium and mild dysplasia) that are

indicative of the irritant and reactive properties of formaldehyde (Ballarin et al. 1992; Boysen et al. 1990;

Edling et al. 1988; Holmstrom et al. 1989c). 

The apparent restriction of formaldehyde-induced noncancer and cancer effects to portals-of-entry is

consistent with the highly reactive nature of formaldehyde and the existence of physiological mechanisms

of protection, such as the nasal mucosal barrier and the detoxifying metabolism of formaldehyde in most,

if not all, cells. The available weight of evidence indicates that distant site effects from formaldehyde

may occur only when the capacity for local disposition of formaldehyde is exceeded.
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Issues relevant to children are explicitly discussed in Sections 2.6 Children’s Susceptibility and

5.6 Exposures of Children.

Minimal Risk Levels for Formaldehyde. 

The details regarding calculations of the MRLs for formaldehyde are described in Appendix A.

Inhalation MRLs

C An MRL of 0.04 ppm has been derived for acute-duration inhalation exposure (14 days or less)

to formaldehyde.

The MRL was calculated from a minimal LOAEL of 0.4 ppm for symptoms of increased itching,

sneezing, mucosal congestion, and transient burning sensation of the eyes and of the nasal passages, and

elevated eosinophil counts and a transient increase in albumin content of nasal lavage fluid in volunteers

exposed to formaldehyde for 2 hours (Pazdrak et al. 1993). The LOAEL was divided by an uncertainty

factor of nine (three for the use of a minimal LOAEL and three for human variability) as described in

Appendix A. 

 

The selection of 0.4 ppm as an acute exposure concentration that produces mild eye, nose, and throat

irritation in some human subjects is supported by reports of: nasal irritation, sneezing, and eye irritation in

3/13 subjects with formaldehyde contact dermatitis and eye irritation in 1/5 normal subjects exposed to

0.4 ppm for 2 hours (Gorski et al. 1992); increased eosinophil counts and protein in nasal lavage fluid in

other groups of 10 healthy subjects and 10 workers with purported formaldehyde-induced bronchial

asthma exposed to 0.4 ppm for 2 hours (Krakowiak et al. 1998); eye and nasal irritation in 3/16 healthy

subjects exposed to 0.2 ppm for 4 hours (Andersen and Molhave 1983); and decreased eye irritation

response time in 5/12 subjects exposed to 0.35 ppm for 6 minutes (Bender et al. 1983). Several other

acute controlled exposure studies with volunteers have noted higher percentages of subjects reporting

mild eye, nose, and throat irritation at concentrations between 1 and 2 ppm (Day et al. 1984; Kulle et al.

1987; Weber-Tschopp et al. 1977; Witek et al. 1986). The Anderson and Molhave (1983) study

identified an apparent effect level (0.2 ppm) based on subjective reports of irritation that is lower than the

effect levels (0.35–0.4 ppm) in the studies by Pazdrak et al. (1993), Krakowiak et al. (1998), and Bender

et al. (1983) which used more objective measures of acute irritation. Because of the use of objective

measures of toxicity and the general weight of the available data indicating that some people will not 
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experience eye or upper respiratory tract irritation from formaldehyde even at 1 ppm, the Pazdrak et al.

(1993) LOAEL of 0.4 ppm was considered a minimal LOAEL in a group of potentially sensitive

individuals (some subjects had dermal hypersensitivity to formaldehyde) and was selected as the basis of

the acute MRL. 

C An MRL of 0.03 ppm has been derived for intermediate-duration inhalation exposure

(15–364 days) to formaldehyde.

The MRL is based on a NOAEL of 0.98 ppm for clinical signs of nasopharyngeal irritation (hoarseness

and nasal congestion and discharge) and lesions in the nasal epithelium (squamous metaplasia and

hyperplasia) observed in Cynomolgus monkeys exposed to formaldehyde for 22 hours/day, 5 days/week

for 26 weeks (Rusch et al. 1983). The LOAEL was 2.95 ppm. As described in Appendix A, the NOAEL

was divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human

variability). 

Intermediate-duration inhalation studies with several species of animals clearly identify the upper

respiratory tract as the critical target tissue for airborne formaldehyde and suggest that degenerative

changes to the upper respiratory tract epithelium may not occur with exposure to concentrations #1 ppm. 

Formaldehyde-induced epithelial damage in the upper respiratory tract similar to that observed in the

Cynomolgus monkeys has been observed in: Rhesus monkeys exposed to 6 ppm for 6 hours/day,

5 days/week for 6 weeks (Monticello et al. 1989); several strains of rats subchronically exposed to

concentrations greater than 2 ppm (Appelman et al. 1988; Feron et al. 1988; Monticello et al. 1991; Rusch

et al. 1983; Woutersen et al. 1987); and mice exposed to concentrations $4 ppm (Chang et al. 1983;

Maronpot et al. 1986). Although there are numerous human studies of acute inhalation toxicity from

formaldehyde (controlled-exposure and occupational exposure studies) and numerous investigations of

toxic effects from chronic occupational exposures, studies of humans strictly exposed for intermediate

durations were not located. In contrast, the database for studies of animals (including primates) exposed

by inhalation to formaldehyde is rich, providing data describing exposure-response relationships for

formaldehyde-induced effects on the upper respiratory tract system in several species (rats, mice,

hamsters, and monkeys). The study by Rusch et al. (1983) examined a number of species and identified

the lowest effect level among the available sets of data. Given this observation, the absence of suitable

human intermediate-duration data, and the putatively greater relevance of monkeys, compared with
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rodents, to humans, the monkey NOAEL of 0.98 ppm and LOAEL of 2.95 ppm for clinical signs of

nasopharyngeal irritation were selected as the basis of the intermediate-duration MRL. 

C An MRL of 0.008 ppm has been derived for chronic-duration inhalation exposure (365 days or

more) to formaldehyde.

The MRL is based on a minimal LOAEL of 0.24 ppm for histological changes (loss of cilia, goblet cell

hyperplasia, and cuboidal and squamous cell metaplasia replacing the columnar epithelium) in nasal

tissue specimens from a group of 70 workers employed for an average 10.4 years (range 1–36 years) in a

chemical plant that produced formaldehyde and formaldehyde resins for impregnating paper (Holmstrom

et al. 1989c). The MRL was derived by dividing the LOAEL by an uncertainty factor of 30 (3 for the use

of a minimal LOAEL and 10 for human variability) as described in Appendix A.

Several cross-sectional studies of groups of formaldehyde-exposed workers chronically exposed to

estimated concentrations ranging from about 0.1 to 0.6 ppm (Ballarin et al. 1992; Boysen et al. 1990;

Edling et al. 1988; Holmstrom et al. 1989c) have found histological evidence for mild damage to nasal

epithelial tissue such as the damage described for exposed workers in the Holmstrom et al. (1989c) study. 

The observed effects were consistently mild, but each study reported a statistically significant, albeit

small, increase in average histological score (increasing scores indicating increasing severity of change)

for exposed groups compared with nonexposed control groups: 2.8 exposed versus 1.8 on an 8-point scale

(Edling et al. 1988); 2.16 versus 1.46 on an 8-point scale (Holmstrom et al. 1989c); 1.9 versus 1.4 on a

5-point scale (Boysen et al. 1990); and 2.3 versus 1.6 on a 6-point scale (Ballarin et al. 1992). The

Holmstrom et al. (1989c) study was selected as the basis of the MRL from among these four crosssectional studies (they each examined equivalent end points and are of similar quality of design) primarily

because the statistically significant effects were found in a group exposed to formaldehyde in the absence

of potentially confounding exposures to wood dust. A full uncertainty factor of 10 was used to account

for human variability because the observed mild effects were seen in groups of chronically exposed

workers that were otherwise in apparent good health; a healthy worker effect may have operated causing

sensitive individuals to avoid employment in the studied workplaces.

Additional supporting evidence for mild histological changes to the nasal epithelium with chronic

exposure to concentrations below 1 ppm comes from rat studies. Although several studies of rats 

exposed for life (generally with an exposure protocol of 6 hours/day, 5 day/week) found no statistically

significant increases in incidences of nonneoplastic lesions in the nasal epithelium of rats exposed to 
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0.1 to 2 ppm (Kerns et al. 1983b [F344 rats]; Monticello et al. 1996 [F344 rats]; Woutersen et al.

1989 [Wistar rats]), Kamata et al. (1997) reported that some F344 rats, after 28 months of exposure,

displayed a mild response at 2 ppm and even at 0.3 ppm. A statistically significantly increased incidence

for nasal epithelial squamous metaplasia without hyperplasia was observed in rats exposed to 2 ppm

compared with control rats (5/32 versus 0/32); the incidence for nasal epithelial cell hyperplasia with

squamous metaplasia was also significantly elevated compared with controls (7/32 versus 0/32). In rats

exposed to 0.3 ppm, incidences of the same respective nasal epithelial lesions were also greater than

control incidences (1/32 versus 0/32 and 4/32 versus 0/32), but not to a statistically significant degree.

Oral MRLs

Case reports of acute poisoning in humans ingesting doses of formaldehyde greater than 200 mg/kg have

reported gastrointestinal effects and symptoms that reflect the chemical reactivity of formaldehyde and

have reported other effects (e.g., cardiovascular dysfunction, coma, and renal and hepatic dysfunctions)

that are consistent with the exceedance of the capacity of local detoxification mechanisms at these high

dose levels (Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986). The acute human poisoning

data, coupled with the results from studies of animals orally exposed to formaldehyde for intermediate

and chronic durations, suggest that gastrointestinal irritation and damage are the most likely critical

effects from acute oral exposure. A no-effect level is not identified by the human data, however, and

available studies of animals exposed for acute durations provide no dose-response information for this

end point. Available acute-exposure animal data are restricted to 2-week, oral administration studies that

only examined body weight in rats (Johannsen et al. 1986) and a 10-day gavage administration study of

testicular weight and sperm variables in rats (Cassidy et al. 1983). In the absence of dose-response data

for gastrointestinal irritation and damage from acute oral exposure, no acute-duration MRL was derived. 

C An MRL of 0.3 mg/kg/day has been derived for intermediate-duration oral exposure

(15–364 days) to formaldehyde.

The MRL was based on a NOAEL of 25 mg/kg/day for gastrointestinal effects in rats exposed to

formaldehyde in drinking water (Til et al. 1988b). The LOAEL was 125 mg/kg/day. An uncertainty

factor of 100 (10 for extrapolation from animals to humans and 10 for human variability) was applied to

the NOAEL to derive the MRL. The Til et al. (1988b) study used groups (10 males and 10 females) of

weanling Wistar rats that received 0, 5, 25, or 125 mg/kg/day formaldehyde in their drinking water for

4 weeks. Control groups (20 males and 20 females) were given unsupplemented tap water. A water-
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restricted group (10 males and 10 females) received the same amount of unsupplemented drinking water

as the amount of liquid consumed by the group given the highest dose of formaldehyde. Dosing solutions

were prepared fresh every week and fresh drinking water containing a calculated concentration of

formaldehyde was provided to the rats every day. The authors did not report if or how often the drinking

water was assayed for actual formaldehyde content, so it is not known, due to possible oxidation,

polymerization, or evaporation, if the full dose of formaldehyde was received. Histopathology revealed

thickening of the limiting ridges, hyperkeratosis in the forestomach, and focal atrophic inflammation in

the glandular stomach in animals given a high concentration of formaldehyde. Moderate papillomatous

hyperplasia was seen in one female given a high concentration of formaldehyde. Types of lesions in

males given 125 mg/kg formaldehyde are as follows: slight-to-moderate focal hyperkeratosis of

forestomach, slight-to-moderate focal gastritis, and slight-to-moderate submucosal mononuclear-cell

infiltrate. Types of lesions in females given 125 mg/kg formaldehyde are as follows: very slight, slightto-moderate focal hyperkeratosis of forestomach; very slight, slight-to-moderate focal gastritis; focal

papillomatous hyperplasia; and polymorphonuclear leucocytic infiltration. No gastrointestinal effects

were noted at the 25 mg/kg/day dose of formaldehyde.

 

Gastrointestinal irritation and damage have been observed in both humans and animals after ingestion of

formaldehyde. In human poisoning studies, effects observed include: ulceration and sloughing of the soft

palate and posterior pharyngeal wall; ulceration of the epiglottis, pyriform fossae, and arytenoids;

edematous and ulcerated esophageal mucosa with patches of black sloughed tissue along the entire length;

hyperemic areas of the stomach; and superficial ulceration in the distal body and antrum after a single

dose of 234 mg/kg formaldehyde (Kochhar et al. 1986); abdominal pain and retching; and hard, white,

and leathery stomach after a dose of 517 mg/kg (Burkhart et al. 1990); or abdominal pain after a dose of

624 mg/kg (as formalin) (Eells et al. 1981). In human poisoning studies in which the dose of

formaldehyde is not known, gastrointestinal symptoms included mucosal damage, ulceration and bleeding

of the buccal cavity and tonsils, and dysphagia due to esophageal mucosal damage (Freestone and

Bentley 1989); necrosis of the esophagus and stomach, extensive congestion, peptic plaques in esophagus

and stomach, colitis, congestion, diffuse necrosis and hemorrhage of gastric and duodenal mucosa, burns

in gastrointestinal mucosa, and ileitis (Koppel et al. 1990). In rat studies in which formaldehyde was

administered orally for longer periods of time, consistent evidence has been found for gastrointestinal

irritation and damage, but the evidence for orally-induced neoplastic lesions is equivocal due to

inconsistent findings among the studies (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe

et al. 1989). 
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C An MRL of 0.2 mg/kg/day has been derived for chronic-duration oral exposure (365 days or

more) to formaldehyde.

The MRL was based on a NOAEL of 15 mg/kg/day for gastrointestinal effects in male rats exposed to

formaldehyde in drinking water (Til et al. 1989). The LOAEL was 82 mg/kg/day. An uncertainty factor

of 100 (10 for extrapolation from animals to humans and 10 for human variability) was applied to the

NOAEL to derive the MRL. The Til et al. (1989) study used groups of Wistar rats that received

formaldehyde in their drinking water for 2 years. Estimated formaldehyde doses in this study were 0, 1.2,

15, or 82 mg/kg/day for males and 0, 1.8, 21, or 109 mg/kg/day for females. Dosing solutions were

prepared fresh every week and fresh drinking water containing a calculated concentration of

formaldehyde was provided to the rats every day. The authors did not report if or how often the drinking

water was assayed for actual formaldehyde content, so it is not known, due to possible oxidation,

polymerization, or evaporation, if the full dose of formaldehyde was received. Necropsy findings of

high-dose rats killed in weeks 53, 79, and 105 revealed a raised and thickened limiting ridge of the

forestomach in most male and female rats of the high-dose group and in some males and females of the

other groups, including the control group. Also, several rats in the high-dose groups showed irregular

mucosal thickenings in the forestomach and/or glandular stomach. These changes were also found in rats

of the other groups as well as the control groups. In high-dose animals, histopathological examination

revealed gastric changes including papillary epithelial hyperplasia accompanied by hyperkeratosis and

focal ulceration in the forestomach and focal chronic atrophic gastritis, occasionally accompanied by

ulceration and/or glandular hyperplasia, in the glandular stomach. There were no gastric tumors observed

apart from two benign papillomas, one in the male of the low-dose group and one in a female control rat.

Death. Cases of death in humans acutely exposed to airborne formaldehyde were not located. Death

after the ingestion of formaldehyde (or a formalin solution) in humans has been reported in connection

with attempted suicides. Metabolic acidosis has been noted prior to death, along with respiratory, cardiac,

and renal failure; autopsy revealed corrosive damage to gastrointestinal mucosa (Burkhart et al. 1990;

Eells et al. 1981; Koppel et al. 1990). Increased rates of cancer-related mortality associated with

occupational exposure to formaldehyde (predominately by inhalation) have been found in some

epidemiological studies, but not in others (see Section 2.2.1.8 and Section 2.5). Animal studies indicate

that subchronic inhalation exposure to concentrations below 20 ppm are not lethal (Feron et al. 1988;

Maronpot et al. 1986; Martin 1990; Rusch et al. 1983; Saillenfait et al. 1989; Woutersen et al. 1987), but

lifetime inhalation exposure to formaldehyde has been associated with early mortalities associated with 
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nasal tumors in rats exposed to concentrations $10 ppm (Albert et al. 1982; Kamata et al. 1997; Kerns et

al. 1983b; Monticello et al. 1996; Woutersen et al. 1989). Lifetime administration of 5,000 ppm

formaldehyde in drinking water (approximate dose of 300 mg/kg/day) to rats resulted in early mortalities

associated with degenerative lesions in the epithelium of the forestomach and the glandular stomach

(Tobe et al. 1989). 

Systemic Effects. 

Respiratory Effects. Results from human and animal studies consistently indicate that the upper

respiratory tract is a critical target of airborne formaldehyde at concentrations ranging from 0.4 to

20 ppm.

Controlled exposure human studies indicate that short-term exposure to air concentrations ranging from

0.4 to 3 ppm induces eye, nose, and throat irritation that is generally described as mild by most subjects,

especially at the lower end of this range, and that is experienced by a greater percentage of subjects at the

upper end, compared with the lower end, of the range (Andersen and Molhave 1983; Bender et al. 1983;

Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle et al. 1987; Pazdrak et al. 1993;

Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986). Changes in nasal lavage fluid

contents (elevated eosinophil counts and protein content), consistent with mild irritation of the nasal

epithelium, have been found in several studies of groups of subjects exposed to 0.4 ppm for 4 hours

(Gorski et al. 1992; Krakowiak et al. 1998; Pazdrak et al. 1993). The studied groups included healthy

subjects, as well as groups of subjects with dermal sensitivity to formaldehyde (Pazdrak et al. 1993) and

groups with purported formaldehyde-induced bronchial asthma (Krakowiak et al. 1998).

Formaldehyde effects on pulmonary function variables, such as FVC, FEV1, and forced expiratory flow

rates, have not been found in most studies between 0.4 and 3 ppm, even in studies of subjects with

bronchial asthma or with dermal sensitivity to formaldehyde (Andersen and Molhave 1983; Day et al.

1984; Gorski et al. 1992; Harving et al. 1986, 1990; Kulle et al. 1987; Schachter et al. 1986; Witek et al.

1986). A few controlled exposure studies have found only subtle or infrequent effects of formaldehyde

on lower respiratory tract function in this concentration range, supporting the hypotheses that the upper

respiratory tract is a more likely target of formaldehyde toxicity than the lower respiratory tract and that

pulmonary hypersensitivity to formaldehyde is rare (Green et al. 1987; Nordman et al. 1985; Sauder et al.

1986). 
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In groups of humans who experienced repeated exposure to airborne formaldehyde under occupational or

residential conditions, symptoms of eye, nose, and throat irritation were frequently reported (Boysen et al.

1990; Edling et al. 1988; Garry et al. 1980; Holmstrom et al. 1989c; Holness and Nethercott 1989;

Horvath et al. 1988; Ritchie and Lehnen 1987). Mild lesions in biopsied nasal epithelium tissue (e.g.,

stratified squamous epithelium and mild dysplasia) that are indicative of the irritant and reactive

properties of formaldehyde were consistently found in four cross-sectional studies of groups of workers

exposed to estimated average workplace air concentrations ranging from about 0.1 to 1 ppm (Ballarin et

al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Some studies assessing

pulmonary function variables (e.g., FVC, FEV1, FEFR) in groups of formaldehyde-exposed workers,

generally experiencing average workplace air concentrations below 2 ppm, have found no changes that

can be attributed to exposure (Bracken et al. 1985; Holness and Nethercott 1989; Horvath et al. 1988). 

Other studies have presented evidence for formaldehyde-induced changes in pulmonary function

variables in groups of subjects exposed in their homes or workplaces, but the changes in these studies

were generally small or subtle (Alexandersson and Hedenstierna 1988, 1989; Khamgaonkar and Fulare

1991; Kriebel et al. 1993; Krzyzanowski et al. 1990; Malaka and Kodama 1990).

Studies in animals confirm that the upper respiratory tract is a critical target for airborne formaldehyde. 

Studies of monkeys, rats, and mice exposed to concentrations in the range of 0.3–40 ppm for acute to

chronic periods of time demonstrate that formaldehyde nonneoplastic effects are restricted to lesions

(squamous metaplasia and hyperplasia) in the epithelium of the upper respiratory tract (Chang et al. 1983;

Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989, 1991, 1996; Morgan

et al. 1986a, 1986c; Rusch et al. 1983; Woutersen et al. 1987, 1989; Zwart et al. 1988). In several

lifetime rat studies, exposure to 0.1–2 ppm formaldehyde (6 hours/day, 5 days/week) produced no

statistically significant increased incidence of rats with nonneoplastic nasal epithelial lesions (Kerns et al.

1983b; Monticello et al. 1996; Woutersen et al. 1989). Another 28-month study, however, found

significantly increased incidence of nasal epithelial lesions (squamous metaplasia without hyperplasia and

epithelial cell hyperplasia with squamous metaplasia) in a group of rats exposed to 2 ppm by the same

exposure protocol (Kamata et al. 1997). Incidences of the same lesions in rats exposed to 0.3 ppm also

were greater than control incidences, but the difference was not statistically significant.

In rats exposed to the lower concentrations in the 2–20 ppm range, formaldehyde-induced lesions

(evidence of which could be found after a few days of exposure) occurred in the anterior regions of the

nasal epithelium just posterior to the vestibule and progressed to more posterior regions of the upper 
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respiratory tract epithelium with higher exposure concentrations (Chang et al. 1983; Monticello et al.

1991; Morgan et al. 1986a, 1986c; Zwart et al. 1988). Results from studies in rats comparing nasal lesion

severity following intermittent or continuous exposure protocols at varying concentrations suggest that

effects are more concentration-dependent than duration-dependent (Wilmer et al. 1987, 1989). Monkeys

exposed to 6 ppm formaldehyde for 6 weeks (Monticello et al. 1989) displayed epithelial lesions similar

to those displayed by rats exposed to the same concentration for 6 weeks (Monticello et al. 1991), but the

lesions in the monkeys showed a different regional distribution that extended into the trachea. Recent

analyses using computational fluid dynamics models to predict airflow and regional uptake of

formaldehyde in the upper respiratory tract of monkeys and rats found that predicted regions of high

airflow were well correlated with epithelial regions with lesions (Kepler et al. 1998; Kimbell et al. 1993,

1997a). These results support the hypothesis that the rat and monkey may be equally susceptible to

formaldehyde-induced tissue damage and that airflow patterns, determined by anatomical features, are

key determinants of the amount of formaldehyde reaching sites where lesions develop.

Data on effects on the respiratory tract changes after oral exposure to formaldehyde in rats show no

changes attributable to formaldehyde with respect to histopathology and/or lung weights in studies of

intermediate (Johannsen et al. 1986; Til et al. 1988b; Vargova et al. 1993) and chronic (Til et al. 1989;

Tobe et al. 1989) duration.

Cardiovascular Effects. It is unlikely that formaldehyde is responsible for any significant toxicological

effects in organs other than the respiratory tract, particularly after inhalation or dermal exposures that

might be encountered in the workplace or home. However, effects on the cardiovascular system, such as

decreased blood pressure and hypotension (Burkhart et al. 1990; Eells et al. 1981), circulatory collapse

(Freestone and Bentley 1989), and sinus tachycardia (Kochhar et al. 1986) due to the ingestion of high

doses of formaldehyde in humans have been reported. It is not clear how formaldehyde induced these

symptoms or if other existing conditions contributed in whole or in part to these cardiac responses, but is

likely related to the large dose of formaldehyde ingested in a very short period of time. 

Rats displayed 5–25% increases in blood pressure, compared with resting values, in response to

intravenous administration of formaldehyde doses ranging from 0.5 to 5 mg/kg (Egle and Hudgins 1974). 

In contrast, an intravenous dose of 20 mg/kg significantly decreased blood pressure by about 30% and

induced a transient cardiac arrest. The depressor effect at the high dose level was abolished by vagotomy

in the neck region, and only the pressor effect was observed in vagotomized rats exposed to 20 mg/kg. 
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Egle and Hudgins (1974) suggested that the low-dose pressor effects are caused by formaldehyde-induced

release of epinephrine from sympathetic nerve endings and catecholamines from the adrenal medulla, and

that the vagal nerve is stimulated at high doses leading to bradycardia and decreased blood pressure. Egle

and Hudgins (1974) reported that 1-minute exposures to formaldehyde in inspired air at a concentration of

2 mg/L (1,628 ppm) did not significantly affect blood pressure or heart rate in anesthetized rats. This

concentration was reported to be 20-times higher than formaldehyde concentrations in inhaled cigarette

smoke. These results indicate that acute cardiovascular effects are not expected at environmentally

relevant exposure levels. 

Results from repeated exposure animal studies suggest that cardiovascular effects due to formaldehyde

toxicity after inhalation are negligible, regardless of the duration of exposure at the concentrations tested

(#40 ppm). After inhalation exposure, organ weights and/or histopathology remained unchanged from

control animals in studies using rats (Appelman et al. 1988; Kerns et al. 1983b; Woutersen et al. 1987,

1989), monkeys (Monticello et al. 1989; Rusch et al. 1983), and mice (Kerns et al. 1983b; Maronpot et al.

1986). Fewer reports were available on cardiovascular toxicity of formaldehyde after oral exposure at

doses up to 300 mg/kg/day; however, the findings of no significant effects (weight or histopathology) on

this system were consistent in both rats (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989;

Vargova et al. 1993) and dogs (Johannsen et al. 1986). 

Gastrointestinal Effects. Formaldehyde did not have a detectable effect on the gastrointestinal tract after

inhalation exposure of animals (Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b; Maronpot

et al. 1986; Monticello et al. 1989; Woutersen et al. 1987) and only nonspecific effects, such as intestinal

cramps, and flatus, were reported in four patients that had been exposed occupationally to formalin or

phenol-formaldehyde resins (Kilburn 1994). Formaldehyde acts as a contact irritant and corrosive agent

after oral exposures of acute, intermediate, and chronic durations. After large doses taken by mouth

(acute exposure), lesions can be found in the oropharynx, consisting of ulceration and/or necrosis of the

soft palate and phalangeal structures, ulceration of the epiglottis, and esophageal lesions (which may

result in dysphagia) (Freestone and Bentley 1989; Kochhar et al. 1986). More vague clinical signs of

emesis (with or without hematoemesis) and abdominal pain or cramping were also present in some cases

(Burkhart et al. 1990; Eells et al. 1981); these are due, at least in part, to a contact irritant effect, but may

also be attributable to corrosive lesions found in the stomach after the ingestion of formaldehyde. In

cases which afforded an examination of the duodenum and other portions of the intestinal tract after the

stomach, no lesions attributable to formaldehyde intoxication were noted, indicating that the oral cavity 
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and the stomach share the brunt of the toxicity of formaldehyde after ingestion. Similar findings in the

stomachs of Wistar rats noted in one intermediate-duration study (Til et al. 1988b) consisted of

hyperkeratosis of the forestomach (indicative of chronic irritation) and focal atrophic inflammation of the

glandular stomach at doses of 125 mg/kg/day. Another study by Til and coworkers (1989) found gastric

anomalies, consisting of hyperplasia/hyperkeratosis, atrophic gastritis, and ulcerations in Wistar rats at

doses ranging from 82 to 109 mg/kg/day in drinking water. Similar effects were also observed in Wistar

rats at doses of 50–300 mg/kg/day for up to 2 years (Tobe et al. 1989) and in Wistar rats, exposed to

250 mg/kg/day in drinking water for up to 32 weeks (Takahashi et al. 1986a). Other studies found no

significant effect on the gastrointestinal system in both Sprague-Dawley rats (Johannsen et al. 1986;

Vargova et al. 1993) and dogs (Johannsen et al. 1986) at doses ranging from 80 to 300 mg/kg/day. The

data suggest that formaldehyde has a strong potential to cause damage to the upper gastrointestinal tract

(oral cavity, esophagus, and stomach) after oral exposure, and although laboratory animal data are similar

to human data, species differences may account for slight differences in the dose required to initiate the

damage to the gastrointestinal tract. Evidence for oral exposure to formaldehyde causing tumors of the

gastrointestinal tract is discussed below under Cancer Effects.

Hematological Effects. Intravascular coagulopathy was reported in one man who ingested a large dose of

formaldehyde (Burkhart et al. 1990); however, the other reports of human ingestion of lower doses

suggest no effects on the blood and blood-forming organs (Eells et al. 1981; Freestone and Bentley 1989;

Kochhar et al. 1986; Koppel et al. 1990). No consistently significant hematological effects were noted in

several studies using the inhalation (Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b;

Woustersen et al. 1987) and oral (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989) routes of

exposure in laboratory animals. The oral studies with rats used drinking water as the vehicle, with doses

ranging from 82 to 150 mg/kg/day, with no hematological effects noted. The lack of toxicity is likely

related to rapid metabolism prior to the formaldehyde reaching the blood and blood-forming components

(bone marrow). Some evidence suggests, however, that the rapid metabolic capabilities can be

overwhelmed to some degree (Vargova et al. 1993), resulting in some minor alterations in blood

parameters. In that study, affected male rats received a gavage dose level of 80 mg/kg/day formaldehyde

for 4 weeks. This dosing method may have resulted in large doses of formaldehyde being absorbed over

a shorter period of time than in the drinking water studies. In this situation, some unmetabolized

formaldehyde may have been responsible for the alterations in erythrocyte count and hemoglobin and

mean cellular hemoglobin values.
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Musculoskeletal Effects. The only reports available that described some manifestations of adverse

musculoskeletal effects in humans included vague signs of muscle and joint stiffness after chronicinhalation exposures to formaldehyde (Holness and Nethercott 1989). It is unlikely that inhalation

exposure to formaldehyde is responsible for these complaints, and they may represent an effect from a

confounding factor in that study. The lack of human data and the lack of musculoskeletal effects in

animal studies (Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Til

et al. 1989), coupled with the available toxicokinetic data, suggest that formaldehyde has no adverse

effects on the musculoskeletal system.

Hepatic Effects. Hepatic effects (e.g., congestion of hepatic parenchyma and increased serum enzymes

associated with liver damage) have been reported for some human cases of acute poisoning from

ingestion (e.g., Freestone and Bentley 1989; Koppel et al. 1990), but not reported for other cases (e.g.,

Burkhart et al. 1990; Eells et al. 1981). Increased incidence of hepatocellular vacuolization was found in

rats exposed to gavage dose level of 80 mg/kg/day for 4 weeks (Vargova et al. 1993), but other studies

found no exposure-related changes in liver weight or histopathology in rats exposed to drinking-water

doses as high as 150 mg/kg/day for 90 days (Johannsen et al. 1986), 125 mg/kg/day for 4 weeks (Til et al.

1988b), 82–109 mg/kg/day for 2 years (Til et al. 1989), and 300 mg/kg/day for 2 years (Tobe et al. 1989). 

Liver weight and histopathology were likewise unaffected in Beagle dogs exposed to up to

100 mg/kg/day in the diet for 90 days (Johannsen et al. 1986), as were serum enzyme activities indicative

of liver damage in rats exposed to up to 300 mg/kg/day for up to 2 years (Tobe et al. 1989). Increased

activities of enzymes indicative of liver damage have been reported in rats exposed to air concentrations

of 35 ppm for 18 hours (Murphy et al. 1964) or 20 ppm 6 hours/day, 5 days/week for 13 weeks

(Woutersen et al. 1987), but accompanying structural changes in the liver were not detected with light

microscopy. Other studies with rats have not found evidence for increased serum liver enzymes in rats

exposed to air concentrations up to 15 ppm, 5 days/week for up to 28 months (Appelman et al. 1988;

Kamata et al. 1997). Several other inhalation studies of intermediate or chronic duration have found no

evidence for formaldehyde-induced histological changes in the livers of monkeys exposed to 6 ppm

(Monticello et al. 1989), rats exposed to up to 14.3 ppm (Kerns et al. 1983b), or mice exposed to up to

40 ppm (Kerns et al. 1983b; Maronpot et al. 1986).

In general, the information from reports of acute poisoning in humans ingesting formaldehyde and reports

of studies of animals exposed to formaldehyde in air, in drinking water, or in the diet indicate that the

liver is not a prime target of formaldehyde toxicity, and that hepatic effects from exposure to
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formaldehyde are expected to occur only when the capacity of dispositional processes for formaldehyde

are exceeded at portals-of-entry. 

Renal Effects. The available data suggest that the renal system is not a major target organ of toxicity for

formaldehyde. Renal failure/anuria was noted in three case reports involving people ingesting various

large or unknown amounts formaldehyde (Eells et al. 1981; Freestone and Bentley 1989; Koppel et al.

1990); however, the mechanism of action for the induction of renal failure is not known. Data for

laboratory animals exposed by inhalation for intermediate- and chronic-duration to formaldehyde

concentrations ranging from 0.19 to 40 ppm are fairly consistent in the failure of formaldehyde to elicit

gross or histological lesions, alterations in renal weight, or to produce significant changes in urine

composition (Appelman et al. 1988; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989;

Woutersen et al. 1987). Appelman et al. (1988) did report oliguria in rats exposed to 10 ppm for

52 weeks, but Kerns et al. (1983b) did not report a similar finding in rats and mice exposed to up to

14.3 ppm for 2 years. Similarly, lack of renal effects was also reported after intermediate- and

chronic-duration oral exposure in most studies (Johannsen et al. 1986; Til et al. 1988b; Tobe et al. 1989;

Vargova et al. 1993), but renal papillary necrosis was reported for rats that received 82–109 mg/kg/day in

drinking water for 2 years (Til et al. 1989), and increased blood urea nitrogen was reported in rats that

received 300 mg/kg/day in drinking water for up to 12 months (Tobe et al. 1989).

Endocrine Effects. No information was available that reported the effects of formaldehyde on the

endocrine system of humans after inhalation, oral, or dermal exposure. Formaldehyde has been reported

not to exert adverse effects on organs of the endocrine system in laboratory animals and, hence, is not a

major target organ for formaldehyde toxicity after inhalation (Appelman et al. 1988; Kamata et al. 1997;

Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Woutersen et al. 1987) or oral

(Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989; Vargova et al. 1993) exposure. No data

regarding endocrine effects in animals after dermal exposure were located.

Dermal Effects. Formaldehyde is a widely recognized skin irritant and dermal sensitization agent in

humans (see also Immunological and Lymphoreticular Effects section). Patch testing for dermal

sensitization to formaldehyde has been carried out with either 1 or 2% solutions because, for most

individuals, acute exposure to such concentrations does not produce signs of nonimmune irritation (e.g.,

erythema [redness], induration, flaking, and/or blistering). Some earlier patch testing procedures utilized

concentrations as high as 5%, a practice that has been largely discontinued, presumably because of the 
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difficulty in discerning between irritant and immune responses at this exposure level (Maibach 1983). 

Increased incidences of contact dermatitis or allergic contact dermatitis associated with dermal exposure

to formaldehyde solutions have been observed in funeral service workers (Nethercott and Holness 1988)

and among medical workers (Rudzki et al. 1989). Allergic contact dermatitis from formaldehyde released

from “no-iron” textiles was frequently reported until textile finishing processes were changed (in the mid

1970s) so that only small amounts of formaldehyde were released from clothing made from such textiles

(Peters and Hesse 1997). Experiments with guinea pigs (Wahlberg 1993) and mice (Iversen 1986)

indicated that repeated exposure of skin to concentrations for acute periods as low as 0.4% can be

damaging (i.e., produce erythema, epidermal hyperplasia, or increased skin-fold thickness). 

Animal studies with repeated exposure to airborne formaldehyde concentrations between 1 and 40 ppm

(Appelman et al. 1988; Kamata et al. 1997; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al.

1989; Woutersen et al. 1987) and oral doses as high as 109 mg/kg/day (Til et al. 1989) indicate that

clinically significant dermal effects are not a concern by these routes of exposure, although mice exposed

to the highest air concentration (40 ppm) in these studies showed a “loss of skin elasticity” (Maronpot et

al. 1986). Eberlein-Konig et al. (1998) reported that a 4-hour exposure of dermally sensitized human

subjects to airborne formaldehyde concentrations as low as 0.08 ppm increased transepidermal water loss

compared with nonsensitized subjects, but the clinical significance of this effect is uncertain. 

Ocular Effects. Eye irritation is one of the most common complaints among people exposed to airborne

formaldehyde. In acute, controlled exposure studies with volunteers, mild to moderate eye irritation has

been reported at low-level concentrations in the range of 0.4–4 ppm; at the upper end of this range,

greater percentages of subjects experienced eye irritation (Akbar-Khanzadeh and Mlynek 1997; AkbarKhanzadeh et al. 1994; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Kulle 1993; Kulle et al.

1987; Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986, 1987). Other results

indicating formaldehyde’s eye-irritation potential include reports that average rates of eye-blinking were

significantly increased during exposure to 2.1 ppm, but not to 1.2 ppm (Weber-Tschopp et al. 1977), and

that percentages of subjects with shortened response times (i.e., the time taken for the subjects to note eye

irritation) were significantly increased with exposure to 1 ppm, but not to lower concentrations (Bender et

al. 1983). In addition, survey studies have reported increased rates of eye irritation in groups of persons

who have been repeatedly exposed to formaldehyde in residences or workplaces, compared with groups

of nonexposed persons (Garry et al. 1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and

Lehnen 1987).
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Histological examinations of eyes from animals repeatedly exposed to airborne formaldehyde

concentrations as high as 6–40 ppm have not found formaldehyde-induced changes (Appelman et al.

1988; Kerns et al. 1983b; Maronpot et al. 1986; Monticello et al. 1989; Swenberg et al. 1980; Woutersen

et al. 1987). Ophthalmoscopic examinations likewise revealed no exposure-related changes in rats or

mice examined at several intervals during 2-year exposures to concentrations as high as 14.3 ppm (Kerns

et al. 1983b), but clinical signs of eye irritation during exposure to 2–15 ppm have been noted in several

animal studies (Dinsdale et al. 1993; Monticello et al. 1989; Morgan et al. 1986c). Chronic exposure of

rats to drinking water doses as high as 89–102 mg/kg/day produced no histological changes in eyes or

Harderian and exorbital lachrymal glands (Til et al. 1989). Direct application of formaldehyde solutions

into eyes is expected to be irritating. Krootila et al. (1986) provided evidence that application of a

1% solution of formaldehyde to the eyes of rats caused a breakdown of the blood-aqueous barrier and that

the irritative response of the eye is dependent on the trigeminal sensory nerve. 

Body Weight Effects. Whereas no reports of body weight effects in formaldehyde-exposed humans were

located, numerous reports are available of biologically significant body weight decreases in animals

repeatedly exposed to formaldehyde by the inhalation route (Appelman et al. 1988; Kamata et al. 1997;

Kerns et al. 1983b; Maronpot et al. 1986; Rusch et al. 1983; Woutersen et al. 1987, 1989) and by the oral

route via drinking water or diet (Johannsen et al. 1986; Til et al. 1989; Tobe et al. 1989). Exposurerelated effects on body weight were not found in pregnant hamsters dermally exposed during gestation to

37% formaldehyde solutions (Overman 1985) or in guinea pigs dermally exposed for 9 days to

4% formaldehyde solutions (Wahlberg 1993). Air concentrations associated with decreased body weights

in repeatedly exposed animals were mostly at or above exposure levels ($10 ppm) that produced severe

upper respiratory tract lesions. Oral dosage levels associated with decreased body weights in repeatedly

exposed animals were generally $80–100 mg/kg/day and also associated with the development of

gastrointestinal tract lesions and decreases in food and water intake. 

Metabolic Effects. Metabolic acidosis has been observed in patients who ingested large (>500 mg/kg)

single doses of formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Koppel et al. 1990). The rapid

metabolic production of formate at these high dose levels was likely involved in the observed acidosis.

Other Systemic Effects. Decreased food and water consumption have been observed in animals exposed

to oral doses generally greater than 100 mg/kg/day (Johannsen et al. 1986; Til et al. 1989; Tobe et al. 
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1989). The decreased consumption was generally associated with decreases in body weight and with

development of gastrointestinal lesions with intermediate or chronic exposure. 

Immunological and Lymphoreticular Effects. Allergic contact dermatitis from formaldehyde is

commonly reported at dermatological clinics throughout the world. Patch test reporting from clinics

indicates that about 1–4% of tested patients with skin problems are dermally sensitive to formaldehyde

(Fischer et al. 1995; see also: Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and

Swanbeck 1990; Menné et al. 1991). Given the widespread use of formaldehyde in cleaning solutions

and cosmetics (Flyvhom 1991; Rastogi 1992), it is likely that most patients presenting with formaldehyde

contact dermatitis experienced sensitization through dermal contact, but dermal sensitization through

contact with airborne formaldehyde cannot be ruled out. Severe allergic responses to formaldehyde

appear to be rare, but one case report was located of a severe response to a patch test with a 1%

formaldehyde solution in a woman who was sensitized after exposure to a dialyzer sterilized with

formaldehyde (Maurice et al. 1986). Twenty-six hours after the application of the patch, the patient

developed anaphylactic symptoms of laryngeal edema and bronchospasm that resolved on administration

of subcutaneous epinephrine.

Although formaldehyde is widely recognized as a dermal irritant that can sensitize the skin in humans, the

evidence for immunologically-mediated sensitization of the respiratory tract is weak. Despite the

widespread use of formaldehyde in several occupational exposure scenarios (and the widespread

occurrence of formaldehyde in tobacco smoke), there are only a few available case reports of

formaldehyde-exposed workers who display marked changes in pulmonary function variables (e.g.,

FEV1 and FEFR) in response to acute challenges with inhaled formaldehyde that are consistent with an

immunologically-mediated mechanism of response (Burge et al. 1985; Hendrick et al. 1982; Lemiere et

al. 1995; Nordman et al. 1985). Other studies found no marked response to challenges of inhaled

formaldehyde in previously-exposed subjects who complained of asthma-like symptoms (Day et al. 1984;

Krakowiak et al. 1998; Reed and Frigas 1984). Several studies have found no consistent evidence for

increased serum levels of formaldehyde-specific IgE antibodies in groups of formaldehyde-exposed

subjects including groups with complaints of respiratory symptoms (Dykewicz et al. 1991; Gorski et al.

1992; Grammar et al. 1990; Krakowiak et al. 1998; Kramps et al. 1989; Thrasher et al. 1987, 1990).

The only other suggestive evidence of IgE-mediated sensitization to formaldehyde comes from a study of

schoolchildren who were exposed to particleboard-paneled classrooms with estimated formaldehyde air 
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2. HEALTH EFFECTS

concentrations of 0.075, 0.069, and 0.043 ppm and reported respiratory tract symptoms consistent with

the irritant properties of formaldehyde (Wantke et al. 1996a). Elevated serum levels of formaldehydespecific IgE antibodies were detected in these children. The investigators noted that the elevated levels

were not correlated with the number and severity of symptoms, but decreased serum levels were

measured in a subgroup of the children 3 months after they were moved to another school with lower air

concentration of formaldehyde (0.023–0.029 ppm). The significance of these findings is uncertain, as the

reported symptoms were more typical of an irritant response than of asthma-like symptoms that are

expected to be mediated through IgE antibodies. 

Animal studies examining the sensitizing properties of formaldehyde present evidence consistent with the

hypothesis that, although formaldehyde can sensitize skin, it apparently lacks a potential to sensitize the

respiratory tract (Hilton et al. 1996). Strong positive responses to formaldehyde were found in three

animal assays indicative of skin-sensitization potential (guinea pig maximization test, Buehler occluded

patch test and the murine local lymph node assay). However, in a mouse IgE test and an assessment of

cytokine secretion patterns by lymph node cells, formaldehyde was negative, producing responses that

were not like those produced by trimellitic anhydride, a well-established respiratory tract allergen in

animals and humans (Hilton et al. 1996). Although these results suggest a lack of ability to sensitize the

respiratory tract, another animal experiment suggests that exposure to formaldehyde may enhance allergic

responses of the respiratory tract to other respiratory allergens (Tarkowski and Gorski 1995). This study

found that that the production of ovalbumin-specific IgE antibodies in response to intranasal

administration of ovalbumin was four-fold greater in mice preexposed to 1.6 ppm formaldehyde for

10 consecutive days, compared to the response in mice without formaldehyde preexposure. In similar

experiments, groups of guinea pigs preexposed to a formaldehyde concentration of 0.25 ppm, 8 hours/day

for 5 days followed by inhalation exposure to 0.5% ovalbumin were found to have a higher percentage of

ovalbumin-sensitized animals than control groups with no preexposure (10/12 versus 3/12) (Riedel et al.

1996). Further research is necessary to confirm the hypothesis of formaldehyde facilitation of other

respiratory allergens and to determine if this is relevant to humans exposed to formaldehyde.

Other animal studies indicate that repeated inhalation exposure to formaldehyde at high concentrations,

between 10 and 15 ppm, did not produce significant effects in several assays of immune function

including resistance to intravenous or subcutaneous injection of neoplastic cells in mice (Dean et al.

1984), resistance to intravenous injection of bacterial cells in mice (Dean et al. 1984), and IgM response

to tetanus immunization and IgG response to tetanus toxoid in rats (Holmstrom et al. 1989b).
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Neurological Effects. Few studies have reported neurological effects after exposure to formaldehyde

in humans; however, these studies tend to report vague symptoms. For example, men exposed to

formaldehyde vapors at concentrations #0.98 ppm for 5.5 hours reported such symptoms as fatigue,

headaches, and "heavy head" (Bach et al. 1990). Reaction times also decreased as formaldehyde

concentrations increased. After the ingestion of formaldehyde in humans, coma (Koppel et al. 1990),

lethargy, seizures (Burkhart et al. 1990), and loss of consciousness (Burkhart et al. 1990; Eells et al.

1981) have been reported. Kilburn and colleagues have reported evidence for neurological symptoms and

impaired performance in neurobehavioral tests in groups of formaldehyde-exposed histology technicians,

but confounding exposure to other neurotoxic solvents prevents drawing definitive conclusions regarding

the neurotoxicity of formaldehyde from this source (Kilburn 1985b; Kilburn et al. 1987; Kilburn and

Warshaw 1992; Kilburn 1994).

Male rats exposed to 15 ppm formaldehyde showed restless behavior within the first 10 minutes of

exposure (Morgan et al. 1986a). Exposure to 5 ppm formaldehyde for 3 hours in male rats resulted in

decreased motor activity within 15 minutes from the beginning of exposure; increased concentrations of

5-hydroxyindoleacetic acid (a 5-hydroxytryptamine metabolite), 3,4-dihydroxyphenylacetic acid (a

dopamine metabolite), and dopamine were present in the hypothalamus at the end of the 3-hour exposure

(Boja et al. 1985). With repeated exposure, mice developed an increased sensitivity to the acute sensory

irritant properties of formaldehyde; the increased sensitivity attributed, at least in part, to a conditioning

(i.e., learning) process (Wood and Coleman 1995). No abnormal clinical signs were noted in mice treated

with doses #10 ppm formaldehyde for 6 hours/day, 5 days/week for 13 weeks; however, listlessness and

hunched posture were observed in the mice exposed to 20 ppm formaldehyde, and these symptoms plus

ataxia were observed in the 40-ppm dose group (Maronpot et al. 1986). No obvious signs of neurological

effects were noted in rats (Appelman et al. 1988; Kerns et al. 1983b; Woutersen et al. 1987) or mice

(Kerns et al. 1983b) in chronic-duration inhalation studies. No obvious neurological effects were

observed in rats receiving 150 mg/kg/day for 90 days in drinking water (Johannsen et al. 1986), in rats

receiving 125 mg/kg/day for 4 weeks in drinking water (Til et al. 1988b), or in rats exposed to

300 mg/kg/day for 12 months in drinking water (Tobe et al. 1989). Beagle dogs exposed to formaldehyde

in drinking water at concentrations #100 mg/kg/day experienced no effect on brain weight or

histopathology. Similar negative findings were noted in studies of chronic duration at doses

#300 mg/kg/day in drinking water in rats (Til et al. 1989; Tobe et al. 1989). It appears that formaldehyde

has major effects on the nervous system only after large doses are ingested; such as low-level and vague

symptoms after chronic, low-level exposure.
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Reproductive Effects. Studies regarding possible reproductive effects in humans exposed to

formaldehyde are restricted to a study that found no evidence for effects on sperm numbers or

morphology in a small number of pathologists (Ward et al. 1984) and a study that found no evidence for

increased rates of miscarriage among a group of 275 persons with presumed residential exposure to

formaldehyde (Garry et al. 1980).

Studies of animals exposed to formaldehyde in air, in drinking water or diet, or applied to the skin

indicate that the reproductive organs are not a critical target for formaldehyde toxicity, but comprehensive

assessments of reproductive performance (e.g., 2-generation studies) in formaldehyde-exposed animals

were not located. 

No effects on histology or weight of reproductive organs were found in rats or mice exposed repeatedly to

air concentrations as high as 20 ppm (Appelman et al. 1988; Maronpot et al. 1986, Woutersen et al.

1987), in dogs repeatedly exposed to formaldehyde in the diet at doses up to 100 mg/kg/day (Johannsen et

al. 1986), or in rats exposed to oral doses up to 300 mg/kg/day (Johannsen et al. 1986; Til et al. 1989;

Tobe et al. 1989; Vargova et al. 1993). Ovarian and uterine hypoplasia were observed in female mice

exposed to air concentrations of 40 ppm for 13 weeks, but was attributed to the general weight loss and

poor health of these animals rather than to a direct effect of formaldehyde (Maronpot et al. 1986). 

Maternal toxicity, expressed as a marked decrease in weight gain, occurred in pregnant rats exposed

during gestation by inhalation to 40 ppm, but reproductive variables (e.g., numbers of implantations or

resorptions) were not affected (Saillenfait et al. 1989). At lower air concentrations, no signs of maternal

toxicity were observed in this and another rat study of gestational exposure (Martin 1990). Exposure

during pregnancy to gavage dose levels of 185 mg/kg/day, but not 145 mg/kg/day, produced severe

maternal toxicity in pregnant mice (22/34 dams died), but did not affect reproductive variables such as

numbers of implantation sites or resorptions (Marks et al. 1980). No effects on reproductive variables

were found in pregnant dogs exposed to 9.4 mg/kg/day in the diet on gestation days 4–56 (Hurni and

Ohder 1973). Dermal exposure of pregnant hamsters to 37% solutions of formaldehyde produced a small

increase in resorption rate without affecting maternal weight gain, but the authors of this study proposed

that the effect may have been caused by stress associated with the applied treatment protocol (Overman

1985). Single gavage dose levels of 200 mg/kg, but not 100 mg/kg/day, produced changes in sperm

morphology in rats (Cassidy et al. 1983), but with no tests of reproductive performance, the toxicological

significance of this finding is uncertain. In a review of available reproductive and developmental toxicity

data, WHO (1989) concluded, “There is no convincing evidence that formaldehyde is a teratogen in either
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animals or human beings. Formaldehyde has not produced any adverse effects on reproduction in test

animals or human beings.” IARC (1995) reached a similar conclusion in a more recent review.

Developmental Effects. Studies of possible developmental effects in humans exposed to

formaldehyde are restricted to a study that found no statistically significant difference in incidence of low

birth weights among groups of mothers who lived in residential districts with differing ambient air levels

(up to 38 ppb) of formaldehyde (Grañulevi...iene et al. 1998). Exposure of pregnant rats to air

concentrations up to 10 ppm during gestation days 6–15 produced no distinct effects on fetal development

(Martin 1990). In another study with several exposure levels, pregnant rats exposed during gestation days

6–20 to the highest concentration, 40 ppm, showed a 51% reduction in weight gain (Saillenfait et al.

1989). Fetal weights were decreased in male offspring from dams exposed to 20 ppm and in female

offspring from dams exposed to 40 ppm, but no effects attributable to formaldehyde were noted in the

incidences of pregnancies, number of implantations or resorptions, number of dead or live fetuses, fetal

sex ratios, or incidences of skeletal or visceral anomalies (Saillenfait et al. 1989). Similarly, no effects on

fetal development were found in studies of pregnant rats exposed during gestation days 6–15 to gavage

dose levels as high as 185 mg/kg/day (Marks et al. 1980), pregnant dogs exposed to up to 9.4 mg/kg/day

in the diet during gestation days 4–56 (Hurni and Ohder 1973), and pregnant hamsters dermally exposed

to a 37% aqueous solution of formaldehyde on gestation day 8, 9, 10, or 11 (Overman 1985).

Genotoxic Effects. Formaldehyde has been demonstrated to have genotoxic properties in human and

laboratory animal studies. Peripheral lymphocytes in anatomy students exposed to 0.73–1.95 ppm

formaldehyde for 8 weeks showed a small increase in SCE (Yager et al. 1986). Lymphocytes from wood

workers chronically exposed to formaldehyde also showed increased levels of chromosomal aberrations;

however, there were no significant changes in the rates of SCE (Chebotarev et al. 1986). Increases in

micronuclei formation, primarily in nasal passage ciliated cells, were found in wood workers chronically

exposed to 0.07–0.08 ppm formaldehyde (Ballarin et al. 1992). An increased incidence in chromosomal

abnormalities in pulmonary macrophages was noted in male rats exposed to 15 ppm formaldehyde for

5 days (Dallas et al. 1992). No reports of genotoxicity strictly related to the oral or dermal exposure

routes were found in the available literature.

Conversely, a number of studies have failed to demonstrate the genotoxic potential of formaldehyde. 

Fleig et al. (1982) performed chromosome analyses on 15 exposed and 15 non-exposed employees from 
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formaldehyde-manufacturing facilities with average exposure concentrations not exceeding 5 ppm prior

to 1971 and 1 ppm after 1971. There were no differences between exposed and control groups in the

incidence of chromosomal aberrations. Connor et al. (1985b) tested urine obtained from hospital autopsy

service workers exposed to formaldehyde who had actual exposures to formaldehyde of 0.1–5.8 ppm,

with the TWA exposures to formaldehyde in work areas were estimated to be 0.61–1.32 ppm. 

Mutagenicity tests using S. typhimurium TA 100 and TA 98 were conducted, with or without rat

S9 suspension. Increases in mutation rates were not produced by the urine of workers exposed to

formaldehyde, compared to control urine, in the presence or absence of S9. 

Formaldehyde has been found to be genotoxic in a number of in vivo and in vitro test systems. Tables 2-6

and 2-7 present a cross-section of some of the genotoxicity data that are available for formaldehyde

examined in in vivo and in vitro test systems. With in vivo test systems, the data are mixed. 

Formaldehyde has been found to induce chromosomal aberrations (Chebotarev et al. 1986; Dallas et al.

1992; Rithidech et al. 1987) and to cause increases in micronucleus formation (Ballarin et al. 1992), SCE

(Yager et al. 1986), DNA-protein cross links (Casavova et al. 1989, 1991b, 1992; Lam et al. 1985;

Shaham et al. 1996a), sperm head abnormalities (Topham 1980), and p53 suppressor gene mutations

(Recio et al. 1992). Other reports present negative genotoxic findings (Kligerman et al. 1984; Natarajan

et al. 1983; Thomson et al. 1984).

Formaldehyde has also been found to be genotoxic in S. typhimurium in most cases (Connor et al. 1983,

1985a; Donovan et al. 1983; Glass et al. 1986; Haworth et al. 1983; Schmid et al. 1986; Takahashi et al.

1985) and not mutagenic in others (DeFlora 1981; DeFlora et al. 1984). A number of human cell lines

have been tested with formaldehyde giving positive results without activation, resulting in mutations,

DNA damage, chromosomal aberrations, and SCEs (Dresp and Bauchinger 1988; Garry et al. 1981;

Goldmacher and Thilly 1983; Grafstrom et al. 1983, 1984, 1985; Krieger and Garry 1983; Liber et al.

1989; Schmid et al. 1986; Snyder and Van Houten 1986). Laboratory animal models, such as the Chinese

hamster cell lines (Basler et al. 1985; Galloway et al. 1985; Grafstrom et al. 1993; Miller and Costa 1989;

Natarajan et al. 1983), Golden Syrian hamsters (Hatch et al. 1983), and rodent cell lines (Basler et al.

1985; Blackburn et al. 1991; Cosma and Marchok 1988; Cosma et al. 1988a; Frazelle et al. 1983; Heck

and Casanova 1987; Ragan and Boreiko 1981, 1983; Ross and Shipley 1980) have demonstrated similar

results. 
Table 2-6. Genotoxicity of Formaldehyde In Vivo

Species (test system) End point Result ReferenceMammals:

Mouse (spleen lymphocytes) Chromosomal aberrations + Rithidech eHuman (occupational exposure) Chromosomal aberrations – Vasudeva a

Human (occupational exposure/nasal mucosa) Micronucleus increase + Ballarin et Human (occupational exposure/urine) Mutagenicity – Connor et aHuman (occupational exposure/lymphocytes) DNA-protein cross links, not

formaldehyde specific

+ Shaham et 

Human (occupational exposure/white bloodcells)

Chromosome aberrations andsister chromatid exchange

– Thomson e

Human (occupational exposure/lymphocytes) Sister chromatid exchange + Yager et alHuman (occupational exposure/lymphocytes) Chromosomal aberrations + CherbatereRat (pulmonary lavage) Chromosomal aberrations + Dallas et alRat (nasal mucosal cells) DNA-protein cross links + Casanova eRat (nasal mucosal cells) DNA-protein cross links + Lam et al. Rat (bone marrow) Chromosomal aberrations – Dallas et alRat (lymphocytes) Mitotic activity, sister chromatid

exchange, chromosomal aberration

– Kligerman 

Monkey (respiratory tract) DNA-protein cross links + Casanova e

Non-mammals:

D. Melanogaster Mortality and sterility + Valencia et D. Melanogaster Lethal mutation + Woodruff e

+ = Positive result; – = negative result; (+) = weakly positive result; DNA = deoxyribonucleic acid
Table 2-7. Genotoxicity of Formaldehyde In Vitro

Result

Species (test system) End point

With

activation

Without

activation Refere

Prokaryotic organisms:

Salmonella typhimurium TA 98, TA 100, TA1535, TA 1537, UTH8414, UTH 8413(Ames test)

Gene mutation (+) (+) Glass et 

S. typhimurium TA 98, TA 100 (Ames test) Gene mutation No data + TakahasS. typhimurium TA 100 (Ames test) Gene mutation + + Schmid Escherichia coli Gene mutation No data + TakahasS. typhimurium TA97, TA98, TA100 (Amestest)

Gene mutation No data + Donova

S. typhimurium TM677, TA100 (Ames test) Gene mutation + + DonovaS. typhimurium TA97, TA98, TA100,TA1535, TA1537, TA1538 (Ames test)

Gene mutation – – DeFlora 

S. typhimurium TA98, TA100, TA1535,

TA1537, TA1538 (Ames test)

Gene mutation –a –a DeFlora 

S. typhimurium TA98, TA100, UTH8413,

UTH8414 (Ames test)

Gene mutation (+) (+) Connor 

S. typhimurium TA98, TA100, UTH8413,UTH8414 (Ames test)

Gene mutation (+)a (+)a Connor 

S. typhimurium TA1535, TA1537, TA98,

and TA100

Gene mutation No data + Haworth 

Eukaryotic organisms:

Mammalian cells:

Human (bronchial fibroblast culture)

Mutations No data + Grafstro

Human (foreskin fibroblast culture) DNA damage No data + Snyder Human (lymphocyte cell culture) Chromosomal aberrations No data + Dresp anHuman (lymphocyte cell culture) DNA damage No data + Liber et 

Table 2-7. Genotoxicity of Formaldehyde In Vitro (continued)
Result

Species (test system) End point

With

activation

Without

activation Refere

Human (lymphocyte cell culture) Sister chromatid exchange

and chromatid-typeaberrations 

+ + Schmid 

Rat (tracheal epithelium culture) DNA damage No data + Cosma eRat (tracheal epithelium culture) DNA damage No data + Cosma aRat (nasal mucosa) DNA binding No data + Heck anMouse (lymphoma L5178Y TK ±) Mutagenicitiy + + BlackbuChinese hamster (V79 cell culture) Sister chromatid exchange – + Basler eChinese hamster (V79 cell culture) Mutations No data + GrafstroChinese hamster (ovary cell culture) DNA damage No data + Miller aChinese hamster (ovary cell culture) Chromosomal aberrations;

sister chromatid exchange

+ + Nataraja

Chinese hamster (ovary cell culture) Chromosomal aberrations;

sister chromatid exchange

(+) (+) Gallowa

Golden Syrian hamster (embryo cellculture)

Viral transformation No data + Hatch et 

C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations (+) – Frazelle Rodent (Yoshida sarcoma cells) DNA cross links No data (+) Bedford Calf (thymus chromatin) Histone redistribution No data + Polacow C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + – Ragan aC3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + – Boreiko C3H/10T1⁄2 mouse embryo fibroblasts Focus transformations + No data Frazelle Mouse leukemia L1210 cells DNA single strand breaks No data (+) Ross anMouse leukemia L1210 cells DNA protein cross links No data + Ross anHuman (lymphocyte cultures) Sister chromatid exchange No data + Kreiger 
Table 2-7. Genotoxicity of Formaldehyde In Vitro (continued)

Result

Species (test system) End point

With

activation

Without

activation Refere

Human (bronchoial fibroblast cells) DNA cross links and singlestrand breaks No data + GrafstroHuman (bronchoial epithelial cells) DNA cross links and singlestrand breaks No data + GrafstroHuman (skin fibroblast cells) DNA cross links and singlestrand breaks No data + GrafstroHuman (bronchoial epihtelial cells) DNA cross links and singlestrand breaks No data + GrafstroHuman (bronchoial fibroblast cells) DNA cross links and singlestrand breaks No data + GrafstroHuman (lymphoblastoid TK6 cells) DNA mutation No data + GoldmaHuman (cultured lymphocytes) Sister chromatid exchange No data + Garry et 

atest compound was formalin

– = negative results; + = positive results; (+) = weakly positive result; DNA = deoxyribonucleic acid
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In summary, no reports of genetic effects in humans were located, but formaldehyde has displayed

genotoxic activity in the majority of studies in a variety of in vivo tests with organisms ranging from

bacteria to rodents and a variety of in vitro tests including tests with cultured human cells. The weight of

evidence indicates that formaldehyde itself is capable of directly reacting with DNA, and producing

genotoxic effects, especially when metabolic capacities are exceeded.

Cancer. As discussed in Section 2.2.1.8, there are more than 40 epidemiology studies (cohort

mortality studies of industrial workers, cohort mortality studies of medical specialists and embalmers, and

case-control studies) examining the potential for occupational formaldehyde exposure to induce cancer. 

Two meta analyses of these studies calculated aggregate relative risks (with 95% CIs noted in

parentheses) for nasopharyngeal cancer deaths in occupationally exposed workers of 1.2 (0.8–1.7) and

2.0 (1.4–2.90), and noted that an exposure-response relationship for nasopharyngeal cancer could be

demonstrated by grouping the studies in exposure categories of “low/medium” and “substantial” (Blair et

al. 1990a; Partanen 1993). A third meta analysis (Collins et al. 1997), using the same studies plus

additional cohort mortality data not available for the earlier analyses, reported meta relative risks of

1.0 (0.5–1.8) for nasopharyngeal cancer across 14 available cohort studies, 1.2 (0.4–2.5) for six available

cohort studies of industrial workers, and 1.3 (0.9–2.1) for seven case-control studies. Collins et al. (1997)

concluded that their analysis of the data did not support an exposure-response relationship for

formaldehyde exposure and nasopharyngeal cancer. 

Other reviewers also have arrived at differing conclusions regarding the evidence from the

epidemiological studies. On one side, IARC (1995) and EPA (1991a) judged that there was limited

evidence in humans and NTP (1998) judged that formaldehyde was reasonably anticipated to be a human

carcinogen; whereas McLaughlin (1994) and ECETOC (1995), on the other side, concluded that a causal

relationship was not established by the available data. A more recent collaborative review of the data by

EPA and CIIT (1998) appears to take a middle stand concluding that “it appears that a weak association

between nasopharyngeal cancer and formaldehyde exposure cannot be completely ruled out”. 

In contrast to the equivocal, limited, or weak nature of the evidence in humans, replicated inhalation

studies have consistently shown that formaldehyde induces nasal tumors in rats exposed to high

concentrations (10–15 ppm) that also induce nasal epithelial necrosis and cellular proliferation, but not

when exposed to lower concentrations (0.3–2 ppm) that do not markedly damage nasal epithelial tissue

(Albert et al. 1982; Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Sellakumar et al. 
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2. HEALTH EFFECTS

1985; Woutersen et al. 1989). Exposure-related cancer or noncancer lesions at sites distant from the

portal-of-entry were not found in these studies, consistent with the water solubility and reactivity of

formaldehyde and the ubiquity of rapid cellular metabolism of formaldehyde. 

No information is available as to whether oral exposure to formaldehyde increases the risk of cancer in

humans. The evidence for formaldehyde-induced carcinogenicity from four available rat drinking water

studies is equivocal due to inconsistent findings (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al.

1989; Tobe et al. 1989). Two studies reported no increased incidence of gastrointestinal tract tumors in

rats exposed for life to formaldehyde in drinking water at doses up to 109 mg/kg/day (Til et al. 1989) or

300 mg/kg/day (Tobe et al. 1989). Another study reported increased incidences of gastrointestinal tumors

(papillomas, adenocarcinomas, and leiomyosarcomas) in some groups of rats exposed for life to drinking

water doses of 188 mg/kg/day, but not in groups exposed to 313 mg/kg/day (Soffritti et al. 1989). The

fourth study reported that benign papillomas were found in the forestomach of 8/10 rats exposed for

32 weeks to drinking water doses of 258 mg/kg/day (Takahashi et al. 1986a), but others (Til et al. 1989)

have questioned whether a different histologist would have classified the observed lesions as papillary

hyperplasia. The weight of the animal evidence suggests that gastrointestinal tract tumors may occur as

portal-of-entry effects in rats chronically exposed to formaldehyde in drinking water only at high doses,

and that tumors are not likely to occur at dose levels that do not damage the gastric mucosa. The animal

studies suggest that there is little likelihood that chronic exposure to non-irritating levels of formaldehyde

in drinking water will increase cancer risks in humans.

No studies were located regarding cancer rates in humans predominantly exposed to formaldehyde via the

dermal route. Animal cancer studies of dermal exposure are restricted to two studies that found no

statistically significant increased incidences of skin tumors in mice exposed twice weekly for 58–60

weeks to solutions containing up to 4% (Iverson 1988) or 10% formaldehyde (Iverson 1986). 

NTP (1998) has determined that formaldehyde may reasonably be anticipated to be a human carcinogen,

and IARC (1995) made the overall evaluation that formaldehyde is probably carcinogenic to humans

(Group 2A) based on specific evaluations that there is limited evidence in humans for the carcinogenicity

of formaldehyde and sufficient evidence in experimental animals. 

EPA (1991a; IRIS 1999) classified formaldehyde in Group B1 - probable human carcinogen based on an

evaluation of limited human evidence and sufficient laboratory animal evidence. EPA (1991a) used dose-
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2. HEALTH EFFECTS

response data for nasal tumors in rats exposed to high concentrations of formaldehyde to extrapolate to

human cancer risk at low exposure concentrations, using rates of DNA-protein cross links in target tissue

as a measure of delivered dose. Relationships between formaldehyde air concentrations and rates of

formation of DNA-protein cross links in nasal epithelial tissue of rats (Casanova et al. 1989) or of Rhesus

monkeys (Casanova et al. 1991; Heck et al. 1989) and adjustments to continuous exposure were used to

calculate lifetime human cancer unit risk estimates of 3.3x10-4 per ppm formaldehyde based on the

monkey data, and 2.8x10-3 per ppm formaldehyde based on the rat data. EPA (1987d, 1991a; IRIS 1999)

did not derive a cancer risk estimate for oral exposure to formaldehyde. EPA and CIIT (CIIT 1998) are

currently working on options to derive new estimates of cancer risk in humans exposed by inhalation

using CFD models of nasal airflow and uptake of formaldehyde in rats, monkeys, and humans;

pharmacokinetic models of nasal tissue disposition of formaldehyde; and two-stage clonal growth cancer

models incorporating data on cellular proliferation rates. 

2.6 CHILDREN’S SUSCEPTIBILITY

This section discusses potential health effects from exposures during the period from conception to

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect

effects on the fetus and neonate due to maternal exposure during gestation and lactation. Relevant animal

and in vitro models are also discussed.

 

Children are not small adults. They differ from adults in their exposures and may differ in their

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the

extent of their exposure. Exposures of children are discussed in Section 5.6 Exposures of Children.

