**************************************************************
http://groups.yahoo.com/group/aspartameNM/message/1111
Toxicological Profile for Formaldehyde 3/4 plain text, 229 to 342 of 468
pages USA DHHS PHS ATSDR 1999 July: Murray 2004.09.03 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 in
http://groups.yahoo.com/group/aspartameNM/message/1109 ,
but are truncated in the archive to 64 KB. They are available in full at
http://health.groups.yahoo.com/group/aspartameNM/files/ and
http://health.groups.yahoo.com/group/aspartame/files/ and
bionet.neuroscience ]
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 229 2. HEALTH EFFECTS
School children who attended particleboard-paneled classrooms with estimated
formaldehyde air concentrations of 0.075, 0.069, and 0.043 ppm reported
respiratory tract symptoms consistent with the irritant properties of
formaldehyde including rhinitis, cough, nosebleed, and headache (Wantke et
al. 1996a).
These concentrations are low compared to workplace air concentrations or
exposure chamber concentrations associated with irritant symptoms in adults
(0.4-3 ppm).
Formaldehyde-specific IgE antibodies were detected in serum of 40% of the
children.
The investigators noted that the elevated levels were not correlated with
the number and severity of symptoms, but serum levels and incidence of
symptoms decreased in a subgroup of the children 3 months after they were
moved to another school with lower air concentration of formaldehyde
(0.023-0.029 ppm).
As stated earlier when discussing this study, the significance of these
findings is uncertain as the reported symptoms were more typical of an
irritant response than of asthma-like symptoms that are expected to be
mediated through IgE antibodies.
Additional research is necessary to confirm or discard the hypothesis that
children may be more susceptible than adults to the irritant effects of
formaldehyde and to understand the mechanistic basis of this possible
difference.
2.7 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly defined as indicators signaling events in biologic
systems or samples. They have
been classified as markers of exposure, markers of effect, and markers of
susceptibility (NAS/NRC 1989).
Due to a nascent understanding of the use and interpretation of biomarkers,
implementation of biomarkers
as tools of exposure in the general population is very limited. A biomarker
of exposure is a xenobiotic
substance or its metabolite(s), or the product of an interaction between a
xenobiotic agent and some target
molecule(s) or cell(s) that is measured within a compartment of an organism
(NAS/NRC 1989). The
preferred biomarkers of exposure are generally the substance itself or
substance-specific metabolites in
readily obtainable body fluid(s) or excreta. However, several factors can
confound the use and
interpretation of biomarkers of exposure. The body burden of a substance may
be the result of exposures
from more than one source. The substance being measured may be a metabolite
of another xenobiotic
substance (e.g., high urinary levels of phenol can result from exposure to
several different aromatic
compounds). Depending on the properties of the substance (e.g., biologic
half-life) and environmental
conditions (e.g., duration and route of exposure), the substance and all of
its metabolites may have left the
FORMALDEHYDE 230 2. HEALTH EFFECTS
body by the time samples can be taken. It may be difficult to identify
individuals exposed to hazardous
substances that are commonly found in body tissues and fluids (e.g.,
essential mineral nutrients such as
copper, zinc, and selenium). Biomarkers of exposure to formaldehyde are
discussed in Section 2.7.1.
Biomarkers of effect are defined as any measurable biochemical, physiologic,
or other alteration within an
organism that, depending on magnitude, can be recognized as an established
or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses
biochemical or cellular signals of
tissue dysfunction (e.g., increased liver enzyme activity or pathologic
changes in female genital epithelial
cells), as well as physiologic signs of dysfunction such as increased blood
pressure or decreased lung
capacity. Note that these markers are not often substance specific. They
also may not be directly
adverse, but can indicate potential health impairment (e.g., DNA adducts).
Biomarkers of effects caused
by formaldehyde are discussed in Section 2.7.2.
A biomarker of susceptibility is an indicator of an inherent or acquired
limitation of an organism's ability
to respond to the challenge of exposure to a specific xenobiotic substance.
It can be an intrinsic genetic
or other characteristic or a preexisting disease that results in an increase
in absorbed dose, a decrease in
the biologically effective dose, or a target tissue response. If biomarkers
of susceptibility exist, they are discussed in Section 2.9.
2.7.1 Biomarkers Used to Identify or Quantify Exposure to Formaldehyde
Formaldehyde is a simple one-carbon molecule and is rapidly absorbed and
metabolized by animals,
including humans. A thorough review of the available literature failed to
produce any reliable biomarkers
of exposure to formaldehyde.
As discussed in Section 2.3, formaldehyde is rapidly absorbed by the
inhalation and oral routes of
exposure. Once absorbed, there are four major metabolic pathways associated
with formaldehyde
metabolism, with the metabolism to formate and CO2 the most heavily used
(see Figure 2-3 in Section 2.3.3).
Attempts have been made to determine if either blood or urinary levels of
formaldehyde or formate could
be used as potential biomarkers of exposure, but with disappointing results.
Heck et al. (1985) exposed
FORMALDEHYDE 231 2. HEALTH EFFECTS
four men and two women to a 1.9±0.06 ppm air concentration of formaldehyde
in a large walk-in
chamber for 40 minutes. Shortly before and shortly after the exposure,
venous blood samples were taken
from each person (each person served as his/her own control) and the blood
was analyzed for
formaldehyde content. No significant differences were found between pre- and
postexposure blood
concentrations of formaldehyde at the concentration tested.
In the same study, male Fischer 344 rats were
placed in a nose-only inhalation chamber and exposed to a 14.4±2.4 ppm air
concentration of
formaldehyde for 2 hours; rats were sacrificed, and venous blood samples
were collected and analyzed for
formaldehyde content. Even by using the higher exposure concentration of
formaldehyde, no significant
differences in blood formaldehyde concentrations were found between the pre-
and postexposure blood
samples. In addition, the rapid intravenous injection of formaldehyde in
monkeys showed a plasma halflife
of only 1.5 minutes, with a corresponding increase in blood formate levels.
Einbrodt et al. (1976) exposed students to 0.26-0.92 ppm formaldehyde vapors
for 3 hours, with urine
samples collected immediately after exposure and 21 hours after exposure.
Urine formaldehyde and urine
formic acid (formate) concentrations were found to be higher immediately
after exposure compared to
21 hours later; however, no baseline sample was obtained prior to exposure.
If historic formaldehyde and
formic acid baseline levels were assumed, then a closer examination of these
data indicates that more
formaldehyde (and metabolite) was excreted in the urine than could have
possibly been absorbed by
inhalation, indicating another route of exposure (perhaps dermal), or
co-exposure to another chemical that
also has formate as a metabolite (e.g., methanol), or higher personal
exposures than were actually
measured. There was also no indication that the urine formate levels were
adjusted to compensate for
urine specific gravity using urine creatinine levels, which may have
markedly influenced the test results.
Gottschling et al. (1984) monitored 35 anatomy laboratory students exposed
for 2 hours, once a week for
3 weeks, with exposures ranging from 0.036 to 0.111 ppm. Urine was obtained
prior to exposure and
during the exposure. Wide variations were noted in the urine formate levels
prior to exposure, with large
intrapersonal and interpersonal variations; mean postexposure urine formate
concentrations were elevated
after exposure to formaldehyde vapors, but not significantly. In the study
by Einbrodt et al. (1976), urine
formate levels were significantly elevated in both anatomy laboratory
students and in four factory
workers exposed to 1 ppm formaldehyde; however, the mass-balance equations
for both groups
indicated other factors may have influenced the amount of formate found in
the urine. Formate
production is not specific to formaldehyde because other chemicals such as
methanol, halomethanes
(e.g., dichloromethane), and acetone have formate in their metabolic
pathways (Ferry et al. 1980;
FORMALDEHYDE 232 2. HEALTH EFFECTS
Kornbrust and Bus 1983; Liesivuori and Savolainen 1987). This indicates that
even if blood or urine
formate levels were elevated, it may be due to individual variation,
formaldehyde exposure, or other
chemical exposures that result in formate formation. Thus formate blood and
urine levels appear to be
equally unreliable as definitive biomarkers for formaldehyde exposure.
Formaldehyde that is not rapidly metabolized to formate can react with a
variety of cellular components including nucleotides, proteins, and
glutathione, forming adducts, such as N6-hydroxymethyldeoxyadenosine
and N2- hydroxymethyldeoxyguanosine, and DNA-protein cross links.
Several of these formaldehyde-induced products have been examined as
potential biomarkers of exposure for repeated exposure to formaldehyde.
A method for detecting biomarkers such as N6-hydroxymethyldeoxyadenosine
and N2-hydroxymethyldeoxyguanosine (the major adducts formed by formaldehyde
in vitro)
had experimental complications and does not appear to provide useful
biomarkers of formaldehyde
exposures (Fennel 1994). Many studies (Casanova-Schmitz et al. 1984a;
Casanova and Heck 1987;
Casanova et al. 1989a, 1989b, 1991, 1994) utilized radiolabeled compounds
tagged with 14C and/or 3H to
facilitate detection of DNA-protein cross links; however, this approach
would not work to detect past exposures in humans.
The formation of DNA-protein cross links in isolated rat nasal epithelial
cells
(respiratory and olfactory epithelial cells) incubated with formaldehyde has
also been reported (Kuykendall et al. 1995).
Utilizing a sensitive technique to detect total DNA-protein cross links,
Shaham
et al. (1996a) reported that cultured human white blood cells showed
increasing quantities of DNA protein cross links when cultured in media with
increasing formaldehyde concentrations and that a small group of
formaldehyde-exposed persons had a significantly greater mean amount of
DNA-protein cross
links in their white blood cells than did a group of nonexposed persons.
Although DNA-protein cross links are known to be formed by other agents such
as ionizing radiation and alkylating agents, Shaham et al. (1996a) concluded
that their results suggested that levels of DNA-protein cross links in white
blood
cells may provide an indicator of formaldehyde-induced tissue damage and a
biomarker of occupational exposure to formaldehyde.
Shaham et al. (1996b) noted that a larger study of the potential of DNA
protein cross links in white blood cells as a biomarker of effect and
exposure was
in progress.
Immunological biomarkers of effect (IgG and IgE antibodies against
formaldehyde conjugated to human serum albumin) have been examined as
potential biomarkers of exposure to airborne formaldehyde.
Some studies have reported that increased serum levels of antibodies against
formaldehyde-human serum albumin in groups of human subjects correlated with
exposure to airborne formaldehyde and symptoms of respiratory distress
(Thrasher et al. 1987, 1988b, 1989, 1990), whereas other studies of human
subjects
FORMALDEHYDE 233 2. HEALTH EFFECTS
have not found similar correlations (Dykewicz et al. 1991; Grammer et al.
1990; Patterson et al. 1989; Wantke et al. 1996a, 1996b).
The hypothesis, put forth by Nordman et al. (1985), concluded that
immunological hypersensitivity of the respiratory tract to airborne
formaldehyde is rare, and casts doubt
that immunological biomarkers for formaldehyde would have been useful
biomarkers to indicate
exposure. However, Carraro et al. (1997) recently reported that the presence
of IgG antibodies against
formaldehyde-human serum albumin was significantly associated with smoking
habits, but not with self reported
occupational exposure to formaldehyde, in a group of 219 healthy subjects.
When only nonsmokers
were included in the analysis, a statistically significant association was
found between the
presence of formaldehyde-specific antibodies and occupational exposure to
formaldehyde. An indirect
competitive immunoenzyme assay for anti-formaldehyde-human serum albumin
antibodies was
developed for this study. These results suggest that smoking produces a
detectable immunological
response to formaldehyde and that the technique employed may be useful to
indicate occupational or
residential exposure to formaldehyde especially in the absence of exposure
to tobacco smoke.
Development of biomarkers for exposure is complicated by the fact that the
metabolism of many xenobiotics can result in formaldehyde production in
vivo. Carbon tetrachloride, endrin, paraquat,
2,3,7,8-tetrachlorodibenzo-p-dioxin (Shara et al. 1992), and dichloromethane
(Dekant and Vamvakas 1993) are all known to generate formaldehyde during
their metabolism.
2.7.2 Biomarkers Used to Characterize Effects Caused by Formaldehyde
Increased eosinophil concentration and increased levels of albumin and total
protein have been found in
nasal lavage fluid taken from subjects exposed to 0.4 ppm formaldehyde for 2
hours (Krakowiak et al. 1998; Pazdrak et al. 1993).
Although these variables are not expected to be only influenced by
formaldehyde, they appear to be promising biomarkers of acute respiratory
irritation from airborne formaldehyde.
As discussed in the previous section, DNA-protein cross links in white blood
cells (Shaham et al. 1996a) and anti-formaldehyde-human serum albumin IgG
antibodies in serum (Carraro et al. 1997) are potential biomarkers of both
exposure and effect associated with intermediate- or chronic-exposure to
formaldehyde.
