**************************************************************
http://groups.yahoo.com/group/aspartameNM/message/1109
Toxicological Profile for Formaldehyde 1/4 plain text, start to 111 of 468
pages USA DHHS PHS ATSDR 1999 July: Murray 2004.08.30 rmforall
[ Rich Murray, MA Room For All
rmforall@...
1943 Otowi Road, Santa Fe, New Mexico 87505 USA 505-501-2298
Comments by Rich Murray are in square brackets. I have taken some time to
provide this passable, complete plain text copy, which can be posted easily
on the Net and readily searched and copied. However, I was not able to
copy all the lengthly Figures and Tables. I have added spacing to somewhat
increase clarity, and to emphasize some points. Each section has the same
introduction and table of contents. The four sections have URLs
/1109, /1110, /1111 , /1112 ]
http://www.atsdr.cdc.gov/toxprofiles/tp111.pdf 4 MB
TOXICOLOGICAL PROFILE FOR FORMALDEHYDE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service Agency for Toxic Substances and Disease Registry
July 1999
[
http://groups.yahoo.com/group/aspartameNM/message/1108
faults in 1999 July EPA 468-page formaldehyde profile:
Elzbieta Skrzydlewska PhD, Assc. Prof., Medical U. of Bialystok, Poland,
abstracts -- ethanol, methanol, formaldehyde, formic acid, acetaldehyde,
lipid peroxidation, green tea, aging, Lyme disease:
Murray 2004.08.08 rmforall
http://groups.yahoo.com/group/aspartameNM/message/1106
hangover research relevant to toxicity of 11% methanol in aspartame
(formaldehyde, formic acid): Calder I (full text): Jones AW:
Murray 2004.08.09 rmforall ]
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. [ I could not locate any more recent updates
than July 1999 via Google. ]
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
[
http://www.atsdr.cdc.gov atsdric@... 888-42-ATSDR
404-498-0110 fax 404-498-0093
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
To order toxicological profiles, contact
National Technical Information Service 5285 Port Royal Road Springfield,
VA 22161 Phone: (800) 553-6847 or (703) 487-4650
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.
http://www.cdc.gov/nceh/ 888-232-6789
http://www2.cdc.gov/nceh/contactnceh/frmSubmit.asp email contact
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.
http://www.cdc.gov/niosh/homepage.html eidtechinfo@...
Contact: NIOSH, 200 Independence Avenue, SW, Washington, DC 20201 . Phone:
513-533-8328 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 fax 513-533-8573
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.
http://www.niehs.nih.gov/
Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,
Research Triangle Park, NC 27709 . Phone: 919-541-3212.
Office of Communications 919-541-3345 TTY 919-541-0731
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
Web Page:
http://www.aoec.org/ e-mail:
AOEC@...
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.
http://www.acoem.org/ http://www.acoem.org/feedback/ email contact
Contact: ACOEM, 55 West Seegers Road, Arlington Heights, IL 60005
Phone: 847-818-1800 FAX: 847-818-9266. ]
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
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.
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 ix
CONTRIBUTORS
CHEMICAL MANAGER(S)/AUTHORS(S):
Sharon Wilbur, M.A. [ Not a PhD level degree ]
[ Environmental Health Scientist ]
ATSDR, Division of Toxicology, Atlanta, GA
M. Olivia Harris, M.A. [ Not a PhD level degree ]
ATSDR, Division of Toxicology, Atlanta, GA
[ Environmental Health Scientist
1600 Clifton Road NE, E29 Atlanta, GA 30333
P: 404-639-5091 F: 404-639-6315
oxh0@... ]
Peter R. McClure, Ph.D., DABT [ Veterinarian ]
Syracuse Research Corporation, North Syracuse, NY
[ Syracuse Research Corporation Environmental Science Center
301 Plainfield Road Suite 350 Syracuse, New York 13212 (315) 452 8420
mcclure@... ]
Wayne Spoo, DVM, DABT, DABVT [ Veterinarian ]
Research Triangle Institute, Research Triangle Park, NC
[ Jerry Wayne Spoo Operations Director, Life Sciences and Toxicology
919-541-6000
jwspoo@... http://www.rti.org
http://www.abvt.org/ ]
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;
[
http://www.ahf.org/contact/ 914-789-7210 914-789-7243
1 Dana Road Valhalla, NY 10595
300 E. 42nd. Street New York, NY 10017
http://www.ifcp.us/Scientists-Scientists-Carson_Conaway.cfm
Carson Clifford Conaway, Ph. D., DABT [ Veterinarian ]
Research Scientist phone: (914) 789-7210 email:
cconaway@...