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less

susceptible than adults to health effects, and the relationship may change with developmental age

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are

critical periods of structural and functional development during both prenatal and postnatal life and a

particular structure or function will be most sensitive to disruption during its critical period(s). Damage

may not be evident until a later stage of development. There are often differences in pharmacokinetics

and metabolism between children and adults. For example, absorption may be different in neonates 
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2. HEALTH EFFECTS

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example,

infants have a larger proportion of their bodies as extracellular water and their brains and livers are

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many

xenobiotic metabolizing enzymes have distinctive developmental patterns and at various stages of growth

and development, levels of particular enzymes may be higher or lower than those of adults and sometimes

unique enzymes may exist at particular developmental stages (Komori 1990; Leeder and Kearns 1997;

NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the child more or

less susceptible also depends on whether the relevant enzymes are involved in activation of the parent

compound to its toxic form or in detoxification. There may also be differences in excretion, particularly

in the newborn who has a low glomerular filtration rate and has not developed efficient tubular secretion

and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). Children and adults

may differ in their capacity to repair damage from chemical insults. Children also have a longer lifetime

in which to express damage from chemicals; this potential is particularly relevant to cancer.

Certain characteristics of the developing human may increase exposure or susceptibility while others may

decrease susceptibility to the same chemical. For example, the fact that infants breathe more air per

kilogram of body weight than adults may be somewhat counterbalanced by their alveoli being less

developed, so there is a disproportionately smaller surface area for absorption (NRC 1993).

Whereas there are numerous studies of adults occupationally exposed to formaldehyde and exposed under

acute controlled conditions, data regarding the toxicological properties of formaldehyde in children are

limited. Nevertheless, the same type of effects that occur in adults are expected to occur in children (e.g.,

damage in portal-of-entry tissues at exposure levels that exceed tissue detoxification mechanisms). 

Symptoms expected to occur in children include eye, nose, and throat irritation from exposure to airborne

concentrations between 0.4 and 3 ppm, and dermal irritation from exposure to dermal contact with liquids

containing more than 2% formaldehyde. Given the water-soluble and reactive nature of formaldehyde

and the apparent ubiquity of rapid cellular metabolism of formaldehyde, it is expected that the irritant

effects of formaldehyde would be restricted in children, as in adults, to portals-of-entry, although no 
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2. HEALTH EFFECTS

information was located comparing rates of formaldehyde metabolism in children’s tissues with rates in

adult tissues, either in humans or animals. However, studies of adult humans or rats exposed for short

periods to air concentrations of 1.9 ppm or 14.4 ppm, respectively (Heck et al. 1985), and monkeys

exposed to 6 ppm for up to 4 weeks (Casanova et al. 1988) found no appreciable changes in circulating

blood levels of formaldehyde; these results are consistent with the protective action of rapid metabolism

of formaldehyde in portal-of-entry tissues. The developing fetus or nursing infant would be expected to

be protected from exposure to formaldehyde (via inhalation, oral, and dermal contact) by the pregnant or

breast-feeding mother. Studies of animals exposed during pregnancy to formaldehyde in air (Martin

1990; Saillenfait et al. 1989), in the diet or by gavage (Hurni and Ohder 1973; Marks et al. 1980), or on

the skin (Overman 1985) have found no distinct or consistent effects on fetal development, even at

exposure levels that produced severe maternal toxicity (e.g., Marks et al. 1980). 

Two studies were available providing suggestive evidence that children may be more sensitive than adults

to the irritant properties of airborne formaldehyde (Krzyzanowski et al. 1990; Wantke et al. 1996a). 

Krzyzanowski et al. (1990) questioned a group of 298 children (aged 6–15 years) and 613 adults

concerning respiratory symptoms, measured PEFR during evenings and mornings for up to 14 days, and

made measurements of household air concentrations of formaldehyde in several rooms of 202 houses. 

Preliminary reports of this study were published in an earlier report (Quackenboss et al. 1989). Bedroom

air concentrations were #0.040 ppm for more than 80% of the subjects, between 0.04 and 0.06 ppm for

about 8–10% of the subjects, and greater than 0.06 ppm in about 3% of children and 6% of adults in the

study. A few cases were measured with air concentrations exceeding 0.09 ppm, with a maximum value of

0.14 ppm. Regression analysis found no significant relationship between exposure category of children

and prevalence rates of subjectively reported respiratory symptoms, but physician-diagnosed chronic

bronchitis or asthma prevalence rates were elevated in children with household air concentrations greater

than 0.06 ppm, especially in households with environmental tobacco smoke. In adults, neither respiratory

symptoms or physician-diagnosed chronic bronchitis or asthma were significantly related to

formaldehyde air concentrations. In children, a statistically significant trend for decreasing PEFR values

with increasing formaldehyde exposure concentrations was found; the estimated decrease in PEFR

associated with 0.06 ppm was 22% compared with mean values for low-level children. In adults, PEFR

values (mornings only) were also related to formaldehyde concentrations, but the effect was relatively

small; the estimated decrement in adults associated with 0.10 ppm was about 1%.
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School children who attended particleboard-paneled classrooms with estimated formaldehyde air

concentrations of 0.075, 0.069, and 0.043 ppm reported respiratory tract symptoms consistent with the

irritant properties of formaldehyde including rhinitis, cough, nosebleed, and headache (Wantke et al.

1996a). These concentrations are low compared to workplace air concentrations or exposure chamber

concentrations associated with irritant symptoms in adults (0.4–3 ppm). Formaldehyde-specific IgE

antibodies were detected in serum of 40% of the children. The investigators noted that the elevated levels

were not correlated with the number and severity of symptoms, but serum levels and incidence of

symptoms decreased in a subgroup of the children 3 months after they were moved to another school with

lower air concentration of formaldehyde (0.023–0.029 ppm). As stated earlier when discussing this

study, the significance of these findings is uncertain as the reported symptoms were more typical of an

irritant response than of asthma-like symptoms that are expected to be mediated through IgE antibodies.

Additional research is necessary to confirm or discard the hypothesis that children may be more

susceptible than adults to the irritant effects of formaldehyde and to understand the mechanistic basis of

this possible difference.

 

2.7 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic

substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in

readily obtainable body fluid(s) or excreta. However, several factors can confound the use and

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures

from more than one source. The substance being measured may be a metabolite of another xenobiotic

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 
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2. HEALTH EFFECTS

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as

copper, zinc, and selenium). Biomarkers of exposure to formaldehyde are discussed in Section 2.7.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an

organism that, depending on magnitude, can be recognized as an established or potential health

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung

capacity. Note that these markers are not often substance specific. They also may not be directly

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused

by formaldehyde are discussed in Section 2.7.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic

or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in

the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are

discussed in Section 2.9.

2.7.1 Biomarkers Used to Identify or Quantify Exposure to Formaldehyde

Formaldehyde is a simple one-carbon molecule and is rapidly absorbed and metabolized by animals,

including humans. A thorough review of the available literature failed to produce any reliable biomarkers

of exposure to formaldehyde.

As discussed in Section 2.3, formaldehyde is rapidly absorbed by the inhalation and oral routes of

exposure. Once absorbed, there are four major metabolic pathways associated with formaldehyde

metabolism, with the metabolism to formate and CO2 the most heavily used (see Figure 2-3 in Section

2.3.3). 

Attempts have been made to determine if either blood or urinary levels of formaldehyde or formate could

be used as potential biomarkers of exposure, but with disappointing results. Heck et al. (1985) exposed 
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2. HEALTH EFFECTS

four men and two women to a 1.9±0.06 ppm air concentration of formaldehyde in a large walk-in

chamber for 40 minutes. Shortly before and shortly after the exposure, venous blood samples were taken

from each person (each person served as his/her own control) and the blood was analyzed for

formaldehyde content. No significant differences were found between pre- and postexposure blood

concentrations of formaldehyde at the concentration tested. In the same study, male Fischer 344 rats were

placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air concentration of

formaldehyde for 2 hours; rats were sacrificed, and venous blood samples were collected and analyzed for

formaldehyde content. Even by using the higher exposure concentration of formaldehyde, no significant

differences in blood formaldehyde concentrations were found between the pre- and postexposure blood

samples. In addition, the rapid intravenous injection of formaldehyde in monkeys showed a plasma halflife of only 1.5 minutes, with a corresponding increase in blood formate levels. 

Einbrodt et al. (1976) exposed students to 0.26–0.92 ppm formaldehyde vapors for 3 hours, with urine

samples collected immediately after exposure and 21 hours after exposure. Urine formaldehyde and urine

formic acid (formate) concentrations were found to be higher immediately after exposure compared to

21 hours later; however, no baseline sample was obtained prior to exposure. If historic formaldehyde and

formic acid baseline levels were assumed, then a closer examination of these data indicates that more

formaldehyde (and metabolite) was excreted in the urine than could have possibly been absorbed by

inhalation, indicating another route of exposure (perhaps dermal), or co-exposure to another chemical that

also has formate as a metabolite (e.g., methanol), or higher personal exposures than were actually

measured. There was also no indication that the urine formate levels were adjusted to compensate for

urine specific gravity using urine creatinine levels, which may have markedly influenced the test results. 

Gottschling et al. (1984) monitored 35 anatomy laboratory students exposed for 2 hours, once a week for

3 weeks, with exposures ranging from 0.036 to 0.111 ppm. Urine was obtained prior to exposure and

during the exposure. Wide variations were noted in the urine formate levels prior to exposure, with large

intrapersonal and interpersonal variations; mean postexposure urine formate concentrations were elevated

after exposure to formaldehyde vapors, but not significantly. In the study by Einbrodt et al. (1976), urine

formate levels were significantly elevated in both anatomy laboratory students and in four factory

workers exposed to 1 ppm formaldehyde; however, the mass-balance equations for both groups 

indicated other factors may have influenced the amount of formate found in the urine. Formate

production is not specific to formaldehyde because other chemicals such as methanol, halomethanes 

(e.g., dichloromethane), and acetone have formate in their metabolic pathways (Ferry et al. 1980; 
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Kornbrust and Bus 1983; Liesivuori and Savolainen 1987). This indicates that even if blood or urine

formate levels were elevated, it may be due to individual variation, formaldehyde exposure, or other

chemical exposures that result in formate formation. Thus formate blood and urine levels appear to be

equally unreliable as definitive biomarkers for formaldehyde exposure.

Formaldehyde that is not rapidly metabolized to formate can react with a variety of cellular components

including nucleotides, proteins, and glutathione, forming adducts, such as N6-hydroxymethyldeoxyadenosine and N2- hydroxymethyldeoxyguanosine, and DNA-protein cross links. Several of these

formaldehyde-induced products have been examined as potential biomarkers of exposure for repeated

exposure to formaldehyde. A method for detecting biomarkers such as N6

-hydroxymethyldeoxyadenosine and N2

-hydroxymethyldeoxyguanosine (the major adducts formed by formaldehyde in vitro)

had experimental complications and does not appear to provide useful biomarkers of formaldehyde

exposures (Fennel 1994). Many studies (Casanova-Schmitz et al. 1984a; Casanova and Heck 1987;

Casanova et al. 1989a, 1989b, 1991, 1994) utilized radiolabeled compounds tagged with 14C and/or 3

H to

facilitate detection of DNA-protein cross links; however, this approach would not work to detect past

exposures in humans. The formation of DNA-protein cross links in isolated rat nasal epithelial cells

(respiratory and olfactory epithelial cells) incubated with formaldehyde has also been reported

(Kuykendall et al. 1995). Utilizing a sensitive technique to detect total DNA-protein cross links, Shaham

et al. (1996a) reported that cultured human white blood cells showed increasing quantities of DNAprotein cross links when cultured in media with increasing formaldehyde concentrations and that a small

group of formaldehyde-exposed persons had a significantly greater mean amount of DNA-protein cross

links in their white blood cells than did a group of nonexposed persons. Although DNA-protein cross

links are known to be formed by other agents such as ionizing radiation and alkylating agents, Shaham et

al. (1996a) concluded that their results suggested that levels of DNA-protein cross links in white blood

cells may provide an indicator of formaldehyde-induced tissue damage and a biomarker of occupational

exposure to formaldehyde. Shaham et al. (1996b) noted that a larger study of the potential of DNAprotein cross links in white blood cells as a biomarker of effect and exposure was in progress. 

Immunological biomarkers of effect (IgG and IgE antibodies against formaldehyde conjugated to human

serum albumin) have been examined as potential biomarkers of exposure to airborne formaldehyde. 

Some studies have reported that increased serum levels of antibodies against formaldehyde-human serum

albumin in groups of human subjects correlated with exposure to airborne formaldehyde and symptoms of

respiratory distress (Thrasher et al. 1987, 1988b, 1989, 1990), whereas other studies of human subjects 
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have not found similar correlations (Dykewicz et al. 1991; Grammer et al. 1990; Patterson et al. 1989;

Wantke et al. 1996a, 1996b). The hypothesis, put forth by Nordman et al. (1985), concluded that

immunological hypersensitivity of the respiratory tract to airborne formaldehyde is rare, and casts doubt

that immunological biomarkers for formaldehyde would have been useful biomarkers to indicate

exposure. However, Carraro et al. (1997) recently reported that the presence of IgG antibodies against

formaldehyde-human serum albumin was significantly associated with smoking habits, but not with selfreported occupational exposure to formaldehyde, in a group of 219 healthy subjects. When only nonsmokers were included in the analysis, a statistically significant association was found between the

presence of formaldehyde-specific antibodies and occupational exposure to formaldehyde. An indirect

competitive immunoenzyme assay for anti-formaldehyde-human serum albumin antibodies was

developed for this study. These results suggest that smoking produces a detectable immunological

response to formaldehyde and that the technique employed may be useful to indicate occupational or

residential exposure to formaldehyde especially in the absence of exposure to tobacco smoke. 

Development of biomarkers for exposure is complicated by the fact that the metabolism of many

xenobiotics can result in formaldehyde production in vivo. Carbon tetrachloride, endrin, paraquat,

2,3,7,8-tetrachlorodibenzo-p-dioxin (Shara et al. 1992), and dichloromethane (Dekant and Vamvakas

1993) are all known to generate formaldehyde during their metabolism.

2.7.2 Biomarkers Used to Characterize Effects Caused by Formaldehyde

Increased eosinophil concentration and increased levels of albumin and total protein have been found in

nasal lavage fluid taken from subjects exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak et al.

1998; Pazdrak et al. 1993). Although these variables are not expected to be only influenced by

formaldehyde, they appear to be promising biomarkers of acute respiratory irritation from airborne

formaldehyde.

As discussed in the previous section, DNA-protein cross links in white blood cells (Shaham et al. 1996a)

and anti-formaldehyde-human serum albumin IgG antibodies in serum (Carraro et al. 1997) are potential

biomarkers of both exposure and effect associated with intermediate- or chronic-exposure to

formaldehyde. 

Li et al. (1995) evaluated the validity of the modified lymphocyte transformation assay for detecting

contact hypersensitivity of formaldehyde. Female Hartley guinea pigs were sensitized to formaldehyde
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by receiving subcutaneous injections of 1.85% formaldehyde (6 sites, 0.1 mL per site) followed 7 days

later by epicutaneous exposure to 0.5 mL of a 1.85% formaldehyde solution. Cells were collected from

lymph nodes tissue. Exposure to increasing concentrations of formaldehyde resulted in significant

increases in T-lymphocyte blastogenesis (p<0.05). Although further refinement of this assay would be

required (i.e., use of peripheral blood lymphocytes in lieu of lymph node samples), it does have potential

for providing nonspecific biomarker of effect for formaldehyde sensitization.

Another potentially useful biomarker of effect for repeated inhalation exposure to formaldehyde involves

the histological examination of nasal biopsy samples. Histological changes in nasal biopsy tissue samples

(e.g., loss of ciliated cells, squamous dysplasia and hyperplasia) have been associated with formaldehyde

exposure in several cross-sectional studies of formaldehyde-exposed and nonexposed workers (Ballarin et

al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Each of these studies used a

morphological grading method that assigned an increasing point value for histological changes ranging in

severity from loss of ciliated cells to the presence of malignant cells. Prevalence of different types of

changes and mean histological scores were compared between exposed and nonexposed groups. The

findings from rat studies indicating that the development of formaldehyde-induced nasal cancer is

preceded by repeated damage to the upper respiratory tract epithelium suggests that monitoring of

formaldehyde-exposed workers for cytological abnormalities in nasal biopsy samples may be useful to

prevent the development of upper respiratory tract tissue damage or cancer. Similar findings of epithelial

squamous dysplasia and hyperplastic nasal mucosa have been found in chronic occupational exposures to

formaldehyde (Boysen et al. 1990; Edling et al. 1988); however, as discussed in Section 2.5, these human

studies do not conclusively prove that formaldehyde was the primary toxicant responsible for the

observed nasal lesions. The squamous metaplasia and mucosal hyperplastic lesions may be useful

indicators of more severe formaldehyde-induced effects; however, its usefulness in human exposures is

likely to be limited.
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2.8 INTERACTIONS WITH OTHER CHEMICALS

The study by Albert et al. (1982) reported the carcinogenic responses to the combined and separate

exposures to formaldehyde and hydrochloric acid in male inbred Sprague-Dawley rats. Rats were

exposed for 588 days to formaldehyde alone (14.2 ppm); formaldehyde (14.1 ppm) and hydrogen chloride

(HCl) (9.5 ppm) combined but not premixed; formaldehyde (14.3 ppm) and HCl (10.0 ppm) combined

and premixed; HCl alone (10.2 ppm); or room air. The data did not indicate a synergistic effect on

mortality from combined formaldehyde and HCl exposure; no synergism was noted between combined

HCl and formaldehyde exposure and the induction of nasal cancers. Rats exposed to formaldehyde alone

experienced about a 9% depression in body weights compared to controls; those exposed to HCl alone

experienced no noticeable weight loss; exposure to formaldehyde and HCl combined resulted in a 14%

depression in body weight, indicating a synergistic adverse effect on body weight from combined HCl

and formaldehyde exposure. Lam et al. (1985) studied the effects of inhalation co-exposure to acrolein

and formaldehyde in male Fischer 344 rats. Rats were exposed for 6 hours to room air (controls), 2 ppm

acrolein, 6 ppm formaldehyde, or a combination of 2 ppm acrolein and 6 ppm formaldehyde. The

animals were sacrificed immediately after completion of exposure and their nasal tissues were harvested. 

Exposure to formaldehyde significantly increased the percentage of interfacial DNA (a measure of

DNA-protein cross linking) compared to rats exposed to room air only (12.5 versus 8.1%, p<0.05). 

Co-exposure to acrolein resulted in further increases in the percentage of interfacial DNA (18.6%) which

were significantly greater than the effect of formaldehyde alone (p<0.05). The authors concluded that

simultaneous exposure to acrolein enhanced formaldehyde-induced DNA-protein cross linking and that

depletion of glutathione by acrolein inhibited the metabolism of formaldehyde, thereby increasing

formaldehyde-induced DNA-protein cross link formation.

To investigate the possibility of additive or potentiating interactions between inhaled aldehydes, Cassee et

al. (1996b) compared responses in nasal epithelial histopathology and cell proliferation in groups of male

Wistar rats exposed for 3 days (6 hours/day) to 1.0, 3.2, or 6.4 ppm formaldehyde alone; to 0.25, 0.67, or

1.40 ppm acrolein alone; to 750 or 1,500 ppm acetaldehyde alone; or to several mixtures of these

aldehydes. At the concentrations tested, the histological and cell proliferation responses measured in the

nasal epithelium of rats exposed to the mixture which produced effects (3.2 ppm formaldehyde;

1,500 ppm acetaldehyde; 0.67 ppm acrolein) were attributed by the investigators to the acrolein alone

with no additional effects from the formaldehyde or acetaldehyde. The investigators concluded that 
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combined exposures to these aldehydes at exposure levels in the vicinity of individual no-effect-levels

was not associated with a greater hazard than that associated with exposure to the individual chemicals.

As discussed previously in Sections 2.2 and 2.5, experiments with mice (Tarkowski and Gorski 1995) and

guinea pigs (Riedel et al. 1996) indicate that exposure to low levels of formaldehyde enhances allergic

responses to intranasal administration of ovalbumin and suggest the possibility of formaldehyde

facilitation of allergic responses to other respiratory allergens. Mice pre-exposed to 1.6 ppm, 6 hours/day

for 10 consecutive days produced four-fold greater ovalbumin-specific IgE antibodies in response to

intranasal administration of ovalbumin mice that were not pre-exposed (Tarkowsi and Gorski 1995). A

group of guinea pigs exposed to 0.25 ppm formaldehyde, 8 hours/day for 5 days showed a greater

percentage of bronchial, presumably allergic, responses to inhaled ovalbumin than a control group

without preexposure to formaldehyde (10/12 versus 3/12) (Riedel et al. 1996). 

2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to formaldehyde than will most

persons exposed to the same level of formaldehyde in the environment. Reasons may include genetic

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters may result in reduced detoxification or excretion of formaldehyde, or compromised

function of target organs affected by formaldehyde. Populations who are at greater risk due to their

unusually high exposure to formaldehyde are discussed in Section 5.6.

Two populations of humans have received considerable attention in the literature as being particularly

sensitive to formaldehyde exposure following inhalation and/or dermal exposure. The first population is

asthmatics, and concern focuses on the changes in lung function parameters that formaldehyde may

produce (Harving et al. 1990; Kulle et al. 1987; Pazdrak et al. 1993; Reed and Frigas 1984; Sauder et al.

1986; Schachter et al. 1986; Witek et al. 1986). Most of these studies concluded that there is no evidence

of increased airway reactivity as a result of formaldehyde exposure in either normal or asthmatic

individuals. Formaldehyde exposures at the concentrations tested (usually >3 ppm) did not exacerbate

existing asthmatic conditions, either at rest or after exercise. However, Nordman et al. (1985), in a human

population of 230 persons suffering asthmatic symptoms and exposed to formaldehyde, found that 

when exposed to 2.04 ppm formaldehyde for 30 minutes, eight subjects demonstrated an immediate

bronchial reaction, four subjects demonstrated a delayed reaction, and two subjects demonstrated both an 
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immediate and a delayed reaction. Peak expiratory flow rates dropped 19–49% in the immediate-reaction

group and 21–47% in the delayed-reaction group. In a study of seven subjects with a history of

occupational exposure to glutaraldehyde and asthma, peak expiratory flow rates were decreased in 3/7

subjects by 27–33% in response to a bronchial challenge with 1% formaldehyde (Gannon et al. 1995). 

Gannon et al. (1995) suggested that respiratory sensitivity produced by exposure to glutaraldehyde may

have cross-reactivity to formaldehyde in some subjects. 

The second population of potential concern is people with dermal sensitization. Several cases have been

reported. Formaldehyde liquid, but neither the gaseous phase nor formalin, is considered to be a dermal

sensitizer (Hilton et al. 1996). Anaphylactic reactions have been reported in the literature (Maurice et al.

1986), in a description of a case in which anaphylaxis occurred in a patient due to skin contact with

adhesives sterilized with formaldehyde prior to her hemodialysis therapy. Dermal allergic reactions have

also been reported in doctors and nurses exposed to formaldehyde (Rudzki et al. 1989) as well as in

fiberglass workers (Kilburn et al. 1985a).

Data from acute controlled-exposure studies, supported by data from animal studies, generally indicate

that formaldehyde does not induce airway hyper-reactivity at concentrations #3 ppm, but further studies

with asthmatics may be required because of somewhat conflicting data in this potentially sensitive

population. Other persons with dermal sensitization to formaldehyde are not likely to develop signs of

respiratory insufficiency. Persons with multiple chemical sensitivities may represent a third potentially

sensitive population, but studies linking this syndrome with exposure to formaldehyde were not located. 

2.10 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of

exposure to formaldehyde. However, because some of the treatments discussed may be experimental and

unproven, this section should not be used as a guide for treatment of exposures to formaldehyde. When

specific exposures have occurred, poison control centers and medical toxicologists should be consulted

for medical advice. The following texts provide specific information about treatment following exposures

to formaldehyde:

Aaron, CK and Howland, MA (eds.) (1994). Goldfrank's Toxicologic Emergencies. Appleton and

Lange, Norwalk, CT.
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Dreisbach, RH and Robertson, WO, (eds.) (1987). Handbook of Poisoning. Appleton and Lange,

Norwalk, CT.

Ellenhorn, MJ and Barceloux, DG, (eds.) (1988). Medical Toxicology: Diagnosis and Treatment of

Human Poisoning. Elsevier Publishing, New York, NY.

Gossel, TA and Bricker JD (1994). Principles of Clinical Toxicology. 3rd edition, Raven Press,

New York, NY.

Haddad, LM and Winchester, JF, (eds.) (1990). Clinical Management of Poisoning and Drug

Overdose (2nd edition). WB Saunders, Philadelphia, PA.

The primary concern after oral intoxication with formaldehyde is correcting the severe acidosis and

decreased blood pressure that this chemical induces. Treatment should aimed at increasing the blood

pressure to a somewhat normal state (sympathomimetic drugs may be used) as well as treating the

acidosis with bicarbonate (Aaron and Howland 1994; Gossel and Bricker 1994). Dialysis may also be

used to remove excess formate (as formic acid) in the blood in order to correct the acidosis (Burkhart et

al. 1990; Eells et al. 1981).

2.10.1 Reducing Peak Absorption Following Exposure

Human exposure to formaldehyde may occur by inhalation, ingestion, or dermal contact. There are no

known antidotes to formaldehyde poisoning in humans, particularly after oral exposure. General

recommendations for reducing absorption of formaldehyde include removing the exposed individual from

the contaminated area and removing contaminated clothing, if applicable. If the eyes and skin were

exposed, they should be flushed with copious amounts of water. Since formaldehyde is highly corrosive,

vomiting after oral ingestion should not be induced. The stomach contents can be diluted with milk or

water by mouth if the patient is alert and responsive, otherwise gastric lavage may be indicated. A bolus

of charcoal and isotonic saline cathartic may also be useful (Aaron and Howland 1994).

2.10.2 Reducing Body Burden

Formaldehyde is not stored to any appreciable extent in the human body and is mostly metabolized to

formate and carbon dioxide (see Section 2.3). The half-life of formaldehyde in monkeys has been

observed to be about 1.5 minutes following an intravenous injection. Furthermore, an inhalation 

exposure study found that no formaldehyde was present in the blood after a 1.9 ppm exposure for 
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40 minutes, indicating formaldehyde is metabolized very quickly either in the respiratory tract tissues or

in the blood.

Despite a relatively fast clearance of formaldehyde from the body, toxic effects may develop in exposed

individuals, particularly in cases of acute oral poisonings which quickly overwhelm the body’s natural

mechanisms to metabolize formaldehyde (particularly via formaldehyde dehydrogenase; see Figure 2-3). 

There is no standard method or practice to enhance the elimination of the absorbed dose of formaldehyde

(Aaron and Howland 1994; Ellenhorn and Barceloux 1988).

2.10.3 Interfering with the Mechanism of Action for Toxic Effects

Target organs of formaldehyde toxicity while in the gaseous phase are the respiratory tract and eyes. 

After oral exposure, the tissues that formaldehyde comes into contact with on its way to the stomach and

intestines (i.e., lips, oral pharynx, esophagus) are the target tissues; after dermal exposure, the adverse

effects of formaldehyde are usually localized to the contact area, although other systemic reactions have

been reported (Maurice et al. 1986) (see Section 2.2). Formaldehyde readily combines with free,

unprotonated amino groups to yield hydroxymethyl adduct derivatives resulting in proton liberation

(Loomis 1979). In higher concentrations (5–10%), formaldehyde will precipitate protein, which is the

reason for its use in current histological techniques. The mechanism that causes the primary irritant

effects is not presently known, but may involve one of the two mechanisms mentioned above. Currently,

there are no procedures or therapies that specifically focus on interfering with the mechanism of action of

formaldehyde. Supportive care by trained medical personnel is highly recommended.

2.11 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of formaldehyde is available. Where adequate information is

not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure

the initiation of a program of research designed to determine the health effects (and techniques for

developing methods to determine such health effects) of formaldehyde.
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The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance-specific research agenda will be proposed.

2.11.1 Existing Information on Health Effects of Formaldehyde

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to

formaldehyde are summarized in Figure 2-5. The purpose of this figure is to illustrate the existing 

information concerning the health effects of formaldehyde. Each dot in the figure indicates that one or

more studies provide information associated with that particular effect. The dot does not necessarily

imply anything about the quality of the study or studies, nor should missing information in this figure be

interpreted as a "data need." A data need, as defined in ATSDR's Decision Guide for Identifying

Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific

information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a

data gap more broadly as any substance-specific information missing from the scientific literature. 

As seen in Figure 2-5, information is available regarding death, acute and chronic systemic effects,

immunological, neurologic, reproductive, developmental, genotoxic, and cancer effects in humans after

inhalation exposure to formaldehyde. Lesser amounts of information are available for humans exposed to

formaldehyde after oral and dermal exposure. The oral and dermal health effects data are primarily

limited to death and acute systemic toxicity data, immunological data (skin sensitization) after dermal

exposure, and neurological data after acute oral poisonings. 

As also seen in Figure 2-5, significantly more information is available on the inhalation, oral, and dermal

effects of formaldehyde in laboratory animals. The information on health effects in animals exposed

orally or by inhalation is particularly rich but data regarding dose-response relationships for

gastrointestinal effects from acute oral exposure and reproductive effects in multiple generations represent

the most notable information gaps (see Section 2.11.2 for further discussion). Information was not

located regarding death, systemic effects from intermediate-duration exposure, neurologic effects, and

genotoxic effects in animals dermally exposed to formaldehyde.
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FORMALDEHYDE 242

2. HEALTH EFFECTS

2.11.2 Identification of Data Needs

Acute-Duration Exposure. Results from human and animal studies indicate that portal-of-entry

tissues are the critical targets of acute-duration exposures to formaldehyde: the nose and eyes with

inhalation exposure; the gastrointestinal tract with oral exposure; and the skin with dermal exposure.

Studies of humans under controlled conditions clearly indicate that acute exposures to air concentrations

ranging from 0.4 to 3 ppm:

C induce reversible eye, nose, and throat irritation (Andersen and Molhave 1983; Bender et al. 1983;

Day et al. 1984; Gorski et al. 1992; Krakowiak et al. 1998; Kulle 1993; Kulle et al. 1987; Pazdrak et

al. 1993; Schachter et al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986);

C produce changes in nasal lavage fluid contents, indicative of irritation of the nasal epithelium

(Gorski et al. 1992; Krakowiak et al. 1998; Pazdrak et al. 1993); and 

C do not consistently or markedly affect pulmonary function variables in most individuals (Andersen

and Molhave 1983; Day et al. 1984; Gorski et al. 1992; Green et al. 1987; Harving et al. 1986,

1990; Kulle et al. 1987; Nordman et al. 1985; Sauder et al. 1986; Schachter et al. 1986; Witek et al.

1986).

Acute inhalation animal studies confirm that air concentrations below 10–20 ppm produce damage only in

specific regions of the epithelium of the upper respiratory tract in rats, mice, and monkeys and not at

distant sites (Bhalla et al. 1991; Cassee and Feron 1994; Chang et al. 1983; Dinsdale et al. 1993; Kamata

et al. 1996b; Monticello et al. 1989, 1991; Monteiro-Riviere and Popp 1986; Morgan et al. 1986a, 1986c;

Wilmer et al. 1987). An acute inhalation MRL of 0.04 ppm was derived based on the LOAEL of 0.4 ppm

for transient symptoms of eye and nose irritation and increased albumin content of nasal lavage fluid in

volunteers exposed to formaldehyde for 2 hours (Pazdrak et al. 1993). Confidence is high that this MRL

will protect the general public health due to the wealth of data, but confidence may increase with

additional information about exposure-response relationships for formaldehyde-induced respiratory

effects in potentially susceptible populations of individuals, such as asthmatics. 

An acute oral MRL for formaldehyde was not derived because data describing dose-response

relationships for gastrointestinal tract irritation in humans or animals after acute oral exposure are lacking. 

The reports of gastrointestinal effects and symptoms in humans who ingested single large doses

(>200 mg/kg) of formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Kochhar et al. 1986), coupled with 
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data from studies of animals exposed orally for intermediate- and chronic-durations (Til et al. 1988b,

1989; Tobe et al. 1989), indicate that gastrointestinal irritation and damage are the most likely critical

effects from acute oral exposure. However, as discussed in Section 2.5, the human data do not identify a

no-effect level, and the available animal studies of acute oral exposure (Cassidy et al. 1983; Johannsen et

al. 1986) did not examine this end point. At least one comprehensive acute oral toxicity study of at least

one animal species exposed to several dosage levels may be needed to generate appropriate data for

deriving an acute oral MRL for formaldehyde.

Formaldehyde is a well-known skin irritant and dermal sensitization agent, but systemic distant-site

effects from acute dermal exposure are not expected given the reactive nature of formaldehyde, the ability

of most cells to rapidly metabolize formaldehyde, and the low rates of formaldehyde absorption through

the skin (Jeffcoat et al. 1983). This expectation is additionally supported by the observation that no

effects on fetal development were found in pregnant hamsters dermally exposed during pregnancy to a

37% formaldehyde solution (Overman 1985). Exposure-response relationships for dermal effects from

acute dermal exposure are well characterized in humans and animals. Experience with various types of

formaldehyde solutions in the workplace and results from widespread patch testing in skin clinics indicate

that acute dermal exposure to formaldehyde concentrations of 2–5% can evoke a mild to moderate nonallergic skin irritation response in some individuals; concentrations greater than 5% are expected to be

irritating to most individuals (Fischer et al. 1995; Maibach 1983). In studies of dermally sensitized

individuals, allergic skin reactions to concentrations as low as 0.025–0.05% have been reported (DeGroot

et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997). The cases of clothing-induced contact dermatitis

that were frequently cited in the literature from the late 1950s until the mid-1970's when newly developed

“no-iron’ textiles that released formaldehyde were used (Peters and Heese 1997) further demonstrate the

skin irritation potential of formaldehyde. Experiments with guinea pigs given daily non-occluded dermal

doses of solutions of formaldehyde indicate that concentrations as low as 0.4% can produce erythema and

increased skin thickness within a 10-day period (Wahlberg 1993).

Intermediate-Duration Intermediate-duration exposure to formaldehyde is expected to affect the

same critical targets as acute exposure: the upper respiratory tract with inhalation exposure; the

gastrointestinal tract with oral exposure; and the skin with dermal exposure. 

Studies of health effects in humans after intermediate-duration inhalation exposure were not located. 

Studies of humans with predominately chronic inhalation exposure to formaldehyde under occupational 
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or residential conditions, however, consistently have reported increased incidences of symptoms of upper

respiratory tract and/or eye irritation among exposed groups of people (Edling et al. 1988; Garry et al.

1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987). Several studies have

found nasal epithelial lesions, consistent with the irritant and reactive properties of formaldehyde, in

biopsy specimens from workers repeatedly exposed to average concentrations ranging from about 0.2 to

0.5 ppm (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Other

studies of similarly exposed groups of workers have either found no, or only small and subtle, exposurerelated changes in pulmonary function variables, thus supporting the identification of the upper

respiratory tract as the critical target of repeatedly inhaled formaldehyde (Alexandersson and

Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and Nethercott 1989; Horvath et al. 1988;

Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990). Although the persons in

these studies are considered to have been exposed for chronic durations, the results, together with the

results from the acute controlled inhalation human studies, provide strong evidence that the critical target

from intermediate-duration inhalation exposure to formaldehyde will be the upper respiratory tract.

Results from studies of animals exposed by inhalation for intermediate durations provide supporting

evidence for the upper respiratory tract as the critical target and describe concentration-response

relationships sufficiently well for describing an intermediate-duration inhalation MRL. Data describing

intermediate-duration exposure-response relationships for upper respiratory tract lesions and

concentrations ranging from 0.2 ppm to as high as 40 ppm are available for rats (Appelman et al. 1988;

Casanova et al. 1994; Monticello et al. 1991; Rusch et al. 1983; Woutersen et al. 1987; Zwart et al. 1988),

Cynomolgus monkeys (Rusch et al. 1983), hamsters (Rusch et al. 1983), and mice (Maronpot et al. 1986). 

Comprehensive histological examination of tissues and organs (including the lungs and eyes) in three of

these studies (Appelman et al. 1988; Maronpot et al. 1986; Woutersen et al. 1987) and in another study of

Rhesus monkeys that included only one exposure concentration (Monticello et al. 1989) found no

consistent evidence for lesions outside of the upper respiratory tract. These results confirm the

identification of the upper respiratory tract as the target of concern. Other intermediate-duration

inhalation exposure studies in rats (Wilmer et al. 1987, 1989) provide evidence that the extent and

severity of formaldehyde-induced epithelial lesions in the upper respiratory tract may be more strongly

influenced by exposure concentration than duration of exposure. 

The intermediate-duration inhalation MRL of 0.03 ppm is based on a NOAEL of 0.98 ppm and a LOAEL

of 2.95 ppm for clinical signs of nasopharyngeal irritation and nasal epithelium lesions observed in 
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Cynomolgus monkeys (Rusch et al. 1983) and an uncertainty factor of 30. Computational fluid dynamic

models of airflow and formaldehyde uptake in nasal passages and pharmacokinetic models of tissue

disposition of formaldehyde in rats and humans are currently under development (Kimbell et al. 1993,

1997a, 1997b; Subramaniam et al. 1998). The application of these models to the rat intermediate-duration

exposure-response data is likely to decrease uncertainty in deriving an intermediate-duration inhalation

MRL from animal data. Such models are being developed for Rhesus monkeys (Kepler et al. 1998;

Kimbell et al. 1997b), not Cynomolgus monkeys, but the available intermediate-duration data for Rhesus

monkeys do not adequately describe concentration-response relationships; therefore a no-effect level

cannot presently be estimated. Application of the monkey and human dosimetric models, when they are

developed, to data from another Rhesus monkey study that would include multiple exposure levels

represents another approach to decreasing uncertainty in the intermediate-duration inhalation MRL.

There is some uncertainty regarding whether or not inhaled formaldehyde can affect the lower respiratory

tract by inducing bronchoconstriction or exacerbating asthma in humans, and whether or not repeated

exposure may influence these possible, but incompletely understood, effects. As discussed earlier,

several acute controlled exposure studies with humans (Andersen and Molhave 1983; Day et al. 1984;

Gorski et al. 1992; Green et al. 1987; Harving et al. 1986, 1990; Kulle et al. 1987; Nordman et al. 1985;

Sauder et al. 1986; Schachter et al. 1986; Witek et al. 1986) and studies of chronically exposed persons in

workplaces or residences (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and

Nethercott 1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and

Kodama 1990) have found only mild or no changes in pulmonary function variables, except in a few rare

cases (see Nordman et al. 1985). However, Amdur (1960) and Swiecichowski et al. (1993) reported that

acute inhalation exposure to fairly low levels of formaldehyde (0.3 to 9 ppm) induced

bronchoconstriction (i.e., increased pulmonary airway resistance) in guinea pigs. Swiecichowski et al.

(1993) further reported that airway reactivity to infused acetylcholine increased after acute exposure to

formaldehyde and that when the duration of exposure to formaldehyde was increased from 2 to 8 hours,

lower concentrations of formaldehyde were effective in increasing airway reactivity to infused

acetylcholine. The mechanism underlying these pulmonary effects is not understood, but Swiecichowski

et al. (1993) have hypothesized that formaldehyde may change airway epithelial biochemistry leading to

release of mediators of bronchoconstriction. Studies to test this hypothesis were not located. The

relevance of the guinea pig findings to the report that a group of children living in homes with 0.06–0.12

ppm formaldehyde showed a greater prevalence of bronchitis and asthma than children living in homes 
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with less than 0.06 ppm (Krzyzanowski et al. 1990) has been questioned (Swiecichowski et al. 1993), but

remains unknown. 

Studies of health effects in humans after intermediate-duration oral exposure to formaldehyde were not

located. Intermediate-duration oral-exposure toxicity studies in animals that examined a range of tissues

and organs are extensive and include a 90-day drinking water rat study that found only weight gain

decreases at dosage levels of 100–150 mg/kg/day (Johannsen et al. 1986), a 4-week drinking water rat

study that identified a NOAEL of 25 mg/kg/day and a LOAEL of 125 mg/kg/day for forestomach and

glandular stomach lesions indicative of irritation (Til et al. 1988b), a 4-week gavage rat study that

identified a NOAEL of 40 mg/kg/day and a LOAEL of 80 mg/mg/day for hepatocellular vacuolation and

a LOAEL of 20 mg/kg/day for a decrease in IgM and IgG titers and increased relative lymph node weight

(Vargova et al. 1993), a 90-day dietary exposure dog study that reported a NOAEL and LOAEL of 75 and

100 mg/kg/day for body weight decreases and no other effects (Johannsen et al. 1986), and a 52-day

dietary exposure pregnant dog study that found no evidence of maternal toxicity and no effects on fetal

development at doses up to 9.4 mg/kg/day (Hurni and Ohder 1973). In addition, a 32-week drinking

water study that focused on the gastrointestinal tract found papillomas in the forestomach and erosions

and/or ulcers in the limiting ridge of the fundic mucosa of the glandular stomach in rats exposed to

258 mg/kg/day (Takahashi et al. 1986a). 

The findings from the intermediate-duration oral exposure studies by themselves do not consistently

identify gastrointestinal tract irritation as the critical effect. However, the weight of evidence from

chronic oral administration animal studies (Til et al. 1989; Tobe et al. 1989) and the numerous

intermediate inhalation toxicity studies (as previously cited), together with mechanistic understanding of

formaldehyde’s mode of toxic action, supports the selection of it as the critical effect from intermediate

duration. Thus the selection of forestomach and glandular stomach lesions in rats (Til et al. 1988b) as the

basis of the intermediate-duration oral MRL of 0.3 mg/kg/day is well-supported. As mentioned in the

introduction to Section 2.2.2, there is uncertainty regarding the actual doses that were experienced by

animals in the published oral exposure studies because of the lack of reporting regarding how frequently

dosing solutions were analyzed for formaldehyde and the well-known instability of aqueous solutions of

formaldehyde. Given this uncertainty and the lack of consistency in the findings from the available

intermediate-duration oral studies, confidence in the MRL may be improved with additional intermediateduration dose-response data from another comprehensive dietary or drinking water study of rats that

includes frequent monitoring of dosing solutions. Dose-response data for gastrointestinal tract 
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effects in a primate species may provide an additional means of decreasing uncertainty in the intermediate

oral MRL. 

Formaldehyde is a well-known skin irritant and skin sensitizer in humans that accounts for about 1–8% of

all cases of allergic dermatitis presented at skin clinics (Fischer et al. 1995; Kiec-Swierczynska 1996;

Marks et al. 1995; Meding and Swanbeck 1990; Menné et al. 1991). Studies of embalmers (Nethercott

and Holness 1988) and medical workers (Rudzki et al. 1989) with expected repeated dermal exposure to

formaldehyde presented evidence for increased prevalence of formaldehyde-induced skin irritation and

dermal allergic reactions. Exposure-response relationships for skin irritation and dermal allergic

responses from acute exposure are well characterized (under patch testing conditions) in both normal and

sensitized individuals, indicating that 1% solutions are not expected to be irritating to most people, and

that allergic dermal reactions in sensitized individuals can occur with concentrations as low as

0.015% (DeGroot et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997; Maibach 1983). No published 

dose-response data were located for dermal irritation or the development of dermal sensitization in

humans for intermediate- or chronic-duration exposure. Given the high reactivity, volatility, and aqueous

solubility of formaldehyde and its rapid metabolism by cells, it is likely that dose-response relationships

for dermal irritation from acute exposure may not be widely different from relationships for intermediateand chronic-duration exposures. This hypothesis is supported by the results from inhalation exposure

studies in rats indicating that exposure concentration is more important than exposure duration in

determining the extent and severity of formaldehyde-induced epithelial lesions in the upper respiratory

tract (Wilmer et al. 1987, 1989). Nevertheless, additional animal studies comparing dose-response

relationships for skin irritation for acute, intermediate, and chronic exposure durations may be useful in

estimating concentrations that will not damage the skin with repeated exposures.

The potency of formaldehyde as a contact allergen is demonstrated by the observation that occluded

dermal exposure of guinea pigs to 5% formaldehyde for 3 weeks sensitized 70% of the animals to later

dermal challenges with 1% formaldehyde (Hilton et al. 1996). However, published studies that describe

dose-response relationship or no-effect levels for the development of dermal sensitization in animals with

intermediate- or chronic-duration exposure were not located. Such studies are likely to be useful in

estimating concentrations of formaldehyde that would minimize the development of dermal sensitization

to formaldehyde in humans.
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Chronic-Duration Exposure and Cancer. As with the shorter durations of exposure, the critical

targets of chronic inhalation, oral, or dermal exposure to formaldehyde are expected to be portal-of-entry

tissues. For the inhalation route, the data are abundant, of good quality, and include both human and

animal data. Less health effects data are available for chronic oral and chronic dermal exposure, but the

weight of the available data is consistent with this expectation.

Studies of humans chronically exposed to airborne formaldehyde concentrations in the approximate range

of 0.1–1 ppm have consistently reported increased incidences of upper respiratory tract and eye irritation

(Edling et al. 1988; Garry et al. 1980; Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and

Lehnen 1987), evidence for mild histological changes in the nasal epithelium (Ballarin et al. 1992;

Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c), and either no or only mild changes in

pulmonary function variables (Alexandersson and Hedenstierna 1988, 1989; Bracken et al. 1985; Holness

and Nethercott 1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka

and Kodama 1990). Several chronic inhalation studies in rats (Kamata et al. 1997; Kerns et al. 1983b;

Monticello et al. 1996; Swenberg et al. 1980; Woutersen et al. 1989) and one study in mice (Kerns et al.

1983b) adequately describe concentration-response relationships for formaldehyde effects on the nasal

epithelium and have identified no-effect levels ranging from 0.1 to 2 ppm. No consistent evidence for

formaldehyde-induced effects at extra-respiratory sites was found in rats (Kamata et al. 1997; Kerns et al.

1983b) or mice (Kerns et al. 1983b) exposed to concentrations as high as 15 ppm. A chronic inhalation

MRL of 0.008 ppm has been derived based on a minimal LOAEL of 0.24 ppm for histological changes in

nasal epithelial specimens from a group of workers involved in the production of formaldehyde and

formaldehyde resins (Holmstrom et al. 1989c) and an uncertainty factor of 30. Although confidence in

this MRL is high due to the wealth of available data, increased confidence may result from additional

prospective longitudinal studies of nasal tissue specimens from groups of workers experiencing varying

formaldehyde exposure levels to investigate if nasal epithelial damage progresses in incidence or severity

with longer duration or higher levels of exposure. Computational fluid dynamics models of airflow and

formaldehyde uptake in nasal passages and pharmacokinetic models of tissue disposition of formaldehyde

in rats and humans are currently under development (Kimbell et al. 1993, 1997a, 1997b; Subramaniam et

al. 1998). Application of these models to chronic rat concentration-response data for nasal lesions

represents another research approach to decreasing uncertainty in the chronic inhalation MRL.
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No studies were located regarding health effects in humans with chronic oral exposure to formaldehyde. 

Two chronic drinking water studies with rats (Til et al. 1989; Tobe et al. 1989) provide enough reliable

data to identify gastrointestinal tract mucosal damage as the critical target for chronic oral exposure and to

describe dose-response relationships and estimates of no-effect levels. Results from the chronic oral

studies are supported by results from the intermediate-duration rat studies showing gastrointestinal tract

effects and associated no-effect levels (Johannsen et al. 1986; Takahashi et al. 1986a; Til et al. 1988b). 

The chronic MRL of 0.2 mg/kg/day was based on a NOAEL of 15 mg/kg/day and a LOAEL of

82 mg/kg/day for tissue damage in the forestomach (papillomatous hyperplasia, atrophic gastritis, and

ulceration) and glandular stomach (hyperplasia) in male rats (Til et al. 1989) and an uncertainty factor

of 100. As with the intermediate-duration data, some uncertainty is associated with the described chronic

dose-response relationships due to a lack of reporting of the frequency of analysis of the drinking water

for formaldehyde content in the available studies. Results from another intermediate-duration drinking

water rat study, rather than a chronic-duration study, that includes frequent monitoring of the drinking

water for formaldehyde, may decrease this source of uncertainty in the both the intermediate and chronic

oral MRLs, given that the weight of evidence that concentration of formaldehyde at the site of toxic

action is likely to be more important in determining cytotoxicity than duration of exposure.

As discussed in the Identification of Data Needs section for intermediate-duration exposure, additional

animal studies comparing exposure-response relationships for skin irritation for acute- intermediate- and

chronic-exposure durations would be useful in estimating concentrations of formaldehyde solutions that

will not damage the skin with repeated exposures. Although no comprehensive toxicity studies in

animals were located regarding chronic dermal exposure, understanding of formaldehyde toxicokinetics

and mechanism of action suggests that distant-site toxicity is not a concern at environmentally or

occupationally relevant dermal exposure levels. 

The potential for occupational exposure to formaldehyde to cause cancer in humans has been examined in

more than 40 epidemiology studies (cohort mortality and case-control studies). In general, these studies

have provided inconsistent evidence for carcinogenicity in humans chronically exposed to low levels of

formaldehyde in workplace air. In most studies finding statistically significant associations between

occupational formaldehyde and human cancer, the associations have not been strong. The

epidemiological studies each have shortcomings, such as limited follow-up, limited exposure 

information, possible misclassification of disease, presence of confounding risk factors, or small numbers

of subjects, that make the establishment of a causal relationship between occupational exposure to 
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formaldehyde and human cancer difficult. Some of the epidemiological studies have found some

scattered evidence for extra-respiratory site cancers in groups of formaldehyde-exposed workers, but the

data are not consistent across studies and adjustment for potential confounding factors often has not been

possible. 

Three meta-analyses of the epidemiologic data are available (Blair et al. 1990a; Collins et al. 1997;

Partanen 1993). Each meta-analysis has focused on findings for respiratory cancer deaths based on the

premise that the respiratory tract is the most biologically plausible site for cancer from exposure to

airborne formaldehyde. Strong support for this premise comes from animal studies showing that chronic

inhalation exposure to formaldehyde concentrations between approximately 6 and 15 ppm, but not lower

concentrations, induces carcinogenic responses in rats that are restricted to the nasal cavity (Albert et al.

1982; Kamata et al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Sellakumar et al. 1985; Swenberg et

al. 1980; Woutersen et al. 1989). Similar tumors were found in chronically exposed mice (Kerns et al.

1983b), but were not found in chronically exposed hamsters (Dalbey 1982). The two earlier metaanalyses showed weak overall associations between formaldehyde exposure and nasopharyngeal cancer. 

Relative risks and associated 95% CIs of 1.2 (0.8–1.7) and 2.0 (1.4–2.9) were reported by Blair et al.

(1990a) and Partanen (1993), respectively. The associations were somewhat stronger in studies classified

with “substantial” (as opposed to “low/medium”) exposure. Relative risks for substantial exposures in the

two analyses were 2.1 (1.1–3.5) and 2.7 (1.4–5.6). The meta-analysis by Collins et al. (1997) also

showed a weak association across all available studies for relative risks of nasopharyngeal cancer

(RR=1.3 [1.2–1.5]), but after adjusting the cohort studies for underreporting of nasopharyngeal cancer

(RR=1.0 [0.5–1.8]) and analyzing the case-control studies separately (RR=1.3 [0.9–2.1]), no statistically

significant associations were found.

Given that exposure information in case-control studies is generally poor, it seems that additional casecontrol studies are unlikely to clarify the potential relationship between occupational formaldehyde

exposure and human cancer. Future research approaches that may be helpful include establishing

prospective cohort mortality studies or updating existing cohort studies focusing on nasal cancer in

groups of workers who have experienced high levels of exposure to formaldehyde or who will experience

varying levels of formaldehyde exposure and in groups of appropriately matched nonexposed workers. It

may be useful to conduct such a prospective study in a country in which occupational exposure levels to

formaldehyde are expected to be higher than those in the United States.
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Mechanistic studies indicate that the carcinogenic response to inhaled formaldehyde in rats originates in

regions of the nasal cavity epithelium that initially show non-neoplastic damage and provide support for

the hypothesis that formaldehyde-induced cancer will occur only at exposure levels that extensively

damage epithelium tissue (e.g., Monticello et al. 1996). Comparison of the non-neoplastic upper

respiratory tract response in rats and monkeys to intermediate-duration formaldehyde exposure has

indicated that both monkeys and rats are similarly susceptible to formaldehyde cytotoxicity but display

some regional differences in sites of tissue damage within the upper respiratory tract (Casanova et al.

1989, 1991; Heck et al. 1989; Monticello et al. 1989). These observations support the use of data from

rodent studies to extrapolatively estimate risks for nasal tissue damage and nasal cancer with human

exposure scenarios.

The application of dosimetric models (e.g., CFD models of airflow and uptake in nasal passages and

PBPK models of nasal disposition of formaldehyde) currently under development (Cohen Hubal et al.

1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a, 1997b; Morgan et al. 1991; Subramaniam et al.

1998) holds promise of reducing uncertainties in estimating human cancer risks from the available rodent

data (Morgan 1997). Ongoing efforts (see CIIT 1998; Conolly et al. 1992; Conolly and Andersen 1993)

to develop two-stage clonal-growth cancer models (i.e., pharmacodynamic models) incorporating data on

formaldehyde-induced cell proliferation rates, numbers of cells at risk, tumor incidence, and site-specific

flux of inhaled formaldehyde are also likely to reduce uncertainties in estimating the risks for neoplastic

damage to the upper respiratory tract in humans exposed to low levels of airborne formaldehyde.

Results from four drinking water rat studies provide some inconsistent evidence for formaldehydeinduced gastrointestinal tract tumors (Soffritti et al. 1989; Takahashi et al. 1986a; Til et al. 1989; Tobe et

al. 1989). As discussed in Section 2.5, the weight of evidence from the rat studies suggests that

gastrointestinal tract tumors may occur as late-developing portal-of-entry effects only from repeated

exposure to high oral doses that damage the gastric mucosa, and that tumors are not likely to develop at

dose levels that do not damage the gastric mucosa. It is unlikely that a human population with high oral

exposures to formaldehyde can be identified to study possible relationships to cancer, but better

characterization of no-effect levels for gastric mucosal damage in animal species exposed repeatedly to

formaldehyde in drinking water may provide additional information to support the hypothesis that low

levels of formaldehyde in water samples associated with hazardous waste sites do not present

considerable risks for cancer.
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No studies were located examining potential relationships between skin cancer in humans and dermal

exposure to formaldehyde, but two mouse-skin cancer bioassays found no evidence for increased

incidence of skin tumors after 58–60 weeks of twice-weekly exposure to formaldehyde solutions at

concentrations of 4% (Iverson 1988) and 10% (Iverson 1986). Additional animal bioassays employing

lifetime dermal exposure scenarios would provide more complete assessments of the possible dermal

carcinogenicity of formaldehyde.

Genotoxicity. Formaldehyde has been demonstrated to have genotoxic properties in human and

laboratory animal studies. Peripheral lymphocytes in anatomy students exposed to 0.73–1.95 ppm

formaldehyde for 10 weeks showed a small average increase in SCEs (Yager et al. 1986). Lymphocytes

from wood workers chronically exposed to formaldehyde also showed increased levels of chromosomal

aberrations; however, there were no significant changes in the rates of SCE (Chebotarev et al. 1986). 

Other positive findings for genotoxicity include increases in micronuclei formation in wood workers

(Ballarin et al. 1992) and an increased incidence in chromosomal abnormalities in pulmonary

macrophages in rats (Dallas et al. 1992).

Formaldehyde has been found to be genotoxic in a number of cells and genetic end points. Formaldehyde

has been found to induce chromosomal aberrations (Dresp and Bauchinger 1988; Natarajan et al. 1983),

increases in micronucleus formation (Ballarin et al. 1992), and SCEs (Yager et al. 1986), as well as

numerous other genotoxic end points (Recio et al. 1992; Topham 1980). Formaldehyde has also been

found to have genotoxic properties in S. typhimurium (Donovan et al. 1983) and in human cell lines

(Grafstrom et al. 1985; Snyder and Van Houten 1986). The weight of evidence indicates that

formaldehyde is capable of directly reacting with DNA. No reports of genotoxicity strictly related to the

oral or dermal exposure routes were found in the available literature. Further cytogenetic analysis of cells

from formaldehyde-exposed individuals would possibly provide useful information about the ability and

mechanisms by which formaldehyde induces its genotoxic end points. 

Reproductive Toxicity. Results from human and animal studies indicate that formaldehyde is not a

likely reproductive toxicant at low levels of exposure. No effects on sperm numbers or sperm

morphology were found in a group of formaldehyde-exposed pathologists (Ward et al. 1984), and

increased rates of miscarriage were not found among persons with presumed residential exposure to

formaldehyde (Garry et al. 1980). Studies of reproductive outcomes in groups of formaldehyde-exposed

workers may be useful to confirm that the potential for reproductive effects from formaldehyde is low. 
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Results from such a study will have a better chance of being conclusive if a population is identified that is

exposed only to formaldehyde.

Animal studies of inhalation exposure found no direct effects of formaldehyde on reproductive organ

histopathology or weight (Appelman et al. 1988; Maronpot et al. 1986; Woutersen et al. 1987) and, with

exposure during gestation, no effects on maternal reproductive variables other than decreased body

weight gains at high exposure levels (Martin 1990; Saillenfait et al. 1989). Similarly, oral exposure of

animals has not been associated with histopathologic or weight changes in reproductive organs

(Johannsen et al. 1986; Til et al. 1989; Tobe et al. 1989; Vargova et al. 1993) or with maternal

reproductive variables such as numbers of resorptions at non-lethal exposure levels in pregnant animals

(Hurni and Ohder 1973; Marks et al. 1980). Changes in sperm morphology were noted in rats given

single gavage doses of 200 mg/kg/day, but not 100 mg/kg/day (Cassidy et al. 1983). Overman (1985)

reported a small increase in resorption rate in pregnant hamsters dermally exposed to 37% formaldehyde

solutions, but attributed this effect to treatment stress rather than to a direct effect of formaldehyde. 

Assays of reproductive performance in formaldehyde-exposed animals were not located, but may be

useful to confirm that formaldehyde is not a reproductive toxicant.

Developmental Toxicity. Results from a human study and several animal studies indicate that

formaldehyde is not a likely developmental toxicant at low levels of exposure. No associations were

found between incidence of low birth weights and ambient air levels of formaldehyde among groups of

mothers living in different residential districts (Grañulevi...iene et al. 1998). No embryolethal or

teratogenic effects of formaldehyde were found in gestational-exposure studies of rats exposed to air

concentrations up to 40 ppm (Martin 1990; Saillenfait et al. 1989), rats exposed to gavage dose levels up

to 185 mg/kg/day (Marks et al. 1980), dogs exposed to dietary doses up to 9.4 mg/kg/day (Hurni and

Ohder 1973), and hamsters dermally exposed to 37% formaldehyde solutions (Overman 1985). 

Formaldehyde was designated as a nonteratogen and nonembryotoxin in the Chernoff/Kavlock

developmental toxicity screening test in mice (Seidenberg and Becker 1987). The need for additional

developmental toxicity studies may not have a high priority, given the evidence from other repeatedexposure animal toxicity and pharmacokinetic studies indicating that health effects from formaldehyde

are likely to be restricted to portals-of-entry. 
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Immunotoxicity. Dermal sensitization to formaldehyde in humans is well recognized from results of

patch testing at dermatological clinics throughout the world (Fischer et al. 1995; Kiec-Swierczynska

1996; Maibach 1983; Marks et al. 1995; Meding and Swanbeck 1990; Menné et al. 1991) and a few

studies of formaldehyde-exposed workers (Nethercott and Holness 1988; Rudzki et al. 1989). Severe

allergic responses to dermally applied formaldehyde, however, appear to be rare; only one case of a

severe anaphylactic response to formaldehyde was located (Maurice et al. 1986). The potency of

formaldehyde as a contact allergen is demonstrated by the observation that occluded dermal exposure of

guinea pigs to 5% formaldehyde for 3 weeks sensitized 70% of the animals to later dermal challenges

with 1% formaldehyde (Hilton et al. 1996). However, published studies that describe dose-response

relationships or no-effect levels for the development of dermal sensitization in animals with intermediateor chronic-duration dermal exposure were not located. Such studies are likely to be useful in estimating

concentrations of formaldehyde that would minimize the development of dermal sensitization to

formaldehyde in humans. 

Although formaldehyde is widely recognized as a dermal irritant that can sensitize the skin in humans, the

evidence for immunologically-mediated sensitization of the respiratory tract from exposure to airborne

formaldehyde is weak. There are only a few available case reports of formaldehyde-exposed workers

who display marked changes in pulmonary function variables in response to acute challenges with inhaled

formaldehyde that are consistent with an immunologically-mediated mechanism of response (Burge et al.

1985; Hendrick et al. 1982; Lemiere et al. 1995). Nordman et al. (1985) reported that, among

230 patients with formaldehyde exposure who reported asthma-like symptoms, only 12 showed marked

pulmonary responses to acute formaldehyde challenges. Other studies found no marked response to

challenges of inhaled formaldehyde in other groups of previously-exposed subjects who complained of

asthma-like symptoms (Day et al. 1984; Krakowiak et al. 1998; Reed and Frigas 1984). Several studies

have found no consistent evidence for increased serum levels of formaldehyde-specific IgE antibodies in

groups of formaldehyde-exposed subjects including groups with complaints of respiratory symptoms

(Dykewicz et al. 1991; Gorski et al. 1992; Grammar et al. 1990; Krakowiak et al. 1998; Kramps et al.

1989; Thrasher et al. 1987, 1990). Elevated serum levels of IgE antibodies and respiratory tract

symptoms were found in groups of children exposed to classroom air concentrations of 0.075, 0.069, and

0.043 ppm formaldehyde (Wantke et al. 1996a). However, the relevance of these findings to the

possibility of respiratory tract sensitization to formaldehyde is uncertain because the elevated levels of

IgE were not correlated with the number and severity of symptoms, and the symptoms were more 
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2. HEALTH EFFECTS

indicative of irritant responses than asthma-type responses expected to be mediated through IgE

antibodies. 

Results from studies with guinea pigs confirm that formaldehyde is a potent skin sensitizer, but does not

elicit IgE responses and lymph node cytokine secretion patterns that are typically induced by other potent

respiratory tract allergens such as trimellitic anhydride (Hilton et al. 1996). Other animal studies indicate

that repeated exposure to formaldehyde at air concentrations between 10 and 15 ppm did not produce

significant effects in several assays of immune function including resistance to intravenous or

subcutaneous injection of neoplastic cells in mice (Dean et al. 1984), resistance to intravenous injection of

bacterial cells in mice (Dean et al. 1984), and IgM response to tetanus immunization and IgG response to

tetanus toxoid in rats (Holmstrom et al. 1989b). However, two other studies indicate that exposure to

airborne formaldehyde may enhance allergic responses of the respiratory tract to other respiratory

allergens (Riedel et al. 1996; Tarkowski and Gorski 1995). Further research is necessary to confirm the

hypothesis that exposure to airborne formaldehyde may facilitate immunological responses to other

respiratory allergens and to determine if this is relevant to humans exposed to formaldehyde. 

Information about immunological and lymphoreticular effects in humans orally exposed to formaldehyde

is restricted to a report of splenomegaly in a case of acute poisoning (Koppel et al. 1990). In animal

studies, decreased IgM and IgG titers in a hemagluttination assay and increased lymph node weights were

found in rats exposed to gavage doses of 20 mg/kg/day and higher, but other measures of IgG and IgM

production were not affected by exposure (Vargova et al. 1993). No effects on weights or histopathology

of spleen and lymph nodes were found in other studies of orally exposed animals (Til et al. 1988b, 1989;

Tobe et al. 1989). The data do not clearly identify immunological effects from oral exposure to

formaldehyde as effects of concern. Further research on the possible immunotoxicity of ingested

formaldehyde may not be warranted given the likelihood that oral exposures to formaldehyde may be low

in most groups of people, due to the instability of formaldehyde in aqueous solutions. 

Neurotoxicity. The nervous system does not appear to be a major target organ for formaldehyde

toxicity; however, some vague neurological symptoms may occur after inhalation exposure in humans. 

These may include headaches, "heavy head," fatigue, and increased reaction time (Bach et al. 1990). 

Kilburn and colleagues have reported evidence for neurological symptoms and impaired performance 

in neurobehavioral tests in groups of formaldehyde-exposed histology technicians, but confounding

exposure to other neurotoxic solvents prevents drawing definitive conclusions regarding the 
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2. HEALTH EFFECTS

neurotoxicity of formaldehyde from this source (Kilburn 1985b; Kilburn et al. 1987; Kilburn and

Warshaw 1992; Kilburn 1994). Restless behavior (Morgan et al. 1986a), increased levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and dopamine in the hypothalamus (Boja et al. 1985),

and evidence for the development of a conditioned avoidance behavior (Wood and Coleman 1995) have

been reported in rats. The restless behavior may be attributable to the respiratory irritant effects of the

formaldehyde vapor; however, the significance of the increased chemical content in the hypothalamus of

rats is unclear. Other studies have found no perceptible effects of formaldehyde on the nervous system of

rats and mice at #15 ppm (Appelman et al. 1988; Kerns et al. 1983b), although obvious clinical signs of

neurological impairment were observed in mice (Maronpot et al. 1986) and rats (Woutersen et al. 1987)

exposed to high concentrations ($20 ppm) of airborne formaldehyde.

Reports of neurotoxicity in humans after an oral exposure to formaldehyde are limited to case reports. 

Coma, lethargy, seizures, and loss of consciousness have been reported in humans after drinking

formaldehyde (Burkhart et al. 1990; Eells et al. 1981; Koppel et al. 1990). No consistent effects on the

nervous system after oral exposure to formaldehyde were found in several toxicity reports using

laboratory animal models (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989). Increased

relative brain weights were observed in one group of rats chronically exposed to drinking water doses of

82–109 mg/kg/day (Til et al. 1989), but not in another group exposed to 300 mg/kg/day (Tobe et al.

1989). The data suggest that the nervous system may be affected by formaldehyde exposure, especially if

it is ingested in large quantities or if chronically inhaled in low doses in an occupational setting. 

Additional prospective evaluations of performance on neurobehavioral tests in groups of formaldehydeexposed workers may be useful in ascertaining if there are subtle neurological effects from chronic

inhalation exposure to formaldehyde. Results from such studies would be most useful if the studied

workers were not exposed to other neurotoxic airborne agents; this is a condition which may be difficult

to find in occupational settings.

Epidemiological and Human Dosimetry Studies. Results from many acute controlled-exposure

human studies and cross-sectional studies of groups of persons repeatedly exposed to airborne

formaldehyde provide strong evidence that the upper respiratory tract is the critical target of airborne

formaldehyde for any duration of exposure, allow reasonable estimates to be made of minimal risk levels

for acute and chronic durations of exposure, and provide strong support for deriving intermediateduration minimal risk levels from animal exposure-response data. There is considerable confidence that

adherence to these values will protect persons living near formaldehyde-contaminated hazardous waste 
FORMALDEHYDE 257

2. HEALTH EFFECTS

sites from developing upper respiratory tract health problems. Longitudinal studies that examine nasal

specimens from groups of workers with varying air exposure levels will provide information that may

further increase confidence in the estimated minimal risk levels. 

There does not appear to be a pressing need for epidemiology studies of people exposed orally to

formaldehyde given the instability of formaldehyde in environmental sources of water and the

implausibility of identifying groups of people exposed to oral doses of formaldehyde that are sufficiently

high to damage gastrointestinal tract tissue. 

The relatively frequent reporting of dermal sensitization to formaldehyde at dermatological clinics

(Fischer et al. 1995; see also: Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and

Swanbeck 1990; Menné et al. 1991) suggests that cross-sectional and longitudinal studies of dermal

exposure levels and prevalence of skin problems in groups of workers with expected dermal exposure to

cleaning and disinfectant solutions (e.g., janitorial and/or medical personnel) may be useful to better

describe exposure-response relationships for the development of formaldehyde-induced skin irritation and

contact dermatitis from intermediate- or chronic-duration exposure to formaldehyde.

Epidemiological studies of occupationally exposed groups of persons have not found consistent or strong

evidence for an association between occupational exposure to airborne formaldehyde and cancer,

although animal studies have found consistent evidence for formaldehyde-induced nasal tumors with

chronic exposure to air concentrations in the range of 6–15 ppm. The available epidemiological studies

have shortcomings such as limited exposure information or follow-up, presence of confounding risk

factors, or small numbers of subjects, but one plausible explanation for the lack of a consistent response

across the studies is that workplace air levels often may be below values necessary for formaldehyde to

induce upper respiratory tract cancer. Studies in animals have shown that no increased incidences of

nasal tumors were found in rats with lifetime exposure to low (0.3–2 ppm) air concentrations (Kamata et

al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al. 1989), that damaged regions of the

nasal epithelium after short-term exposure are correlated with regions that eventually develop tumors 

with chronic exposure (Monticello et al. 1996), and that regions of the nasal epithelium with epithelial 

damage correlate with regions of predicted high airflow and uptake of formaldehyde (Cohen Hubal et al.