Li et al. (1995) evaluated the validity of the modified lymphocyte
transformation assay for detecting
contact hypersensitivity of formaldehyde. Female Hartley guinea pigs were
sensitized to formaldehyde
FORMALDEHYDE 234 2. HEALTH EFFECTS
by receiving subcutaneous injections of 1.85% formaldehyde (6 sites, 0.1 mL
per site) followed 7 days
later by epicutaneous exposure to 0.5 mL of a 1.85% formaldehyde solution.
Cells were collected from
lymph nodes tissue. Exposure to increasing concentrations of formaldehyde
resulted in significant
increases in T-lymphocyte blastogenesis (p<0.05). Although further
refinement of this assay would be
required (i.e., use of peripheral blood lymphocytes in lieu of lymph node
samples), it does have potential
for providing nonspecific biomarker of effect for formaldehyde
sensitization.
Another potentially useful biomarker of effect for repeated inhalation
exposure to formaldehyde involves
the histological examination of nasal biopsy samples. Histological changes
in nasal biopsy tissue samples
(e.g., loss of ciliated cells, squamous dysplasia and hyperplasia) have been
associated with formaldehyde
exposure in several cross-sectional studies of formaldehyde-exposed and
nonexposed workers (Ballarin et
al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c).
Each of these studies used a
morphological grading method that assigned an increasing point value for
histological changes ranging in
severity from loss of ciliated cells to the presence of malignant cells.
Prevalence of different types of
changes and mean histological scores were compared between exposed and
nonexposed groups. The
findings from rat studies indicating that the development of
formaldehyde-induced nasal cancer is
preceded by repeated damage to the upper respiratory tract epithelium
suggests that monitoring of
formaldehyde-exposed workers for cytological abnormalities in nasal biopsy
samples may be useful to
prevent the development of upper respiratory tract tissue damage or cancer.
Similar findings of epithelial
squamous dysplasia and hyperplastic nasal mucosa have been found in chronic
occupational exposures to
formaldehyde (Boysen et al. 1990; Edling et al. 1988); however, as discussed
in Section 2.5, these human
studies do not conclusively prove that formaldehyde was the primary toxicant
responsible for the
observed nasal lesions. The squamous metaplasia and mucosal hyperplastic
lesions may be useful
indicators of more severe formaldehyde-induced effects; however, its
usefulness in human exposures is likely to be limited.
FORMALDEHYDE 235 2. HEALTH EFFECTS
2.8 INTERACTIONS WITH OTHER CHEMICALS
The study by Albert et al. (1982) reported the carcinogenic responses to the
combined and separate
exposures to formaldehyde and hydrochloric acid in male inbred
Sprague-Dawley rats. Rats were
exposed for 588 days to formaldehyde alone (14.2 ppm); formaldehyde (14.1
ppm) and hydrogen chloride
(HCl) (9.5 ppm) combined but not premixed; formaldehyde (14.3 ppm) and HCl
(10.0 ppm) combined
and premixed; HCl alone (10.2 ppm); or room air. The data did not indicate a
synergistic effect on
mortality from combined formaldehyde and HCl exposure; no synergism was
noted between combined
HCl and formaldehyde exposure and the induction of nasal cancers. Rats
exposed to formaldehyde alone
experienced about a 9% depression in body weights compared to controls;
those exposed to HCl alone
experienced no noticeable weight loss; exposure to formaldehyde and HCl
combined resulted in a 14%
depression in body weight, indicating a synergistic adverse effect on body
weight from combined HCl and formaldehyde exposure.
Lam et al. (1985) studied the effects of inhalation co-exposure to acrolein
and formaldehyde in male Fischer 344 rats. Rats were exposed for 6 hours to
room air (controls), 2 ppm
acrolein, 6 ppm formaldehyde, or a combination of 2 ppm acrolein and 6 ppm
formaldehyde. The
animals were sacrificed immediately after completion of exposure and their
nasal tissues were harvested.
Exposure to formaldehyde significantly increased the percentage of
interfacial DNA (a measure of
DNA-protein cross linking) compared to rats exposed to room air only (12.5
versus 8.1%, p<0.05).
Co-exposure to acrolein resulted in further increases in the percentage of
interfacial DNA (18.6%) which
were significantly greater than the effect of formaldehyde alone (p<0.05).
The authors concluded that
simultaneous exposure to acrolein enhanced formaldehyde-induced DNA-protein
cross linking and that
depletion of glutathione by acrolein inhibited the metabolism of
formaldehyde, thereby increasing
formaldehyde-induced DNA-protein cross link formation.
To investigate the possibility of additive or potentiating interactions
between inhaled aldehydes, Cassee et
al. (1996b) compared responses in nasal epithelial histopathology and cell
proliferation in groups of male
Wistar rats exposed for 3 days (6 hours/day) to 1.0, 3.2, or 6.4 ppm
formaldehyde alone; to 0.25, 0.67, or
1.40 ppm acrolein alone; to 750 or 1,500 ppm acetaldehyde alone; or to
several mixtures of these
aldehydes. At the concentrations tested, the histological and cell
proliferation responses measured in the
nasal epithelium of rats exposed to the mixture which produced effects (3.2
ppm formaldehyde;
1,500 ppm acetaldehyde; 0.67 ppm acrolein) were attributed by the
investigators to the acrolein alone
with no additional effects from the formaldehyde or acetaldehyde. The
investigators concluded that
FORMALDEHYDE 236 2. HEALTH EFFECTS
combined exposures to these aldehydes at exposure levels in the vicinity of
individual no-effect-levels
was not associated with a greater hazard than that associated with exposure
to the individual chemicals.
As discussed previously in Sections 2.2 and 2.5, experiments with mice
(Tarkowski and Gorski 1995) and
guinea pigs (Riedel et al. 1996) indicate that exposure to low levels of
formaldehyde enhances allergic
responses to intranasal administration of ovalbumin and suggest the
possibility of formaldehyde
facilitation of allergic responses to other respiratory allergens. Mice
pre-exposed to 1.6 ppm, 6 hours/day
for 10 consecutive days produced four-fold greater ovalbumin-specific IgE
antibodies in response to
intranasal administration of ovalbumin mice that were not pre-exposed
(Tarkowsi and Gorski 1995). A
group of guinea pigs exposed to 0.25 ppm formaldehyde, 8 hours/day for 5
days showed a greater
percentage of bronchial, presumably allergic, responses to inhaled ovalbumin
than a control group
without preexposure to formaldehyde (10/12 versus 3/12) (Riedel et al.
1996).
2.9 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
A susceptible population will exhibit a different or enhanced response to
formaldehyde than will most persons exposed to the same level of
formaldehyde in the environment.
Reasons may include genetic makeup, age, health and nutritional status, and
exposure to other toxic substances (e.g., cigarette smoke).
These parameters may result in reduced detoxification or excretion of
formaldehyde, or compromised function of target organs affected by
formaldehyde.
Populations who are at greater risk due to their unusually high exposure to
formaldehyde are discussed in Section 5.6.
Two populations of humans have received considerable attention in the
literature as being particularly sensitive to formaldehyde exposure
following inhalation and/or dermal exposure.
The first population is asthmatics, and concern focuses on the changes in
lung function parameters that formaldehyde may produce (Harving et al. 1990;
Kulle et al. 1987; Pazdrak et al. 1993; Reed and Frigas 1984; Sauder et al.
1986; Schachter et al. 1986; Witek et al. 1986).
Most of these studies concluded that there is no evidence of increased
airway reactivity as a result of formaldehyde exposure in either normal or
asthmatic individuals.
Formaldehyde exposures at the concentrations tested (usually >3 ppm) did not
exacerbate existing asthmatic conditions, either at rest or after exercise.
However, Nordman et al. (1985), in a human population of 230 persons
suffering asthmatic symptoms and exposed to formaldehyde, found that
when exposed to 2.04 ppm formaldehyde for 30 minutes, eight subjects
demonstrated an immediate bronchial reaction, four subjects demonstrated a
delayed reaction, and two subjects demonstrated both an
FORMALDEHYDE 237 2. HEALTH EFFECTS
immediate and a delayed reaction. Peak expiratory flow rates dropped 19-49%
in the immediate-reaction group and 21-47% in the delayed-reaction group.
In a study of seven subjects with a history of
occupational exposure to glutaraldehyde and asthma, peak expiratory flow
rates were decreased in 3/7 subjects by 27-33% in response to a bronchial
challenge with 1% formaldehyde (Gannon et al. 1995).
Gannon et al. (1995) suggested that respiratory sensitivity produced by
exposure to glutaraldehyde may have cross-reactivity to formaldehyde in some
subjects.
The second population of potential concern is people with dermal
sensitization. Several cases have been reported.
Formaldehyde liquid, but neither the gaseous phase nor formalin, is
considered to be a dermal sensitizer (Hilton et al. 1996).
Anaphylactic reactions have been reported in the literature (Maurice et al.
1986), in a description of a case in which anaphylaxis occurred in a patient
due to skin contact with adhesives sterilized with formaldehyde prior to her
hemodialysis therapy. Dermal allergic reactions have also been reported in
doctors and nurses exposed to formaldehyde (Rudzki et al. 1989) as well as
in fiberglass workers (Kilburn et al. 1985a).
Data from acute controlled-exposure studies, supported by data from animal
studies, generally indicate that formaldehyde does not induce airway
hyper-reactivity at concentrations #3 ppm, but further studies with
asthmatics may be required because of somewhat conflicting data in this
potentially sensitive
population.
Other persons with dermal sensitization to formaldehyde are not likely to
develop signs of respiratory insufficiency.
Persons with multiple chemical sensitivities may represent a third
potentially sensitive population, but studies linking this syndrome with
exposure to formaldehyde were not located.
2.10 METHODS FOR REDUCING TOXIC EFFECTS
This section will describe clinical practice and research concerning methods
for reducing toxic effects of exposure to formaldehyde. However, because
some of the treatments discussed may be experimental and unproven, this
section should not be used as a guide for treatment of exposures to
formaldehyde. When
specific exposures have occurred, poison control centers and medical
toxicologists should be consulted for medical advice. The following texts
provide specific information about treatment following exposures to
formaldehyde:
Aaron, CK and Howland, MA (eds.) (1994). Goldfrank's Toxicologic
Emergencies. Appleton and Lange, Norwalk, CT.
FORMALDEHYDE 238 2. HEALTH EFFECTS
Dreisbach, RH and Robertson, WO, (eds.) (1987). Handbook of Poisoning.
Appleton and Lange, Norwalk, CT.
Ellenhorn, MJ and Barceloux, DG, (eds.) (1988). Medical Toxicology:
Diagnosis and Treatment of Human Poisoning. Elsevier Publishing, New York,
NY.
Gossel, TA and Bricker JD (1994). Principles of Clinical Toxicology. 3rd
edition, Raven Press, New York, NY.
Haddad, LM and Winchester, JF, (eds.) (1990). Clinical Management of
Poisoning and Drug Overdose (2nd edition). WB Saunders, Philadelphia, PA.
The primary concern after oral intoxication with formaldehyde is correcting
the severe acidosis and decreased blood pressure that this chemical induces.
Treatment should aimed at increasing the blood
pressure to a somewhat normal state (sympathomimetic drugs may be used) as
well as treating the
acidosis with bicarbonate (Aaron and Howland 1994; Gossel and Bricker 1994).
Dialysis may also be
used to remove excess formate (as formic acid) in the blood in order to
correct the acidosis (Burkhart et al. 1990; Eells et al. 1981).
2.10.1 Reducing Peak Absorption Following Exposure
Human exposure to formaldehyde may occur by inhalation, ingestion, or dermal
contact. There are no
known antidotes to formaldehyde poisoning in humans, particularly after oral
exposure. General
recommendations for reducing absorption of formaldehyde include removing the
exposed individual from
the contaminated area and removing contaminated clothing, if applicable. If
the eyes and skin were
exposed, they should be flushed with copious amounts of water. Since
formaldehyde is highly corrosive,
vomiting after oral ingestion should not be induced. The stomach contents
can be diluted with milk or
water by mouth if the patient is alert and responsive, otherwise gastric
lavage may be indicated. A bolus
of charcoal and isotonic saline cathartic may also be useful (Aaron and
Howland 1994).
2.10.2 Reducing Body Burden
Formaldehyde is not stored to any appreciable extent in the human body and
is mostly metabolized to formate and carbon dioxide (see Section 2.3).
The half-life of formaldehyde in monkeys has been observed to be about 1.5
minutes following an intravenous injection.
Furthermore, an inhalation exposure study found that no formaldehyde was
present in the blood after a 1.9 ppm exposure for
FORMALDEHYDE 239 2. HEALTH EFFECTS
40 minutes, indicating formaldehyde is metabolized very quickly either in
the respiratory tract tissues or in the blood.