Institute for Cancer Prevention
In addition to his research work, Dr. Conaway is an Adjunct Associate
Professor in the Department of Pharmacology, New York Medical College. In
that capacity, he is called upon to present lectures in toxicology to
graduate students in the College of Basic Medical Sciences and in the School
of Public Health.
2. John Egle, Jr., Professor, Department of Pharmacology and Toxicology,
Medical College of Virginia, Smith Bldg., Room 656, Richmond, VA 23219; and
[
http://www.medschool.vcu.edu/ John L. Egle, Jr no longer listed. Last
PubMed study in 1995 . Studies on formaldehyde, 2 in 1974, 1 in 1972, no
PubMed abstracts for these. ]
3. Vincent Garry, Director, Environmental Medicine, University of Minnesota,
421 29th Ave., SE Minneapolis, MN 55414.
[
http://www.iatp.org/foodandhealth/library/admin/uploadedfiles/Vincent_Garry_Bio.\
pdf
Vincent F Garry Title: Professor
Department: Lab Medicine/Pathology (office: Lab Med/Pathology Department)
Dept Campus: UMN Twin Cities
E-mail Address:
garry001@...
Office Address: Lab Med/Pathology Department
225 Mayo 8609 420 Delaware St SE Minneapolis, MN 55455
Campus Mail: Lab Medicine and Pathology
MMC 609 Mayo 8609 420 Delaware St SE Minneapolis, MN 55455
Office Phone: +1 612-626-3354 Fax:+1 612-626-3380
Address: 4829 Girard Ave So Minneapolis, MN 55409
Phone: +1 612-827-7316
Toxicol Appl Pharmacol. 2004 Jul 15; 198(2): 152-63.
Pesticides and children.
Garry VF.
Department of Laboratory Medicine and Pathology and Program in Toxicology,
University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Prevention and control of damage to health, crops, and property by insects,
fungi, and noxious weeds are the major goals of pesticide applications.
As with use of any biologically active agent, pesticides have unwanted
side-effects. In this review, we will examine the thesis that adverse
pesticide effects are more likely to occur in children who are at special
developmental and behavioral risk. Children's exposures to pesticides in the
rural and urban settings and differences in their exposure patterns are
discussed.
The relative frequency of pesticide poisoning in children is examined.
In this connection, most reported acute pesticide poisonings occur in
children younger than age 5.
The possible epidemiological relationships between parental pesticide use or
exposure and the risk of adverse reproductive outcomes and childhood cancer
are discussed.
The level of consensus among these studies is examined.
Current concerns regarding neurobehavioral toxicity and endocrine disruption
in juxtaposition to the relative paucity of toxicant mechanism-based studies
of children are explored. PMID: 15236951 ]
FORMALDEHYDE xiii
CONTENTS
FOREWORD . . . v [ text omitted ]
LEGISLATIVE BACKGROUND ...vi [ text omitted ]
QUICK REFERENCE FOR HEALTH CARE PROVIDERS . . . vii
CONTRIBUTORS . . . ix
PEER REVIEW . . . xi
CONTENTS . . . xiii
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
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. [ Surely, it is ridiculous to cite
the five extra digits of precision. ]
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. [ This is the most remarkable of the many dubious,
reassuring statements in this summary for the general public. For a
detailed critique of this summary:
http://groups.yahoo.com/group/aspartameNM/message/1108
faults in 1999 July EPA 468-page formaldehyde profile:
Elzbieta Skrzydlewska PhD, Assc. Prof., Medical U. of Bialystok, Poland,
abstracts -- ethanol, methanol, formaldehyde, formic acid, acetaldehyde,
lipid peroxidation, green tea, aging, Lyme disease:
Murray 2004.08.08 rmforall ]
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 -- 3.0 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.
[ I was not able to copy Figure 2-1, pages 13 to 40. ]
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
FORMALDEHYDE 50 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 ã-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 3H-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
3H-thymidine via osmotic pumps to
measure regional rates of cell proliferation in nasal cavity epithelium. No
formaldehyde-induced non-
FORMALDEHYDE 64 2. HEALTH EFFECTS
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
FORMALDEHYDE 65 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
FORMALDEHYDE 66 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
FORMALDEHYDE 67 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
respi
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