1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a). Further development is needed of human nasal

airflow and formaldehyde uptake models, human pharmacokinetic models for formaldehyde disposition,

and human pharmacodynamic models for preneoplastic events in upper respiratory tract tissue. 
FORMALDEHYDE 258

2. HEALTH EFFECTS

Application of such models, with associated rat dosimetric models, to the available rat exposure-response

data for tumors and preneoplastic events will allow better estimations of air levels presenting minimal

risks for cancer in humans. 

Biomarkers of Exposure and Effect. 

Exposure. Attempts have been made to determine if formaldehyde could be used as a potential

biomarker of short-term exposure (Heck et al. 1985); however, no significant difference between pre- and

postexposure blood concentrations of formaldehyde could be demonstrated at the concentration tested. In

the same study, similar findings were noted in male Fischer 344 rats placed in a nose-only inhalation

chamber and exposed to 14.4 ppm formaldehyde for 2 hours. Monitoring blood or urine formate levels

has also been considered. Rapid intravenous injection of formaldehyde in monkeys showed a plasma

half-life of only 1.5 minutes, with a corresponding increase in blood formate levels; however, formate

production is not specific to formaldehyde metabolism (Ferry et al. 1980; Kornbrust and Bus 1983;

Liesivuori and Savolainen 1987). Urine formate levels were examined by Einbrodt et al. (1976) and urine

formaldehyde and urine formic acid (formate) concentrations were found to be higher immediately after

exposure; however, study design posed interpretation concerns. Gottschling et al. (1984) monitored

anatomy students exposed to low levels of formaldehyde vapor; wide variations were noted in the urine

formate levels prior to exposure, with large intrapersonal and interpersonal variations. Mean

postexposure urine formate concentrations were not significantly elevated after exposure. Based on the

available data, it appears that the detection of the intact formaldehyde molecule in the blood and tissues,

as well as blood and urine formate, are unreliable and poor indicators of formaldehyde exposure in

humans and laboratory animals. 

Studies of animals have used radiolabeling techniques to measure DNA-protein cross links in nasal

epithelium tissue (Casanova-Schmitz et al. 1984a; Casanova and Heck 1987; Casanova et al. 1989a,

1989b, 1991, 1994) and described relationships between exposure levels and the amounts of DNA-protein

cross links in regions of the nasal epithelium. Such a technique is impractical for monitoring humans

exposed to formaldehyde, but Shaham et al. (1996a) proposed that measurement of total DNA-protein

cross links by a different technique in white blood cells may be useful as a biomarker of repeated

exposure to formaldehyde. In support of this proposal, it was reported that white blood cells from

12 formaldehyde-exposed anatomists and pathologists had significantly higher average levels of DNAprotein cross links than those from eight subjects without known occupational exposure to formaldehyde 
FORMALDEHYDE 259

2. HEALTH EFFECTS

(Shaham et al. 1996a). Additional research to apply these methods to larger groups of occupationally

exposed and nonexposed persons may help to determine the reliability of this variable as a biomarker of

exposure and to determine the extent to which individuals vary in this response to formaldehyde. 

Additional research to apply the DNA-protein cross link methods to nasal biopsy specimens may lead to

an increased sensitivity of this potential biomarker of exposure and effect. Shaham et al. (1996b)

reported that a larger scale study was in progress, but results are not available. 

Antibodies (IgG and IgE) against formaldehyde conjugated to human serum albumin have been found to

be elevated in some people, but not in others, exposed to formaldehyde (Dykewicz et al. 1991; Grammer

et al. 1990; Patterson et al. 1986; Thrasher et al. 1988b, 1989, 1990; Wantke et al. 1996a). The

apparently rare frequency of IgE-mediated allergy responses to airborne formaldehyde (Grammer et al.

1990; Kramps et al. 1989; Nordman et al. 1985) suggests that elevation of antibodies against

formaldehyde may be too rare to be useful as a generic biomarker of exposure. However, the findings of

significant associations between (1) the presence of IgG antibodies against formaldehyde-human serum

albumin and smoking habit in a group of healthy subjects, and (2) the presence of such antibodies in nonsmokers and occupational exposure to formaldehyde suggest that this biomarker of immunological

response may serve as a qualititative biomarker of exposure (Carraro et al. 1997). Additional studies of

formaldehyde-specific IgG antibodies in non-smoking groups of formaldehyde-exposed and nonexposed

persons may be useful to determine the reliability of this qualitative biomarker of intermediate or chronic

exposure to formaldehyde. Additional research may help to further develop the Carraro et al. (1997)

assay so that it might be useful for quantifying exposure levels or exposure durations.

Effect. Increased eosinophil concentration and increased albumin and total protein levels have been

found in nasal lavage fluid taken from subjects exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak

et al. 1998; Pazdrak et al. 1993). Although these variables are not expected to be specifically influenced

by formaldehyde, they appear to provide biomarkers of acute respiratory irritation from airborne

formaldehyde or other upper respiratory irritants. Further research on relationships between

concentrations of these variables in nasal lavage fluid and prevalence or severity of respiratory symptoms

in humans exposed acutely to varying concentrations of formaldehyde may help to confirm their use as

biomarkers of effect. 

As discussed in the previous section, DNA-protein cross links and anti-formaldehyde-human serum

albumin IgG antibodies are potential biomarkers of effect and exposure from intermediate- or chronic-
FORMALDEHYDE 260

2. HEALTH EFFECTS

duration of exposure. Another potentially useful biomarker of effect for repeated inhalation exposure to

formaldehyde involves the histological examination of nasal biopsy samples (Ballarin et al. 1992; Boysen

et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Whereas detection of these biomarkers can

represent biological responses to repeated exposure to formaldehyde, it is uncertain to what degree their

detection indicates that adverse health effects will occur. Prospective studies of these end points in

formaldehyde-exposed and nonexposed workers may decrease this uncertainty and describe temporal

relationships between formaldehyde-induced upper respiratory tract tissue damage and/or dysfunction and

exposure-related intensity changes in these variables. 

Absorption, Distribution, Metabolism, and Excretion. Results from studies of rats exposed for

short periods (6 hours) to airborne radiolabeled formaldehyde concentrations between 0.63 and 13.1 ppm

indicate that inhaled formaldehyde is rapidly absorbed and metabolized, primarily in the upper respiratory

tract, and that, at these exposure concentrations, very little formaldehyde reaches the blood or is

transported to distant-site tissues and organs (Heck et al. 1983). In these studies, radioactivity recovered

within 70 hours after exposure was found in the expired air (39-42%), the urine (17%), feces (4-5%), and

in tissues and the carcass (35-39%). These results are consistent with rapid oxidative metabolism to

formate and CO2 and rapid incorporation of the carbon from formaldehyde into cellular constituents. 

Consistent with these studies, another experiment showed that 2-hour exposures to formaldehyde of rats

(to 14.4 ppm) and humans (to 1.9 ppm) did not significantly increase formaldehyde concentrations in

blood when measured immediately after exposure (Heck et al. 1985). Casanova et al. (1988) also showed

that blood concentrations of formaldehyde were not elevated, immediately after exposure, in rhesus

monkeys exposed to 6 ppm (6 hours/day, 5 days/week) for 4 weeks. These toxicokinetic results, together

with the weight of evidence from inhalation toxicological studies of animals showing effects only in the

upper respiratory tract, provide high confidence that the disposition of inhaled formaldehyde by the upper

respiratory tract in this concentration range and below is nearly complete. Additional animal studies

designed to compare formaldehyde-specific metabolic capacities in nasal mucosal tissues from adult and

immature animals may be useful in determining a possible mechanistic basis for possible age-related

differences in susceptibility to irritation from airborne formaldehyde (see Children’s Susceptibility data

needs section below).

Ingested formaldehyde is also expected to be rapidly absorbed, rapidly metabolized to formate and CO2,

and rapidly incorporated into cellular consituents, but descriptive toxicokinetic studies of orally

administered formaldehyde in animals were not located. Observations of elevated formate levels and 
FORMALDEHYDE 261

2. HEALTH EFFECTS

metabolic acidosis in cases of acute formaldehyde poisoning (Eells et al. 1981; Burkhart et al. 1990) are

consistent with rapid absorption and metabolism of ingested formaldehyde. A study is available of the

dispositional kinetics of radioactivity in rats and mice after ingestion of a cheese made from milk with

added radiolabeled formaldehyde (Galli et al. 1983), but the radioactivity in the material fed to the

animals was largely (80%) linked to proteins. Given that the levels of formaldehyde in sources of food

and water for humans are expected to be very low due to formaldehyde’s high reactivity, additional

animal studies to more completely describe the absorption, distribution, metabolism, and elimination of

orally administered formaldehyde do not seem to warrant a high priority. 

Results from a study of rats, guinea pigs, and monkeys under nonoccluded dermal exposure conditions

indicated that evaporation from the skin was a major disposition route (Jeffcoat et al. 1983). Additional

animal studies of absorption, distribution, and metabolism under occluded conditions of dermal exposure

would provide information regarding maximal rates of dermal absorption and local tissue metabolism,

and may help to confirm that distant-site effects from dermal exposure are unlikely. 

Comparative Toxicokinetics. Experiments with humans, rats, and monkeys indicate that inhaled

formaldehyde is absorbed and metabolized so rapidly that blood concentrations do not vary during shortterm exposures (Casanova et al. 1988; Heck et al. 1985). These results are consistent with the upper

respiratory tract being the critical target of inhaled formaldehyde in each of these species as indicated by

the available health effects data. The marked differences between rodents and primates in breathing

habits (i.e., rodents are obligate nose breathers) and nasal anatomy led to some early questions about the

human relevance of the well-characterized nonneoplastic and neoplastic responses of nasal epithelium in

rats to chronic exposure to airborne formaldehyde. However, observations of similar non-neoplastic

changes in upper respiratory tract epithelium in Rhesus and Cynomolgus monkeys exposed for

intermediate durations (Monticello et al. 1989; Rusch et al. 1983) and observations of histological

changes in nasal tissue from occupationally exposed subjects (Ballarin et al. 1992; Boysen et al. 1990;

Edling et al. 1988; Holmstrom et al. 1989c) have provided support for the relevance of the rat data. These

results have led to the ongoing development of, for each of these species, anatomical models of nasal

airflow and uptake, pharmacokinetic models for nasal tissue metabolism, and pharmacodynamic models

of development of tumors and preneoplastic tissue changes to be applied to the rodent data to better

estimate air levels that will present minimal risks for upper respiratory tract damage in humans (CIIT

1998; Cohen Hubal et al. 1997; Conolly et al. 1992; Conolly and Andersen 1993; Kepler et al. 1998;

Kimbell et al. 1993, 1997a, 1997b; Morgan 1997; Morgan et al. 1991; Subramaniam et al. 1998). 
FORMALDEHYDE 262

2. HEALTH EFFECTS

In contrast, mice and hamsters appear to be less susceptible to upper respiratory tract damage from

inhaled formaldehyde. The basis for this apparent species difference in susceptibility is unknown, but

may involve, at least partially for the case of the mouse, the greater efficiency of mice, compared with

rats, to reduce minute volumes during exposure to formaldehyde (Chang et al. 1981, 1983).

As with exposure to airborne formaldehyde, portal-of-entry tissues are expected to be the critical targets

of orally or dermally administered formaldehyde in humans and animals. Gastrointestinal effects from

high oral doses are expected based on reports of gastrointestinal tract irritation and symptoms in humans

who ingested large doses of formaldehyde, together with results from studies of rats exposed orally to

formaldehyde for intermediate- and chronic-durations (e.g., Til et al. 1988b, Til et al. 1989; Tobe et al.

1989). Skin irritation in humans with dermal occupational exposure to formaldehyde concentrations in

the range of 2-5% and greater is expected based on occupational experience and clinical experience in

patch-testing (Fischer et al. 1995; Maibach 1983); additionally, the development of dermal sensitization

to formaldehyde is frequently found among patients presenting skin problems at dermatology clinics. The

expectation of skin irritation and dermal sensitization, without systemic distant-site effects, from exposure

to formaldehyde is supported by results from dermal-exposure toxicity studies in animals (e.g., Overman

1985; Wahlberg 1993) and toxicokinetic studies with rats, guinea pigs and Cynomolgus monkeys

(Jeffcoat et al. 1983); although results from the latter studies indicated that monkey skin may be more

permeable to formaldehyde than rat skin. In contrast to inhalation exposure, however, there is no

information indicating that species differ in susceptibility to formaldehyde toxicity by these routes of

exposure. Thus, additional studies comparing species differences in toxicokinetic variables with oral or

dermal exposure to formaldehyde do not appear to have a high priority at this time.

Methods of Reducing Toxic Effects. Due to formaldehyde’s high water solubility and reactivity

and the rapidity of cellular metabolism of formaldehyde to formate and CO2, toxic effects from

formaldehyde are expected to be principally caused by formaldehyde itself (not metabolites) and to be

restricted to portal-of-entry tissues, except at high exposure levels that exceed metabolic capacities of

these tissues. Thus, following acute exposures to formaldehyde, treatments that dilute or remove nonabsorbed or non-reacted formaldehyde from the site of exposure or that present alternative substrates for

reaction (e.g., washing of the skin or eyes or dilution of ingested formaldehyde with milk or water) may

prevent the occurrence of toxic effects if applied in a timely manner. Methods that may enhance the

capacity of portal-of-entry tissues to metabolize formaldehyde may be expected to act against the toxic

action of formaldehyde, but no such methods have been established. There are no established treatment
FORMALDEHYDE 263

2. HEALTH EFFECTS

protocols to repair tissue damage that may have been caused by formaldehyde at portals-of-entry or to

enhance natural repair mechanisms. 

Children’s Susceptibility. Suggestive evidence from two studies is available indicating that children

may be more susceptible to the locally-acting irritant properties of formaldehyde (Krzyzanowski et al.

1990; Wantke et al. 1996a). Additional health survey studies of groups of children known to experience

indoor air concentrations exceeding 0.05–0.1 ppm may be helpful in confirming or discarding this

hypothesis. 

Studies of laboratory animals, as well as studies of adult humans under acute controlled exposure or

occupational exposure conditions, indicate that the irritant effects of formaldehyde are restricted to tissues

at portals-of-entry due to the water-solubility and reactivity of formaldehyde and the ability of cells to

rapidly metabolize (and detoxify) formaldehyde. Studies designed to compare formaldehyde-specific

metabolic capacities and efficiencies in portal-of-entry tissues (e.g., nasal mucosa, gastrointestinal

mucosa) from adult and immature animals of varying ages may be useful in determining a possible

mechanistic basis for possible age-related differences in susceptibility to formaldehyde. 

2.11.3 Ongoing Studies

Ongoing studies pertaining to formaldehyde have been identified and are shown in Table 2-8.
FORMALDEHYDE 264

2. HEALTH EFFECTS

Table 2-8. Ongoing Studies on Formaldehyde

Investigator Affiliation Research description Sponsor

B.K. Andrews, 

B. Morrell and

N.M. Morris

Southern Regional Res Center,

New Orleans, LA

Durable Press Fabrics from

No- and De-minimus LevelFormaldehyde Finishes

US Dept. of Agriculture

A.E. Blair NCI, NIH Studies of Occupational

Cancer

Division of Cancer

Etiology

T.P. Brown and

G.E.

Rottinghaus

University of Georgia College of

Vet Medicine,

Athens, GA

Poultry Toxicosis: Evaluation

and Amelioration

US Dept. of Agriculture

A. Cederbaum VA Medical Center,

New York, NY

Interaction of Pyrazole and

Glycerol with Human

Microsomes and P-450IIEI

National Institute of

Alcohol Abuse and

Alcoholism

B.J. Collier Louisiana State University School

of Human Ecology,

Baton Rouge, LA

Measurement of

Formaldehyde Release from

Durable Press Cotton Fabrics

& Other Products

US Dept. of Agriculture

J.T. Coyle Massachusetts General Hospital,

Boston, MA

Psychosis and Brain

Glutamate

National Institute of

Mental Health

J. Cwi Survey Research Associates,

Baltimore, MD

Support Services for

Occupational Studies

Division of Cancer

Etiology

L.M. Ferrari and

F. Catell

State Pollution Control

Commission,

Sydney, NSW

Indoor Air Quality and

Energy Conservation

NERDDP

J.B. Guttenplan NYU Dental Center,

New York, NY

Smokeless Tobacco

Carcinogenesis and Oral

Tissue

National Institute of

Dental Research

G. Hager NCI, NIH Chromatin Structure and Gene

Expression

Division of Cancer

Etiology

A.T. Hastie Thomas Jefferson University,

Philadelphia, PA

Pollutant Interactive Effects

on Ciliary Defense

NIEHS

G.A. Jamieson American Red Cross,

Rockville, MD

Characterization and Isolation

of Platelet ADP Receptors

National Heart, Lung, and

Blood Institute

K. Knapp,

D. Pahl and 

F. Black

Atmospheric Research and

Assessment Laboratory,

Research Triangle Park, NC

Hazardous Air Pollutant

Regulatory Activities

Office of Research and

Development

J. Merchant University of Iowa,

Iowa City, IA

Core--Occupational Health

Research

NIEHS

S.S. Mirvish University of Nebraska Medical

Center,

Omaha, NE

Nitrosamine Metabolism and

Esophageal Cancer

National Cancer Institute

R. Monson Harvard University,

Boston, MA

Occupational Health NIEHS
FORMALDEHYDE 265

2. HEALTH EFFECTS

Table 2-8. Ongoing Studies on Formaldehyde (continued)

Investigator Affiliation Research description Sponsor

T.N. Pappas Dept. of Veterans Affairs Medical

Center,

Durham, NC

Animals Models of

Inflammatory Bowel Disease:

Relationship to Substance P

Receptor Up Regulation

Dept. of Veterans Affairs 

T. Shibamoto University of California

Environmental Toxicology,

Davis, CA

Isolation and Identification of

Mutagens and Carcinogens in

Foods

US Dept. of Agriculture

G.M. Thiele Omaha VA Medical Center,

Omaha, NE

Alcohol and Liver Endothelial

Cells in Immune Responses

National Institute on

Alcohol Abuse and

Alcoholism

J-P. Von Sattel Massachusetts General Hospital,

Boston, MA

Core--Neuropathology National Institute of

Neurological Disorders

and Stroke

NCI = National Cancer Institute; NIEHS = National Institute of Environmental Health; NIH = National Institutes of

Health; NERDDP = National Energy Research, Development and Demonstration Program

FORMALDEHYDE 267

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Information regarding the chemical identity of formaldehyde is located in Table 3-1.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

Information regarding the physical and chemical properties of formaldehyde is located in Table 3-2.
FORMALDEHYDE 268

3. CHEMICAL AND PHYSICAL INFORMATION

HC H

O

Table 3-1. Chemical Identity of Formaldehyde

Characteristic Information Reference

Chemical name Formaldehyde Lide and Frederikse

1996

Synonym(s) Formic aldehyde, methanal, methyl

aldehyde, methylene oxide

Budavari et al. 1989

Registered trade name(s)

 For 37% aqueous solutiona

 For polymeric formb

Formalin, Formol, Morbicid, Veracur

Paraformaldehyde, Polyoxymethylene,

Paraform, Formagene

Budavari et al. 1989

Budavari et al. 1989

Chemical formula CH2O Aster 1995

Chemical structure Lide and Frederikse

1996

Identification numbers:

CAS Registry

NIOSH RTECS

EPA Hazardous Waste

OHM/TADS

DOT/UN/NA/IMCO

HSDB

NCI

50-00-0

LP8925000

U122

7216732

CLASS 3/UN1198/IMCO 3.2

164

No data

Aster 1995

HSDB 1995

HSDB 1995

HSDB 1995

NFPA 1994 

HSDB 1999

HSDB 1999 

a Aqueous solutions of formaldehyde available commercially often contain 10-15% methanol to inhibit 

polymerization. b Paraformaldehyde is a polymer of formaldehyde and has the formula (CH2O)n.

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substance Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System;

RTECS = Registry of Toxic Effects of Chemical Substances
FORMALDEHYDE 269

3. CHEMICAL AND PHYSICAL INFORMATION

Table 3-2. Physical and Chemical Properties of Formaldehyde

Property Information Reference

Molecular weight 30.03 Lide and Frederikse 1996

Color Colorless Budavari et al. 1989

Physical state Gas Budavari et al. 1989

Melting point -92 EC Budavari et al. 1989

Boiling point -21 EC ASTER 1996

Density at -20 EC 0.815 g/mL Lide and Frederikse 1996

Odor Pungent, suffocating odor; highly irritating

odor

Budavari et al. 1989;

NFPA 1994

Odor threshold:

Water

Air

50 ppm

0.5–1.0 ppm

HSDB 1999

Klaassen 1996

Taste 50 ppm HSDB 1999

Solubility:

Freshwater at 20 EC

Saltwater at 25 EC

Organic solvent(s)

Very soluble; up to 55%

No data

Ether, alcohol, acetone, benzene

Budavari et al. 1989

Lide and Frederikse

1996; Budavari et al.

1989 

Partition coefficients:

Log Kow

Log Koc

0.350

1.567

No data, negligible

SRC 1995b

Calculated from Lyman

1982

HSDB 1999

Vapor pressure at 25 EC Gas: vapor pressure>bp; 3,883 mm Hg HSDB 1999; 

Howard 1989

Polymerization Polymerizes; polymerizes readily in water Budavari et al. 1989

Photolysis Half-life (in sunlight) 1.6–19 hours producing

H2 and CO or H+

 and HCOLewis 1993

Henry's law constant at 25 EC 3.27x10-7 atm-m3

/mol Howard 1989

Autoignition temperature 300 EC NFPA 1994

Flashpoint 60 EC Budavari et al. 1989

Flammability limits at 25 EC 7–73% NFPA 1994

Incompatibilities Reacts with alkalies, acids, and oxidizers NFPA 1994

Conversion factors (25 EC) 1 ppb (v/v) = 1.23 μg/m3

1 μg/m3 = 0.813 ppb (v/v)

Calculated

Explosive limits 7–73% Lewis 1993

FORMALDEHYDE 271

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.1 PRODUCTION

Because of its low cost and high purity, formaldehyde has become one of the most important industrial

and research chemicals in the world. Between 1958 and 1968, the annual growth rate for formaldehyde

production averaged 11.7% (Gerberich et al. 1980). During the late 1960s, production averaged 71% of

capacity. The recession of the mid-1970s, however, caused production to drop as low as 54% of capacity

(Gerberich et al. 1980). From 1988 to 1997, formaldehyde production averaged an annual growth rate of

2.7% per year (Anonymous 1998). In 1992, formaldehyde ranked 22nd (8.28 billion pounds produced)

among the top 50 chemicals produced in the United States (Anonymous 1994). Total annual capacities

for the 15–17 U.S. companies listed as the top formaldehyde manufacturers or processors for 1988, 1990,

and 1992 were 8.94, 9.70, and 10.08 billion pounds, respectively (SRI 1988, 1990, 1992). The estimated

total annual formaldehyde capacity in 1998 was 11.3 billion pounds (Anonymous 1998). With

production volumes varying between 6.43 billion pounds and 8.11 billion pounds for 1990, 1991, and the

period 1993–1995, formaldehyde ranked either 24th or 25th among the top 50 chemicals produced

(Anonymous 1992, 1994, 1995a; Kirschner 1996).

As of 1998, three manufacturers of formaldehyde were responsible for 50% of the annual capacity for the

United States: Georgia-Pacific Resins, Inc. (Albany, Oregon; Columbus, Ohio; Conway, North Carolina;

Crossett, Arkansas; Grayling, Michigan; Hampton, South Carolina; Healing Springs, North Carolina;

Houston, Texas; Lufkin, Texas; Russellville, South Carolina; Taylorsville, Mississippi; Vienna, Georgia; 

White City, Oregon), Hoechst Celanese Corporation (Bishop, Texas; Rock Hill, South Carolina), and

Borden, Inc. (Baytown, Texas; Demopolis, Alabama; Diboll, Texas; Fayetteville, North Carolina;

Fremont, California; Hope, Arkansas; Kent, Washington; La Grande, Oregon; Missoula, Montana;

Sheboygan, Wisconsin; Springfield, Oregon; Vicksburg, Mississippi) (Anonymous 1998; SRI 1997). In

addition to the above facilities, the following companies also contributed to the overall U.S. capacity:

Capital Resin (Columbus, Ohio); D.B. Western (Las Vegas, New Mexico; Virginia, Minnesota); Degussa

(Theodore, Alabama); DuPont (LaPorte, Texas; Parkersburg, West Virginia); Hercules-Aqualon

(Louisiana, Montana); ISP (Calvert City, Kentucky; Texas City, Texas); Monsanto (Alvin, Texas); Neste

Resins (five sites); Perstorp (Toledo, Ohio); Praxair (Geismar, Louisiana); Solutia (Alvin, Texas);

Spurlock (Malvern, Arkansas; Waverly, Virginia); Trimet Technical Products (Mallinckrodt); 
FORMALDEHYDE 272

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

(Allentown, Pennsylvania); and Wright Chemical (Acme, North Carolina) (Anonymous 1998; SRI 1997). 

Formaldehyde production is predicted to increase 2–3% per year through 2002 (Anonymous 1998).

Table 4-1 lists the facilities in each state that manufacture or process formaldehyde, the intended use, and

the range of maximum amounts of formaldehyde that are stored on site. The data listed in Table 4-1 are

derived from the Toxics Release Inventory (TRI96 1998). Only certain types of facilities were required

to report. Therefore, this is not an exhaustive list. Table 4-2 shows capacity and production volumes for

selected years between 1960 and 1978.

Formaldehyde has been manufactured primarily from methanol since the beginning of the century

(Gerberich et al. 1980). Because methanol is manufactured from synthesis gas, usually produced from

methane, there have been extensive efforts to develop a one-step process that partially oxidizes methane

to formaldehyde. Although a successful commercial process has not been developed, a wide range of

catalysts and oxidation conditions have been studied (Gerberich et al. 1980). During the decades

following World War II, approximately 20% of the production volume in the United States was

manufactured by vapor phase, non-catalytic oxidation of propane and butane (Gerberich et al. 1980).

Two primary methods of manufacturing formaldehyde from methanol are used today. The first uses

silver as a metal catalyst in its reactions. In earlier years, facilities used a copper catalyst in this process. 

The simultaneous reactions involved in the metal catalyst process occur at essentially atmospheric

pressure and 600–650 EC (Gerberich et al. 1980). Approximately 50–60% of the formaldehyde produced

using the metal catalyst process is formed during an exothermic reaction; the remainder is formed from an

endothermic reaction. The overall yield for this process is 86–90% formaldehyde. The domestic

licensors for this process include Borden Chemical Company and Davy Powergas, Inc. (Gerberich et al.

1980). 

The second method uses a metal oxide catalyst. All of the formaldehyde is produced from an exothermic

reaction occurring at atmospheric pressure and 300–400 EC. The patent for formaldehyde production

using a vanadium pentoxide catalyst was issued in 1921. Although the patent for an iron oxidemolybdenum oxide catalyst was issued in 1933, the first commercial facility did not begin operating until

1952 (Gerberich et al. 1980).

Gaseous formaldehyde can be regenerated from paraformaldehyde by heating (Gerberich et al. 1980).
FORMALDEHYDE 273

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Table 4-1. Facilities That Manufacture or Process Formaldehyde

Statea

Number of 

facilities

Range of maximum amounts 

on site in poundsb Activities and usesc

AK 1 100,000 - 999,999 8

AL 30 0 - 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

AR 15 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 12

AZ 3 100 - 9,999 1, 5, 7, 9, 12, 13

CA 26 100 - 9,999,999 1, 3, 4, 5, 7, 8, 9, 11, 12 

CO 2 0 - 9,999 12

CT 8 100 - 9,999,999 2, 3, 7, 8, 12 

DE 1 10,000 - 99,999 8

FL 6 0 - 99,999 1, 6, 7, 9, 11, 13

GA 35 0 - 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13

IA 5 1,000 - 999,999 7 ,8 ,9 ,10 

IL 27 0 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13

IN 15 100 - 999,999 1, 5, 7, 8, 9, 11, 12,13

KS 8 100 - 999,999 1, 2, 5, 7, 8, 11, 13

KY 8 1,000 - 9,999,999 1, 3, 4, 7, 8, 10, 11, 12, 13

LA 31 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 13

MA 10 1,000 - 9,999,999 1, 3, 4, 7, 8, 9, 11, 13

MD 2 1,000 - 9,999 7, 8, 9 

ME 3 1,000 - 999,999 1, 5, 6, 7, 12 

MI 33 0 - 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13

MN 15 0 - 999,999 1, 5, 6, 7, 8, 9, 10, 11, 12 

MO 12 0 - 9,999,999 1, 3, 4, 6, 7, 8, 11, 12, 13

MS 16 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9 

MT 4 0 - 9,999,999 1, 3, 4, 6, 7, 8, 9 

NC 39 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13

NH 4 100 - 999,999 7, 11, 12 

NJ 18 100 - 999,999 1, 3, 5, 7, 8, 9, 10, 12, 13

NM 1 100 - 999 9

NV 1 1,000 - 9,999 7

NY 25 100 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13

OH 50 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13

OK 4 100 - 999,999 1, 6, 7, 8 

OR 25 100 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 13

PA 21 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13

PR 4 1,000 - 99,999 2, 3, 7, 11, 12, 13

RI 4 100 - 99,999 1, 3, 5, 7, 8, 9, 10, 11 

SC 40 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13

SD 1 100 - 999 8

TN 8 0 - 9,999,999 1, 5, 7, 8, 11, 12, 13

TX 55 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13

UT 4 1,000 - 9,999 1, 5, 7, 11 

Table 4-1. Facilities That Manufacture or Process Formaldehyde (continued)
FORMALDEHYDE 274

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Statea

Number of

facilities

Range of maximum amounts 

on site in poundsb Activities and usesc

VA 26 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13

VT 1 100 - 999 2, 3, 9, 11 

WA 8 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 11 

WI 24 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 13

WV 10 100 - 9,999,999 1, 3, 5, 7, 8, 10, 11 

Source: TRI96 1998

a

 Post office state abbreviations used

b

 Range represents maximum amounts on site reported by facilities in each state

c Activities/uses:

 1. Produce 8. Formulation component

 2. Import 9. Article component

 3. Onsite 

use/processing

10. Repackaging

 4. Sale/distribution 11. Chemical processing aid

 5. Byproduct 12. Manufacturing aid

 6. Impurity 13. Ancillary/other uses

 7. Reactant
FORMALDEHYDE 275

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Table 4-2. U.S. Formaldehyde Capacity and Production

Year

Capacity

(103 tons/year)

Production volume

(103 tons/year)

1960 1,111 848

1965 1,613 1,409

1970 Not available 2,008

1975 3,803 2,067

1977 4,005 2,742

1978 4,086 2,948

1982 Not available 2,185

1986 Not available 2,517

1990 Not available 3,048

 Source: Gerberich et al. 1980; data for 1982, 1986, and 1990 are from IARC 1995.
FORMALDEHYDE 276

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.2 IMPORT/EXPORT

The Chemical Marketing Reporter (CMR) reported that 140 million pounds of formaldehyde were

imported into the United States in 1997. In 1994, import and export volumes were 87 and 25 million

pounds, respectively (Anonymous 1995b). The export volume for the same year was reported as

25 million pounds (Anonymous 1998). 

4.3 USE

Formaldehyde has been used for many years in consumer goods to deter spoilage caused by microbial

contamination (WHO 1989). It has been used as a preservative in household cleaning agents, dishwashing liquids, fabric softeners, shoe-care agents, car shampoos and waxes, and carpet-cleaning agents

(WHO 1989). Generally, the formaldehyde content in these products is less than 1% (WHO 1989).

Formaldehyde is used as a chemical intermediate in the manufacture of a large variety of organic

compounds, ranging from amino and phenolic resins to slow release fertilizers (Gerberich et al. 1980). 

Table 4-3 shows the distribution of formaldehyde use for select periods between 1963 and 1977. The

demand for formaldehyde in North America was 11.6 billion pounds in 1995, a slight increase from the

11.3 billion pounds reported for 1994 (Anonymous 1995b). These figures include the import and export

volumes discussed in Section 4.2. The demand for formaldehyde will continue to track the demand in the

housing industry and the various board products used in residential construction and furniture

(Anonymous 1998). The most prominent use of formaldehyde in the United States is manufacturing

urea-formaldehyde resins; 23% of the annual capacity is used in this market (Anonymous 1998). In 1993,

the urea-formaldehyde resins market was described as being mature. Approximately 95% of the particle

board products manufactured are based on urea-formaldehyde resins; the remainder are based on

phenolic-resins (Gerberich et al. 1980). The market’s average annual growth rate of 1–1.5% is projected

to continue through 1997 (Anonymous 1993). Urea formaldehyde resins are also used as urea

formaldehyde foam insulation or as reinforcing foams in the insulation of buildings and in mining, where

hollow areas are filled with the foam (WHO 1989). Anonymous (1993) also reports that the fastest

growing formaldehyde market in the United States is in the production of acetylenic chemicals and

methylene diisocyanate (MDI). The most recent breakdown found for formaldehyde use is the following:

urea-formaldehyde, 23%; phenolic resins, 19%; acetylenic chemicals, 12%; polyacetal resins, 11%; 

MDI, 6%; pentaerythritol, 5%; urea-formaldehyde concentrates, 4%; hexamethylenetetramine
FORMALDEHYDE 277

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Table 4-3. Distribution of Formaldehyde Production 

According to Uses in the United States

Percentage of consumption

1963 1969 1972 1975 1977

Phenol-formaldehyde resins 22 22 26 22 25

Urea-formaldehyde resins 21 25 26 25 25

Acetal resins 4 6 7 7 9

Acetylenics Not available 2 4 7 6

Melamine resins 6 7 6 3 5

Pentaerythritol 9 7 7 7 5

Hexamethylenetetramine 6 9 6 5 5

Fertilizer 3 3 4 4 Not available

Trimethylolpropane Not available 1.1 1.5 1.5 Not available

Ethylene glycol 12 4 0 0 0

Miscellaneous 17 14 12 18 20

Source: Gerberich et al. 1980
FORMALDEHYDE 278

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

(HMTA), 4%; melamine resins, 4%; and miscellaneous (including chelating agents, trimethylolpropane,

pyridine chemicals, nitroparaffin derivatives, textiles treating, and trimethylolethane), 12% (Anonymous

1998).

 The use of formaldehyde in the manufacture of chelating agents represents a modest but important

market for formaldehyde. Approximately 75% of the formaldehyde used in the synthesis of chelating

agents is consumed in the manufacture of ethylenediaminetetraacetic acid (EDTA). The remaining 25%

is used to produce nitrilotriacetic acid (NTA), primarily for export (Gerberich et al. 1980).

Products manufactured using organic compounds, where formaldehyde is used as a chemical intermediate

in their production, include: plywood adhesives, abrasive materials, insulation, foundry binders, and

brake linings made from phenolic resins; surface coatings, molding compounds, laminates, and wood

adhesives made from melamine resins; phenolic thermosetting, resins curing agents, and explosives made

from hexamethylenetetramine; urethanes, lubricants, alkyd resins, and multifunctional acrylates made

from trimethylolpropane; plumbing components from polyacetal resins; and controlled- release fertilizers

made from urea formaldehyde concentrates (WHO 1989). Polyacetal plastics produced by

polymerization of formaldehyde are incorporated into automobiles to reduce weight and fuel

consumption. They are also used in the manufacture of functional components of audio and video

electronics equipment (IARC 1995). 

Formaldehyde solutions have also been used for disinfecting dwellings, ships, storage houses, utensils,

and clothing (Windholz et al. 1983). Solutions containing 2–8% formaldehyde have been used as

germicides to disinfect inanimate objects (HSDB 1999). Formaldehyde is used as a tissue preservative

and disinfectant in embalming fluids.

In the agricultural industry, formaldehyde has been used as a fumigant, as a preventative for mildew and

spelt in wheat, and for rot in oats (HSDB 1999). It has been used as a preplanting soil sterilant in

mushroom houses (HSDB 1999). Formaldehyde has been used as a germicide and fungicide for plants

and vegetables; as an insecticide for destroying flies and other insects; and in the manufacture of slowrelease fertilizers. Approximately 80% of the slow-release fertilizer market is based on

urea-formaldehyde-containing products (HSDB 1999). During the early 1980s, seed treatments, starch

formulations, and paper production were included among the minor uses for formaldehyde (IARC 1982). 

Formaldehyde continues to be used in the manufacture of glass mirrors, explosives, artificial silk, and 
FORMALDEHYDE 279

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

dyes; for waterproofing fabrics; for preserving and coagulating rubber latex; and for tanning and

preserving animal hides (Windholz et al. 1983). In the photography industry, formaldehyde has been

used for hardening gelatin plates and papers, toning gelatin-chloride papers, and for chrome printing and

developing (Windholz et al. 1983). 

Formaldehyde is used as an antimicrobial agent in many cosmetics products, including soaps, shampoos,

hair preparations, deodorants, lotions, make-up, mouthwashes, and nail products (IARC 1995). 

Formaldehyde is incompatible with ammonia; alkalies; tannin; iron preparations; and salts of copper, iron,

silver, potassium permanganate, iodine, and peroxide (Windholz et al. 1983). When it is used as a

preservative in shampoos, formaldehyde may interact unfavorably with both fragrance components and

color additives (HSDB 1999). Some cosmetics have reportedly contained 0.6% formaldehyde, while

concentrations as high as 4.5% have been detected in nail hardeners. Formaldehyde concentrations in

dry-skin lotions, creme rinses, and bubble bath oils have reportedly ranged from 0.4 to 0.5% (WHO

1989). Formaldehyde has also been found in sun-tan lotion and hand cream (Bartnik et al. 1985), bath

products, mascara and eye make-up, cuticle softeners, nail creams, vaginal deodorants, and shaving

creams. Trace amounts of formaldehyde found in cosmetic products could also result from its use as a

disinfectant of the manufacturing equipment (WHO 1989). 

Compared to its use in product manufacturing, the use of formaldehyde in the medical fields is relatively

small. Consumption in this area averages approximately 1.5% of the total production volume (WHO

1989). Some of the earlier, minor, medicinal applications for formaldehyde included its use during

vasectomies, as a foot antiperspirant or as a preservative in such products, as a treatment for athlete’s foot,

and as a sterilant for echinococcus cysts prior to their surgical removal (IARC 1982). In veterinary

medicine, formaldehyde has been used therapeutically as an antiseptic and as a fumigant. It has also been

used to treat tympany, diarrhea, mastitis, pneumonia, and internal bleeding in animals (Windholz et al.

1983). In animal nutrition, formaldehyde is used to protect dietary protein in ruminants. It is used as a

food additive to improve the handling characteristics of animal fat and oilseed cattle food mixtures (WHO

1989).

Other industries using formaldehyde in their processes include the sugar industry where formaldehyde is

used as an infection inhibitor in producing juices; the rubber industry where it is used as a biocide for

latex, an adhesive additive, and an anti-oxidizer additive for synthetic rubber; and the food industry 

where it is used for preserving dried foods, disinfecting containers, preserving fish and certain oils and 
FORMALDEHYDE 280

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

fats, and modifying starch for cold swelling (WHO 1989). It has been use as a bacteriostatic agent in

some foods, such as cheese (IARC 1995). In the petroleum industry, formaldehyde is used as a biocide in

oil well-drilling fluids and as an auxiliary agent in refining. Formaldehyde has been used as an anticorrosive agent for metals. In the plastics industry, for the preparations of phenol, urea, and melamine

resins, where the presence of water could interfere with the production process, paraformaldehyde may be

used in place of aqueous formaldehyde solutions (IARC 1995). In addition to its use in selected pesticide

applications, paraformaldehyde has also been used in making varnish resins, thermosets, and foundry

resins, the synthesis of chemical and pharmaceutical products, the preparation of disinfectants and

deodorants, and the production of textile products (IARC 1995). Formaldehyde was used in the textile

industry as early as the 1950s when formaldehyde-based resins were initially used to produce creaseresistant fabrics. Postproduction analysis indicated that these early resins contained a substantial amount

of extractable formaldehyde (more than 0.4% by weight of the fabric) (IARC 1995). With the

introduction of new resins and other process modifications in the 1970s, the level of extractable

formaldehyde in crease-resistant fabrics gradually decreased to 0.01–0.02% (IARC 1995).

4.4 DISPOSAL

The regulations governing the treatment and disposal of formaldehyde-containing wastes are detailed in

Chapter 7. Formaldehyde manufacturing is listed among the regulations for commodity organic

chemicals for which process waste water discharges are regulated by the Clean Water Effluent Guidelines

given in Title 40, Section 414, of the Code of Federal Regulations (CFR) (EPA 1987a). 

The Resource Conservation and Recovery Act (RCRA) identifies formaldehyde as a toxic waste if it is

discarded as a commercial product, manufacturing intermediate, or off-specification commercial chemical

product (EPA 1980). Formaldehyde is identified as the hazardous constituent in waste assigned the

hazardous waste number U122 under RCRA (EPA 1988b). Formaldehyde is also among the chemicals

that are on the listed hazardous waste identified by the #K010 (EPA 1981). The technology-based

standards given in 40 CFR 268.42 identify wet air oxidation, chemical, or electrolytic oxidation followed

by carbon adsorption, or incineration as the treatment process for waste waters containing formaldehyde

(EPA 1986b). For nonwaste waters, the regulations suggest that the materials be used as fuel substitutes

in hazardous waste disposal units (EPA 1986b). When formaldehyde is disposed of in a rotary kiln

incinerator, the unit should be operated at a temperature range of 820–1,600 EC (HSDB 1999). 

Disposal of formaldehyde in a fluidized bed incinerator requires an operating temperature range 
FORMALDEHYDE 281

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

of 450–980 EC (HSDB 1999). The residence time identified for incineration is a matter of seconds. 

Evaporation and alkaline hydrolysis are not recommended for the disposal of formaldehyde or

formaldehyde-containing wastes (IRPTC 1985).

FORMALDEHYDE 283

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Formaldehyde is produced by both anthropogenic and natural sources. Combustion processes account

directly or indirectly for most of the formaldehyde entering the environment. Direct combustion sources

include power plants, incinerators, refineries, wood stoves, kerosene heaters, and cigarettes. 

Formaldehyde is produced indirectly by photochemical oxidation of hydrocarbons or other formaldehyde

precursors that are released from combustion processes (NRC 1981). During smog episodes, indirect

production of formaldehyde may be greater than direct emissions (Fishbein 1992). Oxidation of methane

is the dominant source of formaldehyde in regions remote from hydrocarbon emissions (Staffelbach et al.

1991). Other anthropogenic sources of formaldehyde in the environment include vent gas from

formaldehyde production; exhaust from diesel and gasoline-powered motor vehicles; emissions from the

use of formaldehyde as a fumigant, soil disinfectant, embalming fluid, and leather tanning agent;

emissions from resins in particle board, and plywood; emissions from resin-treated fabrics and paper;

waste water from the production and use of formaldehyde in the manufacture of various resins and as a

chemical intermediate; and waste water from the use of formaldehyde-containing resins (EPA 1976a;

Kleindienst et al. 1986; NRC 1981; Verschueren 1983). Natural sources of formaldehyde include forest

fires, animal wastes, microbial products of biological systems, and plant volatiles.

Formaldehyde has been identified in at least 26 of the 1,428 current or former EPA National Priorities

List (NPL) hazardous wastes sites (HazDat 1996). However, the number of sites evaluated for

formaldehyde is not known. The frequency of these sites within the United States can be seen in

Figure 5-1.

Although formaldehyde is found in remote areas, it probably is not transported there but is generated from

longer-lived precursors that have been transported there (NRC 1981). Formaldehyde is soluble and will

transfer into rain and surface water. Based upon the Henry's law constant for formaldehyde, volatilization

from water is not expected to be significant. No experimental data were found concerning the adsorption

of formaldehyde to soil, but because of the low octanol/water partition coefficient (log Kow=0.35) (SRC

1995b), little adsorption to soil or sediment is expected to occur. No evidence of bioaccumulation has

been found.
Figure 5-1. Frequency of NPL Sites with Formaldehyde Contamination

Derived from HazDat 1996
FORMALDEHYDE 285

5. POTENTIAL FOR HUMAN EXPOSURE

The input of formaldehyde into the environment is counterbalanced by its removal by several pathways. 

Formaldehyde is removed from the air by direct photolysis and oxidation by photochemically produced

hydroxyl and nitrate radicals. Measured or estimated half-lives for formaldehyde in the atmosphere range

from 1.6 to 19 hours, depending upon estimates of radiant energy, the presence and concentrations of

other pollutants, and other factors (Atkinson and Pitts 1978; DOT 1980; EPA 1982; Lowe et al. 1980; Su

et al. 1979). When released to water, formaldehyde will biodegrade to low levels in a few days (Kamata

1966). In water, formaldehyde is hydrated; it does not have a chromophore that is capable of absorbing

sunlight and photochemically decomposing (Chameides and Davis 1983).

Levels of formaldehyde in the atmosphere and in indoor air are well documented. In a survey of ambient

measurements of hazardous air pollutants, a median formaldehyde concentration of 2.5 ppb was found for

a total of 1,358 samples collected at 58 different locations (Kelly et al. 1994). In several separate studies

involving rural and urban areas in the United States, atmospheric concentrations ranged from 1 to 68 ppb

(Grosjean 1982; Salas and Singh 1986; Schulam et al. 1985; Singh et al. 1982). Generally, indoor

residential formaldehyde concentrations are significantly higher than outdoor concentrations. 

Formaldehyde concentrations measured in complaint homes (homes where people have complained of 

adverse symptoms), mobile homes, and homes containing large quantities of particle board or ureaformaldehyde foam insulation (UFFI) have been measured at 0.02 ppm to 0.8 ppm, with levels as high as

4 ppm, sufficient to cause irritating symptoms, observed in some instances (Gold et al. 1993). Since the

time many of the above monitoring studies were performed, plywood and particle board manufacturing

methods have been changed to reduce the formaldehyde emission levels in the finished product (EPA

1996). Similarly, home construction methods have changed and the use of UFFI has been greatly reduced

since the mid-eighties (CPSC 1997). A recent pilot study on a newly constructed home reported localized

formaldehyde concentrations of 0.076 ppm (Hare et al. 1996). Approximately 30 days after the

installation of pressed wood products, the average indoor concentration attained a level of

0.035–0.45 ppm. Older conventional homes tend to have the lowest indoor concentrations of

formaldehyde, with values typically less than 0.05 ppm (Gold et al. 1993), and mobile homes the highest

due to their low rate of air exchange (Wolff 1991).

Although pressed wood products may be a source of formaldehyde in indoor air, there are numerous

others. These include permanent press fabrics, fiberglass products, decorative laminates, paper goods,

paints, wallpaper, and cosmetics (Kelly et al. 1996). Its presence in indoor air also results from

combustion sources, such as stoves, heaters, or burning cigarettes (Matthews et al. 1985; NRC 1981). 
FORMALDEHYDE 286

5. POTENTIAL FOR HUMAN EXPOSURE

Formaldehyde may also arise from the degradation of volatile organic chemicals commonly found in

indoor air (Weschler and Shields 1996; Zhang et al. 1994b).

Formaldehyde is unstable in water; however, it has been detected in municipal and industrial aqueous

effluents, rainwater, lake water, and some waterways (EPA 1976b; Hushon et al. 1980). Formaldehyde

levels in rainwater collected in California are low, ranging from not detectable to 0.06 μg/mL (Grosjean

and Wright 1983). Measured concentrations of formaldehyde range from 0.12 to 6.8 mg/L in fogwater

(Igawa et al. 1989; Muir 1991); from 1.4 to 1.8 mg/L in cloudwater (Igawa et al. 1989); and from 0.25 to

0.56 mg/L in mist samples (Grosjean and Wright 1983). No data on formaldehyde levels in soil could be

found in the literature. 

Formaldehyde was found in three types of chewing tobacco (Chou and Que Hee 1994) and in cigarette

smoke (Mansfield et al. 1977). Formaldehyde has also been found at levels ranging from 1 to 3,517 ppm

in fabric samples (Schorr et al. 1974).

A major route of formaldehyde exposure for the general population is inhalation of indoor air; releases of

formaldehyde from new or recently installed building materials and furnishings may account for most of

the exposure. Environmental tobacco smoke may contribute 10–25% of the exposure. Since

formaldehyde in food is not available in free form, it is not included in estimated exposures (Fishbein

1992). Consumers can be exposed to formaldehyde gas through its use in construction materials, wood

products, textiles, home furnishings, paper, cosmetics, and pharmaceuticals. Dermal contact with

formaldehyde containing materials, including some paper products, fabrics, and cosmetics, may also lead

to consumer exposure. Commuters may be exposed to formaldehyde while riding in automobiles or

subways, walking, and biking (Chan et al. 1991).

Occupational exposure to formaldehyde can occur during its production and during its use in the

production of end products, in the garment industry, in the building materials industry, and in

laboratories. Health care professionals may be exposed to formaldehyde vapors during preparation,

administration, and/or cleanup of various medicines. Pathologists, histology technicians, morticians, and

teachers and students who handle preserved specimens may also be exposed. The National Occupational

Exposure Survey (NOES), conducted from 1981 to 1983 indicated that 1,329,332 workers in various

professions were exposed to formaldehyde in the United States (NIOSH 1995b).
FORMALDEHYDE 287

5. POTENTIAL FOR HUMAN EXPOSURE

A subpopulation with potentially high exposures to formaldehyde are residents of mobile homes due to

the frequent use of pressed wood products and their low rate of air exchange (Wolff 1991). Members of

the general population who come in contact with a large amount of unwashed permanent press fabrics

treated with formaldehyde-releasing resins may also be exposed to high levels.

5.2 RELEASES TO THE ENVIRONMENT

According to the Toxics Release Inventory (TRI), in 1996, 21 million pounds (9.6 million kg) of

formaldehyde were released to the environment from 674 domestic manufacturing and processing

facilities (TRI96 1998). This number represents the sum of all releases of formaldehyde to air, water,

soil, and underground injection wells. An additional 1.8 million pounds (0.8 million kg) were transferred

to publicly owned treatment works (POTWs), and 1.3 million pounds (0.6 million kg) were transferred

off-site (TRI96 1998). Table 5-1 lists amounts released from these facilities. The TRI data should be

used with caution because only certain types of facilities are required to report (EPA 1995). This is not

an exhaustive list.

5.2.1 Air

Formaldehyde is released to outdoor air from both natural and industrial sources. Combustion processes

account directly or indirectly for most of the formaldehyde entering the atmosphere. One important

source of formaldehyde is automotive exhaust from engines not equipped with catalytic converters (WHO

1989). Automobiles were found to emit about 610 million pounds (277 million kg) of formaldehyde each

year (EPA 1976a). Emissions were reduced with the introduction of the catalytic converter in 1975

(Zweidinger et al. 1988); although they have been found to rise again with the introduction of

oxygenated fuels (Kirchstetter et al. 1996). Gaffney and coworkers found that in urban areas the

introduction of oxygenated fuels led to increased anthropogenic emissions of formaldehyde during the

winter, the season these fuels are used (Gaffney et al. 1997). Formaldehyde in vehicle emissions in 1994

were found to increase by 13% within 2 months after the average oxygen content of fuels sold in the San

Francisco Bay area increased from 0.3 to 2.0% by weight (Kirchstetter et al. 1996).
Table 5-1. Releases to the Environment from Facilities that Manufacture or Process Formaldeh

Total of reported amounts released in pounds per year a

Stateb

Number of

Facilities Airc Water Land

Underground

Injection

Total

Environmentd

POTWe

Transfer

AK 1 375 0 0 0 375 0 AL 31 477,346 1,312 361 0 479,019 2,854 AR 15 204,464 735 5 0 205,204 1,015 AZ 3 12,873 0 0 0 12,873 13,000 CA 25 417,661 250 769 0 418,680 68,609 CO 2 2,062 0 0 0 2,062 170 CT 6 27,833 4,581 0 0 32,414 29,641 DE 1 1,965 0 0 0 1,965 0 FL 6 95,126 1,522 37 0 96,685 0 GA 36 702,021 714 500 0 703,235 4,600 IA 4 30,736 400 0 0 31,136 580 IL 24 37,944 2,084 204 0 40,232 22,900 IN 15 76,532 0 0 0 76,532 47,761 KS 8 278,316 0 0 27,000 305,316 10,320 KY 8 65,275 21,902 0 0 87,177 1,510 LA 31 330,423 15,674 382 8,601,956 8,948,435 0 MA 10 60,059 10 1,500 0 61,569 809,791 MD 2 5,517 0 0 0 5,517 0 ME 3 121,198 0 0 0 121,198 5,229 MI 30 205,766 2,396 12,553 250 220,965 493,193 MN 15 536,241 0 0 0 536,241 17,250 MO 12 441,774 1,127 5 0 442,906 19,343 MS 16 477,785 1,102 2 0 478,889 0 MT 4 100,214 0 0 0 100,214 0 NC 39 1,048,939 6,689 1,201 0 1,056,829 15,905 NH 4 5,582 9,419 4,100 0 19,101 6,372 NJ 18 52,595 3,977 250 0 56,822 42,613 NM 1 4,570 0 0 0 4,570 0 
Table 5-1. Releases to the Environment from Facilities that Manufacture or Process Formaldehyde (c

Total of reported amounts released in pounds per year a

Stateb

Number of

Facilities Airc Water Land

Underground

Injection

Total

Environmentd

POTWe

Transfer

NV 1 4,001 0 0 0 4,001 0 NY 23 280,861 8,409 40 0 289,310 8,103 OH 49 1,031,374 87,225 87,335 13,000 1,218,934 126,617 OK 4 64,911 4 0 0 64,915 0 OR 25 1,070,119 3,600 20 0 1,073,739 24,928 PA 21 274,854 1,331 0 0 276,185 0 PR 4 2,766 0 0 0 2,766 20,827 RI 4 4,753 0 0 0 4,753 2,042 SC 39 752,317 57,542 3,800 0 813,659 16,718 SD 1 55,731 0 0 0 55,731 0 TN 8 295,461 1,170 397 0 297,028 8,329 TX 55 996,970 31,770 500 761,069 1,790,309 4,557 UT 4 18,313 0 0 0 18,313 23,568 VA 25 369,447 956 232 0 370,635 15,059 VT 1 333 0 0 0 333 0 WA 8 109,080 45,720 0 0 154,800 3,028 WI 22 138,117 7,422 213 0 145,752 17,204 WV 10 128,600 960 0 0 129,560 5,136 

Totals 11,419,200 320,003 114,406 9,403,275 21,256,884

Source: TRI96 1998

a Data in TRI are maximum amounts released by each facilityb Post office state abbreviations usedc The sum of fugitive and stack releases are included in releases to air by a given facilityd The sum of all releases of the chemical to air, land, water, and underground injection wells; and transfers off-site by a given facilitye POTW = publicly-owned treatment works
FORMALDEHYDE 290

5. POTENTIAL FOR HUMAN EXPOSURE

Formaldehyde concentrations in jet engine exhaust have been found to range from 0.761 to 1.14 ppm

(Miyamoto 1986). Formaldehyde is formed in large quantities in the troposphere by the oxidation of

hydrocarbons (Calvert et al. 1972; WHO 1989) leading to elevated formaldehyde levels shortly after 

periods of high vehicular traffic (Grosjean et al. 1996).

Statistical analyses of formaldehyde data from four sites in New Jersey have been used to evaluate the

effects of automobile traffic and photochemical formation on formaldehyde concentrations (Cleveland et

al. 1977). Integrated formaldehyde concentrations during the hours 5:00 a.m. to 8:00 p.m. decreased from

workdays to Saturdays to Sundays, corresponding to a decrease in motor vehicle traffic. On workdays,

formaldehyde concentrations were higher on days with more photochemical activity.

Altshuller (1993) investigated the sources of aldehydes in the atmosphere during the night and early

morning hours (between 9:00 p.m. and 9:00 a.m.). At night, the predominant sources of aldehydes should

be the reaction of alkenes with O3 and NO3; during the early daylight hours, OH radical reactions with

alkenes and alkanes will also contribute to aldehyde production. Altshuller (1993) found that, although

the emissions of formaldehyde from vehicular exhaust are substantial relative to emissions of alkenes

from vehicular exhaust, the secondary atmospheric production of aldehydes from the alkenes emitted

from all vehicular sources during the period 9:00 p.m. to 9:00 a.m. can exceed the primary emissions of

formaldehyde. However, if there is a large shift in the future to vehicles fueled with methanol and/or

natural gas, formaldehyde emissions from the exhaust could predominate over the secondary emissions of

formaldehyde during the 9:00 p.m. to 9:00 a.m. period. It should be noted that the rate of secondary

production of aldehydes during the period 9:00 p.m. to 9:00 a.m. is much less than during the late

morning and afternoon hours (Altshuller 1993).

Grosjean et al. (1983) estimated the relative contributions of direct emissions and atmospheric

photochemistry to levels of formaldehyde and other carbonyls in Los Angeles using measurements made

simultaneously at a near-source site and at a site where the air quality was dominated by transport of

polluted air masses from the downtown area (downwind smog receptor site). They found that the

formaldehyde/carbon monoxide ratios were substantially higher at the downwind locations (average

values, 3.2–11.7) than at the near-source site (average value, 1.8), indicating that photochemical

production predominates over direct emissions in controlling formaldehyde levels in Los Angeles air. 

Using two models, their data were translated into formaldehyde photochemical production rates of

12–161 tons per day.
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5. POTENTIAL FOR HUMAN EXPOSURE

The amount of formaldehyde released to the atmosphere in 1996 by U.S. industrial facilities sorted by

state is given in Table 5-1 (TRI96 1998). According to TRI96 (1998), an estimated total of 11.4 million

pounds (5.2 million kg) of formaldehyde, amounting to approximately 54% of the total environmental

release, was discharged to the air from 674 manufacturing and processing facilities in the United States in

1996. The TRI data should be used with caution since only certain types of facilities are required to

report. This is not an exhaustive list.

Dempsey (1993) estimated the masses of selected organic emissions from hazardous waste incinerators

(HWIs) on a nationwide scale using "reasonable worst-case" assumptions. Formaldehyde emissions

formed during combustion of hazardous wastes were estimated to be 892 ng/L, which would result in a

release of 7.8 tons of formaldehyde to the air per year. When compared to the 1990 TRI air release data

from U.S. manufacturing operations, formaldehyde emissions from HWIs were found to be very

small (0.12%). 

There is a potential for release of formaldehyde to air from hazardous waste sites. Formaldehyde has

been detected in air samples collected at 5 of the 26 hazardous waste sites where formaldehyde has been

detected in some environmental medium (HazDat 1996).

Pressed wood products contribute to indoor formaldehyde levels. Combustion sources and phenolformaldehyde resin bonded products generally are weak emitters to indoor air. Common indoor

combustion sources include gas burners and ovens, kerosene heaters, and cigarettes (Matthews et al.

1985).

Formaldehyde also arises in the atmosphere from natural sources. In monitoring studies performed in

New Mexico, 1993–94, Gaffney and coworkers looked at total (average) formaldehyde concentrations

and formaldehyde:acetaldehyde ratios (Gaffney et al. 1997). These researchers reported that if

formaldehyde and acetaldehyde were being formed solely from the atmospheric oxidation of naturally

occurring alkenes, the ratio of the two chemicals would be expected to be about 10. In this study, the

formaldehyde:acetaldehyde ratio was lowest during the winter months and highest in the summer months. 

Gaffney et al. (1997) concluded that atmospheric formaldehyde in urban areas resulted from both

anthropogenic emissions and natural sources in the summer and primarily from anthropogenic sources

during the winter.
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5. POTENTIAL FOR HUMAN EXPOSURE

In a study conducted at the Inhalation Toxicology Research Institute, formaldehyde release rate

coefficients were measured for six types of consumer products (Pickrell et al. 1983). Release rates

calculated per unit surface area (μg/m2

/day) were used to rank the products in the following order: pressed

wood products > >clothes . insulation products . paper products > fabric > carpet. Release rates from

pressed wood products ranged from below the limit of detection for an exterior plywood to

36,000 μg/m2

/day for some paneling. Other release rates were: for articles of new clothing not previously

washed, 15–550 μg/m2

/day; for insulation products, 52–620 μg/m2/day; for paper plates and cups,

75–1,000 μg/m2

/day; for fabrics, from below the limit of detection to 350 μg/m2/day; and for carpets,

from below the limit of detection to 65 μg/m2/day. In a follow-up to Pickrell’s study (Pickrell et al.

1984), performed as a result of changes to product manufacturing processes, many of these release rates

were reinvestigated. Formaldehyde release rates for a variety of bare urea-formaldehyde wood products

(1/4 to 3/4") were reported to range from 8.6 to 1,578 μg/m2

/hr, coated urea-formaldehyde wood products

from 1 to 461 μg/m2

/hr, permanent press fabrics from 42 to 214 μg/m2/hr, decorative laminates from 4 to

50 μg/m2

/hr, fiberglass products from 16 to 32 μg/m2/hr, and bare phenol-formaldehyde wood products

from 4 to 9 μg/m2/hr (Kelly et al. 1996). Paper grocery bags and towels had emission rates of 0.4 and

<0.3 μg/m2

/hr, respectively. For wet products, the emission rates were: latex paint 591 μg/m2/hr; more

expensive latex paint 326 μg/m2

/hr; fingernail hardener 215,500 μg/m2/hr; nail polish 20,700 μg/m2/hr;

and commercially applied urea-formaldehyde floor finish 421 and 1,050,000 μg/m2

/hr for base and

topcoats, respectively (Kelly et al. 1996).

Formaldehyde may also arise in indoor air through the degradation of other organic compounds. 

Naturally occurring unsaturated hydrocarbons, such as limonene and pinene (which may also be released

from consumer products), and anthropogenic compounds, such as 4-vinylcyclohexene (an emission from

carpet padding), and other alkenes commonly found in indoor air have been found to produce

formaldehyde via their initial reaction with ozone (Weschler and Shields 1996; Zhang et al. 1994b). 

Reiss and coworkers estimated that the amount of formaldehyde released by this process is 0.87 μg/sec in

winter months and 2.43 μg/sec in the summer (Reiss et al. 1995).

In another study on indoor formaldehyde emissions, quasi steady-state emission rates of formaldehyde

from new carpets were measured in a large-scale environmental chamber (Hodgson et al. 1993). The

emission rates were 57.2 and 18.2 μg/m2

/hour at 24 and 168 hours, respectively, after the start of each

experiment. Similar results were observed in a Swedish study where indoor formaldehyde levels were

found to be higher in homes having wall to wall carpeting (Norback et al. 1995). Another recent 
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5. POTENTIAL FOR HUMAN EXPOSURE

Swedish study on indoor emissions reported that oil-based skin care products known to contain

formaldehyde precursors (donors) released formaldehyde to the air even if the material had been in

storage for one year (Karlberg et al. 1998).

Formaldehyde release from pressed wood products is due to latent formaldehyde. During the pressing

process, hot steam from moist wood particles transfers heat, formaldehyde, and other volatiles from the

surface of the mat to the core of the board where unreacted urea-formaldehyde resin components

accumulate. The resulting formaldehyde concentration in the core is approximately twice that of the

surface. Release of formaldehyde is diffusion-controlled and gradually decreases over time (Meyer and

Hermanns 1985). Formaldehyde can also be produced by hydrolytic cleavage of unreacted hydroxymethyl groups in the formaldehyde resins. Melamine formaldehyde resins generally are more stable, and

the amounts of formaldehyde emitted from them are much lower (WHO 1989). 

A formaldehyde emission rate of 0.48 μg/kilojoule has been determined for normal operation of unvented

gas ranges; however, this emission rate leads to relatively low indoor formaldehyde concentrations

(Moschandreas et al. 1986). Formaldehyde emission rates ranging from 0.43 to 4.2 μg/kilojoule were

measured from eight well tuned, unvented gas-fired space heaters operated at full fuel input in an

environmental chamber with low ventilation (Traynor et al. 1985). In another study, formaldehyde

emissions factors from unvented kerosene heaters ranged from 0.18 to 0.47 μg/kilojoule (Woodring et al.

1985). 

Using an average cigarette consumption rate of approximately 10 cigarettes per indoor compartment per

day with a measured formaldehyde emission rate of 0.97±0.06 mg/hour, Matthews et al. (1985) calculated

an average formaldehyde emission rate of 0.4±0.03 mg/hour over 24 hours. Triebig and Zober (1984)

report that the level of formaldehyde in side stream cigarette smoke is fifty times higher than main stream

smoke, while the National Research Council (NRC 1986) put the value at five to eight times more

formaldehyde in side stream smoke. Levels of formaldehyde in nonsmoking office buildings ranged from

not detected to 0.22 ppm, while they ranged from not detected to 0.6 ppm where smoking was permitted

(Sterling et al. 1987).

Formaldehyde can also be emitted into indoor air from fish during cooking. Amounts of formaldehyde

that formed in a headspace when various kinds of fish flesh were heated at 200 EC ranged from 0.48 μg/g

of mackerel to 5.31 μg/g of sardine (Yasuhara and Shibamoto 1995). 
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5. POTENTIAL FOR HUMAN EXPOSURE

The general population may also participate in activities that release formaldehyde to outdoor air. The

concentration of formaldehyde in mosquito-coil smoke was found to be 10.9–21.3 ppm/g (Chang and Lin

1998). Composting household waste was also found to emit formaldehyde to air (Eitzer et al. 1997).

5.2.2 Water

Formaldehyde is released to water from the discharges of both treated and untreated industrial waste

water from its production and from its use in the manufacture of formaldehyde-containing resins. 

Formaldehyde can also be formed in seawater by photochemical processes (Mopper and Stahovec 1986). 

Calculations of sea-air exchange have indicated that this process is probably a minor source of

formaldehyde in the sea (Mopper and Stahovec 1986).

The amount of formaldehyde released to surface water and POTWs in 1996 by U.S. industrial facilities

sorted by state is shown in Table 5-1 (TRI96 1998). According to TRI96 (1998), an estimated total of

320,003 pounds (145,153 kg) of formaldehyde, amounting to 2% of the total environmental release, was

discharged to surface water in 1996. An additional 1.9 million pounds (0.8 million kg) of formaldehyde

were discharged to POTWs (TRI96 1998). The TRI data should be used with caution since only certain

facilities are required to report (EPA 1995). This is not an exhaustive list. As a result of secondary

treatment processes in POTWs, only a fraction of the formaldehyde that enters POTWs is expected to be

released subsequently to surface water; however, this percentage is not known for formaldehyde. 

Experiments conducted at three full-scale drinking water treatment plants and a pilot plant provided

evidence that ozone treatment resulted in the production of measurable levels of formaldehyde in all of

the plants studied (Glaze et al. 1989). 

There is a potential for release of formaldehyde to water from hazardous waste sites. Formaldehyde has

been detected in surface water samples collected at 5 of the 26 hazardous waste sites and in groundwater

samples collected at 4 of the 26 hazardous waste sites where formaldehyde has been detected in some

environmental medium (HazDat 1996).
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5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Soil

Formaldehyde is released to soils through industrial discharges and through land disposal of

formaldehyde-containing wastes. The amount of formaldehyde released to land in 1996 by U.S.

industrial facilities sorted by state is shown in Table 5-1 (TRI96 1998). According to TRI96 (1998), an

estimated total of 114,406 pounds (51,894 kg) of formaldehyde, amounting to 0.54% of the total

environmental release, was discharged to land from U.S. manufacturing or processing facilities in 1996. 

An additional 9.4 million pounds (4.3 million kg), constituting about 44% of total environmental

emissions, were released via underground injection (TRI96 1998). Also, some of the estimated

1.3 million pounds of formaldehyde wastes transferred off-site (see Table 5-1) may be ultimately

disposed of in land. The TRI data should be used with caution since only certain facilities are required to

report (EPA 1995). This is not an exhaustive list.

There is a potential for the release of formaldehyde to soil from hazardous waste sites. Formaldehyde has

been detected in soil samples collected at 1 of the 26 hazardous waste sites and in sediment samples

collected at 1 of the 26 hazardous waste sites where formaldehyde has been detected in some

environmental medium (HazDat 1996).

5.3 ENVIRONMENTAL FATE

In reviewing the fate of formaldehyde in the environment, it should be noted that the environmental

factors that influence the bioavailability to humans of formaldehyde from contaminated air, water, or

plant material have not been studied.

5.3.1 Transport and Partitioning

Formaldehyde is released to the atmosphere in large amounts and is formed in the atmosphere by the

oxidation of hydrocarbons. However, the input is counterbalanced by several removal paths (Howard

1989). Because of its high solubility, there will be efficient transfer into rain and surface water, which

may be important sinks (NRC 1981). One model has predicted dry deposition and wet removal half-lives

of 19 and 50 hours, respectively (Lowe et al. 1980). Although formaldehyde is found in remote areas, it

probably is not transported there, but is generated from longer-lived precursors that have been transported

(NRC 1981).
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5. POTENTIAL FOR HUMAN EXPOSURE

No information concerning the fate of formaldehyde in groundwater could be found in the literature.