Despite a relatively fast clearance of formaldehyde from the body, toxic
effects may develop in exposed individuals, particularly in cases of acute
oral poisonings which quickly overwhelm the body's natural mechanisms to
metabolize formaldehyde (particularly via formaldehyde dehydrogenase; see
Figure 2-3).
There is no standard method or practice to enhance the elimination of the
absorbed dose of formaldehyde
(Aaron and Howland 1994; Ellenhorn and Barceloux 1988).
2.10.3 Interfering with the Mechanism of Action for Toxic Effects
Target organs of formaldehyde toxicity while in the gaseous phase are the
respiratory tract and eyes.
After oral exposure, the tissues that formaldehyde comes into contact with
on its way to the stomach and intestines (i.e., lips, oral pharynx,
esophagus) are the target tissues; after dermal exposure, the adverse
effects of formaldehyde are usually localized to the contact area, although
other systemic reactions have
been reported (Maurice et al. 1986) (see Section 2.2).
Formaldehyde readily combines with free, unprotonated amino groups to yield
hydroxymethyl adduct derivatives resulting in proton liberation (Loomis
1979).
In higher concentrations (5-10%), formaldehyde will precipitate
protein, which is the reason for its use in current histological techniques.
The mechanism that causes the primary irritant effects is not presently
known, but may involve one of the two mechanisms mentioned above.
Currently, there are no procedures or therapies that specifically focus on
interfering with the mechanism of action of formaldehyde.
Supportive care by trained medical personnel is highly recommended.
2.11 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR
(in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service)
to assess whether
adequate information on the health effects of formaldehyde is available.
Where adequate information is
not available, ATSDR, in conjunction with the National Toxicology Program
(NTP), is required to assure
the initiation of a program of research designed to determine the health
effects (and techniques for
developing methods to determine such health effects) of formaldehyde.
FORMALDEHYDE 240 2. HEALTH EFFECTS
The following categories of possible data needs have been identified by a
joint team of scientists from ATSDR, NTP, and EPA.
They are defined as substance-specific informational needs that if met would
reduce the uncertainties of human health assessment.
This definition should not be interpreted to mean that all data needs
discussed in this section must be filled.
In the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
2.11.1 Existing Information on Health Effects of Formaldehyde
The existing data on health effects of inhalation, oral, and dermal exposure
of humans and animals to formaldehyde are summarized in Figure 2-5. The
purpose of this figure is to illustrate the existing
information concerning the health effects of formaldehyde. Each dot in the
figure indicates that one or
more studies provide information associated with that particular effect. The
dot does not necessarily
imply anything about the quality of the study or studies, nor should missing
information in this figure be
interpreted as a "data need." A data need, as defined in ATSDR's Decision
Guide for Identifying
Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR
1989), is substance-specific
information necessary to conduct comprehensive public health assessments.
Generally, ATSDR defines a
data gap more broadly as any substance-specific information missing from the
scientific literature.
As seen in Figure 2-5, information is available regarding death, acute and
chronic systemic effects, immunological, neurologic, reproductive,
developmental, genotoxic, and cancer effects in humans after inhalation
exposure to formaldehyde.
Lesser amounts of information are available for
humans exposed to formaldehyde after oral and dermal exposure. The oral and
dermal health effects data are primarily limited to death and acute systemic
toxicity data, immunological data (skin sensitization) after dermal
exposure, and neurological data after acute oral poisonings.
As also seen in Figure 2-5, significantly more information is available on
the inhalation, oral, and dermal effects of formaldehyde in laboratory
animals.
The information on health effects in animals exposed
orally or by inhalation is particularly rich but data regarding
dose-response relationships for gastrointestinal effects from acute oral
exposure and reproductive effects in multiple generations represent the most
notable information gaps (see Section 2.11.2 for further discussion).
Information was not located regarding death, systemic effects from
intermediate-duration exposure, neurologic effects, and genotoxic effects in
animals dermally exposed to formaldehyde.
FORMALDEHYDE 241 2. HEALTH EFFECTS
FORMALDEHYDE 242 2. HEALTH EFFECTS
2.11.2 Identification of Data Needs
Acute-Duration Exposure.
Results from human and animal studies indicate that portal-of-entry
tissues are the critical targets of acute-duration exposures to
formaldehyde: the nose and eyes with
inhalation exposure; the gastrointestinal tract with oral exposure; and the
skin with dermal exposure.
Studies of humans under controlled conditions clearly indicate that acute
exposures to air concentrations ranging from 0.4 to 3 ppm:
C induce reversible eye, nose, and throat irritation (Andersen and Molhave
1983; Bender et al. 1983; Day et al. 1984; Gorski et al. 1992; Krakowiak et
al. 1998; Kulle 1993; Kulle et al. 1987; Pazdrak et al. 1993; Schachter et
al. 1986; Weber-Tschopp et al. 1977; Witek et al. 1986);
C produce changes in nasal lavage fluid contents, indicative of irritation
of the nasal epithelium
(Gorski et al. 1992; Krakowiak et al. 1998; Pazdrak et al. 1993);
and C do not consistently or markedly affect pulmonary function variables in
most individuals (Andersen and Molhave 1983; Day et al. 1984; Gorski et al.
1992; Green et al. 1987; Harving et al. 1986, 1990; Kulle et al. 1987;
Nordman et al. 1985; Sauder et al. 1986; Schachter et al. 1986; Witek et al.
1986).
Acute inhalation animal studies confirm that air concentrations below 10-20
ppm produce damage only in specific regions of the epithelium of the upper
respiratory tract in rats, mice, and monkeys and not at distant sites
(Bhalla et al. 1991; Cassee and Feron 1994; Chang et al. 1983; Dinsdale et
al. 1993; Kamata
et al. 1996b; Monticello et al. 1989, 1991; Monteiro-Riviere and Popp 1986;
Morgan et al. 1986a, 1986c; Wilmer et al. 1987).
An acute inhalation MRL of 0.04 ppm was derived
based on the LOAEL of 0.4 ppm for transient symptoms of eye and nose
irritation and increased albumin content of nasal lavage fluid in
volunteers exposed to formaldehyde for 2 hours (Pazdrak et al. 1993).
Confidence is high that this MRL will protect the general public health due
to the wealth of data, but confidence may increase with additional
information about exposure-response relationships for formaldehyde-induced
respiratory
effects in potentially susceptible populations of individuals, such as
asthmatics.
An acute oral MRL for formaldehyde was not derived because data describing
dose-response relationships for gastrointestinal tract irritation in humans
or animals after acute oral exposure are lacking.
The reports of gastrointestinal effects and symptoms in humans who ingested
single large doses
(>200 mg/kg) of formaldehyde (Burkhart et al. 1990; Eells et al. 1981;
Kochhar et al. 1986), coupled with
FORMALDEHYDE 243 2. HEALTH EFFECTS
data from studies of animals exposed orally for intermediate- and
chronic-durations (Til et al. 1988b,
1989; Tobe et al. 1989), indicate that gastrointestinal irritation and
damage are the most likely critical
effects from acute oral exposure.
However, as discussed in Section 2.5, the human data do not identify a
no-effect level, and the available animal studies of acute oral exposure
(Cassidy et al. 1983; Johannsen et al. 1986) did not examine this end point.
At least one comprehensive acute oral toxicity study of at least one animal
species exposed to several dosage levels may be needed to generate
appropriate data for deriving an acute oral MRL for formaldehyde.
Formaldehyde is a well-known skin irritant and dermal sensitization agent,
but systemic distant-site effects from acute dermal exposure are not
expected given the reactive nature of formaldehyde, the ability of most
cells to rapidly metabolize formaldehyde, and the low rates of formaldehyde
absorption through the skin (Jeffcoat et al. 1983).
This expectation is additionally supported by the observation that no
effects on fetal development were found in pregnant hamsters dermally
exposed during pregnancy to a 37% formaldehyde solution (Overman 1985).
Exposure-response relationships for dermal effects from
acute dermal exposure are well characterized in humans and animals.
Experience with various types of formaldehyde solutions in the workplace and
results from widespread patch testing in skin clinics indicate that acute
dermal exposure to formaldehyde concentrations of 2-5% can evoke a mild to
moderate nonallergic skin irritation response in some individuals;
concentrations greater than 5% are expected to be irritating to most
individuals (Fischer et al. 1995; Maibach 1983).
In studies of dermally sensitized individuals, allergic skin reactions to
concentrations as low as 0.025-0.05% have been reported (DeGroot
et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997).
The cases of clothing-induced contact dermatitis that were frequently cited
in the literature from the late 1950s until the mid-1970's when newly
developed "no-iron' textiles that released formaldehyde were used (Peters
and Heese 1997) further demonstrate the skin irritation potential of
formaldehyde.
Experiments with guinea pigs given daily non-occluded dermal doses of
solutions of formaldehyde indicate that concentrations as low as 0.4% can
produce erythema and increased skin thickness within a 10-day period
(Wahlberg 1993).
Intermediate-Duration
Intermediate-duration exposure to formaldehyde is
expected to affect the same critical targets as acute exposure:
the upper respiratory tract with inhalation exposure;
the gastrointestinal tract with oral exposure; and
the skin with dermal exposure.
Studies of health effects in humans after intermediate-duration inhalation
exposure were not located.
Studies of humans with predominately chronic inhalation exposure to
formaldehyde under occupational
FORMALDEHYDE 244 2. HEALTH EFFECTS
or residential conditions, however, consistently have reported increased
incidences of symptoms of upper respiratory tract and/or eye irritation
among exposed groups of people (Edling et al. 1988; Garry et al. 1980;
Holness and Nethercott 1989; Horvath et al. 1988; Ritchie and Lehnen 1987).
Several studies have found nasal epithelial lesions, consistent with the
irritant and reactive properties of formaldehyde, in biopsy specimens from
workers repeatedly exposed to average concentrations ranging from about 0.2
to 0.5 ppm (Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988;
Holmstrom et al. 1989c). Other
studies of similarly exposed groups of workers have either found no, or only
small and subtle, exposurerelated changes in pulmonary function variables,
thus supporting the identification of the upper respiratory tract as the
critical target of repeatedly inhaled formaldehyde (Alexandersson and
Hedenstierna 1988, 1989; Bracken et al. 1985; Holness and Nethercott 1989;
Horvath et al. 1988;
Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990).
Although the persons in these studies are considered to have been exposed
for chronic durations, the results, together with the results from the acute
controlled inhalation human studies, provide strong evidence that the
critical target
from intermediate-duration inhalation exposure to formaldehyde will be the
upper respiratory tract.
Results from studies of animals exposed by inhalation for intermediate
durations provide supporting
evidence for the upper respiratory tract as the critical target and describe
concentration-response
relationships sufficiently well for describing an intermediate-duration
inhalation MRL. Data describing
intermediate-duration exposure-response relationships for upper respiratory
tract lesions and
concentrations ranging from 0.2 ppm to as high as 40 ppm are available for
rats (Appelman et al. 1988;
Casanova et al. 1994; Monticello et al. 1991; Rusch et al. 1983; Woutersen
et al. 1987; Zwart et al. 1988),
Cynomolgus monkeys (Rusch et al. 1983), hamsters (Rusch et al. 1983), and
mice (Maronpot et al. 1986).
Comprehensive histological examination of tissues and organs (including the
lungs and eyes) in three of
these studies (Appelman et al. 1988; Maronpot et al. 1986; Woutersen et al.
1987) and in another study of
Rhesus monkeys that included only one exposure concentration (Monticello et
al. 1989) found no
consistent evidence for lesions outside of the upper respiratory tract.
These results confirm the
identification of the upper respiratory tract as the target of concern.
Other intermediate-duration
inhalation exposure studies in rats (Wilmer et al. 1987, 1989) provide
evidence that the extent and
severity of formaldehyde-induced epithelial lesions in the upper respiratory
tract may be more strongly
influenced by exposure concentration than duration of exposure.
The intermediate-duration inhalation MRL of 0.03 ppm is based on a NOAEL of
0.98 ppm and a LOAEL of 2.95 ppm for clinical signs of nasopharyngeal
irritation and nasal epithelium lesions observed in
FORMALDEHYDE 245 2. HEALTH EFFECTS
Cynomolgus monkeys (Rusch et al. 1983) and an uncertainty factor of 30.
Computational fluid dynamic
models of airflow and formaldehyde uptake in nasal passages and
pharmacokinetic models of tissue
disposition of formaldehyde in rats and humans are currently under
development (Kimbell et al. 1993,
1997a, 1997b; Subramaniam et al. 1998). The application of these models to
the rat intermediate-duration
exposure-response data is likely to decrease uncertainty in deriving an
intermediate-duration inhalation
MRL from animal data. Such models are being developed for Rhesus monkeys
(Kepler et al. 1998;
Kimbell et al. 1997b), not Cynomolgus monkeys, but the available
intermediate-duration data for Rhesus
monkeys do not adequately describe concentration-response relationships;
therefore a no-effect level
cannot presently be estimated. Application of the monkey and human
dosimetric models, when they are
developed, to data from another Rhesus monkey study that would include
multiple exposure levels
represents another approach to decreasing uncertainty in the
intermediate-duration inhalation MRL.