Based upon the Henry's law constant for formaldehyde (3.27x10-7 atm-m3

/mol) (Dong and Dasgupta

1986), volatilization from water should not be significant (Lyman 1982). Also, little adsorption to

sediment would be expected to occur.

No information could be found concerning the adsorption of formaldehyde to soil. However, its low

octanol/water partition coefficient (log Kow = 0.35) (SRC 1995b) suggests that adsorption to soil is low. 

Using the log Kow of 0.35, a log Koc of 1.57 can be calculated (Lyman 1982). This value of log Koc

suggests a very high mobility and leaching potential of formaldehyde in soil (Swann et al. 1983). At high

concentrations, formaldehyde gas adsorbs somewhat to clay mineral, which is important to its use as a

soil fumigant (De and Chandra 1979). 

Plants, such as kidney beans and barley, can absorb gaseous formaldehyde through their leaves (EPA

1976a). Experiments performed on a variety of fish and shrimp showed no evidence of the

bioaccumulation of formaldehyde (Hose and Lightner 1980; Sills and Allen 1979). Because

formaldehyde is rapidly metabolized (Casanova et al. 1988), bioaccumulation is not expected to be

important.

5.3.2 Transformation and Degradation

Formaldehyde undergoes a number of different transformation and degradation reactions in the

environment as discussed in the following sections. The resulting environmental transformation products

within different media are shown in Table 5-2.

5.3.2.1 Air

Formaldehyde is removed from the atmosphere by direct photolysis and oxidation by photochemically

produced hydroxyl radicals. Formaldehyde absorbs ultraviolet (UV) radiation at wavelengths of 360 nm

and longer (DOT 1980); therefore, it is capable of photolyzing in sunlight. A half-life of 6 hours has been

measured for photolysis in simulated sunlight (Su et al. 1979). There are two photolytic pathways, one

producing H2 and CO, and the other producing H and HCO radicals (Calvert et al. 1972; Lowe et al.

1980). When the rates of these reactions are combined with estimates of actinic irradiance, the predicted

half-life of formaldehyde due to photolysis in the lower atmosphere is 1.6 hours at a solar zenith angle of
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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-2. Environmental Transformation Products of Formaldehyde by Medium

Reaction Comments Reference

Air

 CH2O + hν 6 HCO + H

 CH2O + hν 6 H2 + CO

Photolysis, pathway 1

Photolysis, pathway 2

Calvert et al. 1972

Calvert et al. 1972

 CH2O + NO3 6 HCO + HNO3 H-atom abstraction by NO3

radical

Kao 1994

 CH2O + HO 6 H2O + HCO H-atom abstraction by HO

radical 

NRC 1981

Dilute Aqueous Solution

 CH2O + H2O 6 CH2(OH)2 Formation of gem-diol

methylene glycol; k298E =

7.0x103

 M atm -1

Kumar 1986

Concentrated Solution

 CH2O 6 H(CH2O)nOH + C3H6O3 

 

Formation of

paraformaldehyde and trioxane

EPA 1991c

Cloudwater

 CH2(OH)2 + OH 6 CH(OH)2 + H2O (1)

 CH(OH)2 + O2 6 HO2 + (HCOOH)aq (2)

Formation of formic acid;

k1 = 2x109

 M-1 s-1

k2 = 4.5x109 M-1 s-1

Chameides and Davis

1983
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5. POTENTIAL FOR HUMAN EXPOSURE

40 degrees (Calvert et al. 1972). Based on its rate of reaction with photochemically produced hydroxyl

radicals, formaldehyde has a predicted half-life of approximately 19 hours in clean air and about half that

time in polluted air (Atkinson and Pitts 1978; DOT 1980; EPA 1982). Lowe et al. (1980) report the

lifetime of formaldehyde in the sunlit atmosphere, due to photolysis and reaction with hydroxyl radicals,

is 4 hours. Singh et al. (1982) report an estimated daily loss rate of formaldehyde of 88.2% on the basis

of hydroxyl radical activity and photolysis. The hydroxyl-radical-initiated oxidation of formaldehyde

also occurs in cloud droplets to form formic acid, a component of acid rain (Chameides 1986; Chameides

and Davis 1983). Calculations by Benner and Bizjak (1988) suggest that removal of formaldehyde by

H2O2 is probably negligible in atmospheric droplets. When formaldehyde is irradiated in a reactor, the

half-life is 50 minutes in the absence of NO2 and 35 minutes in the presence of NO2 (Bufalini et al. 1979;

EPA 1976a). The primary products formed are formic acid and CO (Su et al. 1979). The reaction of

formaldehyde with nitrate radicals, insignificant in the daytime, may be an important removal mechanism

at night (NRC 1981). Formaldehyde reacts with the NO3 radical by H-atom extraction with a half-life of

12 days, assuming an average nighttime NO3 radical concentration of 2x109

 molecules per cm3 (Atkinson

et al. 1984). 

5.3.2.2 Water

When released to water, formaldehyde will biodegrade to low levels in a few days (Howard 1989). In

nutrient-enriched seawater, there is a long lag period (.40 hours) prior to measurable loss of

formaldehyde by presumably biological processes (Mopper and Stahovec 1986). Formaldehyde in

aqueous effluent is degraded by activated sludge and sewage in 48–72 hours (EPA 1976a; Hatfield 1957;

Heukelekian and Rand 1955; Verschueren 1983). In a die-away test, using water from a stagnant lake,

degradation was complete in 30 hours under aerobic conditions and 48 hours under anaerobic conditions

(EPA 1976a). Bhattacharya and Parkin (1988) used anaerobic chemostats to study fate and kinetic effects

of sludge and continuous additions of formaldehyde to acetate and propionate enrichment systems. The

high reduction of formaldehyde with continuous addition is indicative of biodegradation, since the

combination of volatilization, adsorption, and chemical transformation should account for less than 25%

of the removal. Up to 80% of the formaldehyde was removed, with biodegradation accounting for

55–60%.

Chameides and Davis (1983) postulated that formaldehyde dissolved in cloudwater should not

photolytically decompose because CH2(OH)2 is not a chromophore, and that the more probable fate of 
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5. POTENTIAL FOR HUMAN EXPOSURE

dissolved formaldehyde is oxidation by OH with the ultimate formation of formic acid. Experiments

performed by Mopper and Stahovec (1986) suggest that formaldehyde is formed and consumed in

seawater as a result of a number of interacting photochemical, biological, and physical processes. Diurnal

fluctuations of formaldehyde ranging from 15 to 50 nM were measured in humic-rich waters off the west

coast of Florida over a 3-day sampling period.

Concentrated solutions containing formaldehyde are unstable, both oxidizing slowly to form formic acid

and polymerizing (Gerberich et al. 1980). In the presence of air and moisture, polymerization takes place

readily in concentrated solutions at room temperature to form paraformaldehyde, a solid mixture of linear

polyoxymethylene glycols containing 90–99% formaldehyde (EPA 1984). 

5.3.2.3 Sediment and Soil

The fate of formaldehyde in soil has not been determined (Howard 1989).

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

Reliable evaluation for human exposure to formaldehyde depends in part on the reliability of supporting

analytical data from environmental samples and biological specimens. In reviewing data on

formaldehyde levels monitored in the environment, it should also be noted that the amount of chemical

identified analytically is not necessarily equivalent to the amount that is bioavailable.

5.4.1 Air

A recent survey of emission data from stationary and mobile sources was used as input for an atmospheric

dispersion model to estimate outdoor toxic air contaminant concentrations for 1990 for each of the

60,803 census tracts in the contiguous United States (Woodruff et al. 1998). The average long term

background concentration estimated for formaldehyde was 0.2 ppb (Woodruff et al. 1998).

In a survey of ambient measurements of hazardous air pollutants, a median formaldehyde concentration

of 2.5 ppb was found for a total of 1,358 samples collected at 58 different locations (Kelly et al. 1994). 

Air samples collected daily in Schenectady, New York, during the months of June through August 1983

had formaldehyde concentrations ranging from 1 to 31 ppb. There was a significant daily variation that 
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5. POTENTIAL FOR HUMAN EXPOSURE

appeared to correlate with traffic conditions (Schulam et al. 1985). In the same study, formaldehyde

levels measured on the summit of Whiteface Mountain in Wilmington, New York, ranged from 0.8 to

2.6 ppb. Ambient formaldehyde concentrations at the California State University Los Angeles campus

ranged from 2 to 40 ppb during the period from May to June 1980; concentrations in Claremont,

California, ranged from 3 to 48 ppb from September 19 to October 8, 1980 (Grosjean 1982). 

Formaldehyde was measured in urban ambient air in 8 cities for 2- to 3-day periods from June 1980 to

April 1984. The average concentrations were 11.3 ppb in St. Louis, Missouri (June 5–7, 1980); 12.3 ppb

in Denver, Colorado (June 23–24, 1980); 2.3 ppb in Denver, Colorado (April 1–2, 1984); 19 ppb in

Riverside, California (July 8–10, 1980); 14.3 ppb in Staten Island, New York (April 3–4, 1981); 18.5 ppb

in Pittsburgh, Pennsylvania (April 15–16, 1981); 11.3 ppb in Chicago, Illinois (April 27–28, 1981);

15.5 ppb in Downey, California (February 28–March 1, 1984); and 3.8 ppb in Houston, Texas (March

18–19, 1984). The maximum concentration in each city ranged from 5.5 ppb in Denver in April to

67.7 ppb in Downey (Salas and Singh 1986; Singh et al. 1982).

Formaldehyde was detected in 99% of 48 ambient air samples obtained in Ohio urban centers, June-July

1989, at a mean and maximum concentration of 3.0 and 15.5 ppb, respectively (Spicer et al. 1996). The

diurnal changes in concentration were found to be consistent with initial direct emissions from vehicles

followed by secondary photochemical production and, ultimately, atmospheric removal. These data

indicate that formaldehyde concentrations in urban atmospheres are expected to be the highest during, or

shortly after rush hour, or other periods of high vehicular traffic. Similar results were obtained when

temporal formaldehyde concentrations were measured during a smog event in California, September 1993

(Grosjean et al. 1996). In central Los Angeles, higher formaldehyde concentrations were found to

correlate with vehicular traffic while at a downwind location, the concentration was found to spike later in

the day. The average atmospheric formaldehyde concentration for all sites was 5.3 ppbv (parts per billion

by volume) in this study, while the background concentration from San Nicolas island (off the Southern

California coast) was 0.8 ppmv (parts per million by volume). Average annual formaldehyde

concentrations in California have been reported to vary from a minimum of 3.2 ppbv in the San Francisco

Bay area to 4.9 ppbv in the South Coast Air Basin (Seiber 1996).

Several monitoring studies have been conducted in the United States to measure the concentration of

formaldehyde in indoor environments (EPA 1987d; Gammage and Hawthorne 1985; Hawthorne et al.

1985, 1986b; Stock 1987). The results for a variety of housing types and ages have been compiled by

Gold et al. (1993) and are presented in Table 5-3. Much of the data was collected in older homes, in 
Table 5-3. Indoor Concentrations of Formaldehyde in U.S. Homes

Building type Number

Concentration (ppm)

Range Mean References

With UFFI >1,200 0.01–3.4 0.05–0.12 EPA 1987d; GammagWithout UFFI 131 0.01–0.17 0.025–0.07 Gammage and HawthComplaint Mobile homes >500 0.00–4.2 0.1–0.9 Gammage and HawthNon-complaint

Conventional, randomly selected 560 <0.005–0.48 0.027–0.091 EPA 1987d; Stock 19Mobile homes, randomly selected .1,200 <0.01–2.9 0.091–0.62 EPA 1987d

By age

Mobile homes

newolder, occupied

260—

0.860.25

Gammage and HawthGammage and Hawth

Conventional homes

0–5 years5–15 years>15Overall

18111140 <0.02–0.4

0.080.040.030.06

Hawthorne et al. 198Hawthorne et al. 198Hawthorne et al. 198Hawthorne et al. 198

UFFI = Urea formaldehyde foam insulation
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5. POTENTIAL FOR HUMAN EXPOSURE

homes that had UFFI, or in homes in which occupants had filed complaints of formaldehyde irritant

symptoms. Since the time many of these monitoring studies were performed, plywood and particle board

manufacturing methods have been changed to reduce the formaldehyde emission levels in the finished

product (EPA 1996). Similarly, home construction methods have changed, and the use of UFFI has been

greatly reduced since the mid-eighties (CPSC 1997). A recent pilot study on a newly constructed and

unoccupied house set up to measure formaldehyde emissions from construction materials had a maximum

localized formaldehyde concentration of 0.076 ppm, which occurred shortly after a high loading of

pressed wood materials, such as kitchen cabinets (Hare et al. 1996). The average indoor concentrations

measured in this study were 0.035–0.45 ppm, which was attained approximately 30 days after either high

or low loadings of formaldehyde releasing materials were installed. 

Earlier studies evaluating randomly selected, non-complaint homes have appeared in the literature. 

Despite the wide variety of conditions under which these residential formaldehyde studies were

conducted, results for given types of housing were consistent within certain broad ranges. In general,

indoor residential formaldehyde concentrations were significantly higher than outdoor concentrations

which ranged from 0.002 to 0.006 ppm in remote, unpopulated regions from 0.01 to 0.02 ppm (and

sometimes 0.05 ppm) in highly populated areas and industrial urban air (Gold et al. 1993). The range of

formaldehyde concentrations measured in complaint homes, mobile homes, and homes containing large

quantities of particle board or UFFI were 0.02–0.8 ppm, with levels as high as 4 ppm, sufficient to cause

irritating symptoms, observed in some instances. Formaldehyde levels in more recently built (<1 year

old) conventional homes generally were within the range of 0.05–0.2 ppm, with few measurements

exceeding 0.3 ppm. Older conventional homes had the lowest indoor concentrations of formaldehyde

with values typically less than 0.05 ppm (Gold et al. 1993), consistent with the expected decrease in latent

formaldehyde release from wood-based building materials as they age (EPA 1996; Zinn et al. 1990).

The Texas Department of Health measured formaldehyde in 443 mobile homes between April 1979 and

May 1982 at the request of the occupants. Concentrations ranged from below detectable limits

(<0.5 ppm) to 8 ppm (Norsted et al. 1985). Of the homes #1 year old, 27% had mean concentrations

$2 ppm, while 11.5% of older homes has concentrations $2 ppm. The concentration of formaldehyde in

mobile homes would be expected to be higher than that found in conventional homes due to their lower

rate of air exchange (Wolff 1991).
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5. POTENTIAL FOR HUMAN EXPOSURE

Sexton et al. (1989) selected an age-stratified random sample of 470 mobile homes, from the more than

500,000 in California, for measurement of 1-week, average indoor formaldehyde concentrations during

the periods July–August 1984 and February–March 1985. They observed relatively little variation in

formaldehyde concentrations between summer and winter, with average 1-week formaldehyde values of

0.07–0.09 ppm. Of the homes, 31% exceeded the maximum concentration of 0.1 ppm formaldehyde

recommended at the time of the study by AIHA, EPA, and the American Society of Heating,

Refrigerating and Air Conditioning Engineers. The investigators noted that formaldehyde levels appeared

to have been decreasing in mobile homes manufactured since about 1980, probably as a result of

increased use of low-formaldehyde-emitting building materials.

The Indiana State Board of Health measured formaldehyde in four specific office and commercial

establishments that had poor ventilation. The concentrations ranged from 0.01 to 1.01 ppm. In one case,

the source of formaldehyde was urea-formaldehyde foam. In the others, it was particle board, plywood

subflooring, and furniture (Konopinski 1983).

 Shah and Singh (1988) collected indoor and outdoor data for volatile organic chemicals from both

residential and commercial environments. The average daily outdoor concentration of formaldehyde for

all outdoor site types (remote, rural, suburban, urban, and source-dominated) was 8.3 ppbv; the average

daily indoor concentration of formaldehyde was 49.4 ppbv.

Zhang et al. (1994b) made simultaneous indoor and outdoor measurements of aldehydes at six residential

houses in suburban New Jersey during the summer of 1992. Formaldehyde was the most abundant

aldehyde, with a mean outdoor concentration of 12.53 ppb (.60% of the total outdoor aldehyde

concentration) and a mean indoor concentration of 54.56 ppb (.87% of the total indoor aldehyde

concentration). 

Krzyzanowski et al. (1990) measured formaldehyde concentrations in 202 households in Pima County,

Arizona, and found an average value of 26 ppb. Concentrations varied slightly with locations in the

house, with the highest levels generally found in the kitchens. Only a few concentrations exceeded

90 ppb, with a maximum value of 140 ppb. The average indoor formaldehyde concentrations measured in

homes in Pullman, Washington, ranged from approximately 5–72 ppb (Lamb et al. 1985). 
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5. POTENTIAL FOR HUMAN EXPOSURE

Formaldehyde concentrations measured on two different days inside a tavern during normal smoking

conditions were 85–72 ppb (Lofroth et al. 1989). In the same study, the average airborne formaldehyde

yield of a cigarette was found to be 2 mg. Levels of formaldehyde in nonsmoking office buildings ranged

from not detected to 0.22 ppm, while it ranged from not detected to 0.6 ppm where smoking was

permitted (Sterling et al. 1987).

5.4.2 Water

Formaldehyde is unstable in water; however, it has been detected in municipal and industrial aqueous

effluents, including those resulting from chemical, oil, and coal processing (EPA 1976b; Hushon et al.

1980). Formaldehyde was not detected in the National Organics Reconnaissance Survey of Suspected

Carcinogens in Drinking Water (EPA 1975).

Formaldehyde levels in rainwater collected in California were low, ranging from not detectable to

0.06 μg/mL (Grosjean and Wright 1983). Concentrations of free formaldehyde measured in fogwater in

Corvallis, Oregon, ranged from 0.4 to 3 mg/L with a volume-weighted mean of 1.8 mg/L (Muir 1991). 

Free formaldehyde concentrations in fogwater in Riverside, California, ranged from 4.1 to 228 μM

(0.12–6.8 mg/L), with approximately half of the samples measuring less than 90 μM (3 mg/L) (Igawa et

al. 1989). Stratus cloudwater at Henninger Flats, California, which typically is highly acidic and

concentrated in inorganic pollutants, had concentrations of free formaldehyde ranging from 45.9 to

61.5 μM (1.4–1.8 mg/L), comparable to the mid-range of Corvallis fogwater concentrations (Igawa et al.

1989). Formaldehyde concentrations ranging from 11 to 142 μM were found in cloudwater samples

collected in the Los Angeles Basin (Richards et al. 1983). Formaldehyde concentrations in mist samples

in Long Beach and Marina del Ray, California, were 0.25–0.56 μg/mL, respectively (Grosjean and

Wright 1983).

5.4.3 Sediment and Soil

No data on formaldehyde levels in sediment and soil could be found in the literature.
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5. POTENTIAL FOR HUMAN EXPOSURE

5.4.4 Other Environmental Media

Fresh shrimp from four local commercial markets in Atlanta, Georgia were found to have formaldehyde

levels ranging from 0.39 to 1.44 mg/kg (Radford and Dalsis 1982). In the same study, shrimp kept live in

the laboratory were found to contain 0.99 mg/kg immediately after sacrifice, and the level rose to

2.15 mg/kg after refrigeration for 6 days.

Chou and Que Hee (1994) measured the concentrations of carbonyl compounds in artificial saliva

leachates of three chewing tobaccos. They found formaldehyde concentrations of 110, 670, and

530 ng/mL (0.11, 0.67, and 0.53 μg/mL, respectively) in three different commercial brands. Mansfield et

al. (1977) used liquid chromatography to measure formaldehyde as a combustion product in tobacco

smoke from six different brands of American filter tip cigarettes. The average amount of formaldehyde

by brand ranged from 45.2 to 73.1 μg/cigarette and from 5.1 to 8.9 μg/puff. Triebig and Zober report that

the level of formaldehyde in side stream cigarette smoke is fifty times higher than main stream smoke

(Triebig and Zober 1984) while the National Research Council put the value at five to eight times more

formaldehyde in side stream smoke (NRC 1986).

Formaldehyde has also been found at levels ranging from 1 to 3,517 ppm in 112 fabric samples, with

18 of the samples having a free formaldehyde concentration greater than 750 ppm (mg/kg) (Schorr et al.

1974).

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

The contribution of various atmospheric environments to the average exposure to formaldehyde is given

below (Fishbein 1992):
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5. POTENTIAL FOR HUMAN EXPOSURE

Source mg/day

Air

Outdoor air (10% of time) 0.02

Indoor air

Home (65% of time)

Conventional

Prefabricated (chipboard)

0.5–2.0

1.0–10.0

Workplace (25% of time)

Without occupational exposure

With 1 mg/m3

 occupational exposure

0.2–0.8

5

Environmental tobacco smoke 0.1–1

Smoking (20 cigarettes/day) 1

The major route of exposure is inhalation of indoor air, with releases of formaldehyde from chipboard and

other building and furnishing materials composing the bulk of the exposure. Environmental tobacco

smoke contributes 10–25% of the total indoor exposure. Since formaldehyde in food is not available in

free form, the intake of formaldehyde from the ingestion of food (1–10 mg/day) has not been included

(Fishbein 1992).

Consumers can be exposed to formaldehyde gas through its emission from construction materials, wood

products, textiles, home furnishings, paper, cosmetics, and pharmaceuticals (Bartnik et al. 1985; Pickrell

et al. 1983; WHO 1989). Members of the general population may also be exposed to formaldehyde by

dermal contact with many of these products. Based on a study of dermal absorption of formaldehyde in

rats from cosmetic products, Bartnik et al. (1985) made rough estimates of the formaldehyde that could be

absorbed through the use of products such as hand cream or sun-tan lotion. In the case of hand cream,

approximately 2 g is used per application, containing 2 mg formaldehyde. Assuming 5% absorption,

0.1 mg of formaldehyde would be absorbed. For a whole-body product such as sun-tan lotion,

approximately 17 g of the product (containing 17 mg of formaldehyde) would be used, resulting in an

absorption of 0.85 mg of formaldehyde.

A study was conducted in Boston to examine the commuter’s exposure to six gasoline-related volatile

emissions, including formaldehyde, in four different commuting modes (Chan et al. 1991). The mean

formaldehyde concentrations (in μg/m3

) measured while driving private cars, riding in subways, walking,

and biking were 5.1 (n=40), 4.5 (n=38), 5.5 (n=31), and 6.3 (n=11), respectively. The maximum

concentrations in all commuting modes were usually three to five times higher than the mean
FORMALDEHYDE 307

5. POTENTIAL FOR HUMAN EXPOSURE

concentrations. A similar study in the New York/New Jersey area found that the mean in-vehicle

concentration of formaldehyde during commutes was 0.3 μg/m3

 (Lawryk et al. 1995; Lawryk and Weisel

1996).

Occupational exposure can occur during the production of end products in which formaldehyde is used, in

the garment industry, during various preservation processes, and in laboratories. Health care

professionals (pharmacists, physicians, veterinarians, dentists, nurses, etc.) may be exposed to vapors

during the preparation, administration, and/or cleanup of various medicines. Pathologists and histology

technicians, morticians, and teachers and students who handle preserved specimens may also be exposed

(Fleisher 1987; Holness and Nethercott 1989; Korky et al. 1987; Perkins and Kimbrough 1985; Skisak

1983). The laser cutting of felt, woven fabrics, formica, plexiglass, and acrylic materials has been found

to release formaldehyde (Kiefer and Moss 1997). Formaldehyde exposure for workers at a fiberglass

insulation manufacturing plant were found to range from 49 to 516 μg/m3

 (Milton et al. 1996a). Midrange photocopiers (30–135 copies per minute) have also been found to emit formaldehyde (Leovic et al.

1996).

The National Occupational Exposure Survey (NOES), conducted from 1981 to 1983, indicated that

1,329,332 workers employed in various professions were potentially exposed to formaldehyde in the

United States (NIOSH 1995b). The NOES database does not contain information on the frequency,

concentration, or duration of exposure; the survey provides only estimates of workers potentially exposed

to the chemical in the workplace. OSHA has estimated that in the late 1980s over 2 million workers in

over 112,000 firms were exposed to formaldehyde; about 45% of these workers are estimated to be in the

garment industry. About 1.9 million were exposed to levels of formaldehyde between 0.1 ppm and

0.5 ppm (mainly in apparel, furniture, paper mills, and plastic molding); approximately 123,000 were

exposed to levels of formaldehyde between 0.5 and 0.75 ppm (mainly in apparel, textile finishing,

furniture, laboratories, and foundries); and about 84,000 were exposed to between 0.75 and 1 ppm

(mainly in apparel, furniture, and foundries) (OSHA 1996).

OSHA has estimated that in the United States approximately 107,000 employees are exposed to

formaldehyde concentrations greater than 1 ppm, and approximately 430,000 employees are exposed to

concentrations ranging from 0.5 to 1 ppm (Fishbein 1992). An initial evaluation of formaldehyde

exposures in a sewing plant using fabrics with a postcure resin found time-weighted average (TWA) 
FORMALDEHYDE 308

5. POTENTIAL FOR HUMAN EXPOSURE

exposure levels #1.2 ppm, with a mean of 0.9 ppm (Luker and Van Houten 1990). A modification that

decreased the amount of residual formaldehyde in the fabric reduced worker exposure by 80–85%. Area

concentrations of formaldehyde in a plywood company ranged from 0.28 to 3.48 ppm; the average

personal exposure was 1.13 ppm formaldehyde (Malaka and Kodama 1990). Airborne formaldehyde

concentrations ranging from 0.187 to 0.783 ppm have been measured during particle-board-sanding

operations (Stumpf et al. 1986). Formaldehyde concentrations of 0.5–7 ppm have been measured in

leather tanning facilities (Stern et al. 1987). An average airborne formaldehyde level of 0.36±0.19 ppm

was measured during 22 embalming procedures (Holness and Nethercott 1989). Fire fighters are exposed

to formaldehyde concentrations as high as 8 ppm during knockdown (bringing the main body of fire

under control) and #0.4 ppm during overhaul (searching for and extinguishing hidden fire) (Jankovic et

al. 1991). Formaldehyde levels #0.3 ppm have been measured inside a fire fighter's self-contained

breathing apparatus (Jankovic et al. 1991). 

The current OSHA permissible exposure limit (PEL) for all workplaces covered by OSHA is 0.75 ppm

for an 8-hour TWA, and the short-term exposure limit (STEL) is 2 ppm over a 15-minute period. The

"action level" is 0.5 ppm measured over 8 hours (OSHA 1996). NIOSH has recommended a 0.1 ppm

ceiling exposure concentration over a 15-minute period in the workplace (NIOSH 1992).

5.6 EXPOSURES OF CHILDREN

This section focuses on exposures from conception to maturity at 18 years in humans and briefly

considers potential pre-conception exposure to germ cells. Differences from adults in susceptibility to

hazardous substances are discussed in Section 2.6 Children’s Susceptibility.

 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, and breathe more air per kilogram of body weight, and have a

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s

behavior and lifestyle also influence exposure. Children crawl on the floor; they put things in their

mouths; they may ingest inappropriate things such as dirt or paint chips; they spend more time outdoors. 

Children also are closer to the ground, and they do not have the judgement of adults in avoiding hazards

(NRC 1993).
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5. POTENTIAL FOR HUMAN EXPOSURE

Children are exposed to formaldehyde mainly from its presence in air. Formaldehyde levels are typically

higher indoors (Gold et al. 1993) where younger children may spend a significant amount of time. 

Exposure for children outdoors will be similar to adults. It is likely to be greatest during rush hour

commutes (Spicer et al. 1996) or near known sources of formaldehyde release, such as factories using

formaldehyde or during the use of products (Shah and Singh 1988) that emit formaldehyde. Children

may also be dermally exposed to formaldehyde as a result of its release from permanent press fabrics or

its presence in cosmetic products. Only a limited number of studies that address formaldehyde exposure

to children or body burden measurements have been identified (Krzyzanowski et al. 1990; Wantke et al.

1996a).

In the home, formaldehyde sources include household chemicals, pressed wood products (especially when

new) (EPA 1996), combustion sources (NRC 1986), and some new fabrics (Schorr et al. 1974) and

garments. A number of common household products may release formaldehyde to indoor air, including

antiseptics, medicines, dish-washing liquids, fabric softeners, shoe-care agents, carpet cleaners, glues,

adhesives, and lacquers (Kelly et al. 1996). If children use or play with some of these products, or are

present when they are used, additional exposure to formaldehyde may occur. Many cosmetic products

contain formaldehyde and some, such as nail polish and nail hardeners, contain high levels (Kelly et al.

1996). If children place these products in their mouth or on their skin, or sniff them, they will be exposed

to elevated levels of formaldehyde.

New carpets have been found to release formaldehyde (Hodgson et al. 1993). Older carpets, especially

wall-to-wall carpets, have been found to be a sink for formaldehyde if there are other indoor sources

(Norback et al. 1995). In addition, some carpet cleaners may contain formaldehyde. Infants may be

exposed to formaldehyde while crawling on carpets or on newly cleaned carpets (IARC 1982; WHO

1989). Similarly, young children may be exposed while sitting or playing on indoor carpeting.

Formaldehyde is typically not found in water or soil, and children are not expected to be exposed by these

routes. Because it is a gas, formaldehyde is not brought home on a parent’s work clothes or tools. 

Occupants of newly constructed homes, including children, may be exposed to formaldehyde due to its

release from pressed wood construction materials (see Section 5.7), a process that slowly decreases with

time. As discussed above, formaldehyde is released to indoor air from many sources. Children that live

in mobile homes may be exposed to higher levels of formaldehyde compared to those that live in

conventional homes because mobile homes have lower air exchange rates. Children that live in
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5. POTENTIAL FOR HUMAN EXPOSURE

households that have a cigarette, cigar, or pipe smoker will also be exposed to higher levels of

formaldehyde due to its presence in side stream smoke (Triebig and Zober 1984).

Formaldehyde is released from many pressed wood products used in the construction of furniture

(Konopinski 1983). When placed in a new crib manufactured from these materials, infants may be

exposed because of their proximity to the furniture’s structural components. Also, small rooms that have

new furniture manufactured from pressed wood products installed may have localized, elevated

concentrations of formaldehyde because of their low total volume.

Formaldehyde is highly water soluble, very reactive, and is rapidly metabolized by tissues at portals of

entry. Thus, parental exposure at typical indoor, outdoor, or occupational levels is not expected to result

in exposure to parental germ cells or the developing fetus (See Section 2.6 for additional information).

Since formaldehyde is typically found in the air, and since its concentration in indoor air is typically

higher than that found outdoors, formaldehyde exposure to children can be reduced by bringing fresh air

into the home. This can be accomplished by opening windows or using ventilation fans. It has been

established that coated or laminated pressed wood products release less formaldehyde than those that are

uncoated (Kelly et al. 1996; Pickrell et al. 1983), so sealing these surfaces would be expected to reduce

formaldehyde levels in the home. Since formaldehyde is also formed in indoor air by the degradation of

other volatile organic chemicals, such as solvents (Weschler and Shields 1996), commonly found in the

home, removing the source of these materials or using them with adequate ventilation will reduce indoor

levels of formaldehyde.

Material that acts as a sink for formaldehyde, such as carpets (Norback et al. 1995), can also be removed

from the home to lower levels. Securing cosmetic products and other materials that have higher

formaldehyde concentrations away from children’s reach and not allowing individuals to smoke in the

house will also lower levels of exposure.
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5. POTENTIAL FOR HUMAN EXPOSURE

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Workers in industries where formaldehyde is used or released may receive potentially high exposures.

Members of the general population who live in newly constructed homes or homes where pressed wood

products have recently been installed may be exposed to high levels of formaldehyde by inhalation for

short periods of time until the latent formaldehyde has been released. Exposures in mobile homes are

expected to be higher than conventional homes due to their lower rate of air exchange (Wolff 1991). 

Members of the general population that handle large amounts of permanent press fabrics treated with

formaldehyde-releasing resins may also receive potentially high exposures. The use of some cosmetics,

such as nail hardeners, may result in high short-term exposure.

Smokers and persons who live in a home with a cigarette smoker also may be exposed to higher levels of

formaldehyde. Environmental tobacco smoke, which is a combination of diluted sidestream smoke

released from a cigarette’s burning end and mainstream smoke exhaled by an active smoker, can

contribute 10–25% (0.1–1 mg/day) of the total average indoor exposure to formaldehyde (Fishbein 1992).

5.8 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of formaldehyde is available. Where adequate information is

not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of

research designed to determine the health effects (and techniques for developing methods to determine

such health effects) of formaldehyde.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance-specific research agenda will be proposed.
FORMALDEHYDE 312

5. POTENTIAL FOR HUMAN EXPOSURE

5.8.1 Identification of Data Needs

Physical and Chemical Properties. The physical and chemical properties of formaldehyde are

well characterized and allow prediction of the transport and transformation of the compound in the

environment.

Production, Import/Export, Use, Release, and Disposal. Knowledge of a chemical’s

production volume is important because it may indicate the magnitude of environmental contamination

and human exposure. Data regarding the production, trend, use pattern, and disposal of formaldehyde are

available.

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C.

Section 11023, industries are required to submit chemical release and off-site transfer information to the

EPA. The Toxics Release Inventory (TRI), which contains this information for 1996, became available in

May of 1998. According to the Toxics Release Inventory (TRI), in 1996, 21 million pounds (9.6 million

kg) of formaldehyde were released to the environment. This database will be updated yearly and should

provide a list of industrial production facilities and emissions.

Environmental Fate. The environmental fate of formaldehyde in air has been well studied (Bufalini

et al. 1979; Calvert et al. 1972; Chameides and Davis 1983; DOT 1980; EPA 1976a; Kao 1994; Kelly et

al. 1994; Lowe et al. 1980; Su et al. 1979). Formaldehyde is removed from the atmosphere by direct

photolysis and oxidation by photochemically produced hydroxyl and nitrate radicals. Solutions of

formaldehyde are unstable, both oxidizing slowly to form formic acid and polymerizing. When released

to water, formaldehyde will biodegrade to low levels in a few days, with little adsorption to sediment

(Howard 1989; Lyman 1982). No significant volatilization from water is expected to occur (Lyman

1982). No experimental or estimated values for the half-life of formaldehyde in ambient water were

found in the literature. Aqueous solutions of formaldehyde that are released to soil may leach through the

soil (Lyman 1982; SRC 1995b; Swann et al. 1983). Although formaldehyde is known to biodegrade

under both aerobic and anaerobic conditions, the fate of formaldehyde in soil is still unknown (Howard

1989). There is a need for data on the fate and transport of formaldehyde in soil, including half-life

values. The environmental fate of formaldehyde’s predominant degradation product, formic acid, is well

documented. In air, formic acid is expected to rapidly degrade (half-life approximately 1 month) through 
FORMALDEHYDE 313

5. POTENTIAL FOR HUMAN EXPOSURE

its reaction with hydroxyl radicals or it is expected to undergo wet deposition to the earth’s surface

(HSDB 1999). In water or soil, formic acid is expected to rapidly biodegrade.

Bioavailability from Environmental Media. Inhalation is the major pathway for exposure to

formaldehyde (Fishbein 1992). The environmental factors that may influence the bioavailability of

formaldehyde from contaminated air, water, or plant material have not been studied. The role of sorption

may not be significant in determining the bioavailability of formaldehyde from soil since formaldehyde is

not expected to adsorb to soils and sediments (Lyman 1982). The factors affecting the bioavailability of

formaldehyde from soil and other environmental media need further investigation. The bioavailability of

formaldehyde from the ingestion of food is not known although it is not expected to be significant.

Food Chain Bioaccumulation. Experiments performed on a variety of fish and shrimp showed no

evidence of the bioaccumulation of formaldehyde (Hose and Lightner 1980; Sills and Allen 1979). 

Because formaldehyde is rapidly metabolized (Casanova et al. 1988), bioaccumulation is not expected to

be important. No further information is needed.

Exposure Levels in Environmental Media. The levels of formaldehyde in air are well

documented (EPA 1987d; Gammage and Hawthorne 1985; Gold et al. 1993; Grosjean 1982; Hawthorne

et al. 1985, 1986a; Kelly et al. 1994; Krzyzanowski et al. 1990; Lamb et al. 1985; Lofroth et al. 1989;

Norsted et al. 1985; Salas and Singh 1986; Schulam et al. 1985; Sexton et al. 1989; Shah and Singh 1988;

Singh et al. 1982; Stock 1987; Zhang et al. 1994a). Some data on the concentrations of formaldehyde in

rainwater, fogwater, and mist have been reported (Grosjean and Wright 1983; Igawa et al. 1989; Muir

1991), but more recent data on the levels of formaldehyde in water would be useful in assessing

exposures. No data on levels of formaldehyde in soil were found in the literature. Soil concentrations

also are needed to assess exposures.

Reliable monitoring data for the levels of formaldehyde in contaminated media at hazardous waste sites

are needed so that the information obtained on levels of formaldehyde in the environment can be used to

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste

sites.
FORMALDEHYDE 314

5. POTENTIAL FOR HUMAN EXPOSURE

Exposure Levels in Humans. Data are available concerning exposure levels in occupational

settings (Anonymous 1984a; Fishbein 1992; OSHA 1996). Results of the National Occupational

Exposure Survey (NIOSH 1995b) are indicative of the number of workers potentially exposed to

formaldehyde in various occupations; however, the database does not contain information on the

frequency, concentration, or duration of exposure. Available data indicate that the general population

may be exposed to formaldehyde through inhalation and dermal contact; however, because of the wide

variety of exposure sources (conventional homes versus mobile homes, smoking versus nonsmoking

environment, usage patterns for consumer products, etc.), it is difficult to estimate average daily intakes

by these routes. Up-to-date comprehensive monitoring data would be useful in determining the typical

amount of formaldehyde to which the general population is exposed. This information is necessary for

assessing the need to conduct health studies on these populations and persons residing near hazardous

waste sites.

Exposures of Children. Because formaldehyde is found predominately in the air, the main exposure

pathway for children is the same as adults. Formaldehyde concentrations in indoor air have been

reported, although many of the studies were obtained before manufacturing methods for formaldehydereleasing building materials were changed to reduce emissions. Current, comprehensive studies that

account for all formaldehyde release sources to indoor air would aid in determining the body burden to

children. Studies that take into account the different lifestyles of children would be also helpful. For

example, formaldehyde emissions to indoor air may be source dominated (e.g., emission from pressed

wood furniture). For a given emission level, the resulting formaldehyde concentration would be expected

to be greater in children’s rooms compared to those of adults because the volume is smaller. Information

to address child specific formaldehyde exposure issues is not available.

Exposure Registries. No exposure registries for formaldehyde were located. This substance is not

currently one of the compounds for which a subregistry has been established in the National Exposure

Registry. The substance will be considered in the future when chemical selection is made for

subregistries to be established. The information that is amassed in the National Exposure Registry

facilitates the epidemiological research needed to assess adverse health outcomes that may be related to

exposure to this substance. Workers in industries where formaldehyde is used or produced should be

considered for inclusion in an exposure registry. Given that formaldehyde is routinely found in indoor air

samples, members of the general population should also be considered for inclusion in the exposure

registry.
FORMALDEHYDE 315

5. POTENTIAL FOR HUMAN EXPOSURE

5.8.2 Ongoing Studies

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental

Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for

Disease Control and Prevention, will be analyzing human blood samples for formaldehyde and other

volatile organic compounds. These data will give an indication of the frequency of occurrence and

background levels of these compounds in the general population.

The Federal Research in Progress (FEDRIP 1996) database provides additional information obtainable

from a few ongoing studies that may fill in some of the data needs identified in Section 5.8.1. These

studies are summarized in Table 5-4.
FORMALDEHYDE 316

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-4. Ongoing Studies on the Potential for Human Exposure to Formaldehyde

Investigator Affiliation Research description Sponsor

K. Knapp, 

D. Pahl, and

F. Black

EPA-AREAL

Research Triangle Park, NC

Characterization of emissions, including

formaldehyde, from motor vehicles using both

traditional and alternative fuels.

EPA

B.J. Collier Louisiana State University

Baton Rouge, LA

Development of textile materials for 

environmental compatibility and human

health and safety.

USDA

D.V. Sandberg

and R.D.

Ottmar

Pacific Northwest 

Forest and Range Experiment

Station

Portland, OR

Assessment of firefighter exposures to

potential health hazards, including

formaldehyde.

USDA

T. Shibamoto University of California

Davis, CA

Isolation and identification of mutagens and

carcinogens in foods.

USDA

J.S. Gaffney Argonne National Laboratory

Argonne, IL

Atmospheric chemistry of organic oxidants

and aldehydes.

USDOE

P. Davidovits Boston College

Chestnut Hill, MA

Laboratory studies of heterogeneous gasliquid interaction of atmospheric trace gases,

including formaldehyde.

NSF

R.C. Bales and 

M. Conklin

University of Arizona

Tucson, AZ

Determination of the atmosphere-to-snow

transfer function for peroxide and

formaldehyde, whose deposition is reversible.

NSF

R.C. Bales and 

M. Conklin

University of Arizona

Tucson, AZ

Distribution of reactive chemical species,

including formaldehyde, in ice and snow.

NSF

V.A. Mohnen State University of 

New York

Albany, NY

Examination of the involvement of natural

hydrocarbons for the formation of peroxide

and formaldehyde in air.

NSF

B.G. Heikes University of 

Rhode Island

Kingston, RI

Background atmospheric measurements of

hydrogen peroxide, organic hydro-peroxides,

and formaldehyde.

NSF

S.S. Que Hee UCLA School of 

Public Health

Los Angeles , CA

Carbonyl compounds air sampling method. NIOSH

R.R. Fall University of Colorado 

at Boulder

Boulder, CO

Biogenic sources of oxygenated hydrocarbons

in the troposphere.

NSF

EPA = Environmental Protection Agency; NSF = National Science Foundation; USDA = United States Department

of Agriculture; USDOE = United States Department of Energy; NIOSH = National Institute for Occupational Safety

and Health
FORMALDEHYDE 317

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or

measuring, and/or monitoring formaldehyde, its metabolites, and other biomarkers of exposure and effect

to formaldehyde. The intent is not to provide an exhaustive list of analytical methods. Rather, the

intention is to identify well-established methods that are used as the standard methods of analysis. Many

of the analytical methods used for environmental samples are the methods approved by federal agencies

and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). 

Other methods presented in this chapter are those that are approved by groups such as the Association of

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower

detection limits and/or to improve accuracy and precision.

6.1 BIOLOGICAL SAMPLES

Methods for the determination of formaldehyde in biological samples are given in Table 6-1. 

Formaldehyde has been measured in blood by gas chromatography (GC) in conjunction with mass

spectrometry (MS) after derivatization of the formaldehyde to the pentafluorophenylhydrazone (Heck et

al. 1985) and in rat urine by high-performance liquid chromatography (HPLC) with ultraviolet (UV)

absorbance detection following formation of the 2,4-dinitrophenylhydrazone derivative (Shara et al.

1992). Although the method was used for rat urine, it would be expected that human urine could also be

utilized. The determination of formaldehyde in breath has been demonstrated by Lin et al. (1995)

following the formation of 2,4-dinitrophenylhydrazone using 2,4-dinitrophenylhydrazine-impregnated

silica cartridges. Formaldehyde has been determined in “biologicals” (vaccines) at concentrations as low

as 100 ppb following the formation of the formaldehyde phenylhydrazone (Shrivastaw and Singh 1995). 

It was noted by the authors that this method was free from interferences from proteins and bacterial cells

so it might have applicability to biological fluids such as blood or urine. Formic acid or formate is

produced from formaldehyde arising from both exogenous and endogenous sources and can be measured

as reported by Baumann and Angerer (1979). Although no literature citations were found, it would seem

that formate in urine and blood could be determined by a method based on ion chromatography (IC). The

measurement of formaldehyde conjugates of IgE and IgG in people exposed to formaldehyde has been

shown (Thrasher et al. 1989), but has not resulted in a routine method.
Table 6-1. Analytical Methods for Determining Formaldehyde and Metabolites in Biological Sam

Sample matrix Preparation method

Analyticalmethod

Sampledetection limit

Percentrecovery R

Venous blood Addition of water and pentafluorophenylhydrazine in dilute phosphoric acid; addition

of a known amount of labeled formaldehydeas internal standard; equilibration for 2 hoursat 50 EC; extraction with hexane/methylenechloride.

GC/MS (SIM) No data No data H

Breath Collection of expired air into Douglas bag,

then Tedlar bag; drawing of breath throughDNPH-coated silica; elution with acetonitrile

and addition of internal standard;evaporation of solvent and redissolution.

HPLC/UV No data 95.6 

(SD= 3.6)

L

Urine (rat) Dilution of urine with water, addition of

DNPH in 2 N HCl and pentane followed byintermittent shaking for 30 minutes;extraction with additional aliquot of pentanefollowed by solvent evaporation;redissolution in acetonitrile.

HPLC/UV 10 pmole/mL

(0.3 μg/L,0.3 ppb)

No data 

Biologicals (vaccines) Addition of 1 mL of sample to 3 mL of

water, addition of phenyl hydrazine,concentrated HCl, methanol, and chloroformfollowed by shaking for 10–30 seconds;isolation of chloroform layer forspectrophotometric analysis.

Absorbance at529 nm

100 ng/mL (100ppb)

No data S

1

Blood, urine (formicacid)

Formic acid transformed by concentratedsulfuric acid into water and carbonmonoxide; carbon monoxide converted tomethane in chromatographic system.

GC/FID No data No data B

1
Table 6-1. Analytical Methods for Determining Formaldehyde and Metabolites in Biological Samples (

Sample matrix Preparation method

Analyticalmethod

Sample detectionlimit

Percentrecovery R

Blood (human serumalbumin-formaldehydeconjugate; IgE, IgG)

Addition of diluted sample to coatedmicrotiter test plates; ELISA usingorthophenyldiamine as substrate.

Absorbance at490 nm

No data No data T

DNPH = 2,4-dinitrophenylhydrazine; ELISA = enzyme-linked immunosorbent assay; FID = flame ionization detector; GC = gas chromHPLC = high-performance liquid chromatography; IgE = immunoglobulin E; IgG = immunoglobulin G; MS = mass spectrometry; SD SIM = selected ion monitoring; UV = ultraviolet absorbance detection
FORMALDEHYDE 320

6. ANALYTICAL METHODS

6.2 ENVIRONMENTAL SAMPLES

Methods for the determination of formaldehyde in environmental samples are given in Table 6-2. 

Formaldehyde in air can be trapped using impingers filled with water (Fan and Dasgupta 1994;

Hoogenboom et al. 1987; Petreas et al. 1986); an aqueous solution of sodium bisulfite (NIOSH 1989a;

Petreas et al. 1986); an acidic, aqueous solution of 2,4-dinitrophenylhydrazine (DNPH) (EPA 1988d); or

buffered Girard T reagent (NIOSH 1989b). Formaldehyde released into air from textiles has been

collected onto moist filter paper (Naruse et al. 1995). Cofer and Edahl (1986) have reported a sampling

device that uses a nebulization/reflux approach that is essentially a modification of the impinger device

capable of collecting samples at high flow rates (7–8 L/minute). Formaldehyde trapped into water or

aqueous bisulfite is subjected to chemical derivatization prior to analysis (see below). Formaldehyde

collected into water has been shown to degrade rapidly (a 50% loss in 50 hours) upon ambient and

refrigerated storage (Daggett and Stock 1985) while those samples in bisulfite are stable for periods

ranging from 1 week (Daggett and Stock 1985) to 4 weeks (Balmat and Meadows 1985). The method of

EPA (1988d) traps the formaldehyde as it reacts with DNPH to form the 2,4-dinitrophenylhydrazone

derivative. The formation of the formaldehyde dinitrophenylhydrazone has been extended to solid-phase

samplers including DNPH-coated silica (Grosjean et al. 1993; Millipore Corporation 1992), DNPHcoated glass fiber filters (Dalene et al. 1992), and annular denuders coated with DNPH (Possanzini et al.

1987). These solid-phase samplers are much more convenient, especially for personal samples where

impinger-based devices can easily be spilled. Commercially prepared DNPH-silica cartridges are

available from Millipore Corporation (Milford, Massachusetts) and Supleco (Bellefonte, Pennsylvania). 

Nondek et al. (1991, 1992) have collected formaldehyde as dansylhydrazone through reaction of

formaldehyde as it passed through dansylhydrazine-coated porous glass particles. Yet another approach

is based on the collection of formaldehyde as its oxazolidine derivative using the polymeric sorbent

XAD-2 coated with hydroxymethyl piperidine (NIOSH 1994a). A passive collection device is also

available commercially and is based on the stabilization of formaldehyde as its adduct with sulfite after

passage of formaldehyde through a membrane (3M Company 1985). Formaldehyde adsorbed to

particulate matter has also been recovered using a water extraction of the particles prior to the formation

of the DNPH derivative (NIOSH 1994b).
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samp

Sample matrix Preparation method Analytical method

Sampledetection limit

Percentrecovery 

Air Drawing of air through two impingers in series each of

which contains 1% sodium bisulfite. Addition ofchromotropic acid and concentrated sulfuric acid,heating to 95 EC for 15 minutes, cooling to roomtemperature (Method 3500).

Absorbance at580 nm

0.05 μg/m3

(0.04 ppb in 100 L sample)

No data 

Air Drawing of air through an XAD-2 sorbent coated with

10% 2-hydroxymethyl piperidine, elution of theoxazolidine derivative with toluene (Method 2541).

GC/FID (can useGC/NPD forimproved sensitivity)

0.028 mg/m3

(23 ppb in 36 L sample)

No data 

Air particulates(textile or wood)

Drawing of air through 25 mm PVC filter (5 μm poresize), extraction of formaldehyde from particulates intowater, derivatization with 2,4-dinitrophenylhydrazine(Method 5700).

HPLC/UV 0.076 μg/m3

(0.062 ppb)

96 (1.1% 7 μg/sam

Air Drawing of air through a midget bubbler containing 15

mL buffered (pH = 4.5) Girard T reagent (NIOSH3501).

DC polarography 0.3 mg/m3 

(0.24 ppm)

100 

Air Preparation of passive monitor (3M 3721),

formaldehyde in air diffuses through a membrane andadsorbs onto bisulfite-impregnated paper, desorptionwith water, addition of chromotropic acid andconcentrated sulfuric acid.

Absorbance at580 nm

<34 μg/m3

(<0.028 ppm)

100 (±5%

Air Drawing of sample through impinger containing 2N

HCL/0.05% 2,4-dinitrophenylhydrazine and isooctane;removal of isooctane layer, extraction of aqueous layerwith 70/30 hexane/ methylene chloride, combining oforganic layers and evaporation of solvent;redissolution in methanol (TO5-1).

HPLC/UV 1.2–2.4 μg/m3

(1–2 ppb)

>75 (15–20% 

Air Drawing of air through DNPH-coated silica SPE,

elution with acetonitrile.

HPLC/UV 0.49 μg/m3

(0.40 ppb)

96 (7.1% 
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample matrix Preparation method Analytical method

Sample detectionlimit

Percent r

Air Drawing of air through DNPH-coated silica; elution

with acetonitrile.

HPLC/UV <1.2 μg/m3

(< 1 ppb) 

>95 forsampling up to 2 L

Air(tropospheric)

Drawing of filtered air through a nebulization/refluxconcentrator (scrubber) at rate of 7–8 L/min whereformaldehyde is reacted to form DNPH derivative. 

HPLC/UV 0.12 μg/m3

(0.1 ppb) 

90–96 

Air Drawing of air through impinger filled with 1%

sodium bisulfite; addition of CTA, concentratedsulfuric acid; equilibration for 1 hour.

Absorbance at580 nm

No data 98.7±4.7 

Air Drawing of air through impinger containing water;

addition of pararosaniline (PRA) hydrochloride,sodium sulfite, and equilibration for 60 minutes atroom temperature.

Absorbance at570 nm

No data 91.9±6.9 

Air Drawing of air through glass fiber filter impregnated

with DNPH. After collection, elution of derivativewith acetonitrile and elution through a cation exchangecolumn to remove excess reagent; evaporation ofsolvent and redissolution in toluene containing internalstandard.

GC/TSD 10 μg/m3

(8.1 ppb)

92 at 600 (5% RSD

Air Drawing of air through tube that contains a smaller,

concentric tube made of Nafion (semipermeable)through which water flows in the opposite directionand serves to trap formaldehyde; addition of 1,3-cyclohexanedione, in acidified ammonium acetate to formdihydropyridine derivative in flow injection analysissystem.

Fluorescence (FIA) 0.011 μg/m3

(9 ppt)

.50 (%R0.07 ppb 1.5%)

Air Drawing of air through impingers containing pH 7

phosphate buffer and EDTA; addition of bisulfite,reaction of excess bisulfite with 5,5'-dithiobis(2-nitrobenzoic acid) (indirect measure of formaldehyde).

Absorbance at412 nm

12 μg/m3

(0.01 ppm in 88 L)

99.9 (1.7% RS
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample matrix Preparation method Analytical method

Sample detectionlimit

Percent r

Air Drawing of air through microcartridges packed with

porous glass particles impregnated withdansylhydrazine; cartridge placed in-line with HPLC

mobile phase.

onlineHPLC/Fluorescence

0.01 μg/L(0.01 ppb in 1 L)

No data 

Air (off-gassingfrom textiles)

Placement of filter paper moistened with distilledwater into a vial and incubation of the open vial withtextiles at 40EC for 24 hours in 12.7 L chamber;addition to vial of solution containing ammoniumacetate, water, acetic acid, and acetylacetone andincubation at 40EC for 30 min.

Absorbance at 414nm

< 15 ppm No data 

Atmosphericwater

Reaction of formaldehyde in water with ammoniumacetate and 2,4-pentanedione in FIA system to form

3,5-diacetyl-1,4-dihydrolutidine.

FIA/fluorescence 3 μg/L 

(3 ppb)

No data 

Drinking water Reaction of 1 L water with DNPH in 2M acid,

extraction with chloroform, solvent exchange tomethanol.

HPLC/UV 20 μg/L 

(20 ppb)

>90 at 20μg/L

Drinking water Buffering a volume of water to pH 3 followed by

derivatization at 40 EC for 1 hour with DNPH.Derivative recovered using C18 SPE and elution with

methanol (Method 554).

HPLC/UV 8.1 μg/L 96 (7.9% 

at 250 μg

Fog water Free formaldehyde: addition of 200 μL of DNPH

solution in 2N HCl was added to 200 μL of samplefollowed by addition of 400 μL of iso-octane andreaction for 45 minutes; direct analysis of an aliquot oforganic layer. Total formaldehyde: addition of NaOHto increase pH to 13 to decompose formaldehydebilsulfite adduct followed by addition of DNPH in 2.7N HCl and isooctane; direct analysis of an aliquot ofthe organic layer. 

HPLC/UV 3 μM 

(90 ppb)

No data(analyticvariabilitas ±1 μM
Table 6-2. Analytical Methods for Determining Formaldehyde in Environmental Samples (co

Sample matrix Preparation method Analytical method

Sample detectionlimit

Percent r

Maple syrup Distillation of 3 mL of water from 20 g of sample,

addition of Nash reagent (ammonium acetate, aceticacid, acetyl acetone) followed by heating for 30minutes at 37 EC (Method 964.21).

Absorbance at415 nm.

<1 ppm(<1 mg/L)

No data 

Milk Addition of acidified DNPH and hexane to 2 mL of

sample, reaction with stirring for 30 minutes at roomtemperature; filtration through Celite, washing withhexane; evaporation of solvent; redissolution inacetonitrile.

HPLC/UV Estimated at

0.009 mg/kg(9 ppb)

89.9±3.9(0.1 μg/m

Fish flesh Heating of 100 g of fish to 200 EC and purging of

volatiles through two impingers in series, eachcontaining cysteamine solution; equilibration for 30minutes to form thiazolidine derivative; extraction withmethylene chloride, cleanup using silica-gel; additionof internal standard.

GC/NPD 5.8 pg (for GC

detection only;not a methodLOD)

No data 

Coffee Addition of 0.75 g cysteamine to 250 mL of brewed or

reconstituted instant coffee to liquid-liquid continuousextractor; adjustment of pH to 8 and extraction with70 mL chloroform for 3 hours; removal of water usingsodium sulfate, addition of internal standard, volumeadjustment.

GC/NPD No data >100 at 1 

CTA = chromotropic acid; DNPH = 2,4-dinitrophenylhydrazine; EDTA = ethylene diaminetetraacetic acid; FIA = flow injection analysis; GC = gas cHPLC = high-performance liquid chromatography; LOD = level of detection; NPD =nitrogen-phosphorus detector; PRA = pararosaniline; RSD = rela

SPE = solid phase extraction; TSD = thermionic specific detection; UV = ultraviolet absorbance detection
FORMALDEHYDE 325

6. ANALYTICAL METHODS

Most of the measurement methods reported rely on spectrophotometry or chromatography, either GC or

HPLC, although one of the NIOSH methods (Method 3501, NIOSH 1989b) is based on polarography. 

There are many spectrophotometric methods available. Method 3500 (NIOSH 1989a) is often used as a

reference method during the development of new methods. This method relies on the reaction of the

formaldehyde-bisulfite adduct with chromotropic acid (4,5-dihyroxynaphthalene-2,7-disulfonic acid) in

the presence of concentrated sulfuric acid to form a highly colored product that is measured by its

absorbance at 580 nm. Phenols in 8-fold excess over formaldehyde produce a -10 to -20% bias; small

negative interferences can also result from ethanol and higher molecular-weight alcohols, olefins,

aromatic hydrocarbons, and cyclohexanone (NIOSH 1989a). Little interference is seen from other

aldehydes. 

The method of Fan and Dasgupta (1994) relies on the reaction of formaldehyde with 1,3-cyclohexanedione in acidified ammonium acetate to form the fluorescent dihydropyridine derivative in a flow

injection analysis system. Formaldehyde trapped in water can be reacted with pararosaniline and sodium

sulfite under mild conditions (neutral pH, room temperature equilibration) to produce a colored product

that is measured at 570 nm (Petreas et al. 1986). The presence of bisulfite is an interference in this

reaction so the method cannot be used to sample atmospheres that contain sulfur dioxide. In addition, the

method is reported to suffer from interferences resulting from the presence of other aldehydes and phenol

(Hoogenboom et al. 1987). The indirect method of Hoogenboom et al. (1987) relies on the reaction of

excess bisulfite in an aqueous solution of formaldehyde with 5,5'-dithiobis(2-nitrobenzoic acid) to form a

colored product, the absorbance of which is measured at 412 nm. The method reported by Naruse et al.

(1995) relies on the formation of a colored product obtained by reacting the aqueous formaldehyde with

acetylacetone and ammonium acetate in acetic acid. Absorbance is measured at 414 nm.

The separation of dinitrophenylhydrazones using HPLC and absorbance detection is widely used for the

measurement of formaldehyde and other carbonyl compounds (EPA 1988d; Grosjean et al. 1993;

Millipore Corporation 1992; NIOSH 1994b). The reactivity of carbonyl compounds other than

formaldehyde with DNPH requires the use of a chromatographic method to resolve the derivatives of the

other compounds from that of formaldehyde. Ozone present in the atmosphere being sampled reacts with

DNPH and the DNPH derivative of formaldehyde (Arnts and Tejada 1989), especially when using

DNPH-coated silica gel cartridges. Ozone can be scrubbed from the sample stream by passing the air

through a copper tube coated with potassium iodide before passing the air through the DNPH-coated

silica (Millipore Corporation 1992). In some cases, the DNPH derivatives are separated using GC, but 
FORMALDEHYDE 326

6. ANALYTICAL METHODS

this mode of analysis requires an additional cleanup step to remove the excess DNPH reagent (Dalene et

al. 1992). Caution must be used to avoid exposure of DNPH-silica cartridges or eluted samples to

aldehyde and ketone sources. Laboratory air often holds high concentrations of acetone. Labeling inks,

adhesives, and packaging containers (including vials with plastic caps) are all possible sources of

contamination (Millipore Corporation 1992). Field blanks should always be used.

Methods for the collection and determination of formaldehyde in water show great similarity to those

methods for air described above. The methods of Tomkins et al. (1989) and EPA (1992b) for

formaldehyde in drinking water and the method of Facchini et al. (1990) for formaldehyde in fog water

all rely on the formation of the DNPH derivative followed by HPLC. The method of Dong and Dasgupta

(1987) relies on the reaction of formaldehyde in atmospheric water with a diketone (2,4-pentanedione)

and ammonium acetate to form a fluorescent derivative that is measured spectrophotometrically in a flow

injection analysis system.

A few methods for the determination of formaldehyde in foods were found in the literature. The method

of Kaminski et al. (1993b) for formaldehyde in milk relies on the formation of the DNPH derivative with

analysis by HPLC and absorbance detection. Formaldehyde in maple syrup (Helrich 1990) is determined

spectrophotometrically after the reaction of formaldehyde with acetyl acetone (Nash reagent or

2,4-pentanedione) in the presence of ammonium acetate in an acidic solution. Formaldehyde in fish flesh

(Yasuhara and Shibamoto 1995) and in coffee (Hayashi et al. 1986) has been determined through the

formation of the thiazolidine derivative (a reaction product of formaldehyde with cysteamine) followed

by GC in conjunction with nitrogen-phosphorus detection. Yasuhara and Shibamoto (1995) noted that

the accuracy of formaldehyde determination can be affected by the adsorption of formaldehyde onto glass

surfaces and the generation of artificial formaldehyde during heating of nitrogen-containing compounds

such as trimethylamine oxide.

Two other methods for the determination of formaldehyde in gases and liquids have been described but

are too complex, given the simplicity of the other methods available. One method is based on enzymatic

processes (Barzana et al. 1989; Ho and Richards 1990) followed by spectrophotometry; the other is based

on pH changes associated with formaldehyde metabolism by genetically altered cells (Korpan et al.

1993).
FORMALDEHYDE 327

6. ANALYTICAL METHODS

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of formaldehyde is available. Where adequate information is

not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of

research designed to determine the health effects (and techniques for developing methods to determine

such health effects) of formaldehyde.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance-specific research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Methods for the determination of formaldehyde in blood (Heck et al. 1985), breath (Lin et al.

1995), and urine (Shara et al. 1992) have been published. However, formaldehyde concentration in body

fluids or expired air is not expected to be a reliable biomarker of exposure, even for acute exposure,

because of its high reactivity and rapid metabolism. Methods for the detection of formate, the principal

metabolite of formaldehyde, in urine are also available, but urinary levels of formate did not appear to be

consistently associated with exposure levels in studies of students exposed to formaldehyde in anatomy

laboratories (Einbrodt et al. 1976; Gottschling et al. 1984). One plausible contributing factor to the lack

of consistency in the use of formate concentrations as a measure of exposure is that the metabolism of

other chemicals can lead to the formation of formate. Further research to increase the sensitivity or

reliability of methods to quantify formaldehyde or formate does not seem warranted.

In contrast, DNA-protein cross links in white blood cells (Shaham et al. 1996a) and the presence of serum

IgG antibodies to formaldehyde conjugated to human serum albumin (Carraro et al. 1997) are 
FORMALDEHYDE 328

6. ANALYTICAL METHODS

potentially useful biomarkers of intermediate- or chronic-duration exposure to formaldehyde that may be

developed further with additional research.

Methods to detect DNA-protein cross links have been published (Cohen et al. 1990; Shaham et al. 1996a;

Zhitkovich and Costa 1992) that reportedly have greater sensitivity than earlier methods that relied on

alkaline elution techniques (Brutlag et al. 1969). Although the formation of DNA-protein cross links is

not specific to formaldehyde (i.e., other agents can form them), Shaham et al. (1996a) demonstrated that

cultured human white blood cells showed increasing quantities of DNA-protein cross links when cultured

in media with increasing formaldehyde concentrations and that a small group of formaldehyde-exposed

persons had a significantly greater mean amount of DNA-protein cross links in their white blood cells

than did a group of non-exposed persons. Additional research to apply these methods to larger groups of

occupationally exposed and non-exposed persons may help to determine the reliability of this variable as

a biomarker of exposure and to determine the extent to which individuals vary in this response to

formaldehyde. Additional research to apply the DNA-protein cross link methods to nasal biopsy

specimens may lead to an increased sensitivity of this potential biomarker of exposure and effect.

Carraro et al. (1997) developed an indirect competitive immunoenzyme assay to detect serum IgG

antibodies against formaldehyde conjugated to human serum albumin. This technique was used to

compare the presence or absence of the antibodies in 219 healthy subjects who differed in smoking habits

(tobacco smoke is a significant source of formaldehyde exposure) and occupational exposure to

formaldehyde. The indirect competitive immunoenzyme assay was developed and applied as a qualitative

method. Additional research is needed to determine if the method can be modified to provide a reliable

and precise measure to quantify exposure level or exposure duration.

Effect. As discussed in the previous section, DNA-protein cross links and anti-formaldehyde-human

serum albumin IgG antibodies are potential biomarkers of effect and exposure. Whereas detection of

these biomarkers can represent biological responses to repeated exposure to formaldehyde (the first is not

specific to formaldehyde, but the second is), it is uncertain to what degree their detection indicates that

adverse health effects will occur. Further research on relationships between formaldehyde-induced upper

respiratory tract tissue damage and/or dysfunction and: (1) DNA-protein cross links in either white blood

cells or nasal biopsy tissue; or (2) levels of formaldehyde-specific IgG antibodies may help in

determining if improved detection methods are needed. 
FORMALDEHYDE 329

6. ANALYTICAL METHODS

Various methods have been published to examine nasal lavage fluid for cellular and chemical contents

that may be indices of acute allergic or inflammatory responses to formaldehyde or other respiratory

irritants (Pin et al. 1992; Prat et al. 1993; Wang et al. 1995). Increased eosinophil concentration and

increased albumin and total protein levels have been found in nasal lavage fluid taken from subjects

exposed to 0.4 ppm formaldehyde for 2 hours (Krakowiak et al. 1998; Pazdrak et al. 1993). Although

these variables are not expected to be specifically influenced by formaldehyde, they appear to provide

biomarkers of acute respiratory irritation from airborne formaldehyde or other upper respiratory irritants. 

Further research on relationships between concentrations of these variables in nasal lavage fluid and

prevalence or severity of respiratory symptoms in humans exposed acutely to varying concentrations of

formaldehyde may help to confirm their use as biomarkers of effect. 

Histological changes in nasal biopsy tissue samples have been observed in several cross-sectional studies

of formaldehyde-exposed and non-exposed workers (Ballarin et al. 1992; Boysen et al. 1990; Edling et al.

1988; Holmstrom et al. 1989c). Each of these studies used a morphological grading method that assigned

an increasing point value for histological changes ranging in severity from loss of ciliated cells to the

presence of malignant cells. Prevalence of different types of changes and mean histological scores were

compared between exposed and non-exposed groups. As with the use of cellular and biochemical

changes in nasal lavage fluid, the changes are not expected to be only due to formaldehyde, but appear to

provide biomarkers of upper respiratory tract tissue damage. Further research on the possible progression

of nasal tissue damage in workers with increasing duration of exposure may help in determining if

methods for detecting and quantifying nasal epithelial tissue damage need further improvement.

Methods for Determining Parent Compounds and Degradation Products in Environmental

Media. Methods are available for the determination of formaldehyde in air, water, and a limited

number of foods. Regarding methods for air, very low limits of detection (LODs) are possible. The

chromotropic acid method (NIOSH 3500) (NIOSH 1989a) has an LOD of 0.04 ppb. Typical LODs

possible using dinitro phenyl hydrazine (DNPH) derivatization, either from an impinger-based sample

collection procedure or through derivatization on DNPH-coated silica, are 1–2 ppb (EPA 1988d), 0.4 

ppb (Grosjean et al. 1993), and less than 1 ppb (Millipore Corporation 1992). Other methods that 

form fluorescent derivatives, such as the method of Nondek et al. (1992), can provide greater sensitivity 

(LOD reported to be 0.01 ppb) and are applicable; however, they require specialized equipment 

not available in most laboratories. Assuming an intermediate inhalation exposure minimal 
FORMALDEHYDE 330

6. ANALYTICAL METHODS

risk level (MRL) of 0.01 ppm, all of the above methods are adequate. If a chronic-duration inhalation

MRL of 0.0008 ppm (0.8 ppb) is assumed, the methods of NIOSH (1989a), Grosjean et al. (1993), and

Nondek et al. (1992) are adequate. For monitoring of air, formaldehyde concentrations at the

intermediate (0.01 ppm) and acute (0.05 ppm) MRLs, the above methods, in addition to those of

Millipore Corporation (1992) and EPA (1988d), are adequate. No additional methods for formaldehyde

in air are needed.

Methods for the determination of formaldehyde in drinking water are available and they utilize the same

detection methods as those utilized for the analysis of formaldehyde in air, with LODs reported to be

20 ppb (Tomkins et al. 1989) and 8.1 ppb (EPA 1992b). The MRL for chronic oral exposure to

formaldehyde is 0.2 mg/kg/day. If a 70-kg person is assumed, the maximum intake is 14 mg/day. If a

daily intake of 2 L of water or 2 kg/day of food per day is assumed, then any analytical method must have

an LOD of less than 7 mg/L for water or 7 mg/kg (ppm) for food. The cited methods for detecting

formaldehyde in water have LODs far below the needed value and are sensitive enough to measure

background levels in the environment; no additional methods for formaldehyde detection in water are

required. Other than for milk (Kaminski et al. 1993b, LOD=9 ppb), no methods for formaldehyde

detection in food were found. Additional methods for detection of formaldehyde in foods are needed. 

Methods for the detection of formaldehyde in soil are not adequately described in the available literature.

6.3.2 Ongoing Studies

The Environmental Health Laboratory Sciences Division of the National Center for Environmental

Health, Centers for Disease Control and Prevention, is developing methods for the analysis of

formaldehyde and other volatile organic compounds in blood. These methods use purge and trap

methodology, high resolution gas chromatography, and magnetic sector mass spectrometry which gives

detection limits in the low-parts-per-trillion (ppt) range.

The information in Table 6-3 was found as a result of a search of Federal Research in Progress (FEDRIP

1996). 
FORMALDEHYDE 331

6. ANALYTICAL METHODS

Table 6-3. Ongoing Studies on Formaldehyde

Investigator Affiliation Research description Sponsor

Creighton University Studying products of altered

lipid metabolism, including

formaldehyde, associated with

exposures to TCDD, endrin,

and lindane in pregnant mice. 

Specifically, they are

concerned with the exposures

of the fetus to these products

and will be determining

formaldehyde concentrations

in maternal serum and

amniotic fluid.

NIEHS

Albion Instruments Salt Lake City,

UT

Investigating the utility of

solid-state lasers for

monitoring escaped clinical

gases.

DHHS

Spectral Sciences, Inc. Burlington, MA Development of diode laserbased remote monitoring of

trace gas concentrations over

long open-air paths.

The target analytes include

those covered by the Clean

Air Act (CAA), formaldehyde

among them. 

DOE

Southwest Sciences Santa Fe, NM Diode laser-based sensors for

gases, including

formaldehyde, in harsh hightemperature, high-pressure

environments.

DOE

DHHS = Department of Health and Human Services; DOE = Department of Energy; NIEHS = National

Institute of Environmental Health

FORMALDEHYDE 333

7. REGULATIONS AND ADVISORIES

The international, national, and state regulations and guidelines regarding formaldehyde in air, water, and

other media are summarized in Table 7-1.

ATSDR has derived an acute inhalation MRL of 0.04 ppm on the basis of clinical symptoms (increased

itching, sneezing, mucosal congestion, transient burning sensation of the eyes and of the nasal passages)

and nasal alterations (elevated eosinophil counts and a transient increase in albumin content of nasal

lavage fluid) in humans (Pazdrak et al. 1993). This MRL is based on a minimal LOAEL of 0.4 ppm and

an uncertainty factor of nine (three for use of a minimal LOAEL and three for human variability).

An intermediate-duration inhalation MRL of 0.03 ppm was derived based on a NOAEL of 0.98 ppm and

a LOAEL of 2.95 ppm (22 hours/day, 5 days/week for 26 weeks) for clinical signs of nasopharyngeal

irritation (hoarseness and nasal congestion and discharge) and lesions in the nasal epithelium (squamous

metaplasia and hyperplasia) observed in monkeys (Rusch et al 1983). An uncertainty factor of 30 (3 for

extrapolation from animals to humans and 10 for human variability) was used to derive the MRL. 

A chronic inhalation MRL of 0.008 ppm was derived based on a minimal LOAEL of 0.24 ppm for

histological evidence of mild damage to the nasal epithelial tissue (squamous metaplasia, loss of ciliated

cells, goblet cell hyperplasia, and mild dysplasia in biopsied tissue) in formaldehyde exposed chemical

workers (Holmstrom et al. 1989c). To derive the MRL, the minimal LOAEL was divided by an

uncertainty factor of 30 (3 for the use of a minimal LOAEL and 10 for human variability). 

An intermediate oral MRL of 0.3 mg/kg/day was based on a NOAEL and LOAEL of 25 and

125 mg/kg/day for gastrointestinal tract effects in rats exposed for 4 weeks to formaldehyde in drinking

water (Til et al. 1988b). An uncertainty factor of 100 (10 for extrapolation from animals to humans and

10 for human variability) was applied to the NOAEL to derive the MRL.

ATSDR derived a chronic oral MRL of 0.2 mg/kg/day based on a NOAEL and LOAEL of 15 and

82 mg/kg/day for gastrointestinal tract effect in rats exposed for up to 2 years to formaldehyde in drinking

water (Til et al. 1989). An uncertainty factor of 100 (10 for extrapolation from animals to humans and 10

for human variability) was applied to the NOAEL to derive the MRL.
FORMALDEHYDE 334

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde

Agency Description Information References

INTERNATIONAL

Guidelines:

IARC Carcinogenic classification Group 2Aa IARC 1995

WHO Drinking-water guideline values for

health-related organics

None WHO 1984

NATIONAL

Regulations:

a. Air:

OSHA Permissible Exposure Limit (PEL) 

8-hr. Time weighted average (TWA)

15-min. Short-term exposure limit

(STEL)

0.75 ppm

2 ppm

29 CFR 1910.1048

OSHA 1992

EPA-OAR Hazardous Air Pollutants Yes Clean Air Act

Amendment Title

III, Section 112 (b)

U.S. Congress 1990

Standards of Performance for New

Stationary Sources

Equipment Leaks of VOCs in the

Synthetic Organic Chemicals

Manufacturing Industry (SOCMI)

Yes 40 CFR 60.489

EPA 1983a

VOC Emissions from SOCMI Air

oxidation unit processes-chemicals

affected

Yes 40 CFR 60.617

EPA 1990a

VOC Emissions from SOCMI

Distillation operation-chemical

affected

Yes 40 CFR 60.667

EPA 1990b

VOC Emissions from SOCMI Reactor

processes-chemicals affected

Yes 40 CFR 60.707

EPA 1993a

National Emission Standards for

Organic Hazardous Air Pollution from

the Synthetic Organic Chemical

Manufacturing Industry-Delegation of

Authority

Yes 40 CFR 63.106

EPA 1994a

Chemical Accident Prevention

Provisions-Regulated Toxic Substances

and Threshold Quantities for

Accidental Release PreventionFormaldehyde Solution

15,000 pounds 40 CFR 68.130

EPA 1994b

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

NATIONAL (cont.)
FORMALDEHYDE 335

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

EPA-OAR Regulation of Fuels and Fuel AdditivesReformulated Gasoline-Simple

Emission Model

Yes 40 CFR 80.42 

EPA 1994c

Complex emissions models; baseline

exhaust emission

Phase I

Summer Winter

 (mg/mile) 

4.85 7.27

Phase II

Summer Winter

 (mg/mile) 

9.38 15.84

40 CFR 80.45

EPA 1994d

Vehicle test procedures Yes 40 CFR 80.51

EPA 1994e

Measurement methods for

formaldehyde and actelaldehyde

Yes 40 CFR 80.56

EPA 1994f

Conventional gasoline baseline

emissions determinations

Yes 40 CFR 80.90

EPA 1994g

Control of Air Pollution from New and

In-use Motor Vehicles and New and Inuse Motor Vehicle EnginesCertification and Test Procedures

Yes 40 CFR 86

EPA 1977a

NESHAP for Source Category; Pulp

and Paper Production (proposed rule)

Yes 58 FR 66078

EPA 1993b

List of Regulated Substances and

Thresholds for Accidental Release

Prevention (proposed rule)

500 pounds

(threshold)

58 FR 5102

EPA 1993c

Control of Air Pollution from New and

In-use Motor Vehicles and engines;

Technical Amendments to the Test

Procedures for Methanol-fueled Motor

Vehicles and Motor Vehicle Engines

and Petroleum-fueled Motor Vehicles

(proposed rule)

Yes 58 FR 11816

EPA 1993d

HAP: Proposed Regulations Governing

Constructed, Reconstructed or Modified

Major Sources (proposed rule)

Yes 59 FR 15504

EPA 1994h

b. Water

EPA-OW Designation of Hazardous SubstancesList of Hazardous Substances, Table

116.4

Yes 40 CFR 116.4

EPA 1978

NATIONAL (cont.)
FORMALDEHYDE 336

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

Determination of Reportable Quantities

for Hazardous Substances- RQ Pursuant

to Section 311 CWA, Table 117.3

100 pounds 40 CFR 117.3

EPA 1985b

EPA Permit Programs: NPDES-Toxic

Pollutants and Hazardous Substances

Required to be Identified by Existing

Dischargers if Expected to be Present,

Table V

Yes 40 CFR 122, App.

D

EPA 1983b

Criteria and Standards for the NPDESInstructions for Form 2C, Application

for Permit to Discharge Wastewater

Yes 40 CFR 125

EPA 1984

Organic Chemicals, Plastics, and

Synthetic Fibers

Commodity organic chemicals

(applicability)

Yes 40 CFR 414.60

EPA 1987a

c. Food:

FDA Indirect Food Additives: Adhesives and

Components of Coatings

Yes 21CFR 175.105

FDA 1977a

Indirect Food Additives: Paper and

Paperboard

Components of paper and paperboard

in contact with aqueous and fatty

foods

Yes 21 CFR 176.170

FDA 1977 b

Components of paper and paperboard

in contact with dry food

Yes 21 CFR 176.180

FDA 1977c

d. Other:

EPA-OERR List of Hazardous Substances and

Reportable Quantities

1000 pounds

(453.6 kg)

(statutory)

100 pounds

(45.4 kg)

(final RQ)

40 CFR 302.4

EPA 1985a

EPA-OSW Identification and Listing of Hazardous

Waste

Definition of a Hazardous Waste Yes 40 CFR 261.3

EPA 1992a

Discarded commercial chemical

products, off-specification, container

residues, and spills

Yes 40 CFR 261.33

EPA 1980
FORMALDEHYDE 337

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

NATIONAL (cont.)

Basis for listing hazardous wastesconstituent for listing (K010)Yes 40 CFR 261, App.

VII

EPA 1981

Basis for listing - hazardous

constituent (U122)

Yes 40 CFR 261, App.

VIII

EPA 1988b

Standards for Management of Specific

Hazardous Wastes Facilities

Regulation of residues Yes 40 CFR 266.112

EPA 1985c

Methods Manual for Compliance

with BIF Regulations (Method

0011A, Analysis of Aldehydes and

Ketones by High Performance Liquid

Chromatography)

Yes 40 CFR 266, App.

IX

EPA 1991b

Land Disposal Prohibition and

Establishment of Treatment StandardsWaste to be evaluated by 8/8/88

Yes 40 CFR 268.10

EPA 1986a

Treatment Standards-Applicability Yes 40 CFR 268.4

EPA 1987b

Emergency Planning and NotificationExtremely Hazardous Substances and

Their Threshold Planning Quantities

100 pounds

 (RQ)

500 pounds

(threshold)

40 CFR 355, App.

A

EPA 1987c

Toxic Chemical Release Reporting: 

Community Right-to-Know--Specific

Chemical Listing-Chemicals and

Chemical Categories

Yes 40 CFR 372.65 

EPA 1988c

Hazardous Waste Management System;

Carbamate Production Identification

and Listing of Hazardous Waste and

CERCLA Hazardous Substance

Designation and Reportable Quantities

(notice of proposed rulemaking-K157

waste)

1 pound

(statutory RQ)

59 FR 9808 

EPA 1994i

Land Disposal Restrictions for Newly

Identified and Listed Hazardous Wastes

and Hazardous Soil

Yes 62 FR 7502

EPA 1997
FORMALDEHYDE 338

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

NATIONAL (cont.)

Treatment standards, U122 waste Wastewater 

WETXO or CHOXD;

CARBN; or INCIN

 Nonwastewater 

CMBST

Guidelines:

a. Air:

ACGIH Ceiling Limit for Occupation Exposure

(TLV-STEL)

0.3 ppm

(0.37 mg/m3

)

ACGIH 1998

NIOSH Recommended Exposure Limit for

Occupation Exposure (8-hr TWA)

0.016 ppm NIOSH 1992

Recommended Exposure Limit for

Occupation Exposure (15-min Ceiling)

0.1 ppm

Immediately Dangerous to Life and

Health

20 ppm

b. Water:

EPA 1-d Health Advisory (child)-draft 10 mg/L EPA 1995; IRIS

1999

10-d Health Advisory (child)-draft 5 mg/L

Lifetime Health Advisory (adult)-draft 1 mg/L

Longer-term Health Advisory-draft 5 mg/L (child)

20 mg/L (adult)

d. Other:

ACGIH

Group (Cancer Ranking) A2b ACGIH 1998

EPA Cancer Classification B1c IRIS 1999

RfD 0.2 mg/kg/day

NIOSH Cancer Classification Cad NIOSH 1992,

1994c

STATE

Regulations and Guidelines:

a. Air: Average Acceptable Ambient Air

Concentrations

EPA 1992c

AZ 1 hour 2x101

 μg/m3

24 hours 1.2x101 μg/m3
FORMALDEHYDE 339

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

STATE (cont.)

Annual 8x10-2 μg/m3

CT 8 hours 1.2x101 μg/m3

FL-FtLdle 8 hours 1.5x10-2 μg/m3

FL-Pinella 8 hours 4.5 μg/m3

24 hours 1.8 μg/m3

Annual 7.7x10-2 μg/m3

IN 8 hours 6 μg/m3

Annual 7.7x10-2 μg/m3

IN-Innap 8 hours 1.8x101 μg/m3

KS Annual 7.69x10-2 μg/m3

KS-KC Annual 7.69x10-2 μg/m3

LA Annual 7.69 μg/m3

MA 24 hours 3.3x10-1 μg/m3

Annual 8x10-2 μg/m3

ME 15 minutes 6.7x101 μg/m3

1 year 4x10-2 μg/m3

MI Annual 8x10-2 μg/m3

NC 15 minutes 1.5x10-1 μg/m3

NC-Forco 15 minutes 1.5x101 μg/m3

ND NA BACT

NV 8 hours 7.1x10-2 μg/m3

NY 1 year 5x10 μg/m3

OK 24 hours 1.2x101 μg/m3

PA-Phil 1 year 7.2 μg/m3

Annual 4.82 ppb

SC 24 hours 7.5 μg/m3

SD 8 hours 1.2x101 μg/m3

TX 30 minutes 1.5x101 μg/m3

Annual 1.5 μg/m3

VA 24 hours 1.2x101 μg/m3

VT Annual 8x10-2 μg/m3

WA-Olympia 5x10-2 ppm

STATE (cont.)
FORMALDEHYDE 340

7. REGULATIONS AND ADVISORIES

Table 7-1. Regulations and Guidelines Applicable to Formaldehyde (continued)

Agency Description Information References

WA-SWEST Annual 7.7x10-2 μg/m3

b. Water

Water Quality Criteria: Human Health

CA Drinking water (guideline) 30 μg/L FSTRAC 1995

MD Drinking water (guideline) 10 μg/L

ME Drinking water (guideline) 30 μg/L

NJ Drinking water (guideline) 100 μg/L

a

 2A = probable human carcinogen c B1 = probable human carcinogen b

 A2 = suspected human carcinogen d Ca = potential occupational carcinogen

BACT = Best Available Control Technology; BIF = Boilers and Industrial Furnaces; CARBN = Carbon adsorption; CERCLA =

Comprehensive Environmental Response, Compensation, and Liability Act; CHOXD = Chemical or electrolytic oxidation;

CMBST = Combustion; CWA = Clean Water Act; EPA = Environmental Protection Agency; FDA = Food and Drug

Administration; FSTRAC = Federal State Toxicology and Regulatory Alliance committee; FSUBS = Fuel Substitution; HAP =

Hazardous Air Pollutants; IARC = International Agency for Research on Cancer; INCIN = Incineration; MCLG = Maximum

Contaminant Level Goal; NA = not applicable; NAS = National Academy of Sciences; NESHAP= National Emission Standards

for Hazardous Air Pollutants; NIOSH = National Institute of Occupational Safety and Health; NPDES = National Pollution

Discharge Elimination System; OAR - Office of Air and Radiation; ODW = Office of Drinking Water; OERR = Office of

Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes;

OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; RCRA = Resource Conservation and Recovery Act; RfD

= Reference Dose; RQ = Reportable Quantities; SOCMI = Synthetic Organic Chemicals Manufacturing Industry; STEL = Shortterm exposure Limit; TLV= Threshold Limit Value; TWA = Time-weighted Average; VOC = Volatile Organic Compound;

WHO = World Health Organization; WETOX = Wet Air Oxidation

No acute-duration oral MRL value was derived for formaldehyde. A more detailed discussion of MRLs

for formaldehyde is presented in Section 2.5 and in Appendix A of this profile.

The EPA oral reference dose (RfD) for formaldehyde is 0.2 mg/kg/day for causing gastrointestinal

damage. No reference concentration (RfC) was reported for the compound (IRIS 1999).

The National Toxicology Program (1998) noted that formaldehyde is reasonably anticipated to be a

human carcinogen. The International Agency for Research on Cancer (IARC) has classified

formaldehyde as 2A, probably carcinogenic to humans, based on limited evidence of carcinogenicity in

humans and sufficient evidence of carcinogenicity in animals (IARC 1995). The EPA has classified

formaldehyde as a B1 compound, probable human carcinogen based on limited evidence in humans and

sufficient evidence in animals (EPA 1991a; IRIS 1999).
FORMALDEHYDE 341

7. REGULATIONS AND ADVISORIES

Formaldehyde is on the list of chemicals subject to the requirements of “The Emergency Planning and

Community Right-to-Know act of 1986" (EPCRA) (EPA 1988a). Section 313 of Title III of EPCRA,

requires owners and operators of certain facilities that manufacture, import, process, or otherwise use the

chemicals on this list to report annually their release of those chemicals to any environmental media (U.S.

Congress 1986). 

OSHA requires employers of workers who are occupationally exposed to formaldehyde to institute

engineering controls and work practices to reduce and maintain employee exposure at or below

permissible exposure limits (PELs). The employer must use controls and practices, if feasible, to reduce

exposure to or below an 8-hour time-weighted average (TWA) of 0.75 ppm. The 15-minute, short-term

exposure limit (STEL) for formaldehyde is 2 ppm (OSHA 1992).

The EPA regulates formaldehyde under the Clean Air Act (CAA) and has designated formaldehyde as a

hazardous air pollutant (HAP). The major source category for which formaldehyde emissions are

controlled is the synthetic organic chemicals manufacturing industry (SOCMI)—equipment leaks, air

oxidation unit processes, and distillation operations (EPA 1983a, 1990a, 1990b).

Formaldehyde is regulated by the Clean Water Effluent Guidelines as stated in Title 40, Section 414, of

the Code of Federal Regulations (EPA 1987a). The point source category for which specific Regulatory

Limitations are listed is the waste water discharge from the manufacture of formaldehyde as a commodity

organic chemical (EPA 1987a). The Resource Conservation and Recovery Act (RCRA) identifies

formaldehyde as a toxic waste if it is discarded as a commercial product, manufacturing intermediate, or

off-specification commercial chemical product. Formaldehyde is assigned the hazardous waste

number, U122 (EPA 1980).

Under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA),

owners of vessels or facilities are required to immediately report release of formaldehyde equal to or

greater than the reportable quantity of 100 pounds (45.4 kg) (EPA 1985a). When formaldehyde is used as

a post-harvest fungicide for various raw agricultural commodities that are used only as animal feed (e.g.,

barley, corn, rye grass soybean hay, and oats), the Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA) exempts formaldehyde from the tolerance requirement for residues in or on the commodity

(EPA 1975).
FORMALDEHYDE 342

7. REGULATIONS AND ADVISORIES

The Food and Drug Administration (FDA) identifies formaldehyde as an indirect food additive for use

only as a component of adhesives (FDA 1977a). When used in accordance with specified conditions, the

food additive formaldehyde may be safely used in the manufacture of animal feeds (FDA 1976).
FORMALDEHYDE 343

8. REFERENCES

3M Company. 1985. Organic vapor method no. 4D. 3M Company Occupational Health and Safety

Products Laboratory. May 1985.

*Aaron CK, Howland MA. 1994. Goldfrank's Toxicological emergencies. Norwalk, CT: Appleton and

Lange.

Abbott FV, Franklin KB, Libman RB. 1986. A dose-ratio comparison of Mu and Kappa agonists in

formalin and thermal pain. Life Sci 39:2017-2024.

Abbott FV, Hong Y, Blier P. 1997. Persisting sensitization of the behavioural response to formalininduced injury in the rat through activation of serotonin2A receptors. Neuroscience 77:575-584.

*ACGIH. 1992. Threshold limit values for chemical substances and physical agents and biological

exposure indices. American Conference of Governmental Industrial Hygienists. Cincinnati, OH.

ACGIH. 1995. 1995-1996 Threshold limit values for chemical substances and physical agents and

biological exposure indices. American Conference of Governmental Industrial Hygienists. Cincinnati,

OH.

*ACGIH. 1998. Threshold limit values for chemical substances and physical agents and biological

exposure indices. American Conference of Governmental Industrial Hygienists. Cincinnati, OH.

*Acheson ED, Barnes HR, Gardner MJ, et al. 1984a. Formaldehyde process workers and lung cancer. 

Lancet 1:1066-1067.

Acheson ED, Gardner MJ, Pannett B, et al. 1984b. Formaldehyde in the British chemical industry. 

Lancet 1:611-616.

*Adams DO, Hamilton TA, Lauer LD, et al. 1987. The effect of formaldehyde exposure upon the

mononuclear phagocyte system of mice. Toxicol Appl Pharmacol 88:165-174.

Adams RM, Maibach HI. 1985. A five-year study of cosmetic reactions. J Am Acad Dermatol 13:1062-

1069.

*Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 

27:532-537.

Addy M, Mostafa P. 1988. Dentine hypersensitivity. I. Effects produced by the uptake in vitro of metal

ions, fluoride and formaldehyde onto dentine. J Oral Rehab 15:575-585.

*Akbar-Khanzadeh F, Mlynek JS. 1997. Changes in respiratory function after one and three hours of

exposure to formaldehyde in non-smoking subjects. Occup Environ Med 24:296-300.

*Cited in text
FORMALDEHYDE 344

8. REFERENCES

*Akbar-Khanzadeh F, Vaquerano MU, Akbar-Khanzadeh M, et al. 1994. Formaldehyde exposure, acute

pulmonary response, and exposure control options in a gross anatomy laboratory. Am J Ind Med 26:61-

75.

Akubue PI, Stohs SJ. 1993. Effect of alachlor on the urinary excretion of malondialdehyde,

formaldehyde, acetaldehyde, and acetone by rats. Bull Environ Contam Toxicol 50:565-571.

Akubue PI, Bagchi D, Ihm WJ, et al. 1994. Excretion of malondialdehyde, formaldehyde, acetaldehyde,

acetone and methyl ethyl ketone in the urine of rats given an acute dose of malondialdehyde. Arch

Toxicol 68:338-341.

*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

154:101-110.

*Alexandersson R, Hedenstierna G. 1988. Respiratory hazards associated with exposure to

formaldehyde and solvents in acid-curing paints. Arch Environ Health 43:222-227.

*Alexandersson R, Hedenstierna G. 1989. Pulmonary function in wood workers exposed to

formaldehyde: A prospective study. Arch Environ Health 44:5-11.

Alfheim JA, Langford CH. 1985. Determination of formaldehyde with the thermal lens effect. Anal

Chem 57:861-864.

Alldredge AL, Elias M, Gotschalk CC. 1986. Effects of drilling muds and mud additives on the primary

production of natural assemblages of marine phytoplankton. Mar Environ Res 19:157-176.

Aloisi AM, Zimmermann M, Herdegen T. 1997. Sex-dependent effects of formalin and restraint on CFos expression in the septum and hippocampus of the rat. Neuroscience 81:951-958.

*Altman PK, Dittmer DS. 1974. In: Biological handbooks: Biology data book. Vol. III, 2nd ed. 

Bethesda, MD: Federation of American Societies for Experimental Biology, 1987-2008, 2041.

*Altshuller AP. 1993. Production of aldehydes as primary emissions and from secondary atmospheric

reactions of alkenes and alkanes during the night and early morning hours. Atmos Environ 27:21-32.

*Amdur MO. 1960. The response of guinea pigs to inhalation of formaldehyde and formic acid alone

and with a sodium chloride aerosol. Int J Air Pollut 3:201-220.

Ancona-Alayon A, Jimenez-Castilla JL, Gomez-Alvarez EM. 1976. Dermatitis from epoxy resin and

formaldehyde in shampoo packers. Contact Dermatitis 2:356-364.

Andersen I. 1986. Effects of airborne substances on nasal function in human volunteers. In: Barrow CS,

ed. Toxicology of the nasal passages. Washington, DC: Hemisphere Publishing Corporation, 143-154.

*Andersen I, Molhave L. 1983. Controlled human studies with formaldehyde. In: Gibson JE, ed. 

Formaldehyde toxicity. Washington, DC: Hemisphere Publishing Corporation, 154-165.
FORMALDEHYDE 345

8. REFERENCES

*Andersen ME, Kirshnan K. 1994. Relating in vitro to in vivo exposures with physiologically based

tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement,

reduction, replacement. New York: Marcel Dekker, Inc., 9-25.

*Andersen ME, Clewell HJ 3rd, Gargas ML, et al. 1987. Physiologically based pharmacokinetics and

the risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87:185-205.

*Andjelkovich AA, Mathew RM, Richardson RB, et al. 1990. Mortality of iron foundry workers: I. 

Overall findings. J Occup Med 32:529-540.

Andjelkovich DA, Levine RJ. 1988. Identification of an industrial cohort and verification of its

completeness using a complicated system of plant records. Am J Ind Med 13:593-599.

*Andjelkovich DA, Janszen DB, Brown MH, et al. 1995a. Mortality of iron foundry workers: IV.

Analysis of a subcohort exposed to formaldehyde. J Occup Environ Med 37:826-837.

Andjelkovich DA, Janszen DB, Conolly RB, et al. 1995b. Formaldehyde exposure not associated with

cancer of the respiratory tract in iron foundry workers: A synopsis of CIIT epidemiologic findings. CIIT

Act 15:1-9.

Andjelkovich DA, Mathew RM, Levine RJ. 1994a. Letters to the Editor. J Occup Med 36:468.

Andjelkovich DA, Mathew RM, Yu RC, et al. 1992. Mortality of iron foundry workers. II. Analysis by

work area. J Occup Med 34:391-401.

*Andjelkovich DA, Shy CM, Brown MH, et al. 1994b. Mortality of iron foundry workers. III. Lung

cancer case-control study. J Occup Med 36:1301-1308.

Ang CC, Lipari F, Swarin SJ. 1987. Determination of hydroxymethanesulfonate in wet deposition

samples. Environ Sci Technol 21:102-105.

Anonymous. 1982. Report of the federal panel of formaldehyde. Environ Health Perspect 43:139-168.

*Anonymous. 1984a. Report on the consensus workshop on formaldehyde. Environ Health Perspect

58:323-381.

Anonymous. 1984b. Final report on the safety assessment of formaldehyde. J Am Coll Toxicol 3:157-

184.

Anonymous. 1984c. No title available. Chem Eng News 62: 13, 17-20.

*Anonymous. 1992. Production by the U.S. Chemical Industry: Chemical production held steady in

1991. Chem Eng News 70:34-40.

*Anonymous. 1993. Formaldehyde [Abstract]. Chem Ind News November-December 1993:8.

*Anonymous. 1994. Production by the U.S. Chemical Industry: Growth continues in chemical

production. Chem Eng News 72:30-36.

*Anonymous. 1995a. Production by the U.S. Chemical Industry: Production soared in most chemical

sectors. Chem Eng News 73:36-42.
FORMALDEHYDE 346

8. REFERENCES

*Anonymous. 1995b. Formaldehyde. Chem Mark Rep September 11, 1995:39-41.

*Anonymous. 1998. Formaldehyde. Chem Mark Rep June 22, 1998:49.

Apfelbach R, Reibenspies M. 1991. Olfactory learning is inhibited after low-level formaldehyde gas

exposure in the ferret [Abstract]. Chem Senses 16:498.

Apfelbach R, Weiler E. 1991. Sensitivity to odors in Wistar rats is reduced after low-level

formaldehyde-gas exposure. Naturwissenschaften 78:221-223.

Apfelbach R, Reibenspies M, Schmidt R. 1992. The effect of long-lasting formaldehyde gas exposure on

the olfactory epithelium and on the olfactory discrimination ability in the ferret [Abstract]. 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.

*Arnts RR, Tejada SB. 1989. 2,4-Dinitrophenylhydrazine-coated silica gel cartridge method for

determination of formaldehyde in air: Identification of an ozone interference. Environ Sci Technol

23:1428-1430.

Arts JHE, Dröge SCM, 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 117:229-237.

Ashby J, Lefevre P. 1983. Genetic toxicology studies with formaldehyde and closely related chemicals

including hexamethylphosphoramide (HMPA). In: Gibson JE, ed. Formaldehyde toxicity. Washington,

DC: Hemisphere Publishing Corporation, 85-97.

Ashby J, Callander RC, Rose FL. 1985. Weak mutagenicity to salmonella of the formaldehyde-releasing

anti-tumour agent hexamethylmelamine. Mutat Res 142:121-125.

*ASTER. 1995. ASTER (Assessment Tools for the Evaluation of Risk) ecotoxicity profile. Duluth,

MN: Environmental Research Laboratory, U.S. Environmental Protection Agency.

*ASTER. 1996. ASTER (Assessment Tools for the Evaluation of Risk) ecotoxicity profile. Duluth,

MN: Environmental Research Laboratory, U.S. Environmental Protection Agency.

*Atkinson R, Pitts JNJ. 1978. Kinetics of the reactions of the OH radical with HCHO and CH3CHO over

the temperature range 299-426 K. J Chem Phys 68:3581-3584.

*Atkinson R, Plum CN, Carter WPL, et al. 1984. Rate constants for the gas-phase reactions of nitrate

radicals with a series of organics in air at 298 +/- 1 K. J Phys Chem 88:1210-1215.

*ATSDR. 1989. Decision guide for identifying substance-specific data needs related to toxicological

profiles; Notice. Federal Register 54:37617-37634.

ATSDR. 1990. Biomarkers of organ damage or dysfunction for the renal, hepatobiliary, and immune

systems. Subcommittee on Biomarkers of Organ Damage and Dysfunction, Agency for Toxic Substances

and Disease Registry, Atlanta, GA.
FORMALDEHYDE 347

8. REFERENCES

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, Molhave Ll. 1990. Human performance during experimental formaldehyde

exposure. Environ Int 16:105-113.

Baez AP, Padilla HG, Belmont RD. 1993. Scavenging of atmospheric formaldehyde by wet

precipitation. Environ Pollut 79:271-275.

Bagchi D, Bagchi M, Hassoun E, et al. 1993a. Effects of carbon tetrachloride, menadione, and paraquat

on the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone in rats. J

Biochem Toxicol 8:101-106.

Bagchi D, Bagchi M, Hassoun E, et al. 1993b. Carbon-tetrachloride-induced urinary excretion of

formaldehyde, malondialdehyde, acetaldehyde and acetone in rats. Pharmacology 47:209-216.

Bagchi DE, Stohs SJB M. 1992. Endrin-induced urinary excretion of formaldehyde, acetaldehyde,

malondialdehyde and acetone in rats. Toxicology 75:81-89.

*Ballarin C, Sarto F, Giacomelli L, et al. 1992. Micronucleated cells in nasal mucosa of formaldehydeexposed workers. Mutat Res 280:1-7.

*Balmat JL, Meadows GW. 1985. Monitoring of formaldehyde in air. Am Ind Hyg Assoc J 46:578-584.

Band PR, Le ND, Fang R, et al. 1997. Cohort mortality study of pulp and paper mill workers in British

Columbia, Canada. Am J Epidemiol 146:186-194.

Banky Z, Nagy GM, Halasz B. 1994. Analysis of pituitary prolactin and adrenocortical response to

ether, formalin or restraint in lactating rats: Rise in corticosterone, but no increase in plasma prolactin

levels after exposure to stress. Neuroendocrinology 59:63-71.

Bardana EJ, Montanaro A. 1991. Formaldehyde: an analysis of its respiratory, cutaneous, and

immunologic effects. Ann Allergy 66:441-452.

*Barnes DG, Dourson M. 1988. Reference dose (RfD) description and use in health risk assessments. 

Regul Toxicol Pharmacol 8:471-486.

*Barry JL, Tome D. 1991. Formaldehyde content of milk in goats fed formaldehyde-treated soybean oilmeal. Food Addit Contam 8:633-640.

*Bartnik FG, Gloxhuber C, Zimmermann V. 1985. Percutaneous absorption of formaldehyde in rats. 

Toxicol Lett 25:167-172.

Bartone NF, Grieco RV, Herr BS. 1968. Corrosive gastritis due to ingestion of formaldehyde. JAMA, J

Am Med Assoc 203:104-105.

*Barzana E, Klibanov AM, Karel M. 1989. A colorimetric method for the enzymatic analysis of gases:

The determination of ethanol and formaldehyde vapors using solid alcohol oxidase. Anal Biochem

182:109-115.
FORMALDEHYDE 348

8. REFERENCES

*Basler A, Hude VD, Hude W, et al. 1985. Formaldehyde-induced sister chromatid exchanges in vitro

and the influence of the exogenous metabolizing systems S9 mix and primary rat hepatocytes. Arch

Toxicol 58:10-13.

Bauchinger M, Schmid E. 1985. Cytogenetic effects in lymphocytes of formaldehyde workers of a paper

factory. Mutat Res 58:195-199.

*Baumann K, Angerer J. 1979. Occupational chronic exposure to organic solvents. VI. Formic acid

concentration in blood and urine as an indicator of methanol exposure. Int Arch Occup Environ Health

42:241-249.

Beall JE. 1985. Formaldehyde in dialysis patients: A review. Adv Chem Ser 210:276-286.

Becking GC. 1995. Use of mechanistic information in risk assessment for toxic chemicals. Toxicol Lett

7:15-24.

*Bedford P, Fox BW. 1981. The role of formaldehyde in methylene dimethanesulphonate-induced DNA

cross-links and its relevance to cytotoxicity. Chem Biol Interact 38:119-126.

*Bender JR, Mullin LS, Graepel GJ, et al. 1983. Eye irritation response of humans to formaldehyde. 

Am Ind Hyg Assoc J 44:463-465.

*Benner WH, Bizjak M. 1988. Pseudo first-order reaction rate constant for the formation of

hydroxymethylhydroperoxide from formaldehyde and hydrogen peroxide. Atmos Environ 22:2603-2605.

Benyajati C, Place AR, Sofer W. 1983. Formaldehyde mutagenesis in Drosophila: Molecular analysis

of ADH-negative mutants. Mutat Res 11:1-7.

Berglund B, Nordin S. 1992. Detectability and perceived intensity for formaldehyde in smokers and

non-smokers. Chem Senses 17:291-306.

Berke JH. 1987. Cytologic examination of the nasal mucosa in formaldehyde-exposed workers. J Occup

Med 29:681-684.

Bermudez E. 1986. Assessment of genotoxic effects in rat nasal epithelium. In: Barrow CS, ed. 

Toxicology of the nasal passages. Washington, DC: Hemisphere Publishing Corporation, 275-290.

Bermudez E, Craft TR. 1987. Correlation of DNA-protein crosslinks (DPC) with cytotoxicity and

mutagenicity in formaldehyde (HCHO) treated human lymphoblasts [Abstract]. Environ Mutagen 9:14.

Bermudez E, Chen Z, Gross EA, et al. 1994. Characterization of cell lines derived from formaldehydeinduced nasal tumors in rats. Mol Carcinog 9:193-199.

Bernstein RS, Stayner LT, Elliott LJ, et al. 1984. Inhalation exposure to formaldehyde: An overview of

its toxicology, epidemiology, monitoring, and control. Am Ind Hyg Assoc J 45:778-785.

*Bertazzi PA, Pesatori A, Guercilena S, et al. 1989. Rischio cancerogeno per I produttori di resine

esposti a formaldeide: Estensione del follow-up. Med Lav 80:111-122. (Italian)

*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.
FORMALDEHYDE 349

8. REFERENCES

Betterton EA, Hoffmann MR. 1988. Henry's law constants of some environmentally important

aldehydes. Environ Sci Technol 22:1415-1418.

*Bhalla DK, Mahavni V, Nguyen T, et al. 1991. Effects of acute exposure to formaldehyde on surface

morphology of nasal epithelia in rats. J Toxicol Environ Health 33:171-188.

Bhatt HS, Lober SB, Combes B. 1988. Effect of glutathione depletion on aminopyrine and

formaldehyde metabolism. Biochem Pharmacol 37:1581-1589.

Bhatt HV, Panchal GM. 1992. Behavioral change in rats due to chronic oral and systemic formaldehyde. 

Indian J Physiol Pharmacol 36:270-272.

*Bhattacharya SK, Parkin GF. 1988. Fate and effect of methylene chloride and formaldehyde in

methane fermentation systems. J Water Pollut Control Fed 60:531-536.

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.

Bille H. 1981. [Formaldehyde in textile finishing - Is it necessary?]. Melliand Textilber 10:811-817. 

(German)

Binding N, Witting U. 1990. Exposure to formaldehyde and glutardialdehyde in operating theatres. Int

Arch Occup Environ Health 62:233-238.

*Blackburn GR, Dooley JF, Schreiner CA. 1991. Specific identification of formaldehyde mediated

mutagenicity using the mouse lymphoma L5178Y TK +/- assay supplemented with formaldehyde

dehydrogenase. In Vitro Toxicol 4:121-132.

Blackwell M, Kang H, Thomas A, et al. 1981. Formaldehyde: Evidence of carcinogenicity. Am Ind

Hyg Assoc J 42:34-46.

Blair A, Stewart PA. 1990. Correlation between different measures of occupational exposure to

formaldehyde. Am J Epidemiol 131:510-516.

*Blair A, Saracci R, Stewart PA, et al. 1990a. Epidemiologic evidence on the relationship between

formaldehyde exposure and cancer. Scand J Work Environ Health 16:381-393.

*Blair A, Stewart P, O'Berg M, et al. 1986. Mortality among industrial workers exposed to

formaldehyde. J Natl Cancer Inst 76:1071-1084.

*Blair A, Stewart PA, Hoover RN. 1990b. Mortality from lung cancer among workers employed in

formaldehyde industries. Am J Ind Med 17:683-700.

Boeniger MF. 1987. Formate in urine as a biological indicator of formaldehyde exposure: A review. 

Am Ind Hyg Assoc J 48:900-908.

Bogndanffy 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.

*Boja JW, Nielsen JA, Foldvary E, et al. 1985. Acute low-level formaldehyde behavioural and

neurochemical toxicity in the rat. Prog Neuro-Psychopharmacol Biol Psychiat 9:671-674.
FORMALDEHYDE 350

8. REFERENCES

*Bolt HM. 1987. Experimental toxicology of formaldehyde. J Cancer Res Clin Oncol 113:305-309.

*Bond GG, Flores GH, Shellenberger RJ, et al. 1986. Nested case-control study of lung cancer among

chemical workers. Am J Epidemiol 124:53-66.

Bond JA. 1993. Metabolism and elimination of inhaled drugs and airborne chemicals from the lungs. 

Pharmacol Toxicol 72:36-47.

Booz, Allen, Hamilton, Inc. 1979. Preliminary study of the costs of increased regulation of

formaldehyde exposure in the US workplace. Prepared for Formaldehyde Task Force, Synthetic Organic

Chemical Manufacturers Association, Fiorham Park, NJ. 3-30, 339-341, 359-364, 370-372. 

*Boreiko CJ, 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.

Bostrom C-E, Almen J, Steen B, et al. 1994. Human exposure to urban air pollution. Environ Health

Perspect 102:39-47.

*Boysen M, Zadig E, Digernes V, et al. 1990. Nasal mucosa in workers exposed to formaldehyde: a

pilot study. Br J Ind Med 47:116-121.

*Bracken MJ, Leasa DJ, Morgan WKC. 1985. Exposure to formaldehyde: Relationship to respiratory

symptoms and function. Can J Public Health 76:312-316.

Braga PC. 1989. Agents that affect ciliary activity. In: Braga PC, Allegra L, ed. Drugs in bronchial

mucology. New York, NY: Raven Press Ltd., 335-348.

Braga PC, Allegra L. 1989. Agents that modify glandular activity and mucus secretion. In: Braga PC,

Allegra L, ed. Drugs in bronchial mucology. New York, NY: Raven Press, Ltd, 349-358.

Brandorff NP, Flyvhokm M-A, Beck ID, et al. 1995. National survey on the use of chemicals in the

working environment: Estimated exposure events. Occup Environ Med 52:454-463.

Brandwein M, Pervez N, Biller H. 1987. Nasal squamous carcinoma in an undertaker - does

formaldehyde play a role? Rhinology 25:279-284.

*Brinton LA, Blot WJ, Becker JA, et al. 1984. A case-control study of cancers of the nasal cavity and

paranasal sinuses. Am J Epidemiol 119:896-906.

*Brinton LA, Blot WJ, Fraumeni JFJ. 1985. Nasal cancer in the textile and clothing industries. Br J Ind

Med 42:469-474.

Brockman HE, Yung CY, deSerres FJ. 1981. Potent mutagenicity of formaldehyde in a nucleotide

excision repair-deficient heterokaryon of Neurospora crassa [Abstract]. Environ Mutagen 3:379-380.

Broder I, Corey P, Cole P, et al. 1988a. Comparison of health of occupants and characteristics of houses

among control homes and homes insulated with urea formaldehyde foam. II. Initial health and house

variables and exposure-response relationships. Environ Res 45:156-178.
FORMALDEHYDE 351

8. REFERENCES

Broder I, Corey P, Brasher P, et al. 1988b. Comparison of health of occupants and characteristics of

houses among control homes and homes insulated with urea formaldehyde foam. III. Health and house

variables following remedial work. Environ Res 45:179-203.

Broder I, Corey P, Brasher P, et al. 1991. Formaldehyde exposure and health status in households. 

Environ Health Perspect 95:101-104.

Brown BL, Allis JW, Simmons JE, et al. 1995. Fasting for less than 24 h induces cytochrome P450 2E1

and 2B1⁄2 activities in rats. Toxicol Lett 81:39-44.

Brown KG. 1985. Risk assessment of laboratory rats and mice chronically exposed to formaldehyde

vapors. Risk Anal 5:171-180.

Brown LP. 1989. Do rats comply with EPA policy on cancer risk assessment for formaldehyde? Regul

Toxicol Pharmacol 10:196-200.

*Brutlag D, Schlehuber C, Bonner J. 1969. Properties of formaldehyde-treated nucleohistone. 

Biochemistry 8:3214-3218.

Bruze M. 1988. Patch testing with a mixture of 2 phenol-formaldehyde resins. Contact Dermatitis

19:116-119.

Bruze M, Almgren G. 1988. Occupational dermatoses in workers exposed to resins based on phenol and

formaldehyde. Contact Dermatitis 19:272-277.

Buckley KE, Fisher L J, MacKay VG. 1986. Electron capture gas chromatographic determination of

traces of formaldehyde in milk as the 2,4-dintrophenylhydrazone. J Assoc Off Anal Chem 69:655-657.

*Buckley KE, Fisher LJ, MacKay VG. 1988. Levels of formaldehyde in milk, blood, and tissues of dairy

cows and calves consuming formalin-treated whey. J Agric Food Chem 36:1146-1150.

*Budavari S, O'Neil MJ, Smith A, et al. 1989. The Merck index. 11th ed. Rahway, N.J.: Merck & Co.,

Inc.

Budiansky S. 1980. Indoor air pollution. Environ Sci Technol 14:1023-1027.

Bufalini JJ, Gay B W. Jr, Brubaker KL. 1972. Hydrogen peroxide formation from formaldehyde

photooxidation and its presence in urban atmospheres. Environ Sci Technol 6:816-821.

*Bufalini JJ, Lancaster HT, Namie GR, et al. 1979. Hydrogen peroxide formation from the

photooxidation of formaldehyde and its presence in rainwater. J Environ Sci Health Part A 14:135-141.

*Burge PS, Harries MG, Lam WK, et al. 1985. Occupational asthma due to formaldehyde. Thorax

40:255-260.

Burkhart K, Kulig K, Rumack BH, et al. 1989. Formate and methanol levels following formalin

ingestion [Abstract]. Vet Hum Toxicol 31:375.

*Burkhart KK, Kulig KW, McMartin KE. 1990. Formate levels following a formalin ingestion. Vet

Hum Toxicol 32:135-137.
FORMALDEHYDE 352

8. REFERENCES

Burridge TR, Lavery T, Lam PKS. 1995a. Acute toxicity tests using Phyllospora comosa (labillardiere)

c. agardh (phaeophyta: fucales) and Allorchestes compressa dana (crustacea: amphipoda). Bull Environ

Contam Toxicol 55:621-628.

Burridge TR, Lavery T, Lam PKS. 1995b. Effects of tributyltin and formaldehyde on the germination

and growth of Phyllospora comosa (labillardiere) c. agardh (phaeophyta: fucales). Bull Environ Contam

Toxicol 55:525-532.

Bush ML, Frederick CB, Kimbell JS, et al. 1998. A CFD-PBPK hybrid model for simulating gas and

vapor uptake in the rat nose. Toxicol Appl Pharmacol 150:133-145.

Butterworth BE, Conolly RB, Morgan KT. 1995. A strategy for establishing mode of action of chemical

carcinogens as a guide for approaches to risk assessments. Cancer Lett 93:129-146.

Cadet R, Pajot J, Papon A, et al. 1998. Is there a correlation between scores of nociceptive behavioral

responses to formalin injections given at different body sites in the rat? Neurosci Lett 242:123-126.

Callas PW, Pastides H, Hosmer DW Jr. 1996. Lung cancer mortality among workers in formaldehyde

industries. J Occup Environ Med 38:747-748.

*Calvert JG, Kerr JA, Demerjian KL, et al. 1972. Photolysis of formaldehyde as a hydrogen atom source

in the lower atmosphere. Science 175:751-752.

Cam V. 1985. Issues on health risk assessment a hazardous waste sites and resource recovery facilities in

Region II. Toxicol Ind Health 1:271-276.

Carlson FE, Phillips EK, Tenhaeff SC, et al. 1995. A study of formaldehyde and other organic emissions

from pressing of laboratory oriented strandboard. For Prod J 45:71-77.

Carpenter CP, Smyth HF. 1946. Chemical burns of the rabbit cornea. Am J Ophthalmol 29:1363-1372.

*Carraro E, Gasparini S, Petrini T, et al. 1997. Immune response prevalence to formaldehyde-human

serum albumin molecular adduct in a health population. J Environ Pathol Toxicol Oncol 16:215-218.

Carter WPL. 1990. A detailed mechanism for the gas-phase atmospheric reactions of organic

compounds. Atmos Environ 24A:481-518.

*Casanova M, Heck Hd'A. 1987. Further studies of the metabolic incorporation and covalent binding of

inhaled [3

H]- and [14C] formaldehyde in Fischer-344 rats: Effects of glutathione depletion. Toxicol Appl

Pharmacol 89:105-121.

Casanova M, Heck Hd'A. 1991. The impact of DNA-protein cross-linking studies on quantitative risk

assessments of formaldehyde. CIIT Act 11:1-6.

Casanova M, Heck Hd'A. 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, Conolly RB, Heck Hd'A. 1996a. DNA-protein cross-links (DPC) and cell proliferation in

B6C3F1 mice but not Syrian golden hamsters exposed to dichloromethane: Pharmacokinetics and risk

assessment with DPX as dosimeter. Fundam Appl Toxicol 31:103-116.
FORMALDEHYDE 353

8. REFERENCES

*Casanova M, Deyo DF, Heck Hd'A. 1989. Covalent binding of inhaled formaldehyde to DNA in the

nasal mucosa of Fischer 344 rats: Analysis of formaldehyde and DNA by high-performance liquid

chromatography and provisional pharmacokinetic interpretation. Fundam Appl Toxicol 12:319-417.

*Casanova M, Deyo DF, Heck Hd'A. 1992. Dichloromethane (methylene chloride): Metabolism to

formaldehyde and formation of DNA-protein cross links in B6C3F1 mice and Syrian golden hamsters. 

Toxicol Appl Pharmacol 114:162-165.

*Casanova M, Heck Hd'A, Everitt JI, et al. 1988. Formaldehyde concentrations in the blood of Rhesus

monkeys after inhalation exposure. Food Chem Toxicol 26:715-716.

Casanova M, Heck Hd'A, Janszen D. 1996b. Comments on 'DNA-protein crosslinks, a biomarker of

exposure to formaldehyde-in vitro and in vivo studies' by Shaham et al. [Letter]. Carcinogenesis 17:2097-

2101.

*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, 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 scaling,

and extrapolation to man. Fundam Appl Toxicol 17:409-428.

Casanova-Schmitz M, Heck H. 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, Raymond MD, Heck H d'A. 1984b. Oxidation of formaldehyde and

acetaldehyde by NAD+

-dependent dehydrogenases in rat nasal mucosal homogenates. Biochem

Pharmacol 33:1137-1142.

*Casanova-Schmitz M, Starr TB, Heck Hd'A. 1984a. Differentiation between metabolic incorporation

and covalent binding in the labeling of macromolecules in the rat nasal mucosa and bone marrow by

inhaled [14C]- and [3

H] formaldehyde. Toxicol Appl Pharmacol 76:26-44.

Cascieri TC, Clary JJ. 1992. Formaldehyde-oral toxicity assessment. Comments Toxicol 4:295-304.

Cassee FR, Feron VJ. 1993. Histopathological and biochemical changes in nasal epithelium of rats after

3-day intermittent exposure to a mixture of ozone and formaldehyde [Abstract]. Toxicol Lett 72:142.

Cassee FR, Arts JHE, Groten JP, et al. 1996a. Sensory irritation to mixtures of formaldehyde, acrolein,

and acetaldehyde in rats. Arch Toxicol 70:329-337.

*Cassee FR, Groten JP, Feron VJ. 1996b. Changes in the nasal epithelium of rats exposed by inhalation

to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundam Appl Toxicol 29:208-218.

Cassee FR, Stenhuis WH, Groten JP, et al. 1996c. Toxicity of formaldehyde and acrolein mixtures: in

vitro studies using nasal epithelial cells. Exp Toxicol Pathol 48:481-483.

*Cassee R, 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.
FORMALDEHYDE 354

8. REFERENCES

*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.

Casteel SW, Vernon RJ, Bailery EM. 1987. Formaldehyde: Toxicology and hazards. Vet Hum Toxicol

29:31-33.

Castle ME. 1986. Silage: Pollution problems and their avoidance [Abstract]. Anim Prod 42:447.

*Chameides WL. 1986. Photochemistry of the atmospheric aqueous phase. In: Jaeschke W, ed. 

Chemistry of multiphase atmospheric systems. Berlin: Springer-Verlag, 369-413.

*Chameides WL, Davis DD. 1983. Aqueous-phase source of formic acid in clouds. Nature 304:427-

429.

*Chan C-C, Spengler JD, Ozkaynak H, et al. 1991. Commuter exposures to VOCs in Boston,

Massachusetts. J Air Waste Manage Assoc 41:1594-1600.

*Chang J-Y, Lin J-M. 1998. Aliphatic aldehydes and allethrin in mosquito-coil smoke. Chemosphere

36:617-624.

*Chang JCF, Gross EA, Swenberg JA, et al. 1983. Nasal cavity deposition, histopathology, and cell

proliferation after single or repeated formaldehyde exposure in B6C3F1 mice and F-344 rats. Toxicol

Appl Pharmacol 68:161-176.

*Chang JCF, Steinhagen H, 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.

*Chebotarev AN, Titenko NV, Selezneva TG, et al. 1986. Comparison of the chromosome aberrations,

sister chromatid exchanges, and unscheduled DNA synthesis when evaluating the mutagenicity of

environmental factors. Cytol Genet 20:21-26.

Cheney JE, Collins CH. 1995. Formaldehyde disinfection in laboratories: limitations and hazards. Br J

Biomed Sci 52:195-201.

*Chiazze LJ, Watkins DK, Fryar C, et al. 1993. A case-control study of malignant and non-malignant

respiratory disease among employees of a fibreglass manufacturing facility. II: Exposure assessment. Br

J Ind Med 50:717-725.

Chiazze L Jr, Watkins DK, Fryar C. 1997. Historical cohort mortality study of a continuous filament

fiberglass manufacturing plant. I. White men. J Occup Environ Med 39:432-441.

*Chou C-C, Que Hee SS. 1994. Saliva-available carbonyl compounds in some chewing tobaccos. J

Agric Food Chem 42:2225-2230.

*CIIT. 1998. Chemical Industry Institute of Toxicology. Formaldehyde risk assessment meeting. 

November 14, 1997. Research Triangle Park, NC.

Clement PAR, Stoop AP, Kaufman L. 1987. The influence of formaldehyde on the nasal mucosa. 

Rhinology 25:29-34.
FORMALDEHYDE 355

8. REFERENCES

Clement RE, Langhorst ML, Eiceman GA. 1991. Environmental analysis. Anal Chem 63:270R-292R.

*Cleveland WS, Graedel TE, Kleiner B. 1977. Urban formaldehyde: Observed correlation with source

emissions and photochemistry. Atmos Environ 11:357.

*Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. 

Toxicol Ind Health 1:111-113.

Cocco P, Ward MH, Buiatti E. 1996. Occupational risk factors for gastric cancer: An overview. 

Epidemiol Rev 18:218-234.

Coene RF. 1981. Formaldehyde: Evidence of carcinogenicity. Vet Hum Toxicol 23:282-285.

*Cofer WR, Edahl RA. 1986. A new technique for collection, concentration and determination of

gaseous trophospheric formaldehyde. Atmos Environ 20:979-984.

*Coggon D, Pannett B, Acheson ED. 1984. Use of job-exposure matrix in an occupational analysis of

lung and bladder cancers on the basis of death certificates. J Natl Cancer Inst 72:61-65.

*Cohen MD, Miller CA, Xu LS, et al. 1990. A blotting method for monitoring the formation of

chemically induced DNA-protein complexes. Anal Biochem 186:1-7.

Cohen MR. 1995. Insufficient dose of hepatitis B vaccine given to 1400 newborns; formalin accidents. 

Hosp Pharm 30:938-939.

Cohen N, Modai D, Khahil A, et al. 1989. Acute resin phenol-formaldehyde intoxication. A life

threatening occupational hazard. Hum Toxicol 8:247-250.

*Cohen Hubal EA, Schlosser PM, Conolly RB, et al. 1997. Comparison of inhaled formaldehyde

dosimetry predictions with DNA-protein cross-link measurements in the rat nasal passages. Toxicol Appl

Pharmacol 143:47-55.

Cohn MS. 1985. Description of a carcinogenic risk assessment used in a regulatory proceeding:

Formaldehyde. In: Hoel DG, Merrill RA, Perera FP, ed. Risk quantitation and regulatory policy. Cold

Spring Harbor, NY: Cold Spring Harbor Laboratory, 269-281.

Colizzo F, Krantz MJ, Fish JE, et al. 1992. Ciliated respiratory epithelial surface changes after

formaldehyde exposure. J Toxicol Environ Health 35:221-234.

Colli M, Gironi A, Molina V, et al. 1991. Improved HPLC methodology in occupational exposure

studies on formaldehyde. Chromatographia 32:113-115.

*Collins JJ, Acquavella JF, Esmen NA. 1997. An updated meta-analysis of formaldehyde exposure and

upper respiratory tract cancers. J Occup Environ Med 39:639-651.

Collins JJ, Caporossi J C, Utidjian HMD. 1988. Formaldehyde exposure and nasopharyngeal cancer: Reexamination of the National Cancer Institute study and an update of one plant. J Natl Cancer Inst 80:376-

377.

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.
FORMALDEHYDE 356

8. REFERENCES

*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. 1985a. Genotoxicity of organic chemicals frequently found in

the air of mobile homes. Toxicol Lett 25:33-40.

*Connor TH, Ward JB, Legator MS. 1985b. Absence of mutagenicity in the urine of autopsy service

workers exposed to formaldehyde: factors influencing mutagenicity testing of urine. Int Arch Occup

Environ Health 56:225-237.

*Conolly RB, Andersen ME. 1993. An approach to mechanism-based cancer risk assessment for

formaldehyde. Environ Health Perspect Suppl 101:169-176.

Conolly RB, Andjelkovich DA, Casanova M, et al. 1995. Multidisciplinary, iterative examination of the

mechanism of formaldehyde carcinogenicity: The basis for better risk assessment. CIIT Act 15:1-10.

*Conolly RB, Morgan KT, Andersen ME, et al. 1992. A biologically-based risk assessment strategy for

inhaled formaldehyde. Comments Toxicol 4:269-293.

Contreras KM, Larsen SJV, Harris C. 1996. Differential in vitro toxicity of mouse and rat embryos

following direct intra-amniotic exposure to methanol, form-aldehyde and sodium formate [Abstract]. 

Toxicologist 30:194.

Coon RA, Jones RA, Jenkins LJ Jr, et al. 1970. Animal inhalation studies on ammonia, ethylene, glycol,

formaldehyde, dimethylamine and ethanol. Toxicol Appl Pharmacol 16:646-655.

Cooper JR, Kini MM. 1962. Biochemical aspects of methanol poisoning. Biochem Pharmacol 11:405-

416.

Cosma GN, Marchok AC. 1986. Growth inhibition and DNA damage in rat tracheal epithelial cells

exposed to benzo(a)pyrene and formaldehyde (HCHO) [Abstract]. J Cell Biol 103:173a.

Cosma GN, Marchok AC. 1987. The induction of growth-altered cell populations (tumor-initiation sites)

in rat tracheal implants exposed to benzo(a)pyrene and formaldehyde. Carcinogenesis 8:1951-1953.

*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, Jamabi R, Marchok AC. 1988a. 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, Marchok AC. 1988b. In vivo detection of DNA-protein crosslinks in rat

tracheal implants exposed to benzo(a)pyrene (BAP) and formaldehyde (HCHO) [Abstract]. Proc Am

Assoc Cancer Res 29:108.

Cosma GN, Wilhite AS, Marchok AC. 1988c. 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.
FORMALDEHYDE 357

8. REFERENCES

Costantini AS, Paci E, Miligi L, et al. 1989. Cancer mortality among workers in the Tuscan tanning

industry. Br J Ind Med 46:384-388.

Couch DB, Allen PF, Eales HC. 1982. The mutagenicity of formaldehyde to Salmonella typhimurium

[Abstract]. Environ Mutagen 4:336-337.

Council on Scientific Affairs. 1989. Formaldehyde. JAMA,J Am Med Assoc 261:1183-1187.

*CPSC. 1997. An update on formaldehyde. Washington, DC: U.S. Consumer Product Safety

Commission.

Craft TR, Bermudez E, Skopek TR. 1987. Formaldehyde mutagenesis and formation of DNA-protein

crosslinks in human lymphoblasts in vitro. Mutat Res 176:147-155.

Cronin E. 1991. Formaldehyde is a significant allergen in women with hand eczema. Contact Dermatitis

25:276-282.

Crosby RM, Richardson KK, Craft TR, et al. 1988. Molecular analysis of formaldehyde-induced

mutations in human lymphoblasts and e. coli. Environ Mol Mutagen 12:155-166.

Crump DR. 1995. Volatile organic compounds in indoor air. In: Volatile organic compounds in the

atmosphere. Cambridge: Royal Society of Chemistry, 109-124.

Crump DR, Squire RW, Yu CWF. 1997. Sources and concentrations of formaldehyde and other volatile

organic compounds in the indoor air of four newly built unoccupied test houses. Indoor Built Environ

6:45-55.

*Daggett DL, Stock TH. 1985. An investigation into the storage stability of environmental

formaldehyde samples. Am Ind Hyg Assoc J 46:497-504.

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. Formaldehyde and tumors in hamster respiratory tract. Toxicology 27:9-14.

*Dalene M, Persson P, Skarping G. 1992. Determination of formaldehyde in air by chemisorption on

glass filters impregnated with 2,4-dinitrophenylhydrazine using gas chromatography with thermionic

specific detection. J Chromatogr 626:284-288.

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, Mellard DN, Theiss JC, et al. 1987. Distribution of DNA and RNA content in the bone

marrow and alveolar macrophages of rats after subchronic inhalation of formaldehyde. Environ Res

43:191-202.

*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.
FORMALDEHYDE 358

8. REFERENCES

*Dallas CE, Theiss JC, Harrist RB, et al. 1985. Effect of subchronic formaldehyde inhalation on minute

volume and nasal deposition in Sprague-Dawley rats. J Toxicol Environ Health 16:553-564.

*Dallas CE, Theiss JC, Harrist RB, et al. 1986. Respiratory responses in the lower respiratory tract of

Sprague-Dawley rats to formaldehyde inhalation. J Environ Pathol Toxicol Oncol 6:1-12.

Dally KA, Hanrahan LP, Woodbury MA, et al. 1981. Formaldehyde exposure in nonoccupational

environments. Arch Environ Health 36:277-284.

*Day JH, Lees REM, Clark RH, et al. 1984. Respiratory response to formaldehyde and off-gas of urea

formaldehyde foam insulation. Can Med Assoc J 131:1061-1065.

Deal FH, Swenberg JA, Fennell TR. 1989. Detection of hydroxymethyl adducts in

deoxyribonucleosides, calf thymus DNA from isolated rat liver nuclei treated with formaldehyde

[Abstract]. Carcinogenesis 30:131.

*Dean JH, Lauer LD, House RV, et al. 1984. Studies of immune function and host resistance

B6C3CLF1 mice exposed to formaldehyde. Toxicol Appl Pharmacol 72:519-529.

DeAndrade JB, Tanner RL. 1992. Determination of formaldehyde by HPLC as the DNPH derivative

following high-volume air sampling onto bisulfite-coated cellulose filters. Atmos Environ 26:819-825.

Dearman RJ, Smith S, Basketter DA, et al. 1996. Classification of chemical allergens according to

cytokine secretion profiles murine lymph node cells. J Appl Toxicol 17:53-62.

Dechow M, Sohn H, Steinhanses J. 1997. Concentrations of selected contaminants in cabin air of airbus

aircrafts. Chemosphere 35:21-31.

*De Flora S. 1981. Study of 106 organic and inorganic compounds in the Salmonella/microsome test. 

Carcinogenesis 2:283-298.

*De Flora S, Zanacchi P, Camoirano A, et al. 1984. Genotoxic activity and potency of 135 compounds

in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res 133:161-198.

DeGroot AC, Gerkens F. 1989. Contact urticaria from a chemical textile finish. Contact Dermatitis

20:63-64.

DeGroot AC, Bos JD, Jagtman BA, et al. 1986. Contact allergy to preservatives - II. Contact Dermatitis

15:218-222.

*DeGroot AC, VanJoost T, Bos JD, et al. 1988. Patch test reactivity to DMDM hydantoin: Relationship

to formaldehyde allergy. Contact Dermatitis 18:197-201.

*Dekant W, Vamvakas S. 1993. Glutathione-dependent bioactivation of xenobiotics. Xenobiotica

23:873-887.

Dell L, Teta MJ. 1995. Mortality among workers at a plastics manufacturing and research and

development facility: 1946-1988. Am J Ind Med 28:373-384.

*Dempsey CR. 1993. A comparison of organic emissions from hazardous waste incinerators versus the

1990 Toxics Release Inventory air releases. J Air Waste Manage Assoc 43:1374-1379.
FORMALDEHYDE 359

8. REFERENCES

Denton RA, Parker JE, Abrons HL, et al. 1988. Lack of relationship between low levels of formaldehyde

and airway hyperreactivity or changes in ventilatory function: A prospective study [Abstract]. Am Rev

Respir Dis 137:299.

Dicker E, Cederbaum AI. 1987. Pathways of metabolism of formaldehyde produced from the oxidation

of aminopyrine by intact rat hepatocytes. Ann N Y Acad Sci 494:332-335.

Dillon HK, Gao P. 1994. Laboratory evaluation of a novel reactive passive sampler for the quantitative

determination of formaldehyde in air. Am Ind Hyg Assoc J 55:1061-1068.

*Dinsdale D, Riley RA, Verschoyle RD. 1993. Pulmonary cytochrome P450 in rats exposed to

formaldehyde vapor. Environ Res 62:19-27.

Doman NG, Romanova AK, Terent'eva ZA. 1961. [Conversion of some volatile organic substances

absorbed by leaves from the atmosphere.]. Dokl Akad Nauk SSSR 138:702-705. (Russian)

*Dong S, Dasgupta PK. 1986. Solubility of gaseous formaldehyde in liquid water and generation of

trace standard gaseous formaldehyde. Environ Sci Technol 20:637-640.

*Dong S, Dasgupta PK. 1987. Fast fluorometric flow injection analysis of formaldehyde in atmospheric

water. Environ Sci Technol 21:581-588.

*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

[Abstract]. Environ Mutagen 5:476.

*DOT. 1980. Chemical kinetic and photochemical data sheets for atmospheric reactions. Washington,

DC: U.S. Department of Transportation. AD A 091 631, FAA-EE-80-17.

Dowd MA, Gaulden ME, Proctor BL, et al. 1986. Formaldehyde-induced acetric chromosome fragments

and chromosome stickiness in Chortophaga neuroblasts. Environ Mutagen 8:401-411.

*Dreisbach RH, Robertson WO. 1987. Esters, aldehydes, ketones & ethers. In: Dreisbach RH,

Robertson WO, ed. Handbook of poisoning: prevention, diagnosis & treatment. Norwalk, CT: Appleton

& Lange, 180-188.

*Dresp J, Bauchinger M. 1988. Direct analysis of the clastogenic effect of formaldehyde in unstimulated

human lymphocytes by means of the premature chromosome condensation technique. Mutat Res

204:349-352.

Dulany MA, Batten GLJ, Peck MC, et al. 1996. Papermaking additives. In: Howe-Grant M, ed. KirkOthmer encyclopedia of chemical technology. New York: John Wiley & Sons, Inc., 35-60.

Dumont M, D'Hont C, Moreal A, et al. 1996. Retrograde injections of formaldehyde into the biliary tree

induce alterations of biliary epithelial function in rats. Hepatology 24:1217-1223.

Du Vigneaud V, Verly WG, Wilson JE. 1950. Incorporation of the carbon of formaldehyde and formate

into the methyl groups of choline. J Am Chem Soc 72:2819-2820.
FORMALDEHYDE 360

8. REFERENCES

*Dykewicz MS, Patterson R, Cugell DW, et al. 1991. Serum IgE and IgG to formaldehyde-human serum

albumin: Lack of relation to gaseous formaldehyde exposure and symptoms. J Allergy Clin Immunol

87:48-57.

Ebeler SE, Hinrichs SH, Clifford AJ, et al. 1992. Analysis of reactive carbonyls in the expired air of

transgenic mice. Anal Biochem 205:183-186.

*Eberlein-Konig B, Przybilla B, Kuhnl P, et al. 1998. Influence of airborne nitrogen dioxide or

formaldehyde on parameters of skin function and cellular activation in patients with atopic eczema and

control subjects. J Allergy Clin Immunol 101:141-143.

*ECETOC. 1995. Technical Report No. 65. Formaldehyde and human cancer risk. Brussels, Belgium:

ECETOC.

Echt A, Burr G. 1997. Exposure to formaldehyde during garment manufacturing. Appl Occup Environ

Hyg 12:451-455.

Edling C, Hellquist H, Odkvist L. 1987a. Occupational formaldehyde exposure and the nasal mucosa. 

Rhinology 25:181-187.

Edling C, Jarvholm B, Andersson L, et al. 1987b. Mortality and cancer incidence among workers in an

abrasive manufacturing industry. Br J Ind Med 44:57-59.

*Edling C, Hellquist H, Odkvist L. 1988. Occupational exposure to formaldehyde and histopathological

changes in the nasal mucosa. Br J Ind Med 45:761-765.

Edman B, Moller H. 1982. Trends and forecasts for standard allergens in a 12-year patch test material. 

Contact Dermatitis 8:95-104.

*Eells JT, McMartin KE, Black K, et al. 1981. Formaldehyde poisoning: Rapid metabolism to formic

acid. JAMA,J Am Med Assoc 246:1237-1238.

*Egle JL. 1972. Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Arch

Environ Health 25:119-124.