There is some uncertainty regarding whether or not inhaled formaldehyde can
affect the lower respiratory
tract by inducing bronchoconstriction or exacerbating asthma in humans, and
whether or not repeated
exposure may influence these possible, but incompletely understood, effects.
As discussed earlier,
several acute controlled exposure studies with humans (Andersen and Molhave
1983; Day et al. 1984;
Gorski et al. 1992; Green et al. 1987; Harving et al. 1986, 1990; Kulle et
al. 1987; Nordman et al. 1985;
Sauder et al. 1986; Schachter et al. 1986; Witek et al. 1986) and studies of
chronically exposed persons in
workplaces or residences (Alexandersson and Hedenstierna 1988, 1989; Bracken
et al. 1985; Holness and
Nethercott 1989; Horvath et al. 1988; Khamgaonkar and Fulare 1991; Kriebel
et al. 1993; Malaka and
Kodama 1990) have found only mild or no changes in pulmonary function
variables, except in a few rare
cases (see Nordman et al. 1985). However, Amdur (1960) and Swiecichowski et
al. (1993) reported that
acute inhalation exposure to fairly low levels of formaldehyde (0.3 to 9
ppm) induced
bronchoconstriction (i.e., increased pulmonary airway resistance) in guinea
pigs. Swiecichowski et al.
(1993) further reported that airway reactivity to infused acetylcholine
increased after acute exposure to
formaldehyde and that when the duration of exposure to formaldehyde was
increased from 2 to 8 hours,
lower concentrations of formaldehyde were effective in increasing airway
reactivity to infused
acetylcholine. The mechanism underlying these pulmonary effects is not
understood, but Swiecichowski
et al. (1993) have hypothesized that formaldehyde may change airway
epithelial biochemistry leading to
release of mediators of bronchoconstriction. Studies to test this hypothesis
were not located.
The relevance of the guinea pig findings to the report that a group of
children living in homes with 0.06-0.12 ppm formaldehyde showed a greater
prevalence of bronchitis and asthma than children living in homes
FORMALDEHYDE 246 2. HEALTH EFFECTS
with less than 0.06 ppm (Krzyzanowski et al. 1990) has been questioned
(Swiecichowski et al. 1993), but remains unknown.
Studies of health effects in humans after intermediate-duration oral
exposure to formaldehyde were not located.
Intermediate-duration oral-exposure toxicity studies in animals that
examined a range of tissues and organs are extensive and include a 90-day
drinking water rat study that found only weight gain decreases at dosage
levels of 100-150 mg/kg/day (Johannsen et al. 1986),
a 4-week drinking water rat study that identified a NOAEL of 25 mg/kg/day
and a LOAEL of 125 mg/kg/day for forestomach and glandular stomach lesions
indicative of irritation (Til et al. 1988b),
a 4-week gavage rat study that identified a NOAEL of 40 mg/kg/day and a
LOAEL of 80 mg/mg/day for hepatocellular vacuolation and a LOAEL of 20
mg/kg/day for a decrease in IgM and IgG titers and increased relative lymph
node weight (Vargova et al. 1993),
a 90-day dietary exposure dog study that reported a NOAEL and LOAEL of 75
and 100 mg/kg/day for body weight decreases and no other effects (Johannsen
et al. 1986),
and a 52-day dietary exposure pregnant dog study that found no evidence of
maternal toxicity and no effects on fetal development at doses up to 9.4
mg/kg/day (Hurni and Ohder 1973).
In addition, a 32-week drinking water study that focused on the
gastrointestinal tract found papillomas in the forestomach and erosions
and/or ulcers in the limiting ridge of the fundic mucosa of the glandular
stomach in rats exposed to
258 mg/kg/day (Takahashi et al. 1986a).
The findings from the intermediate-duration oral exposure studies by
themselves do not consistently identify gastrointestinal tract irritation as
the critical effect. However, the weight of evidence from chronic oral
administration animal studies (Til et al. 1989; Tobe et al. 1989) and the
numerous intermediate inhalation toxicity studies (as previously cited),
together with mechanistic understanding of
formaldehyde's mode of toxic action, supports the selection of it as the
critical effect from intermediate duration.
Thus the selection of forestomach and glandular stomach lesions in rats (Til
et al. 1988b) as the
basis of the intermediate-duration oral MRL of 0.3 mg/kg/day is
well-supported. As mentioned in the introduction to Section 2.2.2, there is
uncertainty regarding the actual doses that were experienced by animals in
the published oral exposure studies because of the lack of reporting
regarding how frequently dosing solutions were analyzed for formaldehyde and
the well-known instability of aqueous solutions of formaldehyde.
Given this uncertainty and the lack of consistency in the findings from the
available intermediate-duration oral studies, confidence in the MRL may be
improved with additional intermediate duration dose-response data from
another comprehensive dietary or drinking water study of rats that includes
frequent monitoring of dosing solutions. Dose-response data for
gastrointestinal
tract
FORMALDEHYDE 247 2. HEALTH EFFECTS
effects in a primate species may provide an additional means of decreasing
uncertainty in the intermediate oral MRL.
Formaldehyde is a well-known skin irritant and skin sensitizer in humans
that accounts for about 1-8% of all cases of allergic dermatitis presented
at skin clinics (Fischer et al. 1995; Kiec-Swierczynska 1996; Marks et al.
1995; Meding and Swanbeck 1990; Menné et al. 1991).
Studies of embalmers (Nethercott and Holness 1988) and medical workers
(Rudzki et al. 1989) with expected repeated dermal exposure to formaldehyde
presented evidence for increased prevalence of formaldehyde-induced skin
irritation and dermal allergic reactions.
Exposure-response relationships for skin irritation and dermal allergic
responses from acute exposure are well characterized (under patch testing
conditions) in both normal and sensitized individuals, indicating that 1%
solutions are not expected to be irritating to most people, and that
allergic dermal reactions in sensitized individuals can occur with
concentrations as low as 0.015%
(DeGroot et al. 1988; Fischer et al. 1995; Flyvholm et al. 1997; Maibach
1983).
No published dose-response data were located for dermal irritation or
the development of dermal sensitization in humans for intermediate- or
chronic-duration exposure.
Given the high reactivity, volatility, and aqueous solubility of
formaldehyde and its rapid metabolism by cells, it is likely that
dose-response relationships for dermal irritation from acute exposure may
not be widely different from relationships for intermediate and
chronic-duration exposures.
This hypothesis is supported by the results from inhalation exposure
studies in rats indicating that exposure concentration is more important
than exposure duration in determining the extent and severity of
formaldehyde-induced epithelial lesions in the upper respiratory tract
(Wilmer et al. 1987, 1989). Nevertheless, additional animal studies
comparing dose-response
relationships for skin irritation for acute, intermediate, and chronic
exposure durations may be useful in estimating concentrations that will not
damage the skin with repeated exposures.
The potency of formaldehyde as a contact allergen is demonstrated by the
observation that occluded dermal exposure of guinea pigs to 5% formaldehyde
for 3 weeks sensitized 70% of the animals to later dermal challenges with 1%
formaldehyde (Hilton et al. 1996).
However, published studies that describe dose-response relationship or
no-effect levels for the development of dermal sensitization in animals with
intermediate- or chronic-duration exposure were not located.
Such studies are likely to be useful in estimating concentrations of
formaldehyde that would minimize the development of dermal sensitization to
formaldehyde in humans.
FORMALDEHYDE 248 2. HEALTH EFFECTS
Chronic-Duration Exposure and Cancer.
As with the shorter durations of exposure, the critical targets of chronic
inhalation, oral, or dermal exposure to formaldehyde are expected to be
portal-of-entry tissues.
For the inhalation route, the data are abundant, of good quality, and
include both human and animal data.
Less health effects data are available for chronic oral and chronic dermal
exposure, but the weight of the available data is consistent with this
expectation.
Studies of humans chronically exposed to airborne formaldehyde
concentrations in the approximate range of 0.1-1 ppm have consistently
reported increased incidences of upper respiratory tract and eye irritation
(Edling et al. 1988; Garry et al. 1980; Holness and Nethercott 1989; Horvath
et al. 1988; Ritchie and
Lehnen 1987), evidence for mild histological changes in the nasal epithelium
(Ballarin et al. 1992; Boysen et al. 1990; Edling et al. 1988; Holmstrom et
al. 1989c), and either no or only mild changes in
pulmonary function variables (Alexandersson and Hedenstierna 1988, 1989;
Bracken et al. 1985; Holness and Nethercott 1989; Horvath et al. 1988;
Khamgaonkar and Fulare 1991; Kriebel et al. 1993; Malaka and Kodama 1990).
Several chronic inhalation studies in rats (Kamata et al. 1997; Kerns et al.
1983b;
Monticello et al. 1996; Swenberg et al. 1980; Woutersen et al. 1989) and one
study in mice (Kerns et al. 1983b) adequately describe
concentration-response relationships for formaldehyde effects on the nasal
epithelium and have identified no-effect levels ranging from 0.1 to 2 ppm.
No consistent evidence for
formaldehyde-induced effects at extra-respiratory sites was found in rats
(Kamata et al. 1997; Kerns et al. 1983b) or mice (Kerns et al. 1983b)
exposed to concentrations as high as 15 ppm.
A chronic inhalation MRL of 0.008 ppm has been derived based on a minimal
LOAEL of 0.24 ppm for histological changes in nasal epithelial specimens
from a group of workers involved in the production of formaldehyde and
formaldehyde resins (Holmstrom et al. 1989c) and an uncertainty factor of
30. Although confidence in this MRL is high due to the wealth of available
data, increased confidence may result from additional prospective
longitudinal studies of nasal tissue specimens from groups of workers
experiencing varying
formaldehyde exposure levels to investigate if nasal epithelial damage
progresses in incidence or severity
with longer duration or higher levels of exposure. Computational fluid
dynamics models of airflow and
formaldehyde uptake in nasal passages and pharmacokinetic models of tissue
disposition of formaldehyde
in rats and humans are currently under development (Kimbell et al. 1993,
1997a, 1997b; Subramaniam et
al. 1998). Application of these models to chronic rat concentration-response
data for nasal lesions
represents another research approach to decreasing uncertainty in the
chronic inhalation MRL.
FORMALDEHYDE 249 2. HEALTH EFFECTS
No studies were located regarding health effects in humans with chronic oral
exposure to formaldehyde.
Two chronic drinking water studies with rats (Til et al. 1989; Tobe et al.
1989) provide enough reliable data to identify gastrointestinal tract
mucosal damage as the critical target for chronic oral exposure and to
describe dose-response relationships and estimates of no-effect levels.
Results from the chronic oral studies are supported by results from the
intermediate-duration rat studies showing gastrointestinal tract effects and
associated no-effect levels (Johannsen et al. 1986; Takahashi et al. 1986a;
Til et al. 1988b).
The chronic MRL of 0.2 mg/kg/day was based on a NOAEL of 15 mg/kg/day and a
LOAEL of 82 mg/kg/day for tissue damage in the forestomach (papillomatous
hyperplasia, atrophic gastritis, and
ulceration) and glandular stomach (hyperplasia) in male rats (Til et al.
1989) and an uncertainty factor of 100.
As with the intermediate-duration data, some uncertainty is associated with
the described chronic dose-response relationships due to a lack of reporting
of the frequency of analysis of the drinking water for formaldehyde content
in the available studies.
Results from another intermediate-duration drinking water rat study, rather
than a chronic-duration study, that includes frequent monitoring of the
drinking water for formaldehyde, may decrease this source of uncertainty in
the both the intermediate and chronic oral MRLs, given that the weight of
evidence that concentration of formaldehyde at the site of toxic action is
likely to be more important in determining cytotoxicity than duration of
exposure.
As discussed in the Identification of Data Needs section for
intermediate-duration exposure, additional animal studies comparing
exposure-response relationships for skin irritation for acute- intermediate-
and chronic-exposure durations would be useful in estimating concentrations
of formaldehyde solutions that will not damage the skin with repeated
exposures.
Although no comprehensive toxicity studies in animals were located regarding
chronic dermal exposure, understanding of formaldehyde toxicokinetics and
mechanism of action suggests that distant-site toxicity is not a concern at
environmentally or occupationally relevant dermal exposure levels.
The potential for occupational exposure to formaldehyde to cause cancer in
humans has been examined in more than 40 epidemiology studies (cohort
mortality and case-control studies).
In general, these studies have provided inconsistent evidence for
carcinogenicity in humans chronically exposed to low levels of formaldehyde
in workplace air.
In most studies finding statistically significant associations between
occupational formaldehyde and human cancer, the associations have not been
strong.