*Egle JL, Hudgins PM. 1974. Dose-dependent sympathomimetic and cardioinhibitory effects of acrolein

and formaldehyde in the anesthetized rat. Toxicol Appl Pharmacol 28:358-366.

Egle JLJ, Hudgins PM, Lai FM. 1973. Cardiovascular effects of intravenous acetaldehyde and

propionaldehyde in the anesthetized rat. Toxicol Appl Pharmacol 24:636-644.

Ehling UH. 1985. Dose-effect relationships of germ cell mutations in mice [Abstract]. Mutat Res

147:279-327.

Eikmann T, Prajsnar D, Einbrodt HJ. 1987. Quantitative estimation of formaldehyd exposure in normal

population collectives on the basis of the formic acid excretion in urine [Abstract]. Zentralbl Bakteriol

Mikrobiol Hyg [B] 183:483-484.

*Eitzer BD, Iannucci-Berger WA, Mark G, et al. 1997. Fate of toxic compounds during composting. 

Bull Environ Contam Toxicol 58:953-960.
FORMALDEHYDE 361

8. REFERENCES

Eker P, Sanner T. 1980. Initiation of in vitro cell transformation by formaldehyde and acetaldehyde as

measured by attachment-independent survival of cells in aggregates. Eur J Cancer Clin Oncol 22:671-

676.

*Ellenhorn MJ, Barceloux DG. 1988. Hydrocarbon products. In: Ellenhorn MJ, Barceloux DG, ed. 

Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier, 1001-1004.

Ellwood PA, Groves JA, Pengelly MI. 1990. Evaluation of a diffuse sampler for formaldehyde. Ann

Occup Hyg 34:305-313.

ElSayed F, Seite-Bellezza D, Sans B, et al. 1995. Contact urticaria from formaldehyde in a root-canal

dental paste. Contact Dermatitis 33:353.

Endres P. 1992. [Effects of airborne pollutants on the respiratory tract]. In: Akkermann R, Behrends

HB, Ehrnsberger R, ed. [Allergy and the environment: Medical and ecological contributions]. 

Cloppenburg, Germany: Verlag Guenter Runge, 105-114. (German)

Engelhardt G, Fleig I, Helmstadter G. 1987. Letter to the editor. Mutat Res 180:131-133.

*EPA. 1975. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.1032.

*EPA. 1976a. Investigation of selected potential environmental contaminants: Formaldehyde. U.S.

Environmental Protection Agency, Office of Toxic Substances. PB 256 839, EPA-560/2-76-009.

*EPA. 1976b. Frequency of organic compounds identified in water. Athens, GA: U.S. Environmental

Protection Agency, Environmental Research Laboratory, Office of Research and Development. EPA600/4-76-062.

*EPA. 1977a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 86.

*EPA. 1977b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 176.170.

*EPA. 1977c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 176.180.

*EPA. 1978. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 116.4.

EPA. 1979. Chemical Hazard Information Profile: Formaldehyde. Washington, DC: U.S.

Environmental Protection Agency, Office of Pesticides and Toxic Substances. Draft edition. (November

26, 1979)

*EPA. 1980. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261.33.

*EPA. 1981. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261,

Appendix VII.

*EPA. 1982. Atmospheric chemistry of several toxic compounds. Research Triangle Park, NC: U.S.

Environmental Protection Agency, Environmental Sciences Research Laboratory, Office of Research and

Development. PB83-146340, EPA-600/3-82-092.

*EPA. 1983a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 60.489.
FORMALDEHYDE 362

8. REFERENCES

*EPA. 1983b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 122,

Appendix D.

*EPA. 1984. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 125.

*EPA. 1985a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 302.4

*EPA. 1985b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 117.3.

*EPA. 1985c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 266.112.

*EPA. 1986a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268.10.

*EPA. 1986b. U. S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268.42.

*EPA. 1987a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414.60.

*EPA. 1987b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 268.4.

*EPA. 1987c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 355,

Appendix A.

*EPA. 1987d. Assessment of health risks to garment workers and certain home residents from exposure

to formaldehyde. U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances.

*EPA. 1988a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 372. 

*EPA. 1988b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261,

Appendix VIII. 

*EPA. 1988c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 372.65.

*EPA. 1988d. Compendium of methods for determination of toxic organic compounds in ambient air.

U.S. Environmental Protection Agency. EPA-600/4-89/017. 

*EPA. 1988e. Recommendations for and documentation of biological values for use in risk assessment. 

Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office. 

PB88-179874.

*EPA. 1990a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 60.617.

*EPA. 1990b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 60.667.

*EPA. 1990c. Interim methods for development of inhalation reference doses. U.S. Environmental

Protection Agency. EPA-600/8-90/066A.

*EPA. 1991a. Formaldehyde risk assessment update - final draft. Washington, DC: U.S. Environmental

Protection Agency, Office of Toxic Substances. 

*EPA. 1991b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 266,

Appendix IX.
FORMALDEHYDE 363

8. REFERENCES

*EPA. 1991c. Locating and estimating air emissions from sources of formaldehyde (revised). Research

Triangle Park, NC: U.S. Environmental Protection Agency. PB91-181842, EPA-450/4-91-012.

EPA. 1991d. Urban air toxics monitoring program carbonyl results, 1990. Research Triangle Park, NC: 

U.S. Environmental Protection Agency. PB92-110030, EPA-450/4-91-025.

*EPA. 1992a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 261.3.

*EPA. 1992b. Methods for determination of organic compounds in drinking water. U.S. Environmental

Protection Agency. EPA-600/R-92/129. 

*EPA. 1992c. National Air Toxics Information Clearinghouse: NATICH data base report on state, local,

and EPA air toxics activities. Research Triangle Park, NC: U.S. Environmental Protection Agency,

Office of Air Quality Planning and Standards.

*EPA. 1993a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 60.707.

*EPA. 1993b. U.S. Environmental Protection Agency. NESHAP for source category; pulp and paper

production. Proposed rule. Federal Register 58:66078.

*EPA. 1993c. U.S. Environmental Protection Agency. List of regulated substances and thresholds for

accidental release prevention. Federal Register 58:5102.

*EPA. 1993d. U.S. Environmental Protection Agency. Control of air pollution from new and in use

motor vehicles and engines; technical amendments to the test procedures for methanol-fueled motor

vehicles and motor vehicle engines and petroleum-fueled motor vehicles. Proposed rule. Federal

Register 58:11816.

EPA. 1993e. U.S. Environmental Protection Agency. Land disposal restrictions for newly identified and

listed hazardous wastes and hazardous soil. Federal Register 58:48092.

*EPA. 1994a. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 63.106.

*EPA. 1994b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 68.130.

*EPA. 1994c. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 80.42.

*EPA. 1994d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 80.45.

*EPA. 1994e. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 80.51.

*EPA. 1994f. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 80.56.

*EPA. 1994g. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 80.90.

*EPA. 1994h. U.S. Environmental Protection Agency. HAP: proposed regulations governing

constructed, reconstructed or modified major sources. U.S. Environmental Protection Agency. Federal

Register 59:15504.
FORMALDEHYDE 364

8. REFERENCES

*EPA. 1994i. U.S. Protection Agency. Hazardous waste management system; carbamate production

identification and listing of hazardous waste and CERCLA hazardous substance designation and

reportable quantities. Notice of Proposed Rulemaking--K157 waste. Federal Register 59:9808.

EPA. 1994j. U.S. Environmental Protection Agency. Methods for derivation of inhalation reference

concentrations and application of inhalation dosimetry. Washington, DC: Environmental Criteria and

Assessment Office, Office of Health and Exposure Assessment, Office of Research and Development. 

EPA/600/8-90-066F.

*EPA. 1995. Drinking water regulations and health advisories. U.S. Environmental Protection Agency, 

Office of Water. 

*EPA. 1996. Sources and factors affecting indoor emission from engineered wood products: Summary

and evaluation of current literature. Research Triangle Park, NC: U.S. Environmental Protection

Agency, National Risk Management Research Laboratory, Office of Research and Development. PB96-

183876, EPA-600/R-96-067.

*EPA. 1997. U.S. Environmental Protection Agency. Federal Register. 62:7502.

Estlander T, Jolanki R, Kanerva L, et al. 1990. An artist's allergy to reactive dyes and formaldehyde

[Abstract]. Contact Dermatitis 23:271-272.

Everitt JI, Boreiko CJ, Mangum JB, et al. 1989. Development of a tracheal implant xenograft model to

expose human bronchial epithelial cells to toxic gases. Toxicol Pathol 17:465-473.

*Facchini MC, Lind J, Orsi G, et al. 1990. Chemistry of carbonyl compounds in Po Valley fog water. 

Sci Total Environ 91:79-86.

*Fan Q, Dasgupta PK. 1994. Continuous automated determination of atmospheric formaldehyde at the

parts per trillion level. Anal Chem 66:551-556.

Farooqui M Y.H, 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 53:233-240.

Fayerweather WE, Pell S, Bender JR. 1983. Case control study of cancer deaths in DuPont workers with

potential exposure to formaldehyde (retrieval in progress). In: Clary JJ, Gibson E, Weritz RS, ed. 

Formaldehyde: Toxicology, epidemiology, mechanisms. New York, NY: Marcel Dekker, Inc., 47-125.

*FDA. 1976. U.S. Food and Drug Administration. Code of Federal Regulations. 21 CFR 573.460.

*FDA. 1977a. U.S. Food and Drug Administration. Code of Federal Regulations. 21 CFR 175.105.

FDA. 1977b. U.S. Food and Drug Administration. Code of Federal Regulations. 21 CFR 176.170.

FDA. 1977c. U.S. Food and Drug Administration. Code of Federal Regulations. 21 CFR 176.180.

*FEDRIP. 1996. Federal Research in Progress. Dialog Information Services, Incorporated. October,

1995.
FORMALDEHYDE 365

8. REFERENCES

Feinman SE. 1988. Formaldehyde genotoxicity and teratogenicity. In: Feinman SE, ed. Formaldehyde

sensitivity and toxicity. Boca Raton, FL: CRC Press, 167-178.

Feldman MY. 1976. Reactions of nucleic acids and nucleoproteins with formaldehyde. Prog Nucleic

Acid Res Mol Biol 13:1-49.

Feldman MY, Balabanova H, Bachrach U, et al. 1977. Effect of hydrolyzed formaldehyde-treated RNA

on neoplastic and normal human cells. Cancer Res 37:501-506.

*Fennell TR. 1994. Development of methods for measuring biological markers of formaldehyde

exposure. Res Rep Health Eff Inst 67:1-26.

Fennell TR, Deal FH, Swenberg JA. 1988. Cross-linked adducts formed on reaction of formaldehyde

with amino acids or glutathione, and deoxyribonucleosides or DNA [Abstract]. Proc Am Assoc Cancer

Res 29:88.

*Feron VJ, Bruyntjes JP, Woutersen RA, et al. 1988. Nasal tumours in rats after short-term exposure to a

cytotoxic concentration of formaldehyde. Cancer Lett 39:101-111.

*Feron VJ, Til HP and Woutersen RA. 1990. Letter to the Editor. Toxicol Ind Health 6:237-239.

*Feron VJ, Til HP, de Vrijer F, et al. 1991. Aldehydes: occurrence, carcinogenic potential, mechanism

of action and risk assessment. Mutat Res 259:363-385.

*Ferry DG, Temple WA, McQueen EG. 1980. Methanol monitoring: Comparison of urinary methanol

concentration with formic acid excretion rate as a measure of occupational exposure. Int Arch Occup

Environ Health 47:155-163.

Finlayson-Pitts BJ, Pitts JNJ. 1993. Atmospheric chemistry of tropospheric ozone formation: Scientific

and regulatory implications. J Air Waste Manage Assoc 43:1091-1100.

*Fischer T, Andersen K, Bengesson U, et al. 1995. Clinical standardization of the TRUE Test

formaldehyde patch. Curr Probl Dermatol 22:24-30.

*Fishbein L. 1992. Exposure from occupational versus other sources. Scand J Work Environ Health

18:5-16.

*Fleig I, Petri N, Stocker WG, et al. 1982. Cytogenetic analyses of blood lymphocytes of workers

exposed to formaldehyde in formaldehyde manufacturing and processing. J Occup Med 24:1009-1012.

*Fleisher JM. 1987. Medical students' exposure to formaldehyde in gross anatomy laboratories. N Y

State J Med 87:385-388.

Florence E, Milner DF. 1981. Determination of free and loosely protein-bound formaldehyde in the

tissues of pigs fed formalin-treated skim milk as a protein supplement. J Sci Food Agric 32:288-292.

*Flyvholm MA. 1991. Contact allergens in registered chemical products. Contact Dermatitis 25:49-56.

*Flyvholm M-A, Hall BM, Agner T, et al. 1997. Threshold for occluded formaldehyde patch test in

formaldehyde-sensitive patients: Relationship to repeated open application test with a product containing

formaldehyde releaser. Contact Dermatitis 36:26-33.
FORMALDEHYDE 366

8. REFERENCES

Fontignie-Houbrechts N. 1981. Genetic effects of formaldehyde in the mouse. Mutat Res 88:109-114.

Fontignie-Houbrechts N, Moutschen-dahmen M, Degraeve N, et al. 1982. Genetic effects in the mouse

of formaldehyde in combination with adenosine and hydrogen peroxide. Mutat Res 104:371-376.

*Fomon SJ. 1966. Body composition of the infant. Part I: The male reference infant. In: Falkner F, ed.

Human Development. Philadelphia, PA:WB Saunders, 239-246.

*Fomon SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to

age 10 years. Am J Clin Nutr 35:1169-1175.

Fowler JF, Skinner SM, Belsito DV. 1992. Allergic contact dermatitis from formaldehyde resins in

permanent press clothing: An underdiagnosed cause of generalized dermatitis. J Am Acad Dermatol

27:962-968.

Frakes RA, Sharma RP, Willhite CC. 1986. Comparative metabolism of linamarin and amygdalin in

hamsters. Food Cosmet Toxicol 24:417-420.

Franke JP, Wijsbeek J, deZeeuw RA, et al. 1988. Systematic analysis of solvents and other volatile

substances by gas chromatography. J Anal Toxicol 12:20-24.

*Frazelle JH, Abernethy DJ, Boreiko CJ. 1983. Weak promotion C3H/10T1⁄2 cell transformation by

repeated treatments with formaldehyde. Cancer Res 43:3236-3239.

*Freestone J, Bentley A. 1989. Case of formaldehyde poisoning. Br J Pharm Pract 11:20-21.

Freidman G D, Ury HK. 1983. Screening for possible drug carcinogenicity: Second report of findings. J

Natl Cancer Inst 71:1165-1175.

French D, Edsall JT. 1945. The reactions of formaldehyde with amino acids and proteins. Adv Protein

Chem 2:277-335.

FSTRAC. 1990. Summary of state and federal drinking water standards and guidelines. U.S.

Environmental Protection Agency. Chemical Communications Subcommittee, Federal State Toxicology

and Regulatory Alliance Committee.

Fugas M. 1985. [Radon and formaldehyde the conclusions and recommendations of WHO]. Zast Atmos

13:134-135. (Russian)

Fuji T, Tonomura K. 1972. Oxidation of methanol, formaldehyde and formate by a candida species. 

Agric Biol Chem 36:2297-2306.

Fujimaki H, Imai T, Befus D. 1992a. Mast cell response to formaldehyde: 2. Induction of stress-like

proteins. Int Arch Allergy Immunol 98:332-338.

Fujimaki H, Kawagoe A, Bissonnette E, et al. 1992b. Mast cell response to formaldehyde: 1.

Modulation of mediator release. Int Arch Allergy Immunol 98:324-331.

Furihata C, Yamakoshi A, Matsushima T. 1988. Inductions of ornithine decarboxylase and DNA

synthesis in rat stomach mucosa by formaldehyde. Jpn J Cancer Res 79:917-920.
FORMALDEHYDE 367

8. REFERENCES

Furuta R, Doi T. 1994. Chiral separation of diniconazole, uniconazole and structurally related

compounds by cyclodextrin-modified micellar electrokinetic chromatography. Electrophoresis 15:1322-

1325.

*Gaffney JS, Marley NA, Martin RS, et al. 1997. Potential air quality effects of using ethanol-gasoline

fuel blends: A field study in Albuquerque, New Mexico. Environ Sci Technol 31:3053-3061.

Gailhofer G, Binder H. 1988. Allergic contact dermatitis caused by an acetone-formaldehyde

condensate. Contact Dermatitis 18:110-111.

*Galli CL, Ragusa C, Resmini P, et al. 1983. Toxicological evaluation in rats and mice of the ingestion

of a cheese made from milk with added formaldehyde. Food Chem Toxicol 21:313-317.

Galloway JN, Artz RS, Dayan U, et al. 1988. WATOX-85: An aircraft and ground sampling program to

determine the transport of trace gases and aerosols across the western Atlantic Ocean. Atmos Environ

22:2345-2360.

*Galloway SM, Bloom AD, Resnick M, et al. 1985. Development of standard protocol for in vitro

cytogenetic testing with Chinese hamster ovary cells: Comparison of results of 22 compounds in two

laboratories. Environ Mutagen 7:1-51.

*Gammage RB, Hawthorne AR. 1985. Current status of measurement techniques and concentrations of

formaldehyde in residences. In: Jacobs VA, ed. Indoor air and human health. New York, NY: Lewis

Publishers, Inc., 117-130.

*Gannon PFG, Campbells M, O'Hickey SP, et al. 1995. Occupational asthma due to glutaraldehyde and

formaldehyde in endoscopy and x ray departments. Thorax 50:156-159.

Garcia JP, Beyne-Masclet S, Mouvier G. 1992. Emissions of volatile organic compounds by coal-fired

power stations. Atmos Environ 26A:1589-1597.

Garcia Bracamonte B, Ortiz de Frutos FJ, Iglesias Diez L. 1995. Occupational allergic contact dermatitis

due to formaldehyde and textile finish resins. Contact Dermatitis 33:139-140.

*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.

*Garry VF, Kreiger RA, Wiencke JK. 1981. The mutagenic and cytotoxic effects of formaldehyde in

cultured human lymphocytes [Abstract]. Environ Mutagen 3:341.

*Garry VF, Oatman L, Pleus R, et al. 1980. Formaldehyde in the home: Some environmental disease

perspectives. Minn Med 63:107-111.

Gaylor DW. 1983. Mathematical approaches to risk assessment: Squamous cell nasal carcinoma in rats

exposed to formaldehyde vapor. In: Gibson JE, ed. Formaldehyde Toxicity. Washington, DC:

Hemisphere Publishing Corporation, 279-283.

Gaylor DW. 1992. Incidence of developmental defects at the no observed adverse effect level (NOAEL). 

Regul Toxicol Pharmacol 15:151-160.
FORMALDEHYDE 368

8. REFERENCES

Geier J, Lessmann H, Schnuch A, et al. 1997. [Contact allergy due to formaldehyde-releasing biocides]. 

Allergologie 20:215-224. (German).

*Gerberich HR, Stautzenberger AL, Hopkins WC. 1980. Formaldehyde. In: Kirk-Othmer Encyclopedia

of chemical technology. New York, NY: John Wiley & Sons, 231-250.

Gerhold RM, Malaney GW. 1966. Structural determinants in the oxidation of aliphatic compounds by

activated sludge. J Water Pollut Control Fed 38:562-579.

*Gerin M, Siemiatcki 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.

Gescher A, Hickman JA, Stevens MFG. 1979. Oxidative metabolism of some n-methyl containing

xenobiotics can lead to stable progenitors of formaldehyde. Biochem Pharmacol 28:3235-3238.

*Glass LR, Connor TH, Theiss JC, et al. 1986. Genotoxic evaluation of the offgassing products of

particle board. Toxicol Lett 31:75-83.

*Glaze WH, Koga M, Cancilla D. 1989. Ozonation byproducts 2. Improvement of an aqueous phase

derivatization method for detection of formaldehyde and other carbonyl compounds formed by the

ozonation of drinking water. Environ Sci Technol 23:838-847.

Godish T. 1989. Formaldehyde exposures from tobacco smoke: A review. Am J Public Health 79:1044-

1045.

Godish T, Fell J, Lincoln P. 1984. Formaldehyde levels in New Hampshire urea - formaldehyde foam

insulated houses. Relationship to outdoor temperature. J Air Pollut Control Assoc 34:1051-1052.

Goering PL. 1989. Acute exposure to formaldehyde induces hepatic metallothionein synthesis in mice. 

Toxicol Appl Pharmacol 98:325-337.

*Gold KW, Naugle DF, Berry MA. 1993. Indoor concentrations of environmental carcinogens. In:

Seifert B, van de Wiel HJ, O'Neill IK, ed. Environmental carcinogens: Methods of analysis and exposure

measurement (IARC Scientific Publications No. 109). Lyon: International Agency for Research on

Cancer, 41-71.

*Goldmacher VS, Thilly WG. 1983. Formaldehyde is mutagenic for cultured human cells. Mutat Res

116:417-422.

Goldstein E, Lippert W. 1985. Cellular acid phosphatase activity: correlation of cytochemical and

biochemical measurements. Histochem J 17:381-386.

Goodman JI, Trephly TR. 1971. A comparison of rat and human liver formaldehyde dehydrogenase. 

Biochim Biophys Acta 252:489-505.

Gordon T, Harkema JR. 1995. Mucous cell metaplasia in the airways of rats exposed to machining

fluids. Fundam Appl Toxicol 28:274-282.

Goris JA, Ang S, Navarro C. 1998. Minimizing the toxic effects of formaldehyde. Lab Med 29:39-42.
FORMALDEHYDE 369

8. REFERENCES

*Gorski P, Tarkowski M, Krakowiak A, et al. 1992. Neutrophil chemiluminescence following exposure

to formaldehyde in healthy subjects and in patients with contact dermatitis. Allergol Immunopathol

(Madr) 20:20-23.

*Gossel TA, Bricker JD. 1994. Principles of clinical toxicology. 3rd ed. New York, NY: Raven Press.

*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.

Grabinska-Loniewska A. 1974. Studies on the activated sludge bacteria participating in the

biodegradation of methanol, formaldehyde and ethylene glycol: Part II. Utilization of various carbon and

nitrogen compounds. Acta Microbiol Pol Ser B 6:83-88.

Graedel TE, McGill R. 1986. Degradation of materials in the atmosphere: Common materials are

vulnerable to atmospheric attack. Environ Sci Technol 20:1093-1100.

*Grafstrom RC, Fornace AJ, Autrup H, et al. 1983. Formaldehyde damage to DNA and inhibition of

DNA repair in human bronchial cells. Science 220:216-218.

*Grafstrom RC, Curren RD, Yang LL, et al. 1985. Genotoxicity of formaldehyde in cultured human

bronchial fibroblasts. Science 228:89-91.

*Grafstrom RC, Fornace A, Harris CC. 1984. Repair of DNA damage caused by formaldehyde in human

cells. Cancer Res 44:4323-4327.

*Graftstrom RC, Hsu I-C, 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.

*Grammar LC, Harris KE, Shaughnessy MA, et al. 1990. Clinical and immunologic evaluation of 37

workers exposed to gaseous formaldehyde. J Allergy Clin Immunol 86:177-181.

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.

*Grazuleviciene R, Dulskiene V, Vencloviene J. 1998. Formaldehyde exposure and low birth weight

incidence. J Occup Health 40:61-67.

Green DJ, Kulle TJ. 1986. Generation and measurement of formaldehyde in exposure chambers. Am

Ind Hyg Assoc J 47:505-508.

Green DJ, Bascom R, Healey EM, et al. 1989. Acute pulmonary response in healthy, nonsmoking adults

to inhalation of formaldehyde and carbon. J Toxicol Environ Health 28:261-275.

*Green DJ, Sauder LR, Kulle TJ, et al. 1987. Acute response to 3.0 ppm formaldehyde in exercising

health nonsmokers and asthmatics. Am Rev Respir Dis 135:1261-1266.

Green MA, Egle JLJ. 1983. Effects of intravenous acetaldehyde, acrolein, formaldehyde and

propionaldehyde on arterial blood pressure following acute guanethidine treatment. Res Commun Chem

Pathol Pharmacol 40:337-340.
FORMALDEHYDE 370

8. REFERENCES

Greenberg SR. 1982. Nucleic acid relationships in formalin-injured renal tubules. Proc Inst Med

Chicago 35:83-84.

*Grosjean D. 1982. Formaldehyde and other carbonyls in Los Angeles ambient air. Environ Sci

Technol 16:254-262.

*Grosjean D, Wright B. 1983. Carbonyls in urban fog, ice fog, cloudwater and rainwater. Atmos

Environ 17:2093-2096.

*Grosjean D, Swanson RD, Ellis C. 1983. Carbonyls in Los Angeles air: Contribution of direct

emissions and photochemistry. Sci Total Environ 29:65-85.

*Grosjean E, Grosjean D, Fraser MP, et al. 1996. Air quality model evaluation data for organics. 2. C1-

C14 carbonyls in Los Angeles air. Environ Sci Technol 30:2687-2703.

*Grosjean E, Williams ELII, Grosjean D. 1993. Ambient levels of formaldehyde and acetaldehyde in

Atlanta, Georgia. J Air Waste Manage Assoc 43:469-474.

Gross AF, Given PSJ, Athnasios AK. 1987. Food. Anal Chem 59:212R-252R.

Gross EA, Morgan KT. 1991. Architecture of nasal passages and larynx. In: Parent RA, ed. 

Comparative biology of the normal lung. Boca Raton, FL: CRC Press, 7-25.

Groten JP, Schoen ED, Van Bladeren PJ, et al. 1997. Subacute toxicity of a mixture of nine chemicals in

rats: Detecting interactive effects with a fractionated two-level factorial design. Fundam Appl Toxicol

36:15-29.

Gryllaki-Berger M, Mugny C, Perrenoud D, et al. 1992. A comparative study of formaldehyde detection

using chromotropic acid, acetylacetone and HPLC in cosmetics and household cleaning products. 

Contact Dermatitis 26:149-154.

Guengerich FP. 1995. Influence of nutrients and other dietary materials on cytochrome P-450 enzymes. 

Am J Clin Nutr 61(suppl):651S-658S.

Guicherit R, Schulting FL. 1985. The occurrence of organic chemicals in the atmosphere of the

Netherlands. Sci Total Environ 43:193-219.

Guillot JP, Gonnet JF. 1985. The epicutaneous maximization test. Curr Probl Dermatol 14:220-247.

Guseva VA. 1972. [Gonadotropic effect of formaldehyde on male rats during its simultaneous induction

with air and water]. Gig Sanit 10:102-103. (Russian)

Gustavsson P, Jakobsson R, Johansson 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.

*Guzelian PS, Henry CJ, Olin SS. 1992. Similarities and Differences between children and adults:

Implications for risk assessment. Washington, DC: International Life Sciences Institute Press. 

Haddad LM and Winchester JF. 1990. Clinical Management of Poisoning and Drug Overdose (2nd

edition). Philadelphia, PA: WB Saunders.
FORMALDEHYDE 371

8. REFERENCES

Haggard HW, Greenberg LA. 1939. Studies in the absorption, distribution and elimination of alcohol.

IV. The elimination of methyl alcohol. J Pharmacol Exp Ther 66:479-496.

Hagmar L, Bellander T, Englander V, et al. 1986. Mortality and cancer morbidity among workers in a

chemical factory. Scand J Work Environ Health 12:545-551.

Hagmar L, Bellander T, Hogstedt B, et al. 1988a. Biological effects in a chemical factory with

mutagenic exposure: I. Cytogenic and haematological parameters. Int Arch Occup Environ Health

60:437-444.

Hagmar L, Bellander T, Persson L, et al. 1988b. Biological effects in a chemical factory with mutagenic

exposure: III. Urinary mutagenicity and thioether excretion. Int Arch Occup Environ Health 60:453-456.

Hagmar L, Nielsen J, Skerfving S. 1987. Clinical features and epidemiology of occupational obstructive

respiratory disease caused by small molecular weight organic chemicals. In: Schlumberger HD, ed. 

Epidemiology of allergic diseases. Basel: Karger, 42-58.

*Hall A, Harrington JM, Aw T-C. 1991. Mortality study of British pathologists. Am J Ind Med 20:83-

89.

Hallier E, Schroder KR, Asmuth K, et al. 1994. Metabolism of dichloromethane (methylene chloride) to

formaldehyde in human erythrocytes: influence of polymorphism of glutathione transferase theta (GST

T1-1). Arch Toxicol 68:423-427.

Halperin WE, Goodman M, Stayner L, et al. 1983. Nasal cancer in a worker exposed to formaldehyde. 

JAMA,J Am Med Assoc 249:510-512.

Hansen ES. 1991. Cancer mortality among Danish molders. Am J Ind Med 20:401-409.

*Hansen J, Olsen JH. 1995. Formaldehyde and cancer morbidity among male employees in Denmark. 

Cancer Causes Control 6:354-360.

Hansen J, Olsen JH. 1996. [Occupational exposure to formaldehyde and risk of cancer.]. Ugeskr Laeg

158:4191-4194. (Danish).

Hansen J, Olsen JH, Larsen AI. 1994. Cancer morbidity among employees in a Danish pharmaceutical

plant. Int J Epidemiol 23:891-898.

Hanst PL, Gay BWJ. 1977. Photochemical reactions among formaldehyde, chlorine, and nitrogen

dioxide in air. Environ Sci Technol 11:1105-1109.

*Hare DA, Groah WJ, Schweer LG, et al. 1996. Evaluating the contribution of UF-bonded building

materials to indoor formaldehyde levels in a newly constructed house. Presented at Washington State

University 30th Annual Particleboard/Composite Materials Symposium, Pullman, WA.

Hargis KM, Tillery MI, Ettinger HJ, et al. 1986. Industrial hygiene study of a true in situ oil shale

retorting facility. Am Ind Hyg Assoc J 47:455-464.

Harley RA, Cass GR. 1994. Modeling the concentrations of gas-phase toxic organic air pollutants:

Direct emissions and atmospheric formation. Environ Sci Technol 28:88-98.
FORMALDEHYDE 372

8. REFERENCES

Harman AE, Voigt JM, Frame SR, et al. 1997. Mitogenic responses of rat nasal epithelium to

hexamethylphosphoramide inhalation exposure. Mutat Res 380:155-165.

*Harrington JM, Oakes D. 1984. Mortality study of British pathologists: 1974-1980. Br J Ind Med

41:188-191.

*Harrington JM, Shannon HS. 1975. Mortality study of pathologists and medical laboratory technicians. 

Br Med J 4:329-332.

Harris C, Kenneway M, Lee E, et al. 1995. Formaldehyde embryotoxicity in mouse conceptuses grown

in whole embryo culture [Abstract]. Toxicologist 1:162.

Harris DK. 1953. Health problems in the manufacture and use of plastics. Br J Ind Med 10:255-268.

*Harving H, Korsgaard J, Dahl R, et al. 1986. Low concentrations of formaldehyde in bronchial asthma:

a study of exposure under controlled conditions. Br Med J 293:310.

*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.

Hasegawa T, Tsuji M, Nakayama S, et al. 1993. [Effects of disinfectants on erythrocytes and isolated

hepatocytes from rats and surface tension]. Folia Pharmacol Jpn 101:337-347. (Japanese)

Haselkorn R, Doty P. 1961. The reaction of formaldehyde with polynucleotides. J Biol Chem 236:2738-

2745.

Hasselman A, Kolmael KF. 1995. [Occupational dermatoses of cleaning staff]. Arbeitsmed Sozialmed

Umweltmed 30:106-120. (German)

Hastie AT. 1986. Inhibition of mammalian ciliary activity by formaldehyde [Abstract]. Am Rev Respir

Dis 133:A-84.

Hastie AT, Patrick H, Fish JE. 1990. Inhibition and recovery of mammalian respiratory ciliary function

after formaldehyde exposure. Toxicol Appl Pharmacol 102:282-291.

*Hatch GG, Conklin PM, Christensen CC, et al. 1983. Synergism in the transformation of hamster

embryo cells treated with formaldehyde and adenovirus. Environ Mutagen 5:49-57.

Hatch KL, Maibach HI. 1986. Textile chemical finish dermatitis. Contact Dermatitis 14:1-13.

Hatch KL, Maibach HI. 1995. Textile dermatitis: an update. (I). Resins, additives and fibers. Contact

Dermatitis 32:319-326.

*Hatfield R. 1957. Biological oxidation of some organic compounds. Ind Eng Chem 49:192-196.

*Haworth S, Lawlor T, Mortelmans K, et al. 1983. Salmonella mutagenicity test results for 250

chemicals. Environ Mutagen 5(Suppl. 1):3-142.

*Hawthorne AR, Dudney CS, Cohen MA, et al. 1986a. Multipollutant indoor air quality study of 300

homes in Kingston/Barriman, Tennessee: Study design [Abstract]. Abstr Pap Am Chem Soc 192:ENVR

96.
FORMALDEHYDE 373

8. REFERENCES

*Hawthorne AR, Gammage RB, Dudney CS. 1986b. An indoor air quality study of 40 east Tennessee

homes. Environ Int 12:221-239.

*Hayashi T, Reece CA, Shibamoto T. 1986. Gas chromatographic determination of formaldehyde in

coffee via thiazolidine derivative. J Assoc Off Anal Chem 69:101-105.

*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.

*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.

*HazDat. 1996. Agency for Toxic Substances and Disease Registry (ATSDR), Atlanta, GA.

He JL, Jin LF, Jin HY. 1998. Detection of cytogenic effects in peripheral lymphocytes of students

exposed to formaldehyde with cytokinesis-blocked micronucleus assay. Biomed Environ Sci 11:87-92.

Healey EM, Bascom R, Sauder L, et al. 1987. Acute pulmonary response in healthy non-smoking adults

to inhalation of carbon and formaldehyde [Abstract]. Am Rev Respir Dis 135:A58.

Hecht SS. 1984. Chemical carcinogenesis: An overview. Clin Physiol Biochem 3:89-97.

*Heck Hd'A, Casanova M. 1987. Isotope effects and their implications for the covalent binding of

inhaled [3

H]- and [14C]formaldehyde in the rat nasal mucosa. Toxicol Appl Pharmacol 89:122-134.

*Heck Hd'A, Casanova M. 1994. Nasal dosimetry of formaldehyde: Modeling site specificity and the

effects of preexposure. Inhal Toxicol 6:159-175.

Heck Hd'A, Casanova-Schmitz M. 1983. Biochemical toxicology of formaldehyde. In: Hodgson, Bend,

Philpot, ed. Reviews in biochemical toxicology. New York, NY: Elsevier, 155-189.

Heck Hd'A, Keller DA. 1988. Toxicology of formaldehyde. ISI Atlas Sci Pharmacol 2:5-9.

Heck Hd'A, Casanova M, McNulty MJ, et al. 1986. Mechanisms of nasal toxicity induced by

formaldehyde and acrolein. In: Barrow CS, ed. Toxicology of the nasal passages. Washington, DC:

Hemisphere Publishing Corporation, 235-247.

*Heck Hd'A, Casanova M, Starr TB. 1990. Formaldehyde toxicity - new understanding. CRC Crit Rev

Toxicol 20:397-426.

*Heck Hd’A, Casanova M, Steinhagen WH et al. 1989. DNA-protein cross-linking studies in rats and

nonhuman primates. In: Feron VJ and Bosland MC, eds. Nasal carcinogenesis in rodents: Relevance to

human health risk. The Netherlands: Pudoc Wageningen, 159-164. (Cited in EPA, 1991a)

*Heck Hd'A, 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.
FORMALDEHYDE 374

8. REFERENCES

*Heck Hd'A, Chin TY, Schmitz MC. 1983. Distribution of [14C] formaldehyde in rats after inhalation

exposure. In: Gibson JE, ed. Formaldehyde toxicity. Washington, DC: Hemisphere Publishing

Corporation, 26-37.

*Heck Hd'A, White EL, Casanova-Schmitz M. 1982. Determination of formaldehyde in biological

tissues by gas chromatography/mass spectrometry. Biomed Mass Spectrom 9:347-353.

Hedge A, Erickson WA, Rubin G. 1994. The effects of alternative smoking policies on indoor air quality

in 27 office buildings. Ann Occup Hyg 38:265-278.

Heinzow B, Elltorr T. 1992. [Formic acid in urine: An useful indicator in environmental medicine?]. 

Zentralbl Hyg Umweltmed 192:455-461. (German)

Helander I. 1977. Contact urticaria from leather containing formaldehyde. Arch Dermatol 113:1443.

Helander KG. 1994. Kinetic studies of formaldehyde binding in tissue. Biotechnic Histochem 69:177-

179.

Hellawell JM. 1988. Toxic substances in rivers and streams. Environ Pollut 50:61-85.

*Helrich K. 1990. 964.1 Formaldehyde in maple sirup: Spectrophotometric method. In: Helrich K, ed. 

Official methods of analysis of the Association of Official Analytical Chemists. Arlington, VA:

Association of Official Analytical Chemists, Inc., 1037-1038.

Hemminki K. 1984. Urinary excretion products of formaldehyde in the rat. Chem Biol Interact 48:243-

248.

Hemminki K, Kyyronen P, Lindbohm M-L. 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 Commun Health 39:141-147.

*Hendrick DJ, Lane DJ. 1975. Formalin asthma in hospital staff. Br Med J 1:607-608.

*Hendrick DJ, Lane DJ. 1977. Occupational formalin asthma. Br J Ind Med 34:11-18.

*Hendrick DJ, Rando RJ, Lane DJ, et al. 1982. Formaldehyde asthma: Challenge exposure levels and

fate after five years. J Occup Med 24:893-897.

Herbert FA, Hessel PA, Melenka LS, et al. 1994. Respiratory consequences of exposure to wood dust

and formaldehyde of workers manufacturing oriented strand board. Arch Environ Health 49:465-470.

Herbert FA, Hessel PA, Melenka LS, et al. 1995. Pulmonary effects of simultaneous exposures to MDI

formaldehyde and wood dust on workers in an oriented strand board plant. J Occup Environ Med 37:461-

465.

*Hernberg S, Collan Y, Degerth R, et al. 1983a. Nasal cancer and occupational exposures: Preliminary

report of a joint Nordic case-referent study. Scand J Work Environ Health 9:208-213.

*Hernberg S, Westerholm P, Schultz-Larsen K, et al. 1983b. Nasal and sinonasal cancer: Connection

with occupational exposures in Denmark, Finland and Sweden. Scand J Work Environ Health 9:315-326.
FORMALDEHYDE 375

8. REFERENCES

Herrera JM, Nieves AJ, Gutierrez MDP, et al. 1997. [Citotoxicity produced by formaldehyde

(atmospheric contaminant) in the rat central nervous system]. Rev Mex Cienc Farm 28:21-27. (Spanish).

Hess SM, Fitzhugh OG. 1955. Absorption and excretion of certain triphenyl-methane colors in rats and

dogs. J Pharmacol Exp Ther 114:38-42.

*Heukelekian H, Rand MC. 1955. Biochemical oxygen demand of pure organic compounds. Sewage

Ind Waste 27:1040-1053.

Hileman B. 1983. Indoor air pollution. Environ Sci Technol 17:469A-472A.

*Hilton J, Dearman RJ, Basketter DA, et al. 1996. Experimental assessment of the sensitizing properties

of formaldehyde. Food Chem Toxicol 34:571-578.

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. Contact Dermatitis 9:29-

33.

*Ho MH, Richards RA. 1990. Enzymatic method for the determination of formaldehyde. Environ Sci

Technol 24:201-204.

*Hodgson AT, Wooley JD, Daisey JM. 1993. Emissions of volatile organic compounds from new carpet

measured in a large scale environmental chamber. J Air Waste Manage Assoc 43:316-324.

Hogue CJ, Brewster MA. 1991. The potential of exposure biomarkers in epidemiologic studies of

reproductive health. Environ Health Perspect 90:261-269.

Holcatova I, Bencko V. 1997. Health aspects of formaldehyde in the indoor environment. Czech and

Slovak experience. Cent Eur J Public Health 5:38-42.

Holly EA, Aston DA, Ahn DK, et al. 1996. Intraocular melanoma linked to occupations and chemical

exposures. Epidemiology 7:55-61.

Holmstrom M, Lund VJ. 1991. Malignant melanomas of the nasal cavity after occupational exposure to

formaldehyde. Br J Ind Med 48:9-11.

Holmstrom M, Wihelmsson B. 1988. Respiratory symptoms and pathophysiological effects of

occupational exposure to formaldehyde and wood dust. Scand J Work Environ Health 14:306-311.

*Holmstrom M, Rynnel-Dagoo B, Wilhelmsson B. 1989b. Antibody production in rats after long-term

exposure to formaldehyde. Toxicol Appl Pharmacol 100:328-333.

Holmstrom 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 (Stockh) 108:274-283.

*Holmstrom 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 (Stockh) 107:120-129.

*Holness DL, Nethercott JR. 1989. Health status of funeral service workers exposed to formaldehyde. 

Arch Environ Health 44:222-228.
FORMALDEHYDE 376

8. REFERENCES

Homma Y, Oyasu R. 1986. Transient and persistent hyperplasia in heterotopically transplanted rat

urinary bladders induced by formalin and foreign bodies. J Urol 136:136-140.

Homma Y, Nowels K, Oyasu R. 1986. Effects of formalin-induced injuries on urinary bladder

carcinogenesis. Cancer Lett 32:17-23.

*Hoogenboom BE, Hynes RW, Mann CM, et al. 1987. Validation of a colorimetric method for

determination of atmospheric formaldehyde. Am Ind Hyg Assoc J 48:420-424.

Hoover MD, Harkema JR, Muggenburg BA, et al. 1993. A microspray nozzle for local administration of

liquids or suspensions to lung airways via bronchoscopy. J Aerosol Med 6:67-72.

Hopkins J. 1985. Formaldehyde epidemiology: A mouthful of uncertainty. Food Chem Toxicol

23:1024-1028.

Horsfall FLJ. 1934. Formaldehyde hypersensitiveness. An experimental study. J Immunol 27:569-581.

Horton V L, Higuchi MA, Rickert DE. 1992. Physiologically based pharmacokinetic model for

methanol in rats, monkeys, and humans. Toxicol Appl Pharmacol 117:26-36.

*Horvath EP, Anderson H, Pierce WE, et al. 1988. Effects of formaldehyde on the mucous membranes

and lungs: A study of an industrial population. JAMA,J Am Med Assoc 259:701-707.

*Hose JE, Lightner DV. 1980. Absence of formaldehyde residues in Penaeid shrimp exposed to

formalin. Aquaculture 21:197-201.

*Howard PH. 1989. Formaldehyde. In: Howard PH, ed. Handbook of Environmental Fate and

Exposure Data for Organic Chemicals. Chelsea, MI : Lewis Publishers, 342-350.

Howick CJ, McCarthy SA. 1996. Studies of possible chemical emissions from PVC articles used in

indoor applications and the effect on indoor air quality. J Vinyl Addit Technol 2:134-142.

Howlett CT, Mathias R, Friess S. 1989. Quantitative risk approaches for formaldehyde. Exp Pathol

37:119-127.

Hoxey EV, Soper CJ, Davies DJG. 1985. Biological indicators for low temperature steam formaldehyde

sterilization: Effect of defined media on sporulation, germination index and moist heat resistance at 110

degrees C of bacillus strains. J Appl Bacteriol 58:207-214.

*HSDB. 1999. Hazardous Substance Data Bank. National Library of Medicine, National Toxicology

Information Program, Bethesda MD. March 3, 1999.

Hubal EAC, Schlosser PM, Conolly RB, et al. 1997. Comparison of inhaled formaldehyde dosimetry

predictions with DNA-protein cross-link measurements in the rat nasal passages. Toxicol Appl

Pharmacol 143:47-55.

*Hurni H, Ohder H. 1973. Reproduction study with formaldehyde and hexamethylenetetramine in

beagle dogs. Food Cosmet Toxicol 11:459-462.
FORMALDEHYDE 377

8. REFERENCES

*Hushon J, Clerman R, Small R, et al. 1980. An assessment of potentially carcinogenic energy-related

contaminants in water. McLean, VA: Prepared for US Department of Energy and National Cancer

Institute.

Ianysheva NI, Balenko NV, Chernichenko IA, et al. 1998. [Characteristics of modifying effects of

formaldehyde on carcinogenesis]. Gig Sanit 1:51-54. (Russian) [Translation in progress].

*IARC. 1982. IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Vol.

29: Some industrial chemicals and dyestuffs. World Health Organization, Lyon, France. 

*IARC. 1987. IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Supp.

7: Overall evaluations of carcinogenicity: An updating of volumes 1 to 42. World Health Organization,

Lyon, France. 

*IARC. 1995. IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. Vol.

62: Wood dusts and formaldehyde. World Health Organization, Lyon, France. 

*Igawa M, Munger WJ, Hoffman MR. 1989. Analysis of aldehydes in cloud- and fogwater samples by

HPLC with a postcolumn reaction detector. Environ Sci Technol 23:556-561.

Imbus HR. 1985. Clinical evaluation of patients with complaints related to formaldehyde exposure. J

Allergy Clin Immunol 76:831-840.

Imbus HR. 1988. A review of regulatory risk assessment with formaldehyde as an example. Regul

Toxicol Pharmacol 8:356-366.

Infante PF, Schneiderman MA. 1986. Formaldehyde, lung cancer and bronchitis. Lancet 1:436-437.

Infante PF, Ulsamer AG, Groth D, et al. 1981. Health hazards of formaldehyde. Lancet Oct. 31:980-

982.

Inour T, Ishiwata H, Yoshirhira K. 1987. Chemical, physical and microbiological indexes to the surface

deterioration of melamine resin. J Food Hyg Soc Jpn 28:348-353.

International Expert Panel on Carcinogen Risk Assessment. 1996. The use of mechanistic data in the

risk assessments of ten chemicals: An introduction to the chemical-specific reviews. Pharmacol Ther

71:1-5.

IRIS. 1995. Integrated Risk Information System (IRIS). Online. U.S. Environmental Protection

Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,

Cincinnati, OH. October 1995.

IRIS. 1998. Integrated Risk Information System (IRIS). Online. U.S. Environmental Protection

Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,

Cincinnati, OH. November 1998. http:\\www.epa.gov\ngispgm3\iris\subst.

*IRIS. 1999. Integrated Risk Information System (IRIS). Online. U.S. Environmental Protection

Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,

Cincinnati, OH. April 1999. http:\\www.epa.gov\ngispgm3\iris\subst.
FORMALDEHYDE 378

8. REFERENCES

*IRPTC. 1985. Treatment and disposal methods for waste chemicals. International Registry of

Potentially Toxic Chemicals. United Nations Environmental Programme, Geneva, Switzerland.

Ito K, Sakamoto T, Hayashi Y, et al. 1996. Role of tachykinin and bradykinin receptors and mast cells in

gaseous formaldehyde-induced airway microvascular leakage in rats. Eur J Pharmacol 307:291-298.

*Iversen OH. 1986. Formaldehyde and skin carcinogenesis. Environ Int 12:541-544.

*Iversen OH. 1988. Formaldehyde and skin tumorigenesis in Sencar mice. Environ Int 14:23-28.

*Jankovic J, Jones W, Burkhart J, et al. 1991. Environmental study of firefighters. Ann Occup Hyg

35:581-602.

Jarvholm B, Ljungkivst G, Laventius B, et al. 1995. Acetic aldehyde and formaldehyde in cutting fluids

and their relation to irritant symptoms. Ann Occup Hyg 39:591-601.

*Jeffcoat AR, Chasalow F, Feldman DB. 1983. Disposition of [14C] formaldehyde after topical exposure

to rats, guinea pigs, and monkeys. In: Gibson JE, ed. Formaldehyde toxicity. Washington, DC:

Hemisphere Publishing Corporation, 38-50.

Jeng H-W, Feigal RJ, Messer HH. 1987. Comparison of the cytotoxicity of formocresol, formaldehyde,

cresol, and glutaraldehyde using human pulp fibroblast cultures. Pediatr Dent 9:295-300.

*Jensen OM, Andersen SK. 1982. Lung cancer risk from formaldehyde. Lancet 1:913.

Ji C, Mirvish SS, Nickols J, et al. 1989. Formation of hydroxy derivative, aldehydes, and nitrite from nnitrosomethyl-n-amylamine by rat liver microsomes and by purified cytochrome P-450 IIB1. Cancer Res

49:5299-5304.

Jiang X-zhi, Zhang R-wen. 1988. The toxicity and potential risk of occupational exposure to

formaldehyde. In: Xue S-Z, Liang Y-X, ed. Occupational health in industrialization and modernization. 

Shanghai: Shanghai Medical University Press, 70-74.

*Johannsen FR, Levinskas GJ, Tegeris AS. 1986. Effects of formaldehyde in the rat and dog following

oral exposure. Toxicol Lett 30:1-6.

*Johanson CE. 1980. Permeability and vascularity of the developing brain: cerebellum vs cerebral

cortex. Brain Res 190:3-16.

Johansson EB, Tjalve H. 1978. The distribution of [14C] dimethylnitrosamine in mice. Autoradiographic

studies in mice with inhibited and noninhibited dimethylnitrosamine metabolism and a comparison with

the distribution of [14C]formaldehyde. Toxicol Appl Pharmacol 45:565-575.

John EM, Savitz DA, Shy CM. 1994. Spontaneous abortions among cosmetologists. Epidemiology

5:147-155.

Jones AW. 1987. Elimination half-life of methanol during hangover. Pharmacol Toxicol 60:217-220.

Kalabokas P, Carlier P, Fresnet P, et al. 1988. Field studies of aldehyde chemistry in the Paris area. 

Atmos Environ 22:147-155.
FORMALDEHYDE 379

8. REFERENCES

*Kamata E. 1966. Aldehydes in lake and sea waters. Bull Chem Soc Jpn 39:1227-1229.

*Kamata E, Nakadate M, Uchida O, et al. 1996a. 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, Ogawa Y, et al. 1996b. Acute inhalation toxicity study of formaldehyde in

rats: Effect of vapor on the pulmonary surfactant. Pharmacometrics 51:33-37.

*Kamata E, Nakadate M, Uchida O, et al. 1997. Results of a 28-month chronic inhalation toxicity study

of formaldehyde in male Fischer-344 rats. J Toxicol Sci 22:239-254.

Kamata E, Uchida O, Suzuki S, et al. 1984. Toxicological effects of some inhaled chemicals on the

respiratory tract and the lungs of rats (first report) [Abstract]. Toxicol Sci 9:303.

Kamata E, Uchida O, Suzuki S, et al. 1985. Toxicological effects of some inhaled chemicals on the

respiratory tract and the lungs of rats (2nd report) [Abstract]. Toxicol Sci 10:258.

Kaminski J, Atwal AS, Mahadevan S. 1993a. High performance liquid chromatographic determination

of formaldehyde in milk. J Liquid Chromatogr 16:521-526.

*Kaminski J, Atwal AS, Mahadevan S. 1993b. Determination of formaldehyde in fresh and retail milk

by liquid column chromatography. J Assoc Off Anal Chem 76:1010-1013.

*Kane LE, Alarie Y. 1977. Sensory irritation to formaldehyde and acrolein during single and repeated

exposures in mice. Am Ind Hyg Assoc J 38:509-522.

Kang KM, Corey G, Storrs FJ. 1995. Follow-up study of patients allergic to formaldehyde and

formaldehyde releasers: Retention of information, compliance, course, and persistence of allergy. 

Contact Dermatitis 6:209-215.

*Kao AS. 1994. Formation and removal reactions of hazardous air pollutants. J Air Waste Manage

Assoc 44:683-696.

*Karlberg A-T, Skare L, Lindberg I, et al. 1998. A method for quantification of formaldehyde in the

presence of formaldehyde donors in skin-care products. Contact Dermatitis 38:20-28.

Katakura Y, Kishi R, Okui T, et al. 1993. Distribution of radioactivity from 14C-formaldehyde in

pregnant mice and their fetuses. Br J Ind Med 50:176-182.

Katayama N, Honda Y, Fujimaki H. 1992. Growth and functional modifications in formaldehyde-treated

mouse bone marrow-derived mast cells. Toxicol in Vitro 6:239-243.

Keefer LK, Streeter AJ, Leung LY, et al. 1987. Pharmacokinetic and deuterium isotope effect studies on

the metabolism of formaldehyde and formate to carbon dioxide in rats in vivo. Drug Metab Dispos

15:300-304.

Keller DA, Heck Hd'A, Randall HW, et al. 1990. Histochemical localization of formaldehyde

dehydrogenase in the rat. Toxicol Appl Pharmacol 106:311-326.

*Kelly TJ, Mukund R, Spicer CW, et al. 1994. Concentrations and transformations of hazardous air

pollutants. Environ Sci Technol 28:378A-387A.
FORMALDEHYDE 380

8. REFERENCES

*Kelly TJ, Satola JR, Smith DL. 1996. Emission Rates of Formaldehyde and Other Carbonyls from

Consumer and Industrial Products Found in California Homes. In: Meas. Toxic Relat. Air Pollut., Proc.

Int. Spec. Conf. Pittsburgh, PA: Air & Waste Management Association, 521-526.

Kennedy G, Slaich PK, Golding BT, et al. 1996. Structure and mechanism of formation of a new adduct

from formaldehyde and guanosine. Chem Biol Interact 102:93-100.

*Kepler GM, Joyner DR, Fleishman A, et al. 1995. Method for obtaining accurate geometrical

coordinates of nasal airways for computer dosimetry modeling and lesion mapping. Inhal Toxicol

7:1207-1224.

*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.

Kerns WD, Donofrio DJ, Pavkov KL. 1983a. The chronic effects of formaldehyde inhalation in rats and

mice: A preliminary report. In: Gibson JE, ed. Formaldehyde toxicity. Washington, DC: Hemisphere

Publishing Corporation, 111-131.

*Kerns WD, Pavkov KL, Donofrio DJ, et al. 1983b. Carcinogenicity of formaldehyde in rats and mice

after long-term inhalation exposure. Cancer Res 43:4382-4391.

*Khamgaonkar MB, Fulare MB. 1991. Pulmonary effects of formaldehyde exposure - an environmentalepidemiological study. Indian J Chest Dis Allied Sci 33:9-13.

Khamgaonkar MB, Fulare MB. 1992. Formaldehyde induced symptoms in medical laboratories. Indian

J Ind Med 38:129-131.

Kiec-Swierczynska M. 1995. [Preliminary assessment of the effect of disinfectants on skin changes in

health service workers.]. Med Pr 46:149-150. (Polish)

*Kiec-Swierczynska M. 1996. Occupational allergic contact dermatitis in Lodz: 1990-1994. Occup

Med 48:205-208.

*Kiefer M, Moss CE. 1997. Laser generated air contaminants released during laser cutting of fabrics and

polymers. J Laser Appl 9:7-13.

*Kilburn KH. 1994. Neurobehavioral impairment and seizures from formaldehyde. Arch Environ

Health 49:37-44.

Kilburn KH, Moro A. 1985. Reproductive and maternal effects of formaldehyde (HCHO) in rats

[Abstract]. Fed Proc 44:535.

*Kilburn KH, Warshaw RH. 1992. Neurobehavioral effects of formaldehyde and solvents on histology

technicians: Repeated testing across time. Environ Res 58:134-146.

*Kilburn KH, Warshaw R, Boylen CT, et al. 1985a. Pulmonary and neurobehavioral effects of

formaldehyde exposure. Arch Environ Health 40:254-260.

*Kilburn KH, Seidman BC, Warshaw BA. 1985b. Neurobehavioral and respiratory symptoms of

formaldehyde and xylene exposure in histology technicians. Arch Environ Health 40:229-233.
FORMALDEHYDE 381

8. REFERENCES

*Kilburn KH, Warshaw R, Thornton JC. 1987. Formaldehyde impairs memory, equilibrium and

dexterity in histology technicians: Effects which persist for days after exposure. Arch Environ Health

42:117-120.

Kilburn KH, Warshaw R, Thornton JC. 1989. Pulmonary function in histology technicians compared

with women from Michigan: effects of chronic low dose formaldehyde on a national sample of women. 

Br J Ind Med 46:468-472.

*Kimbell JS, Gross EA, Joyner DR, et al. 1993. Application of computational fluid dynamics to regional

dosimetry of inhaled chemicals in the upper respiratory tract of the rat. Toxicol Appl Pharmacol 121:253-

263.

*Kimbell JS, Gross EA, Richardson RB, et al. 1997a. Correlation of regional formaldehyde flux

predictions with the distribution of formaldehyde-induced squamous metaplasia in F344 rat nasal

passages. Mutat Res 380:143-154.

*Kimbell JS, Subramaniam RP, Miller FJ. 1997b. Computer models of nasal airflow inhaled gas uptake

in the rat, monkey, and human: Implications for interspecies dosimetry. CIIT Act 17:1-12.

King JL, Rappaport SM. 1992. Application of an anova model to evaluate occupational exposure to

formaldehyde [Abstract]. Am Chem Soc Abstr Pap 203rd ACS National Meeting:CHAS 37.

*Kirchstetter TW, Singer BC, Harley RA, et al. 1996. Impact of oxygenated gasoline use on California

light-duty vehicle emissions. Environ Sci Technol 30:661-670.

*Kirschner EM. 1996. Growth of top 50 chemicals slowed in 1995 from very high 1994 rate. Chem Eng

News 74:16-18.

Kitaeva LV, Mikheeva EA, Shelomova LF, et al. 1996. [Genotoxic effect of formaldehyde in somatic

human cells in vivo]. Genetika 32:1287-1290. (Russian) [Translation in progress]

*Klaassen CD. 1996. Air pollution. In: Klaassen CD, Amdur MO, Doull J, ed. Casarett and Doull's

Toxicology: the basic science of poisons. New York: McGraw-Hill, 877-878.

Kleindienst TE, Hudgens EE, Smith DF, et al. 1993. Comparison of chemiluminescence and ultraviolet

ozone monitor responses in the presence of humidity and photochemical pollutants. J Air Waste Manage

Assoc 43:213-222.

*Kleindienst TE, Shepson PB, Edney EO, et al. 1986. Wood smoke: Measurement of the mutagenic

activities of its gas and particulate-phase photooxidation products. Environ Sci Technol 20:493-501.

Klein-Szanto AJP, Ura H, Resau J. 1989. Formaldehyde-induced lesions of xenotransplanted human

nasal respiratory epithelium. Toxicol Pathol 17:33-37.

*Kligerman AD, Phelps MC, Erexsan GL. 1984. Cytogenetic analysis of lymphocytes from rats

following formaldehyde inhalation. Toxicol Lett 21:241-246.

Kline BS. 1925. Formaldehyde poisoning with report of a fatal case. Arch Intern Med 36:220-228.

Koch P. 1995. Occupational contact dermatitis from colophony and formaldehyde in banknote paper. 

Contact Dermatitis 32:371-372.
FORMALDEHYDE 382

8. REFERENCES

*Kochhar R, Nanda V, Nagi B, et al. 1986. Formaldehyde-induced corrosive gastric cicatrization: Case

report. Hum Toxicol 5:381-382.

*Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450

in human liver. Biochemistry 29:4430-4433.

*Konopinski VJ. 1983. Formaldehyde in office and commercial environments. Am Ind Hyg Assoc J

44:205-208.

Koo WWK, Kaplan LA, Krug-Wispe SK. 1988. Aluminum contamination of infant formulas. JPEN,J

Parenter Enteral Nutr 12:170-173.

*Koppel C, Baudisch H, Schneider V, et al. 1990. Suicidal ingestion of formalin with fatal

complications. Intensive Care Med 16:212-214.

*Korky JK, Schwarz SR, Lustigman BK. 1987. Formaldehyde concentrations in biology department

teaching facilities. Bull Environ Contam Toxicol 18:907-910.

*Kornbrust DJ, Bus JS. 1983. The role of glutathione and cytochrome P-450 in the metabolism of

methyl chloride. Toxicol Appl Pharmacol 67:246-256.

*Korpan YI, Gonchar MV, Starodub NF, et al. 1993. A cell biosensor specific for formaldehyde based

on pH-sensitive transistors coupled to methylotrophic yeast cells with genetically adjusted metabolism. 

Anal Biochem 215:216-222.

*Krakowiak A, Gorski P, Pazdrak K, et al. 1998. Airway response to formaldehyde inhalation in

asthmatic subjects with suspected respiratory formaldehyde sensitization. Am J Ind Med 33:274-281.

*Kramps JA, Peltenburg LTC, Kerklaan PRM, et al. 1989. Measurement of specific IgE antibodies in

individuals exposed to formaldehyde. Clin Exp Allergy 19:509-514.

Kranke B, Aberer W. 1997. [Severe anaphylactoid reactions to formaldehyde and paraformaldehyde in

dentistry]. Allergologie 20:246-251. (German)

Kranke B, Szolar-Platzer C, Aberer W. 1996. Reactions to formaldehyde and formaldehyde releasers in

a standard series. Contact Dermatitis 35:192-193.

Kreiger N. 1983. Formaldehyde and nasal cancer mortality. Can Med Assoc J 128:248-249.

*Kreiger RA, Garry VF. 1983. Formaldehyde-induced cytotoxicity and sister-chromatid exchanges in

human lymphocyte cultures. Mutat Res 120:51-55.

*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.

*Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In:

Hayes AW, ed. Principles and methods of toxicology. New York, NY: Raven Press, Ltd., 149-188.

*Krishnan K, Anderson ME, Clewell HJIII, et al. 1994. Physiologically based pharmacokinetic

modeling of chemical mixtures. In: Yang RSH, ed. Toxicology of chemical mixtures. New York, NY:

Academic Press, 399-437.
FORMALDEHYDE 383

8. REFERENCES

*Krivanek ND, Imbus HR. 1992. Formaldehyde - studies on irritation at low levels. Comments Toxicol

4:315-330.

Krokan H, Grafstrom RC, Sundqvist K, et al. 1985. Cytotoxicity, thiol depletion and inhibition of O6

-

methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts. 

Carcinogenesis 6:1755-1760.

*Krootila K, Uusitalo H, Lehtosalo JI, et al. 1986. Effect of topical chemical irritation on the bloodaqueous barrier of the right eye. Ophthalmic Res 18:248-252.

*Krzyzanowski M, Quackenboss JJ, Lebowitz MD. 1990. Chronic respiratory effects of indoor

formaldehyde exposure. Environ Res 52:117-125.

Ku RH, Billings RE. 1986. The role of mitochondrial gluthione and cellular protein sulfhydryls in

formaldehyde toxicity in glutathione-depleted rat hepatocytes. Arch Biochem Biophys 247:183-189.

*Kulle TJ. 1993. Acute odor and irritation response in health nonsmokers with formaldehyde exposure. 

Inhal Toxicol 5:323-332.

Kulle TJ, Green DJ, Sauder LR. 1986. Acute pulmonary effects of 3.0 ppm formaldehyde in exercising

healthy nonsmokers and asthmatics [Abstracts]. Am Rev Respir Dis 133:A 355.

*Kulle TJ, Sauder LR, Hebel JR, et al. 1987. Formaldehyde dose-response in healthy nonsmokers. J Air

Pollut Control Assoc 37:919-924.

*Kumar S. 1986. Reactive scavenging of pollutants by rain: A modeling approach. Atmos Environ

20:1015-1024.

Kuo HW, Jian GJ, Liu CS, et al. 1997. White blood cell count as an indicator of formaldehyde exposure. 

Bull Environ Contam Toxicol 59:261-267.

*Kuykendall JR, Trela BA, Bogdanffy MS. 1995. DNA-protein crosslink formation in rat nasal

epithelial cells by hexamethylphosphoramide and its correlation with formaldehyde production. Mutat

Res 343:209-218.

Ladanyi E, Stalder K. 1986. Differential pulse-polarographic determination of formaldehyde in lung

surfactant. Bioelectrochem Bioenerg 15:89-93.

Lai Y-L. 1991. Comparative ventilation of the normal lung. In: Parent RA, ed. Comparative biology of

the normal lung. Boca Raton, FL: CRC Press, 217-239.

*Lam C-W, Casanova M, Heck Hd'A. 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.

*Lamb B, Westberg H, Bryant P, et al. 1985. Air infiltration rates in pre- and post-weatherized houses. 

J Air Pollut Control Assoc 35:541-551.

Langhorst ML, Coyne LB. 1987. Industrial hygiene. Anal Chem 59:1R-17R.
FORMALDEHYDE 384

8. REFERENCES

*Lawryk NJ, Weisel CP. 1996. Concentrations of volatile organic compounds in the passenger

compartments of automobiles. Environ Sci Technol 30:810-816.

*Lawryk NJ, Lioy PJ, Weisel CP. 1995. Exposure to volatile organic compounds in the passenger

compartment of automobiles during periods of normal and malfunctioning operation. J Expo Anal

Environ Epidemiol 5:511-531.

Le L, Ayer S, Place AR, et al. 1990. Analysis of formaldehyde-induced Adh mutations in Drosophila by

RNA structure mapping and direct sequencing of PCR-amplified genomic DNA. Biochem Gen 28:367-

387.

Lee HK, Alarie Y, Karol MH. 1984. Induction of formaldehyde sensitivity in guinea pigs. Toxicol Appl

Pharmacol 75:147-155.

Lee Y-N, Zhou X. 1993. Method for the determination of some soluble atmospheric carbonyl

compounds. Environ Sci Technol 27:749-756.

*Leeder JS, Kearns GL. 1997. Pharmcogenetics in pediatrics: implications for practice. Pediatr Clin

North Am 44:55-77.

Lehotay J, Hromulakova K. 1994. HPLC determination of trace levels of aliphatic aldehydes C1-C4 in

river and tap water using on-line preconcentration. J Liquid Chromatogr 17:579-588.

Leikauf GD, Doupnik CA. 1989. Formaldehyde-induced bronchial hyperresponsiveness in guinea pig

[Abstract]. Am Rev Respir Dis 139:A392.

Leininger JR, Gross EA, Monticello TM, et al. 1995. Morphogenesis of formaldehyde-induced

neoplastic nasal lesions in male F344 rats [Abstract]. Proc Am Assoc Cancer Res 36:130.

*Lemiere C, Desjardins A, Cloutier Y, et al. 1995. Occupational asthma due to formaldehyde resin dust

with and without reaction to formaldehyde gas. Eur Resp J 8:861-865.

Le Moual N, Orlowski E, Schenker MB, et al. 1995. Occupational exposures estimated by means of job

exposure matrices in relation to lung function in the PAARC survey. Occup Environ Med 52:634-643.

*Leonardos G, Kendall D, Barnard N. 1969. Odor threshold determinations of 53 odorant chemicals. J

Air Pollut Control Assoc 19:91-95.

*Leovic KW, Sheldon LS, Whitaker DA, et al. 1996. Measurement of indoor air emissions from dryprocess photocopy machines. J Air Waste Manage Assoc 46:821-829.

*Leung H-W. 1993. Physiologically-based pharmacokinetic modelling. In: Ballentine B, Marro T,

Turner P, ed. General and applied toxicology. New York: Stockton Press, 153-164.

Levin J-O, Lindahl R, Andersson K. 1989. Monitoring of parts-per-billion levels of formaldehyde using

a diffuse sampler. J Air Waste Manage Assoc 39:44-47.

*Levine RJ, Andjelkovich DA, Shaw LK. 1984a. The mortality of Ontario undertakers and a review of

formaldehyde-related mortality studies. J Occup Med 26:740-746.
FORMALDEHYDE 385

8. REFERENCES

Levine RJ, DalCorso D, Blunden PB, et al. 1984b. The effects of occupational exposure on the

respiratory health of West Virginia morticians. J Occup Med 26:91-98.

Levison LA. 1904. A case of fatal formaldehyd poisoning. JAMA,J Am Med Assoc 42:1492.

Levy RJ, Schoen FJ, Sherman FS, et al. 1986. Calcification of subcutaneously implanted Type I

collagen sponges: Effects of formaldehyde and glutaraldehyde pretreatments. Am J Pathol 122:71-82.

Levy S, Nocentini S, Billardon C. 1983. Induction of cytogenetic effects in human fibroblast cultures

after exposure to formaldehyde or X-rays. Mutat Res 119:309-317.

Lewin S. 1966. Reaction of salmon sperm deoxyribonucleic acid with formaldehyde. Arch Biochem

Biophys 113:584-602.

Lewis BB, Chestner SB. 1981. Formaldehyde in dentistry: a review of mutagenic and carcinogenic

potential. J Am Dent Assoc 103:429-434.

*Lewis RJ. 1993. Hawley's Condensed chemical dictionary. 12th ed. New York, NY: Van Nostrand

Reinhold Company.

Li AP, Gupta RS, Heflich RH, et al. 1988. A review and analysis of the Chinese hamster ovary/

hypoxanthine-guanine phosphoribosyltransferase assay to determine the mutagenicity of chemical agents.

A report of phase III of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res

196:17-36.

*Li Q, Wang ZY, Inagaki H, et al. 1995. Evaluation of contact sensitivity to formaldehyde and

tetramethylthiuram monosulfide using a modified lymphocyte transformation test. Toxicology 104:17-

23.

*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.

*Lide DR, Frederikse HPR. 1996. CRC Handbook of chemistry and physics: A ready-reference book of

chemical and physical data. 77th ed. Boca Raton, FL: CRC Press.

Liden S, Scheynius A, Fischer T, et al. 1993. Absence of specific IgE antibodies in allergic contact

sensitivity to formaldehyde. Allergy 48:525-529.

Liebling T, Rosenman KD, Pastides H, 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.

Liesivuori J, Savolainen H. 1991. Methanol and formic acid toxicity: Biochemical mechanisms. 

Pharmacol Toxicol 69:157-163.

Lin JM, Tang CS. 1994. Characterization and aliphatic aldehyde content of particulates in Chinese

incense smoke. Bull Environ Contam Toxicol 53:895-901.
FORMALDEHYDE 386

8. REFERENCES

*Lin Y, Duecker SR, Jones AD, et al. 1995. Protocol for collection and HPLC analysis of volatile

carbonyl compounds in breath. Clin Chem 41:1028-1032.

Lindskov R. 1982. Contact urticaria to formaldehyde. Contact Dermatitis 8:333-334.

Lipari F, Dasch JM, Scruggs WF. 1984. Aldehyde emissions from wood-burning fireplaces. Environ

Sci Technol 18:326-330.

Liu K-S, Petreas M, Hayward S. 1986. A survey of formaldehyde concentrations inside California

mobile homes [Abstract]. Prepr Pap Natl Meet Am Chem Soc Div Environ Chem September 7-12,

1986:ENVR 94.

Liu KS, Huang FY, Hayward SB, et al. 1991. Survey of formaldehyde concentrations and health effects

in mobile homes [Abstract]. Arch Environ Health 46:181-182.

Loden M. 1986a. The in vitro permeability of human skin to benzene, ethylene glycol, formaldehyde,

and n-hexane. Acta Pharmacol Toxicol (Copenh) 58:382-389.

Loden M. 1986b. The effect of 4 barrier creams on the absorption of water, benzene, and formaldehyde

into excised human skin. Contact Dermatitis 14:292-296.

*Lofroth G, Burton RM, Forehand L, et al. 1989. Characterization of environmental tobacco smoke. 

Environ Sci Technol 23:610-614.

*Logue JN, Barrick MK, Jessup GL. 1986. Mortality of radiologists and pathologists in the Radiation

Registry of Physicians. J Occup Med 28:91-99.

*Loomis TA. 1979. Formaldehyde toxicity. Arch Pathol Lab Med 103:321-324.

Lowe DC, Schmidt U. 1983. Formaldehyde (HCHO) measurements in the nonurban atmosphere. J

Geophys Res 88:10844-10858.

*Lowe DC, Schmidt U, Ehhalt DH. 1980. A new technique for measuring tropospheric formaldehyde

[CH2O]. Geophys Res Lett 7:825-828.

Lowe DC, Schmidt U, Ehhalt DH, et al. 1981. Determination of formaldehyde in clean air. Environ Sci

Technol 15:819-823.

Lowengart RA, Peters JM, Cicioni C, et al. 1987. Childhood leukemia and parents' occupational and

home exposures. J Natl Cancer Inst 79:39-46.

Luce D, Gerin M, Berrino F, et al. 1993a. Sources of discrepancies between a job exposure matrix and a

case by case expert assessment for occupational exposure to formaldehyde and wood-dust. Int J

Epidemiol 22:S113-S120.

*Luce D, Gerin M, Leclerc A, et al. 1993b. Sinonasal cancer and occupational exposure to

formaldehyde and other substances. Int J Cancer 53:224-231.

*Luker MA, Van Houten RW. 1990. Control of formaldehyde in a garment sewing plant. Am Ind Hyg

Assoc J 51:541-544.
FORMALDEHYDE 387

8. REFERENCES

Lutz KL. 1986. Endogenous formaldehyde does not produce detectable DNA-protein crosslinks in rat

liver. Toxicol Pathol 14:462-465.

*Lyman WJ. 1982. Adsorption coefficient for soils and sediments. In: Lyman WJ, Reehl WF,

Rosenblatt DH, ed. Handbook of chemical property estimation methods: Environmental behavior of

organic compounds. New York: McGraw-Hill Book Company, 4-1 to 4-33.

Lynen R, Rothe M, Gallasch E. 1983. Characterization of formaldehyde-related antibodies encountered

in hemodialysis patients at different stages of immunization. Vox Sang 44:81-89.

Ma T-H, Harris MM. 1985. Genotoxicity studies of formaldehyde using Tradescantia-micronucleus test

[Abstract]. Environ Mutagen 7:42.

Ma T-H, Harris MM. 1988. Review of the genotoxicity of formaldehyde. Mutat Res 196:37-59.

Ma T-H, Xu Z, Harris MM, et al. 1986. Dose-response of formaldehyde-fume-induced chromosome

damage in tradescantia pollen mother cells [Abstract]. Environ Mutagen 8:49.

MacGregor JT, Tucker JD, Ziderman II, et al. 1989. Non-clastogenicity in mouse bone marrow of

fructose/lysine and other sugar/amino acid browning products with in vitro genotoxicity. Food Chem

Toxicol 27:715-721.

Mackay DM, Cherry JA. 1989. Groundwater contamination: Pump-and-treat remediation. Environ Sci

Technol 23:630-636.

Magnani C, Comba P, Ferraris F, et al. 1993. A case-control study of carcinomas of the nose and

paranasal sinuses in the woolen textile manufacturing industry. Arch Environ Health 48:94-97.

Magras IN. 1996. Formaldehyde vapour effects in chicken embryo. Anat Histol Embryol 25:197-200.

*Maibach H. 1983. Formaldehyde: effects on animal and human skin. In: Gibson JE, ed. Formaldehyde

toxicity. Washington, DC: Hemisphere Publishing Corporation, 166-174.

Majumder PK, Kumar VL. 1995. Inhibitory effects of formaldehyde on the reproductive system of male

rats. Indian J Physiol Pharmacol 39:80-82.

*Malaka T, Kodama AM. 1990. Respiratory health of plywood workers occupationally exposed to

formaldehyde. Arch Environ Health 45:288-294.

Malcolm AR, Mills LJ, Trosko JE. 1985. Effects of ethanol, phenol, formaldehyde, and selected

metabolites on metabolic cooperation between Chinese hamster V79 lung fibroblasts. Carcinogenesis

8:305-318.

Malek FA, Moritz KU, Bienengraber V, et al. 1997. Influence of formaldehyde on the open field

behavior of rats [Abstract]. Teratology 56:399.

*Mansfield CT, Hodge BT, Hege RB, et al. 1977. Analysis of formaldehyde in tobacco smoke by high

performance liquid chromatography. J Chromatogr Sci 15:301-302.

Manzardo S, Coppi G. 1991. [Protective action of certain compounds against the toxic action of

acetaldehyde, acrolein and formaldehyde in the rat]. Boll Chim Farm 130:399-401. (Italian)
FORMALDEHYDE 388

8. REFERENCES

Marison IW, Attwood MM. 1982. A possible alternative mechanism for the oxidation of formaldehyde

to formate. J Gen Microbiol 128:1441-1446.

*Marks JGJ, Belsito DV, DeLeo VA, et al. 1995. North American contact dermatitis group standard tray

patch test results (1992 to 1994). Am J Contact Dermatitis 6:160-165.

*Marks TA, Worthy WC, Staples RE. 1980. Influence of formaldehyde and Sonacide (potentiated acid

glutaraldehyde) on embryo and fetal development in mice. Teratology 22:51-58.

*Maronpot RR, Miller RA, Clarke WJ, et al. 1986. Toxicity of formaldehyde vapor in B6C3F1 mice

exposed for 13 weeks. Toxicology 41:253-266.

Marsh GM. 1982. Proportional mortality patterns among chemical plant workers exposed to

formaldehyde. Br J Ind Med 39:313-322.

*Marsh GM, Stone RA, Esmen NA, et al. 1994. Mortality patterns among chemical plant workers

exposed to formaldehyde and other substances. J Natl Cancer Inst 86:384-386.

*Marsh GM, Stone RA, Esmen NA, et al. 1996. Mortality among chemical workers in a factory where

formaldehyde was used. Occup Environ Med 53:613-627.

Marshall E. 1987. EPA indicts formaldehyde, 7 years later. Science 236:381.

Martin RE, Hizo CB, Ong AM, et al. 1992. Release of formaldehyde and melamine from melamine

tableware manufactured in the Philippines. J Food Prot 55:632-635.

*Martin WJ. 1990. A teratology study of inhaled formaldehyde in the rat. Reprod Toxicol 4:237-239.

Marzulli FN, Maibach HI. 1973. Antimicrobials: Experimental contact sensitization in man. J Soc

Cosmet Chem 24:399-421.

Mashford PM, Jones AR. 1982. Formaldehyde metabolism by the rat: a re-appraisal. Xenobiotica

12:119-124.

*Matanoski, GM. 1991. Risks of pathologists exposed to formaldehyde. DHHS grant no. 5 RO1

OHO1511-03. PB91-173682.

Mathison BH, Harman AE, Bogdanffy MS. 1997. DNA damage in the nasal passageway: a literature

review. Mutat Res 380:77-96.

Matsuda H, Ose Y, Nagase H, et al. 1991. Mutagenicity of the components of ozonated humic

substance. Sci Total Environ 103:129-140.

Matsuda H, Hibino M, Sato T, et al. 1993a. Mutagenicity of ozonated and chlorinated humic substances. 

J Environ Sci Health Part A 28:821-837.

Matsuda H, Sato T, Nagase H, et al. 1992. Aldehydes as mutagens formed by ozonation of humic

substances. Sci Total Environ 114:205-213.

Matsuda H, Sato T, Nagase H. 1993b. Behavior of mutagenic aldehydes formed by preozonation in

postchlorination. J Environ Sci Health Part A 28:1553-1564.
FORMALDEHYDE 389

8. REFERENCES

Matsumoto K, Moriya F, Nanikawa R. 1990. The movement of blood formaldehyde in methanol

intoxication. II: The movement of blood formaldehyde and its metabolism in the rabbit. Jpn J Legal Med

44(3):205-211.

Matthews TG, Fung KW, Tromberg BJ, et al. 1986. Impact of indoor environmental parameters on

formaldehyde concentrations in unoccupied research houses. J Air Pollut Control Assoc 36:1244-1249.

Matthews TG, Hawthorne AR, Thompson CV. 1987. Formaldehyde sorption and desorption

characteristics of gypsum wallboard. Environ Sci Technol 21:629-634.

*Matthews TG, Reed TJ, Tromberg BJ, et al. 1985. Formaldehyde emission from combustion sources

and solid formaldehyde-resin-containing products: Potential impact on indoor formaldehyde

concentrations. In: Gammage RB, Kaye SV, Jacobs VA, ed. Indoor air and human health. Chelsea, MI:

Lewis Publishers, Inc., 131-150.

Maurice F, Rivory JP, Bousquet J, et al. 1985. Anaphlyactic shock with formaldehyde [Abstract]. J

Allergy Clin Immunol 75:209.

*Maurice F, Rivory JP, Larsson PH, et al. 1986. Anaphylactic shock caused by formaldehyde in a

patient undergoing long-term hemodialysis. J Allergy Clin Immunol 77:594-597.

Maut W, Bufalino C, McClure T, et al. 1988. Antagonistic effects in inhaled formaldehyde and ozone on

lung injury in resting and exercising rats [Abstract]. FASEB J 2:8723.

McCrae IS, Williams ID. 1994. Road traffic pollution and public nuisance. Sci Total Environ

146/147:81-91.

*McLaughlin JK. 1994. Formaldehyde and cancer: a critical review. Int Arch Occup Environ Health

66:295-301.

McMillan A, Whittemore AS, Silvers A, et al. 1994. Use of biological markers in risk assessment. Risk

Anal 14:807-813.

*Meding B, Swanbeck G. 1990. Occupational hand eczema in an industrial city. Contact Dermatitis

22:13-23.

Medinsky MA, Kimbell JS, Morris JB, et al. 1993. Advances in biologically based models for

respiratory tract uptake of inhaled volatiles. Fundam Appl Toxicol 20:265-272.

Mendelsohn ML, Moore DHII, Lohman PHM. 1992. A method for comparing and combining short-term

genotoxicity test data: Results and interpretation. Mutat Res 266:43-60.

*Menne T, Frosch PJ, Veien NK, et al. 1991. Contact sensitization to 5-chloro-2-methyl-4-isothiazolin3-one and 2-methyl-4-isothiazolin-3-one (MCI/MI): A European multicentre study. Contact Dermatitis

24:334-341.

Merkle SE. 1985. Ambient concentrations of formaldehyde and ammonia in a screwworm fly rearing

facility. Am Ind Hyg Assoc J 46:336-340.

Meyer B. 1986. Formaldehyde exposure from building products. Environ Int 12:283-288.
FORMALDEHYDE 390

8. REFERENCES

*Meyer B, Hermanns K. 1985. Reducing indoor air formaldehyde concentrations. J Air Pollut Control

Assoc 35:816-821.

Meylan WM, Howard PH. 1991. Bond contribution method for estimating Henry's Law constant. 

Environ Toxicol Chem 10:1283-1293.

Miampamba M, Chery-Croze S, Chayvialle JA. 1992. Spinal and intestinal levels of substance P,

calcitonin gene-related peptide and vasoactive intestinal polypeptide following perendoscopic injection of

formalin in rat colonic wall. Neuropeptides 22:73-80.

Miceli JN, Misiak PM. 1986. Air formaldehyde and its association with body burdens. Clin Chem

32:1090.

Migliore L, Ventura L, Barale R, et al. 1989. Micronuclei and nuclear anomalies induced in the gastrointestinal epithelium of rats treated with formaldehyde. Mutagenesis 4:327-334.

*Miller CAIII, Costa M. 1989. Analysis of proteins cross-linked to DNA after treatment of cells with

formaldehyde, chromate and cis-diamminechloroplatinum(II). Mol Toxicol 2:11-26.

Miller RG, Kopfler FC, Kelty KC, et al. 1984. The occurrence of aluminum in drinking water. J Am

Water Works Assoc 76:84-91.

*Millipore Corporation. 1992. Waters Sep-Pak DNPH-Silica Cartridge. Care and use manual. Milford,

MA: Waters Chromatography Publications.

Mills SC, Sharry LF, Cook LJ, et al. 1972. Metabolism of [14C]formaldehyde when fed to ruminants as

an aldehyde-casein-oil complex. Aust J Biol Sci 25:807-816.

*Milton DK, Walters MD, Hammond K, et al. 1996a. Worker exposure to endotoxin, phenolic

compounds, and formaldehyde in a fiberglass insulation manufacturing plant. Am Ind Hyg Assoc J

57:889-896.

Milton DK, Wypij D, Kriebel D, et al. 1996b. Endotoxin exposure-response in a fiberglass

manufacturing facility. Am J Ind Med 29:3-13.

*Miyamoto Y. 1986. Eye and respiratory irritants in jet engine exhaust. Aviat Space Environ Med

57:1104-1108.

Mizra MA, Husain K, Misra S. 1987. Carcinogenic effect of formaldehyde in mice: A biochemical and

histopathological study. Biol Membr 13:132-136.

Molhave L, Dueholm S, Jensen LK. 1995. Assessment of exposures and health risks related to

formaldehyde emissions from furniture: a case study. Indoor Air 5:104-119.

Monks TJ, Anders MW, Dekant W, et al. 1990. Glutathione conjugate mediated toxicities. Toxicol

Appl Pharmacol 106:1-19.

Monroe BA, Lee JS, Livingston GK, et al. 1988. Genetic and pulmonary responses to formaldehyde and

phenol in anatomy lab [Abstract]. Clin Res 36:347A.
FORMALDEHYDE 391

8. REFERENCES

Montanaro A. 1997. Chemically induced nonspecific bronchial hyperresponsiveness. Clin Rev Allergy

Immunol 15:187-203.

*Monteiro-Riviere NA, Popp JA. 1986. Ultrastructural evaluation of acute nasal toxicity in the rat

respiratory epithelium in response to formaldehyde gas. Fundam Appl Toxicol 6:251-262.

Monticello TM. 1991. Formaldehyde-induced pathology and cell proliferation [Abstract]. Diss Abstr Int

B 52:2509-B.

Monticello TM, Morgan KT. 1989. Cell kinetics and characterization of 'preneoplastic' lesions in nasal

respiratory epithelium of rats exposed to formaldehyde [Abstract]. Carcinogenesis 30:195.

Monticello TM, Morgan KT. 1994. Cell proliferation and formaldehyde-induced respiratory

carcinogenesis. Risk Anal 14:313-319.

Monticello TM, Morgan KT. 1997. Chemically-induced nasal carcinogenesis and epithelial cell

proliferation: a brief review. Mutat Res 380:33-41.

Monticello TM, Gross EA, Morgan KT. 1993. Cell proliferation and nasal carcinogenesis. Environ

Health Perspect 101(Suppl. 5):121-124.

*Monticello TM, Miller FJ, Morgan KT. 1991. Regional increases in rat nasal epithelial cell

proliferation following acute and subchronic inhalation of formaldehyde. Toxicol Appl Pharmacol

111:409-421.

*Monticello TM, Morgan KT, Everitt JI, et al. 1989. Effects of formaldehyde gas on the respiratory tract

of Rhesus monkeys. Am J Pathol 134:515-527.

*Monticello TM, Swenberg JA, Gross EA, et al. 1996. Correlation of regional and nonlinear

formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res 56:1012-1022.

*Mopper K, Stahovec WL. 1986. Sources and sinks of low molecular weight organic carbonyl

compounds in seawater. Mar Chem 19:305-321.

*Morgan KT. 1997. A brief review of formaldehyde carcinogenesis in relation to rat nasal pathology and

human health risk assessment. Toxicol Pathol 25:291-307.

Morgan KT, Monticello TM. 1990. Airflow, gas deposition, and lesion distribution in the nasal

passages. Environ Health Perspect 88:209-218.

*Morgan KT, Gross EA, Patterson DL. 1986a. Distribution, progression, and recovery of acute

formaldehyde-induced inhibition of nasal mucociliary function of F-344 rats. Toxicol Appl Pharmacol

86:448-456.

*Morgan KT, Jiang X-Z, 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, Kimbell JS, Monticello TM, et al. 1991. Studies of inspiratory airflow patterns in the nasal

passages of the F344 rat and Rhesus monkey using nasal molds: Relevance to formaldehyde toxicity. 

Toxicol Appl Pharmacol 110:223-240.
FORMALDEHYDE 392

8. REFERENCES

*Morgan KT, Patterson DL, Gross EA. 1986c. Responses of the nasal mucociliary apparatus of F-344

rats to formaldehyde gas. Toxicol Appl Pharmacol 82:1-13.

*Morselli PL, Franco-Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants. 

Clin Pharmacokin 5:485-527.

*Moschandreas D, Relwani S, Johnson D, et al. 1986. Emission rates from unvented gas appliances. 

Environ Int 12:247-253.

Moser J, Bagchi D, Akubue PI, et al. 1993. Excretion of malondialdehyde, formaldehyde, acetaldehyde

and acetone in the urine of rats following acute and chronic administration of ethanol. Alcohol Alcohol

28:287-295.

Moura C, Dias M, Vale T. 1994. Contact dermatitis in painters, polishers and varnishers. Contact

Dermatitis 31:51-53.

Moye HA, Weintraub RA, Jex GW. 1986. Fate of 1,2-dibromoethane (EDB) in the subsurface

environment [Abstract]. Abstr Pap Am Chem Soc 191:ENVR 5.

*Muir PS. 1991. Fogwater chemistry in a wood-burning community, western Oregon. J Air Waste

Manage Assoc 41:32-38.

Muller-Herold U, Caderas D, Funck P. 1997. Validity of global lifetime estimates by a simple general

limiting law for the decay of organic compounds with long-range pollution potential. Environ Sci

Technol 31:3511-3515.

Murphy AP, Boegli WJ, Price MK, et al. 1989. A fenton-like reaction to neutralize formaldehyde waste

solutions. Environ Sci Technol 23:166-169.

*Murphy SD, Davis HV, Zaratzian VL. 1964. Biochemical effects in rats from irritating air

contaminants. Toxicol Appl Pharmacol 6:520-528.

Nagayama J, Nagayama M. 1993. Frequency of micronuclei induced in cultured lymphocytes by highly

toxic organochlorine congeners. Fukuoka Igaku Zasshi 84:189-194.

*Naruse M, Naruse H, Aoyama M. 1995. Determination of formaldehyde in textiles using a diffuse

sampler. Bull Environ Contam Toxicol 55:810-816.

NAS/NRC. 1980. Formaldehyde: An assessment of its health effects. Committee on Toxicology,

National Research Council, National Academy of Sciences for the Consumer Product Safety

Commission, Washington, DC. AD A 087 854, NAS/ACT/P-881A.

*NAS/NRC. 1989. Report of the Oversight Committee. In: Biologic markers in reproductive

toxicology. Washington, DC: National Academy Press, 15-35.

*Natarajan AT, Darroudi F, Bussman CJM, et al. 1983. Evaluation of the mutagenicity of formaldehyde

in mammalian cytogenetic assays in vivo and in vitro. Mutat Res 122:355-360.

Neely WB. 1964. The metabolic fate of formaldehyde-14C intraperitoneally administered to the rat. 

Biochem Pharmacol 13:1137-1142.
FORMALDEHYDE 393

8. REFERENCES

Nelson BK. 1986. Behavioral teratology of industrial solvents. In: Riley EP, Vorhees CV, ed. 

Handbook of behavioral teratology. New York: Plenum Press, 391-406.

Nelson E. 1996. Laboratory probing of oncogenes from human liquid and solid specimens as markers of

exposure to toxicants. Crit Rev Toxicol 26:483-549.

*Nethercott JR, Holness DL. 1988. Contact dermatitis in funeral service workers. Contact Dermatitis

18:263-267.

Nethercott JR, Holness DL, Adams RM, et al. 1994. Multivariate analysis of the effect of selected

factors on the elicitation of patch test response to 28 common environmental contactants in North

America. Am J Contact Dermatitis 5:13-18.

Newsome JR, Norman V, Keith CH. 1965. Vapor phase analysis of tobacco smoke. Tob Int :102-110.

*NFPA (National Fire Protection Agency). 1994. Fire Protection Guide to Hazardous Materials. 11th

ed., Quincy, MA: NFPA, 49-72.

Nilsson C-A, Lindahl R, Norstrom A. 1987. Occupational exposure to chain saw exhausts in logging

operations. Am Ind Hyg Assoc J 48:99-105.

NIOSH. 1976. Criteria for a recommended standard. Occupational exposure to formaldehyde. 

Cincinnati, OH: Department of Health, Education and Welfare, National Institute for Occupational Safety

and Health. DHEW (NIOSH) publication no. 77-126. 

*NIOSH. 1989a. Manual of analytical methods, 3rd edition. Cincinnati, OH: U.S. Department of Health

and Human Services, National Institute for Occupational Safety and Health. 

*NIOSH. 1989b. NIOSH Recommendations for occupational safety and health: Compendium of policy

documents and statements. Cincinnati, OH: U.S. Department of Health and Human Services, National

Institute of Occupational Safety and Health.

NIOSH. 1990. Health hazard evaluation report, HETA 88-068-2077. Schmidt Cabinet Company, New

Salisbury, Indiana. Cincinnati, OH: U.S. Department of Health and Human Services, National Institute

for Occupational Safety and Health. PB91-184515.

*NIOSH. 1992. NIOSH Recommendations for occupational safety and health: Compendium of policy

documents and statements. Cincinnati, OH: U.S. Department of Health and Human Services, National

Institute for Occupational Safety and Health. (DHHS) NIOSH publication no. 92-100.

*NIOSH. 1994a. Manual of analytical methods, 4th edition. Cincinnati, OH: U.S. Department of

Health and Human Services, National Institute for Occupational Safety and Health.

*NIOSH. 1994b. Manual of analytical methods, 4th edition. Cincinnati, OH: U.S. Department of

Health and Human Services, National Institute for Occupational Safety and Health. 

*NIOSH. 1994c. NIOSH Pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of

Health and Human Services, National Institute for Occupational Safety and Health. DHHS (NIOSH)

publication no. 94-116. 
FORMALDEHYDE 394

8. REFERENCES

NIOSH. 1995a. Recommendations for occupational safety and health: Compendium of policy

documents and statements. Cincinnati, OH: U.S. Department of Health and Human Services, National

Institute of Occupational Safety and Health.

*NIOSH. 1995b. Formaldehyde numbers of potentially exposed employees. NOSE-Based Job Exposure

Matrix. Am J Ind Med 20:163-174.

Nishi K, Yamada M, Wakasugi C. 1988. Formaldehyde poisoning: Report of an autopsy case. Jpn J

Legal Med 42(1):85-89.

Niyato-Shirkhodaee F, Shibamoto T. 1992. In vitro determination of toxic aldehydes formed from the

skin lipid, triolein, upon ultraviolet irradiation: Formaldehyde and acrolein. J Toxicol Cutaneous Ocul

Toxicol 11:285-292.

Noble JS, Strang CR, Michael PR. 1993. A comparison of active and passive sampling devices for fullshift and short-term monitoring of formaldehyde. Am Ind Hyg Assoc J 54:723-732.

Nocentini S, Moreno G, Coppey J. 1980. Survival, DNA synthesis and ribosomal RNA transcription in

monkey kidney cells treated by formaldehyde. Mutat Res 70:231-240.

*Nondek L, Milofsky RE, Birks JW. 1991. Determination of carbonyl compounds in air by HPLC using

on-line analyzed microcartridges, fluorescence and chemiluminescence detection. Chromatographia

32:33-39.

*Nondek L, Rodier DR, Birks JW. 1992. Measurement of sub-ppb concentrations of aldehydes in a

forest atmosphere using a new HPLC technique. Environ Sci Technol 26:1174-1178.

*Norback D, Bjornsson E, Janson C, et al. 1995. Asthmatic symptoms and volatile organic compounds,

formaldehyde, and carbon dioxide in dwellings. Occup Environ Med 52:388-395.

*Nordman H, Keskinen H, Tuppurainen M. 1985. Formaldehyde asthma - Rare or overlooked? J

Allergy Clin Immunol 75:91-99.

Norman GR, Pengelly LD, Kerigan AT, et al. 1986. Respiratory function of children in homes insulated

with urea formaldehyde foam insulation. Can Med Assoc J 134:1135-1138.

*Norsted SW, Kozinetz CA, Annegers JF. 1985. Formaldehyde complaint investigations in mobile

homes by the Texas Department of Health. Environ Res 37:93-100.

*NRC. 1981. National Research Council. Formaldehyde and other aldehydes. USEPA 600/6-82-002.

*NRC. 1986. National Research Council. Environmental tobacco smoke: Measuring exposures and

assessing health effects. Washington, DC: National Academy Press.

*NRC. 1993. National Research Council. Pesticides in the diets of infants and children. Washinton,

DC: National Academy Press.

NTP. 1994. Seventh annual report on carcinogens. Research Triangle Park, NC: U. S. Department of

Health and Human Services, Public Health Service, National Toxicology Program, National Institute of

Environmental Health Services.
FORMALDEHYDE 395

8. REFERENCES

*NTP. 1998. Eighth annual report on carcinogens. Research Triangle Park, NC: U. S. Department of

Health and Human Services, Public Health Service, National Toxicology Program, National Institute of

Environmental Health Services.

Nunn AJ, Craigen AA, Darbyshire JH, et al. 1990. Six year follow up of lung function in men

occupationally exposed to formaldehyde. Br J Ind Med 47:747-752.

O'Connor PM, Fox BW. 1987. Comparative studies of DNA cross-linking reactions following

methylene dimethanesulphonate and its hydrolytic product, formaldehyde. Cancer Chemother Pharmacol

19:11-15.

Odeigah PGC. 1997. Sperm head abnormalities and dominant lethal effects of formaldehyde in albino

rats. Mutat Res 389:141-148.

Ohtsuka R, Shuto Y, Fujie H, et al. 1997. Response of respiratory epithelium of BN and F344 rats to

formaldehyde inhalation. Exp Anim 46:279-286.

Olsen JH, Dossing M. 1982. Formaldehyde induced symptoms in day care centers. Am Ind Hyg Assoc J

43:366-370.

*Olsen JH, Jensen SP, Hink M, et al. 1984. Occupational formaldehyde exposure and increased nasal

cancer risk in man. Int J Cancer 34:639-644.

Olson JH, Asnaes S. 1986. Formaldehyde and the risk of squamous cell carcinoma of the sinonasal

cavities. Br J Ind Med 43:769-774.

Olson KL, Swarin SJ. 1985. Determination of aldehydes and ketones by derivatization and liquid

chromatography-mass spectrometry. J Chromatogr 333:337-347.

OSHA. 1974. U.S. Department of Labor. Occupational Safety and Health Administration. Code of

Federal Regulations. 29 CFR 1910.

*OSHA. 1992. U.S. Department of Labor. Occupational Safety and Health Administration. Code of

Federal Regulations. 29 CFR 1910.1048.

*OSHA. 1996. Occupational exposure to formaldehyde. OSHA fact sheet No. 92-27. U.S. Department

of Labor, Occupational Safety and Health Administration.

Osinowo OA, Bale JO, Oyedipe EO, et al. 1982. Motility and eosin uptake of formaldehyde-treated ram

spermatozoa. J Reprod Fertil 65:389-394.

OTA. 1990. Neurotoxicology: Identifying and controlling poisons of the nervous system. Washington,

DC: Office of Technology Assessment. OTA-BA-438.

Otson R, Pellin P. 1988. A review of techniques for measurement of airborne aldehydes. Sci Total

Environ 77:95-131.

*Overman DO. 1985. Absence of embryotoxic effects of formaldehyde after percutaneous exposure in

hamsters. Toxicol Lett 24:107-110.
FORMALDEHYDE 396

8. REFERENCES

Owen BA, Dudney CS, Tan EL, et al. 1990. Formaldehyde in drinking water: Comparative hazard

evaluation and an approach to regulation. Regul Toxicol Pharmacol 11:220-236.

*Owen GM, Brozek J. 1966. Influence of age, sex, and nutrition on body composition during childhood

and adolescence. In: Falkner F, ed. Human Development. Philadelphia, PA: WB Saunders, 222-238.

Pabst R. 1987. Exposure to formaldehyde in anatomy: An occupational health hazard? Anat Rec

219:109-112.

Pang SNJ. 1995. Final report on the safety assessment of melamine/formaldehyde resin. J Am Coll

Toxicol 14:373-385.

*Partanen T. 1993. Formaldehyde exposure and respiratory cancer - a meta-analysis of the

epidemiologic evidence. Scand J Work Environ Health 19:8-15.

*Partanen T, Kauppinen T, Hernberg S, et al. 1990. Formaldehyde exposure and respiratory cancer

among woodworkers - an update. Scand J Work Environ Health 16:394-400.

*Partanen T, Kauppinen T, Nurminen M, et al. 1985. Formaldehyde exposure and respiratory and

related cancers: A case-referent study among Finnish woodworkers. Scand J Work Environ Health

11:409-415.

Patel RN, Hoarke DS. 1971. Physiological studies of methane and methanol-oxidizing bacteria:

Oxidation of C-1 compounds by Methylococcus capsulatus. J Bacteriol 107:187-192.

*Patterson R, Dykewicz MS, Evans RIII, et al. 1989. IgG antibody against formaldehyde human serum

proteins: A comparison with other IgG antibodies against inhalant proteins and reactive chemicals. J

Allergy Clin Immunol 84:359-366.

Patterson R, Harris KE, Grammar LC. 1985. Canine antibodies against formaldehyde-dog serum

albumin conjugates: Induction, measurement, and specificity. J Lab Clin Med 106:93-100.

*Patterson R, Pateras V, Grammer LC, et al. 1986. Human antibodies against formaldehyde-human

serum albumin conjugates or human serum albumin in individuals exposed to formaldehyde. Int Arch

Allergy Appl Immunol 79:53-59.

*Paustenbach D, Alarie Y, Kulle T, et al. 1997. A recommended occupational exposure limit for

formaldehyde based on irritation. J Toxicol Environ Health 50:217-263.

Paustenbach DJ, Finley BL, Kacew S. 1996. Biological relevance and consequences of chemical- or

metal-induced DNA cross-linking. Proc Soc Exp Biol Med 211:211-217.

*Pazdrak K, Gorski P, Krakowiak A, et al. 1993. Changes in nasal lavage fluid due to formaldehyde

inhalation. Int Arch Occup Environ Health 64:515-519.

Pereira MA, Chang LW, McMillan L, et al. 1982. Battery of short-term tests in laboratory animals to

corroborate the detection of human population exposures to genotoxic chemicals [Abstract]. Environ

Mutagen 4:317.

*Perkins JL, Kimbrough JD. 1985. Formaldehyde exposure in a gross anatomy laboratory. J Occup

Med 27:813-815.
FORMALDEHYDE 397

8. REFERENCES

*Peters KP, Heese A. 1997. [Formaldehyde and formaldehyde resins - their relevance in reference to

textile dermatitis]. Allergologie 20:239-245. (German)

Peterson JE. 1993. Toxic pyrolysis products of solvents, paints, and polymer films. Occup Med State

Art Rev 8:533-547.

*Petreas M, Twiss S, Pon D, et al. 1986. A laboratory evaluation of two methods for measuring low

levels of formaldehyde in indoor air. Am Ind Hyg Assoc J 4:276-280.

*Pickrell JA, Griffis LC, Mokler BV, et al. 1984. Formaldehyde release from selected consumer

products: Influence of chamber loading, multiple products, relative humidity, and temperature. Environ

Sci Technol 18:682-686.

*Pickrell JA, Mokler BV, Griffis LC, et al. 1983. Formaldehyde release rate coefficients from selected

consumer products. Environ Sci Technol 17:753-757.

*Pin I, Freitag AP, O'Byrne PM, et al. 1992. Changes in the cellular profile of induced sputum after

allergen-induced asthmatic responses. Am Rev Respir Dis 145:1265-1269.

Plesner BH, Hansen K. 1983. Formaldehyde and hexamethylenetetramine in Styles' cell transformation

assay. Carcinogenesis 4:457-459.

Pocker Y, Li H. 1990. Kinetics and mechanism of methanol and formaldehyde interconversion and

formaldehyde oxidation catalyzed by liver alcohol dehydrogenase. Adv Exp Med Biol 284:315-325.

Poitrast BJ, Keller WC, Elves RG. 1988. Estimation of chemical hazards in breast milk. Aviat Space

Environ Med 59:A87-A92.

*Polacow I, Cabasso L, Li HJ. 1976. Histone redistribution and conformational effect on chromatin

induced by formaldehyde. Biochemistry 15:4559-4565.

Pommery J, Mathieu M, Mathieu D, et al. 1993. Atrazine in plasma and tissue following atrazineaminotriazole-ethylene glycol-formaldehyde poisoning. Clin Toxicol 31:323-331.

Porter DH, Cook RJ, Wagner C. 1985. Enzymatic properties of dimethylglycine dehydrogenase and

sarcosine dehydrogenase from rat liver. Arch Biochem Biophys 243:396-407.

Possanzini M, Di Palo V. 1988. Simultaneous measurements of formaldehyde and ozone in air by

annular denuder - HPLC techniques. Chromatographia 25:895-898.

*Possanzini M, Ciccioli P, DiPalo V, et al. 1987. Determination of low boiling aldehydes in air and

exhaust gases by using annular denuders combined with HPLC techniques. Chromatographia 23:829-

834.

*Potter DW, Wederbrand KS. 1995. Total IgE antibody production in BALB/c mice after dermal

exposure to chemicals. Fundam Appl Toxicol 26:129-137.

*Prat J, Xaubet A, Mullol J, et al. 1993. Cell content and albumin concentration in nasal lavage from

patients with rhinitis. Ann Allergy 70:175-178.
FORMALDEHYDE 398

8. REFERENCES

Priha E, Liesivuori J, Santa H, et al. 1996. Reactions of hydrated formaldehyde in nasal mucus. 

Chemosphere 32:1077-1082.

Proctor BL, Gaulden ME, Dowd MA. 1986. Reactivity and fate of benzene and formaldehyde in culture

medium with and without fetal calf serum; relevance to in vitro mutagenicity testing. Mutat Res 160:259-

266.

*Pross HF, Day JH, Clark RH, et al. 1987. Immunological studies of subjects with asthma exposed to

formaldehyde and urea-formaldehyde foam insulation (UFFI) off products. J Allergy Clin Immunol

79:797-810.

Protasova IA, Semin YA, Adler VV, et al. 1982. Influence of formaldehyde and products of its

interaction with amines on processes of DNA transcription in vitro. Biochemistry 47:1509-1521.

*Purchase IFH, Paddle GM. 1989. Does formaldehyde cause nasopharyngeal cancer in man? Cancer

Lett 46:79-85.

Quackenboss JJ, Bronnimann D, Camilli AE, et al. 1988. Bronchial responsiveness in children and

adults in association with formaldehyde, particulate matter, and environmental tobacco smoke exposures

[Abstract]. Am Rev Respir Dis 137:253.

*Quackenboss JJ, Lebowitz MD, Michaud JP, et al. 1989. Formaldehyde exposure and acute health

effects study. Environ Int 15:169-176.

*Radford T, Dalsis DE. 1982. Analysis of formaldehyde in shrimp by high pressure-liquid

chromatography. J Agric Food Chem 30:600-602.

*Ragan DL, Boreiko CJ. 1981. Initiation of C3H/10T1⁄2 cell transformation by formaldehyde. Cancer

Lett 13:325-331.

Raiyani CV, Shah SH, Desai NM, et al. 1993. Characterization and problems of indoor pollution due to

cooking stove smoke. Atmos Environ 27A:1643-1655.

Randerath K, Reddy MV, Gupta RC. 1981. 32P-labeling test for DNA damage. Proc Natl Acad Sci U S

A 78:6126-6129.

Ranly DM. 1985. Assessment of the systemic distribution and toxicity of formaldehyde following

pulpotomy treatment: part one. J Dent Child 52:431-434.

Rappaport BZ, Hoffman MM. 1941. Urticaria due to aliphatic aldehydes. JAMA,J Am Med Assoc

116:2656-2659.

*Rastogi SC. 1992. A survey of formaldehyde in shampoos and skin creams on the Danish market. 

Contact Dermatitis 27:235-240.

Razia Beevi M, Radhakrishnan S. 1987. Haematological effects of sublethal concentration of formalin

on Sarotherodon mossambicus (Peters). Proc Indian Acad Sci Sect B 96:721-725.

Recio L. 1997. Oncogene and tumor suppressor gene alterations in nasal tumors. Mutat Res 380:27-31.
FORMALDEHYDE 399

8. REFERENCES

*Recio L, Sisk S, Pluta L, et al. 1992. p53 mutations in formaldehyde-induced nasal squamous cell

carcinomas in rats. Cancer Res 52:6113-6116.

*Reed CE, Frigas E. 1984. Does formaldehyde cause allergic respiratory disease? In: Gammage RB,

Kaye SV, Jacobs VA, ed. Indoor air and human health. Chelsea, MI: Lewis Publishers, Inc., 379-386.

*Reiss R, Ryan PB, Tibbetts SJ, et al. 1995. Measurement of organic acids, aldehydes, and ketones in

residential environments and their relation to ozone. J Air Waste Manage Assoc 45:811-822.

Rettenmeier AW, Hennings R, Wodarz R. 1993. Determination of butoxyacetic acid and nbutoxyacetyl-glutamine in urine of lacquerers exposed to 2-butoxyethanol. Int Arch Occup Environ

Health 65:S151-S153.

Reuzel PG, Wilmer JW, Woutersen RA, et al. 1990. Interactive effects of ozone and formaldehyde on

the nasal respiratory lining epithelium in rats. J Toxicol Environ Health 29:279-292.

*Richards LW, Anderson JA, Blumenthal DL, et al. 1983. Hydrogen peroxide and sulfur (IV) in Los

Angeles cloud water. Atmos Environ 17:911-914.

*Riedel F, Hasenauer E, Barth PJ, et al. 1996. Formaldehyde exposure enhances inhalative allergic

sensitization in the guinea pig. Allergy 51:94-99.

Risch SJ. 1988. Migration of toxicants, flavors and odor-active substances from flexible packaging

materials to food. Food Technol 42:95-102.

*Ritchie IM, Lehnen RG. 1987. Formaldehyde-related health complaints of residents living in mobile

and conventional homes. Am J Public Health 77:323-328.

*Rithidech K, Au WW, Ramanujam VMS, et al. 1987. Induction of chromosome aberrations in

lymphocytes of mice after subchronic exposure to benzene. Mutat Res 188:135-140.

Robbins JD, Norred WP, Bathija A, et al. 1984. Bioavailability in rabbits of formaldehyde from durablepress textiles. J Toxicol Environ Health 14:453-463.

Robert A, Ducos P, Francin JM. 1995. Determination of urinary 4,4'-methylenedianiline and its

acetylated metabolites by solid-phase extraction and HPLC analysis with UV and electrochemical

detection. Int Arch Occup Environ Health 68:44-51.

Robertson AS, Burge PS, Hedge A, et al. 1985. Comparison of health problems related to work and

environmental measurements in two office buildings with different ventilation systems. Br Med J

291:373-376.

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.

Rohde DS, Detweiler DJ, Basbaum AI. 1997. Formalin-evoked Fos expression in spinal cord is

enhanced in morphine-tolerant rats. Brain Res 766:93-100.

Romaguera C, Grimalt F, Lecha M. 1981. Occupational purpuric textile dermatitis from formaldehyde

resins. Contact Dermatitis 7:152-153.
FORMALDEHYDE 400

8. REFERENCES

Rosen C, Andersson I-M, Juringe L. 1990. Reduction of exposure to solvents and formaldehyde in

surface-coating operations in the woodworking industry. Ann Occup Hyg 34:293-303.

Rosenberg J. 1984. Controversies in the assessment of carcinogenic risk of formaldehyde. In: Becker

CH, Coye MJ, ed. Cancer prevention: Strategies in the workplace. Washington, DC: Hemisphere

Publishing Corporation, 147-152.

*Ross WE, Shipley N. 1980. Relationship between DNA damage and survival in formaldehyde-treated

mouse cell. Mutat Res 79:277-283.

Ross WE, McMillan DR, Ross CF. 1981. Comparison of DNA damage by methymelamines and

formaldehyde. J Natl Cancer Inst 67:217-221.

Rostenberg AJ, Bairstow B, Luther TW. 1952. A study of eczematous sensitivity to formaldehyde. J

Invest Dermatol 19:459-462.

Roto P, Sala E. 1996. Occupational laryngitis caused by formaldehyde: A case report. Am J Ind Med

29:275-277.

*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.

Rudolf W. 1994. Concentration of air pollutants inside cars driving on highways and in downtown areas. 

Sci Total Environ 146/147:433-444.

*Rudzki E, Rebandel P, Grzywa Z. 1989. Patch tests with occupational contactants in nurses, doctors

and dentists. Contact Dermatitis 20:247-259.

*Rusch GM, Clary JJ, Rinehart WE, et al. 1983. A 26-week inhalation toxicity study with formaldehyde

in the monkey, rat, and hamster. Toxicol Appl Pharmacol 68:329-343.

Rycroft RJG. 1986. Occupational dermatoses among office personnel. Occup Med State Art Rev 1:323-

328.

Rylander R. 1974. Pulmonary cell responses to inhaled cigarette smoke. Arch Environ Health 29:329-

333.

Sachs K, Pindel B, Jastrzqb J, et al. 1995. [Histology of respiratory system after exposition on bacterial

infection and formalin vapouries inducing experimental bronchospasm]. Pneumol Alergol Pol 63:259-

263. (Polish)

*Saillenfait AM, Bonnet P, deCeaurriz J. 1989. The effects of maternally inhaled formaldehyde on

embryonal and foetal development in rats. Food Chem Toxicol 27:545-548.

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.

*Salas LJ, Singh HB. 1986. Measurements of formaldehyde and acetaldehyde in the urban ambient air. 

Atmos Environ 20:1301-1304.
FORMALDEHYDE 401

8. REFERENCES

*Saldiva PHN, do Rio Caldera MP, Massad E, et al. 1985. Effects of formaldehyde and acetaldehyde

inhalation on rat pulmonary mechanics. J Appl Toxicol 5:288-292.

Salkie ML. 1991. The prevalence of atopy and hypersensitivity to formaldehyde in pathologists. Arch

Pathol Lab Med 115:614-616.

Sanchez I, Rodreguez F, Quinones D, et al. 1997. Occupational dermatitis due to formaldehyde in

newspaper. Contact Dermatitis 37:131-132.

Sander JE, Steffens WL. 1997. Transmission electron microscopic demonstration of abnormalities on

the tracheal cilia of chicks exposed to formaldehyde during hatching. Avian Dis 41:977-980.

Sarrif AM, Donovan SM, Stewart JA, et al. 1983. Inhibition by semicarbazide of the mutagenic

activities of formaldehyde (HCHO) and hexamethyphosphoramide (HMPA) in Salmonella typhimuriam

reverse suspension assay [Abstract]. Environ Mutagen 5:476.

Sass-Kortsak AM, Holness DL, Pilger CW, et al. 1986. Wood dust and formaldehyde exposures in the

cabinet-making industry. Am Ind Hyg Assoc J 47:747-753.

*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 3:569-577.

*Schachter EN, Witek TJJ, 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.

Schachter EN, Witek TJ, Tosun T, et al. 1985. Respiratory effects of exposure to 2.0 ppm of

formaldehyde in asthmatic subjects [Abstract]. Am Rev Respir Dis 131:A170.

*Schachter EN, Witek TJJ, Tosun T, et al. 1986. A study of respiratory effects from exposure to 2 ppm

formaldehyde in healthy subjects. Arch Environ Health 41:229-239.

Schardein JL, Keller KA. 1989. Potential human developmental toxicants and the role of animal testing

in their identification and characterization. CRC Crit Rev Toxicol 19:251-339.

Schiff HI, Mackey GI, Mayne LK, et al. 1986. Tunable diode laser absorption spectrometer

measurement of HNO3, HCHO and NO2 and luminox NO2 measurements in Claremont CA, September

1985 [Abstract]. Abstr Pap Am Chem Soc 192:ENVR 112.

Schiwara HW, Siegel H, Goebel A. 1992. Increase and decrease in formic acid concentration in urine

samples stored at room temperature. Eur J Clin Chem Clin Biochem 30:75-79.

*Schmid E, Googelmann W, Bauchinger M. 1986. Formaldehyde-induced cytotoxic, genotoxic and

mutagenic response in human lymphocytes and Salmonella typhimurium. Mutagenesis 1:427-431.

Schnuch A, Geier J. 1997. [Sensitization to formaldehyde - Results from the Information Network of

Departments of Dermatology (IVDK) 1992-1995]. Allergologie 20:205-214. (German) [Translation in

progress].
FORMALDEHYDE 402

8. REFERENCES

*Schorr WF, Keran E, Plotka E. 1974. Formaldehyde allergy: The quantitative analysis of American

clothing for free formaldehyde and its relevance in clinical practice. Arch Dermatol 110:73-76.

Schuck EA, Stephens ER, Middleton JT. 1966. Eye irritation response at low concentrations of irritants. 

Arch Environ Health 13:570-575.

*Schulam P, Newbold R, Hull LA. 1985. Urban and rural ambient air aldehyde levels in Schenectady,

New York and on Whiteface Mountain, New York. Atmos Environ 19:623-626.

Schulz P, Jones JL, Patten BM. 1988. Encephalopathy and rhabdomyolysis from ingesting

formaldehyde-dipped cigarettes [Abstract]. Neurology 38:207.

Scott CS, Margosches EH. 1985. Cancer epidemiology relevant to formaldehyde. J Environ Sci Health

C C3:107-144.

Scott MJ, Ward JBJ, Dallas CE, et al. 1985. Chromosome damage observed in lung but not bone marrow

of Sprague-Dawley rats exposed to formaldehyde by inhalation [Abstract]. Environ Mutagen 7:53.

*Seiber JN. 1996. Toxic air contaminants in urban atmospheres: Experience in California. Atmos

Environ 30:751-756.

*Seidenberg JM, Becker RA. 1987. A summary of the results of 55 chemicals screened for

developmental toxicity in mice. Teratogenesis Carcinog Mutagen 7:17-28.

Seidenberg JM, Anderson DG, Becker RA. 1986. Validation of an in vivo developmental toxicity screen

in the mouse. Teratogenesis Carcinog Mutagen 6:361-374.

*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, Chebotar NA. 1996. Effects of gasoline and formaldehyde on prenatal development of

rats with induced iron microelementosis. Ontogenez 27:90-94.

*Setchell BP, Waites GMH. 1975. The blood testis barrier. In: Creep RO, Astwood EB, Geiger SR, eds. 

Handbook of Physiology: Endocrinology V. Washington, DC: American Physiological Society.

Sexton K, Liu K-S, Petras MX. 1986. Formaldehyde concentrations inside private residences: A mailout approach to indoor air monitoring. J Air Pollut Control Assoc 36:698-704.

*Sexton K, Petreas MX, Liu KS. 1989. Formaldehyde exposures inside mobile homes. Environ Sci

Technol 23:985-988.

Shah BM, Vachhrajani KD, Chinoy NJ, et al. 1987. Formaldehyde induced structural and functional

changes in the testis of rats. J Reprod Comp Endocrinol 7:42-52.

*Shah J, Singh HB. 1988. Distribution of volatile organic chemicals in outdoor and indoor air. Environ

Sci Technol 22:1381-1388.

*Shaham J, Bomstein Y, Meltzer A, et al. 1996a. DNA-protein crosslinks, a biomarker of exposure to

formaldehyde - in vitro and in vivo studies. Carcinogenesis 17:121-125.
FORMALDEHYDE 403

8. REFERENCES

*Shaham J, Bomstein Y, Meltzer A, et al. 1996b. Response. [Letter]. Carcinogenesis 17:2098-2101.

*Shara MA, Dickson PH, Bagchi D, et al. 1992. Excretion of formaldehyde, malondialdehyde,

acetaldehyde and acetone in the urine of rats in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, paraquat,

endrin and carbon tetrachloride. J Chromatogr 576:221-233.

Shaver CS, Tong T. 1991. Chemical hazards to agricultural workers. Occup Med 6:391-413.

Sheppard D, Eschenbacher WL, Epstein J. 1984. Lack of bronchomotor response to up to 3 ppm

formaldehyde in subjects with asthma. Environ Res 35:133-139.

Shiba M, Marchok AC, Klein-Szanto AJP, et al. 1987. Pathological changes induced by formaldehyde

in open-ended rat tracheal implants preexposed to benzo(a)pyrene. Toxicol Pathol 15:401-408.

*Shrivastaw KP, Singh S. 1995. A new method for spectrophotometric determination of formaldehyde

in biologicals. Biologicals 23:47-53.

Shusterman D. 1992. Critical review: The health significance of environmental odor pollution. Arch

Environ Health 47:76-87.

Sigsby JEJ, Tejada S, Ray W. 1987. Volatile organic compound emissions from 46 in-use passenger

cars. Environ Sci Technol 21:466-475.

*Sills JB, Allen JL. 1979. Residues of formaldehyde undetected in fish exposed to formalin. Prog Fish

Cult 41:67-68.

Sills RD, Blakeslee PA. 1992. The environmental impact of deicers in airport stormwater runoff. In: 'Itri

FM, ed. Chemical Deicers and the Environment. Boca Raton, FL: Lewis Publishers, 323-340.

Sim VM, Pattle RE. 1957. Effect of possible smog irritants on human subjects. JAMA,J Am Med Assoc

165:1908-1913.

Singer B, Kusmierek JT. 1982. Chemical mutagenesis. Annu Rev Biochem 52:655-693.

*Singh HB, Salas LJ, Stiles RE. 1982. Distribution of selected gaseous organic mutagens and suspect

carcinogens in ambient air. Environ Sci Technol 16:872-880.

Sipilainen-Malm T, Latva-Kala K, Tikkanen L, et al. 1997. Purity of recycled fibre-based materials. 

Food Addit Contam 14:695-703.

Sisk S, Pluta L, Recio L. 1993. Molecular analysis of P53 mutation in formaldehyde-induced rat nasal

squamous cell carcinomas [Abstract]. Environ Mol Mutagen 21:66.

*Skisak CM. 1983. Formaldehyde vapor exposures in anatomy laboratories. Am Ind Hyg Assoc J

44:948-950.

Smedley J. 1996. Is formaldehyde an important cause of allergic respiratory disease? Clin Exp Allergy

26:247-249.

Smith KAJ, Williams PL, Middendorf PJ, et al. 1984. Kidney dialysis: Ambient formaldehyde levels. 

Am Ind Hyg Assoc J 45:48-50.
FORMALDEHYDE 404

8. REFERENCES

Smith MW, Miyashita M, Phelps PC, et al. 1989. The effect of formaldehyde on cytosolic Ca2+ of

transformed human bronchial epithelial cells as measured by digital imaging fluorescence microscopy. 

Proc Am Assoc Cancer Res 30:107.

Smyth HFJ, Seaton J, Fischer L. 1941. The single dose toxicity of some glycols and derivatives. J Ind

Hyg Toxicol 23:259-268.

Sneddon IB. 1968. Dermatitis in an intermittent haemodialysis unit. Br Med J 1:183-184.

Snipes MB, Spoo JE, Brookins LK, et al. 1991. A method for measuring nasal and lung uptake of

inhaled vapor. Fundam Appl Toxicol 16:81-91.

Snow R, Baker L, Crews W, et al. 1989. Characterization of emissions from a methanol fueled motor

vehicle. J Air Pollut Control Assoc 39:48-54.

*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.

Socie EM, Gromen KD, Migliozzi AA, et al. 1997. Work-related skin disease in the plastics industry. 

Am J Ind Med 31:545-550.

*Soffritti M, Maltoni C, Maffei F, et al. 1989. Formaldehyde: An experimental multipotential

carcinogen. Toxicol Ind Health 5:699-730.

Sorg BA, Willis JR, Nowatka TC, et al. 1996. Proposed animal neurosensitization model for multiple

chemical sensitivity in studies with formalin. Toxicology 111:135-145.

Sorg BA, Willis JR, See RE, et al. 1998. Repeated low-level formaldehyde exposure produces crosssensitization to cocaine: Possible relevance to chemical sensitivity in humans. 

Neuropsychopharmacology 18:385-394.

Soro L, Brouh T, Sissoko J, et al. 1997. [Oral formol intoxication. A case report]. Urg Med 16:153-155. 

(French)

Sparks PJ, Simon GE, Katon WJ, et al. 1990. An outbreak of illness among aerospace workers. West J

Med 153:28-33.

Spector I. 1985. AMP: A new form of marijuana. J Clin Psychiatry 46:498-499.

Speese RE. 1983. Anaerobic biotechnology for industrial wastewater treatment. Environ Sci Technol

17:416A-427A.

*Spicer CW, Buxton BE, Holdren MW, et al. 1996. Variability of hazardous air pollutants in an urban

area. Atmos Environ 30:3443-3456.

Spoo JW, Rogers RA, Monteiro-Riviere NA. 1992. Effects of formaldehyde, DMSO, benzoyl peroxide,

and sodium lauryl sulfate on isolated perfused porcine skin. In Vitro Toxicol 5:251-260.

SRC. 1994a. Syracuse Research Corporation. Henry's Law Constant Program (HENRYWIN, Version

2.50, Serial H0142). Chemical Hazard Assessment Division, Environmental Chemistry Center, Syracuse,

NY.
FORMALDEHYDE 405

8. REFERENCES

SRC. 1994b. Syracuse Research Corporation. Aqueous Hydrolysis Rate Program (HYDROWIN,

Version 1.50a, Serial HY0126). Chemical Hazard Assessment Division, Environmental Chemistry

Center, Syracuse, NY.

SRC. 1995a. Syracuse Research Corporation. Atmospheric Oxidation Program (AOPWIN, Version

1.65, Serial 0156). Chemical Hazard Assessment Division, Environmental Chemistry Center, Syracuse,

NY.

*SRC. 1995b. Syracuse Research Corporation. Octanol-Water Partition Coefficient Program

(KOWWIN, Version 1.37, Serial L0148). Chemical Hazard Assessment Division, Environmental

Chemistry Center, Syracuse, NY.

*SRI. 1988. Directory of chemical producers: United States of America. Menlo Park, CA: Stanford

Research Institute International, 668.

*SRI. 1990. Directory of chemical producers: United States of America. Menlo Park, CA: Stanford

Research Institute International, 675-676.

*SRI. 1992. Directory of chemical producers: United States of America. Menlo Park, CA: Stanford

Research Institute International, pp. 677-678.

SRI. 1995. Directory of chemical producers: United States of America. Menlo Park, CA: Stanford

Research Institute International, 654-655.

*SRI. 1997. Directory of chemical producers: United States of America. Menlo Park, CA: Stanford

Research Institute International, 649.

*Staffelbach T, Neftel A, Stauffer B, et al. 1991. A record of the atmospheric methane sink from

formaldehyde in polar ice cores. Nature 349:603-605.

Stankowski LF, Tuman WG, Godek EG, et al. 1986. Induction of mammalian cell mutations by

formaldehyde [Abstract]. Environ Mutagen 8:81.

Staples RE. 1983. Teratogenicity of formaldehyde. In: Gibson JE, ed. Formaldehyde toxicity. 

Washington, DC: Hemisphere Publishing Corporation, 51-59.

Stark A. 1990. Formaldehyde. In: Haddad LM, Winchester JF, ed. Clinical management of poisoning

and drug overdose. Philadelphia, PA: W.B. Saunders Company, 537-541.

Starr TB, Buck RD. 1984. The importance of delivered dose in estimating low-dose cancer risk from

inhalation exposure to formaldehyde. Fundam Appl Toxicol 4:740-753.

Starr TB, Gibson JE. 1985. The mechanistic toxicology of formaldehyde and its implications for

quantitative risk estimation. Annu Rev Pharmacol Toxicol 25:745-767.

*Stayner L, Smith AB, Reeve G, et al. 1985a. Proportionate mortality study of workers in the garment

industry exposed to formaldehyde [Letter]. Am J Ind Med 8:75-76.

*Stayner L, Smith AB, Reeve G, et al. 1985b. Proportionate mortality study of workers in the garment

industry exposed to formaldehyde. Am J Ind Med 7:229-240.
FORMALDEHYDE 406

8. REFERENCES

*Stayner LT, Elliott L, Blade L, et al. 1988. A retrospective cohort mortality study of workers exposed

to formaldehyde in the garment industry. Am J Ind Med 13:667-681.

St. Clair MBG, Gross EA, Morgan KT. 1990. Pathology and cell proliferation induced by intra-nasal

instillation of aldehydes in the rat: Comparison of glutaraldehyde and formaldehyde. Toxicol Pathol

18:353-361.

*Sterling TD, Weinkam JJ. 1989. 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. 1994. Mortality from respiratory cancers (including lung cancer) among

workers employed in formaldehyde industries. Am J Ind Med 25:593-602.

*Sterling TD, Weinkam JJ. 1995. Comments on the Blair and Stewart comments on the Sterling and

Weinkam analysis of data from the National Cancer Institute formaldehyde study. Am J Ind Med 27:301-

305.

*Sterling TD, Collett CW, Sterling EM. 1987. Environmental tobacco smoke and indoor air quality in

modern office work environments. J Occup Med 29:57-61.

*Stern FB, Beaumont JJ, Halperin WE, et al. 1987. Mortality of chrome leather tannery workers and

chemical exposures in tanneries. Scand J Work Environ Health 13(S1):108-117.

Stewart PA, Blair A. 1994. Women in the formaldehyde industry: Their exposures and their jobs. J

Occup Med 36:918-923.

*Stock TH. 1987. Formaldehyde concentrations inside conventional housing. J Air Pollut Control

Assoc 37:913-918.

Storrs FJ, Rosenthal LE, Adams RM, et al. 1989. Prevalence and relevance of allergic reactions in

patients patch tested in North America - 1984 to 1985. J Am Acad Dermatol 20:1038-1045.

Strittmatter P, Ball EG. 1955. Formaldehyde dehydrogenase, a glutathione-dependent enzyme system. J

Biol Chem 213:445-461.

Strom JG, Jun HW. 1993. Effect of urine pH and ascorbic acid on the rate of conversion of methenamine

to formaldehyde. Biopharm Drug Dispos 14:61-69.

*Stroup NE, Blair A, Erikson GE. 1986. Brain cancer and other causes of death in anatomists. J Natl

Cancer Inst 77:1217-1224.

Strubelt O, Brasch H, Pentz R, et al. 1990. Experimental studies on the acute cardiovascular toxicity of

formalin and its antidotal treatment. Clin Toxicol 28:221-233.

Strubelt O, Younes M, Pentz R, et al. 1989. Mechanistic study on formaldehyde-induced hepatotoxicity. 

J Toxicol Environ Health 27:351-366.

Stump FD, Knapp K T, Ray WD, et al. 1992. The composition of motor vehicle organic emissions under

elevated temperature summer driving conditions (75 to 105 degrees F) - part II. J Air Waste Manage

Assoc 42:1328-1335.
FORMALDEHYDE 407

8. REFERENCES

*Stumpf JM, Blehm KD, Buchan RM, et al. 1986. Characterization of particleboard aerosol - size

distribution and formaldehyde content. Am Ind Hyg Assoc J 47:725-730.

Stutts MJ, Gatzy JT, Knowles MR, et al. 1986. Effects of formaldehyde on bronchial ion transport. 

Toxicol Appl Pharmacol 82:360-367.

*Su F, Calvert G, Shaw JH. 1979. Mechanism of the photooxidation of gaseous formaldehyde. J Phys

Chem 83:3185-3191.

*Subramaniam RP, Richardson RB, Morgan KT, et al. 1998. Computational fluid dynamics simulations

of inspiratory airflow in the human nose and nasopharynx. Inhal Toxicol 10:473-502.

Summerhyas J. 1991. Evaluation of risks from urban air pollutants in the Southeast Chicago area. J Air

Waste Manage Assoc 41:844-850.

Sun H, Feigal RJ, Messer HH. 1990. Cytotoxicity of glutaraldehyde and formaldehyde in relation to

time of exposure and concentration. Pediatr Dent 12:303-307.

*Swann RL, Laskowski DA, McCall PJ, et al. 1983. A rapid method for the estimation of the

environmental parameters octanol/water partition coefficient, soil sorption constant, water to air ratio, and

water solubility. Residue Rev 85:17-28.

Swenberg JA, Heck Hd'A, Morgan KT, et al. 1985. A scientific approach to formaldehyde risk

assessment. In: Hoel DG, Merrill RA, Perera FP, ed. Risk quantitation and regulatory policy. Cold

Spring Harbor, New York: Cold Spring Harbor Laboratory, 255-267.

*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.

*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.

Symington P, Coggon D, Holgate S. 1991. Respiratory symptoms in children at schools near a foundry. 

Br J Ind Med 48:588-591.

Szabad J, Soos I, Polgar G, et al. 1983. Testing the mutagenicity of malondialdehyde and formaldehyde

by the drosophila mosaic and the sex-linked recessive lethal tests. Mutat Res 113:117-133.

*Takahashi K, Morita T, Kawazoe Y. 1985. Mutagenic characteristics of formaldehyde on bacterial

systems. Mutat Res 156:153-161.

*Takahashi M, Hasegawa R, Furukawa F, et al. 1986a. Effects of ethanol, potassium metabisulfite,

formaldehyde and hydrogen peroxide on gastric carcinogenesis in rats after initiation with n-methyl-n

nitro-n-nitrosoguanidine. Jpn J Cancer Res 77:118-124.

Takahashi M, Niizuma K, Ohkido M, et al. 1986b. [A case of occupational contact dermatitis due to

preservatives, surfactants and raw materials of detergents and wax. Dermatitis and skin patch: VIII,

Osaka, Japan]. Skin Res 29:24-34. (Japanese)

Takami M, Kasuya I, Mizumoto K, et al. 1988. A receptor for formaldehyde-treated serum albumin on

human placental brush-border membrane. Biochim Biophys Acta 945:291-297.
FORMALDEHYDE 408

8. REFERENCES

Tams IP, Bryson DD. 1987. Respiratory symptoms and function in a group of workers manufacturing

formaldehyde [Abstract]. Bull Eur Physiopathol Respir 23:332 s.

Tani T, Horiguchi Y. 1990. Effects of formaldehyde on cardiac function. Jpn J Pharmacol 52:563-572.

Tani T, Kogi K, Horiguchi Y. 1986. Inhibitory effects of formaldehyde inhalation on the cardiovascular

and respiratory systems in unanesthetized rabbits. Jpn J Pharmacol 40:551-559.

*Tarkowski M, Gorski P. 1995. Increased IgE antiovalbumin level in mice exposed to formaldehyde. 

Int Arch Allergy Immunol 106:422-424.

Taskinen H, Kyyronen P, Hemminki K, et al. 1994. Laboratory work and pregnancy outcome. J Occup

Med 36:311-319.

Temcharoen P, Thilly WG. 1983. Toxic and mutagenic effects of formaldehyde in Salmonella

typhimurium. Mutat Res 119:89-93.

Tephly TR. 1991. The toxicity of methanol. Life Sci 48:1031-1041.

Teschke K, Morgan MS, Checkoway H, et al. 1997. Surveillance of nasal and bladder cancer to locate

sources of exposure to occupational carcinogens. Occup Environ Med 54:443-451.

Thomas TL, Waxweiler RJ. 1986. Brain tumors and occupational risk factors. Scand J Work Environ

Health 12:1-15.

*Thomson 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.

Thomson VE, Jones A, Haemisegger E, et al. 1985. The air toxics problem in the United States: An

analysis of cancer risks posed by selected air pollutants. J Air Pollut Control Assoc 35:535-540.

Thornton-Manning JR, Dahl AR. 1997. Metabolic capacity of nasal tissue interspecies comparisons of

xenobiotic-metabolizing enzymes. Mutat Res 380:43-59.

Thornton-Manning JR, Nikula KJ, Hotchkiss JA, et al. 1997. Nasal cytochrome P450 2A: 

Identification, regional localization, and metabolic activity toward hexamethylphosphoramide, a known

nasal carcinogen. Toxicol Appl Pharmacol 142:22-30.

Thrasher JD, Broughton A, Gard Z. 1988a. Indoor formaldehyde and the elderly. Clin Gerontol 7:63-

66.

*Thrasher JD, Broughton A, Micevich P. 1988b. Antibodies and immune profiles of individuals

occupationally exposed to formaldehyde six case reports. Am J Ind Med 14:479-488.

*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.

*Thrasher JD, Madison R, Broughton A, et al. 1989. Building-related illness and antibodies to albumin

conjugates of formaldehyde, toluene diisocyanate, and trimellitic anhydride. Am J Ind Med 15:187-196.
FORMALDEHYDE 409

8. REFERENCES

*Thrasher JD, Wojdani A, Cheung G, et al. 1987. Evidence for formaldehyde antibodies and altered

cellular immunity in subjects exposed to formaldehyde in mobile homes. Arch Environ Health 42:347-

350.

Til HP, Woutersen RA, Feron VJ, et al. 1988a. Sub-acute (4-week) oral toxicity of acetaldehyde and

formaldehyde in rats [Abstract]. Hum Toxicol 7:86.

*Til HP, Woutersen RA, Feron VJ, et al. 1988b. 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 VJ, Feron V, et al. 1989. Two-year drinking-water study of formaldehyde in rats. 

Food Chem Toxicol 27:77-87.

Tinnerberg H, Skarping G, Dalene M, et al. 1995. Test chamber exposure of humans to 1,6-

hexamethylene diisocyanate and isophorone diisocyanate. Int Arch Occup Environ Health 67:367-374.

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 37:237-248.

*Tobe M, Natio K, Kurokawa Y. 1989. Chronic toxicity study on formaldehyde administered orally to

rats. Toxicology 56:79-86.

Todhunter JA. 1985. Formaldehyde: Refining the risk assessment. In: Turoski V, ed. Formaldehyde:

Analytical chemistry and toxicology. Washington, DC: American Chemical Society, 357-373.

*Tomkins BA, McMahon JM, Caldwell WM, et al. 1989. Liquid chromatographic determination of total

formaldehyde in drinking water. J Assoc Off Anal Chem 72:835-839.

*Traynor GW, Girman JR, Apte MG, et al. 1985. Indoor air pollution due to emissions from unvented

gas-fired space heaters. J Air Pollut Control Assoc 35:231-237.

TRI93. 1995. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology

Information Program, Bethesda, MD.

*TRI96. 1998. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology

Information Program, Bethesda, MD.

*Triebig G, Zober MA. 1984. Indoor air pollution by smoke constituents - a survey. Prev Med 13:570-

581.

Triebig G, Schaller K-H, Beyer B, et al. 1989. Formaldehyde exposure at various workplaces. Sci Total

Environ 79:191-195.