The epidemiological studies each have shortcomings, such as limited
follow-up, limited exposure information, possible misclassification of
disease, presence of confounding risk factors, or small numbers of subjects,
that make the establishment of a causal relationship between occupational
exposure to
FORMALDEHYDE 250 2. HEALTH EFFECTS
formaldehyde and human cancer difficult. Some of the epidemiological studies
have found some scattered evidence for extra-respiratory site cancers in
groups of formaldehyde-exposed workers, but the data are not consistent
across studies and adjustment for potential confounding factors often has
not been possible.
Three meta-analyses of the epidemiologic data are available (Blair et al.
1990a; Collins et al. 1997; Partanen 1993).
Each meta-analysis has focused on findings for respiratory cancer deaths
based on the premise that the respiratory tract is the most biologically
plausible site for cancer from exposure to airborne formaldehyde.
Strong support for this premise comes from animal studies showing that
chronic
inhalation exposure to formaldehyde concentrations between approximately 6
and 15 ppm, but not lower concentrations, induces carcinogenic responses in
rats that are restricted to the nasal cavity (Albert et al. 1982; Kamata et
al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Sellakumar et al.
1985; Swenberg et al. 1980; Woutersen et al. 1989).
Similar tumors were found in chronically exposed mice (Kerns et al. 1983b),
but were not found in chronically exposed hamsters (Dalbey 1982).
The two earlier metaanalyses showed weak overall associations between
formaldehyde exposure and nasopharyngeal cancer.
Relative risks and associated 95% CIs of 1.2 (0.8-1.7) and 2.0 (1.4-2.9)
were reported by Blair et al. (1990a) and Partanen (1993), respectively.
The associations were somewhat stronger in studies classified
with "substantial" (as opposed to "low/medium") exposure.
Relative risks for substantial exposures in the two analyses were 2.1
(1.1-3.5) and 2.7 (1.4-5.6).
The meta-analysis by Collins et al. (1997) also showed a weak association
across all available studies for relative risks of nasopharyngeal cancer
(RR=1.3 [1.2-1.5]), but after adjusting the cohort studies for
underreporting of nasopharyngeal cancer (RR=1.0 [0.5-1.8]) and analyzing the
case-control studies separately (RR=1.3 [0.9-2.1]), no statistically
significant associations were found.
Given that exposure information in case-control studies is generally poor,
it seems that additional case control studies are unlikely to clarify the
potential relationship between occupational formaldehyde exposure and human
cancer.
Future research approaches that may be helpful include establishing
prospective cohort mortality studies or updating existing cohort studies
focusing on nasal cancer in groups of workers who have experienced high
levels of exposure to formaldehyde or who will experience varying levels of
formaldehyde exposure and in groups of appropriately matched nonexposed
workers.
It may be useful to conduct such a prospective study in a country in which
occupational exposure levels to formaldehyde are expected to be higher than
those in the United States.
FORMALDEHYDE 251 2. HEALTH EFFECTS
Mechanistic studies indicate that the carcinogenic response to inhaled
formaldehyde in rats originates in
regions of the nasal cavity epithelium that initially show non-neoplastic
damage and provide support for
the hypothesis that formaldehyde-induced cancer will occur only at exposure
levels that extensively
damage epithelium tissue (e.g., Monticello et al. 1996). Comparison of the
non-neoplastic upper
respiratory tract response in rats and monkeys to intermediate-duration
formaldehyde exposure has
indicated that both monkeys and rats are similarly susceptible to
formaldehyde cytotoxicity but display
some regional differences in sites of tissue damage within the upper
respiratory tract (Casanova et al.
1989, 1991; Heck et al. 1989; Monticello et al. 1989). These observations
support the use of data from
rodent studies to extrapolatively estimate risks for nasal tissue damage and
nasal cancer with human
exposure scenarios.
The application of dosimetric models (e.g., CFD models of airflow and uptake
in nasal passages and
PBPK models of nasal disposition of formaldehyde) currently under
development (Cohen Hubal et al.
1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a, 1997b; Morgan et al.
1991; Subramaniam et al.
1998) holds promise of reducing uncertainties in estimating human cancer
risks from the available rodent
data (Morgan 1997). Ongoing efforts (see CIIT 1998; Conolly et al. 1992;
Conolly and Andersen 1993)
to develop two-stage clonal-growth cancer models (i.e., pharmacodynamic
models) incorporating data on
formaldehyde-induced cell proliferation rates, numbers of cells at risk,
tumor incidence, and site-specific
flux of inhaled formaldehyde are also likely to reduce uncertainties in
estimating the risks for neoplastic
damage to the upper respiratory tract in humans exposed to low levels of
airborne formaldehyde.
Results from four drinking water rat studies provide some inconsistent
evidence for formaldehydeinduced
gastrointestinal tract tumors (Soffritti et al. 1989; Takahashi et al.
1986a; Til et al. 1989; Tobe et
al. 1989). As discussed in Section 2.5, the weight of evidence from the rat
studies suggests that
gastrointestinal tract tumors may occur as late-developing portal-of-entry
effects only from repeated
exposure to high oral doses that damage the gastric mucosa, and that tumors
are not likely to develop at
dose levels that do not damage the gastric mucosa. It is unlikely that a
human population with high oral
exposures to formaldehyde can be identified to study possible relationships
to cancer, but better
characterization of no-effect levels for gastric mucosal damage in animal
species exposed repeatedly to
formaldehyde in drinking water may provide additional information to support
the hypothesis that low
levels of formaldehyde in water samples associated with hazardous waste
sites do not present
considerable risks for cancer.
FORMALDEHYDE 252 2. HEALTH EFFECTS
No studies were located examining potential relationships between skin
cancer in humans and dermal
exposure to formaldehyde, but two mouse-skin cancer bioassays found no
evidence for increased
incidence of skin tumors after 58-60 weeks of twice-weekly exposure to
formaldehyde solutions at
concentrations of 4% (Iverson 1988) and 10% (Iverson 1986). Additional
animal bioassays employing
lifetime dermal exposure scenarios would provide more complete assessments
of the possible dermal
carcinogenicity of formaldehyde.
Genotoxicity.
Formaldehyde has been demonstrated to have genotoxic properties in human and
laboratory animal studies.
Peripheral lymphocytes in anatomy students exposed to 0.73-1.95 ppm
formaldehyde for 10 weeks showed a small average increase in SCEs (Yager et
al. 1986).
Lymphocytes from wood workers chronically exposed to formaldehyde also
showed increased levels of chromosomal aberrations; however, there were no
significant changes in the rates of SCE (Chebotarev et al. 1986).
Other positive findings for genotoxicity include increases in micronuclei
formation in wood workers (Ballarin et al. 1992) and an increased incidence
in chromosomal abnormalities in pulmonary macrophages in rats (Dallas et al.
1992).
Formaldehyde has been found to be genotoxic in a number of cells and genetic
end points.
Formaldehyde has been found to induce chromosomal aberrations (Dresp and
Bauchinger 1988; Natarajan et al. 1983), increases in micronucleus formation
(Ballarin et al. 1992), and SCEs (Yager et al. 1986), as well as
numerous other genotoxic end points (Recio et al. 1992; Topham 1980).
Formaldehyde has also been found to have genotoxic properties in S.
typhimurium (Donovan et al. 1983)
and in human cell lines (Grafstrom et al. 1985; Snyder and Van Houten 1986).
The weight of evidence indicates that formaldehyde is capable of directly
reacting with DNA.
No reports of genotoxicity strictly related to the oral or dermal exposure
routes were found in the available literature.
Further cytogenetic analysis of cells from formaldehyde-exposed individuals
would possibly provide useful information about the ability and mechanisms
by which formaldehyde induces its genotoxic end points.
Reproductive Toxicity.
Results from human and animal studies indicate that formaldehyde is not a
likely reproductive toxicant at low levels of exposure.
No effects on sperm numbers or sperm morphology were found in a group of
formaldehyde-exposed pathologists (Ward et al. 1984), and increased rates of
miscarriage were not found among persons with presumed residential exposure
to formaldehyde (Garry et al. 1980).
Studies of reproductive outcomes in groups of formaldehyde-exposed
workers may be useful to confirm that the potential for reproductive effects
from formaldehyde is low.
FORMALDEHYDE 253 2. HEALTH EFFECTS
Results from such a study will have a better chance of being conclusive if a
population is identified that is exposed only to formaldehyde.
Animal studies of inhalation exposure found no direct effects of
formaldehyde on reproductive organ histopathology or weight (Appelman et al.
1988; Maronpot et al. 1986; Woutersen et al. 1987) and, with exposure during
gestation, no effects on maternal reproductive variables other than
decreased body
weight gains at high exposure levels (Martin 1990; Saillenfait et al. 1989).
Similarly, oral exposure of animals has not been associated with
histopathologic or weight changes in reproductive organs
(Johannsen et al. 1986; Til et al. 1989; Tobe et al. 1989; Vargova et al.
1993) or with maternal reproductive variables such as numbers of resorptions
at non-lethal exposure levels in pregnant animals (Hurni and Ohder 1973;
Marks et al. 1980). Changes in sperm morphology were noted in rats given
single gavage doses of 200 mg/kg/day, but not 100 mg/kg/day (Cassidy et al.
1983).
Overman (1985) reported a small increase in resorption rate in pregnant
hamsters dermally exposed to 37% formaldehyde solutions, but attributed this
effect to treatment stress rather than to a direct effect of formaldehyde.
Assays of reproductive performance in formaldehyde-exposed animals were not
located, but may be useful to confirm that formaldehyde is not a
reproductive toxicant.
Developmental Toxicity.
Results from a human study and several animal studies indicate that
formaldehyde is not a likely developmental toxicant at low levels of
exposure.
No associations were found between incidence of low birth weights and
ambient air levels of formaldehyde among groups of mothers living in
different residential districts (Grańulevi.iene et al. 1998).
No embryolethal or teratogenic effects of formaldehyde were found in
gestational-exposure studies of rats exposed to air
concentrations up to 40 ppm (Martin 1990; Saillenfait et al. 1989), rats
exposed to gavage dose levels up to 185 mg/kg/day (Marks et al. 1980), dogs
exposed to dietary doses up to 9.4 mg/kg/day (Hurni and Ohder 1973), and
hamsters dermally exposed to 37% formaldehyde solutions (Overman 1985).
Formaldehyde was designated as a nonteratogen and nonembryotoxin in the
Chernoff/Kavlock developmental toxicity screening test in mice (Seidenberg
and Becker 1987).
The need for additional developmental toxicity studies may not have a high
priority, given the evidence from other repeatedexposure
animal toxicity and pharmacokinetic studies indicating that health effects
from formaldehydeare likely to be restricted to portals-of-entry.
FORMALDEHYDE 254 2. HEALTH EFFECTS
Immunotoxicity.
Dermal sensitization to formaldehyde in humans is well recognized from
results of
patch testing at dermatological clinics throughout the world (Fischer et al.
1995; Kiec-Swierczynska 1996; Maibach 1983; Marks et al. 1995; Meding and
Swanbeck 1990; Menné et al. 1991) and a few studies of formaldehyde-exposed
workers (Nethercott and Holness 1988; Rudzki et al. 1989). Severe
allergic responses to dermally applied formaldehyde, however, appear to be
rare; only one case of a severe anaphylactic response to formaldehyde was
located (Maurice et al. 1986). The potency of formaldehyde as a contact
allergen is demonstrated by the observation that occluded dermal exposure of
guinea pigs to 5% formaldehyde for 3 weeks sensitized 70% of the animals to
later dermal challenges with 1% formaldehyde (Hilton et al. 1996). However,
published studies that describe dose-response relationships or no-effect
levels for the development of dermal sensitization in animals with
intermediateor
chronic-duration dermal exposure were not located. Such studies are likely
to be useful in estimating concentrations of formaldehyde that would
minimize the development of dermal sensitization to formaldehyde in humans.
Although formaldehyde is widely recognized as a dermal irritant that can
sensitize the skin in humans, the evidence for immunologically-mediated
sensitization of the respiratory tract from exposure to airborne
formaldehyde is weak. There are only a few available case reports of
formaldehyde-exposed workers
who display marked changes in pulmonary function variables in response to
acute challenges with inhaled
formaldehyde that are consistent with an immunologically-mediated mechanism
of response (Burge et al.
1985; Hendrick et al. 1982; Lemiere et al. 1995). Nordman et al. (1985)
reported that, among
230 patients with formaldehyde exposure who reported asthma-like symptoms,
only 12 showed marked
pulmonary responses to acute formaldehyde challenges. Other studies found no
marked response to
challenges of inhaled formaldehyde in other groups of previously-exposed
subjects who complained of
asthma-like symptoms (Day et al. 1984; Krakowiak et al. 1998; Reed and
Frigas 1984). Several studies
have found no consistent evidence for increased serum levels of
formaldehyde-specific IgE antibodies in
groups of formaldehyde-exposed subjects including groups with complaints of
respiratory symptoms
(Dykewicz et al. 1991; Gorski et al. 1992; Grammar et al. 1990; Krakowiak et
al. 1998; Kramps et al.
1989; Thrasher et al. 1987, 1990). Elevated serum levels of IgE antibodies
and respiratory tract
symptoms were found in groups of children exposed to classroom air
concentrations of 0.075, 0.069, and
0.043 ppm formaldehyde (Wantke et al. 1996a). However, the relevance of
these findings to the
possibility of respiratory tract sensitization to formaldehyde is uncertain
because the elevated levels of
IgE were not correlated with the number and severity of symptoms, and the
symptoms were more
FORMALDEHYDE 255 2. HEALTH EFFECTS
indicative of irritant responses than asthma-type responses expected to be
mediated through IgE antibodies.
Results from studies with guinea pigs confirm that formaldehyde is a potent
skin sensitizer, but does not
elicit IgE responses and lymph node cytokine secretion patterns that are
typically induced by other potent
respiratory tract allergens such as trimellitic anhydride (Hilton et al.
1996). Other animal studies indicate
that repeated exposure to formaldehyde at air concentrations between 10 and
15 ppm did not produce
significant effects in several assays of immune function including
resistance to intravenous or
subcutaneous injection of neoplastic cells in mice (Dean et al. 1984),
resistance to intravenous injection of
bacterial cells in mice (Dean et al. 1984), and IgM response to tetanus
immunization and IgG response to
tetanus toxoid in rats (Holmstrom et al. 1989b). However, two other studies
indicate that exposure to
airborne formaldehyde may enhance allergic responses of the respiratory
tract to other respiratory
allergens (Riedel et al. 1996; Tarkowski and Gorski 1995). Further research
is necessary to confirm the
hypothesis that exposure to airborne formaldehyde may facilitate
immunological responses to other
respiratory allergens and to determine if this is relevant to humans exposed
to formaldehyde.
Information about immunological and lymphoreticular effects in humans orally
exposed to formaldehyde
is restricted to a report of splenomegaly in a case of acute poisoning
(Koppel et al. 1990). In animal
studies, decreased IgM and IgG titers in a hemagluttination assay and
increased lymph node weights were
found in rats exposed to gavage doses of 20 mg/kg/day and higher, but other
measures of IgG and IgM
production were not affected by exposure (Vargova et al. 1993). No effects
on weights or histopathology
of spleen and lymph nodes were found in other studies of orally exposed
animals (Til et al. 1988b, 1989;
Tobe et al. 1989). The data do not clearly identify immunological effects
from oral exposure to
formaldehyde as effects of concern. Further research on the possible
immunotoxicity of ingested
formaldehyde may not be warranted given the likelihood that oral exposures
to formaldehyde may be low
in most groups of people, due to the instability of formaldehyde in aqueous
solutions.
Neurotoxicity.
The nervous system does not appear to be a major target organ for
formaldehyde toxicity;
however, some vague neurological symptoms may occur after inhalation
exposure in humans.
These may include headaches, "heavy head," fatigue, and increased reaction
time (Bach et al. 1990).
Kilburn and colleagues have reported evidence for neurological symptoms and
impaired performance in neurobehavioral tests in groups of
formaldehyde-exposed histology technicians, but confounding exposure to
other neurotoxic solvents prevents drawing definitive conclusions regarding
the
FORMALDEHYDE 256 2. HEALTH EFFECTS
neurotoxicity of formaldehyde from this source (Kilburn 1985b; Kilburn et
al. 1987; Kilburn and Warshaw 1992; Kilburn 1994).
Restless behavior (Morgan et al. 1986a),
increased levels of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic
acid, and dopamine in the hypothalamus (Boja et al. 1985),
and evidence for the development of a conditioned avoidance behavior (Wood
and Coleman 1995) have been reported in rats.
The restless behavior may be attributable to the respiratory irritant
effects of the formaldehyde vapor;
however, the significance of the increased chemical content in the
hypothalamus of rats is unclear.
Other studies have found no perceptible effects of formaldehyde on the
nervous system of rats and mice at #15 ppm (Appelman et al. 1988; Kerns et
al. 1983b),
although obvious clinical signs of neurological impairment were
observed in mice (Maronpot et al. 1986)
and rats (Woutersen et al. 1987)
exposed to high concentrations ($20 ppm) of airborne formaldehyde.
Reports of neurotoxicity in humans after an oral exposure to formaldehyde
are limited to case reports.
Coma, lethargy, seizures, and loss of consciousness have been reported in
humans after drinking formaldehyde (Burkhart et al. 1990; Eells et al. 1981;
Koppel et al. 1990).
No consistent effects on the nervous system after oral exposure to
formaldehyde were found in several toxicity reports using laboratory animal
models (Johannsen et al. 1986; Til et al. 1988b, 1989; Tobe et al. 1989).
Increased relative brain weights were observed in one group of rats
chronically exposed to drinking water doses of 82-109 mg/kg/day (Til et al.
1989), but not in another group exposed to 300 mg/kg/day (Tobe et al. 1989).
The data suggest that the nervous system may be affected by formaldehyde
exposure, especially if it is ingested in large quantities
or if chronically inhaled in low doses in an occupational setting.
Additional prospective evaluations of performance on neurobehavioral tests
in groups of formaldehyde exposed workers may be useful in ascertaining if
there are subtle neurological effects from chronic inhalation exposure to
formaldehyde.
Results from such studies would be most useful if the studied
workers were not exposed to other neurotoxic airborne agents; this is a
condition which may be difficult to find in occupational settings.
Epidemiological and Human Dosimetry Studies.
Results from many acute controlled-exposure
human studies and cross-sectional studies of groups of persons repeatedly
exposed to airborne
formaldehyde provide strong evidence that the upper respiratory tract is the
critical target of airborne
formaldehyde for any duration of exposure, allow reasonable estimates to be
made of minimal risk levels
for acute and chronic durations of exposure, and provide strong support for
deriving intermediateduration
minimal risk levels from animal exposure-response data. There is
considerable confidence that
adherence to these values will protect persons living near
formaldehyde-contaminated hazardous waste
FORMALDEHYDE 257 2. HEALTH EFFECTS
sites from developing upper respiratory tract health problems. Longitudinal
studies that examine nasal
specimens from groups of workers with varying air exposure levels will
provide information that may
further increase confidence in the estimated minimal risk levels.
There does not appear to be a pressing need for epidemiology studies of
people exposed orally to formaldehyde given the instability of formaldehyde
in environmental sources of water and the implausibility of identifying
groups of people exposed to oral doses of formaldehyde that are sufficiently
high to damage gastrointestinal tract tissue.
The relatively frequent reporting of dermal sensitization to formaldehyde at
dermatological clinics
(Fischer et al. 1995; see also: Kiec-Swierczynska 1996; Maibach 1983; Marks
et al. 1995; Meding and
Swanbeck 1990; Menné et al. 1991) suggests that cross-sectional and
longitudinal studies of dermal
exposure levels and prevalence of skin problems in groups of workers with
expected dermal exposure to
cleaning and disinfectant solutions (e.g., janitorial and/or medical
personnel) may be useful to better
describe exposure-response relationships for the development of
formaldehyde-induced skin irritation and
contact dermatitis from intermediate- or chronic-duration exposure to
formaldehyde.
Epidemiological studies of occupationally exposed groups of persons have not
found consistent or strong
evidence for an association between occupational exposure to airborne
formaldehyde and cancer,
although animal studies have found consistent evidence for
formaldehyde-induced nasal tumors with
chronic exposure to air concentrations in the range of 6-15 ppm. The
available epidemiological studies
have shortcomings such as limited exposure information or follow-up,
presence of confounding risk
factors, or small numbers of subjects, but one plausible explanation for the
lack of a consistent response
across the studies is that workplace air levels often may be below values
necessary for formaldehyde to
induce upper respiratory tract cancer. Studies in animals have shown that no
increased incidences of
nasal tumors were found in rats with lifetime exposure to low (0.3-2 ppm)
air concentrations (Kamata et
al. 1997; Kerns et al. 1983b; Monticello et al. 1996; Woutersen et al.
1989), that damaged regions of the
nasal epithelium after short-term exposure are correlated with regions that
eventually develop tumors
with chronic exposure (Monticello et al. 1996), and that regions of the
nasal epithelium with epithelial
damage correlate with regions of predicted high airflow and uptake of
formaldehyde (Cohen Hubal et al.
1997; Kepler et al. 1998; Kimbell et al. 1993, 1997a). Further development
is needed of human nasal
airflow and formaldehyde uptake models, human pharmacokinetic models for
formaldehyde disposition,
and human pharmacodynamic models for preneoplastic events in upper
respiratory tract tissue.
FORMALDEHYDE 258 2. HEALTH EFFECTS
Application of such models, with associated rat dosimetric models, to the
available rat exposure-response
data for tumors and preneoplastic events will allow better estimations of
air levels presenting minimal
risks for cancer in humans.
Biomarkers of Exposure and Effect.
Exposure.
Attempts have been made to determine if formaldehyde could be used as a
potential biomarker of short-term exposure (Heck et al. 1985); however, no
significant difference between pre- and
postexposure blood concentrations of formaldehyde could be demonstrated at
the concentration tested. In
the same study, similar findings were noted in male Fischer 344 rats placed
in a nose-only inhalation
chamber and exposed to 14.4 ppm formaldehyde for 2 hours. Monitoring blood
or urine formate levels
has also been considered. Rapid intravenous injection of formaldehyde in
monkeys showed a plasma
half-life of only 1.5 minutes, with a corresponding increase in blood
formate levels; however, formate
production is not specific to formaldehyde metabolism (Ferry et al. 1980;
Kornbrust and Bus 1983;
Liesivuori and Savolainen 1987). Urine formate levels were examined by
Einbrodt et al. (1976) and urine
formaldehyde and urine formic acid (formate) concentrations were found to be
higher immediately after
exposure; however, study design posed interpretation concerns. Gottschling
et al. (1984) monitored
anatomy students exposed to low levels of formaldehyde vapor; wide
variations were noted in the urine
formate levels prior to exposure, with large intrapersonal and interpersonal
variations. Mean
postexposure urine formate concentrations were not significantly elevated
after exposure. Based on the
available data, it appears that the detection of the intact formaldehyde
molecule in the blood and tissues,
as well as blood and urine formate, are unreliable and poor indicators of
formaldehyde exposure in
humans and laboratory animals.
Studies of animals have used radiolabeling techniques to measure DNA-protein
cross links in nasal
epithelium tissue (Casanova-Schmitz et al. 1984a; Casanova and Heck 1987;
Casanova et al. 1989a,
1989b, 1991, 1994) and described relationships between exposure levels and
the amounts of DNA-protein
cross links in regions of the nasal epithelium. Such a technique is
impractical for monitoring humans
exposed to formaldehyde, but Shaham et al. (1996a) proposed that measurement
of total DNA-protein
cross links by a different technique in white blood cells may be useful as a
biomarker of repeated
exposure to formaldehyde. In support of this proposal, it was reported that
white blood cells from
12 formaldehyde-exposed anatomists and pathologists had significantly higher
average levels of DNA protein
cross links than those from eight subjects without known occupational
exposure to formaldehyde
FORMALDEHYDE 259 2. HEALTH EFFECTS
(Shaham et al. 1996a). Additional research to apply these methods to larger
groups of occupationally
exposed and nonexposed persons may help to determine the reliability of this
variable as a biomarker of
exposure and to determine the extent to which individuals vary in this
response to formaldehyde.
Additional research to apply the DNA-protein cross link methods to nasal
biopsy specimens may lead to
an increased sensitivity of this potential biomarker of exposure and effect.
Shaham et al. (1996b)
reported that a larger scale study was in progress, but results are not
available.
Antibodies (IgG and IgE) against formaldehyde conjugated to human serum
albumin have been found to
be elevated in some people, but not in others, exposed to formaldehyde
(Dykewicz et al. 1991; Grammer
et al. 1990; Patterson et al. 1986; Thrasher et al. 1988b, 1989, 1990;
Wantke et al. 1996a). The
apparently rare frequency of IgE-mediated allergy responses to airborne
formaldehyde (Grammer et al.
1990; Kramps et al. 1989; Nordman et al. 1985) suggests that elevation of
antibodies against
formaldehyde may be too rare to be useful as a generic biomarker of
exposure. However, the findings of
significant associations between (1) the presence of IgG antibodies against
formaldehyde-human serum
albumin and smoking habit in a group of healthy subjects, and (2) the
presence of such antibodies in nonsmokers
and occupational exposure to formaldehyde suggest that this biomarker of
immunological
response may serve as a qualititative biomarker of exposure (Carraro et al.
1997). Additional studies of
formaldehyde-specific IgG antibodies in non-smoking groups of
formaldehyde-exposed and nonexposed
persons may be useful to determine the reliability of this qualitative
biomarker of intermediate or chronic
exposure to formaldehyde. Additional research may help to further develop
the Carraro et al. (1997)
assay so that it might be useful for quantifying exposure levels or exposure
durations.