Tsuchiya K, Hayashi Y, Onodera M, et al. 1975. Toxicity of formaldehyde in experimental animals -

concentrations of the chemical in the elution from dishes of formaldehyde resin in some vegetables. Keio

J Med 24:19-37.

Tsuchiya S, Kondo M, Okamoto K, et al. 1985. The cumulative contact enhancement test. Curr Probl

Dermatol 14:208-219.
FORMALDEHYDE 410

8. REFERENCES

Uba G, Pachorek D, Bernstein J, et al. 1989. Prospective study of respiratory effects of formaldehyde

among healthy and asthmatic medical students. Am J Ind Med 15:91-101.

Ueng T-H, Ueng Y-F, Chand T-L, et al. 1993. Induction of cytochrome P450-dependent

monooxygenases in hamster tissues by fasting. Toxicol Appl Pharmacol 119:66-73.

*Universities Associated for Research and Education in Pathology. 1988. Epidemiology of chronic

occupational exposure to formaldehyde: Report of the ad hoc panel on health aspects of formaldehyde. 

Toxicol Ind Health 4:77-90.

Upreti RK, Farooqui MYH, Ahmed AE, et al. 1987. Toxicokinetics and molecular interaction of [14C]-

formaldehyde in rats. Arch Environ Contam Toxicol 16:263-273.

Ura H, Nowak P, Litwin S, et al. 1989. Effects of formaldehyde on normal xenotransplanted human

tracheobronchial epithelium. Am J Pathol 134:99-106.

*U.S. Congress 1986. Superfund Amendments and Reauthorization Act of 1986. Ninety-ninth

Congress of the United States of America.

*U.S. Congress 1990. Clean Air Act Amendments. Title III, hazardous air pollutants, section 112,

hazardous air pollutants as amended, October 26, 1990. One hundred and first Congress of the United

States of America, 2nd session Report 101-952.

*Valencia R, Mason JM, Zimmering S. 1989. Chemical mutagenesis testing in Drosophila. VI.

Interlaboratory comparison of mutagenicity tests after treatment of larvae. Environ Mol Mutagen 14:238-

244.

Vargova M, Janota S, Karelova J, et al. 1992. Analysis of the health risk of occupational exposure to

formaldehyde using biological markers. Analusis 20:451-454.

*Vargova M, Wagnerova J, Liskova A, et al. 1993. Subacute immunotoxicity study of formaldehyde in

male rats. Drug Chem Toxicol 16:255-275.

*Vasudeva N, Anand C. 1996. Cytogenetic evaluation of medical students exposed to formaldehyde

vapor in the gross anatomy dissection level. J Am Coll Health 44:177-179.

*Vaughn 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.

*Vaughn TL, Strader C, Davis S, et al. 1986b. Formaldehyde and cancers of the pharynx, sinus and

nasal cavity: II. Residential exposures. Int J Cancer 38:685-688.

Venkatakrishan-Bhatt H, Panchal GM. 1992. In vitro study of rat uterus after chronic formaldehyde

exposure. Indian J Exp Biol 30:901-903.

*Verschueren K. 1983. Handbook of environmental data on organic chemicals. 2nd ed. New York,

NY: Van Nostrand Reinhold.

Victorin K, Stahlberg M, Alsberg T, et al. 1988. Emission of mutagenic, irritating and odorous

substances from gasoline fueled vehicles with different control substances. Chemosphere 17:1767-1780.
FORMALDEHYDE 411

8. REFERENCES

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver:

hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476-483.

Vojdani A, Ghoneum M, Brautbar N. 1992. Immune alteration associated with exposure to toxic

chemicals. Toxicol Ind Health 8:239-254.

von Hippel P, Wong K-Y. 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 edemainducing capacity of cutting fluids, acids, alkalis, formalin and dimethyl sulfoxide. Contact Dermatitis

28:141-145.

Walker AP. 1985. A more realistic animal technique for predicting human eye response. Food Chem

Toxicol 23:175-178.

*Walrath J, Fraumeni JFJ. 1983. Proportionate mortality among New York embalmers. In: Gibson JE,

ed. Formaldehyde toxicity. Washington, DC: Hemisphere Publishing Corporation, 227-236.

*Walrath J, Fraumeni JFJ. 1984. Cancer and other causes of death among embalmers. Cancer Res 

44:4638-4641.

*Wang D, Clement P, Smitz J, et al. 1995. Concentrations of chemical mediators in nasal secretions after

nasal allergen challenges in atopic patients. Eur Arch Oto-rhino-laryngol 252:S40-S43.

*Wantke F, Demmer CM, Tappler P, et al. 1996a. Exposure to gaseous formaldehyde induces IgEmediated 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.

Wantke F, Hemmer W, Haglmuller T, et al. 1995. Anaphylaxis after dental treatment with a

formaldehyde-containing tooth-filling material. Allergy 50:274-276.

Ward EM, Burnett CA, Ruder A, et al. 1997. Industries and cancer. Cancer Causes Control 8:356-370.

*Ward JBJ, Hokanson JA, Smith ER, et al. 1984. Sperm count, morphology and fluorescent body

frequency in autopsy service workers exposed to formaldehyde. Mutat Res 130:417-424.

Ward JBJ, Legator MS, Chang LW, et al. 1983. Evaluation of occupational exposure to formaldehyde

using a battery of tests for genetic damage. Environ Mutagen 5:433-434.

*Weber-Tschopp A, Fischer T, Grandjean E. 1977. [Irritating effects of formaldehyde on men]. Int

Arch Occup Environ Health 39:207-218. (German)

Weiler E, Apfelbach R. 1992. Age-related differences in olfactory sensitivity in Wistar rats after lowlevel formaldehyde gas exposure [Abstract]. Chem Senses 17:717-718.

*Weschler CJ, Shields HC. 1996. Production of the hydroxyl radical in indoor air. Environ Sci Technol

30:3250-3258.
FORMALDEHYDE 412

8. REFERENCES

*West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and

maximal tubular excretory capacity in infancy. J Pediatr 32:10-18.

*West S, Hildesheim A, Dosemeci M. 1993. Non-viral risk factors for nasopharyngeal carcinoma in the

Philippines: Results from a case-control study. Int J Cancer 55:722-727.

*WHO. 1989. World Health Organization. Formaldehyde: Environmental health criteria. Geneva: 

World Health Organization.

*Widdowson EM, Dickerson JWT. 1964. Chapter 17: Chemical composition of the body. In: Comar

CL, Bronner F, eds. Mineral metabolism: An advanced treatise. Volume II: The elements Part A. New

York: Academic Press.

Wiegand MS. 1997. Volatile organic compound emissions from a recycled paper mill. In: 1997

Environmental Conference & Exhibit, Book 1, Minneapolis Convention Center, May 5-7, 1997. Atlanta,

GA: TAPPI Press, 461-464.

Wilhelmsson B, Holmstrom M. 1987. Positive formaldehyde-rast after prolonged formaldehyde

exposure by inhalation [Abstract]. Lancet 8551:164.

Wilhelmsson B, Holmstrom M. 1992. Possible mechanisms of formaldehyde-induced discomfort in the

upper airways. Scand J Work Environ Health 18:403-407.

Wilkins JRIII, Gerken D, Steele L, et al. 1989. Adverse reproductive outcomes among female

veterinarians - survey results [Abstract]. J Am Vet Med Assoc 194:1788.

Williams TM, Levine RJ, Blunden P. 1984. Exposure of embalmers to formaldehyde and other

chemicals. Am Ind Hyg Assoc J 45:172-176.

*Wilmer JWG, Woutersen RA, Appelman LM, et al. 1987. Subacute (4-week) inhalation toxicity study

of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous exposures. J Appl Toxicol

7:15-16.

*Wilmer JW, Woutersen RA, Appelman LM, et al. 1989. Subchronic (13-week) inhalation toxicity

study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous exposures. Toxicol Lett

47:287-293.

*Windholz M, Budavari S, Blumetti RF, et al. 1983. The Merck index. 10th ed. Rahway, N.J.: Merck &

Co., Inc.

Winters DK, Clejan LA, Cederbaum AI. 1988. Oxidation of glycerol to formaldehyde by rat liver

microsomes. Biochem Biophys Res Commun 153:612-617.

*Witek TJ, Schachter EN, Tosun T, et al. 1986. Controlled human studies on the pulmonary effects of

indoor air pollution: Experiences with sulfur dioxide and formaldehyde. Environ Int 12:129-135.

*Witek TJJ, 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.
FORMALDEHYDE 413

8. REFERENCES

*Wolf DC, Gross EA, Lyght O, et al. 1995. Immunohistochemical localization of p53, PCNA and TGFalpha proteins in formaldehyde-induced rat nasal squamous cell carcinomas. Toxicol Appl Pharmacol

132:27-35.

*Wolff GT. 1991. Air pollution. In: Howe-Grant M, ed. Kirk-Othmer Encyclopedia of chemical

technology. New York: John Wiley & Sons, Inc., 711-749.

Wolff RK. 1986. Effects of airborne pollutants on mucociliary clearance. Environ Health Perspect

66:223-237.

Wong KL, Stock F, Alarie YC. 1983. Evaluation of the pulmonary toxicity of plasticized polyvinyl

chloride thermal decomposition products in guinea pigs by repeated CO2 challenges. Toxicol Appl

Pharmacol 70:236-248.

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 JE, ed. Formaldehyde toxicity. 

Washington, DC: Hemisphere Publishing Corporation, 256-272.

*Wood RW, Coleman JB. 1995. Behavioral evaluation of the irritant properties of formaldehyde. 

Toxicol Appl Pharmacol 130:67-72.

*Woodring JL, Duffy TL, Davis JT, et al. 1985. Measurement of combustion product emission factors

of unvented kerosene heaters. Am Ind Hyg Assoc J 46:350-356.

*Woodruff RC, Mason JM, Valencia R, et al. 1985. Chemical mutagenesis testing in Drosophila. V.

Results of 53 coded compounds tested for the National Toxicology Program. Environ Mutagen 7:677-

702.

*Woodruff TJ, Axelrad DA, Caldwell J, et al. 1998. Public health implications of 1990 Air Toxics

concentrations across the United States. Environ Health Perspect 106:245-251.

Wortley P, Vaughan TL, Davis S, et al. 1992. A case-control study of occupational risk factors for

laryngeal cancer. Br J Ind Med 49:837-844.

Woskie SR, Smith TJ, Hammond SK, et al. 1988. Estimation of the diesel exhaust exposures of railroad

workers: I. Current exposures. Am J Ind Med 13:381-394.

*Woutersen RA, Appleman LM, Wilmer JW, et al. 1987. Subchronic (13-week) inhalation toxicity

study of formaldehyde in rats. J Appl Toxicol 7:43-49.

*Wouterson RA, van Garderen-Hoetmer A, Bruijntjes JP, et al. 1989. Nasal tumors in rats after severe

injury to the nasal mucosa and prolonged exposure to 10 ppm formaldehyde. J Appl Toxicol 9:39-46.

*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.

Yamane K, Kobayashi T. 1988. An analysis of the response to formaldehyde in the guinea-pig tracheal

smooth muscle [Abstract]. Jpn J Pharmacol 46:161 P.

*Yasuhara A, Shibamoto T. 1995. Quantitative analysis of volatile aldehydes formed from various kinds

of fish flesh during heat treatment. J Agric Food Chem 43:94-97.
FORMALDEHYDE 414

8. REFERENCES

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.

*Zhang J, He Q, Lioy PJ. 1994a. Characteristics of aldehydes: Concentrations, sources, and exposures

for indoor and outdoor residential microenvironments. Environ Sci Technol 28:146-152.

*Zhang J, Wilson WE, Lioy PJ. 1994b. Indoor air chemistry: Formation of organic acids and aldehydes. 

Environ Sci Technol 28:1975-1982.

Zhang R-W, Jiang X-Z. 1988. A preliminary report on the analysis of malignant mortality among

anatomists and their assistants. In: Xue S-Z, Liang Y-X, ed. Occupational health in industrialization and

modernization. Shanghai: Shanghai Medical University Press, 89-90.

*Zhitkovich A, Costa M. 1992. A simple, sensitive assay to detect DNA-protein crosslinks in intact cells

and in vivo. Carcinogenesis 13:1485-1489.

*Ziegler EE, Edwards BB, Jensen RL et al. 1978. Absorption and retention of lead by infants. Pediatr

Res 12:29-34.

*Zinn TW, Cline D, Lehmann WF. 1990. Long-term study of formaldehyde emission decay from

particleboard. For Prod J 40:15-18.

Zissu D. 1995. Histopathological changes in the respiratory tract of mice exposed to ten families of

airborne chemicals. J Appl Toxicol 15:207-213.

*Zwart A, Woutersen RA, Wilmer JWGM, 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.

*Zweidinger RB, Sigsby JE, Tejada SB, et al. 1988. Detailed hydrocarbon and aldehyde mobile source

emissions from roadway studies. Environ Sci Technol 22:956-962.
FORMALDEHYDE 415

9. GLOSSARY

Absorption—The taking up of liquids by solids, or of gases by solids or liquids.

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the

Toxicological Profiles.

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the

surfaces of solid bodies or liquids with which they are in contact.

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase)

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or

sediment.

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be

10%. The BMD is determined by modeling the dose response curve in the region of the dose response

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological

or epidemiological data to calculate a BMD.

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms

at a specific time or during a discrete time period of exposure divided by the concentration in the

surrounding water at the same time or during the same period.

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have

been classified as markers of exposure, markers of effect, and markers of susceptibility.

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces

significant increases in the incidence of cancer (or tumors) between the exposed population and its

appropriate control.

Carcinogen—A chemical capable of inducing cancer.

Case-Control Study—A type of epidemiological study which examines the relationship between a

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is

identified and compared to a similar group of people without outcome.

Case Report—Describes a single individual with a particular disease or exposure. These may suggest

some potential topics for scientific research but are not actual research studies.

Case Series—Describes the experience of a small number of individuals with the same disease or

exposure. These may suggest potential topics for scientific research but are not actual research studies.
FORMALDEHYDE 416

9. GLOSSARY

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological

Profiles.

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed

group.

Cross-sectional Study—A type of epidemiological study of a group or groups which examines the

relationship between exposure and outcome to a chemical or to chemicals at one point in time.

Data Needs—Substance-specific informational needs that if met would reduce the uncertainities of

human health assessment.

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result

from exposure to a chemical prior to conception (either parent), during prenatal development, or

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point

in the life span of the organism.

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a

toxicant and the incidence of the adverse effects.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to

a chemical; the distinguishing feature between the two terms is the stage of development during which the

insult occurrs. The terms, as used here, include malformations and variations, altered growth, and

in utero death.

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water

levels for a chemical substance based on health effects information. A health advisory is not a legally

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials.

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of

disease or other health-related conditions within a defined human population during a specified period. 

FEFR25–75—Forced expiratory flowrate between 25 and 75%.

FEV1.0—Forced expiratory volume in 1.0 seconds.

FVC—Forced vital capacity.

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of

affected cells, can be expressed as a mutagenic, clastogenic or carcinogenic event because of specific

alteration of the molecular structure of the genome.

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from

the body or environmental media.
FORMALDEHYDE 417

9. GLOSSARY

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or

irreversible health effects.

Incidence—The ratio of individuals in a population who develop a specified condition to the total

number of individuals in that population who could have developed that condition in a specified time

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15-364 days, as specified in the

Toxicological Profiles.

Immunological Effects—Functional changes in the immune response.

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from

exposure to environmental agents such as chemicals.

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo—Occurring within the living organism.

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air which has been

reported to have caused death in humans or animals.

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for a

specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose(LO) (LDLO)—The lowest dose of a chemical introduced by a route other than inhalation that

has been reported to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical which has been calculated to cause death in 50% of a

defined experimental animal population.

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical

is expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study,

or group of studies, that produces statistically or biologically significant increases in frequency or severity

of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or

function.

Minimal Risk Level (MRL) —An estimate of daily human exposure to a hazardous substance that is

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and

duration of exposure.
FORMALDEHYDE 418

9. GLOSSARY

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a minimal risk

level (MRL) to reflect additional concerns about the database that are not covered by the uncertainity

factors. The default value for a MF is 1.

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific

population.

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time.

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s

DNA. Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a

chemical.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no

statistically or biologically significant increases in frequency or severity of adverse effects seen between

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not

considered to be adverse.

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical

in n-octanol and water, in dilute solution.

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances

and a disease or condition) which represents the best estimate of relative risk (risk as a ratio of the

incidence among subjects exposed to a particular risk factor divided by the incidence among subjects who

were not exposed to the risk factor). An odds ratio of greater than 1 is considered to indicate greater risk

of disease in the exposed group compared to the unexposed.

Organophosphate or Organophosphorus Compound—A phosphorus containing organic compound

and especially a pesticide that acts by inhibiting cholinesterase.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA)

allowable exposure level in workplace air averaged over an 8-hour shift of a 40 hour workweek.

Pesticide—General classification of chemicals specifically developed and produced for use in the control

of agricultural and public health pests.

Pharmacokinetics—The science of quantitatively predicting the fate (disposition) of an exogenous

substance in an organism. Utilizing computational techniques, it provides the means of studying the

absorption, distribution, metabolism and excretion of chemicals by the body.

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based

and physiologically-based. A data-based model divides the animal system into a series of compartments
FORMALDEHYDE 419

9. GLOSSARY

which, in general, do not represent real, identifiable anatomic regions of the body whereby the

physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based doseresponse model which quantitatively describes the relationship between target tissue dose and toxic end

points. These models advance the importance of physiologically based models in that they clearly

describe the biological effect (response) produced by the system following exposure to an exogenous

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments

representing organs or tissue groups with realistic weights and blood flows. These models require a

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar

ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information

such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called

biologically based tissue dosimetry models.

ppbv—Parts per billion by volume.

ppmv—Parts per million by volume.

Proportionate Mortality Ratio (PMR)—The ratio of a cause-specific mortality proportion in an

exposed group to the mortality proportion in an unexposed group; mortality proportions may be adjusted

for confounding variables such as age. Cause-specific mortality proportions can be calculated when the

cohort (the population at risk) cannot be defined due to inadequate records, but the number of deaths and

the causes of deaths are known.

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events

occurring after the start of the study. A group is followed over time.

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and

μg/m3

 for air).

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health

(NIOSH) time-weighted average (TWA) concentrations for up to a 10-hour workday during a 40-hour

workweek.

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of

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

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately

expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious

effects during a lifetime. The RfD is operationally derived from the No-Observed-Adverse-Effect Level

(NOAEL- from animal and human studies) by a consistent application of uncertainty factors that reflect
FORMALDEHYDE 420

9. GLOSSARY

various types of data used to estimate RfDs and an additional modifying factor, which is based on a

professional judgment of the entire database on the chemical. The RfDs are not applicable to

nonthreshold effects such as cancer.

Relative Risk (RR)—The risk expressed as a ratio of the incidence of diseased subjects exposed to a

particular risk factor to the incidence of diseased subjects in a non-exposed referent group.

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a

24-hour period.

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior,

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of

this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed

at some time in the past. Data are collected from routinely recorded events, up to the time the study is

undertaken. Retrospective studies are limited to casual factors that can be ascertained from existing

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or

inherited characteristic, that is associated with an increased occurrence of disease or other health-related

event or condition.

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed

group compared to the unexposed.

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 min

continually. No more than four excursions are allowed per day, and there must be at least 60 min

between exposure periods. The daily Threshold Limit Value - Time Weighted Average (TLV-TWA) may

not be exceeded.

Standardized Mortality Ratio (SMR)—The ratio of a cause-specific mortality rate in an exposed cohort

during a given period to the mortality rate of an unexposed cohort; mortality rates are often adjusted for

age or other confounding variables.

Standardized Proportionate Incidence Ratio (SPIR)—Similar to a Proportionate Mortality Ratio

(PMR) in that it is a ratio of a proportion of a specific disease in an exposed group compared with the

proportion in an unexposed group.
FORMALDEHYDE 421

9. GLOSSARY

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited

exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen—A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit

(STEL), or as a ceiling limit (CL).

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour

workday or 40-hour workweek.

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation,

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population.

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the

living organism.

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to

account for (1) the variation in sensitivity among the members of the human population, (2) the

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LowestObserved-Adverse-Effect Level (LOAEL) data rather than No-Observed-Adverse-Effect Level (NOAEL)

data. A default for each individual UF is 10; if complete certainty in data exists, a value of one can be

used; however a reduced UF of three may be used on a case-by-case basis, three being the approximate

logarithmic average of 10 and 1.

Xenobiotic—Any chemical that is foreign to the biological system.
FORMALDEHYDE A-1

APPENDIX A

ATSDR MINIMAL RISK LEVELS AND WORKSHEETS

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 

99–499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly

with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances

most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological

profiles for each substance included on the priority list of hazardous substances; and assure the initiation

of a research program to fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available toxicological

information and epidemiologic evaluations of a hazardous substance. During the development of

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are

used by ATSDR health assessors to identify contaminants and potential health effects that may be of

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or

action levels.

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor

approach. They are below levels that might cause adverse health effects in the people most sensitive to

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level

above the MRL does not mean that adverse health effects will occur.
FORMALDEHYDE A-2

APPENDIX A

MRLs are intended only to serve as a screening tool to help public health professionals decide where to

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons

may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels

that have been shown to be nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the

Division of Toxicology, expert panel peer reviews, and agency wide MRL Workgroup reviews, with

participation from other federal agencies and comments from the public. They are subject to change as

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in

the most recent toxicological profiles supersede previously published levels. For additional information

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333.
[FORMALDEHYDE] A-3

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Formaldehyde

CAS number(s): 50-00-0

Date: April 20, 1999

Profile status: Final

Route: [X] Inhalation [ ] Oral

Duration: [X] Acute [ ] Intermediate [ ] Chronic

Key to figure: 15

Species: Human

MRL: 0.04 [ ] mg/kg/day [X] ppm [ ] mg/m3

Reference: Pazdrak, K, Gorski, P, Krakowiak, A and Urszula, R (1993). Changes in Nasal Lavage Fluid

Due to Formaldehyde Inhalation. Int Arch Occup Environ Health 64: 515-519.

Experimental design: This study investigated the effects of formaldehyde exposure on the severity of

symptoms of nasal and eye irritation and the cellular makeup of nasal discharge in occupationally

exposed patients with skin hypersensitivity to formaldehyde and unexposed (control) patients. The study

was comprised of 2 study groups, all of whom were non-smokers. Group 1 consisted of 7 male and

3 female volunteers, all of whom suffered from skin hypersensitivity to formaldehyde; group 2 consisted

of 11 healthy males with no history of allergic diseases, normal serum IgE levels, and negative skin tests

to common allergens. Nasal washings were performed in both groups immediately before and after a

2-hour exposure to 0 (placebo) and 0.5 mg/m3

 (0.4 ppm) formaldehyde, and at 4 and 18 hours after

completion of the 2-hour exposure periods. Washings were analyzed for eosinophil, neutrophil, basophil,

and mononuclear cells, and albumin content. Symptoms of irritation (number of sneezes, degree of

mucosal edema, rhinorrhea, and itchy eyes) were evaluated through the exposure period and through 4-

and 18-hour periods after the exposure period. A symptom score was compiled for each subject by

summation of points assigned to the following symptoms (maximum score = 7): sneezing (0 points/0

sneezes; 1 point/1-4 sneezes; 2 points/ > 4 sneezes); rhinorrhea (0 points /none; 1 point/mild; 2

points/abundant); mucosal edema (0 points/none; 1 point/mild; 2 points/nasal block); and itching (0

points/none; 1 point/itchy eyes). 

Effects noted in study and corresponding doses: In both groups, placebo inhalation periods were without

effects on nasal wash cellular contents or symptom score. During exposure to 0.4 ppm formaldehyde,

both groups showed statistically significantly increased average symptom scores compared with average

placebo scores (about 4 versus <0.5). Symptom scores were no longer elevated 18 hours after exposure. 

In both groups, eosinophil counts were elevated at all time points after 0.4 ppm formaldehyde exposure,

while the proportion of epithelial cells declined after formaldehyde exposure. Albumin levels also

increased in both groups after formaldehyde exposure, but remained elevated only briefly (10 minutes).

There were no significant differences between allergic and healthy patients in nasal washing

characteristics after formaldehyde exposure. No changes in basophil numbers were noted in either patient

group and there was no evidence of mast cell degranulation. The authors concluded that the symptoms

observed were the result of a non-specific, non-allergic process in response to low-level formaldehyde

vapor exposure. The authors also noted that further study is required to understand the significance of the

increased release of eosinophils noting that eosinophils may have both protective (e.g., they can neutralize

histamine) and damaging (e.g., they may liberate mediators that damage epithelial surfaces) properties. 
[FORMALDEHYDE] A-4

APPENDIX A

Dose and end point used for MRL derivation:

The only concentration tested, 0.4 ppm, is a minimal LOAEL for nasal and eye irritation

[ ] NOAEL [X] LOAEL

Uncertainty factors used in MRL derivation:

[X] 3 for use of a minimal LOAEL- the observed symptoms of irritation were mild and reversible,

and the clinical significance of the changes in nasal lavage fluid content is uncertain at present .

[ ] 10 for extrapolation from animals to humans

[X] 3 for human variability - the observed symptoms of irritation were observed in a potentially

sensitive group of subjects (they displayed dermal sensitivity to formaldehyde).

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

NA

Was a conversion used from intermittent to continuous exposure?

NA

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:

NA

Other additional studies or pertinent information that lend support to this MRL: 

The Anderson and Molhave (1983) study identified an apparent effect level (0.2 ppm), based on

subjective reports of irritation that is lower than the effect levels (0.35-0.4 ppm) in the studies by Pazdrak

et al. (1993), Krakowiak et al. (1998), and Bender et al. (1993), which used more objective measures of

acute irritation (eosinophil counts and protein concentrations in nasal lavage fluid or time to first

reporting of irritation: see section 2.2.1.2 Systemic Effects - Respiratory Effects Acute Controlled

Exposure Human Studies.) Because of the use of objective measures of toxicity and the general weight of

the available data indicating that some people will not experience eye or upper respiratory tract irritation

from formaldehyde even at 1 ppm (see Day et al. 1984; Kulle et al. 1987, Weber Tschopp et al. 1977, and

Witek et al. 1986), the Pazdrak et al. (1993) LOAEL of 0.4 ppm was considered a minimal LOAEL in a

group of potentially sensitive individuals (some subjects had dermal hypersensitivity to formaldehyde)

and selected as the basis of the acute MRL. 

Agency Contact (Chemical Manager): Sharon Wilbur
[FORMALDEHYDE] A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Formaldehyde

CAS number: 50-00-0

Date: April 20, 1999

Profile status: Final

Route: [X] Inhalation [ ] Oral

Duration: [ ] Acute [X] Intermediate [ ] Chronic

Key to figure: 49

Species: Cynomolgus Monkey

MRL: 0.03 [ ] mg/kg/day [X] ppm [ ] mg/m3

Reference: Rusch, G, Clary, JJ, Rinehart WE and Bolte, HF (1983). A 26 Week Inhalation Toxicity

Study with Formaldehyde in the Monkey, Rat and Hamster. Toxicol Appl Pharmacol 68: 329-343.

Experimental design: Groups of 6 male Cynomolgus monkeys were exposed to 0, 0.19±0.02, 0.98±0.08,

or 2.95±0.18 ppm for 22 hours per day, 7 days per week for 26 weeks. All monkeys were weighed and

clinically assessed weekly. At sacrifice, adrenals, kidneys, liver, and heart were weighed. Sections of

lung, nasal turbinate, trachea, and any other tissue with gross abnormalities were prepared for histologic

examination.

Effects noted in study and corresponding doses: Body weights in the monkeys were normal in all groups

throughout the study. Monkeys in the 2.95-ppm group exhibited increasing hoarseness, nasal congestion,

and nasal discharge, especially during the last 13 weeks of the study. While some nasal symptoms were

noted in the 0.19- and 0.98-ppm groups, they were observed to be inconsistent and were not substantiated

histologically. All organ weight data were unremarkable. No treatment-related effects were noted in

internal organs upon gross inspection. A statistically significant increased incidence of squamous

metaplasia and hyperplasia of the nasal epithelium was clearly observed in the 2.95-ppm group, but no

significant increase in the incidence of epithelial squamous metaplasia/hyperplasia was found in the 0.19

and 0.98-ppm groups. The response was seen most clearly in the mid-region of the nasoturbinates. No

ultrastructural changes were noted in other sections of the turbinates, trachea, or lungs at any of the doses

of formaldehyde tested.

Dose and end point used for MRL derivation:

Clinical signs of nasopharyngeal irritation (hoarseness and nasal congestion and discharge) and lesions in

the nasal epithelium (squamous metaplasia and hyperplasia) were observed at 2.95 ppm; no effects were

observed at 0.98 ppm. Thus, the NOAEL and LOAEL for nasopharyngeal irritation are 0.98 and 2.95

ppm, respectively.

[X] NOAEL [ ] LOAEL

Uncertainty factors used in MRL derivation:

[ ] 10 for use of a LOAEL

[X] 3 for extrapolation from animals to humans - an uncertainty factor of 3 was used, instead of 10,

because similar nasal effects have been reported at similar concentrations in different species and

different studies indicating few pharmacodynamic differences in species susceptibility 
[FORMALDEHYDE] A-6

APPENDIX A

[X] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

NA

Was a conversion used from intermittent to continuous exposure?

The exposure concentration was not adjusted to a continuous exposure basis based on evidence that

concentration is more important than the product of concentration and duration of exposure in

determining the severity of formaldehyde-induced epithelial damage in the upper respiratory tract

(Wilmer et al. 1987). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:

In the absence of reference nasal cavity surface areas and minute ventilations for Cynomolgus monkeys, a

default regional gas dose ratio of 1 was assumed (EPA 1994).

Other additional studies or pertinent information that lend support to this MRL:

Although there are numerous human studies of acute inhalation toxicity from formaldehyde (controlledexposure and occupational exposure studies) and numerous investigations of toxic effects from chronic

occupational exposures, studies of humans exposed for intermediate durations were not located. In

contrast, the database for studies of animals (including primates) exposed by inhalation to formaldehyde

is rich, providing data describing exposure-response relationships for formaldehyde-induced effects on

the upper respiratory tract system in several species (rats, mice, hamsters, and monkeys) . The study by

Rusch et al. (1983) examined a number of species and identified the lowest effect level among the

available sets of data. Given this observation, the absence of human intermediate-duration data, and the

putatively greater relevance of monkeys, compared with rodents, to humans, the monkey NOAEL of 0.98

ppm and LOAEL of 2.95 ppm for clinical signs of nasopharyngeal irritation were selected as the basis of

the intermediate-duration MRL. 

Agency Contact (Chemical Manager) : Sharon Wilbur
[FORMALDEHYDE] A-7

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Formaldehyde

CAS number: 50-00-0

Date: April 20, 1999

Profile status: Final

Route: [X] Inhalation [ ] Oral

Duration: [] Acute [ ] Intermediate [X] Chronic

Key to figure: 86

Species: Human

MRL: 0.008 [ ] mg/kg/day [X ] ppm [ ] mg/m3

Reference: Holmstrom 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 (Stockh) 107:120-129.

Experimental design: Holmstrom et al. (1989c) examined histological changes in nasal tissue specimens

from a group of 70 workers in a chemical plant that produced formaldehyde and formaldehyde resins for

impregnation of paper, a group of 100 furniture factory workers working with particle board and glue

components, and a nonexposed, control group of 36 office workers in the same village as the furniture

factories. Mean durations of employment in the groups were 10.4 years (SD 7.3, range 1–36 years) for

the chemical workers and 9.0 years (SD 6.3, range 1–30 years) for the furniture workers. Estimates of

personal breathing zone air concentrations ranged from 0.04 to 0.4 ppm (median 0.24±0.13 ppm) for the

chemical workers, from 0.16 to 0.4 ppm (median 0.20±0.04 ppm) for the furniture workers, and from

0.07 to 0.13 ppm in the late summer for the office workers with a year-round office worker median

reported as 0.07 ppm with no standard deviation. The mean wood dust concentration in the furniture

factory was reported to have been between 1 and 2 mg/m3

. Nasal mucosa specimens were taken from the

medial or inferior aspect of the middle turbinate. Histology scores were assigned to each specimen based

on a 0–8 scale, identical to the scale used by Edling et al. (1988; described previously). Nasal mucosal

biopsy sections for each subject were examined and assigned scores as follows: 0 - normal respiratory

epithelium; 1- loss of ciliated epithelium cells; 2 - mixed cuboid/squamous epithelium, metaplasia; 3 -

stratified squamous epithelium; 4 - keratosis; 5 - budding of epithelium; 6 - mild or moderate dysplasia; 7

- severe dysplasia; and 8 - carcinoma.

Effects noted in study and corresponding doses: Nasal histology scores ranged from 0 to 4 (mean 2.16;

n=62) for the chemical workers, from 0 to 6 (mean 2.07; n=89) for the furniture workers, and from 0 to 4

(mean 1.46; n=32) for the office workers. The mean histological score for the chemical workers, but not

the furniture workers, was significantly different from the control score, thus supporting the hypothesis

that the development of the nasal lesions is formaldehyde-related and not obligatorily related to possible

interaction between formaldehyde and wood dust. The most severe epithelial change found (light or

moderate epithelial dysplasia) was found in two furniture workers. Among the chemical workers (not

exposed to wood dust), loss of cilia, goblet cell hyperplasia and cuboidal and squamous cell metaplasia

replacing the columnar epithelium occurred more frequently than in the control group of office workers. 

Within both groups of formaldehyde-exposed workers, no evidence was found for associations between

histological score and duration of exposure, index of accumulated dose, or smoking habit. 
[FORMALDEHYDE] A-8

APPENDIX A

Dose and end point used for MRL derivation: 

Clinical symptoms of mild irritation of the eyes and upper respiratory tract and mild damage to the nasal

epithelium were observed in workers exposed for 10.4 years (range 1-36 years) to an average TWA

concentration of 0.24 ppm (range: 0.04 to 0.4 ppm). The LOAEL of 0.24 ppm is considered to be a

minimal LOAEL.

[ ] NOAEL [X] LOAEL

Uncertainty factors used in MRL derivation:

[X] 3 for use of a LOAEL - the exposed histological effects are considered to be mild and subclinical

in nature, suitable for 0.24 ppm to be designated as a minimal LOAEL

[ ] 10 for extrapolation from animals to humans

[X] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

NA

Was a conversion used from intermittent-to-continuous exposure?

The exposure concentration was not adjusted to a continuous exposure basis based on evidence that

concentration is more important than the product of concentration and duration of exposure in

determining the severity of formaldehyde-induced epithelial damage in the upper respiratory tract

(Wilmer et al. 1987). 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:

NA

Other additional studies or pertinent information that lend support to this MRL:

Several cross-sectional studies of groups of formaldehyde-exposed workers chronically exposed to

estimated concentrations ranging from about 0.1 to 0.6 ppm (Holmstrom et al. 1989c; Edling et al. 1988;

Boysen et al. 1990; Ballarin et al. 1992) have found histological evidence for mild damage to nasal

epithelial tissue such as the damage described for exposed workers in the Holmstrom et al. (1989c) study. 

The observed effects were consistently mild, but each study reported a statistically significant, albeit

small, increase in average histological score (increasing scores indicating increasing severity of change)

for exposed groups compared with nonexposed control groups: 2.8 exposed versus 1.8 on an 8-point scale

(Edling et al., 1988); 2.16 versus 1.46 on an 8-point scale (Holmstrom et al., 1989c); 1.9 versus 1.4 on a

5-point scale (Boysen et al., 1990); and 2.3 versus 1.6 on a 6-point scale (Ballarin et al., 1992). The

Holmstrom et al. (1989c) study was selected as the basis of the MRL from among these four crosssectional studies (they each examined equivalent endpoints and are of similar quality of design) primarily

because the statistically significant effects were found in a group exposed to formaldehyde in the absence

of potentially confounding exposures to wood dust. A full uncertainty factor of 10 was used to account

for human variability because the observed mild effects were seen in groups of chronically exposed

workers that were otherwise in apparent good health; a healthy worker effect may have operated causing

sensitive individuals to avoid employment in the studied workplaces.
[FORMALDEHYDE] A-9

APPENDIX A

Additional supporting evidence for mild histological changes to the nasal epithelium with chronic

exposure to concentrations below 1 ppm comes from rat studies. Although several studies of rats exposed

for life (generally with an exposure protocol of 6 hours/day, 5 day/week) found no statistically significant

increases in incidences of nonneoplastic lesions in the nasal epithelium of rats exposed to 0.1 to 2 ppm

[Kerns et al. 1983b (F344 rats); Monticello et al. 1996 (F344 rats); Woutersen et al. 1989 (Wistar rats)], 

Kamata et al. (1997) reported that some F344 rats, after 28 months of exposure, displayed a mild response

at 2 ppm and even at 0.3 ppm. A statistically significantly increased incidence for nasal epithelial

squamous metaplasia without hyperplasia was observed in rats exposed to 2 ppm compared with control

rats (5/32 versus 0/32); the incidence for nasal epithelial cell hyperplasia with squamous metaplasia was

also significantly elevated compared with controls (7/32 versus 0/32). In rats exposed to 0.3 ppm,

incidences of the same respective nasal epithelial lesions were also greater than control incidences

(1/32 versus 0/32 and 4/32 versus 0/32), but not to a statistically significant degree.

Agency Contact (Chemical Manager) : Sharon Wilbur
[FORMALDEHYDE] A-10

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name(s): Formaldehyde

CAS number(s): 50-00-0

Date: Aprile 20, 1999

Profile status: Final

Route: [ ] Inhalation [X] Oral

Duration: [ ] Acute [X] Intermediate [ ] Chronic

Key to figure: 17

Species: Rat

MRL: 0.3 [X] mg/kg/day [ ] ppm [ ] mg/m3

 

Reference: Til HP, Woutersen RA, Feron VJ, Clary JJ (1988b). Evaluation of the oral toxicity of

acetaldehyde and formaldehyde in a 4-week drinking-water study in rats. Fd. Chem. Toxic 26: 447–452.

Experimental design: Groups (10 males and 10 females) of weanling, SPF-bred rats (Cpb:WU; Wistar

random) received 0, 5, 25, or 125 mg/kg/day formaldehyde in their drinking water for 4 weeks. Fresh

formaldehyde dosing solutions were made once per week; however, the authors did not provide

information on if or how often the dosing solutions were analyzed for actual formaldehyde content. Due

to this procedural discrepancy, it is unclear how much formaldehyde each animal actually received in the

drinking water, since polymerization, oxidation, or evaporation may have occurred during the study. 

Control groups (20 males and 20 females) were given unsupplemented tap water. A water-restricted

group (10 males and 10 females) received the same amount of unsupplemented drinking water as the

amount of liquid consumed by the group given the highest dose of formaldehyde. Rats were weighed

weekly and observed daily for condition and behavior. Food and water intake were measured over

weekly periods throughout the study. Hematological parameters (hemoglobin concentration, packed-cell

volume, erythrocyte and leucocyte counts) were determined. Whole blood from fasted animals was

examined for glucose. Blood samples were analyzed for alkaline phosphatase, aspartate

aminotransferase, alanine aminotransferase, total protein, albumin, total bilirubin, urea, creatinine and

calcium, inorganic phosphate, chloride, and sodium and potassium. In week 4 of treatment, rats were

deprived of water for 24 hours and of food for 16 hours. Urine was collected during the last 16 hours of

the deprivation period. Density and volume of urine were determined. The rats were killed in week 5,

organs (adrenals, brain, liver, heart, kidneys, spleen, testes, thymus, thyroid, and ovaries) were weighed

and organ-to-body weight ratios determined. Histopathological examination was performed on the liver,

kidneys, tongue, pharynx, esophagus, stomach, and nose. The fur of rats receiving 125 mg/kg/day

formaldehyde showed yellowish discoloration from week 3 onward. Food intake was significantly

reduced at all dose levels for female rats. At 125 mg/kg/day formaldehyde, water intake was significantly

reduced in both sexes; body weight was not affected. There was no effect on the density (except that in

5 mg/kg treated males and water-restricted males, density significantly decreased) or volume of the urine

collected. Hematological parameters showed no significant changes in animals treated with formaldehyde

at any dose level. Male rats given 125 mg/kg/day formaldehyde showed statistically significant decrease

in plasma protein and albumin concentrations. Female rats given 25 mg/kg/day formaldehyde showed

statistically significant decrease in plasma alkaline phosphatase; alanine aminotransferase activities also

decreased but was not significant. At 125 mg/kg, kidney weights in females were significantly increased. 

There were no other organ weight changes observed at any dose level, treatment-related, or

histopathological changes in any of the tissues examined except the stomach. Necropsy findings revealed

thickening of the limiting ridges and hyperkeratosis in the forestomach and focal atrophic inflammation in

the glandular stomach in animals given the high concentration of formaldehyde. Moderate papillomatous

hyperplasia was seen in one female given a high concentration of formaldehyde. Types of lesions in
[FORMALDEHYDE] A-11

APPENDIX A

males given 125 mg/kg formaldehyde are as follows: slight-to-moderate focal hyperkeratosis of

forestomach, slight-to-moderate focal gastritis (location in stomach not reported), and slight-to-moderate

submucosal mononuclear-cell infiltrate (location in stomach not reported). Types of lesions in females

given 125 mg/kg formaldehyde are as follows: very slight, slight-to-moderate focal hyperkeratosis of

forestomach; very slight, slight-to-moderate focal gastritis (location in stomach not reported); focal

papillomatous hyperplasia (location in stomach not reported); and polymorphonuclear leucocytic

infiltration. 

Effects noted in study and corresponding doses: 

25 mg/kg/day: NOAEL for gastrointestinal effects.

125 mg/kg/day: Thickening of the limiting ridges and hyperkeratosis in the forestomach and focal

atrophic inflammation in the glandular stomach; slight-to-moderate focal hyperkeratosis of forestomach. Slight-to-moderate focal gastritis, and slight-to-moderate

submucosal mononuclear-cell infiltrate in males (location in stomach not reported);

very slight, slight-to-moderate focal hyperkeratosis of forestomach. Very slight,

slight-to-moderate focal gastritis and focal papillomatous hyperplasia (location in

stomach not reported). Polymorphonuclear leucocytic infiltration in females,

moderate papillomatous hyperplasia in one female (less serious LOAEL).

Dose end point used for MRL derivation: NA

[X ] NOAEL [ ] LOAEL 25 mg/kg/day

Uncertainty factors used in MRL derivation:

[X] 1 [ ] 3 [ ] 10 (for use of a LOAEL)

[ ] 1 [ ] 3 [X] 10 (for extrapolation from animals to humans)

[ ] 1 [ ] 3 [X] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

If so, explain: None

Was a conversion used from intermittent to continuous exposure? 

If so, explain: None

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA

Other additional studies or pertinent information that lend support to this MRL : Gastrointestinal irritation

and damage have been observed in both humans and animals after ingestion of formaldehyde. In human

poisoning studies, effects observed include: ulceration and sloughing of the soft palate and posterior

pharyngeal wall; ulceration of the epiglottis, pyriform fossae and arytenoids; edematous and ulcerated

esophageal mucosa with patches of black, sloughed tissue along the entire length; hyperemic areas of the

stomach; and superficial ulceration in the distal body and antrum after a single dose of 234 mg/kg

formaldehyde (Kochhar et al. 1986); abdominal pain and retching; hard, white and leathery stomach after

a dose of 517 mg/kg (Burkhart et al. 1990), or abdominal pain at 624 mg/kg (Eells et al. 1981). In human

poisoning studies in which the dose of formaldehyde is not known, gastrointestinal symptoms including

mucosal damage, ulceration and bleeding of the buccal cavity and tonsils, and dysphagia due to

esophageal mucosal damage (Freestone and Bentley 1989), necrosis of the esophagus and stomach,

extensive congestion, peptic plaques in esophagus and stomach, colitis, congestion, diffuse necrosis and
[FORMALDEHYDE] A-12

APPENDIX A

hemorrhage of gastric and duodenal mucosa, burns in gastrointestinal mucosa, and ileitis (Koppel et al.

1990). In animals, gastrointestinal irritation and damage (Til et al. 1989; Tobe et al. 1989), and neoplastic

lesions (Soffritti et al. 1989; Takahashi et al. 1986a) have been observed in other studies in which

formaldehyde was administered orally for longer periods of time. Vargova et al. (1993) reported

immunological effects related to formaldehyde exposure (increased relative lymph node weight and a

decrease in combined IgM and IgG titers), while Dean et al. (1984) failed to produce observable changes

in immunological parameters. The Vargova et al. (1993) study was not used for MRL calculation because

actual individual IgG and IgM titers were not significantly reduced until the dose reached 40 mg/kg/day,

and because it used a gavage method of dosing, which is less relevant to human exposure than the

drinking water study of Til et al. (1988b). It appears from the available data that immunological changes

resulting from formaldehyde exposure are unclear and perhaps not a viable toxicological endpoint for

determining formaldehyde toxicity. Thus, gastrointestinal effects appear to be an appropriate indicator of

an adverse reaction to oral exposure to formaldehyde.

Agency Contact (Chemical Manager) : Sharon Wilbur
[FORMALDEHYDE] A-13

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name(s): Formaldehyde

CAS number(s): 50-00-0

Date: April 20, 1999

Profile status: Final

Route: [ ] Inhalation [X] Oral

Duration: [ ] Acute [ ] Intermediate [X] Chronic

Key to figure: 38

Species: Rat

MRL: 0.2 [X] mg/kg/day [ ] ppm [ ] mg/m3

 

Reference: Til HP, Woutersen RA, Feron VJ, Hollanders VHM, Falke HE, Clary JJ (1989). Two-year

drinking-water study of formaldehyde in rats. Fd. Chem. Toxic 27: 77-86.

Experimental design: Target concentrations of 5, 25, and 125 mg/kg/day formaldehyde (95%

paraformaldehyde) were administered to groups of weanling SPF-bred rats (Cpb:WU; Wistar random) in

their drinking water for 2 years. Actual formaldehyde concentrations reported in this study were 0, 1.2,

15, or 82 mg/kg/day for males and 0, 1.8, 21, or 109 mg/kg/day for females when adjusted for body

weight. Fresh formaldehyde dosing solutions were made once per week; however, the authors did not

provide information on if or how often the dosing solutions were analyzed for actual formaldehyde

content. Due to this procedural discrepancy, it is unclear how much formaldehyde each animal actually

received in the drinking water, since polymerization, oxidation, or evaporation may have occurred during

the study. Daily observations were made of the condition and behavior of the rats. Body weights were

recorded at the start of the study, at weekly intervals in the first 12 weeks, and once every 4 weeks

thereafter. Water intake was measured over weekly periods throughout the study and food intake was

determined over weekly periods during the first 12 weeks, then over 2-week periods every 3 months. 

Hematological parameters (hemoglobin concentration; packed-cell volume; erythrocyte, leucocyte, and

thrombocyte counts) were determined in weeks 26 and 103 from 10 rats/sex/group. Whole blood taken

from 10 rats/sex/group after overnight fasting in weeks 27, 52, 78, and 104 was examined for glucose. 

Blood samples taken from 10 rats/sex/group on weeks 26, 53, 79, and 105 were analyzed for alkaline

phosphatase, aspartate aminotransferase, alanine aminotransferase, total protein, albumin, total bilirubin,

urea, creatinine, cholesterol, g-glutamyl transferase and calcium, inorganic phosphate, chloride, sodium,

and potassium. Urinalysis was performed from pooled urine samples collected in weeks 27 and 104 and

observed for protein, glucose, occult blood, ketones, urobilinogen, and bilirubin. pH determinations were

carried out in weeks 27, 52, 78 and 104. Surviving rats of the first (10 rats/sex/group), second (10

rats/sex/group) and third (50 rats/sex/group) subsets were killed in weeks 53, 79, and 105, respectively. 

Organs (adrenals, brain, heart, kidneys, liver, ovaries, pituitary, spleen, testes, and thyroid) were weighed

and organ-to-body weight ratios determined. Microscopic examination was performed on the these

organs and samples of the skin, skeletal muscle, mammary glands (females), Harderian and exorbital

lachrymal glands, nose, lungs, aorta, parotid, submandibular and sublingual salivary glands, esophagus,

forestomach, glandular stomach, small and large intestine, pancreas, urinary bladder, epididymides,

prostate, uterus, sternum, mesenteric and axillary lymph nodes, spinal cord, sciatic nerve, and eye in

control and high-dose groups. The liver, lungs, stomach, and nose of the low- and mid-dose groups were

examined as well as the adrenals, kidneys, spleen, testes, thyroid, ovaries, and pituitary and mammary

glands (females) of the third subset killed in week 105. Necropsies were performed on rats found dead or

killed when moribund in the course of the study. A slight yellowing of the fur in the rats given mid- and

high-dose levels were observed from week 3 onward; this effect was more pronounced in the high-dose

group. Liquid consumption decreased 40% in high-dose animals of both sexes; in mid-dose groups,
[FORMALDEHYDE] A-14

APPENDIX A

liquid consumption decreased as compared to controls, but the differences were not statistically

significant. Food consumption at the high dose was significantly decreased in males but showed a less

pronounced effect in females. The mean body weights of the high-dose group were decreased from week

1 onward in males and from week 24 onward in females. At the end of the study, there had been a 15%

decrease in body weight in males at the 82 mg/kg/day dose and a 10% decrease in females at the 109

mg/kg/day dose. There were no significant differences in the hematological parameters monitored. In the

high-dose groups, increased urine density and decreased volume of urine in males (in weeks 27 and 52)

and females (in week 27) were observed. Occult blood was found in males of all dose groups in week 27

and in females of the mid- and high-dose groups in week 104. Clinical chemistry variables evaluated

between groups during weeks 53 and 105 showed no statistically significant differences and, therefore, no

toxicological significance was attached to the slight changes in plasma alkaline phosphatase activity, total

plasma protein content, plasma urea level, cholesterol levels, and plasma potassium concentration in

weeks 27 and 79 of the study. Absolute heart and liver weights in high-dose males were significantly

decreased in weeks 79 and 105, testes weight in week 79, and kidney weight in week 105. These

decreases in weight were attributed to lower body weights of animals in this group. Relative kidney

weight in females increased in the high-dose group in weeks 53, 79, and 105. Relative brain weight

significantly increased in high-dose males in weeks 53, 79, and 105 and in females in week 105. Relative

testes weight increased in the high-dose groups in week 105. Necropsy findings of high-dose rats killed

in weeks 53, 79, and 105 revealed a raised and thickened limiting ridge of the forestomach. The limiting

ridge of the forestomach was raised and thickened in most male and female rats of the high-dose group,

and in some males and females of the other groups, including the control group. Also, several rats in the

high-dose groups showed irregular mucosal thickenings in the forestomach and/or glandular stomach. 

These changes were also found in rats of the other groups as well as the control groups. The incidence of

discoloration and an irregular surface of the kidneys, which was frequently accompanied by enlarged

parathyroids, was lower in males of the high-dose group (12%) than in the controls (33%) in week 105. 

The incidence of testicular atrophy in the high-dose group (6%) was also remarkably low as compared to

controls (24%). In high-dose animals, histopathological examination revealed gastric changes including

papillary epithelial hyperplasia accompanied by hyperkeratosis and focal ulceration in the forestomach,

and focal chronic atrophic gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia,

in the glandular stomach. Histopathological examinations of the kidneys showed that the incidence and

degree of renal papillary necrosis increased in week 105 in high-dose animals. Non-neoplastic lesions

found in organs other than the stomach or kidneys were not treatment-related. There were no gastric

tumors observed apart from two benign papillomas, one in the male of the low-dose group and one in a

female control rat.

Effects noted in study and corresponding doses:

15 mg/kg/day: NOAEL for gastrointestinal effects in males.

82 mg/kg/day: gastric changes including papillary epithelial hyperplasia accompanied by

hyperkeratosis and focal ulceration in the forestomach and focal chronic atrophic

gastritis, occasionally accompanied by ulceration and/or glandular hyperplasia, in

the glandular stomach (less serious LOAEL in males), and renal papillary necrosis.

Dose end point used for MRL derivation: NA

[X ] NOAEL [ ] LOAEL 15 mg/kg/day

Uncertainty factors used in MRL derivation:

[X] 1 [ ] 3 [ ] 10 (for use of a LOAEL)
[FORMALDEHYDE] A-15

APPENDIX A

[ ] 1 [ ] 3 [X] 10 (for extrapolation from animals to humans)

[ ] 1 [ ] 3 [X] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

If so, explain: None

Was a conversion used from intermittent to continuous exposure? 

If so, explain: None

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: NA

Other additional studies or pertinent information that lend support to this MRL : Gastrointestinal irritation

and damage have been observed in both humans and animals after ingestion of formaldehyde. In human

poisoning studies, effects observed include: ulceration and sloughing of the soft palate and posterior

pharyngeal wall; ulceration of the epiglottis, pyriform fossae and arytenoids; edematous and ulcerated

esophageal mucosa with patches of black, sloughed tissue along the entire length; hyperemic areas of the

stomach; and superficial ulceration in the distal body and antrum after a single dose of 234 mg/kg

formaldehyde (Kochhar et al. 1986); abdominal pain and retching; hard, white and leathery stomach after

a dose of 517 mg/kg (Burkhart et al. 1990), or abdominal pain (Eells et al. 1981). In human poisoning

studies, in which the dose of formaldehyde is usually not known with any accuracy, the gastrointestinal

symptoms include mucosal damage, ulceration and bleeding of the buccal cavity and tonsils, and

dysphagia due to esophageal mucosal damage (Freestone and Bentley 1989). In addition, necrosis of the

esophagus and stomach, extensive congestion, peptic plaques in esophagus and stomach, colitis,

congestion, diffuse necrosis and hemorrhage of gastric and duodenal mucosa, burns in gastrointestinal

mucosa, and ileitis (Koppel et al. 1990) have also been reported. In animals, gastrointestinal irritation and

damage also occurs, which includes thickening of the limiting ridges and hyperkeratosis in the

forestomach and focal atrophic inflammation in the glandular stomach. In addition, slight-to-moderate

focal hyperkeratosis of forestomach, slight-to-moderate focal gastritis, slight-to-moderate submucosal

mononuclear-cell infiltrate (males), focal papillomatous hyperplasia, polymorphonuclear leucocytic

infiltration (females), and moderate papillomatous hyperplasia in one female were noted in rats after

administration of 125 mg/kg/day formaldehyde in the drinking water for 4 weeks (Til et al. 1988b). Tobe

et al. (1989) noted forestomach hyperkeratosis in rats given 50 mg/kg/day formaldehyde in the drinking

water for 15–24 months; neoplastic lesions (Soffritti et al. 1989; Takahashi et al. 1986a) have been

observed in other studies in which formaldehyde was administered orally for longer periods of time. 

Thus, gastrointestinal effects appear to be an appropriate indicator of an adverse reaction to oral exposure

to formaldehyde.

It was also noted that the data showed that at 104 weeks of administering 15 mg/kg/day formaldehyde, 27

male rats in the 15 mg/kg group died, which differed significantly from corresponding control values. 

However, the deaths were not dose-related, since deaths at 82 mg/kg/day were not significantly different

from control animals. Otherwise, no toxicologically significant difference in mortality was found

between controls and treated animals. This study was also used to derive the EPA Reference Dose (RfD)

of 0.2 mg/kg/day, which is the same number as this chronic oral MRL.

Agency Contact (Chemical Manager) : Sharon Wilbur
FORMALDEHYDE B-1

APPENDIX B

USER'S GUIDE

Chapter 1

Public Health Statement

This chapter of the profile is a health effects summary written in non-technical language. Its intended

audience is the general public especially people living in the vicinity of a hazardous waste site or

chemical release. If the Public Health Statement were removed from the rest of the document, it would

still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The

topics are written in a question and answer format. The answer to each question includes a sentence that

will direct the reader to chapters in the profile that will provide more information on the given topic.

Chapter 2

Tables and Figures for Levels of Significant Exposure (LSE)

Tables (2-1, 2-4, and 2-5) and figures (2-1 and 2-2) are used to summarize health effects and illustrate

graphically levels of exposure associated with those effects. These levels cover health effects observed at

increasing dose concentrations and durations, differences in response by species, minimal risk levels

(MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper- bound

individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a

quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and

figures should always be used in conjunction with the text. All entries in these tables and figures

represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels

(NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative

examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends

correspond to the numbers in the example table and figure.

LEGEND

See LSE Table 2-1

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using

these tables and figures should be the relevant and appropriate route of exposure. When sufficient

data exists, three LSE tables and two LSE figures are presented in the document. The three LSE

tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE

Table 2-1, 2-4, and 2-5, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1)

and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and

will not therefore have all five of the tables and figures.
FORMALDEHYDE B-2

APPENDIX B

(2) Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15–364 days),

and chronic (365 days or more) are presented within each relevant route of exposure. In this

example, an inhalation study of intermediate exposure duration is reported. For quick reference to

health effects occurring from a known length of exposure, locate the applicable exposure period

within the LSE table and figure.

(3) Health Effect The major categories of health effects included in LSE tables and figures are death,

systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and

LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are

further defined in the "System" column of the LSE table (see key number 18).

(4) Key to Figure Each key number in the LSE table links study information to one or more data points

using the same key number in the corresponding LSE figure. In this example, the study represented

by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2

"18r" data points in Figure 2-1).

(5) Species The test species, whether animal or human, are identified in this column. Section 2.5,

"Relevance to Public Health," covers the relevance of animal data to human toxicity and Section

2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although

NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses

to derive an MRL.

(6) Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen

are provided in this column. This permits comparison of NOAELs and LOAELs from different

studies. In this case (key number 18), rats were exposed to 1,1,2,2-tetrachloroethane via inhalation

for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing

regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et

al. 1981.

(7) System This column further defines the systemic effects. These systems include: respiratory,

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. 

"Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. 

In the example of key number 18, 1 systemic effect (respiratory) was investigated.

(8) NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no

harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm

for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of

0.005 ppm (see footnote "b").

(9) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study

that caused a harmful health effect. LOAELs have been classified into "Less Serious" and

"Serious" effects. These distinctions help readers identify the levels of exposure at which adverse

health effects first appear and the gradation of effects with increasing dose. A brief description of

the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory

effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not

derived from Serious LOAELs.

(10) Reference The complete reference citation is given in chapter 8 of the profile.
FORMALDEHYDE B-3

APPENDIX B

(11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report

doses not causing measurable cancer increases.

(12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in

the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an

MRL of 0.005 ppm.

LEGEND

See Figure 2-1

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the

reader quickly compare health effects according to exposure concentrations for particular exposure

periods.

(13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health

effects observed within the intermediate and chronic exposure periods are illustrated.

(14) Health Effect These are the categories of health effects for which reliable quantitative data exists. 

The same health effects appear in the LSE table.

(15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically

displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. 

Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in mg/kg/day.

(16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation

exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates

to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. 

The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see

entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table).

(17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond

symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to

the entry in the LSE table.

(18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the

upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the

cancer dose response curve at low dose levels (q1*).

(19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure.
SAMPLE

1 6 TABLE 2-1. Levels of Significant Exposure to [Chemical x] – Inhalat

Key tofigurea Species

Exposurefrequency/duration System

NOAEL(ppm)

LOAEL (effect)

Less serious (ppm) Serious (ppm)

2 6 INTERMEDIATE EXPOSURE

5 6 7 8 9 

3 6 Systemic 9 9 9 99 

4 6 18 Rat 13 wk

5d/wk6hr/d

Resp 3b 10 (hyperplasia) 

CHRONIC EXPOSURE

11

Cancer 938 Rat 18 mo

5d/wk7hr/d

20 (CEL, multiple

organs)

39 Rat 89–104 wk

5d/wk6hr/d

10 (CEL, lung tumor

nasal tumors)

40 Mouse 79–103 wk

5d/wk6hr/d

10 (CEL, lung tumor

hemangiosarcom

a The number corresponds to entries in Figure 2-1.

12 6 b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10-3 ppm; dose adjusted for intermittent e

an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).
SAMPLE

0.0000001

0.000001

0.00001

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

Systemic

Death Hematological (ppm) Respiratory

Figure 2-1. Levels of Significant Exposure to [Chemical X] – Inhalation

Acute

(≤14 days)

Intermediate

(15-364 days)

Respiratory Death

16r

Hematological

Systemic

HepaticReproductive Cancer

17r

* Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point.

10-410-510-610-7

Key 

r Ratm Mouseh Rabbitg Guinea Pigk Monkey

The number next to each pointcorresponds to entries in theaccompanying table.

Minimal risk level for effectsother than cancer

LOAEL for serious effects (animals)LOAEL for less serious effects (animals)NOAEL (animals)CEL - Cancer Effect Level

24g 18r

18r

20m

18r 22g 21r

20m 31r

30r33r

28m

22m

29r

35m

37m

34r

34r 27r 40m

38r39r

13141615
FORMALDEHYDE B-6

APPENDIX B

Chapter 2 (Section 2.5)

Relevance to Public Health

The Relevance to Public Health section provides a health effects summary based on evaluations of

existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present

interpretive, weight-of-evidence discussions for human health end points by addressing the following

questions.

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous

waste sites?

The section covers end points in the same order they appear within the Discussion of Health Effects by

Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are

presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro

data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered

in this section. If data are located in the scientific literature, a table of genotoxicity information is

included.

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer

potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if

derived) and the end points from which they were derived are indicated and discussed.

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public

health are identified in the Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for

inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These

MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure

levels at which adverse health effects are not expected to occur in humans. They should help physicians

and public health officials determine the safety of a community living near a chemical emission, given the

concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on

toxicological studies in animals and on reports of human occupational exposure. MRL users should be

familiar with the toxicologic information on which the number is based. Chapter 2.5, "Relevance to

Public Health," contains basic information known about the substance. Other sections such as 2.8,

"Interactions with Other Substances,” and 2.9, "Populations that are Unusually Susceptible" provide

important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a

modified version of the risk assessment methodology the Environmental Protection Agency (EPA)

provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). 
FORMALDEHYDE B-7

APPENDIX B

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,

represents the most sensitive human health effect for a given exposure route and duration. ATSDR

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available

for all potential systemic, neurological, and developmental effects. If this information and reliable

quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive

species (when information from multiple species is available) with the highest NOAEL that does not

exceed any adverse effect levels. When a NOAEL is not available, a lowest-observed-adverse-effect

level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. 

Additional uncertainty factors of 10 must be used both for human variability to protect sensitive

subpopulations (people who are most susceptible to the health effects caused by the substance) and for

interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual

uncertainty factors are multiplied together. The product is then divided into the inhalation concentration

or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL

are provided in the footnotes of the LSE Tables.

FORMALDEHYDE C-1

APPENDIX C

ACRONYMS, ABBREVIATIONS, AND SYMBOLS

ACGIH American Conference of Governmental Industrial Hygienists

ADI Acceptable Daily Intake

ADME Absorption, Distribution, Metabolism, and Excretion

AFID alkali flame ionization detector

AFOSH Air Force Office of Safety and Health

AML acute myeloid leukemia

AOAC Association of Official Analytical Chemists

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BAT Best Available Technology

BCF bioconcentration factor

BEI Biological Exposure Index

BSC Board of Scientific Counselors

C Centigrade

CAA Clean Air Act

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL Cancer Effect Level

CELDS Computer-Environmental Legislative Data System

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFD computational fluid dynamics

CFR Code of Federal Regulations

Ci curie

CI confidence interval

CL ceiling limit value

CLP Contract Laboratory Program

cm centimeter

CML chronic myeloid leukemia

CNS central nervous system

CPSC Consumer Products Safety Commission

CWA Clean Water Act

d day

Derm dermal

DHEW Department of Health, Education, and Welfare

DHHS Department of Health and Human Services

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DOL Department of Labor

DOT Department of Transportation

DOT/UN/ Department of Transportation/United Nations/

DWEL Drinking Water Exposure Level

ECD electron capture detection
FORMALDEHYDE C-2

APPENDIX C

ECG/EKG electrocardiogram

EEG electroencephalogram

EEGL Emergency Exposure Guidance Level

EPA Environmental Protection Agency

F Fahrenheit

F1 first-filial generation

FAO Food and Agricultural Organization of the United Nations

FDA Food and Drug Administration

FDH Formaldehyde dehydrogenase

FEFR25–75 forced expiratory flow rate between 25% and 75% FVC

FEMA Federal Emergency Management Agency

FEV1 forced expiratory volume in 1 second

f-HSA formaldehyde-human serum albumin

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FPD flame photometric detection

fpm feet per minute

ft foot

FR Federal Register

FVC forced vital capacity

g gram

GC gas chromatography

Gd gestational day

gen generation

GLC gas liquid chromatography

GPC gel permeation chromatography

HPLC high-performance liquid chromatography

hr hour

HRGC high resolution gas chromatography

HSDB Hazardous Substance Data Bank 

IDLH Immediately Dangerous to Life and Health

IARC International Agency for Research on Cancer

ILO International Labor Organization

in inch

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

LCLo lethal concentration, low

LC50 lethal concentration, 50% kill

LDLo lethal dose, low

LD50 lethal dose, 50% kill

LT50 lethal time, 50% kill

LOAEL lowest-observed-adverse-effect level

LSE Levels of Significant Exposure

m meter

MA trans,trans-muconic acid

MAL Maximum Allowable Level
FORMALDEHYDE C-3

APPENDIX C

mCi millicurie

MCL Maximum Contaminant Level

MCLG Maximum Contaminant Level Goal

mg milligram

min minute

mL milliliter

mm millimeter

mm Hg millimeters of mercury

mmol millimole

mo month

mppcf millions of particles per cubic foot

MRL Minimal Risk Level

MS mass spectrometry

NA/IMCO North America/International Maritime Dangerous Goods Code

NAAQS National Ambient Air Quality Standard

NaOH sodium hydroxide

NAS National Academy of Science

NATICH National Air Toxics Information Clearinghouse

NATO North Atlantic Treaty Organization

NCE normochromatic erythrocytes

NCI National Cancer Institute

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NIOSHTIC NIOSH's Computerized Information Retrieval System

NFPA National Fire Protection Association

ng nanogram

NLM National Library of Medicine

nm nanometer

NHANES National Health and Nutrition Examination Survey

nmol nanomole

NOAEL no-observed-adverse-effect level

NOES National Occupational Exposure Survey

NOHS National Occupational Hazard Survey

NPD nitrogen phosphorus detection

NPDES National Pollutant Discharge Elimination System

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NSPS New Source Performance Standards

NTIS National Technical Information Service

NTP National Toxicology Program

ODW Office of Drinking Water, EPA

OERR Office of Emergency and Remedial Response, EPA

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System

OPP Office of Pesticide Programs, EPA

OPPT Office of Pollution Prevention and Toxics, EPA

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA

OSHA Occupational Safety and Health Administration

OSW Office of Solid Waste, EPA

OTS Office of Toxic Substances
FORMALDEHYDE C-4

APPENDIX C

OW Office of Water

OWRS Office of Water Regulations and Standards, EPA

PAH Polycyclic Aromatic Hydrocarbon

PBPD Physiologically Based Pharmacodynamic 

PBPK Physiologically Based Pharmacokinetic 

PCE polychromatic erythrocytes

PEFR peak expiratory flow rate

PEL permissible exposure limit

PID photo ionization detector

pg picogram

pmol picomole

PHS Public Health Service

PMR proportionate mortality ratio

ppb parts per billion

ppbv parts per billion volume

ppm parts per million

ppm parts per million volume

ppt parts per trillion

PSNS Pretreatment Standards for New Sources

REL recommended exposure level/limit

RfC Reference Concentration

RfD Reference Dose

RNA ribonucleic acid

RTECS Registry of Toxic Effects of Chemical Substances

RQ Reportable Quantity

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

sd standard deviation

sec second

SIC Standard Industrial Classification

SIM selected ion monitoring

SMCL Secondary Maximum Contaminant Level

SMR standardized mortality ratio

SNARL Suggested No Adverse Response Level

SPEGL Short-Term Public Emergency Guidance Level

STEL short term exposure limit

STORET Storage and Retrieval

TD50 toxic dose, 50% specific toxic effect

TLV threshold limit value

TOC Total Organic Compound

TPQ Threshold Planning Quantity

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TRI Toxics Release Inventory

TWA time-weighted average

U.S. United States

UF uncertainty factor

UFFI urea-formaldehyde foam insulation

VOC Volatile Organic Compound

yr year
FORMALDEHYDE C-5

APPENDIX C

WHO World Health Organization

wk week

> greater than > greater than or equal to

= equal to

< less than < less than or equal to

% percent α alpha β beta γ gamma δ delta

μm micrometer

μg microgram q1

* cancer slope factor

– negative

+ positive

(+) weakly positive result

(–) weakly negative result