Effect.
Increased eosinophil concentration and increased albumin and total protein
levels have been
found in nasal lavage fluid taken from subjects exposed to 0.4 ppm
formaldehyde for 2 hours (Krakowiak
et al. 1998; Pazdrak et al. 1993). Although these variables are not expected
to be specifically influenced
by formaldehyde, they appear to provide biomarkers of acute respiratory
irritation from airborne
formaldehyde or other upper respiratory irritants. Further research on
relationships between
concentrations of these variables in nasal lavage fluid and prevalence or
severity of respiratory symptoms
in humans exposed acutely to varying concentrations of formaldehyde may help
to confirm their use as
biomarkers of effect.
As discussed in the previous section, DNA-protein cross links and
anti-formaldehyde-human serum
albumin IgG antibodies are potential biomarkers of effect and exposure from
intermediate- or chronic-
FORMALDEHYDE 260 2. HEALTH EFFECTS
duration of exposure. Another potentially useful biomarker of effect for
repeated inhalation exposure to
formaldehyde involves the histological examination of nasal biopsy samples
(Ballarin et al. 1992; Boysen
et al. 1990; Edling et al. 1988; Holmstrom et al. 1989c). Whereas detection
of these biomarkers can
represent biological responses to repeated exposure to formaldehyde, it is
uncertain to what degree their
detection indicates that adverse health effects will occur. Prospective
studies of these end points in
formaldehyde-exposed and nonexposed workers may decrease this uncertainty
and describe temporal
relationships between formaldehyde-induced upper respiratory tract tissue
damage and/or dysfunction and
exposure-related intensity changes in these variables.
Absorption, Distribution, Metabolism, and Excretion.
Results from studies of rats exposed for
short periods (6 hours) to airborne radiolabeled formaldehyde concentrations
between 0.63 and 13.1 ppm
indicate that inhaled formaldehyde is rapidly absorbed and metabolized,
primarily in the upper respiratory
tract, and that, at these exposure concentrations, very little formaldehyde
reaches the blood or is
transported to distant-site tissues and organs (Heck et al. 1983). In these
studies, radioactivity recovered
within 70 hours after exposure was found in the expired air (39-42%), the
urine (17%), feces (4-5%), and
in tissues and the carcass (35-39%). These results are consistent with rapid
oxidative metabolism to
formate and CO2 and rapid incorporation of the carbon from formaldehyde into
cellular constituents.
Consistent with these studies, another experiment showed that 2-hour
exposures to formaldehyde of rats
(to 14.4 ppm) and humans (to 1.9 ppm) did not significantly increase
formaldehyde concentrations in
blood when measured immediately after exposure (Heck et al. 1985). Casanova
et al. (1988) also showed
that blood concentrations of formaldehyde were not elevated, immediately
after exposure, in rhesus
monkeys exposed to 6 ppm (6 hours/day, 5 days/week) for 4 weeks. These
toxicokinetic results, together
with the weight of evidence from inhalation toxicological studies of animals
showing effects only in the
upper respiratory tract, provide high confidence that the disposition of
inhaled formaldehyde by the upper
respiratory tract in this concentration range and below is nearly complete.
Additional animal studies
designed to compare formaldehyde-specific metabolic capacities in nasal
mucosal tissues from adult and
immature animals may be useful in determining a possible mechanistic basis
for possible age-related
differences in susceptibility to irritation from airborne formaldehyde (see
Children's Susceptibility data needs section below).
Ingested formaldehyde is also expected to be rapidly absorbed, rapidly
metabolized to formate and CO2,
and rapidly incorporated into cellular consituents, but descriptive
toxicokinetic studies of orally
administered formaldehyde in animals were not located. Observations of
elevated formate levels and
FORMALDEHYDE 261 2. HEALTH EFFECTS
metabolic acidosis in cases of acute formaldehyde poisoning (Eells et al.
1981; Burkhart et al. 1990) are
consistent with rapid absorption and metabolism of ingested formaldehyde. A
study is available of the
dispositional kinetics of radioactivity in rats and mice after ingestion of
a cheese made from milk with
added radiolabeled formaldehyde (Galli et al. 1983), but the radioactivity
in the material fed to the
animals was largely (80%) linked to proteins. Given that the levels of
formaldehyde in sources of food
and water for humans are expected to be very low due to formaldehyde's high
reactivity, additional
animal studies to more completely describe the absorption, distribution,
metabolism, and elimination of
orally administered formaldehyde do not seem to warrant a high priority.
Results from a study of rats, guinea pigs, and monkeys under nonoccluded
dermal exposure conditions
indicated that evaporation from the skin was a major disposition route
(Jeffcoat et al. 1983). Additional
animal studies of absorption, distribution, and metabolism under occluded
conditions of dermal exposure
would provide information regarding maximal rates of dermal absorption and
local tissue metabolism,
and may help to confirm that distant-site effects from dermal exposure are
unlikely.
Comparative Toxicokinetics.
Experiments with humans, rats, and monkeys indicate that inhaled
formaldehyde is absorbed and metabolized so rapidly that blood
concentrations do not vary during short term
exposures (Casanova et al. 1988; Heck et al. 1985). These results are
consistent with the upper
respiratory tract being the critical target of inhaled formaldehyde in each
of these species as indicated by
the available health effects data. The marked differences between rodents
and primates in breathing
habits (i.e., rodents are obligate nose breathers) and nasal anatomy led to
some early questions about the
human relevance of the well-characterized nonneoplastic and neoplastic
responses of nasal epithelium in
rats to chronic exposure to airborne formaldehyde. However, observations of
similar non-neoplastic
changes in upper respiratory tract epithelium in Rhesus and Cynomolgus
monkeys exposed for
intermediate durations (Monticello et al. 1989; Rusch et al. 1983) and
observations of histological
changes in nasal tissue from occupationally exposed subjects (Ballarin et
al. 1992; Boysen et al. 1990;
Edling et al. 1988; Holmstrom et al. 1989c) have provided support for the
relevance of the rat data. These
results have led to the ongoing development of, for each of these species,
anatomical models of nasal
airflow and uptake, pharmacokinetic models for nasal tissue metabolism, and
pharmacodynamic models
of development of tumors and preneoplastic tissue changes to be applied to
the rodent data to better
estimate air levels that will present minimal risks for upper respiratory
tract damage in humans (CIIT
1998; Cohen Hubal et al. 1997; Conolly et al. 1992; Conolly and Andersen
1993; Kepler et al. 1998;
Kimbell et al. 1993, 1997a, 1997b; Morgan 1997; Morgan et al. 1991;
Subramaniam et al. 1998).
FORMALDEHYDE 262 2. HEALTH EFFECTS
In contrast, mice and hamsters appear to be less susceptible to upper
respiratory tract damage from
inhaled formaldehyde. The basis for this apparent species difference in
susceptibility is unknown, but
may involve, at least partially for the case of the mouse, the greater
efficiency of mice, compared with
rats, to reduce minute volumes during exposure to formaldehyde (Chang et al.
1981, 1983).
As with exposure to airborne formaldehyde, portal-of-entry tissues are
expected to be the critical targets
of orally or dermally administered formaldehyde in humans and animals.
Gastrointestinal effects from
high oral doses are expected based on reports of gastrointestinal tract
irritation and symptoms in humans
who ingested large doses of formaldehyde, together with results from studies
of rats exposed orally to
formaldehyde for intermediate- and chronic-durations (e.g., Til et al.
1988b, Til et al. 1989; Tobe et al.
1989). Skin irritation in humans with dermal occupational exposure to
formaldehyde concentrations in
the range of 2-5% and greater is expected based on occupational experience
and clinical experience in
patch-testing (Fischer et al. 1995; Maibach 1983); additionally, the
development of dermal sensitization
to formaldehyde is frequently found among patients presenting skin problems
at dermatology clinics. The
expectation of skin irritation and dermal sensitization, without systemic
distant-site effects, from exposure
to formaldehyde is supported by results from dermal-exposure toxicity
studies in animals (e.g., Overman
1985; Wahlberg 1993) and toxicokinetic studies with rats, guinea pigs and
Cynomolgus monkeys
(Jeffcoat et al. 1983); although results from the latter studies indicated
that monkey skin may be more
permeable to formaldehyde than rat skin. In contrast to inhalation exposure,
however, there is no
information indicating that species differ in susceptibility to formaldehyde
toxicity by these routes of
exposure. Thus, additional studies comparing species differences in
toxicokinetic variables with oral or
dermal exposure to formaldehyde do not appear to have a high priority at
this time.
Methods of Reducing Toxic Effects.
Due to formaldehyde's high water solubility and reactivity and the rapidity
of cellular metabolism of formaldehyde to formate and CO2, toxic effects
from formaldehyde are expected to be principally caused by formaldehyde
itself
(not metabolites) and to be restricted to portal-of-entry tissues, except at
high exposure levels that exceed metabolic capacities of these tissues.
Thus, following acute exposures to formaldehyde, treatments that dilute or
remove nonabsorbed
or non-reacted formaldehyde from the site of exposure or that present
alternative substrates for
reaction (e.g., washing of the skin or eyes or dilution of ingested
formaldehyde with milk or water) may
prevent the occurrence of toxic effects if applied in a timely manner.
Methods that may enhance the
capacity of portal-of-entry tissues to metabolize formaldehyde may be
expected to act against the toxic
action of formaldehyde, but no such methods have been established. There are
no established treatment
FORMALDEHYDE 263 2. HEALTH EFFECTS
protocols to repair tissue damage that may have been caused by formaldehyde
at portals-of-entry or to
enhance natural repair mechanisms.
Children's Susceptibility.
Suggestive evidence from two studies is available indicating that children
may be more susceptible to the locally-acting irritant properties of
formaldehyde (Krzyzanowski et al.
1990; Wantke et al. 1996a). Additional health survey studies of groups of
children known to experience
indoor air concentrations exceeding 0.05-0.1 ppm may be helpful in
confirming or discarding this
hypothesis.
Studies of laboratory animals, as well as studies of adult humans under
acute controlled exposure or
occupational exposure conditions, indicate that the irritant effects of
formaldehyde are restricted to tissues
at portals-of-entry due to the water-solubility and reactivity of
formaldehyde and the ability of cells to
rapidly metabolize (and detoxify) formaldehyde. Studies designed to compare
formaldehyde-specific
metabolic capacities and efficiencies in portal-of-entry tissues (e.g.,
nasal mucosa, gastrointestinal
mucosa) from adult and immature animals of varying ages may be useful in
determining a possible
mechanistic basis for possible age-related differences in susceptibility to
formaldehyde.
2.11.3 Ongoing Studies
Ongoing studies pertaining to formaldehyde have been identified and are
shown in Table 2-8.
FORMALDEHYDE 264 2. HEALTH EFFECTS
Table 2-8. Ongoing Studies on Formaldehyde
Investigator Affiliation Research description Sponsor
B.K. Andrews, B. Morrell and N.M. Morris
Southern Regional Res Center, New Orleans, LA
Durable Press Fabrics from No- and De-minimus Level-Formaldehyde Finishes
US Dept. of Agriculture
A.E. Blair
NCI, NIH Studies of Occupational Cancer Division of Cancer Etiology
T.P. Brown and G.E. Rottinghaus
University of Georgia College of Vet Medicine, Athens, GA
Poultry Toxicosis: Evaluation and Amelioration
US Dept. of Agriculture
A. Cederbaum VA Medical Center, New York, NY
Interaction of Pyrazole and Glycerol with Human
Microsomes and P-450IIEI
National Institute of Alcohol Abuse and Alcoholism
B.J. Collier Louisiana State University School of Human Ecology,
Baton Rouge, LA
Measurement of Formaldehyde Release from Durable Press Cotton Fabrics
& Other Products US Dept. of Agriculture
J.T. Coyle Massachusetts General Hospital, Boston, MA
Psychosis and Brain Glutamate National Institute of Mental Health
J. Cwi Survey Research Associates, Baltimore, MD
Support Services for Occupational Studies Division of Cancer Etiology
L.M. Ferrari and F. Catell State Pollution Control Commission, Sydney,
NSW
Indoor Air Quality and Energy Conservation NERDDP
J.B. Guttenplan NYU Dental Center, New York, NY
Smokeless Tobacco Carcinogenesis and Oral Tissue
National Institute of Dental Research
G. Hager NCI, NIH
Chromatin Structure and Gene Expression Division of Cancer Etiology
A.T. Hastie Thomas Jefferson University, Philadelphia, PA
Pollutant Interactive Effects on Ciliary Defense NIEHS
G.A. Jamieson American Red Cross, Rockville, MD
Characterization and Isolation of Platelet ADP Receptors
National Heart, Lung, and Blood Institute
K. Knapp, D. Pahl and F. Black
Atmospheric Research and Assessment Laboratory,
Research Triangle Park, NC
Hazardous Air Pollutant Regulatory Activities
Office of Research and Development
J. Merchant University of Iowa, Iowa City, IA
Core--Occupational Health Research NIEHS
S.S. Mirvish University of Nebraska Medical Center, Omaha, NE
Nitrosamine Metabolism and Esophageal Cancer
National Cancer Institute
R. Monson Harvard University, Boston, MA
Occupational Health NIEHS
FORMALDEHYDE 265 2. HEALTH EFFECTS
Table 2-8. Ongoing Studies on Formaldehyde (continued)
Investigator Affiliation Research description Sponsor
T.N. Pappas Dept. of Veterans Affairs Medical Center, Durham, NC
Animals Models of Inflammatory Bowel Disease: Relationship to Substance P
Receptor Up Regulation Dept. of Veterans Affairs
T. Shibamoto University of California
Environmental Toxicology, Davis, CA
Isolation and Identification of Mutagens and Carcinogens in Foods
US Dept. of Agriculture
G.M. Thiele Omaha VA Medical Center, Omaha, NE
Alcohol and Liver Endothelial Cells in Immune Responses
National Institute on Alcohol Abuse and Alcoholism
J-P. Von Sattel Massachusetts General Hospital, Boston, MA
Core--Neuropathology National Institute of Neurological Disorders
and Stroke
NCI = National Cancer Institute; NIEHS = National Institute of Environmental
Health; NIH = National Institutes of Health; NERDDP = National Energy
Research, Development and Demonstration Program
FORMALDEHYDE 267 3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Information regarding the chemical identity of formaldehyde is located
in Table 3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Information regarding the physical and chemical properties of formaldehyde
is located in Table 3-2.
FORMALDEHYDE 268 3. CHEMICAL AND PHYSICAL INFORMATION
H C H
O
Table 3-1. Chemical Identity of Formaldehyde
Characteristic Information Reference
Chemical name Formaldehyde Lide and Frederikse 1996
Synonym(s) Formic aldehyde, methanal, methyl aldehyde, methylene oxide
Budavari et al. 1989
Registered trade name(s)
For 37% aqueous solution a
For polymeric form b
Formalin, Formol, Morbicid, Veracur Paraformaldehyde, Polyoxymethylene,
Paraform, Formagene
Budavari et al. 1989 Budavari et al. 1989
Chemical formula CH2O Aster 1995
Chemical structure Lide and Frederikse 1996
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO
HSDB
NCI
50-00-0
LP8925000
U122
7216732
CLASS 3/UN1198/IMCO 3.2
164
No data
Aster 1995
HSDB 1995
HSDB 1995
HSDB 1995
NFPA 1994
HSDB 1999
HSDB 1999
a Aqueous solutions of formaldehyde available commercially often contain
10-15% methanol to inhibit polymerization.
b Paraformaldehyde is a polymer of formaldehyde and has the formula (CH2O)n.
CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of
Transportation/United Nations/North America/International Maritime Dangerous
Goods Code; EPA = Environmental Protection Agency;
HSDB = Hazardous Substance Data Bank; NCI = National Cancer Institute; NIOSH
= National Institute for Occupational Safety and Health; OHM/TADS = Oil and
Hazardous Materials/Technical Assistance Data System;
RTECS = Registry of Toxic Effects of Chemical Substances
FORMALDEHYDE 269 3. CHEMICAL AND PHYSICAL INFORMATION
Table 3-2. Physical and Chemical Properties of Formaldehyde
Property Information Reference
Molecular weight 30.03 Lide and Frederikse 1996
Color Colorless Budavari et al. 1989
Physical state Gas Budavari et al. 1989
Melting point -92 EC Budavari et al. 1989
Boiling point -21 EC ASTER 1996
Density at -20 EC 0.815 g/mL Lide and Frederikse 1996
Odor Pungent, suffocating odor; highly irritating odor Budavari et al.
1989;
NFPA 1994 Odor threshold:
Water
Air
50 ppm
0.5-1.0 ppm
HSDB 1999
Klaassen 1996
Taste 50 ppm HSDB 1999
Solubility:
Freshwater at 20 EC
Saltwater at 25 EC
Organic solvent(s)
Very soluble; up to 55%
No data
Ether, alcohol, acetone, benzene
Budavari et al. 1989
Lide and Frederikse
1996; Budavari et al. 1989
Partition coefficients:
Log Kow
Log Koc
0.350
1.567
No data, negligible
SRC 1995b
Calculated from Lyman 1982 HSDB 1999
Vapor pressure at 25 EC Gas: vapor pressure>bp; 3,883 mm Hg HSDB 1999;
Howard 1989
Polymerization Polymerizes; polymerizes readily in water Budavari et al.
1989
Photolysis Half-life (in sunlight) 1.6-19 hours producing
H2 and CO or H+ and HCO Lewis 1993
Henry's law constant at 25 EC 3.27x10-7 atm-m3/mol Howard 1989
Autoignition temperature 300 EC NFPA 1994
Flashpoint 60 EC Budavari et al. 1989
Flammability limits at 25 EC 7-73% NFPA 1994
Incompatibilities Reacts with alkalies, acids, and oxidizers NFPA 1994
Conversion factors (25 EC) 1 ppb (v/v) = 1.23 µg/m3
1 µg/m3 = 0.813 ppb (v/v)
Calculated Explosive limits 7-73% Lewis 1993
FORMALDEHYDE 271 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
4.1 PRODUCTION
Because of its low cost and high purity, formaldehyde has become one of the
most important industrial and research chemicals in the world.
Between 1958 and 1968, the annual growth rate for formaldehyde
production averaged 11.7% (Gerberich et al. 1980).
During the late 1960s, production averaged 71% of capacity.
The recession of the mid-1970s, however, caused production to drop as low as
54% of capacity (Gerberich et al. 1980).
From 1988 to 1997, formaldehyde production averaged an annual growth rate of
2.7% per year (Anonymous 1998).
In 1992, formaldehyde ranked 22nd (8.28 billion pounds produced)
among the top 50 chemicals produced in the United States (Anonymous 1994).
Total annual capacities for the 15-17 U.S. companies listed as the top
formaldehyde manufacturers or processors for 1988, 1990, and 1992 were
8.94, 9.70, and 10.08 billion pounds, respectively (SRI 1988, 1990, 1992).
The estimated total annual formaldehyde capacity in 1998 was 11.3 billion
pounds (Anonymous 1998).
With production volumes varying between 6.43 billion pounds and 8.11 billion
pounds for 1990, 1991, and the period 1993-1995, formaldehyde ranked either
24th or 25th among the top 50 chemicals produced (Anonymous 1992, 1994,
1995a; Kirschner 1996).
As of 1998, three manufacturers of formaldehyde were responsible for 50% of
the annual capacity for the United States: Georgia-Pacific Resins, Inc.
(Albany, Oregon; Columbus, Ohio; Conway, North Carolina; Crossett, Arkansas;
Grayling, Michigan; Hampton, South Carolina; Healing Springs, North
Carolina; Houston, Texas; Lufkin, Texas; Russellville, South Carolina;
Taylorsville, Mississippi; Vienna, Georgia; White City, Oregon),
Hoechst Celanese Corporation (Bishop, Texas; Rock Hill, South Carolina), and
Borden, Inc. (Baytown, Texas; Demopolis, Alabama; Diboll, Texas;
Fayetteville, North Carolina; Fremont, California; Hope, Arkansas; Kent,
Washington; La Grande, Oregon; Missoula, Montana; Sheboygan, Wisconsin;
Springfield, Oregon; Vicksburg, Mississippi) (Anonymous 1998; SRI 1997).
In addition to the above facilities, the following companies also
contributed to the overall U.S. capacity:
Capital Resin (Columbus, Ohio); D.B. Western (Las Vegas, New Mexico;
Virginia, Minnesota); Degussa (Theodore, Alabama); DuPont (LaPorte, Texas;
Parkersburg, West Virginia); Hercules-Aqualon (Louisiana, Montana); ISP
(Calvert City, Kentucky; Texas City, Texas); Monsanto (Alvin, Texas); Neste
Resins (five sites); Perstorp (Toledo, Ohio); Praxair (Geismar, Louisiana);
Solutia (Alvin, Texas); Spurlock (Malvern, Arkansas; Waverly, Virginia);
Trimet Technical Products (Mallinckrodt);
FORMALDEHYDE 272 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
(Allentown, Pennsylvania); and Wright Chemical (Acme, North Carolina)
(Anonymous 1998; SRI 1997).
Formaldehyde production is predicted to increase 2-3% per year through 2002
(Anonymous 1998).
Table 4-1 lists the facilities in each state that manufacture or process
formaldehyde, the intended use, and the range of maximum amounts of
formaldehyde that are stored on site. The data listed in Table 4-1 are
derived from the Toxics Release Inventory (TRI96 1998). Only certain types
of facilities were required to report. Therefore, this is not an exhaustive
list. Table 4-2 shows capacity and production volumes for selected years
between 1960 and 1978.
Formaldehyde has been manufactured primarily from methanol since the
beginning of the century (Gerberich et al. 1980). Because methanol is
manufactured from synthesis gas, usually produced from methane, there have
been extensive efforts to develop a one-step process that partially oxidizes
methane to formaldehyde. Although a successful commercial process has not
been developed, a wide range of catalysts and oxidation conditions have been
studied (Gerberich et al. 1980). During the decades following World War II,
approximately 20% of the production volume in the United States was
manufactured by vapor phase, non-catalytic oxidation of propane and butane
(Gerberich et al. 1980).
Two primary methods of manufacturing formaldehyde from methanol are used
today.
The first uses silver as a metal catalyst in its reactions.
In earlier years, facilities used a copper catalyst in this process.
The simultaneous reactions involved in the metal catalyst process occur at
essentially atmospheric pressure and 600-650 EC (Gerberich et al. 1980).
Approximately 50-60% of the formaldehyde produced using the metal catalyst
process is formed during an exothermic reaction; the remainder is formed
from an endothermic reaction. The overall yield for this process is 86-90%
formaldehyde. The domestic licensors for this process include Borden
Chemical Company and Davy Powergas, Inc. (Gerberich et al. 1980).
The second method uses a metal oxide catalyst. All of the formaldehyde is
produced from an exothermic reaction occurring at atmospheric pressure and
300-400 EC. The patent for formaldehyde production using a vanadium
pentoxide catalyst was issued in 1921. Although the patent for an iron
oxidemolybdenum oxide catalyst was issued in 1933, the first commercial
facility did not begin operating until 1952 (Gerberich et al. 1980).
Gaseous formaldehyde can be regenerated from paraformaldehyde by heating
(Gerberich et al. 1980).
FORMALDEHYDE 273 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
Table 4-1. Facilities That Manufacture or Process Formaldehyde
State a Number of facilities Range of maximum amounts on site in pounds b
Activities and uses c
AK 1 100,000 - 999,999 8
AL 30 0 - 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
AR 15 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 12
AZ 3 100 - 9,999 1, 5, 7, 9, 12, 13
CA 26 100 - 9,999,999 1, 3, 4, 5, 7, 8, 9, 11, 12
CO 2 0 - 9,999 12
CT 8 100 - 9,999,999 2, 3, 7, 8, 12
DE 1 10,000 - 99,999 8
FL 6 0 - 99,999 1, 6, 7, 9, 11, 13
GA 35 0 - 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13
IA 5 1,000 - 999,999 7 ,8 ,9 ,10
IL 27 0 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13
IN 15 100 - 999,999 1, 5, 7, 8, 9, 11, 12,13
KS 8 100 - 999,999 1, 2, 5, 7, 8, 11, 13
KY 8 1,000 - 9,999,999 1, 3, 4, 7, 8, 10, 11, 12, 13
LA 31 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 13
MA 10 1,000 - 9,999,999 1, 3, 4, 7, 8, 9, 11, 13
MD 2 1,000 - 9,999 7, 8, 9
ME 3 1,000 - 999,999 1, 5, 6, 7, 12
MI 33 0 - 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13
MN 15 0 - 999,999 1, 5, 6, 7, 8, 9, 10, 11, 12
MO 12 0 - 9,999,999 1, 3, 4, 6, 7, 8, 11, 12, 13
MS 16 0 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9
MT 4 0 - 9,999,999 1, 3, 4, 6, 7, 8, 9
NC 39 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13
NH 4 100 - 999,999 7, 11, 12
NJ 18 100 - 999,999 1, 3, 5, 7, 8, 9, 10, 12, 13
NM 1 100 - 999 9
NV 1 1,000 - 9,999 7
NY 25 100 - 999,999 1, 2, 3, 5, 7, 8, 9, 10, 11, 12, 13
OH 50 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13
OK 4 100 - 999,999 1, 6, 7, 8
OR 25 100 - 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 11, 13
PA 21 0 - 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13
PR 4
(Message over 64k, truncated.)
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